Cleavable radioligands targeting cell surface receptors and uses thereof

Abstract

The present application relates to a compound, or a pharma- ceutically acceptable salt and / or solvate thereof, comprising one or more circulation enhancing groups, one or more targeting groups, one or more chelating groups, at least one cleavable linker, and at least one branching group that is at least trivalent. The present application further includes a radionuclide complex, or a pharma- ceutically acceptable salt and / or solvate thereof, comprising a compound of the present application, or a pharma- ceutically acceptable salt and / or solvate thereof, and one or more radionuclides, as well as compositions comprising said compound or said complex. The present application also includes methods of using the compounds, complexes, and compositions to target and / or kill target cells. For example, said compounds include compounds of formula I: JPEG2024542592000377.jpg3165

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of priority to co-pending U.S. Provisional Patent Application No. 63 / 283,361, filed November 26, 2021, the contents of which are incorporated herein by reference in their entirety.

[0002] This application relates generally to the field of cleavable radioligands that target cell surface receptors. In particular, the present invention relates to compounds comprising a cycling-enhancing group, a targeting group, a radioisotope, and a cleavable linker, and compositions thereof. The present invention also relates to methods of using the compounds and compositions to target and / or kill target cells. [Background technology]

[0003] Cancer is a disease in which some of the body's cells grow uncontrollably and metastasize to other parts of the body. Compared to normal cells, cancer cells may overexpress certain receptors on the cell membrane (Sgouros G et al., 2020). For example, prostate cancer cells primarily overexpress the prostate-specific membrane antigen (PSMA) receptor. PSMA is a prostate-specific transmembrane protein that is expressed 100 to 1,000 times more in prostate adenocarcinoma than in benign prostates (Dorff TB et al., 2019). Glucagon-like peptide 1 (GLP-1) receptors are highly overexpressed in nearly 100% of insulinoma tumors (Korner M et al., 2012). Folate receptor α is expressed in the majority of ovarian cancer cells, with a 100% overexpression rate. 6 While expressed at a density of receptor / cell, its expression in normal cells is significantly lower (Kalli KR et al., 2008). Somatostatin receptor 2 (SSTR2) is overexpressed in more than 80% of neuroendocrine tumors (Qian ZR et al., 2017).

[0004] Overexpression of such receptors facilitates targeted cancer therapy, where drugs are often constructed as conjugates, constructs, complexes, or hybrids comprising a cell-killing moiety and a vector for delivering the payload. Most notable examples include antibody-drug conjugates, peptide-drug conjugates, and the cell-based therapy CAR-T. Therapeutic payloads can be cytotoxic small molecules, proteins, immunostimulants, radionuclides, and the like. Examples of approved drugs in this category include Adcetris (brentuximab vedotin), Kadcyla (trastuzumab emtansine), Lutathera (lutetium iodide), and others. 177 Lu) oxodotreotide), Kymriah (tisagencleucel), etc.

[0005] Radioligands typically contain a targeting moiety that seeks out overexpressed receptors of interest and directs the radioisotope to the target site. In the case of radiometal-based radioligand therapeutics, a chelate is linked to the targeting moiety via a linker. When the chelate is complexed with a radionuclide (radiolabeling), the final radioligand complex is formed. The radioligand delivers the radioactive payload to the target cell, followed by the in situ emission of alpha, beta, or gamma particles, causing damage or breakage of DNA strands and ultimately killing the cancer cell. Similarly, when diagnostic radionuclides are used, radioligand diagnostic drugs are produced.

[0006] One of the goals of optimizing a radioligand is to maximize tumor uptake and minimize off-target accumulation in normal organs. When a radioligand binds to a target receptor on the surface of cancer cells, the resulting receptor-radioligand complex is often internalized, concentrating the radioisotope within the cancer cells. To achieve an acceptable therapeutic window, a sufficient amount of the injected radioisotope dose must accumulate in the target cells. Furthermore, radioisotope accumulation in non-target normal tissues must be reasonably low.

[0007] Both small molecules and polymers have been used as targeting vectors for radioligands, but each results in different in vivo radionuclide distribution profiles. Peptide- and small-molecule-based radioligands often clear rapidly from the systemic circulation, mostly through renal filtration. In some cases, such short half-lives provide high tumor-to-normal organ contrast in radioisotope uptake. However, short blood residence times often work against tumor uptake. Furthermore, a significant amount of peptide scaffold- and small-molecule-based radioligands tends to accumulate in the kidney, resulting in poor tumor-to-kidney radionuclide uptake ratios. On the other hand, antibody-based radioligands are distinguished by significantly longer blood circulation half-lives and slower renal clearance, resulting in higher tumor uptake and relatively lower kidney uptake. Nevertheless, prolonged blood exposure inevitably leads to high uptake in normal organs such as the bone marrow, spleen, and liver.

[0008] As a result, there is a need for improved radioligands that can deliver a high percentage of the administered radioisotope to target cancer cells while maintaining or ideally reducing uptake by normal organs such as the kidney, blood, liver, spleen, and bone marrow.

[0009] To circumvent the short circulatory half-life of peptide-based compounds, long polyethylene glycol (PEG) conjugations and the incorporation of serum albumin-binding moieties such as 4-(p-iodophenyl)butyric acid (or methyl analogs), the Evans blue motif, and ibuprofen have been employed (Dapp S et al., 2011; Wang Z et al., 2018; Choy CJ et al., 2017; Kuo HT et al., 2018; Deberle LM et al., 2020; Kramer V et al., 2021). The former extends plasma half-life through the large hydrodynamic size of PEG, while the latter achieves the same by engaging serum albumin, resulting in slower renal clearance of the radioligand. Such modifications have produced mixed results. In the case of PSMA-targeted radioligand therapy, high tumor uptake was achieved, but significantly increased renal uptake limited the clinical application of such radioligands. One representative example is HTK01169 compared to PSMA-617 (Kuo HT et al., 2018). Higher kidney uptake of PSMA radioligands may be due to higher expression of PSMA receptors in the kidney, and therefore any ligand that increases half-life will experience higher uptake in both the kidney and tumor. However, higher uptake may also be due to the unique physicochemical properties of the individually modified radioligands.

[0010] In the case of Mab-based radioligands, cleavable constructs were briefly considered to reduce radioisotope accumulation in the liver and other normal organs (Arano Y. et al., 1996). This was done by introducing a metabolic linkage between the Mab and the radioisotope complex, but only a slight improvement was achieved. This is likely due to the slow pharmacokinetics of covalently modified Mabs, which reduced the benefit of having a metabolic linkage. Apart from this, these metabolic linkers could only release non-targeted radioisotope complexes.

[0011] Overall, there is still a lack of optimized radioisotopes that can simultaneously achieve high tumor uptake and low normal organ accumulation. Such radioisotope biodistribution profiles are expected to significantly improve efficacy and safety profiles and enhance therapeutic indexes. Summary of the Invention

[0012] Considering the aforementioned limitations, new radioligands that target cell surface receptors are described herein. These compounds are designed to optimize cellular response, degradation, clearance, and other fundamental properties.

[0013] Thus, the present application includes a compound or a pharmaceutically acceptable salt and / or solvate thereof, comprising one or more circulation-enhancing groups, one or more target-binding groups, one or more chelating groups, and at least one branching group that is at least trivalent; wherein the at least trivalent branching group is linked to at least one target binding group directly or via a first non-cleavable linker, to at least one cycling-enhancing group directly via a second non-cleavable linker or via a first cleavable linker, and to at least one chelating group directly via a third non-cleavable linker or via a second cleavable linker; provided that the branching group, which is at least trivalent, is linked to at least one cycling-promoting group via a first cleavable linker; or The branching group, which is at least trivalent, is linked to at least one chelating group via a second cleavable linker.

[0014] In some embodiments, the compound has an ex vivo half-life in mouse plasma at about 37°C of about 4 hours to about 360 hours, about 6 hours to about 144 hours, about 12 hours to about 120 hours, about 18 hours to about 108 hours, or about 24 hours to about 96 hours.

[0015] In some embodiments, the compound is a compound of formula I, and the present application also provides compounds of formula I [ka] (In the formula, A is a cycling promoting group; Z is a target binding group; E is a chelating group; T is a branched group that is at least trivalent; L A and L E are each independently a direct bond, a cleavable linker, or a non-cleavable linker; and L Z is a direct bond or a non-cleavable linker, However, L A and L E At least one of the following is a cleavable linker: or a pharmaceutically acceptable salt and / or solvate thereof.

[0016] In some embodiments, L A teeth [ka] and L Z teeth [ka] and L E teeth [ka] Thus, the present application also provides that the compound of formula I is of formula ID [ka] (In the formula, A, Z, E and T are as defined in Formula I; T A , T Z , T E are each independently T as defined in Formula I, and T A , T Z , T E and T may be the same or different; L A1 and L A2 are each independently L as defined in formula I A and; L E1 and L E2 are each independently L as defined in formula I E and; L Z1 and L Z2 are each independently L as defined in formula I Z and; R A teeth, [ka] is selected from R Z teeth, [ka] is selected from R E teeth, [ka] is selected from T A1 , T Z-A , T E-A , T Z1 , T A-Z , T E-Z , T E1 , T Z-E , T A-E are each independently T as defined in Formula I, and T, T A1 , T Z-A , T E-A , T Z1 , T A-Z , T E-Z , T E1 , T Z-E and T A-E are the same or different; L A3 , L A1-Z , L A2-Z , L A1-E and L A2-E are each independently L as defined in formula I A and; L E3 , L E1-A , L E2-A , L E1-Z and L E2-Z are each independently L as defined in formula I E and; L Z3 , L Z1-A , L Z2-A , L Z1-E and L Z2-E are each independently L as defined in formula I Z and; A 1 , A 2 and A 3 are each independently A as defined in formula I, and A 1 , A 2 , A 3 and A may be the same or different; Z 1 , Z 2 and Z 3 are each independently A as defined in formula I, and Z 1 , Z 2 , Z 3 and Z may be the same or different; E 1 , E 2 and E 3 are each independently E as defined in formula I, and E 1 , E 2 , E 3 and E may be the same or different; and m, n, o, p, q, r, s, t, and u are each independently selected from 0 and 1; where L A3 , L E1-A , L E2-A , L A1-Z , L A2-Z , L E1-Z , L E2-Z , L E3 , L A1-E and L A2-E At least one of is a cleavable linker. or a pharmaceutically acceptable salt and / or solvate thereof.

[0017] The present application further includes compounds as defined above or pharmaceutically acceptable salts and / or solvates thereof, as well as radionuclide complexes comprising one or more radionuclides, or pharmaceutically acceptable salts and / or solvates thereof.

[0018] The present application includes compositions comprising one or more of the above compounds or pharmaceutically acceptable salts and / or solvates thereof, or one or more of the above radionuclide complexes or pharmaceutically acceptable salts and / or solvates thereof, and a carrier.

[0019] The present application includes compositions comprising one or more of the above compounds or pharmaceutically acceptable salts and / or solvates thereof, or one or more of the above radionuclide complexes or pharmaceutically acceptable salts and / or solvates thereof, and a pharmaceutically acceptable carrier.

[0020] The present application also includes a kit comprising: one or more of the above compounds or pharmaceutically acceptable salts and / or solvates thereof, and Instructions for administering one or more compounds of Formula I or pharmaceutically acceptable salts and / or solvates thereof to a subject in need thereof.

[0021] The present application further includes a kit comprising: one or more of the above compounds or pharmaceutically acceptable salts and / or solvates thereof, and one or more radionuclides as defined above, and Optionally, instructions for administering one or more compounds or pharmaceutically acceptable salts and / or solvates thereof to a subject in need thereof, and a radioisotope to a subject in need thereof.

[0022] The present application also includes a kit comprising: one or more of the above radionuclide complexes, or pharmaceutically acceptable salts and / or solvates thereof, and Instructions for administering one or more compound complexes to a subject in need thereof.

[0023] Further included is a method of treating a disease or disorder comprising administering to a subject in need thereof a therapeutically effective amount of one or more of the above compounds, or one or more of the above radionuclide complexes, or pharmaceutically acceptable salts and / or solvates thereof.

[0024] In some embodiments, the disease or disorder is cancer.

[0025] The present application also includes a method for inhibiting proliferative activity in a cell, comprising administering to the cell an effective amount of one or more of the above compounds, or one or more of the above radionuclide complexes, or pharmaceutically acceptable salts and / or solvates thereof.

[0026] The present application also includes a method of imaging tissue in a subject by administering an imaging effective amount of one or more of the above compounds, or one or more radionuclide complexes for use in such imaging, or pharmaceutically acceptable salts and / or solvates thereof, and applying an imaging technique to detect emitted gamma rays.

[0027] The present application also includes a method for diagnosing cancer in a subject by administering a diagnostically effective amount of one or more of the above-described compounds, or one or more radionuclide complexes for use in imaging as described above, or pharmaceutically acceptable salts and / or solvates thereof, and applying imaging techniques to detect emitted gamma rays.

[0028] Other features and advantages of the present application will become apparent from the following detailed description. However, it should be understood that the detailed description and specific examples, while indicating embodiments of the present application, are given for illustrative purposes only, and that the claims should not be limited by these embodiments, but should be accorded the broadest interpretation consistent with the specification as a whole.

[0029] Specific embodiments of the present application will now be described in more detail with reference to the accompanying drawings. [Brief explanation of the drawings]

[0030] [Figure 1] 1 shows the biodistribution of an exemplary complex 177Lu-I-21 in PC3-PIP tumor-bearing mice. [Figure 2] 1 shows the biodistribution of an exemplary complex 177Lu-I-35 in PC3-PIP tumor-bearing mice. [Figure 3] 1 shows a radio-HPLC trace of an ex vivo mouse plasma stability sample of exemplary compound 177Lu-I-21. [Figure 4] 1 shows a radio-HPLC trace of an ex vivo mouse plasma stability sample of 177Lu-C-6. [Figure 5A] 68Ga-PSMA11 (gozetotide) PET / CT image (left panel) and 111In-I-21 SPECT / CT image (48 hours after administration) (middle panel: before, right panel: after) of a patient with metastatic castration-resistant prostate cancer (mCRPC). [Figure 5B] 68Ga-PSMA11 (gozetotide) PET / CT image (left panel) and 111In-I-21 SPECT / CT image (48 hours after administration) (middle panel: before, right panel: after) of a patient with metastatic castration-resistant prostate cancer (mCRPC). [Figure 5C] 68Ga-PSMA11 (gozetotide) PET / CT image (left panel) and 111In-I-21 SPECT / CT image (48 hours after administration) (middle panel: before, right panel: after) of a patient with metastatic castration-resistant prostate cancer (mCRPC). [Figure 5D] 68Ga-PSMA11 (gozetotide) PET / CT image (left panel) and 111In-I-21 SPECT / CT image (48 hours after administration) (middle panel: before, right panel: after) of a patient with metastatic castration-resistant prostate cancer (mCRPC). DETAILED DESCRIPTION OF THE INVENTION

[0031] I. Definition Unless otherwise stated, the definitions and embodiments set forth in this and other sections are intended to apply to all embodiments and aspects of the application described herein where they are appropriate, as would be understood by one of ordinary skill in the art.

[0032] All features disclosed in this specification, including the claims, abstract, and drawings, and all steps in the disclosed methods or processes, may be combined in any combination, except combinations in which at least some of such features and / or steps are mutually exclusive. Each feature disclosed in this specification, including the claims, abstract, and drawings, may be replaced by an alternative feature serving the same, equivalent, or similar purpose, unless expressly stated otherwise.

[0033] As used in this application and in the claims, the words "comprising" (and any form of comprising, such as "comprises," "comprises"), "having" (and any form of having, such as "have," "has"), "including" (and any form of including, such as "include," "includes"), or "containing" (and any form of containing, such as "contain," "contains") are inclusive or open-ended and do not exclude additional, unrecited elements or process steps.

[0034] As used herein, the term "consisting of" and its derivatives are intended to be closed terminology that specifies the presence of stated features, elements, components, groups, integers, and / or steps and excludes the presence of other unstated features, elements, components, groups, integers, and / or steps.

[0035] As used herein, the term "consisting essentially of" is intended to specify the presence of recited features, elements, components, groups, integers, and / or steps, as well as the presence of things that do not materially affect the basic and novel characteristics of those features, elements, components, groups, integers, and / or steps.

[0036] As used herein, the terms "about," "substantially," and "approximately" refer to a reasonable amount of deviation from the modified term that does not materially change the end result. These terms of degree should be interpreted as including a deviation of at least ±5% from the modified term unless this deviation would negate the meaning of the word it modifies or the context would suggest otherwise to one of ordinary skill in the art.

[0037] As used in this application, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. For example, an embodiment including "a compound" should be understood to present a particular aspect having one compound, or two or more additional compounds.

[0038] In embodiments that include an "additional" or "second" component or effect, e.g., an additional or second compound, a second compound, as used herein, is different from the other compound or the first compound. A "third" compound is different from the other compound, the first compound, and the second compound, and further listed or "additional" compounds are similarly different.

[0039] As used herein, the term "and / or" means that the listed items are present or used individually or in any combination. In practice, the term means that "at least one" or "one or more" of the listed items are used or present. The term "and / or" with respect to enantiomers, prodrugs, salts and / or solvates thereof means that the compounds of the present application are present as combinations of individual enantiomers, prodrugs, salts and hydrates, as well as salts, e.g., solvates, of the compounds of the present application.

[0040] As used herein, the terms "compound(s) of the application" or "compound(s) of the present application" and the like refer to compounds of formula I, IA, IB, IC, ID, IE, IF, IG, IH, II, IJ, IK, IL, I-A', I-A'(a), I-A'(b), I-A'(c), I-A'(d), I-B', I-C' and I-D', or pharmaceutically acceptable salts and / or solvates thereof.

[0041] As used herein, the terms "complex of the present application" or "complexes of the present application" and the like refer to complexes comprising one or more compounds of Formula I, or pharmaceutically acceptable salts and / or solvates thereof, and one or more radionuclides.

[0042] As used herein, the terms "composition of the application" or "composition of the present application" and the like refer to a composition comprising one or more of the compounds or complexes of the present application.

[0043] As used herein, the term "radioligand" refers to a compound comprising a targeting moiety and a radionuclide. The complexes of the present application are examples of radioligands.

[0044] As used herein, the term "radionuclide" refers to any atom capable of undergoing radioactive decay. As used herein, the term radionuclide is used synonymously with radionuclide, radioisotope, and radioisotope.

[0045] As used herein, the term "suitable" means that the selection of a particular compound or condition will depend on the particular synthetic manipulation being performed, the identity of the molecule being transformed, and / or the particular use of the compound, but that such selection is within the skill of one of ordinary skill in the art.

[0046] This specification uses many chemical terms and abbreviations used by those of ordinary skill in the art. Nonetheless, definitions of selected terms are provided for clarity and consistency.

[0047] As used herein, the term "protecting group" or "PG" refers to a chemical moiety that protects or masks a reactive portion of a molecule to prevent side reactions at that portion while another portion of the molecule is being manipulated or reacted. After the manipulation or reaction is complete, the protecting group is removed under conditions that do not degrade or decompose the remaining portion of the molecule. The selection of an appropriate protecting group can be performed by one skilled in the art. Many conventional protecting groups are known in the art and are described, for example, in "Protective Groups in Organic Chemistry," McOmie, JFW Ed., Plenum Press, 1973; Greene, TW and Wuts, PGM, "Protective Groups in Organic Synthesis," John Wiley & Sons, 3rd Edition, 1999; and Kocienski, P. Protecting Groups, 3rd Edition, 2003, Georg Thieme Verlag (The Americas).

[0048] As used herein, the term "alkyl," whether used alone or as part of another group, refers to a straight or branched chain saturated alkyl group. The number of carbon atoms possible in the referenced alkyl group is indicated by the prefix "C n1-n2 For example, C 1-10 The term alkyl refers to alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. All alkyl groups are optionally fluorine substituted unless otherwise specified.

[0049] The term "alkylene," whether used alone or as part of another group, refers to a straight or branched saturated alkylene group, i.e., a saturated carbon chain containing substituents at two of its termini. The number of possible carbon atoms in the referenced alkylene group is indicated by the prefix "C n1-n2 For example, C 2-6 The term alkylene refers to alkylene groups having 2, 3, 4, 5 or 6 carbon atoms. All alkylene groups are optionally fluorine-substituted unless otherwise specified.

[0050] As used herein, the term "alkenyl," whether used alone or as part of another group, means a straight or branched chain unsaturated alkyl group containing at least one double bond. The number of possible carbon atoms in the referenced alkylene group is indicated by the prefix "C n1-n2 For example, C 2-6 The term alkenyl refers to alkenyl groups having 2, 3, 4, 5, or 6 carbon atoms and at least one double bond. All alkenyl groups are optionally fluorine-substituted unless otherwise specified.

[0051] The term "alkenylene," whether used alone or as part of another group, means a straight or branched chain unsaturated alkyl group containing at least one double bond and containing substituents at two of its termini. The number of carbon atoms possible in the referenced alkylene group is indicated by the prefix "C n1-n2 For example, C 2-6 The term alkenylene refers to alkenylene groups having 2, 3, 4, 5 or 6 carbon atoms. All alkenylene groups are optionally fluorine substituted unless otherwise specified.

[0052] As used herein, the term "aryl," whether used alone or as part of another group, refers to a carbocyclic group containing at least one aromatic ring and containing from 6 to 20 carbon atoms.

[0053] As used herein, the term "cycloalkyl," whether used alone or as part of another group, refers to a saturated carbocyclic group containing 3 to 20 carbon atoms and one or more rings. The number of possible carbon atoms in the referenced cycloalkyl group is indicated by the numerical prefix "C n1-n2 For example, C 3-10 The term cycloalkyl means a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.

[0054] The term "heterocycloalkyl," as used herein, whether used alone or as part of another group, refers to a cyclic group containing at least one non-aromatic ring containing 3 to 20 atoms, where one or more of the atoms are heteroatoms selected from O, S, and N, and the remaining atoms are C. Heterocycloalkyl groups are either saturated or unsaturated (i.e., contain one or more double bonds). Heterocycloalkyl groups are denoted by the prefix C. n1-n2When the prefix includes the symbol "-", the prefix indicates the number of carbon atoms in the corresponding carbocyclic group, where one or more, preferably 1 to 5, of the ring atoms are replaced with a heteroatom selected from O, S and N, and the remaining atoms are C.

[0055] The term "heteroaryl," as used herein, whether used alone or as part of another group, refers to a cyclic group containing at least one heteroaromatic ring containing 5 to 20 atoms, where one or more of the atoms is a heteroatom selected from O, S, and N, and the remaining atoms are C. A heteroaryl group may be denoted by the prefix C. n1-n2 When the prefix "" denotes the number of carbon atoms in the corresponding carbocyclic group, one or more, preferably one to five, ring atoms are replaced with a heteroatom as defined above. Heteroaryl groups are optionally benzo-fused.

[0056] All cyclic groups, including aryl, heteroaryl, heterocycloalkyl, and cycloalkyl groups, contain one or more rings (i.e., are polycyclic). When a cyclic group contains more than one ring, the rings may be fused, bridged, spirofused, or joined by bonds.

[0057] As used herein, "benzofused" refers to a polycyclic group in which a benzene ring is fused to another ring.

[0058] A first ring is "fused" to a second ring means that the first ring and the second ring share two adjacent atoms.

[0059] A first ring is "bridged" with a second ring means that the first ring and the second ring share two non-adjacent atoms.

[0060] A first ring is "spirofused" to a second ring means that the first ring and the second ring share one atom between them.

[0061] As used herein, a "target binding group" refers to a moiety that is recognized by the target moiety to which it binds.

[0062] As used herein, the term "target" or "target site" refers to a cell surface receptor, e.g., a cell surface receptor, antigen, e.g., prostate-specific membrane antigen (PSMA) or other protein, to which a target binding group can bind.

[0063] As used herein, the term "circulation enhancing group" refers to a chemical structure that increases the blood circulation time of the compounds of the present application.

[0064] As used herein, the term "chelating group" refers to a chelating agent capable of complexing a radionuclide.

[0065] As used herein, the term "at least trivalent branched group" refers to a molecular structure that includes at least three terminal functional groups, each of which connects to another molecular structure. The at least three terminal functional groups may be the same or different.

[0066] As used herein, the term "in vivo half-life" refers to the time required for half of a compound administered to a subject to be eliminated from the circulation (e.g., blood) and / or other tissues of the subject.

[0067] The term "half-life" as used herein refers to the pharmacokinetic properties of a compound and is a measure of the average survival time of the compound after administration to a subject. Half-life is the time required for half of the compound administered to a subject to be excreted from the subject's body or a specific compartment thereof (e.g., serum or other tissues).

[0068] As used herein, the term "ex vivo plasma half-life" refers to the time required for half of a compound mixed with plasma, e.g., mouse plasma, to be degraded within the plasma at approximately 37°C and neutral pH. Ex vivo plasma half-life can be measured, for example, by incubating a radioligand in mouse plasma at 37°C. At each desired time point, an aliquot of the sample may be removed, purified, and analyzed by HPLC with a radiodetector. This allows the percentage of intact radioligand remaining to be determined, which can be plotted as an indicator of ex vivo plasma half-life.

[0069] As used herein, the term "linker group" refers to any molecular structure that connects two or more other molecular structures.

[0070] As used herein, the term "non-cleavable linker group" refers to any molecular structure that links two or more other molecular structures together to form a non-cleavable moiety. A non-cleavable linker group contains a functional group at each end that reacts with a complementary functional group on the molecule to be linked to form a non-cleavable moiety. When a compound of the present application contains two or more non-cleavable linkers, each non-cleavable linker is an independent non-cleavable linker, and the one or more non-cleavable linkers can be the same or different.

[0071] As used herein, the term "cleavable linker" refers to any molecular structure that links two or more other molecular structures together and contains at least one cleavable moiety. A cleavable linker group contains a functional group at each end that reacts with a complementary functional group on the molecule to be linked to form a non-cleavable or cleavable moiety. When a compound of the present application contains two or more cleavable linkers, each cleavable linker is an independent cleavable linker, and the one or more cleavable linkers can be the same or different.

[0072] As used herein, the term "non-cleavable moiety(ies)" refers to a chemical functional group that resists degradation by one or more of acids, bases, reducing agents, oxidizing agents, and enzymes. Non-cleavable moieties are generally stable to cleavage, but may be cleavable by enzymes or physiological conditions within a cell, tissue, or organ after a period of time, for example, after the compound or portion of the compound that includes the non-cleavable moiety has been delivered or transported to a target site.

[0073] As used herein, the term "cleavable moiety(s)" refers to a chemical functional group that is degraded by one or more of an acid, a base, a reducing agent, an oxidizing agent, or an enzyme.

[0074] As used herein, the term "stable to cleavage" or "resistant to degradation" refers to a chemical functional group of which less than about 5% is degraded in mouse plasma at about 37°C after at least about 48 hours after mixing the compound containing the chemical functional group with mouse plasma.

[0075] The term "degraded" or "cleavable" as used herein in reference to a cleavable moiety means that more than about 5% of the cleavable moiety is degraded in mouse plasma at about 37°C after at least about 48 hours after mixing a compound containing the cleavable moiety with mouse plasma.

[0076] As used herein, the term "amino acid residue" refers to an amino acid minus the "-OH" moiety of the carboxyl group and the "H" moiety of the amino group.

[0077] As used herein, the term "amino acid" is a compound containing a carboxyl (-CO2H) functional group and an amine (-NH2) functional group.

[0078] As used herein, the term "unnatural amino acid" refers to an amino acid that is not naturally occurring, but is obtained synthetically or by modification of a natural amino acid.

[0079] As used herein, the term "naturally occurring amino acids" refers to amino acids that occur in nature and are encoded by the genetic code, as well as amino acids that are later modified in vivo.

[0080] The term "at least one," when preceding an item, refers to a single element of that item, or, when preceding a list of items, refers to single elements of that item and any combination of those items. For example, "at least one of a, b, c" is intended to cover a, b, c, ab, ac, bc, and abc, as well as combinations with multiples of the same element (e.g., aa, aaa, aab, aac, abb, acc, bb, bbb, bbc, cc, and ccc, or any other sequence of a, b, and c).

[0081] As used herein and as well understood in the art, the terms "treating" or "treatment" refer to an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, reduction in the extent of disease, a stable (i.e., not worsening) disease state, prevention of disease spread, delay or slowing of disease progression, improvement or palliation of the disease state, reduction in disease recurrence, and remission (whether partial or total), whether detectable or undetectable. "Treating" and "treatment" can also mean prolonging survival compared to expected survival if not treated. A subject with early-stage cancer can be treated, for example, to prevent progression, or a subject in remission can be treated with a compound or composition of the present application to prevent recurrence. Methods of treatment include administering a therapeutically effective amount of one or more compounds of the present application to a subject, optionally consisting of a single dose, or alternatively including a series of doses.

[0082] To "ameliorate" a disease, disorder, or condition means to lessen the severity and / or undesirable clinical symptoms of the disease, disorder, or condition and / or slow or prolong the time course of progression compared to not treating the disease.

[0083] As used herein, "preventing," "prevention," or "prophylaxis," or their equivalents, means reducing the risk or probability that a patient will acquire a disease, disorder, or condition, or develop symptoms associated with a disease, disorder, or condition.

[0084] As used herein, the term "therapeutically effective amount" means an amount of a compound or one or more compounds of the present application, or a complex or one or more complexes of the present application, effective at dosages and for periods of time necessary to achieve the desired result.

[0085] The term "imaging-effective amount," when used in connection with one or more complexes of the present application, refers to an amount of complex sufficient to produce a visible image when the complex is administered to a subject and radiation emitted from the complex is detected using positron emission tomography ("PET"), or single photon emission computed tomography ("SPECT"), or autoradiography, or ex vivo or in vitro binding assays.

[0086] As used herein, the term "diagnostically effective amount" means an amount of a compound or one or more compounds of the present application, or a complex or one or more complexes of the present application, effective at dosages and for periods of time necessary to achieve a desired diagnostic effect, including, for example, diagnosis of the particular condition being evaluated.

[0087] As used herein, the term "administered" means administering to a cell, tissue, organ, or subject an imaging-, diagnostically-, and / or therapeutically-effective amount of one or more compounds, complexes, or compositions of the present application.

[0088] As used herein, the term "cancer" refers to a cell proliferative disease state.

[0089] As used herein, the term "subject" includes all members of the animal kingdom, including mammals, and preferably refers to humans. Thus, the methods and uses of the present application are applicable to both human therapy and veterinary uses.

[0090] As used herein, the term "cell" refers to a single cell or multiple cells, including cells in cell culture or in a subject.

[0091] The term "pharmaceutically acceptable" means compatible with the treatment of a subject, e.g., a human.

[0092] "Pharmaceutically acceptable carrier" means a non-toxic solvent, dispersant, excipient, adjuvant, or the like, that is mixed with an active ingredient to enable the formation of a pharmaceutical composition, i.e., a dosage form that can be administered to a subject.

[0093] By "pharmaceutically acceptable salt" is meant either an acid addition salt or a base addition salt that is suitable or compatible with the treatment of a subject.

[0094] Acid addition salts suitable or compatible with the treatment of a subject are non-toxic organic or inorganic acid addition salts of any basic compound.

[0095] The basic addition salts suitable for or compatible with the treatment of a subject are non-toxic organic or inorganic basic addition salts of any acidic compound.

[0096] The term "solvate" as used herein means a compound, or a salt and / or prodrug of a compound, wherein molecules of a suitable solvent are incorporated into the crystal lattice. A suitable solvent is one that is physiologically acceptable at the administered amount.

[0097] As used herein, the term “PSMA-617,” “Vipivotide tetraxetan,” “DOTA-Trx-2Nal-eKuE,” or “C-1” refers to a compound having the chemical name: (((S)-1-carboxy-5-((S)-3-(naphthalen-2-yl)-2-((1r,4S)-4-((2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetamido)methyl)cyclohexane-1-carboxamido)propanamido)pentyl)carbamoyl)-L-glutamic acid tetra(trifluoroacetic acid) and having the following chemical formula: [ka]

[0098] As used herein, the term "HTK01169" or "4pIBA-Glu-Lys(DOTA)-Trx-2Nal-eKuE" refers to a compound having the following chemical formula: [ka]

[0099] As used herein, the term "ESL1" refers to a cleavable linker group having the following chemical formula: [ka]

[0100] As used herein, the term "ESL2" refers to a cleavable linker group having the following chemical formula: [ka]

[0101] As used herein, the term "ESL3" refers to a cleavable linker group having the following chemical formula: [ka]

[0102] As used herein, the term "SSL1" refers to a cleavable linker group having the following chemical formula: [ka]

[0103] As used herein, the term "TrX" refers to a linker group having the following chemical formula: [ka]

[0104] As used herein, the term "OEG" refers to a linker group having the following chemical formula: [ka]

[0105] As used herein, the term "2NaI" refers to a linker group having the following chemical formula: [ka]

[0106] As used herein, the term "Aoc" refers to a linker group having the following chemical formula: [ka]

[0107] As used herein, the term "Aun" refers to a linker group having the following chemical formula: [ka]

[0108] As used herein, the term "Ava" refers to a linker group having the following formula: [ka]

[0109] As used herein, the term "4hBA" refers to a linker group compound having the chemical name 4-hydroxybutanoic acid and the following chemical formula: [ka]

[0110] As used herein, the term "4hPA" refers to a linker group compound having the chemical name 4-hydroxypentanoic acid and the following chemical formula: [ka]

[0111] As used herein, the term "5hPA" refers to a linker group compound having the chemical name 6-hydroxypentanoic acid and the following chemical formula: [ka]

[0112] As used herein, the term "6hPA" refers to a linker group compound having the chemical name 6-hydroxyhexanoic acid and the following chemical formula: [ka]

[0113] As used herein, the term "DAB" refers to a linker group compound having the chemical name 2,4-diaminobutyric acid and the following chemical formula: [ka]

[0114] As used herein, the term "DAP" refers to a linker group compound having the chemical name 2,3-diaminopropionic acid and the following chemical formula: [ka]

[0115] symbol [ka] When drawn perpendicularly across a bond, indicates the point of covalent attachment of a chemical group.

[0116] For example, when used in reference to the methods of treatment, uses, compositions, packages and / or kits of the present application, a subject, e.g., a subject "in need thereof," is a subject who would benefit from the administration of one or more compounds or complexes of the present application, or pharmaceutically acceptable salts and / or solvates thereof.

[0117] II. Compounds and Complexes of the Present Application The present application relates to improved radioligands that target cell surface receptors, methods for preparing the radioligands, and methods for using them to target and / or inhibit target cells. In particular, the present application relates to radioligands and compositions thereof that include a circulation-enhancing group, a targeting moiety, a radionuclide, and a cleavable linker. The inventors have shown that the radioligands described herein enhance radionuclide uptake in target cells while minimizing accumulation in off-target normal organs, including, but not limited to, the kidney and blood.

[0118] When introducing a circulation-enhancing group such as an albumin-binding motif into a radioligand, the chemical structure of such a motif can affect the binding affinity of the resulting radioligand to its target receptor, for example, in vivo biodistribution, tumor uptake of the radionuclide, and the tumor-to-kidney uptake ratio of the radionuclide. Therefore, a problem with albumin binders in the radioligand field is a poor tumor-to-kidney uptake ratio. This is seen, for example, in the case of HTK01169 (C-2), PSMA-ABL-56 (C-10), or another known compound, C-9, compared to PSMA-617 (C-1).

[0119] To minimize the exposure of radionuclides to normal organs and intentionally degrade the radioligand into metabolites that are less likely to accumulate in non-target receptor-expressing cells, the present inventors have introduced a cleavable linker into the radioligand compound. Unlike the concept of drug complexes in the art, the cleavage process of the radioligand compound of the present application is intentionally designed to occur in the plasma and throughout the body, rather than at the target tumor site. Such a cleavage process does not depend on specific tumor-enriched enzymes or the unique chemical conditions within the tumor microenvironment. Therefore, such a design avoids the influence of tumor heterogeneity, which can significantly affect the expected cleavage kinetics, and ensures minimal interpatient variability in the drug (radionuclide) distribution profile in the body.

[0120] For example, the present inventors have shown that introducing a cleavable linker into a radioligand having an albumin binding motif improves the tumor-to-kidney uptake ratio while maintaining high tumor uptake, as exemplified by exemplary compounds of the present application such as I-2, I-11, I-18, I-21, I-34, and I-43 compared to HTK01169 (C-2) in PC3-PIP tumor-bearing mice, and I-18, I-21, I-67, and I-69 compared to ABL-56 (C-10) or C-9 in LNCap tumor-bearing mice (see, e.g., Table 34).

[0121] Furthermore, as exemplified by exemplary compounds of the present application, such as I-21 vs. I-2, I-11, or I-18 vs. I-3 in PC3-PIP tumor-bearing mice, and I-21 vs. I-67 and I-18 vs. I-69 in LNCap tumor-bearing mice, the inventors have shown that, when compared to albumin binders often used in the radioligand field, such as 4-pIBA in HTK01169 (C-2), the use of a long-chain fatty diacid as the albumin-binding motif provides improved biodistribution profiling, e.g., enhanced tumor uptake, and improved or equivalent tumor-to-kidney uptake ratios, despite exhibiting reduced in vitro binding affinity to its receptor (see, e.g., Table 34).

