Antibody-drug conjugates comprising trabectedin and lurbinectedin derivatives

Abstract

The present invention relates novel trabectedin and lurbinectedin derivatives, corresponding antibody-drug conjugates, and a process for the preparation of the antibody-drug conjugates. The invention further relates to pharmaceutical dosage forms comprising the novel trabectedin or lurbinectedin derivatives or the corresponding antibody-drug conjugates. Furthermore, the invention relates to new trabectedin and lurbinectedin derivatives, corresponding antibody-drug conjugates, and corresponding pharmaceutical dosage forms for use as medicament or for use in the treatment of specific cancer types.

Description

ANTIBODY-DRUG CONJUGATESCOMPRISINGTRABECTEDIN AND LURBINECTEDIN DERIVATIVES

[0001] The present patent application claims the priority and benefits of international patent application PCT / SG2023 / 050138 filed on 7 March 2023.

[0002] The invention disclosed herein relates to novel trabectedin and lurbinectedin derivatives, corresponding antibody-drug conjugates and a process for the preparation of the antibody-drug conjugates. The invention further relates to pharmaceutical dosage forms comprising the novel trabectedin or lurbinectedin derivatives or the corresponding antibodydrug conjugates. Furthermore, the invention relates to new trabectedin and lurbinectedin derivatives, corresponding antibody-drug conjugates and corresponding pharmaceutical dosage forms for use as medicament or for use in the treatment of specific cancer types.Background of the invention

[0003] Treatment of cancer has progressed in recent years with the development of pharmaceuticals that target and kill cancer cells more efficiently. In this regard, researchers have taken advantage of cell-surface receptors and antigens that are selectively expressed by target cells, such as cancer cells. This led to the development of pharmaceuticals based on (monoclonal) antibodies (mAb) that bind, for example tumor-specific or tumor-associated antigens. In order to achieve inhibition of tumor cells, cytotoxic compounds such as chemotherapy drugs, bacterial and plant toxins as well as radionuclides can be chemically attached as payloads to target-specific antibodies via a suitable linker. The resulting antibodydrug conjugates (ADCs) are able to deliver the cytotoxic compounds in a targeted manner and thus often allow for a more efficient cancer therapy.

[0004] ADCs represent a challenging area of development given the potential complexity of the payload, the chemistry of the linker and the available antibodies and so there remains a need for the development of alternative or improved ADCs. Therefore, careful consideration is required on the selection of the various components.

[0005] The ADC technology may be considered as being superior to other approaches including improved efficacy over antibody drugs and reduced risk of adverse effects compared to conventional anti-cancer agents, for its ability to target cancer cells with minimum impact to healthy cells, and only release drugs under specific conditions.

[0006] Nevertheless, there also remains a need for the development of alternative or improved cytotoxic compounds that can be useful for both as direct anticancer drug and as payload in corresponding ADCs.

[0007] In this regard, trabectedin, belonging to the family of ecteinascidins, and the structurally related lurbinectedin have recently gained attraction by cancer researchers:Trabectedin LurbinectedinTrabectedin and lurbinectedin are DNA alkylating agents and are capable to induce tumor cell apoptosis, re-structuring of the tumor microenvironment and inhibit angiogenesis. They show potent cytotoxicity in many different cancer cell lines across a broad range of cancer types.

[0008] WO 2011 / 147828 Al discloses syntheses for derivatives of both, trabectedin and lurbinectedin. In turn, WO 2020 / 084115 Al and WO 2021 / 214126 Al disclose lurbinectedin derivatives and corresponding ADCs.Summary of the invention

[0009] The present invention inter alia provides novel compounds derived from trabectedin and lurbinectedin, and corresponding anti-body drug conjugates which are useful in the treatment of cancer.

[0010] While the medical use of the parent compounds, trabectedin and lurbinectedin, has been extensively investigated with regard to both, conventional small molecule therapies and ADC approaches, there has been less progress to date with regard to derivatives.

[0011] By contrast, the trabectedin and lurbinectedin derivatives according to the present invention do show improved in vitro potency over that of the parent drugs and they were successfully tested against several tumor cell lines, both as conventional active ingredient and in a target-specific approach using corresponding ADCs.

[0012] The present invention generally relates to compounds of formula (I) or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof:wherein R1is a substituent having a negative inductive effect;- R2is -H or -X(CH2)PC(=0)o-i(CH2)q(C(RR2)2)o-i(X)o-iRR2with q and p being independently integers from 0 to 10, wherein X is independently O or NH, and RR2is independently -H or -Ci-4 alkyl;- R3is -H or -X(CH2)mC(=0)o-i(CH2)n(C(RR3)2)o-i(X)o-iRR3 with m and n being independently integers from 0 to 10, wherein X is independently O or NH, and RR3 is independently -H or -C1-4alkyl;R4is selected from -H , -CH2ORR4, -CH2NHRR4, and -CH2C(=O)ORR4, wherein RR4 is -H or -C1-4alkyl; and R5is -H or -C1-4alkyl.

[0013] The present invention further relates to compounds of formula (VII) or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof:wherein R1is a substituent having a negative inductive effect;- R2is -H or -X(CH2)pC(=0)o-i(CH2)q(C(RR2)2)o-i(X)o-iRR2with q and p being independently integers from 0 to 10, wherein X is independently O or NH, and RR2is independently -H or -Ci-4 alkyl;- R3is -H or -X(CH2)mC(=0)o-i(CH2)n(C(RR3)2)o-i(X)o-iRR3 with m and n being independently integers from 0 to 10, wherein X is independently O or NH, and RR3 is independently -H or -C1-4alkyl; andR4is -H or -C1-4alkyl.

[0014] The present invention still further relates to a compound of formula (XIII) or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof:wherein R1is a substituent having a negative inductive effect;- R2is -H or -X(CH2)PC(=0)o-i(CH2)q(C(RR2)2)o-i(X)o-iRR2with q and p being independently integers from 0 to 10, wherein X is independently O or NH, and RR2is independently -H or -C1-4alkyl;- R3is -H or -X(CH2)mC(=0)o-i(CH2)n(C(RR3)2)o-i(X)o-iRR3 with m and n being independently integers from 0 to 10, wherein X is independently O or NH, and RR3 is independently -H or -C1-4alkyl; andR4is -H or -CH2NHRR4, wherein RR4 is -H or -C1-4alkyl.

[0015] By “negative inductive effect”, a local change in the electron density due to an electron- withdrawing functional group or atom elsewhere in the molecule is meant, resulting in a permanent dipole in a G (sigma) bond. In the meaning of the present invention, a substituent having a negative inductive effect refers to hydrogen as the reference, i.e. a substituent (including monoatomic substituents) which negative inductive effect is stronger than that of hydrogen. Examples of suitable substituents include carbonyl (-C(=O)R), carboxyl (-C(=O)OR), -OH, -I, -Br, -Cl, -NO2, -NH2, -COOH, -F and -C=N. Preferred suitable substituents may include carbonyl -OH, -NO2, -F and -C=N, more preferably -OH, -F and -C=N, and most preferably -OH and -C=N.

[0016] Unless defined otherwise, the term “alkyl” used herein refers to an unsubstituted and saturated hydrocarbon group (branched or unbranched). Where indicated, the number of carbons refers to all carbons present in that group, including in sidechains. For example, the term “C1-4alkyl” is meant to include to -CH3, -CH2CH3, -CH2CH2CH3(n-propyl), -CH(CH3)2(iso-propyl), -CH2CH2CH2CH3(n-butyl), -CH2CH2CH(CH3)2(iso-butyl), -CH(CH3)CH2CH3(sec -butyl) and -CH(CH3)3 (tert-butyl). Wherever C1-4alkyl is mentioned herein, it should be understood that -CH3is a preferred embodiment thereof.

[0017] More specifically, according to a first aspect of the present invention, a compound of formula (I) or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof is provided:wherein R1is a substituent having a negative inductive effect;- R2is -H or -X(CH2)pC(=0)o-i(CH2)q(C(RR2)2)o-i(X)o-iRR2with q and p being independently integers from 0 to 10, wherein X is independently O or NH, and RR2is independently -H or -C1-4alkyl;- R3is -H or -X(CH2)mC(=0)o-i(CH2)n(C(RR3)2)o-i(X)o-iRR3 with m and n being independently integers from 0 to 10, wherein X is independently O or NH, and RR3 is independently -H or -C1-4alkyl;R4is selected from -H , -CH2ORR4, -CH2NHRR4, and -CH2C(=O)ORR4, wherein RR4 is -H or -C1-4alkyl; and R5is -H or -C1-4alkyl; with the proviso that compounds of formula (I) having the following combination of R2,R3, R4and R5are excluded:R2is -OCH3, R3is -OH, R4is -H and R5is -H.

[0018] According to another aspect of the present invention, a compound of formula (VII) or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof is provided:wherein R1is a substituent having a negative inductive effect;- R2is -H or -X(CH2)pC(=0)o-i(CH2)q(C(RR2)2)o-i(X)o-iRR2with q and p being independently integers from 0 to 10, wherein X is independently O or NH, and RR2is independently -H or -Ci-4 alkyl;- R3is -H or -X(CH2)mC(=0)o-i(CH2)n(C(RR3)2)o-i(X)o-iRR3 with m and n being independently integers from 0 to 10, wherein X is independently O or NH, and RR3 is independently -H or -C1-4alkyl; andR4is -H or -C1-4alkyl; with the proviso that compounds of formula (VII) having the following combination of R2, R3and R4are excluded:R2is -H, R3is -H and R4is -H; andR2is -OCH3, R3is -H and R4is -H.

[0019] According to still another aspect of the present invention, a compound of formula (XIII) or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof is provided:wherein R1is a substituent having a negative inductive effect;- R2is -H or -X(CH2)PC(=0)o-i(CH2)q(C(RR2)2)o-i(X)o-iRR2with q and p being independently integers from 0 to 10, wherein X is independently O or NH, and RR2is independently -H or -C1-4alkyl;- R3is -H or -X(CH2)mC(=0)o-i(CH2)n(C(RR3)2)o-i(X)o-iRR3 with m and n being independently integers from 0 to 10, wherein X is independently O or NH, and RR3 is independently -H or -C1-4alkyl; andR4is -H or -CH2NHRR4, wherein RR4 is -H or -C1-4alkyl.

[0020] The compounds provided according to the present invention may be used as payloads for corresponding antibody-drug conjugates. Therefore, still another aspect of the present invention relates to antibody-drug conjugate of formula (XIX):Ab-k-D]z(XIX) whereinAb denotes an antibody, an antigen-binding fragment, or an immunologically active portion thereof;L denotes a linker; andD denotes a compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof selected from the group consisting of trabectedin, lurbinectedin and the compounds according to formula (I), (VII) or (XIII) disclosed herein,preferably a compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof according to formula (I), (VII) or (XIII) disclosed herein; and whereinD covalently binds to L via nitrogen or oxygen present in D, and L covalently binds to Ab; and z is an integer from 1 to 20.

[0021] Another aspect of the present invention relates to a compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to the foregoing aspects for use as a medicament, or, according to still another aspect, for use in the treatment of cancer, preferably ovarian cancer, stomach cancer or breast cancer.

[0022] Another aspect of the present invention relates to the antibody-drug conjugate defined hereinabove for use as a medicament, or, according to still another aspect, for use in the treatment of cancer, preferably ovarian cancer, stomach cancer or breast cancer.

[0023] According to another aspect of the present invention, a process for the preparation of an antibody-drug conjugate of general formula (XIX) is provided:Ab 1_-D]z(XIX) the method comprising conjugating an antibody, an antigen-binding fragment or an immunologically active portion thereof (Ab) to a compound (D) via a linker (L), whereinD is a compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof selected from the group consisting of trabectedin, lurbinectedin and the compounds according to formula (I), (VII) or (XIII) disclosed herein, preferably a compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof according to formula (I), (VII) or (XIII) disclosed herein;L is a linker as disclosed hereinbelow;D covalently binds to L via nitrogen or oxygen present in D, and L covalently binds to Ab; and z is an integer from 1 to 20.

[0024] Another aspect of the present invention relates to a pharmaceutical dosage form comprising a therapeutically effective amount of the compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to the foregoing as aspects, or a therapeutically effective amount of the antibody-drug conjugate according to the foregoing as aspects.

[0025] Still another aspect of the present invention relates to a method of treating cancer, wherein the method comprises administering to a subject a therapeutically effective amount of the compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to according to the foregoing as aspects, a therapeutically effective amount of the antibody-drug conjugate according to according to the foregoing as aspects, or the pharmaceutical dosage form according to the foregoing as aspects.

[0026] It was found that the compounds according to the present invention exhibit improved efficacy against the proliferation of different tumor cell lines. These tumor cell lines include OV-90 (CRL- 11732) associated with papillary serous adenocarcinoma of the ovary, NCI-N87 (CRL-5822) associated with gastric carcinoma, and MDA-MB-231 associated with breast adenocarcinoma. As shown, the 50% cytotoxic concentration (CC50) of the compounds according to the present invention is significantly lower and thus improved compared to the parent compounds trabectedin and lurbinectedin, respectively. This finding makes these compounds potent active ingredients for the therapy of ovarian cancer, breast cancer and stomach cancer.

[0027] Furthermore, it was found that the compounds of the present invention are potent payloads when used in antibody-drug conjugates. Specifically, the compounds were tested as payloads with different chemical linkers in combination with Cirmtuzumab (anti-RORl), Sacituzumab (anti-TROP2) and Trastuzumab (anti-HER2). Additional antibodies tested include Patritumab (anti-HER3), Mirvetuximab (anti-FRoc) and Cetuximab (anti-EGFR). Of note, some correlation between the cytotoxicity of the compound alone and the effect of the corresponding antibody-drug conjugate on cell lines NCI-N87 and MDA-MB-231 was found (also in terms of CC50). In some cases, it is even assumed that the cytotoxicity of antibody-drug conjugate is superior to the cytotoxic effects attributable to the respective payload and antibody alone. This makes the antibody-drug conjugates of the present invention potent candidates forthe therapy of various cancer types, in particular those associated with the expression of ROR1, TROP2 or HER2(sometimes also referred to as HER2 / new). In terms of cancer types, the antibody-drug conjugates of the present invention allow for a targeted therapy of ovarian cancer, breast cancer and stomach cancer.Description of the embodiments

[0028] In the following, advantageous embodiments will be discussed in more detail. It is to be understood that these details apply to all aspects of the present invention.

[0029] As explained above, one aspect of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof:wherein R1is a substituent having a negative inductive effect;- R2is -H or -X(CH2)pC(=0)o-i(CH2)q(C(RR2)2)o-i(X)o-iRR2with q and p being independently integers from 0 to 10, wherein X is independently O or NH, and RR2is independently -H or -Ci-4 alkyl;- R3is -H or -X(CH2)mC(=0)o-i(CH2)n(C(RR3)2)o-i(X)o-iRR3 with m and n being independently integers from 0 to 10, wherein X is independently O or NH, and RR3 is independently -H or -C1-4alkyl;R4is selected from -H , -CH2ORR4, -CH2NHRR4, and -CH2C(=O)ORR4, wherein RR4 is -H or -C1-4alkyl; and R5is -H or -C1-4alkyl;with the proviso that compounds of formula (I) having the following combination of R2,R3, R4and R5are excluded:- R2is -OCH3, R3is -OH, R4is -H and R5is -H.

[0030] According to one embodiment, R1in formula (I) is -OH or -C≡N . According to a preferred embodiment, R1is -C=N. It has been found that in some cases, the increase in potency over the parent compound trabectedin is more pronounced if R1is -C≡N compared to -OH.

[0031] According to further examples, the present invention relates to a compound of formula (I) as shown above or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof, wherein- R2is -H, -ORR2, -OCH2CH2ORR2, -OCH2C(CH3)2ORR2, -OCH2CH2NHRR2, -OCH2C(=O)ORR2, -NHRR2or-NHC(=O)CH2ORR2, wherein RR2is -H or -C1-4alkyl, preferably R2is -H, -OCH3, -OCH2CH2OH, -OCH2C(CH3)2OH, -OCH2CH2NH2, -OCH2C(=O)OH, -NH2or -NHC(=O)CH2OH; and / orR3is -H, -ORR3, -NHRR3 or -NHC(=O)CH2ORR3, wherein RR3 is -H or -C1-4alkyl, preferably R3is -H, -OH, -NH2or -NHC(=O)CH2OH.

[0032] According to still further examples, the present invention relates to a compound of formula (I) as shown above or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof, whereinR4is -H, -CH2ORR4 or -CH2NHRR4, wherein RR4 is -H or -C1-4alkyl, preferably R4is -H, -CH2OH or -CH2NH2; and / or R5is -H or -C1-4alkyl, preferably R5is -H or -CH3.

[0033] According to still further examples, the present invention relates to a compound of formula (I) as shown above or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof, wherein R1is -OH or -C=N, preferably R1is -C=N;- R2is -H, -OCH3, -OCH2CH2OH, -OCH2C(CH3)2OH, -OCH2CH2NH2, -OCH2C(=O)OH, -NH2or -NHC(=O)CH2OH, preferably R2is -OCH2CH2OH;- R3is -H, -OH, -NH2or -NHC(=O)CH2OH, preferably R3is -NH2;- R4is -H, -CH2OH or -CH2NH2, preferably R4is -CH2NH2; and R5is -H or -CH3, preferably R5is -CH3.

[0034] For example, formula (I) may be one of the following:; or; or

[0035] Additionally or alternatively, formula (I) may for example be one of the following:

[0036] In another embodiment of the present invention:- R2is -H, -ORR2, -OCH2CH2ORR2, -OCH2C(=O)ORR2or -NHRR2, wherein RR2is -H or -C1-4alkyl, preferably R2is -H, -OCH3, -OCH2CH2OH, -OCH2C(=O)OH or -NH2; and / or- R3is -H, -ORR3, -OCH2CH2NHRR3, -NHRR3, -NHC(=O)CH2ORR3or -NHC(=O)CH2NHRR3, wherein RR3is -H or -C1-4alkyl, preferably R3is -H, -OH, OCH2CH2NH2, -NH2, -NHC(=O)CH2OH or -NHC(=O)CH2NH2.

[0037] In still another embodiment of the present invention:R4is -H, -CH2ORR4or -CH2NHRR4, wherein RR4 is -H or -C1-4alkyl, preferably R4is -H; and / or R5is -H or -C1-4alkyl, preferably R5is -H.

[0038] In a preferred embodiment of the present invention:- R1is -OH or -C≡N :- R2is -H, -OCH3, -OCH2CH2OH, -OCH2C(=O)OH or -NH2;- R3is -H, -OH, -OCH2CH2NH2, -NH2, -NHC(=O)CH2OH or -NHC(=O)CH2NH2;R4is -H; and- R5is -H.

[0039] In a more preferred embodiment of the present invention, formula (I) is one of the following:; or

[0040] Some compounds of the present invention show a particularly high activity against individual cell lines, such as OV-90 which is indicative for a superior treatment of ovarian cancer, in particular papillary serous carcinoma of the ovary. Accordingly, in another embodiment, the present invention relates to a compound of formula (I) as shown above or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof, wherein- R1is -C M:- R2is -H, -OCH3or -OCH2CH2OH;- R3is -OH, -OCH2CH2NH2, -NH2, -NHC(=O)CH2OH, or -NHC(=O)CH2NH2;R4is -H; and- R5is -H.

[0041] For example, in another more preferred embodiment of the present invention, formula (I) is one of the following:; or

[0042] Other compounds of the present invention show a particularly high activity against individual cell lines, such as MDA-MB-231 which is indicative for a superior treatment of breast cancer, in particular breast adenocarcinoma. Accordingly, in this embodiment, the present invention relates to a compound of formula (I) as shown above or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof, wherein- R1is -C=N;- R2is -H, -OCH3or -OCH2CH2OH;- R3is -OH, -NH2, -NHC(=O)CH2OH, or -NHC(=O)CH2NH2;R4is -H; andR5is -H.

[0043] For example, in a more preferred embodiment according to the present invention, formula (I) is one of the following:; or

[0044] As explained above, another aspect of the present invention relates to a compound of formula (VII) or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof:wherein R1is a substituent having a negative inductive effect;- R2is -H or -X(CH2)PC(=0)o-i(CH2)q(C(RR2)2)o-i(X)o-iRR2with q and p being independently integers from 0 to 10, wherein X is independently O or NH, and RR2is independently -H or -Ci-4 alkyl;- R3is -H or -X(CH2)mC(=0)o-i(CH2)n(C(RR3)2)o-i(X)o-iRR3 with m and n being independently integers from 0 to 10, wherein X is independently O or NH, and RR3 is independently -H or -C1-4alkyl; andR4is -H or -C1-4alkyl; with the proviso that compounds of formula (VII) having the following combination ofR2, R3and R4are excluded:R2is -H, R3is -H and R4is -H; andR2is -OCH3, R3is -H and R4is -H.

[0045] According to one embodiment, R1in formula (VII) is -OH or -C≡N . According to a preferred embodiment, R1is -C≡N . It has been found that in some cases, the increase in potency over the parent compound lurbinectedin is more pronounced if R1is -C=N compared to -OH.

[0046] According to further examples, the present invention relates to a compound of formula (VII) as shown above or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof, whereinR2is -H, -ORR2, -NHRR2or -NHC(=O)CH2ORR2, wherein RR2is -H or -C1-4alkyl, preferably R2is -H, -OCH3, -NH2or -NHC(=O)CH2OH; and / or- R3is -H, -NHRR3or -NHC(=O)CH2ORR3, wherein RR3is -H or -C1-4alkyl, preferably R3is -H, -NH2or -NHC(=O)CH2OH.

[0047] According to still further examples, the present invention relates to a compound of formula (VII) as shown above or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof, wherein- R4is -H or -CH3.

[0048] According to still further examples, the present invention relates to a compound of formula (VII) as shown above or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof, wherein R1is -OH or -C=N, preferably R1is -C=N;- R2is -H, -OCH3, -NH2or -NHC(=O)CH2OH, preferably R2is -NH2;- R3is -H, -NH2or -NHC(=O)CH2OH, preferably R3is -NH2; andR4is -H or -CH3, preferably R4is -CH3.

[0049] For example, formula (VII) may be one of the following:; or; or

[0050] Additionally or alternatively, formula (VII) may for example be one of the following:; or

[0051] In another embodiment of the present invention:R2is -H, -NHRR2or -NHC(=O)CH2ORR2, wherein RR2is -H or -C1-4alkyl, preferably R2is -H, -NH2or -NHC(=O)CH2OH; and / orR3is -H or -NHRRS, wherein RR3 is -H or -C1-4alkyl, preferably R3is -H or -NH2.

[0052] In still another embodiment of the present invention:- R4is -H or -CH3.

[0053] In a preferred embodiment of the present invention:- R1is -OH or -C=N;- R2is -H, -NH2or -NHC(=O)CH2OH;R3is -H or -NH2; and- R4is -H or -CH3.

[0054] In a more preferred embodiment of the present invention, formula (VII) is one of the following:; or; or

[0055] As explained above, some compounds of the present invention show a particularly high activity against individual cell lines, such as OV-90 which is indicative for a superior treatment of ovarian cancer, in particular papillary serous carcinoma of the ovary. Accordingly, in another embodiment, the present invention relates to a compound of formula (VII) as shown above or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof, wherein- R1is -C M:R2is -NH2;R3is -H; and- R4is -CH3.Accordingly, in this embodiment, formula (VII) is the following:

[0056] Other compounds of the present invention show a particularly high activity against individual cell lines, such as MDA-MB-231 which is indicative for a superior treatment of breast cancer, in particular breast adenocarcinoma. Accordingly, in this embodiment, the present invention relates to a compound of formula (VII) as shown above or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof, wherein- R1is -C ≡NR2is -H, or NH2;R3is -H or -NH2; andR4is -H.

[0057] For example, in a more preferred embodiment according to the present invention, formula (I) is one of the following:

[0058] As explained above, still another aspect of the present invention relates to a compound of formula (XIII) or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof:wherein R1is a substituent having a negative inductive effect;- R2is -H or -X(CH2)pC(=0)o-i(CH2)q(C(RR2)2)o-i(X)o-iRR2with q and p being independently integers from 0 to 10, wherein X is independently O or NH, and RR2is independently -H or -Ci-4 alkyl;- R3is -H or -X(CH2)mC(=0)o-i(CH2)n(C(RR3)2)o-i(X)o-iRR3 with m and n being independently integers from 0 to 10, wherein X is independently O or NH, and RR3 is independently -H or -C1-4alkyl; andR4is -H or -CH2NHRR4, wherein RR4 is -H or -C1-4alkyl.

[0059] According to one embodiment, R1in formula (XIII) is -OH or -C≡N . According to a preferred embodiment, R1is -C=N. It has been found that in some cases, the increase in potency over the parent compound lurbinectedin is more pronounced if R1is -C≡N compared to -OH.

[0060] According to further examples, the present invention relates to a compound of formula (XIII) as shown above or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof, whereinR2is -ORR2or -NHRR2, wherein RR2is -H or -C1-4alkyl, preferably R2is -OCH3or -NH2; and / orR3is -H.

[0061] According to still further examples, the present invention relates to a compound of formula (XIII) as shown above or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof, wherein- R4is -H or -CH2NH2.

[0062] According to still further examples, the present invention relates to a compound of formula (XIII) as shown above or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof, wherein R1is -OH or -C=N, preferably R1is -C=N;R2is -OCH3or -NH2, preferably R2is -NH2;R3is -H; and- R4is -H or -CH2NH2, preferably R4is -CH2NH2.

[0063] For example, formula (XIII) may be one of the following:; or

[0064] Additionally or alternatively, formula (XIII) may for example be the following:

[0065] In another embodiment of the present invention:R2is -ORR2or -NHRR2, wherein RR2is -H or -C1-4alkyl, preferably R2is -OCH3or -NH2; and / or- R3is -H.

[0066] In still another embodiment of the present invention:R4is -H.

[0067] In a preferred embodiment of the present invention: R1is -OH or -C M:R2is -OCH3or -NH2;R3is -H; andR4is -H.

[0068] In a more preferred embodiment of the present invention, formula (XIII) is one of the following:

[0069] In all aspects and corresponding embodiments described hereinabove, RR2, RR3 and RR4 preferably may independently be -H or -CH3.

[0070] Also, as explained above, still another aspect according to the present invention relates to an antibody-drug conjugate of formula (XIX):Ab-^L— D,(XIX)whereinAb denotes an antibody, an antigen-binding fragment, or an immunologically active portion thereof;L denotes a linker; andD denotes a compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof selected from the group consisting of trabectedin, lurbinectedin and the compounds according to the foregoing aspects and embodiments, preferably a compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof according to the foregoing aspects and embodiments; and whereinD covalently binds to L via nitrogen or oxygen present in D, and L covalently binds to Ab; and z is an integer from 1 to 20.

[0071] As defined herein, in the antibody-drug conjugate of the present invention, compound D covalently binds to a linker L via nitrogen or oxygen present in the compound. Those skilled in the art understand this to mean that, formally, linker L takes the place of a proton (H) present in the respective compound according to the present invention. For example, if the compound is the following:then the anti-body drug conjugate may be described by the following structure according to formula (XIX) wherein the compound binds to the linker L via nitrogen present in R2:

[0072] Unless specifically dictated otherwise, the skilled person will understand that D may covalently bind to the linker L via any other nitrogen or oxygen atom present in the compound. However, in a preferred embodiment of the present invention, D covalently binds to L via nitrogen or oxygen present in any of R2, R3or R4, preferably in any of R2or R3(both for the trabectedin and lurbinectedin derivatives disclosed herein).

[0073] The antibody-drug conjugate is characterized by a specific so-called drug-to- antibody ratio (also referred to as DAR). With respect to an individual molecule as shown above, the drug-to-antibody ratio is an integer, herein expressed as “z”. Therefore, in one embodiment of the present invention, z is an integer from 1 to 10, preferably 1 to 6, more preferably 2 to 4 and still more preferably 2 or 4. However, due to the manufacturing process, the measurable drug-to-antibody ratio of a given sample (which consists of a large number of anti-body drug conjugate molecules) is usually not an integer but an average number. Therefore, in another embodiment, the antibody-drug conjugate is characterized by a specific average drug-to- antibody ratio which may be less than 1.5, or in a range from at least 1.5 to less than 2.5, or at least 2.5 to less than 3.5.

[0074] In the antibody-drug conjugate of formula (XIX) according to the present invention, Ab denotes an antibody, an antigen-binding fragment, or an immunologically active portion thereof. In a preferred embodiment of the present invention, Ab denotes an antibody.

[0075] In general, the present invention is not limited to specific antibodies. However, given the structure of the compounds of the present invention and the effect on inhibition towards specific cancer cells lines that is attributable to the structure of the respective compound, certain combinations may be beneficial. In terms of their target, it was found that anti-RORl antibodies, anti-TROP2 antibodies, and anti-HER2antibodies may be beneficial. Other usefulantibodies include anti-HER3antibodies, anti-FRoc antibodies, and anti-EGFR antibodies. Therefore, in another embodiment of the present invention, the antibody, antigen-binding fragment, or an immunologically active portion thereof (Ab) is selected from anti-HER2antibodies, anti-RORl antibodies, anti-TROP2 antibodies, anti-HER3antibodies, anti-FRoc antibodies, and anti-EGFR antibodies. In a preferred embodiment, the antibody, antigenbinding fragment, or an immunologically active portion thereof (Ab) is selected from the group consisting of anti-HER2antibodies, anti-RORl antibodies, anti-TROP2 antibodies, anti-HER3antibodies and anti-EGFR antibodies, more preferably anti-HER2antibodies, anti-TROP2 antibodies and anti-HER3antibodies, still more preferably anti-HER2antibodies and anti- TR0P2 antibodies, and most preferably anti-HER2antibodies. In alternative embodiments, the antibody, antigen-binding fragment, or an immunologically active portion thereof (Ab) is selected from anti-RORl antibodies or anti-EGFR antibodies, preferably anti-RORl antibodies. Specific antibodies useful for the purpose of the present invention therefore include Cirmtuzumab (as example for an anti-RORl antibody), Sacituzumab (as an example for an anti-TROP2 antibody), and Trastuzumab (as an example for an anti-HER2antibody). Other useful antibodies include Patritumab (as example for an anti-HER3antibody), Mirvetuximab (as example for an anti-FRoc antibody) and Cetuximab (as example for an anti-EGFR antibody). Therefore, in a more specific embodiment of the present invention, the antibody, antigenbinding fragment, or an immunologically active portion thereof (Ab) is selected from the group consisting of Cirmtuzumab, Sacituzumab, Trastuzumab, Patritumab, Mirvetuximab and Cetuximab. In a preferred embodiment, the antibody, antigen-binding fragment, or an immunologically active portion thereof (Ab) is selected from the group consisting of Cirmtuzumab, Sacituzumab, Trastuzumab, Patritumab and Cetuximab, more preferably Sacituzumab, Trastuzumab and Patritumab, still more preferably Sacituzumab and Trastuzumab, and most preferably Trastuzumab. In alternative embodiments, the antibody, antigenbinding fragment, or an immunologically active portion thereof (Ab) is Cirmtuzumab or Cetuximab, preferably Cirmtuzumab.

[0076] In still another embodiment of the present invention, the anti-RORl antibody has an antigen-binding fragment (Fab) comprising a heavy chain and a light chain, wherein preferably the sequence of the heavy chain is essentially identical to SEQ ID NO. 3 disclosedin US 2022 / 0133901 Al, and the sequence of the light chain is essentially identical to SEQ ID NO. 4 disclosed in US 2022 / 0133901 Al.

[0077] For example, in another embodiment, the heavy chain of the antigen-binding fragment (Fab) of the anti-RORl antibody has the following sequence (SEQ ID NO. 1): QVQLQESGPGLVKP SQTLSLTCTVSGYAFTAYNIHWVRQAPGQGLEWMGSS FDPYDGGSSYNQKFKDRLTI SKDTSKNQWLTMTNMDPVDTATYYCARGWY YFDYWGHGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNH KPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGP SVFLFPPKPKDTLMISR TPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVL TVLHQDWLNGKEYKCKVSNKALPAP IEKTISKAKGQPREPQVYTLPP SRDE LTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS KLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK and the light chain has the following sequence (SEQ ID NO. 2):DIVMTQTPLSLPVTPGEPAS ISCRASKSISKYLAWYQQKPGQAPRLLIYSG STLQSGIPPRFSGSGYGTDFTLTINNIESEDAAYYFCQQHDESPYTFGEGT KVEIKRTVAAPSVF IFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNA LQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSP VTKSFNRGEC.

[0078] In still another embodiment of the present invention, the anti-TROP2 antibody has an antigen-binding fragment (Fab) comprising a heavy chain and a light chain, wherein preferably the sequence of the heavy chain is essentially identical to Chain ID INN 10418_H, and the sequence of the light chain is essentially identical to Chain ID INN 10418_L as disclosed in the mAb database of the International Immunogenetics Information System (IMGT) under INN number 10418 (IMGT release date: 20-Mar-17).

[0079] For example, in another embodiment, the heavy chain of the antigen-binding fragment (Fab) of the anti-TROP2 antibody has the following sequence (SEQ ID NO. 3):QVQLQQSGSELKKPGASVKVSCKASGYTFTNYGMNWVKQAPGQGLKWMGWI NTYTGEPTYTDDFKGRFAFSLDTSVSTAYLQISSLKADDTAVYFCARGGFGSSYWYFDVWGQGSLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV VSVLTVLHQDWLNGKEYKCKVSNKALPAP IEKTI SKAKGQPREPQVYTLPP SREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF FLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK and the light chain has the following sequence (SEQ ID NO. 4):DIQLTQSPSSLSASVGDRVS ITCKASQDVSIAVAWYQQKPGKAPKLLIYSA SYRYTGVPDRFSGSGSGTDFTLTISSLQPEDFAVYYCQQHYITPLTFGAGT KVEIKRTVAAPSVF IFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNA LQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSP VTKSFNRGEC.

[0080] In still another embodiment of the present invention, the anti-HER2antibody has an antigen-binding fragment (Fab) comprising a heavy chain and a light chain, wherein preferably the sequence of the heavy chain is essentially identical to the Anti-HER2 Heavy chain, and the sequence of the light chain is essentially identical to the Anti-HER2 Light chain disclosed in the DrugBank under Accession Number DB00072.

[0081] For example, in another embodiment, the heavy chain of the antigen-binding fragment (Fab) of the anti-HER2antibody has the following sequence (SEQ ID NO. 5): EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARI YPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGD GFYAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYF PEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICN VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM ISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRW SVLTVLHQDWLNGKEYKCKVSNKALPAP IEKTISKAKGQPREPQVYTLPPS REEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFF LYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK and the light chain has the following sequence (SEQ ID NO. 6):DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSA SFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKRTVAAPSVF IFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC.

[0082] In still another embodiment of the present invention, the anti-HER3antibody has an antigen-binding fragment (Fab) comprising a heavy chain and a light chain, wherein preferably the sequence of the heavy chain is essentially identical to Chain ID INN 9549_H, and the sequence of the light chain is essentially identical to Chain ID INN 9549_L as disclosed in the mAb database of the International Immunogenetics Information System (IMGT) under INN number 9549.

[0083] For example, in another embodiment, the heavy chain of the antigen-binding fragment (Fab) of the anti-HER3antibody has the following sequence (SEQ ID NO. 7): QVQLQQWGAGLLKP SETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGEI NHSGSTNYNPSLKSRVTISVETSKNQFSLKLSSVTAADTAVYYCARDKWTW YFDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNH KPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGP SVFLFPPKPKDTLMISR TPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVL TVLHQDWLNGKEYKCKVSNKALPAP IEKTISKAKGQPREPQVYTLPP SREE MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS KLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK and the light chain has the following sequence (SEQ ID NO. 8):DIEMTQSPDSLAVSLGERATINCRSSQSVLYSSSNRNYLAWYQQNPGQPPK LLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSTPR TFGQGTKVEIKRTVAAPSVF IFPPSDEQLKSGTASWCLLNNFYPREAKVQ WKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH QGLSSPVTKSFNRGEC.

[0084] In still another embodiment of the present invention, the anti-FRoc antibody has an antigen-binding fragment (Fab) comprising a heavy chain and a light chain, wherein preferably the sequence of the heavy chain is essentially identical to Chain ID INN 10187_H, and the sequence of the light chain is essentially identical to Chain ID INN 10187_L asdisclosed in the mAb database of the International Immunogenetics Information System (IMGT) under INN number 10187 (IMGT release date: 26 July 2016).

[0085] For example, in another embodiment, the heavy chain of the antigen-binding fragment (Fab) of the anti-FRoc antibody has the following sequence (SEQ ID NO. 9):QVQLVQSGAEWKPGASVKI SCKASGYTFTGYFMNWVKQSPGQSLEWIGRI HPYDGDTFYNQKFQGKATLTVDKSSNTAHMELLSLTSEDFAVYYCTRYDGS RAMDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPE PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVN HKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMIS RTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSV LTVLHQDWLNGKEYKCKVSNKALPAP IEKTISKAKGQPREPQVYTLPPSRD ELTKNQVSLTCLVKGFYPSD IAVEWESNGQPENNYKTTPPVLDSDGSFFLY SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG and the light chain has the following sequence (SEQ ID NO. 10):DIVLTQSPLSLAVSLGQPAI ISCKASQSVSFAGTSLMHWYHQKPGQQPRLL IYRASNLEAGVPDRFSGSGSKTDFTLTISPVEAEDAATYYCQQSREYPYTF GGGTKLE IKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWK VDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQG LSSPVTKSFNRGEC .

[0086] In still another embodiment of the present invention, the anti-EGFR antibody has an antigen-binding fragment (Fab) comprising a heavy chain and a light chain, wherein preferably the sequence of the heavy chain is essentially identical to the Anti-EGFR Heavy chain, and the sequence of the light chain is essentially identical to the Anti-EGFR Light chain disclosed in the DrugBank under Accession Number DB00002.

[0087] For example, in another embodiment, the heavy chain of the antigen-binding fragment (Fab) of the anti-EGFR antibody has the following sequence (SEQ ID NO. 11):QVQLKQSGPGLVQP SQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVI WSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYY DYEFAYWGQGTLVTVSAASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFP EPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWS VLTVLHQDWLNGKEYKCKVSNKALPAP IEKTISKAKGQPREPQVYTLPPSR DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL YSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK and the light chain has the following sequence (SEQ ID NO. 12):DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYA SESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGT KLELKRTVAAPSVF IFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNA LQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSP VTKSFNRGEC.

[0088] The term “essentially identical” may refer to sequences having a defined percentage of sequential units (e.g., amino acid residues) which are the same when compared and aligned for maximum correspondence over a comparison window, preferably over the entire sequence. Therefore, in a further embodiment it is to be understood that substantially identical sequences are at least 80% identical, preferably at least 90%, more preferably at least 95%, still more preferably at least 98%, and most preferably at least 99%. In an alternative embodiment, the sequences are identical over the entire sequence (100% sequence identity).

[0089] Percent (%) sequence identity with respect to a reference protein sequence refers to the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the reference sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are known to the skilled person. As used herein, the percent sequence identity refers to the identity determined by BLAST using the so-called blastp algorithm (protein-protein BLAST).

[0090] In general, D in formula (XIX) is a compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof selected from the group consisting of trabectedin, lurbinectedin and the compounds according to formula (I), (VII) or (XIII) disclosed herein. In a preferred embodiment, D is a compound according to formula (I), (VII) or (XIII) disclosed herein or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof.

[0091] Useful combinations of antibodies, an antigen-binding fragments or immunologically active portions thereof (Ab) with compounds, pharmaceutically acceptable salts, esters, solvates, tautomers or stereoisomers thereof for use as payloads (D) according to formula (XIX) include any combination of the individual embodiments disclosed hereinabove pertaining to Ab and D, respectively.

[0092] Some particularly useful embodiments will be described in the following. For example, in one embodiment, D is a compound according to formula (I), wherein R1is -OH or -C≡N , R2is selected from -H, -OCRR2and -CH2CH2ORR2with RR2being -H or -C1-4alkyl, R3is selected from -ORR3, -NHRR3, and -NHC(=O)CH2NHRR3 with RR3 being -H or -C1-4alkyl, R4is -H or -C1-4alkyl, and R5is -H or -C1-4alkyl, preferably R1is -OH or -C=N, R2is selected from -H, -OCH3and -CH2CH2OH, R3is selected from -OH, -NH2, and -NHC(=O)CH2NH2, R4is -H, and R5is -H; or according to formula (VII), wherein R1is -OH or -C=N, R2is -NHRR2with RR2being -H or -C1-4alkyl, R3is -H or -C1-4alkyl, and R4is -H or -C1-4alkyl, preferably R1is -C=N, R2is -NH2, R3is -H, and R4is -H; or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer of any of the foregoing.

[0093] Specifically, in a preferred embodiment, D is one of the following:or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer of any of the foregoing.

[0094] In another embodiment of the present invention, D is a compound according to formula (I), wherein R1is -C≡N , R2is selected from -H, -OCRR2and -CH2CH2ORR2with RR2being -H or -C1-4alkyl, R3is selected from -ORR3, -NHRR3, and -NHC(=O)CH2NHRR3with RR3being -H or -C1.4 alkyl,R4is -H or -C1-4alkyl, and R5is -H or -C1-4alkyl, preferably R1is -C≡N , R2is selected from -H, -OCH3and -CH2CH2OH, R3is selected from -OH, -NH2, and -NHC(=O)CH2NH2, R4is -H, and R5is -H; or according to formula (VII), wherein R1is -OH or -C=N, R2is -NHRR2with RR2being -H or -C1-4alkyl, R3is -H or -C1-4alkyl, and R4is -H or -C1-4alkyl, preferably R1is -C≡N , R2is -NH2, R3is -H, and R4is -H; or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer of any of the foregoing.

