Carbonic anhydrase IX ligands for targeted delivery

Abstract

The present invention relates to protein ligands for carbonic anhydrase IX (CAIX) as a biomedically relevant target. In particular, highly specific ligands can interact exclusively with an antigen, i.e., CAIX, expressed on the surface of tumor cells, sparing healthy target-expressing organs, thereby enabling efficient in vivo drug delivery applications. Ligands can exhibit particularly low dissociation constants and / or enzyme isoform specificity, making them 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 CAIX expression.

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 can interact exclusively with an antigen, i.e., CAIX, expressed on the surface of tumor cells, sparing healthy target-expressing organs, thereby enabling efficient in vivo drug delivery applications. Ligands can exhibit particularly low dissociation constants and / or enzyme isoform specificity, making them 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 CAIX expression. [Background technology]

[0002] Carbonic anhydrase IX (CAIX) is a zinc metalloenzyme, of which 15 isozymes have been reported in humans, most of which are involved in maintaining cellular homeostasis and carbon dioxide transport [Non-Patent Documents 1 and 2]. CAIX is expressed at low levels in healthy tissues (GI tract, liver, and gallbladder), but higher levels have been observed in certain solid tumors [Non-Patent Documents 2 and 3]. In particular, CAIX is the most validated marker of renal cell carcinoma (RCC) and hypoxia, providing an attractive target for diagnostic and therapeutic approaches [Non-Patent Documents 4 and 5].

[0003] In clinical trials, radionuclide-loaded CAIX-targeting antibodies (i.e., girentuximab) are being used for the diagnosis of breast cancer (www.clinicaltrials.gov Identifier: NCT04758780), urothelial carcinoma (NCT05046665), and renal cell carcinoma (NCT02883153, NCT02497599, NCT03849118), and are being tested in combination with nivolumab for the treatment of kidney cancer (NCT05239533). The poor penetration of solid tumors is a major limitation of antibody diagnostics and therapy [6]. Cazzamalli and coworkers have demonstrated the rapid extravasation of small organic ligands, in contrast to antibodies, highlighting the suitability of small molecules for targeted inhibition or delivery approaches [7].

[0004] Certain small molecule CAIX ligands are in clinical development as imaging agents or therapeutic agents (monotherapy or in combination with other treatment modalities) for various types of malignancies. For example, acetazolamide is being tested in combination with platinum for localized small cell lung cancer (NCT03467360) and in combination with temozolomide for malignant glioma (NCT03011671). SLC-0111 is being investigated as monotherapy for solid tumors (NCT02215850) or in combination with gemcitabine for metastatic pancreatic ductal carcinoma (NCT03450018). DTP348 is being tested as a radiosensitizer for solid tumors (NCT02216669). E7070 is being 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 a combination therapy for metastatic breast cancer (NCT00165880) and metastatic colorectal cancer (NCT00165867, NCT00165854). [F-18]VM4-037 is being applied as an imaging agent for different cancers (NCT00884520). The COX-2 inhibitor celecoxib is also being studied in the context of CAIX inhibition to treat cervical intraepithelial neoplasia (NCT00081263), with radiation and surgery for advanced head and neck cancer (NCT04162873), and in combination with immunomodulatory agents or chemotherapy for colorectal cancer (NCT01729923), colorectal cancer metastasizing to the liver (NCT03403634), and early-stage triple-negative breast cancer (NCT04081389).

[0005] Most carbonic anhydrase (CA) ligands and inhibitors in clinical development share a sulfonamide functional group. Sulfonamides are a well-known class of carbonic anhydrase inhibitors [Non-Patent Documents 8 and 9]. Sulfonamides (e.g., acetazolamide), which have high affinity for CAIX, have been exploited as targeting moieties within small molecule drug conjugates (SMDCs) to deliver radionuclides and cytotoxic agents for imaging and therapeutic applications, as disclosed in Patent Documents 1 and 2 [Non-Patent Documents 10-14]. Sulfonamides typically coordinate to a zinc ion within the highly conserved active site of CAs

[15] . Thus, sulfonamide-based CA binders 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, and 15]. Due to the expression of CAs in healthy tissues, there is a need to identify specific CAIX ligands to further improve targeted delivery of diagnostic or therapeutic agents to disease sites, e.g., by providing high-affinity ligands that allow for lower doses and / or by reducing off-target toxicity. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] International Publication No. 2015 / 114171 [Patent Document 2] International Publication No. 2018 / 154517 [Non-patent literature]

[0007] [Non-Patent Document 1] M. Aggarwal, CD Boone, B. Kondeti, R. McKenna, Structural annotation of human carbonic anhydrases, J. Enzyme Inhib. Med. Chem. 2013, 28, 267-277. [Non-patent document 2] P. Swietach, A. Hulikova, RD Vaughan-Jones, AL Harris, New insights into the physiological role of carbonic anhydrase IX in tumor pH regulation, Oncogene 2010, 29, 6509-6521. [Non-patent document 3] https: / / www.proteinatlas.org / ENSG00000107159-CA9, accessed on the 20th of August 2021. [Non-patent document 4] CT Supuran, Carbonic anhydrases: novel therapeutic applications for inhibitors and activators, Nat. Rev. Drug Discov. 2008, 7, 168-181. [Non-Patent Document 5] NK Tafreshi, MC Lloyd, MM Bui, RJ Gillies, DL Morse, Carbonic anhydrase IX as an imaging and therapeutic target for tumors and metastases, Subcell. Biochem. 2014, 75, 221-254. [Non-patent document 6] GM Thurber, MM Schmidt, KD Wittrup, Antibody tumor penetration: transport opposed by systemic and antigen-mediated clearance, Advanced drug delivery reviews 2008, 60, 1421-1434. [Non-Patent Document 7] S. Cazzamalli, A. Dal Corso, F. Widmayer, D. Neri, Chemically Defined Antibody- and Small Molecule-Drug Conjugates for in Vivo Tumor Targeting Applications: A Comparative Analysis, J. Am. Chem. Soc. Rev. 2018, 140, 1617–1621.

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[0008] The present invention addresses the problem of providing improved binders (ligands) of a target enzyme, i.e., CAIX, suitable for targeted applications. The binders should be suitable for binding to or inhibiting the target enzyme and / or for targeted delivery of payloads, such as therapeutic and / or diagnostic agents, to sites affected by or at risk of a disease or disorder characterized by expression of CAIX. [Brief explanation of the drawings]

[0009] [Figure 1] LC-MS chromatogram and mass spectrum of intermediate I1. Calculated m / z for C31H39Cl3N7O11S2 [M+H]+: 854.1209 [Figure 2] LC-MS chromatogram and mass spectrum of intermediate I2. Calculated m / z for C31H39Cl3N7O11S2 [M+H]+: 854.1209. [Figure 3] LC-MS chromatogram and mass spectrum of intermediate I3. Calculated m / z for C31H39Cl3N7O11S2 [M+H]+: 854.1209. [Figure 4] LC-MS chromatogram and mass spectrum of intermediate I4, also known as compound C9. Calculated m / z for C31H39Cl3N7O11S2 [M+H]+: 854.1209. [Figure 5] LC-MS chromatogram and mass spectrum of intermediate I5. Calculated m / z for C19H31N8O10S2 [M+H]+: 595.1599. [Figure 6] LC-MS chromatogram and mass spectrum of intermediate I6. Calculated m / z for C10H11ClNO6S2 [MH]-: 339.9722. [Figure 7] LC-MS chromatogram and mass spectrum of intermediate I7. Calculated m / z for C18H17Cl3N3O6S2 [M+H]+: 539.9619 [Figure 8]LC-MS chromatogram and mass spectrum of intermediate I8. Calculated m / z for C12H15ClN3O6S2 [M+H]+: 396.0085. [Figure 9] LC-MS chromatogram and mass spectrum of intermediate I9. Calculated m / z for C15H17Cl2N2O4 [M+H]+: 359.0560. [Figure 10] LC-MS chromatogram and mass spectrum of intermediate I10. Calculated m / z for C27H28N3O7S [M+H]+: 538.1642 [Figure 11] LC-MS chromatogram and mass spectrum of compound C1. Calculated m / z for C52H49Cl3N7O17S2 [M+H]+: 1212.1686 [Figure 12] LC-MS chromatogram and mass spectrum of compound C3. Calculated value of C52H49Cl3N7O17S2 [M+H]+ m / z: 1212.1686 [Figure 13] LC-MS chromatogram and mass spectrum of compound C5. Calculated value of C52H49Cl3N7O17S2 [M+H]+ m / z: 1212.1686 [Figure 14] LC-MS chromatogram and mass spectrum of compound C7. Calculated value of C52H49Cl3N7O17S2 [M+H]+ m / z: 1212.1686 [Figure 15] 1 shows the mass spectrum of compound C2. Calculated m / z for C80H97Cl3N9O24S6 [M+H]+: 1864.4031 [Figure 16] 1 shows the mass spectrum of compound C4. Calculated m / z for C80H97Cl3N9O24S6 [M+H]+: 1864.4031 [Figure 17] 1 shows the mass spectrum of compound C6. Calculated m / z for C80H97Cl3N9O24S6 [M+H]+: 1864.4031 [Figure 18]Figure 1 shows the mass spectrum of C10. Calculated m / z for C80H97Cl3N9O24S6 [M+H]+: 1864.4031 [Figure 19] LC-MS chromatogram and mass spectrum of compound C8. Calculated m / z for C45H42Cl3N6O12S3 [M+H]+: 1059.1083 [Figure 20] LC-MS chromatogram and mass spectrum of compound C12. m / z calculated for C39H40ClN6O12S3 [M+H]+: 915.1549 [Figure 21] LC-MS chromatogram and mass spectrum of compound C13. Calculated m / z for C42H42Cl2N5O10S [M+H]+: 878.2024 [Figure 22] LC-MS chromatogram and mass spectrum of compound C11. Calculated value of C50H69Cl3N11O20S2 [M+H]+ m / z: 1312.3222 [Figure 23] Figure 1 shows HPLC chromatograms of [177Lu]LuCl3 (A) and [177Lu]Lu-C11 (B). The signals were recorded by a radiation detector. [Figure 24] LC-MS chromatogram and mass spectrum of compound C14. Calculated value of C32H30ClN4O10S3 [M+H]+ m / z: 761.0807 [Figure 25] LC-MS chromatogram and mass spectrum of compound C15. Calculated value of m / z for C40H42N9O15S3 [M+H]+: 984.1957 [Figure 26] Figure 1 shows the affinity measurements of compounds C1, C3, C5, C7, C8, C12, C13 and C14 for CAIX by fluorescence polarization (FP). Error bars indicate the standard deviation of three replicates. [Figure 27] Figure 27 shows the affinity measurements of compounds C7 and AAZ* for CAIX and each isozyme by fluorescence polarization. Error bars indicate the standard deviation of three replicates. [Figure 28]Figure 1 shows IVIS imaging of SKRC-52 tumor-bearing Balb / c nude mice 4 hours after intravenous injection of compounds C10, C2, C4, and C6 (from left to right). The SKRC-52 tumor area is indicated by an open circle. Selective targeting of compound C10 was observed, while no preferential accumulation at the tumor site was observed for the other stereoisomers. [Figure 29] Figure 1 shows quantitative biodistribution values ​​in SKRC-52 tumor-bearing Balb / c nude mice 6 hours after intravenous injection of [Lu]Lu-Cl (150 nmol / Kg). Values ​​of %ID / g are given as the mean of four replicate experiments (n=4), and error bars indicate standard deviation. [Figure 30] Figure 1 shows binder selection for carbonic anhydrase IX (CAIX), a marker of hypoxia and renal cell carcinoma. A: Chemical structures of compounds C1–C14. B: Chemical structures of compounds L1–L10. C: Evaluation of compound C9 binding ability 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 each protein (16.6 μM–1.1 μM). D: FP affinity constants (KD) of compound C7 (red / filled bars) and a fluorescent derivative of acetazolamide (AAZ*, blue / open bars) for carbonic anhydrase isozymes. KD values ​​are given as the mean, and error bars indicate the standard deviation of replicate experiments (n=3). E: Flow cytometry analysis of SK-RC-52 tumor cells treated with compounds C1, C3, C5, and C7 compared to unstained control (cells alone). [Figure 31]Figure 1 shows the FP affinity constant values ​​of compound C7(2R,4R) for a panel of serum proteins, immune targets, and unrelated protein targets. KD values ​​are means, and error bars indicate standard deviations of replicate experiments (n=3). ND=not defined; hCAIX=human carbonic anhydrase IX; RSA=rat serum albumin; HSA=human serum albumin; CSA=cynomolgus monkey serum albumin; MSA=mouse serum albumin; rabbitSA=rabbit serum albumin; BSA=bovine serum albumin; OVA=ovalbumin; Hgb=hemoglobin; AGP=alpha(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-1 (IL-9 / -15 / -23). Ikin9 / 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. [Figure 32] Fluorescence polarization measurements of compound C7 against serum proteins (A), immune targets (B) and unrelated protein targets (C) for selectivity profiling. Measurements were performed in triplicate. [Figure 33] Figure 1 shows the affinity measurements of compounds C16, C17 and C18 by fluorescence polarization for hCAIX (A) and the isozyme bCAII (B), showing that similar affinity for CAIX and selectivity for CAII are achieved with these compounds (C). [Figure 34] FP measurements of C19 to C23 for CAIX. Error bars indicate standard deviations of three replicates. [Figure 35]Figure 1 shows FP measurements of I-387, C8, C19, and I-383. Assays were performed at a final ligand concentration of 5 nM. Error bars indicate the standard deviation of three replicates. DETAILED DESCRIPTION OF THE INVENTION

[0010] The present invention relates to potent, stereospecific ligands of, inter alia, CAIX, with particularly low dissociation constants (eg, in the nanomolar range). Because expression of carbonic anhydrase IX isozymes in healthy tissues can lead to the accumulation of nonspecific binders not only at disease sites but also in healthy organs, the present inventors performed quantitative biodistribution experiments in mice with CAIX ligand derivatives according to the present invention, which revealed high selectivity for CAIX-expressing tumors, using the kidney as the only healthy organ with detectable compound accumulation. Thus, the present invention provides CAIX ligands with surprisingly high target specificity. The ligands of the present invention can be applied, for example, as selective inhibitors or targeting agents for disease-related tissues associated with CAIX expression. The ligands of the present invention can be suitably conjugated to a variety of therapeutic and / or diagnostic payloads, including, for example, fluorophores, radioactive metal chelators, cytotoxic agents, immunomodulators, and therapeutic proteins.

[0011] The binders provided herein may have pharmaceutical potential. For example, selective CAIX binders that do not react with other carbonic anhydrases are provided herein. Previously, it has been difficult to isolate sulfonamides with high isoform selectivity for carbonic anhydrases. Surprisingly, the derivatives provided herein can exhibit greater than 100-fold selectivity for CAIX over other carbonic anhydrases, which are selectively localized to tumors in vivo, as confirmed, for example, by the results in Figures 27 and 28. Unlike the CAIX ligands of the present invention, AAZ* bound with high affinity to all carbonic anhydrases tested (bovine CAII, human CAIV, human CAXII, and human CAXIV). Thus, the present invention provides CAIX ligands with surprisingly high isozyme selectivity. Such derivatives may be useful as specific agents particularly suitable for imaging CAIX in hypoxic sites and renal tumors. In addition to imaging applications, CAIX-specific targeting agents can easily deliver cytotoxic agents and can be used as adapters for universal CAR-T cell conditioning therapy. The derivatives described herein can exhibit surprising synergistic affinity enhancement. This is confirmed by the results shown herein, for example, in Figure 26. To analyze which part of the molecule is important for CAIX binding, the sulfonamide-containing thiophene (compound C12) and each proline derivative (compound C14) were incubated with a micromolar CAIX binder (K D = 1.0 ± 0.1 μM and 1.1 ± 0.2 μM). 2-(2,4-Dichlorophenyl)acetic acid proline derivative (compound C13) did not bind to CAIX. In contrast, when combined with sulfonamides, dissociation constants in the nanomolar range (K D =6±1 nM) resulted in a highly potent CAIX ligand (compound C8). The described derivatives also exhibit highly stereoselective binding. One of the four possible stereoisomers of the ligand showed strong binding to CAIX. Thus, well-defined, potent ligands with surprisingly high binding affinity are provided herein. The high stereospecificity translated into high isozyme selectivity for CAIX over 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*), one of the most prominent CAIX binders applied in targeted therapy. This is confirmed by the results presented herein. The affinity for recombinantly expressed human CAIX via fluorescence polarization was measured for four stereoisomers (compounds C1, C3, C5, and C7). The stereoselective binding (2R,4R; K) of compound C7 was significantly higher than that of compound C8. D= 16 ± 2 nM) was observed, whereas binding of the other isomers (compounds C1, C3, and C5, see Figure 26) was not detected. Figure 34 shows that incorporation of the 5-amino-1,3,4-thiadiazole-2-sulfonamide derivative in the ligand further enhanced its affinity for CAIX. Figure 35 shows that the CAIX binding affinity of the ligand is substantially maintained regardless of changes in linker B. Exemplary compounds according to the present invention are listed in Table 1.

