Agents for cleaving labels from biomolecules in vivo

Abstract

Disclosed herein are compounds, combinations, and kits that can be used to more rapidly remove radionuclides from a subject, preferably a human. The compounds, combinations, and kits can also be used to increase the tumor-to-blood ratio, or to more rapidly and / or conveniently achieve such an increase in labeling in targeted imaging or targeted radiotherapy in a subject, preferably a human.

Description

[Technical Field]

[0001] The present invention relates to compounds, combinations and kits for cleaving imaging or radiotherapy labels from (biomolecules) in a subject, e.g. (biomolecules), which are administered to the subject for purposes such as targeted imaging and targeted radiotherapy. [Background technology]

[0002] In many areas of medical diagnosis, imaging, and radiotherapy, it is desirable to selectively deliver an agent, such as a radiotherapeutic or diagnostic agent (e.g., an imaging agent), to a specific site or a limited area within the body of a subject, e.g., a patient. Organ or tissue targeting is typically achieved by conjugating the desired imaging or radiotherapy label (i.e., a radionuclide) to a targeting agent that binds to the cell surface or promotes cellular uptake at or near the target site of interest. The targeting agents used to target such labels are typically constructs with affinity for cell surface targets (e.g., membrane receptors), structural proteins (e.g., amyloid plaques), or intracellular targets (e.g., RNA, DNA, enzymes, cell signaling pathways). These targeting agents can be antibodies (and fragments), proteins, aptamers, oligopeptides, oligonucleotides, oligosaccharides, as well as peptides, peptoids, and / or organic drug compounds known to accumulate in specific diseases or dysfunctions. Alternatively, imaging or radiotherapy agents may target metabolic pathways that are upregulated during disease (such as infection or cancer), such as DNA, protein, and membrane synthesis, and carbohydrate uptake. In diseased tissues, the above-mentioned markers can distinguish diseased cells from healthy tissue and offer unique possibilities for early detection, specific diagnosis, and (targeted) therapy.

[0003] Because radioactive imaging and radiotherapeutic agents (i.e., nuclear imaging and therapeutic agents) contain radioactive radionuclides, it is desirable to conveniently reduce the amount of radionuclide in a patient quickly, efficiently, and / or routinely once the therapeutic and / or imaging objectives have been achieved. For example, this allows for a reduction in the dose of potentially harmful radiation delivered to the whole body. Also, in the context of imaging, clearing the radionuclide from a patient as soon as possible after an imaging procedure allows for the initiation of another imaging procedure in the same patient of the same or a different imaging target (i.e., image cycling). However, natural clearance is very slow.

[0004] Furthermore, a key criterion for the success of imaging / therapeutic agents in general, and nuclear imaging / therapeutic agents in particular, is that they exhibit high target uptake while exhibiting efficient clearance from non-target tissues and from the blood (through the kidneys and / or hepatobiliary system). However, this is often problematic, particularly when using antibodies. For example, human imaging studies have shown that while maximum concentrations of radiolabeled antibodies at tumor sites can be achieved within 24 hours, several additional days are required before the concentration of labeled antibodies in the circulation decreases to a level sufficient for successful imaging. In the context of radioimmunotherapy (RIT), slow antibody clearance from the blood can result in, for example, high radiation doses to the bone marrow, limiting the amount of radioactivity that can be safely administered and limiting therapeutic efficacy.

[0005] Furthermore, targeted imaging (e.g., optical or nuclear) or radiotherapy can be hindered by circulating fractions of the targeted receptor, trapping the imaging or radiotherapy agent before it can reach the target receptor on the target cell surface, adversely affecting the target-to-background ratio.

[0006] Additionally, off-target uptake of the contrast agent (eg, in the liver) can obscure the targeted uptake.

[0007] In effect, the targeting process can be divided into three steps: (I) an administration process, in which a compound comprising a targeting agent is administered to a subject, and a fraction of the compound binds to the target; (II) clearance processes, in which compounds containing targeted agents circulating in the blood (rather than bound to a target) are eliminated from the blood and other non-target tissues (i.e., removed by excretion); (III) Imaging / Therapeutic Processes, in which a compound containing a targeting agent present in a subject is used for imaging or therapeutic purposes.

[0008] It will be appreciated that the tumor-to-blood (T / B) ratio increases in process (I) due to targeting, i.e., the labeled compound accumulates at the target site, in this case the tumor.

[0009] For process (III), the T / B ratio should be high enough so that the fraction of circulating compound or compound bound to non-target tissues does not interfere with the imaging agent / therapy. Typically, this is achieved by waiting an undesirably long time during process (II), for the reasons given above.

[0010] Generally, in process (II) above, methods are desired that more rapidly increase the targeted to non-targeted ratio of imaging or radiotherapeutic agents and have temporal and spatial control over the activity of those agents.

[0011] The low T / B ratio for antibodies improves image quality in radioimmunoimaging and allows the adoption of pre-targeting approaches to increase the therapeutic index in RIT. A long-circulating monoclonal antibody (mAb) is first administered, binds to the tumor, and slowly clears from the circulation. A small radiolabeled probe is then injected. This probe binds to the tumor-bound antibody or is otherwise rapidly cleared from the circulation, resulting in an improved T / B ratio.

[0012] Typically, a clearing agent is administered before probe injection to clear any freely circulating antibodies from the blood, resulting in a further improved T / B ratio [F.C. van de Watering et al., Front. Med. 2014, 1, 44]. However, pretargeting can typically only be used with non-internalizing receptors and is relatively complex, requiring optimization of the administration and timing of three agents.

[0013] An alternative approach is to administer clearing agents to remove radiolabeled antibodies from the circulation after sufficient amounts have bound to the target, but this does not work well in the clinic and delivers high radiation doses to the liver [RHJ Begent et al., Br. J. Cancer 1989, 60, p. 406-412].

[0014] Another approach is to administer an enzyme designed to cleave the bond between the antibody and the label, cleaving the radiolabel from the freely circulating antibody after a sufficient amount of the radiolabeled antibody has bound and been internalized in the target cell. However, the enzymatic cleavage method is quite slow and inefficient, and the T / B ratio improvement was only three-fold [Q. Ren et al., Mol. Pharm. 2019, 16, pp. 1065-1073]. In addition, three injections of the enzyme are typically required, making it an inconvenient method. Summary of the Invention [Problem to be solved by the invention]

[0015] It would be desirable to provide compounds and / or combinations of compounds that allow for rapid reduction of the amount of radionuclides in a patient, for example, after radioimaging has been completed. It would also be desirable to provide compounds and / or combinations of compounds that allow for an increase in the target-to-nontarget ratio of imaging agents or radiotherapeutic agents in the clearance process. It would also be desirable for this increase to be obtained more quickly than with known methods. Furthermore, it would be desirable to provide compounds and / or combinations of compounds that allow for temporal and spatial control over the activity of these agents. In addition, it would be desirable for the compounds and / or combinations of compounds to be versatile, rapid, efficient, and / or convenient. [Means for solving the problem]

[0016] In one aspect, the present invention relates to compounds satisfying the following formula (1) and pharmaceutically acceptable salts thereof: [ka]

[0017] where: each X 1 , X 2 , X 3 , X 4 are independent of each other, and X1 , X 2 , X 3 , X 4 Two or fewer of -C(R 47 )2-, so that C(R 47 )2-, -NR 37 -, -C(O)-, -O-, with the proviso that there is no set of adjacent atoms selected from the group consisting of -OO-, -ON-, -C(O)-O-, -NN-, and -C(O)-C(O)-; X 5 is -C(R 47 )2- or -CHR 48 and preferably, X 5 -C(R 47 )2- and; Each R 48 are independent, -L B and -L A mosquito and preferably R 48 Ha-L B and; R 48 is -O-, -S-, -OC(O)-, -OC(S)-, -SC(O)- or -SC(S)-, R 48 is attached to the remainder of the compound of formula (1) via a moiety L B is the part that satisfies the following formula (2): [ka] where: The dashed line indicates the bond to the remainder of the compound of formula (1); S L is a linker, which is a self-immolative linker L C It may be; Each R 98 are individually a label or clearance-directing group; each d is independently 0 or 1; e is an integer ranging from 0 to 4, preferably e is 0; the label is a moiety that contains a radionuclide; The compound of formula (1) comprises at least one label and at least one administration agent; L A is the part that satisfies the following formula (3); [ka] where: The dashed line indicates the bond to the remainder of the compound of formula (1); each s is independently 0 or 1, preferably, each s is 0; i is an integer ranging from 0 to 4, preferably 0 or 1, most preferably 0; Each S P is independently a spacer, which is a self-immolative linker L C It may be; A A indicates the administered agent, which is an antibody; C C represents Construct-C, wherein each Construct-C is independently selected from the group consisting of a label and an administration agent; preferably, the compound of (1) comprises one or less C C Includes; However, L A R 48 When L A necessarily has both the label and the administration agent; However, R 48 Where L is A When the compound contains both the label and the administered agent, S bound to the label and the administered agent P is a self-immolative linker; Each R 47 are independently a hydrogen atom, -L B , -L A , -(S P ) i -C C , -F, -Cl, -Br, -I, -OR 37 , -N(R 37 )2, -SO3, -PO3 - 、 -NO2, -CF3, -SR 37 , S(=O)2N(R 37)2, OC(=O)R 37 , SC(=O)R 37 , OC(=S)R 37 , SC(=S)R 37 , N.R. 37 C(=O)-R 37 , N.R. 37 C(=S)-R 37 , N.R. 37 C(=O)OR 37 , N.R. 37 C(=S)OR 37 , N.R. 37 C(=O)SR 37 , N.R. 37 C(=S)SR 37 , OC(=O)N(R 37 )2, SC(=O)N(R 37 )2, OC(=S)N(R 37 )2, SC(=S)N(R 37 )2, NR 37 C(=O)N(R 37 )2, NR 37 C(=S)N(R 37 )2, C(=O)R 37、 C(=S)R 37、 C(=O)N(R 37 )2, C(=S)N(R 37 )2, C(=O)OR 37 , C(=O)SR 37 , C(=S)OR 37 , C(=S)SR 37 , S(O)R 37 , -S(O)2R 37 , N.R. 37 S(O)2R 37 , -ON(R 37 ) 2、- NR 37 OR 37 , C1~C 24 Alkyl groups, C2-C 24 Alkenyl groups, C2-C 24 Alkynyl groups, C6-C 24 Aryl groups, C2-C 24 Heteroaryl groups, C3-C 24 Cycloalkyl groups, C5-C 24 Cycloalkenyl group, C 12 ~C 24Cycloalkynyl group, C3-C 24 (Cyclo)alkyl(hetero)aryl groups, C3-C 24 (Hetero)aryl(cyclo)alkyl, C4-C 24 (Cyclo)alkenyl(hetero)aryl group, C4-C 24 (Hetero)aryl(cyclo)alkenyl groups, C4-C 24 (Cyclo)alkynyl(hetero)aryl group, C4-C 24 (Hetero)aryl(cyclo)alkynyl group, C4-C 24 Alkylcycloalkyl groups and C4-C 24 cycloalkylalkyl groups, where i is an integer ranging from 0 to 4, preferably i is an integer ranging from 0 to 1; Here, the above alkyl group, alkenyl group, alkynyl group, aryl, heteroaryl, cycloalkyl group, cycloalkenyl group, cycloalkynyl group, (cyclo)alkyl(hetero)aryl group, (hetero)aryl(cyclo)alkyl group, (cyclo)alkenyl(hetero)aryl group, (hetero)aryl(cyclo)alkenyl group, (cyclo)alkynyl(hetero)aryl group, (hetero)aryl(cyclo)alkynyl group, alkylcycloalkyl group, cycloalkylalkyl group are -Cl, -F, -Br, -I, -OR 37 , -N(R 37 )2, -SO3R 37 , -PO3(R 37 ) 2、 -PO4(R 37 ) 2、 -NO2, -CF3, =O, =NR 37 , and -SR 37 and may be substituted by a moiety selected from the group consisting of O, S, NR 37 , and Si, wherein the N, S, and P atoms are optionally oxidized, and wherein multiple N atoms are optionally quaternized; The Two R's 47 and / or R 37 may be contained within the ring, The Two R's 47and / or R 37 may be contained within a ring to form a ring fused to the 8-membered trans ring of formula (1); Each R 37 are independently a hydrogen atom, -L B , -L A , -(S P ) i -C C , C1~C 24 Alkyl groups, C2-C 24 Alkenyl groups, C2-C 24 Alkynyl groups, C6-C 24 Aryl groups, C2-C 24 Heteroaryl groups, C3-C 24 Cycloalkyl groups, C5-C 24 Cycloalkenyl group, C 12 ~C 24 Cycloalkynyl group, C3-C 24 (Cyclo)alkyl(hetero)aryl groups, C3-C 24 (Hetero)aryl(cyclo)alkyl, C4-C 24 (Cyclo)alkenyl(hetero)aryl group, C4-C 24 (Hetero)aryl(cyclo)alkenyl groups, C4-C 24 (Cyclo)alkynyl(hetero)aryl group, C4-C 24 (Hetero)aryl(cyclo)alkynyl group, C4-C 24 Alkylcycloalkyl groups and C4-C 24 cycloalkylalkyl groups, where i is an integer ranging from 0 to 4, preferably i is 1; R that is not a hydrogen atom 37 Groups include -Cl, -F, -Br, -I, -OH, -NH2, -SO3H, and -PO3H 、 -PO4H 2、 and optionally substituted with a moiety selected from the group consisting of -NO2, -CF3, =O, =NH, and -SH, and optionally containing one or more heteroatoms selected from O, S, NH, P, and Si, wherein the N, S, and P atoms are optionally oxidized, and wherein multiple N atoms are optionally quaternized.

[0018] In another aspect, the present invention relates to a combination comprising a compound according to formula (1) and a cleavage agent, wherein R 48 When at least one of R 48 except that R in formula (1) does not have the same label as 48 When at least one of the cleavage agents is R 48 does not have the same sign as wherein the cleavage agent is a diene.

[0019] In yet another aspect, the present invention relates to a compound according to formula (1) or a combination according to the invention for use as a medicament.

[0020] In yet another aspect, the present invention relates to a compound according to formula (1) or a combination according to the invention for use in the treatment of a disease, preferably cancer, in a subject, preferably a human, wherein the treatment is radiation therapy.

[0021] In a still further aspect, the present invention provides a compound according to formula (1) or a combination according to the invention for use in a diagnostic method, The method comprises: (a) administering to a subject, preferably a human, a compound according to formula (1), as defined herein; (b) administering to said subject a cleaving agent as defined herein; (c) imaging a compound according to Formula (1) present in said subject to collect data; (d) comparing the data with standard values; (e) detecting significant deviations from the standard value during the comparison; (f) attributing said significant deviation to a particular clinical condition, preferably cancer. The present invention relates to the compound or the combination, which comprises the steps of:

[0022] In yet another aspect, the present invention provides a non-therapeutic method for imaging a compound according to formula (1) in a subject, preferably a human, comprising: (a) administering to said subject a compound according to Formula (1), as defined herein; (b) administering to said subject a cleaving agent as defined herein; (c) imaging the compound according to formula (1) present in said subject. The method further comprises the steps of:

[0023] In a still further aspect, the present invention relates to a method of using a compound according to formula (1), or a combination according to the invention, for imaging in a subject, preferably a human. [Brief explanation of the drawings]

[0024] [Figure 1] Figure 1 is a general scheme illustrating the use of the present invention in radioimmunotherapy: a radiolabeled antibody is administered, circulates, and binds an internalized cancer receptor, and after sufficient internalization has occurred, a cleaving agent is administered that cleaves the radiolabel (e.g., a moiety containing a radiometal chelate complex) from the antibody, resulting in rapid renal clearance of radioactivity from the blood and non-target tissues (but not radioactivity internalized by tumor cells). [Figure 2] Figure 2 shows the radioactivity profile in the blood of mice injected with the mAb-trigger-labeled conjugate followed by the cleavage agent or vehicle. The cleavage agent was administered 1 or 24 hours after the mAb injection. The figure demonstrates the rapid clearance of the mAb from the blood in response to the trigger reaction with the cleavage agent in vivo. DETAILED DESCRIPTION OF THE INVENTION

[0025] In a broad sense, the present invention relates to the clever recognition that compounds according to formula (1), and combinations and kits as defined herein, better address one or more of the needs set forth above. The compounds, combinations, and kits of the present invention can be used to rapidly reduce the amount of a radionuclide in a subject. In particular, the compounds, combinations, and kits of the present invention can be used to increase the target-to-non-target ratio of an imaging agent or radiotherapy agent in the clearance process, and more particularly to achieve such an increase more rapidly.

[0026] In one aspect, the present invention presents the concept of administering a compound according to Formula (1) containing a label (a radionuclide-containing moiety) and an administered agent, followed by administration of a diene-containing cleavage agent in a clearance phase, where the dienophile and diene are capable of undergoing a bioorthogonal reaction with each other, resulting in separation of the label from the administered agent, preferably particularly at non-target sites (e.g., blood), and efficient clearance of the released label from the circulation and other non-target tissues and / or the body as a whole. The administered agent should be understood to include any antibody, particularly an antibody for which in vivo imaging of biodistribution or target binding is desired, or an antibody used as a targeting agent for therapeutic radiation.

[0027] This bioorthogonal reaction is very fast and readily results in good release of the radionuclide-containing moiety. Typically, high release yields are obtained after only a single administration of the cleavage agent, making this method efficient and convenient for both patients and physicians.

[0028] Thus, preferably, cleavage of the label from the compound of formula (1) relates to the fraction present in or bound to non-target tissue, while the portion bound to the target tissue is not cleaved or undergoes accelerated clearance.

[0029] The fact that the inverse electron demand Diels-Alder (IEDDA) reaction can be used in the above applications is surprising. First, the IEDDA reaction has never been used to reduce the amount of radionuclides in a subject. Instead, the IEDDA reaction has typically been used to specifically release a drug at a target site, after which the drug has entered cells, tumors, etc. This is therefore contrary to methods that are independent of radionuclides and rapidly remove the released agent from the body. In addition, the IEDDA reaction has previously been used to specifically release a drug at a target site, particularly after a clearance process. Moreover, the IEDDA reaction has been used in applications where release does not occur, but where a clearance-directing group is used to remove the administered agent from the circulation. In contrast, the present invention is based on the clever insight that, using the compounds and combinations of the present invention, separation of the label and administered agent preferably occurs in the blood and other non-target sites, followed by rapid elimination of the label in particular (Figure 1).

[0030] Without wishing to be bound by theory, the inventors believe that the antibodies contained in the compound of formula (1) have a relatively slow clearance rate due to their large size and / or binding to biomolecules and much larger structures, such as cells, which significantly reduces the clearance rate of the compound of formula (1). Upon addition of a cleavage agent, a moiety containing a radionuclide is released. The moiety is, by definition, smaller than the compound of formula (1) and does not have specific affinity for any biomolecules, and therefore typically does not bind to such biomolecules. The inventors believe that, for at least these reasons, the released moiety is eliminated much more rapidly than the compound of formula (1).

[0031] Specifically, if the administered agent is an intact IgG antibody, the antibody will be cleared from the blood very slowly through FcRn-mediated recycling. Additionally, or alternatively, the administered agent may bind to a primary target present in the blood (e.g., shed receptors from blood cells or tumors) or other biomolecules (e.g., serum albumin) and tissues, target tissues, and non-target tissues, resulting in slow elimination from the entire body, target tissues, or non-target tissues. Furthermore, general proteins, including antibodies, are cleared slowly due to their relatively large size. Conversely, moieties containing released radionuclides are generally cleared rapidly because they are much smaller and typically have low affinity for biomolecules and tissues. [See Orcutt et al., Mol. Imaging Biol. 2011, 215-221], which demonstrates the rapid clearance of radiolabeled chelate derivatives.

[0032] Thus, in some embodiments, a compound of Formula (1) containing a label, particularly a radiolabeled chelate, and an administered agent are administered to target or be internalized by a specific tissue in the body, such as a tumor cell receptor or brain target ( FIG. 1 ). Subsequent injection of a cleaving agent, preferably a non-internalizing (i.e., non-cell-permeable) cleaving agent, results in the release of the radiolabeled chelate from the administered agent in the circulation and its rapid elimination, while any released chelate within the target cells is not excreted, resulting in an increase in the target-to-nontarget (T-NT) ratio, particularly more rapidly achieved than known methods.

[0033] In other embodiments, the compound of Formula (1) targets a non-internalizing receptor in a tissue. Preferably, the cleaving agent is then selected so that it does not significantly extravasate from the blood into other tissues, allowing for specific, i.e., off-target, release of the label in the blood.

[0034] The compounds of formula (1) can be specifically designed to be used as imaging agents for specific targets or processes in vivo, for example, in radioimmunoimaging, or to deliver therapeutic radiation to specific targets in vivo, for example, in radioimmunotherapy.

[0035] A cleaving agent is an agent or compound administered to a subject for the purpose of cleaving a label from an administered agent, resulting in different biodistribution and pharmacokinetics of the released label compared to the label when bound to the administered agent, such that the released label has much faster blood clearance than a compound of formula (1) and / or the released label has much lower retention than a compound of formula (1) in one or more non-target tissues, such as epithelial cells, fat, muscle, and kidney, and RES organs, such as the liver and spleen.

[0036] The concept of cleaving compounds of formula (1) in vivo is of general relevance in targeted radiotherapy and imaging.

[0037] definition

[0038] The present invention will be further described with respect to particular embodiments and with reference to certain drawings but the invention is not limited thereto and will be described only by the claims. Any reference signs in the claims should not be construed as limiting the scope of the invention. The drawings described are schematic and not limiting. In the drawings, the size of some of the elements may be exaggerated and not drawn to scale for illustrative purposes. Where an indefinite or definite article is used when referring to a singular noun, such as "a" or "an," "the," this includes the plural of that noun unless otherwise stated.

[0039] When used in the detailed description of the present invention and in the claims, the verb "comprise" and its conjugations are used in an open-ended sense, meaning that the items following the word are included, but items not specifically mentioned are not excluded. Thus, the scope of the expression "a device comprising means A and B" should not be limited to a device consisting of only components A and B. It means that, in the context of the present invention, the only relevant components of the device are A and B.

[0040] Additionally, reference to an element by the indefinite article "a" or "an" does not exclude the possibility that a plurality of elements is present, unless the context clearly requires that there is only one element. Thus, the indefinite article "a" or "an" usually means "at least one."

[0041] The compounds disclosed in the detailed description and claims of the present invention may contain one or more asymmetric centers, and different diastereomers and / or enantiomers may exist in the compound. The description of any compound in the detailed description and claims of the present invention is meant to encompass all diastereomers and mixtures thereof, unless otherwise specified. Additionally, the description of any compound in the detailed description and claims of the present invention is meant to encompass both each enantiomer and any mixture of such enantiomers, racemic or otherwise, unless otherwise specified. When the structure of a compound is shown as a specific enantiomer, it is understood that the invention of the present application is not limited to that specific enantiomer unless otherwise specified. When the structure of a compound is shown as a specific diastereomer, it is understood that the invention of the present application is not limited to that specific diastereomer unless otherwise specified.

[0042] The compounds can occur in various tautomeric forms. The compounds according to the present invention are meant to encompass all tautomeric forms unless otherwise specified. When the structure of a compound is shown as a specific tautomer, it should be understood that the invention of this application is not limited to that specific tautomer unless otherwise specified.

[0043] The compounds disclosed in the detailed description and claims of the present invention may further exist as exo and endo diastereomers. Unless otherwise specified, the description of any compound in the detailed description and claims of the present invention is meant to encompass both the respective exo and endo diastereomers of the compound, as well as mixtures thereof. When the structure of a compound is shown as a particular endo or exo diastereomer, it should be understood that the invention of this application is not limited to that particular endo or exo diastereomer, unless otherwise specified.

[0044] Unless otherwise specified, the compounds of the present invention and / or groups thereof may be protonated or deprotonated. It will be understood that compounds may carry multiple charges, which may be of opposite sign. For example, in a compound containing an amine and a carboxylic acid, the amine may be protonated while the carboxylic acid is simultaneously deprotonated.

[0045] The present invention also provides a combination of a compound of formula (1) and a cleavage agent. The term "combination" should be understood in a broad sense and is not limited to a kit containing both components. Thus, the compound of formula (1) and the cleavage agent can be provided completely separately from each other. It will be understood that the function of the cleavage agent is to act in combination with the compound of formula (1).

[0046] In some formulas, groups or substituents are indicated by reference to letters, such as "A," "B," "X," "Y," and various (numbered) "R" groups. Additionally, the number of repeat units is indicated by reference to letters, such as -(CH) n The definitions of these letters should be read with reference to each formula, i.e., in different formulas, these letters can each independently have different meanings unless otherwise specified.

[0047] In some of the formulas and text that follow, references are made to "alkyl," "heteroalkyl," "aryl," "heteroaryl," "alkenyl," "alkynyl," "alkylene," "alkenylene," "alkynylene," "arylene," "cycloalkyl," "cycloalkenyl," "cycloakynyl," "arenetriyl," and the like. The number of carbon atoms contained in these groups, excluding carbon atoms contained in any substituents defined herein, can be indicated by a designation preceding such term (e.g., "C1-C8 alkyl" means that the alkyl can have from 1 to 8 carbon atoms). For the avoidance of doubt, a butyl group substituted with -OCH3 will be referred to as a C4 alkyl because the carbon atoms in the substituent are not included in the carbon count.

[0048] The unsubstituted alkyl group has the general formula C n H 2n+1 and may be linear or branched. The alkyl group may be optionally substituted with one or more substituents as further specified herein. Examples of alkyl groups include methyl, ethyl, propyl, 2-propyl, t-butyl, 1-hexyl, 1-dodecyl, etc. Unless otherwise specified, alkyl groups include O, NR 36The alkyl group may have one or more heteroatoms independently selected from the group consisting of N, S, P, and Si, where the N, S, and P atoms may be oxidized, and multiple N atoms may be quaternized. In preferred embodiments, up to two heteroatoms may be consecutive, such as in -CH-NH-OCH and -CH-O-Si(CH). In some preferred embodiments, the heteroatoms are not directly bonded to each other. Examples of heteroalkyl include CHCH-O-CH, -CHCH-NH-CH, -CHCH-S(O)-CH, -CH = It includes CH-O-CH3, -Si(CH3)3. In a preferred embodiment, the C1-C4 alkyl has no more than two heteroatoms.

[0049] A cycloalkyl group is a cyclic alkyl group. Unsubstituted cycloalkyl groups have at least 3 carbon atoms and have the general formula C n H 2n-1 The cycloalkyl group is substituted by one or more substituents as further specified herein. Examples of cyclopropyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Unless otherwise specified, cycloalkyl groups include O, NR 36 , S, P, and Si, wherein the N, S, and P atoms may be optionally oxidized, and multiple N atoms may be optionally quaternized.

[0050] Alkenyl groups have one or more carbon-carbon double bonds and can be linear or branched. Unsubstituted alkenyl groups having one C—C double bond have the general formula C n H 2n-1 Unsubstituted alkenyl groups having two C—C double bonds have the general formula C n H 2n-3Alkenyl groups can have terminal and / or internal carbon-carbon double bonds. Terminal alkenyl groups are alkenyl groups in which the carbon-carbon double bond is located at the terminal position of the carbon chain. Alkenyl groups can also have two or more carbon-carbon double bonds. Examples of alkenyl groups include ethenyl, propenyl, isopropenyl, t-butenyl, 1,3-butadienyl, 1,3-pentadienyl, and the like. Unless otherwise specified, alkenyl groups can be optionally substituted with one or more independently selected substituents defined herein. Unless otherwise specified, alkenyl groups can be substituted with any of O, NR 36 , S, P, and Si, wherein the N, S, and P atoms may be optionally oxidized, and multiple N atoms may be optionally quaternized.

[0051] Alkynyl groups have one or more carbon-carbon triple bonds and can be linear or branched. Unsubstituted alkynyl groups having one CC triple bond have the general formula C n H 2n-3 An alkynyl group can have a terminal carbon-carbon triple bond and / or an internal carbon-carbon triple bond. A terminal alkynyl group is an alkynyl group in which the carbon-carbon triple bond is located at the terminal position of the carbon chain. An alkynyl group can also have two or more carbon-carbon triple bonds. Unless otherwise specified, an alkynyl group can be substituted with one or more independently selected substituents defined herein. Examples of alkynyl groups include ethynyl, propynyl, isopropynyl, t-butynyl, and the like. Unless otherwise specified, an alkynyl group can be any of O, NR 36 , S, P, and Si, wherein the N, S, and P atoms may be optionally oxidized, and multiple N atoms may be optionally quaternized.

[0052] An aryl group refers to an aromatic hydrocarbon ring system having 6 to 24 carbon atoms, more preferably 6 to 12 carbon atoms, and may have a monocyclic or polycyclic structure. When the aryl group has a polycyclic structure, it is preferably a bicyclic structure. The aryl group may be substituted with one or more substituents further specified herein. Examples of the aryl group are phenyl and naphthyl.

[0053] The arylalkyl group and the alkylaryl group have at least 7 carbon atoms and can have a monocyclic or polycyclic structure. The arylalkyl group and the alkylaryl group can be substituted with one or more substituents as further specified herein. An example of an arylalkyl group is benzyl. An example of an alkylaryl group is 4-tert-butylphenyl.

[0054] Heteroaryl groups have at least two carbon atoms (i.e., at least C2) and one or more heteroatoms N, O, P, or S. Heteroaryl groups can have a monocyclic or polycyclic structure. The heteroaryl group may be optionally substituted with one or more substituents as further specified herein. Examples of suitable heteroaryl groups include pyridinyl, quinolinyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, thiazolyl, pyrrolyl, furanyl, triazolyl, benzofuranyl, indolyl, purinyl, benzoxazolyl, thienyl, phosphoryl, and oxazolyl. Preferably, heteroaryl groups have 5 to 16 carbon atoms and 1 to 5 heteroatoms.

[0055] Heteroarylalkyl and alkylheteroaryl groups have at least three carbon atoms (i.e., at least C3) and can have monocyclic and bicyclic structures. The heteroaryl groups may be optionally substituted with one or more substituents as further specified herein.

[0056] When an aryl group is designated as a (hetero)aryl group, the designation is meant to encompass aryl and heteroaryl groups. Similarly, alkyl(hetero)aryl groups are meant to encompass alkylaryl and alkylheteroaryl groups, and alkyl(hetero)aryl groups are meant to encompass arylalkyl and heteroarylalkyl groups. Thus, C2-C 24 The (hetero)aryl group is C2-C 24 Heteroaryl groups and C6-C 24 It should be construed to include aryl groups. 24 The alkyl(hetero)aryl group is C7-C 24 Alkylaryl groups and C3-C 24 It is meant to include alkylheteroaryl groups, as well as C3-C 24 (Hetero)arylalkyl is C7-C 24 Aryl alkyl groups and C3-C 24 Heteroarylalkyl groups are meant to be included.

[0057] A cycloalkenyl group is a cyclic alkenyl group. An unsubstituted cycloalkenyl group having one double bond has the general formula C n H 2n-3 The cycloalkenyl group may be further substituted with one or more substituents as further specified herein. An example of a cycloalkenyl group is cyclopentenyl. Unless otherwise specified, a cycloalkenyl group may be O, NR 36 , S, P, and Si, wherein the N, S, and P atoms may be optionally oxidized, and multiple N atoms may be optionally quaternized.

[0058] A cycloalkynyl group is a cyclic alkynyl group. An unsubstituted cycloalkynyl group having one triple bond has the general formula C n H 2n-5The cycloalkynyl group may be further substituted by one or more substituents as further specified herein. An example of a cycloalkynyl group is cyclooctynyl. Unless otherwise specified, a cycloalkynyl group may be O, NR 36 , S, P, and Si, wherein the N, S, and P atoms may be optionally oxidized, and multiple N atoms may be optionally quaternized.

[0059] In general, when (hetero) is placed before a group, it refers to both the version of the group without the prefix hetero- as well as the group with the prefix hetero-. As used herein, the prefix hetero- indicates that the group contains one or more heteroatoms selected from the group consisting of O, N, S, P, and Si. It will be understood that a group with the prefix hetero- contains heteroatoms by definition. Thus, if a group with the prefix hetero- is part of a list of groups defined as optionally containing heteroatoms, then the group with the prefix hetero- does not optionally contain heteroatoms, but does so by definition.

[0060] As used herein, when the prefix hetero- is used to refer to a combination of groups, it will be understood that the prefix hetero- refers only to the group immediately preceding it. For example, heteroarylalkyl refers to a combination of a heteroaryl group and an alkyl group, not a combination of a heteroaryl group and a heteroalkyl group. Thus, when the prefix hetero- is used to refer to a combination of groups that are part of a list of groups that indicate that heteroatoms may be included, it will be understood that it is optional only for groups in the combination without the prefix hetero-, as it is not optional by definition for groups in the combination with the prefix hetero- (see above). For example, when heteroarylalkyl is part of a list of groups that indicate that heteroatoms may be included, the heteroaryl portion is considered to have a heteroatom by definition, while having a heteroatom is optional for the alkyl portion.

[0061] As used herein, the prefix cyclo- indicates that a group is cyclic. When the prefix cyclo- is used in combination with multiple groups, it will be understood that the prefix cyclo- refers to only the group directly adjacent to it. For example, cycloalkylalkenylene refers to the combination of a cycloalkylene group (see the definition of the suffix -ene below) and an alkenylene group, rather than the combination of a cycloalkylene and a cycloalkenylene group.

[0062] In general, when (cyclo) is placed before a group, it refers to both versions of the group without the prefix cyclo- as well as the group with the prefix cyclo-.

[0063] As used herein, the suffix -ene indicates a divalent group, i.e., the group is bonded to at least two other moieties. An example of an alkylene is propylene (-CH-CH-CH-), which is bonded to another moiety at both ends. When a group having the suffix -ene is substituted with -H at one position, it is understood that the group is the same as the group without the suffix. For example, an alkylene substituted with -H is the same as an alkyl group. That is, propylene substituted with -H at one end, i.e., -CH-CH-CH-, is logically the same as propyl, i.e., -CH-CH-CH-.

[0064] In this specification, when a combination of multiple groups is listed with the suffix -ene, it indicates a divalent group, i.e., the group is bonded to at least two other moieties, where each group in the combination has one bond to one of these two moieties. Thus, for example, alkylarylene is understood to be a combination of an arylene group and an alkylene group. An example of an alkylarylene group is -phenyl-CH-, and an example of an arylalkylene group is -CH-phenyl-.

[0065] As used herein, the suffix -triyl indicates a trivalent group, i.e., the group is bonded to at least three other moieties. An example of an arenetriyl is shown below:

[0066] [ka]

[0067] Here, the wavy lines indicate bonds to different groups on the main compound.

[0068] When a group with the suffix -triyl is substituted with -H at one position, it is understood to be the same as a divalent group with the suffix -ene. For example, an arenetriyl substituted with -H is the same as an arylene group. Similarly, when a group with the suffix -triyl is substituted with -H at two positions, it is understood to be the same as a monovalent group. For example, an arenetriyl substituted with two -H is the same as an aryl group.

[0069] When a group, such as an alkyl group, has a heteroatom, it is understood that this group is the same as the hetero variant of this group. For example, when an alkyl group has a heteroatom, this group is the same as a heteroalkyl group. Similarly, when an aryl group has a heteroatom, this group is the same as a heteroaryl group. In this specification, "having" and its conjugations are understood to mean that when a group has a heteroatom, this heteroatom is part of the backbone of the group. For example, C alkylene containing N refers to -NH-CH-CH-, -CH-NH-CH-, and -CH-CH-NH-.

[0070] Unless otherwise specified, a group may have heteroatoms at non-terminal positions or at one or more terminal positions. In this case, "terminal" refers to a terminal position within the group, not necessarily a terminal position within the compound as a whole. For example, if an ethylene group has a nitrogen atom, this could refer to -NH-CH-CH-, -CH-NH-CH-, and -CH-CH-NH-. For example, if an ethyl group has a nitrogen atom, this could refer to -NH-CH-CH, -CH-NH-CH, and -CH-CH-NH.

[0071] In this specification, cyclic compounds (i.e., aryl, cycloalkyl, cycloalkenyl, etc.) are understood to be monocyclic, polycyclic, or branched. The number of carbon atoms in a cyclic compound refers not only to the number of carbon atoms in one ring, but also to the fact that carbon atoms can be contained in multiple rings. These rings can be fused to the main ring or substituted on the main ring. For example, C , which may contain heteroatoms, can be used. 10 Aryl refers inter alia to a naphthyl group (fused ring) or, for example, a bipyridyl group (substituted rings, both containing an N atom).

[0072] Unless otherwise specified, the term "hetero" refers to a (hetero)alkyl group, a (hetero)alkenyl group, a (hetero)alkynyl group, a (hetero)cycloalkyl group, a (hetero)cycloalkenyl group, a (hetero)cycloalkynyl group, a (hetero)alkylcycloalkyl group, a (hetero)alkylcycloalkenyl group, a (hetero)alkylcycloalkynyl group, a (hetero)cycloalkylalkyl group, a (hetero)cycloalkenylalkyl group, a (hetero)cycloalkynylalkyl group, a (hetero)alkenylcycloalkyl group, a (hetero)alkenylcycloalkenyl a (hetero)alkenylcycloalkynyl group, a (hetero)cycloalkylalkenyl group, a (hetero)cycloalkenylalkenyl group, a (hetero)cycloalkynylalkenyl group, a (hetero)alkynylcycloalkyl group, a (hetero)alkynylcycloalkenyl group, a (hetero)alkynylcycloalkynyl group, a (hetero)cycloalkylalkynyl group, a (hetero)cycloalkenylalkynyl group, a (hetero)cycloalkynylalkynyl group, a (hetero)aryl group, a (hetero)arylalkyl group, a (hetero)arylalkenyl a (hetero)arylalkynyl group, an alkyl(hetero)aryl group, an alkenyl(hetero)aryl group, an alkynyl(hetero)aryl group, a cycloalkyl(hetero)aryl group, a cycloalkenyl(hetero)aryl group, a cycloalkynyl(hetero)aryl group, a (hetero)arylcycloalkyl group, a (hetero)arylcycloalkenyl group, a (hetero)arylcycloalkynyl group, a (hetero)alkylene group, a (hetero)alkenylene group, a (hetero)alkynylene group, a (hetero)cycloalkylene group, a (hetero)cyclo The alkenylene group, (hetero)cycloalkynylene group, (hetero)arylene group, alkyl(hetero)arylene group, (hetero)arylalkylene group, (hetero)arylalkenylene group, (hetero)arylalkynylene group, alkenyl(hetero)arylene, alkynyl(hetero)arylene, (hetero)arenetriyl group, (hetero)cycloalkanetriyl group, (hetero)cycloalkenetriyl, and (hetero)cycloalkyntriyl groups include -Cl, -F, -Br, -I, -OH, -NH2, -SO3H, -PO3H 、 -PO4H2, -NO2, -CF3, =O, =NR36 , -SR 36 , C1~C 24 Alkyl groups, C2-C 24 Alkenyl groups, C2-C 24 Alkynyl groups, C6-C 24 Aryl groups, C2-C 24 Heteroaryl groups, C3-C 24 Cycloalkyl groups, C5-C 24 Cycloalkenyl group, C 12 ~C 24 Cycloalkynyl group, C3-C 24 Alkyl(hetero)aryl groups, C3-C 24 (Hetero)arylalkyl groups, C4-C 24 (Hetero)arylalkenyl groups, C4-C 24 (Hetero)arylalkynyl group, C4-C 24 Alkenyl(hetero)aryl groups, C4-C 24 Alkynyl(hetero)aryl groups, C4-C 24 Alkylcycloalkyl groups, C6-C 24 Alkylcycloalkenyl group, C 13 ~C 24 Alkylcycloalkynyl group, C4-C 24 Cycloalkylalkyl groups, C6-C 24 Cycloalkenylalkyl groups, C 13 ~C 24 Cycloalkynylalkyl groups, C5-C 24 Alkenylcycloalkyl groups, C7-C 24 Alkenylcycloalkenyl group, C 14 ~C 24 Alkenylcycloalkynyl group, C5-C 24 Cycloalkylalkenyl group, C7-C 24 Cycloalkenyl alkenyl group, C 14 ~C 24 Cycloalkynylalkenyl group, C5-C 24 Alkynylcycloalkyl groups, C7-C 24 Alkynylcycloalkenyl group, C 14 ~C 24 Alkynylcycloalkynyl group, C5-C 24 Cycloalkylalkynyl group, C7-C24 Cycloalkenylalkynyl group, C 14 ~C 24 Cycloalkynylalkynyl group, C5-C 24 Cycloalkyl(hetero)aryl groups, C7-C 24 Cycloalkenyl(hetero)aryl group, C 14 ~C 24 Cycloalkynyl(hetero)aryl groups, C5-C 24 (Hetero)arylcycloalkyl groups, C7-C 24 (Hetero)arylcycloalkenyl groups, and C 14 ~C 24 (Hetero)arylcycloalkynyl groups may be optionally substituted with one or more substituents independently selected from O, S, NR 36 , P, and Si, where the N, S, and P atoms are optionally oxidized, and where multiple N atoms are optionally quaternized. Preferably, these substituents are O, S, and NR 36 It may contain one or more heteroatoms selected from the group consisting of:

[0073] In a preferred embodiment, the substituents are -Cl, -F, -Br, -I, -OH, -NH2, -SO3H, -PO3H 、 -PO4H2, -NO2, -CF3, =O, =NR 36 , -SR 36 , C1~C 12 Alkyl groups, C2-C 12 Alkenyl groups, C2-C 12 Alkynyl groups, C6-C 12 Aryl groups, C2-C 12 Heteroaryl groups, C3-C 12 Cycloalkyl groups, C5-C 12 Cycloalkenyl group, C 12 Cycloalkynyl group, C3-C 12 Alkyl(hetero)aryl groups, C3-C 12 (Hetero)arylalkyl groups, C4-C 12 (Hetero)arylalkenyl groups, C4-C12 (Hetero)arylalkynyl group, C4-C 12 Alkenyl(hetero)aryl groups, C4-C 12 Alkynyl(hetero)aryl groups, C4-C 12 Alkylcycloalkyl groups, C6-C 12 Alkylcycloalkenyl group, C 13 ~C 16 Alkylcycloalkynyl group, C4-C 12 Cycloalkylalkyl groups, C6-C 12 Cycloalkenylalkyl groups, C 13 ~C 16 Cycloalkynylalkyl groups, C5-C 12 Alkenylcycloalkyl groups, C7-C 12 Alkenylcycloalkenyl group, C 14 ~C 16 Alkenylcycloalkynyl group, C5-C 12 Cycloalkylalkenyl group, C7-C 12 Cycloalkenyl alkenyl group, C 14 ~C 16 Cycloalkynylalkenyl group, C5-C 12 Alkynylcycloalkyl groups, C7-C 12 Alkynylcycloalkenyl group, C 14 ~C 16 Alkynylcycloalkynyl group, C5-C 12 Cycloalkylalkynyl group, C7-C 12 Cycloalkenylalkynyl group, C 14 ~C 16 Cycloalkynylalkynyl group, C5-C 12 Cycloalkyl(hetero)aryl groups, C7-C 12 Cycloalkenyl(hetero)aryl group, C 14 ~C 16 Cycloalkynyl(hetero)aryl groups, C5-C 12 (Hetero)arylcycloalkyl groups, C7-C 12 (Hetero)arylcycloalkenyl groups, and C 14 ~C 16 (hetero)arylcycloalkynyl groups.