[0095] Specifically, in a preferred embodiment, D is one of the following:or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer of any of the foregoing.

[0096] In still another embodiment of the present invention, D is a compound according to formula (I), wherein R1is -C≡N , R2is selected from -H, -OCRR2and -CH2CH2ORR2with RR2being -H or -C1-4alkyl, R3is -ORR3 or -NHRR3 with RR3 being -H or -C1-4alkyl, R4is -H or -C1-4alkyl, and R5is -H or -C1-4alkyl, preferably R1is -C≡N , R2is selected from -H, -OCH3and -CH2CH2OH, R3is -OH or -NH2, R4is -H, and R5is -H; or according to formula (VII), wherein R1is -OH or -C≡N , R2is -NHRR2with RR2being -H or -C1-4alkyl, R3is -H or -C1-4alkyl, and R4is -H or -C1-4alkyl, preferably R1is -C=N, R2is -NH2, R3is -H, and R4is -H; or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer of any of the foregoing.

[0097] Specifically, in a preferred embodiment, D is one of the following:or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer of any of the foregoing.

[0098] In still another embodiment of the present invention, D is a compound according to formula (I), wherein R1is -C≡N , R2is -H or -CH2CH2ORR2with RR2being -H or -C1-4alkyl, R3is -ORR3 or -NHRR3 with RR3 being -H or -C1-4alkyl, R4is -H or -C1-4alkyl, and R5is -H or -C1-4alkyl, preferably R1is -C=N, R2is -H or -OCH3, R3is -OH or -NH2, R4is -H, and R5is -H; or according to formula (VII), wherein R1is -OH or -C=N, R2is -NHRR2with RR2being -H or -C1-4alkyl, R3is -H or -C1-4alkyl, and R4is -H or -C1-4alkyl, preferably R1is -C=N, R2is -NH2, R3is -H, and R4is -H; or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer of any of the foregoing.

[0099] Specifically, in a preferred embodiment, D is one of the following, a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof:; oror a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer of any of the foregoing.

[0100] In still another embodiment of the present invention, D is a compound according to formula (I), wherein R1is -C=N, R2is -H or -CH2CH2ORR2with RR2being -H or -C1-4alkyl, R3is -ORR3 or -NHRR3 with RR3 being -H or -C1-4alkyl, R4is -H or -C1-4alkyl, and R5is -H or -C1-4alkyl, preferably R1is -C=N, R2is -H or -OCH3, R3is -OH or -NH2, R4is -H, and R5is -H; or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer of any of the foregoing.

[0101] Specifically, in a preferred embodiment, D is one of the following:or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer of any of the foregoing.

[0102] The structure of the linker L present in formula (XIX) describing the antibodydrug conjugate of the present invention is believed to be not particularly critical, but it may be defined as follows:whereinT and U are independently spacer units, each having from 1 to 24 chain carbons, wherein t and u are independently 0 or 1, preferably t + u > 1; each A is independently an amino acid unit, wherein a is an integer from 0 to 12;H is a hydrophilic unit, wherein h is 0 or 1 ; andY is a conjugating group that covalently binds to Ab; wherein preferably the conjugating group Y covalently binds to a sulfur atom present in Ab.

[0103] Accordingly, the antibody-drug conjugate of the present invention as defined by formula (XIX) may be described as follows:For example, if the compound is the following:then the anti-body drug conjugate may be described by the following structure according to formula (XIX) wherein the compound binds to the linker L via nitrogen present in R2:

[0104] In a preferred embodiment according to the present invention, the conjugating group Y of the linker L covalently binds to a sulfur atom present in Ab, which means a sulfur atom present in the antibody, an antigen-binding fragment or an immunologically active portion thereof. Therefore, the antibody-drug conjugate represented by formula (XIX) may have the following structure:

[0105] Generally, T and U are spacer units which may be independently selected from spacer units having from 1 to 24 chain carbons. The indices t and u are independently 0 or 1 which means that both units may be absent or, alternatively, both units may be present. Preferably, the linker contains at least one of T and U i.e., t + u > 1. Chain carbons are those carbons present in a chain that links T or U to the respective adjacent unit or compound D, including carbons of a ring forming part of that chain. Where present, carbons of substituents or side chains are not included.

[0106] Those skilled in the art are well familiar with spacer units that are useful in connection with chemical linkers, including in antibody-drug conjugates. Useful spacer units include branched or unbranched polyalkylene chains as well as polyethylene glycol spacer units having up to 24 chain carbons. However, the spacer units may also exhibit more complex structures and may include functional groups such as carbonyls. Also, the spacer unit useful for the purpose of the present invention may include cyclic structures such as aromatic and nonaromatic hydrocarbons or heterocycles (including sugars).

[0107] In one embodiment according to the present invention, spacer unit U is one of the following:; orWhere present, n is preferably an integer from 5 to 10, more preferably 6 to 8, and most preferably 7.

[0108] According to still another embodiment of the present invention, spacer unit T is one of the following:wherein n is preferably an integer from 1 to 8, more preferably 1 to 6, and most preferably 2 or 5wherein m is preferably 1, and n is an integer from 2 to 8, more preferably 4 to 7, and most preferably 5 or 6.

[0109] The linker L may contain a hydrophilic unit H. The skilled person is generally familiar with chemical structures that are capable of introducing hydrophilicity and thereby increasing the tendency of a given compound or, as relevant here, an antibody drug conjugate to be solvated in an aqueous environment. Typically, the hydrophilic unit H will be rich in oxygen. According to one embodiment of the present invention, the hydrophilic unit H is therefore derived from a PEGylated amino acid, and preferably H is one of the following:wherein more preferably n is an integer from 5 to 10, still more preferably 6 to 8, and most preferably 7; orwherein more preferably n is an integer from 5 to 10, still more preferably 6 to 8, and most preferably 7. Additionally or alternatively, the hydrophilic unit H may be the following:wherein n is preferably an integer from 2 to 8, more preferably 4 to 7, and most preferably 5 or6.

[0110] The conjugating group Y present in the antibody-drug conjugate may be derived from any group that, in its unreacted form, is capable of binding to an antibody, an antigenbinding fragment or an immunologically active portion thereof (Ab). Since it is preferred that the conjugating group Y covalently binds to a sulfur atom of the antibody, an antigen-binding fragment or an immunologically active portion thereof, Y is preferably derived from double bond-containing functional groups. To that extent, particularly suitable functional groups are oc,P-unsaturated carbonyls. Therefore, in one embodiment, Y is a conjugating group derived from maleimide, maleamic acid ester, or allenamide, preferably the conjugating group Y is derived from maleimide. In a more specific and more preferred embodiment, Y is such that L is one of the following:wherein, if present, Re is -H or -C1-4alkyl, preferably -H or -CH3.

[0111] The linker L may optionally contain one more amino acid units A so that L may comprise a structural motif that can be represented as (A)o-i2 because a in (A)ais an integer from 0 to 12. In further embodiments, a is an integer from 1 to 10, more preferably from 1 to 5, still more preferably 1 to 4, and most preferably 2 or 4.

[0112] Each individual unit referred to as A has the following structure which shall include all proteinogenic amino acids, and others where R7 is p-hydroxybenzyl or -(CH2)3NHC(C=O)NH2(citrulline):In a preferred embodiment according to the present invention, R7 is independently selected from the group consisting of -H (glycine), -CH3(alanine), -C(H)(CH3)2 (valine), benzyl (phenylalanine), p-hydroxybenzyl and -(CH2)3NHC(C=O)NH2(citrulline); more preferably R7 is independently selected from the group consisting of -H (glycine), -C(H)(CH3)2 (valine), benzyl (phenylalanine) and -(CH2)3NHC(C=O)NH2(citrulline).

[0113] In some cases, specific combinations of amino acids are preferred. In particularly preferred embodiments, this includes the combinations known as “GGFG” (glycine - glycine -phenylalanine-glycine), and the combination known to the skilled person as “Val-Cit” (valine-citrulline). Accordingly, in these embodiments, the linker L may be one of the following:Additionally or alternatively, advantageous combinations include those referred to as “GGGG- Val-Cit” and “Vai- Ala” . Accordingly, the linker L may be one of the following:

[0114] In further embodiments according to the present invention, H and h, and A and a, and U and u are such that L is one of the following:; or; or

[0115] In still further embodiments according to the present invention, L is such thatFormula (XIX) is one of the following:; or; or; or

[0116] Still another aspect of the present invention relates to the compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer disclosed herein for use as a medicament, with a more specific aspect relating to the use in the treatment of cancer, preferably ovarian cancer, stomach cancer or breast cancer. In a more preferred embodiment, cancer types include ovarian cancer and breast cancer. A particularly preferred embodiment relates to the compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer disclosed herein for use in the treatment of papillary serous adenocarcinoma of the ovary or breast adenocarcinoma.

[0117] As has been demonstrated by way of examples, the compounds of the present invention exhibit improved efficacy. This finding makes these compounds potent active ingredients for the conventional chemotherapy of ovarian cancer, breast cancer and stomach cancer, especially ovarian cancer and breast cancer.

[0118] Still another aspect of the present invention relates to the antibody-drug conjugate disclosed herein for use as a medicament, with a more specific aspect relating to the use in the treatment of cancer, preferably ovarian cancer, stomach cancer or breast cancer. Again, in a more preferred embodiment, cancer types include ovarian cancer and breast cancer. In an alternative embodiment, cancer types include stomach cancer and breast cancer. A particularly preferred aspect relates to the antibody-drug conjugate disclosed herein for use in the treatment of gastric carcinoma or breast adenocarcinoma.

[0119] A preferred embodiment of the present invention relates to the antibody-drug conjugate disclosed herein for use as a medicament, wherein the antibody is an anti-RORl antibody, preferably Cirmtuzumab, and / or wherein the invention relates to the antibody-drug conjugate for use in the treatment of ROR1 -positive ovarian cancer; the antibody is an anti-TROP2 antibody, preferably Sacituzumab, and / or wherein the invention relates to the antibody-drug conjugate for use in the treatment of TROP2-positive stomach cancer; the antibody is an anti-HER2antibody, preferably Trastuzumab, and / or wherein the invention relates to the antibody-drug conjugate for use in the treatment of HER2- positive breast cancer; the antibody is an anti-HER3antibody, preferably Patritumab, and / or wherein the invention relates to the antibody-drug conjugate for use in the treatment of HER3-positive stomach cancer; the antibody is an anti-FRoc antibody, preferably Mirvetuximab, and / or wherein the invention relates to the antibody-drug conjugate for use in the treatment of FRoc -positive ovarian cancer;the antibody is an anti-EGFR antibody, preferably Cetuximab, and / or wherein the invention relates to the antibody-drug conjugate for use in the treatment of EGFR - positive breast cancer.In the foregoing embodiments, the antibodies may have the respective structure disclosed hereinabove. According to the present invention, anti-RORl antibodies may be more preferred, in particular Cirmtuzumab.

[0120] According to a further aspect of the present invention, a process for the preparation of an antibody-drug conjugate of general formula (XIX) is provided:Ab^L- D,z(XIX) the method comprising conjugating an antibody, an antigen-binding fragment or an immunologically active portion thereof (Ab) to a compound (D) via a linker (L), whereinD is a compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof selected from the group consisting of trabectedin, lurbinectedin and the compounds according to formula (I), (VII) or (XIII) disclosed herein, preferably a compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof according to formula (I), (VII) or (XIII) disclosed herein;L is a linker as disclosed hereinabove;D covalently binds to L via nitrogen or oxygen present in D, and L covalently binds to Ab; and z is an integer from 1 to 20.

[0121] In a typical process, the compound D is synthesized and reacted first with a linker to provide a linker-payload building block. In accordance with the definitions provided hereinabove, the linker-payload building block of the present invention may thus be represented as follows:Y*— (T)t— (H)h— (A)a— (U)u— D wherein Y* denotes the unreacted form of a conjugating group Y that is capable of reacting with Ab, for example with a thiol group present in an antibody. As such, Y* may be a functionalgroup with a carbon-carbon double bond, such as maleimide, maleamic acid ester, or allene amide.

[0122] In a preferred embodiment, the process according to the present invention comprises a step of covalently attaching D to L via nitrogen or oxygen present in any of R2, R3or R4, preferably in any of R2or R3.

[0123] In order to accomplish the conjugation of the linker-payload building block and the antibody, the antibody, an antigen-binding fragment or an immunologically active portion thereof (Ab) is preferably reacted with a reducing agent first in order to reduce one or more of the disulfide groups contained therein, depending on the amount of reducing agent used and the desired drug-to-antibody ratio. Tris(2-carboxyethyl)phosphine (TCEP) may be preferred as a reducing agent. Only after the reduction, the appropriate amount of linker-payload building block is reacted with the (partially) reduced antibody, antigen-binding fragment or immunologically active portion thereof to provide the antibody-drug conjugate of the present invention having the desired drug-to-antibody ratio according to formula (XIX).

[0124] In one embodiment of the process according to the present invention, z is an integer from 1 to 10, preferably 1 to 6, more preferably 2 to 4 and still more preferably 2 or 4.

[0125] Antibodies generally useful for the process of the present invention include anti- HER2antibodies, anti-RORl antibodies, anti-TROP2 antibodies, anti-HER3antibodies, anti- FRoc antibodies, and anti-EGFR antibodies. Particularly useful antibodies are those explained above as being preferred. These antibodies may further have the structure disclosed hereinabove. For example, the antibody, antigen-binding fragment, or an immunologically active portion thereof (Ab) may be an anti-HER2antibody, such as Trastuzumab.

[0126] The present invention further relates to corresponding pharmaceutical dosage forms comprising a therapeutically effective amount of the compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer disclosed herein, or a therapeutically effective amount of the antibody-drug conjugate disclosed herein.

[0127] Also disclosed herein is a method of treating cancer, wherein the method comprises administering to a subject a therapeutically effective amount of the compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer as disclosed herein, atherapeutically effective amount of the antibody-drug conjugate disclosed herein, or the pharmaceutical dosage form disclosed above. Preferred cancer types include ovarian cancer, stomach cancer or breast cancer, wherein ovarian cancer and breast cancer may be preferred in terms of efficacy.

[0128] The invention disclosed herein is further defined by the following numbered embodiments:1. A compound of formula (I) or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof:wherein R1is a substituent having a negative inductive effect;- R2is -H or -X(CH2)pC(=0)o-i(CH2)q(C(RR2)2)o-i(X)o-iRR2with q and p being independently integers from 0 to 10, wherein X is O or NH, and RR2is independently -H or -Ci-4 alkyl;- R3is -H or -X(CH2)mC(=0)o-i(CH2)n(C(RR3)2)o-i(X)o-iRR3 with m and n being independently integers from 0 to 10, wherein X is O or NH, and RR3 is independently -H or -C1-4alkyl;R4is selected from -H , -CH2ORR4, -CH2NHRR4, and -CH2C(=O)ORR4, wherein RR4 is -H or -C1-4alkyl; and R5is -H or -C1-4alkyl; with the proviso that compounds of formula (I) having the following combination of R2,R3, R4and R5are excluded:- R2is -OCH3, R3is -OH, R4is -H and R5is -H.2. The compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to embodiment 1 , wherein R1is -OH or -C==N, preferably -C=N.3. The compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to any of embodiments 1 or 2, wherein- R2is -H, -ORR2, -OCH2CH2ORR2, -OCH2C(CH3)2ORR2,-OCH2CH2NHRR2, -OCH2C(=O)ORR2, -NHRR2or-NHC(=O)CH2ORR2, wherein RR2is -H or -Ci-4 alkyl, preferably R2is -H, -OCH3, -OCH2CH2OH, -OCH2C(CH3)2OH, -OCH2CH2NH2, -OCH2C(=O)OH, -NH2or -NHC(=O)CH2OH; and / orR3is -H, -ORR3, -NHRR3or -NHC(=O)CH2ORR3, wherein RR3is -H or -Ci-4 alkyl, preferably R3is -H, -OH, -NH2or -NHC(=O)CH2OH.4. The compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to any of embodiments 1 to 3, whereinR4is -H, -CH2ORR4 or -CH2NHRR4, wherein RR4 is -H or -C1-4alkyl, preferably R4is -H, -CH2OH or -CH2NH2; and / or R5is -H or -C1-4alkyl, preferably R5is -H or -CH3.5. The compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to any of embodiments 1 to 4, wherein R1is -OH or -C=N, preferably R1is -O=N;- R2is -H, -OCH3, -OCH2CH2OH, -OCH2C(CH3)2OH, -OCH2CH2NH2, -OCH2C(=O)OH, -NH2or -NHC(=O)CH2OH, preferably R2is -OCH2CH2OH;- R3is -H, -OH, -NH2or -NHC(=O)CH2OH, preferably R3is -NH2;- R4is -H, -CH2OH or -CH2NH2, preferably R4is -CH2NH2; and R5is -H or -CH3, preferably R5is -CH3.6. The compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to embodiment 1, wherein formula (I) is:; or7. A compound of formula (VII) or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof:wherein R1is a substituent having a negative inductive effect;- R2is -H or -X(CH2)pC(=0)o-i(CH2)q(C(RR2)2)o-i(X)o-iRR2with q and p being independently integers from 0 to 10, wherein X is O or NH, and RR2is independently -H or -Ci-4 alkyl;- R3is -H or -X(CH2)mC(=0)o-i(CH2)n(C(RR3)2)o-i(X)o-iRR3 with m and n being independently integers from 0 to 10, wherein X is O or NH, and RR3 is independently -H or -C1-4alkyl; andR4is -H or -C1-4alkyl; with the proviso that compounds of formula (VII) having the following combination of R2, R3and R4are excluded:R2is -H, R3is -H and R4is -H; andR2is -OCH3, R3is -H and R4is -H.8. The compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to embodiment 7, wherein R1is -OH or -C==N, preferably -C=N.9. The compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to any of embodiments 7 or 8, whereinR2is -H, -0RR2, -NHRR2or -NHC(=O)CH2ORR2, wherein RR2is -H or -C1-4alkyl, preferably R2is -H, -OCH3, -NH2or -NHC(=O)CH2OH; and / or- R3is -H, -NHRR3or -NHC(=O)CH2ORR3, wherein RR3is -H or -C1-4alkyl, preferably R3is -H, -NH2or -NHC(=O)CH2OH.10. The compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to any of embodiments 7 to 9, wherein- R4is -H or -CH3.11. The compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to any of embodiments 7 to 10, wherein R1is -OH or -C=N, preferably R1is -C=N;- R2is -H, -OCH3, -NH2or -NHC(=O)CH2OH, preferably R2is -NH2;- R3is -H, -NH2or -NHC(=O)CH2OH, preferably R3is -NH2; andR4is -H or -CH3, preferably R4is -CH3.12. The compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to embodiment 7, wherein formula (VII) is:; or; orA compound of formula (XIII) or a pharmaceutically acceptable salt, ester, solvate,wherein R1is a substituent having a negative inductive effect;- R2is -H or -X(CH2)PC(=0)o-i(CH2)q(C(RR2)2)o-i(X)o-iRR2with q and p being independently integers from 0 to 10, wherein X is O or NH, and RR2is independently -H or -C1-4alkyl;- R3is -H or -X(CH2)mC(=0)o-i(CH2)n(C(RR3)2)o-i(X)o-iRR3 with m and n being independently integers from 0 to 10, wherein X is O or NH, and RR3 is independently -H or -C1-4alkyl; andR4is -H or -CH2NHRR4, wherein RR4is -H or -C1-4alkyl.14. The compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to embodiment 13, wherein R1is -OH or -C=N, preferably -C=N.15. The compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to any of embodiments 13 or 14, whereinR2is -ORR2or -NHRR2, wherein RR2is -H or -C1-4alkyl, preferably R2is -OCH3or -NH2; and / or- R3is -H.16. The compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to any of embodiments 13 to 15, wherein- R4is -H or -CH2NH2.17. The compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to any of embodiments 13 to 16, wherein R1is -OH or -C≡N , preferably R1is -ON:R2is -OCH3or -NH2, preferably R2is -NH2;R3is -H; and- R4is -H or -CH2NH2, preferably R4is -CH2NH2.18. The compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to embodiment 13, wherein formula (XIII) is:An antibody-drug conjugate of formula (XIX):Ab-k-D]z(XIX) whereinAb denotes an antibody, an antigen-binding fragment, or an immunologically active portion thereof;L denotes a linker; andD denotes a compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof selected from the group consisting of trabectedin, lurbinectedin and the compounds according to any of embodiments 1 to 18, preferably a compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof according to any of embodiments 1 to 18; and whereinD covalently binds to L via nitrogen or oxygen present in D, and L covalently binds to Ab; and z is an integer from 1 to 20. The antibody-drug conjugate according to embodiment 19, wherein z is an integer from preferably 1 to 6, more preferably 2 to 4 and still more preferably 2 or 4.21. The antibody-drug conjugate according to any of embodiments 19 or 20, wherein D covalently binds to L via nitrogen or oxygen present in any of R2, R3or R4, preferably in any ofR2or R3.22. The antibody-drug conjugate according to any of embodiments 19 to 21, wherein the antibody is an anti-RORl antibody, preferably Cirmtuzumab; an anti-TROP2 antibody, preferably Sacituzumab; or an anti-HER2antibody, preferably Trastuzumab.23. The antibody-drug conjugate according to any of embodiments 19 to 22, wherein L has the following structure:and whereinT and U are independently spacer units, each having from 1 to 24 chain carbons, wherein t and u are independently 0 or 1, preferably t + u > 1; each A is independently an amino acid unit, wherein a is an integer from 0 to 12;H is a hydrophilic unit, wherein h is 0 or 1 ; andY is a conjugating group that covalently binds to Ab; wherein preferably the conjugating group Y covalently binds to a sulfur atom present in Ab.24. The antibody-drug conjugate according to embodiment 23, wherein Y is such that L is one of the following:; orwherein, if present, R6is -H or -C1-4alkyl, preferably -H or -CH3. The antibody-drug conjugate according to any of embodiments 23 or 24, wherein U is one of the following:wherein preferably n is an integer from 5 to 10, more preferably 6 to 8, and most preferably 7; and / orT is one of the following:wherein preferably n is an integer from 1 to 8, more preferably 1 to 6, and most preferably 2 or 5; orwherein preferably m is 1 and n is an integer from 2 to 8, more preferably 4 to 7, and most preferably 5 or 6; and / orH is derived from a PEGylated amino acid, preferably H is one of the following:wherein more preferably n is an integer from 5 to 10, still more preferably 6 to 8, and most preferably 7; orwherein more preferably n is an integer from 5 to 10, still more preferably 6 to 8, and most preferably 7.26. The antibody-drug conjugate according to any of embodiments 23 to 25, wherein each A has the following structure:and wherein R? is independently selected from the group consisting of -H, -CH3, -C(H)(CH3)2, benzyl, p-hydroxybenzyl and -(CH2)3NHC(C=O)NH2; preferably R7 is independently selected from the group consisting of -H, -C(H)(CH3)2, and benzyl; and / or a is an integer from 1 to 10, more preferably 1 to 5, still more preferably 1 to 4, and most preferably 2 or 4.27. The antibody-drug conjugate according to embodiment 23, wherein H and h, and A and a, and U and u are such that L is one of the following:28. The antibody-drug conjugate according to any of embodiments 19 to 22, wherein L is such that Formula (XIX) is one of the following:; or29. The compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to any of embodiments 1 to 18 for use as a medicament.30. The compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to embodiment 29 for use in the treatment of cancer, preferably ovarian cancer, stomach cancer or breast cancer, more preferably ovarian cancer or breast cancer.31. The antibody-drug conjugate according to any of embodiments 19 to 28 for use as a medicament.32. The antibody-drug conjugate according to embodiment 31 for use in the treatment of cancer, preferably ovarian cancer, stomach cancer or breast cancer, more preferably ovarian cancer or breast cancer.33. A process for the preparation of an antibody-drug conjugate of general formula (XIX):Ab|i— D]Z(XIX) the method comprising conjugating an antibody, an antigen-binding fragment or an immunologically active portion thereof (Ab) to a compound (D) via a linker (L), whereinD is a compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof selected from the group consisting of trabectedin, lurbinectedin and the compounds according to any of embodiments 1 to 18, preferably acompound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof according to any of embodiments 1 to 18;L is a linker according to any of embodiments 19, or 23 to 28;D covalently binds to L via nitrogen or oxygen present in D, and L covalently binds to Ab; and z is an integer from 1 to 20.34. The process according to embodiment 33, wherein z is an integer from 1 to 10, preferably 1 to 6, more preferably 2 to 4 and still more preferably 2 or 4.35. The process according to any of embodiments 33 or 34, wherein the antibody is an anti-RORl antibody, preferably Cirmtuzumab; an anti-TROP2 antibody, preferably Sacituzumab; or an anti-HER2antibody, preferably Trastuzumab.36. A pharmaceutical dosage form comprising a therapeutically effective amount of the compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to any of embodiments 1 to 18, or a therapeutically effective amount of the antibody-drug conjugate according to any of embodiments 19 to 28.37. A method of treating cancer, wherein the method comprises administering to a subject a therapeutically effective amount of the compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to any of embodiments 1 to 18, a therapeutically effective amount of the antibody-drug conjugate according to any of embodiments 19 to 28, or the pharmaceutical dosage form according to embodiment 36.38. The method of embodiment 37, wherein the cancer is ovarian cancer, stomach cancer or breast cancer, preferably ovarian cancer or breast cancer.

[0129] The scope and interest of the invention may be better understood on basis of the following examples which are intended to illustrate embodiments of the present invention. However, they are not to be construed to limit the scope of the claims in any manner whatsoever.Examples

[0130] The following abbreviations will be used throughout this section, in particular in the protocols describing the preparation of the compounds and antibody-drug conjugates of the present invention:ADC, antibody drug conjugateATCC, American type culture collectionCbz, carboxybenzylCDI, l,l'-carbonyldimidazoleCit, citrullineDAR, drug to antibody ratioDCM, dichloromethaneDIPCDI, N,N’ -disopropylcarbodiimideDIPEA, A,A-disopropylethylamineDMEM, Dulbecco's modified eagle's mediumDMF, dimethylformamideDMSO, dimethylsulfoxideDR, dose-responseDTT, dithiothreitolEDCI, A-(3 -di meth y I am i nopropyl )- A' -ethylcarbodimide hydrochlorideEDTA, ethylenediaminetetraacetic acidEtOAc, ethyl acetateFCS, fetal calf serumFmoc, 9-fluorenylmethoxycarbonylGly, glycineHex, hexaneHOBt, 1 -hydroxy benzotriazoleHPLC, high performance liquid chromatographyITS, insulin-transferrin-sodium selenite media supplementMC, 6-maleimidocaproylMeOH, methanolNAC, A- acetylcysteineNMP, N-methyl-2-pyrrolidonePAB, 4-aminobenzyl alcoholPABC, p-aminobenzyl carbamatePBS, phosphate buffered salinePhe, phenylalanine bis-PNP, bis(4-nitrophenyl) carbonatePy, pyridineRPMI, Rosmell Park Memorial Institute mediumR.T., room temperatureSEC, size-exclusion chromatographySMCC, succinimidyl-4-(A-maleimidomethyl)cyclohexane- 1 -carboxylateSRB, sulforhodamine BTCEP, tris[2-carboxyethyl)phosphine hydrochlorideTFA, trifluoroacetic acidTHF, tetrahydrofuranTrt, triphenylmethylUV, ultravioletVai, valineCell lines and toxicity assays

[0131] Cell lines used herein for testing cytotoxicity of compounds and antibody-drug conjugates of the present invention are referred to as follows:Cell line preparation

[0132] Human cell lines MDA-MB-231, NCI-N87, and OV-90 were obtained from American Type Culture Collection (Manassas, USA). MDA-MB-231 cells were cultured in DMEM, supplemented with 10% heat inactivated fetal bovine serum, 100 U / mL penicillin, 100 pg / mL streptomycin, 2 mM glutamine and 1 mM sodium pyruvate. NCI-N87 cells were cultured in RPMI-1640 supplemented with 10% heat inactivated fetal bovine serum, 100 U / mL penicillin and 100 g / mL streptomycin. OV-90 cells were cultured in MCDB 105 medium / medium 199 (1:1) supplemented with 10% heat inactivated fetal bovine serum. All cell lines were maintained at 37 °C with humidified atmosphere of 5% CO2.Compound preparation

[0133] Lyophilized compounds were dissolved in 100% sterile cell culture grade DMSO, aliquoted and stored under -20 °C.Cytotoxicity assay

[0134] The cells were seeded in 96-well white flat-bottom tissue culture plates at 1 x 103to 2 x 103per 100 pL growth media per well in triplicates and allowed to attach and recover for 24 h. Test compounds were serial-diluted in DMSO to create 9-point titration curves, and subsequently added to the seeded cultures with a final DMSO concentration at 0.02% per well. After another 120 h of incubation at 37°C with 5% CO2, cell viability assay was performed using CellTitre-Glo 2.0 (Promega). Equal volumes of CellTitre-Glo 2.0 to media in the wells were added and mixed for 10 minutes to lyse the cells. Luminescence was measured on a ThermoFisher Varioskan Lux plate reader.

[0135] Luminescence values of each test-compound of different concentrations were normalized to the luminescence value of the DMSO-control (0.02%) treated cells and plotted against concentration of test compounds. Sigmoidal curves and CC50 values were generated in GraphPad Prism version 9.4.1, using non-linear regression, variable slope-four parameters curve fit for inhibitor versus response, with R squared values above 0.95. All assays were performed in triplicates and as two independent experiments.Cytotoxicity of parent and synthesized compounds

[0136] The following compounds were synthesized and tested for their cytotoxicity against various cell lines. (++++: < 1 nM; +++: < 10 nM, ++: 10-200 nM; + > 200 nM):Cytotoxicity of selected antibody-drug conjugates

[0137] A selection of payload compounds was used in antibody-drug conjugates and tested for their cytotoxicity against NCI-N87 (gastric) and MDA-MB-231 (breast) cell lines. (++++: < InM; +++: < 50 nM, ++: 50-200 nM; + > 200 nM):Sac = Sacituzumab, Tra = Trastuzumab, Cir = Cirmtuzumab, Pat = Patritumab, Cet = Cetuximab, LP = linker-payload building block, LK = linker, PL = payloadSynthesis of compounds and antibody-drug conjugatesIntermediate AStep 1: Synthesis of benzyl (4-hydroxyphenethyl)carbamate.

[0138] To a solution of 4-(2-aminoethyl)phenol (10 g, 72.9 mmol, 1.0 eq.) in 100 mL dichloromethane and 50 mL saturated aqueous sodium bicarbonate solution at 0 to 10 °C was added Cbz-Cl (22.3 g, 130 mmol, 1.8 eq.). After the addition, the mixture was stirred at r.t. overnight. LCMS showed the reaction was complete. The organic phase was collected, and the aqueous phase was extracted with dichloromethane (100 mL x 2). Combined organic layers were dried with anhydrous sodium sulfate. Then filtered and concentrated. The crude was recrystallized in ethyl acetate / n-heptane to give benzyl (4-hydroxyphenethyl)carbamate as a white solid (16.2 g, 81.8%). LC-MS (ESI) m / z: 272.0 [M+H]+.1H NMR (300 MHz, CHCh-d): d (ppm) 7.35 (s, 5H), 7.05 (d, J = 7.8 Hz, 2H), 6.77 (d, J = 7.8 Hz, 2H), 5.10 (s, 2H), 4.73 (s, 1H), 3.42 (d, J = 6.7 Hz, 2H), 2.74 (s, 2H).Step 2: Synthesis of benzyl (4-hydroxy-3 -nitrophenethyl) carbamate.

[0139] To a solution of benzyl (4-hydroxyphenethyl) carbamate (14 g, 51.6 mmol, 1.0 eq.) in 140 mL acetic acid at r.t. were added a mixture of 140 mL acetic acid and 65% nitric acid (3.57 mL, 51.6 mmol, 1.0 eq.). After the reaction mixture was stirred for 1 h, ethyl acetate and saturated aqueous sodium carbonate solution were added. The aqueous layer was collected, and the aqueous phase was extracted with ethyl acetate. The combined organic layers were dried with anhydrous sodium sulfate and then concentrated. The crude product was purified by flash column chromatography with ethyl acetate: n-heptane (1:4)) to give benzyl (4-hydroxy- 3-nitrophenethyl) carbamate as a dark yellow solid (15.4 g, 94%). LC-MS (ESI) m / z: 317 [M+H]+.1H NMR (300 MHz, DMSO-de) 8 (ppm) 10.49 (s, 1H), 7.93 (s, 1H), 7.48 - 7.31 (m, 6H), 7.10 (d, J = 8.5 Hz, 1H), 5.32 (d, J = 5.1 Hz, 1H), 5.13 (d, J = 15.2 Hz, 2H), 4.83 (s, 1H), 3.45 (q, J = 6.8 Hz, 2H), 2.99 - 2.66 (m, 2H).Step 3: Synthesis of benzyl (4-methoxy-3-nitrophenethyl)carbamate.

[0140] To a solution of benzyl (4-hydroxy-3 -nitrophenethyl) carbamate (12 g, 37.9 mmol, 1.0 eq.) and potassium carbonate (15.7 g, 113 mmol, 3.0 eq.) in 240 mL acetonitrile was added methyl iodide (8.08 g, 56.9 mmol, 1.5 eq.). The slurry was reflux for 2 hrs. TLC shows the reaction was completed. The solid was filtered out and the filtrate was concentrated. To the residue was added 100 mL water and the mixture was extracted with dichloromethane (200 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to afford benzyl (4-methoxy-3-nitrophenethyl)carbamate as a crude. The crude was used in the next step without further purification.1H NMR (300 MHz, CHCh- ) 3 (ppm) 7.80 - 7.61 (m, 1H), 7.37 (d, J = 9.8 Hz, 6H), 7.02 (d, J = 8.6 Hz, 1H), 5.10 (s, 2H), 4.97 - 4.77 (m, 1H), 3.95 (d, J = 5.5 Hz, 3H), 3.45 (q, J = 6.9 Hz, 2H), 2.97 - 2.68 (m, 2H).Step 4: Synthesis of 5 -(2-aminoethyl)-2-methoxyaniline hydrochloride (Intermediate A).

[0141] The previous crude was diluted with 300 mL methanol, then to this was added 1.5g 5% Pd / C under nitrogen. The suspension was degassed under vacuum and purged with hydrogen three times. The mixture was stirred under hydrogen at r.t. overnight. The suspension was filtered through a pad of celite, and the filter cake was washed with methanol. The filtrate was concentrated to dryness and dissolved into 10 mL ethyl acetate. To this was added 1 eq. 2- Ill -M HCl / EtOH solution, the precipitate was collected by filtration and dried under vacuum to afford Intermediate A as a dark brown solid (7.08 g, 93%).1H NMR (300 MHz, D2O) 8 (ppm) 6.98 - 6.88 (m, 1H), 6.88 - 6.73 (m, 2H), 3.79 (d, J = 3.4 Hz, 3H), 3.15 (t, J = 7.2 Hz, 2H), 2.92 - 2.75 (m, 2H).Intermediate BStep 1: Synthesis of 4-(2-(benzyloxy)ethoxy)-3 -hydroxybenzaldehyde.

[0142] To a solution of 3,4-dihydroxybenzaldehyde (5.0 g, 0.036 mol, 1.0 eq.) and ((2- bromoethoxy)methyl)benzene (17.1 g, 0.08 mol, 2.2 eq.) in 50 mL acetonitrile was added CS2CO3 (26.0 g, 0.080 mol, 2.2 eq.). The mixture was refluxed for 1 hr and the solid was filtered out. The filtrate was concentrated, and the residue was purified by flash column chromatography on silica gel (ethyl acetate: petroleum ether (1:5)) to afford 4-(2- (benzyloxy)ethoxy)-3-hydroxybenzaldehyde as a yellow solid (1.30 g, 13%).1H NMR (400 MHz, CHCl3-d) δ (ppm) 9.85 (d, J= 2.1 Hz, 1H), 7.45 (d, J = 2.0 Hz, 1H), 7.43 - 7.29 (m, 5H), 6.99 (dd, J = 8.2, 2.0 Hz, 1H), 6.41 (s, 1H), 4.63 (d, J = 2.0 Hz, 2H), 4.29 (dt, J = 6.7, 2.4 Hz, 2H), 3.87 (dt, J = 6.2, 2.5 Hz, 2H), 1.92 (s, 1H).Step 2: Synthesis of 3-hydroxy-4-(2-hydroxyethoxy) benzaldehyde.

[0143] To a solution of 3,4-dihydroxybenzaldehyde (0.10 g, 0.36 mmol, 1.0 eq.) in 3 mL dichloromethane was added BCI3 (1 M in dichloromethane, 3.65 mL, 3.65 mmol, 10.0 eq.) dropwise at -10 to 20 °C. After the solution was neutralized with saturated sodium bicarbonate and the residue was extracted with dichloromethane. Combined organic layer was washed by brine, dried over anhydrous sodium sulfate, and concentrated to afford 3-hydroxy-4-(2- hydroxyethoxy) benzaldehyde as brown oil without further purification for the next step.1H NMR (300 MHz, CHCI3- ) 6 (ppm) 9.85 (s, 1H), 7.49 - 7.38 (m, 2H), 6.99 (d, J= 8.3 Hz, 1H), 4.32 - 4.22 (m, 2H), 4.13 - 4.03 (m, 2H).Step 3: Synthesis of(E)-2-(2-hydroxyethoxy)-5-(2-nitrovinyl) phenol.

[0144] A solution of 3-hydroxy-4-(2-hydroxyethoxy) benzaldehyde (45 mg, 0.25 mmol, 1.0 eq.) and ammonium acetate (9.52 mg, 0.12 mmol, 0.5 eq.) in 5 mL nitromethane was stirred at 90 °C for 4 hrs. After the reaction was completed, the mixture was concentrated and the residue was dissolved into ethyl acetate, and then washed with brine. The organic layer was concentrated to afford (£’)-2-(2-hydroxyethoxy)-5-(2-nitrovinyl) phenol as brown oil without further purification for the next step.1H NMR (300 MHz, DMSO-cfc) 3 (ppm) 9.06 (d, J = 1.8 Hz, 1H), 8.00 (d, J = 1.8 Hz, 2H), 7.40 - 7.21 (m, 2H), 7.10 - 6.94 (m, 1H), 5.01 - 4.74 (m, 1H), 4.04 (dd, J = 6.6, 3.2 Hz, 2H), 3.74 (q, J = 5.3 Hz, 2H).Step 4: Synthesis of2-(2-hydroxyethoxy)-5-(2-nitroethyl) phenol.

[0145] To a solution of (£’)-2-(2-hydroxyethoxy)-5-(2-nitrovinyl) phenol (50 mg, 0.22 mmol, 1.0 eq.) in 5 mL methanol was added NaBH4 (12.48 mg, 0.33 mmol, 1.5 eq.). After the reaction was completed, the mixture was quenched with 2 N HC1 to have pH 2~4. Methanol was removed under reduced pressure and the residue was dissolved into ethyl acetate, and then washed with brine. The organic layer was concentrated to afford 2-(2-hydroxyethoxy)-5-(2- nitroethyl) phenol as crude brown oil.Step 5: Synthesis of 5-(2-aminoethyl)-2-(2-hydroxyethoxy) phenol (Intermediate B).

[0146] The crude 2-(2-hydroxyethoxy)-5-(2-nitroethyl) phenol was diluted with 10 mL methanol, then to this was added 10 mg 5% Pd / C under N2. The mixture was stirred under H2 at r.t. overnight. The suspension was filtered through a pad of Celite, and the filter cake was washed with methanol. Combined filtrates were concentrated to dryness to afford Intermediate B as brown oil. (26.0 mg, 59.3%).1H NMR (300 MHz, DMSO-cfc) 3 (ppm) 6.83 (dd, 7= 8.1, 3.4 Hz, 1H), 6.75 - 6.62 (m, 1H), 6.56 (d, J= 8.2 Hz, 1H), 3.91 (t, 7 = 4.8 Hz, 2H), 3.80 - 3.59 (m, 2H), 2.81 (t, 7 = 7.5 Hz, 2H), 2.60 (t, 7 = 7.7 Hz, 2H).Intermediate CStep 1: Synthesis of5-nitro-lH-indole-3-carbaldehyde.

[0147] To a solution of 30 mL anhydrous DMF and 4.6 mL POCI3 was added 5-nitro- IH-indole (5 g, 0.0308 mol, 1.0 eq.) in DMF dropwise at 0 °C. The reaction mixture was warmed to 60 °C and stirred for 30 mins. Then the reaction was quenched with saturated aqueous sodium carbonate solution. The precipitate was collected by filtration, washed with water, and dried to afford 5-nitro-lH-indole-3-carbaldehyde as a grey solid (36.9 g, 68%). LC- MS (ESI) m / z: 176 [M+H]+.1H NMR (300 MHz, DMSO-d6) d (ppm) 12.20 (s, 1H), 10.31 (d, J = 1.7 Hz, 1H), 8.08 - 7.97 (m, 1H), 7.20 - 7.07 (m, 2H), 6.75 (dt, J = 7.2, 1.5 Hz, 1H), 3.93 (d, J= 1.6 Hz, 3H).Step 2: Synthesis of (E)-5-nitro-3-(2-nitrovinyl)-lH-indole.