[0122] Furthermore, the inventors have shown that differences in the location of the cleavable linker relative to, for example, the albumin binding site and the chelate position also result in different biodistribution profiles of the radionuclide in vivo. For example, in the case of a PSMA-targeted radioligand, compounds containing cleavable moieties such as ester(s) that specifically release fragments bearing both the chelate (radionuclide) and the targeting binding group exhibited better biodistribution profiles and tumor uptake than compounds containing cleavable moieties such as esters that cleave to release fragments containing only the chelate (radionuclide). Such preference is independent of the type of albumin binder. One skilled in the art might expect that, in the presence of normal organs capable of specifically uptake of the radioligand, release of a fragment bearing both the chelate (radionuclide) and the targeting binding group would not result in a better tumor / non-target ratio relative to release of a non-targeted chelate (radionuclide). However, as exemplified by exemplary compounds I-2 and I-3 in mice bearing PC-3-PIP tumors, and I-21 vs. I-18 in mice bearing PC3-PIP or LNCap tumors, we observed a 2- to 8-fold increase in tumor-to-nontumor ratios at 24 or 96 hours post-dose while maintaining high tumor uptake (Table 34).

[0123] In addition to the aforementioned cleavable moieties such as esters, the cleavage rate and biodistribution profile are also affected by the nature of the circulation-enhancing group such as the albumin binding moiety, the distance from the circulation-enhancing group such as the albumin binding moiety to the cleavable moiety(s) such as the ester, the distance from the radionuclide chelating group to the cleavable moiety(s) such as the ester, the residues adjacent to the ester, the orientation of the ester, and the number of cleavable moieties such as esters (Table 3).

[0124] Thus, the present application includes a compound, or a pharmaceutically acceptable salt and / or solvate thereof, comprising one or more circulation-enhancing groups, one or more targeting groups, one or more chelating groups, and at least one branching group that is at least trivalent; wherein the at least trivalent branching group is linked to at least one target binding group directly or via a first non-cleavable linker, to at least one cycling-enhancing group directly or via a second non-cleavable linker or via a first cleavable linker, and to at least one chelating group directly or via a third non-cleavable linker or via a second cleavable linker; provided that the branching group, which is at least trivalent, is linked to at least one cycling-promoting group via a first cleavable linker; or The branching group, which is at least trivalent, is linked to at least one chelating group via a second cleavable linker.

[0125] In some embodiments, the circulation-enhancing group is selected from an albumin-binding group and a polyethylene glycol chain, hi some embodiments, the circulation-enhancing group is an albumin-binding group.

[0126] In some embodiments, the targeting binding group is bound to a cell, optionally a cancer cell. Thus, in some embodiments, the targeting binding group is a tumor-binding group. In some embodiments, the targeting binding group is bound to an antigen or other protein on the surface of a cell, such as a cell surface receptor. In some embodiments, the targeted binding group is a prostate-specific membrane antigen (PSMA)-binding group, a glucagon-like peptide-1 receptor (GLP-1R)-binding group, a glucose-dependent insulinotropic polypeptide (gastric inhibitory polypeptide; GIP) receptor (GIP-R)-binding group, a folate receptor (FR)-binding group, a cholecystokinin-2 receptor (CCK2R)-binding group, a gastrin-releasing peptide receptor (GRPR)-binding group, a somatostatin receptor 2 (SSTR2)-binding group, and a neurotensin receptor 1 (NTR1)-binding group, a neuropeptide Y receptor type 1 (Y1R)-binding group, a nectin-4-binding group, a delta-like ligand 3 (DLL3)-binding group, an epithelial cell adhesion molecule (EpCAM)-binding group, a tumor-associated calcium signaling substance 2 (Trop-2)-binding group, an insulin-like growth factor-1 (IGF-1) receptor-binding group, or a human epidermal growth factor receptor 2 (HER2)-binding group. In some embodiments, the targeted binding group is a PSMA-binding group.

[0127] In some embodiments, the circulation-enhancing group is an albumin-binding group and the target-binding group is a PSMA-binding group.

[0128] In some embodiments, the at least trivalent branching group is linked to at least one target binding group directly or through a first non-cleavable linker, to at least one cycling-facilitating group through a first cleavable linker, and to at least one chelating group directly or through a third non-cleavable linker. In some embodiments, the at least trivalent branching group is linked to at least one target binding group directly or through a first non-cleavable linker, to at least one cycling-facilitating group through a first cleavable linker, and to at least one chelating group directly.

[0129] In some embodiments, the at least trivalent branching group is linked to at least one target binding group, either directly or via a first non-cleavable linker, to at least one cycling-enhancing group, either directly or via a second non-cleavable linker, and to at least one chelating group, via a second cleavable linker.

[0130] In some embodiments, the compound has an ex vivo half-life in mouse plasma at about 37° C. of about 4 hours to about 360 hours, about 6 hours to about 144 hours, about 12 hours to about 120 hours, about 18 hours to about 108 hours, or about 24 hours to about 96 hours. In some embodiments, the compound has an ex vivo half-life in mouse plasma at about 37° C. of about 24 hours to about 96 hours.

[0131] In some embodiments, the first, second, and third non-cleavable linkers are resistant to degradation, and the first, second, and third non-cleavable linkers are degraded by less than 5%, less than 4%, less than 3%, or less than 2% in ex vivo mouse plasma at least about 4 hours, at least about 8 hours, at least about 12 hours, at least about 16 hours, at least about 32 hours, or at least about 48 hours after administration of the compound to the mouse plasma.

[0132] In some embodiments, the first, second, and third non-cleavable linkers are resistant to degradation, and the compounds comprising the group are degraded by less than 5%, less than 4%, less than 3%, or less than 2% in mouse plasma at least about 8 hours, at least about 12 hours, at least about 16 hours, at least about 24 hours, or at least about 32 hours after administration to mouse plasma.

[0133] In some embodiments, the first, second, and third non-cleavable linkers resist degradation under physiological conditions for at least about 2 to about 8 hours, at least about 4 to about 16 hours, at least about 12 to about 24 hours, at least about 1 to about 5 days, or at least about 5 to about 10 days.

[0134] In some embodiments, the first, second, and third non-cleavable linkers each independently comprise one or more non-cleavable moieties, hi some embodiments, the first, second, and third non-cleavable linkers each comprise one or more non-cleavable moieties that are resistant to degradation by one or more of an acid, a base, a reducing agent, an oxidizing agent, and an enzyme.

[0135] In some embodiments, the first, second, and / or third non-cleavable linkers each comprise one or more non-cleavable moieties that resist degradation by one or more of acid and base. Thus, in some embodiments, the first, second, and / or third non-cleavable linkers resist degradation in plasma. In some embodiments, the first, second, and / or third non-cleavable linkers comprise one or more non-cleavable moieties that resist degradation in ex vivo plasma at about 37° C. for less than 24 hours or at least about 24 hours, to at least about 2 to about 8 hours, at least about 4 to about 16 hours, at least about 12 to about 24 hours, at least about 1 to about 5 days, or at least about 5 to about 10 days after administration of the compound containing the group to plasma.

[0136] In some embodiments, the first, second, and third non-cleavable linkers comprise one or more non-cleavable moieties that independently resist enzymatic degradation.

[0137] In some embodiments, the first, second, and third non-cleavable linkers comprise one or more non-cleavable moieties that resist degradation selected from an amine bond, an ether bond, a thioether bond, an amide bond, a urea bond, a thiourea group, a thioamide group, or a triazole group. In some embodiments, the triazole group is prepared using click chemistry.

[0138] In some embodiments, the first and second cleavable linkers are degraded in ex vivo mouse plasma and have an ex vivo mouse plasma half-life at about 37°C in mouse plasma of about 4 hours to about 360 hours, about 6 hours to about 144 hours, about 12 hours to about 120 hours, about 18 hours to about 108 hours, or about 24 hours to 96 hours.

[0139] In some embodiments, the first and second cleavable linkers are degraded in ex vivo mouse plasma, and more than about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% of the cleavable linkers are degraded after about 48 to about 96 hours, or about 60 to about 96 hours in mouse plasma at about 37°C.

[0140] In some embodiments, the first and second cleavable linkers each comprise one or more cleavable moieties that are degraded by one or more of an acid, a base, a reducing agent, an oxidizing agent, and an enzyme.

[0141] In some embodiments, the first and second cleavable linkers each comprise one or more cleavable moieties that are degraded by an enzyme.

[0142] In some embodiments, the one or more cleavable moieties are independently selected from an ester group, a disulfide bond, a thioester group, a carbamate group, a carbonate group, a hydrazone bond, an oxime bond such as a ketoxime bond or an aldoxime bond, and an enzymatically cleavable peptide sequence.

[0143] In some embodiments, the first and second cleavable linkers comprise one or more cleavable moieties that are degradable by one or more of an acid and a base, and thus, in some embodiments, the first and second cleavable linkers are degraded in circulating blood and ex vivo plasma, such as mouse plasma.

[0144] Thus, in some embodiments, the first and second cleavable linkers each independently comprise at least one cleavable moiety that is cleavable in circulating blood and ex vivo plasma. In some embodiments, the first and second cleavable linkers independently comprise one to four cleavable moieties that are cleavable in circulating blood and ex vivo plasma. In some embodiments, the first and second cleavable linkers independently comprise one to three cleavable moieties that are cleavable in circulating blood and ex vivo plasma. In some embodiments, the first and second cleavable linkers independently comprise one to two cleavable moieties that are cleavable in circulating blood and ex vivo plasma. In some embodiments, the first and second cleavable linkers independently comprise one cleavable moiety that is cleavable in circulating blood and ex vivo plasma. In some embodiments, the first and second cleavable linkers each independently comprise at least one cleavable moiety that is cleavable in ex vivo mouse plasma and has an ex vivo mouse plasma half-life at 37°C of at least about 4 hours to about 360 hours, about 6 hours to about 144 hours, about 12 hours to about 120 hours, about 18 hours to about 108 hours, or about 24 hours to about 96 hours following administration of the compound to the mouse plasma.

[0145] In some embodiments, the compound or its pharmaceutically acceptable salt and / or solvate (optionally, the first and second cleavable linkers) comprises 1 to 4 cleavable moieties. In some embodiments, the compound or its pharmaceutically acceptable salt and / or solvate (optionally, the first and second cleavable linkers) comprises 1 to 3 cleavable moieties. In some embodiments, the compound or its pharmaceutically acceptable salt and / or solvate (optionally, the first and second cleavable linkers) comprises 3 cleavable moieties. In some embodiments, the compound comprises two cleavable moieties. In some embodiments, the compound or its pharmaceutically acceptable salt and / or solvate (optionally, the first and second cleavable linkers) comprises 1 or 2 cleavable moieties. In some embodiments, the compound or its pharmaceutically acceptable salt and / or solvate (optionally, the first and second cleavable linkers) comprises 1 cleavable moiety.

[0146] Those skilled in the art will understand that the first, second, and third non-cleavable linkers do not include a cleavable moiety, while cleavable linkers may further include a non-cleavable moiety. Those skilled in the art will understand that non-cleavable linker groups include functional groups at each end that react with complementary functional groups on the molecules to be linked to form the non-cleavable moiety.

[0147] Those skilled in the art will further understand that non-cleavable and cleavable linkers join two or more molecular structures via a linkage (e.g., a functional group), and that for non-cleavable linkers, the linkage between the linker and the molecule to be joined is non-cleavable, and for cleavable linkers, the linkage between the cleavable linker and the molecule to be joined may also be cleavable.

[0148] Furthermore, one skilled in the art will understand that the at least trivalent branching group contains a functional group on each end that reacts with a complementary functional group on each of the at least three molecules to be linked. In some embodiments, the at least trivalent branching group contains a functional group on each end that reacts with a complementary functional group on a cycling-enhancing group, a target-binding group, and / or a chelating group when directly attached to any one of these groups, or to the first, second, and / or third non-cleavable linkers, and / or the first and second cleavable linkers.

[0149] Those skilled in the art will further understand that the at least trivalent branching group is connected to the cycling facilitating group, the target binding group, and / or the chelating group, or to the first, second, and / or third non-cleavable linker, and / or to the first and second cleavable linker via a linkage (e.g., a functional group); when attached to the first, second, and / or third non-cleavable linker or target binding group, the linkage between the at least trivalent branching group and the first, second, and / or third non-cleavable linker or target binding group to be attached is non-cleavable; and when attached to the first and / or second cleavable linker, cycling facilitating group, and / or target binding group, the linkage between the at least trivalent branching group and the first and / or second cleavable linker, cycling facilitating group, and / or target binding group can be non-cleavable or cleavable.

[0150] In some embodiments, the at least trivalent branching group comprises at least a first terminal functional group, a second terminal functional group, and a third terminal functional group, which are respectively linked to a target binding group directly or via a first non-cleavable linker, to a cycling-enhancing group directly or via a second non-cleavable linker or via a first cleavable linker, and to a chelating group directly or via a third non-cleavable linker or via a second cleavable linker.

[0151] In some embodiments, the non-cleavable linker groups (e.g., the first non-cleavable linker, the second non-cleavable linker, and the third non-cleavable linker) and the cleavable linker groups (e.g., the first cleavable linker group and the second cleavable linker group) optionally include, in addition to the functional group on each end, one target-binding group, one cycling-enhancing group, or one chelating group, a functional group that reacts with a complementary functional group on the molecule to be linked. In some embodiments, in addition to the target-binding group, cycling-enhancing group, or chelating group, the molecule is further target-binding groups, cycling-enhancing groups, and / or chelating groups, and / or other cleavable or non-cleavable linkers.

[0152] In some embodiments, the first non-cleavable linker further links a second target binding group to the branching group, the second non-cleavable linker or the first cleavable linker further links a second cycling-facilitating group to the branching group, and / or the third non-cleavable linker or the second cleavable linker further links a second chelating group to the branching group. In some embodiments, the first non-cleavable linker further links a second target binding group to the branching group. In some embodiments, the second non-cleavable linker or the first cleavable linker further links a second cycling-facilitating group to the branching group. In some embodiments, the third non-cleavable linker or the second cleavable linker further links a second chelating group to the branching group.

[0153] In some embodiments, the first non-cleavable linker further links another chelating group and / or cycling-facilitating group to the branching group, the second non-cleavable linker or the first cleavable linker further links another target binding group and / or chelating group to the branching group, and / or the third non-cleavable linker or the second cleavable linker further links another cycling-facilitating group and / or target binding group to the branching group. In some embodiments, the first non-cleavable linker further links another chelating group and cycling-facilitating group to the branching group, the second non-cleavable linker or the first cleavable linker further links another target binding group and chelating group to the branching group, and / or the third non-cleavable linker or the second cleavable linker further links another cycling-facilitating group and target binding group to the branching group. In some embodiments, a first non-cleavable linker further connects a second chelating group and a second cycling-facilitating group to the branching group. In some embodiments, a second non-cleavable linker or a first cleavable linker further connects a second target binding group and a second chelating group to the branching group. In some embodiments, a third non-cleavable linker or a second cleavable linker connects a second cycling-facilitating group and a second target binding group to the branching group.

[0154] Thus, in some embodiments, the compound has formula I [ka] (In the formula, A is a cycling promoting group; Z is a target binding group; E is a chelating group; T is a branched group that is at least trivalent; L A and L E are each independently a direct bond, a cleavable linker, or a non-cleavable linker; and L Z is a direct bond or a non-cleavable linker, However, L A and L E At least one of the following is a cleavable linker: or a pharmaceutically acceptable salt and / or solvate thereof.

[0155] In some embodiments, A is selected from an albumin binding group and a polyethylene glycol chain. In some embodiments, A is an albumin binding group. In some embodiments, the albumin binding group is selected from: [ka] [ka] Unsubstituted or substituted C(O)C 1-26 Alkylene COH, unsubstituted or substituted C(O)C 2-26 Alkenylene COH, unsubstituted or substituted C(O)C 1-26 Alkyl and unsubstituted or substituted C(O)C 2-26 alkenyl. In some embodiments, the albumin binding group is selected from: [ka] Unsubstituted or substituted C(O)C 6-20 Alkylene COH, unsubstituted or substituted C(O)C 6-20 Alkenylene COH, unsubstituted or substituted C(O)C 6-19 Alkyl and unsubstituted or substituted C(O)C 2-20 alkenyl. In some embodiments, the albumin binding group is selected from: [ka] Unsubstituted or substituted C(O)C 6-20 Alkylene COH, unsubstituted or substituted C(O)C 6-20 Alkenylene COH, unsubstituted or substituted C(O)C 6-18 Alkyl and unsubstituted or substituted C(O)C 2-20 alkenyl. In some embodiments, the albumin binding group is [ka] Unsubstituted or substituted C(O)C 12-18 Alkylenes COH and unsubstituted or substituted C(O)C 12-18 Alkenylene COH, unsubstituted or substituted C(O)C 12-19 Alkyl and unsubstituted or substituted C(O)C 12-18 alkenyl. In some embodiments, the albumin binding group is selected from: [ka] Unsubstituted or substituted C(O)C 12-18 Alkylenes COH and unsubstituted or substituted C(O)C 12-18 Alkenylene COH, unsubstituted or substituted C(O)C 12-18 Alkyl and unsubstituted or substituted C(O)C 12-18 alkenyl. In some embodiments, the albumin binding group is selected from: [ka] Unsubstituted or substituted C(O)C 14-18 Alkylenes COH and unsubstituted or substituted C(O)C 14-18 Alkyl. In some embodiments, the albumin binding group is selected from: [ka]

[0156] In some embodiments, the albumin binding group is selected from: [ka]

[0157] In some embodiments, the albumin binding group is an unsubstituted or substituted C(O)C 12-18 In some embodiments, the albumin binding group is selected from alkyleneCOH. 12-18 alkyleneCOH. In some embodiments, the albumin binding group is selected from: [ka] In some embodiments, the albumin binding group is C(O)C 16 Alkylenes COH and C(O)C 18 In some embodiments, the albumin binding group is selected from alkyleneCOH. 16 It is alkylene CO2H.

[0158] In some embodiments, when substituted, each C(O)C 6-20 Alkylene COH, C(O)C 6-20 Alkenylene COH, C(O)C 6-18 Alkyl and C(O)C 2-20 The alkenyl is substituted with one or more of halo, CO2H, CO2C1-C4 alkyl, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, SO2CH3, C1-C4 alkyl, C1-C4 fluoroalkyl, C2-C6 alkenyl, C2-C6 fluoroalkenyl, C2-C6 alkynyl, C2-C6 fluoroalkynyl, C3-C6 cycloalkyl, and a 3-6 membered heterocycle containing 1-2 ring members selected from O, S, S(O), SO2, N, NH, and NCH3.

[0159] In some embodiments, we use C(O)C as the albumin binding group. 12-18 It has been discovered that compounds of Formula I containing alkylene COH exhibit higher tumor-to-kidney uptake ratios. Thus, in an exemplary embodiment, the albumin binding group (A) is an unsubstituted or substituted C(O)C 12-18 alkyleneCOH. Thus, in some embodiments, the compound of formula I is selected from the group consisting of: [ka] (In the formula, Z, E, T, L A , L E and L Z is as defined in Formula I, and k is an integer from 14 to 20. However, L A and L E At least one of the following is a cleavable linker: is a compound of

[0160] In some embodiments, k is 14 to 18. In some embodiments, k is 16 to 18. In some embodiments, k is 16 or 18.

[0161] In some embodiments, E is any chelating group capable of binding and / or complexing with a metal ion. In some embodiments, E is any chelating group capable of binding and / or complexing with a metal ion to form a heterocycle containing the metal ion. In some embodiments, E is any chelating group known in the art, e.g., as described in Banerjee et al., Nucl. Med. Biol., 2005, 32, 1-20; Wadas et al., Chem. Rev., 2010, 110, 2858-2902; U.S. Pat. Nos. 5,367,080, 5,364,613, 5,021,556, 5,075,099, and 5,886,142.

[0162] In some embodiments, E is a chelating group derived from a chelating agent. In some embodiments, the chelating agent is selected from cyclic and acyclic bifunctional chelating agents capable of complexing one or more radionuclides. In some embodiments, the chelating agent is selected from 1,4,7-triazacyclononane (TACN); 1,4,7-triazacyclononane-triacetic acid (NOTA); 1,4,7-triazacyclononane-N-succinic-N',N"-diacetic acid (NOTASA); 1,4,7-triazacyclononane-N-glutamic-N',N"-diacetic acid (NODAGA); 1,4,7-triazacyclononane-N,N',N"-tris(methylenephosphonic) acid (NOTP); 1,4,7,10-tetramethyl- Azacyclododecane (

[12] aneN4) (cyclen); 1,4,7,10-tetraazacyclotridecane (

[13] aneN4); 1,4,7,11-tetraazacyclotetradecane (iso-cyclam); 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA); 2-(1,4,7,10-tetraazacyclododecan-1-yl)acetate (DO1A); 2,2'-(1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid (DO2A );2,2',2"-(1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (DO3A);1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra(methylphosphonic acid) (DOTP);1,4,7,10-tetraazacyclododecane-1,7-di(methylphosphonic acid) (DO2P);1,4,7,10-tetraazacyclododecane-1,4,7-tri(methylphosphonic acid) (DO3P);1,4,7,10-tetraazacyclodecane-1-glutaminic acid 1,4,7,10-tetraazacyclodecane-1-succinic acid-4,7,10-triacetic acid (DOTAGA); 1,4,7,10-tetraazacyclodecane-1-succinic acid-4,7,10-triacetic acid (DOTASA); 1,4,8,11-tetraazacyclotetradecane (

[14] aneN4) (cyclam); 1,4,8,12-tetraazacyclopentadecane (

[15] aneN4); 1,5,9,13-tetraazacyclohexadecane (

[16] aneN4); 1,4-ethano-1,4,8,11-tetraazacyclotetradecane (etho-cyclam);1,4,8,11-Tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA); 2-(1,4,8,11-tetraazacyclotetradecane-1-yl)acetic acid (TE1A); 2,2'-(1,4,8,11-tetraazacyclotetradecane-1,8-diyl)diacetic acid (TE2A); 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]-hexadecane quinone (CB-TE2A); 3,6,10,13,16,19-hexazabicyclo[6.6.6]eicosane (Sar); 1,4,7,10-tetra-(2-carbamoyl-methyl)-cyclododecane (TCMC); N,N'-bis[(6-carboxy-2-pyridyl)methyl]-4,13-diaza-18-crown-6 (macropa), phthalocyanine and its derivatives; porphyrin and its derivatives. In some embodiments, E is a chelating group derived from a chelating agent selected from DOTA and DOTAGA.

[0163] Those skilled in the art will understand that, as used herein, a "chelating group derived from a chelator" refers to a chelator derivative formed after the chelator is linked to a compound of Formula I, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof. For example, a "chelating group derived from a chelator" can be a chelator that does not contain the "-OH" (or an ester thereof) of an available carboxyl group (or an ester thereof) on the chelator, does not contain the "H" moiety of an available amino group on the chelator, does not contain the "NCS" moiety of an available isothiocyanate on the chelator, does not contain the "H" moiety of an available maleimide group on the chelator, a chelator after reacting an available acetylene group on the chelator to link it to a compound of Formula I, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, or a chelator after reacting an available tetrazole group on the chelator to link it to a compound of Formula I, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof. For example, one skilled in the art would recognize that when E is a chelating group derived from DOTA, one "-OH" can be removed from one of the four available carboxyl groups on DOTA to form L of a compound of Formula I, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof. A (L A It will be understood that when is a direct bond a linkage to T) is formed.

[0164] In some embodiments, E is linked to L through any one of the available functional groups. A or T. In some embodiments, E is a chelating group comprising two or more carboxyl groups, and E is linked to L through the carboxyl functional groups. A or T. In some embodiments, E is a chelating group derived from DOTA or DOTAGA and is linked to L through any one of the available carboxyl functional groups. A or T. In some embodiments, E is a chelating group derived from DOTA and is linked to L through any one of the available carboxyl functional groups. A Or connected to T.

[0165] In some embodiments, the one or more radionuclides are radioactive isotopes of C, N, F, S, Br, Ru, Pd, Tc, Ga, In, Zn, Gd, Bi, At, Cu, Pb, Fe, Ti, F, I, Y, Sr, Ra, P, Re, Sc, Zr, Rh, Pt, Rb, Au, Sn, Tl, Co, Pm, a lanthanide, or an actinide.

[0166] In some embodiments, the lanthanide is Lu, Sm, Pm, Ho, or Tb.

[0167] In some embodiments, the actinide is Ac or Th.

[0168] In some embodiments, the one or more radionuclides are 14 C. 15 N, 18 F, 75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I, 131 I, 35 S, 99 Tc, 99m Tc, 188 Re, 186 Re, 153 Sm, 67 Ga, 68 Ga, 111 In, 59 Fe, 63 Zn, 52 Fe, 45 Ti, 60 Cu, 61 Cu, 67 Cu, 64 Cu, 62 Cu, 82 Rb, 195m Pt, 191m Pt, 193m Pt, 117m Sn, 89 Zr, 177 Lu, 18 F, 123 I, 188 Re, 186 Re,153 Sm, 66 Ho, 86 Y, 87 Y, 90 Y, 89 Sr, 111 In, 153 Gd, 225 Ac, 212 Bi, 213 Bi, 211 At, 198 Au, 199 Au, 193m Pt, 197 Pt, 103 Pd, 109 Pd, 105 Rh, 103m Rh, 223 Ra, 224 Ra, 97 Ru, 227 Th, 229 Th, 32 P, 161 Tb, 33 P, 149 Tb, 125 I, 203 Pb, 212 Pb, 201 Tl, 119 Sb, 58m Co, 55 Co, 47 Sc, 149 Pm and 161 Ho is selected.

[0169] In some embodiments, the one or more radionuclides are for use in imaging or for use in therapy.

[0170] In some embodiments, one or more radionuclides for use in imaging include: 99m Tc, 188 Re, 186 Re, 153 Sm, 67 Ga, 68 Ga, 111 In, 59 Fe, 63 Zn, 52 Fe, 45 Ti, 60 Cu, 61 Cu,67 Cu, 64 Cu, 62 Cu, 82 Rb, 198 Au, 199 Au, 195m Pt, 191m Pt, 193m Pt, 117m Sn, 89 Zr, 177 Lu, 18 F and 123 I. In some embodiments, the one or more radionuclides for use in imaging are selected from: 177 This is Lu.

[0171] In some embodiments, one or more radionuclides for use in therapy include: 188 Re, 186 Re, 153 Sm, 66 Ho, 90 Y, 89 Sr, 111 In, 153 Gd, 225 Ac, 212 Bi, 213 Bi, 211 At, 60 Cu, 61 Cu, 67 Cu, 64 Cu, 62 Cu, 198 Au, 199 Au, 195m Pt, 193m Pt, 197 Pt, 117m Sn, 103 Pd, 105 Rh, 103m Rh, 177 Lu, 223 Ra, 224 Ra, 227 Th, 229 Th, 149 Tb, 32 P, 161 Tb, 33 P, 125 I, 203 Pb, 212 Pb, 201 Tl, 119 Sb, 58mCo, 47 Sc, 149 Pm and 161 Ho is selected.

[0172] In some embodiments, one or more radionuclides for use in therapy include: 177 Lu, 212 Pb, and 225 In some embodiments, the one or more radionuclides for use in therapy are selected from Ac. 177 This is Lu.

[0173] In some embodiments, Z binds to a cell, optionally a cancer cell. Thus, in some embodiments, Z is a tumor-binding group. In some embodiments, Z is bound to an antigen or other protein on the cell surface, such as a cell surface receptor. In some embodiments, Z is selected from the following: a prostate-specific membrane antigen (PSMA)-binding group, a glucagon-like peptide-1 receptor (GLP-1R)-binding group, a glucose-dependent insulinotropic polypeptide (gastric inhibitory polypeptide; GIP) receptor (GIP-R)-binding group, a folate receptor (FR)-binding group, a cholecystokinin-2 receptor (CCK2R)-binding group, a gastrin-releasing peptide receptor (GRPR)-binding group, a somatostatin receptor 2 (SSTR2)-binding group, a neurotensin receptor 1 (NTR1)-binding group, a neuropeptide Y receptor type 1 (Y1R)-binding group, a nectin-4-binding group, a delta-like ligand 3 (DLL3)-binding group, an epithelial cell adhesion molecule (EpCAM)-binding group, a tumor-associated calcium signaling substance 2 (Trop-2)-binding group, an insulin-like growth factor-1 (IGF-1) receptor-binding group, or a human epidermal growth factor receptor 2 (HER2)-binding group.

[0174] In some embodiments, Z is a PSMA-binding group. In some embodiments, the PSMA-binding group is a peptide analog selected from quiscitric acid, aspartic acid-glutamic acid (Asp-Glu), Glu-Glu, glycine-glutamic acid (Gly-Glu), γ-glutamic acid-glutamic acid (γ-Glu-Glu), and β-N-acetyl-L-aspartic acid-L-glutamic acid (β-NAAG). In some embodiments, the PSMA-binding group comprises a phosphorus, thiol, or urea derivative attached to the glutamic acid moiety. In some embodiments, the PSMA-binding group is [ka] is.

[0175] In some embodiments, the PSMA binding group is εKuE and the albumin binding group (A) is unsubstituted or substituted C(O)C 12-18 In some embodiments, the PSMA binding group is εKuE and the albumin binding group (A) is selected from C(O)C 12-18 alkyleneCOH. Thus, in some embodiments, the PSMA-binding group is εKuE and the albumin-binding group (A) is unsubstituted or substituted C(O)C 12-18 alkylene COH, the compound of formula I has formula I-A' [ka] (In the formula, E, T, L A , L E and L Z is as defined in Formula I, and k is an integer from 14 to 20. However, L A , L E At least one of the following is a cleavable linker: is a compound of

[0176] In some embodiments, T is a branched group that is at least trivalent and includes at least a first terminal functional group, a second terminal functional group, and a third terminal functional group, which may be the same or different, and each may be L A (or alternatively A), L Z (or alternatively Z) and L E (or alternatively, E). In some embodiments, T comprises at least a first terminal functional group, a second terminal functional group, and a third terminal functional group, which may be the same or different, each of which is linked to L. A (or alternatively A), L Z (or alternatively Z) and L E (or alternatively, when attached to E), independently form an amide group, a urea group, a thiourea group, or a thioamide group. A (or alternatively A), and / or L E (or alternatively, when attached to E), an ester group, a thioester group, a carbonate group, a carbamate group, a disulfide bond, a hydrazone group, or an oxime group, such as a ketoxime or aldoxime, is further formed. A (or alternatively A), and / or L E (or alternatively E), an enzymatically cleavable sequence is formed.

[0177] In some embodiments, T is a trivalent, tetravalent, or pentavalent branching group. In some embodiments, T is a trivalent branching group. Thus, in some embodiments, T is a trivalent branching group.

[0178] In some embodiments, T comprises at least a first terminal functional group, a second terminal functional group, and a third terminal functional group, which may be the same or different; A (or alternatively A), L Z (or alternatively Z), and L E (or alternatively E), they each independently form an amide group. A(or alternatively A), and / or L E (or alternatively E), an amide group, an ester group, or a disulfide bond group is formed. A (or alternatively A), and / or L E (or alternatively, E), an ester group is formed. In some embodiments, T comprises at least a first terminal functional group, a second terminal functional group, and a third terminal functional group, which may be the same or different, and L A (or alternatively A), L Z (or alternatively Z), and L E (or alternatively E), each independently forms an amide group.

[0179] In some embodiments, T is selected from an amino acid residue derived from lysine, ornithine, homolysine, 2,3-diaminopropionic acid (DAP), 2,4-diaminobutyric acid (DAB), cysteine, homocysteine, or glutamine. [ka] In some embodiments, T is an amino acid residue derived from DAP or DAB. [ka] or an amino acid residue derived from DAB. In some embodiments, T is lysine, [ka] In some embodiments, T is an amino acid residue derived from DAB. Thus, in some embodiments, the compound of formula IB is a compound of formula IB or a pharmaceutically acceptable salt and / or solvate thereof, a compound of formula IC or a pharmaceutically acceptable salt and / or solvate thereof, a compound of formula I-B' or a pharmaceutically acceptable salt and / or solvate thereof, or a compound of formula I-C' or a pharmaceutically acceptable salt and / or solvate thereof. [ka]

[0180] In some embodiments, the compound of Formula IB is a compound of Formula IB or a pharmaceutically acceptable salt and / or solvate thereof, or a compound of Formula IC or a pharmaceutically acceptable salt and / or solvate thereof: [ka]

[0181] In an exemplary embodiment, the albumin binding group (A) is an unsubstituted or substituted C(O)C 12-18 Alkylenes COH and C(O)C 14-18 In an exemplary embodiment, the albumin binding group (A) is selected from unsubstituted or substituted C(O)C alkyl. 12-18 alkylene COH.

[0182] In an exemplary embodiment, the albumin binding group (A) is an unsubstituted or substituted C(O)C 12-18 alkyleneCOH, the PSMA group is εKuE, T is lysine, [ka] In some embodiments, the albumin binding group (A) is an unsubstituted or substituted C(O)C 12-18 alkyleneCOH, the PSMA group is εKuE, T is lysine, [ka] or an amino acid residue derived from DAB. Thus, in some embodiments, the compound of Formula I is a compound of Formula I-A'(a) or a pharmaceutically acceptable salt and / or solvate thereof, a compound of Formula I-A'(b) or a pharmaceutically acceptable salt and / or solvate thereof, a compound of Formula I-A'(c) or a pharmaceutically acceptable salt and / or solvate thereof, and a compound of Formula I-A'(d) or a pharmaceutically acceptable salt and / or solvate thereof: [ka] (In the formulas IA(a), IA(b), IA(c) and IA(d), E, T, L A , L E and L Z is as defined in Formula I, and k is an integer from 14 to 20. However, L A and L E At least one of the following is a cleavable linker:

[0183] In some embodiments, k in formula IA(a), formula IA(b), formula IA(c), and formula IA(d) is 14 to 18. In some embodiments, k in formula IA(a), formula IA(b), formula IA(c), and formula IA(d) is 16 to 18. In some embodiments, k in formula IA(a), formula IA(b), formula IA(c), and formula IA(d) is 16 or 18. In some embodiments, E in formula IA(a), formula IA(b), formula IA(c), and formula IA(d) is 14 to 18. In some embodiments, E in formula IA(a), formula IA(b), formula IA(c), and formula IA(d) is 16 or 18. In some embodiments, E in formula IA(a), formula IA(b), formula IA(c), and formula IA(d) is a chelating group derived from a chelating agent selected from DOTA and DOTAGA.

[0184] In some embodiments, L Zis a direct bond. In some embodiments, L Z is a non-cleavable linker.

[0185] In some embodiments, L A and L E In some embodiments, one of L is a cleavable linker and the other is a direct bond or a non-cleavable linker. A and L E In some embodiments, one of L is a direct bond and the other is a cleavable linker. A and L E In some embodiments, one of L is a non-cleavable linker and the other is a cleavable linker. A and L E In some embodiments, both L A is a cleavable linker, and L E is a direct bond or a non-cleavable linker. In some embodiments, L A is a cleavable linker, and L E is a direct bond. In some embodiments, L A is a cleavable linker, and L E is a non-cleavable linker. In some embodiments, L A is a cleavable linker, and L E is a direct bond. In some embodiments, L A is a cleavable linker, and L E is a non-cleavable linker, and L Z is a non-cleavable linker.

[0186] In some embodiments, L Z is a non-cleavable linker, and / or L A and L E When one of L is a non-cleavable linker, each non-cleavable linker independently comprises one or more groups each comprising one or more non-cleavable moieties. Z is a non-cleavable linker, and / or L A and L Eis a non-cleavable linker, each non-cleavable linker independently comprises one or more non-cleavable moieties that resist degradation, in some embodiments, the one or more non-cleavable moieties that resist degradation are selected from an amine bond, an ether bond, a thioether bond, an amide bond, a thioamide bond, a urea bond, and a thiourea bond.