[0074] In a preferred embodiment, the substituents are -Cl, -F, -Br, -I, -OH, -NH2, -SO3H, -PO3H 、 -PO4H2, -NO2, -CF3, =O, =NR 36 , -SR 36 , C1-C7 alkyl group, C2-C7 alkenyl group, C2-C7 alkynyl group, C6-C7 aryl group, C2-C7 heteroaryl group, C3-C7 cycloalkyl group, C5-C7 cycloalkenyl group, C 12 Cycloalkynyl group, C3-C7 alkyl(hetero)aryl group, C3-C7 (hetero)arylalkyl group, C4-C8 (hetero)arylalkenyl group, C4-C8 (hetero)arylalkynyl group, C4-C8 alkenyl(hetero)aryl group, C4-C8 alkynyl(hetero)aryl group, C4-C7 alkylcycloalkyl group, C6-C7 alkylcycloalkenyl group, C 13 ~C 16 Alkylcycloalkynyl group, C4-C7 cycloalkylalkyl group, C6-C7 cycloalkenylalkyl group, C 13 ~C 16 Cycloalkynylalkyl group, C5-C7 alkenylcycloalkyl group, C7-C7 alkenylcycloalkenyl group, C 14 ~C 16 Alkenylcycloalkynyl group, C5-C7 cycloalkylalkenyl group, C7-C8 cycloalkenylalkenyl group, C 14 ~C 16 Cycloalkynylalkenyl group, C5-C7 alkynylcycloalkyl group, C7-C8 alkynylcycloalkenyl group, C 14 ~C 16 Alkynylcycloalkynyl group, C5-C7 cycloalkylalkynyl group, C7-C8 cycloalkenylalkynyl group, C 14 ~C 16 Cycloalkynylalkynyl group, C5-C9 cycloalkyl(hetero)aryl group, C7-C 11 Cycloalkenyl(hetero)aryl group, C 14 ~C 16Cycloalkynyl(hetero)aryl group, C5-C9(hetero)arylcycloalkyl group, C7-C 11 (Hetero)arylcycloalkenyl groups, and C 14 ~C 16 (hetero)arylcycloalkynyl groups.

[0075] Unless otherwise specified, any non-cyclic group disclosed herein should be understood to be linear or branched. In particular, (hetero)alkyl groups, (hetero)alkenyl groups, (hetero)alkynyl groups, (hetero)alkylene groups, (hetero)alkenylene groups, (hetero)alkynylene groups, etc., are linear or branched unless otherwise specified.

[0076] The general term "sugar" is used herein to refer to monosaccharides such as glucose (Glc), galactose (Gal), mannose (Man), and fucose (Fuc). The term "sugar derivative" is used herein to refer to derivatives of monosaccharide sugars, i.e., monosaccharide sugars having substituents and / or functional groups. Examples of sugar derivatives include amino sugars and sugar acids such as glucosamine (GlcNH), galactosamine (GalNH), N-acetylglucosamine (GlcNAc), N-acetylgalactosamine (GalNAc), sialic acid (Sia), which is also called N-acetylneuraminic acid (NeuNAc) and N-acetylmuramic acid (MurNAc), glucuronic acid (GlcA), and iduronic acid (IdoA).

[0077] A sugar may have no further substitutions and is understood to be a monosaccharide. A sugar may be further substituted at one or more of its hydroxyl groups, in which case it is understood to be a disaccharide or an oligosaccharide. A disaccharide has two monosaccharide moieties linked together. An oligosaccharide chain may be linear or branched and may contain 3 to 10 monosaccharide moieties.

[0078] The term "protein" is used herein in its ordinary scientific sense. Polypeptides having about 10 or more amino acids are considered proteins herein. Proteins may have naturally occurring amino acids, but may also have unnatural amino acids. The term "protein" as used herein is understood to include antibodies and antibody fragments.

[0079] The term "peptide" is used herein in its ordinary scientific sense. As used herein, a peptide is considered to have a number of amino acids ranging from 2 to 9.

[0080] The term "peptoid" is used herein in its ordinary scientific sense.

[0081] An antibody is a protein, typically produced by the immune system, that can recognize and bind to a specific antigen. While antibodies or immunoglobulins derived from IgG antibodies are particularly well suited for use in the present invention, immunoglobulins from any of several classes or subclasses can be selected, such as IgG, IgA, IgM, IgD, and IgE. Suitably, the immunoglobulin is of the IgG subclass (IgG1, IgG2, IgG3, and IgG4) or class IgG, including, but not limited to, class IgM, which can specifically bind to a specific epitope on an antigen. Antibodies can be intact immunoglobulins derived from natural or recombinant sources, and can be immunoreactive portions of intact immunoglobulins.Antibodies can be in a variety of forms, such as polyclonal antibodies, monoclonal antibodies, camelized single domain antibodies, recombinant antibodies, anti-idiotype antibodies, multispecific antibodies, antibody fragments such as Fv, VHH, Fab, F(ab)2, Fab', Fab'-SH, F(ab')2, single chain variable fragment antibodies (scFv), tandem / bis-scFv, Fc, pFc', scFv-Fc, disulfide Fv (dsFv), bispecific antibodies (bc-scFv), such as BiTE antibodies, trispecific antibody derivatives such as tribodies, camelid antibodies, minibodies, nanobodies, resurfaced antibodies, etc. The antibodies may exist in a variety of forms, including, but not limited to, monoclonal antibodies, humanized antibodies, fully human antibodies, single domain antibodies (sdAbs, also known as Nanobodies™), dual-affinity antibodies, chimeric antibodies, antibody fusions, chimeric antibodies with at least one human constant region, dual-affinity retargeting proteins (DART™), and multimers and derivatives thereof, such as bivalent or multivalent single-chain variable fragments (e.g., di-scFvs, tri-scFvs), bivalent or multivalent single-chain variable fragments including, for example, minibodies, diabodies, triabodies, tribodies, tetrabodies, etc., and multivalent antibodies.Reference is made to [Trends in Biotechnology 2015, 33, 2, 65], [Trends Biotechnol. 2012, 30, 575-582] and [Canc. Gen. Prot. 2013 10, 1-18] and [BioDrugs 2014, 28, 331-343], the contents of which are incorporated herein by reference. "Antibody fragment" refers to at least a portion of the variable region of an immunoglobulin that binds to its target, i.e., the antigen-binding region. Other embodiments use antibody mimetics, such as, but not limited to, Affimers, Anticalins, Avimers, Alphabodies, Affibodies, DARPins, and multimers, and derivatives thereof; see Trends in Biotechnology 2015, 33, 2, 65, the contents of which are incorporated herein by reference. As used herein, "antibody" also refers to antibodies with additional functionality, such as labeled antibodies, particularly radiolabeled antibodies, and antibody-drug conjugates. For the avoidance of doubt, in the context of the present invention, the term "antibody" is meant to encompass all of the antibody variants, fragments, derivatives, fusions, analogs, and mimetics outlined in this paragraph, unless otherwise specified.

[0082] A linker is defined herein as a moiety that connects two or more elements of a compound, e.g., in a bioconjugate, a biomolecule and another moiety, such as a label, are covalently attached to each other via a linker.

[0083] A biomolecule is defined herein as any molecule that can be isolated from nature or that is composed of smaller molecular building blocks that are components of naturally occurring macromolecular structures, in particular nucleic acids, proteins, glycans, and lipids. Examples of biomolecules include enzymes, (non-catalytic) proteins, polypeptides, peptides, amino acids, oligonucleotides, monosaccharides, oligosaccharides, polysaccharides, glycans, lipids, and hormones.

[0084] As used herein, an organic molecule is defined as a molecule having a C-H bond. Organic compounds and organic molecules are used synonymously. As used herein, "organic molecules" is understood to include biomolecules, such as nucleic acids (oligonucleotides, polynucleotides, DNA, RNA), peptides, proteins (especially antibodies), carbohydrates (monosaccharides, oligosaccharides and polysaccharides), aptamers, hormones, toxins, steroids, cytokines and lipids; small organic molecules as defined herein; polymers (especially polyethylene glycol); LNA and PNA; amino acids; peptoids; molecules containing radionuclides; fluorescent dyes; drugs; resins (especially polystyrene and agarose); beads; particles (especially polymersomes, liposomes and beads); gels; surfaces; organometallic compounds; cells; and combinations thereof.

[0085] As used herein, inorganic molecule is defined as any molecule that is not an organic molecule, i.e., does not have C-H bond.As used herein, "inorganic molecule" is understood to include surfaces (particularly chips, wafers, gold, metal, silica-based surfaces, such as glass), particles, such as beads (particularly magnetic beads, gold beads), silica-based particles, polymer-based materials, iron oxide particles; carbon nanotubes; carbon allotropes (particularly fullerenes, such as Buckminsterfullerene; graphite; graphene, diamond, Lonsdaleite, Q carbon, linear acetylene carbon, amorphous carbon, and carbon nanotubes); drugs (particularly cisplatin); and combinations thereof.

[0086] As used herein, a "particle" is preferably defined as a microparticle or a nanoparticle.

[0087] The term "salts thereof" refers to compounds formed when an acidic proton, typically an acid proton, is replaced by a cation, such as a metal cation or an organic cation. The term "salts thereof" also refers to compounds formed when an amine is protonated. Where applicable, the salt is a pharmaceutically acceptable salt, although this is not required for salts that are not intended for administration to patients. For example, in the salts of a compound, the compound may be protonated with an inorganic or organic acid to form a cation, where the conjugate base of the inorganic or organic acid is the anionic component of the salt.

[0088] The term "pharmaceutically acceptable salt" means a salt that is acceptable for administration to a patient, e.g., a mammal (a salt having a counterion that has acceptable mammalian safety for a given dosing regimen). Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and pharmaceutically acceptable inorganic or organic acids.

[0089] "Pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts of a compound, which salts are derived from a variety of organic and inorganic counterions known in the art, and include, for example, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc., as well as, where the molecule possesses a basic functional group, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, formate, tartrate, besylate, mesylate, acetate, maleate, oxalate, etc.

[0090] In a preferred embodiment, in the context of the present invention, a "particle" is defined as a nanoparticle or a microparticle.

[0091] The logarithm of the partition-coefficient, or Log P, is used herein as a measure of the hydrophobicity of a compound. Typically, Log P is defined as follows:

[0092]

number

[0093] Those skilled in the art will know how to determine the partition coefficient of a compound without undue experimentation. Alternatively, those skilled in the art will know that software is available to reliably estimate Log P values ​​as a function of, for example, within ChemDraw® software or tools available online.

[0094] The unified atomic mass unit, or Dalton, is abbreviated herein as Da. Those skilled in the art know that the Dalton is a common unit of molecular weight and that 1 Da corresponds to 1 g / mole (gram per mole).

[0095] It will be understood that the words "moiety" and "group" are used interchangeably herein when referring to a portion of a molecule.

[0096] It will be understood that when the heteroatom is -(R')2-, where X is a heteroatom and R' is a moiety, this means that two moieties R' are bonded to the heteroatom.

[0097] The group may be, for example, -((R 51 )2-R 52 )2- or similar notation, where R 51 and R 52 is a part, this means that first the part R 51 and R 52 Instead of selecting parts and writing out the formula, 51 and R 52 -R before the part is selected 51 -R 51 -R 52 -R 51 -R 51 -R 52 - It will be understood that this indicates that the item should be written as

[0098] Inverse Electron Demand Diels-Alder Reaction (IEDDA) Inverse Electron Demand Diels-Alder Reaction (IEDDA) Established IEDDA conjugation chemistry generally involves a pair of reactants, including a suitable diene, such as a derivative of tetrazine (TZ), e.g., an electron-deficient tetrazine, as one reactant (i.e., one bioorthogonal reactive group), and a suitable dienophile, e.g., trans-cyclooctene (TCO), as the other reactant (i.e., the other bioorthogonal reactive group). The extremely fast reaction of a (substituted) tetrazine, particularly an electron-deficient tetrazine, with the TCO moiety results in an intermediate that rearranges to a dihydropyridazine Diels-Alder adduct by eliminating N as the only byproduct. The initially formed 4,5-dihydropyridazine product can tautomerize to either the 1,4- or 2,5-dihydropyridazine product, especially in an aqueous environment. The following reaction scheme shows the [4 + 2] IEDDA reaction between (3,6)-di-(2-pyridyl)-s-tetrazine diene and trans-cyclooctene dienophile, followed by the retro Diels-Alder reaction to form the product and dinitrogen. Because the trans-cyclooctene derivative does not have an electron-withdrawing group like in the classical Diels-Alder reaction, this type of Diels-Alder reaction is distinguished from the classical reaction and is often referred to as the "inverse electron-demand Diels-Alder reaction (IEDDA)." In the following text, both reaction step sequences, i.e., the initial Diels-Alder cycloaddition reaction (typically an inverse electron-demand Diels-Alder cycloaddition reaction) and the subsequent retro Diels-Alder reaction, will be referred to as the "inverse electron-demand Diels-Alder reaction" or "inverse electron-demand Diels-Alder conjugation" or "IEDDA" for short. In this case, the product of the reaction is the IEDDA adduct or conjugate. This is illustrated in Scheme 1 below.

[0099] [ka]

[0100] The two reactive species are abiotic and do not undergo rapid metabolism or side reactions in vitro or in vivo. They are bioorthogonal, i.e., they react selectively with each other in physiological media. Therefore, the compounds and methods of the present invention can be used in living organisms. Moreover, the reactive groups are relatively small and can be introduced into biological samples or organisms without significantly altering the size of the biomolecules in the biological sample or organism. The literature on the inverse electron demand Diels-Alder reaction and the behavior of the pair of reactants includes the following: [Thalhammer et al., Tetrahedron Lett., 1990, 31, 47, 6851-6854], [Wijnen et al., J. Org. Chem., 1996, 61, 2001-2005], [Blackman et al., J. Am. Chem. Soc., 2008, 130, 41, 13518-19], Rossin et al., Angew. Chem. Int. Ed. 2010, 49, 3375], [Devaraj et al., Angew. Chem. Int. Ed. 2009, 48, 7013], [Devaraj et al., Angew. Chem. Int. Ed., 2009, 48, 1-5].

[0101] IEDDA pyridazine elimination reaction Hereinafter, the dienophile TCO that may be included in the combinations and kits of the present invention will be referred to as "Trigger" (T R The dienophile is attached to Construct A at the allylic position. Additionally, the tetrazines used in the IEDDA pyridazine elimination reaction may be referred to as "Cleaving Agents." For ease of reference, the term Construct A is used herein to refer to any Administration Agent or Label that is desired to initially place it in a bound (or masked) state and be capable of triggering its release from that state.

[0102] Without wishing to be bound by theory, the inventors believe that the cleavage agent triggers the release of Construct-A via a cascade mechanism within the IEDDA adduct, i.e., dihydropyridazine. The cascade mechanism may be a simple one-step reaction or may consist of multiple steps involving one or more intermediate structures. These intermediates may be stable for some time or may quickly decompose into a thermodynamic end product or the next intermediate structure. In either case, whether it is a simple step or a multi-step process, the result of the cascade mechanism is the release of Construct-A from the IEDDA adduct. Without wishing to be bound by theory, the design of the diene results in an unfavorable distribution of electrons within the IEDDA adduct, and therefore, a rearrangement of these electrons must occur. This situation initiates the cascade mechanism and, therefore, triggers the release of Construct-A. Specifically, without wishing to be bound by theory, the inventors believe that the NH moieties contained in various dihydropyridazine tautomers of the IEDDA adduct, such as the 1,4-dihydropyridazine tautomer, can initiate an electronic cascade reaction, a concerted or sequential shift of electrons across several bonds, resulting in the release of Construct-A. Because the Trigger-Construct-A conjugate itself is relatively stable, the cascade reaction within the Trigger and / or the release of Construct-A from the Trigger cannot occur efficiently or before the IEDDA reaction. The cascade occurs only after the cleavage agent and the Trigger-Construct conjugate react and are incorporated into the IEDDA adduct.

[0103] Referring to Scheme 2 below, and without wishing to be bound by theory, the inventors believe that pyridazine elimination occurs from the 1,4-dihydropyridazine tautomer 4. Upon formation of 4,5-dihydropyridazine 3, tautomerization affords intermediates 4 and 7, of which 2,5-dihydropyridazine 7 is the intermediate of construct A (C A) cannot be removed. Instead, it can be slowly converted to aromatic 8, which can also be converted to C A can not be removed or it can tautomerize back to intermediate 3. Upon formation of 4, C A is removed almost instantly, leaving free C as the amine. A This gives 8, and the pyridazine elimination products 5 and 6. This elimination reaction has been shown to work equally well for cleaving carbamates, carbonates, esters, and ethers from the TCO trigger [Versteegen et al., Angew. Chem. Int. Ed., 2018, 57, 10494]. The trigger in Scheme 2 can also be used to cleave construct-B (C B ), in which case it cannot be released from the trigger. Construct A can thereby be separated from Construct B by IEDDA pyridazine elimination.

[0104] [ka]

[0105] In a preferred embodiment, the dienophile trigger moiety used in the present invention has a trans-cyclooctene ring. In this specification, for ease of reading, this 8-membered ring moiety is defined as a trans-cyclooctene moiety or abbreviated as a "TCO" moiety. It will be understood that the 8-membered ring essentially acts as a dienophile and can be released from its conjugated construct-A upon reaction.

[0106] The tetrazine and dienophile of the kit of the present invention can react in an inverse electron demand Diels-Alder reaction (i.e., DDA). The IEDDA reaction of a trigger with a cleaving agent results in the release of Construct A via an electron cascade-based elimination, referred to as "pyridazine elimination." When a cleaving agent reacts with a trigger capable of removing Construct A, the combined process of reaction and removal of Construct A is referred to as "IEDDA pyridazine elimination."

[0107] The present invention provides a cleavage agent that reacts with a trigger conjugated to Construct-A, resulting in cleavage of the trigger from Construct-A. In one notable embodiment, this results in cleavage of Construct-A from Construct-B. In other embodiments, the trigger cleavage results in cleavage of one Construct-A from another Construct-A, since the dienophile trigger of Formula (1) can include Construct-A located at two allylic positions, where one or both can be released from the trigger upon reaction with a diene. In other embodiments, the trigger cleavage results in cleavage of one or more Construct-A from one or more Construct-B. Unless Construct-B is attached at an allylic position via a spacer or automimetic linker that is also attached to Construct-A, Construct-B can be either a dosage agent or a label, depending on the nature of the construct, i.e., Construct-A, attached to the dienophile, and cannot be released from the dienophile. In a preferred embodiment, the trigger is used as a reversible covalent bond between two molecular species.

[0108] Scheme 3a below is a general scheme for construct release according to a preferred embodiment of the present invention, where the released construct is Construct-A (C A ), and another construct, Construct-B (C B), may be attached to the dienophile, but not via an allylic position, where Construct-B cannot be released from the dienophile.

[0109] JPEG0007660525000008.jpg125170

[0110] Scheme 3b below is a general scheme for releasing a construct according to another embodiment of the present invention, wherein Construct-B (C B ) is attached to the dienophile via a spacer or self-immolative linker that also attaches to Construct-A, and wherein when the spacer or self-immolative linker is released from the allylic position, Construct-B and Construct-A are released from the Trigger and from each other.

[0111] JPEG0007660525000009.jpg117170

[0112] Scheme 3c below is a general scheme for construct release according to another embodiment of the present invention, wherein the trigger is linked to two allele-disposed constructs A, and wherein one or both constructs A can be released from the trigger in either case, one construct A is cleaved from the other construct A, and one construct A is an administration agent and the other construct A is a label.

[0113] JPEG0007660525000010.jpg129170

[0114] Release of the construct occurs through a potent abiotic, bioorthogonal reaction between a dienophile (trigger) and a diene (cleaver), i.e., IEDDA, ​​as previously described. The combined construct is a construct-dienophile conjugate. Construct A is likely linked to one or more additional constructs A, linked via a spacer, e.g., a self-immolative linker. It will be understood that the dienophile and diene groups shown in Schemes 3a, 3b, and 3c in the IEDDA adduct and in the final product after release are the residues of the dienophile and diene groups, respectively, after these groups are converted in the IEDDA reaction.

[0115] C A and C B The difference is C B and C B The bond between the moiety holding the trigger and the diene is not cleaved upon reaction with the diene, while the bond between the trigger and the diene holding the trigger and the diene is not cleaved upon reaction with the diene. A and C A The bond between the trigger and the moiety holding the C is cleaved upon reaction with the diene. A and C B The portion holding the trigger is a self-immolative linker L C To clarify, C B is connected to the trigger C If it is connected to C B L holding C is released from the trigger upon reaction with the diene, while C B is released L C Similarly, C B If is directly connected to the trigger, C B will not be released from the trigger upon reaction with the diene. Those skilled in the art will understand that if it is necessary to separate a label from a dosage, preferably one of the following requirements must be met: 1) One C A includes the label, and other C Acomprises an administration agent, 2) Either the label or the administered agent is C A and the other is C B That is, 3) Both the label and the administered agent are C B However, one C B R 48 and the other is R 48 L is part of C or, if one of C B The part is the other C B Partially different L C is connected to the part.

[0116] For example, in medically active substances, whose in vitro or in vivo actions often change with small structural changes, the present invention requires, first and foremost, appropriate chemical reactivity combined with sufficient stability for the intended use. Thus, possible structures extend to those well known to those skilled in the art that are reactive as dienes or dienophiles.

[0117] Targeting The term "primary target" as used herein, in connection with both the administered agent and the cleaving agent, refers to a target that is detected by diagnostic and / or imaging methods and / or that is modulated, bound, or otherwise addressed by a pharmaceutically active compound or other therapeutic modality. The primary target can be selected from any suitable target in the human or animal body, or in a pathogen or parasite. For example, the primary target can be any molecule or tissue present in an organism, tissue, or cell. Targets include cellular components, such as cell membranes and cell walls; cell surface targets, such as receptors and glycoproteins; structural proteins, such as amyloid plaques; extracellular targets, such as stromal targets and tumor microenvironment targets; extracellular matrix targets, such as growth factors and proteases; intracellular targets, such as the surface of the Golgi apparatus, the surface of mitochondria, RNA, DNA, enzymes, components of cell signaling pathways; and / or foreign substances, such as pathogens, such as viruses, virus particles, bacteria, fungi, yeast, or parts thereof. Examples of primary targets include compounds, such as proteins, whose presence or expression levels correlate with certain tissue or cell types, or whose expression levels are up-regulated or down-regulated in certain disorders. According to certain embodiments of the present invention, the primary target is a protein, such as an (internalizing or non-internalizing) receptor. According to a preferred embodiment of the present invention, the primary target is an internalizing receptor. According to another preferred embodiment of the present invention, the primary target is a non-internalizing receptor.

[0118] In preferred embodiments, the primary target can be a body system, such as the blood circulation, lymphatic system, nervous system, digestive system, RES system, or an organ, such as the heart or kidney, for example, an imaging agent that visualizes blood flow, the liver, or identifies sentinel lymph nodes of a tumor.

[0119] Alternatively, primary targets may be metabolic pathways that are upregulated during disease, such as infection or cancer, such as DNA synthesis, protein synthesis, membrane synthesis, and carbohydrate uptake. In diseased tissue, the markers described above may differ from healthy tissue, offering unique possibilities for early detection, specific diagnosis, and treatment, especially targeted therapy.

[0120] Other non-limiting examples of primary targets are antibodies, proteins, carbohydrates, monosaccharides, polysaccharides, cytokines, hormones, steroids, somatostatin receptors, monoamine oxidases, muscarinic receptors, cardiomyocytes, leukotriene receptors, e.g., leukocytes, urokinase plasminogen activator receptor (uPAR), folate receptors, apoptosis markers, (anti-)angiogenesis markers, gastrin receptors, dopaminergic system, serotonergic system, GABAergic system, adrenergic system, cholinergic system, opoid receptors, GPIIb / IIIa receptors and other thrombosis-related receptors, fibrin, calcitonin receptor, tuftsin receptor, integrin receptors. receptor), fibronectin, VEGF / EGF and VEGF / EGF receptor, TAG72, CEA, CD19, CD20, CD22, CD40, CD45, CD74, CD79, CD105, CD138, CD174, CD227, CD326, CD340, MUC1, MUC16, GPNMB, PSMA, Cripto, tenascin C, melanocortin-1 receptor, CD44v6, G250, HLA DR, ED-A, ED-B, TMEFF2, EphB2, EphA2, FAP, mesothelin, GD2, CAIX, 5T4, matrix metalloproteinases (MMPs) These include IL-16, IL-17, IL-18, IL-19, IL-20, IL-19, IL-21, IL-19 ...

[0121] According to a further specific embodiment of the present invention, the primary target and targeting agent are selected to result in specific or increased targeting of tissues or diseases, such as cancer, inflammation, infectious diseases, cardiovascular diseases such as thrombosis, atherosclerosis, hypoxic sites such as stroke, tumors, cardiovascular disorders, brain disorders, apoptosis, angiogenesis, organs, and reporter genes / enzymes. This can be achieved by selecting primary targets with tissue-, cell-, or disease-specific expression. For example, membrane folate receptors mediate the intracellular accumulation of folic acid and its analogs, such as methotrexate. While expression is restricted in normal tissues, the receptor is overexpressed in various tumor cell types.

[0122] In a preferred embodiment, the primary target is equivalent to the therapeutic target.

[0123] Preferred internalizing targets are: Transferrin receptor, e.g., leukocyte, urokinase plasminogen activator receptor (uPAR), folate receptor, gastrin receptor, GPIIb / IIIa receptor, calcitonin receptor, tuftsin receptor, integrin receptor, VEGF / EGF receptor, CD19, CD20, CD22, CD25, CD30, CD33, CD40, CD45, CD56, CD70, CD74, CD79, CD105, CD123, CD138, CD163, CD174, CD184, CD227, CD269, CD326, CD340, CD352, MUC1, MUC16, GPNMB, PSMA, Cripto, melanocortin-1 receptor, HLA DR, TMEFF2, EphB2, EphA2, FAP, mesothelin, GD2, CAIX, 5T4, matrix metalloproteinase (MMP), ADAM-9, P / E / L-selectin receptor, LDL receptor, P-glycoprotein, neurotensin receptor, neuropeptide receptor, substance P receptor, NK receptor, CCK receptor, CXCR, tumor endothelial marker (TEM), cMET, IGFR, FGFR, GPA33, hCG, platelet-derived growth factor (PDGF) factor), HER2, HER3, CA19, TAM, LGALS3BP, Nectin-4, IFGR, cMET, PD1, PDL1, GPNMB, AGS-5, AGS-16, endosialin, ETBR, TM4SF1, BCMA, GPC2, TROP-2, AXL, HLA-DR, B7-H3, MTX3, MTX5, EFNA4, NOTCH, tissue factor (TF: tissue factor), PDGFR, GITR, OX40, RIG, MDA-5, NLRP1, NLRP3, AIM2, IDO, MEK, cGAS, NKG2A.

[0124] Preferred non-internalizing targets are fibronectin ED-A, fibronectin ED-B, VEGF, EGF, TAG72, CEA, CD20, CD25, MUC1, MUC16, tenascin C, CD44v6, CAIX, matrix metalloproteinase (e.g., MMP2), A33, mesothelin, LGALS3BP, hCG, nectin-4, CD45, G250, GPA33, GD2, PD1, PDL1, GITR, CD3, CD28, CTLA4, OX40, RIG, MDA-5, NLRP1, NLRP3, AIM2, IDO, MEK, cGAS, and NKG2A.

[0125] Those skilled in the art will appreciate that the foregoing classification is relative, as most targets are not completely internalizing or non-internalizing, but instead can be classified as relatively internalizing or relatively non-internalizing compared to other targets, such as TAG72 (non-internalizing) and HER2 (fast internalizing). Those skilled in the art will appreciate that the rate of internalization is an important factor in this classification, and that the administration or targeting agent T T It will be appreciated that the nature of the method can affect this rate.

[0126] Compound of formula (1) The present invention relates to compounds of formula (1) disclosed herein. Compounds of formula (1) are those having -CHR 48 , -C=C-, and X 1 ~X 5 It will be understood that this includes an eight-membered trans ring formed by

[0127] [ka]

[0128] R 48 -L B and -L A is selected from the group consisting of:

[0129] In a preferred embodiment, R 48 -L B is.

[0130] In a preferred embodiment, R 48 -L A is.

[0131] -L in this specification B and -L A As is clear from the definition of -L B and -L A Both of them are part L C which is optionally a self-immolative linker, which may consist of multiple units arranged in a linear and / or branched manner, and A may release one or more moieties, shown as moieties, while L C The part that is not emitted from C B It can be shown as: L C There are multiple C A If it contains parts, these C A Part is L C Because of the self-immolative character of these C A The moieties can independently be a label or an administration agent, and the spacer S P via L C It will be understood that L may be linked to C There is one C B If it contains, the C B The moiety can be either an administration agent or a label. C Two or more C B If it contains, the C B All of the moieties are either administration agents or labels. 48 The group is a linker L CIt will be appreciated that due to the self-immolative nature of the compound of formula (1), it may contain both a label and an administration agent that is decoupled following reaction of the compound of formula (1) with a cleavage agent.

[0132] For further clarification, R 48 L B When all d and e in formula (2) are 0, the label directly constitutes the leaving group of the release reaction, and when either d or e in formula (2) is 1, it constitutes the self-immolative linker L C and constitutes the leaving group for the release reaction.

[0133] In formula (1), R 48 is R 48 is attached to the remainder of the compound of formula (1) via an -O-, -S-, -OC(O)-, -OC(S)-, -SC(O)-, or -SC(S)-, preferably -O- or -OC(O)-, most preferably -OC(O)N- (i.e., carbamate), which is part of R 48 Preferably, -OC(O)-, -OC(S)-, -SC(O)-, or -SC(S)- is directly attached to an aromatic moiety that is also part of R 48 In a preferred embodiment, in formula (1), R 48 is R 48 -OR is part of 97 -, -SR 97 -, -OC(O)-R 97 -, -OC(S)-R 97 -, -SC(O)-R 97 -, or -SC(S)-R 97 In a preferred embodiment, in formula (1), R 48 is R 48 -O-, -SR is part of 99 -, -OC(O)-, -OC(O)-R 99 -, -OC(S)-R 99 -, -SC(O)-R 99-, or -SC(S)-R 99 - to the remainder of the compound of formula (1).

[0134] Preferably, this notation is, for example, -OC(O)-R 99 - in which the first O is attached to the 8-membered ring of formula (1), and R 99 is R 48 It will be understood that -O- denotes an ether, and can be an aromatic or aliphatic ether. Similarly, -OC(O)- denotes an ester, which can be an aromatic or aliphatic ester, preferably an aromatic ester. R 48 -O-, -OC(O)-, or -OC(S)- which is part of the spacer S P or S L Part of (if present) or spacer S P or S L It will be understood that if not present, it may be part of the administration agent or label.

[0135] In formula (1), R 48 L B and does not contain an administration agent, L B Where R is 48 preferably has a molecular weight of 50 kDa or less, preferably 5 kDa or less, even more preferably 2 kDa or less, even more preferably 1 kDa or less, even more preferably 500 Da or less.

[0136] In formula (1), R 48 L A and does not contain a label, then R 48 Preferably, compounds of formula (1) that do not include L have a molecular weight of 50 kDa or less, more preferably 5 kDa or less, even more preferably 2 kDa or less, and even more preferably 1 kDa or less. A and one R containing no label 48 If it contains L A Where R is 48Preferably, the compound of formula (1) does not have L has a molecular weight of 50 kDa or less, more preferably 5 kDa or less, even more preferably 2 kDa or less, and even more preferably 1 kDa or less. A and do not contain any labels. 48 If both R 48 Compounds of formula (1) that do not include have a molecular weight of 50 kDa or less, more preferably 5 kDa or less, even more preferably 2 kDa or less, and even more preferably 1 kDa or less.

[0137] The compound of formula (1) comprises at least one label and at least one administration agent. Preferably, the compound of formula (1) comprises no more than one label and no more than one administration agent.

[0138] Preferably, at least one R 48 L B If X 1 , X 2 , X 3 and X 4 L B Where R is 48 Preferably, at least one R 48 L A If X 1 , X 2 , X 3 and X 4 is L A Does not include.

[0139] In a particularly preferred embodiment, R 48 One or both of these are in the axial position.

[0140] Preferably, X 5 -C(R 47 )2- and R 48 contains a label, and R 48 If does not contain the administered agent, X 1 ~X 5 is R 48 does not contain the same markings as those contained in

[0141] Preferably, X 5 -C(R 47 )2- and R 48 contains the administration agent, and R 48 If does not contain a label, then X 1 ~X 5 is R 48 does not contain the same dosage as that contained in

[0142] Preferably, X 5 -C(R 47 )2- and R 48 comprises at least one administration agent and at least one label, 1 ~X 5 is R 48 The same dosage form as that included in 48 It may contain any of the same labels as those contained in

[0143] In formula (1), L A R 48 If L A consists of both the label and the administration agent only.

[0144] In formula (1), R 48 Where L is A When the compound contains both a label and an agent to be administered, S linked to the label is P and the administration agent is a self-immolative linker, preferably with the proviso that at least one of the label and the administration agent is a self-immolative linker, C In the definition of C A or, provided that the label and the administered agent are the same R 48 Different L C is connected to the part.

[0145] Preferably, in formula (1), L B R 48 If R 48 contains only both the label and the administering agent.

[0146] Preferably, in formula (1), R 48 L BWhen the compound contains both a label and an administration agent, S linked to the label and the administration agent P is a self-immolative linker, preferably with the proviso that at least one of the label and the administration agent is C In the definition of C A or, provided that the label and the administered agent are the same R 48 Different L C is connected to the part.

[0147] Formula (2) In formula (1), the moiety L B satisfies the following formula (2).

[0148] [ka]

[0149] where the dashed line indicates the bond to the remainder of the compound of formula (1).

[0150] In formula (2), each d is independently 0 or 1. In preferred embodiments, at least one d is 1. In other preferred embodiments, both d are 1. In yet other preferred embodiments, both d are 0.

[0151] In formula (2), e is an integer ranging from 0 to 4, preferably e is 3 or less, more preferably 2 or less, and most preferably e is 1 or less. In a preferred embodiment, e is 1. In another preferred embodiment, e is 0.

[0152] In formula (2), the label is preferably as defined herein.

[0153] Preferably, -L B does not include the administered agent.

[0154] Preferably, formula (2) is -S L - sign, where S Lis polyethylene glycol (PEG), and more preferably, S L is PEG4.

[0155] Linker S L In equation (2), S L is a linker, which is a self-immolative linker L as defined herein C It is possible.

[0156] Preferably, S L is S as defined herein P where S L R 98 In some embodiments, when attached to S L is a trivalent radical, and S P It will be understood that the suffix -ene in the preferred definition of is replaced by -triyl.

[0157] In a preferred embodiment, S P S is the L R 32 Residue of part C M2 , and part C X In a preferred embodiment, the C M , C X , or R 32 The residue of S P A, sign, L C , S P , R 98 , or T R Connect to.

[0158] In a preferred embodiment, S L is L C Preferably, S L L C When S is , e is 0, one d is 0, and one d is 1. In another preferred embodiment, S L is X 1 ~X4 If it is included in one of L is L C In another preferred embodiment, S L is L C No.

[0159] R 98 In formula (2), each R 98 are individually labels or clearance-indicating groups. In a preferred embodiment, R 98 is a sign. R 98 The label is preferably as defined herein and R 98 Not L B The label may be the same as or a different label than that contained in

[0160] R 99 R 99 -O-, -C(R 36 )2-, -S-, and -NR 36 - is selected from the group consisting of

[0161] Clearance indicator A clearance-directing group is a moiety that directs a compound to an organ of excretion, such as the kidney or liver. In this way, it ensures faster clearance of the compound from the blood in a subject and / or it controls which organs of excretion will or will not process the compound in order to improve imaging procedures or non-target tissue dosimetry. In the context of the present invention, it will be understood that the increased clearance rate of the label after separation from the administered agent is primarily due to this separation, and that the clearance-directing group simply further enhances the clearance rate and / or controls the clearance pathway of the label.

[0162] In a preferred embodiment, the clearance-indicating group is hexose-based. Hexose-based clearance-indicating groups incorporate one or more hexoses (six-carbon sugar moieties) recognized by Ashwell receptors or other receptors, such as the mannose / N-acetylglucosamine receptor or the mannose 6-phosphate receptor associated with hepatocytes, endothelial cells, and / or Kupffer cells of the liver.

[0163] Exemplary hexoses are other moieties recognized by the Ashwell receptor, such as galactose, mannose, mannose 6-phosphate, N-acetylglucosamine, pentamannosylphosphate, etc. Other moieties, including glucose, N-galactosamine, N-acetylgalactosamine, pentamannosylphosphate, thioglycosides of galactose, and generally, D-galactosides and glucosides, etc., can also be used in the practice of the invention.

[0164] In a preferred embodiment, the clearance-indicating group is galactose.

[0165] Galactose thioglycoside conjugation is preferably accomplished following procedures generally similar to those taught by Lee et al., "2-Imino-2-methoxyethyl 1-20 Thioglycosides: New Reagents for Attaching Sugars to Proteins," Biochemistry, (18):3956, 1976. Another useful galactose thioglycoside conjugation method is described by Drantz et al., "Attachment of Thioglycosides to Proteins: Enhancement of Liver Membrane Binding," Biochemistry, 15(18):3963, 1976.

[0166] Formula (3) In formula (1), L Ais the part that satisfies the following formula (3).

[0167] [ka]

[0168] where the dashed line indicates the bond to the remainder of the compound of formula (1).

[0169] In formula (3), each s is independently 0 or 1. In a preferred embodiment, at least one s is 1. In another preferred embodiment, both s are 1. In yet another preferred embodiment, both s are 0.

[0170] In formula (3), i is an integer ranging from 0 to 4, preferably 3 or less, more preferably 2 or less, and most preferably 1 or less. In a preferred embodiment, i is 1. In another preferred embodiment, i is 0.

[0171] In equation (3), A A indicates an administered agent that is an antibody.

[0172] In a preferred embodiment, formula (3) is S P -A A where S P is polyethylene glycol (PEG), more preferably S P is PEG8.

[0173] In a preferred embodiment, the moiety L A has a molecular weight of 500 kDa or less, more preferably 200 kDa or less, and most preferably 160 kDa or less.

