TLR agonist conjugate compounds

Abstract

Compound having a structure represented by one or more of the formulas I-a1 and I-c1: or a pharmaceutically acceptable salt, solvate, hydrate, crystal form, tautomer or diastereomer thereof, wherein: A is a tumor-directed unit with a molecular weight of 3000 Da or less and is a PSMA-binding unit; B is a spacer; C is a splittable or non-splittable left; D is a self-destructing spacer; c and d can each be 0 or an integer of 1 or more; preferably 0, 1, 2 or 3; wherein each occurrence of B, C and D may be in any order; and wherein each of E-a1 and E-c1 is a TLR7 agonist unit which is a structure of the formula E-a1 or E-c1 respectively. This includes: where Z a1 C3-Alkynyl is; U 1 -W 1Selected from: and R is selected from H, C 1-3 -Alkyl, C 1-3 -Haloalkyl and C 1-3 -Heteroalkyl; and R 1 selected from C 1-8 -Alkyl, C 2-8 -Cycloalkyl, (C 3-6 -Cycloalkyl) C 1-3 -alkyl, C 1-7 -Heteroalkyl, C 2-7 -Cycloheteroalkyl, -C (=O) NH (C 1-3 -alkyl), -C 1-3 -Alkyl (C=O) OME, -C(=O)NH (C 2-8 -Cycloalkyl), (C 2-7 -Cycloheteroaryl) C 1-3 -alkyl and (C 6-10 -Aryl) C 1-3 -alkyl; each optionally substituted with one or more substituents, preferably selected from OH, CH3, OMe, CN, -C(=O)Me, F2CH, SO2Me and halogen.

Description

AREA OF INVENTION

[0001] The present invention relates to Toll-like receptor (TLR) agonist conjugate compounds that can be used for the treatment of cancer. BACKGROUND OF THE INVENTION

[0002] Recent advances in cancer therapy are largely due to the widespread use of immune checkpoint inhibitors (ICIs). ICIs restore the antitumor immune response by blocking coinhibitory signaling pathways such as PD-1 / PD-L1 and CTLA-4. Although ICIs are successful in certain cancers, few patients respond to treatment. This is either due to the development of resistance mechanisms or because ICIs are ineffective in so-called "cold" tumors. Patients with highly inflamed "hot" tumors often show a good response to these drugs, whereas "cold" tumors, characterized by low T-cell infiltration or low PD-L1 expression, are more resistant to ICIs.

[0003] A promising strategy for overcoming the limitations of immune checkpoint inhibitors (ICIs), particularly in "cold" tumors, involves the targeted treatment of antigen-presenting cells (APCs) by activating pattern recognition receptors (PRRs), including Toll-like receptors (TLRs). Activation of TLRs on APCs leads to the release of pro-inflammatory cytokines and enhances the expression of co-stimulatory molecules, ultimately increasing T-cell activity against tumors. For these reasons, Toll-like receptors (TLRs) have become an important target in cancer immunotherapy.

[0004] Toll-like receptors (TLRs), which comprise a family of ten functional receptors in humans, are a crucial component of the innate pathogen recognition system. (1) TLRs recognize various pathogen- and host-derived molecules and mediate cell activation and inflammation to trigger an immune response.

[0005] Over the years, several TLR7 and TLR8 agonists have been developed and evaluated for therapeutic applications, particularly in antiviral and immuno-oncological therapy. (2) Small molecule TLR7 and TLR8 agonists can indeed induce a strong immune response in humans and animals.

[0006] TLR7 can be activated, in particular, by synthetic guanosine analogs, often based on purine or imidazoquinoline structures, triggering downstream signaling pathways that activate the immune system. This has led to the development of several TLR7 agonists, which have been investigated for use in antiviral and cancer immunotherapy. Although compounds such as those described in US 8,728,486 B2, which have an imidazoquinoline scaffold, and WO2019 / 209811A1, which have a purine scaffold, have shown promising preliminary results, challenges remain regarding the improvement of their efficacy, selectivity, and pharmacokinetic properties.

[0007] A major challenge in the use of TLR7 agonists is the potential for severe systemic toxicity, especially with systemic administration, which can lead to dangerous side effects such as cytokine storms.

[0008] Small molecule drug conjugates (SMDCs) utilize small organic molecules as target vectors to selectively deliver TLR7 agonists to tumor sites, thereby improving drug localization and minimizing systemic exposure. This targeted approach enables better tumor penetration and controlled release of the immunostimulatory agents, reducing the risk of off-target toxicity. Therefore, SMDCs represent a promising strategy to overcome current limitations in the administration of TLR7 agonists. While SMDCs hold considerable potential as a strategy for the targeted delivery of TLR7 agonists, further development is needed, for example, to improve their efficacy, stability, and / or target specificity. Non-patented literature (1) Kawai, T. et al. (2010). Nature immunology, 11(5), 373-384 (2) Patinote, C., et al. (2020). European Journal of Medicinal Chemistry, 193, 112238 Patent literature

[0009] US 8,728,486 B2

[0010] WO2019 / 209811 TASK TO BE SOLVED BY THE INVENTION

[0011] Against the above background, the present invention addresses the need for improved means for the effective activation of the immune system, particularly for therapeutic applications such as immunomodulation and cancer immunotherapy. In a specific aspect, it provides improved conjugates (e.g., SMDCs) that can selectively target tumor lesions and efficiently transport TLR7 agonists to the site of disease, especially in the context of tumor immunotherapy. SUMMARY OF THE INVENTION

[0012] As a solution to the above-mentioned problem, the invention provides conjugates of formula I as defined below and in the attached claims. BRIEF DESCRIPTION OF THE FIGURES Fig. Figure 1 shows EC50 of the compounds MB357, A78 or Resiquimod on human (A) and murine (B) TLR7, measured using NF-κB-SEAP reporter cells (HEK293) expressing the receptor. Fig. Figure 2 shows the quantification of cytokines (hIL-6 and hTNFα) released by human peripheral blood monocytes (PBMCs) after 24-hour stimulation with the compounds MB357 or A78. Fig. Figure 3 shows the quantification of cytokines (mIL-6 and mTNFα) released by murine bone marrow dendritic cells (BMDCs – “Blood Peripheral Blood Monocytes”) and splenocytes after 24-hour stimulation with the compounds MB357 or A78. Fig.Figure 4 shows the flow cytometric evaluation of the upregulation of CD86 and CD40 expression in bone marrow dendritic cells (CD11c+) cultured for 24 hours with the compounds MB357, A78 or IIb-19 (AC); and the upregulation of CD40 expression in B cells (B220+ splenocytes) cultured for 24 hours with the compounds MB357 or A78 (D). Fig.Figure 5 shows the antitumor activity of the PSMA-directed conjugate OncoPSMA-GlyPro-MB357. C57BL / 6 mice injected with PSMA-positive tumor cells were treated with the conjugate (OncoPSMA-GlyPro-MB357, dose = 250 nmol / kg) or with the free substance (MB357, dose = 250 nmol / kg). OncoPSMA-GlyPro-MB357 showed better control of tumor growth compared to MB357 alone, highlighting the positive effect of OncoPSMA-mediated drug release (A). Neither substance showed toxic effects, as demonstrated by the body weight change curves (B). Tumor growth in the individual mice used in the experiment is also shown (C). DETAILED DESCRIPTION OF THE INVENTION

[0013] The inventors have identified Toll-like receptor 7 (TLR7) agonists, i.e., TLR7 agonist conjugates, suitable for use in the treatment of cancer. The TLR7 agonists described here exhibit enhanced antitumor activity. In particular, the TLR7 agonist conjugates are immunomodulatory agents that offer improved efficacy, potency, and minimal toxicity for the targeted therapy of diseases such as cancer compared to existing therapies.

[0014] The conjugates are highly potent and selective TLR7 agonists (e.g., selective for TLR7 vs. TLR8) that highly effectively stimulate cytokine release and promote the activation of immune cells (e.g., upregulation of CD86 and CD40) and exhibit superior in vivo efficacy and tolerability, including minimal toxicity (e.g., in preclinical models). Conjugates for page-specific provisioning

[0015] The TLR7 agonists disclosed here can be selectively transported to the desired site of action, e.g., by targeted release in a conjugate with a target structure. Preferably, the target structure is a small molecule whose antigen is located at the site of action, for example, a tumor-associated antigen if the site of action is a tumor (cancer). Preferably, the tumor-associated antigen is specifically expressed or overexpressed by the cancer cell compared to a normal cell. The tumor-associated antigen may be located on the surface of the cancer cell.

[0016] Conjugation can be achieved through various combinations of components, including a spacer (B), a cleavable or non-cleavable linker (C), and a self-decomposing spacer (D). B, C, and D can be arranged in any order, but the preferred order is -B-(C). c -(D) d-, preferably c and d are each equal to 1. The TLR7 agonist unit (E) is included due to its therapeutic effect after administration to the target site.

[0017] The TLR7 agonist conjugate of the present invention has the following structure: or may be a pharmaceutically acceptable salt, a solvate, a hydrate, a crystalline form, a tautomer or a diastereomer thereof.

[0018] In this formula, A is a PSMA-binding unit. E is a TLR7 agonist unit. B, C, and D can be collectively referred to as the "linking unit" because they link E and A. Within the linking unit, B is a spacer; C is a cleavable or non-cleavable linker; D is a self-decomposing spacer. The indices c and d can each be 0 or an integer of 1 or more; preferably 0, 1, 2, or 3. That is to say, the presence of C and D is optional. In Formula I, any occurrence of B, C, and D can be in any order, but it is preferred that they be in the order -B-(C) c -(D) d - are arranged, wherein each of c and d is preferred 1. A, B, C, D and E are described in more detail in the following paragraphs.

[0019] As used herein, the disclosure refers to the conjugate, including its individual diastereomers, hydrates, solvates, crystal forms, tautomers or pharmaceutically acceptable salts thereof.

[0020] The tumor-directed unit (A) is a component that binds specifically to tumor-associated antigens, guiding the conjugate to the tumor site for targeted therapy. The spacer (B) is a molecular bridge that ensures the correct positioning of the therapeutic components and optimizes their efficacy at the target site. Advantageously, spacer B can modulate physicochemical properties such as permeability or solubility. The cleavable or non-cleavable linker (C) is an optional component that connects the different parts of the conjugate. Advantageously, the linker can be highly stable in plasma and selectively and rapidly release the payload (e.g., the TLR7 agonist) only in the desired tissue. Non-cleavable linkers are preferred when the targeted agent is specific for internalizing antigens (e.g.,PSMA linkers are not suitable because they rely on complete endocytosis of the conjugate and lysosomal degradation to enable payload release. Cleavageable linkers, on the other hand, can be used for both internalizing and non-internalizing antigens because they are degraded in response to tumor-associated factors. The self-degrading spacer (D) is an optional element that facilitates the release of the active TLR7 agonist after linker cleavage in the target tissue. Advantageously, a cleavageable linker is positioned relative to a self-degrading spacer (e.g., immediately upstream); in this case, linker cleavage induces spacer self-degradation and payload release (E). Ultimately, the TLR7 agonist (payload E) is a therapeutic component that, upon reaching the tumor site, activates the immune response and stimulates immune cells against cancer cells.

