Antibody-drug conjugates of camptothecin derivatives and their uses.

Description

1 / 99 “ANTIBODY-DRUG CONJUGATES OF CAMPTEECIN DERIVATIVES AND THEIR USES” FIELD OF THE INVENTION

[001] The present invention relates to compounds, as well as their compositions and methods of use. The compounds include camptothecin derivatives and their antibody-drug conjugates (ADCs). The compounds are useful in the treatment of various diseases, including cancer. BACKGROUND

[002] Antibody-drug conjugates (ADCs) include a payload attached to an antibody, typically via a ligand. ADCs can be used for the targeted delivery of cytotoxic agents to tumor cells. Camptothecin is a pentacyclic alkaloid that exhibits antitumor activity by inhibiting topoisomerase I. However, camptothecin and many of its derivatives have low solubility and inactivity under physiological conditions. Consequently, there is a need for novel camptothecin derivatives and antibody-drug conjugates with these novel camptothecin derivatives. SUMMARY

[003] The present disclosure provides, among others, a compound of Formula (I') Formula (I')

[004] or a pharmaceutically acceptable salt thereof, wherein the constituent variables are defined herein.

[005] This publication also provides, among other things, a Petition 870250090405, dated 03 / 10 / 2025, page 10 / 243 2 / 99 compound of Formula (II') o Formula (II')

[006] or a pharmaceutically acceptable salt thereof, wherein the constituent variables are defined herein.

[007] This publication also provides, among other things, a Formula (III')

[008] or a pharmaceutically acceptable salt thereof, wherein the constituent variables are defined herein.

[009] The present disclosure further provides methods of treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof. DESCRIPTION OF THE FIGURES

[0010] FIG. 1A illustrates a reversed-phase chromatography of a Trastuzumab-PL1 ADC.

[0011] FIG. 1B illustrates a reversed-phase chromatography of a Trastuzumab-PL3 ADC. Petition 870250090405, dated 03 / 10 / 2025, page 11 / 243 3 / 99

[0012] FIG. 1C illustrates a reversed-phase chromatography of a ADC Trastuzumab-PL9.

[0013] FIG. 1D illustrates a reversed-phase chromatograph of a ADC Trastuzumab-PL11.

[0014] FIG. 1E illustrates a reversed-phase chromatography of a ADC Trastuzumab-PL13.

[0015] FIG. 1F illustrates a reversed-phase chromatography of a ADC Trastuzumab-PL15.

[0016] FIG. 2A illustrates a size exclusion chromatography of a Trastuzumab-PL1 ADC.

[0017] FIG. 2B illustrates a size exclusion chromatography of a Trastuzumab-PL3 ADC.

[0018] FIG. 2C illustrates a size exclusion chromatography of a Trastuzumab-PL9 ADC.

[0019] FIG. 2D illustrates a size exclusion chromatography of a Trastuzumab-PL11 ADC.

[0020] FIG. 2E illustrates a size exclusion chromatography of a Trastuzumab-PL13 ADC.

[0021] FIG. 2F illustrates a size exclusion chromatography of a Trastuzumab-PL15 ADC.

[0022] FIG. 3 represents a graph of hydrophobic interaction chromatography profiles of ADCs with Trastuzumab.

[0023] FIG. 4 represents a graph showing the in vitro cytotoxicity of payloads in SK-BR-3 cell lines.

[0024] FIG. 5 represents a graph showing the in vitro cytotoxicity of ADCs with Trastuzumab in SK-BR-3 cell lines.

[0025] FIG. 6 represents a graph showing the in vivo efficacy of ADCs with Trastuzumab.

[0026] FIG. 7 shows a graph showing the change in body weight of mice. Petition 870250090405, dated 03 / 10 / 2025, page 12 / 243 4 / 99

[0027] FIG. 8 represents a graph showing the in vivo efficacy of ADCs with Trastuzumab.

[0028] FIG. 9 shows a graph showing the change in body weight of mice.

[0029] FIG. 10A illustrates a graph showing the total antibody concentration and the antibody-drug conjugate concentration over time for the ADC Trastuzumab-PL1.

[0030] FIG. 10B illustrates a graph showing the total antibody concentration and the antibody-drug conjugate concentration over time for the ADC Trastuzumab-deruxtecan.

[0031] FIG. 11 shows a graph showing the change in body weight of mice treated with Trastuzumab-PL20 ADC.

[0032] FIG. 12 illustrates the structure of Trastuzumab-PL20. DETAILED DESCRIPTION Compounds

[0033] The present disclosure provides a compound of Formula (I'):

[0034]

[0035]

[0036]

[0037] Formula (I') or a pharmaceutically acceptable salt thereof. This disclosure provides a compound of Formula (I): Formula (I) or a pharmaceutically acceptable salt thereof. where in Formula (I') and Formula (I): Petition 870250090405, dated 03 / 10 / 2025, p. 13 / 243 5 / 99

[0038] R1 is selected from H, OH, halo, C1-6 alkyl and C1-6 alkoxy;

[0039] R2 is selected from H, OH, halo, C1-6 alkyl and C1-6 alkoxy;

[0040] Q1 is S or O;

[0041] R3 is selected from OH, SH, -NH2, -NHC(=O)-Ci-6-alkylene-OH and -NHC(=S)-Ci-6-alkylene-OH;

[0042] L1 is C1-6 alkylene; and

[0043] R4 is H; or R4 together with L1 form a carbocycle of 5 to 8 members.

[0044] In some forms, the compound of Formula (I') is a compound of Formula (Ia') Formula (Ia')

[0045] or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, L1, and Q1 are as defined herein.

[0046] In some forms, the compound of Formula (I) is a compound of Formula (Ia)

[0047] or a pharmaceutically acceptable salt thereof, where R1, R2, R3, L1, and Q1 are as defined herein.

[0048] In some forms, the compound of Formula (I') is a compound of Formula (lb') Petition 870250090405, dated 03 / 10 / 2025, p. 14 / 243 6 / 99 )= / )—R R1-G / )— / 0Formula (lb')

[0049] or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and Q1 are as defined herein.

[0050] In some forms, the compound of Formula (I) is a compound of Formula (Ib)

[0051] or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and Q1 are as defined herein.

[0052] In Formula (I'), (I), (la'), (la), (lb') and (Ib), R1 can be H, OH, halo, C1-6 alkyl or C1-6 alkoxy. In some embodiments, R1 is halo. In some embodiments, R1 is fluorine, chlorine or bromine. In some embodiments, R1 is fluorine. In some embodiments, R1 is C1-6 alkyl or C1-6 alkoxy. In some embodiments, R1 is C1-6 alkyl. In some embodiments, R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl or n-hexyl. In some embodiments, R1 is methyl, ethyl, n-propyl or isopropyl. In some embodiments, R1 is methyl. In some embodiments, R1 is ethyl. In some embodiments, R1 is n-propyl. In some embodiments, R1 is isopropyl. In some embodiments, R1 is C1-6 alkoxy. In some embodiments, R1 is methoxy or ethoxy. In some embodiments, R1 is methoxy. In some embodiments, R1 is ethoxy. In some embodiments, R1 is H. In some embodiments, Petition 870250090405, dated 03 / 10 / 2025, p. 15 / 243 7 / 99 R1 is OH.

[0053] In Formula (I'), (I), (Ia'), (Ia), (Ib') and (Ib), R2 can be halo, C1-6 alkyl or C1-6 alkoxy. In some embodiments, R2 is C1-6 alkyl or C1-6 alkoxy. In some embodiments, R2 is C1-6 alkyl. In some embodiments, R2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl or n-hexyl. In some embodiments, R2 is methyl, ethyl, n-propyl or isopropyl. In some embodiments, R2 is methyl. In some embodiments, R2 is ethyl. In some embodiments, R2 is n-propyl. In some embodiments, R2 is isopropyl. In some embodiments, R2 is C1-6 alkoxy. In some embodiments, R2 is methoxy or ethoxy. In some forms, R2 is methoxy. In some forms, R2 is ethoxy. In some forms, R2 is halo. In some forms, R2 is fluorine, chlorine, or bromine.

[0054] In the formula (I'), (I), (Ia'), (Ia), (Ib') and (Ib), Q1 can be O or S. In some modalities, Q1 is O. In some modalities, Q1 is S.

[0055] In Formula (I'), (I), (Ia'), (Ia), (Ib') and (Ib), R3 can be OH, NH2, -NHC(=O)-Ci-6 alkylene-OH and -NHC(=S)-Ci-6 alkylene-OH. In some embodiments, R3 is selected from OH, -NH2, -NHC(=O)Ci-6 alkylene-OH and -NHC(=S)-Ci-6 alkylene-OH. In some embodiments, R3 is OH. In some embodiments, R3 is -NHC(=O)-Ci-6 alkylene-OH. In some embodiments, R3 is NH2.

[0056] In Formula (I'), (I), (Ia') and (Ia), L1 can be C3-4 alkylene. In some embodiments, L1 is C3-4 alkylene.

[0057] In Formula (I'), (I), (Ia') and (Ia), -L1-R3 can be CH2CH2CH2OH or -CH2CH2CH2CH2OH. In some embodiments, L1-R3 is -CH2CH2CH2OH. In some embodiments, -L1-R3 is CH2CH2CH2CH2OH.

[0058] In Formula (I') and (I), R4 can be H. In some modalities, R4 is H.

[0059] In Formula (I') and (I), R4 together with L1 can form a Petition 870250090405, dated 03 / 10 / 2025, p. 16 / 243 8 / 99 5- to 8-membered carbocycle. In some embodiments, R4 together with L1 form a 5- to 8-membered carbocycle. In some embodiments, R4 together with L1 form a 6-membered carbocycle. In some embodiments, R4 together with L1 form a 6-membered carbocycle and R3 is selected from -NH2, -NHC(=O)-C1-6 alkylene-OH and -NHC(=S)C1-6 alkylene-OH. In some embodiments, R4 together with L1 form a 6-membered carbocycle and R3 is selected from -NH2, NHC(=O)-CH2-OH and -NHC(=S)-CH2-OH.

[0060] In some embodiments, in Formula (I') and (I), R1 is selected from halo, C1-6 alkyl and C1-6 alkoxy; R2 is selected from H, OH, C1-6 alkyl and C1-6 alkoxy; Q1 is S or O; R3 is OH; L1 is C1-6 alkylene; and R4 is H.

[0061] In some embodiments, in Formula (I') and (I), R1 is halo; R2 is selected from H, OH, C1-6 alkyl and C1-6 alkoxy; Q1 is S or O; R3 is OH; L1 is C1-6 alkylene; and R4 is H.

[0062] In some embodiments, in Formula (I') and (I), R1 is fluorine; R2 is methoxy; Q1 is O; and -L1—R3 is -CH2CH2CH2OH. In some embodiments, R1 is selected from halo, C1-6 alkyl and C1-6 alkoxy; R2 is selected from H, OH, C1-6 alkyl and C1-6 alkoxy; Q1 is S or O; R3 is selected from OH, SH, -NH2, -NHC(=O)-C1-6 alkylene-OH and -NHC(=S)-C1-6 alkylene-OH; and R4 together with L1 form a 5- to 8-membered carbocycle.

[0063] In some embodiments, in Formula (I') and (I), R1 is halo; R2 is C1-6 alkyl; Q1 is S or O; R3 is selected from OH, SH, -NH2, NHC(=O)-C1-6 alkylene-OH and -NHC(=S)-C1-6 alkylene-OH; and R4 together with L1 form a carbocycle of 5 to 8 members.

[0064] In some embodiments, the compound of Formula (I'), (I), (Ia'), (Ia), (Ib') and (Ib), is a payload in an ADC.

[0065] In some forms, the compound of Formula (I') is: Petition 870250090405, dated 03 / 10 / 2025, p. 17 / 243 9 / 99 Petition 870250090405, dated 03 / 10 / 2025, p. 18 / 243 10 / 99 Petition 870250090405, dated 03 / 10 / 2025, p. 19 / 243 11 / 99

[0066] or pharmaceutically acceptable salt thereof.

[0067] In some forms, the compound of Formula (I) is: Petition 870250090405, dated 03 / 10 / 2025, p. 20 / 243 12 / 99 D5 D7 D8 D9 Petition 870250090405, dated 03 / 10 / 2025, p. 21 / 243 13 / 99

[0068] or a pharmaceutically acceptable salt thereof.

[0069] This disclosure also provides an antibody-drug conjugate comprising a drug and an antibody, wherein the drug includes a compound of Formula (I'), (I), (Ia'), (Ia), (Ib') or (Ib), or a derivative thereof. In some embodiments, the drug Petition 870250090405, dated 03 / 10 / 2025, p. 22 / 243 14 / 99 binds to the antibody via a ligand.

[0070] This disclosure also provides a compound of Formula (II')

[0071] or a pharmaceutically acceptable salt thereof.

[0072] This disclosure also provides a compound of Formula (II):

[0073] or a pharmaceutically acceptable salt thereof.

[0074] where in Formula (II') and Formula (II):

[0075] R1 is selected from halo, C1-6 alkyl and C1-6 alkoxy;

[0076] R2 is selected from H, -OH, C1-6 alkyl and C1-6 alkoxy;

[0077] Q1 is S or O;

[0078] L1 is C1-6 alkylene;

[0079] R4é H; or

[0080] R4 together with L1 forms a carbocycle of 5 to 8 members;

[0081] Q2 is selected from -S-, -O-, *-NHC(=O)-Ci-6 alkyleneO- and *-NHC(=S)-Ci-6 alkylene-O-, where the asterisk represents the point of attachment to L1;

[0082] It is a peptide that includes 2 to 10 amino acids; in which the amino acid is optionally replaced by one or more polyols;

[0083] the N-terminal of the peptide is covalently linked to Z; Petition 870250090405, dated 03 / 10 / 2025, p. 23 / 243 15 / 99

[0084] Z is -C(=O)-L2-E;

[0085] L2 is selected from C1-6 alkylene, -(CH2CH2-O)n-C1-6 alkylene-*, and -C1-6 alkylene-(O-CH2CH2)n-*;

[0086] n is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0087] the asterisk (*) represents the Y-axis attachment point; and

[0088] Y is a reactive group, preferably an electrophilic group.

[0089] In some embodiments, the compound of Formula (II') is a compound of Formula (Ha')

[0090] or a pharmaceutically acceptable salt thereof, where R1, R2, L1, Q1, Q2, E and Z are as defined herein.

[0091] In some embodiments, the compound of Formula (II) is a compound of Formula (Ha) d2 k l1-q2-ch2—nh—ez HO Π o Formula (Ha)

[0092] or a pharmaceutically acceptable salt thereof, where R1, R2, L1, Q1, Q2, E and Z are as defined herein.

[0093] In Formula (H'), (II), (Ha') and (Ha), R1 can be halo, C1-6 alkyl or C1-6 alkoxy. In some embodiments, R1 is halo. In some embodiments, R1 is fluorine, chlorine or bromine. In some embodiments, R1 is fluorine. In some embodiments, R1 is C1-6 alkyl or C1-6 alkoxy. In some embodiments, R1 is C1-6 alkyl. In some embodiments, R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl or n-hexyl. Petition 870250090405, dated 03 / 10 / 2025, p. 24 / 243 16 / 99 In some embodiments, R1 is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R1 is methyl. In some embodiments, R1 is ethyl. In some embodiments, R1 is n-propyl. In some embodiments, R1 is isopropyl. In some embodiments, R1 is C1-6 alkoxy. In some embodiments, R1 is methoxy or ethoxy. In some embodiments, R1 is methoxy. In some embodiments, R1 is ethoxy.

[0094] In Formula (II'), (II), (IIa') and (IIa), R2 can be C1-6 alkyl or C1-6 alkoxy. In some embodiments, R2 is C1-6 alkyl or C1-6 alkoxy. In some embodiments, R2 is C1-6 alkyl. In some embodiments, R2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, or n-hexyl. In some embodiments, R2 is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R2 is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R2 is methyl. In some embodiments, R2 is ethyl. In some embodiments, R2 is n-propyl. In some embodiments, R2 is isopropyl. In some embodiments, R2 is C1-6 alkoxy. In some embodiments, R2 is methoxy or ethoxy. In some embodiments, R2 is methoxy. In some embodiments, R2 is ethoxy.

[0095] In Formula (II'), (II), (IIa') and (IIa), Q1 can be O or S. In some modalities, Q1 is O. In some modalities, Q1 is S.

[0096] In Formula (II'), (II), (IIa') and (IIa), L1 can be C3-4 alkylene. In some embodiments, L1 is C3-4 alkylene.

[0097] In Formula (II'), (II), (IIa') and (IIa), Q2 can be O or S. In some modalities, Q2 is O. In some modalities, Q2 is S.

[0098] In Formula (II'), (II), (IIa') and (IIa), -L1-Q2 can be *CH2CH2CH2O- or *-CH2CH2CH2CH2O-, where the asterisk (*) represents the point of attachment to L1. In some embodiments, -L1-Q2 is *CH2CH2CH2O-, where the asterisk (*) represents the point of attachment to L1. In some embodiments, -L1-P2 is *-CH2CH2CH2CH2O-, where the asterisk (*) represents the point of attachment to L1. Petition 870250090405, dated 03 / 10 / 2025, p. 25 / 243 17 / 99

[0099] In Formula (II') and (II), R4 can be H. In some modalities, R4 is H.

[00100] In Formula (II') and (II), R4 together with L1 can form a 5- to 8-membered carbocycle. In some embodiments, R4 together with L1 form a 5- to 8-membered carbocycle. In some embodiments, R4 together with L1 form a 6-membered carbocycle. In some embodiments, R4 together with L1 form a 6-membered carbocycle and Q2 is selected from *-NHC(=O)-C1-6 alkylene-O- and *-NHC(=S)-C1-6 alkylene-O-, where the asterisk (*) represents the point of attachment to L1. In some embodiments, R4 together with L1 form a 6-membered carbocycle and Q2 is selected from *-NHC(=O)-CH2-O- and *-NHC(=S)—CH2-O-, where the asterisk (*) represents the point of attachment to L1.

[00101] In some embodiments, in Formula (II') and (II), R1 is halo; R2 is selected from H, -OH, C1-6 alkyl and C1-6 alkoxy; Q1 is S or O; R4 is H; L1 is C1-6 alkylene; Q2 is selected from -S- and -O-; E is a peptide that includes from 2 to 10 amino acids; wherein the amino acid is optionally substituted by one or more polyols; the N-terminal of the peptide is covalently linked to Z; Z is -C(=O)-L2-Y; L2 is selected from C1-6 alkylene, -(CH2CH2-O)n-C1-6 alkylene-* and -C1-6 alkylene-(O-CH2CH2)n-*; n is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; The asterisk (*) represents the point of attachment to Y; and Y is a reactive group, preferably an electrophilic group.