[0012] Table 1. Exemplary compounds

[0013] [Table 1] TIFF2025536589000003.tif251170 TIFF2025536589000004.tif246170 Further compounds are listed in Table 2. Table 2. Additional compounds

[0014] [Table 2] TIFF2025536589000006.tif220170 TIFF2025536589000007.tif144170 Further exemplary compounds (conjugates) according to the present invention are listed in Tables 3.1 and 3.2. The numbering of these conjugates is independent of the numbering of the other compounds herein.

[0015] Table 3.1 Exemplary Complexes

[0016] [Table 3] TIFF2025536589000009.tif210170 TIFF2025536589000010.tif223170 TIFF2025536589000011.tif238170 TIFF2025536589000012.tif219170 TIFF2025536589000013.tif220170 TIFF2025536589000014.tif240170 TIFF2025536589000015.tif215170 TIFF2025536589000016.tif215170 TIFF2025536589000017.tif202170 TIFF2025536589000018.tif240170 TIFF2025536589000019.tif231170 TIFF2025536589000020.tif205170 TIFF2025536589000021.tif240170 TIFF2025536589000022.tif233170 TIFF2025536589000023.tif228170 TIFF2025536589000024.tif242170 TIFF2025536589000025.tif239170 TIFF2025536589000026.tif225170 TIFF2025536589000027.tif240170 TIFF2025536589000028.tif203170 TIFF2025536589000029.tif210170 TIFF2025536589000030.tif204170 TIFF2025536589000031.tif221170 TIFF2025536589000032.tif240170 TIFF2025536589000033.tif195170 TIFF2025536589000034.tif193170 TIFF2025536589000035.tif110170 As used herein:

[0017] [ka] indicates an antibody (e.g., a therapeutically and / or diagnostically useful protein);

[0018] [ka] indicates a protein (eg, a therapeutically and / or diagnostically useful protein), and C'-S- indicates a thiol group on the side chain of an amino acid that forms part of the protein. Further preferred conjugates of the present invention are shown in Table 3.2: The following abbreviations for preferred moieties A, B and C are used throughout the specification:

[0019] [ka] TIFF2025536589000039.tif86170 TIFF2025536589000040.tif211170 TIFF2025536589000041.tif247170 TIFF2025536589000042.tif177170Table 3.2 Exemplary Complexes

[0020] [Table 4] TIFF2025536589000044.tif250170 TIFF2025536589000045.tif250170 TIFF2025536589000046.tif250170 TIFF2025536589000047.tif250170 TIFF2025536589000048.tif250170 TIFF2025536589000049.tif250170 TIFF2025536589000050.tif251170 TIFF2025536589000051.tif250170 TIFF2025536589000052.tif250170 TIFF2025536589000053.tif250170 TIFF2025536589000054.tif48170 Part A Without wishing to be bound by any theory, it is believed that the surprising technical effect related to target binding is related to the particular structure of the small molecule binding moiety A. That is, improvements are expected to be observed for compounds that include moiety A over corresponding compounds lacking that moiety. The compounds of the present invention may have higher affinity and slower dissociation rates for their targets compared to prior art compounds, and thus are believed to have extended residence at the disease site at therapeutically or diagnostically relevant levels, preferably for more than 1 hour, more preferably for more than 6 hours after injection. Preferably, concentration is highest after 5, 10, 20, 30, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, or 6 hours; and / or concentration at the disease site is maintained at a therapeutically or diagnostically relevant level for at least 5, 10, 20, 30, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, or 6 hours after injection, more preferably for more than 6 hours.

[0021] Moiety A has the following structure:

[0022] [ka] (In the formula, R 1 , R 2, R, a and b are as defined herein). R 1 and / or R 2 Particularly suitable groups for are provided in Table 4 below.

[0023] Table 4. Table 4. R1 and / or R 2 The outline of the preferred components is as follows, and each code (A... / B...) corresponds to that used in the examples.

[0024] [Table 5] A particularly preferred structure of moiety A, which exhibits extremely high target selectivity, stereospecificity and binding affinity for CAIX, is as follows:

[0025] [ka] is. A further particularly preferred structure of moiety A, which exhibits extremely high target selectivity, stereospecificity and binding affinity for CAIX, is the following:

[0026] [ka] is. A further particularly preferred structure of moiety A is:

[0027] [ka] is.

[0028] Part B Moiety B is a moiety that includes a covalent bond or a chain of atoms that covalently attaches A to 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 payload and / or binding agent moieties to form a targeting complex of the invention. Specifically, moiety B is a polyfunctional moiety that links one or more moieties C and / or A. B can be a single bond or an optionally substituted C 1-50 may be an aliphatic group, optionally with one or more carbon atoms replaced by a heteroatom, C 3-12 Carbocyclic group or C 1-12 The compound may be substituted by a heterocyclic group, may be saturated, and may optionally contain one or more double or triple bonds. The compound structure contains more than one moiety A per molecule, preferably two or three moieties. The compound structure may contain more than one moiety C per molecule, preferably two or three moieties C. Preferably, the compound structure contains two moieties A and one moiety C, or two moieties A and one moiety C per molecule. If a cleavable linker unit is present in moiety B, the release mechanism may be the same as that specific for the antibody linked to the cytotoxic payload. Indeed, the nature of the binding moiety is independent in that respect. Therefore, pH dependence [Leamon, CP et al (2006) Bioconjugate Chem., 17, 1226; Casi, G. et al (2012) J. Am. Chem. Soc., 134, 5887], reducibility [Bernardes, GJ et al (2012) Angew. Chem. Int. Ed. Engl., 51. 941; Yang, J. et al (2006) Proc. Natl. Acad. Sci. USA, 103, 13872], and enzyme release [Doronina SO et al (2008) Bioconjugate Chem, 19, 1960; Sutherland, MSK (2006) J. Biol. Chem, 281, 10540] are expected. In certain settings, when functional groups are present on either the binding moiety or the payload (e.g., thiol, alcohol), a linkerless connection can be established, thus releasing the intact payload, substantially simplifying pharmacokinetic analysis.

[0029] Moiety B may comprise or consist of the units shown in Table 5 below, with the substituents R and R shown in the formula n may be independently selected from H, halogen, substituted or unsubstituted (hetero)alkyl, (hetero)alkenyl, (hetero)alkynyl, (hetero)aryl, (hetero)arylalkyl, (hetero)cycloalkyl, (hetero)cycloalkylaryl, heterocyclylalkyl, peptide, oligosaccharide or steroid group. Preferably, R, R 1 , R 2 and R 3 are each independently selected from H, OH, SH, NH, halogen, cyano, carboxy, alkyl, cycloalkyl, aryl, and heteroaryl, each of which is substituted or unsubstituted. Suitably, R and R n are independently selected from H, or C1 to C7 alkyl or heteroalkyl. More suitably, R and R n is independently selected from H, methyl or ethyl.

[0030] Table 5

[0031] [Table 6] Part B, Unit B L and / or Unit B S 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 allowing traceless cleavage of drug moieties containing thiol groups. Part B, Unit B L and / or Unit B SThe linker may be polar or charged to improve the water solubility of the conjugate. For example, the linker may contain about 1 to about 20, preferably about 2 to about 10, residues of one or more known water-soluble oligomers, such as peptides, oligosaccharides, glycosaminoglycans, polyacrylic acid or its salts, polyethylene glycol, polyhydroxyethyl (meth)acrylate, polysulfonates, etc. Preferably, the linker may contain a polar or charged peptide moiety containing, for example, 2 to 10 amino acid residues. The amino acid may be any natural or unnatural amino acid. The peptide linker suitably contains a free thiol group, preferably an N-terminal cysteine, to form the cleavable disulfide bond with a thiol group on the drug moiety. Any peptide containing L- or D-amino acids may be suitable; particularly suitable peptide linkers of this type are Asp-Arg-Asp-Cys and / or Asp-Lys-Asp-Cys.

[0032] In these and other embodiments, moiety B, unit B L and / or Unit B S The peptide units may comprise cleavable or non-cleavable peptide units specifically tailored for selective enzymatic cleavage from the drug moiety by one or more proteases on the cell surface or extracellular region of the target tissue. The amino acid residue chain length of the peptide units suitably ranges from a single amino acid to approximately eight amino acid residues. Numerous specific cleavable peptide sequences suitable for use in the present invention can be designed and optimized for their selectivity for enzymatic cleavage by specific tumor-associated enzymes, e.g., proteases. Cleavable peptides for use in the present invention include those optimized for proteases MMP-1, 2, or 3, or cathepsin B, C, or D. Peptides cleavable by cathepsin B are particularly suitable. Cathepsin B is a ubiquitous cysteine ​​protease. It is an intracellular enzyme except in pathological conditions such as metastatic tumors or rheumatoid arthritis. An example of a peptide cleavable by cathepsin B comprises the sequence Val-Cit.

[0033] In any of the above embodiments, moiety B, in particular unit BL Preferably, the self-immolative linker further comprises a self-immolative moiety, which may or may not be present after the linker. Self-immolative linkers are also known as electronic cascade linkers. The linker undergoes elimination and fragmentation upon enzymatic cleavage of the peptide, releasing the active, preferably free, form of the drug. The conjugate is stable extracellularly in the absence of an enzyme capable of cleaving the linker. However, upon exposure to an appropriate enzyme, the linker is cleaved, initiating a spontaneous self-immolative reaction, releasing the drug in its underivatized or pharmacologically active form upon cleavage of the bond covalently linking the self-immolative moiety to the drug. In this embodiment, the self-immolative linker 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 initiate the self-immolative reaction. Suitably, the drug moiety is linked to the self-immolative moiety of the linker via a chemically reactive functional group pendant from the drug, such as a primary or secondary amine, hydroxyl, sulfhydryl, or carboxyl group. An example of a self-immolative linker is PABC or PAB (para-aminobenzyloxycarbonyl), which connects the drug moiety to the linker 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 connecting the carboxy terminus of the peptide unit and the para-aminobenzyl of PAB is a substrate that can be cleaved by specific proteases. The aromatic amine becomes electron donating, initiating an electronic cascade that leads to the elimination of the leaving group, which releases the free drug after elimination of carbon dioxide (de Groot, et al. (2001) Journal of Organic Chemistry 66 (26): 8815-8830). Further self-immolative linkers are described in WO 2005 / 082023.

[0034] In yet another embodiment, the linker contains a glucuronyl group that can be cleaved by glucuronidase present on the cell surface or in the extracellular space of the target tissue. Lysosomal β-glucuronidase has been shown to be released extracellularly at high local concentrations in necrotic regions of human cancers, providing a route to targeted chemotherapy (Bosslet, K. et al. Cancer Res. 58, 1195-1201 (1998)).

[0035] In any of the above embodiments, moiety B suitably further comprises a spacer unit. The spacer unit is unit B S and which may be linked to the binding moiety A via, for example, an amide, amine, or thioether bond. The spacer unit may, for example, be of a length that allows the cleavable peptide sequence to be contacted by a cleaving enzyme (e.g., cathepsin B), suitably hydrolyzing the amide bond coupling the cleavable peptide to the self-immolative moiety X. The spacer unit may, for example, comprise repeating units of alkylene, arylene, heteroarylene, alkyloxy (e.g., polyethyleneoxy, PEG, polymethyleneoxy), and alkylamino (e.g., polyethyleneamino), or divalent radicals such as diacid esters and amides, including succinate, succinamide, diglycolate, malonate, and caproamide.

[0036] In any embodiment described herein, * optionally represents the point of attachment to moiety A or a point of attachment where the shortest path to moiety A contains fewer atoms than the path to *; and

[0037] [ka] teeth, In some cases, it represents a point of attachment, a point of attachment to moiety C, or a point of attachment to moiety C where the shortest path to moiety C involves fewer atoms than the path to *. The same applies when a reactive moiety L is present rather than a payload moiety C. The following notation:

[0038] [ka] All refer to the point of attachment of a particular group or atom (eg, R) to a further moiety.

[0039] As used herein, unless otherwise specified, the groups and fragments described herein may be combined in any orientation, but they are intended to be combined in the orientation depicted herein, for example, fragment (a):

[0040] [ka] Fragment (b):

[0041] [ka] Preferred combinations of (a) + (b):

[0042] [ka] Preferably, they are read and combined from left to right, such as:

[0043] If the relevant structure is a peptide monomer or oligomer, each * indicates that the shortest path to moiety A is

[0044] [ka] represents a point of attachment that contains fewer atoms than in the case of

[0045] [ka] represents attachment points that contain fewer atoms than in the case of a , R b and R cWhen shown in any one of the structures, it may be independently present in one or more of the peptide monomer units, preferably in the one peptide monomer unit furthest from the other point of attachment shown in each structure. In any embodiment described herein, the terms "peptide," "dipeptide," "tripeptide," and "tetrapeptide" refer to "peptide mono- or oligomers with a backbone formed by proteinogenic and / or non-proteinogenic amino acids." The term "aminoacyl" or "amino acid" as used herein generally refers to any proteinogenic or non-proteinogenic amino acid. Preferably, in any embodiment described herein, the proteinogenic or non-proteinogenic amino acid is R a , R b and R c Each of these is represented by one of the following:

[0046] [ka] (In the formula, R, R 1 , R 2 and R 3 are each independently selected from H, OH, SH, NH, halogen, cyano, carboxy, alkyl, cycloalkyl, aryl, and heteroaryl, each of which is substituted or unsubstituted; X is independently selected from NH, NR, S, O, and CH, preferably NH; and n and m are each 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. is selected from.

[0047] Preferably, in any embodiment disclosed herein, the side chain residue of a proteinogenic or non-proteinogenic amino acid is R a , R b , R c , R d and R eFor example, the side chain alpha, beta and / or gamma positions of a proteinogenic or non-proteinogenic amino acid may be represented by the following amino acids (proline and hydroxyproline):

[0048] [ka] or they may each independently be part of an unsaturated structure (i.e., there are no geminal H atoms in each of the groups Ra, Rb and Rc), such as in:

[0049] [ka] It may be.

[0050] As used herein, the following notation for peptide sequences:

[0051] [ka] denotes a sequence from the N-terminus to the C-terminus, and the attachment of a group via a horizontal bond (here: moiety C) denotes a covalent attachment to the peptide backbone via an amide bond to each terminal amino acid (here: AA3).

[0052] As used herein, the following notation for peptide sequences:

[0053] [ka] means a sequence from the N-terminus to the C-terminus, and the attachment of a group via a horizontal bond (here: moiety C) means a covalent bond via the side chain of each amino acid (here: AA3). Further preferred non-protein amino acids are those listed below:

[0054] [ka] You can choose from: Particularly preferred embodiments of moiety B as well as of the compounds according to the invention are set out in the appended claims.

[0055] Part C The moiety C in the present invention represents a payload, which can generally be any atom (including H), molecule or particle. Preferably, the moiety C is not a hydrogen atom. The payload may be a chelator for the radiolabel. Suitably, the radionuclide is not released. Chelating agents are well known to those skilled in the art and include, for example, sulfur colloid, diethylenetriaminepentaacetic acid (DTPA), ethylenediaminetetraacetic acid (EDTA), 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA), 1,4,7,10-tetraazacyclodosecane, N-(glutaric 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 of the preferred chelating agent structures described in the appended claims or elsewhere herein.