[0021] The conjugates of the invention, comprising E as defined herein, advantageously exhibit improved anticancer activity (even compared to the respective unconjugated active substances or to reference compounds) and minimal toxicity. In particular, the conjugates effectively deliver the active substance to tumor sites, as has been shown, for example, in tumors characterized by PSMA overexpression. Surprisingly, the conjugates according to the invention exhibit improved therapeutic efficacy compared to the free active substances. The conjugates of the invention are therefore designed to enable the selective delivery and release of the TLR7 agonist only at the tumor lesions, thereby achieving efficient activation of the immune system and an anticancer effect.

[0022] As shown above, the generic structure I can have different arrangements, since the indices c and d can be 0 or an integer of 1 or more; preferably 0, 1, 2 or 3, which includes the following preferred arrangements: where the components are defined below. These combinations can be used with the components described in the following sections.

[0023] The conjugate of formula I can also have a structure according to the following general formula, wherein different “arms” carrying a TLR7 payload E are attached to the same target binding unit:

[0024] Preferably, the generic structure of formula I, as well as all other conjugate structures defined herein, have the following arrangements:

[0025] Preferably, the generic structure of formula I, as well as all other conjugate structures defined herein, have the following arrangements: Targeted Unit (A)

[0026] The targeted unit (A) is a PSMA-binding unit as defined in the claims or as described below.

[0027] In the present disclosure, the targeted unit (A) is preferably a small molecular unit, e.g. having a molecular weight of 3000 Da or less, preferably 2500 Da or less, more preferably 2000 Da or less, and even more preferably from 250 to 2000 Da. Linking units and their components

[0028] As shown above, the linking unit can comprise a spacer B, optionally a cleavable or non-cleavable linker C and optionally a self-dissolving spacer D, c and d can each be 0 or an integer of 1 or more; preferably 0, 1, 2 or 3.

[0029] The linking unit is a covalent bond or a unit comprising a chain of atoms that covalently links A to the payload E, for example, by one or more covalent bonds. The entire linking unit can be a cleavable or non-cleavable, multifunctional group that can be used to link one or more payload and / or binder components to form the desired conjugate of the invention. Unless otherwise specified, in this description, "linking unit" refers to fragment -B-(C). c -(D) d -

[0030] The linking unit or parts thereof, in particular spacer B, can be a single bond or a possibly substituted C. 1-50 -aliphatic group in which one or more carbon atoms may be replaced by a heteroatom, a C 3-12 carbocyclic group or a C 1-12The group may be heterocyclic and may be saturated or may contain one or more double or triple bonds. The structure of the compound may comprise more than one E unit, e.g., 2 to 4 E units per molecule.

[0031] If cleavable linkers are present within the conjugation unit, e.g., as unit C, the release mechanisms can be identical to those of antibodies bound to payloads. The nature of the binding groups is, in fact, independent in this respect. Therefore, a pH-dependent [Leamon, CP et al. (2006) Bioconjugate Chem., 17, 1226; Casi, G. et al (2012) J. Am. Chem. Soc., 134, 5887], reductive [Bernardes, GJ et al. (2012) Angew. Chem. Int. Ed. Engl., 51, 941; Yang, J. et al. (2006) Proc. Natl. Acad. Sci. USA, 103, 13872] and enzymatic release [Doronina SO et al (2008) Bioconjugate Chem, 19, 1960; Sutherland, MSK (2006) J. Biol. Chem, 281, 10540]. In certain cases, when functional groups are present either on the binding group or on the payloads (e.g.Thiols, alcohols), a compound can be produced without a linker, thereby releasing intact payloads, which greatly simplifies pharmacokinetic analysis.

[0032] By attaching a therapeutic effector (in particular, the TLR7 agonist as payload E) via a site-specific cleavable linker to a binding site specific to a disease marker, the effector preferentially accumulates at the target site and exerts its effect there. This increases the effectively delivered dose while simultaneously reducing side effects. The entire linker can be cleavable or non-cleavable. However, a cleavable linker (e.g., with a cleavable unit C) is preferred, as this is advantageous with regard to drug release, accumulation of the (free) drug, and / or antitumor activity. Although a cleavable linker C can be advantageous when the release of payload E is desired, cleavable linkers are not generally mandatory or essential for the function of the compounds according to the invention.

[0033] The linking unit or parts thereof, in particular spacer B, may comprise or consist of a unit shown in the following table, wherein the R and R shown in the formulas n Preferably, each of R, R1, R2, and R3 is independently selected from H, halogen, substituted or unsubstituted (hetero)alkyl, (hetero)alkenyl, (hetero)alkynyl, (hetero)aryl, (hetero)arylalkyl, (hetero)cycloalkyl, (hetero)cycloalkylaryl, heterocyclylalkyl, a peptide group, an oligosaccharide group, or a steroid group. Preferably, each of R, R1, R2, and R3 is independently selected from H, OH, SH, NH2, halogen, cyano, carboxy, alkyl, cycloalkyl, aryl, and heteroaryl, each of which may be substituted or unsubstituted. Preferably, R and R3 are n Independently selected from H or C1-C7 alkyl or heteroalkyl. R and R are more suitable. n Independently selected from H, Methyl or Ethyl. Type Link structure Release mechanism Amide Proteolysis Ester hydrolysis Carbamate hydrolysis Hydrazon hydrolysis Thiazolidine hydrolysis Methylene alkoxycarbamate hydrolysis disulfide reduction

[0034] Spacer B, Unit(s) B Land / or unit(s) B S Suitable linkages include a disulfide bond as the cleavable linkage, since these linkages are stable against hydrolysis and simultaneously enable suitable drug release kinetics at the target in vivo. Furthermore, they can ensure the traceless cleavage of drug residues containing a thiol group.

[0035] Spacer B, Unit(s) B L and / or unit(s) B SThe linking unit can be polar or charged, thus improving the water solubility of the conjugate. For example, the linking unit can comprise approximately 1 to approximately 20, preferably approximately 2 to approximately 10, residues of one or more water-soluble oligomers such as peptides, oligosaccharides, glycosaminoglycans, polyacrylic acid or salts thereof, polyethylene glycol, polyhydroxyethyl(meth)acrylates, polysulfonates, etc. The linking unit can also preferably comprise a polar or charged peptide group, which may include, for example, 2 to 10 amino acid residues. Amino acids can be any natural or non-natural amino acids. The peptide linker preferably contains a free thiol group, in particular an N-terminal cysteine, to form the aforementioned cleavable disulfide bridge with a thiol group of the active ingredient. Any peptide containing L- or D-amino acids may be suitable. Particularly suitable peptide linkers of this type are Asp-Arg-Asp-Cys and / or Asp-Lys-Asp-Cys.

[0036] In these and other embodiments, the linking unit can comprise a cleavable or non-cleavable peptide unit C precisely tailored to be selectively cleaved enzymatically from the drug by one or more proteases on the cell surface or in the extracellular areas of the target tissue. The amino acid residue chain length of the peptide unit can range from a single amino acid to approximately eight amino acid residues. Numerous specific cleavable peptide sequences suitable for use in the present invention can be designed and optimized with respect to their selectivity for enzymatic cleavage by a particular tumor-associated enzyme, e.g., a protease. Cleavable peptides suitable for the present invention include those optimized for the proteases MMP-1, 2, or 3, or cathepsin B, C, or D. Peptides cleaved by cathepsin B are particularly suitable.Cathepsin B is a ubiquitous cysteine ​​protease. It is an intracellular enzyme, except under pathological conditions such as metastatic tumors or rheumatoid arthritis. An example of a peptide cleaved by cathepsin B is the sequence Val-Cit. Other examples of cleavable peptide units are Gly-Pro, Ala-Pro, Val-Pro, Arg-Pro, Ile-Pro, Pro-Pro, Gly-Cit, Ala-Cit, Val-Cit, Arg-Cit, Ile-Cit, Phe-Lys, Val-Ala, GlyGlyPheGly, AlaAlaAsn, and Pro-Cit; preferably Gly-Pro or Val-Cit.

[0037] Preferably, the cleavable linker can be one or more of i, ii, iii, iv, v, vi, vii and viii:

[0038] Preferably, the non-split linker can be one or more of ix, x, xi, xii, xiii, xiv:

[0039] In each of the above embodiments, the linking unit further comprises (one) self-degrading unit(s), which may or may not be present downstream of the (cleavable) linker C (e.g., at the C-terminus or N-terminus). The self-degrading linkers are also referred to as electronic cascade linkers. These linkers are eliminated and fragmented by enzymatic cleavage of the peptide, thereby releasing the drug in its active, preferably free, form. The conjugate is extracellularly stable as long as no enzyme capable of cleaving the linker is present. However, upon action of a suitable enzyme, the linker is cleaved, triggering a spontaneous self-degradation reaction. This leads to the cleavage of the covalent bond between the self-degrading unit and the drug, and thus to the release of the drug in its non-derivatized or pharmacologically active form.In these embodiments, the self-degrading linker is coupled to the binding unit via an enzymatically cleavable peptide sequence. This sequence serves as a substrate for an enzyme to cleave the amide bond, thus initiating the self-degradation reaction. Suitablely, the drug component is linked to the self-degrading component of the linker via a chemically reactive functional group of the drug, such as a primary or secondary amine, hydroxyl, sulfhydryl, or carboxyl group.

[0040] Examples of self-degrading linkers are PABC or PAB (para-aminobenzyloxycarbonyl), which link the drug moiety and the bonding unit of the conjugate (Carl et al. (1981) J. Med. Chem. 24: 479-480; Chakravarty et al. (1983) J. Med. Chem. 26: 638-644). The amide bond linking the carboxyl terminus of a peptide group and the para-aminobenzyl of PAB can be a substrate and cleaved by certain proteases. The aromatic amine becomes electron-donating and initiates an electronic cascade leading to displacement of the leaving group, releasing the free drug after elimination of carbon dioxide (de Groot et al. (2001) Journal of Organic Chemistry 66 (26): 8815-8830). Further self-destructing linkers are described in WO2005 / 082023.

[0041] In cases where C is a cleavable linking unit, it is particularly preferred that it comprises a cleavable peptide unit (e.g., a dipeptide unit as described above), is directly bound to a self-degrading unit D (e.g., PABC or PAB), which in turn is bound to a drug unit (e.g., a therapeutic effector, in particular: the TLR7 agonist payload unit E), as shown, for example, below: preferably or

[0042] In other embodiments, the linker comprises a glucuronyl group that can be cleaved by glucuronidase present on the cell surface or in the extracellular space of the target tissue. It has been shown that lysosomal beta-glucuronidase is released extracellularly in high local concentrations in necrotic areas of human tumors, and that this opens a pathway for targeted chemotherapy.