[0187] In some embodiments, L Z is a non-cleavable linker, and / or L A and L E is a non-cleavable linker, each non-cleavable linker independently comprises an amino acid residue, R 1 NC 1-20 Alkylene NR 2 , R 1 NC 1-20 Alkenylene NR 2 , C(O)C 1-20 Alkylene C(O), C(O)C 1-20 Alkenylene C(O), R 1 NC 1-20 Alkylene C(O), R 1 NC 1-20 Alkenylene C(O), C(O)C 1-20 Alkylene NHR 2 , C(O)C 1-20 Alkenylene NR 2 , C(S)C 1-20 Alkylene C(S), C(S)C 1-20 Alkenylene C(S), C(S)C 1-20 Alkylene C(O), C(S)C 1-20 Alkenylene C(O), C(O)C 1-20 Alkylene C(S), C(O)C 1-20 Alkenylene C(S), C(O)C 1-20 Alkylene O, C(O)C 1-20 Alkenylene O, R 1 NC 1-20 Alkenylene C(S), C(S)C 1-20 Alkylene NR 2 , and C(S)C 1-20 Alkenylene NR 2The latter 19 groups optionally contain one or more of S, O, NH, N(C 1-6 Alkali), C(O), C(O)NH, NHC(O), C(S)NH, NHC(S), NHC(O)NH, NHC(S)NH, NHC(NH), NHC(NC 1-4 alkyl), C(NH)NH, C(NC 1-4 alkyl)NH, NC 4-10 Cycloalkyl, C 4-10 Heterocycloalkyl, C 6-10 Aryl and C 5-10 Each alkyl, alkylene, and alkenylene is optionally interrupted by a heteroaryl, and each alkyl, alkylene, and alkenylene is optionally interrupted by a halo, COH, C 1-6 Alkyl, OH, OC 1-6 Alkyl, SH, SC 1-6 Alkyl, NR 3 R 4 , C 1-4 Alkylene OH, C 1-4 Alkylene OC 1-4 Alkyl, and C 1-4 Alkylene NR 3 R 4 wherein each R 1 , R 2 , R 3 and R 4 is H and C 1-4 In some embodiments, L Z is a non-cleavable linker, and / or L A and L E is a non-cleavable linker, each non-cleavable linker independently comprises an amino acid residue, HNC 1-20 Alkylene NH, HNC 1-20 Alkenylene NH, C(O)C 1-20 Alkylene C(O), C(O)C 1-20 Alkenylene C(O), HNC 1-20 Alkylene C(O), HNC 1-20 Alkenylene C(O), C(O)C 1-20 Alkylene NH, C(O)C 1-20 Alkenylene NH, C(S)C 1-20Alkylene C(S), C(S)C 1-20 Alkenylene C(S), C(S)C 1-20 Alkylene C(O), C(S)C 1-20 Alkenylene C(O), C(O)C 1-20 Alkylene C(S) and C(O)C 1-20 alkenylene C(S), the latter of which optionally contains one or more of S, O, NH, N(C 1-6 Alkali), C(O), C(O)NH, NHC(O), C(S)NH, NHC(S), NHC(O)NH, NHC(S)NH, NHC(NH), NHC(NC 1-4 alkyl), C(NH)NH, C(NC 1-4 alkyl)NH, NC 4-10 Cycloalkyl, C 4-10 Heterocycloalkyl, C 6-10 Aryl and C 5-10 Each alkyl, alkylene, and alkenylene is optionally interrupted by a heteroaryl, and each alkyl, alkylene, and alkenylene is optionally interrupted by a halo, COH, C 1-6 Alkyl, OH, OC 1-6 Alkyl, SH, SC 1-6 Alkyl, NH2, NHC 1-4 Alkyl and N(C 1-4 and substituted with one or more substituents selected from alkyl).

[0188] In some embodiments, L Z is a non-cleavable linker, and / or L A and L E is a non-cleavable linker, each non-cleavable linker independently comprises an amino acid residue, R 1 NC 1-20 Alkylene NR 2 , R 1 NC 1-20 Alkenylene NR 2 , C(O)C 1-20 Alkylene C(O), C(O)C 1-20 Alkenylene C(O), R 1 NC 1-20 Alkylene C(O), R 1 NC 1-20Alkenylene C(O), C(O)C 1-20 Alkylene NR 2 , and C(O)C 1-20 Alkenylene NR 2 The latter eight groups optionally contain one or more of S, O, NH, N(C 1-6 alkali), C(O), C(O)NH, NHC(O), NHC(O)NH, NHC(S)NH, NC 4-6 Cycloalkyl, C 4-6 Heterocycloalkyl, C 6-10 Aryl and C 5-10 Each alkyl, alkylene, and alkenylene is optionally interrupted by a heteroaryl, and each alkyl, alkylene, and alkenylene is optionally interrupted by a halo, COH, C 1-6 Alkyl, OH, OC 1-6 Alkyl, SH, SC 1-6 Alkyl, NR 3 R 4 , C 1-4 Alkylene OH, C 1-4 Alkylene OC 1-4 Alkyl, and C 1-4 Alkylene NR 3 R 4 wherein each R 1 , R 2 , R 3 and R 4 is H and C 1-4 In some embodiments, L Z is a non-cleavable linker, and / or L A and L E is a non-cleavable linker, each non-cleavable linker independently comprises an amino acid residue, HNC 1-20 Alkylene NH, HNC 1-20 Alkenylene NH, C(O)C 1-20 Alkylene C(O), C(O)C 1-20 Alkenylene C(O), HNC 1-20 Alkylene C(O), HNC 1-20 Alkenylene C(O), C(O)C 1-20 Alkylene NH and C(O)C 1-20alkenylene NH, the latter eight groups optionally containing one or more of S, O, NH, N(C 1-6 alkali), C(O), C(O)NH, NHC(O), NHC(O)NH, NHC(S)NH, NC 4-6 Cycloalkyl, C 4-6 Heterocycloalkyl, C 6-10 Aryl and C 5-10 Each alkyl, alkylene, and alkenylene is optionally interrupted by a heteroaryl, and each alkyl, alkylene, and alkenylene is optionally interrupted by a halo, COH, C 1-6 Alkyl, OH, OC 1-6 Alkyl, SH, SC 1-6 Alkyl, NH2, NHC 1-4 Alkyl and N(C 1-4 and substituted with one or more substituents selected from alkyl).

[0189] In some embodiments, L Z is a non-cleavable linker, and / or L A and L E is a non-cleavable linker, each non-cleavable linker independently comprises an amino acid residue, R 1 NC 1-20 Alkylene NR 2 , C(O)C 1-20 Alkylene C(O), R 1 NC 1-20 Alkylene C(O) and C(O)C 1-20 Alkylene NR 2 wherein the latter four groups optionally comprise one or more of S, O, C(O)NH, NHC(O), NC 4-6 Cycloalkyl, C 4-6 The heterocycloalkyl may be interrupted by any of the following: each alkyl, alkylene, and alkenylene may optionally be interrupted by halo, COH, C 1-6 Alkyl, OH, OC 1-6 Alkyl, SH, SC 1-6 Alkyl, NR 3 R 4 , C 1-4 Alkylene OH, C 1-4 Alkylene OC 1-4 Alkyl, and C1-4 Alkylene NR 3 R 4 wherein each R 1 , R 2 , R 3 and R 4 is H and C 1-4 In some embodiments, L Z is a non-cleavable linker, and / or L A and L E is a non-cleavable linker, each non-cleavable linker independently comprises an amino acid residue, HNC 1-20 Alkylene NH, C(O)C 1-20 Alkylene C(O), HNC 1-20 Alkylene C(O) and C(O)C 1-20 alkylene NH, the latter four groups optionally containing one or more of S, O, C(O)NH, NHC(O), NC 4-6 Cycloalkyl, C 4-6 The heterocycloalkyl may be interrupted by any of the following: each alkyl, alkylene, and alkenylene may optionally be interrupted by halo, COH, C 1-6 Alkyl, OH, OC 1-6 Alkyl, SH, SC 1-6 Alkyl, NH2, NHC 1-4 Alkyl and N(C 1-4 and substituted with one or more substituents selected from alkyl).

[0190] In some embodiments, L Z is a non-cleavable linker, and / or L A and L E is a non-cleavable linker, each non-cleavable linker independently comprises an amino acid residue, R 1 NC 1-20 Alkylene NR 2 , C(O)C 1-20 Alkylene C(O), R 1 NC 1-20 Alkylene C(O) and C(O)C 1-20 Alkylene NR 2wherein the latter four groups optionally comprise one or more of S, O, C(O)NH, NHC(O), C 4-6 Cycloalkyl, and C 4-6 The heterocycloalkyl is interrupted by each alkyl and alkylene, and each alkyl and alkylene is optionally interrupted by halo, COH, NR 3 R 4 , and C 1-4 Alkylene NR 3 R 4 wherein each R 1 , R 2 , R 3 and R 4 is H and C 1-4 alkyl.

[0191] In some embodiments, L Z is a non-cleavable linker, and / or L A and L E is a non-cleavable linker, each non-cleavable linker independently comprises an amino acid residue, R 1 NC 1-20 Alkylene NR 2 , C(O)C 1-20 Alkylene C(O), R 1 NC 1-20 Alkylene C(O) and C(O)C 1-20 Alkylene NR 2 wherein the latter four groups optionally comprise one or more of S, O, C(O)NH, NHC(O), C 4-6 Cycloalkyl, and C 4-6 and is interrupted by heterocycloalkyl, wherein each R 1 and R 2 is H and C 1-4 In some embodiments, L Z is a non-cleavable linker, and / or L A and L E is a non-cleavable linker, each non-cleavable linker independently comprises an amino acid residue, HNC 1-20 Alkylene NH, C(O)C 1-20Alkylene C(O), HNC 1-20 Alkylene C(O) and C(O)C 1-20 alkyleneNH, the latter four groups optionally comprising one or more of S, O, C(O)NH, NHC(O), C 4-6 Cycloalkyl, and C 4-6 It is interrupted by heterocycloalkyl.

[0192] In some embodiments, R 1 , R 2 , R 3 and R 4 is independently selected from H, CH, CHCH, CHCHCH, CH(CH), and C(CH). 1 , R 2 , R 3 and R 4 are independently H and C 1-3 In some embodiments, R 1 , R 2 , R 3 and R 4 is independently selected from H, CH, CHCH, and CH(CH). In some embodiments, R 1 , R 2 , R 3 and R 4 is independently selected from H, and CH3.

[0193] In some embodiments, L A and L E One or both of L is a cleavable linker, and each cleavable linker independently comprises at least one group comprising 1 to 4 cleavable moieties, or at least two groups that link to form a cleavable moiety. A and L E One or both of L are cleavable linkers, each cleavable linker independently containing one or two cleavable moieties and / or containing 2 to 4 groups linked to form a cleavable moiety. A and LE In some embodiments, one or both of L is a cleavable linker, and each cleavable linker independently contains one or two cleavable moieties and / or contains two groups that link to form a cleavable moiety. A and L E One or both of L is a cleavable linker, and each cleavable linker independently comprises a group that includes one or two cleavable moieties. A and L E are both cleavable linkers, each containing two cleavable moieties and / or each containing one or two groups that further link to form cleavable moieties.

[0194] In some embodiments, L A and L E is a cleavable linker, each cleavable linker independently comprising one or more amino acid residues, R 5 NC 1-20 Alkylene NR 6 , R 5 NC 1-20 Alkenylene NR 5 , C(O)C 1-20 Alkylene C(O), C(O)C 1-20 Alkenylene C(O), R 5 NC 1-20 Alkylene C(O), R 5 NC 1-20 Alkenylene C(O), C(O)C 1-20 Alkylene NR 6 , C(O)C 1-20 Alkenylene NR 6 , C(S)C 1-20 Alkylene C(S), C(S)C 1-20 Alkenylene C(S), C(S)C 1-20 Alkylene C(O), C(S)C 1-20 Alkenylene C(O), C(O)C 1-20 Alkylene C(S), C(O)C 1-20 Alkenylene C(S), SC 1-20 Alkylene S, SC 1-20 Alkenylene S, SC1-20 Alkylene NR 6 , SC 1-20 Alkenylene NR 6 , R 5 NC 1-20 Alkylene S, R 5 NC 1-20 Alkenylene S, R 5 NC 1-20 Alkylene O, R 5 NC 1-20 Alkenylene O, OC 1-20 Alkylene NR 6 , O.C. 1-20 Alkenylene NR 6 , SC 1-20 Alkylene O, SC 1-20 Alkenylene O, OC 1-20 Alkylene S and OC 1-20 Alkenylene S, C(O)C 1-20 Alkylene O, C(O)C 1-20 Alkenylene O, OC 1-20 Alkylene C(O), OC 1-20 Alkenylene C(O), C(O)C 1-20 Alkylene S, C(O)C 1-20 Alkenylene S, SC 1-20 Alkylene C(O), SC 1-20 Alkenylene C(O), R 5 NC 1-20 Alkylene C(S), R 5 NC 1-20 Alkenylene C(S), C(S)C 1-20 Alkylene NR 6 , C(S)C 1-20 Alkenylene NR 6 , C(S)C 1-20 Alkylene O, C(S)C 1-20 Alkenylene O, OC 1-20 Alkylene C(S), OC 1-20 Alkenylene C(S), SC 1-20 Alkylene C(S), SC 1-20 Alkenylene C(S), OC 1-20 Alkylene O, OC 1-20 Alkenylene CO, SC 1-20 Alkylene S, SC 1-20Alkenylenes may contain one or more groups selected from S, the latter 50 groups being optionally S-S, C(O)O, OC(O), OC(O)O, OC(O)NH, NHC(O)O, SC(O), C(O)S, NC 1-4 Alkyl C(O)O, NHOC(O)NH, NC 1-4 Alkyl OC(O), C=NNH, C=NNH2, C=NOH, C=NO, NH-NH, NH-NC 1-4 Alkyl, NC 1-4 Alkyl-NH, NC 1-4 Alkyl NC 1-4 Alkyl, S, O, NH, N(C 1-6 alkyl), C(O), C(O)NH, NHC(O), NHC(O)NH, NHC(S)NH, C(S)NH, NHC(S), NHC(NH), NHC(NC 1-4 alkyl), C(NH)NH, C(NC 1-4 alkyl)NH, NC 4-18 Cycloalkyl, C 4-10 Heterocycloalkyl, C 6-10 Aryl and C 5-10 and each alkyl, alkylene, and alkenylene is optionally interrupted by one or more of halo, COH, C 1-6 Alkyl, OH, OC 1-6 Alkyl, SH, SC 1-6 Alkyl, NR 7 R 7 , C 1-4 Alkylene OH, C 1-4 Alkylene OC 1-4 Alkyl, and C 1-4 Alkylene NR 7 R 8 and is substituted with one or more substituents selected from where R 5 , R 6 , R 7 and R 8 are independently H and C 1-4 alkyl, provided that at least two groups are linked to form a cleavable moiety; or One or more groups contain at least one cleavable moiety, and The cleavable moiety is SS, C(O)O, OC(O), OC(O)O, OC(O)NH, NHC(O)O, SC(O), C(O)S, C=NNH, C=NO, NC 1-4 Alkyl C(O)O, NHOC(O)NH, NC 1-4 Alkyl OC(O), NH-NH, NH-NC 1-4 Alkyl, NC 1-4 Alkyl-NH, NC 1-4 Alkyl-NC 1-4 In some embodiments, L is selected from the group consisting of alkyl, aryl, arylsulfonyl ... A and L E is a cleavable linker, each cleavable linker independently comprising an amino acid residue, HNC 1-20 Alkylene NH, HNC 1-20 Alkenylene NH, C(O)C 1-20 Alkylene C(O), C(O)C 1-20 Alkenylene C(O), HNC 1-20 Alkylene C(O), HNC 1-20 Alkenylene C(O), C(O)C 1-20 Alkylene NH, C(O)C 1-20 Alkenylene NH, C(S)C 1-20 Alkylene C(S), C(S)C 1-20 Alkenylene C(S), C(S)C 1-20 Alkylene C(O), C(S)C 1-20 Alkenylene C(O), C(O)C 1-20 Alkylene C(S), C(O)C 1-20 Alkenylene C(S), SC 1-20 Alkylene S, SC 1-20 Alkenylene S, SC 1-20 Alkylene NH, SC 1-20 Alkenylene NH, HNC 1-20 Alkylene S, HNC 1-20 Alkenylene S, HNC 1-20 Alkylene O, HNC 1-20 Alkenylene O, OC 1-20 Alkylene NH, OC 1-20 Alkenylene NH, SC 1- 20 Alkylene O, SC1-20 Alkenylene O, OC 1-20 Alkylene S and OC 1-20 Alkenylenes include one or more groups selected from S, the latter 28 groups optionally being S-S, C(O)O, OC(O), OC(O)O, OC(O)NH, NHC(O)O, SC(O), C(O)S, NC 1-4 Alkyl C(O)O, NHOC(O)NH, NC 1-4 Alkyl OC(O), C=NNH, C=NNH2, C=NOH, C=NO, NH-NH, NH-NC 1-4 Alkyl, NC 1-4 Alkyl-NH, NC 1-4 Alkyl NC 1-4 Alkyl, S, O, NH, N(C 1-6 alkyl), C(O), C(O)NH, NHC(O), NHC(O)NH, NHC(S)NH, C(S)NH, NHC(S), NHC(NH), NHC(NC 1-4 alkyl), C(NH)NH, C(NC 1-4 alkyl)NH, NC 4-18 Cycloalkyl, C 4-10 Heterocycloalkyl, C 6-10 Aryl and C 5-10 and each alkyl, alkylene, and alkenylene is interrupted by one or more of halo, COH, C 1-6 Alkyl, OH, OC 1-6 Alkyl, SH, SC 1-6 Alkyl, NH2, NHC 1-4 Alkyl and N(C 1-4 substituted with one or more substituents selected from: However, one or more groups may not be SS, C(O)O, OC(O), OC(O)O, OC(O)NH, NHC(O)O, SC(O), C(O)S, C=NNH, C=NO, NC 1-4 Alkyl C(O)O, NHOC(O)NH, NC 1-4 Alkyl OC(O), NH-NH, NH-NC 1-4 Alkyl, NC 1-4 Alkyl-NH, NC 1-4 Alkyl-NC 1-4The cleavable moiety is selected from an alkyl, an enzymatically cleavable peptide sequence, and at least one cleavable moiety selected from an alkyl, an enzymatically cleavable peptide sequence.

[0195] In some embodiments, L A and L E is a cleavable linker, each cleavable linker independently comprising one or more amino acid residues, R 5 NC 1-20 Alkylene NR 6 , R 5 NC 1-20 Alkenylene NR 6 , C(O)C 1-20 Alkylene C(O), C(O)C 1-20 Alkenylene C(O), R 5 NC 1-20 Alkylene C(O), R 5 NC 1-20 Alkenylene C(O), C(O)C 1-20 Alkylene NR 6 , C(O)C 1-20 Alkenylene NR 6 , C(S)C 1-20 Alkylene C(S), C(S)C 1-20 Alkenylene C(S), C(S)C 1-20 Alkylene C(O), C(S)C 1-20 Alkenylene C(O), C(O)C 1-20 Alkylene C(S), SC 1-20 Alkylene S, SC 1-20 Alkylene NR 6 , R 5 NC 1-20 Alkylene S, R 5 NC 1-20 Alkylene O, R 5 NC 1-20 Alkenylene O, OC 1-20 Alkylene NR 6 , O.C. 1-20 Alkenylene NR 6 , SC 1-20 Alkylene O, OC 1-20 Alkylene S, C(O)C 1-20 Alkylene O, C(O)C 1-20 Alkenylene O, OC 1-20Alkylene C(O) and OC 1-20 Alkenylene C(O), the latter 26 groups optionally including one or more groups selected from S-S, C(O)O, OC(O), OC(O)O, OC(O)NH, NHC(O)O, SC(O), C(O)S, NC 1-4 Alkyl C(O)O, NHOC(O)NH, NC 1-4 Alkyl OC(O), C=NNH, C=NNH2, C=NOH, C=NO, NH-NH, S, O, NH, N(C 1-6 Alkyl), C(O), C(O)NH, NHC(O), NHC(O)NH, NHC(S)NH, C(S)NH, NHC(S), NC 4-18 Cycloalkyl, C 4-10 Heterocycloalkyl, C 6-10 Aryl and C 5-10 and each alkyl, alkylene, and alkenylene is optionally interrupted by one or more of halo, COH, C 1-6 Alkyl, OH, OC 1-6 Alkyl, SH, SC 1-6 Alkyl, NR 7 R 7 , C 1-4 Alkylene OH, C 1-4 Alkylene OC 1-4 Alkyl, and C 1-4 Alkylene NR 7 R 8 and is substituted with one or more substituents selected from where R 5 , R 6 , R 7 and R 8 are independently H and C 1-4 alkyl, provided that at least two groups are linked to form a cleavable moiety; or One or more groups contain at least one cleavable moiety, and The cleavable moiety is SS, C(O)O, OC(O), OC(O)O, OC(O)NH, NHC(O)O, SC(O), C(O)S, C=NNH, C=NO, NC 1-4 Alkyl C(O)O, NHOC(O)NH, NC1-4 Alkyl OC(O), NH-NH, NH-NC 1-4 Alkyl, NC 1-4 Alkyl-NH, NC 1-4 Alkyl-NC 1-4 In some embodiments, L is selected from the group consisting of alkyl, aryl, arylsulfonyl ... A and L E is a cleavable linker, each cleavable linker independently comprising an amino acid residue, HNC 1-20 Alkylene NH, HNC 1-20 Alkenylene NH, C(O)C 1-20 Alkylene C(O), C(O)C 1-20 Alkenylene C(O), HNC 1-20 Alkylene C(O), HNC 1-20 Alkenylene C(O), C(O)C 1-20 Alkylene NH, C(O)C 1-20 Alkenylene NH, C(S)C 1-20 Alkylene C(S), C(S)C 1-20 Alkenylene C(S), C(S)C 1-20 Alkylene C(O), C(S)C 1-20 Alkenylene C(O), C(O)C 1-20 Alkylene C(S), SC 1-20 Alkylene S, SC 1-20 Alkylene NH, HNC 1-20 Alkylene S, HNC 1-20 Alkylene O, HNC 1-20 Alkenylene O, OC 1-20 Alkylene NH, OC 1-20 Alkenylene NH, SC 1-20 Alkylene O and O-C 1-20 alkylene S, the latter 22 groups optionally including one or more groups selected from SS, C(O)O, OC(O), OC(O)O, OC(O)NH, NHC(O)O, SC(O), C(O)S, NC 1-4 Alkyl C(O)O, NHOC(O)NH, NC 1-4 Alkyl OC(O), C=NNH, C=NNH2, C=NOH, C=NO, NH-NH, S, O, NH, N(C 1-6Alkyl), C(O), C(O)NH, NHC(O), NHC(O)NH, NHC(S)NH, C(S)NH, NHC(S), NC 4-18 Cycloalkyl, C 4-10 Heterocycloalkyl, C 6-10 Aryl and C 5-10 and each alkyl, alkylene, and alkenylene is interrupted by one or more of halo, COH, C 1-6 Alkyl, OH, OC 1-6 Alkyl, SH, SC 1-6 Alkyl, NH2, NHC 1-4 Alkyl and N(C 1-4 substituted with one or more substituents selected from: However, one or more groups may not be SS, C(O)O, OC(O), OC(O)O, OC(O)NH, NHC(O)O, C=NNH, C=NO, SC(O), C(O)S, NC 1-4 Alkyl C(O)O, NHOC(O)NH, NC 1-4 It shall contain at least one cleavable moiety selected from alkylOC(O), NH-NH, and an enzymatically cleavable peptide sequence.

[0196] In some embodiments, L A and L E is a cleavable linker, each cleavable linker independently comprising one or more amino acid residues, R 5 NC 1-20 Alkylene NR 6 , R 5 NC 1-20 Alkenylene NR 6 , C(O)C 1-20 Alkylene C(O), C(O)C 1-20 Alkenylene C(O), R 5 NC 1-20 Alkylene C(O), R 5 NC 1-20 Alkenylene C(O), C(O)C 1-20 Alkylene N R6 , C(O)C 1-20 Alkenylene NR 6 , R 5 NC1-20 Alkylene O, R 5 NC 1-20 Alkenylene O, OC 1-20 Alkylene NR 6 , O.C. 1-20 Alkenylene NR 6 , O.C. 1-20 Alkylene S, C(O)C 1-20 Alkylene O, C(O)C 1-20 Alkenylene O, OC 1-20 Alkylene C(O) and OC 1-20 alkenylene C(O), the latter 16 groups optionally containing one or more groups selected from S-S, C(O)O, OC(O), OC(O)O, OC(O)NH, NHC(O)O, SC(O), C(O)S, NC 1-4 Alkyl C(O)O, NHOC(O)NH, NC 1-4 Alkyl OC(O), S, O, NH, N(C 1-6 Alkyl), C(O), C(O)NH, NHC(O), NHC(O)NH, NHC(S)NH, C(S)NH, NHC(S), NC 4-18 Cycloalkyl, C 4-10 Heterocycloalkyl, C 6-10 Aryl and C 5-10 and each alkyl, alkylene, and alkenylene is optionally interrupted by one or more of halo, COH, C 1-6 Alkyl, OH, OC 1-6 Alkyl, SH, SC 1-6 Alkyl, NR 7 R 7 , C 1-4 Alkylene OH, C 1-4 Alkylene OC 1-4 Alkyl, and C 1-4 Alkylene NR 7 R 8 and is substituted with one or more substituents selected from where R 5 , R 6 , R 7 and R 8 are independently H and C 1-4 alkyl, provided that at least two groups are linked to form a cleavable moiety; or One or more groups contain at least one cleavable moiety, and The cleavable moiety may be S-S, C(O)O, OC(O), OC(O)O, OC(O)NH, NHC(O)O, SC(O), C(O)S, NC 1-4 In some embodiments, L is selected from alkylC(O)O, and an enzymatically cleavable peptide sequence. A and L E is a cleavable linker, each cleavable linker independently comprising an amino acid residue, HNC 1-20 Alkylene NH, HNC 1-20 Alkenylene NH, C(O)C 1-20 Alkylene C(O), C(O)C 1-20 Alkenylene C(O), HNC 1-20 Alkylene C(O), HNC 1-20 Alkenylene C(O), C(O)C 1-20 Alkylene NH, C(O)C 1-20 Alkenylene NH, HNC 1-20 Alkylene O, HNC 1-20 Alkenylene O, OC 1-20 Alkylene NH and OC 1-20 alkenylene, optionally containing one or more groups selected from SS, C(O)O, OC(O), OC(O)O, OC(O)NH, NHC(O)O, SC(O), C(O)S, NC 1-4 Alkyl C(O)O, NHOC(O)NH, NC 1-4 Alkyl OC(O), S, O, NH, N(C 1-6 Alkyl), C(O), C(O)NH, NHC(O), NHC(O)NH, NHC(S)NH, C(S)NH, NHC(S), NC 4-18 Cycloalkyl, C 4-10 Heterocycloalkyl, C 6-10 Aryl and C 5-10 and each alkyl, alkylene, and alkenylene is interrupted by one or more of halo, COH, C 1-6 Alkyl, OH, OC1-6 Alkyl, SH, SC 1-6 Alkyl, NH2, NHC 1-4 Alkyl and N(C 1-4 substituted with one or more substituents selected from: However, one or more groups may not be SS, C(O)O, OC(O), OC(O)O, OC(O)NH, NHC(O)O, SC(O), C(O)S, C=NNH, C=NO, NC 1-4 It shall contain at least one cleavable moiety selected from alkylC(O)O and an enzymatically cleavable peptide sequence.

[0197] In some embodiments, L A and L E is a cleavable linker, each cleavable linker independently comprising one or more amino acid residues, R 5 NC 1-20 Alkylene NR 6 , C(O)C 1-20 Alkylene C(O), R 5 NC 1-20 Alkylene C(O), C(O)C 1-20 Alkylene NR 6 , R 5 NC 1-20 Alkylene O, OC 1-20 Alkylene NR 6 , C(O)C 1-20 Alkylene O and O-C 1-20 alkylene C(O), the latter eight groups optionally including one or more groups selected from S-S, C(O)O, OC(O), OC(O)O, OC(O)NH, NHC(O)O, SC(O), C(O)S, NC 1-4 Alkyl C(O)O, NHOC(O)NH, NC 1-4 Alkyl OC(O), S, O, NH, N(C 1-6 Alkyl), C(O), C(O)NH, NHC(O), NHC(O)NH, NHC(S)NH, C(S)NH, NHC(S), C 4-18 Cycloalkyl, C 4-10 Heterocycloalkyl, C 6-10 Aryl and C 5-10and each alkyl and alkylene is optionally interrupted by one or more of halo, COH, C 1-6 Alkyl, OH, OC 1-6 Alkyl, SH, SC 1-6 Alkyl, NR 7 R 7 , C 1-4 Alkylene OH, C 1-4 Alkylene OC 1-4 Alkyl, and C 1-4 Alkylene NR 7 R 8 and is substituted with one or more substituents selected from where R 5 , R 6 , R 7 and R 8 are independently H and C 1-4 alkyl, provided that at least two groups are linked to form a cleavable moiety; or One or more groups contain at least one cleavable moiety, and The cleavable moiety may be S-S, C(O)O, OC(O), OC(O)O, OC(O)NH, NHC(O)O, SC(O), C(O)S, NC 1-4 In some embodiments, L is selected from alkylC(O)O, and an enzymatically cleavable peptide sequence. A and L E is a cleavable linker, each cleavable linker independently comprising an amino acid residue, HNC 1-20 Alkylene NH, C(O)C 1-20 Alkylene C(O), HNC 1-20 Alkylene C(O), C(O)C 1-20 Alkylene NH, HNC 1-20 Alkylene O, OC 1-20 alkylene NH, the latter six groups optionally including one or more groups selected from SS, C(O)O, OC(O), OC(O)O, OC(O)NH, NHC(O)O, SC(O), C(O)S, NC 1-4 Alkyl C(O)O, NHOC(O)NH, NC 1-4Alkyl OC(O), S, O, NH, N(C 1-6 Alkyl), C(O), C(O)NH, NHC(O), NHC(O)NH, NHC(S)NH, C(S)NH, NHC(S), C 4-18 Cycloalkyl, C 4-10 Heterocycloalkyl, C 6-10 Aryl and C 5-10 and each alkyl and alkylene is interrupted by one or more of halo, COH, C 1-6 Alkyl, OH, OC 1-6 Alkyl, SH, SC 1-6 Alkyl, NH2, NHC 1-4 Alkyl and N(C 1-4 substituted with one or more substituents selected from: However, one or more groups may not be SS, C(O)O, OC(O), OC(O)O, OC(O)NH, NHC(O)O, SC(O), C(O)S, C=NNH, C=NO, NC 1-4 It shall contain at least one cleavable moiety selected from alkylC(O)O and an enzymatically cleavable peptide sequence.

[0198] In some embodiments, L A and L E is a cleavable linker, each cleavable linker independently comprising one or more amino acid residues, R 5 NC 1-20 Alkylene NR 6 , C(O)C 1-20 Alkylene C(O), R 5 NC 1-20 Alkylene C(O), C(O)C 1-20 Alkylene NR 6 , R 5 NC 1-20 Alkylene O, OC 1-20 Alkylene NR 6 , C(O)C 1-20 Alkylene O, OC 1-20alkylene C(O), the latter eight groups optionally including one or more groups selected from S-S, C(O)O, OC(O), OC(O)O, OC(O)NH, NHC(O)O, SC(O), C(O)S, S, O, NH, N(C 1-6 Alkyl), C(O), C(O)NH, NHC(O), NHC(O)NH, NHC(S)NH, C(S)NH, NHC(S), C 4-18 Cycloalkyl, C 4-10 and each alkyl and alkylene is optionally interrupted by one or more of halo, COH, C 1-6 Alkyl, OH, OC 1-6 Alkyl, SH, SC 1-6 Alkyl, NR 7 R 7 , C 1-4 Alkylene OH and C 1-4 Alkylene NR 7 R 8 and is substituted with one or more substituents selected from where R 5 , R 6 , R 7 and R 8 are independently H and C 1-4 alkyl, provided that at least two groups are linked to form a cleavable moiety; or One or more groups contain at least one cleavable moiety, and The cleavable moiety is selected from SS, C(O)O, OC(O), OC(O)O, OC(O)NH, NHC(O)O, SC(O), C(O)S, and an enzymatically cleavable peptide sequence. A and L E is a cleavable linker, each cleavable linker independently comprising an amino acid residue, HNC 1-20 Alkylene NH, C(O)C 1-20 Alkylene C(O), HNC 1-20 Alkylene C(O), C(O)C 1-20 Alkylene NH, HNC 1-20 Alkylene O and O-C 1-20alkyleneNH, the latter six groups optionally comprising one or more groups selected from SS, C(O)O, OC(O), OC(O)O, OC(O)NH, SC(O), C(O)S, S, O, NH, N(C 1-6 Alkyl), C(O), C(O)NH, NHC(O), NHC(O)NH, NHC(S)NH, C(S)NH, NHC(S), C 4-18 Cycloalkyl, and C 4-10 Heterocycloalkyl, each alkyl and alkylene is interrupted by one or more of halo, COH, C 1-6 Alkyl, OH, OC 1-6 Alkyl, SH, SC 1-6 Alkyl, NH2, NHC 1-4 Alkyl and N(C 1-4 substituted with one or more substituents selected from: provided that one or more groups contain at least one cleavable moiety selected from S-S, C(O)O, OC(O), OC(O)O, OC(O)NH, NHC(O)O, SC(O), C(O)S, and an enzymatically cleavable peptide sequence.

[0199] In some embodiments, L A and L E is a cleavable linker, each cleavable linker independently comprising one or more amino acid residues, R 5 NC 1-20 Alkylene NR 6 , C(O)C 1-20 Alkylene C(O), R 5 NC 1-20 Alkylene C(O), C(O)C1 -20 Alkylene NR 6 , R 5 NC 1-20 Alkylene O, OC 1-20 Alkylene NR 6 , C(O)C 1-20 Alkylene O and O-C 1-20 alkylene C(O), the latter eight groups optionally including one or more groups selected from SS, C(O)O, OC(O), S, O, C(O)NH, NHC(O), C4-18 Cycloalkyl, and C 4-10 and each alkyl and alkylene is optionally interrupted by one or more of halo, COH, C 1-6 Alkyl, OH, OC 1-6 Alkyl, SH, SC 1-6 Alkyl, NR 7 R 7 , C 1-4 Alkylene OH and C 1-4 Alkylene NR 7 R 8 and is substituted with one or more substituents selected from where R 5 , R 6 , R 7 and R 8 are independently H and C 1-4 alkyl, provided that at least two groups are linked to form a cleavable moiety; or One or more groups contain at least one cleavable moiety, and The cleavable moiety is selected from SS, C(O)O, OC(O), and an enzymatically cleavable peptide sequence.

[0200] In some embodiments, L A and L E is a cleavable linker, each cleavable linker independently comprising one or more amino acid residues, HNC 1-20 Alkylene NH, C(O)C 1-20 Alkylene C(O), HNC 1-20 Alkylene C(O), C(O)C 1-20 Alkylene NH, HNC 1-20 Alkylene O, OC 1-20 alkyleneNH, the latter six groups optionally including one or more groups selected from SS, C(O)O, OC(O), S, O, C(O)NH, NHC(O), C 4-18 Cycloalkyl, and C 4-10 and each alkyl and alkylene is optionally interrupted by one or more of halo, COH, C1-6 Alkyl, OH, OC 1-6 Alkyl, SH, SC 1-6 Alkyl, NH2, NHC 1-4 Alkyl and N(C 1-4 substituted with one or more substituents selected from: provided that one or more groups include at least one cleavable moiety selected from SS, C(O)O, OC(O), and an enzymatically cleavable peptide sequence. A and L E is a cleavable linker, each cleavable linker independently comprising an amino acid residue, R 5 NC 1-20 Alkylene NR 6 , C(O)C 1-20 Alkylene C(O), R 5 NC 1-20 Alkylene C(O), C(O)C 1-20 Alkylene NR 6 , R 5 NC 1-20 Alkylene O, OC 1-20 Alkylene NR 6 , C(O)C 1-20 Alkylene O and O-C 1-20 alkylene C(O), the latter eight groups optionally including one or more groups selected from SS, C(O)O, OC(O), S, O, C(O)NH, NHC(O), C 4-18 Cycloalkyl and C 4-10 heterocycloalkyl, wherein each alkyl and alkylene is interrupted by one or more of halo, COH, NR 7 R 7 , and C 1-4 Alkylene NR 7 R 8 and is substituted with one or more substituents selected from where R 5 , R 6 , R 7 and R 8 are independently H and C 1-4 alkyl, provided that at least two groups are linked to form a cleavable moiety; or One or more groups contain at least one cleavable moiety, and The cleavable moiety is selected from SS, C(O)O, OC(O), and an enzymatically cleavable peptide sequence. A and L E is a cleavable linker, each cleavable linker independently comprising an amino acid residue, HNC 1-20 Alkylene NH, C(O)C 1-20 Alkylene C(O), HNC 1-20 Alkylene C(O), C(O)C 1-20 Alkylene NH, HNC 1-20 Alkylene O and OC 1-20 alkyleneNH, the latter six groups optionally including one or more groups selected from SS, C(O)O, OC(O), S, O, C(O)NH, NHC(O), C 4-18 Cycloalkyl, and C 4-10 is interrupted by one or more heterocycloalkyl; provided that one or more groups contain at least one cleavable moiety selected from SS, C(O)O, OC(O), and an enzymatically cleavable peptide sequence.

[0201] In some embodiments, the cleavable moiety is selected from SS, C(O)O, and OC(O). In some embodiments, the cleavable moiety is selected from C(O)O and OC(O).

[0202] In some embodiments, at least two groups are linked to form a cleavable moiety. In some embodiments, an amino acid residue, R 5 NC 1-20 Alkylene O, OC 1-20 Alkylene NR 6 , C(O)C 1-20 Alkylene O and O-C 1-20alkylene C(O) are linked to form a cleavable moiety selected from C(O)O and OC(O). In some embodiments, an amino acid residue and R 5 NC 1-20 Alkylene O, OC 1-20 Alkylene NR 6 , C(O)C 1-20 Alkylene O and O-C 1-20 In some embodiments, the amino acid residue and one of the alkylene C(O) are linked to form a cleavable moiety selected from C(O)O and OC(O). 1-20 Alkylene O and O-C 1-20 and one of the alkylene C(O)s are linked to form a cleavable moiety selected from C(O)O and OC(O). In some embodiments, OC 1-20 Alkylene C(O) is selected from 4-hydroxybutanoic acid (4hBA), 4-hydroxypentanoic acid (4hPA), 5-hydroxypentanoic acid (5HPA) and 6-hydroxyhexanoic acid (6hHA).

[0203] In some embodiments, C 4-10 Cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0204] In some embodiments, C 4-10 Heterocycloalkyl is selected from azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, 3,4,5,6-tetrahydro-1,2,4-triazinyl, dioxythiomorpholino, tetrahydropyridinyl, dihydropyridinyl, dihydropyranyl, thianyl, piperidinyl, piperazinyl, tetrahydropyranyl, thiomorpholinyl, morpholinyl, dioxanyl, azepanyl, diazepanyl, oxepanyl, and thiepanyl.