[0056] The payload is: 223 Ra, 89 Sr, 94 mTc, 99 mTc, 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, 117 MSn, 169 Er and 227 The group of radioactive substances may comprise or consist of radioisotopes, including isotopes selected from Cu. Preferably, 18 F and 124 a positron emitter such as l, or 99 mTc, 111 In and 123 Gamma emitters such as I are used for diagnostic purposes (e.g., PET), 89 Sr, 131 I and 177 Beta emitters such as Lu are used for therapeutic applications. 211 At, 225 Ac and 223 Alpha emitters such as Ra may also be used in therapy. In a preferred embodiment, the radioisotope is 89 Sr or 223 In a more preferred embodiment, the radioisotope is Ra. 68 It's Ga. The payload may be a chelate of a radioisotope, preferably an isotope listed above, and a chelating agent, preferably a chelating agent listed herein.

[0057] The payload may be a fluorophore group, preferably 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, more preferably selected from the structures listed herein. The payload can be a cytotoxic and / or cytostatic agent. Such agents can inhibit or prevent the function of cells and / or cause destruction of cells. Examples of cytotoxic agents include radioisotopes, chemotherapeutic agents, and toxins, such as small molecule 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 auristatins, DNA minor groove binders, DNA minor groove alkylating agents, enediynes, lexitropsins, duocarmycins, taxanes, puromycins, dolastatins, maytansinoids, and vinca alkaloids, or combinations of two or more thereof. Preferred cytotoxic and / or cytostatic payload moieties are listed herein.

[0058] In one embodiment, the payload is selected from the group consisting of topoisomerase inhibitors, alkylating agents (e.g., nitrogen mustards; ethylenimes; alkyl sulfonates; triazenes; piperazines; and nitrosoureas), antimetabolites (e.g., mercaptopurine, thioguanine, 5-fluorouracil), antibiotics (e.g., anthracyclines, dactinomycin, bleomycin, adriamycin, mithramycin), mitotic disruptors (e.g., plant alkaloids such as vincristine and / or microtubule antagonists such as paclitaxel), DNA methylating agents, DNA intercalators (e.g., For example, the payload (i.e., moiety C) is not derived from an anthracycline, and preferably is not derived from PNU 159682.

[0059] Chemotherapeutic agents include erlotinib (Tarceva®), bortezomib (Velcade®), fulvestrant (Faslodex®), Sutent (SU11248), letrozole (SU), letrozole (FEMARA®), imatinib mesylate (GLEEVEC®), PTK787 / ZK 222584, oxaliplatin (ELOXATIN®), 5-FU (5-fluorouracil), leucovorin, rapamycin (sirolimus, RAPMUNE®), lapatinib (GSK572016), lonafarnib (SCH 66336), sorafenib (BAY43-9006), and gefitinib (Iressa®), AG1478, AG1571 (SU 5271; Sugen), or a combination of two or more thereof.

[0060] The chemotherapeutic agent may be an alkylating agent such as thiotepa, Cytoxan® and / or cyclophosphamide; an alkylsulfonate such as busulfan, improsulfan and / or piposulfan; an aziridine such as benzodopa, carboquone, mesuredopa and / or uredopa; an ethylenimine and / or methylameramine such as altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and / or trimethylmelamine; a methylameramine such as bullatacin and / or bullatacin; Acetogenins such as cinon; camptothecin; bryostatin; kallistatin; cryptophycin; dolastatin; duocarmycin; elefrobin; ezoucovin; pancratistatin; sarcodictin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobembitine, phenesterine, prednimustine, trophosmid and / or uracil mustard; nitroureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine and / or ranimnustine; dynemycin; bisphosphonates such as clodronate; esperamycin; neocarzinostatin chromophore;Aclacinomycin, actinomycin, autramycin, azaserine, bleomycin, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, Adriamycin®, doxorubicin such as morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and / or deoxydoxorubicin, mitomycin such as epirubicin, esorubicin, idarubicin, marcelomycin, mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, pofilomycin, puromycin, chelamycin, rhodorubicin, streptonigrin, streptomycin, antimetabolites such as tozocine, tubercidin, ubenimex, zinostatin, zorubicin, etc.; folic acid analogues such as methotrexate and 5-fluorouracil (5-FU), purine analogues such as denopterin, methotrexate, pteropterin, trimetrexate, etc.; purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine, etc.; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, etc.; androgens such as calusterone, dromostanolone propionate, epithiostanol, mepitiostane, testolactone, etc.; antiadrenal drugs such as aminoglutethimide, mitotane, trilostane, etc.; folic acid supplements such as floric acid, aceglatone; Aldophosphamide glycosides; aminolevulinic acid, eniluracil, amsacrine, bestravcil, bisantrene, edatraxisate, defofamine, demecolcine, diaziquone, elformitin, elliptinium acetate, epothilone, etoglucide, gallium nitrate, hydroxyurea, lentinan, lonidynin, macrocyclic depsipeptides such as maytansine and ansamitocin, mitoguazone, mitoxantrone, mopidamol, nitraelin, pentostatin, phenamet, pirarubicin; losoxantrone; podophyllic acid; 2-ethylhydrazide; procarbazine; razoxane;Rhizoxin, schizofiran, spirogermanium, tenuazonic acid, triazicon, 2,2',2'-trichlorotriethylamine, trichothecenes such as veracrine A, roridin A, and anguidine, urethane, vindesine, dacarbazine, mannomustine, mitobronitol, and mitolactol; pipobroman, gacytosine, arabinoside, cyclophosphamide, thiotepa, and taxoids such as Taxol (registered trademark), paclitaxel, Abraxane, and / or Taxotere (registered trademark), and doxetaxel; chlorambucil; Gemzar (registered trademark), and gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide; ifosfamide; mitoxantrone; vincristine; navelbine (registered trademark), vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; Xeloda; ibandronic acid; the topoisomerase inhibitor RFS2000; difluoromethylorutine (DMFO); retinoids such as retinoic acid; capecitabine; and pharmaceutically acceptable salts, acids, derivatives, or combinations of any two or more of the above.

[0061] Payloads include: taxanes such as paclitaxel and docetaxel, vinca alkaloids, discodermolide, epothilone A and B, desoxypothilone, cryptophycin, curacin A, combretastatin A-4-phosphate, BMS 247550, BMS 184476, BMS 188791; LEP, RPR 109881A, EPO 906, TXD 258, ZD 6126, vinflunine, LU103793, dolastatin 10, E7010, T138067 and T900607, colchicine, phenstatin, chalcone, indanocine, T138067, oncocidin, vincristine, vinblastine, vinorelbine, vinflunine, halichondrin B, isohohohalichondrin B, ER-86526, pironetin, spongistatin 1, spiked P, cryptophycin 1, LU103793 (cematodine or cemadotin), rhizoxin, sarcodictin, eleutherobin, laurylamide, VP-16 and D-24851, and pharmaceutically acceptable salts, acids, derivatives or combinations of any two or more of the foregoing.

[0062] The payload may be a DNA intercalating agent, including, but not limited to, the following: acridine, actinomycin, anthracycline, benzothiopyranoindazole, pixantrone, crisnatol, brostallicin, CI-958, doxorubicin (adriamycin), actinomycin D, daunorubicin (daunomycin), bleomycin, idarubicin, mitoxantrone, cyclophosphamide, melphalan, mitomycin C, bizelesin, etoposide, mitoxantrone, SN-38, carboplatin, cisplatin, actinomycin D, amsacrine, DACA, pyrazoloacridine, irinotecan, and topotecan, and pharmaceutically acceptable salts, acids, derivatives, or combinations of any two or more of the above.

[0063] The payload may be an antihormonal agent that acts to regulate or inhibit hormone action on tumors, such as antiestrogen and selective estrogen receptor modulators, including, but not limited to, tamoxifen, raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, ketoxifene, LY117018, onapristone, and / or fareston toremifene, and pharmaceutically acceptable salts, acids, derivatives, or combinations of any two or more of the above. The payload may be an aromatase inhibitor that inhibits aromatase, which regulates estrogen production in the adrenal gland, such as, for example, 4(5)-imidazole, aminoglutethimide, megestrol acetate, aromasin (AROMASIN®), exemestane, formatestan, fadrozole, RIVISOR®, vorozole, Femara®, and ARIMIDEX® and / or anastrozole, and pharmaceutically acceptable salts, acids, derivatives, or combinations of any two or more of the above. The payload can be an antiandrogen such as flutamide, nilutamide, bicalutamide, leuprolide, goserelin and / or troxacitabine, as well as pharmaceutically acceptable salts, acids, derivatives or combinations of any two or more of the above.

[0064] The payload can be a protein or an antibody. Preferably, the payload is a cytokine (e.g., an interleukin such as IL2, IL10, IL12, IL15; a member of the TNF superfamily; or an interferon such as interferon gamma). Any payload can be used in unmodified or modified form. A combination 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 derivatization of a carbonyl group, such as an aldehyde.

[0065] In a preferred embodiment, the payload moiety C is a topoisomerase inhibitor; preferably camptothecin (CPT) or a derivative thereof; more preferably one derived from (e.g., by replacing a hydrogen atom) topotecan, irinotecan, ciratecan, cocitocan, exatecan, lurtotecan, dimatecan, belotecan, rubitecan; even more preferably exatecan; even more preferably one of the following:

[0066] [ka] or

[0067] [ka] where each n is 0, 1, 2, 3, 4, 5 or 6, and most preferably

[0068] [ka] is.

[0069] In a preferred embodiment, moiety C is an auristatin (i.e., has a structure derived from a member of the auristatin compound family) or an auristatin derivative. More preferably, moiety C has the following formula:

[0070] [ka] (In the formula, R d1 are independently H or C1-C6 alkyl; preferably H or CH3; R d2 are independently C1-C6 alkyl; preferably CH3 or iPr; R d3 are independently H or C1-C6 alkyl; preferably H or CH3; R d4are independently H, 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; R d5 are independently H, OH, C1-C6 alkyl; preferably H or OH; and R d6 are independent, C3~C 10 Aryl or C3-C 10 heteroaryl; preferably optionally substituted phenyl or pyridyl) There is a structure represented by More preferably, the moiety C is derived from MMAE or MMAF.

[0071] In a preferred embodiment, the moiety C has the following formula:

[0072] [ka] (In the formula, n is 0, 1, 2, 3, 4 or 5, preferably 1; R 1e are independently H, COOH, aryl-COOH, or heteroaryl-COOH; preferably COOH; R 2 e is independently H, COOH, aryl-COOH, or heteroaryl-COOH; preferably COOH; R 3e are each independently H, COOH, aryl-COOH, or heteroaryl-COOH; preferably COOH; R 4e are independently H, COOH, aryl-COOH, or heteroaryl-COOH; preferably COOH; and X is O, NH or S; preferably O. There is a structure represented by

[0073] In a preferred embodiment, the moiety C has the following formula:

[0074] [ka] (In the formula, n is 0, 1, 2, 3, 4 or 5, preferably 1; R 1f are independently H, COOH, aryl-COOH, or heteroaryl-COOH; preferably COOH; R 2 f is independently H, COOH, aryl-COOH, or heteroaryl-COOH; preferably COOH; R 3f are independently H, COOH, aryl-COOH, or heteroaryl-COOH; preferably COOH; and X is O, NH or S; preferably O. There is a structure represented by Particularly preferred embodiments of moiety C as well as of the compounds according to the invention are set out in the appended claims or elsewhere in this specification. Preferred compounds according to the invention are:

[0075] [ka] or

[0076] [ka] (In the formula, B S , B L , x, y and n and the remaining groups are as defined herein; More preferably, the following:

[0077] [ka] Most preferably:

[0078] [ka] ) can be expressed as

[0079] Preferred compounds are those having the structure depicted in Tables 1 or 3, or Figure 30 or Figure 31, their individual diastereoisomers, hydrates, solvates, crystalline forms, individual tautomers, or pharmaceutically acceptable salts thereof. In all structures, unless otherwise indicated, all groups and variables are defined as further above in this disclosure. Also disclosed is a pharmaceutical composition comprising a compound according to any of the above aspects and a pharmaceutically acceptable excipient. The pharmaceutical composition may also be used in a method for: (a) treating the human or animal body by surgery or therapy, or a diagnostic method performed on the human or animal body; or (b) treating or preventing a subject suffering from or at risk of a disease or disorder; or (c) a method for guided surgery performed on a subject suffering from or at risk of a disease or disorder; or (d) a method for diagnosing a disease or disorder, performed 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). and (e) a method for the targeted delivery of a therapeutic or diagnostic agent to a subject suffering from or at risk of suffering from a disease or disorder, wherein in each of (b) to (e) above, the disease or disorder is independently selected from hypoxia-related diseases such as cancer, and preferably the cancer is selected from the group consisting of breast cancer, pancreatic cancer, colon cancer, multidrug-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, renal clear cell carcinoma, glioma, astrocytoma, cervical cancer, and kidney cancer.

[0080] treatment The compounds described herein can be used to treat diseases. Treatment can be therapeutic and / or prophylactic, with the goal being to prevent, reduce, or stop an undesired physiological change or disorder. This treatment can also prolong survival compared to expected survival in the absence of treatment. The disease treated by the compounds can be any disease that can benefit from treatment. This includes chronic and acute disorders or diseases, including pathological conditions that predispose to disorders.

[0081] The terms "cancer" and "cancerous" are used in the broadest sense to refer to the physiological condition in mammals typically characterized by unregulated cell growth. A tumor contains one or more cancerous cells. When treating cancer, the observed therapeutic effect may be a reduction in the number of cancer cells; a reduction in tumor size; inhibition or delay of cancer cell invasion into peripheral organs; inhibition of tumor growth; and / or alleviation of one or more symptoms associated with cancer. In animal models, efficacy can be assessed by physical measurements of the tumor during treatment and / or by determining partial and complete remission of the cancer. For cancer treatment, efficacy can be measured, for example, by assessing the time to disease progression (TTP) and / or determining the response rate (RR). Particularly preferred embodiments of the treatment methods related to the present invention are set out in the accompanying claims. Disclosed herein are methods of treating the human or animal body, for example, by surgery or therapy, or diagnostic methods performed on the human or animal body, comprising administering to a subject in need thereof a therapeutically or diagnostically effective amount of a compound or pharmaceutical composition described herein. More particularly, disclosed herein are methods of treating a subject suffering from or at risk of a disease or disorder, or methods of guided surgery performed on a subject suffering from or at risk of a disease or disorder; methods of diagnosing a disease or disorder, for example, methods performed 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); and methods of targeted delivery of a therapeutic or diagnostic agent to a subject suffering from or at risk of a disease or disorder. In the above methods, the disease or disorder may be independently selected from hypoxia-related diseases such as cancer, and preferably the cancer is selected from the group consisting of breast cancer, pancreatic cancer, colon cancer, multidrug-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, bile duct cancer, renal clear cell carcinoma, glioma, astrocytoma, cervical cancer and kidney cancer.

[0082] Pharmaceutical Composition The compounds described herein may be in the form of pharmaceutical compositions for human or animal use in human and veterinary medicine (e.g., as therapeutic or diagnostic compositions) and will typically include any one or more pharmaceutically acceptable diluents, carriers, or excipients. 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. (A.R. Gennaro, editor. 1985). The choice of pharmaceutical carrier, excipient, or diluent can be selected with regard to the intended route of administration and standard pharmaceutical practice. The pharmaceutical compositions may comprise as, or in addition to, the carrier, excipient, or diluent any suitable binder, lubricant, suspending agent, coating agent, solubilizing agent. Preservatives, stabilizers, dyes, and even flavoring agents can be provided in the pharmaceutical composition. Examples of preservatives include sodium benzoate, sorbic acid, and esters of p-hydroxybenzoic acid. Antioxidants and suspending agents can also be used. Different delivery systems may have different composition / formulation requirements. As an example, a pharmaceutical composition can be formulated to be administered using a minipump, or by a mucosal route, e.g., as a nasal spray or aerosol for inhalation or an ingestible solution, or parenterally, where the composition is formulated in an injectable form for delivery by, e.g., intravenous, intramuscular, or subcutaneous routes. Alternatively, the formulation can be designed to be administered by a number of routes. When an agent is administered mucosally through the gastrointestinal mucosa, the agent must remain stable during passage through the gastrointestinal tract; for example, the agent must be resistant to proteolysis, stable at acidic pH, and resistant to the detergent effects of bile. Where appropriate, pharmaceutical compositions can be administered by inhalation, in the form of a suppository or pessary, topically, in the form of a lotion, solution, cream, ointment, or dusting powder, using a skin patch, orally, in the form of tablets containing excipients such as starch or lactose, or in capsules or ovules, alone or mixed with excipients, or in the form of an elixir, solution, or suspension containing flavorings or coloring agents, or the pharmaceutical composition can be injected parenterally, for example, intravenously, intramuscularly, or subcutaneously. For parenteral administration, the composition is best used in the form of a sterile aqueous solution which may contain other substances, for example, enough 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, which can be formulated in a conventional manner.