[0043] In all the above-mentioned embodiments, the connecting unit additionally includes a spacer unit. This spacer unit can be unit B. S The spacer unit is long enough to allow, for example, the cleavable peptide sequence to come into contact with the cleaving enzyme (e.g., cathepsin B) and preferably also to enable the hydrolysis of the amide bond that couples the cleavable peptide to the self-degrading unit D. Spacer units can, for example, comprise a divalent residue such as an alkylene, arylene, a heteroarylene, repeating units of alkyloxy (e.g., polyethyleneoxy, PEG, polymethyleneoxy) and alkylamino (e.g., polyethyleneamino), or dicarboxylic acid esters and amides such as succinate, succinamide, diglycolate, malonate, and caproamide.

[0044] In all embodiments described here, * denotes a connection point to unit A or a connection point whose shortest path to unit A may involve fewer atoms than that of •; and • denotes a connection point to unit C or a connection point to unit E whose shortest path to unit E may involve fewer atoms than that of *. The following designations all signify a connection point of a particular group or atom (e.g., R) to another unit:

[0045] As used herein, and unless otherwise indicated, the groups and fragments described here may be combined in any orientation, but the orientation shown here, to be read from left to right, is preferred, for example:

[0046] Fragment (a):Fragment (b):preferred combination of fragments (a) + (b):

[0047] If the relevant structure is a peptide mono- or oligomer, each * denotes a binding point whose shortest path to unit A involves fewer atoms than that of •; and each • denotes a binding point whose shortest path to unit C involves fewer atoms than that of *, provided that if n > 1 and is a corresponding binding point at one of R a , R b or R c If the ion is specified, it can be present independently in one or more of the peptide monomers, preferably in the one that is furthest away from the other attachment point specified in the respective structure.

[0048] In the embodiments described herein, the terms "peptide," "dipeptide," "tripeptide," "tetrapeptide," etc., refer to peptide mono- or oligomers with a backbone of proteinogenic and / or non-proteinogenic amino acids. The terms "aminoacyl" or "amino acid" generally denote proteinogenic or non-proteinogenic amino acids. Preferably, in all embodiments disclosed herein, the side chain residues of a proteinogenic or non-proteinogenic amino acid are replaced by R a , R b or R c represented, where each of these elements is selected from the following list: where each of R, R 1 , R 2 and R 3 independently selected from H, OH, SH, NH2, halogen, cyano, carboxy, alkyl, cycloalkyl, aryl and heteroaryl, each of which is substituted or unsubstituted; Each X is independently selected from NH, NR, S, O and CH2; preferably NH; and each n and m is independently an integer, preferably selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20. wherein the definition of R, R 1 , R 2 , R 3 , X, m, and n here independently of the definitions of R used elsewhere in this description 1 , R 2 and R 3 , X, m and n are.

[0049] Preferably, the side chain residues of a proteinogenic or non-proteinogenic amino acid in all embodiments disclosed herein are joined by one of R a , R b , R c , R d and R e shown, where each can be a component of a 3-, 4-, 5-, 6-, or 7-membered ring. For example, the alpha, beta, and / or gamma position of the side chain of said proteinogenic or non-proteinogenic amino acid can be a component of a cyclic structure selected from an azetidine ring, a pyrrolidine ring, and a piperidine ring, as in the following amino acids (proline and hydroxyproline): or where each can independently be a component of an unsaturated structure (i.e., where the H atom is common to the respective group R). a , R b and R c (is not available), e.g.:

[0050] The notation of peptide sequences used below refers to a sequence from the N- to the C-terminus, and the attachment of a group via a horizontal bond (here: unit C) means a covalent attachment to the peptide backbone via an amide bond to the respective terminal amino acid (here: AA3):

[0051] The notation of peptide sequences used below refers to a sequence from the N- to the C-terminus, and the attachment of a group via a vertical bond (here: unit C) means a covalent attachment to the peptide backbone via an amide bond to the respective terminal amino acid (here: AA3):

[0052] Furthermore, preferred non-proteinogenic amino acids can be selected from the following list: Payload unit E (“TLR7 agonist”)

[0053] In Formula I, E represents a TLR7 agonist unit. In the present disclosure, E can be more specifically defined in related structures, as defined in the following sections. For example, in Formula I' below:

[0054] E, designated as E', is or comprises a structure derived by removing at least one hydrogen atom or R group in the following formula wherein: Z is selected from C 2-5 -Alkynyl, C 1-5 -Alkenyl, C 1-5 -Alkyl and (C 1-2 -Alkyl) C 6-10 aryl; U is selected from O, NH, N(C 1-3 -Alkyl), S, CH2 and CH (C 1-3 -Alkyl) ; W is selected from C 1-10 -Alkyl, C 2-10 -Alkenyl, (C 2-6 - Alkyl) NHC (=O) (C 1-6 -alkyl) , (C 2-6 -Alkyl) NHC (=O) (C 1-6 -Alkyl) O, (C 2-10 -Alkyl) O, (C 2-10 -Alkenyl) O, (C 2-6 -Alkyl) O (C 2-6 -alkyl), (C 2- 6-Al kyl)O(C 2-6 -alkyl)O, (C 2-10 -Alkyl)NH, (C 2-10 -Alkenyl)NH, (C 2-6 -Alkyl) NHC (=O) (C 1-6 -alkyl) NH and (C 2-6 -Alkyl) O (C 1-6 -alkyl) NH; each optionally substituted with one or more substituents, preferably selected from C 1-3 -Alkyl and (C 1-3 -Alkyl)O. X is selected from CH, N and S; Y is selected from CH and N or is not present; R is selected from H, C 1-3 -Alkyl, C 1-3 -Haloalkyl and C 1-3 -Heteroalkyl; R 1 selected from C 1-8 -Alkyl, C 2-8 -Cycloalkyl, (C 3-6 -Cycloalkyl) C 1-3 -alkyl, C 1-7 -Heteroalkyl, C 2-7 -Cycloheteroalkyl, -C(=O)NH (C 1-3 -Alkyl), -C 1-3 -Alkyl (C=O) OMe, -C (=O) NH (C 2-8 -Cycloalkyl), (C 2-7 -Cycloheteroaryl)C 1-3 -alkyl and (C 6-10 aryl) C 1-3 -alkyl; each optionally substituted with one or more substituents, preferably selected from OH, CH3, OMe, CN, -C(=O)Me, F2CH, SO2Me and halogen.

[0055] It should be noted that N(C 1-3 -Alkyl) denotes a nitrogen atom that is bonded to two other structural elements of E' and has a C 1-3 -alkyl substituents are present. Similarly, CH(C 1-3-Alkyl) a carbon atom that is bonded to two other parts of the molecule and a C 1-3 - alkyl group as a substituent.

[0056] Surprisingly, the inventors found that the TLR7 agonists of the invention, in conjugated form (e.g., as payload E' in the conjugates of formula I'), exhibit superior efficacy, with stronger immune activation and better in vivo efficacy, e.g., compared to imidazoquinoline or purine-like reference compounds (in unconjugated and / or conjugated form), particularly with regard to tumor regression and immune cell activation.

[0057] More precisely, E can be represented as Ea and / or Ec. These variants have the same basic structure but differ in their points of connection to the other components of the conjugate. The advantageous properties described here are essentially retained. Accordingly, the compound of formula I' can be represented by one or more of the formulas Ia and Ic:

[0058] The corresponding structures of formulas Ia and Ic are described separately below, wherein each of Ea and Ec is or comprises a structure of formula Ea or Ec: wherein: In Ea and Ec Z a selected from C 2-5 -Alkynyl, C 2-5 -Alkenyl and C 2-5 -Alkyl. The remaining variables are defined as in the compound of formula I'. R is preferably H.

[0059] Preferably, the connection structure of formula I' can be represented by one or more of the formulas I-a1 and I-c1 provided below: wherein each of E-a1 and E-c1 is or comprises a structure of formula E-a1 or formula E-c1: wherein: Z a1 C3-Alkynyl is; U 1 -W 1 The selected variable is: and the remaining variables are defined as in the compound of formula I'. R is preferably H.

[0060] Preferably, the compound of formula I' can be represented by one or more of the formulas I-a1', I-a1'', I-a1''', I-c1', I-c1'' and I-c1''': wherein each of E-a1', E-a1'', E-a1''', E-c1', E-c1'' and E-c1''' is or comprises a structure of formula E-a1', E-a1'', E-a1''', E-c1', E-c1'' or E-c1''': wherein R 1 , X and Y as defined in the combination of formula I'.

[0061] In an alternative preferred embodiment, the structure of formula I' can be represented by one or more of formulas I-a2 and I-c2, wherein each of E-a2 and E-c2 is or comprises a structure of formula E-a2 or E-c2, wherein Z a2 C 4-5 -Alkyl is; U 1 -W 1 The selected variable is: and the remaining variables are defined as in the compound of formula I'. R is preferably H.

[0062] Preferably, the connection of the I' is represented by one or more of the following formulas I-a2', I-a2'', I-a2''', I-c2', I-c2'' and I-c2''': wherein each of E-a2', E-a2'', E-a2''', E-c2', E-c2'' and E-c2''' is or comprises a structure of the formula E-a2', E-a2'', E-a2''', E-c2', E-c2'' or E-c2''': wherein R 1 , X and Y as defined in the combination of formula I'.

[0063] In each embodiment of formulas I', Ia, Ic, I-a1, I-c1, I-a1', I-a1'', I-a1''', I-c1', I-c1'' and I-c1''', I-a2, I-c2, I-a2', I-a2''', I-a2''', I-c2', I-c2'' and I-c2''', X is preferably selected from CH and N and Y is preferably selected from CH and N or is not present.

[0064] The combinations of X and Y described below are particularly preferred. As noted above, these combinations are preferred and can be applied to all embodiments described above. X = CH and Y = CH, X = N and Y = CH, X = CH and Y = N, X = N and Y = N, or X = S and Y is not present.

[0065] The preferred combination is X = CH and Y = CH.

[0066] In the conjugates described herein, R 1 preferably selected from the group consisting of:

[0067] In each of the above embodiments of formulas I', Ia, Ic, I-a1, I-c1, I-a1', I-a1'', I-a1''', I-c1', I-c1'' and I-c1''', I-a2, I-c2, I-a2', I-a2''', I-c2', I-c2''' and I-c2''', c and d are preferably 1.

[0068] The present also relates to the following compound, which has a structure represented by the following formula I-MB357: wherein MB357 is a compound derived by removing at least one hydrogen atom in the following formula, or comprising it: Preferably, formula I-MB357 is represented by one or more of the following provided formulas I-(MB357') and I-(MB357''): wherein MB357' and MB357'' respectively represent a structure of the following formula MB357' or MB357'': In each of the above embodiments of formulas I-(MB357), I-(MB357') and I-(MB357''), c and d are preferably 1.

