Cancer therapy using TLR7 / 8 agonists

Abstract

The present invention relates to unit dosage forms comprising a therapeutically effective amount of a TLR7 / 8 agonist conjugate or a pharma- ceutically acceptable salt thereof; a TLR7 / 8 agonist conjugate for use in the treatment of cancer, wherein the TLR7 / 8 agonist conjugate is administered via intratumoral administration at a dose ranging from 0.3 mg to 3 mg of TLR7 / 8 agonist per tumor; and specific conjugates and related embodiments of resiquimod.

Description

[Technical Field]

[0001] The present invention relates to unit dosage forms comprising a therapeutically effective amount of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof; a TLR7 / 8 agonist conjugate for use in the treatment of cancer, wherein the TLR7 / 8 agonist conjugate is administered via intratumoral administration at a dose ranging from 0.3 mg to 3 mg of TLR7 / 8 agonist per tumor; and certain conjugates and related embodiments of resiquimod. [Background technology]

[0002] Toll-like receptor (TLR) agonists can induce antitumor activity by activating innate immune cells and promoting a pro-inflammatory microenvironment (Aznar et al., J Immunol. 2017 Jan 1;198(1):31–39; Marabelle et al., Ann Oncol. 2017 Dec 1;28(Suppl_12):xii33–xii43; Hamid et al., Oncologist. 2020 Mar;25(3):e423–e438). Local delivery of TLR agonists has shown enhanced preclinical and clinical antitumor activity (Hamid et al., Oncologist. 2020 March;25(3):e423-e438; et al., Blood. 2015;126:1452-1461; Clark et al., Am J Clin Dermatol. 2014;15:197-216).

[0003] However, intratumoral (IT) delivery of unmodified TLR agonists, such as the TLR7 / 8 agonist resiquimod, can result in rapid diffusion from the tumor, resulting in acute systemic drug exposure and transient but high levels of peripheral pro-inflammatory cytokines, thus potentially limiting antitumor benefit and increasing the risk of cytokine-driven adverse effects.

[0004] Similarly, in a clinical study of orally administered resiquimod, resiquimod was well tolerated at systemic concentrations of approximately 4 ng / mL, whereas systemic toxicity was observed at higher doses. Side effects, including fever, headache, shivering, and lymphopenia, were consistent with systemic cytokine induction (Journal of Hepatology 47 (2007) 174-182). Summary of the Invention [Problem to be solved by the invention]

[0005] Thus, there is a need for more effective and safer treatments using TLR agonists, and it is an object of the present invention to at least partially overcome the shortcomings of current treatment options using TLR agonists. [Means for solving the problem]

[0006] In a first aspect, the present invention relates to a unit dosage form comprising a therapeutically effective amount of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof, wherein the TLR7 / 8 agonist conjugate comprises one or more TLR7 / 8 agonist moieties reversibly conjugated to a polymer moiety, and wherein the unit dosage form comprises between 0.3 mg and 3 mg of the TLR7 / 8 agonist.

[0007] In a second aspect, the present invention relates to a TLR7 / 8 agonist conjugate for use in the treatment of cancer, wherein the TLR7 / 8 agonist conjugate comprises one or more TLR7 / 8 agonist moieties reversibly conjugated to a polymer moiety, wherein the cancer is a solid tumor, and wherein the TLR7 / 8 agonist conjugate is administered via intratumoral administration at a dose ranging from 0.3 mg to 3 mg of TLR7 / 8 agonist per tumor. DETAILED DESCRIPTION OF THE INVENTION

[0008] Surprisingly, robust upregulation of biomarkers was observed in tumor lesions from four patients who received intratumoral injections of the TLR7 / 8 agonist conjugate, demonstrating activation of local tumor immunity across a variety of tumor types. These biomarkers of local and abscopal immune activation by TLR7 / 8 agonists include changes in the expression of type I interferon-related genes and genes otherwise involved in the TLR7 / 8 signaling pathway. Specific biomarkers of local and abscopal immune activation by TLR7 / 8 agonists include upregulation of the genes CXCL10, IFNB1, IRF1, IRF3, IRF4, IRF7, IRF8, STAT1, and STAT2 in patient tumor biopsies after treatment compared to baseline.

[0009] Furthermore, consistent upregulation of biomarkers of activation was observed in two tumor lesions from patients who had not received TLR7 / 8 agonist conjugate injections but had received intratumoral injections of TLR7 / 8 agonist conjugates in other tumor lesions, demonstrating abscopal immune activation. Notably, treatment biopsies were obtained 7 days after administration, suggesting long-term immune activation that was maintained for more than a week after each administration. Furthermore, repeated administration in injected tumors from three patients demonstrated sustained immune activation.

[0010] Furthermore, after intratumoral injection of TLR7 / 8 agonist conjugates into single tumor lesions at up to 0.5 mg per lesion, C max The values ​​were generally below 150 pg / mL, well below the levels reported in the literature to be associated with cytokine release syndrome (approximately 4000 pg / mL), thus significantly reducing the risk of systemic side effects.

[0011] Within the present invention, terms are used which have the following meanings:

[0012] As used herein, the term "dose" or "unit dose" refers to a predetermined amount of a drug, such as a TLR7 / 8 agonist, administered at one time to produce a certain biological response in a patient. The dose of a drug is determined by its inherent potency, in this case, it is a therapeutic dose or a therapeutic unit dose. It is understood that the unit dosage form of the present invention comprises one dose or one unit dose of a TLR7 / 8 agonist.

[0013] The dose can be administered once or multiple times. The drug can be administered for at least 6 months, 1 year, 2 years, until the cancer is cured, or indefinitely. Once cancer is diagnosed, treatment can begin. It is understood that treatment can continue until the patient's death.

[0014] Once a dosage has been determined for a particular drug, e.g., a TLR7 / 8 agonist conjugate of Formula (A-3) or (A-6), this dosage can be used as a guide for other TLR7 / 8 agonist conjugates such that the dosage of the other reversible conjugates will be the same, in terms of moles of TLR7 / 8 agonist, as the dosage for the TLR7 / 8 agonist of Formula (A-3) or (A-6). Such guidance is particularly useful when the other conjugates release their TLR7 / 8 agonist moieties with a release half-life within plus or minus 20% of the release half-life of the TLR7 / 8 agonist conjugate of Formula (A-3) or (A-6).

[0015] The treatments and methods of the present invention can also be used to treat a population of patients with cancer. Such a population can include at least 10, 100, or 1000 patients, or can represent all patients at a particular institution.

[0016] Although clinical trials can be useful for determining new dosages and dosing regimens, the present methods can be performed outside of the course of a clinical trial.

[0017] As used herein, the term "dosage form" refers to a physical form containing an active pharmaceutical ingredient in combination with selected additional ingredients or excipients and intended for delivery to an internal site of action by various drug administration routes. It also refers to a physical form in which a precise mixture of active pharmaceutical ingredient and excipients is presented to aid administration and delivery to the site of action, achieve rapid onset of action, and improve bioavailability. As used herein, the term "unit dosage form" refers to a dosage form configured for a single administration to a patient; i.e., a unit dosage form contains one dose. For example, a unit dosage form can be a single vial or container containing an amount of drug suitable for a single administration.

[0018] As used herein, the term "dosing regimen" refers to the combination of the dose and frequency at which a drug is administered. A dosing regimen may also include the route of administration (e.g., intratumoral) and / or duration of administration.

[0019] As used herein, the terms "treating" and "treatment" refer to curing, alleviating, or inhibiting further worsening of at least one sign or symptom of a disease, or stabilizing at least one sign or symptom of a disease, which can be determined by comparing the sign(s) and symptom(s) in an individual patient before and after receiving treatment (baseline) or by comparing a population of treated patients with a control population, such as in a clinical trial or animal model study.

[0020] As used herein, the term "drug" refers to a substance used in the treatment, cure, prevention, or diagnosis of disease, or to otherwise improve the physical or mental well-being of a patient. When a drug is conjugated to another moiety, the portion of the resulting product derived from the drug is referred to as the "drug moiety."

[0021] As used herein, the terms "immune checkpoint inhibitor" and "immune checkpoint antagonist" are used interchangeably and refer to compounds that interfere with the function of or inhibit the binding of a ligand that induces signaling through a cell membrane-expressed receptor that inhibits inflammatory immune cell function upon receptor activation. Such compounds may be, for example, biologics, such as antibodies, nanobodies, probodies, anticalins, or cyclic peptides, or small molecule inhibitors.

[0022] As used herein, the term "T cell" refers to a type of immune cell that plays a central role in adaptive immune responses. T cells are distinguished from other immune cells by the presence of either an αβ or γδ T cell receptor (TCR) on their cell surface. T cells also express CD3, a protein complex critical for TCR signaling. αβ T cells can be divided into either CD4, CD8, or CD4 / CD8 double-negative subsets. CD4 + and CD8 + Due to the high surface density of CD4 and CD8 on T cells, CD4 and CD8 alone act as CD4 + and CD8 + It can often be used to identify T cells. Following activation via TCR recognition of cognate antigens presented by MHC molecules, T cells can mature and divide to generate effector or memory T cells. Memory T cells are a subset of T cells that have previously encountered and responded to their cognate antigen. Such T cells can recognize pathogenic antigens, such as antigens derived from bacteria or viruses, as well as cancer-associated antigens. T cells can be identified by those skilled in the art using phenotyping techniques, such as flow cytometry. Phenotypic markers used to identify T cells are generally conserved in mammals and include CD3, TCRα, TCRβ, TCRδ, CD4, and CD8. Phenotypic markers used to identify memory T cells may vary by species and tissue, but may include cell surface markers, such as CD45RO, LY6C, CD44, and CD95.

[0023] As used herein, the term "intratumoral administration" refers to a mode of administration in which a drug is administered directly into tumor tissue. In certain embodiments, the term "intratumoral administration" can also refer to administration into or onto the tumor bed before or after resection. In cases where the tumor borders are poorly defined, intratumoral administration is also understood to include administration into tissue adjacent to tumor cells ("peritumoral administration"). Exemplary tumors for intratumoral administration are solid tumors and lymphomas, which are disclosed in more detail elsewhere herein. Administration can occur via injection.

[0024] As used herein, the term "baseline tissue" refers to a tissue sample taken from or adjacent to the area to be treated prior to treatment. For example, a biopsy of the tissue to be treated can be taken immediately prior to treatment. Because it is not always possible to take a reference sample from each area prior to treatment, it is understood that the term "baseline tissue" can also refer to untreated control tissue, which can be taken from a comparable location from the same animal or from a comparable location in a different animal of the same species. The term "animal" is understood to include humans, and in certain embodiments, to mean a mouse, rat, non-human primate, or human.

[0025] As used herein, the term "anti-tumor activity" refers to the ability to inhibit tumors from growing larger, i.e., tumor growth inhibition or tumor stasis, or the ability to cause a reduction in the size of a tumor, i.e., tumor regression.

[0026] Any reference herein to a biological drug, i.e., a drug produced from, extracted from, or semi-synthesized from a biological source, e.g., a protein drug, also encompasses the biosequences of said drug.

[0027] In the case of drugs containing a TLR7 / 8 agonist and another component, e.g., TLR7 / 8 reversibly conjugated to a polymer moiety, the dosage can be given in terms of the mass or moles of the TLR7 / 8 agonist moiety, or in terms of the entire drug, e.g., the TLR7 / 8 agonist conjugate. Unless otherwise clear from the context, dosages of TLR7 / 8 agonist conjugates are given in terms of the TLR7 / 8 agonist moiety. Thus, the phrases "0.5 mg of TLR7 / 8 agonist" and "0.5 mg of TLR7 / 8 agonist conjugate" are used interchangeably to provide a dose of the TLR7 / 8 agonist conjugate based on the amount of the TLR7 / 8 agonist moiety, which is 0.5 mg.

[0028] It is understood that the conjugates of the present invention are prodrugs.

[0029] As used herein, the term "prodrug" refers to a drug moiety that is reversibly and covalently linked to a specialized protecting group via a reversible prodrug linker moiety, which is a linker moiety that comprises a reversible linkage to the drug moiety, and the specialized protecting group alters or eliminates undesirable properties in the parent molecule. This includes enhancing desirable properties and suppressing undesirable properties in the drug. The specialized non-toxic protecting group can also be referred to as a "carrier," e.g., Z. A prodrug releases the reversibly and covalently linked drug moiety in the form of its corresponding drug. In other words, a prodrug is a drug moiety that is reversibly and covalently linked to a reversible linker moiety, e.g., -L. 1 -, wherein the covalent and reversible conjugation of the carrier to the reversible linker moiety is achieved directly or via a spacer, e.g., -L 2 -via a reversible linker. A reversible linker may also be referred to as a "reversible prodrug linker." Such a conjugate can release the previously conjugated drug moiety in the form of a free drug; in this case, the reversible linker or reversible prodrug linker is a traceless linker.

[0030] As used herein, the term "free form" of a drug means the drug in its unmodified, pharmacologically active form.

[0031] As used herein, the term "spacer" refers to a moiety that links at least two other moieties together.

[0032] As used herein, the terms "reversible," "reversibly," "degradable," or "degradably," with respect to the attachment of a first moiety to a second moiety, mean that the linkage connecting the first and second moieties is cleavable under physiological conditions, where physiological conditions are aqueous buffered solution at pH 7.4 and 37°C, and has a half-life ranging from 1 day to 3 months, e.g., 2 days to 2 months, e.g., 3 days to 1 month. Such cleavage is, in certain embodiments, non-enzymatic. Thus, the term "stable," with respect to the attachment of a first moiety to a second moiety, means that the linkage connecting the first and second moieties exhibits a half-life of greater than 3 months under physiological conditions.

[0033] As used herein, the term "reagent" means a chemical compound that contains at least one functional group for reaction with a functional group of another chemical compound or drug. Drugs that contain a functional group are also understood to be reagents.

[0034] As used herein, the term "moiety" refers to a portion of a molecule that lacks one or more atoms compared to a corresponding reagent. For example, when a reagent of the formula "HXH" reacts with another reagent and becomes part of a reaction product, the corresponding moiety in the reaction product has the structure "HX-" or "-X-," where each "-" indicates a bond to another moiety. Thus, the drug moiety, e.g., a TLR7 / 8 agonist moiety, is released from the reversible linkage as a drug, e.g., a TLR7 / 8 agonist drug.

[0035] Where a chemical structure of a group of atoms is provided and the group of atoms is connected to or interrupts two moieties, it is understood that the chemical structure can be connected to the two moieties in either orientation unless otherwise specified. For example, the moiety "-C(O)N(R 1 )-" is "-C(O)N(R 1 )-" or "-N(R 1 )C(O)-" can be used to connect two moieties or to interrupt one moiety.

[0036] [ka] teeth,

[0037] [ka] as or

[0038] [ka] As such, it can either be joined into two parts or broken into one part.

[0039] The term "substituted," as used herein, means that one or more --H atoms of a molecule or moiety are replaced with a different atom or group of atoms, referred to as "substituents."

[0040] As used herein, the term "substituent" includes, in certain embodiments, 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)R x1 , -S(O)R x1 , -N(Rx1 )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, -T 0 , C 1-50 Alkyl, C 2-50 Alkenyl, and C 2-50 Alkynyl may be one or more -R x2 is optionally replaced by C 1-50 Alkyl, C 2-50 Alkenyl, and C 2-50 Alkynyl is -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 )-; -R x1 , -Rx1a , -R x1b -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 may be one or more -R x2 is optionally replaced by C 1-50 Alkyl, C 2-50 Alkenyl, and C 2-50 Alkynyl is -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 )-; Each T 0 is phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, and 8- to 11-membered heterobicyclyl; 0 is one or more -R x2 is independently and optionally replaced by; Each-R x2 is halogen, -CN, oxo(=O), -COOR x4 , -OR x4 , -C(O)R x4 , -C(O)N(R x4 R x4a ), -S(O)2N(R x4 Rx4a ), -S(O)N(R x4 R x4a ), -S(O)R 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, wherein C 1-6 The alkyl is optionally substituted with one or more halogens which may be the same or different; Each-R x3 , -R x3a , -R x4 , -R x4a , -R x4b -H and C 1-6 alkyl, wherein C 1-6 The alkyl is optionally substituted with one or more halogens which may be the same or different.

[0041] In certain embodiments, up to six -H atoms of an optionally substituted molecule are independently replaced by substituents, e.g., five -H atoms are independently replaced by substituents, four -H atoms are independently replaced by substituents, three -H atoms are independently replaced by substituents, two -H atoms are independently replaced by substituents, or one -H atom is replaced by a substituent.

[0042] As used herein, the term "hydrogel" refers to a hydrophilic or amphiphilic polymer network composed of homopolymers or copolymers, which is insoluble due to the presence of hydrophobic interactions, hydrogen bonds, ionic interactions, and / or covalent chemical crosslinks. The crosslinks provide the network structure and physical integrity. In certain embodiments, the hydrogel is insoluble due to the presence of covalent chemical crosslinks.

[0043] As used herein, the term "crosslinker" refers to a moiety that is a link between different elements of a hydrogel, for example, between two or more backbone moieties or between two or more hyaluronic acid strands.

[0044] As used herein, the term "about" in conjunction with a numerical value is used to indicate a range (inclusive) of a numerical value plus or minus 25% of the numerical value, e.g., plus or minus 20% of the numerical value, or, e.g., plus or minus 10% of the numerical value. For example, the phrase "about 200" is used to mean a range of 200 + / - 25% (inclusive), i.e., a range of 150 to 250 (inclusive), e.g., 200 + / - 20%, i.e., a range of 160 to 240 (inclusive), or, e.g., a range of 200 + / - 10% (inclusive), i.e., a range of 180 to 220 (inclusive). A percentage stated as "about 50%" does not mean "50% + / - 25%," i.e., a range of 25% to 75%, inclusive; "about 50%" is understood to mean 37.5% to 62.5%, inclusive, i.e., plus or minus 25% of the numerical value 50. When the range encompassed by "about X" is defined by one or two decimal points at either or both ends of the range, and it is clear that only integers are appropriate values, the one or two decimal points are rounded using the "round half up" rule to obtain the nearest integer.

[0045] The term "approximately" is used synonymously with "about."

[0046] As used herein, the term "polymer" refers to a molecule comprising repeating structural units, i.e., monomers, linked by chemical bonds in a linear, cyclic, branched, cross-linked, dendrimeric, or combination thereof, and may be of synthetic or biological origin, or a combination of both. The monomers may be the same, in which case the polymer is a homopolymer, or different, in which case the polymer is a heteropolymer. Heteropolymers may also be referred to as "copolymers," and include, for example, alternating copolymers in which different types of monomers alternate; periodic copolymers in which different types of monomers are arranged in a repeating sequence; statistical copolymers in which different types of monomers are arranged randomly; block copolymers in which different homopolymeric blocks of only one type of monomer are covalently linked; and gradient copolymers in which the composition of different monomers gradually changes along the polymer chain. It is understood that a polymer can also contain one or more other moieties, such as one or more functional groups. The term "polymer" also refers to peptides or proteins, although the side chains of the individual amino acid residues may differ. It is understood that for covalently crosslinked polymers, such as hydrogels, no meaningful molecular weight range can be provided.

[0047] As used herein, the term "polymeric" refers to an agent or moiety that includes one or more polymers or polymeric moieties. A polymeric agent or moiety can optionally include one or more other moieties, which in certain embodiments are selected from the group consisting of: 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, indanyl, and tetralinyl; branch points, e.g., -CR<, >C< or -N<; and A link selected from the group including:

[0048] [ka] (In the formula, The dashed lines indicate attachment of the moiety or reagent to the remainder of the molecule; -R and -R a are independently selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, and 3,3-dimethylpropyl; These moieties and linkages are optionally further substituted).

[0049] In certain embodiments, the polymeric reagent or moiety can also optionally include one or more other moieties, which in certain embodiments are selected from the group consisting of: 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, indanyl, and tetralinyl; and A link selected from the group including:

[0050] [ka] (In the formula, The dashed line indicates the attachment of the moiety or reagent to the rest of the molecule; -R and -R a are independently selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and 3,3-dimethylpropyl; These moieties and linkages are optionally further substituted).

[0051] Those skilled in the art will understand that the polymerization products resulting from a polymerization reaction do not all have the same molecular weight, but rather exhibit a distribution of molecular weights. Consequently, as used herein, molecular weight range, molecular weight, range of the number of monomers in a polymer, and number of monomers in a polymer refer to the number average molecular weight and monomer number average, i.e., the arithmetic mean of the molecular weight of the polymer or polymer portion, and the arithmetic mean of the number of monomers in the polymer or polymer portion.

[0052] Thus, in a polymer segment comprising "x" monomer units, any integer given for "x" therefore corresponds to the arithmetic average number of monomers. Any range of integers given for "x" provides a range of integers within which the arithmetic average number of monomers lies. An integer "x" given as "about x" means that the arithmetic average number of monomers lies within an integer range of x + / - 25%, such as x + / - 20%, or such as x + / - 10%.

[0053] As used herein, the term "number average molecular weight" means the ordinary arithmetic mean of the molecular weights of the individual polymers.

[0054] As used herein, the term "PEG-based" in reference to a moiety or reagent means that the moiety or reagent comprises PEG. Such a PEG-based moiety or reagent comprises at least 10% (w / w) PEG, such as at least 20% (w / w) PEG, such as at least 30% (w / w) PEG, such as at least 40% (w / w) PEG, such as at least 50% (w / w), such as at least 60% (w / w) PEG, such as at least 70% (w / w) PEG, such as at least 80% (w / w) PEG, such as at least 90% (w / w) PEG, or such as at least 95% (w / w) PEG. The remaining weight percentage of the PEG-based moiety or reagent may be other moieties, such as selected from the group consisting of: C 1-50 Alkyl, C2-50 Alkenyl, C 2-50 Alkynyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, phenyl, naphthyl, indenyl, indanyl, and tetralinyl; and A link selected from the group consisting of:

[0055] [ka] (In the formula, The dashed line indicates the attachment of the moiety or reagent to the rest of the molecule; -R and -R a -H, and C 1-6 are independently selected from the group consisting of alkyl; These moieties and linkages are optionally further substituted).

[0056] The terms "poly(alkylene glycol)-based," "poly(propylene glycol)-based," and "hyaluronic acid-based" are used accordingly.

[0057] The term "interrupted" means that a moiety is inserted between two carbon atoms, or, if the insertion is at one of the termini of the moiety, between a carbon or heteroatom and a hydrogen atom.

[0058] As used herein, the term "C 1-4 "Alkyl," alone or in combination, means a straight or branched chain alkyl moiety having 1 to 4 carbon atoms. When present at the terminal end of a molecule, it is 1-4 Examples of alkyl are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. 1-4 When linked by an alkyl, such C 1-4Examples of alkyl groups are -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)-, and -C(CH3)2-. 1-4 Each hydrogen of an alkyl carbon may be optionally replaced by a substituent as defined above. 1-4 The alkyl may be interrupted by one or more moieties as defined below.

[0059] As used herein, the term "C 1-6 "Alkyl," alone or in combination, means a straight-chain or branched alkyl moiety having 1 to 6 carbon atoms. When present at the terminal end of a molecule, straight-chain and branched 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 linked by an alkyl group, such C 1-6 Examples for alkyl groups are -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)- and -C(CH3)2-. 1-6 Each hydrogen atom of the carbon may be optionally replaced by a substituent as defined above. 1-6 The alkyl may be interrupted by one or more moieties as defined below.

[0060] Therefore, "C 1-10 Alkyl," "C 1-20 Alkyl" or "C 1-50 "Alkyl" means an alkyl chain having 1 to 10, 1 to 20, or 1 to 50 carbon atoms, respectively; C 1-10 , C 1-20 or C 1-50Each hydrogen atom of the carbon may be optionally replaced by a substituent as defined above. 1-10 or C 1-50 The alkyl may be interrupted by one or more moieties as defined below.

[0061] As used herein, the term "C 2-6 "Alkenyl," alone or in combination, means a straight or branched hydrocarbon moiety containing at least one carbon-carbon double bond having 2 to 6 carbon atoms. When present at the end of the molecule, examples are -CH=CH2, -CH=CH-CH3, -CH2-CH=CH2, -CH=CHCH2-CH3, and -CH=CH-CH=CH2. When two portions of the molecule are C 2-6 When linked by an alkenyl group, such C 2-6 An example for alkenyl is -CH=CH-. 2-6 Each hydrogen atom of the alkenyl moiety may be optionally replaced by a substituent as defined above. 2-6 The alkenyl may be interrupted by one or more moieties as defined below.

[0062] Hence the term "C 2-10 alkenyl," "C 2-20 alkenyl" or "C 2-50 The term "alkenyl," alone or in combination, means a straight-chain or branched hydrocarbon moiety containing at least one carbon-carbon double bond, having 2 to 10, 2 to 20, or 2 to 50 carbon atoms, respectively. 2-10 Alkenyl group, C 2-20 Alkenyl group or C 2-50 Each hydrogen atom of the alkenyl group may be optionally replaced by a substituent as defined above. 2-10 Alkenyl, C 2-20 Alkenyl or C 2-50 The alkenyl may be interrupted by one or more moieties as defined below.

[0063] As used herein, the term "C 2-6 "Alkynyl," alone or in combination, means a straight-chain or branched hydrocarbon moiety containing at least one carbon-carbon triple bond having 2 to 6 carbon atoms. When present at the end of the molecule, examples are -C≡CH, -CH2-C≡CH, CH2-CH2-C≡CH, and CH2-C≡C-CH3. When two parts of the molecule are connected by an alkynyl group, an example is -C≡C-. C 2-6 Each hydrogen atom of the alkynyl group may be optionally replaced by a substituent as defined above. Optionally, one or more double bonds may occur. Optionally, C 2-6 The alkynyl may be interrupted by one or more moieties as defined below.

[0064] Therefore, as used herein, the term "C 2-10 alkynyl", "C 2-20 alkynyl" and "C 2-50 The term "alkynyl," alone or in combination, means a straight-chain or branched hydrocarbon moiety containing at least one carbon-carbon triple bond and having 2 to 10, 2 to 20, or 2 to 50 carbon atoms, respectively. 2-10 Alkynyl group, C 2-20 Alkynyl group or C 2-50 Each hydrogen atom of the alkynyl group may be optionally replaced by a substituent as defined above. Optionally, one or more double bonds may occur. Optionally, C 2-10 Alkynyl, C 2-20 Alkynyl or C 2-50 The alkynyl may be interrupted by one or more moieties as defined below.

[0065] As described 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, C2-20 Alkenyl, C 2-50 Alkenyl, C 2-6 Alkynyl, C 2-10 Alkynyl, C 2-20 Alkenyl or C 2-50 Alkynyl is

[0066] [ka] (In the formula, The dashed line indicates the attachment of the moiety or reagent to the rest of the molecule; -R and -R a -H and C 1-6 alkyl) may be optionally interrupted by one or more moieties which may be selected from the group consisting of:

[0067] As used herein, the term "C 3-10 "Cycloalkyl" means a cyclic alkyl chain having 3 to 10 carbon atoms, which may be saturated or unsaturated, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl. 3-10 Each hydrogen atom of a cycloalkyl carbon may be replaced by a substituent as defined above. 3-10 "Cycloalkyl" also includes bridged bicyclic rings such as norbornane or norbornene.

[0068] The term "8- to 30-membered carbopolycyclyl" or "8- to 30-membered carbopolycycle" refers to a cyclic moiety (fully, partially saturated, or unsaturated, aromatic or non-aromatic) having 8 to 30 ring atoms, in which two adjacent rings share at least one ring atom and may contain up to a maximum number of double bonds. In one embodiment, 8- to 30-membered carbopolycyclyl refers to a cyclic moiety having two, three, four, or five rings. In another embodiment, 8- to 30-membered carbopolycyclyl refers to a cyclic moiety having two, three, or four rings.

[0069] As used herein, the term "3- to 10-membered heterocyclyl" or "3- to 10-membered heterocycle" means a ring (fully, partially saturated, or unsaturated, aromatic or non-aromatic) having 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms, which may contain up to a maximum of double bonds, wherein at least one ring atom and up to four ring atoms are replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(O)-), oxygen, and nitrogen (including =N(O)-), and the ring is connected to the remainder 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, azirine, oxirene, thiylene, azetidine, oxetane, thietane, furan, thiophene, pyrrole, pyrroline, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, oxazoline, isoxazole, isoxazoline, thiazole, thiazoline, isothiazole, isothiazol, thiazoline, thiadiazole, thiadiazoline, tetrahydrofuran ... Examples of the 3- to 10-membered heterocyclyl group include pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, thiadiazolidine, sulfolane, pyran, dihydropyran, tetrahydropyran, imidazolidine, pyridine, pyridazine, pyrazine, pyrimidine, piperazine, piperidine, morpholine, tetrazole, triazole, triazolidine, tetrazolidine, diazepane, azepine, and homopiperazine. Each hydrogen atom of the 3- to 10-membered heterocyclyl group or the 3- to 10-membered heterocyclic group may be replaced by a substituent.

[0070] As used herein, the term "8- to 11-membered heterobicyclyl" or "8- to 11-membered heterobicycle" means a bicyclic heterocyclic moiety (fully, partially saturated, or unsaturated, aromatic or non-aromatic rings) having 8 to 11 ring atoms, in which at least one ring atom is shared by both rings and may contain up to a maximum number of double bonds, where at least one ring atom and up to six ring atoms are replaced by heteroatoms selected from the group consisting of sulfur (including -S(O)-, -S(O)-), oxygen, and nitrogen (including =N(O)-), and the rings are linked to the remainder of the molecule through a carbon or nitrogen atom. Examples of 8- to 11-membered heterobicycles are indole, indoline, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzimidazole, benzimidazoline, quinoline, quinazoline, dihydroquinazoline, quinoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, decahydroisoquinoline, tetrahydroisoquinoline, dihydroisoquinoline, benzazepine, purine, and pteridine. The term 8- to 11-membered heterobicycle also includes bicyclic spiro structures such as 1,4-dioxa-8-azaspiro[4.5]decane or bridged heterocycles such as 8-aza-bicyclo[3.2.1]octane. Each hydrogen atom of an 8- to 11-membered heterobicyclyl or an 8- to 11-membered heterobicycle carbon may be replaced by a substituent.

[0071] Similarly, the term "8- to 30-membered heteropolycyclyl" or "8- to 30-membered heteropolycycle" means a heterocyclic moiety (aromatic or non-aromatic rings that may be fully, partially saturated, or unsaturated) having more than two rings (e.g., three, four, or five rings) having 8 to 30 ring atoms, where two adjacent rings share at least one ring atom and may contain up to a maximum number of double bonds, and where at least one ring atom and up to ten ring atoms are replaced by a heteroatom selected from the group of sulfur (including -S(O)-, -S(O)-), oxygen, and nitrogen (including =N(O)-), and the ring is linked to the remainder of the molecule via a carbon or nitrogen atom.

[0072] "Pair R x / R y together with the atoms to which they are attached, C 3-10 The phrase "forms a cycloalkyl or 3- to 10-membered heterocyclyl" refers to the structure

[0073] [ka] In relation to the part of R x and R y But the following structure:

[0074] [ka] (Wherein R is C 3-10 cycloalkyl or 3- to 10-membered heterocyclyl is understood to mean forming

[0075] "Pair R x / R y together with the atoms to which they are attached form ring A" refers to the structure

[0076] [ka] In relation to the part of R x and R y But the following structure:

[0077] [ka] It is also understood to mean forming

[0078] As used herein, "halogen" means fluoro, chloro, bromo, or iodo. In certain embodiments, halogen is fluoro or chloro.

[0079] As used herein, the term "functional group" means a group of atoms that can react with another group of atoms. Exemplary functional groups are carboxylic acid, primary amine, secondary amine, tertiary amine, maleimide, thiol, sulfonic acid, carbonate, carbamate, hydroxyl, aldehyde, ketone, hydrazine, isocyanate, isothiocyanate, phosphoric acid, phosphonic acid, haloacetyl, alkyl halide, acryloyl, aryl fluoride, hydroxylamine, disulfide, sulfonamide, sulfate, vinyl sulfone, vinyl ketone, diazoalkane, oxirane, and aziridine.

[0080] When the conjugates of the present invention contain one or more acidic or basic groups, the present invention also includes their corresponding pharmaceutically or toxicologically acceptable salts, particularly their pharmaceutically acceptable salts. Thus, conjugates of the present invention containing acidic groups can be used in accordance with the present invention, for example, as alkali metal salts, alkaline earth metal salts, or ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts, or salts with ammonia or organic amines, such as ethylamine, ethanolamine, triethanolamine, amino acids, and quaternary ammonium salts such as tetrabutylammonium or cetyltrimethylammonium. Conjugates of the present invention containing one or more basic groups, i.e., protonatable groups, can exist and be used in accordance with the present invention in the form of their addition salts with inorganic or organic acids. Examples of suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, trifluoroacetic acid, and other acids known to those skilled in the art. Additional methods for converting basic groups to cations are known to those skilled in the art, such as alkylation of amine groups to provide a positively charged ammonium group and a suitable counterion for the salt. When the conjugates of the present invention simultaneously contain acidic and basic groups, the present invention also encompasses inner salts or betaines (zwitterions) in addition to the salt forms mentioned above. The respective salts can be obtained by conventional methods known to those skilled in the art, such as by contacting these prodrugs with an organic or inorganic acid or base in a solvent or dispersant, or by anion or cation exchange with other salts.The present invention also includes all salts of the conjugates of the present invention which, due to their low physiological compatibility, are not directly suitable for pharmaceutical use but can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.