[00102] In some embodiments, in Formula (II') and (II), R1 is halo; R2 is C1-6 alkoxy; Q1 is O; R4 is H; L1 is C1-6 alkylene; Q2 is -O-; E is a peptide that includes from 2 to 10 amino acids; wherein the amino acid is optionally substituted by one or more polyols; the N-terminal of the peptide is covalently linked to Z; Z is -C(=O)-L2-Y; L2 is (CH2CH2-O)n-C1-6 alkylene-*; n is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; the asterisk (*) represents the point of attachment for Y; and Y is an electrophilic group. Petition 870250090405, dated 03 / 10 / 2025, p. 26 / 243 18 / 99

[00103] In Formulas (II'), (II), (IIa') and (Ila), E can be a peptide that includes 2 to 10 amino acids, and the N-terminal of the peptide is covalently linked to Z. In some embodiments, E is a peptide that includes 2 to 10 amino acids, and the N-terminal of the peptide is covalently linked to Z. In some embodiments, E is a peptide that includes 2 to 8 amino acids, and the N-terminal of the peptide is covalently linked to Z. In some embodiments, E is a peptide that includes 2 to 6 amino acids, and the N-terminal of the peptide is covalently linked to Z. In some embodiments, E is a peptide that includes 2 to 4 amino acids, and the N-terminal of the peptide is covalently linked to Z. In some embodiments, E is a peptide that includes 2 to 3 amino acids, and the N-terminal of the peptide is covalently linked to Z. In some embodiments, each amino acid in E is an L amino acid, or at least one amino acid in E is a D amino acid.In some embodiments, E includes one or more amino acids selected from glycine, alanine, valine, glutamine, glutamic acid, phenylalanine, and leucine. In some embodiments, one or more amino acids of E are replaced by one or more polyols. In some embodiments, one or more glutamines or glutamic acids of E are replaced by one or more polyols. In some embodiments, e. In some forms, E includes an amino acid with the following... OH OH structure,0. In some modalities, E is Petition 870250090405, dated 03 / 10 / 2025, p. 27 / 243 19 / 99 selected from -Ala-Val-*, -Val-Ala-*, -Gly-Gly-*, -Val-Cit-*, -Cit-Val*, -Leu-Ala-*, -Ala-Leu-*, -Leu-Cit-*, -Cit-Leu-*, -Leu-Ala-*, -Ala-Leu-*, Lys-Lys-*, -Ala-Lys-*, -Lys-Ala-*, -Val-Lys-*, -Lys-Val-*, -Tyr-Arg-*, -ArgTyr-*, -Arg-Arg-*, -Ala-Ala-*, -Phe-Lys-*, -Lys-Phe-*, -Thr-Thr-*, -ThrMet-*, -Met-Thr-*, -Met-Tyr-*, -Tyr-Met-*, -Phe-Gln-*, -Gln-Phe-*, -GlySer-*, -Leu-Gin-*, -Gin-Leu-*, -Ser-Ala-*, -Ser-Gly-*, -Val-Thr-*, -Thr-Val*, -Val-Gln-*, -Ser-Vai-*, -Vai-Ser-*, -Ala-Met-*, -Met-Ala-*, -Val-Arg-*, Arg-Val-*, -Phe-Ala-*, -Ala-Phe-*, -Cit-Val-*, -Gln-Val-*, -Phe-Arg-*, -ArgPhe-*, -Ala-Val-Glu-*, -Ala-Ala-Ala-*, -Gly-Gly-Gly-*, -Ala-Val-Ala-*, -GlyVal-Gly-*, -Ala-Val-Gly-*, -Gly-Phe-Lys-*, -Lys-Phe-Gly-*, -Leu-Ala-Leu*, -Val-Ala-Leu-*, -Leu-Ala-Val-*, -Val-Ala-Val-*, -Ala-Val-Ala-Gly-*, -GlyPhe-Gly-Gly-*, -Gly-Gly-Phe-Gly-*, -Ala-Val-Gly-Gly-*, -Ala-Ala-Ala-Ala*, -Ala-Val-Ala-Ala-*, -Ala-Leu-Ala-Leu-*, -Leu-Ala-Leu-Ala-*, -Gly-PheLeu-Gly-* and -Gly-Leu-Phe-Gly-*,in which Glu is optionally replaced by a polyol, and where (*) represents the N-terminal of peptides covalently linked to Z. In some embodiments, E is selected from -Ala-Val-*, -Val-Ala-*, -Val-Lys-*, -Val-Arg-*, -Val-Cit*, -Val-Arg-*, -Val-Cit-*, -Val-Lys-*, -Val-Arg-*, -Arg-Arg-*, -Ala-Ala-*, Ala-Lys-*, -Ala-Arg-*, -Ala-Val-Glu-*, -Ala-Ala-Ala-*, -Ala-Val-Ala-*, -AlaAla-Gly-* and -Ala-Val-Gly-*, where Glu is optionally replaced by a polyol, and where (*) represents the N-terminal of peptides covalently linked to Z. In In some embodiments, E is selected between -Ala-Val-* and -Ala-Val-Glu-*, where Glu is optionally replaced by a polyol, and where (*) represents the N-terminal of covalently Z-linked peptides. In some embodiments, E is Ala-Val-*, where (*) represents the N-terminal of covalently Z-linked peptides. In some embodiments, E is -Ala-ValGlu-*, in which Glu is replaced by a polyol.and where (*) represents the N-terminal of peptides covalently linked to Z.,

[00104] In some modalities, in Formula (II'), (II), (IIa') and (IIa), Petition 870250090405, of 03 / 10 / 2025, p. 28 / 243 20 / 99 E-NH-CH2- has one of the following structures, where (*) represents the N-terminal of the peptides covalently linked to Z: , where (*) represents the N-terminal of peptides covalently linked to Z.

[00105] In Formula (II'), (II), (IIa') and (IIa), L2 can be C1-6 alkylene, (CH2CH2-O)n-C1-6 alkylene-*, or -C1-6 alkylene-(O-CH2CH2)n-*, where n is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, and where the asterisk (*) represents the attachment point to Y. In some embodiments, L2 is C1-6 alkylene. In some embodiments, L2 is C3-6 alkylene. In some embodiments, L2 is -(CH2)5-. In some embodiments, L2 is selected from -(CH2CH2-O)n-C1-6 alkylene-* and -C1-6 alkylene-(OCH2CH2)n-*, wherein n is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, and wherein the asterisk (*) represents the point of attachment to Y. In some embodiments, n is 2, 3, 4 or 5. In some embodiments, n is 2, 3 or 4. In some embodiments, n is 3 or 4. In some embodiments, n is 4.

[00106] In Formula (II'), (II), (IIa') and (IIa), L2 can be -(CH2CH2-O)4C1-4 alkylene-* and -C1.4 alkylene-(O-CH2CH2)4-*, wherein the asterisk (*) represents the point Y-shaped attachment.In some embodiments, L2 is selected from -(CH2CH2-O)4-C1-4 alkylene-* and -C1-4 alkylene-(OCH2CH2)4-*, where the asterisk (*) represents the attachment point to Y. In some embodiments, L2 is selected from -(CH2CH2-O)4-CH2CH2* and -CH2CH2-(O-CH2CH2)4-*, and where the asterisk (*) represents the attachment point to Y.

[00107] In some categories, in Formula (II'), (II), (IIa') and (IIa), Petition 870250090405, dated 03 / 10 / 2025, p. 29 / 243 21 / 99 Y is selected from 0 eh where mi is selected from 1, 2, 3, 4, 5, or 6.

[00108] In some modalities, h is H, where mi is selected from 1, 2, 3, 4, 5, or 6.

[00109] In some modalities, in Formula (II'), (II), (IIa') and (Ila), Y is selected from 0 Petition 870250090405, dated 03 / 10 / 2025, p. 30 / 243 22 / 99

[00110] In some modalities, Y is 0

[00111] In some forms, Y is h, of preferenceHem where m1 is defined as above, more preferably h

[00112] In some categories, in Formula (II'), (II), (IIa') and (IIa),

[00113] In some categories, in Formula (II'), (II), (IIa') and (IIa), selected from In some modalities, Z is Petition 870250090405, dated 03 / 10 / 2025, p. 31 / 243 23 / 99 In some sports,

[00114] In some categories, in Formula (II'), (II), (IIa') and (IIa), -CH2-NH-EZ has one of the following structures:

[00115] In some categories, in Formula (II'), (II), (IIa') and (IIa), -CH2-NH-EZ has the following structures:

[00116] In some embodiments, the compound of Formula (II'), (II), (IIa') and (IIa) is a payload and a ligand in an ADC. Petition 870250090405, dated 03 / 10 / 2025, p. 32 / 243 24 / 99 Petition 870250090405, dated 03 / 10 / 2025, p. 33 / 243 25 / 99 Petition 870250090405, dated 03 / 10 / 2025, p. 34 / 243 26 / 99 Petition 870250090405, dated 03 / 10 / 2025, p. 35 / 243 27 / 99 PL15' PL16' PL17' PL18' Petition 870250090405, dated 03 / 10 / 2025, p. 36 / 243 28 / 99 Petition 870250090405, dated 03 / 10 / 2025, p. 37 / 243 29 / 99 Petition 870250090405, dated 03 / 10 / 2025, p. 38 / 243 30 / 99 Petition 870250090405, dated 03 / 10 / 2025, p. 39 / 243 99 / 31 PL12 Υ^»·αΥ-βΥα YYaAaA ,s T γ JAnA / / —\ ( 0 / OH 0 PL13 OH OH VVHY\ Y\ / 0 HO ^r^ γ^^^ A^ ÕH OH J iinYA0 S i Ύ Ύ} a F / a S 'ο ο x 0 / OH 0 PL14 OH OH I 1 HAA / N Ά0 ho V γ Y ÕH OH 1 / <........ ΜΑ=:7 tooo - l xaxaAa a Xi An a FN IA \ 0 / OH O PL15 OH OH Ε ΕIHΗ Nγ\ A° A. / 0 YHJ o 0 o - XÒA TA / OH O PL16 OH OH TTH x-\ Y\ A\ .0 H0^\ / γ> ÕH OH JY° sf Y hj yN-^ / AAAríí YNY A o 0 0=0 ,S XaI / Y o ρ A·^AA '? Petition 870250090405, dated 03 / 10 / 2025, p. 40 / 243 32 / 99 PL17 PL18 PL19 ou PL20

[00119] or pharmaceutically acceptable salt of the same.

[00120] This disclosure also provides an antibody-drug conjugate comprising a drug and an antibody, wherein the drug includes a compound of Formula (II'), (II), (IIa') or (IIa), or a derivative thereof.

[00121] This disclosure also provides a compound of Formula (III'): Petition 870250090405, dated 03 / 10 / 2025, p. 41 / 243 33 / 99

[00122] or a pharmaceutically acceptable salt thereof.

[00123] This disclosure also provides a compound of

[00124] or a pharmaceutically acceptable salt thereof.

[00125] where in Formula (III') and Formula (III):

[00126] C is a cell-binding agent;

[00127] R1 is selected from halo, C1-6 alkyl and C1-6 alkoxy;

[00128] R2 is selected from H, -OH, C1-6 alkyl and C1-6 alkoxy;

[00129] Q1éSouO;

[00130] L1 is C1-6 alkylene;

[00131] Q2 is selected from -S-, -O-, *-NHC(=O)-Ci-6 alkyleneO- and *-NHC(=S)-Ci-6 alkylene-O-*, where the asterisk (*) represents the point of attachment to L1;

[00132] It is a peptide that includes 2 to 10 amino acids; in which the amino acid is optionally replaced by one or more polyols;

[00133] the N-terminal of the peptide is covalently linked to Z;

[00134] Z' is -C(=O)-L2-Y',

[00135] L2 is selected from C1-6 alkylene, -(CH2CH2-O)n-C1-6 Petition 870250090405, dated 03 / 10 / 2025, page 42 / 243 34 / 99 alkylene-* and -C1-6 alkylene-(O-CH2CH2)n-*,

[00136] n is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[00137] the asterisk (*) represents the fixation point in Y';

[00138] Y' is a group formed by the reaction of an electrophilic group with a reactive nucleophilic group present in the cell-binding agent; and

[00139] p is the drug-to-antibody ratio (DAR) ep has a value between 1 and 18, for example, a value between 2 and 10, 4 and 8, 7 and 8 or 3.2 and 8.0, such as 1.2, 3, 4, 5, 6, 7, 8, 9 or 10.

[00140] In some forms, the compound of Formula (III') is a compound of Formula (IIIa'),

[00141] or a pharmaceutically acceptable salt thereof, where R1, R2, L1, Q1, Q2, E, Z' and C are as defined herein.

[00142] In some forms, the compound of Formula (III) is a

[00143] or a pharmaceutically acceptable salt thereof, where R1, R2, L1, Q1, Q2, E, Z' and C are as defined herein.

[00144] In Formula (III'), (III), (Illa') and (Illa), R1 can be halo, Ci-6 Petition 870250090405, dated 03 / 10 / 2025, p. 43 / 243 35 / 99 alkyl or C1-6 alkoxy. In some embodiments, R1 is halo. In some embodiments, R1 is fluorine, chlorine, or bromine. In some embodiments, R1 is fluorine. In some embodiments, R1 is C1-6 alkyl or C1-6 alkoxy. In some embodiments, R1 is C1-6 alkyl. In some embodiments, R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, or n-hexyl. In some embodiments, R1 is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R1 is methyl. In some embodiments, R1 is ethyl. In some embodiments, R1 is n-propyl. In some embodiments, R1 is isopropyl. In some embodiments, R1 is C1-6 alkoxy. In some embodiments, R1 is methoxy or ethoxy. In some modalities, R1 is methoxy. In some modalities, R1 is ethoxy.

[00145] In Formula (III'), (III), (IIIa') and (IIIa), R2 can be C1-6 alkyl or C1-6 alkoxy. In some embodiments, R2 is C1-6 alkyl or C1-6 alkoxy. In some embodiments, R2 is C1-6 alkyl. In some embodiments, R2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl or n-hexyl. In some embodiments, R2 is methyl, ethyl, n-propyl or isopropyl. In some embodiments, R2 is methyl. In some embodiments, R2 is ethyl. In some embodiments, R2 is n-propyl. In some embodiments, R2 is isopropyl. In some embodiments, R2 is C1-6 alkoxy. In some embodiments, R2 is methoxy or ethoxy. In some embodiments, R2 is methoxy. In some forms, R2 is ethoxy.

[00146] In Formula (III'), (III), (IIIa') and (IIIa), Q1 can be O or S. In some modalities, Q1 is O. In some modalities, Q1 is S.

[00147] In Formula (III'), (III), (IIIa') and (IIIa), L1 can be C3-4 alkylene. In some embodiments, L1 is C3-4 alkylene.

[00148] In Formula (III'), (III), (IIIa') and (IIIa), Q2 can be O or S. In some modalities, Q2 is O. In some modalities, Q2 is S.

[00149] In Formula (III'), (III), (IIIa') and (IIIa), -L1-Q2 can be *CH2CH2CH2O- or *-CH2CH2CH2CH2O-, where the asterisk (*) represents Petition 870250090405, dated 03 / 10 / 2025, p. 44 / 243 36 / 99 the attachment point to L1. In some embodiments, -L1-Q2 is *CH2CH2CH2O-, where the asterisk (*) represents the attachment point to L1. In some embodiments, -L1-P2 is *-CH2CH2CH2CH2O-, where the asterisk (*) represents the attachment point to L1.

[00150] In Formula (III') and (III), R4 can be H. In some modalities, R4 is H.

[00151] In Formula (III') and (III), R4 together with L1 can form a 5- to 8-membered carbocycle. In some embodiments, R4 together with L1 form a 5- to 8-membered carbocycle. In some embodiments, R4 together with L1 form a 6-membered carbocycle. In some embodiments, R4 together with L1 form a 6-membered carbocycle and Q2 is selected from *-NHC(=O)-C1-6 alkylene-O- and *-NHC(=S)-C1-6 alkylene-O-, where the asterisk represents the point of attachment to L1. In some embodiments, R4 together with L1 form a 6-membered carbocycle and Q2 is selected from *-NHC(=O)-CH2-O- and *-NHC(=S)CH2-O-, where the asterisk (*) represents the point of attachment to L1.

[00152] In some embodiments, in Formula (III') and (III), R1 is fluorine; R2 is C1.4 alkyl or C1-4 alkoxy; Q1 is S or O; R4 is H; L1 is C1-6 alkylene; Q2 is -S- or -O-; E is a peptide that includes from 2 to 10 amino acids; wherein the amino acid is optionally substituted by one or more polyols; the N-terminal of the peptide is covalently linked to Z'; Z' is -C(=O)L2-Y', L2 is selected from C1-6 alkylene, -(CH2CH2-O)n-C1-6 alkylene-* and -C1-6 alkylene-(O-CH2CH2)n-*, n is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; The asterisk (*) represents the point of attachment for Y'; Y' is a group formed by a reaction of an electrophilic group with a reactive nucleophilic group present in the cell-binding agent; ep is the drug-to-antibody ratio (DAR); ep has a value between 1 and 18.

[00153] In some embodiments, in Formula (III') and (III), R1 is fluorine; R2 is C1-4 alkoxy; Q1 is O; R4 is H; L1 is C1-6 alkylene; Q2 is -O-; E is a Petition 870250090405, dated 03 / 10 / 2025, p. 45 / 243 37 / 99 peptide that includes 2 to 10 amino acids; wherein the amino acid is optionally replaced by one or more polyols; the N-terminal of the peptide is covalently linked to Z'; Z' is -C(=O)-L2-Y', L2 is (CH2CH2-O)n-C1-6 alkylene-*, n is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; the asterisk (*) represents the point of attachment to Y'; Y' is a group formed by a reaction of an electrophilic group with a reactive nucleophilic group present in the cell-binding agent; ep is the drug-to-antibody ratio (DAR) ep has a value between 1 and 18.

[00154] In Formula (III'), (III), (IIIa') and (IIIa), E can be a peptide including 2 to 10 amino acids, and the N-terminal of the peptide is covalently linked to Z'. In some embodiments, E is a peptide that includes 2 to 10 amino acids, and the N-terminal of the peptide is covalently linked to Z'. In some embodiments, E is a peptide that includes 2 to 8 amino acids, and the N-terminal of the peptide is covalently linked to Z'. In some embodiments, E is a peptide that includes 2 to 6 amino acids, and the N-terminal of the peptide is covalently linked to Z'. In some embodiments, E is a peptide that includes 2 to 4 amino acids, and the N-terminal of the peptide is covalently linked to Z'. In some embodiments, E is a peptide that includes 2 to 3 amino acids, and the N-terminal of the peptide is covalently linked to Z'. In some embodiments, each amino acid of E is an L amino acid, or at least one amino acid of E is a D amino acid.In some embodiments, E includes one or more amino acids selected from glycine, alanine, valine, glutamine, glutamic acid, phenylalanine, and leucine. In some embodiments, one or more amino acids of E are replaced by one or more polyols. In some embodiments, one or more glutamines or glutamic acids of E are replaced by one or more polyols. In some embodiments, e. Petition 870250090405, dated 03 / 10 / 2025, p. 46 / 243 38 / 99 In some forms, E includes an amino acid with the following... OH OH structure,0. In some modalities, E is selected from -Ala-Val-*, -Val-Ala-*, -Gly-Gly-*, -Val-Cit-*, -Cit-Val*, -Leu-Ala-*, -Ala-Leu-*, -Leu-Cit-*, -Cit-Leu-*, -Leu-Ala-*, -Ala-Leu-*, Lys-Lys-*, -Ala-Lys-*, -Lys-Ala-*, -Val-Lys-*, -Lys-Val-*, -Tyr-Arg-*, -ArgTyr-*, -Arg-Arg-*, -Ala-Ala-*, -Phe-Lys-*, -Lys-Phe-*, -Thr-Thr-*, -ThrMet-*, -Met-Thr-*, -Met-Tyr-*, -Tyr-Met-*, -Phe-Gln-*, -Gln-Phe-*, -GlySer-*, -Leu-Gin-*, -Gin-Leu-*, -Ser-Ala-*, -Ser-Gly-*, -Val-Thr-*, -Thr-Val*, -Val-Gln-*, -Ser-Vai-*, -Vai-Ser-*, -Ala-Met-*, -Met-Ala-*, -Val-Arg-*, Arg-Val-*, -Phe-Ala-*, -Ala-Phe-*, -Cit-Val-*, -Gln-Val-*, -Phe-Arg-*, -ArgPhe-*, -Ala-Val-Glu-*, -Ala-Ala-Ala-*, -Gly-Gly-Gly-*, -Ala-Val-Ala-*, -GlyVal-Gly-*, -Ala-Val-Gly-*, -Gly-Phe-Lys-*, -Lys-Phe-Gly-*, -Leu-Ala-Leu*, -Val-Ala-Leu-*, -Leu-Ala-Val-*, -Val-Ala-Val-*, -Ala-Val-Ala-Gly-*, -GlyPhe-Gly-Gly-*, -Gly-Gly-Phe-Gly-*, -Ala-Val-Gly-Gly-*, -Ala-Ala-Ala-Ala*, -Ala-Val-Ala-Ala-*, -Ala-Leu-Ala-Leu-*, -Leu-Ala-Leu-Ala-*,-Gly-PheLeu-Gly-* and -Gly-Leu-Phe-Gly-*, wherein Glu is optionally replaced by a polyol, and where * represents the N-terminal of peptides covalently linked to Z'. In some modes, E is selected from -Ala-Val-*, -Val-Ala-*, -Val-Lys-*, -Val-Arg-*, -Val-Cit*, -Val-Arg-*, -Val-Cit-*, -Val-Lys-*, -Val-Arg-*, -Arg-Arg-*, -Ala-Ala-*, Ala-Lys-*, -Ala-Arg-*, -Ala-Val-Glu-*, -Ala-Ala-Ala-*, -Ala-Val-Ala-*, -AlaAla-Gly-*, and -Ala-Val-Gly-*, where Glu is optionally replaced. Petition 870250090405, dated 03 / 10 / 2025, page 47 / 243 39 / 99 by a polyol, and where the asterisk (*) represents the N-terminal of peptides covalently linked to Z'. In some embodiments, E is selected between -Ala-Val-* and -Ala-Val-Glu-*, where Glu is optionally replaced by a polyol, and where * represents the N-terminal of peptides covalently linked to Z'. In some embodiments, E is -Ala-Val-*, where the asterisk (*) represents the N-terminal of peptides covalently linked to Z'. In some embodiments, E is -Ala-Val-Glu-*, where Glu is replaced by a polyol, and where the asterisk (*) represents the N-terminal of peptides covalently linked to Z'.