[0069] In the present disclosure, the compound of formula I' can be represented by one or more of formulas Ib and Id. These variants have the same basic structure but differ in their points of connection to the other components of the conjugate. The advantageous properties described here are essentially retained.

[0070] Accordingly, the corresponding structures of formulas Ib and Id are revealed below: wherein each of Eb and Ed is or comprises a structure of formula Eb and formula Ed: wherein Z b (C 1-2 -Alkyl)C6-aryl. The remaining variables are defined as in the compound of formula I'.

[0071] Surprisingly, the inventors found that the conjugates of formulas Ib and Id exhibited remarkably good therapeutic activity with regard to in vivo efficacy and tumor regression. In particular, better results were achieved compared to TLR7 agonists with an imidazoquinoline structure, in both conjugated and unconjugated forms. Surprisingly, the conjugates of formulas Ib and Id themselves also showed improved antitumor activity compared to the respective free drugs (unconjugated purine-like compounds), highlighting the advantage of conjugate-mediated drug release.

[0072] Preferably, the compound of formula I' is represented by one or more of the formulas I-b1 and I-d1 listed below: wherein each of E-b1 and E-d1 is or comprises a structure of formula E-b1 or E-d1: wherein Z b1 (C1-Alkyl)C6-aryl is; U 1 -W 1selected from: and where the remaining variables are defined as in the combination of formula I'.

[0073] Preferably, the combination of formula I' is represented by one or more of the formulas I-b1', I-b1'', I-b1''', I-d1', I-d1'' and I-d1''': wherein each of -b1', E-b1'', E-b1''', E-d1', E-d1'' and E-d1''' is or comprises a structure of the formula E-b1', E-b1'', E-b1''', E-d1', E-d1'' or E-d1''': wherein R 1 , X and Y as defined in the combination of formula I'.

[0074] In all the above-mentioned embodiments of formulas Ib, Id, I-b1, I-d1, I-b1', I-b1'', I-b1''', I-d1', I-d1' and I-d1''', X is preferably selected from CH and N, and Y is preferably selected from CH and N or is not present.

[0075] The following combinations of X and Y are particularly preferred. As mentioned above, these combinations are preferred and can be applied to all embodiments described above. X = CH and Y = CH, X = N and Y = CH, X = CH and Y = N, X = N and Y = N or X = S and Y is not present.

[0076] The preferred combination is X = CH and Y = CH.

[0077] In the conjugates described herein, R 1 preferably selected from the group consisting of:

[0078] In each embodiment of formulas Ib, Id, I-b1, I-d1, I-b1', I-b1'', I-b1''', I-d1', I-d1'' and I-d1'''', c and d are preferably 1. Treatment

[0079] The compounds described here can be used to treat diseases. Treatment can be therapeutic and / or prophylactic and aims to prevent, reduce, or stop undesirable physiological changes or disorders. Treatment can extend survival compared to life expectancy without treatment.

[0080] The disease treated with this compound can be any disease that could benefit from treatment. This includes chronic and acute illnesses, as well as pathological conditions that represent a predisposition for the respective disease.

[0081] The terms "cancer" and "cancerous" are used in the broadest sense and refer to the physiological condition in mammals that is typically characterized by uncontrolled cell growth. A tumor consists of one or more cancer cells.

[0082] In cancer treatment, the observed therapeutic effect may be a reduction in the number of cancer cells, a shrinking of the tumor, an inhibition or slowing of the infiltration of cancer cells into peripheral organs, an inhibition of tumor growth and / or a relief of one or more symptoms associated with the cancer.

[0083] In animal models, efficacy can be assessed by physical measurements of the tumor during treatment and / or by determining partial and complete remission of the cancer. In cancer therapy, efficacy can be measured, for example, by assessing the time to disease progression (TTP) and / or determining the response rate (RR).

[0084] Particularly preferred embodiments of the treatment methods of the present invention are described in the attached claims.

[0085] This also discloses methods for treating the human or animal body, for example, by surgical interventions or therapies performed on the human or animal body. The methods include a step of administering a therapeutically effective amount of a compound or pharmaceutical composition, as described herein, to a patient who requires it. More specifically, this discloses methods for treating, for example, by therapy or prophylaxis, a patient who suffers from or is at risk of developing a disease or disorder; or by targeted surgical interventions on a patient who suffers from or is at risk of developing a disease or disorder; methods for the targeted administration of a therapeutic agent to a patient who suffers from or is at risk of developing a disease or disorder.In the aforementioned methods, the disease or disorder in question can be independently selected from cancer, inflammation, arteriosclerosis, fibrosis, tissue remodeling, and keloid disease, with cancer preferably being selected from the group consisting of breast cancer, pancreatic cancer, small bowel cancer, colon cancer, multidrug-resistant colon cancer, rectal cancer, colorectal cancer, metastatic colorectal cancer, lung cancer, non-small cell lung cancer, head and neck tumors, ovarian cancer, hepatocellular carcinoma, esophageal cancer, hypopharyngeal cancer, nasopharyngeal cancer, laryngeal cancer, myeloma cells, bladder cancer, cholangiocarcinoma, clear cell renal cell carcinoma, neuroendocrine tumor, oncogenic osteomalacia, sarcoma, CUP (carcinoma of unknown primary site), thymic cancer, desmoid tumors, glioma, astrocytoma, cervical cancer, skin cancer, kidney cancer, and prostate cancer.When applied according to the procedures described herein, the compound remains at the site of the disease in a therapeutically relevant concentration for an extended period of time.

[0086] The present disclosure also relates to the use of the compounds described herein (conjugated and unconjugated) for the treatment of a disease, preferably cancer.

[0087] The compounds according to the invention are preferably intended for the treatment of a disease characterized by an overexpression of PSMA.

[0088] In a particular embodiment, the compounds according to the invention are intended for the treatment of cancer characterized by overexpression of PSMA; preferably, this is prostate cancer. Particularly preferably, the disease is selected from hormone-sensitive prostate cancer (HSPC), castration-resistant prostate cancer (CRPC), or metastatic prostate cancer (e.g., metastatic hormone-sensitive prostate cancer (mHSPC) or metastatic castration-resistant prostate cancer (mCRPC)). Pharmaceutical compositions

[0089] The compounds described here may be in the form of pharmaceutical compositions intended for use in humans or animals in human and veterinary medicine, and typically include one or more pharmaceutically acceptable diluents, carriers, or excipients. Acceptable carriers or diluents for therapeutic purposes are well known in pharmaceutical practice and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (AR Gennaro, ed., 1985). The choice of pharmaceutical carrier, excipient, or diluent is determined by the intended route of administration and established pharmaceutical standards. In addition to the carrier, excipient, or diluent, the pharmaceutical compositions may also contain suitable binders, lubricants, suspending agents, coating agents, and solubilizers.

[0090] Preservatives, stabilizers, colorants, and even flavorings can be added to the pharmaceutical composition. Examples of preservatives include sodium benzoate, sorbic acid, and p-hydroxybenzoic acid esters. Antioxidants and suspending agents may also be used.

[0091] The requirements for composition / formulation can vary depending on the application system. For example, the pharmaceutical composition may be formulated for use via a mini-pump or mucosally, such as a nasal spray, inhalation aerosol, or oral solution.

[0092] Alternatively, it can be administered parenterally as an injection solution, for example intravenously, intramuscularly, or subcutaneously. The formulation can also be designed for different routes of administration.

[0093] If the active ingredient is to be administered mucosally via the gastrointestinal mucosa, it must remain stable during its passage through the gastrointestinal tract. For example, it must be proteolytically resistant, stable in an acidic pH range, and resistant to the detergent effect of bile.

[0094] The pharmaceutical compositions can be administered, where appropriate, by inhalation in the form of a suppository or vaginal suppository; topically in the form of a lotion, solution, cream, ointment, or powder, or via a skin patch; orally in the form of tablets with excipients such as starch or lactose, or in capsules or ovules, either alone or in mixture with excipients; or in the form of elixirs, solutions, or suspensions with flavorings or colorings. Alternatively, the pharmaceutical compositions can be administered parenterally, for example, by intravenous, intramuscular, or subcutaneous injection. For parenteral administration, the compositions are best suited as a hydroalcoholic solution, cyclodextrins, surfactants, liposomes, or as a sterile aqueous solution, which may contain additional substances, such as sufficient salts or monosaccharides, to make the solution isotonic with blood.For buccal or sublingual application, the compositions can be administered in the form of tablets or lozenges, which can be manufactured using conventional methods.

[0095] The compound of the present invention can be administered in the form of a pharmaceutically acceptable or active salt. Pharmaceutically acceptable salts are well known to those skilled in the art and include, for example, those mentioned by Berge et al. in J. Pharm. Sci., 66, 1-19 (1977). Salts include, among others, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate salts (e.g. 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)).

[0096] The routes of administration can include, but are not limited to: oral (e.g., as a tablet, capsule, or oral solution), topical, mucosal (e.g., as a nasal spray or aerosol for inhalation), nasal, parenteral (e.g., as an injection), gastrointestinal, intraspinal, intraperitoneal, intramuscular, intravenous, intrauterine, intraocular, intradermal, intracranial, intratracheal, intravaginal, intracerebroventricular, intracerebral, subcutaneous, ophthalmic (including intravitreal or intracameral), transdermal, rectal, buccal, vaginal, epidural, and sublingual.

[0097] A doctor typically determines the most appropriate dosage for each patient. The specific dose and frequency of administration can vary for each patient and depend on a variety of factors, including the activity of the substance used, its metabolic stability and duration of action, age, body weight, general health, sex, diet, route and timing of administration, elimination rate, drug combinations, severity of the disease, and the patient's individual circumstances.

[0098] The formulations can be packaged in single-dose or multi-dose containers, such as sealed ampoules and vials, and stored freeze-dried (lyophilized). For administration, only the addition of a sterile carrier liquid, such as water, is required. Compounded solutions and suspensions are prepared from sterile powders, granules, and tablets of the type described above. Example single-dose preparations contain a daily dose or a daily sub-dose, or a corresponding proportion thereof, of the active ingredient. Definitions

[0099] Unless otherwise stated, all scientific and chemical names and technical terms used here have the same meaning as in general technical understanding. A hyphen (-; A hyphen () at the beginning or end of a chemical group serves to simplify the representation and indicates the linkage point. However, chemical groups can be represented with or without hyphens without changing their usual meaning. Unless otherwise specified, each linkage substituent includes both the forward and reverse forms. For example, C 1-2 -Alkyl-C 6-10 -aryl- both -C 6-10 -Aryl-C 1-2 -alkyl- as well as - C 1-2 -Alkyl-C 6-10 -aryl- and should describe both forms individually. The substituent can be one-sided (e.g., C). 1-2 -Alkyl or C 6-10 -Aryl-) or be bonded on both sides.

