Pharmaceutical compounds comprising albumin binding moieties

Abstract

The present invention relates to a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof, wherein-D-each independently is a drug moiety; -AB1 and-AB2 are each independently an albumin binding moiety; -L1-each independently is a linker moiety covalently and reversibly linked to-D-; l2-are each independently a spacer group or do not exist; x and y are integers; relates to pharmaceutical compositions comprising at least one such compound and uses thereof.

Description

[0001] The present invention relates to a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof, wherein -D- is each independently a drug moiety; -AB 1 and-AB 2 Each independently is an albumin binding moiety; -L 1 -L are each independently a linker moiety that is covalently and reversibly linked to -D-; 2 - are each independently a single chemical bond or absent; and x and y are integers; the present invention relates to pharmaceutical compositions comprising at least one such compound and uses thereof.

[0002] Although some types of therapeutic proteins (including antibodies) themselves have long intrinsic half-lives, many other molecules, especially proteins or peptide hormones, are often susceptible to enzymatic degradation, renal clearance and / or rapid receptor-mediated clearance, which results in a shorter plasma elimination half-life. In addition, due to the challenges associated with oral delivery, most peptide or protein-based drugs require parenteral administration, which, combined with a shorter half-life, requires frequent injections, thus causing discomfort and inconvenience to the patient. This may have a negative impact on compliance and ultimately limit therapeutic efficacy and results.

[0003] It has been shown that compared to non-derivatized peptides, injected lipidated peptides are absorbed more slowly from subcutaneous tissue and have a longer circulation 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 larger molecular weight (which minimizes renal clearance) and to its recycling through the neonatal Fc receptor (FcRn). In this circulation, the larger molecular weight protects the bound peptide from renal clearance and reduces its rate of distribution to the extravascular compartment.

[0004] It is believed that the slower absorption is due to a reduced diffusion rate in tissues, which is caused by a mechanism involving the interaction of fatty acid side chains with cell membranes and / or proteins (e.g., albumin present at the injection site). Due to the larger molecular weight of the albumin-peptide complex, it is expected that the diffusion rate in tissues and the rate of passage through capillary walls after injection will be reduced. Molecules with a molecular weight greater than about 16 kDa may be preferentially absorbed via the lymphatic route rather than directly through the capillary wall into the blood.

[0005] Thus, slower absorption and reversible albumin binding allow the dosing interval of drugs, such as peptide drugs, to be extended to one week. However, it is desirable to extend the dosing interval even further.

[0006] The present invention aims to at least partially overcome the disadvantages of current therapies.

[0007] This object is achieved using a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof,

[0008]

[0009] in

[0010] -D- are each independently a drug moiety;

[0011] -AB 1 and-AB 2 each independently an albumin binding moiety;

[0012] -L 1 - are each independently a linker moiety that is covalently and reversibly linked to -D-;

[0013] -L 2 - are each independently a spacer or absent;

[0014] x is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, and 25; and

[0015] y is an integer selected from 2, 3, 4 and 5.

[0016] Compounds of formula (Ia) and (Ib) may also be referred to as "prodrugs". They release the drug moiety -AB 2 Conjugate, which can also be written as HD-AB 2 , where H- is hydrogen.

[0017] Applicants have discovered that the compounds of the present invention have an extended half-life, thereby enabling less frequent dosing.

[0018] This results in the compound exhibiting further increased albumin binding and slowed absorption of the macromolecular drug-albumin complex. Such compounds also exhibit reduced absorption from the site of administration, such as from subcutaneous tissue, compared to administration of the corresponding unconjugated drug. Thus, such compounds have an extended half-life compared to the corresponding unconjugated drug.

[0019] In the present invention, the terms used have the following meanings.

[0020] As used herein, the term "GLP-1 receptor agonist" refers to an agonist of the GLP-1 receptor (GLP1R) and, optionally, an agonist of one or more other receptors, such as an agonist of the gastric inhibitory peptide receptor (GIPR), the glucagon receptor (GCGR), the amylin receptor, the peptide YY receptor (PYYR), or the glucagon-like peptide-2 receptor (GLP2R). An "agonist" of a receptor, such as an agonist of the GLP-1 receptor, is a chemical compound that activates such a receptor to produce a biological response. If, in addition to being a GLP1R agonist, a GLP-1 receptor agonist is also an agonist of a receptor other than GLP1R, such as an agonist of the GIPR, GCGR, amylin receptor, PYYR, or GLP2R, then such a GLP-1 receptor agonist is also referred to as a "dual GLP-1 receptor agonist" or simply a "dual agonist." Similarly, if a GLP-1 receptor agonist is an agonist of two other receptors in addition to being a GLP1R agonist, and these two receptors can be selected from GIPR, GCGR, amylin receptor, PYYR or GLP2R, then this GLP-1 receptor agonist is also called a "triple GLP-1 receptor agonist" or simply a "triple agonist".

[0021] As used herein, the term "peptide" as used herein refers to a chain of at least 2 and up to 50 and including 50 amino acid monomer parts (also referred to as "amino acid residues") connected by peptide (amide) bonds. The amino acid monomers can be selected from proteinogenic amino acids and non-proteinogenic amino acids, and can be D- or L-amino acids. The term "peptide" also includes peptidomimetics, such as peptoids, β-peptides, cyclic peptides and depsipeptides, and covers such simulated peptide chains of up to and including 50 monomer parts. Cyclic peptides can be monocyclic, bicyclic, tricyclic or tetracyclic peptides. The term "peptide" also includes lasso peptides.

[0022] As used herein, the term "protein" is a chain of 50 or more amino acid monomer moieties (also referred to as "amino acid residues") linked by peptide bonds, wherein preferably there are no more than 12,000 amino acid monomer moieties linked by peptide bonds, e.g., no more than 10,000 amino acid monomer moieties, no more than 8,000 amino acid monomer moieties, no more than 5,000 amino acid monomer moieties, or no more than 2,000 amino acid monomer moieties.

[0023] As used herein, the term "small molecule drug" refers to an organic compound having a molecular weight of less than 1000 Da, such as less than 900 Da or less than 800 Da. It will be understood that nucleobase-based drug moieties, such as adenine or guanine analogs, can also be a class of small molecule drugs.

[0024] As used herein, the term "middle molecule drug" or "middle size molecule drug" refers to organic compounds having a molecular weight of 1 kDa to 7.5 kDa, inclusive, which are not peptides and are not proteins.

[0025] As used herein, the term "oligonucleotide" refers to double-stranded or single-stranded RNA and DNA preferably having 2-1000 nucleotides and any modifications thereof. Modifications include, for example, those that provide modifications of other chemical groups that incorporate additional charge, polarizability, hydrogen bonding, electrostatic interactions, and mobility into the nucleic acid ligand bases or the nucleic acid ligand as a whole. Such modifications include, for example, 2'-position sugar modifications, 5-position pyrimidine modifications, 8-position purine modifications, modifications on the exocyclic amine, substitutions of 4-thiouridine, substitutions of 5-bromo or 5-iodouracil; Main chain modifications, methylation, abnormal base pairing combinations, such as isobases isocytidine and isoguanidine. Modifications can also include 3' and 5' modifications, such as end-capping and stereochemical changes. The term also includes aptamers.

[0026] As used herein, the term "peptide nucleic acid" refers to an organic polymer having a peptide backbone (i.e., a backbone in which monomers are linked to each other by peptide bonds) to which nucleobases such as adenine, cytosine, guanine, thymine, and uracil are linked. In certain embodiments, the peptide backbone comprises N-(2-aminoethyl)-glycine.

[0027] As used herein, the term "random coil" refers to any conformation of a polymeric molecule (including proteins) in which the individual monomeric elements forming the polymeric structure are essentially randomly oriented relative to adjacent monomeric elements while still chemically bound to the adjacent monomeric elements. In particular, polypeptides or proteins having a random coil conformation essentially lack defined secondary and tertiary structures. The properties of random coils in polypeptides and experimental identification methods are known to those skilled in the art. In particular, the lack of secondary and tertiary structure in proteins can be determined by circular dichroism (CD) measurements. CD spectroscopy represents a light absorption spectroscopy method in which the difference in absorbance of a substance for right-handed and left-handed circularly polarized light is measured. The secondary structure of a protein can be determined by CD spectroscopy using far-ultraviolet spectroscopy at wavelengths of approximately 190-250 nm. At these wavelengths, different secondary structures commonly found in conformations each produce characteristic shapes and magnitudes of CD spectra. Therefore, by using CD spectroscopy, those skilled in the art can easily determine whether an amino acid polymer adopts a random coil conformation under physiological conditions.

[0028] When determining whether a peptide or protein adopts a random coil conformation under experimental conditions using the methods described herein, biophysical parameters such as temperature, pH, osmolality, and protein content may differ from the physiological conditions typically found in vivo. It is contemplated that temperatures of 1°C to 42°C, or preferably 4°C to 25°C, can be used to test and / or validate the biophysical properties and biological activity of a peptide or protein under in vitro physiological conditions.

[0029] Several buffers are considered to represent "physiological solutions" or "physiological conditions" in vitro, in particular in experimental settings (e.g. in protein structure determination, in particular circular dichroism (CD) measurements and other methods that allow a person skilled in the art to determine the structural properties of proteins / polypeptides or peptides) or in buffers, solvents and / or excipients of pharmaceutical compositions. Examples of such buffers are, for example, phosphate buffered saline (PBS: 115 mM NaCl, 4 mM KH2PO4, 16 mM Na2HPO4 pH 7.4), Tris buffer, acetate buffer, citrate buffer or similar buffers, such as those used in the accompanying examples. Typically, the pH of a buffer representing physiological conditions should be in the range of 6.5-8.5, preferably 7.0-8.0, most preferably 7.2-7.7, and the osmolality should be in the range of 10-1000 mmol / kg HO, more preferably 50-500 mmol / kg HO, and most preferably 200-350 mmol / kg HO. Optionally, the protein content of the buffer representing physiological conditions may be in the range of 0-100 g / l, without regard to proteins which are themselves biologically active, whereby typical stabilizing proteins such as human or bovine serum albumin may be used.

[0030] Other established biophysical methods for determining random coil conformation include nuclear magnetic resonance (NMR) spectroscopy, absorption spectroscopy, infrared and Raman spectroscopy, measurement of hydrodynamic volume by size exclusion chromatography, analytical ultracentrifugation and dynamic / static light scattering, and measurement of the coefficient of friction or intrinsic viscosity.

[0031] As used herein, the term "physiological conditions" refers to an aqueous buffer at pH 7.4, 37°C.

[0032] As used herein, the term "pharmaceutical composition" refers to a composition comprising one or more active ingredients (e.g., at least one compound of the present invention) and one or more excipients, as well as any product produced directly or indirectly by the combination, coordination, or aggregation of any two or more of the ingredients in the composition, or by the dissociation of one or more ingredients, or by other types of reactions or interactions of one or more ingredients. Therefore, the pharmaceutical compositions of the present invention encompass any composition made by mixing one or more compounds of the present invention and one or more pharmaceutically acceptable excipients.

[0033] As used herein, the term "excipient" refers to a diluent, adjuvant, or vehicle used together with the administered therapeutic agent (e.g., a drug or prodrug). Such pharmaceutical excipients can be sterile liquids, such as water and oil, including those of petroleum, animal, plant, or synthetic origin, including but not limited to peanut oil, soybean oil, mineral oil, sesame oil, etc. When the pharmaceutical composition is administered orally, water is an example of an excipient. When the pharmaceutical composition is administered intravenously, saline and aqueous glucose solutions are examples of excipients. In certain embodiments, saline solutions and aqueous glucose solutions and aqueous glycerol solutions are used as liquid excipients for injection solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, mannitol, trehalose, gelatin, malt products (malt), rice, flour, calcium carbonate (chalk), silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol (propylene, glycol), water, ethanol, etc. If desired, the pharmaceutical composition may also contain a small amount of a wetting agent or emulsifier, a pH buffer such as acetate, succinate, tris, carbonate, phosphate, HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid), MES (2-(N-morpholino)ethanesulfonic acid), or a detergent such as Tween, poloxamer, poloxamine, CHAPS, Igepal, or an amino acid such as glycine, lysine, or histidine. These pharmaceutical compositions may be in the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, or sustained-release formulations. The pharmaceutical composition may be formulated as a suppository using conventional binders and excipients (e.g., triglycerides). Oral formulations may include standard excipients such as pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Such compositions contain a therapeutically effective amount of the drug or drug portion and an appropriate amount of excipients to provide a form suitable for administration to the patient. The formulation should suit the mode of administration.

[0034] As used herein, the term "liquid composition" refers to a mixture comprising a water-soluble compound and one or more solvents (eg, water).

[0035] The term "suspension composition" refers to a mixture comprising at least one water-insoluble compound and one or more solvents (eg, water).

[0036] As used herein, the term "dry composition" refers to a pharmaceutical composition provided in a dried form. Suitable drying methods include spray drying and lyophilization, i.e., freeze drying. According to Karl Fischer, such dry compositions have a residual moisture content of a maximum of 10%, e.g., less than 5% or less than 2%. In certain embodiments, such dry pharmaceutical compositions are dried by lyophilization.

[0037] As used herein, the term "drug" refers to a substance used to treat, cure, prevent, or diagnose disease, or to enhance physical or mental health. If a drug is coupled to another moiety, the portion of the final product derived from the drug is referred to as the "drug moiety."

[0038] As used herein, the term "prodrug" refers to a covalent conjugate in which the drug moiety is reversibly and covalently linked to a dedicated protecting group via a reversible linker moiety (also referred to as a "reversible prodrug linker moiety" or "reversible linker moiety" which is coupled to the drug moiety via a reversible linker bond), and wherein the dedicated protecting group alters or eliminates undesirable properties in the parent molecule. This also includes enhancing the desired properties of the drug and inhibiting undesirable properties. The dedicated non-toxic protecting group is referred to as a "carrier." The prodrug releases the reversibly and covalently bound drug moiety in the form of its corresponding drug. In other words, the prodrug is a conjugate comprising a drug moiety that is covalently and reversibly coupled to a carrier moiety via a reversible linker moiety, wherein the covalent and reversible coupling of the carrier to the reversible linker moiety is performed directly or via a spacer. Such a conjugate releases the previously coupled drug moiety in the form of a free, unmodified drug.

[0039] A "reversible linkage" is a linkage that is degradable (i.e., cleavable) under physiological conditions (pH 7.4, aqueous buffer at 37°C) in the absence of enzymes with a half-life of 1 hour to 3 months. A "stable linkage" is a linkage that has a half-life of more than three months under physiological conditions (pH 7.4, aqueous buffer at 37°C) in the absence of enzymes.

[0040] As used herein, the term "traceless prodrug linker" or "traceless linker" refers to a reversible prodrug linker, i.e., a linker moiety that reversibly and covalently links a drug moiety to a carrier, which upon cleavage releases the drug in its free form. As used herein, the term "free form" of a drug or "free drug" refers to the unmodified pharmacologically active form of the drug.

[0041] As used herein, the term "agent" refers to a chemical compound comprising at least one functional group for reacting with a functional group of another chemical compound or drug. It should be understood that drugs comprising functional groups (e.g., primary or secondary amine or hydroxyl functional groups) are also reagents.

[0042] As used herein, the term "moiety" refers to a portion of a molecule that lacks one or more atoms compared to the corresponding agent. For example, if a reagent of the formula "HXH" 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-", where each "-" represents a link to another moiety. Thus, the drug moiety is released from the prodrug as a drug.

[0043] If a chemical structure is provided that is linked to a radical of at least one other moiety, the chemical structure may be linked to the at least one other moiety in any orientation unless otherwise explicitly stated. For example, the moiety "-C(O)N(R 1 )-” can be replaced by “-C(O)N(R 1 )-" or -N(R 1 )C(O)-" form is connected to the two parts. Similarly, part

[0044]

[0045] Can be

[0046] The form is connected to the two parts.

[0047] As used herein, the term "functional group" refers to an atomic group that can react with other atomic groups. For example, the functional group is selected from 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, sulfonamide, sulfuric acid, vinyl sulfone, vinyl ketone, diazoalkane, ethylene oxide and azetidine.

[0048] As used herein, the term "pharmaceutically acceptable salts thereof" refers to salts that retain the biological effectiveness or properties of the compound and are typically not biologically or otherwise undesirable. In certain embodiments, the compound is capable of forming acidic and / or basic salts due to the presence of amino and / or carboxyl functional groups or groups similar thereto. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids, for example, acetate, aspartate, benzoate, benzenesulfonate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, chloride / hydrochloride, chlortheophyllinate, citrate, edisylate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, polygalacturonate, propionate, stearate, succinate, subsalicylate, tartrate, tosylate, and trifluoroacetate. 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, 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, and sulfosalicylic acid. 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, 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.Pharmaceutically acceptable salts can be synthesized from the parent compound, a basic or acidic moiety, by conventional chemical methods.

[0049] The term "pharmaceutically acceptable" refers to a substance that does not cause harm when administered to a patient and, in certain embodiments, is approved for use in animals, and particularly in humans, by regulatory agencies, such as the EMA (Europe) and / or the FDA (US) and / or any other national regulatory agency.

[0050] As used herein, the term "about" or "approximately" in conjunction with a numerical value is used to indicate a range of plus or minus no more than 10% of the numerical value, including the endpoint. For example, the phrase "about 200" or "approximately 200" is used to indicate a range of 200+ / -10% (including 200+ / -10%), i.e., a range of 180-220 (including 180 and 220). It should be understood that a percentage given as "about 20%" or "approximately 20%" does not mean "20%+ / -10%", i.e., a range of 10-30% including the endpoint, but rather "about 20%" or "approximately 20%" means a range of 18-22% including the endpoint, i.e., plus or minus 10% of the numerical value 20.

[0051] As used herein, the term "polymer" refers to a molecule comprising a repeating structural unit (i.e., a monomer) connected by a chemical bond in a linear, cyclic, branched, cross-linked or dendritic manner or a combination thereof, which can be synthetic or biologically derived or a combination thereof. It should be understood that a polymer can also include one or more other chemical groups and / or moieties, such as one or more functional groups. In certain embodiments, a soluble polymer has a molecular weight of at least 0.5 kDa, such as 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. In certain embodiments, if the polymer is soluble, it 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 should be understood that for water-insoluble polymers, such as hydrogels, a meaningful molecular weight range cannot be provided. It should also be understood that a peptide or protein is a polymer in which amino acids are repeated structural units, but the side chains of each amino acid can be different.

[0052] As used herein, the term "polymeric" refers to an agent or moiety that comprises one or more polymers or polymer moieties. A polymeric agent or moiety may also optionally comprise one or more other moieties, which in certain embodiments are selected from:

[0053] ·C 1-50 Alkyl, C 2-50 Alkenyl, C 2-50 Alkynyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, phenyl, naphthyl, indenyl, dihydroindenyl, and tetrahydronaphthyl; and

[0054] A linker selected from the following:

[0055]

[0056] in

[0057] A dashed line indicates connection to the remainder of a moiety or reagent, and

[0058] -R and -R a are independently selected from -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.

[0059] It will be understood by those skilled in the art that the polymer products obtained from a polymerization reaction do not all have the same molecular weight, but rather exhibit a distribution of molecular weights. Therefore, as used herein, molecular weight ranges, molecular weights, ranges for the number of monomers in a polymer, and the number of monomers in a polymer all refer to number-average molecular weights and the number of monomers, i.e., the arithmetic mean of the molecular weights of a polymer or polymeric portion and the arithmetic mean of the number of monomers in a polymer or polymeric portion.

[0060] Thus, in a polymeric moiety comprising "x" monomer units, any integer specified for "x" corresponds to the arithmetic mean number of monomers. Any integer range specified for "x" provides an integer range within which the arithmetic mean number of monomers lies. An integer specified for "x" given as "about x" means that the arithmetic mean number of monomers lies within an integer range of x + / - 10%, in certain embodiments, x + / - 8%, in certain embodiments, x + / - 5%, and in certain embodiments, x + / - 2%.

[0061] As used herein, the term "number average molecular weight" refers to the common arithmetic mean of the molecular weights of the individual polymers.

[0062] As used herein, the term "water-soluble" in reference to a compound of the present invention means that at least 1 g of the compound can be dissolved in one liter of water to form a homogeneous solution at 20° C. Thus, the term "water-insoluble" in reference to the compound means that less than 1 g of the compound can be dissolved in one liter of water to form a homogeneous solution at 20° C.

[0063] As used herein, the term "PEG-based" in reference to a moiety or agent means that the moiety or agent comprises PEG. In certain embodiments, the PEG-based moiety or agent 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%. In certain embodiments, the remaining weight percent of the PEG-based moiety or agent is selected from the following moieties and linkages:

[0064] ·C 1-50 Alkyl, C 2-50 Alkenyl, C 2-50 Alkynyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, phenyl, naphthyl, indenyl, dihydroindenyl, and tetrahydronaphthyl; and

[0065] A linker selected from the following:

[0066]

[0067] in

[0068] A dashed line indicates connection to the remainder of a moiety or reagent, and

[0069] -R and -R a are independently selected from -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.

[0070] Therefore, the term "hyaluronic acid-based" is used.

[0071] As used herein, the term "substituted" refers to a molecule or moiety in which one or more -H atoms are replaced with a different atom or group of atoms termed a "substituent."

[0072] In certain embodiments, one or more additional optional substituents are independently selected from halogen, -CN, -COOR x1 、-OR x1 、-C(O)R x1 、-C(O)N(R x1 R x1a )、-S(O)2N(R x1 R x1a)、-S(O)N(R x1 R x1a )、-S(O)2R x1 、-S(O)R x1 、-N(R x1 )S(O)2N(R x1a R x1b ),-SR x1 、-N(R x1 R x1a )、-NO2、-OC(O)R x1 、-N(R x1 )C(O)R x1a 、-N(R x1 )S(O)2R x1a 、-N(R x1 )S(O)R x1a 、-N(R x1 )C(O)OR x1a 、-N(R x1 )C(O)N(R x1a R x1b )、-OC(O)N(R x1 R x1a ),-T 0 、C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkynyl; wherein -T 0 、C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkynyl groups are optionally substituted with one or more -R x2 substituted, and wherein C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkynyl groups are optionally separated by one or more groups selected from -T 0 -, -C(O)O-, -O-, -C(O)-, -C(O)N(R x3 )-、-S(O)2N(R x3 )-、-S(O)N(R x3 )-、-S(O)2-、-S(O)-、-N(R x3 )S(O)2N(R x3a )-、-S-、-N(R x3 )-、-OC(OR x3 )(R x3a )-、-N(R x3 )C(O)N(R x3a )-and-OC(O)N(R x3 )-;

[0073] -R x1 、-R x1a 、-R x1b are independently selected from -H, -T 0 、C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkynyl; wherein -T 0 、C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkynyl groups are optionally substituted with one or more -R x2 substituted, and wherein C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkynyl groups are optionally separated by one or more groups selected from -T 0 -, -C(O)O-, -O-, -C(O)-, -C(O)N(R x3 )-、-S(O)2N(R x3 )-、-S(O)N(R x3 )-;-S(O)2-、-S(O)-、-N(R x3 )S(O)2N(R x3a )-、-S-、-N(R x3 )-、-OC(OR x3 )(R x3a )-、-N(R x3 )C(O)N(R x3a )-and-OC(O)N(R x3 )-;

[0074] T 0 Each independently selected from phenyl, naphthyl, indenyl, dihydroindenyl, tetrahydronaphthyl, C 3-10 cycloalkyl, 3 to 10 membered heterocyclyl and 8 to 11 membered heterobicyclyl; wherein T 0 Each independently optionally replaced by one or more -R x2 replace;

[0075] -R x2 Each independently selected from halogen, -CN, oxo (=O), -COOR x4 、-OR x4 、-C(O)R x4 、-C(O)N(R x4 R x4a )、-S(O)2N(R x4 R x4a )、-S(O)N(R x4 R x4a)、-S(O)2R x4 、-S(O)R x4 、-N(R x4 )S(O)2N(R x4a R x4b ),-SR x4 、-N(R x4 R x4a )、-NO2、-OC(O)R x4 、-N(R x4 )C(O)R x4a 、-N(R x4 )S(O)2R x4a 、-N(R x4 )S(O)R x4a 、-N(R x4 )C(O)OR x4a 、-N(R x4 )C(O)N(R x4a R x4b )、-OC(O)N(R x4 R x4a ) and C 1-6 Alkyl; among which C 1-6 The alkyl group is optionally substituted with one or more halogens which may be the same or different;

[0076] -R x3 、-R x3a 、-R x4 、-R x4a 、-R x4b are each independently selected from -H and C 1-6 Alkyl; among which C 1-6 The alkyl group is optionally substituted with one or more halogens which may be the same or different.

[0077] In certain embodiments, one or more additional optional substituents are independently selected from halogen, -CN, -COOR x1 、-OR x1 、-C(O)R x1 、-C(O)N(R x1 R x1a )、-S(O)2N(R x1 R x1a )、-S(O)N(R x1 R x1a )、-S(O)2R x1 、-S(O)R x1 、-N(R x1 )S(O)2N(R x1a R x1b ),-SR x1 、-N(Rx1 R x1a )、-NO2、-OC(O)R x1 、-N(R x1 )C(O)R x1a 、-N(R x1 )S(O)2R x1a 、-N(R x1 )S(O)R x1a 、-N(R x1 )C(O)OR x1a 、-N(R x1 )C(O)N(R x1a R x1b )、-OC(O)N(R x1 R x1a ),-T 0 、C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynyl; wherein -T 0 、C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynyl groups are optionally substituted with one or more -R x2 substituted, and wherein C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynyl groups are optionally separated by one or more groups selected from -T 0 -, -C(O)O-, -O-, -C(O)-, -C(O)N(R x3 )-、-S(O)2N(R x3 )-、-S(O)N(R x3 )-、-S(O)2-、-S(O)-、-N(R x3 )S(O)2N(R x3a )-、-S-、-N(R x3 )-、-OC(OR x3 )(R x3a )-、-N(R x3 )C(O)N(R x3a )-and-OC(O)N(R x3 )-;

[0078] -R x1 、-R x1a 、-R x1b 、-R x3 、-R x3a are independently selected from -H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl;

[0079] T 0 Each independently selected from phenyl, naphthyl, indenyl, dihydroindenyl, tetrahydronaphthyl, C 3-10 cycloalkyl, 3 to 10 membered heterocyclyl and 8 to 11 membered heterobicyclyl; wherein T 0 Each independently optionally replaced by one or more -R x2 replace;

[0080] -R x2 Each independently selected from halogen, -CN, oxo (=O), -COOR x4 、-OR x4 、-C(O)R x4 、-C(O)N(R x4 R x4a )、-S(O)2N(R x4 R x4a )、-S(O)N(R x4 R x4a )、-S(O)2R x4 、-S(O)R x4 、-N(R x4 )S(O)2N(R x4a R x4b ),-SR x4 、-N(R x4 R x4a )、-NO2、-OC(O)R x4 、-N(R x4 )C(O)R x4a 、-N(R x4 )S(O)2R x4a 、-N(R x4 )S(O)R x4a 、-N(R x4 )C(O)OR x4a 、-N(R x4 )C(O)N(R x4a R x4b )、-OC(O)N(R x4 R x4a ) and C 1-6 Alkyl; among which C 1-6 The alkyl group is optionally substituted with one or more halogens which may be the same or different;

[0081] -R x4 、-R x4a 、-R x4b are independently selected from -H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl.

[0082] In certain embodiments, one or more additional optional substituents are independently selected from halogen, -CN, -COOR x1 、-OR x1 、-C(O)R x1 、-C(O)N(R x1 R x1a )、-S(O)2N(R x1 R x1a )、-S(O)N(R x1 R x1a )、-S(O)2R x1 、-S(O)R x1 、-N(R x1 )S(O)2N(R x1a R x1b ),-SR x1 、-N(R x1 R x1a )、-NO2、-OC(O)R x1 、-N(R x1 )C(O)R x1a 、-N(R x1 )S(O)2R x1a 、-N(R x1 )S(O)R x1a 、-N(R x1 )C(O)OR x1a 、-N(R x1 )C(O)N(R x1a R x1b )、-OC(O)N(R x1 R x1a ),-T 0 、C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl; wherein -T 0 、C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl groups are optionally substituted with one or more -R x2 substituted, and wherein C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl groups are optionally separated by one or more groups selected from -T 0 -, -C(O)O-, -O-, -C(O)-, -C(O)N(R x3 )-、-S(O)2N(R x3 )-、-S(O)N(R x3)-、-S(O)2-、-S(O)-、-N(R x3 )S(O)2N(R x3a )-、-S-、-N(R x3 )-、-OC(OR x3 )(R x3a )-、-N(R x3 )C(O)N(R x3a )-and-OC(O)N(R x3 )-;

[0083] -R x1 、-R x1a 、-R x1b 、-R x2 、-R x3 、-R x3a are independently selected from -H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl;

[0084] T 0 Each independently selected from phenyl, naphthyl, indenyl, dihydroindenyl, tetrahydronaphthyl, C 3-10 cycloalkyl, 3 to 10 membered heterocyclyl and 8 to 11 membered heterobicyclyl; wherein T 0 Each independently optionally replaced by one or more -R x2 replace.

[0085] In certain embodiments, up to 6 -H atoms in the optionally substituted molecule are independently substituted with substituents, e.g., 5 -H atoms are independently substituted with substituents, 4 -H atoms are independently substituted with substituents, 3 -H atoms are independently substituted with substituents, 2 -H atoms are independently substituted with substituents, or 1 -H atom is independently substituted with a substituent.

[0086] The term "separated" means that a moiety is inserted between two carbon atoms, or - if inserted at one of the moiety's termini - between a carbon or heteroatom and a hydrogen atom, in certain embodiments, between a carbon atom and a hydrogen atom.

[0087] As used herein, the term "C 1-4 "Alkyl" means a straight or branched chain alkyl moiety having 1 to 4 carbon atoms. If present at the end of a molecule, the straight or branched C 1-4 Examples of alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. 1-4 When the alkyl group is connected, the C 1-4Examples of alkyl groups are -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)-, -C(CH3)2-. 1-4 Each hydrogen of an alkyl carbon may optionally be replaced by a substituent as defined above. 1-4 The alkyl group may be interrupted by one or more moieties as defined below.

[0088] As used herein, the term "nucleophile" refers to an agent or functional group that forms a bond with a reaction partner (ie, an electrophile) by donating two bonding electrons.

[0089] As used herein, the term "C 1-6 "Alkyl" means a straight or branched chain alkyl moiety having 1 to 6 carbon atoms. If present at the end of a molecule, the straight or branched chain C 1-6 Examples of 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. 1-6 When the alkyl group is connected, the C 1-6 Examples of alkyl groups are -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)-, and -C(CH3)2-. 1-6 Each hydrogen atom of an alkyl carbon may optionally be replaced by a substituent as defined above. 1-4 The alkyl group may be interrupted by one or more moieties as defined below.

[0090] Therefore, “C 1-10 Alkyl", "C 1-20 Alkyl" or "C 1-50 "Alkyl" refers to an alkyl chain having 1-10, 1-20 or 1-50 carbon atoms, respectively, wherein C 1-10 、C 1-20 or C 1-50 Each hydrogen atom of a carbon may optionally be replaced by a substituent as defined above. 1-10 or C 1-50 The alkyl group may be interrupted by one or more moieties as defined below.

[0091] As used herein, the term "C 2-6"Alkenyl" means a straight or branched hydrocarbon moiety having 2 to 6 carbon atoms containing at least one carbon-carbon double bond. 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 the two parts of the molecule are connected by C 2-6 When alkenyl is connected, this C 2-6 An example of an alkenyl group is -CH=CH-. 2-6 Each hydrogen atom of the alkenyl group may optionally be replaced by a substituent as defined above. 2-6 An alkenyl group may be interrupted by one or more moieties as defined below.

[0092] Therefore, the term "C 2-10 Alkenyl", "C 2-20 Alkenyl" or "C 2-50 "Alkenyl" means a straight or branched chain hydrocarbon moiety having 2 to 10, 2 to 20 or 2 to 50 carbon atoms containing at least one carbon-carbon double bond. 2-10 Alkenyl, C 2-20 Alkenyl or C 2-50 Each hydrogen atom of the alkenyl group may optionally be replaced by a substituent as defined above. 2-10 Alkenyl, C 2-20 Alkenyl or C 2-50 An alkenyl group may be interrupted by one or more moieties as defined below.

[0093] As used herein, the term "C 2-6 "Alkynyl" means a straight or branched hydrocarbon moiety having 2 to 6 carbon atoms containing at least one carbon-carbon triple bond. 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 parts of a molecule are linked through an alkynyl group, an example is -C≡C-. C 2-6 Each hydrogen atom of the alkynyl group may optionally be replaced by a substituent as defined above. Optionally, one or more double bonds may be present. Optionally, C 2-6 Alkynyl groups may be separated by one or more moieties as defined below.

[0094] Therefore, as used herein, the term " 2-10 Alkynyl", "C 2-20 Alkynyl" and "C 2-50 "Alkynyl" refers to a straight or branched chain hydrocarbon moiety having 2 to 10, 2 to 20 or 2 to 50 carbon atoms, respectively, containing at least one carbon-carbon triple bond. 2-10 Alkynyl, C 2-20 Alkynyl or C2-50 Each hydrogen atom of the alkynyl group may optionally be replaced by a substituent as defined above. Optionally, one or more double bonds may be present. Optionally, C 2-10 Alkynyl, C 2-20 Alkynyl or C 2-50 Alkynyl groups may be separated by one or more moieties as defined below.

[0095] As mentioned above, C 1-4 Alkyl, C 1-6 Alkyl, C 1-10 Alkyl, C 1-20 Alkyl, C 1-50 Alkyl, C 2-6 Alkenyl, C 2-10 Alkenyl, C 2-20 Alkenyl, C 2-50 Alkenyl, C 2-6 Alkynyl, C 2-10 Alkynyl, C 2-20 Alkenyl or C 2-50 Alkynyl groups can be optionally interrupted by one or more moieties, which in certain embodiments are selected from:

[0096]

[0097] in

[0098] Dashed lines indicate attachment to the remainder of a moiety or reagent; and

[0099] -R and -R a are independently selected from -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.

[0100] As used herein, the term "C 3-10 "Cycloalkyl" refers to a cyclic alkyl chain having 3 to 10 carbon atoms, which may be saturated or unsaturated, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl. 3-10 Each hydrogen atom of the cycloalkyl group may be replaced by a substituent as defined above. 3-10 "Cycloalkyl" also includes bridged bicyclic rings such as norbornane or norbornene.

[0101] The term "8- to 30-membered carbon polycyclyl" or "8- to 30-membered carbon polycyclic ring" refers to a cyclic moiety of two or more rings having 8-30 ring atoms, wherein two adjacent rings share at least one ring atom, and may contain up to the maximum number of double bonds (being aromatic rings or fully saturated, partially saturated or unsaturated non-aromatic rings). In certain embodiments, the 8- to 30-membered carbocyclyl refers to a cyclic moiety of two, three, four, or five rings, and in certain embodiments, a cyclic moiety of two, three, or four rings.

[0102] As used herein, the term "3- to 10-membered heterocyclyl" or "3- to 10-membered heterocycle" refers to a ring having 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms, which may contain up to the maximum number of double bonds (being an aromatic ring or a fully saturated, partially saturated or unsaturated non-aromatic ring), wherein at least one ring atom and up to 4 ring atoms are replaced by heteroatoms selected from sulfur (including -S(O)- and -S(O)2-), oxygen and nitrogen (including =N(O)-), and wherein the ring is attached to the rest of the molecule through a carbon or nitrogen atom. Examples of 3- to 10-membered heterocycles include, but are not limited to, aziridine, oxirane, thiirane, aziridine, oxirane, thiirane, azetidine, oxetane, thietane, furan, thiophene, pyrrole, pyrroline, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, oxazoline, isoxazole, isoxazoline, thiazole, thiazoline, isothiazole, isothiazolin, isothiazolin, thiadiazole, thiadiazoline, tetrakis(e). 1-Hydrogen ...

[0103] As used herein, the term "8- to 11-membered heterobicyclyl" or "8- to 11-membered heterobicycle" refers to a heterocyclic moiety having two rings of 8 to 11 ring atoms, wherein at least one ring atom is shared by both rings and may contain up to the maximum number of double bonds (being aromatic rings or fully saturated, partially saturated or unsaturated non-aromatic rings), wherein at least one ring atom up to 6 ring atoms are replaced by heteroatoms selected from sulfur (including -S(O)- and -S(O)2-), oxygen and nitrogen (including =N(O)-), and wherein the ring is attached to the rest of the molecule through a carbon or nitrogen atom. Examples of 8- to 11-membered heterocycles are indole, dihydroindole, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzimidazole, benzimidazolinone, quinoline, quinazoline, dihydroquinazoline, quinoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, decahydroisoquinoline, tetrahydroisoquinoline, dihydroisoquinoline, benzazepine, purine and pteridine. The term 8- to 11-membered heterobicyclic also includes spirocyclic structures of two rings, such as 1,4-dioxa-8-azaspiro[4.5]decane, or bridged heterocycles, such as 8-aza-bicyclo[3.2.1]octane. Each carbon atom of an 8- to 11-membered heterobicyclic group or an 8- to 11-membered heterocyclic carbon can be replaced by a substituent as defined below.