[00155] In some embodiments, in Formula (III'), (III), (IIIa') and (IIIa), -E-NH-CH2- has one of the following structures, where the asterisk (*) represents the N-terminal of the peptides covalently linked to Z': OH OH oo = , where (*) represents the N-terminal of peptides covalently linked to Z'.

[00156] In Formula (III'), (III), (IIIa') and (IIIa), L2 can be C1-6 alkylene, -(CH2CH2-O)n-C1-6 alkylene-*, or -C1-6 alkylene-(O-CH2CH2)n-*, where n is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, and where the asterisk (*) represents the attachment point to Y'. In some embodiments, L2 is C1-6 alkylene. In some embodiments, L2 is C3-6 alkylene. In some embodiments, L2 is -(CH2)5-. In some embodiments, L2 is selected from -(CH2CH2-O)n-C1-6 alkylene-* and C1-6 alkylene-(O-CH2CH2)n-*, where n is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, and where the asterisk (*) represents the attachment point to Y'. In some embodiments, n is 2, 3, 4, or 5. In some embodiments, n is 2, 3, or 4. In some embodiments, n is 3 or 4. In some embodiments, n is 4. In some embodiments, L2 is Petition 870250090405, dated 03 / 10 / 2025, p. 48 / 243 40 / 99 selected from -(CH2CH2-O)4-C1-4 alkylene-* and -C1-4 alkylene-(OCH2CH2)4-*, where the asterisk (*) represents the attachment point to Y'. In some embodiments, L2 is selected from -(CH2CH2-O)4-CH2CH2* and -CH2CH2-(O-CH2CH2)4-*, and where the asterisk (*) represents the attachment point to Y'.

[00157] In some embodiments, in Formulas (III'), (III), (IIIa') and (IIIa), Y' is a group formed by a reaction of a reactive group, such as an electrophilic group, with another reactive group, such as a reactive nucleophilic group present in the cell-binding agent, wherein the reactive group is as defined above for group Y.

[00158] In some embodiments, in Formula (III'), (III), (IIIa') and (IIIa), Y' is a group formed by a reaction of an electrophilic group with a reactive nucleophilic group present in the cell-binding agent, wherein the electrophilic group is selected from In some modalities, Y' is a group formed by a reaction with a reactive nucleophilic group present in the cell-binding agent. In some embodiments, Y' is where the asterisk (*) represents the point of Petition 870250090405, dated 03 / 10 / 2025, page 49 / 243 41 / 99 fixing to C.

[00159] In some modalities, Y' is a group formed by a reaction of h in which mu is defined as above (from preference h) with a reactive group (such as the azide group) present in the cell-binding agent. In some embodiments, Y' is where the asterisk (*) represents the attachment point to C.

[00160] In some embodiments, in Formula (III'), (III), (IIIa') and (IIIa), the cell-binding agent is an antibody or an antigen-binding fragment thereof. In some embodiments, the cell-binding agent is a monoclonal antibody or an antigen-binding fragment thereof. In some embodiments, the antibody or antigen-binding fragment is an anti-Her2 antibody, an anti-Her3 antibody or antigen-binding fragment, an anti-C-Met antibody or antigen-binding fragment, an anti-B7H3 antibody or antigen-binding fragment, an anti-B7-H4 antibody or antigen-binding fragment, an anti-CEACAM5 antibody or antigen-binding fragment, an anti-Trop2 antibody or antigen-binding fragment and / or an anti-CEA antibody or antigen-binding fragment.In some embodiments, the antibody or antigen-binding fragment is an antibody or antigen-binding fragment against PD-1, OX40, LAG3, CD47, IL23, PCSK9, CTLA4, KRAS, OX40L, CD40, CD40L, HER2 (e.g., Trastuzumab (Herceptin®)), PDE4, FRa, PSMA, BCMA, Claudins, and / or PD-L1. In some embodiments, the antibody or a fragment of... Petition 870250090405, dated 03 / 10 / 2025, p. 50 / 243 42 / 99 antigen-binding antibody is an anti-Her2 antibody or antigen-binding fragment, an anti-Her3 antibody or antigen-binding fragment, an anti-C-Met antibody or antigen-binding fragment (for example, an antibody as disclosed in US8455623B2 or US20150147274A1, which are incorporated herein by reference in their entirety), an anti-B7-H3 antibody or antigen-binding fragment, an anti-B7-H4 antibody or antigen-binding fragment, an anti-CEACAM5 antibody or antigen-binding fragment, and / or an anti-Trop2 antibody or antigen-binding fragment. In some embodiments, the antibody is Trastuzumab.

[00161] In some embodiments, the cell-binding agent is linked to Y' by a sulfur atom of the cell-binding agent.

[00162] In some embodiments, the cell-binding agent is linked to Y' by a glycan chain of the cell-binding agent. In some embodiments, the glycan chain of the cell-binding agent is a modified glycan chain. In some embodiments, the glycan chain of the cell-binding agent comprises (preferably at the Y'-binding terminal) or consists of 2 to 10 (such as 2, 3, 4, 5, 6, 7, 8, 9 or 10) simple sugars or derivatives thereof. In some embodiments, the simple sugars or their derivatives are selected from N-acetylglucosamine (GlcNAc), fucose (Fuck), galactose (Gal), mannose (Man), glucose (Glc), N-acetylgalactosamine (GalNAc), glucuronic acid (Gcu) and N-acetylneuraminic acid (sialic acid). In some embodiments, the single sugar or its derivative is linked to other sugar(s) or its derivative(s) by means of a β(1,4)- or α(1,3)- glycosidic linkage and / or an α(1,4)- or α(1,3)- glycosidic linkage.In some embodiments, the glycan chain comprises or consists of (Fuc)bem íGlcNAcGicNAcMan where b is 0 or 1, the asterisk (*) represents the point of attachment to Y', the left terminal of the glycan chain is. Petition 870250090405, dated 03 / 10 / 2025, p. 51 / 243 43 / 99 linked to the remaining part of the cell-binding agent. In some embodiments, a glycan chain is linked to 1, 2, 3, or 4 linkage payloads. In some embodiments, the glycan chains are present at the Asn 297 glycosylation site of the heavy chains.

[00163] In some modalities, in Formula (III'), (III), (IIIa') and (IIIa), p has a value between 2-10, 4-8, 7-8 or 3.2 to 8.0.

[00164] In some embodiments, the compounds of Formula (III'), (III), (IIIa') and (IIIa) are an ADC.

[00165] In some forms, the compound of Formula (III') is: Petition 870250090405, dated 03 / 10 / 2025, p. 52 / 243 44 / 99 Petition 870250090405, dated 03 / 10 / 2025, p. 53 / 243 45 / 99 Petition 870250090405, dated 03 / 10 / 2025, p. 54 / 243 46 / 99 Petition 870250090405, dated 03 / 10 / 2025, p. 55 / 243 47 / 99 Petition 870250090405, dated 03 / 10 / 2025, p. 56 / 243 48 / 99 Petition 870250090405, dated 03 / 10 / 2025, p. 57 / 243 49 / 99 Petition 870250090405, dated 03 / 10 / 2025, p. 58 / 243 50 / 99 Petition 870250090405, dated 03 / 10 / 2025, p. 59 / 243 51 / 99

[00167] Without intending to be limited by theory, it is believed that the compounds in the disclosure have relatively good solubility and potency (in vitro inhibition of growth and / or in vivo inhibition of tumor growth) compared to camptothecin. Without wanting to limit myself to theory, it is believed that the ADCs in the present disclosure can provide a relatively good payload release rate with relatively little ADC aggregation. Furthermore, it is believed that Petition 870250090405, dated 03 / 10 / 2025, p. 60 / 243 52 / 99 the structure provides metabolic pathways to reduce the systemic toxicity of payloads after they are released into the circulatory system.

[00168] It is further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment (whereas the embodiments should be combined as if they were written in multiply dependent form). Conversely, several features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. Thus, it is contemplated that the features described as embodiments of the compounds of the present disclosure may be combined in any suitable combination.

[00169] In several places in this specification, certain characteristics of compounds are disclosed in groups or ranges. It is specifically intended that such disclosure includes each individual subcombination of the members of such groups and ranges. For example, the term “C1-6 alkyl” is specifically intended to disclose individually (without limitation) methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl.

[00170] In several places in this specification, variables defining divalent linking groups may be described. Specifically, it is intended that each linking substituent include both the forward and reverse forms of the linking substituent. For example, -NR(CR'R)n- includes both -NR(CR'R'')n- and -(CR'R'')nNR-, and it is desired to disclose each form individually. When the structure requires a linking group, the Markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists alkyl or aryl, then alkyl or aryl is understood to be a linking group. Petition 870250090405, dated 03 / 10 / 2025, p. 61 / 243 53 / 99 represents an alkylene linkage group or an arylene group, respectively.

[00171] The term substituted means that an atom or group of atoms formally replaces hydrogen as a substituent attached to another group. The term “substituted,” unless otherwise indicated, refers to any level of substitution, e.g., mono-, di-, tri-, tetra-, or penta-substitution, where such substitution is permitted. Substituents are selected independently, and substitution can occur at any chemically accessible position. It should be understood that substitution at a given atom is limited by valence. It should be understood that substitution at a given atom results in a chemically stable molecule. The phrase optionally substituted means unsubstituted or substituted. The term substituted means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent, e.g., oxo, can replace two hydrogen atoms.

[00172] The term Cn-m indicates a range that includes endpoints, where neither are integers and indicate the number of carbons. Examples include C1-4, C1-6, and similar.

[00173] The term alkyl, used alone or in combination with other terms, refers to a saturated hydrocarbon group that may be linear or branched chain. The term Cn-m alkyl refers to an alkyl group with n-m carbon atoms. An alkyl group formally corresponds to an alkane with a CH bond substituted by the alkyl group's attachment point to the rest of the compound. In some embodiments, the alkyl group contains 1 to 6 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. Examples of alkyl groups include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; homologues Petition 870250090405, dated 03 / 10 / 2025, p. 62 / 243 54 / 99 higher, such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2trimethylpropyl and the like.

[00174] The term alkylene, used alone or in combination with other terms, refers to a divalent alkyl linkage group. An alkylene group formally corresponds to an alkane with two CH bonds substituted by alkylene group point attachments to the rest of the compound. The term Cn-m alkylene refers to an alkylene group with nam carbon atoms. Examples of alkylene groups include, but are not limited to, ethan-1,2-di-yl, ethan-1,1-di-yl, propan-1,3-di-yl, propan-1,2-di-yl, propan-1,1-di-yl, butan-1,4-di-yl, butan-1,3-di-yl, butan-1,2-di-yl, 2-methyl-propan-1,3-di-yl and the like.

[00175] The term alkoxy, used alone or in combination with other terms, refers to a group of formula -O-alkyl, wherein the alkyl group is as defined above. The term Cn-m alkoxy refers to an alkoxy group whose alkyl group has n-m carbons. Examples of alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[00176] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. The compounds of the present invention containing asymmetrically substituted carbon atoms may be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds and the like may also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Isomers Petition 870250090405, dated 03 / 10 / 2025, page 63 / 243 55 / 99 cis and trans geometric forms of the compounds of the present invention are described and can be isolated as a mixture of isomers or as separate isomeric forms.

[00177] The resolution of racemic mixtures of compounds can be carried out by any of several methods known in the art. One method includes fractional recrystallization using a chiral resolving acid, which is an optically active salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or the various optically active camphorsulfonic acids such as β-camphorsulfonic acid. Other suitable resolving agents for fractional crystallization methods include stereoisomerically pure forms of α-methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

[00178] Resolution of racemic mixtures can also be performed by elution in a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). The appropriate composition of the elution solvent can be determined by a specialist in the field.

[00179] In some embodiments, the compounds of the invention have the (R)-configuration. In other embodiments, the compounds have the (S)-configuration. In compounds with more than one chiral center, each of the chiral centers in the compound can be independent (R) or (S), unless otherwise indicated.

[00180] The compounds of the invention also include tautomeric forms. Tautomeric forms result from the exchange of a bond. Petition 870250090405, dated 03 / 10 / 2025, page 64 / 243 56 / 99 simple with an adjacent double bond, along with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers, which are isomeric protonation states with the same empirical formula and total charge. Examples of prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-hisoindole, and 1H- and 2H-pyrazole. Tautomeric forms may be in equilibrium or sterically blocked in a form by appropriate substitution.

[00181] The compounds of the invention may also include all isotopes of atoms that occur in intermediate or final compounds. Isotopes include those atoms that have the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. One or more constituent atoms of the compounds of the invention may be substituted or replaced by isotopes of atoms in natural or unnatural abundance. In some embodiments, the compound includes at least one deuterium atom. For example, one or more hydrogen atoms in a compound of the present disclosure may be replaced by deuterium. In some embodiments, the compound includes two or more deuterium atoms. In some embodiments, the compound includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 deuterium atoms. Synthetic methods for including isotopes in organic compounds are known in the art (Deuterium Labeling in Organic Chemistry by Alan F. Thomas (New York, NY))., Appleton-Century-Crofts, 1971; The Renaissance of H / D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765). Isotopically labeled compounds can be used in various studies, such as. Petition 870250090405, dated 03 / 10 / 2025, page 65 / 243 57 / 99 NMR spectroscopy, metabolism experiments and / or assays.

[00182] Substitution with heavier isotopes, such as deuterium, may provide certain therapeutic advantages resulting from greater metabolic stability, for example, increased vivo half-life or reduced dosage requirements, and therefore may be preferable in some circumstances. (A. Kerekes et al. J. Med. Chem. 2011, 54, 201-210; R. Xu et al. J. Label Compd. Radiopharm. 2015, 58, 308-312).

[00183] The term compound, as used herein, is intended to include all stereoisomers, geometric isomers, tautomers and isotopes of the structures represented. The term also refers to the compounds of the inventions, regardless of how they are prepared, for example, synthetically, through a biological process (e.g., metabolism or enzymatic conversion) or a combination thereof.

[00184] All pharmaceutically acceptable compounds and their salts may be found together with other substances, such as water and solvents (e.g., hydrates and solvates), or may be isolated. When in the solid state, the compounds described herein and their salts may occur in various forms and may, for example, take the form of solvates, including hydrates. The compounds may be in any solid-state form, as a polymorph or solvate, therefore, unless clearly indicated otherwise, the reference in the specification to the compounds and their salts should be understood as encompassing any solid-state form of the compound.

[00185] In some embodiments, the compounds of the present disclosure, or their salts, are substantially isolated. By substantially isolated it is understood that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation may include, for example, an enriched composition of the compounds of the invention. Petition 870250090405, dated 03 / 10 / 2025, p. 66 / 243 58 / 99 substantial may include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97% or at least about 99% by weight of the compounds of the invention, or salts thereof.

[00186] The term pharmaceutically acceptable is used here to refer to compounds, materials, compositions and / or dosage forms that are, within the scope of good medical sense, suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic response or other problem or complication, consistent with a reasonable benefit / risk ratio.

[00187] The terms ambient temperature, as used herein, are understood in the art and generally refer to a temperature, for example, a reaction temperature, which is approximately the temperature of the environment in which the reaction is carried out, for example, a temperature of about 20°C to about 30°C.

[00188] The present invention also includes pharmaceutically acceptable salts of the compounds described herein. The term pharmaceutically acceptable salts refers to derivatives of the disclosed compounds in which the original compound is modified by converting an existing acidic or basic fraction into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, salts of mineral or organic acids from basic residues, such as amines; alkaline or organic salts from acidic residues, such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present invention include non-toxic salts of the original compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention Petition 870250090405, dated 03 / 10 / 2025, page 67 / 243 59 / 99 salts can be synthesized from the original compound containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate acid or base in water or an organic solvent, or a mixture of the two; generally, non-aqueous media such as ether, ethyl acetate, alcohols (e.g., methanol, ethanol, isopropanol, or butanol), or acetonitrile (MeCN) are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al., J. Pharm. Sci., 1977, 66(1), 1-19, and in Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002). In some embodiments, the compounds described herein include the N-oxide forms. Synthesis

[00189] The disclosure further provides a method for preparing a conjugate including a cell-binding agent and a drug (for example, a payload, such as a compound of Formula (I'), (I), (Ia'), (Ia), (Ib') or (Ib); or a payload with a ligand, such as a compound of Formula (II'), (II), (IIa') or (IIa)), the method including contacting a cell-binding agent with a compound of the disclosure such that a covalent bond is formed between the cell-binding agent and the compound. In some embodiments, the cell-binding agent is an antibody or antigen-binding fragment thereof. In some embodiments, the cell-binding agent is a monoclonal antibody or antigen-binding fragment thereof.

[00190] The disclosure further provides a conjugate including a cell-binding agent and a drug, wherein the conjugate is prepared according to the method of the disclosure. In some embodiments, the conjugate includes a cell-binding agent that is a Petition 870250090405, dated 03 / 10 / 2025, page 68 / 243 60 / 99 antibody or an antigen-binding fragment thereof. In some embodiments, the conjugate includes a cell-binding agent that is either a monoclonal antibody or an antigen-binding fragment thereof.

[00191] The compounds of the invention, including their salts, can be prepared using known organic synthesis techniques and can be synthesized according to any of the numerous possible synthetic routes, such as those in the Schemes below.

[00192] The reactions to prepare compounds of the invention can be carried out in suitable solvents that can be easily selected by a person skilled in the art of organic synthesis. Suitable solvents can be substantially non-reactive with the starting materials (reagents), intermediates or products at the temperatures at which the reactions are carried out, for example, temperatures that can range from the freezing point of the solvent to the boiling point of the solvent. A given reaction can be carried out in one solvent or in a mixture of more than one solvent. Depending on the specific reaction step, suitable solvents for a specific reaction step can be selected by the skilled technician.

[00193] The preparation of compounds of the invention may involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be easily determined by a specialist in the field. The chemistry of protecting groups is described, for example, in Kocienski, Protecting Groups, (Thieme, 2007); Robertson, Protecting Group Chemistry, (Oxford University Press, 2000); Smith et al., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th Ed. (Wiley, 2007); Peturssion et al., Protecting Groups in Carbohydrate Chemistry, J. Chem. Educ., 1997, 74(11), 1297; and Wuts et al., Protective Groups in Organic Synthesis, 4th Ed., (Wiley, 2006). Petition 870250090405, dated 03 / 10 / 2025, page 69 / 243 61 / 99

[00194] Reactions can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1H or 13C), infrared spectroscopy, spectrophotometry (e.g., UV visible), mass spectrometry, or by chromatographic methods such as high-performance liquid chromatography (HPLC) or thin-layer chromatography (TLC). Methods of Use

[00195] This disclosure provides a method for treating a cell proliferative disease or disorder or inhibiting abnormal cell growth, the method including the administration of a compound described herein, as a compound of any of Formulas (I'), (I), (Ia'), (Ia), (Ib'), (Ib), (II'), (II), (IIa), (IIa), (III'), (III), (IIIa') and (IIIa), or a pharmaceutically acceptable salt thereof. The compounds of this disclosure may be used alone, in combination with other agents or therapies, or as an adjuvant or neoadjuvant for the treatment of diseases or disorders, including cancers. For the uses described herein, any of the compounds of the disclosure, including any of its embodiments, may be used.

