Topoisomerase inhibitors, antibody drug conjugate linkers, methods of making, and methods of use thereof

Abstract

Disclosed arc topoisomerase inhibitor compounds as cytotoxic agents and further as payloads for antibody-drug conjugates. Also disclosed are methods of making and use of the compounds in the treatment of proliferative diseases. Also disclosed are new linker chemistries for antibody-drug conjugates.

Description

[0001]NJB0009PCT TOPOISOMERASE INHIBITORS, ANTIBODY DRUG CONJUGATE LINKERS, METHODS OF MAKING, AND METHODS OF USE THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS 5 This application is related to, and claims the benefit of priority of, U.S. Provisional Patent Application No.63 / 636,499, filed April 19, 2024, and U.S. Provisional Patent Application No.63 / 636,489, filed April 19, 2024, the contents of which are incorporated herein by reference in their entirety for all purposes. 10 SEQUENCE LISTING The Instant Application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on April 18, 2025 and is named “NJB0009PCT” and is 2,195 bytes in size. The Sequence Listing does not go beyond the disclosure in the application as filed. 15 BACKGROUND DNA topoisomerases are essential proteins that control DNA topology. Type I topoisomerases catalyze the formation and re-ligation of single-stranded (ss) breaks and Type II catalyze the formation and re-ligation of double-stranded (ds) DNA breaks. Human DNA 20 topoisomerase I remains an important drug target for the treatment of cell proliferation diseases. Camptothecin is a well-known inhibitor of DNA topoisomerase I but suffers from solubility and stability issues. Derivatives and analogs of camptothecin, including irinotecan, topotecan, exatecan and its derivative deruxtecan, are also potent topoisomerase I inhibitors. Antibody drug conjugates (ADC) include monoclonal antibodies (mAbs) attached to 25 biologically active drugs using chemical linkers with labile bonds. The combination of cytotoxic active agents with the targeting capability of mAbs allows for the specific targeting of cancer cells. Thus, there remains a need for novel, potent topoisomerase inhibitors and payloads for the development of ADCs for the potential use in the treatment of proliferative diseases, 30 including use in cancer therapy. ADCs include mAbs attached to biologically active drug payloads using chemical spacer or linkers that can be cleavable (releasable) and non-cleavable (non-releasable). A non-cleavable linker is a linker that does not contain any biologically or chemically labile 1 NJB0009PCT bond. Two common non-cleavable linkers are maleimidocaproyl (Mc) and succinimidyl trans-4-(maleimidylmethyl)cyclohexane-1-carboxylate (SMCC). Cleavable linkers can vary by motif and release mechanism, but all have a bond that is designed to be broken at either a lower pH, with an enzyme, or in the presence of thiols. 5 One type of cleavable linker is the protease cleavable linker that contains a valine- citrulline-para-aminobenzyl-carbamate moiety (vc-PABC). This is a linker that allows the release of amine containing drug payloads. Many di-, tri-, and tetra-peptide sequences are cleaved by proteases and changing the sequence can facilitate the synthesis of the linker- payload and improve the properties of the ADC construct. There are also cleavable linkers 10 that get cleaved by glucuronidases that offer higher water solubility. Advantages of cleavable linkers are that they have good plasma stability and robust activity in a variety of cell lines and preclinical models. Another means of releasing a payload is to use the acidic environment found in the tumor microenvironment and in the lysosome. Hydrazones and carbonates are two commonly 15 used motifs for pH-sensitive linkers. Another type of cleavable linker contains reducible bonds. These are usually identified by their disulfide bond which breaks in half in the presence of cysteine or glutathione. There also remains a need for novel, improved ADC linker chemistries. 20 SUMMARY Disclosed, in various non-limiting embodiments are topoisomerase inhibitors, methods of making, use of the inhibitors as payloads for ADCs, preparation of the ADCs, intermediate compounds, and ADCs formulated into pharmaceutical formulations; methods 25 of use of the topoisomerase inhibitors, intermediate compounds, and ADCs for treatment of proliferative disorders, particularly in cancer therapy. Disclosed herein are compounds according to Formula (II), or a pharmaceutically acceptable salt thereof, 2 NJB0009PCT wherein R3is H, optionally substituted C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, or halogen; R4is H, optionally substituted C1-6 alkyl, C1-6 haloalkyl, HO-(C1-4 alkyl)-, H2N-(C1-4 alkyl)-, or Y4-Y3-Y2-Y1-; and 5 each X1, X2, X3, and X4individually is N or CR5with the proviso that no more than two of X1, X2, X3, and X4are N; each R5independently is H, optionally substituted C1-6alkyl, C1-6 haloalkyl, C1-6 alkoxy, halogen, optionally substituted C2-6 alkynyl, hydroxyl, amino, mono-C1-6alkylamine, di-C1-6alkylamine, COOH, HO-(C1-4alkyl)-, H2N-(C1-4alkyl)-, B(OH)2, or Y4-Y3-Y2-Y1-; 10 Y1is a bond, aryl, heteroaryl, or C1-4alkyl; Y2is a bond, O, S, N, or NH, wherein when Y2is N then N forms an optionally substituted C5-C7 heterocyclic with Y4; Y3is a bond or C=O; and Y4is H, hydroxyl, amino, mono-C1-6 alkylamine, di-C1-6 alkylamine, optionally 15 substituted C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C2-C6 alkanoyl, C1-6 alkylthio, COOH, optionally substituted C3-C8 cycloalkyl, optionally substituted C4-C8 cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C7heterocyclic, or an amino acid; or Y4together with Y2form an optionally substituted C5-C7heterocyclic; 20 wherein each optionally substituted group of R3, R4, R5, Y2, and Y4independently is optionally substituted with 1 or 2 substituents, wherein each substituent independently is hydroxyl, amino, COOH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C2-C6 alkanoyl, C1-6 alkylthio, cyano, halogen, nitro, mono-C1-6alkylamine, di-C1-6alkylamine, C3-C8cycloalkyl, C4-C8cycloalkenyl, aryl, heteroaryl, C3-C7 heterocyclic, C2-6 alkenyl, C2-6 alkynyl, H(C=O)-, HO- 25 (C1-2alkyl)-, H2N-(C1-2alkyl)-, HO-(C1-2alkyl)-(C=O)-, H2N-(C1-2alkyl)-(C=O)-, HO-(C1-2alkyl)-(C=O)-NH-, H2N-(C1-2 alkyl)-(C=O)-NH-, H2N-(C1-2 alkyl)-(C=O)-NH-(C1-2 alkyl)-O-, or B(OH)2. Disclosed herein are compounds according to Formula (I) or a pharmaceutically acceptable salt thereof, 3 NJB0009PCT R1N O O 2 N O ), each of R1and R2independently is H, optionally substituted C1-6alkyl, C1-6haloalkyl, C2-C6 alkanoyl, COOH, optionally substituted aryl, optionally substituted heteroaryl, HO-(C1- 54alkyl)-, or H2N-(C1-4alkyl)-; or R2is H and R1is Y4-Y3-Y2-Y1-; Y1is a bond, aryl, heteroaryl, or C1-4 alkyl; Y2is a bond, O, S, N, or NH, wherein when Y2is N then each of R1and R210 independently is (Y4-Y3)2-N-Y1-, or the N forms an optionally substituted C5-C7 heterocyclic with Y4; Y3is a bond or C=O; and Y4is H, hydroxyl, amino, mono-C1-6 alkylamine, di-C1-6 alkylamine, optionally substituted C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-C6alkanoyl, C1-6alkylthio, COOH, 15 optionally substituted C3-C8 cycloalkyl, optionally substituted C4-C8 cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C7heterocyclic, or an amino acid; or Y4together with Y2form an optionally substituted C5-C7heterocyclic; R3is H, optionally substituted C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or halogen; and 20 each X1, X2, X3, and X4individually is N or CR5with the proviso that no more than two of X1, X2, X3, and X4are N; each R5independently is H, optionally substituted C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, halogen, optionally substituted C2-6 alkynyl, hydroxyl, amino, mono-C1-6 alkylamine, di-C1-6 alkylamine, COOH, HO-(C1-4 alkyl)-, H2N-(C1-4 alkyl)-, B(OH)2, or Y4-Y3-Y2-Y1-; 25 wherein each optionally substituted group of R1, R2, R3, R5, Y2, and Y4independently is optionally substituted with 1 or 2 substituents, wherein each substituent independently is hydroxyl, amino, COOH, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-C6alkanoyl, C1-6alkylthio, cyano, halogen, nitro, mono-C1-6 alkylamine, di-C1-6 alkylamine, C3-C8 cycloalkyl, C4-C8 4 NJB0009PCT cycloalkenyl, aryl, heteroaryl, C3-C7heterocyclic, C2-6alkenyl, C2-6alkynyl, H(C=O)-, HO- (C1-2alkyl)-, H2N-(C1-2alkyl)-, HO-(C1-2alkyl)-(C=O)-, H2N-(C1-2alkyl)-(C=O)-, HO-(C1-2alkyl)-(C=O)-NH-, H2N-(C1-2 alkyl)-(C=O)-NH-, H2N-(C1-2 alkyl)-(C=O)-NH-(C1-2 alkyl)-O-, or B(OH)2. 5 Further disclosed herein are compounds of Formula (A) or Formula (B) PL*-L-RXFormula (A) (PL*-L)m-Ab Formula (B) wherein L is a linking group; PL* is a structure of Formula (I) or Formula (II) or a structure found in Table 1, covalently attached to L through one of R1, R2, R4, or R5; RXis a reactive 10 group suitable for forming a covalent bond to an antibody or antibody fragment; Ab is an antibody or antibody fragment; and m is 1, 2, 3, 4, 5, 6, 7, or 8. Disclosed, in various non-limiting embodiments is a compound comprising one or more repeat structures of the formula O H N O N n 15 rom 1 to 32; specifically an integer from 2 to 32; and more specifically n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, or 32. In a further embodiment, a compound comprises one or more repeat structures of the formula O H N 20nwherein n is an integer from 1 to 32; specifically an integer from 2 ally n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, or 32; a drug payload; and optionally a conjugation moiety. 25 In yet a further embodiment, a compound comprises one or more repeat structures of the formula 5 NJB0009PCT O H N O N H n wherein n is an integer from 1 to 32; specifically an integer from 2 ally n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, or 32; a drug payload; and 5 an antibody or antibody fragment. Further disclosed are compounds according to Formula (III) OHL1N RXFormula (III) wherei or a linking group; L2is a bond or a linking group; RXis a reactive group suitable for forming a covalent bond to an antibody or antibody 10 fragment; and n is an integer from 1 to 32, specifically 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, or 32. Disclose are compounds according to Formula (IV) OHV) where ond or a linking group; 15 Ab is an antibody or antibody fragment; n is an integer from 1 to 32, specifically 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, or 32; and m is 1, 2, 3, 4, 5, 6, 7, or 8. Other embodiments comprise methods of use of the compounds for treatment of proliferative disorders, particularly in cancer therapy. 20 In yet another embodiment, a method of treating a proliferative disease including a cancer, comprises administering to a patient in need thereof a compound described herein. These and other features and characteristics are more particularly described below. BRIEF DESCRIPTION OF THE DRAWINGS 25 The features and advantages of the invention are apparent from the following description taken in conjunction with the accompanying drawings in which: 6 NJB0009PCT FIG.1 illustrates a schematic for the Proposed Synthesis of Diverse Ring-Up Payload Class With B-Ring Handle. FIG.2 illustrates a schematic for the Proposed Synthesis of Ring-Down Payload Class With B-Ring Handle. 5 FIG.3 illustrates a schematic for the Proposed Synthesis of Diverse Ring-Up Payload Class With Ring-Up Handle. FIG.4 illustrates contains a table of Linker Payload Structures Containing G* Motif PLL48-PLL72. FIG.5 illustrates a schematic for the preparation of ADC (Trastuzumab-PLL 10 Conjugation). FIG.6 illustrates the results of in vivo efficacy testing of ADCs (T-PLL) versus control. DETAILED DESCRIPTION 15 Disclosed are topoisomerase inhibitors, derivatives, and antibody drug conjugates of the novel compounds. The compounds, derivatives, and antibody drug conjugates find use as antiproliferative agents specifically as anticancer agents, optionally in the form of cytotoxic payloads for ADCs. A compound of Formula (I), Formula (II), or a pharmaceutically acceptable salt 20 thereof, R1N O O O Formula (I), 7 NJB0009PCT O O O Formula (II) each of R1and R2independently is H, optionally substituted C1-6 alkyl, C1-6 haloalkyl, C2-C6alkanoyl, COOH, optionally substituted aryl, optionally substituted heteroaryl, HO-(C1-5 4 alkyl)-, or H2N-(C1-4 alkyl)-; or R2is H and R1is Y4-Y3-Y2-Y1-; Y1is a bond, aryl, heteroaryl, or C1-4alkyl; Y2is a bond, O, S, N, or NH, wherein when Y2is N then each of R1and R210 independently is (Y4-Y3)2-N-Y1-, or the N forms an optionally substituted C5-C7 heterocyclic with Y4; Y3is a bond or C=O; and Y4is H, hydroxyl, amino, mono-C1-6alkylamine, di-C1-6alkylamine, optionally substituted C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C2-C6 alkanoyl, C1-6 alkylthio, COOH, 15 optionally substituted C3-C8cycloalkyl, optionally substituted C4-C8cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C7 heterocyclic, or an amino acid; or Y4together with Y2form an optionally substituted C5-C7 heterocyclic; R3is H, optionally substituted C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or halogen; 20 R4is H, optionally substituted C1-6 alkyl, C1-6 haloalkyl, HO-(C1-4 alkyl)-, H2N-(C1-4 alkyl)-, or Y4-Y3-Y2-Y1-; and each X1, X2, X3, and X4individually is N or CR5with the proviso that no more than two of X1, X2, X3, and X4are N; each R5independently is H, optionally substituted C1-6 alkyl, C1-6haloalkyl, C1-6alkoxy, halogen, optionally substituted C2-6alkynyl, hydroxyl, amino, 25 mono-C1-6 alkylamine, di-C1-6 alkylamine, COOH, HO-(C1-4 alkyl)-, H2N-(C1-4 alkyl)-, B(OH)2, or Y4-Y3-Y2-Y1-; 8 NJB0009PCT wherein each optionally substituted group of R1, R2, R3, R4, R5, Y2, and Y4independently is optionally substituted with 1 or 2 substituents, wherein each substituent independently is hydroxyl, amino, COOH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C2-C6 alkanoyl, C1-6alkylthio, cyano, halogen, nitro, mono-C1-6alkylamine, di-C1-6alkylamine, C3- 5 C8 cycloalkyl, C4-C8 cycloalkenyl, aryl, heteroaryl, C3-C7 heterocyclic, C2-6 alkenyl, C2-6 alkynyl, H(C=O)-, HO-(C1-2alkyl)-, H2N-(C1-2alkyl)-, HO-(C1-2alkyl)-(C=O)-, H2N-(C1-2alkyl)-(C=O)-, HO-(C1-2 alkyl)-(C=O)-NH-, H2N-(C1-2 alkyl)-(C=O)-NH-, H2N-(C1-2 alkyl)- (C=O)-NH-(C1-2alkyl)-O-, or B(OH)2. In an embodiment, R3is H or halogen, specifically R3is F. 10 In an embodiment, each of X1, X2, X3, and X4is CR5. In an embodiment X2is N. In an embodiment X3is N. In an embodiment X4is N.In an embodiment, X1and X4are N. In an embodiment, Y4-Y3-Y2-Y1- is HO-(C1-4 alkyl)-, H2N-(C1-4 alkyl)-, HO-(C1-2 15 alkyl)-(C=O)-NH-, H2N-(C1-2 alkyl)-(C=O)-NH-, H2N-(C1-2 alkyl)-(C=O)-NH-(C1-2 alkyl)-O-, or H2N-(C1-2 alkyl)-(C=O)-NH-(C1-2 alkyl)-O-(C1-2 alkyl)-. In an embodiment, the compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein R2is H and R1is optionally substituted C1-6 alkyl, C1-6 haloalkyl, C2-C6 alkanoyl, COOH, optionally substituted aryl, optionally substituted heteroaryl, HO-(C1-420 alkyl)-, or H2N-(C1-4 alkyl)-; or R1is Y4-Y3-Y2-Y1-, wherein Y1is a bond, aryl, heteroaryl, or C1-3alkyl; Y2is a bond, O, S, N, or NH, wherein when Y2is N then R1is (Y4-Y3)2-N-Y1-, or the 25 N forms an optionally substituted C5-C7heterocyclic with Y4; Y3is a bond or C=O; and Y4is H, hydroxyl, amino, mono-C1-6 alkylamine, di-C1-6 alkylamine, optionally substituted C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-C6alkanoyl, C1-6alkylthio, COOH, optionally substituted C3-C8 cycloalkyl, optionally substituted C4-C8 cycloalkenyl, optionally 30 substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C7heterocyclic, or an amino acid; or Y4together with Y2form an optionally substituted C5-C7heterocyclic; wherein each optionally substituted group of R1, Y2, and Y4independently is optionally substituted with 1 or 2 substituents, wherein each substituent independently is 9 NJB0009PCT hydroxyl, amino, COOH, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-C6alkanoyl, C1-6alkylthio, cyano, halogen, nitro, mono-C1-6alkylamine, di-C1-6alkylamine, C3-C8cycloalkyl, C4-C8cycloalkenyl, aryl, heteroaryl, C3-C7 heterocyclic, C2-6 alkenyl, C2-6 alkynyl, H(C=O)-, HO- (C1-2alkyl)-, H2N-(C1-2alkyl)-, HO-(C1-2alkyl)-(C=O)-, H2N-(C1-2alkyl)-(C=O)-, HO-(C1-25 alkyl)-(C=O)-NH-, H2N-(C1-2 alkyl)-(C=O)-NH-, H2N-(C1-2 alkyl)-(C=O)-NH-(C1-2 alkyl)-O-, or B(OH)2; and further wherein any O, S, or N is optionally protected with a suitable protecting group. In an embodiment, the compound of Formula (I) or a pharmaceutically acceptable salt 10 thereof, R1is optionally substituted C1-6alkyl, C1-6haloalkyl, C2-C6alkanoyl, COOH, optionally substituted aryl, optionally substituted heteroaryl, HO-(C1-4 alkyl)-, H2N-(C1-4 alkyl)-, or Y4-Y3-Y2-Y1-; R2is H; R3is H or halogen, specifically R3is F; each of X1, X2, X3, and X4is CR5. Further within this embodiment, R1is substituted C1-6 alkyl or substituted aryl specifically phenyl, wherein the substitution is hydroxyl, amino, or H2N-(C1-2 alkyl)-(C=O)- 15 NH-; and R5is H. In an embodiment, the compound of Formula (I) or a pharmaceutically acceptable salt thereof, R1is optionally substituted C1-6alkyl, C1-6haloalkyl, C2-C6alkanoyl, COOH, optionally substituted aryl, optionally substituted heteroaryl, HO-(C1-4 alkyl)-, H2N-(C1-4 alkyl)-, or Y4-Y3-Y2-Y1-; R2is H; R3is H or halogen, specifically R3is F; one of X1, X2, X3,20 and X4is N and the remainder are CR5. Further within this embodiment, R1is substituted C1- 6 alkyl or substituted aryl specifically phenyl, wherein the substitution is hydroxyl, amino, or H2N-(C1-2 alkyl)-(C=O)-NH-; and R5is H. In an embodiment, X1is N. In an embodiment X2is N. In an embodiment X3is N. In an embodiment X4is N. In an embodiment, the compound of Formula (II) or a pharmaceutically acceptable 25 salt thereof, wherein R3is H, optionally substituted C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, or halogen; R4is H, optionally substituted C1-6 alkyl, C1-6 haloalkyl, HO-(C1-4 alkyl)-, H2N-(C1-4 alkyl)-, or Y4-Y3-Y2-Y1-; Y1is a bond, aryl, heteroaryl, or C1-4 alkyl; 30 Y2is a bond, O, S, N, or NH, wherein when Y2is N then the N forms an optionally substituted C5-C7 heterocyclic with Y4; Y3is a bond or C=O; and Y4is H, hydroxyl, amino, mono-C1-6 alkylamine, di-C1-6 alkylamine, optionally substituted C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-C6alkanoyl, C1-6alkylthio, COOH, 10 NJB0009PCT optionally substituted C3-C8cycloalkyl, optionally substituted C4-C8cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C7heterocyclic, or an amino acid; or Y4together with Y2form an optionally substituted C5-C7heterocyclic; 5 each X1, X2, X3, and X4individually is N or CR5with the proviso that no more than two of X1, X2, X3, and X4are N; each R5independently is H, optionally substituted C1-6alkyl, C1-6 haloalkyl, C1-6 alkoxy, halogen, optionally substituted C2-6 alkynyl, HO-(C1-4 alkyl)-, H2N-(C1-4alkyl)-, B(OH)2, or Y4-Y3-Y2-Y1-; wherein each optionally substituted group of R3, R4, R5, Y2, and Y4independently is 10 optionally substituted with 1 or 2 substituents, wherein each substituent independently is hydroxyl, amino, COOH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C2-C6 alkanoyl, C1-6 alkylthio, cyano, halogen, nitro, mono-C1-6 alkylamine, di-C1-6 alkylamine, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, aryl, heteroaryl, C3-C7 heterocyclic, C2-6 alkenyl, C2-6 alkynyl, H(C=O)-, HO- (C1-2 alkyl)-, H2N-(C1-2 alkyl)-, HO-(C1-2 alkyl)-(C=O)-, H2N-(C1-2 alkyl)-(C=O)-, HO-(C1-2 15 alkyl)-(C=O)-NH-, H2N-(C1-2 alkyl)-(C=O)-NH-, H2N-(C1-2 alkyl)-(C=O)-NH-(C1-2 alkyl)-O-, or B(OH)2; and further wherein any O, S, or N is optionally protected with a suitable protecting group. In an embodiment, the compound of Formula (II) or a pharmaceutically acceptable 20 salt thereof, wherein R3is H or halogen, specifically R3is F; R4is H or optionally substituted C1-6alkyl; each of X1, X2, X3, and X4is CR5; and each R5independently is H, optionally substituted C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, halogen, optionally substituted C2-6 alkynyl, hydroxyl, amino, mono-C1-6alkylamine, di-C1-6alkylamine, COOH, HO-(C1-4alkyl)-, H2N- (C1-4 alkyl)-, B(OH)2, or Y4-Y3-Y2-Y1-. Further within this embodiment, one, two, or three of 25 X1, X2, X3, and X4is CH, specifically three, and the fourth is CR5where R5is optionally substituted C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, halogen, optionally substituted C2-6 alkynyl, hydroxyl, amino, mono-C1-6 alkylamine, di-C1-6 alkylamine, COOH, HO-(C1-4 alkyl)-, H2N- (C1-4alkyl)-, B(OH)2, or Y4-Y3-Y2-Y1-. In an embodiment, the compound of Formula (II) or a pharmaceutically acceptable 30 salt thereof, wherein R3is H or halogen, specifically R3is F; R4is H or optionally substituted C1-6 alkyl; one or two of X1, X2, X3, and X4is N and the remainder are CR5; and each R5independently is H, optionally substituted C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, halogen, optionally substituted C2-6 alkynyl, hydroxyl, amino, mono-C1-6 alkylamine, di-C1-6 alkylamine, COOH, HO-(C1-4alkyl)-, H2N-(C1-4alkyl)-, B(OH)2, or Y4-Y3-Y2-Y1-. Further 11 NJB0009PCT within this embodiment, one or two of X1, X2, X3, and X4is N and the remainder are CR5wherein one of the R5is not H but is optionally substituted C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, halogen, optionally substituted C2-6 alkynyl, hydroxyl, amino, mono-C1-6 alkylamine, di-C1-6alkylamine, COOH, HO-(C1-4alkyl)-, H2N-(C1-4alkyl)-, B(OH)2, or Y4-Y3-Y2-Y1-. 5 In an embodiment, the compound of Formula (II) or a pharmaceutically acceptable salt thereof, wherein R3is H or halogen, specifically R3is F; R4is H or optionally substituted C1-6 alkyl; each of X1, X2, X3, and X4is CR5; and each R5independently is H, optionally substituted C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, halogen, optionally substituted C2-6alkynyl, hydroxyl, amino, mono-C1-6 alkylamine, di-C1-6 alkylamine, COOH, HO-(C1-4 alkyl)-, H2N- 10 (C1-4alkyl)-, B(OH)2, or Y4-Y3-Y2-Y1-; further wherein one of R5is amino, HO-(C1-4alkyl)-, H2N-(C1-4 alkyl)-, HO-(C1-2 alkyl)-(C=O)-NH-, H2N-(C1-2 alkyl)-(C=O)-NH-, H2N-(C1-2 alkyl)-(C=O)-NH-(C1-2 alkyl)-O-(C1-2 alkyl)-, B(OH)2, or phenyl substituted with amino, HO- (C1-4 alkyl)-, H2N-(C1-4 alkyl)-, HO-(C1-2 alkyl)-(C=O)-NH-, H2N-(C1-2 alkyl)-(C=O)-NH-, H2N-(C1-2 alkyl)-(C=O)-NH-(C1-2 alkyl)-O-(C1-2 alkyl)-, or B(OH)2. 15 In an embodiment, the compound of Formula (I), Formula (II), or a pharmaceutically acceptable salt thereof, wherein each optionally substituted aryl or optionally substituted heteroaryl of R1, R2, and Y4independently is substituted with amino or H2N-(C1-2alkyl)- (C=O)-NH-. In an embodiment, the compound of Formula (I), Formula (II), or a pharmaceutically 20 acceptable salt thereof, wherein Y1is aryl or heteroaryl; Y2is a bond; Y3is a bond; and Y4is amino (-NH2). In an embodiment, the compound of Formula (I), Formula (II), or a pharmaceutically acceptable salt thereof comprises an aryl amine or heteroaryl amine moiety. Further disclosed are compounds of Formula (A) or Formula (B) 25 PL*-L-RXFormula (A) (PL*-L)m-Ab Formula (B) wherein L is a linking group; PL*is a structure of Formula (I) or Formula (II) or a structure found in Table 1, 30 covalently attached to L through one of R1, R2, R4, or R5; RXis a reactive group suitable for forming a covalent bond to an antibody or antibody fragment; Ab is an antibody or antibody fragment; and m is 1, 2, 3, 4, 5, 6, 7, or 8. 12 NJB0009PCT In an embodiment, a compound of Formula (A) or Formula (B) wherein PL* comprises an aryl amine or heteroaryl amine moiety covalently attached to L through the amine group. In a further embodiment, PL* comprises an aryl amine or heteroaryl amine moiety covalently attached to L through the amine group and the linking group is cleavable. 5 In an embodiment L, the linking group, is a bond or a group containing 1 to about 250 non-hydrogen atoms including C, N, O, S, halogen, or a combination thereof; further wherein L can optionally include one or more groups including an ether, thioether, amide, carbonyl, ester, carbonate, carbamate, urea, one or more repeat structures of the formula O H N O N n 10 where o 32; specifically an integer from 2 to 32; and more specifically n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, or 32; or a combination thereof. In a further embodiment, L comprises an ethylene glycol unit, specifically about 2 to about 25 repeating ethylene glycol units, more specifically about 5 to about 10 repeating 15 ethylene glycol units; an amino acid unit, specifically 1 to about 12 amino acid units, more specifically about 2 to about 10 amino acid units, and yet more specifically about 4 to about 8 amino acid units; or a combination thereof. Within the amino acid groups of L, individually each amino acid unit can be arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine, 20 cysteine, selenocysteine, glycine, proline, alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, tryptophan, or citrulline (Cit). The amino acid unit may be enzymatically cleaved by one or more enzymes, including a tumor- associated protease. In an embodiment, the amino acid unit is alanine-valine, valine-alanine, valine-citrulline, or citrulline-valine. 25 In an embodiment, the L linking group comprises amino acid sequence GGFG (SEQ ID NO:1). In an embodiment, RXof Formula (A) is an alkyne, amine, aminooxy (-O-NH2), azide, dibromopyridazinedione, 2,5-dioxopyrrolidin-1-yl formate, a disulfide, 13 NJB0009PCT dithiophenolmaleimide, a haloacetamide, hydrazino, N-hydroxysuccinimide ester, maleimide, O a monosulfone, a pentafluorophenyl ester, thiol . Ab is an antibody or antibody fragment et cell. “Antibody” as herein includes monoclonal antibodies, polyclonal antibodies, dimers, 5 multimers, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments that exhibit the desired biological activity. Antibodies can be murine, human, humanized, chimeric, or derived from other species. An antibody includes a full-length immunoglobulin molecule or an immunologically active portion of a full-length immunoglobulin molecule, i.e., a molecule that contains an antigen binding site that immunospecifically binds an antigen 10 of a target of interest or part thereof, such targets including but not limited to, cancer cell or cells that produce autoimmune antibodies associated with an autoimmune disease. The immunoglobulin can be of any type (e.g. IgG, IgE, IgM, IgD, and IgA), class (e.g. IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) or subclass of immunoglobulin molecule. The immunoglobulins can be derived from any species, including human, murine, or rabbit origin. 15 In an embodiment, the antibody-drug conjugate of Formula (B) has a drug loading of drug, e.g. compound of Formula (I) or (II), to antibody / antibody fragment (Ab) of from 1 to about 8, specifically about 2 to about 6, more specifically about 3 to about 4. Disclosed herein are pharmaceutical formulations comprising a compound of Formula (I) or (II), compound of Formula (A), or compound of Formula (B), specifically an antibody- 20 drug conjugate of Formula (B). The compound of Formula (I), Formula (II), compound of Formula (A), or Formula (B), are cytotoxic compounds suitable for use to treat proliferative diseases, specifically as anticancer agents. The compounds are described using standard nomenclature. Unless defined 25 otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this disclosure belongs. Unless clearly contraindicated by the context each compound name includes the free acid or free base form of the compound as well hydrates of the compound and all pharmaceutically acceptable salts of the compound. 