Carbonic anhydrase IX ligands for targeted delivery applications

Abstract

The present invention relates to protein ligands directed against carbonic anhydrase IX (CAIX) as a target with biomedical relevance. In particular, highly specific ligands are capable of interacting exclusively with antigens expressed on the surface of tumor cells (i.e., CAIX) without affecting healthy organs expressing anti-targets, thereby enabling efficient in vivo drug delivery applications. The ligands may exhibit a particularly low dissociation constant and / or enzyme isoform specificity, and may be useful for targeted delivery of payloads, such as therapeutic and / or diagnostic agents, to sites suffering from or at risk of a disease or disorder characterized by expression of CAIX.

Description

Technical Field

[0001] The present invention relates to protein ligands for carbonic anhydrase IX (CAIX) as a biomedically relevant target. In particular, highly specific ligands are capable of interacting exclusively with the antigen (i.e., CAIX) expressed on the surface of tumor cells without affecting healthy organs expressing the anti-target, thereby enabling efficient in vivo drug delivery applications. The ligands may exhibit particularly low dissociation constants and / or enzyme isoform specificity and may be suitable for targeted delivery of payloads such as therapeutic and / or diagnostic agents to sites affected by or at risk of diseases or disorders characterized by the expression of CAIX. Background Art

[0002] Carbonic anhydrase IX (CAIX) is a zinc metalloenzyme for which 15 isoenzymes have been reported in the human body and is mainly involved in maintaining cellular homeostasis and carbon dioxide transport [1-2] . CAIX is expressed at low levels in healthy tissues (gastrointestinal tract, liver, and gallbladder), while higher expression has been observed in a variety of solid tumors [2-3] . In particular, CAIX is the most effective marker for renal cell carcinoma (RCC) and hypoxia, thus providing an attractive target for diagnostic and therapeutic methods [4-5] .

[0003] In several clinical trials, the use of CAIX-targeted antibodies (i.e., Girentuximab) conjugated with radionuclides has been investigated for the diagnosis of breast cancer (www.clinicaltrials.gov identifier: NCT04758780), urothelial cancer (NCT05046665), renal cell carcinoma (NCT02883153, NCT02497599, NCT03849118), and in combination with nivolumab for the treatment of renal cancer (NCT05239533). The low permeability of solid tumors remains a major limiting factor for antibody-based diagnostics and therapies [6] . Cazzamalli and colleagues have demonstrated that small organic ligands extravasate more rapidly compared to antibodies, highlighting the suitability of small molecules for targeted inhibition or delivery methods [7] .

[0004] Several small molecule CAIX ligands have been clinically developed as imaging or therapeutic agents (monotherapy or in combination with other treatment modalities) for various types of malignancies. For example, acetazolamide has been tested in combination with platinum (for locally advanced small cell lung cancer (NCT03467360)) and in combination with temozolomide (for malignant glioma (NCT03011671)). SLC-0111 has been investigated as monotherapy for solid tumors (NCT02215850) or in combination with gemicitabine for metastatic pancreatic ductal carcinoma (NCT03450018). DTP348 has been tested as a radiosensitizer for solid tumors (NCT02216669). E7070 has been investigated for the treatment of gastric cancer (NCT00165594), metastatic breast cancer (NCT00080197), solid tumors (NCT00003976, NCT00003981), renal cell carcinoma (NCT00059735), stage IV melanoma (NCT00014625) and as combination therapy for metastatic breast cancer (NCT00165880) and metastatic colorectal cancer (NCT00165867, NCT00165854). [F-18]VM4-037 has been applied as an imaging agent for different cancers (NCT00884520). The COX-2 inhibitor celecoxib has also been investigated in the context of CAIX inhibitors for the treatment of cervical intraepithelial neoplasia (NCT00081263), in combination with radiation and surgery for advanced head and neck cancer (NCT04162873) and in combination with immunomodulators or chemotherapy (for colorectal cancer (NCT01729923), colorectal cancer metastatic to the liver (NCT03403634) and early triple negative breast cancer (NCT04081389)).

[0005] Most carbonic anhydrase (CA) ligands and inhibitors in clinical development have sulfonamides as a common functional group. Sulfonamides are a well-known class of carbonic anhydrase inhibitors [8-9] . Sulfonamides with high affinity for CAIX (such as acetazolamide) have been utilized as targeting moieties within small molecule drug conjugates (SMDCs) to enable the delivery of radionuclides and cytotoxic agents for imaging and therapeutic applications, as disclosed in WO2015 / 114171 and WO2018 / 154517 [10-14] .

[0006] Sulfonamides typically coordinate with zinc ions within the highly conserved active site of CA

[15] Thus, sulfonamide-based CA conjugates are pan-isotype CA ligands and inhibitors, with only a few selective candidates, all of which remain cross-reactive with one or more isotypes. [4、9、15] Due to the expression of CA in healthy tissues, it is necessary to identify specific CAIX ligands to further improve the targeted delivery of diagnostic or therapeutic agents to the diseased site, for example, by providing high-affinity ligands allowing for low doses, and / or by reducing off-target toxicity. Summary of the Invention

[0007] The present invention addresses the problem of providing improved target enzyme (i.e., CAIX) conjugates (ligands) suitable for targeted applications. The conjugates should be suitable for binding to or inhibiting the target enzyme and / or for targeting the delivery of a payload, such as a therapeutic and / or diagnostic agent, to a site affected by or at risk of a disease or disorder characterized by the expression of CAIX. Brief Description of the Drawings

[0008] Figure 1 The LC-MS chromatogram and mass spectrum of intermediate I1 are shown. For C 31 H 39 Cl3N7O 11 S2 [M+H] + Calculated m / z: 854.1209.

[0009] Figure 2 The LC-MS chromatogram and mass spectrum of intermediate I2 are shown. For C 31 H 39 Cl3N7O 11 S2 [M+H] + Calculated m / z: 854.1209.

[0010] Figure 3 The LC-MS chromatogram and mass spectrum of intermediate I3 are shown. For C 31 H 39 Cl3N7O 11 S2 [M+H] + Calculated m / z: 854.1209.

[0011] Figure 4 The LC-MS chromatogram and mass spectrum of intermediate I4 (also known as compound C9) are shown. For C 31 H 39 Cl3N7O 11 S2 [M+H] + Calculated m / z: 854.1209.

[0012] Figure 5 The LC-MS chromatogram and mass spectrum of intermediate I5 are shown. For C19 H 31 N8O 10 S2 [M+H] + Calculated m / z: 595.1599.

[0013] Figure 6 The LC-MS chromatogram and mass spectrum of intermediate I6 are shown. For C 10 H 11 ClNO6S2 [M-H] - Calculated m / z: 339.9722.

[0014] Figure 7 The LC-MS chromatogram and mass spectrum of intermediate I7 are shown. For C 18 H 17 Cl3N3O6S2 [M+H] + Calculated m / z: 539.9619.

[0015] Figure 8 The LC-MS chromatogram and mass spectrum of intermediate I8 are shown. For C 12 H 15 ClN3O6S2 [M+H] + Calculated m / z: 396.0085.

[0016] Figure 9 The LC-MS chromatogram and mass spectrum of intermediate I9 are shown. For C 15 H 17 Cl2N2O4 [M+H] + Calculated m / z: 359.0560.

[0017] Figure 10 The LC-MS chromatogram and mass spectrum of intermediate I10 are shown. For C 27 H 28 N3O7S [M+H] + Calculated m / z: 538.1642.

[0018] Figure 11 The LC-MS chromatogram and mass spectrum of compound C1 are shown. For C 52 H 49 Cl3N7O 17 S2 [M+H] + Calculated m / z: 1212.1686.

[0019] Figure 12 The LC-MS chromatogram and mass spectrum of compound C3 are shown. For C 52 H 49 Cl3N7O 17S2 [M+H] + Calculated m / z: 1212.1686.

[0020] Figure 13 The LC-MS chromatogram and mass spectrum of compound C5 are shown. For C 52 H 49 Cl3N7O 17 S2 [M+H] + Calculated m / z: 1212.1686.

[0021] Figure 14 The LC-MS chromatogram and mass spectrum of compound C7 are shown. For C 52 H 49 Cl3N7O 17 S2 [M+H] + Calculated m / z: 1212.1686.

[0022] Figure 15 The mass spectrum of compound C2 is shown. For C 80 H 97 Cl3N9O 24 S6 [M+H] + Calculated m / z: 1864.4031.

[0023] Figure 16 The mass spectrum of compound C4 is shown. For C 80 H 97 Cl3N9O 24 S6 [M+H] + Calculated m / z: 1864.4031.

[0024] Figure 17 The mass spectrum of compound C6 is shown. For C 80 H 97 Cl3N9O 24 S6 [M+H] + Calculated m / z: 1864.4031.

[0025] Figure 18 The mass spectrum of compound C10 is shown. For C 80 H 97 Cl3N9O 24 S6 [M+H] + Calculated m / z: 1864.4031.

[0026] Figure 19 The LC-MS chromatogram and mass spectrum of compound C8 are shown. For C 45 H 42 Cl3N6O 12S3 [M+H] + Calculated m / z: 1059.1083.

[0027] Figure 20 The LC-MS chromatogram and mass spectrum of compound C12 are shown. For C 39 H 40 ClN6O 12 S3 [M+H] + Calculated m / z: 915.1549.

[0028] Figure 21 The LC-MS chromatogram and mass spectrum of compound C13 are shown. For C 42 H 42 Cl2N5O 10 S [M+H] + Calculated m / z: 878.2024.

[0029] Figure 22 The LC-MS chromatogram and mass spectrum of compound C11 are shown. For C 50 H 69 Cl3N 11 O 20 S2 [M+H] + Calculated m / z: 1312.3222.

[0030] Figure 23 Shows 177 Lu]LuCl3 (A) and 177 Lu]Lu-C11 (B) HPLC chromatograms. Signals were recorded using a radioactive detector.

[0031] Figure 24 The LC-MS chromatogram and mass spectrum of compound C14 are shown. For C 32 H 30 ClN4O 10 S3 [M+H] + Calculated m / z: 761.0807.

[0032] Figure 25 The LC-MS chromatogram and mass spectrum of compound C15 are shown. For C 40 H 42 N9O 15 S3 [M+H] + Calculated m / z: 984.1957.

[0033] Figure 26Shows the affinity measurements of compounds C1, C3, C5, C7, C8, C12, C13, and C14 for CAIX by fluorescence polarization (FP). Error bars represent the standard deviation of triplicates.

[0034] Figure 27 Shows the affinity measurements of compounds C7 and AAZ* for CAIX and the corresponding isoenzymes by fluorescence polarization. Error bars represent the standard deviation of triplicates.

[0035] Figure 28 Shows the IVIS imaging of Balb / c nude mice bearing SKRC-52 tumors 4 hours after intravenous injection of compounds C10, C2, C4, and C6 (from left to right). The SKRC-52 tumor region is indicated by white circles. Selective targeting was observed for compound C10, while no preferential accumulation at the tumor site was observed for the other stereoisomers.

[0036] Figure 29 Shows the quantitative biodistribution values of Balb / c nude mice bearing SKRC-52 tumors 6 hours after intravenous injection of 177 [[Lu]]Lu-C11 (150 nmol / Kg). The %ID / g values are given as the mean of quadruplicates (n = 4), where error bars represent the standard deviation.

[0037] Figure 30 Shows the conjugate selection for carbonic anhydrase IX (CAIX), which is a marker for hypoxia and renal cell carcinoma. A: Chemical structures of compounds C1 to C14. B: Chemical structures of L1 to L10. C: Evaluation of the binding ability of compound C9 for CAIX (left panel) and CAII (right panel) by surface plasmon resonance (SPR). Compound C9 was immobilized on a CM5 chip (at 963 RU) and subjected to serial dilutions of the corresponding protein (16.6 µM to 1.1 µM). D: Fluorescence polarization affinity constant values (K D ) of compound C7 (red / filled bars) and the fluorescent derivative of acetazolamide (AAZ*, blue / open bars) for carbonic anhydrase isoenzymes. K D values are given as the mean, where error bars represent the standard deviation of replicates (n = 3). E: Flow cytometry analysis of SK-RC-52 tumor cells treated with compounds C1, C3, C5, C7 compared to unstained controls (cells alone).

[0038] Figure 31 Shows the fluorescence polarization affinity constant values of compound C7 (2R,4R) for a panel of serum proteins, immune targets, and non-related protein targets. K DValues are given as mean and error bars represent standard deviation of replicates (n = 3). N.D. = not defined; hCAIX = human carbonic anhydrase IX; RSA = rat serum albumin; HSA = human serum albumin; CSA = cynomolgus monkey serum albumin; MSA = mouse serum albumin; rabbit SA = rabbit serum albumin; BSA = bovine serum albumin; OVA = ovalbumin; Hgb = hemoglobin; AGP = α(1)-acid glycoprotein; hIgG4 = human immunoglobulin G4; CD = cluster of differentiation; NKp46 = natural killer cell p46-related protein; NKG2D = natural killer group 2D; IL-9 / -15 / -23 = interleukin 9 / 15 / 23; LZM = lysozyme; WDR5 = WD repeat-containing protein 5; CREBBP = CREB-binding protein; TEAD = TEA domain family member 1; CTSB = cathepsin B; TCPTP = T cell protein tyrosine phosphatase; TNAP = tissue-nonspecific alkaline phosphatase; SEAP = secreted alkaline phosphatase; PSMA = prostate-specific membrane antigen; h / mFAP = human / mouse fibroblast activation protein; uPA = urokinase; MMP-3 = matrix metalloproteinase-3; CHYM = chymotrypsin.

[0039] Figure 32 Fluorescence polarization measurements of compound C7 against serum proteins (A), immune targets (B), and non-related protein targets (C) for selective profiling are shown. Measurements were performed in triplicate.

[0040] Figure 33 Affinity measurements of compounds C16, C17, and C18 against hCAIX (A) and isozyme bCAII (B) by fluorescence polarization are shown, demonstrating similar affinity for CAIX and selectivity relative to CAII (C) achieved with these compounds.

[0041] Figure 34 FP measurements of C19-C23 against CAIX are shown. Error bars represent standard deviation of triplicates.

[0042] Figure 35 FP measurements of I-387, C8, C19, and I-383 are shown. Assays were performed at a final ligand concentration of 5 nM. Error bars represent standard deviation of triplicates. Detailed Description

[0043] The present invention relates to potent stereospecific ligands for CAIX in particular, which have particularly low dissociation constants (e.g., in the nanomolar range).

[0044] Since the expression of carbonic anhydrase IX isozyme in healthy tissues can lead to the accumulation of non-specific conjugates not only at the diseased site but also in healthy organs, we performed quantitative biodistribution experiments in mice using the CAIX ligand derivatives according to the present invention, which showed high selectivity for tumors expressing CAIX, with the kidney being the only healthy organ with detectable compound accumulation. Accordingly, the present invention provides CAIX ligands with surprisingly high target specificity.

[0045] The ligands of the present invention can be applied as selective inhibitors or targeting agents to disease-related tissues, such as tissues associated with CAIX expression. The ligands of the present invention can be suitably conjugated with various therapeutic and / or diagnostic payloads (such as fluorophores, radiometal chelators, cytotoxic agents, immunomodulators, and therapeutic proteins).

[0046] The conjugates provided herein can have pharmaceutical potential. For example, selective CAIX conjugates are provided herein that do not react with other carbonic anhydrases. Traditionally, it has been difficult to isolate sulfonamides with high isoform selectivity for carbonic anhydrase. Surprisingly, the derivatives provided herein can exhibit over 100-fold selectivity for CAIX relative to other carbonic anhydrases and selectively localize in tumors in vivo, as confirmed by the results in, for example, Figure 27 and Figure 28 In contrast to the CAIX ligands of the present invention, AAZ* binds with high affinity to all tested carbonic anhydrases (bovine CAII, human CAIV, human CAXII, and human CAXIV). Accordingly, the present invention provides CAIX ligands with surprisingly high isozyme selectivity.

[0047] Such derivatives can be used as particularly suitable specific agents for imaging CAIX at hypoxic sites and in renal tumors. In addition to imaging applications, CAIX-specific targeting agents can also facilitate the delivery of cytotoxic agents and can be used as adaptors for general CAR-T cell conditioning therapies.

[0048] The derivatives described herein can exhibit surprisingly enhanced cooperative affinity. This is confirmed by the results presented herein (e.g., in Figure 26 ). To analyze which parts of the molecule are important for the binding to CAIX, the thiophene with sulfonamide (Compound C12) and the corresponding proline derivative (Compound C14) were identified as micromolar CAIX binders (K D= 1.0 ± 0.1 µM and 1.1 ± 0.2 µM). The 2-(2,4-dichlorophenyl) acetic acid proline derivative (Compound C13) does not bind to CAIX. In contrast, the combination with sulfonamide results in a highly efficient CAIX ligand (Compound C8) with a dissociation constant in the nanomolar range (K D = 6 ± 1 nM).

[0049] The derivatives described herein can also exhibit highly stereoselective binding. Only one of the four possible stereoisomers shows strong binding of the ligand to CAIX. Thus, well-defined potent ligands with surprisingly high binding affinities are provided herein. The high stereospecificity translates into high isozyme selectivity for CAIX relative to other carbonic anhydrases (bovine CAII, human CAIV, human CAXII, and human CAXIV). We compared the CAIX ligands of the present invention with a fluorescent acetazolamide derivative (AAZ*) which is one of the most prominent CAIX binders applied to targeted therapy. This is confirmed by the results presented herein. The affinities of the four stereoisomers (Compounds C1, C3, C5, and C7) for recombinantly expressed human CAIX were measured via fluorescence polarization. Stereoselective binding of Compound C7 (2R,4R; K D = 16 ± 2 nM) was observed, while no binding was detected for the other isomers (Compounds C1, C3, and C5, see Figure 26 ). Figure 34 It is shown that the incorporation of 5-amino-1,3,4-thiadiazole-2-sulfonamide derivatives into the ligand results in a further increase in the affinity for CAIX. Figure 35 It is shown that regardless of the variation of the linking group B, the CAIX binding affinity of the ligand remains substantially unchanged.

[0050] Table 1 lists exemplary compounds according to the present invention.

[0051] Table 1. Exemplary Compounds

[0052]

[0053]

[0054]

[0055] Table 2 lists additional compounds.