[0104] Similarly, the term "8- to 30-membered heteropolycyclyl" or "8- to 30-membered heteropolycycle" refers to a heterocyclic moiety having two or more rings of 8-30 ring atoms, in certain embodiments of three, four, or five rings, wherein two adjacent rings share at least one ring atom, and may contain up to the maximum number of double bonds (being aromatic rings or fully saturated, partially saturated, or unsaturated non-aromatic rings), wherein at least one ring atom is replaced by up to 10 heteroatoms selected from sulfur (including -S(O)- and -S(O)2-), oxygen, and nitrogen (including =N(O)-), and wherein the ring is attached to the rest of the molecule through a carbon or nitrogen atom.

[0105] It should be understood that the phrase "R" which refers to a portion of the structure x / R y Together with the atoms to which they are attached, they form C 3-10 Cycloalkyl or 3- to 10-membered heterocyclic group"

[0106]

[0107] Refers to R x and R y The following structure is formed:

[0108]

[0109] Where R is C 3-10 cycloalkyl or 3- to 10-membered heterocyclic group.

[0110] It should also be understood that the phrase "R" which refers to a portion of the structure x / R y Together with the atoms to which they are attached, they form Ring A"

[0111]

[0112] Refers to R x and R y The following structure is formed:

[0113]

[0114] As used herein, "halogen" refers to fluorine, chlorine, bromine, or iodine. In certain embodiments, halogen is fluorine or chlorine.

[0115] Typically, the terms "comprising" or "including" also include "consisting of" or "composed of.

[0116] In certain embodiments, the compound has formula (Ia). In certain embodiments, x of formula (Ia) is 1. In certain embodiments, x of formula (Ia) is 2. In certain embodiments, x of formula (Ia) is 3. In certain embodiments, x of formula (Ia) is 4. In certain embodiments, x of formula (Ia) is 5. In certain embodiments, x of formula (Ia) is 6. In certain embodiments, x of formula (Ia) is 7. In certain embodiments, x of formula (Ia) is 8. In certain embodiments, x of formula (Ia) is 9. In certain embodiments, x of formula (Ia) is 10. In certain embodiments, x of formula (Ia) is 11. In certain embodiments, x of formula (Ia) is 12. In certain embodiments, x of formula (Ia) is 13. In certain embodiments, x of formula (Ia) is 14. In certain embodiments, x of formula (Ia) is 15. In certain embodiments, x of formula (Ia) is 16. In certain embodiments, x of Formula (Ia) is 17. In certain embodiments, x of Formula (Ia) is 18. In certain embodiments, x of Formula (Ia) is 19. In certain embodiments, x of Formula (Ia) is 20. In certain embodiments, x of Formula (Ia) is 21. In certain embodiments, x of Formula (Ia) is 22. In certain embodiments, x of Formula (Ia) is 23. In certain embodiments, x of Formula (Ia) is 24. In certain embodiments, x of Formula (Ia) is 25.

[0117] In certain embodiments, the compound has Formula (Ia) wherein x=1.

[0118] In certain embodiments, the compound has formula (Ib). In certain embodiments, y of formula (Ib) is 1. In certain embodiments, y of formula (Ib) is 2. In certain embodiments, y of formula (Ib) is 3. In certain embodiments, y of formula (Ib) is 4. In certain embodiments, y of formula (Ib) is 5. In certain embodiments, y of formula (Ib) is 6. In certain embodiments, y of formula (Ib) is 7. In certain embodiments, y of formula (Ib) is 8. In certain embodiments, y of formula (Ib) is 9. In certain embodiments, y of formula (Ib) is 10. In certain embodiments, y of formula (Ib) is 11. In certain embodiments, y of formula (Ib) is 12. In certain embodiments, y of formula (Ib) is 13. In certain embodiments, y of formula (Ib) is 14. In certain embodiments, y of formula (Ib) is 15. In certain embodiments, y of formula (Ib) is 16. In certain embodiments, y of Formula (Ib) is 17. In certain embodiments, y of Formula (Ib) is 18. In certain embodiments, y of Formula (Ib) is 19. In certain embodiments, y of Formula (Ib) is 20. In certain embodiments, y of Formula (Ib) is 21. In certain embodiments, y of Formula (Ib) is 22. In certain embodiments, y of Formula (Ib) is 23. In certain embodiments, y of Formula (Ib) is 24. In certain embodiments, y of Formula (Ib) is 25.

[0119] In certain embodiments, the compound has Formula (Ib) wherein y=2.

[0120] In certain embodiments, -D- is a drug moiety selected from the group consisting of a small molecule drug moiety, a medium size molecule drug moiety, an oligonucleotide drug moiety, a peptide nucleic acid drug moiety, a peptide drug moiety, and a protein drug moiety.

[0121] 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-sized 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.

[0122] In certain embodiments, -D- or -D-AB 2 is a GLP-1 receptor agonist moiety. Therefore, the conjugate of the present invention can be a GLP-1 receptor agonist conjugate.

[0123] In certain embodiments, -D- or -D-AB 2 It is a monoagonist of the GLP-1 receptor, ie, it only activates the GLP-1 receptor.

[0124] In certain embodiments, -D- or -D-AB 2 It is an agonist of the GLP-1 receptor and an agonist of another receptor, namely -D- or -D-AB 2 It is a dual GLP-1 receptor agonist. Such another receptor may be selected from the group consisting of a GIP receptor, a GCG receptor, amylin receptor, a PYY receptor, and a GLP-2 receptor.

[0125] In certain embodiments, -D- or -D-AB 2 It is an agonist of GLP-1 receptor and GIP receptor. In certain embodiments, -D- or -D-AB 2 It is an agonist of GLP-1 receptor and GCG receptor. In certain embodiments, -D- or -D-AB 2 It is an agonist of GLP-1 receptor and amylin receptor. In certain embodiments, -D- or -D-AB 2 It is an agonist of GLP-1 receptor and PYY receptor. In certain embodiments, -D- or -D-AB 2 It is an agonist of GLP-1 and GLP-2 receptors.

[0126] In certain embodiments, -D- or -D-AB 2 is an agonist of the GLP-1 receptor and growth / differentiation factor 15 (GDF15). In certain embodiments, -D- or -D-AB 2 It is an agonist of the GLP-1 receptor and fibroblast growth factor 21 (FGF21).

[0127] In certain embodiments, -D- or -D-AB 2 It is a GLP-1 receptor agonist and an agonist of two other receptors, namely -D- or -D-AB 2 In certain embodiments, the additional receptors are selected from the group consisting of a GIP receptor (GIPR), a GCG receptor (GCGR), amylin receptor, a PYY receptor (PYYR), and a GLP-2 receptor.

[0128] In certain embodiments, -D- or -D-AB 2 It is a triple GLP-1 receptor agonist that activates the GLP-1 receptor, GIP receptor and GCG receptor. In certain embodiments, -D- or -D-AB 2 It is a triple GLP-1 receptor agonist that activates the GLP-1 receptor, GIP receptor and amylin receptor. In certain embodiments, -D- or -D-AB 2It is a triple GLP-1 receptor agonist that activates the GLP-1 receptor, GIP receptor and PYY receptor. In certain embodiments, -D- or -D-AB 2 It is a triple GLP-1 receptor agonist that activates the GLP-1 receptor, the amylin receptor, and the PYY receptor. In certain embodiments, -D- or -D-AB 2 It 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 2 It is a triple GLP-1 receptor agonist that activates the GLP-1 receptor, PYY receptor, and GLP-2 receptor.

[0129] In certain embodiments, -D- is human GLP-1 of SEQ ID NO: 1:

[0130] HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG.

[0131] In certain embodiments, -D- is a human GLP-1 analog of SEQ ID NO: 1, and the peptide sequence may comprise one or more amino acid changes compared to SEQ ID NO: 1. Such amino acid changes may be additions of one or more amino acid residues, deletions of one or more amino acid residues, substitutions of one or more amino acid residues, or any combination thereof. Such amino acid changes may occur at the N-terminus, C-terminus, and / or at internal sites of the GLP-1 of SEQ ID NO: 1. In certain embodiments, such a human GLP-1 analog has up to three amino acid changes compared to SEQ ID NO: 1, i.e., has up to three amino acid additions, deletions, or substitutions compared to the sequence of SEQ ID NO: 1.

[0132] In certain embodiments, -D- has the sequence

[0133] HX1EGTFTSDVSSYLEGQAAKEFIAWLVRGRG(SEQ ID NO:2),

[0134] wherein X1 is 2-aminoisobutyric acid (Aib).

[0135] In certain embodiments, -D- has the sequence

[0136] HX1EGTFTSDVSSYLEGQAAKEFIAWLVRGRG(SEQ ID NO:3),

[0137] wherein X1 is Aib, and the C-terminal glycine, ie, the glycine at position 31, is amidated to form a C-terminal primary amide.

[0138] In certain embodiments, -D- is exenatide. Exenatide has the sequence

[0139] HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS (SEQ ID NO: 4).

[0140] In certain embodiments, -D- has the sequence

[0141] HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS(SEQ ID NO:5),

[0142] The C-terminal serine, i.e., the serine at position 39, is amidated to form a C-terminal primary amide.

[0143] In certain embodiments, -D- is lixisenatide. Lixisenatide has the sequence

[0144] HGEGFTTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPSKKKKKK(SEQ ID NO:6),

[0145] The C-terminal lysine, ie, the lysine at position 44, is amidated to form a C-terminal primary amide.

[0146] In certain embodiments, -D- has the sequence

[0147] HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPSKKKKKK (SEQ ID NO: 7).

[0148] In certain embodiments, -D- has the sequence

[0149] HX1EGTFTSDLSKQX2EEEAVRLFIEWLKQGGPSSGAPPPC(SEQ ID NO:8),

[0150] wherein X1 is D-alanine, and X2 is norleucine (Nle).

[0151] In certain embodiments, -D- has the sequence

[0152] HX1EGTFTSDLSKQX2EEEAVRLFIEWLKQGGPSSGAPPPC(SEQ ID NO:9),

[0153] wherein X1 is D-alanine, X2 is Nle, and the C-terminal cysteine, ie, the cysteine ​​at position 39, is amidated to form a C-terminal primary amide.

[0154] In certain embodiments, -D- is PEG-Loxenatide. PEG-Loxenatide has the sequence

[0155] HX1EGTFTSDLSKQX2EEEAVRLFIEWLKQGGPSSGAPPPC(SEQ ID NO:10),

[0156] Where X1 is D-alanine; X2 is Nle; the cysteine ​​at position 39 is chemically modified by coupling the thiol group of the cysteine ​​side chain with the following moieties

[0157]

[0158] in

[0159] The dashed line represents the thiol group of the cysteine ​​side chain attached to the cysteine ​​at position 39, and each mPEG is a methoxypoly(ethylene glycol) with a molecular weight of approximately 20 kDa.

[0160] In certain embodiments, -D- has the sequence

[0161] HX1EGTFTSDLSKQX2EEEAVRLFIEWLKQGGPSSGAPPPC(SEQ ID NO:11),

[0162] Where X1 is D-alanine; X2 is Nle; the cysteine ​​at position 39 is chemically modified by coupling the thiol group of the cysteine ​​side chain with the following moieties

[0163]

[0164] in

[0165] The dotted line represents the thiol group of the cysteine ​​side chain attached to the cysteine ​​at position 39, each mPEG is a methoxypoly(ethylene glycol) having a molecular weight of approximately 20 kDa, and the C-terminal cysteine, i.e., the cysteine ​​at position 39, is amidated as a C-terminal primary amide.

[0166] In certain embodiments, -D- has the sequence

[0167] HAEGTFTSDVSSYLEGQAAKEFIAWLVRGRG (SEQ ID NO: 12).

[0168] In certain embodiments, -D- has the sequence

[0169] HAEGTFTSDVSSYLEGQAAKEFIAWLVRGRG(SEQ ID NO:13),

[0170] And the C-terminal glycine, ie, the glycine at position 31, is amidated to form a C-terminal primary amide.

[0171] In certain embodiments, -D- has the sequence

[0172] HVEGTFTSDVSSYLEEQAAREFIKWLVRGRG (SEQ ID NO: 14).

[0173] In certain embodiments, -D- has the sequence

[0174] HVEGTFTSDVSSYLEEQAAREFIKWLVRGRG(SEQ ID NO:15),

[0175] And the C-terminal glycine, ie, the glycine at position 31, is amidated to form a C-terminal primary amide.

[0176] In certain embodiments, -D- has the sequence

[0177] HGEGTFTSDVSSYLEGQAAKEFIAWLVRGRG (SEQ ID NO: 16).

[0178] In certain embodiments, -D- has the sequence

[0179] HGEGTFTSDVSSYLEGQAAKEFIAWLVRGRG(SEQ ID NO:17),

[0180] And the C-terminal glycine, ie, the glycine at position 31, is amidated to form a C-terminal primary amide.

[0181] In certain embodiments, -D- has the sequence

[0182] HX1EGTFTSDVSSYLEGQAAKEFIAWLVRGRGL(SEQ ID NO:18),

[0183] Where X1 is Aib.

[0184] In certain embodiments, -D- has the sequence

[0185] HX1EGTFTSDVSSYLEGQAAKEFIAWLVRGRGL(SEQ ID NO:19),

[0186] wherein X1 is Aib, and the C-terminal leucine, ie, the leucine at position 32, is amidated to form a C-terminal primary amide.

[0187] In certain embodiments, -D- has the sequence

[0188] YX1EGTFTSDYSIX2LDKIAQKAFVQWLIAGGPSSGAPPPS(SEQ ID NO:20),

[0189] wherein X1 is Aib, X2 is Aib, and the C-terminal serine, ie, the serine at position 39, is amidated to form a C-terminal primary amide.

[0190] In certain embodiments, -D- has the sequence

[0191] YX1EGTFTSDYSIX2LDKIAQKAFVQWLIAGGPSSGAPPPS(SEQ ID NO:21),

[0192] Wherein X1 is Aib, and X2 is Aib.

[0193] In certain embodiments, -D- has the sequence

[0194] HSQGTFTSDKSEYLDSERARDFVAWLEAGG (SEQ ID NO: 22).

[0195] In certain embodiments, -D- has the sequence

[0196] HSQGTFTSDKSEYLDSERARDFVAWLEAGG(SEQ ID NO:23),

[0197] The C-terminal glycine, i.e., the glycine at position 30, is amidated to form a C-terminal primary amide.

[0198] In certain embodiments, -D- has the sequence

[0199] HX1QGTFTSDYSKYLDERAAKDFIKWLESA(SEQ ID NO:24),

[0200] wherein X1 is 1-amino-cyclobutanecarboxylic acid (Ac4c); and the C-terminal alanine, ie, the alanine at position 29, is amidated to form a C-terminal primary amide.

[0201] In certain embodiments, -D- has the sequence

[0202] HX1QGTFTSDYSKYLDERAAKDFIKWLESA(SEQ ID NO:25),

[0203] Wherein X1 is 1-amino-cyclobutanecarboxylic acid (Ac4c).

[0204] In certain embodiments, -D- has the sequence

[0205] HX1QGTFTSDYSKYLDEKAAKEFIQWLLQT(SEQ ID NO:26),

[0206] wherein X1 is Aib, and the glutamic acid at position 16 and the lysine at position 20 are connected by a lactam bridge.

[0207] In certain embodiments, -D- has the sequence

[0208] HX1QGTFTSDYSKYLDEKAAKEFIQWLLQT(SEQ ID NO:27),

[0209] wherein X1 is Aib, the glutamic acid at position 16 and the lysine at position 20 are connected by a lactam bridge, and the C-terminal threonine, ie, the threonine at position 29, is amidated to form a C-terminal primary amide.

[0210] In certain embodiments, -D- has the sequence

[0211] HX1QGTFTSDYSKYLDEKKAKEFVEWLLEGPSSG(SEQ ID NO:28),

[0212] wherein X1 is Aib, and the C-terminal glycine, ie, the glycine at position 34, is amidated to form a C-terminal primary amide.

[0213] In certain embodiments, -D- has the sequence

[0214] HX1QGTFTSDYSKYLDEKKAKEFVEWLLEGPSSG(SEQ ID NO:29),

[0215] Where X1 is Aib.

[0216] In certain embodiments, -D- has the sequence

[0217] HX1EGSFTSELATILDKQAARDFIAWLIQHKITD(SEQ ID NO:30),

[0218] Where X1 is Aib.

[0219] In certain embodiments, -D- has the sequence

[0220] HX1EGSFTSELATILDKQAARDFIAWLIQHKITD(SEQ ID NO:31),

[0221] wherein X1 is Aib, and the C-terminal aspartic acid, ie, the aspartic acid at position 33, is amidated to form a C-terminal primary amide.

[0222] In certain embodiments, -D- has the sequence

[0223] YX1QGTFTSDYSIX2LDKKAQX3AFIEYLLEGGPSSGAPPPS(SEQ ID NO:32),

[0224] wherein X1 is Aib, X2 is α-methyl-leucine (αMeL), and X3 is Aib; and the C-terminal serine, ie, the serine at position 39, is amidated to form a C-terminal primary amide.

[0225] In certain embodiments, -D- has the sequence

[0226] YX1QGTFTSDYSIX2LDKKAQX3AFIEYLLEGGPSSGAPPPS(SEQ ID NO:33),

[0227] wherein X1 is Aib, X2 is α-methyl-leucine (αMeL), and X3 is Aib.

[0228] In certain embodiments, -D- has the sequence

[0229] HX1EGTFTSDVSSYLEEEAAKEFIAWLVRGGPSSGAPPPSK(SEQ ID NO:54),

[0230] Where X1 is Aib.

[0231] In certain embodiments, -D- has the sequence

[0232] HX1EGTFTSDVSSYLEEQAAKEFIAWLVRGGG(SEQ ID NO:55),

[0233] Where X1 is Aib.

[0234] In certain embodiments, -D- has the sequence

[0235] HX1EGTFTSDVSSYLEEQAAKEFIAWLVRGGGGAQPGAQPGAQPGAQPGAQPGAQPGAQPGAQPGAQPGQKP (SEQ ID NO: 56),

[0236] Where X1 is Aib.

[0237] In certain embodiments, -D- has the sequence

[0238] YX1EGTFTSDYSIX2LDKIAQKAFVQWLIAGGPSSGAPPPS(SEQ ID NO:57),

[0239] Wherein X1 and X2 are both Aib.

[0240] In certain embodiments, -D- is a drug selected from the group consisting of insulin; amylin and amylin / calcitonin; PYY; GIP; MSH; C5a binders; GDF15; PCSK9 I; immune stimulants; urocortin 2; MIC-1; IL-1R antagonists; leptin; gastrin; glucagon; exendin-4; GLP-1; GLP-2 and GIP.

[0241] In certain embodiments, -D- is a drug selected from the group consisting of insulin; an insulin analog; amylin; amylin / calcitonin dual agonist; PYY; GIP; MSH; a C5 inhibitor or modulator; GDF15; a PCSK9 inhibitor; an immunostimulant; urocortin II; MIC-1; an IL-1R antagonist; leptin; gastrin; glucagon; oxyntomodulin; neurokinin A; a tachykinin / neurokinin receptor 2 (NK2R) agonist; a neurokinin receptor (NKR) agonist, and GLP-2.

[0242] In certain embodiments, -D- is insulin, such as insulin detemir, insulin degludec, or insulin. In certain embodiments, -D- is amylin or amylin / calcitonin, such as 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 PCSK9i. In certain embodiments, -D- is an immunostimulant, such as romurtide or mifamurtide. In certain embodiments, -D- is muramyl dipeptide. In certain embodiments, -D- is urocortin 2. In certain embodiments, -D- is MIC-1. In certain embodiments, -D- is an IL-1R antagonist. In certain embodiments, -D- is leptin. In certain embodiments, -D- is gastrin.

[0243] In certain embodiments, -D- is selected from the group consisting of a growth hormone, such as human growth hormone; FGF21; EGF(a); and a coagulation factor.

[0244] In certain embodiments, -D- is a growth hormone, such as 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.

[0245] In certain embodiments, -D- is selected from the group consisting of a cytotoxic small molecule drug; a chemotherapeutic small molecule drug; and an immune-activating small molecule drug.

[0246] In certain embodiments, -D- is a cytotoxic small molecule drug. In certain embodiments, -D- is a chemotherapeutic small molecule drug. In certain embodiments, -D- is and is an immune-activating small molecule drug, such as telratolimod.

[0247] In certain embodiments, -D- is paclitaxel. In certain embodiments, -D- is doxorubicin. In certain embodiments, -D- is 5-FU.

[0248] In certain embodiments, -D- is a PTH moiety.

[0249] Part-AB 1 By -L 2 -L 1 - coupled to -D-, where -L 2 - coupled to -AB 1 , and -L 1 - coupled to -D-. In -L 1 After the bond between - and -D- is cleaved, part -AB 1 Keep coupled to -L 2 -. Part-AB 2 Directly coupled to -D-, for example via a stable linker. This means that in -L 1 After the link between - and -D- is cleaved, the conjugate HD-AB 2 is released, where H- is hydrogen. Therefore, part "HD-AB 2 ” Also known as Part-D-AB 2 of the corresponding free drug.

[0250] Part-AB 1 and-AB 2 Binds to albumin, such as human albumin, under physiological conditions (aqueous buffer pH 7.4, 37.4°C).

[0251] In certain embodiments, -AB 1 and-AB 2 In certain embodiments, -AB 1 and-AB 2 Have the same structure.

[0252] -AB 1 and-AB 2 Each may independently be a fatty acid based albumin binding moiety or a peptide albumin binding moiety.

[0253] In certain embodiments, -AB 1 and-AB 2 are independently fatty acid-based albumin binding moieties. In certain embodiments, -AB 1 and-AB 2 are all fatty acid based albumin binding moieties and have the same structure. In certain embodiments, -AB 1 and-AB 2 Both are fatty acid-based albumin binding moieties, but have different structures.

[0254] In certain embodiments, -AB 1 and / or -AB 2 Independently of formula (A):

[0255]

[0256] in

[0257] The dotted lines indicate connections to -L 2 -or-D-;

[0258] -F 0 Having formula (a-1)

[0259]

[0260] in

[0261] The dotted line indicates the connection to -L A -;

[0262] -R 0 Selected from-CR 1 R 1a R 1b 、-COOR 1 、

[0263] -R 1 、-R 1a and -R 1b is selected from -H, methyl, ethyl, propyl and isopropyl;

[0264] n is an integer within the range of and including 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, and 22;

[0265] -L A - does not exist or has formula (a-2)

[0266]

[0267] in

[0268] The unmarked dashed line indicates the connection to -L B -;

[0269] The dashed line marked with an asterisk indicates the connection to the -F 0 ;

[0270] -R a -Selected

[0271] in

[0272] The dashed line marked with an asterisk indicates the connection to the -F 0 ;

[0273] The unmarked dashed line indicates the connection to -L A - the rest of

[0274] -R b -for

[0275] m is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;

[0276] p is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;

[0277] -L B - does not exist or has formula (a-3)

[0278]

[0279] in

[0280] The unmarked dashed line indicates the connection to -L 2 -or-D-;

[0281] The dashed line marked with an asterisk indicates the connection to -L A ;

[0282] -R c -for

[0283] -R d -Selected from C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkynyl, where C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 The alkynyl group may be optionally substituted with one or more -R 1 Substituted, and the C 1-50 Alkyl, C 2-50 Alkenyl or C 2-50 The alkynyl group may be optionally separated by one or more groups selected from -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R 2 )-、-S(O)2N(R 2 )-、-S(O)N(R 2 )-、-S(O)2-、-S(O)-、-N(R 2 )S(O)2N(R 2a )-、-S-、-N(R 2 )-、-OC(OR 2 )(R 2a )-、-N(R 2 )C(O)N(R 2a )-and-OC(O)N(R 2 )-;

[0284] -T- are each independently selected from phenyl, naphthyl, indenyl, dihydroindenyl, tetrahydronaphthyl, C 3-10 Cycloalkyl, 3 to 10 membered heterocyclyl, 8 to 11 membered heterobicyclyl, 8 to 30 membered carbon polycyclyl and 8 to 30 membered heteropolycyclyl; wherein -T- may be independently replaced by one or more -R which may be the same or different 1 replace;

[0285] -R 1 Each independently selected from halogen, -CN, oxo (=O), -COOR 3 、-OR 3 、-C(O)R 3 、-C(O)N(R 3 R 3a )、-S(O)2N(R 3 R 3a )、-S(O)N(R 3 R 3a )、-S(O)2R 3 、-S(O)R 3 、-N(R 3 )S(O)2N(R 3a R 3b ),-SR 3 、-N(R 3 R 3a )、-NO2、-OC(O)R 3 、-N(R 3 )C(O)R 3a 、-N(R 3 )S(O)2R 3a 、-N(R 3 )S(O)R 3a 、-N(R 3 )C(O)OR 3a 、-N(R 3 )C(O)N(R 3a R 3b )、-OC(O)N(R 3 R 3a ) and C 1-6 Alkyl; among which C 1-6 The alkyl group is optionally substituted with one or more halogens which may be the same or different;

[0286] -R 2 、-R 2a 、-R 3 、-R 3a and -R 3b are each independently selected from -H and C 1-6 Alkyl, where C 1-6The alkyl group may be optionally substituted with one or more halogen groups which may be the same or different; and

[0287] -R e -selected from -CH2-,

[0288] If -R b -for And -L B - does not exist, then -R c -for And if -R b -for And -L B - does not exist, then -R c -for

[0289] In certain embodiments, -L A - has formula (a-2), i.e., is absent. In certain embodiments, -L A -does not exist.

[0290] In certain embodiments, -R a -for The dashed line marked with an asterisk indicates the connection to -F 0 , and the unmarked dotted line indicates the connection to -L A -The rest of the.

[0291] In certain embodiments, -R a -for The dashed line marked with an asterisk indicates the connection to -F 0 , and the unmarked dotted line indicates the connection to -L A -The rest of the.

[0292] In certain embodiments, -R b -for In certain embodiments, -R b -for

[0293] 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.

[0294] 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.

[0295] In certain embodiments, -L B - has formula (a-3). In certain embodiments, -L B - does not exist. If -L B - does not exist, the unmarked dotted lines in formula (a-2) represent the connection to -L 2 -or-D-.

[0296] In certain embodiments, -R c -for In certain embodiments, -R c -for

[0297] In certain embodiments, -R e - is -CH2-. In certain embodiments, -R e -for In certain embodiments, -R e -for

[0298] In certain embodiments, -L A -and-L B - does not exist. If -L A -and-L B - do not exist, the dotted lines in formula (a-1) represent connections to -L 2 -or-D-.

[0299] In certain embodiments, -F 0 Selected from

[0300]

[0301]

[0302]

[0303] The dotted line indicates the connection to -L A -.

[0304] If -LA - does not exist, and the dotted line in formula ((a-4)-(a-39) represents the connection to -L B -. If -L A -and-L B - does not exist, the dotted line in formula ((a-4)-(a-39)) represents the connection to -D-.

[0305] In certain embodiments, -F 0 In certain embodiments, -F 0 In certain embodiments, -F 0 In certain embodiments, -F 0 In certain embodiments, -F 0 In certain embodiments, -F 0 In certain embodiments, -F 0 In certain embodiments, -F 0 In certain embodiments, -F 0 In certain embodiments, -F 0 In certain embodiments, -F 0 In certain embodiments, -F 0 In certain embodiments, -F 0 In certain embodiments, -F 0 In certain embodiments, -F 0 In certain embodiments, -F 0 In certain embodiments, -F 0 In certain embodiments, -F 0 In certain embodiments, -F 0 In certain embodiments, -F 0 In certain embodiments, -F 0 In certain embodiments, -F 0 In certain embodiments, -F 0 In certain embodiments, -F 0 In certain embodiments, -F 0In certain embodiments, -F 0 In certain embodiments, -F 0 In certain embodiments, -F 0 In certain embodiments, -F 0 In certain embodiments, -F 0 In certain embodiments, -F 0 In certain embodiments, -F 0 In certain embodiments, -F 0 Having formula (a-36). In certain embodiments, -F 0 In certain embodiments, -F 0 In certain embodiments, -F 0 Having formula (a-39).

[0306] In certain embodiments, -F 0 Having formula (a-4), and -L A -and-L B - is absent. In certain embodiments, -F 0 Having formula (a-5), and -L A -and-L B - is absent. In certain embodiments, -F 0 Having formula (a-6), and -L A -and-L B - is absent. In certain embodiments, -F 0 Having formula (a-7), and -L A -and-L B - is absent. In certain embodiments, -F 0 Having formula (a-8), and -L A -and-L B - is absent. In certain embodiments, -F 0 Having formula (a-9), and -L A -and-L B - is absent. In certain embodiments, -F 0 Having formula (a-10), and -L A -and-L B - is absent. In certain embodiments, -F 0 Having formula (a-11), and -L A -and-L B - is absent. In certain embodiments, -F0 Having formula (a-12), and -L A -and-L B - is absent. In certain embodiments, -F 0 Having formula (a-13), and -L A -and-L B - is absent. In certain embodiments, -F 0 Having formula (a-14), and -L A -and-L B - is absent. In certain embodiments, -F 0 Having formula (a-15), and -L A -and-L B - is absent. In certain embodiments, -F 0 Having formula (a-16), and -L A -and-L B - is absent. In certain embodiments, -F 0 Having formula (a-17), and -L A -and-L B - is absent. In certain embodiments, -F 0 Having formula (a-18), and -L A -and-L B - is absent. In certain embodiments, -F 0 Having formula (a-19), and -L A -and-L B - is absent. In certain embodiments, -F 0 Having formula (a-20), and -L A -and-L B - is absent. In certain embodiments, -F 0 Having formula (a-21), and -L A -and-L B - is absent. In certain embodiments, -F 0 Having formula (a-22), and -L A -and-L B - is absent. In certain embodiments, -F 0 Having formula (a-23), and -L A -and-L B - is absent. In certain embodiments, -F 0 Having formula (a-24), and -L A -and-L B - is absent. In certain embodiments, -F 0 Having formula (a-25), and -L A -and-L B- is absent. In certain embodiments, -F 0 Having formula (a-26), and -L A -and-L B - is absent. In certain embodiments, -F 0 Having formula (a-27), and -L A -and-L B - is absent. In certain embodiments, -F 0 Having formula (a-28), and -L A -and-L B - is absent. In certain embodiments, -F 0 Having formula (a-29), and -L A -and-L B - is absent. In certain embodiments, -F 0 Having formula (a-30), and -L A -and-L B - is absent. In certain embodiments, -F 0 Having formula (a-31), and -L A -and-L B - is absent. In certain embodiments, -F 0 Having formula (a-32), and -L A -and-L B - is absent. In certain embodiments, -F 0 Having formula (a-33), and -L A -and-L B - is absent. In certain embodiments, -F 0 Having formula (a-34), and -L A -and-L B - is absent. In certain embodiments, -F 0 Having formula (a-35), and -L A -and-L B - is absent. In certain embodiments, -F 0 Having formula (a-36), and -L A -and-L B - is absent. In certain embodiments, -F 0 Having formula (a-37), and -L A -and-L B - is absent. In certain embodiments, -F 0 Having formula (a-38), and -L A -and-L B - is absent. In certain embodiments, -F 0 Having formula (a-39), and -L A -and-LB -does not exist.

[0307] In certain embodiments, -L A -Selected

[0308]

[0309]

[0310]

[0311] The dashed line marked with an asterisk indicates the connection to -F 0 -, and the unmarked dotted line indicates connection to -L B -. If -L B If - is not present, the unlabeled dashed line indicates connection to -D-.

[0312] In certain embodiments, -L A - has formula (a-40). In certain embodiments, -L A - has formula (a-41). In certain embodiments, -L A - has formula (a-42). In certain embodiments, -L A - has formula (a-43). In certain embodiments, -L A - has formula (a-44). In certain embodiments, -L A - has formula (a-45). In certain embodiments, -L A - has formula (a-46). In certain embodiments, -L A - has formula (a-47). In certain embodiments, -L A - has formula (a-48). In certain embodiments, -L A - has formula (a-49). In certain embodiments, -L A - has formula (a-50). In certain embodiments, -L A - has formula (a-51). In certain embodiments, -L A - has formula (a-52). In certain embodiments, -L A - has formula (a-53). In certain embodiments, -L A - has formula (a-54). In certain embodiments, -L A - has formula (a-55). In certain embodiments, -L A - has formula (a-56). In certain embodiments, -L A - has formula (a-57). In certain embodiments, -L A- has formula (a-58). In certain embodiments, -L A - has formula (a-59). In certain embodiments, -L A - has formula (a-60). In certain embodiments, -L A - has formula (a-61). In certain embodiments, -L A - has formula (a-62). In certain embodiments, -L A - has formula (a-63). In certain embodiments, -L A - has formula (a-64). In certain embodiments, -L A - has formula (a-65). In certain embodiments, -L A - has formula (a-66). In certain embodiments, -L A - has formula (a-67). In certain embodiments, -L A - has formula (a-68). In certain embodiments, -L A - has formula (a-69). In certain embodiments, -L A - has formula (a-70). In certain embodiments, -L A - has formula (a-71). In certain embodiments, -L A - has formula (a-72). In certain embodiments, -L A - has formula (a-73). In certain embodiments, -L A - has formula (a-74). In certain embodiments, -L A - has formula (a-75). In certain embodiments, -L A - has formula (a-76). In certain embodiments, -L A - has formula (a-77). In certain embodiments, -L A - has formula (a-78). In certain embodiments, -L A - has formula (a-79). In certain embodiments, -L A - has formula (a-80). In certain embodiments, -L A - has formula (a-81). In certain embodiments, -L A -having formula (a-82).

[0313] In certain embodiments, -L B -Selected

[0314]

[0315]

[0316] in

[0317] The dashed line marked with an asterisk indicates the connection to -L A -;

[0318] Unmarked dashed lines indicate connections to -L 2 -or-D-; and

[0319] q is an integer in the range of 2 to 50, inclusive.

[0320] If -L A - does not exist, and the dashed line marked with an asterisk in formulas ((a-83)-(a-94)) indicates the connection to -F 0 .

[0321] In certain embodiments, q of formula (a-84) is an integer in the range of 3-45 and including endpoints. In certain embodiments, q of formula (a-84) is an integer in the range of 4-40 and including endpoints. In certain embodiments, q of formula (a-84) is an integer in the range of 5-35 and including endpoints. In certain embodiments, q of formula (a-84) is an integer in the range of 6-30 and including endpoints. In certain embodiments, q of formula (a-84) is an integer in the range of 7-25 and including endpoints. In certain embodiments, q of formula (a-84) is an integer in the range of 10-20 and including endpoints. In certain embodiments, q of formula (a-84) is 23.

[0322] In certain embodiments, -L B - has formula (a-83). In certain embodiments, -L B - has formula (a-84). In certain embodiments, -L B - has the formula (a-84), wherein q = 23. In certain embodiments, -L B - has formula (a-85). In certain embodiments, -L B - has formula (a-86). In certain embodiments, -L B - has formula (a-87). In certain embodiments, -L B - has formula (a-88). In certain embodiments, -L B - has formula (a-89). In certain embodiments, -L B - has formula (a-90). In certain embodiments, -L B - has formula (a-91). In certain embodiments, -L B - has formula (a-92). In certain embodiments, -L B - has formula (a-93). In certain embodiments, -L B-having the formula (a-94).

[0323] In certain embodiments, -AB 1 and / or -AB 2 Having formula (i)

[0324]

[0325] The dotted lines indicate connections to -L 2 -or-D-;

[0326] n is an integer in the range of 14 to 22, inclusive; and

[0327] Stereocenters marked with an asterisk are in either the S- or R-configuration.

[0328] In certain embodiments, -AB 1 and / or -AB 2 Having formula (i), and n is 14. In certain embodiments, -AB 1 and / or -AB 2 having formula (i), and n is 15. In certain embodiments, -AB 1 and / or -AB 2 Having formula (i), and n is 16. In certain embodiments, -AB 1 and / or -AB 2 Having formula (i), and n is 17. In certain embodiments, -AB 1 and / or -AB 2 Having formula (i), and n is 18. In certain embodiments, -AB 1 and / or -AB 2 Has formula (i), and n is 19. In certain embodiments, -AB 1 and / or -AB 2 Has formula (i), and n is 20. In certain embodiments, -AB 1 and / or -AB 2 Has formula (i), and n is 21. In certain embodiments, -AB 1 and / or -AB 2 It has the formula (i), and n is 22.