[0174] In a preferred embodiment, the moiety L A has a molecular weight of at least 0.1 kDa, more preferably at least 1 kDa, more preferably at least 10 kDa, and most preferably at least 140 kDa.

[0175] In equation (3), each S P are independently spacers, which are self-immolative linkers L as defined herein. C It may be. S P C C If connected to S P is preferably a trivalent radical, and S L It will be understood that the suffix -ene in the definition of S should be replaced by the suffix -triyl. P is a spacer as defined herein. Preferably, S P L C , then i in equation (3) is 0, one s is 0, and one s is 1.

[0176] In equation (3), C C represents Construct-C, where each Construct-C is independently selected from the group consisting of a label and an additional agent. The additional agent is C C L in places where it's not A may be the same dosage contained in or may be a different dosage.

[0177] In a preferred embodiment, the compound of formula (1) has a C C Preferably, when i in formula (3) is at least 1, -S P -C C In S P is L C is.

[0178] In a preferred embodiment, S in formula (3) P R 32 Residue of part C M2 , and part C X In a preferred embodiment, the C M2 , C X , or R 32 The residue of S P Label, administration agent, LC , S P , C C , or T R Connect to.

[0179] In a preferred embodiment, L A In a preferred embodiment, X 5 is C C , L A , or L B Does not include.

[0180] Spacer S P As used herein, "each individual S P When it is stated that "is linked at all ends to the rest of the structure," this refers to the spacer S P It will be understood that this refers to the fact that the spacer connects multiple moieties within a structure and, therefore, the spacer, by definition, has multiple termini. P can be linked to each individual moiety via different or identical moieties, each of which can be individually selected. Typically, these linking moieties are spacers S P It should be considered as part of itself. Spacer S P connects two moieties within a structure, "all ends" should be interpreted as "both ends." For example, if the spacer connects a transcyclooctene moiety to Construct A, the "rest of the molecule" refers to the transcyclooctene moiety and Construct A, while the connecting moiety between the spacer and the transcyclooctene moiety, Construct A (i.e., both ends), can be selected independently.

[0181] Spacer S P is one or more spacer units S arranged linearly and / or branchedly. U and one or more C A or C B Part and / or one or more L C or T R The spacer can be attached to a moiety such as C B One TR (Example A below) or multiple T's R (Examples B and C below), but it can also be used to connect to C B -T R -C A It can be used to adjust the properties, e.g., pharmacokinetic properties, of the conjugate (Example D below). Thus, a spacer does not necessarily have to connect two entities to each other; it can also be used to adjust the properties, e.g., pharmacokinetic properties, of a single component, e.g., T R or L C Alternatively, the spacer may be C A or C B T R The spacer may also contain a spacer unit linking the S to the S, and in addition, may contain another spacer unit that binds only to the spacer and serves to adjust the properties of the conjugate (Example F below). The spacer may also contain two different types of S U Constructs such as PEG linked to a peptide or PEG linked to an alkylene moiety (Example E below). For clarity, Example B is a multivalent branched S U Branched S by using U Example C shows a linear S U Branched polymers, such as peptides, can be used to U Formula 4

[0182] JPEG0007660525000014.jpg82170

[0183] The spacer can be bound to the active agent in similar designs as shown in Examples A-F above.

[0184] The spacer units include, but are not limited to, amino acids, nucleosides, nucleotides, and biopolymer fragments, such as oligopeptides or polypeptides, oligopeptoids or polypeptoids, or oligolactides or polylactides, or oligo- or polycarbohydrates, varying from 2 to 200, particularly 2 to 113, preferably 2 to 50, more preferably 2 to 24, more preferably 2 to 12 repeating units. Exemplary preferred biopolymers S U is a peptide.

[0185] Still other examples are alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, cycloalkenyl, cycloalkenylene, cycloalkynyl, cycloalkynylene, aryl, arylene, alkylaryl, alkylarylene, arylalkyl, arylalkylene, arylalkenyl, arylalkenylene, arylalkynyl, arylalkynylene, polyethyleneamino, polyamine, which may be substituted or unsubstituted, linear or branched, and may contain additional cyclic moieties and / or heteroatoms, preferably O, N and S, more preferably O; where in some embodiments, S in these examples U contains 50 or fewer carbon atoms, more preferably 25 or fewer carbon atoms, more preferably 10 or fewer carbon atoms. U are independent, (CH2) r , (C3-C8 carbocyclo), O-(CH2) r , arylene, (CH2) r -Arylene, arylene-(CH2) r , (CH2) r -(C3-C8 carbocyclo), (C3-C8 carbocyclo)-(CH2) r , (C3-C8 heterocyclo, (CH2) r -(C3-C8 heterocyclo), (C3-C8 heterocyclo)-(CH2) r , -(CH2) rC(O)NR4(CH2) r , (CH2CH2O) r , (CH2CH2O) r CH2, (CH2) r C(O)NR4(CH2CH2O) r , (CH2) r C(O)NR4(CH2CH2O) r CH 2、 (CH2CH2O) r C(O)NR4(CH2CH2O) r , (CH2CH2O) r C(O)NR4(CH2CH2O) r CH2, (CH2CH2O) r C(O)NRCH, -(CH) r C(O)NR 37 (CH2) r , (CH2CH2O) r , (CH2CH2O) r CH2, (CH2) r C(O)NR 37 (CH2CH2O) r , (CH2) r C(O)NR 37 (CH2CH2O) r CH 2、 (CH2CH2O) r C(O)NR 37 (CH2CH2O) r , (CH2CH2O) r C(O)NR 37 (CH2CH2O) r CH2, (CH2CH2O) r C(O)NR 37 CH2; where r is independently an integer from 1 to 10, R4 is as defined herein, and R 37 is as defined herein.

[0186] Spacer Unit S UOther examples are linear or branched polyalkylene glycols, such as polyethylene glycol (PEG) chains or polypropylene glycol (PPG) chains, with repeat units varying from 2 to 200, particularly from 2 to 113, preferably from 2 to 50, more preferably from 2 to 24, and more preferably from 2 to 12. When the polyalkylene glycol, such as PEG and PPG polymers, is attached via only one end of the polymer chain, the other end is preferably terminated with -OCH3, -OCH2CH3, or -OCH2CH2CO2H.

[0187] Other polymer spacer units are polymers and copolymers such as poly-(2-oxazoline), poly(N-(2-hydroxypropyl)methacrylamide) (HPMA), polylactic acid (PLA), polylactic-co-glycolic acid (PLGA), polyglutamic acid (PG), dextran, polyvinylpyrrolidone (PVP), poly(1-hydroxymethylethylenehydroxymethyl-formal) (PHF). Other exemplary polymers are polysaccharides, glycopolysaccharides, glycolipids, polyglycosides, polyacetals, polyketals, polyamides, polyethers, and polyesters. U Examples of naturally occurring polysaccharides that can be used as the polymer S include cellulose, amylose, dextran, dextrin, levan, fucoidan, carraginan, inulin, pectin, amylopectin, glycogen, lyxenan, agarose, hyaluronan, chondroitin sulfate, dermatan sulfate, keratan sulfate, alginic acid, and heparin. In yet another exemplary embodiment, the polymer S U includes copolymers of polyacetals / polyketals and hydrophilic polymers selected from polyacrylates, polyvinyl polymers, polyesters, polyorthoesters, polyamides, oligopeptides, polypeptides and derivatives thereof. Exemplary preferred polymers S U are PEG, HPMA, PLA, PLGA, PVP, PHF, dextran, oligopeptides, and polypeptides.

[0188] In some aspects of the invention, S UThe polymers used in have molecular weights in the range of 2 to 200 kDa, 2 to 100 kDa, 2 to 80 kDa, 2 to 60 kDa, 2 to 40 kDa, 2 to 20 kDa, 3 to 15 kDa, 5 to 10 kDa, 500 daltons to 5 kDa.

[0189] Other exemplary S U are dendrimers, such as poly(propyleneimine) (PPI) dendrimers, PAMAM dendrimers, and glycol-based dendrimers.

[0190] S of the present invention U expressly encompasses, but is not limited to, conjugates prepared using commercially available crosslinker reagents such as BMPEO, BMPS, EMCS, GMBS, HBVS, LC-SMCC, MBS, MPBH, SBAP, SIA, SIAB, SMCC, SMPB, SMPH, sulfo-EMCS, sulfo-GMBS, sulfo-KMUS, sulfo-MBS, sulfo-SIAB, sulfo-SMCC, sulfo-SMPB, and SVSB, DTME, BMB, BMDB, BMH, BMOE, BM(PEO)3, and BM(PEO)4.

[0191] To construct a branched spacer, S-type amines based on one or more natural or unnatural amino acid, amino alcohol, amino aldehyde, or polyamine residues, or combinations thereof, which collectively provide the required functionality for branching, are used. U For example, serine has three functional groups, namely, an acid, an amino, and a hydroxyl group, and can be branched S U The attached amino acid may be viewed as an amino alcohol residue for the purpose of acting as a carboxyl group. Other exemplary amino acids are lysine and tyrosine.

[0192] In preferred embodiments, the spacer consists of one spacer unit, and therefore in those cases, S P is S U In a preferred embodiment, the spacer consists of 2, 3 or 4 spacer units.

[0193] In some aspects of the invention, S P has a molecular weight in the range of 2 to 200 kDa, 2 to 100 kDa, 2 to 80 kDa, 2 to 60 kDa, 2 to 40 kDa, 2 to 20 kDa, 3 to 15 kDa, 5 to 10 kDa, 500 daltons to 5 kDa. P has a mass of 5000 daltons or less, 4000 daltons or less, 3000 daltons or less, 2000 daltons or less, 1000 daltons or less, 800 daltons or less, 500 daltons or less, 300 daltons or less, or 200 daltons or less. P has a mass from 100 daltons, from 200 daltons, from 300 daltons, to 5000 daltons. P has a mass of from 30, 50 or 100 daltons to 1000 daltons, from about 30, 50 or 100 daltons to 500 daltons.

[0194] Preferably, each S P are independent, R 97 , -O-, -OC(O)-, -OC(O)-R 99 -, -OC(S)-R 99 -, -OR 97 -, -OC(O)-R 97 -, -OC(O)-R 99 -R 97 -, -OC(S)-R 99 -R 97 - and L C In another preferred embodiment, S P is X 1 ~X 4 If it is included in one of P is L C In a preferred embodiment, S P is L C No.

[0195] In a preferred embodiment, S P R 32Residue of part C M2 , or part C X In a preferred embodiment, the C M2 , C X , or R 32 The residue of S P Label, administration agent, L C , S P , C C , R 98 , or T R Connect to.

[0196] R 97 In a preferred embodiment, each R 97 are independent, C1~C 24 Alkylene group, C2-C 24 Alkenylene group, C2-C 24 Alkynylene group, C6-C 24 Arylene, C2-C 24 Heteroarylene, C3-C 24 Cycloalkylene group, C5-C 24 Cycloalkenylene group, and C 12 ~C 24 cycloalkynylene groups, which are selected from the group consisting of -Cl, -F, -Br, -I, -OH, -NH2, -SO3H, -PO3H 、 -PO4H2, -NO2, -CF3, =O, =NR 36 , -SR 36 , C1~C 24 Alkyl groups, C2-C 24 Alkenyl groups, C2-C 24 Alkynyl groups, C6-C 24 Aryl groups, C2-C 24 Heteroaryl groups, C3-C 24 Cycloalkyl groups, C5-C 24 Cycloalkenyl group, C 12 ~C 24 Cycloalkynyl group, C3-C 24 Alkyl(hetero)aryl groups, C3-C 24 (Hetero)arylalkyl groups, C4-C 24 (Hetero)arylalkenyl groups, C4-C 24(Hetero)arylalkynyl group, C4-C 24 Alkenyl(hetero)aryl groups, C4-C 24 Alkynyl(hetero)aryl groups, C4-C 24 Alkylcycloalkyl groups, C6-C 24 Alkylcycloalkenyl group, C 13 ~C 24 Alkylcycloalkynyl group, C4-C 24 Cycloalkylalkyl groups, C6-C 24 Cycloalkenylalkyl groups, C 13 ~C 24 Cycloalkynylalkyl groups, C5-C 24 Alkenylcycloalkyl groups, C7-C 24 Alkenylcycloalkenyl group, C 14 ~C 24 Alkenylcycloalkynyl group, C5-C 24 Cycloalkylalkenyl group, C7-C 24 Cycloalkenyl alkenyl group, C 14 ~C 24 Cycloalkynylalkenyl group, C5-C 24 Alkynylcycloalkyl groups, C7-C 24 Alkynylcycloalkenyl group, C 14 ~C 24 Alkynylcycloalkynyl group, C5-C 24 Cycloalkylalkynyl group, C7-C 24 Cycloalkenylalkynyl group, C 14 ~C 24 Cycloalkynylalkynyl group, C5-C 24 Cycloalkyl(hetero)aryl groups, C7-C 24 Cycloalkenyl(hetero)aryl group, C 14 ~C 24 Cycloalkynyl(hetero)aryl groups, C5-C 24 (Hetero)arylcycloalkyl groups, C7-C 24 (Hetero)arylcycloalkenyl groups, and C 14 ~C 24(hetero)arylcycloalkynyl groups, wherein the substituents are O, S, NR 36 , P, and Si, wherein the N, S, and P atoms are optionally oxidized, and wherein multiple N atoms are optionally quaternized; and Preferably, the alkylene group, alkenylene group, alkynylene group, cycloalkylene group, cycloalkenylene group, and cycloalkynylene group are O, S, NR 36 , P, and Si, wherein the N, S, and P atoms are optionally oxidized, and wherein multiple N atoms are optionally quaternized.

[0197] In a preferred embodiment, each R 97 are independent, C1~C 12 Alkylene group, C2-C 12 Alkenylene group, C2-C 12 Alkynylene group, C6-C 12 Arylene, C2-C 12 Heteroarylene, C3-C 12 Cycloalkylene group, C5-C 12 Cycloalkenylene group, and C 12 cycloalkynylene groups; and Preferably, the alkylene group, alkenylene group, alkynylene group, cycloalkylene group, cycloalkenylene group, and cycloalkynylene group are each independently selected from the group consisting of O, S, NR 36 , P, and Si, wherein the N, S, and P atoms are optionally oxidized, and wherein multiple N atoms are optionally quaternized.

[0198] In a preferred embodiment, each R 97are independently selected from the group consisting of a C1-C6 alkylene group, a C2-C6 alkenylene group, a C2-C6 alkynylene group, a C6-C6 arylene, a C2-C6 heteroarylene, a C3-C6 cycloalkylene group, and a C5-C6 cycloalkenylene group; and Preferably, the alkylene group, alkenylene group, alkynylene group, cycloalkylene group, cycloalkenylene group, and cycloalkynylene group are each independently selected from the group consisting of O, S, NR 36 , P, and Si, wherein the N, S, and P atoms are optionally oxidized, and wherein multiple N atoms are optionally quaternized.

[0199] In a preferred embodiment, R 97 Groups include -Cl, -F, -Br, -I, -OH, -NH2, -SO3H, and -PO3H 、 -PO4H2, -NO2, -CF3, =O, =NR 36 , -SR 36 , C1~C 12 Alkyl groups, C2-C 12 Alkenyl groups, C2-C 12 Alkynyl groups, C6-C 12 Aryl groups, C2-C 12 Heteroaryl groups, C3-C 12 Cycloalkyl groups, C5-C 12 Cycloalkenyl group, C 12 Cycloalkynyl group, C3-C 12 Alkyl(hetero)aryl groups, C3-C 12 (Hetero)arylalkyl groups, C4-C 12 (Hetero)arylalkenyl groups, C4-C 12 (Hetero)arylalkynyl group, C4-C 12 Alkenyl(hetero)aryl groups, C4-C 12 Alkynyl(hetero)aryl groups, C4-C 12 Alkylcycloalkyl groups, C6-C 12 Alkylcycloalkenyl group, C 13 ~C 18 Alkylcycloalkynyl group, C4-C 12Cycloalkylalkyl groups, C6-C 12 Cycloalkenylalkyl groups, C 13 ~C 18 Cycloalkynylalkyl groups, C5-C 12 Alkenylcycloalkyl groups, C7-C 12 Alkenylcycloalkenyl group, C 14 ~C 16 Alkenylcycloalkynyl group, C5-C 12 Cycloalkylalkenyl group, C7-C 12 Cycloalkenyl alkenyl group, C 14 ~C 16 Cycloalkynylalkenyl group, C5-C 12 Alkynylcycloalkyl groups, C7-C 12 Alkynylcycloalkenyl group, C 14 ~C 16 Alkynylcycloalkynyl group, C5-C 12 Cycloalkylalkynyl group, C7-C 12 Cycloalkenylalkynyl group, C 14 ~C 16 Cycloalkynylalkynyl group, C5-C 12 Cycloalkyl(hetero)aryl groups, C7-C 12 Cycloalkenyl(hetero)aryl group, C 14 ~C 16 Cycloalkynyl(hetero)aryl groups, C5-C 12 (Hetero)arylcycloalkyl groups, C7-C 12 (Hetero)arylcycloalkenyl groups, and C 14 ~C 16 (hetero)arylcycloalkynyl groups, wherein the substituents are O, S, NR 36 , P, and Si, wherein the N, S, and P atoms are optionally oxidized, and wherein multiple N atoms are optionally quaternized.

[0200] In a preferred embodiment, R 97Groups include -Cl, -F, -Br, -I, -OH, -NH2, -SO3H, and -PO3H 、 -PO4H2, -NO2, -CF3, =O, =NR 36 , -SR 36 , C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C6 aryl group, C2-C6 heteroaryl group, C3-C6 cycloalkyl group, C5-C6 cycloalkenyl group, C3-C6 alkyl(hetero)aryl group, C3-C6 (hetero)arylalkyl group, C4-C6 (hetero)arylalkenyl group, C4-C6 (hetero)arylalkynyl group, C4-C6 alkenyl(hetero)aryl group, C4-C6 alkynyl(hetero)aryl group, C4-C6 alkylcycloalkyl group, C6 alkylcycloalkenyl group, C4-C6 cycloalkenyl group and C5-C6 (hetero)aryl groups, and C5-C6 (hetero)aryl groups, which may be further substituted with one or more substituents selected from the group consisting of O, S, NR 36 , P, and Si, wherein the N, S, and P atoms are optionally oxidized, and wherein multiple N atoms are optionally quaternized.

[0201] In a preferred embodiment, R 97 Groups include -Cl, -F, -Br, -I, -OH, -NH2, -SO3H, and -PO3H 、 -PO4H2, -NO2, -CF3, =O, =NR 36 , -SR 36, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C6 aryl group, C2-C6 heteroaryl group, C3-C6 cycloalkyl group, C5-C6 cycloalkenyl group, C3-C7 alkyl(hetero)aryl group, C3-C7 (hetero)arylalkyl group, C4-C8 (hetero)arylalkenyl group, C4-C8 (hetero)arylalkynyl group, C4-C8 alkenyl(hetero)aryl group, C4-C8 alkynyl(hetero)aryl group, C4-C6 alkylcycloalkyl group, C6-C7 alkylcycloalkenyl group, C4-C6 cycloalkynyl group and C5-C9 (hetero)aryl groups and C5-C9 (hetero)arylcycloalkyl groups, wherein the substituents are selected from the group consisting of O, S, NR 36 , P, and Si, wherein the N, S, and P atoms are optionally oxidized, and wherein multiple N atoms are optionally quaternized.

[0202] In a preferred embodiment, R 97 The group is unsubstituted. In a preferred embodiment, R 97 The group does not contain heteroatoms.

[0203] Linker L C L C is any self-immolative linker, which may be composed of multiple units arranged in a linear and / or branched manner, and which may comprise one or more C A A portion may be released.

[0204] L C There are multiple C A If it contains parts, these CA Part is L C Because of the self-immolative character of these C A The moieties can independently be a label or an administration agent, and the spacer S P via L C It will be understood that L may be linked to C Two or more C B If it contains, the C B All moieties are either administration agents or labels.

[0205] For further clarification, R 48 L B When all d and e in formula (2) are 0, the label directly constitutes the leaving group of the release reaction, and when either d or e in formula (2) is 1, it constitutes the self-immolative linker L C and constitute the leaving group for the release reaction. C Structures, their uses, linkers L C Location and Method of Attachment, Construct C A and Construct C B , and T R are known to those skilled in the art. See, for example, [Papot et al., Anticancer Agents Med. Chem., 2008, 8, 618-637]. Nevertheless, the self-immolative linker L C Typical, but non-limiting examples of are benzyl derivatives, such as the benzyl derivative depicted below. There are two main self-immolation mechanisms: electron cascade elimination and cyclization-mediated elimination. The preferred example on the left below works by a cascade mechanism, where the trigger and L C Y between C (herein referred to as Y C1 ) is cleaved, and Y C1 electron pairs, e.g., NR 6The electron pair of , shifts to the benzyl moiety, and the electron cascade leads to the formation of 4-hydroxybenzyl alcohol, CO2, and Y. C Also contains free C A (In this specification, Y C2 The preferred example in the center below operates via a cyclization mechanism, where Y C1 Cleavage of the bond to the amine results in nucleophilic attack of the amine on the carbonyl to form the pentacyclic 1,3-dimethylimidazolidin-2-one, and Y C2 Contains C A The preferred example on the right combines both mechanisms, where the linker binds CO and one unit of 4-hydroxybenzyl alcohol (Y C1 is O), but will also decompose into a single 1,3-dimethylimidazolidin-2-one unit.

[0206] [ka]

[0207] In this specification, C A Spacer S P via L C may be linked to the remainder of

[0208] The self-immolative linker L C By substituting the benzyl group of A It is possible to adjust the release rate of . Synthetic procedures for preparing such substituted benzyl derivatives are known to those skilled in the art (see, for example, [Greenwald et al., J. Med. Chem., 1999, 42, 3657-3667] and [Thornthwaite et al., Polym. Chem., 2011, 2, 773-790]). Preferred substituted benzyl derivatives with different release rates are depicted below.

[0209] [ka]

[0210] In this specification, C A Spacer S P via L C may be linked to the remainder of

[0211] In a preferred embodiment, the L C satisfies one of the following formulas 23a to 23c.

[0212] [ka]

[0213] where Y C1 is O, S, or NR 6 V, U, W, and Z are each independently CR 7 or N;Y C2 is O, S, a secondary amine, or a tertiary amine, C2 Part C A Part of ;R 6 , R 7 , R 8 , R 9 is as defined herein, and where C A Spacer S P via L C may be linked to the remainder of

[0214] In a preferred embodiment, R 6 is H or methyl, and R 7 is H and R 8 is H or methyl, and R 9 is preferably H. In a preferred embodiment, R 7 is CF3 and Z is N.

[0215] In a preferred embodiment, the LC satisfies the following formula 23d.

[0216] [ka]

[0217] where Y C1 is O, S, or NR 6 and;Y C2 is O, S, a secondary amine, or a tertiary amine, C2 Part C A Part of ;R 6 , R 7 , R 8 , R 9 is as defined herein; preferably, R 7 is C1-C8 alkyl, C6-C 12 Aryl, C1-C8O-Alkyl, C6-C 12 O-aryl, NO, F, Cl, Br, I, CN, where m is an integer from 0 to 4; preferably, each R 8 and R 9 are independently C1 to C8 alkyl, C6 to C 12 Aryl, C1-C8O-Alkyl, C6-C 12 O-aryl, NO, F, Cl, Br, I, CN; and wherein C A Spacer S P via L C Preferably, R 7 is electron donating, and preferably, m is an integer of 0 to 2, more preferably, m is 0. Preferably, R 8 is H, and R 9 is H or methyl.

[0218] Self-immolative linkers that undergo cyclization include, but are not limited to, substituted and unsubstituted aminobutyric acid amides, appropriately substituted bicyclo[2.2.1] and bicyclo[2.2.2] ring systems, 2-aminophenylpropionic acid amides, and trimethyl lock-based linkers (see, e.g., [Chem. Biol. 1995, 2, 223], [J. Am. Chem. Soc. 1972, 94, 5815], [J. Org. Chem. 1990, 55, 5867], the contents of which are incorporated herein by reference). Preferably, cyclization leads to C A Emits L C So, C A The remainder is aromatic oxygen of sulfur, Y C1 via L C For example, an aromatic oxygen will be understood to mean an oxygen that is directly attached to an aromatic group.

[0219] In a preferred embodiment, such cyclized L C satisfies one of the following formulas 24a to 24f.

[0220] [ka]

[0221] where Y C1 is NR 6 and;Y C2 is O or S, where these Y C2 Part C A a is independently 0 or 1; R 6 and R 7 is as defined herein, and where C A Spacer S P via L C Preferably, R 6 and R 7 is H, unsubstituted C1-C8 alkyl, C6 aryl, more preferably R 6is H or methyl, and R 7 is H.

[0222] In a preferred embodiment, C in formula 24a, formula 24b, formula 24c, formula 24d and formula 24e A The remainder of is connected to Y via the aromatic moiety. C2 and the moiety is C A In a preferred embodiment, C in formula 24f A The remainder of the formula is Y via an aliphatic moiety. C2 and the moiety is C A is part of.

[0223] L C Some preferred structures of C are shown below. In these examples, C A is preferably O or S. C2 via L C wherein O or S is C A For the avoidance of doubt, in these examples, Y C1 Although not shown as such, the associated NH group, NR 6 It is embodied by the , S and O groups.

[0224] [ka]

[0225] [ka]

[0226] In this specification, C A Spacer S P via L C and R 6 is as defined herein.

[0227] L C Some other preferred structures of C are shown below. In these examples, CA is preferably a secondary amine or a primary amine, C2 via L C and wherein Y C2 is C A For the avoidance of doubt, in these examples, Y C1 Although not shown as such, the associated NH group, NR 6 embodied by the groups S, O, and C A optionally a spacer S P via L C is linked to the rest of the

[0228] [ka]

[0229] As used herein, R 6 is as defined herein.

[0230] L C Further preferred structures of can be found in WO2009017394(A1), U.S. Pat. No. 7,375,078, WO2015038426A1, WO2004043493, Angew. Chem. Int. Ed. 2015, 54, 7492-7509, the contents of which are incorporated herein by reference.

[0231] In a preferred embodiment of the present invention, L C has a mass of 1000 daltons or less, 500 daltons or less, 400 daltons or less, 300 daltons or less, or 10, 50 or 100 to 1000 daltons, 10, 50, 100 to 400 daltons, 10, 50, 100 to 300 daltons, 10, 50, 100 to 200 daltons, for example 10 to 1000 daltons, for example 50 to 500 daltons, for example 100 to 400 daltons.

[0232] Those skilled in the art will appreciate that one L C But CA Another L that is bound to C where the activator and trigger T R Depending on the reaction with L C -L C -C A T R Emitted from multiple L C Part and C A It will be appreciated that the self-immolative release of both the hydroxyl group and the hydroxyl group will occur. C Regarding the formula, next, T R Other L C L to be connected to C is C A does not emit Y C1 and C A Further linked to.

[0233] R 6 , R 7 , R 8 , R 9 is as defined herein.

[0234] In a preferred embodiment, L C is selected from the group consisting of linkers according to Group I, Group II, and Group III, where linkers according to Group I are:

[0235] [ka]

[0236] where U, V, W, and Z are independently -CR 7 - and -N-, where e is either 0 or 1, and X is selected from the group consisting of -O-, -S-, and -NR 6 Preferably, each R is selected from the group consisting of 8 and R 9 are independently a hydrogen atom, a C1-C4 alkyl group, a C2-C4 alkenyl group, and C 4~6(hetero)aryl groups, where R 8 and R 9 In the above, the alkyl group, alkenyl group, and (hetero)aryl group are -Cl, -F, -Br, -I, -OH, -NH2, =O, -SH, -SO3H, -PO3H 、 It may be substituted with a moiety selected from the group consisting of -PO4H2, and -NO2, and may contain up to two heteroatoms selected from the group consisting of -O-, -S-, -NH-, -P-, and -Si-, wherein the N, S, and P atoms are optionally oxidized.

[0237] where, for linkers according to Group I, C A is linked to LC through a moiety selected from the group consisting of -O-, -N-, -C- and -S-, preferably from the group consisting of secondary amines and tertiary amines, wherein the moiety A is part of.

[0238] Linkers according to Group II are:

[0239] [ka]

[0240] Here, m is an integer of 0 to 2, preferably m is 0, and here, e is either 0 or 1. For linkers according to Group II, C A is connected to L through a moiety selected from the group consisting of -O-, -N-, -C- and -S-, preferably from the group consisting of secondary amines and tertiary amines. C wherein the moiety is linked to C A is part of.

[0241] Linkers according to Group III are:

[0242] [ka]

[0243] where, for linkers according to Group III, C A is selected from -O- and -S-, preferably C 4~6 L through a moiety selected from the group consisting of -O- or -S- attached to a (hetero)aryl group C wherein the moiety is linked to C A is part of.

[0244] For linkers according to Groups I-III, preferably, each R 6 are independently a hydrogen atom, a C1-C4 alkyl group, a C2-C4 alkenyl group, and C 4~6 (hetero)aryl groups, where R 6 In the above, the alkyl group, alkenyl group, and (hetero)aryl group may be -Cl, -F, -Br, -I, -OH, -NH2, ═O, -SH, -SO3H, -PO3H 、 It may be substituted with a moiety selected from the group consisting of -PO4H2, and -NO2, and may contain up to two heteroatoms selected from the group consisting of -O-, -S-, -NH-, -P-, and -Si-, wherein the N, S, and P atoms are optionally oxidized.

[0245] For linkers according to Groups I-III, preferably, each R 7 are independently a hydrogen atom, a C1-C3 alkyl group, a C2-C3 alkenyl group, and C 4~6 (hetero)aryl groups, where R 7 wherein the alkyl, alkenyl, and (hetero)aryl groups are optionally substituted with a moiety selected from the group consisting of -Cl, -F, -Br, -I, -OH, -NH, =O, =NH, -N(CH), -S(O)CH, and -SH, and are optionally flanked by up to one heteroatom selected from the group consisting of -O-, -S-, -NH-, -P-, and -Si-, wherein the N, S, and P atoms are optionally oxidized, and wherein multiple N atoms are optionally quaternized, and wherein R 7is preferably selected from the group consisting of a hydrogen atom, methyl, —CH—CH—N(CH) and —CH—CH—S(O)—CH.

[0246] R included in Groups I, II and III 6 , R 7 , R 8 , R 9 is also -(S P ) i -C B It can be.

[0247] For all linkers according to Group I and Group II, Y C1 is -O-, -S- and -NR 6 -, preferably -NR 6 For all linkers according to Group III, Y C1 Ha-NR 6 For all linkers according to Group I, Group II and Group III, Y C2 is selected from the group consisting of O and S, preferably O.

[0248] In groups I-III, two L C are linked to each other, L attached to -O- or -S- at the allylic position of trans-cyclooctene C is selected from the group consisting of linkers according to Group I and Group II, and is attached to -O- or -S- at the allylic position of trans-cyclooctene; C and C A L between C is selected from Group III, and the wavy line in the Group III structure represents L attached to -O- or -S- at the allylic position in the trans-cyclooctene ring, instead of a bond to the allylic -O- or -S- in the trans-cyclooctene ring. C The double dashed lines in the structures of Groups I and II indicate bonds to C A Instead of a bond to -O- or -S- at the allylic position of trans-cyclooctene, L C and CA L between C The bond to

[0249] In a preferred embodiment, L C is selected from the group consisting of linkers according to Group IV, Group V, Group VI, and Group VII.

[0250] Linkers according to Group IV are:

[0251] [ka]

[0252] where C A is selected from -O- and -S-, preferably -OC 5-8 -Arylene and -SC 5-8 -arylene-, C wherein the moiety is linked to C A is part of.

[0253] Linkers according to Group V are:

[0254] [ka]

[0255] where C A is connected to L through a moiety selected from the group consisting of -O- and -S- C wherein the moiety is linked to C A is part of.

[0256] Linkers according to Group VI are:

[0257] [ka]

[0258] where C A is connected to L through a moiety selected from the group consisting of -O-, -N- and -S-, preferably a secondary or tertiary amine C wherein the moiety is linked to C A is part of.

[0259] Linkers according to Group VII are:

[0260] [ka]

[0261] where C A is connected to L through a moiety selected from the group consisting of -O-, -N- and -S-, preferably from the group consisting of secondary amines and tertiary amines. C wherein the moiety is linked to C A where multiple double dashed lines are part of one L C If indicated within, each C A The portions are independently selected.

[0262] For all linkers according to Group IV, Group V, Group VI and Group VII, Y C1 is -O-, -S- and -NR 6 For all linkers according to groups IV to VII, R 6 and R 7 is as defined herein; i is an integer ranging from 0 to 4, preferably 0 or 1; and j is 0 or 1.

[0263] In a preferred embodiment, particularly in any one of Groups I to VII, L C R in the formula 6 , R 7 , R 8 and R 9 is a hydrogen atom.

[0264] R 6 Preferably, each R 6 are independently hydrogen atoms, -(S P ) i -C C , C1~C 24 Alkyl groups, C2-C 24 Alkenyl groups, C2-C 24 Alkynyl groups, C6-C 24 Aryl groups, C2-C 24 Heteroaryl groups, C3-C 24 Cycloalkyl groups, C5-C 24 Cycloalkenyl group, C 12 ~C 24 Cycloalkynyl group, C3-C 24 (Cyclo)alkyl(hetero)aryl groups, C3-C 24 (Hetero)aryl(cyclo)alkyl, C4-C 24 (Cyclo)alkenyl(hetero)aryl group, C4-C 24 (Hetero)aryl(cyclo)alkenyl groups, C4-C 24 (Cyclo)alkynyl(hetero)aryl group, C4-C 24 (Hetero)aryl(cyclo)alkynyl group, C4-C 24 Alkylcycloalkyl groups and C4-C 24 cycloalkylalkyl groups; where i is an integer ranging from 0 to 4, preferably i is 1; Here, R that is not a hydrogen atom 6 Groups include -Cl, -F, -Br, -I, -OH, -NH2, -SO3H, and -PO3H 、 -PO4H 2、 It may be substituted with a moiety selected from the group consisting of -NO2, -CF3, =O, =NH, and -SH, and may contain one or more heteroatoms selected from the group consisting of O, S, NH, P, and Si, wherein the N, S, and P atoms are optionally oxidized, and wherein multiple N atoms are optionally quaternized.

[0265] In a preferred embodiment, each R 6 are each a hydrogen atom, a C1-C8 alkyl group, a C2-C8 alkenyl group, a C2-C8 alkynyl group, a C6-C12 Aryl, C2-C 12 Heteroaryl, C3-C8 cycloalkyl group, C5-C8 cycloalkenyl group, C3-C 12 Alkyl(hetero)aryl groups, C3-C 12 (Hetero)arylalkyl groups, C4-C 12 Alkylcycloalkyl groups, C4-C 12 Cycloalkylalkyl groups, C5-C 12 Cycloalkyl(hetero)aryl groups and C5-C 12 (hetero)arylcycloalkyl groups, wherein any R that is not a hydrogen atom is selected from the group consisting of 6 Groups include -Cl, -F, -Br, -I, -OH, -NH2, -SO3H, and -PO3H 、 -PO4H 2、 It may be substituted with a moiety selected from the group consisting of -NO2, -CF3, =O, =NH, and -SH, and may contain one or more heteroatoms selected from the group consisting of O, S, NH, P, and Si, wherein the N, S, and P atoms are optionally oxidized, and wherein multiple N atoms are optionally quaternized.

[0266] In a preferred embodiment, R 6 is a hydrogen atom, a C1-C4 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C6-C8 aryl, a C2-C8 heteroaryl, a C3-C6 cycloalkyl group, a C5-C6 cycloalkenyl group, a C3-C 10 Alkyl(hetero)aryl groups, C3-C 10 (Hetero)arylalkyl group, C4-C8 alkylcycloalkyl group, C4-C8 cycloalkylalkyl group, C5-C 10 Cycloalkyl(hetero)aryl groups and C5-C 10 (hetero)arylcycloalkyl groups, wherein any R that is not a hydrogen atom is selected from the group consisting of 6 Groups include -Cl, -F, -Br, -I, -OH, -NH2, -SO3H, and -PO3H 、 -PO4H 2、It may be substituted with a moiety selected from the group consisting of -NO2, -CF3, =O, =NH, and -SH, and may contain one or more heteroatoms selected from the group consisting of O, S, NH, P, and Si, wherein the N, S, and P atoms are optionally oxidized, and wherein multiple N atoms are optionally quaternized.

[0267] In a preferred embodiment, R 6 represents a hydrogen atom, a C1-C4 alkyl group, a C2-C4 alkenyl group, and C 4~6 (hetero)aryl groups, where R 6 In the above, the alkyl group, alkenyl group, and (hetero)aryl group are -Cl, -F, -Br, -I, -OH, -NH2, =O, -SH, -SO3H, -PO3H 、 It may be substituted with a moiety selected from the group consisting of -PO4H2 and -NO2, and may contain up to two heteroatoms selected from the group consisting of -O-, -S-, -NH-, -P- and -Si-, wherein the N, S and P atoms are optionally oxidized.

[0268] In a preferred embodiment, R 6 represents a hydrogen atom, a C1-C3 alkyl group, a C2-C3 alkenyl group, and C 4~6 (hetero)aryl groups, where R 6 In the above, the alkyl group, alkenyl group, and (hetero)aryl group are -Cl, -F, -Br, -I, -OH, -NH2, =O, -SH, -SO3H, -PO3H 、 It may be substituted with a moiety selected from the group consisting of -PO4H2, and -NO2, and may contain up to two heteroatoms selected from the group consisting of -O-, -S-, -NH-, -P-, and -Si-, wherein the N, S, and P atoms are optionally oxidized.

[0269] In a preferred embodiment, R is not a hydrogen atom. 6 The group is unsubstituted. In a preferred embodiment, R 6The group does not contain heteroatoms. In a preferred embodiment, R 6 The group is a hydrogen atom.

[0270] R 7 In a preferred embodiment, each R 7 are independently hydrogen atoms, -(S P ) i -C C , -F, -Cl, -Br, -I, -OR 37 , -N(R 37 )2, -SO3, -PO3 - 、 -NO2, -CF3, -SR 37 , S(=O)2N(R 37 )2, OC(=O)R 37 , SC(=O)R 37 , OC(=S)R 37 , SC(=S)R 37 , N.R. 37 C(=O)-R 37 , N.R. 37 C(=S)-R 37 , N.R. 37 C(=O)OR 37 , N.R. 37 C(=S)OR 37 , N.R. 37 C(=O)SR 37 , N.R. 37 C(=S)SR 37 , OC(=O)N(R 37 )2, SC(=O)N(R 37 )2, OC(=S)N(R 37 )2, SC(=S)N(R 37 )2, NR 37 C(=O)N(R 37 )2, NR 37 C(=S)N(R 37 )2, C(=O)R 37、 C(=S)R 37、 C(=O)N(R 37 )2, C(=S)N(R 37 )2, C(=O)OR 37 , C(=O)SR 37 , C(=S)OR 37 , C(=S)SR37 , S(O)R 37 , -S(O)2R 37 , N.R. 37 S(O)2R 37 , -ON(R 37 ) 2、- NR 37 OR 37 , C1~C 24 Alkyl groups, C2-C 24 Alkenyl groups, C2-C 24 Alkynyl groups, C6-C 24 Aryl groups, C2-C 24 Heteroaryl groups, C3-C 24 Cycloalkyl groups, C5-C 24 Cycloalkenyl group, C 12 ~C 24 Cycloalkynyl group, C3-C 24 (Cyclo)alkyl(hetero)aryl groups, C3-C 24 (Hetero)aryl(cyclo)alkyl, C4-C 24 (Cyclo)alkenyl(hetero)aryl group, C4-C 24 (Hetero)aryl(cyclo)alkenyl groups, C4-C 24 (Cyclo)alkynyl(hetero)aryl group, C4-C 24 (Hetero)aryl(cyclo)alkynyl group, C4-C 24 Alkylcycloalkyl groups and C4-C 24 cycloalkylalkyl groups; where i is an integer ranging from 0 to 4, preferably i is 1; Here, the above alkyl group, alkenyl group, alkynyl group, aryl, heteroaryl, cycloalkyl group, cycloalkenyl group, cycloalkynyl group, (cyclo)alkyl(hetero)aryl group, (hetero)aryl(cyclo)alkyl group, (cyclo)alkenyl(hetero)aryl group, (hetero)aryl(cyclo)alkenyl group, (cyclo)alkynyl(hetero)aryl group, (hetero)aryl(cyclo)alkynyl group, alkylcycloalkyl group, cycloalkylalkyl group are -Cl, -F, -Br, -I, -OR 37 , -N(R 37 )2, -SO3R 37 , -PO3(R37 ) 2、 -PO4(R 37 ) 2、 -NO2, -CF3, =O, =NR 37 , and -SR 37 and may be substituted with a moiety selected from the group consisting of O, S, NR 37 , P, and Si, wherein the N, S, and P atoms are optionally oxidized, and wherein multiple N atoms are optionally quaternized.