14 NJB0009PCT The terms “Formula (I),” “Formula (II),” “Formula (A),” and “Formula (B)”, etc., as used herein, encompass all compounds that satisfy Formula (I), Formula (A), and Formula (B), including any enantiomers, racemates and stereoisomers, as well as all pharmaceutically acceptable salts and radioisotopes of such compounds. The phrases “a compound of Formula 5 (I),” “a compound of Formula (II),” “a compound of Formula (A),” and “a compound of Formula (B)” include all subgeneric groups of Formula (I), Formula (II), Formula (A), and Formula (B), and so forth, as well as all forms of such compounds, including salts and hydrates, unless clearly contraindicated by the context in which this phrase is used. Formula (I) and Formula (II) include all subformulae thereof. In certain situations, 10 the compounds of Formula (I) and Formula (II) may contain one or more asymmetric elements such as stereogenic centers, stereogenic axes and the like, e.g. asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms. These compounds can be, for example, racemates or optically active forms. For compounds with two or more asymmetric elements, these compounds can additionally be mixtures of diastereomers. For 15 compounds having asymmetric centers, it should be understood that all of the optical isomers and mixtures thereof are encompassed. In these situations, single enantiomers, i.e., optically active forms, can be obtained by asymmetric synthesis, synthesis from optically pure precursors, or by resolution of the racemates. Resolution of the racemates can also be accomplished, for example, by conventional methods such as crystallization in the presence 20 of a resolving agent, or chromatography, using, for example, a chiral high performance liquid chromatography (HPLC) column. Where a compound exists in various tautomeric forms, the compound is not limited to any one of the specific tautomers, but rather includes all tautomeric forms. All isotopes of atoms occurring in the present compounds are contemplated. Isotopes 25 include those atoms having the same atomic number but different mass numbers. By way of general example, and without limitation, isotopes of hydrogen include tritium and deuterium; isotopes of carbon include11C,13C, and14C; and an isotope of fluorine includes18F. A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -(CH2)C3-C8cycloalkyl is attached through carbon 30 of the methylene (CH2) group. “Alkanoyl” is an alkyl group as defined herein, covalently bound to the group it substitutes by a keto (-(C=O)-) bridge. Alkanoyl groups have the indicated number of carbon atoms, with the carbon of the keto group being included in the numbered carbon atoms. For example a C2alkanoyl group is an acetyl group having the formula CH3(C=O)-. 15 NJB0009PCT The term “alkyl”, as used herein, means a branched or straight chain saturated aliphatic hydrocarbon group having the specified number of carbon atoms, generally from 1 to about 12 carbon atoms. The term C1-C6alkyl as used herein indicates an alkyl group having from 1, 2, 3, 4, 5, or 6 carbon atoms. Other embodiments include alkyl groups having 5 from 1 to 8 carbon atoms, 1 to 4 carbon atoms or 1 or 2 carbon atoms, e.g. C1-C6alkyl, C1- C4alkyl, and C1-C2alkyl. When C0-Cnalkyl is used herein in conjunction with another group, for example, (cycloalkyl)C0-C4alkyl, the indicated group, in this case cycloalkyl, is either directly bound by a single covalent bond (C0), or attached by an alkyl chain having the specified number of carbon atoms, in this case 1, 2, 3, or 4 carbon atoms. Examples of alkyl10 include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, 3-methylbutyl, t- butyl, n-pentyl, and sec-pentyl. The term “alkoxy” represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, 2-butoxy, t-butoxy, n-pentoxy, 2-pentoxy, 15 3-pentoxy, isopentoxy, neopentoxy, n-hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy. The term “aryl”, as used herein, means aromatic groups containing only carbon in the aromatic ring or rings. Typical aryl groups contain 1 to 3 separate, fused, or pendant rings and from 6 to about 18 ring atoms, without heteroatoms as ring members. When indicated, such aryl groups may be further substituted with carbon or non-carbon atoms or groups. 20 Bicyclic aryl groups may be further substituted with carbon or non-carbon atoms or groups. Bicyclic aryl groups may contain two fused aromatic rings (naphthyl) or an aromatic ring fused to a 5- to 7-membered non-aromatic cyclic group that optionally contains 1 or 2 heteroatoms independently chosen from N, O, and S, for example, a 3,4-methylenedioxy- phenyl group. Aryl groups include, for example, phenyl, naphthyl, including 1-naphthyl and 25 2-naphthyl, and bi-phenyl. The term “cycloalkyl”, as used herein, indicates a saturated hydrocarbon ring group, having only carbon ring atoms and having the specified number of carbon atoms, usually from 3 to about 8 ring carbon atoms, or from 3 to about 7 carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl as well as 30 bridged or caged saturated ring groups such as norborane or adamantane. The term “cycloalkenyl”, as used herein, means a saturated hydrocarbon ring group, comprising one or more unsaturated carbon-carbon bonds, which may occur in any stable point of the ring, and having the specified number of carbon atoms. Monocyclic cycloalkenyl groups typically have from 3 to about 8 carbon ring atoms or from 3 to 7 (3, 4, 5, 6, or 7) 16 NJB0009PCT carbon ring atoms. Cycloalkenyl substituents may be pendant from a substituted nitrogen or carbon atom, or a substituted carbon atom that may have two substituents may have a cycloalkenyl group, which is attached as a spiro group. Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl as well as bridged or 5 caged saturated ring groups such as norbornene. The term “heteroaryl”, as used herein, indicates a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic ring which contains at least 1 aromatic ring that contains from 1 to 4, or specifically from 1 to 3, heteroatoms chosen from N, O, and S, with remaining ring atoms being carbon. When the total number of S and O 10 atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to one another. Specifically, the total number of S and O atoms in the heteroaryl group is not more than 2, more specifically the total number of S and O atoms in the heteroaryl group is not more than 1. A nitrogen atom in a heteroaryl group may optionally be quaternized. When indicated, such heteroaryl groups may be further substituted with carbon or non-carbon atoms or 15 groups. Such substitution may include fusion to a 5 to 7-membered saturated cyclic group that optionally contains 1 or 2 heteroatoms independently chosen from N, O, and S, to form, for example, a [1,3]dioxolo[4,5-c]pyridyl group. In certain embodiments 5- to 6-membered heteroaryl groups are used. Examples of heteroaryl groups include, but are not limited to, pyridyl, indolyl, pyrimidinyl, pyridizinyl, pyrazinyl, imidazolyl, oxazolyl, furanyl, 20 thiophenyl, thiazolyl, triazolyl, tetrazolyl, isoxazolyl, quinolinyl, pyrrolyl, pyrazolyl, benz[b]thiophenyl, isoquinolinyl, quinazolinyl, quinoxalinyl, thienyl, isoindolyl, and 5,6,7,8- tetrahydroisoquinoline. “Haloalkyl” includes both branched and straight-chain alkyl groups having the specified number of carbon atoms, substituted with 1 or more halogen atoms, up to the 25 maximum allowable number of halogen atoms. Examples of haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, 2-fluoroethyl, and penta-fluoroethyl. “Haloalkoxy” is a haloalkyl group as defined herein attached through an oxygen bridge (oxygen of an alcohol radical). “Halo” or “halogen” is any of fluoro, chloro, bromo, and iodo. 30 “Mono- and / or di-alkylamino” is a secondary or tertiary alkyl amino group, wherein the alkyl groups are independently chosen alkyl groups, as defined herein, having the indicated number of carbon atoms. The point of attachment of the alkylamino group is on the nitrogen. Examples of mono- and di-alkylamino groups include ethylamino, dimethylamino, and methyl-propyl-amino. 17 NJB0009PCT The term “substituted”, as used herein, means that any one or more hydrogens on the designated atom or group is replaced with a selection from the indicated group, provided that the designated atom’s normal valence is not exceeded. When the substituent is oxo (i.e., =O) then 2 hydrogens on the atom are replaced. When an oxo group substitutes aromatic 5 moieties, the corresponding partially unsaturated ring replaces the aromatic ring. For example, a pyridyl group substituted by oxo is a pyridone. A stable compound or stable structure is meant to imply a compound that is sufficiently robust to survive isolation from a reaction mixture, and subsequent formulation into an effective therapeutic agent. Unless otherwise specified, e.g. when a dash ("-") is used, substituents are named into 10 the core structure. For example, it is to be understood that when (cycloalkyl)alkyl is listed as a possible substituent the point of attachment of this substituent to the core structure is in the alkyl portion, or when arylalkyl is listed as a possible substituent the point attachment to the core structure is the alkyl portion. Suitable groups that may be present on a “substituted” or “optionally substituted” 15 position include, but are not limited to, halogen; cyano; hydroxyl; nitro; azido; alkanoyl (such as a C2-C6 alkanoyl group such as acyl or the like); carboxamido; alkyl groups (including cycloalkyl groups) having 1 to about 8 carbon atoms, or 1 to about 6 carbon atoms; alkenyl and alkynyl groups including groups having one or more unsaturated linkages and from 2 to about 8, or 2 to about 6 carbon atoms; alkoxy groups having one or more oxygen linkages 20 and from 1 to about 8, or from 1 to about 6 carbon atoms; aryloxy such as phenoxy; alkylthio groups including those having one or more thioether linkages and from 1 to about 8 carbon atoms, or from 1 to about 6 carbon atoms; alkylsulfinyl groups including those having one or more sulfinyl linkages and from 1 to about 8 carbon atoms, or from 1 to about 6 carbon atoms; alkylsulfonyl groups including those having one or more sulfonyl linkages and from 1 25 to about 8 carbon atoms, or from 1 to about 6 carbon atoms; aminoalkyl groups including groups having one or more N atoms and from 1 to about 8, or from 1 to about 6 carbon atoms; aryl having 6 or more carbons and one or more rings, (e.g., phenyl, biphenyl, naphthyl, or the like, each ring either substituted or unsubstituted aromatic); arylalkyl having 1 to 3 separate or fused rings and from 6 to about 18 ring carbon atoms, with benzyl being an 30 exemplary arylalkyl group; arylalkoxy having 1 to 3 separate or fused rings and from 6 to about 18 ring carbon atoms, with benzyloxy being an exemplary arylalkoxy group; or a saturated, unsaturated, or aromatic heterocyclic group having 1 to 3 separate or fused rings with 3 to about 8 members per ring and one or more N, O or S atoms, e.g. coumarinyl, quinolinyl, isoquinolinyl, quinazolinyl, pyridyl, pyrazinyl, pyrimidinyl, furanyl, pyrrolyl, 18 NJB0009PCT thienyl, thiazolyl, triazinyl, oxazolyl, isoxazolyl, imidazolyl, indolyl, benzofuranyl, benzothienyl, benzothiazolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, and pyrrolidinyl. Such heterocyclic groups may be further substituted, e.g. with hydroxy, alkyl, alkoxy, halogen and amino. 5 The term “pharmaceutically acceptable salt”, as used herein, includes derivatives of the disclosed compounds in which the parent compound is modified by making inorganic and organic, acid or base addition salts thereof. The salts of the present compounds can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these 10 compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used, 15 where practicable. Salts of the present compounds further include solvates of the compounds and of the compound salts. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the 20 conventional salts and the quaternary ammonium salts of the parent compound formed, for example, from inorganic or organic acids. For example, conventional acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, 25 hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC-(CH2)q-COOH where q is 0-4, and the like. Lists of additional suitable salts may be found, e.g., in Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p.1418 (1985). 30 The compounds of Formula (I), Formula (II), and their conjugates may be formulated with one or more excipients and prepared into pharmaceutical formulations for any suitable route of administration including oral or parenteral administration. As used herein, parenteral administration includes intravenous, cutaneous, subcutaneous, intramuscular, and the like. 19 NJB0009PCT The pharmaceutical composition generally comprises the compound of Formula (I), Formula (II), or conjugates thereof, and a pharmaceutically acceptable excipient, including carriers, buffers, antioxidants, and the like. Pharmaceutical formulations for oral administration include tablets, capsules, 5 powders, liquid, semisolids, and the like. Known pharmaceutically acceptable excipients used for oral administration may be used. For parenteral administration, including intravenous or other injection, the formulation will comprise the compound of Formula (I), Formula (II), or a conjugate thereof, and a parenterally acceptable aqueous solution. Parenteral solutions are to be pyrogen-free 10 and have suitable pH, isotonicity, and stability. Suitable parenteral vehicles include Sodium Chloride Injection, Ringer’s Injection, Lactated Ringer’s Injection, and the like. The parenteral formulation may further comprise an antioxidant, a buffer, a preservative, a stabilizer, or a combination thereof. The compounds and compositions disclosed herein find use for treating cancer, and in 15 particular, in the form of ADCs for cancer therapy. “Cancer” as used herein can refer to adenocarcinomas, carcinomas, leukemias, lymphomas, sarcomas, solid and lymphoid cancers, and the like. Examples of different types of cancer include, acute lymphocytic leukemia (acute lymphoblastic leukemia), acute myeloid leukemia (acute myelogenous leukemia, acute myeloblastic leukemia, acute 20 myelocytic leukemia, acute granulocytic leukemia, and acute nonlymphocytic leukemia), anal cancer, B-cell lymphoma, bile duct cancer, bladder cancer, blood cancer, bone cancer, breast cancer, Burkitt’s lymphoma, central nervous system cancer, cervical cancer, choriocarcinoma, chronic lymphocytic leukemia, chronic myeloid leukemia (chronic myelogenous leukemia), colon cancer, colorectal cancer, endometrial cancer, epithelial 25 cancer, esophageal cancer, fibrosarcoma, gall bladder cancer, gastrointestinal carcinoid tumors, glioma, head and neck cancer, Large Cell lymphoma, liposarcoma, liver cancer (i.e., hepatocarcinoma), lung cancer (e.g., non-small cell lung cancer or NSCLC), melanoma, monocytic leukemia, multiple myeloma, myelodysplastic syndromes (MDS), myelogenous leukemia, neuroblastoma, non-Hodgkin's lymphoma, ovarian cancer, osteogenic sarcoma, 30 pancreatic cancer, pleural cancer, prostate cancer, rectal cancer, renal cancer (i.e., renal cell carcinoma), skin cancer, Small Cell lymphoma, small intestine cancer, stomach (gastric) cancer, testicular cancer, thyroid cancer, uterine cancer, and the like. The patient may be a mammalian patient, specifically a human. 20 NJB0009PCT The dosage amount of the compound of Formula (I) or Formula (II) for the treatment of a disease, such as a proliferative disease, will depend on the disease to be treated, the severity of the disease, previous therapy and concurrent therapy, the patient’s clinical history, and other factors. The Formula (I), Formula (II), or a conjugate thereof, can be administered 5 to the patient at one time or over a series of treatments over days, weeks, or months. In an exemplary amount, about 1 μg / kg to about 15 mg / kg of the compound of Formula (I) or Formula (II) may be a starting dosage for administration to the patient. The dosage may be by one or more separate administrations, or by continuous infusion. An exemplary daily dosage might range from about 1 μg / kg to about 100 mg / kg or more, depending on the 10 factors previously discussed. An exemplary dosage of the compound of Formula (I) or Formula (II) to be administered to a patient can be in the range of about 0.1 to about 10 mg / kg of patient weight. In an embodiment, an exemplary dosing regimen comprises a course of administering an initial loading dose of about 4 mg / kg, followed by additional doses every week, two weeks, or three weeks of the compound of Formula (I) or Formula (II). 15 In an embodiment, a pharmaceutical composition comprises the compound of Formula (I), Formula (II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In yet another embodiment, a method of treating a proliferative disease including a cancer, comprises administering to a patient in need thereof a compound of Formula (I), 20 Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical formulation thereof. Also disclosed herein are compounds comprising one or more repeat structures of the formula O H N n 25 rom 1 to 32; specifically an integer from 2 to 32; and more specifically n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, O H N 24, 25, 26, 27, 28, 29, 30, 31, or 32. The formunis also referred to herein as [G*]n where n has the same meaning: an nteger rom 1 to 32; specifically an integer from 2 to 32; and more specifically n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 30 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, or 32. 21 NJB0009PCT [G*]n has been found to have advantageous properties as a drug conjugate linker group used as a spacer between a drug payload and an antibody or antibody fragment. These advantages are described in Table 7. [G*]n can be used alone or in combination with an additional linker. 5 In an embodiment, a compound comprises a compound of Formula (III) OHL1ONN X Formula (III) wherei PL is a drug payload; L1is a bond or a linking group; 10 L2is a bond or a linking group; RXis a reactive group suitable for forming a covalent bond to an antibody or antibody fragment; and n is an integer from 1 to 32, specifically 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, or 32. 15 In an embodiment, a compound comprises a compound of Formula (IV) OHb Formula (IV) wherei PL is a drug payload; L1is a bond or a linking group; 20 L2is a bond or a linking group; Ab is an antibody or antibody fragment; n is an integer from 1 to 32, specifically 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, or 32; and m is 1, 2, 3, 4, 5, 6, 7, or 8. 25 In an embodiment, the PL of Formula (III) or Formula (IV) is a drug payload of Table 1 or Table 11. In an embodiment, the compound of Formula (III) or Formula (IV), wherein L1is a bond linked to PL via a NH group. 22 NJB0009PCT Compounds comprising a payload and linker [G*]n, and conjugates thereof, may be formulated with one or more excipients and prepared into pharmaceutical formulations for any suitable route of administration including oral or parenteral administration. As used herein, parenteral administration includes intravenous, cutaneous, subcutaneous, 5 intramuscular, and the like. The pharmaceutical composition generally comprises the compound comprising a payload and linker [G*]n, or conjugates thereof, and a pharmaceutically acceptable excipient, including carriers, buffers, antioxidants, and the like. Pharmaceutical formulations for oral administration include tablets, capsules, powders, 10 liquid, semisolids, and the like. Known pharmaceutically acceptable excipients used for oral administration may be used. For parenteral administration, including intravenous or other injection, the formulation will comprise a compound comprising a payload and linker [G*]n, or a conjugate thereof, and a parenterally acceptable aqueous solution. Parenteral solutions are to be 15 pyrogen-free and have suitable pH, isotonicity, and stability. Suitable parenteral vehicles include Sodium Chloride Injection, Ringer’s Injection, Lactated Ringer’s Injection, and the like. The parenteral formulation may further comprise an antioxidant, a buffer, a preservative, a stabilizer, or a combination thereof. The compounds and compositions disclosed herein find use for treating cancer, and in 20 particular, in the form of ADCs for cancer therapy. In yet another embodiment, a method of treating a proliferative disease including a cancer, comprises administering to a patient in need thereof a compound comprising a payload and linker [G*]n. The following examples are merely illustrative of the topoisomerase inhibitor 25 compounds and linker compounds disclosed herein and are not intended to limit the scope hereof. EXAMPLES General Solvents and reagents were purchased from Sigma-Aldrich, VWR, Ambeed, 30 Combi-Blocks, Inc., or Fisher Scientific, and used without further purification. Reactions were monitored either by thin-layer chromatography (TLC) or by analytical liquid chromatography-mass spectrometry (LC-MS) employing a Waters Acquity Ultra Performance LC system and a Synapt high-definition mass spectrometer. Unless otherwise indicated, compounds were purified by flash column chromatography on a Teledyne ISCO 23 NJB0009PCT Combi-Flash system using normal phase silica gel (SiliCycle Inc.) or reverse phase (Teledyne Gold-C18, GoldC18Aq, or Gemini (5µm C18110Å 150 x 30 mm) with (5% ACN + 0.05% FA) / (H2O + 0.05% FA) to 95% (ACN+ 0.05 % FA) / (H2O + 0.05% FA) gradient). The purity of compounds was determined by analytical HPLC (Waters Acquity Ultra 5 Performance) using an Acquity UPLC CSH C181.7 µm (50 mm x 2.1 mm) column and flow rate of 0.3 mL / min. Gradient conditions: solvent A (0.1% formic acid in water) and solvent B (0.1% formic acid in acetonitrile): 0–0.1 min 95% A, 0.1–4.0 min 5–95% B (linear gradient), 4.0–5.0 min 95% B, UV detection at 254 nm and 220 nm. 10 Table 1: Payloads (X = H or F): (ESI) m / z: Cmpd+Structure [M+H] 24 NJB0009PCT (ESI) m / z: Cmpd+Structure [M+H] 25 NJB0009PCT (ESI) m / z: Cmpd+Structure [M+H] 26 NJB0009PCT (ESI) m / z: Cmpd+Structure [M+H] 27 NJB0009PCT (ESI) m / z: Cmpd+Structure [M+H] 28 NJB0009PCT (ESI) m / z: Cmpd+Structure [M+H] 29 NJB0009PCT (ESI) m / z: Cmpd+Structure [M+H] 30 NJB0009PCT (ESI) m / z: Cmpd+Structure [M+H] 31 NJB0009PCT (ESI) m / z: Cmpd+Structure [M+H] 32 NJB0009PCT (ESI) m / z: Cmpd+Structure [M+H] 33 NJB0009PCT (ESI) m / z: Cmpd+Structure [M+H] 34 NJB0009PCT (ESI) m / z: Cmpd+Structure [M+H] 35 NJB0009PCT (ESI) m / z: Cmpd+Structure [M+H] 36 NJB0009PCT (ESI) m / z: Cmpd+Structure [M+H] 37 NJB0009PCT (ESI) m / z: Cmpd+Structure [M+H] 38 NJB0009PCT (ESI) m / z: Cmpd+Structure [M+H] 39 NJB0009PCT (ESI) m / z: Cmpd+Structure [M+H] 40 NJB0009PCT (ESI) m / z: Cmpd+Structure [M+H] 41 NJB0009PCT (ESI) m / z: Cmpd+Structure [M+H] 42 NJB0009PCT (ESI) m / z: Cmpd+Structure [M+H] 43 NJB0009PCT (ESI) m / z: Cmpd+Structure [M+H] 44 NJB0009PCT (ESI) m / z: Cmpd+Structure [M+H] 45 NJB0009PCT (ESI) m / z: Cmpd+Structure [M+H] 46 NJB0009PCT (ESI) m / z: Cmpd+Structure [M+H] 47 NJB0009PCT (ESI) m / z: Cmpd+Structure [M+H] 48 NJB0009PCT (ESI) m / z: Cmpd+Structure [M+H] 49 NJB0009PCT (ESI) m / z: Cmpd+Structure [M+H] 50 NJB0009PCT (ESI) m / z: Cmpd+Structure [M+H] 51 NJB0009PCT (ESI) m / z: Cmpd+Structure [M+H] 52 NJB0009PCT (ESI) m / z: Cmpd+Structure [M+H] 53 NJB0009PCT (ESI) m / z: Cmpd+Structure [M+H] 54 NJB0009PCT (ESI) m / z: Cmpd+Structure [M+H] 55 NJB0009PCT (ESI) m / z: Cmpd Structure [M+H]+ Table 2: Linker Examples to be Used with Payloads (PL): 56 NJB0009PCT Amino O [G*]n , n = or H N 57 NJB0009PCT O Amino- MC-G-G-F-GON H O HON 58 NJB0009PCT O Amino- O PEG MC-G N O PL N 59 NJB0009PCT O O O OO PLN H N 60 NJB0009PCT O Aryl MC-G- Alcohol- N . n 61 NJB0009PCT Example 1A: A schematic for the Proposed Synthesis of Diverse Ring-Up Payload Class With B-Ring Handle is provided in FIG. 1. Example 1B: A schematic for the Proposed Synthesis of Ring-Down Payload Class With B-Ring Handle is provided in FIG. 2. 5 Example 1C: A schematic for the Proposed Synthesis of Diverse Ring-Up Payload Class With Ring-Up Handle is provided in FIG. 3. Example 2: Synthesis of Ring-Up Camptothecin Payload 15 and 33 Via key Friedlander Cyclization: PTSA, Toluene 120 C, MW, 1.5 h Cl O O 10 mmol, 0.8 eq) at room temperature under Argon. The RBF was cooled to 0 C, then 2- naphthylamine (10 g, 69.837 mmol, 1.0 eq) was added in 4 portions and stirred until a suspension was formed (10 minutes). Chloroacetonitrile (8.357 ml, 83.8 mmol, 1.2 eq) was then 15 added dropwise and stirred for 10 minutes. AlCl3 (12.105g, 90.78 mmol, 1.3 eq) was then added in four portions and then stirred for 10 minutes. The reaction was allowed to warm to room temperature and then was setup for reflux for 72 h. After 72 h, the reaction was cooled to 0 C and then H2O (280 mL) was carefully added, followed by 2 M HCl / H2O (280 mL). The quenched 62 NJB0009PCT reaction was allowed to stir 16 h at room temperature. The crude product was extracted from the reaction mixture by 5x liquid-liquid extraction of DCM (250 mL each). The combined DCM layers were stripped dry and then dissolved in 5% MeOH / DCM (40 mL). The crude product was purified on 330 g silica columns (20 mL 2X) with a DCM to 5% MeOH / DCM gradient over 20 5 minutes. The product fractions were combined and concentrated, followed by high vacuum to give I-1 (7.862 g, 51% yield) as a dark green solid. (ESI) m / z: [M+H]+ = 220.21. MW Irradiation Method: To a MW vial was added I-1 (200 mg, 0.91 mmol, 1 eq) and I-2 (198 mg, 0.756 mmol, 0.83 eq). Toluene (15.2 mL) was added and followed by brief sonication to ensure I-2 dissolved. PTSA (38 mg, 0.151 mmol, 0.16 eq) was added to the MW vial and the 10 headspace was flushed with Argon. The vial was irradiated in the microwave at 120 C for 90 minutes. The crude product was transferred to a RBF by (1:1) (DCM:MeOH) and stripped dry to afford I-3 (410 mg, quant. yield) as a green solid. (ESI) m / z: [M+H]+ = 447.58. Reflux Method: To a 3-neck RBF was added I-1 (1 g, 4.552 mmol, 1 eq), I-2 (1.198 g, 4.552 mmol, 1.0 eq) and toluene (189 mL) under Ar. PTSA (572 mg, 2.276 mmol, 0.5 eq) was 15 added to the RBF and heated to reflux for 16 h. After 16 h the reaction was equipped with a distillation apparatus and the Argon flow needle was placed in the headspace of the round bottom flask to aid in distillation of the reaction to dryness. Once dry, the reaction was resuspended in toluene (189 mL) and once again distilled to dryness. Once more the reaction was resuspended in toluene (189 mL) and distilled to dryness. The crude product was placed under 20 high vacuum to obtain I-3 (2.146 g, quant. yield) as a green solid. (ESI) m / z: [M+H]+ = 447.58. To the RBF containing I-3 (337.8 mg, 0.756 mmol, 1 eq) was added DMSO (20.16 mL) and stirred until a homogenous solution was obtained and shielded from light by aluminum foil. Sodium azide (98 mg, 1.512 mmol, 2 eq) was added and stirred 16 h at room temperature. At 16 h the crude reaction was diluted with H2O (200 mL) and stored for 16 h at 4 C. After 16 h the 25 solid was obtained by iterative centrifugation in a 50 mL centrifuge tube (9000 rpm, 15 min) and decanting of the supernatant until all solid was pooled in a singular tube. The solid was washed with H2O (20 mL) by vortex, brief sonication, centrifugation (9000 rpm, 30 min) and decant. The crude solid was suspended in (1:1) (H2O:ACN) and lyophilized to obtain I-4 (300.6 mg, 87% yield) as a green solid. (ESI) m / z: [M+H]+ = 454.16. During the azidation reaction 30 dehalogenation occurs and results in the formation of byproduct 33 which is found in the final H2O wash. The H2O wash containing 33 is lyophilized to form a green solid, that is then 63 NJB0009PCT dissolved in in 5% MeOH / DCM (5 mL). The crude product was purified on a 40 g silica column with a DCM to 5% MeOH / DCM gradient over 20 minutes to obtain 33 (14 mg, 4% yield) as a light green solid. (ESI) m / z: [M+H]+ = 413.54. To a pressure vessel was added I-4 (150 mg, 0.331 mmol, 1 eq) and dissolved in benzene 5 (43 mL). To the vessel was added triethyl phosphite (0.142 mL, 0.827 mmol, 2.5 eq) and was refluxed sealed for 4 h. At 4 h, the vessel was cooled to room temperature and then 3M HCl / MeOH (2.148 mL) was added (carefully). The vessel was refluxed for 16 h. After 16 h the reaction was transferred to a RBF and stripped dry. The crude product was dissolved in DMF and purified by reverse phase (Teledyne Gemini (5µm C18110Å 150 x 30 mm) with (5% 10 ACN+0.05% TFA) / (H2O+0.05% TFA) to 95% (ACN+0.05% TFA) / (H2O+0.05% TFA) gradient). The product was recovered by lyophilization to obtain 15 (37 mg, 26 % yield) as a white solid. (ESI) m / z: [M+H]+ = 428.08. Example 3: Synthesis of Ring-Down Camptothecin Payload 48 Via key Friedlander Cyclization: chloroacetonitrile O O Cl BCl3, AlCl3DCE Cl N PTSA, Toluene O O O O 15 , 0.8 eq) at room temperature under Argon. The RBF was cooled to 0 C, then 1-naphthylamine (0.5 g, 3.492 mmol, 1.0 eq) was added in 4 portions and stirred until a suspension was formed (10 minutes). Chloroacetonitrile (0.409 ml, 4.103 mmol, 1.2 eq) was then added dropwise and stirred for 10 minutes. AlCl3 (0.61 g, 4.539 mmol, 1.3 eq) was then added in four portions and 20 then stirred for 10 minutes. The reaction was allowed to warm to room temperature and then was setup for reflux for 72 h. After 72 h, the reaction was cooled to 0 C and then H2O (15 mL) was carefully added, followed by 2 M HCl / H2O (15 mL). The quenched reaction was allowed to stir 16 h at room temperature. The crude product was extracted from the reaction mixture by 5x 64 NJB0009PCT liquid-liquid extraction of DCM (250 mL each). The combined DCM layers were stripped dry and then dissolved in 5% MeOH / DCM (40 mL). The crude product was purified on 330 g silica columns (20 mL 2X) with a DCM to 5% MeOH / DCM gradient over 20 minutes. The product fractions were combined and concentrated, followed by high vacuum to give I-5 (0.478 g, 63% 5 yield) as a brown / green solid. (ESI) m / z: [M+H]+ = 220.11. MW Irradiation Method: To a MW vial was added I-5 (50 mg, 0.228 mmol, 1 eq) and I-2 (49.73mg, 0.189 mmol, 0.83 eq). Toluene (3.8 mL) was added and followed by brief sonication to ensure I-2 dissolved. PTSA (9.5 mg, 0.038 mmol, 0.16 eq) was added to the MW vial and the headspace was flushed with Argon. The vial was irradiated in the microwave at 120 C for 8 10 hours. The crude product was transferred to a RBF by (1:1) (DCM:MeOH) and stripped dry to afford I-6 (152 mg, quant. yield) as a green solid. (ESI) m / z: [M+H]+ = 447.26. To the RBF containing I-6 (101 mg, 0.228 mmol, 1 eq) was added DMSO (4.56 mL) and stirred until a homogenous solution was obtained and shielded from light by aluminum foil. Sodium azide (22.23 mg, 0.342 mmol, 2 eq) was added and stirred 16 h at room temperature. At 15 16 h the crude reaction was diluted with H2O (45 mL) and stored for 16 h at 4 C. After 16 h the solid was obtained by iterative centrifugation in a 50 mL centrifuge tube (9000 rpm, 15 min) and decanting of the supernatant until all solid was pooled in a singular tube. The solid was washed with H2O (3 mL) by vortex, brief sonication, centrifugation (9000 rpm, 30 min) and decant. The crude solid was suspended in (1:1) (H2O:ACN) and lyophilized to obtain I-7 (10.2 mg, 10% 20 yield) as a green solid. (ESI) m / z: [M+H]+ = 453.92. To a pressure-cap vial was added I-7 (5 mg, 0.011 mmol, 1 eq) and dissolved in benzene (1.432 mL). To the vial was added triethyl phosphite (0.5 uL, 0.028 mmol, 2.5 eq) and was refluxed sealed for 4 h. At 4 h, the vial was cooled to room temperature and then 3M HCl / MeOH (0.072 mL) was added (carefully). The vial was refluxed for 16 h. After 16 h the reaction was 25 transferred to a RBF and stripped dry. The crude product was dissolved in DMF and purified by reverse phase (Teledyne Gemini (5µm C18110Å 150 x 30 mm) with (5% ACN+0.05% TFA) / (H2O+0.05% TFA) to 95% (ACN+0.05% TFA) / (H2O+0.05% TFA) gradient). The product was recovered by lyophilization to obtain 48 (0.4 mg, 10 % yield) as a light green solid. (ESI) m / z: [M+H]+ = 427.79. 