[00196] A method of treating a proliferative cell disease or disorder or inhibiting abnormal cell growth may include administering to a patient in need a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the proliferative cell disease or disorder or inhibiting abnormal cell growth is cancer. Examples of cancers that may be treated with the compounds of this disclosure include, but are not limited to, adenocarcinoma, brain cancer, bladder cancer, breast cancer, cervical cancer, choriocarcinoma, CNS tumor, Petition 870250090405, dated 03 / 10 / 2025, page 70 / 243 62 / 99 colon or colorectal cancer, diffuse intrinsic pontine glioma (DIPG), endometrial cancer, esophageal cancer, Ewing's sarcoma, fallopian tube cancer, gallbladder cancer, gastric cancer, glioblastoma, head and neck cancer, hematologic cancer, Hodgkin's lymphoma, renal cancer, laryngeal cancer, leukemia, liver cancer, lung cancer, lymphoma, melanoma, Merkel cell carcinoma, mesothelioma, multiple myeloma, myelodysplastic syndrome (MDS), neuroblastoma, non-Hodgkin's lymphoma, osteosarcoma, pancreatic cancer, peritoneal cancer, prostate cancer, ovarian cancer, renal cancer, rhabdomyosarcoma, salivary gland cancer, sarcoma, skin cancer, small bowel cancer, squamous cell carcinoma, testicular cancer, thyroid cancer, uterine cancer or tumor of Wilms.

[00197] In some forms, the cancer is breast cancer, lung cancer, stomach cancer, prostate cancer, pancreatic cancer, or colon cancer. Formulation, Dosage Forms and Administration

[00198] When used as a pharmaceutical product, a compound of this disclosure may be administered in the form of pharmaceutical compositions. Thus, this disclosure provides a composition that includes a compound of Formula (I'), (I), (Ia'), (Ia), (Ib'), (Ib), (II'), (II), (IIa'), (IIa), (III'), (III), (IIIa') and (IIIa) or any of the formulas described herein, a compound described herein, or a pharmaceutically acceptable salt thereof, or any embodiment thereof, and at least one pharmaceutically acceptable vehicle or excipient. The compositions may be prepared in a manner well known in the pharmaceutical art and may be administered by a variety of routes, depending on whether local or systemic treatment is indicated and the area to be treated. Administration may be topical (including transdermal, epidermal, Petition 870250090405, dated 03 / 10 / 2025, p. 71 / 243 63 / 99 ophthalmic and mucous membrane administration (including intranasal, vaginal, and rectal administration), pulmonary administration (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal administration), oral administration, or parenteral administration. Parenteral administration includes intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular, or injection or infusion; or intracranial administration, for example, intrathecal or intraventricular administration. Parenteral administration may be in the form of a single bolus dose or, for example, by a continuous infusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous, powdered, or oily bases, thickeners, and the like may be necessary or desirable.

[00199] This invention also includes pharmaceutical compositions containing, as an active ingredient, the compound of the present disclosure or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable vehicles or excipients. In some embodiments, the composition is suitable for topical administration. In the preparation of the compositions of the present disclosure, the active ingredient is typically mixed with an excipient, diluted by an excipient, or enclosed within such a vehicle in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it may be a solid, semi-solid, or liquid material that acts as a vehicle, carrier, or medium for the active ingredient.Thus, the compositions may be presented in the form of tablets, pills, powders, lozenges, sachets, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid or liquid), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, etc. Petition 870250090405, dated 03 / 10 / 2025, page 72 / 243 64 / 99 sterile injectable solutions and sterile packaged powders.

[00200] When preparing a formulation, the active compound may be milled to provide the appropriate particle size before being combined with the other ingredients. If the active compound is substantially insoluble, it may be milled to a particle size smaller than 200 mesh. If the active compound is substantially soluble in water, the particle size may be adjusted by milling to provide a substantially uniform distribution in the formulation, for example, around 40 mesh.

[00201] The compounds of the invention can be milled using known milling procedures, such as wet milling, to obtain a particle size suitable for tablet formation and other types of formulation. Finely divided (nanoparticle) preparations of the compounds of the invention can be prepared by processes known in the art, see, for example, WO 2002 / 000196.

[00202] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia gum, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. The formulations may additionally include: lubricating agents, such as talc, magnesium stearate, and mineral oil; humectants; emulsifying and suspending agents; preservatives, such as methyl and propyl hydroxybenzoates; sweetening agents; and flavoring agents. The compositions of the invention may be formulated to provide rapid, sustained, or delayed release of the active ingredient after administration to the patient, employing procedures known in the art.

[00203] In some embodiments, the pharmaceutical composition comprises silicified microcrystalline cellulose (SMCC) and at least Petition 870250090405, dated 03 / 10 / 2025, page 73 / 243 65 / 99 a compound described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the silicified microcrystalline cellulose comprises about 98% microcrystalline cellulose and about 2% silicon dioxide w / w.

[00204] In some embodiments, the composition is a sustained-release composition comprising at least one compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient. In some embodiments, the composition comprises at least one compound described herein, or a pharmaceutically acceptable salt thereof, and at least one component selected from microcrystalline cellulose, lactose monohydrate, hydroxypropylmethylcellulose, and polyethylene oxide. In some embodiments, the composition comprises at least one compound described herein, or a pharmaceutically acceptable salt thereof, and microcrystalline cellulose, lactose monohydrate, and hydroxypropylmethylcellulose. In some embodiments, the composition comprises at least one compound described herein, or a pharmaceutically acceptable salt thereof, and microcrystalline cellulose, lactose monohydrate, and polyethylene oxide.In some embodiments, the composition further comprises magnesium stearate or silicon dioxide. In some embodiments, the microcrystalline cellulose is Avicel PH102™. In some embodiments, the lactose monohydrate is Fast-flo 316™. In some embodiments, the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose 2208 K4M (e.g., Methocel K4 M Premier™) and / or hydroxypropyl methylcellulose 2208 K100LV (e.g., Methocel K00LV™). In some embodiments, the polyethylene oxide is polyethylene oxide WSR 1105 (e.g., Polyox WSR 1105™).

[00205] In some embodiments, a wet granulation process is used to produce the composition. In some embodiments, a dry granulation process is used to produce the composition. Petition 870250090405, dated 03 / 10 / 2025, page 74 / 243 66 / 99

[00206] The compositions may be formulated in a unit dosage form, each dosage containing from about 5 to about 1,000 mg (1 g). The term unit dosage forms refers to physically discrete units suitable as unit dosages for humans and other mammals, each unit containing a predetermined amount of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.

[00207] The components used to formulate pharmaceutical compositions may be of high purity and substantially free from potentially harmful contaminants (e.g., at least national food grade or a comparable standard in another country, generally at least analytical grade and, more typically, at least pharmaceutical grade). For example, suitable formulations may be sterile and / or substantially isotonic and / or in full compliance with all Good Manufacturing Practices regulations of the U.S. Food and Drug Administration or a comparable standard in another country.

[00208] The active compound may be effective over a wide dosage range and is generally administered in a therapeutically effective amount. However, it should be understood that the amount of the compound actually administered will generally be determined by a physician, according to the relevant circumstances, including the condition being treated, the chosen route of administration, the compound actually administered, the age, weight and response of the individual patient, the severity of the patient's symptoms and the like.

[00209] The therapeutic dosage of a compound of the present invention may vary according to, for example, the specific use for which the treatment is intended, the method of administration of the compound, the Petition 870250090405, dated 03 / 10 / 2025, page 75 / 243 67 / 99 The patient's health and condition and the prescribing physician's judgment. The proportion or concentration of a compound of the invention in a pharmaceutical composition may vary depending on a number of factors, including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. For example, the compounds of the invention may be supplied in an aqueous physiological buffer solution containing about 0.1 to about 10% w / v of the compound for parenteral administration. Some typical dosage ranges vary from about 1 pg / kg to about 1 g / kg of body weight per day. The dosage will likely depend on variables such as the type and extent of disease or disorder progression, the general health status of the patient in question, the relative biological efficacy of the selected compound, the excipient formulation, and its route of administration.Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model testing systems.

[00210] To prepare solid compositions, such as tablets, the main active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, the active ingredient is normally uniformly dispersed throughout the composition, so that the composition can be easily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above containing, for example, from about 0.1 to about 1000 mg of the active ingredient of the present invention.

[00211] The tablets or pills of the present invention may be coated or otherwise composed to provide a dosage form that offers the advantage of prolonged action. By Petition 870250090405, dated 03 / 10 / 2025, page 76 / 243 68 / 99 For example, the tablet or pill may comprise an internal dosage component and an external dosage component, the latter being in the form of an envelope over the former. The two components may be separated by an enteric coating that serves to resist disintegration in the stomach and allow the internal component to pass intact into the duodenum or have its release delayed. A variety of materials may be used for such enteric coatings, such materials including a range of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol and cellulose acetate.

[00212] The liquid forms in which the compounds and compositions of the present invention can be incorporated for oral or injection administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[00213] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients, as described above. In some embodiments, the compositions are administered via the oral or nasal respiratory route for local or systemic effect. The compositions may be nebulized using inert gases. Nebulized solutions may be inhaled directly from the nebulizer device, or the nebulizer device may be connected to a face mask, tent, or intermittent positive pressure breathing apparatus. Solution, suspension, or powder compositions may be administered orally or nasally from devices that deliver the formulation. Petition 870250090405, dated 03 / 10 / 2025, page 77 / 243 69 / 99 in an appropriate manner.

[00214] Topical formulations may contain one or more conventional vehicles. In some embodiments, ointments may contain water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white petrolatum and the like. The vehicle compositions of creams may be water-based in combination with glycerol and one or more other components, for example, glycerin monostearate, PEG-glycerin monostearate and cetylstearyl alcohol. Gels may be formulated using isopropyl alcohol and water, suitably in combination with other components, such as: for example, glycerol, hydroxyethylcellulose and the like. In some embodiments, the topical formulations contain at least about 0.1, at least about 0.25, at least about 0.5, at least about 1, at least about 2 or at least about 5% by weight of the compound of the invention.Topical formulations can be conveniently packaged in tubes of, for example, 100 g, which are optionally accompanied by instructions for the treatment of the selected indication, for example, psoriasis or another skin disease.

[00215] The amount of compound or composition administered to a patient will vary depending on what is being administered, the purpose of administration, such as prophylaxis or therapy, the patient's condition, the method of administration, and the like. In therapeutic applications, compositions may be administered to a patient already suffering from a disease in a quantity sufficient to cure or at least partially interrupt the symptoms of the disease and its complications. Effective doses will depend on the condition of the disease being treated, as well as the judgment of the attending physician, depending on factors such as the severity of the disease, the patient's age, weight, and general condition, among others. Petition 870250090405, dated 03 / 10 / 2025, page 78 / 243 70 / 99

[00216] The compositions administered to a patient may be in the form of pharmaceutical compositions described above. These compositions may be sterilized by conventional sterilization techniques or may be sterilely filtered. Aqueous solutions may be packaged for use as is or lyophilized, the lyophilized preparation being combined with a sterile aqueous vehicle before administration. The pH of the compound preparations will normally be between 3 and 11, more preferably between 5 and 9, and most preferably between 7 and 8. It is understood that the use of certain excipients, carriers or stabilizers mentioned above will result in the formation of pharmaceutical salts.

[00217] The therapeutic dosage of a compound of the present invention may vary according to, for example, the specific use for which the treatment is intended, the method of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the invention in a pharmaceutical composition may vary depending on a number of factors, including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. For example, the compounds of the invention may be supplied in an aqueous physiological buffer solution containing from about 0.1 to about 10% w / v of the compound for parenteral administration. The dosage will likely depend on variables such as the type and extent of disease or disorder progression, the general health status of the patient in question, the relative biological efficacy of the selected compound, the excipient formulation, and its route of administration.Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model testing systems.

[00218] In some embodiments, the pharmaceutical compositions include a compound from this disclosure and a second agent. Petition 870250090405, dated 03 / 10 / 2025, page 79 / 243 71 / 99 therapeutic. EXAMPLES Example 1. Synthesis of 15-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N ((S)-1-(((S)-1-(((3-((S)-4-ethyl-8-fluoro-4-hydroxy-9-methoxy-3-oxo-14 thioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2 b]quinolin-11-yl)propoxy)methyl)amino)-1-oxopropan-2-yl)amino)-3 methyl-1-oxobutan-2-yl)-3,6,9,12-tetraoxapentadecanamide (PL9) Benzyltrimethylammonium dichloroiodate CaCO3, 0 °C Pd(PPh3)2Cl2 3-butyn-1-ol, Cul, E3N OH Na2S MeOH 5-Fluoro-2-iodo-4-methoxyaniline (2)

[00219] To a solution of 3-fluoro-4-methoxyaniline (0.5 g, 3.5 mmol) in MeOH (4 mL) and DCM (12 mL) were added CaCO3 (0.7 g, 7.0 mmol) and benzyltrimethylammonium dichloroiodate (1.28 g, 3.7 mmol) at 0°C. The reaction mixture was stirred for 2 h at 25°C. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in DCM (20 mL) and washed with H2O (10 mL), saturated aqueous NaHCO3 (10 mL), brine (10 mL), dried over anhydrous Na2SO4 and concentrated. Petition 870250090405, dated 03 / 10 / 2025, page 80 / 243 72 / 99 under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 50:1) to give compound 2 (0.3 g, 32% yield) as a yellow solid.

[00220] LC-MS (ESI): m / z 268.0 [M+H]+. 4-(2-amino-4-fluoro-5-methoxyphenyl)but-3-yn-1-ol (3)

[00221] To a mixture of compounds 2 (0.3 g, 1.12 mmol), Pd(PPha)4 (27 mg, 0.03 mmol) and CuI (3 mg, 0.015 mmol) in Et3N (5 mL) was added 3-butyn-1-ol (0.6 g, 8.57 mmol) at room temperature under a N2 atmosphere. The reaction mixture was stirred overnight at room temperature. The mixture was diluted with EtOAc (20 mL) and washed with H2O (10 mL) and brine (10 mL x 2), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 50:1) to give compound 3 (0.17 g, 85% yield) as a yellow solid.

[00222] LC-MS (ESI): m / z 210.2 [M+H]+. -(2-amino-4-fluoro-5-methoxyphenyl)-4-hydroxybutan-1-one (4)

[00223] To a solution of compound 3 (170 mg, 0.81 mmol) in MeOH (25 mL) was added Na2S (20.4 mg, 0.26 mmol) at room temperature, followed by concentrated hydrochloric acid (1 mL, 12 M). The reaction mixture was stirred overnight at 80°C. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in DCM (20 mL). The resulting mixture was washed with H2O (10 mL) and brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 20:1) to give compound 4 (100 mg, 46% yield) as a brown oil.

[00224] LC-MS (ESI): m / z 228.4 [M+H]+. (S)-4-ethyl-8-fluoro-4-hydroxy-11-(3-hydroxypropyl)-9-methoxy-1,12-di Petition 870250090405, dated 03 / 10 / 2025, page 81 / 243 73 / 99 hydro-14H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H)dione (D1)

[00225] To a solution of compound 4 (100 mg, 0.44 mmol) and (S)-4-ethyl-4-hydroxy-7,8-dihydro-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione (117 mg, 0.44 mmol) in toluene (5 mL) was added PPTS (55 mg, 0.22 mmol) at room temperature. The reaction mixture was stirred at 120°C for 16 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH = 100:1) to give D1 (90 mg, 39% yield).

[00226] LC-MS (ESI): m / z 455.2 [M+H]+. (S)-3-(4-acetoxy-4-ethyl-8-fluoro-9-methoxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-11-yl)propyl acetate (6)

[00227] To a solution of D1 (90 mg, 0.2 mmol) and acetic anhydride (103 mg, 1 mmol) in pyridine (5 mL) was added DMAP (2.5 mg, 0.02 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure. The residue was dissolved in DCM and washed with H2O and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give compound 6 (100 mg, 0.186 mmol, 93% yield).

[00228] LC-MS (ESI): m / z 539.2 [M+H]+. (S)-3-(4-acetoxy-4-ethyl-8-fluoro-9-methoxy-3-oxo-14-thioxo-3,4,12,14tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-11yl)propyl acetate (7)

[00229] To a solution of 6 (100 mg, 0.186 mmol) in 1,4-dioxane (10 mL) was added Lawesson's reagent (150 mg, 0.372 mmol) at room temperature. The reaction mixture was stirred at 90°C for 12 h. The mixture was concentrated under reduced pressure. The residue was purified. Petition 870250090405, dated 03 / 10 / 2025, page 82 / 243 74 / 99 by silica gel chromatography (DCM / MeOH = 50:1) to give compound 7 as a yellow solid (95 mg, 0.171 mmol, 92.3% yield).

[00230] LC-MS (ESI): m / z 555.2 [M+H]+. (S)-4-ethyl-8-fluoro-4-hydroxy-11-(3-hydroxypropyl)-9-methoxy-14-thioxo12,14-dihydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-3(4H)one (D9)

[00231] Compound 7 (95 mg, 0.171 mmol) was added to concentrated hydrochloric acid (5 ml). The reaction was stirred at 90°C for 40 min. The solution was concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH = 50:1) to give D9 as a yellow solid (78 mg, 0.166 mmol, 97% yield).

[00232] LC-MS (ESI): m / z 471.1 [M+H]+. (9H-fluoren-9-yl)methyl ((S)-1 -(((S)-1 -(((3-((S)-4-ethyl-8-fluoro-4-hydroxy9-methoxy-3-oxo-14-thioxo-3,4,12,14-tetrahydro-1Hpyrano[3',4':6,7]indolizino[1,2-b]quinolin-11 yl)propoxy)methyl)amino)-1-oxopropan-2-yl)amino)-3-methyl-1oxobutan-2-yl)carbamate (9)

[00233] To a solution of D9 (78 mg, 0.17 mmol) and compound 8 (120 mg, 0.25 mmol) in 1,4-dioxane (10 mL) was added Zn(OAc)2 (25 mg, 0.14 mmol) at room temperature. The reaction mixture was stirred at 80°C for 12 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH = 50:1) to give compound 9 as a yellow solid (89 mg, 0.1 mmol, 59% yield).

[00234] LC-MS (ESI): m / z 892.3 [M+H]+. (S)-2-amino-N-((S)-1-(((3-((S)-4-ethyl-8-fluoro-4-hydroxy-9-methoxy-3oxo-14-thioxo-3,4,12,14-tetrahydro-1Hpyrano[3',4':6,7]indolizino[1,2-b]quinolin-11 yl)propoxy)methyl)amino)-1-oxopropan-2-yl)-3-methylbutanamide (10) Petition 870250090405, dated 03 / 10 / 2025, p. 83 / 243 75 / 99

[00235] Compound 9 (89 mg, 0.1 mmol) was dissolved in DCM (5 ml), then diethylamine (2 ml) was added to the solution. The reaction mixture was stirred at room temperature for 4 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH = 10:1) to give compound 10 as a yellow solid (62 mg, 0.092 mmol, 92% yield).

[00236] LC-MS (ESI): m / z 670.3 [M+H]+. 15-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-((S)-1 -(((S)-1 -(((3-(((S)-4ethyl-8-fluoro-4-hydroxy-9-methoxy-3-oxo-14-thioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-11yl)propoxy)methyl)amino)-1 -oxopropan-2-yl)amino)-3-methyl-1oxobutan-2-yl)-3,6,9,12-tetraoxapentadecanamide (PL9)

[00237] To a solution of compound 10 (62 mg, 0.092 mmol) and Mal-Peg4-NHS ester (49 mg, 0.11 mmol) in DCM (10 mL), triethylamine (25 mg, 0.25 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 12 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH = 20:1) to give PL9 as a yellow solid (35 mg, 0.035 mmol, 38% yield).

[00238] LC-MS (ESI): m / z 997.4 [M+H]+. Example 2. (S)-2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1yl)hexanamido)-N1-((S)-1 -(((S)-1 -(((3-((S)-4-ethyl-8-fluoro-4-hydroxy-9methoxy-3-oxo-14-thioxo-3,4,12,14-tetrahydro-1Hpyrano[3',4':6,7]indolizino[1,2-b]quinolin-11yl)propoxy)methyl)amino)-1 -oxopropan-2-yl)amino)-3-methyl-1oxobutan-2-yl)-N5-((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)pentanediamide (PL15) Petition 870250090405, dated 03 / 10 / 2025, p. 84 / 243 76 / 99

[00239] A solution of compound 10 (50 mg, 0.075 mmol) and compound 11 (38 mg, 0.075 mmol) in DCM (10 mL), EDCI (18 mg, 0.09 mmol) and HOBt (12 mg, 0.09 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 30 min. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to give PL15 as a yellow solid (10 mg, 0.009 mmol, yield 11.6%).

