Conjugates containing a phosphorus(V) moiety and a drug

Abstract

The present invention relates to a conjugate having formula (I), wherein a receptor binding molecule (RBM) is linked to a drug moiety (D), and the conjugate comprises a phosphate (V) moiety. The present invention also relates to intermediates for producing same, methods for preparing same, pharmaceutical compositions containing same, and uses thereof. TIFF2025542295000988.tif35128

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to European Patent Application No. EP22216022, filed with the European Patent Office on December 22, 2022, the entire contents of which are incorporated herein for all purposes.

[0002] This application claims priority to European Patent Application No. EP23193215, filed with the European Patent Office on August 24, 2023, the entire contents of which are incorporated herein for all purposes.

[0003] Sequence Listing This application contains a Sequence Listing in computer readable format, which is incorporated herein by reference.

[0004] Technical Field The present invention relates to conjugates of receptor binding molecules and drug moieties, intermediates for producing same, methods for preparing same, pharmaceutical compositions containing same, and uses thereof. [Background technology]

[0005] background Antibody-drug conjugates (ADCs) are biotherapeutics that combine cytotoxic molecules with the targeting properties of antibodies to specifically kill cancer cells. Sacituzumab govitecan is an approved ADC marketed under the trade name Trodelvy. In sacituzumab govitecan, the anti-Trop2 antibody sacituzumab (also known as hRS7) is conjugated to the cytotoxic drug SN-38 via a linker called CL2A to form the conjugate hRS7-CL2A-SN-38. The CL2A linker contains a carbonate moiety to which the drug SN-38 is attached via its tertiary aliphatic alcohol. However, in vitro cytotoxicity studies using specific and nonspecific CL2A-SN-38 conjugates (i.e., comparing conjugates containing antibodies that specifically bind to an antigen with conjugates containing antibodies that do not bind to the antigen) showed no difference in efficacy between the specific and nonspecific CL2A-SN-38 conjugates. This is likely because cleavage to the free drug during the assay resulted in the potency of the conjugate being very similar to that of the free drug (see SV Govindan et al., "Improving the Therapeutic Index in Cancer Therapy by Using Antibody-Drug Conjugates Designed with a Moderately Cytotoxic Drug", Mol. Pharmaceutics 2015, 12, 6, 1836-1847, https: / / doi.org / 10.1021 / mp5006195).

[0006] Another ADC approved for medical use is trastuzumab deruxtecan, also known as DS-8201a and sold under the trade name Enhertz. Enhertz (DS-8201a) is an anti-Her2 ADC in which the anti-Her2 antibody trastuzumab is linked to the cytotoxic drug DXD via a peptide-containing linker; see, for example, Ogitani et al., "DS-8201a, A Novel HER2-Targeting ADC with a Novel DNA Topoisomerase I Inhibitor, Demonstrates a Promising Antitumor Efficacy with Differentiation from T-DM1," Clinical Cancer Research (22)20, October 15, 2016, pp. 5097-5108 (DOI: 10.1158 / 1078-0432.CCR-15-2822). However, although Enhertz is an approved and commercially available ADC, several drawbacks remain. In particular, Enhertz has been found to exhibit relatively poor serum stability.

[0007] Thus, there is a continuing need for additional conjugates with good properties for pharmaceutical use, particularly conjugates with good or improved serum stability and / or good efficacy. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] SV Govindan et al., “Improving the Therapeutic Index in Cancer Therapy by Using Antibody-Drug Conjugates Designed with a Moderately Cytotoxic Drug”, Mol. Pharmaceutics 2015, 12, 6, 1836-1847, https: / / doi.org / 10.1021 / mp5006195 [Non-patent document 2] Ogitani et al., “DS-8201a, A Novel HER2-Targeting ADC with a Novel DNA Topoisomerase I Inhibitor, Demonstrates a Promising Antitumor Efficacy with Differentiation from T-DM1”, Clinical Cancer Research (22)20, October 15, 2016, pp. 5097-5108 (DOI: 10.1158 / 1078-0432.CCR-15-2822) Summary of the Invention

[0009] overview This need is addressed by the subject matter as defined in the claims and in the embodiments described herein.

[0010] Thus, the present invention relates to a conjugate having formula (I), or a pharmaceutically acceptable salt or solvate thereof: TIFF2025542295000002.tif35128 formula, RBM is a receptor binding molecule; L is a linker; M, O, NR M60 , or S; R M60 is hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C10 ) aryl; U is O or S; X is O, S, or NR X10 and; R X10 is hydrogen; or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; D is a drug moiety; Y 1 is NR A20 , O, S, or CR A21 R A22 and; R A20 is hydrogen, (C1-C8) alkyl, (C6-C 10 ) aryl, and C1-C8) alkylene (C6-C 10 ) aryl; R A21 and R A22 are each independently hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 ) aryl; E is a spacer; Z is a cleavable group; W is a spacer E, Y after cleavage of group Z. 1 and a moiety capable of forming a ring together with phosphorus; and n is an integer ranging from 1 to 20.

[0011] The moiety U, whenever mentioned herein, may be O (oxygen) or S (sulfur). Preferably, U is oxygen. In the present disclosure, whenever O (oxygen) is shown in the position of U, such as in formulas (Ia), (Ia1), (Ia2), (Ib), (Ib1), (Ic), (Ic1), (Id), (Id1), (IIa), (IIa1), (IIa2), (IIb), (IIb1), (IIc) or (IIc1), oxygen can be replaced with S (sulfur). However, for the sake of brevity, the respective formulas containing S instead of O are not shown. It should be noted again that in this context, U is preferably O.

[0012] The present invention also relates to a conjugate having formula (Ia), or a pharmaceutically acceptable salt or solvate thereof: TIFF2025542295000003.tif40135In formula, RBM is a receptor binding molecule; L is a linker; M, O, NR M60 , or S; R M60 is hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 ) aryl; X is O, S, or NR X10 and; R X10 is hydrogen; or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; D is a drug moiety; Y 1 is NR A20 , O, S, or CR A21 R A22 and; R A20 is hydrogen, (C1-C8) alkyl, (C6-C 10 ) aryl, and C1-C8) alkylene (C6-C 10 ) aryl; R A21 and RA22 are each independently hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 ) aryl; A is CR A30 R A31 or A is (C1-C8)alkylene, where (C1-C8)alkylene is selected from the group consisting of (C1-C8)alkyl, halo, hydroxy, (C1-C8)alkoxy, amino, (C1-C8)alkylamino, di(C1-C8)alkylamino, SH, (C1-C8)alkylthio, (C3-C8)heterocyclyl, carboxylates and esters thereof, carboxy(C1-C8)alkyl, CONHR A36 and CONR A36 R A37 and R A36 and R A37 are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 ) aryl; R A30 and R A31 are each independently hydrogen, (C1-C8) alkyl, (C3-C8) cycloalkyl, (C2-C8) alkenyl, (C5-C8) cycloalkenyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 )aryl; wherein each of (C1-C8)alkyl, (C3-C8)cycloalkyl, (C2-C8)alkenyl, (C5-C8)cycloalkenyl, (C6-C 10 )aryl or (C1-C8)alkylene (C6-C 10)Aryl is (C1-C8)alkyl, halo, hydroxy, (C1-C8)alkoxy, amino, (C1-C8)alkylamino, di(C1-C8)alkylamino, SH, (C1-C8)alkylthio, (C3-C8)heterocyclyl, carboxylates and their esters, carboxy(C1-C8)alkyl, CONHR A36 and CONR A36 R A37 and R A36 and R A37 are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 ) aryl; optionally, R A30 and R A31 can be joined together to form a 3- to 8-membered ring; Y 2 is NR B20 , O, S, or CR B21 R B22 and; R B20 is hydrogen, (C1-C8) alkyl, (C6-C 10 ) aryl, and C1-C8) alkylene (C6-C 10 ) aryl; R B21 and R B22 are each independently hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 ) aryl; B is independently CR B30 R B31 or B is, independently at each occurrence, (C1-C8)alkylene, where (C1-C8)alkylene is selected from (C1-C8)alkyl, halo, hydroxy, (C1-C8)alkoxy, amino, (C1-C8)alkylamino, di(C1-C8)alkylamino, SH, (C1-C8)alkylthio, (C3-C8)heterocyclyl, carboxylates and esters thereof, carboxy(C1-C8)alkyl, CONHR B36 and CONR B36 R B37 and R B36 and R B37 are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 ) aryl; R B30 and R B31 are each independently hydrogen, (C1-C8) alkyl, (C3-C8) cycloalkyl, (C2-C8) alkenyl, (C5-C8) cycloalkenyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 )aryl; wherein each of (C1-C8)alkyl, (C3-C8)cycloalkyl, (C2-C8)alkenyl, (C5-C8)cycloalkenyl, (C6-C 10 )aryl or (C1-C8)alkylene (C6-C 10 )Aryl is (C1-C8)alkyl, halo, hydroxy, (C1-C8)alkoxy, amino, (C1-C8)alkylamino, di(C1-C8)alkylamino, SH, (C1-C8)alkylthio, (C3-C8)heterocyclyl, carboxylates and their esters, carboxy(C1-C8)alkyl, CONHR B36 and CONR B36 R B37 and R B36 and R B37are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 ) aryl; optionally, R B30 and R B31 can be joined together to form a 3- to 8-membered ring; m is an integer ranging from 0 to 15; Y 3 , O, NR C40 , or S, or absent; R C40 is hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 ) aryl; J is TIFF2025542295000004.tif18128, where TIFF2025542295000005.tif7128 is Y 3 Indicates the connection to; C is CR C50 R C51 or C is (C1-C8) alkylene, where (C1-C8) alkylene is selected from the group consisting of (C1-C8) alkyl, halo, hydroxy, (C1-C8) alkoxy, amino, (C1-C8) alkylamino, di(C1-C8) alkylamino, SH, (C1-C8) alkylthio, (C3-C8) heterocyclyl, carboxylates and esters thereof, carboxy(C1-C8) alkyl, CONHR C36 and CONR C36 R C37 and R C36 and R C37 are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 ) aryl; R C50 and R C51are each independently hydrogen, (C1-C8) alkyl, (C3-C8) cycloalkyl, (C2-C8) alkenyl, (C5-C8) cycloalkenyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 )aryl; wherein each of (C1-C8)alkyl, (C3-C8)cycloalkyl, (C2-C8)alkenyl, (C5-C8)cycloalkenyl, (C6-C 10 )aryl or (C1-C8)alkylene (C6-C 10 )Aryl is (C1-C8)alkyl, halo, hydroxy, (C1-C8)alkoxy, amino, (C1-C8)alkylamino, di(C1-C8)alkylamino, SH, (C1-C8)alkylthio, (C3-C8)heterocyclyl, carboxylates and their esters, carboxy(C1-C8)alkyl, CONHR C36 and CONR C36 R C37 and R C36 and R C37 are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 ) aryl; optionally, R C50 and R C51 can be joined together to form a 3- to 8-membered ring; Y 4 , O, NR C53 , S, or CR C54 R C55 is or is not present; R C52 is hydrogen, (C1-C8) alkyl, (C3-C8) cycloalkyl, (C2-C8) alkenyl, (C5-C8) cycloalkenyl, (C3-C8) heterocyclyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10)aryl; wherein each (C1-C8)alkyl, (C3-C8)cycloalkyl, (C2-C8)alkenyl, (C5-C8)cycloalkenyl, (C3-C8)heterocyclyl, (C6-C 10 )aryl or (C1-C8)alkylene (C6-C 10 )Aryl is (C1-C8)alkyl, halo, hydroxy, (C1-C8)alkoxy, amino, (C1-C8)alkylamino, di(C1-C8)alkylamino, SH, (C1-C8)alkylthio, (C3-C8)heterocyclyl, carboxylates and their esters, carboxy(C1-C8)alkyl, CONHR C56 and CONR C56 R C57 and R C56 and R C57 are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 ) aryl; R C53 is hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 ) aryl; R C54 and R C55 are each independently hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 ) aryl; or J is hydrogen, (C1-C8) alkyl, (C3-C8) cycloalkyl, (C2-C8) alkenyl, (C5-C8) cycloalkenyl, (C3-C8) heterocyclyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10)aryl; wherein each (C1-C8)alkyl, (C3-C8)cycloalkyl, (C2-C8)alkenyl, (C5-C8)cycloalkenyl, (C3-C8)heterocyclyl, (C6-C 10 )aryl or (C1-C8)alkylene (C6-C 10 )Aryl is (C1-C8)alkyl, halo, hydroxy, (C1-C8)alkoxy, amino, (C1-C8)alkylamino, di(C1-C8)alkylamino, SH, (C1-C8)alkylthio, (C3-C8)heterocyclyl, carboxylates and their esters, carboxy(C1-C8)alkyl, CONHR C46 and CONR C46 R C47 and R C46 and R C47 are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 ) aryl; and n is an integer ranging from 1 to 20.

[0013] In some embodiments, the conjugate has the formula (Ia1), or a pharmaceutically acceptable salt or solvate thereof: TIFF2025542295000006.tif37128 where RBM, L, M, X, D, Y 1 , A, Y 3 , J and n are as defined herein.

[0014] The present invention also relates to a compound having formula (II), or a pharmaceutically acceptable salt or solvate thereof: TIFF2025542295000007.tif23128 formula, L* is a linker capable of forming a covalent connection to a receptor binding molecule (RBM); M, O, NR M60 , or S; R M60 is hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 ) aryl; U is O or S; X is O, S, or NR X10 and; R X10 is hydrogen; or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; D is a drug moiety; Y 1 is NR A20 , O, S, or CR A21 R A22 and; R A20 is hydrogen, (C1-C8) alkyl, (C6-C 10 ) aryl, and C1-C8) alkylene (C6-C 10 ) aryl; R A21 and R A22 are each independently hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 ) aryl; E is a spacer; Z is a cleavable group; and W is a spacer E, Y after cleavage of group Z. 1 and a moiety that can form a ring together with the phosphorus atom.

[0015] The present invention also relates to a compound having formula (IIa), or a pharmaceutically acceptable salt or solvate thereof: TIFF2025542295000008.tif29128In formula, L* is a linker capable of forming a covalent connection to a receptor binding molecule (RBM); M, O, NR M60 , or S; R M60is hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 ) aryl; X is O, S, or NR X10 and; R X10 is hydrogen; or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; D is a drug moiety; Y 1 is NR A20 , O, S, or CR A21 R A22 and; R A20 is hydrogen, (C1-C8) alkyl, (C6-C 10 ) aryl, and C1-C8) alkylene (C6-C 10 ) aryl; R A21 and R A22 are each independently hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 ) aryl; A is CR A30 R A31 or A is (C1-C8)alkylene, where (C1-C8)alkylene is selected from the group consisting of (C1-C8)alkyl, halo, hydroxy, (C1-C8)alkoxy, amino, (C1-C8)alkylamino, di(C1-C8)alkylamino, SH, (C1-C8)alkylthio, (C3-C8)heterocyclyl, carboxylates and esters thereof, carboxy(C1-C8)alkyl, CONHR A36 and CONR A36 R A37 and R A36 and R A37 are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10) aryl or (C6-C 10 ) aryl; R A30 and R A31 are each independently hydrogen, (C1-C8) alkyl, (C3-C8) cycloalkyl, (C2-C8) alkenyl, (C5-C8) cycloalkenyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 )aryl; wherein each of (C1-C8)alkyl, (C3-C8)cycloalkyl, (C2-C8)alkenyl, (C5-C8)cycloalkenyl, (C6-C 10 )aryl or (C1-C8)alkylene (C6-C 10 )Aryl is (C1-C8)alkyl, halo, hydroxy, (C1-C8)alkoxy, amino, (C1-C8)alkylamino, di(C1-C8)alkylamino, SH, (C1-C8)alkylthio, (C3-C8)heterocyclyl, carboxylates and their esters, carboxy(C1-C8)alkyl, CONHR A36 and CONR A36 R A37 and R A36 and R A37 are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 ) aryl; optionally, R A30 and R A31 can be joined together to form a 3- to 8-membered ring; Y 2 is NR B20 , O, S, or CR B21 R B22 and; R B20 is hydrogen, (C1-C8) alkyl, (C6-C 10 ) aryl, and C1-C8) alkylene (C6-C 10 ) aryl; R B21 and RB22 are each independently hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 ) aryl; B is independently CR B30 R B31 or B is, independently at each occurrence, (C1-C8)alkylene, where (C1-C8)alkylene is selected from (C1-C8)alkyl, halo, hydroxy, (C1-C8)alkoxy, amino, (C1-C8)alkylamino, di(C1-C8)alkylamino, SH, (C1-C8)alkylthio, (C3-C8)heterocyclyl, carboxylates and esters thereof, carboxy(C1-C8)alkyl, CONHR B36 and CONR B36 R B37 and R B36 and R B37 are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 ) aryl; R B30 and R B31 are each independently hydrogen, (C1-C8) alkyl, (C3-C8) cycloalkyl, (C2-C8) alkenyl, (C5-C8) cycloalkenyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 )aryl; wherein each of (C1-C8)alkyl, (C3-C8)cycloalkyl, (C2-C8)alkenyl, (C5-C8)cycloalkenyl, (C6-C 10 )aryl or (C1-C8)alkylene (C6-C 10)Aryl is (C1-C8)alkyl, halo, hydroxy, (C1-C8)alkoxy, amino, (C1-C8)alkylamino, di(C1-C8)alkylamino, SH, (C1-C8)alkylthio, (C3-C8)heterocyclyl, carboxylates and their esters, carboxy(C1-C8)alkyl, CONHR B36 and CONR B36 R B37 and R B36 and R B37 are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 ) aryl; optionally, R B30 and R B31 can be joined together to form a 3- to 8-membered ring; m is an integer ranging from 0 to 15; Y 3 , O, NR C40 , or S, or absent; R C40 is hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 ) aryl; J is TIFF2025542295000009.tif18128, where TIFF2025542295000010.tif7128 is Y 3 Indicates the connection to; C is CR C50 R C51 or C is (C1-C8) alkylene, where (C1-C8) alkylene is selected from the group consisting of (C1-C8) alkyl, halo, hydroxy, (C1-C8) alkoxy, amino, (C1-C8) alkylamino, di(C1-C8) alkylamino, SH, (C1-C8) alkylthio, (C3-C8) heterocyclyl, carboxylates and esters thereof, carboxy(C1-C8) alkyl, CONHR C36 and CONR C36 R C37 and R C36 and R C37 are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 ) aryl; R C50 and R C51 are each independently hydrogen, (C1-C8) alkyl, (C3-C8) cycloalkyl, (C2-C8) alkenyl, (C5-C8) cycloalkenyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 )aryl; wherein each of (C1-C8)alkyl, (C3-C8)cycloalkyl, (C2-C8)alkenyl, (C5-C8)cycloalkenyl, (C6-C 10 )aryl or (C1-C8)alkylene (C6-C 10 )Aryl is (C1-C8)alkyl, halo, hydroxy, (C1-C8)alkoxy, amino, (C1-C8)alkylamino, di(C1-C8)alkylamino, SH, (C1-C8)alkylthio, (C3-C8)heterocyclyl, carboxylates and their esters, carboxy(C1-C8)alkyl, CONHR C36 and CONR C36 R C37 and R C36 and R C37are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 ) aryl; optionally, R C50 and R C51 can be joined together to form a 3- to 8-membered ring; Y 4 , O, NR C53 , S, or CR C54 R C55 is or is not present; R C52 is hydrogen, (C1-C8) alkyl, (C3-C8) cycloalkyl, (C2-C8) alkenyl, (C5-C8) cycloalkenyl, (C3-C8) heterocyclyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 )aryl; wherein each (C1-C8)alkyl, (C3-C8)cycloalkyl, (C2-C8)alkenyl, (C5-C8)cycloalkenyl, (C3-C8)heterocyclyl, (C6-C 10 )aryl or (C1-C8)alkylene (C6-C 10 )Aryl is (C1-C8)alkyl, halo, hydroxy, (C1-C8)alkoxy, amino, (C1-C8)alkylamino, di(C1-C8)alkylamino, SH, (C1-C8)alkylthio, (C3-C8)heterocyclyl, carboxylates and their esters, carboxy(C1-C8)alkyl, CONHR C56 and CONR C56 R C57 and R C56 and R C57 are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 ) aryl; R C53 is hydrogen, (C1-C8) alkyl, (C6-C 10)aryl, and (C1-C8)alkylene (C6-C 10 ) aryl; R C54 and R C55 are each independently hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 ) aryl; or J is hydrogen, (C1-C8) alkyl, (C3-C8) cycloalkyl, (C2-C8) alkenyl, (C5-C8) cycloalkenyl, (C3-C8) heterocyclyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 )aryl; wherein each (C1-C8)alkyl, (C3-C8)cycloalkyl, (C2-C8)alkenyl, (C5-C8)cycloalkenyl, (C3-C8)heterocyclyl, (C6-C 10 )aryl or (C1-C8)alkylene (C6-C 10 )Aryl is (C1-C8)alkyl, halo, hydroxy, (C1-C8)alkoxy, amino, (C1-C8)alkylamino, di(C1-C8)alkylamino, SH, (C1-C8)alkylthio, (C3-C8)heterocyclyl, carboxylates and their esters, carboxy(C1-C8)alkyl, CONHR C46 and CONR C46 R C47 and R C46 and R C47 are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 ) aryl.

[0016] In some embodiments, the compound has the formula (IIa1), or a pharmaceutically acceptable salt or solvate thereof: TIFF2025542295000011.tif29128 where L*, M, X, D, Y 1 , A, Y 3 and J is as defined herein.

[0017] The present invention also relates to a method for preparing a conjugate of formula (I), said method comprising: A compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof: TIFF2025542295000012.tif22128 (in the formula, L* is a linker capable of forming a covalent connection to a receptor binding molecule (RBM); M, O, NR M60 , or S; R M60 is hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 ) aryl; U is O or S; X is O, S, or NR X10 and; R X10 is hydrogen; or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; D is a drug moiety; Y 1 is NR A20 , O, S, or CR A21 R A22 and; R A20 is hydrogen, (C1-C8) alkyl, (C6-C 10 ) aryl, and C1-C8) alkylene (C6-C 10 ) aryl; R A21 and R A22 are each independently hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 ) aryl; E is a spacer; Z is a cleavable group; and W is a spacer E, Y after cleavage of group Z. 1 and a moiety capable of forming a ring together with phosphorus), a receptor binding molecule (RBM) having a functional group reactive to L* of the compound of formula (II); thereby forming a covalent bond between the receptor binding molecule (RBM) and the linker (L), A conjugate of formula (I), or a pharmaceutically acceptable salt or solvate thereof: TIFF2025542295000013.tif35128 (in the formula, RBM is a receptor binding molecule; L is a linker; M, O, NR M60 , or S; R M60 is hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 ) aryl; U is O or S; X is O, S, or NR X10 and; R X10 is hydrogen; or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; D is a drug moiety; Y 1 is NR A20 , O, S, or CR A21 R A22 and; R A20 is hydrogen, (C1-C8) alkyl, (C6-C 10 ) aryl, and C1-C8) alkylene (C6-C 10 ) aryl; R A21 and R A22 are each independently hydrogen, (C1-C8) alkyl, (C6-C 10)aryl, and (C1-C8)alkylene (C6-C 10 ) aryl; E is a spacer; Z is a cleavable group; W is a spacer E, Y after cleavage of group Z. 1 and a moiety capable of forming a ring together with phosphorus; and n is an integer ranging from 1 to 20. The step of generating Includes.

[0018] The present invention also relates to a method for preparing a conjugate of formula (Ia), the method comprising: A compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof: TIFF2025542295000014.tif31128 (in the formula, L* is a linker capable of forming a covalent connection to a receptor binding molecule (RBM); M, O, NR M60 , or S; R M60 is hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 ) aryl; X is O, S, or NR X10 and; R X10 is hydrogen; or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; D is a drug moiety; Y 1 is NR A20 , O, S, or CR A21 R A22 and; R A20 is hydrogen, (C1-C8) alkyl, (C6-C 10 ) aryl, and C1-C8) alkylene (C6-C 10 ) aryl; R A21and R A22 are each independently hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 ) aryl; A is CR A30 R A31 or A is (C1-C8)alkylene, where (C1-C8)alkylene is selected from the group consisting of (C1-C8)alkyl, halo, hydroxy, (C1-C8)alkoxy, amino, (C1-C8)alkylamino, di(C1-C8)alkylamino, SH, (C1-C8)alkylthio, (C3-C8)heterocyclyl, carboxylates and esters thereof, carboxy(C1-C8)alkyl, CONHR A36 and CONR A36 R A37 and R A36 and R A37 are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 ) aryl; R A30 and R A31 are each independently hydrogen, (C1-C8) alkyl, (C3-C8) cycloalkyl, (C2-C8) alkenyl, (C5-C8) cycloalkenyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 )aryl; wherein each of (C1-C8)alkyl, (C3-C8)cycloalkyl, (C2-C8)alkenyl, (C5-C8)cycloalkenyl, (C6-C 10 )aryl or (C1-C8)alkylene (C6-C 10)Aryl is (C1-C8)alkyl, halo, hydroxy, (C1-C8)alkoxy, amino, (C1-C8)alkylamino, di(C1-C8)alkylamino, SH, (C1-C8)alkylthio, (C3-C8)heterocyclyl, carboxylates and their esters, carboxy(C1-C8)alkyl, CONHR A36 and CONR A36 R A37 and R A36 and R A37 are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 ) aryl; optionally, R A30 and R A31 can be joined together to form a 3- to 8-membered ring; Y 2 is NR B20 , O, S, or CR B21 R B22 and; R B20 is hydrogen, (C1-C8) alkyl, (C6-C 10 ) aryl, and C1-C8) alkylene (C6-C 10 ) aryl; R B21 and R B22 are each independently hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 ) aryl; B is independently CR B30 R B31 or B is, independently at each occurrence, (C1-C8)alkylene, where (C1-C8)alkylene is selected from (C1-C8)alkyl, halo, hydroxy, (C1-C8)alkoxy, amino, (C1-C8)alkylamino, di(C1-C8)alkylamino, SH, (C1-C8)alkylthio, (C3-C8)heterocyclyl, carboxylates and esters thereof, carboxy(C1-C8)alkyl, CONHR B36 and CONR B36 R B37 and R B36 and R B37 are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 ) aryl; R B30 and R B31 are each independently hydrogen, (C1-C8) alkyl, (C3-C8) cycloalkyl, (C2-C8) alkenyl, (C5-C8) cycloalkenyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 )aryl; wherein each of (C1-C8)alkyl, (C3-C8)cycloalkyl, (C2-C8)alkenyl, (C5-C8)cycloalkenyl, (C6-C 10 )aryl or (C1-C8)alkylene (C6-C 10 )Aryl is (C1-C8)alkyl, halo, hydroxy, (C1-C8)alkoxy, amino, (C1-C8)alkylamino, di(C1-C8)alkylamino, SH, (C1-C8)alkylthio, (C3-C8)heterocyclyl, carboxylates and their esters, carboxy(C1-C8)alkyl, CONHR B36 and CONR B36 R B37 and R B36 and R B37are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 ) aryl; optionally, R B30 and R B31 can be joined together to form a 3- to 8-membered ring; m is an integer ranging from 0 to 15; Y 3 , O, NR C40 , or S, or absent; R C40 is hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 ) aryl; J is TIFF2025542295000015.tif18128, where TIFF2025542295000016.tif7128 is Y 3 Indicates the connection to; C is CR C50 R C51 or C is (C1-C8) alkylene, where (C1-C8) alkylene is selected from the group consisting of (C1-C8) alkyl, halo, hydroxy, (C1-C8) alkoxy, amino, (C1-C8) alkylamino, di(C1-C8) alkylamino, SH, (C1-C8) alkylthio, (C3-C8) heterocyclyl, carboxylates and esters thereof, carboxy(C1-C8) alkyl, CONHR C36 and CONR C36 R C37 and R C36 and R C37 are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 ) aryl; R C50 and R C51are each independently hydrogen, (C1-C8) alkyl, (C3-C8) cycloalkyl, (C2-C8) alkenyl, (C5-C8) cycloalkenyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 )aryl; wherein each of (C1-C8)alkyl, (C3-C8)cycloalkyl, (C2-C8)alkenyl, (C5-C8)cycloalkenyl, (C6-C 10 )aryl or (C1-C8)alkylene (C6-C 10 )Aryl is (C1-C8)alkyl, halo, hydroxy, (C1-C8)alkoxy, amino, (C1-C8)alkylamino, di(C1-C8)alkylamino, SH, (C1-C8)alkylthio, (C3-C8)heterocyclyl, carboxylates and their esters, carboxy(C1-C8)alkyl, CONHR C36 and CONR C36 R C37 and R C36 and R C37 are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 ) aryl; optionally, R C50 and R C51 can be joined together to form a 3- to 8-membered ring; Y 4 , O, NR C53 , S, or CR C54 R C55 is or is not present; R C52 is hydrogen, (C1-C8) alkyl, (C3-C8) cycloalkyl, (C2-C8) alkenyl, (C5-C8) cycloalkenyl, (C3-C8) heterocyclyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10)aryl; wherein each (C1-C8)alkyl, (C3-C8)cycloalkyl, (C2-C8)alkenyl, (C5-C8)cycloalkenyl, (C3-C8)heterocyclyl, (C6-C 10 )aryl or (C1-C8)alkylene (C6-C 10 )Aryl is (C1-C8)alkyl, halo, hydroxy, (C1-C8)alkoxy, amino, (C1-C8)alkylamino, di(C1-C8)alkylamino, SH, (C1-C8)alkylthio, (C3-C8)heterocyclyl, carboxylates and their esters, carboxy(C1-C8)alkyl, CONHR C56 and CONR C56 R C57 and R C56 and R C57 are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 ) aryl; R C53 is hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 ) aryl; R C54 and R C55 are each independently hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 ) aryl; or J is hydrogen, (C1-C8) alkyl, (C3-C8) cycloalkyl, (C2-C8) alkenyl, (C5-C8) cycloalkenyl, (C3-C8) heterocyclyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10)aryl; wherein each (C1-C8)alkyl, (C3-C8)cycloalkyl, (C2-C8)alkenyl, (C5-C8)cycloalkenyl, (C3-C8)heterocyclyl, (C6-C 10 )aryl or (C1-C8)alkylene (C6-C 10 )Aryl is (C1-C8)alkyl, halo, hydroxy, (C1-C8)alkoxy, amino, (C1-C8)alkylamino, di(C1-C8)alkylamino, SH, (C1-C8)alkylthio, (C3-C8)heterocyclyl, carboxylates and their esters, carboxy(C1-C8)alkyl, CONHR C46 and CONR C46 R C47 and R C46 and R C47 are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 ) aryl) and a receptor binding molecule (RBM) having a functional group reactive to L* of the compound of formula (IIa); thereby forming a covalent bond between the receptor binding molecule (RBM) and the linker (L), A conjugate of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof: TIFF2025542295000017.tif35128 (in the formula, RBM is a receptor binding molecule; L is a linker; M, O, NR M60 , or S; R M60 is hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 ) aryl; X is O, S, or NR X10 and; RX10 is hydrogen; or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; D is a drug moiety; Y 1 is NR A20 , O, S, or CR A21 R A22 and; R A20 is hydrogen, (C1-C8) alkyl, (C6-C 10 ) aryl, and C1-C8) alkylene (C6-C 10 ) aryl; R A21 and R A22 are each independently hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 ) aryl; A is CR A30 R A31 or A is (C1-C8)alkylene, where (C1-C8)alkylene is selected from the group consisting of (C1-C8)alkyl, halo, hydroxy, (C1-C8)alkoxy, amino, (C1-C8)alkylamino, di(C1-C8)alkylamino, SH, (C1-C8)alkylthio, (C3-C8)heterocyclyl, carboxylates and esters thereof, carboxy(C1-C8)alkyl, CONHR A36 and CONR A36 R A37 and R A36 and R A37 are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 ) aryl; R A30 and R A31are each independently hydrogen, (C1-C8) alkyl, (C3-C8) cycloalkyl, (C2-C8) alkenyl, (C5-C8) cycloalkenyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 )aryl; wherein each of (C1-C8)alkyl, (C3-C8)cycloalkyl, (C2-C8)alkenyl, (C5-C8)cycloalkenyl, (C6-C 10 )aryl or (C1-C8)alkylene (C6-C 10 )Aryl is (C1-C8)alkyl, halo, hydroxy, (C1-C8)alkoxy, amino, (C1-C8)alkylamino, di(C1-C8)alkylamino, SH, (C1-C8)alkylthio, (C3-C8)heterocyclyl, carboxylates and their esters, carboxy(C1-C8)alkyl, CONHR A36 and CONR A36 R A37 and R A36 and R A37 are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 ) aryl; optionally, R A30 and R A31 can be joined together to form a 3- to 8-membered ring; Y 2 is NR B20 , O, S, or CR B21 R B22 and; R B20 is hydrogen, (C1-C8) alkyl, (C6-C 10 ) aryl, and C1-C8) alkylene (C6-C 10 ) aryl; R B21 and R B22 are each independently hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C10 ) aryl; B is independently CR B30 R B31 or B is, independently at each occurrence, (C1-C8)alkylene, where (C1-C8)alkylene is selected from (C1-C8)alkyl, halo, hydroxy, (C1-C8)alkoxy, amino, (C1-C8)alkylamino, di(C1-C8)alkylamino, SH, (C1-C8)alkylthio, (C3-C8)heterocyclyl, carboxylates and esters thereof, carboxy(C1-C8)alkyl, CONHR B36 and CONR B36 R B37 and R B36 and R B37 are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 ) aryl; R B30 and R B31 are each independently hydrogen, (C1-C8) alkyl, (C3-C8) cycloalkyl, (C2-C8) alkenyl, (C5-C8) cycloalkenyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 )aryl; wherein each of (C1-C8)alkyl, (C3-C8)cycloalkyl, (C2-C8)alkenyl, (C5-C8)cycloalkenyl, (C6-C 10 )aryl or (C1-C8)alkylene (C6-C 10 )Aryl is (C1-C8)alkyl, halo, hydroxy, (C1-C8)alkoxy, amino, (C1-C8)alkylamino, di(C1-C8)alkylamino, SH, (C1-C8)alkylthio, (C3-C8)heterocyclyl, carboxylates and their esters, carboxy(C1-C8)alkyl, CONHR B36 and CONR B36 RB37 and R B36 and R B37 are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 ) aryl; optionally, R B30 and R B31 can be joined together to form a 3- to 8-membered ring; m is an integer ranging from 0 to 15; Y 3 , O, NR C40 , or S, or absent; R C40 is hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 ) aryl; J is TIFF2025542295000018.tif18128, where TIFF2025542295000019.tif7128 is Y 3 Indicates the connection to; C is CR C50 R C51 or C is (C1-C8) alkylene, where (C1-C8) alkylene is selected from the group consisting of (C1-C8) alkyl, halo, hydroxy, (C1-C8) alkoxy, amino, (C1-C8) alkylamino, di(C1-C8) alkylamino, SH, (C1-C8) alkylthio, (C3-C8) heterocyclyl, carboxylates and esters thereof, carboxy(C1-C8) alkyl, CONHR C36 and CONR C36 R C37 and R C36 and R C37 are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C10 ) aryl or (C6-C 10 ) aryl; R C50 and R C51 are each independently hydrogen, (C1-C8) alkyl, (C3-C8) cycloalkyl, (C2-C8) alkenyl, (C5-C8) cycloalkenyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 )aryl; wherein each of (C1-C8)alkyl, (C3-C8)cycloalkyl, (C2-C8)alkenyl, (C5-C8)cycloalkenyl, (C6-C 10 )aryl or (C1-C8)alkylene (C6-C 10 )Aryl is (C1-C8)alkyl, halo, hydroxy, (C1-C8)alkoxy, amino, (C1-C8)alkylamino, di(C1-C8)alkylamino, SH, (C1-C8)alkylthio, (C3-C8)heterocyclyl, carboxylates and their esters, carboxy(C1-C8)alkyl, CONHR C36 and CONR C36 R C37 and R C36 and R C37 are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 ) aryl; optionally, R C50 and R C51 can be joined together to form a 3- to 8-membered ring; Y 4 , O, NR C53 , S, or CR C54 R C55 is or is not present; R C52 is hydrogen, (C1-C8) alkyl, (C3-C8) cycloalkyl, (C2-C8) alkenyl, (C5-C8) cycloalkenyl, (C3-C8) heterocyclyl, (C6-C 10)aryl, and (C1-C8)alkylene (C6-C 10 )aryl; wherein each (C1-C8)alkyl, (C3-C8)cycloalkyl, (C2-C8)alkenyl, (C5-C8)cycloalkenyl, (C3-C8)heterocyclyl, (C6-C 10 )aryl or (C1-C8)alkylene (C6-C 10 )Aryl is (C1-C8)alkyl, halo, hydroxy, (C1-C8)alkoxy, amino, (C1-C8)alkylamino, di(C1-C8)alkylamino, SH, (C1-C8)alkylthio, (C3-C8)heterocyclyl, carboxylates and their esters, carboxy(C1-C8)alkyl, CONHR C56 and CONR C56 R C57 and R C56 and R C57 are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 ) aryl; R C53 is hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 ) aryl; R C54 and R C55 are each independently hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 ) aryl; or J is hydrogen, (C1-C8) alkyl, (C3-C8) cycloalkyl, (C2-C8) alkenyl, (C5-C8) cycloalkenyl, (C3-C8) heterocyclyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10)aryl; wherein each (C1-C8)alkyl, (C3-C8)cycloalkyl, (C2-C8)alkenyl, (C5-C8)cycloalkenyl, (C3-C8)heterocyclyl, (C6-C 10 )aryl or (C1-C8)alkylene (C6-C 10 )Aryl is (C1-C8)alkyl, halo, hydroxy, (C1-C8)alkoxy, amino, (C1-C8)alkylamino, di(C1-C8)alkylamino, SH, (C1-C8)alkylthio, (C3-C8)heterocyclyl, carboxylates and their esters, carboxy(C1-C8)alkyl, CONHR C46 and CONR C46 R C47 and R C46 and R C47 are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 ) aryl; and n is an integer ranging from 1 to 20. The step of generating Includes.

[0019] In some embodiments, the method comprises: A compound of formula (IIa1), or a pharmaceutically acceptable salt or solvate thereof: TIFF2025542295000020.tif29128 (where L*, M, X, D, Y 1 , A, Y 3 and J is as defined herein), a receptor binding molecule (RBM) having a functional group reactive to L* of the compound of formula (IIa1); thereby forming a covalent bond between the receptor binding molecule (RBM) and the linker (L), A conjugate of formula (Ia1), or a pharmaceutically acceptable salt or solvate thereof: TIFF2025542295000021.tif35128 (in the formula, RBM, L, M, X, D, Y 1 A, Y 3 , J and n are as defined herein. The step of generating Includes.

[0020] The present invention also relates to a conjugate obtainable or obtained by the method of the present invention, or a pharmaceutically acceptable salt or solvate thereof.

[0021] The present invention also relates to pharmaceutical compositions comprising the conjugates of the present invention.

[0022] The present invention also relates to a conjugate of the present invention for use in a method of treating a disease. The disease may be cancer.

[0023] The present invention also relates to a pharmaceutical composition of the present invention for use in a method of treating a disease. The disease may be cancer. [Brief explanation of the drawings]

[0024] [Figure 1] 1 shows an HPLC / UV chromatogram of the compound L-alanine-4-methylbenzylamide. [Figure 2] 1 shows the HPLC / UV chromatogram of compound P5(PEG12)-COOH. [Figure 3] 1 shows the HPLC / UV chromatogram of the compound O-(5-tert.-butoxy-carbonyl-aminopentyl)-N-(L-alanine-tert.-butyl ester)-O-(SN38)-phosphoramidate. [Figure 4] 1 shows the HPLC / UV chromatogram of the compound O-(5-tert.-butoxy-carbonyl-aminopentyl)-N-(4-methylbenzyl)-O-(SN38)-phosphoramidate. [Figure 5]1 shows the HPLC / UV chromatogram of the compound O-(5-tert.-butoxy-carbonyl-aminopentyl)-N-(L-alanine-4-methylbenzylamide)-O-(SN38)-phosphoramidate. [Figure 6] 1 shows the HPLC / UV chromatogram of the compound O-(5-tert.-butoxy-carbonyl-aminopentyl)-N-(L-alanine-L-alanine-tert.-butyl ester)-O-(SN38)-phosphoramidate. [Figure 7] 1 shows the HPLC / UV chromatogram of the compound O-(5-tert.-butoxy-carbonyl-aminopentyl)-N-(β-alanine-L-alanine-tert.-butyl ester)-O-(SN38)-phosphoramidate. [Figure 8] 1 shows the HPLC / UV chromatogram of the compound O-(5-tert.-butoxy-carbonyl-aminopentyl)-N-(L-alanine-tert.-butyl ester)-O-(DxD)-phosphoramidate. [Figure 9] 1 shows the HPLC / UV chromatogram of the compound O-(5-tert.-butoxy-carbonyl-aminopentyl)-N-(L-alanine-L-alanine-tert.-butyl ester)-O-(DxD)-phosphoramidate. [Figure 10] 1 shows the HPLC / UV chromatogram of the compound di-O-(5-tert.-butoxy-carbonyl-aminopentyl)-O-(SN38)-phosphate. [Figure 11] 1 shows the HPLC / UV chromatogram of the compound O-(P5(OEt)-amidopentyl)-N-(L-alanine-tert.-butyl ester)-O-(SN38)-phosphoramidate. [Figure 12] 1 shows the HPLC / UV chromatogram of the compound O-(P5(PEG2)-amidopentyl)-N-(L-alanine-tert.-butyl ester)-O-(SN38)-phosphoramidate. [Figure 13]1 shows the HPLC / UV chromatogram of the compound O-(P5(PEG12)-amidopentyl)-N-(L-alanine-tert.-butyl ester)-O-(SN38)-phosphoramidate. [Figure 14] FIG. 1 shows the HPLC / UV chromatogram of the compound O-(P5(PEG12)-amidopentyl)-N-(4-methylbenzyl)-O-(SN38)-phosphoramidate. [Figure 15] 1 shows the HPLC / UV chromatogram of the compound O-(P5(PEG12)-amidopentyl)-N-(L-alanine-L-alanine-tert.-butyl ester)-O-(SN38)-phosphoramidate. [Figure 16] 1 shows the HPLC / UV chromatogram of the compound O-(P5(PEG12)-amidopentyl)-N-(β-alanine-L-alanine-tert.-butyl ester)-O-(SN38)-phosphoramidate. [Figure 17] Figure 1 shows the HPLC / UV chromatogram of compound O-P5(PEG12)-amidopentyl-phosphate-O-(5-aminopentyl)-O-SN38-phosphate TFA salt. [Figure 18] 1 shows the HPLC / UV chromatogram of the compound O-(P5(PEG2)-amidopentyl)-N-(L-alanine-L-alanine-tert.-butyl ester)-O-(DxD)-phosphoramidate. [Figure 19] 1 shows the HPLC / UV chromatogram of the compound O-(P5(PEG2)-amidopentyl)-N-(L-alanine-tert.-butyl ester)-O-(DxD)-phosphoramidate. [Figure 20] FIG. 1 shows the HPLC / UV chromatogram of the compound O-(P5(PEG2)-amidopentyl)-N-(L-alanine-L-alanine-COOH)-O-(DxD)-phosphoramidate. [Figure 21] Figure 1 shows an analytical SEC chromatogram of trastuzumab, where SEC stands for size exclusion chromatography. [Figure 22]1 shows an analytical HIC chromatogram of trastuzumab, where HIC stands for hydrophobic interaction chromatography. [Figure 23] 1 shows an analytical SEC chromatogram of sacituzumab. [Figure 24] 1 shows an analytical HIC chromatogram of sacituzumab. [Figure 25] 1 shows an analytical SEC chromatogram of palivizumab. [Figure 26] 1 shows an analytical HIC chromatogram of palivizumab. [Figure 27] 1 shows an analytical SEC chromatogram of sacituzumab-O-P5(PEG2)-amidopentyl-phosphoramidate-N-(L-alanine-tert.-butyl ester)-O-SN38. [Figure 28] 1 shows an analytical HIC chromatogram of sacituzumab-O-P5(PEG2)-amidopentyl-phosphoramidate-N-(L-alanine-tert.-butyl ester)-O-SN38. [Figure 29] 1 shows an analytical SEC chromatogram of sacituzumab-O-P5(PEG12)-amidopentyl-phosphoramidate-N-(L-alanine-tert.-butyl ester)-O-SN38. [Figure 30] 1 shows an analytical HIC chromatogram of sacituzumab-O-P5(PEG12)-amidopentyl-phosphoramidate-N-(L-alanine-tert.-butyl ester)-O-SN38. [Figure 31] 1 shows an analytical SEC chromatogram of Palivizumab-O-P5(PEG12)-amidopentyl-phosphoramidate-N-(L-alanine-tert.-butyl ester)-O-SN38. [Figure 32] 1 shows an analytical HIC chromatogram of Palivizumab-O-P5(PEG12)-amidopentyl-phosphoramidate-N-(L-alanine-tert.-butyl ester)-O-SN38. [Figure 33]1 shows an analytical SEC chromatogram of trastuzumab-O-P5(PEG2)-amidopentyl-phosphoramidate-N-(L-alanine-tert.-butyl ester)-O-DxD. [Figure 34] 1 shows an analytical HIC chromatogram of trastuzumab-O-P5(PEG2)-amidopentyl-phosphoramidate-N-(L-alanine-tert.-butyl ester)-O-DxD. [Figure 35] 1 shows an analytical SEC chromatogram of Palivizumab-O-P5(PEG2)-amidopentyl-phosphoramidate-N-(L-alanine-tert.-butyl ester)-O-DxD. [Figure 36] 1 shows an analytical HIC chromatogram of Palivizumab-O-P5(PEG2)-amidopentyl-phosphoramidate-N-(L-alanine-tert.-butyl ester)-O-DxD. [Figure 37] 1 shows an analytical SEC chromatogram of trastuzumab-O-P5(PEG2)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine-tert.-butyl ester)-O-DxD. [Figure 38] 1 shows an analytical HIC chromatogram of trastuzumab-O-P5(PEG2)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine-tert.-butyl ester)-O-DxD. [Figure 39] 1 shows an analytical SEC chromatogram of palivizumab-O-P5(PEG2)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine-tert.-butyl ester)-O-DxD. [Figure 40] 1 shows an analytical HIC chromatogram of Palivizumab-O-P5(PEG2)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine-tert.-butyl ester)-O-DxD. [Figure 41] 1 shows an analytical SEC chromatogram of trastuzumab-O-P5(PEG2)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine-COOH)-O-DxD. [Figure 42] 1 shows an analytical HIC chromatogram of trastuzumab-O-P5(PEG2)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine-COOH)-O-DxD. [Figure 43] 1 shows an analytical SEC chromatogram of Palivizumab-O-P5(PEG2)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine-COOH)-O-DxD. [Figure 44] 1 shows an analytical HIC chromatogram of Palivizumab-O-P5(PEG2)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine-COOH)-O-DxD. [Figure 45-1] 1 shows the results of a direct comparison of an O-P5(PEG12)-amidopentyl-phosphoramidate-N-(L-alanine-tert-butyl ester)-O-SN38-derived ADC according to an embodiment of the present invention with the CLA-SN38-derived ADC used in Trodelvi. The linkers were conjugated to sacituzumab (anti-Trop2) and trastuzumab (anti-Her2, isotype in this setting) and tested in a panel of four different cell lines. All cell lines were Trop+ and Her2-. The trastuzumab conjugate served as an isotype control in this setting. The left panel shows the O-P5(PEG12)-amidopentyl-phosphoramidate-N-(L-alanine-tert-butyl ester)-O-SN38-derived conjugate. The right panel shows the CL2A-SN38-derived conjugate. The solid line represents the sacituzumab conjugate, and the dotted line represents the trastuzumab conjugate. Sacituzumab-Cl2A-SN38 was purchased from Trodelvi and used for the experiments. Trastuzumab-CL2A-SN38 was prepared using the commercially available CL2A linker for the purposes of these experiments. [Figure 45-2] See description of Figure 45-1. [Figure 46]FIG. 1 shows the in vitro potency of an ADC comprising sacituzumab conjugated to cleavable O-P5(PEG12)-amidopentyl-phosphoramidate-N-(L-alanine-tert.-butyl ester)-O-SN38 according to an embodiment of the invention (solid line), and the in vitro potency of an ADC comprising sacituzumab conjugated to non-cleavable control O-P5(PEG12)-amidopentyl-phosphoramidate-N-(4-methylbenzyl)-O-SN38 (dashed line). [Figure 47]