[0081] The term "pharmaceutically acceptable" means a substance that does not cause harm when administered to a patient, and in certain embodiments means approved by a regulatory authority, e.g., the EMA (Europe) and / or the FDA (US) and / or any other national regulatory authority, for use in animals, e.g., for use in humans.

[0082] As used herein, the term "excipient" refers to a diluent, adjuvant, or vehicle with which a therapeutic agent, e.g., a drug or prodrug, is administered. Such pharmaceutical excipients can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as, but not limited to, peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water is a preferred excipient when the pharmaceutical composition is administered orally. Saline and aqueous dextrose are preferred excipients when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions are preferably used as liquid excipients for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, mannitol, trehalose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, hyaluronic acid, propylene glycol, water, ethanol, etc. The pharmaceutical compositions, if desired, can also contain minor amounts of wetting or emulsifying agents such as acetate, succinate, Tris, carbonate, phosphate, HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid), MES (2-(N-morpholino)ethanesulfonic acid), pH buffering agents, or surfactants such as Tween, poloxamer, poloxamine, CHAPS, Igepal, or amino acids such as glycine, lysine, or histidine. These pharmaceutical compositions can take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained-release formulations, and the like. Pharmaceutical compositions can be formulated as suppositories with traditional binders and excipients, such as triglycerides. Oral formulations can include standard excipients, such as pharmaceutical grades of 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 moiety together with an appropriate amount of excipient to provide the form for proper administration to the patient. The formulation should suit the mode of administration.

[0083] The term "peptide" or "polypeptide," as used herein, refers to a chain of at least two and up to, inclusive, 50 amino acid monomer moieties (sometimes referred to as "amino acid residues") linked by peptide (amide) bonds. The amino acid monomers can be selected from the group consisting of proteinogenic and non-proteinogenic amino acids and may be D- or L-amino acids. The term "peptide" also includes peptidomimetics, such as peptoids, beta-peptides, cyclic peptides, and depsipeptides, and encompasses such peptidomimetic chains having up to, inclusive, 50 monomer moieties.

[0084] As used herein, the term "protein" refers to a chain of more than 50 amino acid monomer moieties (sometimes referred to as "amino acid residues") linked by peptide bonds, where preferably no more than 12,000 amino acid monomers, 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 are linked by peptide bonds.

[0085] In general, the terms "comprise" or "comprising" also encompass "consist of" or "consisting of."

[0086] In certain embodiments, the TLR7 / 8 agonist of the first, second, and third embodiments is selected from the group consisting of CL075, CL097, poly(dT), resiquimod (R-848, VML600, S28463), MEDI9197 (3M-052), NKTR262, DV1001, IMO4200, IPH3201, and VTX1463.

[0087] In certain embodiments, the TLR7 / 8 agonist of the first, second, and third embodiments is resiquimod. Resiquimod has the following structure:

[0088] [ka]

[0089] In certain embodiments, the unit dosage form of the first aspect comprises a therapeutically effective amount of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients. In such cases, the unit dosage form comprises a pharmaceutical formulation comprising a therapeutically effective amount of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof.

[0090] A unit dosage form of the first aspect, in certain embodiments, comprises 0.5 mg of a TLR7 / 8 agonist. In certain embodiments, a unit dosage form of the first aspect comprises 1 mg of a TLR7 / 8 agonist. In certain embodiments, a unit dosage form of the first aspect comprises 2 mg of a TLR7 / 8 agonist. A unit dosage form of the first aspect, in certain embodiments, comprises 0.5 mg of a TLR7 / 8 agonist and one or more excipients. In certain embodiments, a unit dosage form of the first aspect comprises 1 mg of TLR7 / 8 and one or more excipients. In certain embodiments, a unit dosage form of the first aspect comprises 2 mg of TLR7 / 8 and one or more excipients. When a unit dosage form comprises, for example, 0.5 mg of a TLR7 / 8 agonist, it is understood that the dose of 0.5 mg of TLR7 / 8 is a unit dose.

[0091] In certain embodiments, the unit dosage form of the first aspect comprises 0.5 mg of resiquimod. In certain embodiments, the unit dosage form of the first aspect comprises 1 mg of resiquimod. In certain embodiments, the unit dosage form of the first aspect comprises 2 mg of resiquimod. In certain embodiments, the unit dosage form of the first aspect comprises 0.5 mg of resiquimod and one or more excipients. In certain embodiments, the unit dosage form of the first aspect comprises 2 mg of resiquimod and one or more excipients.

[0092] In certain embodiments, the unit dosage form of the first aspect comprises a pharmaceutical formulation comprising a TLR7 / 8 agonist, wherein the pharmaceutical formulation is a dry formulation, for example, a lyophilized formulation. Such a dry formulation is resuspended using a liquid, for example, sterile water or a sterile buffer solution, before administration to a patient. In certain embodiments, such a resuspended formulation is a suspension.

[0093] In certain embodiments, the unit dosage form of the first aspect comprises a pharmaceutical formulation comprising a TLR7 / 8 agonist, wherein the pharmaceutical formulation is a liquid formulation, for example a suspension.

[0094] In certain embodiments, the unit dosage form of the first aspect comprises the TLR7 / 8 agonist conjugate in a volume ranging from 0.1 ml to 2 ml. In certain embodiments, the unit dosage form of the first aspect comprises the TLR7 / 8 agonist conjugate in a volume ranging from 0.2 ml to 1.5 ml. In certain embodiments, the unit dosage form of the first aspect comprises the TLR7 / 8 agonist conjugate in a volume of 0.25 ml. In certain embodiments, the unit dosage form of the first aspect comprises the TLR7 / 8 agonist conjugate in a volume of 0.5 ml. In certain embodiments, the unit dosage form of the first aspect comprises the TLR7 / 8 agonist conjugate in a volume of 1 ml.

[0095] In certain embodiments, the unit dosage form of the first aspect comprises a TLR7 / 8 agonist conjugate in a volume ranging from 0.1 ml to 2 ml, wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dosage form of the first aspect comprises a TLR7 / 8 agonist conjugate in a volume ranging from 0.2 ml to 1.5 ml, wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dosage form of the first aspect comprises a TLR7 / 8 agonist conjugate in a volume of 0.25 ml, wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dosage form of the first aspect comprises a TLR7 / 8 agonist conjugate in a volume of 0.5 ml, wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dosage form of the first aspect comprises a TLR7 / 8 agonist conjugate in a volume of 1 ml, wherein the TLR7 / 8 agonist is resiquimod.

[0096] In certain embodiments, the unit dosage form of the first aspect comprises 0.5 mg of TLR7 / 8 agonist in a volume of 1 ml. In certain embodiments, the unit dosage form of the first aspect comprises 0.5 mg of TLR7 / 8 agonist in a volume of 0.25 ml. In certain embodiments, the unit dosage form of the first aspect comprises 1 mg of TLR7 / 8 agonist in a volume of 2 ml. In certain embodiments, the unit dosage form of the first aspect comprises 1 mg of TLR7 / 8 agonist in a volume of 0.5 ml.

[0097] In certain embodiments, the unit dosage form of the first aspect comprises 0.5 mg of the TLR7 / 8 agonist in a volume of 1 ml, wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dosage form of the first aspect comprises 0.5 mg of the TLR7 / 8 agonist in a volume of 0.25 ml, wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dosage form of the first aspect comprises 1 mg of the TLR7 / 8 agonist in a volume of 2 ml, wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dosage form of the first aspect comprises 1 mg of the TLR7 / 8 agonist in a volume of 0.5 ml, wherein the TLR7 / 8 agonist is resiquimod.

[0098] In certain embodiments, the unit dosage form is a vial, dual chamber cartridge, ampoule, or syringe containing a unit dose.

[0099] In certain embodiments, the unit dosage form is a vial containing a unit dose. Such a vial may have a stopper, such as a bromobutyl stopper, and a seal cap, such as an aluminum seal cap. In certain embodiments, the vial is a glass vial, such as a type 1 glass vial. Such a vial may have a size of, for example, 1 ml, 2 ml, or 5 ml.

[0100] In certain embodiments, the unit dosage form is stored at a temperature ranging from -80°C to +25°C. In certain embodiments, the unit dosage form is stored at a temperature ranging from -80°C to 10°C. In certain embodiments, the unit dosage form is stored at a temperature ranging from -80°C to -60°C. In certain embodiments, the unit dosage form is stored at a temperature ranging from -30°C to -15°C. In certain embodiments, the unit dosage form is stored at a temperature ranging from 0°C to +10°C. In certain embodiments, the unit dosage form is stored at about -80°C. In certain embodiments, the unit dosage form is stored at -80°C. In certain embodiments, the unit dosage form is stored at about -20°C. In certain embodiments, the unit dosage form is stored at -20°C. In certain embodiments, the unit dosage form is stored at a temperature ranging from 2°C to 8°C.

[0101] In certain embodiments, the unit dosage form of the first aspect is a vial containing the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof. In certain embodiments, the unit dosage form of the first aspect is a vial containing 0.5 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof. In certain embodiments, the unit dosage form of the first aspect is a vial containing 1 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof. In certain embodiments, the unit dosage form of the first aspect is a vial containing 2 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof.

[0102] In certain embodiments, the unit dosage form of the first aspect is a vial containing a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients. In certain embodiments, the unit dosage form of the first aspect is a vial containing 0.5 mg of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients. In certain embodiments, the unit dosage form of the first aspect is a vial containing 1 mg of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients. In certain embodiments, the unit dosage form of the first aspect is a vial containing 2 mg of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients.

[0103] In certain embodiments, the unit dosage form of the first aspect is a vial containing the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof, the contents of the vial being lyophilized. In certain embodiments, the unit dosage form of the first aspect is a vial containing 0.5 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof, the contents of the vial being lyophilized. In certain embodiments, the unit dosage form of the first aspect is a vial containing 1 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof, the contents of the vial being lyophilized. In certain embodiments, the unit dosage form of the first aspect is a vial containing 2 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof, the contents of the vial being lyophilized.

[0104] In certain embodiments, the unit dosage form of the first aspect is a vial containing a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients, the contents of the vial being lyophilized. In certain embodiments, the unit dosage form of the first aspect is a vial containing 0.5 mg of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients, the contents of the vial being lyophilized. In certain embodiments, the unit dosage form of the first aspect is a vial containing 1 mg of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients, the contents of the vial being lyophilized. In certain embodiments, the unit dosage form of the first aspect is a vial containing 2 mg of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients, the contents of the vial being lyophilized.

[0105] In certain embodiments, the unit dosage form of the first aspect is a vial containing a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof, wherein the contents of the vial are a liquid, such as a suspension. In certain embodiments, the unit dosage form of the first aspect is a vial containing 0.5 mg of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof, wherein the contents of the vial are a liquid, such as a suspension. In certain embodiments, the unit dosage form of the first aspect is a vial containing 1 mg of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof, wherein the contents of the vial are a liquid, such as a suspension. In certain embodiments, the unit dosage form of the first aspect is a vial containing 2 mg of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof, wherein the contents of the vial are a liquid, such as a suspension.

[0106] In certain embodiments, the unit dosage form of the first aspect is a vial containing a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients, the contents of the vial being a liquid, for example, a suspension. In certain embodiments, the unit dosage form of the first aspect is a vial containing 0.5 mg of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients, the contents of the vial being a liquid, for example, a suspension. In certain embodiments, the unit dosage form of the first aspect is a vial containing 1 mg of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients, the contents of the vial being a liquid, for example, a suspension. In certain embodiments, the unit dosage form of the first aspect is a vial containing 2 mg of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients, the contents of the vial being a liquid, for example, a suspension.

[0107] In certain embodiments, the unit dosage form of the first aspect is a vial containing a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof, wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dosage form of the first aspect is a vial containing 0.5 mg of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof, wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dosage form of the first aspect is a vial containing 1 mg of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof, wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dosage form of the first aspect is a vial containing 2 mg of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof, wherein the TLR7 / 8 agonist is resiquimod.

[0108] In certain embodiments, the unit dosage form of the first aspect is a vial containing a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients, wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dosage form of the first aspect is a vial containing 0.5 mg of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients, wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dosage form of the first aspect is a vial containing 1 mg of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients, wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dosage form of the first aspect is a vial containing 2 mg of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients, wherein the TLR7 / 8 agonist is resiquimod.

[0109] In certain embodiments, the unit dosage form of the first aspect is a vial containing a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof, wherein the TLR7 / 8 agonist is resiquimod, and the contents of the vial are lyophilized. In certain embodiments, the unit dosage form of the first aspect is a vial containing 0.5 mg of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof, wherein the TLR7 / 8 agonist is resiquimod, and the contents of the vial are lyophilized. In certain embodiments, the unit dosage form of the first aspect is a vial containing 1 mg of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof, wherein the TLR7 / 8 agonist is resiquimod, and the contents of the vial are lyophilized. In certain embodiments, the unit dosage form of the first aspect is a vial containing 2 mg of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof, wherein the TLR7 / 8 agonist is resiquimod, and the contents of the vial are lyophilized.

[0110] In certain embodiments, the unit dosage form of the first aspect is a vial containing a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients, wherein the TLR7 / 8 agonist is resiquimod, and the contents of the vial are lyophilized. In certain embodiments, the unit dosage form of the first aspect is a vial containing 0.5 mg of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients, wherein the TLR7 / 8 agonist is resiquimod, and the contents of the vial are lyophilized. In certain embodiments, the unit dosage form of the first aspect is a vial containing 1 mg of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients, wherein the TLR7 / 8 agonist is resiquimod, and the contents of the vial are lyophilized. In certain embodiments, the unit dosage form of the first aspect is a vial containing 2 mg of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients, wherein the TLR7 / 8 agonist is resiquimod, and the contents of the vial are lyophilized.

[0111] In certain embodiments, the unit dosage form of the first aspect is a vial containing a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof, wherein the TLR7 / 8 agonist is resiquimod, and the contents of the vial are a liquid, e.g., a suspension. In certain embodiments, the unit dosage form of the first aspect is a vial containing 0.5 mg of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof, wherein the TLR7 / 8 agonist is resiquimod, and the contents of the vial are a liquid, e.g., a suspension. In certain embodiments, the unit dosage form of the first aspect is a vial containing 1 mg of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof, wherein the TLR7 / 8 agonist is resiquimod, and the contents of the vial are a liquid, e.g., a suspension. In certain embodiments, the unit dosage form of the first aspect is a vial containing 2 mg of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof, wherein the TLR7 / 8 agonist is resiquimod, and the contents of the vial are a liquid, e.g., a suspension.

[0112] In certain embodiments, the unit dosage form of the first aspect is a vial containing a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients, wherein the TLR7 / 8 agonist is resiquimod, and the contents of the vial are a liquid, e.g., a suspension. In certain embodiments, the unit dosage form of the first aspect is a vial containing 0.5 mg of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients, wherein the TLR7 / 8 agonist is resiquimod, and the contents of the vial are a liquid, e.g., a suspension. In certain embodiments, the unit dosage form of the first aspect is a vial containing 1 mg of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients, wherein the TLR7 / 8 agonist is resiquimod, and the contents of the vial are a liquid, e.g., a suspension. In certain embodiments, the unit dosage form of the first aspect is a vial containing 2 mg of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients, wherein the TLR7 / 8 agonist is resiquimod, and the contents of the vial are a liquid, e.g., a suspension.

[0113] In certain embodiments, the unit dosage form of the first aspect is a dual-chamber cartridge comprising a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof in the first chamber. In certain embodiments, the unit dosage form of the first aspect is a dual-chamber cartridge comprising 0.5 mg of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof in the first chamber. In certain embodiments, the unit dosage form of the first aspect is a dual-chamber cartridge comprising 1 mg of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof in the first chamber. In certain embodiments, the unit dosage form of the first aspect is a dual-chamber cartridge comprising 2 mg of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof in the first chamber.

[0114] In certain embodiments, the unit dosage form of the first aspect is a dual-chamber cartridge comprising a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients in the first chamber. In certain embodiments, the unit dosage form of the first aspect is a dual-chamber cartridge comprising 0.5 mg of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients in the first chamber. In certain embodiments, the unit dosage form of the first aspect is a dual-chamber cartridge comprising 1 mg of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients in the first chamber. In certain embodiments, the unit dosage form of the first aspect is a dual-chamber cartridge comprising 2 mg of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients in the first chamber.

[0115] In certain embodiments, the unit dosage form of the first aspect is a dual-chamber cartridge comprising a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof in the first chamber, wherein the contents of the first chamber are lyophilized. In certain embodiments, the unit dosage form of the first aspect is a dual-chamber cartridge comprising 0.5 mg of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof in the first chamber, wherein the contents of the first chamber are lyophilized. In certain embodiments, the unit dosage form of the first aspect is a dual-chamber cartridge comprising 1 mg of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof in the first chamber, wherein the contents of the first chamber are lyophilized. In certain embodiments, the unit dosage form of the first aspect is a dual-chamber cartridge comprising 2 mg of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof in the first chamber, wherein the contents of the first chamber are lyophilized.

[0116] In certain embodiments, the unit dosage form of the first aspect is a dual-chamber cartridge comprising a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients in a first chamber, wherein the contents of the first chamber are lyophilized. In certain embodiments, the unit dosage form of the first aspect is a dual-chamber cartridge comprising 0.5 mg of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients in a first chamber, wherein the contents of the first chamber are lyophilized. In certain embodiments, the unit dosage form of the first aspect is a dual-chamber cartridge comprising 1 mg of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients in a first chamber, wherein the contents of the first chamber are lyophilized. In certain embodiments, the unit dosage form of the first aspect is a dual-chamber cartridge comprising 2 mg of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients in a first chamber, wherein the contents of the first chamber are lyophilized.

[0117] In certain embodiments, the unit dosage form of the first aspect is a dual-chamber cartridge comprising a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof in the first chamber, wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dosage form of the first aspect is a dual-chamber cartridge comprising 0.5 mg of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof in the first chamber, wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dosage form of the first aspect is a dual-chamber cartridge comprising 1 mg of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof in the first chamber, wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dosage form of the first aspect is a dual-chamber cartridge comprising 2 mg of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof in the first chamber, wherein the TLR7 / 8 agonist is resiquimod.

[0118] In certain embodiments, the unit dosage form of the first aspect is a dual-chamber cartridge comprising a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients in the first chamber, wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dosage form of the first aspect is a dual-chamber cartridge comprising 0.5 mg of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients in the first chamber, wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dosage form of the first aspect is a dual-chamber cartridge comprising 1 mg of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients in the first chamber, wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dosage form of the first aspect is a dual-chamber cartridge comprising 2 mg of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients in a first chamber, wherein the TLR7 / 8 agonist is resiquimod.

[0119] In certain embodiments, the unit dosage form of the first aspect is a dual-chamber cartridge comprising a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof in a first chamber, wherein the TLR7 / 8 agonist is resiquimod, and the contents of the first chamber are lyophilized. In certain embodiments, the unit dosage form of the first aspect is a dual-chamber cartridge comprising 0.5 mg of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof in a first chamber, wherein the TLR7 / 8 agonist is resiquimod, and the contents of the first chamber are lyophilized. In certain embodiments, the unit dosage form of the first aspect is a dual-chamber cartridge comprising 1 mg of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof in a first chamber, wherein the TLR7 / 8 agonist is resiquimod, and the contents of the first chamber are lyophilized. In certain embodiments, the unit dosage form of the first aspect is a dual-chamber cartridge comprising 2 mg of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof in a first chamber, wherein the TLR7 / 8 agonist is resiquimod, and the contents of the first chamber are lyophilized.

[0120] In certain embodiments, the unit dosage form of the first aspect is a dual-chamber cartridge comprising a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients in a first chamber, wherein the TLR7 / 8 agonist is resiquimod, and the contents of the first chamber are lyophilized. In certain embodiments, the unit dosage form of the first aspect is a dual-chamber cartridge comprising 0.5 mg of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients in a first chamber, wherein the TLR7 / 8 agonist is resiquimod, and the contents of the first chamber are lyophilized. In certain embodiments, the unit dosage form of the first aspect is a dual-chamber cartridge comprising 1 mg of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients in a first chamber, wherein the TLR7 / 8 agonist is resiquimod, and the contents of the first chamber are lyophilized. In certain embodiments, the unit dosage form of the first aspect is a dual-chamber cartridge comprising 2 mg of a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients in a first chamber, wherein the TLR7 / 8 agonist is resiquimod, and the contents of the first chamber are lyophilized.

[0121] In all embodiments, the second chamber of the dual chamber cartridge may contain a resuspension buffer or water.

[0122] In certain embodiments, the unit dosage form of the first aspect comprises a pharmaceutical formulation comprising a TLR7 / 8 agonist, such as resiquimod, wherein the pharmaceutical formulation is a liquid or resuspended formulation having a concentration ranging from 0.5 mg of TLR7 / 8 agonist (e.g., resiquimod) per ml to 2 mg of TLR7 / 8 agonist (e.g., resiquimod) per ml. In certain embodiments, the concentration is 0.5 mg of TLR7 / 8 agonist, such as resiquimod, per ml. In certain embodiments, the concentration is 1 mg of TLR7 / 8 agonist, such as resiquimod, per ml.

[0123] In certain embodiments, the unit dosage form of the first aspect is for use in treating cancer, particularly solid tumors. In certain embodiments, a unit dose of the unit dosage form of the first aspect is administered via intratumoral injection, for example, by using a fanning technique. In certain embodiments, the solid tumor is selected from the group consisting of lip and oral cavity cancer, oral cancer, liver cancer / hepatocellular carcinoma, primary liver cancer, lung cancer, lymphoma, malignant mesothelioma, malignant thymoma, skin cancer, intraocular melanoma, metastatic squamous neck cancer of unknown primary, childhood multiple endocrine neoplasia syndrome, mycosis fungoides, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, oropharyngeal cancer, ovarian cancer, pancreatic cancer, parathyroid cancer, pheochromocytoma, pituitary tumor, adrenocortical carcinoma, AIDS-related malignancies, anal cancer, bile duct cancer, bladder cancer, brain and nervous system cancer, breast cancer, bronchial adenoma / carcinoma The solid tumor is selected from the group consisting of: gastrointestinal carcinoid tumor, carcinoma, colorectal cancer, endometrial cancer, esophageal cancer, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, gallbladder cancer, stomach cancer (gastric cancer), gestational trophoblastic tumor, head and neck cancer, hypopharyngeal cancer, islet cell carcinoma (endocrine pancreas), kidney cancer / renal cell carcinoma, laryngeal cancer, pleuropulmonary blastoma, prostate cancer, transitional cell carcinoma of the renal pelvis and ureter, retinoblastoma, salivary gland cancer, sarcoma, Sézary syndrome, small intestine cancer, genitourinary cancer, malignant thymoma, thyroid cancer, Wilms' tumor, and cholangiocarcinoma. In certain embodiments, the solid tumor is selected from the group consisting of squamous cell carcinoma of the head and neck (SCCHN); HPV-associated cancers, such as anal cancer, vulvar cancer, cervical cancer, penile cancer, and vaginal cancer; melanoma; pancreatic cancer, and breast cancer, such as triple-negative breast cancer (TNBC). In certain embodiments, the solid tumor is selected from the group consisting of pancreatic cancer, prostate cancer, melanoma, SCCHN, cutaneous squamous cell carcinoma (cSCC), and cervical cancer. In certain embodiments, the solid tumor is pancreatic cancer. In certain embodiments, the solid tumor is prostate cancer. In certain embodiments, the solid tumor is melanoma. In certain embodiments, the solid tumor is SCCHN. In certain embodiments, the solid tumor is cSCC. In certain embodiments, the solid tumor is cervical cancer.

[0124] In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose is administered to a patient every two to four weeks. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose is administered to a patient every two weeks. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose is administered to a patient every three weeks. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose is administered to a patient every four weeks.

[0125] In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose is administered to a patient every 5 weeks. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose is administered to a patient every 6 weeks. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose is administered to a patient every 7 weeks. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose is administered to a patient every 8 weeks. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose is administered to a patient every 9 weeks. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose is administered to a patient every 10 weeks. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose is administered to a patient every 12 weeks. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose is administered to a patient every six months. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose is administered to a patient every seven months. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose is administered to a patient every eight months. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose is administered to a patient every nine months. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose is administered to a patient every ten months. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose is administered to a patient every eleven months. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose is administered to a patient once a year.

[0126] In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose is administered at a frequency dependent on disease progression.

[0127] In certain embodiments, the unit dose is 0.5 mg of TLR7 / 8 agonist per tumor. In certain embodiments, the unit dose is 1 mg of TLR7 / 8 agonist per tumor. Such a unit dose may be administered via intratumoral injection, for example, by using fanning techniques.

[0128] In certain embodiments, treating cancer involves administering a unit dose to one tumor in a patient. In certain embodiments, treating cancer involves administering a unit dose to more than one tumor in a patient, for example, two, three, four, or five tumors, or to all tumors in a patient that are of sufficient size and accessible for treatment. When treatment involves administration to more than one tumor per patient, such administration can occur within a maximum of four hours, e.g., within three hours, two hours, or one hour. In certain embodiments, administration to more than one tumor occurs consecutively, with no break between administrations. In certain embodiments, administration to different tumors in a patient occurs at different times, such that the time between one administration and the next administration ranges from one day to three weeks, and in certain embodiments, is one week, two weeks, or three weeks.

[0129] In certain embodiments, the treatment involves the administration of a unit dose to the patient's tumor, e.g., a single dose of 0.5 mg of a TLR7 / 8 agonist (e.g., resiquimod) per tumor, where the unit dose is administered as a single intratumoral injection. In certain embodiments, the treatment involves the administration of multiple unit doses to the patient's tumor, e.g., multiple doses of 0.5 mg of a TLR7 / 8 agonist (e.g., resiquimod) per tumor administered via intratumoral injection, where each unit dose is administered as a single intratumoral injection. Such treatment using multiple administrations per tumor, in certain embodiments, means two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, or more administrations to a particular tumor in the patient. In certain embodiments, more than one tumor in the patient is treated using such multiple administrations.

[0130] In certain embodiments, the unit dose of the unit dosage form of the first aspect comprises 0.5 mg of the TLR7 / 8 agonist conjugate and is for use in the treatment of cancer, wherein the unit dose is administered to a patient every 2 to 4 weeks. In certain embodiments, the unit dose of the unit dosage form of the first aspect comprises 0.5 mg of the TLR7 / 8 agonist conjugate and is for use in the treatment of cancer, wherein the unit dose is administered to a patient every 2 weeks. In certain embodiments, the unit dose of the unit dosage form of the first aspect comprises 0.5 mg of the TLR7 / 8 agonist conjugate and is for use in the treatment of cancer, wherein the unit dose is administered to a patient every 3 weeks. In certain embodiments, the unit dose of the unit dosage form of the first aspect comprises 0.5 mg of the TLR7 / 8 agonist conjugate and is for use in the treatment of cancer, wherein the unit dose is administered to a patient every 4 weeks.

[0131] In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose is administered to a patient every two to four weeks via intratumoral administration. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose is administered to a patient every two weeks via intratumoral administration. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose is administered to a patient every three weeks via intratumoral administration. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose is administered to a patient every four weeks via intratumoral administration.

[0132] In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose comprises 0.5 mg of the TLR7 / 8 agonist conjugate and is administered to a patient every two to four weeks via intratumoral administration. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose comprises 0.5 mg of the TLR7 / 8 agonist conjugate and is administered to a patient every two weeks via intratumoral administration. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose comprises 0.5 mg of the TLR7 / 8 agonist conjugate and is administered to a patient every three weeks via intratumoral administration. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose comprises 0.5 mg of the TLR7 / 8 agonist conjugate and is administered to a patient every four weeks via intratumoral administration.

[0133] In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose is administered to a patient every two to four weeks via intratumoral administration using fanning techniques. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose is administered to a patient every two weeks via intratumoral administration using fanning techniques. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose is administered to a patient every three weeks via intratumoral administration using fanning techniques. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose is administered to a patient every four weeks via intratumoral administration using fanning techniques.

[0134] In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose comprises 0.5 mg of the TLR7 / 8 agonist conjugate and is administered to a patient every two to four weeks via intratumoral administration using fanning techniques. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose comprises 0.5 mg of the TLR7 / 8 agonist conjugate and is administered to a patient every two weeks via intratumoral administration using fanning techniques. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose comprises 0.5 mg of the TLR7 / 8 agonist conjugate and is administered to a patient every three weeks via intratumoral administration using fanning techniques. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dose comprises 0.5 mg of the TLR7 / 8 agonist conjugate and is administered to a patient every four weeks via intratumoral administration using fanning techniques.

[0135] In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose is administered to a patient every two to four weeks, and the treatment is a co-therapy with an immune checkpoint inhibitor, and the immune checkpoint inhibitor may be given before, with, or after administration of the TLR7 / 8 agonist conjugate. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose is administered to a patient every two weeks, and the treatment is a co-therapy with an immune checkpoint inhibitor, and the immune checkpoint inhibitor may be given before, with, or after administration of the TLR7 / 8 agonist conjugate. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose is administered to a patient every three weeks, and the treatment is a co-therapy with an immune checkpoint inhibitor, and the immune checkpoint inhibitor may be given before, with, or after administration of the TLR7 / 8 agonist conjugate. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose is administered to a patient every four weeks, and wherein the treatment is co-treatment with an immune checkpoint inhibitor, which may be given before, with, or after administration of the TLR7 / 8 agonist conjugate.

[0136] In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose comprises 0.5 mg of the TLR7 / 8 agonist conjugate and is administered to a patient every two to four weeks, wherein the treatment is co-therapy with an immune checkpoint inhibitor, which may be given before, with, or after administration of the TLR7 / 8 agonist conjugate. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose comprises 0.5 mg of the TLR7 / 8 agonist conjugate and is administered to a patient every two weeks, wherein the treatment is co-therapy with an immune checkpoint inhibitor, which may be given before, with, or after administration of the TLR7 / 8 agonist conjugate. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose comprises 0.5 mg of the TLR7 / 8 agonist conjugate and is administered to a patient every three weeks, wherein the treatment is co-therapy with an immune checkpoint inhibitor, and wherein the immune checkpoint inhibitor may be given before, with, or after administration of the TLR7 / 8 agonist conjugate. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose comprises 0.5 mg of the TLR7 / 8 agonist conjugate and is administered to a patient every four weeks, wherein the treatment is co-therapy with an immune checkpoint inhibitor, and wherein the immune checkpoint inhibitor may be given before, with, or after administration of the TLR7 / 8 agonist conjugate.

[0137] In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dose is administered to a patient every two to four weeks, and the treatment is co-therapy with an inhibitor of PD-1 or an inhibitor of PD-L1, and the PD-1 inhibitor or PD-L1 inhibitor may be given before, with, or after administration of the TLR7 / 8 agonist conjugate. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dose is administered to a patient every two weeks, and the treatment is co-therapy with an inhibitor of PD-1 or an inhibitor of PD-L1, and the PD-1 inhibitor or PD-L1 inhibitor may be given before, with, or after administration of the TLR7 / 8 agonist conjugate. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose is administered to a patient every three weeks, and the treatment is co-therapy with an inhibitor of PD-1 or an inhibitor of PD-L1, and the PD-1 inhibitor or PD-L1 inhibitor may be given before, with, or after administration of the TLR7 / 8 agonist conjugate. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose is administered to a patient every four weeks, and the treatment is co-therapy with an inhibitor of PD-1 or an inhibitor of PD-L1, and the PD-1 inhibitor or PD-L1 inhibitor may be given before, with, or after administration of the TLR7 / 8 agonist conjugate.