[0271] In a preferred embodiment, each R 7 are independently a hydrogen atom, -F, -Cl, -Br, -I, or -OR 37 , -N(R 37 )2, -SO3, -PO3 - 、 -NO2, -CF3, -SR 37 , S(=O)2N(R 37 )2, OC(=O)R 37 , SC(=O)R 37 , OC(=S)R 37 , SC(=S)R 37 , N.R. 37 C(=O)-R 37 , N.R. 37 C(=S)-R 37 , N.R. 37 C(=O)OR 37 , N.R. 37 C(=S)OR 37 , N.R. 37 C(=O)SR 37 , N.R. 37 C(=S)SR 37 , OC(=O)N(R 37 )2, SC(=O)N(R 37 )2, OC(=S)N(R 37 )2, SC(=S)N(R 37 )2, NR 37 C(=O)N(R 37 )2, NR 37 C(=S)N(R 37 )2, C(=O)R 37、 C(=S)R 37、 C(=O)N(R 37)2, C(=S)N(R 37 )2, C(=O)OR 37 , C(=O)SR 37 , C(=S)OR 37 , C(=S)SR 37 , S(O)R 37 , -S(O)2R 37 , N.R. 37 S(O)2R 37 , -ON(R 37 ) 2、- NR 37 OR 37 , C1-C8 alkyl group, C2-C8 alkenyl group, C2-C8 alkynyl group, C6-C 12 Aryl groups, C2-C 12 Heteroaryl group, C3-C8 cycloalkyl group, C5-C8 cycloalkenyl group, C3-C 12 Alkyl(hetero)aryl groups, C3-C 12 (Hetero)arylalkyl groups, C4-C 12 Alkylcycloalkyl groups, C4-C 12 Cycloalkylalkyl groups, C5-C 12 Cycloalkyl(hetero)aryl groups and C5-C 12 and (hetero)arylcycloalkyl groups, wherein the alkyl group, alkenyl group, alkynyl group, aryl, heteroaryl, cycloalkyl group, cycloalkenyl group, alkyl(hetero)aryl group, (hetero)arylalkyl group, alkylcycloalkyl group, cycloalkylalkyl group, cycloalkyl(hetero)aryl group, and (hetero)arylcycloalkyl group are selected from the group consisting of -Cl, -F, -Br, -I, -OR 37 , -N(R 37 )2, -SO3R 37 , -PO3(R 37 ) 2、 -PO4(R 37 ) 2、 -NO2, -CF3, =O, =NR 37 , and -SR 37 and may be substituted with a moiety selected from the group consisting of O, S, NR 37, P, and Si, wherein the N, S, and P atoms are optionally oxidized, and wherein multiple N atoms are optionally quaternized.

[0272] In a preferred embodiment, each R 7 are independently a hydrogen atom, -F, -Cl, -Br, -I, or -OR 37 , -N(R 37 )2, -SO3, -PO3 - 、 -NO2, -CF3, -SR 37 , S(=O)2N(R 37 )2, OC(=O)R 37 , SC(=O)R 37 , OC(=S)R 37 , SC(=S)R 37 , N.R. 37 C(=O)-R 37 , N.R. 37 C(=S)-R 37 , N.R. 37 C(=O)OR 37 , N.R. 37 C(=S)OR 37 , N.R. 37 C(=O)SR 37 , N.R. 37 C(=S)SR 37 , OC(=O)N(R 37 )2, SC(=O)N(R 37 )2, OC(=S)N(R 37 )2, SC(=S)N(R 37 )2, NR 37 C(=O)N(R 37 )2, NR 37 C(=S)N(R 37 )2, C(=O)R 37、 C(=S)R 37、 C(=O)N(R 37 )2, C(=S)N(R 37 )2, C(=O)OR 37 , C(=O)SR 37 , C(=S)OR 37 , C(=S)SR 37 , S(O)R 37 , -S(O)2R 37, N.R. 37 S(O)2R 37 , -ON(R 37 ) 2、- NR 37 OR 37 , C1-C4 alkyl group, C2-C4 alkenyl group, C2-C4 alkynyl group, C6-C8 aryl group, C2-C8 heteroaryl group, C3-C6 cycloalkyl group, C5-C6 cycloalkenyl group, C3-C 10 Alkyl(hetero)aryl groups, C3-C 10 (Hetero)arylalkyl groups, C4-C 10 Alkylcycloalkyl groups, C4-C 10 Cycloalkylalkyl groups, C5-C 10 Cycloalkyl(hetero)aryl groups and C5-C 10 and (hetero)arylcycloalkyl groups, wherein the alkyl group, alkenyl group, alkynyl group, aryl, heteroaryl, cycloalkyl group, cycloalkenyl group, alkyl(hetero)aryl group, (hetero)arylalkyl group, alkylcycloalkyl group, cycloalkylalkyl group, cycloalkyl(hetero)aryl group, and (hetero)arylcycloalkyl group are selected from the group consisting of -Cl, -F, -Br, -I, -OR 37 , -N(R 37 )2, -SO3R 37 , -PO3(R 37 ) 2、 -PO4(R 37 ) 2、 -NO2, -CF3, =O, =NR 37 , and -SR 37 and may be substituted with a moiety selected from the group consisting of O, S, NR 37 , P, and Si, wherein the N, S, and P atoms are optionally oxidized, and wherein multiple N atoms are optionally quaternized.

[0273] In a preferred embodiment, each R 7 are independently a hydrogen atom, a C1-C3 alkyl group, a C2-C3 alkenyl group, and C 4~6and (hetero)aryl groups, wherein the alkyl, alkenyl, and (hetero)aryl groups are optionally substituted with a moiety selected from the group consisting of -Cl, -F, -Br, -I, -OH, -NH, =O, =NH, -N(CH), -S(O)CH, and -SH, and are optionally flanked by up to one heteroatom selected from the group consisting of -O-, -S-, -NH-, -P-, and -Si-, wherein the N, S, and P atoms are optionally oxidized, and wherein multiple N atoms are optionally quaternized.

[0274] In a preferred embodiment, R 7 are independently selected from the group consisting of a hydrogen atom, methyl, —CH—CH—N(CH) and —CH—CH—S(O)—CH.

[0275] In a preferred embodiment, R is not a hydrogen atom. 7 The group is unsubstituted. In a preferred embodiment, R 7 The group does not contain heteroatoms. In a preferred embodiment, R 7 The group is a hydrogen atom.

[0276] R 8 and R 9 R 8 and R 9 is R 7 In a preferred embodiment, at least one or all of R 8 is —H. In a preferred embodiment, at least one or all of R 8 is —CH3. In a preferred embodiment, at least one or all of R 8 is —H. In a preferred embodiment, at least one or all of R 8 is -CH3. In a preferred embodiment, the R8 and R9 groups that are not hydrogen atoms are unsubstituted. In a preferred embodiment, the R8 and R9 groups that are not hydrogen atoms do not contain heteroatoms. In a preferred embodiment, R 8 and R9 The group is a hydrogen atom.

[0277] X 1 、X 2 、X 3 、X 4 , and X 5 In formula (1), each X 1 , X 2 , X 3 , X 4 are independent of each other, and X 1 , X 2 , X 3 , X 4 Two or fewer of the C(R 47 )2-, so that -C(R 47 )2-, -NR 37 -, -C(O)-, -O-, with the proviso that there is no set of adjacent atoms selected from the group consisting of -OO-, -ON-, -C(O)-O-, -NN-, and -C(O)-C(O)-.

[0278] In a preferred embodiment, X 1 , X 2 , X 3 , and X 4 is -C(R 47 )2-, and preferably R is 4 or less. 47 , more preferably two or less R 47 , most preferably R equal to or less than 1 47 is not H. In formula (1), X 5 is -C(R 47 )2- or -CHR 48 In a preferred embodiment, X 5 -C(R 47 )2-; more preferably, X 5 Ha-CHR 47 and most preferably X 5 is —CH2. In a preferred embodiment, X 5 is CHR 48 is.

[0279] R 36 In a preferred embodiment, R 36 is R 37 is as defined for

[0280] In formula (1), R 36 is preferably a hydrogen atom, a C1 to C8 alkyl group, a C2 to C8 alkenyl group, and C 4~6 and (hetero)aryl groups, wherein the alkyl, alkenyl, and (hetero)aryl groups are selected from the group consisting of -Cl, -F, -Br, -I, -OH, -NH2, =O, -SH, -SO3H, -PO3H. 、 and may contain up to two heteroatoms selected from the group consisting of -O-, -S-, -NH-, -P-, and -Si-, wherein the N, S, and P atoms are optionally oxidized. 36 The group is unsubstituted. In a preferred embodiment, R 36 The group does not contain heteroatoms. In some preferred embodiments, R 36 The group is a hydrogen atom.

[0281] R 47 In formula (1), each R 47 are independently a hydrogen atom, -L B , -L A , -(S P ) i -C C , -F, -Cl, -Br, -I, -OR 37 , -N(R 37 )2, -SO3, -PO3 - 、 -NO2, -CF3, -SR 37 , S(=O)2N(R 37 )2, OC(=O)R 37 , SC(=O)R 37 , OC(=S)R 37 , SC(=S)R37 , N.R. 37 C(=O)-R 37 , N.R. 37 C(=S)-R 37 , N.R. 37 C(=O)OR 37 , N.R. 37 C(=S)OR 37 , N.R. 37 C(=O)SR 37 , N.R. 37 C(=S)SR 37 , OC(=O)N(R 37 )2, SC(=O)N(R 37 )2, OC(=S)N(R 37 )2, SC(=S)N(R 37 )2, NR 37 C(=O)N(R 37 )2, NR 37 C(=S)N(R 37 )2, C(=O)R 37、 C(=S)R 37、 C(=O)N(R 37 )2, C(=S)N(R 37 )2, C(=O)OR 37 , C(=O)SR 37 , C(=S)OR 37 , C(=S)SR 37 , S(O)R 37 , -S(O)2R 37 , N.R. 37 S(O)2R 37 , -ON(R 37 ) 2、- NR 37 OR 37 , C1~C 24 Alkyl groups, C2-C 24 Alkenyl groups, C2-C 24 Alkynyl groups, C6-C 24 Aryl groups, C2-C 24 Heteroaryl groups, C3-C 24 Cycloalkyl groups, C5-C 24 Cycloalkenyl group, C 12 ~C 24 Cycloalkynyl group, C3-C 24 (Cyclo)alkyl(hetero)aryl groups, C3-C 24(Hetero)aryl(cyclo)alkyl, C4-C 24 (Cyclo)alkenyl(hetero)aryl group, C4-C 24 (Hetero)aryl(cyclo)alkenyl groups, C4-C 24 (Cyclo)alkynyl(hetero)aryl group, C4-C 24 (Hetero)aryl(cyclo)alkynyl group, C4-C 24 Alkylcycloalkyl groups and C4-C 24 cycloalkylalkyl groups; where i is an integer ranging from 0 to 4, preferably i is an integer ranging from 0 to 1; Here, the above alkyl group, alkenyl group, alkynyl group, aryl, heteroaryl, cycloalkyl group, cycloalkenyl group, cycloalkynyl group, (cyclo)alkyl(hetero)aryl group, (hetero)aryl(cyclo)alkyl group, (cyclo)alkenyl(hetero)aryl group, (hetero)aryl(cyclo)alkenyl group, (cyclo)alkynyl(hetero)aryl group, (hetero)aryl(cyclo)alkynyl group, alkylcycloalkyl group, cycloalkylalkyl group are -Cl, -F, -Br, -I, -OR 37 , -N(R 37 )2, -SO3R 37 , -PO3(R 37 ) 2、 -PO4(R 37 ) 2、 -NO2, -CF3, =O, =NR 37 , and -SR 37 and may be substituted with a moiety selected from the group consisting of O, S, NR 37 , P, and Si, wherein the N, S, and P atoms are optionally oxidized, and wherein multiple N atoms are optionally quaternized.

[0282] In a preferred embodiment, each R 47 are independently a hydrogen atom, -L B , -L A , -(S P ) i -C C、-F、-Cl、-Br、-I、-OR 37 、-N(R 37 )2, -SO3, -PO3 - 、 -NO2, -CF3, -SR 37 、S(=O)2N(R 37 )2、OC(=O)R 37 、SC(=O)R 37 、OC(=S)R 37 、SC(=S)R 37 NR 37 C(=O)-R 37 NR 37 C(=S)-R 37 NR 37 C(=O)OR 37 NR 37 C(=S)OR 37 NR 37 C(=O)SR 37 NR 37 C(=S)SR 37 、OC(=O)N(R 37 )2、SC(=O)N(R 37 )2、OC(=S)N(R 37 )2、SC(=S)N(R 37 )2、NR 37 C(=O)N(R 37 )2、NR 37 C(=S)N(R 37 )2、C(=O)R 37、 C(=S)R 37、 C(=O)N(R 37 )2、C(=S)N(R 37 )2、C(=O)OR 37 、C(=O)SR 37 、C(=S)OR 37 、C(=S)SR 37 、S(O)R 37 、-S(O)2R 37 NR 37 S(O)2R 37 、-ON(R 37 ) 2、- NR 37 OR 37 , C1~C8 アルキル base, C2~C8 アルケニル base, C2~C8 アルキニル base, C6~C 12 アリール base, C2~C12 Heteroaryl group, C3-C8 cycloalkyl group, C5-C8 cycloalkenyl group, C3-C 12 Alkyl(hetero)aryl groups, C3-C 12 (Hetero)arylalkyl groups, C4-C 12 Alkylcycloalkyl groups, C4-C 12 Cycloalkylalkyl groups, C5-C 12 Cycloalkyl(hetero)aryl groups and C5-C 12 and (hetero)arylcycloalkyl groups, wherein the alkyl group, alkenyl group, alkynyl group, aryl, heteroaryl, cycloalkyl group, cycloalkenyl group, alkyl(hetero)aryl group, (hetero)arylalkyl group, alkylcycloalkyl group, cycloalkylalkyl group, cycloalkyl(hetero)aryl group, and (hetero)arylcycloalkyl group are selected from the group consisting of -Cl, -F, -Br, -I, -OR 37 , -N(R 37 )2, -SO3R 37 , -PO3(R 37 ) 2、 -PO4(R 37 ) 2、 -NO2, -CF3, =O, =NR 37 , and -SR 37 and may be substituted with a moiety selected from the group consisting of O, S, NR 37 , P, and Si, wherein the N, S, and P atoms are optionally oxidized, and wherein multiple N atoms are optionally quaternized.

[0283] In a preferred embodiment, each R 47 are independently a hydrogen atom, -L B , -L A , -(S P ) i -C C , -F, -Cl, -Br, -I, -OR 37 , -N(R 37 )2, -SO3, -PO3 - 、 -NO2, -CF3, -SR 37, S(=O)2N(R 37 )2, OC(=O)R 37 , SC(=O)R 37 , OC(=S)R 37 , SC(=S)R 37 , N.R. 37 C(=O)-R 37 , N.R. 37 C(=S)-R 37 , N.R. 37 C(=O)OR 37 , N.R. 37 C(=S)OR 37 , N.R. 37 C(=O)SR 37 , N.R. 37 C(=S)SR 37 , OC(=O)N(R 37 )2, SC(=O)N(R 37 )2, OC(=S)N(R 37 )2, SC(=S)N(R 37 )2, NR 37 C(=O)N(R 37 )2, NR 37 C(=S)N(R 37 )2, C(=O)R 37、 C(=S)R 37、 C(=O)N(R 37 )2, C(=S)N(R 37 )2, C(=O)OR 37 , C(=O)SR 37 , C(=S)OR 37 , C(=S)SR 37 , S(O)R 37 , -S(O)2R 37 , N.R. 37 S(O)2R 37 , -ON(R 37 ) 2、- NR 37 OR 37 , C1-C4 alkyl group, C2-C4 alkenyl group, C2-C4 alkynyl group, C6-C8 aryl group, C2-C8 heteroaryl group, C3-C6 cycloalkyl group, C5-C6 cycloalkenyl group, C3-C 10 Alkyl(hetero)aryl groups, C3-C 10 (Hetero)arylalkyl groups, C4-C 10Alkylcycloalkyl groups, C4-C 10 Cycloalkylalkyl groups, C5-C 10 Cycloalkyl(hetero)aryl groups and C5-C 10 and (hetero)arylcycloalkyl groups, wherein the alkyl group, alkenyl group, alkynyl group, aryl, heteroaryl, cycloalkyl group, cycloalkenyl group, alkyl(hetero)aryl group, (hetero)arylalkyl group, alkylcycloalkyl group, cycloalkylalkyl group, cycloalkyl(hetero)aryl group, and (hetero)arylcycloalkyl group are selected from the group consisting of -Cl, -F, -Br, -I, -OR 37 , -N(R 37 )2, -SO3R 37 , -PO3(R 37 ) 2、 -PO4(R 37 ) 2、 -NO2, -CF3, =O, =NR 37 , and -SR 37 and may be substituted with a moiety selected from the group consisting of O, S, NR 37 , P, and Si, wherein the N, S, and P atoms are optionally oxidized, and wherein multiple N atoms are optionally quaternized.

[0284] R 37 In formula (1), each R 37 are independently a hydrogen atom, -L B , -L A , -(S P ) i -C C , C1~C 24 Alkyl groups, C2-C 24 Alkenyl groups, C2-C 24 Alkynyl groups, C6-C 24 Aryl groups, C2-C 24 Heteroaryl groups, C3-C 24 Cycloalkyl groups, C5-C 24 Cycloalkenyl group, C 12 ~C 24Cycloalkynyl group, C3-C 24 (Cyclo)alkyl(hetero)aryl groups, C3-C 24 (Hetero)aryl(cyclo)alkyl, C4-C 24 (Cyclo)alkenyl(hetero)aryl group, C4-C 24 (Hetero)aryl(cyclo)alkenyl groups, C4-C 24 (Cyclo)alkynyl(hetero)aryl group, C4-C 24 (Hetero)aryl(cyclo)alkynyl group, C4-C 24 Alkylcycloalkyl groups and C4-C 24 cycloalkylalkyl groups; where i is an integer ranging from 0 to 4, preferably i is 1; and R that is not a hydrogen atom 37 Groups include -Cl, -F, -Br, -I, -OH, -NH2, -SO3H, and -PO3H 、 -PO4H 2、 It may be substituted with a moiety selected from the group consisting of -NO2, -CF3, =O, =NH, and -SH, and may contain one or more heteroatoms selected from the group consisting of O, S, NH, P, and Si, wherein the N, S, and P atoms are optionally oxidized, and wherein multiple N atoms are optionally quaternized.

[0285] In a preferred embodiment, R 37 is a hydrogen atom, -L B , -L A , -(S P ) i -C C , C1-C8 alkyl group, C2-C8 alkenyl group, C2-C8 alkynyl group, C6-C 12 Aryl, C2-C 12 Heteroaryl, C3-C8 cycloalkyl group, C5-C8 cycloalkenyl group, C3-C 12 Alkyl(hetero)aryl groups, C3-C 12 (Hetero)arylalkyl groups, C4-C 12 Alkylcycloalkyl groups, C4-C 12 Cycloalkylalkyl groups, C5-C 12Cycloalkyl(hetero)aryl groups and C5-C 12 (hetero)arylcycloalkyl groups, wherein any R that is not a hydrogen atom is selected from the group consisting of 37 Groups include -Cl, -F, -Br, -I, -OH, -NH2, -SO3H, and -PO3H 、 -PO4H 2、 and optionally substituted with a moiety selected from the group consisting of -NO2, -CF3, =O, =NH, and -SH7, and optionally containing one or more heteroatoms selected from the group consisting of O, S, NH, P, and Si, wherein the N, S, and P atoms are optionally oxidized, and wherein multiple N atoms are optionally quaternized.

[0286] In a preferred embodiment, R 37 is a hydrogen atom, -L B , -L A , -(S P ) i -C C , C1-C4 alkyl group, C2-C4 alkenyl group, C2-C4 alkynyl group, C6-C8 aryl, C2-C8 heteroaryl, C3-C6 cycloalkyl group, C5-C6 cycloalkenyl group, C3-C 10 Alkyl(hetero)aryl groups, C3-C 10 (Hetero)arylalkyl group, C4-C8 alkylcycloalkyl group, C4-C8 cycloalkylalkyl group, C5-C 10 Cycloalkyl(hetero)aryl groups and C5-C 10 (hetero)arylcycloalkyl groups, wherein any R that is not a hydrogen atom 37 Groups include -Cl, -F, -Br, -I, -OH, -NH2, -SO3H, and -PO3H 、 -PO4H 2、 It may be substituted with a moiety selected from the group consisting of -NO2, -CF3, =O, =NH, and -SH, and may contain one or more heteroatoms selected from the group consisting of O, S, NH, P, and Si, wherein the N, S, and P atoms are optionally oxidized, and wherein multiple N atoms are optionally quaternized.

[0287] In a preferred embodiment, R is not a hydrogen atom. 37 The group is unsubstituted. In a preferred embodiment, R 37 The group does not contain heteroatoms. In some preferred embodiments, R 37 is a hydrogen atom.

[0288] S P is a spacer as defined herein, and C C is Construct-C as defined herein.

[0289] In equation (1), two R 47 and / or R 37 may be contained within the ring.

[0290] In equation (1), two R 47 and / or R 37 may be included within a ring to form a ring fused to the 8-membered trans ring of formula (1). 47 and / or R 37 When groups are contained within rings to form rings fused to the 8-membered trans ring, the rings fused to the 8-membered trans ring may be optionally substituted and R 47 Preferably, the cycloalkylene group and the cycloalkenylene group may contain a heteroatom as described above.

[0291] sign The compounds of formula (1) include a label capable of providing a desired diagnostic, imaging, and / or radiotherapeutic effect.

[0292] The label is a moiety that contains a radionuclide.

[0293] Particularly for imaging applications, the label is preferably a detectable label. As used herein, "detectable label" refers to a portion of the compound of formula (1) that allows the compound of formula (1) to be detected when present in a cell, tissue or organism. One type of detectable label envisioned within the context of the present invention is a contrast-providing label. Different types of detectable labels are envisioned within the context of the present invention and are described herein below.

[0294] Thus, according to a particular embodiment of the present invention, the compounds, combinations, kits and methods of the present invention are used in imaging, particularly medical imaging, where a detectable label is used to identify the primary target and / or to assess the biodistribution of the compound of formula (1).

[0295] Preferred detectable labels for imaging are contrast-providing moieties used in classical imaging systems.

[0296] Preferably, the radionuclide contained in the label for imaging is 3 H, 11 C. 13 N, 15 O. 18 F, 19 F, 44 Sc, 51 Cr, 52 Fe, 52 Mn, 55 Co, 60 Cu, 61 Cu, 62 Zn, 62 Cu, 63 Zn, 64 Cu, 66 Ga, 67 Ga, 68 Ga, 70 As, 71 As, 72 As, 74 As, 75 Se, 75 Br, 76Br, 77 Br, 8O Br, 82 Br, 82 Rb, 86 Y, 88 Y, 89 Sr, 89 Zr, 97 Ru, 99m Tc, 110 In, 111 In, 113 In, 114 In, 117 Sn, 120 I, 122 Xe, 123 I, 124 I, 125 I, 166 Ho, 167 Tm, 169 Yb, 193 Pt, 195 Pt, 201 Tl, and 203 Pb is an isotope selected from the group consisting of:

[0297] More preferably, the radionuclide contained in the label for imaging is 18 F, 44 Sc, 64 Cu, 68 Ga, 89 Zr, 99m Tc, 111 In, 123 I, and 124 I is an isotope selected from the group consisting of:

[0298] Other elements and isotopes, such as those used for therapy, may also be adapted for imaging in certain applications.

[0299] In one embodiment, the detectable label is a small sized organic PET and SPECT radioisotope, e.g., 18 F, 11 C. 123 I or 124I. Due to their small size, organic PET or SPECT radioisotopes do not significantly affect the properties of administered agents in general, particularly their membrane transport, making them ideally suited for monitoring intracellular events.

[0300] In a preferred embodiment, particularly when the compound of formula (1) is used in a therapeutic application, the label is a therapeutic label, wherein the label comprises a radioisotope for radiotherapy. The radionuclide used for therapy is preferably 24 Na, 32 P, 33 P, 47 Sc, 59 Fe, 67 Cu, 76 As, 77 As, 80 Br, 82 Br, 89 Sr, 90 Nb, 90 Y, 103 Ru, 105 Rh, 109 Pd, 111 Ag, 111 In, 121 Sn, 127 Te, 131 I, 140 La, 141 Ce, 142 Pr, 143 Pr, 144 Pr, 149 Pm, 149 Tb, 151 Pm, 153 Sm, 159 Gd, 161 Tb, 165 Dy, 166 Dy, 166 Ho, 169 Er, 172 Tm, 175 Yb, 177 Lu, 186 Re, 188 Re, 198 Au, 199 Au, 211 At, 211 Bi,212 Bi, 212 Pb, 213 Bi, 214 Bi, 223 Ra, 224 Ra, 225 Ac, and 227 The isotope is selected from the group consisting of Th.

[0301] More preferably, the radionuclide contained in the therapeutic label is 90 Y, 111 In, 131 I, 177 Lu, 186 Re, 188 Re, 211 At, 212 Pb, 213 Bi, 225 Ac, and 227 The isotope is selected from the group consisting of Th.

[0302] The label may be a metal, e.g., a 111 When it is intended to include In, it is preferably provided in the form of a chelate. In such cases, the label preferably contains a structural moiety capable of forming a coordination complex with such a metal. Good examples thereof are the macrocyclic lanthanide(III) chelates derived from 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (H4dota).

[0303] In a preferred embodiment, the label is -OR 37 , -N(R 37 )2, -CF3, -SR 37 , S(=O)2N(R 37 )2, OC(=O)R 37 , SC(=O)R 37 , OC(=S)R 37 , SC(=S)R 37 , N.R. 37 C(=O)-R 37 , N.R. 37 C(=S)-R 37 , N.R. 37 C(=O)OR 37 , N.R. 37C(=S)OR 37 , N.R. 37 C(=O)SR 37 , N.R. 37 C(=S)SR 37 , OC(=O)N(R 37 )2, SC(=O)N(R 37 )2, OC(=S)N(R 37 )2, SC(=S)N(R 37 )2, NR 37 C(=O)N(R 37 )2, NR 37 C(=S)N(R 37 )2, C(=O)R 37、 C(=S)R 37、 C(=O)N(R 37 )2, C(=S)N(R 37 )2, C(=O)OR 37 , C(=O)SR 37 , C(=S)OR 37 , C(=S)SR 37 , S(O)R 37 , -S(O)2R 37 , N.R. 37 S(O)2R 37 , -ON(R 37 ) 2、- NR 37 OR 37 , C1~C 24 Alkyl groups, C2-C 24 Alkenyl groups, C2-C 24 Alkynyl groups, C6-C 24 Aryl groups, C2-C 24 Heteroaryl groups, C3-C 24 Cycloalkyl groups, C5-C 24 Cycloalkenyl group, C 12 ~C 24 Cycloalkynyl group, C3-C 24 (Cyclo)alkyl(hetero)aryl groups, C3-C 24 (Hetero)aryl(cyclo)alkyl, C4-C 24 (Cyclo)alkenyl(hetero)aryl group, C4-C 24 (Hetero)aryl(cyclo)alkenyl groups, C4-C 24 (Cyclo)alkynyl(hetero)aryl group, C4-C 24(Hetero)aryl(cyclo)alkynyl group, C4-C 24 Alkylcycloalkyl groups and C4-C 24 cycloalkylalkyl groups; 37 Groups, alkyl groups, alkenyl groups, alkynyl groups, aryl groups, heteroaryl groups, cycloalkyl groups, cycloalkenyl groups, cycloalkynyl groups, (cyclo)alkyl(hetero)aryl groups, (hetero)aryl(cyclo)alkyl groups, (cyclo)alkenyl(hetero)aryl groups, (hetero)aryl(cyclo)alkenyl groups, (cyclo)alkynyl(hetero)aryl groups, (hetero)aryl(cyclo)alkynyl groups, alkylcycloalkyl groups, cycloalkylalkyl groups are 3 H, 11 C. 13 N, 15 O. 18 F, 19 F, 51 Cr, 52 Fe, 52 Mn, 55 Co, 60 Cu, 61 Cu, 62 Zn, 62 Cu, 63 Zn, 64 Cu, 66 Ga, 67 Ga, 68 Ga, 70 As, 71 As, 72 As, 74 As, 75 Se, 75 Br, 76 Br, 77 Br, 8O Br, 82 Br, 82 Rb, 86 Y, 88 Y, 90 Y, 89 Sr, 89 Zr, 97 Ru, 99m Tc, 110 In, 111 In, 113 In, 114 In, 117 Sn, 120I、 122 Xe、 123 I、 124 I、 125 I、 166 Ho、 167 Tm、 169 Yb、 193 Pt、 195 Pt、 201 Tl、 203 Pb、 24 Na、 32 P、 33 P、 47 Sc、 59 Fe、 67 Cu、 76 As、 77 As、 90 Nb、 103 Ru、 105 Rh、<000194​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​substituted with and / or chelated with at least one isotope selected from the group consisting of -Th, -Cl, -F, -Br, -I, -OR 37 , -N(R 37 )2, -SO3R 37 , -PO3(R 37 ) 2、 -PO4(R 37 ) 2、 -NO2, -CF3, =O, =NR 37 , and -SR 37 and may be further substituted with a moiety selected from the group consisting of O, S, NR 37 , P, and Si, wherein the N, S, and P atoms are optionally oxidized, and wherein multiple N atoms are optionally quaternized.

[0304] In another preferred embodiment, the label is -OR 37 , -N(R 37 )2, -CF3, -SR 37 , S(=O)2N(R 37 )2, OC(=O)R 37 , SC(=O)R 37 , OC(=S)R 37 , SC(=S)R 37 , N.R. 37 C(=O)-R 37 , N.R. 37 C(=S)-R 37 , N.R. 37 C(=O)OR 37 , N.R. 37 C(=S)OR 37 , N.R. 37 C(=O)SR 37 , N.R. 37 C(=S)SR 37 , OC(=O)N(R 37 )2, SC(=O)N(R 37 )2, OC(=S)N(R 37 )2, SC(=S)N(R 37 )2, NR 37 C(=O)N(R 37 )2, NR 37 C(=S)N(R37 )2, C(=O)R 37、 C(=S)R 37、 C(=O)N(R 37 )2, C(=S)N(R 37 )2, C(=O)OR 37 , C(=O)SR 37 , C(=S)OR 37 , C(=S)SR 37 , C1~C 12 Alkyl groups, C2-C 12 Alkenyl groups, C2-C 12 Alkynyl groups, C6-C 12 Aryl groups, C2-C 12 Heteroaryl groups, C3-C 12 Cycloalkyl groups, C5-C 12 Cycloalkenyl group, C 12 ~C 12 Cycloalkynyl group, C3-C 12 (Cyclo)alkyl(hetero)aryl groups, C3-C 12 (Hetero)aryl(cyclo)alkyl, C4-C 12 (Cyclo)alkenyl(hetero)aryl group, C4-C 12 (Hetero)aryl(cyclo)alkenyl groups, C4-C 12 (Cyclo)alkynyl(hetero)aryl group, C4-C 12 (Hetero)aryl(cyclo)alkynyl group, C4-C 12 Alkylcycloalkyl groups and C4-C 12 cycloalkylalkyl groups; 37 Groups, alkyl groups, alkenyl groups, alkynyl groups, aryl groups, heteroaryl groups, cycloalkyl groups, cycloalkenyl groups, cycloalkynyl groups, (cyclo)alkyl(hetero)aryl groups, (hetero)aryl(cyclo)alkyl groups, (cyclo)alkenyl(hetero)aryl groups, (hetero)aryl(cyclo)alkenyl groups, (cyclo)alkynyl(hetero)aryl groups, (hetero)aryl(cyclo)alkynyl groups, alkylcycloalkyl groups, cycloalkylalkyl groups are 3 H, 11 C. 13 N, 15 O. 18F、 19 F、 44 Sc、 51 Cr、 52 Fe、 52 Mn、 55 Co、 60 Cu、 61 Cu、 62 Zn、 62 Cu、 63 Zn、 64 Cu、 66 Ga、 67 Ga、 68 Ga、 70 As、 71 As、 72 As、 74 As、 75 Se、 75 Br、 76 Br、 77 Br、 8O Br、 82 Br、 82 Rb、 86 Y、 88 Y、 90 Y、 89 Sr、 89 Zr、 97 Ru、 99m Tc、 110 In、 111 In、 113 In、 114 In、 117 Sn、 120 I、 122 Xe、 123 I、 124 I、 125 I、 166 Ho、 167 Tm、 169 Yb、 193 Pt、 195 Pt、 201 Tl、 203 Pb、 24 Na、 32 P、 33 P、 47 Sc、 59 Fe、 67 Cu、 76 As、 77 As、 90 Nb、 103 Ru、 105 Rh、 109 Pd、 111 Ag、121 Sn, 127 Te, 131 I, 140 La, 141 Ce, 142 Pr, 143 Pr, 144 Pr, 149 Pm, 149 Tb, 151 Pm, 153 Sm, 159 Gd, 161 Tb, 165 Dy, 166 Dy, 166 Ho, 169 Er, 172 Tm, 175 Yb, 177 Lu, 186 Re, 188 Re, 198 Au, 199 Au, 211 At, 211 Bi, 212 Bi, 212 Pb, 213 Bi, 214 Bi, 223 Ra, 224 Ra, 225 Ac, and 227 -substituted with and / or chelated with at least one isotope selected from the group consisting of -Th; and -Cl, -F, -Br, -I, -OR 37 , -N(R 37 )2, -SO3R 37 , -PO3(R 37 ) 2、 -PO4(R 37 ) 2、 -NO2, -CF3, =O, =NR 37 , and -SR 37 and may be further substituted with a moiety selected from the group consisting of O, S, NR 37 , P, and Si, wherein the N, S, and P atoms are optionally oxidized, and wherein multiple N atoms are optionally quaternized.

[0305] In a preferred embodiment, each label is independently -OR 37 , -N(R 37 )2, -CF3, -SR 37 , S(=O)2N(R 37 )2, OC(=O)R 37 , SC(=O)R 37 , OC(=S)R 37 , SC(=S)R 37 , N.R. 37 C(=O)-R 37 , N.R. 37 C(=S)-R 37 , N.R. 37 C(=O)OR 37 , N.R. 37 C(=S)OR 37 , N.R. 37 C(=O)SR 37 , N.R. 37 C(=S)SR 37 , OC(=O)N(R 37 )2, SC(=O)N(R 37 )2, OC(=S)N(R 37 )2, SC(=S)N(R 37 )2, NR 37 C(=O)N(R 37 )2, NR 37 C(=S)N(R 37 )2, C(=O)R 37、 C(=S)R 37、 C(=O)N(R 37 )2, C(=S)N(R 37 )2, C(=O)OR 37 , C(=O)SR 37 , C(=S)OR 37 , C(=S)SR 37, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C6 aryl group, a C2-C6 heteroaryl group, a C3-C6 cycloalkyl group, a C5-C6 cycloalkenyl group, a C8 cycloalkynyl group, a C3-C6 (cyclo)alkyl(hetero)aryl group, a C3-C6 (hetero)aryl(cyclo)alkyl, a C4-C6 (cyclo)alkenyl(hetero)aryl group, a C4-C6 (hetero)aryl(cyclo)alkenyl group, a C4-C6 (cyclo)alkynyl(hetero)aryl group, a C4-C6 (hetero)aryl(cyclo)alkynyl group, a C4-C6 alkylcycloalkyl group, and a C4-C6 cycloalkylalkyl group; 37 Groups, alkyl groups, alkenyl groups, alkynyl groups, aryl groups, heteroaryl groups, cycloalkyl groups, cycloalkenyl groups, cycloalkynyl groups, (cyclo)alkyl(hetero)aryl groups, (hetero)aryl(cyclo)alkyl groups, (cyclo)alkenyl(hetero)aryl groups, (hetero)aryl(cyclo)alkenyl groups, (cyclo)alkynyl(hetero)aryl groups, (hetero)aryl(cyclo)alkynyl groups, alkylcycloalkyl groups, cycloalkylalkyl groups are 3 H, 11 C. 13 N, 15 O. 18 F, 19 F, 44 Sc, 51 Cr, 52 Fe, 52 Mn, 55 Co, 60 Cu, 61 Cu, 62 Zn, 62 Cu, 63 Zn, 64 Cu, 66 Ga, 67 Ga, 68 Ga, 70 As, 71 As, 72 As, 74 As, 75 Se, 75 Br, 76 Br, 77 Br, 8O Br,82 Br、 82 Rb、 86 Y、 88 Y、 90 Y、 89 Sr、 89 Zr、 97 Ru、 99m Tc、 110 In、 111 In、 113 In、 114 In、 117 Sn、 120 I、 122 Xe、 123 I、 124 I、 125 I、 166 Ho、 167 Tm、 169 Yb、 193 Pt、 195 Pt、 201 Tl、 203 Pb、 24 Na、 32 P、 33 P、 47 Sc、 59 Fe、 67 Cu、 76 As、 77 As、 90 Nb、 103 Ru、 105 Rh、 109 Pd、 111 Ag、 121 Sn、 127 Te、 131 I、 140 La、 141 Ce、 142 Pr、 143 Pr、 144 Pr、 149 Pm、 149 Tb、 151 Pm、 153 Sm、 159 Gd、 161 Tb、 165 Dy、 166 Dy、 166 Ho、 169 Er、 172 Tm、 175 Yb、 177 Lu、 186 Re、 188 Re、 198 Au、199 Au, 211 At, 211 Bi, 212 Bi, 212 Pb, 213 Bi, 214 Bi, 223 Ra, 224 Ra, 225 Ac, and 227 substituted with and / or chelated with at least one isotope selected from the group consisting of -Th, -Cl, -F, -Br, -I, -OR 37 , -N(R 37 )2, -SO3R 37 , -PO3(R 37 ) 2、 -PO4(R 37 ) 2、 -NO2, -CF3, =O, =NR 37 , and -SR 37 and may be further substituted with a moiety selected from the group consisting of O, S, NR 37 , P, and Si, wherein the N, S, and P atoms are optionally oxidized, and wherein multiple N atoms are optionally quaternized.

[0306] In a preferred embodiment, the label is derived from a prosthetic group. Those skilled in the art will appreciate that a prosthetic group may be a radionuclide, e.g. 131 It will be appreciated that I is a precursor that can be radiolabeled to form a label.

[0307] In another preferred embodiment, the label is C1-C 12 Alkyl groups, C2-C 12 Alkenyl groups, C2-C 12 Alkynyl groups, C6-C 12 Aryl groups, C2-C 12 Heteroaryl groups, C3-C 12 Cycloalkyl groups, C5-C 12 Cycloalkenyl group, C 12 ~C 12 Cycloalkynyl group, C3-C 12(Cyclo)alkyl(hetero)aryl groups, C3-C 12 (Hetero)aryl(cyclo)alkyl, C4-C 12 (Cyclo)alkenyl(hetero)aryl group, C4-C 12 (Hetero)aryl(cyclo)alkenyl groups, C4-C 12 (Cyclo)alkynyl(hetero)aryl group, C4-C 12 (Hetero)aryl(cyclo)alkynyl group, C4-C 12 Alkylcycloalkyl groups and C4-C 12 cycloalkylalkyl groups; 3 H, 11 C. 13 N, 15 O. 18 F, 19 F, 75 Br, 76 Br, 77 Br, 8O Br, 82 Br, 120 I, 123 I, 124 I, 125 I, 32 P, 33 P, 131 I, and 211 At least one isotope selected from the group consisting of At, ... 37 , -N(R 37 )2, -SO3R 37 , -PO3(R 37 ) 2、 -PO4(R 37 ) 2、 -NO2, -CF3, =O, =NR 37 , and -SR 37 and may be further substituted with a moiety selected from the group consisting of O, S, NR 37 , P, and Si, wherein the N, S, and P atoms are optionally oxidized, and wherein multiple N atoms are optionally quaternized.

[0308] In a preferred embodiment, the label comprises a chelating moiety.

[0309] In a preferred embodiment, the label is DTPA (diethylenetriaminepentaacetic acid), DOTA (1,4,7,10-tetraazacyclododecane-N,N',N",N"-tetraacetic acid), DOTAGA anhydride (2,2',2"-(10-(2,6-dioxotetrahydro-2H-pyran-3-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid), NOTA (1,4,7-triazacyclononane-N,N',N"-triacetic acid), TE TA (1,4,8,11-tetraazacyclotetradecane-N,N',N",N'-tetraacetic acid), OTTA (N1-(p-isothiocyanatobenzyl)-diethylenetriamine-N1,N2,N3,N3-tetraacetic acid), deferoxamine, or DFO (N'-[5-[[4-[[5-(acetylhydroxyamino)pentyl]amino]-1,4-dioxobutyl]hydroxyamino]pentyl]-N-(5-aminopentyl)-N-hydroxybutanediamide), and DFO * and a conjugate of HYNIC (hydrazinonicotinamide); and the chelating moiety is selected from the group consisting of: a DFO derivative called 44 Sc, 51 Cr, 52 Fe, 52 Mn, 55 Co, 60 Cu, 61 Cu, 62 Zn, 62 Cu, 63 Zn, 64 Cu, 66 Ga, 67 Ga, 68 Ga, 70 As, 71 As, 72 As, 74 As, 75 Se, 82 Rb, 86 Y, 88 Y, 89 Sr, 89 Zr, 97 Ru, 99mTc, 110 In, 111 In, 113 In, 114 In, 117 Sn, 122 Xe, 166 Ho, 167 Tm, 169 Yb, 193 Pt, <​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​It chelates with a metal selected from the group consisting of Th.