[0205] In some embodiments, C6-10 Aryl is selected from phenyl, indanyl or naphthyl.

[0206] In some embodiments, C 5-11 Heteroaryl is selected from triazolyl, pyrrolyl, imidazolyl, oxazolyl, pyrazolyl, thiazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl.

[0207] In some embodiments, L A , L E and / or L Z In some embodiments, the amino acid residues in A , L E and / or L Z The amino acid residues are derived from naturally occurring amino acids, modified amino acids, β-amino acids, γ-amino acids, D enantiomers of naturally occurring or modified amino acids, and non-naturally occurring amino acids.

[0208] In some embodiments, L A , L E and / or L Z are derived from amino acids that are naturally occurring amino acids. In some embodiments, the naturally occurring amino acids are selected from, but are not limited to, alanine (Ala), arginine (Arg), asparagine (Asn), aspartic acid (Asp), cysteine ​​(Cys), glutamine (Gln), glutamic acid (Glu), glycine (Gly), histidine (His), isoleucine (Ile), leucine (Leu), lysine (Lys), methionine (Met), phenylalanine (Phe), proline (Pro), serine (Ser), threonine (Thr), tryptophan (Trp), tyrosine (Tyr), valine (Val), pyrrolysine (Pyl), selenocycline (Sec), and pyrrolinecarboxylysine (PCL).

[0209] In some embodiments, naturally occurring amino acids are further modified in vivo to provide modified amino acids. Thus, in some embodiments, the amino acid residues are selected from the group consisting of hydroxyproline, γ-carboxyglutamic acid, O-phosphoserine, azetidinecarboxylic acid, 2-aminoadipic acid, 3-aminoadipic acid, β-alanine, aminopropionic acid, 2-aminobutyric acid, 4-aminobutyric acid, 6-aminocaproic acid, 2-aminoheptanoic acid, 2-aminoisobutyric acid, 3-aminoisobutyric acid, 2-aminopimelic acid, tert-butylglycine, 2,4-diaminoisobutyric acid, desmosine, 2,2'-diaminopimelic acid, 2,3-diaminopropionic acid, 2,4'-diaminoisobutyric acid, 2,3'-diaminopropionic acid, 2,3'-diaminopropionic acid, 2,4'-diaminopropionic acid, 2,3 ... and the amino acid is derived from an amino acid selected from, but not limited to, hydroxylysine, N-ethylglycine, N-methylglycine, N-ethylasparagine, homoproline, hydroxylysine, allohydroxylysine, 3-hydroxyproline, 4-hydroxyproline, isodesmosine, alloisoleucine, N-methylalanine, N-methylglycine, N-methylisoleucine, N-methylpentylglycine, N-methylvaline, naphthalanine, norvaline, norleucine, ornithine, pentylglycine, pipecolic acid, and thioproline.

[0210] In some embodiments, the amino acid residues are derived from modified amino acids selected from ornithine, homolysine, 2,3-diaminopropionic acid (DAP), 2,4-diaminobutyric acid (DAB), and homocysteine.

[0211] In some embodiments, the amino acid residue is derived from the D enantiomer of a naturally occurring or modified amino acid.

[0212] In some embodiments, the amino acid residues derived from Glu are linked via the α-amino and α-carboxy termini, or the α-amino and γ-carboxy termini. Thus, in some embodiments, the amino acid residues derived from Glu are linked via the α-amino and α-carboxy termini. [ka] In some embodiments, the amino acid residues derived from Asp are linked via the amino and α-carboxy termini, or via the amino and β-carboxy termini. In some embodiments, the amino acid residues derived from Lys are linked via the α-amino and α-carboxy termini, or via the α-amino and ε-amino termini. Thus, in some embodiments, the amino acid residues are [ka] It comes from.

[0213] In some embodiments, L A , L E and / or L Z is derived from a β-amino acid or a γ-amino acid. In some embodiments, the β-amino acid is β-alanine.

[0214] In some embodiments, L A , L E and / or L Z In some embodiments, the amino acid residue in L is derived from a non-natural amino acid. A , L E and / or L Z The amino acid residues in are selected from: [ka]

[0215] Thus, in some embodiments, L Z is a non-cleavable linker, and / or L A , and L E is a non-cleavable linker, each non-cleavable linker independently comprises one or more amino acid residues derived from Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, Val, Pyl, Sec, or PCL, or their D enantiomers; one or more amino acid residues derived from DAB or DAP; [ka] R 1 NC 1-20 Alkylene NR 2 ;C(O)C 1-20 Alkylene C(O);R 1 NC 1-20 Alkylene C(O); and C(O)C 1-20 Alkylene NR 2 wherein the latter four groups are optionally selected from S, O, C(O)NH, NHC(O), C 4-6 Cycloalkyl, and C 4-6 interrupted by one or more of heterocycloalkyl, where each R 1 and R 2 are independently H and C 1-2 In some embodiments, L is selected from alkyl. Z is a non-cleavable linker, and / or L A and L E is a non-cleavable linker, each non-cleavable linker independently comprises one or more amino acid residues derived from Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, Val, Pyl, Sec, PCL, or their D enantiomers; one or more amino acid residues derived from DAB or DAP; [ka] R 1 NC 1-20 Alkylene NR 2 , C(O)C 1-20 Alkylene C(O), R 1 NC 1-20 Alkylene C(O) and C(O)C 1-20 Alkylene NR 2 wherein each R 1 and R 2 are independently H and C 1-2 In some embodiments, L is selected from alkyl.Z is a non-cleavable linker, and / or L A and L E is a non-cleavable linker, each non-cleavable linker independently comprises one or more amino acid residues derived from Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, Val, Pyl, Sec, and PCL, and their D enantiomers; [ka] The compound includes one or more groups selected from the group consisting of:

[0216] In some embodiments, L Z teeth, [ka] In some embodiments, L is a non-cleavable linker comprising one or more groups selected from Z is a non-cleavable linker and is or comprises: [ka] In some embodiments, L Z is a non-cleavable linker connected to Z, and is the fragment L in the compound of formula I Z -Z is or includes: [ka]

[0217] In some embodiments, L Z is a non-cleavable linker comprising one or more groups selected from one or more amino acid residues derived from Tyr or Phe. Z is a non-cleavable linker connected to Z, and fragment L in compounds of formula I Z -Z is or comprises Tyr-Phe-εKuE.

[0218] In some embodiments, L Z is OEG;R 1 NC 1-20 Alkylene NR 2 , C(O)C 1-20 Alkylene C(O), R 1 NC 1-20 Alkylene C(O) and C(O)C 1-20 Alkylene NR 2 wherein each R 1 and R 2 are independently H and C 1-2 In some embodiments, L is selected from alkyl. Z teeth, [ka] In some embodiments, L further comprises one or more groups selected from Z teeth, [ka] and wherein the fragment L in the compound of formula I further comprises one or more groups selected from Z -Z is [ka] is or contains

[0219] Thus, in some embodiments, L Z ,OEG, [ka] R 1 NC 1-20 Alkylene NR 2 , C(O)C 1-20 Alkylene C(O), R 1 NC 1-20 Alkylene C(O) and C(O)C 1-20 Alkylene NR 2 wherein each R 1 and R 2are independently H and C 1-2 In some embodiments, L is selected from alkyl. Z teeth, [ka] is a non-cleavable linker comprising one or more groups selected from:

[0220] In some embodiments, L A and L E one of which is a non-cleavable linker, and the non-cleavable linker is one or more amino acid residues derived from Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, Val, Pyl, Sec, or PCL, or the D enantiomers thereof; one or more amino acid residues derived from DAB or DAP; OEG, R 1 NC 1-20 Alkylene NR 2 , C(O)C 1-20 Alkylene C(O), R 1 NC 1-20 Alkylene C(O) and C(O)C 1-20 Alkylene NR 2 wherein each R 1 and R 2 are independently H and C 1-2 In some embodiments, L is selected from alkyl. A and L E one of which is a non-cleavable linker, the non-cleavable linker being one or more amino acid residues derived from Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, Val, Pyl, Sec, and PCL, and their D enantiomers; [ka] The compound includes one or more groups selected from the group consisting of:

[0221] In some embodiments, LA and L E one of which is a non-cleavable linker, the non-cleavable linker being one or more amino acid residues derived from Glu, Gly, Lys, Phe, Tyr, and Val, or their D enantiomers; 1 NC 1-20 Alkylene NR 2 , C(O)C 1-20 Alkylene C(O), R 1 NC 1-20 Alkylene C(O) and C(O)C 1-20 Alkylene NR 2 wherein each R 1 and R 2 are independently H and C 1-2 In some embodiments, L is selected from alkyl. A and L E one of which is a non-cleavable linker, the non-cleavable linker being one or more amino acid residues derived from Glu, Gly, Lys, Phe, Tyr, and Val, and their D enantiomers; [ka] The compound includes one or more groups selected from the group consisting of:

[0222] In some embodiments, L A is a non-cleavable linker, and the non-cleavable linker is an amino acid residue derived from Gly, Glu, OEG, R 1 NC 1-20 Alkylene NR 2 , C(O)C 1-20 Alkylene C(O), R 1 NC 1-20 Alkylene C(O) and C(O)C 1-20 Alkylene NR 2 wherein each R 1 and R 2 are independently H and C 1-2 In some embodiments, L is selected from alkyl. A is a non-cleavable linker, and the non-cleavable linker is an amino acid residue derived from Glu, [ka] In some embodiments, L A is a non-cleavable linker, and the non-cleavable linker is an amino acid residue derived from Glu and [ka] The compound includes one or more groups selected from the group consisting of:

[0223] In some embodiments, the amino acid residue derived from Glu is [ka] and L A is a non-cleavable linker, [ka] In some embodiments, L A is a non-cleavable linker, and the non-cleavable linker is one or more [ka] In some embodiments, L A is a non-cleavable linker, and the non-cleavable linker is one or more [ka] In some embodiments, the non-cleavable linker comprises γGlu-(OEG) 1-3 In some embodiments, the non-cleavable linker is or comprises: [ka] is or contains

[0224] In some embodiments, L A is two or more [ka] Includes:

[0225] In some embodiments, L E is a non-cleavable linker, and the non-cleavable linker is OEG, R 1 NC 1-20 Alkylene NR 2 , C(O)C 1-20 Alkylene C(O), R 1 NC 1-20 Alkylene C(O) and C(O)C 1-20 Alkylene NR 2 and each R 1 and R 2 are independently H and C 1-2 In some embodiments, L is selected from alkyl. E is a non-cleavable linker, [ka] In some embodiments, L A is two or more [ka] Includes:

[0226] In some embodiments, L A and L E one or both of which are cleavable linkers, each cleavable linker independently comprising one or more amino acid residues; R 5 NC 1-20 Alkylene C(O); C(O)C 1-20 Alkylene NR 6 ;C(O)C 1-20 Alkylene O and OC 1-20 alkyleneC(O), the latter four groups being optionally interrupted by one or more of S-S, C(O)O, OC(O), O, C(O)NH and NHC(O), and each alkyl and alkylene optionally being interrupted by one or more of halo, COH, NR 7R 7 , and C 1-4 Alkylene NR 7 R 8 and is substituted with one or more substituents selected from: where R 5 , R 6 , R 7 and R 8 are independently H and C 1-4 selected from alkyl provided that at least two groups are linked to form a cleavable moiety; or One or more groups contain at least one cleavable moiety, and The cleavable moiety is selected from SS, C(O)O, OC(O), and an enzymatically cleavable peptide sequence.

[0227] In some embodiments, L A and L E one or both of which is a cleavable linker, the cleavable linker being optionally interrupted by one or more of S-S, C(O)O, O-C(O), O, C(O)NH and NHC(O); 5 NC 1-20 alkylene C(O) (wherein R 5 NC 1-20 The alkylene C(O) is interrupted by at least one of S-S, C(O)O, and O-C(O); or the cleavable linker is C(O)C 1-20 Alkylene O or OC 1-20 In some embodiments, L comprises at least one group linked to an alkylene C(O) to form a cleavable moiety selected from C(O)O and OC(O). A and L E one or both of which is a cleavable linker, the cleavable linker being optionally interrupted by one or more of S-S, C(O)O, O-C(O), O, C(O)NH and NHC(O); 5 NC 1-20 alkylene C(O) (wherein R 5NC 1-20 The alkylene C(O) is interrupted by at least one of S-S, C(O)O, and O-C(O); or the cleavable linker is C(O)C 1-20 Alkylene O or OC 1-20 In some embodiments, L comprises at least one amino acid residue linked to an alkylene C(O) to form a cleavable moiety selected from C(O)O and OC(O). A and L E one or both of which is a cleavable linker, the cleavable linker being optionally interrupted by 1 to 5 of S-S, C(O)O, O-C(O), O, C(O)NH, and NHC(O); 5 NC 1-20 alkylene C(O) (wherein R 5 NC 1-20 The alkylene C(O) is interrupted by at least one of S-S, C(O)O, and O-C(O); or the cleavable linker is C(O)C 1-20 Alkylene O or OC 1-20 It comprises at least one amino acid residue linked to an alkylene C(O) to form a cleavable moiety selected from C(O)O and OC(O).

[0228] In some embodiments, L A and L E one or both of which is a cleavable linker, the cleavable linker being optionally interrupted by 1 to 5 of S-S, C(O)O, O-C(O), O, C(O)NH, and NHC(O); 5 NC 1-20 alkylene C(O) (wherein R 5 NC 1-20 The alkylene C(O) is interrupted by at least one of S-S, C(O)O, and O-C(O). In some embodiments, R is optionally interrupted by 1-5 of S-S, C(O)O, O-C(O), O, C(O)NH, and NHC(O). 5 NC 1-20Alkylene C(O) (where R 5 NC 1-20 Alkylene C(O) (which is intended to be interrupted by at least one of S-S, C(O)O, and O-C(O)) is selected from ESL1, SSL1, ESL2, and ESL3. In some embodiments, L A and L E is a cleavable linker, the cleavable linker being [ka] and an enzymatically cleavable peptide sequence.

[0229] In some embodiments, L A and L E is a cleavable linker, and the cleavable linker is C(O)C 1-20 Alkylene O or OC 1-20 In some embodiments, L comprises at least one amino acid residue linked to an alkylene C(O) to form a cleavable moiety selected from C(O)O and OC(O). A and L E is a cleavable linker, and the cleavable linker is C(O)C 1-10 Alkylene O or OC 1-10 It comprises at least one amino acid residue linked to an alkylene C(O) to form a cleavable moiety selected from C(O)O and OC(O). In some embodiments, C(O)C 1-10 Alkylene O or OC 1-10 At least one amino acid residue linked to the alkylene C(O) is derived from an amino acid selected from naturally occurring amino acids or their D-enantiomers, DAB and DAP. In some embodiments, the amino acid is selected from Gly, Leu, DAB and DAP. Thus, in some embodiments, L A and L E is a cleavable linker, and the cleavable linker is C(O)C 1-10Alkylene O or OC 1-10 It comprises at least one amino acid residue of a naturally occurring amino acid or its D-enantiomer, DAB and DAP, linked to an alkylene C(O) to form a cleavable moiety selected from C(O)O and OC(O).

[0230] In some embodiments, the enzymatically cleavable peptide sequence is a peptide sequence cleavable by a renal brush border enzyme, thermolysin, proline endopeptidase, fibroblast activation protein (FAP), neprilysin, or general endopeptidase. In some embodiments, the peptide sequence cleavable by a renal brush border enzyme is selected from Met-Val-Lys. In some embodiments, the peptide sequence cleavable by thermolysin is Ala-Val. In some embodiments, the peptide sequence cleavable by a proline endopeptidase is Ala-Pro and Gly-Pro. In some embodiments, the peptide sequence cleavable by a FAP is Gly-Pro. In some embodiments, the peptide sequence cleavable by neprilysin is Ser-Ser, Ser-Gly, Gly-Ala, and Ser-Lys. Thus, in some embodiments, the enzymatically cleavable peptide sequence is selected from Met-Val-Lys, Ala-Val, Ala-Pro, Gly-Pro, Ser-Ser, Ser-Gly, Gly-Ala, and Ser-Lys.

[0231] In some embodiments, the cleavable linker optionally comprises an amino acid residue derived from Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, He, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, Val, Pyl, Sec, or PCL, or a D enantiomer thereof; one or more amino acid residues derived from DAB or DAP; [ka] R 5 NC 1-20 Alkylene NR 6and R optionally interrupted by one or more O 5 NC 1-20 In some embodiments, the cleavable linker optionally further comprises one or more groups selected from amino acid residues derived from Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, He, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, Val, Pyl, Sec, and PCL, and their D enantiomers; [ka] The compound further comprises one or more groups selected from:

[0232] In some embodiments, L A and L E is a cleavable linker, each cleavable linker independently containing one or more amino acid residues derived from Gly, Glu, Leu, Phe, Tyr, or Lys, or their D enantiomers; one or more amino acid residues derived from DAP or DAB; R 5 NC 1-20 Alkylene NR 6 and R optionally interrupted by one or more O 5 NC 1-20 alkylene C(O); and at least one R optionally interrupted by one or more of S-S, C(O)O, OC(O), O, C(O)NH, and NHC(O); 5 NC 1-20 Alkylene C(O) (where R 5 NC 1-20 alkylene C(O) is interrupted by at least one of S-S, C(O)O and O-C(O); or C(O)C 1-10 Alkylene O or OC 1-10 at least one amino acid residue linked to an alkylene C(O) to form a cleavable moiety selected from C(O)O and OC(O); or an enzymatically cleavable peptide sequence selected from Met-Val-Lys, Ala-Val, Ala-Pro, Gly-Pro, Ser-Ser, Ser-Gly, Gly-Ala, and Ser-Lys. A and L E is a cleavable linker, each cleavable linker independently comprising an amino acid residue derived from Gly, Glu, Leu, Phe, Tyr, or Lys, or a D enantiomer thereof; one or more amino acid residues derived from DAP or DAB; R 5 NC 1-20 Alkylene NR 6 and optionally interrupted by one or more O, R 5 NC 1-20 alkylene C(O); and C(O)C 1-10 Alkylene O or OC 1-10 and at least one amino acid residue linked to an alkylene C(O) to form a cleavable moiety selected from C(O)O and OC(O). A and L E is a cleavable linker, each cleavable linker independently containing an amino acid residue derived from Gly, Glu, Leu, Phe, Tyr, or Lys, or a D enantiomer thereof; one or more amino acid residues derived from DAP or DAB; R 5 NC 1-20 Alkylene NR 6 and R optionally interrupted by one or more O 5 NC 1-20 alkylene C(O); and at least one group R optionally interrupted by one or more of SS, C(O)O, OC(O), O, C(O)NH and NHC(O); 5 NC 1-20 Alkylene C(O) (where R 5 NC 1-20 alkylene C(O) is interrupted by at least one of SS, C(O)O, OC(O); or an enzymatically cleavable peptide sequence selected from Met-Val-Lys, Ala-Val, Ala-Pro, Gly-Pro, Ser-Ser, Ser-Gly, Gly-Ala, and Ser-Lys. A and L E is a cleavable linker, each cleavable linker independently containing an amino acid residue derived from Glu, Lys, Phe, Tyr, and their D enantiomers; [ka] and an enzymatically cleavable peptide sequence selected from Met-Val-Lys, Ala-Val, Ala-Pro, Gly-Pro, Ser-Ser, Ser-Gly, Gly-Ala, and Ser-Lys. A and L E is a cleavable linker, each cleavable linker independently comprising an amino acid residue derived from Gly, Glu, Leu, Phe, Tyr, or Lys, or a D enantiomer thereof; one or more amino acid residues derived from DAP and DAB; R 5 NC 1-20 Alkylene NR 6 and optionally interrupted by one or more O, R 5 NC 1-20 alkylene C(O); and at least one group R optionally interrupted by one or more of SS, C(O)O, OC(O), O, C(O)NH and NHC(O); 5 NC 1-20 Alkylene C(O) (where R 5 NC 1-20 Alkylene C(O) is interrupted by at least one of S-S, C(O)O, and O-C(O);

[0233] In some embodiments, L Ais a cleavable linker, which is an amino acid residue derived from Gly, Glu, Leu, Phe, Tyr, or Lys, or a D enantiomer thereof; one or more amino acid residues derived from DAP or DAB; R 5 NC 1-20 Alkylene NR 6 and optionally interrupted by one or more O, R 5 NC 1-20 alkylene C(O); and at least one R optionally interrupted by one or more of S-S, C(O)O, OC(O), O, C(O)NH, and NHC(O); 5 NC 1-20 Alkylene C(O) (where R 5 NC 1-20 alkylene C(O) is interrupted by at least one of SS, C(O)O and OC(O); C(O)C 1-10 Alkylene O or OC 1-10 at least one amino acid residue linked to an alkylene C(O) to form a cleavable moiety selected from C(O)O and OC(O); or an enzymatically cleavable peptide sequence selected from Met-Val-Lys, Ala-Val, Ala-Pro, Gly-Pro, Ser-Ser, Ser-Gly, Gly-Ala, and Ser-Lys. A is a cleavable linker, which is one or more amino acid residues derived from Gly, Glu, Leu, Phe, Tyr, or Lys, or their D enantiomers; one or more amino acid residues derived from DAP or DAB; R 5 NC 1-20 Alkylene NR 6 and, optionally interrupted by one or more O, R 5 NC 1-20 alkylene C(O); and C(O)C 1-10 Alkylene O or OC 1-10at least one amino acid residue linked to an alkylene C(O) to form a cleavable moiety selected from C(O)O and OC(O). In some embodiments, L A is a cleavable linker, the cleavable linker being an amino acid residue derived from Glu, Lys, Phe, Tyr, and their D enantiomers; [ka] and an enzymatically cleavable peptide sequence selected from Met-Val-Lys, Ala-Val, Ala-Pro, Gly-Pro, Ser-Ser, Ser-Gly, Gly-Ala and Ser-Lys.

[0234] In some embodiments, L E is a cleavable linker, which may be one or more amino acid residues derived from Gly, Glu, Leu, Phe, Tyr, or Lys, or their D enantiomers; one or more amino acid residues derived from DAP or DAB; R 5 NC 1-20 Alkylene NR 6 and optionally interrupted by one or more O, R 5 NC 1-20 alkylene C(O); and at least one R optionally interrupted by one or more of S-S, C(O)O, OC(O), O, C(O)NH, and NHC(O); 5 NC 1-20 Alkylene C(O) (where R 5 NC 1-20 alkylene C(O) is interrupted by at least one of S-S, C(O)O and O-C(O); or C(O)C 1-10 Alkylene O or OC 1-10 at least one amino acid residue linked to an alkylene C(O) to form a cleavable moiety selected from C(O)O and OC(O); or an enzymatically cleavable peptide sequence selected from Met-Val-Ala-Val, Ala-Pro, Gly-Pro, Ser-Ser, Ser-Gly, Gly-Ala, and Ser-Lys. E is a cleavable linker, which is one or more amino acid residues derived from Gly, Glu, Leu, Phe, Tyr, or Lys, or their D enantiomers; one or more amino acid residues derived from DAP and DAB; R 5 NC 1-20 Alkylene NR 6 and optionally interrupted by one or more O, R 5 NC 1-20 Alkylene C(O); and C(O)C 1-10 Alkylene O or OC 1-10 at least one amino acid residue linked to an alkylene C(O) to form a cleavable moiety selected from C(O)O and OC(O). In some embodiments, L E is a cleavable linker, and the cleavable linker is one or more [ka] and an enzymatically cleavable peptide sequence selected from Met-Val-Lys, Ala-Val, Ala-Pro, Gly-Pro, Ser-Ser, Ser-Gly, Gly-Ala, and Ser-Lys. E is a cleavable linker, and the cleavable linker is [ka] is or contains

[0235] In some embodiments, R 5 , R 6 , R 7 and R 8is independently selected from H, CH, CHCH, CHCHCH, CH(CH), and C(CH). 5 , R 6 , R 7 and R 8 are independently H and C 1-3 In some embodiments, R 5 , R 6 , R 7 and R 8 is independently selected from H, CH, CHCH, and CH(CH). In some embodiments, R 5 , R 6 , R 7 and R 8 are independently selected H and CH3.

[0236] In some embodiments, L A , L E and L Z each independently contains 1 to 15 groups, 1 to 12 groups, 1 to 10 groups, 1 to 8 groups, or 1 to 6 groups linked together. In some embodiments, L A , L E and L Z each independently contains 1 to 15 groups, 1 to 12 groups, or 1 to 10 groups linked together. In some embodiments, L A , L E and L Z are each independently 1 to 5 groups, 1 to 4 groups, 1 to 3 groups, or 1 or 2 groups linked together. In some embodiments, L A , L E and L Z are each independently composed of 1 to 4 groups, 1 to 3 groups, or 1 or 2 groups linked together.

[0237] In some embodiments, L A teeth [ka] L Z teeth [ka] Also, L E teeth [ka] and the compound of formula I has formula ID: [ka] (In the formula, A, Z, E, and T are as defined in Formula I; T A , T Z , T E are each independently T as defined in Formula I, and T A , T Z , T E and T may be the same or different; L A1 and L A2 are each independently L as defined in formula I A and; L E1 and L E2 are each independently L as defined in formula I E and; L Z1 and L Z2 are each independently L as defined in formula I Z and; R A teeth, [ka] is selected from R Z teeth, [ka] is selected from R E teeth, [ka] is selected from T A1 , TZ-A , T E-A , T Z1 , T A-Z , T E-Z , T E1 , T Z-E , T A-E are each independently T as defined in Formula I, and T, T A1 , T Z-A , T E-A , T Z1 , T A-Z , T E-Z , T E1 , T Z-E and T A-E are the same or different; L A3 , L A1-Z , L A2-Z , L A1-E and L A2-E are each independently L as defined in formula I A and; L E1-A , L E2-A , L E1-Z , L E2-Z and L E3 are each independently L as defined in formula I E and; L Z3 , L Z1-A , L Z2-A , L Z1-E and L Z2-E are each independently L as defined in formula I Z and; A 1 , A 2 and A 3 are each independently A as defined in formula I, and A 1 , A 2 , A 3 and A may be the same or different; Z 1 , Z 2 and Z 3 are each independently Z as defined in formula I, and Z 1 , Z 2 , Z 3 and Z may be the same or different; E 1 , E2 and E 3 are each independently E as defined in formula I, and E 1 , E 2 , E 3 and E are the same or different; and m, n, o, p, q, r, s, t, and u are each independently selected from 0 and 1; where L A3 , L E1-A , L E2-A , L A1-Z , L A2-Z , L E1-Z , L E2-Z , L E3 , L A1-E , L A2-E At least one of is a cleavable linker. or a pharmaceutically acceptable salt and / or solvate thereof.

[0238] In some embodiments, T is a branched group that is at least trivalent and includes at least a first terminal functional group, a second terminal functional group, and a third terminal functional group, which may be the same or different, each of which is L A2 (or alternatively T A , L A1 or A), L Z2 (or alternatively T Z , L Z1 or Z), and L E2 (or alternatively T E , L E1 or E). In an exemplary embodiment, T is lysine or DAB. In an exemplary embodiment, T is lysine. Thus, in an exemplary embodiment, the compound of formula ID is a compound of formula IE or IF: [ka]

[0239] In some embodiments, when p and r are each 0, L A1 is defined in formula I A and LZ1 is defined in formula I Z and L E1 is defined in formula I E and the compound of formula ID is the same as the compound of formula I.

[0240] In some embodiments, T A , T Z and T E are each independently a branched group that is at least trivalent and includes at least a first terminal functional group, a second terminal functional group, and a third terminal functional group, which may be the same or different, and each is represented by L A1 , L A2 and R A (or alternatively A and T), L Z1 , L Z2 and R Z (or alternatively Z and T), and L E1 , L E2 and R E (or alternatively, E and T). In some embodiments, T A , T Z and T E are each independently a branched group that is at least trivalent and includes at least a first terminal functional group, a second terminal functional group, and a third terminal functional group, which may be the same or different; L A1 , L A2 and R A (or alternatively A or T), L Z1 , L Z2 and R Z (or alternatively Z and T), and L Ed1 , L E2 and R E (or alternatively E and T), is attached to an amide group, a thiourea group, a urea group, or a thioamide group. A1 , L A2 and R A (or alternatively A or T), and L Ed1 , L E2 and R E(or alternatively, E and T), an ester group, a thioester group, a carbonate group, a carbamate group, a disulfide bond, a hydrazone group, or an oxime group, such as a ketoxime or aldoxime, is further formed. A , T Z and T E are each independently an amino acid residue derived from lysine and / or glutamine, and a trimesic acid residue [ka] In some embodiments, T A , T Z and T E are each independently selected from amino acid residues derived from lysine and / or glutamine, DAB, and TMA. A , T Z and T E are each independently selected from a lysine-derived amino acid residue and a trimesic acid residue.

[0241] In some embodiments, R A teeth [ka] and L A1 , L A2 and L A3 are each independently L as defined in formula I A In some embodiments, A 1 and A are the same. In some embodiments, A 1 and A are different.

[0242] In some embodiments, R Z teeth [ka] and L Z1 , L Z2 and L Z3 are each independently L as defined in formula I ZIn some embodiments, Z 2 and Z are the same. In some embodiments, Z 2 and Z are different.

[0243] In some embodiments, R E teeth [ka] and L E1 , L E2 and L E3 are each independently L as defined in formula I E In some embodiments, E 3 and E are the same. In some embodiments, E 3 and E are different.

[0244] In some embodiments, L A3 , L E1-A , L E2-A , L A1-Z , L A2-Z , L E1-Z , L E2-Z , L E3 , L A1-E , and L A2-E In some embodiments, one to three of L A3 , L E1-A , L E2-A , L A1-Z , L A2-Z , L E1-Z , L E2-Z , L E3 , L A1-E and L A2-E In some embodiments, one or two of the cleavable linkers comprise 1 to 3 cleavable moieties. In some embodiments, each cleavable linker comprises one or two cleavable moieties.

[0245] In some embodiments, m is 1, n and o are both 0, R A teeth [ka] and compounds of formula ID have formula IG: [ka] (In the formula, A, Z, E, and T are as defined in Formula I; L A1 , L A2 and L A3 are each independently L as defined in formula I A and; A 1 is A as defined in formula I, and A 1 and A may be the same or different; L Z1 is L as defined in formula I Z and; L E1 is L as defined in formula I E and; However, L A1 , L A2 , L A3 and L E1 At least one of the linkers is a cleavable linker. is a compound of

[0246] In some embodiments, T in the compound of formula IG A is a branched group that is at least trivalent and includes at least a first terminal functional group, a second terminal functional group, and a third terminal functional group, which may be the same or different; L A1 , L A2 and R A (or alternatively, A and / or T). In an exemplary embodiment, T in a compound of formula IG A is a lysine-derived amino acid residue or a trimesic acid residue.

[0247] In an exemplary embodiment, A in the compound of formula IG 1 and / or A are each independently unsubstituted or substituted C(O)C 12-18 alkylene COH.

[0248] In an exemplary embodiment, Z is [ka] is.

[0249] In an exemplary embodiment, E is selected from DOTA and DOTAGA.

[0250] In some embodiments, in the compound of formula IG, L A1 , L A2 , L A3 and L E1 where one or more of is a non-cleavable linker, each non-cleavable linker is independently selected from the group consisting of Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, Val, Pyl, Sec, and PCL, or a D-enantiomer thereof; one or more amino acid residues derived from DAB or DAP; [ka] R 1 NC 1-20 Alkylene NR 2 ;C(O)C 1-20 Alkylene C(O);R 1 NC 1-20 Alkylene C(O); and C(O)C 1-20 Alkylene NR 2 the latter four groups optionally being selected from S, O, C(O)NH, NHC(O), C 4-6 Cycloalkyl and C 4-6 interrupted by one or more of heterocycloalkyl, where each R 1 and R 2 is H and C 1-2 In some embodiments, L in the compound of formula IG is independently selected from alkyl. A1 , L A2 , L A3 , and L E1is a non-cleavable linker, each non-cleavable linker independently comprises one or more amino acid residues derived from Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, Val, Pyl, Sec, or PCL, or their D enantiomers; [ka] The compound includes one or more groups selected from the group consisting of:

[0251] In some embodiments, L in the compound of formula IG A1 , L A2 , LA3 and L E1 is independently a cleavable linker, each cleavable linker independently optionally containing one or more amino acid residues derived from Gly, Glu, Leu, Phe, Tyr, or Lys, or their D enantiomers; one or more amino acid residues derived from DAP or DAB; R 5 NC 1-20 Alkylene NR 6 and optionally interrupted by one or more O, R 5 NC 1-20 alkylene C(O); and at least one R optionally interrupted by one or more of S-S, C(O)O, OC(O), O, C(O)NH, and NHC(O); 5 NC 1-20 Alkylene C(O) (where R 5 NC 1-20 alkylene C(O) is interrupted by at least one of S-S, C(O)O and O-C(O); or C(O)C 1-10 Alkylene O or OC 1-10 at least one amino acid residue linked to an alkylene C(O) to form a cleavable moiety selected from C(O)O and OC(O); or an enzymatically cleavable peptide sequence selected from Met-Val-Lys, Ala-Val, Ala-Pro, Gly-Pro, Ser-Ser, Ser-Gly, Gly-Ala and Ser-Lys.

[0252] In some embodiments, L in the compound of formula IG A1 , L A2 , L A3 and L E1 one or more of are independently a cleavable linker, each cleavable linker independently optionally containing amino acid residues derived from Glu, Lys, Phe, Tyr and their D enantiomers; [ka] and an enzymatically cleavable peptide sequence selected from Met-Val-Lys, Ala-Val, Ala-Pro, Gly-Pro, Ser-Ser, Ser-Gly, Gly-Ala and Ser-Lys.

[0253] In some embodiments, L in the compound of formula IG A1 , L A2 , L A3 and L E1 is a cleavable linker, and each independently one or more of [ka] and an enzymatically cleavable peptide sequence selected from Met-Val-Lys, Ala-Val, Ala-Pro, Gly-Pro, Ser-Ser, Ser-Gly, Gly-Ala and Ser-Lys.

[0254] In some embodiments, L in the compound of formula IG A1 , L A2 , L A3 and L E1one or more of [ka] The compound includes at least one group selected from the group consisting of:

[0255] In some embodiments, L in the compound of formula IG A1 , L A2 , L A3 and L E1 wherein one or more of the amino acids are enzymatically cleavable peptide sequences independently selected from Met-Val-Lys, Ala-Val, Ala-Pro, Gly-Pro, Ser-Ser, Ser-Gly, Gly-Ala, and Ser-Lys.

[0256] In some embodiments, L in the compound of formula IG A1 , L A2 , L A3 and L E1 one or more of the following are cleavable linkers, each independently consisting of one or more amino acid residues derived from Gly, Glu, Leu, Phe, Tyr, or Lys or their D enantiomers; one or more amino acid residues derived from DAP and DAB; R 5 NC 1-20 Alkylene NR 6 ; optionally interrupted by one or more O, R 5 NC 1-20 Alkylene C(O); and C(O)C 1-10 Alkylene O or OC 1-10 at least one amino acid residue linked to an alkylene C(O) to form a cleavable moiety selected from C(O)O and OC(O).

[0257] In some embodiments, L in the compound of formula IG Z1 teeth, [ka] is a non-cleavable linker comprising one or more groups selected from:

[0258] In some embodiments, A in the compound of formula IG 1 and A are both the same. In some embodiments, L in the compound of formula IG A1 and L A3 are both the same, and A 1 and A are both the same.

[0259] In some embodiments, L in the compound of formula IG A1 , L A2 and L A3 are each independently a direct bond or a non-cleavable linker, and L in the compound of formula IG E1 is a cleavable linker. In some embodiments, L A1 and L A3 are each independently a direct bond or a non-cleavable linker, and L A2 is a cleavable linker, and L E1 is a direct bond or a non-cleavable linker. In some embodiments, L A1 and L A3 are each independently a cleavable linker, and L A2 is a direct bond or a non-cleavable linker, and L E1 is a direct bond or a non-cleavable linker. In some embodiments, L A1 and L A3 are both the same.

[0260] In some embodiments, n is 1, m and o are both 0, R Z teeth [ka] and the compound of formula ID is represented by formula IH: [ka] (In the formula, A, Z, E, and T are as defined in Formula I; Z 3is Z as defined in formula I, which may be the same or different; L A1 is L as defined in formula I A and; L Z1 , L Z2 and L Z3 are each independently L as defined in formula I Z and; L E1 is L as defined in formula I E and; However, L A1 and L E1 At least one of the following is a cleavable linker: is a compound of

[0261] In some embodiments, T in the compound of formula IH Z is a branched group that is at least trivalent and includes at least a first terminal functional group, a second terminal functional group, and a third terminal functional group, which may be the same or different; L Z1 (or alternatively Z), L Z2 (or alternatively T) and Z 3 In an exemplary embodiment, T Z is a lysine-derived amino acid residue or acid residue. Z is a trimesic acid residue.

[0262] In an exemplary embodiment, Z and / or Z 3 teeth, [ka] is.

[0263] In an exemplary embodiment, E is selected from DOTA and DOTAGA.

[0264] In an exemplary embodiment, A in the compound of formula IH is unsubstituted or substituted C(O)C 12-18 alkylene COH.