[0148] To a solution of 5-nitro-lH-indole-3-carbaldehyde (15 g, 0.079 mol, 1.0 eq.) in 75 mL 1,4-dioxane was added ammonium acetate (6.08 g, 0.079 mol, 1.0 eq.) and nitromethane (10.1 g, 15.8 mol, 2.0 eq.). After refluxing for 4 hrs, the reaction mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate and washed with water. The organic phase was dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n-heptane (1:4)) to afford (E)-5- nitro-3-(2-nitrovinyl)-lH-indole as a yellow solid (17 g, 92%).1H NMR (400 MHz, DMSO-cfc) d (ppm) 12.71 (s, 1H), 8.91 (d, J = 2.2 Hz, 1H), 8.53 - 8.43 (m, 2H), 8.21 - 8.09 (m, 2H), 7.69 (d, 7= 8.9 Hz, 1H).Step 3: Synthesis of 3-(2-aminoethyl)-lH-indol-5-amine (Intermediate C).

[0149] To a solution of (£’)-5-nitro-3-(2-nitrovinyl)-lH-indole (5 g, 21.25 mmol, 1.0 eq.) in 25 mL THE was added dropwise 2.5 M LiAlH4 in THE (1.0 eq.) at 0 °C. The reaction mixture was warmed to 60 °C and stirred for 2 hrs. After the reaction was completed, to themixture was added 16 mL water, 16 mL 15% aqueous NaOH, 48 mL water and small amount of MgSO4at 0 °C respectively. Then filtered and the filter cake was washed with THF. The filtrate was concentrated. The residue was purified by flash column chromatography on silica gel (dichloromethane: methanol: NH3H2O (95:5: 1)) to afford Intermediate C as a brown viscous solid (1.72 g, 45%). LC-MS (ESI) m / z: 176 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ (ppm) 10.28 (s, 1H), 7.01 (d, J = 8.5 Hz, 1H), 6.91 (d, J = 2.5 Hz, 1H), 6.64 (d, J = 2.2 Hz, 1H), 6.45 (dd, J = 8.4, 2.3 Hz, 1H), 2.78 (t, J= 7.1 Hz, 2H), 2.64 (t, J = 7.1 Hz, 2H).Intermediate DStep 1: Synthesis of benzyl (4-hydroxyphenethyl)carbamate.

[0150] To a solution of 4-(2-aminoethyl) phenol (10 g, 72.9 mmol, 1.0 eq.) in 100 mL dichloromethane and 50 mL saturated sodium bicarbonate at 0-10 °C was added Cbz-Cl (22.3 g, 130 mmol, 1.8 eq.). After the addition, the mixture was stirred at r.t. overnight. LCMS showed the reaction was completed. The aqueous phase was extracted with dichloromethane (100 mL x 2). Combined organic phase was dried with anhydrous sodium sulfate. Then filtered and concentrated. The residue was dissolved in ethyl acetate and n-heptane to obtain D2 as a white crystal solid. (16.2 g, 81.8%). LC-MS (ESI) m / z: 272 [M+H]+.1H NMR (300 MHz, CHCh- ) δ (ppm) 7.35 (s, 5H), 7.05 (d, J = 7.8 Hz, 2H), 6.77 (d, J = 7.8 Hz, 2H), 5.10 (s, 2H), 4.73 (s,1H), 3.42 (d, J = 6.7 Hz, 2H), 2.74 (s, 2H).Step 2: Synthesis of benzyl (4-hydroxy-3-nitrophenethyl) carbamate.

[0151] To a solution of benzyl (4-hydroxyphenethyl) carbamate (14 g, 51.6 mmol, 1.0 eq.) in 140 mL acetic acid at r.t. was added a mixture of 140 mL acetic acid and 65% nitric acid (3.57 mL, 51.6 mmol, 1.0 eq.). After the reaction mixture was stirred at r.t. for 1 hr, ethyl acetate and saturated sodium carbonate were added. The mixture was extracted with ethyl acetate. Combined organic layers were dried with anhydrous sodium sulfate. The crude was purified by flash column chromatography on silica gel with ethyl acetate: n-heptane (1:4)) to afford benzyl(4-hydroxy-3 -nitrophenethyl) carbamate as a dark yellow solid (15.4 g, 94%). LC-MS (ESI) m / z: 317.2 [M+H]+.1H NMR (300 MHz, DMSO-de) 8 (ppm) 10.49 (s, 1H), 7.93 (s, 1H), 7.48 - 7.31 (m, 6H), 7.10 (d, J = 8.5 Hz, 1H), 5.32 (d, J = 5.7 Hz, 1H), 5.13 (d, J = 15.2 Hz, 2H), 4.83 (s, 1H), 3.45 (q, J = 6.8 Hz, 2H), 2.99 - 2.66 (m, 2H).Step 3: Synthesis of benzyl (4-(2-(benzyloxy)ethoxy)-3-nitrophenethyl)carbamate.

[0152] To a solution of benzyl (4-hydroxy-3-nitrophenethyl)carbamate (1.67 g, 5.28 mmol, 1.0 eq.) in 10 mL CH3CN were added ((2-bromoethoxy)methyl)benzene (2.27 g, 10.56 mmol, 2.0 eq.) and CS2CO3 (1.89 g, 5.8 mmol, 1.1 eq.) in a sealed tube. The slurry was refluxed for 2 hrs. TLC showed the reaction was completed. The mixture was filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography to afford benzyl (4-(2-(benzyloxy)ethoxy)-3-nitrophenethyl)carbamate as a yellow solid (1.5 g, 63%).1H NMR (400 MHz, CHCl3-d) δ (ppm) 7.65 (d, J = 2.3 Hz, 1H), 7.41 - 7.26 (m, 11H), 7.01 (d, J = 8.6 Hz, 1H), 5.08 (s, 2H), 4.86 (s, 1H), 4.64 (s, 2H), 4.24 (t, J = 4.7 Hz, 2H), 3.91 - 3.82 (m, 2H), 3.41 (q, J= 6.8 Hz, 2H), 2.79 (t, J = 7.0 Hz, 2H).Step 4: Synthesis of 2-(2-amino-4-(2-aminoethyl)phenoxy)ethan-l-ol hydrochloride (Intermediate D).

[0153] To a solution of benzyl (4-(2-(benzyloxy)ethoxy)-3-nitrophenethyl)carbamate (2.0 g, 4.4 mmol) in 40 mL methanol was added 5% Pd / C under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (0.5 MPa) at 80 °C for 2 hrs. The suspension was filtered through a pad of Celite, and the filter cake was washed with methanol. The combined filtrates were concentrated to dryness and dissolved into 10 mL ethyl acetate. 1 eq. 2 M HCl / EtOH solution was added to provide a salt precipitate. The precipitate was collected by filtration and dried under vacuum to afford intermediate D as a grey solid (0.73 g, 70.8%). LC-MS (ESI) m / z: 197 [M+H]+.1H NMR (400 MHz, DMSO-cfe) 8 (ppm) 6.65 (d, J = 8.0 Hz, 1H), 6.45 (d, J = 2.1 Hz, 1H), 6.29 (dd, J = 8.1, 2.1 Hz, 1H), 4.73 (s, 2H), 3.86 (t, J = 4.8 Hz, 2H), 3.68 (dd, J = 5.3, 4.3 Hz, 2H), 2.67 (dd, J = 7.9, 6.6 Hz, 2H), 2.44 (t, J = 7.3 Hz, 2H).Intermediate EStep 1: Synthesis of benzyl 2-(4-formyl-2-hydroxyphenoxy) acetate.

[0154] To a suspension of 3,4-dihydroxybenzaldehyde (9.63 g, 42.2 mmol, 1.0 eq.) and K2CO3 (5.94 g, 43 mmol, 1.02 eq.) in 200 mL acetone was added benzyl 2-bromoacetate (9.86 g, 43 mmol, 1.02 eq.). After addition, the slurry was refluxed for 2 hrs and filtered. The filtrate was concentrated and dried under vacuum to obtain benzyl 2-(4-formyl-2-hydroxyphenoxy) acetate as a yellow solid (15.5 g, 77.6%).NMR (400 MHz, CHCL- ) 8 (ppm) 9.87 (s, 1H), 7.53 (d, J= 1.9 Hz, 1H), 7.50 (d, J= 7.2 Hz, 2H), 7.46 - 7.33 (m, 9H), 6.93 (d, J= 8.2 Hz, 1H), 5.25 (d, J= 13.3 Hz, 4H), 4.87 (s, 2H).Step 2: Synthesis of benzyl (E)-2-(2-hydroxy-4-(2-nitrovinyl) phenoxy) acetate.

[0155] To a solution of benzyl 2-(4-formyl-2-hydroxyphenoxy) acetate (0.2 g, 0.53 mmol, 1.0 eq.) in 1 mL nitromethane at r.t. was added ammonium acetate (20 mg, 0.26 mmol, 0.5 eq.). After the reaction mixture was stirred at 90 °C for 2 hrs, the mixture was concentrated and purified by flash column chromatography (ethyl acetate: n-heptane (1:8)) to afford benzyl (£’)-2-(2-hydroxy-4-(2-nitrovinyl) phenoxy) acetate as a yellow solid (0.11 g, 48%).1H NMR (400 MHz, DMSO-<76) 5 (ppm) 8.26 (d, J = 13.5 Hz, 1H), 8.09 (d, J = 13.5 Hz, 1H), 7.71 (d, J = 2.0 Hz, 1H), 7.51 (d, 7 = 7.0 Hz, 3H), 7.46 - 7.41 (m, 3H), 7.41 - 7.37 (m, 8H), 7.05 (d, J = 8.5 Hz, 1H), 5.21 (d, J= 10.0 Hz, 5H), 5.03 (s, 2H).Step 3: Synthesis of2-(4-(2-aminoethyl)-2-hydroxyphenoxy) acetic acid (Intermediate E).

[0156] To a solution of benzyl (£’)-2-(2-hydroxy-4-(2-nitro vinyl) phenoxy) acetate (0.5 g, 4.4 mmol) in 40 mL methanol was added 5% Pd / C under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (0.5 MPa) at 80 °C for 2 hrs. The suspension was filtered through a pad of Celite, and the filter cake waswashed with methanol. The filtrate was concentrated and dried under vacuum to afford Intermediate E as a brown solid (0.20 g, 62%).1H NMR (400 MHz, DMSO-cfc) 8 (ppm) 6.86 (dd, J = 8.0, 3.2 Hz, 1H), 6.66 (d, J = 2.1 Hz, 1H), 6.52 (dt, J = 8.0, 2.8 Hz, 1H), 4.11 (d, J = 1.6 Hz, 2H), 3.09 - 2.92 (m, 2H), 2.74 (dt, J = 16.0, 7.9 Hz, 2H).Intermediate FStep 1: Synthesis of6-nitro-lH-indole-3-carbaldehyde.

[0157] POCI3 (6.2 mL, 2.5 eq.) was added dropwise to 50 mL anhydrous DMF at 0 °C under argon. A solution of 5 g (0.0308 mol, 1.0 eq.) 6-nitro-lH-indole in 5 mL anhydrous DMF was added dropwise at room temperature and the resulting mixture was stirred for 6 hrs. The reaction mixture was poured into a mixture of ice and saturated NaHCCh aqueous solution and extracted with ethyl acetate (3 x 50 mL). The combined organic solutions were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give (2.4 g, 40.9% yield) 6- nitro- 1 H-indole-3-carbaldehyde as yellow solid.1H NMR (400 MHz, DMSO-cfc) 8 (ppm) 12.71 (s, 1H), 10.05 (s, 1H), 8.68 (s, 1H), 8.46 (d, J = 2.1 Hz, 1H), 8.29 (d, J= 8.8 Hz, 1H), 8.14 (dd, 7 = 8.8, 2.0 Hz, 1H).Step 2: Synthesis of (E)-6-nitro-3-(2-nitrovinyl)-lH-indole.

[0158] To the solution of 6-nitro-l H-indole-3-carbaldehyde (90.1 mg, 0.473 mmol, 1.0 eq.) in 20 mL nitromethane was added ammonium acetate (80.2 mg, 1.04 mmol, 2.2 eq.). After reflux for 2 hrs, the solvent was removed under reduced pressure. The residue was washed with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (dichloromethane : methanol : NH3*H2O (90: 10:0.1)) to afford (£’)-6-nitro-3-(2-nitrovinyl)-lH- indole (46.3 mg, 41.9% yield) as a yellow solid.1H NMR (400 MHz, DMSO-cfc) 8 (ppm) 12.75 (s, 1H), 8.95 (d, J= 2.2 Hz, 1H), 8.52 (d, J= 13.2 Hz, 2H), 8.21 (d, J= 13.6 Hz, 1H), 8.16 (dd, J = 9.0, 2.2 Hz, 1H), 7.73 (d, J = 9.0 Hz, 1H).Step 3: Synthesis of 3-(2-aminoethyl)-lH-indol-6-amine (Intermediate F).

[0159] To the solution of (£’)-6-nitro-3-(2-nitro vinyl)- IH-indole (750 g, 3.216 mmol, 1.0 eq.) in 20 mL 1,4-dioxane was added 2.5 M LiAlt (1.0 eq.) with dropwise at 0 °C. The reaction was warmed to 70 °C. After the reaction was completed, the reaction was quenched with 16 mL of water, 16 mL 15% aqueous NaOH, 48 mL water, and small amount of MgSCM at 0 °C sequentially. The solution was filtered and concentrated, and the residue was purified by column chromatography on silica gel (dichloromethane:methanol:NH3*H2O (95:5:1)) to afford crude product as oil. The oil was dissolved into methanol and 6 mL HCl / EtOH (2M), then precipitated in ethyl acetate and filter to afford Intermediate F (125 mg, 22.0% yield) as a brown viscous solid.NMR (400 MHz, D2O) 3 (ppm) 7.71 (d, J = 8.5 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.35 (s, 1H), 7.07 (dd, 7 = 8.5, 1.9 Hz, 1H), 3.28 (t, 7 = 7.1 Hz, 2H), 3.12 (t, J = 7.1 Hz, 2H).Intermediate GStep 1: Synthesis of(E)-5-nitro-3-(2-nitrovinyl)-lH-indole.

[0160] To a solution of 5-nitro-lH-indole-3-carbaldehyde (15 g, 0.079 mol, 1.0 eq.) in 75 mL 1,4-dioxane was added ammonium acetate (6.08 g, 0.079 mol, 1.0 eq.) and nitromethane (10.1 g, 15.8 mol, 2.0 eq.) and heated to reflux. After 4 hrs, the solvent was removed under reduced pressure. The residue was washed with water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate : n-heptane (1:4)) to afford (E)-5-nitro-3- (2-nitrovinyl)-lH-indole (17g, 92% yield) as a yellow solid.1H NMR (400 MHz, DMSO-cfc) 3 (ppm) 12.71 (s, 1H), 8.91 (d, J = 2.2 Hz, 1H), 8.53 - 8.43 (m, 2H), 8.21 - 8.09 (m, 2H), 7.69 (d, 7= 8.9 Hz, 1H).Step 2: Synthesis of 5-nitro-3-(l-nitropropan-2-yl)-lH-indole.

[0161] To a solution of (£’)-5-nitro-3-(2-nitrovinyl)-lH-indole (260 mg, 1.11 mmol, 1.0 eq.) in 25 mL THF was added a solution of IM MeMgBr in THF (1.0 eq.) dropwise at -50 °C. The reaction mixture was stirred at r.t. for 2 hrs. The reaction mixture was cooled and a smallamount of saturated NH4CI solution was added to quench the reaction. The reaction mixture was extracted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated to afford the crude product. The residue was purified by column chromatography on silica gel (ethyl acetate m-heptane (1:3)) to afford to afford 5-nitro-3-(l-nitropropan-2-yl)-lH- indole (110 mg, 36% yield) as a brown solid.1H NMR (400 MHz, CHCl3-d) δ (ppm) 8.64 (d, J = 2.2 Hz, 1H), 8.18 (dd, J = 9.0, 2.2 Hz, 1H), 7.46 (d, J = 9.0 Hz, 1H), 7.27 (d, J = 2.3 Hz, 1H), 7.25 (d, J = 2.6 Hz, 1H), 4.75 (d, J = 7.3 Hz, 1H), 4.62 (dd, J = 12.0, 7.7 Hz, 1H), 4.04 (h, J= 7.2 Hz, 1H), 1.57 (d, J= 7.0 Hz, 3H).Step 3: Synthesis of 3-(l-aminopropan-2-yl)-lH-indol-5-amine (Intermediate G).

[0162] Under a N2 atmosphere, 5% Pd / C (10 mg) was added to a solution of 5-nitro-3- ( 1 -nitropropan-2-yl)- 1H-indole (110 mg, 0.44 mmol, 1.0 eq.) in 5 mL of Methanol. The suspension was degassed under vacuum and purged with H2 several times. The reaction mixture was stirred under an H2 balloon at r.t. for 1.5 hrs. The suspension was filtered through a pad of celite, and the filter cake washed with Methanol. The filtrate was concentrated to provide Intermediate G as a brown oil and used for next step without purification.Intermediate HStep 1: Synthesis of 3-(5-methoxy-lH-indol-3-yl)propan-l-ol.

[0163] To a stirred solution of (4-methoxypheny1)hydrazine hydrochloride (4.0 g, 22.9 mmol) in dimethylacetamide (40 mL), 4% aq. H2SO4 (30 mL) was added at r.t. and reaction mixture heated to 100 °C. Next, 3,4-dihydropyran (2.3 mL, 25.1 mmol) was added at the same temperature. The reaction mixture was stirred at 100 °C for 2 hrs and monitored by TLC for completion. After completion of reaction, the solvent was removed under reduced pressure, 100 mL water was added and extracted with ethyl acetate. The organic layer was concentrated, and crude product purified by column chromatography (ethyl acetate : hexanes (1:1)) to afford 3- (5-methoxy- 17 / -indol-3-yl)propan- 1 -ol as pale brown oil (2.8 g, 59% yield). LC-MS (ESI) m / z: 204.15 [M-H]+.1H NMR (400 MHz, DMSO-d6): δ (ppm) 10.57 (s, 1H), 7.22 (d, J = 8.8 Hz,1H), 7.05 (s, 1H), 6.98 (d, J = 2.0 Hz, 1H), 6.71 (dd, J = 8.8, 2.0 Hz, 1H), 4.45 (t, J = 5.2 Hz, 1H), 3.71 (s, 3H), 3.48 (q, J= 6.0 Hz, 2H), 2.68 (t, J = 7.2 Hz, 2H), 1.80 (q, J = 7.0 Hz, 1H).Step 2: Synthesis of3-(5-methoxy-lH-indol-3-yl)propyl methane sulfonate.

[0164] To a stirred solution of 3-(5-methoxy-lH-indol-3-yl)propan-l-ol (2.0 g, 9.75 mmol) in ethyl acetate (20 mL), DIPEA (3.77 mL, 29.25 mmol) was added at 0 °C. Then, methanesulfonyl chloride (1.3 mL, 11.7 mmol) was added dropwise at same temperature. After addition, the reaction mixture was stirred at room temperature for 1 h. Progress of the reaction was monitored by TLC. After completion of reaction, solvent was evaporated, and crude product was washed with water and extracted with ethyl acetate. The organic layer was concentrated, and crude product purified by column chromatography (ethyl acetate : hexanes (1: 1)) to afford 3-(5-methoxy-lH-indol-3-yl)propyl methanesulfonate as viscous liquid (1.5 g, 55% yield). LC-MS (ESI) m / z: 284.0 [M+H]+.1H NMR (400 MHz, DMSO-de) h (ppm) 10.66 (s, 1H), 7.23 (d, J = 8.8 Hz, 1H), 7.12 (d, J = 2.0 Hz, 1H), 7.0 (d, J = 2.4 Hz, 1H), 6.72 (dd, J = 8.8, 2.4 Hz, 1H), 4.25 (t, J = 6.4 Hz, 1H), 3.76 (s, 3H), 2.76 (t, J = 7.6 Hz, 2H), 2.03 (t, J = 7.0 Hz, 2H).Step 3: Synthesis of 3-(3-azidopropyl)-5-methoxy-lH-indole.

[0165] To a stirred solution of 3-(5-methoxy-lH-indol-3-yl)propyl methanesulfonate (1.5 g, 5.3 mmol) in DMF (10.0 mL) at r.t. was added NaNa (413 mg, 6.3 mmol). The reaction was then heated to 80 °C for 1 hr. Progress of the reaction was monitored by TLC. After completion of reaction, H2O (30 mL) was added and extracted with ethyl acetate. Organic layer was dried over Na2SO4 and concentrated under reduced pressure. Crude product was purified by combi-flash column chromatography (ethyl acetate : hexane (1: 1)) to afford 3-(3- azidopropyl)-5 -methoxy- IH-indole as colorless liquid (700 mg, 85% yield). LC-MS (ESI) m / z: 229.1 [M-H]+.1H NMR (400 MHz, DMSO-de) 6 (ppm) 10.64 (s, 1H), 7.21 (d, J= 8.8 Hz, 1H), 7.09 (s, 1H), 6.98 (s, 1H), 6.71 (d, J = 8.4 Hz, 1H), 3.75 (s, 3H), 3.37 (t, J = 6.6 Hz, 2H), 2.71 (t, J = 7.4 Hz, 2H), 1.89 (q, J= 6.8 Hz, 2H).Step 4: Synthesis of 3-(5-methoxy-lH-indol-3-yl)propan-l -amine (Intermediate I).

[0166] To a stirred solution of 3-(3-azidopropyl)-5-methoxy-lH-indole (700 mg, 3.04 mmol) in methanol (15.0 mL) was added 10% Pd / C (162 mg, 1.52 mmol) under argon. Then,a hydrogen balloon was incorporated into the reaction system and the reaction stirred at r.t. for 2 hrs. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was filtered through celite and was concentrated. The crude (760 mg) was submitted to Prep- HPLC to afford Intermediate H as colorless liquid (295 mg, 47 % yield). LC-MS (ESI) m / z: 205.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 (ppm) 10.66 (s, 1H), 767 (s, 3H), 7.23 (d, J = 8.8 Hz, 1H), 7.01 (d, J= 1.6 Hz, 1H), 6.99 (d, J= 2.0 Hz, 1H), 6.72 (dd, J= 8.8, 2.4 Hz, 1H), 4.25 (t, J = 6.4 Hz, 1H), 3.76 (s, 3H), 2.83 (t, J= 7.6 Hz, 2H), 2.71 (t, J= 7.4 Hz, 2H), 1.89 (q, J = 7.6 Hz, 2H).Intermediate IStep 1: Synthesis of 2, 2-dimethyl-5-((5-nitro-lH-indol-3-yl)methyl)-l,3-dioxane-4, 6-dione.

[0167] To a stirred solution of 5-nitro-lH-indol (5 g, 30.86 mmol) and Meldrum’s acid (4.8 g, 33.95 mmol) in acetonitrile (30 mL); were added 37% aq. formaldehyde (2.7 g, 2.4 mL, 92.58 mmol) and proline (117 mg, 0.05 mmol) the reaction mixture was stirred at r.t. for 18 hrs under argon. After completion of reaction, the resulting yellow slurry was filtered and wash with acetonitrile and ether for twice. Then the solid was dried under vacuum to give 2,2- dimethyl-5-((5-nitro-lH-indol-3-yl)methyl)-l,3-dioxane-4, 6-dione (8.1 g, 82% yield). LC-MS (ESI) m / z: 317.0 [M-H]+.1H NMR (400 MHz, DMSO-de) 6 (ppm) 11.64 (s, 1H), 8.64 (d, J =1.6 Hz, 1H), 7.97 (dd, J= 9.0, 1.8 Hz, 1H), 7.50 (d, J = 8.8 Hz, 1H), 7.33 (s, 1H), 4.85 (t, J =4.6 Hz, 1H), 3.46 (d, J= 4.5 Hz, 2H), 1.79 (s, 3H), 1.56 (s, 3H).Step 2: Synthesis of ethyl 3-(5-nitro-lH-indol-3-yl)propanoate.

[0168] To a stirred solution of 2,2-dimethyl-5-((5-nitro-lH-indol-3-yl)methyl)-l,3- dioxane-4, 6-dione (8.1 g, 30.86 mmol) in pyridine : ethanol (4: 1) 50 mL was added copper powder (169 mg, 2.54 mmol) at r.t. under argon and reaction mass was stirred at 120 °C temperature for 12 hrs, at r.t. for an additional 12 hrs, and monitored by TLC for completion. After completion of reaction, the resulting yellow slurry was filtered, washed with acetonitrile and triturate with ether for twice. Then solid was dried under vacuum to give ethyl 3-(5-nitro-1 H-indol-3-yl)propanoate as yellow solid (5.3 g, 79% yield). LC-MS (ESI) m / z: 261.1 [M-H]+.1H NMR (400 MHz, DMSO-de) 8 (ppm) 11.58 (s, 1H) 8.53 (d, J = 2 Hz 1H), 7.98 (dd, J = 9.0,2.2 Hz, 1H), 7.50 (d, J= 8.8 Hz, 1H), 7.40 (s, 1H), 4.04 (q, J= 7.2 Hz, 2H), 3.04 (t, J= 7.4 Hz, 2H), 2.68 (t, 7= 7.4 Hz, 2H), 1.14 (t, J = 7.0 Hz, 3H).Step 3: Synthesis of 3-(5-nitro-lH-indol-3-yl)propan-l-ol.

[0169] To a stirred solution of ethyl 3-(5-nitro-lH-indol-3-yl)propanoate (5.2 g, 3.66 mmol) in dry THF (20 mL) cooled it at 0 °C then 2M LiAlH4 of THF (10.5 mF, 21.27 mmol) was added under argon and the reaction mass was stirred at same temperature for 7 hrs and monitored by TEC for completion. After completion of reaction, the resulting reaction mixture was quenched with ethyl acetate and IM NaOH aqueous solution, extracted with ethyl acetate and the organic layer was concentrated under reduced pressure to give crude compound. The crude residue was triturated with ether twice. Then solid was dried under vacuo to give 3-(5- nitro- 1 H-indol-3-yl)propan- 1 -ol as off yellow solid (3.8 g, 88% yield). EC-MS (ESI) m / z:219.2 [M-H]+.1H-NMR (400 MHz, DMSO-d6): δ (ppm) 11.55 (s, 1H), 8.50 (d, J = 2 Hz, 1H), 7.98 (dd, J = 9.0, 2.2 Hz, 1H), 7.50 (d, J= 8.8 Hz, 1H), 7.39 (bs, 1H), 4.48 (t, J= 5.2 Hz, 1H ), 3.47 (q, J= 6.0 Hz, 2H), 2.79 (t, J = 7.6 Hz, 2H), 1.83 - 1.76 (m, 2H).Step 4: Synthesis of 3-(5-nitro-lH-indol-3-yl)propyl methanesulfonate.

[0170] To a stirred solution of 3-(5-nitro- 1 H-indol-3-yl)propan- 1 -ol (3.8 g, 17.27 mmol) in dichloromethane (10 mF) was added EtaN (7.16 mF, 51.81 mmol) at 0 °C under argon then MsCl (1.96 mF, 25.90 mmol) was added. The reaction mixture was stirred at same temperature for 5 hrs under argon and monitored by TEC for completion. After completion of reaction, the resulting reaction mixture was quenched with brine and extracted with ethyl acetate, the organic layer was concentrated under reduced pressure to give the crude product. The crude product was triturate with pentane and ether twice. Then the solid was dried under reduced pressure to give 3-(5-nitro- 1 H-indol-3-yl)propyl methanesulfonate as yellow solid (4.1 g, 79% yield). LC- MS (ESI) m / z: 297.1 [M-H]+.Step 6: Synthesis of 3-(3-azidopropyl)-5-nitro-lH-indole.

[0171] To a stirred solution of 3-(5-nitro-lH-indol-3-yl)propyl methanesulfonate (6, 4.1 g, 13.75 mmol) in DMF (12 mL) was added NaNa (1.34 g, 20.63 mmol) under argon atroom temperature, reaction mass was stirred at 60 °C for 16 hrs and monitored by TLC for completion. After completion of reaction, the resulting reaction mixture was quench with brine solution and extracted with ethyl acetate. The organic part was dried with Na2SC>4 and concentrated under reduced pressure to give crude compound. Crude material was purified by silica gel column purification to give 3-(3-azidopropyl)-5-nitro- 1H-indole as yellow solid (2.4 g, 79% yield). LC-MS (ESI) m / z: 244.12 [M-H]+.1H NMR (400 MHz, DMSO-d6): δ (ppm) 11.61 (s, 1H), 8.53 (d, J= 1.6 Hz, 1H), 7.98 (dd, 7= 8.8, 2.0 Hz, 1H), 7.50 (d, 7 = 8.8 Hz, 1H), 7.44 (s, 1H), 3.42 (t, 7 = 9.6 Hz, 2H), 2.83 (q, 7= 7.7 Hz, 2H), 1.91 (q, 7= 7.2 Hz, 2H).Step 7: Synthesis of 3-(3-aminopropyl)-lH-indol-5-amine (Intermediate I).

[0172] To a stirred solution of 3-(3-azidopropyl)-5-nitro- 1 / / -indole (1.0 g, 4.08 mmol) in 100 mL autoclave vessel in methanol (10 mL) was added Pd / C (432 mg, 10% w / w) then filled H2 gas (50 psi) and the reaction mass was stirred at room temperature for 10 hrs. The reaction was monitored by TLC for completion. After completion of reaction, the resulting reaction mixture was filtered through celite, and organic part was concentrated under reduced pressure to give crude product. The crude compound was purified by prep HPLC to provide Intermediate I as white solid. (296 mg, 38% yield). LC-MS (ESI) m / z: 190.25 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ (ppm) 11.13 (s, 1H), 9.70 (brs, 2H), 7.75 (brs, 2H), 7.45 (s, 1H), 7.43 - 7.42 (m, 1H), 7.28 (d, 7 = 2.0 Hz, 1H), 7.03 (dd, 7 = 8.4, 2.0 Hz, 1H), 2.86 - 2.81 (m, 2H), 2.74 (t, 7= 7.4 Hz, 2H), 1.93 - 1.86 (m, 2H).Trabectedin related payloads (PL)General procedure A - Step 1: Synthesis of Tra-CN derivatives.

[0173] A mixture of M24 (disclosed e.g., in CN 107739387 A) (1.0 eq.), the respective intermediate as described above (10 eq.), and NaOAc (11 eq.) in anhydrous EtOH was stirred at 25 °C overnight. After the reaction was completed, the solvent was removed under reduced pressure to give a solid. To the solid was added ethyl acetate and filtered. The filtrate was purified by flash column chromatography.General procedure A - Step 2: Synthesis of Tra-OH derivatives.

[0174] To a solution of Tra-CN derivative (1.0 eq.) in acetonitrile and water (3 / 2, v / v) was added silver nitrate (14 eq.). The suspension was stirred at 25 °C for 24 hrs. Then the reaction mixture was quenched by adding to a mixture of ethyl acetate / 5% ammonium hydroxide. The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography.Synthesis of PL-4 and PL-1.

[0175] According to step 1 in general procedure A, a mixture of M24 (30 mg, 0.048 mmol, 1.0 eq.), Intermediate A (65.2 mg, 0.322 mmol, 10 eq.), and NaOAc (29 mg, 0.354 mmol, 11 eq.) in anhydrous EtOH was stirred at 25 °C overnight. After the reaction was completed, the solvent was removed under reduced pressure to give a solid. To the solid was added ethyl acetate and filtered. The filtrate was purified by flash column chromatography (ethyl acetate: n-heptane (1:1)) to afford PL-4 as a light-yellow solid (19 mg, 76.7%).1H NMR (300 MHz, CHCh- ) 8 (ppm) 6.60 (s, 1H), 6.37 (s, 1H), 6.27 (s, 1H), 6.06 (s, 1H), 5.99 (s, 1H), 5.31 (s, 1H), 5.02 (d, 7= 11.4 Hz, 1H), 4.33 (s, 1H), 4.29 (d, 7 = 4.5 Hz, 1H), 4.19 (s, 1H), 4.12 (d, 7 = 12.3 Hz, 1H), 3.82 (d, 7 = 8.3 Hz, 3H), 3.67 - 3.57 (m, 3H), 3.52 (d, 7 = 5.1 Hz, 1H), 3.43 (s, 1H), 3.13 (s, 1H), 2.96 (s, 2H), 2.83 (s, 2H), 2.60 (s, 3H), 2.33 (s, 3H), 2.32 (s, 1H), 2.28 (d, 7 = 2.7 Hz, 3H), 2.21 (s, 3H), 2.11 - 2.02 (m, 4H).

[0176] According to step 2 in general procedure A, to a solution of PL-4 (19 mg, 0.0246 mmol, 1.0 eq.) in acetonitrile and water (3 / 2, v / v, 1 mL) was added silver nitrate (60 mg, 0.353 mmol, 14 eq.). The suspension was stirred at 25 °C for 24 hrs. Then the reaction mixture was quenched by adding to a mixture of ethyl acetate / 5% ammonium hydroxide. The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (eluting with dichloromethane: methanol (20: 1)) to afford PL-1 (15 mg, 80%) as a yellow solid.1H NMR (300 MHz, CHCl3-d) δ (ppm) 6.61 (s, 1H), 6.31 (d, 7 = 29.4 Hz, 2H), 5.99 (d, 7= 22.5 Hz, 2H), 5.74 (s, 1H), 5.12 (d, 7 = 11.4 Hz, 1H), 4.82 (s, 1H),4.49 (s, 2H), 4.18 (s, 1H), 4.06 (s, 1H), 3.80 (s, 4H), 3.57 (s, 5H), 3.24 (s, 1H), 2.89 (s, 2H),2.33 (s, 4H), 2.27 (s, 3H), 2.18 (s, 3H), 2.03 (s, 3H).Synthesis of PL-6 and PL-2.

[0177] According to step 1 in general procedure A, a mixture of M24 (100 mg, 0.16 mmol, 1.0 eq.), 5-(2-aminoethyl)-2-(2-hydroxyethoxy)phenol (160 mg, 0.8 mmol, 5 eq.), HO Ac (96.1 mg, 1.6 mmol, 10 eq.), and NaOAc (25.6 mg, 0.32 mmol, 2 eq.) in anhydrous EtOH (10 mL) was stirred for 2 hrs at room temperature. The solvent was removed under reduced pressure and purified by flash column chromatography on neutral aluminum oxide (dichloromethane: methanol (50: 1)) to afford PL-2 as a light-yellow solid (68.0 mg, 52.8%). LC-MS (ESI) m / z: 801 [M+H]+.1H NMR (300 MHz, chloroform-^) d (ppm) 6.62 (s, 1H), 6.51 (d, J = 9.1 Hz, 2H), 6.15 (s, 1H), 6.00 (s, 1H), 5.80 (s, 1H), 5.03 (d, J = 11.6 Hz, 1H), 4.60 (s, 1H), 4.44 - 4.25 (m, 2H), 4.21 (s, 1H), 4.12 (d, J = 11.4 Hz, 1H), 3.87 (d, J = 6.2 Hz, 4H), 3.81 (s, 3H), 3.52 (s, 1H), 3.44 (s, 1H), 3.13 (s, 1H), 2.94 (d, J = 19.8 Hz, 3H), 2.86 - 2.38 (m, 3H), 2.35 (s, 3H), 2.28 (s, 3H), 2.22 (s, 3H), 2.16 (s, 1H), 2.07 (s, 3H).

[0178] According to step 2 in general procedure A, to a solution of PL-2 (19 mg, 0.0246 mmol, 1.0 eq.) in acetonitrile and water (3 / 2, v / v, 1 mL) was added silver nitrate (60 mg, 0.353 mmol, 14 eq.). The suspension was stirred at 25 °C for 24 hrs, and then treated with a mixture of 5% ammonium hydroxide in ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by Prep-HPLC to afford PL-6as a yellow solid (6 mg, 31.9% yield). LC-MS (ESI) m / z: 792 [M+H]+.1H NMR (300 MHz, CHCh- ) d (ppm) 6.69 - 6.57 (m, 1H), 6.50 (d, J = 6.5 Hz, 2H), 6.12 (s, 1H), 5.96 (d, J = 4.9 Hz, 1H), 5.13 (d, J= 10.8 Hz, 1H), 4.82 (s, 1H), 4.48 (d, J= 3.5 Hz, 2H), 4.18 (s, 2H), 3.84 (dd, J = 21.5, 4.6 Hz, 8H), 3.58 (s, 1H), 3.34 (d, J = 10.3 Hz, 1H), 3.21 (s, 1H), 3.14 (s, 1H), 2.89 (s, 1H), 2.34 (d, J = 6.4 Hz, 5H), 2.26 (s, 4H), 2.18 (s, 3H), 2.04 (d, J = 2.4 Hz, 6H).Synthesis of PL-7.

[0179] According to step 1 in general procedure A, a mixture of M24 (30 mg, 0.048 mmol, 1.0 eq.), Intermediate D (112.6 mg, 0.48 mmol, 10 eq.), and NaOAc (38.6 mg, 0.48 mmol, 10 eq.) in anhydrous EtOH was stirred at 25 °C overnight. The solvent was removed under reduced pressure to give a solid. The ethyl acetate was added, and the mixture was filtered. The filtrate was purified by flash column chromatography on silica gel (dichloromethane: methanol (50: 1)) to afford PL-7 as a white solid (15 mg, 39%). LC-MS (ESI) m / z: 800 [M+H]+.1H NMR (400 MHz, CHCh-d) 8 (ppm) 6.59 (s, 1H), 6.41 (s, 1H), 6.29 (s, 1H), 6.14 (d, J= 1.4 Hz, 1H), 5.98 (s, 1H), 5.01 (d, J = 11.5 Hz, 1H), 4.57 (s, 1H), 4.32 (s, 1H), 4.28 (d, J = 4.9 Hz, 1H), 4.18 (d, J= 2.7 Hz, 1H), 4.10 (d, J= 12.0 Hz, 1H), 3.91 - 3.80 (m, 4H), 3.79 (s, 3H), 3.50 (d, J= 4.9 Hz, 1H), 3.41 (s, 1H), 3.12 (t, J= 9.1 Hz, 1H), 2.94 (d, J = 6.9 Hz, 2H), 2.80 (d, J = 12.1 Hz, 1H), 2.42 (d, J = 16.1 Hz, 2H), 2.32 (s, 5H), 2.26 (s, 3H), 2.19 (s, 3H), 2.07 (s, 2H), 2.04 (s, 3H).Synthesis of PL-8.PL-8

[0180] A mixture of M24 (20 mg, 0.032 mmol, 1.0 eq.), Intermediate E (67.96 mg, 0.32 mmol, 10 eq.), and NaOAc (5.12 mg, 0.064 mmol, 2.0 eq.) in anhydrous ethanol was stirred at 25 °C overnight. The mixture was purified by Prep-HPLC to afford PL-8 as a white solid (9.0 mg, 34%). LC-MS (ESI) m / z: 815.3 [M+H]+.1H NMR (400 MHz, DMSO-76) 6 (ppm) 8.75 (s, 1H), 6.47 (s, 1H), 6.41 (d, J= 3.9 Hz, 2H), 6.22 (d, J= 11.8 Hz, 2H), 5.05 (d, J= 11.2 Hz, 1H), 4.50 (d, 7 = 3.5 Hz, 2H), 4.27 (s, 1H), 4.21 (d, 7 = 4.5 Hz, 1H), 4.15 (d, 7 = 15.9 Hz, 1H), 4.10 - 4.03 (m, 2H), 3.65 (s, 3H), 3.26 (s, 2H), 3.05 (s, 1H), 2.80 (s, 2H), 2.70 (dd, 7 = 3.9, 2.0 Hz, 1H), 2.37 - 2.35 (m, 1H), 2.31 (s, 4H), 2.24 (s, 3H), 2.06 (s, 3H), 2.01 (s, 3H).Synthesis of PL-9.