30 Example 4: Synthesis of Payload 2: 65 NJB0009PCT NH2N3N N N O O 45.9 ul, 0.716 mmol, 4.0 eq) were added to vial under argon atmosphere. (PPh3)3CuBr (33.3 mg, 20 mol%) was added to the vial and dissolved in anhydrous dichloromethane (11.19 mL). Diisopropylethylamine (0.63 mL, 63.581 5 mmol, 20 eq) was added to the vial and the reaction was stirred at 35°C for 4 hours sealed under argon atmosphere. The crude reaction was concentrated en vacuo and dissolved in (2 mL) DMF. The crude material was purified via reverse phase chromatography (50 g C18) (5% ACN + 0.05% TFA) to (95% ACN+ 0.05 % TFA) / (H2O + 0.05% TFA gradient). The product was recovered by lyophilization to obtain 2 (5.4 mg, 34% yield) as a white solid. (ESI) m / z: [M+H]+ 10 = 508.79. Example 5: Synthesis of Payload 4: OH O O ul, 0.882 mmol, 4.0 eq) were added to vial under argon atmosphere. (PPh3)3CuBr (41 mg, 20 mol%) was added to the vial and 15 dissolved in anhydrous dichloromethane (13.78 mL). Diisopropylethylamine (0.772 mL, 4.411 mmol, 20 eq) was added to the vial and the reaction was stirred at 35°C for 2 hours sealed under argon atmosphere. The crude reaction was concentrated en vacuo and dissolved in (2 mL) DMF. The crude material was purified via reverse phase chromatography (50 g C18) (5% ACN + 0.05% TFA) to (95% ACN+ 0.05 % TFA) / (H2O + 0.05% TFA gradient). The product was 20 recovered by lyophilization to obtain 4 (25.4 mg, 22% yield) as a white solid. (ESI) m / z: [M+H]+ = 538.46. Example 6: Synthesis of Payload 6: 66 NJB0009PCT OH O O (93 ul, 0.882 mmol, 4.0 eq) were added to vial under argon atmosphere. (PPh3)3CuBr (41 mg, 20 mol%) was added to the vial and dissolved in anhydrous dichloromethane (13.78 mL). Diisopropylethylamine (0.772 mL, 4.411 5 mmol, 20 eq) was added to the vial and the reaction was stirred at 35°C for 2 hours sealed under argon atmosphere. The crude reaction was concentrated en vacuo and dissolved in (2 mL) DMF. The crude material was purified via reverse phase chromatography (50 g C18) (5% ACN + 0.05% TFA) to (95% ACN+ 0.05 % TFA) / (H2O + 0.05% TFA gradient). The product was recovered by lyophilization to obtain 6 (19 mg, 16% yield) as a white solid. (ESI) m / z: [M+H]+ 10 = 538.46. Example 7: Synthesis of Payload 8: OH O O 0.882 mmol, 4.0 eq) were added to vial under argon atmosphere. (PPh3)3CuBr (41 mg, 20 mol%) was added to the vial and 15 dissolved in anhydrous dichloromethane (13.78 mL). Diisopropylethylamine (0.772 mL, 4.411 mmol, 20 eq) was added to the vial and the reaction was stirred at 35°C for 2 hours sealed under argon atmosphere. The crude reaction was concentrated en vacuo and dissolved in (2 mL) DMF. The crude material was purified via reverse phase chromatography (50 g C18) (5% ACN + 0.05% TFA) to (95% ACN+ 0.05 % TFA) / (H2O + 0.05% TFA gradient). The product was 20 recovered by lyophilization to obtain 8 (59 mg, 50% yield) as a white solid. (ESI) m / z: [M+H]+ = 538.08. 67 NJB0009PCT Example 8: Synthesis of Payload 9: NH2O O 0.882 mmol, 4.0 eq) were added to vial under argon atmosphere. (PPh3)3CuBr (41 mg, 20 mol%) was added to the vial and 5 dissolved in anhydrous dichloromethane (13.78 mL). Diisopropylethylamine (0.772 mL, 4.411 mmol, 20 eq) was added to the vial and the reaction was stirred at 35°C for 2 hours sealed under argon atmosphere. The crude reaction was concentrated en vacuo and dissolved in (2 mL) DMF. The crude material was purified via reverse phase chromatography (50 g C18) (5% ACN + 0.05% TFA) to (95% ACN+ 0.05 % TFA) / (H2O + 0.05% TFA gradient). The product was 10 recovered by lyophilization to obtain 9 (20.6 mg, 16% yield) as a white solid. (ESI) m / z: [M+H]+ = 571.31. Example 9: Synthesis of Payload 21: O NH2OH NH O O HATU (3.4 mg, 0.089 15 mmol), and HOBt (1.2 mg, 0.089 mmol) were added to a vial containing DMF (1.61 mL) and DIPEA (0.031 mL, 0.177 mmol). The reaction was stirred at room temperature for 1 h whereupon, LCMS indicated formation of the desired product and consumption of 15. The crude material was purified via reverse phase chromatography (50 g C18) (5% ACN + 0.05% TFA) to (95% ACN+ 0.05 % TFA) / (H2O + 0.05% TFA gradient). The product was recovered by 20 lyophilization to obtain 21 (1.6 mg, 5% yield) as a white solid. (ESI) m / z = [M+H]+ = 567.14. 68 NJB0009PCT Example 10: Synthesis of Payload 27: O N O 2 2-am ne Br OH O O .02 mL, 3.017 mmol, 0.8 eq) at room temperature under Argon. The RBF was cooled to 0 C, then 2-naphthylamine 5 (0.54 g, 3.771 mmol, 1.0 eq) was added in 4 portions and stirred until a suspension was formed (10 minutes). 5-bromovaleronitrile (0.602 ml, 4.431 mmol, 1.2 eq) was then added dropwise and stirred for 10 minutes. AlCl3 (0.65 g, 4.903 mmol, 1.3 eq) was then added in four portions and then stirred for 10 minutes. The reaction was allowed to warm to room temperature and then was setup for reflux for 72 h. After 72 h, the reaction was cooled to 0 C and then H2O (10 mL) was 10 carefully added, followed by 2 M HCl / H2O (10 mL). The quenched reaction was allowed to stir 16 h at room temperature. The crude product was extracted from the reaction mixture by 5x liquid-liquid extraction of DCM (10 mL each). The combined DCM layers were stripped dry and then dissolved in 5% MeOH / DCM (5 mL). The crude product was purified on a 40 g silica column with a DCM to 5% MeOH / DCM gradient over 20 minutes. The product fractions were 69 NJB0009PCT combined and concentrated, followed by high vacuum to give I-8 (0.149 g, 13% yield) as a dark green solid. (ESI) m / z: [M+H]+ = 305.96. To a MW vial was added I-8 (149 mg, 0.487 mmol, 1 eq) and I-2 (141 mg, 0.535 mmol, 1.1 eq). Toluene (16.22 mL) was added and followed by brief sonication to ensure I-2 dissolved. 5 PTSA (46 mg, 0.243 mmol, 0.5 eq) was added to the MW vial and the headspace was flushed with Argon. The vial was irradiated in the microwave at 130 C for 60 minutes. The crude product was transferred to a RBF by (1:1) (DCM:MeOH) and stripped dry to afford I-9 (174 mg, 67% yield) as a tan solid. (ESI) m / z: [M+H]+ = 533.10. To an oven dried vial was added I-9 (6.9 mg, 0.130 mmol, 1 eq) was added HMPA (0.393 ml). 10 To the vial was added H2O (0.06 mL) and heated to 101 C for 4 h whereupon LCMS indicated the reaction was mostly complete. The reaction was directly purified by reverse phase (Teledyne 50 g C18 (5µm C18110Å 150 x 30 mm) with (5% ACN+0.05%FA) / (H2O+0.05%FA) to 95% (ACN+0.05%FA) / (H2O+0.05%FA) gradient). The product was obtained by lyophilization to give 27 (25.6 mg, 63% yield) as a white solid. (ESI) m / z: [M+H]+ = 471.23. 15 Example 11: Synthesis of Payload 31: O N O O e, 1h NJB0009PCT To a RBF, was added DCE (27.7 ml), followed by 1M BCl3 / DCM (5.55 mL, 5.55 mmol, 0.8 eq) at room temperature under Argon. The RBF was cooled to 0 C, then 6-amino-quinoline (1.0 g, 6.936 mmol, 1.0 eq) was added in 4 portions and stirred until a suspension was formed (10 minutes). 5-bromovaleronitrile (1.11 ml, 8.15 mmol, 1.2 eq) was then added dropwise and 5 stirred for 10 minutes. AlCl3 (1.2 g, 9.017 mmol, 1.3 eq) was then added in four portions and then stirred for 10 minutes. The reaction was allowed to warm to room temperature and then was setup for reflux for 72 h. After 72 h, the reaction was cooled to 0 C and then H2O (20 mL) was carefully added, followed by 2 M HCl / H2O (20 mL). The quenched reaction was allowed to stir 16 h at room temperature. The crude product was extracted from the reaction mixture by 5x 10 liquid-liquid extraction of DCM (20 mL each). The combined DCM layers were stripped dry and then dissolved in 5% MeOH / DCM (20 mL). The crude product was purified on a 330 g silica column with a DCM to 5% MeOH / DCM gradient over 20 minutes. The product fractions were combined and concentrated, followed by high vacuum to give I-10 (0.536 g, 25% yield) as a white solid. (ESI) m / z: [M+H]+ = 306.88. 15 To a MW vial was added I-10 (120 mg, 0.391 mmol, 1 eq) and I-2 (103 mg, 0.391 mmol, 1. eq). Toluene (13.02 mL) was added and followed by brief sonication to ensure I-2 dissolved. PTSA (37 mg, 0.195 mmol, 0.5 eq) was added to the MW vial and the headspace was flushed with Argon. The vial was irradiated in the microwave at 130 C for 60 minutes. The crude product was transferred to a RBF by (1:1) (DCM:MeOH) then stripped dry. The residue was 20 dissolved in DMF (2 mL) and purified by reverse phase (Teledyne 100 g C18 (5µm C18110Å 150 x 30 mm) with (5% ACN+0.05%TFA) / (H2O+0.05%TFA) to 95% (ACN+0.05%TFA) / (H2O+0.05%TFA) gradient). The product was obtained by lyophilization to give I-11 (39.6 mg, 19% yield) as a white solid. (ESI) m / z: [M+H]+ = 533.78. To an oven dried vial was added I-11 (40 mg, 0.074 mmol, 1 eq) was added HMPA 25 (0.225 ml). To the vial was added H2O (0.034 mL) and heated to 101 C for 8 h whereupon LCMS indicated the reaction was mostly complete. The reaction was directly purified by reverse phase (Teledyne 50 g C18 (5µm C18110Å 150 x 30 mm) with (5% ACN+0.05%FA) / (H2O+0.05%FA) to 95% (ACN+0.05%FA) / (H2O+0.05%FA) gradient). The product was obtained by lyophilization to give 31 (24.6 mg, 69% yield) as a white solid. (ESI) 30 m / z: [M+H]+ = 472.26. Example 12: Synthesis of Payload 32: 71 NJB0009PCT O N O CN Br N O 5-Bromo-pentanenitrile NOBr ne, 100oC, overnight 6-a 80% yield Br OH N O O , 5.55 mmol, 0.8 eq) at room temperature under Argon. The RBF was cooled to 0 C, then 6-aminoquinoxaline (1.0 g, 6.89 mmol, 1.0 eq) was added in 4 portions and stirred until a suspension was formed (10 5 minutes). 5-bromopentanenitrile (3.0 ml, 34.5 mmol, 3.75 eq) was then added dropwise and stirred for 10 minutes. AlCl3 (1.85 g, 13.8 mmol, 2eq) was then added in four portions and then stirred for 10 minutes. The reaction was allowed to warm to room temperature and then was setup for reflux for 72 h. After 72 h, the reaction was cooled to 0 C and then H2O (20 mL) was carefully added, followed by 2 M HCl / H2O (20 mL). The quenched reaction was allowed to stir 10 16 h at room temperature. The reaction was filtered to remove solids and then purified by normal phase chromatography (330 g silica) via dry loading (0.05% TEA DCM / 20% MeOH).. The product fractions were combined and concentrated, followed by high vacuum to give I-12 (1.02 g, 48% yield) as a white solid. (ESI) m / z: [M+H]+ = 308.35. To a RBFwas added I-12 (30 mg, 0.0973 mmol, 1 eq) and I-2 (25.6 mg, 0.0973 mmol, 1. 15 eq). Toluene (2 mL) was added and followed by brief sonication to ensure I-2 dissolved. PTSA (9.3 mg, 0.0487 mmol, 0.5 eq) was added to the MW vial and the headspace was flushed with Argon. The RBF was refluxed at 100 C for 16 h. The crude product was transferred to a RBF by (1:1) (DCM:MeOH) then stripped dry. The residue was dissolved in DMF (2 mL) and purified by reverse phase (Teledyne 100 g C18 (5µm C18110Å 150 x 30 mm) with (5% 72 NJB0009PCT ACN+0.05%TFA) / (H2O+0.05%TFA) to 95% (ACN+0.05%TFA) / (H2O+0.05%TFA) gradient). The product was obtained by lyophilization to give I-13 (17 mg, 80% yield) as a white solid. (ESI) m / z: [M+H]+ = 535.43. To an oven dried vial was added I-13 (17 mg, 0.031 mmol, 1 eq) was added HMPA (0.3 5 ml). To the vial was added H2O (0.06 mL) and heated to 101 C for 8 h whereupon LCMS indicated the reaction was mostly complete. The reaction was directly purified by reverse phase (Gemini C18 (5µm C18110Å 150 x 30 mm) with (5% ACN+0.05%FA) / (H2O+0.05%FA) to 95% (ACN+0.05%FA) / (H2O+0.05%FA) gradient). The product was obtained by lyophilization to give 32 (2 mg, 13% yield) as a white solid. (ESI) m / z: [M+H]+ = 473.51. 10 Example 13: Proposed Synthesis of 43: Br acrylic acid DIPEA, Pd(OAc)2P(o-Tol)3OH TFAA, TFA H2, Pd / C O HAc 15 a p e : opose y es s o a : 73 NJB0009PCT NHAcPTSA, Toluene chloroacetonitrileNHAcONHAcCl O A) BCl3, AlCl3DCE N Cl 120 C, MW, 1 h + O O O O Example 16: Synthesis of Ring-Down Payload 50: O N Br 5 , . , . mL, 0.5587 mmol, 0.8 eq) at room temperature under Argon. The RBF was cooled to 0 C, then 1- naphthylamine (0.100 g, 0.698 mmol, 1.0 eq) was added in 4 portions and stirred until a suspension was formed (10 minutes). 5-bromovaleronitrile (0.098 ml, 0.838 mmol, 1.2 eq) was 74 NJB0009PCT then added dropwise and stirred for 10 minutes. AlCl3(0.121 g, 0.908 mmol, 1.3 eq) was then added in four portions and then stirred for 10 minutes. The reaction was allowed to warm to room temperature and then was setup for reflux for 72 h. After 72 h, the reaction was cooled to 0 C and then H2O (28 mL) was carefully added, followed by 2 M HCl / H2O (28 mL). The 5 quenched reaction was allowed to stir 16 h at room temperature. The crude product was extracted from the reaction mixture by 5x liquid-liquid extraction of DCM (30 mL each). The combined DCM layers were stripped dry and then dissolved in 5% MeOH / DCM (10 mL). The crude product was purified on a 80 g silica column with a DCM to 5% MeOH / DCM gradient over 20 minutes. The product fractions were combined and concentrated, followed by high vacuum to 10 give I-14 (0.100 g, 47% yield) as a tan solid. (ESI) m / z: [M+H]+ = 305.94. To a MW vial was added I-14 (80 mg, 0.262 mmol, 1 eq) and I-2 (69 mg, 0.262 mmol, 1. eq). Toluene (11 mL) was added and followed by brief sonication to ensure I-2 dissolved. PTSA (25 mg, 0.131 mmol, 0.5 eq) was added to the MW vial and the headspace was flushed with Argon. The vial was irradiated in the microwave at 130 C for 17 h. The crude product was 15 transferred to a RBF by (1:1) (DCM:MeOH) then dissolved in 5% MeOH / DCM (5 mL). The crude product was purified on a 40 g silica column with a DCM to 5% MeOH / DCM gradient over 20 minutes. The product fractions were combined and concentrated, followed by high vacuum to give I-15 (54.4 mg, 39% yield) as a white solid. (ESI) m / z: [M+H]+ = 533.00. To an oven dried vial was added I-15 (54 mg, 0.101 mmol, 1 eq) was added HMPA 20 (0.307 ml). To the vial was added H2O (0.055 mL) and heated to 101 C for 8 h whereupon LCMS indicated the reaction was mostly complete. The reaction was directly purified by reverse phase (Teledyne 50 g C18 (5µm C18110Å 150 x 30 mm) with (5% ACN+0.05%FA) / (H2O+0.05%FA) to 95% (ACN+0.05%FA) / (H2O+0.05%FA) gradient). The product was obtained by lyophilization to give 50 (1.2 mg, 2.5% yield) as a white solid. (ESI) 25 m / z: [M+H]+ = 471.08. Example 17: Synthesis of Payloads 97 and 52: 75 NJB0009PCT Br Br Br TiCl4, Dichloromethyl etherOTf2O, DMAPOH Tf 7-brom Ethylene Glycol, PPTS Benzophenoneimine Cs2CO3O l F ield O O O ene 90.49 mmol, 1 eq.) was stirred in anhydrous DCM (200 mL) at 0 °C for 15 minutes. Add 7- bromonapthalen-2-ol (20 g, 90.49 mmol, 1 eq.) portion wise to the resulting mixture. Warm the 5 reaction mixture to room temperature. Allow the reaction to stir overnight. Quench the reaction mixture by ice. Extract the aqueous layer with DCM (3 x 200 mL). The combined organic layer was dried over Na2SO4 and filtered and concentrated to give crude mass which was purified using silica gel column chromatography to afford I-16 as a white solid (15 g, 66 %). (ESI) m / z: [M+1]+ = 251.0. 76 NJB0009PCT To a stirred solution of I-16 (15 gm, 5.97 mmol, 1.0 eq.) in anhydrous DCM (150 ml), DMAP (14.58 gm, 119.52 mmol, 2 eq.) was added at 0 °C under nitrogen atmosphere, followed by addition of Triflic anhydride (12.03 mL, 71.71 mmol, 1.2 eq.) and the resulting mixture was stirred at room temperature for 1 hours. After completion of reaction, it was quenched with ice 5 cold water and extracted with DCM (3 x 30 mL) the combined organic layer was dried over Na2SO4 and filtered and concentrated to give crude mass which was purified using silica gel column chromatography to afford Compound I-17 as a white solid (13 g, 57%). (ESI) m / z: [M+1]+ = 383.0. To a stirred solution of Compound I-17 (27 gm, 70.47 mmol, 1.0 eq.) in Toluene (270 10 mL), PPTS (0.885 gm, 3.52 mmol, 0.05 eq.) and ethylene glycol (12.4 mL, 246.6 mmol, 3.5 eq.) was added under nitrogen atmosphere, and the resulting mixture was heated to reflux for 16h using Dean-Stark apparatus. The progress of reaction was monitored by TLC after completion of reaction it was quenched with ice cold water and extracted with ethyl acetate (3 X 30 mL) the combined organic layer was dried over Na2SO4, filtered and concentrated to give crude mass 15 which was purified using silica gel column chromatography [hexane: Ethyl acetate =40:60) to afford Compound I-18 as a white solid (27 g, 90%). (ESI) m / z: [M+1]+ = 427.0 To a stirred solution of Compound I-18 in (20 g, 46.8 mmol, 1 eq.) in Dioxane (200 mL), Benzophenone imine (7.8 mL, 46.8 mmol, 1 eq.) and Cs2CO3 (30.49 g, 93.6 mol, 2 eq.) was added and reaction was degassed with nitrogen for 10 min. Then Palladium acetate (1 g, 4.68 20 mmol, 0.1 eq.) and BINAP (2.91 g, 4.68 mmol, 0.1 eq.) was added, and reaction was reflux in preheated oil bath to 100 °C for 2 h. After completion of reaction was filtered through celite and filtrate was concentrated to give crude mass which was purified using silica gel column chromatography [hexane: Ethyl acetate =40:60) to afford Compound I-19 as a white solid (5.26 g, 24.51 %). (ESI) m / z: [M+1]+ = 458.0 25 To a stirred solution of Compound I-19 (5.26 g, 11.47 mmol, 1 eq.) in THF (40 mL) was added hydrochloric acid (2M in water; 14 mL) at 0° C and the mixture was stirred at room temperature for 1 h. After completion of reaction aq. Sodium bicarbonate solution was added and extracted with Ethyl acetate (3 x 20 mL) The obtained organic layer was dried over Na2SO4 and concentrated to give crude mass which was purified using silica gel column chromatography 30 [hexane: Ethyl acetate =40:60) to afford I-20 as a brown solid. (2.4 g, 85.71 %). (ESI) m / z: [M+1]+ = 250.0. 77 NJB0009PCT To a RBF was added I-20 (600 mg, 2.399 mmol, 1 eq) and I-2 (632 mg, 2.399 mmol, 1. eq). Toluene (34 mL) was added and followed by brief sonication to ensure I-2 dissolved. PTSA (228 mg, 1.2 mmol, 1.2 eq) was added to the RBF with Argon. The RBF was refluxed for 17 h. The crude reaction was distilled to dryness, followed by (2x) resuspension in (15 mL) toluene 5 and distillation to dryness. The crude product was transferred to a RBF by (1:1) (DCM:MeOH) then dissolved in 5% MeOH / DCM (5 mL). The crude product was purified on a 120 g silica column with a DCM to 30% MeOH / DCM gradient over 20 minutes. The product fractions were combined and concentrated, followed by high vacuum to give I-21 (1.052 g, 91% yield) as a solid. (ESI) m / z: [M+H]+ = 476.99. 10 To a suspension of I-21 (223 mg, 0.466 mmol, 1 eq) in toluene (15 mL), was added bis(pinacolato)diboron (142 mg, 0.56 mmol, 1.2 eq), bistriphenylphosphine palladium (II) chloride (16 mg, 0.023 mmol, 0.05 eq), and potassium acetate (114 mg, 1.166 mmol, 2.5 eq). The solution was sparged with Ar for 15 min, then heated to 100 C for 72 h. The crude product was filtered through celite, washed with methanol, and stripped dry. The residue was dissolved 15 in DMF and purified by reverse phase on C18 (150 g) using H2O / ACN gradient (0.05% TFA additive). The recovered product was obtained via lyophilization to give 97 (65.2 mg, 32% yield) as a white solid. (ESI) m / z: [M+H]+ = 443.16. To a solution of 97(7 mg, 0.015 mmol, 1 eq) in methanol (3 mL) was added hydrogen peroxide urea (16.3 mg, 0.051 mmol, 3.5 eq) and the reaction was stirred at room temperature for 20 1 h. The reaction was stripped dry and the residue was dissolved in DMF and purified via reverse phase (C1850 g) using a gradient of H2O / ACN (0.05% TFA additive). The recovered product was obtained via lyophilization to give 52 (1.3 mg, 18% yield) as a white solid. (ESI) m / z: [M+H]+ = 415.23. Example 18: Synthesis of Payload 98 and 55: 78 NJB0009PCT Br BrTf O, DBrO MAPOTiCl , Dichloromet24hyl ether H H Tf 8-bro Br O Br Benzophenoneimine, Cs Ethylene Glycol, PPTSO2CO3O Pd(OAc)2, BINAP Toluene O Dioxane 68% yield crude taken to next stepPh O N O O O O O A solution of TiC 2.0mL, 22.32 mmol) in anhydrous dichloromethane (50 mL) stirred at 0 °C for 15 minutes. Then 8-bromo- naphthalene-2-ol (5 g, 22.32 mmol) was added portion-wise. The resulting mixture warmed to 5 room temperature and stirred for 16h. The reaction mixture was quenched with ice, extracted the aqueous layer with DCM (3 x 50 mL). Combined organic layer dried over Na2SO4, filtered and concentrated under reduced pressure. The reduce was purified by combi-flash by using a gradient EtOAc / hexane (1-10% EtOAc) to afford Compound I-22 as an off white solid (1.5 g, 27%). (ESI) m / z: [M+H]+= 251.0) 79 NJB0009PCT To a stirred solution of Compound I-22 (1.5 gm, 5.97 mmol) in anhydrous DCM (15 ml), DMAP (1.4 g, 11.94 mmol) was added at 0 °C under nitrogen atmosphere, followed by addition of Triflic anhydride (1.2 mL, 7.16 mmol) and the resulting reaction mixture was stirred at room temperature for 1h. After completion of reaction, it was quenched with ice cold water and 5 extracted with DCM (3 x 20 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated to give crude mass which was purified using silica gel column chromatography to afford Compound I-23 as an off white solid (1.2 g, 52%). (ESI) m / z: [M+H]+= 383.0) To a stirred solution of Compound I-23 (1.2 g, 3.185 mol) in Toluene (12 mL), PPTS (0.04 g, 0.159 mol) and ethylene glycol (0.6 mL, 10.96 mmol) were added under nitrogen 10 atmosphere. The resulting reaction mixture was heated to reflux for 16h using Dean- Stark apparatus. The progress of reaction was monitored by TLC after completion of reaction it was quenched with ice cold water and extracted with ethyl acetate (3 x 20 mL) the combined organic layer was dried over Na2SO4, filtered and concentrated to give crude mass which was purified by combi-flash using a gradient EtOAc / hexane (1-10% EtOAc). Compound I-24 as an off white 15 solid (0.9 g, 68%). (ESI) m / z: [M+H]+= 427.0) To the stirred solution of Cs2CO3(12.18 g, 37.4 mmol) in dioxane (80 mL), palladium acetate (0.20 g, 0.93 mmol) and BINAP (3.4 g, 5.61 mmol) were added. The resulting reaction mixture was degassed with nitrogen for 10 min. and then stirred at 100 °C for 1 h. Then Compound I-24 (8.0 g, 1.87 mmol) was added followed by addition of solution of 20 Benzophenone imine (4.2 mL, 18.7 mmol) in toluene. The resulting reaction mixture was allowed to stir at 80 °C for 12 h. After completion of reaction, the reaction mixture was filtered through celite, and filtrate was concentrated to give crude compound I-25 as a brown solid which was used in next step without purification. (9 g crude). (ESI) m / z: [M+H]+= 458.0) To the stirred solution of Compound I-25 (9.0 g, 0.0131 mol) in THF (40 mL) and water 25 (40 mL) hydrochloric acid (2M in water; 40 mL) was added at 0 °C and the mixture was stirred at room temperature for 1h. After completion of reaction, aq. sodium bicarbonate solution was added and extracted with Ethyl acetate (3 X 100 mL). The combined organic layer was dried over Na2SO4 and concentrated to give crude mass which was purified by combi-flash using a gradient EtOAc / hexane (20-30% EtOAc) to afford I-26 as a brown solid (0.250 g, 5% over 2 30 steps). (ESI) m / z: [M+H]+= 250.0). 80 NJB0009PCT To a RBF, was added I-26 (218 mg, 0.872 mmol, 1 eq) and I-2 (229 mg, 0.872 mmol, 1. eq). Toluene (3.5 mL) was added and followed by brief sonication to ensure I-2 dissolved. PTSA (83 mg, 0.436 mmol, 1.2 eq) was added to the RBF with Argon. The RBF was refluxed for 17 h. The crude reaction was distilled to dryness, followed by (2x) resuspension in (3 mL) toluene and 5 distillation to dryness. The crude product was transferred to a RBF by (1:1) (DCM:MeOH) then dissolved in 5% MeOH / DCM (5 mL). The crude product was purified on a 40 g silica column with a DCM to 30% MeOH / DCM gradient over 20 minutes. The product fractions were combined and concentrated, followed by high vacuum to give 98 (320 mg, 77% yield) as a solid. (ESI) m / z: [M+H]+ = 477.04. 10 To a vial was added 98 (70 mg, 0.147 mmol, 1 eq), copper iodide (33.5 mg, 0.176 mmol, 1.2 eq), NaN3(48 mg, 0.735 mmol, 5 eq), and sodium L-ascorbate (29 mg, 0.147 mmol, 1 eq) and dissolved in a (7:1) solution of (EtOH:H2O) (4 mL). N,N-dimethylethylenediamine (63 uL, 0.588 mmol, 4 eq) was added to the vial and refluxed at 80 C for 16 h. The crude product was concentrated and purified by normal phase chromatography by dissolving in 5% MeOH / DCM (2 15 mL) with 40 g silica DCM to 30% MeOH / DCM gradient over 20 minutes. The product fractions were combined and concentrated, followed by high vacuum to give 55 (30 mg, 49% yield) as a white solid. (ESI) m / z: [M+H]+ = 414.12. Example 19: Synthesis of Payload 57: 81 NJB0009PCT Br Br Br O O TiCl4, Dichloromethyl ether Tf2O, DMAP Ethylene Glycol, PPTS H H DCM DCM Toluene H66% H57% yield Tf90% yieldhalen-2-ol Br Br3Br Benzophenoneimine, Cs2CO O O NH2 N O Br NH23DA O O chlor , 4 mmol) in anhydrous dichloromethane (100 mL) at 0 °C for 15 minutes. The solution of 7-bromo- naphthalene-2-ol (10 g, 4 mmol) in DCM (30 mL) was added dropwise to the reaction mixture. 5 Warm the reaction mixture to room temperature. Allow the reaction to stir overnight. Quench the reaction mixture by adding 1N HCl (10 mL). Extract the aqueous layer with DCM (3 X 100 mL). Combine the organic layers. Dry the organic layers with Na2SO4. Reduce the organic layers to dryness. Purified the residue by using a gradient EtOAc / hexane solvent system (1- 10% EtOAc) afford Compound I-27 as an off white solid (9.8 g, 85%). (ESI) m / z: [M+H]+= 251.0) 10 To the stirred solution of Compound I-27 (5 g, 19.92 mmol) in anhydrous DCM (50 ml), DMAP (2.91 g, 21.91 mmol) was added at 0°C under nitrogen atmosphere, followed by addition of Triflic anhydride (4.0 mL, 21.91 mmol) and the resulting mixture was stirred at RT for 1h. After completion of reaction, it was quenched with ice cold water and extracted with DCM (3 X 100 mL). The combined organic layer was dried over Na2SO4 and filtered and concentrated to 15 give crude mass which was purified using silica gel column chromatography to afford Compound I-28 as a white solid (5.2 g, 67%). (ESI) m / z: [M+H]+= 383.0) 82 NJB0009PCT To the stirred solution of Compound I-28 (5.0 gm, 13.05 mmol) in Toluene (50 mL), PPTS (0.173 gm, 0.69 mmol) and ethylene glycol (2.7 mL, 48 mmol) was added under nitrogen atmosphere, and the resulting mixture was heated to reflux for 16h using Dean- Stark apparatus. The progress of reaction was monitored by TLC. After completion of reaction, it was quenched 5 with ice cold water and extracted with ethyl acetate (3 X 50 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated to give crude mass which was purified using silica gel column chromatography [hexane: Ethyl acetate =40:60) to afford Compound I-29 as an off white solid (4.9 g, 87 %). (ESI) m / z: [M+H]+= 427.0) To the stirred solution of Compound I-29 in (4.0 g, 9.36 mmol) in Dioxane (60 mL), 10 Benzophenone imine (3.83 g, 18.73 mmol) and Cs2CO3(6.87 g, 18.73 mmol) were added and the reaction was degassed with nitrogen for 10 min. Then Palladium acetate (0.118 g, 0.468 mmol) and BINAP (0.658 g, 0.936 mmol) were added, and reaction was heated to 100 °C for 3h. After completion of reaction was filtered through celite and filtrate was concentrated to give crude mass which was purified using silica gel column chromatography [hexane: Ethyl acetate 15 =40:60) to afford Compound I-30 as an off-white solid (2.7 g, 62%). (ESI) m / z: [M+H]+= 458.0). To the stirred solution of Compound I-30 (2.0 g, 4.37 mmol) in THF (50 mL) was added hydrochloric acid (2M in water; 100 mL) and the mixture was stirred at 0 °C for 2h. After completion of reaction, it was extracted with ethyl acetate (3 x 25 mL) The combined organic 20 layer was dried over Na2SO4and concentrated to give crude mass which was purified using silica gel column chromatography [hexane: Ethyl acetate =40:60) to afford I-31 as a pale-yellow solid. (0.7 g, 68%). (ESI) m / z: [M+H]+= 250.0). To a RBF, was added I-31 (683 mg, 2.73 mmol, 1 eq) and I-2 (645 mg, 2.73 mmol, 1. eq). Toluene (11 mL) was added and followed by brief sonication to ensure I-2 dissolved. PTSA 25 (200 mg, 1.37 mmol, 0.5 eq) was added to the RBF with Argon. The RBF was refluxed for 17 h. The crude reaction was distilled to dryness, followed by (2x) resuspension in (10 mL) toluene and distillation to dryness. The crude product was transferred to a RBF by (1:1) (DCM:MeOH) then dissolved in 5% MeOH / DCM (5 mL). The crude product was purified on a 80 g silica column with a DCM to 30% MeOH / DCM gradient over 20 minutes. The product fractions were 30 combined and concentrated, followed by high vacuum to give I-32 (320 mg, 77% yield) as a solid. (ESI) m / z: [M+H]+ = 477.04. 