[0100] Analogue. This term encompasses all enantiomers, racemates and stereoisomers, as well as all pharmaceutically acceptable salts and hydrates of such compounds.

[0101] Unless otherwise specified, the following definitions apply to chemical terms used in connection with compounds of the invention and compositions containing these compounds.

[0102] Alkyl refers to a branched or unbranched saturated hydrocarbon radical. The alkyl group comprises 1 to 100, preferably 3 to 30, and more preferably 5 to 25 carbon atoms. Preferably, alkyl refers to methyl, ethyl, propyl, butyl, pentyl, or hexyl.

[0103] Alkenyl refers to a branched or unbranched hydrocarbon radical with one or more carbon-carbon double bonds. The alkenyl group suitably comprises 2 to 30 carbon atoms, preferably 5 to about 25 carbon atoms.

[0104] Alkynyl refers to a branched or unbranched hydrocarbon radical with one or more carbon-carbon triple bonds. The alkynyl group preferably comprises about 3 to about 30 carbon atoms, for example about 5 to about 25 carbon atoms.

[0105] Halogen refers to fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

[0106] Cycloalkyl refers to an alicyclic group with preferably 3, 4, 5, 6, 7, or 8 carbon atoms. The group can be a bridged or polycyclic ring system. More commonly, cycloalkyl groups are monocyclic. This term includes groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, bicyclo[2.2.2]octyl, and the like.

[0107] Aryl refers to an aromatic carbocyclic ring system with preferably 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 carbon atoms. Aryl can be a polycyclic ring system with two or more rings, at least one of which is aromatic. This term includes groups such as phenyl, naphthylfluorenyl, azulenyl, indenyl, anthryl, and the like.

[0108] Carbamoyl: The term "carbamoyl" here refers to a group with the formula -C(O)NH2, -NH2C(O), R m NHC (=O) Rn, C(O)NHR n .

[0109] Examples of this are: (C 2-6 -Alkyl)NHC(=O) (C 1-6 -alkyl) and (C 2-6 -Alkyl) NHC (=O). R m and R n m and n represent alkyl and alkenyl groups according to the definition above, respectively, and m and n represent the number of carbon atoms in the chain.

[0110] Carbonyl: The term "carbonyl" here refers to a -C(=O) group, which can also be written as -C(O)- or -CO-.

[0111] Amino: The term "amino" here refers to a group with the formula -NH2. The term -(C n -C m -Alkyl)NHR n denotes an amino group bonded to an alkyl group as defined above, with an additional hydrogen atom substituted by an atom or group of atoms. In the definition -(C n -C m -Alkyl)NH- (with or without a hyphen) means that both the alkyl group and the NH group are bonded to another structural element, for example in a cyclic system of the form -UW-, where -(C n -C m -Alkyl)NH represents the element W. C n -C m denotes the number of carbon atoms.

[0112] Derivative. A derivative involves the chemical modification of a compound. Examples of such modifications include replacing a hydrogen atom with a halogen group, an alkyl group, an acyl group, or an amino group, etc. The modification can strengthen or weaken one or more hydrogen bonds, charge interactions, hydrophobic interactions, van der Waals interactions, and / or dipole interactions.

[0113] Unless otherwise specified, diastereomers or diastereoisomers preferably denote stereoisomers of a compound with different configurations at one or more stereocenters in molecular parts other than the tumor-directed residue A. That is to say, unless otherwise specified, the stereochemical configuration of unit A corresponds to the configuration shown in the respective structure, and the individual diastereomers may differ in their stereochemical configuration in molecular parts other than unit A.

[0114] The prefix (hetero) indicates that one or more carbon atoms of the group may be substituted by nitrogen, oxygen, phosphorus, silicon, or sulfur. Heteroalkyl groups include, for example, alkyloxy groups and alkylthio groups. The heterocycloalkyl or heteroaryl groups contained herein may have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 ring atoms, at least one of which is selected from nitrogen, oxygen, phosphorus, silicon, or sulfur. In particular, it is a 3- to 10-membered ring or ring system, preferably a 5- or 6-membered ring, which may be saturated or unsaturated. For example, selected from oxiranyl, azirinyl, 1,2-oxathiolanyl, imidazolyl, thienyl, furyl, tetrahydrofuryl, pyranyl, thiopyranyl, thianthrenyl, isobenzofuranyl, benzofuranyl, chromenyl, 2H-pyrrolyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolidinyl, benzimidazolyl, pyrazolyl, pyrazinyl, pyrazolidinyl,Thiazolyl, Isothiazolyl, Dithiazolyl, Oxazolyl, Isoxazolyl, Pyridyl, Pyrazinyl, Pyrimidinyl, Piperidyl, Piperazinyl, Pyridazinyl, Morpholinyl, Thiomorpholinyl, insbesondere Thiomorpholino, Indolizinyl, 1,3-Dioxo-1,3-dihydro-isoindolyl, 3H-Indolyl, Indolyl, Benzimidazolyl, Cumaryl, Indazolyl, Triazolyl, Tetrazolyl, Purinyl, 4H-Quinolizinyl, Isoquinolyl, Quinolyl, Tetrahydroquinolyl, Tetrahydroisoquinolyl, Decahydroquinolyl, Octahydroisoquinolyl, Benzofuranyl, Dibenzofuranyl, Benzothiophenyl, Dibenzothiophenyl, Phthalazinyl, Naphthyridinyl, Quinoxalyl, Quinazolinyl, Quinazolinyl, Cinnolinyl, Pteridinyl, Carbazolyl, [beta]-Carbolinyl, Phenanthridinyl, Acridinyl, Perimidinyl, Phenanthrolinyl, Furazanyl, Phenazinyl, Phenothiazinyl, Phenoxazinyl, Chromenyl, Isochromanyl, Chromanyl, 3,4-Dihydro-2H-isochinolin-1-on, 3,4-Dihydro-2H-isochinolinyl und dergleichen.,

[0115] "Substituted" means that one or more, in particular up to 5, more precisely 1, 2, or 3, of the hydrogen atoms in the relevant half of the molecule are replaced independently of one another by the corresponding number of substituents. The term "optionally substituted" here encompasses both substituted and unsubstituted compounds. Naturally, the substituents are only located at chemically possible positions. A person skilled in the art can determine experimentally or theoretically, without disproportionate effort, whether a particular substitution is possible. For example, amino or hydroxyl groups with free hydrogen can be unstable if they are bonded to carbon atoms with unsaturated (e.g., olefinic) bonds.Preferably, the term "substituted" means that one or more, in particular up to 5, especially 1, 2 or 3, of the hydrogen atoms in the unit mentioned are replaced independently of one another by the corresponding number of substituents selected from OH, SH, NH2, halogen, cyano, carboxy, alkyl, cycloalkyl, aryl and heteroaryl. Furthermore, the substituents described herein can themselves be substituted by any substituents, subject to the above restriction to suitable substitutions known to those skilled in the art. Preferably, each of the above-mentioned substituents can be further substituted by any of the above-mentioned substituents, and each of these substituents can in turn be substituted by any of the above-mentioned substituents.

[0116] Preferably, the term "substituted" as used here refers to one of the above-mentioned groups (e.g., alkyl, alkylene, alkylcycloalkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, aryloxy, alkylaminyl, alkylcarbonylaminyl, alkylaminylalkyl, aminylcarbonyl, alkylaminylcarbonyl, aminylcarbonylalkyl, aminylcarbonycycloalkylalkyl, thioalkyl, aryl, aralkyl, carboxyalkyl, cyanoalkyl, cycloalkyl, cyanocycloalkyl, cycloalkylaminylcarbonyl, cycloalkylalkyl, halogenalkyl, halogenalkoxy, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl, phosphoalkoxy and / or heteroarylalkyl), wherein at least one hydrogen atom (e.g., 1, 2, 3 or all hydrogen atoms) is replaced by a bond to a non-hydrogen atom, such as a halogen.Atoms such as F, Cl, Br, and I; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, and ester groups; a sulfur atom in groups such as thiol groups, thioalkyl groups, sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; a silicon atom in groups such as trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilyl groups; and other heteroatoms in various other groups. "Substituted" also means any of the above-mentioned groups in which one or more hydrogen atoms are replaced by a higher-order bond (e.g., a double or triple bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups. and nitrogen in groups such as imines, oximes, hydrazones and nitriles.For example, “substituted” includes all the groups mentioned above in which one or more hydrogen atoms are replaced by -NR. g R h , -NR g C(=O)R h - NR g C (=O) NR g R h , -NR g C (=O) OR h , -NR g SO2R h , -OC(=O) NR g R h , -OR g , -SR g , -SOR g , -SO2R g , -OSO2R g , -SO2OR g , =NSO2R g and -SO2NR g R h , are replaced. “Substituted” also means all the above-mentioned groups in which one or more hydrogen atoms are replaced by - C(=O)R g , -C(=O)OR g , -C(=O)NR g R h , -CH2SO2R g and -CH2SO2NR g R h are replaced. The following are R g and R hEach group may be the same or different and independent of one another: hydrogen, alkyl, alkoxy, alkylaminyl, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, halogenalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl, and / or heteroarylalkyl groups. "Substituted" further means that one or more of the above-mentioned groups are replaced by a bond to an aminyl, cyano, hydroxyl, imino, nitro, oxo, thioxo, halogen, alkyl, alkoxy, alkylaminyl, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, halogenalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl, and / or heteroarylalkyl group. Furthermore, each of the aforementioned substituents can optionally be replaced by one or more of the above-mentioned substituents.

[0117] Preferably, the substituents include suitablely halogen atoms and halomethyl groups such as CF3 and CCl3; oxygen-containing groups such as oxo, hydroxy, carboxy, carboxyalkyl, alkoxy, alkoyl, alkoyloxy, aryloxy, aryloyl, and aryloyloxy groups; nitrogen-containing groups such as amino, alkylamino, dialkylamino, cyano, azide, and nitro groups; sulfur-containing groups such as thiol, alkylthiol, sulfonyl, and sulfoxide groups; heterocyclic groups, which may themselves be substituted; alkyl groups, which may themselves be substituted; and aryl groups, which may themselves be substituted, such as phenyl and substituted phenyl. Alkyl includes substituted and unsubstituted benzyl.

[0118] When two or more units are described as being "each independent" from a list of atoms or groups, this means that the units can be the same or different. The identity of each molecular component is therefore independent of the identity of the other molecular components.

[0119] Molecular weight. This term refers to the mass of a molecule and is given here as "weight-average molecular weight" or Mw. In the present disclosure, the molecular weight can be determined by mass spectrometry, preferably with an ESI quadrupole or Orbitrap mass spectrometer, and particularly preferably with an Agilent 6100 Series Single Quadrupole MS instrument.