[0181] To a solution of PL-4 (30 mg, 0.04 mmol, 1.0 eq.) and glycolic acid (12.16 mg, 0.16 mmol, 4.0 eq.) in 2 mL DMF was added HATU (45.6 mg, 0.12 mmol, 3.0 eq.). After stirring for 5-10 mins, DIPEA (25.8 mg, 0.2 mmol, 5.0 eq.) was added and the mixture wasstirred at r.t. for 3 hrs. The reaction mixture was purified by Prep-HPLC to provide PL-9 (20 mg, 61.9% yield) as a white solid. LC-MS (ESI) m / z: 828.3 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ (ppm) 9.03 (s, 1H), 8.75 (s, 1H), 7.90 (s, 1H), 6.47 (s, 2H), 6.18 (s, 2H), 6.13 (t, J = 5.5 Hz, 1H), 5.07 (d, J= 11.6 Hz, 1H), 4.52 (d, J = 2.8 Hz, 2H), 4.22 (d, 7 = 4.8 Hz, 1H), 4.18 - 4.05 (m, 2H), 3.96 (d, J = 5.5 Hz, 2H), 3.66 (s, 3H), 3.61 (s, 3H), 3.30 (s, 1H), 3.01 (s, 1H), 2.78 (s, 2H), 2.70 (t, J = 1.9 Hz, 1H), 2.39 - 2.34 (m, 1H), 2.32 (s, 3H), 2.24 (s, 3H), 2.18 (d, J = 14.6 Hz, 1H), 2.07 (s, 4H), 2.00 (s, 3H).Synthesis of PL-11.PL-11

[0182] A mixture of M24 (5 mg, 0.08 mmol, 1.0 eq.), 3-(2-aminoethyl)phenol hydrochloride (13.84 mg, 0.08 mmol, 5.0 eq.), NaOAc (7.2 mg, 0.088 mmol, 10.0 eq.) in anhydrous EtOH ( 1 mL) was stirred at r.t. overnight. The solvent was removed under reduced pressure and purified by column chromatography on neutral alumina (dichloromethane: methanol (50: 1)) to afford 5 mg of PL-11 (83.9 %) as brown solid. LC-MS (ESI) m / z: 741 [M+H]+.1H NMR (400 MHz, DMSO-76) 5 (ppm) 9.32 (s, 1H), 8.79 (s, 1H), 6.74 (d, J = 8.7 Hz, 1H), 6.46 (d, 7= 10.7 Hz, 2H), 6.38 (s, 1H), 6.29 (s, 1H), 6.18 (s, 1H), 5.08 (d, 7= 11.9 Hz, 1H), 4.48 (s, 1H), 4.22 (s, 1H), 4.08 (s, 1H), 3.99 (d, 7 = 11.4 Hz, 1H), 3.65 (s, 3H), 3.24 (s, 1H), 2.81 (s, 2H), 2.31 (s, 3H), 2.25 (s, 3H), 2.06 (s, 3H), 2.03 (s, 1H), 2.02 (s, 1H), 2.01 (s, 3H).Synthesis of PL-12.

[0183] According to step 1 in general procedure A, a mixture of M24 (10 mg, 0.016 mmol, 1.0 eq), 3-(2-aminoethyl)aniline (138 mg, 0.08 mmol, 5.0 eq), NaOAc (12.8 mg, 0.016 mmol, 10.0 eq) in anhydrous EtOH (10 mL) was stirred at r.t overnight. The solvent was removed under reduced pressure and the residue was purified by Prep-TLC (dichloromethane: methanol (10:1)) to afford PL-12 (6.1 mg, 51.2%) as a light-yellow solid. LC-MS (ESI) m / z: 740.4 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ (ppm) 8.76 (s, 1H), 7.68 - 7.55 (m, 2H), 6.58 (d, 7= 8.5 Hz, 1H), 6.47 (s, 1H), 6.28 (d, J= 1.0 Hz, 1H), 6.23 (d, 7= 9.2 Hz, 1H), 6.17 (d, 7 = 1.3 Hz, 2H), 5.06 (d, 7 = 11.6 Hz, 1H), 4.94 (s, 1H), 4.47 (s, 2H), 4.22 (s, 1H), 4.08 (s, 1H), 3.97 (d, 7= 11.5 Hz, 1H), 3.65 (s, 3H), 2.81 (d, 7= 5.3 Hz, 2H), 2.70 (s, 1H), 2.36 (s, 1H), 2.31 (s, 3H), 2.24 (s, 3H), 2.06 (s, 3H), 2.02 (d, 7 = 6.6 Hz, 2H), 2.01 (s, 3H), 1.94 (s, 1H).Synthesis of PL-13.

[0184] A solution of PL-4 (10 mg, 0.013 mmol, 1.0 eq.) and (((9H-fluoren-9- yl)methoxy)carbonyl)glycine (38.6 mg, 0.13 mmol, 10.0 eq.), HOBt (35 mg, 0.26 mmol, 20.0 eq.), EDCI (49 mg, 0.25 mmol, 20 eq.), HATU (98.8 mg, 0.26 mmol, 20.0 eq.) in 3 mLdichloromethane was stirred at r.t. for 2 hrs. The reaction was converted completely by LC-MS. The reaction mixture was washed with water and the organic layer dried over anhydrous sodium sulfate and concentrated. The residue was used for next step directly without purification.

[0185] The solution of crude N-Fmoc-PL-4 in 4 mL acetonitrile and 1.6 mL Et2N was stirred at r.t. for 1 h. The reaction was converted completely by LC-MS. The reaction mixture was concentrated and dissolved into dichloromethane and the solution washed with water and dried over anhydrous sodium sulfate. The organic layer was concentrated and purified the residue by Prep-HPLC to provide PL-12 ( 4.6 mg, 43% yield) as white solid. LC-MS (ESI) m / z: 827 [M+H]+.1H NMR (400 MHz, DMSO-de) 8 (ppm) 8.41 (s, 2H), 7.93 (s, 1H), 6.46 (d, J = 8.3 Hz, 2H), 6.18 (s, 2H), 5.35 (t, 7 = 4.8 Hz, 1H), 5.07 (d, J= 11.5 Hz, 1H), 4.52 (s, 1H), 4.23 (s, 1H), 4.14 (s, 1H), 4.08 (d, J= 11.7 Hz, 1H), 3.66 (s, 3H), 3.60 (s, 3H), 3.23 (s, 2H), 3.02 (s, 2H), 2.85 - 2.72 (m, 2H), 2.32 (s, 3H), 2.24 (s, 3H), 2.18 (d, J = 14.5 Hz, 1H), 2.07 (s, 3H), 2.05 (d, J= 7.4 Hz, 2H), 2.02 (s, 1H), 2.00 (s, 3H).Synthesis of PL-14.

[0186] To a solution of Ecteinascidin 743 (CAS: 114899-77-3) (20 mg, 0.026 mmol, 1.0 eq.) and (9H-fluoren-9-yl)methyl (2-hydroxyethyl)carbamate (73.42 mg, 0.26 mmol, 10.0 eq.) in 2 mL THF was added PPha (204 mg, 0.78 mmol, 30.0 eq.) and DIAD (157 mg, 0.78 mmol, 30.0 eq.). After the addition, the mixture was stirred at r.t. overnight. LC-MS shows the reaction was complete. The reaction mixture was concentrated and purified by Prep-HPLC to obtain the A-Fmoc-PL-14 (2 mg, 7.4% yield) as a white solid. LC-MS (ESI) m / z: 1036 [M+H]+.

[0187] The solution of A-Fmoc-PL-14 (2 mg, 0.00193 mmol, 1.0 eq.) in 1 mL DMF and 0.2 mL EtaN was stirred at r.t. overnight. The reaction mixture was concentrated, and theresidue purified by Prep-HPLC to obtain PL-14 (0.77 mg, 49% yield) as a white solid. LC-MS (ESI) m / z: 814 [M+H]+.Synthesis of PL-16.

[0188] To a solution of PL-12 (20 mg, 0.027 mmol, 1.0 eq.) and (9H-fluoren-9- yl)methyl (2-chloro-2-oxoethyl)carbamate (59.7 mg, 0.189 mmol, 7.0 eq.) in 2 mL DMF was added pyridine (15 mg, 0.189 mmol, 7.0 eq.) and the reaction mixture stirred at r.t. overnight. After PL-12 was consumed completely, triethylamine (0.1 mL) was added, and the reaction mixture stirred at r.t. for another 4 hrs. The reaction mixture was purified by Prep-HPLC to obtained PL-16 (11 mg, 55% yield) as white solid. LC-MS (ESI) m / z: 797.2 [M+H]+.1H NMR (400 MHz, DMSO-cfc) d (ppm) 8.78 - 8.70 (m, 1H), 8.30 (s, 1H), 7.30 (s, 1H), 7.25 (d, J = 8.2 Hz, 1H), 6.85 (d, 7 = 8.6 Hz, 1H), 6.47 (s, 1H), 6.27 (s, 1H), 6.17 (s, 1H), 5.07 (d, J= 11.3 Hz, 1H), 4.46 (s, 1H), 4.20 (d, 7= 4.4 Hz, 1H), 4.08 (s, 1H), 4.01 (d, 7= 11.2 Hz, 1H), 3.64 (s, 3H), 3.26 (s, 5H), 3.23 (s, 2H), 2.80 (s, 2H), 2.68 (s, 1H), 2.29 (s, 3H), 2.23 (s, 3H), 2.05 (s, 4H), 1.99 (s, 4H).Synthesis of PL-18.

[0189] A solution of M24 (20 mg, 0.032 mmol, 1.0 eq.), 4-(2-aminoethyl)aniline (21.76 mg, 0.16 mmol, 5.0 eq.), and p-TsOH (5.5 mg, 0.032 mmol, 1.0 eq.) in anhydrous n-BuOH (1 mL) was stirred for 1.5 hrs at 110 °C. The reaction mixture was concentrated and purified by Prep-HPLC to provide compound PL-18 (1.3 mg, 5.4% yield) as a brown solid. LC-MS (ESI) m / z: 740 [M+H]+.Synthesis of PL-19.

[0190] To a solution of PL-12 (20 mg, 0.026 mmol, 1.0 eq.) and 2-((tert- butyldimethylsilyl)oxy)acetic acid (8 mg, 0.105 mmol, 4.0 eq.) in 2 mL DMF was added HATU (29.64 mg, 0.078 mmol, 3.0 eq.) and DIPEA (16.77 mg, 0.13 mmol, 5.0 eq.). After the addition, the mixture was stirred at r.t. overnight. After the reaction was completed, a solution of 70% HF / pyridine (12.87 mg, 0.13 mmol, 5.0 eq.) was added. And stirred at r.t .for an additional hour. The reaction mixture was concentrated and purified by Prep-HPLC to provide PL-19 (3.4 mg, 16% yield) as a white solid. LC-MS (ESI) m / z: 798 [M+H]+.1H NMR (400 MHz, DMSO-d6) d (ppm) 9.52 (s, 1H), 8.76 (s, 1H), 7.39 (d, J= 2.3 Hz, 1H), 7.31 (dd, J= 8.7, 2.3 Hz, 1H), 6.85 (d, J = 8.7 Hz, 1H), 6.48 (s, 1H), 6.32 - 6.25 (m, 1H), 6.18 (s, 1H), 5.65 (s, 1H), 5.08 (d, J = 11.5 Hz, 1H), 4.47 (d, J = 2.9 Hz, 2H), 4.25 - 4.20 (m, 1H), 4.09 (s, 1H), 4.06 - 4.00 (m, 1H), 3.94 (d, J = 4.5 Hz, 2H), 3.65 (s, 3H), 3.27 - 3.22 (m, 1H), 3.22 - 3.13 (m, 1H), 2.81 (d, J= 5.2 Hz, 2H), 2.69 (s, 1H), 2.51 - 2.41 (m, 2H), 2.30 (s, 3H), 2.25 (s, 3H), 2.06 (s, 4H), 2.00 (s, 3H).Synthesis of PL-22.

[0191] PL-9 (6 mg, 0.0073 mmol, 1.0 eq.), AgNCh (12.4 mg, 0.0073 mmol, 10.0 eq.) was suspended into acetonitrile: H2O (3:2, v / v). The solution was stirred at r.t. for 24 hr in the absence of light. The suspension was quenched with a mixture of saturated brine and saturated sodium bicarbonate, and filtered. The resulting solution was purified by preparative HPLC to obtain PL-22 (0.97 mg, 16.3% yield) as white solid. LC-MS (ESI) m / z: 819 [M+H]+.Lurbinectedin related payloads (PL)General procedure B - Step 1: Synthesis ofLur-CN derivatives.

[0192] A mixture of M24 (1.0 eq.), the respective intermediate as described above (10.0 eq.), AcOH (10 eq.), and NaOAc (2 eq.) in anhydrous EtOH was stirred for 2 hrs at 60 °C. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography on neutral aluminum oxide.General procedure B - Step 2: Synthesis of Lur-OH derivatives.

[0193] To a solution of Lur-CN derivative (1.0 eq.) in acetonitrile and water (3 / 2, v / v) was added silver nitrate (15 eq.). The suspension was stirred at 25 °C for 24 hrs, and then treated with a mixture of saturated sodium bicarbonate and brine. The precipitated solid was filtered out and the filtrate was extract with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by Prep-HPLC.Synthesis of PL-5 and PL-3.

[0194] According to step 1 in general procedure B, a mixture of M24 (100 mg, 0.16 mmol, 1.0 eq.), Intermediate C (282.2 mg, 1.6mmol, 10.0 eq.), AcOH (96.1 mg, 1.6 mmol, 10 eq.), and NaOAc (25.6 mg, 0.32 mmol, 2 eq.) in anhydrous EtOH (10 mL) was stirred for 2 hrs at 60 °C. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography on neutral aluminum oxide (dichloromethane : methanol = 50:1) to afford PL-5 as a light-yellow solid (80 g, 63.8%). LC-MS (ESI) m / z: 779 [M+H]+.1H NMR (300 MHz, CHCh- ) 6 (ppm) 7.54 (s, 1H), 7.04 (d, J = 8.5 Hz, 1H), 6.76 - 6.64 (m, 2H), 6.56 (dd, J = 8.5, 2.3 Hz, 1H), 6.28 - 6.18 (m, 1H), 6.09 - 6.01 (m, 1H), 5.08 (d, J = 11.5 Hz, 1H), 4.56 (s, 1H), 4.30 (d, J = 11.0 Hz, 2H), 4.25 - 4.15 (m, 2H), 3.82 (s, 3H), 3.49 - 3.38 (m, 2H), 3.12 (d, J = 13.2 Hz, 1H), 3.04 (s, 1H), 2.96 (d, J = 9.0 Hz, 1H), 2.86 - 2.77 (m, 1H), 2.55 (d, J = 5.1 Hz, 2H), 2.49 (s, 1H), 2.38 (d, J = 4.7 Hz, 4H), 2.28 (d, J = 6.1 Hz, 4H), 2.23 (d, J = 3.7 Hz, 3H), 2.07 (d, J = 4.1 Hz, 3H).

[0195] According to step 2 in general procedure B, to a solution of PL-5 (65 mg, 0.0833 mmol, 1.0 eq.) in acetonitrile and water (3 / 2, v / v, 1 mL) was added silver nitrate (212 mg, 1.248 mmol, 15eq.). The suspension was stirred at 25 °C for 24 hrs, and then treated with a mixture of saturated sodium bicarbonate and brine. The precipitated solid was filtered out and the filtrate was extract with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by Prep-HPLC to afford PL-3 as a yellow solid (2.6 mg, 4%). LC-MS (ESI) m / z: 376.8 [(M-H2O) / 2+H]+.1H NMR (300 MHz, CD3OD- <A) 8 (ppm) 8.10 (s, 1H), 7.15 (d, J = 8.6 Hz, 1H), 6.94 (s, 2H), 6.74 (q, J = 14.0 Hz, 3H), 6.28 (s, 1H), 6.09 (d, J= 6.7 Hz, 1H), 5.35 (t, J = 4.8 Hz, 3H), 3.80 (d, J = 7.7 Hz, 5H), 2.60 (s, 2H), 2.52 (s, 2H), 2.40 (s, 3H), 2.32 (d, J = 6.6 Hz, 9H), 2.25 - 2.17 (m, 6H).Synthesis of PL-10.

[0196] To a solution of PL-5 (20 mg, 0.026 mmol, 1.0 eq.) and glycolic acid (7.81 mg, 0.103 mmol, 4.0 eq.) in 2 mL dichloromethane were added HATU (29.6 mg, 0.078 mmol, 3.0 eq.) and DIPEA (16.8 mg, 0.13 mmol, 5.0 eq.). After the addition, the mixture was stirred at r.t. overnight. The reaction was purified by Prep-HPLC to provide compound PL-10 as a white solid (1.53 mg, 7.1%). LC-MS (ESI) m / z: 837.4 [M+H]+.1H NMR (400 MHz, DMSO-de) 8 (ppm) 10.08 (s, 1H), 9.34 (s, 1H), 8.76 (s, 1H), 7.69 (s, 1H), 7.23 (d, J = 1.3 Hz, 2H), 6.47 (s, 1H), 6.22 (d, J= 14.4 Hz, 2H), 5.57 (t, J= 6.0 Hz, 1H), 5.07 (d, J= 11.1 Hz, 1H), 4.46 (s, 2H), 4.19 (s, 1H), 4.06 (d, J= 10.8 Hz, 2H), 3.93 (d, J= 5.7 Hz, 2H), 3.64 (s, 3H), 3.19 (s, 1H), 2.85 - 2.74 (m, 1H), 2.68 - 2.65 (m, 1H), 2.61 (d, J = 15.4 Hz, 1H), 2.41 (s, 2H), 2.34 - 2.30 (m, 2H), 2.28 (s, 3H), 2.25 (s, 3H), 2.04 (s, 4H), 1.97 (s, 3H).Synthesis of PL-15.

[0197] A mixture of M24 (10 mg, 0.016 mmol, 1.0 eq.), Intermediate F (24 mg, 0.16 mmol, 10.0 eq.), AcOH (96.1 mg, 1.6 mmol, 10.0 eq.) and NaOAc (145 mg, 0.176 mmol, 11.0 eq.) in anhydrous EtOH (1 mL) was stirred for r.t. at 40 °C. The solvent was removed under reduced pressure and purified by column chromatography on neutral alumina (dichloromethane: methanol (30: 1)) to afford PL-15 (2.5 mg, 20% yield) product as light-yellow solid. LC-MS (ESI) m / z: 779.2 [M+H]+.1H NMR (400 MHz, CHCl3-d) δ (ppm) 7.46 (s, 1H), 7.19 (d, J= 8.5 Hz, 1H), 6.69 (s, 1H), 6.60 (s, 1H), 6.50 (d, J= 8.4 Hz, 1H), 6.26 (s, 1H), 6.07 (s, 1H), 5.83 (s, 1H), 5.12 (d, J= 11.7 Hz, 1H), 4.59 (s, 1H), 4.36 (s, 1H), 4.31 (d, J= 4.7 Hz, 1H), 4.26 (s, 1H), 4.21 (d, J= 11.7 Hz, 1H), 3.85 (s, 3H), 3.46 (d, J= 11.3 Hz, 2H), 3.18 (s, 1H), 3.10 (d, J = 18.0 Hz, 1H), 2.97 (dd, J = 18.1, 9.0 Hz, 1H), 2.84 (d, J = 12.4 Hz, 1H), 2.68 - 2.59 (m, 1H), 2.54 (d, J = 15.5 Hz, 2H), 2.41 (s, 4H), 2.35 (d, J= 14.4 Hz, 1H), 2.31 (s, 3H), 2.26 (s, 4H), 2.11 (s, 3H).Synthesis of PL-17.

[0198] A mixture of M24 (10 mg, 0.016 mmol, 1.0 eq.), Intermediate G (28 mg, 0.16 mmol, 10.0 eq.), AcOH (9.6 mg, 0.16 mmol, 10.0 eq.), in anhydrous EtOH (lOmL) was stirred for 2 hrs at 60 °C. The solvent was removed under reduced pressure and purified by column chromatography on neutral alumina (dichloromethane: methanol (50: 1)) to afford PL-17 (1 mg, 7.8% yield) as light-yellow solid. LC-MS (ESI) m / z: 793 [M+H]+.Synthesis of PL-20.

[0199] A mixture of M24 (20 mg, 0.032 mmol, 1.0 eq.), Intermediate H (50.88 mg, 0.16 mmol, 5.0 eq.), and p-TsOH (5.5 mg, 0.032 mmol, 1.0 eq.) in anhydrous n-BuOH (1 mL) was stirred for 1.5 hrs at 110 °C. The solution was concentrated and purified by Prep-HPLC to provide PL-20 (1.6 mg, 6.1% yield) as a brown solid. LC-MS (ESI) m / z: 808 [M+H]+.Synthesis of PL-21.

[0200] A mixture of M24 (20 mg, 0.032 mmol, 1.0 eq.), Intermediate I (50.88 mg, 0.16 mmol, 5.0 eq.), and p-TsOH (5.5 mg, 0.032 mmol, 1.0 eq.) in anhydrous n-BuOH (1 mL) was stirred for 1.5 hrs at 110 °C. The solution was concentrated and purified by Prep-HPLC to provide PL-21 (0.8 mg, 3% yield) as a brown solid. LC-MS (ESI) m / z: 793 [M+H]+.Linkers (LK)Synthesis of LK-1.

[0201] To a solution of l-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)-3,6,9, 12,15, 18-hexa- oxahenicosan-21-oic acid (572 g, 1.32 mmol) and HATU (652 mg, 1.72 mmol) in DMF (4 mL) were added (S)-2-((S)-2-amino-3-methylbutanamido)-A-(4-(hydroxymethyl)phenyl)-5-ureido- pentanamide (500 mg, 1.32 mmol) and N, N-diisopropylethyla ine (503 mg, 3.96 mmol) at 0 °C. After the addition, the mixture was stirred at r.t. for 2 hrs. LCMS showed the reaction was completed. The mixture was concentrated to give a crude product, which was purified by reversed phase flash column chromatography (0-60% acetonitrile in H2O) to give l-(2,5-dioxo- 2,5-dihydro- IH-pyrrol- 1 -yl)-A-((S)- 1 -(((S)- 1 -((4-(hydroxymethyl) phenyl) amino)- 1 -oxo-5- ureidopentan-2-yl)amino)-3-methyl-l-oxobutan-2-yl)-3,6,9,12,15,18-hexaoxahenicosan-21- amide as a yellow solid (400 mg, 38% yield). LC-MS: (ESI) m / z = 795.8 [M+H]+.

[0202] To a solution of l-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)-N-((S)-l-(((S)-l-((4- (hydroxymethyl)phenyl)amino)-l-oxo-5-ureidopentan-2-yl)amino)-3-methyl-l-oxobutan-2- yl)-3,6,9,12,15,18-hexaoxahenicosan-21-amide (400 mg, 0.504 mmol) in DMF (2 mL) were added bis(4-nitrophenyl) carbonate (766 mg, 2.52 mmol) and N,N-diisopropylethylamine (320 mg, 2.52 mmol) at 0 °C. After the addition, the mixture was stirred at r.t. for 3 hrs. LCMS showed the reaction was completed. The reaction mixture was concentrated to give a crude product, which was purified by Prep-HPLC to give 4-((23S,26S)-l-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)-23-isopropyl-21,24-dioxo-26-(3-ureidopropyl)-3,6,9,12,15,18-hexaoxa-22,25-di- azaheptacosanamido)benzyl (4-nitrophenyl) carbonate as a white solid (220 mg, 45% yield). LC-MS: (ESI) m / z: 960.4 [M+H]+.1H NMR (400 MHz, DMSO-de): 8 (ppm) 9.94 (s, 1H), 8.31- 8.34 (m, 2H), 7.98 (d, J= 8.0 Hz, 1H), 7.76 (d, J= 8.0 Hz, 1H), 7.67 (d, J= 8.0 Hz, 2H), 7.57- 7.59 (m, 2H), 7.43 (d, J = 8.0 Hz, 2H), 7.01 (s, 2H), 5.91-5.94 (m, 1H), 5.32 (s, 2H), 5.28 (s, 2H), 4.43-4.45 (m, 1H), 4.23-4.27 (m, 1H), 3.48-3.67 (m, 26H), 2.98-3.07 (m, 2H), 2.40-2.51 (m, 2H), 2.01-2.05 (m, 1H), 1.76-1.78 (m, 2H), 1.44-1.66 (m, 2H), 0.90-0.85 (m, 6H).Synthesis of LK-2.

[0203] To a solution of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-(tert- butoxy)-5-oxopentanoic acid (1.00 g, 2.35 mmol) and HATU (1.34 g, 3.53 mmol) in DMF (10 mL) at O °C was added 2,5,8,l l,14,17,20,23-octaoxapentacosan-25-amine (901 mg, 2.35 mmol) and A,A-di isopropylethyl a ine (910 mg, 7.05 mmol). After the addition, the mixture was stirred at r.t. for 2 hrs. LCMS showed the reaction was completed. The mixture was concentrated to give a crude product, which was purified by flash column chromatography on silica gel (0-10% methanol in dichloromethane) to give tert-butyl (S)-28-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-27-oxo-2,5,8,l 1,14, 17,20, 23-octaoxa-26-azahentriacontan-31- oate as a yellow solid (1.50 g, 81% yield). LC-MS: (ESI) m / z: 791.4 [M+H]+.

[0204] To a solution of tert-butyl (S)-28-((((9H-fhroren-9-yl)methoxy)carbonyl)ami- no)-27-oxo-2,5,8,l l,14,17,20,23-octaoxa-26-azahentriacontan-31-oate (1.50 g, 1.89 mmol) in dichloromethane (6 mL) at r.t. was added trifluoroacetic acid (2 mL). The reaction mixture was stirred at r.t. for 2 hrs. LCMS showed the reaction was completed. The reaction mixture was concentrated in vacuo to give the crude (S)-28-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)- 27-oxo-2,5,8,l 1,14, 17, 20, 23-octaoxa-26-azahentriacontan-31-oic acid as yellow oil (1.50 g,crude), which was used for the next reaction without further purification. LC-MS: (ESI) m / z: 735.4 [M+H]+.

[0205] To a solution of (S)-28-((((9H-fhioren-9-yl)methoxy)carbonyl)amino)-27-oxo- 2,5,8, 1 l,14,17,20,23-octaoxa-26-azahentriacontan-31-oic acid (1.50 g, crude) and HATU (1.55 g, 4.08 mmol) in DMF (10 mL) at 0 °C was added (S)-2-((S)-2-amino-3-methylbutanamido)- A-(4-(hydroxymethyl)phenyl)-5-ureidopentanamide (774 mg, 2.04 mmol) and A,A-diisoprop- ylethylamine (791 mg, 6.13 mmol). After the addition, the mixture was stirred at r.t. for 2 hrs. LCMS showed the reaction was completed. The mixture was concentrated to give a crude product, which was purified by reversed phase flash column chromatography (0-50% acetonitrile in H2O) to give 4-(hydroxymethyl)phenyl (28S,33S,36S)-28-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-33-isopropyl-27,31 ,34-trioxo-36-(3-ureidopropyl)-2,5,8, 11,14, 17,20,23-octaoxa-26,32,35-triazaheptatriacontan-37-oate (1.10 g, crude) as a white solid. LCMS: (ESI) m / z: 1097.6 [M+H]+.

[0206] To a solution of 4-(hydroxymethyl)phenyl (28S,33S,36S)-28-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-33-isopropyl-27,31 ,34-trioxo-36-(3-ureidopropyl)-2,5,8, 11,14, 17,20,23-octaoxa-26,32,35-triazaheptatriacontan-37-oate (900 mg, 0.82 mmol) in DMF (10 mL) at r.t. was added triethylamine (2 mL). The reaction mixture was stirred at r.t. for 2 hrs. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give the crude 4- (hydroxymethyl)phenyl-(28S,33S,36S)-28-amino-33-isopropyl-27,31,34-trioxo-36-(3-ureido- propyl)-2,5,8,l 1,14, 17,20, 23-octaoxa-26, 32, 35-triazaheptatriacontan-37-oate as a white solid (1.30 g crude), which was used for the next reaction without further purification. LC-MS: (ESI) m / z: 874.4 [M+H]+.

[0207] To a solution of 4-(hydroxymethyl)phenyl (28S,33S,36S)-28-amino-33- isopropyl-27,31,34-trioxo-36-(3-ureidopropyl)-2,5,8,l l,14,17,20,23-octaoxa-26,32,35-triaza- heptatriacontan-37-oate (1.30 g, crude) and 2,5-dioxopyrrolidin-l-yl 3-(2,5-dioxo-2,5-dihydro- lH-pyrrol-l-yl)propanoate (396 mg, 1.48 mmol) in DMF (6 mL) at 0 °C was added N,N- diisopropylethylamine (576 mg, 4.46 mmol). After the addition, the mixture was stirred at r.t. for 2 hrs. LCMS showed the reaction was completed. The mixture was concentrated to give a crude product, which was purified by reversed phase flash column chromatography (0-70% acetonitrile in H2O) to give (S)-2-(3-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)propanamido)-A5-((S)- 1 -(((S)- 1 -((4-(hydroxymethyl)phenyl)amino)- 1 -oxo-5-ureidopentan-2-yl)amino)-3-meth- yl-l-oxobutan-2-yl)-Nl-(2,5,8,l l,14,17,20,23-octaoxapentacosan-25-yl)pentanediamide as a white solid (400 mg, crude). LC-MS: (ESI) m / z: 1025.4 [M+H]+.

[0208] To a solution of (S)-2-(3-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)propanamido)- N5-((S)-l-(((S)-l-((4-(hydroxymethyl)phenyl)amino)-l-oxo-5-ureidopentan-2-yl)amino)-3- methyl- 1 -oxobutan-2-yl)-AT -(2, 5, 8, 11, 14, 17, 20, 23 -octaoxapentacosan-25-yl)pentanediamide (400 mg, 0.390 mmol) and bis(4-nitrophenyl) carbonate (593 mg, 1.95 mmol) in DMF (6 mL) at 0 °C was added N, N-diisopropyl ethyl a ine (201 mg, 1.56 mmol). After the addition, the mixture was stirred at r.t. for 2 hrs. LCMS showed the reaction was completed. The mixture was concentrated to give a crude product, which was purified by Prep-HPLC to give 4- ((28S,33S,36S)-28-(3-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)propanamido)-33-isopropyl-27, 31 ,34-trioxo-36-(3-ureidopropyl)-2,5,8, 11 , 14, 17,20,23-octaoxa-26,32,35-triazaheptatriacon- tan-37-amido)benzyl (4-nitrophenyl) carbonate as a white solid (118 mg, 25% yield). LC-MS: (ESI) m / z: 1191.6 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ (ppm) 10.04 (s, 1H), 8.33-8.29 (m, 2H), 8.14-8.10 (m, 2H), 7.91-7.88 (m, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.65 (d, J = 8.8 Hz, 2H), 7.58-7.54 (m, 2H), 7.40 (d, J= 8.4 Hz, 2H), 6.99 (s, 2H), 5.99-5.96 (m, 1H) , 5.41 (s, 2H) , 5.24 (s, 2H) , 4.41-4.35 (m, 1H) , 4.21-4.12 (m, 2H) , 3.61 (t, J = 7.2 Hz, 2H) , 3.50-3.49 (m, 26H) , 3.43-3.38 (m, 4H) , 3.23-3.18 (m, 5H) , 3.02-2.95 (m, 2H) , 2.43-2.38 (m, 2H) , 2.18- 2.14 (m, 2H) , 2.01-1.94 (m, 1H) , 1.84-1.81 (m, 1H) , 1.71-1.58 (m, 3H) , 1.46-1.36 (m, 2H) , 0.87-0.82 (m, 6H).Synthesis ofLK-3.

[0209] 4-((S)-2-((S)-2-(3-(2-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)ethoxy)propan- amido)-3-methylbutanamido)-5-ureidopentanamido)benzyl (4-nitrophenyl) carbonate. LC-MS:(ESI) m / z: 740.2 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ (ppm) 10.07 (s, 1H), 8.34 (d, J =9.2 Hz, 2H), 8.14 (d, J = 7.2 Hz, 1H), 7.87 (d, J = 8.8 Hz, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.6 Hz, 2H), 7.03 (s, 2H), 6.00 (s, 1H), 5.43 (s, 2H), 5.27 (s, 2H), 4.44-4.45 (m, 1H), 4.28-4.18 (m, 1H), 3.65-3.47 (m, 6H), 3.11-2.83 (m, 2H), 2.49-2.30 (m, 2H), 2.02-1.93 (m, 1H), 1.75-1.56 (m, 2H), 1.50-1.31 (m, 2H), 0.90-0.81 (m, 6H).Synthesis of LK-4.

[0210] 4-((2S,5S)-14-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)-5-isopropyl-4,7-dioxo- 2-(3-ureidopropyl)-9,12-dioxa-3,6-diazatetradecanamido)benzyl (4-nitrophenyl) carbonate. LC-MS: (ESI) m / z: 770.2 [M+H]+. NMR (400 MHz, DMSO-d6): δ (ppm) 10.13 (s, 1H), 8.32-8.36 (m, 3H), 7.67 (d, J= 8.0 Hz, 2H), 7.57-7.60 (m, 2H), 7.42-7.44 (m, 3H), 7.01 (s, 2H), 6.03-5.97 (m, 1H), 5.44 (s, 2H), 5.27 (s, 2H), 4.34-4.42 (m, 1H), 4.30-4.32 (m, 1H), 3.93 (s, 2H), 3.56-3.58 (m, 8H), 2.98-3.04 (m, 2H), 2.00-2.03 (m, 1H), 1.71-1.98 (m, 2H), 1.40- 1.63 (m, 2H), 0.82-0.90 (m, 6H).Synthesis ofLK-5.

[0211] 4-(( 14S, 17S)- 1 -(2,5 -dioxo-2, 5-dihydro- 1 H-pyrrol- 1 -yl)- 14-isopropyl- 12,15-di- oxo-17-(3-ureidopropyl)-3,6,9-trioxa-13,16-diazaoctadecanamido)benzyl (4-nitrophenyl) car- bonate. LC-MS: (ESI) m / z: 850.4 [M+H]+. NMR (400 MHz, DMSO-d6): δ (ppm) 10.08 (s, 1H), 8.33 (d, J = 9.0 Hz, 2H), 8.18-8.12 (m, 1H), 7.88 (d, J = 8.6 Hz, 1H), 7.68 (d, J = 8.0 Hz,2H), 7.59 (d, J = 9.0 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 7.04 (s, 2H), 5.99 (t, 1H), 5.43 (s, 2H), 5.26 (s, 2H), 4.45-4.35 (m, 1H), 4.29 - 4.15 (m, 1H), 3.68 - 3.44 (m, 14H), 3.10 - 2.85 (m, 2H), 2.50 - 2.29 (m, 2H), 2.05-1.95 (m, 1H), 1.80-1.60 (m, 2H), 1.41-1.35 (m, 2H), 0.91-0.84 (m, 6H).Synthesis ofLK-6.

[0212] 4-(( 17 S,20S)- 1 -(2,5 -dioxo-2, 5-dihydro- 1 H-pyrrol- 1 -yl)- 17 -isopropyl- 15,18-di- oxo-20-(3-ureidopropyl)-3,6,9,12-tetraoxa-16,19-diazahenicosanamido)benzyl (4-nitrophenyl) carbonate. LC-MS: (ESI) m / z: 872.4 [M+H]+.1H NMR (400 MHz, DMSO-d6): 8 (ppm) 10.06 (s, 1H), 8.31 (d, J = 9.2 Hz, 2H), 8.13 (d, J = 7.2 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 9.2 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.02 (s, 2H), 5.98 (t, J = 4.8 Hz, 1H), 5.41 (S, 2H), 5.24 (s, 2H), 4.53-4.30 (m, 1H), 4.30-4.15 (m, 1H), 3.56-3.45 (m, 18H), 3.03-2.94 (m, 2H), 2.48-2.32 (m, 2H), 2.0-1.95 (m, 1H), 1.75-1.55 (m, 2H), 1.50-1.30 (m, 2H), 0.89-0.81 (m, 6H).Synthesis of LK-7.

[0213] 4-((20S,23S)-l-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)-20-isopropyl-18,21-di- oxo-23-(3-ureidopropyl)-3,6,9,12,15-pentaoxa-19,22-diazatetracosanamido)benzyl (4-nitro- phenyl) carbonate. LC-MS: (ESI) m / z: 916.4 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ (ppm) 10.08 (s, 1H), 8.34 (d, J = 12.0 Hz, 2H), 8.15 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H),7.67 (d, J = 8.0 Hz, 2H), 7.58-6.60 (m, 2H), 7.43 (d, J = 8.0 Hz, 2H), 7.04 (s, 2H), 6.01-5.90 (m, 1H), 5.43(s, 2H), 5.26(s, 2H), 4.40-4.41 (m, 1H), 4.23-4.25(m, 1H), 3.48-3.50(m, 4H), 3.46- 3.47(m, 18H), 2.97-3.04 (m, 2H), 2.38-2.49 (m, 2H), 1.98-2.00 (m, 1H), 1.61-1.72 (m, 2H), 1.26-1.47 (m, 2H), 0.88 (q, J= 6.8 Hz, 6H).Synthesis ofLK-8.LK-8

[0214] To a solution of (S)- 11 -benzyl- l-(9H-fluoren-9-yl)-3, 6, 9-trioxo-2-oxa-4, 7,10- triazadodecan- 12-oic acid (11.5 g, 23.0 mmol) and DIEA (11.9 g, 92.0 mmol) in DMF (100 mL) at 0 °C was added EDCI (11.9 g, 92.0 mmol) and HOBt (6.2 g, 46.0 mmol), followed by the addition of benzyl 2-aminoacetate (9.60 g, 46.0 mmol). After the addition, the mixture was stirred at r.t. for 12 hrs. LCMS showed the reaction was complete. The mixture was partitioned between H2O (100 mL) and ethyl acetate (200 mL). The organic phase was separated, dried over anhydrous Na2SC>4, filtered and concentrated to give crude product, which was purified by flash silica gel chromatography (0-15% methanol in dichloromethane) to provide (S)-benzyl11 -benzyl- 1 -(9H-fluoren-9-yl)-3 ,6,9 , 12-tetraoxo-2-oxa-4,7 , 10, 13 -tetraazapentadecan- 15 -oate (2.6 g, 17% yield) as yellow oil. LC-MS: (ESI) m / z: 649.2 [M+H]+.

[0215] To a solution of (S)-benzyl l l-benzyl-l-(9H-fluoren-9-yl)-3,6,9,12-tetraoxo-2- oxa-4,7,10,13-tetraazapentadecan-15-oate (4.50 g, 6.94 mmol) in MeOH (50 mL) and DMF (50 mL) was added Pd / C (500 mg, 10% wt.) under H2. The mixture was stirred under H2 at r.t. for12 hours. LCMS showed the reaction was complete. The mixture was filtered, and the filtrate was concentrated to give (S)-l l-benzyl-l-(9H-fluoren-9-yl)-3,6,9,12-tetraoxo-2-oxa- 4,7,10,13-tetraazapentadecan-15-oic acid (4.00 g, quantitative) as yellow solid. LC-MS: (ESI) m / z: 559.2 [M+H]+.

[0216] To a solution of (S)-l l-benzyl-l-(9H-fluoren-9-yl)-3,6,9,12-tetraoxo-2-oxa- 4,7,10,13-tetraazapentadecan-15-oic acid (3.00 g, 5.38 mmol) and DIEA (1.73 g, 13.4 mmol) in DMF (20 mL) at 0 °C was added HATU (3,88 g, 10.2 mmol) and (4-aminophenyl)methanol(790 mg, 6.45 mmol). After the addition, the mixture was stirred at r.t. for 12 h. LCMS showed the reaction was complete. The mixture was partitioned between H2O (20 ml) and ethyl acetate (40 ml). The organic phase was separated, dried over anhydrous Na2SC>4, filtered and concentrated to give crude product, which was purified by flash silica gel chromatography (0- 10% methanol in dichloromethane) to get (S)-(9H-fhroren-9-yl)methyl (2-((2-((l-((2-((4- (hydroxymethyl)phenyl)amino)-2-oxoethyl)amino)-l-oxo-3-phenylpropan-2-yl)amino)-2-ox- oethyl)amino)-2-oxoethyl)carbamate (2.4 g, 69% yield) as white solid. LC-MS: (ESI) m / z: 646.2 [M+H]+.

[0217] To a solution of (S)-(9H-fluoren-9-yl)methyl (2-((2-((l-((2-((4-(hydroxymethyl) phenyl)amino)-2-oxoethyl)amino)-l -oxo-3 -phenylpropan-2-yl)amino)-2-oxoethyl)amino)-2- oxoethyl)carbamate (2.4 g, 3.62 mmol) in DMF (20 mL) was added TEA (4 mL) at r.t. After the addition, the mixture was stirred at r.t. for 12 hrs. LCMS showed the reaction was complete. The mixture was concentrated to get (S)-2-(2-(2-aminoacetamido)acetamido)-A-(2-((4- (hydroxymethyl)phenyl)amino)-2-oxoethyl)-3-phenylpropanamide (1.97 g, quantitative) as white solid. LC-MS: (ESI) m / z: 442.0 [M+H]+.

[0218] To a solution of (S)-2-(2-(2-aminoacetamido)acetamido)-A-(2-((4-(hydroxy- methyl)phenyl)amino)-2-oxoethyl)-3-phenylpropanamide (1.97 g, 4.47 mmol) in DMF (20 mL) was added DIEA (1.15 g, 8.94 mmol) and 2,5-dioxopyrrolidin-l-yl 6-(2,5-dioxo-2,5-dihydro- lH-pyrrol-l-yl)hexanoate (2.07 g, 6.71 mmol) at 0 °C. After the addition, the mixture was stirred at r.t. for 2 hrs. LCMS showed the reaction was complete. The mixture was concentrated to give crude product, which was purified by flash silica gel chromatography (0-17% methanol in dichloromethane) to get (S)-6-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)-A-(2-((2-((l-((2-((4- (hydroxymethyl)phenyl)amino)-2-oxoethyl)amino)-l-oxo-3-phenylpropan-2-yl)amino)-2- oxoethyl)amino)-2-oxoethyl)hexanamide (820 mg, 34.3% yield) as white solid. LC-MS: (ESI) m / z: 635.3 [M+H]+.