[0138] In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dose comprises 0.5 mg of the TLR7 / 8 agonist conjugate and is administered to a patient every two to four weeks, wherein the treatment is co-therapy with an inhibitor of PD-1 or an inhibitor of PD-L1, and wherein the inhibitor of PD-1 or the inhibitor of PD-L1 may be given before, with, or after administration of the TLR7 / 8 agonist conjugate. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dose comprises 0.5 mg of the TLR7 / 8 agonist conjugate and is administered to a patient every two weeks, wherein the treatment is co-therapy with an inhibitor of PD-1 or an inhibitor of PD-L1, and wherein the inhibitor of PD-1 or the inhibitor of PD-L1 may be given before, with, or after administration of the TLR7 / 8 agonist conjugate. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose comprises 0.5 mg of the TLR7 / 8 agonist conjugate and is administered to a patient every three weeks, wherein the treatment is co-therapy with an inhibitor of PD-1 or an inhibitor of PD-L1, and wherein the inhibitor of PD-1 or the inhibitor of PD-L1 may be given before, with, or after administration of the TLR7 / 8 agonist conjugate. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose comprises 0.5 mg of the TLR7 / 8 agonist conjugate and is administered to a patient every four weeks, wherein the treatment is co-therapy with an inhibitor of PD-1 or an inhibitor of PD-L1, and wherein the inhibitor of PD-1 or the inhibitor of PD-L1 may be given before, with, or after administration of the TLR7 / 8 agonist conjugate.

[0139] The inhibitor of PD-1 (programmed cell death protein 1) may be selected from the group consisting of pembrolizumab, nivolumab, pidilizumab, AMP-224, BMS-936559, cemiplimab, and PDR 001. The inhibitor of PD-L1 (programmed cell death ligand 1) may be selected from the group consisting of MDX-1105, MEDI4736, atezolizumab, avelumab, BMS-936559, and durvalumab.

[0140] In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose is administered to a patient every two to four weeks, and the treatment is co-therapy with an inhibitor of PD-1, and the PD-1 inhibitor may be given before, with, or after administration of the TLR7 / 8 agonist conjugate. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose is administered to a patient every two weeks, and the treatment is co-therapy with an inhibitor of PD-1, and the PD-1 inhibitor may be given before, with, or after administration of the TLR7 / 8 agonist conjugate. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose is administered to a patient every three weeks, and the treatment is co-therapy with an inhibitor of PD-1, and the PD-1 inhibitor may be given before, with, or after administration of the TLR7 / 8 agonist conjugate. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dose is administered to a patient every four weeks, and wherein the treatment is co-treatment with an inhibitor of PD-1, which may be given before, with, or after administration of the TLR7 / 8 agonist conjugate.

[0141] In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dose comprises 0.5 mg of the TLR7 / 8 agonist conjugate and is administered to a patient every two to four weeks, wherein the treatment is co-therapy with an inhibitor of PD-1, which may be given before, with, or after administration of the TLR7 / 8 agonist conjugate. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dose comprises 0.5 mg of the TLR7 / 8 agonist conjugate and is administered to a patient every two weeks, wherein the treatment is co-therapy with an inhibitor of PD-1, which may be given before, with, or after administration of the TLR7 / 8 agonist conjugate. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose comprises 0.5 mg of the TLR7 / 8 agonist conjugate and is administered to a patient every three weeks, wherein the treatment is co-therapy with an inhibitor of PD-1, which may be given before, with, or after administration of the TLR7 / 8 agonist conjugate. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose comprises 0.5 mg of the TLR7 / 8 agonist conjugate and is administered to a patient every four weeks, wherein the treatment is co-therapy with an inhibitor of PD-1, which may be given before, with, or after administration of the TLR7 / 8 agonist conjugate.

[0142] In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose is administered to a patient every two to four weeks, and the treatment is co-therapy with an inhibitor of PD-L1, and the PD-L1 inhibitor may be given before, with, or after administration of the TLR7 / 8 agonist conjugate. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose is administered to a patient every two weeks, and the treatment is co-therapy with an inhibitor of PD-L1, and the PD-L1 inhibitor may be given before, with, or after administration of the TLR7 / 8 agonist conjugate. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose is administered to a patient every three weeks, and the treatment is co-therapy with an inhibitor of PD-L1, and the PD-L1 inhibitor may be given before, with, or after administration of the TLR7 / 8 agonist conjugate. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose is administered to a patient every four weeks, and wherein the treatment is co-treatment with an inhibitor of PD-L1, which may be given before, with, or after administration of the TLR7 / 8 agonist conjugate.

[0143] In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dosage comprises 0.5 mg of the TLR7 / 8 agonist conjugate and is administered to a patient every two to four weeks, and the treatment is co-therapy with an inhibitor of PD-L1, which may be given before, with, or after administration of the TLR7 / 8 agonist conjugate. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dosage comprises 0.5 mg of the TLR7 / 8 agonist conjugate and is administered to a patient every two weeks, and the treatment is co-therapy with an inhibitor of PD-L1, which may be given before, with, or after administration of the TLR7 / 8 agonist conjugate. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dosage comprises 0.5 mg of the TLR7 / 8 agonist conjugate and is administered to a patient every three weeks, wherein the treatment is co-therapy with an inhibitor of PD-L1, which may be given before, with, or after administration of the TLR7 / 8 agonist conjugate. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dosage comprises 0.5 mg of the TLR7 / 8 agonist conjugate and is administered to a patient every four weeks, wherein the treatment is co-therapy with an inhibitor of PD-L1, which may be given before, with, or after administration of the TLR7 / 8 agonist conjugate.

[0144] In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dose is administered to a patient every two to four weeks, and the treatment is co-therapy with pembrolizumab, which may be given before, with, or after administration of the TLR7 / 8 agonist conjugate. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dose is administered to a patient every two weeks, and the treatment is co-therapy with pembrolizumab, which may be given before, with, or after administration of the TLR7 / 8 agonist conjugate. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dose is administered to a patient every three weeks, and the treatment is co-therapy with pembrolizumab, which may be given before, with, or after administration of the TLR7 / 8 agonist conjugate. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dose is administered to a patient every four weeks, and the treatment is co-therapy with pembrolizumab, which may be given before, with, or after administration of the TLR7 / 8 agonist conjugate.

[0145] In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dosage comprises 0.5 mg of the TLR7 / 8 agonist conjugate and is administered to a patient every two to four weeks, and the treatment is co-therapy with pembrolizumab, which may be given before, with, or after administration of the TLR7 / 8 agonist conjugate. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dosage comprises 0.5 mg of the TLR7 / 8 agonist conjugate and is administered to a patient every two weeks, and the treatment is co-therapy with pembrolizumab, which may be given before, with, or after administration of the TLR7 / 8 agonist conjugate. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dosage comprises 0.5 mg of the TLR7 / 8 agonist conjugate and is administered to a patient every three weeks, wherein the treatment is co-therapy with pembrolizumab, which may be given before, with, or after administration of the TLR7 / 8 agonist conjugate. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dosage comprises 0.5 mg of the TLR7 / 8 agonist conjugate and is administered to a patient every four weeks, wherein the treatment is co-therapy with pembrolizumab, which may be given before, with, or after administration of the TLR7 / 8 agonist conjugate.

[0146] Pembrolizumab may be given according to its prescribing information, e.g., 200 mg of pembrolizumab by intravenous infusion every 3 weeks. Infusion times may range from 15 minutes to 4 hours, e.g., 30 minutes to 1 hour, and are typically about 30 minutes. Generally, pembrolizumab is administered at the dose, frequency, and dosage form approved for a given indication.

[0147] In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dose is administered to a patient every two to four weeks, and the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dose is administered to a patient every two weeks, and the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dose is administered to a patient every three weeks, and the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dose is administered to a patient every four weeks, and the TLR7 / 8 agonist is resiquimod.

[0148] In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dosage comprises 0.5 mg of the TLR7 / 8 agonist conjugate and is administered to a patient every two to four weeks, and the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dosage comprises 0.5 mg of the TLR7 / 8 agonist conjugate and is administered to a patient every two weeks, and the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dosage comprises 0.5 mg of the TLR7 / 8 agonist conjugate and is administered to a patient every three weeks, and the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dose is administered to a patient every four weeks, and the TLR7 / 8 agonist is resiquimod.

[0149] In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dose is administered to a patient every two to four weeks via intratumoral administration, and the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dose is administered to a patient every two weeks via intratumoral administration, and the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dose is administered to a patient every three weeks via intratumoral administration, and the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dose is administered to a patient every four weeks via intratumoral administration, and the TLR7 / 8 agonist is resiquimod.

[0150] In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dose comprises 0.5 mg of a TLR7 / 8 agonist conjugate and is administered to a patient every two to four weeks via intratumoral administration, and the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dose comprises 0.5 mg of a TLR7 / 8 agonist conjugate and is administered to a patient every two weeks via intratumoral administration, and the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dose comprises 0.5 mg of a TLR7 / 8 agonist conjugate and is administered to a patient every three weeks via intratumoral administration, and the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dosage comprises 0.5 mg of a TLR7 / 8 agonist conjugate and is administered to a patient via intratumoral administration every four weeks, and wherein the TLR7 / 8 agonist is resiquimod.

[0151] In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dose is administered to a patient every two to four weeks via intratumoral administration using fanning techniques, and the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dose is administered to a patient every two weeks via intratumoral administration using fanning techniques, and the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dose is administered to a patient every three weeks via intratumoral administration using fanning techniques, and the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dose is administered to a patient every four weeks via intratumoral administration using fanning techniques, and the TLR7 / 8 agonist is resiquimod.

[0152] In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dose comprises 0.5 mg of a TLR7 / 8 agonist conjugate and is administered to a patient every two to four weeks via intratumoral administration using fanning techniques, and the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dose comprises 0.5 mg of a TLR7 / 8 agonist conjugate and is administered to a patient every two weeks via intratumoral administration using fanning techniques, and the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dose comprises 0.5 mg of a TLR7 / 8 agonist conjugate and is administered to a patient every three weeks via intratumoral administration using fanning techniques, and the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dosage comprises 0.5 mg of a TLR7 / 8 agonist conjugate and is administered to a patient every four weeks via intratumoral administration using fanning techniques, and wherein the TLR7 / 8 agonist is resiquimod.

[0153] In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose is administered to a patient every two to four weeks, wherein the treatment is co-therapy with an immune checkpoint inhibitor, wherein the immune checkpoint inhibitor may be given before, with, or after administration of a TLR7 / 8 agonist conjugate, and wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose is administered to a patient every two weeks, wherein the treatment is co-therapy with an immune checkpoint inhibitor, wherein the immune checkpoint inhibitor may be given before, with, or after administration of a TLR7 / 8 agonist conjugate, and wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose is administered to a patient every three weeks, wherein the treatment is co-therapy with an immune checkpoint inhibitor, wherein the immune checkpoint inhibitor may be given before, with, or after administration of a TLR7 / 8 agonist conjugate, and wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose is administered to a patient every four weeks, wherein the treatment is co-therapy with an immune checkpoint inhibitor, wherein the immune checkpoint inhibitor may be given before, with, or after administration of a TLR7 / 8 agonist conjugate, and wherein the TLR7 / 8 agonist is resiquimod.

[0154] In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dosage comprises 0.5 mg of the TLR7 / 8 agonist conjugate and is administered to a patient every two to four weeks, wherein the treatment is co-therapy with an immune checkpoint inhibitor, wherein the immune checkpoint inhibitor may be given before, with, or after administration of the TLR7 / 8 agonist conjugate, and wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dosage comprises 0.5 mg of the TLR7 / 8 agonist conjugate and is administered to a patient every two weeks, wherein the treatment is co-therapy with an immune checkpoint inhibitor, wherein the immune checkpoint inhibitor may be given before, with, or after administration of the TLR7 / 8 agonist conjugate, and wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dosage comprises 0.5 mg of the TLR7 / 8 agonist conjugate and is administered to a patient every three weeks, wherein the treatment is co-therapy with an immune checkpoint inhibitor, wherein the immune checkpoint inhibitor may be given before, with, or after administration of the TLR7 / 8 agonist conjugate, and wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dosage comprises 0.5 mg of the TLR7 / 8 agonist conjugate and is administered to a patient every four weeks, wherein the treatment is co-therapy with an immune checkpoint inhibitor, wherein the immune checkpoint inhibitor may be given before, with, or after administration of the TLR7 / 8 agonist conjugate, and wherein the TLR7 / 8 agonist is resiquimod.

[0155] In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dose is administered to a patient every two to four weeks, wherein the treatment is co-therapy with an inhibitor of PD-1 or an inhibitor of PD-L1, wherein the inhibitor of PD-1 or the inhibitor of PD-L1 may be given before, with, or after administration of a TLR7 / 8 agonist conjugate, and wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dose is administered to a patient every two weeks, wherein the treatment is co-therapy with an inhibitor of PD-1 or an inhibitor of PD-L1, wherein the inhibitor of PD-1 or the inhibitor of PD-L1 may be given before, with, or after administration of a TLR7 / 8 agonist conjugate, and wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dose is administered to a patient every three weeks, wherein the treatment is co-therapy with an inhibitor of PD-1 or an inhibitor of PD-L1, wherein the inhibitor of PD-1 or the inhibitor of PD-L1 may be given before, with, or after administration of a TLR7 / 8 agonist conjugate, and wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dose is administered to a patient every four weeks, wherein the treatment is co-therapy with an inhibitor of PD-1 or an inhibitor of PD-L1, wherein the inhibitor of PD-1 or the inhibitor of PD-L1 may be given before, with, or after administration of a TLR7 / 8 agonist conjugate, and wherein the TLR7 / 8 agonist is resiquimod.

[0156] In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dosage comprises 0.5 mg of a TLR7 / 8 agonist conjugate and is administered to a patient every 2 to 4 weeks, wherein the treatment is co-treatment with an inhibitor of PD-1 or a PD-L1 inhibitor, wherein the PD-1 inhibitor or PD-L1 inhibitor may be given before, with, or after administration of the TLR7 / 8 agonist conjugate, and wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dosage comprises 0.5 mg of a TLR7 / 8 agonist conjugate and is administered to a patient every two weeks, wherein the treatment is co-treatment with an inhibitor of PD-1 or an inhibitor of PD-L1, wherein the inhibitor of PD-1 or the inhibitor of PD-L1 may be given before, with, or after administration of the TLR7 / 8 agonist conjugate, and wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dosage comprises 0.5 mg of a TLR7 / 8 agonist conjugate and is administered to a patient every three weeks, wherein the treatment is co-treatment with an inhibitor of PD-1 or an inhibitor of PD-L1, wherein the inhibitor of PD-1 or the inhibitor of PD-L1 may be given before, with, or after administration of the TLR7 / 8 agonist conjugate, and wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dosage comprises 0.5 mg of a TLR7 / 8 agonist conjugate and is administered to a patient every four weeks, wherein the treatment is co-treatment with an inhibitor of PD-1 or an inhibitor of PD-L1, wherein the inhibitor of PD-1 or the inhibitor of PD-L1 may be given before, with, or after administration of the TLR7 / 8 agonist conjugate, and wherein the TLR7 / 8 agonist is resiquimod.

[0157] Examples of PD-1 and PD-L1 inhibitors are described elsewhere herein.

[0158] In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dose is administered to a patient every two to four weeks, wherein the treatment is co-therapy with an inhibitor of PD-1, wherein the inhibitor of PD-1 may be given before, with, or after administration of a TLR7 / 8 agonist conjugate, and wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dose is administered to a patient every two weeks, wherein the treatment is co-therapy with an inhibitor of PD-1, wherein the inhibitor of PD-1 may be given before, with, or after administration of a TLR7 / 8 agonist conjugate, and wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dose is administered to a patient every three weeks, wherein the treatment is co-therapy with an inhibitor of PD-1, wherein the inhibitor of PD-1 may be given before, with, or after administration of a TLR7 / 8 agonist conjugate, and wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dose is administered to a patient every four weeks, wherein the treatment is co-therapy with an inhibitor of PD-1, wherein the inhibitor of PD-1 may be given before, with, or after administration of a TLR7 / 8 agonist conjugate, and wherein the TLR7 / 8 agonist is resiquimod.

[0159] In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dosage comprises 0.5 mg of the TLR7 / 8 agonist conjugate and is administered to a patient every two to four weeks, wherein the treatment is co-therapy with an inhibitor of PD-1, wherein the inhibitor of PD-1 may be given before, with, or after administration of the TLR7 / 8 agonist conjugate, and wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dosage comprises 0.5 mg of the TLR7 / 8 agonist conjugate and is administered to a patient every two weeks, wherein the treatment is co-therapy with an inhibitor of PD-1, wherein the inhibitor of PD-1 may be given before, with, or after administration of the TLR7 / 8 agonist conjugate, and wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dosage comprises 0.5 mg of the TLR7 / 8 agonist conjugate and is administered to a patient every three weeks, wherein the treatment is co-therapy with an inhibitor of PD-1, wherein the inhibitor of PD-1 may be given before, with, or after administration of the TLR7 / 8 agonist conjugate, and wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dosage comprises 0.5 mg of the TLR7 / 8 agonist conjugate and is administered to a patient every four weeks, wherein the treatment is co-therapy with an inhibitor of PD-1, wherein the inhibitor of PD-1 may be given before, with, or after administration of the TLR7 / 8 agonist conjugate, and wherein the TLR7 / 8 agonist is resiquimod.

[0160] In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dose is administered to a patient every two to four weeks, wherein the treatment is co-therapy with an inhibitor of PD-L1, wherein the PD-L1 inhibitor may be given before, with, or after administration of a TLR7 / 8 agonist conjugate, and wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dose is administered to a patient every two weeks, wherein the treatment is co-therapy with an inhibitor of PD-L1, wherein the PD-L1 inhibitor may be given before, with, or after administration of a TLR7 / 8 agonist conjugate, and wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose is administered to a patient every three weeks, wherein the treatment is co-therapy with an inhibitor of PD-L1, wherein the inhibitor of PD-L1 may be given before, with, or after administration of a TLR7 / 8 agonist conjugate, and wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose is administered to a patient every four weeks, wherein the treatment is co-therapy with an inhibitor of PD-L1, wherein the inhibitor of PD-L1 may be given before, with, or after administration of a TLR7 / 8 agonist conjugate, and wherein the TLR7 / 8 agonist is resiquimod.

[0161] In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dosage comprises 0.5 mg of the TLR7 / 8 agonist conjugate and is administered to a patient every two to four weeks, wherein the treatment is co-therapy with an inhibitor of PD-L1, wherein the PD-L1 inhibitor may be given before, with, or after administration of the TLR7 / 8 agonist conjugate, and wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dosage comprises 0.5 mg of the TLR7 / 8 agonist conjugate and is administered to a patient every two weeks, wherein the treatment is co-therapy with an inhibitor of PD-L1, wherein the PD-L1 inhibitor may be given before, with, or after administration of the TLR7 / 8 agonist conjugate, and wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dosage comprises 0.5 mg of the TLR7 / 8 agonist conjugate and is administered to a patient every three weeks, wherein the treatment is co-therapy with an inhibitor of PD-L1, wherein the inhibitor of PD-L1 may be given before, with, or after administration of the TLR7 / 8 agonist conjugate, and wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dosage comprises 0.5 mg of the TLR7 / 8 agonist conjugate and is administered to a patient every four weeks, wherein the treatment is co-therapy with an inhibitor of PD-L1, wherein the inhibitor of PD-L1 may be given before, with, or after administration of the TLR7 / 8 agonist conjugate, and wherein the TLR7 / 8 agonist is resiquimod.

[0162] In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dose is administered to a patient every two to four weeks, wherein the treatment is co-therapy with pembrolizumab, which may be given before, with, or after administration of a TLR7 / 8 agonist conjugate, and wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dose is administered to a patient every two weeks, wherein the treatment is co-therapy with pembrolizumab, which may be given before, with, or after administration of a TLR7 / 8 agonist conjugate, and wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose is administered to a patient every three weeks, wherein the treatment is co-therapy with pembrolizumab, which may be given before, with, or after administration of a TLR7 / 8 agonist conjugate, and wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dose is administered to a patient every four weeks, wherein the treatment is co-therapy with pembrolizumab, which may be given before, with, or after administration of a TLR7 / 8 agonist conjugate, and wherein the TLR7 / 8 agonist is resiquimod.

[0163] In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dosage comprises 0.5 mg of the TLR7 / 8 agonist conjugate and is administered to a patient every two to four weeks, wherein the treatment is co-therapy with pembrolizumab, which may be given before, with, or after administration of the TLR7 / 8 agonist conjugate, and wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in treating cancer, wherein the unit dosage comprises 0.5 mg of the TLR7 / 8 agonist conjugate and is administered to a patient every two weeks, wherein the treatment is co-therapy with pembrolizumab, which may be given before, with, or after administration of the TLR7 / 8 agonist conjugate, and wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dosage comprises 0.5 mg of the TLR7 / 8 agonist conjugate and is administered to a patient every three weeks, wherein the treatment is co-therapy with pembrolizumab, which may be given before, with, or after administration of the TLR7 / 8 agonist conjugate, and wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dose of the unit dosage form of the first aspect is for use in the treatment of cancer, wherein the unit dosage comprises 0.5 mg of the TLR7 / 8 agonist conjugate and is administered to a patient every four weeks, wherein the treatment is co-therapy with pembrolizumab, which may be given before, with, or after administration of the TLR7 / 8 agonist conjugate, and wherein the TLR7 / 8 agonist is resiquimod.

[0164] The dose, frequency of administration, and mode of administration of pembrolizumab are as described elsewhere herein.

[0165] In a second aspect, the present invention relates to a TLR7 / 8 agonist conjugate for use in treating cancer, the TLR7 / 8 agonist conjugate comprising one or more TLR7 / 8 agonist moieties reversibly conjugated to a polymer moiety, wherein the cancer is a solid tumor, and the TLR7 / 8 agonist conjugate is administered via intratumoral administration at a dose ranging from 0.3 mg to 3 mg of TLR7 / 8 agonist per tumor. In certain embodiments, the dose administered to the tumor via intratumoral injection in the second aspect is 0.5 mg of TLR7 / 8 agonist per tumor. In certain embodiments, the dose administered to the tumor via intratumoral injection in the second aspect is 1 mg of TLR7 / 8 agonist per tumor. In certain embodiments, the dose administered to the tumor via intratumoral injection in the second aspect is 2 mg of TLR7 / 8 agonist per tumor.

[0166] In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is administered intratumorally using a fanning technique.

[0167] In certain embodiments, the present invention relates to a TLR7 / 8 agonist conjugate for use in treating cancer, the TLR7 / 8 agonist conjugate comprising one or more TLR7 / 8 agonist moieties reversibly conjugated to a polymer moiety, the cancer being a solid tumor, the TLR7 / 8 agonist conjugate being administered via intratumoral administration at a dose ranging from 0.3 mg to 3 mg of TLR7 / 8 agonist per tumor, and the TLR7 / 8 agonist being resiquimod. In certain embodiments, the dose administered to the tumor via intratumoral injection in the second aspect is 0.5 mg of TLR7 / 8 agonist per tumor, and the TLR7 / 8 agonist is resiquimod. In certain embodiments, the dose administered to the tumor via intratumoral injection in the second aspect is 1 mg of the TLR7 / 8 agonist per tumor, and the TLR7 / 8 agonist is resiquimod. In certain embodiments, the dose administered to the tumor via intratumoral injection in the second aspect is 2 mg of the TLR7 / 8 agonist per tumor, and the TLR7 / 8 agonist is resiquimod.

[0168] In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is administered in a volume ranging from 0.1 ml to 2 ml. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is administered in a volume ranging from 0.2 ml to 1.5 ml. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is administered in a volume of 0.25 ml. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is administered in a volume of 0.5 ml. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is administered in a volume of 1 ml.

[0169] In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is administered in a volume ranging from 0.1 ml to 2 ml, and the TLR7 / 8 agonist is resiquimod. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is administered in a volume ranging from 0.2 ml to 1.5 ml, and the TLR7 / 8 agonist is resiquimod. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is administered in a volume of 0.25 ml, and the TLR7 / 8 agonist is resiquimod. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is administered in a volume of 0.5 ml, and the TLR7 / 8 agonist is resiquimod. In one particular, the TLR7 / 8 agonist conjugate for use according to the second aspect is administered in a volume of 1 ml and the TLR7 / 8 agonist is resiquimod.

[0170] In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is administered at a dose of 0.5 mg of TLR7 / 8 agonist in a volume of 0.5 ml. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is administered at a dose of 0.5 mg of TLR7 / 8 agonist in a volume of 1 ml. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is administered at a dose of 0.5 mg of TLR7 / 8 agonist in a volume of 0.25 ml. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is administered at a dose of 1 mg of TLR7 / 8 agonist in a volume of 1 ml. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is administered at a dose of 1 mg of TLR7 / 8 agonist in a volume of 2 ml. In certain embodiments, the TLR7 / 8 agonist conjugate for use according to the second aspect is administered at a dose of 1 mg of TLR7 / 8 agonist in a volume of 0.5 ml.

[0171] In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is administered at a dose of 0.5 mg of the TLR7 / 8 agonist in a volume of 0.5 ml, wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is administered at a dose of 0.5 mg of the TLR7 / 8 agonist in a volume of 1 ml, wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is administered at a dose of 0.5 mg of the TLR7 / 8 agonist in a volume of 0.25 ml, wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is administered at a dose of 1 mg of the TLR7 / 8 agonist in a volume of 1 ml, wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is administered at a dose of 1 mg of the TLR7 / 8 agonist in a volume of 2 ml, wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is administered at a dose of 1 mg of the TLR7 / 8 agonist in a volume of 0.5 ml, wherein the TLR7 / 8 agonist is resiquimod.

[0172] In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a vial containing the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a vial containing 0.5 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a vial containing 1 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a vial containing 2 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof.

[0173] In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a vial containing the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a vial containing 0.5 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a vial containing 1 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a vial containing 2 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients.

[0174] In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a vial containing the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof, the contents of the vial being lyophilized. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a vial containing 0.5 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof, the contents of the vial being lyophilized. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a vial containing 1 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof, the contents of the vial being lyophilized. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a vial containing 2 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof, the contents of the vial being lyophilized.

[0175] In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a vial containing the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof, the contents of the vial being a liquid, e.g., a suspension. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a vial containing 0.5 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof, the contents of the vial being a liquid, e.g., a suspension. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a vial containing 1 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof, the contents of the vial being a liquid, e.g., a suspension. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a vial containing 2 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof, the contents of the vial being a liquid, e.g., a suspension.

[0176] In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a vial containing the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients, the contents of the vial being lyophilized. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a vial containing 0.5 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients, the contents of the vial being lyophilized. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a vial containing 1 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients, the contents of the vial being lyophilized. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a vial containing 2 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients, the contents of the vial being lyophilized.

[0177] In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a vial containing the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients, the contents of the vial being a liquid, e.g., a suspension. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a vial containing 0.5 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients, the contents of the vial being a liquid, e.g., a suspension. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a vial containing 1 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients, the contents of the vial being a liquid, e.g., a suspension. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a vial containing 2 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients, wherein the contents of the vial are a liquid, e.g., a suspension.

[0178] In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a vial containing the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof, wherein the TLR7 / 8 agonist is resiquimod. In certain particular embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a vial containing 0.5 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof, wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a vial containing 1 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof, wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a vial containing 2 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof, wherein the TLR7 / 8 agonist is resiquimod.

[0179] In certain embodiments, the TLR7 / 8 agonist conjugate for use according to the second aspect is provided in a vial containing the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients, wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the unit dosage form of the first aspect is a vial containing 0.5 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients, wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the TLR7 / 8 agonist conjugate for use according to the second aspect is provided in a vial containing 1 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients, wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a vial containing 2 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients, wherein the TLR7 / 8 agonist is resiquimod.

[0180] In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a vial containing the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof, wherein the TLR7 / 8 agonist is resiquimod, and the contents of the vial are lyophilized. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a vial containing 0.5 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof, wherein the TLR7 / 8 agonist is resiquimod, and the contents of the vial are lyophilized. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a vial containing 1 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof, wherein the TLR7 / 8 agonist is resiquimod, and the contents of the vial are lyophilized. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a vial containing 2 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof, wherein the TLR7 / 8 agonist is resiquimod, and the contents of the vial are lyophilized.

[0181] In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a vial containing the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof, wherein the TLR7 / 8 agonist is resiquimod, and the contents of the vial are a liquid, e.g., a suspension. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a vial containing 0.5 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof, wherein the TLR7 / 8 agonist is resiquimod, and the contents of the vial are a liquid, e.g., a suspension. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a vial containing 1 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof, wherein the TLR7 / 8 agonist is resiquimod, and the contents of the vial are a liquid, e.g., a suspension. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a vial containing 2 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof, wherein the TLR7 / 8 agonist is resiquimod, and the contents of the vial are a liquid, e.g., a suspension.

[0182] In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a vial comprising the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients, wherein the TLR7 / 8 agonist is resiquimod, and the contents of the vial are lyophilized. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a vial comprising 0.5 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients, wherein the TLR7 / 8 agonist is resiquimod, and the contents of the vial are lyophilized. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a vial containing 1 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients, wherein the TLR7 / 8 agonist is resiquimod, and the contents of the vial are lyophilized. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a vial containing 2 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients, wherein the TLR7 / 8 agonist is resiquimod, and the contents of the vial are lyophilized.

[0183] In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a vial comprising the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients, wherein the TLR7 / 8 agonist is resiquimod, and the contents of the vial are a liquid, e.g., a suspension. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a vial comprising 0.5 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients, wherein the TLR7 / 8 agonist is resiquimod, and the contents of the vial are a liquid, e.g., a suspension. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a vial containing 1 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients, wherein the TLR7 / 8 agonist is resiquimod, and the contents of the vial are a liquid, e.g., a suspension. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a vial containing 2 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients, wherein the TLR7 / 8 agonist is resiquimod, and the contents of the vial are a liquid, e.g., a suspension.

[0184] In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a dual-chamber cartridge comprising the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof in the first chamber. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a dual-chamber cartridge comprising 0.5 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof in the first chamber. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a dual-chamber cartridge comprising 1 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof in the first chamber. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a dual-chamber cartridge comprising 2 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof in the first chamber.

[0185] In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a dual-chamber cartridge comprising the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients in a first chamber. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a dual-chamber cartridge comprising 0.5 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients in a first chamber. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a dual-chamber cartridge comprising 1 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients in a first chamber. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a dual-chamber cartridge comprising 2 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients in a first chamber.

[0186] In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a dual-chamber cartridge comprising the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof in a first chamber, wherein the contents of the first chamber are lyophilized. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a dual-chamber cartridge comprising 0.5 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof in a first chamber, wherein the contents of the first chamber are lyophilized. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a dual-chamber cartridge comprising 1 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof in a first chamber, wherein the contents of the first chamber are lyophilized. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a dual-chamber cartridge comprising 2 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof in a first chamber, the contents of said first chamber being lyophilized.

[0187] In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a dual-chamber cartridge comprising the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients in a first chamber, wherein the contents of the first chamber are lyophilized. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a dual-chamber cartridge comprising 0.5 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients in a first chamber, wherein the contents of the first chamber are lyophilized. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a dual-chamber cartridge comprising 1 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients in a first chamber, wherein the contents of the first chamber are lyophilized. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a dual-chamber cartridge comprising 2 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients in a first chamber, wherein the contents of said first chamber are lyophilized.

[0188] In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a dual-chamber cartridge comprising the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof in the first chamber, wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a dual-chamber cartridge comprising 0.5 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof in the first chamber, wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a dual-chamber cartridge comprising 1 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof in the first chamber, wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a dual-chamber cartridge comprising 2 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof in the first chamber, wherein the TLR7 / 8 agonist is resiquimod.

[0189] In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a dual-chamber cartridge comprising the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients in a first chamber, wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a dual-chamber cartridge comprising 0.5 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients in a first chamber, wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a dual-chamber cartridge comprising 1 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients in a first chamber, wherein the TLR7 / 8 agonist is resiquimod. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a dual-chamber cartridge comprising 2 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients in a first chamber, wherein the TLR7 / 8 agonist is resiquimod.

[0190] In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a dual-chamber cartridge comprising the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof in a first chamber, wherein the TLR7 / 8 agonist is resiquimod, and the contents of the first chamber are lyophilized. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a dual-chamber cartridge comprising 0.5 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof in a first chamber, wherein the TLR7 / 8 agonist is resiquimod, and the contents of the first chamber are lyophilized. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a dual-chamber cartridge comprising 1 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof in a first chamber, wherein the TLR7 / 8 agonist is resiquimod, and the contents of the first chamber are lyophilized. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a dual-chamber cartridge comprising 2 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof in a first chamber, wherein the TLR7 / 8 agonist is resiquimod, and the contents of the first chamber are lyophilized.

[0191] In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a dual-chamber cartridge comprising the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients in a first chamber, wherein the TLR7 / 8 agonist is resiquimod, and the contents of the first chamber are lyophilized. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a dual-chamber cartridge comprising 0.5 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients in a first chamber, wherein the TLR7 / 8 agonist is resiquimod, and the contents of the first chamber are lyophilized. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a dual-chamber cartridge comprising 1 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients in a first chamber, wherein the TLR7 / 8 agonist is resiquimod, and the contents of the first chamber are lyophilized. In certain embodiments, the TLR7 / 8 agonist conjugate for use in the second aspect is provided in a dual-chamber cartridge comprising 2 mg of the TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof and one or more excipients in a first chamber, wherein the TLR7 / 8 agonist is resiquimod, and the contents of the first chamber are lyophilized.