[0023] Figure 1 shows the results of an in vitro potency assay of ADCs derived from compound O-P5(PEG2)-amidopentyl-phosphoramidate-N-(L-alanine-tert-butyl ester)-O-DxD and antibodies trastuzumab (anti-Her2, solid line) and palivizumab (isotype, dashed line). In vitro efficacy against targeted cell lines (SKBR-3, Her2+) and non-targeted cell lines (MDAMB-468, Her2-) is shown. [Figure 48]

[0023] Figure 1 shows the results of an in vitro potency assay of ADCs derived from compound O-P5(PEG2)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine-tert.-butyl ester)-O-DxD and antibodies trastuzumab (anti-Her2, solid line) and palivizumab (isotype, dashed line). In vitro efficacy against targeted cell lines (SKBR-3, Her2+) and non-targeted cell lines (MDAMB-468, Her2-) is shown. [Figure 49]

[0023] Figure 1 shows the results of an in vitro potency assay of ADCs derived from compound O-P5(PEG2)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine-COOH)-O-DxD and antibodies trastuzumab (anti-Her2, solid line) and palivizumab (isotype, dashed line). In vitro efficacy against targeted cell lines (SKBR-3, Her2+) and non-targeted cell lines (MDAMB-468, Her2-) is shown. [Figure 50]1 shows the results of an in vitro efficacy assay of compound O-P5(PEG2)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine-COOH)-O-DxD and an ADC derived from trastuzumab (in accordance with an embodiment of the present invention, black) and Enherz (gray). In vitro efficacy is shown against targeted cell lines (SKBR-3, Her2+) and non-targeted cell lines (MDAMB-468, Her2-). [Figure 51] 1 shows the results of a direct comparison of an ADC derived from the compound O-P5(PEG12)-amidopentyl-phosphoramidate-N-(L-alanine-tert.-butyl ester)-O-SN38 conjugated to sacituzumab (in accordance with an embodiment of the invention, solid line) with Trodelbi (dashed line) for stability in the presence of serum at 37° C. The drug-antibody ratio over time is shown as measured by mass spectrometry (MS) after pulldown from rat serum. [Figure 52] 1 shows the results of a direct comparison of an ADC derived from the compound O-P5(PEG2)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine-COOH)-O-DxD conjugated to trastuzumab (in accordance with an embodiment of the invention, solid line) with Enherz (dashed line) for stability in the presence of serum at 37° C. The drug-antibody ratio over time is shown as measured by mass spectrometry (MS) after pulldown from rat serum. [Figure 53] 1 shows the HPLC / UV chromatogram of the compound O-(5-tert.-butoxy-carbonyl-aminopentyl)-N-(β-alanine-L-alanine-tert.-butyl ester)-O-(DxD)-phosphoramidate. [Figure 54] 1 shows the HPLC / UV chromatogram of the compound O-(5-tert.-butoxy-carbonyl-aminopentyl)-N-(γ-aminobutyric acid-L-alanine-tert.-butyl ester)-O-(DxD)-phosphoramidate. [Figure 55]1 shows the HPLC / UV chromatogram of the compound O-(5-tert.-butoxy-carbonyl-aminopentyl)-N-(5-aminovaleric acid-L-alanine-tert.-butyl ester)-O-(DxD)-phosphoramidate. [Figure 56] 1 shows the HPLC / UV chromatogram of the compound O-(5-tert.-butoxy-carbonyl-aminopentyl)-N-(L-alanine-tert.-butyl ester)-O-(OTS-964)-phosphoramidate. [Figure 57] 1 shows the HPLC / UV chromatogram of the compound O-(5-tert.-butoxy-carbonyl-aminopentyl)-N-(L-alanine-tert.-butyl ester)-O-(ganetespib)-phosphoramidate. [Figure 58] 1 shows the HPLC / UV chromatogram of the compound O-(5-tert.-butoxy-carbonyl-aminopentyl)-N-(L-alanine-tert.-butyl ester)-O-(bilabresive)-phosphoramidate. [Figure 59] 1 shows the HPLC / UV chromatogram of the compound O-(5-tert.-butoxy-carbonyl-aminopentyl)-N-(L-alanine-L-alanine-tert.-butyl)-O-(SNX-2112)-phosphoramidate. [Figure 60] 1 shows the HPLC / UV chromatogram of the compound O-(5-tert.-butoxy-carbonyl-aminopentyl)-N-(L-alanine-L-alanine-tert.-butyl)-O-(gemcitabine)-phosphoramidate. [Figure 61] 1 shows the HPLC / UV chromatogram of the compound O-(5-tert.-butoxy-carbonyl-aminopentyl)-N-(L-alanine-L-alanine-tert.-butyl)-O-(balasertib)-phosphoramidate. [Figure 62] 1 shows the HPLC / UV chromatogram of the compound O-(P5(PEG24)-amidopentyl)-N-(L-alanine-tert.-butyl ester)-O-(DxD)-phosphoramidate. [Figure 63]FIG. 1 shows the HPLC / UV chromatogram of the compound O-(P5(PEG24)-amidopentyl)-N-(L-alanine-L-alanine-COOH)-O-(DxD)-phosphoramidate. [Figure 64] FIG. 1 shows the HPLC / UV chromatogram of the compound O-(6-maleimidocaproic acid-amidopentyl)-N-(L-alanine-L-alanine-COOH)-O-(DxD)-phosphoramidate. [Figure 65] 1 shows the HPLC / UV chromatogram of the compound O-(iodoacetic acid-amidopentyl)-N-(L-alanine-L-alanine-COOH)-O-(DxD)-phosphoramidate. [Figure 66] FIG. 1 shows the HPLC / UV chromatogram of the compound O-(P5(PEG24)-amidopentyl)-N-(β-alanine-L-alanine-COOH)-O-(DxD)-phosphoramidate. [Figure 67] FIG. 1 shows the HPLC / UV chromatogram of the compound O-(P5(PEG24)-amidopentyl)-N-(γ-aminobutyric acid-L-alanine-COOH)-O-(DxD)-phosphoramidate. [Figure 68] FIG. 1 shows the HPLC / UV chromatogram of the compound O-(P5(PEG24)-amidopentyl)-N-(5-aminovaleric acid-L-alanine-COOH)-O-(DxD)-phosphoramidate. [Figure 69] 1 shows the HPLC / UV chromatogram of the compound O-(P5(PEG24)-amidopentyl)-N-(L-alanine-tert.-butyl ester)-O-(OTS-964)-phosphoramidate. [Figure 70] FIG. 1 shows the HPLC / UV chromatogram of the compound O-(P5(PEG24)-amidopentyl)-N-(L-alanine-tert.-butyl ester)-O-(ganetespib)-phosphoramidate. [Figure 71] 1 shows the HPLC / UV chromatogram of the compound O-(P5(PEG24)-amidopentyl)-N-(L-alanine-tert.-butyl ester)-O-(bilabresive)-phosphoramidate. [Figure 72] 1 shows the HPLC / UV chromatogram of the compound O-(P5(PEG24)-amidopentyl)-N-(L-alanine-L-alanine-tert.-butyl ester)-O-(SNX-2112)-phosphoramidate. [Figure 73] 1 shows the HPLC / UV chromatogram of the compound O-(P5(PEG24)-amidopentyl)-N-(L-alanine-L-alanine)-O-(SNX-2112)-phosphoramidate. [Figure 74] 1 shows the HPLC / UV chromatogram of the compound O-(P5(PEG24)-amidopentyl)-N-(L-alanine-L-alanine-tert.-butyl ester)-O-(gemcitabine)-phosphoramidate. [Figure 75] 1 shows the HPLC / UV chromatogram of the compound O-(P5(PEG24)-amidopentyl)-N-(L-alanine-L-alanine)-O-(gemcitabine)-phosphoramidate. [Figure 76] 1 shows the HPLC / UV chromatogram of the compound O-(P5(PEG24)-amidopentyl)-N-(L-alanine-L-alanine-tert.-butyl ester)-O-(balasertib)-phosphoramidate. [Figure 77] 1 shows the HPLC / UV chromatogram of the compound O-(P5(PEG24)-amidopentyl)-N-(L-alanine-L-alanine)-O-(balasertib)-phosphoramidate. [Figure 78] FIG. 1 shows an analytical SEC chromatogram of trastuzumab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-tert.-butyl ester)-O-OTS-964. [Figure 79] 1 shows an analytical HIC chromatogram of trastuzumab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-tert.-butyl ester)-O-OTS-964. [Figure 80]1 shows an analytical SEC chromatogram of Palivizumab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-tert.-butyl ester)-O-OTS-964. [Figure 81] 1 shows an analytical HIC chromatogram of Palivizumab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-tert.-butyl ester)-O-OTS-964. [Figure 82] 1 shows an analytical SEC chromatogram of trastuzumab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-tert.-butyl ester)-O-ganetespib. [Figure 83] 1 shows an analytical HIC chromatogram of trastuzumab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-tert.-butyl ester)-O-ganetespib. [Figure 84] 1 shows an analytical SEC chromatogram of palivizumab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-tert.-butyl ester)-O-ganetespib. [Figure 85] 1 shows an analytical HIC chromatogram of palivizumab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-tert.-butyl ester)-O-ganetespib. [Figure 86] 1 shows an analytical SEC chromatogram of trastuzumab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-tert.-butyl ester)-O-bilabresib. [Figure 87] 1 shows an analytical HIC chromatogram of trastuzumab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-tert.-butyl ester)-O-bilabresib. [Figure 88]1 shows an analytical SEC chromatogram of Palivizumab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-tert.-butyl ester)-O-bilabresib. [Figure 89] 1 shows an analytical HIC chromatogram of Palivizumab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-tert.-butyl ester)-O-bilabresib. [Figure 90] 1 shows an analytical SEC chromatogram of trastuzumab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine)-O-SNX-2112. [Figure 91] 1 shows an analytical HIC chromatogram of trastuzumab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine)-O-SNX-2112. [Figure 92] 1 shows an analytical SEC chromatogram of Palivizumab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine)-O-SNX-2112. [Figure 93] 1 shows an analytical HIC chromatogram of Palivizumab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine)-O-SNX-2112. [Figure 94] 1 shows an analytical SEC chromatogram of trastuzumab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine)-O-gemcitabine. [Figure 95] 1 shows an analytical HIC chromatogram of trastuzumab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine)-O-gemcitabine. [Figure 96] 1 shows an analytical SEC chromatogram of Palivizumab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine)-O-gemcitabine. [Figure 97]1 shows an analytical HIC chromatogram of Palivizumab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine)-O-gemcitabine. [Figure 98] 1 shows an analytical SEC chromatogram of trastuzumab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine)-O-balasertib. [Figure 99] 1 shows an analytical HIC chromatogram of trastuzumab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine)-O-balasertib. [Figure 100] 1 shows an analytical SEC chromatogram of Palivizumab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine)-O-balasertib. [Figure 101] 1 shows an analytical HIC chromatogram of Palivizumab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine)-O-balasertib. [Figure 102] 1 shows an analytical SEC chromatogram of trastuzumab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-tert.-butyl ester)-O-Dxd. [Figure 103] 1 shows an analytical HIC chromatogram of trastuzumab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-tert.-butyl ester)-O-Dxd. [Figure 104] 1 shows an analytical SEC chromatogram of Palivizumab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-tert.-butyl ester)-O-Dxd. [Figure 105] 1 shows an analytical HIC chromatogram of Palivizumab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-tert.-butyl ester)-O-Dxd. [Figure 106]FIG. 1 shows an analytical SEC chromatogram of trastuzumab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine)-O-Dxd. [Figure 107] 1 shows an analytical HIC chromatogram of trastuzumab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine)-O-Dxd. [Figure 108] FIG. 1 shows an analytical SEC chromatogram of Palivizumab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine)-O-Dxd. [Figure 109] 1 shows an analytical HIC chromatogram of Palivizumab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine)-O-Dxd. [Figure 110] FIG. 1 shows an analytical SEC chromatogram of trastuzumab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(β-alanine-L-alanine)-O-Dxd. [Figure 111] FIG. 1 shows an analytical HIC chromatogram of trastuzumab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(β-alanine-L-alanine)-O-Dxd. [Figure 112] FIG. 1 shows an analytical SEC chromatogram of Palivizumab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(β-alanine-L-alanine)-O-Dxd. [Figure 113] 1 shows an analytical HIC chromatogram of Palivizumab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(β-alanine-L-alanine)-O-Dxd. [Figure 114] FIG. 1 shows an analytical SEC chromatogram of trastuzumab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(γ-aminobutyric acid-L-alanine)-O-Dxd. [Figure 115]1 shows an analytical HIC chromatogram of trastuzumab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(γ-aminobutyric acid-L-alanine)-O-Dxd. [Figure 116] FIG. 1 shows an analytical SEC chromatogram of Palivizumab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(γ-aminobutyric acid-L-alanine)-O-Dxd. [Figure 117] 1 shows an analytical HIC chromatogram of Palivizumab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(γ-aminobutyric acid-L-alanine)-O-Dxd. [Figure 118] FIG. 1 shows an analytical SEC chromatogram of trastuzumab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(5-aminovaleric acid-L-alanine)-O-Dxd. [Figure 119] 1 shows an analytical HIC chromatogram of trastuzumab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(5-aminovaleric acid-L-alanine)-O-Dxd. [Figure 120] 1 shows an analytical SEC chromatogram of Palivizumab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(5-aminovaleric acid-L-alanine)-O-Dxd. [Figure 121] 1 shows an analytical HIC chromatogram of Palivizumab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(5-aminovaleric acid-L-alanine)-O-Dxd. [Figure 122] FIG. 1 shows a head-to-head comparison of the in vivo efficacy of an ADC O-P5(PEG12)-amidopentyl-phosphoramidate-N-(L-alanine-tert.-butyl ester)-O-SN38 comprising a linker according to an embodiment of the invention with the approved ADC Trodelvy. [Figure 123-1] Figure 1 shows the in vitro efficacy of ADCs according to embodiments of the invention for cell killing in various cancer cell lines. The ADCs tested have spacer E of different lengths, such that different ring sizes can be formed with the phosphorus atom after cleavage of group Z. [Figure 123-2] See description of Figure 123-1. [Figure 123-3] See description of Figure 123-1. [Figure 124] FIG. 1 shows the in vitro efficacy of ADCs according to embodiments of the invention that include an aromatic alcohol as the drug moiety for cell killing in various cancer cell lines. [Figure 125] FIG. 1 shows the in vitro efficacy of ADCs according to embodiments of the invention comprising an aliphatic alcohol as the drug moiety for cell killing in various cancer cell lines. [Figure 126] Figure 1 shows the in vitro efficacy of ADCs according to embodiments of the present invention, including SN38 as the drug and the antibodies datopotamab (Trop2-targeting) and brentuximab (non-targeting isotype control). In vitro efficacy is shown against two different Trop2-positive cell lines (MDA-MB-468 and HCC-78). The ADCs tested each have a different chemical nature of the spacer group E and a different chemical nature of the cleavable group Z. [Figure 127] Figure 1 shows the in vitro efficacy of ADCs according to embodiments of the present invention, including SN38 as the drug and the antibodies brentuximab (CD30-targeting) and datopotamab (non-targeting isotype control). In vitro efficacy is shown against two different CD30-positive cell lines (L-540) and (SR-786). The ADCs tested each have a different chemical nature of the spacer group E and a different chemical nature of the cleavable group Z. [Figure 128] Figure 1 shows the in vitro efficacy of ADCs according to embodiments of the invention, including SN38 as the drug and the antibodies datopotamab (Trop2-targeting) and brentuximab (non-targeting isotype control). In vitro efficacy is shown against two different Trop2-positive cell lines (MDA-MB-468) and (HCC-78). The ADCs tested contain a cyclic group (cyclohexyl) in the linker L, and each has a spacer group E of different chemical nature and a cleavable group Z of different chemical nature. [Figure 129]Figure 1 shows the in vitro efficacy of ADCs according to embodiments of the present invention, including SN38 as the drug and the antibodies brentuximab (CD30-targeting) and datopotamab (non-targeting isotype control). In vitro efficacy against two different CD30-positive cell lines (L-540) and (SR-786) is shown. The ADCs tested contain a cyclic group (cyclohexyl) in the linker L, and each has a spacer group E of different chemical nature and a cleavable group Z of different chemical nature. [Figure 130] Figure 1 shows the in vitro efficacy of ADCs according to embodiments of the present invention, including SN38 as the drug and the antibodies datopotamab (Trop2-targeting) and brentuximab (non-targeting isotype control). In vitro efficacy is shown against two different Trop2-positive cell lines (MDA-MB-468 and HCC-78). The ADCs tested contain various combinations of spacer groups E, moieties W, and cleavable groups Z of different chemical natures. [Figure 131] Figure 1 shows the in vitro efficacy of ADCs according to embodiments of the present invention, including SN38 as the drug and the antibodies brentuximab (CD30-targeting) and datopotamab (non-targeting isotype control). In vitro efficacy against two different CD30-positive cell lines (L-540) and (SR-786) is shown. The ADCs tested contain various combinations of spacer groups E, moieties W, and cleavable groups Z of different chemical natures. [Figure 132] Figure 1 shows the in vitro efficacy of ADCs according to embodiments of the present invention, including DXd as the drug and the antibodies datopotamab (Trop2-targeting) and brentuximab (non-targeting isotype control). In vitro efficacy is shown against two different Trop2-positive cell lines (MDA-MB-468 and HCC-78). The ADCs tested contain various combinations of spacer groups E, moieties W, and cleavable groups Z of different chemical natures. [Figure 133]Figure 1 shows the in vitro efficacy of ADCs according to embodiments of the present invention, including DXd as the drug and the antibodies brentuximab (CD30-targeting) and datopotamab (non-targeting isotype control). In vitro efficacy against two different CD30-positive cell lines (L-540) and (SR-786) is shown. The ADCs tested contain various combinations of spacer groups E, moieties W, and cleavable groups Z of different chemical natures. [Figure 134A]

[0023] Figure 1 shows the in vitro efficacy of ADCs according to embodiments of the present invention comprising different drugs and variations in moieties X, Y1, and M. An ADC was tested comprising SN38 as the drug, NH as moiety M, O as moieties Y1 and X, and the antibodies datopotamab (Trop2-targeting) and brentuximab (non-targeting isotype control). An ADC was also tested comprising exetecan as the drug, O as moieties M and Y1, NH as X (to which exetecan is attached), and the antibodies datopotamab (Trop2-targeting) and brentuximab (non-targeting isotype control). In vitro efficacy against two different Trop2-positive cell lines (MDA-MB-468) and (HCC-78) is shown. [Figure 134B] The in vitro efficacy of ADCs according to embodiments of the present invention comprising different drugs and variations in moieties X, Y1, and M is shown. An ADC comprising SN38 as the drug, NH as moiety M, O as moieties Y1 and X, and the antibodies brentuximab (CD30-targeting) and datopotamab (non-targeting isotype control) was tested. An ADC comprising exetecan as the drug, O as moieties M and Y1, NH as X (to which exetecan is attached), and the antibodies brentuximab (CD30-targeting) and datopotamab (non-targeting isotype control) was also tested. The in vitro efficacy against two different CD30-positive cell lines (L-540) and (SR-786) is shown. [Figure 135]Figure 1 shows the in vitro efficacy of ADCs according to embodiments of the present invention, including DXd as the drug and the antibodies datopotamab (Trop2-targeting) and brentuximab (non-targeting isotype control). In vitro efficacy is shown against two different Trop2-positive cell lines (MDA-MB-468 and HCC-78). The ADCs tested have linkers L of different chemical natures. [Figure 136] Figure 1 shows the in vitro efficacy of an ADC according to an embodiment of the present invention, which includes DXd as the drug and the antibodies brentuximab (CD30-targeting) and datopotamab (non-targeting isotype control). In vitro efficacy is shown against two different CD30-positive cell lines (L-540) and (SR-786). The ADCs tested have linkers L of different chemical natures. [Figure 137] Figure 1 shows the in vitro efficacy of ADCs according to embodiments of the present invention, including different dihydroorotate dehydrogenase (DHODH) inhibitors as drugs and the antibodies datopotamab (Trop2-targeting) and brentuximab (non-targeting isotype control). In vitro efficacy is shown against two different Trop2-positive cell lines (MDA-MB-468) and (HCC-78). The ADCs tested included Bay-2402234 and DHODH-IN-16, respectively. [Figure 138] Figure 1 shows the in vitro efficacy of ADCs according to embodiments of the present invention, including different DHODH inhibitors as drugs and the antibodies brentuximab (CD30-targeting) and datopotamab (non-targeting isotype control). Figure 2 shows the in vitro efficacy against two different CD30-positive cell lines (SUDHL1) and (Karpas-299). The ADCs tested included Bay-2402234 and DHODH-IN-16, respectively. [Figure 139]

[0023] Figure 1 shows the in vitro efficacy of an ADC according to an embodiment of the invention comprising paclitaxel as the drug and the antibodies trastuzumab (Her2-targeting) and brentuximab (non-targeting isotype control).

[0024] Figure 1 shows the in vitro efficacy against two different HER2-positive cell lines (N87) and (SKBR3). [Figure 140]Figure 1 shows the in vitro efficacy of ADCs according to embodiments of the present invention, including the HSP90 inhibitor ganetespib as a drug and the antibodies trastuzumab (Her2-targeting) and brentuximab or palivizumab (non-targeting isotype controls). In vitro efficacy against Her2-positive cells (N-87) is shown. The ADCs tested contain cleavable groups Z of different chemical natures. [Figure 141] Figure 1 shows the in vitro efficacy of ADCs according to embodiments of the present invention containing an eIF4E inhibitor as a drug. The conjugates tested contained either the antibody datopotamab (Trop2-targeting) and brentuximab (non-targeting isotype control for Trop2-positive cell lines) or brentuximab (CD30-targeting) and datopotamab (non-targeting isotype control for CD30-positive cell lines). In vitro efficacy is shown against Trop2-positive cell lines (HCC-78) and CD30-positive cell lines (L-540). The ADCs tested contain cleavable groups Z of different chemical natures. [Figure 142] 1 shows the HPLC / UV chromatogram of the compound boc-aminopentanephenyl phosphite. [Figure 143] FIG. 1 shows the HPLC / UV chromatogram of compound O-(5-tert.-butoxy-carbonyl)-aminopentyl-phosphoramidate-N-(L-alanine-iso-propyl ester)-O-SN38. [Figure 144] Figure 1 shows the HPLC / UV chromatogram of compound O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-iso-propyl ester)-O-SN38. [Figure 145] Figure 1 shows the HPLC / UV chromatogram of compound O-(5-tert.-butoxy-carbonyl)-aminopentyl-phosphoramidate-N-(L-alanine-iso-propyl ester)-O-ON-013100. [Figure 146] Figure 1 shows the HPLC / UV chromatogram of compound O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-iso-propyl ester)-O-ON-013100. [Figure 147]1 shows the HPLC / UV chromatogram of the compound O-(5-tert.-butoxy-carbonyl)-aminopentyl-phosphoramidate-N-(L-alanine-iso-propyl ester)-O-ganetespib. [Figure 148] FIG. 1 shows the HPLC / UV chromatogram of compound O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-iso-propyl ester)-O-ganetespib. [Figure 149] 1 shows the HPLC / UV chromatogram of the compound O-(5-tert.-butoxy-carbonyl)-amidopentyl-phosphoramidate-N-(glycine-tert.-butyl ester)-O-4-nitrophenyl. [Figure 150] FIG. 1 shows the HPLC / UV chromatogram of compound O-(5-tert.-butoxy-carbonyl)-amidopentyl-phosphoramidate-N-(glycine-tert.-butyl ester)-O-SN38. [Figure 151] Figure 1 shows the HPLC / UV chromatogram of compound O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-iso-propyl ester)-O-SN38. [Figure 152] 1 shows the HPLC / UV chromatogram of the compound O-(5-tert.-butoxy-carbonyl)-amidopentyl-phosphoramidate-N-(2,2-dimethylaminobutyric acid-tert.-butyl ester)-O-4-nitrophenyl. [Figure 153] 1 shows the HPLC / UV chromatogram of compound O-(5-tert.-butoxy-carbonyl)-amidopentyl-phosphoramidate-N-(2,2-dimethylaminobutyric acid-tert.-butyl ester)-O-SN38. [Fig. 154] FIG. 1 shows the HPLC / UV chromatogram of compound O-P5(PEG24)-amidopentyl-phosphoramidate-N-(2,2-dimethylaminobutyric acid-tert.-butyl ester)-O-SN38. [Figure 155]FIG. 1 shows the HPLC / UV chromatogram of compound O-5-(5-tert.-butoxy-carbonyl)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine-tert.-butyl ester)-O-SN38. [Figure 156] FIG. 1 shows the HPLC / UV chromatogram of compound O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine)-O-SN38. [Figure 157] FIG. 1 shows the HPLC / UV chromatogram of compound O-5-tert.-butoxy-carbonyl-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine-tert.-butyl ester)-O-ON-013100. [Figure 158] FIG. 1 shows the HPLC / UV chromatogram of compound O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine)-O-ON-013100. [Figure 159] 1 shows the HPLC / UV chromatogram of the compound O-5-(tert.-butoxy-carbonyl)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine-tert.-butyl ester)-O-ganetespib. [Figure 160] FIG. 1 shows the HPLC / UV chromatogram of compound O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine)-O-ganetespib. [Figure 161] 1 shows the HPLC / UV chromatogram of the compound O-(5-tert.-butoxy-carbonyl)-amidocyclohexyl-phosphoramidate-N-(L-alanine-L-alanine-tert.-butyl ester)-O-4-nitrophenyl. [Figure 162] FIG. 1 shows the HPLC / UV chromatogram of compound O-5-(tert.-butoxy-carbonyl)-amidocyclohexyl-phosphoramidate-N-(L-alanine-L-alanine-tert.-butyl ester)-O-SN38. [Figure 163]FIG. 1 shows the HPLC / UV chromatogram of compound O-P5(PEG24)-amidocyclohexyl-phosphoramidate-N-(L-alanine-L-alanine)-O-SN38. [Fig. 164] 1 shows the HPLC / UV chromatogram of the compound O-5-(tert.-butoxy-carbonyl)-amidocyclohexyl-phosphoramidate-N-(L-alanine-tert.-butyl ester)-O-4-nitrophenyl. [Figure 165] FIG. 1 shows the HPLC / UV chromatogram of compound O-P5(PEG24)-amidocyclohexyl-phosphoramidate-N-(L-alanine-tert.-butyl ester)-O-SN38. [Figure 166] Figure 1 shows the HPLC / UV chromatogram of the compound O-5-(tert.-butoxy-carbonyl)-amidocyclohexyl-phosphoramidate-N-(L-alanine-iso-propyl ester)-O-4-nitrophenyl. [Figure 167] FIG. 1 shows the HPLC / UV chromatogram of compound O-5-(tert.-butoxy-carbonyl)-amidocyclohexyl-phosphoramidate-N-(L-alanine-iso-propyl ester)-O-SN38. [Figure 168] Figure 1 shows the HPLC / UV chromatogram of compound O-P5(PEG24)-amidocyclohexyl-phosphoramidate-N-(L-alanine-iso-propyl ester)-O-SN38. [Figure 169] 1 shows the HPLC / UV chromatogram of the compound O-5-(tert.-butoxy-carbonyl)-amidocyclohexyl-phosphoramidate-N-(2,2-aminobutyric acid-tert.-butyl ester)-O-4-nitrophenyl. [Figure 170] 1 shows the HPLC / UV chromatogram of compound O-5-(tert.-butoxy-carbonyl)-amidocyclohexyl-phosphoramidate-N-(2,2-aminobutyric acid-tert.-butyl ester)-O-SN38. [Figure 171]1 shows the HPLC / UV chromatogram of compound O-P5(PEG24)-amidocyclohexyl-phosphoramidate-N-(2,2-aminobutyric acid-tert.-butyl ester)-O-SN38. [Fig. 172] FIG. 1 shows the HPLC / UV chromatogram of the compound O-5-(tert.-butoxy-carbonyl)-amidopentyl-phosphoramidate-N-(2-tert.-butyl-disulfide-ethyl)-O-4-nitrophenyl. [Figure 173] FIG. 1 shows the HPLC / UV chromatogram of compound O-5-(tert.-butoxy-carbonyl)-amidopentyl-phosphoramidate-N-(2-tert.-butyl-disulfide-ethyl)-SN38. [Fig. 174] Figure 1 shows the HPLC / UV chromatogram of compound O-P5(PEG24)-amidopentyl-phosphoramidate-N-(2-tert.-butyl-disulfide-ethyl)-SN38. [Figure 175] 1 shows the HPLC / UV chromatogram of the compound O-5-(tert.-butoxy-carbonyl)-amidopentyl-phosphoramidate-N-(2-tert.-butyl-disulfide-ethyl)-DXD. [Figure 176] FIG. 1 shows the HPLC / UV chromatogram of compound O-P5(PEG24)-amidopentyl-phosphoramidate-N-(2-tert.-butyl-disulfide-ethyl)-DXD. [Figure 177] Figure 1 shows the HPLC / UV chromatogram of the compound O-5-(phenylmethoxy-carbonyl)-amidopentyl-phosphoramidate-N-(2-2-diethoxy-ethyl)-O-4-nitrophenyl. [Figure 178] Figure 1 shows the HPLC / UV chromatogram of the compound O-5-(phenylmethoxy-carbonyl)-amidopentyl-phosphoramidate-N-(2-2-diethoxy-ethyl)-O-DXD. [Figure 179] Figure 1 shows the HPLC / UV chromatogram of compound O-P5(PEG24)-amidopentyl-phosphoramidate-N-(2-2-diethoxy-ethyl)-O-DXD. [Figure 180] FIG. 1 shows the HPLC / UV chromatogram of compound O-5-(tert.-butoxy-carbonyl)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine-tert.-butyl ester)-O-DHODH-IN-16. [Figure 181] FIG. 1 shows the HPLC / UV chromatogram of compound O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine-tert.-butyl ester)-O-DHODH-IN-16. [Figure 182] 1 shows the HPLC / UV chromatogram of the compound O-5-(tert.-butoxy-carbonyl)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine-tert.-butyl ester)-O-roniciclib. [Figure 183] FIG. 1 shows the HPLC / UV chromatogram of compound O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine-tert.-butyl ester)-O-roniciclib. [Figure 184] FIG. 1 shows the HPLC / UV chromatogram of compound O-5-(tert.-butoxy-carbonyl)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine-tert.-butyl ester)-O-Nampt-IN-1. [Figure 185] 1 shows the HPLC / UV chromatogram of compound O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine-tert.-butyl ester)-O-Nampt-IN-1. [Figure 186] 1 shows the HPLC / UV chromatogram of the compound O-5-(tert.-butoxy-carbonyl)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine-tert.-butyl ester)-O-paclitaxel. [Figure 187]FIG. 1 shows the HPLC / UV chromatogram of compound O-P5 (PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine-tert.-butyl ester)-O-paclitaxel. [Figure 188] 1 shows the HPLC / UV chromatogram of compound O-5-(tert.-butoxy-carbonyl)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine-tert.-butyl ester)-O-triptolide. [Figure 189] FIG. 1 shows an analytical SEC chromatogram of brentuximab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-iso-propyl ester)-O-SN38. [Figure 190] Figure 1 shows an analytical HIC chromatogram of brentuximab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-iso-propyl ester)-O-SN38. [Figure 191] Figure 1 shows an analytical SEC chromatogram of datopotamab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-iso-propyl ester)-O-SN38. [Figure 192] Figure 1 shows an analytical HIC chromatogram of datopotamab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-iso-propyl ester)-O-SN38. [Figure 193] Figure 1 shows an analytical SEC chromatogram of brentuximab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(glycine-tert.-butyl ester)-O-SN38. [Figure 194] Figure 1 shows an analytical HIC chromatogram of brentuximab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(glycine-tert.-butyl ester)-O-SN38. [Figure 195]Figure 1 shows an analytical SEC chromatogram of datopotamab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(glycine-tert.-butyl ester)-O-SN38. [Figure 196] Figure 1 shows an analytical HIC chromatogram of datopotamab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(glycine-tert.-butyl ester)-O-SN38. [Figure 197] Figure 1 shows an analytical SEC chromatogram of brentuximab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(2,2-dimethylaminobutyric acid-tert.-butyl ester)-O-SN38. [Figure 198] Figure 1 shows an analytical HIC chromatogram of brentuximab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(2,2-dimethylaminobutyric acid-tert.-butyl ester)-O-SN38. [Figure 199] Figure 1 shows an analytical SEC chromatogram of datopotamab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(2,2-dimethylaminobutyric acid-tert.-butyl ester)-O-SN38. [Figure 200] Figure 1 shows an analytical HIC chromatogram of datopotamab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(2,2-dimethylaminobutyric acid-tert.-butyl ester)-O-SN38. [Figure 201] FIG. 1 shows an analytical SEC chromatogram of brentuximab-O-P5(PEG24)-amidocyclohexyl-phosphoramidate-N-(L-alanine-L-alanine)-O-SN38. [Figure 202] Figure 1 shows an analytical HIC chromatogram of brentuximab-O-P5(PEG24)-amidocyclohexyl-phosphoramidate-N-(L-alanine-L-alanine)-O-SN38. [Figure 203] Figure 1 shows an analytical SEC chromatogram of datopotamab-O-P5(PEG24)-amidocyclohexyl-phosphoramidate-N-(L-alanine-L-alanine)-O-SN38. [Figure 204] Figure 1 shows an analytical HIC chromatogram of datopotamab-O-P5(PEG24)-amidocyclohexyl-phosphoramidate-N-(L-alanine-L-alanine)-O-SN38. [Figure 205] Figure 1 shows an analytical SEC chromatogram of brentuximab-O-P5(PEG24)-amidocyclohexyl-phosphoramidate-N-(L-alanine-tert.-butyl ester)-O-SN38. [Figure 206] Figure 1 shows an analytical HIC chromatogram of brentuximab-O-P5(PEG24)-amidocyclohexyl-phosphoramidate-N-(L-alanine-tert.-butyl ester)-O-SN38. [Figure 207] Figure 1 shows an analytical SEC chromatogram of datopotamab-O-P5(PEG24)-amidocyclohexyl-phosphoramidate-N-(L-alanine-tert.-butyl ester)-O-SN38. [Figure 208] Figure 1 shows an analytical HIC chromatogram of datopotamab-O-P5(PEG24)-amidocyclohexyl-phosphoramidate-N-(L-alanine-tert.-butyl ester)-O-SN38. [Figure 209] Figure 1 shows an analytical SEC chromatogram of brentuximab-O-P5(PEG24)-amidocyclohexyl-phosphoramidate-N-(L-alanine-iso-propyl ester)-O-SN38. [Figure 210] Figure 1 shows an analytical HIC chromatogram of brentuximab-O-P5(PEG24)-amidocyclohexyl-phosphoramidate-N-(L-alanine-iso-propyl ester)-O-SN38. [Figure 211] Figure 1 shows an analytical SEC chromatogram of datopotamab-O-P5(PEG24)-amidocyclohexyl-phosphoramidate-N-(L-alanine-iso-propyl ester)-O-SN38. [Figure 212]Figure 1 shows an analytical HIC chromatogram of datopotamab-O-P5(PEG24)-amidocyclohexyl-phosphoramidate-N-(L-alanine-iso-propyl ester)-O-SN38. [Figure 213] 1 shows an analytical SEC chromatogram of brentuximab-5-pentylacetamido-phosphoramidate-N-(L-alanine-L-alanine)-O-DXd. [Figure 214] 1 shows an analytical HIC chromatogram of brentuximab-5-pentylacetamido-phosphoramidate-N-(L-alanine-L-alanine)-O-DXd. [Figure 215] 1 shows an analytical SEC chromatogram of datopotamab-O-pentylacetamide-phosphoramidate-N-(L-alanine-L-alanine)-O-DXd. [Figure 216] 1 shows an analytical HIC chromatogram of datopotamab-O-pentylacetamide-phosphoramidate-N-(L-alanine-L-alanine)-O-DXd. [Figure 217] Figure 1 shows an analytical SEC chromatogram of brentuximab-6-(2,5-dioxopyrrolidin-1-yl)-N-(5-hydroxypentyl)hexanamide-phosphoramidate-N-(L-alanine-L-alanine)-O-DXd. [Figure 218] Figure 1 shows an analytical HIC chromatogram of brentuximab-6-(2,5-dioxopyrrolidin-1-yl)-N-(5-hydroxypentyl)hexanamide-phosphoramidate-N-(L-alanine-L-alanine)-O-DXd. [Figure 219] Figure 1 shows an analytical SEC chromatogram of datopotamab-6-(2,5-dioxopyrrolidin-1-yl)-N-(5-hydroxypentyl)hexanamide-phosphoramidate-N-(L-alanine-L-alanine)-O-DXd. [Figure 220] Figure 1 shows an analytical HIC chromatogram of datopotamab-6-(2,5-dioxopyrrolidin-1-yl)-N-(5-hydroxypentyl)hexanamide-phosphoramidate-N-(L-alanine-L-alanine)-O-DXd. [Figure 221] Figure 1 shows an analytical SEC chromatogram of brentuximab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine)-O-DHODH-IN-16. [Figure 222] Figure 1 shows an analytical HIC chromatogram of brentuximab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine)-O-DHODH-IN-16. [Figure 223] Figure 1 shows an analytical SEC chromatogram of datopotamab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine)-O-DHODH-IN-16. [Figure 224] 1 shows an analytical HIC chromatogram of datopotamab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine)-O-DHODH-IN-16. [Figure 225] FIG. 1 shows an analytical SEC chromatogram of brentuximab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine)-O-roniciclib. [Figure 226] 1 shows an analytical HIC chromatogram of brentuximab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine)-O-roniciclib. [Figure 227] 1 shows an analytical SEC chromatogram of trastuzumab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine)-O-roniciclib. [Figure 228] 1 shows an analytical HIC chromatogram of trastuzumab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine)-O-roniciclib. [Figure 229] 1 shows an analytical SEC chromatogram of brentuximab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine)-O-Nampt-IN-1. [Figure 230] 1 shows an analytical HIC chromatogram of brentuximab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine)-O-Nampt-IN-1. [Figure 231] 1 shows an analytical SEC chromatogram of datopotamab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine)-O-Nampt-IN-1. [Figure 232] 1 shows an analytical HIC chromatogram of datopotamab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine)-O-Nampt-IN-1. [Figure 233] Figure 1 shows an analytical SEC chromatogram of brentuximab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine-tert.-butyl ester)-O-paclitaxel. [Figure 234] 1 shows an analytical HIC chromatogram of brentuximab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine-tert.-butyl ester)-O-paclitaxel. [Figure 235] 1 shows an analytical SEC chromatogram of trastuzumab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine-tert.-butyl ester)-O-paclitaxel. [Figure 236] 1 shows an analytical HIC chromatogram of trastuzumab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine-tert.-butyl ester)-O-paclitaxel. [Figure 237] 1 shows an analytical SEC chromatogram of brentuximab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine-tert.-butyl ester)-O-triptolide. [Figure 238]1 shows an analytical HIC chromatogram of brentuximab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine-tert.-butyl ester)-O-triptolide. [Figure 239] 1 shows an analytical SEC chromatogram of trastuzumab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine-tert.-butyl ester)-O-triptolide. [Figure 240] 1 shows an analytical HIC chromatogram of trastuzumab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine-tert.-butyl ester)-O-triptolide. [Figure 241] Figure 1 shows an analytical SEC chromatogram of brentuximab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine-)-O-ON013100. [Figure 242] Figure 1 shows an analytical HIC chromatogram of brentuximab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine-)-O-ON013100. [Figure 243] Figure 1 shows an analytical SEC chromatogram of datopotamab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine-)-O-ON013100. [Figure 244] Figure 1 shows an analytical HIC chromatogram of datopotamab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine-)-O-ON013100. [Figure 245] FIG. 1 shows an analytical SEC chromatogram of brentuximab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine)-O-ganetespib. [Figure 246] 1 shows an analytical HIC chromatogram of brentuximab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine)-O-ganetespib. [Figure 247] FIG. 1 shows an analytical SEC chromatogram of datopotamab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine)-O-ganetespib. [Figure 248] 1 shows an analytical HIC chromatogram of datopotamab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine)-O-ganetespib. [Figure 249] HPLC / UV chromatogram of P5(PEG24)-COOH is shown. [Figure 250] 1 shows an analytical SEC chromatogram of brentuximab. [Figure 251] 1 shows an analytical HIC chromatogram of brentuximab. [Figure 252] 1 shows an analytical SEC chromatogram of datopotamab. [Figure 253] 1 shows an analytical HIC chromatogram of datopotamab. [Figure 254] 1 shows the HPLC / UV chromatogram of the compound O-(5-tert.-butoxy-carbonyl)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine-tert.-butyl ester)-O-BAY-2402234. [Figure 255] FIG. 1 shows the HPLC / UV chromatogram of the compound O-P5-(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine)-O-BAY-2402234. [Figure 256] FIG. 1 shows an analytical SEC chromatogram of brentuximab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-tert.-butylester)-O-SN38. [Figure 257] Figure 1 shows an analytical HIC chromatogram of brentuximab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-tert.-butyl ester)-O-SN38. [Figure 258]Figure 1 shows an analytical SEC chromatogram of datopotamab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-tert.-butyl ester)-O-SN38. [Figure 259] Figure 1 shows an analytical HIC chromatogram of datopotamab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-tert.-butyl ester)-O-SN38. [Figure 260] FIG. 1 shows an analytical SEC chromatogram of trastuzumab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine)-O-ganetespib. [Figure 261] 1 shows an analytical HIC chromatogram of trastuzumab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine)-O-ganetespib. [Figure 262] FIG. 1 shows an analytical SEC chromatogram of Palivizumab-O-P5-(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine)-O-BAY-2402234. [Figure 263] 1 shows an analytical HIC chromatogram of Palivizumab-O-P5-(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine)-O-BAY-2402234. [Figure 264] Figure 1 shows an analytical SEC chromatogram of datopotamab-O-P5-(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine)-O-BAY-2402234. [Figure 265] 1 shows an analytical HIC chromatogram of datopotamab-O-P5-(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine)-O-BAY-2402234. [Figure 266] FIG. 1 shows the HPLC / UV chromatogram of compound O-(5-tert.-butoxy-carbonyl)-amidopentyl-phosphoramidate-N-(alanine-tert.-butyl ester)-O-SN38. [Figure 267] FIG. 1 shows the HPLC / UV chromatogram of compound O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-tert.-butyl ester)-O-SN38. [Figure 268] 1 shows the HPLC / UV chromatogram of compound O-P5(PEG24)-amidopentyl-phosphoramidate-N-(2-ethoxy-6-(3R,4S,5S,6S)-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate)-O-SN38. [Figure 269] 1 shows the HPLC / UV chromatogram of the compound O-(5-tert.-butoxy-carbonyl)-amidopentyl-phosphoramidate-N-(2-acetoxy-ethyl)-O-4-nitrophenyl. [Figure 270] 1 shows the HPLC / UV chromatogram of the compound O-(5-tert.-butoxy-carbonyl)-amidopentyl-phosphoramidate-N-(2-acetoxy-ethyl)-O-DXD. [Fig. 271] Figure 1 shows the HPLC / UV chromatogram of compound O-P5(PEG24)-amidopentyl-phosphoramidate-N-(2-acetoxy-ethyl)-O-DXD. [Fig. 272] 1 shows the HPLC / UV chromatogram of the compound O-(5-tert.-butoxy-carbonyl)-amidopentyl-phosphoramidate-N-(2-acetamido-ethyl)-O-4-nitrophenyl. [Fig. 273] FIG. 1 shows the HPLC / UV chromatogram of compound O-(5-tert.-butoxy-carbonyl)-amidopentyl-phosphoramidate-N-(2-acetamido-ethyl)-O-SN38. [Fig. 274] Figure 1 shows the HPLC / UV chromatogram of compound O-P5-(PEG24)-amidopentyl-phosphoramidate-N-(2-acetamido-ethyl)-O-SN38. [Figure 275]Figure 1 shows the HPLC / UV chromatogram of compound O-5-(phenylmethoxy-carbonyl)-amidopentyl-phosphoramidate-N-(2-2-diethoxy-ethyl)-O-SN38. [Figure 276] Figure 1 shows the HPLC / UV chromatogram of compound O-P5(PEG24)-amidopentyl-phosphoramidate-N-(2-2-diethoxy-ethyl)-O-SN38. [Figure 277] Figure 1 shows the HPLC / UV chromatogram of the compound O-(5-tert.-butoxy-carbonyl)-amidopentyl-phosphoramidate-O-(lactic acid-iso-propyl ester)-O-4-nitrophenyl. [Fig. 278] Figure 1 shows the HPLC / UV chromatogram of compound O-(5-tert.-butoxy-carbonyl)-amidopentyl-phosphoramidate-O-(lactic acid-iso-propyl ester)-O-SN38. [Figure 279] Figure 1 shows the HPLC / UV chromatogram of compound O-P5-(PEG24)-amidopentyl-phosphoramidate-O-(lactic acid-iso-propyl ester)-O-SN38. [Figure 280] 1 shows the HPLC / UV chromatogram of the compound O-(5-tert.-butoxy-carbonyl)-amidopentyl-phosphoramidate-O-(glycolic acid-iso-propyl ester)-N-exatecan. [Figure 281] 1 shows the HPLC / UV chromatogram of the compound O-P5-(PEG24)-amidopentyl-phosphoramidate-O-(glycolic acid-iso-propyl ester)-N-exatecan. [Figure 282] 1 shows the HPLC / UV chromatogram of compound O-(5-tert.-butoxy-carbonyl)-amidopentyl-phosphoramidate-N-(L-alanine-tert.-butyl ester)-O-ON-013100. [Figure 283] 1 shows the HPLC / UV chromatogram of compound O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-tert.-butyl ester)-O-ON-013100. [Fig. 284] Figure 1 shows an analytical SEC chromatogram of brentuximab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(2-tert.-butyl-disulfide-ethyl)-O-SN38. [Figure 285] Figure 1 shows an analytical HIC chromatogram of brentuximab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(2-tert.-butyl-disulfide-ethyl)-O-SN38. [Figure 286] Figure 1 shows an analytical SEC chromatogram of datopotamab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(2-tert.-butyl-disulfide-ethyl)-O-SN38. [Figure 287] Figure 1 shows an analytical HIC chromatogram of datopotamab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(2-tert.-butyl-disulfide-ethyl)-O-SN38. [Figure 288] 1 shows an analytical SEC chromatogram of brentuximab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(2-tert.-butyl-disulfide-ethyl)-O-DXD. [Figure 289] 1 shows an analytical HIC chromatogram of brentuximab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(2-tert.-butyl-disulfide-ethyl)-O-DXD. [Figure 290] 1 shows an analytical SEC chromatogram of O-P5(PEG24)-amidopentyl-phosphoramidate-N-(2-tert.-butyl-disulfide-ethyl)-O-DXD. [Figure 291] 1 shows an analytical HIC chromatogram of O-P5(PEG24)-amidopentyl-phosphoramidate-N-(2-tert.-butyl-disulfide-ethyl)-O-DXD. [Figure 292]Figure 1 shows an analytical SEC chromatogram of brentuximab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(2-ethoxy-6-(3R,4S,5S,6S)-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate)-O-SN38. [Figure 293] Figure 1 shows an analytical HIC chromatogram of brentuximab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(2-ethoxy-6-(3R,4S,5S,6S)-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate)-O-SN38. [Fig. 294] Figure 1 shows an analytical SEC chromatogram of datopotamab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(2-ethoxy-6-(3R,4S,5S,6S)-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate)-O-SN38. [Figure 295] Figure 1 shows an analytical HIC chromatogram of datopotamab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(2-ethoxy-6-(3R,4S,5S,6S)-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate)-O-SN38. [Figure 296] 1 shows an analytical SEC chromatogram of brentuximab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(2-acetoxy-ethyl)-O-DXD. [Figure 297] 1 shows an analytical HIC chromatogram of brentuximab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(2-acetoxy-ethyl)-O-DXD. [Figure 298] 1 shows an analytical SEC chromatogram of datopotamab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(2-acetoxy-ethyl)-O-DXD. [Figure 299]1 shows an analytical HIC chromatogram of datopotamab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(2-acetoxy-ethyl)-O-DXD. [Figure 300] Figure 1 shows an analytical SEC chromatogram of brentuximab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(2-acetamido-ethyl)-O-SN38. [Figure 301] Figure 1 shows an analytical HIC chromatogram of brentuximab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(2-acetamido-ethyl)-O-SN38. [Figure 302] Figure 1 shows an analytical SEC chromatogram of datopotamab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(2-acetamido-ethyl)-O-SN38. [Figure 303] Figure 1 shows an analytical HIC chromatogram of datopotamab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(2-acetamido-ethyl)-O-SN38. [Figure 304] Figure 1 shows an analytical SEC chromatogram of brentuximab-O-P5-(PEG24)-amidopentyl-phosphoramidate-O-(lactic acid-iso-propyl ester)-O-SN38. [Figure 305] Figure 1 shows an analytical HIC chromatogram of brentuximab-O-P5-(PEG24)-amidopentyl-phosphoramidate-O-(lactic acid-iso-propyl ester)-O-SN38. [Figure 306] Figure 1 shows an analytical SEC chromatogram of datopotamab-O-P5-(PEG24)-amidopentyl-phosphoramidate-O-(lactic acid-iso-propyl ester)-O-SN38. [Figure 307] Figure 1 shows an analytical HIC chromatogram of datopotamab-O-P5-(PEG24)-amidopentyl-phosphoramidate-O-(lactic acid-iso-propyl ester)-O-SN38. [Figure 308]Figure 1 shows an analytical SEC chromatogram of brentuximab-O-P5-(PEG24)-amidopentyl-phosphoramidate-O-(glycolic acid-iso-propyl ester)-N-exatecan. [Figure 309] Figure 1 shows an analytical HIC chromatogram of brentuximab-O-P5-(PEG24)-amidopentyl-phosphoramidate-O-(glycolic acid-iso-propyl ester)-N-exatecan. [Figure 310] Figure 1 shows an analytical SEC chromatogram of datopotamab-O-P5-(PEG24)-amidopentyl-phosphoramidate-O-(glycolic acid-iso-propyl ester)-N-exatecan. [Figure 311] 1 shows an analytical HIC chromatogram of datopotamab-O-P5-(PEG24)-amidopentyl-phosphoramidate-O-(glycolic acid-iso-propyl ester)-N-exatecan. [Figure 312] FIG. 1 shows an analytical SEC chromatogram of trastuzumab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine-)-O-ON013100. [Figure 313] FIG. 1 shows an analytical HIC chromatogram of trastuzumab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-L-alanine-)-O-ON013100. [Figure 314] Figure 1 shows an analytical SEC chromatogram of brentuximab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-iso-propyl ester)-O-ON013100. [Figure 315] Figure 1 shows an analytical HIC chromatogram of brentuximab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-iso-propyl ester)-O-ON013100. [Figure 316] Figure 1 shows an analytical SEC chromatogram of datopotamab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-iso-propyl ester)-O-ON013100. [Figure 317] Figure 1 shows an analytical HIC chromatogram of datopotamab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-iso-propyl ester)-O-ON013100. [Figure 318] FIG. 1 shows an analytical SEC chromatogram of trastuzumab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-iso-propyl ester)-O-ON013100. [Figure 319] FIG. 1 shows an analytical HIC chromatogram of trastuzumab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-iso-propyl ester)-O-ON013100. [Figure 320] FIG. 1 shows an analytical SEC chromatogram of brentuximab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-isopropyl ester)-O-ganetespib. [Figure 321] 1 shows an analytical HIC chromatogram of brentuximab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-isopropyl ester)-O-ganetespib. [Figure 322] 1 shows an analytical SEC chromatogram of datopotamab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-isopropyl ester)-O-ganetespib. [Figure 323] 1 shows an analytical HIC chromatogram of datopotamab-O-P5(PEG24)-amidopentyl-phosphoramidate-N-(L-alanine-isopropyl ester)-O-ganetespib. [Figure 324]Figure 1 shows the results of an investigation into the release mechanism using an esterase-cleavable construct according to the present invention. LC / MS spectra of the observed reaction products of the construct after incubation with different concentrations of esterase, as well as the LC / MS spectrum of a negative control after incubation in the absence of esterase, are shown. Incubation with esterase leads to traceless release of the drug and the formation of fragments of the construct, whereas in the absence of esterase, the construct remained intact. Additionally, structures of construct A (O-P5(PEG24)-amidocyclohexyl-phosphoramidate-N-(L-alanine-isopropyl ester)-O-SN38), an intermediate of the esterase cleavage reaction, the released drug B (SN38), and the formed fragment C are shown. DETAILED DESCRIPTION OF THE INVENTION