[0083] The compounds of the present invention may be administered in the form of a pharmaceutically acceptable salt or active salt. Pharmaceutically acceptable salts are well known to those skilled in the art and include, for example, those described in Berge et al., J. Pharm. Sci., 66, 1-19 (1977). Salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, acid tartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts.

[0084] Routes of administration (delivery) may include, but are not limited to, one or more of oral (e.g., as a tablet, capsule, or ingestible solution), topical, mucosal (e.g., as a nasal spray or aerosol for inhalation), nasal, parenteral (e.g., by injection), gastrointestinal, intraspinal, intraperitoneal, intramuscular, intravenous, intrauterine, intraocular, intradermal, intracranial, intratracheal, intravaginal, intraventricular, intracerebral, subcutaneous, ocular (including intravitreal or intracameral), transdermal, rectal, buccal, vaginal, epidural, and sublingual.

[0085] A physician will typically determine the actual dosage that will be most suitable for an individual subject. The specific dose level and frequency of administration for any particular patient can vary and will depend on a variety of factors, including the activity of the particular compound used, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual being treated. The formulations can be packaged in unit-dose or multi-dose containers, for example, sealed ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example, water, for administration. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules, and tablets of the kind described above. Exemplary unit-dose formulations contain a daily dose or daily sub-dose, or an appropriate fraction thereof, of the active ingredient.

[0086] General Methods The practice of the present invention will employ, unless otherwise indicated, conventional methods of chemistry, biochemistry, molecular biology, cell biology, genetics, immunology and pharmacology, which are known to those skilled in the art and are fully explained in the literature. For example, Gennaro, AR, ed. (1990) Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Co.; Hardman, JG, Limbird, LE, and Gilman, AG, eds. (2001) The Pharmacological Basis of Therapeutics, 10th ed., McGraw-Hill Co.; Colowick, S. et al., eds., Methods In Enzymology, Academic Press, Inc.;Weir, DM , and Blackwell, CC, eds. (1986) Handbook of Experimental Immunology, Vols. I-IV, Blackwell Scientific Publications;Maniatis, T. et al., eds. (1989) Molecular Cloning: A Laboratory Manual, 2nd edition, Vols. I-III, Cold Spring Harbor Laboratory Press;Ausubel, FM et al., eds. (1999) Short Protocols in Molecular Biology, 4th edition, John Wiley & Sons; Ream et al., eds. (1998) Molecular Biology Techniques: An Intensive Laboratory Course, Academic Press; Newton, CR, and Graham, A., eds. (1997) PCR (Introduction to Biotechniques Series), 2nd ed., Springer Verlag.

[0087] chemical synthesis The compounds described herein can be prepared by chemical synthesis techniques. It will be apparent to those skilled in the art that sensitive functional groups may need to be protected and deprotected during compound synthesis. This can be accomplished by conventional techniques, such as those described in "Protective Groups in Organic Synthesis" by T.W. Greene and P.G.M. Wuts, John Wiley and Sons Inc. (1991) and P.J. Kocienski, in "Protecting Groups," Georg Thieme Verlag (1994). For example, when a base is used in a reaction with a substrate having an optical center containing a base-sensitive group, any stereocenters present may be epimerized under certain conditions during some of the reactions. It should be possible to avoid such potential problems by selecting the reaction sequence, conditions, reagents, protection / deprotection methods, etc., as is well known in the art.

[0088] definition antibody Antibody: The term "antibody" is used in its broadest sense and includes monoclonal antibodies, polyclonal antibodies, dimers, multimers, multispecific antibodies (e.g., bispecific antibodies), veneered antibodies, antibody fragments, and small immune proteins (SIPs) (see Int. J. Cancer (2002) 102, 75-85). Antibodies are proteins produced by the immune system that can recognize and bind to specific antigens. A target antigen generally has multiple binding sites, also known as epitopes, recognized by CDRs on multiple antibodies. Each antibody that specifically binds to a different epitope has a different structure; that is, one antigen can have multiple corresponding antibodies. Antibodies include full-length immunoglobulin molecules or immunologically active portions of full-length immunoglobulin molecules, i.e., molecules that contain an antigen-binding site that immunospecifically binds to a target antigen or portion thereof of interest. The antibody 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 subclass thereof. The antibody can be or be derived from murine, human, rabbit, or other species.

[0089] Antibody fragment: The term "antibody fragment" refers to a portion of a full-length antibody, generally the antigen-binding or variable region thereof. Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab')2, and Fv fragments; diabodies; linear antibodies; and single-domain antibodies (including dAbs, camelid VHH antibodies, and cartilaginous fish IGnAR antibodies). Antibodies and fragments thereof may be substituted with alternative non-immunoglobulin scaffold-based binding molecules, peptide aptamers, nucleic acid aptamers, structured polypeptides containing polypeptide loops present on non-peptide scaffolds, natural receptors, or domains thereof.

[0090] Derivative: Derivatives include chemical modifications of compounds, such as the replacement of hydrogen with halo, alkyl, acyl, or amino groups. The modifications can increase or decrease one or more hydrogen bonding interactions, charge interactions, hydrophobic interactions, van der Waals interactions, and / or dipole-dipole interactions.

[0091] Analogues: The term includes any enantiomers, racemates and stereoisomers, as well as all pharmaceutically acceptable salts and hydrates of the compound. Unless otherwise stated, the following definitions apply to chemical terms used in connection with the compounds of the present invention and compositions containing such compounds. Alkyl refers to a branched or unbranched saturated hydrocarbon group. Suitably, an alkyl group contains 1 to 100, preferably 3 to 30, more preferably 5 to 25 carbon atoms. Preferably, alkyl means methyl, ethyl, propyl, butyl, pentyl or hexyl. Alkenyl refers to a branched or unbranched hydrocarbon group containing one or more carbon-carbon double bonds. Suitably, alkenyl groups contain from 2 to 30 carbon atoms, preferably from 5 to about 25 carbon atoms. Alkynyl refers to a branched or unbranched hydrocarbon group containing one or more carbon-carbon triple bonds. Suitably, the alkynyl group contains from about 3 to about 30 carbon atoms, for example, from about 5 to about 25 carbon atoms.

[0092] Halogen refers to fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine. Cycloalkyl refers to an alicyclic moiety having 3, 4, 5, 6, 7, or 8 carbon atoms, as appropriate. The group may be a bridged or polycyclic ring system. More often, the cycloalkyl group is monocyclic. The term includes groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, bicyclo[2.2.2]octyl, and the like. Aryl refers to an aromatic carbon system, preferably having 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 ring carbon atoms. Aryl may also be a polycyclic system having two or more rings, at least one of which is aromatic. The term includes groups such as phenyl, naphthyl, fluorenyl, azulenyl, indenyl, and anthryl.

[0093] Diastereomers or diastereoisomers, unless otherwise specified, refer to stereoisomers of a compound that differ in configuration at one or more stereocenters in portions of the molecule other than portion A, where the stereochemical configuration of said portion A is as depicted in each structure, and the individual diastereomers differ in stereochemical configuration in portions of the molecule other than portion A. The prefix (hetero) herein means that one or more of the carbon atoms of the group can be replaced by nitrogen, oxygen, phosphorus, silicon, or sulfur. Heteroalkyl groups include, for example, alkyloxy and alkylthio groups. Heterocycloalkyl or heteroaryl groups herein can have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 ring atoms, at least one of which is selected from nitrogen, oxygen, phosphorus, silicon, and sulfur. Specifically, they are 3- to 10-membered rings or ring systems, more specifically 5- or 6-membered rings, which can be saturated or unsaturated. For example, oxiranyl, azirinyl, 1,2-oxathiolanyl, imidazolyl, thienyl, furyl, tetrahydrofuryl, pyranyl, thiopyranyl, thianthrenyl, isobenzofuranyl, benzofuranyl, chromenyl, 2H-pyrrolyl, pyrrolyl, pyrrolidinyl, imidazolyl, imidazolyl, imidazolidinyl, benzimidazolyl, pyrazolyl, pyrazinyl, pyrazolidinyl, thiazolyl, isothiazolyl, dithiazolyl, oxazolyl, pyrazolidinyl, thiazolyl, isothiazolyl, dithiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, piperidyl, piperazinyl, pyridazinyl, morpholinyl, thiomorpholinyl, in particular thiomorpholino, indolizinyl, 1,3-dioxo-1,3-dihydro-isoindolyl, 3H-indolyl and n is 0 or 1. In some embodiments, the aryl group is selected from the group consisting of hydroxyl, indolyl, benzimidazolyl, coumaryl, indazolyl, triazolyl, tetrazolyl, purinyl, 4H-quinolidyl, isoquinolyl, quinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, octahydroisoquinolyl, benzofuranyl, dibenzofuranyl, benzothiophenyl, dibenzothiophenyl, phthalazinyl, naphthyridinyl, quinoxalyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthronyl, furazanyl, phenazinyl, phenothiazinyl, phenoxazinyl, chromenyl, isochromanyl, chromanyl, and 3,4-dihydro-2H-isoquinoline-1-1,3,4-dihydro-2H-isoquinolinyl. The term "substituted" means that one or more, particularly up to five, and especially one, two, or three hydrogen atoms in the moiety are independently replaced with a corresponding number of substituents. As used herein, the term "optionally substituted" includes substituted or unsubstituted. Of course, it will be understood that substituents are present only in chemically possible positions, and that one skilled in the art can determine (experimentally or theoretically) whether a particular substitution is possible without undue effort. For example, an amino or hydroxy group having a free hydrogen may be unstable if bonded to a carbon atom having an unsaturated (e.g., olefinic) bond. Preferably, the term "substituted" means that one or more, particularly up to five, more especially one, two, or three hydrogen atoms in the moiety are independently replaced with a corresponding number of substituents selected from the following: OH, SH, NH, halogen, cyano, carboxyalkyl, cycloalkyl, aryl, and heteroaryl. Furthermore, the substituents described herein may themselves be substituted with any substituent, subject to the above restrictions on suitable substitution as recognized by those skilled in the art. Preferably, any of the above substituents may be further substituted with any of the above substituents, and each of the substituents may be further substituted with any of the above substituents.

[0094] The substituents may suitably include halogen atoms and halomethyl groups such as CF3 and CCl3; oxygen-containing groups such as oxo, hydroxy, carboxy, carboxyalkyl, alkoxy, alkoyl (alkyl), alkoyloxy, aryloxy, aryloyl, and aryloyloxy; nitrogen-containing groups such as amino, alkylamino, dialkylamino, cyano, azido, and nitro; sulfur-containing groups such as thiol, alkylthiol, sulfonyl, and sulfoxide; heterocyclic groups which may themselves be substituted; alkyl groups which may themselves be substituted; and aryl groups which may themselves be substituted, such as phenyl and substituted phenyl. Alkyl includes substituted and unsubstituted benzyl. When two or more moieties are described as being "each independently" selected from a list of atoms or groups, this means that the moieties can be the same or different, and thus the identity of each moiety is independent of the identity of one or more other moieties.

[0095] Aspects In view of the above, the present disclosure further provides the following specific aspects. 1. The structure of the compound is:

[0096] [ka] (In the formula, a and b are each 0 or 1, and a+b is at least 1, preferably a and b are each 1; R 1 is -C(Y)-R 1a -SO2NR(R') or (G 1 )q-(CR(R')) r -(G 2 ) s -R 1a - represented by SO2NR(R'); R 1a are independently a 6- to 10-membered aromatic group, a 5- to 10-membered heteroaromatic group having up to three heteroatoms independently selected from N, O, and S, or a group represented by C((CR(R'))nSONR(R'))(CR(R'))nSONR(R'), where SO2NR(R') and one or more substituents R 3 where: G1 is independently selected from C(Y), SO, SO2, CR(R'), triazolyl, and CR(R')triazolyl; G2 is independently selected from C(Y), C(Y)NR, SONR, SO2NR, CR(R')NR, NRC(Y), NRSO, NRSO2, NRCR(R'), triazolyl, triazolylNR, triazolylCR(R'), NRtriazolyl, and CR(R')-triazolyl; q and s are each independently selected from 0 and 1; r is independently selected from 0, 1, 2, 3 and 4, preferably 2; However, preferably, at least one of q and s is 1, and more preferably, both q and s are 1; provided that q+r+s≧1, more preferably ≧2, and most preferably ≧3; u is independently selected from 0, 1, 2, 3 and 4, preferably 3; R 2 is R 2a -(CR(R'))pC(Y)- or R 2 and the group RN- are both R 2a -(G 4 )v-(CR(R'))u-(G 3 ) form a residue represented by t-; R 2a has up to 5 or 3 heteroatoms independently selected from N, O and S; C 1-4 A 6- to 10-membered aromatic group or a 5- to 10-membered heteroaromatic group optionally substituted with alkyl, and represented by NRC(Y)-N(R)-C 6-10 aryl- (wherein R 2a is R 4 and preferably, one or more substituents R 4 may be substituted with, where: G 3 is independently selected from C(Y)NR, SONR, SONR, CR(R')NR, triazolyl, triazolylCR(R'), and CR(R')triazolyl; 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'); t and v are each independently 0 or 1; u is independently selected from 0, 1, 2, 3 and 4, preferably 3; However, preferably, at least one of t and v is 1, more preferably both t and v are 1; However, preferably, t+u+v≧1, more preferably ≧2, and most preferably ≧3; and p is independently 1, 2, 3 or 4, preferably 1 or 2, more preferably 1; wherein CR(R'), when present one or more times, may be optionally substituted with a group independently selected from O, S and NR, provided that no two O atoms are adjacent to each other; Y, if present, is independently selected from O, S, NR, and CR(R'); R 3 and R 4 are each independently 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 selected from heteroalkyl, NO, C(O)NH, C(O)NR(R'), CN, oxo, and halogen; where R 3 and R 4 may each independently optionally form a 4- to 7-membered carbocyclic or heterocyclic ring together with any C—R(R′); and R and R′, if present, are independently H or 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)C1-6 Alkyl and (C 1-10 Heteroaryl)C 1-6 alkyl, each of which is optionally selected from C 1-6 substituted with 1 to 3 substituents selected from alkyl, OH, oxo, and halogen, or R and R' together represent oxo; A compound, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof, comprising at least one group A independently represented by:

[0097] 2. The following formula:

[0098] [ka] (Wherein, RB is R 2a -(CR(R'))pC(Y)- or R 2a -(G 4 )v-(CR(R'))u-(G 3 )t-represents) 2. The compound according to embodiment 1, wherein

[0099] 3. The structure of the compound is:

[0100] [ka] (In the ceremony a and b are each 0 or 1, and a+b is at least 1, preferably a and b are each 1; R 1 is -C(Y)-R 1a - represented by SO2NR(R'); R 1a is independently a 5- to 10-membered heteroaromatic group having up to three heteroatoms independently selected from N, O, and S, wherein the heteroaromatic group is a group consisting of SONR(R') and one or more substituents R 3 is replaced by R 2 is R 2a-(CR(R'))pC(Y)-; R 2a is a 6- to 10-membered aromatic group, optionally containing one or more substituents R 4 and p is independently 1, 2, 3 or 4, preferably 1 or 2, more preferably 1; wherein CR(R'), when present one or more times, may be optionally substituted with a group independently selected from O, S and NR, provided that no two O atoms are adjacent to each other; Y, if present, is independently selected from O, S, NR, and CR(R'); R 3 and R 4 are each independently 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 selected from heteroalkyl, NO, C(O)NH, C(O)NR(R'), CN, oxo, and halogen; where R 3 and R 4 may each independently optionally form a 4- to 7-membered carbocyclic or heterocyclic ring together with any C—R(R′); and R and R′, if present, are independently H or 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)C1-6 Alkyl and (C 1-10 Heteroaryl)C 1-6 alkyl, each of which is optionally selected from C 1-6 substituted with 1 to 3 substituents selected from alkyl, OH, oxo, and halogen, or R and R' together represent oxo; a compound, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof, comprising at least one group A independently represented by

[0101] 4. The following:

[0102] [ka] (In the formula, a and b are each 0 or 1, and a+b is at least 1, preferably a and b are each 1; R 1 is -C(Y)-R 1a - represented by SO2NR(R'); R 1a is a 5-membered heteroaromatic group having up to three heteroatoms independently selected from N, O, and S, where SONR(R') and one or more substituents R 3 is replaced by; R 2 is R 2a -(CR(R'))pC(Y)-; R 2a is a 6- to 10-membered aromatic group, optionally containing one or more substituents R 4 May be substituted with; p is independently 1 or 2, more preferably 1; Y, if present, is independently selected from O, S, NR, and CR(R'); R 3 and R 4 are each independently NH2, OH, COOH, COOR, C 1-6 Alkyl, C 1-6 haloalkyl, oxo and halogen; and R and R′, if present, are independently H or 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 is optionally selected from C 1-6 may be substituted with 1 to 3 substituents selected from alkyl, OH, oxo and halogen) a compound, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof, comprising at least one group A independently represented by

[0103] 5. The group A has the formula:

[0104] [ka] or a pharmaceutically acceptable salt thereof. 6. The group A has the formula:

[0105] [ka] or a pharmaceutically acceptable salt thereof.