[00240] LC-MS (ESI): m / z 1155.4 [M+H]+. Example 3. (5S,8S)-1 -(9H-fluoren-9-yl)-5-isopropyl-8-methyl-3,6,9trioxo-2-oxa-4,7,10-triazaundecan-11-yl acetate (8) tert-butyl (((9H-fluoren-9-yl)methoxy)carbonyl)-L-valyl-L-alanylglycinate (11)

[00241] To a solution of (((9H-fluoren-9-yl)methoxy)carbonyl)-L-valylL-alanine (4.1 g, 10 mmol) and tert-butyl glycinate (1.31 g, 10 mmol) in DCM (50 mL) was added EDCI (2.36 g, 12 mmol) and HOBt (1.57 g, 12 mmol) at room temperature. The reaction mixture was stirred at room temperature for 5 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH = 50:1) to give compound 11 as a solid. Petition 870250090405, dated 03 / 10 / 2025, p. 85 / 243 77 / 99 whitish (4.4 g, 8.5 mmol, 84% yield).

[00242] LC-MS (ESI): m / z 524.3 [M+H]+. (((9H-fluoren-9-yl)methoxy)carbonyl)-L-valyl-L-alanylglycine (12)

[00243] Compound 11 (1 g, 1.9 mmol) was added to TFA (10 mL) and stirred at room temperature for 15 min. The mixture was concentrated under reduced pressure to give compound 12 as a light yellow oil (0.89 g, 1.9 mmol, 100% yield).

[00244] LC-MS (ESI): m / z 466.2 [M+H]-. (5S,8S)-1-(9H-fluoren-9-yl)-5-isopropyl-8-methyl-3,6,9-trioxo-2-oxa4,7,10-triazaundecan-11-yl acetate (8)

[00245] To a mixture of compounds 12 (0.89 g, 1.9 mmol) in THF (15 mL) and toluene (5 mL) were added pyridine (0.18 mL, 2.27 mmol) and Pb(OAc)4 (1 g, 2.27 mmol). The reaction mixture was refluxed for 5 h. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 30:1) to give compound 8 (0.8 g, yield 87%) as a colorless solid.

[00246] LC-MS (ESI): m / z 482.2 [M+H]+. Exemplo 4. Síntese de 15-(2,5-dioxo-2,5-di-hidro-1H-pirrol-1-il)-N((S)-1-(((S)-1-(((3-((S)-4-ethyl-8-fluoro-4-hidróxi-9-metóxi-3,14-dioxo3,4,12,14-tetra-hidro-1H-pirano[3',4':6,7]indolizino[1,2-b]quinolin11 -il)propóxi)metil)amino)-1 -oxopropan-2-il)amino)-3-metil-1 oxobutan-2-il)-3,6,9,12-tetraoxapentadecanamida (PL1) Petition 870250090405, 03 / 10 / 2025, pág. 86 / 243 78 / 99 (9H-fluoren-9-yl)methyl ((S)-1 -(((S)-1 -(((3-((S)-4-ethyl-8-fluoro-4-hydroxy9-methoxy-3,14-dioxo-3,4,12,14-tetra-hydro-1Hpyrano[3',4':6,7]indolizino[1,2-b]quinolin-11 yl)propoxy)methyl)amino)-1 -oxopropan-2-yl)amino)-3-methyl-1oxobutan-2-yl)carbamate (13)

[00247] To a solution of D1 (50 mg, 0.11 mmol) and compound 8 (79 mg, 0.25 mmol) in 1,4-dioxane (10 mL) was added Zn(OAc)2 (16 mg, 0.088 mmol) at room temperature. The reaction mixture was stirred at 80°C for 12 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH = 50:1) to give compound 9 as a yellow solid (55 mg, 0.062 mmol, 57% yield).

[00248] LC-MS (ESI): m / z 876.3 [M+H]+. (S)-2-amino-N-((S)-1-(((3-((S)-4-ethyl-8-fluoro-4-hydroxy-9-methoxy3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2b]quinolin-11-yl)propoxy)methyl)amino)-1 -oxopropan-2-yl)-3methylbutanamide (14)

[00249] Compound 13 (55 mg, 0.062 mmol) was dissolved in DCM (5 ml), then diethylamine (2 ml) was added to the solution. The reaction mixture was stirred at room temperature for 4 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH = 10:1) to give compound 14 as a yellow solid (37 mg, 0.057 mmol, yield Petition 870250090405, dated 03 / 10 / 2025, p. 87 / 243 79 / 99 (92%).

[00250] LC-MS (ESI): m / z 654.3 [M+H]+. 15-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-((S)-1 -(((S)-1 -(((3-((S)-4ethyl-8-fluoro-4-hydroxy-9-methoxy-3,14-dioxo-3,4,12,14-tetrahydro-1Hpyrano[3',4':6,7]indolizino[1,2-b]quinolin-11yl)propoxy)methyl)amino)-1 -oxopropan-2-yl)amino)-3-methyl-1oxobutan-2-yl)-3,6,9,12-tetraoxapentadecanamide (PL1)

[00251] To a solution of compound 14 (37 mg, 0.057 mmol) and Mal-Peg4-NHS ester (30 mg, 0.068 mmol) in DCM (10 mL) was added triethylamine (11 mg, 0.114 mmol) at room temperature. The reaction mixture was stirred at room temperature for 12 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH = 20:1) to give PL1 as a white solid (24 mg, 0.024 mmol, 42% yield).

[00252] LC-MS (ESI): m / z 981.4 [M+H]+. Example 5. 15-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-((S)-1 -(((S)-1 (((3-((S)-4-ethyl-8-fluoro-4-hydroxy-9-methyl-3-oxo-14-thioxo-3,4,12,14tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-11yl)propoxy)methyl)amino)-1 -oxopropan-2-yl)amino)-3-methyl-1oxobutan-2-yl)-3,6,9,12-tetraoxapentadecanamide (PL11) Benzyltrimethylammonium dichloroiodate Petition 870250090405, dated 03 / 10 / 2025, p. 88 / 243 80 / 99 Benzyltrimethylammonium dichloroiodate CaCO3, 0°C Lawessen reagent Ester Mal-peg4-NHS 5-fluoro-2-iodo-4-methylaniline (16)

[00253] To a solution of compound 15 (0.44 g, 3.5 mmol) in MeOH (4 mL) and DCM (12 mL) were added CaCO3 (0.7 g, 7.0 mmol) and benzyltrimethylammonium dichloroiodate (1.28 g, 3.7 mmol) at 0°C. The reaction mixture was stirred for 2 h at 25°C. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in DCM (20 mL) and washed with H2O (10 mL), saturated aqueous NaHCO3 (10 mL), brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 50:1) to give compound 16 (0.28 g, 32% yield) as a yellow solid.

[00254] LC-MS (ESI): m / z 252.0 [M+H]+. 4-(2-amino-4-fluoro-5-methylphenyl)but-3-yn-1-ol (17)

[00255] To a mixture of compounds 16 (0.28 g, 1.12 mmol), Pd(PPh3)4 (27 mg, 0.03 mmol) and Cul (3 mg, 0.015 mmol) in Et3N (5 mL) Petition 870250090405, dated 03 / 10 / 2025, p. 89 / 243 81 / 99 3-butyn-1-ol (0.6 g, 8.57 mmol) was added at room temperature under N2 atmosphere. The reaction mixture was stirred overnight at room temperature. The mixture was diluted with EtOAc (20 mL) and washed with H2O (10 mL) and brine (10 mL x 2), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 50:1) to give compound 17 (0.183 g, 85% yield) as a yellow solid.

[00256] LC-MS (ESI): m / z 194.2 [M+H]+. -(2-amino-4-fluoro-5-methylphenyl)-4-hydroxybutan-1-one (18)

[00257] To a solution of compound 17 (183 mg, 0.95 mmol) in MeOH (25 mL) was added Na2S (20.4 mg, 0.26 mmol) at room temperature and then concentrated hydrochloric acid (1 mL). The reaction mixture was stirred overnight at 80°C. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in DCM (20 mL). The resulting mixture was washed with H2O (10 mL) and brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 20:1) to give compound 18 (93 mg, 46% yield) as a brown solid.

[00258] LC-MS (ESI): m / z 212.4 [M+H]+. (S)-4-ethyl-8-fluoro-4-hydroxy-11-(3-hydroxypropyl)-9-methyl-1,12-dihydro-14H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H)dione (D6)

[00259] To a solution of compound 18 (93 mg, 0.44 mmol) and (S)-4-ethyl-4-hydroxy-7,8-dihydro-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione (117 mg, 0.44 mmol) in toluene (5 mL) were added PPTS (55 mg, 0.22 mmol) at room temperature. The reaction mixture was stirred at 120°C for 16 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by Petition 870250090405, dated 03 / 10 / 2025, p. 90 / 243 82 / 99 silica gel chromatography (DCM / MeOH = 100:1) to provide D6 (87 mg, 39% yield).

[00260] LC-MS (ESI): m / z 439.2 [M+H]+. Propyl (S)-3-(4-acetoxy-4-ethyl-8-fluoro-9-methyl-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-11-yl)acetate (19)

[00261] To a solution of D6 (87 mg, 0.2 mmol) and acetic anhydride (103 mg, 1 mmol) in pyridine (5 mL) was added DMAP (2.5 mg, 0.02 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure. The residue was dissolved in DCM and washed with H2O and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give compound 19 (97 mg, 0.186 mmol, 93% yield).

[00262] LC-MS (ESI): m / z 523.2 [M+H]+. (S)-3-(4-acetoxy-4-ethyl-8-fluoro-9-methyl-3-oxo-14-thioxo-3,4,12,14tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-11yl)propyl acetate (20)

[00263] To a solution of 19 (97 mg, 0.186 mmol) in 1,4-dioxane (10 mL) was added Lawesson's reagent (145 mg, 0.372 mmol) at room temperature. The reaction mixture was stirred at 90°C for 12 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH = 50:1) to give compound 20 as a yellow solid (92 mg, 0.171 mmol, yield 92.3%).

[00264] LC-MS (ESI): m / z 539.2 [M+H]+. (S)-4-ethyl-8-fluoro-4-hydroxy-11-(3-hydroxypropyl)-9-methyl-14-thioxo12,14-dihydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-3(4H)one(D10)

[00265] Compound 20 (92 mg, 0.171 mmol) was added to the acid Petition 870250090405, dated 03 / 10 / 2025, page 91 / 243 83 / 99 concentrated hydrochloric acid (5 ml). The reaction was stirred at 90°C for 40 min. The solution was concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH = 50:1) to give D10 as a yellow solid (75 mg, 0.166 mmol, 97% yield).

[00266] LC-MS (ESI): m / z 455.1 [M+H]+. (9H-fluoren-9-yl)methyl ((S)-1 -(((S)-1 -(((3-((S)-4-ethyl-8-fluoro-4-hydroxy9-methyl-3-oxo-14-thioxo-3,4,12,14-tetrahydro-1Hpyrano[3',4':6,7]indolizino[1,2-b]quinolin-11 yl)propoxy)methyl)amino)-1-oxopropan-2-yl)amino)-3-methyl-1oxobutan-2-yl)carbamate (21)

[00267] To a solution of D10 (75 mg, 0.166 mmol) and compound 8 (120 mg, 0.25 mmol) in 1,4-dioxane (10 mL) was added Zn(OAc)2 (25 mg, 0.14 mmol) at room temperature. The reaction mixture was stirred at 80°C for 12 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH = 50:1) to give compound 21 as a yellow solid (87 mg, 0.1 mmol, 59% yield).

[00268] LC-MS (ESI): m / z 876.3 [M+H]+. (S)-2-amino-N-((S)-1 -(((3-((S)-4-ethyl-8-fluoro-4-hydroxy-9-methyl-3-oxo14-thioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2b]quinolin-11-yl)propoxy)methyl)amino)-1 -oxopropan-2-yl)-3methylbutanamide (22)

[00269] Compound 21 (87 mg, 0.1 mmol) was dissolved in DCM (5 mL), then diethylamine (2 mL) was added to the solution. The reaction mixture was stirred at room temperature for 4 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH = 10:1) to give compound 22 as a yellow solid (60 mg, 0.092 mmol, 92% yield).

[00270] LC-MS (ESI): m / z 654.3 [M+H]+. Petition 870250090405, dated 03 / 10 / 2025, p. 92 / 243 84 / 99 15-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-((S)-1 -(((S)-1 -(((3-((S)-4ethyl-8-fluoro-4-hydroxy-9-methyl-3-oxo-14-thioxo-3,4,12,14-tetrahydro1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-11yl)propoxy)methyl)amino)-1 -oxopropan-2-yl)amino)-3-methyl-1oxobutan-2-yl)-3,6,9,12-tetraoxapentadecanamide (PL11)

[00271] To a solution of compound 22 (60 mg, 0.092 mmol) and Mal-Peg4-NHS ester (49 mg, 0.11 mmol) in DCM (10 mL) was added triethylamine (25 mg, 0.25 mmol) at room temperature. The reaction mixture was stirred at room temperature for 12 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH = 20:1) to give PL11 as a yellow solid (34 mg, 0.035 mmol, 38% yield).

[00272] LC-MS (ESI): m / z 981.4 [M+H]+. Example 6. (S)-2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1yl)hexanamido)-N1-((S)-1 -(((S)-1 -(((3-((S)-4-ethyl-8-fluoro-4-hydroxy-9methyl-3-oxo-14-thioxo-3,4,12,14-tetrahydro-1Hpyrano[3',4':6,7]indolizino[1,2-b]quinolin-11yl)propoxy)methyl)amino)-1 -oxopropan-2-yl)amino)-3-methyl-1oxobutan-2-yl)-N5-((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)pentanediamide (PL13)

[00273] To a solution of compound 22 (48.8 mg, 0.075 mmol) and compound 11 (38 mg, 0.075 mmol) in DCM (10 mL) was added EDCI (18 mg, 0.09 mmol) and HOBt (12 mg, 0.09 mmol) at room temperature. The reaction mixture was stirred at room temperature for 30 min. The mixture was concentrated under reduced pressure. The residue was purified. Petition 870250090405, dated 03 / 10 / 2025, p. 93 / 243 85 / 99 by HPLC preparation to provide PL13 as a yellow solid (9.9 mg, 0.009 mmol, yield of 11.6%).

[00274] LC-MS (ESI): m / z 1139.4 [M+H]+. Example 7. 15-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-((S)-1 -(((S)-1 (((3-((S)-4-ethyl-8-fluoro-4-hydroxy-9-methyl-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-11yl)propoxy)methyl)amino)-1 -oxopropan-2-yl)amino)-3-methyl-1oxobutan-2-yl)-3,6,9,12-tetraoxapentadecanamide (PL3) (9H-fluoren-9-yl)methyl ((S)-1 -(((S)-1 -(((3-((S)-4-ethyl-8-fluoro-4-hydroxy9-methyl-3,14-dioxo-3,4,12,14-tetrahydro-1Hpyrano[3',4':6,7]indolizino[1,2-b]quinolin-11 yl)propoxy)methyl)amino)-1-oxopropan-2-yl)amino)-3-methyl-1oxobutan-2-yl)carbamate (23)

[00275] To a solution of D6 (48 mg, 0.11 mmol) and compound 8 (79 mg, 0.25 mmol) in 1,4-dioxane (10 mL) was added Zn(OAc)2 (16 mg, 0.088 mmol) at room temperature. The reaction mixture was stirred at 80°C for 12 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH = 50:1) to give compound 23 as a yellow solid (54 mg, 0.062 mmol, 57% yield).

[00276] LC-MS (ESI): m / z 860.3 [M+H]+. (S)-2-amino-N-((S)-1-(((3-((S)-4-ethyl-8-fluoro-4-hydroxy-9-methyl-3,14 Petition 870250090405, dated 03 / 10 / 2025, p. 94 / 243 86 / 99 dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2b]quinolin-11-yl)propoxy)methyl)amino)-1-oxopropan-2-yl)-3methylbutanamide (24)

[00277] Compound 23 (54 mg, 0.062 mmol) was dissolved in DCM (5 ml), then diethylamine (2 ml) was added to the solution. The reaction mixture was stirred at room temperature for 4 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH = 10:1) to give compound 24 as a yellow solid (36 mg, 0.057 mmol, 92% yield).

[00278] LC-MS (ESI): m / z 638.3 [M+H]+. 15-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-((S)-1 -(((S)-1 -(((3-((S)-4ethyl-8-fluoro-4-hydroxy-9-methyl-3,14-dioxo-3,4,12,14-tetrahydro-1Hpyrano[3',4':6,7]indolizino[1,2-b]quinolin-11yl)propoxy)methyl)amino)-1 -oxopropan-2-yl)amino)-3-methyl-1oxobutan-2-yl)-3,6,9,12-tetraoxapentadecanamide (PL3)

[00279] To a solution of compound 24 (36 mg, 0.057 mmol) and Mal-Peg4-NHS ester (30 mg, 0.068 mmol) in DCM (10 mL) was added triethylamine (11 mg, 0.114 mmol) at room temperature. The reaction mixture was stirred at room temperature for 12 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH = 20:1) to give PL3 as a white solid (23.6 mg, 0.024 mmol, 42% yield).

[00280] LC-MS (ESI): m / z 965.4 [M+H]+. Example 8. (S)-4-ethyl-8-fluoro-4-hydroxy-11-(3-hydroxypropyl)-1,12-dihydro-14H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H)dione (D5) Petition 870250090405, dated 03 / 10 / 2025, p. 95 / 243 87 / 99 4-(2-amino-4-fluorophenyl)but-3-yn-1-ol (25)

[00281] To a mixture of 5-fluoro-2-iodoaniline (0.265 g, 1.12 mmol), Pd(PPha)4 (27 mg, 0.03 mmol) and CuI (3 mg, 0.015 mmol) in EtaN (5 mL) was added 3-butyn-1-ol (0.6 g, 8.57 mmol) at room temperature under a N2 atmosphere. The reaction mixture was stirred overnight at room temperature. The mixture was diluted with EtOAc (20 mL) and washed with H2O (10 mL) and brine (10 mL x 2), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 50:1) to give compound 25 (0.146 g, 85% yield) as a yellow solid.

[00282] LC-MS (ESI): m / z 180.2 [M+H]+. 1-(2-amino-4-fluorophenyl)-4-hydroxybutan-1-one (26)

[00283] To a solution of compound 25 (146 mg, 0.81 mmol) in MeOH (25 mL) was added Na2S (20.4 mg, 0.26 mmol) at room temperature, followed by the addition of concentrated hydrochloric acid (1 mL). The reaction mixture was stirred overnight at 80°C. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in DCM (20 mL). The resulting mixture was washed with H2O (10 mL) and brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by Petition 870250090405, dated 03 / 10 / 2025, page 96 / 243 88 / 99 silica gel column chromatography (DCM / MeOH = 20:1) to give compound 26 (87 mg, 46% yield) as a brown oil.

[00284] LC-MS (ESI): m / z 198.4 [M+H]+. (S)-4-ethyl-8-fluoro-4-hydroxy-11-(3-hydroxypropyl)-1,12-dihydro-14Hpyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H)-dione (D5)

[00285] To a solution of compound 26 (87 mg, 0.44 mmol) and (S)-4-ethyl-4-hydroxy-7,8-dihydro-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione (117 mg, 0.44 mmol) in toluene (5 mL) was added PPTS (55 mg, 0.22 mmol) at room temperature. The reaction mixture was stirred at 120 °C for 16 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH = 100:1) to give D5 (84 mg, 39% yield).