[0192] In all embodiments, the second chamber of the dual chamber cartridge may contain a resuspension buffer or water.

[0193] The TLR7 / 8 agonist conjugate for use in the second aspect, in certain embodiments, is for use in treating solid tumors. In certain embodiments, the TLR7 / 8 agonist of the second aspect is administered via intratumoral injection, for example, by using the fanning technique. In certain embodiments, the solid tumor is selected from the group consisting of lip and oral cavity cancer, oral cancer, liver cancer / hepatocellular carcinoma, primary liver cancer, lung cancer, lymphoma, malignant mesothelioma, malignant thymoma, skin cancer, intraocular melanoma, metastatic squamous neck cancer of unknown primary, childhood multiple endocrine neoplasia syndrome, mycosis fungoides, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, oropharyngeal cancer, ovarian cancer, pancreatic cancer, parathyroid cancer, pheochromocytoma, pituitary tumor, adrenocortical carcinoma, AIDS-related malignancies, anal cancer, bile duct cancer, bladder cancer, brain and nervous system cancer, breast cancer, bronchial adenoma / carcinoma The solid tumor is selected from the group consisting of: gastrointestinal carcinoid tumor, carcinoma, colorectal cancer, endometrial cancer, esophageal cancer, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, gallbladder cancer, stomach cancer (gastric cancer), gestational trophoblastic tumor, head and neck cancer, hypopharyngeal cancer, islet cell carcinoma (endocrine pancreas), kidney cancer / renal cell carcinoma, laryngeal cancer, pleuropulmonary blastoma, prostate cancer, transitional cell carcinoma of the renal pelvis and ureter, retinoblastoma, salivary gland cancer, sarcoma, Sézary syndrome, small intestine cancer, genitourinary cancer, malignant thymoma, thyroid cancer, Wilms' tumor, and cholangiocarcinoma. In certain embodiments, the solid tumor is selected from the group consisting of squamous cell carcinoma of the head and neck (SCCHN); HPV-associated cancers, such as anal cancer, vulvar cancer, cervical cancer, penile cancer, and vaginal cancer; melanoma; pancreatic cancer, and breast cancer, such as triple-negative breast cancer (TNBC).

[0194] In certain embodiments, the TLR7 / 8 agonist for use in the second aspect is administered to a patient every 2 to 4 weeks. In certain embodiments, the TLR7 / 8 agonist for use in the second aspect is administered to a patient every 2 weeks. In certain embodiments, the TLR7 / 8 agonist for use in the second aspect is administered to a patient every 3 weeks. In certain embodiments, the TLR7 / 8 agonist for use in the second aspect is administered to a patient every 4 weeks.

[0195] In certain embodiments, the TLR7 / 8 agonist for use in the second aspect is administered to a patient every two to four weeks, and the treatment is co-therapy with an immune checkpoint inhibitor, which may be given before, with, or after administration of the TLR7 / 8 agonist conjugate. In certain embodiments, the TLR7 / 8 agonist for use in the second aspect is administered to a patient every two weeks, and the treatment is co-therapy with an immune checkpoint inhibitor, which may be given before, with, or after administration of the TLR7 / 8 agonist conjugate. In certain embodiments, the TLR7 / 8 agonist for use in the second aspect is administered to a patient every three weeks, and the treatment is co-therapy with an immune checkpoint inhibitor, which may be given before, with, or after administration of the TLR7 / 8 agonist conjugate. In certain embodiments, the TLR7 / 8 agonist for use according to the second aspect is administered to the patient every four weeks, and the treatment is a co-treatment with an immune checkpoint inhibitor, which may be given before, with or after administration of the TLR7 / 8 agonist conjugate.

[0196] In certain embodiments, the TLR7 / 8 agonist for use in the second aspect is administered to a patient every two to four weeks, and the treatment is co-therapy with an inhibitor of PD-1 or an inhibitor of PD-L1, which may be given before, with, or after administration of the TLR7 / 8 agonist conjugate. In certain embodiments, the TLR7 / 8 agonist for use in the second aspect is administered to a patient every two weeks, and the treatment is co-therapy with an inhibitor of PD-1 or an inhibitor of PD-L1, which may be given before, with, or after administration of the TLR7 / 8 agonist conjugate. In certain embodiments, the TLR7 / 8 agonist for use in the second aspect is administered to a patient every three weeks, and the treatment is co-therapy with an inhibitor of PD-1 or an inhibitor of PD-L1, which may be given before, with, or after administration of the TLR7 / 8 agonist conjugate. In certain embodiments, the TLR7 / 8 agonist for use in the second aspect is administered to a patient every four weeks, and the treatment is co-therapy with an inhibitor of PD-1 or an inhibitor of PD-L1, which may be given before, with, or after administration of the TLR7 / 8 agonist conjugate.

[0197] The inhibitor of PD-1 (programmed cell death protein 1) may be selected from the group consisting of pembrolizumab, nivolumab, pidilizumab, AMP-224, BMS-936559, cemiplimab, and PDR 001. The inhibitor of PD-L1 (programmed cell death ligand 1) may be selected from the group consisting of MDX-1105, MEDI4736, atezolizumab, avelumab, BMS-936559, and durvalumab.

[0198] In certain embodiments, the TLR7 / 8 agonist for use in the second aspect is administered to a patient every two to four weeks, and the treatment is co-therapy with an inhibitor of PD-1, which may be given before, with, or after administration of the TLR7 / 8 agonist conjugate. In certain embodiments, the TLR7 / 8 agonist for use in the second aspect is administered to a patient every two weeks, and the treatment is co-therapy with an inhibitor of PD-1, which may be given before, with, or after administration of the TLR7 / 8 agonist conjugate. In certain embodiments, the TLR7 / 8 agonist for use in the second aspect is administered to a patient every three weeks, and the treatment is co-therapy with an inhibitor of PD-1, which may be given before, with, or after administration of the TLR7 / 8 agonist conjugate. In certain embodiments, the TLR7 / 8 agonist for use in the second aspect is administered to the patient every four weeks, and the treatment is co-treatment with an inhibitor of PD-1, which may be given before, with, or after administration of the TLR7 / 8 agonist conjugate.

[0199] In certain embodiments, the TLR7 / 8 agonist for use in the second aspect is administered to a patient every two to four weeks, and the treatment is co-therapy with a PD-L1 inhibitor, which may be given before, with, or after administration of the TLR7 / 8 agonist conjugate. In certain embodiments, the TLR7 / 8 agonist for use in the second aspect is administered to a patient every two weeks, and the treatment is co-therapy with a PD-L1 inhibitor, which may be given before, with, or after administration of the TLR7 / 8 agonist conjugate. In certain embodiments, the TLR7 / 8 agonist for use in the second aspect is administered to a patient every three weeks, and the treatment is co-therapy with a PD-L1 inhibitor, which may be given before, with, or after administration of the TLR7 / 8 agonist conjugate. In certain embodiments, the TLR7 / 8 agonist for use according to the second aspect is administered to the patient every four weeks, and the treatment is co-treatment with an inhibitor of PD-L1, which may be given before, with or after administration of the TLR7 / 8 agonist conjugate.

[0200] In certain embodiments, the TLR7 / 8 agonist for use in the second aspect is administered to a patient every two to four weeks, and the treatment is co-treatment with pembrolizumab, and pembrolizumab may be given before, with, or after administration of the TLR7 / 8 agonist conjugate. In certain embodiments, the TLR7 / 8 agonist for use in the second aspect is administered to a patient every two weeks, and the treatment is co-treatment with pembrolizumab, and pembrolizumab may be given before, with, or after administration of the TLR7 / 8 agonist conjugate. In certain embodiments, the TLR7 / 8 agonist for use in the second aspect is administered to a patient every three weeks, and the treatment is co-treatment with pembrolizumab, and pembrolizumab may be given before, with, or after administration of the TLR7 / 8 agonist conjugate. In certain embodiments, the TLR7 / 8 agonist for use according to the second aspect is administered to the patient every four weeks, and the treatment is co-treatment with pembrolizumab, which may be given before, with, or after administration of the TLR7 / 8 agonist conjugate.

[0201] The dose, frequency of administration, and mode of administration of pembrolizumab are as described elsewhere herein.

[0202] In a third aspect, the present invention relates to a method for treating cancer, comprising administering a pharmaceutically effective dose of a TLR7 / 8 agonist conjugate to a patient in need thereof, wherein the TLR7 / 8 agonist conjugate comprises one or more TLR7 / 8 agonist moieties reversibly conjugated to a polymer moiety, and the pharmaceutically effective dose ranges from 0.3 mg to 3 mg of the TLR7 / 8 agonist. In certain embodiments, the pharmaceutically effective dose is 0.5 mg of the TLR7 / 8 agonist. In certain embodiments, the pharmaceutically effective dose is 1 mg.

[0203] In certain embodiments, the method of the third aspect comprises intratumorally administering a pharmaceutically effective dose ranging from 0.3 to 3 mg of TLR7 / 8 agonist per tumor. In certain embodiments, the effective dose is 0.5 mg of TLR7 / 8 agonist per tumor. In certain embodiments, the effective dose is 1 mg per tumor.

[0204] In certain embodiments, the TLR7 / 8 agonist of the third aspect is resiquimod.

[0205] In certain embodiments, the intratumoral administration is an intratumoral injection. In certain embodiments, such intratumoral injection uses a fanning technique.

[0206] In certain embodiments, the pharmaceutically effective dose of the third aspect is provided in a volume ranging from 0.1 ml to 2 ml. In certain embodiments, the pharmaceutically effective dose of the third aspect is provided in a volume ranging from 0.2 ml to 1.5 ml. In certain embodiments, the pharmaceutically effective dose of the third aspect is provided in a volume of 0.25 ml. In certain embodiments, the pharmaceutically effective dose of the third aspect is provided in a volume of 0.5 ml. In certain embodiments, the pharmaceutically effective dose of the third aspect is provided in a volume of 1 ml.

[0207] In certain embodiments, the pharmaceutically effective dose of the third aspect is provided in a vial. In certain embodiments, the pharmaceutically effective dose of the third aspect is provided in a dual-chamber cartridge.

[0208] In certain embodiments, the pharmaceutically effective dose of the third aspect is provided in the form of a pharmaceutical formulation. In certain embodiments, such pharmaceutical formulations are provided as dried formulations, for example, in the form of lyophilized formulations. Such lyophilized formulations are resuspended prior to administration to a patient to provide a resuspended formulation, which may be a solution or a suspension. In certain embodiments, the pharmaceutical formulations are provided as liquids, for example, suspension formulations. In certain embodiments, the pharmaceutical formulations are provided as suspension formulations. In certain embodiments, the pharmaceutical formulations are provided as suspension formulations that are stored at temperatures ranging from -80°C to 12°C. In certain embodiments, the pharmaceutical formulations are provided as suspension formulations that are stored at a temperature of about -20°C.

[0209] In certain embodiments, the cancer of the third aspect is a solid tumor. In certain embodiments, the solid tumor is selected from the group consisting of lip and oral cavity cancer, oral cancer, liver cancer / hepatocellular carcinoma, primary liver cancer, lung cancer, lymphoma, malignant mesothelioma, malignant thymoma, skin cancer, intraocular melanoma, metastatic squamous neck cancer of unknown primary, childhood multiple endocrine neoplasia syndrome, mycosis fungoides, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, oropharyngeal cancer, ovarian cancer, pancreatic cancer, parathyroid cancer, pheochromocytoma, pituitary tumor, adrenocortical carcinoma, AIDS-related malignancies, anal cancer, bile duct cancer, bladder cancer, brain and nervous system cancer, breast cancer, bronchial adenoma / carcinoma The solid tumor is selected from the group consisting of: gastrointestinal carcinoid tumor, carcinoma, colorectal cancer, endometrial cancer, esophageal cancer, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, gallbladder cancer, stomach cancer (gastric cancer), gestational trophoblastic tumor, head and neck cancer, hypopharyngeal cancer, islet cell carcinoma (endocrine pancreas), kidney cancer / renal cell carcinoma, laryngeal cancer, pleuropulmonary blastoma, prostate cancer, transitional cell carcinoma of the renal pelvis and ureter, retinoblastoma, salivary gland cancer, sarcoma, Sézary syndrome, small intestine cancer, genitourinary cancer, malignant thymoma, thyroid cancer, Wilms' tumor, and cholangiocarcinoma. In certain embodiments, the solid tumor is selected from the group consisting of squamous cell carcinoma of the head and neck (SCCHN); HPV-associated cancers, such as anal cancer, vulvar cancer, cervical cancer, penile cancer, and vaginal cancer; melanoma; pancreatic cancer, and breast cancer, such as triple-negative breast cancer (TNBC).

[0210] In certain embodiments, the pharmaceutically effective dose of the third aspect is administered to a patient every two to four weeks. In certain embodiments, the pharmaceutically effective dose of the third aspect is administered to a patient every two weeks. In certain embodiments, the pharmaceutically effective dose of the third aspect is administered to a patient every three weeks. In certain embodiments, the pharmaceutically effective dose of the third aspect is administered to a patient every four weeks.

[0211] In certain embodiments, the pharmaceutically effective dose of the third aspect is administered to a patient every two to four weeks, and the treatment is a co-therapy with an immune checkpoint inhibitor, and the immune checkpoint inhibitor may be given before, with, or after administration of the TLR7 / 8 agonist conjugate. In certain embodiments, the pharmaceutically effective dose of the third aspect is administered to a patient every two weeks, and the treatment is a co-therapy with an immune checkpoint inhibitor, and the immune checkpoint inhibitor may be given before, with, or after administration of the TLR7 / 8 agonist conjugate. In certain embodiments, the pharmaceutically effective dose of the third aspect is administered to a patient every three weeks, and the treatment is a co-therapy with an immune checkpoint inhibitor, and the immune checkpoint inhibitor may be given before, with, or after administration of the TLR7 / 8 agonist conjugate. In certain instances, the pharmaceutically effective dose of the third aspect is administered to the patient every four weeks, and the treatment is a co-treatment with an immune checkpoint inhibitor, which may be given before, with, or after administration of the TLR7 / 8 agonist conjugate.

[0212] In certain embodiments, the immune checkpoint inhibitor of the third aspect is an inhibitor of PD-1 or an inhibitor of PD-L1. The PD-1 (programmed cell death protein 1) inhibitor may be selected from the group consisting of pembrolizumab, nivolumab, pidilizumab, AMP-224, BMS-936559, cemiplimab, and PDR001. The PD-L1 (programmed cell death ligand 1) inhibitor may be selected from the group consisting of MDX-1105, MEDI4736, atezolizumab, avelumab, BMS-936559, and durvalumab.

[0213] In certain embodiments, the immune checkpoint inhibitor is an inhibitor of PD-1. In certain embodiments, the immune checkpoint inhibitor is pembrolizumab.

[0214] In the following sections, the TLR7 / 8 agonist conjugates of all aspects of the present invention are described in further detail.

[0215] The TLR7 / 8 agonist conjugate may comprise one or more -L 2 -L 1 -D moieties are conjugated to a polymer moiety Z, wherein each -L 2 - is individually a chemical bond or a spacer moiety; each -L 1 - is individually a linker moiety to which -D is reversibly and covalently conjugated; each -D is a TLR7 / 8 agonist.

[0216] One or more -L 2 -L 1 The -D moiety is covalently conjugated to Z. In certain embodiments, one or more -L 2 -L 1 The -D moiety is stably conjugated to Z. When Z is a hydrogel, the -L moiety is conjugated to such a hydrogel carrier. 2 -L 1 It is understood that the number of -D portions is too large to specify.

[0217] In certain embodiments, -D is a TLR7 / 8 agonist selected from the group consisting of CL075, CL097, poly(dT), resiquimod (R-848, VML600, S28463), MEDI9197 (3M-052), NKTR262, DV1001, IMO4200, IPH3201, and VTX1463.

[0218] In certain embodiments, -D is resiquimod.

[0219] In certain embodiments, at least some of the -D moieties of the conjugate, e.g., about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or 100% (i.e., all) of the -D moieties present in the conjugate, are resiquimod.

[0220] In certain embodiments, a conjugate comprises only one type of -D moiety, i.e., all -D moieties of the conjugate are identical. In certain embodiments, a conjugate comprises more than one type of -D, e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 different types of -D.

[0221] If the conjugate contains more than one type of -D, all -D moieties must be of the same type of -L. 1 - or a different type of -L 1 -, i.e., the first type of -D can be conjugated to the first type of -L 1 -, and the second type of -D may be conjugated to a second type of -L 1 In certain embodiments, all -L 1 - moieties are of the same type, i.e., have the same structure. Alternatively, individual -D moieties of the same type may be substituted with -L moieties of different types. 1 - may be conjugated to a different -L moiety. 1The use of the - moiety allows for the release of the conjugated drug moiety-D with different release kinetics. For example, the first linker moiety -L 1 - may have a short half-life, and therefore the second linker moiety -L may have a longer half-life. 1 - provides drug release within a shorter time after administration to a patient than -. Different -L with different release half-lives 1 The use of the -moiety allows for optimized dosing regimens of one or more drugs.

[0222] -L 1 The - moiety is conjugated to -D via a functional group on -D, which in certain embodiments is selected from the group consisting of carboxylic acid, primary amine, secondary amine, thiol, sulfonic acid, carbonate, carbamate, hydroxyl, aldehyde, ketone, hydrazine, isothiocyanate, phosphoric acid, phosphonic acid, acryloyl, hydroxylamine, sulfate, vinyl sulfone, vinyl ketone, diazoalkane, guanidine, aziridine, amide, imide, imine, urea, amidine, guanidine, sulfonamide, phosphonamide, phosphoramide, hydrazide, and selenol. 1 - is conjugated to -D through a functional group of -D that is selected from the group consisting of carboxylic acid, primary amine, secondary amine, thiol, sulfonic acid, carbonate, carbamate, hydroxyl, aldehyde, ketone, hydrazine, isothiocyanate, phosphate, phosphonate, acryloyl, hydroxylamine, sulfate, vinyl sulfone, vinyl ketone, diazoalkane, guanidine, amidine, and aziridine. 1 - is conjugated to -D through a functional group of -D that is selected from the group consisting of hydroxyl, primary amine, secondary amine, amidine, and carboxylic acid.

[0223] In certain embodiments, -L 1 - is conjugated to -D via the hydroxyl group of -D.

[0224] In certain embodiments, -L 1 - is conjugated to -D via the primary amine group of -D.

[0225] In certain embodiments, -L 1 - is conjugated to -D via the secondary amine group of -D.

[0226] In certain embodiments, -L 1 - is conjugated to -D via the carboxylic acid group of -D.

[0227] In certain embodiments, -L 1 - is conjugated to -D via the amidine group of -D.

[0228] If -D is resiquimod, then -L 1 - is, in certain embodiments, conjugated to -D via its aromatic amine, i.e., the amine functionality marked with an asterisk.

[0229] [ka]

[0230] -L 1 The - moiety may be linked to -D via any type of linkage, provided that it is reversible. 1- is linked to -D through a linkage selected from the group consisting of amide, ester, carbamate, acetal, aminal, imine, oxime, hydrazone, disulfide, acylguanidine, acylamidine, carbonate, phosphate, sulfate, urea, hydrazide, thioester, thiophosphate, thiosulfate, sulfonamide, sulfamidine, sulfaguanidine, phosphoramide, phosphoamidine, phosphoguanidine, phosphonamide, phosphonamidine, phosphoguanidine, phosphonate, borate, and imide. 1 - is linked to -D through a linkage selected from the group consisting of amide, ester, carbonate, carbamate, acetal, aminal, imine, oxime, hydrazone, disulfide, acylamidine, and acylguanidine. 1 - is linked to -D via a linkage selected from the group consisting of amide, ester, carbonate, acylamide and carbamate. Some of these links may not be reversible themselves, but in the present invention, -L 1 It is understood that the presence of adjacent groups in - makes these links reversible.

[0231] In certain embodiments, -L 1 - is linked to -D via an ester bond.

[0232] In certain embodiments, -L 1 - is linked to -D via a carbonate bond.

[0233] In certain embodiments, -L 1 - is linked to -D via an acylamidine bond.

[0234] In certain embodiments, -L 1 - is linked to -D via a carbamate bond.

[0235] In certain embodiments, -L 1- is linked to -D via an amide bond.

[0236] If -D is resiquimod, -D and -L 1 In certain embodiments, the linkage between -D and -L is via an amide bond, where the aromatic amine functionality of -D is 1 - forms an amide bond with the carbonyl (-(C=O)-)

[0237] [ka] (In the formula, the dashed line represents -L 1 - indicates the bond to the rest of the

[0238] In certain embodiments, -D and -L 1 Cleavage of the linkage between - occurs under physiological conditions (aqueous buffer, pH 7.4, 37°C) with a release half-life of at least 3 days, e.g., at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 12 days, at least 15 days, at least 17 days, at least 20 days, or at least 25 days.

[0239] -L 1 The -moiety is a linker moiety in which -D is released in its free form, i.e., generally in the form of D-H or D-OH. Such moieties are also known as "prodrug linkers" or "reversible prodrug linkers" and are known in the art, for example, the reversible linker moieties disclosed in WO2005 / 099768A2, WO2006 / 136586A2, WO2011 / 089216A1, WO2013 / 024053A1, WO2011 / 012722A1, WO2011 / 089214A1, WO2011 / 089215A1, WO2013 / 024052A1, and WO2013 / 160340A1, which are incorporated herein by reference.

[0240] In one embodiment, -L 1- has the structure as disclosed in WO2009 / 095479A2. Thus, in certain embodiments, -L 1 The - moiety has formula (II):

[0241] [ka] (wherein the dashed line indicates the attachment of -D to the nitrogen by forming an amide bond; -X- is -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 )-; or -C(R 7 R 7a )-and; X 1 is C; or S(O); -X 2 - is -C(R 8 R 8a )-; or -C(R 8 R 8a )-C(R 9 R 9a )-and; =X 3 is =O; =S; or =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 , -R 9a is -H; and C 1-6 independently selected from the group consisting of alkyl; -R 3 , -R 3a is -H; and C 1-6 alkyl, with the proviso that -R 3 , -R 3a In the case where one or both of are other than -H, they are sp 3 - provided that it is connected to an N bonded via a hybridized carbon atom; -R 7 is -N(R 10 R 10a ); or -NR 10 -(C=O)-R 11 and; -R 7a , -R 10 , -R 10a , -R 11 are, independently of each other, -H; or C 1-6 is alkyl; Optionally, Pair-R 1a / -R 4a , Pair-R 1a / -R 5a , Pair-R 1a / -R 7a , Pair-R 4a / -R 5a , Pair-R 8a / -R 9a one or more of the following forms a chemical bond; Optionally, Pair-R 1 / -R 1a , Pair-R 2 / -R 2a , Pair-R 4 / -R 4a , Pair-R 5 / -R 5a , Pair-R 8 / -R 8a , Pair-R 9 / -R 9a One or more of the following, together with the atoms to which they are attached, form a C3-10 cycloalkyl; or 3- to 10-membered heterocyclyl; Optionally, Pair-R 1 / -R 4 , Pair-R 1 / -R 5 , Pair-R 1 / -R 6 , Pair-R 1 / -R 7a , Pair-R 4 / -R 5 , Pair-R 4 / -R 6 , Pair-R 8 / -R 9 , Pair-R 2 / -R 3 one or more of, together with the atoms to which they are attached, form a ring A; Optionally, R 3 / R 3a together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic ring; A is phenyl; naphthyl; indenyl; indanyl; tetralinyl; C 3-10 cycloalkyl; 3- to 10-membered heterocyclyl; and 8- to 11-membered heterobicyclyl; where -L 1 - At least one -L 2 - is replaced by -L 1 - is optionally further substituted, provided that the hydrogen marked with an asterisk in formula (II) is -L 2 - or provided that it is not substituted by a substituent) is.

[0242] Preferably, -L of formula (II) 1 - is one -L 2 - is replaced by the moiety.

[0243] In one embodiment, -L of formula (II) 1 - is not further substituted.

[0244] -R in formula (II) 3 / -R 3aHowever, when they are combined with the nitrogen atom to form a 3- to 10-membered heterocycle, the atom directly bonded to the nitrogen atom is sp 3 It is understood that only 3- to 10-membered heterocycles can be formed in which the -hybridized carbon atoms are -R together with the nitrogen atom to which they are attached. 3 / -R 3a Such 3- to 10-membered heterocycles formed by the following structure:

[0245] [ka] (In the formula, The dashed line is -L 1 - indicates the connection to the rest; the ring contains 3 to 10 atoms, including at least one nitrogen; R # and R ## sp 3 - represents a hybridized (hydridized) carbon atom It has.

[0246] It is also understood that the 3- to 10-membered heterocycle may be further substituted.

[0247] -R of formula (II) together with the nitrogen atom to which they are attached 3 / -R 3a Exemplary embodiments of suitable 3- to 10-membered heterocycles formed by are as follows:

[0248] [ka] (In the formula, The dashed line indicates the bond to the rest of the molecule; -R is -H and C 1-6 alkyl).

[0249] -L in formula (II) 1- may be optionally further substituted. In general, any substituent may be used as long as the principle of cleavage is not affected, i.e., the hydrogen marked with an asterisk in formula (II) is not replaced, and the hydrogen in formula (II)

[0250] [ka] The nitrogen of the moiety remains part of a primary, secondary, or tertiary amine, i.e., -R 3 and -R 3a are each independently -H or sp 3 - is linked to -N< through a hybridized carbon atom.

[0251] In one embodiment, -R of formula (II) 1 or -R 1a -L 2 In another embodiment, -R of formula (II) is substituted by -. 2 or -R 2a -L 2 In another embodiment, -R of formula (II) is substituted by 3 or -R 3a -L 2 In another embodiment, -R of formula (II) is substituted by -. 4 -L 2 In another embodiment, -R of formula (II) is substituted by -. 5 or -R 5a -L 2 In another embodiment, -R of formula (II) is substituted by -. 6 -L 2 In another embodiment, -R of formula (II) is substituted by -. 7 or -R 7a -L 2 In another embodiment, -R of formula (II) is substituted by -. 8 or -R 8a -L 2 In another embodiment, -R of formula (II) is substituted by -. 9 or -R 9a -L 2In another embodiment, -R of formula (II) is substituted by -. 10 or -R 10a -L 2 In another embodiment, -R of formula (II) is substituted by -. 11 -L 2 - has been replaced by

[0252] In certain embodiments, -L 1 - has a structure as disclosed in WO2016 / 020373A1. Thus, in certain embodiments, -L 1 The - moiety has formula (III):

[0253] [ka] (In the formula, The dashed line indicates the attachment of -D to a primary or secondary amine or hydroxyl by forming an amide or ester bond, respectively; -R 1 , -R 1a , -R 2 , -R 2a , -R 3 and -R 3a -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; -R 4 , -R 5 and -R 5a -H, -C(R 9 R 9a R 9b ) and -T; a1 and a2 are, independently of each other, 0 or 1; Each-R 6 , -R 6a, -R 7 , -R 7a , -R 8 , -R 8a , -R 8b , -R 9 , -R 9a , -R 9b -H, halogen, -CN, -COOR 10 , -OR 10 , -C(O)R 10 , -C(O)N(R 10 R 10a ), -S(O)2N(R 10 R 10a ), -S(O)N(R 10 R 10a ), -S(O)R 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 may be one or more -R 11 is optionally replaced by C 1-20 Alkyl, C 2-20 Alkenyl, and C 2-20Alkynyl is -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 )-; Each-R 10 , -R 10a , -R 10b -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 may be one or more -R 11 is optionally replaced by C 1-20 Alkyl, C 2-20 Alkenyl, and C 2-20 Alkynyl is -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 )-; Each T is phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3-10 and each T is independently selected from the group consisting of cycloalkyl, 3- to 10-membered heterocyclyl, and 8- to 11-membered heterobicyclyl, wherein each T is the same or different and is selected from one or more —R 11 is independently and optionally replaced by; Each-R 11 is 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)R 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, wherein C 1-6 The alkyl is optionally substituted with one or more halogens which may be the same or different; Each-R 12 , -R 12a , -R 13 , -R 13a , -R 13b -H and C 1-6 alkyl, wherein C 1-6The alkyl is optionally substituted with one or more halogens which may be the same or different; Optionally, Pair-R 1 / -R 1a , Pair-R 2 / -R 2a , Pair-R 3 / -R 3a , Pair-R 6 / -R 6a , Pair-R 7 / -R 7a One or more of the following, together with the atoms to which they are attached, form a C 3-10 forming a cycloalkyl or a 3- to 10-membered heterocyclyl; Optionally, Pair-R 1 / -R 2 , Pair-R 1 / -R 3 , Pair-R 1 / -R 4 , Pair-R 1 / -R 5 , Pair-R 1 / -R 6 , Pair-R 1 / -R 7 , Pair-R 2 / -R 3 , Pair-R 2 / -R 4 , Pair-R 2 / -R 5 , Pair-R 2 / -R 6 , Pair-R 2 / -R 7 , Pair-R 3 / -R 4 , Pair-R 3 / -R 5 , Pair-R 3 / -R 6 , Pair-R 3 / -R 7 , Pair-R 4 / -R 5 , Pair-R 4 / -R 6 , Pair-R 4 / -R 7 , Pair-R 5 / -R 6 , Pair-R 5 / -R 7 , Pair-R6 / -R 7 one or more of, together with the atoms to which they are attached, form a ring A; A is phenyl; naphthyl; indenyl; indanyl; tetralinyl; C 3-10 cycloalkyl; 3- to 10-membered heterocyclyl; and 8- to 11-membered heterobicyclyl; where -L 1 - At least one -L 2 - is replaced by -L 1 - is optionally further substituted) is.

[0254] -L in formula (III) 1 The optional further substituents of - are preferably as described above.

[0255] Preferably, -L of formula (III) 1 - is one -L 2 - is replaced by the moiety.

[0256] In one embodiment, -L of formula (III) 1 - is not further substituted.

[0257] In another embodiment, -L 1 has a structure as disclosed in EP1536334B1, WO2009 / 009712A1, WO2008 / 034122A1, WO2009 / 143412A2, WO2011 / 082368A2, and U.S. Pat. No. 8,618,124 B2, which are incorporated herein by reference.

[0258] In another embodiment, -L 1 - has a structure as disclosed in U.S. Pat. No. 8,946,405 B2 and U.S. Pat. No. 8,754,190 B2, which are incorporated herein by reference. Thus, in certain embodiments, -L 1 - is a group represented by the formula (IV):

[0259] [ka] (In the formula, The dashed line indicates the point of attachment to -D through a functional group of -D selected from the group consisting of -OH, -SH, and -NH; m is 0 or 1; -R 1 and -R 2 At least one or both of are -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 are independently selected from the group consisting of: -R 1 and -R 2 is selected from the group consisting of: -H, optionally substituted alkyl, optionally substituted arylalkyl, and optionally substituted heteroarylalkyl; -R 3 is -H, optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -OR 9 and -N(R 9 )2 is selected from the group consisting of; -R 4 is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; Each-R 5is independently selected from the group consisting of -H, optionally substituted alkyl, optionally substituted alkenylalkyl, optionally substituted alkynylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; -R 9 is selected from the group consisting of —H and optionally substituted alkyl; -Y- is absent and -X- is -O- or -S-; or -Y- is -N(Q)CH2- and -X- is -O-; Q is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; Optionally, -R 1 and -R 2 can be taken together to form a 3- to 8-membered ring; Optionally, both -R 9 form, together with the nitrogen to which they are attached, a heterocyclic ring; where -L 1 - At least one -L 2 - is replaced by -L 1 - is optionally further substituted) is.

[0260] In the context of formula (IV) only, the terms used have the following meanings:

[0261] The term "alkyl," as used herein, includes straight-chain, branched, or cyclic saturated hydrocarbon groups of 1 to 8 carbons, or in some embodiments, 1 to 6 or 1 to 4 carbon atoms.

[0262] The term "alkoxy" includes alkyl groups attached to oxygen, including methoxy, ethoxy, isopropoxy, cyclopropoxy, cyclobutoxy and the like.

[0263] The term "alkenyl" includes non-aromatic unsaturated hydrocarbons containing a carbon-carbon double bond.

[0264] The term "alkynyl" includes non-aromatic unsaturated hydrocarbons containing a carbon-carbon triple bond.

[0265] The term "aryl" includes aromatic hydrocarbon groups of 6 to 18 carbons, preferably 6 to 10 carbons, including, for example, phenyl, naphthyl, and anthracenyl groups. The term "heteroaryl" includes aromatic rings of 3 to 15 carbons, preferably 3 to 7 carbons, 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.