[0106] 7. a and b are each 1; R 1a is independently a 5-membered heteroaromatic group having up to three heteroatoms independently selected from N, O, and S, preferably thiophene, where SONR(R') and one or more substituents R 3 is replaced by R 2a is 0, 1, 2 or 3 substituents R 4 a 6- to 10-membered aromatic group substituted with , preferably phenyl; p is 1; Y, if present, is O; and / or R 3 and R 4 are each independently selected from OCH, OCHCH, OCHCHCH, OCH(CH), O-cyclopropyl, OCF, OCFCF, COOH, COOCH, NO, CN, F; Cl; Br; and I; A compound according to any one of Aspects 1 to 6, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof. 8.R 3 and R 4 are each independently selected from F, Cl, Br, and I, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0107] 9. A is the following structure A 1 , A 2 or A 3 :

[0108] [ka] (In the formula, 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, preferably S; R 3a is independently selected from F, Cl, Br and I, preferably Cl; R 3b is independently selected from F, Cl, Br, I and H, preferably H; and R 4a and R 4b are each independently selected from OCH, OCHCH, OCHCHCH, OCH(CH), O-cyclopropyl, OCF, OCFCF, COOH, COOCH, NO, CN, F, Cl, Br and I, preferably each is Cl or OCH. or a pharmaceutically acceptable salt thereof, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof,

[0109] 10.A is the following structure A 4 :

[0110] [ka] A compound according to any one of Aspects 1 to 9, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein 11.R 3 and R 4 are each independently selected from F, Cl, Br, and I, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0111] 12. A has the following structure A-1:

[0112] [ka] A compound according to any one of Aspects 1 to 11, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein

[0113] 13. A is the following structure A-5:

[0114] [ka] A compound according to any one of Aspects 1 to 12, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein

[0115] 14. A is the following structure A 11 , A 12 , A 13 or A 14 :

[0116] [ka] (In the formula, c is independently 1 or 2, preferably 1; d is independently 0, 1, 2, 3, 4 or 5, preferably 1; W is independently selected from NR, O, S, S(O) and SO, preferably S; R 3a is independently selected from F, Cl, Br, and I; R 3b is independently selected from F, Cl, Br, I and H, preferably H; and R 4a and R 4bare each independently selected from OCH, OCHCH, OCHCHCH, OCH(CH), O-cyclopropyl, OCF, OCFCF, COOH, COOCH, NO, CN, F, Cl, Br and I, preferably each is Cl or OCH; and R 4C is independently selected from OCH3, OCH2CH3, OCH2CH2CH3, OCH2(CH3)2, O-cyclopropyl, OCF3, OCF2CF3, COOH, COOCH3, NO2, CN, F, Cl, Br and I, preferably NO2; and R 4d are independently selected from H, OCH, OCHCH, OCHCHCH, OCH(CH), O-cyclopropyl, OCF, OCFCF, COOH, COOCH, NO, CN, F, Cl, Br and I, preferably H. or a pharmaceutically acceptable salt thereof, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof,

[0117] 15. A is the following structure A-4:

[0118] [ka] A compound according to any one of Aspects 1 to 14, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein

[0119] 16. A has the following structure:

[0120] [ka] or a pharmaceutically acceptable salt thereof, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof,

[0121] 17. A has the following structure:

[0122] [ka] or a pharmaceutically acceptable salt thereof.

[0123] 18. A has the following structure:

[0124] [ka] (In the formula, W 1 , W 3 , W 4 are each independently selected from CH, S, O, and N, at least one being S or O, preferably W 1 is S or O, more preferably W 1 is S and W 3 and W 4 are each N) or a pharmaceutically acceptable salt thereof.

[0125] 19. A has the following structure:

[0126] [ka] or a pharmaceutically acceptable salt thereof.

[0127] 20. A has the following structure A-3:

[0128] [ka] or a pharmaceutically acceptable salt thereof.

[0129] 21. A has the following structure:

[0130] [ka] or a pharmaceutically acceptable salt thereof.

[0131] 22. A has the following structure:

[0132] [ka] (In the formula, W 1 , W 3 , W 4 are each independently selected from CH, S, O, and N, at least one being S or O, preferably W 1 is S or O, more preferably W 1 is S and W 3 and W 4 are each N) or a pharmaceutically acceptable salt thereof.

[0133] 23. A has the following structure:

[0134] [ka] or a pharmaceutically acceptable salt thereof, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof,

[0135] 24. A has the following structure A-2:

[0136] [ka] or a pharmaceutically acceptable salt thereof, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof,

[0137] 25.R 3 are each halogen, and R 4 are each independently O(C 1-6 25. A compound according to any one of aspects 1 to 24, wherein the compound is selected from alkyl, NO, and halogen, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof. 26.R 1a SO2NR(R') and three or more substituents R 3 is substituted with R 2a is one or two substituents R 4 A compound according to any one of aspects 1 to 25, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein 27.R 2a has two groups R at the 4- and 2-positions on the phenyl ring 4 or R 4a and R 4b are each at the 4- and 2-positions of the phenyl ring, respectively, relative to the point of attachment to CR(R'), an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof. 28.R1a but one group R is halogen 3 is substituted with R 2a are each independently O(C 1-6 one or two groups R selected from alkyl, NO and halogen; 4 A compound according to any one of aspects 1 to 27, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein 29.R 3 is Cl and R 4 is selected from OCH3, NO2 and Cl, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof. 30.R 3a is Cl and R 3b is H and R 4a is Cl or OCH3, and R 4b is Cl, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof. 31.R 3a is Cl and R 3b is H and R 4c is NO2 and R 4d is Cl, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0138] 32.R 1 But the following structure:

[0139] [ka] A compound according to any one of Aspects 1 to 31, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein

[0140] 33.R 1 But the following structure:

[0141] [ka] or a pharmaceutically acceptable salt thereof.

[0142] 34.R 1 But the following structure:

[0143] [ka] or a pharmaceutically acceptable salt thereof, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof,

[0144] 35.R 1 But the following structure:

[0145] [ka] A compound according to any one of Aspects 1 to 34, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein

[0146] 36.R 2 But the following structure:

[0147] [ka] A structure selected from, preferably

[0148] [ka] or a pharmaceutically acceptable salt thereof.

[0149] 37.R 2 But the following structure:

[0150] [ka] A compound according to any one of Aspects 1 to 36, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein

[0151] 38.R 2 But the following structure:

[0152] [ka] A compound according to any one of Aspects 1 to 36, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein

[0153] 39. R 2 But the following structure:

[0154] [ka] A compound according to any one of Aspects 1 to 36, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein

[0155] 40.R 2 and the group RN- together have the following structure:

[0156] [ka] or a pharmaceutically acceptable salt thereof, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound of any one of claims 1 to 39 forms a residue RB represented by any one of

[0157] 41.R 2 and the group RN- together have the following structure:

[0158] [ka] or a pharmaceutically acceptable salt thereof, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound of any one of claims 1 to 40 forms a residue RB represented by 42. A compound according to any one of aspects 1 to 41, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof or a pharmaceutically acceptable salt thereof, wherein SO2NH2, if present, is substituted with a group represented by -OSO2NH2.

[0159] 43. The compound has the following formula I, Ia, or Ib:

[0160] [ka] wherein each A is independently as defined in any one of embodiments 1 to 42; B is a single bond or an optionally substituted C 1-50 an aliphatic group, where optionally one or more carbon atoms are replaced by a heteroatom, C 3-12 Carbocyclic or C 1-12 The heterocyclic group may be substituted, saturated, or may optionally contain one or more double or triple bonds; and C is each an atomic, molecular, or particulate compound and / or a therapeutic or diagnostic agent. or a pharmaceutically acceptable salt thereof.

[0161] 44. B is a single bond or a group of the following general formula II-V, IIa-Va, or IIb-Vb:

[0162] [ka] (In the formula, Each x is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; y is independently 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 at least one of z and x and y in Formulae IIa-Va and IIb-Vb is not 0; * represents the point of attachment to moiety A;

[0163] [ka] represents the point of attachment to moiety C; and B S and B Lare each independently selected from alkylene, cycloalkylene, arylalkylene, heteroarylalkylene, heteroalkylene, heterocycloalkylene, alkenylene, cycloalkenylene, arylalkenylene, heteroarylalkenylene, heteroalkenylene, heterocycloalkenylene, alkynylene, heteroalkynylene, arylene, heteroarylene, aminoacyl, oxyalkylene, aminoalkylene, diacid ester, dialkylsiloxane, amide, thioamide, thioether, thioester, ester, carbamate, hydrazone, thiazolidine, methylenealkoxycarbamate, disulfide, vinylene, imine, imidamide, phosphoramide, saccharide, phosphate ester, phosphoramide, carbamate, dipeptide, tripeptide, and tetrapeptide, each of which is optionally substituted. or a pharmaceutically acceptable salt thereof, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0164] 45.B is (Bs)x (In the formula, Each x is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; B Sare each independently selected from the group consisting of alkylene, cycloalkylene, arylalkylene, heteroarylalkylene, heteroalkylene, heterocycloalkylene, alkenylene, cycloalkenylene, arylalkenylene, heteroarylalkenylene, heteroalkenylene, heterocycloalkenylene, alkynylene, heteroalkynylene, arylene, heteroarylene, aminoacyl, oxyalkylene, aminoalkylene, diacid ester, dialkylsiloxane, amide, thioamide, thioether, thioester, ester, carbamate, hydrazone, thiazolidin, methylenealkoxycarbamate, disulfide, vinylene, imine, imidamide, phosphoramide, saccharide, phosphate ester, phosphoramide, carbamate, dipeptide, tripeptide, and tetrapeptide. 45. A compound according to aspect 43 or 44, represented by:

[0165] 46.B S and B L but, independently of each other,

[0166] [ka] TIFF2025536589000120.tif244170 TIFF2025536589000121.tif229170 TIFF2025536589000122.tif62170(in the formula, n is independently 0, 1, 2, 3, 4, 5, 6, 7, or 8; m is independently 0, 1, 2, 3, or 4; R c , R d , and R e are each independently H, optionally substituted C 1-6 Alkyl, (C3-C 10 Carbocyclyl)C 1-6Alkyl, (C6-C 10 Aryl)C 1-6 Alkyl, (C1-C 10 Heterocyclyl)C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C6-C 10 aryl, in each of which one or more carbon atoms may optionally be replaced by a heteroatom; preferably selected from the side chain residues of proteinogenic or non-proteinogenic amino acids; R and R′, if present, are each independently H or 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 is optionally selected from C 1-6 optionally substituted with 1 to 3 substituents selected from alkyl, OH, oxo, and halogen;

[0167] [ka] each represents an attachment point where the shortest path to moiety C contains fewer atoms than the path to *, provided that n is >1 and each attachment point is R c , R d and R eWhen shown on any one of the structures, it can independently be present in one or more of the peptide monomer units, preferably in the one peptide monomer unit furthest from the other attachment points shown in each structure; wherein each of the above structures optionally includes an additional point of attachment to moiety A or C. 46. ​​A compound according to any one of aspects 43 to 45, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof, selected from:

[0168] 47. Part B has the following structure: (a) Single bond, (B S )x

[0169] [ka] TIFF2025536589000125.tif196170 and

[0170] [ka] (In the formula, AA3, AA4, AA5, AA6, AA7 and AA8 represent proteinogenic or non-proteinogenic amino acids or are absent; Preferably, the proteinogenic or non-proteinogenic amino acids each preferably independently have the following structure:

[0171] [ka] or

[0172] [ka] and / or AA4 is an amino acid with a charged side chain and AA7 is an amino acid with an aliphatic side chain; Here, more preferably, AA3 is selected from Asp, Glu, and Lys or is absent, preferably Asp; AA4 is selected from Arg, homoArg, Lys, Asp, and Glu, or is absent; preferably Lys or Arg; AA5 is selected from Asp, Glu, and Lys; preferably Asp; AA6 is selected from Cys, Lys, Gly and Val; preferably Cys or Lys; AA7 is selected from Gly, Ala, Val, Arg, Ile, and Pro; and AA8 is selected from Pro and citrulline (Cit); Even more preferably, the following table:

[0173] [Table 7] According to one of the sequences shown in: ) or (b) a single bond,

[0174] [ka] TIFF2025536589000131.tif246170 TIFF2025536589000132.tif248170 TIFF2025536589000133.tif248170 TIFF2025536589000134.tif231170 TIFF2025536589000135.tif247170 TIFF2025536589000136.tif218170 TIFF2025536589000137.tif72170 and

[0175] [ka] (This is one of the structures A compound according to any one of Aspects 1 to 46, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0176] 48. The following structure: (a)

[0177] [ka] (b)

[0178] [ka] (c)

[0179] [ka] or (d)

[0180] [ka] wherein, unless otherwise specified, all groups and variables are as defined in any one of embodiments 1 to 46. There is one, where A compound according to any one of aspects 1 to 47, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein -D represents -BC as defined in any one of aspects 1 to 47.

[0181] 49. Each -D or -BC independently has the following structure:

[0182] [ka] TIFF2025536589000144.tif234170 TIFF2025536589000145.tif155170, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound according to any one of embodiments 1 to 47 represents -BC as defined in any one of embodiments 1 to 48,

[0183] 50. -D or -BC each independently represent the following structure:

[0184] [ka] or a pharmaceutically acceptable salt thereof, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof,

[0185] 51. The moiety C is a chelator group suitable for radiolabeling; a radioactive group comprising a radioisotope; a chelate of a radioisotope and a chelator; a fluorophore group; a cytotoxic and / or cytostatic drug; an immunomodulator; or a protein, wherein preferably (a) A group of chelating agents suitable for radiolabeling includes colloidal sulfur, 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, and 6-hydrazinopyridine-3-carboxylic acid (HYNIC).

[0186] [ka] TIFF2025536589000148.tif191170, or The following formula:

[0187] [ka] (In the formula, n is 0, 1, 2, 3, 4 or 5, preferably 1; R 1e are independently H, COOH, aryl-COOH, or heteroaryl-COOH; preferably COOH; R 2e are independently H, COOH, aryl-COOH, or heteroaryl-COOH; preferably COOH; R 3e are each independently H, COOH, aryl-COOH, or heteroaryl-COOH; preferably COOH; R 4e are independently H, COOH, aryl-COOH, or heteroaryl-COOH; preferably COOH; and X is O, NH, or S; preferably O; or The following formula:

[0188] [ka] (In the formula, n is 0, 1, 2, 3, 4 or 5, preferably 1; R 1f are independently H, COOH, aryl-COOH, or heteroaryl-COOH; preferably COOH; R 2f are 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) A radioactive group containing a radioisotope is 223 Ra, 89 Sr,94 mTc, 99 mTc, 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, 117 MSn, 169 Er and 227 Selected from Cu; (c) the chelate of the radioisotope is a chelate of an isotope listed in (b) above and / or a chelate with a chelating agent listed in (a) above; or moiety C has the following structure:

[0189] [ka] wherein X is CH, O, N or S, preferably CH.