[0056] Table 2. Additional Compounds

[0057]

[0058]

[0059]

[0060] Tables 3.1 and 3.2 list additional exemplary compounds (conjugates) according to the present invention. The numbering of these conjugates is independent of the numbering of the remaining compounds in this specification.

[0061] Table 3.1. Exemplary Conjugates

[0062]

[0063]

[0064]

[0065]

[0066]

[0067]

[0068]

[0069]

[0070]

[0071]

[0072]

[0073]

[0074]

[0075]

[0076]

[0077]

[0078]

[0079]

[0080]

[0081]

[0082]

[0083]

[0084]

[0085]

[0086]

[0087]

[0088] As used herein, represents an antibody (e.g., a protein useful therapeutically and / or diagnostically); represents a protein (e.g., a protein useful therapeutically and / or diagnostically); and C'-S- represents a thiol group on the side chain of an amino acid that forms part of the protein.

[0089] Table 3.2 shows further preferred conjugates of the present invention. The following abbreviations for the preferred A, B, and C moieties will be used throughout this specification.

[0090]

[0091]

[0092]

[0093]

[0094]

[0095]

[0096] Table 3.2. Exemplary Conjugates

[0097]

[0098]

[0099]

[0100]

[0101]

[0102]

[0103]

[0104]

[0105]

[0106]

[0107]

[0108]

[0109] Part A

[0110] Without wishing to be bound by any theory, it is contemplated that the surprising technical effects associated with binding to the target are related to the specific structure of the small binding moiety A. In other words, an improvement of compounds comprising moiety A relative to the corresponding compounds not having such a moiety is expected to be observed.

[0111] Compared to prior art compounds, the compounds of the present invention can have increased affinity for one or more targets, a slower dissociation rate, and are therefore also considered to have an extended retention time at therapeutic or diagnostic relevant levels at the disease site, preferably for more than 1 hour after injection, more preferably for more than 6 hours after injection. Preferably, the maximum enrichment is reached after 5 minutes, 10 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours or 6 hours; and / or the enrichment at the disease site is maintained at a therapeutic or diagnostic relevant level for a period of time or at a therapeutic or diagnostic relevant level after injection for at least 5 minutes, 10 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours or 6 hours, more preferably for more than 6 hours.

[0112] Moiety A is represented by the following structure:

[0113]

[0114] wherein R 1 , R 2 , R, a and b are defined elsewhere herein. Groups particularly suitable as R 1 and / or R 2 are provided in Table 4 below.

[0115] Table 4. Overview of building blocks suitable as R 1 and / or R 2 and the corresponding codes (A… / B…) used in the Examples section.

[0116]

[0117] A particularly preferred structure of moiety A that exhibits very high target selectivity, stereospecificity, and binding affinity for CAIX is:

[0118] .

[0119] Other particularly preferred structures of moiety A that exhibit very high target selectivity, stereospecificity, and binding affinity for CAIX are:

[0120] and .

[0121] Other particularly preferred structures of moiety A are:

[0122] and .

[0123] Moiety B

[0124] Moiety B is a covalent bond or a moiety that contains an atomic chain covalently linking A to the payload C (e.g., via one or more covalent bonds). Moiety B can be a cleavable or non-cleavable multifunctional moiety that can be used to link one or more payloads and / or conjugate moieties to form the targeted conjugates of the present invention.

[0125] Specifically, moiety B is a multifunctional moiety that links one or more moieties C and / or moieties A. B can be a single bond, or an optionally substituted C 1-50 aliphatic group, wherein optionally one or more carbon atoms can be replaced by heteroatoms, C 3-12 carbocyclic groups or C 1-12 heterocyclic groups, and it can be saturated, optionally containing one or more double or triple bonds. The structure of the compound contains more than one, preferably 2 or 3, moieties A / molecule. The structure of the compound can contain more than one moiety C, preferably 2 or 3 moieties C / molecule. Preferably, the structure of the compound contains 2 moieties A and 1 moiety C / molecule, or contains 2 moieties A and 1 moiety C / molecule.

[0126] When a cleavable linker group unit is present within moiety B, the release mechanism can be the same as those specific for antibodies conjugated to cytotoxic payloads. In fact, the nature of the binding moiety is independent in this regard. Thus, pH-dependent release is envisioned [Leamon, C.P. et al. (2006) Bioconjugate Chem., 17 , 1226; Casi, G. et al. (2012) J. Am. Chem. Soc., 134, 5887], reductive release [Bernardes, G.J. 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 S.O. et al. (2008) Bioconjugate Chem, 19, 1960; Sutherland, M.S.K. (2006) J. Biol. Chem, 281 , 10540]. In certain cases, when functional groups (such as thiols, alcohols) are present on the binding moiety or payload, a linker-free linkage can be established, thereby releasing the intact payload, which greatly simplifies pharmacokinetic analysis.

[0127] Part B may contain or consist of the units shown in Table 5 below, where the substituents R and R n shown in the formula may suitably be independently selected from H, halogen, substituted or unsubstituted (hetero)alkyl, (hetero)alkenyl, (hetero)alkynyl, (hetero)aryl, (hetero)arylalkyl, (hetero)cycloalkyl, (hetero)cycloalkylaryl, heterocyclic alkyl, peptide, oligosaccharide or steroid groups. Preferably, each of R, R1, R2 and R3 is independently selected from H, OH, SH, NH2, halogen, cyano, carboxyl, alkyl, cycloalkyl, aryl and heteroaryl, each of which is substituted or unsubstituted. Suitably, R and R n are independently selected from H or C1-C7 alkyl or heteroalkyl. More suitably, R and R n are independently selected from H, methyl or ethyl.

[0128] Table 5

[0129]

[0130] Part B, one or more B L units and / or one or more B S units may suitably contain disulfide bonds as cleavable bonds, since these bonds are stable to hydrolysis, while providing suitable drug release kinetics at the target in vivo and can provide a traceless cleavage of the drug moiety including thiol groups.

[0131] Part B, one or more B L units and / or one or more B SThe unit can be polar or charged to improve the water solubility of the conjugate. For example, the linking group can contain from about 1 to about 20, suitably from about 2 to about 10 residues, which are residues of one or more known water-soluble oligomers such as peptides, oligosaccharides, glycosaminoglycans, polyacrylic acid or its salts, polyethylene glycol, poly(hydroxyethyl)(meth)acrylate, polysulfonates, etc. Suitably, the linking group can contain a polar or charged peptide moiety which contains, for example, 2 to 10 amino acid residues. The amino acids can refer to any natural or unnatural amino acids. The peptide linking group suitably includes a free thiol group, preferably an N-terminal cysteine, for forming the cleavable disulfide bond with the thiol group on the drug moiety. Any peptide containing L- or D-amino acids can be suitable; particularly suitable peptide linking groups of this type are Asp-Arg-Asp-Cys and / or Asp-Lys-Asp-Cys.

[0132] In these and other embodiments, the B moiety, one or more B L units and / or one or more B S units can contain cleavable or non-cleavable peptide units which are specifically tailored such that they will be selectively enzymatically cleaved from the drug moiety by one or more proteases on the cell surface or extracellular region of the target tissue. The chain length of the amino acid residues of the peptide unit suitably ranges from a single amino acid to about eight amino acid residues. A variety of specific cleavable peptide sequences suitable for use in the present invention can be designed and optimized in terms of their selectivity for enzymatic cleavage by specific tumor-associated enzymes such as proteases. Cleavable peptides for use in the present invention include those optimized for protease MMP-1, 2 or 3 or cathepsin B, C or D. Particularly suitable are peptides cleavable by cathepsin B. Cathepsin B is a ubiquitously present cysteine protease. It is an intracellular enzyme, except under pathological conditions such as metastatic tumors or rheumatoid arthritis. An example of a peptide cleavable by cathepsin B contains the sequence Val-Cit.

[0133] In any of the above embodiments, the B moiety and particularly one or more B LThe unit suitably also contains a self-immolative moiety, which may or may not be present after the linking group. Self-immolative linking groups are also referred to as electron cascade linking groups. These linking groups undergo elimination and cleavage upon enzymatic cleavage of the peptide to release the drug in its active form, preferably in its free form. In the absence of an enzyme capable of cleaving the linking group, the conjugate is stable extracellularly. However, when exposed to a suitable enzyme, the linking group is cleaved, triggering a spontaneous self-immolative reaction, resulting in cleavage of the bond covalently linking the self-immolative moiety to the drug, thereby enabling release of the drug in its underivatized or pharmacologically active form. In these embodiments, the self-immolative linking group is coupled to the binding moiety via an enzymatically cleavable peptide sequence that provides a substrate for the enzyme to cleave the amide bond and thereby trigger the self-immolative reaction. Suitably, the drug moiety is linked to the self-immolative moiety of the linking group via a chemically reactive functional group flanking the drug, such as a primary or secondary amine, a hydroxyl, a thiol, or a carboxyl group.

[0134] Examples of self-immolative linking groups are PABC or PAB (p-aminobenzyloxycarbonyl), which link the drug moiety to the binding moiety in 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 between the carboxyl terminus of the linking peptide unit and the p-aminobenzyl group of PAB can be a substrate and can be cleaved by certain proteases. The aromatic amine becomes electron-donating and triggers an electron cascade, which results in the expulsion 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). WO2005 / 082023 describes additional self-immolative linking groups.

[0135] In other embodiments, the linking group contains a glucuronyl group that can be cleaved by glucuronidase present on the cell surface or in the extracellular region of the target tissue. It has been shown that lysosomal β-glucuronidase is released extracellularly at high local concentrations in necrotic regions of human cancers, and this provides a route for targeted chemotherapy (Bosslet, K. et al. Cancer Res. 58, 1195-1201 (1998)).

[0136] In any of the above embodiments, moiety B suitably also contains a spacer unit. The spacer unit can be B SA unit which may be linked to moiety A, for example via an amide bond, an amine bond or a thioether bond. The spacer unit has such a length that, for example, a cleavable peptide sequence can be accessed by a cleaving enzyme (such as cathepsin B), and also suitably such that an amide bond coupling the cleavable peptide to the self-destructing moiety X can be hydrolysed. The spacer unit may for example comprise repeating units of a divalent group such as an alkylene, arylene, heteroarylene, alkoxy (such as polyethoxy, PEG, polymethoxy) and alkamino (such as polyethylamino) or diesters and amides (including succinates, succinamides, diglycolates, malonates and hexamides).

[0137] In any of the embodiments described herein, * represents the point of attachment to moiety A, or such a point of attachment for which the shortest path to moiety A contains fewer atoms (as appropriate) than for •; and • represents the point of attachment to moiety C, or such a point of attachment to moiety C for which the shortest path to moiety C contains fewer atoms (as appropriate) than for *. This also applies in cases where there is a reactive moiety L instead of a payload moiety C. The following designations all have the meaning of a point of attachment of a certain group or atom (such as R) to another moiety:

[0138]

[0139] As used herein, and unless otherwise indicated, the groups and fragments described herein may be combined in any orientation, but preferably they are combined in the orientation as depicted herein, reading from left to right, for example:

[0140] Fragment (a): ; Fragment (b): ; Preferred combination of fragment (a) + (b): .

[0141] If the relevant structure is a peptide monomer or oligomer, each * represents a point of attachment for which the shortest path to moiety A contains fewer atoms than for •; and each • represents a point of attachment for which the shortest path to moiety C contains fewer atoms than for *, the precursor being when n > 1 and where the respective points of attachment are indicated on any of R a , R b and R c , then they may independently be present in one or more peptide monomer units, preferably in the peptide monomer unit furthest from another point of attachment indicated in their respective structures.

[0142] In any of the embodiments described herein, the terms "peptide", "dipeptide", "tripeptide", "tetrapeptide", etc. refer to peptide monomers or oligomers having a backbone formed from protein amino acids and / or non-protein amino acids. As used herein, the term "aminoacyl" or "amino acid" generally refers to any protein amino acid or non-protein amino acid. Preferably, in any of the embodiments disclosed herein, the side chain residues of the protein amino acid or non-protein amino acid are represented by R a , R b , and R c , any one of which is selected from the following list:

[0143]

[0144]

[0145] wherein each of R, R 1 , R 2 , and R 3 is independently selected from H, OH, SH, NH2, halogen, cyano, carboxyl, alkyl, cycloalkyl, aryl, and heteroaryl, each of which is substituted or unsubstituted;

[0146] Each X is independently selected from NH, NR, S, O, and CH2, preferably NH; and

[0147] 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.

[0148] Preferably, in any of the embodiments disclosed herein, the side chain residues of the protein amino acid or non-protein amino acid are represented by R a , R b , R c , R d , and R e , any one of which

[0149] can be part of a 3-, 4-, 5-, 6-, or 7-membered ring. For example, the α, β, and / or γ positions of the side chain of the protein amino acid or non-protein amino acid can be part of a cyclic structure selected from azetidine rings, pyrrolidine rings, and piperidine rings, such as in the following amino acids (proline and hydroxyproline):

[0150] ; or

[0151] each of which can independently be an unsaturated structure (i.e., wherein the corresponding groups R a , R b , and R cPart of which the associated H atom does not exist), for example:

[0152] 。

[0153] As used herein, the following designation of a peptide sequence refers to the sequence from the N-terminus to the C-terminus, and the connection of a group by a horizontal bond (here: part C) means covalent attachment to the peptide backbone via an amide bond with the corresponding terminal amino acid (here: AA3):

[0154]

[0155] As used herein, the following designation of a peptide sequence refers to the sequence from the N-terminus to the C-terminus, and the connection of a group by a vertical bond (here: part C) means covalent attachment via the side chain of the corresponding amino acid (here: AA3):

[0156] 。

[0157] Further preferred non-protein amino acids may be selected from the following list:

[0158]

[0159] Part B and particularly preferred embodiments of the compounds according to the invention are shown in the appended claims.

[0160] Part C D 6>Part C in the present invention represents a payload, which can generally be any atom (including H), molecule or particle. Preferably, part C is not a hydrogen atom.

[0162] The payload can be a chelating agent for radiolabeling. Suitably, the radionuclide is not released. Chelating agents are well known to those skilled in the art and include, for example, such chelating agents as sulfur colloid, diethylenetriaminepentaacetic acid (DTPA), ethylenediaminetetraacetic acid (EDTA), 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA), 1,4,7,10-tetraazacyclododecane, N-(pentanedioic acid)-N',N',N'''-triacetic acid (DOTAGA), 1,4,7-triazacyclononane-N,N',N''-triacetic acid (NOTA), 1,4,8,11-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid (TETA) or any preferred chelating agent structure recited in the appended claims or elsewhere in this document.

[0163] The payload can be a radioactive group containing or consisting of a radioisotope, and the radioisotopes include such as 223 Ra,89 Sr, 94m Tc, 99m Tc, 186 Re, 188 Re, 203 Pb, 67 Ga, 68 Ga, 47 Sc, 111 In, 97 Ru, 62 Cu, 64 Cu, 86 Y, 88 Y, 90 Y, 121 Sn, 161 Tb, 153 Sm, 166 Ho, 105 Rh, 177 Lu, 123 I, 124 I, 125 I, 131 I, 18 F, 211 At, 225 Ac, 89 Sr, 225 Ac, 117m Sn, 169 Er and 227 isotopes of Th. Preferably, positron emitters (such as 18 F and 124 I) or gamma emitters (such as 99m Tc, 111 In and 123 I) are used for diagnostic applications (e.g., for PET), while beta emitters (such as 89 Sr, 131 I and 177 Lu) are preferably used for therapeutic applications. Alpha emitters (such as 211 At, 225 Ac and 223 Ra) can also be used for therapy. In a preferred embodiment, the radioisotope is 89 Sr or 223 Ra. In another preferred embodiment, the radioisotope is 68 Ga.

[0164] The payload can be a chelate of a radioisotope (preferably the isotopes listed above) and a chelating agent (preferably the chelating agents listed herein).

[0165] The payload can be a fluorophore group, preferably selected from xanthene dyes, acridine dyes, oxazine dyes, cyanine dyes, styryl dyes, coumarin dyes, porphyrin dyes, fluorescent metal-ligand complexes, fluorescent proteins, nanocrystals, perylene dyes, boron-dipyrromethene dyes, and phthalocyanine dyes, more preferably selected from the structures listed herein.

[0166] The payload can be a cytotoxic agent and / or a cytostatic agent. Such agents can inhibit or prevent the function of cells and / or cause the destruction of cells. Examples of cytotoxic agents include radioisotopes, chemotherapeutic agents, and toxins (such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant, or animal origin), including synthetic analogs and derivatives thereof. The cytotoxic agent can be selected from the group consisting of auristatin, DNA minor groove binders, DNA minor groove alkylating agents, enediyne, lexitropsin, duocarmycin, taxane, puromycin, dolastatin, maytansinoid, and vinca alkaloid or a combination of two or more thereof. Preferred cytotoxic and / or cytostatic payload moieties are listed herein.

[0167] In one embodiment, the payload is a chemotherapeutic agent selected from the group consisting of: topoisomerase inhibitors, alkylating agents (e.g., nitrogen mustards; ethylenimes; alkylsulfonates; triazenes; piperazines; and nitrosureas), antimetabolites (e.g., mercaptopurine, thioguanine, 5-fluorouracil), antibiotics (e.g., anthracyclines, dactinomycin, bleomycin, adriamycin, mithramycin, dactinomycin), mitotic disruptors (e.g., plant alkaloids such as vincristine, and / or microtubule antagonists such as paclitaxel), DNA methylating agents, DNA intercalating agents (e.g., carboplatin and / or cisplatin, daunomycin and / or doxorubicin and / or bleomycin and / or thalidomide), DNA synthesis inhibitors, DNA-RNA transcription regulators, enzyme inhibitors, gene regulators, hormone response regulators, hypoxia-selective cytotoxins (e.g., tirapazamine), epidermal growth factor inhibitors, antiangiogenic agents (e.g., xanthones, 5,6-dimethylxanthone-4-acetic acid), radiation-activated prodrugs (e.g., nitroaryl methyl quaternary (NMQ) salts) or bioreductive drugs or a combination of two or more thereof. In some embodiments, the payload (i.e., part C) is not derived from anthracyclines, preferably not derived from PNU 159682.