[0120] Specific binding. Unless otherwise stated, "specific binding" refers to a higher binding affinity (Kd) to a particular target molecule or antigen compared to binding to other proteins in mammals, preferably humans.

[0121] The term "pharmaceutically acceptable" refers to compounds and materials that are generally safe, non-toxic, and neither biologically nor otherwise undesirable. It also includes those approved for both veterinary and human medicine.

[0122] The terms “subject”, “patient” or “recipient” are used synonymously and refer to mammals, preferably humans.

[0123] The term "therapeutically effective amount" refers to the amount of an active substance or drug that produces the desired biological or medical response in a tissue, system, animal, individual or human.

[0124] In this document, the term "treatment" refers to the inhibition of the disease, condition, or disorder in an individual exhibiting the pathology or symptomatology of the disease, condition, or disorder, and / or the alleviation of the disease. For example, this includes the relief of a disease, condition, or disorder in a person experiencing or exhibiting the pathology or symptomatology of the disease, condition, or disorder (i.e., the reversal of the pathology and / or symptomatology), such as reducing the severity of the disease. EXAMPLES

[0125] Example 1: Synthesis of the compounds Synthesis of Compound 1

[0126] Borane-tetrahydrofuran complex was added dropwise to a solution of 3-hydroxy-4-iodobenzoic acid in THF at 0 °C under a nitrogen atmosphere. The mixture was stirred at 25 °C for 16 h. The reaction was carefully quenched with MeOH and diluted with saturated NaHCO3, and EtOAc was extracted. The organic phases were combined and washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by direct liquid chromatography (petroleum ether / EtOAc) to obtain compound 1. Synthesis of Compound 2

[0127] Tert-butylcyclobutylcarbamate was dissolved in DMF under nitrogen, and the mixture was cooled to 0 °C. NaH was added in portions, and the mixture was stirred at 0 °C. After 30 minutes, propargyl bromide was added dropwise. The mixture was stirred at 25 °C for 3 hours. The reaction was quenched with saturated NH₄Cl and extracted with EtOAc. The organic phases were combined and washed with brine, dried over Na₂SO₄, and dried under vacuum. The residue was purified by direct liquid chromatography (petroleum ether / EtOAc) to obtain compound 2. Synthesis of Compound 3

[0128] To a solution of 4,6-dichloro-2-(methylthio)-5-nitropyrimidine and TEA in dioxane, NH3 in dioxane was added dropwise at -20 °C under nitrogen. The mixture was stirred at 0 °C for 16 hours. The reaction was concentrated under vacuum, and the residue was diluted with water and extracted with EtOAc. The organic phases were combined and dried over Na2SO4 under vacuum to give compound 3. Synthesis of Compound 4

[0129] Compound 3 and TEA were dissolved in THF, and ethyl chloroformate was added dropwise at 0 °C under nitrogen. The mixture was stirred at 25 °C for 16 hours. The reaction was quenched with water and extracted with EtOAc. The organic phases were combined and dried over Na₂SO₄, concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether / EtOAc) to obtain compound 4. Synthesis of Compound 5

[0130] Compounds 4 and 1 were dissolved in THF, followed by the dropwise addition of PPh3 and DIAD at 0 °C under a nitrogen atmosphere. The mixture was stirred at 25 °C for 6 hours. The reaction was quenched with water and extracted with EtOAc. The organic phases were combined and dried over Na2SO4, concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether / EtOAc) to obtain compound 5. Synthesis of Compound 6

[0131] Compound 5 was solubilized in THF and NH3·H2O was added. The mixture was stirred at 25 °C for 6 hours. The reaction material was purified by silica gel chromatography (petroleum ether / EtOAc) to obtain compound 5. Compound 6. Synthesis of Compound 7

[0132] Cs₂CO₃ and allyl bromide were added to a solution of compound 6 in DMF. The mixture was stirred at 25 °C for 16 hours. The reaction was quenched with water (and extracted with EtOAc). The organic phases were combined and washed with brine, dried over Na₂SO₄, and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether / EtOAc) to obtain compound 7. Synthesis of Compound 8

[0133] m-CPBA was added to a solution of compound 7 in DCM, and the mixture was stirred at 25 °C for 16 hours. The reaction was quenched with saturated sodium thiosulfate and extracted with DCM. The organic phases were combined and washed with brine, dried over Na₂SO₄, and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether / EtOAc) to obtain compound 8. Synthesis of Compound 9

[0134] TEA was added to a solution of compound 8 in allyl alcohol, and the reaction was stirred at 25 °C for 16 hours. The mixture was quenched with water and extracted with EtOAc. The organic phases were combined and washed with brine, dried over Na₂SO₄, and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether / EtOAc) to obtain compound 9. Synthesis of Compound 10

[0135] Hoveyda-Grubbs catalyst (II) was added to a solution of compound 9 in DCE, and the mixture was stirred at 80 °C for 4 hours. Imidazole was added to the remaining stirred mixture at 80 °C for an additional hour. The mixture was cooled to room temperature and washed with HCl and brine. The organic phase was pressed over Na₂SO₄ and dried under vacuum. The residue was purified by column chromatography (petroleum ether / EtOAc) to obtain compound 10. Synthesis of Compound 11

[0136] Tris(triphenylphosphine)rhodium(I) chloride was added to a solution of compound 10 in THF and MeOH, and the mixture was stirred at 40 °C for 16 hours under H₂ (0.35 MPa). After this time, the mixture was diluted with water and extracted with EtOAc. The organic phases were combined and washed with brine, dried over Na₂SO₄, and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether / EtOAc) to obtain compound 10. Synthesis of Compound 12

[0137] Compound 11 in DMF was treated with CuI, TEA, Pd(dppf)Cl₂, and Compound 2. The mixture was stirred under nitrogen at 50 °C for 16 hours. The mixture was then filtered, and the filtrate was quenched with water and extracted with EtOAc. The organic phases were combined and washed with brine, dried over Na₂SO₄, and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether / EtOAc) to obtain Compound 12. Synthesis of MB357

[0138] Iron was added to a solution of Intermediate 12 in AcOH and water. The mixture was stirred at 100 °C for 16 hours and then concentrated under vacuum. The residue was purified by reverse phae column chromatography followed by prep-HPLC to obtain MB357. Synthesis of compounds 14-16

[0139] Compounds 14, 15 and 16 were prepared as previously described by Millul et al (Millul et al., PNAS, 2021, 118 (16) e2101852118) and Bocci et al (Bocci et al., JCR, 2024, 367, 779-790). Synthesis of Compound 17

[0140] MB357 was dissolved in DMF and compound 16, HOAt, and DIPEA were added. The mixture was stirred for 3 hours at room temperature, and the crude material was purified by RP-HPLC to obtain compound 17. Synthesis of OncoPSMA-GlyPro-MB357 (compound 23)

[0141] NaHCO3 and compound 17 were added to a solution of OncoPSMA-SH (which can be prepared as described by Georgiev et al., Mol Cancer Ther, 2025) in PBS / DMF 1:1. The mixture was stirred at room temperature for 30 minutes, followed by RP-HPLC purification to obtain the target compound. Example 2: In vitro activation of human TLR7 and murine TLR7 expressed on NF-xB-SEAP reporter HEK293 cells

[0142] NF-κB-SEAP reporter HEK293 cells expressing human or murine TLR7 were cultured in 96-well plates at a cell density of 200,000 cells / ml (200 µl / well) for 24 hours at 37 °C. After 24 hours, the medium was removed from the wells and replaced with 200 µl of medium containing dilution series of MB357, A78, or resiquimod.

[0143] After a 24-hour incubation, 20 µl of the cell culture supernatant was withdrawn from each well and transferred to a new 96-well plate. Each well was treated with 200 µl of QUANTI-Blue solution and incubated for 30 minutes at 37 °C. The optical density was measured using a plate reader at an absorbance of 655 nm. EC50 values ​​were determined by fitting the data to the four-parameter logistic equation using Prism 9 software (GraphPad Software) for data analysis.

[0144] The activity of MB357 on TLR7 was measured in two different HEK293 cell lines expressing the human and murine isoforms of the receptor, respectively, and compared to reference substances based on an imidazoquinoliamine scaffold: resiquimod (1-(4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol or R848) or A78 (1-(4-(aminomethyl)benzyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine) or compound 7d (US 8,728,486 B2)). The results were obtained in Fig.The data shown in section 1 represent the EC 50 for each compound on HEK cells expressing hTLR7 or mTLR7. MB357 showed beneficial activity on both isoforms with an EC10. 50 in the single-digit nanomolar range (2.4 and 8.8 nM for human and murine TLR7, respectively). Example 3: Expression of cytokines after incubation with TLR agonists. Quantification of cytokines released by human peripheral blood mononuclear cells (PBMCs).

[0145] Humane PBMCs were isolated in a 96-well plate with a density of 2.5 × 10 5Cells per well were seeded in 100 µL of medium (RPMI supplemented with 10% FBS, 1% penicillin / streptomycin). Subsequently, 100 µL of medium containing dilution series of MB357 or A78 was added. The cells were incubated for 24 hours at 37 °C in a humidified incubator with 5% CO2. The cell culture supernatants were collected, and the concentrations of the cytokines hIL-6 and hTNF-α were determined using commercially available ELISA kits.

[0146] After incubation, the media were collected and the cytokines were measured using ELISA. The data in Fig. Figure 2 shows that MB357 was able to stimulate the expression and release of hIL-6 (A) and hTNF-α (B) even at very low concentrations and exhibited higher efficacy than A78. This suggests superior in vivo activity of MB357. Quantification of cytokines released by murine bone marrow-derived dendritic cells (BMDCs) and murine splenocytes

[0147] To obtain bone marrow, naïve Balb / C mice were euthanized, and both tibiae and both femora were removed. The bones were sectioned and rinsed with sterile PBS to extract the marrow. The cells were seeded in a 6-well plate, and their differentiation into dendritic cells was promoted by adding 20 ng / ml GM-CSF every other day for 6 days. The cells were harvested and stimulated for 24 hours with dilution series of MB357 or A78.

[0148] Splenocytes were obtained from the spleen of naïve Balb / C mice. The mice were euthanized, the spleen removed, and homogenized through a 70-µm cell sieve to obtain the splenocytes. The cells were counted and treated with dilution series of the substances for 24 hours. The supernatants of the splenocytes and dendritic cells were collected, and the concentrations of the cytokines mIL-6 and mTNF-α were determined using commercially available ELISA kits (Biolegend).

[0149] As in Fig. As shown in Figures 3A and B, MB357 demonstrated the ability to promote the release of cytokines (mIL6 and mTNFα) from bone marrow-derived dendritic cells (BMDCs) at least as well as, or better than, A78. As shown in Fig. As shown, MB357 was a significantly more potent agonist in stimulating cytokine expression and release from splenocytes than A78. Example 4: Activation of murine bone marrow-derived dendritic cells (BMDCs) and splenocytes after incubation with TLR agonists, measured by flow cytometry.