[0265] In some embodiments, L in the compound of formula IH A1 and L E1 one of which is a non-cleavable linker, and the non-cleavable linker is selected from the group consisting of one or more amino acid residues derived from Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, Val, Pyl, Sec, or PCL or their D enantiomers; one or more amino acid residues derived from DAB or DAP; OEG, R 1 NC 1-20 Alkylene NR 2 , C(O)C 1-20 Alkylene C(O), R 1 NC 1-20 Alkylene C(O) and C(O)C 1-20 Alkylene NR 2 (where each R 1 and R 2 are independently H and C 1-2 In some embodiments, L in the compound of formula IH comprises one or more groups selected from: A1 and L E1 one of which is a non-cleavable linker, the non-cleavable linker being one or more amino acid residues derived from Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, Val, Pyl, Sec, PCL and their D enantiomers; [ka] The compound includes one or more groups selected from the group consisting of:

[0266] In some embodiments, L in the compound of formula IH A1 and L E1 one of which is a non-cleavable linker, the non-cleavable linker being an amino acid residue derived from Glu, [ka] and the other is a direct bond. A1 and L E1 are each independently a non-cleavable linker, and the non-cleavable linker is an amino acid residue derived from Glu and [ka] In some embodiments, L A1 and L E1 are the same. In some embodiments, L A1 and L E1 is two or more [ka] Includes:

[0267] In some embodiments, L in the compound of formula IH A1 and / or L E1 is independently a cleavable linker, each cleavable linker independently optionally containing one or more amino acid residues derived from Gly, Glu, Leu, Phe, Tyr, or Lys or their D enantiomers; one or more amino acid residues derived from DAP or DAB; R 5 NC 1-20 Alkylene NR 6 and optionally interrupted by one or more O, R 5 NC 1-20 alkylene C(O); and at least one R optionally interrupted by one or more of S-S, C(O)O, OC(O), O, C(O)NH, and NHC(O); 5 NC 1-20 Alkylene C(O) (where R 5 NC 1-20 alkylene C(O) is interrupted by at least one of S-S, C(O)O and O-C(O); or C(O)C 1-10 Alkylene O or OC 1-10at least one amino acid residue linked to an alkylene C(O) to form a cleavable moiety selected from C(O)O and OC(O); or an enzymatically cleavable peptide sequence selected from Met-Val-Lys, Ala-Val, Ala-Pro, Gly-Pro, Ser-Ser, Ser-Gly, Gly-Ala and Ser-Lys.

[0268] In some embodiments, L in the compound of formula IH A1 and / or L E1 is independently a cleavable linker, each cleavable linker independently optionally containing amino acid residues derived from Glu, Lys, Phe, Tyr, and their D enantiomers; [ka] and an enzymatically cleavable peptide sequence selected from Met-Val-Lys, Ala-Val, Ala-Pro, Gly-Pro, Ser-Ser, Ser-Gly, Gly-Ala and Ser-Lys.

[0269] In some embodiments, L in the compound of formula IH E1 is a cleavable linker, and the cleavable linker is one or more [ka] and an enzymatically cleavable peptide sequence selected from Met-Val-Lys, Ala-Val, Ala-Pro, Gly-Pro, Ser-Ser, Ser-Gly, Gly-Ala and Ser-Lys.

[0270] In some embodiments, L in the compound of formula IH Z1 and / or L Z3 are each independently, [ka] In some embodiments, L is a non-cleavable linker comprising one or more groups selected from Z1 and L Z3 In some embodiments, L Z1 and / or L Z3 are each independently, [ka] In some embodiments, L further comprises one or more groups selected from Z1 and / or L Z3 are each independently one or more [ka] In some embodiments, L Z1 and L Z3 are both the same.

[0271] In some embodiments, L in the compound of formula IH Z2 teeth, [ka] is a non-cleavable linker comprising one or more groups selected from:

[0272] In some embodiments, L A1 is a direct bond or a non-cleavable linker, and L E1 is a cleavable linker. In some embodiments, L A1 is a cleavable linker, and L E1 is a direct bond or a non-cleavable linker. In some embodiments, L Z1 and L Z3 are both the same non-cleavable linker.

[0273] In some embodiments, Z in the compound of formula IH 2 and Z are both the same. In some embodiments, L in the compound of formula IH Z1 and L Z3are the same for both, and Z 1 and Z are both the same.

[0274] In some embodiments, o is 1, m and n are both 0, R E teeth [ka] The compound of formula ID is represented by formula II: [ka] (In the formula, A, Z, E, and T are as defined in Formula I; E 3 is E as defined in formula I, and E 3 and E may be the same or different; L A1 is L as defined in formula I A and; L E1 , L E2 and L E3 are each independently L as defined in formula I E and; L A1 is L as defined in formula I A and; L Z1 is L as defined in formula I Z is However, L E1 , L E2 , and L E3 and L A1 At least one of is a cleavable linker. is a compound of

[0275] In some embodiments, T in the compound of formula II E is a branched group that is at least trivalent and includes at least a first terminal functional group, a second terminal functional group, and a third terminal functional group, which may be the same or different; L E1 (or alternatively E), L E2 (or alternatively T), and L E3In an exemplary embodiment, T in a compound of Formula II E is a lysine-derived amino acid residue or a trimesic acid residue.

[0276] In an exemplary embodiment, Z is [ka] is.

[0277] In an exemplary embodiment, E and / or E 3 are each independently selected from DOTA and DOTAGA.

[0278] In an exemplary embodiment, A in the compound of Formula II is unsubstituted or substituted C(O)C 12-18 alkylene COH.

[0279] In some embodiments, L in the compound of formula II E1 , L E2 and L E3 is a non-cleavable linker, each of the non-cleavable linkers is independently selected from the group consisting of Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, Val, Pyl, Sec, and PCL, or a D enantiomer thereof; one or more amino acid residues derived from DAB or DAP; [ka] R 1 NC 1-20 Alkylene NR 2 ;C(O)C 1-20 Alkylene C(O);R 1 NC 1-20 Alkylene C(O); and C(O)C 1-20 Alkylene NR 2 wherein the latter four groups are optionally selected from S, O, C(O)NH, NHC(O), C 4-6 Cycloalkyl and C 4-6wherein each R is interrupted by one or more of heterocycloalkyl; 1 and R 2 are independently H and C 1-2 In some embodiments, L in the compound of Formula II is selected from alkyl. E1 , L E2 and L E3 is a non-cleavable linker, each of the non-cleavable linkers independently comprises one or more amino acid residues derived from Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, Val, Pyl, Sec, PCL, and their D enantiomers; [ka] The compound includes one or more groups selected from the group consisting of:

[0280] In some embodiments, L in the compound of formula IG E1 , L E2 and L E3 is a non-cleavable linker, each non-cleavable linker independently comprises one or more amino acid residues derived from Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, Val, Pyl, Sec, PCL, and their D enantiomers; [ka] The compound includes one or more groups selected from the group consisting of:

[0281] In some embodiments, L in the compound of formula IG E1 and L E3 are each independently a non-cleavable linker, and each non-cleavable linker independently comprises an amino acid residue derived from Glu, [ka] and L E2is a direct bond. In some embodiments, L E1 and L E3 are each independently a non-cleavable linker, and each non-cleavable linker independently comprises an amino acid residue derived from Glu and [ka] and L E3 is a direct bond or one or more [ka] In some embodiments, L E1 and L E3 are each independently two or more [ka] Includes:

[0282] In some embodiments, L in the compound of formula II E1 , L E2 , L E3 and L A1 is independently a cleavable linker, each cleavable linker independently optionally containing one or more amino acid residues derived from Gly, Glu, Leu, Phe, Tyr, or Lys, or their D enantiomers; one or more amino acid residues derived from DAP or DAB; R 5 NC 1-20 Alkylene NR 6 and optionally interrupted by one or more O, R 5 NC 1-20 alkylene C(O); and at least one R optionally interrupted by one or more of S-S, C(O)O, OC(O), O, C(O)NH, and NHC(O); 5 NC 1-20 Alkylene C(O) (where R 5 NC 1-20 alkylene C(O) is interrupted by at least one of S-S, C(O)O and O-C(O); or C(O)C 1-10 Alkylene O or OC 1-10 at least one amino acid residue linked to an alkylene C(O) to form a cleavable moiety selected from C(O)O and OC(O); or an enzymatically cleavable peptide sequence selected from Met-Val-Lys, Ala-Val, Ala-Pro, Gly-Pro, Ser-Ser, Ser-Gly, Gly-Ala and Ser-Lys.

[0283] In some embodiments, L in the compound of formula II E1 , L E2 , L E3 and L A1 one or more of are independently a cleavable linker, each cleavable linker independently optionally containing amino acid residues derived from Glu, Lys, Phe, Tyr and their D enantiomers; [ka] and an enzymatically cleavable peptide sequence selected from Met-Val-Lys, Ala-Val, Ala-Pro, Gly-Pro, Ser-Ser, Ser-Gly, Gly-Ala and Ser-Lys.

[0284] In some embodiments, L in the compound of formula II A1 is a cleavable linker, and the cleavable linker is one or more [ka] and an enzymatically cleavable peptide sequence selected from Met-Val-Lys, Ala-Val, Ala-Pro, Gly-Pro, Ser-Ser, Ser-Gly, Gly-Ala and Ser-Lys.

[0285] In some embodiments, L in the compound of formula IIZ1 is a direct bond, or [ka] is a non-cleavable linker comprising one or more groups selected from:

[0286] In some embodiments, L in the compound of formula IG E1 , L E2 and L E3 are each independently a direct bond or a non-cleavable linker, and L in the compound of formula II A1 is L in formula I A In some embodiments, L E1 and L E3 are each independently a direct bond or a non-cleavable linker, and L E2 is L in formula I A and L is a cleavable linker defined in A1 is a direct bond or a non-cleavable linker. In some embodiments, L E1 and L E3 are each independently a cleavable linker, and L E2 is L in formula I A and L is a direct bond or non-cleavable linker as defined for A1 is a direct bond or a non-cleavable linker. In some embodiments, L E1 and L E3 are both the same.

[0287] In some embodiments, E in the compound of formula II 3 and E are both the same. In some embodiments, L in the compound of formula II E1 and L E3 are both the same, E 3 and E are both the same.

[0288] In some embodiments, m is 1, n and o are both 0, R A teeth [ka] where q and p are 0, and the compound of formula ID is of formula IJ: [ka] (In the formula, A, Z, T, and E are as defined in Formula I; E 1 is E as defined in formula I, and E 1 and E may be the same or different; Z 1 is Z as defined in formula I, and Z 1 and Z may be the same or different; L A1 , L A2 and L A3 are each independently L as defined in formula I A and; T A and T A1 are each independently T as defined in formula I, and T A , T A1 and T may be the same or different; L Z1 and L Z1-A are each independently L as defined in formula I Z and; L E1 and L E1-A are each independently L as defined in formula I E and; However, L A1 , L A2 , L A3 , L E1 and L E1-A At least one of the following is a cleavable linker: is a compound of

[0289] In some embodiments, T, T A and T A1are branched groups that are at least trivalent and include at least a first terminal functional group, a second terminal functional group, and a third terminal functional group, which may be the same or different, and each of L A2 (or alternatively T A ), L Z1 (or alternatively Z), and L E1 (or alternatively E), L A1 (or alternatively A), L A2 (or alternatively T) and L A3 (or alternatively T A1 ) and L A3 (or alternatively T A ), L Z1-A (or alternatively Z 1 ) and L E1-A (or alternatively E 1 In some embodiments, T, T A , and T A1 are each independently selected from an amino acid residue derived from lysine or glutamine, and a trimesic acid residue.

[0290] In an exemplary embodiment, A in the compound of formula IJ is unsubstituted or substituted C(O)C 12-18 alkylene COH.

[0291] In an exemplary embodiment, Z in the compound of formula IJ 1 and / or Z [ka] is.

[0292] In an exemplary embodiment, E of the compound of formula IJ 1 and / or E is selected from DOTA and DOTAGA.

[0293] In some embodiments, any L in the compound of formula IJ A1 , L A2 , L A3 , L E1 and L E1-Ais a non-cleavable linker, each non-cleavable linker is independently selected from the group consisting of Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, Val, Pyl, Sec, or PCL, or a D enantiomer thereof; one or more amino acid residues derived from DAB or DAP; [ka] R 1 NC 1-20 Alkylene NR 2 ;C(O)C 1-20 Alkylene C(O);R 1 NC 1-20 Alkylene C(O); and C(O)C 1-20 Alkylene NR 2 wherein the latter four groups are optionally selected from S, O, C(O)NH, NHC(O), C 4-6 Cycloalkyl and C 4-6 wherein each R is interrupted by one or more of heterocycloalkyl; 1 and R 2 are independently H and C 1-2 In some embodiments, any L in a compound of formula IJ is selected from alkyl. A1 , L A2 , L A3 , L E1 and L E1-A is a non-cleavable linker, each non-cleavable linker independently comprises one or more amino acid residues derived from Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, Val, Pyl, Sec, PCL and their D enantiomers; [ka] The compound includes one or more groups selected from the group consisting of:

[0294] In some embodiments, any L in the compound of formula IJ A1 , L A2 , LA3 , L E1 and L E1-A is a non-cleavable linker, each non-cleavable linker independently comprises one or more amino acid residues derived from Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, Val, Pyl, Sec, PCL and their D enantiomers; [ka] The compound includes one or more groups selected from the group consisting of:

[0295] In some embodiments, any L in the compound of formula IJ A1 , L A2 , L A3 , L E1 and L E1-A is a non-cleavable linker, each non-cleavable linker independently comprises an amino acid residue derived from Glu, [ka] In some embodiments, any L in the compound of formula IJ comprises one or more groups selected from A1 , L A2 , L A3 , L E1 and L E1-A is a non-cleavable linker, each non-cleavable linker independently comprises an amino acid residue derived from Glu, and [ka] The compound includes one or more groups selected from the group consisting of:

[0296] In some embodiments, L in the compound of formula IJ A1 , L A2 , L A3 , L E1 and L E1-Ais independently a cleavable linker, each cleavable linker independently optionally containing one or more amino acid residues derived from Gly, Glu, Leu, Phe, Tyr, or Lys, or their D enantiomers; one or more amino acid residues derived from DAP and DAB; R 5 NC 1-20 Alkylene NR 6 and optionally interrupted by one or more O, R 5 NC 1-20 alkylene C(O); and at least one R optionally interrupted by one or more of S-S, C(O)O, OC(O), O, C(O)NH, and NHC(O); 5 NC 1-20 Alkylene C(O) (where R 5 NC 1-20 alkylene C(O) is interrupted by at least one of S-S, C(O)O and O-C(O); or C(O)C 1-10 Alkylene O or OC 1-10 at least one amino acid residue linked to an alkylene C(O) to form a cleavable moiety selected from C(O)O and OC(O); or enzymatically cleavable peptide sequences selected from Met-Val-Lys, Ala-Val, Ala-Pro, Gly-Pro, Ser-Ser, Ser-Gly, Gly-Ala and Ser-Lys.

[0297] In some embodiments, L in the compound of formula IJ A1 , L A2 , L A3 , L E1 and L E1-A is independently a cleavable linker, and each cleavable linker independently comprises: [ka] and an enzymatically cleavable peptide sequence selected from Met-Val-Lys, Ala-Val, Ala-Pro, Gly-Pro, Ser-Ser, Ser-Gly, Gly-Ala and Ser-Lys, and optionally amino acid residues derived from Glu, Lys, Phe, Tyr and their D enantiomers; [ka] The compound includes one or more groups selected from the group consisting of:

[0298] In some embodiments, L in the compound of formula IJ A1 , L A2 , L A3 , L E1 and L E1-A is independently a cleavable linker, and each cleavable linker independently optionally comprises one or more [ka] and an enzymatically cleavable peptide sequence selected from Met-Val-Lys, Ala-Val, Ala-Pro, Gly-Pro, Ser-Ser, Ser-Gly, Gly-Ala and Ser-Lys.

[0299] In some embodiments, L in the compound of formula IJ A1 , L A2 , L A3 , L E1 and / or L E1-A one or more of are independently cleavable linkers, and each cleavable linker independently comprises one or more [ka] Further includes:

[0300] In some embodiments, L in the compound of formula IJ Z1 and L Z1-A are each independently, [ka] is a non-cleavable linker comprising one or more groups selected from:

[0301] In some embodiments, L E1 , L E1-A , L A1 , L Z1 and L Z1-A are each independently a direct bond or a non-cleavable linker, and L A2 and L A3 are each independently a cleavable linker. In some embodiments, L E1 , L E1-A , L A1 , L Z1 and L Z1-A are each independently a direct bond or a non-cleavable linker, and L A2 and L A3 In some embodiments, one of L is a non-cleavable linker and the other is a cleavable linker. A1 is a cleavable linker, and L E1 , L E1-A , L Z1 , L Z1-A , L A2 and L A3 are each independently a direct bond or a non-cleavable linker. A2 and L A3 In some embodiments, L Z1 and L Z1-A In some embodiments, L E1 and L E1-A are both the same.

[0302] In some embodiments, o is 1, n and m are both 0, R E teeth [ka] where t and u are 0, and the compound of formula ID is of formula IK: [ka] (In the formula, A, Z, T, and E are as defined in Formula I; A 3 is A as defined in formula I, and A 3 and A may be the same or different; Z 3 is Z as defined in formula I, and Z 3 and Z may be the same or different; L A1 and L A1-E are each independently L as defined in formula I A and; T E and T E1 are each independently T as defined in Formula I, and T, T E , T E1 are the same or different; L Z1 and L Z1-E are each independently L as defined in formula I Z and; L E1 , L E2 and L E3 are each independently L as defined in formula I E and; However, L E1 , L E2 , L E3 , L A1 , L A1-E At least one of the following is a cleavable linker: is a compound of

[0303] In some embodiments, T, T E , and T E1 each of L is a branched group that is at least trivalent and includes at least a first terminal functional group, a second terminal functional group, and a third terminal functional group, which may be the same or different; A1 (or alternatively A), L Z1 (or alternatively Z) and L E2 (or alternatively T E) to L E1 (or alternatively E), L E2 (or alternatively T) and L A3 (or alternatively T E1 ) and L E3 (or alternatively T E ), L A1-E (or alternatively A 3 ) and L Z1-2 (or alternatively Z 3 In some embodiments, T, T E , and T E1 are each independently selected from an amino acid residue derived from lysine or glutamine, and a trimesic acid residue.

[0304] In an exemplary embodiment, A and / or A in the compound of formula IK 3 is unsubstituted or substituted C(O)C 12-18 alkylene COH.

[0305] In an exemplary embodiment, Z in the compound of formula IK 3 and / or Z [ka] is.

[0306] In an exemplary embodiment, E in the compound of formula IK is selected from DOTA and DOTAGA.

[0307] In some embodiments, any L in the compound of formula IK E1 , L E2 , L E3 , L A1 and L A1-E is a non-cleavable linker, each non-cleavable linker independently comprises one or more amino acid residues derived from Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, Val, Pyl, Sec, PCL, and their D enantiomers; [ka] The compound includes one or more groups selected from the group consisting of:

[0308] In some embodiments, any L in the compound of formula IK E1 , L E2 , L E3 , L A1 and L A1-E is a non-cleavable linker, each non-cleavable linker is independently selected from the group consisting of Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, Val, Pyl, Sec, and PCL, or a D enantiomer thereof; one or more amino acid residues derived from DAB or DAP; [ka] R 1 NC 1-20 Alkylene NR 2 ;C(O)C 1-20 Alkylene C(O);R 1 NC 1-20 Alkylene C(O); and C(O)C 1-20 Alkylene NR 2 wherein the latter four groups are optionally selected from S, O, C(O)NH, NHC(O), C 4-6 Cycloalkyl and C 4-6 interrupted by one or more of heterocycloalkyl, where each R 1 and R 2 are independently H and C 1-2 In some embodiments, any L in a compound of formula IK is selected from alkyl. E1 , L E2 , L E3 , L A1 and L A1-Eis a non-cleavable linker, each non-cleavable linker independently comprises one or more amino acid residues derived from Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, Val, Pyl, Sec, PCL, and their D enantiomers; [ka] The compound includes one or more groups selected from the group consisting of:

[0309] In some embodiments, any L in the compound of formula IK E1 , L E2 , L E3 , L A1 and L A1-E is a non-cleavable linker, each non-cleavable linker independently comprises an amino acid residue derived from Glu, [ka] In some embodiments, any L in the compound of formula IK comprises one or more groups selected from E1 , L E2 , L E3 , L A1 and L A1-E is a non-cleavable linker, each non-cleavable linker independently comprises an amino acid residue derived from Glu, and [ka] The compound includes one or more groups selected from the group consisting of:

[0310] In some embodiments, in the compound of formula IK, L E1 , L E2 , L E3 , L A1 and L A1-Eone or more of the cleavable linkers are independently cleavable linkers, each cleavable linker independently containing one or more amino acid residues derived from Gly, Glu, Leu, Phe, Tyr, or Lys, or their D enantiomers; one or more amino acid residues derived from DAP and DAB; R 5 NC 1-20 Alkylene NR 6 and optionally interrupted by one or more O, R 5 NC 1-20 alkylene C(O); and at least one R optionally interrupted by one or more of S-S, C(O)O, OC(O), O, C(O)NH, and NHC(O); 5 NC 1-20 Alkylene C(O) (where R 5 NC 1-20 alkylene C(O) is interrupted by at least one of S-S, C(O)O and O-C(O); or C(O)C 1-10 Alkylene O or OC 1-10 at least one amino acid residue linked to an alkylene C(O) to form a cleavable moiety selected from C(O)O and OC(O); or an enzymatically cleavable peptide sequence selected from Met-Val-Lys, Ala-Val, Ala-Pro, Gly-Pro, Ser-Ser, Ser-Gly, Gly-Ala and Ser-Lys.

[0311] In some embodiments, L in the compound of formula IK E1 , L E2 , L E3 , L A1 and L A1-E is independently a cleavable linker, and each cleavable linker independently comprises: [ka] and enzymatically cleavable peptide sequences selected from Met-Val-Lys, Ala-Val, Ala-Pro, Gly-Pro, Ser-Ser, Ser-Gly, Gly-Ala and Ser-Lys, and optionally amino acid residues derived from Glu, Lys, Phe, Tyr and their D enantiomers; [ka] The compound includes one or more groups selected from the group consisting of:

[0312] In some embodiments, L in the compound of formula IK E1 , L E2 , L E3 , L A1 and L A1-E is independently a cleavable linker, and each cleavable linker independently optionally comprises one or more [ka] and an enzymatically cleavable peptide sequence selected from Met-Val-Lys, Ala-Val, Ala-Pro, Gly-Pro, Ser-Ser, Ser-Gly, Gly-Ala and Ser-Lys.

[0313] In some embodiments, L in the compound of formula IK E1 , L E2 , L E3 , L A1 and L A1-E is a cleavable linker, and each cleavable linker optionally comprises one or more [ka] Further includes:

[0314] In some embodiments, L in the compound of formula IK Z1 and L Z1-E are each independently, [ka] is a non-cleavable linker comprising one or more groups selected from:

[0315] In some embodiments, L A1 , L A1-E , L E1 , L Z1 and L Z1-E are each independently a direct bond or a non-cleavable linker, and L E2 and L E3 are each independently a cleavable linker. In some embodiments, L A1 , L A1-E , L E1 , L Z1 and L Z1-E are each independently a direct bond or a non-cleavable linker, and L E2 and L E3 In some embodiments, one of L is a non-cleavable linker and the other is a cleavable linker. E1 is a cleavable linker, and L A1 , L A1-E , L Z1 , L Z1-E , L E2 and L E3 are each independently a direct bond or a non-cleavable linker. E2 and L E3 In some embodiments, L Z1 and L Z1-E In some embodiments, L A1 and L A1-E are both the same.

[0316] In some embodiments, n is 1, m and o are both 0, R Z teeth [ka] where r and s are 0, and the compound of formula ID is of formula IL: [ka] (In the formula, A, Z, T, and E are as defined in Formula I; A 2 is A as defined in formula I, and A 2 and A may be the same or different; E 2 is E as defined in formula I, and E 2 and E may be the same or different; L A1 and L A1-Z are each independently L as defined in formula I A and; T Z and T Z1 are each independently T as defined in Formula I, and T, T Z , T Z1 are the same or different; L A1 and L A1-Z are each independently L as defined in formula I E and; L E1 and L E1-Z are each independently L as defined in formula I E and; L Z1 , L Z2 and L Z3 are each independently L as defined in formula I Z is However, L A1 , L A1-Z , L E1 and L E1-Z At least one of the linkers is a cleavable linker. is a compound of

[0317] In some embodiments, T, T Z , and T Z1 each of L is a branched group that is at least trivalent and includes at least a first terminal functional group, a second terminal functional group, and a third terminal functional group, which may be the same or different; A1(or alternatively A), L E1 (or alternatively E) and L Z2 (or alternatively T Z ) to L Z1 (or alternatively Z), L Z2 (or alternatively T) and L Z3 (or alternatively T Z1 ) and L Z3 (or alternatively T Z ), L A1-Z (or alternatively A 2 ) and L E1-Z (or alternatively E 2 In some embodiments, T, T Z , and T Z1 are each independently selected from an amino acid residue derived from lysine or glutamine, and a trimesic acid residue.

[0318] In an exemplary embodiment, A and / or A in the compound of formula IL 2 are independently unsubstituted or substituted C(O)C 12-18 alkylene COH.

[0319] In an exemplary embodiment, Z in the compound of formula IL is [ka] is.

[0320] In an exemplary embodiment, E and / or E of the compound of formula IL 2 is selected from DOTA and DOTAGA.

[0321] In some embodiments, any L in the compound of formula IL A1 , L A1-Z , L E1 and L E1-Zis a non-cleavable linker, each non-cleavable linker is independently selected from the group consisting of Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, Val, Pyl, Sec, or PCL, or a D enantiomer thereof; one or more amino acid residues derived from DAB or DAP; [ka] R 1 NC 1-20 Alkylene NR 2 ;C(O)C 1-20 Alkylene C(O);R 1 NC 1-20 Alkylene C(O); and C(O)C 1-20 Alkylene NR 2 wherein the latter four groups are optionally selected from S, O, C(O)NH, NHC(O), C 4-6 Cycloalkyl and C 4-6 interrupted by one or more of heterocycloalkyl, where each R 1 and R 2 are independently H and C 1-2 In some embodiments, any L in a compound of formula IL is selected from alkyl. A1 , L A1-Z , L E1 and L E1-Z is a non-cleavable linker, each non-cleavable linker independently comprises one or more amino acid residues derived from Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, Val, Pyl, Sec, PCL and their D enantiomers; [ka] The compound includes one or more groups selected from the group consisting of:

[0322] In some embodiments, any L in the compound of formula IL A1 , L A1-Z , L E1and L E1-Z is a non-cleavable linker, each non-cleavable linker independently comprises one or more amino acid residues derived from Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, Val, Pyl, Sec, PCL and their D enantiomers; [ka] The compound includes one or more groups selected from the group consisting of:

[0323] In some embodiments, any L in the compound of formula IL A1 , L A1-Z , L E1 and L E1-Z is a non-cleavable linker, each non-cleavable linker independently comprises an amino acid residue derived from Glu, [ka] In some embodiments, any L in a compound of formula IL comprises one or more groups selected from A1 , L A1-Z , L E1 and L E1-Z is a non-cleavable linker, each non-cleavable linker independently comprises an amino acid residue derived from Glu, and [ka] The compound includes one or more groups selected from the group consisting of:

[0324] In some embodiments, L in the compound of formula IL A1 , L A1-Z , L E1 and L E1-Z one or more of the cleavable linkers are independently cleavable linkers, each cleavable linker independently comprising one or more amino acid residues derived from Gly, Glu, Leu, Phe, Tyr, or Lys, or their D enantiomers; one or more amino acid residues derived from DAP and DAB; R 5 NC 1-20 Alkylene NR6 and optionally interrupted by one or more O, R 5 NC 1-20 alkylene C(O); and at least one R optionally interrupted by one or more of S-S, C(O)O, OC(O), O, C(O)NH, and NHC(O); 5 NC 1-20 Alkylene C(O) (where R 5 NC 1-20 alkylene C(O) is interrupted by at least one of S-S, C(O)O and O-C(O); or C(O)C 1-10 Alkylene O or OC 1-10 at least one amino acid residue linked to an alkylene C(O) to form a cleavable moiety selected from C(O)O and OC(O); or an enzymatically cleavable peptide sequence selected from Met-Val-Lys, Ala-Val, Ala-Pro, Gly-Pro, Ser-Ser, Ser-Gly, Gly-Ala and Ser-Lys.

[0325] In some embodiments, L in the compound of formula IL A1 , L A1-Z , L E1 and L E1-Z is independently a cleavable linker, and each cleavable linker independently comprises: [ka] and enzymatically cleavable peptide sequences selected from Met-Val-Lys, Ala-Val, Ala-Pro, Gly-Pro, Ser-Ser, Ser-Gly, Gly-Ala and Ser-Lys, and optionally amino acid residues derived from Glu, Lys, Phe, Tyr and their D enantiomers; [ka] The compound includes one or more groups selected from the group consisting of:

[0326] In some embodiments, L in the compound of formula IL A1 , L A1-Z , L E1 and L E1-Z is independently a cleavable linker, and each cleavable linker independently optionally comprises one or more [ka] and an enzymatically cleavable peptide sequence selected from Met-Val-Lys, Ala-Val, Ala-Pro, Gly-Pro, Ser-Ser, Ser-Gly, Gly-Ala and Ser-Lys.

[0327] In some embodiments, L in the compound of formula IL A1 , L A1-Z , L E1 and L E1-Z is a cleavable linker, and each cleavable linker independently comprises one or more [ka] Further includes:

[0328] In some embodiments, L in the compound of formula IL Z1 , L Z2 and L Z3 are each independently, [ka] In some embodiments, L in the compound of formula IL is a non-cleavable linker comprising one or more groups selected from Z2 and L Z3 are each independently, [ka] In some embodiments, L in the compound of formula IL is a non-cleavable linker comprising one or more groups selected fromZ1 are each independently, [ka] is a non-cleavable linker comprising one or more groups selected from:

[0329] In some embodiments, L Z1 , L Z2 , L Z3 , L E1 and L E1-Z are each independently a direct bond or a non-cleavable linker, and L A1 and L A1-Z are each independently a cleavable linker. In some embodiments, L Z1 , L Z2 , L Z3 , L E1 and L E1-Z are each independently a direct bond or a non-cleavable linker, and L A1 and L A1-Z In some embodiments, one of L is a non-cleavable linker and the other is a cleavable linker. Z1 , L Z2 , L Z3 , L A1 and L A1-Z are each independently a direct bond or a non-cleavable linker, and L E1 and L E1-Z are each independently a cleavable linker. In some embodiments, L Z1 , L Z2 , L Z3 , L A1 and L A1-Z are each independently a direct bond or a non-cleavable linker, and L E1 and L E1-Z In some embodiments, one of L is a non-cleavable linker and the other is a cleavable linker. Z2 and L Z3 In some embodiments, L E1 and L E1-Z In some embodiments, L A1 and L A1-Zare both the same.

[0330] In some embodiments, the compound of formula I is selected from the following list of compounds or a pharmaceutically acceptable salt and / or solvate thereof: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16] [Table 1-17] [Table 1-18] [Table 1-19] [Table 1-20] [Table 1-21]

[0331] The chelating group is capable of complexing a radionuclide. Thus, in some embodiments, the compound of Formula I further comprises a radioisotope complexed to the chelating group.

[0332] Thus, the present application also includes radionuclide complexes, or pharmaceutically acceptable salts and / or solvates thereof, comprising a compound of the present application, or a pharmaceutically acceptable salt and / or solvate thereof, and one or more radionuclides.

[0333] In some embodiments, the one or more radionuclides are radioactive isotopes of C, N, F, S, Br, Ru, Tc, Ga, In, Zn, Gd, Bi, At, Cu, Pb, Fe, Ti, F, I, Y, Sr, Ra, P, Re, Sc, Zr, Rh, Pt, Rb, Au, Sn, Tl, Co, Pm, a lanthanide, or an actinide.

[0334] In some embodiments, the lanthanide is Lu, Sm, Ho, or Tb.

[0335] In some embodiments, the actinide is Ac or Th.

[0336] In some embodiments, the one or more radionuclides are 14 C. 15 N, 18 F, 75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I, 131 I, 35 S, 99 Tc, 99m Tc, 188 Re, 186 Re, 153 Sm, 67 Ga, 68 Ga, 111 In, 59 Fe, 63 Zn, 52 Fe, 45 Ti, 60 Cu, 61 Cu, 67 Cu, 64 Cu, 62 Cu, 82 Rb, 195m Pt, 191m Pt, 193m Pt, 117m Sn, 89 Zr, 177 Lu, 18 F, 123 I, 188 Re, 186 Re, 153 Sm, 66 Ho, 86 Y, 87 Y, 90 Y, 89 Sr, 111 In, 153 Gd, 225 Ac, 212 Bi, 213 Bi, 211 At, 198 Au, 199 Au, 193m Pt, 197 Pt, 103 Pd, 109 Pd, 105 Rh, 103m Rh, 223 Ra, 224 Ra, 97Ru, 227 Th, 229 Th, 32 P, 161 Tb, 33 P, 149 Tb, 125 I, 203 Pb, 212 Pb, 201 Tl, 119 Sb, 58m Co, 55 Co, 47 Sc, 149 Pm and 161 Ho is selected.

[0337] In some embodiments, the one or more radionuclides are for use in imaging or for use in therapy.

[0338] In some embodiments, one or more radionuclides for use in imaging include: 99m Tc, 188 Re, 186 Re, 153 Sm, 67 Ga, 68 Ga, 111 In, 59 Fe, 63 Zn, 52 Fe, 45 Ti, 60 Cu, 61 Cu, 67 Cu, 64 Cu, 62 Cu, 82 Rb, 198 Au, 199 Au, 195m Pt, 191m Pt, 193m Pt, 117m Sn, 89 Zr, 177 Lu, 18 F, 203 Pb and 123 I. In some embodiments, the one or more radionuclides for use in imaging are selected from: 111 In some embodiments, the one or more radionuclides for use in imaging are 177 This is Lu.

[0339] In some embodiments, the one or more radionuclides for use in therapy include: 188 Re, 186 Re, 153 Sm, 66 Ho, 90 Y, 89 Sr, 111 In, 153 Gd, 225 Ac, 212 Bi, 213 Bi, 211 At, 60 Cu, 61 Cu, 67 Cu, 64 Cu, 6 2 Cu, 198 Au, 199 Au, 195m Pt, 193m Pt, 197 Pt, 117m Sn, 103 Pd, 105 Rh, 103m Rh, 177 Lu, 223 Ra, 224 Ra, 227 Th, 229 Th, 149 Tb, 32 P, 161 Tb, 33 P, 125 I, 203 Pb, 212 Pb, 201 Tl, 119 Sb, 58m Co, 47 Sc, 149 Pm and 161 Ho is selected.

[0340] In some embodiments, the radionuclide for use in therapy is 177 Lu, 212 Pb and 225 In some embodiments, the one or more radionuclides for use in imaging are selected from: 177 This is Lu.

[0341] In one embodiment, the pharmaceutically acceptable salt is an acid addition salt or a base addition salt. The selection of an appropriate salt can be made by one skilled in the art (see, for example, S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977, 66, 1-19).

[0342] Acid addition salts suitable for or compatible with the treatment of a subject are non-toxic organic or inorganic acid addition salts of any basic compound. Basic compounds that form acid addition salts include, for example, compounds containing an amine group. Exemplary inorganic acids that form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Exemplary organic acids that form suitable salts include mono-, di-, and tricarboxylic acids. Examples of such organic acids include acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutamic acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, mandelic acid, salicylic acid, 2-phenoxybenzoic acid, p-toluenesulfonic acid, and sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, and 2-hydroxyethanesulfonic acid. In one embodiment, mono- or di-acid salts are formed, and such salts exist in either hydrated, solvated, or substantially anhydrous form. Acid addition salts are more soluble in water and various hydrophilic organic solvents and generally exhibit higher melting points than the free base form. Criteria for selecting an appropriate salt will be known to those skilled in the art. Other non-pharmaceutically acceptable salts, such as, but not limited to, oxalates, may also be used, for example, in isolating the compounds of the present application for laboratory use or for subsequent conversion to a pharmaceutically acceptable acid addition salt.

[0343] Base addition salts suitable for or compatible with the treatment of subjects are non-toxic organic or inorganic base addition salts of any acidic compound.Analytic compounds that form base addition salts include, for example, compounds containing a carboxylic acid group.Exemplary inorganic bases that form suitable salts include hydroxides of lithium, sodium, potassium, calcium, magnesium, or barium, as well as ammonia.Exemplary organic salts that form suitable salts include aliphatic, alicyclic, or aromatic organic amines, such as isopropylamine, methylamine, trimethylamine, picoline, dimethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, and polyamine resins. Exemplary organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, caffeine, etc. Selecting an appropriate salt is useful, for example, to prevent hydrolysis of ester functional groups, if any, elsewhere in the compound. Criteria for selecting an appropriate salt will be known to those skilled in the art.

[0344] Solvates of the compounds of the present application include, for example, those prepared using pharmaceutically acceptable solvents. Examples of such solvents include water (the resulting solvates are called hydrates), ethanol, etc. Suitable solvents are those that are physiologically acceptable at the dosages administered.

[0345] In embodiments of the present application, the compounds described herein can have at least one asymmetric center. When compounds have two or more asymmetric centers, they may exist as diastereomers. It is understood that all such isomers and mixtures thereof, in any proportion, are encompassed within the scope of the present application. While the stereochemistry of a compound may be as depicted in any compound described herein, it is further understood that such compounds may contain a certain amount (e.g., less than 20%, preferably less than 10%, more preferably less than 5%) of compounds of the present invention having an alternative stereochemistry. Any optical isomer, as separated, pure, or partially purified optical isomer, or a racemic mixture thereof, is intended to be encompassed within the scope of the present application.

