Trans-cyclooctene with improved T-linker

Abstract

For example, trans-cyclooctene (TCO) which may have improved properties in clinical use is disclosed herein. In some embodiments, the TCO may have improved in vitro and in vivo properties compared to other TCOs. The disclosure also relates to in vivo and in vitro methods using the trans-cyclooctene, as well as its pharmaceutically useful applications, methods for producing the TCO, and compositions and / or combinations comprising the TCO.

Description

[Technical Field]

[0001] The disclosure herein relates to trans-cyclooctene (TCO) having improved properties. Compositions and combinations containing the TCO of this disclosure, as well as methods for using them, are also provided. [Background technology]

[0002] In the field of bioorthogonal chemistry, the ligation between TCO and dienes, particularly tetrazines, has been extensively studied. While this ligation functions well both in vitro and in vivo, identifying the optimal compounds for clinical use remains a focus of research.

[0003] In line with these considerations, it is desirable to identify novel TCOs that possess one or more of the following overall favorable characteristics in vitro and in vivo: fast blood clearance rate, high uptake at target sites (e.g., tumors), low extratarget uptake, a good metabolic profile, good stability, good reactivity with tetrazine, and / or high payload release (especially in vivo). [Overview of the project] [Problems that the invention aims to solve]

[0004] Therefore, a new TCO is needed to address one or more of the above-mentioned problems and / or requirements. [Means for solving the problem]

[0005] This disclosure relates to at least the following embodiments.

[0006] Embodiment 1. A compound, or a salt, hydrate or solvate thereof; wherein the compound has a structural formula according to the following formula (1): [Chemical formula] wherein L 1 is selected from the group consisting of linear or branched C4-C 12 alkylene, C3-C8 (hetero) cycloalkylene, C6-C 12 arylene and C4-C 11 heteroarylene; L 2a , L 2b and L 2d are each independently a linker; L 2c is selected from the group consisting of C1-C8 (hetero) alkanetriyl, C5-C6 (hetero) arenetriyl, C3-C7 cycloalkanetriyl and C2-C7 heterocycloalkanetriyl; T 1 is -OT 1A , a hydrogen atom, C2-C6 alkyl, C6 aryl, C4-C5 heteroaryl, C3-C6 cycloalkyl, C5-C 12 alkyl(hetero)aryl, C5-C 12 (hetero)arylalkyl, C4-C 12 alkylcycloalkyl, -N(T 1A )2, -ST 1A , -SO3H, -C(O)T 1A , -C(O)OT 1A , -O-C(O)T 1A , -C(O)N(T 1A )2, -N(T 1A )2-CO-T 1A , and -Si(T 1A )3; each T 1A is independently selected from the group consisting of a hydrogen atom, (hetero)alkyl, (hetero)alkenyl, (hetero)alkynyl, (hetero)aryl and an amino acid residue; T 2 is a bioconjugation moiety or the group -L 3 -C B wherein L 3 is the residue of a bioconjugation moiety, and, CB This is selected from the group consisting of proteins, nucleic acids, peptides, carbohydrates, aptamers, lipids, small organic molecules, polymers, LNA, PNA, amino acids, peptoids, chelate moieties, fluorescent dyes, phosphorescent dyes, organic particles, gels, cells, and combinations thereof; T 3 is a polymer; and R 48 These are -OH, -O-acetyl, -OC 1~4 Selected from the group consisting of alkyl, halogen atoms, active carbonates and releaseable groups; and preferably, L 1 C4-C4 is a linear or branched C4-C4. 12 It is alkylene, more preferably L 1 C4-C4 is a linear or branched C4-C4. 10 It is an alkylene, most preferably L 1 is a linear C5-C6 alkylene; preferably, L 2a , L 2b and L 2d Each is a linker containing 20 or fewer atoms independently; more preferably, L 2a , L 2b and L 2d Independently, -C(O)NL 2T -, -NL 2T C(O)-, -O-, -S-, -NL 2T -, -N=N- and -C(O)- are selected from the group; where L 2T is a hydrogen atom or a methyl atom, preferably L 2T is a hydrogen atom; preferably, L 2c is C1-C8 (hetero)alkantriyl, more preferably L 2c is C1-C8 alkantriyl, most preferably L 2c is C4-C6 alkantriyl; preferably, T 1 HA-OT 1A And; most preferably, T 1 is -OH; preferably, T 1A is a hydrogen atom or a methyl atom, more preferably T 1A is a hydrogen atom; preferably, T 2 This refers to maleimidyl, N-hydroxysuccinimidyl, or -L3 -C B And; preferably, L 3 is a residue of the maleimidyl moiety or a residue of the N-hydroxysuccinimidyl moiety; preferably, C B It is a protein, more preferably C B is an antibody or a diabody, and more more, C B is a diamond body, most preferably C B AVP0458 consists of two monomers, where each of the two monomers has an amino acid sequence according to sequence ID number: 1; preferably, T 3 is a polymer containing a polyethylene glycol portion; preferably, R 48 This is a releaseable group.

[0007] Embodiment 2. The compound described in Embodiment 1, or a salt, hydrate, or solvate thereof; wherein the compound conforms to the following formula (2): [ka] Here, y is an integer in the range of 1 to 50; preferably y is an integer in the range of 2 to 45; more preferably y is an integer in the range of 10 to 40, more preferably an integer in the range of 12 to 37, even more preferably an integer in the range of 15 to 35, even more preferably an integer in the range of 20 to 30, and most preferably an integer in the range of 23 to 25.

[0008] Embodiment 3. The compound described in Embodiment 1 or 2, or a salt, hydrate, or solvate thereof; wherein the compound conforms to the following formula (3): [ka] Here, y is as defined in Embodiment 2; x is an integer in the range of 4 to 12; preferably x is an integer in the range of 4 to 8, and more preferably x is an integer in the range of 4 to 6.

[0009] Embodiment 4. A compound according to any one of Embodiments 1 to 3, or a salt, hydrate, or solvate thereof; where R 48 is a releaseable group, and the releaseable group is -O-CO-C A And here, C A is a drug; preferably, the drug is linked to the -O-CO- moiety via a secondary or tertiary nitrogen atom that is part of the drug to form a carbamate; preferably, the drug is monomethyl auristatin E (MMAE), exatecan, or an exatecan derivative, and more preferably, the drug is MMAE.

[0010] Embodiment 5. A compound according to any one of Embodiments 1 to 4, or a salt, hydrate, or solvate thereof; where T 2 but, [ka] Selected from the group consisting of; Here, C B is a protein; preferably C B However, the antibody or diabody, more preferably a diabody, most preferably AVP0458 consisting of two monomers, where each of the two monomers has an amino acid sequence according to sequence ID number: 1; preferably C B However, C B S or N, more preferably S, via T, which is part of S or N. 2 It is connected to the remaining part.

[0011] Embodiment 6. A compound according to any one of Embodiments 1 to 5, or a salt, hydrate, or solvate thereof; wherein the compound is [ka] That is the case.

[0012] Embodiment 7. A compound according to any one of Embodiments 1 to 6, or a salt, hydrate, or solvate thereof; wherein the compound is [ka] or [ka] That is the case.

[0013] Embodiment 8. A compound according to any one of Embodiments 1 to 5, or a salt, hydrate, or solvate thereof; wherein the compound is [ka] And, Here, C B However, AVP0458 consists of two monomers, where each of the two monomers has an amino acid sequence according to sequence ID number: 1; preferably, C B However, C B It is linked to the malemidyl group via a sulfur atom which is part of the cysteine ​​group, preferably the sulfur atom which is part of the cysteine ​​group.

[0014] Embodiment 9. The compound described in Embodiment 8, or a salt, hydrate, or solvate thereof; wherein the compound is [ka] or [ka] That is the case.

[0015] Embodiment 10. A compound, or a salt, hydrate, or solvate thereof; wherein the compound comprises an 8-membered ring nonaromatic cyclic monoalkenylene moiety, wherein the moiety comprises a nonvinyl carbon atom, wherein the nonvinyl carbon atom is substituted with at least one structure according to the following formula (A): [ka] Here, L 1 and L 2 are each independently a linker; and, T 2 and T 3 are organic moieties.

[0016] Embodiment 11. A conjugate, or a salt, hydrate or solvate thereof: Here, the conjugate comprises a protein conjugated to at least one compound according to formula (1) as defined in any one of Embodiments 1 to 9, where L 1 , L 2a , L 2b , L 2c , L 2d , T 1 , T 3 and R 48 are as defined in any one of Embodiments 1 to 9, and, here, T 2 is a residue of a bioconjugation moiety, and the protein and the compound are conjugated via T 2 ; preferably, the protein is a diabody or an antibody; more preferably, the protein is a diabody; most preferably, the protein is AVP0458 consisting of two monomers, where each of the two monomers has an amino acid sequence according to SEQ ID NO: 1; preferably, the protein is conjugated to 12 or fewer of the compounds; more preferably, the protein is conjugated to 8 or fewer of the compounds; most preferably, the protein is conjugated to 4 or fewer of the compounds; preferably, the protein and the compound are conjugated via T 2 with a sulfhydryl residue, a hydroxyl residue or an amine residue of the protein; more preferably, the protein and the compound are conjugated via T 2 with a sulfhydryl residue of the said protein; preferably, T 2is a residue of a maleimidyl moiety or a residue of an N-hydroxysuccinimidyl moiety; more preferably, T 2 is a residue of a maleimidyl moiety.

[0017] Embodiment 12. The conjugate according to Embodiment 11, or a salt, hydrate or solvate thereof, wherein the conjugate is

Chemical formula

[0018] Embodiment 13. The conjugate according to Embodiment 12, or a salt, hydrate or solvate thereof, wherein the conjugate is

Chemical formula

Chemical formula

[0019] Embodiment 14. A composition comprising (a) the compound according to any one of Embodiments 1 to 10, or a salt, hydrate or solvate thereof; and / or (b) the conjugate according to any one of Embodiments 11 to 13, or a salt, hydrate or solvate thereof and preferably, the composition is a pharmaceutical composition. The above composition.

[0020] Embodiment 15. The composition described in Embodiment 14, wherein the composition is (a) A compound according to any one of Embodiments 1 to 10, or a salt, hydrate, or solvate thereof; and, (b) Enantiomers of the compound, or its salt, hydrate, or solvate. Includes, Preferably, the composition is a racemic mixture of (a) and (b).

[0021] Embodiment 16. (A1) A compound described in any one of Embodiments 1 to 10, or a salt, hydrate, or solvate thereof; (A2) Conjugates, or salts, hydrates, or solvates thereof, as described in any one of Embodiments 11 to 13; and / or (A3) The composition described in Embodiment 14 or 15; and, (B) A diene, or a salt, solvate, or hydrate thereof; where preferably the diene is tetrazine. A combination of items.

[0022] Embodiment 17. The combination described in Embodiment 16, or a salt, hydrate and / or solvate thereof, wherein the diene is selected from the group consisting of the following: [ka]

[0023] Embodiment 18. A compound according to any one of Embodiments 1 to 10, or a salt, hydrate, or solvate thereof; a conjugate according to any one of Embodiments 11 to 13, or a salt, hydrate, or solvate thereof; a composition according to Embodiment 14 or 15; or a combination according to Embodiment 16 or 17.

[0024] Embodiment 19. A compound according to any one of Embodiments 1 to 10, or a salt, hydrate, or solvate thereof; a conjugate according to any one of Embodiments 11 to 13, or a salt, hydrate, or solvate thereof; a composition according to Embodiment 14 or 15; or a combination according to Embodiment 16 or 17; wherein the subject is human; and preferably the disease is cancer.

[0025] Embodiment 20. A method for treating a disease in a subject, wherein the method is (a) A compound according to any one of Embodiments 1 to 10, or a salt, hydrate, or solvate thereof; (b) A conjugate according to any one of embodiments 11 to 13, or a salt, hydrate, or solvate thereof; (c) The composition described in Embodiment 14 or 15; and / or (d) Combination described in Embodiment 16 or 17 The process includes administering the substance to the subject, Preferably, the subject is a human; preferably, the disease is cancer.

[0026] Embodiment 21. (ia) A compound according to any one of Embodiments 1 to 10, or a salt, hydrate, or solvate thereof; (iia) A conjugate, or a salt, hydrate, or solvate thereof, as described in any one of embodiments 11 to 13; and / or (iiia) Composition according to Embodiment 14 or 15 A non-therapeutic method of reacting with a diene, or a salt, solvate, or hydrate thereof, The method includes the step of contacting (ia), (iia), or (iiia) with the diene, or its salt, solvate, or hydrate, Preferably, the non-treatment method is an in vitro method; and preferably, the diene is tetrazine.

[0027] Embodiment 22. In a click response, (a) A compound according to any one of Embodiments 1 to 10, or a salt, hydrate, or solvate thereof; (b) A conjugate according to any one of embodiments 11 to 13, or a salt, hydrate, or solvate thereof; (c) The composition described in Embodiment 14 or 15; and / or (d) Combination described in Embodiment 16 or 17 Non-therapeutic use of it.

[0028] Embodiment 23. A method for synthesizing a compound described in any one of Embodiments 1 to 10, or a salt, hydrate, or solvate thereof; wherein the method is (A) Coupling the compound of formula (R) below with the compound of formula (S) below: [ka] Here, R 48 , T 1 and y are defined in any one of embodiments 1 to 10. [ka] Here, T 2 And x are as defined in any one of embodiments 1 to 10, and S 10 is a -COOH or an active ester, preferably S 10 is -COOH; Or, (B) Coupling the compound of formula (T) below with the compound of formula (U) below: [ka] Here, R 48 and T 1 This is as defined in any one of embodiments 1 to 10, and S 11 is a -COOH or an active ester, preferably S 11 It is an active ester; [ka] Here, T 2 x and y are defined in any one of embodiments 1 to 10.

[0029] Embodiment 24. A method for synthesizing a conjugate, or a salt, hydrate, or solvate thereof, as described in any one of Embodiments 11 to 13; wherein the method comprises the step of coupling a protein to a compound, or a salt, hydrate, or solvate thereof, as described in any one of Embodiments 1 to 10, wherein the compound contains T 2 This is the bioconjugation portion; here, preferably, the disulfide bond is reduced in the protein. [Modes for carrying out the invention]

[0030] As an example in the field of bioorthogonal chemistry, International Publication No. WO2022 / 197182 describes AVP0458-22-PEG24, which is referred to herein as Compound 1. Compound 1 is an AVP0458 diabody modified with four TCO-containing moieties and has the following structure. [ka]

[0031] However, the inventors have for the first time confirmed that a certain property of compound 1 is improved.

[0032] Firstly, while compound 1 exhibits good clearance from the blood, further improvement is desired. Compound 1 has a blood half-life of 4.22 hours in healthy mice, and a concentration of compound 1 in the blood of healthy mice was observed at 1.14% ID / g 48 hours after administration. Based on this, it is desirable to provide a new TCO that exhibits a faster clearance rate compared to compound 1.

[0033] Secondly, although compound 1 showed good tumor uptake of 18.42% ID / g in xenograft-bearing mice, further improvement was deemed desirable. Therefore, it is also desirable to provide a TCO with even higher tumor uptake.

[0034] Thirdly, compound 1 was observed to exhibit uptake at off-target sites, such as the heart and lungs, rather than as a total cost of ownership (TCO). Low off-target uptake is also desirable.

[0035] Fourth, compound 1 was observed to exhibit an improved metabolic profile. Therefore, it is also desirable to provide a TCO that exhibits a better metabolic profile.

[0036] Therefore, several aspects and embodiments are based on the insightful observation that, in a broad sense, the TCO of this disclosure may satisfy one or more of the aforementioned requirements. In particular, it has been surprisingly found that substituting the PEG4 portion of compound 1 may result in higher clearance rates, higher tumor uptake, lower off-target uptake, a higher metabolic profile, and / or further improved in vitro and in vivo properties.

[0037] In particular, the combination of faster clearance rates and higher tumor uptake is remarkable, because it means that faster clearance from the blood is not, for example, due to excretion. Instead, the compounds of the Disclosure can be rapidly taken up into the tumor. Even more advantageously, uptake of the compounds of the Disclosure into off-target tissue may be much lower compared to uptake in the tumor. This means that a higher percentage of the payload may be released at the desired target site, and that the trigger (typically a diene, e.g., tetrazine) that activates this payload release may be administered at an earlier time, thereby shortening the overall treatment. Consequently, the compounds of the Disclosure may result in greater convenience for the patient because fewer and / or milder side effects, as well as shorter treatment times, can be expected.

[0038] Preferred embodiments of this disclosure are further described below, also associated with the following list of clauses. All of these embodiments, whether described in the whole of the specification or disclosed as part of the following list of clauses, can be combined unless they are mutually exclusive.

[0039] Compounds of the Disclosure

[0040] The compounds of this disclosure conform to clause 1 as defined below, and preferably conform to formula (1) above. Any compound provided herein may be in form, formulation or solution, existing as a salt, solvate or hydrate of the compound. Accordingly, where a compound or a genus of compounds is provided herein, or where “one compound of this disclosure” or “multiple compounds of this disclosure” is referred to, it will be understood that a salt, hydrate or solvate of the compound is also included in such description, even if the terms salt, hydrate or solvate are not specifically mentioned in each example. In some embodiments, the compounds of this disclosure are purified or exist in a form or state that does not exist as a salt, hydrate or solvate of the compound. However, unless specifically indicated otherwise, it is intended that the compounds herein may be in the form of a salt, hydrate or solvate.

[0041] Preferred embodiments of the compounds in this disclosure are further described below in relation to several formulas and variables.

[0042] formula Preferably, the compounds of the present disclosure follow a formula selected from the group consisting of formulas (1), (2), (3), (B), (C), (D), (E), (F), (G), (H), (I), (J), (K), (L), (M), (N), (O), (P), and (Q).

[0043] Preferably, the compounds of the disclosed herein conform to formula (B). More preferably, the compounds of the disclosed herein conform to formula (C). Even more preferably, the compounds of the disclosed herein conform to formula (1). Even more preferably, the compounds of the disclosed herein conform to formula (D). Even more preferably, the compounds of the disclosed herein conform to formula (E). Even more preferably, the compounds of the disclosed herein conform to formula (F). Even more preferably, the compounds of the disclosed herein conform to formula (G). Even more preferably, the compounds of the disclosed herein conform to formula (2). Even more preferably, the compounds of the disclosed herein conform to formula (H). Even more preferably, the compounds of the disclosed herein conform to formula (I). Even more preferably, the compounds of the disclosed herein conform to formula (J). Even more preferably, the compounds of the disclosed herein conform to formula (K). Even more preferably, the compounds of the disclosed herein conform to formula (L). Even more preferably, the compounds of the disclosed herein conform to formula (M). Even more preferably, the compounds of the disclosed herein conform to formula (N). More preferably, the compounds of the disclosed herein conform to formula (O). Even more preferably, the compounds of the disclosed herein conform to formula (3). Even more preferably, the compounds of the disclosed herein conform to formula (P). Even more preferably, the compounds of the disclosed herein conform to formula (Q).

[0044] Equation (1) is, [ka] That is the case.

[0045] Equation (2) is, [ka] That is the case.

[0046] Equation (3) is, [ka] That is the case.

[0047] Equation (B) is, [ka] That is the case.

[0048] Equation (C) is, [ka] That is the case.

[0049] Equation (D) is, [ka] That is the case.

[0050] Equation (E) is, [ka] That is the case.

[0051] Equation (F) is, [ka] That is the case.

[0052] Equation (G) is, [ka] That is the case.

[0053] Equation (H) is, [ka] That is the case.

[0054] Equation (I) is, [ka] That is the case.

[0055] Equation (J) is, [ka] That is the case.

[0056] Equation (K) is, [ka] That is the case.

[0057] Equation (L) is, [ka] That is the case.

[0058] Equation (M) is, [ka] That is the case.

[0059] Equation (N) is, [ka] That is the case.

[0060] Equation (O) is, [ka] That is the case.

[0061] Equation (P) is, [ka] That is the case.

[0062] Equation (Q) is, [ka] That is the case.

[0063] L 1 L 1 is a linker. Preferably, L 1 This conforms to radical group 2 as defined herein.

[0064] Preferably, L 1 It contains 1 to 100 atoms, preferably 2 to 75 atoms, more preferably 3 to 60 atoms, even more preferably 4 to 50 atoms, even more preferably 5 to 40 atoms, even more preferably 6 to 35 atoms, even more preferably 7 to 30 atoms, even more preferably 8 to 25 atoms, even more preferably 9 to 22 atoms, and most preferably 10 to 20 atoms. Preferably, L 1 It contains approximately 15 atoms.

[0065] More preferably, L 1 C1-C are linear or branched C1-C 12 (hetero)alkylene, C3-C8; (hetero)cycloalkylene, C6-C 12 Arylene and C4~C 11 It is selected from the group consisting of heteroarylenes.

[0066] More comfortable than those mentioned above, L 1 C1-C are linear or branched C1-C 12 Alkylene, C3-C8 (hetero)cycloalkylene, C6-C 12 Arylene and C4~C 11 Selected from the group consisting of heteroarylenes. More preferably than those described above, L 1 C2-C is a linear or branched C2-C 12 Alkylene, C3-C8 (hetero)cycloalkylene, C6-C 12 Arylene and C4~C 11 Selected from the group consisting of heteroarylenes. More preferably than those described above, L 1 C3-C is a linear or branched C3-C 12 Alkylene, C3-C8 (hetero)cycloalkylene, C6-C 12 Arylene and C4~C 11 Selected from the group consisting of heteroarylenes. More preferably than those described above, L 1 C4-C4 is a linear or branched C4-C4. 12 Alkylene, C3-C8 (hetero)cycloalkylene, C6-C12 Arylene and C4~C 11 Selected from the group consisting of heteroarylenes. More preferably than those described above, L 1 C1-C are linear or branched C1-C 12 It is an alkylene. More preferably than those mentioned above, L 1 C2-C is a linear or branched C2-C 12 Alkylenes, i.e., linear C2 alkylenes, linear or branched C3 alkylenes, linear or branched C4 alkylenes, linear or branched C5 alkylenes, linear or branched C6 alkylenes, linear or branched C7 alkylenes, linear or branched C8 alkylenes, linear or branched C9 alkylenes, linear or branched C 10 Alkylene, linear or branched C 11 Alkylene, or linear or branched C 12 Alkylene. More preferably than those mentioned above, L 1 C3-C is a linear or branched C3-C 12 It is an alkylene. More preferably than those mentioned above, L 1 C4-C4 is a linear or branched C4-C4. 12 It is an alkylene. More preferably than those mentioned above, L 1 C4-C4 is a linear or branched C4-C4. 11 It is an alkylene. More preferably than those mentioned above, L 1 C4-C4 is a linear or branched C4-C4. 10 It is an alkylene. More preferably than those mentioned above, L 1 is a linear or branched C4-C9 alkylene. More preferably than the above, L 1 is a linear or branched C4-C8 alkylene. More preferably than the above, L 1 is a linear or branched C4-C7 alkylene. More preferably than the above, L 1 is a linear or branched C4-C6 alkylene. More preferably than the above, L 1is a linear or branched C5 alkylene. More preferably than the above, L 1 This is a linear C1-C 12 It is an alkylene. More preferably than those mentioned above, L 1 It is a linear C2-C 12 Alkylenes, specifically linear C2 alkylenes, linear C3 alkylenes, linear C4 alkylenes, linear C5 alkylenes, linear C6 alkylenes, linear C7 alkylenes, linear C8 alkylenes, linear C9 alkylenes, and linear C 10 Alkylene, linear carbon 11 Alkylene, or linear C 12 It is an alkylene. More preferably than those mentioned above, L 1 This is a linear C3-C 12 It is an alkylene. More preferably than those mentioned above, L 1 This is a linear C4-C 12 It is an alkylene. More preferably than those mentioned above, L 1 This is a linear C4-C 11 It is an alkylene. More preferably than those mentioned above, L 1 This is a linear C4-C 10 It is an alkylene. More preferably than those mentioned above, L 1 is a linear C4-C9 alkylene. More preferably than the above, L 1 is a linear C4-C8 alkylene. More preferably than the above, L 1 It is a linear C4-C7 alkylene. More preferably than the above, L 1 is a linear C4-C6 alkylene. Most preferably, L 1 It is a linear C5 alkylene.

[0067] L 1 L may or may not be substituted. Preferably, 1 is not substituted. Most preferably, L 1 It is an unsubstituted, linear C5 alkylene.

[0068] Although not bound by theory, the present inventors consider the linker L of the compound of formula (1) of this disclosure. 1 This is thought to provide a faster blood clearance rate while maintaining high uptake of the compound of formula (1) at the target site. Although not bound by theory, the linker L has the length as defined in claim 1. 1 , especially linear C4~C 12 The advantage of alkylene is that of partial C B A sufficient distance can be achieved between the linker L and trans-cyclooctene, and therefore the double bond of trans-cyclooctene will be able to react readily with the diene. Although not bound by theory, the linker L has the length defined in claim 1. 1 , especially linear C4~C 12 The advantage of alkylenes is that they are not too long, and therefore, for example, they can prevent deactivation of the C portion. B It can still be shielded by this. The advantage of relatively short alkylene linkers, such as C4-C6 alkylenes, is that their solubility may be higher than that of relatively long alkylene linkers.

[0069] L 2 L 2 is a linker. Preferably, L 2 This conforms to radical group 2 as defined herein.

[0070] Preferably, L 2 This comprises 1 to 200 atoms, preferably 2 to 150 atoms, more preferably 3 to 100 atoms, even more preferably 4 to 90 atoms, even more preferably 5 to 80 atoms, even more preferably 6 to 70 atoms, even more preferably 7 to 60 atoms, even more preferably 8 to 50 atoms, even more preferably 9 to 45 atoms, and most preferably 10 to 35 atoms.

[0071] Preferably, L2 C1-C are linear or branched C1-C 12 (hetero)alkantriyl, C3-C8; (hetero)cycloalkantriyl, C6-C 12 Allen Trill, and C4~C 11 Selected from the group consisting of heteroarene triyls. More preferably than those described above, L 2 C1-C are linear or branched C1-C 12 It is a (hetero)alkantriyl. More preferably than those described above, L 2 C1-C are linear or branched C1-C 12 It is a heteroalkantriyl. More preferably than those described above, L 2 This is a branched C1~C 12 It is a (hetero)alkantriyl. More preferably than those described above, L 2 This is a branched C1~C 12 It is a heteroalkantriyl. More preferably than those described above, L 2 This is a branched C3~C 11 It is a heteroalkantriyl. More preferably than those described above, L 2 This is a branched C6~C 10 It is a heteroalkantriyl. More preferably than those described above, L 2 is a branched C8 heteroalkantriyl. More preferably than the above, L 2 is a branched C8 heteroalkantriyl substituted with 5 or fewer =O groups. More preferably than the above, L 2 It is a branched C8 heteroalkantriyl substituted with three =O groups. More preferably than the above, L 2 is a branched C8 heteroalkantriyl containing 5 or fewer -NH- groups. More preferably than the above, L 2 It is a branched C8 heteroalkanetriyl containing three -NH- groups. More preferably than the above, L 2This is a branched C8 heteroalkanetriyl containing three -NH- groups, where the C8 heteroalkanetriyl is substituted with three =O groups.

[0072] More preferably, L 2 teeth, [ka] That is the case.

[0073] Even more comfortably, L 2 teeth, [ka] That is the case.

[0074] More preferably, L 2 teeth, [ka] That is the case.

[0075] Most preferably, L 2 teeth, [ka] That is the case.

[0076] In a preferred embodiment, L 2 It has the following structural formula. [ka] In this specification, L 2a , L 2b , L 2c and L 2d Each is an independent linker. Preferably, L 2a , L 2b , L 2c and L 2d Each of these independently conforms to the radical group 2 as defined herein.

[0077] L2a L 2a is a linker. Preferably, L 2a This conforms to radical group 2 as defined herein.

[0078] More preferably, L 2a This is a linker containing 20 or fewer atoms. More preferably than the above, L 2a is a linker containing 15 or fewer atoms. More preferably than the above, L 2a is a linker containing 10 or fewer atoms. More preferably than the above, L 2a is a linker containing 5 or fewer atoms. More preferably than the above, L 2a is -C(O)NL 2T -, -NL 2T C(O)-, -O-, -S-, -NL 2T -, -N=N- and -C(O)- are selected from the group; where L 2T is a hydrogen atom or a methyl atom. More preferably than those described above, L 2a is -C(O)NL 2T -and-NL 2T Selected from the group consisting of C(O)-. More preferably than those described above, L 2a is selected from the group consisting of -C(O)NH- and -NHC(O)-. Most preferably, L 2a It is -NHC(O)-.

[0079] L 2b L 2b is a linker. Preferably, L 2b This conforms to radical group 2 as defined herein.

[0080] More preferably, L 2b This is a linker containing 20 or fewer atoms. More preferably than the above, L 2bis a linker containing 15 or fewer atoms. More preferably than the above, L 2b is a linker containing 10 or fewer atoms. More preferably than the above, L 2b is a linker containing 5 or fewer atoms. More preferably than the above, L 2b is -C(O)NL 2T -, -NL 2T C(O)-, -O-, -S-, -NL 2T -, -N=N- and -C(O)- are selected from the group; where L 2T is a hydrogen atom or a methyl atom. More preferably than those described above, L 2b is -C(O)NL 2T -and-NL 2T Selected from the group consisting of C(O)-. More preferably than those described above, L 2b is selected from the group consisting of -C(O)NH- and -NHC(O)-. Most preferably, L 2b It is -NHC(O)-.

[0081] L 2c L 2c is a linker. Preferably, L 2c This conforms to radical group 2 as defined herein.

[0082] More comfortable than those mentioned above, L 2c This is a linker containing 50 or fewer atoms. More preferably than the above, L 2c This is a linker containing 40 or fewer atoms. More preferably than the above, L 2c This is a linker containing 30 or fewer atoms. More preferably than the above, L 2c This is a linker containing 20 or fewer atoms. More preferably than the above, L 2c is a linker containing 15 or fewer atoms. More preferably than the above, L 2cThe is selected from the group consisting of C1-C8 (hetero)alkantriyl, C5-C6 (hetero)arenetriyl, C3-C7 cycloalkantriyl, and C2-C7 heterocycloalkantriyl. More preferably than those described above, L 2c These are C1-C8 (hetero)alkantriyl. More preferably than those described above, L 2c is C1-C8 alkantriyl. More preferably than those described above, L 2c is C2-C7 alkantriyl. More preferably than those described above, L 2c is C3-C6 alkantriyl. More preferably than those described above, L 2c is C4-C5 alkantriyl. More preferably than those described above, L 2c It is C5 alkantriyl. Most preferably, L 2c This is >CH-CH2-CH2-CH2-CH2-.

[0083] L 2d L 2d is a linker. Preferably, L 2d This conforms to radical group 2 as defined herein.

[0084] More comfortable than those mentioned above, L 2d This is a linker containing 20 or fewer atoms. More preferably than the above, L 2d is a linker containing 15 or fewer atoms. More preferably than the above, L 2d is a linker containing 10 or fewer atoms. More preferably than the above, L 2d is a linker containing 5 or fewer atoms. More preferably than the above, L 2d is -C(O)NL 2T -, -NL 2T C(O)-, -O-, -S-, -NL 2T -, -N=N- and -C(O)- are selected from the group; where L 2Tis a hydrogen atom or a methyl atom. More preferably than those described above, L 2d is -C(O)NL 2T -and-NL 2T Selected from the group consisting of C(O)-. More preferably than those described above, L 2d is selected from the group consisting of -C(O)NH- and -NHC(O)-. Most preferably, L 2d It is -C(O)NH-.

[0085] T 1 T 1 This corresponds to radical group 1, radical group 3, radical group 4, or radical group 5 as defined herein. Preferably, each T 1 This independently conforms to radical group 1 as defined herein.

[0086] more, each T 1 It operates independently, -OT 1A , hydrogen atom, C1~C 12 (hetero)alkyl, C6 aryl, C4-C5 heteroaryl, C3-C6 (hetero)cycloalkyl, C5-C 12 Alkyl (hetero)aryl, C5-C 12 (hetero)arylalkyl, C4~C 12 Alkylcycloalkyl, -N(T 1A )2, -ST 1A -SO3H, -C(O)T 1A , -C(O)OT 1A ,-OC(O)T 1A ,-C(O)N(T 1A )2, -N(T 1A )2-CO-T 1A , and -Si(T 1A ) Selected from the group consisting of 3. More preferably, each T 1 It operates independently, -OT 1A , hydrogen atom, C2-C6 alkyl, C6 aryl, C4-C5 heteroaryl, C3-C6 cycloalkyl, C5-C 12 Alkyl (hetero)aryl, C5-C12 (hetero)arylalkyl, C4~C 12 Alkylcycloalkyl, -N(T 1A )2, -ST 1A -SO3H, -C(O)T 1A , -C(O)OT 1A ,-OC(O)T 1A ,-C(O)N(T 1A )2, -N(T 1A )2-CO-T 1A , and -Si(T 1A ) Selected from the group consisting of 3. More preferably, each T 1 It operates independently, -OT 1A , C2-C6 alkyl, C6 aryl, C4-C5 heteroaryl, C3-C6 cycloalkyl, C5-C 12 Alkyl (hetero)aryl, C5-C 12 (hetero)arylalkyl, C4~C 12 Alkylcycloalkyl, -N(T 1A )2, -ST 1A -SO3H, -C(O)T 1A , -C(O)OT 1A ,-OC(O)T 1A ,-C(O)N(T 1A )2, -N(T 1A )2-CO-T 1A , and -Si(T 1A ) Selected from the group consisting of 3. More preferably, T 1 is, -OT 1A That is the case.

[0087] Most preferably, T 1 It is -OH.

[0088] When used herein, each T 1A Each T is independently selected from the group consisting of a hydrogen atom, (hetero)alkyl, (hetero)alkenyl, (hetero)alkynyl, (hetero)aryl, and amino acid residues. More preferably, each T 1AEach T is independently selected from the group consisting of a hydrogen atom, C1-C6 (hetero)alkyl, C1-C6 (hetero)alkenyl, C1-C6 (hetero)alkynyl, C2-C5 heteroaryl, phenyl, and amino acid residues. More preferably, each T 1A Each T is independently selected from the group consisting of a hydrogen atom, a C1-C4 (hetero)alkyl, a C1-C4 (hetero)alkenyl, a C1-C4 (hetero)alkynyl, a C3-C5 heteroaryl, a phenyl, an aspartic acid residue, a glutamic acid residue, and a glycine residue. More preferably, each T 1A This is independently selected from the group consisting of a hydrogen atom, a C1-C3 alkyl group, an aspartic acid residue, a glutamic acid residue, and a glycine residue. Most preferably, T 1A It is a hydrogen atom.

[0089] Preferably, T 1 It is in the axial position. Although not bound by theory, the inventors believe that R 48 When is a releaseable group, when the compound of this disclosure reacts with a diene, T 1 This is thought to facilitate the release of the payload. As a result, optimal release yield and / or release kinetics are achieved.

[0090] T 2 T 2 is an organic part. Preferably, T 2 This corresponds to any one of radical group 1, radical group 3, or radical group 5 as defined herein, or T 2 However, -L 3 -C B It is the basis. More preferably, T 2 This refers to the bioconjugation moiety, residues of the bioconjugation moiety, or -L 3 -C B It is the basis. More preferably, T 2 This refers to the bioconjugation portion, or -L 3 -CB It is the basis.

[0091] In a preferred embodiment, T 2 This is the bioconjugation moiety. These embodiments typically relate to compounds that can be coupled to proteins, for example. More preferably, T 2 This conforms to the radical group 1f as defined herein. These bioconjugation residues are known in the art. More preferably, T 2 This is N-maleimidyl. In these embodiments, T 2 but, [ka] It is most preferable that this be the case.

[0092] In another preferred embodiment, T 2 However, these are residues of the bioconjugation moiety. These embodiments typically relate to the conjugate of the present disclosure, where T 2 For example, it is linked to a protein. Such residues are well known to those skilled in the art. In these embodiments, T 2 but, [ka] It is most preferable that the compounds be bound to a protein, where an asterisk indicates binding to a protein and a wavy line indicates binding to the rest of the compounds of this disclosure.

[0093] In another preferred embodiment, T 2 ga-L 3 -C B These embodiments are based on T 2 Construct B(C) is itself a protein. B Regarding cases including C B L is as defined herein. 3 This follows radical group 2. Preferably, L 3is a residue of the bioconjugation region. More preferably, L 3 is a residue of the N-maleimidyl moiety or a residue of the N-hydroxy-succinimidyl moiety. In these embodiments, L 3 is, T 2 but [ka] It is preferable to select from the group consisting of the following:

[0094] These embodiments, T 2 but, [ka] It is most preferable that this be the case.

[0095] -L 3 -C B Regarding the part, L 3 And, C B The sulfur atom, secondary nitrogen atom, or tertiary nitrogen atom, preferably a sulfur atom, together with the following structure -L 3 -C B Form one of the following: [ka] Here, C B1 C B The dashed line indicates S, secondary N, or tertiary N, preferably S, which is part of the spectrum: 1 The asterisk indicates a bond to a part, and the asterisk is C B The remainder, preferably AVP0458, shows bonding to the remainder.