[0025] Detailed Description The present invention is described in detail below and is further illustrated by the accompanying examples and figures.

[0026] definition Unless otherwise indicated, the term "alkyl," by itself or as part of another term, generally refers to a substituted or unsubstituted straight- or branched-chain saturated hydrocarbon having the indicated number of carbon atoms; for example, "-(C1-C8)alkyl" or "-(C1-C 10") alkyl" refers to an alkyl group having 1 to 8 or 1 to 10 carbon atoms, respectively. If the number of carbon atoms is not specified, the alkyl group can have 1 to 8 carbon atoms. Representative straight-chain -(C1-C8) alkyl groups include, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, and -n-octyl; branched-chain -(C1-C8) alkyl groups include, but are not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, and -2-methylbutyl. In some aspects, an alkyl group can be unsubstituted. Optionally, an alkyl group can be substituted, for example, with one or more groups.

[0027] Unless otherwise indicated, the term "alkylene" by itself or as part of another term generally refers to an alkylene group having the indicated number of carbon atoms, preferably 1 to 10 carbon atoms (-(C-C 10 (-C1-C8)alkylene-) or preferably 1 to 8 carbon atoms (-(C1-C8)alkylene-), and having two monovalent radical centers derived by removing two hydrogen atoms from the same or two different carbon atoms of a parent alkane. When the number of carbon atoms is not indicated, the alkylene group can have 1 to 8 carbon atoms. Typical alkylene radicals include, but are not limited to, methylene (-CH2-), 1,2-ethylene (-CH2CH2-), 1,3-n-propylene (-CH2CH2CH2-), and 1,4-n-butylene (-CH2CH2CH2CH2-). In some embodiments, the alkylene group can be unsubstituted. Optionally, the alkylene group can be substituted, for example with one or more groups.

[0028] Unless otherwise indicated, the term "alkenyl," by itself or as part of another term, generally refers to a substituted or unsubstituted straight or branched chain unsaturated hydrocarbon having a double bond and the indicated number of carbon atoms; for example, "-(C2-C8)alkenyl" or "-(C2-C10 "-(C2-C8)alkenyl" refers to an alkenyl group having 2 to 8 or 2 to 10 carbon atoms, respectively. If the number of carbon atoms is not specified, the alkenyl group can have 2 to 8 carbon atoms. Representative -(C2-C8)alkenyl groups include, but are not limited to, -ethenyl, -1-propenyl, -2-propenyl, -1-butenyl, -2-butenyl, -isobutenyl, -1-pentenyl, -2-pentenyl, -3-methyl-1-butenyl, -2-methyl-2-butenyl, and -2,3-dimethyl-2-butenyl. In some aspects, an alkenyl group can be unsubstituted. Optionally, an alkenyl group can be substituted, for example, with one or more groups.

[0029] Unless otherwise indicated, the term "alkenylene," by itself or as part of another term, generally refers to an alkenylene having the indicated number of carbon atoms, preferably 2 to 10 carbon atoms (-(C-C 10 (C2-C8)alkenylene-) or preferably 2 to 8 carbon atoms (-(C2-C8)alkenylene-), and having a double bond and two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkene, refers to a substituted or unsubstituted unsaturated branched or straight-chain hydrocarbon radical. If the number of carbon atoms is not indicated, the alkenylene group can have 1 to 8 carbon atoms. Typical alkenylene radicals include, but are not limited to, -ethenylene-, -1-propenylene-, 2-propenylene-, -1-butenylene-, -2-butenylene-, -isobutenylene-, -1-pentenylene-, -2-pentenylene-, -3-methyl-1-butenylene-, -2-methyl-2-butenylene-, and -2,3-dimethyl-2-butenylene-. In some aspects, the alkenylene group can be unsubstituted. Alkenylene groups can be optionally substituted, for example with one or more groups.

[0030] Unless otherwise indicated, the term "alkynyl," by itself or as part of another term, generally refers to a substituted or unsubstituted straight or branched chain unsaturated hydrocarbon having a triple bond and the indicated number of carbon atoms; for example, "-(C2-C8)alkynyl" or "-(C2-C 10 "-(C2-C8)alkynyl" refers to an alkynyl group having 2 to 8 or 2 to 10 carbon atoms, respectively. If the number of carbon atoms is not specified, the alkynyl group can have 2 to 8 carbon atoms. Representative -(C2-C8)alkynyl groups include, but are not limited to, -acetylenyl, -1-propynyl, -2-propynyl, -1-butynyl, -2-butynyl, -1-pentynyl, -2-pentynyl, and -3-methyl-1-butynyl. In some aspects, an alkynyl group can be unsubstituted. Optionally, an alkynyl group can be substituted, for example, with one or more groups.

[0031] Unless otherwise indicated, the term "alkynylene," by itself or as part of another term, generally refers to an alkynylene having the indicated number of carbon atoms, preferably 2 to 10 carbon atoms (-(C-C 10 (C2-C8)alkynylene-) or preferably 2 to 8 carbon atoms (-(C2-C8)alkynylene-), and having a triple bond and two monovalent radical centers derived by removing two hydrogen atoms from the same or two different carbon atoms of a parent alkyne. When the number of carbon atoms is not indicated, the alkynylene group can have 2 to 8 carbon atoms. Typical alkynylene radicals include, but are not limited to, -ethynylene-, -1-propynylene-, -2-propynylene-, -1-butynylene-, -2-butynylene-, -1-pentynylene-, -2-pentynylene-, and -3-methyl-1-butynylene-. In some aspects, the alkynylene group can be unsubstituted. Optionally, the alkynylene group can be substituted, for example with one or more groups.

[0032] Unless otherwise indicated, the term "aryl," by itself or as part of another term, generally refers to a substituted or unsubstituted monovalent carbocyclic aromatic hydrocarbon radical of 6 to 20 carbon atoms (preferably 6 to 14 carbon atoms, more preferably 6 to 10 carbon atoms, and in a highly preferred embodiment, 6 carbon atoms) derived by removing one hydrogen atom from a single carbon atom of a parent aromatic ring system. Some aryl groups are represented in the exemplary structures as "Ar." Typical aryl groups include, but are not limited to, radicals derived from benzene, substituted benzene, naphthalene, anthracene, and biphenyl. An exemplary aryl group is the phenyl group. In some aspects, an aryl group can be unsubstituted. Optionally, an aryl group can be substituted, for example, with one or more groups.

[0033] Unless otherwise indicated, the term "arylene," by itself or as part of another term, generally refers to an aryl group in which one of the hydrogen atoms has been replaced with a bond (i.e., it is divalent), with phenyl as an exemplary group, having the following structure: As shown in TIFF2025542295000022.tif21128, the arylene is an aryl group as defined above, which may be para-, meta-, or ortho-oriented. In selected embodiments, the arylene is an aryl group as defined above, for example, where two or more of the hydrogen atoms of the aryl group are replaced with bonds (i.e., the arylene may be trivalent). In some aspects, the arylene group may be unsubstituted. Optionally, the alkynylene group may be substituted, for example, with one or more groups.

[0034] Unless otherwise indicated, the terms "heterocycle," "heterocyclyl," "heterocyclic ring," and the like, by themselves or as part of another term, generally refer to a heterocycle having the indicated number of carbon atoms (e.g., "(C3-C8)heterocycle" or "(C3-C 10)Heterocycle" refers to a monovalent substituted or unsubstituted aromatic or non-aromatic monocyclic or bicyclic ring system having a heterocycle having 3 to 8 or 3 to 10 carbon atoms, respectively) and one to four heteroatom ring members independently selected from N, O, P, or S, and derived by the removal of a hydrogen atom from a ring atom of the parent ring system. One or more N, C, or S atoms in a heterocycle can be oxidized. The ring containing the heteroatom can be aromatic or non-aromatic. Unless otherwise specified, a heterocycle is attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. Representative examples of (C3-C8) heterocycle include, but are not limited to, pyrrolidinyl, azetidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, benzofuranyl, benzothiophene, indolyl, benzopyrazolyl, pyrrolyl, thiophenyl (thiophene), furanyl, thiazolyl, imidazolyl, pyrazolyl, pyrimidinyl, pyridinyl, pyrazinyl, pyridazinyl, isothiazolyl and isoxazolyl.In some aspects, heterocyclic group can be unsubstituted.Optionally, heterocyclic group can be substituted, for example, with one or more groups.

[0035] Unless otherwise indicated, the terms "heterocyclo," "heterocyclyl," "heterocyclic ring," and the like, by themselves or as part of another term, generally refer to a heterocyclic group as defined above and having the indicated number of carbon atoms (e.g., (C-C)heterocycle or (C-C) 10 ) heterocycle). In selected embodiments, the heterocyclo is a heterocyclic group as defined above, e.g., where two or more of the heterocyclic group's hydrogen atoms are replaced with bonds (i.e., the heterocyclo can be trivalent). In some aspects, the heterocyclo or heterocyclic ring can be unsubstituted. Optionally, the heterocyclo, heterocyclyl, or heterocyclic ring can be substituted, e.g., with one or more groups.

[0036] Unless otherwise indicated, the terms "carbocycle," "carbocyclyl," "carbocyclic ring," and the like, by themselves or as part of another term, generally refer to a ring system having the indicated number of carbon atoms derived by removing one hydrogen atom from a ring atom of the parent ring system (e.g., "(C3-C8)carbocycle" or "(C3-C 10 ")Carbocycle" refers to a monovalent substituted or unsubstituted aromatic or non-aromatic monocyclic or bicyclic carbocyclic ring system having 3 to 8 or 3 to 10 carbon atoms, respectively. As an illustrative, but non-limiting example, a carbocycle can be a 3-, 4-, 5-, 6-, 7-, or 8-membered carbocycle. The terms "carbocycle," "carbocyclyl," "carbocyclic ring," and the like can also include cycloalkyl, such as (C3-C8)cycloalkyl, particularly 3-, 4-, 5-, 6-, 7-, or 8-membered cycloalkyl. The terms "carbocycle," "carbocyclyl," "carbocyclic ring," and the like can also include cycloalkenyl, such as (C5-C8)cycloalkenyl, particularly 5-, 6-, 7-, or 8-membered cycloalkenyl. Representative (C3-C8) carbocyclic rings include, but are not limited to, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, cycloheptyl, 1,3-cycloheptadienyl, 1,3,5-cycloheptatrienyl, cyclooctyl, and cyclooctadienyl. In some aspects, the carbocyclic ring can be unsubstituted. Optionally, the carbocyclic ring can be substituted, for example, with one or more groups.

[0037] Unless otherwise indicated, the terms "carbocyclo," "carbocyclyl," "carbocyclic ring," and the like, by themselves or as part of another term, generally refer to a carbocyclic ring having the indicated number of carbon atoms (e.g., "(C3-C8)carbocyclo" or "(C3-C8)carbocyclo," where another hydrogen atom of the carbocyclic ring has been replaced with a bond (i.e., it is divalent). 10")Carbocyclo" refers to a carbocyclic group as defined above having 3 to 8 or 3 to 10 carbon atoms, respectively. The terms "carbocyclo," "carbocyclyl," "carbocyclic ring," and the like can also include cycloalkyl, e.g., (C3-C8)cycloalkyl, and cycloalkenyl, e.g., (C5-C8)cycloalkenyl. In selected embodiments, a carbocyclo or carbocyclic ring is a carbocyclic group as defined above, e.g., in which two or more of the carbocyclic group's hydrogen atoms are replaced with bonds (i.e., the carbocyclo, carbocyclyl, or carbocyclic ring can be trivalent). In some aspects, a carbocyclo, carbocyclyl, or carbocyclic ring can be unsubstituted. Optionally, a carbocyclo, carbocyclyl, or carbocyclic ring can be substituted, e.g., with one or more groups.

[0038] The terms "halogen" or "halo", unless otherwise defined, generally refer to elements of main group 7; preferably fluorine, chlorine, bromine and iodine; more preferably fluorine, chlorine and bromine; even more preferably fluorine and chlorine.

[0039] The terms "substituted," "optionally substituted," "optionally substituted," and the like, unless otherwise indicated, generally mean that one or more hydrogen atoms can each be independently replaced by a substituent. Exemplary substituents include -X, -R, -O, and the like. - , -OR, -SR, -S - , -NR2, -NR3, =NR, -CX3, -CN, -OCN, -SCN, -N=C=O, -NCS, -NO, -NO2, =N2, -N3, -NRC(=O)R, -C(=O)R, -C(=O)NR2, -SO3 - , -SO3H, -S(=O)2R, -OS(=O)2OR, -S(=O)2NR, -S(=O)R, -OP(=O)(OR) 2、 -P(=O)(OR)2, -PO4 3-, -PO3H2, -C(=O)R, -C(=O)X, -C(=S)R, -CO2R, -CO2, -C(=S)OR, -C(=O)SR, -C(=S)SR, -C(=O)NR2, -C(=S)NR2, or -C(=NR)NR2. R may be the same or different and independently represent (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 ) aryl, and optionally two R substituents together can form a 3- to 8-membered ring.

[0040] The term "leaving group," as used herein, generally refers to a moiety, e.g., an atom or group of atoms, that can be cleaved from the main or remaining moiety of a substrate during a reaction or elementary step of a reaction. In particular, a leaving group can be replaced with another moiety, e.g., an atom or group of atoms, during a substitution reaction. The substitution reaction may be, for example, a nucleophilic substitution.

[0041] The terms "aliphatic or aromatic residue," or "aliphatic residue" or "aromatic residue," etc., as used herein generally refer to an aliphatic substituent, such as, but not limited to, an alkyl residue, which may, however, be substituted by further aliphatic and / or aromatic substituents. As a non-limiting example, an aliphatic residue is a radical that is a direct link (R 80As long as the linkage (e.g., to the oxygen atom attached to the phosphorus in the case of (C), or, e.g., to the group X attached to the phosphorus in the case of (D), is aliphatic, it may be a nucleic acid, an enzyme, a coenzyme, a nucleotide, an oligonucleotide, a monosaccharide, a polysaccharide, a polymer, a fluorophore, an optionally substituted benzene, etc. An aromatic residue is a substituent where the direct linkage to the core structure is part of an aromatic system, e.g., an optionally substituted phenyl or triazolyl or pyridyl, or a nucleotide; non-limiting examples include when the direct linkage of a nucleotide to the core structure is via, for example, a phenyl residue. The term "aromatic residue" as used herein also includes heteroaromatic residues.

[0042] The terms "peptide" or "polypeptide," unless otherwise indicated, generally refer to organic compounds containing two or more amino acids covalently linked by peptide bonds (amide bonds). Peptides may be referred to in terms of the number of constituent amino acids, i.e., a dipeptide contains two amino acid residues, a tripeptide contains three, etc. Peptides containing 10 or fewer amino acids are called oligopeptides, while those having 10 or more amino acid residues, e.g., up to about 30 amino acid residues, are polypeptides.

[0043] The term "amino acid" as used herein generally refers to an organic compound having a -CH(NH3)-COOH group. In one embodiment, the term "amino acid" refers to naturally occurring amino acids. Illustrative examples of naturally occurring amino acids include arginine, lysine, aspartic acid, glutamic acid, glutamine, asparagine, histidine, serine, threonine, tyrosine, cysteine, methionine, tryptophan, alanine, isoleucine, leucine, phenylalanine, valine, proline and glycine. However, in a broader sense, this term also includes non-naturally occurring amino acids.

[0044] Amino acids and peptides according to the present disclosure can also be modified at functional groups, non-limiting examples being sugars, such as N-acetylgalactosamine (GalNAc), or protecting groups, such as fluorenylmethoxycarbonyl (Fmoc) modifications or esters.

[0045] The term "antibody," as used herein, is preferably intended to refer to an immunoglobulin molecule composed of four polypeptide chains, two heavy (H) chains and two light (L) chains, typically interconnected by disulfide bonds. Each heavy chain is composed of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region can contain, for example, three domains: CH1, CH2, and CH3. Each light chain is composed of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region is composed of one domain (CL). The VH and VL regions can be further subdivided into regions of hypervariability called complementarity-determining regions (CDRs), interspersed with more conserved regions called framework regions (FRs). Each VH and VL is typically composed of three CDRs and up to four FRs, arranged from amino terminus to carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4, for example.

[0046] Depending on the amino acid sequence of the constant domain of their heavy chains, intact antibodies can be assigned to different "classes." There are five major classes of intact antibodies: IgA, IgD, IgE, IgG, and IgM, and some of these can be further divided into "subclasses" (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The preferred class of immunoglobulin for use in the present invention is IgG.

[0047] The heavy chain constant domains corresponding to different classes of antibodies are called "alpha," "delta," "epsilon," "gamma," and "mu," respectively. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known. As used herein, "antibody" refers to conventionally known antibodies and functional fragments thereof.

[0048] A "human" antibody or antigen-binding fragment thereof is generally defined as one that is not chimeric (e.g., not "humanized") and not derived (in whole or in part) from a non-human species. A human antibody or antigen-binding fragment thereof may be of human origin or may be a synthetic human antibody. A "synthetic human antibody" is defined herein as an antibody having a sequence derived in silico, in whole or in part, from a synthetic sequence based on analysis of known human antibody sequences. In silico design of a human antibody sequence or fragment thereof can be achieved, for example, by analyzing a database of human antibody or antibody fragment sequences and devising a polypeptide sequence using the data obtained therefrom. Another example of a human antibody or antigen-binding fragment thereof is one encoded by a nucleic acid isolated from a library of antibody sequences of human origin (e.g., such a library is based on antibodies taken from natural human sources).

[0049] A "humanized antibody" or humanized antigen-binding fragment thereof is generally defined herein as (i) an antibody derived from a non-human source (e.g., a transgenic mouse with a heterologous immune system) based on human germline sequences; (ii) an antibody in which amino acids in the framework regions of a non-human antibody have been partially replaced with human amino acid sequences by genetic engineering; or (iii) a CDR-grafted antibody in which the CDRs of the variable domain are derived from a non-human source, but one or more frameworks of the variable domain are of human origin, and the constant domains, if present, are of human origin.

[0050] A "chimeric antibody" or antigen-binding fragment thereof is generally defined herein as one in which the variable domains are derived from non-human origin and some or all of the constant domains are derived from human origin.

[0051] The term "monoclonal antibody," as used herein, generally refers to an antibody obtained from a population of substantially homogeneous antibodies; i.e., the individual antibodies comprising the population are identical except for possible minor mutations, e.g., naturally occurring mutations. Thus, the term "monoclonal" indicates the character of the antibody as not being a mixture of individual antibodies. In contrast to polyclonal antibody preparations, which typically contain different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen. In addition to their specificity, monoclonal antibody preparations are advantageous in that they are typically uncontaminated by other immunoglobulins. The term "monoclonal" should not be construed as requiring production of the antibody by any particular method. The term monoclonal antibody specifically includes chimeric, humanized, and human antibodies.

[0052] "Binding affinity" or "affinity" generally refers to the strength of the sum total of non-covalent interactions between a single binding site of a molecule and its binding partner. Unless otherwise indicated, as used herein, "binding affinity" refers to the intrinsic binding affinity that reflects a 1:1 interaction between members of a binding pair (e.g., an antibody and an antigen). The dissociation constant "K D " is generally used to describe the affinity between a molecule (e.g., an antibody) and its binding partner (e.g., an antigen), i.e., how tightly a ligand binds to a particular protein. Ligand-protein affinity is influenced by non-covalent intermolecular interactions between the two molecules. Affinity can be measured by common methods known in the art, including those described herein. In one embodiment, "K" in accordance with the present invention is D " or "K DThe "value" is measured by using a surface plasmon resonance assay using a suitable device, including but not limited to a Biacore instrument such as a Biacore T100, Biacore T200, Biacore 2000, Biacore 4000, Biacore 3000 (GE Healthcare Biacore, Inc.), or a ProteOn XPR36 instrument (Bio-Rad Laboratories, Inc.).

[0053] The term "antibody drug conjugate" or abbreviated ADC is well known to those skilled in the art and, as used herein, generally refers to the linkage of an antibody or antigen-binding fragment thereof with a drug such as a chemotherapeutic agent, a toxin, an immunotherapeutic agent, an imaging probe, and the like.

[0054] The term "small molecule," as used herein, generally refers to an organic molecule containing at least two carbon atoms, having a molecular weight in the range of 100-2000 daltons, preferably 100-1000 daltons, and optionally containing one or two metal atoms. Optionally, a small molecule may also contain one or more heteroatoms, such as, for example, N, O, S, P, and / or halogens.

[0055] The present disclosure also relates to "pharmaceutically acceptable salts." Any pharmaceutically acceptable salt can be used. In particular, the term "pharmaceutically acceptable salts" refers to salts of the conjugates or compounds of the present invention that are pharmaceutically acceptable and possess the desired pharmacological activity of the parent compound. In particular, such salts have low toxicity and can be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include (1) salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or salts formed with acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2 or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or when coordinated with an organic base, e.g., ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc. Salts further include, but are not limited to, salts formed with organic acids such as .2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc. Salts further include, purely by way of example, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc.; and, if the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, e.g., hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, etc. To maintain electronic neutrality, counterions or anionic counterions can be used in quaternary amines. Exemplary counterions include halide ions (e.g., F -, Cl - , Br - , I - ), NO3 - , ClO4 - , O.H. - , H2PO4 - , HSO4 - , sulfonate ions (e.g., methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, 10-camphorsulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1-sulfonic acid-5-sulfonic acid, etc.), and carboxylate ions (e.g., acetic acid, ethanoic acid, propanoic acid, benzoic acid, glyceric acid, lactic acid, tartaric acid, glycolic acid, etc.).

[0056] As used herein, the term "solvate" may refer to an aggregate containing one or more molecules of a conjugate or compound described herein and one or more molecules of a solvent. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the conjugate or compound of the present disclosure may exist as a hydrate, including a monohydrate, a dihydrate, a hemihydrate, a sesquihydrate, a trihydrate, a tetrahydrate, etc., as well as corresponding solvated forms. The compounds of the present invention may be true solvates, while in other cases, the compounds of the present invention may simply retain incidental water or may be a mixture of water and incidental solvent.

[0057] Conjugates of formula (I) The present invention relates to a conjugate having formula (I), or a pharmaceutically acceptable salt or solvate thereof: TIFF2025542295000023.tif35128 formula, RBM is a receptor binding molecule; L is a linker; M, O, NR M60 , or S; R M60 is hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C10 ) aryl; U is O or S; X is O, S, or NR X10 and; R X10 is hydrogen; or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; D is a drug moiety; Y 1 is NR A20 , O, S, or CR A21 R A22 and; R A20 is hydrogen, (C1-C8) alkyl, (C6-C 10 ) aryl, and C1-C8) alkylene (C6-C 10 ) aryl; R A21 and R A22 are each independently hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 ) aryl; E is a spacer; Z is a cleavable group; W is a spacer E, Y after cleavage of group Z. 1 and a moiety capable of forming a ring together with phosphorus; and n is an integer ranging from 1 to 20.

[0058] The moiety U, whenever referred to herein, can be O (oxygen) or S (sulfur). Preferably, U is oxygen. Thus, in a preferred embodiment, the conjugate has the following structure: TIFF2025542295000024.tif35128. In the present disclosure, whenever O (oxygen) is shown in place of U, such as in formula (I), (Ia), (Ia1), (Ia2), (Ib), (Ib1), (Ic), (Ic1), (Id), (Id1), (Ie), (Ie1), (If), (If1), (II), (IIa), (IIa1), (IIa2), (IIb), (IIb1), (IIc), (IIc1), (IId1), (IIe), (IIe1), (IIf) or (IIf1), oxygen can be replaced with S (sulfur). However, for the sake of brevity, the respective formulas containing S instead of O are not shown. It should be noted again that in this context, U is preferably O.

[0059] The conjugate of formula (I) has the structure: a receptor binding molecule (RBM), such as an antibody, linked to a drug moiety (D) via a phosphorus (V) moiety and a linker, having TIFF2025542295000025.tif18128; where: M is as described herein; U is O or S; X is O, S, or NR X10 and; D is a drug moiety; Y 1 is NR A20 , O, S, or CR A21 R A22 and; E is a spacer; Z is a cleavable group; and W is a spacer E, Y after cleavage of group Z. 1 and a moiety capable of forming a ring together with the phosphorus. The conjugates of formula (I) have been found to have advantageous properties, as shown below.

[0060] The conjugates of Formula (I) having a phosphorus (V) moiety as described herein exhibit good cytotoxicity, which is selective for cell lines targeted by receptor-binding molecules such as antibodies (Example 3 and Figures 45, 46, 47, 48, 49, and 50). Thus, the conjugates of Formula (I) enable targeted delivery of drugs mediated by specific binding of receptor-binding molecules such as antibodies. The conjugates of Formula (I) having a phosphorus (V) moiety as described herein can even achieve improved efficacy compared to the commercially available Trodelvy when the same antibody (sacituzumab) and drug (SN38) are used, with only the CL2A linker of Trodelvy replaced by a linker according to an embodiment of the present invention (Example 3 and Figure 45). In particular, the conjugates of Formula (I) exhibit superior serum stability over the commercially available conjugates Trodelvy and Enhertz (Example 4 and Figures 51 and 52). The conjugates of formula (I) also exhibit superior efficacy in vivo, for example, when compared to Trodelvy (Example 5 and Figure 122; for comparison with Trodelvy, the same antibody (sacituzumab) and drug (SN38) are used, and the CL2A linker of Trodelvy is replaced with a linker according to an embodiment of the present invention). Good efficacy is also demonstrated for different structures of linker and drug, allowing for broad applicability of the technology described herein (Examples 6, 7, and 8; and Figures 123, 124, and 125). In summary, the inventors have surprisingly found that the conjugates of the present invention exhibit superior properties that make them useful as pharmaceuticals, including enhanced serum stability and superior in vitro and in vivo efficacy.Conjugates containing a phosphorus (V) moiety are described, for example, in J.C. Kern et al., “Discovery of pyrophosphate diesters as tunable, soluble, and biorthogonal linkers for site-specific antibody-drug conjugates,” J. Am. Chem. Soc. 2016, 138, 4, 1430-1445 (https: / / doi.org / 10.1021 / jacs.5b12547); P. Brandish et al., “Development of Anti-CD74 Antibody-Drug Conjugates to Target Glucocorticoids to Immune Cells,” Bioconjugate Chem. 2018, 29, 7, 2357-2369 (https: / / doi.org / 10.1021 / acs.bioconjchem.8b00312); J.C. Kern et al., “Novel Phosphate Modified Cathepsin B Linkers: Improving Aqueous Solubility and Enhancing Payload Scope of ADCs”, Bioconjugate Chem. 2016, 27, 9, 2081-2088 (https: / / doi.org / 10.1021 / acs.bioconjchem.6b00337); WO 2018 / 041985; WO 2019 / 170710; and WO 2022 / 223783.The methylene alkoxy carbamate unit has been described for targeted delivery of hydroxy-containing drugs by RV Kolakowski et al., “The Methylene Alkoxy Carbamate Self-Immolative Unit: Utilization for the Targeted Delivery of Acohol-Containing Payloads with Antibody-Drug Conjugates”, Angew. Chem. Int. Ed. 2016, 55, 28, 7948-7951 (https: / / doi.org / 10.1002 / anie.201601506).

[0061] Without wishing to be bound by theory, the inventors believe that the mechanism of drug release from the conjugate of formula (I) is as provided below. As described herein, the conjugate of formula (I) comprises a moiety TIFF2025542295000026.tif10128. The group Z is a cleavable group (or, in other words, a removable or separable group). In this context, the term "cleavable group" specifically means that the bond between groups W and Z is cleavable, such that group Z is separable from group W. Thus, the bond between groups W and Z is susceptible to cleavage, such as, for example, enzymatic cleavage, acid-induced cleavage, light-induced cleavage, or disulfide bond cleavage, preferably under conditions under which the drug moiety and / or receptor-binding molecule remain active. As explained, the bond between groups W and Z is susceptible to enzymatic cleavage. Enzymatic cleavage includes, but is not limited to, protease-induced cleavage, peptidase-induced cleavage, esterase-induced cleavage, thioesterase-induced cleavage, glycosidase-induced cleavage (e.g., glucuronidase-induced cleavage), phosphatase-induced cleavage, and sulfatase-induced cleavage. Moiety TIFF2025542295000027.tif10128 (wherein Z is a cleavable group as contained in the conjugate of formula (I)) are known to those skilled in the art and can be readily selected; illustrative, but non-limiting examples can include ester groups, thioester groups, amide groups, glycosides, disulfides; phosphates and sulfates. The group Z can be any suitable group, for example, an optionally substituted aliphatic residue or an optionally substituted aromatic residue.

[0062] An illustrative but non-limiting example of TIFF2025542295000028.tif10128 is an ester group TIFF2025542295000029.tif16128, where R can be, for example, an alkyl group such as isopropyl; the ester group can be hydrolyzed, for example, by an esterase, to a carboxylic acid or carboxylate, i.e., TIFF2025542295000030.tif19128 and alcohol cleavage of the ester group by hydrolysis can occur inside the cell without the aid of an enzyme; therefore, the cleavable group Z can be TIFF2025542295000032.tif10128; after cleavage of group Z, the moiety W is a carboxylic acid or carboxylate, i.e. The file is TIFF2025542295000033.tif17128.

[0063] According to another illustrative but non-limiting example: TIFF2025542295000034.tif9128 is a thioester group TIFF2025542295000035.tif17128, where R can be, for example, an alkyl group such as isopropyl; the thioester group is hydrolyzed by a thioesterase to a carboxylic acid or carboxylate, i.e., TIFF2025542295000036.tif19128 and thiol TIFF2025542295000037.tif8128; thus, the cleavable group Z is TIFF2025542295000038.tif10128; after cleavage of group Z, the moiety W is a carboxylic acid or carboxylate, i.e. TIFF2025542295000039.tif18128.

[0064] According to another illustrative but non-limiting example: TIFF2025542295000040.tif10128 indicates an amide group, e.g., TIFF2025542295000041.tif17128, where R can be, for example, an alkyl group, or an amino acid, or a peptide; the amide group can be hydrolyzed by a peptidase or protease to a carboxylic acid or carboxylate, i.e., TIFF2025542295000042.tif18128 and Amine TIFF2025542295000043.tif8128; thus, the cleavable group Z is TIFF2025542295000044.tif12128; after cleavage of group Z, the moiety W is a carboxylic acid or carboxylate, i.e., The file is TIFF2025542295000045.tif18128.

[0065] According to another illustrative but non-limiting example: TIFF2025542295000046.tif9128 is a glycoside TIFF2025542295000047.tif10128, where Su is a sugar moiety; glycosides are hydrolyzed by glycosidases to give alcohols. TIFF2025542295000048.tif9128 and sugars TIFF2025542295000049.tif8128; thus, the cleavable group Z is Su; after cleavage of group Z, the moiety W is a hydroxy group TIFF2025542295000050.tif9128.

[0066] According to another illustrative but non-limiting example: TIFF2025542295000051.tif10128 is a disulfide TIFF2025542295000052.tif10128, where R can be an alkyl group such as isopropyl; the disulfide bond can be enzymatically reduced to form two thiols. TIFF2025542295000053.tif10128; thus, the cleavable group Z is TIFF2025542295000054.tif9128; after cleavage of group Z, moiety W is a thiol group The file is TIFF2025542295000055.tif9128.

[0067] According to another illustrative but non-limiting example: TIFF2025542295000056.tif10128 indicates an amide group, e.g., TIFF2025542295000057.tif17128, where R can be, for example, an alkyl group, or an amino acid, or a peptide; the amide group can be hydrolyzed by a peptidase or protease to form an amine TIFF2025542295000058.tif10128 and carboxylic acid TIFF2025542295000059.tif15128; thus, the cleavable group Z is TIFF2025542295000060.tif15128; after cleavage of group Z, moiety W becomes an amine TIFF2025542295000061.tif10128.

[0068] According to another illustrative but non-limiting example: TIFF2025542295000062.tif10128 refers to ester groups, e.g., TIFF2025542295000063.tif15128, where R can be an alkyl group such as, for example, methyl, ethyl, or isopropyl; the ester group can be hydrolyzed, for example, by an esterase, to give an alcohol. TIFF2025542295000064.tif9128 and carboxylic acid TIFF2025542295000065.tif15128; thus, the cleavable group Z is TIFF2025542295000066.tif15128; after cleavage of group Z, moiety W is an alcohol TIFF2025542295000067.tif9128. Such cleavage mechanisms can occur, for example, at the target site, as known to those skilled in the art, or such cleavage mechanisms can occur intracellularly after internalization of the conjugate.

[0069] As described herein, in the conjugate of formula (I), "W is a spacer E, Y after cleavage of group Z." 1 and a moiety capable of forming a ring together with phosphorus. Preferably, W is a moiety that, after cleavage of group Z, is free to form a ring containing spacers E, Y 1 and a moiety capable of forming a 4- to 7-membered ring together with phosphorus. More preferably, W is a moiety capable of forming a 5- or 6-membered ring after cleavage of group Z. Thus, without wishing to be bound by theory, it is speculated that at a mechanistic level, group W performs an intramolecular attack on the phosphorus atom after cleavage of group Z. TIFF2025542295000068.tif10128 is then released from the conjugate, i.e., the drug is liberated. A possible mechanistic sequence involving cleavage of group Z, followed by intramolecular attack of W on the phosphorus atom in intermediate A and release of the drug moiety (XD), can be depicted as follows: TIFF2025542295000069.tif41147

[0070] However, other pathways for further reaction of intermediate A are possible. For example, another possible mechanistic sequence is postulated to involve cleavage of group Z followed by intramolecular attack of W on the phosphorus atom in intermediate A; Release of TIFF2025542295000070.tif9128 and hydrolysis of intermediate B-2 can lead to intermediate C-1, from which the drug moiety (XD) can be released under intracellular conditions, for example, by hydrolysis or with the aid of phosphordiesterase; this possible mechanism is depicted as follows: TIFF2025542295000071.tif63148

[0071] As a further possible alternative, the speculated mechanism may again involve cleavage of group Z followed by intramolecular attack of W on the phosphorus atom in intermediate A; W, phosphorus atom, Y 1 and E; 1 Release of the compound (XD), hydrolysis to give intermediate C-3, and release of the drug moiety (XD) under intracellular conditions, e.g., by hydrolysis or with the aid of a phosphordiesterase, can be further steps, as depicted below. TIFF2025542295000072.tif58149

[0072] According to the above discussion of possible release mechanisms, moiety W may be capable of nucleophilic attack on the phosphorus atom after cleavage of group Z. Thus, after cleavage of group Z, moiety W is particularly nucleophilic. In this regard, after cleavage of group Z, moiety W as described herein above, i.e. TIFF2025542295000073.tif19128 is nucleophilic, as would be readily understood by one skilled in the art. TIFF2025542295000074.tif10128 can be considered a leaving group. TIFF2025542295000075.tif10128 may be considered a releasable portion. TIFF2025542295000076.tif10128 can be released after cleavage of group Z. TIFF2025542295000077.tif9128 may be released upon or after attack of group W on phosphorus after cleavage of group Z. In particular, the moiety TIFF2025542295000078.tif10128 shows the cleavage of group Z, as well as W, spacers E and Y. 1 and phosphorus, followed by the formation of a ring, preferably a 4- to 7-membered ring, more preferably a 5- or 6-membered ring. Thus, without wishing to be bound by theory, in the proposed possible mechanistic sequence, the reaction of A to give B-1, B-2, or B-3 can be considered an intramolecular nucleophilic substitution. In particular, group Z can be cleaved at the target site to initiate a reaction leading to the release of moiety XD.

[0073] As can be seen, the proposed mechanisms found herein all follow those proposed for prodrugs of nucleoside analogs, in which the hydroxy group of the monophosphate or monophosphonate group is masked; see, e.g., Y. Mehellou et al., "The ProTide Prodrug Technology: From the Concept to the Clinic", J. Med. Chem. 2018, 61, 2211-2226 (DOI: 10.1021 / acs.jmedchem.7b00734).

[0074] As also described herein, the moiety W may be formed by cleaving the group Z followed by the spacers E, Y 1 and phosphorus to form a ring. Preferably, the moiety W is connected to the spacer E, Y after cleavage of the group Z. 1 and phosphorus to form a 4- to 7-membered ring. More preferably, the moiety W is preferably a 4- to 7-membered ring after cleavage of the group Z, which is then joined to the spacers E, Y 1 and phosphorus together to form a 5- or 6-membered ring. As described herein, Y 1 is NRA20 , O, S or CR A21 R A22 where R A20 , R A21 and R A22 is as described herein. Those skilled in the art will appreciate that Y 1 and the portion of group W (or group Z before cleavage) together with phosphorus to give a suitable ring size. TIFF2025542295000079.tif9128) and E can be readily selected. The term "spacer" as used herein generally refers to a group Y 1 and W. The spacer E refers to a chemical group or moiety that serves to link Y 1 There is no particular limitation as long as it is suitable for forming a ring (preferably a 4- to 7-membered ring, more preferably a 5- or 6-membered ring) together with W and phosphorus. It can be a suitable alkylene group containing 1, 2, 3 or 4 main chain atoms, such as TIFF2025542295000080.tif42149; the group R indicates that the alkylene group may be substituted; it should be noted that the number and position of optional substituents may vary and can be easily adjusted by those skilled in the art as needed; it is also possible that two substituents of the alkylene group can form a ring. Furthermore, spacer E can include a cyclic moiety. Thus, as a further illustrative but non-limiting example, spacer E can be: TIFF2025542295000081.tif22128, which may be an optionally substituted 4- to 7-membered, preferably 5- or 6-membered, carbocyclic or heterocyclic ring; or, as a more specific example, spacer E may be TIFF2025542295000082.tif19128. Optionally, the spacer E may contain one or more heteroatoms, such as O, N, or S, and / or may be substituted. The moiety Y 1 Further examples of E, W and Z are described herein.

[0075] Base Y 1Whenever referred to herein, NR A20 , O, S, or CR A21 R A22 wherein R A20 , R A21 and R A22 is as defined herein. Thus, R A20 is hydrogen, (C1-C8) alkyl (e.g., methyl, ethyl, or propyl), (C6-C 10 ) aryl (e.g., phenyl), and (C1-C8) alkylene (C6-C 10 ) aryl (e.g., benzyl). Preferably, R A20 is hydrogen or (C1-C8) alkyl. More preferably, R A20 is hydrogen or (C1-C6) alkyl, even more preferably hydrogen or (C1-C4) alkyl, and even more preferably hydrogen or (C1-C2) alkyl. In a preferred embodiment, R A20 is hydrogen. R A21 and R A22 are each independently hydrogen, (C1-C8) alkyl (e.g., methyl, ethyl, or propyl), (C6-C 10 ) aryl (e.g., phenyl), and (C1-C8) alkylene (C6-C 10 ) aryl (e.g., benzyl). Preferably, R A21 and R A22 are each independently selected from the group consisting of hydrogen or (C1-C8) alkyl. More preferably, R A21 and R A22 are each independently hydrogen or (C1-C6) alkyl, even more preferably hydrogen or (C1-C4) alkyl, and even more preferably hydrogen or (C1-C2) alkyl. In a preferred embodiment, R A21 and R A22 is hydrogen. In some embodiments, Y 1 is NR A20 where R A20 is as defined herein. In some embodiments, Y 1is O. In some embodiments, Y 1 is S. In some embodiments, Y 1 is CR A21 R A22 where R A20 and R A21 is as defined herein.

[0076] Preferably, Y 1 is NR A20 , O and S, where R A20 is as defined herein. More preferably, Y 1 is NR A20 or O, where R A20 is as defined herein. More preferably, Y 1 is NH or O. Even more preferably, Y 1 is NR A20 where R A20 is as defined herein.

[0077] In some preferred embodiments, Y 1 is NH.