[0310] In a preferred embodiment, the metal chelate comprises an acyclic derivative of ethylenediaminotetraacetic acid (EDTA) or diethylenediaminotetraacetic acid (DTPA).

[0311] [ka]

[0312] Here, the dashed line indicates the bond to the rest of the molecule.

[0313] In another preferred embodiment, the metal chelate comprises an acyclic chelator containing a carboxy-pyridine group as shown below.

[0314] [ka]

[0315] Here, the dashed line indicates the bond to the rest of the molecule.

[0316] In another preferred embodiment, the metal chelate comprises a cyclic derivative of 1,4,7,10-tetraazadodecane (cyclen).

[0317] [ka]

[0318] Here, the dashed line indicates the bond to the rest of the molecule.

[0319] In another preferred embodiment, the metal chelate comprises a derivative of 1,4,7-triazacyclononane (TACN):

[0320] [ka]

[0321] Here, the dashed line indicates the bond to the rest of the molecule.

[0322] In yet another preferred embodiment, the metal chelate comprises a macrocyclic chelator containing N and O heteroatoms, as described below.

[0323] [ka]

[0324] Here, the dashed line indicates the bond to the rest of the molecule.

[0325] In another preferred embodiment, the metal chelate comprises a derivative of the cryptand agent sarcofazine (Sar), described below.

[0326] [ka]

[0327] Here, the dashed line indicates the bond to the rest of the molecule.

[0328] In another preferred embodiment, the metal chelate comprises a linear or cyclic chelating agent containing a hydroxamate group, as described below.

[0329] [ka]

[0330] Here, the dashed line indicates the bond to the rest of the molecule.

[0331] In yet another preferred embodiment, the metal chelate comprises a linear or cyclic chelating agent comprising a 3-hydroxy-4-pyridinone (3,4-HOPO) group, as described below.

[0332] [ka]

[0333] Here, the dashed line indicates the bond to the rest of the molecule.

[0334] In other preferred embodiments, the metal chelate comprises a linear or cyclic chelating agent containing N, S, and P heteroatoms, as described below.

[0335] [ka]

[0336] where the dashed line indicates the bond to the rest of the molecule and M is 99m Tc, 186 Re, and 188 Re indicates a radionuclide selected from the group consisting of:

[0337] In other preferred embodiments, the metal chelates contain the following residues: glycine, serine, cysteine, lysine, and alanine.

[0338] [ka]

[0339] where the dashed line indicates the bond to the rest of the molecule and M is 99m Tc, 186 Re, and 188 Re indicates a radionuclide selected from the group consisting of:

[0340] In another preferred embodiment, the metal chelate comprises a hydrazinonicotinic acid derivative (HYNIC) and a co-ligand, as described below.

[0341] [ka]

[0342] where the dashed line indicates the bond to the rest of the molecule and M is 99m Tc,186 Re, and 188 Re indicates a radionuclide selected from the group consisting of:

[0343] In another preferred embodiment, the chelate comprises a carbonyl group and a chelator containing N, O, and S heteroatoms or cyclopentadienyl, as described below.

[0344] [ka]

[0345] where the dashed line indicates the bond to the rest of the molecule and M is 99m Tc, 186 Re, and 188 Re indicates a radionuclide selected from the group consisting of:

[0346] In some preferred embodiments of the invention, the label is 18 They contain F and can be prepared by those skilled in the art based on known synthetic routes using known labeled synthons or prosthetic groups. 18 Some non-limiting examples of labels containing F are shown below.

[0347] [ka]

[0348] Here, the dashed line indicates the bond to the rest of the molecule.

[0349] In a preferred embodiment of the invention, the label is 123 I, 124 I, 125 I, 131 I, and 211 and are synthesized by one skilled in the art based on known synthetic routes using prosthetic groups. Some preferred embodiments of such labels are set forth below.

[0350] [ka]

[0351] where the dashed line indicates the bond to the rest of the molecule and X is 123 I, 124 I, 125 I, 131 I, or 211 Indicates At.

[0352] In yet another preferred embodiment of the present invention, the label comprises: 123 I, 124 I, 125 I, 131 I, and 211 At; and is synthesized by one skilled in the art based on known synthetic routes using the closo-decaborate (2-) group.

[0353] [ka]

[0354] where the dashed line indicates the bond to the rest of the molecule and X is 123 I, 124 I, 125 I, 131 I, or 211 Indicates At.

[0355] Administered drug The agent is an antibody. The agent can be any construct, where it is desired to modify the construct with a label for radioimaging or radiotherapy and to remove the imaging or radiotherapy label at a specific time after injection. This is particularly true for targeted imaging and radiotherapy to a site, such as a tumor, within the body of a subject, particularly a human. The only requirement is that a trigger TR, an additional linker to the label, can be provided. The exact attachment of the trigger to the agent will depend on the molecular structure of both molecules, but it should be noted that this does not usually present a particular challenge to those skilled in the art, as many proven conjugation methods and attachment moieties exist for a variety of biomolecules. The attachment may be via a spacer, such as a polyethylene glycol (PEG) chain.

[0356] Typically, the administered agent can bind to a primary target, as defined herein. The primary target can be a target to which a targeting agent binds, or the administered agent can be a therapeutic target depending on the effect of the drug. In a preferred embodiment, the primary target is a therapeutic target, and the targeting agent is a drug and binds to the primary target.

[0357] In a preferred embodiment, the administered agent is a targeted agent as defined herein, provided that the targeted agent is described as an antibody.

[0358] In another preferred embodiment, the administration agent is equivalent to a targeting agent, and the targeting agent is radiolabeled with a therapeutic radioisotope to target the therapeutic radiation to tissues expressing the primary target.

[0359] In another preferred embodiment, the administered agent is equivalent to a targeting agent, and the targeting agent is radiolabeled with a therapeutic radioisotope for imaging tissues expressing the primary target.

[0360] In a preferred embodiment, the agent is an antibody comprising an FcRn-binding domain, more preferably an intact IgG antibody. Preferably, the agent is an intact antibody.

[0361] In another preferred embodiment, the agent is an antibody comprising an albumin binding moiety.

[0362] In another preferred embodiment, the dosage form is a drug. In another preferred embodiment, the dosage form is a drug, and the drug is labeled using the present invention for the purpose of imaging drug distribution in vivo. Drugs that can be used in dosage forms related to the present invention are pharmaceutically active compounds.

[0363] In preferred embodiments, the pharmaceutically active compound or agent is selected from the group consisting of cytotoxins, antiproliferative / antitumor agents, antivirals, antibiotics, anti-inflammatory agents, chemosensitizers, radiosensitizers, immunomodulators, immunosuppressants, immunostimulators, anti-angiogenic factors, and enzyme inhibitors.

[0364] In other preferred embodiments, the agent is designed to act in the central nervous system, for example in the context of Alzheimer's and Parkinson's disease, for example antibodies against beta amyloid and Tau proteins.

[0365] Exemplary classes of cytotoxic agents, e.g., for use in cancer therapy, include, but are not limited to, DNA damaging agents, DNA crosslinking agents, DNA binding agents, DNA alkylating agents, DNA intercalators, DNA cleaving agents, microtubule stabilizing and destabilizing agents, topoisomerase inhibitors, radiosensitizers, antimetabolites, natural products and their analogs, peptides, oligonucleotides, enzyme inhibitors, e.g., dihydrofolate reductase inhibitors and thymidylate synthase inhibitors.

[0366] Exemplary immunomodulatory agents are antibodies against PD-L1, PD-1, LAG-3, OX40, TIGIT, TIM-3, B7H4, Vista, CTLA-4, APRIL, GITR, CD3, CD28, CD40, CD74, RIG, MDA-5, NLRP1, NLRP3, AIM2, IDO, MEK, cGAS, and CD25, NKG2A.

[0367] It will be appreciated that chemical modifications may also be made to the agent to make it more convenient to react that compound for the purpose of preparing the conjugates of the invention.

[0368] In a preferred embodiment, the administered agent prior to conjugation to the remainder of the compound of Formula (1) is selected from the group consisting of -OH, -NHR', -COH, -SH, -SS-, -SCH-, -N, terminal alkynyl, terminal alkenyl, -C(O)R', C-C 12 and R' comprises at least one moiety selected from the group consisting of (hetero)cycloalkynyl, nitrone, nitrile oxide, (imino)sydnone, isonitrile, (oxa)norbornene, and tetrazine, wherein R' is R 37 where the moiety used for conjugation to the moiety satisfies formula (1) and is equal to C M2 or C X To form a compound containing the moiety, a dienophile, the label, and R 32 Includes.

[0369] In a preferred embodiment, the administration agent is a C selected from the group consisting of amines, amides, thioamides, aminooxys, carbamates, thiocarbamates, ureas, thioureas, sulfonamides, and sulfonecarbamates. M2 is attached to the remainder of the compound of formula (1) via

[0370] In a preferred embodiment, C M2 is R as defined herein 10 is equal to.

[0371] In a preferred embodiment, when the agent is conjugated via -SH or -SS-, C M2 is selected from the group consisting of:

[0372] [ka]

[0373] where the wavy line indicates the bond to the rest of the molecule and the dashed line indicates the bond to the administering agent, and where R′ is R as defined herein. 37 is equal to.

[0374] In a preferred embodiment, when the agent is conjugated via -SCH3-, C M2 is preferably as follows:

[0375] [ka]

[0376] Here, the wavy line indicates the bond to the rest of the molecule and the dashed line indicates the bond to the administering agent.

[0377] In a preferred embodiment, when the agent is conjugated via -NR'-, C M2 is selected from the group consisting of:

[0378] [ka]

[0379] where R' is R as defined herein. 37 where the wavy line indicates the bond to the rest of the molecule and the dashed line indicates the bond to the administering agent.

[0380] In a preferred embodiment, when the agent is conjugated via —C(O)R′ or —C— derived from a moiety that was —C(O)R′—, CM2 is selected from the group consisting of:

[0381] [ka]

[0382] Here, the wavy line indicates the bond to the rest of the molecule and the dashed line indicates the bond to the administering agent.

[0383] In a preferred embodiment, when the agent is conjugated via —C(O)— derived from a moiety that was —C(O)OH, C M2 is preferably selected from the group consisting of:

[0384] [ka]

[0385] where R' is R as defined herein. 37 where the wavy line indicates the bond to the rest of the molecule and the dashed line indicates the bond to the administering agent.

[0386] In a preferred embodiment, when the agent is conjugated via -O-, C M2 is selected from the group consisting of:

[0387] [ka]

[0388] where R' is R as defined herein. 37 where the wavy line indicates the bond to the rest of the molecule and the dashed line indicates the bond to the administering agent.

[0389] In a preferred embodiment, the administration agent is an R 32 When conjugated via -N3, the resulting C Xcontains a triazole ring, where each C X are independently selected from the group consisting of:

[0390] [ka]

[0391] Here, the wavy line indicates the bond to the rest of the molecule and the dashed line indicates the bond to the administering agent.

[0392] Preferably, the dosage form is modified with additional moieties equivalent to formula (1), except that these additional moieties do not include any dosage forms (because the first-mentioned dosage form is already attached to the moiety). In a preferred embodiment, the dosage form is attached to an additional moiety at positions 1-8, more preferably positions 1-6, and even more preferably positions 1-4, as defined in this paragraph.

[0393] Further embodiments of compounds of formula (1) In the compounds of the present invention, the administered agent is an antibody.

[0394] In a preferred embodiment, in the compounds of the invention, the label is a radiolabel, preferably a chelating moiety that chelates a radioisotope.

[0395] Because it is known that 8-membered heterocyclic monoalkenylene rings also have dienophilic activity, those skilled in the art are familiar with the fact that dienophilic activity does not necessarily depend on the presence of all carbon atoms in the ring.Therefore, in general, the present invention is not strictly limited to trans-cyclooctene.Those skilled in the art of organic chemistry will recognize that there are other 8-membered ring-based dienophiles that contain the same intracyclic double bond as trans-cyclooctene, but may have one or more heteroatoms in other positions in the ring.That is, the present invention generally relates to 8-membered non-aromatic cyclic alkene moieties, preferably cyclooctene moieties, more preferably trans-cyclooctene moieties.

[0396] Trans-cyclooctene or E-cyclooctene derivatives are particularly suitable as triggers, given their high reactivity. Optionally, the trans-cyclooctene (TCO) moiety may contain at least two exocyclic bonds fixed in substantially the same plane, preferably as described in WO 2012 / 156919 A1, and / or the trans-cyclooctene (TCO) moiety may contain at least one substituent in an axial position, rather than an equatorial position. Those skilled in the art of organic chemistry will understand that the term "fixed in substantially the same plane" refers to a bonding theory in which bonds are generally considered to be fixed in the same plane. Typical examples of such fixation in the same plane can include double bonds and strained fused rings; for example, at least two exocyclic bonds can be two bonds of a double bond to an oxygen atom (i.e., C=O). The at least two exocyclic bonds can also be single bonds between two adjacent carbon atoms, provided that these bonds are part of a fused ring (i.e., fused to the TCO ring) that has a substantially planar structure, thereby fixing the two single bonds to substantially one and the same plane. Examples of the latter include strained rings, such as cyclopropyl and cyclobutyl. Without wishing to be bound by theory, the inventors believe that the presence of at least two exocyclic bonds in the same plane will result in at least partial planarization of the TCO ring, which can result in higher reactivity in the IEDDA reaction. Background material providing further guidance is WO 2013 / 153254. The at least two exocyclic bonds fixed to substantially the same plane are preferably as described on page 16 and further in WO 2012 / 156919 A1.

[0397] The TCO moiety may be composed of multiple isomers, including the equatorial versus axial position of the substituents on the TCO. In this regard, reference is made to Whitham et al. J. Chem. Soc. (C), 1971, 883-896, which describes the synthesis and characterization of the equatorial and axial isomers of trans-cyclooct-2-en-ol, defined as (1RS,2RS) and (1SR,2RS), respectively. In these isomers, the OH substituents are in either the equatorial or axial position. In a preferred embodiment, R 48 R 48 For TCO structures that can be either in the equatorial or 48 is in the axial position. Without wishing to be bound by theory, the inventors believe that the presence of the axial substituent increases the strain on the TCO ring, resulting in higher reactivity in the IEDDA reaction. Background material providing further guidance is WO 2012 / 049624.

[0398] Moreover, in the case of aryl substituents in the TCO in some embodiments, it is preferred that they are positioned equatorially rather than axially.

[0399] It should be noted that depending on the choice of nomenclature, TCO dienophiles can also be referred to as E-cyclooctene. Referring to conventional nomenclature, it will be understood that as a result of substitution on the cyclooctene ring, the same cyclooctene isomer may be formally designated as a Z-isomer, depending on the position and molecular weight of the substituent. In the present invention, any substitution variant of the present invention, regardless of whether it is formally an "E" or "Z" isomer, or a "cis" or "trans" isomer, will be considered a derivative of unsubstituted trans-cyclooctene or unsubstituted E-cyclooctene. The terms "trans-cyclooctene" (TCO) and E-cyclooctene are used interchangeably, and are maintained for all dienophiles according to the present invention, even when the substituent formally requires the opposite nomenclature. That is, the present invention relates to cyclooctene in which carbon atoms 1 and 6, numbered below, are in the E (entgegen) or trans position.

[0400] [ka]

[0401] The dienophiles for use in the present invention can be synthesized by those skilled in the art based on known synthetic routes to cyclooctene and the corresponding ring containing one or more heteroatoms. Those skilled in the art are also aware of the abundance of cyclooctene derivatives that can be synthesized via ring-closing metathesis reactions using Grubbs catalysts. As mentioned above, TCOs may contain one or more heteroatoms in the ring. This is itself well accessible to those skilled in the art (e.g., WO 2016025480). For example, the presence of thioethers in TCOs has been mentioned (Cere et al. J. Org. Chem. 1980, 45, 261). Also, for example, the presence of -O-SiR2-O moieties in TCOs has been mentioned (Prevost et al. J. Am. Chem. Soc. 2009, 131, 14182). The leaving group (R) located at the allylic position has also been mentioned (Cere et al. J. Org. Chem. Soc. 2009, 131, 14182). 48 References have been made to TCO syntheses in which Z is an ether, ester, carbonate, carbamate, or thiocarbamate: [Versteegen et al Angew.Chem.Int.Ed.2018,57,10494] and [Steiger et al Chem Comm 2017,53,1378]. Exemplary TCOs include the following structures, shown with multiple literature references below: When a cyclooctene derivative is depicted as Z-cyclooctene, it is believed that it can be converted to the E-cyclooctene analogue.

[0402] [ka]

[0403] In preferred embodiments, the compound of formula (1) satisfies any one of the following structures:

[0404] [ka]

[0405] [ka]

[0406] [ka]

[0407] In a preferred embodiment, the compound of formula (1) is any one of the racemic and enantiomerically pure compounds listed below.

[0408] [ka]

[0409] where the wavy line indicates the bond to the remainder of the compound of formula (1).

[0410] Particularly preferred compounds of formula (1) are the enantiomerically pure compounds listed below.

[0411] [ka]

[0412] where the wavy line indicates the bond to the remainder of the compound of formula (1).

[0413] Other preferred compounds of formula (1) are as follows:

[0414] [ka]

[0415] In a preferred embodiment, R 48 Not L A , R 48 Not L B , label, administration agent, R 98 , and / or C C is defined herein, R32 residue or moiety C M2 , or C X to the remainder of the compound of formula (1) via 32 The residue or moiety C M2 , or C X is equal to or is included in the spacer. Those skilled in the art will appreciate that "R 32 "residue" is a conjugate, e.g., C C and the remainder of the compound according to formula (1), 32 It will be understood that the term "conjugation reaction product" refers to the conjugation reaction product of a hydroxyl group with another chemical group.

[0416] In a preferred embodiment, R 48 Not L A , R 48 Not L B , label, administration agent, R 98 , and / or C C is C as defined herein M2 is attached to the rest of the molecule via M2 is equal to or included in the spacer.

[0417] In still other preferred embodiments, R 48 Not L A , R 48 Not L B , label, administration agent, R 98 , and / or C C is C as defined herein X is attached to the rest of the molecule via X is equal to or included in the spacer.

[0418] In a preferred embodiment, moiety C X , C M2 and R 32 The above residues are R 48 Not L A , R 48 Not L B, label, administration agent, R 98 , and / or C C is included in.

[0419] C M2 In a preferred embodiment, C M2 is selected from the group consisting of amines, amides, thioamides, aminooxys, carbamates, thiocarbamates, ureas, thioureas, ethers, sulfonamides, and sulfonecarbamates. M2 is R 10 is equal to.

[0420] In a preferred embodiment, C M2 is as follows:

[0421] [ka]

[0422] where R' is R as defined herein. 37 where the dashed line is equal to R 48 Not L A , R 48 Not L B ,Label,Administered Agent,S P , L C , R 98 or C C and the wavy line indicates the bond to or towards the remainder of the dienophile. 48 Not L A , R 48 Not L B ,Label,Administered Agent,S P , L C , R 98 or C C The dashed line indicates the bond to or towards the remainder of the dienophile.

[0423] C X In a preferred embodiment, CX is as follows:

[0424] [ka]

[0425] Here, the dashed line indicates R 48 Not L A , R 48 Not L B ,Label,Administered Agent,S P , L C , R 98 or C C and the wavy line indicates the bond to or towards the remainder of the dienophile. 48 Not L A , R 48 Not L B ,Label,Administered Agent,S P , L C , R 98 or C C The dashed line indicates the bond to or towards the remainder of the dienophile.

[0426] C M2 and C X Referring to the scheme above with examples of 48 Not L A , R 48 Not L B , label, administration agent, R 98 or C C is preferably a protein, e.g., an antibody. Here, the dashed line indicates R 48 Not L A , R 48 Not L B , label, administration agent, R 98 or C C indicates a bond to or towards

[0427] Intermediates for the preparation of compounds of formula (1) Preferred intermediates for preparing the compound of formula (1) of the present invention are listed below. Particularly preferred intermediates from the list below are enantiomerically pure compounds A to F, especially A, D, E, and F. Those skilled in the art will recognize that compounds E and F still need to be isomerized to E-cyclooctene, and then the enantiomer with an axial OH can be separated from the enantiomer with an equatorial OH, as described in Rossin et al. Bioconj. Chem., 2016 27(7):1697-1706.

[0428] [ka]

[0429] A general method for synthesizing TCO triggers and corresponding compounds of formula (1) is provided immediately below. The synthetic method is as reported in Rossin et al. Nature Communications 2018, 9, 1484 and Rossin et al. Bioconj. Chem., 2016 27(7):1697-1706, except for the conversion of D-F, which is currently performed by mixing D with a hydroxide solution in methanol, followed by evaporation and reaction with iodomethane. It should be noted that for clarity, only one of the two enantiomers, E-K, is shown. Those skilled in the art will understand that established chiral resolution methods can be used to separate the enantiomers at various stages of the synthesis to obtain enantiomerically pure B, E, F, and H, e.g., as chiral salts.

[0430] [ka]

[0431] Here, the wavy line is R 48 indicates the bond to the rest of the molecule, and the dashed line indicates the bond to the rest of the molecule.

[0432] Cleavage Agent From the structure of formula (1), one or more moieties R 48 The compound used to release the cleavage agent is referred to herein as a "cleavage agent."

[0433] In a preferred embodiment, the combination of the present invention comprises a cleavage agent, provided that at least one R 48 L B When the cleavage agent is L B provided that at least one R 48 L A When the cleavage agent is L A wherein the cleavage agent is a diene.

[0434] In a preferred embodiment, the cleavage agent does not contain a label.

[0435] In a preferred embodiment, the cleavage agent does not include an administration agent.

[0436] In preferred embodiments where the primary target is an internalizing receptor and it is desired to selectively cleave the label from the administered agent in the blood rather than the primary target, the active agent is preferentially designed to be cell impermeable. In the above embodiment where the label is a chelate, the active agent can be either internalizing or non-internalizing, since the cleaved chelate cannot escape from the target cell.

[0437] In preferred embodiments where the primary target is a non-internalizing receptor and it is desired to cleave the label in the blood rather than at the primary target, the active agent is preferentially designed to have poor extravasation into tissues and be rapidly cleared, minimizing reaction at the primary target while achieving cleavage in the blood.

[0438] In a preferred embodiment, the combination of the present invention is a kit.

[0439] In some embodiments, the cleavage agent preferably comprises at least one R 48 does not contain a label L A If it is, it has a molecular weight of 150 kDa or less, more preferably 70 kDa or less, and most preferably 1 kDa or less.

[0440] In another embodiment, preferably the cleaving agent has a molecular weight of at least 300 kDa to minimize extravasation.

[0441] In a preferred embodiment, the cleavage agent is cell-impermeable to further increase selective cleavage of compounds of formula (1) present in non-target sites (eg, blood).

[0442] In a preferred embodiment, the properties of the cleaving agent (e.g., cell permeability and extravasation level) are determined by an appropriately selected R 87 This is achieved by the use of groups (see below).

[0443] Preferably, in vivo, reaction of the cleaving agent with the administered agent present in the tissue of interest results in at least a 20% reduction in radioactivity, more preferably at least a 40% reduction, more preferably at least a 60% reduction, and even more preferably at least an 80% reduction.

[0444] In a preferred embodiment, the cleavage agent is a tetrazine. Tetrazine is a diene and is highly reactive with dienophiles, particularly TCO constructs (see above). The diene of the cleavage agent is selected so that it can react with a dienophile, such as TCO, for example, via Diels-Alder cycloaddition followed by a retro-Diels-Alder reaction to give an IEDDA adduct. This intermediate adduct then releases construct-A.

[0445] In general, synthetic routes to tetrazines are readily available to those skilled in the art based on standard knowledge in the art. For example, Lions et al,J.Org.Chem.,1965,30,318-319;Horwitz et al,J.Am.Chem.Soc.,1958,80,3155-3159;Hapiot et al,New J.Chem.,2004,28,387-392,Kaim et al. al,Z.Naturforsch.,1995,50b,123-127;Yang et al.,Angew.Chem.2012,124,5312-5315;Mao et al.,Angew.Chem.Int.Ed.2019,58,1106-1109;Qu et al. al.Angew.Chem.Int.Ed.2018,57,12057-12061;Selvaraj et al.,Tetrahedron Lett. 2014, 55, 4795-4797; Fan et al., Angew. Chem. Int. Ed. 2016, 55, 14046-14050 contain references to tetrazine synthesis routes.

[0446] Preferably, the cleaving agent is a tetrazine satisfying formula (4) below, preferably a pharmaceutically acceptable salt thereof:

[0447] [ka]

[0448] wherein each moiety Q1 and Q2 is independently a hydrogen atom, -F, -Cl, -Br, -I, -OR 37 , -N(R 37 )2, -SO3, -PO3 - 、 -NO2, -CF3, -SR 37 , S(=O)2N(R 37 )2, OC(=O)R 37 , SC(=O)R 37 , OC(=S)R 37 , SC(=S)R 37 , N.R. 37 C(=O)-R 37 , N.R. 37C(=S)-R 37 , N.R. 37 C(=O)OR 37 , N.R. 37 C(=S)OR 37 , N.R. 37 C(=O)SR 37 , N.R. 37 C(=S)SR 37 , OC(=O)N(R 37 )2, SC(=O)N(R 37 )2, OC(=S)N(R 37 )2, SC(=S)N(R 37 )2, NR 37 C(=O)N(R 37 )2, NR 37 C(=S)N(R 37 )2, C(=O)R 37、 C(=S)R 37、 C(=O)N(R 37 )2, C(=S)N(R 37 )2, C(=O)OR 37 , C(=O)SR 37 , C(=S)OR 37 , C(=S)SR 37 , S(O)R 37 , -S(O)2R 37 , N.R. 37 S(O)2R 37 , -ON(R 37 ) 2、- NR 37 OR 37 , alkyl groups, alkenyl groups, alkynyl groups, aryl groups, heteroaryl groups, cycloalkyl groups, cycloalkenyl groups, cycloalkynyl groups, (cyclo)alkyl(hetero)aryl groups, (hetero)aryl(cyclo)alkyl, (cyclo)alkenyl(hetero)aryl groups, (hetero)aryl(cyclo)alkenyl groups, (cyclo)alkynyl(hetero)aryl groups, (hetero)aryl(cyclo)alkynyl groups, alkylcycloalkyl groups, and cycloalkylalkyl groups.

[0449] In formula (4), H, -F, -Cl, -Br, -I, -OH, -NH2, -SO3, -PO3 - 、Q1 and Q2 groups other than -NO2 and -CF3 are -Cl, -F, -Br, -I, -OR 37 , -N(R 37 )2, -SO3R 37 , -PO3(R 37 ) 2、 -PO4(R 37 ) 2、 -NO2, -CF3, =O, =NR 37 , and -SR 37 and optionally substituted with a moiety selected from the group consisting of O, S, NR 37 , P, and Si, wherein the N, S, and P atoms are optionally oxidized, and wherein multiple N atoms are optionally quaternized.

[0450] In formula (4), the Q1 and Q2 groups are selected from the group consisting of polymers, particles, peptides, peptoids, dendrimers, proteins, aptamers, carbohydrates, oligonucleotides, oligosaccharides, lipids, steroids, liposomes, micelles, targeting agents, and the like. T , -(S P ) D -R 87 , an albumin binding moiety, and a chelating moiety; where D is 0 or 1.

[0451] In formula (4), preferably, at least one of the moieties Q1 and Q2 is not a hydrogen atom.

[0452] In formula (4), preferably, each moiety Q1 and Q2 independently represents a hydrogen atom, -F, -Cl, -Br, -I, -OR 37 , -N(R 37 )2, -SO3, -PO3 - 、 -NO2, -CF3, -SR 37 , S(=O)2N(R 37 )2, OC(=O)R 37 , SC(=O)R 37 , OC(=S)R 37 , SC(=S)R 37 , N.R. 37 C(=O)-R37 , N.R. 37 C(=S)-R 37 , N.R. 37 C(=O)OR 37 , N.R. 37 C(=S)OR 37 , N.R. 37 C(=O)SR 37 , N.R. 37 C(=S)SR 37 , OC(=O)N(R 37 )2, SC(=O)N(R 37 )2, OC(=S)N(R 37 )2, SC(=S)N(R 37 )2, NR 37 C(=O)N(R 37 )2, NR 37 C(=S)N(R 37 )2, C(=O)R 37、 C(=S)R 37、 C(=O)N(R 37 )2, C(=S)N(R 37 )2, C(=O)OR 37 , C(=O)SR 37 , C(=S)OR 37 , C(=S)SR 37 , S(O)R 37 , -S(O)2R 37 , N.R. 37 S(O)2R 37 , -ON(R 37 ) 2、- NR 37 OR 37 , C1~C 24 Alkyl groups, C2-C 24 Alkenyl groups, C2-C 24 Alkynyl groups, C6-C 24 Aryl groups, C2-C 24 Heteroaryl groups, C3-C 24 Cycloalkyl groups, C5-C 24 Cycloalkenyl group, C 12 ~C 24 Cycloalkynyl group, C3-C 24 (Cyclo)alkyl(hetero)aryl groups, C3-C 24 (Hetero)aryl(cyclo)alkyl, C4-C 24(Cyclo)alkenyl(hetero)aryl group, C4-C 24 (Hetero)aryl(cyclo)alkenyl groups, C4-C 24 (Cyclo)alkynyl(hetero)aryl group, C4-C 24 (Hetero)aryl(cyclo)alkynyl group, C4-C 24 Alkylcycloalkyl groups and C4-C 24 cycloalkylalkyl groups.

[0453] In a preferred embodiment, the Q1 and Q2 groups that are not hydrogen atoms are unsubstituted.

[0454] In a preferred embodiment, Q1 and Q2 in formula (4) are each independently a hydrogen atom, -F, -Cl, -Br, -I, -OR 37 , -N(R 37 )2, -SO3, -PO3 - 、 -NO2, -CF3, -SR 37 , S(=O)2N(R 37 )2, OC(=O)R 37 , SC(=O)R 37 , OC(=S)R 37 , SC(=S)R 37 , N.R. 37 C(=O)-R 37 , N.R. 37 C(=S)-R 37 , N.R. 37 C(=O)OR 37 , N.R. 37 C(=S)OR 37 , N.R. 37 C(=O)SR 37 , N.R. 37 C(=S)SR 37 , OC(=O)N(R 37 )2, SC(=O)N(R 37 )2, OC(=S)N(R 37 )2, SC(=S)N(R 37 )2, NR 37 C(=O)N(R 37 )2, NR 37 C(=S)N(R 37 )2, C(=O)R37、 C(=S)R 37、 C(=O)N(R 37 )2, C(=S)N(R 37 )2, C(=O)OR 37 , C(=O)SR 37 , C(=S)OR 37 , C(=S)SR 37 , S(O)R 37 , -S(O)2R 37 , N.R. 37 S(O)2R 37 , -ON(R 37 )2, - NR 37 OR 37 , C1-C8 alkyl group, C2-C8 alkenyl group, C2-C8 alkynyl group, C6-C 12 Aryl groups, C2-C 12 Heteroaryl group, C3-C8 cycloalkyl group, C5-C8 cycloalkenyl group, C3-C 12 Alkyl(hetero)aryl groups, C3-C 12 (Hetero)arylalkyl groups, C4-C 12 Alkylcycloalkyl groups, C4-C 12 Cycloalkylalkyl groups, C5-C 12 Cycloalkyl(hetero)aryl groups and C5-C 12 (hetero)arylcycloalkyl groups.

[0455] In a preferred embodiment, Q1 and Q2 in formula (4) are each independently a hydrogen atom, -F, -Cl, -Br, -I, -OR 37 , -N(R 37 )2, -SO3, -PO3 - 、 -NO2, -CF3, -SR 37 , S(=O)2N(R 37 )2, OC(=O)R 37 , SC(=O)R 37 , OC(=S)R 37 , SC(=S)R 37 , N.R. 37 C(=O)-R 37 , N.R. 37 C(=S)-R 37 , N.R.37 C(=O)OR 37 , N.R. 37 C(=S)OR 37 , N.R. 37 C(=O)SR 37 , N.R. 37 C(=S)SR 37 , OC(=O)N(R 37 )2, SC(=O)N(R 37 )2, OC(=S)N(R 37 )2, SC(=S)N(R 37 )2, NR 37 C(=O)N(R 37 )2, NR 37 C(=S)N(R 37 )2, C(=O)R 37、 C(=S)R 37、 C(=O)N(R 37 )2, C(=S)N(R 37 )2, C(=O)OR 37 , C(=O)SR 37 , C(=S)OR 37 , C(=S)SR 37 , S(O)R 37 , -S(O)2R 37 , N.R. 37 S(O)2R 37 , -ON(R 37 ) 2、- NR 37 OR 37 , C1-C4 alkyl group, C2-C4 alkenyl group, C2-C4 alkynyl group, C6-C8 aryl group, C2-C8 heteroaryl group, C3-C6 cycloalkyl group, C5-C6 cycloalkenyl group, C3-C 10 Alkyl(hetero)aryl groups, C3-C 10 (Hetero)arylalkyl groups, C4-C 10 Alkylcycloalkyl groups, C4-C 10 Cycloalkylalkyl groups, C5-C 10 Cycloalkyl(hetero)aryl groups and C5-C 10 (hetero)arylcycloalkyl groups.

[0456] In a preferred embodiment, Q1 and Q2 in formula (4) are selected from the group consisting of a hydrogen atom, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2,6-pyrimidyl, 2,5-pyrimidyl, 3,5-pyrimidyl, and 2,4-pyrimidyl; and Q1 and Q2 that are not hydrogen atoms are selected from the group consisting of -F, -Cl, -Br, -I, -OR 37 , -N(R 37 )2, -SO3, -PO3 - 、 -NO2, -CF3, -SR 37 , S(=O)2N(R 37 )2, OC(=O)R 37 , SC(=O)R 37 , OC(=S)R 37 , SC(=S)R 37 , N.R. 37 C(=O)-R 37 , N.R. 37 C(=S)-R 37 , N.R. 37 C(=O)OR 37 , N.R. 37 C(=S)OR 37 , N.R. 37 C(=O)SR 37 , N.R. 37 C(=S)SR 37 , OC(=O)N(R 37 )2, SC(=O)N(R 37 )2, OC(=S)N(R 37 )2, SC(=S)N(R 37 )2, NR 37 C(=O)N(R 37 )2, NR 37 C(=S)N(R 37 )2, C(=O)R 37、 C(=S)R 37、 C(=O)N(R 37 )2, C(=S)N(R 37 )2, C(=O)OR 37 , C(=O)SR 37 , C(=S)OR 37 , C(=S)SR 37 , S(O)R 37 , -S(O)2R 37 , N.R. 37 S(O)2R 37, -ON(R 37 ) 2、- NR 37 OR 37 , C1~C 24 Alkyl groups, C2-C 24 Alkenyl groups, C2-C 24 Alkynyl groups, C6-C 24 Aryl groups, C2-C 24 Heteroaryl groups, C3-C 24 Cycloalkyl groups, C5-C 24 Cycloalkenyl group, C 12 ~C 24 Cycloalkynyl group, C3-C 24 (Cyclo)alkyl(hetero)aryl groups, C3-C 24 (Hetero)aryl(cyclo)alkyl, C4-C 24 (Cyclo)alkenyl(hetero)aryl group, C4-C 24 (Hetero)aryl(cyclo)alkenyl groups, C4-C 24 (Cyclo)alkynyl(hetero)aryl group, C4-C 24 (Hetero)aryl(cyclo)alkynyl group, C4-C 24 Alkylcycloalkyl groups and C4-C 24 A moiety selected from the group consisting of cycloalkylalkyl groups, preferably -F, -Cl, -Br, -I, -OR 37 , -N(R 37 )2, -SO3, -PO3 - 、 -NO2, -CF3, -SR 37 , S(=O)2N(R 37 )2, OC(=O)R 37 , SC(=O)R 37 , OC(=S)R 37 , SC(=S)R 37 , N.R. 37 C(=O)-R 37 , N.R. 37 C(=S)-R 37 , N.R. 37 C(=O)OR 37 , N.R. 37 C(=S)OR 37 , N.R. 37 C(=O)SR 37 , N.R.37 C(=S)SR 37 , OC(=O)N(R 37 )2, SC(=O)N(R 37 )2, OC(=S)N(R 37 )2, SC(=S)N(R 37 )2, NR 37 C(=O)N(R 37 )2, NR 37 C(=S)N(R 37 )2, C(=O)R 37、 C(=S)R 37、 C(=O)N(R 37 )2, C(=S)N(R 37 )2, C(=O)OR 37 , C(=O)SR 37 , C(=S)OR 37 , C(=S)SR 37 , S(O)R 37 , -S(O)2R 37 , N.R. 37 S(O)2R 37 , -ON(R 37 ) 2、- NR 37 OR 37 , C1-C8 alkyl group, C2-C8 alkenyl group, C2-C8 alkynyl group, C6-C 12 Aryl groups, C2-C 12 Heteroaryl group, C3-C8 cycloalkyl group, C5-C8 cycloalkenyl group, C3-C 12 Alkyl(hetero)aryl groups, C3-C 12 (Hetero)arylalkyl groups, C4-C 12 Alkylcycloalkyl groups, C4-C 12 Cycloalkylalkyl groups, C5-C 12 Cycloalkyl(hetero)aryl groups and C5-C 12 A moiety selected from the group consisting of (hetero)arylcycloalkyl groups, more preferably -F, -Cl, -Br, -I, -OR 37 , -N(R 37 )2, -SO3, -PO3 - 、 -NO2, -CF3, -SR 37 , S(=O)2N(R 37 )2, OC(=O)R37 , SC(=O)R 37 , OC(=S)R 37 , SC(=S)R 37 , N.R. 37 C(=O)-R 37 , N.R. 37 C(=S)-R 37 , N.R. 37 C(=O)OR 37 , N.R. 37 C(=S)OR 37 , N.R. 37 C(=O)SR 37 , N.R. 37 C(=S)SR 37 , OC(=O)N(R 37 )2, SC(=O)N(R 37 )2, OC(=S)N(R 37 )2, SC(=S)N(R 37 )2, NR 37 C(=O)N(R 37 )2, NR 37 C(=S)N(R 37 )2, C(=O)R 37、 C(=S)R 37、 C(=O)N(R 37 )2, C(=S)N(R 37 )2, C(=O)OR 37 , C(=O)SR 37 , C(=S)OR 37 , C(=S)SR 37 , S(O)R 37 , -S(O)2R 37 , N.R. 37 S(O)2R 37 , -ON(R 37 ) 2、- NR 37 OR 37 , C1-C4 alkyl group, C2-C4 alkenyl group, C2-C4 alkynyl group, C6-C8 aryl group, C2-C8 heteroaryl group, C3-C6 cycloalkyl group, C5-C6 cycloalkenyl group, C3-C 10 Alkyl(hetero)aryl groups, C3-C 10 (Hetero)arylalkyl groups, C4-C 10 Alkylcycloalkyl groups, C4-C 10Cycloalkylalkyl groups, C5-C 10 Cycloalkyl(hetero)aryl groups and C5-C 10 It may be optionally substituted with a moiety selected from the group consisting of (hetero)arylcycloalkyl groups.

[0457] In a preferred embodiment, in formula (4), (a) Q1 and Q2 are selected from the group consisting of 2-pyridyl, 3-pyridyl, and 4-pyridyl; (b) Q1 is selected from the group consisting of 2,6-pyrimidyl, 2,5-pyrimidyl, 3,5-pyrimidyl, and 2,4-pyrimidyl; and Q2 is (hetero)alkyl; or (c) Q1 is phenyl and Q2 is a hydrogen atom; (d) Q1 is alkyl and Q2 is alkyl; (e) Q1 is phenyl and Q2 is alkyl; (f) Q1 is phenyl and Q2 is phenyl; and In (a) to (f), all Q1 and Q2 that are not hydrogen atoms may be substituted as defined in the previous paragraph.

[0458] In a preferred embodiment, in formula (4), the alkyl is C1 to C 24 Alkyl groups, preferably C1-C 12 It is an alkyl group, more preferably a C1 to C6 (hetero)alkyl group.

[0459] In a preferred embodiment, in formula (4), the (hetero)aryl is C6-C 24 Aryl group, preferably C6-C 12 Aryl, more preferably phenyl.