[0168] The chemotherapeutic agent can be selected from the group consisting of: Erlotinib (TARCEVA®), Bortezomib (VELCADE®), Fulvestrant (FASLODEX®), Sutent (SU11248), Letrozole (FEMARA®), Imatinib mesylate (GLEEVEC®), PTK787 / ZK 222584, Oxaliplatin (Eloxatin®.), 5-FU (5-fluorouracil), Leucovorin, Rapamycin (Sirolimus, RAPAMUNE®.), Lapatinib (GSK572016), Lonafarnib (SCH 66336), Sorafenib (BAY43-9006), and Gefitinib (IRESSA®.), AG1478, AG1571 (SU 5271; Sugen) or a combination of two or more thereof.

[0169] The chemotherapeutic agent can be an alkylating agent such as thiotepa, CYTOXAN® and / or cyclophosphamide; an alkyl sulfonate such as busulfan, improsulfan and / or piposulfan; an aziridine such as benzodopa, carboquone, meturedopa and / or uredopa; an ethylenimine and / or a methylamelamine such as altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and / or trimethylomelamine; an acetogenin such as bullatacin and / or bullatacinone; camptothecin; bryostatin; callystatin; cryptophycins; dolastatin; duocarmycin; eleutherobin; pancratistatin; sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide and / or uracil mustard;Nitrosureas, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and / or ranimnustine; dynemicin; bisphosphonates, such as clodronate; esperamicin; the neocarzinostatin chromophore; aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (such as morpholino-doxorubicin, cyano-morpholino-doxorubicin, 2-pyrrolino-doxorubicin, and / or deoxy-doxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins (such as mitomycin C), mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfimromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites, such as methotrexate and 5-fluorouracil (5-FU);Folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid supplements such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate; epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; macrocyclic depsipeptides such as maytansine and ansamitocins;Mitoguazone; Mitoxantrone; Mopidanmol; Nitraerine; Pentostatin; Phenamet; Pirarubicin; Losoxantrone; Podophyllinic acid; 2-Ethylhydrazide; Procarbazine; Razoxane; Rhizoxin; Sizofiran; Spirogermanium; Tenuazonic acid; Triaziquone; 2,2',2''-Trichloroethylamine; Trichothecenes, such as Verracurin A, Roridin A, and / or Anguidine; Urethan; Vindesine; Dacarbazine; Mannomustine; Mitobronitol; Mitolactol; Pipobroman; Gacytosine; Arabinoside; Cyclophosphamide; Thiotepa; Taxoids, such as TAXOL®, Paclitaxel, Abraxane, and / or TAXOTERE®, Doxetaxel; Chlorambucil; GEMZAR®, Gemcitabine; 6-Thioguanine; Mercaptopurine; Methotrexate; Platinum analogs, such as Cisplatin and Carboplatin; Vinblastine; Platinum; Etoposide; Ifosfamide; Mitoxantrone; Vincristine; NAVELBINE®, Vinorelbine; Novantrone; Teniposide; Edatrexate; Daunomycin;Aminopterin; Xeloda; Ibandronate; Topoisomerase inhibitor RFS 2000; Difluoromethylornithine (DMFO); Retinoids such as retinoic acid; Capecitabine; and pharmaceutically acceptable salts, acids, derivatives or combinations of two or more of any of the foregoing.

[0170] The payload can be a microtubule-disrupting agent, including but not limited to: taxanes such as paclitaxel and docetaxel, vinca alkaloids, discodermolide, epothilone A and B, desoxyepothilone, cryptophycins, curacin A, combretastatin A-4-phosphate, BMS 247550, BMS 184476, BMS 188791; LEP, RPR 109881A, EPO 906, TXD 258, ZD 6126, vinflunine, LU 103793, dolastatin 10, E7010, T138067, and T900607, colchicine, phenstatin, chalcones, indanocine, T138067, oncocidin, vincristine, vinblastine, vinorelbine, vinflunine, halichondrin B, isohomohalichondrin B, ER-86526, pironetin, spongistatin 1, spiket P, cryptophycin 1, LU103793 (cematodin or cematodin), rhizoxin, sarcodictyin, eleutherobin, laulilamide, VP-16 and D-24851, as well as pharmaceutically acceptable salts, acids, derivatives or combinations of two or more of any of the foregoing.

[0171] The payload can be a DNA intercalator, including but not limited to: acridines, actinomycins, anthracyclines, benzothiopyranoindazoles, pixantrone, crisnatol, brostallicin, CI-958, doxorubicin (adriamycin), actinomycin D, daunorubicin (daunomycin), bleomycin, idarubicin, mitoxantrone, cyclophosphamide, melphalan, mitomycin C, bizelesin, etoposide, mitoxantrone, SN-38, carboplatin, cis-platin, actinomycin D, amsacrine, DACA, pyrazoloacridine, irinotecan, and topotecan, as well as pharmaceutically acceptable salts, acids, derivatives, or combinations of any two or more of the foregoing.

[0172] The payload can be an antihormonal agent that acts to modulate or inhibit the action of hormones on tumors, such as antiestrogens and selective estrogen receptor modulators, including but not limited to tamoxifen, raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and / or fareston (toremifene) and pharmaceutically acceptable salts, acids, derivatives, or combinations of two or more of any of the foregoing. The payload can be an aromatase inhibitor that inhibits aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, megestrol acetate, AROMASIN® exemestane, formestanie, fadrozole, RIVISOR® vorozole, FEMARA® letrozole, and ARIMIDEX® and / or anastrozole and pharmaceutically acceptable salts, acids, derivatives, or combinations of two or more of any of the foregoing.

[0173] The payload can be an antiandrogen, such as flutamide, nilutamide, bicalutamide, leuprolide, goserelin, and / or troxacitabine and pharmaceutically acceptable salts, acids, derivatives, or combinations of two or more of any of the foregoing.

[0174] The payload can be a protein or an antibody. Preferably, the payload is a cytokine (e.g., interleukin such as IL2, IL10, IL12, IL15; a member of the TNF superfamily; or interferon such as interferon γ).

[0175] Any payload can be used in an unmodified or modified form. Combinations of payloads can be used, some of which are unmodified and some of which are modified. For example, the payload can be chemically modified. One form of chemical modification is the derivatization of a carbonyl group - such as an aldehyde.

[0176] In a preferred embodiment, the Payload C moiety is a topoisomerase inhibitor; preferably camptothecin (CPT) or a derivative thereof; more preferably derived (e.g., by substituting a hydrogen atom) from topotecan, irinotecan, silatecan, cositecan, exatecan, lurtotecan, gimatecan, belotecan, rubitecan; even more preferably exatecan; and even more preferably

[0177] 、 or ,

[0178] where each n is 0, 1, 2, 3, 4, 5 or 6; and most preferably 。

[0179] In a preferred embodiment, the moiety C is an auristatin (i.e., having a structure derived from a member of the auristatin compound family) or an auristatin derivative. More preferably, the moiety C has a structure according to the following formula:

[0180]

[0181] where:

[0182] R d1 is independently H or a C1-C6 alkyl; preferably H or CH3;

[0183] R d2 is independently a C1-C6 alkyl; preferably CH3 or iPr;

[0184] R d3 is independently H or a C1-C6 alkyl; preferably H or CH3;

[0185] R d4 is independently H, a C1-C6 alkyl, COO(C1-C6 alkyl), CON(H or C1-C6 alkyl), C3-C 10 aryl or C3-C 10 heteroaryl; preferably H, CH3, COOH, COOCH3 or thiazolyl;

[0186] R d5 is independently H, OH, a C1-C6 alkyl; preferably H or OH; and

[0187] R d6 is independently C3-C 10 aryl or C3-C10 Heteroaryl; preferably optionally substituted phenyl or pyridyl.

[0188] More preferably, moiety C is derived from MMAE or MMAF.

[0189] In a preferred embodiment, moiety C has a structure according to the following formula:

[0190]

[0191] Wherein:

[0192] n is 0, 1, 2, 3, 4 or 5; preferably 1;

[0193] R 1e Independently is H, COOH, aryl-COOH or heteroaryl-COOH; preferably COOH;

[0194] R 2e Independently is H, COOH, aryl-COOH or heteroaryl-COOH; preferably COOH;

[0195] Each R 3e Independently is H, COOH, aryl-COOH or heteroaryl-COOH; preferably COOH;

[0196] R 4e Independently is H, COOH, aryl-COOH or heteroaryl-COOH; preferably COOH; and

[0197] X is O, NH or S; preferably O.

[0198] In a preferred embodiment, moiety C has a structure according to the following formula:

[0199]

[0200] Wherein:

[0201] n is 0, 1, 2, 3, 4 or 5; preferably 1

[0202] R 1f Independently is H, COOH, aryl-COOH or heteroaryl-COOH; preferably COOH;

[0203] R 2f Independently is H, COOH, aryl-COOH or heteroaryl-COOH; preferably COOH;

[0204] R 3f Independently is H, COOH, aryl-COOH or heteroaryl-COOH; preferably COOH; and

[0205] X is O, NH or S; preferably O.

[0206] Part C and particularly preferred embodiments of the compounds according to the invention are shown in the appended claims or elsewhere herein.

[0207] Preferred compounds according to the invention can be represented by:

[0208]

[0209] or

[0210] ,

[0211] wherein B S , B L , x, y and n and the remaining groups are as defined elsewhere herein;

[0212] More preferably

[0213]

[0214] More preferably

[0215] .

[0216] Preferred compounds are those compounds having the structure according to Table 1 or 3 or Figure 30 or Figure 31 , their individual diastereoisomers, hydrates, solvates, crystal forms, individual tautomers or their pharmaceutically acceptable salts.

[0217] In all structures, unless otherwise specified, all groups and variables are as further defined above in this disclosure.

[0218] Also disclosed is a pharmaceutical composition, which comprises the compound according to any one of the foregoing aspects and a pharmaceutically acceptable excipient. Also disclosed is the use of such a pharmaceutical composition in the following methods: (a) a method for treating the human or animal body by surgery or therapy or a diagnostic method practiced on the human or animal body; or (b) a method for the treatment or prevention of a subject suffering from a disease or disorder or at risk thereof; or (c) a method for guiding surgery practiced on a subject suffering from a disease or disorder or at risk thereof; or (d) a method for diagnosing a disease or disorder, which is practiced on the human or animal body and involves nuclear medicine imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT); or (e) a method for targeted delivery of a therapeutic or diagnostic agent to a subject suffering from a disease or disorder or at risk thereof, wherein in each of the foregoing (b)-(e), the disease or disorder is independently selected from hypoxia-related diseases, such as cancer, preferably wherein the cancer is selected from the group consisting of breast cancer, pancreatic cancer, colon cancer, multi-drug resistant colon cancer, rectal cancer, colorectal cancer, metastatic colorectal cancer, lung cancer, non-small cell lung cancer, head and neck cancer, ovarian cancer, hypopharyngeal cancer, nasopharyngeal cancer, laryngeal cancer, bladder cancer, cholangiocarcinoma, clear cell renal carcinoma, glioma, astrocytoma, cervical cancer and renal cancer.

[0219] Treatment

[0220] The compounds described herein can be used to treat diseases. Treatment can be therapeutic and / or prophylactic treatment, where the aim is to prevent, alleviate or halt an undesired physiological change or disorder. Treatment can prolong survival compared to the expected survival in the absence of treatment. The diseases treatable by the compounds can be any diseases that may benefit from treatment. This includes chronic and acute conditions or diseases, including those pathological conditions that predispose to the condition.

[0221] The terms “cancer” and “cancerous” are used in their broadest sense to mean a physiological condition in mammals typically characterized by unregulated cell growth. A tumor comprises one or more cancer cells. When treating cancer, the observed therapeutic effects can be a reduction in the number of cancer cells; a decrease in tumor size; inhibition or retardation of cancer cell invasion into surrounding organs; inhibition of tumor growth; and / or alleviation of one or more cancer-related symptoms.

[0222] In animal models, efficacy can be evaluated by physical measurement of the tumor during treatment and / or by determining partial and complete remission of cancer. For cancer treatment, efficacy can be measured, for example, by evaluating the time to progression (TTP) of the disease and / or determining the response rate (RR).

[0223] Particularly preferred embodiments of the treatment methods according to the invention are shown in the appended claims.

[0224] The present invention also discloses methods for treating a human or animal body (e.g., by surgery or therapy) or diagnostic methods practiced on a human or animal body, said methods involving the step of administering to a subject in need thereof a therapeutically or diagnostically effective amount of a compound or pharmaceutical composition described herein. More specifically, methods for treatment are disclosed herein, such as treatment or prophylaxis of a subject suffering from or at risk of a disease or disorder; or guided surgery practiced on a subject suffering from or at risk of a disease or disorder; methods for diagnosing a disease or disorder, such as diagnostic methods practiced on a human or animal body and / or involving nuclear medicine imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT); methods for targeted delivery of a therapeutic or diagnostic agent to a subject suffering from or at risk of a disease or disorder. In the foregoing methods, the disease or disorder may independently be selected from hypoxia-related diseases, such as cancer, preferably wherein the cancer is selected from the group consisting of breast cancer, pancreatic cancer, colon cancer, multi-drug resistant colon cancer, rectal cancer, colorectal cancer, metastatic colorectal cancer, lung cancer, non-small cell lung cancer, head and neck cancer, ovarian cancer, hypopharyngeal cancer, nasopharyngeal cancer, laryngeal cancer, bladder cancer, cholangiocarcinoma, clear cell renal carcinoma, glioma, astrocytoma, cervical cancer, and renal cancer.

[0225] Pharmaceutical composition

[0226] The compounds described herein may be in the form of a pharmaceutical composition, which may be used for human or animal use in human and veterinary medicine (e.g., as a therapeutic or diagnostic composition), and will typically contain any one or more of a pharmaceutically acceptable diluent, carrier, or excipient. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (edited by A. R. Gennaro, 1985). The choice of a pharmaceutical carrier, excipient, or diluent may be selected according to the intended route of administration and standard pharmaceutical practice. The pharmaceutical composition may contain any suitable one or more binders, one or more lubricants, one or more suspending agents, one or more coating agents, one or more solubilizing agents as a carrier, excipient, or diluent, or in addition to a carrier, excipient, or diluent, may contain any suitable one or more binders, one or more lubricants, one or more suspending agents, one or more coating agents, one or more solubilizing agents.

[0227] Preservatives, stabilizers, dyes, and even flavoring agents may be provided in the pharmaceutical composition. Examples of preservatives include sodium benzoate, sorbic acid, and parabens. Antioxidants and suspending agents may also be used.

[0228] Depending on the different delivery systems, different composition / formulation requirements may exist. For example, a pharmaceutical composition can be formulated for administration using a micropump or via a mucosal route, such as in the form of a nasal spray or aerosol for inhalation or an ingestible solution, or parenterally, where the composition is formulated in an injectable form for delivery via, for example, intravenous, intramuscular or subcutaneous routes. Alternatively, the formulation can be designed for administration via multiple routes.

[0229] If the agent is to be administered mucosally via the gastrointestinal mucosa, it should be able to remain stable during transit through the gastrointestinal tract; for example, it should resist proteolytic degradation, be stable at acidic pH and resist the detergency of bile.

[0230] In appropriate cases, the pharmaceutical composition can be administered by inhalation; in the form of a suppository or pessary; administered topically in the form of a lotion, solution, cream, ointment or dusting powder; administered by using a skin patch; orally administered in the form of tablets containing excipients (such as starch or lactose), or capsules or ovules alone or mixed with excipients, or elixirs, solutions or suspensions containing flavoring or coloring agents; or the pharmaceutical composition can be injected parenterally (e.g., intravenously, intramuscularly or subcutaneously). For parenteral administration, the composition can preferably be used in the form of a sterile aqueous solution, which can contain other substances, such as sufficient salts or monosaccharides to make the solution isotonic with blood. For buccal or sublingual administration, the composition can be administered in the form of tablets or lozenges that can be formulated in a conventional manner.

[0231] The compounds of the present invention can be administered in the form of a pharmaceutically acceptable salt or a pharmaceutically 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). The salts include but are not limited to sulfates, citrates, acetates, oxalates, chlorides, bromides, iodides, nitrates, bisulfates, phosphates, acid phosphates, isonicotinates, lactates, salicylates, acid citrates, tartrates, oleates, tannates, pantothenates, bitartrates, ascorbates, succinates, maleates, gentisates, fumarates, gluconates, glucaronates, saccharates, formates, benzoates, glutamates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates and pamoates (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoates)).

[0232] The route of administration (delivery) may include, but is not limited to, one or more of the following: oral (e.g., in the form of a tablet, capsule, or ingestible solution), topical, mucosal (e.g., in the form of a nasal spray or aerosol for inhalation), nasal, parenteral (e.g., by injectable form), gastrointestinal, intraspinal, intraperitoneal, intramuscular, intravenous, intrauterine, intraocular, intradermal, intracranial, intratracheal, intravaginal, intracerebroventricular, intracerebral, subcutaneous, ocular (including intravitreal or intracameral), transdermal, rectal, buccal, vaginal, epidural, sublingual.

[0233] Typically, a physician will determine the actual dosage that is most suitable for an individual subject. For any particular patient, the specific dosage level and frequency of administration may vary and will depend on a variety of factors, including the activity of the specific compound employed, the metabolic stability and duration of action of the compound, age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, severity of the particular condition, and the individual being treated.

[0234] The preparation can be packaged in unit dose or multidose containers, such as sealed ampoules and vials, and can be stored under freeze drying (lyophilization) conditions, requiring only the addition of a sterile liquid carrier (such as water) for administration. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules, and tablets of the aforementioned types. Exemplary unit dose formulations contain an active ingredient in a daily dose or unit daily subdose or an appropriate fraction thereof.

[0235] General Technology

[0236] Unless otherwise indicated, the practice of the present invention employs conventional methods of chemistry, biochemistry, molecular biology, cell biology, genetics, immunology, and pharmacology known to those of ordinary skill in the art. Such techniques are well explained in the literature. See, for example, Gennaro, A. R., ed. (1990) Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Co.; Hardman, J. G., Limbird, L. E., and Gilman, A. G., eds. (2001) The Pharmacological Basis of Therapeutics, 10th ed., McGraw-Hill Co.; Colowick, S. et al., eds., Methods In Enzymology, Academic Press, Inc.; Weir, D. M. and Blackwell, C. C., eds. (1986) Handbook of Experimental Immunology, Vols. I-IV, Blackwell Scientific Publications; Maniatis, T. et al., eds. (1989) Molecular Cloning: A Laboratory Manual, 2nd ed., Vols. I-III, Cold Spring Harbor Laboratory Press; Ausubel, F. M. et al., eds. (1999) Short Protocols in Molecular Biology, 4th ed., John Wiley & Sons; Ream et al., eds. (1998) Molecular Biology Techniques: An Intensive Laboratory Course, Academic Press; Newton, C. R. and Graham, A., eds. (1997) PCR (Introduction to Biotechniques Series), 2nd ed., Springer Verlag.