[0266] In some instances, the alkenyl, alkynyl, aryl, or heteroaryl moiety can be coupled to the remainder of the molecule via an alkylene bond. In such situations, the substituent is referred to as alkenylalkyl, alkynylalkyl, arylalkyl, or heteroarylalkyl, indicating that an alkylene moiety is between the alkenyl, alkynyl, aryl, or heteroaryl moiety and the molecule to which the alkenyl, alkynyl, aryl, or heteroaryl is coupled.

[0267] The term "halogen" includes bromo, fluoro, chloro and iodo.

[0268] The term "heterocyclic ring" refers to a 4- to 8-membered aromatic or non-aromatic ring containing 3 to 7 carbon atoms and at least one N, O, or S atom. Examples are piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidine, and tetrahydrofuranyl, as well as the exemplary groups provided above for the term "heteroaryl."

[0269] If the ring system is optionally substituted, suitable substituents are selected from the group consisting of alkyl, alkenyl, alkynyl, or additional rings, each of which is optionally further substituted. Optional substituents on any of the above groups include halo, nitro, cyano, -OR, -SR, -NR, -OCOR, -NRCOR, -COOR, -CONR, -SOR, -SOR, -SONR, -SONR, where 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.

[0270] Preferably, -L in formula (IV) 1 - is one -L 2 - is replaced by the moiety.

[0271] In another embodiment, -L 1 - has a structure as disclosed in WO2013 / 036857A1, which is incorporated herein by reference. Thus, in certain embodiments, -L 1 - is a compound of formula (V):

[0272] [ka] (In the formula, The dashed line indicates the attachment point to -D via the amine functionality of -D; -R 1 is an optionally substituted C1-C6 straight chain, branched, or cyclic alkyl; an optionally substituted aryl; an optionally substituted heteroaryl; an alkoxy; and -NR 5 2; -R2 is selected from the group consisting of -H; optionally substituted C1-C6 alkyl; optionally substituted aryl; and optionally substituted heteroaryl; -R 3 is selected from the group consisting of -H; optionally substituted C1-C6 alkyl; optionally substituted aryl; and optionally substituted heteroaryl; -R 4 is selected from the group consisting of -H; optionally substituted C1-C6 alkyl; optionally substituted aryl; and optionally substituted heteroaryl; Each-R 5 are independently selected from the group consisting of: -H; optionally substituted C-C alkyl; optionally substituted aryl; and optionally substituted heteroaryl, or when taken together, two -R 5 may be cycloalkyl or cycloheteroalkyl; where -L 1 - At least one -L 2 - is replaced by -L 1 - is optionally further substituted) is.

[0273] In the context of formula (V) only, the terms used have the following meanings:

[0274] "Alkyl," "alkenyl," and "alkynyl" include straight-chain, branched, or cyclic hydrocarbon groups of 1 to 8 carbons or 1 to 6 carbons or 1 to 4 carbons, where alkyl is a saturated hydrocarbon, alkenyl contains one or more carbon-carbon double bonds, and alkynyl contains one or more carbon-carbon triple bonds. Unless otherwise specified, they contain 1 to 6 C.

[0275] "Aryl" includes aromatic hydrocarbon groups of 6 to 18 carbons, preferably 6 to 10 carbons, including, for example, phenyl, naphthyl, and anthracene groups. "Heteroaryl" includes aromatic rings of 3 to 15 carbons, preferably 3 to 7 carbons, containing at least one N, O, or S atom, including, for example, pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiszolyl, isothiazolyl, quinolyl, indolyl, indenyl, and the like.

[0276] The term "substituted" refers to an alkyl, alkenyl, alkynyl, aryl, or heteroaryl group that contains one or more substituents in place of one or more hydrogen atoms. The substituents are generally selected from the group consisting of 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, carboxylic acid ester, amide of carboxylic acid, aminocarbonyl; aminoacyl; carbamate; urea; thiocarbamate; thiourea; ketone (ketone). tne); 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.

[0277] Preferably, -L in formula (V) 1 - is one -L 2 - is replaced by the moiety.

[0278] In another embodiment, -L 1 - has a structure as disclosed in U.S. Pat. No. 7,585,837 B2, which is incorporated herein by reference. Thus, in certain embodiments, -L 1 is a group represented by the formula (VI):

[0279] [ka] (In the formula, The dashed line indicates the attachment point to -D via the amine functionality of -D; R 1 and R 2 is hydrogen, alkyl, alkoxy, alkoxyalkyl, aryl, alkaryl, aralkyl, halogen, nitro, -SO3H, -SO2NHR 5 independently selected from the group consisting of amino, ammonium, carboxyl, PO3H2, and OPO3H2; R 3 , R 4 , and R 5 are independently selected from the group consisting of hydrogen, alkyl, and aryl; where -L 1 - At least one -L 2 - is replaced by -L 1 - is optionally further substituted) is.

[0280] Suitable substituents for formula (VI) include alkyl (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- to 7-membered heterocycle), or halogen moiety.

[0281] In the context of formula (VI) only, the terms used have the following meanings:

[0282] The terms "alkyl," "alkoxy," "alkoxyalkyl," "aryl," "alkaryl," and "aralkyl" refer to alkyl radicals of 1 to 8, preferably 1 to 4, carbon atoms, such as methyl, ethyl, propyl, isopropyl, and butyl, and aryl radicals of 6 to 10 carbon atoms, such as phenyl and naphthyl. The term "halogen" includes bromo, fluoro, chloro, and iodo.

[0283] Preferably, -L of formula (VI) 1 - is one -L 2 - is replaced by the moiety.

[0284] In another embodiment, -L 1 - has the structure as disclosed in WO2002 / 089789A1, which is incorporated herein by reference. Thus, in certain embodiments, -L 1 - is a group represented by the formula (VII):

[0285] [ka] (In the formula, The dashed line indicates the attachment point to -D via the amine functionality of -D; L1 is a bifunctional linking group; Y1 and Y2 are independently O, S, or NR 7 and; R 2 , R 3 , R 4 , R 5 , R 6 and R 7 is 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 1-6Heteroalkyl, substituted C 1-6 Heteroalkyl, C 1-6 Alkoxy, phenoxy, and C 1-6 independently selected from the group consisting of heteroalkoxy; Ar is a moiety that, when included in formula (VII), forms a polysubstituted aromatic hydrocarbon or polysubstituted heterocyclic group; X is a chemical bond, a moiety that is actively transported into the target cell, a hydrophobic moiety, or a combination thereof; y is 0 or 1; where -L 1 - At least one -L 2 - is replaced by -L 1 - is optionally further substituted) is.

[0286] In the context of formula (VII) only, the terms used have the following meanings:

[0287] The term "alkyl" includes, for example, alkoxy, C 3-8 Straight chain, branched, substituted C, including cycloalkyl or substituted cycloalkyl 1-12 It is understood that alkyl is included.

[0288] The term "substituted" is understood to include the addition of, or replacement of, one or more atoms contained within a functional group or compound with one or more different atoms.

[0289] Substituted alkyl includes carboxyalkyl, aminoalkyl, dialkylamino, hydroxyalkyl, and mercaptoalkyl, substituted cycloalkyl includes a moiety such as 4-chlorocyclohexyl, aryl includes a moiety such as naphthyl, substituted aryl includes a moiety such as 3-bromo-phenyl, aralkyl includes a moiety such as toluyl, heteroalkyl includes a moiety such as ethylthiophene, substituted heteroalkyl includes a moiety such as 3-methoxythiophene, alkoxy includes a moiety such as methoxy, and phenoxy includes a moiety such as 3-nitrophenoxy. Halo- is understood to include fluoro, chloro, iodo, and bromo.

[0290] Preferably, -L in formula (VII) 1 - is one -L 2 - is replaced by the moiety.

[0291] In certain embodiments, -L 1 - is a group represented by the formula (VIII)

[0292] [ka] (In the formula, The dashed line with an asterisk indicates the attachment of -D to the nitrogen by forming an amide bond; Unmarked dashed lines are -L 1 - indicates the bond to the rest of; where -L 1 - At least one -L 2 - is replaced by -L 1 - is optionally further substituted) Contains the substructure:

[0293] Preferably, -L in formula (VIII) 1 - is one -L 2 - is replaced by the moiety.

[0294] In one embodiment, -L of formula (VIII) 1 - is not further substituted.

[0295] In certain embodiments, -L 1 - is a group represented by the formula (IX)

[0296] [ka] (In the formula, The dashed line with an asterisk indicates the attachment of -D to the nitrogen by forming a carbamate bond; Unmarked dashed lines are -L 1 - indicates the bond to the rest of; where -L 1 - At least one -L 2 - is replaced by -L 1 - is optionally further substituted) Contains the substructure:

[0297] Preferably, -L in formula (IX) 1 - is one -L 2 - is replaced by the moiety.

[0298] In one embodiment, -L of formula (IX) 1 - is not further substituted.

[0299] In certain embodiments, -L 1 - is a group represented by the formula (IX-a):

[0300] [ka] [In the formula, The dashed line with an asterisk indicates the attachment of -D to the nitrogen, and the unmarked dashed line indicates the attachment of -L 2 - indicates the bond to; n is 0, 1, 2, 3, or 4; =Y1, =Y5 are independently selected from the group consisting of =O and =S; -Y2- is selected from the group consisting of -O- and -S-; -Y3- is selected from the group consisting of -O- and -S-; -Y4- is -O-, -NR 5 - and -C(R 6 R 6a )-selected from the group consisting of; -R 3 , -R 5 , -R 6 , -R 6a are independently selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and 3,3-dimethylpropyl; -R 4 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and 3,3-dimethylpropyl; -W- is C 3-10 Cycloalkyl, 8-30 membered carbopolycyclyl, 3-10 membered heterocyclyl, -C(O)-, -C(O)N(R 7 )-, -O-, -S- and -N(R 7 C optionally interrupted by one or more groups selected from the group consisting of 1-20 selected from the group consisting of alkyl; -Nu is -N(R 7 R 7a ), -N(R 7 OH), -N(R 7 )-N(R 7a R 7b ), -S(R 7 ), -COOH,

[0301] [ka] is a nucleophilic group selected from the group consisting of: -Ar- is

[0302] [ka] (In the formula, The dashed line is -L 1 - indicates the bond to the remainder of -Z 1 - is -O-, -S- and -N(R 7 )-, -Z 2 - is -N(R 7 )-is) selected from the group consisting of: -R 7 , -R 7a , -R 7b -H, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 alkynyl; where -L 1 - is optionally further substituted] is.

[0303] In one embodiment, -L of formula (IX-a) 1 - is not further substituted.

[0304] In certain embodiments, -L 1 - is a group represented by the formula (IX-b):

[0305] [ka] [In the formula, The dashed line with an asterisk indicates the attachment of -D to the nitrogen, and the unmarked dashed line indicates the attachment of -L 2 - indicates the bond to; n is 0, 1, 2, 3, or 4; =Y1, =Y5 are independently selected from the group consisting of =O and =S; -Y2- is selected from the group consisting of -O- and -S-; -Y3- is selected from the group consisting of -O- and -S-; -Y4- is -O-, -NR 5 - and -C(R 6 R 6a )-selected from the group consisting of; -R 2 , -R 3 , -R 5 , -R 6 , -R 6a are independently selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and 3,3-dimethylpropyl; -R 4 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and 3,3-dimethylpropyl; -W- is C 3-10 Cycloalkyl, 8-30 membered carbopolycyclyl, 3-10 membered heterocyclyl, -C(O)-, -C(O)N(R 7 )-, -O-, -S- and -N(R 7 C optionally interrupted by one or more groups selected from the group consisting of 1-20 selected from the group consisting of alkyl; -Nu is -N(R 7 R 7a ), -N(R 7 OH), -N(R 7 )-N(R 7a R 7b ), -S(R 7 ), -COOH,

[0306] [ka] is a nucleophilic group selected from the group consisting of: -Ar- is

[0307] [ka] (In the formula, The dashed line is -L 1 - indicates the bond to the remainder of -Z 1 - is -O-, -S- and -N(R 7 )-, -Z 2 - is -N(R 7 )-is) selected from the group consisting of: -R 7 , -R 7a , -R 7b -H, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 alkynyl; where -L 1 - is optionally further substituted] is.

[0308] In one embodiment, -L of formula (IX-b) 1 - is not further substituted.

[0309] In certain embodiments, -L 1 - is the formula (X)

[0310] [ka] (In the formula, The dashed line indicates the attachment of the -D to the nitrogen of the amine functional group; =X 1 is selected from the group consisting of =O, =S and =N; -X 2 - is selected from the group consisting of -O-, -S- and -N-; -R is C 1-50 This C is an alkyl 1-50 Alkyl is -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R z1 )-, -S(O)2N(R z1 )-, -S(O)N(R z1 )-, -S(O)2-, -S(O)-, -N(R z1 )S(O)2N(R z1a )-, -S-, -N(R z1 )-, -OC(OR z1 )(R z1a )-, -N(R z1 )C(O)N(R z1a )- and -OC(O)N(R z1 )-, optionally interrupted by one or more groups selected from the group consisting of C 1-50 Alkyl is one or more -R z2 is optionally replaced by; Each T is phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8- to 30-membered carbopolycyclyl, and 8- to 30-membered heteropolycyclyl, wherein each T is the same or different and is selected from the group consisting of one or more -R z2 is independently and optionally replaced by; Each-R z2 is halogen, -CN, oxo(=O), -COOR z3 , -OR z3 , -C(O)R z3 , -C(O)N(R z3 R z3a ), -S(O)2N(R z3 R z3a ), -S(O)N(R z3 R z3a ), -S(O)R z3 , -S(O)R z3 , -N(R z3 )S(O)2N(R z3a R z3b ), -SR z3 , -N(R z3 R z3a ), -NO2, -OC(O)R z3, -N(R z3 )C(O)R z3a , -N(R z3 )S(O)2R z3a , -N(R z3 )S(O)R z3a , -N(R z3 )C(O)OR z3a , -N(R z3 )C(O)N(R z3a R z3b ), -OC(O)N(R z3 R z3a ), and C 1-6 alkyl, wherein C 1-6 The alkyl is optionally substituted with one or more halogens which may be the same or different; Each-R z1 , -R z1a , -R z3 , -R z3a and -R z3b -H, and C 1-6 alkyl, wherein C 1-6 The alkyl is optionally substituted with one or more halogens which may be the same or different; where -L 1 - At least one -L 2 - is replaced by -L 1 - is optionally further substituted) is.

[0311] In certain embodiments, -L 1 - is one -L 2 - has been replaced by

[0312] In one embodiment, -L of formula (X) 1 - is not further substituted.

[0313] In certain embodiments, =X in formula (X) 1 is selected from the group consisting of =N and =O. In certain embodiments, the =X in formula (X) 1 is =N. In certain embodiments, the =X in formula (X) 1 is =O.

[0314] In certain embodiments, -X in formula (X) 2 - is selected from the group consisting of -N- and -O-. In certain embodiments, -X in formula (X) 2 - is -N-. In certain embodiments, -X in formula (X) 2 - is -O-.

[0315] In certain embodiments, =X in formula (X) 1 is =N, and -X in formula (X) 2 - is -O-. In certain embodiments, =X in formula (X) 1 is =O, and -X in formula (X) 2 - is -N-. In certain embodiments, =X in formula (X) 1 is =N, and -X in formula (X) 2 - is -N-. In certain embodiments, =X in formula (X) 1 is =O, and -X in formula (X) 2 - is -O-.

[0316] In certain embodiments, —R in formula (X) is C 1-20 This C is an alkyl 1-20 Alkyl is -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R z1 )-, -S(O)2N(R z1 )-, -S(O)N(R z1 )-, -S(O)2-, -S(O)-, -S-, -N(R z1 )-, -OC(OR z1 )(R z1a )-, -N(R z1 )C(O)N(R z1a )- and -OC(O)N(R z1 )-, optionally interrupted by one or more groups selected from the group consisting of C 1-20 Alkyl is one or more -R z2 is optionally replaced by; Each-R z1 and -R z1a -H, and C 1-6alkyl, wherein C 1-6 The alkyl is optionally substituted with one or more halogens which may be the same or different; Each T is phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, and 8- to 11-membered heterobicyclyl, wherein each T is the same or different and is selected from the group consisting of one or more —R z2 is independently and optionally replaced by; Each-R z2 is a halogen, and C 1-6 alkyl, wherein C 1-6 The alkyl is optionally substituted with one or more halogens which may be the same or different.

[0317] In certain embodiments, the moiety of formula (X) is represented by formulas (X-1), (X-2), (X-3), (X-4), (X-5), (X-6), (X-7), (X-8), (X-9), (X-10), (X-11), and (X-12):

[0318] [ka] TIFF2024546134000034.tif46165 (in the formula, The dashed line with an asterisk indicates the attachment of the amine functional group of -D to the nitrogen; Unmarked dashed lines are -L 2 indicates the bond to; -R 1 -H, C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 alkynyl; -R 2 and -R 2a -H, halogen, C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 independently selected from the group consisting of alkynyl; n is an integer selected from the group consisting of 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; m is an integer selected from the group consisting of 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; o is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; p is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; q is an integer selected from the group consisting of 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. is selected from the group consisting of:

[0319] In certain embodiments, n in formula (X-1), (X-2), (X-3), (X-4), (X-5), (X-6), (X-7), (X-8), (X-9), or (X-12) is 1. In certain embodiments, n in formula (X-1), (X-2), (X-3), (X-4), (X-5), (X-6), (X-7), (X-8), (X-9), or (X-12) is 2. In certain embodiments, n in formula (X-1), (X-2), (X-3), (X-4), (X-5), (X-6), (X-7), (X-8), (X-9), or (X-12) is 3. In certain embodiments, n in formula (X-1), (X-2), (X-3), (X-4), (X-5), (X-6), (X-7), (X-8), (X-9), or (X-12) is 4. In certain embodiments, n in formula (X-1), (X-2), (X-3), (X-4), (X-5), (X-6), (X-7), (X-8), (X-9), or (X-12) is 5. In certain embodiments, n in formula (X-1), (X-2), (X-3), (X-4), (X-5), (X-6), (X-7), (X-8), (X-9), or (X-12) is 6. In certain embodiments, n in formula (X-1), (X-2), (X-3), (X-4), (X-5), (X-6), (X-7), (X-8), (X-9), or (X-12) is 7. In certain embodiments, n in formula (X-1), (X-2), (X-3), (X-4), (X-5), (X-6), (X-7), (X-8), (X-9), or (X-12) is 8. In certain embodiments, n in formula (X-1), (X-2), (X-3), (X-4), (X-5), (X-6), (X-7), (X-8), (X-9), or (X-12) is 9. In certain embodiments, n in formula (X-1), (X-2), (X-3), (X-4), (X-5), (X-6), (X-7), (X-8), (X-9), or (X-12) is 10.

[0320] In certain embodiments, m in formula (X-8), (X-9), or (X-12) is 1. In certain embodiments, m in formula (X-8), (X-9), or (X-12) is 2. In certain embodiments, m in formula (X-8), (X-9), or (X-12) is 3. In certain embodiments, m in formula (X-8), (X-9), or (X-12) is 4. In certain embodiments, m in formula (X-8), (X-9), or (X-12) is 5. In certain embodiments, m in formula (X-8), (X-9), or (X-12) is 6. In certain embodiments, m in formula (X-8), (X-9), or (X-12) is 7. In certain embodiments, m in formula (X-8), (X-9), or (X-12) is 8. In certain embodiments, m in formula (X-8), (X-9), or (X-12) is 9. In certain embodiments, m in formula (X-8), (X-9), or (X-12) is 10.

[0321] In certain embodiments, o in formula (X-10) or (X-11) is 0. In certain embodiments, o in formula (X-10) or (X-11) is 1. In certain embodiments, o in formula (X-10) or (X-11) is 2. In certain embodiments, o in formula (X-10) or (X-11) is 3. In certain embodiments, o in formula (X-10) or (X-11) is 4. In certain embodiments, o in formula (X-10) or (X-11) is 5. In certain embodiments, o in formula (X-10) or (X-11) is 6. In certain embodiments, o in formula (X-10) or (X-11) is 7. In certain embodiments, o in formula (X-10) or (X-11) is 8. In certain embodiments, o in formula (X-10) or (X-11) is 9. In certain embodiments, o in formula (X-10) or (X-11) is 10.

[0322] In certain embodiments, p in formula (X-10) or (X-11) is 0. In certain embodiments, p in formula (X-10) or (X-11) is 1. In certain embodiments, p in formula (X-10) or (X-11) is 2. In certain embodiments, p in formula (X-10) or (X-11) is 3. In certain embodiments, p in formula (X-10) or (X-11) is 4. In certain embodiments, p in formula (X-10) or (X-11) is 5. In certain embodiments, p in formula (X-10) or (X-11) is 6. In certain embodiments, p in formula (X-10) or (X-11) is 7. In certain embodiments, p in formula (X-10) or (X-11) is 8. In certain embodiments, p in formula (X-10) or (X-11) is 9. In certain embodiments, p in formula (X-10) or (X-11) is 10.

[0323] In certain embodiments, q in Formula (X-11) is 1. In certain embodiments, q in Formula (X-11) is 2. In certain embodiments, q in Formula (X-11) is 3. In certain embodiments, q in Formula (X-11) is 4. In certain embodiments, q in Formula (X-11) is 5. In certain embodiments, q in Formula (X-11) is 6. In certain embodiments, q in Formula (X-11) is 7. In certain embodiments, q in Formula (X-11) is 8. In certain embodiments, q in Formula (X-11) is 9. In certain embodiments, q in Formula (X-11) is 10.

[0324] In certain embodiments, -R of formula (X-5), (X-6), (X-7), (X-8), (X-9), (X-10), (X-11), or (X-12) 1 In certain embodiments, -R of formula (X-5), (X-6), (X-7), (X-8), (X-9), (X-10), (X-11), or (X-12) is -H. 1 is C 1-10In certain embodiments, -R of formula (X-5), (X-6), (X-7), (X-8), (X-9), (X-10), (X-11), or (X-12) is an alkyl, such as 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, or 3,3-dimethylpropyl. 1 is C 2-10 In certain embodiments, -R of formula (X-5), (X-6), (X-7), (X-8), (X-9), (X-10), (X-11), or (X-12) is alkenyl. 1 is C 2-10 It is alkynyl.

[0325] In certain embodiments, -R of formula (X-10) or (X-11) 2 is —H. In certain embodiments, —R of formula (X-10) or (X-11) 2 is halogen, for example, fluoro or chloro. In certain embodiments, —R of formula (X-10) or (X-11) 2 is C 1-10 In certain embodiments, -R of formula (X-10) or (X-11) is an alkyl, such as 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, or 3,3-dimethylpropyl. 2 is C 2-10 alkenyl, for example, C alkenyl, C alkenyl, C alkenyl, C alkenyl, or C alkenyl. In certain embodiments, -R of formula (X-10) or (X-11) 2 is C 2-10 Alkynyl is, for example, C2 alkynyl, C3 alkynyl, C4 alkynyl, C5 alkynyl or C6 alkynyl.

[0326] In certain embodiments, -R of formula (X-10) or (X-11) 2a is —H. In certain embodiments, —R of formula (X-10) or (X-11) 2a is a halogen. In certain embodiments, —R of formula (X-10) or (X-11) 2a is C 1-10 In certain embodiments, -R of formula (X-10) or (X-11) is an alkyl, such as 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, or 3,3-dimethylpropyl. 2a is C 2-10 alkenyl, for example, C alkenyl, C alkenyl, C alkenyl, C alkenyl, or C alkenyl. In certain embodiments, -R of formula (X-10) or (X-11) 2a is C 2-10 Alkynyl is, for example, C2 alkynyl, C3 alkynyl, C4 alkynyl, C5 alkynyl or C6 alkynyl.

[0327] In certain embodiments, -R in formulas (X-10) and (X-11) 2 and -R 2a At least one of the is not -H.

[0328] In certain embodiments, -L 1 - is formula (X-1). In certain embodiments, -L 1 - is formula (X-1) where n=1. In certain embodiments, -L 1 - is formula (X-1) where n=2. In certain embodiments, -L 1 - is formula (X-1) where n=3. In certain embodiments, -L 1 - is formula (X-1) where n=4. In certain embodiments, -L 1 - is the formula (X-1) where n=5.

[0329] In certain embodiments, -L 1 - is formula (X-2). In certain embodiments, -L 1 - is formula (X-2) where n=1. In certain embodiments, -L 1 - is formula (X-2) where n=2. In certain embodiments, -L 1 - is formula (X-2) where n=3. In certain embodiments, -L 1 - is formula (X-2) where n=4. In certain embodiments, -L 1 - is the formula (X-2) where n=5.

[0330] In certain embodiments, -L 1 - is formula (X-3). In certain embodiments, -L 1 - is formula (X-3) where n=1. In certain embodiments, -L 1 - is formula (X-3) where n=2. In certain embodiments, -L 1 - is formula (X-3) where n=3. In certain embodiments, -L 1 - is formula (X-3) where n=4. In certain embodiments, -L 1 - is the formula (X-3) where n=5.

[0331] In certain embodiments, -L 1 - is formula (X-4). In certain embodiments, -L 1 - is formula (X-4) where n=1. In certain embodiments, -L 1 - is formula (X-4) where n=2. In certain embodiments, -L 1 - is formula (X-4) where n=3. In certain embodiments, -L 1 - is formula (X-4) where n=4. In certain embodiments, -L 1 - is the formula (X-4) where n=5.

[0332] In certain embodiments, -L 1- is formula (X-5). In certain embodiments, -L 1 - is formula (X-5), and -R 1 is -H. In certain embodiments, -L 1 - is formula (X-5), and -R 1 is methyl. In certain embodiments, -L 1 - is formula (X-5), and -R 1 is ethyl. In certain embodiments, -L 1 - is formula (X-5) and n is 1. In certain embodiments, -L 1 - is formula (X-5) and n is 2. In certain embodiments, -L 1 - is formula (X-5) and n is 3. In certain embodiments, -L 1 - is formula (X-5), and -R 1 is -H and n is 1. In certain embodiments, -L 1 - is formula (X-5), and -R 1 is -H and n is 2. In certain embodiments, -L 1 - is formula (X-5), and -R 1 is -H and n is 3. In certain embodiments, -L 1 - is formula (X-5), and -R 1 is methyl and n is 1. In certain embodiments, -L 1 - is formula (X-5), and -R 1 is methyl and n is 2. In certain embodiments, -L 1 - is formula (X-5), and -R 1 is methyl and n is 3.

[0333] In certain embodiments, -L 1 - is formula (X-6). In certain embodiments, -L 1 - is formula (X-6), and -R 1 is -H. In certain embodiments, -L 1 - is formula (X-6), and -R 1 is methyl. In certain embodiments, -L 1 - is formula (X-6), and -R 1is ethyl. In certain embodiments, -L 1 - is formula (X-6) and n is 1. In certain embodiments, -L 1 - is formula (X-6) and n is 2. In certain embodiments, -L 1 - is formula (X-6) and n is 3. In certain embodiments, -L 1 - is formula (X-6), and -R 1 is -H and n is 1. In certain embodiments, -L 1 - is formula (X-6), and -R 1 is -H and n is 2. In certain embodiments, -L 1 - is formula (X-6), and -R 1 is -H and n is 3. In certain embodiments, -L 1 - is formula (X-6), and -R 1 is methyl and n is 1. In certain embodiments, -L 1 - is formula (X-6), and -R 1 is methyl and n is 2. In certain embodiments, -L 1 - is formula (X-6), and -R 1 is methyl and n is 3.

[0334] In certain embodiments, -L 1 - is formula (X-7). In certain embodiments, -L 1 - is formula (X-7), and -R 1 is -H. In certain embodiments, -L 1 - is formula (X-7), and -R 1 is methyl. In certain embodiments, -L 1 - is formula (X-7), and -R 1 is ethyl. In certain embodiments, -L 1 - is formula (X-7) and n is 1. In certain embodiments, -L 1 - is formula (X-7) and n is 2. In certain embodiments, -L 1 - is formula (X-7) and n is 3. In certain embodiments, -L 1 - is formula (X-7), and -R1 is -H and n is 1. In certain embodiments, -L 1 - is formula (X-7), and -R 1 is -H and n is 2. In certain embodiments, -L 1 - is formula (X-7), and -R 1 is -H and n is 3. In certain embodiments, -L 1 - is formula (X-7), and -R 1 is methyl and n is 1. In certain embodiments, -L 1 - is formula (X-7), and -R 1 is methyl and n is 2. In certain embodiments, -L 1 - is formula (X-7), and -R 1 is methyl and n is 3.

[0335] In certain embodiments, -L 1 - is formula (X-8). In certain embodiments, -L 1 - is formula (X-8), and -R 1 is -H. In certain embodiments, -L 1 - is formula (X-8), and -R 1 is methyl. In certain embodiments, -L 1 - is formula (X-8), and -R 1 is ethyl. In certain embodiments, -L 1 - is formula (X-8) and n is 1. In certain embodiments, -L 1 - is formula (X-8) and n is 2. In certain embodiments, -L 1 - is formula (X-8) and n is 3. In certain embodiments, -L 1 - is formula (X-8) and m is 1. In certain embodiments, -L 1 - is formula (X-8) and m is 2. In certain embodiments, -L 1 - is formula (X-8) and m is 3. In certain embodiments, -L 1 - is formula (X-8), and -R 1 is -H, n is 1, and m is 1. In certain embodiments, -L1 - is formula (X-8), and -R 1 is -H, n is 1, and m is 2. In certain embodiments, -L 1 - is formula (X-8), and -R 1 is -H, n is 1, and m is 3. In certain embodiments, -L 1 - is formula (X-8), and -R 1 is -H, n is 2, and m is 1. In certain embodiments, -L 1 - is formula (X-8), and -R 1 is -H, n is 2, and m is 2. In certain embodiments, -L 1 - is formula (X-8), and -R 1 is -H, n is 2, and m is 3. In certain embodiments, -L 1 - is formula (X-8), and -R 1 is -H, n is 3, and m is 1. In certain embodiments, -L 1 - is formula (X-8), and -R 1 is -H, n is 3, and m is 2. In certain embodiments, -L 1 - is formula (X-8), and -R 1 is -H, n is 3, and m is 3.

[0336] In certain embodiments, -L 1 - is formula (X-9). In certain embodiments, -L 1 - is formula (X-9), and -R 1 is -H. In certain embodiments, -L 1 - is formula (X-9), and -R 1 is methyl. In certain embodiments, -L 1 - is formula (X-9), and -R 1 is ethyl. In certain embodiments, -L 1 - is formula (X-9) and n is 1. In certain embodiments, -L 1 - is formula (X-9) and n is 2. In certain embodiments, -L 1 - is formula (X-9) and n is 3. In certain embodiments, -L1 - is formula (X-9) and m is 1. In certain embodiments, -L 1 - is formula (X-9) and m is 2. In certain embodiments, -L 1 - is formula (X-9) and m is 3. In certain embodiments, -L 1 - is formula (X-9), and -R 1 is -H, n is 1, and m is 1. In certain embodiments, -L 1 - is formula (X-9), and -R 1 is -H, n is 1, and m is 2. In certain embodiments, -L 1 - is formula (X-9), and -R 1 is -H, n is 1, and m is 3. In certain embodiments, -L 1 - is formula (X-9), and -R 1 is -H, n is 2, and m is 1. In certain embodiments, -L 1 - is formula (X-9), and -R 1 is -H, n is 2, and m is 2. In certain embodiments, -L 1 - is formula (X-9), and -R 1 is -H, n is 2, and m is 3. In certain embodiments, -L 1 - is formula (X-9), and -R 1 is -H, n is 3, and m is 1. In certain embodiments, -L 1 - is formula (X-9), and -R 1 is -H, n is 3, and m is 2. In certain embodiments, -L 1 - is formula (X-9), and -R 1 is -H, n is 3, and m is 3.

[0337] In certain embodiments, -L 1 - is formula (X-10). In certain embodiments, -R of formula (X-10) 1is -H. In certain embodiments, o in formula (X-10) is 0. In certain embodiments, o in formula (X-10) is 1. In certain embodiments, o in formula (X-10) is 2. In certain embodiments, o in formula (X-10) is 3. In certain embodiments, p in formula (X-10) is 0. In certain embodiments, p in formula (X-10) is 1. In certain embodiments, p in formula (X-10) is 2. In certain embodiments, p in formula (X-10) is 3. In certain embodiments, -R ... -R in formula (X-10) is 1. In certain embodiments, -R in formula (X-10) is 2. In certain embodiments, -R in formula (X-10) is 3. 2 is —H. In certain embodiments, —R in formula (X-10) 2 is a halogen, for example, fluor. In certain embodiments, -R in formula (X-10) 2 In certain embodiments, —R of formula (X-10) is methyl. 2 In certain embodiments, —R in formula (X-10) is ethyl. 2 In certain embodiments, —R in formula (X-10) is n-propyl. 2 In certain embodiments, —R in formula (X-10) is isopropyl. 2 In certain embodiments, —R of formula (X-10) is 2-methylpropyl. 2 In certain embodiments, —R of formula (X-10) is 2-methylpropyl. 2 In certain embodiments, —R in formula (X-10) is 1-methylpropyl. 2a is —H. In certain embodiments, —R in formula (X-10) 2 and -R 2a In certain embodiments, both of -R in formula (X-10) are methyl. 2 is fluorine, and -R in formula (X-10) 2a is —H. In certain embodiments, —R in formula (X-10) 2 is isopropyl, and -R in formula (X-10) 2a is —H. In certain embodiments, —R in formula (X-10) 2 is 2-methylpropyl, and -R in formula (X-10) 2ais -H.