83 NJB0009PCT To a vial was added I-32 (100 mg, 0.209 mmol, 1 eq), copper iodide (60 mg, 0.314 mmol, 1.5 eq), NaN3 (37 mg, 1.046 mmol, 5 eq), and sodium L-ascorbate (62 mg, 0.314 mmol, 1.5 eq) and dissolved in a (7:3) solution of (EtOH:H2O) (5 mL). N,N-dimethylethylenediamine (90 uL, 0.838 mmol, 4 eq) was added to the vial and refluxed at 80 C for 16 h. The crude product 5 was concentrated and purified by normal phase chromatography by dissolving in 5% MeOH / DCM (2 mL) with 80 g silica DCM to 30% MeOH / DCM gradient over 20 minutes. The product fractions were combined and concentrated, followed by high vacuum to give 57 (59.7 mg, 69% yield) as a white solid. (ESI) m / z: [M+H]+ = 414.34. Example 20: Synthesis of Payload 59: Br BrTf O,BrO DMAP TiCl , Dichlo2 O4romethyl ether H D M H O NH2O 10 , 4 mmol) in anhydrous dichloromethane (100 mL) at 0 °C for 15 minutes. Add a solution of 6- bromo-2-naphthol (10 g, 4 mmol) in DCM (30 mL) dropwise to the resulting mixture. Warm the reaction mixture to room temperature. Allow the reaction to stir overnight. Quench the reaction 15 mixture by adding 1N HCl (10 mL). Extract the aqueous layer with DCM (3 X 100 mL). Combine the organic layers. Dry the organic layers with Na2SO4. Reduce the organic layers to dryness. Purified the residue by using a gradient EtOAc / hexane solvent system (1- 10% EtOAc) afford Compound I-33 as an off white solid (9.8 g, 85%). (ESI) m / z: [M+H]+= 251.0) 84 NJB0009PCT To the stirred solution of Compound I-33 (5 g, 19.92 mmol) in anhydrous DCM (50 ml), DMAP (2.91 g, 21.91 mmol) was added at 0°C under nitrogen atmosphere, followed by addition of Triflic anhydride (4.0 mL, 21.91 mmol) and the resulting mixture was stirred at RT for 1h. After completion of reaction, it was quenched with ice cold water and extracted with DCM (3 X 5 100 mL). Then, the combined organic layer was dried over Na2SO4 and filtered and concentrated to give crude mass which was purified using silica gel column chromatography to afford Compound I-34 as a white solid (5.2 g, 67 %). To a stirred solution of Compound I-34 (5.0 gm, 13.05 mmol) in Toluene (50 mL), PPTS (0.173 gm, 0.69 mmol) and ethylene glycol (2.7 mL, 48 mmol) was added under nitrogen 10 atmosphere, and the resulting mixture was heated to reflux for 16h using Dean- Stark apparatus. The progress of reaction was monitored by TLC. After completion of the reaction, it was quenched with ice cold water and extracted with ethyl acetate (3 X 50 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated to give crude mass which was purified using silica gel column chromatography [hexane: Ethyl acetate =40:60) to afford 15 Compound I-35 as an off white solid (4.9 g, 87 %). To a stirred solution of Compound I-35 in (4.0 g, 9.36 mmol) in Dioxane (60 mL), Benzophenone imine (3.83 g, 18.73 mmol) and Cs2CO3(6.87 g, 18.73 mmol) was added, and the reaction was degassed with nitrogen for 10 min. Then, Palladium acetate (0.118 g, 0.468 mmol) and BINAP (0.658 g, 0.936 mmol) were added, and the reaction was heated to 100 °C for 3h. 20 After completion of the reaction, it was filtered through celite and filtrate was concentrated to give crude mass which was purified using silica gel column chromatography [hexane: Ethyl acetate =40:60) to afford Compound I-36 as an off white solid (2.7 g, 62 %). (ESI) m / z: [M+H]+= 458.0) To a stirred solution of Compound I-36 (2.0 g, 4.37 mmol) in THF (50 mL) was added 25 hydrochloric acid (2M in water; 100 mL) and the mixture was stirred at 0 °C for 2h. After completion of the reaction, it was extracted with Ethyl acetate (3 x 25 mL). The combined organic layer was dried over Na2SO4and concentrated to give crude mass which was purified using silica gel column chromatography [hexane: Ethyl acetate =40:60) to afford I-37 as a pale- yellow solid. (0.7 g, 68 %). (ESI) m / z: [M+H]+= 250.0). 30 To a RBF, was added I-37 (600 mg, 2.40 mmol, 1 eq) and I-2 (632 mg, 2.40 mmol, 1. eq). Toluene (34 mL) was added and followed by brief sonication to ensure I-2 dissolved. PTSA 85 NJB0009PCT (228 mg, 1.20 mmol, 0.5 eq) was added to the RBF with Argon. The RBF was refluxed for 17 h. The crude reaction was distilled to dryness, followed by (2x) resuspension in (25 mL) toluene and distillation to dryness. The crude product was transferred to a RBF by (1:1) (DCM:MeOH) then dissolved in 5% MeOH / DCM (5 mL). The crude product was purified on a 80 g silica 5 column with a DCM to 30% MeOH / DCM gradient over 20 minutes. The product fractions were combined and concentrated, followed by high vacuum to give I-38 (833 mg, 73% yield) as a solid. (ESI) m / z: [M+H]+ = 476.99. To a vial was added I-38 (220 mg, 0.41 mmol, 1 eq), copper iodide (96 mg, 0.504 mmol, 1.2 eq), NaN3 (136 mg, 2.1 mmol, 5 eq), and sodium L-ascorbate (84 mg, 0.210 mmol, 1.5 eq) 10 and dissolved in a (7:3) solution of (EtOH:H2O) (10 mL). N,N-dimethylethylenediamine (184 uL, 1.64 mmol, 4 eq) was added to the vial and refluxed at 80 C for 16 h. The crude product was concentrated and purified by normal phase chromatography by dissolving in 5% MeOH / DCM (2 mL) with 80 g silica DCM to 30% MeOH / DCM gradient over 20 minutes. The product fractions were combined and concentrated, followed by high vacuum to give 59 (184 mg, 97% yield) as a 15 white solid. (ESI) m / z: [M+H]+ = 414.12. Example 21: Synthesis of Payload 63: Br O O tributylstannyl)methanol (31.7 mg, 0.099 mmol, 1.5 eq), and dioxane (1 mL). The solution was 20 sparged with N2for 10 minutes to degas, followed by the addition of Pd(Ph3)4(3.8 mg, 0.003 mmol, 0.05 eq). The reaction was stirred at 80 C for 16 h. The reaction was loaded directly on reverse phase (Gemini Column) ACN / H2O (0.05% formic acid additive). The recovered desired product was lyophilized to obtain 63 (3.4 mg, 12% yield) as a white solid. (ESI) m / z: [M+H]+ = 429.07. 25 Example 22: Synthesis of Payload 64: 86 NJB0009PCT OH Br O O tributylstannyl)methanol (350 mg, 1.091 mmol, 1.5 eq), and dioxane (18 mL). The solution was sparged with N2for 10 minutes to degas, followed by the addition of Pd(Ph3)4(42 mg, 0.042 5 mmol, 0.05 eq). The reaction was stirred at 80 C for 72 h. The reaction was loaded directly on reverse phase (150 g C18Aq Column) ACN / H2O (0.05% trifluoroacetic acid additive). The recovered desired product was lyophilized to obtain 64 (3.4 mg, 12% yield) as a white solid. (ESI) m / z: [M+H]+ = 429.17. Example 23: Synthesis of Payload 65: OH O 10 O tributylstannyl)methanol (327 mg, 1.02 mmol, 1.5 eq), and dioxane (19 mL). The solution was sparged with N2for 10 minutes to degas, followed by the addition of Pd(Ph3)4(39 mg, 0.034 mmol, 0.05 eq). The reaction was stirred at 80 C for 48 h. The reaction was loaded directly on 15 reverse phase (150 g C18Aq Column) ACN / H2O (0.05% trifluoroacetic acid additive). The recovered desired product was lyophilized to obtain 65 (101 mg, 35% yield) as a white solid. (ESI) m / z: [M+H]+ = 429.03. Example 24: Synthesis of Payload 100: 87 NJB0009PCT NH2NH2Cl HO O O q), and copper iodide (1.4 mg, 0.008 mmol, 0.10 eq) was added lithium tert-butoxide (12.1 mg, 0.151 mmol, 2 eq). The vial was evacuated and backfilled (3x) with Ar. To the vial was added I-3 (34 5 mg, 0.076 mmol, 1 eq) in DMF (1 mL). The reaction was heated at 110 C for 4 h whereupon the LCMS indicated product formation and consumption of I-3. The reaction was loaded directly on reverse phase (Gemini Column) ACN / H2O (0.05% trifluoroacetic acid additive). The recovered desired product was lyophilized to obtain 100 (0.6 mg, 1.6% yield) as a white solid. (ESI) m / z: [M+H]+ = 504.29. 10 Example 25: Synthesis of Payload 101: O O t O O 88 NJB0009PCT To the suspension of 7-bromo-naphthalen-2-amine (7.0 g, 31.51 mmol) in DCE (20 mL), BCl3 (31.5mL, 31.5 mmol, 1M in DCM) was added at 0 °C under nitrogen atmosphere, followed by addition of isovaleronitrile (6.6 mL, 63.37 mmol) and AlCl3 (5.02 g, 37.81 mmol), The resulting mixture was stirred at room temperature for 10 min. and then heated to reflux for 72h. 5 After completion of reaction, reaction mixture quenched with dil. HCl. Reaction mixture again heated at 80 °C for 16h. reaction mixture cooled to room temperature and extracted with Ethyl acetate (2 X 150 ml). Organic layer collectively washed with brine, dried over sodium sulphate and concentrated to give crude mass. The obtained crude was subjected to column purification using silica gel column chromatography [Pet ether: EtOAc =80: 20 to afford I-39 as a yellow 10 solid (3.3 g, 34 %). (ESI) m / z: [M+H]+= 306.0). To a RBF, was added I-39 (1.07 g, 3.508 mmol, 1 eq) and I-2 (923 mg, 3.508 mmol, 1. eq). Toluene (50 mL) was added and followed by brief sonication to ensure I-2 dissolved. PTSA (334 mg, 1.754 mmol, 0.5 eq) was added to the RBF with Argon. The RBF was refluxed for 17 h. The crude reaction was distilled to dryness, followed by (2x) resuspension in (25 mL) toluene 15 and distillation to dryness. The crude product was transferred to a RBF by (1:1) (DCM:MeOH) then dissolved in 5% MeOH / DCM (5 mL). The crude product was purified on a 120 g silica column with a DCM to 30% MeOH / DCM gradient over 20 minutes. The product fractions were combined and concentrated, followed by high vacuum to give I-40 (833 mg, 73% yield) as a solid. (ESI) m / z: [M+H]+ = 476.99. 20 To an oven dried vial was added Pd2(dba)3(17.6 mg, 0.019 mmol, 0.1 eq), Pd (t-BuPh3)2(9.8 mg, 0.019 mmol, 0.1 eq), and I-40 (102 mg, 0.191 mmol, 1 eq). The vial was purged with Ar for 10 min at room temperature. Dioxane (2.4 mL) was added to the vial and stirred for 10 min at room temperature. A solution of allyl alcohol (13 mg, 0.23 mmol, 1.2 eq) and dicyclohexyl-NMe amine (37 mg, 0.192 mmol, 1 eq) in dioxane (2.4 mL) was added to the vial 25 containing the Pd catalysts and stirred at room temperature for 5 minutes. The reaction was then heated at 60 C for 1 h where the LCMS indicated the product was formed and I-40 was consumed. The solvent was evaporated and the residue was dissolved in (1:1) (MeOH:ACN) and purified by reverse phase chromatography (50 g C18) H2O / ACN (+0.05% formic acid). The product fractions were combined and lyophilized to give 101 (62 mg, 64% yield) as a white 30 solid. (ESI) m / z: [M+H]+ = 511.37. Example 26: Synthesis of Payload 102: 89 NJB0009PCT O HO O O id (0.5 uL, 0.009 mmol, 1.2 eq) in toluene (1 mL). NaBH(OAc)3(2.5 mg, 0.012 mmol, 1.5 eq) was added to the vial and stirred overnight at room temperature. Additional acetic acid (15 uL, 0.027 mmol, 3.6 eq) and 5 NaBH(OAc)3 (10 mg, 0.048 mmol, 6 eq) was added to push the reaction to completion. The reaction was evaporated to dryness and the residue was dissolved in (1:1) (MeOH:DCM), then diluted with (1:1) (ACN:H2O) and purified by reverse phase chromatography (24 g C18) H2O / ACN (+0.05% formic acid) gradient. The product fractions were combined and lyophilized to give 102 (3.2 mg, 80% yield) as a white solid. (ESI) m / z: [M+H]+ = 513.39. 10 Example 27: Synthesis of Payloads 103 and 105: OH O O O (1.1 mg, 0.002 mmol, 0.1 eq), and I-40 (12 mg, 0.022 mmol, 1 eq). The vial was purged with Ar for 10 min at room temperature. Dioxane (1.1 mL) was added to the vial and stirred for 10 min at 15 room temperature. A solution of homo-allyl alcohol (3.2 mg, 0.045 mmol, 2.0 eq) and dicyclohexyl-NMe amine (4.4 mg, 0.022 mmol, 1 eq) in dioxane (1.1 mL) was added to the vial containing the Pd catalysts and stirred at room temperature for 5 minutes. The reaction was then heated at 60 C for 1 h where the LCMS indicated the product was formed and I-40 was consumed. The solvent was evaporated and the residue was dissolved in (1:1) (MeOH:ACN) and 20 purified by reverse phase chromatography (50 g C18) H2O / ACN (+0.05% formic acid). The 90 NJB0009PCT product fractions (indenpendently) were combined and lyophilized to give 103 (8 mg, 68% yield) as a white solid. (ESI) m / z: [M+H]+ = 525.40 and 105 (2 mg, 17% yield) as a white solid. (ESI) m / z: [M+H]+ = 525.40. Example 28: Synthesis of Payload 104: OH OH O 5 O Pd / C (0.2 mg, 0.002 mmol, 0.1 eq). The vial was blanketed with Ar, then suspended in methanol (4 mL). The vial was evacuated and backfilled with H2. The vial was stirred for 2 h, whereupon the reaction was filtered through celite and concentrated. The residue was dissolved in methanol (1 mL) and 10 purified by reverse phase chromatography (24 g C18) H2O / ACN (+0.05% formic acid) gradient over 20 minutes. The recovered product fractions were combined and lyophilized to obtain 104 (5 mg, 60% yield) as a yellow solid. (ESI) m / z: [M+H]+ = 527.44. Example 29: Synthesis of Payload 106: NH Cl N O O 15 , , 9 mg, 0.336 mmol, 3 eq) followed by DMF (2.23 mL). The reaction was stirred for 45 minutes whereupon LCMS indicated the reaction was complete. The reaction was loaded on 100 g C18Aq (+0.05% trifluoroacetic acid) H2O / ACN gradient over 20 minutes. The product fractions were combined and lyophilized to obtain 106 (14.4 mg, 25% yield) as a white solid. (ESI) m / z: [M+H]+ = 20 497.10. 91 NJB0009PCT Example 30: Synthesis of Payload 107: N NBoc Cl H HN N O O zaspiro[2.5]octane (71.26 mg, 0.336 mmol, 3 eq) followed by DMF (2.23 mL). The reaction was stirred for 45 5 minutes whereupon LCMS indicated the reaction was complete. The reaction was loaded on 100 g C18Aq (+0.05% trifluoroacetic acid) H2O / ACN gradient over 20 minutes. The product fractions were combined and lyophilized to obtain I-41 as a white solid. (ESI) m / z: [M+H]+ = 623.39. To a vial containing I-41 (assumed 0.112 mmol) was added 4M HCl / dioxane (1.6 mL). 10 The reaction was stirred at room temperature for 2 h. The reaction was stripped dry upon completion and the residue was dissolved in (1:1) (H2O:ACN) (2 mL) and purified via reverse phase (50 g C18Aq) H2O / ACN (+0.05% trifluoroacetic acid) gradient over 20 minutes. The product fractions were recovered and lyophilized to obtain 107 (25 mg, 43% yield over two steps) as a white solid. (ESI) m / z: [M+H]+ = 523.28. 15 Example 31: Synthesis of Payload 108: 92 NJB0009PCT NHBoc Cl NHBoc N F F F O O ropiperazine (75 mg, 0.336 mmol, 3 eq) followed by DMF (2.23 mL). The reaction was stirred for 45 minutes whereupon LCMS indicated the reaction was complete. The reaction was loaded on 100 g 5 C18Aq (+0.05% trifluoroacetic acid) H2O / ACN gradient over 20 minutes. The product fractions were combined and lyophilized to obtain I-42 as a white solid. (ESI) m / z: [M+H]+ = 647.09. To a vial containing I-42 (assumed 0.112 mmol) was added 4M HCl / dioxane (1.6 mL). The reaction was stirred at room temperature for 2 h. The reaction was stripped dry upon completion and the residue was dissolved in (1:1) (H2O:ACN) (2 mL) and purified via reverse 10 phase (50 g C18Aq) H2O / ACN (+0.05% trifluoroacetic acid) gradient over 20 minutes. The product fractions were recovered and lyophilized to obtain 108 (29.7 mg, 50% yield over two steps) as a white solid. (ESI) m / z: [M+H]+ = 547.44. Example 32: Synthesis of Payload 109: 93 NJB0009PCT O O Cl HNNHBocNNHBocolin-2-ylmethyl- carbamate (73 mg, 0.336 mmol, 3 eq) followed by DMF (2.23 mL). The reaction was stirred for 45 minutes whereupon LCMS indicated the reaction was complete. The reaction was loaded on 5 100 g C18Aq (+0.05% trifluoroacetic acid) H2O / ACN gradient over 20 minutes. The product fractions were combined and lyophilized to obtain I-43 as a white solid. (ESI) m / z: [M+H]+ = 627.38. To a vial containing I-43 (assumed 0.112 mmol) was added 4M HCl / dioxane (1.6 mL). The reaction was stirred at room temperature for 2 h. The reaction was stripped dry upon 10 completion and the residue was dissolved in (1:1) (H2O:ACN) (2 mL) and purified via reverse phase (50 g C18Aq) H2O / ACN (+0.05% trifluoroacetic acid) gradient over 20 minutes. The product fractions were recovered and lyophilized to obtain 109 (23 mg, 39% yield over two steps) as a white solid. (ESI) m / z: [M+H]+ = 527.34. Example 33: Synthesis of Payload 110: 94 NJB0009PCT Cl HN N NHBocO O ridin-3-ylcarbamate (67 mg, 0.336 mmol, 3 eq) followed by DMF (2.23 mL). The reaction was stirred for 45 minutes whereupon LCMS indicated the reaction was complete. The reaction was loaded on 100 g 5 C18Aq (+0.05% trifluoroacetic acid) H2O / ACN gradient over 20 minutes. The product fractions were combined and lyophilized to obtain I-44 as a white solid. (ESI) m / z: [M+H]+ = 611.39. To a vial containing I-44 (assumed 0.112 mmol) was added 4M HCl / dioxane (1.6 mL). The reaction was stirred at room temperature for 2 h. The reaction was stripped dry upon completion and the residue was dissolved in (1:1) (H2O:ACN) (2 mL) and purified via reverse 10 phase (50 g C18Aq) H2O / ACN (+0.05% trifluoroacetic acid) gradient over 20 minutes. The product fractions were recovered and lyophilized to obtain 110 (15 mg, 26% yield over two steps) as a white solid. (ESI) m / z: [M+H]+ = 511.35. Example 34: Synthesis of Payload 111: 95 NJB0009PCT NBoc NBocCl O clohexyldiamine (85 mg, 0.336 mmol, 3 eq) followed by DMF (2.23 mL). The reaction was stirred for 45 minutes whereupon LCMS indicated the reaction was complete. The reaction was loaded on 100 g 5 C18Aq (+0.05% trifluoroacetic acid) H2O / ACN gradient over 20 minutes. The product fractions were combined and lyophilized to obtain I-45 as a white solid. (ESI) m / z: [M+H]+ = 665.44. To a vial containing I-45 (assumed 0.112 mmol) was added 4M HCl / dioxane (1.6 mL). The reaction was stirred at room temperature for 2 h. The reaction was stripped dry upon completion and the residue was dissolved in (1:1) (H2O:ACN) (2 mL) and purified via reverse 10 phase (50 g C18Aq) H2O / ACN (+0.05% trifluoroacetic acid) gradient over 20 minutes. The product fractions were recovered and lyophilized to obtain 111 (12 mg, 19% yield over two steps) as a white solid. (ESI) m / z: [M+H]+ = 565.54. Example 35: Synthesis of Payload 112: 96 NJB0009PCT Br Br Acetonitrile BCl AlCl O H2 In a 3-neck RBF, 7-bromonaphthalen-2-amine (2 g, 9.00 mmol, 1 eq) was dissolved in dichloroethane (20 mL) and cooled to 0 C. To the RBF, was added BCl3 / DCM (1 M), (7.2 mL, 7.204 mmol, 0.8 eq) and stirred for 5 minutes at 0 C. To the RBF, was added ACN (0.55 mL) 5 and the reaction was stirred for 5 minutes at 0 C. To the RBF, was added aluminum trichloride (1.561 g, 11.707 mmol, 1.3 eq) and stirred for 5 minutes at 0 C. The RBF was allowed to warm to room temperature and then setup for reflux at 120 C for 72 h. The reaction was cooled to room temperature and then was quenched with 5 N HCl (~50 mL) and stirred overnight at room temperature. The reaction was stripped dry and the residue was dissolved in (50:50)(H2O:ACN) 10 and injected onto C18415 g (+0.05% formic acid) gradient of H2O / ACN. The recovered product was combined and lyophilized to obtain I-46 (405 mg, 17% yield) as a tan solid. To a RBF, was added I-46 (108 mg, 0.410 mmol, 1 eq) and I-2 (108 mg, 0.410 mmol, 1. eq). Toluene (7 mL) was added and followed by brief sonication to ensure I-2 dissolved. PTSA (13 mg, 0.068 mmol, 0.2 eq) was added to the RBF with Argon. The RBF was refluxed for 17 h. 15 The crude reaction was distilled to dryness, followed by (2x) resuspension in (25 mL) toluene and distillation to dryness. The crude product was transferred to a RBF by (1:1) (DCM:MeOH) then dissolved in 5% MeOH / DCM (5 mL). The crude product was purified on a 40 g silica column with a DCM to 30% MeOH / DCM gradient over 20 minutes. The product fractions were combined and concentrated, followed by high vacuum to give 112 (81.8 mg, 40% yield) as a 20 solid. (ESI) m / z: [M+H]+ = 491.01. 97 NJB0009PCT Example 36: Synthesis of Payload 113: Br NH2O O 0.370 mmol, 1.5 eq), NaN3 (43 mg, 1.23 mmol, 5 eq), and sodium L-ascorbate (73 mg, 0.369 mmol, 1.5 eq) 5 and dissolved in a (7:3) solution of (EtOH:H2O) (6 mL). N,N-dimethylethylenediamine (106 uL, 0.985 mmol, 4 eq) was added to the vial and refluxed at 80 C for 16 h. The crude product was concentrated and purified by normal phase chromatography by dissolving in 5% MeOH / DCM (2 mL) with 40 g silica DCM to 30% MeOH / DCM gradient over 20 minutes. The product fractions were combined and concentrated, followed by high vacuum to give 113 (130.2 mg, 68% yield) 10 as a tan solid. (ESI) m / z: [M+H]+ = 428.35. Example 37: Synthesis of Payload 114: O N 7-brom Br NH2O O 98 NJB0009PCT To the suspension of 7-bromonaphthalen-2-amine (7.0 g, 31.53 mmol, ) in DCE (20 mL), BCl3 (31.5 mL, 31.5 mmol, 1M in DCM) was added at 0 °C under nitrogen atmosphere, followed by addition of propionitrile (4.4 mL, 63.06 mmol) and AlCl3 (5.03 gm, 37.83 mmol) the resulting mixture was stirred at RT for 10 min. and heated to reflux for 72h. After completion 5 of reaction, reaction mixture quenched with dil. HCl. Reaction mixture again heated at 80 °C for 16h. reaction mixture cooled to room temperature and extracted with ethyl acetate (2 X 150 ml). Organic layer collectively washed with brine, dried over sodium sulphate and concentrated to give crude mass. The obtained crude was subjected to column purification using silica gel column chromatography [EtOAc: Pet ether =80:20 to afford I-47 as a yellow solid (2.3 g, 26%). 10 (ESI) m / z: [M+H]+= 278.0). To a RBF, was added I-47 (1.0 g, 3.595 mmol, 1 eq) and I-2 (0.946 mg, 3.595 mmol, 1. eq). Toluene (51 mL) was added and followed by brief sonication to ensure I-2 dissolved. PTSA (342 mg, 1.798 mmol, 0.5 eq) was added to the RBF with Argon. The RBF was refluxed for 17 h. The crude reaction was distilled to dryness, followed by (2x) resuspension in (40 mL) toluene 15 and distillation to dryness. The crude product was transferred to a RBF by (1:1) (DCM:MeOH) then dissolved in 5% MeOH / DCM (5 mL). The crude product was purified on a 120 g silica column with a DCM to 30% MeOH / DCM gradient over 20 minutes. The product fractions were combined and concentrated, followed by high vacuum to give I-48 (1.290 g, 71% yield) as a solid. (ESI) m / z: [M+H]+ = 505.08. 20 To a vial was added I-48 (70 mg, 0.138 mmol, 1 eq), copper iodide (39 mg, 0.208 mmol, 1.5 eq), NaN3(24 mg, 0.693 mmol, 5 eq), and sodium L-ascorbate (41 mg, 0.208 mmol, 1.5 eq) and dissolved in a (7:3) solution of (EtOH:H2O) (5 mL). N,N-dimethylethylenediamine (60 uL, 0.554 mmol, 4 eq) was added to the vial and refluxed at 80 C for 16 h. The crude product was concentrated and purified by normal phase chromatography by dissolving in 5% MeOH / DCM (2 25 mL) with 40 g silica DCM to 30% MeOH / DCM gradient over 20 minutes. The product fractions were combined and concentrated, followed by high vacuum to give 114 (46 mg, 75% yield) as a white solid. (ESI) m / z: [M+H]+ = 442.31. Example 38: Synthesis of Payload 115: 99 NJB0009PCT O N O O ne, ight d 5-br O O O O mL), BCl3(38 mL, 37.8 mmol, 1M in DCM) was added at 0 °C under nitrogen atmosphere followed by addition propionitrile (2.64 mL, 37.8 mmol) and AlCl3(2.5 g, 18.91 mmol). The resulting 5 mixture was stirred at room temperature for 10 min. and heated to reflux for 72h. After completion of reaction, reaction mixture quenched with dil. HCl. The reaction mixture was heated to 80 °C for 16h. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (2 x 150 mL). Organic layer collectively washed with brine, dried over sodium sulphate and concentrated to give crude mass. The obtained crude was subjected to column 10 purification using silica gel column chromatography [Pet-ether-EtOAc =80: 20 to afford I-49 as a yellow solid (1.5 g, 50%). (ESI) m / z: [M+H]+= 278.0). To a RBF, was added I-49 (0.5 g, 1.798 mmol, 1 eq) and I-2 (0.473 mg, 1.798 mmol, 1. eq). Toluene (60 mL) was added and followed by brief sonication to ensure I-2 dissolved. PTSA (171 mg, 0.899 mmol, 0.5 eq) was added to the RBF with Argon. The RBF was refluxed for 17 15 h. The crude reaction was distilled to dryness, followed by (2x) resuspension in (40 mL) toluene and distillation to dryness. The crude product was transferred to a RBF by (1:1) (DCM:MeOH) then dissolved in 5% MeOH / DCM (5 mL). The crude product was purified on a 120 g silica column with a DCM to 30% MeOH / DCM gradient over 20 minutes. The product fractions were 100 NJB0009PCT combined and concentrated, followed by high vacuum to give I-50 (0.527 g, 58% yield) as a solid. (ESI) m / z: [M+H]+ = 505.22. To a vial was added I-50 (50 mg, 0.099 mmol, 1 eq), copper iodide (28 mg, 0.148 mmol, 1.5 eq), NaN3(17 mg, 0.494 mmol, 5 eq), and sodium L-ascorbate (29 mg, 0.148 mmol, 1.5 eq) 5 and dissolved in a (7:3) solution of (EtOH:H2O) (3 mL). N,N-dimethylethylenediamine (43 uL, 0.395 mmol, 4 eq) was added to the vial and refluxed at 80 C for 16 h. The crude product was concentrated and purified by normal phase chromatography by dissolving in 5% MeOH / DCM (2 mL) with 40 g silica DCM to 30% MeOH / DCM gradient over 20 minutes. The product fractions were combined and concentrated, followed by high vacuum to give 115 (9.2 mg, 21% yield) as a 10 white solid. (ESI) m / z: [M+H]+ = 442.36. Example 39: Synthesis of 116: O O tributylstannyl)methanol (85 mg, 0.266 mmol, 1.5 eq), and dioxane (4.4 mL). The solution was 15 sparged with N2 for 10 minutes to degas, followed by the addition of Pd(Ph3)4 (10 mg, 0.009 mmol, 0.05 eq). The reaction was stirred at 80 C for 48 h. The reaction was loaded directly on reverse phase (150 g C18Aq Column) ACN / H2O (0.05% trifluoroacetic acid additive). The recovered desired product was lyophilized to obtain 116 (9.6 mg, 12% yield) as a white solid. (ESI) m / z: [M+H]+ = 457.29. 20 Example 40: Synthesis of 117: O O NJB0009PCT To a vial was added I-40 (56 mg, 0.104 mmol, 1 eq), copper iodide (24 mg, 0.125 mmol, 1.2 eq), NaN3 (34 mg, 0.520 mmol, 5 eq), and sodium L-ascorbate (20 mg, 0.104 mmol, 1.0 eq) and dissolved in a (7:1) solution of (EtOH:H2O) (3 mL). N,N-dimethylethylenediamine (22 uL, 0.208 mmol, 2 eq) was added to the vial and refluxed at 80 C for 16 h. The crude product was 5 concentrated and purified by normal phase chromatography by dissolving in 5% MeOH / DCM (2 mL) with 40 g silica DCM to 30% MeOH / DCM gradient over 20 minutes. The product fractions were combined and concentrated, followed by high vacuum to give 117 (33.5 mg, 69% yield) as a white solid. (ESI) m / z: [M+H]+ = 470.33. Example 41: Synthesis of Payload 118: OH Br O O 10 tributylstannyl)methanol (109 mg, 0.342 mmol, 1.5 eq), and dioxane (5.7 mL). The solution was sparged with N2for 10 minutes to degas, followed by the addition of Pd(Ph3)4(13.2 mg, 0.011 mmol, 0.05 eq). The reaction was stirred at 80 C for 48 h. The reaction was loaded directly on 15 reverse phase (150 g C18Aq Column) ACN / H2O (0.05% trifluoroacetic acid additive). The recovered desired product was lyophilized to obtain 118 (36.6 mg, 36% yield) as a white solid. (ESI) m / z: [M+H]+ = 443.05. Example 42: Synthesis of Payload 119: O O 20 tributylstannyl)methanol (143 mg, 0.445 mmol, 1.5 eq), and dioxane (15 mL). The solution was 102 NJB0009PCT sparged with N2for 10 minutes to degas, followed by the addition of Pd(Ph3)4(17 mg, 0.015 mmol, 0.05 eq). The reaction was stirred at 80 C for 48 h. The reaction was loaded directly on reverse phase (150 g C18Aq Column) ACN / H2O (0.05% trifluoroacetic acid additive). The recovered desired product was lyophilized to obtain 119 (68.1 mg, 50% yield) as a white solid. 5 (ESI) m / z: [M+H]+ = 457.22. Example 43: Synthesis of Payload 120: O N O O O e, ht 7-brom Br O O o e suspens on o - romo-nap a en- -am ne . g, . mmo n CE (10 mL), BCl3(40.9 mL, 40.52 mmol, 1M in DCM) was added at 0 °C under nitrogen atmosphere, 10 followed by addition of compound isobutyronitrile (3.66 mL, 40.52 mmol) and AlCl3 ( 2.70 g, 20.26 mmol). The resulting mixture was stirred at room temperature for 10 min. and heated to reflux for 72h. After completion of reaction, reaction mixture quenched with dil. HCl. Reaction mixture again heated at 100 °C for 72h. reaction mixture cooled to room temperature and extracted with Ethyl acetate (2 x 100 mL). Organic layer collectively washed with brine, dried 15 over sodium sulphate and concentrated to give crude mass. The obtained crude was subjected to column purification using silica gel column chromatography [Pet ether: EtOAc =80: 20 to afford I-51 as a yellow solid (180 mg, 5 %). (ESI) m / z: [M+H]+= 292.0). 