[0237] Chemical synthesis

[0238] The compounds described herein can be prepared by chemical synthesis techniques. It will be apparent to those skilled in the art that protection and deprotection of sensitive functional groups may be required during the synthesis of the compounds. This can be achieved by conventional techniques, such as those described in T W Greene and P G M Wuts, "Protective Groups in Organic Synthesis", John Wiley and Sons Inc. (1991) and P.J.Kocienski, "Protecting Groups", Georg Thieme Verlag (1994). It is possible that during some reactions, any stereocenters present may be epimerized under certain conditions, such as in the case of using a base in a reaction with a substrate having an optical center containing a base-sensitive group. It should be possible to avoid potential problems such as these by choosing the reaction sequence, conditions, reagents, protection / deprotection schemes, etc., as is well known in the art.

[0239] Definitions

[0240] Antibody. The term "antibody" is used in its broadest sense and encompasses monoclonal antibodies, polyclonal antibodies, dimers, multimers, multispecific antibodies (e.g., bispecific antibodies), veneered antibodies, antibody fragments, and small immunoproteins (SIPs) (see Int. J. Cancer (2002) 102, 75 - 85). Antibodies are proteins produced by the immune system that are capable of recognizing and binding to specific antigens. The target antigen typically has multiple binding sites, also known as epitopes, which are recognized by the CDRs on multiple antibodies. Each antibody that binds specifically to a different epitope has a different structure. Thus, an antigen can have more than one corresponding antibody. Antibodies include full-length immunoglobulin molecules or immunologically active portions of full-length immunoglobulin molecules, i.e., molecules or portions thereof that contain antigen-binding sites that immunospecifically bind to the target antigen of interest. Antibodies can be of any type (such as IgG, IgE, IgM, IgD, and IgA), any class (such as IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or their subclasses. Antibodies can be murine, human, rabbit, or of other species, or can be derived from murine, human, rabbit, or other species.

[0241] Antibody fragment. The term "antibody fragment" refers to a portion of a full-length antibody, generally its antigen-binding region or variable region. Examples of antibody fragments include, but are not limited to: Fab, Fab', F(ab')2, and Fv fragments; diabodies; linear antibodies; single-domain antibodies, including dAb, camel V HHAntibodies and cartilaginous fish IgNAR antibodies. Antibodies and fragments thereof can be replaced by binding molecules based on alternative non-immunoglobulin scaffolds, peptide aptamers, nucleic acid aptamers, structured polypeptides containing polypeptide loops directed against non-peptide backbones, natural receptors or domains thereof.

[0242] Derivatives. Derivatives include chemical modifications of a compound. Examples of such modifications include replacement of hydrogen with a halogen group, alkyl, acyl or amino group, etc. Modifications can increase or decrease one or more hydrogen bond interactions, charge interactions, hydrophobic interactions, van der Waals interactions and / or dipole interactions.

[0243] Analogues. The term encompasses any enantiomers, racemates and stereoisomers, as well as all pharmaceutical salts and hydrates of such compounds.

[0244] Unless otherwise specified, the following definitions apply to chemical terms used in connection with the compounds of the invention and compositions containing such compounds.

[0245] Alkyl refers to a branched or unbranched saturated hydrocarbon group. Suitably, alkyl contains from 1 to 100 carbon atoms, preferably from 3 to 30 carbon atoms, more preferably from 5 to 25 carbon atoms. Preferably, alkyl refers to methyl, ethyl, propyl, butyl, pentyl or hexyl.

[0246] Alkenyl refers to a branched or unbranched hydrocarbon group containing one or more carbon-carbon double bonds. Suitably, alkenyl contains from 2 to 30 carbon atoms, preferably from 5 to about 25 carbon atoms.

[0247] Alkynyl refers to a branched or unbranched hydrocarbon group containing one or more carbon-carbon triple bonds. Suitably, alkynyl contains from about 3 to about 30 carbon atoms, such as from about 5 to about 25 carbon atoms.

[0248] Halogen refers to fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

[0249] Cycloalkyl refers to an alicyclic moiety suitably having 3, 4, 5, 6, 7 or 8 carbon atoms. The group can be a bridged or polycyclic ring system. More commonly, cycloalkyl is monocyclic. The term includes reference to groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, bicyclo[2.2.2]octyl, etc.

[0250] Aryl refers to an aromatic carbocyclic ring system suitably containing 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 ring carbon atoms. Aryl can be a polycyclic ring system having two or more rings, wherein at least one ring is aromatic. The term includes reference to groups such as phenyl, naphthyl, fluorenyl, azulyl, indenyl, anthracenyl, etc.

[0251] Unless otherwise specified, diastereomers or diastereoisomers are stereoisomers of a compound that have different configurations at one or more stereocenters in parts of the molecule other than part A. In other words, unless otherwise specified, the stereochemistry of the configuration of part A is always as presented in the corresponding structure, and the individual diastereomers have different stereochemical configurations in parts of the molecule other than part A.

[0252] The prefix (hetero) as used herein indicates that one or more carbon atoms of a group may be replaced by nitrogen, oxygen, phosphorus, silicon or sulfur. Heteroalkyl includes, for example, alkoxy and alkylthio. Heterocycloalkyl or heteroaryl as used herein may have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 ring atoms, with at least one ring atom selected from nitrogen, oxygen, phosphorus, silicon and sulfur. In particular, 3- to 10-membered rings or ring systems, and more particularly 5- or 6-membered rings, 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, piperidinyl, piperazinyl, pyridazinyl, morpholinyl, thiomorpholinyl (especially thiomorpholino), indolizinyl, 1,3-dioxo-1,3-dihydro-isoindolyl, 3H-indolyl, indolyl, benzimidazolyl, cumaryl, indazolyl, triazolyl, tetrazolyl, purinyl, 4H-quinolizinyl, isoquinolinyl, quinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, benzofuranyl, dibenzofuranyl, benzothienyl, dibenzothienyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, [β]-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, furazanyl, phenazinyl, phenothiazinyl, phenoxazinyl, chromenyl, isochromanyl, chromanyl, 3,4-dihydro-2H-isoquinolin-1-one, 3,4-dihydro-2H-isoquinolinyl, etc.

[0253] "Substituted" means that one or more (especially up to 5, more especially 1, 2 or 3) hydrogen atoms in the moiety are independently replaced by the corresponding number of substituents. As used herein, the term "optionally substituted" includes substituted or unsubstituted. Of course, it should be understood that the substituents are only at chemically possible positions, and those skilled in the art can determine (experimentally or theoretically) whether a particular substitution is possible without undue effort. For example, an amino or hydroxyl group with a free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (e.g., olefinic) bond. Preferably, the term "substituted" means that one or more (especially up to 5, more especially 1, 2 or 3) hydrogen atoms in the moiety are independently replaced by the corresponding number of substituents selected from OH, SH, NH2, halogen, cyano, carboxyl, alkyl, cycloalkyl, aryl and heteroaryl. Additionally, the substituents described herein may themselves be substituted by any substituent, subject to the above limitations on suitable substitution recognized by those skilled in the art. Preferably, any of the above substituents may be further substituted by any of the above substituents, and each of the substituents may be further substituted by any of the above substituents.

[0254] Suitable substituents may include halogen atoms and halomethyl groups (such as CF3 and CCl3); oxygen-containing groups, such as oxo, hydroxyl, carboxyl, carboxyalkyl, alkoxy, alkanoyl, alkanoyloxy, aryloxy, aroyl and aroyloxy; nitrogen-containing groups, such as amino, alkylamino, dialkylamino, cyano, azido and nitro; sulfur-containing groups, such as thio, alkylthio, sulfonyl and sulfoxide; heterocyclic groups, which may themselves be substituted; alkyl, which may itself be substituted; and aryl, which may itself be substituted, such as phenyl and substituted phenyl. Alkyl includes substituted or unsubstituted benzyl.

[0255] Where two or more moieties are described as "each independently" selected from a series of atoms or groups, this means that the moieties may be the same or different. Thus, the identity of each moiety is independent of the identity of one or more other moieties.

[0256] Aspect

[0257] In view of the above, the present disclosure also provides the following specific aspects.

[0258] 1. A compound, its individual diastereoisomers, its hydrates, its solvates, its crystal forms, its individual tautomers or their pharmaceutically acceptable salts, wherein the compound structure contains at least one group A independently represented by the following structure:

[0259]

[0260] Wherein:

[0261] Each of a and b is 0 or 1, where a + b is at least 1, preferably where each of a and b is 1;

[0262] R 1 -C(Y)-R 1a -SO2NR(R') or -(G 1 ) q -(CR(R')) r -(G 2 ) s -R 1a represented by -SO2NR(R');

[0263] R 1a is independently a 6- to 10-membered aromatic group, a 5- to 10-membered heteroaromatic group having at most 5 (preferably 3) heteroatoms independently selected from N, O, and S, or a group represented by -C((CR(R')) n SO2NR(R'))(CR(R')) n SO2NR(R'), where in addition to SO2NR(R'), R 1a is also optionally substituted by one or more substituents (preferably represented by R 3 ), where:

[0264] G 1 is independently selected from C(Y), SO, SO2, CR(R'), triazolyl, and CR(R')triazolyl;

[0265] G 2 is independently selected from C(Y), C(Y)NR, SONR, SO2NR, CR(R')NR, NRC(Y), NRSO, NRSO2, NRCR(R'), triazolyl, triazolyl-NR, triazolyl-CR(R'), NR-triazolyl, and CR(R')-triazolyl;

[0266] Each of q and s is independently selected from 0 and 1;

[0267] r is independently selected from 0, 1, 2, 3, and 4, preferably 2;

[0268] Preferably provided that at least one of q and s is 1, more preferably both q and s are 1;

[0269] Preferably provided that q + r + s ≥ 1, more preferably ≥ 2, most preferably ≥ 3;

[0270] n is independently selected from 0, 1, 2, 3, and 4, preferably 3;

[0271] R 2 by R 2a-(CR(R')) p -C(Y)- represents, or R 2 together with the group RN- forms a residue represented by R 2a -(G 4 ) v -(CR(R')) u -(G 3 ) t - represents;

[0272] R 2a is a 6- to 10-membered aromatic group, a 5- to 10-membered heteroaromatic group having at most 5 (preferably 3) heteroatoms independently selected from N, O, and S and optionally substituted by C 1-4 alkyl, or a group represented by C 6-10 aryl-NR-C(Y)-N(R)-C 6-10 aryl-, wherein R 2a is optionally substituted by one or more substituents (preferably represented by R 4 ), wherein:

[0273] G 3 is independently selected from C(Y)NR, SONR, SO2NR, CR(R')NR, triazolyl, triazolylCR(R'), and CR(R')triazolyl;

[0274] G 4 is independently selected from C(Y), NRC(Y), NRSO, NRSO2, NRCR(R'), C(Y)NR, SONR, SO2NR, CR(R')NR, triazolyl, NRtriazolyl, triazolylNR, CR(R')triazolyl, and triazolylCR(R');

[0275] Each of t and v is independently 0 or 1;

[0276] u is independently selected from 0, 1, 2, 3, and 4, preferably 3;

[0277] Preferably provided that at least one of t and v is 1, more preferably both t and v are 1;

[0278] Preferably provided that t + u + v ≥ 1, more preferably ≥ 2, most preferably ≥ 3; and

[0279] p is independently 1, 2, 3, or 4, preferably 1 or 2, more preferably 1;

[0280] Wherein one or more occurrences of CR(R') may optionally be replaced by a group independently selected from O, S, C(Y), and NR, provided that no two O atoms are adjacent to each other;

[0281] Each occurrence of Y is independently selected from O, S, NR, and CR(R');

[0282] Each R 3 and R 4 is independently selected from: NH2, OH, COOH, COOR, C 1-6 alkyl, C 1-6 haloalkyl, O(C 1-6 alkyl), O(C 1-6 haloalkyl), O(C 2-6 alkenyl), C 1-6 heteroalkyl, NO2, C(O)NH2, C(O)NR(R'), CN, oxo, and halogen,

[0283] wherein R 3 and R 4 each independently may optionally form, together with any CR(R'), a 4- to 7-membered carbocyclic or heterocyclic ring; and

[0284] Each occurrence of R and R' is independently H or is selected from C 1-6 -alkyl, O(C 1-6 alkyl), 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 of which may optionally be substituted with 1 to 3 substituents selected from C 1-6 -alkyl, OH, oxo, and halogen, or R and R' together represent oxo.

[0285] 2. The compound according to aspect 1, which is represented by the following formula:

[0286]

[0287] wherein R B represents R 2a -(CR(R')) p -C(Y)-N(R)- or R 2a -(G 4 ) v -(CR(R'))u -(G 3 ) v -.

[0288] 3. A compound, its individual diastereoisomers, its hydrates, its solvates, its crystal forms, its individual tautomers, or their pharmaceutically acceptable salts, wherein the structure of the compound comprises at least one group A independently represented by the following structure:

[0289]

[0290] Wherein:

[0291] a and b are each 0 or 1, where a + b is at least 1, preferably where a and b are each 1;

[0292] R 1 is represented by -C(Y)-R 1a -SO2NR(R');

[0293] R 1a is independently a 5-membered heteroaromatic group having at most 3 heteroatoms independently selected from N, O, and S, and wherein in addition to SO2NR(R'), the heteroaromatic group is further substituted by one or more substituents R 3 substituted;

[0294] R 2 is represented by R 2a -(CR(R')) p -C(Y)-;

[0295] R 2a is a 6- to 10-membered aromatic group and is optionally substituted by one or more substituents R 4 substituted; and

[0296] p is independently 1, 2, 3, or 4, preferably 1 or 2, more preferably 1;

[0297] Wherein one or more occurrences of CR(R') may optionally be replaced by a group independently selected from O, S, and NR, provided that no two O atoms are adjacent to each other;

[0298] Each occurrence of Y is independently selected from O, S, NR, and CR(R');

[0299] Each R 3 and R 4 are independently selected from: NH2, OH, COOH, COOR, C 1-6 alkyl, C 1-6 haloalkyl, O(C 1-6 alkyl), O(C 1-6 haloalkyl), O(C2-6 alkenyl), C 1-6 heteroalkyl, NO2, C(O)NH2, C(O)NR(R'), CN, oxo, and halogen,

[0300] wherein R 3 and R 4 each independently may optionally combine with any CR(R') to form a 4- to 7-membered carbocyclic or heterocyclic ring; and

[0301] each occurrence of R and R' is independently H or selected from C 1-6 -alkyl, O(C 1-6 alkyl), 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 of which may optionally be substituted by 1 to 3 substituents selected from C 1-6 -alkyl, OH, oxo, and halogen.

[0302] 4. A compound, its individual diastereoisomers, its hydrates, its solvates, its crystal forms, its individual tautomers, or their pharmaceutically acceptable salts, wherein the compound structure comprises at least one group A independently represented by the following structure:

[0303]

[0304] Wherein:

[0305] a and b are each 0 or 1, where a + b is at least 1, preferably where a and b are each 1;

[0306] R 1 is represented by -C(Y)-R 1a -SO2NR(R');

[0307] R 1a is independently a 5-membered heteroaromatic group having at most 3 heteroatoms independently selected from N, O, and S, and wherein in addition to SO2NR(R'), the heteroaromatic group is further substituted by one or more substituents R 3 ;

[0308] R 2 represented by R 2a -(CR(R')) p -C(Y)-;

[0309] R 2a is a 6- to 10-membered aromatic group and is optionally substituted by one or more substituents R 4 ; and

[0310] p is independently 1 or 2, preferably 1;

[0311] Each occurrence of Y is independently selected from O, S, NR, and CR(R');

[0312] Each R 3 and R 4 is independently selected from: NH2, OH, COOH, COOR, C 1-6 alkyl, C 1-6 haloalkyl, oxo, and halogen; and

[0313] Each occurrence of R and R' is independently H or is selected from C 1-6 -alkyl, O(C 1-6 alkyl), 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 of which may optionally be substituted by 1 to 3 substituents selected from C 1-6 -alkyl, OH, oxo, and halogen.

[0314] 5. A compound according to any one of the foregoing aspects, wherein group A is represented by the formula:

[0315] .

[0316] 6. A compound according to any one of the foregoing aspects, wherein group A is represented by the formula:

[0317] .

[0318] 7. A compound according to any one of the foregoing aspects, wherein:

[0319] a and b are each 1;

[0320] R 1a is independently a 5-membered heteroaromatic group having at most 3 heteroatoms independently selected from N, O, and S, preferably thiophene, and wherein in addition to SO2NR(R'), the heteroaromatic group is further substituted by 1 or 2 substituents R 3 substituted;

[0321] R 2a is a 6- to 10-membered aromatic group, preferably phenyl, substituted by 0, 1, 2, or 3 substituents R 4 substituted;

[0322] p is 1;

[0323] Y is O each time it appears; and / or

[0324] Each R 3 and R 4 are independently selected from OCH3, OCH2CH3, OCH2CH2CH3, OCH2(CH3)2, O-cyclopropyl, OCF3, OCF2CF3, COOH, COOCH3, NO2, CN, F, Cl, Br, and I.

[0325] 8. A compound according to aspect 7, wherein each R 3 and R 4 are independently selected from F, Cl, Br, and I.

[0326] 9. A compound according to any one of the foregoing aspects, wherein A is represented by the following structure A 1 、A 2 or A 3 as follows:

[0327]

[0328] wherein:

[0329] c is independently 1 or 2, preferably 1;

[0330] d is independently 0, 1, 2, 3, 4, or 5, preferably 2;

[0331] W is independently selected from NR, O, S, S(O), and SO2, and preferably S;

[0332] R 3a is independently selected from F, Cl, Br, and I, and preferably Cl;

[0333] R 3bindependently selected from F, Cl, Br, I, and H, and preferably H; and

[0334] R 4a and R 4b are each independently selected from OCH3, OCH2CH3, OCH2CH2CH3, OCH2(CH3)2, O-cyclopropyl, OCF3, OCF2CF3, COOH, COOCH3, NO2, CN, F, Cl, Br, and I, and each is preferably Cl or OCH3.

[0335] 10. A compound according to any of the foregoing aspects, wherein A is represented by the following structure A 4 as follows:

[0336] .