[0329] In certain embodiments, -AB 1 and / or -AB 2 Having formula (i), n is 14, and the stereocenter marked with an asterisk is in the R-configuration. In certain embodiments, -AB 1 and / or -AB 2Having formula (i), n is 15, and the stereocenter marked with an asterisk is in the R-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (i), n is 16, and the stereocenter marked with an asterisk is in the R-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (i), n is 17, and the stereocenter marked with an asterisk is in the R-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (i), n is 18, and the stereocenter marked with an asterisk is in the R-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (i), n is 19, and the stereocenter marked with an asterisk is in the R-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (i), n is 20, and the stereocenter marked with an asterisk is in the R-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (i), n is 21, and the stereocenter marked with an asterisk is in the R-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (i), n is 22, and the stereocenter marked with an asterisk is in the R-configuration.

[0330] In certain embodiments, -AB 1 and / or -AB 2 Having formula (i), n is 14, and the stereocenter marked with an asterisk is in the S-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (i), n is 15, and the stereocenter marked with an asterisk is in the S-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (i), n is 16, and the stereocenter marked with an asterisk is in the S-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (i), n is 17, and the stereocenter marked with an asterisk is in the S-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (i), n is 18, and the stereocenter marked with an asterisk is in the S-configuration. In certain embodiments, -AB 1 and / or -AB 2Having formula (i), n is 19, and the stereocenter marked with an asterisk is in the S-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (i), n is 20, and the stereocenter marked with an asterisk is in the S-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (i), n is 21, and the stereocenter marked with an asterisk is in the S-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (i), n is 22, and the stereocenter marked with an asterisk is in the S-configuration.

[0331] In certain embodiments, -AB 1 and / or -AB 2 With formula (ia):

[0332]

[0333] in

[0334] The dotted lines indicate connections to -L 2 -or-D-.

[0335] In certain embodiments, -AB 1 and / or -AB 2 Having formula (ib):

[0336]

[0337] in

[0338] The dotted lines indicate connections to -L 2 -or-D-.

[0339] In certain embodiments, -AB 1 and / or -AB 2 Having the formula (ic):

[0340]

[0341] in

[0342] The dotted lines indicate connections to -L 2 -or-D-.

[0343] In certain embodiments, -AB 1 and / or -AB 2 With the formula (id):

[0344]

[0345] in

[0346] The dotted lines indicate connections to -L 2 -or-D-.

[0347] In certain embodiments, -AB 1 and / or -AB 2 With formula (ie):

[0348]

[0349] in

[0350] The dotted lines indicate connections to -L 2 -or-D-.

[0351] In certain embodiments, -AB 1 and / or -AB 2 With the formula (if):

[0352]

[0353] in

[0354] The dotted lines indicate connections to -L 2 -or-D-.

[0355] In certain embodiments, -AB 1 and / or -AB 2 Having formula (ii)

[0356]

[0357] The dotted lines indicate connections to -L 2 -or-D-;

[0358] n is an integer from 14 to 22; and

[0359] Stereocenters marked with an asterisk are in either the S- or R-configuration.

[0360] In certain embodiments, -AB 1 and / or -AB 2 having formula (ii), and n is 14. In certain embodiments, -AB 1 and / or -AB 2 having formula (ii), and n is 15. In certain embodiments, -AB 1 and / or -AB 2 having formula (ii), and n is 16. In certain embodiments, -AB 1 and / or -AB 2 having formula (ii), and n is 17. In certain embodiments, -AB1 and / or -AB 2 having formula (ii), and n is 18. In certain embodiments, -AB 1 and / or -AB 2 having formula (ii), and n is 19. In certain embodiments, -AB 1 and / or -AB 2 Has formula (ii), and n is 20. In certain embodiments, -AB 1 and / or -AB 2 having formula (ii), and n is 21. In certain embodiments, -AB 1 and / or -AB 2 It has the formula (ii), and n is 22.

[0361] In certain embodiments, -AB 1 and / or -AB 2 Having formula (ii), n is 14, and the stereocenter marked with an asterisk is in the R-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (ii), n is 15, and the stereocenter marked with an asterisk is in the R-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (ii), n is 16, and the stereocenter marked with an asterisk is in the R-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (ii), n is 17, and the stereocenter marked with an asterisk is in the R-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (ii), n is 18, and the stereocenter marked with an asterisk is in the R-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (ii), n is 19, and the stereocenter marked with an asterisk is in the R-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (ii), n is 20, and the stereocenter marked with an asterisk is in the R-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (ii), n is 21, and the stereocenter marked with an asterisk is in the R-configuration. In certain embodiments, -AB 1 and / or -AB 2 It has the formula (ii), and n is 22, and the stereocenter marked with an asterisk is in the R-configuration.

[0362] In certain embodiments, -AB 1 and / or -AB 2 Having formula (ii), n is 14, and the stereocenter marked with an asterisk is in the S-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (ii), n is 15, and the stereocenter marked with an asterisk is in the S-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (ii), n is 16, and the stereocenter marked with an asterisk is in the S-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (ii), n is 17, and the stereocenter marked with an asterisk is in the S-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (ii), n is 18, and the stereocenter marked with an asterisk is in the S-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (ii), n is 19, and the stereocenter marked with an asterisk is in the S-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (ii), n is 20, and the stereocenter marked with an asterisk is in the S-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (ii), n is 21, and the stereocenter marked with an asterisk is in the S-configuration. In certain embodiments, -AB 1 and / or -AB 2 It has the formula (ii), and n is 22, and the stereocenter marked with an asterisk is in the S-configuration.

[0363] In certain embodiments, -AB 1 and / or -AB 2 Having formula (ii-a):

[0364]

[0365] in

[0366] The dotted lines indicate connections to -L 2 -or-D-.

[0367] In certain embodiments, -AB 1 and / or -AB 2 Having formula (ii-b):

[0368]

[0369] in

[0370] The dotted lines indicate connections to -L 2 -or-D-.

[0371] In certain embodiments, -AB 1 and / or -AB 2 Having formula (ii-c):

[0372]

[0373] in

[0374] The dotted lines indicate connections to -L 2 -or-D-.

[0375] In certain embodiments, -AB 1 and / or -AB 2 Having formula (ii-d):

[0376]

[0377] in

[0378] The dotted lines indicate connections to -L 2 -or-D-.

[0379] In certain embodiments, -AB 1 and / or -AB 2 Having formula (ii-e):

[0380]

[0381] in

[0382] The dotted lines indicate connections to -L 2 -or-D-.

[0383] In certain embodiments, -AB 1 and / or -AB 2 Having formula (ii-f):

[0384]

[0385] in

[0386] The dotted lines indicate connections to -L 2 -or-D-.

[0387] In certain embodiments, -AB 1 and / or -AB 2 Having formula (iii)

[0388]

[0389] in

[0390] The dotted lines indicate connections to -L 2 -or-D-;

[0391] t is an integer within the range of and including 14 to 22; and

[0392] Stereocenters marked with an asterisk are in either the S- or R-configuration.

[0393] In certain embodiments, -AB 1 and / or -AB 2 Has formula (iii), and t is 14. In certain embodiments, -AB 1 and / or -AB 2 having formula (iii), and t is 15. In certain embodiments, -AB 1 and / or -AB 2 has formula (iii), and t is 16. In certain embodiments, -AB 1 and / or -AB 2 having formula (iii), and t is 17. In certain embodiments, -AB 1 and / or -AB 2 Has formula (iii), and t is 18. In certain embodiments, -AB 1 and / or -AB 2 Has formula (iii), and t is 19. In certain embodiments, -AB 1 and / or -AB 2 Has formula (iii), and t is 20. In certain embodiments, -AB 1 and / or -AB 2 Has formula (iii), and t is 21. In certain embodiments, -AB 1 and / or -AB 2 It has the formula (iii), and t is 22.

[0394] In certain embodiments, -AB 1 and / or -AB 2 Having formula (iii), t is 14, and the stereocenter marked with an asterisk is in the R-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (iii), t is 15, and the stereocenter marked with an asterisk is in the R-configuration. In certain embodiments, -AB 1 and / or -AB 2Having formula (iii), t is 16, and the stereocenter marked with an asterisk is in the R-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (iii), t is 17, and the stereocenter marked with an asterisk is in the R-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (iii), t is 18, and the stereocenter marked with an asterisk is in the R-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (iii), t is 19, and the stereocenter marked with an asterisk is in the R-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (iii), t is 20, and the stereocenter marked with an asterisk is in the R-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (iii), t is 21, and the stereocenter marked with an asterisk is in the R-configuration. In certain embodiments, -AB 1 and / or -AB 2 It has the formula (iii), and t is 22, and the stereocenter marked with an asterisk is in the R-configuration.

[0395] In certain embodiments, -AB 1 and / or -AB 2 Having formula (iii), t is 14, and the stereocenter marked with an asterisk is in the S-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (iii), t is 15, and the stereocenter marked with an asterisk is in the S-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (iii), t is 16, and the stereocenter marked with an asterisk is in the S-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (iii), t is 17, and the stereocenter marked with an asterisk is in the S-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (iii), t is 18, and the stereocenter marked with an asterisk is in the S-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (iii), t is 19, and the stereocenter marked with an asterisk is in the S-configuration. In certain embodiments, -AB 1 and / or -AB2 Having formula (iii), t is 20, and the stereocenter marked with an asterisk is in the S-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (iii), t is 21, and the stereocenter marked with an asterisk is in the S-configuration. In certain embodiments, -AB 1 and / or -AB 2 It has the formula (iii), and t is 22, and the stereocenter marked with an asterisk is in the S-configuration.

[0396] In certain embodiments, -AB 1 and / or -AB 2 Having formula (iii-a)

[0397]

[0398] in

[0399] The dotted lines indicate connections to -L 2 -or-D-.

[0400] In certain embodiments, -AB 1 and / or -AB 2 Having formula (iii-b)

[0401]

[0402] in

[0403] The dotted lines indicate connections to -L 2 -or-D-;

[0404] In certain embodiments, -AB 1 and / or -AB 2 Having formula (iii-c)

[0405]

[0406] in

[0407] The dotted lines indicate connections to -L 2 -or-D-.

[0408] In certain embodiments, -AB 1 and / or -AB 2 Having formula (iii-d)

[0409]

[0410] in

[0411] The dotted lines indicate connections to -L 2-or-D-.

[0412] In certain embodiments, -AB 1 and / or -AB 2 Having formula (iii-e)

[0413]

[0414] in

[0415] The dotted lines indicate connections to -L 2 -or-D-.

[0416] In certain embodiments, -AB 1 and / or -AB 2 Having formula (iii-f)

[0417]

[0418] in

[0419] The dotted lines indicate connections to -L 2 -or-D-.

[0420] In certain embodiments, -AB 1 and / or -AB 2 Having formula (iv)

[0421]

[0422] in

[0423] The dotted lines indicate connections to -L 2 -or-D-, and

[0424] u is an integer in the range of 14 to 22, inclusive.

[0425] In certain embodiments, -AB 1 and / or -AB 2 has formula (iv), and u is 14. In certain embodiments, -AB 1 and / or -AB 2 has formula (iv), and u is 15. In certain embodiments, -AB 1 and / or -AB 2 has formula (iv), and u is 16. In certain embodiments, -AB 1 and / or -AB 2 has formula (iv), and u is 17. In certain embodiments, -AB 1 and / or -AB 2 has formula (iv), and u is 18. In certain embodiments, -AB 1and / or -AB 2 has formula (iv), and u is 19. In certain embodiments, -AB 1 and / or -AB 2 has formula (iv), and u is 20. In certain embodiments, -AB 1 and / or -AB 2 has formula (iv), and u is 21. In certain embodiments, -AB 1 and / or -AB 2 It has the formula (iv), and u is 22.

[0426] In certain embodiments, -AB 1 and / or -AB 2 Having formula (v)

[0427]

[0428] in

[0429] The dotted lines indicate connections to -L 2 -or-D-;

[0430] v is an integer in the range of 14 to 22, inclusive; and

[0431] Stereocenters marked with an asterisk are in either the S- or R-configuration.

[0432] In certain embodiments, -AB 1 and / or -AB 2 Has formula (v), and v is 14. In certain embodiments, -AB 1 and / or -AB 2 Has formula (v), and v is 15. In certain embodiments, -AB 1 and / or -AB 2 Has formula (v), and v is 16. In certain embodiments, -AB 1 and / or -AB 2 Has formula (v), and v is 17. In certain embodiments, -AB 1 and / or -AB 2 Has formula (v), and v is 18. In certain embodiments, -AB 1 and / or -AB 2 Has formula (v), and v is 19. In certain embodiments, -AB 1 and / or -AB 2 Has formula (v), and v is 20. In certain embodiments, -AB 1 and / or -AB 2 Has formula (v), and v is 21. In certain embodiments, -AB1 and / or -AB 2 It has the formula (v), and v is 22.

[0433] In certain embodiments, -AB 1 and / or -AB 2 Having formula (v), wherein v is 14, and the stereocenter marked with an asterisk is in the R-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (v), wherein v is 15, and the stereocenter marked with an asterisk is in the R-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (v), wherein v is 16, and the stereocenter marked with an asterisk is in the R-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (v), wherein v is 17, and the stereocenter marked with an asterisk is in the R-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (v), wherein v is 18, and the stereocenter marked with an asterisk is in the R-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (v), wherein v is 19, and the stereocenter marked with an asterisk is in the R-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (v), wherein v is 20, and the stereocenter marked with an asterisk is in the R-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (v), wherein v is 21, and the stereocenter marked with an asterisk is in the R-configuration. In certain embodiments, -AB 1 and / or -AB 2 It has the formula (v), wherein v is 22, and the stereocenter marked with an asterisk is in the R-configuration.

[0434] In certain embodiments, -AB 1 and / or -AB 2 Having formula (v), wherein v is 14, and the stereocenter marked with an asterisk is in the S-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (v), wherein v is 15, and the stereocenter marked with an asterisk is in the S-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (v), wherein v is 16, and the stereocenter marked with an asterisk is in the S-configuration. In certain embodiments, -AB1 and / or -AB 2 Having formula (v), wherein v is 17, and the stereocenter marked with an asterisk is in the S-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (v), wherein v is 18, and the stereocenter marked with an asterisk is in the S-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (v), wherein v is 19, and the stereocenter marked with an asterisk is in the S-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (v), wherein v is 20, and the stereocenter marked with an asterisk is in the S-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (v), wherein v is 21, and the stereocenter marked with an asterisk is in the S-configuration. In certain embodiments, -AB 1 and / or -AB 2 It has the formula (v), wherein v is 22, and the stereocenter marked with an asterisk is in the S-configuration.

[0435] In certain embodiments, -AB 1 and / or -AB 2 With formula (va)

[0436]

[0437] in

[0438] The dotted lines indicate connections to -L 2 -or-D-.

[0439] In certain embodiments, -AB 1 and / or -AB 2 With formula (vb)

[0440]

[0441] in

[0442] The dotted lines indicate connections to -L 2 -or-D-;

[0443] In certain embodiments, -AB 1 and / or -AB 2 With formula (vc)

[0444]

[0445] in

[0446] The dotted lines indicate connections to -L 2 -or-D-.

[0447] In certain embodiments, -AB 1 and / or -AB 2 With formula (vd)

[0448]

[0449] in

[0450] The dotted lines indicate connections to -L 2 -or-D-.

[0451] In certain embodiments, -AB 1 and / or -AB 2 Having formula (vi-e)

[0452]

[0453] in

[0454] The dotted lines indicate connections to -L 2 -or-D-.

[0455] In certain embodiments, -AB 1 and / or -AB 2 Having formula (vi-f)

[0456]

[0457] in

[0458] The dotted lines indicate connections to -L 2 -or-D-.

[0459] In certain embodiments, -AB 1 and / or -AB 2 Having formula (vii)

[0460]

[0461] The dotted lines represent connections to -L 2 -or-D-;

[0462] w is an integer in the range of 14 to 22, inclusive; and

[0463] Stereocenters marked with an asterisk are in either the S- or R-configuration.

[0464] In certain embodiments, -AB 1 and / or -AB 2 Has formula (vii), and w is 14. In certain embodiments, -AB1 and / or -AB 2 has formula (vii), and w is 15. In certain embodiments, -AB 1 and / or -AB 2 has formula (vii), and w is 16. In certain embodiments, -AB 1 and / or -AB 2 Has formula (vii), and w is 17. In certain embodiments, -AB 1 and / or -AB 2 has formula (vii), and w is 18. In certain embodiments, -AB 1 and / or -AB 2 Has formula (vii), and w is 19. In certain embodiments, -AB 1 and / or -AB 2 Has formula (vii), and w is 20. In certain embodiments, -AB 1 and / or -AB 2 Has formula (vii), and w is 21. In certain embodiments, -AB 1 and / or -AB 2 It has the formula (vii), and w is 22.

[0465] In certain embodiments, -AB 1 and / or -AB 2 Having formula (vii), and w is 14, and the stereocenter marked with an asterisk is in the R-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (vii), w is 15, and the stereocenter marked with an asterisk is in the R-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (vii), w is 16, and the stereocenter marked with an asterisk is in the R-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (vii), w is 17, and the stereocenter marked with an asterisk is in the R-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (vii), w is 18, and the stereocenter marked with an asterisk is in the R-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (vii), w is 19, and the stereocenter marked with an asterisk is in the R-configuration. In certain embodiments, -AB 1 and / or -AB 2Having formula (vii), w is 20, and the stereocenter marked with an asterisk is in the R-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (vii), w is 21, and the stereocenter marked with an asterisk is in the R-configuration. In certain embodiments, -AB 1 and / or -AB 2 It has the formula (vii), and w is 22, and the stereocenter marked with an asterisk is in the R-configuration.

[0466] In certain embodiments, -AB 1 and / or -AB 2 Having formula (vii), and w is 14, and the stereocenter marked with an asterisk is in the S-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (vii), w is 15, and the stereocenter marked with an asterisk is in the S-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (vii), and w is 16, and the stereocenter marked with an asterisk is in the S-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (vii), w is 17, and the stereocenter marked with an asterisk is in the S-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (vii), w is 18, and the stereocenter marked with an asterisk is in the S-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (vii), w is 19, and the stereocenter marked with an asterisk is in the S-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (vii), w is 20, and the stereocenter marked with an asterisk is in the S-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (vii), w is 21, and the stereocenter marked with an asterisk is in the S-configuration. In certain embodiments, -AB 1 and / or -AB 2 It has the formula (vii), and w is 22, and the stereocenter marked with an asterisk is in the S-configuration.

[0467] In certain embodiments, -AB 1 and / or -AB 2 Having formula (vii-a):

[0468]

[0469] in

[0470] The dotted lines indicate connections to -L 2 -or-D-.

[0471] In certain embodiments, -AB 1 and / or -AB 2 Having formula (vii-b):

[0472]

[0473] in

[0474] The dotted lines indicate connections to -L 2 -or-D-.

[0475] In certain embodiments, -AB 1 and / or -AB 2 Having formula (vii-c):

[0476]

[0477] in

[0478] The dotted lines indicate connections to -L 2 -or-D-.

[0479] In certain embodiments, -AB 1 and / or -AB 2 Having formula (vii-d):

[0480]

[0481] in

[0482] The dotted lines indicate connections to -L 2 -or-D-.

[0483] In certain embodiments, -AB 1 and / or -AB 2 Having formula (vii-e):

[0484]

[0485] in

[0486] The dotted lines indicate connections to -L 2 -or-D-.

[0487] In certain embodiments, -AB 1 and / or -AB 2 Having formula (vii-f):

[0488]

[0489] in

[0490] The dotted lines indicate connections to -L 2 -or-D-.

[0491] In certain embodiments, -AB 1 and / or -AB 2 Having formula (viii)

[0492]

[0493] The dotted lines represent connections to -L 2 -or-D-;

[0494] w is an integer in the range of 14 to 22, inclusive; and

[0495] Stereocenters marked with an asterisk are in either the S- or R-configuration.

[0496] In certain embodiments, -AB 1 and / or -AB 2 Has formula (viii), and x is 14. In certain embodiments, -AB 1 and / or -AB 2 having formula (viii), and x is 15. In certain embodiments, -AB 1 and / or -AB 2 having formula (viii), and x is 16. In certain embodiments, -AB 1 and / or -AB 2 having formula (viii), and x is 17. In certain embodiments, -AB 1 and / or -AB 2 having formula (viii), and x is 18. In certain embodiments, -AB 1 and / or -AB 2 Has formula (viii), and x is 19. In certain embodiments, -AB 1 and / or -AB 2 having formula (viii), and x is 20. In certain embodiments, -AB 1 and / or -AB 2 Has formula (viii), and x is 21. In certain embodiments, -AB 1 and / or -AB 2 It has the formula (viii), and x is 22.

[0497] In certain embodiments, -AB1 and / or -AB 2 Having formula (viii), and x is 14, and the stereocenter marked with an asterisk is in the R-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (viii), and x is 15, and the stereocenter marked with an asterisk is in the R-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (viii), and x is 16, and the stereocenter marked with an asterisk is in the R-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (viii), and x is 17, and the stereocenter marked with an asterisk is in the R-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (viii), and x is 18, and the stereocenter marked with an asterisk is in the R-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (viii), and x is 19, and the stereocenter marked with an asterisk is in the R-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (viii), and x is 20, and the stereocenter marked with an asterisk is in the R-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (viii), and x is 21, and the stereocenter marked with an asterisk is in the R-configuration. In certain embodiments, -AB 1 and / or -AB 2 It has the formula (viii), and x is 22, and the stereocenter marked with an asterisk is in the R-configuration.

[0498] In certain embodiments, -AB 1 and / or -AB 2 Having formula (viii), and x is 14, and the stereocenter marked with an asterisk is in the S-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (viii), and x is 15, and the stereocenter marked with an asterisk is in the S-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (viii), and x is 16, and the stereocenter marked with an asterisk is in the S-configuration. In certain embodiments, -AB 1 and / or -AB 2Having formula (viii), and x is 17, and the stereocenter marked with an asterisk is in the S-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (viii), and x is 18, and the stereocenter marked with an asterisk is in the S-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (viii), and x is 19, and the stereocenter marked with an asterisk is in the S-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (viii), and x is 20, and the stereocenter marked with an asterisk is in the S-configuration. In certain embodiments, -AB 1 and / or -AB 2 Having formula (viii), and x is 21, and the stereocenter marked with an asterisk is in the S-configuration. In certain embodiments, -AB 1 and / or -AB 2 It has the formula (viii), and x is 22, and the stereocenter marked with an asterisk is in the S-configuration.

[0499] In certain embodiments, -AB 1 and / or -AB 2 Having formula (viii-a)

[0500]

[0501] The dotted lines indicate connections to -L 2 -or-D-.

[0502] In certain embodiments, -AB 1 and / or -AB 2 Having formula (viii-b)

[0503]

[0504] The dotted lines indicate connections to -L 2 -or-D-.

[0505] In certain embodiments, -AB 1 and / or -AB 2 Having formula (viii-c)

[0506]

[0507] The dotted lines indicate connections to -L 2 -or-D-.

[0508] In certain embodiments, -AB 1and / or -AB 2 Having formula (viii-d)

[0509]

[0510] The dotted lines indicate connections to -L 2 -or-D-.

[0511] In certain embodiments, -AB 1 and / or -AB 2 Having formula (viii-e)

[0512]

[0513] The dotted lines indicate connections to -L 2 -or-D-.

[0514] In certain embodiments, -AB 1 and / or -AB 2 Having formula (viii-f)

[0515]

[0516] The dotted lines indicate connections to -L 2 -or-D-.

[0517] In certain embodiments, -AB 1 and / or -AB 2 Having formula (ix-i)

[0518]

[0519] in

[0520] X 1 -for -X 2 for Wherein Ph is phenyl,

[0521] a is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0522] b is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0523] c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0524] d is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0525] m is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0526] n is 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24;

[0527] p is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0528] In certain embodiments, -AB 1 and / or -AB 2 It has the formula (ix-i) wherein a is 1, b is 1, c is 1, d is 1, m is 1, n is 18, and m is 1.

[0529] In certain embodiments, -AB 1 and / or -AB 2 Having formula (ix-i), and X 1 -for And -X 2 for In certain embodiments, -AB 1 and / or -AB 2 Having formula (ix-i), and X 1 -for And -X 2 for In certain embodiments, -AB 1 and / or -AB 2 Having formula (ix-i), and X 1 -for And -X 2 for In certain embodiments, -AB 1 and / or -AB 2 Having formula (ix-i), and X 1 -for And -X 2 for In certain embodiments, -AB 1 and / or -AB 2 Having formula (ix-i), and X 1 -for And -X 2 for In certain embodiments, -AB 1 and / or -AB 2 Having formula (ix-i), and X 1 -for And -X 2 for In certain embodiments, -AB 1 and / or -AB 2 Having formula (ix-i), and X 1 -for And -X 2 for In certain embodiments, -AB 1 and / or -AB 2 Having formula (ix-i), and X 1 -for And -X 2 for In certain embodiments, -AB 1 and / or -AB 2 Having formula (ix-i), and X 1 -for And -X 2 for In certain embodiments, -AB 1 and / or -AB 2 Having formula (ix-i), and X 1 -for And -X 2 for In certain embodiments, -AB 1 and / or -AB 2 Having formula (ix-i), and X 1 -for And -X 2 for In certain embodiments, -AB 1 and / or -AB 2 Having formula (ix-i), and X 1 -for And -X 2 for

[0530] In certain embodiments, -AB 1 and / or -AB 2 It is the peptide albumin binding part.

[0531] If -D- is a peptide or protein drug moiety, then the peptide moiety -AB 2 Can be directly or through -D- and -AB 2 The peptide spacer is fused to the N- or C-terminus of -D-.

[0532] In certain embodiments, -AB 1 and / or -AB 2 Selected from:

[0533] WWEQDRDWDFDVFGGGTP(SEQ ID NO:34);

[0534] DICLPRWGCLW (SEQ ID NO: 35),

[0535] The cysteines at positions 3 and 9 are connected by a disulfide bridge;

[0536] RLIEDICLPRWGCLWEDD(SEQ ID NO:36),

[0537] The cysteines at positions 7 and 13 are linked by a disulfide bridge;

[0538] LAEAKVLANRELDKYGVSDFYKRLINKAKTVEGVEALKLHILAALP(SEQ ID NO:37);

[0539] IAEAKEAANAELDSYGVSDFYKRLIDKAKTVEGVEALKDAILAALP (SEQ ID NO:38); and X1EYEX2EYE (SEQ ID NO:39),

[0540] wherein X1 is fluorescein-(AEEA), X2 is K(palmitate) and AEEA is 2-(2-(2-aminoethoxy)acetyl.

[0541] In certain embodiments, -AB 1 and / or -AB 2 Having SEQ ID NO: 34. In certain embodiments, -AB 1 and / or -AB 2 Having SEQ ID NO: 35. In certain embodiments, -AB 1 and / or -AB 2 Having SEQ ID NO: 36. In certain embodiments, -AB 1 and / or -AB 2 Having SEQ ID NO: 37. In certain embodiments, -AB 1 and / or -AB 2 Having SEQ ID NO: 38. In certain embodiments, -AB 1 and / or -AB 2 Having SEQ ID NO:39.

[0542] In certain embodiments, -AB 1 Having formula (XIX)

[0543]

[0544] in

[0545] The dotted line indicates the connection to -L 2 -;and

[0546] a is 14, 15, 16, 17, 18, 19, 20, 21 or 22.

[0547] In certain embodiments, a of Formula (XIX) is 18.

[0548] In certain embodiments, -AB 1 and / or -AB 2 With formula (Aa):

[0549]

[0550] in

[0551] The dotted lines indicate connections to -L 2 -or-D-;

[0552] -F 0 and -L A - use as defined in formula (A),

[0553] -L B’ - is the polymeric part.

[0554] Part-L B’- is a polymeric portion, meaning that it comprises at least one polymer portion. In certain embodiments, one or more polymer portions have a molecular weight of at least 450 Da. In certain embodiments, one or more polymer portions have a molecular weight of at least 1 kDa. In certain embodiments, one or more polymer portions have a molecular weight of at least 1.5 kDa. In certain embodiments, one or more polymer portions have a molecular weight of at least 2 kDa. In certain embodiments, one or more polymer portions have a molecular weight of at least 2.5 kDa. In certain embodiments, one or more polymer portions have a molecular weight of at least 3 kDa. In certain embodiments, one or more polymer portions have a molecular weight of at least 3.5 kDa. In certain embodiments, one or more polymer portions have a molecular weight of at least 4 kDa. In certain embodiments, one or more polymer portions have a molecular weight of at least 5 kDa. In certain embodiments, one or more polymer portions have a maximum molecular weight of 160 kDa. In certain embodiments, one or more polymer portions have a maximum molecular weight of 120 kDa. In certain embodiments, one or more polymer portions have a maximum molecular weight of 100 kDa. In certain embodiments, one or more polymer portions have a maximum molecular weight of 80 kDa. In certain embodiments, one or more polymer portions have a maximum molecular weight of 70 kDa. In certain embodiments, one or more polymer moieties have a maximum molecular weight of 60 kDa. In certain embodiments, one or more polymer moieties have a maximum molecular weight of 50 kDa. In certain embodiments, one or more polymer moieties have a maximum molecular weight of 40 kDa. In certain embodiments, one or more polymer moieties have a molecular weight of approximately 450 Da. In certain embodiments, one or more polymer moieties have a molecular weight of approximately 1 kDa. In certain embodiments, one or more polymer moieties have a molecular weight of approximately 1.5 kDa. In certain embodiments, one or more polymer moieties have a molecular weight of approximately 2 kDa. In certain embodiments, one or more polymer moieties have a molecular weight of approximately 2.5 kDa. In certain embodiments, one or more polymer moieties have a molecular weight of approximately 3 kDa. In certain embodiments, one or more polymer moieties have a molecular weight of approximately 3.5 kDa. In certain embodiments, one or more polymer moieties have a molecular weight of approximately 4 kDa. In certain embodiments, one or more polymer moieties have a molecular weight of approximately 4.5 kDa. In certain embodiments, one or more polymer moieties have a molecular weight of approximately 5 kDa. In certain embodiments, one or more polymer moieties have a molecular weight of approximately 5.5 kDa. In certain embodiments, one or more polymer moieties have a molecular weight of approximately 6 kDa. In certain embodiments, one or more polymer moieties have a molecular weight of about 6.5 kDa.In certain embodiments, one or more polymer moieties have a molecular weight of about 7 kDa. In certain embodiments, one or more polymer moieties have a molecular weight of about 7.5 kDa. In certain embodiments, one or more polymer moieties have a molecular weight of about 8 kDa. In certain embodiments, one or more polymer moieties have a molecular weight of about 8.5 kDa. In certain embodiments, one or more polymer moieties have a molecular weight of about 9 kDa. In certain embodiments, one or more polymer moieties have a molecular weight of about 9.5 kDa. In certain embodiments, one or more polymer moieties have a molecular weight of about 10 kDa. It should be understood that if -L. B’ - contains one polymer portion, the minimum and maximum molecular weights provided above apply to this one polymer portion, and if -L B’ - comprises more than one polymer portion, the minimum and maximum molecular weights provided above refer to the minimum and maximum molecular weights common to all polymer portions.

[0555] In certain embodiments, -L B’ -One or more polymer moieties of the invention have a Flory radius of at least 1.2 nm. In certain embodiments, -L B’ -One or more polymer moieties of the invention have a Flory radius of at least 1.5 nm. In certain embodiments, -L B’ -One or more polymer moieties have a Flory radius of at least 2 nm. In certain embodiments, -L B’ -One or more polymer moieties have a Flory radius of at least 2.5 nm. In certain embodiments, -L B’ -One or more polymer moieties have a Flory radius of at least 3 nm. In certain embodiments, -L B’ -one or more polymer moieties have a Flory radius of at least 3.5 nm. In certain embodiments, -L B’ -one or more polymer moieties have a Flory radius of at least 4 nm. In certain embodiments, -L B’ -one or more polymer moieties have a Flory radius of at least 4.5 nm. In certain embodiments, -L B’ -one or more polymer moieties have a Flory radius of at least 5 nm. In certain embodiments, -L B’ -One or more polymer moieties have a Flory radius of no more than 200 nm. In certain embodiments, -L B’ -One or more polymer moieties have a Flory radius of no more than 175 nm. In certain embodiments, -L B’-One or more polymer moieties have a Flory radius of no more than 150 nm. In certain embodiments, -L B’ -One or more polymer moieties have a Flory radius of no more than 125 nm. In certain embodiments, -L B’ -One or more polymer moieties have a Flory radius of no more than 100 nm. In certain embodiments, -L B’ -One or more polymer moieties have a Flory radius of no more than 75 nm. In certain embodiments, -L B’ -One or more polymer moieties of the invention have a Flory radius of no more than 50 nm. In certain embodiments, -L B’ -One or more polymer moieties have a Flory radius of no more than 45 nm. In certain embodiments, -L B’ -One or more polymer moieties of the invention have a Flory radius of no more than 40 nm. In certain embodiments, -L B’ -One or more polymer moieties of the invention have a Flory radius of no more than 35 nm. In certain embodiments, -L B’ -One or more polymer moieties have a Flory radius of no more than 30 nm. In certain embodiments, -L B’ -One or more polymer moieties of - have a Flory radius of about 1.2 nm. In certain embodiments, -L B’ -One or more polymer moieties of - have a Flory radius of about 1.5 nm. In certain embodiments, -L B’ -One or more polymer moieties of - have a Flory radius of about 2 nm. In certain embodiments, -L B’ -One or more polymer moieties of - have a Flory radius of about 2.5 nm. In certain embodiments, -L B’ -One or more polymer moieties of the - have a Flory radius of about 3 nm. In certain embodiments, -L B’ -One or more polymer moieties of - have a Flory radius of about 3.5 nm. In certain embodiments, -L B’ -One or more polymer moieties of - have a Flory radius of about 4 nm. In certain embodiments, -L B’ -One or more polymer moieties of - have a Flory radius of about 4.5 nm. In certain embodiments, -L B’ -One or more polymer moieties of - have a Flory radius of about 5 nm. In certain embodiments, -L B’ -One or more polymer moieties of - have a Flory radius of about 5.5 nm. In certain embodiments, -LB’ -One or more polymer moieties of the - have a Flory radius of about 6 nm. In certain embodiments, -L B’ -One or more polymer moieties of - have a Flory radius of about 6.5 nm. In certain embodiments, -L B’ -One or more polymer moieties of the - have a Flory radius of about 7 nm. In certain embodiments, -L B’ -One or more polymer moieties of - have a Flory radius of about 8.5 nm. In certain embodiments, -L B’ -One or more polymer moieties of - have a Flory radius of about 9 nm. In certain embodiments, -L B’ - has a Flory radius of about 10 nm. It will be understood that if -L B’ - contains one polymer part, then the Flory radius provided above applies to this one polymer part, and if -L B’ - comprises more than one polymer portion, the Flory radius provided above refers to the common Flory radius of all polymer portions.

[0556] -L B’- comprising one or more polymeric moieties, for example, a polymeric moiety selected from the group consisting of poly(2-methacryloyloxyethylphosphorylcholine), poly(acrylic acid), poly(acrylate), poly(acrylamide), poly(alkoxy) polymers, poly(amide), poly(amidoamine), poly(amino acid), poly(anhydride), poly(asparagine), poly(butyric acid), poly(glycolic acid), polybutylene terephthalate, poly(caprolactone), poly(carbonate), poly(cyanoacrylate), poly(dimethylacrylamide), poly(ester), poly(ethylene), poly(ethylene glycol), poly(ethylene oxide), poly(ethyl phosphate), poly(ethyloxazoline), poly(glycolic acid), poly(hydroxyethyl acrylate), poly(hydroxyethyl-oxazoline), poly(hydroxymethacrylate), poly(hydroxypropyl methacrylamide), poly(hydroxypropyl methacrylate), poly(hydroxypropyloxazoline), poly(iminocarbonate), poly(lactic acid), ), poly(lactic-co-glycolic acid), poly(methacrylamide), poly(methacrylate), poly(methyloxazoline), poly(organophosphazenes), poly(orthoesters), poly(oxazoline), poly(propylene glycol), poly(siloxanes), poly(urethanes), poly(vinyl alcohol), poly(vinylamine), poly(vinyl methyl ether), poly(vinyl pyrrolidone), silicone, cellulose, carboxymethylcellulose, hydroxypropyl methylcellulose, chitin, chitosan, dextran, dextrin, gelatin, hyaluronic acid and derivatives, functionalized hyaluronic acid, alginates, mannans, pectin, rhamnogalacturonans, starch, hydroxyalkyl starch, hydroxyethyl starch and other carbohydrate-based polymers, xylan and copolymers thereof.