[0150] Bone marrow dendritic cells (BMDCs) and splenocytes were obtained as described in Example 3. The cells were incubated for 24 hours at 37 °C in a humidified incubator with 5% CO2 using compounds MB357, A78, or IIb-19 (compound IIb-19 from WO2019 / 209811A1). The medium was then removed, and the cells were washed twice with PBS. After washing, the cells were incubated for 30 minutes with fluorophore-labeled antibodies (APC-Cy7-αI-A / IE, PE-αCD40, FITC-αCD86, Alexa647-αCD11c for BMDCs, Alexa647-αB220 for splenocytes). The cells were then washed again with PBS and analyzed by flow cytometry (CytoFLEX S). CD11c-positive and IA / IE-positive cells were identified as dendritic cells and antigen-presenting cells (APCs), respectively. B220-positive cells were defined as B cells. CD86 and CD40 expression levels were expressed as relative MFI values.

[0151] As in Fig.As shown in Figures 4A, B and D, MB357 was able to induce the upregulation of CD86 in dendritic cells. As shown in FIG. 4C, MB357 was able to induce the upregulation of CD86 in dendritic cells (CD11c-positive) at lower concentrations than IIb-19. Example 5: In vivo therapy experiments Materials and methods

[0152] MC-38.hPSMA cells were cultured in DMEM with 10% fetal bovine serum (FBS) and 1% antibiotic-antifungal until 95% confluence was achieved and detached with 0.05% trypsin-EDTA (ethylenediaminetetraacetic acid). The tumor cells were resuspended in Hanks' balanced salt solution. Aliquots of 2 million cells (100 µL suspension) of the MC-38.hPSMA cell line were injected subcutaneously into the right flank of immunocompetent female C57BL / 6 mice (6–8 weeks old). Once the tumors reached an average volume of 100 ± 20 mm³, 3Once the mice had reached the target level, they were randomly assigned to groups (n = 4 or 5) and injected intravenously with the substances.

[0153] In Fig. Five animals were administered intravenously with OncoPSMA-GlyPro-MB357 and free MB357 at a dose of 250 nmol / kg over five doses at two-day intervals (black arrows). Changes in body weight and tumor volume were measured and recorded. Tumor dimensions were determined using electronic calipers, and tumor volume was calculated using the formula (long side, mm) × (short side, mm) × (short side, mm) × 0.5. Animals were euthanized as soon as one or more of the termination criteria specified in the study authorization were met. Data analysis was performed using Prism 9 software (GraphPad software). Results

[0154] Fig.Figure 5 shows the antitumor activity of the PSMA-targeting OncoPSMA-GlyPro-MB357 conjugate. C57BL / 6 mice injected with PSMA-positive tumor cells were administered either the conjugate or the free payload (MB357). OncoPSMA-GlyPro-MB357 showed better tumor growth control compared to MB357 alone, highlighting the positive effect of OncoPSMA-mediated drug release (A). No toxicity was observed with either substance, as demonstrated by the body weight change curves (B).

[0155] The present invention further provides the following embodiments. 1. Compound having the following structure: or a pharmaceutically acceptable salt, solvate, hydrate, crystalline form, tautomer or diastereomer thereof, wherein: A is a PSMA-binding unit; B is a spacer; C is a splittable or non-splittable left; D is a self-destructing spacer; E is a TLR7 agonist unit; and c and d may each be 0 or an integer of 1 or more; preferably 0, 1, 2 or 3; wherein each occurrence of B, C and D may optionally be in any order. 2. Compound according to embodiment 1, wherein the compound structure is represented by the following formula I': wherein E' is a structure that is formed by removing at least one hydrogen atom or one R group in the following general formula, or comprises: wherein: Z is selected from C 2-5 -Alkynyl, C 1-5 -Alkenyl, C 1-5 -Alkyl and (C 1-2 -Alkyl) C 6-10 -aryl; U is selected from O, NH, N(C 1-3 -Alkyl), S, CH2 and CH (C 1-3 -Alkyl) ; W is selected from C 1-10 -Alkyl, C 2-10 -Alkenyl, (C 2-6 -Alkyl) NHC (=O) (C 1-6 -alkyl), (C 2-6-Alkyl) NHC (=O) (C 1-6 -alkyl) O, (C 2-10 -Alkyl) O, (C 2-10 -Alkenyl) O, (C 2-6 -Alkyl) O (C 2-6 -alkyl), (C 26 -Alkyl) O (C2-6-alkyl) O, (C 2-10 -Alkyl) NH, (C 2-10 -Alkenyl) NH, (C 2-6 -Alkyl) NHC (=O) (C 1-6 -alkyl) NH and (C 2-6 -Alkyl) O (C 2-6 -alkyl) NH; each optionally substituted with one or more substituents, preferably selected from C 1-3 -Alkyl and (C 1-3 -Alkyl) O; X is selected from CH, N and S; Y is selected from CH and N or is not present; R is selected from H, C 1-3 -Alkyl, C 1-3 -Haloalkyl and C 1-3 -Heteroalkyl; R 1 selected from C 1-8 -Alkyl, C 2-8 -Cycloalkyl, (C 3-6 -Cycloalkyl) C 1-3 -alkyl, C 1-7 -Heteroalkyl, C 2-7 -Cycloheteroalkyl, -C(=O)NH (C1-3 -alkyl), -C 1-3 -alkyl (C=O) OMe, -C (=O) NH (C 2-8 -Cycloalkyl), (C 2-7 -Cycloheteroaryl) C 1-3 -alkyl and (C 6-10 -Aryl) C 1-3 -alkyl; each optionally substituted with one or more substituents, preferably selected from OH, CH3, OMe, CN, -C(=O)Me, F2CH, SO2Me and halogen. 3. Connection according to embodiment 2, wherein the connection structure is represented by one or more of formulas Ia and Ic: wherein each of Ea and Ec is or comprises a structure of formula Ea or Ec: wherein Z a selected from C 2-5 -Alkynyl, C 2-5 -Alkenyl and C 2-5 -Alkyl. 4. Connection according to embodiment 2 or 3, wherein the connection structure is represented by one or more of formulas I-a1 and I-c1: wherein each of Ea1 and E-c1 is or comprises a structure of formula E-a1 or E-c1: wherein Z a1 C3-Alkynyl is; U 1 -W 1selected from: and 5. Compound according to any one of the preceding claims, wherein the compound structure is represented by one or more of the formulas I-a1', I-a1'', I-a1''', I-c1', I-c1'', and I-c1''': wherein each of E-a1', E-a1'', E-a1'', E-c1', E-c1'' and E-c1''' is or comprises a structure of the formula E-a1', E-a1', E-a1''', E-c1', E-c1'' or E-c1''': 6. Connection according to embodiments 1 to 3, wherein the connection structure is represented by one of formulas I-a2 and I-c2: wherein each of E-a2 and E-c2 is or comprises a structure of formula E-a2 or E-c2: wherein Z a2 C 4-5 -Alkyl is; U 1 -W 1 Selected from: 7. Connection according to embodiment 6, wherein the connection structure is represented by one or more of the formulas I-a2', I-a2'', I-a2''', I-c2', I-c2'' and I-c2''': wherein each of E-a2', E-a2'', E-a2''', E-c2', E-c2'' and E-c2''' is or comprises a structure of the formula E-a2', E-a2'', E-a2''', E-c2', E-c2'' or E-c2''': 8. Compound according to one of the preceding embodiments, wherein: X = CH and Y = CH, X = N and Y = CH, X = CH and Y = N, X = N and Y = N or X = S and Y is not present. 9. Compound according to one of the preceding embodiments, wherein: R 1 The selected item is from the group consisting of: 10. Compound according to any one of embodiments 1 to 9, comprising a compound represented by the following formula: wherein MB357 is or comprises a structure derived by removing at least one H atom in the following formula: 11. Connection according to embodiment 10, wherein the connection structure is represented by one or more of the formulas I-(MB357') and I-(MB357''): wherein each of MB357' and MB357'' represents a structure of the following formula MB357' or MB357'': 12. Connection according to embodiment 2, wherein the connection structure is represented by one or more of formulas Ib and Id: wherein each of Eb and Ed is or comprises a structure of formula Eb or Ed: wherein Z b (C 1-2 -Alkyl) C6-aryl is. 13. Connection according to embodiment 12, wherein the connection structure is represented by one or more of formulas I-b1 and I-d1: wherein each of E-b1 and E-d1 is or comprises a structure of formula E-b1 or E-d1: wherein Z b1 (C1-alkyl) C6-aryl is; U 1 -W 1 selected from: and 14. Connection according to embodiment 13, wherein the connection structure is represented by one or more of the formulas I-b1', I-b1'', I-b1''', I-d1', I-d1'' and I-d1''': wherein each of E-b1', E-b1'', E-b1''', E-d1', E-d1'' and E-d1''' is or comprises a structure of the formula E-b1', E-b1'', E-b1''', E-d1', E-d1'' or E-d1''': 15. Connection according to one of embodiments 12-14, wherein X and Y are defined as in embodiment 8. 16. Compound according to one of embodiments 12-14, wherein R 1 as defined in embodiment 9. 17. A connection according to one of the preceding embodiments, comprising a structure selected from: and 18. Compound according to one of the preceding embodiments, wherein A is a small molecular unit having a molecular weight of 3000 Da or less, preferably 2500 Da or less, more preferably 2000 Da or less, and more preferably 250 to 2000 Da. 19. Compound according to one of embodiments 1-18, wherein A is a PSMA bonding unit. 20. Compound according to one of embodiments 1-18, wherein A is a PSMA bonding unit comprising the following structure: 21. Compound according to one of embodiments 1-18, wherein A is a PSMA bonding unit having the following structure: 22. Compound according to one of the preceding embodiments, wherein B is: (a) a single bond or a possibly substituted C 1-50 -aliphatic group in which one or more carbon atoms may be replaced by a heteroatom, a C 3-12 -carbocyclic or a C 1-12 heterocyclic group, and which contains saturated or optionally one or more double or triple bonds; (b) represented by one of the following general formulas III-VI: wherein Each x is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; Each y is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; each z is 0, 1, 2, 3 or 4; preferably 1; preferably with the proviso that at least one of x and y is not 0; * a link point to a unit R 1 -Y- or R 1 represents; • represents a link point to a unit C; and each of B S and B L independently selected from alkylenes, Cycloalkylenes, arylalkylenes, heteroarylalkylenes, heteroalkylenes, heterocycloalkylenes, alkenylenes, cycloalkenylenes, arylalkenylenes, heteroarylalkenylenes, heteroalkenylenes, heterocycloalkenylenes, alkynylenes, heteroalkynylenes, arylenes, heteroarylenes, aminoacyl, oxyalkylenes, aminoalkylenes, diacid esters, dialkylsiloxane, amide, thioamide, thioether, thioester, ester, carbamate, hydrazone, thiazolidine, methylenealkoxycarbamate, disulfide, vinylene, imine, imidamide, phosphoramide, saccharide, phosphate ester, phosphoramide, carbamate, dipeptide, tripeptide, tetrapeptide, each optionally substituted; or (c) represented by (B S ) x , in which: Each x selected is from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; each B Sindependently selected from the group consisting of alkylene, cycloalkylene, arylalkylene, heteroarylalkylene, heteroalkylene, heterocycloalkylene, alkenylene, cycloalkenylene, arylalkenylene, heteroarylalkenylene, heteroalkenylene, heterocycloalkenylene, alkynylene, heteroalkynylene, arylene, heteroarylene, aminoacyl, oxyalkylene, aminoalkylene, diacid ester, dialkylsiloxane, amide, thioamide, thioether, thioester, ester, carbamate, hydrazone, thiazolidine, methylenealkoxycarbamate, disulfide, vinylene, imine, imidamide, phosphoramide, saccharide, phosphate ester, phosphoramide, carbamate, dipeptide, tripeptide, tetrapeptide. (d) as defined in (b) or (c), wherein each B S and B L independently selected is from: where, in each of the above structures: each n is independently 0, 1, 2, 3, 4, 5, 6, 7 or 8; Each m is independently 0, 1, 2, 3 or 4; each R c , R d and R eindependently selected from H, possibly substituted C 1-6 -Alkyl, (C 3-10 -Carbocyclyl) C 1-6 -alkyl, (C 6-10 Aryl) C 1-6 -alkyl, (C 1-10 -Heterocyclyl) C 1-6 -Alkyl, C 2-6 -Alkenyl, C 2-6 -Alkynyl and C 6-10 -Aryl, wherein one or more carbon atoms in each may optionally be replaced by heteroatoms; preferably selected from side chain residues of proteinogenic or non-proteinogenic amino acids; Each occurrence of R and R' is independent of H or selected from C 1-6 -Alkyl, O (C 1-6 -Alkyl), S (C 1-6 -Acyl), C 3-10 -Cycloalkyl, O (C 3-10 -Cycloalkyl), S (C 3-10 -Cycloalkyl), C 2-6 -Alkenyl, C 2-6 -Alkynyl, C 1-6 -Heteroalkenyl, C 1-6 -Heteroalkynyl, C 3-10 -Cycloalkenyl, C 1-10 -Cycloheteroalkenyl, C 6-10 -Aryl, C 1-10 -Heteroaryl, (C 6-10 -Aryl) C 1-6-alkyl and (C 1-10 -Heteroaryl) C 1-6 alkyl, each optionally being substituted with 1 to 3 substituents, selected from C 1-6 -Alkyl, OH, oxo and halogen, or consisting of OH, oxo and halogen; Each * denotes a connection point for which the shortest path to a unit R 1 -Y- or R 1 - comprises fewer atoms than the one for •; and each • denotes a connection point for which the shortest path to a unit C comprises fewer atoms than the one for *, provided that if n > 1 and a corresponding connection point exists on one of the elements R c , R d or R e As specified, it can be present independently in one or more of the peptide monomer units; preferably in the one in which Peptide monomer unit that is furthest away from the other attachment point specified in the respective structure. (e) represented by a structure selected from: single bond, (B S ) x , Each n is independently 0, 1, 2, 3, 4, 5, 6, 7 or 8; Each m is independently 0, 1, 2, 3 or 4; each R c , R d and R e independently selected from H, possibly substituted C 1-6 -Alkyl, (C 3-10 -Carbocyclyl) C 1-6 -alkyl, (C 6-10 Aryl) C 1-6 -alkyl, (C 1-10 -Heterocyclyl) C 1-6 -Alkyl, C 2-6 -Alkenyl, C 2-6 -Alkynyl and C 6-10 -Aryl, wherein one or more carbon atoms in each may optionally be replaced by heteroatoms; preferably selected from side chain residues of proteinogenic or non-proteinogenic amino acids; Each occurrence of R and R' is independent of H or selected from C 1-6 -Alkyl, O(C 1-6 -Alkyl), S(C 1-6 -Acyl), C 3-10 -Cycloalkyl, O (C 3-10-Cycloalkyl), S (C 3-10 -Cycloalkyl), C 2-6 -Alkenyl, C 2-6 -Alkynyl, C 1-6 -Heteroalkenyl, C 1-6 -Heteroalkynyl, C 3-10 -Cycloalkenyl, C 1-10 -Cycloheteroalkenyl, C 6-10 -Aryl, C 1-10 -Heteroaryl, (C 6-10 -Aryl) C 1-6 -alkyl and (C 1-10 -Heteroaryl) C 1-6 alkyl, each optionally being substituted with 1 to 3 substituents, selected from C 1-6 -Alkyl, OH, oxo and halogen, or consisting of OH, oxo and halogen; wherein each of AA3, AA4, AA5, AA6, AA7 and AA8 is a proteinogenic or non-proteinogenic amino acid or is absent; preferably: Each proteinogenic or non-proteinogenic amino acid is preferably represented independently by one of the following structures: or and / or AA4 is an amino acid with a charged side chain and AA7 is an amino acid with an aliphatic side chain; in which preferred: AA3 is selected from Asp, Glu and Lys or is not present; preferably Asp; AA4 is selected from Arg, HomoArg, Lys, Asp and Glu or is not present; preferably Lys or Arg; AA5 is selected from Asp, Glu and Lys; preferably Asp; AA6 is selected from Cys, Lys, Gly and Val; preferably Cys or Lys; AA7 is selected from Gly, Ala, Val, Arg, Ile, Pro; preferably Gly or Val; and AA8 is selected from Pro and Citrulline (Cit); preferably Pro; even more preferably according to one of the sequences shown in the table below: 23. Compound according to one of the preceding embodiments, wherein B is selected from: a. a bond b. Asp-Lys-Asp-Cys-MaleimidoCaproyl c. Asp-Arg-Asp-Lys-Succinic 24. Compound according to one of the preceding embodiments, wherein one or more C are independent: a. a splittable left, selected from: b. a non-cleavable linker selected from: ix.n = 1 to 8, preferably 2 to 6 x. PEG:n = 1 to 12, preferably 2 to 10, more preferably 2 to 8 xi.n = 1 to 8, preferably 2 to 6 xii. MC (Maleimidocaproyl): xiii. MCC (Maleimidomethylcyclohexane-1-carboxylate): 14. MC-like: 25. Compound according to one of the preceding embodiments, wherein one or more D are self-destructive spacers, independently selected from: 26. Compound according to one of the preceding embodiments, wherein the fragment -BCD has one of the following structures, wherein all variables are defined as above: and preferably 27. A connection according to one of the preceding embodiments, comprising a structure selected from: and 28. Compound according to one of the preceding embodiments for use in the treatment of a disease. 29. Compound according to one of embodiments 1-27 for use in the treatment of a disease characterized by overexpression of PSMA. 30. Compound for use according to embodiment 28 or 29, wherein the disease is cancer. 31. Compound for use according to embodiment 30, wherein the cancer is characterized by PSMA overexpression; preferably prostate cancer; more preferably a cancer selected from hormone-sensitive prostate cancer (HSPC), castration-resistant prostate cancer (CRPC) or metastatic prostate cancer (i.e., metastatic hormone-sensitive prostate cancer (mHSPC) or metastatic castration-resistant prostate cancer (mCRPC)). QUOTES INCLUDED IN THE DESCRIPTION