[0337] 11. A compound according to aspect 9 or 10, wherein each R 3 and R 4 is independently selected from F, Cl, Br, and I.

[0338] 12. A compound according to any of the foregoing aspects, wherein A is represented by the following structure A-1:

[0339] .

[0340] 13. A compound according to any of the foregoing aspects, wherein A is represented by the following structure A-5:

[0341] .

[0342] 14. A compound according to any of aspects 1 to 8, wherein A is represented by the following structure A 11 , A 12 , A 13 , or A 14 as follows:

[0343]

[0344] wherein:

[0345] c is independently 1 or 2, preferably 1;

[0346] d is independently 0, 1, 2, 3, 4, or 5, preferably 1;

[0347] W is independently selected from NR, O, S, S(O), and SO2, and preferably S;

[0348] R 3a is independently selected from F, Cl, Br, and I;

[0349] R3b independently selected from F, Cl, Br, I, and H, and preferably H; and

[0350] R 4c independently selected from OCH3, OCH2CH3, OCH2CH2CH3, OCH2(CH3)2, O-cyclopropyl, OCF3, OCF2CF3, COOH, COOCH3, NO2, CN, F, Cl, Br, and I, and preferably NO2; and

[0351] R 4d independently selected from H, OCH3, OCH2CH3, OCH2CH2CH3, OCH2(CH3)2, O-cyclopropyl, OCF3, OCF2CF3, COOH, COOCH3, NO2, CN, F, Cl, Br, and I, and preferably H.

[0352] 15. A compound according to any one of the preceding aspects, wherein A is represented by the following structure A-4:

[0353] .

[0354] 16. A compound according to any one of the preceding aspects, wherein A is represented by any one of the following structures:

[0355]

[0356] .

[0357] 17. A compound according to any one of the preceding aspects, wherein A is represented by the following structure:

[0358] .

[0359] 18. A compound according to any one of the preceding aspects, wherein A is represented by the following structure:

[0360] ,

[0361] wherein W 1 , W 3 , W 4 each independently selected from CH, S, O, and N, where at least one is S or O, preferably where W 1 is S or O, more preferably where W 1 is S and W 3 and W 4 each is N.

[0362] 19. A compound according to any one of the preceding aspects, wherein A is represented by the following structure:

[0363] 。

[0364] 20. A compound according to any of the foregoing aspects, wherein A is represented by the following Structure A-3:

[0365] 。

[0366] 21. A compound according to any of the foregoing aspects, wherein A is represented by the following structure:

[0367] 。

[0368] 22. A compound according to any of the foregoing aspects, wherein A is represented by the following structure:

[0369]

[0370] wherein each of W 1 、W 3 、W 4 is independently selected from CH, S, O, and N, wherein at least one is S or O, preferably wherein W 1 is S or O, more preferably wherein W 1 is S and each of W 3 and W 4 is N.

[0371] 23. A compound according to any of the foregoing aspects, wherein A is represented by any of the following structures:

[0372] 。

[0373] 24. A compound according to any of the foregoing aspects, wherein A is represented by the following Structure A-2:

[0374] 。

[0375] 25. A compound according to any of the foregoing aspects, wherein each R 3 is halogen, and each R 4 is independently selected from O(C 1-6 alkyl), NO2, and halogen.

[0376] 26. A compound according to any of the foregoing aspects, wherein in addition to SO2NR(R'), R 1a is further substituted by a group R 3 , and R 2a is substituted by one or two groups R 4 .

[0377] 27. A compound according to any of the foregoing aspects, wherein R 2a is a phenyl group substituted at positions 4 and 2 on the benzene ring by two groups R 4 or wherein R 4a and R 4b are at positions 4 and 2 of the benzene ring respectively, each position relative to the point of attachment to CR(R').

[0378] 28. A compound according to any of the foregoing aspects, wherein R 1a is substituted by a group R 3 (which is a halogen), and R 2a is substituted by one or two groups R 4 (each independently selected from O(C 1-6 alkyl), NO2 and halogen).

[0379] 29. A compound according to any of the foregoing aspects, wherein R 3 is Cl, and R 4 is selected from OCH3, NO2 and Cl.

[0380] 30. A compound according to any of the foregoing aspects, wherein R 3a is Cl, R 3b is H, R 4a is Cl or OCH3, and R 4b is Cl.

[0381] 31. A compound according to any of the foregoing aspects, wherein R 3a is Cl, R 3b is H, R 4c is NO2, and R 4d is Cl.

[0382] 32. A compound according to any of the foregoing aspects, wherein R 1 is represented by any of the following structures

[0383] or .

[0384] 33. A compound according to any of the foregoing aspects, wherein R 1 is represented by the following structure

[0385] .

[0386] 34. A compound according to any of aspects 1 to 31, wherein R 1 is represented by any of the following structures:

[0387]

[0388] .

[0389] 35. A compound according to any one of aspects 1 to 31, wherein R 1 Represented by the following structure:

[0390] .

[0391] 36. A compound according to any one of the preceding aspects, wherein R 2 is represented by a structure selected from the group consisting of:

[0392] 、 、 、 、 、 、

[0393] 、 、 and ;

[0394] Preferably selected from 、 and .

[0395] 37. A compound according to any one of the preceding aspects, wherein R 2 Depend on express.

[0396] 38. A compound according to any one of aspects 1 to 36, wherein R 2 Depend on express.

[0397] 39. The compound according to any one of aspects 1 to 36, wherein R 2 Depend on express.

[0398] 40. A compound according to any one of the preceding aspects, wherein R 2 Together with the group RN-, it forms a residue R represented by any of the following structures B :

[0399]

[0400]

[0401] .

[0402] 41. A compound according to any one of the foregoing aspects, wherein R 2 and the group RN- together form a residue R represented by the following structure B :

[0403] .

[0404] 42. A compound according to any one of the foregoing aspects, wherein one or more occurrences of the group -SO2NH2 are replaced by a group represented by -OSO2NH2.

[0405] 43. A compound according to any one of the foregoing aspects, wherein the compound is represented by formula I, Ia or Ib

[0406]

[0407] wherein each A is independently defined as in any one of the foregoing aspects;

[0408] B is a single bond or an optionally substituted C 1-50 aliphatic group, wherein optionally one or more carbon atoms may be replaced by a heteroatom, a C 3-12 carbocyclic group or a C 1-12 heterocyclic group, and it may be saturated or optionally contain one or more double or triple bonds; and

[0409] each C is an atom, molecule or particle, and / or a therapeutic or diagnostic agent.

[0410] 44. A compound according to aspect 43, wherein B is a single bond or is represented by any one of the following general formulas II-V, IIa-Va or IIb-Vb:

[0411]

[0412] wherein

[0413] each x is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0414] each y is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0415] each z is 0, 1, 2, 3 or 4, preferably 1;

[0416] provided that in formulas IIa-Va and IIb-Vb, z and at least one of x and y are not 0;

[0417] * represents the point of attachment to the A moiety;

[0418] • represents the point of attachment to the C moiety; and

[0419] B S and B L each independently selected from alkylene, cycloalkylene, aralkylene, heteroaralkylene, heteroalkylene, heterocycloalkylene, alkenylene, cycloalkenylene, aralkenylene, heteroaralkenylene, heteroalkenylene, heterocycloalkenylene, alkynylene, heteroalkynylene, aryl, heteroaryl, aminoacyl, oxyalkylene, iminoalkylene, diester, dialkylsiloxane, amide, thioamide, thioether, thioester, ester, carbamate, hydrazone, thiazolidine, methylenealkoxycarbamate, disulfide, vinylidene, imine, amidine, phosphoramide, sugar, phosphate, phosphoramide, carbamate, dipeptide, tripeptide, tetrapeptide, each of which is optionally substituted.

[0420] 45. A compound according to any one of aspects 43 and 44, wherein B is represented by (B S ) x wherein:

[0421] each x is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;

[0422] each B S is independently selected from the group consisting of alkylene, cycloalkylene, aralkylene, heteroaralkylene, heteroalkylene, heterocycloalkylene, alkenylene, cycloalkenylene, aralkenylene, heteroaralkenylene, heteroalkenylene, heterocycloalkenylene, alkynylene, heteroalkynylene, aryl, heteroaryl, aminoacyl, oxyalkylene, iminoalkylene, diester, dialkylsiloxane, amide, thioamide, thioether, thioester, ester, carbamate, hydrazone, thiazolidine, methylenealkoxycarbamate, disulfide, vinylidene, imine, amidine, phosphoramide, sugar, phosphate, phosphoramide, carbamate, dipeptide, tripeptide, tetrapeptide.

[0423] 46. A compound according to any one of aspects 43 to 45, wherein each B S and B L are independently selected from:

[0424]

[0425]

[0426]

[0427]

[0428]

[0429]

[0430]

[0431]

[0432]

[0433]

[0434] In each of the above structures:

[0435] Each n is independently 0, 1, 2, 3, 4, 5, 6, 7, or 8;

[0436] Each m is independently 0, 1, 2, 3, or 4;

[0437] Each R c , R d and R e is independently selected from H, optionally substituted C 1-6 alkyl, (C3-C 10 carbocyclic)C 1-6 alkyl, (C6-C 10 aryl)C 1-6 alkyl, (C1-C 10 heterocyclic)C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C6-C 10 aryl, in each of which one or more of the carbon atoms may optionally be replaced by a heteroatom; preferably selected from the side chain residues of protein amino acids or non-protein amino acids;

[0438] Each occurrence of R and R' is independently H or selected from C 1-6 -alkyl, O(C 1-6 alkyl), S(C 1-6 -alkyl), 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 of which may optionally be substituted by 1 to 3 selected from C1-6 - substituted with substituents of alkyl, OH, oxo and halogen.

[0439] Each * represents such a point of attachment for which the shortest path to the A moiety contains fewer atoms than for •; and each • represents such a point of attachment for which the shortest path to the C moiety contains fewer atoms than for *, provided that when n is > 1 and the respective points of attachment are indicated on any of R c 、R d and R e then they can independently be present in one or more peptide monomer units, preferably in a peptide monomer unit that is furthest from another point of attachment indicated in their respective structures.

[0440] Each of the above structures optionally contains another point of attachment to the A moiety or the C moiety.

[0441] 47. A compound according to any of the foregoing aspects, wherein the B moiety has one of the following structures:

[0442] (a) a single bond, (B S ) x ,

[0443] 、

[0444]

[0445] 、 、

[0446] 、 、

[0447] 、 、 、 、 、 、

[0448] 、 、

[0449] 、 、 、 、 、 、 ,

[0450] , ,

[0451] and ,

[0452] wherein each of AA3, AA4, AA5, AA6, AA7, and AA8 represents a protein amino acid or a non-protein amino acid, or is absent;

[0453] wherein preferably:

[0454] each protein amino acid or non-protein amino acid is preferably independently represented by one of the following structures:

[0455] , or ;

[0456] and / or AA4 is an amino acid with a charged side chain, and AA7 is an amino acid with an aliphatic side chain;

[0457] wherein more preferably:

[0458] AA3 is selected from Asp, Glu, and Lys, or is absent; preferably Asp;

[0459] AA4 is selected from Arg, HomoArg, Lys, Asp, and Glu, or is absent; preferably Lys or Arg;

[0460] AA5 is selected from Asp, Glu, and Lys; preferably Asp;

[0461] AA6 is selected from Cys, Lys, Gly, and Val; preferably Cys or Lys;

[0462] AA7 is selected from Gly, Ala, Val, Arg, Ile, Pro; and

[0463] AA8 is selected from Pro and citrulline (Cit);

[0464] even more preferably according to one of the sequences shown in the following table:

[0465]

[0466] or

[0467] (b) a single bond, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

[0468] 48. A compound according to any one of the foregoing aspects, having one of the following structures, wherein -D represents -B-C as defined in any one of the foregoing aspects:

[0469] (a) , , , , , , , , or ;

[0470] (b) , ,

[0471] ,

[0472] (c) 、 、

[0473] 、 、

[0474] 、 、

[0475] 、 、

[0476] 、 ;

[0477] or

[0478] (d) 、 or

[0479] wherein, unless otherwise specified, all groups and variables are defined as in any of the foregoing aspects.

[0480] 49. The compound according to any of the foregoing aspects, each -D or -B-C is independently represented by any one of the following structures:

[0481] ; ;

[0482] ; ;

[0483] ; ;

[0484] ; ; ; ; ; ;

[0485] ; ;

[0486] ; ;

[0487] ; ; ; ;

[0488] ; ;

[0489] ;

[0490] ;

[0491] .

[0492] 50. A compound according to any one of the foregoing aspects, wherein each -D or -B-C is independently represented by any one of the following structures:

[0493]

[0494]

[0495] .

[0496] 51. A compound according to any one of the foregoing aspects, wherein the C moiety is a chelating agent group suitable for radiolabeling; a radioactive group containing a radioisotope; a chelate of a radioisotope and a chelating agent; a fluorophore group; a cytotoxic agent and / or a cytostatic agent; an immunomodulator; or a protein,

[0497] wherein preferably:

[0498] (a) The chelating agent group suitable for radiolabeling is selected from sulfur colloid, diethylenetriaminepentaacetic acid (DTPA), ethylenediaminetetraacetic acid (EDTA), 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA), 1,4,7-triazacyclononane-N,N',N''-triacetic acid (NOTA), 1,4,8,11-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid (TETA), iminodiacetic acid, bis(carboxymethylimidazole)glycine, 6-hydrazinopyridine-3-carboxylic acid (HYNIC),

[0499] ; ; ; ; ; ; ; ; ; ; ; ; ;

[0500] ; ; ; ; or

[0501] has a structure according to the following formula:

[0502]

[0503] wherein:

[0504] n is 0, 1, 2, 3, 4 or 5; preferably 1;

[0505] R 1e is independently H, COOH, aryl-COOH or heteroaryl-COOH; preferably COOH;

[0506] R 2e is independently H, COOH, aryl-COOH or heteroaryl-COOH; preferably COOH;

[0507] each R 3e is independently H, COOH, aryl-COOH or heteroaryl-COOH; preferably COOH;

[0508] R 4e is independently H, COOH, aryl-COOH or heteroaryl-COOH; preferably COOH; and

[0509] X is O, NH or S; preferably O; or

[0510] has a structure according to the following formula:

[0511]

[0512] wherein:

[0513] n is 0, 1, 2, 3, 4 or 5; preferably 1;

[0514] R 1f is independently H, COOH, aryl-COOH or heteroaryl-COOH; preferably COOH;

[0515] R 2f is independently H, COOH, aryl-COOH or heteroaryl-COOH; preferably COOH;

[0516] R 3f is independently H, COOH, aryl-COOH or heteroaryl-COOH; preferably COOH; and

[0517] X is O, NH or S; preferably O;

[0518] (b) The radioactive group containing a radioisotope is selected from 223 Ra,89 Sr, 94m Tc, 99m Tc, 186 Re, 188 Re, 203 Pb, 67 Ga, 68 Ga, 47 Sc, 111 In, 97 Ru, 62 Cu, 64 Cu, 86 Y, 88 Y, 90 Y, 121 Sn, 161 Tb, 153 Sm, 166 Ho, 105 Rh, 177 Lu, 123 I, 124 I, 125 I, 131 I, 18 F, 211 At, 225 Ac, 89 Sr, 225 Ac, 117m Sn, 169 Er and 227 Th;

[0519] (c) The chelate of the radioisotope is a chelate of the isotope listed in (b) above and / or with the chelating agent listed in (a) above; or Part C is a group selected from any one of the following structures:

[0520]

[0521] and

[0522] wherein X is CH, O, N or S, preferably CH;

[0523]

[0524] wherein M is a radioisotope, preferably selected from the list in (b) above; more preferably:

[0525]

[0526]

[0527] or

[0528] (d) The fluorophore group is selected from xanthene dyes, acridine dyes, oxazine dyes, cyanine dyes, styryl dyes, coumarin dyes, porphine dyes, fluorescent metal-ligand complexes, fluorescent proteins, nanocrystals, perylene dyes, boron-dipyrromethene dyes, and phthalocyanine dyes, and is preferably selected from the following structures:

[0529]

[0530]

[0531]

[0532]

[0533]

[0534]

[0535] (e) The cytotoxic agent and / or cytostatic agent is selected from chemotherapeutic agents, and the chemotherapeutic agents are selected from the group consisting of: topoisomerase inhibitors, alkylating agents, antimetabolites, antibiotics, mitotic disruptors, DNA intercalators, DNA synthesis inhibitors, DNA-RNA transcription regulators, enzyme inhibitors, gene regulators, hormone response regulators, hypoxia-selective cytotoxins, epidermal growth factor inhibitors, antiangiogenic agents, and combinations of two or more thereof, and is preferably selected from the following structures:

[0536]

[0537]

[0538]

[0539]

[0540]

[0541]

[0542]

[0543]

[0544]

[0545]

[0546]

[0547]

[0548]

[0549] or

[0550] Part C is an auristatin derivative, preferably having a structure according to the following formula:

[0551]

[0552] wherein:

[0553] R 1d is independently H or a C1-C6 alkyl; preferably H or CH3;

[0554] R 2d is independently a C1-C6 alkyl; preferably CH3 or iPr;

[0555] R 3d is independently H or a C1-C6 alkyl; preferably H or CH3;

[0556] R 4d is independently H, a C1-C6 alkyl, COO(C1-C6 alkyl), CON(H or C1-C6 alkyl), C3-C 10 aryl or C3-C 10 heteroaryl; preferably H, CH3, COOH, COOCH3 or thiazolyl;

[0557] R 5d is independently H, OH, a C1-C6 alkyl; preferably H or OH; and

[0558] R6d independently is C3-C 10 aryl or C3-C 10 heteroaryl; preferably optionally substituted phenyl or pyridyl,

[0559] wherein preferably, the C moiety is derived from MMAE or MMAF; or

[0560] a topoisomerase inhibitor; preferably camptothecin (CPT) or a derivative thereof; more preferably derived (e.g., by substituting a hydrogen atom) from topotecan, irinotecan, silatecan, cositecan, exatecan, lurtotecan, gimatecan, belotecan, rubitecan, deruxtecan, DXd; even more preferably exatecan; even more preferably

[0561] 、 、 or where each n is 0, 1, 2, 3, 4, 5 or 6; and most preferably ,

[0562] (f) The immunomodulator is selected from molecules known to be able to modulate the immune system, such as ligands of CD3, CD25, TLRs, STING, 4-1BBL, 4-1BB, PD-1, mTor, PDL-1, NKG-2D IMiDs, where these ligands can be agonists and / or antagonists; or

[0563] (g) The protein is selected from cytokines, such as IL2, IL10, IL12, IL15, TNF, interferon γ, or is an antibody.