[0557] In certain embodiments, -L B’ - comprises a PEG-based polymer. In certain embodiments, -L B’ - comprises a hyaluronic acid-based polymer. In certain embodiments, -L B’ - comprises a random coil polymer. In certain embodiments, -L B’ - Contains a poly-sarcosine polymer.

[0558] In certain embodiments, the distance between any two albumin-binding moieties 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 of the albumin-binding moieties can bind to different albumin molecules and / or two or more albumin-binding moieties can bind to one albumin molecule. Generally, if a compound has x albumin-binding moieties, then they can bind to at most x albumin molecules. It will be understood that not all of the albumin-binding moieties of a compound may be bound to an albumin molecule at any given time.

[0559] If the compound has the formula (Ia) wherein x=1, then the moiety -AB 1 Can bind to the first albumin molecule, and part -AB 2 Alternatively, if the compound has formula (Ia) wherein x=1, then the moiety -AB 1 Can bind to the first binding site on the first albumin molecule, and the part -AB 2 Can bind to a second binding site on the same albumin molecule, wherein the second binding site is different from the first binding site.

[0560] Binding to two or more different albumin molecules significantly increases the molecular weight of the compound, which has a favorable effect on the circulation half-life.

[0561] In certain embodiments, -L of formula (Aa) B’ -having the formula (a-3')

[0562]

[0563] in

[0564] The unmarked dashed line indicates the connection to -L 2 -or-D-;

[0565] The dashed line marked with an asterisk indicates the connection to -L A ;

[0566] -R c -for

[0567] -R d’ - is a polymeric moiety; and

[0568] -R e -selected from -CH2-,

[0569] If -R b -for Then R in formula (a-3') c -for And if -R b -for Then -R in formula (a-3') c -for

[0570] Part -R of formula (a-3') d’- is a polymeric portion, meaning that it comprises at least one polymer portion. In certain embodiments, one or more polymer portions have a molecular weight of at least 450 Da. In certain embodiments, one or more polymer portions have a molecular weight of at least 1 kDa. In certain embodiments, one or more polymer portions have a molecular weight of at least 1.5 kDa. In certain embodiments, one or more polymer portions have a molecular weight of at least 2 kDa. In certain embodiments, one or more polymer portions have a molecular weight of at least 2.5 kDa. In certain embodiments, one or more polymer portions have a molecular weight of at least 3 kDa. In certain embodiments, one or more polymer portions have a molecular weight of at least 3.5 kDa. In certain embodiments, one or more polymer portions have a molecular weight of at least 4 kDa. In certain embodiments, one or more polymer portions have a molecular weight of at least 5 kDa. In certain embodiments, one or more polymer portions have a maximum molecular weight of 160 kDa. In certain embodiments, one or more polymer portions have a maximum molecular weight of 120 kDa. In certain embodiments, one or more polymer portions have a maximum molecular weight of 100 kDa. In certain embodiments, one or more polymer portions have a maximum molecular weight of 80 kDa. In certain embodiments, one or more polymer portions have a maximum molecular weight of 70 kDa. In certain embodiments, one or more polymer moieties have a maximum molecular weight of 60 kDa. In certain embodiments, one or more polymer moieties have a maximum molecular weight of 50 kDa. In certain embodiments, one or more polymer moieties have a maximum molecular weight of 40 kDa. In certain embodiments, one or more polymer moieties have a molecular weight of approximately 450 Da. In certain embodiments, one or more polymer moieties have a molecular weight of approximately 1 kDa. In certain embodiments, one or more polymer moieties have a molecular weight of approximately 1.5 kDa. In certain embodiments, one or more polymer moieties have a molecular weight of approximately 2 kDa. In certain embodiments, one or more polymer moieties have a molecular weight of approximately 2.5 kDa. In certain embodiments, one or more polymer moieties have a molecular weight of approximately 3 kDa. In certain embodiments, one or more polymer moieties have a molecular weight of approximately 3.5 kDa. In certain embodiments, one or more polymer moieties have a molecular weight of approximately 4 kDa. In certain embodiments, one or more polymer moieties have a molecular weight of approximately 4.5 kDa. In certain embodiments, one or more polymer moieties have a molecular weight of approximately 5 kDa. In certain embodiments, one or more polymer moieties have a molecular weight of approximately 5.5 kDa. In certain embodiments, one or more polymer moieties have a molecular weight of approximately 6 kDa. In certain embodiments, one or more polymer moieties have a molecular weight of about 6.5 kDa.In certain embodiments, one or more polymer moieties have a molecular weight of about 7 kDa. In certain embodiments, one or more polymer moieties have a molecular weight of about 7.5 kDa. In certain embodiments, one or more polymer moieties have a molecular weight of about 8 kDa. In certain embodiments, one or more polymer moieties have a molecular weight of about 9 kDa. In certain embodiments, one or more polymer moieties have a molecular weight of about 8.5 kDa. In certain embodiments, one or more polymer moieties have a molecular weight of about 9 kDa. In certain embodiments, one or more polymer moieties have a molecular weight of about 10 kDa. It should be understood that if -R of formula (a-3') d’ - comprises one polymer portion, the minimum and maximum molecular weights provided above apply to this one polymer portion, and if -R d’ - comprises more than one polymer portion, the minimum and maximum molecular weights provided above refer to the minimum and maximum molecular weights common to all polymer portions.

[0571] In certain embodiments, one or more polymer moieties of formula (a-3') -R d’-Has a Flory radius of at least 1.2 nm. In certain embodiments, one or more polymer moieties have a Flory radius of at least 1.5 nm. In certain embodiments, one or more polymer moieties have a Flory radius of at least 2 nm. In certain embodiments, one or more polymer moieties have a Flory radius of at least 2.5 nm. In certain embodiments, one or more polymer moieties have a Flory radius of at least 3 nm. In certain embodiments, one or more polymer moieties have a Flory radius of at least 3.5 nm. In certain embodiments, one or more polymer moieties have a Flory radius of at least 4 nm. In certain embodiments, one or more polymer moieties have a Flory radius of at least 4.5 nm. In certain embodiments, one or more polymer moieties have a Flory radius of at least 5 nm. In certain embodiments, one or more polymer moieties have a Flory radius of no more than 200 nm. In certain embodiments, one or more polymer moieties have a Flory radius of no more than 175 nm. In certain embodiments, one or more polymer moieties have a Flory radius of no more than 150 nm. In certain embodiments, one or more polymer moieties have a Flory radius of no more than 125 nm. In certain embodiments, one or more polymer moieties have a Flory radius of no more than 100 nm. In certain embodiments, one or more polymer moieties have a Flory radius of no more than 75 nm. In certain embodiments, one or more polymer moieties have a Flory radius of no more than 50 nm. In certain embodiments, one or more polymer moieties have a Flory radius of no more than 45 nm. In certain embodiments, one or more polymer moieties have a Flory radius of no more than 40 nm. In certain embodiments, one or more polymer moieties have a Flory radius of no more than 35 nm. In certain embodiments, one or more polymer moieties have a Flory radius of no more than 30 nm. In certain embodiments, one or more polymer moieties have a Flory radius of approximately 1.2 nm. In certain embodiments, one or more polymer moieties have a Flory radius of approximately 1.5 nm. In certain embodiments, one or more polymer moieties have a Flory radius of approximately 2 nm. In certain embodiments, one or more polymer moieties have a Flory radius of approximately 2.5 nm. In certain embodiments, one or more polymer moieties have a Flory radius of approximately 3 nm. In certain embodiments, one or more polymer moieties have a Flory radius of approximately 3.5 nm. In certain embodiments, one or more polymer moieties have a Flory radius of approximately 4 nm. In certain embodiments, one or more polymer moieties have a Flory radius of approximately 4.5 nm.In certain embodiments, one or more polymer moieties have a Flory radius of about 5 nm. In certain embodiments, one or more polymer moieties have a Flory radius of about 5.5 nm. In certain embodiments, one or more polymer moieties have a Flory radius of about 6 nm. In certain embodiments, one or more polymer moieties have a Flory radius of about 6.5 nm. In certain embodiments, one or more polymer moieties have a Flory radius of about 7 nm. In certain embodiments, one or more polymer moieties have a Flory radius of about 8.5 nm. In certain embodiments, one or more polymer moieties have a Flory radius of about 9 nm. In certain embodiments, one or more polymer moieties have a Flory radius of about 10 nm. It should be understood that if -R of formula (a-3') d’ - comprises one polymer portion, the Flory radius provided above applies to this one polymer portion, and if -R d’ - comprises more than one polymer portion, the Flory radius provided above refers to the common Flory radius of all polymer portions.

[0572] -R in formula (a-3') d’- comprising one or more polymeric moieties, for example, a polymeric moiety selected from the group consisting of poly(2-methacryloyloxyethylphosphorylcholine), poly(acrylic acid), poly(acrylates), poly(acrylamides), poly(alkoxy) polymers, poly(amides), poly(amidoamines), poly(amino acids), poly(anhydrides), poly(asparagine), poly(butyric acid), poly(glycolic acid), polybutylene terephthalate, poly(caprolactone), poly(carbonates), poly(cyanoacrylates), poly(dimethylacrylamide), poly(esters), poly(ethylene), poly(ethylene glycol), poly(ethylene oxide), poly(ethyl phosphate), poly(ethyloxazoline), poly(glycolic acid), poly(hydroxyethyl acrylate), poly(hydroxyethyl-oxazoline), poly(hydroxymethacrylate), poly(hydroxypropyl methacrylamide), poly(methyl methacrylate),

[0014] Examples of the present invention include polyols, e.g., oligosaccharides, oligosaccharides, oligosaccharides (e.g., oligoacrylic acid), oligosaccharides (e.g., oligoacrylic acid), oligosaccharides (e.g., oligoacrylic acid), oligosaccharides (e.g., oligoacrylic acid), oligosaccharides (e.g., oligoacrylic acid), oligosaccharides (e.g., oligoacrylic acid), oligosaccharides (e.g., oligoacrylic acid), oligosaccharides (e.g., oligoacrylic acid), oligosaccharides (e.g., oligoacrylic acid), oligosaccharides (e.g., oligoacrylic acid), oligosaccharides (e.g., oligoacrylic acid), oligosaccharides (e.g., oligoacrylic acid), oligosaccharides (e.g., oligosaccharides), ...

[0573] In certain embodiments, -R d’ - comprises a PEG-based polymer. In certain embodiments, -R d’ -comprising a hyaluronic acid-based polymer. In certain embodiments, -R d’ - comprises a random coil polymer. In certain embodiments, -R d’ - Contains a poly-sarcosine polymer.

[0574] In certain embodiments, -D- is a protein or peptide drug moiety, and -AB 2 The -D- functional group provided is coupled to the N-terminal amine, C-terminal carboxyl or the side chain of an amino acid residue. In certain embodiments, -AB 2 In certain embodiments, -AB 2 In certain embodiments, -AB 2The functional group provided by the amino acid residue coupled to -D-, such as lysine, serine, aspartic acid, glutamic acid, arginine, histidine, threonine, glutamine, asparagine, cysteine, proline, tyrosine or tryptophan. In certain embodiments, -AB 2 In certain embodiments, -AB 2 In certain embodiments, -AB 2 In certain embodiments, -AB 2 In certain embodiments, -AB 2 In certain embodiments, -AB 2 In certain embodiments, -AB 2 In certain embodiments, -AB 2 In certain embodiments, -AB 2 In certain embodiments, -AB 2 In certain embodiments, -AB 2 In certain embodiments, -AB 2 In certain embodiments, -AB 2 Functional group coupled to the -D- tryptophan side chain.

[0575] In certain embodiments, -D-AB 2 Selected from semaglutide, liraglutide, enoglutide, GZR18, GL0034, telpotide, cotadutide, BI-456906, pemvidutide, mazdutide, dapiglutide and retatrutide.

[0576] In certain embodiments, -D-AB 2 Selected from semaglutide, liraglutide, enoglutide, GZR18 and GL0034.

[0577] In certain embodiments, -D-AB 2 is semaglutide. Semaglutide is a compound of the formula,

[0578] HX1EGTFTSDVSSYLEGQAAKEFIAWLVRGRG(SEQ ID NO:40),

[0579] in

[0580] X1 is α-aminobutyric acid (Aib); and

[0581] Lysine at position 20 is chemically modified by coupling the ε-amine group of the lysine side chain to the following moieties:

[0582]

[0583] in

[0584] The dashed line represents the ε-amine group of the lysine side chain attached to the lysine at position 20.

[0585] Semaglutide can be prepared using methods known to those skilled in the art, such as those described in WO2006 / 097537.

[0586] In certain embodiments, -D-AB 2 Liraglutide is a compound of the formula

[0587] HAEGTFTSDVSSYLEGQAAKEFIAWLVRGRG(SEQ ID NO:41),

[0588] in

[0589] Lysine at position 20 is chemically modified by coupling the ε-amine group of the lysine side chain to the following moieties:

[0590]

[0591] in

[0592] The dashed line represents the ε-amine group of the lysine side chain attached to the lysine at position 20.

[0593] In certain embodiments, -D-AB 2 Enoglutide is a compound of the formula

[0594] HVEGTFTSDVSSYLEEQAAREFIKWLVRGRG(SEQ ID NO:42),

[0595] in

[0596] Lysine at position 24 is chemically modified by coupling the ε-amine group of the lysine side chain to the following moieties:

[0597]

[0598] The dotted line represents the ε-amine group of the lysine side chain attached to the lysine at position 24.

[0599] In certain embodiments, -D-AB 2 GZR18 is a compound of the following formula

[0600] HGEGTFTSDVSSYLEGQAAKEFIAWLVRGRG(SEQ ID NO:43),

[0601] in

[0602] Lysine at position 20 is chemically modified by coupling the ε-amine group of the lysine side chain to the following moieties:

[0603]

[0604] The dotted line represents the ε-amine group of the lysine side chain attached to the lysine at position 20.

[0605] In certain embodiments, -D-AB 2 GL0034 is also known as utreglutide and is a compound of the formula

[0606] HX1EGTFTSDVSSYLEGQAAKEFIAWLVRGRGL(SEQ ID NO:44),

[0607] in

[0608] X1 is Aib; and

[0609] Lysine at position 20 is chemically modified by coupling the ε-amine group of the lysine side chain to the following moieties:

[0610]

[0611] The dotted line represents the ε-amine group of the lysine side chain attached to the lysine at position 20.

[0612] In certain embodiments, -D-AB 2 It is a dual GLP-1 receptor agonist selected from tilpotide, cotyledonide, BI-456906, pianvidonide and mashiduide.

[0613] In certain embodiments, -D-AB 2 It is a dual GLP-1 receptor agonist that activates both the GLP-1 receptor and the GIP receptor. An example of such a dual GLP-1 receptor agonist is tirpotide. In certain embodiments, -D-AB 2Telpotide is a compound of the formula

[0614] YX1EGTFTSDYSIX2LDKIAQKAFVQWLIAGGPSSGAPPPS(SEQ ID NO:45),

[0615] in

[0616] X1 is Aib;

[0617] X2 is Aib;

[0618] Lysine at position 20 is cleaved by the ε-amine group of the lysine side chain and ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γGlu)1-CO-(CH2) 18 -CO2H coupling and chemical modification; and

[0619] The C-terminal serine, ie, the serine at position 39, is amidated to form a C-terminal primary amide.

[0620] Moiety ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γGlu)1-CO-(CH2) 18 -CO2H has the following structure

[0621]

[0622] The dotted line indicates the connection to -D-.

[0623] In certain embodiments, -D-AB 2 It is a dual GLP-1 receptor agonist that activates both the GLP-1 receptor and the glucagon receptor, selected from cotyledonide, BI-456906, pianviduide and mashiduide.

[0624] In certain embodiments, -D-AB 2 Cotudin is a compound of the formula

[0625] HSQGTFTSDKSEYLDSERARDFVAWLEAGG(SEQ ID NO:46),

[0626] in

[0627] The lysine at position 10 is chemically modified by coupling the ε-amine group of the lysine side chain with a γ-Glu-palmitoyl group.

[0628] Some γ-Glu-palmitoyl groups have the following structure:

[0629]

[0630] The dotted line indicates the connection to -D-.

[0631] In certain embodiments, -D-AB 2 BI-456906. BI-456906 is also known as survodutide and is a compound of the formula

[0632] HX1QGTFTSDYSKYLDERAAKDFIKWLESA(SEQ ID NO:47),

[0633] in

[0634] X1 is 1-amino-cyclobutanecarboxylic acid (Ac4c);

[0635] The lysine at position 24 is chemically modified by coupling the ε-amine group of the lysine side chain with [17-carboxy-heptadecanoyl]-isoGlu-GSGSGG; and

[0636] The C-terminal alanine, ie, the alanine at position 29, is amidated to form a C-terminal primary amide.

[0637] The moiety [17-carboxy-heptadecanoyl]-isoGlu-GSGSGG has the following structure:

[0638]

[0639] The dotted line indicates the connection to -D-.

[0640] In certain embodiments, -D-AB 2 Pianweidu peptide is a compound of the following formula

[0641] HX1QGTFTSDYSKYLDEKAAKEFIQWLLQT(SEQ ID NO:48),

[0642] in

[0643] X1 is Aib;

[0644] Glutamic acid at position 16 and lysine at position 20 are connected by a lactam bridge;

[0645] Lysine at position 17 is chemically modified by coupling the ε-amine group of the lysine side chain to glucuronic acid C-18, which is part of the formula

[0646]

[0647] in

[0648] The dotted line represents the ε-amine group attached to the lysine at position 17; and

[0649] The C-terminal threonine, ie, the threonine at position 29, is amidated to form a C-terminal primary amide.

[0650] In certain embodiments, -D-AB 2 Mashidu peptide is a compound of the following formula:

[0651] HX1QGTFTSDYSKYLDEKKAKEFVEWLLEGPSSG(SEQ ID NO:49),

[0652] in

[0653] X1 is Aib,

[0654] Lysine at position 20 is cleaved by the ε-amine group of the lysine side chain and ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γGlu)1-CO-(CH2) 18 -CO2H coupling and chemically modified; and

[0655] The C-terminal serine, glycine at position 34, is amidated.

[0656] Moiety ([2-(2-amino-ethoxy)-ethoxy]-acetyl) 2-(γ-Glu)-CO-(CH2) 18 -CO2H has the following structure:

[0657]

[0658] The dotted line indicates the connection to -D-.

[0659] In certain embodiments, -D-AB 2 It is a dual GLP-1 receptor agonist that activates both the GLP-1 receptor and the GLP-2 receptor, such as dapiglutide. Dapiglutide is a compound of the formula

[0660] HX1EGSFTSELATILDKQAARDFIAWLIQHKITD(SEQ ID NO:50),

[0661] in

[0662] X1 is Aib; and

[0663] The lysine at position 16 was chemically modified by coupling the ε-amine group of the lysine side chain with [17-carboxy-heptadecanoyl]-isoGlu.

[0664] The part [17-carboxy-heptadecanoyl]-isoGlu has the following structure:

[0665]

[0666] The dotted line indicates the connection to -D-.

[0667] In certain embodiments, -D-AB 2 Retaglutide is a triple GLP-1 receptor agonist that activates GLP-1 receptor, GIP receptor and GCG receptor. Retaglutide is a compound of the formula

[0668] YX1QGTFTSDYSIX2LDKKAQX3AFIEYLLEGGPSSGAPPPS(SEQ ID NO:51),

[0669] in

[0670] X1 is Aib;

[0671] X2 is α-methyl-leucine (αMeL);

[0672] X3 is Aib;

[0673] Lysine at position 17 binds to ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γGlu)-CO-(CH2) through the ε-amine group of the lysine side chain. 18 -CO2H coupling and chemically modified; and

[0674] The C-terminal serine, ie, the serine at position 39, is amidated.

[0675] Retaglutide can also be described as Y-Aib-QGTFTSDYSI-αMeL-LDKK((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γGlu)-CO-(CH2) 18 -CO2H)AQ-Aib-AFIEYLLEGPGPSSGAPPPS-NH2 (SEQ ID NO: 51).

[0676] Part (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γGlu)-CO-(CH2) 18 -CO2H has the following structure:

[0677]

[0678] In certain embodiments, -D-AB 2 It is noiiglutide, also known as SHR20004.

[0679] In certain embodiments, -D-AB 2 It is ZT002.

[0680] In certain embodiments, -D-AB 2 Having formula (b-1)

[0681]

[0682] in

[0683] X 1 -for and

[0684] -X 2 for

[0685] Wherein Ph is phenyl.

[0686] The portion -D- of formula (b-1) has the sequence of SEQ ID NO: 57

[0687] YX1EGTFTSDYSIX2LDKIAQKAFVQWLIAGGPSSGAPPPS,

[0688] Where X1 and X2 are Aib.

[0689] Compounds of formula (b-1) are disclosed in WO2022159395 and WO2023 / 044290, the contents of which are incorporated herein by reference in their entirety.

[0690] In certain embodiments, -D-AB has formula (b-1), and X 1 -for And -X 2 for In certain embodiments, D-AB has formula (b-1), and X 1 -for And -X 2 for In certain embodiments, D-AB has formula (b-1), and X 1 -for And -X 2 for In certain embodiments, D-AB has formula (b-1), and X 1 -for And -X 2 for In certain embodiments, D-AB has formula (b-1), and X 1 -for And -X 2 for In certain embodiments, D-AB has formula (b-1), and X 1 -for And -X 2 for In certain embodiments, D-AB has formula (b-1), and X 1 -for And -X 2 for In certain embodiments, D-AB has formula (b-1), and X 1 -for And -X 2 for In certain embodiments, D-AB has formula (b-1), and X 1 -for And -X 2 for In certain embodiments, D-AB has formula (b-1), and X 1 -for And -X 2 for In certain embodiments, D-AB has formula (b-1), and X 1 -for And -X 2 for In certain embodiments, D-AB has formula (b-1), and X 1 -for And -X 2 for

[0691] In certain embodiments, -D-AB 2 Selected from semaglutide, liraglutide, enoglutide, GZR18, GL0034, tilportide, codutide, BI-456906, pianvidutide, mashidutide, dapiglutide and retaglutide.

[0692] In certain embodiments, -D-AB 2 With the following formula

[0693] k(γE-(miniPEG)2-γE-COC 16 H 32 CO2H)(N-Me)GSVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHK(γE-(miniPEG)2-γE-COC 16 H 32 CO2H)-OH (SEQ ID NO: 52),

[0694] in

[0695] k is d-Lys;

[0696] γE is the L-isomer of γ-glutamic acid;

[0697] miniPEG is COCH2OCH2CH2OCH2CH2NH;

[0698] COC 16 H 32 CO2H is a C18 diacid;

[0699] (N-Me)G is sarcosine;

[0700] K is the L-isomer of lysine; and

[0701] -OH represents a C-terminal amino acid with a terminal carboxylic acid.

[0702] In certain embodiments, -D-AB 2 With the following formula

[0703] k(γE-(miniPEG)2-γE-COC 16 H 32 CO2H)(N-Me)GSVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHK(γE-(miniPEG)2-γE-COC 16 H 32 CO2H)-OH (SEQ ID NO: 53),

[0704] in

[0705] k is d-Lys;

[0706] γE is the L-isomer of γ-glutamic acid;

[0707] (miniPEG)2 is COCH2OCH2CH2OCH2CH2NH;

[0708] COC 16 H 32 CO2H is a C18 diacid;

[0709] (N-Me)G is sarcosine;

[0710] K is the L-isomer of lysine; and

[0711] -OH represents a C-terminal amino acid with a terminal carboxylic acid.

[0712] If -D- is a peptide or protein drug moiety, -L 1 - is coupled to a functional group of the side chain of the amino acid residue of -D-, the N-terminal amine functional group or the C-terminal carboxyl functional group of -D-, or one of the nitrogen atoms in the main chain of -D-.

[0713] In certain embodiments, if -D- is a peptide or protein drug moiety, then -L1 - is coupled to a functional group of -D-, wherein the functional group of -D- is 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, diazolane, ethylene oxide, guanidine and azetidine. In certain embodiments, if -D- is a peptide or protein drug moiety, -L 1 - is coupled to a functional group of -D-, wherein the functional group of -D- is selected from hydroxyl, primary amine, secondary amine and guanidine. In certain embodiments, if -D- is a peptide or protein drug moiety, then -L 1 - is coupled to a functional group of -D-, wherein the functional group of -D- is selected from a primary amine and a secondary amine. In certain embodiments, if -D- is a peptide or protein drug moiety, then -L 1 - coupled to a primary amine of -D-.

[0714] If -D- is a peptide or protein drug moiety, then -L 1 -A functional group that can be coupled to the side chain of an amino acid residue of -D-, which can be a proteinogenic amino acid residue or a non-proteinogenic amino acid residue.

[0715] If -D- is a peptide or protein drug moiety, in certain embodiments, -L 1 -A functional group of an amino acid residue side chain coupled to a proprotein of -D-. In certain embodiments, such amino acid residues are selected from histidine, lysine, tryptophan, serine, threonine, tyrosine, aspartic acid, glutamic acid, and arginine. In certain embodiments, such amino acid residues are selected from lysine, aspartic acid, arginine, and serine. In certain embodiments, such amino acid residues are selected from lysine, arginine, and serine.

[0716] In certain embodiments, if -D- is a peptide or protein drug moiety, then -L 1 - is coupled to a lysine residue of -D-. In certain embodiments, if -D- is a peptide or protein drug moiety, then -L 1 - is coupled to a functional group of a histidine residue of -D-. In certain embodiments, if -D- is a peptide or protein drug moiety, then -L 1 - is a functional group of a tryptophan residue coupled to -D-. In certain embodiments, if -D- is a peptide or protein drug moiety, then -L 1 - is coupled to a functional group of a serine residue of -D-. In certain embodiments, if -D- is a peptide or protein drug moiety, then -L 1- is a functional group coupled to a threonine residue of -D-. In certain embodiments, if -D- is a peptide or protein drug moiety, then -L 1 - is coupled to a tyrosine residue of -D-. In certain embodiments, if -D- is a peptide or protein drug moiety, then -L 1 - is coupled to the functional group of the aspartic acid residue of -D-. In certain embodiments, if -D- is a peptide or protein drug moiety, then -L 1 - is coupled to a functional group of a glutamic acid residue of -D-. In certain embodiments, if -D- is a peptide or protein drug moiety, then -L 1 - Functional group of an arginine residue coupled to -D-.

[0717] In certain embodiments, if -D- is a peptide or protein drug moiety, then -L 1 -A functional group coupled to the side chain of a non-proteinogenic amino acid residue of -D-.

[0718] It will be understood that not every peptide or protein drug moiety -D- may contain all of these amino acid residues.

[0719] In certain embodiments, if -D- is a peptide or protein drug moiety, then -L 1 - is coupled to the N-terminal amine functionality of -D-.

[0720] In certain embodiments, if -D- is a peptide or protein drug moiety, then -L 1 - is coupled to the C-terminal functional group of -D-.

[0721] Part-L 1 - can be connected to -D- by any type of linkage as long as it is reversible. In certain embodiments, -L 1 - is linked to -D- via a linkage selected from the group consisting of an amide, ester, carbamate, acetal, aminal, imine, oxime, hydrazone, disulfide, and acylguanidine. In certain embodiments, -L 1 - is linked to -D- via a linker selected from the group consisting of amides, esters, carbamates, and acylguanidines. It will be appreciated that some of these links are irreversible per se, but in the present invention, -L 1 The presence of adjacent groups in - makes these linkages reversible.

[0722] In certain embodiments, -L 1 - is linked to -D- through an amide linkage. In certain embodiments, -L 1 - is linked to -D- through a carbamate linkage. In certain embodiments, -L 1 - is connected to -D- via an ester linkage. In certain embodiments, -L1 - is linked to -D- through an acylguanidine linkage.

[0723] Part-L 1 - is a reversible prodrug linker, wherein the drug (i.e. HD-AB 2 ) is released in its free form, i.e., it is a traceless prodrug linker. It should be understood that the "H-" in "HD-AB" is hydrogen. Suitable prodrug linkers are known in the art, for example, the reversible prodrug linker moieties disclosed in WO 2005 / 099768 A2, WO 2006 / 136586 A2, WO 2011 / 089216 A1, and WO 2013 / 024053 A1, which are incorporated herein by reference.

[0724] In certain embodiments, -L 1 - disclosed in WO 2009 / 095479 A2. Thus, in certain embodiments, the moiety -L 1 - having formula (II):

[0725]

[0726] Wherein the dashed line represents the nitrogen, hydroxyl, or thiol group attached to -D-;

[0727] -X- is selected from -C(R 4 R 4a )-;-N(R 4 )-;-O-;-C(R 4 R 4a )-C(R 5 R 5a )-;-C(R 5 R 5a )-C(R 4 R 4a )-;-C(R 4 R 4a )-N(R 6 )-;-N(R 6 )-C(R 4 R 4a )-;C(R 4 R 4a )-O-;-OC(R 4 R 4a )-; and -C(R 7 R 7a )-;

[0728] X 1 selected from C; and S(O);

[0729] -X 2 -selected from -C(R 8 R8a )-; and -C(R 8 R 8a )-C(R 9 R 9a )-;

[0730] =X 3 Selected from =O; =S; and =N-CN;

[0731] -R 1 、-R 1a 、-R 2 、-R 2a 、-R 4 、-R 4a 、-R 5 、-R 5a 、-R 6 、-R 8 、-R 8a 、-R 9 and -R 9a are independently selected from -H; and C 1-6 alkyl;

[0732] -R 3 and -R 3a are independently selected from -H; and C 1-6 Alkyl, provided that, in -R 3 、-R 3a If one or both of them are not -H, they are passed to SP 3 - Hybridized carbon atoms are attached to the nitrogen to which they are attached;

[0733] -R 7 Selected from -N(R 10 R 10a ); and -NR 10 -(C=O)-R 11 ;

[0734] -R 7a 、-R 10 、-R 10a and -R 11 are independently selected from -H; and C 1-6 alkyl;

[0735] Optionally, -R 1a / -R 4a 、-R 1a / -R 5a 、-R 1a / -R 7a 、-R 4a / -R 5a and -R 8a / -R 9aOne or more pairs of them form chemical bonds;

[0736] Optionally, -R 1 / -R 1a 、-R 2 / -R 2a 、-R 4 / -R 4a 、-R 5 / -R 5a 、-R 8 / -R 8a and -R 9 / -R 9a One or more of them are joined together with the atoms to which they are attached to form C 3-10 Cycloalkyl; or 3 to 10-membered heterocyclic group;

[0737] Optionally, -R 1 / -R 4 、-R 1 / -R 5 、-R 1 / -R 6 、-R 1 / -R 7a 、-R 4 / -R 5 、-R 4 / -R 6 、-R 8 / -R 9 and -R 2 / -R 3 One or more of them are linked together with the atoms to which they are attached to form ring A;

[0738] Optionally, R 3 / R 3a Together with the nitrogen atom to which they are attached, they form a 3- to 10-membered heterocyclic ring;

[0739] A is selected from phenyl; naphthyl; indenyl; dihydroindenyl; tetrahydronaphthyl; C 3-10 cycloalkyl; 3- to 10-membered heterocyclyl; and 8- to 11-membered heterobicyclyl; and

[0740] Where -L 1 -Being at least one -L 2 -substituted, and wherein -L 1 - is optionally further substituted, provided that the hydrogen marked with an asterisk in formula (II) is not replaced by -L 2 - or substituted by a substituent.

[0741] In certain embodiments, -L of formula (II) 1 -Being a part-L 2 -replace.

[0742] In certain embodiments, -L of formula (II) 1 - is not further superseded.

[0743] It should be understood that if -R 3 / -R 3a Together with the nitrogen atom to which they are attached, they form a 3- to 10-membered heterocyclic ring, and only the atom directly attached to the nitrogen atom is SP 3 -hybridized carbon atoms of such 3 to 10 membered heterocyclic rings. In other words, -R 3 / -R 3a Such 3- to 10-membered heterocyclic rings, together with the nitrogen atom to which they are attached, have the following structure:

[0744]

[0745] in

[0746] The dotted line indicates the connection to -L 1 - the rest of

[0747] The ring contains 3-10 atoms including at least one nitrogen; and

[0748] R # and R ## Indicates sp 3 -Hybridized carbon atoms.

[0749] It is also to be understood that the 3- to 10-membered heterocyclic ring may be further substituted.

[0750] -R of formula (II) 3 / -R 3a Illustrative embodiments of suitable 3- to 10-membered heterocyclic rings formed together with the nitrogen atom to which they are attached are as follows:

[0751]

[0752] in

[0753] The dashed line indicates connection to the rest of the molecule; and

[0754] -R is selected from -H and C 1-6 alkyl.

[0755] -L of formula (II) 1 - can be optionally further substituted. Generally speaking, any substituent can be used as long as it does not affect the cracking principle, that is, the hydrogen marked with an asterisk in formula (II) is not replaced, and Part of the nitrogen is still a component of the primary, secondary or tertiary amine, that is, -R 3 and -R 3aIndependently of each other -H or through sp 3 -hybridized carbon atom is connected to N<.

[0756] In one embodiment, -R 1 or -R 1a L 2 In another embodiment, -R 2 or -R 2a L 2 In another embodiment, -R 3 or -R 3a L 2 In another embodiment, -R 4 L 2 In another embodiment, -R 5 or -R 5a L 2 In another embodiment, -R 6 L 2 In another embodiment, -R 7 or -R 7a L 2 In another embodiment, -R 8 or -R 8a L 2 In another embodiment, -R 9 or -R 9a L 2 In another embodiment, -R 10 L 2 In another embodiment, -R 11 L 2 In certain embodiments, -R 3 L 2 -replace.

[0757] In certain embodiments, -X- of formula (II) is selected from -C(R 4 R 4a )-、-N(R 4 )- and -C(R 7 R 7a In certain embodiments, -X- of formula (II) is -C(R 4 R 4a In certain embodiments, -X- of formula (II) is -C(R 7 R7a )-.

[0758] In certain embodiments, -R 7 -NR 10 -(C=O)-R 11 .

[0759] In certain embodiments, -R 7a In certain embodiments, -R 7a is -H.

[0760] In certain embodiments, -R 10 In certain embodiments, -R 10 It is a methyl group.

[0761] In certain embodiments, -R 11 In certain embodiments, -R 11 In certain embodiments, -R 11 L 2 -replace.

[0762] In certain embodiments, -X- of formula (II) is -N(R 4 )-.

[0763] In certain embodiments, -R 4 In certain embodiments, -R 4 is -H.

[0764] In certain embodiments, X of formula (II) 1 For C.

[0765] In certain embodiments, =X of formula (II) 3 =O.

[0766] In certain embodiments, -X of formula (II) 2 -for-C(R 8 R 8a )-.

[0767] In certain embodiments, -R 8 and -R 8a In certain embodiments, -R 8 and -R 8a In certain embodiments, at least one of -R 8 and -R 8a Both are -H.

[0768] In certain embodiments, -R 1 and -R 1a Independently selected from -H, methyl and ethyl.

[0769] In certain embodiments, -R 1 and -R 1a In certain embodiments, at least one of -R 1 and -R 1a is -H.

[0770] In certain embodiments, -R 1 and -R 1a In certain embodiments, at least one of -R 1 and -R 1a Both are methyl groups.

[0771] In certain embodiments, -R 2 and -R 2a In certain embodiments, -R 2 and -R 2a In certain embodiments, at least one of -R 2 and -R 2a Both are H.

[0772] In certain embodiments, -R 3 and -R 3a Independently selected from -H, methyl, ethyl, propyl and butyl.

[0773] In certain embodiments, -R 3 and -R 3a In certain embodiments, at least one of -R 3 is methyl, and -R 3a is -H.

[0774] In certain embodiments, -R 3 and -R 3a Both are -H.

[0775] In certain embodiments, -D- is linked to -L through the nitrogen by forming an amide linkage. 1 -.

[0776] In certain embodiments, -L 1 - having formula (II), wherein X is -C(R 7 R7a )-;X 1 C; -X 2 -for-C(R 8 R 8a )-C(R 9 R 9a )-;=X 3 =O; -R 1 and -R 1a -H; -R 2 and -R 2a -H; -R 3 and -R 3a is methyl; -R 7 -N(R 10 R 10a );-R 7a -H; -R 8 、-R 8a 、-R 9 and -R 9a is -H, and -R 10 is methyl, and -R 10a is -H.

[0777] In certain embodiments, -L 1 - having formula (IIa)

[0778]

[0779] in

[0780] The dashed line marked with an asterisk represents the nitrogen attached to -D-; and

[0781] The unmarked dashed line indicates the connection to -L 2 -.