[0346] The compounds of the present application may also exist in different tautomeric forms, and it is intended that all tautomeric forms that the compounds may form, as well as mixtures thereof, are included within the scope of the present application.

[0347] The compounds of the present application may further exist in different polymorphic forms, and it is intended that any polymorphs formed or mixtures thereof are included within the scope of the present application.

[0348] III. COMPOSITIONS AND KITS OF THE INVENTION The compounds and complexes of the present invention are suitably formulated into compositions using one or more carriers in a conventional manner. Accordingly, the present application also includes compositions comprising one or more compounds or complexes of the present application and a carrier. The compounds or complexes of the present invention are suitably formulated into pharmaceutical compositions for administration to a subject in a biologically compatible form suitable for in vivo administration. Accordingly, the present application further includes pharmaceutical compositions comprising one or more compounds or complexes of the present application and a pharmaceutically acceptable carrier. In embodiments of the present application, the pharmaceutical composition is used to treat any of the diseases, disorders, or conditions described herein.

[0349] The present application also includes a kit comprising: one or more compounds of formula I as defined above, or pharmaceutically acceptable salts and / or solvates thereof, and Instructions for administering one or more compounds of Formula I, or pharmaceutically acceptable salts and / or solvates thereof, to a subject in need thereof.

[0350] The present application also includes a kit comprising: one or more compounds of formula I as defined above, or pharmaceutically acceptable salts and / or solvates thereof, and one or more radioisotopes as defined above, and Optionally, instructions for administering one or more compounds of formula I, or pharmaceutically acceptable salts and / or solvates thereof, to a subject in need thereof, and instructions for administering a radioisotope to a subject in need thereof.

[0351] The present application also includes a kit comprising: one or more complexes of the invention of the present application as defined above, or pharmaceutically acceptable salts and / or solvates thereof, and Instructions for administering one or more compound complexes to a subject in need thereof.

[0352] In some embodiments, one or more compounds of Formula I as defined above or pharmaceutically acceptable salts and / or solvates thereof, one or more complexes as defined above or pharmaceutically acceptable salts and / or solvates thereof, or one or more radioisotopes as defined above are present in the kit in one or more pharmaceutical compositions, respectively.

[0353] In some embodiments, pharmaceutical compositions comprising one or more compounds of Formula I as defined above or pharmaceutically acceptable salts and / or solvates thereof, one or more complexes as defined above or pharmaceutically acceptable salts and / or solvates thereof, or one or more radioisotopes as defined above are formulated for parenteral administration, as described below. In some embodiments, parenteral administration is by injection.

[0354] In some embodiments, the kit further comprises a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate buffered saline, Ringer's solution, or dextrose solution, hi some embodiments, the pharmaceutically acceptable buffer is present in the kit in one or more containers, such as a vial or an ampoule.

[0355] In some embodiments, the kit is for use in imaging. In some embodiments, the kit is for use in therapy. In some embodiments, the kit is for use in the treatment of cancer. In some embodiments, the kit is adapted and / or configured to perform any of the methods of the present application. Accordingly, the present application also includes pharmaceutical packages or kits adapted and configured to perform any of the methods of the present application.

[0356] The compounds or complexes of the present invention may be administered to a subject in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art. For example, the compounds of the present invention may be administered orally, by inhalation, parenterally, buccally, sublingually, nasally, rectally, vaginally, by patch, pump, minipump, topically, or transdermally, using pharmaceutical compositions formulated accordingly. In some embodiments, administration is via a pump for periodic or continuous delivery. Conventional procedures and ingredients for the selection and preparation of suitable compositions are described, for example, in Remington's Pharmaceutical Sciences (2000-20th edition) and The United States Pharmacopeia: The National Formulary, 1999 (USP 24 NF19).

[0357] Parenteral administration includes systemic delivery routes other than the gastrointestinal (GI) tract, and includes, for example, intravenous, intraarterial, intraperitoneal, subcutaneous, intramuscular, transdermal, nasal, intrapulmonary (e.g., by use of an aerosol), intrathecal, rectal, and topical (including use of a patch or other transdermal delivery device) modes of administration. Parenteral administration may be by continuous infusion over a selected period of time.

[0358] In some embodiments, the compounds or complexes of the present application are orally administered, for example, with an inert diluent or with an assimilable edible carrier, or enclosed in a hard or soft shell gelatin capsule, or compressed into a tablet, or directly incorporated into the diet. In some embodiments, the compounds are combined with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, caplets, pellets, granules, lozenges, chewing gum, powders, syrups, elixirs, wafers, aqueous solutions and suspensions, etc. In the case of tablets, carriers used include lactose, corn starch, sodium citrate, phosphates, etc. Pharmaceutically acceptable excipients include binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone, or hydroxypropylmethylcellulose); fillers (e.g., lactose, microcrystalline cellulose, or calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). In embodiments, tablets are coated by methods well known in the art. For tablets, capsules, caplets, pellets, or granules for oral administration, a pH-sensitive enteric coating, such as Eudragits™, designed to control the release of the active ingredient, is optionally used. Dosage forms for oral administration also include modified-release formulations, such as immediate-release and timed-release formulations. Examples of modified-release formulations include sustained release (SR), extended release (ER, XR, or XL), timed-release, controlled release (CR), or continuous release (CR or Contin) formulations, and are employed, for example, in the form of coated tablets, osmotic delivery devices, coated capsules, microencapsulated microspheres, agglomerated particles, e.g., molecular sieve-type particles, or bundles of fine hollow permeable fibers, or chopped hollow permeable fibers agglomerated or held together in fibrous packets. Timed-release compositions are formulated, for example, as liposomes, or in which the active compound is protected with different degradable coatings, such as microencapsulation, multiple coatings, etc.Liposomal delivery systems include, for example, small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. In some embodiments, liposomes are formed from various phospholipids, such as cholesterol, stearylamine, or phosphatidylcholine. For oral administration in capsule form, useful carriers or diluents include lactose and dried corn starch.

[0359] In some embodiments, liquid preparations for oral administration may take the form of, for example, solutions, syrups, or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. When aqueous suspensions and / or emulsions are administered orally, the compounds of the present application are suitably suspended or dissolved in an oily phase combined with an emulsifying and / or suspending agent. If desired, certain sweeteners and / or flavorings and / or coloring agents may be added. Such liquid preparations for oral administration are prepared by conventional means using pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methylcellulose, or hydrogenated edible fats and oils); emulsifiers (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid). Useful diluents include lactose and high molecular weight polyethylene glycols.

[0360] The compounds of the present application can also be lyophilized and the resulting lyophilizates used, for example, for the preparation of injections.

[0361] In some embodiments, the compounds or complexes of the present application are administered parenterally. For example, solutions of the compounds of the present application are prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. In some embodiments, dispersions are prepared in glycerol, liquid polyethylene glycol, DMSO, and mixtures thereof, with or without alcohol, and in oils. Under ordinary conditions of storage and use, these formulations contain preservatives to prevent microbial growth. Those skilled in the art will know how to prepare suitable formulations. For parenteral administration, sterile solutions of the compounds of the present application are typically prepared, and the pH of the solution is appropriately adjusted and buffered. For intravenous administration, the total concentration of solutes is adjusted to render the formulation isotonic. For ocular administration, ointments or droppable liquids are delivered by ocular delivery systems known in the art, such as applicators or eyedroppers. In some embodiments, such compositions contain a mucus-mimetic agent such as hyaluronic acid, chondroitin sulfate, hydroxypropylmethylcellulose, or polyvinyl alcohol, a preservative such as sorbic acid, EDTA, or benzyl chromium chloride, and the usual amount of a diluent or carrier. For pulmonary administration, a diluent or carrier is selected that is appropriate to allow the formation of an aerosol.

[0362] In some embodiments, the compounds or complexes of the present application are formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion. Injectable formulations are presented, for example, in unit dosage form, e.g., in ampoules or multi-dose containers, with an added preservative. In some embodiments, the compositions take the form of a sterile suspension, solution, or emulsion in an oily or aqueous vehicle, and contain formulatory agents such as suspending, stabilizing, and / or dispersing agents. In all cases, the form must be sterile and fluid enough for easy injection. Alternatively, the compounds or complexes of the present application are preferably in sterile powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0363] In some embodiments, compositions for nasal administration are conveniently formulated as aerosols, drops, solutions, gels and powders.

[0364] Compositions suitable for buccal or sublingual administration include tablets, lozenges, pastilles, and the like, wherein the compound or complex of the present application is formulated with a carrier such as sugar, acacia, tragacanth, gelatin, glycerin, or the like.

[0365] Suppository forms of the compounds or complexes of the present application are useful for vaginal, urethral, ​​and rectal administration.

[0366] In some embodiments, the compounds or complexes of the present application are conjugated with soluble polymers as targetable drug carriers. Such polymers include, for example, polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamide-phenol, polyhydroxy-ethylaspartamide-phenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. Furthermore, in some embodiments, the compounds of the present application are conjugated to classes of biodegradable polymers useful for achieving controlled drug release, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels.

[0367] Although the compounds or complexes of the present application, including pharmaceutically acceptable salts and / or solvates thereof, are suitable for use per se, they are generally administered in the form of a pharmaceutical composition in which one or more compounds of the present invention (active ingredients) are associated with a pharmaceutically acceptable carrier. Depending on the mode of administration, the pharmaceutical composition may contain from about 0.05 wt% to about 99 wt%, or from about 0.10 wt% to about 70 wt%, of the active ingredient, and from about 1 wt% to about 99.95 wt%, or from about 30 wt% to about 99.90 wt% of the pharmaceutically acceptable carrier, all weight percentages being based on the total composition.

[0368] III. Methods and Uses of the Present Application Accordingly, the present application also includes methods for treating a disease or disorder, comprising administering a therapeutically effective amount of one or more compounds or complexes of the present application, or pharmaceutically acceptable salts and / or solvates thereof, to a subject in need thereof. The present application also includes the use of one or more compounds or complexes of the present application, or pharmaceutically acceptable salts and / or solvates thereof, for the treatment of a disease or disorder, as well as the use of one or more compounds or complexes of the present application, or pharmaceutically acceptable salts and / or solvates thereof, for the preparation of a medicament for the treatment of a disease or disorder. The present application further includes one or more compounds or complexes of the present application, or pharmaceutically acceptable salts and / or solvates thereof, for use in the treatment of a disease or disorder.

[0369] In one embodiment, the target of the targeting binding group of the compound or complex is present on diseased cells. Indeed, the presence and / or overexpression of receptors on the cell surface is a characteristic of many disease-related cells, including cancer cells. In another embodiment, the target of the targeting binding group (e.g., a cell surface receptor) is present on cancer cells, and the disease or disorder is cancer. For example, in one embodiment, the target of the targeting binding group is PSMA, and the disease or disorder is prostate cancer. In another embodiment, the target of the targeting binding group is somatostatin receptor 2, and the disease or disorder is neuroendocrine tumors.

[0370] In one embodiment, the disease or disorder is cancer.

[0371] In one embodiment, the cancer is selected from, but is not limited to: acute lymphoblastic leukemia, adult; acute lymphoblastic leukemia, pediatric; acute myeloid leukemia, adult; adrenocortical carcinoma; adrenocortical carcinoma, pediatric; AIDS-related lymphoma; AIDS-related malignancies; anal cancer; astrocytoma, cerebellar, pediatric; astrocytoma, cerebral, pediatric; cholangiocarcinoma, extrahepatic; bladder cancer; bladder cancer, pediatric; bone cancer, osteosarcoma / malignant fibrous histiocytoma; brain stem glioma, pediatric; brain tumor, adult; brain tumor, brain stem glioma, pediatric; brain tumor, cerebellar astrocytoma, pediatric; brain tumor, cerebral astrocytoma / malignant glioma, pediatric; brain tumor, ependymoma, pediatric; brain Tumors, medulloblastoma, pediatric;Brain tumors, upper brain primitive neuroectodermal tumors, pediatric;Brain tumors, visual pathway and hypothalamic gliomas, pediatric;Brain tumors, pediatric (other);Breast cancer;Breast cancer and pregnancy;Breast cancer, pediatric;Breast cancer, male;Bronchial adenoma / carcinoid, pediatric;Carcinoid tumors, pediatric;Carcinoid tumors, gastrointestinal tract;Carcinoma, adrenal cortex;Carcinoma, pancreatic islet cell;Carcinoma of unknown primary;Central nervous system lymphoma, primary;Cerebellar astrocytoma, pediatric;Cerebral astrocytoma / malignant glioma, pediatric;Cervical cancer;Pediatric cancer;Chronic lymphocytic leukemia;Chronic myeloid leukemia;Chronic myeloproliferative disorder;Clear cell sarcoma of tendon sheath;Colon cancer;Colon cancer, pediatric;Cutaneous T-cell lymphoma Pancreatic cancer; Endometrial cancer; Ependymoma, pediatric; Epithelial carcinoma, ovarian; Esophageal cancer; Esophageal cancer, pediatric; Ewing's family of tumors; Extracranial germ cell tumors, pediatric; Extracranial germ cell tumors; Extrahepatic bile duct cancer; Eye cancer, intraocular melanoma; Eye cancer, retinoblastoma; Gallbladder cancer; Gastric (stomach) cancer; Gastric (stomach) cancer, pediatric; Gastrointestinal carcinoid tumors; Extracranial germ cell tumors, pediatric; Germ cell tumors, extraovarian; Germ cell tumors, ovarian; Gestational trophoblastic tumor; Glioma, pediatric brainstem; Glioma, pediatric visual pathway and hypothalamic; Hairy cell leukemia; Head and neck cancer; Hepatocellular (liver) carcinoma , adult (primary); hepatocellular (liver) carcinoma, pediatric (primary); Hodgkin's lymphoma, adult; Hodgkin's lymphoma, pediatric; Hodgkin's lymphoma in pregnancy; hypopharyngeal carcinoma; hypothalamic and visual pathway glioma, pediatric; intraocular melanoma; pancreatic islet cell carcinoma (endocrine pancreas); Kaposi's sarcoma; kidney cancer; laryngeal cancer; laryngeal cancer, pediatric; leukemia, acute lymphoblastic, adult; leukemia, acute lymphoblastic, pediatric; leukemia, acute myeloid, adult; leukemia, acute myeloid, pediatric; leukemia, chronic lymphocytic; leukemia, chronic myeloid; leukemia, hairy cell; lip and oral cavity cancer; liver cancer, adult (primary); liver cancer, pediatric (primary); lung cancer, non-small cell;Lung cancer, small cell; Lymphoblastic leukemia, adult acute; Lymphoblastic leukemia, childhood acute; Lymphocytic leukemia, chronic; Lymphoma, AIDS-related; Lymphoma, central nervous system (primary); Lymphoma, cutaneous T-cell; Lymphoma, Hodgkin's disease, adult; Lymphoma, Hodgkin's disease, childhood; Lymphoma, Hodgkin's disease, pregnancy; Lymphoma, non-Hodgkin's disease, adult; Lymphoma, non-Hodgkin's disease, childhood; Lymphoma, non-Hodgkin's disease, pregnancy; Lymphoma, central nervous system primary; Macroglobulinemia, Waldenstrom's disease; Male breast cancer; Malignant mesothelioma, adult; Malignant mesothelioma, childhood; Malignant thymoma; Medulloblastoma, childhood; Melanoma; Melanoma, intraocular; Merkel cell carcinoma; Mesothelioma, malignant; Metastatic squamous cell carcinoma of unknown primary; Multiple endocrine neoplasia syndrome, pediatric; Multiple myeloma / plasma cell neoplasm; Mycosis fungoides; Myelodysplastic syndrome; Myeloid leukemia, chronic; Myeloid leukemia, acute, pediatric; Myeloma, multiple; Myeloproliferative disorders, chronic; Nasal cavity and paranasal sinus cancer; Nasopharyngeal carcinoma; Nasopharyngeal carcinoma, pediatric; Neuroblastoma; Adult non-Hodgkin's lymphoma; Pediatric non-Hodgkin's lymphoma; Non-Hodgkin's lymphoma in pregnancy; Non-small cell lung cancer; Oral cavity cancer, pediatric; Oral cavity and lip cancer; Oropharyngeal cancer; Osteosarcoma / malignant osteofibrous histiocytoma; Ovarian cancer, pediatric; Ovarian epithelial carcinoma; Ovarian germ cell tumors; Ovarian low malignant potential tumors; Pancreatic cancer; Pancreatic cancer, pediatric; Pancreatic islet cell cancer; Paranasal sinus and nasal cavity cancer; Parathyroid cancer; Penile cancer; Pheochromocytoma; Pediatric primitive neuroectodermal tumors of the pineal gland and supraventricles; Pituitary tumors; Plasma cell neoplasms / multiple myeloma; Pleuropulmonary blastoma; Pregnancy and breast cancer; Pregnancy and Hodgkin's lymphoma; Pregnancy and non-Hodgkin's lymphoma; Primary central nervous system lymphoma; Primary liver cancer, adult; Primary liver cancer, pediatric; Prostate cancer; Rectal cancer; Renal cell (kidney) cancer; Renal cell carcinoma, pediatric; Renal pelvis and ureter, transitional cell carcinoma; Retinoblastoma; Rhabdomyosarcoma, pediatric; Salivary gland cancer; Salivary gland cancer, pediatric; Ewing's sarcoma Tumor family;Sarcoma, Kaposi's sarcoma;Sarcoma (osteosarcoma) / malignant fibrous histiocytoma of bone;Sarcoma, rhabdomyosarcoma, pediatric;Sarcoma, soft tissue, adult;Sarcoma, soft tissue, pediatric;Sézary syndrome;Skin cancer;Skin cancer, pediatric;Skin cancer (melanoma);Skin cancer (Merkel cell);Small cell lung cancer;Small intestinal cancer;Adult soft tissue sarcoma;Pediatric soft tissue sarcoma;Squamous cell carcinoma with metastatic primary;Gastric (Stomach) cancer;Gastric (Stomach) cancer, pediatric;Ventricular epigenous neuroectodermal tumor, pediatric;T-cell lymphoma, skin;Testicular cancer;Thymoma, pediatric;Thymoma, malignant;Thyroid cancer;Thyroid cancer, pediatric; transitional cell carcinoma of the renal pelvis and ureter; gestational trophoblastic tumor; cancer of unknown primary site, pediatric; rare cancers of childhood; transitional cell carcinoma of the ureter and renal pelvis; urethral cancer; uterine sarcoma; vaginal cancer; glioma of the visual pathway and hypothalamus, pediatric; vulvar cancer; Waldenstrom's giant cell globulinemia; Wilms' tumor and neuroendocrine tumors. Metastases of the aforementioned cancers can also be treated according to the methods described herein.

[0372] In one embodiment, the cancer is prostate cancer or a neuroendocrine tumor.

[0373] In one embodiment, the cancer is a PSMA-positive cancer. In one embodiment, the PSMA-positive cancer is prostate cancer.

[0374] Efficacy of treatment is determined in association with any known method for diagnosing or treating the particular cancer. Alleviation of one or more symptoms of the cancer indicates that the compound or complex provides clinical benefit.

[0375] The compound or complex can be administered in combination with at least one additional cancer therapy, including chemotherapy, radiation therapy, and / or immuno-oncology therapy. The other cancer therapies can be administered in any order, e.g., simultaneously, sequentially, or separately, with the at least one additional cancer therapy.

[0376] As used herein, "treating cancer" includes, but is not limited to, reversing, alleviating, or inhibiting the progression of cancer or symptoms or conditions associated with cancer. "Treating cancer" also includes extending survival of a subject. Survival is optionally extended by at least 1, 2, 3, 6, or 12 months, or at least 2, 3, 4, 5, or 10 years beyond expected survival in the absence of treatment with a cytotoxic agent or composition described herein. "Treating cancer" also includes reducing tumor mass and / or reducing tumor size. Optionally, tumor mass and / or tumor burden is reduced by at least 5, 10, 25, 50, 75, or 100% after treatment with a cytotoxic agent or composition described herein. "Treating cancer" also includes reducing tumor aggressiveness, malignancy, and / or invasiveness.

[0377] The present application also includes a method for inhibiting proliferative activity in a cell, the method comprising administering to a cell an effective amount of one or more compounds or complexes of the present application, or pharmaceutically acceptable salts and / or solvates thereof. The present application also includes the use of one or more compounds or complexes of the present application, or pharmaceutically acceptable salts and / or solvates thereof, for inhibiting proliferative activity in a cell, as well as the use of one or more compounds or complexes of the present application, or pharmaceutically acceptable salts and / or solvates thereof, for the preparation of a medicament for inhibiting proliferative activity in a cell. The present application further includes one or more compounds or complexes of the present application, or pharmaceutically acceptable salts and / or solvates thereof, for use in inhibiting proliferative activity in a cell. In one embodiment, the one or more compounds or complexes comprise a radionuclide for use in therapy, which optionally includes: 188 Re, 186 Re, 153 Sm, 66 Ho, 90 Y, 89 Sr, 111 In, 153 Gd, 225 Ac, 212 Bi, 213 Bi, 211 At,60 Cu, 61 Cu, 67 Cu, 64 Cu, 62 Cu, 198 Au, 199 Au, 195m Pt, 193m Pt, 197 Pt, 117m Sn, 103 Pd, 103m Rh, 177 Lu, 223 Ra, 224 Ra, 227 Th, 32 P, 161 Tb, 33 P, 125 I, 203 Pb, 212 Pb, 201 Tl, 119 Sb, 58m Co or 161 In some embodiments, the one or more radionuclides are 111 In some embodiments, the one or more radionuclides are 177 This is Lu.

[0378] The present application also includes a method of imaging tissue in a subject by administering to a subject in need thereof an imaging-effective amount of one or more compounds or complexes of the present application, or pharmaceutically acceptable salts and / or solvates thereof, for use in imaging, and applying an imaging technique to detect emitted gamma rays.

[0379] The present application also includes the use of one or more compounds or complexes of the present application, or pharmaceutically acceptable salts and / or solvates thereof, for use in imaging, for imaging of tissue, as well as the use of one or more compounds or complexes of the present application, or pharmaceutically acceptable salts and / or solvates thereof, comprising a radionuclide for use in imaging, for the preparation of a pharmaceutical for imaging tissue. The present application further includes one or more compounds or complexes of the present application, or pharmaceutically acceptable salts and / or solvates thereof, comprising a radionuclide for use in imaging, for use in imaging of tissue. In some embodiments, the use further includes applying an imaging technique to detect emitted gamma rays. In some embodiments, the one or more compounds or complexes comprise a radionuclide for use in imaging, which optionally 99m Tc, 188 Re, 186 Re, 153 Sm, 67 Ga, 68 Ga, 111 In, 59 Fe, 63 Zn, 52 Fe, 45 Ti, 60 Cu, 61 Cu, 67 Cu, 64 Cu, 62 Cu, 198 Au, 199 Au, 195m Pt, 191m Pt, 193m Pt, 117m Sn, 89 Zr, 177 Lu, 18 F, 203 Pb or 123 I. In some embodiments, the one or more radionuclides are 111 In some embodiments, the one or more radionuclides are 177 This is Lu.

[0380] The present application also includes a method of diagnosing cancer in a subject by administering to a subject in need thereof a diagnostically effective amount of one or more compounds or complexes of the present application, or pharmaceutically acceptable salts and / or solvates thereof, and applying an imaging technique to detect emitted gamma rays. The present application also includes the use of one or more compounds or complexes of the present application, or pharmaceutically acceptable salts and / or solvates thereof, for diagnosing cancer. The present application further includes one or more compounds or complexes of the present application, or pharmaceutically acceptable salts and / or solvates thereof, comprising a radionuclide for use in imaging for use in diagnosing cancer. In some embodiments, the use further includes applying an imaging technique to detect emitted gamma rays. In some embodiments, one or more compounds or complexes of the present application, or pharmaceutically acceptable salts and / or solvates thereof, comprising a radionuclide for use in imaging, optionally 99m Tc, 188 Re, 186 Re, 153 Sm, 67 Ga, 68 Ga, 111 In, 59 Fe, 63 Zn, 52 Fe, 45 Ti, 60 Cu, 61 Cu, 67 Cu, 64 Cu, 62 Cu, 198 Au, 199 Au, 195m Pt, 191m Pt, 193m Pt, 117m Sn, 89 Zr, 177 Lu, 18 F or 123 I. In some embodiments, the one or more radionuclides are 111 In some embodiments, the one or more radionuclides are 177 This is Lu.

[0381] In some embodiments, treating a disease or disorder such as cancer, or imaging a tissue, or diagnosing cancer, involves greater uptake of a compound or complex of the present invention, or a pharmaceutically acceptable salt and / or solvate thereof, in target cells, tissues, and / or organs compared to non-target cells, tissues, and / or organs. In some embodiments, treating a disease or disorder such as cancer, or imaging a tissue, or diagnosing cancer, involves greater uptake of a compound or complex of the present invention, or a pharmaceutically acceptable salt and / or solvate thereof, in target cells, tissues, and / or organs compared to non-target cells, tissues, and / or organs and compared to an otherwise identical compound or complex except for the presence of the cleavable moiety(s) in the compound or complex of the present invention.

[0382] To minimize exposure of normal organs to the radionuclide and to intentionally degrade the radioligand into metabolites that are less likely to accumulate in non-target receptor-expressing cells, we have incorporated a cleavable linker into the radioligand compound.

[0383] In one embodiment, an effective amount varies depending on factors such as the disease state, age, sex, and / or weight of the subject. In a further embodiment, the amount of a given compound or complex that corresponds to an effective amount will vary depending on factors such as the given compound or complex, pharmaceutical formulation, route of administration, type of condition, disease or disorder, and the identity of the subject being treated, but can nevertheless be routinely determined by one of ordinary skill in the art. In one embodiment, an effective amount is one that manifests as an improvement or alleviation of any disease symptoms following treatment therewith.

[0384] In one embodiment, the compound or complex is administered at least once a week. However, in another embodiment, the compound or complex is administered to a subject from about once every two weeks, three weeks, or a month. In another embodiment, the compound or complex is administered from about once a week to about once a day. In another embodiment, the compound or complex is administered 2, 3, 4, 5, or 6 times a day. The length of treatment depends on various factors, such as the severity of the disease, disorder, or condition, the age of the subject, the concentration and / or activity of the compound of the present application, and / or combinations thereof. It will also be understood that the effective dosage of the compound or complex used for treatment may increase or decrease over the course of a particular treatment regimen. Changes in dosage may occur and be evident using standard diagnostic assays known in the art. In some cases, chronic administration is necessary. For example, the compound or complex is administered to a subject in an amount and for a duration sufficient to treat the subject.

[0385] In one embodiment, the subject is a mammal. In another embodiment, the subject is a human. In one embodiment, the subject is a non-human animal. In one embodiment, the subject is a dog. In one embodiment, the subject is a cat. Thus, the compounds, methods, and uses of the present application are directed to diseases, disorders, and conditions of both humans and domestic animals.

[0386] The dosage of the compounds or complexes of the present invention varies depending on many factors, including the pharmacodynamic properties of the compound, the mode of administration, the age, health, and weight of the subject being treated, the nature and severity of symptoms, the frequency and type of concurrent treatment, if any, and the clearance rate of the compound in the treated subject. Those skilled in the art can determine the appropriate dosage based on the above factors. In some embodiments, the compounds or complexes of the present invention are initially administered at an appropriate dose, which is adjusted as necessary depending on the clinical response. The dosage is generally selected to maintain serum levels of the compounds of the present invention between about 0.01 μg / cc and about 1000 μg / cc, or between about 0.1 μg / cc and about 100 μg / cc. Typically, the oral dosage of one or more compounds of the present invention ranges from about 1 mg to about 1000 mg per day for an adult, preferably between about 1 mg and about 500 mg per day, and more preferably between about 1 mg and about 200 mg per day. For parenteral administration, a typical dose is about 0.001 mg / kg to about 10 mg / kg, about 0.01 mg / kg to about 10 mg / kg, about 0.01 mg / kg to about 1 mg / kg, or about 0.1 mg / kg to about 1 mg / kg. For oral administration, a typical dose is about 0.001 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 10 mg / kg, about 0.01 mg / kg to about 1 mg / kg, or about 0.1 mg / kg to about 1 mg / kg. For administration in the form of a suppository, a typical dose is about 0.1 mg / kg to about 10 mg / kg, or about 0.1 mg / kg to about 1 mg / kg.

[0387] IV. Methods of Preparing the Compounds of the Present Application The compounds and / or complexes of the present invention, or comparative compounds, can be prepared by a variety of synthetic processes. The selection of certain structural features and / or substituents may influence the selection of one process over another. The selection of a particular process for preparing a given compound and / or complex of the present invention or comparative compounds I is within the skill of one in the art. Some starting materials for preparing the compounds of the present invention are available from commercial chemical sources. Other starting materials are readily prepared from available precursors using straightforward transformations well known in the art, for example, as described below.

[0388] In some embodiments, a compound of Formula I or a comparator compound is prepared using solid phase peptide synthesis (SPPS) or solution phase coupling techniques known in the art, e.g., Stewart and Young, 1984, Solid Phase Synthesis, Second Edition, Pierce Chemical Co., Rockford, Ill.; Fields and Noble, 1990, "Solid phase peptide synthesis utilizing 9-fluorenylmethyloxycarbonyl amino acids," Int. J. Pept. Protein Res. 35:161-214; Geysen et al., 1987, J. Immunol. Methods 102:259-274.

[0389] Thus, in some embodiments, in SPPS, an N-protected linker group, such as a tert-butoxycarbonyl (Boc) or 9-fluorenylmethyloxycarbonyl (Fmoc) amino acid linker group, is activated at the α-carbonyl and coupled to a deprotected N-function of the solid support. The newly added N-protected linker group is then deprotected and coupled with the next N-protected linker group as needed, until the final cleavage step. Those skilled in the art will appreciate that the chemistry of the linker coupling, deprotection, and final cleavage steps from the solid support will depend on the choice of αN-protecting group. In some embodiments, cleavage is achieved by treatment with an acid, such as trifluoroacetic acid (TFA), optionally in the presence of a scavenger reagent such as triisopropylsilane. In some embodiments, when the αN-protecting group is Fmoc, cleavage with acid also results in side chain deprotection.

[0390] Thus, in exemplary embodiments, the compound of Formula I or a comparator compound is prepared using fluorenylmethyloxycarbonyl (Fmoc) solid-phase peptide synthesis chemistry known in the art. Thus, in some embodiments, the compound of Formula I or a fragment thereof is prepared using Wang resin, Rink resin, or other suitable solid-phase peptide synthesis chemistry. Amide-MBHA or equivalent resin and Fmoc-protected linker group derivatives with appropriate side chain protection, such as Fmoc-Ala-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Cys(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Gly-OH, Fmoc-His(Trt)-OH, Fmoc-Ile-OH, Fmoc-Leu-OH, Fmoc-Lys(Boc)-OH, Fmoc-Met-OH, Fmoc-Phe-OH, Fmoc-Pro-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, )-OH, Fmoc-Trp(Boc)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Val-OH, Fmoc-Lys(Mtt)-OH, Fmoc-Aib-OH, Fmoc-Nle-OH, Fmoc-8-amino-3,6-dioxaoctanoic acid (Fmoc-OEG-OH), Fmoc-tranexamic acid (Fmoc-Trx-OH), Fmoc-Glu-OtBu, octadecanedioic acid mono-tert-butyl ester, nonadecanedioic acid mono-tert-butyl ester, eicosanedioic acid mono-tert-butyl ester, and tetradecanedioic acid mono-tert-butyl ester are prepared manually or using an automated multiphase solid-phase peptide synthesizer. The resin is swelled with an appropriate solvent, such as a combination of dichloromethane (DCM) and dichloromethane (DMF). Prior to each coupling step, the base-labile Nα-protecting group, Fmoc, is cleaved from the Fmoc-protected linker group with a suitable base, such as piperidine, in a suitable solvent, such as DMF, for a period of time to cleave the Fmoc protecting group, e.g., about 10-15 minutes, after which the resin is washed with a suitable solvent, such as DMF, to remove, e.g., piperidine.An excess of the Fmoc-linker group (e.g., 4-8 molar equivalents) is then coupled using coupling reagents known in the art, such as N,N'-diisopropylcarbodiimide (DIC) and ethyl cyanohydroxyiminoacetate (Oxyma, e.g., Oxyma Pure®), or (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP) and 1-hydroxybenzotriazole (HOBt) in a suitable solvent such as DMF for about 1 to about 2 hours, followed by washing with a suitable solvent such as DMF. The coupling step is repeated once for each linker group.

[0391] If necessary, the deprotected Lys(Mtt)-residue in the Fmoc-Lys(Mtt)-OH (i.e., N-α-Fmoc-N-ε-4-methyltrityl-L-lysine) linker group or linker fragment is removed by treating the group or residue with hexafluoroisopropanol (HFIP) in a suitable solvent such as dichloromethane (DCM) (e.g., about 30% v / v) for a suitable time, for example, about 1 hour, followed by washing of the resin with the appropriate solvent and repeated treatment with HFIP in DCM, followed by a final wash with DCM.

[0392] After coupling, the compound of Formula I, the reference compound, or a fragment thereof is cleaved from the solid phase by treatment with a suitable acid, such as trifluoroacetic acid (TFA), optionally in the presence of a trialkylsilane, such as triisopropylsilane (TIP), and water, followed by precipitation with a suitable solvent, such as diethyl ether. The product is dissolved in a suitable solvent, such as water or acetonitrile, and purified using high-performance liquid chromatography (HPLC), such as reverse-phase HPLC, using a suitable solvent or solvent mixture, such as water or TFA, with an increasing gradient of acetonitrile. Relevant fractions are checked by analytical UPLC. Fractions containing the pure target compound are pooled and lyophilized.

[0393] Chelating groups such as DOTA are attached to, for example, the ε-amine of a lysine residue on the linker fragment, or to a linker fragment attached to a tumor-binding group and / or a circulation-enhancing group using active ester chemistry known in the art. For example, DOTA is attached to the linker fragment in the presence of a base such as an amine.

[0394] The tumor-binding group or derivatives thereof can be synthesized by methods known in the art or are commercially available. For example, the tumor-binding group εKuE [ka] can be synthesized by coupling a Wang resin bearing an appropriately protected lysine with an appropriately protected glutamic acid that has been preactivated with 4-nitrophenyl chloroformate in a suitable solvent such as CHCl in the presence of a suitable base such as N,N-diisopropylethylamine (DIEA) at a low temperature such as about 0°C.

[0395] Chelating groups can be synthesized by methods known in the art or are commercially available, for example, DOTA is available from Sigma-Aldrich (St. Louis, Missouri, United States).

[0396] In some embodiments, when the linker comprises a triazole (i.e., X 3 is a triazole), the triazole ring is incorporated into the linker group by reacting an appropriate azide precursor compound with an appropriate acetylene precursor compound using click reaction conditions (e.g., Tetrahedron 2016, 72, 5257-5283; Tetrahedron 2016, 72, 6136-6141).

[0397] Formation of a desired compound salt is achieved using standard techniques, for example, treating a neutral compound with an acid or base in a suitable solvent and isolating the formed salt by filtration, extraction, or other suitable method.

[0398] The formation of solvates varies depending on the compound and the solvate. Generally, solvates are formed by dissolving the compound in an appropriate solvent and isolating the solvate by cooling or using an antisolvating agent. The solvate is usually dried or azeotroped under ambient conditions. The selection of appropriate conditions for forming a particular solvate can be performed by one of ordinary skill in the art. Examples of suitable solvents are ethanol, water, etc. When water is the solvent, the molecule is called a "hydrate." The formation of solvates of the compounds of the present application varies depending on the compound and the solvate. Generally, solvates are formed by dissolving the compound in an appropriate solvent and isolating the solvate by cooling or using an antisolvating agent. The solvate is usually dried or azeotroped under ambient conditions. The selection of appropriate conditions for forming a particular solvate can be performed by one of ordinary skill in the art.

[0399] It is understood that throughout the processes described herein, suitable protecting groups are added to, and subsequently removed from, various reactants and intermediates, where appropriate, in a manner that would be readily understood by one of ordinary skill in the art. Conventional procedures for the use of such protecting groups and examples of suitable protecting groups are described, for example, in "Protective Groups in Organic Synthesis," T.W. Green, P.G.M. Buts, Wiley-Interscience, New York, (1999). It is also understood that the conversion of a group or substituent to another group or substituent by chemical manipulation can be performed on any intermediate or final product on the synthetic route toward the final product, with the types of transformations possible being limited only by the inherent incompatibility of other functional groups possessed by the molecule at that stage with the conditions or reagents employed for the transformation. Such inherent incompatibilities, and how to circumvent them by performing appropriate transformations and synthetic steps in a suitable order, will be readily apparent to one of ordinary skill in the art. While example transformations are presented herein, it is understood that the described transformations are not limited to only the generic groups or substituents for which the transformations are exemplified. References and descriptions of other suitable transformations can be found in "Comprehensive Organic Transformations - A Guide to Functional Group Preparations," R.C. Larock, VHC Publishers, Inc. (1989). References and descriptions of other suitable reactions can be found in organic chemistry textbooks, such as "Advanced Organic Chemistry," March, 4th ed., McGraw Hill (1992) and "Organic Synthesis," Smith, McGraw Hill (1994). Purification techniques for intermediates and final products include, for example, straight- and reverse-phase chromatography on columns or spinning plates, recrystallization, distillation, liquid-liquid or solid-liquid extraction, and will be readily apparent to those skilled in the art. [Example]

[0400] The following non-limiting examples are illustrative of the present application.