103 NJB0009PCT To a RBF, was added I-51 (0.1 g, 0.342 mmol, 1 eq) and I-2 (0.09 g, 0.342 mmol, 1. eq). Toluene (11 mL) was added and followed by brief sonication to ensure I-2 dissolved. PTSA (33 mg, 0.171 mmol, 0.5 eq) was added to the RBF with Argon. The RBF was refluxed for 17 h. The crude reaction was distilled to dryness, followed by (2x) resuspension in (11 mL) toluene and 5 distillation to dryness. The crude product was transferred to a RBF by (1:1) (DCM:MeOH) then dissolved in 5% MeOH / DCM (5 mL). The crude product was purified on a 120 g silica column with a DCM to 30% MeOH / DCM gradient over 20 minutes. The product fractions were combined and concentrated, followed by high vacuum to give I-52 (54.1 mg, 30.4% yield) as a solid. (ESI) m / z: [M+H]+ = 519.22. 10 To an oven dried vial was added I-52 (54 mg, 0.104 mmol, 1 eq), tributylstannyl)methanol (50 mg, 0.156 mmol, 1.5 eq), and dioxane (2.6 mL). The solution was sparged with N2 for 10 minutes to degas, followed by the addition of Pd(Ph3)4 (6 mg, 0.005 mmol, 0.05 eq). The reaction was stirred at 80 C for 48 h. The reaction was loaded directly on reverse phase (80 g C18Aq Column) ACN / H2O (0.05% trifluoroacetic acid additive). The 15 recovered desired product was lyophilized to obtain 120 (17.8 mg, 41% yield) as a white solid. (ESI) m / z: [M+H]+ = 471.31. Example 44: Synthesis of Payload 121: OH O O 20 tributylstannyl)methanol (262 mg, 0.816 mmol, 1.5 eq), and dioxane (36 mL). The solution was sparged with N2 for 10 minutes to degas, followed by the addition of Pd(Ph3)4 (31 mg, 0.027 mmol, 0.05 eq). The reaction was stirred at 80 C for 48 h. The reaction was loaded directly on reverse phase (150 g C18Aq Column) ACN / H2O (0.05% trifluoroacetic acid additive). The recovered desired product was lyophilized to obtain 121 (119 mg, 45% yield) as a white solid. 25 (ESI) m / z: [M+H]+ = 485.26. Example 45: Synthesis of Payload 122: 104 NJB0009PCT Br O O stannyl) ethanol (50 mg, 0.141 mmol, 1.5 eq), and dioxane (10 mL). The solution was sparged with N2 for 10 minutes to degas, followed by the addition of Pd(Ph3)4(5 mg, 0.005 mmol, 0.05 eq). The 5 reaction was stirred at 80 C for 48 h. The reaction was loaded directly on reverse phase (150 g C18Aq Column) ACN / H2O (0.05% trifluoroacetic acid additive). The recovered desired product was lyophilized to obtain 122 (3.9 mg, 9% yield) as a white solid. (ESI) m / z: [M+H]+ = 426.16. Example 46: Synthesis of Payload 123: OH O O 10 stannyl) ethanol (47 mg, 0.141 mmol, 1.5 eq), and dioxane (5 mL). The solution was sparged with N2 for 10 minutes to degas, followed by the addition of Pd(Ph3)4(5 mg, 0.005 mmol, 0.05 eq). The reaction was stirred at 80 C for 48 h. The reaction was loaded directly on reverse phase (150 g C18Aq Column) ACN / H2O (0.05% trifluoroacetic acid additive). The recovered desired product 15 was lyophilized to obtain 123 (48.6 mg, 100% yield) as a white solid. (ESI) m / z: [M+H]+ = 455.07. Example 47: Synthesis of Payload 124: 105 NJB0009PCT O N O N Propionitrile, BCl3, AlCl3NODCE, Reflux 23% yield yqui N O O O To a suspension of quinoli 8 mmol) in DCE (8 mL), BCl3(1.66 mL, 1.66 mmol, 1M in DCM) was added at 0 °C under nitrogen atmosphere followed by addition propionitrile (0.175 mL, 2.45 mmol) and AlCl3 (361 mg, 2.71 mmol). The resulting 5 mixture was stirred at room temperature for 10 min. and heated to reflux for 72h. After completion of reaction, reaction mixture quenched with dil. HCl. The reaction mixture was heated to 80 °C for 16h. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (2 x 150 mL). Organic layer collectively washed with brine, dried over sodium sulphate and concentrated to give crude mass. The obtained crude was subjected to column 10 purification using silica gel column chromatography (DCM:MeOH) = (80:20) to afford I-53 as a yellow solid (13 mg, 3%). (ESI) m / z: [M+H]+= 201.35). To a RBF, was added I-53 (13 mg, 0.065 mmol, 1 eq) and I-2 (17 mg, 0.065 mmol, 1. eq). Toluene (1.5 mL) was added and followed by brief sonication to ensure I-2 dissolved. PTSA (6 mg, 0.0325 mmol, 0.5 eq) was added to the RBF with Argon. The RBF was refluxed for 17 h. 15 The crude reaction was distilled to dryness, followed by (2x) resuspension in (2 mL) toluene and distillation to dryness. The crude product was transferred to a RBF by (1:1) (DCM:MeOH) then dissolved in 5% MeOH / DCM (5 mL). The crude product was purified on a 20 g silica column with a DCM to 30% MeOH / DCM gradient over 20 minutes. The product fractions were 106 NJB0009PCT combined and concentrated, followed by high vacuum to give 124 (14 mg, 51% yield) as a solid. (ESI) m / z: [M+H]+ = 428.54. Example 48: Synthesis of Payload 125: O N O O C 5 To a suspension of quinoline-7-ylamine (300 mg, 2.08 mmol) in DCE (8 mL), BCl3 (1.66 mL, 1.66 mmol, 1M in DCM) was added at 0 °C under nitrogen atmosphere followed by addition propionitrile (0.175 mL, 2.45 mmol) and AlCl3(361 mg, 2.71 mmol). The resulting mixture was stirred at room temperature for 10 min. and heated to reflux for 72h. After completion of reaction, reaction mixture quenched with dil. HCl. The reaction mixture was 10 heated to 80 °C for 16h. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (2 x 150 mL). Organic layer collectively washed with brine, dried over sodium sulphate and concentrated to give crude mass. The obtained crude was subjected to column purification using silica gel column chromatography (DCM:MeOH) = (80:20) to afford I-54 as a yellow solid (58 mg, 14%). (ESI) m / z: [M+H]+= 201.35). 15 To a RBF, was added I-54 (20.8 mg, 0.104 mmol, 1 eq) and I-2 (27 mg, 0.104 mmol, 1. eq). Toluene (2 mL) was added and followed by brief sonication to ensure I-2 dissolved. PTSA (10 mg, 0.052 mmol, 0.5 eq) was added to the RBF with Argon. The RBF was refluxed for 17 h. The crude reaction was distilled to dryness, followed by (2x) resuspension in (2 mL) toluene and distillation to dryness. The crude product was transferred to a RBF by (1:1) (DCM:MeOH) then 107 NJB0009PCT dissolved in 5% MeOH / DCM (5 mL). The crude product was purified on a 20 g silica column with a DCM to 30% MeOH / DCM gradient over 20 minutes. The product fractions were combined and concentrated, followed by high vacuum to give 125 (14 mg, 31% yield) as a solid. (ESI) m / z: [M+H]+ = 428.48. 5 Example 49: Synthesis of Payload 126: O N O C L), BCl3 (1.66 mL, 1.66 mmol, 1M in DCM) was added at 0 °C under nitrogen atmosphere followed by addition propionitrile (0.175 mL, 2.45 mmol) and AlCl3(361 mg, 2.71 mmol). The resulting 10 mixture was stirred at room temperature for 10 min. and heated to reflux for 72h. After completion of reaction, reaction mixture quenched with dil. HCl. The reaction mixture was heated to 80 °C for 16h. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (2 x 150 mL). Organic layer collectively washed with brine, dried over sodium sulphate and concentrated to give crude mass. The obtained crude was subjected to column 15 purification using silica gel column chromatography (DCM:MeOH) = (80:20) to afford I-55 as a yellow solid (10 mg, 3%). (ESI) m / z: [M+H]+= 201.37). To a RBF, was added I-55 (28 mg, 0.140 mmol, 1 eq) and I-2 (37 mg, 0.140 mmol, 1 eq). Toluene (2 mL) was added and followed by brief sonication to ensure I-2 dissolved. PTSA (13.3 mg, 0.07 mmol, 0.5 eq) was added to the RBF with Argon. The RBF was refluxed for 17 h. The 108 NJB0009PCT crude reaction was distilled to dryness, followed by (2x) resuspension in (2 mL) toluene and distillation to dryness. The crude product was transferred to a RBF by (1:1) (DCM:MeOH) then dissolved in 5% MeOH / DCM (5 mL). The crude product was purified on a 20 g silica column with a DCM to 30% MeOH / DCM gradient over 20 minutes. The product fractions were 5 combined and concentrated, followed by high vacuum to give 126 (4 mg, 7% yield) as a solid. (ESI) m / z: [M+H]+ = 428.52. Example 50: Synthesis of Payload 127: O N O O O oC To a suspension of 6-aminoquinoxaline (300 mg, 2.08 mmol) in DCE (8 mL), BCl3(1.66 10 mL, 1.66 mmol, 1M in DCM) was added at 0 °C under nitrogen atmosphere followed by addition propionitrile (0.175 mL, 2.45 mmol) and AlCl3 (361 mg, 2.71 mmol). The resulting mixture was stirred at room temperature for 10 min. and heated to reflux for 72h. After completion of reaction, reaction mixture quenched with dil. HCl. The reaction mixture was heated to 80 °C for 16h. The reaction mixture was cooled to room temperature and extracted 15 with ethyl acetate (2 x 150 mL). Organic layer collectively washed with brine, dried over sodium sulphate and concentrated to give crude mass. The obtained crude was subjected to column purification using silica gel column chromatography (DCM:MeOH) = (80:20) to afford I-56 as a yellow solid (60 mg, 14%). (ESI) m / z: [M+H]+= 202.32). 109 NJB0009PCT To a RBF, was added I-56 (15 mg, 0.075 mmol, 1 eq) and I-2 (20 mg, 0.075 mmol, 1 eq). Toluene (2 mL) was added and followed by brief sonication to ensure I-2 dissolved. PTSA (7.1 mg, 0.04 mmol, 0.5 eq) was added to the RBF with Argon. The RBF was refluxed for 17 h. The crude reaction was distilled to dryness, followed by (2x) resuspension in (2 mL) toluene and 5 distillation to dryness. The crude product was transferred to a RBF by (1:1) (DCM:MeOH) then dissolved in 5% MeOH / DCM (5 mL). The crude product was purified on a 20 g silica column with a DCM to 30% MeOH / DCM gradient over 20 minutes. The product fractions were combined and concentrated, followed by high vacuum to give 127 (8.5 mg,27% yield) as a solid. (ESI) m / z: [M+H]+ = 429.46. 10 Example 51: Synthesis of Payload 145, 128, and 128: O N O O Cl3(7.17 mL, 7.17 mmol, 1M in DCM) was added at 0 °C under nitrogen atmosphere followed by addition of acetonitrile (0.55 mL, 10.54 mmol) and AlCl3 (1.55 g, 11.66 mmol). The resulting 15 mixture was stirred at room temperature for 10 min. and heated to reflux for 72h. After completion of reaction, reaction mixture quenched with dil. HCl. The reaction mixture was heated to 80 °C for 16h. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (2 x 300 mL). Organic layer collectively washed with brine, dried over sodium 110 NJB0009PCT sulphate and concentrated to give crude mass. The obtained crude was subjected to column purification using silica gel column chromatography (DCM:MeOH) = (80:20) to afford I-57 as a yellow solid (1.609 g, 68%). (ESI) m / z: [M+H]+= 264.77). To a RBF, was added I-57 (512 mg, 1.93 mmol, 1 eq) and I-2 (508 mg, 1.93 mmol, 1 eq). 5 Toluene 50 mL) was added and followed by brief sonication to ensure I-2 dissolved. PTSA (184 mg, 0.966 mmol, 0.5 eq) was added to the RBF with Argon. The RBF was refluxed for 17 h. The crude reaction was distilled to dryness, followed by (2x) resuspension in (2 mL) toluene and distillation to dryness. The crude product was transferred to a RBF by (1:1) (DCM:MeOH) then dissolved in 5% MeOH / DCM (5 mL). The crude product was purified on a 150 g silica column 10 with a DCM to 30% MeOH / DCM gradient over 20 minutes. The product fractions were combined and concentrated, followed by high vacuum to give 145 (342 mg, 36 % yield) as a solid. (ESI) m / z: [M+H]+ = 421.97. To a solution of 145 (102 mg, 0.208 mmol, 1 eq), 4-aminophenylboronic acid pinocol ester (68 mg, 0.312 mmol, 1.5 eq), bis(diisopropylphosphino)ferrocene)dichloropalladium 15 dichloride (31 mg, 0.052 mmol, 0.25 eq) and DMF (15 mL) was added 2M Na2CO3 solution (1.73 mL) under Argon. The vial was sparged with Ar for 15 minutes at room temperature. The reaction was heated to 101 C for 2 h whereupon LCMS indicated the reaction was complete. The crude product was purified by reverse phase (C18Aq 100g) H2O / ACN (+0.05% TFA) gradient over 20 minutes. The product and byproducts were combined separately and lyophilized to give 20 128 (4.2 mg, 4% yield) and 151 (59 mg, 56% yield) as white powders. 128- (ESI) m / z: [M+H]+= 413.97. 151- (ESI) m / z: [M+H]+= 505.03. Example 52: Synthesis of Payload 129: 111 NJB0009PCT H H2N N FmocHN O MF d 2 mmol, 2 eq), and N-methylmorpholine (75 uL, 0.684 mmol, 4 eq) dissolved in DMF (1.5 mL). The vial was stirred for 5 minutes at room temperature, whereupon 59 (71 mg, 0.171 mmol, 1 5 eq) was added. The reaction showed completion by LCMS after 1 h at room temperature. The crude reaction was purified by reverse phase (C1850 g) H2O / ACN (+0.05% trifluoroacetic acid) gradient over 20 minutes. The product fractions were combined and lyophilized to give I-58 (32 mg, 27% yield) as a white solid. (ESI) m / z: [M+H]+= 707.50. To a vial containing I-58 (32 mg, 0.044 mmol, 1 eq) was added (1:4) (Morpholine:DMF) 10 (0.55 mL) and the reaction was stirred for 40 minutes at room temperature. The crude product was recovered by precipitation by diluting the crude reaction with diethyl ether (5 mL) and the solid was obtained by iterative centrifugation. The crude solid was dissolved in (1:1) (H2O:ACN) (+0.05% trifluoroacetic acid) and lyophilized to obtain 129 (18 mg, 68% yield) as a white solid. (ESI) m / z: [M+H]+= 485.39. 15 Example 53: Synthesis of Payload 130: 112 NJB0009PCT O FmocHN NH2NH MF .702 mmol, 2 eq), and N-methylmorpholine (154 uL, 1.404 mmol, 4 eq) dissolved in DMF (3 mL). The vial was stirred for 5 minutes at room temperature, whereupon 113 (150 mg, 0.351 mmol, 1 5 eq) was added. The reaction showed completion by LCMS after 1 h at room temperature. The crude reaction was purified by reverse phase (C18150 g) H2O / ACN (+0.05% trifluoroacetic acid) gradient over 20 minutes. The product fractions were combined and lyophilized to give I- 59 (66.8 mg, 26% yield) as a white solid. (ESI) m / z: [M+H]+= 721.43. To a vial containing I-59 (67 mg, 0.093 mmol, 1 eq) was added (1:4) (Morpholine:DMF) 10 (1.16 mL) and the reaction was stirred for 40 minutes at room temperature. The crude product was recovered by precipitation by diluting the crude reaction with diethyl ether (10 mL) and the solid was obtained by iterative centrifugation. The crude solid was dissolved in (1:1) (H2O:ACN) (+0.05% trifluoroacetic acid) and lyophilized to obtain 130 (42 mg, 74% yield) as a white solid. (ESI) m / z: [M+H]+= 499.33. 15 Example 54: Synthesis of Payload 131: 113 NJB0009PCT O FmocHN NH2NH MF mmol, 2 eq), and N-methylmorpholine (35 uL, 0.302 mmol, 4 eq) dissolved in DMF (3 mL). The vial was stirred for 5 minutes at room temperature, whereupon 114 (35 mg, 0.080 mmol, 1 eq) 5 was added. The reaction showed completion by LCMS after 1 h at room temperature. The crude reaction was purified by reverse phase (C1850 g) H2O / ACN (+0.05% trifluoroacetic acid) gradient over 20 minutes. The product fractions were combined and lyophilized to give I-60 (58.3 mg, 99% yield) as a white solid. (ESI) m / z: [M+H]+= 735.33. To a vial containing I-60 (58 mg, 0.079 mmol, 1 eq) was added (1:4) (Morpholine:DMF) 10 (0.99 mL) and the reaction was stirred for 40 minutes at room temperature. The crude product was recovered by precipitation by diluting the crude reaction with diethyl ether (10 mL) and the solid was obtained by iterative centrifugation. The crude solid was dissolved in (1:1) (H2O:ACN) (+0.05% trifluoroacetic acid) and lyophilized to obtain 131 (39.6 mg, 79% yield) as a white solid. (ESI) m / z: [M+H]+= 513.39. 15 Example 55: Synthesis of Payload 132: 114 NJB0009PCT O FmocHN NH2NH MFd mmol, 2 eq), and N-methylmorpholine (33 uL, 0.304 mmol, 4 eq) dissolved in DMF (2 mL). The vial was stirred for 5 minutes at room temperature, whereupon 117 (36 mg, 0.076 mmol, 1 eq) 5 was added. The reaction showed completion by LCMS after 1 h at room temperature. The crude reaction was purified by reverse phase (C1850 g) H2O / ACN (+0.05% trifluoroacetic acid) gradient over 20 minutes. The product fractions were combined and lyophilized to give I-61 (39 mg, 67% yield) as a white solid. (ESI) m / z: [M+H]+= 763.38. To a vial containing I-61 (39 mg, 0.051 mmol, 1 eq) was added (1:4) (Morpholine:DMF) 10 (0.73 mL) and the reaction was stirred for 40 minutes at room temperature. The crude product was recovered by precipitation by diluting the crude reaction with diethyl ether (3 mL) and the solid was obtained by iterative centrifugation. The crude solid was dissolved in (1:1) (H2O:ACN) (+0.05% trifluoroacetic acid) and lyophilized to obtain 132 (22.4 mg, 68% yield) as a white solid. (ESI) m / z: [M+H]+= 541.43. 15 Example 56: Synthesis of Payload 133: 115 NJB0009PCT O NHFmoc OH N O H MF d ly- Fmoc (434 mg, 1.179 mmol, 5 eq) and suspended in Anhydrous DMF (3.37 mL) with a brief sonication under Ar. To the vial, 1M HCl etherate (0.236 mL, 0.471 mmol, 2 eq) was added 5 dropwise. The vial was stirred for 4 h at room temperature. LCMS indicated that the reaction had stalled, and the ether was stripped off. The DMF residue was purified via reverse phase (Teledyne 100 g C18 with (5% ACN+0.05% TFA) / (H2O+0.05% TFA) to 95% (ACN+0.05% TFA) / (H2O+0.05% TFA) gradient). The product was recovered by lyophilization to obtain I-62 (53.3 mg, 31% yield) as a white solid. (ESI) m / z: [M+H]+ = 737.43. 10 To an oven dried vial was added I-62 (53 mg, 0.072 mmol, 1 eq) and dissolved in (1:4) (Morpholine:DMF) (1.03 mL) and stirred at room temperature under Ar. LCMS at 15 minutes indicated that I-62 was consumed. The crude reaction was precipitated with diethyl ether (10 mL) and the solid was obtained by centrifugation. The solid was washed with diethyl ether (1x) (8 mL) and the solid was obtained by centrifugation. This obtained solid was redissolved in (1:1) 15 (H2O:ACN) and lyophilized to give 133 (36.6 mg, 81% yield) as a white solid. (ESI) m / z: [M+H]+ = 515.33. Example 57: Synthesis of Payload 134: 116 NJB0009PCT OH H O N NHFmoc H AcO N O MF Gly-Fmoc (152 mg, 0.414 mmol, 5 eq) and suspended in Anhydrous DMF (1.18 mL) with a brief sonication under Ar. To the vial, 1M HCl etherate (0.083 mL, 0.165 mmol, 2 eq) was added 5 dropwise. The vial was stirred for 4 h at room temperature. LCMS indicated that the reaction had stalled, and the ether was stripped off. The DMF residue was purified via reverse phase (Teledyne 150 g C18 with (5% ACN+0.05% TFA) / (H2O+0.05% TFA) to 95% (ACN+0.05% TFA) / (H2O+0.05% TFA) gradient). The product was recovered by lyophilization to obtain I-63 (41 mg, 66% yield) as a white solid. (ESI) m / z: [M+H]+ = 751.35. 10 To an oven dried vial was added I-63 (41 mg, 0.055 mmol, 1 eq) and dissolved in (1:4) (Morpholine:DMF) (0.78 mL) and stirred at room temperature under Ar. LCMS at 15 minutes indicated that I-63 was consumed. The crude reaction was precipitated with diethyl ether (8 mL) and the solid was obtained by centrifugation. The solid was washed with diethyl ether (1x) (8 mL) and the solid was obtained by centrifugation. This obtained solid was redissolved in (1:1) 15 (H2O:ACN) and lyophilized to give 134 (27.4 mg, 78% yield) as a white solid. (ESI) m / z: [M+H]+ = 529.26. Example 58: Synthesis of Payload 135: 117 NJB0009PCT OH H O N NHFmoc MF y- Fmoc (271 mg, 0.737 mmol, 5 eq) and suspended in Anhydrous DMF (1.64 mL) with a brief 5 sonication under Ar. To the vial, 1M HCl etherate (0.147 mL, 0.295 mmol, 2 eq) was added dropwise. The vial was stirred for 4 h at room temperature. LCMS indicated that the reaction had stalled, and the ether was stripped off. The DMF residue was purified via reverse phase (Teledyne 100 g C18 with (5% ACN+0.05% TFA) / (H2O+0.05% TFA) to 95% (ACN+0.05% TFA) / (H2O+0.05% TFA) gradient). The product was recovered by lyophilization to obtain I-64 10 (76.2 mg, 67% yield) as a white solid. (ESI) m / z: [M+H]+ = 765.39. To an oven dried vial was added I-64 (76 mg, 0.100 mmol, 1 eq) and dissolved in (1:4) (Morpholine:DMF) (1.107 mL) and stirred at room temperature under Ar. LCMS at 15 minutes indicated that I-64 was consumed. The crude reaction was precipitated with diethyl ether (11 mL) and the solid was obtained by centrifugation. The solid was washed with diethyl ether (1x) 15 (10 mL) and the solid was obtained by centrifugation. This obtained solid was redissolved in (1:1) (H2O:ACN) and lyophilized to give 135 (59.4 mg, 91.4% yield) as a white solid. (ESI) m / z: [M+H]+ = 543.34. Example 59: Synthesis of Payload 136: 118 NJB0009PCT H N NHFmoc OH O O MF Gly-Fmoc (447 mg, 1.215 mmol, 5 eq) and suspended in Anhydrous DMF (3.5 mL) with a brief sonication under Ar. To the vial, 1M HCl etherate (0.243 mL, 0.486 mmol, 2 eq) was added 5 dropwise. The vial was stirred for 4 h at room temperature. LCMS indicated that the reaction had stalled, and the ether was stripped off. The DMF residue was purified via reverse phase (Teledyne 150 g C18 with (5% ACN+0.05% TFA) / (H2O+0.05% TFA) to 95% (ACN+0.05% TFA) / (H2O+0.05% TFA) gradient). The product was recovered by lyophilization to obtain I-65 (317 mg mg, impure quant yield) as a white solid. (ESI) m / z: [M+H]+ = 793.47. 10 To an oven dried vial was added I-65 (317 mg, 0.400 mmol, 1 eq) and dissolved in (1:4) (Morpholine:DMF) (3.336 mL) and stirred at room temperature under Ar. LCMS at 15 minutes indicated that I-65 was consumed. The crude reaction was precipitated with diethyl ether (33 mL) and the solid was obtained by centrifugation. The solid was washed with diethyl ether (1x) (10 mL) and the solid was obtained by centrifugation. This obtained solid was redissolved in 15 (1:1) (H2O:ACN) and lyophilized to give 136 (76.4 mg, 28% yield) as a white solid. (ESI) m / z: [M+H]+ = 571.39. Example 60: Synthesis of Payload 137: 119 NJB0009PCT NH2NH2O O acid pinocol ester (44 mg, 0.188 mmol, 1.5 eq), bis(diisopropylphosphino)ferrocene)dichloropalladium dichloride (11 mg, 0.019 mmol, 0.15 eq) and DMF (5.2 mL) was added 2M Na2CO3 solution 5 (0.52 mL) under Argon. The vial was sparged with Ar for 15 minutes at room temperature. The reaction was heated to 101 C for 16 h whereupon LCMS indicated the reaction was complete. The crude product was purified by reverse phase (C18Aq 100g) H2O / ACN (+0.05% TFA) gradient over 20 minutes. The product fractions were combined and lyophilized to give 137 (25.6 mg, 38% yield) (ESI) m / z: [M+H]+= 532.31. 10 Example 61: Synthesis of Payload 138: OH OH O O , , , onic acid pinocol ester (118 mg, 0.476 mmol, 1.5 eq), bis(diisopropylphosphino)ferrocene)dichloropalladium dichloride (28 mg, 0.048 mmol, 0.15 eq) 15 and DMF (13 mL) was added 2M Na2CO3 solution (1.32 mL) under Argon. The vial was sparged with Ar for 15 minutes at room temperature. The reaction was heated to 101 C for 16 h 120 NJB0009PCT whereupon LCMS indicated the reaction was complete. The crude product was purified by reverse phase (C18Aq 100g) H2O / ACN (+0.05% TFA) gradient over 20 minutes. The product fractions were combined and lyophilized to give 138 (66.3 mg, 38% yield) (ESI) m / z: [M+H]+= 547.27. 5 Example 62: Synthesis of Payload 139: O OH NHFmoc O N MF y- Fmoc (223 mg, 0.606 mmol, 5 eq) and suspended in Anhydrous DMF (1.73 mL) with a brief sonication under Ar. To the vial, 1M HCl etherate (0.121 mL, 0.243 mmol, 2 eq) was added 10 dropwise. The vial was stirred for 4 h at room temperature. LCMS indicated that the reaction had stalled, and the ether was stripped off. The DMF residue was purified via reverse phase (Teledyne 50 g C18 with (5% ACN+0.05% TFA) / (H2O+0.05% TFA) to 95% (ACN+0.05% TFA) / (H2O+0.05% TFA) gradient). The product was recovered by lyophilization to obtain I-66 (97 mg, 93% yield) as a white solid. (ESI) m / z: [M+H]+ = 855.51. 121 NJB0009PCT To an oven dried vial was added I-66 (97 mg, 0.113 mmol, 1 eq) and dissolved in (1:4) (Morpholine:DMF) (1.1 mL) and stirred at room temperature under Ar. LCMS at 15 minutes indicated that I-66 was consumed. The crude reaction was precipitated with diethyl ether (11 mL) and the solid was obtained by centrifugation. The solid was washed with diethyl ether (1x) 5 (10 mL) and the solid was obtained by centrifugation. This obtained solid was redissolved in (1:1) (H2O:ACN) and lyophilized to give 139 (34.7 mg, 41% yield) as a white solid. (ESI) m / z: [M+H]+ = 633.15. Example 63: Synthesis of Payload 140: HO OHBr O O B B B O O 10 ), was added bis(pinacolato)diboron (31.4 mg, 0.124 mmol, 1.2 eq), bistriphenylphosphine palladium (II) chloride (3.6 mg, 0.005 mmol, 0.05 eq), and potassium acetate (25.3 mg, 0.257 mmol, 2.5 eq). The solution was sparged with Ar for 15 min, then heated to 100 C for 72 h. The crude product was filtered through celite, washed with methanol, and stripped dry. The residue was dissolved 15 in DMF and purified by reverse phase on C18 (150 g) using H2O / ACN gradient (0.05% TFA additive). The recovered product was obtained via lyophilization to give 140 (19.8 mg, 42% yield) as a white solid. (ESI) m / z: [M+H]+ = 457.00. Example 64: Synthesis of Payload 141: NH2NH2O O NJB0009PCT To a suspension of 112 (82 mg, 0.167 mmol, 1 eq), anilinophenyl boronic acid (115 mg, 0.668 mmol, 4 eq), Pd(OAc)2 (18.7 mg, 0.083 mmol, 0.5 eq) in THF (5.56) was added potassium carbonate (816 mg, 5.34 mmol, 8 eq). The solution was sparged with Ar for 15 min, then heated to 70 C for 72 h. The crude product was filtered through celite, washed with methanol, and 5 stripped dry. The residue was loaded onto a 80 g silica column (30% MeOH / DCM) and the product fractions were combined and concentrated to give 141 (49.2 mg, 60% yield) as a white solid. (ESI) m / z: [M+H]+ = 504.05. Example 65: Synthesis of Payload 142: OH OH O O 10 ronic acid pinocol ester (95 mg, 0.383 mmol, 1.5 eq), bis(diisopropylphosphino)ferrocene)dichloropalladium dichloride (23 mg, 0.038 mmol, 0.15 eq) and dioxane (8.5 mL) was added 2M Na2CO3solution (1.07 mL) under Argon. The vial was sparged with Ar for 15 minutes at room temperature. The reaction was heated to 80 C for 2 h 15 whereupon LCMS indicated the reaction was complete. The crude product was purified by reverse phase (C18Aq 100g) H2O / ACN (+0.05% TFA) gradient over 20 minutes. The product fractions were combined and lyophilized to give 142 (81.5 mg, 60% yield) (ESI) m / z: [M+H]+= 533.02. Example 66: Synthesis of Payload 142: 123 NJB0009PCT O OH NHFmoc O N H MF - Fmoc (330 mg, 0.896 mmol, 5 eq) and suspended in Anhydrous DMF (2.56 mL) with a brief sonication under Ar. To the vial, 1M HCl etherate (0.179 mL, 0.358 mmol, 2 eq) was added 5 dropwise. The vial was stirred for 4 h at room temperature. LCMS indicated that the reaction had stalled, and the ether was stripped off. The DMF residue was purified via reverse phase (Teledyne 50 g C18 with (5% ACN+0.05% TFA) / (H2O+0.05% TFA) to 95% (ACN+0.05% TFA) / (H2O+0.05% TFA) gradient). The product was recovered by lyophilization to obtain I-67 (72.6 mg, 48% yield) as a white solid. (ESI) m / z: [M+H]+ = 841.34. 10 To an oven dried vial was added I-67 (73 mg, 0.086 mmol, 1 eq) and dissolved in (1:4) (Morpholine:DMF) (1.08 mL) and stirred at room temperature under Ar. LCMS at 15 minutes indicated that I-67 was consumed. The crude reaction was precipitated with diethyl ether (11 mL) and the solid was obtained by centrifugation. The solid was washed with diethyl ether (1x) (10 mL) and the solid was obtained by centrifugation. This obtained solid was redissolved in 124 NJB0009PCT (1:1) (H2O:ACN) and lyophilized to give 143 (31.3 mg, 49% yield) as a white solid. (ESI) m / z: [M+H]+ = 619.29. Example 67: Synthesis of Payload 144: OH O O 5 boronic acid pinocol ester (77 mg, 0.507 mmol, 1.5 eq), bis(diisopropylphosphino)ferrocene)dichloropalladium dichloride (30 mg, 0.051 mmol, 0.15 eq) and dioxane (11 mL) was added 2M Na2CO3solution (1.41 mL) under Argon. The vial was sparged with Ar for 15 minutes at room temperature. The reaction was heated to 80 C for 3 h whereupon LCMS indicated the reaction was complete. The 10 crude product was purified by reverse phase (C18Aq 100g) H2O / ACN (+0.05% TFA) gradient over 20 minutes. The product fractions were combined and lyophilized to give 144 (184 mg, quant % yield) (ESI) m / z: [M+H]+= 519.19. Example 68: Synthesis of Payload 146: O OHO OHBr B B B O O 15 , , ), was added bis(pinacolato)diboron (7.6 mg, 0.03 mmol, 1.2 eq), bistriphenylphosphine palladium (II) chloride (0.9 mg, 0.001 mmol, 0.05 eq), and potassium acetate (6.1 mg, 0.062 mmol, 2.5 eq). The solution was sparged with Ar for 15 min, then heated to 130 C for 16 h. The crude product was filtered through celite, washed with methanol, and stripped dry. The residue was dissolved 125 NJB0009PCT in DMF and purified by reverse phase on C18 (50 g) using H2O / ACN gradient (0.05% TFA additive). The recovered product was obtained via lyophilization to give 146 (5 mg, 44% yield) as a white solid. (ESI) m / z: [M+H]+ = 458.03. Example 69: Synthesis of Payload 147: Br NH2O 5 O mg, 0.304 mmol, 1.5 eq), NaN3 (36 mg, 1.015 mmol, 5 eq), and sodium L-ascorbate (60 mg, 0.305 mmol, 1.0 eq) and dissolved in a (7:3) solution of (EtOH:H2O) (3 mL). N,N-dimethylethylenediamine (87 uL, 0.812 mmol, 2 eq) was added to the vial and refluxed at 90 C for 16 h. The crude product was 10 concentrated and purified by normal phase chromatography by dissolving in 5% MeOH / DCM (2 mL) with 40 g silica DCM to 30% MeOH / DCM gradient over 20 minutes. The product fractions were combined and concentrated, followed by high vacuum to give 147 (25 mg, 29% yield) as a white solid. (ESI) m / z: [M+H]+ = 429.35. Example 70: Synthesis of Payload 148: OH Br O O 15 o an oven r e v a was a e ( mg, . mmo , eq), tr utylstannyl) ethanol (11 mg, 0.034 mmol, 1.5 eq), and dioxane (0.45 mL). The solution was sparged with N2for 10 minutes to degas, followed by the addition of Pd(Ph3)4 (1.1 mg, 0.001 mmol, 0.05 eq). The reaction was stirred at 80 C for 16 h. The reaction was loaded directly on reverse phase (30 g 20 C18Aq Column) ACN / H2O (0.05% trifluoroacetic acid additive). The recovered desired product was lyophilized to obtain 148 (3.5 mg, 35% yield) as a white solid. (ESI) m / z: [M+H]+ = 443.84. 