[0219] To a solution of (S)-6-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)-N-(2-((2-((l-((2- ((4-(hydroxymethyl)phenyl)amino)-2-oxoethyl)amino)-l-oxo-3-phenylpropan-2-yl)amino)-2- oxoethyl)amino)-2-oxoethyl)hexanamide (800 mg, 1.26 mmol) in DMF (4 mL) was added DIEA (650 mg, 5.04 mmol) and bis(4-nitrophenyl) carbonate (1.92 g, 6.30 mmol) at 0 °C. After the addition, the mixture was stirred at r.t. for 2 hrs. LCMS showed the reaction was complete.The mixture was concentrated to give crude product, which was purified by C18 (0-55% acetonitrile in H2O) to give LK-8 (250 mg, 34% yield) as white solid. LC-MS: (ESI) m / z: 617.3 [M+H]+.1H NMR (400 MHz, DMSO-de): 8 (ppm) 9.92 (s, 1H), 8.40 (t, 1H), 8.30 (d, J = 8.4 Hz, 2H), 8.18 (d, J = 7.2 Hz, 1H), 8.15 - 8.10 (m, 1H), 8.08 - 8.02 (m, 2H), 7.67 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 4.4 Hz, 4H), 7.20-7.19 (m, 1H), 6.99 (s, 2H), 6.95 - 6.89 (m, 1H), 5.25 (s, 2H), 4.56-4.46 (m, 1H), 4.00 - 3.52 (m, 4H), 3.38-3.32 (m, 2H), 3.16 - 3.01 (m, 1H), 2.90 - 2.78 (m, 1H), 2.15-2.05 (m, 2H), 1.54-1.40 (m, 4H), 1.20-1.15 (m, 2H).Synthesis ofLK-9.LK-9

[0220] To a solution of 2-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)acetamido)- acetic acid (20.0g, 56.5 mmol) in THF (600 mL) and toluene (200 mL) at r.t. was added Pb(OAc)4 (34.7 g, 78.3 mmol) and pyridine (5.4 mL). After the addition, the mixture was stirred at 75 °C for 12 hrs. LCMS showed the reaction was complete. The mixture was filtered and concentrated to give crude product, which was purified by flash silica gel chromatography (0- 100% ethyl acetate in petroleum ether) to give (2-((((9H-fluoren-9-yl)methoxy)carbonyl) amino) acetamido)methyl acetate (13.6 g, 66% yield) as white solid. LC-MS: (ESI) m / z: 390.9 [M+Na]+.

[0221] To a solution of (2-((((9H-fhioren-9-yl)methoxy)carbonyl)amino)acetamido)- methyl acetate (6.60 g, 17.9 mmol) in THF (150 mL) was added benzyl 2-hydroxyacetate (5.95 g, 35.8 mmol) and PTSA (1.04 g, 6.05 mmol) at 0 °C. After the addition, the mixture was stirred at r.t. for 4 h. TLC showed the reaction was complete. The mixture was partitioned between H2O (150 mL) and ethyl acetate (150 mL x 3). The organic phase was separated, washed with brine (80 mL), dried over anhydrous Na2SC>4, filtered, and concentrated to give crude product, which was purified by silica gel chromatography (0-80% ethyl acetate in petroleum ether) to give benzyl l-(9H-fluoren-9-yl)-3,6-dioxo-2,9-dioxa-4,7-diazaundecan-l 1-oate (4.9g, 58% yield) as white solid.1H NMR (400 MHz, DMSO-de): 5 (ppm) 8.79-8.73 (m, 1H), 7.89 (d, J =8.0 Hz, 2H), 7.71 (d, J= 8.0 Hz, 2H), 7.60-7.50 (m, 1H), 7.33-7.42 (m, 9H), 5.75 (s, 1H), 4.63 (d, J= 8.0 Hz, 2H), 4.15-4.30 (m, 5H), 3.63 (d, J = 8.0 Hz, 2H), 3.18 (d, J = 4.0 Hz, 1H).

[0222] To a solution of benzyl l-(9H-fluoren-9-yl)-3,6-dioxo-2,9-dioxa-4,7-diazaun- decan-11-oate (4.00 g, 8.40 mmol) in DMF (20 mL) at 0 °C, piperidine (4 mL) was added. The reaction mixture was stirred at r.t. for 2 h. The reaction mixture was concentrated in vacuo to give the crude benzyl 2-((2-aminoacetamido)methoxy)acetate (5.0 g crude) as white solid , that was used without further purification in the next step.

[0223] To a solution of 2-(2-((((9H-fhioren-9-yl)methoxy)carbonyl)amino)- acetamido) acetic acid (50.0 g, 141 mmol) in THF (800 mL) was added 4-nitrophenol (49.1 g, 353 mmol) and DCC (72.7 g, 353 mmol) at r.t. After the addition, the mixture was stirred at r.t. for 12 hrs. LCMS showed the reaction was complete. The mixture was filtered to get 4- nitrophenyl 2-(2-((((9H-fhioren-9-yl)methoxy)carbonyl)amino)acetamido)acetate (42.0 g, 63% yield) as white solid, that was used without further purification in the next step. LC-MS: (ESI) m / z: 476.2 [M+H]+.

[0224] To a solution of 4-nitrophenyl 2-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)- amino) acetamido) acetate (22.0 g, 46.3 mmol) in THF (300 mL) was added a solution of Na2CC>3 (7.94 g, 92.6 mmol) in H2O (99 ml) at r.t., followed by the addition of (S)-2-amino-3- phenylpropanoic acid (6.11 g, 37.1 mmol). This resulting mixture was stirred at r.t. for 12 hrs. LCMS showed the reaction was complete. The mixture was partitioned between H2O (100 mL) and ethyl acetate (200 mL). The organic phase was separated, dried over anhydrous Na2SC>4, filtered, and concentrated to give crude product, which was purified by flash silica gel chromatography (0-15% methanol in dichloromethane) to get (S)- l 1 -benzyl- l -(9H-fhioren-9- yl)-3,6,9-trioxo-2-oxa-4,7,10-triazadodecan- 12-oic acid (11 g, 59% yield) as white solid. LCMS: (ESI) m / z: 501.9 [M+H]+.

[0225] To a solution of (S)- 11 -benzyl- l-(9H-fluoren-9-yl)-3, 6, 9-trioxo-2-oxa-4, 7,10- triazadodecan- 12-oic acid (5.00 g, 9.98 mmol) and HATU (7.58 g, 19.9 mmol) in DMF (20 mL) at 0 °C was added benzyl 2-((2-aminoacetamido)methoxy)acetate (5.01 g, 19.9 mmol) and N,N- diisopropylethylamine (5.06 g, 39.9 mmol). After the addition, the mixture was stirred at r.t. for 1 hr. LCMS showed the reaction was complete. The mixture was concentrated to give crude product, which was purified by flash silica gel chromatography (0-10% MeOH in DCM) to give(S)-benzyl 1 l-benzyl-l-(9H-fluoren-9-yl)-3,6,9, 12, 15-pentaoxo-2, 18-dioxa-4,7, 10, 13,16-pen- taazaicosan-20-oate (1.00 g, 14% yield) as yellow solid. LC-MS: (ESI) m / z: 569.9 [M+H]+.

[0226] To a solution of (S)-benzyl l l-benzyl-l-(9H-fluoren-9-yl)-3,6,9,12,15- pentaoxo-2,18-dioxa-4,7,10,13,16-pentaazaicosan-20-oate (1.00 g, 1.36 mmol) in MeOH (20 mL) at r.t., Pd / C (10% with water, 100 mg) was added. The reaction mixture was stirred at r.t. for 12 hrs. The reaction mixture was filtrated and concentrated in vacuo to give the crude (S)- 11 -benzyl- 1 -(9H-fluoren-9-yl)-3 ,6,9, 12, 15-pentaoxo-2, 18-dioxa-4,7, 10, 13,16-pentaazaicosan- 20-oic acid (900 mg crude) as yellow solid, that was used without further purification in the next step. LC-MS: (ESI) m / z: 569.8 [M+H]+.

[0227] To a solution of (S)-benzyl (S)-l l-benzyl-l-(9H-fluoren-9-yl)-3,6,9,12,15- pentaoxo-2,18-dioxa-4,7,10,13,16-pentaazaicosan-20-oic acid (900 mg, 1.39 mmol) in DMF (10 mL) at r.t., TEA (2 mL) was added. The reaction mixture was stirred at r.t. for 12 hrs. The reaction mixture was filtrated and concentrated in vacuo to give the crude (S)-16-amino-10- benzyl-6,9,12,15-tetraoxo-3-oxa-5,8,l l,14-tetraazahexadecan-l-oic acid (1.50 g crude) as yellow solid, that was used without further purification in the next step. LC-MS: (ESI) m / z: 424.2 [M+H]+.

[0228] To a solution of (S)-16-amino-10-benzyl-6,9,12,15-tetraoxo-3-oxa-5,8,l 1,14- tetraazahexadecan-l-oic acid (1.0 g, 2.36 mmol) in DMF (5 mL) was added 2,5- dioxopyrrolidin- 1 -yl 6-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)hexanoate (1.08 g, 3.54 mmol) and A, N-di isopropylethyl a ine (1.20 g, 9.45 mmol) at 0 °C. After the addition, the mixture was stirred at r.t. for 2 hrs. LCMS showed the reaction was complete. The mixture was concentrated to give the crude product, which was purified by C18 (0-70% acetonitrile in H2O) to give LK- 9 (201 mg, 14% yield) as white solid. LC-MS: (ESI) m / z: 617.0 [M+H]+.1H NMR (400 MHz, DMSO-r / e): 8 (ppm) 8.60-8.50 (m, 1H), 8.32-8.27 (m, 1H), 8.15-7.97 (m, 3H), 7.31-7.11 (m, 5H), 7.00 (s, 2H), 4.61 (d, J = 6.4 Hz, 1H), 4.54-4.45 (m, 1H), 3.98 (s, 2H), 3.81-3.53 (m, 6H), 3.10-3.00 (m, 1H), 2.84-2.74 (m, 2H), 2.11 (t, J = 7.4 Hz, 2H), 1.55-1.40 (m, 5H), 1.25-1.00 (m, 3H).Synthesis ofLK-10.

[0229] Mc-Gly-Gly-Phe-Gly (CAS# 2413428-36-9, also referred to as Mc-GGFG) was purchased from a commercial supplier and used without further purification.Synthesis ofLK-11.LK-11

[0230] To a solution of (S)-benzyl l l-benzyl-l-(9H-fluoren-9-yl)-3,6,9,12-tetraoxo-2- oxa-4,7,10,13-tetraazapentadecan-15-oate (3.00 g, 4.63 mmol) in DMF (20.0 mL) was added diethylamine (508 mg, 6.95 mmol) and the reaction mixture was stirred at r.t. for 2 hrs. Then the reaction mixture was filtered, and the filtrate concentrated to give the crude (S)-benzyl 2- (2-(2-(2-aminoacetamido)acetamido)-3-phenylpropanamido)acetate as yellow oil (2.50 g, crude), which was used in the next step without further purification. LC-MS: (ESI) m / z: 426.9 [M+H]+.

[0231] To a solution of (S)-benzyl 2-(2-(2-(2-aminoacetamido)acetamido)-3- phenylpropanamido) acetate (2.50 g, crude), HATU (4.46 g, 11.7 mmol) in DMF (30.0 mL) at 0 °C was added (S)-2-(((benzyloxy)carbonyl)amino)-5-(tert-butoxy)-5-oxopentanoic acid (2.96 g, 8.78 mmol) and A,A-diisopropylethylamine (3.03 g, 23.5 mmol). After the addition, the mixture was stirred at r.t. for 2 hrs. The mixture was concentrated and purified by flash silica gel chromatography (0-10 % methanol in dichloromethane) to give (5S,14S)-1 -benzyl 17-tert- butyl 5 -benzyl- 14-(((benzyloxy)carbonyl)amino)-4,7, 10,13 -tetraoxo-3 , 6,9, 12-tetraazahepta- decane-l,17-dioate as a yellow solid (1.20 g, 27%). LC-MS: (ESI) m / z: 745.7 [M+H]+.

[0232] To a solution of (7S,16S)-7-benzyl-16-(((benzyloxy)carbonyl)amino)- 3,6,9,12,15-pentaoxo-l-phenyl-2-oxa-5,8,l l,14-tetraazanonadecan-19-oic acid (1.20 g, crude) and HATU (1.32 g, 3.47 mmol) in DMF (20 mL) at 0 °C were added MPEG12-NH2(778 mg, 1.39 mmol) and A, A-di isopropyl ethyl amine (898 mg, 6.96 mmol). After the addition, themixture was stirred at r.t. for 2 hrs and LCMS showed the reaction was complete. The mixture was concentrated to give a crude product, which was purified by reversed phase flash column chromatography (0-65% acetonitrile in H2O) to give (42S,51S)-benzyl 51-benzyl-42- (((benzyloxy)carbonyl)amino)-39,43,46,49,52-pentaoxo-2,5,8,l l,14,17,20,23,26,29,32,35- dodecaoxa-38,44,47,50,53-pentaazapentapentacontan-55-oate as a white solid (645 mg, 30%). LC-MS: (ESI) m / z: 616.3 [M+H]+.

[0233] To a solution of benzyl ((S)-42-(((benzyloxy)carbonyl)amino)-39-oxo- 2,5,8, 1 l,14,17,20,23,26,29,32,35-dodecaoxa-38-azatritetracontan-43-oyl)glycylglycyl-L-phe- nylalanylglycinate (645 mg, 0.52 mmol) in methanol (10.0 mL) was added Pd / C (500 mg, 10% wt.) under N2. After replacing N2 with H2, the reaction mixture was stirred at r.t. for 12 hrs. The reaction was filtered and the filtrate was concentrated to give the crude (42S,51S)-42-amino- 51-benzyl-39,43,46,49,52-pentaoxo-2,5,8,l l,14,17,20,23,26,29,32,35-dodecaoxa-38,44,47, 50,53-pentaazapentapentacontan-55-oic acid as yellow oil (320 mg, crude), which was used in the next step without further purification. LC-MS: (ESI) m / z: 1006.9 [M+H]+.

[0234] To a solution of (42S,51S)-42-amino-51-benzyl-39,43,46,49,52-pentaoxo- 2,5,8, 1 l,14,17,20,23,26,29,32,35-dodecaoxa-38,44,47,50,53-pentaazapentapentacontan-55- oic acid (320 mg, 0.31 mmol) and 2,5-dioxopyrrolidin-l-yl 6-(2,5-dioxo-2,5-dihydro-lH- pyrrol-l-yl)hexanoate (147 mg, 0.48 mmol) in DMF (4.00 mL) at 0 °C was added N,N- diisopropylethylamine (164 mg, 1.27 mmol). After the addition, the mixture was stirred at r.t. for 2 hrs. LCMS showed the reaction was complete. The mixture was concentrated to give the crude product, which was purified by Prep-HPLC (0-70% acetonitrile in H2O) to give LK-11 as a yellow oil (100 mg, 26%). LC-MS: (ESI) m / z: 1201.6 [M+H]+.1H NMR (400 MHz, DMSO-de): 8 8.36-8.38 (m, 1H), 8.10-8.13 (m, 2H), 8.01-8.03 (m, 2H), 7.85-7.87 (m, 1H), 7.19-7.33 (m, 5H), 7.01 (s, 2H), 4.52-4.58 (m, 1H), 4.19-4.23 (m, 1H), 3.59-3.79 (m, 44H), 3.36-3.46 (m, 9H) , 3.25 (s, 3H) , 3.01-3.08 (m, 1H) , 2.75-2.81 (m, 1H) , 2.10-2.12 (m, 5H) , 1.86-1.89 (m, 2H) , 1.70-1.75 (m, 1H) , 1.47-1.51 (m, 5H) , 1.19-1.22 (m, 2H).Synthesis ofLK-12.

[0235] To a solution of (S)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3- methylbutanamido)-5-ureidopentanoic acid (2.10 g, 4.23 mmol) in DMF (20.00 mL) at 0 °C was added diethylamine 6.12 g, 8.46 mmol). After the addition, the mixture was stirred at 25 °C for 2 hrs. LC-MS showed the reaction was complete. The mixture was concentrated to give (S)- 2-((S)-2-amino-3-methylbutanamido)-5-ureidopentanoic acid (2.00 g, quantitative) as white solid. LC-MS (ESI) m / z: 274.9 [M+H]+.

[0236] To a solution of (S)-2-((S)-2-amino-3-methylbutanamido)-5-ureidopentanoic acid (2.00 g, 4.23 mmol, crude) in DMF (20 mL) was added 2,5-dioxopyrrolidin-l-yl l-(2,5- dioxo-2,5-dihydro-lH-pyrrol-l-yl)-3,6,9,12,15,18-hexaoxahenicosan-21-oate (1.12 g, 2.12 mmol) and DIPEA (657 mg, 5.09 mmol) at 0 °C. After the addition, the mixture was stirred at 25 °C for 2 hrs. LC-MS showed the reaction was complete. The mixture was concentrated to give product, which was purified by Cis (0-35% ACN in H2O, 0.1% TFA) to give LK-12 (242 mg, 35% yield) as white solid. LC-MS (ESI) m / z: 689.7 [M+H]+.1H NMR (400 MHz, CH3OD) d (ppm) 6.86 (s, 2H), 4.37 - 4.06 (m, 3H), 3.79 - 3.70 (m, 2H), 3.75 - 3.58 (m, 20H), 3.50 - 3.40 (m, 1H), 3.23 - 3.04 (m, 3H), 2.66 - 2.53 (m, 2H), 2.23 - 2.08 (m, 1H), 1.95 - 1.81 (m, 1H), 1.72 - 1.65 (m, 1H), 1.62 - 1.46 (m, 2H), 0.99 - 0.90 (m, 6H).Synthesis ofLK-13.

[0237] To a solution of benzyl (S)-l l-benzyl-l-(9H-fluoren-9-yl)-3,6,9,12,15- pentaoxo-2,18-dioxa-4,7,10,13,16-pentaazaicosan-20-oate (10.0 g, 13.6 mmol) in DMF (20.0mL) at 0 °C was added diethylamine (1.98 g, 27.2 mmol). After the addition, the mixture was stirred at 25 °C for 2 hrs. LC-MS showed the reaction was complete. The mixture was concentrated to give benzyl (S)-16-amino-10-benzyl-6,9,12,15-tetraoxo-3-oxa-5,8,l l,14- tetraazahexadecanoate (8.00 g, crude) as yellow oil, which was used without further purification for the next step. LC-MS (ESI) m / z: 515.3 [M+H]+.

[0238] To a solution of benzyl (S)-16-amino-10-benzyl-6,9,12,15-tetraoxo-3-oxa- 5,8,11,14-tetraazahexadecanoate (8.00 g, crude) in DMF (10 mL) was added (S)-2- (((benzyloxy)carbonyl)amino)-5-(tert-butoxy)-5-oxopentanoic acid (7.70 g, 22.8 mmol) at 0 °C, followed by HATU (21.0 g, 57.4 mmol) and DIPEA (9.80 g, 75.9 mmol). After the addition, the mixture was stirred at 25 °C under N2for 2 hrs. LC-MS showed the reaction was complete. The mixture was concentrated, and the residue purified by Cis (0-45% ACN in H2O, 0.1 %TFA) to givel-benzyl 22-(tert-butyl) (10S,19S)-10-benzyl-19-(((benzyloxy)carbonyl)amino)- 6,9,12,15,18-pentaoxo-3-oxa-5,8,l 1,14,17-pentaazadocosanedioate (4.0 g, 35% yield two steps) as white solid. LC-MS (ESI) m / z: 832.6 [M+H]+.

[0239] To a solution of 22-(tert-butyl) (10S,19S)-10-benzyl-19- (((benzyloxy)carbonyl)amino)-6,9, 12, 15, 18-pentaoxo-3-oxa-5,8, 11 , 14, 17- pentaazadocosanedioate ( 1.0 g, 1.20 mmol) in dichloromethane (10 mL) was added TFA (2 mL) at 0°C. After the addition, the mixture was stirred at 25 °C for 2 hrs. LC-MS showed the reaction was complete. The mixture was concentrated to give (12S,21S)-12-benzyl-21- (((benzyloxy)carbonyl)amino)-3,8, 11,14, 17,20-hexaoxo- l-phenyl-2,5-dioxa-7, 10, 13,16,19- pentaazatetracosan-24-oic acid (800 mg, crude) as yellow oil. LC-MS (ESI) m / z: 798.5 [M+Na]+.

[0240] To a solution of (12S,21S)-12-benzyl-21-(((benzyloxy)carbonyl)amino)- 3,8, 11, 14, 17,20-hexaoxo- l-phenyl-2,5-dioxa-7, 10, 13, 16, 19-pentaazatetracosan-24-oic acid (800 mg, crude) in DMF (2 mL) was added MPEG12-NH2(672 mg, 1.20 mmol), HATU (912 mg, 2.40 mmol), HOBt (162 mg, 1.20 mmol) and DIPEA (610 mg, 4.80 mmol). The mixture was stirred at 25 °C for 2 hrs. LC-MS showed the reaction was complete. The mixture was concentrated and the residue was purified by Cis (0-35% ACN in H2O, 0.1% TFA ) to give (42S,51S)-51-benzyl-42-(((benzyloxy)carbonyl)amino)-39,43,46,49,52,55-hexaoxo-2,5,8, 1 l,14,17,20,23,26,29,32,35,58-tridecaoxa-38,44,47,50,53,56-hexaazahexacontan-60- oate (220 mg, 14% yield two steps) as white solid. LC-MS (ESI) m / z: 1339.4 [M+Na]+.

[0241] To a solution of benzyl (42S,5 lS)-51-benzyl-42-(((benzyloxy)carbonyl)amino)-39.43.46.49.52.55-hexaoxo-2,5,8,l l,14,17,20,23,26,29,32,35,58-tridecaoxa-38.44.47.50.53.56-hexaazahexacontan-60-oate (220 mg, 0.17 mmol) in DMF (2 mL) was added Pd / C (20 mg, 10% wt.%, 55% H2O) at 25 °C. The mixture was stirred at 25 °C under a hydrogen atmosphere for 12 hrs. LC-MS showed the reaction was complete. The mixture was filtered and concentrated to give (42S,51S)-42-amino-51-benzyl-39,43,46,49,52,55-hexaoxo- 2,5,8, 1 l,14,17,20,23,26,29,32,35,58-tridecaoxa-38,44,47,50,53,56-hexaazahexacontan-60-oic acid (200 mg, crude) as yellow oil. LC-MS (ESI) m / z: 1094.0 [M+Na]+.

[0242] To a solution of 1-benzyl (42S,51S)-42-amino-51-benzyl-39,43,46,49,52,55- hexaoxo-2,5,8,l l,14,17,20,23,26,29,32,35,58-tridecaoxa-38,44,47,50,53,56- hexaazahexacontan-60-oic acid (200 mg, crude) in DMF (2 mL) was added 2,5- dioxopyrrolidin- 1 -yl 6-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)hexanoate (102 mg, 0.330 mmol) at 0 °C, followed by DIPEA (42.4 mg, 0.330 mmol). The mixture was stirred at 25°C for 2 hrs. LC-MS showed the reaction was complete. The mixture was concentrated, and the residue was purified by Cis (0-40% ACN in H2O, 0.1% TFA) to give LK-13 (55 mg, 26% yield, two steps) as a white solid. LC-MS (ESI) m / z: 1287.3 [M+H]+.1H NMR (400 MHz, DMSO- d6) 8 (ppm) 8.81 - 8.17 (m, 5H), 7.89 - 7.86 (m, 1H), 7.24 - 7.15 (m, 5H), 7.00 (s, 2H), 4.71 - 4.61 (m, 2H), 4.41 - 4.35 (m, 1H), 4.21 - 4.15 (m, 1H), 3.90 - 3.60 (m, 7H), 3.50 - 3.45 (m, 37H), 3.42 - 3.37 (m, 5H), 3.24 (s, 3H), 3.17 - 3.15 (m, 2H), 3.07-3.00 (m, 1H), 2.90 - 2.80 (m, 2H), 2.65-2.60 (m, 1H), 2.15 - 2.09 (m, 4H), 2.00 - 1.90 (m, 1H), 1.93 - 1.83 (m, 1H), 1.80 - 1.69 (m, 1H), 1.65 - 1.56 (m, 1H), 1.49 - 1.40 (m, 5H), 1.30 - 1.12 (m, 3H).Synthesis of LK-14.

[0243] To a solution of 1-benzyl (42S,51S)-42-amino-51-benzyl-39,43,46,49,52,55- hexaoxo-2,5,8,11,14,17 ,20,23,26,29,32,35,58-tridecaoxa-38,44,47 ,50,53,56- hexaazahexacontan-60-oic acid (180 mg, 0.160 mmol) in DMF (2 mL) was added 2,5- dioxopyrrolidin-l-yl l-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)-3,6,9,12,15,18- hexaoxahenicosan-21-oate (87 mg, 0.160 mmol) at 0 °C, followed by DIPEA (41.0 mg, 0.32 mmol). The mixture was stirred at 25 °C for 2 hrs. LC-MS showed the reaction was complete. The mixture was concentrated to give the crude product, which was purified by Prep-HPLC (Cis; 20 to 70% ACN in H2O, 0.1% TFA) to provide LK-14 (50 mg, 20% yield) as yellow solid. LC-MS (ESI) m / z: 1531.3 [M+Na]+.1H NMR (400 MHz, DMSO-de) 8 (ppm) 8.55 - 8.52 (m, 1H), 8.36 - 8.29 (m, 1H), 8.17 - 8.07 (m, 3H), 8.02 - 7.99 (m, 1H), 7.84 - 7.81 (m, 1H), 7.22 - 7.15 (m, 5H), 7.02 (s, 2H), 4.61 (d, J = 6.5 Hz, 2H), 4.51 - 4.45 (m, 1H), 4.22 - 4.12 (m, 1H), 3.98 (s, 2H), 3.80 - 3.64 (m, 7H), 3.63 - 3.42 (m, 69H), 3.24 (s, 3H), 3.18 - 3.10 (m, 2H), 3.05 - 2.90 (m, 1H), 2.80 - 2.70 (m, 2H), 2.43 - 2.30 (m, 3H), 2.10 - 2.08 (m, 2H), 2.03 - 1.94 (m, 1H), 1.87 - 1.80 (m, 1H), 1.73 - 1.65 (m, 1H).Synthesis ofLK-15.

[0244] To a solution of Fmoc-Gly-Gly-Gly-Gly (1.0 g, 2.13 mmol, 1.0 eq.), HOBt (862 mg, 6.39 mmol, 3.0 eq.) and EDCI (1.22 g, 6.39 mmol, 3.0 eq.) in 10 mL anhydrous DMF was added Val-Cit-PAB-OH (887 mg, 2.34 mmol, 1.1 eq.). After addition, the solution was stirred for 1 hr until the reaction was completed by LC-MS. The reaction mixture was purified by Cis chromatography (ACN / H2O from 10%~100%) and lyophilized to provide Fmoc-Gly-Gly-Gly- Gly- Val-Cit-PAB-OH (1.4 g, 80% yield) as a white powder. LC-MS (ESI) m / z: 830 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ (ppm) 9.91 (s, 1H), 8.20 (d, J = 8.9 Hz, 2H), 8.15 (s, 2H), 7.92 (d, J = 7.5 Hz, 2H), 7.86 (d, J = 8.7 Hz, 1H), 7.75 (d, J = 1.5 Hz, 2H), 7.60 (s, 1H), 7.57 (d, J = 8.4 Hz, 2H), 7.45 (t, J = 7.5 Hz, 2H), 7.36 (t, J = 1A Hz, 2H), 7.26 (d, J = 8.3 Hz, 2H), 6.01 (s, 1H), 5.45 (s, 2H), 5.13 (s, 1H), 4.45 (d, J = 5.6 Hz, 2H), 4.40 (d, J = 6.4 Hz, 1H), 4.32(d, J = 6.9 Hz, 2H), 4.26 (d, J = 6.5 Hz, 2H), 3.79 (dt, J = 13.1, 6.6 Hz, 7H), 3.70 (d, J = 6.0 Hz, 2H), 2.01 (d, J = 6.4 Hz, 1H), 1.68 (d, J = 35.7 Hz, 2H), 0.89 (d, J = 6.7 Hz, 3H), 0.85 (d, J = 6.8 Hz, 3H).

[0245] Fmoc-Gly-Gly-Gly-Gly-Val-Cit-PAB-OH (200 mg, 0.24 mmol, 1.0 eq.) was dissolved into 5 mL Et2N / DMSO (1:1) and stirred for Ihr. After the reaction was completed, the solution was concentrated and purified by Cis column chromatography (ACN / H2O from 10%~100%) and lyophilized to provide Gly-Gly-Gly-Gly-Val-Cit-PAB-OH (139 mg, 95% yield) as a white powder. LC-MS (ESI) m / z: 608 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ (ppm) 10.06 (s, 1H), 8.61 (s, 1H), 8.41 (t, J = 6.0 Hz, 1H), 8.30 - 8.18 (m, 2H), 7.88 (d, J = 8.5 Hz, 1H), 7.60 (d, J = 8.2 Hz, 2H), 7.25 (d, J = 8.2 Hz, 2H), 6.23 (s, 1H), 5.52 (s, 2H), 4.45 (s, 2H), 4.40 (d, J = 6.8 Hz, 1H), 4.24 (t, J = 1.1 Hz, 1H), 3.86 - 3.72 (m, 6H), 3.19 (s, 1H), 2.99 (d, J = 7.0 Hz, 3H), 2.57 (s, 10H), 2.04 (dd, J = 13.3, 6.4 Hz, 1H), 1.74 (s, 1H), 1.64 (d, J = 10.2 Hz, 1H), 1.48 (s, 1H), 1.40 (s, 1H), 1.22 (dd, J = 16.9, 9.7 Hz, 2H), 0.87 (dd, J = 14.7, 6.7 Hz, 6H).

[0246] To a solution of Gly-Gly-Gly-Gly-Val-Cit-P AB-OH (180 mg, 0.296 mmol, 1.0 eq.) in 15ml DMSO was added A-succinimidyl maleimidoacetate (224 mg, 0.889 mmol, 3.0 eq.) and solution stirred at r.t. for 1 hr. After the reaction was completed, the solution was concentrated and purified by Cis column chromatography (ACN / 0.1% TFA aqueous solution from 10%~100%) and lyophilized to obtain LK-15 (160 mg, 73% yield) as a white powder. LC-MS (ESI) m / z: 745 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ (ppm) 9.92 (s, 1H), 8.48 (s, 1H), 8.22 (s, 3H), 7.84 (d, J = 8.7 Hz, 1H), 7.55 (d, J = 7.9 Hz, 2H), 7.23 (d, J = 8.2 Hz, 2H), 7.09 (s, 1H), 7.02 (s, 2H), 5.44 (s, 1H), 5.11 (t, J = 5.7 Hz, 1H), 4.42 (d, J = 5.5 Hz, 2H), 4.15 - 4.10 (m, 3H), 3.82 - 3.69 (m, 9H), 3.16 (d, J = 5.1 Hz, 5H), 0.86 (d, J = 6.7 Hz, 3H), 0.82 (d, J = 6.9 Hz, 3H).Synthesis of LK-16.LK-16

[0247] To a solution of 2,5-dioxopyrrolidin-l-yl l-(2,5-dioxo-2,5-dihydro-lH-pyrrol- l-yl)-3,6,9,12,15,18-hexaoxahenicosan-21-oate (626 mg, 1.18 mmol) in DMF (4.00 mL) was added (S)-16-amino-10-benzyl-6,9,12,15-tetraoxo-3-oxa-5,8,l 1,14-tetraazahexadecanoic acid (500 mg, crude) and N,N-di isopropylethyl a ine (609 mg, 4.72 mmol) at 0 °C. After the addition, the mixture was stirred at r.t. for 2 hrs. LCMS showed the reaction was complete. The mixture was concentrated, and the residue was purified by Prep-HPLC (0-60% acetonitrile in water) to give LK-16 (90 mg, 9% yield) as a yellow oil. LC-MS (ESI) m / z: 861.4 [M+Na]+.1H NMR (400 MHz, DMSO-d6): δ (ppm) 8.51-8.57 (m, 1H), 8.26-8.29 (m, 1H), 8.12-8.15 (m, 1H), 8.08-8.10 (m, 1H), 7.96-7.99 (m, 1H), 7.15-7.27 (m, 6H), 7.01 (s, 2H), 4.61 (d, J = 6.8 Hz, 2H), 4.47-4.52 (m, 1H), 3.98 (s, 2H), 3.49-3.73 (m, 32H), 3.03-3.08 (m, 1H), 2.77-2.83 (m, 1H), 2.37-2.41 (m, 2H).Linker-payload building blocks (LP)Synthesis of LP-1.

[0248] To a solution of PL-1 (16 mg, 0.0210 mmol, 1.0 eq.), Mc-Val-Cit-PABC-PNP (46.5 mg, 0.0631 mmol, 3.0 eq.) in 0.25 mL pyridine and 1 mL anhydrous DMF were added HOAt (2.86 mg, 0.0210 mmol, 1.0 eq.) and DIPEA (43.4 mg, 0.3364 mmol, 16.0 eq.) under argon. The mixture was stirred overnight at 40 °C. After the reaction was completed, the mixture was purified by Prep-HPLC to afford LP-1 as a white solid (1.5 mg, 5.2% yield). LC- MS (ESI) m / z: 1340 [M-0H]+.1H NMR (400 MHz, DMSO-r / 6) 8 (ppm) 9.99 (s, 1H), 8.55 (s, 1H), 8.07 (d, J = 7.5 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.57 (d, J = 8.2 Hz, 2H), 7.44 (d, J = 8.3 Hz, 1H), 7.29 (d, J = 8.5 Hz, 2H), 6.98 (d, J = 5.6 Hz, 2H), 6.63 (s, 1H), 6.31 (s, 1H), 6.13 (d, J = 10.7 Hz, 1H), 6.02 (d, J= 29.5 Hz, 1H), 5.41 (s, 1H), 5.06 (s, 1H), 5.00 (s, 1H), 4.90 (s, 1H), 4.65 (s, 1H), 4.50 (d, 7= 13.6 Hz, 1H), 4.35 (s, 1H), 4.23 - 4.04 (m, 2H), 3.84 (d, J = 46.7Hz, 2H), 3.64 (d, J = 4.3 Hz, 4H), 3.48 (s, 6H), 2.92 (s, 9H), 2.30 - 2.23 (m, 5H), 2.22 - 2.05 (m, 4H), 1.95 (d, J = 5.5 Hz, 5H), 1.66 (s, 1H), 1.51 - 1.39 (m, 6H), 1.22 (s, 3H), 1.15 (q, J = 7.1 Hz, 3H), 1.04 (t, J= 7.0 Hz, 2H), 0.82 (dt, J= 12.4, 6.0 Hz, 8H).Synthesis of LP-2.

[0249] To a solution of PL-5 (80 mg, 0.10 mmol, 1.0 eq.) and Mc-Val-Cit-PABC-PNP(227 mg, 0.308 mmol, 3.0 eq.) in 0.25 mL pyridine and 1 mL anhydrous DMF were added HOAt (14 mg, 0.103 mmol, 1.0 eq.) and DIPEA (212 mg, 1.64 mmol, 16.0 eq.). After the addition, the mixture was stirred at 40 °C overnight. The reaction mixture was purified by Prep- HPLC to provide LP-2 (55 mg, 38.8% yield) as a white solid. LC-MS (ESI) m / z: 689 [M / 2+H]+.1H NMR (400 MHz, DMSO-d6): δ (ppm) 10.76 (s, 1H), 10.00 (s, 1H), 9.54 (s, 1H), 9.19 (s, 1H), 8.08 (d, J= 7.4 Hz, 1H), 7.81 (d, J = 8.6 Hz, 1H), 7.61 (d, J= 8.7 Hz, 3H), 7.34 (d, J= 8.2 Hz, 2H), 7.27 (d, J = 9.0 Hz, 1H), 7.12 (d, J = 8.5 Hz, 1H), 6.99 (s, 2H), 6.59 (s, 1H), 6.26 (d, J = 25.7 Hz, 2H), 6.03 (s, 1H), 5.28 (d, J = 11.4 Hz, 1H), 5.05 (s, 2H), 4.58 (s, 2H), 4.33 (dd, J = 26.5, 6.7 Hz, 4H), 4.18 (d, J = 8.9 Hz, 3H), 3.69 (s, 7H), 3.36 (t, J = 7.1 Hz, 5H), 3.32 (d, J = 4.3 Hz, 2H), 3.17 (s, 4H), 2.88 (tdd, J = 40.9, 23.0, 9.1 Hz, 12H), 2.32 (d, J = 15.2 Hz, 7H), 2.22 - 2.09 (m, 7H), 2.07 (s, 8H), 1.99 (s, 5H), 1.75 - 1.55 (m, 4H), 1.47 (p, J = 7.4 Hz, 6H), 1.19 (dd, J = 19.5, 11.6 Hz, 5H), 0.83 (dd, J = 12.4, 6.7 Hz, 7H).Synthesis of LP-3.LP-3

[0250] To a solution of PL-1 (20 mg, 0.064 mmol, 1.0 eq.) and LK-1 (76 mg, 0.0792 mmol, 3.0 eq.) in 1 mL anhydrous DMF and 1 mL pyridine were added HOAt (3.57 mg, 0.52 mmol, 1.0 eq.) and DIPEA (13.57 mg, 0.42 mmol, 16 eq.). After the addition, the mixture was stirred at r.t. overnight. The reaction mixture was purified by Prep-HPLC to provide LP-3 as a white solid (7.2 mg, 17.3% yield). LC-MS (ESI) m / z: 782 [(M-H2O) / 2+H]+.1H NMR (400 MHz, DMSO-cfe) 8 (ppm) 10.00 (s, 1H), 9.54 (s, 1H), 8.55 (s, 1H), 8.12 (s, 1H), 7.88 (d, J= 8.4 Hz, 1H), 7.59 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 9.0 Hz, 3H), 7.01 (s, 2H), 6.64 (s, 1H), 6.34 (s, 1H), 6.14 (d, J = 11.2 Hz, 2H), 6.03 (s, 1H), 5.05 (d, J = 17.7 Hz, 3H), 4.91 (s, 1H), 4.67 (s, 1H), 4.21 (s, 2H), 4.08 (s, 1H), 3.80 (s, 2H), 3.66 (s, 7H), 3.55 (s, 8H), 3.48 (s, 20H), 3.14 - 2.92 (m, 7H), 2.28 (d, J = 9.6 Hz, 6H), 2.21 (s, 1H), 1.97 (s, 4H), 1.23 (s, 2H), 0.84 (dd, J = 12.5, 6.7 Hz, 8H).Synthesis of LP-4.LP-4

[0251] To a solution of PL-1 (20 mg, 0.026 mmol, 1.0 eq.) and LK-7 (18 mg, 0.0197 mmol, 0.75 eq.) in 1 mL pyridine and 4 mL anhydrous DMF were added HOAt (3.5 mg, 0.026 mmol, 1.0 eq.) and DIPEA (13.57 mg, 0.42 mmol, 16 eq.). After the addition, the mixture was stirred at 40 °C overnight. The reaction mixture was purified by Prep-HPLC to obtain LP-4 as a white solid (2.2 mg, 7.2% yield). LC-MS (ESI) m / z: 760 [(M-H2O) / 2+H]+.1H NMR (400MHz, DMSO-de) d (ppm) 9.99 (s, 1H), 9.60 (s, 1H), 8.63 (s, 1H), 8.11 (d, J= 7.3 Hz, 1H), 7.88 (d, J= 8.6 Hz, 1H), 7.59 (d, J= 8.2 Hz, 2H), 7.38 (s, 1H), 7.31 (d, J= 8.2 Hz, 2H), 7.00 (s, 2H), 6.66 (s, 1H), 6.29 (s, 1H), 6.16 (d, J = 15.5 Hz, 2H), 6.01 (s, 1H), 5.08 (d, J = 11.8 Hz, 1H), 5.03 (s, 2H), 4.93 (s, 1H), 4.68 (s, 2H), 4.36 (s, 1H), 4.24 - 4.11 (m, 2H), 3.92 (s, 1H), 3.80 (s, 1H), 3.66 (s, 5H), 3.17 (s, 2H), 3.12 (s, 3H), 2.97 (d, J = 22.7 Hz, 2H), 2.67 (s, 1H), 2.47 (s, 3H), 2.28 (d, J= 8.6 Hz, 6H), 1.97 (s, 5H), 1.72 - 1.39 (m, 1H), 1.23 (s, 2H), 0.84 (dd, J= 12.6, 6.7 Hz, 8H).Synthesis ofLP-5.