[0338] In certain embodiments, -L 1 - is formula (X-11). In certain embodiments, -R of formula (X-11) 1 is —H. In certain embodiments, —R in formula (X-11) 1 is methyl. In certain embodiments, —R in formula (X-11) 1 is ethyl. In certain embodiments, o in Formula (X-11) is 0. In certain embodiments, o in Formula (X-11) is 1. In certain embodiments, o in Formula (X-11) is 2. In certain embodiments, p in Formula (X-11) is 0. In certain embodiments, p in Formula (X-11) is 1. In certain embodiments, p in Formula (X-11) is 2. In certain embodiments, -R in Formula (X-11) is 0. In certain embodiments, p in Formula (X-11) is 1. In certain embodiments, -R in Formula (X-11) is 2. 2 is —H. In certain embodiments, —R in formula (X-11) 2 is halogen, for example, fluorine. In certain embodiments, —R in formula (X-11) 2 In certain embodiments, —R in formula (X-11) is methyl. 2 In certain embodiments, —R in formula (X-11) is ethyl. 2 In certain embodiments, -R in formula (X-11) is n-propyl. 2 In certain embodiments, —R in formula (X-11) is isopropyl. 2 In certain embodiments, —R in formula (X-11) is 2-methylpropyl. 2 In certain embodiments, —R in formula (X-11) is 2-methylpropyl. 2 In certain embodiments, —R in formula (X-11) is 1-methylpropyl. 2a is —H. In certain embodiments, —R in formula (X-11) 2 and -R 2a In certain embodiments, both of -R in formula (X-11) are methyl. 2 is fluorine, and -R in formula (X-11) 2ais —H. In certain embodiments, —R in formula (X-11) 2 is isopropyl, and -R in formula (X-11) 2a is —H. In certain embodiments, —R in formula (X-11) 2 is 2-methylpropyl, and -R in formula (X-11) 2a is —H. In certain embodiments, q in formula (X-11) is 1. In certain embodiments, q in formula (X-11) is 2. In certain embodiments, q in formula (X-11) is 3.

[0339] In certain embodiments, -L 1 - is formula (X-12). In certain embodiments, L 1 - is formula (X-12) and n is 1. In certain embodiments, L 1 - is formula (X-12) and n is 2. In certain embodiments, L 1 - is formula (X-12) and n is 3. In certain embodiments, L 1 - is formula (X-12) and m is 1. In certain embodiments, L 1 - is formula (X-12) and m is 2. In certain embodiments, L 1 - is formula (X-12) and m is 3. In certain embodiments, L 1 - is formula (X-12), and both n and m are 1. In certain embodiments, L 1 - is formula (X-12), and -R 1 is —H. In certain embodiments, L 1 - is formula (X-12), and -R 1 is methyl. In certain embodiments, L 1 - is formula (X-12), and -R 1 is ethyl.

[0340] In certain embodiments, -L 1 is selected from the group consisting of:

[0341] [ka] TIFF2024546134000036.tif240163TIFF2024546134000037.tif235163TIFF2024546134000038.tif35163(in the formula, The dashed line with an asterisk indicates the attachment of the amine functional group of -D to the nitrogen; Unmarked dashed lines are -L 2 - indicates the bond to

[0342] In certain embodiments, -L 1 - is of formula (X-a1). In certain embodiments, -L 1 - is formula (X-a2). In certain embodiments, -L 1 - is formula (X-a3). In certain embodiments, -L 1 - is formula (X-a4). In certain embodiments, -L 1 - is formula (X-a5). In certain embodiments, -L 1 - is formula (X-a6). In certain embodiments, -L 1 - is formula (X-a7). In certain embodiments, -L 1 - is formula (X-a8). In certain embodiments, -L 1 - is formula (X-a9). In certain embodiments, -L 1 - is formula (X-a10). In certain embodiments, -L 1 - is of formula (X-a11). In certain embodiments, -L 1 - is formula (X-a12). In certain embodiments, -L 1 - is formula (X-a13). In certain embodiments, -L 1 - is formula (X-a14). In certain embodiments, -L 1 - is formula (X-a15). In certain embodiments, -L 1 - is formula (X-a16). In certain embodiments, -L 1 - is formula (X-a17). In certain embodiments, -L 1- is formula (X-a18). In certain embodiments, -L 1 - is formula (X-a19). In certain embodiments, -L 1 - is formula (X-a20). In certain embodiments, -L 1 - is formula (X-a21). In certain embodiments, -L 1 - is formula (X-a22). In certain embodiments, -L 1 - is formula (X-a23). In certain embodiments, -L 1 - is formula (X-24). In certain embodiments, -L 1 - is formula (X-a25). In certain embodiments, -L 1 - is formula (X-a26). In certain embodiments, -L 1 - is formula (X-a27). In certain embodiments, -L 1 - is formula (X-a28). In certain embodiments, -L 1 - is formula (X-a29). In certain embodiments, -L 1 - is formula (X-a30). In certain embodiments, -L 1 - is formula (X-a31). In certain embodiments, -L 1 - is formula (X-a32). In certain embodiments, -L 1 - is formula (X-a33). In certain embodiments, -L 1 - is formula (X-a34). In certain embodiments, -L 1 - is formula (X-a35). In certain embodiments, -L 1 - is formula (X-a36). In certain embodiments, -L 1 - is formula (X-a37). In certain embodiments, -L 1 - is formula (X-a38). In certain embodiments, -L 1 - is formula (X-a39). In certain embodiments, -L 1 - is formula (X-a40). In certain embodiments, -L 1 - is formula (X-a41). In certain embodiments, -L1 - is formula (X-a42). In certain embodiments, -L 1 - is formula (X-a43). In certain embodiments, -L 1 - is formula (X-a44). In certain embodiments, -L 1 - is formula (X-a45). In certain embodiments, -L 1 - is formula (X-a46). In certain embodiments, -L 1 - is formula (X-a47). In certain embodiments, -L 1 - is formula (X-a48). In certain embodiments, -L 1 - is formula (X-a49). In certain embodiments, -L 1 - is formula (X-a50). In certain embodiments, -L 1 - is formula (X-a51). In certain embodiments, -L 1 - is formula (X-a52). In certain embodiments, -L 1 - is formula (X-a53). In certain embodiments, -L 1 - is formula (X-a54). In certain embodiments, -L 1 - is formula (X-a55). In certain embodiments, -L 1 - is formula (X-a56). In certain embodiments, -L 1 - is formula (X-a57). In certain embodiments, -L 1 - is formula (X-a58). In certain embodiments, -L 1 - is formula (X-a59). In certain embodiments, -L 1 - is formula (X-a60). In certain embodiments, -L 1 - is formula (X-a61). In certain embodiments, -L 1 - is formula (X-a62). In certain embodiments, -L 1 - is formula (X-a63). In certain embodiments, -L 1 - is formula (X-a64). In certain embodiments, -L 1- is formula (X-a65). In certain embodiments, -L 1 - is formula (X-a66). In certain embodiments, -L 1 - is formula (X-a67). In certain embodiments, -L 1 - is formula (X-a68). In certain embodiments, -L 1 - is formula (X-a69). In certain embodiments, -L 1 - is formula (X-a70). In certain embodiments, -L 1 - is formula (X-a71). In certain embodiments, -L 1 - is formula (X-a72). In certain embodiments, -L 1 - is formula (X-a73). In certain embodiments, -L 1 - is formula (X-a74). In certain embodiments, -L 1 - is formula (X-a75). In certain embodiments, -L 1 - is formula (X-a76). In certain embodiments, -L 1 - is formula (X-a77). In certain embodiments, -L 1 - is the formula (X-a78).

[0343] In certain embodiments, the release half-life, i.e., half of all -D moieties are -L 1 The release time from the drug is pH independent, particularly independent of pH in the range of about 6.8 to about 7.4. Such pH-independent release is advantageous because the pH in tumor tissue can vary, allowing for more uniform and therefore more predictable drug release.

[0344] Surprisingly, -L of formula (X-a11) and (X-a12) 1 The - moiety was found to have a release half-life that was pH independent for a pH range of 6.8 to 7.4.

[0345] In certain embodiments, -L 1 The -D portion is represented by the formula (X-b1)

[0346] [ka] (In the formula, the dashed line represents -L 2 - indicates the bond to is.

[0347] In certain embodiments, -L 1 The -D portion is represented by the formula (X-b2)

[0348] [ka] (In the formula, the dashed line represents -L 2 - indicates the bond to is.

[0349] In certain embodiments, -L 1 The -D portion is represented by the formula (X-b5)

[0350] [ka] (In the formula, the dashed line represents -L 2 - indicates the bond to is.

[0351] In certain embodiments, -L 1 The -D portion is represented by the formula (X-b6)

[0352] [ka] (In the formula, the dashed line represents -L 2 - indicates the bond to is.

[0353] In the conjugates of the present invention, -L 2 - is a chemical bond or a spacer moiety. In certain embodiments, -L 2 - does not include a reversible linkage, i.e., -L 2 All linkages in -L are stable linkages. 1- is connected via a stable linkage to -L 2 In certain embodiments, -L 2 - is linked to -Z via a stable linkage.

[0354] In certain embodiments, -L 2 - is a chemical bond.

[0355] In certain embodiments, -L 2 - is a spacer moiety.

[0356] In certain embodiments, -L 2 - stands for -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 1-50 Alkyl, C 2-50 Alkenyl, and C 2-50 Alkynyl may be one or more -R y2 is optionally replaced by C 1-50 Alkyl, C 2-50 Alkenyl, and C 2-50 Alkynyl is -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 )-; -R y1 and -R y1a -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 may be one or more -R y2 is optionally replaced by C 1-50 Alkyl, C 2-50 Alkenyl, and C 2-50 Alkynyl is -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 )-; Each T is phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8- to 30-membered carbopolycyclyl, and 8- to 30-membered heteropolycyclyl, wherein each T is the same or different and is selected from the group consisting of one or more -R y2 is independently and optionally replaced by; Each-Ry2 is 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)R 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, wherein C 1-6 alkyl is optionally substituted with one or more halogens which may be the same or different; Each-R y3 , -R y3a , -R y4 , -R y4a , -R y5 , -R y5a and -R y5b -H, and C 1-6 alkyl, wherein C 1-6 The alkyl is optionally substituted with one or more halogens which may be the same or different.

[0357] In certain embodiments, -L 2- stands for -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 may be one or more -R y2 is optionally replaced by C 1-20 Alkyl, C 2-20 Alkenyl, and C 2-20 Alkynyl is -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 )-; -R y1 and -R y1a -H, -T, C 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 alkynyl, wherein -T, C 1-10Alkyl, C 2-10 Alkenyl, and C 2-10 Alkynyl may be one or more -R y2 is optionally replaced by C 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 Alkynyl is -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 )-; Each T is phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8- to 30-membered carbopolycyclyl, and 8- to 30-membered heteropolycyclyl, wherein each T is the same or different and is selected from the group consisting of one or more -R y2 and optionally independently substituted by: -R y2 is 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)R y5 , -S(O)R y5 , -N(R y5 )S(O)2N(R y5a R y5b ), -SR y5 , -N(Ry5 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, wherein C 1-6 The alkyl is optionally substituted with one or more halogens which may be the same or different; Each-R y3 , -R y3a , -R y4 , -R y4a , -R y5 , -R y5a and -R y5b -H, and C 1-6 alkyl, wherein C 1-6 The alkyl is optionally substituted with one or more halogens which may be the same or different.

[0358] In certain embodiments, -L 2 - stands for -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 C2-50 alkynyl, wherein -T-, C 1-50 Alkyl, C 2-50 Alkenyl, and C 2-50 Alkynyl may be one or more -R y2 is optionally replaced by C 1-50 Alkyl, C 2-50 Alkenyl, and C 2-50 Alkynyl is -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 )-; -R y1 and -R y1a -H, -T, C 1-10 Alkyl, C 2-10 Alkenyl, and C 2-10 independently selected from the group consisting of alkynyl; Each T is phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 independently selected from the group consisting of cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8- to 30-membered carbopolycyclyl, and 8- to 30-membered heteropolycyclyl; Each-R y2 is a halogen, and C 1-6 independently selected from the group consisting of alkyl; Each-R y3 , -R y3a , -R y4 , -R y4a , -R y5 , -R y5a and -R y5b-H and C 1-6 alkyl, wherein C 1-6 The alkyl is optionally substituted with one or more halogens which may be the same or different.

[0359] In certain embodiments, -L 2 - is -O-, -T- and -C(O)N(R y1 C optionally interrupted by one or more groups independently selected from 1-20 This C is an alkyl chain. 1-20 The alkyl chains are -OH, -T and -C(O)N(R y6 R y6a ) optionally substituted with one or more groups independently selected from -R y1 , -R y6 , -R y6a is H and C 1-4 alkyl, and T is phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 It is selected from the group consisting of cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8- to 30-membered carbopolycyclyl, and 8- to 30-membered heteropolycyclyl.

[0360] In certain embodiments, -L 2 - has a molecular weight in the range of 14 g / mol to 750 g / mol.

[0361] In certain embodiments, -L 2 -teeth,

[0362] [ka] The compound includes a moiety selected from

[0363] In certain embodiments, -L 2 - has a chain length of 1 to 20 atoms.

[0364] As used herein, -L 2With respect to the - moiety, the term "chain length" refers to -L 1 -L in the shortest link between - and -Z 2 -refers to the number of atoms.

[0365] In certain embodiments, -L 2 - is the formula (A-1)

[0366] [ka] (In the formula, The dashed line with the star indicates -L 1 - indicates the bond to The unmarked dashed line indicates the bond to Z; r is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; s is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; t is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; u is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; v is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; -R 1 -H, C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 alkynyl) is.

[0367] In certain embodiments, r in Formula (A-1) is 1. In certain embodiments, r in Formula (A-1) is 2. In certain embodiments, r in Formula (A-1) is 3. In certain embodiments, r in Formula (A-1) is 4. In certain embodiments, r in Formula (A-1) is 5. In certain embodiments, r in Formula (A-1) is 6. In certain embodiments, r in Formula (A-1) is 7. In certain embodiments, r in Formula (A-1) is 8. In certain embodiments, r in Formula (A-1) is 9. In certain embodiments, r in Formula (A-1) is 10.

[0368] In certain embodiments, s in Formula (A-1) is 1. In certain embodiments, s in Formula (A-1) is 2. In certain embodiments, s in Formula (A-1) is 3. In certain embodiments, s in Formula (A-1) is 4. In certain embodiments, s in Formula (A-1) is 5. In certain embodiments, s in Formula (A-1) is 6. In certain embodiments, s in Formula (A-1) is 7. In certain embodiments, s in Formula (A-1) is 8. In certain embodiments, s in Formula (A-1) is 9. In certain embodiments, s in Formula (A-1) is 10.

[0369] In certain embodiments, t in Formula (A-1) is 1. In certain embodiments, t in Formula (A-1) is 2. In certain embodiments, t in Formula (A-1) is 3. In certain embodiments, t in Formula (A-1) is 4. In certain embodiments, t in Formula (A-1) is 5. In certain embodiments, t in Formula (A-1) is 6. In certain embodiments, t in Formula (A-1) is 7. In certain embodiments, t in Formula (A-1) is 8. In certain embodiments, t in Formula (A-1) is 9. In certain embodiments, t in Formula (A-1) is 10.

[0370] In certain embodiments, u in Formula (A-1) is 1. In certain embodiments, u in Formula (A-1) is 2. In certain embodiments, u in Formula (A-1) is 3. In certain embodiments, u in Formula (A-1) is 4. In certain embodiments, u in Formula (A-1) is 5. In certain embodiments, u in Formula (A-1) is 6. In certain embodiments, u in Formula (A-1) is 7. In certain embodiments, u in Formula (A-1) is 8. In certain embodiments, u in Formula (A-1) is 9. In certain embodiments, u in Formula (A-1) is 10.

[0371] In certain embodiments, v in Formula (A-1) is 1. In certain embodiments, v in Formula (A-1) is 2. In certain embodiments, v in Formula (A-1) is 3. In certain embodiments, v in Formula (A-1) is 4. In certain embodiments, v in Formula (A-1) is 5. In certain embodiments, v in Formula (A-1) is 6. In certain embodiments, v in Formula (A-1) is 7. In certain embodiments, v in Formula (A-1) is 8. In certain embodiments, v in Formula (A-1) is 9. In certain embodiments, v in Formula (A-1) is 10.

[0372] In certain embodiments, -R of formula (A-1) 1 is —H. In certain embodiments, —R in formula (A-1) 1 In certain embodiments, —R in formula (A-1) is methyl. 1 In certain embodiments, —R in formula (A-1) is ethyl. 1 In certain embodiments, -R in formula (A-1) is n-propyl. 1 In certain embodiments, -R in formula (A-1) is isopropyl. 1 In certain embodiments, -R in formula (A-1) is n-butyl. 1 In certain embodiments, -R in formula (A-1) is isobutyl. 1 In certain embodiments, -R in formula (A-1) is sec-butyl.1 In certain embodiments, -R in formula (A-1) is tert-butyl. 1 In certain embodiments, -R in formula (A-1) is n-pentyl. 1 In certain embodiments, -R in formula (A-1) is 2-methylbutyl. 1 In certain embodiments, -R in formula (A-1) is 2,2-dimethylpropyl. 1 In certain embodiments, -R in formula (A-1) is n-hexyl. 1 In certain embodiments, -R in formula (A-1) is 2-methylpentyl. 1 In certain embodiments, -R in formula (A-1) is 3-methylpentyl. 1 In certain embodiments, -R in formula (A-1) is 2,2-dimethylbutyl. 1 In certain embodiments, -R in formula (A-1) is 2,3-dimethylbutyl. 1 is 3,3-dimethylpropyl.

[0373] In certain embodiments, r in formula (A-1) is 1, s in formula (A-1) is 2, t in formula (A-1) is 2, u in formula (A-1) is 1, v in formula (A-1) is 2, and -R in formula (A-1) 1 is -H.

[0374] In certain embodiments, r in formula (A-1) is 1, s in formula (A-1) is 2, t in formula (A-1) is 3, u in formula (A-1) is 1, v in formula (A-1) is 2, and -R in formula (A-1) 1 is -H.

[0375] In certain embodiments, r of formula (A-1) is 1, s of formula (A-1) is 2, t of formula (A-1) is 4, u of formula (A-1) is 1, v of formula (A-1) is 2, and -R of formula (A-1) is 1. 1 is -H.

[0376] In certain embodiments, r of formula (A-1) is 1, s of formula (A-1) is 2, t of formula (A-1) is 5, u of formula (A-1) is 1, v of formula (A-1) is 2, and -R of formula (A-1) is 1. 1 is -H.

[0377] In certain embodiments, DL 1 -L 2 The - moiety has the formula (A-2):

[0378] [ka] (In the formula, The dashed line indicates the bond to Z. is.

[0379] In certain embodiments, Z comprises a polymer.

[0380] In certain embodiments, Z is not degradable. In certain embodiments, Z is degradable. A degradable moiety, Z, has the effect that the carrier moiety degrades over time, which can be advantageous in certain applications.

[0381] In certain embodiments, Z is a hydrogel. Such hydrogels may be degradable or non-degradable, i.e., stable. In certain embodiments, such hydrogels are degradable. In certain embodiments, such hydrogels are non-degradable.

[0382] In certain embodiments, such hydrogels Z may be prepared from 2-methacryloyl-oxyethylphosphoylcholine, poly(acrylic acid), poly(acrylate), poly(acrylamide), poly(alkyloxy)polymers, poly(amide), poly(amidoamine), poly(amino acid), poly(anhydride), poly(aspartamide), poly(butyric acid), poly(glycolic acid), polybutylene terephthalate, poly(caprolactone), poly(carbonate), poly(cyanoacrylate), poly(dimethylacrylamide), poly(ester), poly(ethylene), poly(alkylene glycol), such as poly(ethylene glycol) and poly(propylene glycol), poly(ethylene oxide), poly(ethyl phosphate), poly(ethyl oxazoline), poly(glycolic acid), poly(hydroxyethyl acrylate), poly(hydroxyethyl-oxazoline), poly(hydroxymethacrylate), poly(hydroxypropyl methacrylamide), poly(hydroxypropyl methyl acrylate), poly(hydroxypropyl methyl meth ... and polymers selected from the group consisting of 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(orthoester), poly(oxazoline), poly(propylene glycol), poly(siloxane), poly(urethane), poly(vinyl alcohol), poly(vinylamine), poly(vinyl methyl ether), poly(vinylpyrrolidone), silicone, cellulose, carbomethylcellulose, hydroxypropyl methylcellulose, chitin, chitosan, dextran, dextrin, gelatin, hyaluronic acid and derivatives, functionalized hyaluronic acid, mannan, pectin, rhamnogalacturonan, starch, hydroxyalkyl starch, hydroxyethyl starch, and other carbohydrate-based polymers, xylan, and copolymers thereof.

[0383] In certain embodiments, Z is a poly(alkylene glycol)-based hydrogel, such as a poly(propylene glycol)-based hydrogel or a poly(ethylene glycol)-based (PEG-based) hydrogel, or a hyaluronic acid-based hydrogel.

[0384] In certain embodiments, Z is a PEG-based hydrogel. Such PEG-based hydrogels may be degradable or non-degradable, i.e., stable. In certain embodiments, such PEG-based hydrogels are degradable. In certain embodiments, such PEG-based hydrogels are non-degradable. Suitable hydrogels are known in the art. Examples are WO2006 / 003014, WO2011 / 012715, and WO2014 / 056926, which are incorporated herein by reference.

[0385] In certain embodiments, such PEG-based hydrogels may be provided with a crosslinker moiety, -CL. p Optionally, a spacer moiety, -SP, is inserted between the backbone moiety and the crosslinker moiety. 1 In certain embodiments, such a spacer -SP 1 -L 2 - is defined as described above.

[0386] In certain embodiments, the backbone moiety has a molecular weight in the range of 1 kDa to 20 kDa.

[0387] In certain embodiments, the backbone moiety has the formula (pA): B * -(A-Hyp) x (pA), (In the formula, B * is the branching core, A is a PEG-based polymer, Hyp is the branching moiety, x is an integer from 3 to 16; Each backbone moiety may comprise one or more crosslinker moieties and one or more -L 2 -L 2 - moiety is linked to Hyp either directly or via a spacer moiety).

[0388] In certain embodiments, B of formula (pA) * is selected from the group consisting of a polyalcohol moiety and a polyamine moiety. * is a polyalcohol moiety. In certain embodiments, B in formula (pA) * is a polyamine moiety.

[0389] In certain embodiments, B of formula (pA) * The polyalcohol moiety for is selected from the group consisting of a pentaerythritol moiety, a tripentaerythritol moiety, a hexaglycerin moiety, a sucrose moiety, a sorbitol moiety, a fructose moiety, a mannitol moiety, and a glucose moiety. * is the pentaerythritol moiety, i.e., the formula

[0390] [ka] (wherein the dashed line indicates the bond to -A-) This is the part.

[0391] In certain embodiments, B of formula (pA) * The polyamine moiety for is selected from the group consisting of an ornithine moiety, a diaminobutyric acid moiety, a trilysine moiety, a tetralysine moiety, a pentalysine moiety, a hexalysine moiety, a heptalysine moiety, an octalysine moiety, a nonalizine moiety, a decalidine moiety, an undecalidine moiety, a dodecalidine moiety, a tridecalidine moiety, a tetradecalidine moiety, and a pentadecalidine moiety. * is selected from the group consisting of an ornithine moiety, a diaminobutyric acid moiety, and a trilysine moiety.

[0392] The backbone moiety of formula (pA) may consist of the same or different PEG-based -A- moieties, and each -A- moiety may be independently selected. In certain embodiments, all -A- moieties present in the backbone moiety of formula (pA) have the same structure. With respect to a polymer moiety, e.g., a PEG-based polymer-A-, the phrase "having the same structure" is understood to mean that the number of monomers, e.g., the number of ethylene glycol monomers, of the polymer can vary due to the polydisperse nature of the polymer. In certain embodiments, the number of monomer units does not vary by more than two-fold among all -A- moieties of the hydrogel.

[0393] In certain embodiments, each -A- in formula (pA) has a molecular weight in the range of 0.3 kDa to 40 kDa, e.g., 0.4 to 30 kDa, 0.4 to 25 kDa, 0.4 to 20 kDa, 0.4 to 15 kDa, 0.4 to 10 kDa, or 0.4 to 5 kDa. In certain embodiments, each -A- has a molecular weight of 0.4 to 5 kDa. In certain embodiments, -A- has a molecular weight of about 0.5 kDa. In certain embodiments, -A- has a molecular weight of about 1 kDa. In certain embodiments, -A- has a molecular weight of about 2 kDa. In certain embodiments, -A- has a molecular weight of about 3 kDa. In certain embodiments, -A- has a molecular weight of about 5 kDa.

[0394] In certain embodiments, -A- in formula (pA) is a group represented by formula (pB-i): -(CH2) n1 (OCH2CH2) n X- (pB-i), (In the formula, n1 is 1 or 2; n is an integer ranging from 3 to 250, for example, from 5 to 200, for example, from 8 to 150 or from 10 to 100; X is a chemical bond or a linkage covalently connecting A and Hyp is.

[0395] In certain embodiments, -A- in formula (pA) is formula (pB-ii): -(CH2) n1 (OCH2CH2) n -(CH2) n2 X- (pB-ii), (In the formula, n1 is 1 or 2; n is an integer ranging from 3 to 250, for example, from 5 to 200, for example, from 8 to 150 or from 10 to 100; n2 is 0 or 1; X is a chemical bond or a linkage covalently connecting A and Hyp is.

[0396] In certain embodiments, -A- in formula (pA) is a group represented by formula (pB-i′):

[0397] [ka] (In the formula, The dashed line with the star indicates B * indicates the bond to The unmarked dashed line indicates the bond to -Hyp; n3 is an integer ranging from 10 to 50. is.

[0398] In certain embodiments, n3 in formula (pB-i') is 25. In certain embodiments, n3 in formula (pB-i') is 26. In certain embodiments, n3 in formula (pB-i') is 27. In certain embodiments, n3 in formula (pB-i') is 28. In certain embodiments, n3 in formula (pB-i') is 29. In certain embodiments, n3 in formula (pB-i') is 30.

[0399] In certain embodiments, moiety B * -(A)4 is a compound of the formula (pB-a)

[0400] [ka] (In the formula, The dashed line indicates the binding site for Hyp; Each n3 is an integer independently selected from 10 to 50. is.

[0401] In certain embodiments, n3 in Formula (pB-a) is 25. In certain embodiments, n3 in Formula (pB-a) is 26. In certain embodiments, n3 in Formula (pB-a) is 27. In certain embodiments, n3 in Formula (Ba) is 28. In certain embodiments, n3 in Formula (pB-a) is 29. In certain embodiments, n3 in Formula (pB-a) is 30.

[0402] The backbone moiety of formula (pA) may be composed of the same or different dendritic moieties -Hyp, each of which may be independently selected. In certain embodiments, all -Hyp moieties present in the backbone moiety of formula (pA) have the same structure.

[0403] In certain embodiments, each -Hyp of formula (pA) has a molecular weight in the range of 0.3 kDa to 5 kDa.

[0404] In certain embodiments, -Hyp has the formula (pHyp-i):

[0405] [ka] (In the formula, The dashed line with an asterisk indicates the bond to -A-; The unmarked dashed lines represent the spacer segments - SP 1 -, crosslinker moiety -CL p -or-L 2 - indicates the bond to; p2, p3 and p4 are the same or different and each independently represents an integer from 1 to 5. part of; Formula (pHyp-ii)

[0406] [ka] (In the formula, The dashed line with an asterisk indicates the bond to -A-; The unmarked dashed lines represent the spacer segments - SP 1 -, crosslinker moiety -CL p -or-L 2 - indicates the bond to; p5 to p11 are the same or different and each independently represents an integer of 1 to 5. part of; Formula (pHyp-iii)

[0407] [ka] (In the formula, The dashed line with an asterisk indicates the bond to -A-; The unmarked dashed lines represent the spacer segments - SP 1 -, crosslinker moiety -CL p -or-L 2 - indicates the bond to; p12 to p26 are the same or different and each independently represents an integer of 1 to 5. Part of; and Formula (pHyp-iv)

[0408] [ka] (In the formula, The dashed line with an asterisk indicates the bond to -A-; The unmarked dashed lines represent the spacer segments - SP 1 -, crosslinker moiety -CL p -or-L 2 - indicates the bond to; p27 and p28 are the same or different and each independently represents an integer from 1 to 5; q is an integer from 1 to 8. part of; is selected from the group consisting of Here, moieties (pHyp-i) to (pHyp-iv) can be in either the R- or S-configuration at each chiral center.

[0409] In certain embodiments, all chiral centers in moieties (pHyp-i), (pHyp-ii), (pHyp-iii), or (pHyp-iv) are of the same configuration. In certain embodiments, all chiral centers in moieties (pHyp-i), (pHyp-ii), (pHyp-iii), or (pHyp-iv) are of the R-configuration. In certain embodiments, all chiral centers in moieties (pHyp-i), (pHyp-ii), (pHyp-iii), or (pHyp-iv) are of the S-configuration.

[0410] In certain embodiments, p2, p3, and p4 of formula (pHyp-i) are 4.

[0411] In certain embodiments, p5 to p11 in formula (pHyp-ii) are 4.

[0412] In certain embodiments, p12 to p26 in formula (pHyp-iii) are 4.

[0413] In certain embodiments, q in formula (pHyp-iv) is 2 or 6. In certain embodiments, q in formula (pHyp-iv) is 6.

[0414] In certain embodiments, p27 and p28 of formula (pHyp-iv) are 4.

[0415] In certain embodiments, -Hyp of formula (pA) comprises a branched polypeptide moiety.

[0416] In certain embodiments, -Hyp of formula (pA) comprises a lysine moiety. In certain embodiments, each -Hyp of formula (pA) is independently selected from the group consisting of a trilysine moiety, a tetralysine moiety, a pentalysine moiety, a hexalysine moiety, a heptalysine moiety, an octalysine moiety, a nonalizine moiety, a decalidine moiety, an undecalidine moiety, a dodecalidine moiety, a tridecalidine moiety, a tetradecalidine moiety, a pentadecalidine moiety, a hexadecalidine moiety, a heptadecalidine moiety, an octadecalidine moiety, and a nonadecalidine moiety.

[0417] In certain embodiments, -Hyp comprises 3 lysine moieties. In certain embodiments, -Hyp comprises 7 lysine moieties. In certain embodiments, -Hyp comprises 15 lysine moieties. In certain embodiments, -Hyp comprises heptalidinyl.

[0418] In certain embodiments, x in Formula (pA) is 3. In certain embodiments, x in Formula (pA) is 4. In certain embodiments, x in Formula (pA) is 6. In certain embodiments, x in Formula (pA) is 8.

[0419] In certain embodiments, the backbone moiety has the formula (pC1):

[0420] [ka] (In the formula, The dashed line indicates the spacer portion -SP 1 -, crosslinker moiety -CL p -or-L 2 - indicates the bond to; (n is in the range of 10 to 40) is.

[0421] In certain embodiments, n in formula (pC1) is about 28.

[0422] In certain embodiments, the backbone moiety has the formula (pC2):

[0423] [ka] (In the formula, The dashed line indicates the spacer portion -SP 1 -, crosslinker moiety -CL p -or-L 2 - indicates the bond to; (n is in the range of 10 to 40) is.

[0424] In certain embodiments, the backbone moiety and the crosslinker moiety -CL p -Spacer part between -SP 1 -, not -CL p - is directly linked to -Hyp.

[0425] Crosslinker for PEG-based hydrogels -CL p In certain embodiments, the crosslinker is poly(alkylene glycol) (PAG)-based. In certain embodiments, the crosslinker is poly(propylene glycol)-based. In certain embodiments, the crosslinker -CL p - is a PEG-based compound.