126 NJB0009PCT Example 71: Synthesis of Payload 149: OH O O c acid pinocol ester (55 mg, 0.366 mmol, 1.5 eq), bis(diisopropylphosphino)ferrocene)dichloropalladium 5 dichloride (36 mg, 0.061 mmol, 0.25 eq) and dioxane (17 mL) was added 2M Na2CO3solution (2.03 mL) under Argon. The vial was sparged with Ar for 15 minutes at room temperature. The reaction was heated to 80 C for 2 h whereupon LCMS indicated the reaction was complete. The crude product was purified by reverse phase (C18Aq 100g) H2O / ACN (+0.05% TFA) gradient over 20 minutes. The product fractions were combined and lyophilized to give 149 (59 mg, 47% 10 yield) (ESI) m / z: [M+H]+= 519.19. Example 72: Synthesis of Payload 150: 127 NJB0009PCT OH H O N NHFmoc O MF Gly-Fmoc (402 mg, 1.092 mmol, 5 eq) and suspended in Anhydrous DMF (2.43 mL) with a brief sonication under Ar. To the vial, 1M HCl etherate (0.218 mL, 0.437mmol, 2 eq) was added 5 dropwise. The vial was stirred for 4 h at room temperature. LCMS indicated that the reaction had stalled, and the ether was stripped off. The DMF residue was purified via reverse phase (Teledyne 50 g C18 with (5% ACN+0.05% TFA) / (H2O+0.05% TFA) to 95% (ACN+0.05% TFA) / (H2O+0.05% TFA) gradient). The product was recovered by lyophilization to obtain I-68 (85.4 mg, 47% yield) as a white solid. (ESI) m / z: [M+H]+ = 828.42. 10 To an oven dried vial was added I-68 (85 mg, 0.103 mmol, 1 eq) and dissolved in (1:4) (Morpholine:DMF) (1.03 mL) and stirred at room temperature under Ar. LCMS at 15 minutes indicated that I-68 was consumed. The crude reaction was precipitated with diethyl ether (11 mL) and the solid was obtained by centrifugation. The solid was washed with diethyl ether (1x) (10 mL) and the solid was obtained by centrifugation. This obtained solid was redissolved in 15 (1:1) (H2O:ACN) and lyophilized to give 150 (18 mg, 29% yield) as a white solid. (ESI) m / z: [M+H]+ = 606.21. 128 NJB0009PCT Example 73: Synthesis of Payload 152: O NH2NHFmoc HN MF 32 mmol, 2 eq), and N-methylmorpholine (51 uL, 0.465 mmol, 4 eq) dissolved in DMF (2.3 mL). 5 The vial was stirred for 5 minutes at room temperature, whereupon 151 (59 mg, 0.116 mmol, 1 eq) was added. The reaction showed completion by LCMS after 3 h at room temperature. The crude reaction was purified by reverse phase (C1850 g) H2O / ACN (+0.05% trifluoroacetic acid) gradient over 20 minutes. The product fractions were combined and lyophilized to give I-69 (89.3 mg, 96% yield) as a white solid. (ESI) m / z: [M+H]+= 798.16. 10 To a vial containing I-69 (89 mg, 0.112 mmol, 1 eq) was added (1:4) (Morpholine:DMF) (1.4 mL) and the reaction was stirred for 40 minutes at room temperature. The crude product was recovered by precipitation by diluting the crude reaction with diethyl ether (11 mL) and the solid was obtained by iterative centrifugation. The crude solid was dissolved in (1:1) (H2O:ACN) 129 NJB0009PCT (+0.05% trifluoroacetic acid) and lyophilized to obtain 152 (39.4 mg, 51% yield) as a white solid. (ESI) m / z: [M+H]+= 576.10. Example 74: Synthesis of Payload 153: OH Br OH O O 5 boronic acid pinocol ester (69 mg, 0.280 mmol, 1.5 eq), bis(diisopropylphosphino)ferrocene)dichloropalladium dichloride (27 mg, 0.047 mmol, 0.25 eq) and dioxane (13.3 mL) was added 2M Na2CO3 solution (1.56 mL) under Argon. The vial was sparged with Ar for 15 minutes at room temperature. The reaction was heated to 80 C for 2 h whereupon LCMS indicated the reaction was complete. The 10 crude product was purified by reverse phase (C18Aq 100g) H2O / ACN (+0.05% TFA) gradient over 20 minutes. The product fractions were combined and lyophilized to give 153 (81.5 mg, 82% yield) (ESI) m / z: [M+H]+= 534.01. Example 75: Synthesis of Payload 154: 130 NJB0009PCT O NHFmoc OH O N H MF y- Fmoc (281 mg, 0.764 mmol, 5 eq) and suspended in Anhydrous DMF (2.18 mL) with a brief sonication under Ar. To the vial, 1M HCl etherate (0.153 mL, 0.305 mmol, 2 eq) was added 5 dropwise. The vial was stirred for 4 h at room temperature. LCMS indicated that the reaction had stalled, and the ether was stripped off. The DMF residue was purified via reverse phase (Teledyne 50 g C18 with (5% ACN+0.05% TFA) / (H2O+0.05% TFA) to 95% (ACN+0.05% TFA) / (H2O+0.05% TFA) gradient). The product was recovered by lyophilization to obtain I-70 (88 mg, 69% yield) as a white solid. (ESI) m / z: [M+H]+ = 842.34. 10 To an oven dried vial was added I-70 (155 mg, 0.184 mmol, 1 eq) and dissolved in (1:4) (Morpholine:DMF) (2.30 mL) and stirred at room temperature under Ar. LCMS at 15 minutes indicated that I-70 was consumed. The crude reaction was precipitated with diethyl ether (23 mL) and the solid was obtained by centrifugation. The solid was washed with diethyl ether (1x) (10 mL) and the solid was obtained by centrifugation. This obtained solid was redissolved in 131 NJB0009PCT (1:1) (H2O:ACN) and lyophilized to give 154 (29.1 mg, 21% yield) as a white solid. (ESI) m / z: [M+H]+ = 720.29. Example 76: Synthesis of Payload 155 and 156: Br Br Br hexamethylenetetramineOTf2O DMAPOO NH25 25 mL) was added hexamethylenetetramine (31.25 g, 223.21 mmol). The resulting reaction mixture was heated at 100 °C for 2 hours. Allowed the reaction mixture to cool at room temperature. Added methanol (120 mL) to the reaction mixture. Evaporated the solvent to afford a dark residue. Water (50 mL) was added to this residue. Filtered the resulting precipitation, on drying 10 afforded compound I-71 as a white solid (24.0 g, 85%). (ESI) m / z: [M+H]+=252.0) To a stirred solution of Compound I-71 (26 g, 103.17 mmol) in anhydrous DCM (260 ml), DMAP (25.20 g, 203.34 mmol) was added at 0 °C under nitrogen atmosphere, followed by addition of Triflic anhydride (21.0 mL,123.80 mmol) and the resulting mixture was stirred at 0 °C for 1 h. After completion of reaction, it was quenched with ice cold water and extracted with 15 DCM (3 X 100 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure to give an orange residue, which was purified using silica gel column chromatography [hexane: Ethyl acetate =40:60) to afford Compound I-72 as a white solid (15.0 g, 38%). 132 NJB0009PCT To a stirred solution of Compound I-72 (15.0 g, 39.06 mmol) in Toluene (150 mL), PPTS (0.5 g, 1.95 mmol) and ethylene glycol (3.5 mL, 136.7 mmol) were added under nitrogen atmosphere. The resulting reaction mixture was heated to reflux for 16h using Dean-Stark apparatus. The progress of reaction was monitored by TLC after completion of reaction it was 5 quenched with ice cold water and extracted with ethyl acetate (3 X 100 mL) the combined organic layer was dried over Na2SO4, Concentrated to give crude mass which was purified using silica gel column chromatography [hexane: Ethyl acetate =40:60) to afford Compound I-73 as off white solid (15.0 g, 90%). (ESI) m / z: [M+H]+= 428.0) To a stirred solution of Compound I-73 in (1.2 g, 2.8 mmol) in Toluene (12 mL), 10 Benzophenone imine (0.5 mL, 2.8 mmol) and Cs2CO3(1.82 g, 5.60 mol) was added, and reaction was degassed with nitrogen for 10 min. Then palladium acetate (0.062 g,0.28 mmol) and BINAP (0.18 g,0.28 mmol) were added, and the reaction was heated to 100 °C for 3h. After completion of reaction, it was quenched with water and extracted with ethyl acetate (3 X 100 mL) the combined organic layer was dried over Na2SO4. Concentrated to give crude mass which was 15 purified using silica gel column chromatography [hexane: Ethyl acetate =80:20) to afford Compound I-74 as an off white solid (200 mg, 15 %). (ESI) m / z: [M+H]+=459.0) To a stirred solution of Compound I-74 (2.0 g, 4.36 mmol) in THF (10 mL) was added hydrochloric acid (2M in water; 10mL) and the mixture was stirred at room temperature for 2h. After completion of reaction, NaHCO3 was added, and then extracted with ethyl acetate (3 x 20 20 mL). The combined organic layer was washed with brine solution, dried over Na2SO4and concentrated to give crude mass which was purified using silica gel column chromatography [hexane: Ethyl acetate =80:20) to afford I-75 as a pale-yellow solid. (125mg, 12.0%). (ESI) m / z: [M+H]+= 251.0). To a RBF, was added I-75 (0.321 g, 1.28 mmol, 1 eq) and I-2 (337 mg, 1.28 mmol, 1. 25 eq). Toluene (60 mL) was added and followed by brief sonication to ensure I-2 dissolved. PTSA (122 mg, 0.639 mmol, 0.5 eq) was added to the RBF with Argon. The RBF was refluxed for 17 h. The crude reaction was distilled to dryness, followed by (2x) resuspension in (40 mL) toluene and distillation to dryness. The crude product was transferred to a RBF by (1:1) (DCM:MeOH) then dissolved in 5% MeOH / DCM (5 mL). The crude product was purified on a 80 g silica 30 column with a DCM to 30% MeOH / DCM gradient over 20 minutes. The product fractions were 133 NJB0009PCT combined and concentrated, followed by high vacuum to give 155 (0.196 g, 32% yield) as a solid. (ESI) m / z: [M+H]+ = 480.36. To a vial was added 155 (70 mg, 0.147 mmol, 1 eq), copper iodide (33.5 mg, 0.176 mmol, 1.2 eq), NaN3(48 mg, 0.735 mmol, 5 eq), and sodium L-ascorbate (29 mg, 0.147 mmol, 1 5 eq) and dissolved in a (7:1) solution of (EtOH:H2O) (4 mL). N,N-dimethylethylenediamine (63 uL, 0.588 mmol, 4 eq) was added to the vial and refluxed at 80 C for 16 h. The crude product was concentrated and purified by normal phase chromatography by dissolving in 5% MeOH / DCM (2 mL) with 40 g silica DCM to 30% MeOH / DCM gradient over 20 minutes. The product fractions were combined and concentrated, followed by high vacuum to give 156 (2 mg, 10 7% yield) as a white solid. (ESI) m / z: [M+H]+ = 415.09. Example 77: Synthesis of Payload 157: O N O Br O O BCl3 (0.897 mL, 0.897 mmol, 1M in DCM) was added at 0 °C under nitrogen atmosphere 15 followed by addition propionitrile (0.128 mL, 1.7932 mmol) and AlCl3 (155 mg, 1.166 mmol). The resulting mixture was stirred at room temperature for 10 min. and heated to reflux for 72 h. After completion of reaction, reaction mixture quenched with dil. HCl. The reaction mixture was heated to 80 °C for 16h. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (2 x 150 mL). Organic layer collectively washed with brine, dried over sodium 20 sulphate and concentrated to give crude mass. The obtained crude was subjected to column 134 NJB0009PCT purification using silica gel column chromatography (DCM:MeOH) = (80:20) to afford I-76 as a yellow solid (280 mg, 38%). (ESI) m / z: [M+H]+= 279.12). To a RBF, was added I-76 (1.05 mg, 3.762 mmol, 1 eq) and I-2 (0.99 g, 3.762 mmol, 1 eq). Toluene (54 mL) was added and followed by brief sonication to ensure I-2 dissolved. PTSA 5 (358 mg, 1.881 mmol, 0.5 eq) was added to the RBF with Argon. The RBF was refluxed for 17 h. The crude reaction was distilled to dryness, followed by (2x) resuspension in (50 mL) toluene and distillation to dryness. The crude product was transferred to a RBF by (1:1) (DCM:MeOH) then dissolved in 5% MeOH / DCM (5 mL). The crude product was purified on a 100 g silica column with a DCM to 30% MeOH / DCM gradient over 20 minutes. The product fractions were 10 combined and concentrated, followed by high vacuum to give I-77 (1.179 g, 62% yield) as a solid. (ESI) m / z: [M+H]+ = 506.29. To a vial was added I-77 (50 mg, 0.0987 mmol, 1 eq), copper iodide (28 mg, 0.148 mmol, 1.5 eq), NaN3 (17 mg, 0.494 mmol, 5 eq), and sodium L-ascorbate (29 mg, 0.148 mmol, 1 eq) and dissolved in a (7:3) solution of (EtOH:H2O) (3 mL). N,N-dimethylethylenediamine (43 15 uL, 0.395 mmol, 4 eq) was added to the vial and refluxed at 80 C for 16 h. The crude product was concentrated and purified by normal phase chromatography by dissolving in 5% MeOH / DCM (2 mL) with 40 g silica DCM to 30% MeOH / DCM gradient over 20 minutes. The product fractions were combined and concentrated, followed by high vacuum to give 157 (18 mg, 41% yield) as a white solid. (ESI) m / z: [M+H]+ = 443.37. 20 Example 78: Synthesis of Payload 158: 135 NJB0009PCT O FmocHN NH2NH MF d mmol, 2 eq), and N-methylmorpholine (16 uL, 0.149 mmol, 4 eq) dissolved in DMF (1 mL). The vial was stirred for 5 minutes at room temperature, whereupon 157 (16 mg, 0.037 mmol, 1 eq) 5 was added. The reaction showed completion by LCMS after 3 h at room temperature. The crude reaction was purified by reverse phase (C1850 g) H2O / ACN (+0.05% trifluoroacetic acid) gradient over 20 minutes. The product fractions were combined and lyophilized to give I-78 (23 mg, 87% yield) as a white solid. (ESI) m / z: [M+H]+= 736.57. To a vial containing I-78 (24 mg, 0.033 mmol, 1 eq) was added (1:4) (Morpholine:DMF) 10 (0.4 mL) and the reaction was stirred for 40 minutes at room temperature. The crude product was recovered by precipitation by diluting the crude reaction with diethyl ether (5 mL) and the solid was obtained by iterative centrifugation. The crude solid was dissolved in (1:1) (H2O:ACN) (+0.05% trifluoroacetic acid) and lyophilized to obtain 158 (18 mg, 89% yield) as a white solid. (ESI) m / z: [M+H]+= 514.34. 15 Example 79: Synthesis of Payload 159: 136 NJB0009PCT NH2OO c acid pinocol ester (44 mg, 0.188 mmol, 1.5 eq), bis(diisopropylphosphino)ferrocene)dichloropalladium dichloride (11 mg, 0.019 mmol, 0.25 eq) and dioxane (5 mL) was added 2M Na2CO3 solution 5 (0.52 mL) under Argon. The vial was sparged with Ar for 15 minutes at room temperature. The reaction was heated to 80 C for 2 h whereupon LCMS indicated the reaction was complete. The crude product was purified by reverse phase (C18Aq 50g) H2O / ACN (+0.05% TFA) gradient over 20 minutes. The product fractions were combined and lyophilized to give 159 (25.6 mg, 38% yield) (ESI) m / z: [M+H]+= 532.31. 10 Example 80: Synthesis of Payload 160: NH NH22O O , , , pinocol ester (49 mg, 0.223 mmol, 1.5 eq), bis(diisopropylphosphino)ferrocene)dichloropalladium dichloride (17 mg, 0.030 mmol, 0.20 eq) and dioxane (12 mL) was added 2M Na2CO3solution (0.62 mL) under 15 Argon. The vial was sparged with Ar for 15 minutes at room temperature. The reaction was heated to 80 C for 4 h whereupon LCMS indicated the reaction was complete. The crude product was purified by reverse phase (C18Aq 50g) H2O / ACN (+0.05% TFA) gradient over 20 minutes. 137 NJB0009PCT The product fractions were combined and lyophilized to give 160 (51.9 mg, 67% yield) (ESI) m / z: [M+H]+= 519.13. Example 81: Synthesis of Payload 161: O NH2NHFmoc HN MF 5 mmol, 2 eq), and N-methylmorpholine (43 uL, 0.392 mmol, 4 eq) dissolved in DMF (2.8 mL). The vial was stirred for 5 minutes at room temperature, whereupon 160 (51 mg, 0.098 mmol, 1 eq) was added. The reaction showed completion by LCMS after 3 h at room temperature. The crude reaction was purified by reverse phase (C1850 g) H2O / ACN (+0.05% trifluoroacetic acid) 10 gradient over 20 minutes. The product fractions were combined and lyophilized to give I-79 (39.3 mg, 49% yield) as a white solid. (ESI) m / z: [M+H]+= 812.53. To a vial containing I-79 (38 mg, 0.048 mmol, 1 eq) was added (1:4) (Morpholine:DMF) (0.599 mL) and the reaction was stirred for 40 minutes at room temperature. The crude product was recovered by precipitation by diluting the crude reaction with diethyl ether (6 mL) and the 138 NJB0009PCT solid was obtained by iterative centrifugation. The crude solid was dissolved in (1:1) (H2O:ACN) (+0.05% trifluoroacetic acid) and lyophilized to obtain 161 (31.8 mg, 94% yield) as a white solid. (ESI) m / z: [M+H]+= 590.45. Example 82: Synthesis of Payload 162: O N O O O e, 5 (28 mL), BCl3 (5.55 mL, 5.55 mmol, 1M in DCM) was added at 0 °C under nitrogen atmosphere followed by addition 4-bromo butanenitrile (0.8804 mL, 8.15 mmol) and AlCl3(1.2 g, 9.017 mmol). The resulting mixture was stirred at room temperature for 10 min. and heated to reflux for 72 h. After 10 completion of reaction, reaction mixture quenched with dil. HCl. The reaction mixture was heated to 80 °C for 16h. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (2 x 500 mL). Organic layer collectively washed with brine, dried over sodium sulphate and concentrated to give crude mass. The obtained crude was subjected to column purification using silica gel column chromatography (DCM:MeOH) = (80:20) to afford I-80 as a 15 yellow solid (255 mg, 15%). (ESI) m / z: [M+H]+= 249.14). To a RBF, was added I-80 (178 mg, 0.716 mmol, 1 eq) and I-2 (188 mg, 0.716 mmol, 1 eq). Toluene (24 mL) was added and followed by brief sonication to ensure I-2 dissolved. PTSA (68 mg, 0.358 mmol, 0.5 eq) was added to the RBF with Argon. The RBF was refluxed for 17 h. 139 NJB0009PCT The crude reaction was distilled to dryness, followed by (2x) resuspension in (20 mL) toluene and distillation to dryness. The crude product was transferred to a RBF by (1:1) (DCM:MeOH) then dissolved in 5% MeOH / DCM (5 mL). The crude product was purified on a 100 g silica column with a DCM to 30% MeOH / DCM gradient over 20 minutes. The product fractions were 5 combined and concentrated, followed by high vacuum to give I-81 (75 mg, 22% yield) as a solid. (ESI) m / z: [M+H]+ = 476.06. To an oven dried vial was added I-81 (40 mg, 0.074 mmol, 1 eq) was added HMPA (0.225 ml). To the vial was added H2O (0.034 mL) and heated to 101 C for 4 h whereupon LCMS indicated the reaction was mostly complete. The reaction was directly purified by reverse 10 phase (Teledyne 50 g C18 (5µm C18110Å 150 x 30 mm) with (5% ACN +0.05%FA) / (H2O+0.05%FA) to 95% (ACN+0.05%FA) / (H2O+0.05%FA) gradient). The product was obtained by lyophilization to give 162 (24 mg, 69% yield) as a white solid. (ESI) m / z: [M+H]+ = 472.26. Example 83: Synthesis of Payload 163 and 164: HO OHB NH2O 15 O mmol, 1.5 eq), NiCl2 glyme (0.4 mg, 0.002 mmol, 0.06 eq), prolinol (1 uL, 0.003 mmol, 0.12 eq), and isopropanol (0.3 mL) was added KHMDS (1 M / THF) solution (0.030 mL) under Argon. The vial was sparged with Ar for 15 minutes at room temperature. The reaction was heated to 60 20 C for 16 h whereupon LCMS indicated the reaction was complete. The crude product was purified by reverse phase (C18Aq 50g) H2O / ACN (+0.05% TFA) gradient over 20 minutes. The product fractions corresponding to both 163 and 164 were combined separately and lyophilized 140 NJB0009PCT to give 164 (1.4 mg, 9% yield) as a white solid (ESI) m / z: [M+H]+= 547.47 and 163 (1 mg, 7% yield) as a white solid (ESI) m / z: [M+H]+= 591.08. Example 84: Synthesis of Payload 165: Br N3ene 6h 5 sodium azide (14 mg, 0.216 mmol, 1.5 eq). The reaction was stirred for 16 h at room temperature. Water was added to the reaction (8 mL) causing the product to precipitate upon storing in the freezer for 16 h. The crude solid product was obtained by centrifugation, decanting, and redissolved in (1:1) (H2O:ACN) (+0.05% trifluoroacetic acid) and lyophilized to obtain I-82 10 (60.8 mg, 85% yield) as a white solid. (ESI) m / z: [M+H]+= 497.19. To a suspension of I-82 (61 mg, 0.122 mmol, 1 eq) in benzene (16 mL) was added triethyl phosphite (52 uL, 0.306 mmol, 2.5 eq). The reaction was stirred at 90 C for 4 hours, where upon 3 M HCl / MeOH (0.8 mL) was added and stirred at 90 C for 16 h. The solvent was evaporated and the residue was dissolved in (1:1) (H2O:ACN) (+0.05% trifluoroacetic acid) and 15 lyophilized to obtain 165 (31 mg, 44% yield) as a white solid. (ESI) m / z: [M+H]+= 584.54. Example 85: Synthesis of Payload 166 and 167: 141 NJB0009PCT O N O Br Br Propinonitrile, BCl3, AlCl3DCE, Reflux, 3 Days O 248% yield H2 47% yield3-bromo lin-6-amine Br NH 2O O mL), BCl3(4.15 mL, 4.15 mmol, 1M in DCM) was added at 0 °C under nitrogen atmosphere followed by addition propionitrile (1.776 mL, 24.89 mmol) and AlCl3(0.72 g, 5.393 mmol). The 5 resulting mixture was stirred at room temperature for 10 min. and heated to reflux for 72 h. After completion of reaction, reaction mixture quenched with dil. HCl. The reaction mixture was heated to 80 °C for 16h. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (2 x 500 mL). Organic layer collectively washed with brine, dried over sodium sulphate and concentrated to give crude mass. The obtained crude was subjected to column 10 purification using silica gel column chromatography (DCM:MeOH) = (80:20) to afford I-83 as a yellow solid (588 mg, 48%). (ESI) m / z: [M+H]+= 297.14). To a RBF, was added I-83 (234 mg, 0.788 mmol, 1 eq) and I-2 (207 mg, 0.788 mmol, 1 eq). Toluene (11.2 mL) was added and followed by brief sonication to ensure I-2 dissolved. PTSA (105 mg, 0.551 mmol, 0.7 eq) was added to the RBF with Argon. The RBF was refluxed 15 for 17 h. The crude reaction was distilled to dryness, followed by (2x) resuspension in (10 mL) toluene and distillation to dryness. The crude product was transferred to a RBF by (1:1) (DCM:MeOH) then dissolved in 5% MeOH / DCM (5 mL). The crude product was purified on a 100 g silica column with a DCM to 30% MeOH / DCM gradient over 20 minutes. The product 142 NJB0009PCT fractions were combined and concentrated, followed by high vacuum to give 166 (194.3 g, 47% yield) as a solid. (ESI) m / z: [M+H]+ = 524.20. To a vial was added 166 (76 mg, 0.146 mmol, 1 eq), copper iodide (33 mg, 0.175 mmol, 1.2 eq), NaN3(47 mg, 0.729 mmol, 5 eq), and sodium L-ascorbate (29 mg, 0.146 mmol, 1 eq) 5 and dissolved in a (7:1) solution of (EtOH:H2O) (4 mL). N,N-dimethylethylenediamine (47 uL, 0.385 mmol, 4 eq) was added to the vial and refluxed at 90 C for 16 h. The crude product was concentrated and purified by normal phase chromatography by dissolving in 5% MeOH / DCM (2 mL) with 40 g silica DCM to 30% MeOH / DCM gradient over 20 minutes. The product fractions were combined and concentrated, followed by high vacuum to give 167 (65 mg, 97% yield) as a 10 white solid. (ESI) m / z: [M+H]+ = 461.33. Example 86: Synthesis of Payload 168: Br HO O O butylstannyl) ethanol (32 mg, 0.099 mmol, 1.5 eq), and dioxane (1.0 mL). The solution was sparged with N2for 10 15 minutes to degas, followed by the addition of Pd(Ph3)4(3.8 mg, 0.0033 mmol, 0.05 eq). The reaction was stirred at 80 C for 16 h. The reaction was loaded directly on reverse phase (30 g C18Aq Column) ACN / H2O (0.05% trifluoroacetic acid additive). The recovered desired product was lyophilized to obtain 168 (5.0 mg, 16% yield) as a white solid. (ESI) m / z: [M+H]+ = 476.15. Example 87: Synthesis of Payload 169: 143 NJB0009PCT O N O O Cl Cl O Propinonitrile, BCl3, AlCl3e, DCE, Reflux, 3 Days O 110oC, overnight 295% yieldH2 17% yield3-chlor mine Cl O O To a suspension of 3-chlo , 3.807 mmol) in DCE (15.23 mL), BCl3 (3.81 mL, 3.807 mmol, 1M in DCM) was added at 0 °C under nitrogen atmosphere followed by addition propionitrile (1.629 mL, 22.842 mmol) and AlCl3(0.66 g, 4.949 mmol). 5 The resulting mixture was stirred at room temperature for 10 min. and heated to reflux for 72 h. After completion of reaction, reaction mixture quenched with dil. HCl. The reaction mixture was heated to 80 °C for 16h. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (2 x 500 mL). Organic layer collectively washed with brine, dried over sodium sulphate and concentrated to give crude mass. The obtained crude was subjected to column 10 purification using silica gel column chromatography (DCM:MeOH) = (80:20) to afford I-84 as a yellow solid (850 mg, 95%). (ESI) m / z: [M+H]+= 235.18). To a RBF, was added I-84 (200 mg, 0.852 mmol, 1 eq) and I-2 (224 mg, 0.852 mmol, 1 eq). Toluene (4 mL) was added and followed by brief sonication to ensure I-2 dissolved. PTSA (81 mg, 0.426 mmol, 0.5 eq) was added to the RBF with Argon. The RBF was refluxed for 17 h. 15 The crude reaction was distilled to dryness, followed by (2x) resuspension in (5 mL) toluene and distillation to dryness. The crude product was transferred to a RBF by (1:1) (DCM:MeOH) then dissolved in 5% MeOH / DCM (5 mL). The crude product was purified on a 100 g silica column with a DCM to 30% MeOH / DCM gradient over 20 minutes. The product fractions were 144 NJB0009PCT combined and concentrated, followed by high vacuum to give 169 (66 mg, 17% yield) as a solid. (ESI) m / z: [M+H]+ = 462.10. Example 88: Synthesis of Payload 170: O N O O e, ht O 5 (25 mL), BCl3(5.02 mL, 5.02 mmol, 1M in DCM) was added at 0 °C under nitrogen atmosphere followed by addition 5-bromovaleronitrile (1.0 mL, 7.374 mmol) and AlCl3 (1.09 g, 8.159 mmol). The resulting mixture was stirred at room temperature for 10 min. and heated to reflux for 72 h. After completion of reaction, reaction mixture quenched with dil. HCl. The reaction mixture was 10 heated to 80 °C for 16h. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (2 x 500 mL). Organic layer collectively washed with brine, dried over sodium sulphate and concentrated to give crude mass. The obtained crude was subjected to column purification using silica gel column chromatography (DCM:MeOH) = (80:20) to afford I-85 as a yellow solid (266 mg, 11%). (ESI) m / z: [M+H]+= 384.81). 15 To a RBF, was added I-85 (247 mg, 0.640 mmol, 1 eq) and I-2 (168 mg, 0.640 mmol, 1 eq). Toluene (16 mL) was added and followed by brief sonication to ensure I-2 dissolved. PTSA (61 mg, 0.320 mmol, 0.5 eq) was added to the RBF with Argon. The RBF was refluxed for 17 h. 145 NJB0009PCT The crude reaction was distilled to dryness, followed by (2x) resuspension in (15 mL) toluene and distillation to dryness. The crude product was transferred to a RBF by (1:1) (DCM:MeOH) then dissolved in 5% MeOH / DCM (5 mL). The crude product was purified on a 120 g silica column with a DCM to 30% MeOH / DCM gradient over 20 minutes. The product fractions were 5 combined and concentrated, followed by high vacuum to give I-86 (168 mg, 43% yield) as a solid. (ESI) m / z: [M+H]+ = 611.96. To an oven dried vial was added I-86 (170 mg, 0.277 mmol, 1 eq) was added HMPA (0.838 ml). To the vial was added H2O (0.127 mL) and heated to 101 C for 4 h whereupon LCMS indicated the reaction was mostly complete. The reaction was directly purified by reverse phase (Teledyne 10 50 g C18 (5µm C18110Å 150 x 30 mm) with (5% ACN +0.05%FA) / (H2O+0.05%FA) to 95% (ACN+0.05%FA) / (H2O+0.05%FA) gradient). The product was obtained by lyophilization to give 170 (12.6 mg, 8% yield) as a white solid. (ESI) m / z: [M+H]+ = 550.03. Example 89: Synthesis of Payload 171: H OH O N NHFmoc MF NJB0009PCT To an oven dried vial was added 144 (184 mg, 0.355 mmol, 1 eq) and OAc-CH2-NH- Gly-Fmoc (654 mg, 1.774 mmol, 5 eq) and suspended in Anhydrous DMF (3.94 mL) with a brief sonication under Ar. To the vial, 1M HCl etherate (0.355 mL, 0.710 mmol, 2 eq) was added dropwise. The vial was stirred for 4 h at room temperature. LCMS indicated that the reaction had 5 stalled, and the ether was stripped off. The DMF residue was purified via reverse phase (Teledyne 50 g C18 with (5% ACN+0.05% TFA) / (H2O+0.05% TFA) to 95% (ACN+0.05% TFA) / (H2O+0.05% TFA) gradient). The product was recovered by lyophilization to obtain I-87 (237.1 mg, 81% yield) as a white solid. (ESI) m / z: [M+H]+ = 827.21. To an oven dried vial was added I-87 (237 mg, 0.316 mmol, 1 eq) and dissolved in (1:4) 10 (Morpholine:DMF) (3.5 mL) and stirred at room temperature under Ar. LCMS at 15 minutes indicated that I-87 was consumed. The crude reaction was precipitated with diethyl ether (35 mL) and the solid was obtained by centrifugation. The solid was washed with diethyl ether (1x) (10 mL) and the solid was obtained by centrifugation. This obtained solid was redissolved in (1:1) (H2O:ACN) and lyophilized to give 171 (88 mg, 39% yield) as a white solid. (ESI) m / z: 15 [M+H]+ = 605.31. Example 90: Synthesis of Payload 172: MF NJB0009PCT To an oven dried vial was added 31 (134 mg, 0.284 mmol, 1 eq) and OAc-CH2-NH-Gly- Fmoc (523 mg, 1.421 mmol, 5 eq) and suspended in Anhydrous DMF (1.89 mL) with a brief sonication under Ar. To the vial, 1M HCl etherate (0.568 mL, 0.568 mmol, 2 eq) was added dropwise. The vial was stirred for 4 h at room temperature. LCMS indicated that the reaction had 5 stalled, and the ether was stripped off. The DMF residue was purified via reverse phase (Teledyne 100 g C18 with (5% ACN+0.05% TFA) / (H2O+0.05% TFA) to 95% (ACN+0.05% TFA) / (H2O+0.05% TFA) gradient). The product was recovered by lyophilization to obtain I-88 (121.8 mg, 55% yield) as a white solid. (ESI) m / z: [M+H]+ = 780.41. To an oven dried vial was added I-88 (114 mg, 0.146 mmol, 1 eq) and dissolved in (1:4) 10 (Morpholine:DMF) (1.83 mL) and stirred at room temperature under Ar. LCMS at 15 minutes indicated that I-88 was consumed. The crude reaction was precipitated with diethyl ether (20 mL) and the solid was obtained by centrifugation. The solid was washed with diethyl ether (1x) (10 mL) and the solid was obtained by centrifugation. This obtained solid was redissolved in (1:1) (H2O:ACN) and lyophilized to give 172 (71.8 mg, 73% yield) as a white solid. (ESI) m / z: 15 [M+H]+ = 558.14. Example 91: Synthesis of Payload 173: H MF g, . , q y- Fmoc (369mg, 1.002 mmol, 5 eq) and suspended in Anhydrous DMF (2.86 mL) with a brief 148 NJB0009PCT sonication under Ar. To the vial, 1M HCl etherate (0.20 mL, 0.401 mmol, 2 eq) was added dropwise. The vial was stirred for 4 h at room temperature. LCMS indicated that the reaction had stalled, and the ether was stripped off. The DMF residue was purified via reverse phase (Teledyne 100 g C18 with (5% ACN+0.05% TFA) / (H2O+0.05% TFA) to 95% (ACN+0.05% 5 TFA) / (H2O+0.05% TFA) gradient). The product was recovered by lyophilization to obtain I-89 (69 mg, 47% yield) as a white solid. (ESI) m / z: [M+H]+ = 737.46. To an oven dried vial was added I-89 (69 mg, 0.094 mmol, 1 eq) and dissolved in (1:4) (Morpholine:DMF) (1.34 mL) and stirred at room temperature under Ar. LCMS at 15 minutes indicated that I-89 was consumed. The crude reaction was precipitated with diethyl ether (15 10 mL) and the solid was obtained by centrifugation. The solid was washed with diethyl ether (1x) (10 mL) and the solid was obtained by centrifugation. This obtained solid was redissolved in (1:1) (H2O:ACN) and lyophilized to give 173 (48.6 mg, 83% yield) as a white solid. (ESI) m / z: [M+H]+ = 515.34. Example 92: Synthesis of Payload 174: OH MF 15 , . , Gly-Fmoc (107 mg, 0.291 mmol, 5 eq) and suspended in Anhydrous DMF (0.39 mL) with a brief sonication under Ar. To the vial, 1M HCl etherate (0.116 mL, 0.116 mmol, 2 eq) was added dropwise. The vial was stirred for 4 h at room temperature. LCMS indicated that the reaction had 149 NJB0009PCT stalled, and the ether was stripped off. The DMF residue was purified via reverse phase (Teledyne 100 g C18 with (5% ACN+0.05% TFA) / (H2O+0.05% TFA) to 95% (ACN+0.05% TFA) / (H2O+0.05% TFA) gradient). The product was recovered by lyophilization to obtain I-90 (32 mg, 72% yield) as a white solid. (ESI) m / z: [M+H]+ = 766.25. 