[0401] A. Synthesis of Exemplary Compounds of Formula I General method i) Synthesis of Exemplary Linker Group Moieties Synthesis of the protected linker group ESL1 [ka] A mixture of Fmoc-Gly-OH (2.45 g, 8.25 mmol) and DIC (1.04 g, 8.25 mmol) in THF (15 mL) was stirred at room temperature (rt) for 10 min, followed by the addition of DMAP (67 mg, 0.55 mmol) and tert-butyl 4-hydroxybutanoate (880 mg, 5.5 mmol). The resulting mixture was stirred overnight at rt. The solvent was removed on a rotary evaporator, and the crude product was extracted with ethyl acetate (EA) (50 mL × 3). The combined organic layers were washed with brine, dried over NaSO, concentrated, and purified by flash chromatography to give the ester intermediate as a white solid (1.6 g, 75% yield). The ester intermediate (1.6 g, 3.65 mmol) was dissolved in hydrochloric acid / dioxane (2.5 M, 5 mL) and stirred at rt for 3 h. The resulting crude product was purified by preparative reverse-phase HPLC to give Fmoc-protected ESL1 carboxylic acid (800 mg) as a white solid.

[0402] Synthesis of the protected ESL2 linker group moiety [ka] A mixture of succinic anhydride (2.0 g, 20 mmol) and ethylene glycol (0.5 mL, 10 mmol) in pyridine (1.6 mL) was stirred at 120 °C overnight. The reaction mixture was concentrated to give the crude diacid intermediate as an oil (2.9 g, purity: 50%, yield: 61%). A mixture of such intermediate (975 mg, 3.72 mmol), mono-Fmoc ethylenediamine hydrochloride (1 g, 3.1 mmol), HBTU (1.78 g, 5.58 mmol), and DIEA (2.6 mL, 15.5 mmol) in DMF (5 mL) was stirred at rt for 2 h. The crude product was purified by preparative reverse-phase HPLC to give the protected ESL2 carboxylic acid (320 mg) as a white solid.

[0403] Synthesis of the protected ESL3 linker group moiety [ka] A solution of Fmoc-Cl (630 mg, 6 mmol) and 2-(2-aminoethoxy)ethanol (1.3 g, 5 mmol) in DCM (10 mL) was added dropwise to a solution of KCO (1.4 g, 10 mmol) in HO (10 mL) at 0 °C. The resulting mixture was stirred at rt for 4 h. The organic phase was separated, washed three times with HO (20 mL), and then concentrated. The resulting residue was dissolved in methyl t-butyl ether (20 mL) and reconcentrated. The crude product was mixed with n-hexane (20 mL), cooled to -20 °C, and centrifuged. The pellet was washed with n-hexane and dried under vacuum at 35 °C to give the 2-(Fmoc-2-aminoethoxy)ethanol intermediate (1.1 g) as a white solid, which was used directly without further purification. To a solution of such intermediate (1.1 g, 3.4 mmol) and DMAP (83 mg, 0.68 mmol) in DCM (20 mL) was added a solution of succinic anhydride (680 mg, 6.8 mmol) in DCM (10 mL) dropwise. The resulting reaction solution was stirred at rt for 24 h. The solvent was evaporated, and the residue was purified by preparative reverse-phase HPLC to give the protected ESL3 carboxylic acid (800 mg) as a white solid.

[0404] Synthesis of the protected linker SSL1 linker group moiety [ka] To a solution of 2,2'-dithiobis(ethylamine) dihydrochloride (2.25 g, 10 mmol) in HO (10 mL) was added NaHCO (2.52 g, 30 mmol) at 0 °C. The resulting solution was stirred for 10 min, followed by the addition of dioxane (100 mL) and succinic anhydride (1 g, 10 mmol). The reaction mixture was stirred at rt for 16 h, and then a solution of Fmoc-OSu (3.4 g, 10 mmol) and DIEA (3.3 mL) in DMF (10 mL) was added dropwise at 0 °C. The final reaction mixture was stirred at rt for 2 h and diluted with ethyl acetate. The organic phase was washed three times with HO (100 mL), dried over NaSO, concentrated, and purified by flash chromatography to give SSL1 (1.5 g) as a white solid.

[0405] Synthesis of an exemplary linker: Fmoc-Lys(-CO-CH2CH2CO2H)-OtBu fragment [ka] A solution of H-Lys(Cbz)-OtBu·HCl (5 g, 13.5 mmol), Fmoc-OSu (3.8 g, 11.25 mmol), and NaHCO₃ (3.4 g, 40.5 mmol) in dioxane (45 mL) and HO (15 mL) was stirred at rt for 2 h. The mixture was extracted three times with EA (50 mL), and the combined organic layers were washed with brine, dried over Na₂SO₄, concentrated, and purified by flash chromatography to give Fmoc-Lys(Cbz)-OtBu (6.5 g, 95% yield) as a white solid. To a solution of Fmoc-Lys(Cbz)-OtBu (3.0 g, 5.4 mmol) in EtOH (20 mL) and AcOH (2 mL) was added Pb / C (150 mg) under a hydrogen atmosphere. The mixture was stirred at 40 °C for 1 h, filtered, and the filtrate was concentrated to give Fmoc-Lys-OtBu (2.0 g) as a solid. To a solution of Fmoc-Lys-OtBu (2.7 g, 4.8 mmol) and succinic anhydride (0.48 g, 4.8 mmol) in DCM (20 mL) was added DIEA (1.24 g, 9.6 mmol). The resulting mixture was stirred at rt for 2 h, then concentrated and purified by preparative reverse-phase HPLC to give Fmoc-Lys(-CO-CHCHCOH)-OtBu (800 mg) as a white solid.

[0406] Synthesis of an exemplary linker Fmoc-NH2-CH2CH2-NH-TMA fragment [ka] To a solution of mono-Fmoc ethylenediamine hydrochloride (2.0 g, 6.2 mmol) in DMSO (30 mL) was added trimesic acid (TMA) (1.36 g, 6.6 mmol), COMU (3.2 g, 7.4 mmol), and DIEA (3.2 g, 24.8 mmol). The reaction mixture was stirred at rt for 4 h, diluted with ethyl acetate (100 mL), and extracted three times with HO (100 mL). The combined HO phase was adjusted to pH 6 by the addition of hydrochloric acid (aq.) to precipitate the product. The solid was collected by filtration and washed three times with HO (100 mL) to give Fmoc-NH-CHCH-NH-TMA (1.0 g) as a white solid.

[0407] ii) Peptide synthesis and characterization Solid Phase Peptide Synthesis Protocol The resin used was Wang resin (loading 1.1 mmol / g). The Fmoc-protected amino acid derivatives used were the standard recommended ones unless otherwise noted: Fmoc-Ala-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Cys(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Gly-OH, Fmoc-His(Trt)-OH, Fmoc-Ile-OH, Fmoc-Leu-OH, Fmoc-Lys(Boc)-OH, Fmoc-Met-OH. OH, Fmoc-Phe-OH, Fmoc-Pro-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Trp(Boc)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Val-OH, Fmoc-Lys(Mtt)-OH, Fmoc-8-amino-3,6-dioxaoctanoic acid (Fmoc-OEG-OH), Fmoc-tranexamic acid (Fmoc-Trx-OH), Fmoc-Glu-OtBu, Fmoc-3-(2-naphthyl)-L-alanine (Fmoc-2-Nal-OH), etc. Other reagents used included DOTA-tris(tert-butyl ester), palmitic acid, octadecanedioic acid mono-tert-butyl ester, and eicosanedioic acid mono-tert-butyl ester.

[0408] Preparation of [Glu(tBu)-OtBu]-urea-Lys-Wang resin [ka] Wang resin (loading 1.1 mmol / g, 5.0 mmol) was swollen in DCM (50 mL) for 30 min with N bubbling in an SPPS reaction vessel. The resin was drained and washed three times with DMF (50 mL). In a separate flask, a mixture of Fmoc-Lys(Mtt)-OH (15 mmol), DIC (15 mmol), and DMAP (0.5 mmol) in DMF (60 mL) was stirred at room temperature for 15 min and then transferred to the reaction vessel. The resulting mixture was bubbled with N for 4 h, then drained and washed six times with DMF (50 mL), followed by the addition of DMF (60 mL), acetic anhydride (50 mmol), and DMAP (0.50 mmol). The resulting mixture was bubbled with N for 2 h, then drained, and the resin was washed six times with DMF (50 mL). To remove the Fmoc group, the resulting resin was treated with 20% piperidine in DMF (60 mL) for 10 min, and this step was repeated once. The resulting resin was washed six times with DMF (50 mL). In a separate flask, DIEA (3.65 mL, 21 mmol) was added dropwise to a solution of L-glutamic acid di-tert-butyl ester hydrochloride (3.1 g, 10.5 mmol) and 4-nitrophenyl chloroformate (2 g, 10 mmol) in DCM (80 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, warmed to room temperature, and stirred for an additional 30 min before being transferred to the SPPS reaction vessel. The reaction mixture was stirred with N bubbling for 1 h, after which the resin was drained and washed six times with DMF (50 mL). To remove the Mtt group, the resin was treated with a 30% HFIP / 2.5% TIPS solution in DCM (60 mL) for 45 min with N bubbling. This step was repeated once, and the final resin was washed six times with DMF (50 mL) and used as the starting resin for assembling the PSMA-binding peptide.

[0409] Standard solid phase peptide synthesis: Assembly protocol The synthesis was carried out manually using Fmoc-based chemistry. The stepwise assembly was carried out as follows: 1) Pre-swell the resin with DCM and DMF. 2) Remove the Fmoc group with 20% piperidine (2 x 10 min treatments). 3) The resin is washed with DMF to remove piperidine. 4) Fmoc-amino acid (1 mmol), PyBOP (1 mmol), HOBt (0.2 mmol), and DMF (5 mL) are added to a reaction vessel containing 0.20 mmol of resin, followed by DIEA (2 mmol), and the resulting mixture is mixed with nitrogen bubbling for 1-2 h. 5) Drain the resin and wash with DMF. 6) If necessary, the N-ε-lysine Mtt protecting group can be removed by treating the resin with 30% (v / v) HFIP in DCM twice for 1 hour. Drain the resin and wash it with DCM and DMF. 7) If necessary, the linker Fmoc-NHCH2CH2-NH-TMA was preactivated by mixing it with DIC and HOSu in a 1:2:2 molar ratio in DMF to a final concentration of 0.20 M and stirring at room temperature for 4 hours. The activated linker (0.25 eq. resin substitution) was transferred to the peptidyl resin, and the mixture was stirred for 1 hour with N2 bubbling. This step was repeated twice, each time using 0.125 eq. (relative to resin substitution) of activated linker. 8) Final washing was performed with DMF (3 times), DCM (3 times), and MeOH (3 times).

[0410] Resin cleavage conditions and purification After completion of solid-phase peptide assembly, the resin was washed with DCM and treated with TFA / TIS / HO (95:2.5:2.5, v / v / v) for 1.5–3 h. The resin was filtered and washed once with TFA. The combined filtrates were treated with methyl tert-butyl ether (MTBE) to precipitate the crude peptide from solution. The precipitate was collected by centrifugation, washed three times with diethyl ether, and then dissolved in a minimal amount of DMF to obtain a clear solution. The DMF solution of the crude peptide was purified by reverse-phase preparative HPLC (Waters Delta Prep 4000) using a C18-reverse-phase column. Mobile phase A: 0.1% TFA HO; B: 0.1% TFA acetonitrile (ACN). Relevant fractions were analyzed by analytical UPLC. Pure fractions were pooled and lyophilized.

[0411] Post-solid-phase dimerization of peptides in solution. Isophthalic acid was preactivated by mixing it with DIC and HOSu in a 1:2:2 molar ratio in DMF to a final concentration of 0.20 M and stirring at room temperature for 4 h. The activated isophthalic acid (1.0 eq.) was transferred to a solution of peptide (2.2 eq.) in DMSO with DIEA (5 eq.), and the resulting mixture was stirred at room temperature for 16 h. One to two drops of concentrated NH4OH solution were added to the reaction mixture before reverse-phase HPLC purification.

[0412] LC-MS conditions Equipment: Agilent prime-6125B_2LCMS. Column: Boltimate EXT C18 CoreShell 4.6 x 50 mm, 2.7 μm. Detection: UV (254 nm, 214 nm, 280 nm) and MS (ESI, 100-1000 amu). Mobile phase: A: HO (0.05% formic acid); B: ACN (0.05% formic acid). Flow rate: 2.0mL / min. Column temperature: 45°C. Gradient: 10% to 95% B in 1.5 min, then 95% B for 1.0 min.

[0413] Analytical HPLC conditions Apparatus: WATERS ARC UPLC. Column: XBridge BEH Peptide BEH C18, 3.5 μm, 2.1 mm × 150 mm. Detection: UV 254nm, 214nm, 280nm. Mobile phase: A: H2O (0.1% TFA); B: ACN (0.1% TFA). Column temperature: 40°C. Flow rate: 0.6mL / min. Gradient: [Table 2]

[0414] iii) Radiochemical method 125I-complex synthesis To 38 μL of a solution of the example compound or comparative compound (20 μM in 100 mM pH 7.5 sodium phosphate), add Na 125 After adding I solution (2.0 mCi, Perkin Elmer), 14 μL of chloramine-T solution (500 μM in 100 mM pH 7.5 sodium phosphate) was added. The resulting solution was mixed well and left at room temperature for 5 min, after which 2 μL of fresh sodium ascorbate solution (50 mM in HO) was added. The resulting crude product was mixed at room temperature for 2 min and then loaded onto an Oasis HLB cartridge (10 mg) for purification. The cartridge was first washed with 0.80 mL × 3 of HO, and the product was eluted with 0.40 mL × 3 of 80% aqueous ethanol. Fractions were analyzed by radio-TLC on polyamide film using methanol and 1 M ammonium acetate (v / v: 4:1) as the mobile phase and detected on a Mini Scan (Eckert & Ziegler Radiopharma Inc.). Selected fractions were pooled and diluted with 100 mM sodium phosphate buffer, pH 7.5, containing 1% BSA and 5 mg / mL sodium ascorbate to a final activity of approximately 50–100 μCi / mL. The aliquots were stored at -80°C until use in radioligand binding assays and expired within 4 weeks of synthesis.

[0415] Using the above protocol 125 The IC-8 complex was prepared.

[0416] 177 Lu complex synthesis In 0.5 M NaOAc buffer (20-50 μL, pH = 4.5), 4 μL of the example compound or comparison compound in DMSO stock solution (2000 μM) and 2 mCi of 177Lu (ITM Isotope Technologies, Munich) was added, and the resulting mixture was heated at 95°C for 15 min. The resulting product was analyzed by radio-TLC and radio-HPLC (column: Shim-pack GIST, 5 µm, 4.6 × 150 mm; buffer A: 0.2% formic acid in HO; buffer B: 0.1% formic acid in acetonitrile; flow rate: 1 mL / min; gradient: 0–5 min: 10% B to 95% B; then 5–8 min: 95% B).

[0417] Using the same protocol as above, 177 Lu complexes were prepared.

[0418] Synthesis of Exemplary Compounds of Formula I The following exemplary compounds of Formula I were prepared by the above method:

[0419] Example 1: 4pIBA-Glu-SSL1-Lys(DOTA)-Trx-2Nal-eKuE (I-1) [ka] Calculated molecular weight (average): 1805.86 g / mol. Determined by LC-MS: (M+2H)2+: 903.3; (M+3H)3+: 602.8. Purity by UPLC (214 nm): 98.8%.

[0420] Example 2: 4pIBA-Glu-ESL1-Lys(DOTA)-Trx-2Nal-eKuE(I-2) [ka] Calculated molecular weight (average): 1714.67 g / mol. Determined by LC-MS: (M+2H)2+: 858.3; (M+3H)3+: 572.5. Purity by UPLC (214 nm): 97.4%.

[0421] Example 3: 4pIBA-Glu-Lys(-ESL1-DOTA)-Trx-2Nal-eKuE(I-3) [ka] Calculated molecular weight (average): 1714.67 g / mol. Determined by LC-MS: (M+2H)2+: 858.4; (M+3H)3+: 572.4. Purity by UPLC (214 nm): 95.5%.

[0422] Example 4: 4pIBA-Glu-Lys(-SSL1-DOTA)-Trx-2Nal-eKuE, (I-4) [ka] Calculated molecular weight (average): 1805.86 g / mol. Determined by LC-MS: (M+2H)2+: 903.8; (M+3H)3+: 602.8. Purity by UPLC (214 nm): 96.8%.

[0423] Example 5: 4pIBA-Glu-Lys(-ESL2-DOTA)-Aun-Trx-2Nal-eKuE(I-5) [ka] Calculated molecular weight (average): 2041.1 g / mol. LC-MS determination: (M+3H)3+: 681.2. Purity by UPLC (214 nm): 98.3%.

[0424] Example 6: DOTA-ESL2-Lys(-Glu-4pIBA)-Trx-2Nal-eKuE(I-6) [ka] Calculated molecular weight (average): 1857.81 g / mol. Determined by LC-MS: (M+2H)2+: 929.8; (M+3H)3+: 620.3. Purity by UPLC (214 nm): 97.13%.

[0425] Example 7: 4pIBA-Glu-OEG-Lys(-OEG-OEG-Glu-4pIBA)-Lys(-ESL1-DOTA)-OEG-Trx-2Nal-eKuE(I-7) [ka] Calculated molecular weight (average): 2969.84 g / mol. Determined by LC-MS: (M+2H)2+: 1486.4; (M+3H)3+: 991.6. Purity by UPLC (214 nm): 98.7%.

[0426] Example 8: 4pIBA-Glu-OEG-Lys(-OEG-OEG-Glu-4pIBA)-OEG-ESL1-Lys(DOTA)-Trx-2Nal-eKuE(I-8) [ka] Calculated molecular weight (average): 2969.84 g / mol. Determined by LC-MS: (M+2H)2+: 1485.5; (M+3H)3+: 990.5. Purity by UPLC (214 nm): 98.9%.

[0427] Example 9: 4pIBA-Glu-Lys[-Suc-eLys-Val-Met-Gly-DOTA]-Trx-2Nal-eKuE(I-9) [ka] Calculated molecular weight (average): 2087.16 g / mol. Determined by LC-MS: (M+2H)2+: 1044.4; (M+3H)3+: 696.5. Purity by UPLC (214 nm): 96.5%.

[0428] Example 10: HO-C18-gGlu-Lys(-ESL1-DOTA)-OEG-OEG-Trx-2Nal-eKuE(I-10) [ka] Calculated molecular weight (average): 2174.51 g / mol. Determined by LC-MS: (M+3H)3+: 725.7; (M+4H)4+: 544.6. Purity by UPLC (214 nm): 97.1%.

[0429] Example 11: HO-C18-gGlu-Lys(-ESL1-DOTA)-OEG-OEG-OEG-OEG-Trx-2Nal-eKuE(I-11) [ka] Calculated molecular weight (average): 2610.00 g / mol. Determined by LC-MS: (M+3H)3+: 870.7; (M+4H)4+: 653.4; (M+5H)5+: 523.0. Purity by UPLC (214 nm): 100%.

[0430] Example 12: HO-C18-gGlu-Lys(-ESL2-DOTA)-OEG-OEG-Trx-2Nal-eKuE(I-12) [ka] Calculated molecular weight (average): 2172.50 g / mol. Determined by LC-MS: (M+3H)3+: 724.9; (M+4H)4+: 544.0. Purity by UPLC (214 nm): 95.3%.

[0431] Example 13: HO-C18-gGlu-Lys(-ESL2-DOTA)-OEG-OEG-Trx-2Nal-eKuE(I-13) [ka] Calculated molecular weight (average): 2317.55 g / mol. Determined by LC-MS: (M+2H)2+: 1159.3; (M+3H)3+: 773.3; (M+4H)4+: 580.4. Purity by UPLC (214 nm): 96.6%.

[0432] Example 14: HO-C20-gGlu-Lys(-ESL2-DOTA)-OEG-OEG-Trx-2Nal-eKuE(I-14) [ka] Calculated molecular weight (average): 2345.71 g / mol. Determined by LC-MS: (M+2H)2+: 1173.6; (M+3H)3+: 782.6; (M+4H)4+: 587.3. Purity by UPLC (214 nm): 99.2%.

[0433] Example 15: HO-C18-gGlu-Lys(-ESL2-DOTA)-OEG-OEG-OEG-Trx-2Nal-eKuE(I-15) [ka] Calculated molecular weight (average): 2462.81 g / mol. Determined by LC-MS: (M+2H)2+: 1232.0; (M+3H)3+: 821.7; (M+4H)4+: 616.6. Purity by UPLC (214 nm): 99.6%.

[0434] Example 16: HO-C18-gGlu-OEG-OEG-Lys(-ESL2-DOTA)-OEG-Trx-2Nal-eKuE(I-16) [ka] Calculated molecular weight (average): 2317.65 g / mol. Determined by LC-MS: (M+2H)2+: 1159.3; (M+3H)3+: 773.3; (M+4H)4+: 580.4. Purity by UPLC (214 nm): 96.6%.

[0435] Example 17: HO-C20-gGlu-OEG-Lys(-ESL1-DOTA)-OEG-OEG-Trx-2Nal-eKuE(I-17) [ka] Calculated molecular weight (average): 2202.57 g / mol. Determined by LC-MS: (M+2H)2+: 1101.8; (M+3H)3+: 735.0; (M+4H)4+: 551.7. Purity by UPLC (214 nm):

[0436] Example 18: HO-C18-gGlu-OEG-OEG-Lys(-ESL1-DOTA)-OEG-Trx-2Nal-eKuE(I-18) [ka] Calculated molecular weight (average): 2173.51 g / mol. Determined by LC-MS: (M+2H)2+: 1087.8; (M+3H)3+: 725.7; (M+4H)4+: 544.6. Purity by UPLC (214 nm): 96.6%.

[0437] Example 19: HO-C18-gGlu-OEG-OEG-OEG-OEG-ESL1-Lys(DOTA)-Trx-2Nal-eKuE(I-19) [ka] Calculated molecular weight (average): 2610.00 g / mol. Determined by LC-MS: (M+2H)2+: 1306.0; (M+3H)3+: 870.7; (M+4H)4+: 653.3. Purity by UPLC (214 nm): 99.3%.

[0438] Example 20: HO-C18-gGlu-OEG-OEG-ESL2-Lys(DOTA)-OEG-Trx-2Nal-eKuE(I-20) [ka] Calculated molecular weight (average): 2317.65 g / mol. Determined by LC-MS: (M+2H)2+: 1159.4; (M+3H)3+: 773.4. Purity by UPLC (214 nm): 97.1%.

[0439] Example 21: HO-C18-gGlu-OEG-OEG-ESL1-Lys(DOTA)-OEG-Trx-2Nal-eKuE(I-21) [ka] Calculated molecular weight (average): 2174.51 g / mol. Determined by LC-MS: (M+2H)2+: 1087.8; (M+3H)3+: 725.7. Purity by UPLC (214 nm): 98.4%.

[0440] Example 22: HO-C18-gGlu-OEG-ESL1-ESL1-Lys(DOTA)-OEG-Trx-2Nal-eKuE(I-22) [ka] Calculated molecular weight (average): 2172.50 g / mol. Determined by LC-MS: (M+2H)2+: 1087.1; (M+3H)3+: 725.0. Purity by UPLC (214 nm): >99.0%.

[0441] Example 23: HO-C18-gGlu-ESL1-ESL1-ESL1-Lys(DOTA)-OEG-Trx-2Nal-eKuE(I-23) [ka] Calculated molecular weight (average): 2170.48 g / mol. Determined by LC-MS: (M+2H)2+: 1086.0; (M+3H)3+: 724.4. Purity by UPLC (214 nm): 97.7%.

[0442] Example 24: HO-C18-gGlu-OEG-OEG-OEG-ESL1-Lys(DOTA)-OEG-Trx-2Nal-eKuE(I-24) [ka] Calculated molecular weight (average): 2609.99 g / mol. Determined by LC-MS: (M+2H)2+: 1305.3; (M+3H)3+: 870.8; (M+4H)4+: 653.4. Purity by UPLC (214 nm): >99.0%.

[0443] Example 25: HO-C20-gGlu-OEG-OEG-ESL1-Lys(DOTA)-OEG-Trx-2Nal-eKuE(I-25) [ka] Calculated molecular weight (average): 2202.57 g / mol. Determined by LC-MS: (M+2H)2+: 1101.8; (M+3H)3+: 735.0. Purity by UPLC (214 nm): 98.8%.

[0444] Example 26: HO-C18-gGlu-OEG-OEG-ESL1-OEG-Lys(DOTA)-Trx-2Nal-eKuE(I-26) [ka] Calculated molecular weight (average): 2174.51 g / mol. Determined by LC-MS: (M+2H)2+: 1087.8; (M+3H)3+: 725.6. Purity by UPLC (214 nm): 94.0%.

[0445] Example 27: HO-C18-gGlu-ESL1-OEG-OEG-Lys(DOTA)-OEG-Trx-2Nal-eKuE(I-27) [ka] Calculated molecular weight (average): 2174.51 g / mol. Determined by LC-MS: (M+2H)2+: 1087.6; (M+3H)3+: 725.7. Purity by UPLC (214 nm): 95.6%.

[0446] Example 28: HO-C18-gGlu-gGlu-OEG-OEG-ESL1-Lys(DOTA)-OEG-Trx-2Nal-eKuE(I-28) [ka] Calculated molecular weight (average): 2432.74 g / mol. Determined by LC-MS: (M+2H)2+: 1217.2; (M+3H)3+: 811.8. Purity by UPLC (214 nm): >99.0%.

[0447] Example 29: HO-C20-gGlu-OEG-ESL1-ESL1-Lys(DOTA)-OEG-Trx-2Nal-eKuE(I-29) [ka] Calculated molecular weight (average): 2200.55 g / mol. Determined by LC-MS: (M+2H)2+: 1101.0; (M+3H)3+: 734.3. Purity by UPLC (214 nm): >99.0%.

[0448] Example 30: HO-C16-gGlu-OEG-OEG-ESL1-Lys(DOTA)-OEG-Trx-2Nal-eKuE(I-30) [ka] Calculated molecular weight (average): 2146.46 g / mol. Determined by LC-MS: (M+2H)2+: 1074.0; (M+3H)3+: 716.6. Purity by UPLC (214 nm): 95.4%.

[0449] Example 31: HO-C18-gGlu-OEG-OEG-ESL3-Lys(DOTA)-OEG-Trx-2Nal-eKuE(I-31) [ka] Calculated molecular weight (average): 2218.56 g / mol. Determined by LC-MS: (M+2H)2+: 1109.8; (M+3H)3+: 740.3. Purity by UPLC (214 nm): >99.0%.

[0450] Example 32: (HO-C18)-gGlu-OEG-OEG-OEG-Glu-Arg-Gly-Thr-Gly-Pro-Ser-Gly-OEG-Lys(-ESL1-DOTA)-Trx-2Nal-eKuE(I-32) [ka] Calculated molecular weight (average): 3480.86 g / mol. Determined by LC-MS: (M+2H)2+: 1741.2; (M+3H)3+: 1160.8; (M+4H)4+: 871.0. Purity by UPLC (214 nm): 99.7%.

[0451] Example 33: 4pIBA-Glu-OEG-NHCHCHNH-TMA[-ESL-Lys(DOTA)-Trx-2Nal-eKuE] (I-33) [ka] Calculated molecular weight (average): 3389.50 g / mol. Determined by LC-MS: (M+2H)2+: 1694.9; (M+3H)3+: 1130.3; (M+4H)4+: 848.0. Purity by UPLC (214 nm): 99.2%.

[0452] Example 34: HO-C18-gGlu-Lys(-ESL1-DOTA)-OEG-OEG-OEG-N NH2CH2CH2NH-TMA(-OEG-Trx-2Nal-eKuE)2(I-34) [ka] Calculated molecular weight (average): 3336.77 g / mol. Determined by LC-MS: (M+2H)2+: 1670.4; (M+3H)3+: 1114.0; 835.7. Purity by UPLC (214 nm): 97.1%.

[0453] Example 35: HO-C20-gGlu-OEG-OEG-Lys(-ESL1-DOTA)-OEG-NH2CH2CH2NH-TMA(-OEG-Trx-2Nal-eKuE)2(I-35) [ka] Calculated molecular weight (average): 3364.83 g / mol. Determined by LC-MS: (M+2H)2+: 1682.6; (M+3H)3+: 1122.3; (M+4H)4+: 842.0; (M+5H)5+: 673.9. Purity by UPLC (214 nm): 99.6%.

[0454] Example 36: HO-C20-gGlu-Lys(-ESL2-DOTA)-OEG-OEG-OEG-NH2CH2CH2NH-TMA(-OEG-Trx-2Nal-eKuE)2(I-36) [ka] Calculated molecular weight (average): 3507.97 g / mol. Determined by LC-MS: (M+3H)3+: 1169.9; (M+4H)4+: 877.8; (M+5H)5+: 702.5. Purity by UPLC (214 nm): 99.6%.

[0455] Example 37: HO-C20-gGlu-Lys(-ESL1-ESL1-DOTA)-OEG-OEG-NH2CH2CH2NH-TMA(-OEG-Trx-2Nal-eKuE)2(I-37) [ka] Calculated molecular weight (average): 3507.97 g / mol. Determined by LC-MS: (M+3H)3+: 1169.9; (M+4H)4+: 877.8; (M+5H)5+: 702.4. Purity by UPLC (214 nm): 99.6%.

[0456] Example 38: HO-C18-gGlu-OEG-OEG-Lys(-ESL1-DOTA)-OEG-NH2CH2CH2NH-TMA(-OEG-Trx-2Nal-eKuE)2(I-38) [ka] Calculated molecular weight (average): 3336.77 g / mol. Determined by LC-MS: (M+2H)2+: 1668.6; (M+3H)3+: 1112.9; (M+4H)4+: 835.0; (M+5H)5+: 668.4. Purity by UPLC (214 nm): 98.9%.

[0457] Example 39: HO-C18-gGlu-Lys(-ESL2-DOTA)-OEG-OEG-NH2CH2CH2NH-TMA(-OEG-Trx-2Nal-eKuE)2(I-39) [ka] Calculated molecular weight (average): 3479.91 g / mol. Determined by LC-MS: (M+2H)2+: (M+3H)3+: 1160.6; (M+4H)4+: 870.8; (M+5H)5+: 696.8. Purity by UPLC (214 nm): 96.8%.

[0458] Example 40: HO-C18-gGlu-OEG-Lys(-ESL1-DOTA)-OEG-NH2CH2CH2NH-TMA(-OEG-Trx-2Nal-eKuE)2(I-40) [ka] Calculated molecular weight (average): 3191.61 g / mol. Determined by LC-MS: (M+2H)2+: 1596.5; (M+3H)3+: 1064.6; (M+4H)4+: 798.8. Purity by UPLC (214 nm): >99.0%.

[0459] Example 41: HO-C18-gGlu-OEG-OEG-NH2CH2CH2NH-TMA[-ESL1-Lys(DOTA)-Trx-2Nal-eKuE]2(I-41) [ka] Calculated molecular weight (average): 3559.02 g / mol. Determined by LC-MS: (M+2H)2+: (M+3H)3+: 1186.9; (M+4H)4+: 890.4; (M+5H)5+: 712.7. Purity by UPLC (214 nm): 98.2%.

[0460] Example 42: HO-C20-gGlu-OEG-OEG-NH2CH2CH2NH-TMA[-ESL1-Lys(DOTA)-Trx-2Nal-eKuE]2(I-42) [ka] Calculated molecular weight (average): 3587.07 g / mol. Determined by LC-MS: (M+3H)3+: 1196.4; (M+4H)4+: 897.5; (M+5H)5+: 718.4. Purity by UPLC (214 nm): 99.2%.

[0461] Example 43: [HO-C18-gGlu-OEG-OEG-ESL1-Lys(DOTA)-OEG-NH2CH2CH2NH-]-TMA-(-OEG-Trx-2Nal-eKuE)2(I-43) [ka] Calculated molecular weight (average): 3336.77 g / mol. Determined by LC-MS: (M+2H)2+: 1669.0; (M+3H)3+: 1112.9; (M+4H)4+: 835. Purity by UPLC (214 nm): >99.0%.

[0462] Example 44: [HO-C20-gGlu-Lys(-ESL1-ESL1-ESL1-DOTA)-OEG-OEG-OEG-NH2CH2CH2NH-]-TMA-(-OEG-Trx-2Nal-eKuE)2(I-44) [ka] Calculated molecular weight (average): 3651.11 g / mol. Determined by LC-MS: (M+3H)3+: 1217.7; (M+4H)4+: 913.5; (M+5H)5+: 731.2. Purity by UPLC (214 nm): >99.0%.

[0463] Example 45: HO-C18-gGlu-OEG-OEG-Lys(-ESL1-Gly-Gly-DOTA)-OEG-Trx-2Nal-eKuE(I-45) [ka] Calculated molecular weight (average): 2288.6 g / mol. Determined by LC-MS: (M+2H)2+: 1145.0; (M+3H)3+: 763.6; (M+4H)4+: 573.0. Purity by UPLC (214 nm): >99.0%.

[0464] Example 46: HO-C18-gGlu-OEG-OEG-Lys(-ESL1-Gly-Gly-Gly-DOTA)-OEG-Trx-2Nal-eKuE(I-46) [ka] Calculated molecular weight (average): 2345.7 g / mol. Determined by LC-MS: (M+2H)2+: 1173.4; (M+3H)3+: 782.6; (M+4H)4+: 587.3. Purity by UPLC (214 nm): >99.0%.

[0465] Example 47: HO-C18-gGlu-OEG-OEG-Lys(-ESL1-OEG-DOTA)-OEG-Trx-2Nal-eKuE(I-47) [ka] Calculated molecular weight (average): 2319.7 g / mol. Determined by LC-MS: (M+2H)2+: 1160.5; (M+3H)3+: 774.0; (M+4H)4+: 580.8. Purity by UPLC (214 nm): 95.4%.

[0466] Example 48: HO-C18-gGlu-OEG-OEG-Lys(-ESL1-Gly-OEG-DOTA)-OEG-Trx-2Nal-eKuE [ka] Calculated molecular weight (average): 2376.7 g / mol. Determined by LC-MS: (M+2H)2+: 1188.9; (M+3H)3+: 793.1; (M+4H)4+: 595.2. Purity by UPLC (214 nm): 98.1%.

[0467] Example 49: HO-C18-gGlu-OEG-OEG-Gly-5hPA-Lys(DOTA)-OEG-Trx-2Nal-eKuE(I-49) [ka] Calculated molecular weight (average): 2188.5 g / mol. Determined by LC-MS: (M+2H)2+: 1094.8; (M+3H)3+: 730.3. Purity by UPLC (214 nm): >94.8%.

[0468] Example 50: HO-C18-gGlu-OEG-OEG-Gly-6hHA-Lys(DOTA)-OEG-Trx-2Nal-eKuE(I-50) [ka] Calculated molecular weight (average): 2202.6 g / mol. Determined by LC-MS: (M+2H)2+: 1101.8; (M+3H)3+: 735.0. Purity by UPLC (214 nm): 95.3%.

[0469] Example 51: HO-C18-gGlu-OEG-OEG-ESL1-Gly-Lys(DOTA)-OEG-Trx-2Nal-eKuE(I-51) [ka] Calculated molecular weight (average): 2231.6 g / mol. Determined by LC-MS: (M+2H)2+: 1116.3; (M+3H)3+: 744.7. Purity by UPLC (214 nm): >99.0%.

[0470] Example 52: HO-C18-gGlu-OEG-OEG-ESL1-Gly-Gly-Lys(DOTA)-OEG-Trx-2Nal-eKuE(I-52) [ka] Calculated molecular weight (average): 2288.6 g / mol. Determined by LC-MS: (M+2H)2+: 1144.7; (M+3H)3+: 763.7. Purity by UPLC (214 nm): 96.7%.

[0471] Example 53: HO-C18-gGlu-OEG-OEG-Gly-4hPA-OEG-Lys(DOTA)-Trx-2Nal-eKuE(I-53) [ka] Calculated molecular weight (average): 2188.5 g / mol. Determined by LC-MS: (M+2H)2+: 1095.1; (M+3H)3+: 730.3. Purity by UPLC (214 nm): >99.0%.

[0472] Example 54: HO-C18-gGlu-OEG-OEG-Leu-4hBA-OEG-Lys(DOTA)-Trx-2Nal-eKuE(I-54) [ka] Calculated molecular weight (average): 2230.6 g / mol. Determined by LC-MS: (M+2H)2+: 1115.9; (M+3H)3+: 744.3. Purity by UPLC (214 nm): >99.0%.

[0473] Example 55(a): HO-C18-gGlu-OEG-Leu-4hPA-OEG-Lys(DOTA)-Trx-2Nal-eKuE(I-55(a)) [ka] and Example 55(b): HO-C18-gGlu-OEG-Leu-4hPA-OEG-Lys(DOTA)-Trx-2Nal-eKuE(I-55(b)) [ka] I-55 was prepared as a mixture of two diastereomers using racemic 4hPA. Each diastereomer was separated and isolated using HPLC. The characteristics of each isomer by UPLC are shown below. It was not determined which of the two compounds had the (R) configuration with 4hPA and which had the (S) configuration with 4hPA. Data in (i) refer to one of I-55(a) and I-55(b), and data in (ii) refer to the other of I-55(a) or I-55(b).