[0564] 52. The compound according to any one of the foregoing aspects, wherein:

[0565] (a) A-B is represented by a structure selected from the following:

[0566] 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ;

[0567] and / or

[0568] (b) C is represented by a structure selected from the following:

[0569] , , , , , , , , , , , , , , , ,

[0570] , , , , , , , , , , , , , , ,

[0571] , , , ,

[0572] , , , , , , ,

[0573]

[0574] wherein the combination of A - B and C is preferably selected such that the covalent bond connecting B and C is represented by S - S, S - C, C - S, C(O) - R a , C(O) - N, C(O) - O, C(O) - N, N - C(O), N - C(O)O, N - C(S) or OC(O) - N.

[0575] 53. A compound according to any one of the foregoing aspects, wherein the A moiety is selected from A - 1 to A - 5.

[0576] 54. A compound according to any one of the foregoing aspects, wherein the B moiety is selected from B - 1 to B - 21.

[0577] 55. A compound according to any one of the foregoing aspects, wherein the C moiety is selected from C - 1 to C - 31.

[0578] 56. A compound having a structure selected from Table 1, Table 3.1, Table 3.2, Figure 30 , Figure 31 , Figure 33 or Figure 34 listed, its individual diastereoisomers, its hydrates, its solvates, its crystalline forms, its individual tautomers or their pharmaceutical salts.

[0579] 57. A pharmaceutical composition comprising a compound according to any one of the foregoing aspects and a pharmaceutical excipient.

[0580] 58. A compound or pharmaceutical composition according to any one of the foregoing aspects, for use in:

[0581] (a) a method for treating the human or animal body by surgery or therapy or a diagnostic method practiced on the human or animal body; or

[0582] (b) A method for the treatment or prevention of a subject suffering from a disease or disorder or at risk of having a disease or disorder; or

[0583] (c) A method for performing guided surgery on a subject suffering from a disease or disorder or at risk of having a disease or disorder; or

[0584] (d) A method for diagnosing a disease or disorder, the method being performed on a human or animal body and involving nuclear medicine imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT); or

[0585] (e) A method for the targeted delivery of a therapeutic or diagnostic agent to a subject suffering from a disease or disorder or at risk of having a disease or disorder.

[0586] 59. The compound or pharmaceutical composition used according to aspect 58, wherein the disease or disorder is independently selected from hypoxia-related diseases such as cancer, preferably wherein the cancer is selected from the group consisting of breast cancer, pancreatic cancer, colon cancer, multi-drug resistant colon cancer, rectal cancer, colorectal cancer, metastatic colorectal cancer, lung cancer, non-small cell lung cancer, head and neck cancer, ovarian cancer, hypopharyngeal cancer, nasopharyngeal cancer, laryngeal cancer, bladder cancer, cholangiocarcinoma, clear cell renal cell carcinoma, glioma, astrocytoma, cervical cancer and renal cancer.

[0587] Examples

[0588] Example 1 - Synthesis of Derivatives

[0589] 1.1 General

[0590] Liquid chromatography / mass spectrometry (LC / MS) spectra were recorded on a Waters Acquity UPLC H-Class system coupled to an ESI-ToF-MS (Waters Xevo G2XS Qtof), equipped with a Waters Acquity BEH C18 column (2.1 × 50 mm, 130 Å, 1.7 µm). A gradient of eluent A (MilliQ water with 0.1% formic acid) and eluent B (acetonitrile with 0.1% formic acid) (5% to 80% B, in 6 minutes) was applied at a column temperature of 40°C and a flow rate of 0.6 mL / min.

[0591] Medium pressure liquid chromatography (MPLC) in the reverse phase

[0592] Purify small organic molecules that may be produced in relatively high amounts (>10 mg) by medium-pressure reverse-phase liquid chromatography (BUCHI) on a C18 40 μM irregular 12 g column (BUCHI, #145152103) using mQ micropure water 0.1% formic acid (FA) (eluent A) and acetonitrile 0.1% FA (eluent B) as mobile phases with the following gradient: 0 - 5 min 98% A, 5 - 45 min 98% to 0% A, 45 - 50 min 0% A, 50 - 50.1 min 0% to 98% A, and 50.1 - 55 min 98% A. Set the flow rate to 30 mL / min.

[0593] Reverse-phase high-performance liquid chromatography (HPLC)

[0594] Purify the final products and conjugates by semi-preparative RP-HPLC on an Agilent 1200 series reverse-phase high-performance liquid chromatography (RP-HPLC) equipped with a PDA UV detector. The system is equipped with a Synergi 4 μm, Polar-RP 80 Å 10 × 150 mm C18 column and uses a flow rate of 5 mL / min with the following gradient of eluent A (mQ micropure water 0.1% TFA) and eluent B (acetonitrile with 0.1% TFA): 0 - 15 min 90% to 0% A, 15 - 16 min 0% A, 16 - 17 min 0% to 90% A, 17 - 18 min 90% A.

[0595] 1.2 Solid-phase synthesis

[0596] General solid-phase synthesis procedure

[0597] Perform solid-phase synthesis using pre-packed Fmoc-Lys(Boc)-Wang resin (200 - 400 mesh, 0.5 mmol / g; Bachem, #4003241.0005). Generally, prior to any reaction step, swell the resin in dimethylformamide (DMF) for 30 minutes. Incubate at room temperature in a 10 mL reaction column (CEM Corporation, #32.276) on a rotary mixer (Reax 2, Heidolph Instruments GmbH & Co. KG).

[0598] Fmoc deprotection

[0599] Incubate the resin with 20% piperidine in DMF for 2 × 15 minutes. After deprotection, wash the resin 5 - 10 times with DMF to remove residual piperidine.

[0600] Micro-cleavage for LC-MS analysis

[0601] Transfer a small portion of the resin into an Eppendorf tube and incubate it with 20 µL of trifluoroacetic acid (TFA) for 15 minutes at room temperature. Before LC-MS analysis, quench the cleavage by adding 100 µL of DMF and centrifuging the suspension (1 minute, at 10’000 rcf).

[0602] Azide reduction

[0603] After swelling in DMF, incubate the resin with a solution of trimethylphosphine (5 equivalents) in THF:water (10% water in THF). The reaction is carried out for 2 hours at room temperature, and then the beads are washed 10 times with DMF.

[0604] Amide coupling

[0605] Typically, dissolve the acid (2 equivalents), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 1.9 equivalents), and diisopropylethylamine (DIPEA, 4 equivalents) in DMF and add to the resin bearing the chemical moiety with a free amino group. After incubation for 4 hours, the resin is then washed five times with DMF. The coupling efficiency can be monitored by LC-MS analysis (micro-cleavage).

[0606] Resin cleavage and purification

[0607] Prepare the cleavage solution as follows: 95% trifluoroacetic acid (TFA), 2.5% water, and 2.5% triisopropylsilane (TIPS). In the case specifically indicated, add 2.5% thioanisol and 2.5% m-cresol as scavengers. The highest yield is obtained when three consecutive cleavages are performed (1 hour each at room temperature). Combine the cleavage fractions and purify directly via RPHPLC or precipitate in diethyl ether for subsequent purification (see below).

[0608] Peptide precipitation

[0609] For peptide constructs, the product can be precipitated from the cleavage solution by adding 5 - 10 volumes of ice-cold diethyl ether. The precipitation is carried out at -20 °C for 30 minutes to obtain the peptide as a pellet by centrifugation (3200 rcf, 5 minutes, 4 °C). Dissolve the crude product in water:acetonitrile (1:1) for purification by reverse-phase chromatography.

[0610] 1.2.1 Synthesis of Intermediates I1 - I4 (Intermediate I4 = Compound C9)

[0611]

[0612]

[0613]

[0614] The pre-loaded Fmoc-Lys(Boc)-Wang resin (1 g scale) was swollen for subsequent Fmoc deprotection. The tripeptide Lys-Asp-βAla-NH2 was generated by iterative amide coupling and Fmoc deprotection according to the general procedure, however the equivalents used for amide coupling were doubled (4 eq. acid, 3.9 eq. HATU, 8 eq. DIPEA). The loading sequence was: N-(fluorenylmethoxycarbonyl)-N6-(tert-butoxycarbonyl)-L-lysine (pre-loaded), N-(fluorenylmethoxycarbonyl)-L-aspartic acid tert-butyl ester, N-(fluorenylmethoxycarbonyl)-β-alanine. The tripeptide linker synthesized on the resin was divided into four 250 mg batches (each batch corresponding to a loading capacity of 0.125 mmol). Each batch was coupled with one isomer (RR, SS, RS, SR) of the proline derivative according to the standard protocol for amide coupling. After Fmoc deprotection, I6 was coupled at lower equivalents (47 mg, 0.138 mmol, 1.1 eq. acid; 47.5 mg, 0.125 mmol, 1 eq. HATU and 174 μL DIPEA, 1 mmol, 8 eq. DIPEA), leaving the reaction overnight. Subsequently, azide reduction was carried out by coupling 2-(2,4-dichlorophenyl)acetic acid using 6 eq. acid (154 mg, 0.75 mmol), 5 eq. HATU (238 mg, 0.625 mmol) and 8 eq. DIPEA (174 μL, 1 mmol). The reaction was carried out overnight at room temperature. Finally, I1, I2, I3 and I4 were cleaved from the resin, precipitated with ice-cold diethyl ether and purified via RP-HPLC to give the products as white solids: I1 (SS, 5.3 mg, 5% yield), I2 (SR, 4.1 mg, 4% yield), I3 (RS, 6.2 mg, 6% yield), I4 = C9 (RR, 7.8 mg, 7% yield). C 31 H 39 Cl3N7O 11 S2 [M+H] + Calculated m / z for : 854.1209, found (TOF MS ES+): 854.0676, 855.1398 (I1); 854.0635, 859.1329 (I2); 854.1383, 856.1353 (I3); 854.1379 (I4 = C9).

[0615] 1.2.2 Synthesis of Intermediate I5

[0616]

[0617] As described above, the tripeptide linker Lys-Asp-βAla-NH2 was synthesized on resin (125 mg, 0.06 mmol) and reacted with the acetazolamide derivative (4-oxo-4-[(5-sulfamoyl-1,3,4-thiadiazol-2-yl)amino]butyric acid, 73 mg, 0.21 mmol, 4 equivalents) in DMF in the presence of HATU (81 mg, 0.21 mmol, 4 equivalents) and DIPEA (300 μL, 1.72 mmol, 8 equivalents). After 4 h at room temperature, the resin was washed with DMF and then I5 was cleaved from the resin and purified by RP-HPLC to give I5 as a white solid (2.7 mg, 7.6% yield). C 19 H 31 N8O 10 S2 [M+H] + Calculated m / z for: 595.1599, found (TOF MS ES+): 595.1688.

[0618] 1.3 Solution-phase synthesis

[0619] 1.3.1 Synthesis of Intermediate I6

[0620]

[0621] Fisher esterification, Boc protection, and ester hydrolysis were carried out without purification of the reaction intermediates. 5-Chloro-2-sulfamoylthiophene-3-carboxylic acid (500 mg, 2.07 mmol, 1 equivalent) was dissolved in 25 mL of methanol and 2.6 mL of 4 M HCl dioxane solution (10.4 mmol, 5 equivalents). The solution was refluxed overnight and the solvent was evaporated under reduced pressure to give the crude product. The residue was dissolved in 20 mL of dichloromethane (DCM) and 569 μL of bis(2-methyl-2-propyl) dicarbonate (540 mg, 2.47 mmol, 1.2 equivalents), 101 mg of N,N-dimethylpyridin-4-amine (DMAP; 0.83 mmol, 0.4 equivalents), and 342 μL of triethylamine (TEA, 2.47 mmol, 1.2 equivalents) were added thereto. After 3 h at room temperature, LC-MS analysis showed completion of the reaction. The solvent was evaporated under reduced pressure and the crude product was placed in 20 mL of water:THF (1:1). 1.3 mL of 8 M NaOH aq (10.4 mmol, 5 equivalents) was added to initiate ester hydrolysis, which was carried out at room temperature for 3 h. The solution was adjusted to pH 2 with 1 M HCl aqNeutralize and evaporate the solvent. Dissolve the crude product in acetonitrile:water (1:1) and purify by RP-MPLC to obtain I6 as a white solid (320 mg, 45% yield). C 10 H 11 ClNO6S2 [M-H] - Calculated m / z for 11 : 339.9722, found (TOF MS ES-): 339.9702.

[0622] 1.3.2 Synthesis of Intermediate I7

[0623]

[0624] Dissolve 2-(2,4-dichlorophenyl)acetic acid (5 mg, 23 μmol, 1 equiv) in DMF and preactivate for 10 min by adding EDC (4 μL, 23 μmol, 1 equiv), HOBt (3 mg, 23 μmol, 1 equiv), and DIPEA (15.9 μL, 91 μmol, 4 equiv). Add (2R,4R)-4-amino-1,2-pyrrolidinedicarboxylic acid 1-tert-butyl 2-methyl ester hydrochloride (6.4 mg, 23 μmol, 1 equiv) to the preactivated solution and incubate at room temperature for 4 h. Evaporate the solution and place the residue in 200 μL of TFA. After 1 h at room temperature, evaporate the TFA under reduced pressure, place the residue in water, and lyophilize to continue coupling to I6 (7.7 mg, 23 μmol, 1 equiv) under the same conditions described for the first coupling step. After 1 h of Boc deprotection in TFA (200 μL) at room temperature, evaporate the TFA and neutralize with 1 M NaOH aq Subsequently, perform ester hydrolysis at room temperature for 2 h using NaOH (230 μL of 1 M NaOH aq , 230 μmol, 10 equiv) in 500 μL of water:THF (1:1). After neutralization with 1 M HCl aq , evaporate the solvent under reduced pressure to purify the crude product by RP-HPLC. Lyophilize the product to obtain I7 as a white solid: RR (3.9 mg, 32% yield). C 18 H 17 Cl3N3O6S2 [M+H] + Calculated m / z for 17 : 539.9619, found (TOF MS ES+): 539.9050, 540.9713.

[0625] 1.3.3 Synthesis of Intermediate I8

[0626]

[0627] Dissolve (2R,4R)-4-amino-1,2-pyrrolidinedicarboxylic acid 1-tert-butyl 2-methyl ester hydrochloride (5.5 mg, 19.6 μmol, 1 equiv) in 500 μL of DCM for acetylation reaction by adding acetic anhydride (18.5 μL, 196 μmol, 10 equiv) and TEA (13.7 μL, 98.3 μmol, 5 equiv). After 1 h at room temperature, evaporate the solvent and place the dry residue in 200 μL of TFA for Boc deprotection at room temperature for 1 h. Evaporate TFA under reduced pressure and place the residue in 10 mL of water:acetonitrile (1:1) to lyophilize the crude overnight. Preactivate I6 (6.7 mg, 19.6 μmol, 1 equiv) with a DMF solution of EDC (3.5 μL, 19.8 μmol, 1 equiv), HOBt (2.6 mg, 19.2 μmol, 1 equiv) and DIPEA (13.7 μL, 78.6 μmol, 4 equiv) at room temperature for 10 min, then add the solution to the acetylated intermediate. Leave the coupling at room temperature for 4 h, followed by Boc deprotection in TFA and saponification with NaOH (200 μL 1 M NaOH aq , 200 μmol, 10 equiv) in 400 μL of water:THF (1:1). Neutralize the hydrolysis mixture with 1 M HCl aq to evaporate the solvent and purify the product via RP-HPLC to give I8 as a white solid (2.4 mg, 31% yield). C 12 H 15 ClN3O6S2 [M+H] + Calculated m / z: 396.0085, found (TOF MS ES+): 396.0050.

[0628] 1.3.4 Synthesis of Intermediate I9

[0629]

[0630] At room temperature, 2-(2,4-dichlorophenyl)acetic acid (3.9 mg, 17.6 μmol, 1 equiv) was pre-activated for 10 min with a DMF solution of EDC (3.1 μL, 17.6 μmol, 1 equiv), HOBt (2.4 mg, 17.8 μmol, 1 equiv), and DIPEA (12.2 μL, 70 μmol, 4 equiv) to initiate coupling by the addition of (2R,4R)-4-amino-1,2-pyrrolidinedicarboxylic acid 1-tert-butyl 2-methyl ester hydrochloride (4.9 mg, 17.5 μmol, 1 equiv). After 4 h at room temperature, the solvent was evaporated and the residue was dissolved in water:THF (1:1) containing NaOH (180 μL 1 M NaOH aq , 180 μmol, 10 equiv). Esterification was carried out for 2 h at room temperature and terminated by neutralizing the solution with 1 M HCl aq and evaporating the solvent. The crude product was purified by RP-HPLC to give I9 as a white solid (2.7 mg, 39% yield). C 15 H 17 Cl2N2O4 [M+H] + Calculated m / z for: 359.0560, found (TOF MS ES+): 359.0451.

[0631] 1.3.5 Synthesis of Intermediate I10

[0632]

[0633] At room temperature, tert-butyl N-[2-[2-(2-aminoethoxy)ethoxy]ethyl]carbamate (50 mg, 0.20 mmol, 1 equiv) was dissolved in 5 mL of DMF and mixed with a DMF solution of FITC (78 mg, 0.20 mmol, 1 equiv) and DIPEA (140 μL, 0.80 mmol, 4 equiv) for 1 h. The solvent was evaporated under reduced pressure and the residue was placed in 2 mL of TFA. After 30 min at room temperature, the TFA was evaporated and the crude product was purified by RP-MPLC. The product I10 was obtained as a yellow solid (36.8 mg, 34% yield). C 27 H 28 N3O7S [M+H] + Calculated m / z for: 538.1642, found (TOF MS ES+): 538.1675.