[0078] In some preferred embodiments, Y 1 is O.

[0079] In the conjugate of formula (I), for example, RBM, L, M, X, D, Y 1 Any variable such as , E, W, Z, and n can be as defined herein.

[0080] Conjugates having groups cleavable by hydrolysis, esterases, thioesterases, proteases, or peptidases In some preferred embodiments, the conjugate has formula (Ia), or a pharmaceutically acceptable salt or solvate thereof: TIFF2025542295000083.tif40128 formula, RBM is a receptor binding molecule; L is a linker; M, O, NR M60, or S; R M60 is hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 ) aryl; X is O, S, or NR X10 and; R X10 is hydrogen; or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; D is a drug moiety; Y 1 is NR A20 , O, S, or CR A21 R A22 and; R A20 is hydrogen, (C1-C8) alkyl, (C6-C 10 ) aryl, and C1-C8) alkylene (C6-C 10 ) aryl; R A21 and R A22 are each independently hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 ) aryl; A is CR A30 R A31 or A is (C1-C8)alkylene, where (C1-C8)alkylene is selected from the group consisting of (C1-C8)alkyl, halo, hydroxy, (C1-C8)alkoxy, amino, (C1-C8)alkylamino, di(C1-C8)alkylamino, SH, (C1-C8)alkylthio, (C3-C8)heterocyclyl, carboxylates and esters thereof, carboxy(C1-C8)alkyl, CONHR A36 and CONR A36 R A37 and R A36 and R A37are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 ) aryl; R A30 and R A31 are each independently hydrogen, (C1-C8) alkyl, (C3-C8) cycloalkyl, (C2-C8) alkenyl, (C5-C8) cycloalkenyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 )aryl; wherein each of (C1-C8)alkyl, (C3-C8)cycloalkyl, (C2-C8)alkenyl, (C5-C8)cycloalkenyl, (C6-C 10 )aryl or (C1-C8)alkylene (C6-C 10 )Aryl is (C1-C8)alkyl, halo, hydroxy, (C1-C8)alkoxy, amino, (C1-C8)alkylamino, di(C1-C8)alkylamino, SH, (C1-C8)alkylthio, (C3-C8)heterocyclyl, carboxylates and their esters, carboxy(C1-C8)alkyl, CONHR A36 and CONR A36 R A37 and R A36 and R A37 are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 ) aryl; optionally, R A30 and R A31 can be joined together to form a 3- to 8-membered ring; Y 2 is NR B20 , O, S, or CR B21 R B22 and; R B20 is hydrogen, (C1-C8) alkyl, (C6-C 10 ) aryl, and C1-C8) alkylene (C6-C 10) aryl; R B21 and R B22 are each independently hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 ) aryl; B is independently CR B30 R B31 or B is, independently at each occurrence, (C1-C8)alkylene, where (C1-C8)alkylene is selected from (C1-C8)alkyl, halo, hydroxy, (C1-C8)alkoxy, amino, (C1-C8)alkylamino, di(C1-C8)alkylamino, SH, (C1-C8)alkylthio, (C3-C8)heterocyclyl, carboxylates and esters thereof, carboxy(C1-C8)alkyl, CONHR B36 and CONR B36 R B37 and R B36 and R B37 are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 ) aryl; R B30 and R B31 are each independently hydrogen, (C1-C8) alkyl, (C3-C8) cycloalkyl, (C2-C8) alkenyl, (C5-C8) cycloalkenyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 )aryl; wherein each of (C1-C8)alkyl, (C3-C8)cycloalkyl, (C2-C8)alkenyl, (C5-C8)cycloalkenyl, (C6-C 10 )aryl or (C1-C8)alkylene (C6-C 10)Aryl is (C1-C8)alkyl, halo, hydroxy, (C1-C8)alkoxy, amino, (C1-C8)alkylamino, di(C1-C8)alkylamino, SH, (C1-C8)alkylthio, (C3-C8)heterocyclyl, carboxylates and their esters, carboxy(C1-C8)alkyl, CONHR B36 and CONR B36 R B37 and R B36 and R B37 are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 ) aryl; optionally, R B30 and R B31 can be joined together to form a 3- to 8-membered ring; m is an integer ranging from 0 to 15; Y 3 , O, NR C40 , or S, or absent; R C40 is hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 ) aryl; J is TIFF2025542295000084.tif18128, where TIFF2025542295000085.tif7128 is Y 3 Indicates the connection to; C is CR C50 R C51 or C is (C1-C8) alkylene, where (C1-C8) alkylene is selected from the group consisting of (C1-C8) alkyl, halo, hydroxy, (C1-C8) alkoxy, amino, (C1-C8) alkylamino, di(C1-C8) alkylamino, SH, (C1-C8) alkylthio, (C3-C8) heterocyclyl, carboxylates and esters thereof, carboxy(C1-C8) alkyl, CONHR C36 and CONR C36 R C37 and R C36 and R C37 are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 ) aryl; R C50 and R C51 are each independently hydrogen, (C1-C8) alkyl, (C3-C8) cycloalkyl, (C2-C8) alkenyl, (C5-C8) cycloalkenyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 )aryl; wherein each of (C1-C8)alkyl, (C3-C8)cycloalkyl, (C2-C8)alkenyl, (C5-C8)cycloalkenyl, (C6-C 10 )aryl or (C1-C8)alkylene (C6-C 10 )Aryl is (C1-C8)alkyl, halo, hydroxy, (C1-C8)alkoxy, amino, (C1-C8)alkylamino, di(C1-C8)alkylamino, SH, (C1-C8)alkylthio, (C3-C8)heterocyclyl, carboxylates and their esters, carboxy(C1-C8)alkyl, CONHR C36 and CONR C36 R C37 and R C36 and R C37are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 ) aryl; optionally, R C50 and R C51 can be joined together to form a 3- to 8-membered ring; Y 4 , O, NR C53 , S, or CR C54 R C55 is or is not present; R C52 is hydrogen, (C1-C8) alkyl, (C3-C8) cycloalkyl, (C2-C8) alkenyl, (C5-C8) cycloalkenyl, (C3-C8) heterocyclyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 )aryl; wherein each (C1-C8)alkyl, (C3-C8)cycloalkyl, (C2-C8)alkenyl, (C5-C8)cycloalkenyl, (C3-C8)heterocyclyl, (C6-C 10 )aryl or (C1-C8)alkylene (C6-C 10 )Aryl is (C1-C8)alkyl, halo, hydroxy, (C1-C8)alkoxy, amino, (C1-C8)alkylamino, di(C1-C8)alkylamino, SH, (C1-C8)alkylthio, (C3-C8)heterocyclyl, carboxylates and their esters, carboxy(C1-C8)alkyl, CONHR C56 and CONR C56 R C57 and R C56 and R C57 are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 ) aryl; R C53 is hydrogen, (C1-C8) alkyl, (C6-C 10)aryl, and (C1-C8)alkylene (C6-C 10 ) aryl; R C54 and R C55 are each independently hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 ) aryl; or J is hydrogen, (C1-C8) alkyl, (C3-C8) cycloalkyl, (C2-C8) alkenyl, (C5-C8) cycloalkenyl, (C3-C8) heterocyclyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 )aryl; wherein each (C1-C8)alkyl, (C3-C8)cycloalkyl, (C2-C8)alkenyl, (C5-C8)cycloalkenyl, (C3-C8)heterocyclyl, (C6-C 10 )aryl or (C1-C8)alkylene (C6-C 10 )Aryl is (C1-C8)alkyl, halo, hydroxy, (C1-C8)alkoxy, amino, (C1-C8)alkylamino, di(C1-C8)alkylamino, SH, (C1-C8)alkylthio, (C3-C8)heterocyclyl, carboxylates and their esters, carboxy(C1-C8)alkyl, CONHR C46 and CONR C46 R C47 and R C46 and R C47 are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 ) aryl; and n is an integer ranging from 1 to 20.

[0081] Thus, in these embodiments, the group of formula (I) TIFF2025542295000086.tif12128 is TIFF2025542295000087.tif33128, where: TIFF2025542295000088.tif7128 is Y 1 indicates a connection to; and A, Y 2 , B, Y 3 and J is as defined herein.

[0082] In particular, the group A represents the spacer E; TIFF2025542295000089.tif28128 represents a cleavable group Z when m is not 0, or a group TIFF2025542295000090.tif11128 represents the cleavable group Z when m is 0; and the moiety W is a carboxylic acid or carboxylate after cleavage of group Z. TIFF2025542295000091.tif18128. In these embodiments, the group Z may be, for example, a protease-induced cleavage (Y 2 or Y 3 is NR B20 ), peptidase-induced cleavage (Y 2 or Y 3 is NR B20 ), esterase-induced cleavage (Y 2 or Y 3 is O) or thioesterase-induced cleavage (Y 2 or Y 3 is S); Y 2 or Y 3 is O (i.e., the group If the ester group is TIFF2025542295000092.tif10128, cleavage can occur by hydrolysis inside the cell without the aid of an enzyme. The carbonyl carbon atom adjacent to A and, if present, Y 2 (m is not 0), or the bond between the carbonyl carbon atom adjacent to A and Y 3(m is 0) can be cleaved. The group Z can be cleaved at the target site to initiate a reaction leading to release of the XD moiety.

[0083] The integer m ranges from 0 to 15. Thus, the integer m can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. The integer m can range from 0 to 12. Preferably, the integer m ranges from 0 to 10. More preferably, the integer m ranges from 0 to 8. Even more preferably, the integer m ranges from 0 to 5. Even more preferably, the integer m ranges from 0 to 3. Even more preferably, the integer m is 0 or 1. When the integer m is 0, the group Y 2 and B does not exist.

[0084] In some preferred embodiments, the integer m is 0. Thus, the conjugate has the formula (Ia1), or a pharmaceutically acceptable salt or solvate thereof: TIFF2025542295000093.tif37128 where RBM, L, M, X, D, Y 1 , A, Y 3 , J and n are as defined herein.

[0085] Groups Y1 and A Base Y 1 is as described herein for any conjugate of formula (I). 1 is NR A20 , O, S, or CR A21 R A22 where R A20 , R A21 and R A22 is as defined herein. A20 is hydrogen, (C1-C8) alkyl (e.g., methyl, ethyl, or propyl), (C6-C 10 ) aryl (e.g., phenyl), and (C1-C8) alkylene (C6-C 10 ) aryl (e.g., benzyl). Preferably, R A20is hydrogen or (C1-C8) alkyl. More preferably, R A20 is hydrogen or (C1-C6) alkyl, even more preferably hydrogen or (C1-C4) alkyl, and even more preferably hydrogen or (C1-C2) alkyl. In a preferred embodiment, R A20 is hydrogen. R A21 and R A22 are each independently hydrogen, (C1-C8) alkyl (e.g., methyl, ethyl, or propyl), (C6-C 10 ) aryl (e.g., phenyl), and (C1-C8) alkylene (C6-C 10 ) aryl (e.g., benzyl). Preferably, R A21 and R A22 are each independently selected from the group consisting of hydrogen or (C1-C8) alkyl. More preferably, R A21 and R A22 are each independently hydrogen or (C1-C6) alkyl, even more preferably hydrogen or (C1-C4) alkyl, and even more preferably hydrogen or (C1-C2) alkyl. In a preferred embodiment, R A21 and R A22 is hydrogen. In some embodiments, Y 1 is NR A20 where R A20 is as defined herein. In some embodiments, Y 1 is O. In some embodiments, Y 1 is S. In some embodiments, Y 1 is CR A21 R A22 where R A20 and R A21 is as defined herein.

[0086] Preferably, Y 1 is NR A20 , O and S, where R A20 is as defined herein. More preferably, Y 1 is NR A20 or O, where RA20 is as defined herein. More preferably, Y 1 is NH or O. Even more preferably, Y 1 is NR A20 where R A20 is as defined herein.

[0087] In some preferred embodiments, Y 1 is NH.

[0088] In some preferred embodiments, Y 1 is O.

[0089] In some preferred embodiments, A is CR A30 R A31 where R A30 and R A31 is as defined herein. Preferably, R A30 and R A31 are each independently hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 ) aryl. More preferably, R A30 and R A31 are each independently hydrogen, (C1-C8) alkyl, and (C1-C8) alkylene (C6-C 10 ) aryl. Even more preferably, R A30 and R A31 are each independently selected from the group consisting of hydrogen and (C-C) alkyl. Even more preferably, R A30 and R A31 are each independently selected from the group consisting of hydrogen, CH, CHCH, CHCHCH, CH(CH), CHCHCHCH, CH(CH)CHCH, CHCH(CH), C(CH), and benzyl. Even more preferably, R A30 and R A31are each independently selected from hydrogen and CH. In any one of these embodiments, R A30 and R A31 is (C1-C8) alkyl, halo, hydroxy, (C1-C8) alkoxy, amino, (C1-C8) alkylamino, di(C1-C8) alkylamino, SH, (C1-C8) alkylthio, (C3-C8) heterocyclyl, carboxylate and its esters, carboxy(C1-C8) alkyl, CONHR A36 and CONR A36 R A37 and R A36 and R A37 are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 ) aryl. Optionally, R A30 and R A31 can be taken together to form a 3- to 8-membered ring. In any one of these embodiments, R A30 and R A31 may be the same or different. Therefore, R A30 and R A31 can be the same. Alternatively, R A30 and R A31 In any one of these embodiments, Y 1 and may be as defined herein. Preferably, in any one of these embodiments, Y 1 is NR A20 or O, where R A20 is as defined herein. More preferably, in any one of these embodiments, Y 1 can be NH or O. Even more preferably, in any one of these embodiments, Y 1 is NR A20 where R A20 is as defined herein. Even more preferably, in any one of these embodiments, Y 1can be NH.

[0090] In some preferred embodiments, A is CR A30 R A31 where R A30 is hydrogen and R A31 is as defined herein. Therefore, R A30 can be hydrogen, and R A31 is hydrogen, (C1-C8) alkyl, (C3-C8) cycloalkyl, (C2-C8) alkenyl, (C5-C8) cycloalkenyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 In one of these embodiments, R A31 is not hydrogen. Preferably, R A30 is hydrogen and R A31 is hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 In one of these embodiments, R A31 is not hydrogen. More preferably, R A30 is hydrogen and R A31 is (C1-C8) alkyl, and (C1-C8) alkylene (C6-C 10 ) aryl. Even more preferably, R A30 is hydrogen and R A31 is (C1-C8) alkyl. Even more preferably, R A30 is hydrogen and R A31 is selected from the group consisting of hydrogen, CH3, CH2CH3, CH2CH3CH3, CH(CH3)2, CH2CH2CH2CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, and benzyl. A31 is not hydrogen. Even more preferably, R A30 is hydrogen and R A31 is CH3. In any one of these embodiments, R A31is (C1-C8) alkyl, halo, hydroxy, (C1-C8) alkoxy, amino, (C1-C8) alkylamino, di(C1-C8) alkylamino, SH, (C1-C8) alkylthio, (C3-C8) heterocyclyl, carboxylate and its esters, carboxy(C1-C8) alkyl, CONHR A36 and CONR A36 R A37 and R A36 and R A37 are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 In any one of these embodiments, Y is selected from aryl. 1 and may be as defined herein. Preferably, in any one of these embodiments, Y 1 is NR A20 or O, where R A20 is as defined herein. More preferably, in any one of these embodiments, Y 1 can be NH or O. Even more preferably, in any one of these embodiments, Y 1 is NR A20 where R A20 is as defined herein. Even more preferably, in any one of these embodiments, Y 1 can be NH.

[0091] A is CR A30 R A31 In the case where the group A is a carbonyl group adjacent to the carbonyl group and Y 1 may be combined with each other to form the group (Aa), which may be depicted as follows: TIFF2025542295000094.tif25128 where, An asterisk (*) indicates a connection to phosphorus; # is Y if present 2 (m is not 0) to or Y 3(m is 0) and Y 1 , R A30 and R A31 is as defined herein. A30 and R A31 may be the same or different. A30 and R A31 If different, R A30 and R A31 The carbon atom to which R is attached is a chiral center. A30 and R A31 The carbon atom to which is attached, if chiral, may be in the (S) or (R) configuration.

[0092] Preferably, R A30 is hydrogen and R A31 is as defined herein. Thus, the group (Aa) can be (Ab): TIFF2025542295000095.tif25128, where: An asterisk (*) indicates a connection to phosphorus; # is Y if present 2 (m is not 0) to or Y 3 (m is 0) and Y 1 and R A31 is as defined herein. A31 If is not hydrogen, then R A31 The carbon atom to which R is attached is a chiral center. A31 The carbon atom to which is attached, if chiral, may be in the (S) or (R) configuration.

[0093] More preferably, Y 1 is N RA20 Therefore, the group (Ab) is (Ac): TIFF2025542295000096.tif25128, where: An asterisk (*) indicates a connection to phosphorus; # is Y if present2 (m is not 0) to or Y 3 (m is 0) indicates the connection; R A20 is as defined herein; preferably, R A20 is hydrogen; and R A31 is as defined herein. In these embodiments, the group (Ac) represents an amino acid, particularly an α-amino acid. R A31 If is not hydrogen, then R A31 The carbon atom to which R is attached is a chiral center. A31 The carbon atom to which R is attached, if chiral, may be in the (S) or (R) configuration. A31 The carbon atom to which is attached, if chiral, is in the (S) configuration. In particular, the amino acid (i.e., group (Ac)) may be in the L or D configuration, except for non-chiral amino acids such as glycine. Preferably, in any one of the embodiments described herein, the amino acid (i.e., group (Ac)) is in the L configuration (i.e., the naturally occurring configuration). In some preferred embodiments, the amino acid is alanine, particularly L-alanine.

[0094] As mentioned above, A is CR A30 R A31 However, A is CR A30 R A31A is not limited to, but in some embodiments can be (C1-C8) alkylene. Preferably, in these embodiments, A is (C1-C6) alkylene. More preferably, A is (C1-C4) alkylene. Even more preferably, A is (C1-C3) alkylene. Even more preferably, A is (C2-C3) alkylene. In some embodiments, A is (C1-C2) alkylene. In some embodiments, A is C1-alkylene (methylene). In any one of these embodiments, alkylene ((C-C)alkylene, (C-C)alkylene, (C-C)alkylene, (C-C)alkylene, (C-C)alkylene, (C-C)alkylene, (C-C)alkylene, or C-alkylene(methylene)) is selected from the group consisting of (C-C)alkyl, halo, hydroxy, (C-C)alkoxy, amino, (C-C)alkylamino, di(C-C)alkylamino, SH, (C-C)alkylthio, (C-C)heterocyclyl, carboxylates and esters thereof, carboxy(C-C)alkyl, CONHR A36 and CONR A36 R A37 and R A36 and R A37 are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 ) aryl.

[0095] In some embodiments, A is TIFF2025542295000097.tif19128, where TIFF2025542295000098.tif7128 is a group Y 1 and indicates the connection to the carbonyl carbon atom. In TIFF2025542295000099.tif18128, one or more hydrogen atoms (particularly one hydrogen atom) may be selected from the group consisting of (C1-C8) alkyl, halo, hydroxy, (C1-C8) alkoxy, amino, (C1-C8) alkylamino, di(C1-C8) alkylamino, SH, (C1-C8) alkylthio, (C3-C8) heterocyclyl, carboxylates and esters thereof, carboxy(C1-C8) alkyl, CONHR A36 and CONR A36 R A37 wherein R may be the same or different. A36 and R A37 are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 In these embodiments, Y is selected from aryl. 1 is NR A20 where R A20 is as defined herein; preferably, where NR A20 is hydrogen. Therefore, Y 1 NR A20 In these embodiments, the group Y 1 , A and the adjacent carbonyl group form a β-amino acid: TIFF2025542295000100.tif24128 where: An asterisk (*) indicates a connection to phosphorus; # is Y if present 2 (m is not 0) to or Y 3 (m is 0) and R A20 is as defined herein; preferably R A20 is hydrogen; Optionally, part In TIFF2025542295000101.tif19128, one or more hydrogen atoms (particularly one hydrogen atom) may be selected from the group consisting of (C1-C8) alkyl, halo, hydroxy, (C1-C8) alkoxy, amino, (C1-C8) alkylamino, di(C1-C8) alkylamino, SH, (C1-C8) alkylthio, (C3-C8) heterocyclyl, carboxylates and esters thereof, carboxy(C1-C8) alkyl, CONHR A36 and CONR A36 R A37 wherein R may be the same or different. A36 and R A37 are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 ) aryl. In one embodiment, the β-amino acid can be β-alanine.

[0096] In some embodiments, A is TIFF2025542295000102.tif19128, where TIFF2025542295000103.tif7128 is a group Y 1 and indicates the connection to the carbonyl carbon atom. In TIFF2025542295000104.tif19128, one or more hydrogen atoms (particularly one hydrogen atom) may be selected from the group consisting of (C1-C8) alkyl, halo, hydroxy, (C1-C8) alkoxy, amino, (C1-C8) alkylamino, di(C1-C8) alkylamino, SH, (C1-C8) alkylthio, (C3-C8) heterocyclyl, carboxylate and its esters, carboxy(C1-C8) alkyl, CONHR A36 and CONR A36 R A37 wherein R may be the same or different. A36 and R A37are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 In these embodiments, Y is selected from aryl. 1 is NR A20 where R A20 is as defined herein; preferably, where NR A20 is hydrogen. Therefore, Y 1 NR A20 In these embodiments, the group Y 1 , A and the adjacent carbonyl group form a γ-amino acid: TIFF2025542295000105.tif23128, where: An asterisk (*) indicates a connection to phosphorus; # is Y if present 2 (m is not 0) to or Y 3 (m is 0) and R A20 is as defined herein; preferably R A20 is hydrogen; Optionally, part In TIFF2025542295000106.tif19128, one or more hydrogen atoms (particularly one hydrogen atom) may be selected from the group consisting of (C1-C8) alkyl, halo, hydroxy, (C1-C8) alkoxy, amino, (C1-C8) alkylamino, di(C1-C8) alkylamino, SH, (C1-C8) alkylthio, (C3-C8) heterocyclyl, carboxylate and its esters, carboxy(C1-C8) alkyl, CONHR A36 and CONR A36 R A37 wherein R may be the same or different. A36 and R A37 are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 ) aryl.

[0097] Base Y 2 and B Base Y 2 are, if present, each independently NR B20 , O, S, or CR B21 R B22 where R B20 , R B21 and R B22 is as defined herein. Therefore, R B20 is hydrogen, (C1-C8) alkyl (e.g., methyl, ethyl, or propyl), (C6-C 10 ) aryl (e.g., phenyl), and (C1-C8) alkylene (C6-C 10 ) aryl (e.g., benzyl). Preferably, R B20 is hydrogen or (C1-C8) alkyl. More preferably, R B20 is hydrogen or (C1-C6) alkyl, even more preferably hydrogen or (C1-C4) alkyl, and even more preferably hydrogen or (C1-C2) alkyl. In a preferred embodiment, R B20 is hydrogen. R B21 and R B22 are each independently hydrogen, (C1-C8) alkyl (e.g., methyl, ethyl, or propyl), (C6-C 10 ) aryl (e.g., phenyl), and (C1-C8) alkylene (C6-C 10 ) aryl (e.g., benzyl). Preferably, R B21 and R B22 are each independently selected from the group consisting of hydrogen or (C1-C8) alkyl. More preferably, R B21 and R B22 are each independently hydrogen or (C1-C6) alkyl, even more preferably hydrogen or (C1-C4) alkyl, and even more preferably hydrogen or (C1-C2) alkyl. In a preferred embodiment, R B21 and R B22 is hydrogen. In some embodiments, Y 2 is NRB20 where R B20 is as defined herein. In some embodiments, Y 2 is O. In some embodiments, Y 2 is S. In some embodiments, Y 2 is CR B21 R B22 where R B20 and R B21 is as defined herein.

[0098] Preferably, Y 2 are each independently, NR B20 , O and S, where R B20 is as defined herein. More preferably, Y 2 are each independently, NR B20 or O, where R B20 is as defined herein. More preferably, Y 2 are each independently NH or O. Even more preferably, each Y 2 is NR B20 where R B20 are each independently as defined herein.

[0099] In some preferred embodiments, each Y 2 is NH.

[0100] In some embodiments, each group B, if present, is independently selected from the group CR B30 R B31 where R B30 and R B31 is as defined herein. Preferably, R B30 and R B31 are each independently hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 ) aryl. More preferably, R B30 and R B31are each independently hydrogen, (C1-C8) alkyl, and (C1-C8) alkylene (C6-C 10 ) aryl. Even more preferably, R B30 and R B31 are each independently selected from the group consisting of hydrogen and (C-C) alkyl. Even more preferably, R B30 and R B31 are each independently selected from the group consisting of hydrogen, CH, CHCH, CHCHCH, CH(CH), CHCHCHCH, CH(CH)CHCH, CHCH(CH), C(CH), and benzyl. Even more preferably, R B30 and R B31 are each independently selected from hydrogen and CH. In any one of these embodiments, R B30 and R B31 is (C1-C8) alkyl, halo, hydroxy, (C1-C8) alkoxy, amino, (C1-C8) alkylamino, di(C1-C8) alkylamino, SH, (C1-C8) alkylthio, (C3-C8) heterocyclyl, carboxylate and its esters, carboxy(C1-C8) alkyl, CONHR B36 and CONR B36 R B37 and R B36 and R B37 are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 ) aryl. Optionally, R B30 and R B31 can be taken together to form a 3- to 8-membered ring. In any one of these embodiments, R B30 and R B31 may be the same or different. Therefore, R B30 and R B31 can be the same. Alternatively, R B30 and R B31In any one of these embodiments, Y 2 and may be as defined herein. Preferably, in any one of these embodiments, Y 2 is NR B20 or O, where R B20 is as defined herein. More preferably, in any one of these embodiments, Y 2 can be NH or O. Even more preferably, in any one of these embodiments, each Y 2 is NR B20 where R B20 and are each independently as defined herein. Even more preferably, in any one of these embodiments, Y 2 can be NH.

[0101] In some embodiments, group B, when present, is CR B30 R B31 where R B30 is hydrogen and R B31 is as defined herein. Therefore, R B30 can be hydrogen, and R B31 is hydrogen, (C1-C8) alkyl, (C3-C8) cycloalkyl, (C2-C8) alkenyl, (C5-C8) cycloalkenyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 In one of these embodiments, R B31 is not hydrogen. Preferably, R B30 is hydrogen and R B31 is hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 In one of these embodiments, R B31 is not hydrogen. More preferably, R B30 is hydrogen and R B31 is (C1-C8) alkyl, and (C1-C8) alkylene (C6-C 10) aryl. Even more preferably, R B30 is hydrogen and R B31 is (C1-C8) alkyl. Even more preferably, R B30 is hydrogen and R B31 is selected from the group consisting of hydrogen, CH3, CH2CH3, CH2CH3CH3, CH(CH3)2, CH2CH2CH2CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, and benzyl. B31 is not hydrogen. Even more preferably, R B30 is hydrogen and R B31 is CH3. In any one of these embodiments, R B31 is (C1-C8) alkyl, halo, hydroxy, (C1-C8) alkoxy, amino, (C1-C8) alkylamino, di(C1-C8) alkylamino, SH, (C1-C8) alkylthio, (C3-C8) heterocyclyl, carboxylate and its esters, carboxy(C1-C8) alkyl, CONHR B36 and CONR B36 R B37 and R B36 and R B37 are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 In any one of these embodiments, Y is selected from aryl. 2 and may be as defined herein. Preferably, in any one of these embodiments, Y 2 is NR B20 or O, where R B20 is as defined herein. More preferably, in any one of these embodiments, Y 2 can be NH or O. Even more preferably, in any one of these embodiments, each Y 2 is NR B20 where RB20 and are each independently as defined herein. Even more preferably, in any one of these embodiments, Y 2 can be NH.

[0102] B is CR B30 R B31 When Y is 2 In combination with the following group (Ba): TIFF2025542295000107.tif27128 can be formed, where: An asterisk (*) indicates the connection to the carbonyl carbon atom; # is Y 3 indicates a connection to; and Y 2 , R B30 and R B31 is as defined herein. B30 and R B31 may be the same or different. B30 and R B31 If different, R B30 and R B31 The carbon atom to which R is attached is a chiral center. B30 and R B31 The carbon atom to which is attached, if chiral, may be in the (S) or (R) configuration.

[0103] Preferably, R B30 is hydrogen and R B31 is as defined herein. Thus, the group (Ba) can be (Bb): TIFF2025542295000108.tif26128, where: An asterisk (*) indicates the connection to the carbonyl carbon atom; # is Y 3 indicates a connection to; and Y 2 and R B31 is as defined herein. B31 If is not hydrogen, then RB31 The carbon atom to which R is attached is a chiral center. B31 The carbon atom to which is attached, if chiral, may be in the (S) or (R) configuration.

[0104] More preferably, Y 2 is NR B20 Therefore, the group (Bb) is (Bc): TIFF2025542295000109.tif27128, where: An asterisk (*) indicates the connection to the carbonyl carbon atom; # is Y 3 Indicates the connection to; R B20 is as defined herein; preferably, R B20 is hydrogen; and R B31 is as defined herein. In these embodiments, the group (Bc) represents an amino acid. R B31 If is not hydrogen, then R B31 The carbon atom to which R is attached is a chiral center. B31 The carbon atom to which R is attached, if chiral, may be in the (S) or (R) configuration. B31 The carbon atom to which is attached, if chiral, is in the (S) configuration. In particular, the amino acid (i.e., group (Bc)) may be in the L or D configuration, except for non-chiral amino acids such as glycine. Preferably, in any one of the embodiments described herein, the amino acid (i.e., group (Bc)) is in the L configuration (i.e., the naturally occurring configuration). In some preferred embodiments, the amino acid is alanine, particularly L-alanine.

[0105] As mentioned above, B is CR B30 R B31 However, B is CR B30 R B31

[0023] While not limited to, in some embodiments, the group B, when present, can be (C1-C8) alkylene. Preferably, in these embodiments, B is (C1-C6) alkylene. More preferably, B is (C1-C4) alkylene. Even more preferably, B is (C1-C3) alkylene. Even more preferably, B is (C2-C3) alkylene. In some embodiments, B is (C1-C2) alkylene. In some embodiments, B is C1- alkylene (methylene). In any one of these embodiments, alkylene ((C-C)alkylene, (C-C)alkylene, (C-C)alkylene, (C-C)alkylene, (C-C)alkylene, (C-C)alkylene, (C-C)alkylene, or C-alkylene(methylene)) is selected from the group consisting of (C-C)alkyl, halo, hydroxy, (C-C)alkoxy, amino, (C-C)alkylamino, di(C-C)alkylamino, SH, (C-C)alkylthio, (C-C)heterocyclyl, carboxylates and esters thereof, carboxy(C-C)alkyl, CONHR B36 and CONR B36 R A37 and R B36 and R B37 are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 ) aryl.

[0106] Base Y 3 and J. Base Y 3 , O, NR C40 , O, or S, where R C40 is as defined herein. Therefore, R C40 is hydrogen, (C1-C8) alkyl (e.g., methyl, ethyl, or propyl), (C6-C 10 ) aryl (e.g., phenyl), and (C1-C8) alkylene (C6-C10 ) aryl (e.g., benzyl). Preferably, R C40 is hydrogen or (C1-C8) alkyl. More preferably, R C40 is hydrogen or (C1-C6) alkyl, even more preferably hydrogen or (C1-C4) alkyl, and even more preferably hydrogen or (C1-C2) alkyl. In a preferred embodiment, R C40 is hydrogen. In some embodiments, Y 3 is NR C40 where R C40 is as defined herein. In some embodiments, Y 3 is O. In some embodiments, Y 3 is S. In some embodiments, Y 3 does not exist.

[0107] Preferably, Y 3 is NR C40 , O and S, where R C40 is as defined herein. More preferably, Y 3 is NR C40 or O, where R C40 is as defined herein. Even more preferably, Y 3 is NH or O.

[0108] In some preferred embodiments, Y 3 is O.

[0109] In some preferred embodiments, Y 3 is NR C40 where R C40 is as defined herein. In some preferred embodiments, Y 3 is NH.

[0110] In some preferred embodiments, the group J is TIFF2025542295000110.tif16128, where: TIFF2025542295000111.tif7128, C, Y 4 and R C52 is as defined herein. In any one of these embodiments, Y 3 and may be as defined herein. Preferably, in any one of these embodiments, Y 3 is NR C40 or O, where R C40 is as defined herein. More preferably, in any one of these embodiments, Y 3 can be NH or O. More preferably, in any one of these embodiments, Y 3 is NR C40 where R C40 is as defined herein. Even more preferably, in any one of these embodiments, Y 3 can be NH.

[0111] By way of illustrative but non-limiting example, J If TIFF2025542295000112.tif16128, then J is Y 3 together may represent an amino acid or an ester thereof. 3 is NH and the group C is, according to embodiments further described hereinbelow, CR C50 R C51 (where R C50 is hydrogen and R C51 is CH3) and Y 4 is O and R C52 is hydrogen or as further defined herein (e.g., R C52 can be (C1-C8) alkyl), the group J is Y 3 and together represent alanine or an ester of alanine. In addition to the examples above, Y 1 can be NH and A is CR A30 R A31 (where R A30 is hydrogen and R A31is methyl), and the integer m can be 0; thus, in such an illustrative but non-limiting example, the group in formula (I) TIFF2025542295000113.tif10128, or the group in formula (Ia) TIFF2025542295000114.tif17128 has the following structure: TIFF2025542295000115.tif23128 represents the dialanyl moiety; R C52 is as defined herein, for example, R C52 can be (C1-C8) alkyl or hydrogen.

[0112] In some preferred embodiments, the group C is CR C50 CR C51 Thus, in some preferred embodiments, the group J is TIFF2025542295000116.tif22128, where R C50 , R C51 , Y 4 , R C52 and TIFF2025542295000117.tif7128 is as defined herein. C50 and R C51 are each independently hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 ) aryl. More preferably, R C50 and R C51 are each independently hydrogen, (C1-C8) alkyl, and (C1-C8) alkylene (C6-C 10 ) aryl. Even more preferably, R C50 and R C51 are each independently selected from the group consisting of hydrogen and (C-C) alkyl. Even more preferably, R C50 and R C51are each independently selected from the group consisting of hydrogen, CH, CHCH, CHCHCH, CH(CH), CHCHCHCH, CH(CH)CHCH, CHCH(CH), C(CH), and benzyl. Even more preferably, R C50 and R C51 are each independently selected from the group consisting of hydrogen and CH. In any one of these embodiments, R C50 and R C51 is (C1-C8) alkyl, halo, hydroxy, (C1-C8) alkoxy, amino, (C1-C8) alkylamino, di(C1-C8) alkylamino, SH, (C1-C8) alkylthio, (C3-C8) heterocyclyl, carboxylate and its esters, carboxy(C1-C8) alkyl, CONHR C36 and CONR C36 R C37 and R C36 and R C37 are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 ) aryl. Optionally, R C50 and R C51 can be taken together to form a 3- to 8-membered ring. In any one of these embodiments, R C50 and R C51 may be the same or different. Therefore, R C50 and R C51 can be the same. Alternatively, R C50 and R C51 In any one of these embodiments, Y 3 and may be as defined herein. Preferably, in any one of these embodiments, Y 3 is NR C40 or O, where R C40 is as defined herein. More preferably, in any one of these embodiments, Y 3can be NH or O. More preferably, in any one of these embodiments, Y 3 is NR C40 where R C40 is as defined herein. Even more preferably, in any one of these embodiments, Y 3 can be NH.

[0113] In some preferred embodiments, R C50 is hydrogen and R C51 is hydrogen, (C1-C8) alkyl, (C3-C8) cycloalkyl, (C2-C8) alkenyl, (C5-C8) cycloalkenyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 In one of these embodiments, R C51 is not hydrogen. More preferably, R C50 is hydrogen and R C51 is hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 In one of these embodiments, R C51 is not hydrogen. Even more preferably, R C50 is hydrogen and R C51 is (C1-C8) alkyl, and (C1-C8) alkylene (C6-C 10 ) aryl. Even more preferably, R C50 is hydrogen and R C51 is (C1-C8) alkyl. Even more preferably, R C50 is hydrogen and R C51 is selected from the group consisting of hydrogen, CH3, CH2CH3, CH2CH3CH3, CH(CH3)2, CH2CH2CH2CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, and benzyl. C51 is not hydrogen. Even more preferably, R C50 is hydrogen and RC51 is CH3. In any one of these embodiments, R C51 is (C1-C8) alkyl, halo, hydroxy, (C1-C8) alkoxy, amino, (C1-C8) alkylamino, di(C1-C8) alkylamino, SH, (C1-C8) alkylthio, (C3-C8) heterocyclyl, carboxylate and its esters, carboxy(C1-C8) alkyl, CONHR C36 and CONR C36 R C37 and R C36 and R C37 are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 In any one of these embodiments, Y is selected from aryl. 3 and may be as defined herein. Preferably, in any one of these embodiments, Y 3 is NR C40 or O, where R C40 is as defined herein. More preferably, in any one of these embodiments, Y 3 can be NH or O. More preferably, in any one of these embodiments, Y 3 is NR C40 where R C40 is as defined herein. Even more preferably, in any one of these embodiments, Y 3 can be NH.

[0114] Y 4 is as defined herein. Therefore, Y 4 , O, NR C53 , S and CR C54 R C55 R C53 is hydrogen, (C1-C8) alkyl (e.g., methyl, ethyl, or propyl), (C6-C 10) aryl (e.g., phenyl), and (C1-C8) alkylene (C6-C 10 ) aryl (e.g., benzyl). Preferably, R C53 is hydrogen or (C1-C8) alkyl. More preferably, R C53 is hydrogen or (C1-C6) alkyl, even more preferably hydrogen or (C1-C4) alkyl, and even more preferably hydrogen or (C1-C2) alkyl. In a preferred embodiment, R C53 is hydrogen. R C54 and R C55 are each independently hydrogen, (C1-C8) alkyl (e.g., methyl, ethyl, or propyl), (C6-C 10 ) aryl (e.g., phenyl), and (C1-C8) alkylene (C6-C 10 ) aryl (e.g., benzyl). Preferably, R C54 and R C55 are each independently selected from the group consisting of hydrogen or (C1-C8) alkyl. More preferably, R C54 and R C55 are each independently hydrogen or (C1-C6) alkyl, even more preferably hydrogen or (C1-C4) alkyl, and even more preferably hydrogen or (C1-C2) alkyl. In a preferred embodiment, R C54 and R C55 is hydrogen. In some embodiments, Y 4 is O. In some embodiments, Y 4 is NR C53 where R C53 is as defined herein. In some embodiments, Y 4 is S. In some embodiments, Y 4 is CR C54 R C55 where R C54 and R C55 is as defined herein. In some embodiments, Y 4 does not exist.

[0115] Preferably, Y4 is O or NR C53 where R C53 is as defined herein. More preferably, Y 4 is O or NH. In some preferred embodiments, Y 4 is O.

[0116] R C52 is as defined herein. Preferably, R C52 is hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 ) aryl. More preferably, R C52 is hydrogen, (C1-C8) alkyl, and (C1-C8) alkylene (C6-C 10 ) aryl. Even more preferably, R C52 is selected from the group consisting of hydrogen and (C1-C8) alkyl. Even more preferably, R C52 is selected from the group consisting of hydrogen, CH3, CH2CH3, CH2CH3CH3, CH(CH3)2, CH2CH2CH2CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, and benzyl. Even more preferably, R C52 is selected from the group consisting of hydrogen, CH(CH3)2 and C(CH3)3. Even more preferably, R C52 is hydrogen. In a preferred embodiment, R C52 is (C1-C8) alkyl. In some embodiments, R C52 is CH(CH). In some embodiments, R C52 is C(CH3)3. In any one of these embodiments, R C52 is (C1-C8) alkyl, halo, hydroxy, (C1-C8) alkoxy, amino, (C1-C8) alkylamino, di(C1-C8) alkylamino, SH, (C1-C8) alkylthio, (C3-C8) heterocyclyl, carboxylate and its esters, carboxy(C1-C8) alkyl, CONHR C56and CONR C56 R C57 and R C56 and R C57 are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 In any one of these embodiments, Y is selected from aryl. 3 and may be as defined herein. Preferably, in any one of these embodiments, Y 3 is NR C40 or O, where R C40 is as defined herein. More preferably, in any one of these embodiments, Y 3 can be NH or O. More preferably, in any one of these embodiments, Y 3 is NR C40 where R C40 is as defined herein. Even more preferably, in any one of these embodiments, Y 3 In any one of these embodiments, Y 4 and may be as defined herein. Preferably, in any one of these embodiments, Y 4 can be O (oxygen).

[0117] Base J TIFF2025542295000118.tif22128, where group J is group Y 3 and in combination with a group (Ja): TIFF2025542295000119.tif26128 can be formed, where: An asterisk (*) indicates the attachment to the carbonyl carbon atom; and Y 3 , R C50 , R C51 , Y 4 and R C52 is as defined herein.C50 and R C51 may be the same or different. C50 and R C51 If different, R C50 and R C51 The carbon atom to which R is attached is a chiral center. C50 and R C51 The carbon atom to which is attached, if chiral, may be in the (S) or (R) configuration.

[0118] Preferably, R C50 is hydrogen and R C51 is as defined herein. Thus, the group (Ja) can be (Jb): TIFF2025542295000120.tif27128, where: An asterisk (*) indicates the attachment to the carbonyl carbon atom; and Y 3 , R C51 , Y 4 and R C52 is as defined herein. C51 If is not hydrogen, then R C51 The carbon atom to which R is attached is a chiral center. C51 The carbon atom to which is attached, if chiral, may be in the (S) or (R) configuration.

[0119] More preferably, Y 3 is NR C40 Therefore, the group (Jb) becomes (Jc): TIFF2025542295000121.tif26128, where: An asterisk (*) indicates the connection to the carbonyl carbon atom; R C51 , Y 4 and R C52 is as defined herein; and R C40 is as defined herein; preferably, R C40is hydrogen. In these embodiments, the group (Jc) represents an amino acid. R C51 If is not hydrogen, then R C51 The carbon atom to which R is attached is a chiral center. C51 The carbon atom to which R is attached, if chiral, may be in the (S) or (R) configuration. C51 The carbon atom to which is attached, if chiral, is in the (S) configuration. In particular, the amino acid (i.e., group (Jc)) may be in the L or D configuration, except for non-chiral amino acids such as glycine. Preferably, in any one of the embodiments described herein, the amino acid (i.e., group (Jc)) is in the L configuration (i.e., the naturally occurring configuration). In some preferred embodiments, the amino acid is alanine, particularly L-alanine.

[0120] In some preferred embodiments, A is CR A30 R A31 and J is TIFF2025542295000122.tif20128, where R A30 , R A31 , R C50 , R C51 , Y 4 , R C52 and TIFF2025542295000123.tif7128 is as defined herein. In any one of these embodiments, the integer m can be 0.

[0121] In some more preferred embodiments, A is CR A30 R A31 and J is TIFF2025542295000124.tif21128, where R A30 , R A31 , R C50 , R C51 , R C52 and TIFF2025542295000125.tif7128 is as defined herein; Y 1is NR A20 and Y 3 is NR C40 and Y 4 is O, where R A20 and R C40 is as defined herein. More preferably, in any one of these embodiments, Y 1 is NH and Y 3 is NH and Y 4 is O. In any one of these embodiments, the integer m can be 0.

[0122] In some also preferred embodiments, A is CR A30 R A31 and J is TIFF2025542295000126.tif21128, where R A30 is hydrogen and R A31 is CH3 and R C50 is hydrogen and R C51 is CH3 and R C52 is hydrogen, TIFF2025542295000127.tif7128 is as defined herein, and Y 1 is NR A20 and Y 3 is NR C40 and Y 4 is O, where R A20 and R C40 is as defined herein. Preferably, in any one of these embodiments, Y 1 is NR A20 and Y 3 is NR C40 and Y 4 is O, where R A20 and R C40 is as defined herein. More preferably, in any one of these embodiments, Y 1 is NH and Y 3 is NH and Y 4 is O. In any one of these embodiments, the integer m can be 0.

[0123] As mentioned above, J is TIFF2025542295000128.tif16128, where the group C is CR C50 R C51 However, In the structure of TIFF2025542295000129.tif16128, C is CR C50 R C51 C is not limited to, but in some embodiments can be (C1-C8) alkylene. Preferably, in these embodiments, C is (C1-C6) alkylene. More preferably, C is (C1-C4) alkylene. Even more preferably, C is (C1-C3) alkylene. Even more preferably, C is (C2-C3) alkylene. In some embodiments, C is (C1-C2) alkylene. In some embodiments, C is C1-alkylene (methylene). In any one of these embodiments, alkylene ((C-C)alkylene, (C-C)alkylene, (C-C)alkylene, (C-C)alkylene, (C-C)alkylene, (C-C)alkylene, (C-C)alkylene, or C-alkylene(methylene)) is selected from the group consisting of (C-C)alkyl, halo, hydroxy, (C-C)alkoxy, amino, (C-C)alkylamino, di(C-C)alkylamino, SH, (C-C)alkylthio, (C-C)heterocyclyl, carboxylates and esters thereof, carboxy(C-C)alkyl, CONHR A36 and CONR A36 R A37 and R A36 and R A37 are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 ) aryl.

[0124] As mentioned above, J is It could be TIFF2025542295000130.tif16128. But J is Although not limited to the structure of TIFF2025542295000131.tif16128, in alternative embodiments, the alkyl group may be (C1-C8) alkyl, (C3-C8) cycloalkyl, (C2-C8) alkenyl, (C5-C8) cycloalkenyl, (C3-C8) heterocyclyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 More preferably, J is selected from the group consisting of (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 Even more preferably, J is selected from the group consisting of (C1-C8) alkyl and (C1-C8) alkylene (C6-C 10 )aryl. Even more preferably, J is (C1-C8)alkyl. Even more preferably, J is selected from the group consisting of CH3, CH2CH3, CH2CH3CH3, CH(CH3)2, CH2CH2CH2CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, and benzyl. Even more preferably, J is CH(CH3)2 or C(CH3)3. In some embodiments, J is CH(CH3)2. In some embodiments, J is C(CH3)3. In any one of these embodiments, J is selected from the group consisting of (C1-C8)alkyl, halo, hydroxy, (C1-C8)alkoxy, amino, (C1-C8)alkylamino, di(C1-C8)alkylamino, SH, (C1-C8)alkylthio, (C3-C8)heterocyclyl, carboxylates and esters thereof, carboxy(C1-C8)alkyl, CONHR C46 and CONR C46 R C47 and R C46 and R C47 are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10) aryl or (C6-C 10 ) aryl. In any one of these embodiments, the integer m can be 0. In any one of these embodiments, Y 3 and may be as defined herein. Preferably, in any one of these embodiments, Y 3 is O or NR C40 where R C40 is as defined herein. More preferably, in any one of these embodiments, Y 3 may be O. In any one of these embodiments, A may be as defined herein. Preferably, in any one of these embodiments, A is CR A30 R A31 where R A30 and R A31 is as defined herein. In any one of these embodiments, Y 1 and Y 3 and may be as defined herein. Preferably, in any one of these embodiments, Y 1 is NR A20 and Y 3 can be O, where R A20 is as defined herein. More preferably, in any one of these embodiments, Y 1 can be NH, and Y 3 may be O. In any one of these embodiments, the integer m may be 0.