[0190] [ka] wherein M is a radioisotope preferably selected from list (b) above. , and more preferably the following:

[0191] [ka] or is a group selected from any of: (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; preferably, the fluorophore group has the following structure:

[0192] [ka] TIFF2025536589000155.tif210170 Selected from TIFF2025536589000156.tif96170, (e) the cytotoxic and / or cytostatic agent is selected from a chemotherapeutic agent selected from the group consisting of topoisomerase inhibitors, alkylating agents, antimetabolites, antibiotics, mitotic disrupting agents, DNA intercalators, DNA synthesis inhibitors, DNA-RNA transcription regulators, enzyme inhibitors, gene regulators, hormone response modifiers, hypoxia-selective cytotoxins, epidermal growth factor inhibitors, antivascular agents, and combinations of two or more thereof; preferably, a chemotherapeutic agent having the following structure:

[0193] [ka] TIFF2025536589000158.tif231170 TIFF2025536589000159.tif246170 TIFF2025536589000160.tif244170 TIFF2025536589000161.tif239170 TIFF2025536589000162.tif112170, or Ring C is an auristatin derivative, preferably having the following formula:

[0194] [ka] (In the formula, R d1 are independently H or C1-C6 alkyl; preferably H or CH3; R d2 are independently C1-C6 alkyl; preferably CH3 or iPr; R d3 are independently H or C1-C6 alkyl; preferably H or CH3; R d4 are independently H, 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; R d5 are independently H, OH, C1-C6 alkyl; preferably H or OH; and R d6 are independent, C3~C 10 Aryl or C3-C 10 heteroaryl; preferably optionally substituted phenyl or pyridyl) and preferably the moiety C is derived from MMAE or MMAF; or a topoisomerase inhibitor; preferably camptothecin (CPT) or a derivative thereof; more preferably derived from topotecan, irinotecan, ciratecan, cocitocan, exatecan, lurtotecan, dimatecan, belotecan, rubitecan, deruxtecan, DXd (e.g., by replacing a hydrogen atom); even more preferably exatecan; even more preferably the following:

[0195] [ka] or

[0196] [ka] wherein each n is 0, 1, 2, 3, 4, 5, or 6; and most preferably:

[0197] [ka] is) is; (f) the immunomodulatory agent is selected from molecules known to be capable of modulating the immune system, such as ligands for CD3, CD25, TLR, STING, 4-1BBL, 4-1BB, PD-1, mTor, PDL-1, NKG-2D IMiD, where the ligands may be agonists and / or antagonists; or (g) the protein is selected from cytokines such as IL2, IL10, IL12, IL15, TNF, interferon gamma, etc., or is an antibody. A compound according to any one of Aspects 1 to 50, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0198] 52.(a)AB is the following:

[0199] [ka] TIFF2025536589000168.tif235170 TIFF2025536589000169.tif246170 TIFF2025536589000170.tif248170 TIFF2025536589000171.tif212170 TIFF2025536589000172.tif204170 TIFF2025536589000173.tif248170 and / or represented by a structure selected from: (b) C is:

[0200] [ka] TIFF2025536589000176.tif249170 TIFF2025536589000177.tif247170 TIFF2025536589000178.tif248170 TIFF2025536589000179.tif104170 (wherein the combination of A, B and C is preferably selected so that the covalent bond connecting B and C is represented by S-S, S-C, C-S, C(O)-Ra, C(O)-N, C(O)-O, C(O)-N, NC(O), NC(O)O, NC(S), or OC(O)-N) or a pharmaceutically acceptable salt thereof, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound of any one of Aspects 1-51 is represented by a structure selected from:

[0201] 53. The compound according to any one of aspects 1 to 52, wherein moiety A is selected from A-1 to A-5, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof. 54. The compound according to any one of aspects 1 to 53, wherein moiety B is selected from B-1 to B-21, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof. 55. The compound according to any one of aspects 1 to 54, wherein the moiety C is selected from C-1 to C-31, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof. 56. A compound having a structure selected from those listed in Table 1, Table 3.1, Table 3.2, Figure 30, Figure 31, Figure 33, or Figure 34, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof. 57. A pharmaceutical composition comprising a compound according to any one of aspects 1 to 56, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 58. The following: (a) a method for the treatment of the human or animal body by surgery or therapy, or a diagnostic method practised on the human or animal body; or (b) a method for the treatment or prevention of a subject suffering from or at risk of a disease or disorder; or (c) a method of induced surgery performed on a subject suffering from or at risk of suffering from a disease or disorder; or (d) a method for diagnosing a disease or disorder, the method comprising a nuclear medicine imaging technique, positron emission tomography (PET) or single photon emission computed tomography (SPECT), performed on the human or animal body; or (e) methods for targeted delivery of therapeutic or diagnostic agents to a subject suffering from or at risk of a disease or disorder; A compound according to any one of Aspects 1 to 56, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Aspect 57, for use in 59. The compound, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof, according to aspect 58, wherein the disease or disorder is independently selected from hypoxia-related diseases such as cancer, and preferably said cancer is selected from the group consisting of breast cancer, pancreatic cancer, colon cancer, multidrug-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, bile duct cancer, renal clear cell carcinoma, glioma, astrocytoma, cervical cancer, and kidney cancer. [Example]

[0202] Synthesis of derivatives 1.1 General Notes 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 (0.1% formic acid in MilliQ water) and eluent B (0.1% formic acid in acetonitrile) was applied at a column temperature of 40 °C and a flow rate of 0.6 mL / min (5% to 80% B in 6 min). Reversed-phase medium pressure liquid chromatography (MPLC) Small organic molecules that could be produced in larger quantities (>10 mg) were purified by reversed-phase medium-pressure liquid chromatography (BUCHI) on a C18 40 μM irregular 12 g column (BUCHI, #145152103) using mQ Millipore water 0.1% formic acid (FA) (eluent A) and acetonitrile 0.1% FA (eluent B) as the mobile phase with the following gradient: 0–5 min 98% A, 5–45 min 98%–0% A, 45–50 min 0% A, 50–50.1 min 0%–98% A, and 50.1–55 min 98% A. The flow rate was set at 30 mL / min. Reversed-phase high-pressure liquid chromatography (HPLC) The final products and conjugates were purified by semi-preparative reversed-phase high-pressure liquid chromatography (RP-HPLC) on an Agilent 1200 Series RP-HPLC equipped with a PDA UV detector. The system was equipped with a Synergi 4 μm, Polar-RP 80 Angstrom 10 × 150 mm C18 column, using a flow rate of 5 mL / min with a gradient of eluent A (millipore water with 0.1% TFA) and eluent B (acetonitrile with 0.1% TFA): 0–15 min 90%–0% A, 15–16 min 0% A, 16–17 min 0%–90% A, and 17–18 min 90% A.

[0203] 1.2 Solid phase synthesis General solid phase synthesis procedure Solid-phase synthesis was performed using pre-packed Fmoc-Lys(Boc)-Wang resin (200-400 mesh, 0.5 mmol / g; Bachem, #4003241.0005). Generally, the resin was swollen in dimethylformamide (DMF) for 30 min before any reaction step. Incubations were performed at room temperature in a 10 mL reaction column (CEM Corporation, #32.276) on a rotating mixer (Reax 2, Heidolph Instruments GmbH & Co. KG). Fmoc deprotection The resin was incubated with 20% piperidine in DMF for 2 x 15 min. After deprotection, the resin was washed 5-10 times with DMF to remove residual piperidine. Mini-cleavage for LC-MS analysis A small amount of resin was transferred to an Eppendorf tube and incubated with 20 μL of trifluoroacetic acid (TFA) for 15 min at room temperature. Before LC-MS analysis, cleavage was quenched by adding 100 μL of DMF and centrifuging the suspension (10,000 rcf for 1 min). Azide reduction After swelling in DMF, the resin was incubated with a solution of trimethylphosphine (5 equiv.) in THF:water (10% water in THF). The reaction was allowed to proceed at room temperature for 2 hours, after which the beads were washed 10 times with DMF.

[0204] Amide Coupling Typically, the acid (2 equivalents), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 1.9 equivalents), and diisopropylethylamine (DIPEA, 4 equivalents) were dissolved in DMF and added to the resin bearing a chemical moiety with a free amino group. After a 4-hour incubation, the resin was washed five times with DMF. The coupling efficiency could be monitored by LC-MS analysis (mini-cleavage). Resin cleavage and purification The cleavage solution was prepared as follows: 95% trifluoroacetic acid (TFA), 2.5% water, and 2.5% triisopropylsilane (TIPS). Where specified, 2.5% thioanisole and 2.5% m-cresol were added as scavengers. The highest yields were obtained when three consecutive cleavages (each for 1 h at room temperature) were performed. The cleavage fractions were combined and either directly purified via RP HPLC or precipitated in diethyl ether for subsequent purification (see below). Peptide precipitation The peptide structure was precipitated from the cleavage solution by adding 5-10 volumes of ice-cold diethyl ether. The precipitation proceeded for 30 min at -20 °C, and the peptide was obtained as a pellet by centrifugation (3200 rcf, 5 min, 4 °C). The crude product was dissolved in water:acetonitrile (1:1) and purified by reverse-phase chromatography.

[0205] 1.2.1 Synthesis of Intermediates I1 to I4 (Intermediate I4 = Compound C9)

[0206] [ka] Preloaded Fmoc-Lys(Boc)-Wang resin (1 g scale) was swollen for subsequent Fmoc deprotection. The tripeptide Lys-Asp-βAla-NH was generated by repeated amide coupling and Fmoc deprotection according to the general procedure, with the amide coupling equivalents doubled (4 equivalents acid, 3.9 equivalents HATU, 8 equivalents DIPEA). The loading order was N-(fluorenylmethoxycarbonyl)-N-(tert-butoxycarbonyl)-L-lysine (preloaded), N-(fluorenylmethoxycarbonyl)-L-aspartic acid tert-butyl ester, and N-(fluorenylmethoxycarbonyl)-β-alanine. The tripeptide linker synthesized on the resin was divided into four 250 mg batches (each corresponding to a loading capacity of 0.125 mmol). Following the standard amide coupling protocol, each batch was coupled with one isomer of a proline derivative (RR, SS, RS, SR). After Fmoc deprotection, I6 was coupled with lower equivalents (47 mg, 0.138 mmol, 1.1 equivalents, acid; 47.5 mg, 0.125 mmol, 1 equivalent of HATU and 174 μL of DIPEA; 1 mmol, 8 equivalents of DIPEA). The reaction was left overnight. Subsequent azide reduction was followed by coupling of 2-(2,4-dichlorophenyl)acetic acid using 6 equivalents of acid (154 mg, 0.75 mmol), 5 equivalents of HATU (238 mg, 0.625 mmol), and 8 equivalents of DIPEA (174 μL, 1 mmol). The reaction was allowed to proceed overnight at room temperature. Finally, I1, I2, I3, and I4 were cleaved from the resin, precipitated with ice-cold diethyl ether, and purified by 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), and I4 = C9 (RR, 7.8 mg, 7% yield). 31 H 39 Cl3N7O 11 S2 [M+H] + Calculated m / z for: 854.1209, Found (TOF MS ES+):

[0207] [ka] 1.2.2 Synthesis of intermediate I5

[0208] [ka] The tripeptide linker Lys-Asp-βAla-NH was synthesized on resin (125 mg, 0.06 mmol) as described above and reacted with the acetazolamide derivative (4-oxo-4-[(5-sulfamoyl-1,3,4-thiadiazol-2-yl)amino]butanoic acid, 73 mg, 0.21 mmol, 4 equiv.) in the presence of HATU (81 mg, 0.21 mmol, 4 equiv.) and DIPEA (300 μL, 1.72 mmol, 8 equiv.) in DMF. After 4 h at room temperature, the resin was washed with DMF, after which I5 was cleaved from the resin and purified by RP-HPLC to give I5 as a white solid (2.7 mg, 7.6% yield). 19 H 31 N8O 10 m / z calculated for S2[M+H]+: 595.1599, found (TOF MS ES+): 595.1688.

[0209] 1.3 Liquid phase synthesis 1.3.1 Synthesis of intermediate I6

[0210] [ka] Fischer esterification, Boc protection, and ester hydrolysis were carried out without purifying the reaction intermediates. 500 mg (2.07 mmol, 1 equiv.) of 5-chloro-2-sulfamoylthiophene-3-carboxylic acid was dissolved in 25 mL of methanol and 2.6 mL of 4 M HCl (10.4 mmol, 5 equiv.) in dioxane. 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-propanyl)dicarbonate (540 mg, 2.47 mmol, 1.2 equiv.), 101 mg of N,N-dimethylpyridin-4-amine (DMAP; 0.83 mmol, 0.4 equiv.), and 342 μL of triethylamine (TEA, 2.47 mmol, 1.2 equiv.) were added. After 3 h at room temperature, LC-MS analysis revealed the reaction was complete. The solvent was evaporated under reduced pressure, and the crude product was dissolved in 20 mL of water:THF (1:1). Ester hydrolysis was initiated by the addition of 1.3 mL of 8 M aqueous NaOH (10.4 mmol, 5 equiv.) and allowed to proceed for 3 h at room temperature. The solution was neutralized with 1 M aqueous HCl, and the solvent was evaporated. The crude product was dissolved in acetonitrile:water (1:1) and purified by RP-MPLC to give I6 as a white solid (320 mg, 45% yield). m / z calculated for C10H11ClNO6S2[MH]-: 339.9722, found (TOF MS ES-): 339.9702. 1.3.2 Synthesis of intermediate I7

[0211] [ka] 2-(2,4-Dichlorophenyl)acetic acid (5 mg, 23 μmol, 1 equiv.) was dissolved in DMF and preactivated 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.). 1-tert-Butyl 2-methyl(2R,4R)-4-amino-1,2-pyrrolidinedicarboxylate hydrochloride (6.4 mg, 23 μmol, 1 equiv.) was added to the preactivated solution and incubated at room temperature for 4 h. The solvent was evaporated and the residue was dissolved in 200 μL of TFA. After 1 h at room temperature, TFA was evaporated under reduced pressure, and the residue was dissolved in water and lyophilized. The coupling to I6 (7.7 mg, 23 μmol, 1 equiv.) was continued under the same conditions as described for the first coupling step. After Boc deprotection in TFA (200 μL) at room temperature for 1 h, the TFA was evaporated and neutralized with 1M aqueous NaOH. Ester hydrolysis was then carried out at room temperature for 2 h using NaOH (230 μL of 1M aqueous NaOH, 230 μmol, 10 equiv.) in 500 μL of water:THF (1:1). After neutralization with 1M aqueous HCl, the solvent was evaporated under reduced pressure, and the crude product was purified by RP-HPLC. The product was lyophilized to give I7 as a white solid: RR (3.9 mg, 32% yield). 18 H 17 Cl3N3O6S2[M+H] + Calculated m / z for: 539.9619, detected (TOF MS ES+): 539.9050, 540.9713.

[0212] 1.3.3 Synthesis of intermediate I8

[0213] [ka] 1-tert-Butyl 2-methyl(2R,4R)-4-amino-1,2-pyrrolidinedicarboxylate hydrochloride (5.5 mg, 19.6 μmol, 1 equiv.) was dissolved in 500 μL of DCM, and acetic anhydride (18.5 μL, 196 μmol, 10 equiv.) and triethyl acetic acid (TEA) (13.7 μL, 98.3 μmol, 5 equiv.) were added to carry out the acetylation reaction. After 1 h at room temperature, the solvent was evaporated, and the dry residue was dissolved in 200 μL of TFA. Boc deprotection proceeded at room temperature for 1 h. TFA was evaporated under reduced pressure, and the residue was dissolved in 10 mL of water:acetonitrile (1:1). The crude product was lyophilized overnight. I6 (6.7 mg, 19.6 μmol, 1 equiv.) was preactivated with 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.) in DMF for 10 min at room temperature, after which this solution was added to the acetylated intermediate. The coupling was left at room temperature for 4 h, followed by Boc deprotection in TFA and saponification with NaOH (200 μL of 1 M aqueous NaOH, 200 μmol, 10 equiv.) in 400 μL of water:THF (1:1). The hydrolysis mixture was neutralized with 1 M aqueous HCl, the solvent was evaporated, and the product was purified by RP-HPLC to give I8 as a white solid (2.4 mg, 31% yield). 12 H 15 m / z calculated for ClN3O6S2 [M+H]+: 396.0085, found (TOF MS ES+): 396.0050.