[0634] 1.3.6 Synthesis of Compounds C1, C3, C5 and C7

[0635]

[0636] Dissolve I1, I2, I3, and I4 (2 mg, 2.3 µmol, 1 equiv) separately in 200 µL of DMSO. After adding 1.1 mg of NHS-Fluorescein (2.3 µmol, 1 equiv) and 1 µL of DIPEA (5.7 µmol, 2.5 equiv), the mixture was incubated at room temperature in an orbital incubator for 1 h. The crude product was purified by RP-HPLC, and the product fractions were lyophilized to give yellow powders: C1 (SS, 1.2 mg, 43% yield), C3 (SR, 0.71 mg, 29% yield), C5 (RS, 0.70 mg, 29% yield), C7 (RR, 0.90 mg, 32% yield). C 52 H 49 Cl3N7O 17 S2 [M+H] + Calculated m / z for: 1212.1686, found (TOF MS ES+): 1212.1664, 1213.2268 (C1); 1212.2241, 1214.2233 (C3), 1212.2245, 1214.2238 (C5); 1212.2231, 1214.2224 (C7).

[0637] 1.3.7 Synthesis of Compounds C2, C4, C6 and C10

[0638]

[0639] Load I1, I2, I3, and I4 (72 µg, in 72 µL of DMSO, 0.084 µmol, 1 equiv) separately into Eppendorf tubes to which 0.3 µL of DIPEA (1.7 µmol, 20 equiv) was added. After adding 50 µL of IRDye® 750 NHS ester (LI-COR Biosciences) pre-dissolved in DMSO (100 µg, 0.084 µmol, 1 equiv), the reaction was carried out overnight at room temperature in an orbital incubator. The product was separated by RP-HPLC, lyophilized (green solid) and dissolved in 100 µL of sterile PBS to measure the concentration by Nandrop (absorbance at λ = 756 nm, extinction coefficient = 260’000 M -1 cm -1 ): C2 (SS, 0.035 µmol, 42% yield), C4 (SR, 0.040 µmol, 48% yield), C6 (RS, 0.028 µmol, 33% yield), C10 (RR, 0.033 µmol, 39% yield). C80 H 97 Cl3N9O 24 S6 [M+H] + Calculated m / z value: 1864.4031, detected values (MALDI-TOF MS +): 1864.40, 1866.41 (C2); 1864.39, 1866.39 (C4); 1864.40, 1866.40 (C6); 1864.41, 1866.41 (C10).

[0640] 1.3.8 Synthesis of Compounds C8, C12 and C13

[0641]

[0642] C8, C12, and C13 were carried out according to the conventional procedure: acid pre-activation was carried out for 10 minutes at room temperature using a DMF solution of EDC (1 equivalent), HOBt (1 equivalent), and DIPEA (4 equivalents), followed by the addition of I10 (1 equivalent). After 1 hour at room temperature, the mixture was purified by RP-HPLC to obtain the products as yellow solids: C8 (1.1 mg, 53% yield), C12 (0.6 mg, 21% yield), C13 (0.8 mg, 38% yield).

[0643] C8 C 45 H 42 Cl3N6O 12 S3 [M+H] + Calculated m / z value: 1059.1083, detected values (TOF MS ES+): 1059.1521, 1063.1473.

[0644] C12 C 39 H 40 ClN6O 12 S3 [M+H] + Calculated m / z value: 915.1549, detected values (TOF MS ES+): 915.1887, 917.1851.

[0645] C13 C 42 H 42 Cl2N5O 10 S [M+H] + Calculated m / z value: 878.2024, detected values (TOF MS ES+): 878.2299, 880.2289.

[0646] 1.3.9 Synthesis of Compound C11

[0647]

[0648]

[0649] I4 (0.5 mg, 0.58 µmol, 1 equiv), DOTA-GA anhydride (0.27 mg, 0.58 µmol, 1 equiv), DIPEA (1 µL, 5.8 µmol, 10 equiv), DMAP (2.9 µL of a 100 mM DMSO solution, 0.29 µmol, 0.5 equiv) and 95 µL of DMSO were loaded into an Eppendorf tube. The mixture was incubated at room temperature for 3 h and the crude product was purified by RP-HPLC to give product C11 as a white solid (0.30 mg, 39% yield). C 50 H 69 Cl3N 11 O 20 S2 [M+H] + Calculated m / z for: 1312.3222, found (TOF MS ES+): 1312.3872, 1314.3866.

[0650] 1.3.10 Compound C11 was labeled with 177 Lu]Lu radioactivity

[0651]

[0652] C11 was dissolved in MilliQ water with 4% DMSO to a concentration of 1 mM and 39 µL (39 nmol, 1 equiv) of this was diluted with 74 µL of 1 M acetate buffer pH 4.5. After addition of 4.2 µL 177 Lu]LuCl3 (11 MBq, ITM Radio Pharma), the mixture was heated at 95 °C for 10 min and passively cooled to room temperature to allow complexation. 177 Lu]Lu-C11 was diluted with 663 µL of PBS. The labeling efficiency was monitored by RP-HPLC (see Figure 23 ).

[0653] 1.3.11 Synthesis of Compound C14

[0654]

[0655] Dissolve I6 (1.2 mg, 3.5 μmol, 1 equiv) in 100 μL of DMF for pre-activation with EDC (0.6 μL, 3.4 μmol, 1 equiv), HOBt (0.5 mg, 3.7 μmol, 1 equiv), and DIPEA (2.5 μL, 14 μmol, 4 equiv). After 10 minutes at room temperature, add I10 (1.9 mg, 3.5 μmol, 1 equiv) for coupling at room temperature in the dark for 1 h. Evaporate the solvent under reduced pressure and dissolve the residue in TFA for Boc deprotection at room temperature for 15 min, then purify directly by RP-HPLC to give C14 as a yellow solid (1.1 mg, 43% yield). C 32 H 30 ClN4O 10 S3 [M+H] + Calculated m / z for : 761.0807, found (TOF MS ES+): 761.1006.

[0656] 1.3.12 Synthesis of Compound C15 (AAZ*)

[0657]

[0658] Place I5 (1.2 mg, 2.0 μmol, 1 equiv) in 100 μL of DMF and add to it FITC (3',6'-dihydroxy-6-isothiocyanatospiro[2-benzofuran-3,9'-xanthene]-1-one, 0.8 mg, 2.1 μmol, 1 equiv) and DIPEA (1.4 μL, 8.0 μmol, 4 equiv). After 1 h at room temperature, purify the crude product by RP-HPLC and lyophilize the combined product fractions overnight. Obtain the final product C15 (AAZ*) as a yellow solid (0.51 mg, 26% yield). C 40 H 42 N9O 15 S3 [M+H] + Calculated m / z for : 984.1957, found (TOF MS ES+): 984.2300.

[0659] 1.3.13 Synthesis of Intermediate I11

[0660]

[0661] At 0 °C, (2R,4R)-4-aminopyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl ester) 2-methyl ester (50 mg, 205 μmol, 1 equiv) was treated with a solution of 4-nitrophenyl chloroformate (41 mg, 205 μmol, 1 equiv) and DIPEA (71 μL, 409 μmol, 2 equiv) in anhydrous DCM for 10 minutes. 5-Amino-1,3,4-thiadiazole-2-sulfonamide (41 mg, 225 μmol, 1.1 equiv) was added, and the reaction mixture was stirred at room temperature for 1 h. The solvent was evaporated, and the residue was taken up in 1 mL of TFA. After 1 h at room temperature, the TFA was evaporated, and the crude product was purified by RP-HPLC to give I11 as a colorless oil (59 mg, 82%).

[0662] 1.3.14 Synthesis of Intermediate I12

[0663]

[0664] I6 (20.4 mg, 50.7 μmol, 1.1 equiv) was dissolved in DMF and pre-activated for 1 minute by the addition of benzotriazol-1-yloxy(tripyrrolidin-1-yl)phosphonium hexafluorophosphate (PyBOP, 36.7 mg, 70.5 μmol, 1.3 equiv) and DIPEA (28.3 μL, 162.7 μmol, 3 equiv). I11 (19 mg, 54.2 μmol, 1 equiv) was added to the pre-activated solution, and the mixture was incubated at room temperature for 16 h. The solvent was evaporated, and the residue was taken up in 500 μL of TFA. After 1 h at room temperature, the TFA was evaporated, followed by neutralization with 1 M NaOH aq Subsequently, the ester hydrolysis was carried out at room temperature for 3 h using NaOH (540 μL of 1 M NaOH aq , 540 μmol, 10 equiv) in 1 mL of water:THF (1:1). After neutralization with 1 M HCl aq , the solvent was evaporated under reduced pressure, and the crude product was purified by RP-HPLC to give I12 as a white solid (5 mg, 17%).

[0665] 1.3.15 Synthesis of Intermediate I13

[0666]

[0667] 2-(2,4-Dichlorophenyl)acetic acid (3 mg, 15 μmol, 1 equiv) was dissolved in DMF and pre-activated for 10 min by addition of EDC (2.6 μL, 15 μmol, 1 equiv), HOBt (1.8 mg, 15 μmol, 1 equiv) and DIPEA (10.5 μL, 60 μmol, 4 equiv). (2R,4R)-4-Amino-1,2-pyrrolidinedicarboxylic acid 1-tert-butyl 2-methyl ester hydrochloride (4.2 mg, 15 μmol, 1 equiv) was added to the pre-activated solution and incubated at room temperature for 4 h. The solvent was evaporated and the residue was placed in 200 μL of TFA. After 1 h at room temperature, the TFA was evaporated under reduced pressure, the residue was placed in water and lyophilized to proceed with coupling to 4-oxo-4-[(5-sulfamoyl-1,3,4-thiadiazol-2-yl)amino]butyric acid (4.65 mg, 16.6 μmol, 1.1 equiv) pre-activated with PyBOP (10.2 mg, 19.6 μmol, 1.3 equiv) and DIPEA (7.9 μL, 45.3 μmol, 3 equiv). After incubation at room temperature for 16 h, the solvent was evaporated. Subsequently, ester hydrolysis was carried out at room temperature for 3 h using NaOH (150 μL 1 M NaOH aq , 150 μmol, 10 equiv) in 300 μL of water:THF (1:1). After neutralization with 1 M HCl aq , the solvent was evaporated under reduced pressure and the crude product was purified by RP-HPLC to afford I13 as a white solid (2.3 mg, 26%).

[0668] 1.3.16 Synthesis of Intermediate I14

[0669]

[0670] (2R,4R)-1-(((9H-Fluoren-9-yl)methoxy)carbonyl)-4-azidopyrrolidine-2-carboxylic acid (25 mg, 66 µmol, 1 equiv) was dissolved in a solution of 10 mL of methanol and 83 µL of 4 M HCl in dioxane (330 µmol, 5 equiv). The solution was refluxed for 16 h to give the crude product after evaporation of the solvent under reduced pressure. The residue was dissolved in DMF containing 20% piperidine. After stirring for 1 h, the solvent was evaporated. A pre-activated solution of I6 (22.6 mg, 66 µmol, 1 equiv), HATU (22.6 mg, 59 µmol, 0.9 equiv) and DIPEA (23 µL, 132 µmol, 2 equiv) was stirred for 10 min and then added to the dried intermediate. After 3 h at room temperature, the crude product was purified by RP-HPLC to give I14 (21.5 mg, 73%) as a white solid.

[0671] 1.3.17 Synthesis of Intermediate I15

[0672]

[0673] I14 (5 mg, 10.1 µmol, 1 equiv) was placed in tBuOH:water (1:1) together with N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl)hex-5-ynamide (2.8 mg, 10.1 µmol, 1 equiv), CuSO4(H2O)5 (2 mg, 10.1 µmol, 1 equiv) and sodium ascorbate (2.5 mg, 10.1 µmol, 1 equiv). The reaction mixture was stirred at 60 °C for 16 h and then the solvent was evaporated. Subsequently, ester hydrolysis was carried out at room temperature for 3 h using NaOH (100 µL of 1 M NaOH aq , 100 µmol, 10 equiv) in 200 µL of water:THF (1:1). After neutralization with 1 M HCl aq , the solvent was evaporated under reduced pressure and the crude product was purified by RP-HPLC to give I15 as a white solid (5.3 mg, 80%).

[0674] 1.3.18 Synthesis of Intermediate I16

[0675]

[0676] 2-(2,4-Dichlorophenyl)acetic acid (3 mg, 15 μmol, 1 equiv) was dissolved in DMF and pre-activated for 10 min by addition of EDC (2.6 μL, 15 μmol, 1 equiv), HOBt (1.8 mg, 15 μmol, 1 equiv) and DIPEA (10.5 μL, 60 μmol, 4 equiv). (2R,4R)-4-Amino-1,2-pyrrolidinedicarboxylic acid 1-tert-butyl 2-methyl ester hydrochloride (4.2 mg, 15 μmol, 1 equiv) was added to the pre-activated solution and incubated at room temperature for 4 h. The solvent was evaporated and the residue was placed in 200 μL of TFA. After 1 h at room temperature, the TFA was evaporated under reduced pressure, the residue was placed in water and freeze-dried. In a separate flask, 5-Amino-1,3,4-thiadiazole-2-sulfonamide (2.7 mg, 15 μmol, 1 equiv) was treated with an anhydrous ACN solution of 4-nitrophenyl chloroformate (3 mg, 15 μmol, 1 equiv) and DIPEA (5.3 μL, 30 μmol, 2 equiv) at 0 °C for 30 min. Then, the freeze-dried crude was added and after incubation at room temperature for 1 h, the solvent was evaporated. Subsequently, aq ester hydrolysis was carried out at room temperature for 3 h using NaOH (150 μL 1 M NaOH aq , 150 μmol, 10 equiv) in 300 μL of water:THF (1:1). After neutralization with 1 M HCl

[0677] 1.3.19 Synthesis of Intermediates I17, I18, I19, I20 and I21

[0678]

[0679] I17, I18, I19, I20 and I21 were synthesized by pre-activating the acid (I7, I12, I13, I15 or I16) with a DMF solution of EDC (1 equiv), HOBt (1 equiv) and DIPEA (3 equiv) at room temperature for 15 min and then adding N 6-(tert-Butoxycarbonyl)-L-lysine tert-butyl ester hydrochloride (1 eq). After 20 h at room temperature, the solvent was evaporated and TFA was added. The mixture was stirred for 1 h at room temperature, then the TFA was removed and the mixture was purified by RP-HPLC to give the products as white solids: I17 (0.25 mg, 89% yield), I18 (0.9 mg, 37% yield), I19 (1.4 mg, 57% yield)), I20 (0.8 mg, 32% yield), I21 (1.15 mg, 58% yield).

[0680] 1.3.20 Synthesis of Compounds C19, C20, C21, C22 and C23

[0681]

[0682] C19, C20, C21, C22 and C23 were synthesized by mixing the amine (I17, I18, I19, I20 or I21) with a DMF solution of FITC (0.8 eq) and DIPEA (3.5 eq) at room temperature for 45 min. The mixture was purified by RP-HPLC to give the products as yellow solids: C19 (0.19 mg, 60% yield), C20 (0.1 mg, 80% yield), C21 (0.08 mg, 52% yield), C22 (0.09 mg, 60% yield), C23 (0.07 mg, 55% yield).

[0683] Example 2 - Affinity and Selectivity Measurements of Compounds by Fluorescence Polarization

[0684] 2.1 General

[0685] Fluorescence polarization was measured on a Tecan Spark® multimode microplate reader (λ 激发 = 485 ± 20 nm, λ 发射 = 535 ± 25 nm) in black 384-well microplates. Typically, a dilution series of the protein in the appropriate buffer (typically 1:1) was prepared to achieve a volume of 5 µL / well. The fluorophore-conjugated compound was diluted in the protein buffer to achieve a concentration of 20 nM, 10 nM ( Figure 35 ) or 2 nM ( Figure 34 ), and 5 µL was added to each well. The plate was centrifuged (400 rcf, 1 min) and incubated in the dark for 15 min before measurement.

[0686] 2.2 Affinity Measurement

[0687] We synthesized fluoresceinylated conjugates of four stereoisomers (compounds C1, C3, C5, and C7) to assay the affinity for recombinantly expressed human CAIX via fluorescence polarization measurements. We observed stereoselective binding for compound C7 (2R,4R; K D = 15 ± 2 nM), while no binding was detected for the other isomers (compounds C1, C3, and C5, see Figure 26 , upper panel above).

[0688] To analyze which parts of the molecule are important for CAIX binding, we performed fragment screening and identified thiophene bearing a sulfonamide (compound C12) and the corresponding proline derivative (compound C14) as micromolar CAIX binders (K D = 1.0 ± 0.1 μM and 1.1 ± 0.2 μM).

[0689] The proline derivative of 2-(2,4-dichlorophenyl)acetic acid (compound C13) does not bind CAIX, while the combination with the sulfonamide gives rise to a high-potency CAIX ligand (compound C8) with a dissociation constant in the nanomolar range (K D = 6 ± 1 nM, see Figure 26 , lower panel below).

[0690] 2.3 Selectivity measurements

[0691] Compounds C7 and acetazolamide (AAZ*) were screened against human CAIX and CAIX isoenzymes (bovine CAII, human CAIV, human CAXII, and human CAXIV). Compound C7 was identified as a highly selective CAIX ligand with low affinity for human CAXII (no fit applicable) and no detectable binding to the other isoenzymes (see Figure 27 and Table 6). In contrast, AAZ* binds tightly to all screened carbonic anhydrases with no apparent selectivity for CAIX (see Figure 27 and Table 6).

[0692] The analysis was extended to a panel of other protein targets, confirming the selectivity (see Figure 31 and 32 ).

[0693] Table 6. Dissociation constants (K D ) of compounds C7 and AAZ* for CAIX and corresponding isoenzymes. Each value is given as mean ± standard deviation (n = 3). h = human, b = bovine, N.D. = not detected.

[0694]

[0695] By using the same fluorescence polarization (seeFigure 33 The analysis was extended to a further set of conjugates, namely compounds C16, C17 and C18 (where R is L6, i.e. a DNA / LNA(bodipy) multiplex), and selectivity was also confirmed (Table 7). The exemplary DNA had a 74-mer sequence linked via a 5'-C6 amino modification:

[0696]

[0697] where each X can independently be any one of A, C, T and G; and the LNA(bodipy) is a 3'-amino modified 8-mer LNA (5' GGCTACTA-C6-amino 3') which had been conjugated to BODIPY-TMR-X (Thermo Fisher Scientific, #D6117), where the DNA had been annealed to the complementary BODIPY-modified 8-mer LNA in a 1:1 molar ratio by mixing 25 μL of a 2 μM solution (in PBS) of each, subsequently heating the mixture to 70 °C for 5 minutes and allowing the solution to cool passively to room temperature for 30 minutes.

[0698] Table 7. Dissociation constants (K D )) of compounds C16, C17 and C18 for CAIX and the isoenzyme CAII (h = human, b = bovine).