[0252] To a solution of PL-5 (20 mg, 0.026 mmol, 1.0 eq.) and LK-1 (74.88 mg, 0.078 mmol, 3.0 eq.) in 1 mL pyridine and 3 mL anhydrous DMF were added HOAt (3.54 mg, 0.026 mmol, 1.0 eq.) and DIPEA (53.66 mg, 0.416 mmol, 16.0 eq.) under argon. The mixture was stirred overnight at 40 °C. After the reaction was completed, the mixture was purified by Prep- HPLC to afford LP-5 as a white solid (16 mg, 38.9% yield). LC-MS (ESI) m / z: 800 [M / 2+H]+.1H NMR (400 MHz, DMSO-d6): δ (ppm) 10.02 (d, J= 14.3 Hz, 2H), 9.39 (s, 1H), 8.77 (s, 1H), 8.12 (d, J = 7.2 Hz, 1H), 7.88 (d, J = 8.3 Hz, 1H), 7.61 (d, J = 8.1 Hz, 2H), 7.49 (s, 1H), 7.34 (d, J = 8.1 Hz, 2H), 7.21 (d, J = 8.8 Hz, 1H), 7.02 (s, 2H), 6.48 (s, 1H), 6.22 (d, J = 13.0 Hz, 2H), 5.98 (s, 1H), 5.41 (s, 2H), 5.06 (d, J= 17.0 Hz, 3H), 4.46 (s, 1H), 4.21 (d, J= 8.8 Hz, 2H), 4.07 (d, J= 10.8 Hz, 2H), 3.65 (s, 3H), 3.55 (d, J= 5.2 Hz, 2H), 3.50 (s, 3H), 3.47 (s, 4H), 3.46 (s, 5H), 2.27 (d, J = 12.7 Hz, 6H), 2.05 (s, 3H), 1.98 (s, 3H), 0.84 (dd, J = 13.2, 6.7 Hz, 8H).Synthesis of LP-6.LP-6

[0253] To a solution of LK-10 (13.6 mg, 0.0263 mmol, 1.0 eq.), EDCI (99.68 mg, 0.528 mmol, 20.0 eq.), HOBt (70.26 mg, 0.528 mmol, 20.0 eq.) in 3 mL anhydrous DMF was added PL-5 (20 mg, 0.0263 mmol, 1.0 eq.) under argon. The mixture was stirred at r.t. for 3 hrs. After the reaction was completed, the mixture was purified by Prep-HPLC to afford LP-6 as a white solid (14 mg, 42.2% yield). LC-MS (ESI) m / z: 645 [M / 2+H]+.1H NMR (400 MHz, DMSO-76) d (ppm) 10.11 (s, 1H), 9.59 (s, 1H), 8.38 (s, 1H), 8.19 (d, J = 7.9 Hz, 1H), 8.08 (d, 7 = 6.1 Hz,2H), 7.68 (s, 1H), 7.25 (d, 7 = 4.7 Hz, 6H), 7.20 - 7.11 (m, 2H), 6.98 (s, 2H), 6.48 (s, 1H), 6.22(d, J = 14.0 Hz, 2H), 5.07 (d, J= 11.1 Hz, 1H), 4.46 (s, 2H), 4.20 (s, 1H), 4.08 (d, J= 12.5 Hz,2H), 3.84 (s, 2H), 3.65 (s, 6H), 3.19 (s, 2H), 5.48 - 1.57 (m, 462H), 2.27 (d, 7 = 13.5 Hz, 7H),2.09 (t, J = 7.5 Hz, 3H), 2.05 (s, 5H), 1.98 (s, 4H), 1.46 (q, 7= 7.6 Hz, 5H), 1.23 (s, 8H).Synthesis of LP-7.LP-7

[0254] To a solution of PL-5 (20 mg, 0.026 mmol, 1.0 eq.) and LK-9 (16.2 mg, 0.026 mmol, 1.0 eq.) in 5 mL anhydrous DMF were added HOBt (71.36 mg, 0.52 mmol, 20 eq.) and EDCI (101.2 mg, 0.52 mmol, 20 eq.). After the addition, the mixture was stirred at r.t. overnight. The reaction mixture was purified by Prep-HPLC to provide LP-7 as a white solid (8.8 mg,24.7% yield). LC-MS (ESI) m / z: 1377.8 [M+Hf^H NMR (400 MHz, CHCl3-d) δ (ppm) 9.57 (s, 1H), 8.70 (s, 1H), 8.33 (s, 1H), 8.13 (d, J = 8.2 Hz, 1H), 8.07 (s, 1H), 8.01 (s, 1H), 7.83 (s, 1H), 7.28 (dd, 7 = 17.7, 8.3 Hz, 3H), 7.21 (d, 7 = 13.8 Hz, 6H), 6.98 (s, 2H), 6.57 (s, 1H), 6.29 (s, 1H), 6.22 (s, 1H), 4.66 (d, 7 = 6.3 Hz, 2H), 4.56 (s, 2H), 4.48 (s, 1H), 4.29 (s, 2H), 4.18 (s, 1H), 4.02 (s, 2H), 3.74 (d, 7= 8.3 Hz, 4H), 3.67 (d, 7 = 11.2 Hz, 6H), 3.34 (d, 7 = 7.3 Hz, 7H), 3.31 (s, 3H), 2.83 (d, 7 = 12.3 Hz, 4H), 2.67 (s, 1H), 2.33 (s, 3H), 2.30 (s, 3H), 2.09 (d, 7= 5.1 Hz, 5H), 1.99 (s, 4H), 1.46 (d, 7 = 8.2 Hz, 5H), 1.24 (s, 6H), 1.18 (s, 3H), 0.86 (s, 1H).Synthesis ofLP-8.

[0255] To a solution of PL-5 (20 mg, 0.026 mmol, 1.0 eq.) and LK-2 (91.67 mg, 0.077 mmol, 3.0 eq.) in 0.4 mL pyridine and 1.6 mL anhydrous DMF was added HO At (3.63 mg, 0.0267 mmol, 1.0 eq.) and A,A-di isopropylethyl a ine (55.1 mg, 0.427 mmol, 16.0 eq.). After the addition, the mixture was stirred at r.t. overnight. LC-MS showed the reaction was completed. The reaction mixture was purified by Prep-HPLC to provide LP-8 as a white solid (7.9 mg, 16.8% yield). LC-MS (ESI) m / z: 915 [M / 2+H]+.1H NMR (400 MHz, DMSO-d6): δ (ppm) 10.04 (d, J = 8.1 Hz, 2H), 9.40 (s, 1H), 8.80 (s, 1H), 8.39 (s, 1H), 8.14 (d, J = 8.1 Hz, 2H), 7.93 (d, J = 5.7 Hz, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.60 (d, J = 8.3 Hz, 2H), 7.48 (s, 1H), 7.33 (d, J = 8.3 Hz, 2H), 7.21 (d, J = 8.7 Hz, 1H), 7.02 (s, 1H), 6.98 (s, 2H), 6.48 (s, 1H), 6.22 (d, J = 12.0 Hz, 2H), 6.02 (s, 1H), 5.43 (s, 2H), 5.06 (d, J= 16.8 Hz, 3H), 4.42 (d, J = 33.4 Hz, 3H), 4.22 - 4.03 (m, 5H), 3.65 (s, 3H), 3.60 (t, 7= 7.4 Hz, 3H), 3.49 (d, J = 1.5 Hz, 32H), 3.21 (d, J = 15.0 Hz, 6H), 3.05 - 2.73 (m, 1H), 2.70 - 2.56 (m, 1H), 2.40 (t, J = 7.2 Hz, 2H), 2.27 (d, J = 12.2 Hz, 5H), 2.15 (t, J = 7.9 Hz, 1H), 2.05 (s, 3H), 1.97 (s, 3H), 1.83 (d, J = 8.7 Hz, 1H), 1.69 (d, J = 9.0 Hz, 2H), 0.83 (dd, J = 13.9, 6.7 Hz, 8H).Synthesis of LP-9.LP-9

[0256] To a solution of PL-6 (20 mg, 0.026 mmol, 1.0 eq.) and Mc-Val-Cit-PAB-PNP (38.3 mg, 0.052 mmol, 2.0 eq.) in 1 mL DMSO was added DIPEA (13.4 g, 0.104 mmol, 4.0 eq.). After the addition, the mixture was stirred at 40 °C overnight. LC-MS showed the reaction was completed. The reaction was purified by Prep-HPLC to provide LP-9 (4.5 mg, 12.8% yield) as a white solid. LC-MS (ESI) m / z: 700 [M / 2+H]+.1H NMR (400 MHz, DMSO-d6): δ (ppm) 10.10 (d, 7 = 6.3 Hz, 1H), 8.41 (s, 1H), 8.14 (d, J = 7.1 Hz, 1H), 7.85 (dd, 7= 8.6, 4.3 Hz, 1H), 7.63 (d, J = 8.1 Hz, 2H), 7.34 (d, J = 8.2 Hz, 2H), 7.00 (d, J = 1.8 Hz, 2H), 6.85 (s, 1H), 6.48 (d, J= 23.6 Hz, 2H), 6.19 (d, J= 14.5 Hz, 2H), 6.07 (s, 1H), 5.45 (s, 2H), 5.15 (s, 2H), 5.06 (d, J = 12.2 Hz, 1H), 4.51 (s, 2H), 4.38 (s, 1H), 4.24 - 4.16 (m, 2H), 4.09 (d, J = 24.5 Hz, 2H), 3.70 (d, J = 6.4 Hz, 1H), 3.64 (s, 3H), 3.61 (d, J = 6.1 Hz, 4H), 3.28 (d, J = 5.0 Hz, 1H), 3.00 (q, J= 9.2, 6.4 Hz, 2H), 2.79 (d, J= 18.1 Hz, 1H), 2.30 (s, 2H), 2.22 (s, 2H), 2.15 (td, J= 14.6, 7.1 Hz, 2H), 2.06 (s, 2H), 1.99 (s, 3H), 1.49 (q, J = 8.0, 7.6 Hz, 4H), 1.29 - 1.14 (m, 4H), 0.85 (dd, J = 12.8, 6.7 Hz, 7H).Synthesis ofLP-10.LP-10

[0257] To a solution of PL-4 (20 mg, 0.026 mmol, 1.0 eq.) and LK-9 (16.2 mg, 0.026 mmol, 1.0 eq.) in 5 mL anhydrous DMF were added HOBt (71.36 mg, 0.52 mmol, 20.0 eq.) and EDCI (101.2 mg, 0.52 mmol, 20.0 eq.). After the addition, the mixture was stirred at r.t. overnight. The reaction mixture was purified by Prep-HPLC to provide LP-10 as a white solid (4.6 mg, 12.9% yield). LC-MS (ESI) m / z: 1368.8 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ (ppm) 8.86 (s, 1H), 8.64 (s, 1H), 8.30 (s, 1H), 8.12 (d, J = 8.4 Hz, 1H), 8.06 (s, 1H), 8.00 (s, 1H), 7.88 (s, 1H), 7.23 (d, J = 8.5 Hz, 4H), 6.98 (s, 2H), 6.51 (s, 1H), 6.32 (s, 1H), 6.19 (d, J = 7.9 Hz, 2H), 4.67 (s, 2H), 4.56 (s, 1H), 4.24 (s, 2H), 4.04 (s, 2H), 3.71 (s, 2H), 3.66 (d, J= 6.2 Hz, 6H), 3.59 (s, 4H), 3.35 (s, 6H), 2.31 (s, 3H), 2.24 (s, 3H), 2.10 (t, J = 7.5 Hz, 2H), 2.02 (s, 3H), 1.97 (s, 3H), 1.46 (d, 7= 7.7 Hz, 5H), 1.24 (s, 6H), 1.19 (d, J = 8.4 Hz, 3H), 0.85 (s, 1H).Synthesis of LP-11.

[0258] To a solution of PL-5 (10 mg, 0.013 mmol, 1.0 eq.) and LK-10 (32.6 mg, 0.013 mmol, 1.0 eq.) in 5 mL anhydrous DMF was added HOBt (35.7 mg, 0.26 mmol, 20.0 eq.) and EDCI (101.2 mg, 0.52 mmol, 20.0 eq.). After the addition, the mixture was stirred at r.t. overnight. The reaction mixture was purified by Prep-HPLC to provide LP-11 as a white solid (2.5 mg, 12.9% yield). LC-MS (ESI) m / z: 981.3 [M^+Hf.'H NMR (400 MHz, DMSO-d6): δ (ppm) 10.09 (s, 1H), 9.55 (s, 1H), 8.34 (s, 4H), 8.13 (s, 2H), 7.84 (s, 1H), 7.67 (s, 1H), 7.24 (d, J = 4.6 Hz, 6H), 7.16 (d, J= 14.0 Hz, 4H), 6.98 (s, 2H), 6.48 (s, 1H), 6.22 (d, J= 14.2 Hz, 3H), 4.45 (s, 2H), 4.19 (s, 3H), 4.06 (s, 2H), 3.69 (s, 2H), 3.65 (s, 3H), 3.49 (d, J = 3.0 Hz, 74H), 2.67 (d, J = 2.8 Hz, 4H), 2.33 (d, J = 2.7 Hz, 3H), 2.28 (s, 2H), 2.25 (s, 3H), 2.05 (s, 4H), 1.98 (s, 4H), 1.45 (s, 7H), 0.86 (s, 2H).Synthesis ofLP-12.

[0259] To the solution of PL-6 (25 mg, 0.031 mmol, 1.0 eq.) and LK-8 (50 mg, 0.062 mmol, 2.0 eq.) in 1 mL DMSO was added DIPEA (16.14 g, 0.125 mmol, 4.0 eq.). After the addition, the mixture was stirred at 40 °C overnight. LC-MS shows the reaction was complete. The reaction was purified by Prep-HPLC to provide LP-12 (10 mg, 21.9 % yield) as a white solid. LC-MS (ESI) m / z: 731 [M+H]+ / 2.1H NMR (400 MHz, DMSO-de) 8 (ppm) 9.95 (s, 1H), 8.38 (d, J = 21.4 Hz, 2H), 8.19 (d, J = 7.9 Hz, 1H), 8.13 - 8.06 (m, 2H), 7.64 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.5 Hz, 2H), 7.28 (d, J = 4.4 Hz, 5H), 7.23 - 7.18 (m, 1H), 6.97 (s, 2H), 6.85 (s, 1H), 6.48 (d, J= 21.3 Hz, 2H), 6.18 (d, J= 16.5 Hz, 2H), 5.16 (s, 2H), 5.06 (d, J= 11.1 Hz, 1H), 4.93 (s, 1H), 4.50 (s, 3H), 4.21 (s, 1H), 4.10 (d, J = 23.1 Hz, 2H), 3.90 (dd, J = 9.4, 5.9 Hz, 2H), 3.80 (d, J = 5.8 Hz, 3H), 3.76 (d, J = 6.2 Hz, 3H), 3.37 (t, J = 7.0 Hz, 4H), 3.28 (s, 1H), 3.14 - 3.06 (m, 2H), 2.89 - 2.72 (m, 3H), 2.71 - 2.67 (m, 1H), 2.37 - 2.34 (m, 1H), 2.30 (s, 3H), 2.23 (s, 3H), 2.12 (t, J = 7.5 Hz, 3H), 2.06 (s, 3H), 1.99 (s, 4H), 1.48 (q, J = 8.5 Hz, 6H).Synthesis ofLP-13.LP-13

[0260] To the solution of PL-12 (20 mg, 0.027 mmol, 1.0 eq.) and LK-16 (22.8 mg, 0.027 mmol, 1.0 eq.) in 1 mL anhydrous DMF was added HOBt (73 mg, 0.54 mmol, 20.0 eq.)and EDCI (103.6 mg, 0.54 mmol, 20.0 eq.). After the addition, the mixture was stirred at r.t. overnight. The reaction mixture was purified by Prep-HPLC to obtain LP-13 (11.5 mg, 27.3% yield) as white solid. LC-MS (ESI) m / z: 780.9 [1 / 2M+H]+.1H NMR (400 MHz, DMSO-^) d (ppm) 9.61 (s, 1H), 8.75 (s, 1H), 8.69 (t, J = 6.5 Hz, 1H), 8.32 (dd, J = 11.5, 5.5 Hz, 1H), 8.19 - 8.09 (m, 1H), 8.00 (t, J = 5.8 Hz, 1H), 7.34 - 7.14 (m, 7H), 7.01 (s, 2H), 6.84 (d, J = 8.7 Hz, 1H), 6.45 (s, 1H), 6.24 (s, 1H), 6.14 (s, 1H), 5.05 (d, J= 11.7 Hz, 1H), 4.61 (d, J= 6.7 Hz, 2H), 4.45 (s, 3H), 4.19 (d, J = 4.5 Hz, 1H), 4.06 (s, 1H), 4.00 (d, J = 13.5 Hz, 3H), 3.76 - 3.66 (m, 5H), 3.63 (s, 3H), 3.62 - 3.50 (m, 10H), 3.48 (d, J = 2.2 Hz, 10H), 3.46 (s, 15H), 3.24 - 3.00 (m, 2H), 2.78 (d, J = 8.6 Hz, 2H), 2.68 (d, J = 35.2 Hz, 1H), 2.46 - 2.34 (m, 3H), 2.27 (s, 3H), 2.22 (s, 3H), 2.04 (s, 3H), 2.01 (s, 2H), 1.98 (s, 3H).Synthesis of LP -14.LP-14

[0261] To a solution of PL-16 (5 mg, 0.0063 mmol, 1.0 eq) and LK-8 (10 mg, 0.0126 mmol, 1.0 eq.) in 1 mL anhydrous pyridine:DMF (1:4) was added HOAt (0.85 mg, 0.252 mmol, 1.0 eq) and DIEA (13.15 mg, 0.1 mmol, 16.0 eq.). After the addition, the mixture was stirred at r.t. overnight. The reaction mixture was purified by Prep-HPLC to obtain LP-14 (3.8 mg, 41.0% yield) as white solid. LC-MS (ESI) m / z: 729.0 [1 / 2M+H]+.1H NMR (400 MHz, DMSO-d6): δ (ppm) 9.85 (d, J = 7.6 Hz, 2H), 8.76 (s, 1H), 8.38 (s, 1H), 8.17 (t, J = 8.8 Hz, 1H), 8.06 (dd, J = 12.6, 6.2 Hz, 2H), 7.59 (d, J = 8.1 Hz, 2H), 7.45 (t, J = 6.1 Hz, 1H), 7.33 - 7.14 (m, 10H), 6.97 (s, 2H), 6.84 (d, J = 8.7 Hz, 1H), 6.45 (s, 1H), 6.25 (s, 1H), 6.16 (s, 1H), 5.05 (d, J = 11.4 Hz, 1H), 4.95 (s, 2H), 4.47 (d, J = 21.7 Hz, 3H), 4.19 (d, J= 4.6 Hz, 1H), 4.09 - 3.97 (m, 2H), 3.88 (dd, J = 10.9, 5.5 Hz, 2H), 3.80 - 3.65 (m, 6H), 3.63 (s, 4H), 3.22 - 3.15 (m, 2H), 3.15 - 3.04 (m, 2H), 2.89 - 2.81 (m, 1H), 2.79 (s, 2H), 2.67 (s, 1H), 2.27 (s, 3H), 2.22 (s, 3H), 2.10 (t, J = 7.4 Hz, 2H), 2.03 (s, 3H), 1.98 (s, 3H), 1.45 (p, J = 7.7 Hz, 5H), 1.22 - 1.13 (m, 2H).Synthesis of LP-15.

[0262] To the solution of PL-16 (10 mg, 0.0126 mmol, 1.0 eq.) and LK-10 (6.7 mg, 0.0126 mmol, 1.0 eq.) in 1 mL anhydrous DMF was added HOBt (34 mg, 0.252 mmol, 20.0 eq.) and EDCI (48 mg, 0.252 mmol, 20.0 eq.). After the addition, the mixture was stirred at r.t. overnight. The reaction mixture was purified by Prep-HPLC to obtain LP-15 (4.96 mg, 30.0% yield) as white solid. LC-MS (ESI) m / z: 654.5 [1 / 2M+H]+.1H NMR (400 MHz, DMSO-^) 5 9.73 (s, 1H), 8.76 (s, 1H), 8.35 (d, J = 14.4 Hz, 1H), 8.17 - 7.95 (m, 4H), 7.29 - 7.12 (m, 8H), 6.97 (s, 2H), 6.84 (d, J = 8.7 Hz, 1H), 6.45 (s, 1H), 6.24 (s, 1H), 6.15 (s, 1H), 5.05 (d, J = 11.1 Hz, 1H), 4.45 (s, 3H), 4.19 (s, 1H), 4.10 - 3.95 (m, 2H), 3.83 (d, J = 5.7 Hz, 2H), 3.73 (s, 2H), 3.69 (s, 1H), 3.65 (d, J = 5.8 Hz, 2H), 3.63 (s, 3H), 3.60 (d, J = 5.6 Hz, 1H), 3.55 (d, J = 4.9 Hz, 1H), 3.21 (d, J = 4.3 Hz, 1H), 3.16 (s, 1H), 3.08 - 3.01 (m, 1H), 2.83 - 2.75 (m, 3H), 2.66 (s, 1H), 2.42 (s, 2H), 2.27 (s, 3H), 2.22 (s, 3H), 2.09 (t, J = 7.5 Hz, 2H), 2.03 (s, 4H), 1.98 (s, 3H).Synthesis of LP-16.LP-16

[0263] To the solution of PL-4 (20 mg, 0.026 mmol, 1.0 eq.), LK-16 (43.62 mg, 0.052 mmol, 2.0 eq.), DMAP (1.6 mg, 0.013 mmol, 0.5 eq.) and HOAt (70.78 mg, 0.52 mmol, 20.0 eq.) in 1 mL anhydrous DMF was added EDCI (53.9 mg, 0.52 mmol, 20.0 eq.) in portions. After the addition, the mixture was stirred at r.t. overnight. The reaction mixture was purified by Prep-HPLC to obtain LP-16 (15 mg, 34.5% yield) as a white solid. LC-MS (ESI) m / z: 795.6[1 / 2M+H]+.1H NMR (400 MHz, DMSO-A) 8 (ppm) 8.73 (d, J = 5.5 Hz, 2H), 8.65 (t, J = 6.7 Hz, 1H), 8.32 (t, J = 5.9 Hz, 1H), 8.20 - 8.09 (m, 2H), 8.00 (t, J = 5.8 Hz, 1H), 7.74 (s, 1H), 7.29 - 7.14 (m, 6H), 7.01 (s, 2H), 6.43 (d, J = 7.0 Hz, 2H), 6.13 (s, 2H), 5.04 (d, J = 11.5 Hz, 1H), 4.66 (d, J = 7.0 Hz, 2H), 4.48 (d, J = 3.1 Hz, 3H), 4.19 (d, J = 4.6 Hz, 1H), 4.11 (s, 1H), 4.09 - 3.99 (m, 3H), 3.79 - 3.66 (m, 5H), 3.63 (s, 3H), 3.62 - 3.53 (m, 9H), 3.52 - 3.49 (m, 2H), 3.49 - 3.43 (m, 23H), 3.27 (d, J = 5.6 Hz, 2H), 3.07 - 2.92 (m, 3H), 2.85 - 2.65 (m, 4H), 2.38 (t, J= 6.5 Hz, 3H), 2.29 (s, 3H), 2.21 (s, 3H), 2.15 (d, J= 14.4 Hz, 1H), 2.04 (s, 4H), 1.97 (s, 3H).Synthesis ofLP-17.

[0264] The mixture of PL-12 (18 mg, 0.024 mmol, 1.0 eq.), Fmoc-Val-Cit-COOH (15 mg, 0.036 mmol, 1.5 eq.) and HATU (16 mg, 0.04 mmol, 1.7 eq.) was stirred in DMF at r.t. for 10 mins, then DIPEA (13 pL, 0.072 mmol, 3.0 eq.) was added to the mixture and stirred for 4 hrs. LC-MS showed the target product, and the mixture was immediately used in the next step. LC-MS (ESI) m / z: 1132.4 [M+l]+.

[0265] Fmoc removal was facilitated by addition of TEA (150 pL) and the mixture stirred at r.t. for 3 hrs. LC-MS showed the target product which was purified by Prep-HPLC to give the target product (4.3 mg, 24.6% yield) as a white solid. LC-MS (ESI) m / z: 910.3 [M+l]+.1H NMR (400 MHz, DMSO-^) 8 (ppm) 10.33 (s, 1H), 9.13 (s, 1H), 8.85-8.73 (m, 1H), 8.12 (s, 3H), 7.48 (d, J = 16 Hz, 1H), 7.34-7.32 (d, J = 8 Hz 1H), 6.90 (s, 1H), 6.56 (s, 1H), 6.27-6.20 (m, 2H), 5.23(d, J= 8 Hz, 1H), 4.58 (s, 2H), 4.56-4.43 (m, 1H), 4.28 (s, 2H), 4.21(s, 1H), 3.69 (s, 3H), 2.72-2.68 (m, 2H), 2.30 (s, 6H), 2.07-1.99 (m, 7H), 1.32-1.24 (m, 3H), 0.94-0.93 (m, 6H), 0.83 (s, 2H).

[0266] A solution of the product from the previous step (4.3 mg, 0.0047 mmol, 1.0 eq.), Mal-PEGe-NHS (6 mg, 0.0095 mmol, 2.0 eq.) and DIPEA (2.3 pL, 0.0141 mmol, 6.0 eq) wasstirred in DMF (400 p ) at r.t. overnight. LC-MS showed the target product. The reaction mixture was concentrated, and the residue purified by Prep-HPLC tlkl3o provide LP-17 (1.2 mg, 18.2% yield) as a white solid. LC-MS (ESI) m / z: 1419.6 [M+23]+.1H NMR (400 MHz, DMSO-de) d (ppm) 9.88-9.75 (m, 1H), 8.39-8.16 (m, 1H), 8.04-7.87 (m, 2H), 7.30 (s, 1H), 7.26- 7.23 (m, 1H), 7.00(s, 1H), 6.87 (s, 1H), 6.49 (s, 1H), 6.26 (s, 1H), 6.19 (s, 1H), 5.12 (s, 1H), 4.74-4.72 (m, 1H), 4.49 (s, 4H), 4.45-4.05 (m, 10H), 3.65-3.3 (m, 22H), 3.17-3.14 (m, 3H), 2.83-2.60 (m, 8H), 2.39-2.25 (m, 9H), 2.04-1.99 (m, 6H), 1.26-1.24 (m, 3H), 0.85-0.80 (m, 6H).Synthesis of LP-18.

[0267] To the solution of PL-4 (10 mg, 0.013 mmol, 1.0 eq.), LK-13 (33.4 mg, 0.026 mmol, 2.0 eq.), DMAP (7 mg, 0.006 mmol, 0.5 eq.) and HOAt (35.4 mg, 0.26 mmol, 20.0 eq.) in 1 mL anhydrous DMF was added EDCI (27 mg, 0.26 mmol, 20.0 eq.) in portions. After the addition, the mixture was stirred at r.t. overnight. The reaction mixture concentrated, and the residue was purified by Prep-HPLC to obtain LP-18 (7.7 mg, 29.0% yield) as a white solid. LC- MS (ESI) m / z: 828.1[1 / 2M+H]+.1H NMR (400 MHz, CHCl3-d) δ (ppm) 8.74 (s, 2H), 8.65 (s, 1H), 8.33 (s, 1H), 8.12 (d, J = 7.2 Hz, 2H), 8.08 - 7.98 (m, 2H), 7.86 (d, J = 5.6 Hz, 1H), 7.73 (s, 1H), 7.40 (d, J = 8.3 Hz, 1H), 7.27 - 7.16 (m, 5H), 6.96 (d, J = 6.2 Hz, 2H), 6.43 (d, J = 7.2 Hz, 2H), 6.13 (s, 2H), 5.33 (s, 1H), 5.03 (d, J= 11.7 Hz, 1H), 4.66 (d, J= 6.8 Hz, 2H), 4.48 (s, 3H), 4.18 (t, 7= 7.0 Hz, 2H), 4.11 (s, 1H), 4.05 (d, J= 10.9 Hz, 1H), 4.01 (s, 2H), 3.75 (s, 1H), 3.70 (d, J= 5.9 Hz, 5H), 3.63 (s, 4H), 3.55 (s, 6H), 3.50 (s, 52H), 3.23 (s, 3H), 3.20 - 3.14 (m, 2H), 3.08 - 2.94 (m, 2H), 2.83 - 2.69 (m, 3H), 2.29 (s, 3H), 2.21 (s, 3H), 2.17 - 2.06 (m, 5H), 2.04 (s, 3H), 1.96 (s, 3H), 1.46 (s, 5H), 1.21 - 1.12 (m, 2H).Synthesis of LP-19.

[0268] To a solution of PL-4 (20 mg, 0.026 mmol, 1.0 eq.), LK-14 (78.46 mg, 0.052 mmol, 2.0 eq.), DMAP (1.6 mg, 0.013 mmol, 0.5 eq.) and HOAt (70.78 mg, 0.52 mmol, 20.0 eq.) in 1 mL anhydrous DMF was added EDCI (53.9 mg, 0.52 mmol, 20.0 eq.) in portions. After the addition, the mixture was stirred at r.t. overnight. The reaction mixture was concentrated, and the residue purified by Prep-HPLC to obtained LP-19 (13.84 mg, 24% yield) as a brown oil. LC-MS (ESI) m / z: 1131 [1 / 2M+2H]+.Synthesis of LP-20.

[0269] To the solution of PL-5 (5 mg, 0.0064 mmol, 1.0 eq.) and LK-7 (17.64 mg, 0.0197 mmol, 3.0 eq.) in 0.1 mL pyridine and 0.4 mL anhydrous DMF was added HOAt (0.87 mg, 0.00642 mmol, 1.0 eq.) and DIPEA (13.25 mg, 0.102 mmol, 16 eq). After the addition, the mixture was stirred at 40 °C overnight. The reaction mixture was purified by Prep-HPLC to obtain LP-20 (1.28 mg, 12.8% yield) as a white solid. LC-MS (ESI) m / z: 778.5 [1 / 2M+H]+.NMR (400 MHz, DMSO-L / 6) 8 (ppm) 10.05 (d, J = 18.8 Hz, 2H), 8.43 (s, 3H), 7.92 (d, J = 8.2 Hz, 1H), 7.62 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.3 Hz, 2H), 7.23 (d, J = 8.5 Hz, 1H), 7.02 (s, 2H), 6.50 (s, 1H), 6.24 (d, J = 10.5 Hz, 2H), 6.05 (s, 1H), 5.45 (s, 2H), 5.06 (s, 3H), 4.48 (s,1H), 4.21 (s, 2H), 4.10 (d, J = 18.4 Hz, 2H), 3.68 (s, 5H), 3.62 (s, 10H), 3.20 (s, 1H), 2.31 (s, 2H), 2.28 (s, 3H), 2.09 (s, 7H), 2.08 (s, 3H), 2.00 (s, 4H), 1.08 (t, J = 7.0 Hz, 2H), 0.86 (dd, J = 12.9, 6.5 Hz, 10H).Synthesis ofLP-21.

[0270] To the solution of PL-5 (5 mg, 0.0064 mmol, 1.0 eq.) and Mal-di-PEG-Val-Cit- PNP (16.46 mg, 0.0197 mmol, 3.0 eq.) in 0.1 mL pyridine and 0.4 mL anhydrous DMF was added HOAt (0.87 mg, 0.00642 mmol, 1.0 eq.) and DIPEA (13.25 mg, 0.102 mmol, 16.0 eq.). After the addition, the mixture was stirred at 40 °C overnight. The reaction mixture was purified by Prep-HPLC to obtain LP-21 (2.26 mg, 23.5% yield) as a white solid. LC-MS (ESI) m / z: 747.9 [1 / 2M+H]+.1H NMR (400 MHz, DMSO-^) d (ppm) 10.05 (d, J = 14.8 Hz, 2H), 8.81 (s, 1H), 8.38 (s, 2H), 7.92 (s, 1H), 7.63 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.5 Hz, 2H), 7.24 (d, J = 9.0 Hz, 2H), 7.02 (s, 2H), 6.51 (s, 1H), 6.26 (s, 1H), 6.23 (s, 1H), 5.78 (s, 1H), 5.44 (s, 2H), 5.07 (s, 2H), 4.49 (s, 1H), 4.23 (s, 2H), 4.09 (s, 2H), 3.68 (s, 3H), 3.61 (t, J = 7.2 Hz, 5H), 3.16 (d, J = 5.6 Hz, 1H), 2.92 (s, 1H), 2.76 (s, 1H), 2.31 (s, 3H), 2.28 (s, 3H), 2.08 (s, 4H), 2.04 (s, 1H), 2.00 (s, 4H), 0.91 - 0.83 (m, 13H).Synthesis ofLP-22.LP-22

[0271] To a solution of PL-16 (5 mg, 0.0063 mmol, 1.0 eq.) and LK-1 (18.15 mg, 0.0189 mmol, 3.0 eq.) in 1 mL anhydrous DMF : pyridine (4: 1) was added HOAt (0.9 mg, 0.252 mmol, 1.0 eq.) and DIPEA (13.15 mg, 0.1 mmol, 16.0 eq.). After the addition, the mixture was stirred at r.t. overnight. The reaction mixture was purified by Prep-HPLC to obtain LP-22 (5 mg, 49.1% yield) as a white solid. LC-MS (ESI) m / z: 809.8 [1 / 2M+1]+.1H NMR (400 MHz, DMSO-de) 6 (ppm) 9.84 (s, 1H), 8.76 - 8.74 (m, 1H), 7.58 (d, J = 8.6 Hz, 1H), 7.26 (s, 2H), 7.01 - 6.99 (m, 2H), 6.45 (d, J= 1.8 Hz, 1H), 6.26 - 6.24 (m, 1H), 6.17 - 6.14 (m, 1H), 5.45 - 5.37 (m, 2H), 5.33 - 5.27 (m, 1H), 4.94 (s, 2H), 4.44 (d, J = 1.3 Hz, 1H), 4.06 (d, J = 2.2 Hz, 1H), 3.62 (s, 2H), 3.51 (s, 2H), 3.47 (d, J = 9.7 Hz, 30H), 3.17 (s, 1H), 2.79 (s, 1H), 2.27 (s, 2H), 2.22 (s, 3H), 2.03 (s, 4H), 1.98 (s, 4H), 0.87 - 0.82 (m, 7H).Synthesis ofLP-23.

[0272] To the solution of PL-4 (5 mg, 0.0065 mmol, 1.0 eq) and LK-10 (5.2 mg, 0.0095 mmol, 1.5 eq.) in 2 mL anhydrous DMF was added HOBt (9.5 mg, 0.13 mmol, 20.0 eq.) and EDCI (13.5 mg, 0.22 mmol, 20.0 eq.). After the addition, the mixture was stirred at r.t. overnight. The reaction mixture was purified by Prep-HPLC to obtain LP-23 (0.8 mg, 6.8% yield) as a white solid. LC-MS (ESI) m / z: 641.4 [1 / 2M+H]+.1H NMR (400 MHz, DMSO-^) d (ppm) 8.98 (s, 1H), 8.42 (s, 3H), 8.15 (s, 1H), 7.68 (s, 1H), 7.26 (d, J = 4.4 Hz, 4H), 6.99 (s, 2H), 6.46 (s, 1H), 6.43 (s, 1H), 6.16 (d, J= 6.2 Hz, 2H), 5.34 (s, 1H), 4.51 (s, 2H), 4.13 (s, 1H), 3.88 (s, 1H), 3.69 - 3.64 (m, 5H), 3.56 (s, 3H), 2.56 (s, 2H), 2.31 (s, 3H), 2.23 (s, 3H), 2.14 - 2.08 (m, 2H), 2.07 (s, 3H), 2.02 (d, J = 8.7 Hz, 3H), 1.99 (s, 4H), 1.48 (d, J = 7.6 Hz, 5H).Synthesis of LP-24.LP-24

[0273] To the solution of PL-16 (5.0 mg, 0.0063 mmol, 1.0 eq.) and LK-8 (10 mg, 0.0126 mmol, 1.0 eq.) in 1 mL anhydrous DMF : pyridine (4:1) was added HOAt (0.85 mg, 0.252 mmol, 1.0 eq.) and DIPEA (13.15 mg, 0.1 mmol, 16.0 eq.). After the addition, the mixture was stirred at r.t. overnight. The reaction mixture was purified by Prep-HPLC to obtain LP-24 (3.8mg, 41% yield) as a white solid. LC-MS (ESI) m / z: 729 [M+2] / 2.1H NMR (400 MHz, DMSO-d6) d (ppm) 9.85 (d, J= 7.6 Hz, 2H), 8.76 (s, 1H), 8.38 (s, 1H), 8.17 (t, J= 8.8 Hz, 1H), 8.06 (dd, J = 12.6, 6.2 Hz, 2H), 7.59 (d, J = 8.1 Hz, 2H), 7.45 (t, J = 6.1 Hz, 1H), 7.33 - 7.14 (m, 10H), 6.97 (s, 2H), 6.84 (d, J = 8.7 Hz, 1H), 6.45 (s, 1H), 6.25 (s, 1H), 6.16 (s, 1H), 5.05 (d, J = 11.4 Hz, 1H), 4.95 (s, 2H), 4.47 (d, J = 21.7 Hz, 3H), 4.19 (d, J = 4.6 Hz, 1H), 4.09 - 3.97 (m, 2H), 3.88 (dd, J = 10.9, 5.5 Hz, 2H), 3.80 - 3.65 (m, 6H), 3.63 (s, 4H), 3.22 - 3.15 (m, 2H), 3.15 - 3.04 (m, 2H), 2.89 - 2.81 (m, 1H), 2.79 (s, 2H), 2.67 (s, 1H), 2.27 (s, 3H), 2.22 (s, 3H), 2.10 (t, J = 7.4 Hz, 2H), 2.03 (s, 3H), 1.98 (s, 3H), 1.45 (p, J = 7.7 Hz, 5H), 1.22 - 1.13 (m, 2H).Synthesis ofLP-25.

[0274] To the solution of PL-16 (10 mg, 0.0126 mmol, 1.0 eq.) and LK-9 (7.8 mg, 0.0126 mmol, 1.0 eq.) in 1 mL anhydrous DMF was added HOBt (34 mg, 0.252 mmol, 20.0 eq.) and EDCI (34 mg, 0.252 mmol, 20.0 eq.). After the addition, the mixture was stirred at r.t.overnight. The reaction mixture was purified by Prep-HPLC to obtain LP-25 (4.3 mg, 24.5% yield) as a white solid. LC-MS (ESI) m / z: 855.0 [1 / 2M+H]+.1H NMR (400 MHz, DMSO-^) d (ppm) 9.88 (s, 1H), 8.75 (s, 1H), 8.62 (t, J = 6.6 Hz, 1H), 8.32 (t, J = 5.9 Hz, 1H), 8.14 (d, J = 7.9 Hz, 1H), 8.06 (t, J = 5.8 Hz, 1H), 8.00 (t, J = 5.7 Hz, 1H), 7.94 (t, J = 5.9 Hz, 1H), 7.28 - 7.13 (m, 7H), 6.98 (s, 2H), 6.84 (d, J = 8.6 Hz, 1H), 6.46 (s, 1H), 6.25 (s, 1H), 6.16 (s, 1H), 5.06 (d, J = 11.6 Hz, 1H), 4.63 (d, J = 6.7 Hz, 2H), 4.51 - 4.42 (m, 3H), 4.20 (d, J = 4.6 Hz, 1H), 4.07 (s, 1H), 4.04 - 3.97 (m, 1H), 3.91 (s, 2H), 3.87 (d, J = 5.7 Hz, 2H), 3.75 (ddd, J = 19.1, 9.4, 5.0 Hz, 3H), 3.67 (d, J = 5.7 Hz, 2H), 3.63 (s, 4H), 3.58 (d, J = 5.4 Hz, 1H), 3.22 (s, 2H), 3.14 (s, 2H), 3.05 (dd, J = 13.8, 4.5 Hz, 2H), 2.91 - 2.82 (m, 1H), 2.81 - 2.77 (m, 2H), 2.44 (d, J= 15.2 Hz, 1H), 2.28 (s, 3H), 2.23 (s, 3H), 2.10 (t, J = 7.4 Hz, 2H), 2.04 (s, 4H), 1.98 (s, 3H), 1.47 (h, J = 7.1 Hz, 4H), 1.23 - 1.15 (m, 2H).Synthesis ofLP-26.

[0275] To a solution of PL-13 (4 mg, 0.00484 mmol, 1.0 eq.) and Mc-Val-Cit-PAB- PNP (38.28 mg, 0.0145 mmol, 3.0 eq.) in 1 mL pyridine:DMF (1:4) was added DIPEA (10 mg, 0.0774 mmol, 16.0 eq.) and HO At (0.65 mg, 0.00484 mmol, 1.0 eq.) and the reaction mixture stirred at 40 °C overnight. LC-MS showed the reaction was complete. The reaction mixture was concentrated and purified by Prep-HPLC to provide LP-26 (0.9 mg, 13% yield) as a white solid. LC-MS (ESI) m / z: 713 [l / 2M+2]+.1H NMR (400 MHz, DMSO-d6): δ (ppm) 10.03 (s, 1H), 9.08 (s, 1H), 8.12 (d, J = 6.4 Hz, 1H), 7.86 (d, J = 8.2 Hz, 1H), 7.65 (s, 1H), 7.60 (d, J = 8.6 Hz, 2H), 7.30 (d, J = 8.3 Hz, 2H), 6.99 (s, 2H), 6.44 (d, J = 12.3 Hz, 2H), 6.16 (d, J = 6.9 Hz, 2H), 6.05 (s, 1H), 5.46 (s, 2H), 5.34 (s, 1H), 5.04 (s, 1H), 4.98 (s, 2H), 4.50 (s, 1H), 4.20 (s, 2H), 4.13 (s, 1H), 4.07 (s, 1H), 3.29 (s, 1H), 2.31 (d, J = 4.1 Hz, 3H), 2.23 (s, 2H), 2.14 (s, 1H), 2.05 (d, J = 11.4 Hz, 3H), 1.99 (s, 6H), 1.49 (s, 7H), 0.86 - 0.81 (m, 6H).Synthesis of LP-27.