[0214] 1.3.4 Synthesis of Intermediate I9

[0215] [ka] Preactivation of 2-(2,4-dichlorophenyl)acetic acid (3.9 mg, 17.6 μmol, 1 equiv.) was carried out with 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.) in DMF at room temperature for 10 min. Coupling was initiated by the addition of 1-tert-butyl 2-methyl(2R,4R)-4-amino-1,2-pyrrolidinedicarboxylate 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 1M aqueous NaOH solution, 180 μmol, 10 equiv.). Esterification proceeded for 2 h at room temperature and was stopped by neutralizing the solution with 1M aqueous HCl and evaporating the solvent. The crude product was purified by RP-HPLC to give I9 ​​as a white solid (2.7 mg, 39% yield). 15 H 17 m / z calculated for Cl2N2O4 [M+H]+: 359.0560, found (TOF MS ES+): 359.0451.

[0216] 1.3.5 Synthesis of Intermediate I10

[0217] [ka] 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 FITC (78 mg, 0.20 mmol, 1 equiv.) and DIPEA (140 μL, 0.80 mmol, 4 equiv.) in DMF at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and the residue was dissolved 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). 27 H 28 m / z calculated for N3O7S[M+H]+: 538.1642, found (TOF MS ES+): 538.1675.

[0218] 1.3.6 Synthesis of Compounds C1, C3, C5 and C7

[0219] [ka] I1, I2, I3, and I4 (2 mg, 2.3 μmol, 1 equiv.) were separately dissolved 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 in a shaking incubator at room temperature for 1 hour. 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), and C7 (RR, 0.90 mg, 32% yield). 52 H 49 Cl3N7O 17 m / z calculated for S2 [M+H]: 1212.1686, found (TOF MS ES):

[0220] [ka] .

[0221] 1.3.7 Synthesis of Compounds C2, C4, C6, and C10

[0222] [ka] I1, I2, I3, and I4 (72 μg, 0.084 μmol, 1 equiv. in 72 μL DMSO) were placed separately in Eppendorf tubes, and 0.3 μL of DIPEA (1.7 μmol, 20 equiv.) was added. After adding 50 μL of IRDye® 750 NHS ester (LI-COR Biosciences) predissolved in DMSO (100 μg, 0.084 μmol, 1 equiv.), the reaction was allowed to proceed overnight at room temperature in a shaking incubator. The product was isolated by RP-HPLC, lyophilized (green solid), dissolved in 100 μL of sterile PBS, and the concentration was determined 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). m / z calculated for CHClNOS[M+H]: 1864.4031, found (MALDI-TOF MS+): 1864.40, 1866.41 (C2); 1864.39, 1866.39 (C4); 1864.40, 1866.40 (C6); 1864.41, 1866.41 (C10). 1.3.8 Synthesis of Compounds C8, C12, and C13

[0223] [ka] C8, C12, and C13 were synthesized according to the general procedure using EDC (1 equiv.), HOBt (1 equiv.), and DIPEA (4 equiv.) in DMF for 10 min at room temperature, followed by the addition of I10 (1 equiv.). After 1 h at room temperature, the mixture was purified by RP-HPLC to give the products as yellow solids: C8 (1.1 mg, 53% yield), C12 (0.6 mg, 21% yield), and C13 (0.8 mg, 38% yield).

[0224] [ka] 1.3.9 Synthesis of Compound C11

[0225] [ka] An Eppendorf tube was charged with 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, 100 mM in DMSO, 0.29 μmol, 0.5 equiv.), and 95 μL of DMSO. The mixture was incubated at room temperature for 3 hours, and the crude product was purified by RP-HPLC to give product C11 as a white solid (0.30 mg, 39% yield). 50 H69 Cl3N 11 O 20 S 2 m / z calculated for [M+H]+: 1312.3222, found (TOF MS ES+): 1312.3872, 1314.3866.

[0226] 1.3.10 Radiolabeling of compound C11 with [177Lu]Lu

[0227] [ka] C11 was dissolved in MilliQ water containing 4% DMSO to a concentration of 1 mM, and 39 μL (39 nmol, 1 equivalent) of the solution was diluted with 74 μL of 1 M acetate buffer, pH 4.5. 177 After adding [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. Labeling efficiency was monitored by RP-HPLC (see Figure 23).

[0228] 1.3.11 Synthesis of Compound C14

[0229] [ka] I6 (1.2 mg, 3.5 μmol, 1 equiv.) was dissolved in 100 μL of DMF and preactivated 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 min at room temperature, I10 (1.9 mg, 3.5 μmol, 1 equiv.) was added, and the coupling proceeded for 1 h at room temperature in the dark. The solvent was evaporated under reduced pressure, and the residue was dissolved in TFA and subjected to Boc deprotection at room temperature for 15 min. After direct purification by RP-HPLC, C14 was obtained as a yellow solid (1.1 mg, 43% yield). 32 H 30 ClNO 10m / z calculated for S3[M+H]+: 761.0807, found (TOF MS ES+): 761.1006. 1.3.12 Synthesis of Compound C15(AAZ*)

[0230] [ka] I5 (1.2 mg, 2.0 μmol, 1 equiv.) was dissolved in 100 μL of DMF, and 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.) were added. After 1 h at room temperature, the crude product was purified by RP-HPLC, and the combined product fractions were lyophilized overnight. The final product, C15(AAZ*), was obtained as a yellow solid (0.51 mg, 26% yield). 40 H 42 N9O 15 m / z calculated for S3 [M+H]+: 984.1957, found (TOF MS ES+): 984.2300.

[0231] 1.3.13 Synthesis of Intermediate I11

[0232] [ka] 1-(tert-Butyl) 2-methyl(2R,4R)-4-aminopyrrolidine-1,2-dicarboxylate (50 mg, 205 μmol, 1 equiv.) was treated with 4-nitrophenyl carbonochloridate (41 mg, 205 μmol, 1 equiv.) and DIPEA (71 μL, 409 μmol, 2 equiv.) in dry DCM at 0° C. for 10 min. 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 dissolved in 1 mL of TFA. After 1 h at room temperature, TFA was evaporated, and the crude product was purified by RP-HPLC to give I11 as a colorless oil (59 mg, 82%).

[0233] 1.3.14 Synthesis of Intermediate I12

[0234] [ka] I6 (20.4 mg, 50.7 μmol, 1.1 equiv.) was dissolved in DMF and preactivated with benzotriazol-1-yloxy(tripyrrolidin-1-yl)phosphanium; hexafluorophosphate (PyBOP, 36.7 mg, 70.5 μmol, 1.3 equiv.) and DIPEA (28.3 μL, 162.7 μmol, 3 equiv.) for 1 min. I11 (19 mg, 54.2 μmol, 1 equiv.) was added to the preactivated solution and incubated at room temperature for 16 h. The solvent was evaporated, and the residue was dissolved in 500 μL of TFA. After 1 h at room temperature, the TFA was evaporated, followed by neutralization with 1 M aqueous NaOH. Subsequent ester hydrolysis was carried out with NaOH (540 μL of 1 M aqueous NaOH, 540 μmol, 10 equiv.) in 1 mL of water:THF (1:1) for 3 h at room temperature. After neutralization with 1M aqueous HCl, 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%).

[0235] 1.3.15 Synthesis of Intermediate I13

[0236] [ka] 2-(2,4-Dichlorophenyl)acetic acid (3 mg, 15 μmol, 1 equiv.) was dissolved in DMF and preactivated for 10 min by adding 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.). 1-tert-Butyl 2-methyl(2R,4R)-4-amino-1,2-pyrrolidinedicarboxylate hydrochloride (4.2 mg, 15 μmol, 1 equiv.) was added to the preactivated solution and incubated at room temperature for 4 h. The solvent was evaporated, and the residue was dissolved in 200 μL of TFA. After 1 h at room temperature, the TFA was evaporated under reduced pressure, and the residue was dissolved in water and lyophilized for subsequent coupling to 4-oxo-4-[(5-sulfamoyl-1,3,4-thiadiazol-2-yl)amino]butanoic acid (4.65 mg, 16.6 μmol, 1.1 equiv.), which had been preactivated 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. Ester hydrolysis was then carried out using NaOH (150 μL of 1 M aqueous NaOH, 150 μmol, 10 equiv.) in 300 μL of water:THF (1:1) for 3 h at room temperature. After neutralization with 1 M aqueous HCl, the solvent was evaporated under reduced pressure, and the crude product was purified by RP-HPLC to give I13 as a white solid (2.3 mg, 26%).

[0237] 1.3.16 Synthesis of Intermediate I14

[0238] [ka] (2R,4R)-1-(((9H-Fluoren-9-yl)methoxy)carbonyl)-4-azidopyrrolidine-2-carboxylic acid (25 mg, 66 μmol, 1 equiv.) was dissolved in 10 mL of methanol and 83 μL of 4 M HCl in dioxane (330 μmol, 5 equiv.). The solution was refluxed for 16 h, and the crude product was obtained after evaporation of the solvent under reduced pressure. The residue was dissolved in 20% piperidine in DMF. After stirring for 1 h, the solvent was evaporated. A pre-activated solution containing 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 added to the dried intermediate after stirring for 10 min. 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.

[0239] 1.3.17 Synthesis of Intermediate I15

[0240] [ka] I14 (5 mg, 10.1 μmol, 1 equiv.) was dissolved in tBuOH:water (1:1) along with N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl)hex-5-ynamide (2.8 mg, 10.1 μmol, 1 equiv.), CuSO(HO) (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, after which the solvent was evaporated. Ester hydrolysis was then carried out with NaOH (100 μL of 1 M aqueous NaOH, 100 μmol, 10 equiv.) in 200 μL of water:THF (1:1) at room temperature for 3 h. After neutralization with 1M aqueous HCl, the solvent was evaporated under reduced pressure and the crude material was purified by RP-HPLC to afford I15 as a white solid (5.3 mg, 80%).

[0241] 1.3.18 Synthesis of Intermediate I16

[0242] [ka] 2-(2,4-Dichlorophenyl)acetic acid (3 mg, 15 μmol, 1 equiv.) was dissolved in DMF and preactivated for 10 min by adding 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.). 1-tert-Butyl 2-methyl(2R,4R)-4-amino-1,2-pyrrolidinedicarboxylate hydrochloride (4.2 mg, 15 μmol, 1 equiv.) was added to the preactivated solution and incubated at room temperature for 4 h. The solvent was evaporated, and the residue was dissolved in 200 μL of TFA. After 1 h at room temperature, the TFA was evaporated under reduced pressure, and the residue was dissolved in water and lyophilized. In a separate flask, 5-amino-1,3,4-thiadiazole-2-sulfonamide (2.7 mg, 15 μmol, 1 equiv.) was treated with 4-nitrophenyl carbonochloridate (3 mg, 15 μmol, 1 equiv.) and DIPEA (5.3 μL, 30 μmol, 2 equiv.) in dry ACN at 0 °C for 30 min. The lyophilized crude product was then added, and after incubation at room temperature for 1 h, the solvent was evaporated. Ester hydrolysis was then carried out using NaOH (150 μL of 1 M aqueous NaOH, 150 μmol, 10 equiv.) in 300 μL of water:THF (1:1) for 3 h at room temperature. After neutralization with 1 M aqueous HCl, the solvent was evaporated under reduced pressure, and the crude material was purified by RP-HPLC to give I16 (1.6 mg, 20%) as a white solid.

[0243] 1.3.19 Synthesis of Intermediates I17, I18, I19, I20, and I21

[0244] [ka] I17, I18, I19, I20, and I21 were synthesized by preactivating the acid (I7, I12, I13, I15, or I16) with EDC (1 equiv.), HOBt (1 equiv.), and DIPEA (3 equiv.) in DMF for 15 min at room temperature, followed by the addition of tert-butyl N6-(tert-butoxycarbonyl)-L-lysinate hydrochloride (1 equiv.). After 20 h at room temperature, the solvent was evaporated and TFA was added. After stirring at room temperature for 1 h, 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), and I21 (1.15 mg, 58% yield).

[0245] 1.3.20 Synthesis of Compounds C19, C20, C21, C22, and C23

[0246] [ka] C19, C20, C21, C22, and C23 were synthesized by mixing an amine (I17, I18, I19, I20, or I21) with FITC (0.8 equiv.) and DIPEA (3.5 equiv.) in DMF at room temperature for 45 min. The mixture was purified by RP-HPLC to give the following 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), and C23 (0.07 mg, 55% yield). [Example]

[0247] Determining compound affinity and selectivity by fluorescence polarization 2.1 General Notes Fluorescence polarization was measured in black 384-well microplates on a Tecan Spark® Multimode Microplate Reader (λ excitation = 485 ± 20 nm, λ emission = 535 ± 25 nm). Typically, a dilution series (usually 1:1) of the protein in each buffer was prepared to reach a volume of 5 μL per well. Fluorophore-conjugated compounds were diluted in protein buffer to reach concentrations of 20 nM, 10 nM (Figure 35), or 2 nM (Figure 34), and 5 μL was added to each well. Plates were centrifuged (400 rcf, 1 min) and incubated in the dark for 15 min before measurement.

[0248] 2.2 Affinity measurement We synthesized fluoresceinated conjugates of four stereoisomers (compounds C1, C3, C5, and C7) and measured their affinity for recombinantly expressed human CAIX via fluorescence polarization. We observed stereoselective binding of compound C7 (2R, 4R; K D =15±2 nM), no binding of the other isomers (compounds C1, C3 and C5, see Figure 26, above) was detected. To analyze which parts of the molecule are important for CAIX binding, we performed a fragment screen and identified a sulfonamide-bearing thiophene (compound C12) and its respective proline derivative (compound C14) 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) did not bind to CAIX, but when combined with sulfonamides, it exhibited a dissociation constant in the nanomolar range (K D =6±1 nM, see FIG. 26, bottom) resulting in a highly potent CAIX ligand (compound C8).

[0249] 2.3 Selectivity measurements Compound C7 and acetazolamide (AAZ*) were screened against human CAIX and CAIX isozymes (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 (fitting was not applicable) and no detectable binding to other isozymes (see Figure 27 and Table 6). In contrast, AAZ* bound strongly to all carbonic anhydrases screened, with no apparent selectivity for CAIX (see Figure 27 and Table 6). The selectivity was confirmed by extending the analysis to a set of other protein targets (see Figures 31 and 32). Table 6. Dissociation constants (K) of compounds C7 and AAZ* for CAIX and each isoenzyme D Each value is given as the mean ± standard deviation (n=3). h=human, b=bovine, ND=not detected.

[0250] [Table 8] Selectivity was also confirmed using the same fluorescence polarization by extending the analysis to an additional set of binders, namely compounds C16, C17, and C18 (where R is L6), i.e., DNA / LNA(bodipy) multiplex (see Figure 33 and Table 7). An exemplary DNA has a 74-mer sequence attached via a 5'C6 amino modification:

[0251] [ka] (wherein each X can independently be A, C, T, or G; LNA(bodipy) comprises a complementary BODIPY-modified octameric LNA (5'GGCTACTA-C6-amino-3') conjugated to 3'-BODIPY-TMR-X (Thermo Fisher Scientific, #D6117), where DNA is annealed to the complementary BODIPY-modified octameric LNA at a 1:1 molar ratio by mixing 25 μL of each 2 μM solution (in PBS). Table 7. Dissociation constants (K D ) (h=human, b=bovine)

[0252] [ka] The results suggest that similar affinity for CAIX and selectivity for CAII is achieved across the range of the present invention. [Example]

[0253] Qualitative and quantitative biodistribution studies 3.1 Cell culture The human renal cell carcinoma cell line SKRC-52 was grown in RPMI-1640 supplemented with 10% FBS and 1x antibiotic-antimycotic at 37°C and 5% CO2. Cell passage was performed every 2 days using trypsin-EDTA 0.25% to detach the cells. The cells were used to grow tumors in mice.