[0096] C B C B This corresponds to radical group 4 or radical group 5 as defined herein. Preferably, C B However, this is a targeting agent as defined herein. Preferably, C BThe material is selected from the group consisting of proteins, nucleic acids, peptides, carbohydrates, aptamers, lipids, small organic molecules, polymers, LNA, PNA, amino acids, peptoids, chelate moieties, fluorescent dyes, phosphorescent dyes, organic particles, gels, cells, and combinations thereof. More preferably, C B It is a protein. More preferably, C B However, it is an antibody or a diabody. More preferably, C B That is the diamond body.

[0097] Antibodies are proteins produced by the immune system that have the ability to recognize and bind to specific antigens. Antibodies or immunoglobulins derived from IgG antibodies are particularly preferred for use in this disclosure, but immunoglobulins from any class or subclass, such as IgG, IgA, IgM, IgD, and IgE, may be selected. Preferably, the immunoglobulin is an IgG class encompassing but not limited to IgG subclasses (IgG1, 2, 3, and 4), or an IgM class capable of specifically binding to a particular epitope on an antigen. Antibodies may be whole immunoglobulins of natural or recombinant origin, or they may be the immunoreactive portion of a whole immunoglobulin. Antibodies can exist in various forms and are not limited to these, but examples include 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, triplicate antibody derivatives such as tribodies, camelid antibodies, minibodies, nanobodies, resurfaced antibodies, humanized antibodies, and fully human antibodies. Antibodies), single-domain antibodies (sdAb, Nanobody) 商標Chimeric antibodies, chimeric antibodies containing at least one human constant region, dual-affinity antibodies, such as dual-affinity retargeting proteins (DART) 商標 ), as well as their polymers and derivatives, for example, divalent or polyvalent single-chain variable fragments (e.g., di-scFv, tri-scFv), which may exist as minibodies, diabodies, triabodies, tetrabodies, etc., and divalent or polyvalent single-chain variable fragments containing polyvalent antibodies. See [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” means at least a portion of the variable region of an immunoglobulin that binds to its target, i.e., the antigen-binding region. Other embodiments are drug D D or targeting agent T T Antibody mimetics are used to refer to, for example, but not limited to, affimers, antiticalins, avimers, alphabodies, affibodies, DARPins, and multimers, as well as their derivatives. [Trends in Biotechnology 2015, 33, 2, 65] is referenced, and its contents are incorporated herein by reference. To avoid misunderstanding, in the context of this disclosure, the term “antibody” encompasses all antibody variants, fragments, derivatives, fusions, analogs and mimetics described in this paragraph unless otherwise specified.

[0098] Preferably, the antibodies are AVP0458, CC49, 3F8, avagovomab, abiciximab, abituzumab, abrezekimab, abrilumab, actoxumab, adalimumab, adecatumumab, aducanumab, afasevikumab, afelimomab, alacizumab pegol, alemtuzumab, alirocumab, altumomab pentetate. pentetate), amatuximab, amivantamab, anatumomab mafenatox, andecaliximab, anetumab ravtansine, anifrolumab, ansuvimab, anrukinzumab, apolizumab, aprutumab ixadotin ixadotin, arcitumomab, ascrinvacumab, aselizumab, atezolizumab, atidortoxumab, atinumab, atoltivimab, maftivimab, odesivimab, atorolimumab, avelumab, azintuximab vedotinVedotin, bamlanivimab, bapineuzumab, basiliximab, bavituximab, BCD-100, bebtelovimab, bectumomab, bedinvetmab, begelomab, berantamab, mahodotin (belantamab) mafodotin), belimumab, bemarituzumab, benralizumab, berimatoxumab, bermekimab, bersanlimab, bertilimumab, besilesomab, bevacizumab, bezlotoxumab, Bicilomab, bimagrumab, bimekizumab, birtamimab, bivatuzumab, bleselumab, blinatumomab, blontuvetmab, blosozumab, bococizumab, brazikumab, brentuximab Vedotin (brentuximab vedotin), briakinumab, brodalumab, brolucizumab, brontictuzumab, burosumab, cabiralizumab, camidanlumab tesirine, camrelizumab, canakinumab, cantuzumab mertansine, cantuzumab labtansineravtansine), caplacizumab, casirivimab, capromab, carlumab, carotuximab, catumaxomab, cBR96-doxorubicin immunoconjugate, cedelizumab, cemiplimab, cergutuzumab amunaleukin, certolizumab pegol pegol), cetrelimab, cetuximab, cibisatamab, cilgavimab, cirmutuzumab, citatuzumab bogatox, cixutumumab, clazakizumab, clenoliximab, clivatuzumab tetraxetan, codrituzumab, cofetuzumab pelidotin, coltuximab labtansine ravtansine), conatumumab, concizumab, cosfroviximab, crenezumab, crizanlizumab, crotedumab, CR6261, cusatuzumab, dacetuzumab, daclizumab, dalotuzumab, dapirolizumab pegol, daratumumab, dectrekumab, demcizumab, denintuzumab mafodotin, denosumab, depatuxizumabMafodotin (depatuxizumab mafodotin), derlotuximab biotin, detumomab, dezamizumab, dinutuximab, dinutuximab beta, diridavumab, divozilimab, domagrozumab, donanemab, dorlimomab aritox), dostarlimab, drozitumab, DS-8201, duligotuzumab, dupilumab, durvalumab, dusigitumab, duvortuxizumab, eclomeximab, eculizumab, edobacomab, edrecolomab (e drecolomab, efalizumab, efungumab, eldelumab, elezanumab, elgemtumab, elotuzumab, elsilimomab, emactuzumab, emapalumab, emibetuzumab, emicizumab, enapotamab Vedotin (enapotamab vedotin), enavatuzumab, enfortumab vedotin, enlimomab pegol, enoblituzumab, enokizumab, enoticumab, ensituximab, epcoritamab, epitumomab cituxetancituxetan), epratuzumab, eptinezumab, erenumab, erlizumab, ertumaxomab, etaracizumab, etesevimab, etigilimab, etrolizumab, evinacumab, evolocumab mab), exbivirumab, fanolesomab, faralimomab, faricimab, farletuzumab, fasinumab, FBTA05, felvizumab, fezakinumab, fibatuzumab, ficlatuzumab, figi fivitumumab, firivumab, flanvotumab, fletikumab, flotetuzumab, fontolizumab, foralumab, foravirumab, fremanezumab, fresolimumab, frovocimab, Flunevetmab, fluranumab, futuximab, galcanezumab, galiximab, gancotamab, ganitumab, gantenerumab, gatipotuzumab, gavilimomab, gedivumab, gemtuzumab, ozogamicinOzogamicin), gevokizumab, gilvetmab, gimsilumab, girentuximab, glembatumumab vedotin, glofitamab, golimumab, gomiliximab, gosuranemab, guselkumab, ianalumab, ibalizumab, sintilimab, ibritumomab tiuxetan Tiuxetan), icrucumab, idarucizumab, ifabotuzumab, igovomab, iladatuzumab vedotin, imalumab, imaprelimab, imciromab, imdevimab, imgatuzumab, inclacumab, indatuximab ravtansine, indusatumab vedotin Vedotin, inebilizumab, infliximab, intetumumab, inolimomab, inotuzumab, ozogamicin, ipilimumab, iomab-B, iratumumab, isatuximab, iscalimab, istilatumab, itolizumab, ixekizumab, keliximab, labetuzumab, lacnotuzumab, ladiratuzumabVedotin, lampalizumab, lanadelumab, landogrozumab, laprituximab emtansine, larcaviximab, lebrikizumab, lecanemab, lemalesomab, lendalizumab, lenvervimab, lenzilumab, lerdelimumab, leronlimab, lesofavumab, letolizumab, lexatumumab, libivirumab, rifastuzumab Vedotin (lifastuzumab vedotin), ligelizumab, loncastuximab tesirine, losatuxizumab vedotin, lilotomab satetraxetan, lintuzumab, lirilumab, lodelcizumab, lokivetmab, lorvotuzumab mertansine, lucatumumab, lulizumab pegol pegol), lumiliximab, lumretuzumab, lupartumab, lupartumab amadotinamadotin, lutikizumab, maftivimab, mapatumumab, margetuximab, marstacimab, maslimomab, mavrilimumab, matuzumab, mepolizumab, metelimumab, milatuzumab, minretumomab, mirikizumab, mirbetuximab, sorabutansine (mirvetuximab) soravtansine), mitumomab, modotuximab, mogamulizumab, monalizumab, morolimumab, mosunetuzumab, motavizumab, moxetumomab pasudotox, muromonab-CD3, nacolomab tafenatox, namilumab, naptumomab estafenatox, naratuximab emtansine emtansine), narnatumab, natalizumab, navicixizumab, navivumab, naxitamab, nebacumab, necitumumab, nemolizumab, NEOD001, nerelimomab, nesvacumab, netakimab, nimotuzumab, nirsevimab, nivolumab (nivolumab), nofetumomab merpentan, obiltoxaximab, obinutuzumab, ocaratuzumab, ocrelizumab, odesivimab, odulimomab, ofatumumab, olaratumab, oleculumab (o leclumab), olendalizumab, olokizumab, omalizumab, omburtamab, OMS721, onartuzumab, ontuxizumab, onvatilimab, opicinumab, oporutuzumab monatox Monatox), oregobomab, orticumab, otelixizumab, otilimab, otlertuzumab, oxelumab, ozanezumab, ozoralizumab, pagibaximab, palivizumab, pamrevlumab, panitumumab, pankomab, pa Novacumab, parsatuzumab, pascolizumab, pasotuxizumab, pateclizumab, patrizumab, PDR001, pembrolizumab, pemtumomab, perakizumab, pertuzumab, pexelizumab, pidilizumab, pinatuzumab vedotinVedotin, pintumomab, placulumab, pozelimab, prezalumab, plozalizumab, pogalizumab, polatuzumab vedotin, ponezumab, porgaviximab, prasinezumab, prezalizumab, priliximab, pritoxaximab, pritumumab, PRO 140. Quilizumab, racotumomab, radretumab, rafivirumab, ralpancizumab, ramucirumab, ranevetmab, ranibizumab, raxibacumab, ravagalimab, ravulizumab refanezumab, regavirumab, regdanvimab, relatlimab, remtolumab, reslizumab, retifanlimab, rilotumumab, rinucumab, risankizumab, rituximab, rivabazumab Pegol (rivabazumab pegol), robatumumab, Rmab, roledumab, romilkimab, romosozumab, rontalizumab, rosmantuzumab, rovalpituzumab TecillinTesirine, Robelizumab, Rozanolixizumab, Ruplizumab, SA237, Sacituzumab govitecan, Samalizumab, Samrotamab vedotin, Sarilumab, Satralizumab, Satumomab pendetide pendetide), secukinumab, selicrelumab, seribantumab, setoxaximab, setrusumab, sevilumab, sibrotuzumab, SGN-CD19A, SHP647, sifalimumab, siltuximab, simtuzumab, siplizumab, sirtratumab vedotin, sirukumab, sofituzumab vedotin Vedotin, solanezumab, solitomab, sonepcizumab, sontuzumab, sotrovimab, spartalizumab, spesolimab, stamulumab, sulesomab, sustavumab, sutimlimab, suvizumab, suvartoxumab, tabalumab, tacuzumab, tetraxetantetraxetan), tadocizumab, tafasitamab, talacotuzumab, talizumab, talquetamab, tamtuvetmab, tanezumab, taplitumomab paptox, tarextumab, tavolimab, teclistamab, tefibazumab, telimomab aritox, telisotuzumab, telisotuzumab vedotin Vedotin, tenatumomab, teneliximab, teplizumab, tepoditamab, teprotumumab, tesidolumab, tetulomab, tezepelumab, TGN1412, tibulizumab, tildrakizumab, tigatuzumab, timigutuzumab, timolumab, tiragolumab, tiragotumab, tislelizumab, tisotumab Vedotin (tisotumab vedotin), tixagevimab, TNX-650, tocilizumab, tomuzotuximab, toralizumab, tosatoxumab, tositumomab, tovetumab, tralokinumab, trastuzumab, trastuzumab duocarmazine, trastuzumab emtansineemtansine), TRBS07, tregalizumab, tremelimumab, trevogrumab, tucotuzumab celmoleukin, tuvirumab, ublituximab, ulocuplumab, urelumab, urtoxazumab, ustekinumab, utomilumab, vadastuximab talirine, vanalimab, vandortuzumab vedotin Vedotin, vantictumab, vanucizumab, vapaliximab, varisacumab, varlilumab, vatelizumab, vedolizumab, veltuzumab, vepalimomab, vesencumab, vilobelimab, visilizumab, vobarilizumab, volociximab, vonlerolizumab, vopratelimab, borsetuzumab, mahodotin (vorsetuzumab) The following are selected from the group consisting of mafodotin, votumumab, vunakizumab, xentuzumab, XMAB-5574, zalutumumab, zanolimumab, zatuximab, zenocutuzumab, ziralimumab, zolbetuximab, and zolimomab aritox.

[0099] Preferably, C B The group consists of AVP0458, CC49, insulin, transferrin, fibrinogen-gamma fragment, thrombospongin, claudin, apolipoprotein E, afibody molecules such as ABY-025, ankyrin repeat proteins, ankyrin-like repeat proteins, interferons such as α, β, and γ-interferons, interleukins, lymphokines, colony-stimulating factors, and protein growth factors such as tumor growth factors such as α and β-tumor growth factors, platelet-derived growth factor (PDGF), uPAR target proteins, apolipoproteins, LDL, annexin V, endostatin, and angiostatin. Examples of peptides as targeting agents 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 is an affibody. 商標 The polymers and derivatives thereof are also used.

[0100] more, C B However, it is AVP0458 or CC49. Most preferably, C B However, AVP0458 consists of two monomers, each of which has an amino acid sequence according to sequence ID number 1.

[0101] Preferably, C B However, C B It is linked to the remainder of the compound or conjugate of the disclosure via S or N, which are part of the compound. Preferably C BIt is linked to the remainder of the compound or conjugate of the disclosed herein via S, which is part of it.

[0102] AVP0458 As used herein, AVP0458 refers to a TAG72-binding diabody derived from the CC49 antibody. AVP0458 is a diabody consisting of two monomers, each monomer having an amino acid sequence according to Sequence ID No. 1.

[0103] Sequence ID: 1 (Amino acid sequence of AVP0458 diabody monomer): JPEG2026509291000050.jpg39170

[0104] In this specification, underlined cysteine ​​residues are preferably modified or linked thereto in the compounds of the present invention, or in the remainder of AVP0458 itself if it is part of the compounds of this disclosure.

[0105] Therefore, in sequence ID number 1, it is preferable that at least one of the underlined cysteines, more preferably both of the underlined cysteines, is modified with or linked to the compound according to this disclosure. In other words, the sulfur atom of the underlined cysteine ​​is T as defined herein. 2 Preferably, it is bonded to a portion, preferably T 2 This is a residue of the N-maleimidyl group.

[0106] Targeting agent Targeting agent T T It binds to the Primary Target. As used in this disclosure, “Primary Target” can mean any molecule present in an organism, tissue, or cell. Preferably, “Primary Target” means the target of a targeting agent for therapeutic, imaging, theranostics, diagnostic, or in vitro research.

[0107] To enable specific targeting of the primary targets listed above, the targeting agent T TThis includes, but is not limited to, compounds encompassing antibodies, antibody derivatives, antibody fragments, antibody (fragment) fusions (e.g., bispecific and trispecific mAb fragments or derivatives), proteins, peptides (e.g., octreotide and its derivatives), VIP, MSH, LHRH, chemotactic peptides, cell-permeable peptides, membrane translocation moieties, bombesin, elastin, peptide mimes, 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 envisioned in the context of this disclosure include dyes, compounds targeting CAIX and PSMA, estrogens such as estradiol, androgens, progestins, corticosteroids, methotrexate, folic acid, and cholesterol, or derived from these. Examples of protein-derived targeting agents include insulin, transferrin, fibrinogen gamma fragments, thrombospondin, claudin, apolipoprotein E, aphibody molecules such as ABY-025, ankyrin repeat proteins, ankyrin-like repeat proteins, interferons such as α, β, and γ-interferons, interleukins, lymphokines, colony-stimulating factors, and protein growth factors such as tumor growth factors such as α and β-tumor growth factors, platelet-derived growth factor (PDGF), uPAR target proteins, apolipoproteins, LDL, annexin V, endostatin, and angiostatin.Examples of peptides as targeting agents 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 is affibodies. TM The polymer and its derivatives are also used.

[0108] In one embodiment, the antibody is T TIt is used as such. In this disclosure, antibodies or immunoglobulins derived from IgG antibodies are particularly preferred, but immunoglobulins from any class or subclass, such as IgG, IgA, IgM, IgD, and IgE, may also be selected. Preferably, the immunoglobulin is an IgG class encompassing but not limited to IgG subclasses (IgG1, 2, 3, and 4), or an IgM class capable of specifically binding to a particular epitope on an antigen. The antibody may be a complete immunoglobulin of natural or recombinant origin, or it may be the immunoreactive portion of a complete immunoglobulin. Antibodies can exist in various forms and are not limited to these, but examples include 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, triplicate antibody derivatives such as tribodies, camelid antibodies, minibodies, nanobodies, resurfaced antibodies, humanized antibodies, and fully human antibodies. Antibodies), single-domain antibodies (sdAb, Nanobody) 商標 Chimeric antibodies, chimeric antibodies containing at least one human constant region, dual-affinity antibodies, such as dual-affinity retargeting proteins (DART)商標 ), as well as their polymers and derivatives, for example, divalent or polyvalent single-chain variable fragments (e.g., di-scFv, tri-scFv), which may include but not be limited to minibodies, diabodies, triabodies, tetrabodies, etc., and polyvalent antibodies. [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] are referenced, and their contents are incorporated herein by reference. “Antibody fragment” means at least a portion of the variable region of an immunoglobulin that binds to its target, i.e., the antigen-binding region. Other embodiments include drug D D or targeting agent T T Antibody mimetics are used to refer to, for example, but not limited to, affimers, antiticalins, avimers, alphabodies, affibodies, DARPins, and multimers, as well as their derivatives. [Trends in Biotechnology 2015, 33, 2, 65] is referenced, and its contents are incorporated herein by reference. To avoid misunderstanding, in the context of this disclosure, the term “antibody” encompasses all antibody variants, fragments, derivatives, fusions, analogs and mimetics described in this paragraph unless otherwise specified.

[0109] Preferably, T T This is selected from antibodies and antibody derivatives, such as antibody fragments, fragment fusions, proteins, peptides, peptide mimes, organic molecules, dyes, fluorescent molecules, and enzyme substrates.

[0110] Preferably, the organic molecule T TIt 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.

[0111] In another preferred embodiment, T T This is selected from antibody fragments, fragment fusions, and any other antibody derivatives that do not contain an Fc domain.

[0112] In another embodiment, T T The polymer is a polymer and accumulates at the primary target by the EPR effect. Typical polymers used in this embodiment, but not limited to these, include polyethylene glycol (PEG), poly(N-(2-hydroxypropyl)methacrylamide) (HPMA), polylactic acid (PLA), polylactic acid-glycolic acid (PLGA), polyglutamic acid (PG), polyvinylpyrrolidone (PVP), and poly(1-hydroxymethylethylenehydroxymethyl-formal) (PHF). Other examples are copolymers of polyacetals / polyketals with hydrophilic polymers selected from the group consisting of polyacrylates, polyvinyl polymers, polyesters, polyorthoesters, polyamides, oligopeptides, polypeptides and their derivatives. Other examples include oligopeptides, polypeptides, glycopolysaccharides, and polysaccharides, e.g., dextran and hyaluronan. In addition, see [G. Pasut, FM Veronese, Prog. Polym. Sci. 2007, 32, 933~961]. In some embodiments, T T This can be a cell-penetrating moiety, for example, a cell-penetrating peptide. In other embodiments, T T This includes polymers, particles, gels, biomolecules, or other T listed above. T It is a portion and is injected locally to form a local storage site for the prodrug, which is subsequently activated by an activator. In another embodiment, targeting agent TT The targeting agent T is a solid material, for example, but not limited to polymers, metals, and ceramics, wherein the solid material is contained in or composed of a cartridge, reservoir, or depot, where preferably the cartridge, reservoir, or depot is used for in vivo drug release. In some embodiments, the targeting agent T T It also functions as a drug, D D It may be written as follows:

[0113] T 3 T 3 is an organic part. Preferably, T 3 This corresponds to one of radical group 1, radical group 3, or radical group 5 as defined herein. More preferably, T 3 This corresponds to radical group 3 as defined herein. More preferably, T 3 is a polymer. More preferably, T 3 It is a polymer containing a polyethylene glycol portion.

[0114] futuristic, T 3 is -(CH2CH2-O-) y -T 4 This includes a portion. In this specification, y is an integer in the range of 1 to 50, preferably an integer in the range of 2 to 45, more preferably an integer in the range of 10 to 40, more preferably 12 to 37, even more preferably 15 to 35, even more preferably 20 to 30, even more preferably 23 to 25, and most preferably y is 24. This definition and preferred embodiments for y also apply to compounds of formula (2), formula (3), formula (G), formula (O), formula (P) and formula (Q), where y is used similarly.

[0115] T 4This corresponds to radical group 1, radical group 3, radical group 4, or radical group 5 as defined herein. Preferably, T 4 This follows radical group 1. More preferably, T 4 This follows radical group 1a. More preferably, T 4 This follows radical group 1b. More preferably, T 4 This follows the radical group 1c. More preferably, T 4 This follows the radical group 1d. More preferably, T 4 This follows the radical group 1e. Most preferably, T 4 It is methyl.

[0116] Furthermore, comfort, T 3 is -(CH2CH2-O-) y -T 4 It is a part. Most preferably, T 3 is -(CH2CH2-O-) 24 -This is the CH3 section.

[0117] Variants of equation (B)

[0118] In equation (B), R 48 and T 1 In formula (B) as defined herein, the TL is structured according to formula (A) as defined in any one of clauses 1 to 128, and preferably the TL is as defined in any one of clauses 216 to 227.

[0119] In equation (B), y1 is an integer between 0 and 4, preferably between 1 and 2, and most preferably y1 is 1.

[0120] In equation (B), y2 is an integer between 0 and 5, preferably between 1 and 4, more preferably between 1 and 3, and even more preferably between 1 and 2, and most preferably y2 is 1.

[0121] In equation (B), y3 is an integer from 1 to 5, preferably an integer from 1 to 4, more preferably an integer from 1 to 3, and even more preferably an integer from 1 to 2, and most preferably y3 is 1.

[0122] In equation (B), X 1 , X 2 , X 3 , X 4 , X 5 and X 6 Each of them is independently selected from the group consisting of substituted or unsubstituted carbon atoms, nitrogen atoms, or oxygen atoms, provided that X 1 , X 2 , X 3 , X 4 , X 5 and X 6 If one of them is a nitrogen atom or an oxygen atom, then adjacent X 1 , X 2 , X 3 , X 4 , X 5 and X 6 It is neither a nitrogen atom nor an oxygen atom.

[0123] Preferably, X 1 , X 2 , X 3 , X 4 , X 5 and X 6 Each of them is independently a substituted or unsubstituted carbon atom. More preferably, X 1 and / or X 6 R is independent of R 48 A carbon atom substituted with X. More preferably, X 1 R 48 A carbon atom substituted with X 1 ha-CHR 48 - is. More preferably, X 1 ha-CHR 48 - and X 4 Ha-CT 1 It is TL-. Preferably, X 2 , X 3 , X 5は、 and X 6is an unsubstituted carbon atom, more preferably -CH2-.

[0124] The variable x in equations (3), (O), (P), and (Q)

[0125] In equations (3), (O), (P), and (Q), x is an integer in the range of 4 to 12; preferably x is an integer in the range of 4 to 8, more preferably x is an integer in the range of 4 to 6, and most preferably x is 5.

[0126] R 48 R 48 These are -OH, -O-acetyl, -OC 1~4 Selected from the group consisting of alkyl groups, halogen atoms, active carbonates, and releaseable groups.

[0127] Preferably, R 48 However, these are substituents on the allyl carbon of the compound of this disclosure.

[0128] Preferably, R 48 However, it is in the axial position. This preferred embodiment is R 48 This is especially true when the group is a releaseable group. When the releaseable group is located at the axial position, it results in better payload release compared to when the releaseable group is located at the equatorial position.

[0129] Preferably, R 48 The group is a releaseable group. Such releaseable groups are well known and have clear meaning in the art. In particular, in the context of click-to-release reactions as described herein, those skilled in the art will know that the releaseable group on the allyl carbon of transcyclooctene (i.e., R in formula (1)) 48 It will be immediately apparent that ) is a group that can be detached from transcyclooctene when transcyclooctene is brought into contact with an activator, such as a diene.

[0130] In a preferred embodiment, the releaseable group is -(Y 1 -C(=Y 2 )) i -(S P ) j -C A In this specification, Y 1 and Y 2 Each of these is independently selected from O and S; preferably, Y 1 and Y 2 It is O.

[0131] In the case of the releaseable group, j is 0 or 1; preferably j is 0; and i is 0 or 1; preferably i is 1. When i is 0, -(S P ) j -C A However, -(S P ) j -C A The remainder of the compound is connected via O or S, which is part of it. On the other hand, when i is 1, -(S P ) j -C A However, -(S P ) j -C A -C(=Y 2 )- is connected. Preferably, when i is 1, -(S P ) j -C A However, -(S P ) j -C A -C(=Y 2 ) - Connected.

[0132] More preferably, the releaseable group is -(OC(=Y 2 )) i -(S P ) j -C A More preferably, the releaseable group is -(Y 1 -C(=O)) i -(S P )j -C A More preferably, the releaseable group is -(OC(=O)) i -(S P ) j -C A More preferably, the releaseable group is -OC(=O)-(S P ) j -C A That is the case.

[0133] Most preferably, the releaseable group is -OC(=O)-C A That is the case.

[0134] C A However, the payload is structure A. Preferably, C A However, it is an organic molecule or an inorganic molecule. More preferably, C A However, it is a drug. Preferably, C A However, it is nomethyl auristatin E (MMAE), exatecan, or an exatecan derivative. Most preferably, C A However, it is monomethyl auristatin E (MMAE).

[0135] Preferably, C A However, C A -(Y 1 -C(=Y 2 )) i -Partially, preferably -OC(=O)-, are linked to form a carbamate. Preferably, C A However, via a secondary or tertiary nitrogen atom that is part of monomethyl auristatin E (MMAE), -(Y 1 -C(=Y 2 )) i -A monomethyl auristatin E (MMAE) linked to a portion, preferably -OC(=O)-, forming a carbamate; or C A -(Y 1 -C(=Y 2 )) i-A portion, preferably -OC(=O)-, of exatecan or an exatecan derivative linked to form a carbamate. More preferably C A However, via a secondary or tertiary nitrogen atom that is part of monomethyl auristatin E (MMAE), -(Y 1 -C(=Y 2 )) i It is monomethyl auristatin E (MMAE) linked to a portion, preferably -OC(=O)-, which forms a carbamate.

[0136] Preferably, R 48 The basis is, [ka] ; or [ka] And, Here, E 1 is -H or -CH3, preferably E 1 is -H.

[0137] Most preferably, R 48 The basis is, [ka] That is the case.

[0138] S P This is a spacer, and a preferred embodiment thereof is defined below. Preferably, S P When S is part of the group that can be released, P This is a self-sacrificing linker, and in this specification, L C It is also referred to as such. Such self-sacrificing linkers are well known to those skilled in the art, and preferred embodiments of self-sacrificing linkers are defined below. When the spacer in the releaseable group is a self-sacrificing linker, and the compound of the present disclosure reacts with the diene, first construct-L C -C AIt is released. After that, the self-sacrificing linker undergoes self-decomposition, and then payload C A It is released.