[00286] LC-MS (ESI): m / z 455.2 [M+H]+. Example 9. N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo2,3,9,10,13,15-hexahydro-1H,12H benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-2 hydroxyethanethioamide (D11) and N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4 methyl-10-oxo-13-thioxo-2,3,9,10,13,15-hexahydro-1H,12H benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-2hydroxyacetamide (D12) 2-(((1S,9S)-9-acetoxy-9-ethyl-5-fluoro-4-methyl-10,13-dioxo Petition 870250090405, dated 03 / 10 / 2025, page 97 / 243 89 / 99 2,3,9,10,13,15-hexahydro-1H,12Hbenzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)amino)-2oxoethyl acetate (27)

[00287] To a solution of Dxd (98 mg, 0.2 mmol) and acetic anhydride (103 mg, 1 mmol) in pyridine (5 mL) was added DMAP (2.5 mg, 0.02 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure. The residue was dissolved in DCM and washed with H2O and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give compound 27 (100 mg, 0.186 mmol, 93% yield).

[00288] LC-MS (ESI): m / z 577.2 [M+H]+. 2-(((1S,9S)-9-acetoxy-9-ethyl-5-fluoro-4-methyl-10,13-dioxo2,3,9,10,13,15-hexahydro-1H,12Hbenzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)amino)-2acetate thioxoethyl / 2-(((1S,9S)-9-acetoxy-9-ethyl-5-fluoro-4-methyl-10oxo-13-thioxo-2,3,9,10,13,15-hexahydro-1H,12Hbenzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)amino)-2acetate oxoethyl (28 / 29)

[00289] To a solution of 27 (100 mg, 0.186 mmol) in 1,4-dioxane (10 mL), Lawesson's reagent (145 mg, 0.372 mmol) was added at room temperature. The reaction mixture was stirred at 90°C for 12 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH = 50:1) to give the compound 28 and 29 mixture as a yellow solid (94 mg, 47:53, 0.171 mmol, yield 92.3%).

[00290] LC-MS (ESI): m / z 594.2 [M+H]+. (S)-4-ethyl-8-fluoro-4-hydroxy-11-(3-hydroxypropyl)-9-methyl-14-thioxo12,14-dihydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-3(4H)one(D11e D12) Petition 870250090405, dated 03 / 10 / 2025, page 98 / 243 90 / 99

[00291] The Compound 28 and 29 mixture (94 mg, 0.171 mmol) was added to concentrated hydrochloric acid (5 ml). The reaction was stirred at 90°C for 40 min. The solution was concentrated under reduced pressure. The residue was purified by preparative HPLC to give D11 (12 mg) and D12 (15 mg) as a yellow solid (total yield 31%).

[00292] LC-MS (ESI): m / z 510.1 [M+H]+. Example 10. (1S,9S)-1-amino-9-ethyl-5-fluoro-9-hydroxy-4-methyl-13thioxo-1,2,3,9,13,15-hexahydro-10H,12H benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-10-one (D13) (9H-fluoren-9-yl)methyl ((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12Hbenzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)carbamate (30)

[00293] To a solution of exatecane (100 mg, 0.23 mmol) and Fmoc chloride (89 mg, 0.344 mmol) in 1,4-dioxane (10 mL) was added DIPEA (0.2 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH = 100:1) to give compound 30 as a white solid (127 mg, 84% yield).

[00294] LC-MS (ESI): m / z 658.2 [M+H]+. (1S,9S)-1-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-9-ethyl-5-fluoroPetition 870250090405, of 03 / 10 / 2025, p. 99 / 243 91 / 99 4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12Hbenzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl acetate (31)

[00295] To a solution of 30 (127 mg, 0.19 mmol) and acetic anhydride (103 mg, 1 mmol) in pyridine (5 mL) was added DMAP (2.5 mg, 0.02 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure. The residue was dissolved in DCM and washed with H2O and brine, dried over Na2SO4 and concentrated under reduced pressure to give compound 31 (126 mg, 0.18 mmol, 95% yield).

[00296] LC-MS (ESI): m / z 700.2 [M+H]+. (1S,9S)-1-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-9-ethyl-5-fluoro-4-methyl-10-oxo-13-thioxo-2,3,9,10,13,15-hexahydro-1H,12Hbenzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl acetate (32)

[00297] To a solution of 31 (126 mg, 0.18 mmol) in 1,4-dioxane (10 mL) was added Lawesson's reagent (145 mg, 0.372 mmol) at room temperature. The reaction mixture was stirred at 90°C for 12 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH = 50:1) to give compound 32 mixture as a yellow solid (111 mg, 0.155 mmol, yield 86.5%).

[00298] LC-MS (ESI): m / z 716.2 [M+H]+. (9H-fluoren-9-yl)methyl ((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10oxo-13-thioxo-2,3,9,10,13,15-hexahydro-1H,12Hbenzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)carbamate (33)

[00299] Compound 32 (111 mg, 0.155 mmol) was added to concentrated hydrochloric acid (5 ml). The reaction was stirred at 90°C for 40 min. The solution was concentrated under reduced pressure. The residue was purified by preparative HPLC to give compound 33 (100 mg, 0.15 mmol, 98% yield). Petition 870250090405, dated 03 / 10 / 2025, pp. 100 / 243 92 / 99

[00300] LC-MS (ESI): m / z 659.1 [M+H]+. (1S,9S)-1-amino-9-ethyl-5-fluoro-9-hydroxy-4-methyl-13-thioxo1,2,3,9,13,15-hexahydro-10H,12H benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-10-one (D13)

[00301] Compound 33 (20 mg, 0.03 mmol) was dissolved in DCM (5 ml), then diethylamine (2 ml) was added to the solution. The reaction mixture was stirred at room temperature for 4 h. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to give D13 as a yellow solid (8 mg, 0.018 mmol, 59% yield). LC-MS (ESI): m / z 452.2 [M+H]+. Example 11. ((1R,8S,9s)-bicyclo[6.1.0]non-4-yn-9-yl)methyl ((16S,19S)26-((S)-4-ethyl-8-fluoro-4-hydroxy-9-methoxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-11-yl)-16 isopropyl-19-methyl-14,17,20-trioxo-3,6,9,12,23-pentaoxa-15,18,21triazahexacosyl)carbamate (PL20) VH j? H2N'n< Ξ Η > BCN-peg4-NHS Ester ”0 0H0 IA / V H H II 1 H > κυη' k \ Ο / OHOPL2° Τ ϊ ΧζΥ λ Ο / ΟΗ Ο

[00302] To a solution of compound 14 (20 mg, 0.031 mmol) and endo-BCN-PEG4-NHS ester (16.5 mg, 0.031 mmol) in DMF (1 mL) was added DIPEA (15.8 mg, 0.12 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1.5 h. The mixture was diluted with acetonitrile (1 mL). The mixture was purified by preparative HPLC to give PL20 as a yellow solid (3 mg, 0.0028 mmol, 9% yield). LC-MS (ESI): m / z 1077.5 [M+H]+. Example 12. Conjugation Method A

[00303] Trastuzumab solution (<10 mg / mL in histidine buffer) Petition 870250090405, dated 03 / 10 / 2025, page 101 / 243 The concentration of 93 / 99 mM, pH 6.5, was reduced with a certain amount (12 eq.) of TCEP. The mixture was incubated in a water bath at 30°C for 1 hour. In the conjugation reaction, 10% (v / v) DMSO was added to the Trastuzumab solution, followed by the addition of DMSO PL1 solution. The reaction was maintained away from light at 30°C in a rotary mixer for 1.5 hours. The ADC sample was purified by Spin Zebm™ desalting columns to remove excess ligand payload before transferring it to 20 mM Histidine 5.5 buffer. The ADC concentration was determined by Nano Drop (280 nm).

[00304] Additional ADCs, such as Trastuzumab-PL3, Trastuzumab-PL9, Trastuzumab-PL11, Trastuzumab-PL13 and Trastuzumab-PL15, were prepared according to the same method above, replacing the payload of the PL1 ligand with the payload of the corresponding ligand (PL3, PL9, PL11, PL13 and PL15, respectively). Method B

[00305] To a solution of trastuzumab in PB buffer 50 mM (20 mg / mL, pH = 7.0) was added Endo-S2 (0.1% w / w, purchased from Glycogene Inc., product no. SE-3002) and ManGIcNAc oxazoline( ) (30 eq, prepared according to the procedure described in WO2022226420, see Fig. 9 of the aforementioned PCT publication), and the solution was maintained at 30 °C for 1 to 2 hours until complete consumption of the starting material, monitored by LC-MS. The intermediate was purified on a Protein A column and the buffer was changed to 50 mM PB buffer (pH = 7.0). To the antibody solution created with glycan, 10% (v / v) DMSO was added, followed by the addition of DMSO PL20 solution. The reaction was kept away from light at 30 °C in a rotary mixer overnight. The ADC product was purified by Spin Zebm™ desalting columns to remove the Petition 870250090405, dated 03 / 10 / 2025, page 102 / 243 94 / 99 excess payload of the ligand before transferring them to 20 mM Histidine buffer 5.5. Trastuzumab-PL20 was obtained, DAR is 4. The ADC concentration was determined by Nano Drop (280 nm). Trastuzumab-PL20 has the structure shown in Fig. 12. Example 13. Reversed-phase chromatography

[00306] A 50 pg sample of ADC was reduced with 20 mM DTT at 37°C for 1 h. The pH of the reduction buffer was adjusted with 1.5 µl of 1M Tris 7.4 buffer. A 10 μL volume of reduced samples was injected into a Waters, BioResolve RP mAb Polyphenyl column (mobile phase A: 0.1% TFA in MilliQ water, mobile phase B: 0.1% TFA in acetonitrile) at a rate of 0.3 mL / min for 45 min (with a gradient of B from 30% to 42% in 30 min). The reduced sample species were separated at a column temperature of 70°C and monitored by UV absorbance at 280 nm and 360 nm. Reversed-phase chromatographies of the ADC Trastuzumab-PL1, Trastuzumab-PL3, Trastuzumab-PL9, Trastuzumab-PL11, Trastuzumab-PL13, and Trastuzumab-PL15 are shown in FIGS. 1A-F, respectively. Example 14. Size Exclusion Chromatography (SEC)

[00307] SEC was used to determine the purity of the ADC and the aggregate content. ~30 μg of ADC were injected onto a Zenix-C SEC-300 column (7.8 x 30 cm, 3 μm) (mobile phase was 0.15 M phosphate buffer, pH 7.0) at a rate of 0.75 mL / min for 16 min. Aggregates and monomeric species in the ADC were monitored at UV absorbances of 280 nm and 360 nm and reported as a percentage of the total area for all protein-related peaks. Size exclusion chromatographies of the ADCs Trastuzumab-PL1, Trastuzumab-PL3, Trastuzumab-PL9, Trastuzumab-PL11, Trastuzumab-PL13, and Trastuzumab-PL15 are shown in FIGS. 2A-F, respectively. Example 15. Drug-free analysis.

[00308] To determine the amount of free drug (payload of Petition 870250090405, dated 03 / 10 / 2025, page 103 / 243 95 / 99 ligand and any related species) in ADC products, protein precipitation was performed by adding 3M NaCl salt and a mixture of acetonitrile and DMSO. Samples were mixed and incubated at -40°C for 1 hour and centrifuged at 120,000 RPM for 30 minutes. The supernatant was collected and analyzed by an Acquity UPLC BEH C18 column (mobile phase A: 0.1% TFA in MilliQ water, mobile phase B: 0.1% TFA in acetonitrile) at a rate of 0.3 mL / min for 20 min (with a gradient of B from 10% to 100% in 10 min and a column temperature of 40°C). UV detection was monitored at 360 nm for analysis using an external calibration curve of free ligand payload concentration series. In this experiment, a control sample for the percentage of residual free drug recovery was measured with 5% payload of the ligand added to the trastuzumab solution, in addition to the ADC sample not added simultaneously.It was observed that all samples contained less than 5% free drug. Example 16. Aqueous Solubility of Useful Charges

[00309] The payloads were suspended in distilled water, the mixture was sonicated for 1 h and stirred at 25°C for 6 h. The insoluble payload was removed by filtration with a 20 μm filter, and the payload concentration in the filtrate was determined by HPLC. The aqueous solubility of the payload molecules is presented in Table 1. Table 1. Aqueous solubility of payload molecules. Samples D1 D5 D6 Aqueous solubility (mg / ml) 0.036 0.001 0.0005 Example 17. Hydrophilicity

[00310] An Agilent 1260 Infinity II butyl column and a Thermo MabPac were used for DAR analysis at a flow rate of 0.75 mL / min by hydrophobic interaction chromatography (HIC). HIC was performed under non-denaturing conditions at neutral pH with a high gradient. Petition 870250090405, dated 03 / 10 / 2025, p. 104 / 243 96 / 99% salt content (100% mobile phase A of 1-1.5 M ammonium sulfate) to low salt content (100% mobile phase B) for 25 minutes, with 20% isopropanol. Although some of the interchain disulfides were broken due to the conjugation reaction (while some remained intact), the combination of covalent bonding and strong non-covalent forces between the chains were sufficient to keep the mAb intact during the analysis.

[00311] FIG. 3 represents a graph of hydrophobic interaction chromatography profiles of ADCs with Trastuzumab as a function of retention time. The payloads measured by the ADCs were Dxd, PLC1, PLC3, PLC11 and PLC13. It was observed that PLC1 is the most hydrophilic payload ligand conjugate, followed by PLC13, PLC3, Dxd ligand conjugate and PLC11. Example A. Inhibition of growth in vitro

[00312] SK-BR-3 cells were seeded at a density of 1χ104 cells / well in a 96-well white plate (50 μL / well) and incubated at 37°C, 5% CO2. After overnight incubation, 50 μL of each diluted substance was added. Cell viability was assessed after 6 days using a CellTiter-Glo luminescent cell viability assay from Promega Corp. according to the manufacturer's instructions.

[00313] FIG. 4 represents a graph showing the in vitro cytotoxicity of payloads in SK-BR-3 cell lines. Cell viability is plotted as a function of payload concentration. The payloads tested were Exatecan, Dxd, D1, D6, D9, and D10. D9 was observed to be the most cytotoxic payload, followed by D1, D10, Exatecan, D6, and Dxd. D9 was the most cytotoxic of the compounds tested. The IC50 values ​​of the payloads are summarized in Table 2. The enhancements of D9 and D10 were compared relative to D1 and D6, respectively. Table 2. In vitro cytotoxicity of payloads in SK cell lines. Petition 870250090405, dated 03 / 10 / 2025, page 105 / 243 97 / 99 BR-3 Samples Exatecano Dxd D9 D10 D1 D6 IC50(nM) 1.055 2.165 0.2749 0.7879 0.7492 0.8288 Enhancement 2.7 1.1

[00315] FIG. 5 represents a graph showing the in vitro cytotoxicity of ADCs with Trastuzumab in SK-BR-3 cell lines. Cell viability is graphically represented as a function of concentration. The ADCs tested were Trastuzumab with deruxtecan, PL1, PL3, PL9, PL11, PL13, and PL15. The Trastuzumab-PL13 conjugate was observed to be the most active compound. Example B. Tumor volume (mm3) and survival curves in a xenograft model of the NCI-N87 tumorigenic epithelial cell line dosed once intravenously with 2 mg / kg of ADCs.

[00316] The NCI-N87 tumorigenic epithelial cell line was implanted subcutaneously into 4-week-old female CB17 / SCID mice. The above ADCs were administered once intravenously at a dose of 2 mg / kg when tumors reached approximately 200 mm3 (day 13, 7 animals per group, assigned to minimize differences in initial tumor volumes between groups). Tumor volume was measured every 3-5 days using calipers and calculated using the formula (C x L2) / 2. Mice were sacrificed when tumor volume exceeded 1000 mm3.

[00317] FIGS. 6 and 8 show graphs illustrating the in vivo efficacy of trastuzumab-containing ADCs targeting HER2. Tumor volume (in mm3) is plotted as a function of days after tumor implantation. In FIG. 6, the ADCs tested were trastuzumab with deruxtecan, PL1, and PL5. It was observed that the conjugate Petition 870250090405, dated 03 / 10 / 2025, page 106 / 243 98 / 99 Trastuzumab-PLI showed the greatest potency in inhibiting tumor growth. In FIG. 8, the ADCs tested were Trastuzumab with deruxtecan, PL1, PL9, PL11, PL13, and PL15. It was observed that the Trastuzumab-PL9 conjugate showed the greatest potency in inhibiting tumor growth.

[00318] FIGS. 7 and 9 illustrate graphs showing the change in body weight of mice for each trastuzumab-containing ADC from FIGS. 6 and 8, respectively. The change in body weight is plotted as a function of days after tumor implantation. The body weight of the mice in each group increased steadily or slightly. Example C. Pharmacokinetic profile (total antibody concentration over time) in mice after a single intravenous dose of 2 mg / kg of ADCs

[00319] A PL1 ADC was injected at 2 mg / kg into CB17 / SCID male mice (4-6 weeks old) via the tail vein (four animals per dose group, randomly assigned). Blood was collected in citrate tubes via retroorbital bleeding at multiple time points and processed into plasma. Total ADC concentration was assessed using a human IgG ELISA kit (Stemcell™ Technologies) according to the manufacturer's protocol. Trastuzumab standard curves were used for quantification. Pharmacokinetic parameters (clearance and AUC) were calculated by non-compartmental analysis using Microsoft® Excel® software incorporating pharmacokinetic functions.

[00320] FIG. 10A and FIG. 10B depict graphs showing the total antibody concentration (TAB) and the antibody-drug conjugate (ADC) concentration as a function of hours after injection for Trastuzumab-PL1 and Trastuzumab-deruxtecan, respectively. Several hours after injection, the amount of ADC is higher for PL1 (FIG. 10A) compared to Trastuzumab-deruxtecan (FIG. 10B). Petition 870250090405, dated 03 / 10 / 2025, page 107 / 243 99 / 99

[00321] Several modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the preceding description. Such modifications shall also be within the scope of the appended claims. Every reference, including, without limitation, all patents, patent applications and publications, cited in this application is incorporated herein by reference in its entirety. Example D. Single-dose toxicity study of TrastuzumabPL20 in mice

[00322] Ten female BALB / c mice (6-8 weeks old, Vitalriver) were randomly divided into two groups, including the IgG group (300 mpk, Equitech-Bio) and the Trastuzumab-PL20 group (300 mpk), five mice in each group. Both drugs were administered intravenously once. After administration, body weight was monitored once daily. No mice died in either group. Transient body weight loss was observed in the PL20 group and then rapidly recovered from the third day onwards. FIG. 11 shows the change in body weight of mice treated with Trastuzumab-PL20 ADC. Petition 870250090405, dated 03 / 10 / 2025, page 108 / 243

Claims

1 / 56 CLAIMS 1. Compound, characterized in that it has Formula (I') or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from H, OH, halo, C1-6 alkyl and C1-6 alkoxy; R2 is selected from H, OH, halo, C1-6 alkyl and C1-6 alkoxy; Q1 is S or O; R3 is selected from OH, SH, -NH2, -NHC(=O)-C1-6 alkylene-OH and -NHC(=S)-C1-6 alkylene-OH; L1 is C1-6 alkylene; and R4 is H; or R4 together with L1 form a 5 to 8 membered carbocycle.

2. Compound according to claim 1, characterized in that R1 is a halo.

3. Compound according to claim 1, characterized in that R1 is fluorine, chlorine or bromine.

4. Compound according to claim 1, characterized in that R1 is fluorine.

5. Compound according to claim 1, characterized in that R1 is C1-6 alkyl or C1-6 alkoxy.

6. Compound according to claim 1, characterized in that R1 is C1-6 alkyl.

7. Compound according to claim 1, characterized in that R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl or n-hexyl. Petition 870250090405, dated 03 / 10 / 2025, p. 166 / 243 2 / 56 8. Compound according to claim 1, characterized in that R1 is methyl, ethyl, n-propyl or isopropyl.

9. Compound according to claim 1, characterized in that R1 is a C1-6 alkoxy.

10. Compound according to claim 1, characterized in that R1 is methoxy or ethoxy.

11. Compound according to any one of claims 1 to 10, characterized in that R2 is C1-6 alkyl or C1-6 alkoxy.

12. Compound according to any one of claims 1 to 10, characterized in that R2 is C1-6 alkyl.

13. Compound according to any one of claims 1 to 10, characterized in that R2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl or n-hexyl.