[0125] As an illustrative, non-limiting example, J is as defined in the preceding paragraph and Y 3 is O and Y 1 is NH and the integer m is 0, the group J is Y 3 , A and Y 1 and together represent an ester of an amino acid. In particular, by way of illustrative but non-limiting example, J is as defined in the preceding paragraph and Y 3 is O, the integer m is 0, and A is CR A30 R A31 (where R A30is hydrogen and R A31 is CH3), and Y 1 is NH, the group in formula (I) TIFF2025542295000132.tif11128, or the group in formula (Ia) TIFF2025542295000133.tif19128 has the following structure: TIFF2025542295000134.tif25128; and J is as defined in the preceding paragraph, for example, J can be (C1-C8) alkyl.

[0126] In some preferred embodiments, R A30 is hydrogen and R A31 is CH3 and Y 1 is NH and Y 3 is O. Preferably, in any one of these embodiments, J can be CH(CH3)2 or C(CH3)3. Thus, in some of these embodiments, J can be CH(CH3)2. In some of these embodiments, J can be C(CH3)3. In any one of these embodiments, the integer m can be 0.

[0127] In the conjugate of formula (Ia) or (Ia1), for example, RBM, L, M, X, D, Y 1 , A, Y 2 , B, m, Y 3 Any variable, such as , J, and n, can be as defined herein.

[0128] Conjugates with cleavable sugar moieties In some embodiments, the conjugate has formula (Ib), or a pharmaceutically acceptable salt or solvate thereof: TIFF2025542295000135.tif39128 formula, RBM is a receptor binding molecule; L is a linker; M, O, NR M60 , or S; R M60 is hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 ) aryl; X is O, S, or NR X10 and; R X10 is hydrogen; or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; D is a drug moiety; Y 1 is NR A20 , O, S, or CR A21 R A22 and; R A20 is hydrogen, (C1-C8) alkyl, (C6-C 10 ) aryl, and C1-C8) alkylene (C6-C 10 ) aryl; R A21 and R A22 are each independently hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 ) aryl; E is a spacer; Su is a sugar moiety attached to an oxygen atom (O) via a cleavable bond; and Here, oxygen is the spacer E, Y after cleavage of the sugar moiety Su. 1 and together with phosphorus can form a ring, preferably a 4- to 7-membered ring, more preferably a 5- or 6-membered ring; and n is an integer ranging from 1 to 20.

[0129] Thus, in these embodiments, the group in formula (I) TIFF2025542295000136.tif13128 is TIFF2025542295000137.tif12128, where E is a spacer as described herein; Su is a sugar moiety attached to an oxygen atom (O) via a cleavable bond; and Here, oxygen is the spacer E, Y after cleavage of the sugar moiety Su. 1 and together with phosphorus can form a ring, preferably a 4- to 7-membered ring, more preferably a 5- or 6-membered ring.

[0130] In these embodiments, the sugar moiety Su represents a cleavable group Z, and the moiety W represents a hydroxy group after cleavage of group Z. TIFF2025542295000138.tif9128. The sugar moiety Su, i.e., the cleavable group Z, can be cleaved, for example, by glycosidase-induced cleavage. In particular, the bond between the sugar moiety Su and oxygen (O) can be cleaved. The group Z, i.e., the sugar moiety Su, can be cleaved at a target site to initiate a reaction leading to the release of the XD moiety. The bond between the sugar moiety Su and oxygen (O) can be a glycosidic bond. The term "glycosidic bond" generally refers to the bond between the carbon atom of the hemiacetal portion of the sugar moiety Su (i.e., the anomeric carbon atom) and oxygen (O). The sugar moiety is not particularly limited and can be any suitable glycoside, including glycosides modified with a suitable protecting group at the hydroxyl function. Suitable protecting groups are commonly known and include, for example, acyl esters such as acetyl esters, lactate esters, ethers, sulfate groups, or phosphate moieties. The protecting groups at each hydroxy function of the sugar moiety can be the same or different from each other. The sugar moiety may be selected from the group consisting of, for example, glucuronic acid, galactose, glucose, arabinose, mannose-6-phosphate, fucose, rhamnose, gulose, allose, 6-deoxy-glucose, lactose, maltose, cellobiose, gentiobiose, maltotriose, GlcNAc, GalNAc, and maltohexaose, with and without protecting groups on the hydroxyl functions.

[0131] Without wishing to be bound by theory, a possible mechanism of drug release is illustrated for an exemplary compound of formula (Ib) in the following scheme. TIFF2025542295000139.tif45149

[0132] In some generally preferred embodiments, the sugar moiety is a sugar moiety that has been modified at its hydroxyl functionality with a suitable protecting group. A sugar moiety that has been modified at its hydroxyl functionality with a suitable protecting group may also be referred to herein as a "protected sugar moiety."

[0133] Preferably, each hydroxy function of the sugar moiety Su is protected with an acetyl ester.

[0134] In some embodiments, the sugar moiety is glucuronic acid: TIFF2025542295000140.tif33128, where: TIFF2025542295000141.tif9128 shows the position of the oxygen atom (O). In particular, glucuronic acid can be recognized and the glycosidic bond to the oxygen atom (O) can be cleaved by a glucuronidase, such as β-glucuronidase.

[0135] In some embodiments, the sugar moiety is glucuronic acid with a suitable protecting group on the hydroxyl functionality. Preferably, the protected glucuronic acid has the following structure: TIFF2025542295000142.tif44128, where: TIFF2025542295000143.tif9128 shows the position of the oxygen atom (O). In particular, glucuronic acid can be recognized after the protecting group is removed to release the glucuronic acid, and the glycosidic bond to the oxygen atom (O) can be cleaved by a glucuronidase, such as β-glucuronidase.

[0136] In the conjugate of formula (Ib), the spacer E has the following structure A: TIFF2025542295000144.tif26128, which is an optionally substituted 4- to 7-membered, preferably 5- or 6-membered, carbocyclic or heterocyclic ring; where: TIFF2025542295000145.tif9128 contains oxygen atoms and Y 1 Preferably, in any one of these embodiments, the oxygen atom and Y 1 The points of attachment of A to are two adjacent atoms of the ring. TIFF2025542295000146.tif21128 has the following structure: TIFF2025542295000147.tif23128, where: TIFF2025542295000148.tif9128 contains oxygen atoms and Y 1 Indicates the location of.

[0137] In the conjugate of formula (Ib), Y 1 may be as defined herein. Preferably, Y 1 is NR A20 or O, where R A20 is as defined herein. More preferably, Y 1 is NH or O. Even more preferably, Y 1 is NH.

[0138] Preferably, the conjugate of formula (Ib) has formula (Ib1) or a pharmaceutically acceptable salt or solvate thereof: TIFF2025542295000149.tif38128 where RBM, L, M, X, D, Y 1 , TIFF2025542295000150.tif22128, Su and n are as defined herein.

[0139] In the conjugate of formula (Ib) or (Ib1), for example, RBM, L, M, X, D, Y 1 , TIFF2025542295000151.tif22128, any variables such as E, Su, and n may be as defined herein.

[0140] Conjugates with a cleavable disulfide moiety In some embodiments, the conjugate has the formula (Ic), or a pharmaceutically acceptable salt or solvate thereof: TIFF2025542295000152.tif36128In formula, RBM is a receptor binding molecule; L is a linker; M, O, NR M60 , or S; R M60 is hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 ) aryl; X is O, S, or NR X10 and; R X10 is hydrogen; or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; D is a drug moiety; Y 1 is NR A20 , O, S, or CR A21 R A22 and; R A20 is hydrogen, (C1-C8) alkyl, (C6-C 10 ) aryl, and C1-C8) alkylene (C6-C 10 ) aryl; R A21 and R A22 are each independently hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10) aryl; E is a spacer; Z* is an optionally substituted aliphatic residue or an optionally substituted aromatic residue; Here, the sulfur bonded to the spacer E is bonded to the spacer E, Y after cleavage of the disulfide bond. 1 and together with phosphorus can form a ring, preferably a 4- to 7-membered ring, more preferably a 5- or 6-membered ring; and n is an integer ranging from 1 to 20.

[0141] Thus, in these embodiments, the group in formula (I) TIFF2025542295000153.tif13128 is TIFF2025542295000154.tif13128, where E is a spacer as described herein; Z* is an optionally substituted aliphatic residue or an optionally substituted aromatic residue; and Here, the sulfur bonded to the spacer E is bonded to the spacer E, Y after cleavage of the disulfide bond. 1 and together with phosphorus can form a ring, preferably a 4- to 7-membered ring, more preferably a 5- or 6-membered ring.

[0142] In these embodiments, the moiety TIFF2025542295000155.tif10128 represents a cleavable group Z, and moiety W represents a thiol group after cleavage of group Z. TIFF2025542295000156.tif10128. TIFF2025542295000157.tif9128, i.e., the cleavable group Z, can be cleaved, for example, by enzymatic reduction. In particular, disulfide bonds can be cleaved by enzymatic reduction. Group Z, i.e., the group TIFF2025542295000158.tif9128 can be cleaved at the target site to initiate a reaction leading to the release of the XD moiety.

[0143] Without wishing to be bound by theory, a possible mechanism of drug release is illustrated for an exemplary compound of formula (Ic) in the following scheme. TIFF2025542295000159.tif44150

[0144] In the conjugate of formula (Ic), the spacer E is -(CH2) i - It can be, which may be substituted; and Here, i is an integer ranging from 1 to 4. Preferably, i is 2, 3, or 4. More preferably, i is 2 or 3. Even more preferably, i is 2. Optionally, -(CH2) i One or more hydrogen atoms (particularly one hydrogen atom) of - may be selected from (C1-C8)alkyl, halo, hydroxy, (C1-C8)alkoxy, amino, (C1-C8)alkylamino, di(C1-C8)alkylamino, SH, (C1-C8)alkylthio, (C3-C8)heterocyclyl, carboxylates and esters thereof, carboxy(C1-C8)alkyl, CONHR A36 and CONR A36 R A37 wherein R may be the same or different. A36 and R A37 are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 ) aryl.

[0145] In the conjugate of formula (Ic), Z* is an optionally substituted aliphatic residue or an optionally substituted aromatic residue. In some embodiments, Z* can be an optionally substituted (C1-C8) alkyl. In some embodiments, Z* is methyl, ethyl, propyl (e.g., isopropyl), or butyl (e.g., tert-butyl).

[0146] Preferably, the conjugate of formula (Ic) has formula (Ic1) or a pharmaceutically acceptable salt or solvate thereof: TIFF2025542295000160.tif36128In formula, RBM, L, M, X, D, Y 1 , Z* and n are as defined herein; E is -(CH2) i - and and wherein i is an integer ranging from 1 to 4; preferably 2, 3 or 4; more preferably 2 or 3; even more preferably 2.

[0147] In the conjugate of formula (Ic) or (Ic1), for example, RBM, L, M, X, D, Y 1 , E, i, Z*, and n may be as defined herein.

[0148] Conjugates with a cleavable acetal moiety In some embodiments, the conjugate has formula (Id), or a pharmaceutically acceptable salt or solvate thereof: TIFF2025542295000161.tif36128 formula, RBM is a receptor binding molecule; L is a linker; M, O, NR M60 , or S; R M60 is hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 ) aryl; X is O, S, or NR X10 and; R X10 is hydrogen; or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; D is a drug moiety; Y 1 is NR A20 , O, S, or CR A21 R A22 and; R A20 is hydrogen, (C1-C8) alkyl, (C6-C 10 ) aryl, and C1-C8) alkylene (C6-C 10 ) aryl; R A21 and R A22 are each independently hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 ) aryl; E is a spacer; R Ac1 and R Ac2 are each independently an optionally substituted aliphatic residue or an optionally substituted aromatic residue; and n is an integer ranging from 1 to 20.

[0149] Thus, in these embodiments, the group in formula (I) TIFF2025542295000162.tif10128 is TIFF2025542295000163.tif21128, where E is a spacer as described herein.

[0150] Without wishing to be bound by theory, a possible mechanism of drug release is illustrated for an exemplary compound of formula (Id) in the following scheme. TIFF2025542295000164.tif64140

[0151] Thus, at the mechanistic level, it can be assumed that the acetal moiety can be cleaved, for example, by hydrolysis, to give an aldehyde. Oxidation of the aldehyde by aldehyde oxidase can form a carboxylic acid or carboxylate moiety, which represents the group W, which can attack the phosphorus atom and affect the release of the drug moiety (XD), for example, according to the mechanisms described hereinabove. TIFF2025542295000165.tif13128 may be considered as the cleavable group Z. Thus, the conjugate of formula (Id) is an illustrative example where, in addition to cleavage of group Z, one or more further steps may occur, particularly after cleavage of group Z (in this example, an oxidation step), to provide group W, which may then be bonded to a spacer E, Y, 1 and together with phosphorus, can form a ring (preferably a 4- to 7-membered ring, more preferably a 5- or 6-membered ring). This example also shows that the acetal group can be used as a masking group for the carbonyl group of an aldehyde or ketone, etc. This shows that it is also within the scope of the present invention to use an aldehyde or ketone compound (moiety) to provide the group W.

[0152] In the conjugate of formula (Id), R Ac1 and R Ac2 are each independently an optionally substituted aliphatic residue or an optionally substituted aromatic residue. Ac1 and R Ac2 are each independently an optionally substituted (C-C) alkyl. In some embodiments, R Ac1 and R Ac2 are each independently methyl, ethyl, propyl (e.g., isopropyl), or butyl (e.g., tert-butyl). In any one of these embodiments, R Ac1 and R Ac2 may be the same or different; preferably, R Ac1 and R Ac2 are the same. Optionally, R Ac1 and RAc2 can form a 3- to 8-membered ring together with the oxygen atom and the carbon atom.

[0153] In the conjugate of formula (Id), the spacer E can be any spacer as defined herein. In some embodiments, the spacer E is a group A as defined herein, such as for the conjugate of formula (Ia). Thus, in some embodiments, the conjugate of formula (Id) has formula (Id1), or a pharmaceutically acceptable salt or solvate thereof: TIFF2025542295000166.tif40128 formula, RBM, L, M, X, D, Y 1 , R Ac1 , R Ac2 and n is as defined herein; A is CR A30 R A31 or A is (C1-C8)alkylene, where (C1-C8)alkylene is selected from the group consisting of (C1-C8)alkyl, halo, hydroxy, (C1-C8)alkoxy, amino, (C1-C8)alkylamino, di(C1-C8)alkylamino, SH, (C1-C8)alkylthio, (C3-C8)heterocyclyl, carboxylates and esters thereof, carboxy(C1-C8)alkyl, CONHR A36 and CONR A36 R A37 and R A36 and R A37 are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 ) aryl; and R A30 and R A31 are each independently hydrogen, (C1-C8) alkyl, (C3-C8) cycloalkyl, (C2-C8) alkenyl, (C5-C8) cycloalkenyl, (C6-C10 )aryl, and (C1-C8)alkylene (C6-C 10 )aryl; wherein each of (C1-C8)alkyl, (C3-C8)cycloalkyl, (C2-C8)alkenyl, (C5-C8)cycloalkenyl, (C6-C 10 )aryl or (C1-C8)alkylene (C6-C 10 )Aryl is (C1-C8)alkyl, halo, hydroxy, (C1-C8)alkoxy, amino, (C1-C8)alkylamino, di(C1-C8)alkylamino, SH, (C1-C8)alkylthio, (C3-C8)heterocyclyl, carboxylates and their esters, carboxy(C1-C8)alkyl, CONHR A36 and CONR A36 R A37 and R A36 and R A37 are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 ) aryl; optionally, R A30 and R A31 can be joined together to form a 3- to 8-membered ring.

[0154] In the conjugate of formula (Id) or (Id1), for example, RBM, L, M, X, D, Y 1 , E, A, R Ac1 , R Ac2 and any variables such as n can be as defined herein. In particular, A can be as defined herein for the conjugate of formula (Ia).

[0155] Conjugates with a cleavable amide moiety In some embodiments, the conjugate has formula (Ie) or a pharmaceutically acceptable salt or solvate thereof: TIFF2025542295000167.tif38128 formula, RBM is a receptor binding molecule; L is a linker; M, O, NR M60 , or S; R M60 is hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 ) aryl; X is O, S, or NR X10 and; R X10 is hydrogen; or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; D is a drug moiety; Y 1 is NR A20 , O, S, or CR A21 R A22 and; R A20 is hydrogen, (C1-C8) alkyl, (C6-C 10 ) aryl, and C1-C8) alkylene (C6-C 10 ) aryl; R A21 and R A22 are each independently hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 ) aryl; E is a spacer; Z* is an optionally substituted aliphatic residue or an optionally substituted aromatic residue; Here, the nitrogen atom bonded to the spacer E is, after cleavage of the acetyl bond, spacer E, Y 1 and together with phosphorus can form a ring, preferably a 4- to 7-membered ring, more preferably a 5- or 6-membered ring; and n is an integer ranging from 1 to 20.

[0156] Thus, in these embodiments, the group in formula (I) TIFF2025542295000168.tif13128 is TIFF2025542295000169.tif22128, where E is a spacer as described herein; Z* is an optionally substituted aliphatic residue or an optionally substituted aromatic residue; and Here, the nitrogen atom bonded to the spacer E is, after cleavage of the acetyl bond, spacer E, Y 1 and together with phosphorus can form a ring, preferably a 4- to 7-membered ring, more preferably a 5- or 6-membered ring.

[0157] In these embodiments, the moiety TIFF2025542295000170.tif17128 represents the cleavable group Z, and the moiety W is an amino group after cleavage of the group Z. TIFF2025542295000171.tif11128. TIFF2025542295000172.tif17128, i.e., the cleavable group Z can be cleaved, for example, by a peptidase or protease, to yield an amine TIFF2025542295000173.tif10128. TIFF2025542295000174.tif17128 can be cleaved at the target site to initiate a reaction leading to the release of the XD moiety.

[0158] Without wishing to be bound by theory, a possible mechanism of drug release is illustrated for an exemplary compound of formula (If) in the following scheme. TIFF2025542295000175.tif48150

[0159] In the conjugate of formula (Ie), the spacer E can be any spacer E as described herein. In some embodiments of formula (Ie), the spacer E is: -(CH2) i - It can be, which may be substituted; and Here, i is an integer ranging from 1 to 4. Preferably, i is 2, 3, or 4. More preferably, i is 2 or 3. Even more preferably, i is 2. Optionally, -(CH2) i One or more hydrogen atoms (particularly one hydrogen atom) of - may be selected from (C1-C8)alkyl, halo, hydroxy, (C1-C8)alkoxy, amino, (C1-C8)alkylamino, di(C1-C8)alkylamino, SH, (C1-C8)alkylthio, (C3-C8)heterocyclyl, carboxylates and esters thereof, carboxy(C1-C8)alkyl, CONHR A36 and CONR A36 R A37 wherein R may be the same or different. A36 and R A37 are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 ) aryl.

[0160] In the conjugate of formula (Ie), Z* is an optionally substituted aliphatic residue or an optionally substituted aromatic residue. In some embodiments, Z* can be an optionally substituted (C1-C8) alkyl. In some embodiments, Z* is methyl, ethyl, propyl (e.g., isopropyl), or butyl (e.g., tert-butyl).

[0161] Preferably, the conjugate of formula (Ie) has formula (Ie1) or a pharmaceutically acceptable salt or solvate thereof: TIFF2025542295000176.tif38128 formula, RBM, L, M, X, D, Y 1 , Z* and n are as defined herein; E is -(CH2) i - and and wherein i is an integer ranging from 1 to 4; preferably 2, 3 or 4; more preferably 2 or 3; even more preferably 2.

[0162] In the conjugate of formula (Ie) or (Ie1), for example, RBM, L, M, X, D, Y 1 , E, i, Z*, and n may be as defined herein.

[0163] Conjugates with a cleavable ester moiety In some embodiments, the conjugate has the formula (If) or a pharmaceutically acceptable salt or solvate thereof: TIFF2025542295000177.tif42128 formula, RBM is a receptor binding molecule; L is a linker; M, O, NR M60 , or S; R M60 is hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 ) aryl; X is O, S, or NR X10 and; R X10 is hydrogen; or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; D is a drug moiety; Y 1 is NR A20 , O, S, or CR A21 R A22 and; R A20 is hydrogen, (C1-C8) alkyl, (C6-C 10 ) aryl, and C1-C8) alkylene (C6-C 10 ) aryl; R A21 and R A22are each independently hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 ) aryl; E is a spacer; Z* is an optionally substituted aliphatic residue or an optionally substituted aromatic residue; Here, the oxygen atom bonded to the spacer E is, after cleavage of the acetyl bond, spacer E, Y 1 and together with phosphorus can form a ring, preferably a 4- to 7-membered ring, more preferably a 5- or 6-membered ring; and n is an integer ranging from 1 to 20.

[0164] Thus, in these embodiments, the group in formula (I) TIFF2025542295000178.tif13128 is TIFF2025542295000179.tif23128, where E is a spacer as described herein; Z* is an optionally substituted aliphatic residue or an optionally substituted aromatic residue; and Here, the nitrogen atom bonded to the spacer E is, after cleavage of the acetyl bond, spacer E, Y 1 and together with phosphorus can form a ring, preferably a 4- to 7-membered ring, more preferably a 5- or 6-membered ring.

[0165] In these embodiments, the moiety TIFF2025542295000180.tif17128 represents the cleavable group Z, and the moiety W is an alcohol after cleavage of group Z. TIFF2025542295000181.tif17128, i.e., the cleavable group Z can be cleaved, for example, by a peptidase or protease, to yield an amine. TIFF2025542295000182.tif10128. TIFF2025542295000183.tif17128 can be cleaved at the target site to initiate a reaction leading to the release of the XD moiety.

[0166] Without wishing to be bound by theory, a possible mechanism of drug release is illustrated for an exemplary compound of formula (Ie) in the following scheme. TIFF2025542295000184.tif45149

[0167] In the conjugate of formula (Ie), the spacer E can be any spacer E as described herein. In some embodiments of formula (Ie), the spacer E is: -(CH2) i - It can be, which may be substituted; and Here, i is an integer ranging from 1 to 4. Preferably, i is 2, 3, or 4. More preferably, i is 2 or 3. Even more preferably, i is 2. Optionally, -(CH2) i One or more hydrogen atoms (particularly one hydrogen atom) of - may be selected from (C1-C8)alkyl, halo, hydroxy, (C1-C8)alkoxy, amino, (C1-C8)alkylamino, di(C1-C8)alkylamino, SH, (C1-C8)alkylthio, (C3-C8)heterocyclyl, carboxylates and esters thereof, carboxy(C1-C8)alkyl, CONHR A36 and CONR A36 R A37 wherein R may be the same or different. A36 and R A37 are independently (C1-C8) alkyl, (C1-C8) alkylene (C6-C 10 ) aryl or (C6-C 10 ) aryl.

[0168] In the conjugate of formula (Ie), Z* is an optionally substituted aliphatic residue or an optionally substituted aromatic residue. In some embodiments, Z* can be an optionally substituted (C1-C8) alkyl. In some embodiments, Z* is methyl, ethyl, propyl (e.g., isopropyl), or butyl (e.g., tert-butyl).

[0169] Preferably, the conjugate of formula (If) has formula (If1) or a pharmaceutically acceptable salt or solvate thereof: TIFF2025542295000185.tif42128 formula, RBM, L, M, X, D, Y 1 , Z* and n are as defined herein; E is -(CH2) i - and and wherein i is an integer ranging from 1 to 4; preferably 2, 3 or 4; more preferably 2 or 3; even more preferably 2.

[0170] In the conjugate of formula (Ie) or (Ie1), for example, RBM, L, M, X, D, Y 1 , E, i, Z*, and n may be as defined herein.

[0171] integer n The integer n can range from 1 to 20. Thus, the integer n can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In the conjugates described herein, the integer n denotes the ratio of drug moiety (D) to receptor binding molecule (RBM).

[0172] In some embodiments, the integer n ranges from 1 to 14. Thus, the integer n can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14.

[0173] In some embodiments, integer n is in the range of 1 to 14. Preferably, integer n is in the range of 2 to 14. Even more preferably, integer n is in the range of 3 to 14. Even more preferably, integer n is in the range of 4 to 14. Even more preferably, integer n is in the range of 5 to 12. Even more preferably, integer n is in the range of 6 to 12, and even more preferably, 7 to 10. Even more preferably, integer n is 7 or 8. Even more preferably, integer n is 8.

[0174] In some embodiments, integer n is in the range of 1 to 14. Preferably, integer n is in the range of 1 to 12. Even more preferably, integer n is in the range of 2 to 10. Even more preferably, integer n is in the range of 2 to 8. Even more preferably, integer n is in the range of 2 to 6. Even more preferably, integer n is in the range of 3 to 5. Even more preferably, integer n is 4.

[0175] Receptor-binding molecules (RBM) RBM is a receptor-binding molecule. The term "receptor-binding molecule" generally refers to any molecule that can bind to a receptor. As an illustrative but non-limiting example, the receptor that the receptor-binding molecule can bind to may be expressed on the cell surface. As an illustrative but non-limiting example, the cell that expresses the receptor may be a cancer cell. Those skilled in the art will know how to select a suitable receptor-binding molecule.

[0176] In some embodiments, the receptor may be a tumor-associated surface antigen. Thus, the receptor-binding molecule can specifically bind to the tumor-associated surface antigen. The term "tumor-associated surface antigen," as used herein, generally refers to an antigen that is or can be presented on the surface of a tumor cell or tumor cell. These antigens may have an extracellular portion presented on the cell surface, which is often combined with the transmembrane and cytoplasmic portions of the molecule. In some embodiments, these antigens may be presented only by tumor cells and not by normal, i.e., non-tumor cells. Tumor antigens may be expressed only on tumor cells or may exhibit tumor-specific mutations compared to non-tumor cells. In such embodiments, each antigen may be referred to as a tumor-specific antigen. Some antigens may be presented by both tumor and non-tumor cells and may be referred to as tumor-associated antigens. These tumor-associated antigens may be overexpressed in tumor cells compared to non-tumor cells and be accessible to antibody binding on tumor cells due to the less compact structure of tumor tissue compared to non-tumor tissue. In some embodiments, tumor-associated surface antigens are located on the tumor vasculature. Illustrative but non-limiting examples of tumor-associated surface antigens include Trop2 or Her2. Tumor-associated surface antigens are known to those skilled in the art. In particular, those that have been found to be useful for the development of ADCs are described in the review article, for example, Criscitello et al., "Antibody-drug conjugates in solid tumors: a look into novel targets", Journal of Hematology and Oncology, (2021) 14:20 (https: / / doi.org / 10.1186 / s13045-021-01035-z).

[0177] In some embodiments, the receptor-binding molecule may be selected from the group consisting of an antibody, an antibody fragment, a proteinaceous binding molecule with antibody-like binding properties, an aptamer, and a small molecule. In some embodiments, the receptor-binding molecule is an aptamer. In some embodiments, the receptor-binding molecule is a small molecule.

[0178] Preferably, the receptor-binding molecule is an antibody. More preferably, the antibody is selected from the group consisting of monoclonal antibodies, chimeric antibodies, humanized antibodies, human antibodies, and single-domain antibodies, such as camel or shark single-domain antibodies. Even more preferably, the antibody is a monoclonal antibody. Preferably, the antibody is capable of specifically binding to a tumor-associated surface antigen. In some embodiments, the antibody may be brentuximab. In some embodiments, the antibody may be trastuzumab.

[0179] The receptor-binding molecule may be an antibody fragment. Preferably, the antibody fragment is a bivalent antibody fragment. More preferably, the bivalent antibody fragment is selected from the group consisting of a (Fab)2' fragment, a bivalent single-chain Fv fragment, a dual affinity re-targeting (DART) antibody, and a diabody. Alternatively, preferably, the antibody fragment is a monovalent antibody fragment. More preferably, the monovalent antibody fragment is selected from the group consisting of a Fab fragment, an Fv fragment, and a single-chain Fv fragment (scFv). The monovalent antibody fragment may be a fragment of a single-domain camelid or shark single-domain antibody. Preferably, the antibody fragment is capable of specifically binding to a tumor-associated surface antigen.

[0180] The receptor-binding molecule may be a proteinaceous binding molecule with antibody-like binding properties. Examples of proteinaceous binding molecules with antibody-like binding properties that can be used as receptor-binding molecules include aptamers, muteins based on polypeptides of the lipocalin family, glubodies, proteins based on ankyrin scaffolds, proteins based on crystallin scaffolds, adnectins, avimers, EGF-like domains, kringle domains, fibronectin type I domains, fibronectin type II domains, fibronectin type III domains, PAN domains, G1a domains, SRCR domains, and Kunitz / bovine pancreatic trypsin inhibitor. domain, tendamistat, Kazal-type serine protease inhibitor domain, trefoil (P-type) domain, von Willebrand factor type C domain, anaphylatoxin-like domain, CUB domain, thyroglobulin type I repeat, LDL receptor class A domain, sushi domain, link domain, thrombospondin type I domain, immunoglobulin domain or immunoglobulin-like domain (e.g., domain antibody or camel heavy chain antibody), C-type lectin domain, MAM domain, von Willebrand factor type A domain, somatomedin B domain, WAP-type 4-disulfide core domain, F5 / 8 C-type domain, hemopexin domain, SH2 domain, SH3 domain, laminin-type EGF-like domain, C2 domain, "kappabody" (Ill. et al. "Design and construction of a hybrid immunoglobulin domain with properties of both heavy and light chain variable regions" Protein Eng 10:949-57 (1997)), "minibody" (Martin et al. "The affinity-selection of a minibody polypeptide inhibitor of human interleukin-6" EMBO J 13:5303-9 (1994)), "Janusin" (Traunecker et al."Bispecific single chain molecules (Janusins) target cytotoxic lymphocytes on HIV-infected cells" EMBO J 10:3655-3659 (1991) and Traunecker et al. "Janusin: new molecular design for bispecific reagents" Int J Cancer Suppl 7:51-52 (1992), nanobodies, adnectins, tetranectins, microbodies, affilins, affibodies or ankyrins, crystallins, knottins, ubiquitins, zinc finger proteins, autofluorescent proteins, ankyrins or ankyrin repeat proteins or leucine-rich repeat proteins, avimers (Silverman, Lu Q, Bakker A, To W, Duguay A, Alba BM, Smith R, Rivas A, Li P, Le H, Whitehorn E, Moore KW, Swimmer C, Perlroth V, Vogt M, Kolkman J, Stemmer WP 2005, Nat Biotech, Dec;23(12):1556-61, E-Publication in Nat Biotech. 2005 Nov 20 edition); and Silverman J, Lu Q, Bakker A, To W, Duguay A, Alba BM, Smith R, Rivas A, Li P, Le H, Whitehorn E, Moore KW, Swimmer C, Perlroth V, Vogt M, Kolkman J, Stemmer WP, Nat Biotech, Dec;23(12):1556-61, E-Publication in Nat. Biotechnology.Examples of suitable proteinaceous binding molecules include, but are not limited to, multivalent avimer proteins evolved by exon shuffling of human receptor domain families, as described in the 2005 Nov 20 edition. Preferably, the proteinaceous binding molecule with antibody-like binding properties is selected from the group consisting of muteins based on polypeptides of the lipocalin family, glubodies, proteins based on ankyrin scaffolds, proteins based on crystallin scaffolds, adnectins, avimers, DARPins, and affibodies. Preferably, the proteinaceous binding molecule with antibody-like binding properties is capable of specifically binding to tumor-associated surface antigens.

[0181] Group X and Drug Moiety (D) The group X serves to link the drug moiety (D) to the phosphorus atom. The group X may be provided by the drug moiety. In particular, the group X may form part of the drug prior to attachment to the phosphorus. Illustrative, but non-limiting, examples in which the group X is provided by the drug moiety are represented by the drugs SN-38 and DXD, as shown below: These drug moieties may be attached to the phosphorus via the hydroxy group marked with an asterisk (*). Thus, in these embodiments, the oxygen (O) of the hydroxy group marked with an asterisk represents the group X. Those skilled in the art will readily recognize that the hydrogen atom linked to the X group (i.e., the hydrogen atom linked to the oxygen atom marked with an asterisk in the structure above, for example) may be present when the drug is not connected to the phosphorus; thus, the hydrogen atom may be present before attachment of the drug moiety to the phosphorus or after release of the drug from the conjugate. Those skilled in the art will know how to modify the drug, if necessary, to include a group X suitable for attachment to the phosphorus.

[0182] In any one of the embodiments described herein, the group X is O, S, or NR X10 It can be. R X10 may be hydrogen; or an optionally substituted aliphatic residue or an optionally substituted aromatic residue. In particular, in any one of the embodiments described herein, RX10 is hydrogen, (C1-C8) alkyl (e.g., methyl, ethyl, or propyl), (C6-C 10 ) aryl (e.g., phenyl), and (C1-C8) alkylene (C6-C 10 ) aryl (e.g., benzyl). Preferably, R X10 is hydrogen or (C1-C8) alkyl. More preferably, R X10 is hydrogen or (C1-C6) alkyl, even more preferably hydrogen or (C1-C4) alkyl, and even more preferably hydrogen or (C1-C2) alkyl. In a preferred embodiment, R X10 is hydrogen. R X10 In some embodiments, X is O, S, and NR X10 where R X10 is as defined herein. In some embodiments, X is O. In some embodiments, X is S. In some embodiments, X is NR X10 where R X10 is as defined herein, preferably R X10 is hydrogen. In some embodiments, X is O or NR X10 where R X10 is as defined herein. In some embodiments, X is O or S.

[0183] Preferably, the group X is O (oxygen).

[0184] More preferably, the group X is NH.

[0185] The moiety XD can be derived from an aliphatic alcohol. The moiety XD can be derived from an aromatic alcohol. In these embodiments, X is O. The term "aromatic alcohol" refers to an aromatic ring system, by itself or as part of a larger structure, particularly substituted with a hydroxyl functional group -OH. Thus, the term "aromatic alcohol" refers to any aryl, heteroaryl, arylene, and heteroarylene moiety, as described herein, having a hydroxyl functional group bonded to an aromatic carbon of the aromatic ring system. The aromatic alcohol may be part of a larger moiety, particularly a drug moiety (D), such as when the aromatic ring system is a substituent on the moiety, or it may be embedded in a larger moiety, particularly a drug moiety (D), by ring fusion and may be substituted with one or more other hydroxyl substitutents, as described herein. A phenolic alcohol is an aromatic alcohol having a phenol group as the aromatic ring. The term "aliphatic alcohol" refers to a moiety, by itself or as part of a larger structure, particularly having a non-aromatic carbon bonded to a hydroxyl functional group -OH. The hydroxyl-bearing carbon may be unsubstituted (i.e., methyl alcohol) or may have one, two, or three optionally substituted branched or unbranched alkyl substituents, defining a primary alcohol or a secondary or tertiary aliphatic alcohol within a linear or cyclic structure. When forming part of a larger structure, particularly a drug moiety (D), the alcohol may be a substituent on the structure by attachment to the hydroxyl-bearing carbon through the hydroxyl-bearing carbon, through a carbon of an alkyl or other moiety, as described herein, or through a substituent of the alkyl or other moiety. The term "aliphatic alcohol" also contemplates non-aromatic cyclic structures (i.e., optionally substituted carbocyclic and heterocarbocyclic rings) in which a hydroxyl functionality is attached to a non-aromatic carbon of the cyclic ring system.The terms "derived from an aromatic alcohol" or "derived from an aliphatic alcohol" specifically mean that the hydrogen atom of the hydroxy group (-OH) is replaced by phosphorus of a conjugate or compound described herein, such that the oxygen of the hydroxy group (-OH) (i.e., group X) is bonded to phosphorus of a conjugate or compound described herein.

[0186] In a preferred embodiment, X is O and the drug moiety (D) is an optionally substituted aliphatic residue. In a preferred embodiment, X is O and the drug moiety (D) is an optionally substituted aromatic residue.

[0187] The present disclosure provides conjugates, such as antibody-drug conjugates, comprising a drug moiety D. The terms "drug moiety" and "payload," which can be used interchangeably, as used herein refer to a chemical or biochemical moiety conjugated to a receptor-binding molecule (RBM), such as an antibody or antigen-binding fragment. In this regard, reference is again made to the conjugate of formula (I) described herein. The receptor-binding molecule (RBM) can be conjugated to several identical or different drug moieties using any method described herein or known in the art. In some embodiments, the drug moiety can be a molecule that has a cytotoxic effect on mammalian cells, can cause apoptosis, and / or can have a regulatory effect on malignant cells.

[0188] Drug moiety D is not particularly limited and can be any suitable drug moiety. In some preferred embodiments, the drug moiety is a mitotic spindle inhibitor such as (-)-epipodophyllotoxin, a dehydrogenase A inhibitor such as (R)-GNE-140, a kinase inhibitor such as (S)-3-hydroxymidostaurin and (R)-3-hydroxymidostaurin, a BET inhibitor such as ABBV-744, an estrogen receptor agonist such as acolbifene, a Wee1 inhibitor such as adavosertib, an HSP90 inhibitor such as alvespimycin, a kinase inhibitor such as ARS-1620, an FGFR inhibitor such as ASP5878, or an MCT1 inhibitor such as AZD3965. , mTOR inhibitors such as AZD-8055, kinase inhibitors such as verizatinib, HIF-2α inhibitors such as velzutifan, BCL inhibitors such as BM-1197, VEGFR inhibitors such as brivanib, STAT3 inhibitors such as C188, antitumor drugs such as CB1151, kinase inhibitors such as dasatinib, EGFR inhibitors such as DBPR112, CDK inhibitors such as dinaciclib, TRPC4 and TRCP5 channel activators such as englerin A, PRMT inhibitors such as EPZ015666, topoisomerase inhibitors such as etoposide, mTOR inhibitors such as everolimus, EZMMethyltransferase inhibitors such as 2302, CDK inhibitors such as fadraciclib, USP7 inhibitors such as FT671, estrogen receptor agonists such as fulvestrant, estrogen receptor agonists such as fulvestrant, HSP90 inhibitors such as geldanamycin, estrogen receptor agonists such as GNE-274, kinase inhibitors such as GNE-493, PRMT inhibitors such as GSK3326595, kinase inhibitors such as hypothemycin, CDK inhibitors such as IIIM-290, Illudin S, etc. DNA alkylating agents, kinase inhibitors such as irolasertib, kinase inhibitors such as larotrectinib, kinase inhibitors such as larotrectinib, IGF-1 inhibitors such as linsitinib, PRMT inhibitors such as LLY-283, HSP90 inhibitors such as luminespib, FGFR inhibitors such as LY2874455, kinase inhibitors such as mirdametinib, kinase inhibitors such as MRTX1133, kinase inhibitors such as MRTX1133, kinase inhibitors such as ningetinib, lurbinectidin in) or DNA minor groove binders such as trabectidin, HSP90 inhibitors such as NMS-E973, ribonucleotide reductase inhibitors such as NSAH, PLK1 inhibitors such as onvansertib, mTOR inhibitors such as Palomid 529, kinase inhibitors such as PD166326, NEDD8 inhibitors such as pevonedistat, kinase inhibitors such as PF-04217903, kinase inhibitors such as PF-06843195, HSP90 inhibitors such as PI-103, and pinometostat Methyltransferase inhibitors such as, topoisomerase inhibitors such as PNU-159682, topoisomerase inhibitors such as podofilox, HDAC inhibitors such as QTX125, mTOR inhibitors such as rapamycin, tankyrase inhibitors such as RK-287107, kinase inhibitors such as RO4987655, kinase inhibitors such as RP-3500, BCL inhibitors such as S55746, BCL inhibitors such as S65487, EGFR inhibitors such as SDZ281-977, kinase inhibitors such as SU14813, TC-A2317, kinase inhibitors such as teleocidin A1, ribonucleotide reductase inhibitors such as tezacitabine, kinase inhibitors such as TG 100572, RNA splicing inhibitors such as tylanstatin A, kinase inhibitors such as UNC5293, kinase inhibitors such as UNC5293, HSP90 inhibitors such as VER-50589, eIF4A inhibitors such as zotatifin, and analogs or prodrugs thereof.

[0189] In further embodiments, the drug moiety is an anti-cancer drug.Accordingly, in any one of the compounds described herein, the drug moiety can be a camptothecin compound, a TOPK inhibitor (e.g., OTS-964), a CDK inhibitor (e.g., ganetespib or roniciclib), a bromodomain inhibitor (e.g., brirabresibe), an HSP70 inhibitor (e.g., triptolide), an HSP90 inhibitor (e.g., SNX-2112), a ribonucleotide reductase inhibitor (e.g., gemcitabine), an Aurora B kinase inhibitor (e.g., barasertib), an auristatin (e.g., monomethyl auristatin E (MMAE) or monomethyl auristatin F (MMAF)), a maytansinoid, a calicheamicin, a tubulysin, an amatoxin, The inhibitor may be selected from the group consisting of dolastatins, pyrrolobenzodiazepine dimers, indolino-benzodiazepine dimers, radioisotopes, therapeutic proteins and peptides (or fragments thereof), KSP inhibitors, eIF4E inhibitors (e.g., ON-013100), nicotinamide phosphoribosyltransferase (Nampt) inhibitors (e.g., Nampt-IN-1), dihydroorotate dehydrogenase (DHODH) inhibitors (e.g., Bay-2402234 or DHODH-IN-16), taxanes (e.g., paclitaxel, albumin-bound paclitaxel (nab-paclitaxel), docetaxel, cabazitaxel, or abraxane), and analogs or prodrugs thereof.

[0190] Preferably, the drug moiety is a camptothecin compound. The term "camptothecin compound" includes camptothecin itself and analogs of camptothecin. Camptothecin is a topoisomerase poison discovered in 1966 by ME Wall and MC Wani in a systematic screening of natural products for anticancer drugs. Camptothecin was isolated from the bark and stem of Camptotheca acuminata (camptotheca, happy tree), a tree native to China used as a cancer treatment in traditional Chinese medicine. Camptothecin has the following structure: The term "camptothecin compound" also includes camptothecin analogs. In this regard, the term "camptothecin compound" refers to a compound having the structure of camptothecin: Optional substituents include, but are not limited to, (C1-C 10 The camptothecin compound may include, for example, a (C3-C8) alkyl, a (C3-C8) carbocyclo, a (C3-C8) heterocyclo, an aryl, an amino group, a hydroxy group, a carbonyl group, an amide group, an ester group, a carbamate group, a carbonate group, and / or a silyl group. The camptothecin compound may have one or more functional groups capable of forming a bond to the linker L. Those skilled in the art will readily select a suitable camptothecin compound having the desired biological activity. For example, camptothecin analogs such as topotecan, irinotecan, or belotecan are currently approved and used in cancer chemotherapy.

[0191] The following camptothecin analogs are also contemplated by the term camptothecin compound: TIFF2025542295000189.tif238154 Further camptothecin analogues that can be used as camptothecin compounds are described in WO 2019 / 236954 and EP 0 495 432, which are incorporated herein by reference.

[0192] In some embodiments, the camptothecin compound is selected from the group consisting of DXD, SN38, exatecan, camptothecin, topotecan, irinotecan, belotecan, lurtotecan, rubitecan, ciratecan, cositecan and gimatecan. Preferably, the camptothecin compound is DXD or SN38.

[0193] Preferably, the drug moiety D is DXD, which has the following structure: TIFF2025542295000190.tif68128 In some preferred embodiments, DXD has the following structure: TIFF2025542295000191.tif68128 Preferably, in any one of these embodiments, DXD may be bonded to the phosphorus atom via a hydroxy group marked with an asterisk (*); thus, in these embodiments, the oxygen atom of the hydroxy group marked with an asterisk represents the group X.

[0194] Preferably, the drug moiety is SN38, which has the following structure: TIFF2025542295000192.tif36128 In some preferred embodiments, SN38 has the following structure: Preferably, in any one of these embodiments, SN38 may be attached to the phosphorus atom via the hydroxy group marked with an asterisk (*). Thus, in these embodiments, the oxygen atom of the hydroxy group marked with an asterisk represents the group X.

[0195] Preferably, the drug moiety is exatecan, which has the following structure: TIFF2025542295000194.tif73128 In some preferred embodiments, exatecan has the following structure: TIFF2025542295000195.tif74128 Preferably, in any one of these embodiments, exatecan may be attached to the phosphorus atom via the amino group marked with an asterisk (*). Thus, in these embodiments, the nitrogen atom of the amino group marked with an asterisk represents the group X.

[0196] Preferably, the drug moiety is a TOPK inhibitor. The TOPK inhibitor can be OTS-964. In some preferred embodiments, the drug moiety is OTS-964. OTS-964 has the following structure: TIFF2025542295000196.tif76128 In some more preferred embodiments, OTS-964 has the following structure: TIFF2025542295000197.tif76128 Preferably, in any one of these embodiments, OTS-964 can be attached to the phosphorus atom via the hydroxy group marked with an asterisk (*). Thus, in these embodiments, the oxygen atom of the hydroxy group marked with an asterisk represents the group X.

[0197] Preferably, the drug moiety is a CDK inhibitor. The CDK inhibitor can be ganetespib or roniciclib. In some preferred embodiments, the drug moiety is ganetespib. Ganetespib has the following structure: TIFF2025542295000198.tif56128 Preferably, in any one of these embodiments, ganetespib may be attached to the phosphorus atom via any of the hydroxy groups marked with an asterisk (*). Thus, in these embodiments, the oxygen atom of the hydroxy group marked with an asterisk represents group X. In some embodiments, any conjugate or compound described herein comprising ganetespib may be a mixture of two isomers resulting from attachment via a hydroxy group.

[0198] In some preferred embodiments, the drug moiety is roniciclib, which has the following structure: TIFF2025542295000199.tif43128 Preferably, in any one of these embodiments, roniciclib may be attached to the phosphorus atom via the hydroxy group marked with an asterisk (*). Thus, in these embodiments, the oxygen atom of the hydroxy group marked with an asterisk represents the group X.

[0199] Preferably, the drug moiety is a bromodomain inhibitor. The bromodomain inhibitor can be birapresib. In some preferred embodiments, the drug moiety is birapresib. Birapresib has the following structure: TIFF2025542295000200.tif61128 In some preferred embodiments, bilabresive has the following structure: Preferably, in any one of these embodiments, the bilabresitive may be attached to the phosphorus atom via a hydroxy group marked with an asterisk (*). Thus, in these embodiments, the oxygen atom of the hydroxy group marked with an asterisk represents the group X.

[0200] Preferably, the drug moiety is an HSP70 inhibitor. The HSP700 inhibitor can be triptolide. In some preferred embodiments, the drug moiety is triptolide. Triptolide has the following structure: Preferably, in any one of these embodiments, triptolide can be attached to the phosphorus atom via the hydroxy group marked with an asterisk (*). Thus, in these embodiments, the oxygen atom of the hydroxy group marked with an asterisk represents the group X.