[0139] drugs The drugs that can be used in the compound of formula (1) are pharmaceutically active compounds. Preferably, the pharmaceutically active compounds are selected from the group consisting of cytotoxic substances (cytotoxins), antiproliferative / antitemocyte agents, antiviral agents, antibiotics, anti-inflammatory agents, chemosensitizing agents, radiosensitizing agents, immunomodulators, immunosuppressants, immunostimulants, anti-angiogenic factors, and enzyme inhibitors. Preferably, these pharmaceutically active compounds are selected from the group consisting of antibodies, antibody derivatives, antibody fragments, proteins, aptamers, oligopeptides, oligonucleotides, oligosaccharides, carbohydrates, and peptides, peptoids, steroids, toxins, hormones, cytokines, and chemokines. Most preferably, the drug is a protein, a toxin, a chelate moiety, monomethyl auristatin E, or doxorubicin, where preferably the chelate moiety comprises a radionuclide. Preferably, these drugs are compounds with low to medium molecular weight, more preferably organic compounds (e.g., about 200 to about 2500 Da, preferably about 300 to about 1750 Da, more preferably about 300 to about 1000 Da).Examples of cytotoxic drug types for use in cancer treatment, for example, that are conjugated to triggers and released by IEDDA reactions with activators, include, but are not limited to, DNA damaging agents, DNA crosslinkers, DNA binders, DNA alkylators, DNA intercalators, DNA cleavers, microtubule stabilizing agents and destabilizers, topoisomerase inhibitors, radiosensitizers, antimetabolites, natural products and their analogues, peptides, oligonucleotides, and enzyme inhibitors, such as dihydrofolate reductase inhibitors and thymidylate synthase inhibitors.Examples include, but are not limited to, colchicine, vinca alkaloids, anthracyclines (e.g., doxorubicin, epirubicin, idarubicin, daunorubicin), camptothecin, taxanes, taxol, vinblastine, vincristine, vindesine, calicheamycin, tubulicin, tubulicin M, cryptophycin, methotrexate, metopterin, aminopterin, dichloromethotrexate, irinotecan, engine, amanitin, debouganin, dactinomycin, CC1065 and its analogues, duocalmycin, meitansine, meitansinoids, dorastatin, auristatin, pyrrolobenzodiazepines, and This category includes bisorbate dimers (PBDs), indolinobenzodiazepines and their dimers, pyridinobenzodiazepines and their dimers, mitomycins (e.g., mitomycin C, mitomycin A, caminomycin), melphalans, leurosine, leurosideine, actinomycin, tallysomycin, lexitropsins, bleomycins, podophyllotoxins, etoposide, etoposide phosphate, staurosporin, esperamicin, pteridine-based drugs, SN-38 and its analogues, platinum-based drugs, and cytotoxic nucleosides. Other exemplary drug classes include angiogenesis inhibitors, cell cycle progression inhibitors, PI3K / mTOR / AKT pathway inhibitors, MAPK signaling pathway inhibitors, kinase inhibitors, protein chaperone inhibitors, HDAC inhibitors, PARP inhibitors, Wnt / Hedgehog signaling pathway inhibitors, and RNA polymerase inhibitors.In some embodiments, the drug is auristatin. Examples of auristatins include dolastatin 10, monomethyl auristatin E (MMAE), auristatin F, monomethyl auristatin F (MMAF), auristatin F hydroxypropylamide (AF HPA), auristatin F phenylenediamine (AFP), monomethyl auristatin D (MMAD), auristatin PE, auristatin EB, auristatin EFP, auristatin TP, and auristatin AQ. MMAE is a preferred auristatin. Suitable auristatins are also found in U.S. Patent Application Publication No. 2003 / 0083263, U.S. Patent Application Publication No. 2011 / 0020343, and U.S. Patent Application Publication No. 2011 / 0070248; PCT Publication Numbers International Publication No. WO09 / 117531, International Publication No. WO2005 / 081711, International Publication No. WO04 / 010957; International Publication No. WO02 / 088172 and International Publication No. Publication No. WO01 / 24763, and U.S. Patent Nos. 7,498,298; U.S. Patent Nos. 6,884,869; U.S. Patent Nos. 6,323,315; U.S. Patent Nos. 6,239,104; U.S. Patent Nos. 6,124,431; U.S. Patent Nos. 6,034,065; U.S. Patent Nos. 5,780,588; U.S. Patent Nos. 5,767,237; U.S. Patent Nos. 5,66 These disclosures are described in U.S. Patent No. 5,860; U.S. Patent No. 5,663,149; U.S. Patent No. 5,635,483; U.S. Patent No. 5,599,902; U.S. Patent No. 5,554,725; U.S. Patent No. 5,530,097; U.S. Patent No. 5,521,284; U.S. Patent No. 5,504,191; U.S. Patent No. 5,410,024; U.S. Patent No. 5,138,036; U.S. Patent No. 5,076,973; U.S. Patent No. 4,986,988; U.S. Patent No. 4,978,744; U.S. Patent No. 4,879,278; U.S. Patent No. 4,879,278; U.S. Patent No. 4,816,444; and U.S. Patent No. 4,486,414, and their disclosures are incorporated herein by reference in their entirety.Exemplary drugs include drastatin and its analogues, which include drastatin A (U.S. Patent No. 4,486,414), drastatin B (U.S. Patent No. 4,486,414), drastatin 10 (U.S. Patent Nos. 4,486,444, 5,410,024, 5,504,191, 5,521,284, 5,530,097, 5,599,902, 5,635,483, 5,663,149, 5,665,860, U.S. Patent No. 10). This includes U.S. Patent No. 5,780,588, U.S. Patent No. 6,034,065, U.S. Patent No. 6,323,315), Drastatin 13 (U.S. Patent No. 4,986,988), Drastatin 14 (U.S. Patent No. 5,138,036), Drastatin 15 (U.S. Patent No. 4,879,278), Drastatin 16 (U.S. Patent No. 6,239,104), Drastatin 17 (U.S. Patent No. 6,239,104), and Drastatin 18 (U.S. Patent No. 6,239,104), each of which is incorporated herein by reference in its entirety.Exemplary maytansines or maytansinoids, such as DM-1 and DM-4, ​​or maytansinol and its analogues, are included in U.S. Patent Nos. 4,424,219; 4,256,746; 4,294,757; 4,307,016; 4,313,946; 4,315,929; 4,331,598; 4,361,650; U.S. Patent Nos. 4, These are described in U.S. Patent Nos. 362,663; U.S. Patent Nos. 4,364,866; U.S. Patent Nos. 4,450,254; U.S. Patent Nos. 4,322,348; U.S. Patent Nos. 4,371,533; U.S. Patent Nos. 5,208,020; U.S. Patent Nos. 5,416,064; U.S. Patent Nos. 5,475,092; U.S. Patent Nos. 5,585,499; U.S. Patent Nos. 5,846,545; U.S. Patent Nos. 6,333,410; U.S. Patent Nos. 6,441,163; U.S. Patent Nos. 6,716,821; and U.S. Patent Nos. 7,276,497. Other examples include mertansine and ansamitocin. Pyrrolobenzodiazepines (PBDs) expressly include, but are not limited to, dimers and their analogues, as described in [Denny, Exp. Opin. Ther. Patents, 10(4):459~474 (2000)], [Hartley et al., Expert Opin Investig Drugs. 2011, 20(6):733~44], Antonow et al., Chem Rev. 2011, 111(4), 2815~64]. Calicheamicins include, for example, enediynes, esperamicin, and those described in U.S. Patent Nos. 5,714,586 and 5,739,116.Examples of duocarmycins and their analogues include CC1065, duocarmycin SA, duocarmycin A, duocarmycin B1, duocarmycin B2, duocarmycin C1, duocarmycin C2, duocarmycin D, DU-86, KW-2189, adozelesin, bizelesin, carzelesin, seco-adozelesin, CPI, and CBI. Other examples include, for instance, U.S. Patent No. 5,070,092; U.S. Patent No. 5,101,092; U.S. Patent No. 5,187,186; U.S. Patent No. 5,475,092; U.S. Patent No. 5,595,499; U.S. Patent No. 5,846,545; U.S. Patent No. 6,534,660; U.S. Patent No. 6,548,530; U.S. Patent No. 6,586,618; U.S. Patent No. 6,660,742; U.S. Patent No. 6,756,397. This includes the specifications; U.S. Patent No. 7,049,316; U.S. Patent No. 7,553,816; U.S. Patent No. 8,815,226; U.S. Patent No. US20150104407; U.S. Patent Application No. 61 / 988,011 filed on 2 May 2014; and U.S. Patent Application No. 62 / 010,972 filed on 11 June 2014, the disclosures of each of these are incorporated herein by reference in their entirety. Exemplary vinca alkaloids include vincristine, vinblastine, vindesine, and navelbine, as disclosed in U.S. Patent Publication No. 2002 / 0103136 and U.S. Patent Publication No. 2010 / 0305149, and U.S. Patent No. 7,303,749, the disclosures of which are incorporated herein by reference in their entirety. Exemplary epotilone compounds include epotilones A, B, C, D, E, and F, as well as their derivatives.Suitable epotilone compounds and their derivatives are, for example, U.S. Patent No. 6,956,036; U.S. Patent No. 6,989,450; U.S. Patent No. 6,121,029; U.S. Patent No. 6,117,659; U.S. Patent No. 6,096,757; U.S. Patent No. 6,043,372; U.S. Patent No. 5,969,145; and U.S. Patent No. 5,886,026; and International Publication No. WO97 / 19086; International Publication No. WO98 / These are described in U.S. Patent Nos. 08849; WO98 / 22461; WO98 / 25929; WO98 / 38192; WO99 / 01124; WO99 / 02514; WO99 / 03848; WO99 / 07692; WO99 / 27890; and WO99 / 28324, the disclosures of which are incorporated herein by reference in their entirety. Exemplary cryptophycin compounds are described in U.S. Patent Nos. 6,680,311 and 6,747,021, the disclosures of which are incorporated herein by reference in their entirety. Exemplary platinum compounds include cisplatin, carboplatin, oxaliplatin, iproplatin, ormaplatin, and tetraplatin. Exemplary DNA-binding or alkylating agents include CC-1065 and its analogues, anthracyclines, calicheamicins, dactinomycines, mitomycines, pyrrolobenzodiazepines, indolinobenzodiazepines, pyridinobenzodiazepines, etc. Exemplary microtubule stabilizers and destabilizers include taxane compounds, such as paclitaxel, docetaxel, tesetaxel, and others. This includes carbaditaxel; maytansinoids, auristatins and their analogues, vinca alkaloid derivatives, epothilones, and cryptophycins. Exemplary topoisomerase inhibitors include camptothecin and camptothecin derivatives, camptothecin analogs, and non-natural camptothecins, such as CPT-11, SN-38, topotecan, 9-aminocamptothecin, rubitecan, gimatecan, karenitecin, silatecan, lurtotecan, exatecan, diflometotecan, belotecan, lurtotecan, and S39625. Other camptothecin compounds that may be used in this disclosure include, for example, those described in J.Med.Chem., 29:2358~2363 (1986); J.Med.Chem., 23:554 (1980); and J.Med Chem., 30:1774 (1987). Angiogenesis inhibitors include, but are not limited to, MetAP2 inhibitors, VEGF inhibitors, PIGF inhibitors, VGFR inhibitors, PDGFR inhibitors, and MetAP2 inhibitors. Exemplary VGFR and PDGFR inhibitors include sorafenib, sunitinib, and vatalanib. Exemplary MetAP2 inhibitors include fumagillol analogs, i.e., compounds containing the basic structure of fumagarine.Exemplary cell cycle progression inhibitors include CDK inhibitors, e.g., BMS-387032 and PD0332991; Rho kinase inhibitors, e.g., AZD7762; Aurora kinase inhibitors, e.g., AZD1152, MLN8054 and MLN8237; PLK inhibitors, e.g., BI2536, BI6727, GSK461364, ON-01910; and KSP inhibitors, e.g., SB743921, SB715992, MK-0731, AZD8477, AZ3146 and ARRY-520, etc. Exemplary PI3K / mTOR / AKT signaling pathway inhibitors include phosphoinositide 3-kinase (PI3K) inhibitors, GSK-3 inhibitors, ATM inhibitors, DNA-PK inhibitors, and PDK-1 inhibitors. Exemplary PI3 kinases are disclosed in U.S. Patent No. 6,608,053 and include BEZ235, BGT226, BKM120, CAL263, demethoxyviridin, GDC-0941, GSK615, IC87114, LY294002, Palomid 529, perifosine, PF-04691502, PX-866, SAR245408, SAR245409, SF1126, Wortmannin, XL147, and XL765. Exemplary AKT inhibitors include, but are not limited to, AT7867. Exemplary MAPK signaling pathway inhibitors include MEK, Ras, JNK, B-Raf, and p38 MAPK inhibitors. Exemplary MEK inhibitors are disclosed in U.S. Patent No. 7,517,944 and include GDC-0973, GSK1120212, MSC1936369B, AS703026, RO5126766 and RO4987655, PD0325901, AZD6244, AZD8330 and GDC-0973. Exemplary B-raf inhibitors include CDC-0879, PLX-4032 and SB590885. Exemplary B p38 MAPK inhibitors include BIRB 796, LY2228820 and SB202190.Exemplary receptor tyrosine kinase inhibitors include, but are not limited to, AEE788 (NVP-AEE 788), BIBW2992 (Afatinib), Lapatinib, Erlotinib (Tarceva), Gefitinib (Iressa), AP24534 (Ponatinib), ABT-869 (Linifanib), AZD2171, CHR-258 (Dovitinib), Sunitinib (Sutent), Sorafenib (Nexavar), and Vatalinib. Exemplary protein chaperone inhibitors include HSP90 inhibitors. Exemplary inhibitors include 17AAG derivatives, BIIB021, BIIB028, SNX-5422, NVP-AUY-922, and KW-2478. Exemplary HDAC inhibitors include Belinostat (PR). 48This includes 101), CUDC-101, droxinostat, ITF2357 (givinostat, gavinostat), JNJ-26481585, LAQ824 (NVP-LAQ824, dacinostat), LBH-589 (panobinostat), MC1568, MGCD0103 (mocetinostat), MS-275 (entinostat), PCI-24781, pyroxamide (NSC 696085), SB939, trichostatin A, and vorinostat (SAHA). Exemplary PARP inhibitors include iniparib (BSI201), olaparib (AZD-2281), ABT-888 (veliparib), AG014699, CEP9722, MK4827, KU-0059436 (AZD2281), LT-673, 3-aminobenzamide, A-966492, and AZD2461. Exemplary Wnt / Hedgehog signaling pathway inhibitors include vismodegib, cyclopamine, and XAV-939. Exemplary RNA polymerase inhibitors include amatoxins. Exemplary amatoxins include alpha-amanitins, beta-amanitins, gamma-amanitins, eta-amanitins, amanullin, amanullic acid, amanisamide, amanon, and proamanullin.Exemplary immunomodulators include APRIL, cytokines (including IL-2, IL-7, IL-10, IL-12, IL-15, IL-21, TNF, interferon-gamma, GM-CSF, NDV-GMCSF), STING agonists and antagonists, TLRs (including TLR1 / 2, TLR3, TLR4, TLR7 / 8, TLR9, TLR12) agonists and antagonists, GITR, CD3, CD28, CD40, CD74, CTLA4, OX40, PD1, PDL1, RIG, MDA-5, NLRP1, NLRP3, AIM2, IDO, MEK, cGAS, and CD25, NKG2A agonists and antagonists. Other exemplary drugs include puromycins, topetecan, rhizoxin, echinomycin, combretastatin, netropsin, estramustine, cemadotin, discordermolide, eleutherobin, mitoxantrone, pyrrolobenzimidazoles (PBI), gamma-interferon, thialanostatin (A) and its analogues, CDK11, and immunotoxins (e.g., lysine A, diphtheria toxin, cholera toxin). In exemplary embodiments of the present disclosure, the drug portion includes mitomycin compounds, vinca alkaloid compounds, taxol or analogues, anthracycline compounds, calicheamicin compounds, meitansinoid compounds, auristatin compounds, duocalmycin compounds, SN38 or analogues, pyrrolobenzodiazepine compounds, indolinobenzodiazepine compounds, pyridinobenzodiazepine compounds, tubulisin compounds, non-natural camptothecin compounds, DNA binding agents, kinase inhibitors, MEK inhibitors, KSP inhibitors, PI3 kinase inhibitors, topoisomerase inhibitors, or analogues thereof.In one preferred embodiment, the drug is a non-natural camptothecin compound, vinca alkaloid, kinase inhibitor (e.g., PI3 kinase inhibitors: GDC-0941 and PI-103), MEK inhibitor, KSP inhibitor, RNA polymerase inhibitor, PARP inhibitor, docetaxel, paclitaxel, doxorubicin, dolastatin, calicheamicins, SN38, pyrrolobenzodiazepines, pyridinobenzodiazepines, indolinobenzodiazepines, or DNA-binding agents. These include drugs, maytansinoids DM1 and DM4, auristatin MMAE, CC1065 and its analogues, camptothecin and its analogues, SN-38 and its analogues. In another preferred embodiment, the drug is selected from DNA-binding drugs and microtubule-acting drugs (including pyrrolobenzodiazepines, indolinobenzodiazepines, pyridinobenzodiazepines, maytansinoids, maytansines, auristatins, tubulysins, duocarmycins, anthracyclines, and taxanes). In another preferred embodiment, the drug is selected from colchicine, vinca alkaloids, tubulysins, irinotecans, inhibitory peptides, amanitin, and debuganin. In another preferred embodiment, the drug is a radioactive moiety, which contains radioisotopes for radiotherapy.In another preferred embodiment, the drug is selected from colchicine, vinca alkaloids, tubulsin, irinotecan, inhibitory peptides, amanitin, and debuganin. In another preferred embodiment, the drug is a radioactive moiety, wherein the moiety comprises a radioisotope for radiotherapy. The radionuclides used for treatment are 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 American and 227It is an isotope selected from the group consisting of Th. The radioactive part is a metal, for example. 177 If Lu is to be included, such radioactive metals are preferably provided in the form of chelates. In such cases, the radioactive portion preferably includes a structural portion capable of forming a coordination complex with such metal. A good example of these is a macrocyclic lanthanide(III) chelate derived from 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (H4dota). Preferably, the structural portion capable of forming a coordination complex with such metal is a chelate portion as defined herein. In other embodiments, the radioactive portion is a nonmetallic radionuclide, for example 131 I, comprising a prosthetic group (i.e., phenol) linked by Trigger or Linker L. The drug optionally includes a membrane-permeable moiety (e.g., part of a membrane-permeable moiety (e.g., adamantane, polylysine / arginine, TAT, human lactoferrin) and / or a targeting agent (e.g., one for tumor cell receptors) linked via a stable or unstable linker. Exemplary references include Trends in Biochemical Sciences, 2015, 40, 12, 749; J.Am.Chem.Soc. 2015, 137, 12153~12160; Pharmaceutical Research, 2007, 24, 11, 1977. Trigger or Linker L C One or more targeting agents that can adhere to (or C B In addition to the targeting agent T T Optionally, spacer S P It should be further understood that the drug may be further attached via a targeting agent (or C B ) can be cleaved by other types of linkers, such as proteases, pH, thiols, or catabolism, to target the agent. It will be further understood that the conjugates may contain one or more additional drugs. It will also be understood that, for the purpose of preparing the conjugates of this disclosure, the desired compounds may be chemically modified to facilitate the reaction. Drugs containing an amine functional group for coupling to the trigger include mitomycin C, mitomycin A, daunorubicin, doxorubicin, aminopterin, actinomycin, bleomycin, 9-aminocamptothecin, N8-acetylspermidine, 1-(2-chloroethyl)-1,2-dimethanesulfonylhydrazide, tarisomycin, cytarabine, dolastatins (including auristatins) and their derivatives. Drugs containing a hydroxyl functional group for coupling to a trigger include etoposide, camptothecin, taxol, esperamycin, 1,8-dihydroxy-bicyclo[7.3.1]trideca-4,9-dien-2,6-diin-13-one (U.S. Patent No. 5,198,560), podophyllotoxin, angidine, vincristine, vinblastine, morpholine-doxorubicin, n-(5,5-diacetoxypentyl)doxorubicin, and their derivatives. Drugs containing a sulfhydryl functional group for coupling to a trigger include esperamycin and 6-mercaptopurine, and their derivatives.

[0140] Log P In a preferred embodiment, the Log P of the compound of formula (1) has a value in the range of 2.0 to -2.0, more preferably in the range of 1.0 to -1.0.

[0141] In embodiments where the compounds disclosed herein, particularly the dienes, are required to have extracellular volume of distribution, it is preferable that the Log P value of the compounds is at most 2, preferably at most 1, more preferably at most 0, and even more preferably at most -1. In embodiments where the compounds disclosed herein, particularly the dienes, are required to have intracellular volume of distribution, it is preferable that the Log P value of the compounds is at least -1, preferably at least 0, more preferably at least 1, and even more preferably at least 2.

[0142] molecular weight T 2 In the case of a compound of formula (1) in which is the bioconjugation moiety, the molecular weight of the compound is preferably 5 kDa or less, more preferably 4 kDa or less, even more preferably 3.5 kDa or less, even more preferably 3 kDa or less, and most preferably 2.5 kDa or less. 2 ga-L 3 -C B In the case of the compound of formula (1) as the base, the molecular weight of the compound is preferably 100 kDa or less, more preferably 85 kDa or less, even more preferably 75 kDa or less, even more preferably 65 kDa or less, and most preferably 62.5 kDa or less.

[0143] Spacer S P All linkers used in this specification are, each independently, spacer S P This may also be the case. As those skilled in the art will recognize, the specific structure of the spacer used in either the dienophile or diene described herein typically does not affect whether the payload is released. However, in some cases, a particular spacer is preferred. For example, if the payload is to be released, the spacer between the allyl carbon of, for example, an 8-membered ring non-aromatic cyclic monoalkenylene moiety and the payload is preferably a self-sacrificing linker. CSuch linkers, typically referred to as such, undergo further rearrangement or reaction when the linker end bonded to the allyl carbon is released, after which the payload becomes linker L C This ensures that it is separated from the other components. Below, spacers in general are explained first, followed by a more specific explanation of self-sacrificing linkers.

[0144] Generally, the spacer S used in this specification P This is a portion conforming to RG2, or any one of their preferred and / or specific embodiments.

[0145] Preferably, spacer S P This refers to one or more spacer units S arranged in a linear and / or branched manner. U Composed of, and one or more C B Part and / or one or more L C Part or T R It can be connected to part C. B to one T R to (see Example A below; Equations 5a and 5b: f, e, a = 1) or multiple T R It can be used to connect to (see examples B and C below; equations 5a and 5b: f,e=1,a≧1), but the spacer can also be C B -T R -C A It can be used to modulate the properties of a conjugate, such as its pharmacokinetic properties (see Example D below; Equations 5a and 5b: one or more of c, e, g, and h are one or more). Therefore, a spacer unit does not necessarily connect two elements together, and the spacer can also connect only one component, for example, T R or L C It can be coupled to, Alternatively, the spacer is C B to T RThe spacer may also include a spacer unit connected to the spacer, and in addition, it may include another spacer unit that is coupled only to the spacer and modulates the properties of the conjugate (see Example F below; Equations 5a and 5b: e≧1). The spacer may also include two different types of S U The construct may consist of, for example, PEG linked to the peptide or PEG linked to the alkylene moiety (see Example E below; Formulas 5a and 5b: e≧1). For clarity, Example B is a polyvalent branched S U By using this, the branched S U This shows that Example C is a linear S U Branched S by using polymers, such as peptides U This indicates that its side chain residues serve as conjugation groups. [ka]

[0146] The spacer can be coupled to the activator in a similar design as illustrated in examples A to F above.

[0147] Each individual spacer unit S U The spacer unit can be independently selected from the group of radicals following RG2. The spacer unit includes, but is not limited to, amino acids, nucleosides, nucleotides, and biopolymer fragments, such as oligopeptides or polypeptides, oligopeptoids or polypeptoids, or oligolactides or polylactides, or oligosaccharides or polysaccharides, and the number of repeating units varies from 2 to 200, particularly 2 to 113, preferably 2 to 50, more preferably 2 to 24, and more preferably 2 to 12 repeating units. Preferred biopolymer S U It is a peptide. Preferably, each S U This includes 50 or fewer carbon atoms, more preferably 25 or fewer carbon atoms, and more preferably 10 or fewer carbon atoms. In some embodiments, the S U (CH2) r(C3~C8 carbocyclo), O-(CH2) r , Arirene, (CH2) r -Arirenn, Arirenn-(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) r C(O)NR'(CH2) r (CH2CH2O) r (CH2CH2O) r CH2, (CH2) r C(O)NR'(CH2CH2O) r , (CH2) r C(O)NR'(CH2CH2O) r CH 2、 (CH2CH2O) r C(O)NR'(CH2CH2O) r (CH2CH2O) r C(O)NR'(CH2CH2O) r CH2, (CH2CH2O) r A radical is independently selected from the group consisting of C(O)NR'CH2; where r is independently an integer from 1 to 10. In its use herein, each R' is independently selected from the group consisting of radicals following RG1. Preferably, R' is a hydrogen atom. Spacer unit S UOther examples include linear or branched polyalkylene glycols, such as polyethylene glycol (PEG) or polypropylene glycol (PPG) chains, which vary in repeating units of 2 to 200, particularly 2 to 113, preferably 2 to 50, more preferably 2 to 24, and more preferably 2 to 12. When polyalkylene glycols, such as PEG and PPG polymers, are linked only via one end of the polymer chain, the other end is preferably terminated with -OCH3, -OCH2CH3, or OCH2CH2CO2H. Other polymeric spacer units include polymers and copolymers, such as poly-(2-oxazoline), poly(N-(2-hydroxypropyl)methacrylamide) (HPMA), polylactic acid (PLA), polylactic acid-glycolic acid (PLGA), polyglutamic acid (PG), dextran, polyvinylpyrrolidone (PVP), and poly(1-hydroxymethylethylenehydroxymethyl-formal) (PHF). Other exemplary polymers include polysaccharides, glycopolysaccharides, glycolipids, polyglycosides, polyacetals, polyketals, polyamides, polyethers, and polyesters. U Examples of naturally occurring polysaccharides that can be used as polymers include cellulose, amylose, dextran, dextrin, levan, fucoidan, carrageenan, inulin, pectin, amylopectin, glycogen, lixenan, agarose, hyaluronan, chondroitin sulfate, dermatan sulfate, keratan sulfate, alginic acid, and heparin. In yet another embodiment, polymeric S U This includes copolymers of polyacetal / polyketal and hydrophilic polymers selected from the group consisting of polyacrylate, polyvinyl polymer, polyester, polyorthoester, polyamide, oligopeptide, polypeptide and derivatives thereof. Preferred polymericity S U These are PEG, HPMA, PLA, PLGA, PVP, PHF, dextran, oligopeptides, and polypeptides. In some embodiments, S UThe polymers used in this have molecular weights in the range of 2-200 kDa, 2-100 kDa, 2-80 kDa, 2-60 kDa, 2-40 kDa, 2-20 kDa, 3-15 kDa, 5-10 kDa, and 500 Daltons-5 kDa. Other exemplary S U These are dendrimers, such as poly(propyleneimine) (PPI) dendrimers, PAMAM dendrimers, and glycol-based dendrimers. U This expressly includes, but is not limited to, conjugates prepared using commercially available crosslinking agents 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. To construct a branching spacer, one or more natural or non-natural amino acids, amino alcohols, amino aldehydes or polyamine residues, or combinations thereof, are used. U These components may be used, and these components together provide the functions required for branching. For example, serine has three functional groups, namely an acid group, an amino group and a hydroxyl group, and is branched S U For the purpose of functioning as such, it can be considered as a combination of an amino acid and an amino alcohol residue. Other exemplary amino acids are lysine and tyrosine. In some embodiments, the spacer consists of one spacer unit; therefore, in these cases, S P is S U Equivalent to. Preferably, the spacer consists of two, three, or four spacer units. In some embodiments, S PThe molecular weight is in the range of 2-200 kDa, 2-100 kDa, 2-80 kDa, 2-60 kDa, 2-40 kDa, 2-20 kDa, 3-15 kDa, 5-10 kDa, or 500 daltons-5 kDa. In some embodiments, S P It has masses 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, and 200 Daltons or less. From several perspectives, S P It has masses ranging from 100 Daltons to 5000 Daltons, from 200 Daltons to 5000 Daltons, and from 300 Daltons to 5000 Daltons. In some respects, S P It has masses ranging from 30, 50, or 100 Daltons to 1000 Daltons, and from approximately 30, approximately 50, or approximately 100 Daltons to approximately 500 Daltons.

[0148] Preferably, S P This includes residues of the RG2a, RG2b, RG2c, or RG1f moieties as described herein. Preferably, the residues of RG2a, RG2b, RG2c, or RG1f are S P to C B , L C or T R Connect to it.

[0149] Self-sacrificing Linker L C L C Linker L is an optional self-sacrificing linker, which may consist of multiple units arranged in a linear and / or branched configuration. C , C A and T R Possible L C The structure (trigger, i.e., the trans-cyclooctene moiety), their use, arrangement, and methods of linking are known to those skilled in the art (e.g., [Papot et al., Anticancer Agents Med. Chem., 2008, 8, 618-637]). Nevertheless, preferred but not limited to self-degrading linkers LC An example is the benzyl derivative shown below. There are two main autodegradation mechanisms: namely, electron cascade elimination and cyclization-mediated elimination. The preferred example below on the left functions by the cascade mechanism, where the bond between the trigger allyl carbon and the -O- or -S- bonded to that carbon is cleaved, and Y C1 electron pairs, for example NR 6 The electron pair moves into the benzyl moiety, resulting in an electron cascade reaction and forming 4-hydroxybenzyl alcohol, CO2, and a free payload. A preferred example in the middle functions by a cyclization mechanism, where the trigger side NR 6 The cleavage of the bond with leads to a nucleophilic attack of the amine on the carbonyl group, forming a five-membered ring of 1,3-dimethylimidazolidin-2-one, and then releasing the payload. The preferred example on the right combines both mechanisms. This linker is CO2 and one unit of 4-hydroxybenzyl alcohol (Y C1 It decomposes not only when it is O, but also into one unit of 1,3-dimethylimidazolidined-2-one. [ka] Here, the wavy line may indicate a bond to -O- or -S- at the allylic position of trans-cyclooctene, and the double wavy line indicates C A This indicates a connection to [the specified location].

[0150] The aforementioned self-sacrificing linker L CBy substituting the benzyl group, it is possible to adjust the payload release rate resulting from steric and / or electronic effects in cyclization and / or cascade release. 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]). Several preferred substituted benzyl derivatives with different release rates are shown below.

[0151] Self-sacrificing linkers that undergo cyclization reactions 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 linkers based on trimethyl locks (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). C Further preferred examples are found in International Publication No. WO2009017394(A1), U.S. Patent No. US7375078, International Publication No. WO2015038426A1, International Publication No. WO2004043493, and Angew.Chem.Int.Ed.2015, 54, 7492-7509, the contents of which are incorporated herein by reference.

[0152] Preferably, L C It has a mass of 1000 Daltons or less, 500 Daltons or less, 400 Daltons or less, 300 Daltons or less, or from 10, 50 or 100 Daltons to 1000 Daltons, from 10, 50, 100 Daltons to 400 Daltons, from 10, 50, 100 Daltons to 300 Daltons, or from 10, 50, 100 Daltons to 200 Daltons, for example 10 to 1000 Daltons, for example 50 to 500 Daltons, for example 100 to 400 Daltons.

[0153] Those skilled in the art will know that one L C C A Another L connected C It can be linked to, here, the activator triggers T R When it reacts, L C -L C -C A is T R Freed from, both L C It will be understood that this will result in the autodegradation and release of parts and payloads. C Regarding the formula, T R to other L C L that links to C Next, instead of releasing the payload, Y C1 They are joined via C A L that links further C It releases. Those skilled in the art will see that this principle is L C Further linker L connected to C For example, L C -L C -L C -L C -C A They will realize that this also applies to them.

[0154] Preferably, if the releaseable group includes a self-sacrificing linker, the releaseable group follows one of the following groups: Group I, Group II, Group III, and Group IV. In the structures shown in these groups, for reasons of clarification, only the bond to construct A and the bond to the atom (typically an oxygen atom) at the allylic position of the 8-membered non-aromatic cyclic monoalkenylene moiety (preferably a trans-cyclooctene ring) are shown, although construct A and the atom are part of the releaseable group.

[0155] The emitting groups belonging to group I are: [ka] Here, the wavy line may also indicate a bond to -S- at the allylic position of transcyclooctene, where U, V, W, and Z are each independently -CR 7 Selected from the group consisting of - and -N-, where e is 0 or 1, where X is -O-, -S- and -NR 6 - Selected from the group consisting of, where preferably each R 8 and R 9 These are independently a hydrogen atom, a C1-C4 (hetero)alkyl, a C2-C4 (hetero)alkenyl, and C 4~6 Independently selected from the group consisting of (hetero)aryls; where R 8 and R 9 In this case, (hetero)alkyl, (hetero)alkenyl and (hetero)aryl are optionally -Cl, -F, -Br, -I, -OH, -NH2, =O, -SH, -SO3H, -PO3H 、 The moiety may be substituted with a moiety selected from the group consisting of -PO4H2 and -NO2, preferably containing two or fewer heteroatoms selected from the group consisting of -O-, -S-, -NH-, -P- and -Si-, where the N, S and P atoms may optionally be oxidized. Preferably, in the case of a releaseable group of group I, R 8 and R 9 Both are hydrogen atoms.

[0156] The releaseable groups belonging to Group II are: [ka] Here, the tilde may also indicate a bond with -S- at the allyl position of trans-cyclooctene, where m is an integer from 0 to 2, preferably m is 0, where e is 0 or 1. Preferably, in the case of a releaseable group of group II, R 8 and R 9 Both are hydrogen atoms. Preferably, in the case of a releaseable group of group II, R 7 is a methyl group or an isopropyl group. Optionally, R included in groups I and II. 6 , R 7 , R8 , R 9 is, -(S P ) i -C B That is the case.

[0157] For all releaseable groups belonging to Group I and Group II, Y C1 -O-, -S-, and -NR 6 - Selected from the group consisting of -, preferably -NR 6 - For all linkers belonging to Group I and Group II, Y C2 The group is selected from a group consisting of O and S, and is preferably O.

[0158] The releaseable groups according to Group III are: [ka] Here, the wavy line may also indicate a bond with -S- at the allylic position of trans-cyclooctene.

[0159] The releaseable groups belonging to group IV are: [ka] Here, the wavy line may also indicate a bond with -S- at the allylic position of trans-cyclooctene.

[0160] Preferably, R 6 , R 7 , R 8 , R 9 This conforms to RG1, or any preferred embodiment thereof. Preferably, R used in the present invention 6 , R 7 , R 8 , R 9 is not substituted. Most preferably, R used in the present invention 6 , R 7 , R 8 , R 9 This is a hydrogen atom.

[0161] Conjugate of this disclosure

[0162] This disclosure also relates to conjugates, or salts, hydrates or solvates thereof; wherein the conjugate comprises a protein conjugated to at least one compound according to this disclosure, wherein T 2 is a residue of the bioconjugation portion, and the protein and the compound are T 2 It is conjugated via T. Therefore, the conjugate of this disclosure is T 2 The compound of the present disclosure linked to a protein via (where T 2 (which is originally the bioconjugation portion), and here, the coupling of the compound and the protein results in the T in the conjugate of this disclosure. 2 is a residue in the bioconjugation moiety, preferably an N-maleimidyl group residue, i.e., [ka] Here, an asterisk indicates binding to a protein, and a wavy line indicates binding to the rest of the compound of this disclosure.

[0163] In the conjugate of the present disclosure, the protein is preferably a diabody or an antibody, more preferably a diabody, and most preferably the protein is AVP0458 consisting of two monomers, each of which has an amino acid sequence according to sequence ID number 1.

[0164] Preferably, in the conjugate of the present disclosure, the protein and the compound of the present disclosure are T 2 and more preferably via a sulfidyl residue of the protein, a hydroxyl residue of the protein, or an amine residue of the protein. 2 The proteins are conjugated via sulfidyl residues, and preferably, the sulfidyl residues of the proteins are a portion of the cysteine ​​residues of the proteins.

[0165] Preferably, the conjugate of this disclosure is [ka] Or, [ka] And, Here, E 1 is -H or -CH3, preferably E 1 is -H.

[0166] More preferably, the conjugate of this disclosure is [ka] That is the case.

[0167] In relation to the conjugates of this disclosure, CJ is in the range of 1 to 12, preferably 2 to 10, more preferably 2.5 to 8, even more preferably 3 to 6, and most preferably 3.5 to 4. For individual conjugates, it will be understood that CJ is typically an integer, most preferably about 4. However, when measuring CJ for multiple conjugates, an average value that is not necessarily an integer may be obtained. Since CJ is generally determined in common for multiple conjugates, in relation to this disclosure, CJ typically refers to an average value.

[0168] More preferably, the conjugate is [ka] And here, E 1 is -H or -CH3, preferably E 1 is -H.

[0169] More preferably, the conjugate is [ka] And here, E 1 is -H or -CH3, preferably E 1 is -H.

[0170] More preferably, the conjugate is [ka] That is the case.

[0171] More preferably, the conjugate is [ka] That is the case.

[0172] Composition of the present disclosure This disclosure also relates to compositions comprising compounds relating to this disclosure, or salts, hydrates, or solvates thereof. Preferably, the composition is a pharmaceutical composition. Preferably, the composition of this disclosure further comprises a pharmaceutically acceptable carrier. When a salt of a compound of this disclosure is included in the composition of this disclosure, it is also preferable that a pharmaceutically acceptable salt is used.

[0173] Combinations of this disclosure This disclosure also relates to (A1) compounds, or salts, hydrates, or solvates thereof, (A2) conjugates, or salts, hydrates, or solvates thereof, and / or (A3) compositions thereof, and (B) dienes, or salts, solvates, or hydrates thereof. In this specification, it will be understood that compounds, and / or containing a dienophile portion, may be referred to as “triggers.” The dienes may be referred to as “activators.”

[0174] Preferably, a combination of (A1) and (B). Preferably, a combination of (A2) and (B). Preferably, a combination of (A3) and (B). Preferably, a combination of (A1), (A2), and (B). Preferably, a combination of (A1), (A3), and (B). Preferably, a combination of (A2), (A3), and (B). Preferably, a combination of (A1), (A2), (A3), and (B).

[0175] Preferably, the combinations of the present disclosure are kits. More preferably, the combinations of the present disclosure are kits in which (A1), (A2) and / or (A3) are physically separated from (B).

[0176] Preferably, the diene is tetrazine. More preferably, the diene is [ka] or selected from the group consisting of salts, hydrates, and / or solvates thereof.

[0177] Preferably, the diene is (TZ1), or a salt, hydrate, and / or solvate thereof. More preferably, the diene is (TZ2), or a salt, hydrate, and / or solvate thereof. More preferably, the diene is (TZ3), or a salt, hydrate, and / or solvate thereof. More preferably, the diene is (TZ4), or a salt, hydrate, and / or solvate thereof. Most preferably, the diene is (TZ5), or a salt, hydrate, and / or solvate thereof.

[0178] (TZ1) is the most well-studied tetrazine in the literature for in vivo use and is the most promising candidate for clinical use. Above all, Rossin et al.,Angew.Chem.Int.Ed.2010,volume 49,pages 3375~3378;Rossin et al.,J.Nucl.Med.2013,volume 54;pages 1989~1995;Rossin et al.,Bioconjugate Chem.2013,volume 24,pages 1210~1217;Rossin et al.,Mol.Pharm.2014,volume 11,pages 3090~3096;Van Duijnhoven et al.,J.Nucl.Med.2015,volume 56,pages 1422~1428;Edem et al.Molecules 2020,volume 25, page 463; See al., Bioconjugate Chem. 2016, volume 27, pages 1697-1706; Rossin et al., Nature Commun. 2018, volume 9, article 1484; and International Publication No. WO2020 / 256546 (especially Example 5 on pages 294-296).

[0179] However, the inventors have identified several previously unknown drawbacks of (TZ1). These problems primarily arise when (TZ1) is used in vivo as an activator for payload release from an 8-membered ring non-aromatic cyclic monoalkenylene moiety (e.g., trans-cyclooctene), which requires higher doses than when (TZ1) is used for radioimaging and / or radiotherapy.

[0180] Firstly, it was revealed that compound (TZ1) potently inhibits the physiologically important enzymes cyclooxygenase (COX-1), acetylcholinesterase (ACES), monoamine oxidase (MAO-B), and calcium channel L-type dihydropyridine. Each of these proteins is important for maintaining health in the subject, and unnecessary inhibition of these enzymes and / or transporters can lead to side effects.

[0181] Secondly, (TZ1) was found to have a relatively low maximum tolerated dose (MTD) of approximately 39 μmol / kg in mice.

[0182] Furthermore, the synthesis of (TZ1) involves many steps, while it is preferable to use tetrazine, which can be synthesized in fewer steps.

[0183] Finally, it is desirable to provide tetrazine having overall good in vitro and in vivo properties, namely good stability, good reactivity with trans-cyclooctene and / or high payload release (especially in vivo), low membrane permeability, low cytotoxicity, and low genotoxicity.

[0184] (TZ2), (TZ3), (TZ4), and especially (TZ5) have been found to overcome one or more of the shortcomings of (TZ1). Therefore, combinations including at least one of (TZ2), (TZ3), (TZ4), and (TZ5) are preferred over combinations including (TZ1), and combinations including (TZ5) are most preferred.

[0185] Non-therapeutic methods and uses for the compounds disclosed herein. In some embodiments, this disclosure relates to non-therapeutic methods and non-therapeutic uses. Preferably, the dienophiles used herein are as described in relation to the combinations of this disclosure.

[0186] In the case of the non-therapeutic methods of the present disclosure, the compound of the present disclosure (i.e., (ia)), the conjugate of the present disclosure (i.e., (iia)) and / or the composition of the present disclosure (i.e., (iiia)), and the diene are preferably further contacted with a solvent. Those skilled in the art will recognize suitable solvents for the reaction between trans-cyclooctene (TCO) and tetrazine. Preferably, the solvent contains water, and more preferably, the solvent is water.

[0187] In non-therapeutic use, the click reaction is preferably a bioorthogonal click reaction. Preferably, the click reaction is performed in vitro, although a non-therapeutic reaction can also be performed in vivo.

[0188] Medicinal use This disclosure also relates to the compounds of this disclosure, or salts, hydrates or solvates thereof; conjugates of this disclosure, or salts, hydrates or solvates thereof; compositions of this disclosure; or combinations of this disclosure for use in the treatment of diseases in the subject.

[0189] The Disclosure also relates to a method for treating a disease in a subject, the method comprising the step of administering to the subject (a) a compound according to the Disclosure, or a salt, hydrate, or solvate thereof; (b) a conjugate according to the Disclosure, or a salt, hydrate, or solvate thereof; (c) a composition according to the Disclosure and / or (d) a combination according to the Disclosure.

[0190] Use of (a) compounds, or salts, hydrates or solvates thereof, as pursuant to the Disclosure; (b) conjugates, or salts, hydrates or solvates thereof, as pursuant to the Disclosure; (c) compositions thereof; and / or (d) combinations thereof, for the manufacture of pharmaceuticals for the treatment of diseases in the subject.

[0191] With regard to medicinal use, the subject is preferably a human. Preferably, the disease is cancer.

[0192] Method for synthesizing the compounds of this disclosure The Disclosure also relates to a method for synthesizing the compounds of the Disclosure, the method comprising coupling the following formula (R) to the following formula (S). [ka] Here, R 48 , T 1 And y are as defined herein. [ka] Here, T 2 and x are as defined herein, and S 10 is a -COOH or an active ester, preferably S 10 is -COOH. Preferably, in formula (S), x is an integer between 4 and 6, and most preferably x is 5.

[0193] In a method for synthesizing the compounds of this disclosure, S 10 When is -COOH, the compound of formula (S) is preferably brought into contact with at least one coupling reagent, preferably a base, preferably a non-nucleophilic base. Preferred non-nucleophilic bases are N,N-diisopropylethylamine (DIPEA), 1,8-diazabicycloundeca-7-ene (DBU), and 1,5-diazabicyclo(4.3.0)nona-5-ene (DBN). Preferably, the at least one coupling reagent is as defined in clause 583.

[0194] Those skilled in the art understand the conditions suitable for carrying out a coupling reaction between a compound of formula (R) and a compound of formula (S).

[0195] Preferably, the coupling is carried out at a temperature of -20°C to 80°C, more preferably 0°C to 60°C, even more preferably 4°C to 50°C, still more preferably 10°C to 40°C, and most preferably 15°C to 30°C.

[0196] Preferably, the coupling is carried out in the presence of a solvent, preferably an organic solvent.

[0197] This disclosure also provides alternative methods for synthesizing the compounds of this disclosure, wherein the method comprises coupling a compound of formula (T) to a compound of formula (U) as described above: [ka] Here, T 1 and R 48 However, as defined herein; and S 11 However, it is a -COOH or an active ester, preferably S 11 is an active ester, and more preferably S 11 However, it is selected from the group consisting of -C(O)ON-succinimidyl, -C(O)O-pentafluorophenyl, -C(O)O-tetrafluorophenyl, -C(O)O-4-nitrophenyl, and -C(O)Cl; more preferably, S 11 However, the compound is -C(O)ON-succinimidyl or -C(O)O-pentafluorophenyl; most preferably, S 11 However, it is -C(O)O-pentafluorophenyl, [ka] Here, T 2 X and y are as defined herein, Preferably, in equation (U), x is an integer between 4 and 6, and most preferably x is 5.

[0198] In an alternative method for synthesizing the compounds of this disclosure, S 11When is -COOH, the compound of formula (S) is preferably contacted with at least one coupling reagent, preferably a base, preferably a non-nucleophilic base. Preferred non-nucleophilic bases are N,N-diisopropylethylamine (DIPEA), 1,8-diazabicycloundeca-7-ene (DBU), and 1,5-diazabicyclo(4.3.0)nona-5-ene (DBN). Preferably, the at least one coupling reagent is as defined in clause 583.

[0199] Those skilled in the art will recognize the steps and conditions for carrying out a coupling reaction between a compound of formula (T) and a compound of formula (U). Preferably, the coupling is carried out at a temperature of -20°C to 80°C, more preferably 0°C to 60°C, even more preferably 4°C to 50°C, even more preferably 10°C to 40°C, and most preferably 15°C to 30°C. Preferably, the coupling is carried out in the presence of a solvent, where preferably the solvent is an organic solvent.