[0460] In a preferred embodiment, in formula (4), the (hetero)aryl is C2-C 24 Heteroaryl, preferably C2-C 12 Heteroaryl, more preferably C2 to C5 heteroaryl.

[0461] In a preferred embodiment, in formula (4), the alkenyl is C2 to C 24 Alkenyl, preferably C2-C 12 Alkenyl, more preferably C2 to C6 alkenyl.

[0462] In a preferred embodiment, in formula (4), the alkynyl is C2-C 24 Alkynyl, preferably C2-C 12 Alkynyl, more preferably C2 to C6 alkynyl.

[0463] In a preferred embodiment, in formula (4), the cycloalkyl is C3 to C 24 Cycloalkyl, preferably C3-C 12 It is cycloalkyl, more preferably C3 to C6 cycloalkyl.

[0464] In a preferred embodiment, in formula (4), the cycloalkenyl is C5 to C 24 Cycloalkenyl group, preferably C5-C 12 It is cycloalkenyl, more preferably C5 to C6 cycloalkenyl.

[0465] In a preferred embodiment, in formula (4), the cycloalkynyl is C6-C 24 Cycloalkynyl, preferably C8-C 12 It is preferably a cycloalkynyl, more preferably a C8 cycloalkyl.

[0466] In a preferred embodiment, the cleaving agent can be a multimeric compound containing multiple dienes, as defined herein, including, but not limited to, biomolecules, proteins, peptides, peptoids, polymers, dendrimers, liposomes, micelles, particles, gels, polymeric particles, or other polymeric constructs.

[0467] Preferred tetrazines Formula (4a) Preferred tetrazines are those according to formula (4) below, preferably pharmaceutically acceptable salts thereof:

[0468] [ka]

[0469] wherein each moiety Q1 and Q2 is independently selected from the group consisting of a hydrogen atom and a moiety according to formula (5):

[0470] [ka]

[0471] where the dashed line indicates the bond to the rest of the molecule, where R 10 , R 11 , and R 12 is as defined herein.

[0472] As understood herein, with respect to formula (5), the dashed line may indicate a bond to the tetrazine group of (4a), another moiety according to formula (5), or the remainder of a compound according to formulas (6) through (13), as defined below.

[0473] In a preferred embodiment, each f in formula (5) is an integer independently selected from the range of 0 to 24, preferably from the range of 1 to 12, more preferably from the range of 2 to 6, and even more preferably from 1 to 3. In a preferred embodiment, f is 1. In another preferred embodiment, f is an integer in the range of 12 to 24.

[0474] In a preferred embodiment, in formula (5), g is an integer in the range of 0 to 12, preferably in the range of 1 to 6, and more preferably in the range of 2 to 4.

[0475] In a preferred embodiment, in formula (5), each h is independently 0 or 1. In a preferred embodiment, g is 0 and f is 1. In a preferred embodiment, g is 1 and f is 1.

[0476] When a compound according to the invention contains multiple moieties satisfying formula (5), each g, h, and f is independently selected.

[0477] In preferred embodiments, the moiety according to formula (5) may be substituted with other moieties independently selected from the moieties according to formula (5). In preferred embodiments, the moiety according to formula (5) may be unsubstituted with other moieties independently selected from the moieties according to formula (5). In preferred embodiments, the moiety according to formula (5) is selected from R, as further defined below. 87 is.

[0478] In a preferred embodiment, the moiety according to formula (5) is R M Fill the molecule from the group.

[0479] It is preferred that at least one of the moieties Q1 and Q2 in formula (4a) is not a hydrogen atom.

[0480] In a preferred embodiment, Q1 in formula (4a) is a C6-C 24 Aryl and C2-C 24 heteroaryl and optionally further substituted with a moiety according to formula (5), preferably with no more than two, more preferably no more than one moiety according to formula (5).

[0481] In a preferred embodiment, Q1 in formula (4a) is a C6-C 24 Aryl and C2-C 24 heteroaryl and optionally further substituted with a moiety according to formula (5), preferably with up to two, more preferably up to one moiety according to formula (5), and Q2 in formula (4a) is selected from the group consisting of C6-C 24 Aryl and C2-C24 heteroaryl and optionally further substituted with a moiety according to formula (5), preferably with no more than two, more preferably no more than one moiety according to formula (5).

[0482] In a preferred embodiment, Q1 in formula (4a) is selected from the group consisting of C6 aryl and C3-C5 heteroaryl, and is optionally further substituted with at least one moiety according to formula (5), preferably with up to two, more preferably up to one moiety according to formula (5). Preferred heteroaryls herein are 2-pyridyl, 3-pyridyl, 4-pyridyl, 2,6-pyrimidyl, 3,5-pyrimidyl, 2,5-pyrimidyl, 2,4-pyrimidyl, 2,4-imidazyl, 2,5-imidazyl, phenyl, 2,3-pyrazyl, 3,4-pyrazyl, pyrazyl, isoxazole, thiazole, oxazoline, 2-pyrryl, 3-pyrryl, 2-thiophene, and 3-thiophene.

[0483] In a preferred embodiment, Q1 in formula (4a) is a C3-C5 heteroaryl and is optionally further substituted with at least one moiety according to formula (5), preferably with up to two, more preferably up to one moiety according to formula (5), and Q2 is a C3-C5 heteroaryl and is optionally further substituted with a moiety according to formula (5), preferably with up to two, more preferably up to one moiety according to formula (5). Preferred heteroaryls herein are 2-pyridyl, 3-pyridyl, 4-pyridyl, 2,6-pyrimidyl, 3,5-pyrimidyl, 2,5-pyrimidyl, 2,4-pyrimidyl, 2,4-imidazyl, 2,5-imidazyl, phenyl, 2,3-pyrazyl, 3,4-pyrazyl, pyrazyl, isoxazole, thiazole, oxazoline, 2-pyrryl, 3-pyrryl, 2-thiophene, and 3-thiophene.

[0484] In a preferred embodiment, Q1 in formula (4a) is C3-C5 heteroaryl and is optionally further substituted with at least one moiety according to formula (5), preferably no more than two, more preferably no more than one moiety according to formula (5), and Q2 is -H.

[0485] In a preferred embodiment, Q1 in formula (4a) is a phenyl ring and is optionally further substituted with at least one moiety according to formula (5), preferably no more than two, more preferably no more than one moiety according to formula (5), and Q2 is -H.

[0486] In a preferred embodiment, Q1 in formula (4a) is a phenyl ring and is optionally further substituted with at least one moiety according to formula (5), preferably with no more than two, more preferably no more than one moiety according to formula (5), and Q2 is a phenyl ring and is optionally further substituted with at least one moiety according to formula (5), preferably with no more than two, more preferably no more than one moiety according to formula (5).

[0487] In a preferred embodiment, Q1 in formula (4a) is a phenyl ring and is optionally further substituted with at least one moiety according to formula (5), preferably no more than two, more preferably no more than one moiety according to formula (5), and Q2 is selected from the group consisting of C6 aryl and C 3~5 heteroaryl, and optionally further substituted with at least one moiety according to formula (5), preferably no more than two, more preferably no more than one moiety according to formula (5).

[0488] In a preferred embodiment, Q1 in formula (4a) is C1 to C 12 alkyl and optionally further substituted with at least one moiety according to formula (5), preferably no more than two, more preferably no more than one moiety according to formula (5), and Q2 is C aryl and C 3~5heteroaryl, and optionally further substituted with at least one moiety according to formula (5), preferably no more than two, more preferably no more than one moiety according to formula (5).

[0489] In a preferred embodiment, Q1 in formula (4a) is C1 to C 12 alkyl and optionally further substituted with at least one moiety according to formula (5), preferably no more than two, more preferably no more than one moiety according to formula (5), and Q2 in formula (4a) is C1-C 12 It is alkyl and may be further substituted with at least one moiety according to formula (5), preferably with no more than two, more preferably no more than one moiety according to formula (5).

[0490] In a preferred embodiment, Q2 is equal to Q1.

[0491] R 10 In a preferred embodiment, each R 10are independently -O-, -S-, -SS-, -NR4-, -N=N-, -C(O)-, -C(O)NR4-, -OC(O)-, -C(O)O-, -OC(O)O-, -OC(O)NR4-, -NR4C(O)-, -NR4C(O)O-, -NR4C(O)NR4-, -SC(O)-, -C(O)S-, -SC(O)O-, -OC(O)S-, -SC(O)NR4-, -NR4C(O)S-, -S(O)-, -S(O)2-, -OS(O)2-, - S(O2)O-, -OS(O)2O-, -OS(O)2NR4-, -NR4S(O)2O-, -C(O)NR4S(O)2NR4-, -OC(O)NR4S(O)2NR4-, -OS(O)-, -OS(O)O-, -OS (O)NR4-, -ONR4C(O)-, -ONR4C(O)O-, -ONR4C(O)NR4-, -NR4OC(O)-, -NR4OC(O)O-, -NR4OC(O)NR4-, -ONR4C(S)-, -ONR4C( S)O-, -ONR4C(S)NR4-, -NR4OC(S)-, -NR4OC(S)O-, -NR4OC(S)NR4-, -OC(S)-, -C(S)O-, -OC(S)O-, -OC(S)NR4-, -NR4C(S )-, -NR4C(S)O-, -SS(O)2-, -S(O)2S-, -OS(O2)S-, -SS(O)2O-, -NR4OS(O)-, -NR4OS(O)O-, -NR4OS(O)NR4-, -NR4OS(O)2- , -NR4OS(O)2O-, -NR4OS(O)2NR4-, -ONR4S(O)-, -ONR4S(O)O-, -ONR4S(O)NR4-, -ONR4S(O)2O-, -ONR4S(O)2NR4-, -ONR4S(O)2-, -OP(O)(R4)2-, -SP(O)(R4)2-, -NR4P(O)(R4)2-, and combinations thereof, wherein R4 is defined as described herein.

[0492] In a preferred embodiment, each R 10are independently -O-, -S-, -SS-, -NR4-, -N=N-, -C(O)-, -C(O)NR4-, -OC(O)-, -C(O)O-, -OC(O)NR4-, -NR4C(O)-, -NR4C(O)O-, -NR4C(O)NR4-, -SC(O)-, -C(O)S-, -SC(O)O-, -OC(O)S-, -SC(O )NR—, —NRC(O)S—, —S(O)—, —S(O)—, —C(O)NRS(O)NR—, —OC(O)NRS(O)NR—, —OC(S)—, —C(S)O—, —OC(S)NR—, —NRC(S)—, —NRC(S)O—, and —SS(O)—.

[0493] R 11 In a preferred embodiment, each R 11 are independent, C1~C 24 Alkylene group, C2-C 24 Alkenylene group, C2-C 24 Alkynylene group, C6-C 24 Arylene, C2-C 24 Heteroarylene, C3-C 24 Cycloalkylene group, C5-C 24 Cycloalkenylene group, and C 12 ~C 24 cycloalkynylene groups, which are selected from the group consisting of -Cl, -F, -Br, -I, -OH, -NH2, -SO3H, -PO3H 、 -PO4H2, -NO2, -CF3, =O, =NR 36 , -SR 36 , C1~C 24 Alkyl groups, C2-C 24 Alkenyl groups, C2-C 24 Alkynyl groups, C6-C 24 Aryl groups, C2-C 24 Heteroaryl groups, C3-C 24 Cycloalkyl groups, C5-C 24 Cycloalkenyl group, C 12 ~C 24 Cycloalkynyl group, C3-C 24 Alkyl(hetero)aryl groups, C3-C24 (Hetero)arylalkyl groups, C4-C 24 (Hetero)arylalkenyl groups, C4-C 24 (Hetero)arylalkynyl group, C4-C 24 Alkenyl(hetero)aryl groups, C4-C 24 Alkynyl(hetero)aryl groups, C4-C 24 Alkylcycloalkyl groups, C6-C 24 Alkylcycloalkenyl group, C 13 ~C 24 Alkylcycloalkynyl group, C4-C 24 Cycloalkylalkyl groups, C6-C 24 Cycloalkenylalkyl groups, C 13 ~C 24 Cycloalkynylalkyl groups, C5-C 24 Alkenylcycloalkyl groups, C7-C 24 Alkenylcycloalkenyl group, C 14 ~C 24 Alkenylcycloalkynyl group, C5-C 24 Cycloalkylalkenyl group, C7-C 24 Cycloalkenyl alkenyl group, C 14 ~C 24 Cycloalkynylalkenyl group, C5-C 24 Alkynylcycloalkyl groups, C7-C 24 Alkynylcycloalkenyl group, C 14 ~C 24 Alkynylcycloalkynyl group, C5-C 24 Cycloalkylalkynyl group, C7-C 24 Cycloalkenylalkynyl group, C 14 ~C 24 Cycloalkynylalkynyl group, C5-C 24 Cycloalkyl(hetero)aryl groups, C7-C 24 Cycloalkenyl(hetero)aryl group, C 14 ~C 24 Cycloalkynyl(hetero)aryl groups, C5-C 24 (Hetero)arylcycloalkyl groups, C7-C 24 (Hetero)arylcycloalkenyl groups, and C 14~C 24 (hetero)arylcycloalkynyl groups, wherein the substituents are O, S, NR 36 , P, and Si, wherein the N, S, and P atoms are optionally oxidized, and wherein multiple N atoms are optionally quaternized; and Preferably, the alkylene group, alkenylene group, alkynylene group, cycloalkylene group, cycloalkenylene group, and cycloalkynylene group are each independently selected from the group consisting of O, S, NR 36 , P, and Si, wherein the N, S, and P atoms are optionally oxidized, and wherein multiple N atoms are optionally quaternized.

[0494] In a preferred embodiment, each R 11 are independent, C1~C 12 Alkylene group, C2-C 12 Alkenylene group, C2-C 12 Alkynylene group, C6-C 12 Arylene, C2-C 12 Heteroarylene, C3-C 12 Cycloalkylene group, C5-C 12 Cycloalkenylene group, and C 12 cycloalkynylene groups; and Preferably, the alkylene group, alkenylene group, alkynylene group, cycloalkylene group, cycloalkenylene group, and cycloalkynylene group are each independently selected from the group consisting of O, S, NR 36 , P, and Si, wherein the N, S, and P atoms are optionally oxidized, and wherein multiple N atoms are optionally quaternized.

[0495] In a preferred embodiment, each R 11are independently selected from the group consisting of a C1-C6 alkylene group, a C2-C6 alkenylene group, a C2-C6 alkynylene group, a C6-C6 arylene, a C2-C6 heteroarylene, a C3-C6 cycloalkylene group, and a C5-C6 cycloalkenylene group; and wherein the above alkylene group, alkenylene group, alkynylene group, cycloalkylene group, cycloalkenylene group, and cycloalkynylene group are preferably selected from the group consisting of O, S, NR 36 , P, and Si, wherein the N, S, and P atoms are optionally oxidized, and wherein multiple N atoms are optionally quaternized.

[0496] In a preferred embodiment, R 11 Groups include -Cl, -F, -Br, -I, -OH, -NH2, -SO3H, and -PO3H 、 -PO4H2, -NO2, -CF3, =O, =NR 36 , -SR 36 , C1~C 12 Alkyl groups, C2-C 12 Alkenyl groups, C2-C 12 Alkynyl groups, C6-C 12 Aryl groups, C2-C 12 Heteroaryl groups, C3-C 12 Cycloalkyl groups, C5-C 12 Cycloalkenyl group, C 12 Cycloalkynyl group, C3-C 12 Alkyl(hetero)aryl groups, C3-C 12 (Hetero)arylalkyl groups, C4-C 12 (Hetero)arylalkenyl groups, C4-C 12 (Hetero)arylalkynyl group, C4-C 12 Alkenyl(hetero)aryl groups, C4-C 12 Alkynyl(hetero)aryl groups, C4-C 12 Alkylcycloalkyl groups, C6-C 12 Alkylcycloalkenyl group, C 13 ~C 18 Alkylcycloalkynyl group, C4-C 12 Cycloalkylalkyl groups, C6-C12 Cycloalkenylalkyl groups, C 13 ~C 18 Cycloalkynylalkyl groups, C5-C 12 Alkenylcycloalkyl groups, C7-C 12 Alkenylcycloalkenyl group, C 14 ~C 16 Alkenylcycloalkynyl group, C5-C 12 Cycloalkylalkenyl group, C7-C 12 Cycloalkenyl alkenyl group, C 14 ~C 16 Cycloalkynylalkenyl group, C5-C 12 Alkynylcycloalkyl groups, C7-C 12 Alkynylcycloalkenyl group, C 14 ~C 16 Alkynylcycloalkynyl group, C5-C 12 Cycloalkylalkynyl group, C7-C 12 Cycloalkenylalkynyl group, C 14 ~C 16 Cycloalkynylalkynyl group, C5-C 12 Cycloalkyl(hetero)aryl groups, C7-C 12 Cycloalkenyl(hetero)aryl group, C 14 ~C 16 Cycloalkynyl(hetero)aryl groups, C5-C 12 (Hetero)arylcycloalkyl groups, C7-C 12 (Hetero)arylcycloalkenyl groups, and C 14 ~C 16 (hetero)arylcycloalkynyl groups, wherein the substituents are O, S, NR 36 , P, and Si, wherein the N, S, and P atoms are optionally oxidized, and wherein multiple N atoms are optionally quaternized.

[0497] In a preferred embodiment, R 11 Groups include -Cl, -F, -Br, -I, -OH, -NH2, -SO3H, and -PO3H 、-PO4H2, -NO2, -CF3, =O, =NR 36 , -SR 36 , C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C6 aryl group, C2-C6 heteroaryl group, C3-C6 cycloalkyl group, C5-C6 cycloalkenyl group, C3-C6 alkyl(hetero)aryl group, C3-C6 (hetero)arylalkyl group, C4-C6 (hetero)arylalkenyl group, C4-C6 (hetero)arylalkynyl group, C4-C6 alkenyl(hetero)aryl group, C4-C6 alkynyl(hetero)aryl group, C4-C6 alkylcycloalkyl group, C6 alkylcycloalkenyl group, C4-C and C5-C6 cycloalkylalkyl group, C6 cycloalkenylalkyl group, C5-C6 alkenylcycloalkyl group, C7 alkenylcycloalkenyl group, C5-C6 cycloalkylalkenyl group, C7 cycloalkenylalkenyl group, C5-C6 alkynylcycloalkyl group, C7 alkynylcycloalkenyl group, C5-C6 cycloalkylalkynyl group, C5-C6 cycloalkyl(hetero)aryl group, and C5-C6 (hetero)arylcycloalkyl group, wherein the substituents are selected from O, S, NR 36 , P, and Si, wherein the N, S, and P atoms are optionally oxidized, and wherein multiple N atoms are optionally quaternized.

[0498] In a preferred embodiment, R 11 Groups include -Cl, -F, -Br, -I, -OH, -NH2, -SO3H, and -PO3H 、 -PO4H2, -NO2, -CF3, =O, =NR 36 , -SR 36, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C6 aryl group, C2-C6 heteroaryl group, C3-C6 cycloalkyl group, C5-C6 cycloalkenyl group, C3-C7 alkyl(hetero)aryl group, C3-C7 (hetero)arylalkyl group, C4-C8 (hetero)arylalkenyl group, C4-C8 (hetero)arylalkynyl group, C4-C8 alkenyl(hetero)aryl group, C4-C8 alkynyl(hetero)aryl group, C4-C6 alkylcycloalkyl group, C6-C7 alkylcycloalkenyl group, C4-C6 cyclo and optionally further substituted with one or more substituents selected from alkylalkyl groups, C6-C7 cycloalkenylalkyl groups, C5-C6 alkenylcycloalkyl groups, C7-C8 alkenylcycloalkenyl groups, C5-C6 cycloalkylalkenyl groups, C7-C8 cycloalkenylalkenyl groups, C5-C6 alkynylcycloalkyl groups, C7-C8 alkynylcycloalkenyl groups, C5-C6 cycloalkylalkynyl groups, C5-C9 cycloalkyl(hetero)aryl groups, and C5-C6 (hetero)arylcycloalkyl groups, wherein the substituents are O, S, NR 36 , P, and Si, wherein the N, S, and P atoms are optionally oxidized, and wherein multiple N atoms are optionally quaternized.

[0499] If f>2, R 11 are preferably independently selected from the group consisting of a C1-C6 alkylene group, a C2-C6 alkenylene group, a C2-C6 alkynylene group, a C6-C6 arylene, a C2-C6 heteroarylene, a C3-C6 cycloalkylene group, and a C5-C6 cycloalkenylene group, and wherein the alkylene group, alkenylene group, alkynylene group, cycloalkylene group, cycloalkenylene group, and cycloalkynylene group are preferably selected from the group consisting of O, S, NR 36 , P, and Si, wherein the N, S, and P atoms are optionally oxidized, and wherein multiple N atoms are optionally quaternized.

[0500] In a preferred embodiment, R 11 The substituents do not contain heteroatoms. In a preferred embodiment, R 11 The group is unsubstituted. In another preferred embodiment, R 11 The group does not contain heteroatoms.

[0501] R 12 R 12 -H, -OH, -NH2, -N3, -Cl, -Br, -F, -I, polymers, particles, peptides, peptoids, dendrimers, proteins, biomolecules, carbohydrates, oligonucleotides, oligosaccharides, lipids, liposomes, micelles, imaging moieties, targeting agents T , R 87 , an albumin binding moiety, and a chelating moiety.

[0502] R 12 Non-limiting examples of chelating moieties for use in the method are DTPA (diethylenetriaminepentaacetic acid), DOTA (1,4,7,10-tetraazacyclododecane-N,N',N",N"-tetraacetic acid), NOTA (1,4,7-triazacyclononane-N,N',N"-triacetic acid), TETA (1,4,8,11-tetraazacyclotetradecane-N,N',N",N'-tetraacetic acid), OTTA (N1-(p-isothiocyanatobenzyl)-diethylenetriamine-N1,N2,N3,N3-tetraacetic acid), deferoxamine, or DFO (N'-[5-[[4-[[5-(acetylhydroxyamino)pentyl]amino]-1,4-dioxobutyl]hydroxyamino]pentyl]-N-(5-aminopentyl)-N-hydroxybutanediamide), or HYNIC (hydrazinonicotinamide).

[0503] In a preferred embodiment, R 12 Polymers, particles, peptides, peptoids, dendrimers, proteins, biomolecules, oligonucleotides, oligosaccharides, lipids, liposomes, micelles, targeting agents T , or R 87When f is 2 or less, or preferably 1 or less.

[0504] Equation (6), Equation (7), Equation (8), Equation (9), Equation (10), Equation (11), Equation (12), and Equation (13) In a preferred embodiment of the present invention, the tetrazine is according to any one of the following formulas (6), (7), (8), (9), (10), (11), (12), or (13):

[0505] [ka]

[0506] wherein each moiety Q, Q1, Q2, Q3, and Q4 is independently selected from the group consisting of a hydrogen atom and a moiety according to formula (5), as defined herein; and wherein R1, R2, and R3 are as defined herein.

[0507] In a preferred embodiment, in the tetrazine according to any one of formulas (6), (7), (8), (9), (10), (11), (12), and (13), not more than one moiety selected from the group consisting of Q, Q1, Q2, Q3, and Q4 is a hydrogen atom.

[0508] In a preferred embodiment, in the tetrazine according to any one of formulas (7), (8), (9), (10), (11), (12) and (13), not more than two moieties selected from the group consisting of Q, Q1, Q2, Q3 and Q4 are hydrogen atoms.

[0509] In a preferred embodiment, in the tetrazine according to any one of formulas (7), (8), (9), (10), (11), (12) and (13), not more than three moieties selected from the group consisting of Q, Q1, Q2, Q3 and Q4 are hydrogen atoms.

[0510] In a preferred embodiment, in the tetrazine according to any one of formulas (7), (8), (9), (10), (11), (12) and (13), all moieties selected from the group consisting of Q, Q1, Q2, Q3 and Q4 are hydrogen atoms.

[0511] In a preferred embodiment, in the tetrazine according to any one of formulas (7), (8), (9), (10), (11), (12) and (13), not more than one moiety selected from the group consisting of Q, Q1, Q2, Q3 and Q4 is not a hydrogen atom.

[0512] In a preferred embodiment, in the tetrazine according to any one of formulas (7), (8), (9), (10), (11), (12) and (13), not more than two moieties selected from the group consisting of Q, Q1, Q2, Q3 and Q4 are not hydrogen atoms.

[0513] molecular weight Preferably, the Q group, the Q1 group, the Q2 group, the Q3 group, the Q4 group or -(CH2) y -((R1) p -R2) n -(R1) p For all compounds disclosed herein that include an -R3 group, at least one of these groups has a molecular weight in the range of 100 Da to 3000 Da. Preferably, at least one of these groups has a molecular weight in the range of 100 Da to 2000 Da. More preferably, at least one of these groups has a molecular weight in the range of 100 Da to 1500 Da, even more preferably in the range of 150 Da to 1500 Da. Even more preferably, at least one of these groups has a molecular weight in the range of 150 Da to 1000 Da, and most preferably in the range of 200 Da to 1000 Da.

[0514] Preferably, the Q group, the Q1 group, the Q2 group, the Q3 group, the Q4 group or -(CH2) y -((R1) p -R2) n -(R1)p For all compounds disclosed herein that contain -R3 groups, none of these groups have a molecular weight greater than 3000 Da, especially if the cleavage agent needs to efficiently extravasate into tissues.

[0515] -(CH 2 ) y -((R 1 ) p -R 2 ) n -(R 1 ) p -R 3 basis In a preferred embodiment, y is an integer ranging from 1 to 12, preferably from 1 to 10, more preferably from 1 to 8, even more preferably from 2 to 6, and most preferably from 2 to 4. In a preferred embodiment, y is at least 2, preferably y is at least 3. In a preferred embodiment, p is 0 or 1, where each p is independently selected. In a preferred embodiment, each n is independently selected from the range of 0 to 24, preferably from 1 to 12, more preferably from 1 to 6, even more preferably from 1 to 3, and most preferably n is 0 or 1. In a preferred embodiment, n is preferably an integer from 12 to 24. In a preferred embodiment, n is 1.

[0516] In a preferred embodiment, -((R1) p -R2) n -(R1) p The entire -R3 group has a molecular weight in the range of 100 Da to 3000 Da. Preferably, -((R1) p -R2) n -(R1) p The entire -R3 group has a molecular weight in the range of 100 Da to 2000 Da. More preferably, -((R1) p -R2) n -(R1) pThe entire -R3 group has a molecular weight in the range of 100 Da to 1500 Da, and even more preferably in the range of 150 Da to 1500 Da. Even more preferably, -((R1) p -R2) n -(R1) p The entire -R3 group has a molecular weight in the range of 150 Da to 1000 Da, most preferably in the range of 200 Da to 1000 Da.

[0517] When n>2, R2 is preferably independently selected from the group consisting of a C1-C6 alkylene group, a C2-C6 alkenylene group, a C2-C6 alkynylene group, a C6-C6 arylene, a C2-C6 heteroarylene, a C3-C6 cycloalkylene group, and a C5-C6 cycloalkenylene group, and preferably, the alkylene group, alkenylene group, alkynylene group, cycloalkylene group, cycloalkenylene group, and cycloalkynylene group are each independently selected from the group consisting of O, S, NR 36 , P, and Si, wherein the N, S, and P atoms are optionally oxidized, and wherein multiple N atoms are optionally quaternized.

[0518] In a preferred embodiment, -((R1) p -R2) n -(R1) p -R3 overall group is R shown below M Fill the molecule from the group.

[0519] R M :

[0520] [ka]

[0521] [ka]

[0522] Here, the wavy line indicates the bond to the tetrazine group or to the R1 or R2 group disclosed herein.

[0523] In a preferred embodiment, -((R1) p -R2) n -(R1) p The -R group is R M Fill the molecule from the group, where n is greater than 1, -((R1) p -R2) n -(R1) p -R3 before -((R1) p -R2)- group is attached, -((R1) p -R2)-((R1) p -R2) n-1 -(R1) p -R3 group. This is understood to be based on the definition of how the repeating units are written, i.e., -((R1) p -R2)2- is first, before R1, p, -(R1) p -R2-(R1) p -R2-, where R2 is independently selected.

[0524] R1, R2, and R3 R1 is R 10 R2 is as defined for R 11 R3 is as defined for R 12 is as defined for

[0525] R 4 Preferably, each R4 is independently a hydrogen atom, a C1-C 24 Alkyl groups, C2-C 24 Alkenyl groups, C2-C 24 Alkynyl groups, C6-C 24 Aryl, C2-C 24 Heteroaryl, C3-C 24 Cycloalkyl groups, C5-C 24 Cycloalkenyl groups, and C 12 ~C 24 cycloalkynyl groups.

[0526] In a preferred embodiment, each R4 is independently a hydrogen atom, a C1-C 12 Alkyl groups, C2-C 12 Alkenyl groups, C2-C 12 Alkynyl groups, C6-C 12 Aryl, C2-C 12 Heteroaryl, C3-C 12 Cycloalkyl groups, C5-C 12 Cycloalkenyl groups, and C 12 cycloalkynyl groups.

[0527] In a preferred embodiment, each R4 is independently selected from the group consisting of a hydrogen atom, a C1-C4 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C6 aryl, a C2-C6 heteroaryl, a C3-C8 cycloalkyl group, a C5-C8 cycloalkenyl group, and a C8 cycloalkynyl group.

[0528] Preferably, the R4 groups that are not hydrogen atoms may contain one or more heteroatoms selected from the group consisting of O, S, NR5, P and Si, wherein the N, S and P atoms are optionally oxidized, and wherein multiple N atoms are optionally quaternized.

[0529] Preferably, the R4 group that is not a hydrogen atom is -Cl, -F, -Br, -I, -OH, -NH2, -SO3H, -PO3H 、 -PO4H2, -NO2, -CF3, =O, =NR5, -SR5, C1~C 24 Alkyl groups, C2-C 24 Alkenyl groups, C2-C 24 Alkynyl groups, C6-C 24 Aryl groups, C2-C 24 Heteroaryl groups, C3-C 24 Cycloalkyl groups, C5-C 24 Cycloalkenyl group, C 12 ~C 24 Cycloalkynyl group, C3-C 24 Alkyl(hetero)aryl groups, C3-C24 (Hetero)arylalkyl groups, C4-C 24 (Hetero)arylalkenyl groups, C4-C 24 (Hetero)arylalkynyl group, C4-C 24 Alkenyl(hetero)aryl groups, C4-C 24 Alkynyl(hetero)aryl groups, C4-C 24 Alkylcycloalkyl groups, C6-C 24 Alkylcycloalkenyl group, C 13 ~C 24 Alkylcycloalkynyl group, C4-C 24 Cycloalkylalkyl groups, C6-C 24 Cycloalkenylalkyl groups, C 13 ~C 24 Cycloalkynylalkyl groups, C5-C 24 Alkenylcycloalkyl groups, C7-C 24 Alkenylcycloalkenyl group, C 14 ~C 24 Alkenylcycloalkynyl group, C5-C 24 Cycloalkylalkenyl group, C7-C 24 Cycloalkenyl alkenyl group, C 14 ~C 24 Cycloalkynylalkenyl group, C5-C 24 Alkynylcycloalkyl groups, C7-C 24 Alkynylcycloalkenyl group, C 14 ~C 24 Alkynylcycloalkynyl group, C5-C 24 Cycloalkylalkynyl group, C7-C 24 Cycloalkenylalkynyl group, C 14 ~C 24 Cycloalkynylalkynyl group, C5-C 24 Cycloalkyl(hetero)aryl groups, C7-C 24 Cycloalkenyl(hetero)aryl group, C 14 ~C 24 Cycloalkynyl(hetero)aryl groups, C5-C 24 (Hetero)arylcycloalkyl groups, C7-C 24 (Hetero)arylcycloalkenyl groups, and C 14~C 24 (hetero)arylcycloalkynyl groups, which may further be substituted with one or more substituents selected from the group consisting of O, S, NR5, P, and Si, wherein the N, S, and P atoms are optionally oxidized, and wherein multiple N atoms are optionally quaternized.

[0530] Preferably, R4, which is not a hydrogen atom, is -Cl, -F, -Br, -I, -OH, -NH2, -SO3H, -PO3H. 、 -PO4H2, -NO2, -CF3, =O, =NR5, -SR5, C1-C4 alkyl group, C2-C4 alkenyl group, C2-C4 alkynyl group, C6 aryl group, C2-C4 heteroaryl group, C3-C4 cycloalkyl group, C5-C4 cycloalkenyl group, C 12 Cycloalkynyl group, C3-C 12 Alkyl(hetero)aryl groups, C3-C 12 (Hetero)arylalkyl groups, C4-C 12 (Hetero)arylalkenyl groups, C4-C 12 (Hetero)arylalkynyl group, C4-C 12 Alkenyl(hetero)aryl groups, C4-C 12 Alkynyl(hetero)aryl groups, C4-C 12 Alkylcycloalkyl groups, C6-C 12 Alkylcycloalkenyl group, C 13 -C 12 Alkylcycloalkynyl group, C4-C 12 Cycloalkylalkyl groups, C6-C 12 Cycloalkenylalkyl groups, C 13 Cycloalkynylalkyl groups, C5-C 12 Alkenylcycloalkyl groups, C7-C 12 Alkenylcycloalkenyl group, C 14 Alkenylcycloalkynyl group, C5-C 12 Cycloalkylalkenyl group, C7-C 12 Cycloalkenyl alkenyl group, C 14 Cycloalkynylalkenyl group, C5-C12 Alkynylcycloalkyl groups, C7-C 12 Alkynylcycloalkenyl group, C 14 ~C 12 Alkynylcycloalkynyl group, C5-C 12 Cycloalkylalkynyl group, C7-C 12 Cycloalkenylalkynyl group, C 14 Cycloalkynylalkynyl group, C5-C 12 Cycloalkyl(hetero)aryl groups, C7-C 12 Cycloalkenyl(hetero)aryl group, C 14 Cycloalkynyl(hetero)aryl groups, C5-C 12 (Hetero)arylcycloalkyl groups, C7-C 12 (Hetero)arylcycloalkenyl groups, and C 14 (hetero)arylcycloalkynyl groups, which may further be substituted with one or more substituents selected from the group consisting of O, S, NR5, P, and Si, wherein the N, S, and P atoms are optionally oxidized, and wherein multiple N atoms are optionally quaternized.

[0531] In a preferred embodiment, the R4 substituent does not contain a heteroatom. In a preferred embodiment, the R4 group is unsubstituted.

[0532] In other preferred embodiments, the R4 group does not contain any heteroatoms.

[0533] R 5 Preferably, each R5 is independently a hydrogen atom, a C1 to C8 alkyl group, a C2 to C8 alkenyl group, a C2 to C8 alkynyl group, a C6 to C 12 Aryl, C2-C 12 Heteroaryl, C3-C8 cycloalkyl group, C5-C8 cycloalkenyl group, C3-C 12 Alkyl(hetero)aryl groups, C3-C 12 (Hetero)arylalkyl groups, C4-C 12Alkylcycloalkyl groups, C4-C 12 Cycloalkylalkyl groups, C5-C 12 Cycloalkyl(hetero)aryl groups and C5-C 12 (hetero)arylcycloalkyl groups, wherein the non-hydrogen R5 groups may contain one or more heteroatoms selected from the group consisting of -Cl, -F, -Br, -I, -OH, -NH2, -S03H, -PO3H, -PO4H2, -NO2, -CF3, ═O, ═NH, and -SH, wherein the N, S, and P atoms are optionally oxidized, and wherein multiple N atoms are optionally quaternized.

[0534] In a preferred embodiment, the R5 group is unsubstituted.

[0535] In other preferred embodiments, the R5 group does not contain heteroatoms.

[0536] Part Q, Q 1 、Q 2 、Q 3 、Q 4 In preferred embodiments, g is an integer ranging from 0 to 12, preferably from 0 to 10, more preferably from 0 to 8, even more preferably from 1 to 6, and most preferably from 2 to 4. In other preferred embodiments, g is 0. When multiple moieties selected from the group consisting of Q, Q1, Q2, Q3, and Q4 within a single compound satisfy formula (5), each g is independently selected.

[0537] In preferred embodiments, h is 0 or 1. When two or more moieties selected from the group consisting of Q, Q1, Q2, Q3, and Q4 within a compound satisfy formula (5), each h is independently selected.

[0538] In preferred embodiments, each f belonging to the moieties Q, Q1, Q2, Q3, or Q4 is an integer independently selected from the range of 0 to 24, preferably 1 to 12, more preferably 1 to 6, even more preferably 1 to 3, and most preferably f is 0 or 1. In preferred embodiments, f is preferably an integer from 12 to 24. In other preferred embodiments, f is 1.

[0539] In a preferred embodiment, -((R 10 ) h -R 11 ) n -(R 10 ) h -R 12 The group is the R M Fill the molecule from the group.

[0540] In a preferred embodiment, -((R 10 ) h -R 11 ) n -(R 10 ) h -R 12 The group is R M groups, where n is greater than 1, e.g., -((R 10 ) h -R 11 ) n-1 -(R 10 ) h -R 12 before -(R 10 ) h -R 11 -group is attached, -(R 10 ) h -R 11 -((R 10 ) h -R 11 ) n-1 -(R 10 ) h -R 12 This is understood based on the definition of how to write the repeating unit, i.e., -((R 10 ) h -R 11 )2- is first, R 10 , before h, -(R10 ) h -R 11 -(R 10 ) h -R 11 - and R 11 are independently selected.

[0541] Equation (14), Equation (14a), Equation (14b), Equation (14c), Equation (14d), Equation (14e), and Equation (14f) In a preferred embodiment, the cleaving agent is a tetrazine, preferably a pharmaceutically acceptable salt thereof, satisfying formula (14):

[0542] [ka]

[0543] where Y a is selected from the group consisting of Y1, Y2, Y3, Y4, Y5, and Y6.