[0000] This list of documents cited by the applicant was automatically generated and is included solely for the reader's convenience. The list is not part of the German patent or utility model application. The DPMA accepts no liability for any errors or omissions. Cited patent literature

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[0141]

Claims

[1] Compound having a structure represented by one or more of the formulas I-a1 and I-c1: or a pharmaceutically acceptable salt, solvate, hydrate, crystal form, tautomer or diastereomer thereof, wherein: A is a tumor-directed unit with a molecular weight of 3000 Da or less and is a PSMA-binding unit; B is a spacer; C is a splittable or non-splittable left; D is a self-destructing spacer; c and d can each be 0 or an integer of 1 or more; preferably 0, 1, 2 or 3; wherein each occurrence of B, C and D may be in any order; and wherein each of E-a1 and E-c1 is a TLR7 agonist unit which is a structure of the formula E-a1 or E-c1 respectively. This includes: where Z a1 C3-Alkynyl is; U 1 -W 1selected from: and R is selected from H, C 1-3 -Alkyl, C 1-3 -Haloalkyl and C 1-3 -Heteroalkyl; and R 1 selected from C 1-8 -Alkyl, C 2-8 -Cycloalkyl, (C 3-6 -Cycloalkyl) C 1-3 -alkyl, C 1-7 -Heteroalkyl, C 2-7 -Cycloheteroalkyl, -C (=O) NH (C 1-3 -alkyl), -C 1-3 -Alkyl (C=O) OME, -C(=O)NH (C 2-8 -Cycloalkyl), (C 2-7 -Cycloheteroaryl) C 1-3 -alkyl and (C 6-10 -Aryl) C 1-3 -alkyl; each optionally substituted with one or more substituents, preferably selected from OH, CH3, OMe, CN, -C(=O)Me, F2CH, SO2Me and halogen. [2] Compound according to claim 1, wherein the compound structure is represented by one or more of the formulas I-a1', I-a1'', I-a1''', I-c1', I-c1'' and I-c1''': wherein each of E-a1', E-a1'', E-a1''', E-c1', E-c1'' and E-c1''' is a structure of the formula E-a1', E-a1'', E-a1''', E-c1', E-c1'' or E-c1''': [3] Compound according to any one of the preceding claims, wherein: X = CH and Y = CH, or X = N and Y = CH, or X = CH and Y = N, or X = N and Y = N, or X = S and Y is not present; and R 1 The selected item is from the group consisting of: [4] Compound according to any one of claims 1 to 3, comprising a structure represented by the following formula: wherein MB357 is a structure derived by removing at least one H atom in the following formula, or comprising: [5] Compound according to any one of the preceding claims, wherein A is a PSMA-bonding unit comprising the structure: [6] Compound according to any one of the preceding claims, wherein B is: a. a single bond or a possibly substituted C 1-50 -aliphatic group in which one or more carbon atoms may be replaced by a heteroatom, a C 3-12 carbocyclic or a C 1-12 -heterocyclic group, and which may be saturated or may contain one or more double or triple bonds; or [7] Compound according to any of the preceding claims, wherein one or more C are independent: a. a splittable left, selected from: and b. a non-splittable left, selected from: and [8] Compound according to any one of the preceding claims, wherein one or more D are self-dissolving spacers, independently selected from: and [9] Compound according to any one of the preceding claims, comprising a structure selected from: and

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