[0200] Method for synthesizing the conjugates of this disclosure The Disclosure also relates to a method for synthesizing the conjugates of the Disclosure, the method comprising the step of coupling a protein to the compound of the Disclosure, or a salt, hydrate, or solvate thereof; wherein the compound is T 2 The method is characterized in that the bioconjugation portion is, preferably, a disulfide bond in the protein.

[0201] T in the compounds disclosed herein 2It is preferable that the protein has a free sulfidyl group because it is a bioconjugation moiety that can react with a sulfidyl group, such as an N-maleimide group. Typically, such a sulfidyl group is obtained by reducing a disulfide bond present in the protein. For this reason, it is preferable that the protein be brought into contact with a reducing agent before the coupling. Preferably, the reducing agent is selected from the group consisting of dithiothreitol (DTT) and tris-2-carboxyethylphosphine hydrochloride (TCEP).

[0202] If the protein is brought into contact with a reducing agent before the coupling, the reduction is preferably DTT. In addition or alternatively, the formation of free sulfidyl groups on the protein can also be carried out in situ. For this purpose, the coupling is preferably carried out in the presence of a reducing agent. In this case, it is preferable to use a reducing agent that does not contain free sulfidyl groups. Therefore, if the coupling is carried out in the presence of a reducing agent, the reducing agent is preferably TCEP.

[0203] Those skilled in the art will recognize suitable conditions for carrying out the method for synthesizing the conjugates of this disclosure.

[0204] Preferably, the coupling is carried out at a temperature of 0°C to 40°C, more preferably 1°C to 30°C, even more preferably 2°C to 20°C, even more preferably 4°C to 10°C, and most preferably about 4°C.

[0205] Preferably, the coupling is carried out in an aqueous solution, which is preferably an aqueous buffer solution.

[0206] Preferably, the coupling is performed at a pH of 6.0 to 8.5, preferably 6.2 to 8.0, more preferably 6.4 to 7.8, even more preferably 6.5 to 7.4, and still more preferably 6.6 to 7.0, most preferably at a pH of about 6.8.

[0207] While this disclosure describes specific embodiments, it is not limited to them and is limited only by the claims. Where an indefinite or definite article (e.g., "a" or "an," "the") is used when referring to a singular noun, this includes the plural form of the noun unless otherwise specified.

[0208] The verb "to include" (and its conjugations) as used in this specification and the claims is not restrictive, but rather means that the following item is included, and does not mean that any item not specifically mentioned is excluded.

[0209] Furthermore, when referring to an element using the indefinite article "a" or "an," the possibility of multiple elements being present is not excluded, unless the context clearly indicates that there is only one of that element. Therefore, the indefinite article "a" or "an" usually means "at least one."

[0210] Therefore, the expression “a device comprising means A and B” should not be limited to a device consisting solely of components A and B. It means that, with respect to this disclosure, the relevant components of the device are only A and B.

[0211] The compounds described herein may arise in various tautomers. Unless otherwise specified, compounds relating to this disclosure encompass all tautomers. Where the structure of a compound is shown as a specific tautomer, unless otherwise specified, the disclosure of this application should be understood not to be limited to that specific tautomer.

[0212] The compounds described herein may exist in various enantiomer forms. Unless otherwise specified, compounds relating to this disclosure include all enantiomer forms. Where the structure of a compound is shown as a specific enantiomer, unless otherwise specified, the disclosure herein should be understood not to be limited to that specific enantiomer.

[0213] Unless otherwise specified, the compounds and / or groups thereof of this disclosure may be protonated or deprotonated. It will be understood that compounds may have multiple charges, and these charges may be of opposite signs. For example, in a compound comprising an amine and a carboxylic acid, the amine may be protonated while the carboxylic acid is deprotonated.

[0214] Unless otherwise specified, when a molecular structure, such as a "compound," "diene," or "tetrazine," is mentioned herein, it will be understood that such a molecular structure may also include its salt, hydrate, and / or solvate forms.

[0215] In some formulas, groups or substituents are represented by letters, e.g., "A", "B", "X", "Y", and various (numbered) "R" groups. In addition, the number of repeating units is represented by a letter, e.g., -(CH2) n - may be referred to as n. The definitions of these letters should be interpreted by reference in each expression, i.e., in different expressions, and these letters can have different meanings independently unless otherwise specified.

[0216] In this specification, terms such as "alkyl" are used. The number of carbon atoms in these groups (excluding carbon atoms contained in any substituent following radical group 1) can be indicated by the notation preceding the words (for example, "C1-C8 alkyl" means that the alkyl group may have 1 to 8 carbon atoms). To avoid misunderstanding, a butyl group substituted with an -OCH3 group is denoted as C4 alkyl, because carbon atoms in substituents are not included in the carbon number count.

[0217] Cycloalkyl groups are cyclic alkyl groups. Unsubstituted cycloalkyl groups contain at least three carbon atoms, and their general formula is C n H 2n-1 It has the following properties. Optionally, the cycloalkyl group may be substituted with one or more substituents further specified herein. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0218] An alkenyl group contains one or more carbon-carbon double bonds and may be linear or branched. An unsubstituted alkenyl group containing one carbon-carbon double bond has the general formula C n H 2n-1 It has. An unsubstituted alkenyl group containing two carbon-carbon double bonds has the general formula C n H 2n-3 The alkenyl group may contain a terminal carbon-carbon double bond and / or an internal carbon-carbon double bond. A terminal alkenyl group is an alkenyl group in which the carbon-carbon double bond is located at the terminal position of the carbon chain. The alkenyl group may also contain two or more carbon-carbon double bonds. Examples of alkenyl groups include ethenyl, propenyl, isopropenyl, t-butenyl, 1,3-butadienyl, and 1,3-pentadienyl. Unless otherwise specified, the alkenyl group may be substituted with one or more independently selected substituents following radical group 1.

[0219] A cycloalkenyl group is a cyclic alkenyl group. An unsubstituted cycloalkenyl group containing one double bond has the general formula C n H 2n-3 It has the following properties. Optionally, the cycloalkenyl group may be substituted with one or more substituents further described herein. An example of a cycloalkenyl group is the cyclopentenyl group.

[0220] An alkynyl group contains one or more carbon-carbon triple bonds and may be linear or branched. An unsubstituted alkynyl group containing one carbon-carbon triple bond has the general formula C n H 2n-3 The alkynyl group may contain 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. The alkynyl group may also contain two or more carbon-carbon triple bonds. Unless otherwise specified, the alkynyl group may be substituted with one or more substituents independently selected from the substituent following radical group 1. Examples of alkynyl groups include ethynyl, propynyl, isopropynyl, t-butynyl, etc.

[0221] A cycloalkynyl group is a cyclic alkynyl group. An unsubstituted cycloalkynyl group containing one triple bond is a general C n H 2n-5 It has the following properties. Optionally, the cycloalkynyl group may be substituted with one or more substituents further specified herein. An example of a cycloalkynyl group is cyclooctinyl.

[0222] An aryl group refers to an aromatic hydrocarbon ring system containing 6 to 24 carbon atoms, more preferably 6 to 12 carbon atoms, and may include monocyclic and polycyclic structures. When the aryl group has a polycyclic structure, it is preferably bicyclic. Optionally, the aryl group may be substituted with one or more substituents further specified herein. Examples of aryl groups are phenyl and naphthyl. Preferably, the aryl group is a phenyl group.

[0223] The arylalkyl group and alkylaryl group contain at least seven carbon atoms and may include monocyclic and bicyclic structures. Optionally, the arylalkyl group and alkylaryl group may be substituted with one or more substituents further specified herein. An example of an arylalkyl group is benzyl. An example of an alkylaryl group is 4-tert-butylphenyl.

[0224] Preferably, the heteroaryl group comprises 5 to 16 carbon atoms and 1 to 5 heteroatoms. The heteroaryl group comprises at least 2 carbon atoms (i.e., at least C2) and 1 or more heteroatoms of N, O, P, or S. The heteroaryl group may have a monocyclic or bicyclic structure. Optionally, the heteroaryl group may be substituted with one or more substituents further specified herein. Suitable examples of heteroaryl groups include pyridinyl, quinolinyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, thiazolyl, pyrrolyl, furanyl, triazolyl, benzofuranyl, indolyl, prinyl, benzoxazolyl, thienyl, phosphoryl, and oxazolyl.

[0225] Heteroarylalkyl groups and alkylheteroaryl groups contain at least three carbon atoms (i.e., at least C3) and may encompass monocyclic and bicyclic structures. Optionally, the heteroaryl group may be substituted with one or more substituents further specified herein.

[0226] When an aryl group is written as a (hetero)aryl group, this notation means that it includes both an aryl group and a heteroaryl group. Similarly, an alkyl(hetero)aryl group means that it includes both an alkylaryl group and an alkylheteroaryl group, and a (hetero)arylalkyl means that it includes both an arylalkyl group and a heteroarylalkyl group. Therefore, C2~C 24 (hetero)aryl groups are C2~C 24 Heteroaryl group and C6~C 24It should be interpreted as including an aryl group. Similarly, C3~C 24 Alkyl (hetero)aryl groups are C7~C 24 Alkylaryl group and C3-C 24 This means that it contains an alkyl heteroaryl group, C3~C 24 (hetero)arylalkyls are C7~C 24 Arylalkyl groups and C3-C 24 This means that it contains a heteroaryl alpha group.

[0227] Generally, when (hetero) is placed before a group, it refers to both the variation of the group without the prefix "hetero" and the group with the prefix "hetero". In this specification, the prefix "hetero" indicates that the group contains one or more heteroatoms selected from the group consisting of O, N, S, P, and Si. Preferably, the one or more heteroatoms are selected from the group consisting of O, N, S, and P. In any compound containing heteroatoms, it will be understood that the N, S, and P atoms may optionally be oxidized, and the N atom may optionally be quaternized. Preferably, up to two heteroatoms may be consecutive, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. However, more preferably, the heteroatoms are not directly bonded to each other.

[0228] Examples of heteroalkyls include -CH2CH2-O-CH3, -CH2CH2-NH-CH3, -CH2CH2-S(O)-CH3, -CH=CH-O-CH3, CH2CH2-NH2, CH2CH2-SH, -CH2CH2-OH, -CH2CH2-COOH, -CH2C(O)H, -C(O)HCH3, and -Si(CH3)3. Preferably, C1-C4 heteroalkyls contain two or fewer heteroatoms.

[0229] In this specification, when the prefix "hetero" is used for a combination of multiple groups, it will be understood that the prefix refers to only the single group immediately preceding it. For example, "heteroarylalkyl" indicates a combination of a heteroaryl group and an alkyl group, and does not mean a combination of a heteroaryl group and a heteroalkyl group.

[0230] In this specification, the prefix "cyclo-" indicates that the group is cyclic. When the prefix "cyclo-" is used for a combination of multiple groups, it will be understood that the prefix "cyclo-" refers to only the single group immediately preceding it. For example, "cycloalkylalkenylene" refers to a combination of a cycloalkylene group (see the definition of the suffix "-ene" below) and an alkenylene group, and does not mean a combination of a cycloalkylene group and a cycloalkenylene group. In general, when "(cyclo)" is placed before a group, it refers to both the group without the prefix "cyclo-" and the group with the prefix "cyclo-".

[0231] In this specification, the suffix "-ene" indicates a divalent group, i.e., a group linked to at least two other parts. An example of an alkylene group is propylene (-CH2-CH2-CH2-), which is linked to other parts at both ends. When a group having the suffix "-ene" is substituted with -H at one end, this group is understood to be identical to the group without the suffix. For example, an alkylene group with -H attached is identical to an alkyl group. That is, propylene-CH2-CH2-CH2-, i.e., -CH2-CH2-CH2-H, with -H attached at one end, is logically identical to propyl-CH2-CH2-CH3.

[0232] In this specification, when multiple groups are listed with the suffix "-ene", it means that they are divalent groups, i.e., the group is bonded to at least two other parts, where each group in the combination is bonded to one of these two parts. Thus, for example, alkylalylene is understood as a combination of an allylene group and an alkylene group. An example of an alkylalylene group is -phenyl-CH2-, and an example of an arylalkylene group is -CH2-phenyl-.

[0233] In this specification, the suffix "-trill" indicates a trivalent group, that is, a group that is linked to at least three other parts. An example of an allene trill is illustrated below. [ka] Here, the wavy lines indicate bonding to different groups of the main compound.

[0234] A group with the suffix "-triyl" is understood to be identical to a divalent group with the suffix "-ene" when it is substituted with -H at one position. For example, arenttriyl, substituted with -H, is identical to the arylene group. Similarly, a group with the suffix "-triyl" is understood to be identical to a monovalent group when it is substituted with -H at two positions. For example, arentriyl, substituted with two -H, is identical to the aryl group.

[0235] Unless otherwise specified, a heterogroup may contain heteroatoms at non-terminal positions or at one or more terminal positions. In this case, "terminal" refers to a terminal position within the group and not necessarily to the terminal position of the entire compound. For example, C2 heteroalkylenes may refer to -NH-CH2-CH2-, -CH2-NH-CH2-, and -CH2-CH2-NH-. For example, C2 heteroalkyls may refer to -NH-CH2-CH3, -CH2-NH-CH3, and -CH2-CH2-NH2.

[0236] In this specification, cyclic compounds (i.e., aryl, cycloalkyl, cycloalkenyl, etc.) are understood to be monocyclic, polycyclic, or branched. The carbon atom count of a cyclic compound is understood to refer not only to the carbon atoms in a single ring, but also to the carbon atoms that may be contained in multiple rings. These rings may be fused to a major ring or substituted on a major ring. For example, a C compound may optionally contain heteroatoms. 10 The term "aryl" can refer, in particular, to the naphthyl group (a fused ring) or, for example, the bipyridyl group (a substituted ring, both containing a nitrogen atom).

[0237] Unless otherwise specified, all noncyclic groups disclosed herein are 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.

[0238] When used herein, unless otherwise specified, the following groups, namely (hetero)alkyl, (hetero)alkenyl, (hetero)alkynyl, (hetero)cycloalkyl, (hetero)cycloalkenyl, (hetero)cycloalkynyl, (hetero)aryl, (hetero)alkylene, (hetero)alkenylene, (hetero)alkynylene, (hetero)cycloalkylene, (hetero)cycloalkenylene, (hetero)cycloalkynylene, (hetero)arylene, (hetero)alkanetriyl, (hetero)cycloalkanetriyl, arenetriyl, heteroarenetriyl, and combinations thereof, may be substituted or unsubstituted. Preferably, these groups are unsubstituted. If the group is substituted, the group preferably contains up to four substituents, more preferably up to three, even more preferably up to two, and most preferably one, according to radical group 1 as defined herein.

[0239] Where used herein, the general term “sugar” is used to refer to monosaccharides, such as glucose (Glc), galactose (Gal), mannose (Man), and fucose (Fuc). The term “sugar derivative” is used to refer to a derivative of a monosaccharide, i.e., a monosaccharide containing substituents and / or functional groups. Examples of sugar derivatives include amino sugars and sugar acids, such as glucosamine (GlcNH2), galactosamine (GalNH2), N-acetylglucosamine (GlcNAc), N-acetylgalactosamine (GalNAc), sialic acid (Sia) (which is also referred to as N-acetylneuraminic acid (NeuNAc)), N-acetylmuramic acid (MurNAc), glucuronic acid (GlcA), and iduronic acid (IdoA). A sugar may not have further substituents, in which case it is understood to be a monosaccharide. The sugar may be further substituted with one or more hydroxyl groups, in which case it is understood to be a disaccharide or oligosaccharide. A disaccharide contains two monosaccharide parts linked together. An oligosaccharide chain may be linear or branched and may contain 3 to 10 monosaccharide parts.

[0240] The term "amino acid" is used herein in its ordinary scientific sense. In particular, the amino acids relating to this disclosure include both natural and unnatural amino acids. Preferably, the amino acids used herein are alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, azidrisine, beta-alanine (bAla), 4-aminomethylphenylalanine (Amf), 4-guanidinephenylalanine (Gnf), 4-aminomethyl-N-isopropylphenylalanine (Iaf), 3-pyridylalanine (Pya), 4-piperidylalanine (Ppa), 4-aminomethylcyclohexylalanine (Ama), 4-aminocyclohexylalanine (Aca), ornithine (Orn), citrulline, hydroxylysine (Hyl), allo-hydroxylysine (aHyl), 6-N-methyllysine (MeLys), and decyl lysine. Mosine (Des), isodesmosine (Ide), 2-aminoadipic acid (Aad), 3-aminoadipic acid (bAad), 2-aminobutyric acid (Abu), 4-aminobutyric acid (4Abu), 6-aminohexonic acid (Acp), 2-aminoheptanoic acid (Ahe), 2-aminoisobutyric acid (Aib), 3-aminoisobutyric acid (bAib), 2-aminopimeric acid (Apm), 2,4-diaminobutyric acid (Dbu), 2,2'-diaminopimeric acid (Dpm) The following substances are selected from the group consisting of ), 2-3-diaminopropionic acid (Dpr), N-ethylglycine (EtGly), N-ethylasparagine (EtAsn), 3-hydroxyproline (3Hyp), 4-hydroxyproline (4Hyp), allo-isoleucine (AIle), sarcosine (MeGly), N-methylisoleucine (MeIle), N-methylvaline (MeVal), norvaline (Nva), and norleucine (Nle).

[0241] The term "protein" is used herein in its ordinary scientific sense. Herein, a polypeptide containing approximately 10 or more amino acids is considered a protein. Proteins may contain not only naturally occurring amino acids but also non-natural ones. Herein, the term "protein" is understood to include antibodies and antibody fragments.

[0242] The term "peptide" is used herein in its ordinary scientific sense. In this specification, a peptide is considered to contain a number of amino acids ranging from 2 to 9.

[0243] The term "peptoid" is used herein in its ordinary scientific sense.

[0244] In this specification, a spacer is defined as a portion that connects two or more elements of a compound. In this specification, the terms "spacer" and "linker" are used interchangeably. Typically, in this specification, a spacer is S P It is written as, and a more specific self-sacrificing linker is L C In this specification, each individual S P If it is stated that "it is connected to the rest of the structure at all ends", this means that spacer S P It will be understood that the spacer has multiple ends by definition, given that it connects multiple parts within the structure. P However, each individual part may be connected via different or identical parts that can be selected independently. Typically, these connecting parts are spacers S P It should be considered a part of itself. Spacer S PWhen the spacer connects two parts within a structure, “all ends” should be interpreted as “both ends.” For example, when the spacer connects the trans-cyclooctene portion to construct B, “the remainder of the molecule” refers to the trans-cyclooctene portion and construct B, while the connection between the spacer and the trans-cyclooctene portion and construct B (i.e., at both ends) may be selected individually.

[0245] As used herein, an organic molecule is defined as a molecule containing a CH bond. The terms organic compound and organic molecule are used synonymously.

[0246] As used herein, an inorganic molecule is defined as any molecule that is not an organic molecule, i.e., a molecule that does not contain a CH bond. “Inorganic molecules” will also typically be understood to include hydrogen atoms, -COOH groups, etc.

[0247] As used herein, "small molecule" preferably refers to a small organic molecule. Generally, small molecules have a molecular weight of 2 kDa or less, more preferably 1 kDa or less, more preferably 750 Da or less, more preferably 500 Da or less, and most preferably 300 Da or less. Preferably, low molecular weight compounds have a molecular weight of at least 15 Da, more preferably at least 50 Da, more preferably at least 75 Da, and most preferably at least 100 Da.

[0248] As used herein, “particles” is preferably defined as microparticles or nanoparticles.

[0249] The term "salt" refers to a compound formed when an acidic proton, typically an acid proton, is substituted by a cation, such as a metal cation or an organic cation. The term "salt" also refers to a compound formed when an amine is protonated. Where applicable, the salt is pharmaceutically acceptable; however, this requirement is not necessary for salts not intended for administration to a patient. For example, in a salt of a certain compound, the compound may be protonated by an inorganic or organic acid to form a cation, in which case the conjugate base of the inorganic or organic acid may be the anionic component of the salt.

[0250] The term "medically acceptable salt" means a salt suitable for administration to a patient, such as a mammal (a salt having a counterion that is safe for mammals at a given dose). Such salts may be derived from medically acceptable inorganic or organic bases and medically acceptable inorganic or organic acids.

[0251] "Medically acceptable salts" refer to pharmaceutically acceptable salts of compounds, which are derived from various organic and inorganic counterions known in the art, and include, for example, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc., and also include salts of organic or inorganic acids, such as hydrochloride, hydrobromide, formate, tartrate, besylate, mesylate, acetate, maleate, oxalate, etc., when the molecule contains a basic functional group.

[0252] As used herein, the term "solvate" means a compound that further comprises a main molecule (e.g., the compounds and dienes of this disclosure) and a stoichiometric or non-stoichiometric amount of solvent bonded to the main molecule by non-covalent intermolecular forces. In particular, the term "solvate" may refer to a crystalline compound, the crystalline lattice structure of which contains one or more solvent molecules.

[0253] As used herein, the term "hydrate" means a compound that, in addition to a main molecule (e.g., the compounds and dienes of this disclosure), contains a stoichiometric or non-stoichiometric amount of water bonded to the main molecule by non-covalent intermolecular forces. In particular, the term "hydrate" may refer to a crystalline compound, the crystalline lattice structure of which contains one or more water molecules.

[0254] The logarithm of the partition coefficient, i.e., Log P, is used as a measure of the hydrophobicity of a compound when used herein. Typically, Log P is:

number

[0255] Those skilled in the art are aware of methods for determining the partition coefficient of a compound without performing excessive experiments. Alternatively, those skilled in the art know of software that can accurately estimate the Log P value, such as ChemDraw. 登録商標 Knowing that software features or online tools are available.

[0256] The unified atomic mass unit, or dalton, is abbreviated as Da in this specification. Those skilled in the art will recognize that the dalton is a common unit of molecular weight, and that 1 Da corresponds to 1 g / mol (grams per mole).

[0257] In this specification, the terms "part" and "base" are used interchangeably when referring to a portion of a molecule.

[0258] When a heteroatom is represented as -X(R')2-, where X is the heteroatom and R' is a part, it will be understood that two R' parts are attached to the heteroatom.

[0259] For example, if a certain base is -((R51 )2-R 52 )2- or when indicated as a similar notation (where R 51 and R 52 (This is a part of it), this is the individual R 51 and R 52 Before the part is selected, first, -R 51 -R 51 -R 52 -R 51 -R 51 -R 52 - indicates that it should be written as R 51 and R 52 It will be understood that this does not mean selecting a part first and then writing out the expression.

[0260] As used herein, the terms "activated carboxylic acid" and "active ester" may be used interchangeably. As is recognized by those skilled in the art, an "activated carboxylic acid" or "active ester" is a derivative of a carboxylic acid (-C(O)OH) in which the -OH portion is substituted with a better leaving group. Preferred activated carboxylic acids or active esters are selected from the group consisting of -C(O)ON-succinimidyl, -C(O)O-pentafluorophenyl, -C(O)O-tetrafluorophenyl, -C(O)O-4-nitrophenyl, and -C(O)Cl. More preferably, the activated carboxylic acid or active ester is -C(O)ON-succinimidyl or -C(O)O-pentafluorophenyl.

[0261] As is recognized by those skilled in the art, an "active carbonate" is a derivative in which the -OH moiety of a carbonate (-OC(O)-OH) is replaced with a better leaving group. Preferred active carbonates are -OC(O)ON-succinimidyl, -OC(O)O-pentafluorophenyl, -OC(O)O-tetrafluorophenyl, -OC(O)O-4-nitrophenyl, and -OC(O)Cl. More preferably, the active carbonate ester is -OC(O)ON-succinimidyl or -OC(O)O-pentafluorophenyl.

[0262] As used herein, “drug” means a pharmaceutical product. Therefore, “drug,” “pharmaceutical product,” “therapeutic agent,” and “medicine” are typically interchangeable. Preferred drugs in connection with this disclosure are monomethyl auristatin E (MMAE), exatecan, and exatecan derivatives. Preferably, exatecan and exatecan derivatives have the following structure: [ka] Here, E 1 is -H, or optionally a C1-C4 alkyl group. 1 When is -H, the structure will be understood to be exatecan. Preferably, E 1 is -H, -CH3, or -C(O)-CH2-OH. 1 When is -H or -CH3, exatecan or an exatecan derivative is preferably E 1 R is attached to the nitrogen atom via the nitrogen atom. 48 It is connected to the remaining part. E 1 When is -C(O)-CH2-OH, the exatecan derivative is preferably E 1 R 48 It is connected to the remainder of E. 1 is -H or -CH3. Most preferably, E 1 is -H.

[0263] Most preferably, the drug is monomethyl auristatin E (MMAE).

[0264] Radical groups (RG)

[0265] Radical group 1: Terminal group In the case of radical group 1 (RG1), the radical is -H, -Cl, -F, -Br, -I, -OH, -NH2, -COOH, -CONH2, -CN, -N3, -NCS, -SCN, -SO3H, -PO3H 、 -PO4H2, -NO2, -CF3, -CF2H, -CFH2, =O, =NH, -SH, -SO2H, -(S P ) i -C B Selected from the group consisting of (hetero)alkyl, (hetero)alkenyl, (hetero)alkynyl, (hetero)cycloalkyl, (hetero)cycloalkenyl, (hetero)cycloalkynyl, (hetero)aryl, and combinations thereof. In this specification, S P C is a spacer as defined herein, B is a structure B as defined herein, and i is an integer in the range of 0 to 4, preferably i is 0 or 1.

[0266] In the case of RG1, "combinations of those" are, in particular, (hetero)alkylcycloalkyl, (hetero)alkylcycloalkenyl, (hetero)alkylcycloalkynyl, (hetero)cycloalkylalkyl, (hetero)cycloalkenylalkyl, (hetero)cycloalkynylalkyl, (hetero)alkenylcycloalkyl, (hetero)alkenylcycloalkenyl, (hetero)alkenylcycloalkynyl, (hetero)cycloalkylalkenyl, (hetero)cycloalkenylalkenyl, (hetero)cycloalkynylalkenyl, (hetero)alkynylcycloalkyl, (hetero)alkynylcycloalke This refers to nyl, (hetero)alkynylcycloalkynyl, (hetero)cycloalkylalkynyl, (hetero)cycloalkenylalkynyl, (hetero)cycloalkynylalkynyl, (hetero)arylalkyl, (hetero)arylalkenyl, (hetero)arylalkynyl, alkyl(hetero)aryl, alkenyl(hetero)aryl, alkynyl(hetero)aryl, cycloalkyl(hetero)aryl, cycloalkenyl(hetero)aryl, cycloalkynyl(hetero)aryl, (hetero)arylcycloalkyl, (hetero)arylcycloalkenyl, and (hetero)arylcycloalkynyl. In addition, with respect to RG1, "combinations thereof" also refers to alkyl groups substituted with one or more -Cl and / or -OH groups, for example. Thus, RG1 also includes radicals that are combinations of heteroalkyl groups and -COOH groups, such as NH-CH2-COOH (glycine residue).

[0267] Preferably, in the case of RG1, the radical is -H, -Cl, -F, -Br, -I, -OH, -NH2, -COOH, -CONH2, -SO3H, -PO3H 、 -PO4H2, -NO2, -CF3, =O, =NH, -SH, -(S P ) i -C B , C1~C 24 (hetero)alkyl, C2~C 24 (hetero)alkenyl, C2~C 24 (hetero)alkynyl, C3~C24 Cycloalkyl, C2 - C 24 Heterocycloalkyl, C5 - C 24 Cycloalkenyl, C3 - C 24 Heterocycloalkenyl, C7 - C 24 Cycloalkynyl, C5 - C 24 (Hetero)cycloalkynyl, C6 - C 24 Aryl, C2 - C 24 Selected from the RG1a groups consisting of heteroaryl and combinations thereof.

[0268] More preferably, in the case of RG1, the radical is -H, -Cl, -F, -Br, -I, -OH, -NH2, -COOH, -CONH2, -SO3H, -PO3H 、 -PO4H2, -NO2, -CF3, =O, =NH, -SH, -(S P ) i -C B , C1 - C 12 (Hetero)alkyl, C2 - C 12 (Hetero)alkenyl, C2 - C 12 (Hetero)alkynyl, C3 - C 12 Cycloalkyl, C2 - C 12 Heterocycloalkyl, C5 - C 12 Cycloalkenyl, C3 - C 12 Heterocycloalkenyl, C7 - C 12 Cycloalkynyl, C5 - C 12 (Hetero)cycloalkynyl, C6 - C 12 Aryl, C2 - C 12 Selected from the RG1b groups consisting of heteroaryl and combinations thereof.

[0269] Even more preferably, in the case of RG1, the radical is -H, -Cl, -F, -Br, -I, -OH, -NH2, -COOH, -CONH2, -SO3H, -PO3H 、 -PO4H2, -NO2, -CF3, =O, =NH, -SH, -(S P ) i -C BThe RG1c group is selected from C1-C8 (hetero)alkyl, C2-C8 (hetero)alkenyl, C2-C8 (hetero)alkynyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C5-C8 cycloalkenyl, C3-C8 heterocycloalkenyl, C7-C8 cycloalkynyl, C5-C8 (hetero)cycloalkynyl, C6-C8 aryl, C2-C8 heteroaryl, and combinations thereof.

[0270] More preferably, in the case of RG1, the radical is -H, -Cl, -F, -Br, -I, -OH, -NH2, -COOH, -CONH2, -SO3H, -PO3H 、 -PO4H2, -NO2, -CF3, =O, =NH, -SH, -(S P ) i -C B The RG1d group is selected from C1-C6 (hetero)alkyl, C2-C6 (hetero)alkenyl, C2-C6 (hetero)alkynyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, C5-C7 cycloalkenyl, C3-C5 heterocycloalkenyl, C8 cycloalkynyl, C6-C7 (hetero)cycloalkynyl, phenyl, C3-C5 heteroaryl, and combinations thereof.

[0271] Most preferably, in the case of RG1, the radical is -H, -Cl, -F, -Br, -I, -OH, -NH2, -COOH, -CONH2, -SO3H, -PO3H 、 -PO4H2, -NO2, -CF3, =O, =NH, -SH, -(S P ) i -C B The RG1e group is selected from C1-C3 (hetero)alkyl, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, phenyl, C4-C5 heteroaryl, and combinations thereof.

[0272] In some embodiments, in the case of RG1, the radical is a conjugation moiety, which is a chemical group that can be used to bond, conjugate, or couple a construct, e.g., construct B, a spacer, or another molecule or construct of interest. Those skilled in the art are aware of the numerous strategies available for causing one molecule or construct to couple or conjugate to another molecule or construct chemoselectively, nonselectively, or enzymatically.

[0273] In some embodiments, RG1 is a portion that enables conjugation to proteins containing natural and / or non-natural amino acids. Preferred portions for conjugation are known to those skilled in the art. Conjugation strategies can be seen, for example, in [O. Boutureira, GJLBernardes, Chem. Rev., 2015, 115, 2174~2195].

[0274] When RG1 is the conjugation moiety, it is preferably N-maleimidyl, halogenated N-alkylamide, sulfonyloxy N-alkylamide, vinyl sulfone, (activated) carboxylic acid, activated ester, benzenesulfonyl halide, ester, carbonate, sulfonyl halide, thiol or derivative thereof, C 2~6 Alkenil, C 2~6 Alkinyl, C 7~18 Cycloalkynyl, C 5~18 Heterocycloalkynyl, bicyclo[6.1.0]nona-4-in-9-yl], C 3~12Cycloalkenyl, azide, phosphine, nitrile oxide, nitrone, nitrile imine, isonitrile, diazo, ketone, (O-alkyl)hydroxylamino, hydrazine, halogenated N-maleimidyl, aryloxymaleimide, dithiophenolmaleimide, bromo- and dibromopyridazinedione, 2,5-dibromohexanediamide, alquinone, 3-arylpropioronitrile, 1,1-bis(sulfonylmethyl)-methylcarbonyl or its removal (e The RG1f group is selected from ligation derivatives, carbonyl halides, arenamides, 1,2-quinones, isothiocyanates, isocyanates, aldehydes, triazines, squalate, 2-imino-2-methoxyethyl, (oxa)norbornene, (oxa)norbornane, (oxa)norbornadiene, (imino)cydonone, methylsulfonylphenyloxadiazole, aminooxy, 2-aminobenzamidoxime, ethinylphosphonamide, reactivity in Pictet-Spengler ligation and hydrazine-Pictet-Spengler (HIPS) ligation, DNA intercalators, tetrazine, trans-cyclooctene, and photocrosslinkers. More preferably, RG1f is N-maleimidyl.

[0275] In other embodiments, RG1f is selected from the group consisting of hydroxyl, amine, halogen, vinylpyridine, disulfide, pyridyl disulfide, sulfonyloxy, mercaptoacetamide, anhydride, sulfonylated hydroxyacetamide, sulfonyl chloride, thiosemicarbazone, hydrazine carboxylate, and arylhydrazide. In other embodiments, RG1f is a group that can be bound to another group by an enzyme, such as sortase or tubulin tyrosine ligase.

[0276] Radical group 2: Connecting group In the case of radical group 2 (RG2), the radical is selected from groups consisting of (hetero)alkylene, (hetero)alkenylene, (hetero)alkylene, (hetero)cycloalkylene, (hetero)cycloalkenylene, (hetero)cycloalkylene, (hetero)arylene, amino acids, peptides, proteins, polymers, oligonucleotides, nucleotides, carbohydrates, RG2a, RG2b, RG2c, and combinations thereof.

[0277] The radical from RG2 may optionally be attached to one or more radicals following RG1. Thus, RG2 also includes, for example, -NH-CH(CH2OH)-C(O)- (i.e., a serine residue), which is a heteroalkylene attached to -OH and =O.

[0278] In the case of RG2, "those combinations" specifically refers to alkyl(hetero)arylenes, (hetero)arylalkylenes, (hetero)arylalkenylenes, (hetero)arylalkynylenes, alkenyl(hetero)arylenes, and alkynyl(hetero)arylenes.

[0279] Preferably, in the case of RG2, the radical is C1~C 24 (hetero)alkylene, C2~C 24 (hetero)alkenylene, C2~C 24 (hetero)alkynylene, C3~C 24 Cycloalkylene, C2~C 24 Heterocycloalkylene, C5~C 24 Cycloalkenylene, C3~C 24 Heterocycloalkenylene, C7~C 24 Cycloalkylene, C5~C 24 (hetero)cycloalkylene, C6~C 24 Arirene, C2~C 24 The group is selected from heteroarylenes, amino acids, peptides, proteins, polymers, oligonucleotides, nucleotides, carbohydrates, RG2a, RG2b, RG2c, and combinations thereof.

[0280] More preferably, in the case of RG2, the radical is C1~C 12 (hetero)alkylene, C2~C 12 (hetero)alkenylene, C2~C 12 (hetero)alkynylene, C3~C 12 Cycloalkylene, C2~C 12 Heterocycloalkylene, C5~C 12 Cycloalkenylene, C3~C 12 Heterocycloalkenylene, C7~C 12 Cycloalkylene, C5~C 12 (hetero)cycloalkylene, C6~C 12 Arirene, C2~C 12 The group is selected from heteroarylenes, amino acids, peptides, proteins, polymers, oligonucleotides, nucleotides, carbohydrates, RG2a, RG2b, RG2c, and combinations thereof.

[0281] More preferably, in the case of RG2, the radical is selected from groups consisting of C1-C8 (hetero)alkylene, C2-C8 (hetero)alkenylene, C2-C8 (hetero)alkylene, C3-C8 cycloalkylene, C2-C8 heterocycloalkylene, C5-C8 cycloalkenylene, C3-C8 heterocycloalkenylene, C7-C8 cycloalkylene, C5-C8 (hetero)cycloalkylene, C6-C8 arylene, C2-C8 heteroarylene, amino acids, peptides, proteins, polymers, oligonucleotides, nucleotides, carbohydrates, RG2a, RG2b, RG2c, and combinations thereof.

[0282] More preferably, in the case of RG2, the radical is selected from groups consisting of C1-C6 (hetero)alkylene, C2-C6 (hetero)alkenylene, C2-C6 (hetero)alkylene, C3-C6 cycloalkylene, C2-C6 heterocycloalkylene, C5-C7 cycloalkenylene, C3-C5 heterocycloalkenylene, C8 cycloalkylene, C6-C7 (hetero)cycloalkylene, phenylene, C3-C5 heteroarylene, amino acids, peptides, proteins, polymers, oligonucleotides, nucleotides, carbohydrates, RG2a, RG2b, RG2c, and combinations thereof.

[0283] More preferably, in the case of RG2, the radical is selected from groups consisting of C1-C3 (hetero)alkylenes, C3-C6 cycloalkylenes, C2-C5 heterocycloalkylenes, phenylenes, C4-C5 heteroarylenes, amino acids, peptides, proteins, polymers, oligonucleotides, nucleotides, carbohydrates, RG2a, RG2b, RG2c, and combinations thereof.

[0284] RG2a is -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-, -O C(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( The group is selected from those consisting of 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-, and -NR4P(O)(R4)2-.

[0285] In this specification, R4 conforms to RG1, preferably R4 is a hydrogen atom or a methyl atom, and more preferably R4 is a hydrogen atom.