[0544] [ka]

[0545] where Y b are Y1, Y2, Y3, Y4, Y5, Y6, hydrogen atoms, X 47 , and -(S P ) D -R 87 wherein S is selected from the group consisting of P is a spacer as defined herein, where D is 0 or 1, preferably D is 0; a If Y6, then Y b is a hydrogen atom, where each Q1 and Q5 individually represents X 45 , hydrogen atom, X 47 , and -(S P ) D -R 87 wherein each Q3 is independently selected from the group consisting of a hydrogen atom, X 47 , and -(S P )D -R 87 Preferably, the compound of formula (14) is selected from the group consisting of at least one X 45 or X 46 groups, where each X 45 are individually, N(X 50 )2, C(X 51 )2N(X 50 ) 2、 NX 50 C(O)X 51 , NX 50 C(S)X 51、 OH, SH, C(O)OH, C(S)OH, C(O)SH, C(S)SH, NX 50 C(O)OX 51 , NX 50 C(S)OX 51 , NX 50 C(O)SX 51 , NX 50 C(S)SX 51 , NX 50 C(O)N(X 51 )2, NX 50 C(S)N(X 51 )2, NX 50 SO2X 51 - 、 NX 50 SO3X 51、 NX 50 OX 51 , SO3H, SO2N(X 51 )2, and PO3H2; wherein each X 46 are individually, N(X 50 )2, C(X 51 )2N(X 50 ) 2、 NX 50 C(O)X 51 , NX 50 C(S)X 51 ,OH,SH,C(O)OH,C(S)OH,C(O)SH,C(S)SH,NX 50 C(O)OX 51 , NX 50 C(S)OX 51 -,NX 50 C(O)SX 51 , NX 50 C(S)SX 51 , NX50 C(O)N(X 51 )2, NX 50 C(S)N(X 51 )2, NX 50 SO2X 51、 NX 50 SO3X 51、 NX 50 OX 51 , SO3H, and PO3H2; wherein each X 50 and X 51 are hydrogen atoms, X 48 , and -(S P ) D -R 87 wherein each X 48 are independently preferably a hydrogen atom, a C1-C4 alkyl group, a C2-C4 alkenyl group, and C 4~6 (hetero)aryl groups; 48 In the above, the alkyl group, alkenyl group, and (hetero)aryl group are -Cl, -F, -Br, -I, -OH, -NH2, =O, -SH, -SO3H, -PO3H 、 and optionally substituted with a moiety selected from the group consisting of -PO4H2, and -NO2, and containing up to two heteroatoms selected from the group consisting of -O-, -S-, -NH-, -P-, and -Si-, wherein the N, S, and P atoms are optionally oxidized, and wherein each X 47 -F, -Cl, -Br, -I, -OX 49 , -N(X 49 )2, -SO3, -PO3 - 、 -NO2, -CF3, -SX 49 , S(=O)2N(X 49 ) 2、 OC(=O)X 49 , SC(=O)X 49 , OC(=S)X 49 , SC(=S)X 49、 NX 49 C(=O)-X 49 , NX 49 C(=S)-X 49 , NX 49 C(=O)OX 49, NX 49 C(=S)OX 49 , NX 49 C(=O)SX 49 , NX 49 C(=S)SX 49 , OC(=O)N(X 49 )2, SC(=O)N(X 49 )2, OC(=S)N(X 49 )2, SC(=S)N(X 49 )2, NX 49 C(=O)N(X 49 )2, NX 49 C(=S)N(X 49 ) 2、 C(=O)X 49、 C(=S)X 49、 C(=O)N(X 49 )2, C(=S)N(X 49 )2, C(=O)OX 49 , C(=O)SX 49 , C(=S)OX 49 , C(=S)SX 49 , -S(O)X 49 , -S(O)2X 49 , NX 49 S(O)2X 49 , -ON(X 49 ) 2、- NX 49 OX 49 , C1-C8 alkyl group, C2-C8 alkenyl group, C2-C8 alkynyl group, C6-C 12 Aryl, C2-C 12 Heteroaryl, C3-C8 cycloalkyl group, C5-C8 cycloalkenyl group, C3-C 12 Alkyl(hetero)aryl groups, C3-C 12 (Hetero)arylalkyl groups, C4-C 12 Alkylcycloalkyl groups, C4-C 12 Cycloalkylalkyl groups, C5-C 12 Cycloalkyl(hetero)aryl groups and C5-C 12and (hetero)arylcycloalkyl groups, wherein the alkyl group, alkenyl group, alkynyl group, aryl, heteroaryl, cycloalkyl group, cycloalkenyl group, alkyl(hetero)aryl group, (hetero)arylalkyl group, alkylcycloalkyl group, cycloalkylalkyl group, cycloalkyl(hetero)aryl group, and (hetero)arylcycloalkyl group are selected from the group consisting of -Cl, -F, -Br, -I, -OX 49 , -N(X 49 )2, -SO3X 49 , -PO3(X 49 ) 2、 -PO4(X 49 ) 2、 -NO2, -CF3, =O, =NX 49 , and -SX 49 and may be substituted with a moiety selected from the group consisting of O, S, NX 49 , P, and Si, wherein the N, S, and P atoms are optionally oxidized, and wherein a plurality of N atoms are optionally quaternized; 49 is a hydrogen atom, a C1-C8 alkyl group, a C2-C8 alkenyl group, a C2-C8 alkynyl group, a C6-C 12 Aryl, C2-C 12 Heteroaryl, C3-C8 cycloalkyl group, C5-C8 cycloalkenyl group, C3-C 12 Alkyl(hetero)aryl groups, C3-C 12 (Hetero)arylalkyl groups, C4-C 12 Alkylcycloalkyl groups, C4-C 12 Cycloalkylalkyl groups, C5-C 12 Cycloalkyl(hetero)aryl groups and C5-C 12 (hetero)arylcycloalkyl groups, wherein X is not a hydrogen atom. 49 Groups include -Cl, -F, -Br, -I, -OH, -NH2, -SO3H, and -PO3H 、 -PO4H 2、and optionally substituted with a moiety selected from the group consisting of —NO2, —CF3, ═O, ═NH, and —SH, and optionally containing one or more heteroatoms selected from the group consisting of O, S, NH, P, and Si, wherein the N, S, and P atoms are optionally oxidized, and wherein a plurality of N atoms are optionally quaternized; a and Y b Preferably, Q1, Q2, Q3, Q 4、 and Q5 are not more than two, more preferably not more than one, of the R 87 wherein compounds according to formula (14) preferably contain no more than four R 87 moieties, more preferably no more than two R 87 moiety, most preferably R 1 or less 87 wherein the compound according to formula (14) preferably comprises at least one R 87 wherein preferably, each respective Y a and Y b Regarding Q1, Q2, Q3, Q 4、 and no more than three, more preferably no more than two, of Q5 are not hydrogen atoms; a and Y b Regarding Q1, Q2, Q3, Q 4、 and two or less of Q5 are X 45 or X 46 where preferably, each respective Y a and Y b For Q1, Q2, Q4, and Q5, one of them is X 45 or X 46 wherein preferably, Y a and Y b Both have at least one X 45 or X 46 wherein preferably, Y a and Y b Both are in one X 45 or X 46 wherein preferably, Y a and Y b Both are in one X 45 or X 46 where Ya X included in 45 But, Y b X included in 45 and / or Y a X included in 46 But, Y b X included in 465 where preferably, Y a and Y b are both independently selected Y1, or both independently selected Y2, or both independently selected Y3, or both independently selected Y4, or both independently selected Y5.

[0546] In a preferred embodiment, in formula (14) or in any one of formulas (14a) to (14f), Q1 is X 47 or -(S P ) D -R 87 If so, then for Q1, X 47 and R 87 is X 45 is not a group conforming to the definition of

[0547] In a preferred embodiment, in formula (14) or in any one of formulas (14a) to (14f), Q5 is X 47 or -(S P ) D -R 87 If so, then for Q5, X 47 and R 87 is X 45 is not a group conforming to the definition of

[0548] In a preferred embodiment, in formula (14) or in any one of formulas (14a) to (14f), Q2 is X 47 or -(S P ) D -R 87 If so, then for Q2, X 47 and R 87 is X 46 is not a group conforming to the definition of

[0549] In a preferred embodiment, in formula (14) or in any one of formulas (14a) to (14f), Q4 is X 47 or -(S P ) D -R 87 If so, then for Q4, X 47 and R 87 is X 46 is not a group conforming to the definition of

[0550] In a preferred embodiment, Y a is Y b In a preferred embodiment, Y a is selected from Y1, Y2, Y3, Y4 or Y5, and Y b is a hydrogen atom, X 47 or -(S P ) D -R 87 In a preferred embodiment, Y a is selected from Y1, Y2, Y3, Y4 or Y5, and Y b is a hydrogen atom. In a preferred embodiment, the compound according to formula (14) is 87 In a preferred embodiment, X 50 is a hydrogen atom. In a preferred embodiment, X 45 or X 46 is N(X 50 )2, then one X 50 is a hydrogen atom, and one X 50 is X 48 or -(S P ) D -R 87 In a preferred embodiment, formula (14) is X 46 Does not include.

[0551] In a preferred embodiment, the cleaving agent is a tetrazine satisfying any one of the following formulas (14a) to (14f):

[0552] [ka]

[0553] where Q6 is as defined for Q1 in equation (14), Q7 is as defined for Q2 in equation (14), Q8 is as defined for Q3 in equation (14), Q9 is as defined for Q4 in equation (14), and Q 10 is as defined for Q5 in equation (14), Here, preferably, Q1, Q2, Q3, Q 4、 and Q5 are not more than two, more preferably not more than one, of the above-(S P ) D -R 87 wherein preferably Q6, Q7, Q8, Q 9、 and Q 10 Two or less, more preferably one or less of the above -(S P ) D -R 87 and the compound according to any one of formulas (14a) to (14f) has four or less R 87 moieties, more preferably no more than two R 87 moiety; wherein the compound according to any one of formulas (14a) to (14f) preferably comprises at least one R 87 wherein preferably Q1, Q2, Q3, Q 4、 Q 5、 Q6, Q7, Q8, Q 9、 Q 10 are not hydrogen atoms, and preferably not more than six, more preferably not more than four of X 45 group or X 46 The groups are identical.

[0554] In a preferred embodiment, in formula (14b), formula (14b) and formula (14f), Q6 is X 47 or -(S P ) D -R 87 If so, then for Q6, X 47 and R 87 is X 45 is not a group conforming to the definition of

[0555] In a preferred embodiment, in formulas (14c) to (14f), Q 10 is X 47 or -(S P ) D -R 87 If Q 10 About X 47 and R 87 is X 45 is not a group conforming to the definition of

[0556] In a preferred embodiment, in formula (14a), formula (14c) and formula (14e), Q7 is X 47 or -(S P ) D -R 87 If so, then for Q7, X 47 and R 87 is X 46 is not a group conforming to the definition of

[0557] In a preferred embodiment, in formula (14a), formula (14b), formula (14e) and formula (14f), Q9 is X 47 or -(S P ) D -R 8 If so, then for Q9, X 47 and R 87 is X 46 is not a group conforming to the definition of

[0558] X 45 In a preferred embodiment, each X 45 are individually, N(X 50 )2, NX 50 C(O)X 51 , NX 50 C(S)X 51、 OH, SH, NX 50 C(O)OX 51 , NX 50 C(S)OX 51 , NX 50 C(O)SX 51 , NX 50 C(S)SX 51 , NX 50 C(O)N(X 51)2, NX 50 C(S)N(X 51 )2, NX 50 SO2X 51、 NX 50 SO3X 51 , NX 50 OX 51 , and SO2N(X 51 )2.

[0559] In a preferred embodiment, each X 45 are individually, N(X 50 )2, NX 50 C(O)X 51 , NX 50 C(S)X 51 , OH and SH.

[0560] In a preferred embodiment, each X 45 are individually, NX 50 C(O)OX 51、 NX 50 C(S)OX 51、 NX 50 C(O)SX 51、 NX 50 C(S)SX 51、 NX 50 C(O)N(X 51 )2, NX 50 C(S)N(X 51 )2, NX 50 SO2X 51、 NX 50 SO3X 51、 NX 50 OX 51 is selected from the group consisting of:

[0561] In a preferred embodiment, X 45 is NHX 50 , C(X 51 )2NH2, CHX 51 NH2, CH2N(X 50 )2, CH2NHX 50 , NHC(O)X 51 , NHC(S)X 51 In a preferred embodiment, X is selected from the group consisting of , OH, and SH. 45is NHX 50 In a preferred embodiment, X 45 is C(X 51 In a preferred embodiment, X 45 is CHX 51 In a preferred embodiment, X 45 is CH2N(X 50 In a preferred embodiment, X 45 is CH2NHX 50 In a preferred embodiment, X 45 is NH2. In a preferred embodiment, X 45 is CH2NH2. In a preferred embodiment, X 45 is NHC(O)X 51 In a preferred embodiment, X 45 NHC(S)X 51 In a preferred embodiment, X 45 is OH. In a preferred embodiment, X 45 is SH. In a preferred embodiment, X 45 is SO2NH2.

[0562] X 46 In a preferred embodiment, X 46 are individually, N(X 50 )2, NX 50 C(O)X 51、 NX 50 C(O)OX 51、 and NX 50 C(O)N(X 51 In a preferred embodiment, X 46 is N(X 50 )2 and NX 50 C(O)X 51 In a preferred embodiment, X 46 is NHX 50 and NHC(O)X 51 In a preferred embodiment, X 46 is NHX 50 In a preferred embodiment, X46 is NH2. In a preferred embodiment, X 46 is NHC(O)X 51 is.

[0563] X 47 In a preferred embodiment, each X 47 are F, -OH, -NH2, -SO3 respectively. - 、 In a more preferred embodiment, each X is selected from the group consisting of -NO2, -CF3, -SH, a C1-C6 alkyl group, a C6 aryl group, a C4-C5 heteroaryl group, a C5-C8 alkyl(hetero)aryl group, a C5-C8 (hetero)arylalkyl group, a C4-C8 alkylcycloalkyl group, and a C4-C8 cycloalkylalkyl group. 47 are individually, -SO3 - 、 It is selected from the group consisting of -NO2, -CF3, a C1-C6 alkyl group, a C6 aryl group, a C4-C5 heteroaryl group, a C5-C8 alkyl(hetero)aryl group, a C5-C8 (hetero)arylalkyl group, a C4-C8 alkylcycloalkyl group, and a C4-C8 cycloalkylalkyl group.

[0564] In a preferred embodiment, X 47 The substituents do not contain heteroatoms.

[0565] In a preferred embodiment, X 47 The group is unsubstituted.

[0566] In another preferred embodiment, X 47 The group does not contain heteroatoms.

[0567] X 48 In a preferred embodiment, each X 48 are independently a hydrogen atom, a C1-C4 alkyl group, a C2-C4 alkenyl group, and C 4~6 (hetero)aryl groups. X 48In the above, the alkyl group, the alkenyl group, and the (hetero)aryl group are -Cl, -F, -Br, -I, -OH, -NH2, ═O, -SH, -SO3H, -PO3H 、 and may contain up to two heteroatoms selected from the group consisting of -O-, -S-, -NH-, -P-, and -Si-, wherein the N, S, and P atoms are optionally oxidized. 48 is C1-C4 alkyl.

[0568] In a preferred embodiment, X 48 The substituents do not contain heteroatoms.

[0569] In a preferred embodiment, X 48 The group is unsubstituted.

[0570] In another preferred embodiment, X 48 The group does not contain heteroatoms.

[0571] X 49 In a preferred embodiment, X 49 is a hydrogen atom, a C1-C8 alkyl group, a C2-C8 alkenyl group, a C2-C8 alkynyl group, a C6-C 12 Aryl, C2-C 12 Heteroaryl, C3-C8 cycloalkyl group, C5-C8 cycloalkenyl group, C3-C 12 Alkyl(hetero)aryl groups, C3-C 12 (Hetero)arylalkyl groups, C4-C 12 Alkylcycloalkyl groups, C4-C 12 Cycloalkylalkyl groups, C5-C 12 Cycloalkyl(hetero)aryl groups and C5-C 12 (hetero)arylcycloalkyl groups, wherein X is not a hydrogen atom. 49 Groups include Cl, -F, -Br, -I, -OH, -NH2, -SO3H, and -PO3H 、-PO4H 2、 It may be substituted with a moiety selected from the group consisting of -NO2, -CF3, =O, =NH, and -SH, and may contain one or more heteroatoms selected from the group consisting of O, S, NH, P, and Si, wherein the N, S, and P atoms are optionally oxidized, and wherein multiple N atoms are optionally quaternized.

[0572] In a preferred embodiment, X 49 is a hydrogen atom, a C1-C4 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C6-C8 aryl, a C2-C8 heteroaryl, a C3-C6 cycloalkyl group, a C5-C6 cycloalkenyl group, a C3-C 10 Alkyl(hetero)aryl groups, C3-C 10 (Hetero)arylalkyl group, C4-C8 alkylcycloalkyl group, C4-C8 cycloalkylalkyl group, C5-C 10 Cycloalkyl(hetero)aryl groups and C5-C 10 (hetero)arylcycloalkyl groups, wherein X is not a hydrogen atom. 49 Groups include -Cl, -F, -Br, -I, -OH, -NH2, -SO3H, and -PO3H 、 -PO4H 2、 and optionally substituted with a moiety selected from -NO2, -CF3, =O, =NH, and -SH, and optionally containing one or more heteroatoms selected from O, S, NH, P, a, and Si, wherein the N, S, and P atoms are optionally oxidized, and wherein multiple N atoms are optionally quaternized. 49 The substituents do not contain heteroatoms. In a preferred embodiment, X 49 The group is unsubstituted. In another preferred embodiment, X 49 The group does not contain heteroatoms.

[0573] X 50 In a preferred embodiment, each X 50 are hydrogen atoms, X 48 , and -(SP ) D -R 87 In a preferred embodiment, X 50 is X 48 In a preferred embodiment, X 50 Ha-(S P ) D -R 87 In a preferred embodiment, X 50 is H.

[0574] X 51 In a preferred embodiment, each X 51 are hydrogen atoms, X 48 , and -(S P ) D -R 87 In a preferred embodiment, X 51 is X 48 In a preferred embodiment, X 51 Ha-(S P ) D -R 87 In a preferred embodiment, X 51 is H.

[0575] Q 1 In a preferred embodiment, in any one of formulas (14) to (14f), Q1 is a hydrogen atom, X 47 , and -(S P ) D -R 87 In a preferred embodiment, Q1 in any one of formulas (14) to (14f) is a hydrogen atom. In a preferred embodiment, Q1 in any one of formulas (14) to (14f) is selected from the group consisting of X 47 In a preferred embodiment, Q1 in any one of formulas (14) to (14f) is R 8 and preferably Q2, Q3, Q4, Q5, Q6, Q7, Q8, Q9, and Q 10 is X 45 , X 46, or a hydrogen atom.

[0576] Q 2 In a preferred embodiment, Q2 in any one of formulas (14) to (14f) is a hydrogen atom, X 47 , and -(S P ) D -R 87 In a preferred embodiment, Q2 in any one of formulas (14) to (14f) is a hydrogen atom. In a preferred embodiment, Q2 in any one of formulas (14) to (14f) is selected from the group consisting of X 47 In a preferred embodiment, Q2 in any one of formulas (14) to (14f) is -(S P ) D -R 87 and preferably Q1, Q3, Q4, Q5, Q6, Q7, Q8, Q9, and Q 10 is X 45 , X 46 , or a hydrogen atom.

[0577] Q 3 In a preferred embodiment, Q3 in any one of formulas (14) to (14f) is a hydrogen atom, X 47 , and -(S P ) D -R 877 In a preferred embodiment, Q3 in any one of formulas (14) to (14f) is a hydrogen atom. In a preferred embodiment, Q2 in any one of formulas (14) to (14f) is selected from the group consisting of X 47 In a preferred embodiment, Q3 in any one of formulas (14) to (14f) is -(S P ) D -R 87 and preferably Q1, Q2, Q4, Q5, Q6, Q7, Q8, Q9, and Q 10 is X 45 , X 46 , or a hydrogen atom.

[0578] Q 4 In a preferred embodiment, Q4 in any one of formulas (14) to (14f) is a hydrogen atom, X 47 , and -(S P ) D -R 87 In a preferred embodiment, Q4 in any one of formulas (14) to (14f) is a hydrogen atom. In a preferred embodiment, Q4 in any one of formulas (14) to (14f) is selected from the group consisting of X 47 In a preferred embodiment, Q4 in any one of formulas (14) to (14f) is -(S P ) D -R 87 and preferably Q1, Q2, Q3, Q5, Q6, Q7, Q8, Q9, and Q 10 is X 45 , X 46 , or a hydrogen atom.

[0579] Q 5 In a preferred embodiment, Q5 in any one of formulas (14) to (14f) is a hydrogen atom, X 47 , and -(S P ) D -R 87 In a preferred embodiment, Q5 in any one of formulas (14) to (14f) is a hydrogen atom. In a preferred embodiment, Q5 in any one of formulas (14) to (14f) is selected from the group consisting of X 47 In a preferred embodiment, Q5 is -(S P ) D -R 87 and preferably Q1, Q2, Q3, Q4, Q6, Q7, Q8, Q9, and Q 10 is X 45 , X 46 , or a hydrogen atom.

[0580] Q 6 In a preferred embodiment, Q6 in any one of formulas (14) to (14f) is a hydrogen atom, X 47 , and -(S P ) D -R 87 In a preferred embodiment, Q6 in any one of formulas (14) to (14f) is a hydrogen atom. In a preferred embodiment, Q6 in any one of formulas (14) to (14f) is selected from the group consisting of X 47 In a preferred embodiment, Q6 in any one of formulas (14) to (14f) is -(S P ) D -R 87 and preferably Q1, Q2, Q3, Q4, Q5, Q7, Q8, Q9, and Q 10 is X 45 , X 46 , or a hydrogen atom.

[0581] Q 7 In a preferred embodiment, Q7 in any one of formulas (14) to (14f) is a hydrogen atom, X 47 , and -(S P ) D -R 87 In a preferred embodiment, Q7 in any one of formulas (14) to (14f) is a hydrogen atom. In a preferred embodiment, Q7 in any one of formulas (14) to (14f) is selected from the group consisting of X 47 In a preferred embodiment, Q7 in any one of formulas (14) to (14f) is -(S P ) D -R 87 and preferably Q1, Q2, Q3, Q4, Q5, Q6, Q8, Q9, and Q 10 is X 45 , X 46 , or a hydrogen atom.

[0582] Q 8 In a preferred embodiment, Q8 in any one of formulas (14) to (14f) is a hydrogen atom, X 47 , and -(S P ) D -R 87 In a preferred embodiment, Q8 in any one of formulas (14) to (14f) is a hydrogen atom. In a preferred embodiment, Q8 in any one of formulas (14) to (14f) is selected from the group consisting of X 47 In a preferred embodiment, Q8 in any one of formulas (14) to (14f) is -(S P ) D -R 87 and preferably Q1, Q2, Q3, Q4, Q5, Q6, Q7, Q9, and Q 10 is X 45 , X 46 , or a hydrogen atom.

[0583] Q 9 In a preferred embodiment, Q9 in any one of formulas (14) to (14f) is a hydrogen atom, X 47 , and -(S P ) D -R 87 In a preferred embodiment, Q9 in any one of formulas (14) to (14f) is a hydrogen atom. In a preferred embodiment, Q9 in any one of formulas (14) to (14f) is selected from the group consisting of X 47 In a preferred embodiment, Q9 in any one of formulas (14) to (14f) is -(S P ) D -R 87 and preferably Q1, Q2, Q3, Q4, Q5, Q6, Q7, Q8, and Q 10 is X 45 , X 46 , or a hydrogen atom.

[0584] Q 10 In a preferred embodiment, Q in any one of formulas (14) to (14f) 10 is a hydrogen atom, X 47 , and -(S P ) D -R 87 In a preferred embodiment, Q in any one of formulas (14) to (14f) is selected from the group consisting of: 10 In a preferred embodiment, Q in any one of formulas (14) to (14f) is a hydrogen atom. 10 is X 47 In a preferred embodiment, Q in any one of formulas (14) to (14f) 10 is -(S P ) D -R 87 and preferably, Q1, Q2, Q3, Q4, Q5, Q6, Q7, Q8, and Q9 are X 45 , X 46 , or a hydrogen atom.

[0585] Formula (14a) In a preferred embodiment, the compound according to the invention is a compound according to formula (14a), wherein preferably each individual X 45 and Q2 to Q4, Q7 to Q9 are as described herein.

[0586] In a preferred embodiment, the compound according to the invention is a compound according to formula (14a), wherein both X 45 are the same, and NH2, NHC(O)X 51 , NX 50 C(O)OX 51 , NX 50 C(O)N(X 51 )2, NX 50 C(S)N(X 51 )2, OH, and SH; and Q2 to Q4, Q7 to Q9 are hydrogen atoms.

[0587] In a preferred embodiment, the compound according to the invention is a compound according to formula (14a), wherein both X45 are the same, and NH2, NHC(O)X 51 and Q2 to Q4, Q7 to Q9 are hydrogen atoms.

[0588] Formula (14b) In a preferred embodiment, the compound according to the invention is a compound according to formula (14a), wherein preferably each individual X 46 and Q1, Q3 to Q4, Q6, Q8 to Q9 are as described herein.

[0589] In a preferred embodiment, the compound according to the invention is a compound according to formula (14b), wherein both X 46 are the same and are NH2 or NHC(O)X 51 and Q1, Q3 to Q4, Q6, Q8 and Q9 are hydrogen atoms.

[0590] Formula (14c) In a preferred embodiment, the compound according to the invention is a compound according to formula (14c), wherein preferably each individual X 45 and Q2~Q3, Q5, Q7, Q8, Q 10 is as described herein.

[0591] In a preferred embodiment, the compound according to the invention is a compound according to formula (14c), wherein both X 45 are the same, and NH2, NHC(O)X 51 , NX 50 C(O)OX 51、 NX 50 C(O)N(X 51 )2, NX 50 C(S)N(X 51 )2, OH, and SH; and Q2 to Q3, Q5, Q7, Q8, Q 10 is a hydrogen atom.

[0592] In a preferred embodiment, the compound according to the invention is a compound according to formula (14c), wherein both X45 are the same, and NH2, NHC(O)X 51 , and OH, and Q2 to Q3, Q5, Q7, Q8, Q 10 is a hydrogen atom.

[0593] Formula (14d) In a preferred embodiment, the compound according to the invention is a compound according to formula (14d), wherein preferably each individual X 46 and Q1, Q3, Q5, Q6, Q8, Q 10 is as described herein.

[0594] In a preferred embodiment, the compound according to the invention is a compound according to formula (14d), wherein both X 46 are the same and are NH2 or NHC(O)X 51 and Q1, Q3, Q5, Q6, Q8, Q 10 is a hydrogen atom.

[0595] Formula (14e) In a preferred embodiment, the compounds according to the invention are compounds according to formula (14e), wherein preferably each individual X 45 and Q2, Q4, Q5, Q7, Q9, Q 10 is as described herein.

[0596] In a preferred embodiment, the compound according to the invention is a compound according to formula (14e), wherein both X 45 are the same, and NH2, NHC(O)X 51 , NX 50 C(O)OX 51 - , NX 50 C(O)N(X 51 )2, NX 50 C(S)N(X 51 )2, OH, and SH; and Q2, Q4, Q5, Q7, Q9, Q 10 is a hydrogen atom.

[0597] In a preferred embodiment, the compound according to the invention is a compound according to formula (14e), wherein both X 45 are the same, and NH2, NHC(O)X 51 and OH; and Q2, Q4, Q5, Q7, Q9, Q 10 is a hydrogen atom.

[0598] Formula (14f) In a preferred embodiment, the compound according to the invention is a compound according to formula (14f), wherein preferably each individual X 46 and Q1, Q4, Q5, Q6, Q9, Q 10 is as described herein.

[0599] In a preferred embodiment, the compound according to the invention is a compound according to formula (14f), wherein both X 46 are the same and are NH2 or NHC(O)X 51 and Q1, Q4, Q5, Q6, Q9, Q 10 is a hydrogen atom.

[0600] In a preferred embodiment, the cleavage agent is according to formula (14) and has at least one, preferably two, X 45 Contains a group.

[0601] In a preferred embodiment, the cleavage agent is according to formula (14a), (14c), or (14e).

[0602] R 87 Preferably, R in connection with the present invention 87 is a moiety that modulates the pharmacokinetics of the compound. Thus, in a preferred embodiment, R 87 is the pharmacokinetics-modulating moiety (P K part). R 87The functions of include, but are not limited to, slowing the clearance of the compound, influencing the volume of distribution of the compound (e.g., decreasing or increasing the volume of distribution), influencing the biodistribution of the compound, achieving spatial control via reaction with a trigger, influencing (more particularly avoiding) the metabolism of the compound, and / or influencing (more particularly avoiding) (undesirable) adhesion or (undesirable) uptake of the compound into tissues. Those skilled in the art are well aware of such groups and how to synthesize them.

[0603] In a preferred embodiment, each R 87 are independently selected from the group consisting of organic molecules, inorganic molecules, organometallic molecules, resins, beads, glass, microparticles, nanoparticles, gels, surfaces, and cells. 87 are independently selected from the group consisting of organic molecules and inorganic molecules.

[0604] In a preferred embodiment, R 87 This helps to increase blood circulation time and reaction time to triggers.

[0605] In a preferred embodiment, R 87 serves to modulate the pharmacokinetics of the reaction product between the dienophile of the present invention and the diene as defined herein.

[0606] Without wishing to be bound by theory, the function and performance of tetrazines as defined herein in bioorthogonal reactions may be due to the R 87 It is believed that the properties of the

[0607] In a preferred embodiment, each R 87 are individually biomolecules, polymers, peptides, peptoids, dendrimers, proteins, carbohydrates, oligonucleotides, oligosaccharides, aptamers, steroids, lipids, albumin, albumin-binding moieties, dye moieties, fluorescent moieties, imaging probes, and targeting agents (TT and wherein R 87 is a spacer (S P ) may be attached to the tetrazine. Typically, R 87 A suitable polymer is polyethylene glycol (PEG). Suitable PEGs include those having a number of repeating units ranging from 2 to 4000 and molecular weights ranging from 200 Da to 100,000 Da.

[0608] In a preferred embodiment, R 87 is the part that follows equation (5).

[0609] In a preferred embodiment, R 87 is a moiety according to formula (5), and for example, R 87 and the part Y of equation (14) a or Y b and the remainder of the formula (14a) to the pyridyl moiety of the compound according to any one of the formulas (14a) to (14f), P without a linker, and is directly linked to the remainder of the compound according to any one of formulas (14a) to (14f).

[0610] In a preferred embodiment, R 87 is a moiety according to formula (5), and for example, R 87 and any one of the parts Y of formula (4), formula (11), and formula (14) a or Y b and the remainder of the formula (14a) to the pyridyl moiety of the compound according to any one of the formulas (14a) to (14f), P directly linked to the remainder of the compound according to any one of formulas (14a) to (14f), without X 45 or X 46 When the compound is attached to an amine functional group, z in formula (5) is not 0.

[0611] In a preferred embodiment, R 87 is a spacer S as defined herein Pis linked to the rest of the compound via

[0612] In a preferred embodiment, R 87 optionally a spacer S as defined herein P and each R 87 The groups may individually be biomolecules, polymers, peptides, peptoids, dendrimers, proteins, carbohydrates, oligonucleotides, oligosaccharides, lipids, micelles, liposomes, polymersomes, particles, nanoparticles, microparticles, beads, gels, metal complexes, organometallic moieties, albumin, albumin-binding moieties, dye moieties, fluorescent moieties, imaging probes, and targeting agents (T T ) is selected from the group consisting of

[0613] In a preferred embodiment, one or more copies of a compound of the invention are coupled to a membrane-translocating moiety (e.g., adamantine, polylysine / arginine, TAT, human lactoferrin) R to achieve an intracellular prodrug. 87 Exemplary references for such moieties include: Trends in Biochemical Sciences, 2015, 40, 12, 749; J. Am. Chem. Soc. 2015, 137, 12153-12160; Pharmaceutical Research, 2007, 24, 11, 1977.

[0614] For use in a cellular environment, e.g., in vivo, the cleavage agent is designed to efficiently reach the trigger construct depending on its location (e.g., inside or outside the cell). Therefore, the cleavage agent can be tuned, for example, by changing its log P value, its reactivity, or its charge, and this can optionally be achieved by changing the R 87 This can be achieved by:

[0615] In a preferred embodiment, the tetrazine compounds of the present invention are R 87In other embodiments, R 87 is or comprises an imaging moiety. In this preferred embodiment, the imaging moiety is R 87 In this embodiment, 87 is equal to the imaging moiety. In a preferred embodiment, the compounds of the present invention comprise one or more imaging moieties and one or more R 87 and a group.

[0616] In a preferred embodiment, R 87 is or comprises an imaging moiety.

[0617] Preferred imaging moieties are radionuclide-chelate complexes, radiolabeled molecules (e.g., 18 F, 124 I), and fluorescent dyes.

[0618] In a preferred embodiment, R 87 has at least one 18 The imaging moiety contains an F isotope.

[0619] In a preferred embodiment, R 87 comprises a chelating moiety, preferably a chelating moiety described herein.

[0620] In a preferred embodiment, R 87 These include, but are not limited to, amino acids, nucleosides, nucleotides, carbohydrates, and biopolymer fragments such as oligopeptides or polypeptides, oligopeptoids or polypeptoids, or oligopeptides or polypeptides, or oligo- or poly-carbohydrates, oligonucleotides, varying in 2 to 200, particularly 2 to 113, preferably 2 to 50, more preferably 2 to 24, more preferably 2 to 12 repeating units.

[0621] According to one embodiment, the cleavage agent comprises one R 87These multimeric compounds can be, but are not limited to, biomolecules, peptides, peptoids, proteins, oligonucleotides, oligosaccharides, polymersomes, beads, gels, polymers, dendrimers, liposomes, micelles, particles, polymer particles, or other polymeric constructs.

[0622] In a preferred embodiment, R 87 is a polymer. This includes linear or branched polyalkylene glycols, such as polyethylene glycol (PEG) chains or polypropylene glycol (PPG) chains, varying in repeating units from 2 to 200, particularly from 2 to 113, preferably from 2 to 50, more preferably from 2 to 24, and more preferably from 2 to 12. When the polyalkylene glycol, such as a PEG polymer or a PPG polymer, is bonded only via one end of the polymer chain, the other end is preferably terminated with -OCH3, -OCH2CH3, or -OCH2CH2CO2H.

[0623] Other polymeric R 87Moieties include polymers and copolymers such as poly-(2-oxazoline), poly(N-(2-hydroxypropyl)methacrylamide) (HPMA), polylactic acid (PLA), polylactic-glycolic acid (PLGA), polyglutamic acid (PG), dextran, polyvinylpyrrolidone (PVP), poly(1-hydroxymethylethylenehydroxymethyl-formal) (PHF). Other exemplary polymers are polysaccharides, glycopolysaccharides, glycolipids, polyglycosides, polyacetals, polyketals, polyamides, polyethers, polyesters. Naturally occurring polysaccharides that can be used include cellulose, amylose, dextran, dextrin, levan, fucoidan, carraginan, inulin, pectin, amylopectin, glycogen, lyxenan, agarose, hyaluronan, chondroitin sulfate, dermatan sulfate, keratan sulfate, alginic acid, and heparin. In yet another exemplary embodiment, the polymer is a copolymer of a polyacetal / polyketal and a hydrophilic polymer selected from the group consisting of polyacrylates, polyvinyl polymers, polyesters, polyorthoesters, polyamides, oligopeptides, polypeptides, and derivatives thereof. Exemplary preferred polymeric R 87 The moieties are PEG, HPMA, PLA, PLGA, PVP, PHF, dextran, oligopeptides, and polypeptides.

[0624] In some aspects of the invention, the polymeric R 87 The moieties have molecular weights ranging from 2 to 200 kDa, 2 to 100 kDa, 2 to 80 kDa, 2 to 60 kDa, 2 to 40 kDa, 2 to 20 kDa, 3 to 15 kDa, 5 to 10 kDa, 500 daltons to 5 kDa.

[0625] Other exemplary R 87 The moieties are dendrimers, such as poly(propyleneimine) (PPI) dendrimers, PAMAM dendrimers, and glycol-based dendrimers.

[0626] In a preferred embodiment, R 87 is RM Equal to the base.

[0627] In a preferred embodiment, R 87 This helps to increase blood circulation time and reaction time to triggers.

[0628] In a preferred embodiment, R 87 serves to modulate the pharmacokinetics of the reaction product between the dienophile and the diene of the present invention.

[0629] In a preferred embodiment, the cleavage agent is designed to be cell impermeable as a result of its log P value or its charge, and this means that R 87 This can be achieved by:

[0630] In embodiments where the cleavage agent is required to have an extracellular volume of distribution, it is preferred that the Log P of the cleavage agent is 2 or less, preferably 1 or less, more preferably 0 or less, and even more preferably -1 or less.

[0631] In embodiments where the cleavage agent is required to have an intracellular volume of distribution, it is preferred that the Log P of the cleavage agent is at least −1, preferably at least 0, more preferably at least 1, and even more preferably at least 2.

[0632] In embodiments where the cleavage agent is required to have an extracellular volume of distribution, it is preferred that the agent have a negative net charge at pH 7.

[0633] In embodiments where the cleavage agent is required to have an intracellular volume of distribution, it is preferred that the agent has a molecular weight of less than 1000 Da, preferably less than 500 Da.

[0634] In embodiments where the cleavage agent is required to have an extracellular volume of distribution, it is preferred that the agent has a molecular weight of greater than 500 Da, preferably greater than 1 kDa, more preferably greater than 2 kDa.

[0635] In embodiments where the cleaving agent is required to have slow or inefficient extravasation from the circulation, it is preferred that the agent have a molecular weight of greater than 5 kDa, preferably greater than 60 Da, more preferably greater than 150 Da, and even more preferably greater than 500 kDa.

[0636] In a preferred embodiment, where the cleavage agent is not cell permeable, R 87 can be a protein or a polymer.

[0637] In a preferred embodiment, the R 87 is a hydroxyl group due to its large size and / or the lack of a clearance-directing group (i.e., R 98 The presence of the cleavage agent (as a granule) reduces extravasation of the cleavage agent from the blood to the target tissue. For example, the presence of the PLGA microparticles R 87 The galactose moieties (i.e., clearance-directing groups, R) are used to allow efficient IEDDA reaction with the administered agent in the circulation or to prevent efficient extravasation of the cleaved agent into tumor tissue, resulting in rapid clearance by the liver. Similarly, the galactose moieties (i.e., clearance-directing groups, R) are used to ensure rapid uptake by the liver. 98 R, which is an albumin protein modified with 87 provides an efficient IEDDA reaction in the blood with minimal or no mimicking of extravasation into tumor tissue. [Rossin et al J.Nucl.Med.2013,4,11,1989-1995]. Similarly, R 87 can be a small moiety containing a clearance-directing group to promote IEDDA reaction in the blood and tumor tissue.

[0638] Conversely, if systemic extracellular label cleavage is desired, R 87can be 20 or 40 kDa PEG or albumin, or an albumin binding moiety that ensures long-term retention in the circulation, optionally combined with EPR-based targeting of tumor tissue.

[0639] In one embodiment, the administered agent specifically binds to or complexes with a cell surface molecule, such as a cell surface receptor or antigen, for a given cell population. Following specific binding to or complexing with the receptor, the cell allows the administered agent to be taken up, which is then internalized by the cell. A subsequently administered cleaving agent then enters the cell and cleaves the administered agent, releasing an effector moiety within the cell. In another embodiment, the administered agent specifically binds to or complexes with a cell surface molecule, such as a cell surface receptor or antigen, for a given cell population. After specifically binding to or complexing with the receptor, the cell does not allow the administered agent to be taken up. A subsequently administered cleaving agent will cleave the administered agent outside the cell.

[0640] In image cycling embodiments that involve sequential imaging procedures of the same or different primary targets, it is preferred that the cleaving agent act systemically (i.e., throughout the body). In other image cycling embodiments, the cleaving agent acts as a T T and R selectively cleaves the label as the primary target being imaged. 87 It is preferred that the compound contains:

[0641] Targeting agent T T In a preferred embodiment, the targeting agent T T is used to bind to the primary target.

[0642] In a preferred embodiment, the dienes of the present invention are used as targeting agents T T T bonded to a diene Tcan direct or retain the diene at the location where it needs to be released from the compound of formula (1), so that the T T can be advantageously used in the present invention. For example, to increase the target / non-target ratio of the label, it may be preferable to direct the diene into the blood or retain the diene in the blood when it is not the target. The cleaving agent then primarily releases the label in the blood, which is then rapidly removed. The label at the target (e.g., tumor) is not released, thus increasing the target / non-target ratio of the label.

[0643] In a preferred embodiment, T T is used to influence (more specifically, to prevent) the metabolism of dienes and / or to influence (more specifically, to prevent) the (undesirable) deposition or (undesirable) uptake of dienes into tissues.

[0644] In a preferred embodiment, the T T is the administered agent.

[0645] Those skilled in the art are familiar with such groups and methods for synthesizing them.

[0646] In a preferred embodiment, the T T is selected from the group consisting of polymers, polymer particles, peptides, peptoids, dendrimers, proteins, carbohydrates, oligonucleotides, oligosaccharides, lipids, liposomes, albumin, and albumin-binding moieties. Typically, a suitable polymer is polyethylene glycol (PEG). Such suitable PEGs include PEGs having a number of repeating units ranging from 2 to 4000 and PEGs having molecular weights ranging from 200 Da to 100,000 Da.

[0647] In a preferred embodiment, the T TThese include, but are not limited to, amino acids, nucleosides, nucleotides, carbohydrates, and biopolymer fragments such as oligopeptides or polypeptides, oligopeptoids or polypeptoids, or oligopeptides or polypeptides, or oligo- or poly-carbohydrates, oligonucleotides, varying in 2 to 200, particularly 2 to 113, preferably 2 to 50, more preferably 2 to 24, more preferably 2 to 12 repeating units.

[0648] In a preferred embodiment, the diene-bound T T is a polymer. This includes linear or branched polyalkylene glycols, such as polyethylene glycol (PEG) chains or polypropylene glycol (PPG) chains, varying in repeating units from 2 to 200, particularly from 2 to 113, preferably from 2 to 50, more preferably from 2 to 24, and more preferably from 2 to 12. When the polyalkylene glycol, such as a PEG polymer or a PPG polymer, is bonded via only one end of the polymer chain, the other end is preferably terminated with -OCH3, -OCH2CH3, or -OCH2CH2CO2H.

[0649] Other Suitable Polymeric T TMoieties include polymers and copolymers such as poly-(2-oxazoline), poly(N-(2-hydroxypropyl)methacrylamide) (HPMA), polylactic acid (PLA), polylactic-glycolic acid (PLGA), polyglutamic acid (PG), dextran, polyvinylpyrrolidone (PVP), poly(1-hydroxymethylethylenehydroxymethyl-formal) (PHF). Other exemplary polymers are polysaccharides, glycopolysaccharides, glycolipids, polyglycosides, polyacetals, polyketals, polyamides, polyethers, polyesters. Examples of naturally occurring polysaccharides that can be used are cellulose, amylose, dextran, dextrin, levan, fucoidan, carraginan, inulin, pectin, amylopectin, glycogen, lyxenan, agarose, hyaluronan, chondroitin sulfate, dermatan sulfate, keratan sulfate, alginic acid, and heparin. In yet another exemplary embodiment, the polymer is a copolymer of a polyacetal / polyketal and a hydrophilic polymer selected from the group consisting of polyacrylates, polyvinyl polymers, polyesters, polyorthoesters, polyamides, oligopeptides, polypeptides, and derivatives thereof. Exemplary preferred polymeric T T The moieties are PEG, HPMA, PLA, PLGA, PVP, PHF, dextran, oligopeptides, and polypeptides.

[0650] In some aspects of the invention, the polymeric T T The moieties have molecular weights ranging from 2 to 200 kDa, 2 to 100 kDa, 2 to 80 kDa, 2 to 60 kDa, 2 to 40 kDa, 2 to 20 kDa, 3 to 15 kDa, 5 to 10 kDa, 500 daltons to 5 kDa.