5 To an oven dried vial was added I-90 (32 mg, 0.042 mmol, 1 eq) and dissolved in (1:4) (Morpholine:DMF) (0.348 mL) and stirred at room temperature under Ar. LCMS at 15 minutes indicated that I-90 was consumed. The crude reaction was precipitated with diethyl ether (5 mL) and the solid was obtained by centrifugation. The solid was washed with diethyl ether (1x) (5mL) and the solid was obtained by centrifugation. This obtained solid was redissolved in (1:1) 10 (H2O:ACN) and lyophilized to give 174 (21.2 mg, 79% yield) as a white solid. (ESI) m / z: [M+H]+ = 544.25. 15 20 25 30 150 NJB0009PCT Table 3: Aryl-Extended Linker Payload Structures: Cmpd Structure PLL1 O H O H O H O 151 NJB0009PCT Cmpd Structure PLL5 O H O H O 152 NJB0009PCT Cmpd Structure PLL9 O H O H O H O 153 NJB0009PCT Cmpd Structure PLL13 O O 154 NJB0009PCT Cmpd Structure PLL17 O 155 NJB0009PCT Cmpd Structure PLL21 O 156 NJB0009PCT Cmpd Structure PLL25 O 157 NJB0009PCT Cmpd Structure PLL29 O 158 NJB0009PCT Cmpd Structure PLL32 O 159 NJB0009PCT Cmpd Structure PLL35 H O 160 NJB0009PCT Cmpd Structure PLL38 Ph O 161 NJB0009PCT Cmpd Structure PLL42 Ph O NH 162 NJB0009PCT Cmpd Structure PLL46 O NH Example 93: Synthesis of Linker Payloads: Example 94: Synthesis of Linker Payload PLL1: O H O H O H O O N N N NH2NH N N N H H 5 O- CH2COOH (8.4 mg, 0.014 mmol, 1.11 eq) under Ar. Anhydrous DMF (0.38 mL) was added to the vial to yield a solution. NMM (2 uL, 0.015 mmol, 1.25 eq) was added to the vial followed by DMTMM (6.8 mg, 0.024 mmol, 2 eq) and briefly sonicated to yield a suspension. The vial was stirred at room temperature for 0.5 h whereupon the LCMS indicated 2 was consumed. The 10 crude reaction was purified via reverse phase (Teledyne Gemini (5µm C18110Å 150 x 30 mm) with (5% ACN+0.05%TFA) / (H2O+0.05%TFA) to 95% (ACN+0.05%TFA) / (H2O+0.05%TFA) gradient). The product was recovered by lyophilization to obtain PLL1 (3.8 mg, 28% yield) as a white solid. (ESI) m / z: [M+H]+= 1107.64. 163 NJB0009PCT Example 95: Synthesis of Linker Payload PLL2: Ph O O H O HON N N NH2N N N O 6 mmol, 1.11 eq) in anhydrous DMF under Argon at RT, NMM (0.001 mL, 0.007 mmol, 1.25 eq) 5 was added followed by DMTMM (3 mg, 0.011 mmol, 2 eq). The reaction was stirred at room temperature until consumption of starting material. LCMS after 10 min showed complete consumption of 2. The crude reaction was purified via reverse phase (Teledyne Gemini (5 µm C18110 Å 150 x 30 mm) with (5% ACN) / (H2O) to 95% (ACN) / (H2O) gradient) (0.05% TFA). The product was recovered by lyophilization to obtain PLL2 (0.6 mg, 11% yield) as off-white 10 solid. (ESI) m / z: [M+H]+= 1020.86. Example 96: Synthesis of Linker Payload PLL3: O oc 77% yieldTo an oven dried vial was added propargyl alcohol (60 mg, 1.07 mmol, 1 eq) and OAc- CH2-NH-Gly-Fmoc (433.7 mg, 1.177 mmol, 1 eq) and suspended in Anhydrous DMF (7.14 mL) 15 with a brief sonication under Ar. To the vial, 1M HCl etherate (2.141 mL, 2.141 mmol, 2 eq) was added dropwise. The vial was stirred for 4 h at room temperature. LCMS indicated that the reaction had stalled, and the reaction was purified via reverse phase (Teledyne 100 g C18 with (5% ACN+0.05% TFA) / (H2O+0.05% TFA) to 95% (ACN+0.05% TFA) / (H2O+0.05% TFA) gradient). The product was recovered by lyophilization to obtain I-91 (298 mg, 76.5% yield) as a 20 white solid. (ESI) m / z: [M+Na]+= 387.03. 164 NJB0009PCT 77% yield ONHFmocN O H O under argon atmosphere. (PPh3)3CuBr (29.5 mg, 20 mol%) was added to the vial and dissolved in anhydrous dichloromethane (9.92 mL). Diisopropylethylamine (0.56 mL, 3.176 mmol, 20 eq) 5 was added to the vial and the reaction was stirred at 35°C for 2 hours sealed under argon atmosphere. The crude reaction was concentrated en vacuo and dissolved in (2 mL) DMF. The crude material was purified via reverse phase chromatography (50 g C18) (5% ACN + 0.05% TFA) to (95% ACN+ 0.05 % TFA) / (H2O + 0.05% TFA gradient). The product was recovered by lyophilization to obtain I-92 (25.2 mg, 19% yield) as a white solid. (ESI) m / z: [M+H]+ = 818.55. 10 To an oven dried vial was added I-92 (32 mg, 0.039 mmol, 1 eq) and dissolved in (1:4) (Morpholine:DMF) (0.486 mL) and stirred at room temperature under Ar. LCMS at 15 minutes indicated that I-92 was consumed. The crude reaction was precipitated with diethyl ether (5 mL) and the solid was obtained by centrifugation. The solid was washed with diethyl ether (1x) (5 mL) and the solid was obtained by centrifugation. This obtained solid was redissolved in (1:1) 15 (H2O:ACN) and lyophilized to give I-93 (28.8 mg, quant. yield) as a white solid. (ESI) m / z: [M+H]+ = 596.14. To an oven dried vial was added I-93 (29 mg, 0.048 mmol, 1 eq) and MC-GGF-COOH (25.4 mg, 0.054 mmol, 1.11 eq) under Ar. Anhydrous DMF (1.49 mL) was added to the vial to 165 NJB0009PCT yield a solution. NMM (7 uL, 0.060 mmol, 1.25 eq) was added to the vial followed by DMTMM (26.8 mg, 0.097 mmol, 2 eq) and briefly sonicated to yield a suspension. The vial was stirred at room temperature for 0.5 h whereupon the LCMS indicated I-93 was consumed. The crude reaction was purified via reverse phase (Teledyne Gemini (5µm C18110Å 150 x 30 mm) with 5 (5% ACN+0.05%FA) / (H2O+0.05%FA) to 95% (ACN+0.05%FA) / (H2O+0.05%FA) gradient). The product was recovered by lyophilization to obtain PLL3 (8.6 mg, 17% yield) as a white solid. (ESI) m / z: [M+H]+= 1050.81. Example 97: Synthesis of Linker Payload PLL4: H OH O N NHFmoc N H N O O 10 - Fmoc (87 mg, 0.236 mmol, 5 eq) and suspended in Anhydrous DMF (0.315 mL) with a brief sonication under Ar. To the vial, 1M HCl etherate (0.094 mL, 0.094 mmol, 2 eq) was added dropwise. The vial was stirred for 22 h at room temperature. LCMS indicated that the reaction had stalled, and the ether was stripped off. The DMF residue was purified via reverse phase 15 (Teledyne 100 g C18 with (5% ACN+0.05% TFA) / (H2O+0.05% TFA) to 95% (ACN+0.05% TFA) / (H2O+0.05% TFA) gradient). The product was recovered by lyophilization to obtain I-94 (19.6 mg, 49% yield) as a white solid. (ESI) m / z: [M+H]+= 846.81. To an oven dried vial was added I-94 (23.2 mg, 0.0232 mmol, 1 eq) and dissolved in (1:4) (Morpholine:DMF) (0.799 mL) and stirred at room temperature under Ar. LCMS at 15 20 minutes indicated that I-94 was consumed. The crude reaction was precipitated with diethyl ether (8 mL) and the solid was obtained by centrifugation. The solid was washed with diethyl ether 166 NJB0009PCT (1x) (8 mL) and the solid was obtained by centrifugation. This obtained solid was redissolved in (1:1) (H2O: ACN) and lyophilized to give I-95 (10 mg, 69% yield) as a white solid. (ESI) m / z: [M+H]+= 624.35. To an oven dried vial was added I-95 (10 mg, 0.016 mmol, 1 eq) and MC-GGF-COOH 5 (8.4 mg, 0.018 mmol, 1.11 eq) under Ar. Anhydrous DMF (0.49 mL) was added to the vial to yield a solution. NMM (2 uL, 0.020 mmol, 1.25 eq) was added to the vial followed by DMTMM (8.9 mg, 0.032 mmol, 2 eq) and briefly sonicated to yield a suspension. The vial was stirred at room temperature for 0.5 h whereupon the LCMS indicated I-95 was consumed. The crude reaction was purified via reverse phase (Teledyne Gemini (5µm C18110Å 150 x 30 mm) with 10 (5% ACN+0.05%FA) / (H2O+0.05%FA) to 95% (ACN+0.05%FA) / (H2O+0.05%FA) gradient). The product was recovered by lyophilization to obtain PLL4 (7.4 mg, 43% yield) as a white solid. (ESI) m / z: [M+H]+= 1078.44. Example 98: Synthesis of Linker Payload PLL5: H OH O N NHFm O 15 Fmoc (63 mg, 0.172 mmol, 5 eq) and suspended in Anhydrous DMF (0.23 mL) with a brief sonication under Ar. To the vial, 1M HCl etherate (0.069 mL, 0.069 mmol, 2 eq) was added dropwise. The vial was stirred for 22 h at room temperature. LCMS indicated that the reaction had stalled, and the ether was stripped off. The DMF residue was purified via reverse phase 20 (Teledyne 100 g C18 with (5% ACN+0.05% TFA) / (H2O+0.05% TFA) to 95% (ACN+0.05% 167 NJB0009PCT TFA) / (H2O+0.05% TFA) gradient). The product was recovered by lyophilization to obtain I-96 (26.4 mg, 91% yield) as a white solid. (ESI) m / z: [M+H]+= 860.06. To an oven dried vial was added I-96 (26 mg, 0.0307 mmol, 1 eq) and dissolved in (1:4) (Morpholine:DMF) (1.059 mL) and stirred at room temperature under Ar. LCMS at 15 minutes 5 indicated that I-96 was consumed. The crude reaction was precipitated with diethyl ether (10 mL) and the solid was obtained by centrifugation. The solid was washed with diethyl ether (1x) (10 mL) and the solid was obtained by centrifugation. This obtained solid was redissolved in (1:1) (H2O: ACN) and lyophilized to give I-97 (9 mg, 47% yield) as a white solid. (ESI) m / z: [M+H]+= 638.65. 10 To an oven dried vial was added I-97 (9 mg, 0.014 mmol, 1 eq) and MC-GGF-COOH (7.6 mg, 0.016 mmol, 1.11 eq) under Ar. Anhydrous DMF (0.44 mL) was added to the vial to yield a solution. NMM (2 µL, 0.018 mmol, 1.25 eq) was added to the vial followed by DMTMM (8 mg, 0.029 mmol, 2 eq) and briefly sonicated to yield a suspension. The vial was stirred at room temperature for 0.5 h whereupon the LCMS indicated I-97 was consumed. The crude 15 reaction was purified via reverse phase (Teledyne Gemini (5µm C18110Å 150 x 30 mm) with (5% ACN+0.05%FA) / (H2O+0.05%FA) to 95% (ACN+0.05%FA) / (H2O+0.05%FA) gradient). The product was recovered by lyophilization to obtain PLL5 (0.4 mg, 3% yield) as a white solid. (ESI) m / z: [M+H]+= 1092.59. Example 99: Synthesis of Linker Payload PLL6: O NHFmoc O oc 20 To an oven dried vial was added 3-butyne-1-ol (200 mg, 2.854 mmol, 1 eq) and OAc- CH2-NH-Gly-Fmoc (1.051 g, 2.853 mmol, 1 eq) and suspended in Anhydrous DMF (14.27 mL) with a brief sonication under Ar. To the vial, 1M HCl etherate (5.707 mL, 5.707 mmol, 2 eq) was added dropwise. The vial was stirred for 4 h at room temperature. LCMS indicated that the 25 reaction had stalled, and the ether was stripped off. The DMF residue was purified via reverse phase (Teledyne 100 g C18 with (5% ACN+0.05% TFA) / (H2O+0.05% TFA) to 95% (ACN+0.05% TFA) / (H2O+0.05% TFA) gradient). The product was recovered by lyophilization to obtain I-98 (531 mg, 49% yield) as a white solid. (ESI) m / z: [M+Na]+= 401.22. 168 NJB0009PCT O O HN H NHFmoc O N O under argon atmosphere. (PPh3)3CuBr (61 mg, 20 mol%) was added to the vial and dissolved in anhydrous dichloromethane (21 mL). Diisopropylethylamine (1.16 mL, 6.616 mmol, 20 eq) was 5 added to the vial and the reaction was stirred at 35°C for 2 hours sealed under argon atmosphere. The crude reaction was concentrated en vacuo and dissolved in (2 mL) DMF. The crude material was purified via reverse phase chromatography (50 g C18) (5% ACN + 0.05% TFA) to (95% ACN+ 0.05 % TFA) / (H2O + 0.05% TFA gradient). The product was recovered by lyophilization to obtain I-99 (81.2 mg, 30% yield) as a white solid. (ESI) m / z: [M+H]+= 832.52. 10 To an oven dried vial was added I-99 (36 mg, 0.043 mmol, 1 eq) and dissolved in (1:4) (Morpholine:DMF) (0.62 mL) and stirred at room temperature under Ar. LCMS at 15 minutes indicated that I-99 was consumed. The crude reaction was precipitated with diethyl ether (6mL) and the solid was obtained by centrifugation. The solid was washed with diethyl ether (1x) (6 mL) and the solid was obtained by centrifugation. This obtained solid was redissolved in (1:1) 15 (H2O: ACN) and lyophilized to give I-100 (21 mg, 80% yield) as a white solid. (ESI) m / z: [M+H]+= 610.35. To an oven dried vial was added I-100 (21 mg, 0.034 mmol, 1 eq) and MC-GGF-COOH (18.1 mg, 0.038 mmol, 1.11 eq) under Ar. Anhydrous DMF (1.06 mL) was added to the vial to yield a solution. NMM (5 uL, 0.005 mmol, 1.25 eq) was added to the vial followed by DMTMM 169 NJB0009PCT (19.1 mg, 0.069 mmol, 2 eq) and briefly sonicated to yield a suspension. The vial was stirred at room temperature for 0.5 h whereupon the LCMS indicated I-100 was consumed. The crude reaction was purified via reverse phase (Teledyne Gemini (5µm C18110Å 150 x 30 mm) with (5% ACN+0.05%FA) / (H2O+0.05%FA) to 95% (ACN+0.05%FA) / (H2O+0.05%FA) gradient). 5 The product was recovered by lyophilization to obtain PLL6 (1.2 mg, 3% yield) as a white solid. (ESI) m / z: [M+H]+= 1064.20. Example 100: Synthesis of Linker Payload PLL7: NHFmoc O 10 Fmoc (67 mg, 0.182 mmol, 5 eq) and suspended in Anhydrous DMF (0.24 mL) with a brief sonication under Ar. To the vial, 1M HCl etherate (0.073 mL, 0.072 mmol, 2 eq) was added dropwise. The vial was stirred for 22 h at room temperature. LCMS indicated that the reaction had stalled, and the ether was stripped off. The DMF residue was purified via reverse phase (Teledyne 100 g C18 with (5% ACN+0.05% TFA) / (H2O+0.05% TFA) to 95% (ACN+0.05% 15 TFA) / (H2O+0.05% TFA) gradient). The product was recovered by lyophilization to obtain I-101 (9.2 mg, 48% yield) as a white solid. (ESI) m / z: [M+H]+= 846.63. To an oven dried vial was added I-101 (9.2 mg, 0.011 mmol, 1 eq) and dissolved in (1:4) (Morpholine:DMF) (0.375 mL) and stirred at room temperature under Ar. LCMS at 15 minutes indicated that I-101 was consumed. The crude reaction was precipitated with diethyl ether (4 170 NJB0009PCT mL) and the solid was obtained by centrifugation. The solid was washed with diethyl ether (1x) (4 mL) and the solid was obtained by centrifugation. This obtained solid was redissolved in (1:1) (H2O: ACN) and lyophilized to give I-102 (5 mg, 75% yield) as a white solid. (ESI) m / z: [M+H] + = 624.31. 5 To an oven dried vial was added I-102 (5 mg, 0.007 mmol, 1 eq) and MC-GGF-COOH (3.9 mg, 0.008 mmol, 1.11 eq) under Ar. Anhydrous DMF (0.23 mL) was added to the vial to yield a solution. NMM (1 uL, 0.009 mmol, 1.25 eq) was added to the vial followed by DMTMM (4 mg, 0.015 mmol, 2 eq) and briefly sonicated to yield a suspension. The vial was stirred at room temperature for 0.5 h whereupon the LCMS indicated I-102 was consumed. The crude 10 reaction was purified via reverse phase (Teledyne Gemini (5µm C18110Å 150 x 30 mm) with (5% ACN+0.05%FA) / (H2O+0.05%FA) to 95% (ACN+0.05%FA) / (H2O+0.05%FA) gradient). The product was recovered by lyophilization to obtain PLL7 (2.6 mg, 33% yield) as a white solid. (ESI) m / z: [M+H]+= 1078.57. Example 101: Synthesis of Linker Payload PLL8: O H O H O H O O N N N NH2HN N N N O H HO15 H2- O-CH2COOH (12 mg, 0.0195 mmol, 1.11 eq) under Ar. Anhydrous DMF (0.487 mL) was added to the vial to yield a solution. NMM (2 uL, 0.0219 mmol, 1.25 eq) was added to the vial followed by DMTMM (9.7 mg, 0.035 mmol, 2 eq) and briefly sonicated to yield a suspension. The vial 20 was stirred at room temperature for 0.5 h whereupon the LCMS indicated 9 was consumed. The crude reaction was purified via reverse phase (Teledyne Gemini (5µm C18110Å 150 x 30 mm) with (5% ACN+0.05%TFA) / (H2O+0.05%TFA) to 95% (ACN+0.05%TFA) / (H2O+0.05%TFA) gradient). The product was recovered by lyophilization to obtain PLL8 (10 mg, 56% yield) as a white solid. (ESI) m / z: [M+H]+ = 1169.72. 25 Example 102: Synthesis of Linker Payload PLL9: 171 NJB0009PCT O H O H O H O O N N N NH2NH N N N GGFG-NH-CH2-O-CH2COOHOH H MC- O PhO CH2-O-CH2COOH (6.24 mg, 0.010 mmol, 1.11 eq) under Ar. Anhydrous DMF (0.25 mL) was added to the vial to yield a solution. NMM (1 uL, 0.011 mmol, 1.25 eq) was added to the vial 5 followed by DMTMM (5.05 mg, 0.018 mmol, 2 eq) and briefly sonicated to yield a suspension. The vial was stirred at room temperature for 0.5 h whereupon the LCMS indicated 15 was consumed. The crude reaction was purified via reverse phase (Teledyne Gemini (5µm C18110Å 150 x 30 mm) with (5% ACN) / (H2O) to 95% (ACN) / (H2O) gradient). The product was recovered by lyophilization to obtain PLL9 (4.2 mg, 29% yield) as a white solid. (ESI) m / z: 10 [M+H]+= 1026.42. Example 103: Synthesis of Linker Payload PLL10: Ph O O H O H O N N N O 7.5 mg, 0.052 mmol, 1.11 eq) under Ar. Anhydrous DMF (1.44 mL) was added to the vial to yield a 15 solution. NMM (6 uL, 0.058 mmol, 1.25 eq) was added to the vial followed by DMTMM (25.9 mg, 0.058 mmol, 2 eq) and briefly sonicated to yield a suspension. The vial was stirred at room temperature for 0.5 h whereupon the LCMS indicated 15 was consumed. The crude reaction was purified via reverse phase (Teledyne Gemini (5µm C18110Å 150 x 30 mm) with (5% ACN) / (H2O) to 95% (ACN) / (H2O) gradient). The product was recovered by lyophilization to 20 obtain PLL10 (14.4 mg, 33% yield) as an off-white solid. (ESI) m / z: [M+H]+= 939.21. Example 104: Synthesis of Linker Payload PLL11: 172 NJB0009PCT OH O NH O O mg, 0.029 mmol, 1 eq) in anhydrous DMF under Argon at RT, HCl-etherate (1M in ether) (0.057 mL, 0.057 mmol, 2 eq) was added. After 1h 30 minutes, another equivalent of OAc-CH2-NH- 5 Gly-Fmoc (13.1 mg, 0.029 mmol, 1 eq) was added to the reaction mixture. The addition of OAc- CH2-NH-Gly-Fmoc (13.1 mg, 0.029 mmol, 1 eq) was repeated every 1h 30 minutes to the total of 5 eq. The reaction stirred at RT overnight. The crude reaction was purified via reverse phase (Teledyne Gemini (5 µm C18110 Å 150 x 30 mm) with (5% ACN) / (H2O) to 95% (ACN) / (H2O) gradient) (0.05% TFA). The product was recovered by lyophilization to obtain I-103 (16.2 10 mg, 73% yield) as an off-white solid. (ESI) m / z: [M+H]+= 779.41. The compound I-103 (16 mg, 0.021 mmol, 1 eq) was dissolved in (1:4) morpholine / DMF (0.297 mL) under Argon and stirred at RT until consumption of starting material. LCMS after 20 min showed complete consumption of I-103. The crude reaction was precipitated with diethyl ether (2 mL) and the solid was obtained by centrifugation. The solid was washed with diethyl 15 ether (1mL) and the solid was obtained by centrifugation. This obtained solid was redissolved in (1:1) (H2O: ACN) (0.05% TFA) and lyophilized to give I-104 (7 mg, 60% yield) as off-white solid. (ESI) m / z: [M+H]+= 557.10. To the solution of I-104 (7 mg, 0.013 mmol, 1 eq) and MC-GGF (6.6 mg, 0.014 mmol, 1.11 eq) in anhydrous DMF under Argon at RT, NMM (0.002 mL, 0.016 mmol, 1.25 eq) was 173 NJB0009PCT added followed by DMTMM (7 mg, 0.025 mmol, 2 eq). The reaction was stirred at room temperature until consumption of starting material. LCMS after 15 min showed complete consumption of I-104. The crude reaction was purified via reverse phase (Teledyne Gemini (5 µm C18110 Å 150 x 30 mm) with (5% ACN) / (H2O) to 95% (ACN) / (H2O) gradient) (0.05% 5 TFA). The product was recovered by lyophilization to obtain PLL11 (5 mg, 39% yield) as off- white solid. (ESI) m / z: [M+H]+= 1011.06. Example 105: Synthesis of Linker Payload PLL12: O NH O NH O O O g, 10 0.067 mmol, 1.2 eq) in anhydrous DMF under Argon at RT, NMM (0.031 mL, 0.223 mmol, 4 eq) was added. The reaction was stirred at room temperature until consumption of starting material. LCMS after 45 min showed complete consumption of I-104. The crude reaction was purified via reverse phase (Teledyne Gemini (5 µm C18110 Å 150 x 30 mm) with (5% ACN) / (H2O) to 95% (ACN) / (H2O) gradient) (0.05% TFA). The product was recovered by 15 lyophilization to obtain PLL12 (23.8 mg, 57% yield) as off-white solid. (ESI) m / z: [M+H]+= 750.53. Example 106: Synthesis of Linker Payload PL13: 174 NJB0009PCT O FmocHN NH2NH O O 0.169 mmol, 2 eq) in anhydrous DMF under Argon at RT, NMM (0.0037 mL, 0.339 mmol, 4 eq) was added. After 3 min, the reaction mixture transferred to the one-dram vial containing 57 (35 5 mg, 0.085 mmol, 1 eq) under Argon. After 3h, the crude reaction mixture was purified with reverse phase C18 (50g) using water / Acetonitrile gradient (10%-100%). The product was recovered by lyophilization to obtain I-105 (15 mg, 25% yield) as off-white solid. (ESI) m / z: [M+H]+= 707.39. The compound I-105 (15 mg, 0.021 mmol, 1 eq) was dissolved in (1:4) piperidine / DMF 10 (1 mL) under Argon and stirred at RT until consumption of starting material. LCMS after 20 min showed complete consumption of I-105. The crude reaction was precipitated with diethyl ether (2 mL) and the solid was obtained by centrifugation. The solid was washed with diethyl ether (1mL) and the solid was obtained by centrifugation. This obtained solid was kept in high vacuum overnight to give I-106 (4 mg, 40% yield) as off-white solid. (ESI) m / z: [M+H]+= 485.38. 15 To the solution of compound I-106 (2 mg, 0.004 mmol, 1 eq), MC-V (2.6 mg, 0.008 mmol, 2 eq), and HOBt (0.7 mg, 0.005 mmol, 1.3 eq) in anhydrous DMF under Argon at RT, NMM (0.001 mL, 0.016 mmol, 4 eq) was added followed by PyBOP (3.2 mg, 0.006 mmol, 1.5 eq). The reaction was stirred at RT until consumption of starting material. LCMS after 15 min showed complete consumption of I-106. The crude reaction purified with reverse phase C18 20 (50g) using water / Acetonitrile gradient (10%-100%). The product was recovered by 175 NJB0009PCT lyophilization to obtain PLL13 (1.4 mg, 44% yield) as dark-brown solid. (ESI) m / z: [M+H]+= 777.61. Example 107: Synthesis of Linker Payload PLL14: O N O O O O NH H H N N N N 5 (10.1 mg, 0.012 mmol, 1.2 eq) in anhydrous DMF under Argon at RT, DIPEA (0.005 mL, 0.030 mmol, 3 eq) was added. The reaction was stirred at RT overnight. Upon completion, the crude reaction mixture purified with reverse phase C18 (50g) using water acetonitrile (0.05% formic acid) (10%-100% gradient). The product was obtained by lyophilization to obtain I-107 (6.8 mg, 10 57% yield) as off-white solid. (ESI) m / z: [M+H]+= 1194.09. The compound I-107 (6.8 mg, 0.006 mmol, 1 eq) was dissolved in (1:4) TFA / DCM (1 mL) under Argon and stirred at RT until consumption of starting material. LCMS after 1h showed complete consumption of I-107. The solvent evaporated, dissolved in DMF and purified with reverse phase C18 (50g) using water acetonitrile (0.05% TFA) (10%-100% gradient). The 15 product was obtained by lyophilization to obtain PLL14 (1.4 mg, 22% yield) as off-white solid. (ESI) m / z: [M+H]+= 1138.87. Example 108: Synthesis of Linker Payload PLL15: 176 NJB0009PCT O N O O H O H O NH N N N N N N N (46.1 mg, 0.055 mmol, 1.2 eq) in anhydrous DMF under Argon at RT, DIPEA (0.024 mL, 0.138 mmol, 3 eq) was added. The reaction was stirred at RT overnight. Upon completion, the crude 5 reaction mixture purified with reverse phase C18 (50g) using water acetonitrile (0.05% formic acid) (10%-100% gradient). The product was obtained by lyophilization to obtain I-108 (56.14 mg, quant. yield) as off-white solid. (ESI) m / z: [M+H]+= 1220.90. The compound I-108 (56.14 mg, 0.046 mmol, 1 eq) was dissolved in (1:4) TFA / DCM (8 mL) under Argon and stirred at RT until consumption of starting material. LCMS after 1h 10 showed complete consumption of I-108. The solvent evaporated, dissolved in DMF and purified with reverse phase C18 (100g) using water acetonitrile (0.05% FA) (10%-100% gradient). The product was obtained by lyophilization to obtain PLL15 (3.4 mg, 6% yield over two steps) as off-white solid. (ESI) m / z: [M+H]+= 1164.94. Example 109: Synthesis of Linker Payload PLL16: 177 NJB0009PCT O NH N O O H O H O N N N N N (20.1 mg, 0.024 mmol, 1.2 eq) in anhydrous DMF under Argon at RT, DIPEA (0.010 mL, 0.0.060 mmol, 3 eq) was added. The reaction was stirred at RT overnight. Upon completion, the 5 crude reaction mixture purified with reverse phase C18 (50g) using water acetonitrile (0.05% formic acid) (10%-100% gradient). The product was obtained by lyophilization to obtain I-109 (25.25 mg, quant. yield) as off-white solid. (ESI) m / z: [M+H]+= 1262.86. The compound I-109 (25.25 mg, 0.020 mmol, 1 eq) was dissolved in (1:4) TFA / DCM (3.5 mL) under Argon and stirred at RT until consumption of starting material. LCMS after 2h 10 showed complete consumption of I-109. The solvent evaporated, dissolved in DMF and purified with reverse phase C18 (100g) using water acetonitrile (0.05% FA) (10%-100% gradient). The product was obtained by lyophilization to obtain PLL16 (4.8 mg, 20% yield) as off-white solid. (ESI) m / z: [M+H]+= 1206.95. Example 110: Synthesis of Linker Payload PLL17: O O NH N O O O O 15 NJB0009PCT To the solution of compound 111 (15.1 mg, 0.027 mmol, 1 eq) and MC-VC-PAB-PNP (29.59 mg, 0.040 mmol, 1.5 eq) in anhydrous DMF under Argon at RT, DIPEA (0.014 mL, 0.080 mmol, 3 eq) was added. LCMS after 1h showed complete consumption of 111. The crude reaction mixture was purified with reverse phase C18 (100g) using water acetonitrile (0.05% 5 formic acid) (10%-100% gradient). The product was obtained by lyophilization to obtain PLL17 (22 mg, 71% yield) as off-white solid. (ESI) m / z: [M+H]+= 1163.85. Example 111: Synthesis of Linker Payload PLL18: O FmocH N O N H2N O N H N O O O 10 0.045 mmol, 2 eq) in anhydrous DMF under Argon at RT, NMM (0.010 mL, 0.091 mmol, 4 eq) was added. After 3 min, the reaction mixture transferred to the one-dram vial containing 115 (10 mg, 0.023 mmol, 1 eq) under Argon. After 6h, a solution of 2 eq of HATU, 2 eq Fmoc Ala-OH and 4 eq NMM in DMF was added to the reaction mixture and stirred at RT overnight. The crude reaction mixture purified with reverse phase C18 (50g) using water / Acetonitrile (0.05%15 TFA modifier) gradient (10%-100%). The product was recovered by lyophilization to obtain I- 110 (2 mg, 12% yield) as off-white solid. (ESI) m / z: [M+H]+= 735.57. The compound I-110 (2 mg, 0.003 mmol, 1 eq) was dissolved in (1:4) morpholine / DMF (0.034 mL) under Argon and stirred at RT until consumption of starting material. LCMS after 30 min showed complete consumption of I-110. The crude reaction was precipitated with diethyl 20 ether (2 mL) and the solid was obtained by centrifugation. The solid was washed with diethyl ether (1mL) and the solid was obtained by centrifugation. This obtained solid was redissolved in (1:1) (H2O: ACN) (0.05% TFA) and lyophilized to give I-111 (1.9 mg, 85% yield) as off-white solid. (ESI) m / z: [M+H]+= 513.40. 