[0286] Preferably, RG2a is -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-, -S The group is selected from those consisting of C(O)NR4-, -NR4C(O)S-, -S(O)-, -S(O)2-, -C(O)NR4S(O)2NR4-, -OC(O)NR4S(O)2NR4-, -OC(S)-, -C(S)O-, -OC(S)O-, -OC(S)NR4-, -NR4C(S)-, -NR4C(S)O-, and -SS(O)2-.

[0287] More preferably, in the case of RG2, the radical is RG2b or RG2c, and most preferably RG2b.

[0288] RG2b is, [ka] It is selected from the group consisting of the following.

[0289] In this specification, R' is a radical according to RG1, and preferably R' is a hydrogen atom or C 1~3 It is an alkyl group. The dotted and wavy lines indicate bonding to other parts of the molecule.

[0290] RG2c is, [ka] It is selected from the group consisting of the following.

[0291] In this specification, R' is a radical according to RG1, and preferably R' is a hydrogen atom or C 1~3 It is an alkyl group. The dotted and wavy lines indicate bonding to other parts of the molecule.

[0292] Radical group 3: Organic molecule In the case of radical group 3 (RG3), the radical is an organic molecule selected from a group consisting of nucleic acids, peptides, proteins, carbohydrates, aptamers, hormones, toxins, steroids, cytokines, lipids, small organic molecules as defined herein, polymers, LNA, PNA, amino acids, peptoids, chelate moieties, molecules containing radionuclides, fluorescent dyes, phosphorescent dyes, drugs, resins, beads, organic particles, gels, organic surfaces, organometallic compounds, cells, and combinations thereof.

[0293] Preferably, in the case of RG3, the radical is a nucleic acid, peptide, protein, carbohydrate, lipid, polymer, amino acid, chelate, drug, or gel.

[0294] When used herein, nucleic acids are preferably selected from the group consisting of oligonucleotides, polynucleotides, DNA, and RNA.

[0295] When used herein, the protein is preferably an antibody or a diabody. A preferred antibody is CC49, and a preferred diabody is AVP0458.

[0296] When used herein, carbohydrates are preferably selected from the group consisting of monosaccharides, oligosaccharides, and polysaccharides.

[0297] When used herein, the polymer is typically selected from the group consisting of polyethylene glycol (PEG), poly(N-(2-hydroxypropyl)methacrylamide) (HPMA), polylactic acid (PLA), polylactic acid-glycolic acid (PLGA), polyglutamic acid (PG), polyvinylpyrrolidone (PVP), poly(1-hydroxymethylethylenehydroxymethyl-formal) (PHF), polyacetal / polyketal copolymers, and hydrophilic polymers, oligopeptides, polypeptides, glycopolysaccharides, and polysaccharides, such as dextran and hyaluronan, selected from the group consisting of polyacrylates, polyvinyl polymers, polyesters, polyorthoesters, polyamides, oligopeptides, polypeptides and their derivatives. Preferably, when used herein, the polymer is polyethylene glycol (PEG).

[0298] When used herein, the resin is preferably a polystyrene resin or an agarose resin.

[0299] When used herein, organic particles are preferably liposomes or polymerosomes.

[0300] When used herein, the chelate portion is preferably 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,N The following are selected from the group consisting of 3-tetraacetic acid), deferoxamine, or DFA (N'-[5-[[4-[[5-(acetylhydroxyamino)pentyl]amino]-1,4-dioxobutyl]hydroxyamino]pentyl]-N-(5-aminopentyl)-N-hydroxybutanediamide), or HYNIC (hydrazinonicotinamide), EDTA (ethylenediaminetetraacetic acid), OTAM, TACN, sarcophagine, and 3,4-HOPO-based chelating agents.

[0301] More preferably, in this specification, the chelate portion is [ka] Selected from the group consisting of, where the wavy line indicates a bond to the rest of the molecule, and the bond may optionally be via -C(O)NH-, where the chelating portion belonging to the group may optionally chelate a metal, where the metal is preferably, 44 Sc, 62 Cu, 64 Cu, 66 Ga, 67 Ga, 67 Cu, 68 Ga, 86 Y, 89 Zr, 90 Y, 99m Tc, 111 In, 166 Ho, 177 Lu, 186 Re, 188 Re, 211 Bi, 212 Bi, 212 Pb,213 Bi 214 Bi and 225 is selected from the group consisting of Ac.

[0302] Radical group 4: Inorganic molecule In the case of the radical group 4 (RG4), the radical is an inorganic molecule selected from the group consisting of an inorganic surface, inorganic particles, allotropes of carbon, inorganic drugs, radionuclides, and combinations thereof.

[0303] As used herein, the inorganic surface is preferably selected from the group consisting of a chip, a wafer, a metal, such as gold, and a silica-based surface, such as glass.

[0304] As used herein, the inorganic particles are preferably selected from the group consisting of beads, silica-based particles, polymer-based materials, and iron oxide particles. Preferably, the beads are magnetic beads or gold beads.

[0305] As used herein, the allotropes of carbon are preferably selected from the group consisting of fullerenes, such as Buckminsterfullerene; graphite, graphene, diamond, lonsdaleite, Q-carbon, linear acetylenic carbon, amorphous carbon, and carbon nanotubes.

[0306] As used herein, the inorganic drug is preferably Cisplatin.

[0307] Radical group 5: Further terminal group In the case of RG5, the radical is

Chemical formula

[0308] In the case of RG5, each R 10 This is independently selected from RG2, preferably from RG2a.

[0309] In the case of RG5, each R 11 It is independently selected from RG2, preferably not RG2a, RG2b, or RG2c.

[0310] In the case of RG5, R 12 This is selected from RG1 or RG3, preferably RG3, and more preferably a protein, polymer, or chelate moiety.

[0311] Preferably, z is an integer in the range of 0 to 12, preferably 0 to 10, more preferably 0 to 8, even more preferably 1 to 6, and most preferably 2 to 4. Preferably, z is 0. If the compound according to this disclosure contains two or more RG5 moieties, each z is selected independently.

[0312] Preferably, h is 0 or 1. If the compound according to this disclosure contains two or more RG5 moieties, each h, z, and n are independently selected. Preferably, each n belonging to RG5 is an integer independently selected from the range of 0 to 24, preferably 1 to 12, more preferably 1 to 6, and even more preferably 1 to 3. Preferably, n is 1. In another preferred embodiment, n is an integer in the range of 12 to 24.

[0313] Preferably, z is 0 and n is 1. In other embodiments, z is 1 and n is 1. Preferably, the RG5 portion has a molecular weight in the range of 100Da to 3000Da, preferably 100Da to 2000Da, more preferably 100Da to 1500Da, and even more preferably 150Da to 1500Da. Even more preferably, the RG5 portion has a molecular weight in the range of 150Da to 1000Da, most preferably 200Da to 1000Da.

[0314] Preferably, RG5 is [ka] [ka] Selected from RG5a, where the wavy line indicates bonding to the remainder of the molecule.

[0315] When n is greater than 1, -((R 10 ) h -R 11 ) n -(R 10 ) h -R 12 Before -(R 10 ) h -R 11 -Bonded by a group, -(R 10 ) h -R 11 -((R 10 ) h -R 11 ) n -(R 10 ) h -R 12 It is understood that a base is formed. This is understood to be based on the definition of the notation for repeating units. That is, -((R 10 ) h -R 11 )2- is R 10 , h and R 11 Before being independently selected, first -(R 10 ) h -R 11 -(R 10 ) h -R 11 It will likely be written as -.

[0316] List of phrases This disclosure relates to any one of the following clauses:

[0317] phrase 1A compound, or a salt, hydrate, or solvate thereof; wherein the compound comprises an 8-membered ring nonaromatic cyclic monoalkenylene moiety, wherein the moiety comprises a nonvinyl carbon atom, wherein the nonvinyl carbon atom is substituted with at least one structure according to the following formula (A): [ka] Here, L 1 and L 2 However, each is independently a linker; and T 2 and T 3 However, this is the organic part.

[0318] phrase 2 The compound of clause 1, or its salt, hydrate, or solvate; where L 1 However, it conforms to radical group 2 as defined herein.

[0319] phrase 3 A compound described in any one of clauses 1 to 2, or a salt, hydrate, or solvate thereof; where L 1 However, linear or branched C1-C 12 (hetero)alkylene, C3-C8; (hetero)cycloalkylene, C6-C 12 Arylene and C4~C 11 It is selected from the group consisting of heteroarylenes.

[0320] phrase 4 A compound described in any one of clauses 1 to 3, or a salt, hydrate, or solvate thereof; where L 1 However, linear or branched C1-C 12 Alkylene, C3-C8 (hetero)cycloalkylene, C6-C 12 Arylene and C4~C 11 It is selected from the group consisting of heteroarylenes.

[0321] Clause 5 A compound described in any one of clauses 1 to 4, or a salt, hydrate, or solvate thereof; where L 1 However, linear or branched C2-C12 Alkylene, C3-C8 (hetero)cycloalkylene, C6-C 12 Arylene and C4~C 11 It is selected from the group consisting of heteroarylenes.

[0322] phrase 6 A compound described in any one of clauses 1 to 5, or a salt, hydrate, or solvate thereof; where L 1 However, linear or branched C3-C 12 Alkylene, C3-C8 (hetero)cycloalkylene, C6-C 12 Arylene and C4~C 11 It is selected from the group consisting of heteroarylenes.

[0323] phrase 7 A compound described in any one of clauses 1 to 6, or a salt, hydrate, or solvate thereof; where L 1 However, linear or branched C4-C 12 Alkylene, C3-C8 (hetero)cycloalkylene, C6-C 12 Arylene and C4~C 11 It is selected from the group consisting of heteroarylenes.

[0324] phrase 8 A compound described in any one of clauses 1 to 7, or a salt, hydrate, or solvate thereof; where L 1 However, linear or branched C1-C 12 It is alkylene.

[0325] phrase 9 A compound described in any one of clauses 1 to 8, or a salt, hydrate, or solvate thereof; where L 1 However, linear or branched C2-C 12 It is alkylene.

[0326] phrase 10 A compound described in any one of clauses 1 to 9, or a salt, hydrate, or solvate thereof; where L 1 However, linear or branched C3-C 12 It is alkylene.

[0327] Clause 11 A compound described in any one of clauses 1 to 10, or a salt, hydrate, or solvate thereof; where L 1 However, linear or branched C4-C 12 It is alkylene.

[0328] Clause 12 A compound described in any one of clauses 1 to 11, or a salt, hydrate, or solvate thereof; where L 1 However, linear or branched C4-C 11 It is alkylene.

[0329] Clause 13 A compound described in any one of clauses 1 to 12, or a salt, hydrate, or solvate thereof; where L 1 However, linear or branched C4-C 10 It is alkylene.

[0330] Clause 14 A compound described in any one of clauses 1 to 13, or a salt, hydrate, or solvate thereof; where L 1 However, these are linear or branched C4-C9 alkylenes.

[0331] Verse 15 A compound described in any one of clauses 1 to 14, or a salt, hydrate, or solvate thereof; where L 1 However, these are linear or branched C4-C8 alkylenes.

[0332] phrase 16 A compound described in any one of clauses 1 to 15, or a salt, hydrate, or solvate thereof; where L 1 However, these are linear or branched C4-C7 alkylenes.

[0333] Verse 17 A compound described in any one of clauses 1 to 16, or a salt, hydrate, or solvate thereof; where L 1 However, these are linear or branched C4-C6 alkylenes.

[0334] Clause 18 A compound described in any one of clauses 1 to 17, or a salt, hydrate, or solvate thereof; where L 1 However, these are linear or branched C5 alkylenes.

[0335] Clause 19 A compound described in any one of clauses 1 to 8, or a salt, hydrate, or solvate thereof; where L 1 However, linear C1~C 12 It is alkylene.

[0336] phrase 20 A compound described in any one of clauses 1 to 9, or a salt, hydrate, or solvate thereof; where L 1 However, linear C2~C 12 It is alkylene.

[0337] phrase 21 A compound described in any one of clauses 1 to 10, or a salt, hydrate, or solvate thereof; where L 1 However, linear C3~C 12 It is alkylene.

[0338] phrase 22 A compound described in any one of clauses 1 to 11, or a salt, hydrate, or solvate thereof; where L 1 However, linear C4~C 12 It is alkylene.

[0339] phrase 23 A compound described in any one of clauses 1 to 12, or a salt, hydrate, or solvate thereof; where L 1 However, linear C4~C 11 It is alkylene.

[0340] phrase 24 A compound described in any one of clauses 1 to 13, or a salt, hydrate, or solvate thereof; where L 1 However, linear C4~C 10 It is alkylene.

[0341] phrase 25A compound described in any one of clauses 1 to 14, or a salt, hydrate, or solvate thereof; where L 1 However, it is a linear C4-C9 alkylene.

[0342] phrase 26 A compound described in any one of clauses 1 to 15, or a salt, hydrate, or solvate thereof; where L 1 However, it is a linear C4-C8 alkylene.

[0343] phrase 27 A compound described in any one of clauses 1 to 16, or a salt, hydrate, or solvate thereof; where L 1 However, it is a linear C4-C7 alkylene.

[0344] phrase 28 A compound described in any one of clauses 1 to 17, or a salt, hydrate, or solvate thereof; where L 1 However, it is a linear C4-C6 alkylene.

[0345] phrase 29 A compound described in any one of clauses 1 to 28, or a salt, hydrate, or solvate thereof; where L 1 However, it is a linear C5 alkylene.

[0346] phrase 30 A compound described in any one of clauses 1 to 29, or a salt, hydrate, or solvate thereof; where L 2 However, it conforms to radical group 2 as defined herein.

[0347] phrase 31 A compound described in any one of clauses 1 to 30, or a salt, hydrate, or solvate thereof; where L 2However, it contains 1 to 200 atoms, preferably 2 to 150 atoms, more preferably 3 to 100 atoms, even more preferably 4 to 90 atoms, even more preferably 5 to 80 atoms, even more preferably 6 to 70 atoms, even more preferably 7 to 60 atoms, even more preferably 8 to 50 atoms, even more preferably 9 to 45 atoms, and most preferably 10 to 35 atoms.

[0348] phrase 32 A compound described in any one of clauses 1 to 31, or a salt, hydrate, or solvate thereof; where L 2 However, linear or branched C1-C 12 (hetero)alkantriyl, C3-C8; (hetero)cycloalkantriyl, C6-C 12 Allen Trill and C4~C 11 The group is selected from a group consisting of heteroarene triyls.

[0349] phrase 33 A compound described in any one of clauses 1 to 32, or a salt, hydrate, or solvate thereof; where L 2 However, linear or branched C1-C 12 It is (hetero)alkantriyl.

[0350] phrase 34 A compound described in any one of clauses 1 to 33, or a salt, hydrate, or solvate thereof; where L 2 However, linear or branched C1-C 12 It is a heteroalkantriyl.

[0351] phrase 35 A compound described in any one of clauses 1 to 33, or a salt, hydrate, or solvate thereof; where L 2 However, branched C1~C 12 It is (hetero)alkantriyl.

[0352] phrase 36 A compound described in any one of clauses 1 to 35, or a salt, hydrate, or solvate thereof; where L 2 However, branched C1~C 12It is a heteroalkantriyl.

[0353] phrase 37 A compound described in any one of clauses 1 to 36, or a salt, hydrate, or solvate thereof; where L 2 However, branched C3~C 11 It is a heteroalkantriyl.

[0354] phrase 38 A compound described in any one of clauses 1 to 37, or a salt, hydrate, or solvate thereof; where L 2 However, branched C6~C 10 It is a heteroalkantriyl.

[0355] phrase 39 A compound described in any one of clauses 1 to 38, or a salt, hydrate, or solvate thereof; where L 2 However, it is a branched C8 heteroalkantriyl.

[0356] phrase 40 A compound described in any one of clauses 1 to 39, or a salt, hydrate, or solvate thereof; where L 2 However, it is a branched C8 heteroalkantriyl substituted with five or fewer =O groups.

[0357] phrase 41 A compound described in any one of clauses 1 to 40, or a salt, hydrate, or solvate thereof; where L 2 However, it is a branched C8 heteroalkantriyl substituted with three =O groups.

[0358] phrase 42 A compound described in any one of clauses 1 to 41, or a salt, hydrate, or solvate thereof; where L 2 However, it is a branched C8 heteroalkantriyl containing five or fewer -NH- groups.

[0359] phrase 43 A compound described in any one of clauses 1 to 42, or a salt, hydrate, or solvate thereof; where L 2However, it is a branched C8 heteroalkantriyl containing three -NH- groups.

[0360] phrase 44 A compound described in any one of clauses 1 to 43, or a salt, hydrate, or solvate thereof; where L 2 However, it is a branched C8 heteroalkanetriyl containing three -NH- groups, and the C8 heteroalkanetriyl is substituted with three =O groups.

[0361] phrase 45 A compound described in any one of clauses 1 to 44, or a salt, hydrate, or solvate thereof; where L 2 but, [ka] That is the case.

[0362] phrase 46 A compound described in any one of clauses 1 to 45, or a salt, hydrate, or solvate thereof; where L 2 but, [ka] That is the case.

[0363] phrase 47 A compound described in any one of clauses 1 to 45, or a salt, hydrate, or solvate thereof; where L 2 but, [ka] That is the case.

[0364] phrase 48 A compound described in any one of clauses 1 to 47, or a salt, hydrate, or solvate thereof; where L 2 but, [ka] That is the case.

[0365] phrase 49A compound described in any one of clauses 1 to 48, or a salt, hydrate, or solvate thereof; where T 2 However, it is one of radical group 1, radical group 3, or radical group 5 as defined herein, or T 2 However, -L 3 -C B It is the basis; Here, L 3 However, it follows radical group 2, and C B The material is selected from the group consisting of proteins, nucleic acids, peptides, carbohydrates, aptamers, lipids, small organic molecules, polymers, LNA, PNA, amino acids, peptoids, chelates, fluorescent dyes, phosphorescent dyes, organic particles, gels, cells, and combinations thereof.

[0366] phrase 50 A compound described in any one of clauses 1 to 49, or a salt, hydrate, or solvate thereof; where T 2 However, this conforms to the radical group 1 as defined herein.

[0367] phrase 51 A compound described in any one of clauses 1 to 50, or a salt, hydrate, or solvate thereof; where T 2 However, this conforms to the radical group 1a as defined herein.

[0368] phrase 52 A compound described in any one of clauses 1 to 51, or a salt, hydrate, or solvate thereof; where T 2 However, this conforms to the radical group 1b as defined herein.

[0369] phrase 53 A compound described in any one of clauses 1 to 52, or a salt, hydrate, or solvate thereof; where T 2 However, this conforms to the radical group 1c as defined herein.

[0370] phrase 54A compound described in any one of clauses 1 to 53, or a salt, hydrate, or solvate thereof; where T 2 However, this conforms to the radical group 1d as defined herein.

[0371] phrase 55 A compound described in any one of clauses 1 to 54, or a salt, hydrate, or solvate thereof; where T 2 However, this conforms to the radical group 1e as defined herein.

[0372] phrase 56 A compound described in any one of clauses 1 to 55, or a salt, hydrate, or solvate thereof; where T 2 However, this conforms to the radical group 1f as defined herein.

[0373] phrase 57 A compound described in any one of clauses 1 to 56, or a salt, hydrate, or solvate thereof; where T 2 However, it is N-maleimidyl.

[0374] phrase 58 A compound described in any one of clauses 1 to 57, or a salt, hydrate, or solvate thereof; where T 2 but, [ka] That is the case.

[0375] phrase 59 A compound described in any one of clauses 1 to 49, or a salt, hydrate, or solvate thereof; where T 2 However, -L 3 -C B It is the basis.

[0376] phrase 60 A compound described in any one of clauses 1-49 and 59, or a salt, hydrate, or solvate thereof; where L 3 However, these are residues in the bioconjugation region.

[0377] phrase 61 A compound described in any one of clauses 1-49 and 59-60, or a salt, hydrate, or solvate thereof; where L 3 However, these are residues of the N-maleimidyl moiety or the N-hydroxysuccinimidyl moiety.

[0378] phrase 62 A compound described in any one of clauses 1-49 and 59-61, or a salt, hydrate, or solvate thereof; where T 2 but, [ka] It is selected from the group consisting of the following.

[0379] phrase 63 A compound described in any one of clauses 1-49 and 59-62, or a salt, hydrate, or solvate thereof; where T 2 but, [ka] That is the case.

[0380] phrase 64 A compound described in any one of clauses 1-49 and 59-63, or a salt, hydrate, or solvate thereof; where C B It is a protein.

[0381] phrase 65 A compound described in any one of clauses 1-49 and 59-64, or a salt, hydrate, or solvate thereof; where C B However, it is an antibody or a diabody.

[0382] phrase 66 A compound described in any one of clauses 1-49 and 59-65, or a salt, hydrate, or solvate thereof; where C B However, it is a diamond body.

[0383] phrase 67 A compound described in any one of clauses 1-49 and 59-66, or a salt, hydrate, or solvate thereof; where CB However, AVP0458 consists of two monomers, each of which has an amino acid sequence according to sequence ID number 1.

[0384] phrase 68 A compound described in any one of clauses 1-49 and 59-67, or a salt, hydrate, or solvate thereof; where C B However, C B T via S or N, which is part of T 2 It is connected to the remaining part.

[0385] phrase 69 A compound described in any one of clauses 1-49 and 59-68, or a salt, hydrate, or solvate thereof; where C B However, C B T via S, which is part of 2 It is connected to the remaining part.

[0386] phrase 70 A compound described in any one of clauses 1 to 69, or a salt, hydrate, or solvate thereof; where T 3 However, it conforms to any one of radical group 1, radical group 3, or radical group 5 as defined herein.

[0387] phrase 71 A compound described in any one of clauses 1 to 70, or a salt, hydrate, or solvate thereof; where T 3 However, this conforms to the radical group 3 as defined herein.

[0388] phrase 72 A compound described in any one of clauses 1 to 71, or a salt, hydrate, or solvate thereof; where T 3 It is a polymer.

[0389] phrase 73 A compound described in any one of clauses 1 to 72, or a salt, hydrate, or solvate thereof; where T 3 However, it is a polymer that includes a polyethylene glycol portion.

[0390] phrase 74 A compound described in any one of clauses 1 to 73, or a salt, hydrate, or solvate thereof; where T 3 ga-(CH2CH2-O-) y -T 4 Including the portion, Here, y is an integer in the range of 1 to 50, and T 4 This refers to a radical group 1, radical group 3, radical group 4, or radical group 5 as defined herein; Preferably, y is an integer in the range of 10 to 40, more preferably 12 to 37, even more preferably 15 to 35, still more preferably 20 to 30, and even more preferably 23 to 25, and most preferably y is 24.

[0391] phrase 75 The compounds described in clause 74, or their salts, hydrates, or solvates; where T 3 However, -(CH2CH2-O-) y -T 4 It is a part.

[0392] phrase 76 The compounds described in clause 74 or 75, or their salts, hydrates, or solvates; where y is an integer in the range of 10 to 40.

[0393] phrase 77 A compound described in any one of clauses 74-76, or a salt, hydrate, or solvate thereof; where y is an integer in the range of 12-37.

[0394] phrase 78 A compound described in any one of clauses 74-77, or a salt, hydrate, or solvate thereof; where y is an integer in the range of 15-35.

[0395] phrase 79 A compound described in any one of clauses 74-78, or a salt, hydrate, or solvate thereof; where y is an integer in the range of 20-30.

[0396] phrase 80 A compound described in any one of clauses 74-79, or a salt, hydrate, or solvate thereof; where y is an integer in the range of 23-25.

[0397] phrase 81 A compound described in any one of clauses 74-80, or a salt, hydrate, or solvate thereof; where y is 24.

[0398] phrase 82 A compound described in any one of clauses 74-81, or a salt, hydrate, or solvate thereof; where T 4 However, it follows radical group 1.

[0399] phrase 83 A compound described in any one of clauses 74-82, or a salt, hydrate, or solvate thereof; where T 4 However, it follows radical group 1a.

[0400] phrase 84 A compound described in any one of clauses 74-83, or a salt, hydrate, or solvate thereof; where T 4 However, it follows radical group 1b.

[0401] phrase 85 A compound described in any one of clauses 74-84, or a salt, hydrate, or solvate thereof; where T 4 However, it follows the radical group 1c.

[0402] phrase 86 A compound described in any one of clauses 74-85, or a salt, hydrate, or solvate thereof; where T 4 However, it follows the radical group 1d.

[0403] phrase 87 A compound described in any one of clauses 74-86, or a salt, hydrate, or solvate thereof; where T 4 However, it follows the radical group 1e.

[0404] phrase 88A compound described in any one of clauses 74-87, or a salt, hydrate, or solvate thereof; where T 4 It is methyl.

[0405] phrase 89 A compound described in any one of clauses 1 to 81, or a salt, hydrate, or solvate thereof; where T 3 However, -(CH2CH2-O-) 24 -This is the CH3 section.

[0406] phrase 90 A compound described in any one of clauses 1-29 and 49-89, or a salt, hydrate, or solvate thereof; where formula (A) follows formula (A1): [ka] Here, L 1 It follows one of the clauses 1 through 29; Here, T 2 This follows either clause 1 or one of clauses 49-69; Here, T 3 This follows either clause 1 or one of clauses 70-89; and, L 2a , L 2b , L 2c and L 2d However, each of them is an independent linker.

[0407] phrase 91 The compounds described in clause 90, or their salts, hydrates, or solvates; where L 2a , L 2b , L 2c and L 2d However, each independently conforms to the radical group 2 as defined herein.

[0408] phrase 92 The compounds described in clause 90 or 91, or their salts, hydrates or solvates; where L 2a This is a linker containing 20 or fewer atoms.

[0409] phrase 93 A compound described in any one of clauses 90-92, or a salt, hydrate, or solvate thereof; where L 2a This is a linker containing 15 or fewer atoms.

[0410] phrase 94 A compound described in any one of clauses 90-93, or a salt, hydrate, or solvate thereof; where L 2a This is a linker containing 10 or fewer atoms.

[0411] phrase 95 A compound described in any one of clauses 90-94, or a salt, hydrate, or solvate thereof; where L 2a This is a linker containing five or fewer atoms.

[0412] phrase 96 A compound described in any one of clauses 90-95, or a salt, hydrate, or solvate thereof; where L 2a is -C(O)NL 2T -, -NL 2T C(O)-, -O-, -S-, -NL 2T -, -N=N- and -C(O)- are selected from the group; where L 2T is either a hydrogen atom or a methyl atom.

[0413] phrase 97 The compounds described in clause 96, or their salts, hydrates, or solvates; where L 2a is -C(O)NL 2T -and-NL 2T It is selected from the group consisting of C(O)-.

[0414] phrase 98 A compound described in any one of clauses 90-97, or a salt, hydrate, or solvate thereof; where L 2a The group is selected from the group consisting of -C(O)NH- and -NHC(O)-.

[0415] phrase 99 A compound described in any one of clauses 90-98, or a salt, hydrate, or solvate thereof; where L2a It is -NHC(O)-.

[0416] 100 phrases A compound described in any one of clauses 90-99, or a salt, hydrate, or solvate thereof; where L 2b This is a linker containing 20 or fewer atoms.

[0417] Haiku 101 A compound described in any one of clauses 90 to 100, or a salt, hydrate, or solvate thereof; where L 2b This is a linker containing 15 or fewer atoms.

[0418] phrase 102 A compound described in any one of clauses 90 to 101, or a salt, hydrate, or solvate thereof; where L 2b This is a linker containing 10 or fewer atoms.

[0419] phrase 103 A compound described in any one of clauses 90-102, or a salt, hydrate, or solvate thereof; where L 2b This is a linker containing five or fewer atoms.

[0420] phrase 104 A compound described in any one of clauses 90-103, or a salt, hydrate, or solvate thereof; where L 2b is -C(O)NL 2T -, -NL 2T C(O)-, -O-, -S-, -NL 2T -, -N=N- and -C(O)- are selected from the group; where L 2T is either a hydrogen atom or a methyl atom.

[0421] phrase 105 The compounds described in clause 104, or their salts, hydrates, or solvates; where L 2b is -C(O)NL 2T -and-NL 2T It is selected from the group consisting of C(O)-.

[0422] phrase 106 A compound described in any one of clauses 90-105, or a salt, hydrate, or solvate thereof; where L 2b The group is selected from the group consisting of -C(O)NH- and -NHC(O)-.

[0423] phrase 107 A compound described in any one of clauses 90 to 106, or a salt, hydrate, or solvate thereof; where L 2b It is -NHC(O)-.

[0424] phrase 108 A compound described in any one of clauses 90-107, or a salt, hydrate, or solvate thereof; where L 2d This is a linker containing 20 or fewer atoms.

[0425] phrase 109 A compound described in any one of clauses 90-108, or a salt, hydrate, or solvate thereof; where L 2d This is a linker containing 15 or fewer atoms.

[0426] phrase 110 A compound described in any one of clauses 90 to 109, or a salt, hydrate, or solvate thereof; where L 2d This is a linker containing 10 or fewer atoms.

[0427] phrase 111 A compound described in any one of clauses 90 to 110, or a salt, hydrate, or solvate thereof; where L 2d This is a linker containing five or fewer atoms.

[0428] phrase 112 A compound described in any one of clauses 90 to 111, or a salt, hydrate, or solvate thereof; where L 2d is -C(O)NL 2T -, -NL 2T C(O)-, -O-, -S-, -NL 2T -, -N=N- and -C(O)- are selected from the group; where L 2Tis either a hydrogen atom or a methyl atom.

[0429] phrase 113 The compounds described in clause 112, or their salts, hydrates, or solvates; where L 2d is -C(O)NL 2T -and-NL 2T It is selected from the group consisting of C(O)-.

[0430] phrase 114 A compound described in any one of clauses 90-113, or a salt, hydrate, or solvate thereof; where L 2d The group is selected from the group consisting of -C(O)NH- and -NHC(O)-.

[0431] phrase 115 A compound described in any one of clauses 90-114, or a salt, hydrate, or solvate thereof; where L 2d It is -C(O)NH-.

[0432] phrase 116 A compound described in any one of clauses 90 to 115, or a salt, hydrate, or solvate thereof; where L 2c This is a linker containing 50 or fewer atoms.

[0433] phrase 117 A compound described in any one of clauses 90 to 116, or a salt, hydrate, or solvate thereof; where L 2c This is a linker containing 40 or fewer atoms.

[0434] phrase 118 A compound described in any one of clauses 90 to 117, or a salt, hydrate, or solvate thereof; where L 2c This is a linker containing 30 or fewer atoms.

[0435] phrase 119 A compound described in any one of clauses 90-118, or a salt, hydrate, or solvate thereof; where L 2c This is a linker containing 20 or fewer atoms.

[0436] phrase 120 A compound described in any one of clauses 90 to 119, or a salt, hydrate, or solvate thereof; where L 2c This is a linker containing 15 or fewer atoms.

[0437] phrase 121 A compound described in any one of clauses 90 to 120, or a salt, hydrate, or solvate thereof; where L 2c The group is selected from the group consisting of C1-C8 (hetero)alkantriyl, C5-C6 (hetero)arenetriyl, C3-C7 cycloalkantriyl, and C2-C7 heterocycloalkantriyl.

[0438] phrase 122 A compound described in any one of clauses 90 to 121, or a salt, hydrate, or solvate thereof; where L 2c These are C1-C8 (hetero) alkantriyl compounds.

[0439] phrase 123 A compound described in any one of clauses 90 to 122, or a salt, hydrate, or solvate thereof; where L 2c These are C1-C8 alkantriyl.

[0440] phrase 124 A compound described in any one of clauses 90-123, or a salt, hydrate, or solvate thereof; where L 2c These are C2-C7 alkantriyl compounds.

[0441] phrase 125 A compound described in any one of clauses 90-124, or a salt, hydrate, or solvate thereof; where L 2c It is a C3-C6 alkantriyl.

[0442] phrase 126 A compound described in any one of clauses 90 to 125, or a salt, hydrate, or solvate thereof; where L 2c It is a C4-C5 Alcantria yl.

[0443] phrase 127 A compound described in any one of clauses 90 to 126, or a salt, hydrate, or solvate thereof; where L 2c It is C5 Alcantria.

[0444] phrase 128 A compound described in any one of clauses 90 to 127, or a salt, hydrate, or solvate thereof; where L 2c This is >CH-CH2-CH2-CH2-CH2-.

[0445] phrase 129 A compound described in any one of clauses 1 to 128, or a salt, hydrate, or solvate thereof; wherein the non-vinyl carbon atom is substituted with one or fewer structures according to formula (A).

[0446] phrase 130 A compound described in any one of clauses 1 to 129, or a salt, hydrate, or solvate thereof; wherein the non-vinyl carbon atom is a non-allyl carbon atom.

[0447] phrase 131 A compound described in any one of clauses 1 to 130, or a salt, hydrate, or solvate thereof; wherein the 8-membered ring non-aromatic cyclic monoalkenylene moiety is substituted with 3 or fewer structures according to formula (A).

[0448] phrase 132 A compound described in any one of clauses 1 to 131, or a salt, hydrate, or solvate thereof; wherein the 8-membered ring non-aromatic cyclic monoalkenylene moiety is substituted with 2 or fewer structures according to formula (A).

[0449] phrase 133 A compound described in any one of clauses 1 to 132, or a salt, hydrate, or solvate thereof; wherein the 8-membered ring non-aromatic cyclic monoalkenylene moiety is substituted with one or fewer structures according to formula (A).

[0450] phrase 134A compound described in any one of clauses 1 to 133, or a salt, hydrate, or solvate thereof; wherein the 8-membered ring nonaromatic cyclic monoalkenylene moiety contains 2 or fewer heteroatoms.

[0451] phrase 135 A compound described in any one of clauses 1 to 134, or a salt, hydrate, or solvate thereof; wherein the 8-membered ring nonaromatic cyclic monoalkenylene moiety contains 2 or fewer heteroatoms, wherein the heteroatoms are N or O.

[0452] phrase 136 A compound described in any one of clauses 1 to 135, or a salt, hydrate, or solvate thereof; wherein the 8-membered ring nonaromatic cyclic monoalkenylene moiety contains one or fewer heteroatoms, wherein the heteroatoms are N or O.

[0453] phrase 137 A compound described in any one of clauses 1 to 136, or a salt, hydrate, or solvate thereof; wherein the 8-membered ring nonaromatic cyclic monoalkenylene moiety contains one or fewer heteroatoms, wherein the heteroatom is nitrogen.

[0454] phrase 138 A compound described in any one of clauses 1 to 137, or a salt, hydrate, or solvate thereof; wherein the 8-membered ring nonaromatic cyclic monoalkenylene moiety comprises at least 5 carbon atoms.

[0455] phrase 139 A compound described in any one of clauses 1 to 138, or a salt, hydrate, or solvate thereof; wherein the 8-membered ring nonaromatic cyclic monoalkenylene moiety comprises at least 6 carbon atoms.

[0456] phrase 140 A compound described in any one of clauses 1 to 139, or a salt, hydrate, or solvate thereof; wherein the 8-membered ring nonaromatic cyclic monoalkenylene moiety comprises at least 7 carbon atoms.

[0457] phrase 141A compound described in any one of clauses 1 to 140, or a salt, hydrate, or solvate thereof; wherein the 8-membered ring nonaromatic cyclic monoalkenylene moiety is entirely composed of carbon rings.

[0458] phrase 142 A compound described in any one of clauses 1 to 141, or a salt, hydrate, or solvate thereof; wherein the 8-membered ring nonaromatic cyclic monoalkenylene moiety is further substituted with a moiety according to any one of radical group 1, radical group 3, radical group 4, or radical group 5 as defined herein.

[0459] phrase 143 A compound described in any one of clauses 1 to 142, or a salt, hydrate, or solvate thereof; wherein the 8-membered ring nonaromatic cyclic monoalkenylene moiety is further substituted with 5 or fewer moieties according to any one of radical group 1, radical group 3, radical group 4, or radical group 5 as defined herein.

[0460] phrase 144 A compound described in any one of clauses 1 to 143, or a salt, hydrate, or solvate thereof; wherein the 8-membered ring nonaromatic cyclic monoalkenylene moiety is further substituted with 4 or fewer moieties according to any one of radical group 1, radical group 3, radical group 4, or radical group 5 as defined herein.

[0461] phrase 145 A compound described in any one of clauses 1 to 144, or a salt, hydrate, or solvate thereof; wherein the 8-membered ring nonaromatic cyclic monoalkenylene moiety is further substituted with 3 or fewer moieties according to any one of radical group 1, radical group 3, radical group 4, or radical group 5 as defined herein.

[0462] phrase 146A compound described in any one of clauses 1 to 145, or a salt, hydrate, or solvate thereof; wherein the 8-membered ring nonaromatic cyclic monoalkenylene moiety is further substituted with 2 or fewer moieties according to any one of radical group 1, radical group 3, radical group 4, or radical group 5 as defined herein.

[0463] phrase 147 A compound described in any one of clauses 1 to 146, or a salt, hydrate, or solvate thereof; wherein the 8-membered ring non-aromatic cyclic monoalkenylene moiety is R 48 It is substituted with the base, where R 48 These are -OH, -O-acetyl, -OC 1~4 Selected from the group consisting of alkyl groups, halogen atoms, active carbonates, and releaseable groups.