[0426] In certain embodiments, the crosslinker moiety of such a PAG system, -CL p - is the formula (pD)

[0427] [ka] [In the formula, The dashed line represents the backbone or spacer moiety -SP 1 - indicates the bond to; -Y 1 - is the formula

[0428] [ka] (In the formula, the dashed line with an asterisk represents -D 1 - indicates the bond to -D 2 - indicates the bond to and; -Y 2 - is the formula

[0429] [ka] (In the formula, the dashed line with an asterisk represents -D 4 - indicates the bond to -D 3 - indicates the bond to and; -E 1 - is the formula

[0430] [ka] wherein the dashed line with an asterisk indicates the bond to -(C=O)- and the unmarked dashed line indicates the bond to -O-. and; -E 2 - is the formula

[0431] [ka] (In the formula, the dashed line with an asterisk represents -G 1 The unmarked dashed line indicates the bond to -, and the unmarked dashed line indicates the bond to -(C=O)-. and; -G 1 - is the formula

[0432] [ka] (wherein the dashed line with an asterisk indicates the bond to -O- and the unmarked dashed line indicates the bond to -E 2 - indicates the bond to and; -G 2 - is the formula

[0433] [ka] wherein the dashed line with an asterisk indicates the bond to -O- and the unmarked dashed line indicates the bond to -(C=O)-. and; -G 3 - is the formula

[0434] [ka] wherein the dashed line with an asterisk indicates the bond to -O- and the unmarked dashed line indicates the bond to -(C=O)-. and; -D 1 -, -D 2 -, -D 3 -, -D 4 -, -D 5 -and-D 6 - are the same or different, and each independently represent -O-, -NR 11 -, -N + R 12 R 12a -, -S-, -(S=O)-, -(S(O)2)-, -C(O)-, -P(O)R 13 -, -P(O)(OR 13 ) and -CR 14 R 14a - selected from the group comprising; -R 1 , -R 1a , -R 2 , -R 2a , -R 3 , -R 3a , -R 4 , -R 4a , -R 5 , -R 5a , -R 6 , -R 6a , -R 7 , -R 7a , -R 8 , -R 8a , -R 9 , -R 9a , -R 10 , -R 10a , -R 11 , -R 12 , -R 12a , -R 13 , -R14 and -R 14a are the same or different and each independently represent -H and C 1-6 selected from the group consisting of alkyl; Optionally, Pair-R 1 / -R 1a , Pair-R 2 / -R 2a , Pair-R 3 / -R 3a , Pair-R 4 / -R 4a , Pair-R 1 / -R 2 , Pair-R 3 / -R 4 , Pair-R 1a / -R 2a , Pair-R 3a / -R 4a , Pair-R 12 / -R 12a , and Pair-R 14 / -R 14a One or more of the following forms a chemical bond, or together with the atoms to which they are bonded, C 3-8 form a cycloalkyl or form ring A, or together with the atom to which they are attached form a 4- to 7-membered heterocyclyl or an 8- to 11-membered heterobicyclyl or adamantyl; A is selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, and tetralinyl; r1, r2, r5, r6, r13, r14, r15 and r16 are independently 0 or 1; r3, r4, r7, r8, r9, r10, r11, r12 are independently 0, 1, 2, 3, or 4; r17, r18, r19, r20, r21, and r22 are independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; s1, s2, s4, s5 are independently 1, 2, 3, 4, 5 or 6; s3 ranges from 1 to 900] is.

[0435] In certain embodiments, s3 is in the range of 1 to 500. In certain embodiments, s3 is in the range of 1 to 200.

[0436] In certain embodiments, r1 of formula (pD) is 0. In certain embodiments, r1 of formula (pD) is 1. In certain embodiments, r2 of formula (pD) is 0. In certain embodiments, r2 of formula (pD) is 1. In certain embodiments, r5 of formula (pD) is 0. In certain embodiments, r5 of formula (pD) is 1.

[0437] In certain embodiments, r1, r2, r5, and r6 of formula (pD) are 0.

[0438] In certain embodiments, r6 in Formula (pD) is 0. In certain embodiments, r6 in Formula (pD) is 1. In certain embodiments, r13 in Formula (pD) is 0. In certain embodiments, r13 in Formula (pD) is 1. In certain embodiments, r14 in Formula (pD) is 0. In certain embodiments, r14 in Formula (pD) is 1. In certain embodiments, r15 in Formula (pD) is 0. In certain embodiments, r15 in Formula (pD) is 1. In certain embodiments, r16 in Formula (pD) is 0. In certain embodiments, r16 in Formula (pD) is 1.

[0439] In certain embodiments, r3 in Formula (pD) is 1. In certain embodiments, r3 in Formula (pD) is 2. In certain embodiments, r4 in Formula (pD) is 1. In certain embodiments, r4 in Formula (pD) is 2. In certain embodiments, r3 and r4 in Formula (pD) are both 1. In certain embodiments, r3 and r4 in Formula (pD) are both 2. In certain embodiments, r3 and r4 in Formula (pD) are both 3.

[0440] In certain embodiments, r7 of Formula (pD) is 0. In certain embodiments, r7 of Formula (pD) is 1. In certain embodiments, r7 of Formula (pD) is 2. In certain embodiments, r8 of Formula (pD) is 0. In certain embodiments, r8 of Formula (pD) is 1. In certain embodiments, r8 of Formula (pD) is 2. In certain embodiments, r9 of Formula (pD) is 0. In certain embodiments, r9 of Formula (pD) is 1. In certain embodiments, r9 of Formula (pD) is 2. In certain embodiments, r10 of Formula (pD) is 0. In certain embodiments, r10 of Formula (pD) is 1. In certain embodiments, r10 of Formula (pD) is 2. In certain embodiments, r11 of Formula (pD) is 0. In certain embodiments, r11 of Formula (pD) is 1. In certain embodiments, r11 of formula (pD) is 2. In certain embodiments, r12 of formula (pD) is 0. In certain embodiments, r12 of formula (pD) is 1. In certain embodiments, r12 of formula (pD) is 2.

[0441] In certain embodiments, r17 of Formula (pD) is 1. In certain embodiments, r18 of Formula (pD) is 1. In certain embodiments, r19 of Formula (pD) is 1. In certain embodiments, r20 of Formula (pD) is 1. In certain embodiments, r21 of Formula (pD) is 1.

[0442] In certain embodiments, s1 of formula (pD) is 1. In certain embodiments, s1 of formula (pD) is 2. In certain embodiments, s2 of formula (pD) is 1. In certain embodiments, s2 of formula (pD) is 2. In certain embodiments, s4 of formula (pD) is 1. In certain embodiments, s4 of formula (pD) is 2.

[0443] In certain embodiments, s3 in formula (pD) is in the range of 5 to 500. In certain embodiments, s3 in formula (pD) is in the range of 10 to 250. In certain embodiments, s3 in formula (pD) is in the range of 12 to 150. In certain embodiments, s3 in formula (pD) is in the range of 15 to 100. In certain embodiments, s3 in formula (pD) is in the range of 18 to 75. In certain embodiments, s3 in formula (pD) is in the range of 20 to 50.

[0444] In certain embodiments, -R of formula (pD) 1 is —H. In certain embodiments, —R of formula (pD) 1 is methyl. In certain embodiments, -R of formula (pD) 1 is ethyl. In certain embodiments, -R of formula (pD) 1a is —H. In certain embodiments, —R of formula (pD) 1a is methyl. In certain embodiments, -R of formula (pD) 1a is ethyl. In certain embodiments, -R of formula (pD) 2 is —H. In certain embodiments, —R of formula (pD) 2 is methyl. In certain embodiments, -R of formula (pD) 2 is ethyl. In certain embodiments, -R of formula (pD) 2a is —H. In certain embodiments, —R of formula (pD) 2a is methyl. In certain embodiments, -R of formula (pD) 2a is ethyl. In certain embodiments, -R of formula (pD) 3 is —H. In certain embodiments, —R of formula (pD) 3 is methyl. In certain embodiments, -R of formula (pD) 3 is ethyl. In certain embodiments, -R of formula (pD) 3a is —H. In certain embodiments, —R of formula (pD) 3a is methyl. In certain embodiments, -R of formula (pD) 3ais ethyl. In certain embodiments, -R of formula (pD) 4 is —H. In certain embodiments, —R of formula (pD) 4 is methyl. In certain embodiments, -R of formula (pD) 4 is methyl. In certain embodiments, -R of formula (pD) 4a is —H. In certain embodiments, —R of formula (pD) 4a is methyl. In certain embodiments, -R of formula (pD) 4a is ethyl. In certain embodiments, -R of formula (pD) 5 is —H. In certain embodiments, —R of formula (pD) 5 is methyl. In certain embodiments, -R of formula (pD) 5 is ethyl. In certain embodiments, -R of formula (pD) 5a is —H. In certain embodiments, —R of formula (pD) 5a is methyl. In certain embodiments, -R of formula (pD) 5a is ethyl. In certain embodiments, -R of formula (pD) 6 is —H. In certain embodiments, —R of formula (pD) 6 is methyl. In certain embodiments, -R of formula (pD) 6 is ethyl. In certain embodiments, -R of formula (pD) 6a is —H. In certain embodiments, —R of formula (pD) 6a is methyl. In certain embodiments, -R of formula (pD) 6a is ethyl. In certain embodiments, -R of formula (pD) 7 is —H. In certain embodiments, —R of formula (pD) 7 is methyl. In certain embodiments, -R of formula (pD) 7 is ethyl. In certain embodiments, -R of formula (pD) 8 is —H. In certain embodiments, —R of formula (pD) 8 is methyl. In certain embodiments, -R of formula (pD) 8is ethyl. In certain embodiments, -R of formula (pD) 8a is —H. In certain embodiments, —R of formula (pD) 8a is methyl. In certain embodiments, -R of formula (pD) 8a is ethyl. In certain embodiments, -R of formula (pD) 9 is —H. In certain embodiments, —R of formula (pD) 9 is methyl. In certain embodiments, -R of formula (pD) 9 is ethyl. In certain embodiments, -R of formula (pD) 9a is —H. In certain embodiments, —R of formula (pD) 9a is methyl. In certain embodiments, -R of formula (pD) 9a is ethyl. In certain embodiments, -R of formula (pD) 9a is —H. In certain embodiments, —R of formula (pD) 9a is methyl. In certain embodiments, -R of formula (pD) 9a is ethyl. In certain embodiments, -R of formula (pD) 10 is —H. In certain embodiments, —R of formula (pD) 10 is methyl. In certain embodiments, -R of formula (pD) 10 is ethyl. In certain embodiments, -R of formula (pD) 10a is —H. In certain embodiments, —R of formula (pD) 10a is methyl. In certain embodiments, -R of formula (pD) 10a is ethyl. In certain embodiments, -R of formula (pD) 11 is —H. In certain embodiments, —R of formula (pD) 11 is methyl. In certain embodiments, -R of formula (pD) 11 is ethyl. In certain embodiments, -R of formula (pD) 12 is —H. In certain embodiments, —R of formula (pD) 12 is methyl. In certain embodiments, -R of formula (pD) 12is ethyl. In certain embodiments, -R of formula (pD) 12a is —H. In certain embodiments, —R of formula (pD) 12a is methyl. In certain embodiments, -R of formula (pD) 12a is ethyl. In certain embodiments, -R of formula (pD) 13 is —H. In certain embodiments, —R of formula (pD) 13 is methyl. In certain embodiments, -R of formula (pD) 13 is ethyl. In certain embodiments, -R of formula (pD) 14 is —H. In certain embodiments, —R of formula (pD) 14 is methyl. In certain embodiments, -R of formula (pD) 14 is ethyl. In certain embodiments, -R of formula (pD) 14a is —H. In certain embodiments, —R of formula (pD) 14a is methyl. In certain embodiments, -R of formula (pD) 14a is ethyl.

[0445] In certain embodiments, -D of formula (pD) 1 - is -O-. In certain embodiments, -D in formula (pD) 1 -, -NR 11 In certain embodiments, -D of formula (pD) 1 -, -N + R 12 R 12a In certain embodiments, -D of formula (pD) 1 - is -S-. In certain embodiments, -D in formula (pD) 1 - is -(S=O). In certain embodiments, -D in formula (pD) 1 - is -(S(O)2)-. In certain embodiments, -D in formula (pD) 1 - is -C(O)-. In certain embodiments, -D in formula (pD) 1 - is -P(O)R 13 In certain embodiments, -D of formula (pD)1 - is -P(O)(OR 13 In certain embodiments, -D of formula (pD) 1 - is -CR 14 R 14a -It is.

[0446] In certain embodiments, -D of formula (pD) 2 - is -O-. In certain embodiments, -D in formula (pD) 2 -, -NR 11 In certain embodiments, -D of formula (pD) 2 -, -N + R 12 R 12a In certain embodiments, -D of formula (pD) 2 - is -S-. In certain embodiments, -D in formula (pD) 2 - is -(S=O). In certain embodiments, -D in formula (pD) 2 - is -(S(O)2)-. In certain embodiments, -D in formula (pD) 2 - is -C(O)-. In certain embodiments, -D in formula (pD) 2 - is -P(O)R 13 In certain embodiments, -D of formula (pD) 2 - is -P(O)(OR 13 In certain embodiments, -D of formula (pD) 2 - is -CR 14 R 14a -It is.

[0447] In certain embodiments, -D of formula (pD) 3 - is -O-. In certain embodiments, -D in formula (pD) 3 -, -NR 11 In certain embodiments, -D of formula (pD) 3 -, -N + R 12 R 12a In certain embodiments, -D of formula (pD) 3 - is -S-. In certain embodiments, -D in formula (pD)3 - is -(S=O). In certain embodiments, -D in formula (pD) 3 - is -(S(O)2)-. In certain embodiments, -D in formula (pD) 3 - is -C(O)-. In certain embodiments, -D in formula (pD) 3 - is -P(O)R 13 In certain embodiments, -D of formula (pD) 3 - is -P(O)(OR 13 In certain embodiments, -D of formula (pD) 3 - is -CR 14 R 14a -It is.

[0448] In certain embodiments, -D of formula (pD) 4 - is -O-. In certain embodiments, -D in formula (pD) 4 -, -NR 11 In certain embodiments, -D of formula (pD) 4 -, -N + R 12 R 12a In certain embodiments, -D of formula (pD) 4 - is -S-. In certain embodiments, -D in formula (pD) 4 - is -(S=O). In certain embodiments, -D in formula (pD) 4 - is -(S(O)2)-. In certain embodiments, -D in formula (pD) 4 - is -C(O)-. In certain embodiments, -D in formula (pD) 4 - is -P(O)R 13 In certain embodiments, -D of formula (pD) 4 - is -P(O)(OR 13 In certain embodiments, -D of formula (pD) 4 - is -CR 14 R 14a -It is.

[0449] In certain embodiments, -D of formula (pD) 5- is -O-. In certain embodiments, -D in formula (pD) 5 -, -NR 11 In certain embodiments, -D of formula (pD) 5 -, -N + R 12 R 12a In certain embodiments, -D of formula (pD) 5 - is -S-. In certain embodiments, -D in formula (pD) 5 - is -(S=O)-. In certain embodiments, -D in formula (pD) 5 - is -(S(O)2)-. In certain embodiments, -D in formula (pD) 5 - is -C(O)-. In certain embodiments, -D in formula (pD) 5 - is -P(O)R 13 In certain embodiments, -D of formula (pD) 5 - is -P(O)(OR 13 In certain embodiments, -D of formula (pD) 5 - is -CR 14 R 14a -It is.

[0450] In certain embodiments, -D of formula (pD) 6 - is -O-. In certain embodiments, -D in formula (pD) 6 -, -NR 11 In certain embodiments, -D of formula (pD) 6 -, -N + R 12 R 12a In certain embodiments, -D of formula (pD) 6 - is -S-. In certain embodiments, -D in formula (pD) 6 - is -(S=O). In certain embodiments, -D in formula (pD) 6 - is -(S(O)2)-. In certain embodiments, -D in formula (pD) 6 - is -C(O)-. In certain embodiments, -D in formula (pD) 6 - is -P(O)R 13In certain embodiments, -D of formula (pD) 6 - is -P(O)(OR 13 In certain embodiments, -D of formula (pD) 6 - is -CR 14 R 14a -It is.

[0451] In one embodiment, -CL p - is the formula (pE)

[0452] [ka] TIFF2024546134000064.tif35148 (in the formula, The dashed line with an asterisk indicates the connection point between the upper and lower substructures; The unmarked dashed lines represent the backbone or spacer moieties -SP 1 - indicates the bond to; -R b1 , -R b1a , -R b2 , -R b2a , -R b3 , -R b3a , -R b4 , -R b4a , -R b5 , -R b5a , -R b6 and -R b6 -H and C 1-6 independently selected from the group consisting of alkyl; c1, c2, c3, c4, c5 and c6 are independently selected from the group consisting of 1, 2, 3, 4, 5 and 6; d is an integer ranging from 2 to 250. is.

[0453] In certain embodiments, d in formula (pE) is in the range of 3 to 200. In certain embodiments, d in formula (pE) is in the range of 4 to 150. In certain embodiments, d in formula (pE) is in the range of 5 to 100. In certain embodiments, d in formula (pE) is in the range of 10 to 50. In certain embodiments, d in formula (pE) is in the range of 15 to 30. In certain embodiments, d in formula (pE) is about 23.

[0454] In certain embodiments, -R of formula (pE) b1 and -R b1a is —H. In certain embodiments, —R of formula (pE) b1 and -R b1a is —H. In certain embodiments, —R of formula (pE) b2 and -R b2a is —H. In certain embodiments, —R of formula (pE) b3 and -R b3a is —H. In certain embodiments, —R of formula (pE) b4 and -R b4a is —H. In certain embodiments, —R of formula (pE) b5 and -R b5a is —H. In certain embodiments, —R of formula (pE) b6 and -R b6a is -H.

[0455] In certain embodiments, -R of formula (pE) b1 , -R b1a , -R b2 , -R b2a , -R b3 , -R b3a , -R b4 , -R b4a , -R b5 , -R b5a , -R b6 and -R b6 are all -H.

[0456] In certain embodiments, c1 of formula (pE) is 1. In certain embodiments, c1 of formula (pE) is 2. In certain embodiments, c1 of formula (pE) is 3. In certain embodiments, c1 of formula (pE) is 4. In certain embodiments, c1 of formula (pE) is 5. In certain embodiments, c1 of formula (pE) is 6.

[0457] In certain embodiments, c2 in formula (pE) is 1. In certain embodiments, c2 in formula (pE) is 2. In certain embodiments, c2 in formula (pE) is 3. In certain embodiments, c2 in formula (pE) is 4. In certain embodiments, c2 in formula (pE) is 5. In certain embodiments, c2 in formula (pE) is 6.

[0458] In certain embodiments, c3 in formula (pE) is 1. In certain embodiments, c3 in formula (pE) is 2. In certain embodiments, c3 in formula (pE) is 3. In certain embodiments, c3 in formula (pE) is 4. In certain embodiments, c3 in formula (pE) is 5. In certain embodiments, c3 in formula (pE) is 6.

[0459] In certain embodiments, c4 of Formula (pE) is 1. In certain embodiments, c4 of Formula (pE) is 2. In certain embodiments, c4 of Formula (pE) is 3. In certain embodiments, c4 of Formula (pE) is 4. In certain embodiments, c4 of Formula (pE) is 5. In certain embodiments, c4 of Formula (pE) is 6.

[0460] In certain embodiments, c5 of Formula (pE) is 1. In certain embodiments, c5 of Formula (pE) is 2. In certain embodiments, c5 of Formula (pE) is 3. In certain embodiments, c5 of Formula (pE) is 4. In certain embodiments, c5 of Formula (pE) is 5. In certain embodiments, c5 of Formula (pE) is 6.

[0461] In certain embodiments, c6 in Formula (pE) is 1. In certain embodiments, c6 in Formula (pE) is 2. In certain embodiments, c6 in Formula (pE) is 3. In certain embodiments, c6 in Formula (pE) is 4. In certain embodiments, c6 in Formula (pE) is 5. In certain embodiments, c6 in Formula (pE) is 6.

[0462] In certain embodiments, the crosslinker moiety -CL p - is the formula (pE-i)

[0463] [ka] (In the formula, The dashed line represents the backbone or spacer moiety -SP 1 - indicates the bond to is.

[0464] In certain embodiments, -Z is a hyaluronic acid-based hydrogel. Such hyaluronic acid-based hydrogels are known in the art, for example, from WO2018 / 175788, which is incorporated herein by reference.

[0465] In certain embodiments, the TLR7 / 8 agonist conjugate has the formula (A-3):

[0466] [ka] [Wherein, "hydrogel" refers to a compound represented by formula (A-4):

[0467] [ka] (where n is approximately in the range of 25 to 29, and the dashed line represents the moiety

[0468] [ka] to, part

[0469] [ka] to, or formula (A-5):

[0470] [ka] (In the formula, m is in the range of approximately 41 to 45, and the dashed line in (A-5) indicates the bond to the skeleton portion of formula (A-4)). (showing the bond to the crosslinker) a hydrogel containing a backbone portion of is.

[0471] In certain embodiments, n in formula (A-4) is approximately 28. In certain embodiments, n in formula (A-5) is approximately 27.

[0472] In certain embodiments, m in formula (A-5) is approximately 44. In certain embodiments, m in formula (A-5) is approximately 45.

[0473] In certain embodiments, n in formula (A-4) is approximately 28 and m in formula (A-5) is approximately 45.

[0474] In certain embodiments, the TLR7 / 8 agonist conjugate has the formula (Ai-6):

[0475] [ka] (In the formula, m ranges from approximately 25 to 29; n is in the range of approximately 41 to 45; "a" indicates the backbone moiety, "b" indicates the crosslinker moiety, "c" indicates the reversibly conjugated resiquimod moiety, and "d" indicates the acetamide moiety; The ratio of "a":"b":"c":"d" moieties in the conjugate is approximately 1:13:c:d, where c+d=6. is.

[0476] In certain embodiments, the TLR7 / 8 agonist conjugate has the formula (A-6):

[0477] [ka] (In the formula, m ranges from approximately 25 to 29; n is in the range of approximately 41 to 45; "a" indicates the backbone moiety, "b" indicates the crosslinker moiety, "c" indicates the reversibly conjugated resiquimod moiety, and "d" indicates the acetamide moiety; The ratio of "a":"b":"c":"d" moieties in the conjugate is approximately 1:13:2:4) is.

[0478] The wavy lines are understood to indicate attachment to further "b," "c," or "d" moieties (not shown for simplicity).

[0479] In certain embodiments, the ratio of "a":"b":"c":"d" in (A-6) is approximately 1:13:2.4:3.6.

[0480] In certain embodiments, the TLR7 / 8 agonist conjugate has the formula (A-7):

[0481] [ka] (In the formula, m ranges from approximately 25 to 29; n is in the range of approximately 41 to 45; "a" indicates the backbone moiety, "b" indicates the crosslinker moiety, "c" indicates the reversibly conjugated resiquimod moiety, and "d" indicates the acetamide moiety; The ratio of "a":"b":"c":"d" moieties in the conjugate is approximately 1:13:4:2) is.

[0482] In certain embodiments, the TLR7 / 8 agonist conjugate has the formula (A-8):

[0483] [ka] (In the formula, m ranges from approximately 25 to 29; n is in the range of approximately 41 to 45; "a" indicates the backbone moiety, "b" indicates the crosslinker moiety, "c" indicates the reversibly conjugated resiquimod moiety, and "d" indicates the acetamide moiety; The ratio of "a":"b":"c":"d" moieties in the conjugate is approximately 1:13:3:3) is.

[0484] In a fourth aspect, the present invention relates to a conjugate of formula (A-3):

[0485] In a fifth aspect, the present invention relates to a conjugate of formula (A-6): In certain embodiments, the conjugate of the fifth aspect has a ratio of "a":"b":"c":"d" of approximately 1:13:2.4:3.6.

[0486] In a sixth aspect, the present invention relates to a conjugate of formula (A-7):

[0487] In a seventh aspect, the present invention relates to a conjugate of formula (A-8):

[0488] In an eighth aspect, the present invention relates to a conjugate of formula (Ai-6):

[0489] In a ninth aspect, the present invention relates to a pharmaceutical formulation comprising one or more TLR7 / 8 agonist conjugates of formula (Ai-6), (A-6), (A-7), or (A-8), or pharmaceutically acceptable salts thereof. In certain embodiments, such pharmaceutical formulations are dry formulations, e.g., lyophilized formulations. In certain embodiments, such pharmaceutical formulations are suspensions.

[0490] In certain embodiments, the pharmaceutical formulation comprises a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof at a concentration ranging from 0.5 mg to 2 mg of TLR7 / 8 agonist per ml. In certain embodiments, the pharmaceutical formulation comprises a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof at a concentration of 1 mg of TLR7 / 8 agonist per ml. In certain embodiments, the pharmaceutical formulation comprises a TLR7 / 8 agonist conjugate or a pharmaceutically acceptable salt thereof at a concentration of 2 mg of TLR7 / 8 agonist per ml.

[0491] In certain embodiments, the conjugate of the fourth, fifth, sixth, seventh, or eighth aspect, or a pharmaceutically acceptable salt thereof, or the pharmaceutical formulation of the ninth aspect, is for use as a medicament. In certain embodiments, such a medicament is for treating cancer, particularly solid tumors. In certain embodiments, such solid tumors include lip and oral cavity cancer, oral cancer, liver cancer / hepatocellular carcinoma, primary liver cancer, lung cancer, lymphoma, malignant mesothelioma, malignant thymoma, skin cancer, intraocular melanoma, metastatic squamous neck cancer of unknown primary, childhood multiple endocrine neoplasia syndrome, mycosis fungoides, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, oropharyngeal cancer, ovarian cancer, pancreatic cancer, parathyroid cancer, pheochromocytoma, pituitary tumor, adrenocortical carcinoma, AIDS-related malignancies, anal cancer, bile duct cancer, bladder cancer, brain and nervous system cancer, breast cancer, bronchial adenoma / carcinoma, and the like. thyroid, gastrointestinal carcinoid tumor, carcinoma, colorectal cancer, endometrial cancer, esophageal cancer, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, gallbladder cancer, cancer of the stomach (gastric cancer), gestational trophoblastic tumor, head and neck cancer, hypopharyngeal cancer, islet cell carcinoma (endocrine pancreas), kidney cancer / renal cell carcinoma, laryngeal cancer, pleuropulmonary blastoma, prostate cancer, transitional cell carcinoma of the renal pelvis and ureter, retinoblastoma, salivary gland cancer, sarcoma, Sezary syndrome, small intestine cancer, genitourinary cancer, malignant thymoma, thyroid cancer, Wilms' tumor, and cholangiocarcinoma.

[0492] In certain embodiments, the solid tumor is selected from the group consisting of squamous cell carcinoma of the head and neck (SCCHN); HPV-associated cancers, such as anal cancer, vulvar cancer, cervical cancer, penile cancer, and vaginal cancer; melanoma; pancreatic cancer, and breast cancer, such as triple-negative breast cancer (TNBC). In certain embodiments, the solid tumor is selected from the group consisting of pancreatic cancer, prostate cancer, melanoma, SCCHN, cutaneous squamous cell carcinoma (cSCC), and cervical cancer. In certain embodiments, the solid tumor is pancreatic cancer. In certain embodiments, the solid tumor is prostate cancer. In certain embodiments, the solid tumor is melanoma. In certain embodiments, the solid tumor is SCCHN. In certain embodiments, the solid tumor is cSCC. In certain embodiments, the solid tumor is cervical cancer. In certain embodiments, the medicament is administered via intratumoral injection, for example, by using a fanning technique.

[0493] In certain embodiments, such medicaments are administered to patients at a dose ranging from 0.3 mg to 3 mg of TLR7 / 8 agonist per tumor. In certain embodiments, such medicaments are administered via intratumoral injection at a dose ranging from 0.3 mg to 3 mg of TLR7 / 8 agonist per tumor. In certain embodiments, the medicament is administered at a dose of 0.5 mg of TLR7 / 8 agonist per tumor. In certain embodiments, the medicament is administered at a dose of 0.5 mg of TLR7 / 8 agonist per tumor via intratumoral injection. In certain embodiments, the medicament is administered at a dose of 1 mg of TLR7 / 8 agonist per tumor. In certain embodiments, the medicament is administered at a dose of 1 mg of TLR7 / 8 agonist per tumor via intratumoral injection. In certain embodiments, the medicament is administered using a fanning technique.

[0494] In certain embodiments, the medicament is administered to the patient every 2 to 4 weeks. In certain embodiments, the medicament is administered to the patient every 3 weeks. In certain embodiments, the medicament is administered to the patient every 2 weeks. In certain embodiments, the medicament is administered to the patient every 4 weeks.

[0495] In certain embodiments, the medicament is administered to the patient every 5 weeks. In certain embodiments, the medicament is administered to the patient every 6 weeks. In certain embodiments, the medicament is administered to the patient every 7 weeks. In certain embodiments, the medicament is administered to the patient every 8 weeks. In certain embodiments, the medicament is administered to the patient every 9 weeks. In certain embodiments, the medicament is administered to the patient every 10 weeks. In certain embodiments, the medicament is administered to the patient every 12 weeks. In certain embodiments, the medicament is administered to the patient every 6 months. In certain embodiments, the medicament is administered to the patient every 7 months. In certain embodiments, the medicament is administered to the patient every 8 months. In certain embodiments, the medicament is administered to the patient every 9 months. In certain embodiments, the medicament is administered to the patient every 10 months. In certain embodiments, the medicament is administered to the patient every 11 months. In certain embodiments, the medicament is administered to the patient once a year. In certain embodiments, the medicament is administered to the patient at a frequency dependent on disease progression.

[0496] In certain embodiments, the medicament is administered to one tumor in a patient. In certain embodiments, the medicament is administered to more than one tumor in a patient, for example, two tumors, three tumors, four tumors, or five tumors, or to all tumors in a patient that are of sufficient size and accessible for treatment. In certain embodiments, treatment of one tumor produces an abscopal effect on one or more untreated tumors.

[0497] In certain embodiments, the medicament is administered to the patient in co-therapy with an inhibitor of PD-1 or an inhibitor of PD-L1, which may be given before, with, or after administration of the medicament.

[0498] In certain embodiments, the medicament is administered to a patient in co-therapy with a PD-1 inhibitor, which may be given before, with, or after administration of the medicament. The PD-1 inhibitor may be selected from the group consisting of pembrolizumab, nivolumab, pidilizumab, AMP-224, BMS-936559, cemiplimab, and PDR001. The PD-L1 inhibitor may be selected from the group consisting of MDX-1105, MEDI4736, atezolizumab, avelumab, BMS-936559, and durvalumab. In certain embodiments, the PD-1 inhibitor is pembrolizumab. Details regarding the administration of pembrolizumab are as described elsewhere herein.

[0499] In certain embodiments, the medicament is provided in a vial. Such a vial may have a stopper, such as a bromobutyl stopper, and a seal cap, such as an aluminum seal cap. In certain embodiments, the vial is a glass vial, such as a Type 1 glass vial. Such a vial may have a size of, for example, 1 ml, 2 ml, or 5 ml. In certain embodiments, the vial has a size of 2 ml. In certain embodiments, the vial has a size of 1 ml. In certain embodiments, the vial has a size of 5 ml. In certain embodiments, such a vial contains a unit dose. Such a unit dose, in certain embodiments, contains 0.5 mg of a TLR7 / 8 agonist. In certain embodiments, the unit dose is a liquid, such as a suspension, having a volume in the range of 0.1 to 1.5 ml. In certain embodiments, the unit dose is provided as a suspension and has a volume of 0.5 ml.

[0500] The embodiments of the tumor to which the medicament is administered are as described elsewhere herein.

[0501] In certain embodiments, the conjugate of the fourth, fifth, sixth, seventh or eighth aspect or the pharmaceutical formulation of the ninth aspect is for use in the treatment of cancer, e.g., a solid tumor.

[0502] In certain embodiments, such solid tumors include lip and oral cavity cancer, oral cancer, liver cancer / hepatocellular carcinoma, primary liver cancer, lung cancer, lymphoma, malignant mesothelioma, malignant thymoma, skin cancer, intraocular melanoma, metastatic squamous neck cancer of unknown primary, childhood multiple endocrine neoplasia syndrome, mycosis fungoides, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, oropharyngeal cancer, ovarian cancer, pancreatic cancer, parathyroid cancer, pheochromocytoma, pituitary tumor, adrenocortical carcinoma, AIDS-related malignancies, anal cancer, bile duct cancer, bladder cancer, brain and nervous system cancer, breast cancer, bronchial adenoma / carcinoma, thyroid, gastrointestinal carcinoid tumor, carcinoma, colorectal cancer, endometrial cancer, esophageal cancer, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, gallbladder cancer, cancer of the stomach (gastric cancer), gestational trophoblastic tumor, head and neck cancer, hypopharyngeal cancer, islet cell carcinoma (endocrine pancreas), kidney cancer / renal cell carcinoma, laryngeal cancer, pleuropulmonary blastoma, prostate cancer, transitional cell carcinoma of the renal pelvis and ureter, retinoblastoma, salivary gland cancer, sarcoma, Sezary syndrome, small intestine cancer, genitourinary cancer, malignant thymoma, thyroid cancer, Wilms' tumor, and cholangiocarcinoma.