[0782] In certain embodiments, -L 1 -having formula (IIa-a)

[0783]

[0784] in

[0785] The dashed line marked with an asterisk represents the nitrogen attached to -D-; and

[0786] The unmarked dashed line indicates the connection to -L 2 -.

[0787] In certain embodiments, -L 1 -having formula (IIa-b)

[0788]

[0789] in

[0790] The dashed line marked with an asterisk represents the nitrogen attached to -D-; and

[0791] The unmarked dashed line indicates the connection to -L 2 -.

[0792] The moieties of formula (IIa), (IIa-a) and (IIa-b) are linked to -D- via an amide bond formed by the nitrogen of the amine functionality and the carbonyl group to the left of the dashed line marked with an asterisk.

[0793] In certain embodiments, -L 1 - having formula (II), wherein X is -C(R 7 R 7a )-;X 1 C; -X 2 -for-C(R 8 R 8a )-C(R 9 R 9a )-;=X 3 =O; -R 1 and -R 1a -H; -R 2 and -R 2a -H; -R 3 and -R 3a is methyl; -R 7 -NR 10 -(C=O)-R 11 ;-R 7a -H; -R 8 、-R 8a 、-R 9 and -R 9a is -H, and -R 10 is methyl, and -R 11 is -H.

[0794] In certain embodiments, -L 1 - having formula (II), wherein X is -C(R 7 R 7a )-;X 1 C; -X 2 -for-C(R 8 R 8a )-C(R 9 R 9a )-;=X 3 =O; -R 1 and -R 1a -H; -R 2 and -R 2a -H; -R 3 and -R 3ais methyl; -R 7 -NR 10 -(C=O)-R 11 ;-R 7a -H; -R 8 、-R 8a 、-R 9 and -R 9a is -H, and -R 10 is -H, and -R 11 is -H.

[0795] In certain embodiments, -L 1 -having formula (IIab)

[0796]

[0797] in

[0798] The dashed line marked with an asterisk represents the nitrogen attached to -D-; and

[0799] The unmarked dashed line indicates the connection to -L 2 -.

[0800] In certain embodiments, -L 1 -having formula (IIab-a)

[0801]

[0802] in

[0803] The dashed line marked with an asterisk represents the nitrogen attached to -D-; and

[0804] The unmarked dashed line indicates the connection to -L 2 -.

[0805] In certain embodiments, -L 1 -having formula (IIab-b)

[0806]

[0807] in

[0808] The dashed line marked with an asterisk represents the nitrogen attached to -D-; and

[0809] The unmarked dashed line indicates the connection to -L 2 -.

[0810] The moieties of formula (IIab), (IIab-a) and (IIab-b) are linked to -D- via an amide bond formed by the nitrogen of the amine functionality and the carbonyl group to the left of the dashed line marked with an asterisk.

[0811] In certain embodiments, -L1 - disclosed in WO2016 / 020373A1. Therefore, in certain embodiments, the moiety -L 1 - having formula (III):

[0812]

[0813] in

[0814] Dashed lines represent primary or secondary amines or hydroxyl groups connected to -D- via amide or ester linkages, respectively;

[0815] -R 1 、-R 1a 、-R 2 、-R 2a 、-R 3 and -R 3a independently selected from -H, -C(R 8 R 8a R 8b ),-C(=O)R 8 、-C≡N、-C(=NR 8 )R 8a 、-CR 8 (=CR 8a R 8b ), -C≡CR 8 and -T;

[0816] -R 4 、-R 5 and -R 5a independently selected from -H, -C(R 9 R 9a R 9b ) and -T;

[0817] a1 and a2 are independently 0 or 1;

[0818] -R 6 、-R 6a 、-R 7 、-R 7a 、-R 8 、-R 8a 、-R 8b 、-R 9 、-R 9a and -R 9b Each independently selected from -H, halogen, -CN, -COOR 10 、-OR 10 、-C(O)R 10 、-C(O)N(R 10 R 10a )、-S(O)2N(R 10 R10a )、-S(O)N(R 10 R 10a )、-S(O)2R 10 、-S(O)R 10 、-N(R 10 )S(O)2N(R 10a R 10b ),-SR 10 、-N(R 10 R 10a )、-NO2、-OC(O)R 10 、-N(R 10 )C(O)R 10a 、-N(R 10 )S(O)2R 10a 、-N(R 10 )S(O)R 10a 、-N(R 10 )C(O)OR 10a 、-N(R 10 )C(O)N(R 10a R 10b )、-OC(O)N(R 10 R 10a ), -T, C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20 Alkynyl; wherein -T, C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20 Alkynyl groups are optionally substituted with one or more -R 11 substituted, and wherein C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20 The alkynyl group is optionally separated by one or more groups selected from -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R 12 )-、-S(O)2N(R 12 )-、-S(O)N(R 12 )-、-S(O)2-、-S(O)-、-N(R 12 )S(O)2N(R 12a )-、-S-、-N(R 12 )-、-OC(OR 12 )(R 12a )-、-N(R 12 )C(O)N(R 12a )-and-OC(O)N(R 12 )-;

[0819] -R 10、-R 10a and -R 10b Each independently selected from -H, -T, C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20 Alkynyl; wherein -T, C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20 Alkynyl groups are optionally substituted with one or more -R 11 substituted, and wherein C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20 The alkynyl group is optionally separated by one or more groups selected from -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R 12 )-、-S(O)2N(R 12 )-、-S(O)N(R 12 )-、-S(O)2-、-S(O)-、-N(R 12 )S(O)2N(R 12a )-、-S-、-N(R 12 )-、-OC(OR 12 )(R 12a )-、-N(R 12 )C(O)N(R 12a )-and-OC(O)N(R 12 )-;

[0820] T are each independently selected from phenyl, naphthyl, indenyl, dihydroindenyl, tetrahydronaphthyl, C 3-10 Cycloalkyl, 3 to 10 membered heterocyclyl and 8 to 11 membered heterobicyclyl; wherein each T is independently optionally replaced by one or more -R which may be the same or different 11 replace;

[0821] -R 11 Each independently selected from halogen, -CN, oxo (=O), -COOR 13 、-OR 13 、-C(O)R 13 、-C(O)N(R 13 R 13a )、-S(O)2N(R 13 R 13a )、-S(O)N(R 13 R 13a )、-S(O)2R 13 、-S(O)R 13 、-N(R 13 )S(O)2N(R 13a R 13b),-SR 13 、-N(R 13 R 13a )、-NO2、-OC(O)R 13 、-N(R 13 )C(O)R 13a 、-N(R 13 )S(O)2R 13a 、-N(R 13 )S(O)R 13a 、-N(R 13 )C(O)OR 13a 、-N(R 13 )C(O)N(R 13a R 13b )、-OC(O)N(R 13 R 13a ) and C 1-6 Alkyl; among which C 1-6 The alkyl group is optionally substituted with one or more halogens which may be the same or different;

[0822] -R 12 、-R 12a 、-R 13 、-R 13a and -R 13b are each independently selected from -H and C 1-6 Alkyl; among which C 1-6 The alkyl group is optionally substituted with one or more halogens which may be the same or different;

[0823] Optionally, -R 1 / -R 1a 、-R 2 / -R 2a 、-R 3 / -R 3a 、-R 6 / -R 6a and -R 7 / -R 7a One or more of them are joined together with the atoms to which they are attached to form C 3-10 cycloalkyl or 3- to 10-membered heterocyclic group;

[0824] Optionally, -R 1 / -R 2 、-R 1 / -R 3 、-R 1 / -R 4 、-R 1 / -R 5 、-R 1 / -R 6 、-R 1 / -R7 、-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 、-R 3 / -R 7 、-R 4 / -R 5 、-R 4 / -R 6 、-R 4 / -R 7 、-R 5 / -R 6 、-R 5 / -R 7 and -R 6 / -R 7 One or more of them are linked together with the atoms to which they are attached to form ring A;

[0825] A is selected from phenyl; naphthyl; indenyl; dihydroindenyl; tetrahydronaphthyl; C 3-10 cycloalkyl; 3- to 10-membered heterocyclyl; and 8- to 11-membered heterobicyclyl;

[0826] Where -L 1 -Being at least one -L 2 -substituted, and wherein -L 1 - is optionally further substituted.

[0827] In certain embodiments, -L of formula (III) 1 The optional additional substituents of - are as defined above.

[0828] In certain embodiments, -L of formula (III) 1 -Being a part-L 2 -replace.

[0829] In certain embodiments, -L of formula (III) 1 - is not further superseded.

[0830] In certain embodiments, -L 1- as disclosed in EP1536334B1, WO2009 / 009712A1, WO2008 / 034122A1, WO2009 / 143412A2, WO2011 / 082368A2 and US8618124B2, which are incorporated herein by reference in their entirety.

[0831] In certain embodiments, -L 1 - as disclosed in US8946405B2 and US8754190B2, which are incorporated herein by reference in their entirety. Thus, in certain embodiments, -L 1 - having formula (IV):

[0832]

[0833] in

[0834] The dotted line indicates attachment to -D-, and wherein the attachment is through a functional group of -D- selected from -OH, -SH, and -NH2;

[0835] m is 0 or 1;

[0836] -R 1 and -R 2 At least one or both of them are independently selected from -CN, -NO2, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkenyl, optionally substituted alkynyl, -C(O)R 3 、-S(O)R 3 、-S(O)2R 3 and-SR 4 ,

[0837] -R 1 and -R 2 There is only one selected from -H, optionally substituted alkyl, optionally substituted arylalkyl and optionally substituted heteroarylalkyl;

[0838] -R 3 is selected from -H, optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -OR 9 and -N(R 9 )2;

[0839] -R 4 is selected from optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl;

[0840] -R 5each independently selected from -H, optionally substituted alkyl, optionally substituted alkenylalkyl, optionally substituted alkynylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl;

[0841] -R 9 is selected from -H and optionally substituted alkyl;

[0842] -Y- is absent and –X- is -O- or -S-; or

[0843] -Y- is -N(Q)CH2-, and -X- is -O-;

[0844] Q is selected from optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl;

[0845] Optionally, -R 1 and -R 2 can be linked to form 3-8 membered rings; and

[0846] Optionally, two -R 9 Together with the nitrogen to which they are attached, they form a heterocyclic ring;

[0847] Where -L 1 -Being at least one -L 2 -substituted, and wherein -L 1 - is optionally further substituted.

[0848] In the context of formula (IV) only, the terms used have the following meanings:

[0849] As used herein, the term "alkyl" includes straight chain, branched, or cyclic saturated hydrocarbon groups containing 1-8 carbons, or in certain embodiments, 1-6 or 1-4 carbon atoms.

[0850] The term "alkoxy" includes alkyl groups bonded to oxygen, including methoxy, ethoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, and the like.

[0851] The term "alkenyl" includes non-aromatic unsaturated hydrocarbons having carbon-carbon double bonds.

[0852] The term "alkynyl" includes non-aromatic unsaturated hydrocarbons having a carbon-carbon triple bond.

[0853] The term "aryl" includes aromatic hydrocarbon groups of 6-18 carbon atoms, such as 6-10 carbon atoms, including, for example, phenyl, naphthyl, and anthracenyl. The term "heteroaryl" includes aromatic rings containing 3-15 carbon atoms, containing at least one N, O, or S atom, such as 3-7 carbon atoms, containing at least one N, O, or S atom, including, for example, pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, indolyl, indenyl, and the like.

[0854] In some cases, the alkenyl, alkynyl, aryl, or heteroaryl moiety can be coupled to the rest of the molecule through an alkylene linkage. In those cases, the substituent is referred to as an alkenylalkyl, alkynylalkyl, arylalkyl, or heteroarylalkyl group, indicating that the alkylene moiety is between the alkenyl, alkynyl, aryl, or heteroaryl moiety and the molecule to which the alkenyl, alkynyl, aryl, or heteroaryl moiety is coupled.

[0855] The term "halogen" includes bromine, fluorine, chlorine and iodine.

[0856] The term "heterocycle" refers to a 4-8 membered aromatic or non-aromatic ring containing 3-7 carbon atoms and at least one atom of N, O or S. Examples are piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl and tetrahydrofuranyl, as well as the exemplary groups provided above for the term "heteroaryl".

[0857] When the ring system is optionally substituted, suitable substituents are selected from alkyl, alkenyl, alkynyl or another ring, each of which is optionally further substituted. Optional substituents on any group (including the above groups) include halogen, nitro, cyano, -OR, -SR, -NR2, -OCOR, -NRCOR, -COOR, -CONR2, -SOR, -S02R, -SONR2, -SONR2, wherein each R is independently alkyl, alkenyl, alkynyl, aryl or heteroaryl, or two R groups together with the atoms to which they are attached form a ring.

[0858] In certain embodiments, -L of formula (IV) 1 -Being a part-L 2 -replace.

[0859] In certain embodiments, -L of formula (IV) 1 - is not further superseded.

[0860] In certain embodiments, -L 1 - as disclosed in WO2013 / 036857A1, which is incorporated herein by reference in its entirety. Thus, in certain embodiments, -L 1 - having formula (V):

[0861]

[0862] in

[0863] The dotted line indicates the HD-AB 2 The amine functional group of is connected to -D-;

[0864] -R 1 is selected from optionally substituted C1-C6 linear, branched or cyclic alkyl; optionally substituted aryl; optionally substituted heteroaryl; alkoxy; and -NR 5 2;

[0865] -R 2 is selected from -H; optionally substituted C1-C6 alkyl; optionally substituted aryl; and optionally substituted heteroaryl;

[0866] -R 3 is selected from -H; optionally substituted C1-C6 alkyl; optionally substituted aryl; and optionally substituted heteroaryl;

[0867] -R 4 is selected from -H; optionally substituted C1-C6 alkyl; optionally substituted aryl; and optionally substituted heteroaryl;

[0868] -R 5 Each independently selected from -H; optionally substituted C1-C6 alkyl; optionally substituted aryl; and optionally substituted heteroaryl; or when two -R 5 When combined together they may be cycloalkyl or cycloheteroalkyl;

[0869] Where -L 1 -Being at least one -L 2 -substituted, and wherein -L 1 - is optionally further substituted.

[0870] In the context of formula (V) only, the terms used have the following meanings:

[0871] "Alkyl," "alkenyl," and "alkynyl" include linear, branched, or cyclic hydrocarbon groups of 1-8 carbons, 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, they contain 1-6 C.

[0872] "Aryl" includes aromatic hydrocarbon groups of 6-18 carbon atoms, such as 6-10 carbon atoms, including, for example, phenyl, naphthyl, and anthracenyl. "Heteroaryl" includes aromatic rings of 3-15 carbon atoms, such as 3-7 carbon atoms, containing at least one N, O, or S atom, including, for example, pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, indolyl, indenyl, and the like.

[0873] The term "substituted" refers to an alkyl, alkenyl, alkynyl, aryl or heteroaryl group containing one or more substituents replacing one or more hydrogen atoms. The substituents can generally be selected from halogen, including F, Cl, Br and I; lower alkyl, including straight chain, branched and cyclic; lower haloalkyl, including fluoroalkyl, chloroalkyl, bromoalkyl and iodoalkyl; OH; lower alkoxy, including straight chain, branched and cyclic; SH; lower alkylthio, including straight chain, branched and cyclic; amino, alkylamino, dialkylamino, silyl, including alkylsilyl, alkoxysilyl and arylsilyl; nitro; cyano; carbonyl; carboxylic acid, carboxyl Acid esters, carboxamides, aminocarbonyl; aminoacyl; carbamate; urea; thiocarbamate; thiourea; ketone; sulfone; sulfonamide; aryl, including phenyl, naphthyl and anthracenyl; heteroaryl, including 5-membered heteroaryl, including pyrrole, imidazole, furan, thiophene, oxazole, thiazole, isoxazole, isothiazole, thiadiazole, triazole, oxadiazole and tetrazole, 6-membered heteroaryl, including pyridine, pyrimidine, pyrazine, and fused heteroaryl, including benzofuran, benzothiophene, benzoxazole, benzimidazole, indole, benzothiazole, benzisoxazole and benzisothiazole.

[0874] In certain embodiments, -L of formula (V) 1 -Being a part-L 2 -replace.

[0875] In certain embodiments, -L of formula (V) 1 - is not further superseded.

[0876] In certain embodiments, -L 1 - as disclosed in US7585837B2, which is incorporated herein by reference in its entirety. Thus, in certain embodiments, -L 1 - having formula (VI):

[0877]

[0878] in

[0879] The dotted line indicates the HD-AB 2 The amine functional group of is connected to -D-;

[0880] R 1 and R 2 independently selected from hydrogen, alkyl, alkoxy, alkoxyalkyl, aryl, alkaryl, aralkyl, halogen, nitro, -SO3H, -SO2NHR 5 , amino, ammonium, carboxyl, PO3H2 and OPO3H2;

[0881] R 3 、R 4and R 5 independently selected from hydrogen, alkyl, and aryl;

[0882] Where -L 1 -Being at least one -L 2 -substituted, and wherein -L 1 - is optionally further substituted.

[0883] Suitable substituents of formula (VI) are alkyl groups (e.g. C 1-6 Alkyl), alkenyl (e.g. C 2-6 alkenyl), alkynyl (e.g. C 2-6 alkynyl), aryl (e.g., phenyl), heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl (e.g., aromatic 4-7 membered heterocycle), or halogen moiety.

[0884] In the context of formula (VI) only, the terms used have the following meanings:

[0885] The terms "alkyl", "alkoxy", "alkoxyalkyl", "aryl", "alkaryl" and "aralkyl" refer to alkyl groups having 1 to 8, for example 1 to 4, carbon atoms, such as methyl, ethyl, propyl, isopropyl and butyl, and aryl groups having 6 to 10 carbon atoms, such as phenyl and naphthyl. The term "halogen" includes bromine, fluorine, chlorine and iodine.

[0886] In certain embodiments, -L of formula (VI) 1 -Being a part-L 2 -replace.

[0887] In certain embodiments, -L of formula (VI) 1 - is not further superseded.

[0888] -L 1 Another preferred embodiment of - is disclosed in WO2002 / 089789A1, which is incorporated herein by reference in its entirety. 1 - having formula (VII):

[0889]

[0890] in

[0891] The dotted line indicates the HD-AB 2 The amine functional group of is connected to -D-;

[0892] L1 is a bifunctional linking group,

[0893] Y1 and Y2 are independently O, S or NR 7 ;

[0894] R 2 、R3 、R 4 、R 5 、R 6 and R 7 are independently selected from hydrogen, C 1-6 Alkyl, C 3-12 Branched alkyl, C 3-8 Cycloalkyl, C 1-6 Substituted alkyl, C 3-8 Substituted cycloalkyl, aryl, substituted aryl, aralkyl, C 1-6 Heteroalkyl, substituted C 1-6 Heteroalkyl, C 1-6 Alkoxy, phenoxy and C 1-6 heteroalkoxy;

[0895] Ar, when included in formula (VII), is a moiety that forms a polysubstituted aromatic hydrocarbon or a polysubstituted heterocyclic group;

[0896] X is a chemical bond or a moiety that is actively transported to the target cell, a hydrophobic moiety, or a combination thereof,

[0897] y is 0 or 1;

[0898] Where -L 1 -Being at least one -L 2 -substituted, and wherein -L 1 - is optionally further substituted.

[0899] In the context of formula (VII) only, the terms used have the following meanings:

[0900] The term "alkyl" is understood to include, for example, straight chain, branched, substituted C 1-12 Alkyl, including alkoxy, C 3-8 cycloalkyl or substituted cycloalkyl, etc.

[0901] The term "substituted" is understood to include the addition of one or more different atoms or the replacement of one or more atoms contained in a functional group or compound with one or more different atoms.

[0902] Substituted alkyl includes carboxyalkyl, aminoalkyl, dialkylamino, hydroxyalkyl, and mercaptoalkyl; substituted cycloalkyl includes moieties such as 4-chlorocyclohexyl; aryl includes moieties such as naphthyl; substituted aryl includes moieties such as 3-bromophenyl; aralkyl includes moieties such as toluoyl; heteroalkyl includes moieties such as ethylthiophene; substituted heteroalkyl includes moieties such as 3-methoxythiophene (thiophone); alkoxy includes moieties such as methoxy; phenoxy includes moieties such as 3-nitrophenoxy. Halo- is understood to include fluorine, chlorine, iodine, and bromine.

[0903] In certain embodiments, -L of formula (VII) 1 -Being a part-L 2 -replace.

[0904] In certain embodiments, -L of formula (VII) 1 - is not further superseded.

[0905] In certain embodiments, -L 1 - comprising a substructure of formula (VIII)

[0906]

[0907] in

[0908] The dashed line marked with an asterisk indicates the nitrogen connected to -D- via an amide bond;

[0909] The unmarked dashed line indicates the connection to -L 1 -the remainder; and

[0910] Where -L 1 -Being at least one -L 2 -substituted, and wherein -L 1 - is optionally further substituted.

[0911] In certain embodiments, -L of formula (VIII) 1 -Being a part-L 2 -replace.

[0912] In certain embodiments, -L of formula (VIII) 1 - is not further superseded.

[0913] In certain embodiments, -L 1 - comprising a substructure of formula (IX)

[0914]

[0915] in

[0916] The dashed line marked with an asterisk represents the nitrogen connected to -D- via a carbamate bond;

[0917] The unmarked dashed line indicates the connection to -L 1 -the remainder; and

[0918] Where -L 1 -Being at least one -L 2 -substituted, and wherein -L 1 - is optionally further substituted.

[0919] In certain embodiments, -L of formula (IX)1 -Being a part-L 2 -replace.

[0920] In certain embodiments, -L of formula (IX) 1 - is not further superseded.

[0921] In certain embodiments, -L 1 - has a structure as disclosed in WO2020 / 206358A1. Therefore, in certain embodiments, the moiety -L 1 -having the formula (X):

[0922]

[0923] in

[0924] Unlabeled dashed lines indicate connections to -D-;

[0925] The dashed line marked with an asterisk indicates the connection to -L 2 -;

[0926] n is an integer selected from 0, 1, 2, 3, 4, 5 and 6;

[0927] -R 1 and -R 2 are each independently an electron-withdrawing group, an alkyl group or -H, and wherein -R 1 or -R 2 At least one of them is an electron-withdrawing group;

[0928] -R 4 Each is independently a C1-C3 alkyl group or two -R 4 Together with the carbon atoms to which they are attached, they form a 3- to 6-membered ring; and

[0929] When -D- is a drug moiety linked through an amine, -Y- is absent, or when -D- is a drug moiety linked through a phenol, alcohol, thiol, thiophenol, imidazole, or non-basic amine, -Y- is -N(R 6 )CH 2- ; where -R 6 is an optionally substituted C1-C6 alkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group.

[0930] 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 selected 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.

[0931] In certain embodiments, -R 1 and -R 2 The electron withdrawing group is selected from -CN; -NO2; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted alkenyl; optionally substituted alkynyl; -COR 3 、-SOR 3 or-SO2R 3 , where -R 3 is -H, optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -OR 8 or -NR 8 2, where -R 8 are each independently -H or an optionally substituted alkyl group, or two -R 8 The groups together with the nitrogen atom to which they are attached form a heterocyclic ring; or -SR 9 , where -R 9 is optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl.

[0932] In certain embodiments, -R 1 and -R 2 The electron withdrawing group of formula (X) is -CN. 1 and -R 2 The electron withdrawing group of formula (X) is -NO2. 1 and -R 2 The electron withdrawing group of is an optionally substituted aryl group containing 6-10 carbon atoms. In certain embodiments, -R 1 and -R 2 The electron withdrawing group of is an optionally substituted phenyl, naphthyl or anthracenyl. In certain embodiments, -R 1 and -R 2 The electron withdrawing group of is an optionally substituted heteroaryl group containing 3-7 carbon atoms and at least one N, O or S atom. In certain embodiments, -R 1 and -R 2 The electron withdrawing group of is an optionally substituted pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, indolyl or indenyl. In certain embodiments, -R of formula (X) 1 and -R 2 The electron withdrawing group of is an optionally substituted alkenyl group containing 2 to 20 carbon atoms. In certain embodiments, -R of formula (X) 1 and -R 2The electron withdrawing group of is an optionally substituted alkynyl group containing 2-20 carbon atoms. In certain embodiments, -R of formula (X) 1 and -R 2 The electron withdrawing group is -COR 3 、-SOR 3 or-SO2R 3 , where -R 3 is -H, optionally substituted alkyl containing 1 to 20 carbon atoms, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -OR 8 or -NR 8 2, where -R 8 are each independently -H or an optionally substituted alkyl group containing 1 to 20 carbon atoms, or two -R 8 The groups together with the nitrogen to which they are attached form a heterocyclic ring. In certain embodiments, -R 1 and -R 2 The electron-withdrawing group is -SR 9 , where -R 9 is an optionally substituted alkyl group containing 1 to 20 carbon atoms, an optionally substituted aryl group, an optionally substituted arylalkyl group, an optionally substituted heteroaryl group or an optionally substituted heteroarylalkyl group.

[0933] In certain embodiments, -R 1 or -R 2 At least one of -CN, -SOR 3 or-SO2R 3 In certain embodiments, -R 1 and -R 2 At least one of -CN or -SO2R 3 In certain embodiments, -R 1 and -R 2 At least one of -CN or -SO2R 3 , where -R 3 is optionally substituted alkyl, optionally substituted aryl or -NR 8 2. In certain embodiments, -R 1 and -R 2 At least one of the following is -CN, -SO2N(CH3)2, -SO2CH3, phenyl substituted by -SO2, phenyl substituted by -SO2 and -Cl, -SO2N(CH2CH2)2O, -SO2CH(CH3)2, -SO2N(CH3)(CH2CH3) or -SO2N(CH2CH2OCH3)2.

[0934] In certain embodiments, -R4 Each is independently C1-C3 alkyl. In certain embodiments, two -R 4 All are methyl.

[0935] In certain embodiments, -Y- of formula (X) is absent. In certain embodiments, -Y- of formula (X) is -N(R 6 )CH2-.

[0936] In certain embodiments, -L 1 - having the formula (X), wherein n is 1, -R 1 -CN, -R 2 is -H, and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 1, -R 1 -SO2N(CH3)2, -R 2 is -H, and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 1, -R 1 SO2CH3, -R 2 For -H and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 1, -R 1 -SO2N(CH2CH2)2CHCH3, -R 2 is -H, and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 1, -R 1 Phenyl substituted by -SO2, -R 2 is -H, and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 1, -R 1 is a phenyl group substituted by -SO2 and -Cl, -R 2 is -H, and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 1, -R 1 -SO2N(CH2CH2)2O, -R 2 For -H and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 1, -R 1 -SO2CH(CH3)2, -R 2is -H, and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 1, -R 1 is -SO2N(CH3)(CH2CH3), -R 2 is -H, and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 1, -R 1 -SO2N(CH2CH2OCH3)2, -R 2 is -H, and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 1, -R 1 is a phenyl group substituted by -SO2 and -CH3, -R 2 is -H, and -R 4 is -CH3.

[0937] In certain embodiments, -L 1 - having the formula (X), wherein n is 2, -R 1 -CN, -R 2 is -H, and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 2, -R 1 -SO2N(CH3)2, -R 2 is -H, and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 2, -R 1 SO2CH3, -R 2 is -H, and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 2, -R 1 -SO2N(CH2CH2)2CHCH3, -R 2 is -H, and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 2, -R 1 Phenyl substituted by -SO2, -R 2 is -H, and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 2, -R 1 Phenyl substituted by -SO2 and -Cl, -R 2is -H, and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 2, -R 1 -SO2N(CH2CH2)2O, -R 2 For -H and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 2, -R 1 -SO2CH(CH3)2, -R 2 is -H, and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 2, -R 1 is -SO2N(CH3)(CH2CH3), -R 2 is -H, and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 2, -R 1 -SO2N(CH2CH2OCH3)2, -R 2 is -H, and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 2, -R 1 Phenyl substituted by -SO2 and -CH3, -R 2 is -H, and -R 4 is -CH3.

[0938] In certain embodiments, -L 1 - having the formula (X), wherein n is 3, -R 1 -CN, -R 2 is -H, and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 3, -R 1 -SO2N(CH3)2, -R 2 is -H, and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 3, -R 1 SO2CH3, -R 2 is -H, and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 3, -R 1 -SO2N(CH2CH2)2CHCH3, -R2 is -H, and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 3, -R 1 is a phenyl group substituted by -SO2, -R 2 For -H and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 3, -R 1 is a phenyl group substituted by -SO2 and -Cl, -R 2 is -H, and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 3, -R 1 -SO2N(CH2CH2)2O, -R 2 is -H, and R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 3, -R 1 -SO2CH(CH3)2, -R 2 is -H, and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 3, -R 1 is -SO2N(CH3)(CH2CH3), -R 2 For -H and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 3, -R 1 -SO2N(CH2CH2OCH3)2, -R 2 is -H, and -R 4 In certain embodiments, -L 1 - having the formula (X), wherein n is 3, -R 1 is a phenyl group substituted by -SO2 and -CH3, -R 2 is -H, and -R 4 is -CH3.

[0939] In the context of formula (X) only, the terms used have the following meanings:

[0940] The term "alkyl" refers to a straight chain, branched chain, or cyclic saturated hydrocarbon group of 1-20, 1-12, 1-8, 1-6, or 1-4 carbon atoms. In certain embodiments, the alkyl group is straight chain or branched chain. Examples of straight chain or branched chain alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl. In certain embodiments, the alkyl group is cyclic. Examples of cyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentadienyl, and cyclohexyl.

[0941] The term "alkoxy" refers to an alkyl group bonded to oxygen and includes methoxy, ethoxy, isopropoxy, cyclopropyloxy, and cyclobutyloxy.

[0942] The term "alkenyl" refers to a non-aromatic, unsaturated hydrocarbon having a carbon-carbon double bond and 2-20, 2-12, 2-8, 2-6, or 2-4 carbon atoms.

[0943] The term "alkynyl" refers to a non-aromatic, unsaturated hydrocarbon having a carbon-carbon triple bond and 2-20, 2-12, 2-8, 2-6, or 2-4 carbon atoms.

[0944] The term "aryl" refers to an aromatic hydrocarbon group of 6 to 18 carbon atoms, preferably 6 to 10 carbon atoms, including groups such as phenyl, naphthyl, and anthracenyl. The term "heteroaryl" refers to an aromatic ring containing 3 to 15 carbon atoms, containing at least one nitrogen, oxygen, or sulfur atom; preferably containing 3 to 7 carbon atoms, containing at least one nitrogen, oxygen, or sulfur atom, including groups such as pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, indolyl, and indenyl.

[0945] In certain embodiments, the alkenyl, alkynyl, aryl, or heteroaryl moiety can be coupled to the remainder of the molecule through an alkyl linkage. In those cases, the substituent is referred to as an alkenylalkyl, alkynylalkyl, arylalkyl, or heteroarylalkyl group, indicating that the alkylene moiety is between the alkenyl, alkynyl, aryl, or heteroaryl moiety and the molecule to which the alkenyl, alkynyl, aryl, or heteroaryl group is coupled.

[0946] The term "halogen" or "halo" refers to bromine, fluorine, chlorine and iodine.

[0947] The term "heterocycle" or "heterocyclyl" refers to a 3- to 15-membered aromatic or non-aromatic ring containing at least one N, O, or S atom. Examples include piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, and tetrahydrofuranyl, as well as the exemplary groups provided above for the term "heteroaryl." In certain embodiments, the heterocycle or heterocyclyl is non-aromatic. In certain embodiments, the heterocycle or heterocyclyl is aromatic.

[0948] The term "optionally substituted" means that the group may be unsubstituted or substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents, which may be the same or different. Examples of substituents include alkyl, alkenyl, alkynyl, halogen, -CN, -OR aa 、-SR aa 、-NR aa R bb 、-NO2、-C=NH(OR aa ),-C(O)R aa 、-OC(O)R aa 、-C(O)OR aa 、-C(O)NR aa R bb 、-OC(O)NR aa R bb 、-NR aa C(O)R bb 、-NR aa C(O)OR bb 、-S(O)R aa 、-S(O)2R aa 、-NR aa S(O)R bb 、-C(O)NR aa S(O)R bb 、-NR aa S(O)2R bb 、-C(O)NR aa S(O)2R bb 、-S(O)NR aa R bb 、-S(O)2NR aa R bb 、-P(O)(OR aa )(OR bb ), heterocyclyl, heteroaryl or aryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl and aryl are each independently optionally replaced by -R cc Substitution, where -R aa and -R bb are each independently -H, alkyl, alkenyl, alkynyl, heterocyclyl, heteroaryl or aryl, or -R aa and -R bb Together with the nitrogen atom to which they are attached, they form a heterocyclic group, which is optionally substituted with alkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy or -CN, and wherein: -R cc Each is independently alkyl, alkenyl, alkynyl, halogen, heterocyclyl, heteroaryl, aryl, -CN or -NO2.

[0949] In certain embodiments, -L 1- has a structure as disclosed in the formula of WO2021 / 242756A1. Therefore, in certain embodiments, the moiety -L 1 - having formula (XIIa):

[0950]

[0951] in

[0952] Unlabeled dashed lines indicate connections to -D-;

[0953] The dashed line marked with an asterisk indicates the connection to -L 2 -;

[0954] -R 2 、-R 4 and -R 8 Independently selected from -H or C 1-4 alkyl;

[0955] -R 3 C 1-4 Alkyl, or -R 3 and -R 4 together with the atoms to which they are attached, form a 5- or 6-membered heterocyclic ring;

[0956] -R 5 is -NH2;

[0957] The condition is that when -R 4 and -R 3 When -R is taken together with the atoms to which it is attached to form a 5- or 6-membered heterocyclic ring, 2 is not -H; and

[0958] wherein -L of formula (XIIa) 1 - is optionally substituted.

[0959] In certain embodiments, -R 4 and -R 8 Both are -H.

[0960] In certain embodiments, -R 3 In certain embodiments, -R 3 is -H.

[0961] In certain embodiments, -R 2 is -H.

[0962] In certain embodiments, -L 1 -having formula (XIIa-i)

[0963]

[0964] The unlabeled dashed line indicates connection to -D-; and

[0965] The dashed line marked with an asterisk indicates the connection to -L 2 -.

[0966] In certain embodiments, -L 1 -having formula (XIIa-ii)

[0967]

[0968] The unlabeled dashed line indicates connection to -D-; and

[0969] The dashed line marked with an asterisk indicates the connection to -L 2 -.

[0970] In certain embodiments, -L 1 -having formula (XIIa-iii)

[0971]

[0972] The unlabeled dashed line indicates connection to -D-; and

[0973] The dashed line marked with an asterisk indicates the connection to -L 2 -.

[0974] In certain embodiments, -L 1 - has a structure as disclosed in Formula II of WO2022 / 096636A1. Thus, in certain embodiments, the moiety -L 1 - having formula (XIIb):

[0975]

[0976] in

[0977] The unlabeled dashed line indicates connection to -D-; and

[0978] The dashed line marked with an asterisk indicates the connection to -L 2 -.

[0979] In certain embodiments, -L 2 -does not exist.

[0980] In certain embodiments, -L 2 - is a spacer moiety, in particular a group selected from the group consisting of: -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y1 )-、-S(O)2N(R y1 )-、-S(O)N(R y1 )-、-S(O)2-、-S(O)-、-N(Ry1 )S(O)2N(R y1a )-、-S-、-N(R y1 )-、-OC(OR y1 )(R y1a )-、-N(R y1 )C(O)N(R y1a )-、-OC(O)N(R y1 )-、C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkynyl; wherein -T-, C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkynyl groups are optionally substituted with one or more -R y2 substituted, and wherein C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 The alkynyl group is optionally separated by one or more groups selected from -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y3 )-、-S(O)2N(R y3 )-、-S(O)N(R y3 )-、-S(O)2-、-S(O)-、-N(R y3 )S(O)2N(R y3a )-、-S-、-N(R y3 )-、-OC(OR y3 )(R y3a )-、-N(R y3 )C(O)N(R y3a )-and-OC(O)N(R y3 )-;

[0981] -R y1 and -R y1a are independently selected from -H, -T, C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkynyl; wherein -T, C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkynyl groups are optionally substituted with one or more -R y2 substituted, and wherein C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 The alkynyl group is optionally separated by one or more groups selected from -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y4 )-、-S(O)2N(Ry4 )-、-S(O)N(R y4 )-、-S(O)2-、-S(O)-、-N(R y4 )S(O)2N(R y4a )-、-S-、-N(R y4 )-、-OC(OR y4 )(R y4a )-、-N(R y4 )C(O)N(R y4a )-and-OC(O)N(R y4 )-;

[0982] T is independently selected from phenyl, naphthyl, indenyl, dihydroindenyl, tetrahydronaphthyl, 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 replaced by one or more -R which may be the same or different y2 replace;

[0983] -R y2 Each independently selected from halogen, -CN, oxo (=O), -COOR y5 、-OR y5 、-C(O)R y5 、-C(O)N(R y5 R y5a )、-S(O)2N(R y5 R y5a )、-S(O)N(R y5 R y5a )、-S(O)2R y5 、-S(O)R y5 、-N(R y5 )S(O)2N(R y5a R y5b ),-SR y5 、-N(R y5 R y5a )、-NO2、-OC(O)R y5 、-N(R y5 )C(O)R y5a 、-N(R y5 )S(O)2R y5a 、-N(R y5 )S(O)R y5a 、-N(R y5 )C(O)OR y5a 、-N(R y5 )C(O)N(R y5a R y5b )、-OC(O)N(Ry5 R y5a ) and C 1-6 Alkyl; among which C 1-6 The alkyl group is optionally substituted with one or more halogen groups which may be the same or different; and

[0984] -R y3 、-R y3a 、-R y4 、-R y4a 、-R y5 、-R y5a and -R y5b are each independently selected from -H and C 1-6 Alkyl, where C 1-6 The alkyl group is optionally substituted with one or more halogens which may be the same or different.