[0464] phrase 148 The compounds described in clause 147, or their salts, hydrates, or solvates; wherein the 8-membered ring nonaromatic cyclic monoalkenylene moiety comprises at least one allyl carbon, and the at least one allyl carbon is the R 48 It is substituted with the base.

[0465] phrase 149 The compounds described in clause 147 or 148, or their salts, hydrates, or solvates; where R 48 The base is in the axial position.

[0466] phrase 150 A compound described in any one of clauses 147 to 149, or a salt, hydrate, or solvate thereof; where R 48 The group is a group that can be released.

[0467] phrase 151 A compound described in any one of clauses 147 to 150, or a salt, hydrate, or solvate thereof; wherein the 8-membered ring non-aromatic cyclic monoalkenylene moiety comprises one or fewer releaseable groups.

[0468] phrase 152A compound described in any one of clauses 147 to 151, or a salt, hydrate, or solvate thereof; wherein the releaseable group is -(Y 1 -C(=Y 2 )) i -(S P ) j -C A And here, Y 1 and Y 2 Each of them is independently selected from O and S; C A S is the payload, which is structure A; P is a linker; j is 0 or 1; i is 0 or 1; if i is 0, -(S P ) j -C A is, -(S P ) j -C A The remainder of the compound is connected via O or S, which is part of the compound; when i is 1, -(S P ) j -C A ha-(S P ) j -C A -C(=Y 2 ) - Connected.

[0469] phrase 153 A compound described in any one of clauses 147 to 152, or a salt, hydrate, or solvate thereof; wherein the releaseable group is -(OC(=Y 2 )) i -(S P ) j -C A That is the case.

[0470] phrase 154 A compound described in any one of clauses 147 to 152, or a salt, hydrate, or solvate thereof; wherein the releaseable group is -(Y 1 -C(=O)) i -(S P ) j -C A That is the case.

[0471] phrase 155 A compound described in any one of clauses 147-154, or a salt, hydrate, or solvate thereof; wherein the releaseable group is -(OC(=O)) i -(S P ) j -C A That is the case.

[0472] phrase 156 A compound described in any one of clauses 147 to 155, or a salt, hydrate, or solvate thereof; wherein the releaseable group is -OC(=O)-(S P ) j -C A That is the case.

[0473] phrase 157 A compound described in any one of clauses 147-156, or a salt, hydrate, or solvate thereof; where S P However, it follows radical group 2.

[0474] phrase 158 A compound described in any one of clauses 147-157, or a salt, hydrate, or solvate thereof; where S P However, he is a self-sacrificing linker.

[0475] phrase 159 A compound described in any one of clauses 147 to 158, or a salt, hydrate, or solvate thereof; wherein the releaseable group is -OC(=O)-C A That is the case.

[0476] phrase 160 The compounds described in clause 159, or their salts, hydrates, or solvates; where C A However, C A It is linked to the -OC(=O)- moiety via a secondary or tertiary nitrogen atom that is part of it, forming a carbamate.

[0477] phrase 161 A compound described in any one of clauses 147-160, or a salt, hydrate, or solvate thereof; where C AHowever, the drug is preferably monomethyl auristatin E (MMAE), exatecan, or an exatecan derivative.

[0478] phrase 162 A compound described in any one of clauses 147-161, or a salt, hydrate, or solvate thereof; where C A This is monomethyl auristatin E (MMAE).

[0479] phrase 163 A compound described in any one of clauses 1 to 162, or a salt, hydrate, or solvate thereof; wherein the 8-membered ring nonaromatic cyclic monoalkenylene moiety comprises at least one allyl carbon, and the at least one allyl carbon is R 48 It is replaced by the base, where the R 48 The base is in the axial position, and here, the R 48 The base is -OC(=O)-C A And here, C A It is a drug.

[0480] phrase 164 The compounds described in clause 163, or their salts, hydrates, or solvates; where C A However, it is monomethyl auristatin E (MMAE) linked to the -OC(=O)- moiety via a secondary or tertiary nitrogen atom which is part of monomethyl auristatin E (MMAE), and forms a carbamate.

[0481] phrase 165 The compounds described in clause 164, or their salts, hydrates, or solvates; where C A However, it is monomethyl auristatin E (MMAE) linked to the -OC(=O)- moiety via a tertiary nitrogen atom which is part of monomethyl auristatin E (MMAE), and forms a carbamate.

[0482] phrase 166 A compound described in any one of clauses 147 to 165, or a salt, hydrate, or solvate thereof; where R 48 The basis is, [ka] That is the case.

[0483] phrase 167 A compound described in any one of clauses 1 to 166, or a salt, hydrate, or solvate thereof; wherein the 8-membered ring non-aromatic cyclic monoalkenylene moiety comprises at least one T 1 It is substituted with a base, where T 1 However, this is in accordance with radical group 1, radical group 3, radical group 4, or radical group 5 as defined herein.

[0484] phrase 168 The compounds described in clause 167, or their salts, hydrates, or solvates; where the 8-membered ring non-aromatic cyclic monoalkenylene moiety has 5 or fewer T 1 It is substituted with the base.

[0485] phrase 169 A compound described in any one of clauses 167 to 168, or a salt, hydrate, or solvate thereof; wherein the 8-membered ring non-aromatic cyclic monoalkenylene moiety has 4 or fewer T 1 It is substituted with the base.

[0486] phrase 170 A compound described in any one of clauses 167 to 169, or a salt, hydrate, or solvate thereof; wherein the 8-membered ring non-aromatic cyclic monoalkenylene moiety has 3 or fewer T 1 It is substituted with the base.

[0487] phrase 171 A compound described in any one of clauses 167 to 170, or a salt, hydrate, or solvate thereof; wherein the 8-membered ring non-aromatic cyclic monoalkenylene moiety has 2 or fewer T 1 It is substituted with the base.

[0488] phrase 172 A compound described in any one of clauses 167 to 171, or a salt, hydrate, or solvate thereof; wherein the 8-membered ring non-aromatic cyclic monoalkenylene moiety comprises one or fewer T1 It is substituted with the base.

[0489] phrase 173 A compound described in any one of clauses 167-172, or a salt, hydrate, or solvate thereof; where each T 1 However, independently, it conforms to radical group 1 as defined herein.

[0490] phrase 174 A compound described in any one of clauses 167-173, or a salt, hydrate, or solvate thereof; where each T 1 However, independently, -OT 1A , hydrogen atom, C1~C 12 (hetero)alkyl, C6 aryl, C4-C5 heteroaryl, C3-C6 (hetero)cycloalkyl, C5-C 12 Alkyl (hetero)aryl, C5-C 12 (hetero)arylalkyl, C4~C 12 Alkylcycloalkyl, -N(T 1A )2, -ST 1A -SO3H, -C(O)T 1A , -C(O)OT 1A ,-OC(O)T 1A ,-C(O)N(T 1A )2, -N(T 1A )2-CO-T 1A , and -Si(T 1A Selected from a group consisting of 3; Each T 1A However, independently selected from the group consisting of hydrogen atoms, (hetero)alkyl, (hetero)alkenyl, (hetero)alkynyl, (hetero)aryl, and amino acid residues; Preferably, each T 1A However, independently selected from the group consisting of hydrogen atoms, C1-C6 (hetero)alkyl groups, C1-C6 (hetero)alkenyl groups, C1-C6 (hetero)alkynyl groups, C2-C5 heteroaryl groups, phenyl groups, and amino acid residues; more preferably, each T 1AHowever, independently selected from the group consisting of hydrogen atoms, C1-C4 (hetero)alkyls, C1-C4 (hetero)alkenyls, C1-C4 (hetero)alkynyls, C3-C5 heteroaryls, phenyl, aspartic acid residues, glutamic acid residues, and glycine residues; more preferably, each T 1A However, independently selected from the group consisting of a hydrogen atom, a C1-C3 alkyl group, an aspartic acid residue, a glutamic acid residue, and a glycine residue; most preferably, T 1A That is a hydrogen atom.

[0491] phrase 175 The compounds described in clause 174, or their salts, hydrates, or solvates; where each T 1 However, independently, -OT 1A , hydrogen atom, C2-C6 alkyl, C6 aryl, C4-C5 heteroaryl, C3-C6 cycloalkyl, C5-C 12 Alkyl (hetero)aryl, C5-C 12 (hetero)arylalkyl, C4~C 12 Alkylcycloalkyl, -N(T 1A )2, -ST 1A -SO3H, -C(O)T 1A , -C(O)OT 1A ,-OC(O)T 1A ,-C(O)N(T 1A )2, -N(T 1A )2-CO-T 1A , and -Si(T 1A ) Selected from the group consisting of 3.

[0492] phrase 176 A compound described in any one of clauses 167-175, or a salt, hydrate, or solvate thereof; where T 1 However, -OT 1A That is the case.

[0493] phrase 177 A compound described in any one of clauses 167-176, or a salt, hydrate, or solvate thereof; where T 1 However, it is -OH.

[0494] phrase 178 A compound described in any one of clauses 167-177, or a salt, hydrate, or solvate thereof; where T 1 It is in the axial position.

[0495] phrase 179 A compound described in any one of clauses 167-178, or a salt, hydrate, or solvate thereof; where T 1 However, the 8-membered ring non-aromatic cyclic monoalkenylene portion is not substituted with a vinyl carbon or allyl atom.

[0496] phrase 180 A compound described in any one of clauses 1 to 179, or a salt, hydrate, or solvate thereof; wherein the 8-membered ring nonaromatic cyclic monoalkenylene moiety comprises at least one allyl carbon, and the at least one allyl carbon is R 48 It is replaced by the base, where the R 48 The base is in the axial position, and here, the R 48 The base is -OC(=O)-C A And here, C A is a drug; and, Here, the 8-membered ring non-aromatic cyclic monoalkenylene moiety has one or fewer T 1 It is substituted with a base, where T 1 is -OH, and here, T 1 However, the vinyl carbon or allyl atom of the 8-membered ring non-aromatic cyclic monoalkenylene moiety is not substituted.

[0497] phrase 181 A compound described in any one of clauses 1 to 180, or a salt, hydrate, or solvate thereof; where R 48 The basis is, [ka] That is the case.

[0498] phrase 182 A compound described in any one of clauses 1 to 180, or a salt, hydrate, or solvate thereof; wherein the compound conforms to the following formula (B): [ka] Here, R 48 This is defined in any one of clauses 147-166; T 1 This is defined in any one of clauses 167-179; TL is a structural formula that follows formula (A) defined in any one of clauses 1 to 128; y1 is an integer between 0 and 4; y2 is an integer between 0 and 5; y3 is an integer between 1 and 5; and, X 1 , X 2 , X 3 , X 4 , X 5 and X 6 Each of them is independently selected from the group consisting of substituted or unsubstituted carbon atoms, nitrogen atoms, or oxygen atoms, provided that X 1 , X 2 , X 3 , X 4 , X 5 and X 6 If one of the atoms is a nitrogen atom or an oxygen atom, then the adjacent X 1 , X 2 , X 3 , X 4 , X 5 and X 6 It is neither a nitrogen atom nor an oxygen atom.

[0499] phrase 183 The compounds described in clause 182, or their salts, hydrates, or solvates; where y1 is an integer between 1 and 2.

[0500] phrase 184 The compounds described in clause 182 or 183, or their salts, hydrates, or solvates; where y1 is 1.

[0501] phrase 185A compound described in any one of clauses 182 to 184, or a salt, hydrate, or solvate thereof; where y2 is an integer from 1 to 4.

[0502] phrase 186 A compound described in any one of clauses 182 to 185, or a salt, hydrate, or solvate thereof; where y2 is an integer between 1 and 3.

[0503] phrase 187 A compound described in any one of clauses 182 to 186, or a salt, hydrate, or solvate thereof; where y2 is an integer between 1 and 2.

[0504] phrase 188 A compound described in any one of clauses 182-187, or a salt, hydrate, or solvate thereof; where y2 is 1.

[0505] phrase 189 A compound described in any one of clauses 182 to 188, or a salt, hydrate, or solvate thereof; where y3 is an integer from 1 to 4.

[0506] phrase 190 A compound described in any one of clauses 182 to 189, or a salt, hydrate, or solvate thereof; where y3 is an integer between 1 and 3.

[0507] phrase 191 A compound described in any one of clauses 182-190, or a salt, hydrate, or solvate thereof; where y3 is an integer between 1 and 2.

[0508] phrase 192 A compound described in any one of clauses 182 to 191, or a salt, hydrate, or solvate thereof; where y3 is 1.

[0509] phrase 193 A compound described in any one of clauses 182 to 192, or a salt, hydrate, or solvate thereof; where X 1 , X 2 , X 3 , X 4 , X5 and X 6 Each of these is independently a substituted or unsubstituted carbon atom.

[0510] phrase 194 A compound described in any one of clauses 182-193, or a salt, hydrate, or solvate thereof; where X 1 , X 2 , X 3 , X 4 , X 5 and X 6 At least three of these are independently substituted carbon atoms.

[0511] phrase 195 A compound described in any one of clauses 182-194, or a salt, hydrate, or solvate thereof; where each substituted carbon atom is independently R 48 , T 1 , TL, and / or a moiety that follows any one of radical group 1, radical group 3, radical group 4, or radical group 5.

[0512] phrase 196 A compound described in any one of clauses 182 to 195, or a salt, hydrate, or solvate thereof; where each substituted carbon atom is independently R 48 , T 1 , TL, and / or the part following radical group 1 are substituted.

[0513] phrase 197 A compound described in any one of clauses 182-196, or a salt, hydrate, or solvate thereof; where each substituted carbon atom is independently R 48 , T 1 , and / or replaced with TL.

[0514] phrase 198 A compound described in any one of clauses 182-197, or a salt, hydrate, or solvate thereof; where X 1 , X 2 , X 3 , X 4 , X 5 and X6 Three or fewer of these are independently substituted carbon atoms.

[0515] phrase 199 A compound described in any one of clauses 182-198, or a salt, hydrate, or solvate thereof; where X 1 and / or X 6 However, independently, R 48 It is a carbon atom that has been substituted with [a specific atom].

[0516] 200 phrases A compound described in any one of clauses 182-199, or a salt, hydrate, or solvate thereof; where X 1 and X 6 One of them is R 48 It is a carbon atom that has been substituted with [a specific atom].

[0517] phrase 201 A compound described in any one of clauses 182-200, or a salt, hydrate, or solvate thereof; where X 1 However, R 48 It is a carbon atom that has been substituted with [a specific atom].

[0518] phrase 202 A compound described in any one of clauses 182-201, or a salt, hydrate, or solvate thereof; where X 1 ga-CHR 48 - is

[0519] phrase 203 A compound described in any one of clauses 182 to 202, or a salt, hydrate, or solvate thereof; where X 2 , X 3 , X 4 and X 5 At least one of them independently, T 1 It is a carbon atom substituted with and / or TL.

[0520] phrase 204 A compound described in any one of clauses 182-204, or a salt, hydrate, or solvate thereof; where X 2 , X 3 , X 4and X 5 At least one of them independently, T 1 It is a carbon atom substituted with and / or TL.

[0521] phrase 205 A compound described in any one of clauses 182-204, or a salt, hydrate, or solvate thereof; where X 2 , X 3 , X 4 and X 5 At least one of them independently, T 1 and carbon atoms substituted with TL.

[0522] phrase 206 A compound described in any one of clauses 182 to 205, or a salt, hydrate, or solvate thereof; where X 4 However, T 1 It is a carbon atom substituted with and / or TL.

[0523] phrase 207 A compound described in any one of clauses 182-206, or a salt, hydrate, or solvate thereof; where X 4 However, T 1 and carbon atoms substituted with TL.

[0524] phrase 208 A compound described in any one of clauses 182-206, or a salt, hydrate, or solvate thereof; where X 1 R 48 A carbon atom substituted with, and X 4 is T 1 It is a carbon atom substituted with and / or TL.

[0525] phrase 209 A compound described in any one of clauses 182-208, or a salt, hydrate, or solvate thereof; where X 1 R 48 A carbon atom substituted with, and X 4 is T 1 and carbon atoms substituted with TL.

[0526] phrase 210 A compound described in any one of clauses 182-209, or a salt, hydrate, or solvate thereof; where X 1 ga-CHR 48 - and X 4 ga-CT 1 It is TL-.

[0527] phrase 211 A compound described in any one of clauses 182-210, or a salt, hydrate, or solvate thereof; where X 2 , X 3 , X 5 and X 6 However, it is an unsubstituted carbon atom.

[0528] phrase 212 A compound described in any one of clauses 182 to 211, or a salt, hydrate, or solvate thereof; where X 2 , X 3 , X 5 and X 6 However, it is -CH2-.

[0529] phrase 213 A compound described in any one of clauses 182 to 212, or a salt, hydrate, or solvate thereof; where X 1 ga-CHR 48 - and X 4 ga-CT 1 TL- and X 2 , X 3 , X 5 and X 6 It is -CH2-.

[0530] Sentence 214 The compounds described in clause 213, or their salts, hydrates, or solvates; where R 48 but, [ka] That is the case.

[0531] Sentence 215 The compounds described in clause 213 or 214, or their salts, hydrates or solvates; where T1 It is -OH.

[0532] Sentence 216 A compound described in any one of clauses 213 to 215, or a salt, hydrate, or solvate thereof; where TL is [ka] And, Here, x is an integer in the range of 4 to 12; y is an integer in the range of 15 to 35; and, T 2 However, the group is selected from the following: [ka] Here, C B It is a protein.

[0533] Sentence 217 The compounds described in clause 216, or their salts, hydrates, or solvates; where x is an integer between 4 and 6.

[0534] Sentence 218 The compounds described in clause 216 or 217, or their salts, hydrates, or solvates; where x is 5.

[0535] Sentence 219 A compound described in any one of clauses 216-218, or a salt, hydrate, or solvate thereof; where y is an integer between 20 and 30.

[0536] Sentence 220 A compound described in any one of clauses 216-219, or a salt, hydrate, or solvate thereof; where y is an integer between 23 and 25.

[0537] Sentence 221 A compound described in any one of clauses 216-220, or a salt, hydrate, or solvate thereof; where y is 24.

[0538] Sentence 222 A compound described in any one of clauses 216 to 221, or a salt, hydrate, or solvate thereof; where T 2 but, [ka] , is.

[0539] Sentence 223 A compound described in any one of clauses 216 to 222, or a salt, hydrate, or solvate thereof; where T 2 but, [ka] That is the case.

[0540] Sentence 224 A compound described in any one of clauses 216-223, or a salt, hydrate, or solvate thereof; where C B AVP0458 consists of two monomers, each of which has an amino acid sequence according to sequence ID number 1.

[0541] Sentence 225 The compounds described in clause 223, or their salts, hydrates, or solvates; where C B However, C B It is linked to the malemidyl group via a sulfur atom that is part of the cysteine ​​group.

[0542] Sentence 226 The compounds described in clause 225, or their salts, hydrates, or solvates; where C B However, AVP0458 consists of two monomers, each of which has an amino acid sequence according to sequence ID number 1.

[0543] Sentence 227 A compound described in any one of clauses 216 to 221, or a salt, hydrate, or solvate thereof; where T 2 but, [ka] That is the case.

[0544] Sentence 228 A compound described in any one of clauses 1 to 227, or a salt, hydrate, or solvate thereof; wherein the compound conforms to the following formula (C): [ka] Here, R 48 This is as defined in any one of clauses 147-166; T 1 This is as defined in any one of clauses 167-179; T 2 This is as defined in clause 1 and any one of clauses 49-69; T 3 This is as defined in clause 1 and any one of 70-89; L 1 This is as defined in any one of clauses 1 through 29; L 2a This is as defined in any one of clauses 90-99; L 2b This is as defined in any one of clauses 90, 91, and 100-107; L 2c This is as defined in any one of clauses 90, 91 and 116-128; and L 2d This is as defined in any one of clauses 90, 91, and 108-115.

[0545] Sentence 229 The compounds described in clause 228, or their salts, hydrates, or solvates; where L 1 However, linear or branched C4-C 12 Alkylene, C3-C8 (hetero)cycloalkylene, C6-C 12 Arylene and C4~C 11 It is selected from the group consisting of heteroarylenes.

[0546] Sentence 230 The compounds described in clause 229, or their salts, hydrates, or solvates; where L 1 However, linear or branched C4-C 12 It is alkylene.

[0547] Sentence 231 The compounds described in clause 230, or their salts, hydrates, or solvates; where L 1 However, linear or branched C4-C 10 It is alkylene.

[0548] Sentence 232 The compounds described in clause 231, or their salts, hydrates, or solvates; where L 1 However, it is a linear C5-C6 alkylene.

[0549] Sentence 233 The compounds described in clause 232, or their salts, hydrates, or solvates; where L 1 However, it is a linear C5 alkylene.

[0550] Sentence 234 The compounds described in clause 233, or their salts, hydrates, or solvates; where L 1 However, it is a linear, unsubstituted C5 alkylene.

[0551] Sentence 235 A compound described in any one of clauses 228-234, or a salt, hydrate, or solvate thereof; where L 2a , L 2b and L 2d However, each of them is an independent linker.

[0552] Sentence 236 A compound described in any one of clauses 228-235, or a salt, hydrate, or solvate thereof; where L 2a , L 2b and L 2d However, each linker independently contains 20 or fewer atoms.

[0553] Sentence 237A compound described in any one of clauses 228-236, or a salt, hydrate, or solvate thereof; where L 2a , L 2b and L 2d However, each operates independently, -C(O)NL 2T -, -NL 2T C(O)-, -O-, -S-, -NL 2T -, -N=N- and -C(O)- are selected from the group; where L 2T However, it is either a hydrogen atom or a methyl atom.

[0554] Sentence 238 The compounds described in clause 237, or their salts, hydrates, or solvates; where L 2T That is a hydrogen atom.

[0555] Sentence 239 A compound described in any one of clauses 228-238, or a salt, hydrate, or solvate thereof; where L 2a , L 2b and L 2d However, each is independently selected from the group consisting of -C(O)NH- and -NHC(O)-.

[0556] Sentence 240 A compound described in any one of clauses 228-239, or a salt, hydrate, or solvate thereof; where L 2c However, the selection is made from the group consisting of C1-C8 (hetero)alkantriyl, C5-C6 (hetero)arentriyl, C3-C7 cycloalkantriyl, and C2-C7 heterocycloalkantriyl.

[0557] Sentence 241 A compound described in any one of clauses 228-240, or a salt, hydrate, or solvate thereof; where L 2c However, it is C1-C8 (hetero) alkantriyl.

[0558] Sentence 242 A compound described in any one of clauses 228 to 241, or a salt, hydrate, or solvate thereof; where L 2c However, it is C1-C8 Alcantria.

[0559] Sentence 243 A compound described in any one of clauses 228 to 242, or a salt, hydrate, or solvate thereof; where L 2c However, it is C4-C6 Alcantria.

[0560] Sentence 244 A compound described in any one of clauses 228-243, or a salt, hydrate, or solvate thereof; where L 2c However, it is C5 Alcantria.

[0561] Sentence 245 A compound described in any one of clauses 228-244, or a salt, hydrate, or solvate thereof; where L 2c However, it is >CH-CH2-CH2-CH2-CH2-.

[0562] Sentence 246 A compound described in any one of clauses 228-245, or a salt, hydrate, or solvate thereof; where T 1 However, -OT 1A , hydrogen atom, C2-C6 alkyl, C6 aryl, C4-C5 heteroaryl, C3-C6 cycloalkyl, C5-C 12 Alkyl (hetero)aryl, C5-C 12 (hetero)arylalkyl, C4~C 12 Alkylcycloalkyl, -N(T 1A )2, -ST 1A -SO3H, -C(O)T 1A , -C(O)OT 1A ,-OC(O)T 1A ,-C(O)N(T 1A )2, -N(T 1A )2-CO-T 1A , and -Si(T 1A Selected from a group consisting of 3; Each T 1A However, independently selected from the group consisting of hydrogen atoms, (hetero)alkyl, (hetero)alkenyl, (hetero)alkynyl, (hetero)aryl, and amino acid residues; Preferably, each T 1AHowever, independently selected from the group consisting of hydrogen atoms, C1-C6 (hetero)alkyl groups, C1-C6 (hetero)alkenyl groups, C1-C6 (hetero)alkynyl groups, C2-C5 heteroaryl groups, phenyl groups, and amino acid residues; more preferably, each T 1A However, independently selected from the group consisting of hydrogen atoms, C1-C4 (hetero)alkyls, C1-C4 (hetero)alkenyls, C1-C4 (hetero)alkynyls, C3-C5 heteroaryls, phenyl, aspartic acid residues, glutamic acid residues, and glycine residues; more preferably, each T 1A However, independently selected from the group consisting of a hydrogen atom, a C1-C3 alkyl group, an aspartic acid residue, a glutamic acid residue, and a glycine residue; most preferably, T 1A That is a hydrogen atom.

[0563] Sentence 247 A compound described in any one of clauses 228-246, or a salt, hydrate, or solvate thereof; where T 1 ga-OT 1A That is the case.

[0564] Sentence 248 A compound described in any one of clauses 246-247, or a salt, hydrate, or solvate thereof; where T 1A However, it is either a hydrogen atom or a methyl atom.

[0565] Sentence 249 A compound described in any one of clauses 246-248, or a salt, hydrate, or solvate thereof; where T 1A However, it is a hydrogen atom.

[0566] Sentence 250 A compound described in any one of clauses 228-249, or a salt, hydrate, or solvate thereof; where T 1 However, it is -OH.

[0567] Sentence 251 A compound described in any one of clauses 228-250, or a salt, hydrate, or solvate thereof; where T 2 However, the bioconjugation portion or -L 3-C B It is the base; here, L 3 However, these are residues in the bioconjugation region, and C B The material is selected from the group consisting of proteins, nucleic acids, peptides, carbohydrates, aptamers, lipids, small organic molecules, polymers, LNA, PNA, amino acids, peptoids, chelates, fluorescent dyes, phosphorescent dyes, organic particles, gels, cells, and combinations thereof.

[0568] Sentence 252 The compounds described in clause 251, or their salts, hydrates, or solvates; wherein the bioconjugation moiety is N-maleimidyl, halogenated N-alkylamide, sulfonyloxy N-alkylamide, vinyl sulfone, (activated) carboxylic acid, activated ester, benzenesulfonyl halide, ester, carbonate, sulfonyl halide, thiol, or derivative thereof, C 2~6 Alkenil, C 2~6 Alkinyl, C 7~18 Cycloalkynyl, C 5~18 Heterocycloalkynyl, bicyclo[6.1.0]nona-4-in-9-yl], C 3~12Cycloalkenyl, azide, phosphine, nitrile oxide, nitrone, nitrile imine, isonitrile, diazo, ketone, (O-alkyl)hydroxylamino, hydrazine, halogenated N-maleimidyl, aryloxymaleimide, dithiophenolmaleimide, bromo- and dibromopyridazinedione, 2,5-dibromohexanediamide, alquinone, 3-arylpropioronitrile, 1,1-bis(sulfonylmethyl)-methylcarbonyl or its removal derivative, carbonyl halide, arenamide, 1,2-quinone, isothiocyanate The following are selected from the group consisting of isocyanates, aldehydes, triazines, squalate, 2-imino-2-methoxyethyl, (oxa)norbornene, (oxa)norbornadiene, (imino)cydonone, methylsulfonylphenyloxadiazole, aminooxy, 2-aminobenzamidoxime, ethinylphosphonamide, reactivity in Pictet-Spengler ligation and hydrazine-Picte-Spengler (HIPS) ligation, DNA intercalators, tetrazine, trans-cyclooctene, and photocrosslinkers.

[0569] Sentence 253 The compounds described in clause 252, or their salts, hydrates, or solvates; wherein the bioconjugation portion is N-maleimidyl, halogenated N-alkylamide, sulfonyloxy N-alkylamide, vinyl sulfone, carboxylic acid, benzenesulfonyl halide, ester, carbonate, sulfonyl halide, thiol, C 2~6 Alkenil, C 2~6 Alkinyl, C 7~18 Cycloalkynyl, C 5~18 Heterocycloalkynyl, bicyclo[6.1.0]nona-4-in-9-yl], C 3~12Selected from the group consisting of cycloalkenyl, azide, phosphine, nitrile oxide, nitrone, nitrile imine, isonitrile, diazo, ketone, (O-alkyl)hydroxylamino, hydrazine, halogenated N-maleimidyl, aryloxymaleimide, dithiophenolmaleimide, bromo- and dibromopyridazinedione, 2,5-dibromohexanediamide, alquinone, 3-arylpropioronitrile, 1,1-bis(sulfonylmethyl)-methylcarbonyl, carbonyl halide, arenamide, 1,2-quinone, isothiocyanate, isocyanate, aldehyde, triazine, squalate, 2-imino-2-methoxyethyl, (oxa)norbornene, (oxa)norbornane, (oxa)norbornadiene, (imino)cydonone, methylsulfonylphenyloxadiazole, aminooxy, 2-aminobenzamidoxime, and ethinylphosphonamide.

[0570] Sentence 254 The compounds described in clause 253, or their salts, hydrates, or solvates; wherein the bioconjugation moiety is N-maleimidyl.

[0571] Sentence 255 A compound described in any one of clauses 228-254, or a salt, hydrate, or solvate thereof; where T 2 However, this is the bioconjugation part.

[0572] Sentence 256 The compounds described in clause 255, or their salts, hydrates, or solvates; where T 2 However, it is N-maleimidyl.

[0573] Sentence 257 The compounds described in clause 256, or their salts, hydrates, or solvates; where T 2 but, [ka] That is the case.

[0574] Sentence 258A compound described in any one of clauses 228-254, or a salt, hydrate, or solvate thereof; where T 2 However, -L 3 -C B It is the basis.

[0575] Sentence 259 A compound described in any one of clauses 228-254 and 258, or a salt, hydrate or solvate thereof; where L 3 However, these are residues of the maleimidyl moiety or the N-hydroxysuccinimidyl moiety.

[0576] Sentence 260 A compound described in any one of clauses 228-254 and 258-259, or a salt, hydrate, or solvate thereof; where L 3 However, this is a residue in the maleimidyl portion.

[0577] Sentence 261 A compound described in any one of clauses 228-254 and 258-260, or a salt, hydrate, or solvate thereof; where T 2 but, [ka] It is selected from the group consisting of the following.

[0578] Sentence 262 A compound described in any one of clauses 228-254 and 258-261, or a salt, hydrate, or solvate thereof; where C B However, it is a protein.

[0579] Sentence 263 A compound described in any one of clauses 228-254 and 258-262, or a salt, hydrate, or solvate thereof; where C B However, it is an antibody or a diabody.

[0580] Sentence 264 A compound described in any one of clauses 228-254 and 258-263, or a salt, hydrate, or solvate thereof; where C B However, it is a diamond body.

[0581] Sentence 265 A compound described in any one of clauses 228-254 and 258-264, or a salt, hydrate, or solvate thereof; where C B However, AVP0458 consists of two monomers, each of which has an amino acid sequence according to sequence ID number 1.

[0582] Sentence 266 A compound described in any one of clauses 228-254 and 258-265, or a salt, hydrate, or solvate thereof; where C B However, via a sulfur atom or nitrogen atom, T 2 The remainder is connected, where the sulfur atom or nitrogen atom is C B It is part of it.

[0583] Sentence 267 A compound described in any one of clauses 228-254 and 258-266, or a salt, hydrate, or solvate thereof; where C B However, via the sulfur atom, T 2 The remainder is connected, where the sulfur atom is C B It is part of it.

[0584] Sentence 268 A compound described in any one of clauses 228-254 and 258-267, or a salt, hydrate, or solvate thereof; where C B However, C B T 2 It is connected to the remainder, where the sulfur atom is part of the cysteine ​​residue.

[0585] Sentence 269 A compound described in any one of clauses 228-268, or a salt, hydrate, or solvate thereof; where T 3 It is a polymer.

[0586] Sentence 270 A compound described in any one of clauses 228-269, or a salt, hydrate, or solvate thereof; where T3 However, it is a polymer that includes a polyethylene glycol portion.

[0587] Sentence 271 A compound described in any one of clauses 228-270, or a salt, hydrate, or solvate thereof; where T 3 ga-(CH2CH2-O-) y -T 4 The part includes, where y is an integer in the range of 1 to 50, and T 4 However, y is a radical group 1, radical group 3, radical group 4, or radical group 5 as defined herein; preferably, y is an integer in the range of 10 to 40, more preferably 12 to 37, even more preferably 15 to 35, even more preferably 20 to 30, even more preferably 23 to 25, and most preferably y is 24.

[0588] Sentence 272 A compound described in any one of clauses 228 to 271, or a salt, hydrate, or solvate thereof; where T 3 However, -(CH2CH2-O-) y -T 4 It is a part.

[0589] Sentence 273 The compounds described in clause 271 or 272, or their salts, hydrates, or solvates; where y is an integer in the range of 10 to 40.

[0590] Sentence 274 A compound described in any one of clauses 271 to 273, or a salt, hydrate, or solvate thereof; where y is an integer in the range of 12 to 37.

[0591] Sentence 275 A compound described in any one of clauses 271 to 274, or a salt, hydrate, or solvate thereof; where y is an integer in the range of 15 to 35.

[0592] Sentence 276A compound described in any one of clauses 271 to 275, or a salt, hydrate, or solvate thereof; where y is an integer in the range of 20 to 30.

[0593] Sentence 277 A compound described in any one of clauses 271 to 276, or a salt, hydrate, or solvate thereof; where y is an integer in the range of 23 to 25.

[0594] Sentence 278 A compound described in any one of clauses 271 to 277, or a salt, hydrate, or solvate thereof; where y is 24.

[0595] Sentence 279 A compound described in any one of clauses 271 to 278, or a salt, hydrate, or solvate thereof; where T 4 It is methyl.

[0596] Sentence 280 A compound described in any one of clauses 228-279, or a salt, hydrate, or solvate thereof; where T 3 However, -(CH2CH2-O-) 24 -This is the CH3 section.

[0597] Sentence 281 A compound described in any one of clauses 228-280, or a salt, hydrate, or solvate thereof; where R 48 However, -OH, -O-acetyl, -OC 1~4 Selected from the group consisting of alkyl groups, halogen atoms, active carbonates, and releaseable groups.

[0598] Sentence 282 A compound described in any one of clauses 228 to 281, or a salt, hydrate, or solvate thereof; where R 48 This is a group that can be released.

[0599] Sentence 283 A compound described in any one of clauses 228 to 282, or a salt, hydrate, or solvate thereof; where the releaseable group is -(Y 1 -C(=Y 2)) i -(S P ) j -C A And here, Y 1 and Y 2 Each of them is independently selected from O and S; C A S is the payload, which is structure A; P is a linker; j is 0 or 1; i is 0 or 1; if i is 0, -(S P ) j -C A However, -(S P ) j -C A The remainder of the compound is connected via O or S, which is part of the compound; when i is 1, -(S P ) j -C A However, -(S P ) j -C A -C(=Y 2 ) - Connected.

[0600] Sentence 284 A compound described in any one of clauses 228-283, or a salt, hydrate, or solvate thereof; wherein the releaseable group is -(OC(=O)) i -(S P ) j -C A That is the case.

[0601] Sentence 285 A compound described in any one of clauses 228 to 284, or a salt, hydrate, or solvate thereof; wherein the releaseable group is -OC(=O)-(S P ) j -C A That is the case.

[0602] Sentence 286 A compound described in any one of clauses 228 to 285, or a salt, hydrate, or solvate thereof; where S P However, it follows radical group 2.

[0603] Sentence 287 A compound described in any one of clauses 228 to 286, or a salt, hydrate, or solvate thereof; where S P However, he is a self-sacrificing linker.

[0604] Sentence 288 A compound described in any one of clauses 228 to 287, or a salt, hydrate, or solvate thereof; wherein the releaseable group is -OC(=O)-C A That is the case.

[0605] Sentence 289 A compound described in any one of clauses 228 to 288, or a salt, hydrate, or solvate thereof; where C A However, C A The -OC(=O)- portion is linked to the -OC(=O)- portion via secondary or tertiary nitrogen atoms that form part of it, forming a carbamate.

[0606] Sentence 290 A compound described in any one of clauses 228 to 289, or a salt, hydrate, or solvate thereof; where C A It is a drug.

[0607] Sentence 291 A compound described in any one of clauses 228-290, or a salt, hydrate, or solvate thereof; where C A However, it is monomethyl auristatin E (MMAE).

[0608] Sentence 292 A compound described in any one of clauses 228 to 291, or a salt, hydrate, or solvate thereof; where C A However, it is monomethyl auristatin E (MMAE) linked to the -OC(=O)- moiety via a secondary or tertiary nitrogen atom which is part of monomethyl auristatin E (MMAE), and forms a carbamate.

[0609] Sentence 293 A compound described in any one of clauses 228 to 292, or a salt, hydrate, or solvate thereof; where C AHowever, it is monomethyl auristatin E (MMAE) linked to the -OC(=O)- moiety via a tertiary nitrogen atom which is part of monomethyl auristatin E (MMAE), and forms a carbamate.

[0610] Sentence 294 A compound described in any one of clauses 228 to 293, or a salt, hydrate, or solvate thereof; where R 48 The base is in the axial position.

[0611] Sentence 295 A compound described in any one of clauses 228 to 294, or a salt, hydrate, or solvate thereof; where R 48 The basis is, [ka] That is the case.