[0201] Preferably, the drug moiety is an HSP90 inhibitor. The HSP90 inhibitor can be SNX-2112. In some preferred embodiments, the drug moiety is SNX-2112. SNX-2112 has the following structure: TIFF2025542295000203.tif65128 In some preferred embodiments, SNX-2112 has the following structure: Preferably, in any one of these embodiments, SNX-2112 can be attached to the phosphorus atom via the hydroxy group marked with an asterisk (*). Thus, in these embodiments, the oxygen atom of the hydroxy group marked with an asterisk represents the group X.

[0202] Preferably, the drug moiety is a ribonucleotide reductase inhibitor. The ribonucleotide reductase inhibitor can be gemcitabine. In some preferred embodiments, the drug moiety is gemcitabine. Gemcitabine has the following structure: TIFF2025542295000205.tif51128 In some preferred embodiments, gemcitabine has the following structure: TIFF2025542295000206.tif51128 Preferably, in any one of these embodiments, gemcitabine can be attached to the phosphorus atom via any of the hydroxy groups marked with an asterisk (*). Thus, in these embodiments, the oxygen atom of the hydroxy group marked with an asterisk represents group X. In some embodiments, any conjugate or compound described herein comprising gemcitabine can be a mixture of two isomers resulting from attachment via a hydroxy group.

[0203] Preferably, the drug moiety is an Aurora B kinase inhibitor. The Aurora B kinase inhibitor can be barasertib. In some preferred embodiments, the drug moiety is barasertib. Barasertib has the following structure: TIFF2025542295000207.tif59137 Preferably, in any one of these embodiments, barasertib may be attached to the phosphorus atom via the hydroxy group marked with an asterisk (*). Thus, in these embodiments, the oxygen atom of the hydroxy group marked with an asterisk represents the group X.

[0204] Preferably, drug moiety D is an auristatin. In some embodiments, the auristatin is monomethylauristatin E (MMAE). In some embodiments, the auristatin is monomethylauristatin F (MMAF).

[0205] Monomethyl auristatin E (MMAE) is represented by the following structural formula: MMAE can be attached to the phosphorus, for example, via the N-terminus indicated by an asterisk (*); thus, in these embodiments, the N-methyl group marked with an asterisk (*) represents the group X. In alternative embodiments, MMAE can be attached to the phosphorus via a hydroxy group marked with two asterisks (**); in these embodiments, the oxygen atom of the hydroxy group marked with two asterisks (**) represents the group X; optionally, when MMAE is attached to the phosphorus via a hydroxy group marked with two asterisks (**), the N-terminus indicated by the asterisk (*) can be protected with a suitable protecting group, such as, for example, a tert-butyloxycarbonyl group (BOC group).

[0206] Monomethyl auristatin F (MMAF) is represented by the following structural formula: TIFF2025542295000209.tif33128MMAF may be attached to the phosphorus, for example, via the N-terminus indicated by an asterisk (*); thus, in these embodiments, the N-methyl group marked with an asterisk (*) represents the group X.

[0207] These molecules have been shown to non-competitively inhibit the binding of vincristine to tubulin (at a location known as the vinca / peptide domain), but bind to the RZX / MAY domain.

[0208] In some embodiments, the drug moiety is a maytansinoid drug moiety and has the structure: TIFF2025542295000210.tif48128, where the wavy line indicates the covalent attachment of the sulfur atom of the maytansinoid to the linker of a conjugate, such as an antibody-drug conjugate. R at each occurrence is independently H or C1-C6 alkyl. The alkylene chain connecting the amide group to the sulfur atom can be methanyl, ethanyl, or propanyl, i.e., m is 1, 2, or 3 (U.S. Pat. No. 633,410, U.S. Pat. No. 5,208,020, Chari et al. (1992) Cancer Res. 52; 127-131, Lui et al. (1996) Proc. Natl. Acad. Sci. 93:8618-8623). Thus, in these embodiments, the sulfur atom can represent group X.

[0209] All stereoisomers of the maytansinoid drug moiety, i.e., any combination of R and S configurations at the chiral carbon of the maytansinoid, are contemplated for the conjugates disclosed herein. In some embodiments, the maytansinoid drug moiety has the following stereochemistry: TIFF2025542295000211.tif49128. Thus, in these embodiments, the sulfur atom may represent the group X.

[0210] In some embodiments, the maytansinoid drug moiety is N 2' -Deacetyl-N 2' -(3-mercapto-1-oxopropyl)-maytansine (also known as DM1). DM1 has the following structural structure: TIFF2025542295000212.tif48128. Thus, in these embodiments, the sulfur atom may represent the group X.

[0211] In some embodiments, the maytansinoid drug moiety is N 2' -Deacetyl-N 2' -(4-mercapto-1-oxopentyl)-maytansine (also known as DM3). DM3 has the following structural structure: TIFF2025542295000213.tif54128. Thus, in these embodiments, the sulfur atom may represent the group X.

[0212] In some embodiments, the maytansinoid drug moiety is N 2' -Deacetyl-N 2' -(4-methyl-4-mercapto-1-oxopentyl)-maytansine (also known as DM4), which has the following structure: TIFF2025542295000214.tif45128. Thus, in these embodiments, the sulfur atom may represent the group X.

[0213] Preferably, in the conjugates disclosed herein that include a maytansinoid drug moiety, the maytansinoid is N 2' -Deacetyl-N 2' -(3-mercapto-1-oxopropyl)-maytansine (DM1) or N 2' -Deacetyl-N 2’ -(4-mercapto-4-methyl-1-oxopentyl)-maytansine (DM4).

[0214] The drug moiety can be a calicheamicin. "Calicheamicin," as used herein, refers to a class of enediyne antitumor antibiotics derived from the bacterium Micromonospora echinospora, most notably calicheamicin γ1. It was originally isolated in the mid-1980s from the chalk earth, or "Calich Pits," in Kerrville, Texas. It is highly toxic to all cells. Therefore, the drug moiety may be substituted or derivatized for coupling to a linker and / or receptor-binding molecule, as in the following structure: It can be calicheamicin gamma 1, exemplified by TIFF2025542295000215.tif42128.

[0215] The drug moiety can be tubulysin. Tubulysin functions as an anti-microtubule agent, anti-mitotic agent, apoptosis inducer, anti-cancer agent, anti-angiogenic agent, and anti-proliferative agent. Tubulysin is a cytotoxic peptide containing nine members (A-I). Preferably, the tubulysin is tubulysin A. Tubulysin A has potential application as an anti-cancer agent. It arrests cells in the G2 / M phase. Tubulysin A has the following structure: I have TIFF2025542295000216.tif38128.

[0216] The drug moiety can be an amatoxin. Amatoxins are a collective term for a subgroup of at least eight related toxic compounds found in several genera of poisonous mushrooms, particularly Amanita phalloides and several other members of the Amanita genus, as well as several Conocybe, Galerina, and Lepiota mushroom species. Amatoxins are lethal even in small amounts. These compounds share a similar structure: eight amino acid residues arranged in a conserved macrobicyclic motif (an overall pentacyclic structure, counting the rings intrinsic to the proline and tryptophan residues). All amatoxins are oligopeptides, synthesized as a 35-amino acid proprotein from which the final eight amino acids are cleaved by prolyl oligopeptidase. The approximate amino acid sequence of an amatoxin is Ile-Trp-Gly-Ile-Gly-Cys-Asn-Pro (SEQ ID NO: 1), with a bridge between Trp and Cys via a sulfoxide (S=O) moiety and, in variants of the molecule, hydroxylation. Currently, there are 10 known amatoxins, which can be drug moieties. TIFF2025542295000217.tif129128

[0217] The drug moiety can be a dolastatin, such as dolastatin 10 or dolastatin 15. Both are marine natural products isolated from the Indian Ocean sea hare Dollabella auricularia. This potent antitumor agent has also been isolated from the Palauan marine cyanobacterium Symploca sp. VP642. Dolastatins 10 and 15, small linear peptide molecules, are considered potential anticancer drugs with efficacy against breast cancer, liver cancer, solid tumors, and some leukemias. Preclinical studies have demonstrated efficacy in experimental antineoplastic and tubulin assembly systems. Dolastatins are mitotic inhibitors. They inhibit microtubule assembly by interfering with tubulin formation, thereby disrupting mitotic cell division and inducing apoptosis and Bcl-2 phosphorylation in several malignant cell types. Dolostatin 10 (N,N-dimethyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino}propyl]-1-pyrrolidinyl}-5-methyl-1-oxo-4-heptanyl]-N-methyl-L-valinamide) has the following structure: I have TIFF2025542295000218.tif36128.

[0218] Dolastatin 15 ((2S)-1-[(2S)-2-benzyl-3-methoxy-5-oxo-2,5-dihydro-1H-pyrrol-1-yl]-3-methyl-1-oxo-2-butanyl N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-prol) has the following structure: I have TIFF2025542295000219.tif48128.

[0219] The drug moiety may be substituted or derivatized for coupling to a linker and / or receptor binding molecule, having the following structure: The compound may be a pyrrolobenzodiazepine dimer, such as the compound having TIFF2025542295000220.tif19128.

[0220] The drug moiety has the following structure: The compound may be an indolinobenzodiazepine dimer, such as the compound having TIFF2025542295000221.tif28128.

[0221] The drug moiety can be a nicotinamide phosphoribosyltransferase (Nampt) inhibitor. The Nampt inhibitor can be Nampt-IN-1. In some preferred embodiments, the drug moiety is Nampt-IN-1. Nampt-IN-1 has the following structure: Preferably, in any one of these embodiments, Nampt-IN-1 can be attached to the phosphorus atom of a hydroxy group marked with an asterisk (*). Thus, in these embodiments, the oxygen atom of the hydroxy group marked with an asterisk represents the group X.

[0222] The drug moiety can be a radioisotope. Exemplary radioisotopes described herein can be associated with brachyradiation sources, typically gamma or beta emitters such as iodine-125, iodine-131, iridium-192, or palladium-103.

[0223] The drug moiety can be a therapeutic protein or peptide or a fragment thereof. Typical examples are cytokines such as interleukins, ricin, diphtheria toxin, and Pseudomonas exotoxin PE38.

[0224] The drug moiety can be a KSP (kinesin spindle protein) inhibitor. Examples of KSP inhibitors include ispinesib (SB-715992), SB743921, AZ 3146, GSK923295, BAY 1217389, MPI-0479605, and ARQ 621.

[0225] The drug moiety can be an inhibitor of eukaryotic translation initiation factor 4E (eIF4E). An example of an eIF4E inhibitor is ON-013100. The structure of ON-013100 is shown below: TIFF2025542295000223.tif27128ON-013100 may be attached to the phosphorus, for example, via the terminal OH group (marked with an asterisk *); thus, in these embodiments, the O of the OH group represents the group X.

[0226] The drug moiety can be an inhibitor of dihydroorotate dehydrogenase (DHODH). Examples of DHODH inhibitors include Bay-2402234 and DHODH-IN-16. Bay-2402234 has the following structure: TIFF2025542295000224.tif62128Bay-2402234 may be attached to the phosphorus, for example, via the terminal OH group (marked with an asterisk *); thus, in these embodiments, the O of the OH group represents the group X.

[0227] DHODH-IN-16 has the following structure: TIFF2025542295000225.tif35128DHODH-IN-16 may be attached to the phosphorus, for example, via the terminal OH group (marked with an asterisk *); thus, in these embodiments, the O of the OH group represents the group X.

[0228] The drug moiety can be a taxane.Taxanes are a class of chemotherapeutic agents that act by binding to tubulin / microtubules, thereby causing cell cycle inhibition at the G2 / M phase, which plays an important role in cell division.Examples of taxanes include paclitaxel, albumin-bound paclitaxel (nab-paclitaxel), docetaxel, cabazitaxel, and abraxane.In a preferred embodiment, the taxane is paclitaxel.The structure of paclitaxel is shown below: TIFF2025542295000226.tif55128 Paclitaxel may be attached to the phosphorus, for example, via one of the OH groups; thus, in these embodiments, the O of the OH group represents group X. In a currently preferred embodiment, Pacliataxel may be attached via the OH group marked with an asterisk *.

[0229] Group M and linker L The present disclosure provides conjugates in which a receptor-binding molecule is linked to a drug moiety as described herein. According to the present disclosure, the receptor-binding molecule can be linked to the drug moiety, in particular, via a covalent bond by a group M and a linker L. As used herein, a "linker" L is any chemical moiety capable of linking the group M, such as oxygen (O), to the receptor-binding molecule. In this regard, the present disclosure provides conjugates of formula (I): Referring again to TIFF2025542295000227.tif36128, the receptor binding molecule can thus be linked to M via a linker L. In formula (I), RBM, L, M, X, D, Y 1 , E, W, Z and n are as defined herein.

[0230] The group M is O, NR M60 , S or CR M61 R M62 It can be. R M60 is hydrogen, (C1-C8) alkyl (e.g., methyl, ethyl, or propyl), (C6-C 10 ) aryl (e.g., phenyl), and (C1-C8) alkylene (C6-C 10 ) aryl (e.g., benzyl). Preferably, R M60 is hydrogen or (C1-C8) alkyl. More preferably, R M60 is hydrogen or (C1-C6) alkyl, even more preferably hydrogen or (C1-C4) alkyl, and even more preferably hydrogen or (C1-C2) alkyl. In a preferred embodiment, R M60 is hydrogen. R M61 and RM62 are each independently hydrogen, (C1-C8) alkyl (e.g., methyl, ethyl, or propyl), (C6-C 10 ) aryl (e.g., phenyl), and (C1-C8) alkylene (C6-C 10 ) aryl (e.g., benzyl). Preferably, R M61 and R M62 are each independently selected from the group consisting of hydrogen or (C1-C8) alkyl. More preferably, R M61 and R M62 are each independently hydrogen or (C1-C6) alkyl, even more preferably hydrogen or (C1-C4) alkyl, and even more preferably hydrogen or (C1-C2) alkyl. In a preferred embodiment, R M61 and R M62 is hydrogen. In some embodiments, M is O or NR M60 where R M60 is as defined herein. In some embodiments, M is NR M60 where R M60 is as defined herein. In some embodiments, M is S (sulfur). In some embodiments, M is CR M61 R M62 where R M61 and R M62 is as defined herein.

[0231] In some preferred embodiments, M is O.

[0232] In some preferred embodiments, M is NH.

[0233] In some preferred embodiments, M is O, X is O, and Y 1 is NR A20 where R A20 is as defined herein. In a more preferred embodiment, M is O, X is O, and Y 1is NH. In any one of these embodiments, the integer m can be 0. Preferably, in any one of these embodiments, the drug moiety can be a camptothecin compound. More preferably, the camptothecin compound can be SN38 or DXD. Even more preferably, the camptothecin compound can be SN38.

[0234] The linker L serves to link the moiety M to the receptor binding molecule (RBM). The linker L is any chemical moiety capable of linking M to the receptor binding molecule (RBM). In particular, the linker L connects M to the receptor binding molecule (RBM) by a covalent bond. A linker reagent is a bifunctional or multifunctional moiety that can be used to link the receptor binding molecule (RBM) and M to form a conjugate of formula (I). The terms "linker reagent," "crosslinking reagent," "linker derived from a crosslinking reagent," and "linker" can be used interchangeably throughout this disclosure. Preferably, the linker is substantially resistant to cleavage, e.g., the linker is a stable linker or a non-cleavable linker. A non-cleavable linker is any chemical moiety capable of linking the receptor binding molecule (RBM) to M in a stable covalent manner. In particular, a non-cleavable linker is substantially resistant to acid-induced cleavage, light-induced cleavage, peptidase-induced cleavage, protease-induced cleavage, glycosidase-induced cleavage, phosphatase-induced cleavage, esterase-induced cleavage, and disulfide bond cleavage. Furthermore, "non-cleavable" refers, inter alia, to the ability of a chemical bond within or adjacent to the linker to withstand cleavage induced by acids, photolabile cleaving agents, peptidases, proteases, glycosidases, phosphatases, esterases, or chemical or physiological compounds that cleave disulfide bonds under conditions under which the drug moiety or receptor-binding molecule does not lose its activity.

[0235] Virtually any linker can be used. The linker can be, for example, a linear or branched hydrocarbon-based moiety. The linker can also include a cyclic moiety. When the linking moiety is a hydrocarbon-based moiety, the backbone of the linker can include only carbon atoms, but can also include heteroatoms such as oxygen (O), nitrogen (N), or sulfur (S) atoms. The linker can be, for example, (C1-C 20 ) carbon atom chains, or polyether-based chains such as polyethylene glycol-based chains having -(O-CH2-CH2)- repeating units. In exemplary embodiments of hydrocarbon-based linkers, the linking moiety may contain 1 to about 150, 1 to about 100, 1 to about 75, 1 to about 50, 1 to about 40, 1 to about 30, or 1 to about 20, including 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, and 19, main chain atoms.

[0236] The receptor-binding molecule (RBM) has a functional group capable of forming a bond with a functional group of the linker (L). Useful functional groups that can be present on the receptor-binding molecule, either naturally or through chemical manipulation, include, but are not limited to, sulfhydryl (-SH), amino, hydroxyl, carboxy, the anomeric hydroxyl group of a carbohydrate, and carboxyl. Preferred functional groups on receptor-binding molecules are sulfhydryl and amino. Sulfhydryl groups can be generated, for example, by reduction of intramolecular disulfide bonds in the receptor-binding molecule. Suitable reducing agents for reducing disulfide bonds to sulfhydryl groups are known to those skilled in the art, and non-limiting examples include tris(2-carboxyethyl)phosphine (TCEP), dithiothreitol (DTT), sodium dithionite, sodium thiosulfate, and sodium sulfite. As an illustrative example, the receptor-binding molecule may be an antibody, which contains one or more disulfide bonds that can be reduced to provide sulfhydryl groups. Alternatively, sulfhydryl groups can be generated by reaction of amino groups of lysine moieties of the receptor-binding molecule with, for example, 2-iminothiolane (Traut's reagent) or another sulfhydryl-generating reagent. Sulfhydryl groups can also be generated by (genetically) incorporating additional cysteine ​​residues into the structure of the receptor-binding molecule.

[0237] In some embodiments, the linker forms a bond with a sulfur atom of the receptor binding molecule. The sulfur atom can be derived from a sulfhydryl group of the receptor binding molecule. Preferably, the receptor binding molecule is an antibody. Representative linkers attached to receptor binding molecules (RBMs) are shown in formulas (IIIa) and (IIIb), where Q is a connector unit and # indicates a connection to the group M. Such linkers are described, for example, in WO 2004 / 010957. TIFF2025542295000228.tif59128

[0238] In some embodiments, the linker contains a functional group that can form a bond with the primary or secondary amino group of the receptor binding molecule. Examples of such functional groups include, but are not limited to, activated esters, such as succinimide esters, 4-nitrophenyl esters, pentafluorophenyl esters, tetrafluorophenyl esters, anhydrides, acid chlorides, sulfonyl chlorides, isocyanates, and isothiocyanates. Representative linkers attached to receptor binding molecules (RBMs) are shown in formulas (Va), (Vb), and (Vc), where Q is a connector unit and # indicates the connection to the group M. Such linkers are described, for example, in WO 2004 / 010957. TIFF2025542295000229.tif77128

[0239] In some embodiments, the linker is an aldehyde group (referred to herein as -CHO or -CHO) of a carbohydrate that may be present on the receptor binding molecule. TIFF2025542295000230.tif13128). For example, carbohydrates can be mildly oxidized using reagents such as sodium periodate, and the -CHO group of the resulting oxidized carbohydrate can be condensed with linkers containing functional groups such as hydrazides, oximes, primary or secondary amines, hydrazines, thiosemicarbazones, hydrazine carboxylic acids, and arylhydrazides, such as those described by Kaneko, T. et al. Bioconjugate Chem. 1991, 2, 133-41. Representative linkers attached to receptor binding molecules (RBMs) are shown in formulas (VIa), (VIb), and (VIc), where Q is a connector unit and # indicates a connection to the group M. Such linkers are described, for example, in WO 2004 / 010957. TIFF2025542295000231.tif59128

[0240] The term "connector unit Q," whenever used herein, refers to a chemical moiety that forms part of a linker L and serves to connect the linker to a group M. Any chemical moiety that can form a bond with M can be used. In some embodiments, whenever a connector unit Q is referenced herein, the connector unit Q can be any of -(C-C 10 ) alkylene-, -(C3-C8) carbocyclo-, -arylene-, -(C1-C 10 ) alkylene-arylene- # , -arylene-(C1-C 10 ) alkylene- # , -(C1-C 10 ) alkylene-(C3-C8) carbocyclo- # , -(C3-C8)carbocyclo-(C1-C 10 ) alkylene- # , -(C3-C8)heterocyclo-, -(C1-C 10 ) alkylene-(C3-C8)heterocyclo- # , -(C3-C8)heterocyclo-(C1-C 10 ) alkylene- # and -(CH2CH2O) r -CH2-CH2- # where r is an integer ranging from 1 to 9; and #, if present, indicates the connection to M. Each connector unit may be optionally substituted.

[0241] In a preferred embodiment, Q is (C2-C 10 ) alkylene; more preferably (C2-C8) alkylene; even more preferably (C2-C6) alkylene. Even more preferably, Q is -(CH2) q -, where q is an integer ranging from 2 to 10, preferably from 2 to 8, more preferably from 3 to 6, even more preferably from 4 to 5; even more preferably, q is 5.

[0242] In a preferred embodiment, Q is a (C3-C8) carbocyclic ring, C6-C 10)aryl (phenyl), a 5- or 6-membered heterocyclic ring containing 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S, more preferably (C3-C8)cycloalkyl or (C5-C8)cycloalkenyl, even more preferably a 5-, 6-, or 7-membered cycloalkyl, and even more preferably cyclohexyl. In some embodiments, Q is cyclohexyl.

[0243] In a preferred embodiment, Q is TIFF2025542295000232.tif24128, where: Q A are independently (C1-C 10 ) alkylene; preferably (C1-C8) alkylene; more preferably (C2-C5) alkylene; Q B are independently (C2-C 10 ) alkylene; preferably (C2-C8) alkylene; more preferably (C2-C5) alkylene; R Q is hydrogen, (C1-C8) alkyl (e.g., methyl, ethyl, or propyl), (C6-C 10 )aryl (phenyl), and (C1-C8)alkylene (C6-C 10 ) aryl (e.g., benzyl); preferably, R Q is hydrogen or (C-C) alkyl; more preferably, R Q is hydrogen or (C-C) alkyl; even more preferably, R Q is hydrogen or (C-C) alkyl; even more preferably, R Q is hydrogen or (C-C) alkyl; even more preferably, R Q is hydrogen; # indicates a connection to M; and TIFF2025542295000233.tif6128 shows the connection to the rest of L.

[0244] More preferably, Q is TIFF2025542295000234.tif27128, where: R Q is hydrogen, (C1-C8) alkyl (e.g., methyl, ethyl, or propyl), (C6-C 10 ) aryl (e.g., phenyl), and (C1-C8) alkylene (C6-C 10 ) aryl (e.g., benzyl); preferably, R Q is hydrogen or (C-C) alkyl; more preferably, R Q is hydrogen or (C-C) alkyl; even more preferably, R Q is hydrogen or (C-C) alkyl; even more preferably, R Q is hydrogen or (C-C) alkyl; even more preferably, R Q is hydrogen; x is independently an integer ranging from 1 to 10; preferably from 2 to 8; more preferably from 3 to 6; even more preferably from 4 to 6; in some preferred embodiments, x is 5; y is independently an integer ranging from 2 to 10; preferably from 2 to 8; more preferably from 3 to 6; even more preferably from 4 to 6; in some preferred embodiments, y is 5; # indicates a connection to M; and TIFF2025542295000235.tif6128 shows the connection to the rest of L.

[0245] In a preferred embodiment, Q is TIFF2025542295000236.tif24128, where: TIFF2025542295000237.tif14128 is a 5- or 6-membered carbocyclic ring; or TIFF2025542295000238.tif14128 is a 5- or 6-membered heterocyclic ring containing 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S; R Qis hydrogen, (C1-C8) alkyl (e.g., methyl, ethyl, or propyl), (C6-C 10 ) aryl (e.g., phenyl), and (C1-C8) alkylene (C6-C 10 ) aryl (e.g., benzyl); preferably, R Q is hydrogen or (C-C) alkyl; more preferably, R Q is hydrogen or (C-C) alkyl; even more preferably, R Q is hydrogen or (C-C) alkyl; even more preferably, R Q is hydrogen or (C-C) alkyl; even more preferably, R Q is hydrogen; Q C is (C2-C 20 ) alkylene; preferably (C-C 10 ) alkylene; more preferably (C2-C8) alkylene; even more preferably (C2-C6) alkylene; or (C3-C8) carbocyclic, (C6-C 10 ) aryl (phenyl), a 5- or 6-membered heterocyclic ring containing 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S, (C3-C8)cycloalkyl; preferably 5-, 6-, or 7-membered cycloalkyl, even more preferably cyclohexyl; # indicates a connection to M; and TIFF2025542295000239.tif6128 shows the connection to the rest of L.

[0246] In a preferred embodiment, whenever referred to herein, Q C (CH2) p where p is an integer ranging from 2 to 20, preferably from 2 to 10, more preferably from 3 to 8, and even more preferably from 4 to 6; in some preferred embodiments, p is 5.

[0247] Carbocyclic rings may be aromatic or non-aromatic. Heterocyclic rings may be aromatic or non-aromatic.

[0248] More preferably, Q is TIFF2025542295000240.tif99128; where A Q , B Q , C Q and D Q are each independently selected from N (nitrogen) and CH; preferably, A Q , B Q , C Q and D Q At least one of A is CH; more preferably, A Q , B Q , C Q and D Q at least two of A are CH; even more preferably Q , B Q , C Q and D Q At least three of A are CH, and even more preferably Q , B Q , C Q and D Q each of which is CH; R Q is as defined herein; preferably R Q is hydrogen; Q C is as defined herein; # indicates a connection to M; and TIFF2025542295000241.tif6128 shows the connection to the rest of L.

[0249] Even more preferably, Q is TIFF2025542295000242.tif62128; where A Q , B Q , C Q and D Q are each independently selected from N (nitrogen) and CH; preferably, A Q , B Q , C Q and D QAt least one of A is CH; more preferably, A Q , B Q , C Q and D Q at least two of A are CH; even more preferably Q , B Q , C Q and D Q At least three of A are CH, and even more preferably Q , B Q , C Q and D Q each of which is CH; R Q is as defined herein; preferably R Q is hydrogen; Q C is as defined herein; # indicates a connection to M; and TIFF2025542295000243.tif6128 shows the connection to the rest of L.

[0250] Even more preferably, Q is TIFF2025542295000244.tif27128, where A Q , B Q , C Q and D Q are each independently selected from N (nitrogen) and CH; preferably, A Q , B Q , C Q and D Q At least one of A is CH; more preferably, A Q , B Q , C Q and D Q at least two of A are CH; even more preferably Q , B Q , C Q and D Q At least three of A are CH, and even more preferably Q , B Q , C Q and D Q each of which is CH; RQ is as defined herein; preferably R Q is hydrogen; Q C is as defined herein; # indicates a connection to M; and TIFF2025542295000245.tif6128 shows the connection to the rest of L.

[0251] In some preferred embodiments, Q is TIFF2025542295000246.tif29128, wherein p is an integer ranging from 2 to 20, preferably from 2 to 10, more preferably from 3 to 8, and even more preferably from 4 to 6; in some preferred embodiments, p is 5; # indicates a connection to M; and TIFF2025542295000247.tif6128 shows the connection to the rest of L; or TIFF2025542295000248.tif41128, where: TIFF2025542295000249.tif12128 is (C3-C8) carbocyclic, (C6-C 10 ) a 5- or 6-membered heterocyclic ring containing 1, 2, or 3 heteroatoms independently selected from the group consisting of aryl (phenyl), N, O, and S; preferably (C3-C8)cycloalkyl; more preferably 5-, 6-, or 7-membered cycloalkyl, even more preferably cyclohexyl; # indicates connection to M; and TIFF2025542295000250.tif6128 shows the connection to the rest of L.

[0252] In a preferred embodiment, the linker L is TIFF2025542295000251.tif29128, where Q is as defined herein, the asterisk (*) indicates the connection to the receptor binding molecule (RBM), and the # indicates the connection to the group M.

[0253] Preferably, the linker is connected to the receptor binding molecule (RBM) via a sulfur atom (S). Thus, in such embodiments, the combination of linker and receptor binding molecule can be depicted as follows: TIFF2025542295000252.tif29128 where RBM and Q are as defined herein and # indicates connection to group M.

[0254] Preferably, in any one of these embodiments, the receptor-binding molecule is an antibody. The sulfur atom that provides the bond to the linker L can arise from a sulfhydryl group, which may be obtained by reduction of a disulfide bond of the antibody.

[0255] In any one of these embodiments, the connector unit Q can be any connector unit Q as defined herein. Thus, in any one of these embodiments, Q can be any of the following: (C2-C 10 ) alkylene; more preferably (C2-C8) alkylene; even more preferably (C2-C6) alkylene; even more preferably, Q is -(CH2) q -, where q is an integer ranging from 2 to 10, preferably from 2 to 8, more preferably from 3 to 6, even more preferably from 4 to 5; even more preferably, q is 5. In any one of these embodiments, Q may be a (C6-C 10 ) arylene.

[0256] Preferably, in any one of these embodiments, Q is TIFF2025542295000253.tif24128, Here, Q A , R Q and Q B is as defined herein; # indicates a connection to M; and TIFF2025542295000254.tif6128 shows the connection of L to the remainder of the moiety. Thus, in these embodiments, the linker L has the following structure: TIFF2025542295000255.tif32128, Here, Q A , R Q and Q B is as defined herein; an asterisk (*) indicates a connection to a receptor binding molecule (RBM), and a # indicates a connection to an M.

[0257] More preferably, in any one of these embodiments, Q is TIFF2025542295000256.tif27128, where x, R Q and y is as defined herein; preferably R Q is hydrogen; # indicates connection to M; and TIFF2025542295000257.tif6128 shows the connection of L to the remainder of the moiety. Thus, in these embodiments, the linker L has the following structure: TIFF2025542295000258.tif31128, where x, R Q and y are as defined herein; preferably R Q is hydrogen; an asterisk (*) indicates a connection to a receptor binding molecule (RBM), and # indicates a connection to M.

[0258] In some embodiments, the linker L is TIFF2025542295000259.tif29128, where: R AM is hydrogen, (C1-C8) alkyl (e.g., methyl, ethyl, or propyl), (C6-C 10 ) aryl (e.g., phenyl), and (C1-C8) alkylene (C6-C 10 ) aryl (e.g., benzyl); preferably, R AM is hydrogen or (C-C) alkyl; more preferably, R AMis hydrogen or (C-C) alkyl; even more preferably, R AM is hydrogen or (C-C) alkyl; even more preferably, R AM is hydrogen or (C-C) alkyl; even more preferably, R AM is hydrogen; Q is as defined herein; An asterisk (*) indicates a connection to a receptor binding molecule (RBM); and # indicates a connection to the group M.

[0259] Preferably, the linker is connected to the receptor binding molecule (RBM) via a sulfur atom (S). Thus, in such embodiments, the combination of linker and receptor binding molecule can be depicted as follows: TIFF2025542295000260.tif26128 where RBM, R AM and Q are as defined herein, and # indicates the connection to the group M.

[0260] Preferably, in any one of these embodiments, the receptor-binding molecule is an antibody. The sulfur atom that provides the bond to the linker L can arise from a sulfhydryl group, which may be obtained by reduction of a disulfide bond of the antibody.

[0261] In any one of these embodiments, the connector unit Q can be any connector unit Q as defined herein. In particular, in any one of these embodiments, Q can be any connector unit Q as defined herein. 10 ) alkylene; more preferably (C2-C8) alkylene; even more preferably (C2-C6) alkylene; even more preferably, Q is -(CH2) q -, where q is an integer ranging from 2 to 10, preferably from 2 to 8, more preferably from 3 to 6, even more preferably from 4 to 5; even more preferably, q is 5. In any one of these embodiments, Q may be a (C6-C 10 ) arylene.

[0262] Preferably, in any one of these embodiments, the linker L has the following structure: I have TIFF2025542295000261.tif24128, where: R AM is as defined herein; therefore, R AM is hydrogen, (C1-C8) alkyl (e.g., methyl, ethyl, or propyl), (C6-C 10 ) aryl (e.g., phenyl), and (C1-C8) alkylene (C6-C 10 ) aryl (e.g., benzyl); preferably, R AM is hydrogen or (C-C) alkyl; more preferably, R AM is hydrogen or (C-C) alkyl; even more preferably, R AM is hydrogen or (C-C) alkyl; even more preferably, R AM is hydrogen or (C-C) alkyl; even more preferably, R AM is hydrogen; q is as defined herein; thus, q is an integer ranging from 2 to 10, preferably from 2 to 8, more preferably from 3 to 6, even more preferably from 4 to 5; even more preferably, q is 5; An asterisk (*) indicates a connection to a receptor binding molecule (RBM); and # indicates a connection to M.

[0263] In a preferred embodiment, the linker L has the formula (LI): TIFF2025542295000262.tif30128, During the ceremony, TIFF2025542295000263.tif5128 is a double bond; or TIFF2025542295000264.tif5128 is a single bond; V 2 teeth, TIFF2025542295000265.tif5128 is absent if it is a double bond; or V 2 teeth, If TIFF2025542295000266.tif5128 is a single bond, it is hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 ) aryl; V 1 teeth, If TIFF2025542295000267.tif5128 is a double bond, use R V11 -C; or V 1 teeth, If TIFF2025542295000268.tif5128 is a single bond, TIFF2025542295000269.tif11128; G is NR G70 , S, O, or CR G71 R G72 and; Q is the connector unit; R V11 is hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 ) aryl; R V12 is hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 ) aryl; R G70 is hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 ) aryl; R G71 and R G72 are each independently hydrogen, (C1-C8) alkyl, (C6-C 10)aryl, and (C1-C8)alkylene (C6-C 10 ) aryl; R 80 is an optionally substituted aliphatic residue or an optionally substituted aromatic residue; An asterisk (*) indicates a connection to a receptor binding molecule (RBM); and # indicates a connection to the group M.

[0264] The phosphonamidate, phosphonothiolate and phosphonate moieties contained in the linker (LI), and their preparation, are generally known, for example from WO 2018 / 041985 and WO 2019 / 170710, which are incorporated herein by reference in their entirety.

[0265] Preferably, the linker LI is connected to the receptor binding molecule (RBM) via a sulfur atom (S). In such an embodiment, the combination of the linker (LI) and the receptor binding molecule can be depicted as follows: TIFF2025542295000270.tif26128 where RBM, V 1 , V 2 , R 80 , G and Q are as defined herein; and # indicates the connection to the group M. Thus, in some embodiments, the conjugate has formula (Ia2) or a pharmaceutically acceptable salt or solvate thereof: TIFF2025542295000271.tif34128 in formula, RBM, V 1 , V 2 , TIFF2025542295000272.tif6128,R 80 , G, Q, M, X, D, Y 1 , A, Y 3 , J and n are as defined herein.

[0266] Preferably, in any one of these embodiments, the receptor binding molecule is an antibody. The sulfur atom that provides the bond to the linker L may arise from a sulfhydryl group, which may be obtained by reduction of a disulfide bond in the receptor binding molecule (RBM), e.g., an antibody.

[0267] Preferably R V11 is H or (C1-C8) alkyl; more preferably R V11 is H. Preferably, R V12 When present, R is H or (C-C) alkyl; more preferably R V12 When present, R is H. Preferably, R G70 When present, R is H or (C-C) alkyl; more preferably R G70 When present, R is H. Preferably, R G71 When present, R is H or (C-C) alkyl; more preferably R G71 When present, R is H. Preferably, R G72 When present, R is H or (C-C) alkyl; more preferably R G72 is H, if present.

[0268] Preferably, TIFF2025542295000273.tif5128 is a double bond; V 2 does not exist;V 1 is R V11 -C; and R V11 is hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 ) aryl; preferably R V11 is hydrogen or (C1-C8) alkyl; more preferably R V11 is hydrogen.

[0269] More preferably, TIFF2025542295000274.tif6128 is a double bond; V 2 does not exist;V1 is R V11 -C; and R V11 is H or (C1-C8) alkyl. Preferably, R V11 is H or (C1-C6) alkyl, more preferably H or (C1-C4) alkyl, even more preferably H or (C1-C2) alkyl. In a preferred embodiment, R3 is H.

[0270] In some embodiments, TIFF2025542295000275.tif5128 is a single bond; V 2 is hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 ) aryl; preferably, V 2 is hydrogen or (C1-C8) alkyl; more preferably, V 2 is hydrogen; V 1 teeth, TIFF2025542295000276.tif11128;R V11 is hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 ) aryl; preferably R V11 is hydrogen or (C1-C8) alkyl, more preferably R V11 is hydrogen; R V12 is hydrogen, (C1-C8) alkyl, (C6-C 10 )aryl, and (C1-C8)alkylene (C6-C 10 ) aryl; preferably R V12 is hydrogen or (C1-C8) alkyl, more preferably R V12 is hydrogen.

[0271] In some embodiments, TIFF2025542295000277.tif6128 is a single bond; V 2 can be H or (C1-C8) alkyl; V1 teeth, TIFF2025542295000278.tif11128; and R V11 and R V12 may independently be H or (C1-C8) alkyl. Preferably, R V11 and R V12 independently represent H or (C1-C6) alkyl, more preferably H or (C1-C4) alkyl, even more preferably H or (C1-C2) alkyl. Preferably, R V11 and R V12 are the same; even more preferably, R V11 , R V12 and V 2 are the same. More preferably, R V11 and R V12 are both H. Preferably, V 2 is H or (C1-C6) alkyl, more preferably H or (C1-C4) alkyl, even more preferably H or (C1-C2) alkyl. Even more preferably, V 2 is H. In a preferred embodiment, R V11 , R V12 and V 2 are H respectively.

[0272] The group G is NR G70 , S, O, and CR G71 R G72 R G70 is hydrogen, (C1-C8) alkyl (e.g., methyl, ethyl, or propyl), (C6-C 10 ) aryl (e.g., phenyl), and (C1-C8) alkylene (C6-C 10 ) aryl (e.g., benzyl). Preferably, R G70 is hydrogen or (C1-C8) alkyl. More preferably, R G70 is hydrogen or (C1-C6) alkyl, even more preferably hydrogen or (C1-C4) alkyl, and even more preferably hydrogen or (C1-C2) alkyl. In a preferred embodiment, R G70 is hydrogen. RG71 and R G72 are each independently hydrogen, (C1-C8) alkyl (e.g., methyl, ethyl, or propyl), (C6-C 10 )aryl (phenyl), and (C1-C8)alkylene (C6-C 10 ) aryl (e.g., benzyl). Preferably, R G71 and R G72 are each independently selected from the group consisting of hydrogen or (C1-C8) alkyl. More preferably, R G71 and R G72 are each independently hydrogen or (C1-C6) alkyl, even more preferably hydrogen or (C1-C4) alkyl, and even more preferably hydrogen or (C1-C2) alkyl. In a preferred embodiment, R G71 and R G72 is hydrogen.

[0273] The group G is S, O and CR G71 R G72 where R G71 and R G72 is as defined herein. G can be S or O. In some embodiments, G is CH. In some embodiments, G is O. In some embodiments, G is S.

[0274] In a preferred embodiment, G is NR G70 where R G70 is as defined herein. In a more preferred embodiment, G is NH.

[0275] In a linker having formula (LI), the connector unit Q serves to connect the group G to the group M. Any chemical moiety capable of connecting G with M can be used. In particular, in a linker having formula (LI), the connector unit Q can be any connector unit Q as described herein.

[0276] In a preferred embodiment, in the linker having formula (LI), the connector unit Q is TIFF2025542295000279.tif24128, where: TIFF2025542295000280.tif14128 is a 5- or 6-membered carbocyclic ring; or TIFF2025542295000281.tif14128 is a 5- or 6-membered heterocyclic ring containing 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S; R Q is hydrogen, (C1-C8) alkyl (e.g., methyl, ethyl, or propyl), (C6-C 10 ) aryl (e.g., phenyl), and (C1-C8) alkylene (C6-C 10 ) aryl (e.g., benzyl); preferably, R Q is hydrogen or (C-C) alkyl; more preferably, R Q is hydrogen or (C-C) alkyl; even more preferably, R Q is hydrogen or (C-C) alkyl; even more preferably, R Q is hydrogen or (C-C) alkyl; even more preferably, R Q is hydrogen; Q C is (C2-C 20 ) alkylene; preferably (C-C 10 ) alkylene; more preferably (C2-C8) alkylene; even more preferably (C2-C6) alkylene; or (C3-C8) carbocyclic, (C6-C 10 ) aryl (phenyl), or a 5- or 6-membered heterocyclic ring containing 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S; preferably (C3-C8)cycloalkyl; more preferably 5-, 6-, or 7-membered cycloalkyl, even more preferably cyclohexyl; # indicates a connection to M; and TIFF2025542295000282.tif6128 shows the connection to G.

[0277] Thus, the linker (LI) has the structure: TIFF2025542295000283.tif30128, where V 1 , V 2 , R 80 , G, TIFF2025542295000284.tif14128,R Q and Q C is as defined herein; * indicates a connection to a receptor binding molecule (RBM); and # indicates a connection to the group M. In a preferred embodiment, Q C (CH2) p where p is an integer ranging from 2 to 20, preferably from 2 to 10, more preferably from 3 to 8, and even more preferably from 4 to 6; in some preferred embodiments, p is 5. Carbocyclic rings may be aromatic or non-aromatic. Heterocyclic rings may be aromatic or non-aromatic.

[0278] More preferably, for the linker (LI), the connector unit Q is TIFF2025542295000285.tif103128; where A Q , B Q , C Q and D Q are each independently selected from N (nitrogen) and CH; preferably, A Q , B Q , C Q and D Q At least one of A is CH; more preferably, A Q , B Q , C Q and D Q at least two of A are CH; even more preferably Q , B Q , C Q and D QAt least three of A are CH, and even more preferably Q , B Q , C Q and D Q each of which is CH; R Q is as defined herein; preferably R Q is hydrogen; Q C is as defined herein; # indicates a connection to M; and TIFF2025542295000286.tif6128 shows the connection to G.

[0279] Even more preferably, for the linker (LI), the connector unit Q is TIFF2025542295000287.tif62128; where A Q , B Q , C Q and D Q are each independently selected from N (nitrogen) and CH; preferably, A Q , B Q , C Q and D Q At least one of A is CH; more preferably, A Q , B Q , C Q and D Q at least two of A are CH; even more preferably Q , B Q , C Q and D Q At least three of A are CH, and even more preferably Q , B Q , C Q and D Q each of which is CH; R Q is as defined herein; preferably R Q is hydrogen; Q C is as defined herein; # indicates a connection to M; and TIFF2025542295000288.tif6128 shows the connection to G.

[0280] Even more preferably, for the linker (LI), the connector unit Q is TIFF2025542295000289.tif27128, where A Q , B Q , C Q and D Q are each independently selected from N (nitrogen) and CH; preferably, A Q , B Q , C Q and D Q At least one of A is CH; more preferably, A Q , B Q , C Q and D Q at least two of A are CH; even more preferably Q , B Q , C Q and D Q At least three of A are CH, and even more preferably Q , B Q , C Q and D Q each of which is CH; R Q is as defined herein; preferably R Q is hydrogen; Q C is as defined herein; # indicates a connection to M; and TIFF2025542295000290.tif6128 shows the connection to G.

[0281] In some preferred embodiments of the linker (LI), the connector unit Q is TIFF2025542295000291.tif29128, wherein p is an integer ranging from 2 to 20, preferably from 2 to 10, more preferably from 3 to 8, and even more preferably from 4 to 6; in some preferred embodiments, p is 5; # indicates a connection to M; and TIFF2025542295000292.tif6128 shows the connection to G; or TIFF2025542295000293.tif41128, where: TIFF2025542295000294.tif12128 is (C3--C8) carbocyclic, (C6-C 10 ) aryl (phenyl), or a 5- or 6-membered heterocyclic ring containing 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S; preferably (C3-C8)cycloalkyl; more preferably 5-, 6-, or 7-membered cycloalkyl, even more preferably cyclohexyl; # indicates connection to M; and TIFF2025542295000295.tif6128 shows the connection to G.

[0282] base R 80 can be an optionally substituted aliphatic residue or an optionally substituted aromatic residue. 80 encompasses a wide range of aliphatic or aromatic residues, such as groups that modify water solubility (e.g., polyethylene glycol units). Those skilled in the art will be able to identify suitable residues R that are compatible with the conjugates, compounds, methods and uses described herein. 80 Know what to choose.

[0283] In some embodiments, R 80 is optionally substituted (C1-C8) alkyl. In particular, R 80 can be (C1-C8)alkyl optionally substituted with at least one of F, Cl, Br, I, —NO2, —N((C1-C8)alkyl)H, —NH2, —N3, —N((C1-C8)alkyl)2, ═O, (C3-C8)cycloalkyl, (C2-C8)alkenyl, or (C2-C8)alkynyl.

[0284] In some embodiments, R 80 is optionally substituted phenyl. In particular, R 80can be phenyl optionally independently substituted with at least one of (C1-C8)alkyl, F, Cl, I, Br, —NO2, —N((C1-C8)alkyl)H, —NH2, or —N((C1-C8)alkyl)2.

[0285] In some embodiments, R 80 is an optionally substituted 5- or 6-membered aromatic heterocycle, such as, for example, pyridyl.

[0286] In some embodiments, R 80 is (C1-C8) alkyl, (C1-C8) alkyl substituted with optionally substituted phenyl; or phenyl; or phenyl substituted with -NO2. Preferably, R 80 is (C1-C8) alkyl. More preferably, R 80 is (C1-C6) alkyl. Even more preferably, R 80 is (C1-C4) alkyl. Even more preferably, R 80 is (C1-C2) alkyl.

[0287] In some preferred embodiments, R 80 is methyl, ethyl, propyl or butyl. More preferably, R 80 is methyl or ethyl. Even more preferably, R 80 is ethyl.

[0288] In some preferred embodiments, R 80 is a polyalkylene glycol unit. Polyalkylene glycols, particularly polyethylene glycols, are generally hydrophilic. Thus, polyalkylene glycol units, particularly polyethylene glycol units, can be used, for example, to adjust the hydrophilicity and thus water solubility of the conjugates described herein.

[0289] The term "polyalkylene glycol unit," as used herein, refers to a polyalkylene glycol unit bonded to an O atom that is connected to the phosphorus (V) moiety of a linker (LI).

[0290] R 80 The polyalkylene glycol unit used as R contains at least one alkylene glycol subunit. 80 The polyalkylene glycol unit used as the TIFF2025542295000296.tif14128. More preferably, R 80 The polyalkylene glycol unit used as the TIFF2025542295000297.tif14128. Thus, R 80 The polyalkylene glycol unit used as R may be a polytetramethylene glycol unit, a polypropylene glycol unit, or a polyethylene glycol unit. Even more preferably, R 80 The polyalkylene glycol unit used as the TIFF2025542295000298.tif13128 and contains one or more alkylene glycol subunits.