[0985] In certain embodiments, -L 2 - is selected from -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y1 )-、-S(O)2N(R y1 )-、-S(O)N(R y1 )-、-S(O)2-、-S(O)-、-N(R y1 )S(O)2N(R y1a )-、-S-、-N(R y1 )-、-OC(OR y1 )(R y1a )-、-N(R y1 )C(O)N(R y1a )-、-OC(O)N(R y1 )-、C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkynyl; wherein -T-, C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20 Alkynyl groups are optionally substituted with one or more -R y2 substituted, and wherein C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20 The alkynyl group is optionally separated by one or more groups selected from -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y3 )-、-S(O)2N(R y3 )-、-S(O)N(R y3 )-、-S(O)2-、-S(O)-、-N(R y3 )S(O)2N(R y3a )-、-S-、-N(Ry3 )-、-OC(OR y3 )(R y3a )-、-N(R y3 )C(O)N(R y3a )-and-OC(O)N(R y3 )-;

[0986] -R y1 and -R y1a are independently selected from -H, -T, C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynyl; wherein -T, C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynyl groups are optionally substituted with one or more -R y2 substituted, and wherein C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 The alkynyl group is optionally separated by one or more groups selected from -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y4 )-、-S(O)2N(R y4 )-、-S(O)N(R y4 )-、-S(O)2-、-S(O)-、-N(R y4 )S(O)2N(R y4a )-、-S-、-N(R y4 )-、-OC(OR y4 )(R y4a )-、-N(R y4 )C(O)N(R y4a )-and-OC(O)N(R y4 )-;

[0987] T is independently selected from phenyl, naphthyl, indenyl, dihydroindenyl, tetrahydronaphthyl, 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 replaced by one or more -R which may be the same or different y2 replace;

[0988] -R y2 Selected from halogen, -CN, oxo (=O), -COOR y5 、-OR y5 、-C(O)R y5 、-C(O)N(R y5 R y5a )、-S(O)2N(Ry5 R y5a )、-S(O)N(R y5 R y5a )、-S(O)2R y5 、-S(O)R y5 、-N(R y5 )S(O)2N(R y5a R y5b ),-SR y5 、-N(R y5 R y5a )、-NO2、-OC(O)R y5 、-N(R y5 )C(O)R y5a 、-N(R y5 )S(O)2R y5a 、-N(R y5 )S(O)R y5a 、-N(R y5 )C(O)OR y5a 、-N(R y5 )C(O)N(R y5a R y5b )、-OC(O)N(R y5 R y5a ) and C 1-6 Alkyl; among which C 1-6 The alkyl group is optionally substituted with one or more halogen groups which may be the same or different; and

[0989] -R y3 、-R y3a 、-R y4 、-R y4a 、-R y5 、-R y5a and -R y5b Each independently selected from -H and C 1-6 Alkyl; among which C 1-6 The alkyl group is optionally substituted with one or more halogens which may be the same or different.

[0990] In certain embodiments, -L 2 - is selected from -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y1 )-、-S(O)2N(R y1 )-、-S(O)N(R y1 )-、-S(O)2-、-S(O)-、-N(R y1 )S(O)2N(R y1a )-、-S-、-N(R y1 )-、-OC(OR y1 )(Ry1a )-、-N(R y1 )C(O)N(R y1a )-、-OC(O)N(R y1 )-、C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkynyl; wherein -T-, C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkynyl groups are optionally substituted with one or more -R y2 substituted, and wherein C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 The alkynyl group is optionally separated by one or more groups selected from -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y3 )-、-S(O)2N(R y3 )-、-S(O)N(R y3 )-、-S(O)2-、-S(O)-、-N(R y3 )S(O)2N(R y3a )-、-S-、-N(R y3 )-、-OC(OR y3 )(R y3a )-、-N(R y3 )C(O)N(R y3a )-and-OC(O)N(R y3 )-;

[0991] -R y1 and -R y1a Independently selected from -H, -T, C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynyl;

[0992] T is independently selected from phenyl, naphthyl, indenyl, dihydroindenyl, tetrahydronaphthyl, 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;

[0993] -R y2 are each independently selected from halogen and C 1-6 alkyl; and

[0994] -R y3 、-R y3a 、-R y4 、-R y4a 、-R y5 、-R y5a and -Ry5b Each independently selected from -H and C 1-6 Alkyl; among which C 1-6 The alkyl group is optionally substituted with one or more halogens which may be the same or different.

[0995] In certain embodiments, -L 2 - for C 1-20 Alkyl chains, optionally separated by one or more groups independently selected from -O-, -S-, -T- and -C(O)N(R y1 )-; and said C 1-20 The alkyl chain is optionally substituted with one or more groups independently selected from -OH, -T and -C(O)N(R y6 R y6a ); where -R y1 、-R y6 、-R y6a Independently selected from H and C 1-4 Alkyl, and wherein T is selected from phenyl, naphthyl, indenyl, dihydroindenyl, tetrahydronaphthyl, 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.

[0996] In certain embodiments, -L 2 -Has a molecular weight of 14 g / mol to 750 g / mol.

[0997] In certain embodiments, -L 2 -Contains a selection of

[0998]

[0999]

[1000] in

[1001] -R and -R a are independently selected from -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.

[1002] In certain embodiments, -L 2 - has a chain length of 1 to 20 atoms. In certain embodiments, -L 2 -Has a chain length of 2-10 atoms.

[1003] In certain embodiments, -L 2- has a chain length of at least 35 atoms. In certain embodiments, -L 2 - has a chain length of at least 50 atoms. In certain embodiments, -L 2 - has a chain length of at least 75 atoms. In certain embodiments, -L 2 - has a chain length of at least 100 atoms. In certain embodiments, -L 2 - has a chain length of at least 150 atoms. In certain embodiments, -L 2 - has a chain length of at least 200 atoms. In certain embodiments, -L 2 - has a chain length of at least 250 atoms. In certain embodiments, -L 2 - has a chain length of at least 300 atoms. In certain embodiments, -L 2 - has a chain length of up to 3000 atoms. In certain embodiments, -L 2 - has a chain length of up to 2500 atoms. In certain embodiments, -L 2 - has a chain length of up to 2000 atoms. In certain embodiments, -L 2 - has a chain length of up to 1500 atoms. In certain embodiments, -L 2 - has a chain length of 35 to 3000 atoms. In certain embodiments, -L 2 - has a chain length of 50 to 2500 atoms. In certain embodiments, -L 2 - has a chain length of 75 to 2000 atoms. In certain embodiments, -L 2 - has a chain length of 100-1500 atoms. In certain embodiments, -L 2 -Has a chain length of 125-1000 atoms.

[1004] In certain embodiments, -L 2 - having formula (XI)

[1005]

[1006] in

[1007] The unmarked dashed line indicates the connection to -L 1 -;

[1008] The dashed line marked with an asterisk indicates the connection to -AB 1 ;

[1009] h is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16.

[1010] In certain embodiments, -L2 - has formula (XI), and h is 1. In certain embodiments, -L 2 - has formula (XI), and h is 2. In certain embodiments, -L 2 - has formula (XI), and h is 3. In certain embodiments, -L 2 - has formula (XI), and h is 4. In certain embodiments, -L 2 - has formula (XI), and h is 5. In certain embodiments, -L 2 - has formula (XI), and h is 6. In certain embodiments, -L 2 - has formula (XI), and h is 7. In certain embodiments, -L 2 - has formula (XI), and h is 8. In certain embodiments, -L 2 - has formula (XI), and h is 9. In certain embodiments, -L 2 - has formula (XI), and h is 10. In certain embodiments, -L 2 - has formula (XI), and h is 11. In certain embodiments, -L 2 - has formula (XI), and h is 12. In certain embodiments, -L 2 - has formula (XI), and h is 13. In certain embodiments, -L 2 - has formula (XI), and h is 14. In certain embodiments, -L 2 - has the formula (XI), and h is 15.

[1011] In certain embodiments, -L 2 - has a molecular weight of at least 450 Da. In certain embodiments, -L 2 - has a molecular weight of at least 1 kDa. In certain embodiments, -L 2 - has a molecular weight of at least 1.5 kDa. In certain embodiments, -L 2 - has a molecular weight of at least 2 kDa. In certain embodiments, -L 2 - has a molecular weight of at least 2.5 kDa. In certain embodiments, -L 2 - has a molecular weight of at least 3 kDa. In certain embodiments, -L 2 - has a molecular weight of at least 3.5 kDa. In certain embodiments, -L 2 - has a molecular weight of at least 4 kDa. In certain embodiments, -L 2 - has a molecular weight of at least 5 kDa. In certain embodiments, -L 2 - has a maximum molecular weight of 160 kDa. In certain embodiments, -L 2- has a maximum molecular weight of 120 kDa. In certain embodiments, -L 2 - has a maximum molecular weight of 100 kDa. In certain embodiments, -L 2 - has a maximum molecular weight of 80 kDa. In certain embodiments, -L 2 - has a maximum molecular weight of 70 kDa. In certain embodiments, -L 2 - has a maximum molecular weight of 60 kDa. In certain embodiments, -L 2 - has a maximum molecular weight of 50 kDa. In certain embodiments, -L 2 - has a maximum molecular weight of 40 kDa. In certain embodiments, -L 2 - has a molecular weight of about 450 Da. In certain embodiments, -L 2 - has a molecular weight of about 1 kDa. In certain embodiments, -L 2 - has a molecular weight of about 1.5 kDa. In certain embodiments, -L 2 - has a molecular weight of about 2 kDa. In certain embodiments, -L 2 - has a molecular weight of about 2.5 kDa. In certain embodiments, -L 2 - has a molecular weight of about 3 kDa. In certain embodiments, -L 2 - has a molecular weight of about 3.5 kDa. In certain embodiments, -L 2 - has a molecular weight of about 4 kDa. In certain embodiments, -L 2 - has a molecular weight of about 4.5 kDa. In certain embodiments, -L 2 - has a molecular weight of about 5 kDa. In certain embodiments, -L 2 - has a molecular weight of about 5.5 kDa. In certain embodiments, -L 2 - has a molecular weight of about 6 kDa. In certain embodiments, -L 2 - has a molecular weight of about 6.5 kDa. In certain embodiments, -L 2 - has a molecular weight of about 7 kDa. In certain embodiments, -L 2 - has a molecular weight of about 7.5 kDa. In certain embodiments, -L 2 - has a molecular weight of about 8 kDa. In certain embodiments, -L 2 - has a molecular weight of about 8.5 kDa. In certain embodiments, -L 2 - has a molecular weight of about 9 kDa. In certain embodiments, -L 2 - has a molecular weight of about 9.5 kDa. In certain embodiments, -L 2- has a molecular weight of approximately 10 kDa.

[1012] In certain embodiments, -L 2 - contains a polymeric moiety, means that it contains at least one polymeric moiety. It should be understood that if -L 2 - contains one polymer portion, the minimum and maximum molecular weights provided above apply to this polymer portion, and if -L 2 - contains more than one polymer portion, the minimum and maximum molecular weights provided above refer to the minimum and maximum molecular weights common to all polymer portions.

[1013] In certain embodiments, -L 2 -One or more polymer moieties of the invention have a Flory radius of at least 1.2 nm. In certain embodiments, -L 2 -One or more polymer moieties of the invention have a Flory radius of at least 1.5 nm. In certain embodiments, -L 2 -One or more polymer moieties have a Flory radius of at least 2 nm. In certain embodiments, -L 2 -One or more polymer moieties have a Flory radius of at least 2.5 nm. In certain embodiments, -L 2 -One or more polymer moieties have a Flory radius of at least 3 nm. In certain embodiments, -L 2 -one or more polymer moieties have a Flory radius of at least 3.5 nm. In certain embodiments, -L 2 -one or more polymer moieties have a Flory radius of at least 4 nm. In certain embodiments, -L 2 -one or more polymer moieties have a Flory radius of at least 4.5 nm. In certain embodiments, -L 2 -one or more polymer moieties have a Flory radius of at least 5 nm. In certain embodiments, -L 2 -One or more polymer moieties have a Flory radius of no more than 200 nm. In certain embodiments, -L 2 -One or more polymer moieties have a Flory radius of no more than 175 nm. In certain embodiments, -L 2 -One or more polymer moieties have a Flory radius of no more than 150 nm. In certain embodiments, -L 2 -One or more polymer moieties have a Flory radius of no more than 125 nm. In certain embodiments, -L 2-One or more polymer moieties have a Flory radius of no more than 100 nm. In certain embodiments, -L 2 -One or more polymer moieties have a Flory radius of no more than 75 nm. In certain embodiments, -L 2 -One or more polymer moieties of the invention have a Flory radius of no more than 50 nm. In certain embodiments, -L 2 -One or more polymer moieties have a Flory radius of no more than 45 nm. In certain embodiments, -L 2 -One or more polymer moieties of the invention have a Flory radius of no more than 40 nm. In certain embodiments, -L 2 -One or more polymer moieties of the invention have a Flory radius of no more than 35 nm. In certain embodiments, -L 2 -One or more polymer moieties have a Flory radius of no more than 30 nm. In certain embodiments, -L 2 -One or more polymer moieties of - have a Flory radius of about 1.2 nm. In certain embodiments, -L 2 -One or more polymer moieties of - have a Flory radius of about 1.5 nm. In certain embodiments, -L 2 -One or more polymer moieties of - have a Flory radius of about 2 nm. In certain embodiments, -L 2 -One or more polymer moieties of - have a Flory radius of about 2.5 nm. In certain embodiments, -L 2 -One or more polymer moieties of the - have a Flory radius of about 3 nm. In certain embodiments, -L 2 -One or more polymer moieties of - have a Flory radius of about 3.5 nm. In certain embodiments, -L 2 -One or more polymer moieties of - have a Flory radius of about 4 nm. In certain embodiments, -L 2 -One or more polymer moieties of - have a Flory radius of about 4.5 nm. In certain embodiments, -L 2 -One or more polymer moieties of - have a Flory radius of about 5 nm. In certain embodiments, -L 2 -One or more polymer moieties of - have a Flory radius of about 5.5 nm. In certain embodiments, -L 2 -One or more polymer moieties of the - have a Flory radius of about 6 nm. In certain embodiments, -L 2 -One or more polymer moieties of - have a Flory radius of about 6.5 nm. In certain embodiments, -L2 -One or more polymer moieties of have a Flory radius of about 7 nm. In certain embodiments, -L 2 - one or more polymer moieties have a Flory radius of about 8.5 nm. In certain embodiments, -L 2 -One or more polymer moieties of - have a Flory radius of about 9 nm. In certain embodiments, -L 2 - has a Flory radius of about 10 nm. It will be understood that if -L 2 - contains a polymer part, then the Flory radius provided above applies to this polymer part, and if -L 2 - comprises more than one polymer portion, the Flory radius provided above refers to the common Flory radius of all polymer portions.

[1014] -L 2 - comprising one or more polymeric moieties, for example, a polymeric moiety selected from the group consisting of poly(2-methacryloyloxyethylphosphorylcholine), poly(acrylic acid), poly(acrylates), poly(acrylamides), poly(alkoxy) polymers, poly(amides), poly(amidoamines), poly(amino acids), poly(anhydrides), poly(asparagine), poly(butyric acid), poly(glycolic acid), polybutylene terephthalate, poly(caprolactone), poly(carbonates), poly(cyanoacrylates), poly(dimethylacrylamide), poly(esters), poly(ethylene), poly(ethylene glycol), poly(ethylene oxide), poly(ethyl phosphate), poly(ethyloxazoline), poly(glycolic acid), poly(hydroxyethyl acrylate), poly(hydroxyethyl-oxazoline), poly(hydroxymethacrylate), poly(hydroxypropyl methacrylamide), poly(methyl methacrylate),

[0014] Examples of the present invention include polyols, e.g., oligosaccharides, oligosaccharides, oligosaccharides (e.g., oligoacrylic acid), oligosaccharides (e.g., oligoacrylic acid), oligosaccharides (e.g., oligoacrylic acid), oligosaccharides (e.g., oligoacrylic acid), oligosaccharides (e.g., oligoacrylic acid), oligosaccharides (e.g., oligoacrylic acid), oligosaccharides (e.g., oligoacrylic acid), oligosaccharides (e.g., oligoacrylic acid), oligosaccharides (e.g., oligoacrylic acid), oligosaccharides (e.g., oligoacrylic acid), oligosaccharides (e.g., oligoacrylic acid), oligosaccharides (e.g., oligoacrylic acid), oligosaccharides (e.g., oligosaccharides), ...

[1015] In certain embodiments, -L 2 - comprises a PEG-based polymer. In certain embodiments, -L 2- comprises a hyaluronic acid-based polymer. In certain embodiments, -L 2 - comprises a random coil polymer. In certain embodiments, -L 2 - Contains a poly-sarcosine polymer.

[1016] In certain embodiments, -L 2 - having formula (XII)

[1017]

[1018] in

[1019] -X 1 -and-X 2 - independently selected from -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y1 )-、-S(O)2N(R y1 )-、-S(O)N(R y1 )-、-S(O)2-、-S(O)-、-N(R y1 )S(O)2N(R y1a )-、-S-、-N(R y1 )-、-OC(OR y1 )(R y1a )-、-N(R y1 )C(O)N(R y1a )-、-OC(O)N(R y1 )-、C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20 Alkynyl; wherein -T-, C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20 Alkynyl groups are optionally substituted with one or more -R y2 substituted, and wherein C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20 The alkynyl group is optionally separated by one or more groups selected from -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y3 )-、-S(O)2N(R y3 )-、-S(O)N(R y3 )-、-S(O)2-、-S(O)-、-N(R y3 )S(O)2N(R y3a )-、-S-、-N(R y3 )-、-OC(OR y3 )(R y3a )-、-N(Ry3 )C(O)N(R y3a )-and-OC(O)N(R y3 )-;

[1020] -R y1 and -R y1a are independently selected from -H, -T, C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynyl; wherein -T, C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynyl groups are optionally substituted with one or more -R y2 substituted, and wherein C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 The alkynyl group is optionally separated by one or more groups selected from -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y4 )-、-S(O)2N(R y4 )-、-S(O)N(R y4 )-、-S(O)2-、-S(O)-、-N(R y4 )S(O)2N(R y4a )-、-S-、-N(R y4 )-、-OC(OR y4 )(R y4a )-、-N(R y4 )C(O)N(R y4a )-and-OC(O)N(R y4 )-;

[1021] T is independently selected from phenyl, naphthyl, indenyl, dihydroindenyl, tetrahydronaphthyl, 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 replaced by one or more -R which may be the same or different y2 replace;

[1022] -R y2 Selected from halogen, -CN, oxo (=O), -COOR y5 、-OR y5 、-C(O)R y5 、-C(O)N(R y5 R y5a )、-S(O)2N(R y5 R y5a )、-S(O)N(R y5 R y5a)、-S(O)2R y5 、-S(O)R y5 、-N(R y5 )S(O)2N(R y5a R y5b ),-SR y5 、-N(R y5 R y5a )、-NO2、-OC(O)R y5 、-N(R y5 )C(O)R y5a 、-N(R y5 )S(O)2R y5a 、-N(R y5 )S(O)R y5a 、-N(R y5 )C(O)OR y5a 、-N(R y5 )C(O)N(R y5a R y5b )、-OC(O)N(R y5 R y5a ) and C 1-6 Alkyl; among which C 1-6 The alkyl group is optionally substituted with one or more halogens which may be the same or different;

[1023] -R y3 、-R y3a 、-R y4 、-R y4a 、-R y5 、-R y5a and -R y5b Each independently selected from -H and C 1-6 Alkyl; among which C 1-6 The alkyl group is optionally substituted with one or more halogen groups which may be the same or different; and

[1024] -POL- is the polymerizing part.

[1025] In certain embodiments, -X of formula (XII) 1 -and-X 2 - independently selected from C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20 Alkynyl; wherein -T-, C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20 Alkynyl groups are optionally substituted with one or more -R y2 substituted, and wherein C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20The alkynyl group is optionally separated by one or more groups selected from -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y3 )-、-S-、-N(R y3 )-、-OC(OR y3 )(R y3a )-、-N(R y3 )C(O)N(R y3a )-and-OC(O)N(R y3 )-;

[1026] T is independently selected from phenyl, naphthyl, indenyl, dihydroindenyl, tetrahydronaphthyl, C 3-10 Cycloalkyl and 3 to 10 membered heterocyclyl; wherein each T is independently optionally replaced by one or more -R which may be the same or different y2 replace;

[1027] -R y2 Selected from halogen, -CN, oxo (=O) and C 1-6 Alkyl; among which C 1-6 The alkyl group is optionally substituted with one or more halogen groups which may be the same or different; and

[1028] -R y3 、-R y3a 、-R y4 、-R y4a 、-R y5 、-R y5a and -R y5b Each independently selected from -H and C 1-6 Alkyl; among which C 1-6 The alkyl group is optionally substituted with one or more halogens which may be the same or different.

[1029] In certain embodiments, -POL- of formula (XII) has the formula (XII-i)

[1030]

[1031] in

[1032] y is an integer in the range of 2-1000.

[1033] In certain embodiments, y of formula (XII-i) is selected such that the molecular weight of the moiety of formula (XII-i) is about 1 kDa. In certain embodiments, y of formula (XII-i) is selected such that the molecular weight of the moiety of formula (XII-i) is about 2 kDa. In certain embodiments, y of formula (XII-i) is selected such that the molecular weight of the moiety of formula (XII-i) is about 3 kDa. In certain embodiments, y of formula (XII-i) is selected such that the molecular weight of the moiety of formula (XII-i) is about 4 kDa. In certain embodiments, y of formula (XII-i) is selected such that the molecular weight of the moiety of formula (XII-i) is about 5 kDa. In certain embodiments, y of formula (XII-i) is selected such that the molecular weight of the moiety of formula (XII-i) is about 6 kDa. In certain embodiments, y of formula (XII-i) is selected such that the molecular weight of the moiety of formula (XII-i) is about 7 kDa. In certain embodiments, y of formula (XII-i) is selected such that the molecular weight of the moiety of formula (XII-i) is about 8 kDa. In certain embodiments, y of formula (XII-i) is selected such that the molecular weight of the moiety of formula (XII-i) is about 9 kDa. In certain embodiments, y of formula (XII-i) is selected such that the molecular weight of the moiety of formula (XII-i) is about 10 kDa. In certain embodiments, y of formula (XII-i) is selected such that the molecular weight of the moiety of formula (XII-i) is about 11 kDa. In certain embodiments, y of formula (XII-i) is selected such that the molecular weight of the moiety of formula (XII-i) is about 12 kDa. In certain embodiments, y of formula (XII-i) is selected such that the molecular weight of the moiety of formula (XII-i) is about 13 kDa. In certain embodiments, y of formula (XII-i) is selected such that the molecular weight of the moiety of formula (XII-i) is about 14 kDa. In certain embodiments, y of formula (XII-i) is selected such that the molecular weight of the moiety of formula (XII-i) is about 15 kDa. In certain embodiments, y of formula (XII-i) is selected such that the molecular weight of the moiety of formula (XII-i) is about 20 kDa. In certain embodiments, y of formula (XII-i) is selected such that the molecular weight of the moiety of formula (XII-i) is about 25 kDa. In certain embodiments, y of formula (XII-i) is selected such that the molecular weight of the moiety of formula (XII-i) is about 30 kDa. In certain embodiments, y of formula (XII-i) is selected such that the molecular weight of the moiety of formula (XII-i) is about 40 kDa.

[1034] In certain embodiments, y of formula (XII-i) is 2. In certain embodiments, y of formula (XII-i) is about 22. In certain embodiments, y of formula (XII-i) is about 45. In certain embodiments, y of formula (XII-i) is about 68. In certain embodiments, y of formula (XII-i) is about 91. In certain embodiments, y of formula (XII-i) is about 113. In certain embodiments, y of formula (XII-i) is about 136. In certain embodiments, y of formula (XII-i) is about 160. In certain embodiments, y of formula (XII-i) is about 182. In certain embodiments, y of formula (XII-i) is about 204. In certain embodiments, y of formula (XII-i) is about 227. In certain embodiments, y of formula (XII-i) is about 250. In certain embodiments, y of formula (XII-i) is about 340. In certain embodiments, y of formula (XII-i) is about 455. In certain embodiments, y of Formula (XII-i) is about 910.

[1035] In certain embodiments, -L 2 -having formula (XII-ii)

[1036]

[1037] in

[1038] The dashed line marked with an asterisk indicates the connection to -L 1 -;

[1039] The unlabeled dashed line indicates the connection to -AB 1 ;

[1040] a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15;

[1041] b is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15;

[1042] c is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15;

[1043] The range of x is 2-1000;

[1044] -R 1 and -R 2 are independently selected from -H and C 1-6 alkyl.

[1045] In certain embodiments, x of formula (XII-ii) is 2. In certain embodiments, x of formula (XII-ii) is about 22. In certain embodiments, x of formula (XII-ii) is about 45. In certain embodiments, x of formula (XII-ii) is about 68. In certain embodiments, x of formula (XII-ii) is about 91. In certain embodiments, x of formula (XII-ii) is about 113. In certain embodiments, x of formula (XII-ii) is about 136. In certain embodiments, x of formula (XII-ii) is about 160. In certain embodiments, x of formula (XII-ii) is about 182. In certain embodiments, x of formula (XII-ii) is about 204. In certain embodiments, x of formula (XII-ii) is about 227. In certain embodiments, x of formula (XII-ii) is about 250. In certain embodiments, x of formula (XII-ii) is about 340. In certain embodiments, x of formula (XII-ii) is about 455. In certain embodiments, x of Formula (XII-ii) is about 910.

[1046] In certain embodiments, a of formula (XII-ii) is 5, b of formula (XII-ii) is 2, c of formula (XII-ii) is 2, and -R 1 and -R 2 All are -H.

[1047] In certain embodiments, the albumin binding portion of the compounds disclosed herein binds to one albumin, for example via different binding domains. Suitably, the albumin binding portion of the compounds disclosed herein binds to at least two albumins, for example two albumins.

[1048] In certain embodiments, -L 1 -L 2 -Selected

[1049]

[1050] in

[1051] The dashed line marked with an asterisk represents the nitrogen attached to -D-; and

[1052] The unlabeled dashed line indicates the connection to -AB 1 .

[1053] In certain embodiments, -L 1 -L 2 - has formula (XIa). In certain embodiments, -L 1 -L 2 - has formula (XIb). In certain embodiments, -L 1-L 2 - has formula (XIc). In certain embodiments, -L 1 -L 2 - has formula (XId). In certain embodiments, -L 1 -L 2 - has formula (XIe). In certain embodiments, -L 1 -L 2 -having the formula (XIf).

[1054] In certain embodiments, -L 1 -L 2 -Selected

[1055]

[1056] in

[1057] The dashed line marked with an asterisk represents the nitrogen attached to -D-; and

[1058] The unlabeled dashed line indicates the connection to -AB 1 .

[1059] In certain embodiments, -L 1 -L 2 - has the formula (Xia'). In certain embodiments, -L 1 -L 2 - has formula (XIb'). In certain embodiments, -L 1 -L 2 - has the formula (XIc'). In certain embodiments, -L 1 -L 2 - has the formula (XId'). In certain embodiments, -L 1 -L 2 - has the formula (XIe'). In certain embodiments, -L 1 -L 2 -having the formula (XIf').

[1060] In certain embodiments, -L 1 -L 2 -Selected

[1061]

[1062] in

[1063] The dashed line marked with an asterisk represents the nitrogen attached to -D-; and

[1064] The unlabeled dashed line indicates the connection to -AB 1 .

[1065] In certain embodiments, -L 1 -L 2 - has the formula (Xia"). In certain embodiments, -L 1 -L 2 - has formula (XIb"). In certain embodiments, -L 1 -L 2 - has the formula (XIc"). In certain embodiments, -L 1 -L 2 - has the formula (XId"). In certain embodiments, -L 1 -L 2 - has formula (XIe"). In certain embodiments, -L 1 -L 2 -having the formula (XIf').

[1066] In certain embodiments, -L 1 -L 2 -Selected

[1067]

[1068]

[1069] in

[1070] The dashed line marked with an asterisk represents the nitrogen attached to -D-; and

[1071] The unlabeled dashed line indicates the connection to -AB 1 .

[1072] In certain embodiments, -L 1 -L 2 - has formula (XIg). In certain embodiments, -L 1 -L 2 - has formula (XIh). In certain embodiments, -L 1 -L 2 - has formula (XIi). In certain embodiments, -L 1 -L 2 - has formula (XIj). In certain embodiments, -L 1 -L 2 - has formula (XIk). In certain embodiments, -L 1 -L 2 - having the formula (XI1).

[1073] In certain embodiments, -L 1 -L 2 -Selected

[1074]

[1075]

[1076] in

[1077] The dashed line marked with an asterisk represents the nitrogen attached to -D-; and

[1078] The unlabeled dashed line indicates the connection to -AB 1 .

[1079] In certain embodiments, -L 1 -L 2 - has the formula (XIg'). In certain embodiments, -L 1 -L 2 - has the formula (XIh'). In certain embodiments, -L 1 -L 2 - has formula (XIi'). In certain embodiments, -L 1 -L 2 - has the formula (XIj'). In certain embodiments, -L 1 -L 2 - has the formula (XIk'). In certain embodiments, -L 1 -L 2 - having the formula (XI1').

[1080] In certain embodiments, -L 1 -L 2 -Selected

[1081]

[1082]

[1083] in

[1084] The dashed line marked with an asterisk represents the nitrogen attached to -D-; and

[1085] The unlabeled dashed line indicates the connection to -AB 1 .

[1086] In certain embodiments, -L 1 -L 2 - has the formula (XIg"). In certain embodiments, -L 1 -L 2 - has the formula (XIh"). In certain embodiments, -L 1 -L 2 - has formula (XIi"). In certain embodiments, -L 1 -L 2- has the formula (XIj"). In certain embodiments, -L 1 -L 2 - has the formula (XIk"). In certain embodiments, -L 1 -L 2 - having the formula (XI1").

[1087] In certain embodiments, the compound has formula (XIII)

[1088]

[1089] in

[1090] a is 14, 15, 16, 17, 18, 19, 20, 21 or 22;

[1091] n is an integer in the range of 2-1000;

[1092] The dotted line indicates the connection to the following part

[1093]

[1094] in

[1095] The unlabeled dashed line represents the connection to the dashed line in formula (XIII); and

[1096] The dashed line marked with an asterisk indicates connection to -D-.

[1097] In certain embodiments, the compound has formula (XIII), wherein a is 18, n is 2, and the dashed line marked with an asterisk represents the N-terminal amine functionality attached to semaglutide.

[1098] In certain embodiments, the compound has formula (XIII), wherein a is 16, n is 2, and the dashed line marked with an asterisk represents the N-terminal amine functionality attached to semaglutide.

[1099] In certain embodiments, the compound has formula (XIII), wherein a is 18, n is about 23, and the dashed line marked with an asterisk represents the N-terminal amine functionality attached to semaglutide.

[1100] In certain embodiments, the compound has formula (XIII), wherein a is 16, n is about 23, and the dashed line marked with an asterisk represents the N-terminal amine functionality attached to semaglutide.

[1101] In certain embodiments, the compound has formula (XIII), wherein a is 18, n is about 108, and the dashed line marked with an asterisk represents the N-terminal amine functionality attached to semaglutide.

[1102] In certain embodiments, the compound has formula (XIII), wherein a is 16, n is about 108, and the dashed line marked with an asterisk represents the N-terminal amine functionality attached to semaglutide.

[1103] In certain embodiments, moiety AB 1 -with-AB 2 The distance between the AB moieties is such that they can bind to two binding domains of different albumins or to two different binding domains of the same albumin. 1 -with-AB 2 The distance between them enables them to bind to the binding domains of two different albumins.

[1104] 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.

[1105] In another aspect, the invention relates to a compound of the invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the invention for use as a medicament, optionally in combination with one or more additional therapeutically active compounds.

[1106] The present invention also relates to a compound of the present invention or a pharmaceutically acceptable salt or pharmaceutical composition thereof for use as a medicament.

[1107] The present invention also relates to the compound of the present invention or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in preparing a medicament.

[1108] This medicine can be used to treat or prevent HD-AB 2 Diseases to be treated or prevented.

[1109] 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 the compound of the present invention for use in a method for treating or preventing a disease that can be treated with HD-AB 2 or a pharmaceutically acceptable salt thereof, optionally in combination with one or more additional therapeutically active compounds for treatment or prevention.

[1110] In another aspect, the present invention relates to a method for treating a patient with HD-AB. 2 A method for treating or preventing a disease in a patient, wherein the method comprises administering to a patient in need thereof a pharmaceutically acceptable amount of a compound of the present invention or a pharmaceutically acceptable salt or pharmaceutical composition thereof, optionally in combination with one or more additional therapeutically active compounds.

[1111] Administration of the compounds of the present invention, their pharmaceutically acceptable salts or pharmaceutical compositions can be carried out by external administration, injection or infusion, including intra-articular, peri-articular, intradermal, subcutaneous, intramuscular, intravenous, intraosseous, intraperitoneal, intrathecal, intracapsular, intraorbital, intravitreal, intratympanic, intravesical, intracardial, intratracheal, subcutaneous, subcapsular, subarachnoid, intraspinal, intraventricular, intrasternal injection and infusion; direct delivery to the brain by an implanted device (e.g., Ommaya Reservoir) that allows delivery of the present invention or analogs to brain tissue or brain fluid; direct intracerebroventricular injection or infusion, injection or infusion into the brain or brain-related areas, injection into the subchoroidal space, retro-orbital injection and eye drops. In certain embodiments, the drug is for subcutaneous injection, which can be done with a pen injector or by syringe.

[1112] Compound (wherein -D- or -D-AB 2 The invention relates to a pharmaceutical composition comprising a GLP-1 receptor agonist moiety or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound, which can be used to treat or prevent 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 disease, (vi) chronic kidney disease (CKD), (vii) diabetic nephropathy (DKD), (viii) peripheral arterial disease (PAD), and / or (ix) heart failure (HF).

[1113] Exemplary cardiovascular diseases can be selected from syndrome X, atherosclerosis, myocardial infarction, coronary heart disease, reperfusion injury, stroke, cerebral ischemia, early heart disease or early cardiovascular disease, left ventricular hypertrophy, coronary artery disease, hypertension, essential hypertension, acute hypertensive emergency, cardiomyopathy, cardiac insufficiency, exercise intolerance, acute and / or chronic heart failure, arrhythmia, arrhythmia, syncope, angina pectoris, heart bypass surgery and / or stent reocclusion, intermittent claudication (atheroschlerosis oblitterens), diastolic dysfunction and / or systolic dysfunction and hypotension, e.g., hyposystolic blood pressure.

[1114] Compound (wherein -D- or -D-AB 2The invention relates to a pharmaceutical composition comprising a compound comprising a GLP-1 receptor agonist portion thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound, which can be used to treat or prevent a disease selected from dyslipidemia and / or a disease with one or more of the following clinical outcomes as therapeutic goals: 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 humans; and inhibiting the production of apolipoprotein A (apo(A)).

[1115] Exemplary neurodegenerative diseases may be selected from Alzheimer's disease and Parkinson's disease.

[1116] Exemplary forms of HF may be selected from heart failure with reduced ejection fraction (HFrEF), heart failure with moderate ejection fraction (HFmrEF), and heart failure with preserved ejection fraction (HFpEF).