[0612] Sentence 296 A compound described in any one of clauses 1 to 295, or a salt, hydrate, or solvate thereof; wherein the compound has a structural formula according to the following formula (1): [ka] Here, L 1 However, linear or branched C4-C 12 Alkylene, C3-C8 (hetero)cycloalkylene, C6-C 12 Arylene and C4~C 11 Selected from the group consisting of heteroarrenes; L 2a , L 2b and L 2d However, each is an independent linker; L 2c However, it is selected from the group consisting of C1-C8 (hetero)alkantriyl, C5-C6 (hetero)arentriyl, C3-C7 cycloalkantriyl, and C2-C7 heterocycloalkantriyl; T 1 However, -OT 1A , hydrogen atom, C2-C6 alkyl, C6 aryl, C4-C5 heteroaryl, C3-C6 cycloalkyl, C5-C 12Alkyl (hetero)aryl, C5-C 12 (hetero)arylalkyl, C4~C 12 Alkylcycloalkyl, -N(T 1A )2, -ST 1A -SO3H, -C(O)T 1A , -C(O)OT 1A ,-OC(O)T 1A ,-C(O)N(T 1A )2, -N(T 1A )2-CO-T 1A and -Si(T 1A ) Selected from the group consisting of 3; each T 1A However, independently selected from the group consisting of hydrogen atoms, (hetero)alkyl, (hetero)alkenyl, (hetero)alkynyl, (hetero)aryl and amino acid residues; T 2 However, the bioconjugation portion or -L 3 -C B It is the base; here, L 3 These are the residues in the bioconjugation region, and C B However, it is selected from the group consisting of proteins, nucleic acids, peptides, carbohydrates, aptamers, lipids, small organic molecules, polymers, LNA, PNA, amino acids, peptoids, chelate moieties, fluorescent dyes, phosphorescent dyes, organic particles, gels, cells, and combinations thereof; T 3 is a polymer; and R 48 However, -OH, -O-acetyl, -OC 1~4 Selected from the group consisting of alkyl, halogen atoms, active carbonates and releaseable groups; preferably, L 1 However, linear or branched C4-C 12 It is alkylene, more preferably L 1 However, linear or branched C4-C 10 It is an alkylene, most preferably L 1 However, it is a linear C5-C6 alkylene; preferably, L 2a , L 2b and L 2d However, each linker independently contains 20 or fewer atoms; more preferably, L 2a , L 2b and L 2dHowever, each operates independently, -C(O)NL 2T -, -NL 2T C(O)-, -O-, -S-, -NL 2T -, -N=N- and -C(O)- are selected from the group; where L 2T However, it is a hydrogen atom or a methyl atom, preferably L 2T is a hydrogen atom; preferably, L 2c is C1-C8 (hetero)alkantriyl, more preferably L 2c is C1-C8 alkantriyl, most preferably L 2c is C4-C6 alkantriyl; preferably, T 1 ga-OT 1A And; most preferably, T 1 is -OH; preferably, T 1A is a hydrogen atom or a methyl atom, more preferably T 1A is a hydrogen atom; preferably, T 2 However, maleimidyl, N-hydroxysuccinimidyl or -L 3 -C B And; preferably, L 3 However, the residue is either a maleimidyl residue or an N-hydroxysuccinimidyl residue; preferably, C B is a protein, more preferably C B However, it is an antibody or a diabody, and more preferably C B The diamond body is most preferably C B However, AVP0458 consists of two monomers, where each of the two monomers has an amino acid sequence according to sequence ID number: 1; preferably, T 3 However, it is a polymer containing a polyethylene glycol portion; preferably, R 48 However, it is a group that can be released.

[0613] Sentence 297 The compounds described in clause 296, or their salts, hydrates, or solvates; here, R 48 However, it is in the axial position.

[0614] Sentence 298 A compound described in any one of clauses 1 to 296, or a salt, hydrate, or solvate thereof; wherein the compound has a structural formula according to the following formula (D): [ka] Here, R 48 However, as defined in any one of clauses 147-166 and 281-295; T 1 However, as defined in either clauses 167-179 or 246-250; T 2 However, as defined in any one of clauses 1, 49-69 and 251-268; T 3 However, as defined in any one of clauses 1, 70-89 and 269-280; L 1 However, as defined in any one of clauses 1-29 and 229-234; L 2a However, as defined in either clauses 90-99 or 235-239; L 2b However, as defined in any one of clauses 90, 91, 100-107 and 235-239; L 2c However, as defined in any one of clauses 90, 91, 116-128 and 240-245; and L 2d However, this is defined in any one of the following clauses: 90, 91, 108-115, and 235-239.

[0615] Sentence 299 The compounds described in clause 298, or their salts, hydrates, or solvates; where R 48 It is in the axial position.

[0616] 300 sentences A compound described in any one of clauses 1 to 296, or a salt, hydrate, or solvate thereof; wherein the compound has a structural formula according to the following formula (E): [ka] Here, R 48 However, as defined in any one of clauses 147-166 and 281-295; T1 However, as defined in either clauses 167-179 or 246-250; T 2 However, as defined in any one of clauses 1, 49-69 and 251-268; T 3 However, as defined in any one of clauses 1, 70-89 and 269-280; L 1 However, as defined in any one of clauses 1-29 and 229-234; L 2a However, as defined in either clauses 90-99 or 235-239; L 2b However, as defined in any one of clauses 90, 91, 100-107 and 235-239; L 2c However, as defined in any one of clauses 90, 91, 116-128 and 240-245; and L 2d However, this is defined in any one of the following clauses: 90, 91, 108-115, and 235-239.

[0617] Sentence 301 The compounds described in clause 300, or their salts, hydrates, or solvates; where R 48 It is in the axial position.

[0618] Sentence 302 A compound described in any one of clauses 1 to 301, or a salt, hydrate, or solvate thereof; wherein the compound has a structural formula according to the following formula (F): [ka] Here, R 48 However, as defined in any one of clauses 147-166 and 281-295; T 1 However, as defined in either clauses 167-179 or 246-250; T 2 However, as defined in any one of clauses 1, 49-69 and 251-268; T 3 However, as defined in any one of clauses 1, 70-89 and 269-280; L 1 However, as defined in any one of clauses 1-29 and 229-234; L2a However, as defined in either clauses 90-99 or 235-239; L 2b However, as defined in any one of clauses 90, 91, 100-107 and 235-239; L 2c However, as defined in any one of clauses 90, 91, 116-128 and 240-245; and L 2d However, this is defined in any one of the following clauses: 90, 91, 108-115, and 235-239.

[0619] Sentence 303 The compounds described in clause 302, or their salts, hydrates, or solvates; where R 48 It is in the axial position.

[0620] Sentence 304 A compound described in any one of clauses 1 to 302, or a salt, hydrate, or solvate thereof; wherein the compound has a structural formula according to the following formula (G): [ka] Here, R 48 However, as defined in any one of clauses 147-166 and 281-295; T 1 However, as defined in either clauses 167-179 or 246-250; T 2 However, as defined in any one of clauses 1, 49-69 and 251-268; y is as defined in any one of clauses 271 and 273-278; L 1 However, as defined in any one of clauses 1-29 and 229-234; L 2a However, as defined in either clauses 90-99 or 235-239; L 2b However, as defined in any one of clauses 90, 91, 100-107 and 235-239; L 2c However, as defined in any one of clauses 90, 91, 116-128 and 240-245; and L 2d However, this is defined in any one of the following clauses: 90, 91, 108-115, and 235-239.

[0621] Sentence 305 The compounds described in clause 304, or their salts, hydrates, or solvates; where R 48 It is in the axial position.

[0622] Sentence 306 A compound as described in clause 296, or a salt, hydrate, or solvate thereof; wherein the compound has a structural formula according to the following formula (2): [ka] Here, y is an integer in the range of 1 to 50; preferably, y is an integer in the range of 10 to 40; more preferably, in the range of 12 to 37; even more preferably, in the range of 15 to 35, still more preferably, in the range of 20 to 30, and most preferably, in the range of 23 to 25.

[0623] Sentence 307 The compounds described in clause 306, or their salts, hydrates, or solvates; where R 48 It is in the axial position.

[0624] Sentence 308 A compound described in any one of clauses 1 to 296, or a salt, hydrate, or solvate thereof; wherein the compound has a structural formula according to the following formula (H): [ka] Here, R 48 However, as defined in any one of clauses 147-166 and 281-295; T 1 However, as defined in either clauses 167-179 or 246-250; T 2 However, as defined in any one of clauses 1, 49-69 and 251-268; y is as defined in any one of clauses 271 and 273-278; L 1 However, as defined in any one of clauses 1-29 and 229-234; L 2a However, as defined in either clauses 90-99 or 235-239; L2b However, as defined in any one of clauses 90, 91, 100-107 and 235-239; L 2c However, as defined in any one of clauses 90, 91, 116-128 and 240-245; and L 2d However, this is defined in any one of the following clauses: 90, 91, 108-115, and 235-239.

[0625] Sentence 309 The compounds described in clause 308, or their salts, hydrates, or solvates; where R 48 It is in the axial position.

[0626] Sentence 310 A compound described in any one of clauses 1 to 296, or a salt, hydrate, or solvate thereof; wherein the compound has a structural formula according to the following formula (I): [ka] Here, R 48 However, as defined in any one of clauses 147-166 and 281-295; T 1 However, as defined in either clauses 167-179 or 246-250; T 2 However, as defined in any one of clauses 1, 49-69 and 251-268; y is as defined in any one of clauses 271 and 273-278; L 1 However, as defined in any one of clauses 1-29 and 229-234; L 2a However, as defined in either clauses 90-99 or 235-239; L 2b However, as defined in any one of clauses 90, 91, 100-107 and 235-239; L 2c However, as defined in any one of clauses 90, 91, 116-128 and 240-245; and L 2d However, this is defined in any one of the following clauses: 90, 91, 108-115, and 235-239.

[0627] Sentence 311The compounds described in clause 310, or their salts, hydrates, or solvates; where R 48 It is in the axial position.

[0628] Sentence 312 A compound described in any one of clauses 1 to 296, or a salt, hydrate, or solvate thereof; wherein the compound has a structural formula according to the following formula (J): [ka] Here, R 48 However, as defined in any one of clauses 147-166 and 281-295; T 1 However, as defined in either clauses 167-179 or 246-250; T 2 However, as defined in any one of clauses 1, 49-69 and 251-268; y is as defined in any one of clauses 271 and 273-278; L 1 However, as defined in any one of clauses 1-29 and 229-234; L 2a However, as defined in either clauses 90-99 or 235-239; L 2b However, as defined in any one of clauses 90, 91, 100-107 and 235-239; L 2c However, as defined in any one of clauses 90, 91, 116-128 and 240-245; and L 2d However, this is defined in any one of the following clauses: 90, 91, 108-115, and 235-239.

[0629] Sentence 313 The compounds described in clause 312, or their salts, hydrates, or solvates; where R 48 It is in the axial position.

[0630] Sentence 314 The compounds described in clause 312 or 313, or their salts, hydrates or solvates; where T 1 It is -OH.

[0631] Sentence 315A compound described in any one of clauses 312 to 314, or a salt, hydrate, or solvate thereof; where T 1 is -OH, and R 48 It is in the axial position.

[0632] Sentence 316 The compounds described in clause 315, or their salts, hydrates, or solvates; where R 48 However, -OC(O)-C A And here, C A is a drug, preferably C A However, it is monomethyl auristatin E (MMAE), exatecan, or an exatecan derivative.

[0633] Sentence 317 The compounds described in clause 316, or their salts, hydrates, or solvates; where R 48 but, [ka] That is the case.

[0634] Sentence 318 A compound described in any one of clauses 1 to 296, or a salt, hydrate, or solvate thereof; wherein the compound has a structural formula according to the following formula (K): [ka] Here, R 48 However, as defined in any one of clauses 147-166 and 281-295; T 1 However, as defined in either clauses 167-179 or 246-250; T 2 However, as defined in any one of clauses 1, 49-69 and 251-268; y is as defined in any one of clauses 271 and 273-278; L 1 However, as defined in any one of clauses 1-29 and 229-234; L 2a However, as defined in either clauses 90-99 or 235-239; L 2bHowever, as defined in any one of clauses 90, 91, 100-107 and 235-239; L 2c However, as defined in any one of clauses 90, 91, 116-128 and 240-245; and L 2d However, this is defined in any one of the following clauses: 90, 91, 108-115, and 235-239.

[0635] Sentence 319 The compounds described in clause 318, or their salts, hydrates, or solvates; where R 48 It is in the axial position.

[0636] Sentence 320 A compound described in either clause 318 or 319, or a salt, hydrate, or solvate thereof; where T 1 It is -OH.

[0637] Sentence 321 A compound described in any one of clauses 318-320, or a salt, hydrate, or solvate thereof; where T 1 is -OH, and R 48 It is in the axial position.

[0638] Sentence 322 The compounds described in clause 321, or their salts, hydrates, or solvates; where R 48 However, -OC(O)-C A And here, C A is a drug, preferably C A However, it is monomethyl auristatin E (MMAE), exatecan, or an exatecan derivative.

[0639] Sentence 323 The compounds described in clause 322, or their salts, hydrates, or solvates; where R 48 but, [ka] That is the case.

[0640] Sentence 324A compound described in any one of clauses 1 to 323, or a salt, hydrate, or solvate thereof; wherein the compound has a structural formula according to the following formula (L): [ka] Here, R 48 However, as defined in any one of clauses 147-166 and 281-295; T 1 However, as defined in either clauses 167-179 or 246-250; T 2 However, as defined in any one of clauses 1, 49-69 and 251-268; y is as defined in any one of clauses 271 and 273-278; L 1 However, as defined in any one of clauses 1-29 and 229-234; L 2a However, as defined in either clauses 90-99 or 235-239; L 2b However, as defined in any one of clauses 90, 91, 100-107 and 235-239; L 2c However, as defined in any one of clauses 90, 91, 116-128 and 240-245; and L 2d However, this is defined in any one of the following clauses: 90, 91, 108-115, and 235-239.

[0641] Sentence 325 The compounds described in clause 324, or their salts, hydrates, or solvates; where T 1 It is -OH.

[0642] Sentence 326 The compounds described in clause 325, or their salts, hydrates, or solvates; where R 48 However, -OC(O)-C A C A is a drug, preferably C A However, it is monomethyl auristatin E (MMAE), exatecan, or an exatecan derivative.

[0643] Sentence 327The compounds described in clause 326, or their salts, hydrates, or solvates; where R 48 but, [ka] That is the case.

[0644] Sentence 328 A compound described in any one of clauses 324-327, or a salt, hydrate, or solvate thereof; where L 1 However, linear or branched C4-C 12 Alkylene, C3-C8 (hetero)cycloalkylene, C6-C 12 Arylene and C4~C 11 It is selected from the group consisting of heteroarylenes.

[0645] Sentence 329 A compound described in any one of clauses 324-328, or a salt, hydrate, or solvate thereof; where L 1 However, linear or branched C4-C 12 It is alkylene.

[0646] Sentence 330 A compound described in any one of clauses 324-329, or a salt, hydrate, or solvate thereof; where L 1 However, linear or branched C4-C 10 It is alkylene.

[0647] Sentence 331 A compound described in any one of clauses 324-330, or a salt, hydrate, or solvate thereof; where L 1 However, it is a linear C5-C6 alkylene.

[0648] Sentence 332 A compound described in any one of clauses 324 to 331, or a salt, hydrate, or solvate thereof; where L 1 However, it is a linear C5 alkylene.

[0649] Sentence 333A compound described in any one of clauses 324 to 332, or a salt, hydrate, or solvate thereof; where L 1 However, it is a linear, unsubstituted C5 alkylene.

[0650] Sentence 334 A compound described in any one of clauses 324-333, or a salt, hydrate, or solvate thereof; where L 2a , L 2b and L 2d However, each of them is an independent linker.

[0651] Sentence 335 A compound described in any one of clauses 324-334, or a salt, hydrate, or solvate thereof; where L 2a , L 2b and L 2d However, each linker independently contains 20 or fewer atoms.

[0652] Sentence 336 A compound described in any one of clauses 324 to 335, or a salt, hydrate, or solvate thereof; where L 2a , L 2b and L 2d However, each operates independently, -C(O)NL 2T -, -NL 2T C(O)-, -O-, -S-, -NL 2T -, -N=N- and -C(O)- are selected from the group; where L 2T However, it is either a hydrogen atom or a methyl atom.

[0653] Sentence 337 A compound described in any one of clauses 324 to 336, or a salt, hydrate, or solvate thereof; where L 2T That is a hydrogen atom.

[0654] Sentence 338 A compound described in any one of clauses 324-337, or a salt, hydrate, or solvate thereof; where L 2a , L 2b and L 2d However, each is independently selected from the group consisting of -C(O)NH- and -NHC(O)-.

[0655] Sentence 339 A compound described in any one of clauses 324-338, or a salt, hydrate, or solvate thereof; where L 2c However, the selection is made from the group consisting of C1-C8 (hetero)alkantriyl, C5-C6 (hetero)arentriyl, C3-C7 cycloalkantriyl, and C2-C7 heterocycloalkantriyl.

[0656] Sentence 340 A compound described in any one of clauses 324-339, or a salt, hydrate, or solvate thereof; where L 2c However, it is C1-C8 (hetero) alkantriyl.

[0657] Sentence 341 A compound described in any one of clauses 324-340, or a salt, hydrate, or solvate thereof; where L 2c However, it is C1-C8 Alcantria.

[0658] Sentence 342 A compound described in any one of clauses 324 to 341, or a salt, hydrate, or solvate thereof; where L 2c However, it is C4-C6 Alcantria.

[0659] Sentence 343 A compound described in any one of clauses 324 to 342, or a salt, hydrate, or solvate thereof; where L 2c However, it is C5 Alcantria.

[0660] Sentence 344 A compound described in any one of clauses 324 to 343, or a salt, hydrate, or solvate thereof; where L 2c However, it is >CH-CH2-CH2-CH2-CH2-.

[0661] Sentence 345 A compound described in any one of clauses 324-344, or a salt, hydrate, or solvate thereof; where T 1 However, -OT 1A, hydrogen atom, C2-C6 alkyl, C6 aryl, C4-C5 heteroaryl, C3-C6 cycloalkyl, C5-C 12 Alkyl (hetero)aryl, C5-C 12 (hetero)arylalkyl, C4~C 12 Alkylcycloalkyl, -N(T 1A )2, -ST 1A -SO3H, -C(O)T 1A , -C(O)OT 1A ,-OC(O)T 1A ,-C(O)N(T 1A )2, -N(T 1A )2-CO-T 1A and -Si(T 1A ) Selected from the group consisting of 3; each T 1A However, independently selected from the group consisting of hydrogen atoms, (hetero)alkyl, (hetero)alkenyl, (hetero)alkynyl, (hetero)aryl and amino acid residues; Preferably, each T 1A However, independently selected from the group consisting of hydrogen atoms, C1-C6 (hetero)alkyls, C1-C6 (hetero)alkenyls, C1-C6 (hetero)alkynyls, C2-C5 heteroaryls, phenyls, and amino acid residues; more preferably, each T 1A However, independently selected from the group consisting of hydrogen atoms, C1-C4 (hetero)alkyl, C1-C4 (hetero)alkenyl, C1-C4 (hetero)alkynyl, C3-C5 heteroaryl, phenyl, aspartic acid residue, glutamic acid residue and glycine residue; more preferably, each T 1A However, independently selected from the group consisting of a hydrogen atom, a C1-C3 alkyl group, an aspartic acid residue, a glutamic acid residue, and a glycine residue; most preferably, T 1A That is a hydrogen atom.

[0662] Sentence 346 A compound described in any one of clauses 324 to 345, or a salt, hydrate, or solvate thereof; where T 1 ga-OT 1A That is the case.

[0663] Sentence 347A compound described in any one of clauses 324-346, or a salt, hydrate, or solvate thereof; where T 1A However, it is either a hydrogen atom or a methyl atom.

[0664] Sentence 348 A compound described in any one of clauses 324-347, or a salt, hydrate, or solvate thereof; where T 1A That is a hydrogen atom.

[0665] Sentence 349 A compound described in any one of clauses 324-348, or a salt, hydrate, or solvate thereof; where T 1 It is -OH.

[0666] Sentence 350 A compound described in any one of clauses 324-349, or a salt, hydrate, or solvate thereof; where T 2 However, the bioconjugation portion or -L 3 -C B It is the base; here, L 3 However, these are residues in the bioconjugation region, and C B The material is selected from the group consisting of proteins, nucleic acids, peptides, carbohydrates, aptamers, lipids, small organic molecules, polymers, LNA, PNA, amino acids, peptoids, chelates, fluorescent dyes, phosphorescent dyes, organic particles, gels, cells, and combinations thereof.

[0667] Sentence 351 The compounds described in clause 350, or their salts, hydrates, or solvates; wherein the bioconjugation portion is N-maleimidyl, halogenated N-alkylamide, sulfonyloxy N-alkylamide, vinyl sulfone, (activated) carboxylic acid, activated ester, benzenesulfonyl halide, ester, carbonate, sulfonyl halide, thiol or derivative thereof, C 2~6 Alkenil, C 2~6 Alkinyl, C 7~18 Cycloalkynyl, C 5~18 Heterocycloalkynyl, bicyclo[6.1.0]nona-4-in-9-yl], C3~12 Cycloalkenyl, azide, phosphine, nitrile oxide, nitrone, nitrile imine, isonitrile, diazo, ketone, (O-alkyl)hydroxylamino, hydrazine, halogenated N-maleimidyl, aryloxymaleimide, dithiophenolmaleimide, bromo- and dibromopyridazinedione, 2,5-dibromohexanediamide, alquinone, 3-arylpropioronitrile, 1,1-bis(sulfonylmethyl)-methylcarbonyl or its removal derivative, carbonyl halide, arenamide, 1,2-quinone, isothiocyanate The following are selected from the group consisting of isocyanates, aldehydes, triazines, squalate, 2-imino-2-methoxyethyl, (oxa)norbornene, (oxa)norbornadiene, (imino)cydonone, methylsulfonylphenyloxadiazole, aminooxy, 2-aminobenzamidoxime, ethinylphosphonamide, reactivity in Pictet-Spengler ligation and hydrazine-Picte-Spengler (HIPS) ligation, DNA intercalators, tetrazine, trans-cyclooctene, and photocrosslinkers.

[0668] Sentence 352 The compounds described in clause 351, or their salts, hydrates, or solvates; wherein the bioconjugation portion is N-maleimidyl, halogenated N-alkylamide, sulfonyloxy N-alkylamide, vinyl sulfone, carboxylic acid, benzenesulfonyl halide, ester, carbonate, sulfonyl halide, thiol, C 2~6 Alkenil, C 2~6 Alkinyl, C 7~18 Cycloalkynyl, C 5~18 Heterocycloalkynyl, bicyclo[6.1.0]nona-4-in-9-yl], C 3~12Selected from the group consisting of cycloalkenyl, azide, phosphine, nitrile oxide, nitrone, nitrile imine, isonitrile, diazo, ketone, (O-alkyl)hydroxylamino, hydrazine, halogenated N-maleimidyl, aryloxymaleimide, dithiophenolmaleimide, bromo- and dibromopyridazinedione, 2,5-dibromohexanediamide, alquinone, 3-arylpropioronitrile, 1,1-bis(sulfonylmethyl)-methylcarbonyl, carbonyl halide, arenamide, 1,2-quinone, isothiocyanate, isocyanate, aldehyde, triazine, squalate, 2-imino-2-methoxyethyl, (oxa)norbornene, (oxa)norbornane, (oxa)norbornadiene, (imino)cydonone, methylsulfonylphenyloxadiazole, aminooxy, 2-aminobenzamidoxime, and ethinylphosphonamide.

[0669] Sentence 353 The compounds described in clause 352, or their salts, hydrates, or solvates; wherein the bioconjugation portion is N-maleimidyl.

[0670] Sentence 354 A compound described in any one of clauses 324-353, or a salt, hydrate, or solvate thereof; where T 2 However, this is the bioconjugation part.

[0671] Sentence 355 The compounds described in clause 354, or their salts, hydrates, or solvates; where T 2 This is N-maleimidyl.

[0672] Sentence 356 The compounds described in clause 355, or their salts, hydrates, or solvates; where T 2 but, [ka] That is the case.

[0673] Sentence 357A compound described in any one of clauses 324-353, or a salt, hydrate, or solvate thereof; where T 2 However, -L 3 -C B It is the basis.

[0674] Sentence 358 A compound described in any one of clauses 324 to 353, or a salt, hydrate, or solvate thereof; where L 3 However, these are residues of the maleimidyl moiety or the N-hydroxysuccinimidyl moiety.

[0675] Sentence 359 A compound described in any one of clauses 324-353 and 357-358, or a salt, hydrate, or solvate thereof; where L 3 However, this is a residue in the maleimidyl portion.

[0676] Sentence 360 A compound described in any one of clauses 324-353 and 357-359, or a salt, hydrate, or solvate thereof; where T 2 but, [ka] It is selected from the group consisting of the following.

[0677] Sentence 361 A compound described in any one of clauses 324-353 and 357-360, or a salt, hydrate, or solvate thereof; where C B It is a protein.

[0678] Sentence 362 A compound described in any one of clauses 324-353 and 357-361, or a salt, hydrate, or solvate thereof; where C B However, it is an antibody or a diabody.

[0679] Sentence 363 A compound described in any one of clauses 324-353 and 357-362, or a salt, hydrate, or solvate thereof; where C B However, it is a diamond body.

[0680] Sentence 364 A compound described in any one of clauses 324-353 and 357-363, or a salt, hydrate, or solvate thereof; where C B However, AVP0458 consists of two monomers, where each of the two monomers is an amino acid sequence following sequence ID number: 1.

[0681] Sentence 365 A compound described in any one of clauses 324-353 and 357-364, or a salt, hydrate, or solvate thereof; where C B However, via a sulfur atom or nitrogen atom, T 2 The remainder is connected, where the sulfur atom or nitrogen atom is C B It is part of it.

[0682] Sentence 366 A compound described in any one of clauses 324-353 and 357-365, or a salt, hydrate, or solvate thereof; where C B However, via the sulfur atom, T 2 The remainder is connected, where the sulfur atom is C B It is part of it.

[0683] Sentence 367 A compound described in any one of clauses 324-353 and 357-365, or a salt, hydrate, or solvate thereof; where C B However, C B T 2 It is connected to the remainder, where the sulfur atom is part of the cysteine ​​residue.

[0684] Sentence 368 A compound described in any one of clauses 324-353 and 357-367, or a salt, hydrate, or solvate thereof; where T 3 It is a polymer.

[0685] Sentence 369A compound described in any one of clauses 324-353 and 357-368, or a salt, hydrate, or solvate thereof; where T 3 However, it is a polymer that includes a polyethylene glycol portion.

[0686] Sentence 370 A compound described in any one of clauses 324-353 and 357-369, or a salt, hydrate, or solvate thereof; where T 3 However, -(CH2CH2-O-) y -T 4 The part includes, where y is an integer in the range of 1 to 50, and T 4 However, y is a radical group 1, radical group 3, radical group 4, or radical group 5 as defined herein; preferably, y is an integer in the range of 10 to 40, more preferably 12 to 37, even more preferably 15 to 35, even more preferably 20 to 30, even more preferably 23 to 25, and most preferably y is 24.

[0687] Sentence 371 A compound described in any one of clauses 324-370, or a salt, hydrate, or solvate thereof; where T 3 However, -(CH2CH2-O-) y -T 4 It is a part.

[0688] Sentence 372 A compound described in any one of clauses 324 to 371, or a salt, hydrate, or solvate thereof; where y is an integer in the range of 10 to 40.

[0689] Sentence 373 A compound described in any one of clauses 324 to 372, or a salt, hydrate, or solvate thereof; where y is an integer in the range of 12 to 37.

[0690] Sentence 374 A compound described in any one of clauses 324-373, or a salt, hydrate, or solvate thereof; where y is an integer in the range of 15-35.

[0691] Sentence 375 A compound described in any one of clauses 324 to 374, or a salt, hydrate, or solvate thereof; where y is an integer in the range of 20 to 30.

[0692] Sentence 376 A compound described in any one of clauses 324 to 375, or a salt, hydrate, or solvate thereof; where y is an integer in the range of 23 to 25.

[0693] Sentence 377 A compound described in any one of clauses 324-376, or a salt, hydrate, or solvate thereof; where y is 24.

[0694] Sentence 378 A compound described in any one of clauses 324 to 377, or a salt, hydrate, or solvate thereof; where T 4 It is methyl.

[0695] Sentence 379 A compound described in any one of clauses 324-378, or a salt, hydrate, or solvate thereof; where T 3 However, -(CH2CH2-O-) 24 -This is the CH3 section.

[0696] Sentence 380 A compound described in any one of clauses 324-379, or a salt, hydrate, or solvate thereof; where R 48 However, -OH, -O-acetyl, -OC 1~4 Selected from the group consisting of alkyl groups, halogen atoms, active carbonates, and releaseable groups.

[0697] Sentence 381 A compound described in any one of clauses 324-380, or a salt, hydrate, or solvate thereof; where R 48 However, it is a group that can be released.

[0698] Sentence 382 A compound described in any one of clauses 324 to 381, or a salt, hydrate, or solvate thereof; wherein the releaseable group is -(Y1 -C(=Y 2 )) i -(S P ) j -C A And here, Y 1 and Y 2 Each of them is independently selected from O and S; C A However, the payload is structure A; S P is a linker; j is 0 or 1; i is 0 or 1; if i is 0, -(S P ) j -C A However, -(S P ) j -C A The remainder of the compound is connected via O or S, which is part of the compound; when i is 1, -(S P ) j -C A However, -(S P ) j -C A -C(=Y 2 ) - Connected.

[0699] Sentence 383 A compound described in any one of clauses 324 to 382, ​​or a salt, hydrate, or solvate thereof; wherein the releaseable group is -(OC(=O)) i -(S P ) j -C A That is the case.

[0700] Sentence 384 A compound described in any one of clauses 324 to 383, or a salt, hydrate, or solvate thereof; wherein the releaseable group is -OC(=O)-(S P ) j -C A That is the case.

[0701] Sentence 385 A compound described in any one of clauses 324-384, or a salt, hydrate, or solvate thereof; where S P However, it follows radical group 2.

[0702] Sentence 386 A compound described in any one of clauses 324 to 385, or a salt, hydrate, or solvate thereof; where S P However, he is a self-sacrificing linker.

[0703] Sentence 387 A compound described in any one of clauses 324 to 386, or a salt, hydrate, or solvate thereof; wherein the releaseable group is -OC(=O)-C A That is the case.

[0704] Sentence 388 A compound described in any one of clauses 324-387, or a salt, hydrate, or solvate thereof; where C A However, C A It is linked to the -OC(=O)- moiety via a secondary or tertiary nitrogen atom that is part of it, forming a carbamate.

[0705] Sentence 389 A compound described in any one of clauses 324-388, or a salt, hydrate, or solvate thereof; where C A is a drug, preferably C A However, it is monomethyl auristatin E (MMAE), exatecan, or an exatecan derivative.

[0706] Sentence 390 A compound described in any one of clauses 324-389, or a salt, hydrate, or solvate thereof; where C A However, it is monomethyl auristatin E (MMAE).

[0707] Sentence 391 A compound described in any one of clauses 324-390, or a salt, hydrate, or solvate thereof; where C A However, it is monomethyl auristatin E (MMAE) linked to the -OC(=O)- moiety via a secondary or tertiary nitrogen atom which is part of monomethyl auristatin E (MMAE), and forms a carbamate.

[0708] Sentence 392 A compound described in any one of clauses 324 to 391, or a salt, hydrate, or solvate thereof; where C A However, it is monomethyl auristatin E (MMAE) linked to the -OC(=O)- moiety via a tertiary nitrogen atom which is part of monomethyl auristatin E (MMAE), and forms a carbamate.

[0709] Sentence 393 A compound described in any one of clauses 324 to 392, or a salt, hydrate, or solvate thereof; wherein the compound has the following formula (M): [ka]

[0710] Sentence 394 A compound described in any one of clauses 393, or a salt, hydrate, or solvate thereof; where T 1 It is -OH.

[0711] Sentence 395 A compound described in any one of clauses 393 to 394, or a salt, hydrate, or solvate thereof; where R 48 -OC(O)-C A And here, C A is a drug, preferably C A However, it is monomethyl auristatin E (MMAE), exatecan, or an exatecan derivative.

[0712] Sentence 396 A compound described in any one of clauses 393 to 395, or a salt, hydrate, or solvate thereof; where T 1 is -OH, and R 48 -OC(O)-C A And here, C A is a drug, preferably C A However, it is monomethyl auristatin E (MMAE), exatecan, or an exatecan derivative.

[0713] Sentence 397A compound described in any one of clauses 393 to 396, or a salt, hydrate, or solvate thereof; where R 48 but, [ka] That is the case.

[0714] Sentence 398 A compound described in any one of clauses 393 to 397, or a salt, hydrate, or solvate thereof; where T 1 is -OH, and R 48 but, [ka] That is the case.

[0715] Sentence 399 A compound described in any one of clauses 324 to 392, or a salt, hydrate, or solvate thereof; wherein the compound has the following formula (N): [ka]

[0716] 400 sentences The compounds described in clause 399, or their salts, hydrates, or solvates; where T 1 It is -OH.

[0717] Sentence 401 A compound described in any one of clauses 399-400, or a salt, hydrate, or solvate thereof; where R 48 -OC(O)-C A And here, C A is a drug, preferably C A However, it is monomethyl auristatin E (MMAE), exatecan, or an exatecan derivative.

[0718] Sentence 402 A compound described in any one of clauses 399 to 401, or a salt, hydrate, or solvate thereof; where T 1 is -OH, and R 48-OC(O)-C A And here, C A is a drug, preferably C A However, it is monomethyl auristatin E (MMAE), exatecan, or an exatecan derivative.

[0719] Sentence 403 A compound described in any one of clauses 399 to 402, or a salt, hydrate, or solvate thereof; where R 48 but, [ka] That is the case.

[0720] Sentence 404 A compound described in any one of clauses 399 to 403, or a salt, hydrate, or solvate thereof; where T 1 is -OH, and R 48 but, [ka] That is the case.

[0721] Sentence 405 A compound described in any one of clauses 324 to 392, or a salt, hydrate, or solvate thereof; wherein the compound is of the following formula (O). [ka]

[0722] Sentence 406 The compounds described in clause 405, or their salts, hydrates, or solvates; where T 1 It is -OH.

[0723] Sentence 407 A compound described in any one of clauses 405 to 406, or a salt, hydrate, or solvate thereof; where R 48 -OC(O)-C A And here, C A is a drug, preferably C AHowever, it is monomethyl auristatin E (MMAE), exatecan, or an exatecan derivative.

[0724] Sentence 408 A compound described in any one of clauses 405 to 407, or a salt, hydrate, or solvate thereof; where T 1 is -OH, and R 48 -OC(O)-C A And here, C A is a drug, preferably C A However, it is monomethyl auristatin E (MMAE), exatecan, or an exatecan derivative.

[0725] Sentence 409 A compound described in any one of clauses 405 to 408, or a salt, hydrate, or solvate thereof; where R 48 but, [ka] That is the case.

[0726] Sentence 410 A compound described in any one of clauses 405 to 409, or a salt, hydrate, or solvate thereof; where T 1 is -OH, and R 48 but, [ka] That is the case.

[0727] Sentence 411 A compound described in any one of clauses 324-392 and 405-410, or a salt, hydrate, or solvate thereof; wherein the compound is of the following formula (3): [ka] Here, y is as defined in clause 306; x is an integer in the range of 4 to 12; preferably x is an integer in the range of 4 to 8, and more preferably x is an integer in the range of 4 to 6.

[0728] Sentence 412 A compound described in any one of clauses 324 to 411, or a salt, hydrate, or solvate thereof; wherein the compound is represented by the following formula (P). [ka]

[0729] Sentence 413 The compounds of clause 412, or their salts, hydrates, or solvates; where T 1 It is -OH.

[0730] Sentence 414 A compound described in any one of clauses 412 to 413, or a salt, hydrate, or solvate thereof; where R 48 -OC(O)-C A And here, C A is a drug, preferably C A However, it is monomethyl auristatin E (MMAE), exatecan, or an exatecan derivative.

[0731] Sentence 415 A compound described in any one of clauses 412 to 414, or a salt, hydrate, or solvate thereof; where T 1 is -OH, and R 48 -OC(O)-C A And here, C A is a drug, preferably C A However, it is monomethyl auristatin E (MMAE), exatecan, or an exatecan derivative.

[0732] Sentence 416 A compound described in any one of clauses 412 to 414, or a salt, hydrate, or solvate thereof; where R 48 but, [ka] That is the case.

[0733] Sentence 417A compound described in any one of clauses 412 to 416, or a salt, hydrate, or solvate thereof; where T 1 is -OH, and R 48 but, [ka] That is the case.

[0734] Sentence 418 A compound described in any one of clauses 412 to 417, or a salt, hydrate, or solvate thereof; where x is an integer between 3 and 8.

[0735] Sentence 419 A compound described in any one of clauses 412 to 418, or a salt, hydrate, or solvate thereof; where x is an integer between 4 and 6.