[0699]

[0700] The results show that a similar affinity for CAIX and selectivity relative to CAII was achieved within the scope of the present invention.

[0701] Example 3 - Qualitative and quantitative biodistribution studies

[0702] 3.1 Cell Culture

[0703] The human renal cell carcinoma cell line SKRC-52 was grown in RPMI-1640 supplemented with 10% FBS and 1× antibiotic-antimycoticum at 37 °C, 5% CO2. Cells were detached using 0.25% trypsin-EDTA and passaged every other day. The cells were used to grow tumours in mice.

[0704] 3.2 In Vivo IVIS Imaging for Qualitative Biodistribution Analysis

[0705] To test whether stereoselective CAIX binding could be translated into stereoselective in vivo targeting of tumours expressing CAIX, we synthesised the corresponding IRDye conjugates (compounds C2, C4, C6 and C10).

[0706] Balb / c nude mice bearing subcutaneous SKRC-52 tumors (150 - 300 mm 3 ) were intravenously injected with 3 nmol of each compound dissolved in 150 μL of sterile PBS to obtain fluorescence images 4 hours after injection.

[0707] The mice were anesthetized with Attane TM isoflurane to obtain fluorescence images on an IVIS Spectrum imaging system (Xenogen; 1-second exposure; binning factor = 8; λ 激发 = 745 nm; λ 发射 = 800 nm; f-stop 2; field of view 13.1). Images were taken at 10 minutes, 1 hour, 2 hours, 4 hours, and 6 hours after injection.

[0708] Only compound C10 (2R,4R) showed accumulation in the tumor site (see Figure 28 ).

[0709] 3.3 Quantitative Biodistribution Analysis Using Radio - labeled Compound C11

[0710] The CAIX ligand was synthesized as a DOTAGA conjugate (compound C11) to allow radiolabeling with 177 Lu.

[0711] Balb / c nude mice bearing subcutaneous SKRC-52 tumors (200 - 300 mm 3 ) were intravenously injected with 3 nmol (0.85 MBq) of 177 Lu]Lu-C11. The mice were sacrificed 6 hours after injection to isolate the following organs and measure their radioactivity: tumor, liver, kidney, spleen, stomach, intestine, lung, heart, tail, muscle, and blood. Radioactivity was measured using a Packard Cobra γ-counter and plotted as % ID / g ± SEM (n = 4). These values were normalized for the normal radioactive decay of 177 Lu]Lu-C11 (normalized according to the batch used for injection).

[0712] The radiolabeled compound was detected in the tumor and kidney. The other healthy organs showed only 177 traces of Figure 29 Lu]Lu-C11, highlighting the selectivity of the novel CAIX ligand (see

[0713] References

[0714]

Claims

1. A compound, its individual diastereoisomers, its hydrates, its solvates, its crystal forms, its individual tautomers, or their pharmaceutically acceptable salts, wherein the structure of the compound comprises at least one group A independently represented by the following structure: Wherein: R 1 represented by -C(Y)-R 1a -SO2NR(R') or -(G 1 ) q -(CR(R')) r -(G 2 ) s -R 1a -SO2NR(R') R 1a is independently a 6- to 10-membered aromatic group or a 5- to 10-membered heteroaromatic group having up to 3 heteroatoms independently selected from N, O, and S, and wherein, other than SO2NR(R'), R 1a is further substituted by one or more substituents R 3 substituted, wherein: G 1 independently selected from C(Y), SO, SO2, CR(R'), triazolyl, and CR(R')triazolyl; G 2 independently selected from C(Y), C(Y)NR, SONR, SO2NR, CR(R')NR, NRC(Y), NRSO, NRSO2, NRCR(R'), triazolyl, triazolyl-NR, triazolyl-CR(R'), NR-triazolyl, and CR(R')-triazolyl; Each of q and s independently selected from 0 and 1; r is independently selected from 0, 1, 2, 3 and 4, preferably 2; Provided that at least one of q and s is 1; Provided that q + r + s ≥ 1; R 2 is represented by R 2a -(CR(R')) p -C(Y)-, or R 2 together with the group RN- forms a residue represented by R 2a -(G 4 ) v -(CR(R')) u -(G 3 ) t -; R 2a is a 6- to 10-membered aromatic group or a 5- to 10-membered heteroaromatic group having at most 5, preferably at most 3, heteroatoms independently selected from N, O and S and optionally substituted by C 1-4 alkyl, wherein R 2a is optionally substituted by one or more substituents R 4 substituted, wherein: G 3 independently selected from C(Y)NR, SONR, SO2NR, CR(R')NR, triazolyl, triazolylCR(R'), and CR(R')triazolyl; G 4 independently selected from C(Y), NRC(Y), NRSO, NRSO2, NRCR(R'), C(Y)NR, SONR, SO2NR, CR(R')NR, triazolyl, NR-triazolyl, triazolyl-NR, CR(R')-triazolyl and triazolyl-CR(R'), Each of t and v is independently 0 or 1; u is independently selected from 0, 1, 2, 3 and 4, preferably 3; Preferably provided that at least one of t and v is 1, more preferably both t and v are 1; Preferably provided that t + u + v ≥ 1, more preferably ≥ 2, most preferably ≥ 3; and p is independently 1, 2, 3 or 4, preferably 1 or 2, more preferably 1; Wherein one or more occurrences of CR(R') may optionally be replaced by a group independently selected from O, S and NR, provided that no two O atoms are adjacent to each other; Each occurrence of Y is independently selected from O, S, NR and CR(R'); Each R 3 and R 4 is independently selected from: NH2, OH, COOH, COOR, C 1-6 alkyl, C 1-6 haloalkyl, O(C 1-6 alkyl), O(C 1-6 haloalkyl), O(C 2-6 alkenyl), C 1-6 heteroalkyl, NO2, C(O)NH2, C(O)NR(R'), CN, oxo, and halogen, wherein R 3 and R 4 each independently may optionally together with any CR(R') form a 4- to 7-membered carbocyclic or heterocyclic ring; and Each occurrence of R and R' is independently H or is selected from C 1-6 -alkyl, O(C 1-6 alkyl), 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 of which may optionally be substituted with 1 to 3 substituents selected from C 1-6 -alkyl, OH, oxo, and halogen; Wherein unless otherwise specified, the term "diastereoisomer" refers to a stereoisomer of a compound that has a different configuration at one or more stereocenters in the part of the molecule other than the A part, such that the stereochemical configuration of the A part is as presented in the corresponding structure, and the individual diastereoisomers have different stereochemical configurations in the part of the molecule other than the A part.

2. The compound according to claim 1, wherein: R 1a independently is a 5-membered heteroaromatic group having at most 3 heteroatoms independently selected from N, O and S, and wherein, except for SO2NR(R'), the heteroaromatic group is substituted with 1 or 2 substituents R 3 substituted; R 2a is a 6- to 10-membered aromatic group substituted with 0, 1, 2 or 3 substituents R 4 substituted; p is 1; Each occurrence of Y is O; and Each R 3 and R 4 are independently selected from OCH3, OCH2CH3, OCH2CH2CH3, OCH2(CH3)2, O-cyclopropyl, OCF3, OCF2CF3, COOH, COOCH3, NO2, CN, F; Cl; Br; and I.

3. The compound according to any one of the preceding claims, wherein A is represented by any one of the following structures: Wherein: c is independently 1 or 2, preferably 1; d is independently 0, 1, 2, 3, 4 or 5, preferably 2; W is independently selected from NR, O, S, S(O) and SO2.

4. The compound according to any one of the preceding claims, wherein A is represented by any one of the following structures: ， wherein W 1 , W 3 , W 4 each independently selected from CH, S, O, and N, where at least one is S or O.

5. The compound according to any one of the preceding claims, wherein A is represented by any one of the following structures: ， Wherein W is independently selected from S and O; W 1 is S or O; and W 3 、W 4 Each of which is independently selected from CH, S, O, and N.

6. The compound according to any one of the preceding claims, wherein A is represented by any one of A-1 to A-5 below: 。 7. The compound according to any one of the preceding claims, wherein the compound is represented by formula I, Ia or Ib below, Wherein each A is independently defined as in any one of the preceding claims; B is a single bond or an optionally substituted C 1-50 aliphatic group, wherein optionally one or more carbon atoms can be replaced by a heteroatom, C 3-12 carbocyclic group or C 1-12 heterocyclic group, and it can be saturated or optionally contain one or more double bonds or triple bonds; and Each C is an atom, molecule or particle, and / or a therapeutic or diagnostic agent.

8. The compound according to claim 7, wherein B is a single bond or represented by any one of the following general formulas II-V, IIa-Va or IIb-Vb: 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; Provided that in formulas IIa-Va and IIb-Vb, z and at least one of x and y are not 0; * indicates the connection point with part A; • indicates the connection point with part C; and B S and B L each independently selected from alkylene, cycloalkylene, aralkylene, heteroaralkylene, heteroalkylene, heterocycloalkylene, alkenylene, cycloalkenylene, aralkenylene, heteroaralkenylene, heteroalkenylene, heterocycloalkenylene, alkynylene, heteroalkynylene, aryl, heteroaryl, aminoacyl, oxyalkylene, iminoalkylene, diester, dialkylsiloxane, amide, thioamide, thioether, thioester, ester, carbamate, hydrazone, thiazolidine, methylenealkoxycarbamate, disulfide, vinylidene, imine, amidine, phosphoramide, sugar, phosphate, phosphoramide, carbamate, dipeptide, tripeptide, tetrapeptide, each of which is optionally substituted.

9. The compound according to any one of claims 7 and 8, wherein B is represented by (B S ) x wherein: each x is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; Each B S is independently selected from the group consisting of: alkylene, cycloalkylene, aralkylene, heteroaralkylene, heteroalkylene, heterocycloalkylene, alkenylene, cycloalkenylene, aralkenylene, heteroaralkenylene, heteroalkenylene, heterocycloalkenylene, alkynylene, heteroalkynylene, aryl, heteroaryl, aminoacyl, oxyalkylene, iminoalkylene, diester, dialkylsiloxane, amide, thioamide, thioether, thioester, ester, carbamate, hydrazone, thiazolidine, methylenealkoxycarbamate, disulfide, vinylidene, imine, amidine, phosphoramide, sugar, phosphate, phosphonamide, carbamate, dipeptide, tripeptide, and tetrapeptide.

10. The compound according to any one of claims 7-9, wherein part C is a chelator group suitable for radiolabeling; a radioactive group containing a radioisotope; a chelate of a radioisotope and a chelator; a fluorophore group; a cytotoxic agent and / or a cytostatic agent; an immunomodulator; or a protein.

11. The compound according to claim 10, wherein: (a) The chelator group suitable for radiolabeling is selected from sulfur colloid, diethylenetriaminepentaacetic acid (DTPA), ethylenediaminetetraacetic acid (EDTA), 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA), 1,4,7-triazacyclononane-N,N',N''-triacetic acid (NOTA), 1,4,8,11-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid (TETA), iminodiacetic acid, bis(carboxymethylimidazole)glycine, 6-hydrazinylpyridine-3-carboxylic acid; or has a structure according to the following formula: wherein: n is 0, 1, 2, 3, 4, or 5; preferably 1; R 1e is independently H, COOH, aryl-COOH or heteroaryl-COOH; preferably COOH; R 2e is independently H, COOH, aryl-COOH or heteroaryl-COOH; preferably COOH; Each R 3e is independently H, COOH, aryl-COOH or heteroaryl-COOH; preferably COOH; R 4e is independently H, COOH, aryl-COOH or heteroaryl-COOH; preferably COOH; and X is O, NH, or S; preferably O; or has a structure according to the following formula: wherein: n is 0, 1, 2, 3, 4, or 5; preferably 1; R 1f is independently H, COOH, aryl-COOH or heteroaryl-COOH; preferably COOH; R 2f is independently H, COOH, aryl-COOH or heteroaryl-COOH; preferably COOH; R 3f is independently H, COOH, aryl-COOH or heteroaryl-COOH; preferably COOH; and X is O, NH, or S; preferably O; (b) The radioactive group containing a radioactive isotope is selected from 223 Ra, 89 Sr, 94m Tc, 99m Tc, 186 Re, 188 Re, 203 Pb, 67 Ga, 68 Ga, 47 Sc, 111 In, 97 Ru, 62 Cu, 64 Cu, 86 Y, 88 Y, 90 Y, 121 Sn, 161 Tb, 153 Sm, 166 Ho, 105 Rh, 177 Lu, 123 I, 124 I, 125 I, 131 I, 18 F, 211 At, 225 Ac, 89 Sr, 225 Ac, 117m Sn, 169 Er and 227 Th; (c) The chelate of the radioisotope is the isotope listed in (b) above and / or a chelate with the chelator listed in (a) above; or (d) The fluorophore group is selected from xanthene dyes, acridine dyes, oxazine dyes, cyanine dyes, styryl dyes, coumarin dyes, porphine dyes, fluorescent metal-ligand complexes, fluorescent proteins, nanocrystals, perylene dyes, boron-dipyrromethene dyes, and phthalocyanine dyes; (e) The cytotoxic agent and / or cytostatic agent is selected from chemotherapeutic agents, and the chemotherapeutic agents are selected from the group consisting of topoisomerase inhibitors, alkylating agents, antimetabolites, antibiotics, mitotic disruptors, DNA intercalating agents, DNA synthesis inhibitors, DNA-RNA transcription regulators, enzyme inhibitors, gene regulators, hormone response regulators, hypoxia-selective cytotoxins, epidermal growth factor inhibitors, anti-angiogenic agents, and combinations of two or more thereof, (f) The immunomodulator is selected from molecules known to be able to modulate the immune system, such as ligands of CD3, CD25, TLRs, STING, 4-1BBL, 4-1BB, PD-1, mTor, PDL-1, NKG-2D IMiDs, where these ligands can be agonists and / or antagonists; or (g) The protein is selected from cytokines, such as IL2, IL10, IL12, IL15, TNF, interferon γ, or is an antibody.

12. The compound according to any one of claims 7-11, each -B-C is independently represented by any one of the following structures: ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ， wherein each of AA3, AA4, AA5, AA6, AA7, and AA8 represents a protein amino acid or a non-protein amino acid, or is absent; Each B S is independently selected from the group consisting of: alkylene, cycloalkylene, aralkylene, heteroaralkylene, heteroalkylene, heterocycloalkylene, alkenylene, cycloalkenylene, aralkenylene, heteroaralkenylene, heteroalkenylene, heterocycloalkenylene, alkynylene, heteroalkynylene, aryl, heteroaryl, aminoacyl, oxyalkylene, iminoalkylene, diester, dialkylsiloxane, amide, thioamide, thioether, thioester, ester, carbamate, hydrazone, thiazolidine, methylenealkoxycarbamate, disulfide, vinylidene, imine, amidine, phosphoramide, sugar, phosphate, phosphoramide, carbamate, dipeptide, tripeptide, and tetrapeptide; 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 x is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; Each R c , R d and R e is independently selected from H, optionally substituted C 1-6 alkyl, (C3-C 10 carbocyclic)C 1-6 alkyl, (C6-C 10 aryl)C 1-6 alkyl, (C1-C 10 heterocyclic)C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C6-C 10 aryl, in each of which one or more of the carbon atoms may optionally be replaced by a heteroatom; preferably selected from side chain residues of protein amino acids or non-protein amino acids; Each occurrence of R and R' is independently H or is selected from C 1-6 -alkyl, O(C 1-6 -alkyl), S(C 1-6 -alkyl), 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 of which may optionally be substituted by 1 to 3 substituents selected from C 1-6 -alkyl, OH, oxo and halogen.

13. The compound according to any one of claims 7 - 12, wherein: (a) A-B is represented by a structure selected from the following: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ; and / or (b) C is represented by a structure selected from the following: and and and and and and and and and and and and and and and and and and and and and and and and and and and and and and and and and and and and and and and and and , The combination of A-B and C is preferably chosen such that the covalent bond connecting B and C is represented by S-S, S-C, C-S, C(O)-R a , C(O)-N, C(O)-O, C(O)-N, N-C(O), N-C(O)O, N-C(S) or OC(O)-N.

14. The compound according to any one of claims 7 - 13, wherein -B-C is represented by any one of the following structures: 。 15. The compound according to any one of the preceding claims, wherein the A moiety is selected from A-1 to A-5 as defined in the specification.

16. The compound according to any one of the preceding claims, wherein the B moiety is selected from B-1 to B-21 as defined in the specification.

17. The compound according to any one of the preceding claims, wherein the C moiety is selected from C-1 to C-31 as defined in the specification.

18. A compound having a structure selected from those listed in Table 1, Table 3.1, and / or Table 3.2, its individual diastereoisomers, its hydrates, its solvates, its crystal forms, its individual tautomers, or its pharmaceutically acceptable salts, wherein unless otherwise specified, the term "diastereoisomer" refers to a stereoisomer of a compound that has a different configuration at one or more stereocenters in a part of the molecule other than the A moiety, such that the stereochemical configuration of the A moiety is as presented in the corresponding structure, and the individual diastereoisomers have different stereochemical configurations in the part of the molecule other than the A moiety.

19. A pharmaceutical composition comprising the compound according to any one of the preceding claims and a pharmaceutically acceptable excipient.

20. The compound or pharmaceutical composition according to any one of the preceding claims, for use in the following methods: (a) for a method of treating the human or animal body by surgery or therapy or a diagnostic method practiced on the human or animal body; or (b) for a method of treating or preventing in a subject suffering from or at risk of a disease or disorder; or (c) for a method of guiding surgery in a subject suffering from or at risk of a disease or disorder; or (d) for a method of diagnosing a disease or disorder, the method being practiced on the human or animal body and involving nuclear medicine imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT); or (e) for a method of targeted delivery of a therapeutic or diagnostic agent to a subject suffering from or at risk of a disease or disorder.

21. The compound or pharmaceutical composition used according to claim 20, wherein the disease or disorder is independently selected from hypoxia-related diseases, such as cancer, preferably wherein the cancer is selected from the group consisting of: breast cancer, pancreatic cancer, colon cancer, multi-drug resistant colon cancer, rectal cancer, colorectal cancer, metastatic colorectal cancer, lung cancer, non-small cell lung cancer, head and neck cancer, ovarian cancer, hypopharyngeal cancer, nasopharyngeal cancer, laryngeal cancer, bladder cancer, cholangiocarcinoma, clear cell renal carcinoma, glioma, astrocytoma, cervical cancer, and renal cancer.

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