14. Compound according to any one of claims 1 to 10, characterized in that R2 is methyl, ethyl, n-propyl or isopropyl.

15. Compound according to any one of claims 1 to 10, characterized in that R2 is a C1-6 alkoxy.

16. Compound according to any one of claims 1 to 10, characterized in that R2 is methoxy or ethoxy.

17. Compound according to any one of claims 1 to 16, characterized in that Q1 is O.

18. Compound according to any one of claims 1 to 16, characterized in that Q1 is S.

19. Compound according to any one of claims 1 to 18, characterized in that R3 is selected from OH, -NH2, -NHC(=O)-C1-6 alkylene-OH and -NHC(=S)-C1-6 alkylene-OH. Petition 870250090405, dated 10 / 03 / 2025, p. 167 / 243 3 / 56 20. Compound according to any one of claims 1 to 18, characterized in that R3 is OH.

21. Compound according to any one of claims 1 to 18, characterized in that R3 is -NHC(=O)C1-6 alkylene-OH.

22. Compound according to any one of claims 1 to 18, characterized in that R3 is NH2.

23. Compound according to any one of claims 1 to 22, characterized in that L1 is C3-4 alkylene.

24. Compound according to any one of claims 1 to 22, characterized in that -L1-R3 is CH2CH2CH2OH.

25. Compound according to any one of claims 1 to 22, characterized in that -L1-R3 is CH2CH2CH2CH2OH.

26. Compound according to any one of claims 1 to 25, characterized in that R4 is H.

27. A compound, according to any one of claims 1 to 22, characterized in that R4 together with L1 form a carbocycle of 5 to 8 members.

28. A compound, according to any one of claims 1 to 22, characterized in that R4 together with L1 form a 6-membered carbocycle.

29. Compound, according to any one of claims 1 to 22, characterized in that R4 together with L1 form a 6-membered carbocycle and R3 is selected from -NH2, NHC(=O)-C1-6 alkylene-OH and -NHC(=S)-C1-6 alkylene-OH.

30. Compound, according to any one of claims 1 to 22, characterized in that R4 together with L1 form a 6-membered carbocycle and R3 is selected from -NH2, - Petition 870250090405, dated 03 / 10 / 2025, page 168 / 243 4 / 56 NHC(=O)-CH2-OH and -NHC(=S)-CH2-OH.

31. Compound according to claim 1, characterized in that the compound is a compound of Formula (Ia1) Formula (Ia') or a pharmaceutically acceptable salt thereof.

32. Compound according to claim 1, characterized in that the compound is a compound of Formula (Ib1) or a pharmaceutically acceptable salt thereof.

33. Compound according to claim 1, characterized in that: R1 is selected from halo, C1-6 alkyl and C1-6 alkoxy; R2 is selected from H, OH, C1-6 alkyl and C1-6 alkoxy; Q1 is S or O; R3 is OH; L1 is C1-6 alkylene; and R4 is H.

34. Compound according to claim 1, characterized in that: R1 is halo; Petition 870250090405, dated 03 / 10 / 2025, page 169 / 243 5 / 56 R2 is selected from H, OH, C1-6 alkyl and C1-6 alkoxy; Q1 is S or O; R3 is OH; L1 is C1-6 alkylene; and R4 is H.

35. Compound according to claim 1, characterized in that: R1 is fluorine; R2 is methoxy; Q1 is O; and -L1-R3 is -CH2CH2CH2OH.

36. Compound according to claim 1, characterized in that: R1 is selected from halo, C1-6 alkyl and C1-6 alkoxy; R2 is selected from H, OH, C1-6 alkyl and C1-6 alkoxy; Q1 is S or O; R3 is selected from OH, SH, -NH2, -NHC(=O)-C1-6 alkylene-OH and -NHC(=S)-C1-6 alkylene-OH; and R4 together with L1 form a 5- to 8-membered carbocycle.

37. Compound according to claim 1, characterized in that: R1 is halo; R2 is C1-6 alkyl; Q1 is S or O; R3 is selected from OH, SH, -NH2, -NHC(=O)-C1-6 alkylene-OH and -NHC(=S)-C1-6 alkylene-OH; and R4 together with L1 form a 5- to 8-membered carbocycle.

38. Compound according to claim 1, characterized in that the compound is: Petition 870250090405, dated 03 / 10 / 2025, p. 170 / 243 6 / 56 Petition 870250090405, dated 03 / 10 / 2025, p. 171 / 243 7 / 56 HO-^ \ ° 'A, 0 A / ~NF fb? ° D7' HoAJAA. Al —^XJ / ^0F XXo D8' o HcA^^A^ / \^NH \ ,o XA AM F^·- \ o HoX o Petition 870250090405, of 10 / 03 / 2025, p. 172 / 243 8 / 56 39. Antibody-drug conjugate, characterized in that it comprises a drug and an antibody, wherein the drug comprises a compound, as defined in any one of claims 1 to 38, or a derivative thereof.

40. Antibody-drug conjugate, according to claim 39, characterized in that the drug binds to the antibody via a ligand.

41. Compound, characterized by the fact that it presents Formula (II') Petition 870250090405, dated 03 / 10 / 2025, page.173 / 243 9 / 56 or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from H, OH, halo, C1-6 alkyl and C1-6 alkoxy; R2 is selected from H, OH, C1-6 alkyl and C1-6 alkoxy; Q1 is S or O; L1 is C1-6 alkylene; R4 is H; or R4 together with L1 forms a 5- to 8-membered carbocycle; Q2 is selected from -S-, -O-, *-NHC(=O)-C1-6 alkyleneO- and *-NHC(=S)-C1-6 alkylene-O-, wherein the asterisk (*) represents the point of attachment to L1; E is a peptide comprising 2 to 10 amino acids; wherein the amino acid is optionally substituted by one or more polyols; the N-terminal of the peptide is covalently linked to Z; Z is -C(=O)-L2-Y; L2 is selected from C1-6 alkylene, -(CH2CH2-O)n-C1-6 alkylene-* and -C1-6 alkylene-(O-CH2CH2)n-*; n is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; the asterisk (*) represents the attachment point on Y; and Y is a reactive group, preferably an electrophilic group.

42. Compound according to claim 41, characterized in that R1 is a halo.

43. Compound according to claim 41, characterized in that R1 is fluorine, chlorine or bromine.

44. Compound, according to claim 41, Petition 870250090405, dated 10 / 03 / 2025, page 174 / 243 10 / 56 characterized in that R1 is fluorine.

45. Compound according to claim 41, characterized in that R1 is C1-6 alkyl or C1-6 alkoxy.

46. ​​Compound according to claim 41, characterized in that R1 is C1-6 alkyl.

47. Compound according to claim 41, characterized in that R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl or n-hexyl.

48. Compound according to claim 41, characterized in that R1 is methyl, ethyl, n-propyl or isopropyl.

49. Compound according to claim 41, characterized in that R1 is a C1-6 alkoxy.

50. Compound according to claim 41, characterized in that R1 is methoxy or ethoxy.

51. Compound according to any one of claims 41 to 50, characterized in that R2 is C1-6 alkyl or C1-6 alkoxy.

52. Compound according to any one of claims 41 to 50, characterized in that R2 is C1-6 alkyl.

53. Compound according to any one of claims 41 to 50, characterized in that R2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl or n-hexyl.

54. Compound according to any one of claims 41 to 50, characterized in that R2 is methyl, ethyl, n-propyl or isopropyl.

55. Compound according to any one of claims 41 to 50, characterized in that R2 is a C1-6 alkoxy.

56. Compound, according to any one of claims 41 to 50, characterized in that R2 is methoxy or ethoxy. Petition 870250090405, dated 10 / 03 / 2025, p. 175 / 243 11 / 56 57. Compound according to any one of claims 41 to 56, characterized in that Q1 is O.

58. Compound according to any one of claims 41 to 56, characterized in that Q1 is S.

59. Compound according to any one of claims 41 to 58, characterized in that L1 is C3-4 alkylene.

60. Compound according to any one of claims 41 to 59, characterized in that Q2 is O.

61. Compound according to any one of claims 41 to 59, characterized in that Q2 is S.

62. Compound, according to any one of claims 41 to 58, characterized in that -11-02 is *CH2CH2CH2O-, where the asterisk (*) represents the attachment point to L1.

63. Compound, according to any one of claims 41 to 58, characterized in that -L1- Q2 is *CH2CH2CH2CH2O-, where the asterisk (*) represents the point of attachment to L1.

64. Compound according to any one of claims 41 to 63, characterized in that R4 is H.

65. A compound according to any one of claims 41 to 58, characterized in that R4 together with L1 form a carbocycle of 5 to 8 members.

66. A compound according to any one of claims 41 to 58, characterized in that R4 together with L1 form a 6-membered carbocycle.

67. Compound, according to any one of claims 41 to 58, characterized in that R4 together with L1 form a 6-membered carbocycle and Q2 is selected from *NHC(=O)-C1-6 alkylene-O- and *-NHC(=S)-C1-6 alkylene-O-, where the asterisk (*) represents the point of connection for L1.

68. A compound according to any one of claims 41 to 58, characterized in that R4 together with L1 form a 6-membered carbocycle and Q2 is selected from *NHC(=O)-CH2-O- and *-NHC(=S)-CH2-O-, where the asterisk represents the point of attachment to L1.

69. Compound according to claim 41, characterized in that the compound is a compound of Formula (Ha1) or a pharmaceutically acceptable salt thereof.

70. Compound according to claim 41, characterized in that: R1 is halo; R2 is selected from H, -OH, C1-6 alkyl and C1-6 alkoxy; Q1 is S or O; R4 is H; L1 is C1-6 alkylene; Q2 is selected from -S- and -O-; E is a peptide comprising 2 to 10 amino acids; wherein the amino acid is optionally substituted by one or more polyols; the N-terminal of the peptide is covalently linked to Z; Z is -C(=O)-L2-Y; L2 is selected from C1-6 alkylene, -(CH2CH2-O)n-C1-6 alkylene-* and -C1-6 alkylene-(O-CH2CH2)n-*; Petition 870250090405, dated 03 / 10 / 2025, p. 177 / 243 13 / 56 n is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; the asterisk (*) represents the attachment point on Y; and Y is an electrophilic group.

71. Compound according to claim 41, characterized in that: R1 is halo; R2 is C1-6 alkoxy; Q1 is O; R4 is H; L1 is C1-6 alkylene; Q2 is -O-; E is a peptide comprising from 2 to 10 amino acids; wherein the amino acid is optionally substituted by one or more polyols; the N-terminal of the peptide is covalently linked to Z; Z is -C(=O)-L2-Y; L2 is -(CH2CH2-O)n-C1-6 alkylene-*; n is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; the asterisk (*) represents the attachment point on Y; and Y is a reactive group, preferably an electrophilic group.

72. A compound according to any one of claims 41 to 71, characterized in that E is a peptide comprising 2 to 10 amino acids, and the N-terminal of the peptide is covalently linked to Z.

73. A compound according to any one of claims 41 to 71, characterized in that E is a peptide comprising 2 to 8 amino acids, and the N-terminal of the peptide is covalently linked to Z.

74. Compound, according to any one of claims 41 to 71, characterized in that E is a peptide comprising 2 to 6 amino acids, and the N-terminal of the peptide is covalently linked to Z.

75. A compound according to any one of claims 41 to 71, characterized in that E is a peptide comprising 2 to 4 amino acids, and the N-terminal of the peptide is covalently linked to Z.

76. A compound according to any one of claims 41 to 71, characterized in that E is a peptide comprising 2 to 3 amino acids, and the N-terminal of the peptide is covalently linked to Z.

77. A compound according to any one of claims 41 to 71, characterized in that each amino acid of E is an L amino acid, or at least one amino acid of E is a D amino acid.

78. A compound according to any one of claims 41 to 71, characterized in that E comprises one or more amino acids selected from glycine, alanine, valine, glutamine, glutamic acid, phenylalanine, and leucine.

79. Compound, according to any one of claims 41 to 71, characterized in that one or more amino acids of E are replaced by one or more polyols.

80. Compound, according to any one of claims 41 to 71, characterized in that one or more glutamine or glutamic acid groups of E are replaced by one or more polyols.

81. Compound, according to any one of claims 41 to 71, characterized in that E comprises an amino acid with the following structure, Petition 870250090405, dated 03 / 10 / 2025, p. 179 / 243 15 / 56 OH OH IIH ho OH OH J 82. Compound according to any one of claims 41 to 71, characterized in that E comprises an amino acid having the following structure, 83. Compound according to any one of claims 41 to 71, characterized in that E is selected from -Ala-Val-*, -Val-Ala-*, -Gly-Gly-*, -Val-Cit-*, -Cit-Val-*, -Leu-Ala-*, -Ala-Leu-*, -Leu-Cit-*, -Cit-Leu-*, -Leu-Ala-*, -Ala-Leu-*, -Lys-Lys-*, -AlaLys-*, -Lys-Ala-*, -Val-Lys-*, -Lys-Val-*, -Tyr-Arg-*, -Arg-Tyr-*, -Arg-Arg*, -Ala-Ala-*, -Phe-Lys-*, -Lys-Phe-*, -Thr-Thr-*, -Thr-Met-*, -Met-Thr-*, Met-Tyr-*, -Tyr-Met-*, -Phe-Gln-*, -Gln-Phe-*, -Gly-Ser-*, -Leu-Gin-*, Gin-Leu-*, -Ser-Ala-*, -Ser-Gly-*, -Val-Thr-*, -Thr-Val- *, -Val-Gln-*, -SerVai-*, -Vai-Ser-*, -Ala-Met-*, -Met-Ala-*, -Val-Arg-*, -Arg-Val-*, -Phe-Ala*, -Ala-Phe-*, -Cit-Val-*, -Gln-Val-*, -Phe-Arg-*, -Arg-Phe-*, -Ala-Val-Glu*, -Ala-Ala-Ala-*, -Gly-Gly-Gly-*, -Ala-Val-Ala-*, -Gly-Val-Gly-*, -Ala-ValGly-*, -Gly-Phe-Lys-*, -Lys-Phe-Gly-*, -Leu-Ala-Leu-*, -Val-Ala-Leu-*, Leu-Ala-Val-*, -Val-Ala-Val-*, -Ala-Val-Ala-Gly-*, -Gly-Phe-Gly-Gly-*, Gly-Gly-Phe-Gly-*, -Ala-Val-Gly-Gly-*, - Ala-Ala-Ala-Ala-*,-Ala-Val-AlaAla-*, -Ala-Leu-Ala-Leu-*, -Leu-Ala-Leu-Ala-*, -Gly-Phe-Leu-Gly-* and Gly-Leu-Phe-Gly-*, where Glu is optionally replaced by a polyol, and where the asterisk (*) represents the N-terminal of peptides covalently linked to Z.

84. Composed, in accordance with any of the Petition 870250090405, dated 03 / 10 / 2025, p. 180 / 243 16 / 56 claims 41 to 71, characterized in that E is selected from -Ala-Val-*, -Val-Ala-*, -Val-Lys-*, -Val-Arg-*, -Val-Cit-*, -Val-Arg*, -Val-Cit-*, -Val-Lys-*, -Val-Arg-*, -Arg-Arg-*, -Ala-Ala-*, -Ala-Lys-*, Ala-Arg-*, -Ala-Val-Glu-*, -Ala-Ala-Ala-*, -Ala-Val-Ala-*, -Ala-Ala-Gly-* and -Ala-Val-Gly-*, where Glu is optionally replaced by a polyol, and where the asterisk (*) represents the N-terminal of the peptides covalently linked to Z.

85. Compound, according to any one of claims 41 to 71, characterized in that E is selected from -Ala-Val-* and -Ala-Val-Glu-*, wherein Glu is optionally replaced by a polyol, and wherein the asterisk (*) represents the N-terminal of the peptides covalently linked to Z.

86. Compound, according to any one of claims 41 to 71, characterized in that E is -Ala-Val-*, wherein the asterisk (*) represents the N-terminal of the peptides covalently linked to Z.

87. Compound, according to any one of claims 41 to 71, characterized in that E is -Ala-Val-Glu*, wherein Glu is replaced by a polyol, and wherein the asterisk (*) represents the N-terminal of peptides covalently linked to Z.

88. Compound according to any one of claims 41 to 71, characterized in that -E-NH-CH2 has one of the following structures, wherein the asterisk (*) represents the N-terminal of the peptides covalently linked to Z: OH OH wherein the asterisk (*) represents the N-terminal of the peptides covalently linked to Z. Petition 870250090405, dated 03 / 10 / 2025, p. 181 / 243 17 / 56 89. Compound according to any one of claims 41 to 88, characterized in that L2 is C1-6 alkylene.

90. Compound according to any one of claims 41 to 88, characterized in that L2 is C3-6 alkylene.

91. Compound according to any one of claims 41 to 88, characterized in that L2 is -(CH2)5-.

92. Compound, according to any one of claims 41 to 88, characterized in that L2 is selected from -(CH2CH2-O)n-C1-6 alkylene-* and -C1-6 alkylene-(O-CH2CH2)n-* , wherein n is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, and wherein the asterisk (*) represents the point of attachment to Y.

93. Compound according to claim 92, characterized in that n is 2, 3, 4 or 5.

94. Compound according to claim 92, characterized in that n is 2, 3 or 4.

95. Compound according to claim 92, characterized in that n is 3 or 4.

96. Compound according to claim 92, characterized in that n is 4.

97. Compound, according to any one of claims 41 to 88, characterized in that L2 is selected from -(CH2CH2-O)4-C1-4 alkylene-* and -C1-4 alkylene-(O-CH2CH2)4-*, where the asterisk (*) represents the point of attachment to Y.

98. Compound, according to any one of claims 41 to 88, characterized in that L2 is selected from -(CH2CH2-O)4-CH2CH2-* and -CH2CH2-(O-CH2CH2)4-*, and where the asterisk (*) represents the point of attachment to Y.

99. Compound, according to any of the claims 41 to 98 of Petition 870250090405, dated 10 / 03 / 2025, pp. 182 / 243 18 / 56, characterized in that Y is selected from H wherein m1 is selected from 1, 2, 3, 4, 5 or 6.

100. Compound according to any one of claims 41 to 98, characterized in that Y is 0 or H 101. A compound, according to any one of claims 41 to 88, characterized in that Z is selected 102. Compound, according to any of claims 41 to 88, characterized in that Z is Petition 870250090405, dated 03 / 10 / 2025, page 183 / 243 19 / 56 ο 103. A compound according to any one of claims 41 to 71, characterized in that -CH2-NH-EZ has one of the following structures:

104. Compound, according to claim 41, Petition 870250090405, dated 10 / 03 / 2025, p. 184 / 243 20 / 56 Petition 870250090405, dated 10 / 03 / 2025, p. 185 / 243 21 / 56 Petition 870250090405, dated 10 / 03 / 2025, p. 186 / 243 22 / 56 Petition 870250090405, dated 10 / 03 / 2025, p. 187 / 243 23 / 56 PL15' PL16' PL17' PL18' Petition 870250090405, dated 03 / 10 / 2025, p. 188 / 243 24 / 56 or a pharmaceutically acceptable salt thereof.

105. Antibody-drug conjugate comprising a drug and an antibody, characterized in that the drug comprises a compound, as defined in any one of claims 41 to 104, or a derivative thereof.

106. Compound, characterized in that it has Formula (III'), or a pharmaceutically acceptable salt thereof, wherein: C is a cell-binding agent; R1 is selected from halo, C1-4 alkyl and C1-4 alkoxy; Petition 870250090405, dated 03 / 10 / 2025, p.189 / 243 25 / 56 R2 is selected from H, -OH, C1-6 alkyl and C1-6 alkoxy; Q1 is S or O; L1 is C1-6 alkylene; Q2 is selected from -S-, -O-, *-NHC(=O)-C1-6 alkylene-O- and *-NHC(=S)-C1-6 alkylene-O-*, where the asterisk represents the point of attachment to L1; E is a peptide comprising 2 to 10 amino acids; wherein the amino acid is optionally substituted by one or more polyols; the N-terminal of the peptide is covalently linked to Z'; Z' is -C(=O)-L2-Y', L2 is selected from C1-6 alkylene, -(CH2CH2-O)n-C1-6 alkylene-* and -C1-6 alkylene-(O-CH2CH2)n-*, n is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; the asterisk (*) represents the attachment point on Y'; Y' is a group formed by a reaction of a reactive group, such as an electrophilic group, with another reactive group, such as a reactive nucleophilic group present in the cell-binding agent; ep is the drug-to-antibody ratio (DAR) ep has a value between 1 and 18.