[0736] Sentence 420 A compound described in any one of clauses 412 to 419, or a salt, hydrate, or solvate thereof; where x is 5.

[0737] Sentence 421 A compound described in any one of clauses 412 to 420, or a salt, hydrate, or solvate thereof; where y is an integer between 12 and 37.

[0738] Sentence 422 A compound described in any one of clauses 412 to 420, or a salt, hydrate, or solvate thereof; where y is an integer between 20 and 30.

[0739] Sentence 423 A compound described in any one of clauses 412 to 422, or a salt, hydrate, or solvate thereof; where y is an integer between 23 and 25.

[0740] Sentence 424 A compound described in any one of clauses 412 to 423, or a salt, hydrate, or solvate thereof; where y is 24.

[0741] Sentence 425A compound described in any one of clauses 324 to 411, or a salt, hydrate, or solvate thereof; wherein the compound is of the following formula (Q). [ka]

[0742] Sentence 426 The compounds described in clause 425, or their salts, hydrates, or solvates; where T 1 It is -OH.

[0743] Sentence 427 A compound described in any one of clauses 425 to 426, or a salt, hydrate, or solvate thereof; where R 48 -OC(O)-C A And here, C A is a drug, preferably C A However, it is nomethyl auristatin E (MMAE), exatecan, or an exatecan derivative.

[0744] Sentence 428 A compound described in any one of clauses 425 to 427, or a salt, hydrate, or solvate thereof; where T 1 is -OH, and R 48 -OC(O)-C A And here, C A is a drug, preferably C A However, it is monomethyl auristatin E (MMAE), exatecan, or an exatecan derivative.

[0745] Sentence 429 A compound described in any one of clauses 425 to 428, or a salt, hydrate, or solvate thereof; where R 48 but, [ka] That is the case.

[0746] Sentence 430A compound described in any one of clauses 425 to 429, or a salt, hydrate, or solvate thereof; where T 1 is -OH, and R 48 but, [ka] That is the case.

[0747] Sentence 431 A compound described in any one of clauses 425-430, or a salt, hydrate, or solvate thereof; where x is an integer between 3 and 8.

[0748] Sentence 432 A compound described in any one of clauses 425-431, or a salt, hydrate, or solvate thereof; where x is an integer between 4 and 6.

[0749] Sentence 433 A compound described in any one of clauses 425-432, or a salt, hydrate, or solvate thereof; where x is 5.

[0750] Sentence 434 A compound described in any one of clauses 425-433, or a salt, hydrate, or solvate thereof; where y is an integer between 12 and 37.

[0751] Sentence 435 A compound described in any one of clauses 425-434, or a salt, hydrate, or solvate thereof; where y is an integer between 20 and 30.

[0752] Sentence 436 A compound described in any one of clauses 425 to 435, or a salt, hydrate, or solvate thereof; where y is an integer between 23 and 25.

[0753] Sentence 437 A compound described in any one of clauses 425-436, or a salt, hydrate, or solvate thereof; where y is 24.

[0754] Sentence 438The compound described in clause 1, or its salt, hydrate, or solvate; where the compound is [ka] That is the case.

[0755] Sentence 439 The compound described in clause 1, or its salt, hydrate, or solvate; where the compound is [ka] That is the case.

[0756] Sentence 440 The compound described in clause 1, or its salt, hydrate, or solvate; where the compound is [ka] That is the case.

[0757] Sentence 441 The compound described in clause 1, or its salt, hydrate, or solvate; where the compound is [ka] That is the case.

[0758] Sentence 442 The compounds described in clause 441, or their salts, hydrates, or solvates; where C B However, AVP0458 consists of two monomers, where each of the two monomers has an amino acid sequence according to sequence ID number: 1; preferably, C B However, C B It is linked to the maleidyl group via a sulfur atom which is part of the cysteine ​​residue, and preferably, the sulfur atom is part of the cysteine ​​residue.

[0759] Sentence 443 The compound described in clause 1, or its salt, hydrate, or solvate; where the compound is [ka] That is the case.

[0760] Sentence 444 The compounds described in clause 443, or their salts, hydrates, or solvates; where C B However, AVP0458 consists of two monomers, where each of the two monomers has an amino acid sequence according to sequence ID number: 1; preferably, C B However, C B It is linked to the maleidyl group via a sulfur atom which is part of the cysteine ​​residue, and preferably, the sulfur atom is part of the cysteine ​​residue.

[0761] Sentence 445 The compound described in clause 1, or its salt, hydrate, or solvate; where the compound is [ka] That is the case.

[0762] Sentence 446 The compounds described in clause 445, or their salts, hydrates, or solvates; where C B However, AVP0458 consists of two monomers, where each of the two monomers has an amino acid sequence according to sequence ID number: 1; preferably, C B However, C B It is linked to the maleidyl group via a sulfur atom which is part of the cysteine ​​residue, and preferably, the sulfur atom is part of the cysteine ​​residue.

[0763] Sentence 447 . Conjugate, or a salt, hydrate, or solvate thereof; wherein the conjugate comprises a protein conjugated to at least one compound described in any one of clauses 1 to 446, wherein T 2 However, these are residues of the bioconjugation portion, and the protein and the compound are T 2 It is conjugated via [a specific method / platform].

[0764] Sentence 448The conjugate described in clause 447, or a salt, hydrate, or solvate thereof; where the protein is a diabody or antibody.

[0765] Sentence 449 The conjugate described in clause 447 or 448, or a salt, hydrate, or solvate thereof; where the protein is the diabody.

[0766] Sentence 450 A conjugate, or a salt, hydrate, or solvate thereof, as described in any one of clauses 447 to 449; wherein the protein is AVP0458 comprising two monomers, each of which has an amino acid sequence according to sequence ID number: 1.

[0767] Sentence 451 A conjugate, or a salt, hydrate, or solvate thereof, as described in any one of clauses 447 to 450; wherein the protein is conjugated to 12 or fewer of the compounds.

[0768] Sentence 452 A conjugate, or a salt, hydrate, or solvate thereof, as described in any one of clauses 447 to 451; wherein the protein is conjugated to eight or fewer of the compound.

[0769] Sentence 453 A conjugate, or a salt, hydrate, or solvate thereof, as described in any one of clauses 447 to 452; wherein the protein is conjugated to four or fewer of the compound.

[0770] Sentence 454 A conjugate, or a salt, hydrate, or solvate thereof, as described in any one of clauses 447 to 452; wherein the protein is conjugated to about 4 of the compound.

[0771] Sentence 455 A conjugate, or a salt, hydrate, or solvate thereof, as described in any one of clauses 447 to 454; wherein the protein and the compound are T2 It is conjugated via a sulfidyl residue of the protein, a hydroxyl residue of the protein, or an amine residue of the protein.

[0772] Sentence 456 A conjugate, or a salt, hydrate, or solvate thereof, as described in any one of clauses 447 to 455; wherein the protein and the compound are T 2 It is conjugated via a sulfidyl residue of the protein.

[0773] Sentence 457 .A conjugate, or a salt, hydrate, or solvate thereof, as described in any one of clauses 447-456; where T 2 However, these are residues of the maleimidyl moiety or the N-hydroxysuccinimidyl moiety.

[0774] Sentence 458 .A conjugate, or a salt, hydrate, or solvate thereof, as described in any one of clauses 447 to 457; where T 2 However, this is a residue in the maleimidyl portion.

[0775] Sentence 459 A conjugate, or a salt, hydrate, or solvate thereof, as described in any one of clauses 447 to 458; wherein the protein and the compound are T 2 It is conjugated via the sulfidyl residue of the protein, and T 2 However, this is a residue in the maleimidyl portion.

[0776] Sentence 460 A conjugate, or a salt, hydrate, or solvate thereof, as described in any one of clauses 447 to 459; wherein the compound is defined as described in any one of clauses 1 to 181.

[0777] Sentence 461A conjugate, or a salt, hydrate, or solvate thereof, as described in any one of clauses 447 to 459; wherein the compound is defined as described in any one of clauses 182 to 227.

[0778] Sentence 462 A conjugate, or a salt, hydrate, or solvate thereof, as described in any one of clauses 447-459; wherein the compound is defined as described in any one of clauses 228-295.

[0779] Sentence 463 A conjugate, or a salt, hydrate, or solvate thereof, as described in any one of clauses 447-459; wherein the compound is defined as described in any one of clauses 296-297.

[0780] phrase 464 A conjugate, or a salt, hydrate, or solvate thereof, as described in any one of clauses 447-459; wherein the compound is defined as described in any one of clauses 298-299.

[0781] phrase 465 A conjugate, or a salt, hydrate, or solvate thereof, as described in any one of clauses 447 to 459; wherein the compound is defined as described in any one of clauses 300 to 301.

[0782] phrase 466 A conjugate, or a salt, hydrate, or solvate thereof, as described in any one of clauses 447 to 459; wherein the compound is defined as described in any one of clauses 302 to 303.

[0783] phrase 467 A conjugate, or a salt, hydrate, or solvate thereof, as described in any one of clauses 447 to 459; wherein the compound is defined as described in any one of clauses 304 to 305.

[0784] phrase 468A conjugate, or a salt, hydrate, or solvate thereof, as described in any one of clauses 447 to 459; wherein the compound is defined as described in any one of clauses 306 to 307.

[0785] phrase 469 A conjugate, or a salt, hydrate, or solvate thereof, as described in any one of clauses 447-459; wherein the compound is defined as described in any one of clauses 308-309.

[0786] phrase 470 A conjugate, or a salt, hydrate, or solvate thereof, as described in any one of clauses 447 to 459; wherein the compound is defined as described in any one of clauses 310 to 311.

[0787] phrase 471 A conjugate, or a salt, hydrate, or solvate thereof, as described in any one of clauses 447 to 459; wherein the compound is defined as described in any one of clauses 312 to 317.

[0788] phrase 472 A conjugate, or a salt, hydrate, or solvate thereof, as described in any one of clauses 447-459; wherein the compound is defined as described in any one of clauses 318-323.

[0789] phrase 473 A conjugate, or a salt, hydrate, or solvate thereof, as described in any one of clauses 447 to 459; wherein the compound is defined as described in any one of clauses 324 to 392.

[0790] phrase 474 A conjugate, or a salt, hydrate, or solvate thereof, as described in any one of clauses 447 to 459; wherein the compound is defined as described in any one of clauses 393 to 404.

[0791] phrase 475A conjugate, or a salt, hydrate, or solvate thereof, as described in any one of clauses 447-459; wherein the compound is defined as described in any one of clauses 405-410.

[0792] phrase 476 A conjugate, or a salt, hydrate, or solvate thereof, as described in any one of clauses 447 to 459; wherein the compound is as defined in clause 411.

[0793] phrase 477 A conjugate, or a salt, hydrate, or solvate thereof, as described in any one of clauses 447 to 459; wherein the compound is defined as described in any one of clauses 412 to 424.

[0794] phrase 478 A conjugate, or a salt, hydrate, or solvate thereof, as described in any one of clauses 447-459; wherein the compound is defined as described in any one of clauses 425-437.

[0795] phrase 479 .A conjugate, or a salt, hydrate, or solvate thereof, as described in any one of clauses 447 to 478; wherein the conjugate is [ka] And, Here, CJ is in the range of 1 to 12, preferably CJ is 2 to 10, more preferably 2.5 to 8, even more preferably 3 to 6, and even more preferably 3.5 to 4.

[0796] phrase 480 The conjugates, or salts, hydrates, or solvates thereof, as described in clause 479; where C B It is a protein.

[0797] phrase 481 The conjugate described in clause 480, or a salt, hydrate, or solvate thereof; where the protein is an antibody or a diabody.

[0798] phrase 482 The conjugate described in clause 481, or a salt, hydrate, or solvate thereof; where the protein is the diabody.

[0799] phrase 483 The conjugate described in clause 482, or a salt, hydrate, or solvate thereof; wherein the protein is AVP0458 consisting of two monomers, each of which has an amino acid sequence according to sequence ID number: 1.

[0800] phrase 484 The conjugates, salts, hydrates, or solvates thereof described in any one of clauses 479-483; where CJ is between 2 and 10.

[0801] phrase 485 The conjugates, salts, hydrates, or solvates thereof described in any one of clauses 479-484; where CJ is 2.5-8.

[0802] phrase 486 The conjugates, salts, hydrates, or solvates thereof described in any one of clauses 479-485; where CJ is 3-6.

[0803] phrase 487 The conjugates, salts, hydrates, or solvates thereof described in any one of clauses 479-486; where CJ is 3.5-4.

[0804] phrase 488 The conjugate, or salt, hydrate, or solvate thereof, as described in any one of clauses 479-487; where CJ is approximately 4.

[0805] phrase 489 .A conjugate, or a salt, hydrate, or solvate thereof, as described in any one of clauses 479 to 488; where C B However, it is linked to each maleidyl group via a sulfur atom.

[0806] phrase 490 A conjugate, or a salt, hydrate, or solvate thereof, as described in any one of clauses 479 to 489; wherein the sulfur atom is part of a cysteine ​​residue.

[0807] phrase 491 The conjugate described in any one of clauses 447 to 490, or a salt, hydrate, or solvate thereof; wherein the conjugate is [ka] And, Here, CJ is in the range of 1 to 12.

[0808] phrase 492 The conjugates, or salts, hydrates, or solvates thereof, as described in clause 491; where C B It is a protein.

[0809] phrase 493 The conjugate described in clause 492, or a salt, hydrate, or solvate thereof; where the protein is an antibody or a diabody.

[0810] phrase 494 The conjugate described in clause 493, or a salt, hydrate, or solvate thereof; where the protein is the diabody.

[0811] phrase 495 The conjugate described in clause 494, or a salt, hydrate, or solvate thereof; wherein the protein is AVP0458 consisting of two monomers, each of which has an amino acid sequence according to sequence ID number: 1.

[0812] phrase 496 The conjugates, salts, hydrates, or solvates thereof described in any one of clauses 491-495; where CJ is between 2 and 10.

[0813] phrase 497The conjugates, salts, hydrates, or solvates thereof described in any one of clauses 491-496; where CJ is between 2.5 and 8.

[0814] phrase 498 The conjugates, salts, hydrates, or solvates thereof described in any one of clauses 491-497; where CJ is 3-6.

[0815] phrase 499 The conjugates, salts, hydrates, or solvates thereof described in any one of clauses 491-498; where CJ is 3.5-4.

[0816] 500 phrases The conjugate, or salt, hydrate, or solvate thereof, as described in any one of clauses 491-499; where CJ is approximately 4.

[0817] phrase 501 .A conjugate, or a salt, hydrate, or solvate thereof, as described in any one of clauses 491 to 500; where C B However, it is linked to each maleidyl group via a sulfur atom.

[0818] phrase 502 A conjugate, or a salt, hydrate, or solvate thereof, as described in any one of clauses 491 to 501; wherein the sulfur atom is part of a cysteine ​​residue.

[0819] phrase 503 The conjugate described in any one of clauses 447 to 490, or a salt, hydrate, or solvate thereof; wherein the conjugate is [ka] And, Here, CJ is in the range of 1 to 12.

[0820] phrase 504 The conjugates, or salts, hydrates, or solvates thereof, as described in clause 503; where C BIt is a protein.

[0821] phrase 505 The conjugate described in clause 504, or a salt, hydrate, or solvate thereof; where the protein is an antibody or a diabody.

[0822] phrase 506 The conjugate described in clause 505, or a salt, hydrate, or solvate thereof; where the protein is the diabody.

[0823] phrase 507 The conjugate described in clause 506, or a salt, hydrate, or solvate thereof; wherein the protein is AVP0458 consisting of two monomers, each of which has an amino acid sequence according to sequence ID number: 1.

[0824] phrase 508 The conjugates, salts, hydrates, or solvates thereof described in any one of clauses 503 to 507; where CJ is between 2 and 10.

[0825] phrase 509 The conjugates, salts, hydrates, or solvates thereof described in any one of clauses 503 to 508; where CJ is between 2.5 and 8.

[0826] phrase 510 The conjugate, or salt, hydrate, or solvate thereof, as described in any one of clauses 503 to 509; where CJ is 3 to 6.

[0827] phrase 511 The conjugates, salts, hydrates, or solvates thereof described in any one of clauses 503 to 510; where CJ is 3.5 to 4.

[0828] phrase 512 The conjugate, or salt, hydrate, or solvate thereof, as described in any one of clauses 503 to 511; where CJ is approximately 4.

[0829] phrase 513 .A conjugate, or a salt, hydrate, or solvate thereof, as described in any one of clauses 503 to 512; where C B However, it is linked to each maleidyl group via a sulfur atom.

[0830] phrase 514 A conjugate, or a salt, hydrate, or solvate thereof, as described in any one of clauses 503 to 513; wherein the sulfur atom is part of a cysteine ​​residue.

[0831] phrase 515 . (a) A compound described in any one of clauses 1 to 446, or a salt, hydrate or solvate thereof; and / or (b) Conjugates, or salts, hydrates, or solvates thereof, as described in any one of clauses 447 to 514. A composition containing the following:

[0832] phrase 516 The composition of clause 515, wherein the composition is a pharmaceutical composition.

[0833] phrase 517 The composition according to clause 515 or 516, wherein the composition comprises a compound described in any one of clauses 1 to 446, or a salt, hydrate, or solvate thereof.

[0834] phrase 518 The composition according to any one of clauses 515 to 517, wherein the composition comprises a conjugate according to any one of clauses 447 to 514, or a salt, hydrate, or solvate thereof.

[0835] phrase 519 The composition according to any one of clauses 515 to 518, wherein the composition comprises (a) a compound according to any one of clauses 1 to 446, or a salt, hydrate, or solvate thereof; and (b) a conjugate according to any one of clauses 447 to 514, or a salt, hydrate, or solvate thereof.

[0836] phrase 520The composition is one of any one of clauses 515 to 519, comprising (a) a compound described in any one of clauses 1 to 446, or a salt, hydrate, or solvate thereof; and (b) an enantiomer of the compound, or a salt, hydrate, or solvate thereof.

[0837] phrase 521 The composition according to clause 520, wherein the composition comprises the compound, and the enantiomer is in a weight ratio of 1:10 to 10:1, preferably 1:8 to 8:1, more preferably 1:7 to 7:1, even more preferably 1:6 to 6:1, even more preferably 1:5 to 5:1, even more preferably 1:4 to 4:1, even more preferably 1:3 to 3:1, even more preferably 1:2 to 2:1, even more preferably 1:1.5 to 1.5:1, most preferably about 1:1.

[0838] phrase 522 The composition according to clause 521, wherein the composition is a racemic mixture of the compound and the enantiomer.

[0839] phrase 523 The composition according to any one of clauses 515 to 522, wherein the composition further comprises a carrier.

[0840] phrase 524 The composition according to any one of clauses 515 to 523, wherein the composition further comprises a pharmaceutically acceptable carrier.

[0841] phrase 525 . (A1) A compound described in any one of clauses 1 to 446, or a salt, hydrate, or solvate thereof; (A2) Conjugates, or salts, hydrates, or solvates thereof, as described in any one of clauses 447 to 514; and / or (A3) A composition described in any one of clauses 515 to 524; and, (B) Diene, or its salt, solvate, or hydrate A combination of items.

[0842] phrase 526A combination following (A1) and (B) of clause 525.

[0843] phrase 527 A combination following (A2) and (B) of clause 525.

[0844] phrase 528 A combination following (A3) and (B) of clause 525.

[0845] phrase 529 A combination following (A1), (A2), and (B) of clause 525.

[0846] phrase 530 A combination following (A1), (A3), and (B) of clause 525.

[0847] phrase 531 A combination following (A2), (A3), and (B) of clause 525.

[0848] phrase 532 A combination following (A1), (A2), (A3) and (B) of clause 525.

[0849] phrase 533 The combination according to any one of clauses 525 to 532, wherein the diene is tetrazine.

[0850] phrase 534 The diene, [ka] A combination of any one of clauses 525 to 535, selected from the group consisting of the above, or a salt, hydrate and / or solvate thereof.

[0851] phrase 535 The diene, [ka] , or a combination thereof, which is a salt, hydrate and / or solvate, as described in clause 534.

[0852] phrase 536 The diene, [ka] , or a combination thereof, which is a salt, hydrate and / or solvate, as described in clause 534.

[0853] phrase 537 The diene, [ka] , or a combination thereof, which is a salt, hydrate and / or solvate, as described in clause 534.

[0854] phrase 538 The diene, [ka] , or a combination thereof, which is a salt, hydrate and / or solvate, as described in clause 534.

[0855] phrase 539 The diene, [ka] , or a combination thereof, which is a salt, hydrate and / or solvate, as described in clause 534.

[0856] phrase 540 Compounds described in any one of clauses 1 to 446, or salts, hydrates or solvates thereof, for use as pharmaceuticals; conjugates described in any one of clauses 447 to 514, or salts, hydrates or solvates thereof; compositions described in any one of clauses 515 to 524; or combinations described in any one of clauses 525 to 539.

[0857] phrase 541 A compound described in any one of clauses 1 to 446, or a salt, hydrate, or solvate thereof, for use as a pharmaceutical.

[0858] phrase 542A conjugate, or a salt, hydrate, or solvate thereof, as described in any one of clauses 447 to 514, for use as a pharmaceutical product.

[0859] phrase 543 A composition described in any one of clauses 515 to 524 for use as a pharmaceutical product.

[0860] phrase 544 A combination of substances described in any one of clauses 525-539, intended for use as a pharmaceutical product.

[0861] phrase 545 A compound, or a salt, hydrate, or solvate thereof, described in any one of clauses 1 to 446, for use in the treatment of a disease in a subject; a conjugate, or a salt, hydrate, or solvate thereof, described in any one of clauses 447 to 514; a composition, described in any one of clauses 515 to 524; or a combination, described in any one of clauses 525 to 539; wherein the subject is human; and preferably the disease is cancer.

[0862] phrase 546 Compounds, or salts, hydrates or solvates thereof, for use in the context of clause 545; conjugates, or salts, hydrates or solvates thereof; compositions; or combinations thereof; wherein the subject is human.

[0863] phrase 547 Compounds, or salts, hydrates or solvates thereof, for use in accordance with any one of clauses 545 to 546; conjugates, or salts, hydrates or solvates thereof; compositions; or combinations thereof; where the disease is cancer.

[0864] phrase 548 A compound, or a salt, hydrate, or solvate thereof, described in any one of clauses 1 to 446, for use in the treatment of a disease in a subject; wherein the subject is preferably human; and preferably the disease is cancer.

[0865] phrase 549A conjugate, or a salt, hydrate, or solvate thereof, as described in any one of clauses 447 to 514, for use in the treatment of a disease in a subject; wherein the subject is preferably human; and preferably the disease is cancer.

[0866] phrase 550 A composition according to any one of clauses 515 to 524 for use in the treatment of a disease in a subject; wherein the subject is preferably a human; and preferably the disease is cancer.

[0867] phrase 551 A combination of any one of clauses 525 to 539 for use in the treatment of a disease in a subject; wherein the subject is preferably a human; and preferably the disease is cancer.

[0868] phrase 552 A method for treating a disease in a subject, wherein the method is (a) A compound described in any one of clauses 1 to 446, or a salt, hydrate, or solvate thereof; (b) Conjugates, or salts, hydrates or solvates thereof, as described in any one of clauses 447 to 514; and / or (c) The composition described in any one of clauses 515 to 524; and / or (d) A combination of any one of the items in clauses 525-539 The process includes administering the substance to the subject, Preferably, the subject is a human; preferably, the disease is cancer.

[0869] phrase 553 . (a) A compound described in any one of clauses 1 to 446, or a salt, hydrate, or solvate thereof; (b) Conjugates, or salts, hydrates or solvates thereof, as described in any one of clauses 447 to 514; and / or (c) The composition described in any one of clauses 515 to 524; and / or (d) A combination of any one of the items in clauses 525-539 Use of; where preferably, the subject is human; preferably, the disease is cancer.

[0870] phrase 554 Use of a compound, or a salt, hydrate, or solvate thereof, described in any one of clauses 1 to 446, for the manufacture of a pharmaceutical product for the treatment of a disease in a subject; wherein the subject is preferably human; and preferably the disease is cancer.

[0871] phrase 555 Use of a conjugate, or a salt, hydrate, or solvate thereof, as described in any one of clauses 447 to 514, for the manufacture of a pharmaceutical product for the treatment of a disease in a subject; wherein the subject is preferably human; and preferably the disease is cancer.

[0872] phrase 556 Use of the composition described in any one of clauses 515 to 524 for the manufacture of a pharmaceutical product for the treatment of a disease in a subject; wherein the subject is preferably a human; and preferably the disease is cancer.

[0873] phrase 557 Use of any one of the combinations described in clauses 525 to 539 for the manufacture of a pharmaceutical product for the treatment of a disease in a subject; wherein the subject is preferably a human; and preferably the disease is cancer.

[0874] phrase 558 . (ia) A compound described in any one of clauses 1 to 446, or a salt, hydrate, or solvate thereof; (iia) Conjugates, or salts, hydrates or solvates thereof, as described in any one of clauses 447-514; and / or (iiia) The composition described in any one of clauses 515 to 524 A non-therapeutic method of reacting with a diene, or a salt, solvate, or hydrate thereof, The method comprises the step of contacting (ia), (iia), or (iiia) with the diene, or a salt, solvate, or hydrate thereof, wherein the non-therapeutic method is preferably an in vitro method; and preferably the diene is tetrazine.

[0875] phrase 559 (ia) A non-therapeutic method comprising reacting a composition described in any one of clauses 1 to 446 with a diene, or a salt, solvate, or hydrate thereof, wherein the method comprises the step of contacting (ia) with the diene, or a salt, solvate, or hydrate thereof, wherein the non-therapeutic method is preferably an in vitro method; and preferably the diene is tetrazine.

[0876] phrase 560 (iia) A non-therapeutic method comprising reacting a conjugate, or a salt, hydrate, or solvate thereof, described in any one of clauses 447 to 514, with a diene, or a salt, solvate, or hydrate thereof, wherein the method comprises the step of contacting (iia) with the diene, or a salt, solvate, or hydrate thereof, wherein the non-therapeutic method is preferably an in vitro method; and preferably the diene is tetrazine.

[0877] phrase 561 (iiia) A non-therapeutic method comprising reacting a composition descr...

Claims

1. Compounds having a structural formula according to the following formula (1): 【Chemistry 1】 Here, L 1 is selected from the group consisting of linear or branched C 4 -C 12 alkylene, C 3 -C 8 (hetero)cycloalkylene, C 6 -C 12 arylene and C 4 -C 11 heteroarylene; L 2a , L 2b and L 2d Each is an independent linker; L 2c C 1 ~C 8 (hetero)alcantriyl, C 5 ~C 6 (hetero)arene triyl, C 3 ~C 7 Cycloalkantriyl and C 2 ~C 7 Selected from the group consisting of heterocycloalkantriyl; T 1 is, -OT 1A , hydrogen atom, C 2 ~C 6 Alkyl, C 6 Ariel, C 4 ~C 5 Heteroaryl, C 3 ~C 6 Cycloalkyl, C 5 ~C 12 Alkyl (hetero)aryl, C 5 ~C 12 (hetero)arylalkyl, C 4 ~C 12 Alkylcycloalkyl, -N(T 1A ) 2 , -ST 1A , -SO 3 H, -C(O)T 1A , -C(O)OT 1A ,-OC(O)T 1A ,-C(O)N(T 1A ) 2 , -N(T 1A ) 2 -CO-T 1A and -Si(T 1A ) 3 Selected from the group consisting of; Each T 1A These are independently selected from the group consisting of hydrogen atoms, (hetero)alkyl, (hetero)alkenyl, (hetero)alkynyl, (hetero)aryl and amino acid residues; T 2 This refers to the bioconjugation portion or base-L 3 -C B And here, L 3 These are residues in the bioconjugation region, and C B This is selected from the group consisting of proteins, nucleic acids, peptides, carbohydrates, aptamers, lipids, small organic molecules, polymers, LNA, PNA, amino acids, peptoids, chelate moieties, fluorescent dyes, phosphorescent dyes, organic particles, gels, cells, and combinations thereof; T 3 is a polymer; and, R 48 These are -OH, -O-acetyl, -OC 1～4 Selected from the group consisting of alkyl, halogen atoms, active carbonates and releaseable groups; and, Preferably, L 1 C is a linear or branched C 4 ~C 12 It is alkylene, more preferably L 1 C is a linear or branched C 4 ~C 10 It is an alkylene, most preferably L 1 is a linear C 5 ~C 6 It is alkylene; Preferably, L 2a , L 2b and L 2d Each is a linker containing 20 or fewer atoms independently; more preferably, L 2a , L 2b and L 2d is -C(O)NL 2T -, -NL 2T C(O)-, -O-, -S-, -NL 2T -, -N=N- and -C(O)- are selected from the group; where L 2T is a hydrogen atom or a methyl atom, preferably L 2T is a hydrogen atom; Preferably, L 2c is C 1 ~C 8 (hetero)alkantriyl, more preferably L 2c is C 1 ~C 8 It is an alkantriyl, most preferably L 2c is C 4 ~C 6 It is Alcantria; Preferably, T 1 is -OT 1A and most preferably, T 1 is -OH; Preferably, T 1A is a hydrogen atom or a methyl atom, more preferably T 1A is a hydrogen atom; Preferably, T 2 This refers to maleimidyl, N-hydroxysuccinimidyl, or -L 3 -C B And; Preferably, L 3 is a residue of a maleimidyl moiety or a residue of an N-hydroxysuccinimidyl moiety; Preferably, C B It is a protein, more preferably C B is an antibody or a diabody, and more more, C B is a diamond body, most preferably C B AVP0458 is composed of two monomers, each of which has an amino acid sequence according to sequence ID number 1; Preferably, T 3 is a polymer containing a polyethylene glycol portion; and, Preferably, R 48 It is a releaseable group.

2. The compound according to claim 1, wherein the compound conforms to the following formula (2): 【Chemistry 2】 Here, y is an integer in the range of 1 to 50; Preferably, y is an integer in the range of 10 to 40, more preferably an integer in the range of 12 to 37, even more preferably an integer in the range of 15 to 35, still more preferably an integer in the range of 20 to 30, and most preferably an integer in the range of 23 to 25.

3. The compound according to claim 1 or 2, wherein the compound conforms to the following formula (3): 【Transformation 3】 Here, y is as defined in claim 2; x is an integer in the range of 4 to 12; preferably x is an integer in the range of 4 to 8, and more preferably x is an integer in the range of 4 to 6.

4. R 48 is a releaseable group, and the releaseable group is -O-CO-C A And here, C A It is a drug; Preferably, the drug is linked to the -O-CO- moiety via a secondary or tertiary nitrogen atom that is part of the drug to form a carbamate; Preferably, the drug is monomethyl auristatin E (MMAE). The compound according to any one of claims 1 to 3.

5. T 2 but, 【Chemistry 4】 Selected from the group consisting of; Here, C B It is a protein; Preferably, C B is an antibody or diabody, more preferably a diabody, most preferably AVP0458 consisting of two monomers, each of which has an amino acid sequence according to sequence ID number: 1; Preferably, C B C B S or N, more preferably S, via T, which is part of S or N. 2 The remaining part is connected, The compound according to any one of claims 1 to 4.

6. The aforementioned compound, 【Transformation 5】 The compound according to any one of claims 1 to 5.

7. The aforementioned compound, 【Transformation 6】 or 【Transformation 7】 The compound according to any one of claims 1 to 6.

8. The aforementioned compound, 【Transformation 8】 And, Here, C B However, AVP0458 consists of two monomers, where each of the two monomers has an amino acid sequence according to sequence ID number: 1; Preferably, C B However, C B It is linked to the maleidyl group via a sulfur atom which is part of it. Preferably, the sulfur atom is part of cysteine. The compound according to any one of claims 1 to 5.

9. The aforementioned compound, 【Chemistry 9】 or 【Chemistry 10】 The compound according to claim 8.

10. A compound comprising an 8-membered ring nonaromatic cyclic monoalkenylene moiety, wherein the moiety comprises a nonvinyl carbon atom, wherein the nonvinyl carbon atom is substituted with at least one structure according to the following formula (A): 【Chemistry 11】 Here, L 1 and L 2 However, each is an independent linker; and, T 2 and T 3 However, the organic part is The aforementioned compound.

11. A conjugate comprising a protein conjugated to at least one compound according to formula (1) as defined in any one of claims 1 to 9, L 1 , L 2a , L 2b , L 2c , L 2d , T 1 , T 3 and R 48 The definition of is as defined in any one of claims 1 to 9, and furthermore, T 2 is a residue of the bioconjugation portion, and the protein and the compound are T 2 It is conjugated via; Preferably, the protein is a diabody or an antibody; more preferably, the protein is a diabody; most preferably, the protein is AVP0458 consisting of two monomers, each of which has an amino acid sequence according to sequence ID number 1; Preferably, the protein is conjugated with 12 or fewer compounds; more preferably, the protein is conjugated with 8 or fewer compounds; most preferably, the protein is conjugated with 4 or fewer compounds; Preferably, the protein and the compound are T 2 The protein and the compound are conjugated via a sulfidyl residue of the protein, a hydroxyl residue of the protein, or an amine residue of the protein; more preferably, the protein and the compound are conjugated via T 2 It is conjugated via a sulfidyl residue of the aforementioned protein; Preferably, T 2 However, the residue is a maleimidyl residue or an N-hydroxysuccinimidyl residue; more preferably, T 2 However, the residue in the maleimidyl portion, The aforementioned conjugate.

12. The aforementioned conjugate, 【Chemistry 12】 And, Here, CJ is in the range of 1 to 12; Here, C B AVP0458 is composed of two monomers, each of which has an amino acid sequence according to sequence ID number 1; Preferably, CJ is 2 to 10, more preferably 2.5 to 8, even more preferably 3 to 6, even more preferably 3.5 to 4, most preferably about 4; Preferably, C B It is linked to each maleidyl group via a sulfur atom, preferably the sulfur atom is part of cysteine. The conjugate according to claim 11.

13. The aforementioned conjugate, 【Chemistry 13】 or 【Chemistry 14】 The conjugate according to claim 12.

14. A composition, (a) The compound according to any one of claims 1 to 10; and / or, (b) The conjugate according to any one of claims 11 to 13 Includes, Preferably, the composition is a pharmaceutical composition. The aforementioned composition.

15. The composition is (a) The compound according to any one of claims 1 to 10; and, (b) Enantiomer of the compound Includes, Preferably, the composition is a racemic mixture of (a) and (b). The composition according to claim 14.

16. (A1) The compound according to any one of claims 1 to 10; (A2) The conjugate according to any one of claims 11 to 13; and / or (A3) The composition according to claim 14 or 15; and, (B) Diene; here, preferably the diene is tetrazine. combination

17. The diene is selected from the group consisting of the following: 【Chemistry 15】 The combination described in claim 16.

18. A compound according to any one of claims 1 to 10 for use as a pharmaceutical; a conjugate according to any one of claims 11 to 13; a composition according to claim 14 or 15; or a combination according to claim 16 or 17.

19. A compound according to any one of claims 1 to 10 for use in the treatment of a disease in the subject; a conjugate according to any one of claims 11 to 13; a composition according to claim 14 or 15; or a combination according to claim 16 or 17 Preferably, the subject is a human; Preferably, the disease is cancer.

20. A method for treating a disease in a subject, wherein the method is (a) The compound according to any one of claims 1 to 10; (b) The conjugate according to any one of claims 11 to 13; (c) The composition according to claim 14 or 15; and / or, (d) The combination described in claim 16 or 17 The process includes administering the above to the subject, Preferably, the subject is a human; Preferably, the disease is cancer. The aforementioned method.

21. (ia) The compound according to any one of claims 1 to 10; (iia) The conjugate according to any one of claims 11 to 13; and / or, (iiia) The composition according to claim 14 or 15 A non-therapeutic method that involves reacting with a diene, The method includes the step of bringing (ia), (iia), or (iiia) into contact with the diene, Preferably, the non-therapeutic method is an in vitro method; and, Preferably, the diene is tetrazine. The aforementioned non-treatment method.

22. In click response, (a) The compound according to any one of claims 1 to 10; (b) The conjugate according to any one of claims 11 to 13; (c) The composition according to claim 14 or 15; and / or, (d) The combination described in claim 16 or 17 Non-therapeutic use of it.

23. A method for synthesizing the compound according to any one of claims 1 to 10, (A) Coupling the compound of formula (R) below with the compound of formula (S) below: 【Chemistry 16】 Here, R 48 , T 1 and y are defined in any one of claims 1 to 10. 【Chemistry 17】 Here, T 2 and x are as defined in any one of claims 1 to 10, and S 10 is a -COOH or an active ester, preferably S 10 is -COOH; Or, (B) Coupling the compound of formula (T) below with the compound of formula (U) below: [Chemistry 18] Here, R 48 and T 1 is as defined in any one of claims 1 to 10; and S 11 is a -COOH or an active ester, preferably S 11 It is an active ester; 【Chemistry 19】 Here, T 2 x and y are defined in any one of claims 1 to 10. The method, including the method described above.

24. A method for synthesizing a conjugate according to any one of claims 11 to 13, the method comprising the step of coupling a protein to a compound according to any one of claims 1 to 10, wherein the compound contains T 2 The method wherein the bioconjugation portion is, preferably, a disulfide bond in the protein is reduced.

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