[0651] Other exemplary T T The moieties are dendrimers, such as poly(propyleneimine) (PPI) dendrimers, PAMAM dendrimers, and glycol-based dendrimers.

[0652] In a preferred embodiment, the diene is an imaging moiety, such as an optical or fluorescent dye, or a radioisotope, e.g. 18 F. Preferably, the diene does not contain radionuclides.

[0653] It will be appreciated that chemical modifications can also be made to the tetrazine and targeting agent to make the compounds more convenient to react for the purpose of preparing the conjugates of the invention.

[0654] In a preferred embodiment, the targeting agent T T binds to the primary target. To allow specific targeting of the primary targets listed above, the targeting agent T T These include, but are not limited to, antibodies, antibody derivatives, antibody fragments, antibody (fragment) fusions (e.g., bispecific and trispecific mAb fragments or derivatives thereof), proteins, peptides such as octreotide and its derivatives, VIP, MSH, LHRH, chemotactic peptides, cell-penetrating peptides, membrane-translocating moieties, bombesin, elastin, peptidomimetics, organic compounds, inorganic compounds, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, oligonucleotides, aptamers, viruses, whole cells, phages, drugs, polymers, liposomes, chemotherapeutic agents, receptor agonists and antagonists, cytokines, hormones, steroids, and toxins. Examples of organic compounds contemplated within the context of the present invention are or are derived from dyes, compounds targeting CAIX and PSMA, estrogens such as estradiol, androgens, progestins, corticosteroids, methotrexate, folic acid, and cholesterol.

[0655] According to a specific embodiment of the present invention, the primary target is a receptor, and a targeting agent capable of specifically binding to the primary target is used. Suitable targeting agents include, but are not limited to, ligands of such receptors or portions thereof that still bind to the receptor, such as receptor-binding peptides in the case of receptor-binding protein ligands. Other examples of protein targeting agents include insulin, transferrin, fibrinogen-gamma fragment, thrombospondin, claudins, apolipoprotein E, affibody molecules such as ABY-025, ankyrin repeat proteins, ankyrin-like repeat proteins, interferons such as alpha, beta, and gamma interferons, interleukins, lymphokines, colony-stimulating factors, and protein growth factors such as tumor growth factors, such as alpha, beta, tumor growth factors, platelet-derived growth factor (PDGF), uPAR targeting proteins, apolipoproteins, LDL, annexin V, endostatin, and angiostatin. Alternative examples of targeting agents include DNA, RNA, PNA and LNA, which are complementary to the primary target.

[0656] Examples of targeting peptides include LHRH receptor targeting peptides, EC-1 peptides, RGD peptides, HER2-targeting peptides, PSMA-targeting peptides, somatostatin-targeting peptides, and bombesin. Other examples of targeting agents include lipocalins, such as anticalins. One particular embodiment uses Affibodies™, as well as multimers and derivatives thereof.

[0657] In a preferred embodiment, T T is an antibody. In a preferred embodiment, T T is selected from antibodies and antibody derivatives, such as antibody fragments, fragment fusions, proteins, peptides, peptidomimetics, organic molecules, dyes, fluorescent molecules, enzyme substrates.

[0658] In a preferred embodiment, the T is an organic molecule. T has a molecular weight of less than 2000 Da, more preferably less than 1500 Da, more preferably less than 1000 Da, and even more preferably less than 500 Da.

[0659] In another preferred embodiment, the T T is selected from antibody fragments, fragment fusions, and other antibody derivatives that do not contain an Fc domain.

[0660] In other embodiments, the T T is a polymer. Typical polymers used in this embodiment include, but are not limited to, polyethylene glycol (PEG), poly(N-(2-hydroxypropyl)methacrylamide) (HPMA), polylactic acid (PLA), polylactic-co-glycolic acid (PLGA), polyglutamic acid (PG), polyvinylpyrrolidone (PVP), poly(1-hydroxymethylethylenehydroxymethyl-formal) (PHF). Other examples are copolymers of polyacetal / polyketal with hydrophilic polymers selected from the group consisting of polyacrylates, polyvinyl polymers, polyesters, polyorthoesters, polyamides, oligopeptides, polypeptides, and derivatives thereof. Other examples are oligopeptides, polypeptides, glycopolysaccharides, and polysaccharides such as dextran and hyaluronan. In addition, reference is made to [G. Pasut, FM Veronese, Prog. Polym. Sci. 2007, 32, 933-961]. In a preferred embodiment, T is a polymer. T accumulates at the primary target due to the EPR effect.

[0661] According to a further specific embodiment of the present invention, the primary target and targeting agent are selected to result in specific or increased targeting of tissues or diseases, such as cancer, inflammation, infectious diseases, cardiovascular diseases such as thrombosis, atherosclerosis, hypoxic sites such as stroke, tumors, cardiovascular disorders, brain disorders, apoptosis, angiogenesis, organs, and reporter genes / enzymes. This can be achieved by selecting a primary target with tissue-, cell-, or disease-specific expression. For example, the CC49 antibody targets TAG72, whose expression is restricted in normal tissues, but the receptor is overexpressed in various solid tumor cell types.

[0662] As used herein, a T cell is a molecule that "specifically binds to or complexes with," or "targets," a cell surface molecule, an extracellular matrix target, or another target. T The ligand preferentially associates with the target through intermolecular forces. For example, the ligand has a dissociation constant (K) of less than about 50 nM, less than about 5 nM, or less than about 500 pM. d or K D ) can preferentially associate with the target.

[0663] In other embodiments, the targeting agent T T is localized in the target tissue by the EPR effect. T is a polymer.

[0664] In a preferred embodiment, the targeting agent T T are localized or retained in a particular system, tissue, or organ in the body, such as the blood circulation, lymphatic system, nervous system, digestive system, RES system, or organs such as the heart or kidney. For example, microparticles will localize in the liver, and large hydrophilic polymers will be retained in the circulation. Similarly, T T The use of an albumin binding moiety as a medicament will result in long-term retention in the circulation.

[0665] In a preferred embodiment, T Tis used to alter the pharmacokinetics of the moiety to which it is attached. This can include, but is not limited to, slowing the blood clearance of the moiety, affecting the volume of distribution of the moiety (e.g., decreasing or increasing the volume of distribution), affecting the metabolism of the moiety, and / or affecting (preferably avoiding) the deposition or uptake of the moiety into non-target tissues. Exemplary T in this regard are: T Examples of suitable polymers include polymers, peptides, peptoids, dendrimers, proteins, carbohydrates, oligonucleotides, oligosaccharides, lipids, liposomes, micelles, nanoparticles, microparticles, albumin, albumin-binding moieties, and small to medium-sized organic molecules, such as steroids and dyes. Typically, suitable polymers are polyethylene glycol (PEG) or polypropylene glycol (PPG). Suitable PEGs include those having a number of repeating units ranging from 2 to 4,000 and molecular weights ranging from 200 Da to 100,000 Da.

[0666] In a preferred embodiment, T T If is the administered agent, then it is C B is equal to.

[0667] R 32 R 32 is a conjugation moiety, which may be, for example, a label, an administration agent, a construct C, R 98 , L A , L B , S L , S P , and L C A conjugate is a chemical group that can be used for binding, conjugation, or coupling to a molecule or construct. Those skilled in the art are aware of the myriad strategies available for chemoselective, non-selective, or enzymatic coupling or conjugation of one molecule or construct to another.

[0668] In a preferred embodiment, R 32is a moiety that allows conjugation to proteins containing natural and / or unnatural amino acids. Moieties suitable for conjugation are known to those skilled in the art. Conjugation strategies can be found, for example, in [O. Boutureira, GJL Bernardes, Chem. Rev., 2015, 115, 2174-2195].

[0669] In a particularly preferred embodiment, R 32 is an N-maleimidyl group, a halogenated N-alkylamide group, a sulfonyloxy N-alkylamide group, a vinyl sulfone group, an activated carboxylic acid, a benzenesulfonyl halide, an ester group, a carbonate group, a sulfonyl halide group, a thiol group, or a derivative thereof, C 2~6 Alkenyl group, C 2~6 Alkynyl group, C 7~18 Cycloalkynyl group, C 5~18 Heterocycloalkynyl group, bicyclo[6.1.0]non-4-yn-9-yl] group, C 3~12Cycloalkenyl groups, azide groups, phosphine groups, nitrile oxide groups, nitrone groups, nitrile imine groups, isonitrile groups, diazo groups, ketone groups, (O-alkyl)hydroxylamino groups, hydrazine groups, N-maleimidyl halide groups, aryloxymaleimides, dithiophenolmaleimides, bromo- and dibromo-pyridazinediones, 2,5-dibromohexanediamide groups, alkynone groups, 3-arylpropiolonitrile groups, 1,1-bis(sulfonylmethyl)-methylcarbonyl groups, or elimination derivatives thereof. derivatives), carbonyl halide groups, arenamide groups, 1,2-quinone groups, isocyanate groups, isothiocyanate groups, aldehyde groups, triazine groups, squaric acid, 2-imino-2-methoxyethyl groups, (oxa)norbornene groups, (imino)sydnone, methylsulfonylphenyloxadiazole groups, aminoxy groups, 2-aminobenzamidoxime groups, ethynylphosphonamidate, groups reactive in Pictet-Spengler ligation and hydrazino-Pictet-Spengler (HIPS) ligation, DNA intercalators, tetrazine groups, and photocrosslinkers.

[0670] In a preferred embodiment, R 32 is an N-maleimidyl group connected to the remainder of the compound according to formula (20) via the N atom of the N-maleimidyl group. In another preferred embodiment, R 32 is selected from the group consisting of a hydroxyl group, an amine group, a halogen, a vinylpyridine group, a disulfide group, a pyridyl disulfide group, a sulfonyloxy group, a mercaptoacetamide group, an anhydride group, a sulfonylated hydroxyacetamide group, a sulfonyl chloride, a thiosemicarbazone, a hydrazine carboxylate, and an aryl hydrazide.

[0671] In other embodiments, R 32is a group that can be attached to another group by an enzyme, such as a sortase or tubulin tyrosine ligase.

[0672] R’ In a preferred embodiment, each R' is independently a hydrogen atom, a C1 to C6 alkylene group, a C2 to C6 alkenylene group, a C2 to C6 alkynylene group, a C6 arylene, a C4 to C5 heteroarylene, a C3 to C6 cycloalkylene group, a C5 to C8 cycloalkenylene group, a C5 to C 12 Alkyl(hetero)arylene groups, C5-C 12 (Hetero)arylalkylene group, C4-C 12 Alkylcycloalkylene groups and C4-C 12 cycloalkyl alkylene groups.

[0673] In a preferred embodiment, each R' is independently a hydrogen atom, a C1-C4 alkylene group, a C2-C4 alkenylene group, a C2-C4 alkynylene group, a C6 arylene, a C4-C5 heteroarylene, a C3-C6 cycloalkylene group, a C5-C8 cycloalkenylene group, a C5-C8 alkyl(hetero)arylene group, a C5-C8 (hetero)arylalkylene group, a C4-C 12 It is selected from the group consisting of alkylcycloalkylene groups, and C4 to C8 cycloalkylalkylene groups.

[0674] Unless otherwise specified, for R', the above alkylene group, alkenylene group, alkynylene group, (hetero)arylene group, cycloalkylene group, cycloalkenylene group, alkyl(hetero)arylene group, (hetero)arylalkylene group, alkylcycloalkylene group, and cycloalkylalkylene group include -Cl, -F, -Br, -I, -OH, -NH2, ═O, -SH, -SO3H, and -PO3H. 、It may be substituted with a moiety selected from the group consisting of -PO4H2, -NO2, and may contain one or more heteroatoms selected from the group consisting of -O-, -S-, -NH-, -P-, and -Si, wherein the N, S, and P atoms are optionally oxidized.

[0675] Medical and Non-Therapeutic Uses

[0676] therapeutic use In one aspect, the present invention relates to compounds, combinations, and kits for use as pharmaceuticals. Alternatively, the kits of the present invention are used in methods for treating or imaging a patient, the method comprising administering to the subject a compound included in the kit of the present invention.

[0677] In another aspect, the present invention relates to a compound, combination, or kit of the present invention for use in the treatment of a disease, preferably cancer, in a subject, preferably a human. Preferably, the treatment is radiation therapy.

[0678] Preferably, the radiotherapy comprises: (a) administering to said subject a compound according to Formula (1), as defined herein; (b) administering to said subject a cleaving agent as defined herein; (c) irradiating the compound according to formula (1) present in the object. The process includes the steps of:

[0679] The present disclosure also relates to a method of treatment in a subject as defined herein, the method comprising steps (a) to (c) as defined in the preceding paragraph. Preferably, the method is for treating cancer in the subject.

[0680] In a preferred embodiment, step (a) is performed first, step (b) is performed second, and then step (c) is performed. In this embodiment, step (b) is preferably performed after waiting a sufficient time after step (a), so that a significant portion, preferably at least 10%, more preferably at least 50%, of the maximum achievable dose of the compound according to formula (1) reaches the target. Preferably, the cleavage agent and / or its dose is selected in this embodiment to ensure that a significant amount, preferably less than 30%, more preferably less than 10%, of the compound according to formula (1) that reaches the target is not cleaved. In this way, in step (b), the target-to-background ratio of the radionuclide can be optimized before irradiation in step (c). Preferably, in this embodiment, a further step (b) is performed after step (c) to rapidly reduce the amount of the radionuclide in the subject after irradiation.

[0681] In other embodiments, step (a) is performed first, step (c) is performed second, and then step (b) is performed. In this manner, the amount of radionuclide in the subject can be rapidly reduced after imaging to minimize the radiation dose received by non-target tissue.

[0682] In other embodiments, step (b) is performed first, allowing the cleaving agent to accumulate in non-target tissues requiring protection from radiation; a second step (a) is performed, providing targeting of the radiation to the target tissues while the label is cleaved and removed in the non-target tissues by the pre-localized cleaving agent; and then step (c) is performed.

[0683] Similarly, the cleaving agent can be administered locally, ie, injected directly into selected non-target tissue, as opposed to systemic intravenous administration.

[0684] One notable application of the present invention is radioimmunotherapy targeting internalized cancer receptors, such as HER2. In this approach, trastuzumab (Tmab), an antibody targeting HER2, is modified with, for example, the three TCO chelate constructs shown below. The TCO chelate construct (NHS-TCO-DOTA) contains a TCO linker, which is an active ester for lysine conjugation, and 117 and a therapeutic beta-emitter, a DOTA chelate for Lu labeling. 117 Following Lu labeling and intravenous (i.v.) injection, 117 The Lu-Tma is allowed time to circulate, bind to HER2 targets at the breast or ovarian cancer site, and be internalized (approximately 2 days), after which a tetrazine containing cleaving agent is injected intravenously, which separates the freely circulating Tmab from the HER2 target. 117 Cleavage of the Lu-DOTA construct via the kidney 117 This results in rapid clearance of the Lu-DOTA construct and significantly reduces the radiation dose to the bone marrow. Typically, the cleavage agents are hydrophilic, and therefore cell-impermeable, and therefore, do not penetrate into the target cells. 117 However, the cleavage agent is cell-permeable and does not cleave Lu-Tmab within the target cell. 117 Even when Lu-Tmab is cleaved, the released 117 Lu-DOTA would remain trapped inside the cells.

[0685] [ka]

[0686] Alternatively, if the cleaving agent is designed to have low or slow uptake in tumors, a non-internalized cancer receptor can be used as the primary target in the above example. For example, the cleaving agent can comprise a biodegradable PLGA particle core with a diameter of approximately 500 nm modified with a tetrazine moiety. Such particles exhibit rapid clearance from the blood by the liver, can only react with circulating TCO-containing constructs, and ensure that they do not accumulate in tumors, as previously shown for tetrazine clearance agents (Rossin et al., J. Nucl. Med. 2013, 4, 11, 1989-1995; and WO 2012085789 A1). For imaging applications, slow accumulation at the target site may be acceptable, in which case the tetrazine can be modified with an albumin-binding moiety, a protein, or a polymer, such as PEG, to maximize its retention in the circulation and thereby promote its reaction with circulating TCO constructs.

[0687] In another preferred embodiment of the present invention, the administration of a compound of formula (1) followed by a cleavage agent allows for the regulation of the blood circulation and excretion pathways of the released label.

[0688] 117 In the context of Lu-Tmab RIT, after cell internalization, a cleaving agent, e.g., a cleaving agent comprising a tetrazine functionalized with a short polyethylene glycol (PEG) polymer, is injected and binds to the TCO trigger, resulting in cleavage of the bond between the TCO and the antibody. 177 The Lu-DOTA chelate is released into the circulation and, because of the PEG, it is cleared via the kidney.

[0689] [ka]

[0690] In a similar approach, instead of a linear or branched polymer, the cleaving agent carries one or more functional groups that affect the clearance pathway of the released moiety. For example, a cleaving agent containing a tetrazine and several galactose groups generates a released moiety that binds to the Ashwell receptor on hepatocytes, thus resulting in rapid hepatobiliary clearance of the label.

[0691] In another preferred embodiment of the invention, the administered agent is an antibody fragment carrying an imageable or therapeutic radiometal chelate, which specifically accumulates in tumor or other diseased tissue and is internalized within target cells, but is nonspecifically retained in non-target organs, such as, but not limited to, kidneys, salivary glands, and lacrimal glands. In this approach, the label (e.g., 177 Lu or 225 Ac-labeled DOTA, or 89 Zr-labeled DFO is linked to a targeting moiety via a TCO trigger. Following intravenous injection of the agent, and subsequent accumulation of the agent in the affected tissue and internalization within the target cells (e.g., 4-24 hours after injection), the patient is intravenously administered a cleaving agent. The cleaving agent specifically binds to the TCO trigger in the agent in non-target organs and releases the label, thereby inducing washout of radioactivity from these organs via urine. This reduces the radioactive dose delivered to non-target organs, thus increasing the therapeutic index of the agent of interest and reducing the potential for toxic side effects for patients during nuclear imaging procedures.

[0692] In another preferred embodiment of the present invention, the compound of formula (1) is functionalized at both allylic positions. The compound of formula (1) is intravenously injected into an animal or human subject, followed after a suitable time (e.g., 2 days) by intravenous administration of the cleaving agent. Here, the cleaving agent specifically reacts with a trigger, resulting in the release of at least one of the two moieties conjugated at the TCO allylic position. This approach allows for very fast and complete release of small fragments (e.g., labels) that are rapidly cleared from non-target tissues, preferentially via the kidney, regardless of the pyridazine tautomer (compounds 1, 4 or 2, 5) subsequently formed. For very fast and complete release, the tetrazine conforms to formula (14), where Y a is Y1, Y3, or Y5, and Q1 is X 45 , and preferably X 45 is OH and Y b is Y a or H. A non-limiting example of this approach is 177 A mAb labeled with Lu is shown below.

[0693] [ka]

[0694] In yet another preferred embodiment of the present invention, the compound of formula (1) comprises a TCO trigger conjugated to a targeting agent and to an imaging or therapeutic moiety (label) via a self-immolative linker. The compound of formula (1) is intravenously injected into an animal or human subject, where it accumulates at the target site, followed by intravenous administration of a tetrazine cleavage agent after a suitable time (e.g., 1 or 2 days). The tetrazine reacts with the trigger, resulting in an intermediate that electronically rearranges, resulting in fragmentation of the linker and separation of the label from the targeting agent. As a result, the label, which is a small molecule, is rapidly removed from the subject's circulation, preferentially via the kidney. Non-limiting examples of the present invention are shown below.

[0695] [ka]

[0696] In another preferred embodiment of the present invention, a compound of Formula (1) comprises an imageable or therapeutic moiety that binds to a targeting agent that binds to a specific receptor or molecule present both at the disease site and in the circulation due to shedding via a TCO trigger. Non-limiting examples of shedding targets are carcinoembryonic antigen (CEA), prostate-specific antigen (PSA), and tumor necrosis factor α (TNF-α) receptors. In the presence of target shedding, binding of the administered agent to the circulating target can be harmful due to loss of image contrast and / or toxic side effects in the subject of medical intervention. In this approach, a compound of Formula (1) is intravenously injected into an animal or human subject and binds to its target at the disease site and in the circulation. After an appropriate time (one or two days), the subject is intravenously injected with a tetrazine cleaving agent, which is designed to specifically react with the TCO trigger in the circulating (bound) administered agent. Upon reaction of the tetrazine with the TCO, the imageable or therapeutic moiety is released from the administered agent, which is rapidly cleared from the circulation.

[0697] In one preferred embodiment, the present invention is used to reduce kidney dose instead of bone marrow dose. In this embodiment, the administered agent is an intact IgG antibody. 225 It is labeled with Ac and is capable of binding to its primary target, eg, HER2, PSMA. 225 Ac has a chain of daughter isotopes, 225 Upon initial decay of Ac, the nuclide dissociates from DOTA and the administered agent, and a free daughter 221 Timely injection of the cleavage agent results in cleavage in the blood and transport of DOTA-Fr through the kidney. 225 Rapidly removes Ac and promotes kidney function 221Reduces Fr radiation dose.

[0698] In another embodiment, the primary target is a receptor on a hematological cancer cell, i.e., CD33 on an AML cell, and the agent is an anti-CD33 mAb, and the label is a DOTA- 225 After CD33 binding and internalization, the freely circulating mAb DOTA- 225 The Ac label is cleaved, reducing radiotoxicity to the kidneys and also to the bone marrow, liver, and spleen.

[0699] Moreover, the disclosure (a) administering to a subject, preferably a human, a compound according to formula (1), as defined herein; (b) administering to said subject a cleaving agent as defined herein; (c) imaging a compound according to Formula (1) present in said subject and collecting data; (d) comparing the data with standard values; (e) detecting significant deviations from the standard value during the comparison; (f) attributing said significant deviation to a particular clinical condition, preferably cancer. The present invention relates to a diagnostic method comprising the steps of:

[0700] Diagnostic methods The present invention also relates to a compound of formula (1) as defined herein, a combination as defined herein, or a process comprising the steps of: (a) administering to a subject, preferably a human, a compound according to formula (1), as defined herein; (b) administering to said subject a cleaving agent as defined herein; (c) imaging a compound according to Formula (19) present in said subject and collecting data; (d) comparing the data with standard values; (e) detecting significant deviations from the standard value during the comparison; (f) attributing said significant deviation to a particular clinical condition, preferably cancer. The present invention relates to a kit as defined herein for use in a diagnostic method comprising:

[0701] non-therapeutic methods The present invention also relates to a non-therapeutic method for imaging a compound of formula (1), as defined herein, in a subject, preferably a human, as defined herein, said non-therapeutic method comprising: (a) administering to a subject a compound according to Formula (1), as defined herein; (b) administering to said subject a cleaving agent as defined herein; (c) imaging the compound according to formula (1) present in said subject. The process includes the steps of:

[0702] In a preferred embodiment, step (a) is performed first, step (b) is performed second, and then step (c) is performed. In this embodiment, step (b) is preferably performed after waiting a sufficient time after step (a), so that a significant portion, preferably at least 10%, more preferably at least 50%, of the maximum achievable initial dose of the compound according to formula (1) reaches the target. Preferably, the cleavage agent and / or its dose is selected in this embodiment to ensure that a significant amount, preferably less than 30%, more preferably less than 10%, of the compound according to formula (19) that reaches the target is not cleaved. In this way, in step (b), the target-to-background ratio of the radionuclide can be optimized before imaging in step (c).

[0703] Preferably, in this embodiment, a further step (b) is carried out after step (c) to rapidly reduce the amount of radionuclide in the subject after imaging.

[0704] In other embodiments, step (a) is performed first, step (c) is performed second, and then step (b) is performed. In this manner, the amount of radionuclide in the subject can be rapidly reduced after imaging to reduce whole-body radiation dose and / or optionally allow for another imaging procedure (image cycling).

[0705] In other embodiments, step (b) is performed first, allowing the cleaving agent to accumulate in non-target tissues that require protection from radiation or that would otherwise obscure imaging of the primary target; a second step (a) is performed, providing targeting of the radiation to the target tissues, while the label is cleaved and removed in the non-target tissues by the pre-localized cleaving agent; and then step (c) is performed.

[0706] Similarly, the cleaving agent can be administered locally, ie, injected directly into selected non-target tissue, as opposed to systemic intravenous administration.

[0707] The present invention can be used to improve radioimmunoimaging of HER2 with trastuzumab (Tmab). In this approach, Tmab is modified with, for example, two TCO-DFO chelate constructs, as shown below, where Tmab is conjugated via thiol maleimide chemistry. 9 Following Zr-labeling and intravenous (i.v.) injection, 89 The Zr-Tmab is allowed to circulate, bind to HER2 targets at breast or ovarian cancer sites, and is given time to be internalized (approximately 2 days), after which it is injected intravenously with a cleaving agent containing tetrazine, which separates the freely circulating Tmab from the Tmab. 89 Cleavage of Zr-DFO labeling and kidney-mediated 89 This results in rapid clearance of the Zr-DFO construct and a significantly improved tumor-to-blood ratio for imaging of the target.

[0708] [...

Claims

1. A compound satisfying the following formula (1) or a pharma- ceutically acceptable salt thereof: 【Chemistry 01】 Where: The compound of formula (1) comprises at least one label and at least one administration agent; the label is a moiety that contains a radionuclide; The agent is an antibody, where the term "antibody" refers to an antibody, an antibody fragment that is at least a portion of the variable region of an immunoglobulin that binds to its target, or an antibody mimetic; each X 1 , X 2 , X 3 , X 4 are independent of each other, -C(R 47 ) 2 - and X 5 is -C(R 47 ) 2 -or-CHR 48 and Each R 48 are independent, -L B and -L A selected from the group consisting of: R 48 is -O-, -S-, -OC(O)-, -OC(S)-, -SC(O)- or -SC(S)-; R 48 is attached to the remainder of the compound of formula (1) via a moiety L B is a portion that satisfies the following formula (2): 【Chemistry 02】 Where: The dashed line indicates the bond to the remainder of the compound of formula (1); S L is a linker, which is a self-immolative linker L C may be; Each R 98 are individually said label or clearance-indicating group, where the clearance-indicating group is a moiety that directs a compound to an excretory organ, said clearance-indicating group comprising one or more hexoses; each d is independently 0 or 1; e is an integer ranging from 0 to 4; L A is a portion that satisfies the following formula (3): 【Chemistry 03】 Where: The dashed line indicates the bond to the remainder of the compound of formula (1); Each s is independently 0 or 1; i is an integer ranging from 0 to 4; Each S P is independently a spacer, which is a self-immolative linker L C may be; A A represents the administration agent; C C represents Construct-C, wherein each Construct-C is independently selected from the group consisting of said label and said administration agent; However, L A R 48 When L A necessarily has both the label and the agent; With the proviso that when R 48 is LB, at least one R 47 is LA; However, R 48 Where L is A When the compound contains both the label and the administration agent, S bound to the label and the administration agent P is a self-immolative linker, wherein the label and the administering agent are decoupled following reaction of the compound of formula (1) with a cleavage agent due to the self-immolative nature of the linker, wherein the cleavage agent is a diene; Each R 47 are independently a hydrogen atom, -L B , -L A , -(S P ) i -C C , -F, -Cl, -Br, -I, -OR 37 , -N(R 37 ) 2 , -SO 3 , -PO 3 - 、 -NO 2 , -CF 3 , -SR 37 , S(=O) 2 N(R 37 ) 2 ,OC(=O)R 37 , SC(=O)R 37 ,OC(=S)R 37 , SC(=S)R 37 , N.R. 37 C(=O)-R 37 , N.R. 37 C(=S)-R 37 , N.R. 37 C(=O)OR 37 , N.R. 37 C(=S)OR 37 , N.R. 37 C(=O)SR 37 , N.R. 37 C(=S)SR 37 ,OC(=O)N(R 37 ) 2 , SC(=O)N(R 37 ) 2 ,OC(=S)N(R 37 ) 2 , SC(=S)N(R 37 ) 2 , N.R. 37 C(=O)N(R 37 ) 2 , N.R. 37 C(=S)N(R 37 ) 2 , C(=O)R 37、 C(=S)R 37、 C(=O)N(R 37 ) 2 , C(=S)N(R 37 ) 2 , C(=O)OR 37 , C(=O)SR 37 , C(=S)OR 37 , C(=S)SR 37 , S(O)R 37 , -S(O) 2 R 37 , N.R. 37 S(O) 2 R 37 , -ON(R 37 ) 2、- NR 37 OR 37 , C 1 ~C 24 Alkyl group, C 2 ~C 24 Alkenyl group, C 2 ~C 24 Alkynyl group, C 6 ~C 24 Aryl group, C 2 ~C 24 Heteroaryl groups, C 3 ~C 24 Cycloalkyl groups, C 5 ~C 24 Cycloalkenyl group, C 12 ~C 24 Cycloalkynyl group, C 3 ~C 24 (Cyclo)alkyl(hetero)aryl groups, C 3 ~C 24 (Hetero)aryl(cyclo)alkyl, C 4 ~C 24 (Cyclo)alkenyl(hetero)aryl groups, C 4 ~C 24 (Hetero)aryl(cyclo)alkenyl groups, C 4 ~C 24 (Cyclo)alkynyl(hetero)aryl groups, C 4 ~C 24 (Hetero)aryl(cyclo)alkynyl groups, C 4 ~C 24 Alkylcycloalkyl groups, and C 4 ~C 24 cycloalkylalkyl groups, where i is an integer ranging from 0 to 4; Here, the above alkyl group, alkenyl group, alkynyl group, aryl group, heteroaryl group, cycloalkyl group, cycloalkenyl group, cycloalkynyl group, (cyclo)alkyl(hetero)aryl group, (hetero)aryl(cyclo)alkyl group, (cyclo)alkenyl(hetero)aryl group, (hetero)aryl(cyclo)alkenyl group, (cyclo)alkynyl(hetero)aryl group, (hetero)aryl(cyclo)alkynyl group, alkylcycloalkyl group, and cycloalkylalkyl group are each independently selected from the group consisting of -Cl, -F, -Br, -I, -OR, -C1, -C2, -C3, -C4, -C5, -C6, -C7, -C8, -C9, -C10, -C11, -C12, -C13, -C14, -C15, -C16, -C17, -C18, -C19, -C20, -C21, -C22, -C23, -C24, -C25, -C36, -C37, -C38, -C39, -C41, -C42, -C43, -C44, -C55, -C56, -C57, -C58, -C59, -C60, -C61, -C62, -C73, -C74, -C75, -C75, -C76, -C77, -C88, -C99, -C91, -C92, -C93, -C94, -C95, -C96, -C97, -C98, -C99 37 , -N(R 37 ) 2 , -SO 3 R 37 , -PO 3 (R 37 ) 2、 -PO 4 (R 37 ) 2、 -NO 2 , -CF 3 , =O, =NR 37 , and -SR 37 and may be substituted by a moiety selected from the group consisting of O, S, NR 37 , P and Si, wherein the N, S and P atoms are optionally oxidized, and wherein a plurality of N atoms are optionally quaternized; The Two R's 47 and / or R 37 may be contained within the ring, The Two R's 47 and / or R 37 may be included within a ring to form a ring fused to the 8-membered trans ring of formula (1); Each R 37 are independently a hydrogen atom, -L B , -L A , -(S P ) i -C C , C 1 ~C 24 Alkyl group, C 2 ~C 24 Alkenyl group, C 2 ~C 24 Alkynyl group, C 6 ~C 24 Aryl group, C 2 ~C 24 Heteroaryl groups, C 3 ~C 24 Cycloalkyl groups, C 5 ~C 24 Cycloalkenyl group, C 12 ~C 24 Cycloalkynyl group, C 3 ~C 24 (Cyclo)alkyl(hetero)aryl groups, C 3 ~C 24 (Hetero)aryl(cyclo)alkyl, C 4 ~C 24 (Cyclo)alkenyl(hetero)aryl groups, C 4 ~C 24 (Hetero)aryl(cyclo)alkenyl groups, C 4 ~C 24 (Cyclo)alkynyl(hetero)aryl groups, C 4 ~C 24 (Hetero)aryl(cyclo)alkynyl groups, C 4 ~C 24 Alkylcycloalkyl groups, and C 4 ~C 24 cycloalkylalkyl groups, where i is an integer ranging from 0 to 4; R that is not a hydrogen atom 37 The groups are -Cl, -F, -Br, -I, -OH, -NH 2 , -SO 3 H, -PO 3 H 、 -PO 4 H 2、 -NO 2 , -CF 3 , =O, =NH, and -SH, and may contain one or more heteroatoms selected from the group consisting of O, S, NH, P, and Si, where the N, S, and P atoms are optionally oxidized, and where multiple N atoms are optionally quaternized.

2. The radioactive nuclide is 3 H, 11 C, 13 N, 15 O, 18 F, 19 F, 51 Cr, 52 Fe, 52 Mn, 55 Co, 60 Cu, 61 Cu, 62 Zn, 62 Cu, 63 Zn, 64 Cu, 66 Ga, 67 Ga, 68 Ga, 70 As, 71 As, 72 As, 74 As, 75 Se, 75 Br, 76 Br, 77 Br, 8O Br, 82 Br, 82 Rb, 86 Y, 88 Y, 90 Y, 89 Sr, 89 Zr, 97 Ru, 99m Tc, 110 In, 111 In, 113 In, 114 In, 117 Sn, 120 I, 122 Xe, 123 I, 124 I, 125 I, 166 Ho, 167 Tm, 169 Yb, 193 Pt, 195 Pt, 201 Tl, 203 Pb, 24 Na, 32 P, 33 P, 47 Sc, 59 Fe, 67 Cu, 76 As, 77 As, 80 Br, 82 Br, 89 Sr, 90 Nb, 90 Y, 103 Ru, 105 Rh, 109 Pd, 111 Ag, 111 In, 121 Sn, 127 Te, 131 I, 140 La, 141 Ce, 142 Pr, 143 Pr, 144 Pr, 149 Pm, 149 Tb, 151 Pm, 153 Sm, 159 Gd, 161 Tb, 165 Dy, 166 Dy, 166 Ho, 169 Er, 172 Tm, 175 Yb, 177 Lu, 186 Re, 188 Re, 198 Au, 199 Au, 211 At, 211 Bi, 212 Bi, 212 Pb, 213 Bi, 214 Bi, 223 Ra, 224 Ra, 225 Ac, and 227 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of: Th.

3. 3. The compound of claim 1 or 2, or a pharma- ceutically acceptable salt thereof, wherein the label is a chelating moiety that chelates a radionuclide.

4. X 1 , X 2 , X 3 , and X 4 -C(R 47 ) 2 The compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof, wherein:

5. The compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof, having no more than one label and no more than one administration agent.

6. A kit comprising the compound of any one of claims 1 to 5, or a pharma- ceutical acceptable salt thereof, and a cleavage agent, wherein R 48 When at least one of the cleavage agents has a label, the cleavage agent is R 48 except that R 48 When at least one of the cleavage agents is R 48 does not have the same sign as wherein the cleavage agent is a diene.

7. The kit of claim 6, wherein the diene is a tetrazine or a pharma- ceutically acceptable salt thereof, and the tetrazine may be a tetrazine or a pharma- ceutically acceptable salt thereof that satisfies formula (4). 【Chemistry 04】 Where: Each part Q 1 and Q 2 are independently a hydrogen atom, -F, -Cl, -Br, -I, or -OR 37 , -N(R 37 ) 2 , -SO 3 , -PO 3 - 、 -NO 2 , -CF 3 , -SR 37 , S(=O) 2 N(R 37 ) 2 ,OC(=O)R 37 , SC(=O)R 37 ,OC(=S)R 37 , SC(=S)R 37 , N.R. 37 C(=O)-R 37 , N.R. 37 C(=S)-R 37 , N.R. 37 C(=O)OR 37 , N.R. 37 C(=S)OR 37 , N.R. 37 C(=O)SR 37 , N.R. 37 C(=S)SR 37 ,OC(=O)N(R 37 ) 2 , SC(=O)N(R 37 ) 2 ,OC(=S)N(R 37 ) 2 , SC(=S)N(R 37 ) 2 , N.R. 37 C(=O)N(R 37 ) 2 , N.R. 37 C(=S)N(R 37 ) 2 , C(=O)R 37、 C(=S)R 37、 C(=O)N(R 37 ) 2 , C(=S)N(R 37 ) 2 , C(=O)OR 37 , C(=O)SR 37 , C(=S)OR 37 , C(=S)SR 37 , S(O)R 37 , -S(O) 2 R 37 , N.R. 37 S(O) 2 R 37 , -ON(R 37 ) 2、- NR 37 OR 37 , alkyl groups, alkenyl groups, alkynyl groups, aryl groups, heteroaryl groups, cycloalkyl groups, cycloalkenyl groups, cycloalkynyl groups, (cyclo)alkyl(hetero)aryl groups, (hetero)aryl(cyclo)alkyl, (cyclo)alkenyl(hetero)aryl groups, (hetero)aryl(cyclo)alkenyl groups, (cyclo)alkynyl(hetero)aryl groups, (hetero)aryl(cyclo)alkynyl groups, alkylcycloalkyl groups, and cycloalkylalkyl groups; Here, H, -F, -Cl, -Br, -I, -OH, -NH 2 , -SO 3 , -PO 3 - 、 -NO 2 , -CF 3 Q where it's not 1 Group and Q 2 The groups are -Cl, -F, -Br, -I, -OR 37 , -N(R 37 ) 2 , -SO 3 R 37 , -PO 3 (R 37 ) 2、 -PO 4 (R 37 ) 2、 -NO 2 , -CF 3 , =O, =NR 37 , and -SR 37 and may be substituted with a moiety selected from the group consisting of O, S, NR 37 , P and Si, wherein the N, S and P atoms are optionally oxidized, and wherein a plurality of N atoms are optionally quaternized; Here, Q 1 Group and Q 2 The groups include polymers, particles, peptides, peptoids, dendrimers, proteins, aptamers, carbohydrates, oligonucleotides, oligosaccharides, lipids, steroids, liposomes, targeting agents, T , -(S P ) D -R 87 , an albumin binding moiety, and a chelating moiety; where D is 0 or 1; S P is a spacer; Each R 87 are independently selected from the group consisting of organic molecules, inorganic molecules, organometallic molecules, resins, beads, glass, microparticles, nanoparticles, gels, surfaces, and cells; and part Q 1 and Q 2 At least one of the following is not a hydrogen atom:

8. Q 1 and Q 2 is a hydrogen atom, C 1 ~C 8 is selected from the group consisting of alkyl, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2,6-pyrimidyl, 2,5-pyrimidyl, 3,5-pyrimidyl, and 2,4-pyrimidyl; and Q is not a hydrogen atom. 1 and Q 2 The kit of claim 7, wherein:

9. In formula (4), (a)Q 1 and Q 2 is selected from the group consisting of 2-pyridyl, 3-pyridyl, and 4-pyridyl; (b)Q 1 is selected from the group consisting of 2,6-pyrimidyl, 2,5-pyrimidyl, 3,5-pyrimidyl, and 2,4-pyrimidyl; and Q 2 is (hetero)alkyl; or (c)Q 1 is phenyl, and Q 2 is a hydrogen atom; And in (a) to (c), all Q that are not hydrogen atoms 1 and Q 2 is optionally substituted as defined in claim 7, The kit according to claim 7 or 8.

10. A compound according to any one of claims 1 to 5 or a pharma- ceutically acceptable salt thereof, or a kit according to any one of claims 6 to 9, for use as a pharmaceutical.

11. 10. A compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof, or a kit according to any one of claims 6 to 9, for use in the treatment of a disease in a subject, wherein the treatment is radiation therapy.

12. A compound according to any one of claims 1 to 5 or a pharma- ceutically acceptable salt thereof or a kit according to any one of claims 6 to 9 for use in a diagnostic method, The method comprises: (a) administering to a subject a compound according to formula (1) as defined in any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof; (b) administering to the subject a cleavage agent according to any one of claims 6 to 9; (c) imaging the compound according to Formula (1), or a pharma- ceutically acceptable salt thereof, present in said subject to collect data; (d) comparing said data with a standard value; (e) detecting significant deviations from said standard values ​​during the comparison; (f) attributing the significant deviation to a particular clinical condition. The compound or a pharma- ceutically acceptable salt thereof, or the kit, comprising the steps of:

13. An agent for use in imaging, said agent comprising a compound according to any one of claims 1 to 5 or a pharma- ceutical acceptable salt thereof, said imaging comprising the steps of: (a) administering said compound or said pharma- ceutical acceptable salt to a subject; (b) administering to the subject a cleavage agent according to any one of claims 6 to 9; (c) imaging said compound or said pharma- ceutical acceptable salt present in said subject. The agent comprising:

14. 10. An agent for use in imaging in a subject, the agent comprising a compound according to any one of claims 1 to 5 or a pharma- ceutically acceptable salt thereof, or a kit according to any one of claims 6 to 9.

Images