[0503] In certain embodiments, the solid tumor is selected from the group consisting of squamous cell carcinoma of the head and neck (SCCHN); HPV-associated cancers, such as anal cancer, vulvar cancer, cervical cancer, penile cancer, and vaginal cancer; melanoma; pancreatic cancer, and breast cancer, such as triple-negative breast cancer (TNBC). In certain embodiments, the solid tumor is selected from the group consisting of pancreatic cancer, prostate cancer, melanoma, SCCHN, cutaneous squamous cell carcinoma (cSCC), and cervical cancer. In certain embodiments, the solid tumor is pancreatic cancer. In certain embodiments, the solid tumor is prostate cancer. In certain embodiments, the solid tumor is melanoma. In certain embodiments, the solid tumor is SCCHN. In certain embodiments, the solid tumor is cSCC. In certain embodiments, the solid tumor is cervical cancer. In certain embodiments, the medicament is administered via intratumoral injection, for example, by using a fanning technique.

[0504] In certain embodiments, the conjugate of the fourth, fifth, sixth, seventh, or eighth aspect or the pharmaceutical formulation of the ninth aspect is for use in treating cancer, e.g., a solid tumor, and is administered at a dose ranging from 0.3 mg to 3 mg of TLR7 / 8 agonist per tumor, e.g., 0.5 mg of TLR7 / 8 agonist per tumor. In certain embodiments, administration is at a dose of 1 mg of TLR7 / 8 agonist per tumor. In certain embodiments, administration is at a dose of 2 mg of TLR7 / 8 agonist per tumor.

[0505] In certain embodiments, the conjugate of the fourth, fifth, sixth, or seventh aspect or the pharmaceutical formulation of the eighth aspect is for use in treating cancer and is administered to a patient every 2 to 4 weeks, for example, every 3 weeks. In certain embodiments, administration of the conjugate or pharmaceutical formulation to a patient occurs every 2 weeks. In certain embodiments, administration of the conjugate or pharmaceutical formulation to a patient occurs every 4 weeks.

[0506] In certain embodiments, the administration of the conjugate or pharmaceutical formulation to the patient occurs every 5 weeks. In certain embodiments, the administration of the conjugate or pharmaceutical formulation to the patient occurs every 6 weeks. In certain embodiments, the administration of the conjugate or pharmaceutical formulation to the patient occurs every 7 weeks. In certain embodiments, the administration of the conjugate or pharmaceutical formulation to the patient occurs every 8 weeks. In certain embodiments, the administration of the conjugate or pharmaceutical formulation to the patient occurs every 9 weeks. In certain embodiments, the administration of the conjugate or pharmaceutical formulation to the patient occurs every 10 weeks. In certain embodiments, the administration of the conjugate or pharmaceutical formulation to the patient occurs every 12 weeks. In certain embodiments, the administration of the conjugate or pharmaceutical formulation to the patient occurs every 6 months. In certain embodiments, the administration of the conjugate or pharmaceutical formulation to the patient occurs every 7 months. In certain embodiments, the administration of the conjugate or pharmaceutical formulation to the patient occurs every 8 months. In certain embodiments, the administration of the conjugate or pharmaceutical formulation to the patient occurs every 9 months. In certain embodiments, the administration of the conjugate or pharmaceutical formulation to the patient occurs every 10 months. In certain embodiments, the administration of the conjugate or pharmaceutical formulation to the patient occurs every 11 months. In certain embodiments, the administration of the conjugate or pharmaceutical formulation to the patient occurs once a year. In certain embodiments, the administration of the conjugate or pharmaceutical formulation to the patient occurs at a frequency dependent on disease progression.

[0507] In certain embodiments, the conjugate of the fourth, fifth, sixth, seventh, or eighth aspect or the pharmaceutical formulation of the ninth aspect is for use in treating cancer, and the conjugate or pharmaceutical formulation is administered to one tumor in a patient. In certain embodiments, the conjugate of the fourth, fifth, sixth, seventh, or eighth aspect or the pharmaceutical formulation of the ninth aspect is for use in treating cancer, and the conjugate or pharmaceutical formulation is administered to more than one tumor in a patient, for example, two tumors, three tumors, four tumors, or five tumors, or to all tumors in a patient that are of sufficient size and accessible for treatment. In certain embodiments, treating one tumor results in an abscopal effect on one or more untreated tumors.

[0508] In certain embodiments, the conjugate of the fourth, fifth, sixth, seventh, or eighth aspect or the pharmaceutical formulation of the ninth aspect is for use in the treatment of cancer, and the treatment is co-treatment with a PD-1 inhibitor or a PD-L1 inhibitor, which may be given before, with, or after administration of the conjugate or pharmaceutical formulation. In certain embodiments, the treatment is co-treatment with a PD-1 inhibitor, which may be given before, with, or after administration of the conjugate or pharmaceutical formulation. Such a PD-1 inhibitor may be selected from the group consisting of pembrolizumab, nivolumab, pidilizumab, AMP-224, BMS-936559, cemiplimab, and PDR001, and in certain embodiments is pembrolizumab. Details regarding the administration of pembrolizumab are as described e...

Claims

1. A unit dosage form comprising a therapeutically effective amount of a TLR7 / 8 agonist conjugate or a pharma- ceutically acceptable salt thereof, wherein the TLR7 / 8 agonist conjugate comprises one or more TLR7 / 8 agonist moieties reversibly conjugated to a polymer moiety, and wherein the unit dosage form contains between 0.3 mg and 3 mg of the TLR7 / 8 agonist.

2. 2. The unit dosage form of claim 1, wherein the unit dosage form comprises 0.5 mg of the TLR7 / 8 agonist.

3. 2. The unit dosage form of claim 1, wherein the unit dosage form comprises 1 mg of the TLR7 / 8 agonist.

4. 4. The unit dosage form of any one of claims 1 to 3, wherein the unit dosage form comprises the TLR7 / 8 agonist conjugate in a volume ranging from 0.1 ml to 2 ml.

5. 5. The unit dosage form of any one of claims 1 to 4, wherein the unit dosage form comprises the TLR7 / 8 agonist conjugate in a volume of 0.5 ml.

6. 5. The unit dosage form of any one of claims 1 to 4, wherein the unit dosage form comprises the TLR7 / 8 agonist conjugate in a volume of 1 ml.

7. 5. The unit dosage form of any one of claims 1 to 4, wherein the unit dosage form comprises the TLR7 / 8 agonist conjugate in a volume of 0.25 ml.

8. The unit dosage form of any one of claims 1 to 7, wherein the TLR7 / 8 agonist is resiquimod.

9. The unit dosage form of any one of claims 1 to 8, wherein the polymer portion is a hydrogel.

10. The unit dosage form of any one of claims 1 to 9, wherein the polymer moiety is a PEG-based hydrogel.

11. The unit dosage form of any one of claims 1 to 10, wherein the unit dosage form is a vial containing the TLR7 / 8 agonist conjugate or a pharma- ceutically acceptable salt thereof.

12. The unit dosage form according to any one of claims 1 to 10, wherein the unit dosage form is a dual-chamber cartridge comprising the TLR7 / 8 agonist conjugate or a pharma- ceutically acceptable salt thereof.

13. The TLR7 / 8 agonist conjugate is represented by the formula (A-3): [Formula 1] [In the formula, "hydrogel" means a compound represented by the formula (A-4): [chemical 2] (wherein n is in the range of approximately 25 to 29, and the dashed line represents the moiety [C3] to, part [C4] or to the formula (A-5): [C5] (wherein m is in the range of approximately 41 to 45, and the dashed line in (A-5) indicates the bond to the skeleton moiety of formula (A-4).) (showing the bond to the crosslinker) The hydrogel contains a skeletal portion of The unit dosage form according to any one of claims 1 to 12, wherein the unit dosage form is represented by the formula:

14. The TLR7 / 8 agonist conjugate has the formula (Ai-6): [C6] (In the formula, m is in the range of approximately 25 to 29; n is in the range of approximately 41 to 45; "a" denotes a backbone moiety, "b" denotes a crosslinker moiety, "c" denotes a reversibly conjugated resiquimod moiety, and "d" denotes an acetamide moiety; The ratio of "a":"b":"c":"d" moieties in the conjugate is approximately 1:13:c:d, where c+d=6. The unit dosage form according to any one of claims 1 to 13, wherein the unit dosage form is represented by the formula:

15. The TLR7 / 8 agonist conjugate has the formula (A-8): [C7] (In the formula, m is in the range of approximately 25 to 29; n is in the range of approximately 41 to 45; "a" denotes a backbone moiety, "b" denotes a crosslinker moiety, "c" denotes a reversibly conjugated resiquimod moiety, and "d" denotes an acetamide moiety; The ratio of "a":"b":"c":"d" moieties in the conjugate is approximately 1:13:3:

3. The unit dosage form according to any one of claims 1 to 14, wherein

16. The TLR7 / 8 agonist conjugate has the formula (A-6): [C8] (In the formula, m is in the range of approximately 25 to 29; n is in the range of approximately 41 to 45; "a" denotes a backbone moiety, "b" denotes a crosslinker moiety, "c" denotes a reversibly conjugated resiquimod moiety, and "d" denotes an acetamide moiety; The ratio of "a":"b":"c":"d" moieties in the conjugate is approximately 1:13:2:

4. The unit dosage form according to any one of claims 1 to 14, wherein

17. The TLR7 / 8 agonist conjugate has the formula (A-7): [C9] (In the formula, m is in the range of approximately 25 to 29; n is in the range of approximately 41 to 45; "a" denotes a backbone moiety, "b" denotes a crosslinker moiety, "c" denotes a reversibly conjugated resiquimod moiety, and "d" denotes an acetamide moiety; The ratio of "a":"b":"c":"d" moieties in the conjugate is approximately 1:13:4:

2. The unit dosage form according to any one of claims 1 to 14, wherein

18. 18. The unit dosage form of any one of claims 1 to 17, wherein the unit dosage form comprises a TLR7 / 8 agonist conjugate or a pharma- ceutically acceptable salt thereof and one or more excipients.

19. A unit dosage form according to any one of claims 1 to 18 for use in the treatment of cancer.

20. 20. The unit dosage form for use according to claim 19, wherein the cancer is a solid tumor.

21. 21. The unit dosage form for use according to claim 19 or 20, wherein the unit dose of the unit dosage form is administered via intratumoral injection.

22. 22. The unit dosage form for use according to claim 21, wherein the intratumoral injection is performed using the fanning technique.

23. 23. The unit dosage form for use according to any one of claims 19 to 22, wherein the unit dose is administered every 2 to 4 weeks.

24. A unit dosage form for use according to any one of claims 19 to 23, wherein the unit dose is administered every three weeks.

25. Solid tumors include: lip and oral cavity cancer, oral cancer, liver cancer / hepatocellular carcinoma, primary liver cancer, lung cancer, lymphoma, malignant mesothelioma, malignant thymoma, skin cancer, intraocular melanoma, metastatic squamous neck cancer of unknown primary, childhood multiple endocrine neoplasia syndrome, mycosis fungoides, nasal and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, oropharyngeal cancer, ovarian cancer, pancreatic cancer, parathyroid cancer, pheochromocytoma, pituitary tumor, adrenal cortical carcinoma, AIDS-related malignancies, anal cancer, bile duct cancer, bladder cancer, brain and nervous system cancer, breast cancer, bronchial adenoma / carcinoid, gastrointestinal carcinoid tumor, carcinoma, colorectal cancer, 25. The unit dosage form for use according to any one of claims 20 to 24, wherein the cancer is selected from the group consisting of intestinal cancer, endometrial cancer, esophageal cancer, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, gallbladder cancer, cancer of the stomach (gastric cancer), gestational trophoblastic tumor, head and neck cancer, hypopharyngeal cancer, islet cell carcinoma (endocrine pancreas), kidney cancer / renal cell carcinoma, laryngeal cancer, pleuropulmonary blastoma, prostate cancer, transitional cell carcinoma of the renal pelvis and ureter, retinoblastoma, salivary gland cancer, sarcoma, Sezary syndrome, small intestine cancer, genitourinary cancer, malignant thymoma, thyroid cancer, Wilms' tumor and cholangiocarcinoma.

26. The unit dosage form for use according to any one of claims 20 to 25, wherein the solid tumor is selected from the group consisting of pancreatic cancer, prostate cancer, melanoma, SCCHN, cutaneous squamous cell carcinoma (cSCC) and cervical cancer.

27. The unit dosage form for use according to any one of claims 19 to 26, wherein the TLR7 / 8 agonist conjugate is administered to one tumor of the patient.

28. The unit dosage form for use according to any one of claims 19 to 26, wherein the TLR7 / 8 agonist conjugate is administered to more than one tumor of a patient.

29. 29. The unit dosage form for use according to any one of claims 19 to 28, wherein administration of the TLR7 / 8 agonist conjugate to one tumor results in an abscopal effect in one or more untreated tumors.

30. 30. The unit dosage form for use according to any one of claims 19 to 29, wherein the treatment is a co-treatment with an immune checkpoint inhibitor, which may be given before, together with or after administration of the TLR7 / 8 agonist conjugate.

31. 31. The unit dosage form for use according to any one of claims 19 to 30, wherein the treatment is co-treatment with an inhibitor of PD-1 or an inhibitor of PD-L1, the inhibitor of PD-1 or the inhibitor of PD-L1 may be given before, together with or after administration of the TLR7 / 8 agonist conjugate.

32. 32. The unit dosage form for use according to any one of claims 19 to 31, wherein the treatment is a co-treatment with an inhibitor of PD-1, which may be given before, together with or after administration of the TLR7 / 8 agonist conjugate.

33. 33. The unit dosage form for use according to any one of claims 19 to 32, wherein the treatment is co-treatment with pembrolizumab, and pembrolizumab may be given before, with or after administration of the TLR7 / 8 agonist conjugate.

34. 34. The unit dosage form for use according to claim 33, wherein pembrolizumab is administered via intravenous injection every three weeks.

35. A TLR7 / 8 agonist conjugate, or a pharma- ceutically acceptable salt thereof, for use in the treatment of cancer, wherein the TLR7 / 8 agonist conjugate comprises one or more TLR7 / 8 agonist moieties reversibly conjugated to a polymer moiety, and wherein the cancer is a solid tumor, and wherein the TLR7 / 8 agonist conjugate is administered via intratumoral administration at a dose ranging from 0.3 mg to 3 mg of TLR7 / 8 agonist per tumor.

36. 36. The TLR7 / 8 agonist conjugate or a pharma- ceutically acceptable salt thereof for use according to claim 35, wherein the TLR7 / 8 agonist conjugate is administered at a dose of 0.5 mg of TLR7 / 8 agonist per tumor.

37. 36. The TLR7 / 8 agonist conjugate or a pharma- ceutically acceptable salt thereof for use according to claim 35, wherein the TLR7 / 8 agonist conjugate is administered at a dose of 1 mg of TLR7 / 8 agonist per tumor.

38. 38. The TLR7 / 8 agonist conjugate or a pharma- ceutically acceptable salt thereof for use according to any one of claims 35 to 37, wherein the dose is administered in a volume ranging from 0.1 ml to 2 ml.

39. The TLR7 / 8 agonist conjugate or a pharma- ceutically acceptable salt thereof for use according to any one of claims 35 to 38, wherein the dose is administered in a volume of 0.5 ml.

40. The TLR7 / 8 agonist conjugate or a pharma- ceutically acceptable salt thereof for use according to any one of claims 35 to 38, wherein the dose is administered in a volume of 1 ml.

41. The TLR7 / 8 agonist conjugate or a pharma- ceutically acceptable salt thereof for use according to any one of claims 35 to 38, wherein the dose is administered in a volume of 0.25 ml.

42. 42. The TLR7 / 8 agonist conjugate or a pharma- ceutically acceptable salt thereof for use according to any one of claims 35 to 41, wherein the TLR7 / 8 agonist conjugate or a pharma- ceutically acceptable salt thereof is provided as a pharmaceutical formulation comprising one TLR7 / 8 agonist conjugate or a pharma- ceutically acceptable salt thereof and one or more excipients.

43. 43. The TLR7 / 8 agonist conjugate or a pharma- ceutically acceptable salt thereof for use according to any one of claims 35 to 42, wherein the TLR7 / 8 agonist is resiquimod.

44. The TLR7 / 8 agonist conjugate or a pharma- ceutically acceptable salt thereof for use according to any one of claims 35 to 43, wherein the polymer moiety is a hydrogel.

45. The TLR7 / 8 agonist conjugate or a pharma- ceutically acceptable salt thereof for use according to any one of claims 35 to 44, wherein the polymer moiety is a PEG-based hydrogel.

46. The TLR7 / 8 agonist conjugate is represented by the formula (A-3): [C10] [In the formula, "hydrogel" means a compound represented by the formula (A-4): [C11] (wherein n is in the range of approximately 25 to 29, and the dashed line represents the moiety [C12] to, part [C13] or to the formula (A-5): [C14] (wherein m is in the range of approximately 41 to 45, and the dashed line in (A-5) indicates the bond to the skeleton moiety of formula (A-4).) (showing the bond to the crosslinker) The hydrogel contains a skeletal portion of The TLR7 / 8 agonist conjugate for use according to any one of claims 35 to 45, which is represented by the following formula: or a pharma- ceutically acceptable salt thereof.

47. The TLR7 / 8 agonist conjugate has the formula (Ai-6): [C15] (In the formula, m is in the range of approximately 25 to 29; n is in the range of approximately 41 to 45; "a" denotes a backbone moiety, "b" denotes a crosslinker moiety, "c" denotes a reversibly conjugated resiquimod moiety, and "d" denotes an acetamide moiety; The ratio of "a":"b":"c":"d" moieties in the conjugate is approximately 1:13:c:d, where c+d=6. The TLR7 / 8 agonist conjugate for use according to any one of claims 35 to 46, which is represented by the formula: or a pharma- ceutically acceptable salt thereof.

48. The TLR7 / 8 agonist conjugate has the formula (A-8): [C16] (In the formula, m is in the range of approximately 25 to 29; n is in the range of approximately 41 to 45; "a" denotes a backbone moiety, "b" denotes a crosslinker moiety, "c" denotes a reversibly conjugated resiquimod moiety, and "d" denotes an acetamide moiety; The ratio of "a":"b":"c":"d" moieties in the conjugate is approximately 1:13:3:

3. The TLR7 / 8 agonist conjugate for use according to any one of claims 35 to 47, which is represented by the formula: or a pharma- ceutically acceptable salt thereof.

49. The TLR7 / 8 agonist conjugate has the formula (A-6): [C17] (In the formula, m is in the range of approximately 25 to 29; n is in the range of approximately 41 to 45; "a" denotes a backbone moiety, "b" denotes a crosslinker moiety, "c" denotes a reversibly conjugated resiquimod moiety, and "d" denotes an acetamide moiety; The ratio of "a":"b":"c":"d" moieties in the conjugate is approximately 1:13:2:

4. The TLR7 / 8 agonist conjugate for use according to any one of claims 35 to 47, which is represented by the formula: or a pharma- ceutically acceptable salt thereof.

50. The TLR7 / 8 agonist conjugate has the formula (A-7): [C18] (In the formula, m is in the range of approximately 25 to 29; n is in the range of approximately 41 to 45; "a" denotes a backbone moiety, "b" denotes a crosslinker moiety, "c" denotes a reversibly conjugated resiquimod moiety, and "d" denotes an acetamide moiety; The ratio of "a":"b":"c":"d" moieties in the conjugate is approximately 1:13:4:

2. The TLR7 / 8 agonist conjugate for use according to any one of claims 35 to 47, which is represented by the formula: or a pharma- ceutically acceptable salt thereof.

51. The TLR7 / 8 agonist conjugate or a pharma- ceutically acceptable salt thereof for use according to any one of claims 35 to 50, wherein the dose is provided in a vial.

52. The TLR7 / 8 agonist conjugate or a pharma- ceutically acceptable salt thereof for use according to any one of claims 35 to 50, wherein the dose is provided in a dual-chamber cartridge.

53. The TLR7 / 8 agonist conjugate or a pharma- ceutically acceptable salt thereof for use according to any one of claims 35 to 52, wherein the intratumoral injection is performed using the fanning technique.

54. 54. The TLR7 / 8 agonist conjugate or a pharma- ceutically acceptable salt thereof for use according to any one of claims 35 to 53, wherein the dose is administered every 2 to 4 weeks.

55. The TLR7 / 8 agonist conjugate or a pharma- ceutically acceptable salt thereof for use according to any one of claims 35 to 54, wherein the dose is administered every three weeks.

56. Solid tumors include: lip and oral cavity cancer, oral cancer, liver cancer / hepatocellular carcinoma, primary liver cancer, lung cancer, lymphoma, malignant mesothelioma, malignant thymoma, skin cancer, intraocular melanoma, metastatic squamous neck cancer of unknown primary, childhood multiple endocrine neoplasia syndrome, mycosis fungoides, nasal and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, oropharyngeal cancer, ovarian cancer, pancreatic cancer, parathyroid cancer, pheochromocytoma, pituitary tumor, adrenal cortical carcinoma, AIDS-related malignancies, anal cancer, bile duct cancer, bladder cancer, brain and nervous system cancer, breast cancer, bronchial adenoma / carcinoid, gastrointestinal carcinoid tumor, carcinoma, colorectal cancer, endometrial cancer, and esophageal cancer.

56. The TLR7 / 8 agonist conjugate or a pharmacologic agent thereof for use according to any one of claims 35 to 55, wherein the TLR7 / 8 agonist conjugate or a pharmacologic agent thereof is selected from the group consisting of cancer of the stomach (gastric cancer), gestational trophoblastic tumor, head and neck cancer, hypopharyngeal cancer, islet cell carcinoma (endocrine pancreas), kidney cancer / renal cell carcinoma, laryngeal cancer, pleuropulmonary blastoma, prostate cancer, transitional cell carcinoma of the renal pelvis and ureter, retinoblastoma, salivary gland cancer, sarcoma, Sezary syndrome, small intestine cancer, genitourinary cancer, malignant thymoma, thyroid cancer, Wilms' tumor, and cholangiocarcinoma.

57. 57. The TLR7 / 8 agonist conjugate or a pharma- ceutically acceptable salt thereof for use according to any one of claims 35 to 56, wherein the solid tumor is selected from the group consisting of pancreatic cancer, prostate cancer, melanoma, SCCHN, cutaneous squamous cell carcinoma (cSCC) and cervical cancer.

58. 58. The TLR7 / 8 agonist conjugate or a pharma- ceutically acceptable salt thereof for use according to any one of claims 35 to 57, wherein the TLR7 / 8 agonist conjugate is administered to one tumor of the patient.

59. 58. The TLR7 / 8 agonist conjugate or a pharma- ceutically acceptable salt thereof for use according to any one of claims 35 to 57, wherein the TLR7 / 8 agonist conjugate is administered to more than one tumor of the patient.

60. 60. The TLR7 / 8 agonist conjugate or a pharma- ceutically acceptable salt thereof for use according to any one of claims 35 to 59, wherein administration of the TLR7 / 8 agonist conjugate to one tumor results in an abscopal effect in one or more untreated tumors.

61. 61. The TLR7 / 8 agonist conjugate or a pharma- ceutically acceptable salt thereof for use according to any one of claims 35 to 60, wherein the treatment is a co-treatment with an immune checkpoint inhibitor, which may be given before, with or after administration of the TLR7 / 8 agonist conjugate.

62. 62. The TLR7 / 8 conjugate or a pharma- ceutically acceptable salt thereof for use according to any one of claims 35 to 61, wherein the treatment is co-treatment with an inhibitor of PD-1 or an inhibitor of PD-L1, the inhibitor of PD-1 or the inhibitor of PD-L1 optionally being given before, together with or after administration of the TLR7 / 8 agonist conjugate.

63. 63. The TLR7 / 8 agonist conjugate or a pharma- ceutically acceptable salt thereof for use according to any one of claims 35 to 62, wherein the treatment is a co-treatment with an inhibitor of PD-1, which may be given before, with or after administration of the TLR7 / 8 agonist conjugate.

64. 64. The TLR7 / 8 agonist conjugate or a pharma- ceutically acceptable salt thereof for use according to any one of claims 35 to 63, wherein the treatment is co-treatment with pembrolizumab, which may be given before, with or after administration of the TLR7 / 8 agonist conjugate.

65. 65. The TLR7 / 8 agonist conjugate or a pharma- ceutically acceptable salt thereof for use according to claim 64, wherein pembrolizumab is administered via intravenous injection every three weeks.

66. Formula (A-3) [C19] [In the formula, "hydrogel" means a compound represented by the formula (A-4): [C20] (wherein n is in the range of approximately 25 to 29, and the dashed line represents the moiety [C21] to, part [C22] or to the formula (A-5): [C23] (wherein m is in the range of approximately 41 to 45, and the dashed line in (A-5) indicates the bond to the skeleton moiety of formula (A-4).) (showing the bond to the crosslinker) The hydrogel contains a skeletal portion of or a pharma- ceutically acceptable salt thereof.

67. The conjugate is represented by the formula (A-6) [C24] (In the formula, m is in the range of approximately 25 to 29; n is in the range of approximately 41 to 45; "a" denotes a backbone moiety, "b" denotes a crosslinker moiety, "c" denotes a reversibly conjugated resiquimod moiety, and "d" denotes an acetamide moiety; The ratio of "a":"b":"c":"d" moieties in the conjugate is approximately 1:13:2:

4.

43. The conjugate of claim 42, wherein the conjugate is represented by the formula:

68. 44. The conjugate or pharma- ceutically acceptable salt thereof of claim 43, wherein the ratio of "a":"b":"c":"d" is approximately 1:13:2.4:3.

6.

69. Equation (Ai-6) [C25] (In the formula, m is in the range of approximately 25 to 29; n is in the range of approximately 41 to 45; "a" denotes a backbone moiety, "b" denotes a crosslinker moiety, "c" denotes a reversibly conjugated resiquimod moiety, and "d" denotes an acetamide moiety; The ratio of "a":"b":"c":"d" moieties in the conjugate is approximately 1:13:c:d, where c+d=6. or a pharma- ceutically acceptable salt thereof.

70. 70. The conjugate of claim 69, or a pharma- ceutically acceptable salt thereof, wherein the ratio of "a":"b":"c":"d" moieties in the conjugate is approximately 1:13:3:

3.

71. 70. The conjugate of claim 69, or a pharma- ceutically acceptable salt thereof, wherein the ratio of "a":"b":"c":"d" moieties in the conjugate is approximately 1:13:2:

4.

72. 70. The conjugate of claim 69, or a pharma- ceutically acceptable salt thereof, wherein the ratio of "a":"b":"c":"d" moieties in the conjugate is approximately 1:13:4:

2.

73. 73. A pharmaceutical formulation comprising one or more conjugates according to any one of claims 66 to 72, or pharma- ceutically acceptable salts thereof, and one or more excipients.

74. 74. A conjugate according to any one of claims 66 or 72, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical formulation according to claim 73, for use as a medicament.

75. 74. A conjugate according to any one of claims 66 or 72, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical formulation according to claim 73, for use in the treatment of cancer.

76. 76. The conjugate or a pharma- ceutically acceptable salt or pharmaceutical formulation thereof for use according to claim 75, wherein the cancer is a solid tumor.

77. 77. The conjugate or a pharma- ceutically acceptable salt thereof or a pharmaceutical formulation thereof for use according to claim 75 or 76, wherein the conjugate is administered at a dose ranging from 0.3 mg to 3 mg per tumor.

78. 78. The conjugate or a pharma- ceutically acceptable salt thereof or a pharmaceutical formulation thereof for use according to any one of claims 75 to 77, wherein the conjugate is administered at a dose of 0.5 mg per tumor.

79. 79. The conjugate or a pharma- ceutically acceptable salt thereof or a pharmaceutical formulation thereof for use according to any one of claims 75 to 78, wherein the conjugate is administered in a volume ranging from 0.1 to 2 ml.

80. The conjugate or a pharma- ceutically acceptable salt thereof or a pharmaceutical formulation thereof for use according to any one of claims 75 to 79, wherein the conjugate is administered in a volume of 1 ml.

81. The conjugate or a pharma- ceutically acceptable salt thereof or a pharmaceutical formulation thereof for use according to any one of claims 75 to 79, wherein the conjugate is administered in a volume of 0.25 ml.

82. The conjugate or a pharma- ceutically acceptable salt or pharmaceutical formulation thereof for use according to any one of claims 75 to 81, wherein the conjugate is administered via intratumoral injection.

83. 83. The conjugate or a pharma- ceutically acceptable salt or pharmaceutical formulation thereof for use according to claim 82, wherein the intratumoral injection uses a fanning technique.

84. 84. The conjugate or a pharma- ceutically acceptable salt thereof or a pharmaceutical formulation thereof for use according to any one of claims 75 to 83, wherein the conjugate is administered to a patient every 2 to 4 weeks.

85. The conjugate or a pharma- ceutically acceptable salt thereof or a pharmaceutical formulation thereof for use according to any one of claims 75 to 84, wherein the conjugate is administered to a patient every three weeks.

86. Solid tumors include: lip and oral cavity cancer, oral cancer, liver cancer / hepatocellular carcinoma, primary liver cancer, lung cancer, lymphoma, malignant mesothelioma, malignant thymoma, skin cancer, intraocular melanoma, metastatic squamous neck cancer of unknown primary, childhood multiple endocrine neoplasia syndrome, mycosis fungoides, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, oropharyngeal cancer, ovarian cancer, pancreatic cancer, parathyroid cancer, pheochromocytoma, pituitary tumor, adrenal cortical carcinoma, AIDS-related malignancies, anal cancer, bile duct cancer, bladder cancer, brain and nervous system cancer, breast cancer, bronchial adenoma / carcinoid, gastrointestinal carcinoid tumor, carcinoma, colorectal cancer, endometrial cancer, esophageal 86. The conjugate or its pharmacologicaly acceptable salt or pharmaceutical formulation for use according to any one of claims 75 to 85, selected from the group consisting of cancer, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, gallbladder cancer, cancer of the stomach (gastric cancer), gestational trophoblastic tumor, head and neck cancer, hypopharyngeal cancer, islet cell carcinoma (endocrine pancreas), kidney cancer / renal cell carcinoma, laryngeal cancer, pleuropulmonary blastoma, prostate cancer, transitional cell carcinoma of the renal pelvis and ureter, retinoblastoma, salivary gland cancer, sarcoma, Sezary syndrome, small intestine cancer, genitourinary cancer, malignant thymoma, thyroid cancer, Wilms' tumor and cholangiocarcinoma.

87. 87. The conjugate or a pharma- ceutically acceptable salt thereof or a pharmaceutical formulation thereof for use according to any one of claims 75 to 86, wherein the solid tumor is selected from the group consisting of pancreatic cancer, prostate cancer, melanoma, SCCHN, cutaneous squamous cell carcinoma (cSCC) and cervical cancer.

88. The conjugate or a pharma- ceutically acceptable salt thereof or a pharmaceutical formulation thereof for use according to any one of claims 75 to 87, wherein the conjugate is administered to one tumor of a patient.

89. The conjugate or a pharma- ceutically acceptable salt thereof or a pharmaceutical formulation thereof for use according to any one of claims 75 to 87, wherein the conjugate is administered to more than one tumor.

90. 90. The conjugate or a pharma- ceutically acceptable salt or pharmaceutical formulation thereof for use according to any one of claims 75 to 89, wherein administration of the conjugate to one tumor results in an abscopal effect in one or more untreated tumors.

91. 91. The conjugate or a pharma- ceutically acceptable salt thereof, or a pharmaceutical formulation thereof, for use according to any one of claims 75 to 90, wherein the treatment is co-treatment with an inhibitor of PD-1 or PD-L1, which may be given prior to, together with or after administration of the conjugate.

92. 92. The conjugate or a pharma- ceutically acceptable salt thereof or a pharmaceutical formulation thereof for use according to any one of claims 75 to 91, wherein the treatment is co-treatment with an inhibitor of PD-1, which inhibitor of PD-1 may be given before, with or after administration of the conjugate.

93. 93. The conjugate or a pharma- ceutically acceptable salt thereof or a pharmaceutical formulation thereof for use according to any one of claims 75 to 92, wherein the treatment is co-treatment with pembrolizumab, and pembrolizumab may be given before, with or after administration of the conjugate.

94. 94. The conjugate or a pharma- ceutically acceptable salt thereof, or a pharmaceutical formulation thereof for use according to claim 93, wherein pembrolizumab is administered via intravenous infusion at a dose of 200 mg.

95. 95. The conjugate or a pharma- ceutically acceptable salt thereof or a pharma- ceutically acceptable salt thereof or a pharmaceutical formulation for use according to claim 93 or 94, wherein pembrolizumab is administered every three weeks.

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