[0291] Preferably, R 80 The polyalkylene glycol unit used as R contains 1 to 100 alkylene glycol subunits as described herein. 80 The polyalkylene glycol unit used as R contains 2 to 50 alkylene glycol subunits as described herein. Even more preferably, R 80 The polyalkylene glycol unit used as R contains 3 to 45 alkylene glycol subunits as described herein. Even more preferably, R 80The polyalkylene glycol unit used as R contains 4 to 40 alkylene glycol subunits as described herein. Even more preferably, R 80 The polyalkylene glycol unit used as R contains 6 to 35 alkylene glycol subunits as described herein. Even more preferably, R 80 The polyalkylene glycol unit used as comprises 8 to 30 alkylene glycol subunits as described herein.

[0292] Preferably, R 80 The polyalkylene glycol unit used as R contains 1 to 40 alkylene glycol subunits as described herein. 80 The polyalkylene glycol unit used as R contains 1 to 32 alkylene glycol subunits as described herein. Even more preferably, R 80 The polyalkylene glycol unit used as a hydroxyl group comprises 2 to 28 alkylene glycol subunits as described herein. In some embodiments, the polyalkylene glycol unit comprises 2, 3, or 4 alkylene glycol subunits as described herein. The polyalkylene glycol unit may comprise 2 or 3, particularly 2, alkylene glycol subunits as described herein. In some embodiments, the polyalkylene glycol unit comprises 10, 11, 12, 13, or 14 alkylene glycol subunits as described herein. The polyalkylene glycol unit may comprise 11, 12, or 13, particularly 12, alkylene glycol subunits as described herein. In some embodiments, the polyalkylene glycol unit comprises 22, 23, 24, 25, or 26 alkylene glycol subunits as described herein. The polyalkylene glycol unit may comprise 23, 24, or 25, particularly 24, alkylene glycol subunits as described herein.

[0293] R 80The polyalkylene glycol unit used as the TIFF2025542295000299.tif14128, and may be a polyalkylene glycol unit containing 1 to 100, preferably 2 to 50, more preferably 3 to 45, even more preferably 4 to 40, even more preferably 6 to 35, and still more preferably 8 to 30 subunits having the formula: 80 The polyalkylene glycol unit used as the TIFF2025542295000300.tif14128, it may be a polyalkylene glycol unit containing 1 to 100, preferably 2 to 50, more preferably 3 to 45, even more preferably 4 to 40, even more preferably 6 to 35, and still more preferably 8 to 30 subunits having R 80 The polyalkylene glycol unit used as the In a highly preferred embodiment, the polyalkylene glycol unit may comprise 1 to 100, preferably 2 to 50, more preferably 3 to 45, even more preferably 4 to 40, even more preferably 6 to 35, and still more preferably 8 to 30 subunits having the formula TIFF2025542295000301.tif13128. 80 The polyalkylene glycol unit used as the It may be a polyethylene glycol unit containing 1 to 100, preferably 2 to 50, more preferably 3 to 45, even more preferably 4 to 40, even more preferably 6 to 35, and still more preferably 8 to 30 subunits each having TIFF2025542295000302.tif9128.

[0294] R 80 The polyalkylene glycol unit used as the In some embodiments, the polyalkylene glycol unit may be a polyalkylene glycol unit comprising 1 to 40, preferably 1 to 32, and more preferably 2 to 28 subunits having the structure: TIFF2025542295000304.tif14128. The polyalkylene glycol unit comprises two, three, or four alkylene glycol subunits having the structure: In some embodiments, the polyalkylene glycol unit may comprise two or three, particularly two, alkylene glycol subunits having the structure: TIFF2025542295000306.tif14128. The polyalkylene glycol unit comprises 10, 11, 12, 13 or 14 alkylene glycol subunits having the structure: In some embodiments, the polyalkylene glycol unit may comprise 11, 12, or 13, particularly 12, alkylene glycol subunits having the structure: TIFF2025542295000308.tif14128. The polyalkylene glycol unit comprises 22, 23, 24, 25 or 26 alkylene glycol subunits having the structure: It may contain 23, 24 or 25, especially 24, alkylene glycol subunits having the formula TIFF2025542295000309.tif14128.

[0295] Preferably, R 80 The polyalkylene glycol unit used as the In some embodiments, the polyalkylene glycol unit may be a polyalkylene glycol unit comprising 1 to 40, preferably 1 to 32, and more preferably 2 to 28 subunits having the structure: TIFF2025542295000311.tif14128. The polyalkylene glycol unit comprises two, three, or four alkylene glycol subunits having the structure: In some embodiments, the polyalkylene glycol unit may comprise two or three, particularly two, alkylene glycol subunits having the structure: TIFF2025542295000313.tif14128. The polyalkylene glycol unit comprises 10, 11, 12, 13 or 14 alkylene glycol subunits having the structure: In some embodiments, the polyalkylene glycol unit may comprise 11, 12, or 13, particularly 12, alkylene glycol subunits having the structure: TIFF2025542295000315.tif14128. The polyalkylene glycol unit comprises 22, 23, 24, 25 or 26 alkylene glycol subunits having the structure: It may contain 23, 24 or 25, especially 24, alkylene glycol subunits having the formula TIFF2025542295000316.tif14128.

[0296] More preferably, R 80 The first polyalkylene glycol unit used as In some embodiments, the polyalkylene glycol unit may be a polyalkylene glycol unit comprising 1 to 40, preferably 1 to 32, and more preferably 2 to 28 subunits having the structure: TIFF2025542295000318.tif13128. The polyalkylene glycol unit comprises two, three, or four alkylene glycol subunits having the structure: In some embodiments, the polyalkylene glycol unit may comprise two or three, particularly two, alkylene glycol subunits having the structure: TIFF2025542295000320.tif13128. The polyalkylene glycol unit comprises 10, 11, 12, 13 or 14 alkylene glycol subunits having the structure: In some embodiments, the polyalkylene glycol unit may comprise 11, 12, or 13, particularly 12, alkylene glycol subunits having the structure: TIFF2025542295000322.tif14128. The polyalkylene glycol unit comprises 22, 23, 24, 25 or 26 alkylene glycol subunits having the structure: It may contain 23, 24 or 25, especially 24, alkylene glycol subunits having the formula TIFF2025542295000323.tif14128.

[0297] In a highly preferred embodiment, R 80 The polyalkylene glycol unit used as the In some embodiments, the polyalkylene glycol unit may be a polyethylene glycol unit comprising 1 to 40, preferably 1 to 32, more preferably 2 to 28 subunits each having the structure: TIFF2025542295000325.tif9128. The polyalkylene glycol unit comprises 2, 3, or 4 subunits having the structure: In some embodiments, the polyalkylene glycol unit may comprise two or three, particularly two, subunits having the structure: TIFF2025542295000327.tif9128. The polyalkylene glycol unit comprises 10, 11, 12, 13 or 14 alkylene glycol subunits having the structure: In some embodiments, the polyalkylene glycol unit may comprise 11, 12, or 13, particularly 12, alkylene glycol subunits having the structure: TIFF2025542295000329.tif9128. The polyalkylene glycol unit comprises 22, 23, 24, 25 or 26 alkylene glycol subunits having the structure: It may contain 23, 24 or 25, especially 24, alkylene glycol subunits having the formula TIFF2025542295000330.tif9128.

[0298] Preferably, R 80 The polyalkylene glycol unit used as TIFF2025542295000331.tif14128, where: TIFF2025542295000332.tif9128 shows the position of O connected to phosphorus; K F is H or a capping group; preferably K F are -H (hydrogen), -PO3H, -(C1-C 10 ) alkyl, -(C1-C 10 ) alkyl-SO3H, -(C2-C 10 ) alkyl-CO2H, -(C2-C 10 ) alkyl-OH, -(C2-C 10 ) alkyl-NH2, -(C2-C 10 ) alkyl-NH(C1-C3) alkyl and -(C2-C 10 ) alkyl-N((C1-C3) alkyl)2; more preferably K F is H; and o is an integer ranging from 1 to 100.

[0299] A "capping group," as referred to herein, can be any moiety that can function as the terminal group of a polyalkylene glycol unit. Examples of first capping groups that can be used in the present disclosure include -POH, -(C-C 10 ) alkyl, -(C1-C 10 ) alkyl-SO3H, -(C2-C 10 ) alkyl-CO2H, -(C2-C 10 ) alkyl-OH, -(C2-C 10 ) alkyl-NH2, -(C2-C 10 ) alkyl-NH(C1-C3) alkyl and -(C2-C 10 In some embodiments, the capping group is -(C1-C3)alkyl-N((C1-C3)alkyl). 10 ) alkyl, especially methyl.

[0300] Preferably, K F is H (hydrogen).

[0301] The integer o is the repeating unit in the polyalkylene glycol unit: TIFF2025542295000333.tif11128. The integer o can be in the range of 1 to 100. Preferably, o is in the range of 2 to 50. More preferably, o is in the range of 3 to 45. Even more preferably, o is in the range of 4 to 40. Even more preferably, o is in the range of 6 to 35. Even more preferably, o is in the range of 8 to 30. In a preferred embodiment, o is 12 or about 12. In a preferred embodiment, o is 24 or about 24. Preferably, the repeating unit is TIFF2025542295000334.tif11128. More preferably, the repeating unit is The file is TIFF2025542295000335.tif12128.

[0302] In the polyalkylene glycol unit, the integer o can range from 1 to 40. Preferably, o is in the range of 1 to 32. More preferably, o is in the range of 2 to 28. In some embodiments, the integer o is 2, 3, or 4. The integer o can be 2 or 3, particularly 2. In some embodiments, the integer o is 10, 11, 12, 13, or 14. The integer o can be 11, 12, or 13, particularly 12. In some embodiments, the integer o is 22, 23, 24, 25, or 26. The integer o can be 23, 24, or 25, particularly 24. Preferably, the repeating unit is TIFF2025542295000336.tif11128. More preferably, the repeating unit is The file is TIFF2025542295000337.tif12128.

[0303] Preferably, R 80 The polyalkylene glycol unit used as the TIFF2025542295000338.tif9128, i.e., this subunit is designated as "ethylene glycol subunit". 80 The polyalkylene glycol unit used herein is a polyethylene glycol unit. The polyethylene glycol unit comprises at least one ethylene glycol subunit.

[0304] Preferably, R 80 The polyalkylene glycol unit used as the TIFF2025542295000339.tif9128, and may be a polyethylene glycol unit containing 1 to 100, preferably 2 to 50, more preferably 3 to 45, even more preferably 4 to 40, even more preferably 6 to 35, and still more preferably 8 to 30 ethylene glycol subunits each having the formula:

[0305] Preferably, R 80 The polyalkylene glycol unit used as the In some embodiments, the polyethylene glycol unit may be a polyethylene glycol unit comprising 1 to 40, preferably 1 to 32, and more preferably 2 to 28 ethylene glycol subunits each having the structure: TIFF2025542295000341.tif9128. The polyethylene glycol units contain two, three, or four ethylene glycol subunits, each having the structure: In some embodiments, the polyethylene glycol unit may comprise two or three, particularly two, ethylene glycol subunits each having the structure: TIFF2025542295000343.tif9128. The polyethylene glycol units comprise 10, 11, 12, 13 or 14 ethylene glycol subunits, each having the structure: In some embodiments, the polyethylene glycol unit may comprise 11, 12, or 13, particularly 12, ethylene glycol subunits each having the structure: TIFF2025542295000345.tif9128. The polyethylene glycol units comprise 22, 23, 24, 25 or 26 ethylene glycol subunits, each having the structure: TIFF2025542295000346.tif9128.

[0306] Preferably, R 80 The polyalkylene glycol unit used as the TIFF2025542295000347.tif14128, where: TIFF2025542295000348.tif9128 shows the position of O connected to phosphorus; KF is H (hydrogen) or a first capping group as described herein; preferably K F are -H (hydrogen), -PO3H, -(C1-C 10 ) alkyl, -(C1-C 10 ) alkyl-SO3H, -(C2-C 10 ) alkyl-CO2H, -(C2-C 10 ) alkyl-OH, -(C2-C 10 ) alkyl-NH2, -(C2-C 10 ) alkyl-NH(C1-C3) alkyl and -(C2-C 10 ) alkyl-N((C1-C3) alkyl)2; more preferably K F is H; and o is an integer ranging from 1 to 100.

[0307] The integer o is the repeating unit in the polyethylene glycol unit: TIFF2025542295000349.tif11128 is displayed. The integer o can be in the range of 1 to 100. Preferably, o is in the range of 2 to 50. More preferably, o is in the range of 3 to 45. Even more preferably, o is in the range of 4 to 40. Even more preferably, o is in the range of 6 to 35. Even more preferably, o is in the range of 8 to 30. In a preferred embodiment, o is 12 or about 12. In a preferred embodiment, o is 24 or about 24.

[0308] R 80 In polyethylene glycol units used as (a), the integer o can range from 1 to 40. Preferably, o ranges from 1 to 32. More preferably, o ranges from 2 to 28. In some embodiments, the integer o is 2, 3, or 4. The integer o can be 2 or 3, particularly 2. In some embodiments, the integer o is 10, 11, 12, 13, or 14. The integer o can be 11, 12, or 13, particularly 12. In some embodiments, the integer o is 22, 23, 24, 25, or 26. The integer o can be 23, 24, or 25, particularly 24.

[0309] In general, R 80 The polyalkylene glycol unit (preferably, polyethylene glycol unit) used as the copolymer may be a polydisperse polyalkylene glycol (preferably, polydisperse polyethylene glycol), a monodisperse polyalkylene glycol (preferably, monodisperse polyethylene glycol), or an individual polyalkylene glycol (preferably, individual polyethylene glycol). Polydisperse polyalkylene glycols (preferably, polydisperse polyethylene glycols) are heterogeneous mixtures of sizes and molecular weights, whereas monodisperse polyalkylene glycols (preferably, monodisperse polyethylene glycols) are typically purified from heterogeneous mixtures and thus provide a single chain length and molecular weight. Preferred polyalkylene glycol units are individual polyalkylene glycols (preferably, individual polyethylene glycols), i.e., compounds that are synthesized stepwise rather than by a polymerization process. Individual polyalkylene glycols (preferably, individual polyethylene glycols) provide single molecules with defined and specified chain lengths.

[0310] As provided herein, R 80 The polyalkylene glycol unit (preferably, polyethylene glycol unit) used as may comprise one or more polyalkylene glycol chains (preferably, polyethylene glycol chains). The polyalkylene glycol chains (preferably, polyethylene glycol chains) can be linked together, for example, in a linear, branched, or star configuration. Optionally, at least one of the polyalkylene glycol chains (preferably, polyethylene glycol chains) may be derivatized at one end for covalent attachment to an oxygen atom bonded to phosphorus.

[0311] R 80The polyalkylene glycol unit (preferably a polyethylene glycol unit) used as (D) is connected to the conjugate (or its intermediate) through an oxygen atom bonded to phosphorus. The other end(s) of the polyalkylene glycol unit (preferably a polyethylene glycol unit) is free and untethered and may take the form of a hydrogen, methoxy, carbox...

Claims

1. A conjugate having formula (I), or a pharmaceutically acceptable salt or solvate thereof: During the ceremony, RBM is a receptor binding molecule; L is a linker; M, O, NR M60 , or S; R M60 is hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; U is O or S; X is O, S, or NR X10 and R X10 is hydrogen; or an optionally substituted aliphatic or an optionally substituted aromatic residue; D is a drug moiety; Y 1 is NR A20 , O, S, or CR A21 R A22 and R A20 is hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; R A21 and R A22 are each independently hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; E is a spacer; Z is a cleavable group; W is a spacer E, Y after cleavage of group Z. 1 and a moiety capable of forming a ring together with the phosphorus; and n is an integer ranging from 1 to 20.

2. W is a spacer E, Y after cleavage of group Z 1 and a moiety capable of forming, together with phosphorus, a 4- to 7-membered ring, preferably a 5- or 6-membered ring.

3. 3. The conjugate of claim 1 or 2 having formula (Ia), or a pharmaceutically acceptable salt or solvate thereof: During the ceremony, RBM, L, M, X, D, Y 1 and n is as defined in claim 1; A is CR A30 R A31 or A is (C 1 -C 8 ) alkylene, where (C 1 -C 8 ) alkylene is (C 1 -C 8 ) alkyl, halo, hydroxy, (C 1 -C 8 ) alkoxy, amino, (C 1 -C 8 ) alkylamino, di(C 1 -C 8 ) alkylamino, SH, (C 1 -C 8 ) alkylthio, (C 3 -C 8 ) heterocyclyl, carboxylates and their esters, carboxy (C 1 -C 8 ) alkyl, CONHR A36 and CONR A36 R A37 and R A36 and R A37 are independently (C 1 -C 8 ) alkyl, (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl or (C 6 -C 10 ) aryl; R A30 and R A31 are each independently hydrogen, (C 1 -C 8 ) alkyl, (C 3 -C 8 ) cycloalkyl, (C 2 -C 8 ) alkenyl, (C 5 -C 8 ) cycloalkenyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 )aryl; wherein each (C 1 -C 8 ) alkyl, (C 3 -C 8 ) cycloalkyl, (C 2 -C 8 ) alkenyl, (C 5 -C 8 ) cycloalkenyl, (C 6 -C 10 ) aryl or (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl is (C 1 -C 8 ) alkyl, halo, hydroxy, (C 1 -C 8 ) alkoxy, amino, (C 1 -C 8 ) alkylamino, di(C 1 -C 8 ) alkylamino, SH, (C 1 -C 8 ) alkylthio, (C 3 -C 8 ) heterocyclyl, carboxylates and their esters, carboxy (C 1 -C 8 ) alkyl, CONHR A36 and CONR A36 R A37 and R A36 and R A37 are independently (C 1 -C 8 ) alkyl, (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl or (C 6 -C 10 ) aryl; optionally, R A30 and R A31 can be taken together to form a 3- to 8-membered ring; Y 2 is NR B20 , O, S, or CR B21 R B22 and R B20 is hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; R B21 and R B22 are each independently hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; B is independently CR B30 R B31 or B is independently (C 1 -C 8 ) alkylene, where (C 1 -C 8 ) alkylene is (C 1 -C 8 ) alkyl, halo, hydroxy, (C 1 -C 8 ) alkoxy, amino, (C 1 -C 8 ) alkylamino, di(C 1 -C 8 ) alkylamino, SH, (C 1 -C 8 ) alkylthio, (C 3 -C 8 ) heterocyclyl, carboxylates and their esters, carboxy (C 1 -C 8 ) alkyl, CONHR B36 and CONR B36 R B37 and R B36 and R B37 are independently (C 1 -C 8 ) alkyl, (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl or (C 6 -C 10 ) aryl; R B30 and R B31 are each independently hydrogen, (C 1 -C 8 ) alkyl, (C 3 -C 8 ) cycloalkyl, (C 2 -C 8 ) alkenyl, (C 5 -C 8 ) cycloalkenyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 )aryl; wherein each (C 1 -C 8 ) alkyl, (C 3 -C 8 ) cycloalkyl, (C 2 -C 8 ) alkenyl, (C 5 -C 8 ) cycloalkenyl, (C 6 -C 10 ) aryl or (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl is (C 1 -C 8 ) alkyl, halo, hydroxy, (C 1 -C 8 ) alkoxy, amino, (C 1 -C 8 ) alkylamino, di(C 1 -C 8 ) alkylamino, SH, (C 1 -C 8 ) alkylthio, (C 3 -C 8 ) heterocyclyl, carboxylates and their esters, carboxy (C 1 -C 8 ) alkyl, CONHR B36 and CONR B36 R B37 and R B36 and R B37 are independently (C 1 -C 8 ) alkyl, (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl or (C 6 -C 10 ) aryl; optionally, R B30 and R B31 can be taken together to form a 3- to 8-membered ring; m is an integer ranging from 0 to 15; Y 3 , O, NR C40 , or S, or absent; R C40 is hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; J is where: is Y 3 Show the connection to C is CR C50 R C51 or C is (C 1 -C 8 ) alkylene, where (C 1 -C 8 ) alkylene is (C 1 -C 8 ) alkyl, halo, hydroxy, (C 1 -C 8 ) alkoxy, amino, (C 1 -C 8 ) alkylamino, di(C 1 -C 8 ) alkylamino, SH, (C 1 -C 8 ) alkylthio, (C 3 -C 8 ) heterocyclyl, carboxylates and their esters, carboxy (C 1 -C 8 ) alkyl, CONHR C36 and CONR C36 R C37 and R C36 and R C37 are independently (C 1 -C 8 ) alkyl, (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl or (C 6 -C 10 ) aryl; R C50 and R C51 are each independently hydrogen, (C 1 -C 8 ) alkyl, (C 3 -C 8 ) cycloalkyl, (C 2 -C 8 ) alkenyl, (C 5 -C 8 ) cycloalkenyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 )aryl; wherein each (C 1 -C 8 ) alkyl, (C 3 -C 8 ) cycloalkyl, (C 2 -C 8 ) alkenyl, (C 5 -C 8 ) cycloalkenyl, (C 6 -C 10 ) aryl or (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl is (C 1 -C 8 ) alkyl, halo, hydroxy, (C 1 -C 8 ) alkoxy, amino, (C 1 -C 8 ) alkylamino, di(C 1 -C 8 ) alkylamino, SH, (C 1 -C 8 ) alkylthio, (C 3 -C 8 ) heterocyclyl, carboxylates and their esters, carboxy (C 1 -C 8 ) alkyl, CONHR C36 and CONR C36 R C37 and R C36 and R C37 are independently (C 1 -C 8 ) alkyl, (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl or (C 6 -C 10 ) aryl; optionally, R C50 and R C51 can be taken together to form a 3- to 8-membered ring; Y 4 , O, NR C53 , S, or CR C54 R C55 or absent; R C52 is hydrogen, (C 1 -C 8 ) alkyl, (C 3 -C 8 ) cycloalkyl, (C 2 -C 8 ) alkenyl, (C 5 -C 8 ) cycloalkenyl, (C 3 -C 8 ) heterocyclyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 )aryl; wherein each (C 1 -C 8 ) alkyl, (C 3 -C 8 ) cycloalkyl, (C 2 -C 8 ) alkenyl, (C 5 -C 8 ) cycloalkenyl, (C 3 -C 8 ) heterocyclyl, (C 6 -C 10 ) aryl or (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl is (C 1 -C 8 ) alkyl, halo, hydroxy, (C 1 -C 8 ) alkoxy, amino, (C 1 -C 8 ) alkylamino, di(C 1 -C 8 ) alkylamino, SH, (C 1 -C 8 ) alkylthio, (C 3 -C 8 ) heterocyclyl, carboxylates and their esters, carboxy (C 1 -C 8 ) alkyl, CONHR C56 and CONR C56 R C57 and R C56 and R C57 are independently (C 1 -C 8 ) alkyl, (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl or (C 6 -C 10 ) aryl; R C53 is hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; R C54 and R C55 are each independently hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; or J is (C 1 -C 8 ) alkyl, (C 3 -C 8 ) cycloalkyl, (C 2 -C 8 ) alkenyl, (C 5 -C 8 ) cycloalkenyl, (C 3 -C 8 ) heterocyclyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 )aryl; wherein each (C 1 -C 8 ) alkyl, (C 3 -C 8 ) cycloalkyl, (C 2 -C 8 ) alkenyl, (C 5 -C 8 ) cycloalkenyl, (C 3 -C 8 ) heterocyclyl, (C 6 -C 10 ) aryl or (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl is (C 1 -C 8 ) alkyl, halo, hydroxy, (C 1 -C 8 ) alkoxy, amino, (C 1 -C 8 ) alkylamino, di(C 1 -C 8 ) alkylamino, SH, (C 1 -C 8 ) alkylthio, (C 3 -C 8 ) heterocyclyl, carboxylates and their esters, carboxy (C 1 -C 8 ) alkyl, CONHR C46 and CONR C46 R C47 and R C46 and R C47 are independently (C 1 -C 8 ) alkyl, (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl or (C 6 -C 10 ) aryl.

4. 4. The conjugate of claim 3, wherein m is an integer ranging from 0 to 12, preferably from 0 to 10, more preferably from 0 to 8, even more preferably from 0 to 5, and even more preferably from 0 to 3.

5. 5. The conjugate of claim 3 or 4, having the formula (Ia1), or a pharmaceutically acceptable salt or solvate thereof: In the formula, RBM, L, M, X, D, Y 1 , A, Y 3 , J and n are as defined in any one of the preceding claims.

6. Y 1 NR A20 or O, where R A20 is as defined in any one of the preceding claims; Preferably, where Y 1 is NH or O; More preferably, Y 1 is NH, The conjugate of any one of claims 2 to 5.

7. A is CR A30 R A31 where R A30 and R A31 The conjugate of any one of claims 2 to 6, wherein is as defined in any one of the preceding claims.

8. R A30 is hydrogen and R A31 But hydrogen, (C 1 -C 8 ) alkyl, (C 3 -C 8 ) cycloalkyl, (C 2 -C 8 ) alkenyl, (C 5 -C 8 ) cycloalkenyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; Preferably, where R A30 is hydrogen and R A31 is hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; More preferably, where R A30 is hydrogen and R A31 is (C 1 -C 8 ) alkyl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; More preferably, where R A30 is hydrogen and R A31 (C 1 -C 8 ) alkyl; Even more preferably, wherein R A30 is hydrogen and R A31 is hydrogen, CH 3 , C.H. 2 CH 3 , C.H. 2 CH 3 CH 3 , CH(CH 3 ) 2 , C.H. 2 CH 2 CH 2 CH 3 , CH(CH 3 )CH 2 CH 3 , C.H. 2 CH(CH 3 ) 2 , C(CH 3 ) 3 and benzyl; Even more preferably, wherein R A30 is hydrogen and R A31 is CH 3 That is, The conjugate of any one of claims 2 to 7.

9. Y 3 The conjugate of any one of claims 2 to 8, wherein is O.

10. Y 3 NR C40 where R C40 is as defined in any one of the preceding claims; Preferably, where Y 3 is NH, The conjugate of any one of claims 2 to 8.

11. J, where R C50 , R C51 , Y 4 , R C52 and is as defined in any one of the preceding claims, The conjugate of any one of claims 2 to 10.

12. Y 4 is O or NR C53 where R C53 is as defined in any one of the preceding claims; Preferably, where Y 4 is O or NH; Preferably, where Y 4 is O, The conjugate of any one of claims 2 to 11.

13. R C50 and R C51 are independently hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; Preferably, where R C50 and R C51 are each independently hydrogen, (C 1 -C 8 ) alkyl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; More preferably, where R C50 and R C51 are each independently hydrogen and (C 1 -C 8 ) alkyl; Even more preferably, wherein R C50 and R C51 are each independently hydrogen, CH 3 , C.H. 2 CH 3 , C.H. 2 CH 3 CH 3 , CH(CH 3 ) 2 , C.H. 2 CH 2 CH 2 CH 3 , CH(CH 3 )CH 2 CH 3 , C.H. 2 CH(CH 3 ) 2 , C(CH 3 ) 3 and benzyl; Even more preferably, wherein R C50 and R C51 are each independently hydrogen and CH 3 Selected from: The conjugate of any one of claims 2 to 12.

14. R C50 is hydrogen and R C51 But hydrogen, (C 1 -C 8 ) alkyl, (C 3 -C 8 ) cycloalkyl, (C 2 -C 8 ) alkenyl, (C 5 -C 8 ) cycloalkenyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; Preferably, where R C50 is hydrogen and R C51 is hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; More preferably, where R C50 is hydrogen and R C51 is (C 1 -C 8 ) alkyl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; Further more here, R C50 is hydrogen and R C51 (C 1 -C 8 ) alkyl; Even more preferably, wherein R C50 is hydrogen and R C51 is hydrogen, CH 3 , C.H. 2 CH 3 , C.H. 2 CH 3 CH 3 , CH(CH 3 ) 2 , C.H. 2 CH 2 CH 2 CH 3 , CH(CH 3 )CH 2 CH 3 , C.H. 2 CH(CH 3 ) 2 , C(CH 3 ) 3 and benzyl; Even more preferably, wherein R C50 is hydrogen and R C51 is CH 3 That is, The conjugate of any one of claims 2 to 13.

15. R C52 But hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; Preferably, where R C52 is hydrogen, (C 1 -C 8 ) alkyl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; More preferably, where R C52 is hydrogen and (C 1 -C 8 ) alkyl; Even more preferably, wherein R C52 is hydrogen, CH 3 , C.H. 2 CH 3 , C.H. 2 CH 3 CH 3 , CH(CH 3 ) 2 , C.H. 2 CH 2 CH 2 CH 3 , CH(CH 3 )CH 2 CH 3 , C.H. 2 CH(CH 3 ) 2 , C(CH 3 ) 3 and benzyl; Even more preferably, wherein R C52 is hydrogen, CH(CH 3 ) 2 and C(CH 3 ) 3 selected from the group consisting of: Even more preferably, wherein R C52 is hydrogen, The conjugate of any one of claims 2 to 14.

16. A is CR A30 R A31 and J is where R A30 , R A31 , R C50 , R C51 , Y 4 , R C52 and is as defined in any one of the preceding claims; Preferably, m is 0. The conjugate of any one of claims 2 to 15.

17. Y 1 NR A20 and Y 3 NR C40 and Y 4 is O, where R A20 and R C40 is as defined in any one of the preceding claims; Preferably, where Y 1 is NH and Y 3 is NH and Y 4 is O; Preferably, m is 0.

17. The conjugate of claim 16.

18. R A30 is hydrogen and R A31 is CH 3 and R C50 is hydrogen and R C51 is CH 3 and R C52 18. The conjugate of claim 17, wherein is hydrogen.

19. J is (C 1 -C 8 ) alkyl, (C 3 -C 8 ) cycloalkyl, (C 2 -C 8 ) alkenyl, (C 5 -C 8 ) cycloalkenyl, (C 3 -C 8 ) heterocyclyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; Preferably, where J is (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; More preferably, J is (C 1 -C 8 ) alkyl and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; Even more preferably, wherein J is (C 1 -C 8 ) alkyl; Even more preferably, wherein J is CH 3 , C.H. 2 CH 3 , C.H. 2 CH 3 CH 3 , CH(CH 3 ) 2 , C.H. 2 CH 2 CH 2 CH 3 , CH(CH 3 )CH 2 CH 3 , C.H. 2 CH(CH 3 ) 2 , C(CH 3 ) 3 and benzyl; Even more preferably, wherein J is CH(CH 3 ) 2 or C(CH 3 ) 3 and Preferably, m is 0. The conjugate of any one of claims 2 to 10.

20. Y 3 is O or NR C40 where R C40 is as defined in any one of the preceding claims; Preferably, where Y 3 is O or NH; More preferably, Y 3 is O; Preferably, m is 0.

20. The conjugate of claim 19.

21. A is CR A30 R A31 where R A30 and R A31 21. The conjugate of claim 19 or 20, wherein is as defined in any one of the preceding claims.

22. Y 1 NR A20 and Y 3 is O, where R A20 is as defined in any one of the preceding claims; Preferably, where Y 1 is NH and Y 3 is O; Preferably, m is 0.

22. The conjugate of claim 21.

23. R A30 is H and R A31 is CH 3 and Y 1 is NH and Y 3 is O; Preferably, where J is CH(CH 3 ) 2 or C(CH 3 ) 3 and Preferably, m is 0.

23. The conjugate of claim 22.

24. 10. The conjugate of claim 1 having formula (Ib), or a pharmaceutically acceptable salt or solvate thereof: During the ceremony, RBM, L, M, X, D, Y 1 and n is as defined in claim 1; E is a spacer; Su is a sugar moiety attached to the oxygen atom via a cleavable bond; and Here, oxygen is the spacer E, Y after cleavage of the sugar moiety Su. 1 and can form a ring together with phosphorus.

25. 25. The conjugate of claim 24, wherein the sugar moiety Su is protected or unprotected.

26. The sugar moiety, Su, is glucuronic acid: and where: indicates the position of the oxygen atom, 26. The conjugate of claim 24 or 25.

27. Spacer E has the following structure A: which is an optionally substituted 4- to 7-membered, preferably 5- or 6-membered, carbocyclic or heterocyclic ring; where: is an oxygen atom and Y 1 indicates the location of; and Preferably, the oxygen atom and Y 1 The attachment points of A to are two adjacent atoms of the ring.

27. The conjugate of claim 24, 25 or 26.

28. The compound of claim 27, wherein the compound has the following structure: and where: is an oxygen atom and Y 1 Indicates the location of 28. The conjugate of claim 27.

29. Y 1 NR A20 or O, where R A20 is as defined in any one of the preceding claims; Preferably, where Y 1 is NH or O; More preferably, Y 1 is NH, The conjugate of any one of claims 24 to 28.

30. 10. The conjugate of claim 1 having formula (Ic), or a pharmaceutically acceptable salt or solvate thereof: During the ceremony, RBM, L, M, X, D, Y 1 and n is as defined in claim 1; E is a spacer; Z* is an optionally substituted aliphatic residue or an optionally substituted aromatic residue; and Here, the sulfur bonded to the spacer E is bonded to the spacer E, Y after cleavage of the disulfide bond. 1 and can form a ring together with phosphorus.

31. Spacer E is -(CH 2 ) i - and which may be substituted; and wherein i is an integer ranging from 1 to 4; preferably 2, 3 or 4; more preferably 2 or 3; even more preferably 2.

31. The conjugate of claim 30.

32. Z* is optionally substituted (C 1 -C 8 32. The conjugate of claim 30 or 31, wherein:

33. 10. The conjugate of claim 1 having formula (Id), or a pharmaceutically acceptable salt or solvate thereof: During the ceremony, RBM, L, M, X, D, Y 1 and n is as defined in claim 1; E is a spacer; and R Ac1 and R Ac2 are each independently an optionally substituted aliphatic residue or an optionally substituted aromatic residue; optionally, R Ac1 and R Ac2 can form a 3- to 8-membered ring together with the oxygen and carbon atoms.

34. R Ac1 and R Ac2 are each independently optionally substituted (C 1 -C 8 ) alkyl, preferably R Ac1 and R Ac2 34. The conjugate of claim 33, wherein each independently is methyl, ethyl, propyl, such as isopropyl, or butyl, such as tert-butyl.

35. R Ac1 and R Ac2 35. The conjugate of claim 33 or 34, wherein:

36. Y 1 is NR A20 or O, where R A20 is as defined in any one of the preceding claims; Preferably, where Y 1 is NH or O; More preferably, Y 1 is NH, 36. The conjugate of any one of claims 33 to 35.

37. 10. The conjugate of claim 1 having formula (Ie), or a pharmaceutically acceptable salt or solvate thereof: During the ceremony, RBM, L, M, X, D, Y 1 and n is as defined in claim 1; E is a spacer; Z* is an optionally substituted aliphatic residue or an optionally substituted aromatic residue; and Here, the nitrogen atom bonded to the spacer E is, after cleavage of the acetyl bond, spacer E, Y 1 and together with the phosphorus can form a ring, preferably a 4- to 7-membered ring, more preferably a 5- or 6-membered ring.

38. Spacer E is -(CH 2 ) i - and which may be substituted; and wherein i is an integer ranging from 1 to 4; preferably 2, 3 or 4; more preferably 2 or 3; even more preferably 2.

38. The conjugate of claim 37.

39. Z* is optionally substituted (C 1 -C 8 39. The conjugate of claim 37 or 38, wherein:

40. Y 1 NR A20 or O, where R A20 is as defined in any one of the preceding claims; Preferably, where Y 1 is NH or O; More preferably, Y 1 is NH, 40. The conjugate of any one of claims 37 to 39.

41. 10. The conjugate of claim 1 having the formula (If), or a pharmaceutically acceptable salt or solvate thereof: During the ceremony, RBM, L, M, X, D, Y 1 and n is as defined in claim 1; E is a spacer; Z* is an optionally substituted aliphatic residue or an optionally substituted aromatic residue; and Here, the oxygen atom bonded to the spacer E is, after cleavage of the acetyl bond, spacer E, Y 1 and together with the phosphorus can form a ring, preferably a 4- to 7-membered ring, more preferably a 5- or 6-membered ring.

42. Spacer E is -(CH 2 ) i - and which may be substituted; and wherein i is an integer ranging from 1 to 4; preferably 2, 3 or 4; more preferably 2 or 3; even more preferably 2.

42. The conjugate of claim 41.

43. Z* is optionally substituted (C 1 -C 8 43. The conjugate of claim 41 or 42, wherein:

44. Y 1 NR A20 or O, where R A20 is as defined in any one of the preceding claims; Preferably, where Y 1 is NH or O; More preferably, Y 1 is NH, 44. The conjugate of any one of claims 41 to 43.

45. 10. The conjugate of any one of the preceding claims, wherein n is an integer in the range of 1 to 14, preferably 2 to 14, more preferably 3 to 14, even more preferably 4 to 14, even more preferably 5 to 12, even more preferably 6 to 12, even more preferably 7 to 10, and still more preferably 8.

46. 10. The conjugate according to any one of the preceding claims, wherein the receptor binding molecule (RBM) is selected from the group consisting of an antibody, an antibody fragment, a proteinaceous binding molecule with antibody-like binding properties, an aptamer and a small molecule; preferably the receptor binding molecule is an antibody.

47. 10. The conjugate of any one of the preceding claims, wherein X is O.

48. 47. The conjugate of any one of claims 1 to 46, wherein X is NH.

49. A conjugate according to any one of the preceding claims, in particular claim 47, wherein the moiety X-D is derived from an aliphatic or aromatic alcohol.

50. The drug moiety may be a mitotic spindle inhibitor such as (-)-epipodophyllotoxin, a dehydrogenase A inhibitor such as (R)-GNE-140, a kinase inhibitor such as (S)-3-hydroxymidostaurin and (R)-3-hydroxymidostaurin, a BET inhibitor such as ABBV-744, an estrogen receptor agonist such as acolbifene, a Wee1 inhibitor such as adavosertib, an HSP90 inhibitor such as alvespimycin, a kinase inhibitor such as ARS-1620, an FGFR inhibitor such as ASP5878, an MCT1 inhibitor such as AZD3965, or an AZD-805 mTOR inhibitors such as 5, kinase inhibitors such as berizatinib, HIF-2α inhibitors such as velzutifan, BCL inhibitors such as BM-1197, VEGFR inhibitors such as brivanib, STAT3 inhibitors such as C188, antitumor drugs such as CB1151, kinase inhibitors such as dasatinib, EGFR inhibitors such as DBPR112, CDK inhibitors such as dinaciclib, TRPC4 and TRCP5 channel activators such as englerin A, PRMT inhibitors such as EPZ015666, topoisomerase inhibitors such as etoposide, mTOR inhibitors such as everolimus, EZMMethyltransferase inhibitors such as 2302, CDK inhibitors such as fadraciclib, USP7 inhibitors such as FT671, estrogen receptor agonists such as fulvestrant, estrogen receptor agonists such as fulvestrant, HSP90 inhibitors such as geldanamycin, estrogen receptor agonists such as GNE-274, kinase inhibitors such as GNE-493, PRMT inhibitors such as GSK3326595, kinase inhibitors such as hypothemycin, CDK inhibitors such as IIIM-290, Illudin S, etc. Which DNA alkylating agents, kinase inhibitors such as irolasertib, kinase inhibitors such as larotrectinib, kinase inhibitors such as larotrectinib, IGF-1 inhibitors such as linsitinib, PRMT inhibitors such as LLY-283, HSP90 inhibitors such as luminespib, FGFR inhibitors such as LY2874455, kinase inhibitors such as mirdametinib, kinase inhibitors such as MRTX1133, kinase inhibitors such as MRTX1133, kinase inhibitors such as ningetinib, lurbinectidin in) or DNA minor groove binders such as trabectidin, HSP90 inhibitors such as NMS-E973, ribonucleotide reductase inhibitors such as NSAH, PLK1 inhibitors such as onvansertib, mTOR inhibitors such as Palomid 529, kinase inhibitors such as PD166326, NEDD8 inhibitors such as pevonedistat, kinase inhibitors such as PF-04217903, kinase inhibitors such as PF-06843195, HSP90 inhibitors such as PI-103, and pinometostat Methyltransferase inhibitors such as, topoisomerase inhibitors such as PNU-159682, topoisomerase inhibitors such as podofilox, HDAC inhibitors such as QTX125, mTOR inhibitors such as rapamycin, tankyrase inhibitors such as RK-287107, kinase inhibitors such as RO4987655, kinase inhibitors such as RP-3500, BCL inhibitors such as S55746, BCL inhibitors such as S65487, EGFR inhibitors such as SDZ281-977, kinase inhibitors such as SU14813, TC-A2317, kinase inhibitors such as teleocidin A1, ribonucleotide reductase inhibitors such as tezacitabine, kinase inhibitors such as TG 100572, RNA splicing inhibitors such as tylanstatin A, kinase inhibitors such as UNC5293, kinase inhibitors such as UNC5293, HSP90 inhibitors such as VER-50589, eIF4A inhibitors such as zotatifine, and analogs or prodrugs thereof.

51. 10. The conjugate of any one of the preceding claims, wherein the drug moiety is a camptothecin compound, preferably a camptothecin compound selected from the group consisting of DXD, SN38, exatecan, camptothecin, topotecan, irinotecan, belotecan, lurtotecan, rubitecan, ciratecan, cositecan, and gimatecan, more preferably the camptothecin compound is DXD or SN38.

52. 51. The conjugate of any one of claims 1 to 50, wherein the drug moiety is a TOPK inhibitor, preferably wherein the TOPK inhibitor is OTS-964.

53. 51. The conjugate of any one of claims 1 to 50, wherein the drug moiety is a CDK inhibitor, preferably wherein the CDK inhibitor is ganetespib or roniciclib.

54. 51. The conjugate of any one of claims 1 to 50, wherein the drug moiety is a bromodomain inhibitor, preferably wherein the bromodomain inhibitor is a bilabresive.

55. 51. The conjugate of any one of claims 1 to 50, wherein the drug moiety is an HSP90 inhibitor, preferably wherein the HSP90 inhibitor is SNX-2112.

56. 51. The conjugate of any one of claims 1 to 50, wherein the drug moiety is a ribonucleotide reductase inhibitor, preferably wherein the ribonucleotide reductase inhibitor is gemcitabine.

57. 51. The conjugate of any one of claims 1 to 50, wherein the drug moiety is an Aurora B kinase inhibitor, preferably wherein the Aurora B kinase inhibitor is barasertib.

58. 51. The conjugate of any one of claims 1 to 50, wherein the drug moiety is an HSP70 inhibitor, preferably wherein the HSp 70 inhibitor is triptolide.

59. 51. The conjugate of any one of claims 1 to 50, wherein the drug moiety is a nicotinamide phosphoribosyltransferase (Nampt) inhibitor, preferably wherein the Nampt inhibitor is Nampt-IN-1.

60. 51. The conjugate of any one of claims 1 to 50, wherein the drug moiety is a eukaryotic translation initiation factor 4E (eIF4E) inhibitor, preferably wherein the eIF4E inhibitor is ON-01300.

61. 51. The conjugate of any one of claims 1 to 50, wherein the drug moiety is a dihydroorotate dehydrogenase (DHODH) inhibitor, preferably wherein the DHODH inhibitor is Bay-240223 or DHODH-IN-16.

62. 51. The conjugate of any one of claims 1 to 50, wherein the drug moiety is a taxane, preferably wherein the taxane is paclitaxel, albumin-bound paclitaxel (nab-paclitaxel), docetaxel, cabazitaxel or abraxane, more preferably wherein the taxane is paclitaxel.

63. 51. The conjugate of any one of claims 1 to 50, wherein the drug moiety is an auristatin, preferably wherein the drug moiety is monomethyl auristatin E (MMAE) or monomethyl auristatin F (MMAF).

64. 10. The conjugate of any one of the preceding claims, wherein M is O or NH.

65. M is O, preferably (i) M is O, X is O, and Y 1 NR A20 where R A20 is as defined in any one of the preceding claims; Preferably, M is O, X is O, and Y 1 is NH; or (ii) M is O, X is NH, and Y 1 is O; Preferably, m is 0.

65. The conjugate of claim 64.

66. M is NH, preferably M is NH, X is O, and Y 1 The conjugate of claim 64, wherein is O.

67. The linker L is represented by the formula (LI): and During the ceremony, is a double bond; or is a single bond; V 2 teeth, is absent when is a double bond; or V 2 teeth, is a single bond, hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; V 1 teeth, If is a double bond, R V11 -C; or V 1 teeth, If is a single bond, and G is NR G70 , S, O, or CR G71 R G72 and Q is the connector unit; R V11 is hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; R V12 is hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; R G70 is hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; R G71 and R G72 are each independently hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; R 80 is an optionally substituted aliphatic residue or an optionally substituted aromatic residue; * indicates connection to receptor binding molecule (RBM); and A conjugate according to any one of the preceding claims, wherein # indicates connection to M.

68. is a double bond; V 2 does not exist; V 1 R V11 -C; and R V11 But hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; preferably R V11 is hydrogen or (C 1 -C 8 ) alkyl; more preferably R V11 68. The conjugate of claim 67, wherein is hydrogen.

69. is a single bond; V 2 But hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; preferably, V 2 is hydrogen or (C 1 -C 8 ) alkyl; more preferably, V 2 is hydrogen; V 1 but, and R V11 But hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; preferably R V11 is hydrogen or (C 1 -C 8 ) alkyl, more preferably R V11 is hydrogen; R V12 But hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; preferably R V12 is hydrogen or (C 1 -C 8 ) alkyl, more preferably R V12 68. The conjugate according to item 67, wherein is hydrogen.

70. G is NR G70 where R G70 is as defined in any one of claims 67 to 69; Preferably, G is NH.

70. The conjugate of any one of claims 67 to 69.

71. Q is, and where: p is an integer ranging from 2 to 20; indicates the connection to G; and # indicates connection to M, 71. The conjugate of any one of claims 67 to 70.

72. Q is, and where: is (C 3 --C 8 ) carbocycle, (C 6 -C 10 ) aryl (phenyl), a 5- or 6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms independently selected from the group consisting of N, O and S; preferably (C 3 -C 8 ) cycloalkyl; more preferably 5-, 6- or 7-membered cycloalkyl, even more preferably cyclohexyl; indicates the connection to G; and # indicates connection to M, 71. The conjugate of any one of claims 67 to 70.

73. The conjugate of claim 72, wherein is cyclohexyl.

74. R 80 is a polyalkylene glycol unit; Preferably, the polyalkylene glycol unit herein has the structure: and 1 to 100 subunits having the formula: Preferably, the polyalkylene glycol unit is and where: indicates the position of O; K F -H, -PO 3 H, -(C 1 -C 10 ) alkyl, -(C 1 -C 10 )Alkyl-SO 3 H, -(C 2 -C 10 )Alkyl-CO 2 H, -(C 2 -C 10 ) alkyl-OH, -(C 2 -C 10 )Alkyl-NH 2 , -(C 2 -C 10 ) alkyl-NH(C 1 -C 3 ) alkyl and -(C 2 -C 10 ) alkyl-N((C 1 -C 3 )Alkyl) 2 is selected from the group consisting of: F is H; and o is an integer ranging from 1 to 100; 74. The conjugate of any one of claims 67 to 73.