[0474] (i) Calculated molecular weight (average): 2244.7 g / mol. Determined by LC-MS: (M+2H)2+: 1122.9; (M+3H)3+: 749.0. Purity by UPLC (214 nm): >99.0%. Retention time: 7.58 min, and

[0475] (ii) Calculated molecular weight (average): 2244.7 g / mol. Determined by LC-MS: (M+2H)2+: 1122.8; (M+3H)3+: 749.0. Purity by UPLC (214 nm): 97.6%. Retention time: 7.66 minutes.

[0476] Example 56: HO-C18-gGlu-OEG-OEG-OEG-ESL1-Lys(DOTA)-Trx-2Nal-eKuE(I-56) [ka] Calculated molecular weight (average): 2174.5 g / mol. Determined by LC-MS: (M+2H)2+: 1087.7; (M+3H)3+: 725.6. Purity by UPLC (214 nm): >99.0%.

[0477] Example 57: HO-C18-gGlu-OEG-Gly-OCH2CO-Lys(DOTA)-OEG-Trx-2Nal-eKuE(I-57) [ka] Calculated molecular weight (average): 2146.5 g / mol. Determined by LC-MS: (M+2H)2+: 1073.6; (M+3H)3+: 716.3. Purity by UPLC (214 nm): 86.8%.

[0478] Example 58: HO-C18-gGlu-OEG-ESL1-Gly-Gly-Lys(DOTA)-OEG-Trx-2Nal-eKuE(I-58) [ka] Calculated molecular weight (average): 2345.7 g / mol. Determined by LC-MS: (M+2H)2+: 1173.4; (M+3H)3+: 782.8. Purity by UPLC (214 nm): 99.2%.

[0479] Example 59: HO-C18-gGlu-OEG-OEG-Dab-4hBA-Lys(DOTA)-OEG-Trx-2Nal-eKuE(I-59) [ka] Calculated molecular weight (average): 2217.6 g / mol. Determined by LC-MS: (M+2H)2+: 1109.7; (M+3H)3+: 740.0. Purity by UPLC (214 nm): 88.1%.

[0480] Example 60: HO-C18-gGlu-OEG-OEG-Leu-4hBA-Lys(DOTA)-Trx-2Nal-eKuE(I-60) [ka] Calculated molecular weight (average): 2085.5 g / mol. Determined by LC-MS: (M+2H)2+: 1043.5; (M+3H)3+: 696.0. Purity by UPLC (214 nm): 94.1%.

[0481] Example 61: HO-C18-gGlu-OEG-ESL1-Lys(DOTA)-OEG-Gly-Tyr-Phe-eKuE(I-61) [ka] Calculated molecular weight (average): 2205.5 g / mol. Determined by LC-MS: (M+2H)2+: 1103.5; (M+3H)3+: 736.0. Purity by UPLC (214 nm): >99.0%.

[0482] Example 62: HO-C18-gGlu-OEG-OEG-ESL1-k(DOTA)-OEG-Trx-2Nal-eKuE(I-62) [ka] Calculated molecular weight (average): 2174.5 g / mol. Determined by LC-MS: (M+2H)2+: 1087.8; (M+3H)3+: 725.6. Purity by UPLC (214 nm): 95.8%.

[0483] Example 63: HO-C18-gGlu-OEG-OEG-ESL1-Dab(DOTA)-OEG-Trx-2Nal-eKuE(I-63) [ka] Calculated molecular weight (average): 2146.5 g / mol. Determined by LC-MS: (M+2H)2+: 1074.1; (M+3H)3+: 716.4. Purity by UPLC (214 nm): >99.0%.

[0484] Example 64: HO-C18-gGlu-OEG-ESL1-Gly-Gly-Lys(DOTA)-OEG-Gly-Tyr-Phe-eKuE(I-64) [ka] Calculated molecular weight (average): 2319.6 g / mol. Determined by LC-MS: (M+2H)2+: 1160.4; (M+3H)3+: 774.0. Purity by UPLC (214 nm): >99.0%.

[0485] Example 65: HO-C18-gGlu-OEG-ESL1-Gly-Gly-Lys(DOTA)-OEG-Gly-Tyr-Phe-eKuE(I-65) [ka] Calculated molecular weight (average): 2376.6 g / mol. Determined by LC-MS: (M+2H)2+: 1189.0; (M+3H)3+: 793.0. Purity by UPLC (214 nm): 97.9%.

[0486] Example 66: HO-C18-gGlu-OEG-Gly-5hPA-Lys(DOTA)-OEG-Gly-Tyr-Phe-eKuE(I-66) [ka] Calculated molecular weight (average): 2219.5 g / mol. Determined by LC-MS: (M+2H)2+: 1110.3; (M+3H)3+: 740.7. Purity by UPLC (214 nm): >99.0%.

[0487] Example 67: 4pIBA-gGlu-OEG-ESL1-Lys(DOTA)-OEG-Trx-2Nal-eKuE (I-67) [ka] Calculated molecular weight (average): 2150.2 g / mol. Determined by LC-MS: (M+2H)2+: 1075.7; (M+3H)3+: 717.5. Purity by UPLC (214 nm): 94.9%.

[0488] Example 68: C18-gGlu-OEG-OEG-ESL1-Lys(DOTA)-OEG-Trx-2Nal-eKuE(I-68) [ka] Calculated molecular weight (average): 2144.5 g / mol. Determined by LC-MS: (M+2H)2+: 1072.7; (M+3H)3+: 715.7. Purity by UPLC (214 nm): 97.8%.

[0489] Example 69: 4pIBA-gGlu-OEG-OEG-Lys(-ESL1-DOTA)-OEG-Trx-2Nal-eKuE(I-69) [ka] Calculated molecular weight (average): 2150.2 g / mol. Determined by LC-MS: (M+2H)2+: 1075.6; (M+3H)3+: 717.4. Purity by UPLC (214 nm): 97.8%.

[0490] Synthesis of comparative compounds The following comparative compounds were synthesized using the above method.

[0491] Control 1: PSMA-617, DOTA-Trx-2Nal-eKuE (C-1) [ka] Calculated molecular weight (average): 1042.14 g / mol. LC-MS determined: (M+2H)2+: 521.8. Purity by UPLC (214 nm): >99.0%.

[0492] Comparison control 2: HTK01169, 4pIBA-Glu-Lys(DOTA)-Trx-2Nal-eKuE(C-2) [ka] Calculated molecular weight (average): 1571.53 g / mol. Determined by LC-MS: (M+2H)2+: 786.4; (M+3H)3+: 524.7. Purity by UPLC (214 nm): 96.8%.

[0493] Control 3: C16-gGlu-OEG-OEG-K(DOTA)-Trx-2Nal-eKuE (C-3) [ka] Calculated molecular weight (average): 1973.33 g / mol. Determined by LC-MS: (M+2H)2+: 987.5; (M+3H)3+: 658.7. Purity by UPLC (214 nm): 99.8%.

[0494] Comparison control 4: HO-C18-gGlu-K(DOTA)-Trx-2Nal-eKuE(C-4) [ka] Calculated molecular weight (average): 1595.50 g / mol. Determined by LC-MS: (M+2H)2+: 799.0; (M+3H)3+: 532.9. Purity by UPLC (214 nm): 97.0%.

[0495] Comparison with reference image 5: C16-gGlu-K(DOTA)-Trx-2Nal-eKuE(C-5)

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[0496] Comparison photo 6: HO-C18-gGlu-OEG-OEG-Lys(DOTA)-OEG-Trx-2Nal-eKuE(C-6)

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[0497] Comparison photo 7: (HO-C18-gGlu-Lys(-OEG-DOTA)-OEG-OEG-NH2CH2CH2NH-TMA(-OEG-Trx-2Nal-eKuE))2(C-7)

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[0498] Comparison with photo 8 (C-8)

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[0499] Control 9: DOTA-gGlu(-eLys-4pI.BA)-Trx-2Nal-eKuE(C-9) [ka] Calculated molecular weight (average): 1571.5 g / mol. Determined by LC-MS: (M+2H)2+: 786.4; (M+3H)3+: 524.8. Purity by UPLC (214 nm): 99.3%. Comparator 9 (DOTA-gGlu(-eLys-4pIBA)-Trx-2Nal-eKuE) is disclosed in US Pat. No. 11,147,889.

[0500] Comparison control 10:DOTA-Lys(pTBA)-Trx-2Nal-eKuE(PSMA-ALB-56)(C-10) [ka] Calculated molecular weight (average): 1330.6 g / mol. LC-MS determination: (M+2H)2+: 666.1. Purity by UPLC (214 nm): >99.0%.

[0501] Control 10 (DOTA-Lys(pTBA)-Trx-2Nal-eKuE) is also known as PSMA-ALB-56 (Muller et al. Mol. Pharmaceutics, 2018, 15, 2297-2306).

[0502] B: Biological data Cell-based binding assays cell culture LNCaP cells (ATCC) were maintained in RPMI-1640 medium (Gibco) supplemented with 15% fetal bovine serum (Gibco) and 1% penicillin-streptomycin (BI) in a humidified incubator at 37°C and 5% CO2. The medium was replaced with fresh medium every 2–3 days. Experiments were performed on cells at 70–80% confluence.

[0503] Binding Assay Protocol The binding affinity of the test compound was determined by 125 The binding activity was determined by a competitive cell binding assay using I-C8 as a radioligand. 1–3 × 10 cells were added to the binding buffer (RPMI-1640 medium supplemented with 0.25% bovine serum albumin) in a 5% COOH / 2000 mM MHC1 / 20 ... 6 LNCaP cells suspended at a density of 10 ... 125 The cells were incubated with IC-8 (0.02 μCi / well) at 37°C for 1 hour (n=3). The final volume of each well was maintained at 200 μL, and the insufficient volume was adjusted with binding buffer. After 1 hour of incubation, unbound 125 IC-8 was filtered using a Multiscreen vacuum manifold (Millipore) and washed three times with binding buffer. The filters were recovered, and radioactivity was measured individually using a γ-counter (2480 WIZARD2, PerkinElmer). Nonlinear regression was performed using GraphPad Prism 8.0.1 to determine the best-approximated IC value for the test compound. 50 The inhibitory concentration (the concentration at which 50% of the 125I-C-8 bound to the cells disappeared) was calculated.

[0504] Stability testing Plasma stability test (mouse and human) Mouse blood was collected by cardiac puncture of the left ventricle. The blood was placed in a heparin-coated microfuge tube and centrifuged at 3500 rpm for 10 minutes to separate plasma for stability testing. Human plasma was purchased directly.

[0505] 2.0mCi 177Lu-labeled peptide was placed in 50 μL of labeling buffer, mixed with 0.20 mL of mouse serum and 50 μL of 0.8 M sodium phosphate buffer (pH 7.4), and incubated at 37°C. At each time point (0, 1, 2, 4, 24, 48, and 72 h), 25 μL samples were taken and mixed with 100 μL of 1% formic acid in methanol. After 30–60 s of incubation, the samples were centrifuged at 20,000 rpm for 10 min. 100 μL of the supernatant was collected and diluted with 40 μL of HO. 100 μL of the resulting mixture was injected into a radio-HPLC system for stability evaluation, as shown in Figures 2 and 3. Data were fitted using linear or nonlinear regression in GraphPad Prism 8.0.1 to calculate the best approximation of the T1 / 2 value of the test compound.

[0506] Buffer solution stability test (pH 4.5 and pH 7.4) 177 Lu-labeled peptides were diluted with 25 mM NaOAc buffer (pH 4.5), 25 mM NaOAc buffer and 3 mg / mL ascorbic acid, PBS, and PBS and 3 mg / mL ascorbic acid to approximately 1.5 mCi / 0.30 mL. Samples were incubated at room temperature. At 0, 1, 4, 24, 48, and 72 hours, 25 μL aliquots were withdrawn and injected into radio-HPLC for stability evaluation. Linear or nonlinear regression was performed using GraphPad Prism 8.0.1 to calculate best-approximation T values ​​for test compounds.

[0507] Biodistribution studies Biodistribution study in PC3-PIP tumor-bearing SCID mice These studies used severe combined immunodeficiency (ICR-SCID) mice from the Institute of Cancer Research (Taconic Farms, Germantown, NY). Mice were housed four per cage in sterile microisolator cages under temperature- and humidity-controlled conditions with a 12-hour light / 12-hour dark cycle. They were fed autoclaved rodent chow (Ralston Purina 300 Company, St. Louis, MO) and oxygenated water ad libitum. In preparation for tumor cell inoculation, SCID mice were anesthetized with isoflurane (Baxter Healthcare Corp., Deerfield, IL) at a 4% induction rate and maintained at a 2.5% anesthesia rate with 0.4 L of oxygen using a precision vaporizer and nonrebreathing device. These mice received approximately 10 × 10 cytotoxic T cells suspended in 0.9% NaCl. 6 100 μL of PC-3 PIP cells (prostate cancer cells PC-3 stably expressing human PSMA) were injected subcutaneously into both dorsal regions. Xenograft tumors were allowed to grow for approximately 3-5 weeks after inoculation, with masses ranging from 0.05 to 2.26 g (average tumor size 0.39 g). Biodistribution studies were performed using SCID mice (average body weight 28.4 g) by tail vein injection of approximately 5.0-30 μCi (approximately 0.185-1.11 MBq) of test compound with a specific activity of 83-300 μCi / nmol in 100 μL of 0.9% NaCl. Mice were euthanized, and tissues and organs were harvested 1, 4, 24, 48, 72, 96, 120, and 168 hours after injection. Tissues and organs were weighed and counted on a PerkinElmer Wizard 3 automated gamma counter, and the injected dose rate (%ID) and %ID / g for each organ or tissue were calculated as shown in Tables 5-24 and Figures 1 and 2. The %ID in whole blood was estimated assuming a total blood volume of 6.5% of body weight.

[0508] Biodistribution study using LNCap tumor-bearing CB-17 SCID mice All animal care and experimental procedures were performed in accordance with animal protocols approved by the Ethics Committee of the China Institute of Radiation Protection. CB-17 SCID mice (Charles River, Beijing) were used for these studies. Mice were housed in sterile microisolator cages, no more than five per cage, under temperature- and humidity-controlled conditions with a 12-hour light / 12-hour dark cycle. They were provided with irradiated rodent chow and reverse osmosis (RO) sterilized water ad libitum. In preparation for tumor cell inoculation, mice were anesthetized with isoflurane (RWD Life Science Inc.) at a 4% induction rate and maintained at a 2.5% induction rate while providing 0.4 L of oxygen using a precision vaporizer and a non-rebreathing device. These mice received approximately 4 × 10 6 LNCap cells were suspended in 200 μL of phosphate-buffered saline (PBS) and Matrigel (Corning) (1:1) and injected subcutaneously into the dorsal flank. Xenograft tumors were allowed to grow for approximately 2-4 weeks after inoculation, reaching masses of 0.05-0.50 g (average tumor size 0.20 g). Biodistribution studies in nude mice were performed by tail vein injection of approximately 10-50 μCi (approximately 0.37-1.85 MBq) of test compound with a specific activity of 50-250 μCi / nmol in 100 μL of 0.9% NaCl. Mice were euthanized, and tissues and organs were harvested 1, 4, 24, 48, 72, 96, 120, and 168 hours postinjection. Tissues and organs were weighed and counted on a PerkinElmer 2480 WIZARD2 gamma counter, and the percent injected dose (%ID) and %ID / g for each organ or tissue were calculated as shown in Tables 25-33.

[0509] Human image data Whole-body PET / CT scans were performed using a United Imaging uMI780 scanner at a dose of 0.05 mCi per kg of body weight. 68 The whole-body scintigraphy and SPECT / CT imaging were performed approximately 60 minutes after administration of Ga-PSMA11 (gozetotide). 111The scans were performed using a Siemens symbia T16 scanner at 4, 24, 48, and 96 hours after administration of IN-FXN001 (3.3-4.4 mCi per patient).

[0510] Results and Discussion Radioligand binding assay IC of selected exemplary compounds of the present application in a radioligand competitive binding assay 50 was determined as described above. The results are shown in Table 1. IC 50 The relative binding affinities of selected exemplary compounds of the present application, based on numerical mean values, are shown in Table 2.

[0511] All compounds of the present application have an IC in the range of about 1 nM to about 1 μM in the radioligand competitive binding assay described above. 50 The binding affinity to PSMA was shown in terms of the RI. It was observed that modifications of groups on the radioligand, such as PSMA binding motifs, such as long-chain fatty acids (e.g., palmitic acid) and long-chain fatty diacids (e.g., octadecanedioic acid), can affect binding affinity. [Table 3] [Table 4-1] [Table 4-2]

[0512] Stability testing Stability testing was performed as described above.

[0513] Exemplary compounds with cleavable linkers tested in mouse plasma stability studies all showed significant degradation over time, with T1 / 2 values ​​ranging from a few hours to approximately 100 hours, as shown in Figure 3. 177 Lu-C-2, 177 Lu-C-7, and 177Non-cleavable compounds such as Lu-C-6 were completely stable in the test, with no decomposition observed for over 72 hours, as shown in Figure 4. 177 Cleavable compounds such as Lu-I-21 were completely stable under the buffer conditions tested. [Table 5] [Table 6]

[0514] Biodistribution studies Biodistribution studies of selected compounds were performed as described above.

[0515] All of the exemplified compounds tested demonstrated good to excellent tumor radionuclide uptake, regardless of their binding affinity to PSMA. Radionuclide uptake in normal organs, including blood, kidney, and liver, was found to depend on the modification groups introduced to extend circulation time in the blood and the cleavable and non-cleavable linkers placed between the chelator, albumin-binding domain, and PSMA-binding domain. Furthermore, these modification groups and linkers were found to play a role in determining the tumor residence time of the radionuclide and its washout kinetics in normal organs, including blood, kidney, and liver.

[0516] Tables 5 to 24 show the biodistribution of various compounds in PC3-PIP tumor-bearing mice, and Tables 25 to 33 show the biodistribution of various compounds in LNCap tumor-bearing mice. Table 34 shows the biodistribution of various compounds in PC3-PIP or LNCap tumor-bearing mice. 177 The uptake of Lu-labeled compounds in tumors and kidneys is compared. [Table 7] [Table 8] Table 9 Table 10 Table 11 Table 12 Table 13 Table 14 Table 15 Table 16-1 Table 16-2 Table 17-1 Table 17-2 Table 18 Table 19 Table 20 Table 21 Table 22 Table 23 Table 24 [Table 25] [Table 26] [Table 27] [Table 28] [Table 29] [Table 30] [Table 31] [Table 32] [Table 33] [Table 34] [Table 35] [Table 36]

[0517] Human image data Figure 5 (A, B, C, and D) shows the results of four patients with metastatic castration-resistant prostate cancer (mCRPC). 68 PET / CT image of Ga-PSMA11 (gozetotide) (left panel) and exemplary complexes. 111 Figure 5, panels A-D, shows SPECT / CT images of In-I-21 (48 hours after administration) (middle panel: before, right panel: after). Figure 5, panels A-D, shows the results of an approved diagnostic agent that showed high uptake in the same patient compared to uptake in the tumor and other organs. 68Exemplary complexes compared to Ga-PSMA11 111 This indicates that In-I-21 is poorly taken up by the salivary glands.

[0518] Although the present application has been described with reference to examples, it should be understood that the scope of the claims should not be limited by the embodiments set forth in the examples, but should be accorded the broadest interpretation consistent with the specification as a whole.

[0519] All patents, patent applications, and publications cited herein are incorporated by reference in their entireties. The disclosures of these publications in their entireties are incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled in the art as of the filing date of the application described and claimed herein.

[0520] Full citations for documents referenced herein Many publications are cited herein, full references to which are set forth below, each of which is incorporated by reference in its entirety into this disclosure to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference.

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[0525] Dorff TB,Fanti S,Farolfi A,et al.“The evolving role of prostate-specific membrane antigen-based diagnostics and therapeutics in prostate cancer”.Am Soc Clin Oncol Educ Book.2019 Jan;39:321-30.

[0526] Kalli KR,Oberg AL,Keeney GL,et al.“Folate receptor alpha as a tumor target in epithelial ovarian cancer”.Gynecol Oncol.2008 Mar;108(3):619-26.

[0527] Korner M,Christ E,Wild D,et al.“Glucagon-like peptide-1 receptor overexpression in cancer and its impact on clinical applications”.Front Endocrinol(Lausanne).2012 Dec 6;3:158.doi:10.3389 / fendo.2012.00158.

[0528] Kramer V,Fernandez R,Lehnert W,et al.“Biodistribution and dosimetry of a single dose of albumin-binding ligand[ 177 Lu]Lu-PSMA-ALB-56 in patients with mCRPC”.Eur J Nucl Med Mol Imaging.2021 Mar;48(3):893-903.

[0529] Kuo HT,Merkens H,Zhang Z,et al.“Enhancing treatment efficacy of 177 Lu-PSMA-617 with the conjugation of an albumin-binding motif:preclinical dosimetry and endoradiotherapy studies”.Mol Pharm.2018 Nov 5;15(11):5183-91.

[0530] Qian ZR,Li T,Ter-Minassian M,et al.“Association between somatostatin receptor expression and clinical outcomes in neuroendocrine tumors”.Pancreas.2016 Nov;45(10):1386-93.

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[0532] Wang Z,Tian R,Niu G,et al.,“Single low-dose injection of Evans blue modified PSMA-617 radioligand therapy eliminates prostate-specific membrane antigen positive tumors”.Bioconjug Chem.2018 Sep 19;29(9):3213-21.

Claims

1. Formula I 【Chemistry 1】 (In the formula, A is 【Chemistry 2】 an albumin binding group selected from the group consisting of unsubstituted or substituted C(O)C 1-26 alkyleneCO 2 H, unsubstituted or substituted C(O)C 2-26 alkenyleneCO 2 H, unsubstituted or substituted C(O)C 1-26 alkyl, and unsubstituted or substituted C(O)C 2-26 alkenyl; Z is a tumor-binding group; E is a chelating group; T is a branched group that is at least trivalent, where T is lysine, ornithine, homolysine, 2,3-diaminopropionic acid (DAP), 2,4-diaminobutyric acid (DAB), cysteine, homocysteine, glutamine, or trimesic acid (TMA); L Ａ and L Ｅ are each independently a direct bond, a cleavable linker, or a non-cleavable linker, wherein a non-cleavable linker is one or more amino acid residues derived from Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, Val, Pyl, Sec, or PCL, or a D enantiomer thereof; one or more amino acid residues derived from DAB or DAP; OEG, R 1 NC 1-20 alkyleneNR 2 ; C(O)C 1-20 alkyleneC(O); R 1 NC 1-20 alkyleneC(O); and C(O)C 1-20 alkyleneNR 2 wherein the latter four groups are optionally interrupted by one or more of S, O, C(O)NH, NHC(O), C 4-6 cycloalkyl, and C 4-6 heterocycloalkyl, where each R 1 and R 2 is independently selected from H and C 1-2 alkyl; and L Ｚ is a direct bond or a non-cleavable linker, wherein the non-cleavable linker is one or more amino acid residues, R 1 NC 1-20 alkyleneNR 2 , R 1 NC 1-20 alkenyleneNR 2 , C(O)C 1-20 alkyleneC(O), C(O)C 1-20 alkenyleneC(O), R 1 NC 1-20 alkyleneC(O), R 1 NC 1-20 alkenyleneC(O), C(O)C 1-20 alkyleneNHR 2 , C(O)C 1-20 alkenyleneNR 2 , C(S)C 1-20 alkyleneC(S), C(S)C 1-20 alkenyleneC(S), C(S)C 1-20 alkyleneC(O), C(S)C 1-20 and R 1 NC 1-20 alkenylene C(S), C(O)C 1-20 alkylene C(S), C(O)C 1-20 alkenylene C(S), C(O)C 1-20 alkylene O, C(O)C 1-20 alkenylene O, R 1 NC 1-20 alkenylene C(S), C(S)C 1-20 alkylene NR 2 , and C(S)C 1-20 alkenylene NR 2 , the latter of which optionally contains one or more of S, O, NH, N(C 1-6 alkyl), C(O), C(O)NH, NHC(O), C(S)NH, NHC(S), NHC(O)NH, NHC(S)NH, NHC(NH), NHC(NC 1-4 alkyl), C(NH)NH, C(NC 1-4 alkyl)NH, NC 4-10 cycloalkyl, C 4-10 heterocycloalkyl, C 6-10 aryl and C 5-10 heteroaryl, each alkyl, alkylene and alkenylene optionally substituted with one or more substituents selected from halo, CO 2 H, C 1-6 alkyl, OH, OC 1-6 alkyl, SH, SC 1-6 alkyl, NR 3 R 4 , C 1-4 alkyleneOH, C 1-4 alkyleneOC 1-4 alkyl, and C 1-4 alkyleneNR 3 R 4 , where each R 1 , R 2 , R 3 and R 4 is independently selected from H and C 1-4 alkyl; However, L Ａ and L Ｅ is a cleavable linker, the cleavable linker comprises a cleavable moiety, and the cleavable moiety is 【Transformation 3】 is) or a pharmaceutically acceptable salt and / or solvate thereof.

2. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein the albumin binding group is unsubstituted or substituted C(O)C 6-20 alkyleneCO 2 H.

3. The albumin binding group is 4-pIBA, C(O)C １５ Alkyl, C(O)C １７ Alkyl, C(O)C 15 alkylene CO 2 H, C(O)C １６ Alkylene CO ２ H, C(O)C 17 alkylene CO 2 H, and C(O)C １８ Alkylene CO ２ 10. The compound of claim 1, wherein the compound is selected from: H, or a pharmaceutically acceptable salt or solvate thereof.

4. The albumin binding group is C(O)C １６ Alkylene CO ２ 4. The compound of claim 3, wherein R is H or C(O)Ci 8 alkyleneCO 2 H, or a pharmaceutically acceptable salt or solvate thereof.

5. The chelating group is selected from the group consisting of 1,4,7-triazacyclononane (TACN); 1,4,7-triazacyclononane-triacetic acid (NOTA); 1,4,7-triazacyclononane-N-succinic-N',N"-diacetic acid (NOTASA); 1,4,7-triazacyclononane-N-glutamic-N',N"-diacetic acid (NODAGA); 1,4,7-triazacyclononane-N,N',N"-tris(methylenephosphonic) acid (NOTP); 1,4,7,10-tetraazacyclododecane ([12]anN4) (cyclene); 1,4,7,10-tetraazacyclotri Decane ([13]anN4); 1,4,7,11-tetraazacyclotetradecane (iso-cyclam); 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA); 2-(1,4,7,10-tetraazacyclododecan-1-yl)acetic acid (DO1A); 2,2'-(1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid (DO2A); 2,2',2"-(1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (DO3A); 1,4,7,10-tetraazacyclododecane-1 , 4,7,10-tetra(methanephosphonic acid) (DOTP); 1,4,7,10-tetraazacyclododecane-1,7-di(methanephosphonic acid) (DO2P); 1,4,7,10-tetraazacyclododecane-1,4,7-tri(methanephosphonic acid) (DO3P); 1,4,7,10-tetraazacyclodecane-1-glutamic acid-4,7,10-triacetic acid (DOTAGA); 1,4,7,10-tetraazacyclodecane-1-succinic acid-4,7,10-triacetic acid (DOTASA); 1,4,8,11-tetraazacyclotetradecane ([14]anN4) ( Cyclam); 1,4,8,12-tetraazacyclopentadecane ([15]an N4); 1,5,9,13-tetraazacyclohexadecane ([16]an N4); 1,4-ethano-1,4,8,11-tetraazacyclotetradecane (etho-cyclam); 1,4,8,11-tetraazacyclotetradecane-1,4,8,1-tetraacetic acid (TETA); 2-(1,4,8,11-tetraazacyclotetradecane-1-yl)acetic acid (TE1A); 2,2'-(1,4,8,11-tetraazacyclotetradecane-1,8-diyl)diacetic acid (TE2A);The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, selected from 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]-hexadecane (CB-TE2A); 3,6,10,13,16,19-hexazabicyclo[6.6.6]icosane (sal); 1,4,7,10-tetra-(2-carbamoylmethyl)-cyclododecane (TCMC); N,N'-bis[(6-carboxy-2-pyridyl)methyl]-4,13-diaza-18-crown-6 (macropa), phthalocyanine and its derivatives; and porphyrin and its derivatives.

6. 6. The compound of claim 5, or a pharmaceutically acceptable salt or solvate thereof, wherein the chelating agent is selected from DOTA and DOTAGA.

7. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein the tumor-binding group is a peptide.

8. The tumor-binding group is a prostate-specific membrane antigen (PSMA)-binding group, a glucagon-like peptide-1 receptor (GLP-1R)-binding group, a glucose-dependent insulin-stimulating polypeptide (gastric inhibitory polypeptide; GIP) receptor (GIP-R)-binding group, a folate receptor (FR)-binding group, a cholecystokinin-2 receptor (CCK2R)-binding group, a gastrin-releasing peptide receptor (GRPR)-binding group, a somatostatin receptor 2 (SSTR2)-binding group, a neurotensin receptor 1 (NT1)-binding group, a folate receptor (FR)-binding group, a cholecystokinin-2 receptor (CCK2R)-binding group, a gastrin-releasing peptide receptor (GRPR)-binding group, a somatostatin receptor 2 (SSTR2)-binding group, a neurotensin receptor 1 (NT2)-binding group, a folate receptor (FR)-binding group, a cholecystokinin-2 receptor (CCK2R)-binding group, a gastrin-releasing peptide receptor (GRPR)-binding group, a somatostatin receptor 2 (SSTR2)-binding group, a neurotensin receptor 1 (NT1 ... folate receptor (FR) 2. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein the R1 binding group is selected from a neuropeptide Y receptor type 1 (Y1R) binding group, a nectin-4 binding group, a delta-like ligand 3 (DLL3) binding group, an epithelial cell adhesion molecule (EpCAM) binding group, a tumor-associated calcium signal transducer 2 (Trop-2) binding group, an insulin-like growth factor-1 (IGF-1) receptor binding group, and a human epidermal growth factor receptor 2 (HER2) binding group.

9. The compound of claim 8, or a pharmaceutically acceptable salt or solvate thereof, wherein the tumor-binding group is a prostate-specific membrane antigen (PSMA)-binding group, a glucagon-like peptide-1 receptor (GLP-1R)-binding group, a glucose-dependent insulin-stimulating polypeptide (gastric inhibitory polypeptide; GIP) receptor (GIP-R)-binding group, or a folate receptor (FR)-binding group.

10. 10. The compound of claim 9, or a pharmaceutically acceptable salt or solvate thereof, wherein the tumor-binding group is a PSMA-binding group.

11. the PSMA binding group 【Chemistry 4】 11. The compound of claim 10, wherein:

12. the PSMA binding group is εKuE and the albumin binding group is C(O)C １２－１８ Alkylene CO ２ H, or a pharmaceutically acceptable salt or solvate thereof.

13. 2. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein T is an amino acid residue derived from lysine, ornithine, homolysine, 2,3-diaminopropionic acid (DAP), 2,4-diaminobutyric acid (DAB), cysteine, homocysteine, or glutamine.

14. 14. The compound of claim 13, or a pharmaceutically acceptable salt or solvate thereof, wherein T is an amino acid residue derived from lysine.

15. L Ａ is a cleavable linker, and L Ｅ is a direct bond or a non-cleavable linker, where L E is 【Transformation 5】 10. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, comprising at least one group selected from the group consisting of:

16. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein L A is a non-cleavable linker.

17. Each non-cleavable linker independently comprises an amino acid residue, R １ NC １－２０ Alkylene NR ２ , C(O)C １－２０ Alkylene C(O), R １ NC １－２０ Alkylene C(O) and C(O)C １－２０ Alkylene NR ２ wherein the latter four groups optionally comprise one or more of S, O, C(O)NH, NHC(O), NC ４－６ Cycloalkyl, C ４－６ and each alkyl and alkylene is optionally interrupted by halo, CO. ２ H, C １－６ Alkyl, OH, OC １－６ Alkyl, SH, SC １－６ Alkyl, NR ３ R ４ , C １－４ Alkylene OH, C １－４ Alkylene OC １－４ Alkyl and C １－４ Alkylene NR ３ R, wherein each R １ , R ２ , R ３ and R ４ are independently H and C １－４ 2. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein:

18. Each cleavable linker independently comprises at least one cleavable moiety. 【Transformation 6】 and one or more amino acid residues, R ５ NC １－２０ Alkylene NR ６ , C(O)C １－２０ Alkylene C(O), R ５ NC １－２０ Alkylene C(O), C(O)C １－２０ Alkylene NR ６ , R ５ NC １－２０ Alkylene O, OC １－２０ Alkylene NR ６ , C(O)C １－２０ Alkylene O and OC １－２０ alkylene C(O), the latter eight groups optionally being selected from S, O, C(O)NH, NHC(O), C ４－１８ Cycloalkyl, and C ４－１０ and each alkyl and alkylene is optionally interrupted by one or more of halo, CO ２ H, N.R. ７ R ７ , and C １－４ Alkylene NR ７ R ８ and is substituted with one or more substituents selected from Here, R ５ , R ６ , R ７ and R ８ are independently H and C １－４ alkyl; The amino acid residue is derived from a naturally occurring amino acid selected from the group consisting of alanine (Ala), arginine (Arg), asparagine (Asn), aspartic acid (Asp), cysteine ​​(Cys), glutamine (Gln), glutamic acid (Glu), glycine (Gly), histidine (His), isoleucine (Ile), leucine (Leu), lysine (Lys), methionine (Met), phenylalanine (Phe), proline (Pro), serine (Ser), threonine (Thr), tryptophan (Trp), tyrosine (Tyr) and valine (Val); 2. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof.

19. L Ｚ is one or more amino acid residues derived from Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, Val, Pyl, Sec, or PCL, or their D enantiomers; one or more amino acid residues derived from DAB or DAP; 【Transformation 7】 R １ NC １－２０ Alkylene NR ２ , C(O)C １－２０ Alkylene C(O), R １ NC １－２０ Alkylene C(O) and C(O)C １－２０ Alkylene NR ２ wherein each R １ and R ２ independently, H and C １－２ 2. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein:

20. L Ａ and L Ｅ is a cleavable linker, each cleavable linker independently comprising: 【Transformation 8】 10. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, comprising at least one group selected from:

21. L Ａ is a cleavable linker, and L Ｅ is a direct bond or a non-cleavable linker, and L A is 【Chemistry 9】 10. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, comprising at least one group selected from:

22. L Ａ is a cleavable linker, and L Ｅ 2. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein: is a direct bond.

23. The compound of claim 1, wherein the compound of formula I is selected from the following list of compounds: Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 or a pharmaceutically acceptable salt and / or solvate thereof.

24. 10. A radionuclide complex, or a pharmaceutically acceptable salt and / or solvate thereof, comprising the compound of claim 1 or a pharmaceutically acceptable salt and / or solvate thereof and one or more radionuclides.

25. I'm sorry, I'm sorry, I'm sorry. １４ 3、 １５ 8、 １８ 6、 ７５ 、、 ７６ 、、 ７７ 、、 １２３ 9、 １２４ 9、 １２５ 9、 １３１ 9、 ３５ 、 ９９ Tc、 ９９ｍ Tc、 １８８ e、 １８６ e、 １５３ ｳm、 ６７ Ga、 ６８ Ga、 １１１ 9n、 ５９ e、 ６３ Zn、 ５２ e、 ４５ 4i、 ６０ Cu、 ６１ Cu、 ６７ Cu、 ６４ Cu、 ６２ Cu、 ８２ 2b、 １９５ｍ Pt、 １９１ｍ Pt、 １９３ｍ Pt、 １１７ｍ 3n、 ８９ Zr、 １７７ Lu、 666o、 ８６ 9、 ８７ 9、 ９０ 9、 ８９ 3r、 １１１ 9n、 １５３ Gd、 ２２５ Ac、 ２１２ Bi、 ２１３ Bi、 ２１１ At、 １９８ Au、 １９９ Au、 １９３ｍ Pt、 １９７ Pt、 １０３ Pd、 １０９ Pd、 １０５ 2h、 １０３ｍ 2h、 ２２３ 2a、 ２２４ 2a、 ９７ 2u、 ２２７ Th、 ２２９ Th、 ３２ P、 １６１ 4b、 ３３ P、 １４９ Tb, 203Pb, ２１２ Pb, ２０１ Tl, １１９ Sb, ５８ｍ Co, ５５ Co, ４７ Sc, １４９ Pm and １６１ 25. The radionuclide complex of claim 24, or a pharmaceutically acceptable salt or solvate thereof, wherein the radionuclide complex is selected from the group consisting of:

26. The radionuclide complex of claim 25, or a pharmaceutically acceptable salt or solvate thereof, wherein the one or more radionuclides are selected from 111In, 149Tb, 177Lu, 12Pb and 225Ac.

27. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 23 or pharmaceutically acceptable salts and / or solvates thereof and a pharmaceutically acceptable carrier.

28. A pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of formula I as defined in any one of claims 1 to 23 or pharmaceutically acceptable salts and / or solvates thereof, or one or more radionuclide complexes as defined in any one of claims 24 to 26 or pharmaceutically acceptable salts and / or solvates thereof, for treating a disease or disorder.

29. 29. The pharmaceutical composition of claim 28, wherein the disease or disorder is cancer.

30. 30. The pharmaceutical composition of claim 29, wherein the cancer is a PSMA-positive cancer.

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