[0276] To a solution of PL-5 (5 mg, 0.0064 mmol, 1.0 eq.) and LK-3 (15 mg, 0.019 mmol, 3.0 eq.) in 1 mL anhydrous pyridine:DMF (1:4) was added HOAt (0.87 mg, 0.0064 mmol, 1.0 eq.) and DIPEA (13.2 mg, 0.10 mmol, 16.0 eq.) and the reaction mixture was stirred at r.t. overnight. The reaction mixture was concentrated and purified by Prep-HPLC to provide LP-27 (2.03 mg, 23% yield) as white solid. LC-MS (ESI) m / z: 690 [l / 2M+2]+.1H NMR (400 MHz, DMSO-cfe) 6 (ppm) 10.04 (d, J = 18.5 Hz, 2H), 8.80 (s, 1H), 7.89 (s, 1H), 7.64 (s, 1H), 7.62 (s, 1H), 7.36 (d, J = 8.3 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H), 7.03 (s, 2H), 6.50 (s, 1H), 6.26 (s, 1H), 6.23 (s, 1H), 5.43 (s, 2H), 5.35 (s, 1H), 5.06 (s, 2H), 4.49 (s, 1H), 4.22 (s, 2H), 4.08 (s, 2H), 3.68 (s, 3H), 3.58 (s, 2H), 3.56 (s, 1H), 3.54 (s, 1H), 2.31 (s, 4H), 2.28 (s, 3H), 2.08 (s, 4H), 2.03 (s, 1H), 2.00 (s, 4H), 0.87 (d, J = 7.0 Hz, 6H), 0.83 (d, J = 6.7 Hz, 4H).Synthesis ofLP-28.

[0277] To the solution of PL-5 (5 mg, 0.0064 mmol, 1.0 eq.) and LK-5 (15 mg, 0.019mmol,3.0eq) in 1 mL anhydrous pyridine:DMF (1:4) was added HOAt (0.87 mg, 0.0064mmol, 1.0 eq.) and DIPEA (13.2 mg, 0.10 mmol, 16.0 eq.) and the reaction mixture was stirred at r.t. overnight. The reaction mixture was concentrated and purified by Prep-HPLC to provide LP-28 (3.3 mg, 35% yield) as white solid. LC-MS (ESI) m / z: 734 [l / 2M+2]+.1H NMR (400 MHz, DMSO-cfc) 5 (ppm) 10.04 (d, J = 18.5 Hz, 2H), 8.80 (s, 1H), 7.89 (s, 1H), 7.64 (s, 1H), 7.62 (s, 1H), 7.36 (d, J = 8.3 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H), 7.03 (s, 2H), 6.50 (s, 1H), 6.26 (s, 1H), 6.23 (s, 1H), 5.43 (s, 2H), 5.35 (s, 1H), 5.06 (s, 2H), 4.49 (s, 1H), 4.22 (s, 2H), 4.08 (s, 2H), 3.68 (s, 3H), 3.58 (s, 2H), 3.56 (s, 1H), 3.54 (s, 1H), 2.31 (s, 4H), 2.28 (s, 3H), 2.08 (s, 4H), 2.03 (s, 1H), 2.00 (s, 4H), 0.87 (d, J = 7.0 Hz, 6H), 0.83 (d, J = 6.7 Hz, 4H).Synthesis ofLP-29.

[0278] To a solution of LK-10 (3.58 mg, 0.00676 mmol, 1.0 eq.), EDCI (25.92 mg, 0.135 mmol, 20.0 eq.), HOBt (18.27 mg, 0.135 mmol, 20.0 eq.) in 1 mL anhydrous DMF was added PL-12 (5 mg, 0.00676 mmol, 1.0 eq.) under argon and stirred at r.t. overnight. After rection completion, the reaction was concentrated and purified by p Prep-HPLC to afford LP- 29 (0.6 mg, 5% yield) as white solid. LC-MS (ESI) m / z: 626 [l / 2M+2]+.1H NMR (400 MHz, DMSO-de) 8 (ppm) 9.74 (s, 1H), 8.83 (s, 1H), 8.36 (d, J = 5.2 Hz, 2H), 8.11 - 8.06 (m, 1H), 7.31 (s, 1H), 7.25 (s, 5H), 7.20 (s, 1H), 6.98 (s, 2H), 6.47 (s, 1H), 6.26 (s, 1H), 6.17 (s, 1H), 5.34 (s, 1H), 4.46 (s, 2H), 4.08 (s, 1H), 3.24 - 3.14 (m, 1H), 2.81 (s, 2H), 2.29 (s, 3H), 2.24 (s, 3H), 2.11 (s, 3H), 2.06 (s, 3H), 2.03 (s, 2H), 2.00 (d, J= 3.0 Hz, 6H), 1.48 (d, J = 7.8 Hz, 2H), 1.19 (s, 2H), 1.07 (d, J = 7.0 Hz, 1H), 0.87 (s, 2H).Synthesis of LP-30.

[0279] To a solution of PL-5 (10 mg, 0.013 mmol, 1.0 eq.) and LK-4 (30 mg, 0.039 mmol, 3.0 eq.) in 2 mL anhydrous pyridine:DMF (1:4) was added HOAt (1.8 mg, 0.013 mmol, 1.0 eq.) and DIPEA (26.8 mg, 0.21 mmol, 16.0 eq.), and stirred at r.t. overnight. The reaction mixture was concentrated and purified by Prep-HPLC to provide compound LP-30 (6.5 mg, 36% yield) as white solid. LC-MS (ESI) m / z: 705 [l / 2M+2]+.1H NMR (400 MHz, DMSO-d6) d (ppm) 10.08 (d, J = 5.2 Hz, 2H), 8.83 (s, 1H), 8.35 (s, 2H), 8.03 (d, J = 9.1 Hz, 1H), 7.62 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 8.5 Hz, 1H), 7.46 (d, J = 9.2 Hz, 2H), 7.36 (d, J = 8.2 Hz, 2H), 7.25 (t, J= 8.9 Hz, 2H), 7.02 (s, 1H), 7.00 (s, 2H), 6.50 (s, 1H), 6.25 (d, J = 11.4 Hz, 2H), 6.03 (s, 2H), 5.45 (s, 3H), 5.07 (s, 2H), 4.49 (s, 1H), 4.45 (s, 1H), 4.31 (t, J = 7.7 Hz, 1H), 4.22 (s, 1H), 4.08 (s, 1H), 3.93 (s, 3H), 3.68 (s, 3H), 3.58 (s, 4H), 3.56 (s, 3H), 3.53 (s, 3H), 3.19 (s, 2H), 2.92 (s, 2H), 2.57 (s, 5H), 2.31 (s, 3H), 2.28 (s, 3H), 2.08 (s, 4H), 2.02 (d, J= 8.0 Hz, 2H), 2.00 (s, 3H), 0.88 (d, J = 6.5 Hz, 6H), 0.85 - 0.80 (m, 5H).Synthesis ofLP-31.

[0280] To a solution of PL-5 (10 mg, 0.013 mmol, 1.0 eq.) and LK-6 (34 mg, 0.039 mmol, 3.0 eq.) in 2 mL anhydrous pyridine:DMF (1:4) was added HOAt (1.8 mg, 0.013 mmol, 1.0 eq.) and DIPEA (26.8 mg, 0.21 mmol, 16.0 eq.) and stirred at r.t. overnight. The reaction mixture was concentrated and purified by Prep-HPLC to provide compound LP-31 (3.3 mg, 17% yield) as a white solid. LC-MS (ESI) m / z: 756 [l / 2M+2]+.1H NMR (400 MHz, DMSO- d6) 8 (ppm) 10.03 (d, J= 13.7 Hz, 2H), 8.79 (s, 1H), 8.41 (s, 1H), 8.13 (d, J= 7.0 Hz, 1H), 7.93 (d, J = 9.1 Hz, 1H), 7.88 (d, J= 8.8 Hz, 1H), 7.60 (d, J = 8.4 Hz, 2H), 7.34 (d, J= 8.0 Hz, 2H), 7.20 (d, J= 8.9 Hz, 1H), 7.02 (s, 1H), 7.01 (s, 2H), 6.48 (s, 2H), 6.22 (d, J= 12.3 Hz, 2H), 5.99 (s, 1H), 5.75 (s, 1H), 5.42 (s, 2H), 5.04 (s, 2H), 4.46 (s, 1H), 4.21 (d, J = 8.5 Hz, 2H), 4.05 (s, 2H), 3.65 (s, 3H), 3.54 (d, J= 5.2 Hz, 3H), 3.50 (d, J = 5.1 Hz, 5H), 3.47 (d, J= 2.7 Hz, 12H), 2.27 (d, J= 12.7 Hz, 6H), 2.05 (s, 3H), 1.98 (d, J = 4.1 Hz, 5H), 0.88 - 0.79 (m, 11H).Synthesis ofLP-32.

[0281] To a solution of Mal-Gly-Gly-Gly-Gly-Val-Cit-PAB-OH (10 mg, 0.0133 mmol, 1.0 eq. ) and bis(4-nitrophenyl)carbonate (6.12 mg, 0.2 mmol, 1.5 eq.) in 0.5 mL DMSO was added DIPEA (8.39 mg, 0.065 mmol, 5.0 eq.) and the reaction stirred at 40 °C overnight. PL-5 (5 mg, 0.00642 mmol) was added and maintained for another 18 hrs at 40 °C. The reaction was concentrated and purified by Prep-HPLC to obtain LP-32 (1.03 mg, 10% yield) as a white solid. LC-MS (ESI) m / z: 775 [l / 2M+2]+.1H NMR (400 MHz, DMSO-d6) 5 9.96 (s, 1H), 9.92 (s, 1H), 8.31 (s, 4H), 7.50 (s, 3H), 7.26 (s, 1H), 7.24 (s, 1H), 7.11 (s, 1H), 7.00 (s, 2H), 6.40 (s, 1H), 6.15 (s, 1H), 6.12 (s, 1H), 5.35 (s, 2H), 5.24 (s, 2H), 4.95 (s, 2H), 4.02 (s, 2H), 3.97 (s, 2H), 3.69 (s, 2H), 3.68 (s, 2H), 3.57 (s, 3H), 2.20 (s, 3H), 2.17 (s, 4H), 1.99 (s, 1H), 1.97 (s, 4H), 1.93 (d, J = 7.6 Hz, 4H), 0.74 (d, J = 9.1 Hz, 6H).Synthesis of LP-33.

[0282] To the solution of PL-5 (10 mg, 0.0129 mmol, 1.0 eq.) and LK-12 (8.9 mg, 0.0129 mmol, 1.0 eq.) in 2 mL anhydrous DMF was added HOBt (50 mg, 0.258 mmol, 20.0 eq.) and EDCI (35 mg, 0.258 mmol, 20.0 eq.). After the addition, the mixture was stirred at r.t. overnight. The reaction was concentrated and purified by Prep-HPLC to obtain LP-33 (0.82 mg, 4.3% yield) as a white solid. LC-MS (ESI) m / z: 726.1 [1 / 2M+H]+.Synthesis of LP-34.LP-34

[0283] To a solution of PL-12 (20 mg, 0.027 mmol, 1.0 eq.) and LK-9 (16.64 mg, 0.027 mmol, 3.0 eq.) in 5 mL DMF, was added HOBt (72.96 mg, 0.54 mmol, 20.0 eq.) and EDCI (103.5 mg, 0.54 mmol, 20.0 eq.). After the addition, the mixture was stirred at r.t. overnight. The reaction mixture was concentrated and purified by Prep-HPLC to provide compound LP- 34 (8 mg, 22.1% yield) as a white solid. LC-MS (ESI) m / z: 670.0 [l / 2M+2]+.1H NMR (400 MHz, DMSO-de) 6 (ppm) 9.66 (s, 1H), 8.40 (d, J = 19.0 Hz, 4H), 8.18 (d, J = 8.0 Hz, 1H), 8.11 (s, 1H), 8.05 (s, 1H), 7.38 - 7.29 (m, 3H), 7.26 (d, J = 7.0 Hz, 6H), 7.22 (s, 2H), 7.01 (s, 2H), 6.87 (d, J = 8.5 Hz, 1H), 6.48 (s, 1H), 6.27 (s, 1H), 6.18 (s, 1H), 5.35 (s, 1H), 5.08 (d, J = 12.0 Hz, 1H), 4.64 (d, J = 6.5 Hz, 2H), 4.48 (s, 4H), 4.22 (s, 1H), 4.10 (s, 1H), 4.05 (s, 1H), 4.01 (s, 3H), 3.78 (s, 1H), 3.70 (s, 1H), 3.68 (s, 1H), 3.66 (s, 4H), 2.82 (s, 3H), 2.31 (s, 3H), 2.25 (s,3H), 2.11 (d, J = 9.2 Hz, 3H), 2.07 (s, 4H), 2.04 (s, 1H), 2.01 (s, 4H), 1.49 (q, J = 7.7 Hz, 6H), 0.87 (d, 7= 6.7 Hz, 4H).Synthesis of LP-35.LP-35

[0284] LP-35 was prepared following the procedure for LP-34. LC-MS (ESI) m / z:684.6 [1 / 2M+H]+.1H NMR (400 MHz, CHCl3-d) δ (ppm) 8.74 (s, 2H), 8.65 (t, J = 6.6 Hz, 1H), 8.31 (t, J = 5.9 Hz, 1H), 8.13 (d, J = 7.9 Hz, 1H), 8.07 (t, J = 5.8 Hz, 1H), 8.01 (t, J = 5.7 Hz, 1H), 7.73 (s, 1H), 7.26 - 7.16 (m, 6H), 6.96 (s, 2H), 6.43 (s, 2H), 6.41 (s, 2H), 6.12 (s, 1H), 5.03 (d, J = 8.0 Hz, 1H), 4.66 (d, J = 6.7 Hz, 2H), 4.48 - 4.43 (m, 3H), 4.19 (d, J = 4.6 Hz, 1H), 4.10 (s, 1H), 4.06 (s, 1H), 4.04 (m, 1H), 4.01 (s, 3H), 3.76 - 3.65 (m, 5H), 3.62 (s, 4H), 3.05 - 2.98 (m, 2H), 2.82 - 2.74 (m, 2H), 2.44 (m, 3H), 2.20 (s, 3H), 2.16 (s, 3H), 2.09 (m, 3H), 2.04 (s, 3H), 1.96 (s, 3H), 1.45 (m, 5H), 1.18 - 1.16 (m, 2H).Antibody-drug conjugatesGeneral procedure C

[0285] Monoclonal antibody (1 eq.) was placed in a 0.5 mL centrifugation tube, and then 30 mM His-HAc pH 5.5 buffer was added to dilute the antibody concentration to 5 mg / mL, followed by addition of 100 mM EDTA aqueous solution according to 5% of the total volume of reaction solution. After vortexing, to the mixture was added 2 mg / mL TCEP (1.5 eq. to 9 eq.) aqueous solution for antibody reduction. After vortexing, the reaction was placed on a Constant Temperature Mixer, and the reduction was conducted at 20 °C for 1.5 hrs. A solution of 10 mg / mL linker payload building block (LP) (4.0 eq. to 10 eq.) in DMSO was added and DMSO was then added according to 20% of the total volume of the final reaction solution respectively.After vortexing, the solution was placed on a Constant Temperature Mixer for reaction and conjugated at 20 °C for 0.5 hour.

[0286] Unconjugated residual linker payloads in the reaction solution were removed by treating with 300 mg / mL dextran coated charcoal (Sigma). A 10% dextran coated charcoal suspension by volume was added into the reaction solution. After vortexing, the mixture was shaken for 2 hrs at 4 °C, then the supernatant was taken for detection of residual linker payload content, if percentage of free linker payload is above 1%, the above process should be repeated for several times until the free linker payload reaches the standard (3 times of treatment can meet the requirement). When the treatment was complete, the mixture was centrifugated and the supernatant was collected by using a syringe and a hydrophilic membrane filter to filter out the activated carbon. The buffer of the desired ADC was replaced with a suitable storage buffer through 4 times of ultrafiltration and stored at -80 °C.Common characterization protocols for antibody-drug conjugates(a) ADC DAR value measurement by RP-HPLC analysis

[0287] HPLC instrument: Waters e2695 High performance Liquid chromategraphy system. Column: BioResolve® RP mAb Polyphenyl (4.6x100 mm, 2.7 pm) (Waters). Mobile phase: mobile phase A (MPA): 0.1% TFA-H2O; Mobile phase B (MPB): 0.1% TFA-ACN; the following elution procedure (35%-45%) was followed, in which the volume of mobile phase A was 90%-90% and that of mobile phase B was 10%-10% in 0-3 min. The volume of mobile phase A was 90%-65% and that of mobile phase B was 10%-35 % in 3-5 min. The volume of mobile phase A is 5%-0% and that of mobile phase B is 95%-100% in 5-20 min. From 24 to 26 min, the volume of mobile phase A was 0-100%, and the volume of mobile phase B was 100%- 0%. The volume of mobile phase A was 100%-100% and that of mobile phase B was 0%-0% in 26-30 min.

[0288] Detection conditions: The flow rate of mobile phase was set at 1 mL / min, the detection wavelength was set at 280 nm, and the column temperature was 65 °C.

[0289] Experimental procedure: Take 50 pg ADC sample (converted into volume according to concentration), add 5 pL IM DTT, add storage buffer to have the final volume of 50 pL. After vortexing, the sample was incubated at 37 °C for 30 min. After being warmed toroom temperature, the sample was centrifuged at 12000 rpm for 5 min. 20 pL supernatant was injected into the HPLC, eluted by the above elution procedure, and the chromatogram was recorded.

[0290] DAR value calculation formula: DAR = (L0 peak area ratio x 0 + LI peak area ratio x 1 + HO peak area ratio x o + Hl peak area ratio x 1 + H2 peak area ratio x 2 + H3 peak area ratio x 3) / 100 x 2.(b) ADC DAR value measurement by HIC-HPLC analysis

[0291] HPLC instrument: Waters e2695 High Performance Liquid Chromatography system. Column: MabPac™ HIC -Butyl 5 pm 4.6 x 100 mm (Thermo). Mobile phase: mobile phase A (MPA): 1.5 M (NH4)2SC>4 + 50 mM potassium phosphate (pH 7.0); Mobile phase B (MPB): 50 mM sodium phosphate (pH 7.0) / isopropyl alcohol (75 : 25 V / V); the following elution procedure (5%-95%) was followed, in which the volume of mobile phase A was 100%- 95% and that of mobile phase B was 0%-5% in 0-2 min. The volume of mobile phase A and B was 95%-5% and 5%-95% respectively during 2-22 min. The volume of mobile phase A was 5%-0% and that of mobile phase B was 95%-100% during 22-24 min. From 24 to 26 min, the volume of mobile phase A was 0-100%, and the volume of mobile phase B was 100%-0%. The volume of mobile phase A was 100%-100% and that of mobile phase B was 0%-0% in 26-30 min.

[0292] Detection conditions: The flow rate of mobile phase was set at 1 mL / min, the detection wavelength was set at 280 nm, and the column temperature was set at 30 °C.

[0293] Experimental procedure: 50 pg ADC sample (the volume depends on the concentration of the sample) was injected into the HPLC, eluted by the above elution procedure, and the chromatogram was recorded.

[0294] DAR value is calculated as follows: DAR = S (relative peak area x number of loaded drugs) / 100.(c) ADC DAR value measurement by SEC-HPLC analysis

[0295] HPLC instrument: 1260 Agilent High Performance Liquid Chromatography system. Column: Waters Xbridge® BEH200 SEC (7.8 x 300 mm, 3.5 pm). Mobile phase: 50mM PB + 200 mM Arg (pH 6.80) +10% IPA, elution according to the following procedure, 0- 30 min mobile phase A volume of 100%-100%.

[0296] Detection conditions: The flow rate of mobile phase was set at 0.5 mL / min, the detection wavelength was 280 nm and 254 nm, and the column temperature was 26 °C.

[0297] Experimental procedure: 20 pg ADC sample (the volume depends on the concentration of the sample) was injected into the HPLC, eluted by the above elution procedure, and the chromatogram was recorded.

[0298] Calculation formula: SEC-DAR = Cdrug / CmAb. In which, the sum of absorbance of small molecule drug and antibody at 280 nm is A280 =Cdrug +e™b CmAb)L; total absorbance of small molecule drug at maximum absorption X (254 nm) A254 = (s^. Cdrug(d) Free Linker Payload (mol / mol%) measurement by Cis-HPLC analysis

[0299] HPLC instrument: Waters e2695 High Performance Liquid Chromatography system. Column: XBridge® C18 3.5pm 4.6 * 150 mm (Waters). Mobile phase: mobile phase A (MPA): 0.1% TFA-H2O; Mobile phase B (MPB): 0.1% TFA-ACN; the following elution procedure (5%-95%) was followed, in which the volume of mobile phase A was 90%-20% and the volume of mobile phase B was 10%-80% in 0-30 min. At 30-31 min, the volume of mobile phase A is 20%-90%, and that of mobile phase B is 80%-10%. The volume of mobile phase A was 90%-90% and that of mobile phase B was 10%- 10% in 31-35 mins.

[0300] Detection conditions: The flow rate of mobile phase was set at 0.5 mL / min, the detection wavelength was set at 254 nm, and the column temperature was set at 30 °C.

[0301] Reagent I Preparation: A solution of 10 g sodium chloride in 30 mL anhydrous methanol and 50 mL acetonitrile was stirred at room temperature for more than one hour, and then let stand for one hour. The supernatant was filtered by 0.22 pm organic membrane and stored at room temperature for three months.

[0302] Reagent II Preparation: A mixture of 100 mL reagent I, 15 mL DMSO and 85 mL ADC storage buffer was well mixed and stored at room temperature (valid for 2 months).(e) Sample solution preparation

[0303] Free linker payload reference: ADC related linker payload was dissolved in the above reagent II to have a concentration of 1.0 mg / mL.

[0304] 10 pL of above free linker payload reference with a concentration of 1.0 mg / mL was added into 90 pL reagent II to prepare a solution with a concentration of 100 pg / mL. Then the sample was diluted with reagent II according to the table below to prepare samples with required concentrations.Note: The above prepared samples with required concentration were sequentially injected to HPLC from low concentration to high concentration.

[0305] Sample for testing: 85 pg of ADC was mixed with 3 pL DMSO for 5 min, then to this was added 60 pL of reagent I. The mixture was mixed well for 5-10 min and centrifuged at 2000 rpm for 2 min. Finally, 20 pL supernatant was injected into HPLC, eluted by the above elution procedure, and the chromatogram was recorded.

[0306] The amount of free linker payload in ADC was calculated according to the standard binary linear regression curve equation. Free linker payload (mol / mol%) = molar concentration of residual linker payload / molar concentration of antibody X100.(f) ADC aggregate measurement by SEC-HPLC analysis

[0307] HPLC instrument: 1260 Agilent High Performance Liquid Chromatography system. Column: Waters Xbridge® BEH200 SEC (7.8 * 300 mm, 3.5 pm). Mobile phase: 50 mM PB + 200 mM Arg (pH 6.80) +10% IPA, the following elution procedure was followed, 0- 30 min mobile phase A volume of 100%-100%;

[0308] Detection conditions: Flow rate of mobile phase was set at 0.5 mL / min, detection wavelength was set at 280 nm, and column temperature was set at 26 °C.

[0309] Experimental procedure: 20 pg ADC sample (the volume depends on the concentration of the sample) was injected into the HPLC, eluted by the above elution procedure, and the chromatogram was recorded.

[0310] Calculation formula: Monomer purity (%) = A monomer / A total x 100%; aggregate purity (%) = A aggregate / A total x 100%.Synthesis of ADC-1.

[0311] According to general conjugation procedure for preparing ADCs, Sacituzumab (3.0 mg, 11.26 mg / mL, 1.0 eq.) in 50 mM PBS pH 8.0 was partially reduced by adding TCEP (2 mg / mL, 1.0 eq.) aqueous solution. The reduction was conducted at 20 °C for 1.5 hrs, and then conjugated with LP-1 (10 mg / mL, 4.0 eq.) in DMSO at 20 °C for 0.5 hour. The mixture was purified by treating with dextran coated charcoal three times and filtered through hydrophilic membrane filter, followed by four times of ultrafiltration to afford ADC-1 (CADC (mg / mL): 2.58, volume (ml): 0.743, yield: 64.0%). The following characteristic values were obtained according to common characterization protocols for ADCs. SEC-DAR: 0.46, SEC purity: 82.69% and free linker payload (mol / mol%): 0.42%.Synthesis of ADC-2.

[0312] According to general conjugation procedure for preparing ADCs, Sacituzumab (3.0 mg, 11.26 mg / mL, 1.0 eq.) in 50 mM PBS pH 8.0 was partially reduced by adding TCEP (2 mg / mL, 1.0 eq.) aqueous solution. The reduction was conducted at 20 °C for 1.5 hrs, and then conjugated with LP-2 (10 mg / mL, 4.0 eq.) in DMSO at 20 °C for 0.5 hour. The mixture was purified by treating with dextran coated charcoal three times and filtered through hydrophilic membrane filter, followed by four times of ultrafiltration to afford ADC-2 (CADC (mg / mL): 1.74, volume (mL): 0.938, yield: 54.3%). The following characteristic values were obtained according to common characterization protocols for ADCs. SEC-DAR: 1.40, SEC purity: 89.68% and free linker payload (mol / mol%): 1.25%.Synthesis of ADC-3.

[0313] According to general conjugation procedure for preparing ADCs, Sacitu- zumab (3.0 mg, 11.26 mg / mL, 1.0 eq.) in 50 mM PBS pH 8.0 was partially reduced by adding TCEP (2 mg / mL, 2.0 eq.) aqueous solution. The reduction was conducted at 20 °C for 1.5 hrs, and then conjugated with LP-3 (10 mg / mL, 4.0 eq.) in DMSO at 20 °C for 0.5 hour. The mixture was purified by treating with dextran coated charcoal three times and filtered through hydrophilic membrane filter, followed by four times of ultrafiltration to afford ADC-3 (CADC (mg / mL): 1.78, volume (mL): 0.815, yield: 48.3%). The following characteristic values were obtained according to common characterization protocols for ADCs. SEC-DAR: 0.68, SEC purity: 74.94% and free linker payload (mol / mol%): -0.07%.Synthesis of ADC-4.

[0314] According to general conjugation procedure for preparing ADCs, Sacitu- zumab (3.0 mg, 11.26 mg / mL, 1.0 eq.) in 50 mM PBS pH 8.0 was partially reduced by adding TCEP (2 mg / mL, 1.0 eq.) aqueous solution. The reduction was conducted at 20 °C for 1.5 hrs, and then conjugated with LP-4 (10 mg / mL, 4.0 eq.) in DMSO at 20 °C for 0.5 hour. The mixture was purified by treating with dextran coated charcoal three times and filtered through hydrophilic membrane filter, followed by four times of ultrafiltration to afford ADC-4 (CADC (mg / mL): 2.39, volume (mL): 0.676, yield: 53.6%). The following characteristic values were obtained according to common characterization protocols for ADCs. SEC-DAR: 0.69, SEC purity: 80.76% and free linker payload (mol / mol%): -0.95%.Synthesis of ADC-5.

[0315] According to general conjugation procedure for preparing ADCs, Trastuzumab (3.0 mg, 38.7 mg / mL, 1.0 eq.) in 50 mM PBS pH 8.0 was partially reduced by adding TCEP (2 mg / mL, 1.0 eq.) aqueous solution. The reduction was conducted at 20 °C for 1.5 hrs, and then conjugated with LP-1 (10 mg / mL, 4.0 eq.) in DMSO at 20 °C for 0.5 hour. The mixture was purified by treating with dextran coated charcoal three times and filtered through hydrophilic membrane filter, followed by four times of ultrafiltration to afford ADC-5 (CADC (mg / mL): 2.94, volume (mL): 0.861, yield: 84.3%). The following characteristic values wereobtained according to common characterization protocols for ADCs. SEC-DAR: 1.58, SEC purity: 83.30% and free linker payload (mol / mol%): 0.37%.Synthesis of ADC-6.

[0316] According to general conjugation procedure for preparing ADCs, Trastuzumab (3.0 mg, 38.7 mg / mL, 1.0 eq.) in 50 mM PBS pH 8.0 was partially reduced by adding TCEP (2 mg / mL, 1.0 eq.) aqueous solution. The reduction was conducted at 20 °C for 1.5 hrs, and then conjugated with LP-2 (10 mg / mL, 4.0 eq.) in DMSO at 20 °C for 0.5 hour. The mixture was purified by treating with dextran coated charcoal three times and filtered through hydrophilic membrane filter, followed by four times of ultrafiltration to afford ADC-6 (CADC (mg / mL): 2.69, volume (mL): 0.849, yield: 76.3%). The following characteristic values were obtained according to common characterization protocols for ADCs. SEC-DAR: 2.38, SEC purity: 92.51% and free linker payload (mol / mol%): 0.91%.Synthesis of ADC-7.

[0317] According to general conjugation procedure for preparing ADCs, Trastuzumab (3.0 mg, 38.7 mg / mL, 1.0 eq.) in 50 mM PBS pH 8.0 was partially reduced by adding TCEP (2 mg / mL, 1.0 eq.) aqueous solution. The reduction was conducted at 20 °C for 1.5 hrs, and then conjugated with LP-3 (10 mg / mL, 4.0 eq.) in DMSO at 20 °C for 0.5 hour. The mixture was purified by treating with dextran coated charcoal three times and filtered through hydrophilic membrane filter, followed by four times of ultrafiltration to afford ADC-7 (CADC (mg / mL): 3.19, volume (mL): 0.715, yield: 76.0%). The following characteristic values were obtained according to common characterization protocols for ADCs. SEC-DAR: 0.76, SEC purity: 83.43% and free linker payload (mol / mol%): -0.04%.Synthesis of ADCS.

[0318] According to general conjugation procedure for preparing ADCs, Trastuzumab (5 mg, 38.7 mg / mL, 1.0 eq.) in 50 mM PBS pH 8.0 was partially reduced by adding TCEP (2 mg / mL, 2.6 eq.) aqueous solution. The reduction was conducted at 20 °C for 1.5 hrs, and then conjugated with LP-3 (10 mg / mL, 7.5 eq.) in DMSO at 20 °C for 0.5 hour. The mixture was treated with dextran coated charcoal three times and filtered through hydrophilic membrane filter, and further purified by SEC chromatography with a fraction collector to afford ADC-8(CADC (mg / mL): 1.857, volume (mL): 0.300, yield: 19.4%). The following characteristic values were obtained according to common characterization protocols for ADCs. RP-DAR: 3.82, SEC purity: 84.9% and free linker payload (mol / mol%): 0.52%.Synthesis of ADC-9.

[0319] According to general conjugation procedure for preparing ADCs, Trastuzumab (3.0 mg, 38.7 mg / mL, 1.0 eq.) in 50 mM PBS pH 8.0 was partially reduced by adding TCEP (2 mg / mL, 1.0 eq.) aqueous solution. The reduction was conducted at 20 °C for 1.5 hrs, and then conjugated with LP-4 (10 mg / mL, 4.0 eq.) in DMSO at 20 °C for 0.5 hour. The mixture was purified by treating with dextran coated charcoal three times and filtered through hydrophilic membrane filter, followed by four times of ultrafiltration to afford ADC-9 (CADC (mg / mL): 2.53, volume (mL): 0.985, yield: 83.0%). The following characteristic values were obtained according to common characterization protocols for ADCs. SEC-DAR: 1.51, SEC purity: 81.55% and free linker payload (mol / mol%): -1.11%.Synthesis of ADC-10.

[0320] According to general conjugation procedure for preparing ADCs, Cirmtuzumab (3.0 mg, 4.21 mg / mL, 1.0 eq.) in 50 mM PBS pH 8.0 was partially reduced by adding TCEP (2 mg / mL, 1.0 eq.) aqueous solution. The reduction was conducted at 20 °C for 1.5 hrs, and then conjugated with LP-2 (10 mg / mL, 4.0 eq.) in DMSO at 20 °C for 0.5 hour. The mixture was purified by treating with dextran coated charcoal once and filtered through hydrophilic membrane filter, followed by five times of ultrafiltration to afford ADC-10 (CADC (mg / mL): 2.89, V (mL): 0.766, yield: 74.0%). The following characteristic values were obtained according to common characterization protocols for ADCs. SEC-DAR: 2.50, RP- DAR: 1.77, SEC purity: 95.73% and free linker payload (mol / mol%): 0.68%.Synthesis of ADC-11.

[0321] According to general conjugation procedure for preparing ADCs, Cirmtuzumab (1.0 mg, 4.21 mg / mL, 1.0 eq.) in 50 mM PBS pH 8.0 was partially reduced by adding TCEP (2 mg / mL, 3.2 eq.) aqueous solution. The reduction was conducted at 20 °C for 1.5 hrs, and then conjugated with LP-5 (10 mg / mL, 4.0 eq.) in DMSO at 20 °C for 0.5 hour. The mixture was purified by treating with dextran coated charcoal three times and filteredthrough hydrophilic membrane filter, followed by four times of ultrafiltration to afford ADC- 11 (CADC (mg / mL): 2.80, V (mL): 0.114, yield: 32.0%). The following characteristic values were obtained according to common characterization protocols for ADCs. SEC-DAR: 1.78, SEC purity: 85.39% and free linker payload (mol / mol%): 0.28%.Synthesis of ADC-12.

[0322] According to general conjugation procedure for preparing ADCs, Cirmtuzumab (1.0 mg, 4.21 mg / mL, 1.0 eq.) in 50 mM PBS pH 8.0 was partially reduced by adding TCEP (2 mg / mL, 2.4 eq.) aqueous solution. The reduction was conducted at 20 °C for1.5 hrs, and then conjugated with LP-6 (10 mg / mL, 4.0 eq.) in DMSO at 20 °C for 0.5 hour. The mixture was purified by treating with dextran coated charcoal three times and filtered through hydrophilic membrane filter, followed by four times of ultrafiltration to afford AT01- lA12D2.1-bl (CADC (mg / mL): 3.14, V (mL): 0.130, yield: 41.0%). The following characteristic values were obtained according to common characterization protocols for ADCs. SEC-DAR: 2.14, SEC purity: 94.35% and free linker payload (mol / mol%): -0.49%.Synthesis of ADC-13.

[0323] According to general conjugation procedure for preparing ADCs, Cirmtuzumab (3.0 mg, 4.21 mg / mL, 1.0 eq.) in 50 mM PBS pH 8.0 was partially reduced by adding TCEP (2 mg / mL, 3.0 eq.) aqueous solution. The reduction was conducted at 20 °C for1.5 hrs, and then conjugated with LP-7 (10 mg / mL, 12 eq.) in DMSO at 20 °C for 0.5 hour. The mixture was purified by treating with dextran coated charcoal three times and filtered through hydrophilic membrane filter, followed by four times of ultrafiltration to afford ADC- 13 (CADC (mg / mL): 2.09, V (mL): 0.875, yield: 61.0%). The following characteristic values were obtained according to common characterization protocols for ADCs. SEC-DAR: 3.48, SEC purity: 95.99% and free linker payload (mol / mol%): -0.31%.Synthesis of ADC-14.

[0324] According to general conjugation procedure for preparing ADCs, Cirmtuzumab (1.0 mg, 4.21 mg / mL, 1.0 eq.) in 50 mM PBS pH 8.0 was partially reduced by adding TCEP (2 mg / mL, 1.0 eq.) aqueous solution. The reduction was conducted at 20 °C for1.5 hrs, and then conjugated with LP-8 (10 mg / mL, 4 eq.) in DMSO at 20 °C for 0.5 hour. Themixture was purified by treating with dextran coated charcoal four times and filtered through hydrophilic membrane filter, followed by four times of ultrafiltration to afford ADC-14 (CADC (mg / mL): 2.49, V (mL): 0.128, yield: 32.0%). The following characteristic values were obtained according to common characterization protocols for ADCs. SEC-DAR: 0.47, SEC purity: 96.33% and free linker payload (mol / mol%): 0.95%.Synthesis of ADC-15.

[0325] According to general conjugation procedure for preparing ADCs, Cirmtuzumab (1.0 mg, 4.21 mg / mL, 1.0 eq.) in 50 mM PBS pH 8.0 was partially reduced by adding TCEP (2 mg / mL, 2.0 eq.) aqueous solution. The reduction was conducted at 20 °C for 1.5 hrs, and then conjugated with LP-9 (10 mg / mL, 4 eq.) in DMSO at 20 °C for 0.5 hour. The mixture was purified by treating with dextran coated charcoal two times and filtered through hydrophilic membrane filter, followed by three times of ultrafiltration to afford ADC-15 (CADC (mg / mL): 3.56, V (mL): 0.126, yield: 45.0%). The following characteristic values were obtained according to common characterization protocols for ADCs. SEC-DAR: 1.53, SEC purity: 81.16% and free linker payload (mol / mol%): 0.63%.Synthesis of ADC-16.

[0326] According to general conjugation procedure for preparing ADCs, Patritumab (1.0 mg, 3.77 mg / mL, 1.0 eq.) in 50 mM PBS pH 6.0 was partially reduced by adding TCEP (2 mg / mL, 2.0 eq.) aqueous solution. The reduction was conducted at 20 °C for 1.5 hrs, and then conjugated with LP-5 (10 mg / mL, 4.0 eq.) in DMSO at 20 °C for 0.5 hrs. The mixture was purified by treating with dextran coated charcoal, twice and filtered through a hydrophilic membrane filter, followed by three times ultrafiltration to afford ADC-16 (CADC (mg / mL): 5.12, V (mL): 0.070, yield: 35.8%). The following characteristic values were obtained according to common characterization protocols for ADCs. HIC-DAR: 1.32, SEC purity: 91.74% and free linker payload (mol / mol%): 0.37%.Synthesis of ADC- 17.

[0327] According to general conjugation procedure for preparing ADCs, Patritumab (1.0 mg, 3.77 mg / mL, 1.0 eq.) in 50 mM PBS pH 6.0 was partially reduced by adding TCEP (2 mg / mL, 2.0 eq.) aqueous solution. The reduction was conducted at 20 °C for1.5 hrs, then conjugated with LP-9 (10 mg / mL, 4.0 eq.) in DMSO at 20 °C for 0.5 hrs. The mixture was purified by treating with dextran coated charcoal and filtered through a hydrophilic membrane filter, followed by three times ultrafiltration to afford ADC-17 (CADC (mg / mL): 2.90,V (mL): 0.114, yield: 33%). The following characteristic values were obtained according to common characterization protocols for ADCs. HIC-DAR: 1.72, SEC-DAR: 1.39, SEC purity: 96.22% and free linker payload (mol / mol%): 0.14%.Synthesis of ADC- 18.

[0328] According to general conjugation procedure for preparing ADCs, Patritumab (1.0 mg, 3.77 mg / mL, 1.0 eq.) in 50 mM PBS pH 6.0 was partially reduced by adding TCEP (2 mg / mL, 2.5 eq.) aqueous solution. The reduction was conducted at 20 °C for1.5 hrs and conjugated with LP-14 (10 mg / mL, 4.0 eq.) in DMSO at 20 °C for 0.5 hrs. The mixture was purified by treating with dextran coated charcoal twice and filtered through a hydrophilic membrane filter, followed by three times ultrafiltration to afford ADC-18 (CADC (mg / ml): 3.71, V (mL): 0.108, yield: 40%). The following characteristic values were obtained according to common characterization protocols for ADCs. HIC-DAR: 1.67, SEC-DAR: 2.09, SEC purity: 98.61% and free linker payload (mol / mol%): not detected.Synthesis of ADC- 19.

[0329] According to general conjugation procedure for preparing ADCs, Sacituzumab (1.0 mg, 11.26 mg / mL, 1.0 eq.) in 50 mM PBS pH 6.0 was partially reduced by adding TCEP (2 mg / mL, 2.0 eq.) aqueous solution. The reduction was conducted at 20 °C for1.5 hrs, and then conjugated with LP-9 (10 mg / mL, 4.0 eq.) in DMSO at 20 °C for 0.5 hrs. The mixture was purified by treating with dextran coated charcoal and filtered through a hydrophilic membrane filter, followed by three times ultrafiltration to afford ADC-19 (CADC (mg / mL): 3.93,V (mL): 0.099, yield: 39%). The following characteristic values were obtained according to common characterization protocols for ADCs. HIC-DAR: 1.79, SEC-DAR: 1.48, SEC purity: 95.8% and free linker payload (mol / mol%): not detected.Synthesis of ADC-20.

[0330] According to general conjugation procedure for preparing ADCs, Sacituzumab (1.0 mg, 11.26 mg / mL, 1.0 eq.) in 50 mM PBS pH 6.0 was partially reduced byadding TCEP (2 mg / mL, 2.5 eq.) aqueous solution. The reduction was conducted at 20 °C for 1.5 hrs, and then conjugated with LP-14 (10 mg / mL, 4.0 eq.) in DMSO at 20 °C for 0.5 hrs. The mixture was purified by treating with dextran coated charcoal twice and filtered through a hydrophilic membrane filter, followed by three times ultrafiltration to afford ADC-20 (CADC (mg / mL): 3.70, V (mL): 0.092, yield: 34%). The following characteristic values were obtained according to common characterization protocols for ADCs. HIC-DAR: 1.45, SEC-DAR: 1.90, SEC purity: 97.61% and free linker payload (mol / mol%): not detected.Synthesis of ADC-21.