107. Compound according to claim 106, characterized in that R1 is a halo.

108. Compound according to claim 106, characterized in that R1 is fluorine, chlorine or bromine.

109. Compound according to claim 106, characterized in that R1 is fluorine.

110. Compound according to claim 106, characterized in that R1 is C1-6 alkyl or C1-6 alkoxy.

111. Compound according to claim 106, characterized in that R1 is C1-6 alkyl. Petition 870250090405, dated 03 / 10 / 2025, pp. 190 / 243 26 / 56 112. Compound according to claim 106, characterized in that R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl or n-hexyl.

113. Compound according to claim 106, characterized in that R1 is methyl, ethyl, n-propyl or isopropyl.

114. Compound according to claim 106, characterized in that R1 is a C1-6 alkoxy.

115. Compound according to claim 106, characterized in that R1 is methoxy or ethoxy.

116. Compound according to any one of claims 106 to 115, characterized in that R2 is C1-6 alkyl or C1-6 alkoxy.

117. Compound according to any one of claims 106 to 115, characterized in that R2 is C1-6 alkyl.

118. Compound according to any one of claims 106 to 115, characterized in that R2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl or n-hexyl.

119. Compound according to any one of claims 106 to 115, characterized in that R2 is methyl, ethyl, n-propyl or isopropyl.

120. Compound according to any one of claims 106 to 115, characterized in that R2 is a C1-6 alkoxy.

121. Compound according to any one of claims 106 to 115, characterized in that R2 is methoxy or ethoxy.

122. Compound, according to any one of claims 106 to 121, characterized in that Q1 is O.

123. Compound, according to any of the Petition 870250090405, dated 03 / 10 / 2025, pp. 191 / 243 27 / 56 claims 106 to 121, characterized by the fact that Q1 is S.

124. Compound according to any one of claims 106 to 123, characterized in that L1 is C3-4 alkylene.

125. Compound according to any one of claims 106 to 124, characterized in that Q2 is O.

126. Compound according to any one of claims 106 to 124, characterized in that Q2 is S.

127. Compound, according to any one of claims 106 to 123, characterized in that -L1-Q2 is *CH2CH2CH2O-, where the asterisk (*) represents the point of attachment to L1.

128. Compound, according to any one of claims 106 to 123, characterized in that -L1- P2 is *CH2CH2CH2CH2O-, where the asterisk (*) represents the point of attachment to L1.

129. Compound according to any one of claims 106 to 128, characterized in that R4 is H.

130. Compound, according to any one of claims 106 to 123, characterized in that R4 together with L1 form a carbocycle of 5 to 8 members.

131. A compound, according to any one of claims 106 to 123, characterized in that R4 together with L1 form a 6-membered carbocycle.

132. Compound, according to any one of claims 106 to 123, characterized in that R4 together with L1 form a 6-membered carbocycle and Q2 is selected from *NHC(=O)-C1-6 alkylene-O- and *-NHC(=S)-C1-6 alkylene-O-, where the asterisk (*) represents the point of attachment to L1.

133. Compound, according to any one of claims 106 to 123, characterized in that R4 together with Petition 870250090405, dated 03 / 10 / 2025, page 192 / 243 28 / 56 L1 form a 6-membered carbocycle and Q2 is selected from *NHC(=O)-CH2-O- and *-NHC(=S)-CH2-O-, where the asterisk represents the point of attachment to L1.

134. Compound according to claim 106, characterized in that the compound is a compound of Formula (Hla1), or a pharmaceutically acceptable salt thereof.

135. Compound according to claim 106, characterized in that: R1 is fluorine; R2 is C1-4 alkyl or C1-4 alkoxy; Q1 is S or O; R4 is H; L1 is C1-6 alkylene; Q2 is -S- or -O-; E is a peptide comprising from 2 to 10 amino acids; wherein the amino acid is optionally substituted by one or more polyols; the N-terminal of the peptide is covalently linked to Z'; Z' is -C(=O)-L2-Y', L2 is selected from C1-6 alkylene, -(CH2CH2-O)n-C1-6 alkylene-* and -C1-6 alkylene-(O-CH2CH2)n-*, n is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; The asterisk (*) represents the attachment point in Y'; Petition 870250090405, dated 03 / 10 / 2025, page 193 / 243 29 / 56 Y' is a group formed by the reaction of an electrophilic group with a reactive nucleophilic group present in the cell-binding agent; ep is the drug-to-antibody ratio (DAR) ep has a value between 1 and 18.

136. Compound according to claim 105, characterized in that: R1 is fluorine; R2 is C1-4 alkoxy; Q1 is O; R4 is H; L1 is C1-6 alkylene; Q2 is -O-; E is a peptide comprising from 2 to 10 amino acids; wherein the amino acid is optionally substituted by one or more polyols; the N-terminal of the peptide is covalently linked to Z'; Z' is -C(=O)-L2-Y', L2 is -(CH2CH2-O)n-C1-6 alkylene-*, n is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; the asterisk (*) represents the attachment point on Y'; Y' is a group formed by the reaction of an electrophilic group with a reactive nucleophilic group present in the cell-binding agent; ep is the drug-to-antibody ratio (DAR), and ep has a value between 1 and 18.

137. Compound, according to any one of claims 106 to 136, characterized in that E is a peptide comprising 2 to 10 amino acids, and the N-terminal of the peptide is covalently linked to Z'. Petition 870250090405, dated 10 / 03 / 2025, p. 194 / 243 30 / 56 138. Compound, according to any one of claims 106 to 136, characterized in that E is a peptide comprising 2 to 8 amino acids, and the N-terminal of the peptide is covalently linked to Z'.

139. Compound, according to any one of claims 106 to 136, characterized in that E is a peptide comprising 2 to 6 amino acids, and the N-terminal of the peptide is covalently linked to Z'.

140. Compound, according to any one of claims 106 to 136, characterized in that E is a peptide comprising 2 to 4 amino acids, and the N-terminal of the peptide is covalently linked to Z'.

141. Compound, according to any one of claims 106 to 136, characterized in that E is a peptide comprising 2 to 3 amino acids, and the N-terminal of the peptide is covalently linked to Z'.

142. Compound, according to any one of claims 106 to 136, characterized in that each amino acid of E is an L amino acid, or at least one amino acid of E is a D amino acid.

143. A compound according to any one of claims 106 to 136, characterized in that E comprises one or more amino acids selected from glycine, alanine, valine, glutamine, glutamic acid, phenylalanine, and leucine.

144. Compound, according to any one of claims 106 to 136, characterized in that one or more amino acids of E are replaced by one or more polyols.

145. Compound, according to any one of claims 106 to 136, characterized in that one or more glutamine or glutamic acid of E is replaced by one or more polyols. Petition 870250090405, dated 10 / 03 / 2025, p. 195 / 243 31 / 56 146. Compound, according to any one of claims 106 to 136, characterized in that E comprises an amino acid with the following structure, OH OH 147. Compound, according to any one of claims 106 to 136, characterized in that E comprises an amino acid with the following structure, OH OH O 148. Compound, according to any one of claims 106 to 136, characterized in that E is selected from -Ala-Val-*, -Val-Ala-*, -Gly-Gly-*, -Val-Cit-*, -Cit-Val*, -Leu-Ala-*, -Ala-Leu-*, -Leu-Cit-*, -Cit-Leu-*, -Leu-Ala-*, -Ala-Leu-*, Lys-Lys-*, -Ala-Lys-*, -Lys-Ala-*, -Val-Lys-*, -Lys-Val-*, -Tyr-Arg-*, -ArgTyr-*, -Arg-Arg-*, -Ala-Ala-*, -Phe-Lys-*, -Lys-Phe-*, -Thr-Thr-*, -ThrMet-*, -Met-Thr-*, -Met-Tyr-*, -Tyr-Met-*, -Phe-Gln-*, -Gln-Phe-*, -GlySer-*, -Leu-Gin-*, -Gin-Leu-*, -Ser-Ala-*, -Ser-Gly-*, -Val-Thr-*, -Thr-Val*, -Val-Gln-*, -Ser-Vai-*, -Vai-Ser-*, -Ala-Met-*, -Met-Ala-*, -Val-Arg-*, Arg-Val-*, -Phe-Ala-*, -Ala-Phe-*, -Cit-Val-*, -Gln-Val-*, -Phe-Arg-*, -ArgPhe-*, -Ala-Val-Glu-*, -Ala-Ala-Ala-*, -Gly-Gly-Gly-*, -Ala-Val-Ala-*, -GlyVal-Gly-*, -Ala-Val-Gly-*, -Gly-Phe-Lys-*, -Lys-Phe-Gly-*, -Leu-Ala-Leu*, -Val-Ala-Leu-*, -Leu-Ala-Val-*, -Val-Ala-Val-*, -Ala-Val-Ala-Gly-*, -GlyPhe-Gly-Gly-*, -Gly-Gly-Phe-Gly-*, -Ala-Val-Gly-Gly-*, - Ala-Ala-Ala-Ala*,-Ala-Val-Ala-Ala-*, -Ala-Leu-Ala-Leu-*, -Leu-Ala-Leu-Ala-*, -Gly-PheLeu-Gly-* and -Gly-Leu-Phe-Gly-*, where Glu is optionally replaced by a polyol, and where * represents the N-terminal of peptides covalently linked to Z'.

149. Compound according to any one of claims 106 to 136, characterized in that E is selected from -Ala-Val-*, -Val-Ala-*, -Val-Lys-*, -Val-Arg-*, -Val-Cit*, -Val-Arg-*, -Val-Cit-*, -Val-Lys-*, -Val-Arg-*, -Arg-Arg-*, -Ala-Ala-*, Ala-Lys-*, -Ala-Arg-*, -Ala-Val-Glu-*, -Ala-Ala-Ala-*, -Ala-Val-Ala-*, -AlaAla-Gly-* and -Ala-Val-Gly-*, where Glu is optionally replaced by a polyol, and where * represents the N-terminal of peptides covalently linked to Z'.

150. Compound, according to any one of claims 106 to 136, characterized in that E is selected from -Ala-Val-* and -Ala-Val-Glu-*, wherein Glu is optionally replaced by a polyol, and wherein * represents the N-terminal of peptides covalently linked to Z'.

151. Compound, according to any one of claims 106 to 136, characterized in that E is -Ala-Val*, where * represents the N-terminal of peptides covalently linked to Z'.

152. Compound, according to any one of claims 106 to 136, characterized in that E is -Ala-ValGlu-*, wherein Glu is substituted for a polyol, and wherein * represents the N-terminal of peptides covalently linked to Z'.

153. Compound, according to any one of claims 106 to 136, characterized in that -E-NH-CH2 has one of the following structures, where * represents the N-terminal of peptides covalently linked to Z': Petition 870250090405, dated 03 / 10 / 2025, p. 197 / 243 33 / 56 OH OH where * represents the N-terminal of peptides covalently linked to Z'.

154. Compound according to any one of claims 106 to 153, characterized in that L2 is C1-6 alkylene.

155. Compound according to any one of claims 106 to 153, characterized in that L2 is C3-6 alkylene.

156. Compound according to any one of claims 106 to 153, characterized in that L2 is -(CH2)5-.

157. Compound, according to any one of claims 106 to 153, characterized in that L2 is selected from -(CH2CH2-O)n-C1-6 alkylene-* and -C1-6 alkylene-(OCH2CH2)n-* , wherein n is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, and wherein the asterisk (*) represents the point of attachment to Y'.

158. Compound according to claim 157, characterized in that n is 2, 3, 4 or 5.

159. Compound according to claim 157, characterized in that n is 2, 3 or 4.

160. Compound according to claim 157, characterized in that n is 3 or 4.

161. Compound according to claim 157, characterized in that n is 4.

162. Compound, according to any one of claims 106 to 153, characterized in that L is selected from -(CH2CH2-O)4-C1-4 alkylene-* and -C1-4 alkylene-(O Petition 870250090405, dated 03 / 10 / 2025, page 198 / 243 34 / 56 CH2CH2)4-*, wherein the asterisk (*) represents the point of attachment to Y'.

163. Compound, according to any one of claims 106 to 153, characterized in that L2 is selected from -(CH2CH2-OYCH2CH2-* and -CH2CH2-(O-CH2CH2)4-* , and where the asterisk (*) represents the point of attachment to Y'.

164. Compound, according to any one of claims 106 to 163, characterized in that Y' is a group formed by a nucleophilic reactive reaction of an electrophilic group with a group present in the cell-binding agent, wherein the NH electrophilic group is selected from OBr, ,ofo FF , , HN Br NIN Br O , HN , ** between 1, 2, 3, 4, 5 or 6.

165. Compound, , of mj H according in which m1 is selected with any of claims 106 to 163, characterized in that Y' is a group formed by a reaction of 0 with a reactive nucleophilic group present in the cell-binding agent, or Y' is a group formed by a reaction of Petition 870250090405, of 03 / 10 / 2025, page 199 / 243 35 / 56 ο ν / mi 7\__ / η in which mi is defined as above with a reactive group (such as the azide group) present in the cell-binding agent.

166. A compound, according to any one of claims 106 to 163, characterized in that Y' is O, where the asterisk (*) represents the point of attachment to C, or k°\ Λ Τ' / / / ~N o S \pr Y' is H *, where the asterisk (*) represents the point of attachment to C.

167. Compound, according to any one of claims 106 to 166, characterized in that the cell-binding agent is an antibody or an antigen-binding fragment thereof.

168. Compound according to any one of claims 106 to 167, characterized in that p has a value between 2-10, 4-8, 7-8 or 3.2 to 8.

0.

169. Compound according to claim 106, characterized in that the compound of Formula (III') is: Petition 870250090405, dated 03 / 10 / 2025, p. 200 / 243 36 / 56 Petition 870250090405, dated 03 / 10 / 2025, p. 201 / 243 37 / 56 Petition 870250090405, dated 03 / 10 / 2025, p. 202 / 243 38 / 56 Petition 870250090405, dated 03 / 10 / 2025, p. 203 / 243 39 / 56 PLC14' PLC15' PLC16' c or PLC17' Petition 870250090405, dated 03 / 10 / 2025, p. 204 / 243 40 / 56 or a pharmaceutically acceptable salt thereof.

170. Compound according to claim 1, characterized in that the compound is a compound of Formula (Ia) Formula (Ia) or a pharmaceutically acceptable salt thereof.

171. Compound according to claim 1 or 170, characterized in that the compound is a compound of Formula (Ia) Formula (Ia) or a pharmaceutically acceptable salt thereof.

172. Compound according to claim 1 or 170, characterized in that the compound is a compound of Formula (Ib) Petition 870250090405, dated 10 / 03 / 2025, p. 205 / 243 41 / 56 Formula (Ib) or a pharmaceutically acceptable salt thereof.

173. Compound, according to claim 1, Petition 870250090405, dated 10 / 03 / 2025, p. 206 / 243 42 / 56 D6 D7 D8 D9 D10 Petition 870250090405, dated 10 / 03 / 2025, p. 207 / 243 43 / 56 or a pharmaceutically acceptable salt thereof.

174. Compound according to claim 41, characterized in that the compound is a compound of Formula Petition 870250090405, dated 03 / 10 / 2025, page 208 / 243 44 / 56 (II) or a pharmaceutically acceptable salt thereof.

175. Compound according to claim 41 or 174, characterized in that the compound is a compound of Formula (IIa) or a pharmaceutically acceptable salt thereof.

176. Compound, according to claim 41, Petition 870250090405, dated 10 / 03 / 2025, p. 209 / 243 45 / 56 Petition 870250090405, dated 10 / 03 / 2025, p. 210 / 243 46 / 56 Petition 870250090405, dated 10 / 03 / 2025, p. 211 / 243 47 / 56 Petition 870250090405, dated 10 / 03 / 2025, p. 212 / 243 48 / 56 Petition 870250090405, dated 10 / 03 / 2025, p. 213 / 243 49 / 56 or pharmaceutically acceptable salt thereof.

177. Compound according to claim 106, characterized in that the compound is a compound of Formula (III), or a pharmaceutically acceptable salt thereof.

178. Compound according to claim 106 or 177, characterized in that the compound is a compound of Formula (IIIa), or a pharmaceutically acceptable salt thereof.

179. Compound, according to claim 106, characterized in that the compound is in some embodiments, Petition 870250090405, dated 03 / 10 / 2025, pp. 214 / 243 50 / 56 Petition 870250090405, dated 03 / 10 / 2025, pp. 215 / 243 51 / 56 Petition 870250090405, dated 03 / 10 / 2025, pp. 216 / 243 52 / 56 Petition 870250090405, dated 03 / 10 / 2025, p. 217 / 243 53 / 56 PLC14 PLC15 PLC16 PLC17 Petition 870250090405, dated 03 / 10 / 2025, pp. 218 / 243 54 / 56 or a pharmaceutically acceptable salt thereof.

180. Pharmaceutical composition, characterized in that it comprises the compound as defined in any one of claims 1 to 38, 41 to 104 or 106 to 179.

181. Pharmaceutical composition, characterized in that it comprises the compound, as defined in any one of claims 1 to 38, 41 to 104 or 106 to 179, and a second therapeutic agent.

182. Method for preparing a conjugate comprising a cell-binding agent and a drug, characterized in that it comprises placing a cell-binding agent in contact with the compound, as defined in any one of claims 1 to 38, 41 to 104 or 170 to 176, such that a covalent bond is formed between the cell-binding agent and the compound.

183. Method according to claim 182, characterized in that the cell-binding agent is an antibody or an antigen-binding fragment thereof.

184. Method according to claim 182, characterized in that the cell-binding agent is a monoclonal antibody or an antigen-binding fragment thereof.

185. Conjugate comprising a cell-binding agent and a drug, characterized in that the conjugate is prepared according to the method as defined in any one of claims 182 to 184.

186. Conjugate, according to claim 185, characterized in that it comprises a cell-binding agent that is an antibody or an antigen-binding fragment thereof. Petition 870250090405, dated 03 / 10 / 2025, pp. 219 / 243 55 / 56 187. Conjugate, according to claim 185, characterized in that it comprises a cell-binding agent that is either a monoclonal antibody or an antigen-binding fragment thereof.

188. Method for treating a cell proliferative disease or disorder or inhibiting abnormal cell growth, characterized in that it comprises administering the compound, as defined in any one of claims 1 to 38, 41 to 104 or 106 to 179, or the pharmaceutical composition, as defined in claim 170 or 171, to an individual in need thereof.

189. Method according to claim 188, characterized in that the method is for treating cancer.

190. Method, according to claim 189, characterized in that the cancer is adenocarcinoma, brain cancer, bladder cancer, breast cancer, cervical cancer, choriocarcinoma, CNS tumor, colon or colorectal cancer, diffuse intrinsic pontine glioma (DIPG), endometrial cancer, esophageal cancer, Ewing's sarcoma, fallopian tube cancer, gallbladder cancer, gastric cancer, glioblastoma, head and neck cancer, hematologic cancer, Hodgkin's lymphoma, renal cancer, laryngeal cancer, leukemia, liver cancer, lung cancer, lymphoma, melanoma, Merkel cell carcinoma, mesothelioma, multiple myeloma, myelodysplastic syndrome (MDS), neuroblastoma, non-Hodgkin's lymphoma, osteosarcoma, pancreatic cancer, peritoneal cancer, prostate cancer, ovarian cancer, renal cancer, rhabdomyosarcoma, cancer salivary gland cancer, sarcoma, skin cancer, small bowel cancer, squamous cell carcinoma, testicular cancer, thyroid cancer,Uterine cancer, or Wilms' tumor.

191. Method, according to claim 189, characterized in that the cancer is breast cancer, lung cancer, gastric cancer, prostate cancer, pancreatic cancer or colon cancer.

192. Method according to claim 189, characterized in that the cancer is breast cancer.

193. Use of a compound as defined in any one of claims 1 to 38, 41 to 104 or 106 to 179, or of the pharmaceutical composition as defined in claim 170 or 171, or of the conjugate as defined in any one of claims 185 to 187, characterized in that it is for the manufacture of a medicament for use in therapy. Petition 870250090405, dated 03 / 10 / 2025, pp. 221 / 243

Images