75. A conjugate according to any one of the preceding claims, preferably claims 67 to 74, wherein the connection to the receptor binding molecule (RBM) is via a sulfur atom.

76. 76. The conjugate of claim 75 having the formula (Ia2), or a pharmaceutically acceptable salt or solvate thereof: In the formula, RBM, V 1 V 2 , , R 80 , G, Q, M, X, D, Y 1 , A, Y 3 , J and n are as defined in any one of the preceding claims.

77. A conjugate having the formula (Ib1), or a pharmaceutically acceptable salt or solvate thereof: During the ceremony, RBM is a receptor binding molecule; L is a linker; M, O, NR M60 , or S; R M60 is hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; X is O, S, or NR X10 and R X10 is hydrogen; or an optionally substituted aliphatic or an optionally substituted aromatic residue; D is a drug moiety; Y 1 is NR A20 , O, S, or CR A21 R A22 and R A20 is hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; R A21 and R A22 are each independently hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; is an optionally substituted 4- to 7-membered, preferably 5- or 6-membered, carbocyclic or heterocyclic ring; is an oxygen atom and Y 1 preferably, the oxygen atom and Y 1 the points of attachment to are two adjacent atoms of the ring; Su is a sugar moiety; and n is an integer ranging from 1 to 20.

78. RBM、L、M、X、D、Y 1 、 78. The conjugate of claim 77, wherein Su and n are as defined in any one of the preceding claims.

79. A conjugate having the formula (Ic1), or a pharmaceutically acceptable salt or solvate thereof: During the ceremony, RBM is a receptor binding molecule; L is a linker; M, O, NR M60 , or S; R M60 is hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; X is O, S, or NR X10 and R X10 is hydrogen; or an optionally substituted aliphatic or an optionally substituted aromatic residue; D is a drug moiety; Y 1 is NR A20 , O, S, or CR A21 R A22 and R A20 is hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; R A21 and R A22 are each independently hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; E is -(CH 2 ) i - and which may be substituted; and wherein i is an integer ranging from 1 to 4; preferably 2, 3 or 4; more preferably 2 or 3; even more preferably 2; Z* is an optionally substituted aliphatic residue or an optionally substituted aromatic residue; and n is an integer ranging from 1 to 20.

80. RBM, L, M, X, D, Y 1 80. The conjugate of claim 79, wherein E, i, Z* and n are as defined in any one of the preceding claims.

81. A conjugate having the formula (Id1), or a pharmaceutically acceptable salt or solvate thereof: During the ceremony, RBM is a receptor binding molecule; L is a linker; M, O, NR M60 , or S; R M60 is hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; X is O, S, or NR X10 and R X10 is hydrogen; or an optionally substituted aliphatic or an optionally substituted aromatic residue; D is a drug moiety; Y 1 is NR A20 , O, S, or CR A21 R A22 and R A20 is hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; R A21 and R A22 are each independently hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; A is CR A30 R A31 or A is (C 1 -C 8 ) alkylene, where (C 1 -C 8 ) alkylene is (C 1 -C 8 ) alkyl, halo, hydroxy, (C 1 -C 8 ) alkoxy, amino, (C 1 -C 8 ) alkylamino, di(C 1 -C 8 ) alkylamino, SH, (C 1 -C 8 ) alkylthio, (C 3 -C 8 ) heterocyclyl, carboxylates and their esters, carboxy (C 1 -C 8 ) alkyl, CONHR A36 and CONR A36 R A37 and R A36 and R A37 are independently (C 1 -C 8 ) alkyl, (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl or (C 6 -C 10 ) aryl; R A30 and R A31 are each independently hydrogen, (C 1 -C 8 ) alkyl, (C 3 -C 8 ) cycloalkyl, (C 2 -C 8 ) alkenyl, (C 5 -C 8 ) cycloalkenyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 )aryl; wherein each (C 1 -C 8 ) alkyl, (C 3 -C 8 ) cycloalkyl, (C 2 -C 8 ) alkenyl, (C 5 -C 8 ) cycloalkenyl, (C 6 -C 10 ) aryl or (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl is (C 1 -C 8 ) alkyl, halo, hydroxy, (C 1 -C 8 ) alkoxy, amino, (C 1 -C 8 ) alkylamino, di(C 1 -C 8 ) alkylamino, SH, (C 1 -C 8 ) alkylthio, (C 3 -C 8 ) heterocyclyl, carboxylates and their esters, carboxy (C 1 -C 8 ) alkyl, CONHR A36 and CONR A36 R A37 and R A36 and R A37 are independently (C 1 -C 8 ) alkyl, (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl or (C 6 -C 10 ) aryl; optionally, R A30 and R A31 can be taken together to form a 3- to 8-membered ring; R Ac1 and R Ac2 are each independently an optionally substituted aliphatic residue or an optionally substituted aromatic residue; optionally, R Ac1 and R Ac2 can form a 3- to 8-membered ring together with the oxygen and carbon atoms; and n is an integer ranging from 1 to 20.

82. RBM, L, M, X, D, Y 1 , A, R Ac1 , R Ac2 82. The conjugate of claim 81, wherein n is as defined in any one of the preceding claims.

83. A conjugate having the formula (Ie1), or a pharmaceutically acceptable salt or solvate thereof: During the ceremony, RBM is a receptor binding molecule; L is a linker; M, O, NR M60 , or S; R M60 is hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; X is O, S, or NR X10 and R X10 is hydrogen; or an optionally substituted aliphatic or an optionally substituted aromatic residue; D is a drug moiety; Y 1 is NR A20 , O, S, or CR A21 R A22 and R A20 is hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; R A21 and R A22 are each independently hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; E is -(CH 2 ) i - and which may be substituted; and wherein i is an integer ranging from 1 to 4; preferably 2, 3 or 4; more preferably 2 or 3; even more preferably 2; Z* is an optionally substituted aliphatic residue or an optionally substituted aromatic residue; Here, the nitrogen atom bonded to the spacer E is, after cleavage of the acetyl bond, spacer E, Y 1 and together with phosphorus can form a ring, preferably a 4- to 7-membered ring, more preferably a 5- or 6-membered ring; and n is an integer ranging from 1 to 20.

84. RBM, L, M, X, D, Y 1 84. The conjugate of claim 83, wherein E, i, Z* and n are as defined in any one of the preceding claims.

85. A conjugate having the formula (If1), or a pharmaceutically acceptable salt or solvate thereof: During the ceremony, RBM is a receptor binding molecule; L is a linker; M, O, NR M60 , or S; R M60 is hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; X is O, S, or NR X10 and R X10 is hydrogen; or an optionally substituted aliphatic or an optionally substituted aromatic residue; D is a drug moiety; Y 1 is NR A20 , O, S, or CR A21 R A22 and R A20 is hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; R A21 and R A22 are each independently hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; E is -(CH 2 ) i - and which may be substituted; and wherein i is an integer ranging from 1 to 4; preferably 2, 3 or 4; more preferably 2 or 3; even more preferably 2; Z* is an optionally substituted aliphatic residue or an optionally substituted aromatic residue; Here, the nitrogen atom bonded to the spacer E is, after cleavage of the acetyl bond, spacer E, Y 1 and together with phosphorus can form a ring, preferably a 4- to 7-membered ring, more preferably a 5- or 6-membered ring; and n is an integer ranging from 1 to 20.

86. RBM, L, M, X, D, Y 1 86. The conjugate of claim 85, wherein E, i, Z* and n are as defined in any one of the preceding claims.

87. A compound having the formula (II), or a pharmaceutically acceptable salt or solvate thereof: During the ceremony, L* is a linker capable of forming a covalent connection to a receptor binding molecule (RBM); M, O, NR M60 , or S; R M60 is hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; U is O or S; X is O, S, or NR X10 and R X10 is hydrogen; or an optionally substituted aliphatic or an optionally substituted aromatic residue; D is a drug moiety; Y 1 is NR A20 , O, S, or CR A21 R A22 and R A20 is hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; R A21 and R A22 are each independently hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; E is a spacer; Z is a cleavable group; and W is a spacer E, Y after cleavage of group Z. 1 and a moiety that can form a ring together with the phosphorus atom.

88. A compound having the formula (IIa), or a pharmaceutically acceptable salt or solvate thereof: During the ceremony, L*, M, X, D and Y 1 is as defined in claim 71; A is CR A30 R A31 or A is (C 1 -C 8 ) alkylene, where (C 1 -C 8 ) alkylene is (C 1 -C 8 ) alkyl, halo, hydroxy, (C 1 -C 8 ) alkoxy, amino, (C 1 -C 8 ) alkylamino, di(C 1 -C 8 ) alkylamino, SH, (C 1 -C 8 ) alkylthio, (C 3 -C 8 ) heterocyclyl, carboxylates and their esters, carboxy (C 1 -C 8 ) alkyl, CONHR A36 and CONR A36 R A37 and R A36 and R A37 are independently (C 1 -C 8 ) alkyl, (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl or (C 6 -C 10 ) aryl; R A30 and R A31 are each independently hydrogen, (C 1 -C 8 ) alkyl, (C 3 -C 8 ) cycloalkyl, (C 2 -C 8 ) alkenyl, (C 5 -C 8 ) cycloalkenyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 )aryl; wherein each (C 1 -C 8 ) alkyl, (C 3 -C 8 ) cycloalkyl, (C 2 -C 8 ) alkenyl, (C 5 -C 8 ) cycloalkenyl, (C 6 -C 10 ) aryl or (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl is (C 1 -C 8 ) alkyl, halo, hydroxy, (C 1 -C 8 ) alkoxy, amino, (C 1 -C 8 ) alkylamino, di(C 1 -C 8 ) alkylamino, SH, (C 1 -C 8 ) alkylthio, (C 3 -C 8 ) heterocyclyl, carboxylates and their esters, carboxy (C 1 -C 8 ) alkyl, CONHR A36 and CONR A36 R A37 and R A36 and R A37 are independently (C 1 -C 8 ) alkyl, (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl or (C 6 -C 10 ) aryl; optionally, R A30 and R A31 can be taken together to form a 3- to 8-membered ring; Y 2 is NR B20 , O, S, or CR B21 R B22 and R B20 is hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; R B21 and R B22 are each independently hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; B is independently CR B30 R B31 or B is independently (C 1 -C 8 ) alkylene, where (C 1 -C 8 ) alkylene is (C 1 -C 8 ) alkyl, halo, hydroxy, (C 1 -C 8 ) alkoxy, amino, (C 1 -C 8 ) alkylamino, di(C 1 -C 8 ) alkylamino, SH, (C 1 -C 8 ) alkylthio, (C 3 -C 8 ) heterocyclyl, carboxylates and their esters, carboxy (C 1 -C 8 ) alkyl, CONHR B36 and CONR B36 R B37 and R B36 and R B37 are independently (C 1 -C 8 ) alkyl, (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl or (C 6 -C 10 ) aryl; R B30 and R B31 are each independently hydrogen, (C 1 -C 8 ) alkyl, (C 3 -C 8 ) cycloalkyl, (C 2 -C 8 ) alkenyl, (C 5 -C 8 ) cycloalkenyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 )aryl; wherein each (C 1 -C 8 ) alkyl, (C 3 -C 8 ) cycloalkyl, (C 2 -C 8 ) alkenyl, (C 5 -C 8 ) cycloalkenyl, (C 6 -C 10 ) aryl or (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl is (C 1 -C 8 ) alkyl, halo, hydroxy, (C 1 -C 8 ) alkoxy, amino, (C 1 -C 8 ) alkylamino, di(C 1 -C 8 ) alkylamino, SH, (C 1 -C 8 ) alkylthio, (C 3 -C 8 ) heterocyclyl, carboxylates and their esters, carboxy (C 1 -C 8 ) alkyl, CONHR B36 and CONR B36 R B37 and R B36 and R B37 are independently (C 1 -C 8 ) alkyl, (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl or (C 6 -C 10 ) aryl; optionally, R B30 and R B31 can be taken together to form a 3- to 8-membered ring; m is an integer ranging from 0 to 15; Y 3 , O, NR C40 , or S, or absent; R C40 is hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; J is where: is Y 3 Show the connection to C is CR C50 R C51 or C is (C 1 -C 8 ) alkylene, where (C 1 -C 8 ) alkylene is (C 1 -C 8 ) alkyl, halo, hydroxy, (C 1 -C 8 ) alkoxy, amino, (C 1 -C 8 ) alkylamino, di(C 1 -C 8 ) alkylamino, SH, (C 1 -C 8 ) alkylthio, (C 3 -C 8 ) heterocyclyl, carboxylates and their esters, carboxy (C 1 -C 8 ) alkyl, CONHR C36 and CONR C36 R C37 and R C36 and R C37 are independently (C 1 -C 8 ) alkyl, (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl or (C 6 -C 10 ) aryl; R C50 and R C51 are each independently hydrogen, (C 1 -C 8 ) alkyl, (C 3 -C 8 ) cycloalkyl, (C 2 -C 8 ) alkenyl, (C 5 -C 8 ) cycloalkenyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 )aryl; wherein each (C 1 -C 8 ) alkyl, (C 3 -C 8 ) cycloalkyl, (C 2 -C 8 ) alkenyl, (C 5 -C 8 ) cycloalkenyl, (C 6 -C 10 ) aryl or (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl is (C 1 -C 8 ) alkyl, halo, hydroxy, (C 1 -C 8 ) alkoxy, amino, (C 1 -C 8 ) alkylamino, di(C 1 -C 8 ) alkylamino, SH, (C 1 -C 8 ) alkylthio, (C 3 -C 8 ) heterocyclyl, carboxylates and their esters, carboxy (C 1 -C 8 ) alkyl, CONHR C36 and CONR C36 R C37 and R C36 and R C37 are independently (C 1 -C 8 ) alkyl, (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl or (C 6 -C 10 ) aryl; optionally, R C50 and R C51 can be taken together to form a 3- to 8-membered ring; Y 4 , O, NR C53 , S, or CR C54 R C55 or absent; R C52 is hydrogen, (C 1 -C 8 ) alkyl, (C 3 -C 8 ) cycloalkyl, (C 2 -C 8 ) alkenyl, (C 5 -C 8 ) cycloalkenyl, (C 3 -C 8 ) heterocyclyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 )aryl; wherein each (C 1 -C 8 ) alkyl, (C 3 -C 8 ) cycloalkyl, (C 2 -C 8 ) alkenyl, (C 5 -C 8 ) cycloalkenyl, (C 3 -C 8 ) heterocyclyl, (C 6 -C 10 ) aryl or (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl is (C 1 -C 8 ) alkyl, halo, hydroxy, (C 1 -C 8 ) alkoxy, amino, (C 1 -C 8 ) alkylamino, di(C 1 -C 8 ) alkylamino, SH, (C 1 -C 8 ) alkylthio, (C 3 -C 8 ) heterocyclyl, carboxylates and their esters, carboxy (C 1 -C 8 ) alkyl, CONHR C56 and CONR C56 R C57 and R C56 and R C57 are independently (C 1 -C 8 ) alkyl, (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl or (C 6 -C 10 ) aryl; R C53 is hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; R C54 and R C55 are each independently hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; or J is hydrogen, (C 1 -C 8 ) alkyl, (C 3 -C 8 ) cycloalkyl, (C 2 -C 8 ) alkenyl, (C 5 -C 8 ) cycloalkenyl, (C 3 -C 8 ) heterocyclyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 )aryl; wherein each (C 1 -C 8 ) alkyl, (C 3 -C 8 ) cycloalkyl, (C 2 -C 8 ) alkenyl, (C 5 -C 8 ) cycloalkenyl, (C 3 -C 8 ) heterocyclyl, (C 6 -C 10 ) aryl or (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl is (C 1 -C 8 ) alkyl, halo, hydroxy, (C 1 -C 8 ) alkoxy, amino, (C 1 -C 8 ) alkylamino, di(C 1 -C 8 ) alkylamino, SH, (C 1 -C 8 ) alkylthio, (C 3 -C 8 ) heterocyclyl, carboxylates and their esters, carboxy (C 1 -C 8 ) alkyl, CONHR C46 and CONR C46 R C47 and R C46 and R C47 are independently (C 1 -C 8 ) alkyl, (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl or (C 6 -C 10 ) aryl.

89. 89. The compound of claim 88 having the formula (IIa1), or a pharmaceutically acceptable salt or solvate thereof: In the formula, L*, M, X, D, Y 1 , A, Y 3 and J is as defined in claim 66.

90. 90. The compound of claim 89 having the formula (IIa2), or a pharmaceutically acceptable salt or solvate thereof: In the formula, M, X, D, Y 1 , A, Y 3 and J is as defined in claim 66 or 67; is a triple bond; or is a double bond; V 2 teeth, is absent when is a triple bond; or V 2 teeth, is a double bond, hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; V 1 teeth, If is a triple bond, R V11 -C; or V 1 teeth, If is a double bond and G is NR G70 , S, O, or CR G71 R G72 and Q is the connector unit; R V11 is hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; R V12 is hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; R G70 is hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; R G71 and R G72 are each independently hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; and R 80 is an optionally substituted aliphatic residue or an optionally substituted aromatic residue.

91. L*、V 1 、V 2 、 , R 80 , G, Q, M, X, D, Y 1 , A, Y 2 , B, Y 3 91. The compound of any one of claims 88-90, wherein J and m are as defined in any one of the preceding claims.

92. 88. The compound of claim 87 having the formula (IIb), or a pharmaceutically acceptable salt or solvate thereof: During the ceremony, L*, M, X, D and Y 1 is as defined in claim 87; E is a spacer; Su is a sugar moiety attached to the oxygen atom via a cleavable bond; and Here, oxygen is the spacer E, Y after cleavage of the sugar moiety Su. 1 and can form a ring together with phosphorus.

93. 93. The compound of claim 92, wherein the sugar moiety Su is protected or unprotected.

94. 94. The compound of claim 92 or 93 having the formula (IIb1), or a pharmaceutically acceptable salt or solvate thereof: During the ceremony, L*, M, X, D, Y 1 and Su is as defined in claim 92; is an optionally substituted 4- to 7-membered, preferably 5- or 6-membered, carbocyclic or heterocyclic ring; and is an oxygen atom and Y 1 preferably, the oxygen atom and Y 1 The points of attachment to are two adjacent atoms in the ring.

95. L*、M、X、D、Y 1 、 95. The compound of any one of claims 92 to 94, wherein E and Su are as defined in any one of the preceding claims.

96. 88. The compound of claim 87 having the formula (IIc), or a pharmaceutically acceptable salt or solvate thereof: During the ceremony, L*, M, X, D and Y 1 is as defined in claim 87; E is a spacer; and Z* is an optionally substituted aliphatic residue or an optionally substituted aromatic residue.

97. 97. The compound of claim 96 having the formula (IIc1), or a pharmaceutically acceptable salt or solvate thereof: During the ceremony, L*, M, X, D, Y 1 and Z* are as defined in claim 96; and E is -(CH 2 ) i - and and wherein i is an integer ranging from 1 to 4; preferably 2, 3 or 4; more preferably 2 or 3; even more preferably 2.

98. L*, M, X, D, Y 1 98. The compound of claim 96 or 97, wherein E, i and Z* are as defined in any one of the preceding claims.

99. 88. The compound of claim 87 having the formula (IId), or a pharmaceutically acceptable salt or solvate thereof: During the ceremony, L*, M, X, D, Y 1 and E are as defined in claim 87; and R Ac1 and R Ac2 are each independently an optionally substituted aliphatic residue or an optionally substituted aromatic residue; optionally, R Ac1 and R Ac2 can form a 3- to 8-membered ring together with the oxygen and carbon atoms.

100. 100. The compound of claim 99 having the formula (IId1), or a pharmaceutically acceptable salt or solvate thereof: During the ceremony, L*, M, X, D, Y 1 , R Ac1 and R Ac2 is as defined in claim 99; and A is CR A30 R A31 or A is (C 1 -C 8 ) alkylene, where (C 1 -C 8 ) alkylene is (C 1 -C 8 ) alkyl, halo, hydroxy, (C 1 -C 8 ) alkoxy, amino, (C 1 -C 8 ) alkylamino, di(C 1 -C 8 ) alkylamino, SH, (C 1 -C 8 ) alkylthio, (C 3 -C 8 ) heterocyclyl, carboxylates and their esters, carboxy (C 1 -C 8 ) alkyl, CONHR A36 and CONR A36 R A37 and R A36 and R A37 are independently (C 1 -C 8 ) alkyl, (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl or (C 6 -C 10 ) aryl; R A30 and R A31 are each independently hydrogen, (C 1 -C 8 ) alkyl, (C 3 -C 8 ) cycloalkyl, (C 2 -C 8 ) alkenyl, (C 5 -C 8 ) cycloalkenyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 )aryl; wherein each (C 1 -C 8 ) alkyl, (C 3 -C 8 ) cycloalkyl, (C 2 -C 8 ) alkenyl, (C 5 -C 8 ) cycloalkenyl, (C 6 -C 10 ) aryl or (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl is (C 1 -C 8 ) alkyl, halo, hydroxy, (C 1 -C 8 ) alkoxy, amino, (C 1 -C 8 ) alkylamino, di(C 1 -C 8 ) alkylamino, SH, (C 1 -C 8 ) alkylthio, (C 3 -C 8 ) heterocyclyl, carboxylates and their esters, carboxy (C 1 -C 8 ) alkyl, CONHR A36 and CONR A36 R A37 and R A36 and R A37 are independently (C 1 -C 8 ) alkyl, (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl or (C 6 -C 10 ) aryl; optionally, R A30 and R A31 can be taken together to form a 3- to 8-membered ring.

101. RBM, L, M, X, D, Y 1 , E, A, R Ac1 and R Ac2 101. The compound of claim 99 or 100, wherein:

102. 88. The compound of claim 87 having the formula (IIe), or a pharmaceutically acceptable salt or solvate thereof: During the ceremony, L*, M, X, D, Y 1 and E are as defined in claim 87; and Z* is an optionally substituted aliphatic residue or an optionally substituted aromatic residue.

103. 103. The compound of claim 102 having the formula (IIe1), or a pharmaceutically acceptable salt or solvate thereof: During the ceremony, L*, M, X, D, Y 1 and Z* are as defined in claim 102; and E is -(CH 2 ) i - and and wherein i is an integer ranging from 1 to 4; preferably 2, 3 or 4; more preferably 2 or 3; even more preferably 2.

104. L*, M, X, D, Y 1 104. The compound of claim 102 or 103, wherein E, i and Z* are as defined in any one of the preceding claims.

105. 88. The compound of claim 87 having the formula (IIf), or a pharmaceutically acceptable salt or solvate thereof: During the ceremony, L*, M, X, D, Y 1 and E are as defined in claim 87; and Z* is an optionally substituted aliphatic residue or an optionally substituted aromatic residue.

106. 106. The compound of claim 105 having the formula (IIf1), or a pharmaceutically acceptable salt or solvate thereof: During the ceremony, L*, M, X, D, Y 1 and Z* are as defined in claim 105; and E is -(CH 2 ) i - and and wherein i is an integer ranging from 1 to 4; preferably 2, 3 or 4; more preferably 2 or 3; even more preferably 2.

107. L*, M, X, D, Y 1 107. The compound of claim 105 or 106, wherein E, i and Z* are as defined in any one of the preceding claims.

108. A method for preparing a conjugate of formula (I), comprising the steps of: A compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof: (In the formula, L* is a linker capable of forming a covalent connection to a receptor binding molecule (RBM); M, O, NR M60 , or S; R M60 is hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; U is O or S; X is O, S, or NR X10 and R X10 is hydrogen; or an optionally substituted aliphatic or an optionally substituted aromatic residue; D is a drug moiety; Y 1 is NR A20 , O, S, or CR A21 R A22 and R A20 is hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; R A21 and R A22 are each independently hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; E is a spacer; Z is a cleavable group; and W is a spacer E, Y after cleavage of group Z. 1 and a moiety capable of forming a ring together with phosphorus; a receptor binding molecule (RBM) having a functional group reactive to L* of the compound of formula (II); thereby forming a covalent bond between the receptor binding molecule (RBM) and the linker (L), A conjugate of formula (I), or a pharmaceutically acceptable salt or solvate thereof: (In the formula, RBM is a receptor binding molecule; L is a linker; M, O, NR M60 , or S; R M60 is hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; U is O or S; X is O, S, or NR X10 and R X10 is hydrogen; or an optionally substituted aliphatic or an optionally substituted aromatic residue; D is a drug moiety; Y 1 is NR A20 , O, S, or CR A21 R A22 and R A20 is hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; R A21 and R A22 are each independently hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; E is a spacer; Z is a cleavable group; W is a spacer E, Y after cleavage of group Z. 1 and a moiety capable of forming a ring together with the phosphorus; and n is an integer ranging from 1 to 20. The step of generating the above.

109. 109. The method of claim 108, comprising the steps of: A compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof: (In the formula, L*, M, X, D and Y 1 is as defined in claim 90; A is CR A30 R A31 or A is (C 1 -C 8 ) alkylene, where (C 1 -C 8 ) alkylene is (C 1 -C 8 ) alkyl, halo, hydroxy, (C 1 -C 8 ) alkoxy, amino, (C 1 -C 8 ) alkylamino, di(C 1 -C 8 ) alkylamino, SH, (C 1 -C 8 ) alkylthio, (C 3 -C 8 ) heterocyclyl, carboxylates and their esters, carboxy (C 1 -C 8 ) alkyl, CONHR A36 and CONR A36 R A37 and R A36 and R A37 are independently (C 1 -C 8 ) alkyl, (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl or (C 6 -C 10 ) aryl; R A30 and R A31 are each independently hydrogen, (C 1 -C 8 ) alkyl, (C 3 -C 8 ) cycloalkyl, (C 2 -C 8 ) alkenyl, (C 5 -C 8 ) cycloalkenyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 )aryl; wherein each (C 1 -C 8 ) alkyl, (C 3 -C 8 ) cycloalkyl, (C 2 -C 8 ) alkenyl, (C 5 -C 8 ) cycloalkenyl, (C 6 -C 10 ) aryl or (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl is (C 1 -C 8 ) alkyl, halo, hydroxy, (C 1 -C 8 ) alkoxy, amino, (C 1 -C 8 ) alkylamino, di(C 1 -C 8 ) alkylamino, SH, (C 1 -C 8 ) alkylthio, (C 3 -C 8 ) heterocyclyl, carboxylates and their esters, carboxy (C 1 -C 8 ) alkyl, CONHR A36 and CONR A36 R A37 and R A36 and R A37 are independently (C 1 -C 8 ) alkyl, (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl or (C 6 -C 10 ) aryl; optionally, R A30 and R A31 can be taken together to form a 3- to 8-membered ring; Y 2 is NR B20 , O, S, or CR B21 R B22 and R B20 is hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; R B21 and R B22 are each independently hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; B is independently CR B30 R B31 or B is independently (C 1 -C 8 ) alkylene, where (C 1 -C 8 ) alkylene is (C 1 -C 8 ) alkyl, halo, hydroxy, (C 1 -C 8 ) alkoxy, amino, (C 1 -C 8 ) alkylamino, di(C 1 -C 8 ) alkylamino, SH, (C 1 -C 8 ) alkylthio, (C 3 -C 8 ) heterocyclyl, carboxylates and their esters, carboxy (C 1 -C 8 ) alkyl, CONHR B36 and CONR B36 R B37 and R B36 and R B37 are independently (C 1 -C 8 ) alkyl, (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl or (C 6 -C 10 ) aryl; R B30 and R B31 are each independently hydrogen, (C 1 -C 8 ) alkyl, (C 3 -C 8 ) cycloalkyl, (C 2 -C 8 ) alkenyl, (C 5 -C 8 ) cycloalkenyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 )aryl; wherein each (C 1 -C 8 ) alkyl, (C 3 -C 8 ) cycloalkyl, (C 2 -C 8 ) alkenyl, (C 5 -C 8 ) cycloalkenyl, (C 6 -C 10 ) aryl or (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl is (C 1 -C 8 ) alkyl, halo, hydroxy, (C 1 -C 8 ) alkoxy, amino, (C 1 -C 8 ) alkylamino, di(C 1 -C 8 ) alkylamino, SH, (C 1 -C 8 ) alkylthio, (C 3 -C 8 ) heterocyclyl, carboxylates and their esters, carboxy (C 1 -C 8 ) alkyl, CONHR B36 and CONR B36 R B37 and R B36 and R B37 are independently (C 1 -C 8 ) alkyl, (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl or (C 6 -C 10 ) aryl; optionally, R B30 and R B31 can be taken together to form a 3- to 8-membered ring; m is an integer ranging from 0 to 15; Y 3 , O, NR C40 , or S, or absent; R C40 is hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; J is where: is Y 3 Show the connection to C is CR C50 R C51 or C is (C 1 -C 8 ) alkylene, where (C 1 -C 8 ) alkylene is (C 1 -C 8 ) alkyl, halo, hydroxy, (C 1 -C 8 ) alkoxy, amino, (C 1 -C 8 ) alkylamino, di(C 1 -C 8 ) alkylamino, SH, (C 1 -C 8 ) alkylthio, (C 3 -C 8 ) heterocyclyl, carboxylates and their esters, carboxy (C 1 -C 8 ) alkyl, CONHR C36 and CONR C36 R C37 and R C36 and R C37 are independently (C 1 -C 8 ) alkyl, (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl or (C 6 -C 10 ) aryl; R C50 and R C51 are each independently hydrogen, (C 1 -C 8 ) alkyl, (C 3 -C 8 ) cycloalkyl, (C 2 -C 8 ) alkenyl, (C 5 -C 8 ) cycloalkenyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 )aryl; wherein each (C 1 -C 8 ) alkyl, (C 3 -C 8 ) cycloalkyl, (C 2 -C 8 ) alkenyl, (C 5 -C 8 ) cycloalkenyl, (C 6 -C 10 ) aryl or (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl is (C 1 -C 8 ) alkyl, halo, hydroxy, (C 1 -C 8 ) alkoxy, amino, (C 1 -C 8 ) alkylamino, di(C 1 -C 8 ) alkylamino, SH, (C 1 -C 8 ) alkylthio, (C 3 -C 8 ) heterocyclyl, carboxylates and their esters, carboxy (C 1 -C 8 ) alkyl, CONHR C36 and CONR C36 R C37 and R C36 and R C37 are independently (C 1 -C 8 ) alkyl, (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl or (C 6 -C 10 ) aryl; optionally, R C50 and R C51 can be taken together to form a 3- to 8-membered ring; Y 4 , O, NR C53 , S, or CR C54 R C55 or absent; R C52 is hydrogen, (C 1 -C 8 ) alkyl, (C 3 -C 8 ) cycloalkyl, (C 2 -C 8 ) alkenyl, (C 5 -C 8 ) cycloalkenyl, (C 3 -C 8 ) heterocyclyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 )aryl; wherein each (C 1 -C 8 ) alkyl, (C 3 -C 8 ) cycloalkyl, (C 2 -C 8 ) alkenyl, (C 5 -C 8 ) cycloalkenyl, (C 3 -C 8 ) heterocyclyl, (C 6 -C 10 ) aryl or (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl is (C 1 -C 8 ) alkyl, halo, hydroxy, (C 1 -C 8 ) alkoxy, amino, (C 1 -C 8 ) alkylamino, di(C 1 -C 8 ) alkylamino, SH, (C 1 -C 8 ) alkylthio, (C 3 -C 8 ) heterocyclyl, carboxylates and their esters, carboxy (C 1 -C 8 ) alkyl, CONHR C56 and CONR C56 R C57 and R C56 and R C57 are independently (C 1 -C 8 ) alkyl, (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl or (C 6 -C 10 ) aryl; R C53 is hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; R C54 and R C55 are each independently hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; or J is hydrogen, (C 1 -C 8 ) alkyl, (C 3 -C 8 ) cycloalkyl, (C 2 -C 8 ) alkenyl, (C 5 -C 8 ) cycloalkenyl, (C 3 -C 8 ) heterocyclyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 )aryl; wherein each (C 1 -C 8 ) alkyl, (C 3 -C 8 ) cycloalkyl, (C 2 -C 8 ) alkenyl, (C 5 -C 8 ) cycloalkenyl, (C 3 -C 8 ) heterocyclyl, (C 6 -C 10 ) aryl or (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl is (C 1 -C 8 ) alkyl, halo, hydroxy, (C 1 -C 8 ) alkoxy, amino, (C 1 -C 8 ) alkylamino, di(C 1 -C 8 ) alkylamino, SH, (C 1 -C 8 ) alkylthio, (C 3 -C 8 ) heterocyclyl, carboxylates and their esters, carboxy (C 1 -C 8 ) alkyl, CONHR C46 and CONR C46 R C47 and R C46 and R C47 are independently (C 1 -C 8 ) alkyl, (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl or (C 6 -C 10 ) aryl) and a receptor binding molecule (RBM) having a functional group reactive to L* of the compound of formula (IIa); thereby forming a covalent bond between the receptor binding molecule (RBM) and the linker (L), A conjugate of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof: (In the formula, RBM, L, M, X, D, Y 1 and n is as defined in claim 76; A is CR A30 R A31 or A is (C 1 -C 8 ) alkylene, where (C 1 -C 8 ) alkylene is (C 1 -C 8 ) alkyl, halo, hydroxy, (C 1 -C 8 ) alkoxy, amino, (C 1 -C 8 ) alkylamino, di(C 1 -C 8 ) alkylamino, SH, (C 1 -C 8 ) alkylthio, (C 3 -C 8 ) heterocyclyl, carboxylates and their esters, carboxy (C 1 -C 8 ) alkyl, CONHR A36 and CONR A36 R A37 and R A36 and R A37 are independently (C 1 -C 8 ) alkyl, (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl or (C 6 -C 10 ) aryl; R A30 and R A31 are each independently hydrogen, (C 1 -C 8 ) alkyl, (C 3 -C 8 ) cycloalkyl, (C 2 -C 8 ) alkenyl, (C 5 -C 8 ) cycloalkenyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 )aryl; wherein each (C 1 -C 8 ) alkyl, (C 3 -C 8 ) cycloalkyl, (C 2 -C 8 ) alkenyl, (C 5 -C 8 ) cycloalkenyl, (C 6 -C 10 ) aryl or (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl is (C 1 -C 8 ) alkyl, halo, hydroxy, (C 1 -C 8 ) alkoxy, amino, (C 1 -C 8 ) alkylamino, di(C 1 -C 8 ) alkylamino, SH, (C 1 -C 8 ) alkylthio, (C 3 -C 8 ) heterocyclyl, carboxylates and their esters, carboxy (C 1 -C 8 ) alkyl, CONHR A36 and CONR A36 R A37 and R A36 and R A37 are independently (C 1 -C 8 ) alkyl, (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl or (C 6 -C 10 ) aryl; optionally, R A30 and R A31 can be taken together to form a 3- to 8-membered ring; Y 2 is NR B20 , O, S, or CR B21 R B22 and R B20 is hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; R B21 and R B22 are each independently hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; B is independently CR B30 R B31 or B is independently (C 1 -C 8 ) alkylene, where (C 1 -C 8 ) alkylene is (C 1 -C 8 ) alkyl, halo, hydroxy, (C 1 -C 8 ) alkoxy, amino, (C 1 -C 8 ) alkylamino, di(C 1 -C 8 ) alkylamino, SH, (C 1 -C 8 ) alkylthio, (C 3 -C 8 ) heterocyclyl, carboxylates and their esters, carboxy (C 1 -C 8 ) alkyl, CONHR B36 and CONR B36 R B37 and R B36 and R B37 are independently (C 1 -C 8 ) alkyl, (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl or (C 6 -C 10 ) aryl; R B30 and R B31 are each independently hydrogen, (C 1 -C 8 ) alkyl, (C 3 -C 8 ) cycloalkyl, (C 2 -C 8 ) alkenyl, (C 5 -C 8 ) cycloalkenyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 )aryl; wherein each (C 1 -C 8 ) alkyl, (C 3 -C 8 ) cycloalkyl, (C 2 -C 8 ) alkenyl, (C 5 -C 8 ) cycloalkenyl, (C 6 -C 10 ) aryl or (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl is (C 1 -C 8 ) alkyl, halo, hydroxy, (C 1 -C 8 ) alkoxy, amino, (C 1 -C 8 ) alkylamino, di(C 1 -C 8 ) alkylamino, SH, (C 1 -C 8 ) alkylthio, (C 3 -C 8 ) heterocyclyl, carboxylates and their esters, carboxy (C 1 -C 8 ) alkyl, CONHR B36 and CONR B36 R B37 and R B36 and R B37 are independently (C 1 -C 8 ) alkyl, (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl or (C 6 -C 10 ) aryl; optionally, R B30 and R B31 can be taken together to form a 3- to 8-membered ring; m is an integer ranging from 0 to 15; Y 3 , O, NR C40 , or S, or absent; R C40 is hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; J is where: is Y 3 Show the connection to C is CR C50 R C51 or C is (C 1 -C 8 ) alkylene, where (C 1 -C 8 ) alkylene is (C 1 -C 8 ) alkyl, halo, hydroxy, (C 1 -C 8 ) alkoxy, amino, (C 1 -C 8 ) alkylamino, di(C 1 -C 8 ) alkylamino, SH, (C 1 -C 8 ) alkylthio, (C 3 -C 8 ) heterocyclyl, carboxylates and their esters, carboxy (C 1 -C 8 ) alkyl, CONHR C36 and CONR C36 R C37 and R C36 and R C37 are independently (C 1 -C 8 ) alkyl, (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl or (C 6 -C 10 ) aryl; R C50 and R C51 are each independently hydrogen, (C 1 -C 8 ) alkyl, (C 3 -C 8 ) cycloalkyl, (C 2 -C 8 ) alkenyl, (C 5 -C 8 ) cycloalkenyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 )aryl; wherein each (C 1 -C 8 ) alkyl, (C 3 -C 8 ) cycloalkyl, (C 2 -C 8 ) alkenyl, (C 5 -C 8 ) cycloalkenyl, (C 6 -C 10 ) aryl or (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl is (C 1 -C 8 ) alkyl, halo, hydroxy, (C 1 -C 8 ) alkoxy, amino, (C 1 -C 8 ) alkylamino, di(C 1 -C 8 ) alkylamino, SH, (C 1 -C 8 ) alkylthio, (C 3 -C 8 ) heterocyclyl, carboxylates and their esters, carboxy (C 1 -C 8 ) alkyl, CONHR C36 and CONR C36 R C37 and R C36 and R C37 are independently (C 1 -C 8 ) alkyl, (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl or (C 6 -C 10 ) aryl; optionally, R C50 and R C51 can be taken together to form a 3- to 8-membered ring; or Y 4 , O, NR C53 , S, or CR C54 R C55 or absent; R C52 is hydrogen, (C 1 -C 8 ) alkyl, (C 3 -C 8 ) cycloalkyl, (C 2 -C 8 ) alkenyl, (C 5 -C 8 ) cycloalkenyl, (C 3 -C 8 ) heterocyclyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 )aryl; wherein each (C 1 -C 8 ) alkyl, (C 3 -C 8 ) cycloalkyl, (C 2 -C 8 ) alkenyl, (C 5 -C 8 ) cycloalkenyl, (C 3 -C 8 ) heterocyclyl, (C 6 -C 10 ) aryl or (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl is (C 1 -C 8 ) alkyl, halo, hydroxy, (C 1 -C 8 ) alkoxy, amino, (C 1 -C 8 ) alkylamino, di(C 1 -C 8 ) alkylamino, SH, (C 1 -C 8 ) alkylthio, (C 3 -C 8 ) heterocyclyl, carboxylates and their esters, carboxy (C 1 -C 8 ) alkyl, CONHR C56 and CONR C56 R C57 and R C56 and R C57 are independently (C 1 -C 8 ) alkyl, (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl or (C 6 -C 10 ) aryl; R C53 is hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; R C54 and R C55 are each independently hydrogen, (C 1 -C 8 ) alkyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl; or J is hydrogen, (C 1 -C 8 ) alkyl, (C 3 -C 8 ) cycloalkyl, (C 2 -C 8 ) alkenyl, (C 5 -C 8 ) cycloalkenyl, (C 3 -C 8 ) heterocyclyl, (C 6 -C 10 ) aryl, and (C 1 -C 8 ) Alkylene (C 6 -C 10 )aryl; wherein each (C 1 -C 8 ) alkyl, (C 3 -C 8 ) cycloalkyl, (C 2 -C 8 ) alkenyl, (C 5 -C 8 ) cycloalkenyl, (C 3 -C 8 ) heterocyclyl, (C 6 -C 10 ) aryl or (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl is (C 1 -C 8 ) alkyl, halo, hydroxy, (C 1 -C 8 ) alkoxy, amino, (C 1 -C 8 ) alkylamino, di(C 1 -C 8 ) alkylamino, SH, (C 1 -C 8 ) alkylthio, (C 3 -C 8 ) heterocyclyl, carboxylates and their esters, carboxy (C 1 -C 8 ) alkyl, CONHR C46 and CONR C46 R C47 and R C46 and R C47 are independently (C 1 -C 8 ) alkyl, (C 1 -C 8 ) Alkylene (C 6 -C 10 ) aryl or (C 6 -C 10 ) aryl) The step of generating the above.

110. 109. The method of claim 108, comprising the steps of: A compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof: (In the formula, L*, M, X, D and Y 1 is as defined in claim 90; E is a spacer; Su is a sugar moiety attached to the oxygen atom via a cleavable bond; and Here, oxygen is the spacer E, Y after cleavage of the sugar moiety Su. 1 and capable of forming a ring together with phosphorus) and a receptor binding molecule (RBM) having a functional group reactive to L* of the compound of formula (IIb); thereby forming a covalent bond between the receptor binding molecule (RBM) and the linker (L), A conjugate of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof: (In the formula, RBM, L, M, X, D, Y 1 and n is as defined in claim 108; E is a spacer; Su is a sugar moiety attached to the oxygen atom via a cleavable bond; and Here, oxygen is the spacer E, Y after cleavage of the sugar moiety Su. 1 and can form a ring with phosphorus) The step of generating the above.

111. 109. The method of claim 108, comprising the steps of: A compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof: (In the formula, L*, M, X, D and Y 1 is as defined in claim 108; E is a spacer; and Z* is an optionally substituted aliphatic residue or an optionally substituted aromatic residue; Here, the sulfur bonded to the spacer E is bonded to the spacer E, Y after cleavage of the disulfide bond. 1 and capable of forming a ring together with phosphorus) and a receptor binding molecule (RBM) having a functional group reactive to L* of the compound of formula (IIc); thereby forming a covalent bond between the receptor binding molecule (RBM) and the linker (L), A conjugate of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof: (In the formula, RBM, L, M, X, D, Y 1 and n is as defined in claim 108; E is a spacer; and Z* is an optionally substituted aliphatic residue or an optionally substituted aromatic residue; Here, the sulfur bonded to the spacer E is bonded to the spacer E, Y after cleavage of the disulfide bond. 1 and can form a ring together with the phosphorus atom) The step of generating the above.

112. 109. The method of claim 108, comprising the steps of: A compound of formula (IId) or a pharmaceutically acceptable salt or solvate thereof: (In the formula, L*, M, X, D, Y 1 and E are as defined in claim 108; and R Ac1 and R Ac2 are each independently an optionally substituted aliphatic residue or an optionally substituted aromatic residue; optionally, R Ac1 and R Ac2 can form a 3- to 8-membered ring together with the oxygen and carbon atoms) and a receptor binding molecule (RBM) having a functional group reactive to L* of the compound of formula (IId); thereby forming a covalent bond between the receptor binding molecule (RBM) and the linker (L), A conjugate of formula (Id), or a pharmaceutically acceptable salt or solvate thereof: (In the formula, RBM, L, M, X, D, Y 1 , E, and n are as defined in claim 108; and R Ac1 and R Ac2 are each independently an optionally substituted aliphatic residue or an optionally substituted aromatic residue; optionally, R Ac1 and R Ac2 can form a 3- to 8-membered ring together with the oxygen and carbon atoms) The step of generating the above.

113. 109. The method of claim 108, comprising the steps of: A compound of formula (IIe), or a pharmaceutically acceptable salt or solvate thereof: (In the formula, L*, M, X, D, Y 1 and E are as defined in claim 108; and Z* is an optionally substituted aliphatic residue or an optionally substituted aromatic residue; a receptor binding molecule (RBM) having a functional group reactive to L* of the compound of formula (IIe); thereby forming a covalent bond between the receptor binding molecule (RBM) and the linker (L), A conjugate of formula (Ie), or a pharmaceutically acceptable salt or solvate thereof: (In the formula, RBM, L, M, X, D, Y 1 , E and n are as defined in claim 108; and Z* is an optionally substituted aliphatic residue or an optionally substituted aromatic residue. The step of generating the above.

114. 109. The method of claim 108, comprising the steps of: A compound of formula (IIf) or a pharmaceutically acceptable salt or solvate thereof: (In the formula, L*, M, X, D, Y 1 and E are as defined in claim 108; and Z* is an optionally substituted aliphatic residue or an optionally substituted aromatic residue; a receptor binding molecule (RBM) having a functional group reactive to L* of the compound of formula (IIe); thereby forming a covalent bond between the receptor binding molecule (RBM) and the linker (L), A conjugate of formula (If), or a pharmaceutically acceptable salt or solvate thereof: (In the formula, RBM, L, M, X, D, Y 1 , E and n are as defined in claim 108; and Z* is an optionally substituted aliphatic residue or an optionally substituted aromatic residue. The step of generating the above.

115. 115. A conjugate, or a pharmaceutically acceptable salt or solvate thereof, obtainable or obtainable by the method of any one of claims 108 to 114.

116. 116. A pharmaceutical composition comprising the conjugate of any one of claims 1 to 86 and 115.

117. 117. The pharmaceutical composition of claim 116, wherein the pharmaceutical composition comprises a population of the conjugates of any one of claims 1-86 and 115, wherein the average number of drug moieties per receptor-binding molecule in the composition is from more than 0 to about 14, preferably from about 1 to about 14, more preferably from about 2 to about 14, even more preferably from about 3 to about 14, even more preferably from about 4 to about 14, even more preferably from about 5 to about 12, even more preferably from about 6 to about 12, even more preferably from about 6 to about 10, and still more preferably about 8.

118. 118. The pharmaceutical composition of claim 116 or 117, further comprising one or more pharmaceutically acceptable carriers and / or stabilizers and / or excipients.

119. 116. The conjugate of any one of claims 1 to 86 and 115 for use in a method of treating a disease.

120. 116. The conjugate of any one of claims 1 to 86 and 115 for use in the manufacture of a medicament for treating a disease.

121. 116. The conjugate of any one of claims 1 to 86 and 115 for use as a medicament.

122. 122. The conjugate for use according to any one of claims 119 to 121, wherein the disease is cancer.

123. 119. The pharmaceutical composition of any one of claims 116 to 118 for use as a medicament or in a method of treating a disease.

124. 124. The pharmaceutical composition for use according to claim 123, wherein the disease is cancer.

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