[0331] According to general conjugation procedure for preparing ADCs, Sacituzumab (0.7 mg, 3.09 mg / mL, 1.0 eq.) in PBS pH 7.4 was partially reduced by adding TCEP (1 mg / mL, 2.0 eq.) aqueous solution. The reduction was conducted at 20 °C for 1.5 hrs, and then conjugated with LP-5 (10 mg / mL, 4.0 eq.) in DMSO at 20 °C for 0.5 hrs. The mixture was purified by three times ultrafiltration to afford ADC-21 (CADC (mg / mL): 3.07, V (mL): 0.14, yield: 61.4%). The following characteristic values were obtained according to common characterization protocols for ADCs. HIC-DAR: 1.58, SEC purity: 94.6%.Synthesis of ADC-22.

[0332] According to general conjugation procedure for preparing ADCs, Sacituzumab (0.45 mg, 3.09 mg / mL, 1.0 eq.) in PBS pH 7.4 was partially reduced by adding TCEP (1 mg / mL, 2.0 eq.) aqueous solution. The reduction was conducted at 20 °C for 1.5 hrs, and then conjugated with LP-6 (10 mg / mL, 4.0 eq.) in DMSO at 20 °C for 0.5 hrs. The mixture was purified by three times ultrafiltration to afford ADC-22 (CADC (mg / mL): 2.80, V (mL): 0.11, yield: 68.4%).The following characteristic values were obtained according to common characterization protocols for ADCs. HIC-DAR: 1.11, SEC purity: 100%.Synthesis of ADC-23.

[0333] According to general conjugation procedure for preparing ADCs, Sacituzumab (0.45 mg, 3.09 mg / mL, 1.0 eq.) in PBS pH 7.4 was partially reduced by adding TCEP (1 mg / mL, 2.0 eq.) aqueous solution. The reduction was conducted at 20 °C for 1.5 hrs, and then conjugated with LP-8 (10 mg / mL, 4.0 eq.) in DMSO at 20 °C for 0.5 hrs. The mixture was purified by three times ultrafiltration to afford ADC-23 (CADC (mg / mL): 2.07, V (mL):0.14, yield: 64.4%). The following characteristic values were obtained according to common characterization protocols for ADCs. HIC-DAR: 0.78, SEC purity: 93.2%.Synthesis of ADC-24.

[0334] According to general conjugation procedure for preparing ADCs, Mirvetuximab (1.0 mg, 6.70 mg / mL, 1.0 eq.) in 50 mM PBS pH 6.0 was partially reduced by adding TCEP (2 mg / mL, 2.0 eq.) aqueous solution. The reduction was conducted at 20 °C for1.5 hrs, and then conjugated with LP-9 (10 mg / mL, 4.0 eq.) in DMSO at 20 °C for 0.5 hrs. The mixture was purified by treating with dextran coated charcoal and filtered through a hydrophilic membrane filter, followed by three times of ultrafiltration to afford ADC-24 (CADC (mg / mL): 3.62, V (mL): 0.094, yield: 34%). The following characteristic values were obtained according to common characterization protocols for ADCs. HIC-DAR: 1.89, SEC-DAR: 1.92, SEC purity: 95.38% and free linker payload (mol / mol%): 0.3%.Synthesis of ADC-25.

[0335] According to general conjugation procedure for preparing ADCs, Mirvetuximab (1.0 mg, 6.70 mg / mL, 1.0 eq.) in 50 mM PBS pH 6.0 was partially reduced by adding TCEP (2 mg / mL, 2.5 eq.) aqueous solution. The reduction was conducted at 20 °C for1.5 hrs, and then conjugated with LP-14 (10 mg / mL, 4.0 eq.) in DMSO at 20 °C for 0.5 hrs. The mixture was purified by treating with dextran coated charcoal twice and filtered through a hydrophilic membrane filter, followed by three times of ultrafiltration to afford ADC-25 (CADC (mg / mL): 3.88, V (mL): 0.098, yield: 38%).The following characteristic values were obtained according to common characterization protocols for ADCs. HIC-DAR: 1.55, SEC-DAR: 2.37, SEC purity: 98.41% and free linker payload (mol / mol%): not detected.Synthesis of ADC-26.

[0336] According to general conjugation procedure for preparing ADCs, Cetuximab (1.0 mg, 6.47 mg / mL, 1.0 eq.) in 50 mM PBS pH 6.0 was partially reduced by adding TCEP (2 mg / mL, 2.0 eq.) aqueous solution. The reduction was conducted at 20 °C for1.5 hrs, and then conjugated with LP-5 (10 mg / mL, 4.0 eq.) in DMSO at 20 °C for 0.5 hrs. The mixture was purified by treating with dextran coated charcoal twice and filtered through a hydrophilic membrane filter, followed by three times of ultrafiltration to afford ADC-25 (CADC(mg / mL): 1.79, V (mL): 0.095, yield: 17%). The following characteristic values were obtained according to common characterization protocols for ADCs. HIC-DAR: 1.18, SEC purity: 97.37% and free linker payload (mol / mol%): 0.91%.Synthesis of ADC-27.

[0337] According to general conjugation procedure for preparing ADCs, Cetuximab (1.0 mg, 6.47 mg / mL, 1.0 eq.) in 50 mM PBS pH 6.0 was partially reduced by adding TCEP (2 mg / mL, 2.0 eq.) aqueous solution. The reduction was conducted at 20 °C for1.5 hrs, and then conjugated with LP-9 (10 mg / mL, 4.0 eq.) in DMSO at 20 °C for 0.5 hrs. The mixture was purified by treating with dextran coated charcoal twice and filtered through a hydrophilic membrane filter, followed by four times of ultrafiltration to afford ADC-27 (CADC (mg / mL): 3.31, V (mL): 0.106, yield: 35%). The following characteristic values were obtained according to common characterization protocols for ADCs. HIC-DAR: 1.23, SEC-DAR: 1.14, SEC purity: 98.44% and free linker payload (mol / mol%): not detected.Synthesis of ADC-28.

[0338] According to general conjugation procedure for preparing ADCs, Cetuximab (1.0 mg, 6.47 mg / mL, 1.0 eq.) in 50 mM PBS pH 6.0 was partially reduced by adding TCEP (2 mg / mL, 2.5 eq.) aqueous solution. The reduction was conducted at 20 °C for1.5 hrs, and then conjugated with LP-9 (10 mg / mL, 4.0 eq.) in DMSO at 20 °C for 0.5 hrs. The mixture was purified by treating with dextran coated charcoal twice and filtered through hydrophilic membrane filter, followed by three times of ultrafiltration to afford ADC-28 (CADC (mg / mL): 3.67, V (mL): 0.095, yield: 35%). The following characteristic values were obtained according to common characterization protocols for ADCs. HIC-DAR: 1.32, SEC-DAR: 2.35, SEC purity: 98.92% and free linker payload (mol / mol%): not detected.Synthesis of ADC-29.

[0339] According to general conjugation procedure for preparing ADCs, Trastuzumab (1.0 mg, 38.9 mg / mL, 1.0 eq.) in 50 mM PBS pH 8.0 was partially reduced by adding TCEP (2 mg / mL, 1.8 eq.) aqueous solution. The reduction was conducted at 20 °C for1.5 hrs, and then conjugated with LP-5 (10 mg / mL, 4.0eq.) in DMSO at 20 °C for 0.5 hrs. The mixture was purified by treating with dextran coated charcoal four times and filtered through ahydrophilic membrane filter, followed by four times of ultrafiltration to afford ADC-29 (CADC (mg / mL): 12.21, V (mL): 0.05, yield: 61.05%). The following characteristic values were obtained according to common characterization protocols for ADCs. HIC-DAR: 1.04, SEC purity: 85.13% and free linker payload (mol / mol%): < 1%.Synthesis of ADC-30.

[0340] According to general conjugation procedure for preparing ADCs, Trastuzumab (1.0 mg, 38.9 mg / mL, 1.0 eq.) in 50 mM PBS pH 8.0 was partially reduced by adding TCEP (2 mg / mL, 1.8 eq.) aqueous solution. The reduction was conducted at 20 °C for 1.5 hrs, and then conjugated with LP-6 (10 mg / mL, 4 eq.) in DMSO at 20 °C for 0.5 hrs. The mixture was purified by treating with dextran coated charcoal four times and filtered through a hydrophilic membrane filter, followed by four times of ultrafiltration to afford ADC-30 (CADC (mg / mL): 14.96, V (mL): 0.04, yield: 59.84%). The following characteristic values were obtained according to common characterization protocols for ADCs. HIC-DAR: 1.21, SEC purity: 95.11% and free linker payload (mol / mol%): < 1%.Synthesis of ADC-31.

[0341] According to general conjugation procedure for preparing ADCs, Trastuzumab (1.0 mg, 38.9 mg / mL, 1.0 eq.) in 50 mM PBS pH 8.0 was partially reduced by adding TCEP (2 mg / mL, 1.8 eq.) aqueous solution. The reduction was conducted at 20 °C for 1.5 hrs, and then conjugated with LP-34 (10 mg / mL, 4.0 eq.) in DMSO at 20 °C for 0.5 hrs. The mixture was purified by treating with dextran coated charcoal four times and filtered through a hydrophilic membrane filter, followed by four times of ultrafiltration to afford ADC- 31 (CADC (mg / mL): 10.59, V (mL): 0.05, yield: 51.18%). The following characteristic values were obtained according to common characterization protocols for ADCs. HIC-DAR: 0.71, SEC purity: 98.99% and free linker payload (mol / mol%): < 1%.Synthesis of ADC-32.

[0342] According to general conjugation procedure for preparing ADCs, Trastuzumab (1.0 mg, 38.9 mg / mL, 1.0 eq.) in 50 mM PBS pH 7.4 was partially reduced by adding TCEP (10 mM, 1.8 eq.) aqueous solution. The reduction was conducted at 22 °C for 2.0hrs, and then conjugated with LP-7 (10 mg / mL, 4.0 eq.) in DMSO at 22 °C for 1.0 h. The mixture was purified by treating with dextran coated charcoal three times and filtered through a hydrophilic membrane filter, followed by twelve times of ultrafiltration to afford ADC-32 (CADC (mg / mL): 6.32, V (mL): 0.12, yield: 75.8%). The following characteristic values were obtained according to common characterization protocols for ADCs. HIC-DAR: 2.0, SEC purity: 99.95% and free linker payload (mol / mol%): not detected.Synthesis of ADC-33.

[0343] According to general conjugation procedure for preparing ADCs, Trastuzumab (1.0 mg, 38.9 mg / mL, 1.0 eq.) in 50 mM PBS pH 8.0 was partially reduced by adding TCEP (2 mg / mL, 1.8 eq.) aqueous solution. The reduction was conducted at 20 °C for 1.5 hrs, and then conjugated with LP-8 (10 mg / mL, 4.0 eq.) in DMSO at 20 °C for 0.5 hrs. The mixture was purified by treating with dextran coated charcoal four times and filtered through a hydrophilic membrane filter, followed by four times of ultrafiltration to afford ADC-33 (CADC (mg / mL): 13.00, V (mL): 0.045, yield: 58.50%). The following characteristic values were obtained according to common characterization protocols for ADCs. HIC-DAR: 1.01, SEC purity: 84.42% and free linker payload (mol / mol%): < 1%.Synthesis of ADC-34.

[0344] According to general conjugation procedure for preparing ADCs, Trastuzumab (1.0 mg, 38.7 mg / mL, 1.0 eq.) in 50 mM PBS pH 6.0 was partially reduced by adding TCEP (2 mg / mL, 2.0 eq.) aqueous solution. The reduction was conducted at 20 °C for 1.5 hrs, and then conjugated with LP-9 (10 mg / mL, 4.0 eq.) in DMSO at 20 °C for 0.5 hrs. The mixture was purified by treating with dextran coated charcoal twice and filtered through a hydrophilic membrane filter, followed by four times of ultrafiltration to afford ADC-34 (CADC (mg / mL): 3.92, V (mL): 0.097, yield: 38%). The following characteristic values were obtained according to common characterization protocols for ADCs. HIC-DAR: 1.52, SEC-DAR: 1.69, SEC purity: 97.17% and free linker payload (mol / mol%): not detected.Synthesis of ADC-35.

[0345] According to general conjugation procedure for preparing ADCs, Trastuzumab (1.0 mg, 38.9 mg / mL, 1.0 eq.) in 50 mM PBS pH 7.4 was partially reduced byadding TCEP (10 mM, 1.8 eq.) aqueous solution. The reduction was conducted at 22 °C for 2.0 hrs, and then conjugated with LP-12 (10 mg / mL, 4.0 eq.) in DMSO at 22 °C for 1 hr. The mixture was purified by treating with dextran coated charcoal three times and filtered through a hydrophilic membrane filter, followed by twelve times of ultrafiltration to afford ADC-35 (CADC (mg / mL): 3.15, V (mL): 0.16, yield: 50.4 %). The following characteristic values were obtained according to common characterization protocols for ADCs. HIC-DAR: 2.4, SEC purity: 94.72% and free linker payload (mol / mol%): 0.71 %.Synthesis of ADC-36.

[0346] According to general conjugation procedure for preparing ADCs, Trastuzumab (1.0 mg, 38.9 mg / mL, 1.0 eq.) in 50 mM PBS pH 7.4 was partially reduced by adding TCEP (10 mM, 1.8 eq.) aqueous solution. The reduction was conducted at 22 °C for 2.0 hrs, and then conjugated with LP-11 (10 mg / mL, 4.0 eq.) in DMSO at 22 °C for 1.0 hr. The mixture was purified by treating with dextran coated charcoal three times and filtered through a hydrophilic membrane filter, followed by twelve times of ultrafiltration to afford ADC-36 (CADC (mg / mL): 6.24, V (mL): 0.12, yield: 74.9 %). The following characteristic values were obtained according to common characterization protocols for ADCs. HIC-DAR: 1.9, SEC purity: 99.92% and free linker payload (mol / mol%): not detected.Synthesis of ADC-37.

[0347] According to general conjugation procedure for preparing ADCs, Trastuzumab (1.0 mg, 38.9 mg / mL, 1.0 eq.) in 50 mM PBS pH 7.4 was partially reduced by adding TCEP (10 mM, 1.8 eq.) aqueous solution. The reduction was conducted at 22 °C for 2.0 hrs, and then conjugated with LP-30 (10 mg / mL, 4.0 eq.) in DMSO at 22 °C for 1 h. The mixture was purified by treating with dextran coated charcoal three times and filtered through a hydrophilic membrane filter, followed by twelve times of ultrafiltration to afford ADC-37 (CADC (mg / mL): 1.24, V (mL): 0.3, yield: 37.2 %). The following characteristic values were obtained according to common characterization protocols for ADCs. HIC-DAR: 0.5, SEC purity: 99.95% and free linker payload (mol / mol%): 0.23 %.Synthesis of ADC-38.

[0348] According to general conjugation procedure for preparing ADCs, Trastuzumab (1.0 mg, 38.7 mg / mL, 1.0 eq.) in 50 mM PBS pH 6.0 was partially reduced by adding TCEP (2 mg / mL, 2.5 eq.) aqueous solution. The reduction was conducted at 20 °C for 1.5 hrs, and then conjugated with LP-14 (10 mg / mL, 4.0 eq.) in DMSO at 20 °C for 0.5 hrs. The mixture was purified by treating with dextran coated charcoal twice and filtered through a hydrophilic membrane filter, followed by three times of ultrafiltration to afford ADC-38 (CADC (mg / mL): 3.71, V (mL): 0.105, yield: 39%). The following characteristic values were obtained according to common characterization protocols for ADCs. HIC-DAR: 1.56, SEC-DAR: 3.04, SEC purity: 99.35% and free linker payload (mol / mol%): not detected.Synthesis of ADC-39.

[0349] According to general conjugation procedure for preparing ADCs, Trastuzumab (1.0 mg, 38.9 mg / mL, 1.0 eq.) in 50 mM PBS pH 7.4 was partially reduced by adding TCEP (lOmM, 1.8 eq.) aqueous solution. The reduction was conducted at 22 °C for 2.0 hrs, and then conjugated with LP-29 (10 mg / mL, 4.0 eq.) in DMSO at 22 °C for 1 h. The mixture was purified by treating with dextran coated charcoal three times and filtered through a hydrophilic membrane filter, followed by twelve times of ultrafiltration to afford ADC-39 (CADC (mg / mL): 6.56, V (mL): 0.11, yield: 72.2 %). The following characteristic values were obtained according to common characterization protocols for ADCs. HIC-DAR: 1.9, SEC purity: 96.8 % and free linker payload (mol / mol%): not detected.Synthesis of ADC-40.

[0350] According to general conjugation procedure for preparing ADCs, Trastuzumab (1.0 mg, 38.9 mg / mL, 1.0 eq.) in 50 mM PBS pH 7.4 was partially reduced by adding TCEP (2 mg / mL, 1.8 eq.) aqueous solution. The reduction was conducted at 22 °C for 2.0 hrs, and then conjugated with LP-33 (10 mg / mL, 4.0 eq.) in DMSO at 22 °C for 1 hr. The mixture was purified by treating with dextran coated charcoal three times and filtered through a hydrophilic membrane filter, followed by four times of ultrafiltration to afford ADC-40 (CADC (mg / mL): 8.6, V (mL): 0.09, yield: 77.4 %). The following characteristic values were obtainedaccording to common characterization protocols for ADCs. HIC-DAR: 0.5, SEC purity: 95.0% and free linker payload (mol / mol%): not detected.Synthesis of ADC-41.

[0351] According to general conjugation procedure for preparing ADCs, Trastuzumab (1.0 mg, 38.9 mg / mL, 1.0 eq.) in 50 mM PBS pH 7.4 was partially reduced by adding TCEP (10 mM, 1.8 eq.) aqueous solution. The reduction was conducted at 22 °C for 2.0 hrs, and then conjugated with LP-13 (10 mg / mL, 4.0 eq.) in DMSO at 22 °C for 1 hr. The mixture was purified by treating with dextran coated charcoal three times and filtered through a hydrophilic membrane filter, followed by twelve times of ultrafiltration to afford ADC-41 (CADC (mg / mL): 5.46, V (mL): 0.13, yield: 80.0 %). The following characteristic values were obtained according to common characterization protocols for ADCs. HIC-DAR: 1.73, SEC purity: 99.92 % and free linker payload (mol / mol%): 0.83 %.Synthesis of ADC-42.

[0352] According to general conjugation procedure for preparing ADCs, Trastuzumab (1.0 mg, 38.9 mg / mL, 1.0 eq.) in 50 mM PBS pH 7.4 was partially reduced by adding TCEP (2 mg / mL, 1.8 eq.) aqueous solution. The reduction was conducted at 22 °C for 2.0 hrs, and then conjugated with LP-23 (10 mg / mL, 4.0 eq.) in DMSO at 22 °C for Ihr. The mixture was purified by treating with dextran coated charcoal three times and filtered through a hydrophilic membrane filter, followed by four times of ultrafiltration to afford ADC-42 (CADC (mg / mL): 6.1, V (mL): 0.13, yield: 79.3%). The following characteristic values were obtained according to common characterization protocols for ADCs. HIC-DAR: 1.3, SEC purity: 96.50% and free linker payload (mol / mol%): not detected.Synthesis of ADC-43.

[0353] According to general conjugation procedure for preparing ADCs, Trastuzumab (1.0 mg, 38.9 mg / mL, 1.0 eq.) in 50 mM PBS pH 7.4 was partially reduced by adding TCEP (2 mg / mL, 1.8 eq.) aqueous solution. The reduction was conducted at 22 °C for 2.0 hrs, and then conjugated with LP-22 (10 mg / mL, 4.0 eq.) in DMSO at 22 °C for 1 h. The mixture was purified by treating with dextran coated charcoal three times and filtered through a hydrophilic membrane filter, followed by four times of ultrafiltration to afford ADC-43 (CADC(mg / mL): 7.6, V (mL): 0.11, yield: 83.6 %). The following characteristic values were obtained according to common characterization protocols for ADCs. HIC-DAR: 2.2, SEC purity: 88.7% and free linker payload (mol / mol%): not detected.Synthesis of ADC-44.

[0354] According to general conjugation procedure for preparing ADCs, Trastuzumab (1.0 mg, 38.9 mg / mL, 1.0 eq.) in 50 mM PBS pH 7.4 was partially reduced by adding TCEP (2 mg / mL, 1.8 eq.) aqueous solution. The reduction was conducted at 22 °C for 2.0 hrs, and then conjugated with LP-15 (10 mg / mL, 4.0 eq.) in DMSO at 22 °C for 1.0 hour. The mixture was purified by treating with dextran coated charcoal three times and filtered through a hydrophilic membrane filter, followed by four times of ultrafiltration to afford ADC- 44 (CADC (mg / mL): 3.3, V (mL): 0.25, yield: 82.5 %). The following characteristic values were obtained according to common characterization protocols for ADCs. HIC-DAR: 2.8, SEC purity: 99.4% and free linker payload (mol / mol%): not detected.Synthesis of ADC-45.

[0355] According to general conjugation procedure for preparing ADCs, Trastuzumab (1.0 mg, 38.9 mg / mL, 1.0 eq.) in 50 mM PBS pH 7.4 was partially reduced by adding TCEP (2 mg / mL, 1.8 eq.) aqueous solution. The reduction was conducted at 22 °C for 2.0 hrs, and then conjugated with LP-24 (10 mg / mL, 4.0 eq.) in DMSO at 22 °C for 1 h. The mixture was purified by treating with dextran coated charcoal three times and filtered through a hydrophilic membrane filter, followed by four times of ultrafiltration to afford ADC-45 (CADC (mg / mL): 7.3, V (mL): 0.11, yield: 80.3 %). The following characteristic values were obtained according to common characterization protocols for ADCs. HIC-DAR: 1.2, SEC purity: 78.8 % and free linker payload (mol / mol%): not detected.Synthesis of ADC-46.

[0356] According to general conjugation procedure for preparing ADCs, Trastuzumab (1.0 mg, 38.9 mg / mL, 1.0 eq.) in 50 mM PBS pH 7.4 was partially reduced by adding TCEP (2 mg / mL, 1.8 eq.) aqueous solution. The reduction was conducted at 22 °C for 2.0 hrs, and then conjugated with LP-25 (10 mg / mL, 4.0 eq.) in DMSO at 22 °C for 1 h. The mixture was purified by treating with dextran coated charcoal three times and filtered througha hydrophilic membrane filter, followed by four times of ultrafiltration to afford ADC-46 (CADC (mg / mL): 7.7, V (mL): 0.11, yield: 84.7 %). The following characteristic values were obtained according to common characterization protocols for ADCs. HIC-DAR: 1.0, SEC purity: 98.7 % and free linker payload (mol / mol%): not detected.Synthesis of ADC-47.

[0357] According to general conjugation procedure for preparing ADCs, Trastuzumab (1.0 mg, 38.9 mg / mL, 1.0 eq.) in 50 mM PBS pH 7.4 was partially reduced by adding TCEP (2 mg / mL, 1.8 eq.) aqueous solution. The reduction was conducted at 22 °C for 2.0 hrs, and then conjugated with LP-16 (10 mg / mL, 4.0 eq.) in DMSO at 22 °C for 1 h. The mixture was purified by treating with dextran coated charcoal three times and filtered through a hydrophilic membrane filter, followed by four times of ultrafiltration to afford ADC-47 (CADC (mg / mL): 7.6, V (mL): 0.11, yield: 83.6 %). The following characteristic values were obtained according to common characterization protocols for ADCs. HIC-DAR: 2.2, SEC purity: 97.9 % and free linker payload (mol / mol%): not detected.Synthesis of ADC-48.

[0358] According to general conjugation procedure for preparing ADCs, Trastuzumab (1.0 mg, 38.9 mg / mL, 1.0 eq.) in 50 mM PBS pH 7.4 was partially reduced by adding TCEP (2 mg / mL, 1.8 eq.) aqueous solution. The reduction was conducted at 22 °C for 2.0 hrs, and then conjugated with LP-18 (10 mg / mL, 4.0 eq.) in DMSO at 22 °C for 1 h. The mixture was purified by treating with dextran coated charcoal three times and filtered through a hydrophilic membrane filter, followed by four times of ultrafiltration to afford ADC-48 (CADC (mg / mL): 5.9, V (mL): 0.14, yield: 82.6 %). The following characteristic values were obtained according to common characterization protocols for ADCs. HIC-DAR: 2.1, SEC purity: 99.3 % and free linker payload (mol / mol%): not detected.Synthesis of ADC-49.

[0359] According to general conjugation procedure for preparing ADCs, Trastuzumab (1.0 mg, 38.9 mg / mL, 1.0 eq.) in 50 mM PBS pH 7.4 was partially reduced by adding TCEP (lOmM, 1.8 eq.) aqueous solution. The reduction was conducted at 22 °C for 2.0 hrs, and then conjugated with LP-19 (10 mg / mL, 4.0 eq.) in DMSO at 22 °C for 1 hr. Themixture was purified by treating with dextran coated charcoal three times and filtered through a hydrophilic membrane filter, followed by twelve times of ultrafiltration to afford ADC-49 (CADC (mg / mL): 5.78, V (mL): 0.11, yield: 63.6 %). The following characteristic values were obtained according to common characterization protocols for ADCs. HIC-DAR: 0.9, SEC purity: 99.39% and free linker payload (mol / mol%): not detected.Synthesis of ADC-50.

[0360] According to general conjugation procedure for preparing ADCs, Cirmtuzumab (3.0 mg, 4.21 mg / mL, 1.0 eq.) in 50 mM PBS pH 8.0 was partially reduced by adding TCEP (2 mg / mL, 1.0 eq.) aqueous solution. The reduction was conducted at 20 °C for 1.5 hrs, and then conjugated with LP-1 (10 mg / mL, 4.0 eq.) in DMSO at 20 °C for 0.5 hrs. The mixture was purified by treating with dextran coated charcoal twice and filtered through a hydrophilic membrane filter, followed by three times of ultrafiltration to afford ADC-50 (CADC (mg / mL): 1.99, V (mL): 1.08, yield: 71.3%). The following characteristic values were obtained according to common characterization protocols for ADCs. SEC-DAR: 1.60, SEC purity: 88.63% and free linker payload (mol / mol%): -0.17.Synthesis of ADC-51.

[0361] According to general conjugation procedure for preparing ADCs, Cirmtuzumab (3.0 mg, 4.21 mg / mL, 1.0 eq.) in 50 mM PBS pH 8.0 was partially reduced by adding TCEP (2 mg / mL, 1.0 eq.) aqueous solution. The reduction was conducted at 20 °C for 1.5 hrs, and then conjugated with LP-3 (10 mg / mL, 4.0 eq.) in DMSO at 20 °C for 0.5 hrs. The mixture was purified by treating with dextran coated charcoal twice and filtered through a hydrophilic membrane filter, followed by three times of ultrafiltration to afford ADC-51 (CADC (mg / mL): 2.31, V (mL): 0.776, yield: 59.6%). The following characteristic values were obtained according to common characterization protocols for ADCs. SEC-DAR: 0.69, RP- DAR: 1.32, SEC purity: 89.75% and free linker payload (mol / mol%): -2.09.Synthesis of ADC-52.

[0362] According to general conjugation procedure for preparing ADCs, Cirmtuzumab (3.0 mg, 4.21 mg / mL, 1.0 eq.) in 50 mM PBS pH 8.0 was partially reduced by adding TCEP (2 mg / mL, 1.0 eq.) aqueous solution. The reduction was conducted at 20 °C for1.5 hrs, and then conjugated with LP-4 (10 mg / mL, 4.0 eq.) in DMSO at 20 °C for 0.5 hrs. The mixture was purified by treating with dextran coated charcoal twice and filtered through a hydrophilic membrane filter, followed by three times of ultrafiltration to afford ADC-52 (CADC (mg / mL): 2.15, V (mL): 1.032, yield: 74.0%). The following characteristic values were obtained according to common characterization protocols for ADCs. SEC-DAR: 1.40, SEC purity: 87.71% and free linker payload (mol / mol%): -0.62.Synthesis of ADC-53.

[0363] According to general conjugation procedure for preparing ADCs, Cirmtuzumab (1.0 mg, 4.21 mg / mL, 1.0 eq.) in 50 mM PBS pH 8.0 was partially reduced by adding TCEP (2 mg / mL, 1.0 eq.) aqueous solution. The reduction was conducted at 20 °C for1.5 hrs, and then conjugated with LP-9 (10 mg / mL, 4.0 eq.) in DMSO at 20 °C for 0.5 hrs. The mixture was purified by treating with dextran coated charcoal four times and filtered through a hydrophilic membrane filter, followed by four times of ultrafiltration to afford ADC-53 (CADC (mg / mL): 1.93, V (mL): 0.155, yield: 30%). The following characteristic values were obtained according to common characterization protocols for ADCs. HIC-DAR: 0.47, SEC-DAR: 0.86, SEC purity: 95.31% and free linker payload (mol / mol%): 1.07.Synthesis of ADC-54.

[0364] According to general conjugation procedure for preparing ADCs, Cirmtuzumab (1.0 mg, 4.21 mg / mL, 1.0 eq.) in 50 mM PBS pH 8.0 was partially reduced by adding TCEP (2 mg / mL, 2.5 eq.) aqueous solution. The reduction was conducted at 20 °C for1.5 hrs, and then conjugated with LP-14 (10 mg / mL, 4.0 eq.) in DMSO at 20 °C for 0.5 hrs. The mixture was purified by treating with dextran coated charcoal twice and filtered through a hydrophilic membrane filter, followed by three times of ultrafiltration to afford ADC-54 (CADC (mg / mL): 3.08, V (mL): 0.097, yield: 30%). The following characteristic values were obtained according to common characterization protocols for ADCs. HIC-DAR: 1.78, SEC purity: 91.99% and free linker payload (mol / mol%): not detected.Synthesis of ADC-55.

[0365] According to general conjugation procedure for preparing ADCs, Trastuzumab (1.0 mg, 38.9 mg / mL, 1.0 eq.) in 50 mM PBS pH 7.4 was partially reduced by addingTCEP (10 mM, 15.0 eq.) aqueous solution. The reduction was conducted at 22 °C for 2.0 hrs, and then conjugated with LP-18 (10 mg / mL, 15.0 eq.) in DMSO at 22 °C for 1.0 hr. The mixture was purified by treating with dextran coated charcoal three times and filtered through a hydrophilic membrane filter, followed by 8 times ultrafiltration to afford ADC-55 (CADC (mg / mL): 5.4, V (mL): 0.09, yield: 50%). The following characteristic values were obtained according to common characterization protocols for ADCs. HIC-DAR: 8.0, SEC purity: 100% and free linker payload (mol / mol%): not detected.

Claims

Claims1. A compound of formula (I) or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof:wherein R1is a substituent having a negative inductive effect;- R2is -H or -X(CH2)pC(=0)o-i(CH2)q(C(RR2)2)o-i(X)o-iRR2with q and p being independently integers from 0 to 10, wherein X is independently O or NH, and RR2is independently -H or -Ci-4 alkyl;- R3is -H or -X(CH2)mC(=0)o-i(CH2)n(C(RR3)2)o-i(X)o-iRR3 with m and n being independently integers from 0 to 10, wherein X is independently O or NH, and RR3 is independently -H or -C1-4alkyl;R4is selected from -H , -CH2ORR4, -CH2NHRR4, and -CH2C(=O)ORR4, wherein RR4 is -H or -C1-4alkyl; and R5is -H or -C1-4alkyl; with the proviso that compounds of formula (I) having the following combination of R2,R3, R4and R5are excluded:- R2is -OCH3, R3is -OH, R4is -H and R5is -H.

2. The compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to claim 1, wherein R1is -OH or -C=N.

3. The compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to any of claims 1 or 2, whereinR2is -H, -ORR2, -OCH2CH2ORR2, -OCH2C(=O)ORR2or -NHRR2, wherein RR2is -H or -C1-4alkyl, preferably R2is -H, -OCH3, -OCH2CH2OH, -OCH2C(=O)OH or -NH2; and / or- R3is -H, -ORR3, -OCH2CH2NHRR3, -NHRR3, -NHC(=O)CH2ORR3or -NHC(=O)CH2NHRR3, wherein RR3is -H or -C1-4alkyl, preferably R3is -H, -OH, OCH2CH2NH2, -NH2, -NHC(=O)CH2OH or -NHC(=O)CH2NH2.

4. The compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to any of claims 1 to 3, whereinR4is -H, -CH2ORR4 or -CH2NHRR4, wherein RR4 is -H or -C1-4alkyl, preferably R4is -H; and / or R5is -H or -C1-4alkyl, preferably R5is -H.

5. The compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to any of claims 1 to 4, wherein- R1is -OH or -C=N;- R2is -H, -OCH3, -OCH2CH2OH, -OCH2C(=O)OH or -NH2;- R3is -H, -OH, -OCH2CH2NH2, -NH2, -NHC(=O)CH2OH or -NHC(=O)CH2NH2;R4is -H; and- R5is -H.

6. The compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to claim 1, wherein formula (I) is:

7. A compound of formula (VII) or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof:wherein R1is a substituent having a negative inductive effect;- R2is -H or -X(CH2)pC(=0)o-i(CH2)q(C(RR2)2)o-i(X)o-iRR2with q and p being independently integers from 0 to 10, wherein X is independently O or NH, and RR2is independently -H or -Ci-4 alkyl;- R3is -H or -X(CH2)mC(=0)o-i(CH2)n(C(RR3)2)o-i(X)o-iRR3 with m and n being independently integers from 0 to 10, wherein X is independently O or NH, and RR3 is independently -H or -C1-4alkyl; andR4is -H or -C1-4alkyl; with the proviso that compounds of formula (VII) having the following combination ofR2, R3and R4are excluded:R2is -H, R3is -H and R4is -H; andR2is -OCH3, R3is -H and R4is -H.

8. The compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to claim 7, wherein R1is -OH or -C=N.

9. The compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to any of claims 7 or 8, whereinR2is -H, -NHRR2or -NHC(=O)CH2ORR2, wherein RR2is -H or -C1-4alkyl, preferably R2is -H, -NH2or -NHC(=0)CH20H; and / orR3is -H or -NHRRS, wherein RR3 is -H or -C1-4alkyl, preferably R3is -H or -NH2.

10. The compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to any of claims 7 to 9, whereinR4is -H or -CH3.

11. The compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to any of claims 7 to 10, wherein R1is -OH or -C M:R2is -H, -NH2or -NHC(=O)CH2OH;R3is -H or -NH2; andR4is -H or -CH3.

12. The compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to claim 7, wherein formula (VII) is:; or13. A compound of formula (XIII) or a pharmaceutically acceptable salt, ester, solvate,wherein R1is a substituent having a negative inductive effect;- R2is -H or -X(CH2)pC(=0)o-i(CH2)q(C(RR2)2)o-i(X)o-iRR2with q and p being independently integers from 0 to 10, wherein X is independently O or NH, and RR2is independently -H or -Ci-4 alkyl;- Rs is -H or -X(CH2)mC(=0)o-i(CH2)n(C(RR3)2)o-i(X)o-iRR3 with m and n being independently integers from 0 to 10, wherein X is independently O or NH, and RR3 is independently -H or -Ci-4 alkyl; andR4is -H or -CH2NHRR4, wherein RR4 is -H or -C1-4alkyl.

14. The compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to claim 13, wherein R1is -OH or -C=N.

15. The compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to any of claims 13 or 14, whereinR2is -ORR2or -NHRR2, wherein RR2is -H or -C1-4alkyl, preferably R2is -OCH3or -NH2; and / or- R3is -H.

16. The compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to any of claims 13 to 15, whereinR4is -H.

17. The compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to any of claims 13 to 16, wherein- R1is -OH or -C=N;- R2is -OCH3or -NH2;R3is -H; andR4is -H.

18. The compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to claim 13, wherein formula (XIII) is:

19. An antibody-drug conjugate of formula (XIX):A L-D]Z(XIX) whereinAb denotes an antibody, an antigen-binding fragment, or an immunologically active portion thereof;L denotes a linker; andD denotes a compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof selected from the group consisting of trabectedin, lurbinectedin and the compounds according to any of claims 1 to 18, preferably a compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof according to any of claims 1 to 18; and whereinD covalently binds to L via nitrogen or oxygen present in D, and L covalently binds to Ab; and z is an integer from 1 to 20.

20. The antibody-drug conjugate according to claim 19, wherein z is an integer from 1 to 10, preferably 1 to 6, more preferably 2 to 4 and still more preferably 2 or 4.

21. The antibody-drug conjugate according to any of claims 19 or 20, wherein D covalently binds to L via nitrogen or oxygen present in any of R2, R3or R4, preferably in any of R2or R3.

22. The antibody-drug conjugate according to any of claims 19 to 21, wherein the antibody is an anti-RORl antibody, preferably Cirmtuzumab; an anti-TROP2 antibody, preferably Sacituzumab; an anti-HER2antibody, preferably Trastuzumab; an anti-HER3antibody, preferably Patritumab; an anti-FRoc antibody, preferably Mirvetuximab; or an anti-EGFR antibody, preferably Cetuximab.

23. The antibody-drug conjugate according to any of claims 19 to 22, wherein L has the following structure:and whereinT and U are independently spacer units, each having from 1 to 24 chain carbons, wherein t and u are independently 0 or 1, preferably t + u > 1; each A is independently an amino acid unit, wherein a is an integer from 0 to 12;H is a hydrophilic unit, wherein h is 0 or 1 ; andY is a conjugating group that covalently binds to Ab; wherein preferably the conjugating group Y covalently binds to a sulfur atom present in Ab.

24. The antibody-drug conjugate according to claim 23, wherein Y is such that L is one of the following:wherein, if present, Re is -H or -C1-4alkyl, preferably -H or -CH3.

25. The antibody-drug conjugate according to any of claims 23 or 24, wherein U is one of the following:; orwherein preferably n is an integer from 5 to 10, more preferably 6 to 8, and most preferably 7; and / orT is one of the following:wherein preferably n is an integer from 1 to 8, more preferably 1 to 6, and most preferably 2 or 5; orwherein preferably m is 1 and n is an integer from 2 to 8, more preferably 4 to 7, and most preferably 5 or 6; and / orH is derived from a PEGylated amino acid, preferably one of the following:wherein more preferably n is an integer from 5 to 10, still more preferably 6 to 8, and most preferably 7; orwherein more preferably n is an integer from 5 to 10, still more preferably 6 to 8, and most preferably 7; orH is the following:wherein preferably n is an integer from 2 to 8, more preferably 4 to 7, and most preferably 5 or 6.

26. The antibody-drug conjugate according to any of claims 23 to 25, wherein each A has the following structure:and wherein R? is independently selected from the group consisting of -H, -CH3, -C(H)(CH3)2, benzyl, p-hydroxybenzyl and -(CH2)3NHC(C=O)NH2; preferably R7 is independently selected from the group consisting of -H, -C(H)(CH3)2, benzyl and -(CH2)3NHC(C=O)NH2; and / or a is an integer from 1 to 10, more preferably from 1 to 5, still more preferably 1 to 4, and most preferably 2 or 4.

27. The antibody-drug conjugate according to claim 23, wherein H and h, and A and a, andU and u are such that L is one of the following:; or28. The antibody-drug conjugate according to any of claims 19 to 22, wherein L is such that Formula (XIX) is one of the following:; or29. The compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to any of claims 1 to 18 for use as a medicament.

30. The compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to claim 31 for use in the treatment of cancer, preferably ovarian cancer, stomach cancer or breast cancer.

31. The antibody-drug conjugate according to any of claims 19 to 28 for use as a medicament.

32. The antibody-drug conjugate according to claim 31 for use in the treatment of cancer, preferably ovarian cancer, stomach cancer or breast cancer.

33. A process for the preparation of an antibody-drug conjugate of general formula (XIX):Ab L-D]z(XIX) the method comprising conjugating an antibody, an antigen-binding fragment or an immunologically active portion thereof (Ab) to a compound (D) via a linker (L), whereinD is a compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof according to any of claims 1 to 18;L is a linker according to any of claims 19, or 23 to 27;D covalently binds to L via nitrogen or oxygen present in D, and L covalently binds to Ab; and z is an integer from 1 to 20.

34. The process according to claim 35, wherein z is an integer from 1 to 10, preferably 1 to 6, more preferably 2 to 4 and still more preferably 2 or 4.

35. The process according to any of claims 34 or 35, wherein the antibody is an anti-RORl antibody, preferably Cirmtuzumab; an anti-TROP2 antibody, preferably Sacituzumab; an anti-HER2antibody, preferably Trastuzumab; an anti-HER3antibody, preferably Patritumab; an anti-FRoc antibody, preferably Mirvetuximab; or an anti-EGFR antibody, preferably Cetuximab.

36. A pharmaceutical dosage form comprising a therapeutically effective amount of the compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to any of claims 1 to 18, or a therapeutically effective amount of the antibody-drug conjugate according to any of claims 19 to 28.

37. A method of treating cancer, wherein the method comprises administering to a subject a therapeutically effective amount of the compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to any of claims 1 to 18, a therapeutically effective amount of the antibody-drug conjugate according to any of claims 19 to 28, or the pharmaceutical dosage form according to claim 36.

38. The method of claim 37, wherein the cancer is ovarian cancer, stomach cancer or breast cancer.

Images