[1117] Compound (wherein -D- or -D-AB 2 The present invention relates to a pharmaceutical composition comprising a GLP-1 receptor agonist moiety or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound, which can be used to treat non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

[1118] In certain embodiments, the compound (wherein -D- or -D-AB 2 The invention relates to a pharmaceutical composition comprising a GLP-1 receptor agonist portion thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound, which can be used to treat a disease selected from obesity and eating disorders, with one or more of the following clinical outcomes as the treatment goal: reducing food intake, increasing energy expenditure, reducing body weight, suppressing appetite, and inducing satiety.

[1119] Compound (wherein -D- or -D-AB 2The compound of the present invention or its pharmaceutically acceptable salt or pharmaceutical composition comprising the compound can also be combined with one or more other drugs, for example, drugs selected from cardiovascular drugs, antidiabetic drugs and / or anti-obesity drugs. Examples of these pharmacologically active substances are: positive 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 inhibitors, relaxin, PCSK9 inhibitors, BNP and NEP inhibitors, GLP-1 analogs, insulin, sulfonylureas, biguanides, meglitinides, glucosidase inhibitors, glucagon antagonists, DPP-IV inhibitors, SGLT2 inhibitors. Treatment with the compound of the present invention or its pharmaceutically acceptable salt or pharmaceutical composition can also be combined with cardiac surgery.

[1120] The compounds of the present invention (wherein -D-AB 2 is a GLP-1 receptor agonist) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof can also be administered in combination with a growth hormone, such as human growth hormone. Such human growth hormone can be in the form of an unmodified drug (e.g., human growth hormone of SEQ ID NO: 58), or in the form of a conjugate or complex comprising human growth hormone. Suitably, the compound (wherein -D-AB 2 is a GLP-1 receptor agonist) administered to patients in co-therapy with lonapegsomatropin, which has the following structure:

[1121]

[1122] in

[1123] D is the human growth hormone polypeptide of SEQ ID NO: 58, which is linked to the rest of the molecule via the amine functionality provided by the lysine side chain; and

[1124] p1, p2, p3, and p4 are each independently an integer within the range of 210-240.

[1125] SEQ ID NO:58 has the following sequence:

[1126] FPTIPLSRLFDNAMLRAHRLHQLAFDTYQEFEEAYIPKEQKYSFLQNPQTSLCFSESIPTPSNREETQQKSNLELLRISLLLIQSWLEPVQFLRSVFANSLVYGASDSNVYDLLKDLEEGIQTLMGRLEDGSPRTGQIFKQTYSKFDTNSHNDDALLKNYGLLYCFRKDMDKVETFLRIVQCRSVEGSCGF

[1127] In such co-treatment, the compound (wherein -D-AB 2 is a GLP-1 receptor agonist).

[1128] The compound of the present invention, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, may be administered weekly, biweekly, triweekly, or monthly, for example, by subcutaneous administration.

[1129] In certain embodiments, a compound of the present invention, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, may be administered weekly, biweekly, triweekly, or monthly.

[1130] The present invention is further described by the following non-limiting items.

[1131] 1. A compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof

[1132]

[1133] in

[1134] -D- are each independently a drug moiety;

[1135] -AB 1 and-AB 2 each independently an albumin binding moiety;

[1136] -L 1 - are each independently a linker moiety that is covalently and reversibly linked to -D-;

[1137] -L 2 - are each independently a spacer or absent;

[1138] x is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, and 25; and

[1139] y is an integer selected from 2, 3, 4 and 5.

[1140] 2. The compound of item 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (Ia).

[1141] 3. The compound according to item 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X is 1.

[1142] 4. The compound or pharmaceutically acceptable salt thereof according to any one of items 1 to 3, wherein -D- or -D-AB 2 It is the GLP-1 receptor agonist part.

[1143] 5. The compound or pharmaceutically acceptable salt thereof according to any one of items 1 to 4, wherein -D-AB 2 It is semaglutide.

[1144] 6. The compound according to any one of items 1 to 5 or a pharmaceutically acceptable salt thereof, wherein -L 1 - having the formula (XIIb).

[1145] 7. The compound according to any one of items 1 to 5 or a pharmaceutically acceptable salt thereof, wherein -L 1 - having the formula (XIIa).

[1146] 8. The compound or pharmaceutically acceptable salt thereof according to any one of items 1-5 or 7, wherein -L 1 - having the formula (XIIa-i).

[1147] 9. The compound according to any one of items 1-5, 7 or 8, or a pharmaceutically acceptable salt thereof, wherein -L 1 - having the formula (XIIa-ii).

[1148] 10. The compound according to any one of items 1-5, 7 or 8, or a pharmaceutically acceptable salt thereof, wherein -L 1 - having the formula (XIIa-iii).

[1149] 11. The compound according to any one of items 1 to 5 or a pharmaceutically acceptable salt thereof, wherein -L 1 - having formula (II).

[1150] 12. The compound of item 11 or a pharmaceutically acceptable salt thereof, wherein -R 1 and R 1a All are -H.

[1151] 13. The compound of item 11 or a pharmaceutically acceptable salt thereof, wherein -R 1 is -H, and R of formula (II) 1a It is a methyl group.

[1152] 14. The compound of item 11 or a pharmaceutically acceptable salt thereof, wherein -R 1 and R 1a All are methyl.

[1153] 15. The compound of item 11 or a pharmaceutically acceptable salt thereof, wherein -R 1 and R 1a All are -H.

[1154] 16. The compound or pharmaceutically acceptable salt thereof according to any one of items 11 to 15, wherein -X- in formula (II) is -C(R 7 R 7a )-.

[1155] 17. The compound or pharmaceutically acceptable salt thereof according to any one of items 11 to 15, wherein -X- in formula (II) is -C(R 4 R 4a )-.

[1156] 18. The compound or pharmaceutically acceptable salt thereof according to any one of items 11 to 15, wherein -X- in formula (II) is -C(R 4 R 4a )-C(R 5 R 5a )-.

[1157] 19. The compound of item 16 or a pharmaceutically acceptable salt thereof, wherein -R 7 -NR 10 -(C=O)-R 11 .

[1158] 20. The compound of item 16 or a pharmaceutically acceptable salt thereof, wherein -R 7 -N(R 10 R 10a ).

[1159] 21. The compound of item 19 or 20 or a pharmaceutically acceptable salt thereof, wherein -R 10 It is a methyl group.

[1160] 22. The compound of item 19 or 20 or a pharmaceutically acceptable salt thereof, wherein -R 10 For H.

[1161] 23. The compound or pharmaceutically acceptable salt thereof according to any one of items 20 to 22, wherein -R 10a is -H.

[1162] 24. The compound or pharmaceutically acceptable salt thereof according to any one of items 20 to 22, wherein -R 10a It is a methyl group.

[1163] 25. The compound or pharmaceutically acceptable salt thereof according to any one of items 16, 19 or 21-23, wherein -R 11 is -H, which is -L 2 -replace.

[1164] 26. The compound or pharmaceutically acceptable salt thereof according to any one of items 11 to 25, wherein X of formula (II) 1 For C.

[1165] 27. The compound according to any one of items 11 to 26 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (II) is 3 It is O.

[1166] 28. The compound according to any one of items 11 to 27 or a pharmaceutically acceptable salt thereof, wherein -X 2 -for-C(R 8 R 8a )-C(R 9 R 9a )-.

[1167] 29. The compound or pharmaceutically acceptable salt thereof according to any one of items 11 to 27, wherein -X 2 -for-C(R 8 R 8a )-.

[1168] 30. The compound of item 28 or 29 or a pharmaceutically acceptable salt thereof, wherein -R 8 and -R 8a All are -H.

[1169] 31. The compound of item 28 or 30 or a pharmaceutically acceptable salt thereof, wherein -R 9 and -R 9a All are -H.

[1170] 32. The compound or pharmaceutically acceptable salt thereof according to any one of items 11 to 31, wherein -R 2 and -R 2a All are -H.

[1171] 33. The compound or pharmaceutically acceptable salt thereof according to any one of items 11 to 31, wherein -R 2 is methyl; and -R 2a is -H.

[1172] 34. The compound or pharmaceutically acceptable salt thereof according to any one of items 11 to 31, wherein -R 2 and -R 2a All are methyl.

[1173] 35. The compound according to any one of items 11 to 34 or a pharmaceutically acceptable salt thereof, wherein -R 2 and -R 2a All are methyl.

[1174] 36. The compound or pharmaceutically acceptable salt thereof according to any one of items 11 to 34, wherein -R 2 and -R 2a All are -H.

[1175] 37. The compound or pharmaceutically acceptable salt thereof according to any one of items 11 to 34, wherein -R 2 is methyl; and -R 2a is -H.

[1176] 38. The compound according to any one of items 1 to 5, or a pharmaceutically acceptable salt thereof, wherein -L 1 - having the formula (III).

[1177] 39. The compound according to any one of items 1 to 5 or a pharmaceutically acceptable salt thereof, wherein -L 1 - having formula (IV).

[1178] 40. The compound according to any one of items 1 to 5, or a pharmaceutically acceptable salt thereof, wherein -L 1 - having formula (V).

[1179] 41. The compound according to any one of items 1 to 5 or a pharmaceutically acceptable salt thereof, wherein -L 1 - having formula (VI).

[1180] 42. The compound according to any one of items 1 to 5 or a pharmaceutically acceptable salt thereof, wherein -L 1 - having the formula (VII).

[1181] 43. The compound according to any one of items 1 to 5 or a pharmaceutically acceptable salt thereof, wherein -L 1 - having the formula (VIII).

[1182] 44. The compound according to any one of items 1 to 5, or a pharmaceutically acceptable salt thereof, wherein -L 1 - having the formula (IX).

[1183] 45. The compound according to any one of items 1 to 5, or a pharmaceutically acceptable salt thereof, wherein -L 1 - having the formula (X).

[1184] 46. ​​The compound of any one of items 1 to 45 or a pharmaceutically acceptable salt thereof, wherein -L 1 - is coupled to the N-terminal amine functional group of -D-.

[1185] 47. The compound or pharmaceutically acceptable salt thereof according to any one of items 1 to 46, wherein -AB 1 It has formula (A).

[1186] 48. The compound of item 47 or a pharmaceutically acceptable salt thereof, wherein -F 0 Selected from formula (a-4), (a-5), (a-6), (a-7), (a-8), (a-9), (a-10), (a-11), (a-12), (a -13), (a-14), (a-15), (a-16), (a-17), (a-18), (a-19), (a-20), (a-21), ( a-22), (a-23), (a-24), (a-25), (a-26), (a-27), (a-28), (a-29), (a-30), (a-31), (a-32), (a-33), (a-34), (a-35), (a-36), (a-37), (a-38) and (a-39).

[1187] 49. The compound of item 47 or 48 or a pharmaceutically acceptable salt thereof, wherein -F of formula (A) 0 It has the formula (a-4).

[1188] 50. The compound of item 47 or 48 or a pharmaceutically acceptable salt thereof, wherein -F of formula (A) 0 It has the formula (a-5).

[1189] 51. The compound of item 47 or 48 or a pharmaceutically acceptable salt thereof, wherein -F 0 It has the formula (a-6).

[1190] 52. The compound of item 47 or 48 or a pharmaceutically acceptable salt thereof, wherein -F of formula (A) 0 It has the formula (a-7).

[1191] 53. The compound of item 47 or 48 or a pharmaceutically acceptable salt thereof, wherein -F 0 It has the formula (a-8).

[1192] 54. The compound of item 47 or 48 or a pharmaceutically acceptable salt thereof, wherein -F of formula (A) 0 It has the formula (a-9).

[1193] 55. The compound of item 47 or 48 or a pharmaceutically acceptable salt thereof, wherein -F 0 It has the formula (a-10).

[1194] 56. The compound of item 47 or 48 or a pharmaceutically acceptable salt thereof, wherein -F of formula (A) 0 Having formula (a-11).

[1195] 57. The compound of item 47 or 48 or a pharmaceutically acceptable salt thereof, wherein -F of formula (A) 0 Having formula (a-12).

[1196] 58. The compound of item 47 or 48 or a pharmaceutically acceptable salt thereof, wherein -F 0 Having formula (a-13).

[1197] 59. The compound of item 47 or 48 or a pharmaceutically acceptable salt thereof, wherein -F of formula (A) 0 Having formula (a-14).

[1198] 60. The compound of item 47 or 48 or a pharmaceutically acceptable salt thereof, wherein -F of formula (A) 0 Having formula (a-15).

[1199] 61. The compound of item 47 or 48 or a pharmaceutically acceptable salt thereof, wherein -F of formula (A) 0 Having formula (a-16).

[1200] 62. The compound of item 47 or 48 or a pharmaceutically acceptable salt thereof, wherein -F of formula (A) 0 Having formula (a-17).

[1201] 63. The compound of item 47 or 48 or a pharmaceutically acceptable salt thereof, wherein -F of formula (A) 0 Having formula (a-18).

[1202] 64. The compound of item 47 or 48 or a pharmaceutically acceptable salt thereof, wherein -F of formula (A) 0 Having formula (a-19).

[1203] 65. The compound of item 47 or 48 or a pharmaceutically acceptable salt thereof, wherein -F of formula (A) 0 Having formula (a-20).

[1204] 66. The compound of item 47 or 48 or a pharmaceutically acceptable salt thereof, wherein -F of formula (A) 0 Having formula (a-21).

[1205] 67. The compound of item 47 or 48 or a pharmaceutically acceptable salt thereof, wherein -F of formula (A) 0 Having formula (a-22).

[1206] 68. The compound of item 47 or 48 or a pharmaceutically acceptable salt thereof, wherein -F of formula (A) 0 Having formula (a-23).

[1207] 69. The compound of item 47 or 48 or a pharmaceutically acceptable salt thereof, wherein -F of formula (A) 0 Having formula (a-24).

[1208] 70. The compound of item 47 or 48 or a pharmaceutically acceptable salt thereof, wherein -F of formula (A) 0 Having formula (a-25).

[1209] 71. The compound of item 47 or 48 or a pharmaceutically acceptable salt thereof, wherein -F of formula (A) 0 Having formula (a-26).

[1210] 72. The compound of item 47 or 48 or a pharmaceutically acceptable salt thereof, wherein -F of formula (A) 0 Having formula (a-27).

[1211] 73. The compound of item 47 or 48 or a pharmaceutically acceptable salt thereof, wherein -F of formula (A) 0 Having formula (a-28).

[1212] 74. The compound of item 47 or 48 or a pharmaceutically acceptable salt thereof, wherein -F of formula (A) 0 Having formula (a-29).

[1213] 75. The compound of item 47 or 48 or a pharmaceutically acceptable salt thereof, wherein -F of formula (A) 0 Having formula (a-30).

[1214] 76. The compound of item 47 or 48 or a pharmaceutically acceptable salt thereof, wherein -F of formula (A) 0 Having formula (a-31).

[1215] 77. The compound of item 47 or 48 or a pharmaceutically acceptable salt thereof, wherein -F of formula (A) 0 Having formula (a-32).

[1216] 78. The compound of item 47 or 48 or a pharmaceutically acceptable salt thereof, wherein -F of formula (A) 0 Having formula (a-33).

[1217] 79. The compound of item 47 or 48 or a pharmaceutically acceptable salt thereof, wherein -F of formula (A) 0 Having formula (a-34).

[1218] 80. The compound of item 47 or 48 or a pharmaceutically acceptable salt thereof, wherein -F of formula (A) 0 Having formula (a-35).

[1219] 81. The compound of item 47 or 48 or a pharmaceutically acceptable salt thereof, wherein -F of formula (A) 0 Having formula (a-36).

[1220] 82. The compound of item 47 or 48 or a pharmaceutically acceptable salt thereof, wherein -F 0 Having formula (a-37).

[1221] 83. The compound of item 47 or 48 or a pharmaceutically acceptable salt thereof, wherein -F of formula (A) 0 Having formula (a-38).

[1222] 84. The compound of item 47 or 48 or a pharmaceutically acceptable salt thereof, wherein -F of formula (A) 0 Having formula (a-39).

[1223] 85. The compound according to any one of items 1 to 84 or a pharmaceutically acceptable salt thereof, wherein -L of formula (A) A -does not exist.

[1224] 86. The compound according to any one of items 47 to 84 or a pharmaceutically acceptable salt thereof, wherein -L of formula (A) A-Selected from formula ((a-40), (a-41), (a-42), (a-43), (a-44), (a-45), (a-46), (a-47), (a-48), (a-49), ( a-50), (a-51), (a-52), (a-53), (a-54), (a-55), (a-56), (a-57), (a-58), (a-59), (a-60), ( a-61), (a-62), (a-63), (a-64), (a-65), (a-66), (a-67), (a-68), (a-69), (a-70), (a-71), (a-72), (a-73), (a-74), (a-75), (a-76), (a-77), (a-78), (a-79), (a-80), (a-81), and (a-82).

[1225] 87. The compound or pharmaceutically acceptable salt thereof according to any one of items 47-84 or 86, wherein -L of formula (A) A -having the formula (a-40).

[1226] 88. The compound or pharmaceutically acceptable salt thereof according to any one of items 47-84 or 86, wherein -L of formula (A) A -having the formula (a-41).

[1227] 89. The compound or pharmaceutically acceptable salt thereof according to any one of items 47-84 or 86, wherein -L of formula (A) A -having the formula (a-42).

[1228] 90. The compound or pharmaceutically acceptable salt thereof according to any one of items 47-84 or 86, wherein -L of formula (A) A -having the formula (a-43).

[1229] 91. The compound of any one of items 47-84 or 86 or a pharmaceutically acceptable salt thereof, wherein -L A - Formula (A) has the formula (a-44).

[1230] 92. The compound or pharmaceutically acceptable salt thereof according to any one of items 47-84 or 86, wherein -L of formula (A) A -having the formula (a-45).

[1231] 93. The compound or pharmaceutically acceptable salt thereof according to any one of items 47-84 or 86, wherein -L of formula (A) A -having the formula (a-46).

[1232] 94. The compound or pharmaceutically acceptable salt thereof according to any one of items 47-84 or 86, wherein -L of formula (A) A -having the formula (a-47).

[1233] 95. The compound or pharmaceutically acceptable salt thereof according to any one of items 47-84 or 86, wherein -L of formula (A) A -having the formula (a-48).

[1234] 96. The compound or pharmaceutically acceptable salt thereof according to any one of items 47-84 or 86, wherein -L of formula (A) A -having the formula (a-49).

[1235] 97. The compound or pharmaceutically acceptable salt thereof according to any one of items 47-84 or 86, wherein -L of formula (A) A -having the formula (a-50).

[1236] 98. The compound or pharmaceutically acceptable salt thereof according to any one of items 47-84 or 86, wherein -L of formula (A) A -having the formula (a-51).

[1237] 99. The compound or pharmaceutically acceptable salt thereof according to any one of items 47-84 or 86, wherein -L of formula (A) A -having the formula (a-52).

[1238] 100. The compound or pharmaceutically acceptable salt thereof according to any one of items 47-84 or 86, wherein -L of formula (A) A -having the formula (a-53).

[1239] 101. The compound or pharmaceutically acceptable salt thereof according to any one of items 47-84 or 86, wherein -L of formula (A) A -having the formula (a-54).

[1240] 102. The compound or pharmaceutically acceptable salt thereof according to any one of items 47-84 or 86, wherein -L of formula (A) A -having the formula (a-55).

[1241] 103. The compound or pharmaceutically acceptable salt thereof according to any one of items 47-84 or 86, wherein -L of formula (A) A -having the formula (a-56).

[1242] 104. The compound or pharmaceutically acceptable salt thereof according to any one of items 47-84 or 86, wherein -L of formula (A) A -having the formula (a-57).

[1243] 105. The compound or pharmaceutically acceptable salt thereof according to any one of items 47-84 or 86, wherein -L of formula (A) A -having the formula (a-58).

[1244] 106. The compound or pharmaceutically acceptable salt thereof according to any one of items 47-84 or 86, wherein -L of formula (A) A -having the formula (a-59).

[1245] 107. The compound or pharmaceutically acceptable salt thereof according to any one of items 47-84 or 86, wherein -L of formula (A) A -having the formula (a-60).

[1246] 108. The compound or pharmaceutically acceptable salt thereof according to any one of items 47-84 or 86, wherein -L of formula (A) A -having the formula (a-61).

[1247] 109. The compound or pharmaceutically acceptable salt thereof according to any one of items 47-84 or 86, wherein -L of formula (A) A -having formula (a-62).

[1248] 110. The compound or pharmaceutically acceptable salt thereof according to any one of items 47-84 or 86, wherein -L of formula (A) A -having the formula (a-63).

[1249] 111. The compound or pharmaceutically acceptable salt thereof according to any one of items 47-84 or 86, wherein -L of formula (A) A -having formula (a-64).

[1250] 112. The compound or pharmaceutically acceptable salt thereof according to any one of items 47-84 or 86, wherein -L of formula (A) A -having the formula (a-65).

[1251] 113. The compound or pharmaceutically acceptable salt thereof according to any one of items 47-84 or 86, wherein -L of formula (A) A -having the formula (a-66).

[1252] 114. The compound or pharmaceutically acceptable salt thereof according to any one of items 47-84 or 86, wherein -L of formula (A) A -having the formula (a-67).

[1253] 115. The compound or pharmaceutically acceptable salt thereof according to any one of items 47-84 or 86, wherein -L of formula (A) A -having the formula (a-68).

[1254] 116. The compound or pharmaceutically acceptable salt thereof according to any one of items 47-84 or 86, wherein -L of formula (A) A -having the formula (a-69).

[1255] 117. The compound or pharmaceutically acceptable salt thereof according to any one of items 47-84 or 86, wherein -L of formula (A) A -having the formula (a-70).

[1256] 118. The compound or pharmaceutically acceptable salt thereof according to any one of items 47-84 or 86, wherein -L of formula (A) A -having formula (a-71).

[1257] 119. The compound or pharmaceutically acceptable salt thereof according to any one of items 47-84 or 86, wherein -L of formula (A) A -having formula (a-72).

[1258] 120. The compound or pharmaceutically acceptable salt thereof according to any one of items 47-84 or 86, wherein -L of formula (A) A -having the formula (a-73).

[1259] 121. The compound of any one of items 47-84 or 86 or a pharmaceutically acceptable salt thereof, wherein -L of formula (A) A -having the formula (a-74).

[1260] 122. The compound or pharmaceutically acceptable salt thereof according to any one of items 47-84 or 86, wherein -L of formula (A) A -having the formula (a-75).

[1261] 123. The compound or pharmaceutically acceptable salt thereof according to any one of items 47-84 or 86, wherein -L of formula (A) A -having the formula (a-76).

[1262] 124. The compound or pharmaceutically acceptable salt thereof according to any one of items 47-84 or 86, wherein -L of formula (A) A -having the formula (a-77).

[1263] 125. The compound or pharmaceutically acceptable salt thereof according to any one of items 47-84 or 86, wherein -L of formula (A) A -having formula (a-78).

[1264] 126. The compound or pharmaceutically acceptable salt thereof according to any one of items 47-84 or 86, wherein -L of formula (A) A-having the formula (a-79).

[1265] 127. The compound or pharmaceutically acceptable salt thereof according to any one of items 47-84 or 86, wherein -L of formula (A) A -having the formula (a-80).

[1266] 128. The compound or pharmaceutically acceptable salt thereof according to any one of items 47-84 or 86, wherein -L of formula (A) A -having the formula (a-81).

[1267] 129. The compound or pharmaceutically acceptable salt thereof according to any one of items 47-84 or 86, wherein -L of formula (A) A -having formula (a-82).

[1268] 130. The compound or pharmaceutically acceptable salt thereof according to any one of items 47 to 129, wherein -L of formula (A) B -does not exist.

[1269] 131. The compound of any one of items 47-129 or a pharmaceutically acceptable salt thereof, wherein -L of formula (A) B -Selected from formulas (a-83), (a-84), (a-85), (a-86), (a-87), (a-88), (a-89), (a-90), (a-91), (a-92), (a-93) and (a-94).

[1270] 132. The compound or pharmaceutically acceptable salt thereof according to any one of items 47-129 or 131, wherein -L of formula (A) B -having the formula (a-83).

[1271] 133. The compound or pharmaceutically acceptable salt thereof according to any one of items 47-129 or 131, wherein -L of formula (A) B -having the formula (a-84).

[1272] 134. The compound of Item 133 or a pharmaceutically acceptable salt thereof, wherein q in Formula (a-84) is an integer in the range of 3-45.

[1273] 135. The compound of item 133 or 134 or a pharmaceutically acceptable salt thereof, wherein q in formula (a-84) is an integer in the range of 4-40.

[1274] 136. The compound of any one of items 133 to 135 or a pharmaceutically acceptable salt thereof, wherein q in formula (a-84) is an integer in the range of 5 to 35.

[1275] 137. The compound of any one of items 133 to 136 or a pharmaceutically acceptable salt thereof, wherein q in formula (a-84) is an integer in the range of 6 to 30.

[1276] 138. The compound of any one of items 133 to 137 or a pharmaceutically acceptable salt thereof, wherein q in formula (a-84) is an integer in the range of 7 to 25.

[1277] 139. The compound of any one of items 133 to 138 or a pharmaceutically acceptable salt thereof, wherein q in formula (a-84) is an integer in the range of 10-20.

[1278] 140. The compound of any one of items 133-138 or a pharmaceutically acceptable salt thereof, wherein q in formula (a-84) is 23.

[1279] 141. The compound or pharmaceutically acceptable salt thereof according to any one of items 47-129 or 131, wherein -L of formula (A) B -having the formula (a-85).

[1280] 142. The compound or pharmaceutically acceptable salt thereof according to any one of items 47-129 or 131, wherein -L of formula (A) B -having the formula (a-86).

[1281] 143. The compound or pharmaceutically acceptable salt thereof according to any one of items 47-129 or 131, wherein -L of formula (A) B -having the formula (a-87).

[1282] 144. The compound or pharmaceutically acceptable salt thereof according to any one of items 47-129 or 131, wherein -L of formula (A) B -having the formula (a-88).

[1283] 145. The compound or pharmaceutically acceptable salt thereof according to any one of items 47-129 or 131, wherein -L of formula (A) B -having the formula (a-89).

[1284] 146. The compound or pharmaceutically acceptable salt thereof according to any one of items 47-129 or 131, wherein -L of formula (A) B -having the formula (a-90).

[1285] 147. The compound or pharmaceutically acceptable salt thereof according to any one of items 47-129 or 131, wherein -L of formula (A) B -having the formula (a-91).

[1286] 148. The compound or pharmaceutically acceptable salt thereof according to any one of items 47-129 or 131, wherein -L of formula (A) B -having the formula (a-92).

[1287] 149. The compound or pharmaceutically acceptable salt thereof according to any one of items 47-129 or 131, wherein -L of formula (A) B -having the formula (a-93).

[1288] 150. The compound or pharmaceutically acceptable salt thereof according to any one of items 47-129 or 131, wherein -L of formula (A) B -having the formula (a-84).

[1289] 151. The compound of any one of items 1-47 or a pharmaceutically acceptable salt thereof, wherein -AB 1 It has the formula (i).

[1290] 152. The compound of claim 151 or a pharmaceutically acceptable salt thereof, wherein n in formula (i) is 14.

[1291] 153. The compound of claim 151 or a pharmaceutically acceptable salt thereof, wherein n in formula (i) is 15.

[1292] 154. The compound of Item 151 or a pharmaceutically acceptable salt thereof, wherein n in Formula (i) is 16.

[1293] 155. The compound of claim 151 or a pharmaceutically acceptable salt thereof, wherein n in formula (i) is 17.

[1294] 156. The compound of claim 151 or a pharmaceutically acceptable salt thereof, wherein n in formula (i) is 18.

[1295] 157. The compound of claim 151 or a pharmaceutically acceptable salt thereof, wherein n in formula (i) is 19.

[1296] 158. The compound of Item 151 or a pharmaceutically acceptable salt thereof, wherein n in Formula (i) is 20.

[1297] 159. The compound of Item 151 or a pharmaceutically acceptable salt thereof, wherein n in Formula (i) is 21.

[1298] 160. The compound of Item 151 or a pharmaceutically acceptable salt thereof, wherein n in Formula (i) is 22.

[1299] 161. The compound of any one of items 151-160, or a pharmaceutically acceptable salt thereof, wherein the stereocenter marked with an asterisk is in the R-configuration.

[1300] 162. The compound of any one of items 151-160, or a pharmaceutically acceptable salt thereof, wherein the stereocenter marked with an asterisk is in the S-configuration.

[1301] 163. The compound of any one of items 1-46 or a pharmaceutically acceptable salt thereof, wherein -AB 1 With the following formula

[1302]

[1303] The dotted line indicates the connection to -L 2 -.

[1304] 164. The compound of any one of items 1-46 or a pharmaceutically acceptable salt thereof, wherein -AB 1 With the following formula

[1305]

[1306] The dotted line indicates the connection to -L 2 -.

[1307] 165. The compound of any one of items 1-164 or a pharmaceutically acceptable salt thereof, wherein -L 2 - has a chain length of at least 35 atoms.

[1308] 166. The compound of any one of items 1-165 or a pharmaceutically acceptable salt thereof, wherein -L 2 - has a chain length of at least 50 atoms.

[1309] 167. The compound of any one of items 1-166 or a pharmaceutically acceptable salt thereof, wherein -L 2 - has a chain length of at least 75 atoms.

[1310] 168. The compound of any one of items 1-167 or a pharmaceutically acceptable salt thereof, wherein -L 2 - have a chain length of at least 100 atoms.

[1311] 169. The compound of any one of items 1-168 or a pharmaceutically acceptable salt thereof, wherein -L 2 - has a chain length of at least 150 atoms.

[1312] 170. The compound of any one of items 1-169 or a pharmaceutically acceptable salt thereof, wherein -L 2 - have a chain length of at least 200 atoms.

[1313] 171. The compound of any one of items 1-170 or a pharmaceutically acceptable salt thereof, wherein -L 2 - has a chain length of at least 250 atoms.

[1314] 172. The compound of any one of items 1-171 or a pharmaceutically acceptable salt thereof, wherein -L 2 - have a chain length of at least 300 atoms.

[1315] 173. The compound of any one of items 1-172 or a pharmaceutically acceptable salt thereof, wherein -L 2 - have a chain length of up to 3000 atoms.

[1316] 174. The compound of any one of items 1-173 or a pharmaceutically acceptable salt thereof, wherein -L 2 - have a chain length of up to 2500 atoms.

[1317] 175. The compound of any one of items 1-174 or a pharmaceutically acceptable salt thereof, wherein -L 2 - have a chain length of up to 2000 atoms.

[1318] 176. The compound of any one of items 1-175 or a pharmaceutically acceptable salt thereof, wherein -L 2 - have a chain length of up to 1500 atoms.

[1319] 177. The compound of any one of items 1-165 or a pharmaceutically acceptable salt thereof, wherein -L 2 -Has a chain length of 35-3000 atoms.

[1320] 178. The compound of any one of items 1-165 or 34 or a pharmaceutically acceptable salt thereof, wherein -L 2 -Has a chain length of 50-2500 atoms.

[1321] 179. The compound of any one of items 1-165, 177 or 178, or a pharmaceutically acceptable salt thereof, wherein -L 2 -Has a chain length of 75-2000 atoms.

[1322] 180. The compound of any one of items 1-165 or 177-179 or a pharmaceutically acceptable salt thereof, wherein -L 2 -Has a chain length of 100-1500 atoms.

[1323] 181. The compound of any one of items 1-165 or 177-180 or a pharmaceutically acceptable salt thereof, wherein -L 2 -Has a chain length of 125-1000 atoms.

[1324] 182. The compound of any one of items 1-164 or a pharmaceutically acceptable salt thereof, wherein -L 2- has a molecular weight of at least 450 Da.

[1325] 183. The compound of any one of items 1-164 or 182 or a pharmaceutically acceptable salt thereof, wherein -L 2 - has a molecular weight of at least 1 kDa.

[1326] 184. The compound of any one of items 1-164, 182 or 183, or a pharmaceutically acceptable salt thereof, wherein -L 2 - has a molecular weight of at least 1.5 kDa.

[1327] 185. The compound of any one of items 1-164 or 182-184 or a pharmaceutically acceptable salt thereof, wherein -L 2 - has a molecular weight of at least 2 kDa.

[1328] 186. The compound of any one of items 1-164 or 182-185 or a pharmaceutically acceptable salt thereof, wherein -L 2 - has a molecular weight of at least 2.5 kDa.

[1329] 187. The compound of any one of items 1-164 or 182-186 or a pharmaceutically acceptable salt thereof, wherein -L 2 - has a molecular weight of at least 3 kDa.

[1330] 188. The compound of any one of items 1-164 or 182-187 or a pharmaceutically acceptable salt thereof, wherein -L 2 - has a molecular weight of at least 3.5 kDa.

[1331] 189. The compound of any one of items 1-164 or 182-188 or a pharmaceutically acceptable salt thereof, wherein -L 2 - has a molecular weight of at least 4 kDa.

[1332] 190. The compound of any one of items 1-164 or 182-189 or a pharmaceutically acceptable salt thereof, wherein -L 2 - has a molecular weight of at least 4.5 kDa.

[1333] 191. The compound of any one of items 1-164 or 182-190 or a pharmaceutically acceptable salt thereof, wherein -L 2 - has a molecular weight of at least 5 kDa.

[1334] 192. The compound of any one of items 1-164 or 182-191 or a pharmaceutically acceptable salt thereof, wherein -L 2 -Has a molecular weight of at most 160 kDa.

[1335] 193. The compound of any one of items 1-164 or 182-192 or a pharmaceutically acceptable salt thereof, wherein -L 2 -Has a molecular weight of at most 120 kDa.

[1336] 194. The compound of any one of items 1-164 or 182-193 or a pharmaceutically acceptable salt thereof, wherein -L 2 - has a molecular weight of at most 100 kDa.

[1337] 195. The compound of any one of items 1-164 or 182-194 or a pharmaceutically acceptable salt thereof, wherein -L 2 - has a molecular weight of at most 80 kDa.

[1338] 196. The compound of any one of items 1-164 or 182-195 or a pharmaceutically acceptable salt thereof, wherein -L 2 - has a molecular weight of at most 70 kDa.

[1339] 197. The compound of any one of items 1-164 or 182-196 or a pharmaceutically acceptable salt thereof, wherein -L 2 - has a molecular weight of at most 60 kDa.

[1340] 198. The compound of any one of items 1-164 or 182-197 or a pharmaceutically acceptable salt thereof, wherein -L 2 - has a molecular weight of at most 50 kDa.

[1341] 199. The compound of any one of items 1-164 or 182-198 or a pharmaceutically acceptable salt thereof, wherein -L 2 - has a molecular weight of at most 40 kDa.

[1342] 200. The compound of any one of items 1-164 or a pharmaceutically acceptable salt thereof, wherein -L 2 - has a molecular weight of approximately 450 Da.

[1343] 201. The compound of any one of items 1-164 or a pharmaceutically acceptable salt thereof, wherein -L 2 - has a molecular weight of approximately 1 kDa.

[1344] 202. The compound of any one of items 1-164 or a pharmaceutically acceptable salt thereof, wherein -L 2 - has a molecular weight of approximately 1.5 kDa.

[1345] 203. The compound of any one of items 1-164 or a pharmaceutically acceptable salt thereof, wherein -L 2 - has a molecular weight of approximately 2 kDa.

[1346] 204. The compound of any one of items 1-164 or a pharmaceutically acceptable salt thereof, wherein -L 2 - has a molecular weight of approximately 2.5 kDa.

[1347] 205. The compound of any one of items 1-164 or a pharmaceutically acceptable salt thereof, wherein -L 2 - has a molecular weight of approximately 3 kDa.

[1348] 206. The compound of any one of items 1-164 or a pharmaceutically acceptable salt thereof, wherein -L 2 - has a molecular weight of approximately 3.5 kDa.

[1349] 207. The compound of any one of items 1-164 or a pharmaceutically acceptable salt thereof, wherein -L 2 - has a molecular weight of approximately 4 kDa.

[1350] 208. The compound of any one of items 1-164 or a pharmaceutically acceptable salt thereof, wherein -L 2 - has a molecular weight of approximately 4.5 kDa.

[1351] 209. The compound of any one of items 1-164 or a pharmaceutically acceptable salt thereof, wherein -L 2 - has a molecular weight of approximately 5 kDa.

[1352] 210. The compound of any one of items 1-164 or a pharmaceutically acceptable salt thereof, wherein -L 2 - has a molecular weight of approximately 5.5 kDa.

[1353] 211. The compound of any one of items 1-164 or a pharmaceutically acceptable salt thereof, wherein -L 2 - has a molecular weight of approximately 6 kDa.

[1354] 212. The compound of any one of items 1-164 or a pharmaceutically acceptable salt thereof, wherein -L 2 - has a molecular weight of approximately 6.5 kDa.

[1355] 213. The compound of any one of items 1-164 or a pharmaceutically acceptable salt thereof, wherein -L 2 - has a molecular weight of approximately 7 kDa.