[0254] 3.2 In vivo IVIS imaging for qualitative biodistribution analysis To test whether stereoselective CAIX binding could be translated into stereoselective in vivo targeting of CAIX-expressing tumors, we synthesized each of the IRDye conjugates (compounds C2, C4, C6, and C10). Subcutaneous SKRC-52 tumor (150-300 mm 3) Balb / c nude mice were intravenously injected with 3 nmol of each compound dissolved in 150 μL of sterile PBS, and fluorescence images were acquired 4 hours after injection. Mice were anesthetized with Attane™ isoflurane and fluorescence images were acquired with an IVIS Spectral Imaging System (Xenogen; 1 second exposure; binning factor = 8; λ excitation = 745 nm; λ emission = 800 nm; f-number 2; field of view 13.1). Images were taken 10 minutes, 1 hour, 2 hours, 4 hours, and 6 hours after injection. Only compound C10(2R,4R) showed accumulation at the tumor site (see Figure 28).

[0255] 3.3 Quantitative biodistribution analysis using radiolabeled compound C11 CAIX ligands are 177 It was synthesized as a DOTAGA conjugate (compound C11) to allow radiolabeling with Lu. Subcutaneous SKRC-52 tumor (200-300 mm 3 ) to Balb / c nude mice, 3 nmol (0.85 MBq) [ 177 [Lu]Lu-C11 was intravenously injected. Mice were sacrificed 6 hours after injection, and the following organs were isolated and measured for radioactivity: tumor, liver, kidney, spleen, stomach, intestine, lung, heart, tail, muscle, and blood. Radioactivity was measured using a Packard Cobra Gamma Counter and plotted as %ID / g ± SEM (n = 4). Values ​​were expressed as [ 177 Lu]Lu-C11 (normalized to the batch used for injection). The radiolabeled compound was detected in tumors and kidneys. Other healthy organs were [ 177 Only the [Lu]Lu-C11 trace is shown, highlighting the selectivity of the novel CAIX ligand (see Figure 29).

[0256] References

[0257] [Table 9]

Claims

1. The structure of the compound is as follows: 【Chemistry 1】 (In the formula, R １ is -C(Y)-R １ａ -SO ２ NR(R') or (G １ )q-(CR(R')) ｒ - (G ２ ) ｓ -R １ａ -SO ２ represented by NR(R'); R １ａ are independently a 6- to 10-membered aromatic group or a 5- to 10-membered heteroaromatic group having up to three heteroatoms independently selected from N, O, and S, where SO ２ NR(R′) and one or more substituents R ３ where: G1 independently represents C(Y), SO, SO ２ CR(R'), triazolyl, and CR(R')triazolyl; G2 independently represents C(Y), C(Y)NR, SONR, SO ２ NR, CR(R')NR, NRC(Y), NRSO, NRSO ２ , NRCR(R'), triazolyl, triazolylNR, triazolylCR(R'), NRtriazolyl, and CR(R')-triazolyl; q and s are each 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 R ２ａ -(CR(R'))p-C(Y)-, or R ２ and the group RN- are both R ２ａ - (G ４ )v-(CR(R'))u-(G ３ ) form a residue represented by t-; R ２ａ is independently selected from N, O, and S, and １－４ a 6- to 10-membered aromatic group or a 5- to 10-membered heteroaromatic group optionally substituted with alkyl, and one or more substituents R ４ may be substituted with, where: G ３ are independently C(Y)NR, SONR, SO ２ selected from NR, CR(R')NR, triazolyl, triazolylCR(R'), and CR(R')triazolyl; G ４ are independently C(Y), NRC(Y), NRSO, NRSO ２ ,NRCR(R'),C(Y)NR,SONR,SO ２ selected from NR, CR(R')NR, triazolyl, NR triazolyl, triazolylNR, CR(R') triazolyl, and triazolylCR(R'); t and v are each independently 0 or 1; u is independently selected from 0, 1, 2, 3 and 4, preferably 3; However, preferably, at least one of t and v is 1, more preferably both t and v are 1; However, preferably, t+u+v≧1, more preferably ≧2, and most preferably ≧3; and p is independently 1, 2, 3 or 4, preferably 1 or 2, more preferably 1; wherein CR(R'), if present one or more times, may be optionally substituted with a group independently selected from O, S, and NR, provided that no two O atoms are adjacent to each other; Y, if present, is independently selected from O, S, NR, and CR(R'); R ３ and R ４ are each independently NH ２ ,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, NO ２ , C(O)NH ２ , C(O)NR(R′), CN, oxo, and halogen; Here, R ３ and R ４ may each independently optionally form a 4- to 7-membered carbocyclic or heterocyclic ring together with any CR(R'); and R and R′, if present, are independently H or 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 is optionally selected from C １－６ optionally substituted with 1 to 3 substituents selected from alkyl, OH, oxo and halogen; As used herein, the term "diastereoisomer," unless otherwise specified, refers to stereoisomers of a compound that differ in configuration at one or more stereocenters in portions of the molecule other than portion A, where the stereochemical configuration of portion A is as depicted in each structure, and the individual diastereomers differ in stereochemical configuration in portions of the molecule other than portion A. A compound, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof, comprising at least one group A independently represented by:

2. R １ａ is independently a 5- to 10-membered heteroaromatic group having up to three heteroatoms independently selected from N, O, and S, wherein the heteroaromatic group is SO ２ NR(R′) and one or two substituents R ３ is substituted with; R ２ａ is 0, 1, 2 or 3 substituents R ４ a 6- to 10-membered aromatic group substituted with p is 1; Y, if present, is O; and R ３ and R ４ are each independently OCH ３ , OCH ２ CH ３ , OCH ２ CH ２ CH ３ , OCH ２ (CH ３ ) ２ , O-cyclopropyl, OCF ３ , OCF ２ CF ３ , COOH, COOCH ３ , NO ２ CN, F; Cl; Br; and I; 10. The compound of claim 1, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof.

3. A has the following structure: 【Chemistry 2】 (In the formula, c is independently 1 or 2, preferably 1; d is independently 0, 1, 2, 3, 4 or 5, preferably 2; W is independently NR, O, S, S(O), and SO ２ (selected from 3. The compound according to claim 1 or 2, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof, represented by any one of:

4. A has the following structure: 【Transformation 3】 (In the formula, W １ , W ３ , W ４ are each independently selected from CH, S, O, and N, and at least one is S or O. The compound according to any one of claims 1 to 3, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof, represented by any one of:

5. A has the following structure: 【Chemistry 4】 (In the formula, W is independently selected from S and O; W １ is S or O; and W ３ , W ４ are each independently selected from CH, S, O, and N. The compound according to any one of claims 1 to 4, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof, represented by any one of:

6. A is one of the following structures A-1 to A-5: 【Transformation 5】 The compound according to any one of claims 1 to 5, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof, represented by any one of:

7. The compound has the following formula I, Ia, or Ib: 【Transformation 6】 wherein each A is independently as defined in any one of claims 1 to 10; B is a single bond or an optionally substituted C １－５０ an aliphatic group, where optionally one or more carbon atoms are replaced by a heteroatom, C ３－１２ Carbocyclic or C １－１２ The heterocyclic group may be substituted and may be saturated or may optionally contain one or more double or triple bonds; and Each C is an atom, molecule, or particle, and / or a therapeutic or diagnostic agent. The compound according to any one of claims 1 to 6, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof, represented by:

8. B is a single bond or a group represented by the following general formula II-V, IIa-Va or IIb-Vb: 【Transformation 7】 (In the formula, 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; With the proviso that in formulas IIa, Va and IIb, Vb, z and at least one of x and y are not 0; * represents the point of attachment to moiety A; and 【Transformation 8】 represents the point of attachment to said moiety C; and B Ｓ and B Ｌ are each independently selected from alkylene, cycloalkylene, arylalkylene, heteroarylalkylene, heteroalkylene, heterocycloalkylene, alkenylene, cycloalkenylene, arylalkenylene, heteroarylalkenylene, heteroalkenylene, heterocycloalkenylene, alkynylene, heteroalkynylene, arylene, heteroarylene, aminoacyl, oxyalkylene, aminoalkylene, diacid ester, dialkylsiloxane, amide, thioamide, thioether, thioester, ester, carbamate, hydrazone, thiazolidine, methylenealkoxycarbamate, disulfide, vinylene, imine, imidamide, phosphoramide, saccharide, phosphate ester, phosphoramide, carbamate, dipeptide, tripeptide, and tetrapeptide, each of which is optionally substituted.

8. The compound of claim 7, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof, represented by any one of:

9. B is (Bs) x (In the formula, Each x is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; B Ｓ are each independently selected from the group consisting of alkylene, cycloalkylene, arylalkylene, heteroarylalkylene, heteroalkylene, heterocycloalkylene, alkenylene, cycloalkenylene, arylalkenylene, heteroarylalkenylene, heteroalkenylene, heterocycloalkenylene, alkynylene, heteroalkynylene, arylene, heteroarylene, aminoacyl, oxyalkylene, aminoalkylene, diacid ester, dialkylsiloxane, amide, thioamide, thioether, thioester, ester, carbamate, hydrazone, thiazolidin, methylenealkoxycarbamate, disulfide, vinylene, imine, imidamide, phosphoramide, saccharide, phosphate ester, phosphoramide, carbamate, dipeptide, tripeptide, and tetrapeptide.

9. The compound according to claim 7 or 8, represented by:

10. 10. The compound according to any one of claims 7 to 9, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof or a pharmaceutically acceptable salt thereof, wherein the moiety C is a chelator group suitable for radiolabeling; a radioactive group comprising a radioisotope; a chelate of a radioisotope and a chelator; a fluorophore group; a cytotoxic and / or cytostatic drug; an immunomodulator; or a protein.

11. (a) the group of chelating agents 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; or The following formula: 【Chemistry 9】 (In the formula, n is 0, 1, 2, 3, 4 or 5, preferably 1; R １ｅ are independently H, COOH, aryl-COOH, or heteroaryl-COOH; preferably COOH; R ２ｅ are independently H, COOH, aryl-COOH, or heteroaryl-COOH; preferably COOH; R ３ｅ are each independently H, COOH, aryl-COOH, or heteroaryl-COOH; preferably COOH; R ４ｅ are independently H, COOH, aryl-COOH, or heteroaryl-COOH; preferably COOH; and X is O, NH or S; preferably O; or The following formula: 【Chemistry 10】 (In the formula, n is 0, 1, 2, 3, 4 or 5, preferably 1; R １ｆ are independently H, COOH, aryl-COOH, or heteroaryl-COOH; preferably COOH; R ２ｆ are 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) A radioactive group containing a radioisotope is ２２３ Ra, ８９ Sr, ９４ mTc, ９９ mTc, 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, １１７ MSn, １６９ Er and ２２７ Cu; (c) the chelate of the radioisotope is a chelate of an isotope listed in (b) above and / or a chelate with a chelating agent 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 and / or cytostatic agent is selected from a chemotherapeutic agent selected from the group consisting of topoisomerase inhibitors, alkylating agents, antimetabolites, antibiotics, mitotic disrupting agents, DNA intercalators, DNA synthesis inhibitors, DNA-RNA transcription regulators, enzyme inhibitors, gene regulators, hormone response modifiers, hypoxia-selective cytotoxins, epidermal growth factor inhibitors, antivascular agents, and combinations of two or more thereof; (f) the immunomodulatory agent is selected from molecules known to be capable of modulating the immune system, such as ligands for CD3, CD25, TLR, STING, 4-1BBL, 4-1BB, PD-1, mTor, PDL-1, NKG-2D IMiD, where the ligands may be agonists and / or antagonists; or (g) the protein is selected from cytokines such as IL2, IL10, IL12, IL15, TNF, interferon gamma, etc., or is an antibody; 11. The compound of claim 10, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof.

12. -B-C each independently represent the following structure: 【Chemistry 11】 【change】 【change】 (In the formula, A.A. ３ , A.A. ４ , A.A. ５ , A.A. ６ , A.A. ７ and A.A. ８ represents a proteinogenic or non-proteinogenic amino acid or is absent; B Ｓ are each independently selected from the group consisting of alkylene, cycloalkylene, arylalkylene, heteroarylalkylene, heteroalkylene, heterocycloalkylene, alkenylene, cycloalkenylene, arylalkenylene, heteroarylalkenylene, heteroalkenylene, heterocycloalkenylene, alkynylene, heteroalkynylene, arylene, heteroarylene, aminoacyl, oxyalkylene, aminoalkylene, diacid ester, dialkylsiloxane, amide, thioamide, thioether, thioester, ester, carbamate, hydrazone, thiazolidin, methylenealkoxycarbamate, disulfide, vinylene, imine, imidamide, phosphoramide, saccharide, phosphate ester, phosphoramide, carbamate, dipeptide, tripeptide, and tetrapeptide; n is independently 0, 1, 2, 3, 4, 5, 6, 7, or 8; m is independently 0, 1, 2, 3, or 4; x is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; R ｃ , R ｄ , and R ｅ are each independently H, optionally substituted C １－６ Alkyl, (C ３ ~C １０ Carbocyclyl) C １－６ Alkyl, (C ６ ~C １０ Aryl)C １－６ Alkyl, (C １ ~C １０ Heterocyclyl)C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, and C ６ ~C １０ aryl, in each of which one or more carbon atoms may optionally be replaced by a heteroatom; preferably selected from the side chain residues of proteinogenic or non-proteinogenic amino acids; R and R′, if present, are each independently H or 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 is optionally selected from C １－６ may be substituted with 1 to 3 substituents selected from alkyl, OH, oxo and halogen The compound according to any one of claims 7 to 11, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof, represented by any one of:

13. (a) A-B is one of the following: 【Chemistry 12】 【change】 【change】 【change】 【change】 represented by a structure selected from: and / or (b) C is one of the following: 【Chemistry 13】 【change】 【change】 【change】 represented by a structure selected from: wherein the combinations of A-B and C are preferably selected so that the covalent bond connecting B to C is represented by S-S, S-C, C-S, C(O)-Ra, C(O)-N, C(O)-O, C(O)-N, N-C(O), N-C(O)O, N-C(S), or OC(O)-N; 13. The compound according to any one of claims 7 to 12, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof.

14. -B-C has the following structure: 【Chemistry 14】 The compound according to any one of claims 7 to 13, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof, represented by any one of:

15. 15. The compound according to any one of claims 1 to 14, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof or a pharmaceutically acceptable salt thereof, wherein the moiety A is selected from A-1 to A-5 as defined herein.

16. 16. The compound according to any one of claims 1 to 15, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof or a pharmaceutically acceptable salt thereof, wherein the moiety B is selected from B-1 to B-21 as defined in the specification.

17. 17. The compound according to any one of claims 1 to 16, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof or a pharmaceutically acceptable salt thereof, wherein the moiety C is selected from C-1 to C-31 as defined in the specification.

18. The term "diastereoisomers," unless otherwise specified, refers to stereoisomers of a compound that differ in the configuration of one or more stereocenters in portions of the molecule other than portion A, wherein the stereochemical configuration of said portion A is as depicted in each structure, and the individual diastereomers differ in the stereochemical configuration in portions of the molecule other than portion A. A compound having a structure selected from the compounds set forth in Table 1, Table 3.1 and / or Table 3.2, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition comprising the compound of any one of claims 1 to 18, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

20. (a) a method of treatment of the human or animal body by surgery or therapy, or a diagnostic method practised on the human or animal body; or (b) a method for the treatment or prevention of a disease or disorder in a subject suffering from or at risk of developing a disease or disorder; or (c) a method of induced surgery performed on a subject suffering from or at risk of suffering from a disease or disorder; or (d) a method for diagnosing a disease or disorder, the method comprising a nuclear medicine imaging technique, positron emission tomography (PET) or single photon emission computed tomography (SPECT), performed on the human or animal body; or (e) a method for targeted delivery of a therapeutic or diagnostic agent to a subject suffering from or at risk of a disease or disorder; A compound according to any one of claims 1 to 18, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 19, for use in

21. 21. The compound of claim 20, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, wherein the disease or disorder is independently selected from hypoxia-related diseases such as cancer, and preferably the cancer is selected from the group consisting of breast cancer, pancreatic cancer, colon cancer, multidrug-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, bile duct cancer, renal clear cell carcinoma, glioma, astrocytoma, cervical cancer, and kidney cancer.

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