[1356] 214. The compound of any one of items 1-164 or a pharmaceutically acceptable salt thereof, wherein -L 2 - has a molecular weight of approximately 7.5 kDa.

[1357] 215. The compound of any one of items 1-164 or a pharmaceutically acceptable salt thereof, wherein -L 2 - has a molecular weight of approximately 8 kDa.

[1358] 216. The compound of any one of items 1-164 or a pharmaceutically acceptable salt thereof, wherein -L 2 - has a molecular weight of approximately 8.5 kDa.

[1359] 217. The compound of any one of items 1-164 or a pharmaceutically acceptable salt thereof, wherein -L 2 - has a molecular weight of approximately 9 kDa.

[1360] 218. The compound of any one of items 1-164 or a pharmaceutically acceptable salt thereof, wherein -L 2 - has a molecular weight of approximately 9.5 kDa.

[1361] 219. The compound of any one of items 1-164 or a pharmaceutically acceptable salt thereof, wherein -L 2 - has a molecular weight of approximately 10 kDa.

[1362] 220. The compound of any one of items 1-219 or a pharmaceutically acceptable salt thereof, wherein -L 2 -Contains aggregated parts.

[1363] 221. The compound of claim 220 or a pharmaceutically acceptable salt thereof, wherein the polymeric portion comprises one or more polymeric portions.

[1364] 222. The compound of claim 221 or a pharmaceutically acceptable salt thereof, wherein the one or more polymer moieties are selected from the group consisting of poly(2-methacryloyloxyethylphosphorylcholine), poly(acrylic acid), poly(acrylate), poly(acrylamide), poly(alkoxy) polymers, poly(amide), poly(amidoamine), poly(amino acid), poly(anhydride), poly(asparagine), poly(butyric acid), poly(glycolic acid), polybutylene terephthalate, poly(caprolactone), poly(carbonate), poly(cyanoacrylate), poly(dimethylacrylamide), poly(ester), poly(ethylene), poly(ethylene glycol), poly(ethylene oxide), poly(ethyl phosphate), poly(ethyloxazoline), poly(glycolic acid), poly(hydroxyethyl acrylate), poly(hydroxyethyl-oxazoline), poly(hydroxymethacrylate), poly(hydroxypropyl methacrylamide) , poly(hydroxypropyl methacrylate), poly(hydroxypropyl oxazoline), poly(iminocarbonate), poly(lactic acid), poly(lactic-co-glycolic acid), poly(methacrylamide), poly(methacrylate), poly(methyloxazoline), poly(organophosphazene), poly(orthoesters), poly(oxazoline), poly(propylene glycol), poly(siloxanes), poly(urethane), poly(vinyl alcohol), poly(vinylamine), poly(vinyl methyl ether), poly(vinyl pyrrolidone), silicone, cellulose, carboxymethyl cellulose, hydroxypropyl methylcellulose, chitin, chitosan, dextran, dextrin, gelatin, hyaluronic acid and derivatives, functionalized hyaluronic acid, alginates, mannans, pectins, rhamnogalacturonan, starch, hydroxyalkyl starch, hydroxyethyl starch and other carbohydrate-based polymers, xylan and copolymers thereof.

[1365] 223. The compound of claim 221 or 222, or a pharmaceutically acceptable salt thereof, wherein one or more polymer moieties are PEG-based polymers.

[1366] 224. The compound of claim 221 or 222, or a pharmaceutically acceptable salt thereof, wherein one or more polymer moieties are hyaluronic acid-based polymers.

[1367] 225. The compound of claim 221 or 222, or a pharmaceutically acceptable salt thereof, wherein one or more polymer moieties comprise a random coil peptide or protein polymer.

[1368] 226. The compound of claim 221 or 222, or a pharmaceutically acceptable salt thereof, wherein one or more polymer moieties are poly-sarcosine-based polymers.

[1369] 227. The compound of any one of items 220-226 or a pharmaceutically acceptable salt thereof, wherein -L 2 - has a Flory radius of at least 1.2 nm.

[1370] 228. The compound of any one of items 220-227 or a pharmaceutically acceptable salt thereof, wherein -L 2 - has a Flory radius of at least 1.5 nm.

[1371] 229. The compound of any one of items 220-228 or a pharmaceutically acceptable salt thereof, wherein -L 2 - has a Flory radius of at least 2 nm.

[1372] 230. The compound of any one of items 220-86229 or a pharmaceutically acceptable salt thereof, wherein -L 2 - has a Flory radius of at least 2.5 nm.

[1373] 231. The compound of any one of items 220-230 or a pharmaceutically acceptable salt thereof, wherein -L 2 - has a Flory radius of at least 3 nm.

[1374] 232. The compound of any one of items 220-231 or a pharmaceutically acceptable salt thereof, wherein -L 2 - has a Flory radius of at least 3.5 nm.

[1375] 233. The compound of any one of items 220-232 or a pharmaceutically acceptable salt thereof, wherein -L 2 - has a Flory radius of at least 4 nm.

[1376] 234. The compound of any one of items 220-233 or a pharmaceutically acceptable salt thereof, wherein -L 2 - has a Flory radius of at least 4.5 nm.

[1377] 235. The compound of any one of items 220-234 or a pharmaceutically acceptable salt thereof, wherein -L 2 - has a Flory radius of at least 5 nm.

[1378] 236. The compound of any one of items 220-235 or a pharmaceutically acceptable salt thereof, wherein -L 2 -Has a Flory radius of not more than 200 nm.

[1379] 237. The compound of any one of items 220-236 or a pharmaceutically acceptable salt thereof, wherein -L 2 -Has a Flory radius not exceeding 175 nm.

[1380] 238. The compound of any one of items 220-237 or a pharmaceutically acceptable salt thereof, wherein -L 2-Has a Flory radius of not more than 150 nm.

[1381] 239. The compound of any one of items 220-238 or a pharmaceutically acceptable salt thereof, wherein -L 2 -Has a Flory radius of not more than 125 nm.

[1382] 240. The compound of any one of items 220-239 or a pharmaceutically acceptable salt thereof, wherein -L 2 -Has a Flory radius of no more than 100 nm.

[1383] 241. The compound of any one of items 220-240 or a pharmaceutically acceptable salt thereof, wherein -L 2 -Has a Flory radius of no more than 75 nm.

[1384] 242. The compound of any one of items 220-241 or a pharmaceutically acceptable salt thereof, wherein -L 2 -Has a Flory radius of no more than 50 nm.

[1385] 243. The compound of any one of items 220-242 or a pharmaceutically acceptable salt thereof, wherein -L 2 -Has a Flory radius of not more than 45 nm.

[1386] 244. The compound of any one of items 220-243 or a pharmaceutically acceptable salt thereof, wherein -L 2 -Has a Flory radius of no more than 40 nm.

[1387] 245. The compound of any one of items 220-244 or a pharmaceutically acceptable salt thereof, wherein -L 2 -Has a Flory radius of no more than 35 nm.

[1388] 246. The compound of any one of items 220-245 or a pharmaceutically acceptable salt thereof, wherein -L 2 -Has a Flory radius of no more than 30 nm.

[1389] 247. The compound of any one of items 220-226 or a pharmaceutically acceptable salt thereof, wherein -L 2 -Has a Flory radius of approximately 1.2 nm.

[1390] 248. The compound of any one of items 220-227 or a pharmaceutically acceptable salt thereof, wherein -L 2 -Has a Flory radius of approximately 1.5 nm.

[1391] 249. The compound of any one of items 220-227 or a pharmaceutically acceptable salt thereof, wherein -L 2 -Has a Flory radius of approximately 2 nm.

[1392] 250. The compound of any one of items 220-227 or a pharmaceutically acceptable salt thereof, wherein -L 2 -Has a Flory radius of approximately 2.5 nm.

[1393] 251. The compound of any one of items 220-227 or a pharmaceutically acceptable salt thereof, wherein -L 2 -Has a Flory radius of approximately 3 nm.

[1394] 252. The compound of any one of items 220-227 or a pharmaceutically acceptable salt thereof, wherein -L 2 -Has a Flory radius of approximately 3.5 nm.

[1395] 253. The compound of any one of items 220-227 or a pharmaceutically acceptable salt thereof, wherein -L 2 -Has a Flory radius of approximately 4 nm.

[1396] 254. The compound of any one of items 220-227 or a pharmaceutically acceptable salt thereof, wherein -L 2 -Has a Flory radius of approximately 4.5 nm.

[1397] 255. The compound of any one of items 220-227 or a pharmaceutically acceptable salt thereof, wherein -L 2 -Has a Flory radius of approximately 5 nm.

[1398] 256. The compound of any one of items 220-227 or a pharmaceutically acceptable salt thereof, wherein -L 2 -Has a Flory radius of approximately 5.5 nm.

[1399] 257. The compound of any one of items 220-227 or a pharmaceutically acceptable salt thereof, wherein -L 2 -Has a Flory radius of approximately 6 nm.

[1400] 258. The compound of any one of items 220-227 or a pharmaceutically acceptable salt thereof, wherein -L 2 -Has a Flory radius of approximately 6.5 nm.

[1401] 259. The compound of any one of items 220-227 or a pharmaceutically acceptable salt thereof, wherein -L 2 -Has a Flory radius of approximately 7 nm.

[1402] 260. The compound of any one of items 220-227 or a pharmaceutically acceptable salt thereof, wherein -L 2 -Has a Flory radius of approximately 7.5 nm.

[1403] 261. The compound of any one of items 220-227 or a pharmaceutically acceptable salt thereof, wherein -L 2 -Has a Flory radius of approximately 8 nm.

[1404] 262. The compound of any one of items 220-227 or a pharmaceutically acceptable salt thereof, wherein -L 2 -Has a Flory radius of approximately 8.5 nm.

[1405] 263. The compound of any one of items 220-227 or a pharmaceutically acceptable salt thereof, wherein -L 2 -Has a Flory radius of approximately 9 nm.

[1406] 264. The compound of any one of items 220-227 or a pharmaceutically acceptable salt thereof, wherein -L 2 -Has a Flory radius of approximately 9.5 nm.

[1407] 265. The compound of any one of items 220-227 or a pharmaceutically acceptable salt thereof, wherein -L 2 -Has a Flory radius of approximately 10 nm.

[1408] 266. The compound of any one of items 1-164 or a pharmaceutically acceptable salt thereof, wherein -L 2 - having the formula (XII).

[1409] 267. The compound of item 266 or a pharmaceutically acceptable salt thereof, wherein -X 1 -and-X 2 - independently selected from C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20 Alkynyl; wherein -T-, C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20 Alkynyl groups are optionally substituted with one or more -R y2 substituted, and wherein C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20 The alkynyl group is optionally separated by one or more groups selected from -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y3 )-、-S-、-N(R y3)-、-OC(OR y3 )(R y3a )-、-N(R y3 )C(O)N(R y3a )-and-OC(O)N(R y3 )-;

[1410] T is independently selected from phenyl, naphthyl, indenyl, dihydroindenyl, tetrahydronaphthyl, C 3-10 Cycloalkyl and 3 to 10 membered heterocyclyl; wherein each T is independently optionally replaced by one or more -R which may be the same or different y2 replace;

[1411] -R y2 Selected from halogen, -CN, oxo (=O) and C 1-6 Alkyl; among which C 1-6 The alkyl group is optionally substituted with one or more halogen groups which may be the same or different; and

[1412] -R y3 、-R y3a 、-R y4 、-R y4a 、-R y5 、-R y5a and -R y5b Each independently selected from -H and C 1-6 Alkyl; among which C 1-6 The alkyl group is optionally substituted with one or more halogens which may be the same or different.

[1413] 268. The compound of item 266 or 267 or a pharmaceutically acceptable salt thereof, wherein -POL- of formula (XII) has formula (XII-i).

[1414] 269. The compound of claim 268 or a pharmaceutically acceptable salt thereof, wherein y is selected such that the molecular weight of the moiety of formula (XII-i) is approximately 1 kDa.

[1415] 270. The compound of claim 268 or a pharmaceutically acceptable salt thereof, wherein y is selected such that the molecular weight of the moiety of formula (XII-i) is approximately 2 kDa.

[1416] 271. The compound of claim 268 or a pharmaceutically acceptable salt thereof, wherein y is selected such that the molecular weight of the moiety of formula (XII-i) is approximately 3 kDa.

[1417] 272. The compound of claim 268 or a pharmaceutically acceptable salt thereof, wherein y is selected such that the molecular weight of the moiety of formula (XII-i) is approximately 4 kDa.

[1418] 273. The compound of claim 268 or a pharmaceutically acceptable salt thereof, wherein y is selected such that the molecular weight of the moiety of formula (XII-i) is approximately 5 kDa.

[1419] 274. The compound of claim 268 or a pharmaceutically acceptable salt thereof, wherein y is selected such that the molecular weight of the moiety of formula (XII-i) is approximately 6 kDa.

[1420] 275. The compound of claim 268 or a pharmaceutically acceptable salt thereof, wherein y is selected such that the molecular weight of the moiety of formula (XII-i) is approximately 7 kDa.

[1421] 276. The compound of claim 268 or a pharmaceutically acceptable salt thereof, wherein y is selected such that the molecular weight of the moiety of formula (XII-i) is approximately 8 kDa.

[1422] 277. The compound of claim 268 or a pharmaceutically acceptable salt thereof, wherein y is selected such that the molecular weight of the moiety of formula (XII-i) is approximately 9 kDa.

[1423] 278. The compound of claim 268 or a pharmaceutically acceptable salt thereof, wherein y is selected such that the molecular weight of the moiety of formula (XII-i) is approximately 10 kDa.

[1424] 279. The compound of claim 268 or a pharmaceutically acceptable salt thereof, wherein y is selected such that the moiety of formula (XII-i) has a molecular weight of approximately 11 kDa.

[1425] 280. The compound of claim 268 or a pharmaceutically acceptable salt thereof, wherein y is selected such that the molecular weight of the moiety of formula (XII-i) is approximately 12 kDa.

[1426] 281. The compound of claim 268 or a pharmaceutically acceptable salt thereof, wherein y is selected such that the molecular weight of the moiety of formula (XII-i) is approximately 13 kDa.

[1427] 282. The compound of claim 268 or a pharmaceutically acceptable salt thereof, wherein y is selected such that the molecular weight of the moiety of formula (XII-i) is approximately 14 kDa.

[1428] 283. The compound of claim 268 or a pharmaceutically acceptable salt thereof, wherein y is selected such that the molecular weight of the moiety of formula (XII-i) is approximately 15 kDa.

[1429] 284. The compound of claim 268 or a pharmaceutically acceptable salt thereof, wherein y is selected such that the molecular weight of the moiety of formula (XII-i) is approximately 20 kDa.

[1430] 285. The compound of claim 268 or a pharmaceutically acceptable salt thereof, wherein y is selected such that the molecular weight of the moiety of formula (XII-i) is approximately 25 kDa.

[1431] 286. The compound of claim 268 or a pharmaceutically acceptable salt thereof, wherein y is selected such that the molecular weight of the moiety of formula (XII-i) is approximately 30 kDa.

[1432] 287. The compound of claim 268 or a pharmaceutically acceptable salt thereof, wherein y is selected such that the molecular weight of the moiety of formula (XII-i) is approximately 40 kDa.

[1433] 288. The compound of item 268 or its pharmaceutically acceptable salt, wherein y in formula (XII-i) is 2.

[1434] 289. The compound of claim 268 or a pharmaceutically acceptable salt thereof, wherein y of formula (XII-i) is approximately 22.

[1435] 290. The compound of claim 268 or a pharmaceutically acceptable salt thereof, wherein y of formula (XII-i) is approximately 45.

[1436] 291. The compound of item 268 or a pharmaceutically acceptable salt thereof, wherein y of formula (XII-i) is approximately 68.

[1437] 292. The compound of item 268 or a pharmaceutically acceptable salt thereof, wherein y of formula (XII-i) is approximately 91.

[1438] 293. The compound of item 268 or a pharmaceutically acceptable salt thereof, wherein y of formula (XII-i) is approximately 113.

[1439] 294. The compound of item 268 or a pharmaceutically acceptable salt thereof, wherein y of formula (XII-i) is approximately 136.

[1440] 295. The compound of claim 268 or a pharmaceutically acceptable salt thereof, wherein y of formula (XII-i) is approximately 160.

[1441] 296. The compound of item 268 or a pharmaceutically acceptable salt thereof, wherein y of formula (XII-i) is approximately 204.

[1442] 297. The compound of item 268 or a pharmaceutically acceptable salt thereof, wherein y of formula (XII-i) is approximately 227.

[1443] 298. The compound of item 268 or a pharmaceutically acceptable salt thereof, wherein y of formula (XII-i) is approximately 250.

[1444] 299. The compound of item 268 or a pharmaceutically acceptable salt thereof, wherein y of formula (XII-i) is approximately 340.

[1445] 300. The compound of claim 268 or a pharmaceutically acceptable salt thereof, wherein y of formula (XII-i) is approximately 455.

[1446] 301. The compound of item 268 or a pharmaceutically acceptable salt thereof, wherein y of formula (XII-i) is approximately 910.

[1447] 302. The compound of any one of items 1-268 or a pharmaceutically acceptable salt thereof, wherein -L 2 - having the formula (XII-ii).

[1448] 303. The compound of Item 302 or a pharmaceutically acceptable salt thereof, wherein a in Formula (XII-ii) is 1.

[1449] 304. The compound of Item 302 or a pharmaceutically acceptable salt thereof, wherein a in Formula (XII-ii) is 2.

[1450] 305. The compound of Item 302 or a pharmaceutically acceptable salt thereof, wherein a in Formula (XII-ii) is 3.

[1451] 306. The compound of Item 302 or a pharmaceutically acceptable salt thereof, wherein a in Formula (XII-ii) is 4.

[1452] 307. The compound of Item 302 or a pharmaceutically acceptable salt thereof, wherein a in Formula (XII-ii) is 5.

[1453] 308. The compound of Item 302 or a pharmaceutically acceptable salt thereof, wherein a in Formula (XII-ii) is 6.

[1454] 309. The compound of Item 302 or a pharmaceutically acceptable salt thereof, wherein a in Formula (XII-ii) is 7.

[1455] 310. The compound of Item 302 or a pharmaceutically acceptable salt thereof, wherein a in Formula (XII-ii) is 8.

[1456] 311. The compound of Item 302 or a pharmaceutically acceptable salt thereof, wherein a in Formula (XII-ii) is 9.

[1457] 312. The compound of Item 302 or a pharmaceutically acceptable salt thereof, wherein a in Formula (XII-ii) is 10.

[1458] 313. The compound of Item 302 or a pharmaceutically acceptable salt thereof, wherein a in Formula (XII-ii) is 11.

[1459] 314. The compound of Item 302 or a pharmaceutically acceptable salt thereof, wherein a in Formula (XII-ii) is 12.

[1460] 315. The compound of Item 302 or a pharmaceutically acceptable salt thereof, wherein a in Formula (XII-ii) is 13.

[1461] 316. The compound of Item 302 or a pharmaceutically acceptable salt thereof, wherein a in Formula (XII-ii) is 14.

[1462] 317. The compound of Item 302 or a pharmaceutically acceptable salt thereof, wherein a in Formula (XII-ii) is 15.

[1463] 318. The compound of any one of items 302-317 or a pharmaceutically acceptable salt thereof, wherein b in formula (XII-ii) is 1.

[1464] 319. The compound of any one of items 302-317 or a pharmaceutically acceptable salt thereof, wherein b in formula (XII-ii) is 2.

[1465] 320. The compound of any one of items 302-317 or a pharmaceutically acceptable salt thereof, wherein b in formula (XII-ii) is 3.

[1466] 321. The compound of any one of items 302-317 or a pharmaceutically acceptable salt thereof, wherein b in formula (XII-ii) is 4.

[1467] 322. The compound of any one of items 302-317 or a pharmaceutically acceptable salt thereof, wherein b in formula (XII-ii) is 5.

[1468] 323. The compound of any one of items 302-317 or a pharmaceutically acceptable salt thereof, wherein b in formula (XII-ii) is 6.

[1469] 324. The compound of any one of items 302-317 or a pharmaceutically acceptable salt thereof, wherein b in formula (XII-ii) is 7.

[1470] 325. The compound of any one of items 302-317 or a pharmaceutically acceptable salt thereof, wherein b in formula (XII-ii) is 8.

[1471] 326. The compound of any one of items 302-317 or a pharmaceutically acceptable salt thereof, wherein b in formula (XII-ii) is 9.

[1472] 327. The compound of any one of items 302-317 or a pharmaceutically acceptable salt thereof, wherein b in formula (XII-ii) is 10.

[1473] 328. The compound of any one of items 302-317 or a pharmaceutically acceptable salt thereof, wherein b in formula (XII-ii) is 11.

[1474] 329. The compound of any one of items 302-317 or a pharmaceutically acceptable salt thereof, wherein b in formula (XII-ii) is 12.

[1475] 330. The compound of any one of items 302-317 or a pharmaceutically acceptable salt thereof, wherein b in formula (XII-ii) is 13.

[1476] 331. The compound of any one of items 302-317 or a pharmaceutically acceptable salt thereof, wherein b in formula (XII-ii) is 14.

[1477] 332. The compound of any one of items 302-317 or a pharmaceutically acceptable salt thereof, wherein b in formula (XII-ii) is 15.

[1478] 333. The compound of any one of items 302-332 or a pharmaceutically acceptable salt thereof, wherein c in formula (XII-ii) is 1.

[1479] 334. A compound according to any one of items 302-332 or a pharmaceutically acceptable salt thereof, wherein c in formula (XII-ii) is 2.

[1480] 335. The compound of any one of items 302-332 or a pharmaceutically acceptable salt thereof, wherein c in formula (XII-ii) is 3.

[1481] 336. A compound according to any one of items 302-332 or a pharmaceutically acceptable salt thereof, wherein c in formula (XII-ii) is 4.

[1482] 337. A compound according to any one of items 302-332 or a pharmaceutically acceptable salt thereof, wherein c in formula (XII-ii) is 5.

[1483] 338. The compound of any one of items 302-332 or a pharmaceutically acceptable salt thereof, wherein c in formula (XII-ii) is 6.

[1484] 339. The compound of any one of items 302-332 or a pharmaceutically acceptable salt thereof, wherein c in formula (XII-ii) is 7.

[1485] 340. The compound of any one of items 302-332 or a pharmaceutically acceptable salt thereof, wherein c in formula (XII-ii) is 8.

[1486] 341. The compound of any one of items 302-332 or a pharmaceutically acceptable salt thereof, wherein c in formula (XII-ii) is 9.

[1487] 342. The compound of any one of items 302-332 or a pharmaceutically acceptable salt thereof, wherein c in formula (XII-ii) is 10.

[1488] 343. The compound of any one of items 302-332 or a pharmaceutically acceptable salt thereof, wherein c in formula (XII-ii) is 11.

[1489] 344. A compound according to any one of items 302-332 or a pharmaceutically acceptable salt thereof, wherein c in formula (XII-ii) is 12.

[1490] 345. The compound of any one of items 302-332 or a pharmaceutically acceptable salt thereof, wherein c in formula (XII-ii) is 13.

[1491] 346. The compound of any one of items 302-332 or a pharmaceutically acceptable salt thereof, wherein c in formula (XII-ii) is 14.

[1492] 347. A compound according to any one of items 302-332 or a pharmaceutically acceptable salt thereof, wherein c in formula (XII-ii) is 15.

[1493] 348. The compound of any one of items 302-347 or a pharmaceutically acceptable salt thereof, wherein -R 1 is -H.

[1494] 349. The compound of any one of items 302-347 or a pharmaceutically acceptable salt thereof, wherein -R 1 C 1-6 alkyl.

[1495] 350. The compound of any one of items 302-347 or a pharmaceutically acceptable salt thereof, wherein -R 1 It is a methyl group.

[1496] 351. The compound of any one of items 302-349 or a pharmaceutically acceptable salt thereof, wherein -R 2 is -H.

[1497] 352. The compound of any one of items 302-349 or a pharmaceutically acceptable salt thereof, wherein -R 2 C 1-6 alkyl.

[1498] 353. The compound of any one of items 302-349 or a pharmaceutically acceptable salt thereof, wherein -R 2 It is a methyl group.

[1499] 354. The compound of any one of items 302-353 or a pharmaceutically acceptable salt thereof, wherein x in formula (XII-ii) is 2.

[1500] 355. The compound of any one of items 302-353 or a pharmaceutically acceptable salt thereof, wherein x of formula (XII-ii) is about 22.

[1501] 356. The compound of any one of items 302-353 or a pharmaceutically acceptable salt thereof, wherein x of formula (XII-ii) is about 45.

[1502] 357. The compound of any one of items 302-353 or a pharmaceutically acceptable salt thereof, wherein x in formula (XII-ii) is approximately 68.

[1503] 358. The compound of any one of items 302-353 or a pharmaceutically acceptable salt thereof, wherein x of formula (XII-ii) is approximately 91.

[1504] 359. The compound of any one of items 302-353 or a pharmaceutically acceptable salt thereof, wherein x in formula (XII-ii) is approximately 136.

[1505] 360. The compound of any one of items 302-353 or a pharmaceutically acceptable salt thereof, wherein x of formula (XII-ii) is about 160.

[1506] 361. The compound of any one of items 302-353 or a pharmaceutically acceptable salt thereof, wherein x in formula (XII-ii) is approximately 182.

[1507] 362. The compound of any one of items 302-353 or a pharmaceutically acceptable salt thereof, wherein x in formula (XII-ii) is approximately 204.

[1508] 363. The compound of any one of items 302-353 or a pharmaceutically acceptable salt thereof, wherein x in formula (XII-ii) is approximately 227.

[1509] 364. The compound of any one of items 302-353 or a pharmaceutically acceptable salt thereof, wherein x of formula (XII-ii) is approximately 250.

[1510] 365. The compound of any one of items 302-353 or a pharmaceutically acceptable salt thereof, wherein x of formula (XII-ii) is approximately 340.

[1511] 366. The compound of any one of items 302-353 or a pharmaceutically acceptable salt thereof, wherein x of formula (XII-ii) is approximately 455.

[1512] 367. The compound of any one of items 302-353 or a pharmaceutically acceptable salt thereof, wherein x of formula (XII-ii) is approximately 910.

[1513] 368. The compound of any one ...

Claims

1. A compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof in -D- are each independently a drug moiety; -AB 1 and-AB 2 each independently an albumin binding moiety; -L 1 - are each independently a linker moiety that is covalently and reversibly linked to -D-; -L 2 - are each independently a spacer or absent; x is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, and 25; and y is an integer selected from 2, 3, 4 and 5.

2. The compound of claim 1, wherein the compound has formula (Ia) wherein x=1.

3. The compound of claim 1 or 2, wherein -AB 1 and / or -AB 2 Independently a fatty acid based albumin binding moiety.

4. The compound of any one of claims 1 to 3, wherein -AB 1 and / or -AB 2 Independently have formula (A): in The dotted lines indicate connections to -L 2 -or-D-; -F 0 Having formula (a-1) in The dotted line indicates the connection to -L A -; -R 0 Selected from-CR 1 R 1a R 1b 、-COOR 1 、 -R 1 、-R 1a and -R 1b is selected from -H, methyl, ethyl, propyl and isopropyl; n is an integer within the range of and including 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, and 22; -L A - does not exist or has formula (a-2) in The unmarked dashed line indicates the connection to -L B -; The dashed line marked with an asterisk indicates the connection to the -F 0 ; -R a -Selected in The dashed line marked with an asterisk indicates the connection to the -F 0 ; The unmarked dashed line indicates the connection to -L A - the rest of -R b -for m is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; p is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; -L B - does not exist or has formula (a-3) in The unmarked dashed line indicates the connection to -L 2 -or-D-; The dashed line marked with an asterisk indicates the connection to -L A ; -R c -for -R d -Selected from C 1-50 Alkyl, C 2-50 Alkenyl or C 2-50 Alkynyl, where C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 The alkynyl group may be optionally substituted with one or more -R 1 Substituted, and the C 1-50 Alkyl, C 2-50 Alkenyl or C 2-50 The alkynyl group may be optionally separated by one or more groups selected from -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R 2 )-、-S(O)2N(R 2 )-、-S(O)N(R 2 )-、-S(O)2-、-S(O)-、-N(R 2 )S(O)2N(R 2a )-、-S-、-N(R 2 )-、-OC(OR 2 )(R 2a )-、-N(R 2 )C(O)N(R 2a )-and-OC(O)N(R 2 )-; -T- are each independently selected from phenyl, naphthyl, indenyl, dihydroindenyl, tetrahydronaphthyl, C 3-10 Cycloalkyl, 3 to 10 membered heterocyclyl, 8 to 11 membered heterobicyclyl, 8 to 30 membered carbon polycyclyl and 8 to 30 membered heteropolycyclyl; wherein -T- may be independently replaced by one or more -R which may be the same or different 1 replace; -R 1 Each independently selected from halogen, -CN, oxo (=O), -COOR 3 、-OR 3 、-C(O)R 3 、-C(O)N(R 3 R 3a )、-S(O)2N(R 3 R 3a )、-S(O)N(R 3 R 3a )、-S(O)2R 3 、-S(O)R 3 、-N(R 3 )S(O)2N(R 3a R 3b ),-SR 3 、-N(R 3 R 3a )、-NO2、-OC(O)R 3 、-N(R 3 )C(O)R 3a 、-N(R 3 )S(O)2R 3a 、-N(R 3 )S(O)R 3a 、-N(R 3 )C(O)OR 3a 、-N(R 3 )C(O)N(R 3a R 3b )、-OC(O)N(R 3 R 3a ) and C 1-6 Alkyl; among which C 1-6 The alkyl group is optionally substituted with one or more halogens which may be the same or different; -R 2 、-R 2a 、-R 3 、-R 3a and -R 3b are each independently selected from -H and C 1-6 Alkyl, where C 1-6 The alkyl group may be optionally substituted with one or more halogen groups which may be the same or different; and -R e -selected from -CH2-, 5. The compound of any one of claims 1 to 4, wherein -AB 1 and / or -AB 2 Independently a peptide albumin binding moiety.

6. The compound of any one of claims 1 to 5, wherein -L 1 - having formula (II): Wherein the dashed line represents the nitrogen, hydroxyl, or thiol group attached to -D-; -X- is selected from -C(R 4 R 4a )-; -N(R 4 )-; -O-; -C(R 4 R 4a )-C(R / / 这里似乎多了个右括号,原文是否有误? 5 R 5a )-; -C(R 5 R 5a )-C(R 4 R 4a )-; -C(R 4 R 4a )-N(R 6 )-; -N(R 6 )-C(R 4 R 4a )-; C(R 4 R 4a )-O-; -O-C(R 4 R 4a )-; and -C(R 7 R 7a )-; 说明:原文中存在一些格式和内容上可能不太规范的地方,比如“-C(R ”这样的表述,翻译时尽量按照原文结构呈现,但对可能存在的错误也进行了标注。 X 1 selected from C; and S(O); -X 2 -selected from -C(R 8 R 8a )-; and -C(R 8 R 8a )-C(R 9 R 9a )-; =X 3 Selected from =O; =S; and =N-CN; -R 1 、-R 1a 、-R 2 、-R 2a 、-R 4 、-R 4a 、-R 5 、-R 5a 、-R 6 、-R 8 、-R 8a 、-R 9 and -R 9a are independently selected from -H; and C 1-6 alkyl; -R 3 and -R 3a are independently selected from -H; and C 1-6 Alkyl, provided that, in -R 3 、-R 3a If one or both of them are not -H, they are passed to SP 3 - Hybridized carbon atoms are linked to the nitrogen to which they are attached; -R 7 Selected from -N(R 10 R 10a ); and -NR 10 -(C=O)-R 11 ; -R 7a 、-R 10 、-R 10a and -R 11 are independently selected from -H; and C 1-6 alkyl; Optionally, -R 1a / -R 4a 、-R 1a / -R 5a 、-R 1a / -R 7a 、-R 4a / -R 5a and -R 8a / -R 9a One or more pairs of them form chemical bonds; Optionally, -R 1 / -R 1a 、-R 2 / -R 2a 、-R 4 / -R 4a 、-R 5 / -R 5a 、-R 8 / -R 8a and -R 9 / -R 9a One or more of them are joined together with the atoms to which they are attached to form C 3-10 Cycloalkyl; or 3 to 10-membered heterocyclic group; Optionally, -R 1 / -R 4 、-R 1 / -R 5 、-R 1 / -R 6 、-R 1 / -R 7a 、-R 4 / -R 5 、-R 4 / -R 6 、-R 8 / -R 9 and -R 2 / -R 3 One or more of them are linked together with the atoms to which they are attached to form ring A; Optionally, R 3 / R 3a Together with the nitrogen atom to which they are attached, they form a 3- to 10-membered heterocyclic ring; A is selected from phenyl; naphthyl; indenyl; dihydroindenyl; tetrahydronaphthyl; C 3-10 cycloalkyl; 3- to 10-membered heterocyclyl; and 8- to 11-membered heterobicyclyl; and Where -L 1 -Being at least one -L 2 -substituted, and wherein -L 1 - is optionally further substituted, provided that the hydrogen marked by an asterisk in formula (II) is not replaced by -L 2 - or substituted by a substituent.

7. The compound of any one of claims 1 to 6, wherein -L 1 - having formula (IIa) in The dashed line marked with an asterisk represents the nitrogen attached to -D-; and The unmarked dashed line indicates the connection to -L 2 -.

8. The compound of any one of claims 1 to 7, wherein -L 2 -having formula (XII-ii) in The dashed line marked with an asterisk indicates the connection to -L 1 -; The unlabeled dashed line indicates the connection to -AB 1 ; a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15; b is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15; c is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15; The range of x is 2-1000; -R 1 and -R 2 are independently selected from -H and C 1-6 alkyl.

9. The compound of claim 8, wherein a is 5, b is 2, c is 2, and -R 1 and -R 2 All are -H.

10. The compound of claim 8 or 9, wherein x is about 108.

11. The compound of claim 8 or 9, wherein x is about 23.

12. The compound of any one of claims 1 to 11, wherein -D- or -D-AB 2 It is the GLP-1 receptor agonist part.

13. The compound of any one of claims 1 to 11, wherein -D-AB 2 Selected from semaglutide, liraglutide, enoglutide, GZR18, GL0034, tilportide, codutide, BI-456906, pianvidutide, mashidutide, dapiglutide and retaglutide.

14. The compound of any one of claims 1 to 13, wherein -D-AB 2 It is semaglutide.

15. The compound according to any one of claims 12 to 14, wherein -D- is a molecule which is linked to -L via an N-terminal amine functional group. 1 -coupling.

16. The compound of any one of claims 1 to 15, wherein -AB 1 Having formula (XIX) in The dotted line indicates the connection to -L 2 -;and a is 14, 15, 16, 17, 18, 19, 20, 21 or 22.

17. The compound of claim 16, wherein a is 18.

18. Pharmaceutical composition comprising at least one compound according to any one of claims 1 to 17 and at least one excipient.

19. A compound according to any one of claims 1 to 17 or a pharmaceutical composition according to claim 18 for use as a medicament.

20. The compound of any one of claims 1 to 17 or the pharmaceutical composition of claim 18 for use in the treatment of HD-AB 2 Treat the disease.

21. A compound according to any one of claims 12 to 17, or a pharmaceutical composition comprising at least one such compound, 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 diseases, (vi) chronic kidney disease (CKD), (vii) diabetic nephropathy (DKD), (viii) peripheral arterial disease (PAD) and / or (ix) heart failure (HF).

22. Compounds 12-17 according to any one of claims 12 to 17, or a pharmaceutical composition comprising at least one such compound, for use in treating a disease selected from the group consisting of dyslipidemia and / or a disease with one or more of the following clinical outcomes as therapeutic targets: lowering total serum lipids; increasing HDL; lowering small, dense LDL; lowering VLDL; lowering triglycerides; lowering cholesterol; lowering plasma levels of body lipoprotein a (Lp(a)) in humans; and inhibiting the production of apolipoprotein A (apo(A)).

23. A compound according to any one of claims 12 to 17, or a pharmaceutical composition comprising at least one such compound, for use in the treatment of a disease selected from the group consisting of Alzheimer's disease and Parkinson's disease.

24. A compound according to any one of claims 12 to 17, comprising a pharmaceutical composition comprising at least one such compound, for use in therapy together with one or more additional drugs selected from cardiovascular drugs, antidiabetic drugs and antiobesity drugs.

25. The compound or pharmaceutically acceptable salt thereof or pharmaceutical composition for use according to claim 22 or 23, wherein the compound or pharmaceutically acceptable salt thereof or pharmaceutical composition is administered in combination with growth hormone.

26. The compound for use according to claim 27, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, wherein the growth hormone is romazotocin.

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