179 NJB0009PCT To the solution of compound I-111 (1.9 mg, 0.003 mmol, 1 eq), MC-V (1.9 mg, 0.006 mmol, 2 eq), and HOBt (0.8 mg, 0.006 mmol, 2 eq) in anhydrous DMF under Argon at RT, NMM (0.001 mL, 0.012 mmol, 4 eq) was added followed by PyBOP (2.4 mg, 0.005 mmol, 1.5 eq). The reaction was stirred at RT until consumption of starting material. LCMS after 15 min 5 showed complete consumption of I-111. The crude reaction was purified via reverse phase (Teledyne Gemini (5 µm C18110 Å 150 x 30 mm) with (5% ACN) / (H2O) to 95% (ACN) / (H2O) gradient) (0.05% TFA). The product was recovered by lyophilization to obtain PLL18 (0.9 mg, 38% yield) as off-white solid. (ESI) m / z: [M+H]+= 805.60. Example 112: Synthesis of Linker Payload PLL19: O H O H N N N N O O 10 mmol, 2 eq), and HOBt (7.5 mg, 0.055 mmol, 2 eq) in anhydrous DMF under Argon at RT, NMM (0.012 mL, 0.111 mmol, 4 eq) was added followed by PyBOP (21.6 mg, 0.042 mmol, 1.5 eq). The reaction was stirred at RT until consumption of starting material. LCMS after 20 min 15 showed complete consumption of 129. The crude reaction was purified via reverse phase (Teledyne Gemini (5 µm C18110 Å 150 x 30 mm) with (5% ACN) / (H2O) to 95% (ACN) / (H2O) gradient) (0.05% TFA). The product was recovered by lyophilization to obtain PLL19 (4.4 mg, 21% yield) as off-white solid. (ESI) m / z: [M+H]+= 777.61. Example 113: Synthesis of Linker Payload PLL20: O O O H O O 20 O p g, . , q , . g, . mmol, 2 eq), and HOBt (17.3 mg, 0.128 mmol, 2 eq) in anhydrous DMF under Argon at RT, 180 NJB0009PCT NMM (0.028 mL, 0.256 mmol, 4 eq) was added followed by PyBOP (50 mg, 0.096 mmol, 1.5 eq). The reaction was stirred at RT until consumption of starting material. LCMS after 15 min showed complete consumption of 131. The crude reaction was purified in two portions via reverse phase (Teledyne Gemini (5 µm C18110 Å 150 x 30 mm) with (5% ACN) / (H2O) to 95% 5 (ACN) / (H2O) gradient) (0.05% TFA). The product was recovered by lyophilization to obtain PLL20 (18.4 mg, 36% yield) as off-white solid. (ESI) m / z: [M+H]+= 791.63. Example 114: Synthesis of Linker Payload PLL21: O O O H O H2N N N O O 10 mmol, 2 eq), and HOBt (11.6 mg, 0.086 mmol, 2 eq) in anhydrous DMF under Argon at RT, NMM (0.019 mL, 0.172 mmol, 4 eq) was added followed by PyBOP (33.6 mg, 0.065 mmol, 1.5 eq). The reaction was stirred at RT until consumption of starting material. LCMS after 15 min showed complete consumption of 131. The crude reaction was purified via reverse phase (Teledyne Gemini (5 µm C18110 Å 150 x 30 mm) with (5% ACN) / (H2O) to 95% (ACN) / 15 (H2O) gradient) (0.05% TFA). The product was recovered by lyophilization to obtain PLL21 (16.5 mg, 48% yield) as off-white solid. (ESI) m / z: [M+H]+= 805.59. Example 115: Synthesis of Linker Payload PLL22: O O O H O O O p . g, . , q , . g, . 20 mmol, 2 eq), and HOBt (8.3 mg, 0.061 mmol, 2 eq) in anhydrous DMF under Argon at RT, 181 NJB0009PCT NMM (0.014 mL, 0.123 mmol, 4 eq) was added followed by PyBOP (24 mg, 0.046 mmol, 1.5 eq). The reaction was stirred at RT until consumption of starting material. LCMS after 15 min showed complete consumption of 132. The crude reaction was purified via reverse phase (Teledyne Gemini (5 µm C18110 Å 150 x 30 mm) with (5% ACN) / (H2O) to 95% (ACN) / 5 (H2O) gradient) (0.05% TFA). The product was recovered by lyophilization to obtain PLL22 (15.1 mg, 59% yield) as off-white solid. (ESI) m / z: [M+H]+= 833.69. Example 116: Synthesis of Linker Payload PLL23: O O H O NH2N N N N u (26 mg, 10 0.085 mmol, 1.5 eq) in anhydrous DMF under Argon at RT, NMM (0.032 mL, 0.227 mmol, 4 eq) was added. The reaction was stirred at room temperature until consumption of starting material. LCMS after 1h 40 min showed complete consumption of 133. The crude reaction was purified via reverse phase C18 Aq (50g) using water / acetonitrile (0.05% TFA) gradient (10%- 100%). The impure product after reverse phase was purified again via reverse phase (Teledyne 15 Gemini (5 µm C18110 Å 150 x 30 mm) with (5% ACN) / (H2O) to 95% (ACN) / (H2O) gradient) (0.05% TFA). The product was recovered by lyophilization to obtain PLL23 (8 mg, 20% yield) as off-white solid. (ESI) m / z: [M+H]+= 708.45. Example 117: Synthesis of Linker Payload PLL24: 182 NJB0009PCT O H O H O N O N N O su (18 mg, 0.059 mmol, 1.5 eq) in anhydrous DMF under Argon at RT, NMM (0.022 mL, 0.156 mmol, 4 eq) was added. The reaction was stirred at room temperature until consumption of starting 5 material. LCMS after 30 min showed complete consumption of 134. The crude reaction was purified via reverse phase (Teledyne Gemini (5 µm C18110 Å 150 x 30 mm) with (5% ACN) / (H2O) to 95% (ACN) / (H2O) gradient) (0.05% TFA). The product was recovered by lyophilization to obtain PLL24 (12 mg, 43% yield) as off-white solid. (ESI) m / z: [M+H]+= 722.37. 10 Example 118: Synthesis of Linker Payload PLL25: O O O su (39 mg, 0.126 mmol, 1.5 eq) in anhydrous DMF under Argon at RT, NMM (0.044 mL, 0.337 mmol, 4 eq) was added. The reaction was stirred at room temperature until consumption of starting 15 material. LCMS after 30 min showed complete consumption of 135. The crude reaction was purified via reverse phase (Teledyne Gemini (5 µm C18110 Å 150 x 30 mm) with (5% ACN) / (H2O) to 95% (ACN) / (H2O) gradient) (0.05% TFA). The product was recovered by 183 NJB0009PCT lyophilization to obtain PLL25 (14.1 mg, 23% yield) as off-white solid. (ESI) m / z: [M+H]+= 736.39. Example 119: Synthesis of Linker Payload PLL26: O H O HN NH2N 5 u (51 mg, 0.165 mmol, 1.5 eq) in anhydrous DMF under Argon at RT, NMM (0.0.057 mL, 0.440 mmol, 4 eq) was added. The reaction was stirred at room temperature until consumption of starting material. LCMS after 45 min showed complete consumption of 136. The crude reaction was purified via reverse phase C18 Aq (50g) using water / acetonitrile (0.05% TFA) gradient (10%-10 100%). The product was recovered by lyophilization to obtain PLL26 (42 mg, 50% yield) as off- white solid. (ESI) m / z: [M+H]+= 764.31. Example 120: Synthesis of Linker Payload PLL27: H O O p g, . , q MalCap-Osu (17 mg, 15 0.057 mmol, 1.5 eq) in anhydrous DMF under Argon at RT, NMM (0.021 mL, 0.151 mmol, 4 eq) was added. The reaction was stirred at room temperature until consumption of starting 184 NJB0009PCT material. LCMS after 40 min showed complete consumption of 137. The crude reaction was purified via reverse phase (Teledyne Gemini (5 µm C18110 Å 150 x 30 mm) with (5% ACN) / (H2O) to 95% (ACN) / (H2O) gradient) (0.05% TFA). The product was recovered by lyophilization to obtain PLL27 (10.8 mg, 39% yield) as off-white solid. (ESI) m / z: [M+H]+= 5 725.42. Example 121: Synthesis of Linker Payload PLL28: O O H O NH ON 2T m mg, 0.065 mmol, 1.5 eq) in anhydrous DMF under Argon at RT, NMM (0.023 mL, 0.175 mmol, 4 10 eq) was added. The reaction was stirred at room temperature until consumption of starting material. LCMS after 30 min showed complete consumption of 138. The crude reaction was purified via reverse phase (Teledyne Gemini (5 µm C18110 Å 150 x 30 mm) with (5% ACN) / (H2O) to 95% (ACN) / (H2O) gradient) (0.05% TFA). The product was recovered by lyophilization to obtain PLL28 (18.9 mg, 52% yield) as off-white solid. (ESI) m / z: [M+H]+= 15 826.15. Example 122: Synthesis of Linker Payload PLL29: 185 NJB0009PCT O NHFmoc NH2HN MF O 158 mmol, 2 eq) in anhydrous DMF under Argon at RT, DIPEA (0.055 mL, 0.316 mmol, 2 eq) was added. After 15 min, the reaction mixture transferred to the one-dram vial containing 141 (49 5 mg, 0.158 mmol, 1 eq) under Argon. The reaction was stalled after 3h. The crude reaction was purified via reverse phase (Teledyne Gemini (5 µm C18110 Å 150 x 30 mm) with (5% ACN) / (H2O) to 95% (ACN) / (H2O) gradient) (0.05% TFA). The product was recovered by lyophilization to obtain I-112 (22.7 mg, 36% yield) as off-white solid. (ESI) m / z: [M+H]+= 797.59. 10 The compound I-112 (28 mg, 0.035 mmol, 1 eq) was dissolved in (1:4) morpholine / DMF (0.5 mL) under Argon and stirred at RT until consumption of starting material. LCMS after 30 min showed complete consumption of I-112. The crude reaction was precipitated with diethyl ether (2 mL) and the solid was obtained by centrifugation. The solid was washed with diethyl 186 NJB0009PCT ether (1mL) and the solid was obtained by centrifugation. This obtained solid was kept in high vacuum overnight to obtain I-113 (16 mg, 80% yield) as off-white solid. (ESI) m / z: [M+H]+= 575.26. To the solution of compound I-113 (16 mg, 0.028 mmol, 1 eq), MC-V (17.3 mg, 0.056 5 mmol, 2 eq), and PyBOP (21.7 mg, 0.042 mmol, 1.5 eq). in anhydrous DMF under Argon at RT, NMM (0.012 mL, 0.111 mmol, 4 eq) was added. The reaction was stirred at RT until consumption of starting material. LCMS after 15 min showed complete consumption of I-113. The crude reaction was purified via reverse phase (Teledyne Gemini (5 µm C18110 Å 150 x 30 mm) with (5% ACN) / (H2O) to 95% (ACN) / (H2O) gradient) (0.05% TFA). The product was 10 recovered by lyophilization to obtain PLL29 (6.4 mg, 27% yield) as off-white solid. (ESI) m / z: [M+H]+= 867.70. Example 123: Synthesis of Linker Payload PLL30: O O H O mg, 15 0.059 mmol, 1.5 eq) in anhydrous DMF under Argon at RT, NMM (0.022 mL, 0.158 mmol, 4 eq) was added. The reaction was stirred at room temperature until consumption of starting material. LCMS after 1h showed complete consumption of 143. The crude reaction was purified via reverse phase (Teledyne Gemini (5 µm C18110 Å 150 x 30 mm) with (5% ACN) / (H2O) to 95% (ACN) / (H2O) gradient) (0.05% TFA). The product was recovered by lyophilization to 20 obtain PLL30 (14.5 mg, 45% yield) as off-white solid. (ESI) m / z: [M+H]+= 812.44. Example 124: Synthesis of Linker Payload PLL31: 187 NJB0009PCT O H H O O N O N N O 11 mg, 0.036 mmol, 1.5 eq) in anhydrous DMF under Argon at RT, NMM (0.014 mL, 0.097 mmol, 4 eq) was added. The reaction was stirred at room temperature until consumption of starting 5 material. LCMS after 50 min showed complete consumption of 150. The crude reaction was purified via reverse phase (Teledyne Gemini (5 µm C18110 Å 150 x 30 mm) with (5% ACN) / (H2O) to 95% (ACN) / (H2O) gradient) (0.05% TFA). The product was recovered by lyophilization to obtain PLL31 (9.3 mg, 48% yield) as off-white solid. (ESI) m / z: [M+H]+= 799.42. 10 Example 125: Synthesis of Linker Payload PLL32: O O O H O O . , . , , . , . mmol, 2 eq), and HOBt (14.9 mg, 0.110 mmol, 2 eq) in anhydrous DMF under Argon at RT, NMM (0.024 mL, 0.220 mmol, 4 eq) was added followed by PyBOP (42.9 mg, 0.082 mmol, 1.5 15 eq). The reaction was stirred at RT until consumption of starting material. LCMS after 30 min 188 NJB0009PCT showed complete consumption of 152. The crude reaction was purified via reverse phase (Teledyne Gemini (5 µm C18110 Å 150 x 30 mm) with (5% ACN) / (H2O) to 95% (ACN) / (H2O) gradient) (0.05% TFA). The product was recovered by lyophilization to obtain PLL32 (22.9 mg, 48% yield) as off-white solid. (ESI) m / z: [M+H]+= 868.59. 5 Example 126: Synthesis of Linker Payload PLL33: O O H O ONNH2N O N N mg, 0.054 mmol, 1.5 eq) in anhydrous DMF under Argon at RT, NMM (0.020 mL, 0.143 mmol, 4 eq) was added. The reaction was stirred at room temperature until consumption of starting 10 material. LCMS after 50 min showed complete consumption of 154. The crude reaction was purified via reverse phase (Teledyne Gemini (5 µm C18110 Å 150 x 30 mm) with (5% ACN) / (H2O) to 95% (ACN) / (H2O) gradient) (0.05% TFA). The product was recovered by lyophilization to obtain PLL33 (19.9 mg, 68% yield) as off-white solid. (ESI) m / z: [M+H]+= 813.44. 15 Example 127: Synthesis of Linker Payload PLL34: O O O H O O O p g, . , q , . g, . mmol, 2 eq), and HOBt (7.4 mg, 0.054 mmol, 2 eq) in anhydrous DMF under Argon at RT, 189 NJB0009PCT NMM (0.012 mL, 0.109 mmol, 4 eq) was added followed by PyBOP (21.3 mg, 0.041 mmol, 1.5 eq). The reaction was stirred at RT until consumption of starting material. LCMS after 15 min showed complete consumption of 158. The crude reaction was purified via reverse phase (Teledyne Gemini (5 µm C18110 Å 150 x 30 mm) with (5% ACN) / (H2O) to 95% (ACN) / 5 (H2O) gradient) (0.05% TFA). The product was recovered by lyophilization to obtain PLL34 (8.2 mg, 37% yield) as off-white solid. (ESI) m / z: [M+H]+= 806.58. Example 128: Synthesis of Linker Payload PLL35: H O NH2N O MalCap-Osu (37 mg, 10 0.120 mmol, 1.5 eq) in anhydrous DMF under Argon at RT, NMM (0.045 mL, 0.320 mmol, 4 eq) was added. The reaction was stirred at room temperature until consumption of starting material. LCMS after 40 min showed complete consumption of 159. The crude reaction was purified via reverse phase (Teledyne Gemini (5 µm C18110 Å 150 x 30 mm) with (5% ACN) / (H2O) to 95% (ACN) / (H2O) gradient) (0.05% TFA). The product was recovered by 15 lyophilization to obtain PLL35 (28.7 mg, 50% yield) as off-white solid. (ESI) m / z: [M+H]+= 726.48. Example 129: Synthesis of Linker Payload PLL36: 190 NJB0009PCT O O O O H NH2N N HN HN N O mmol, 2 eq), and HOBt (11.3 mg, 0.083 mmol, 2 eq) in anhydrous DMF under Argon at RT, NMM (0.018 mL, 0.167 mmol, 4 eq) was added followed by PyBOP (32.5 mg, 0.062 mmol, 1.5 5 eq). The reaction was stirred at RT until consumption of starting material. LCMS after 1h showed complete consumption of 161. The crude reaction was purified via reverse phase C18 Aq (50g) using water / acetonitrile (0.05% TFA) gradient (10%-100%). The product was recovered by lyophilization to obtain PLL36 (12.4 mg, 34% yield) as off-white solid. (ESI) m / z: [M+H]+= 882.38. 10 Example 130: Synthesis of Linker Payload PLL37: 191 NJB0009PCT O NHFmoc NH2HN O , 0.013 mmol, 2 eq) in anhydrous DCM / MeOH (1:4) under Argon at RT, EEDQ (6.5 mg, 0.026 mmol, 2 eq) was added. The reaction was stirred at room temperature overnight. Next day, 5 LCMS showed that reaction still had starting material. Another 2 eq. of EEDQ and Fmoc-Ala- OH was added to the reaction mixture. Next day, another 2 eq. of EEDQ and Fmoc-Ala-OH were added to the reaction mixture. LCMS on 3rdday showed complete consumption of 164. The reaction mixture was evaporated to get the crude which was dissolved in DMF and purified via reverse phase (Teledyne Gemini (5 µm C18110 Å 150 x 30 mm) with (5% ACN) / (H2O) to 95%10 (ACN) / (H2O) gradient) (0.05% TFA). The product was recovered by lyophilization to obtain I- 114 (3.6 mg, 32% yield) as off-white solid. (ESI) m / z: [M+H]+= 840.52. The compound I-114 (6.4 mg, 0.008 mmol, 1 eq) was dissolved in (1:4) morpholine / DMF (0.109 mL) under Argon and stirred at RT until consumption of starting material. LCMS after 30 min showed complete consumption of I-114. The crude reaction was 192 NJB0009PCT precipitated with diethyl ether (2 mL) and the solid was obtained by centrifugation. The solid was washed with diethyl ether (1mL) and the solid was obtained by centrifugation. This obtained solid was redissolved in (1:1) (H2O: ACN) (0.05% TFA) and lyophilized to give I-115 (5.2 mg, 88% yield) as off-white solid. (ESI) m / z: [M+H]+= 618.25. 5 To the solution of compound I-115 (5.2 mg, 0.007 mmol, 1 eq), MC-V (4.4 mg, 0.014 mmol, 2 eq), and HOBt (1.9 mg, 0.014 mmol, 2 eq) in anhydrous DMF under Argon at RT, NMM (0.003 mL, 0.028 mmol, 4 eq) was added followed by PyBOP (5.5 mg, 0.011 mmol, 1.5 eq). The reaction was stirred at RT until consumption of starting material. LCMS after 20 min showed complete consumption of I-115. The crude reaction was purified via reverse phase 10 (Teledyne Gemini (5 µm C18110 Å 150 x 30 mm) with (5% ACN) / (H2O) to 95% (ACN) / (H2O) gradient) (0.05% TFA). The product was recovered by lyophilization to obtain PLL37 (3.4 mg, 52% yield) as off-white solid. (ESI) m / z: [M+H]+= 910.53. Example 131: Synthesis of Linker Payload PLL38: Ph O O H O H O O 15 , 0.043 mmol, 1.11 eq) in anhydrous DMF under Argon at RT, NMM (0.005 mL, 0.048 mmol, 1.25 eq) was added followed by DMTMM (21.4 mg, 0.077 mmol, 2 eq). The reaction was stirred at room temperature until consumption of starting material. LCMS after 15 min showed complete consumption of 165. The crude reaction was purified via reverse phase (Teledyne 20 Gemini (5 µm C18110 Å 150 x 30 mm) with (5% ACN) / (H2O) to 95% (ACN) / (H2O) gradient) (0.05% TFA). The product was recovered by lyophilization to obtain PLL38 (11.6 mg, 31% yield) as off-white solid. (ESI) m / z: [M+H]+= 982.43. Example 132: Synthesis of Linker Payload PLL39: 193 NJB0009PCT O H O H O H O O N N N NH2HN N N N O H O H PhOO- CH2COOH (9.1 mg, 0.015 mmol, 1.11 eq) in anhydrous DMF under Argon at RT, NMM (0.002 mL, 0.017 mmol, 1.25 eq) was added followed by DMTMM (7.4 mg, 0.027 mmol, 2 eq). The 5 reaction was stirred at room temperature until consumption of starting material. LCMS after 15 min showed complete consumption of 165. The crude reaction was purified via reverse phase (Teledyne Gemini (5 µm C18110 Å 150 x 30 mm) with (5% ACN) / (H2O) to 95% (ACN) / (H2O) gradient) (0.05% TFA). The product was recovered by lyophilization to obtain PLL39 (9.4 mg, 66% yield) as off-white solid. (ESI) m / z: [M+H]+= 1069.89. 10 Example 133: Synthesis of Linker Payload PLL40: O NH2FmocHN NH O O . , . , , . , 0.282 mmol, 2 eq) in anhydrous DMF under Argon at RT, NMM (0.062 mL, 0.565 mmol, 4 eq) was added. After 3 min, the reaction mixture transferred to the one-dram vial containing 167 (65 15 mg, 0.141 mmol, 1 eq) under Argon. The reaction was stirred at room temperature overnight. 194 NJB0009PCT The crude reaction mixture purified with reverse phase C18 (100g) using water / Acetonitrile (0.05% TFA modifier) gradient (10%-100%). The product was recovered by lyophilization to obtain I-116 (8.8 mg, 14% yield) as off-white solid. (ESI) m / z: [M+H]+= 754.56. The compound I-116 (9 mg, 0.012 mmol, 1 eq) was dissolved in (1:4) morpholine / DMF 5 (0.146 mL) under Argon and stirred at RT until consumption of starting material. LCMS after 30 min showed complete consumption of I-116. The crude reaction was precipitated with diethyl ether (2 mL) and the solid was obtained by centrifugation. The solid was washed with diethyl ether (1mL) and the solid was obtained by centrifugation. This obtained solid was redissolved in (1:1) (H2O: ACN) (0.05% TFA) and lyophilized to give I-117 (6.8 mg, 85% yield) as off-white 10 solid. (ESI) m / z: [M+H]+= 532.39. To the solution of compound I-117 (6.8 mg, 0.011 mmol, 1 eq), MC-V (6.5 mg, 0.021 mmol, 2 eq), and HOBt (2.8 mg, 0.021 mmol, 2 eq) in anhydrous DMF under Argon at RT, NMM (0.005 mL, 0.042 mmol, 4 eq) was added followed by PyBOP (8.2 mg, 0.016 mmol, 1.5 eq). The reaction was stirred at RT until consumption of starting material. LCMS after 15 min 15 showed complete consumption of I-117. The crude reaction was purified via reverse phase (Teledyne Gemini (5 µm C18110 Å 150 x 30 mm) with (5% ACN) / (H2O) to 95% (ACN) / (H2O) gradient) (0.05% TFA). The product was recovered by lyophilization to obtain PLL40 (2.1 mg, 24% yield) as off-white solid. (ESI) m / z: [M+H]+= 824.55. Example 134: Synthesis of Linker Payload PLL41: O O 20 p g, . , q p 2 mg, 0.105 mmol, 1.5 eq) in anhydrous DMF under Argon at RT, NMM (0.039 mL, 0.281 mmol, 4 eq) was added. The reaction was stirred at room temperature until consumption of starting 195 NJB0009PCT material. LCMS after 15 min showed complete consumption of 171. The crude reaction was purified via reverse phase (Teledyne Gemini (5 µm C18110 Å 150 x 30 mm) with (5% ACN) / (H2O) to 95% (ACN) / (H2O) gradient) (0.05% TFA). The product was recovered by lyophilization to obtain PLL41 (15 mg, 27% yield) as off-white solid. (ESI) m / z: [M+H]+= 5 798.52. Example 135: Synthesis of Linker Payload PLL42: Ph O O NH O NH H O H O N N N O O N N O 02 mmol, 1.11 eq) in anhydrous DMF under Argon at RT, NMM (0.003 mL, 0.02 mmol, 1.25 eq) 10 was added followed by DMTMM (10.2 mg, 0.037 mmol, 2 eq). The reaction was stirred at room temperature until consumption of starting material. LCMS after 15 min showed complete consumption of 172. The crude reaction was purified via reverse phase (Teledyne Gemini (5 µm C18110 Å 150 x 30 mm) with (5% ACN) / (H2O) to 95% (ACN) / (H2O) gradient) (0.05% TFA). The product was recovered by lyophilization to obtain PLL42 (7.9 mg, 42% yield) as off-white 15 solid. (ESI) m / z: [M+H]+= 1012.71. Example 136: Synthesis of Linker Payload PLL43: O p g, . , q p g, 0.160 mmol, 1.5 eq) in anhydrous DMF under Argon at RT, NMM (0.060 mL, 0.428 mmol, 4 20 eq) was added. The reaction was stirred at room temperature until consumption of starting 196 NJB0009PCT material. LCMS after 15 min showed complete consumption of 172. The crude reaction was purified via reverse phase (Teledyne Gemini (5 µm C18110 Å 150 x 30 mm) with (5% ACN) / (H2O) to 95% (ACN) / (H2O) gradient) (0.05% TFA). The product was recovered by lyophilization to obtain PLL43 (34.2 mg, 43% yield) as off-white solid. (ESI) m / z: [M+H]+= 5 751.41. Example 137: Synthesis of Linker Payload PLL44: O H O N NH2O T d (4 su (26 mg, 0.083 mmol, 1.1 eq) in anhydrous DMF under Argon at RT, NMM (0.042 mL, 0.302 mmol, 4 10 eq) was added. The reaction was stirred at room temperature until consumption of starting material. LCMS after 45 min showed complete consumption of 173. The crude reaction was purified via reverse phase (Teledyne Gemini (5 µm C18110 Å 150 x 30 mm) with (5% ACN) / (H2O) to 95% (ACN) / (H2O) gradient (0.05% TFA)). The product was recovered by lyophilization to obtain PLL44 (10.1 mg, 19% yield) as off-white solid. (ESI) m / z: [M+H]+= 15 708.57. Example 138: Synthesis of Linker Payload PLL45: Ph O O NH O NH H O H O O , . , . , 0.036 mmol, 1.11 eq) in anhydrous DMF under Argon at RT, NMM (0.004 mL, 0.04 mmol, 1.25 20 eq) was added followed by DMTMM (17.8 mg, 0.064 mmol, 2 eq). The reaction was stirred at 197 NJB0009PCT room temperature until consumption of starting material. LCMS after 15 min showed complete consumption of 174. The crude reaction was purified via reverse phase (Teledyne Gemini (5 µm C18110 Å 150 x 30 mm) with (5% ACN) / (H2O) to 95% (ACN) / (H2O) gradient) (0.05% TFA). The product was recovered by lyophilization to obtain PLL45 (11.8 mg, 37% yield) as off-white 5 solid. (ESI) m / z: [M+H]+= 998.59. Example 139: Synthesis of Linker Payload PLL46: O NH O NHHON O O N 0.048 mmol, 1.5 eq) in anhydrous DMF under Argon at RT, NMM (0.018 mL, 0.129 mmol, 4 10 eq) was added. The reaction was stirred at room temperature until consumption of starting material. LCMS after 35 min showed complete consumption of 174. The crude reaction was purified via reverse phase (Teledyne Gemini (5 µm C18110 Å 150 x 30 mm) with (5% ACN) / (H2O) to 95% (ACN) / (H2O) gradient (0.05% TFA)). The product was recovered by lyophilization to obtain PLL46 (12.2 mg, 51% yield) as off-white solid. (ESI) m / z: [M+H]+= 15 737.43. * ACN = acetonitrile; AlCl3 = aluminum trichloride; BCl3 = boron trichloride; BCN = bicyclo[6.1.0]nonyne; DBCO = Dibenzocyclooctyne; DCE = 1,2-dichloroethane; DCM = dichloromethane; DIPEA = diisopropylethylamine; DMA = dimethylacetamide; DMF = 20 dimethylformamide; DMSO = dimethyl sulfoxide; DMTMM = 4-(4,6-dimethoxy-1,3,5-triazin-2- yl)-4-methylmorpholinium chloride; EEDQ = N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; EtOH = ethanol; FA = formic acid; HATU = Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium; HBTU = hexafluorophosphate benzotriazole tetramethyl uronium; HCl = hydrochloric acid; HFIP = hexafluoroisopropanol; HOBt = Hydroxybenzotriazole; HMPA =25 hexamethylphosphoramide; Mal = maleimide; MalCapOsu = 6-Maleimidohexanoic acid N- hydroxysuccinimide ester; MeOH = methanol; MW = microwave irradiation; NaN3= sodium 198 NJB0009PCT azide; NHS = N-hydroxysuccinimide ester; NMM = 4-methylmorpholine; PL = payload; PTSA = para-toluene sulfonic acid; PyBOP = Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate; RBF = round bottom flask; RT = room temperature; TEA = triethylamine. Example 140: Preparation of ADC (Trastuzumab-PLL Conjugation): 5 A schematic for the preparation of ADC (Trastuzumab-PLL Conjugation) is illustrated in FIG. 5. Table 4: Synthesis of ADC Conjugates (T-PLL1 – T-PLL46). Co-Solvent (DMA DAR n 199 NJB0009PCT Co-Solvent (DMA DAR n Example 141: Small Scale Conjugation Method: A stock solution of Trastuzumab (T-, CAS# AC-NJB-077; 500 mg, 100 mL, 5.1 mg / mL) was prepared in 1x phosphate-buffered saline (PBS) with 1mM diethylenetriaminepentaacetic 5 acid (DTPA) (pH 6). Tris (2-carboxyethyl) phosphine (TCEP) solution (2.27 mL, 15 mM, 10 eq) was added to the antibody solution (500 mg, 100 mL, 5.1 mg / mL) and allowed to reduce at 37 ℃ for 90 min. The solution was purified using TFF to remove excess TCEP in presence of 1X PBS with 1 mM DTPA. Aliquoted stock solutions equivalent to 5.1 mg / mL of reduced Trastuzumab were stored in -80 and thawed as required for each payload-linker conjugation. Solution of PLL 10 in dimethylacetamide (DMA) (10 µL-15 eq, 10 mM) was added to the 1.0 mg of reduced antibody solution along with 10-20 %v / v DMA (25-50 µL) allowed to incubate at room temperature for two hours on rotor for end-to-end mixing. Crude analysis at 2 hours was performed for DAR analysis using RP-LC / MS. 200 NJB0009PCT Drug to Antibody Ratio (DAR) by RP-LC / MS was determined by analytical liquid chromatography-mass spectrometry (LC-MS), employing a Waters Acquity Ultra Performance LC system and a Synapt high-definition mass spectrometer. 15 µg of ADC was injected over a PLRP-S column (1000 Å, 8 µm, 2.1 x 50 mm) against a 25 – 45 % gradient (ACN + 0.1 % 5 formic acid; 0.35 mL / min flow). Monomeric purity was found via size exclusion chromatography, employed on an Agilent 1260 HPLC. 20 µg of ADC was injected over a TSKgelG3000SWXL column against a 10% isopropanol (IPA) in PBS gradient (0.5 mL / min flow). The crude ADC solution was dialyzed using 10K cut-off dialysis cassette generation 3 or passed through 40K Zeba desalting columns against 1X PBS buffer, pH-7.4 to remove free 10 payload, co-solvent and buffer additives. The final solution was filtered using 0.2 µm syringe filter. Final analysis was performed on an aliquoted sample of the filtered ADC. Bioconjugates were reduced with dithiothreitol (0.5 M; 1 µL / 10 µg ADC) and allowed to incubate at 37 ℃ x 30 min. Reduced light chain and heavy chain charge envelopes were deconvoluted and reduced light chain and heavy chain species were identified and quantified. 15 Example 142: Large Scale Conjugation Method: A stock solution of Trastuzumab (CAS# 180288-69-1; 1 mg, 0.22 mL, 4.5 mg / mL) was prepared in 1x PBS, (pH 7.4). Tris (2-carboxyethyl) phosphine (TCEP) solution (6.7 uL, 10 mM, 10eq) was added to the antibody solution (1 mg, 0.22 mL, 4.5 mg / mL) with 10% DTPA (23ul, 10 mM) and allowed to reduce at 37 ℃ for 90 min. A solution of PLL (20 uL-15eq, 5 mM) was 20 added to the 1.0 mg of reduced antibody solution along with 10% DMA (29ul) allowed to incubate at room temperature for two hours on rotor for end-to-end mixing. Crude analysis at 2 hours using RP-LC / MS showed DAR 5. An additional bolus of PLL (25 uL-19eq, 5 mM) was added to the reaction solution and allowed to incubate at room temperature for 30 min on rotor for end-to-end mixing to achieve the intended DAR 8. 25 Drug to Antibody Ratio (DAR) by RP-LC / MS was determined by analytical liquid chromatography-mass spectrometry (LC-MS), employing a Waters Acquity Ultra Performance LC system and a Synapt high-definition mass spectrometer. 15 µg of ADC was injected over a PLRP-S column (1000 Å, 8 µm, 2.1 x 50 mm) against a 25 – 45 % gradient (ACN + 0.1 % formic acid; 0.35 mL / min flow). Monomeric purity was found via size exclusion 30 chromatography, employed on an Agilent 1260 HPLC. 20 µg of ADC was injected over a TSKgelG3000SWXL column against a 100 % PBS gradient (0.8 mL / min flow). The T-PLL 201 NJB0009PCT crude ADC solution was dialyzed against 1X-PBS buffer, pH-7.4 using 0.5ml dialysis cassette generation 2 at room temperature for 5-6 h followed up overnight at cold room with continuous stirring using magnetic stirrer to remove free payload, buffer additives, and TCEP. The final solution was filtered using 0.2 µm syringe filter. Final analysis was performed on an aliquoted 5 sample of the filtered ADC. Bioconjugates were reduced with dithiothreitol (0.5 M; 1 µL / 10 µg ADC) and allowed to incubate at 37 ℃ x 30 min. Reduced light chain and heavy chain charge envelopes were deconvoluted and reduced light chain and heavy chain species were identified and quantified. Example 143: Cytotoxicity Assay: 10 Protocol: Day 1: 2,000 cells / well were plated and incubated at 37°C overnight. Day 2: Payload / ADC / vehicle control dilutions were made in respective media and added to cells. Volume added: 50uL to each well. Starting treatment concentration was 1 mM for free payloads / 1 µM for ADC’s / 10% for vehicle control and then diluted 10-fold down for a total of 15 11 treatment dilutions. Each concentration was analyzed in triplicates. Media-only wells were used as a control to calculate percent viability. Day 5: Cell titer glow reagent (volume: 50uL) was added to each well, the plate was shaken for 5 mins and the luminescence was recorded. Drug Treatment Time: 72 hours. Data Analysis: Percent viability was calculated by dividing the luminescence signal obtained for each 20 treated well by the untreated well (media-only control) and multiplying by 100. Data was next transformed using X= Log (x) and then analyzed with nonlinear regression (curve fit), Dose Response inhibition – log (inhibitor) vs response (3 parameters) using PRISM software to determine the IC50 value. The results of cytotoxicity of SKBR-3 cell line (human breast cancer) and are provided in Tables 5 and 6. 25 Table 5: In Vitro Cytotoxicity Assay of Payloads: Payload IC50 (nM) IC50 (nM) (DXD Control) Normalized IC5o (PLL 202 NJB0009PCT Payload IC50 (nM) IC50 (nM) (DXD Control) Normalized IC5o (PLL SKBR-3 (1599440-33-1) SKBR-3 IC50 / DXD IC50) 203 NJB0009PCT Payload IC50 (nM) IC50 (nM) (DXD Control) Normalized IC5o (PLL SKBR-3 (1599440-33-1) SKBR-3 IC50 / DXD IC50) 204 NJB0009PCT Payload IC50 (nM) IC50 (nM) (DXD Control) Normalized IC5o (PLL SKBR-3 (1599440-33-1) SKBR-3 IC50 / DXD IC50) T a e : n tro ytotoxcty ssay o s ( - – - ): IC50 (pM) IC5O (pM) (T-DXD Normalized IC5o (T- Conjugates SKBR-3 Control) SKBR-3 PLL / T-DXD) SKBR-3 205 NJB0009PCT IC50 (pM) IC5O (pM) (T-DXD Normalized IC5o (T- Conjugates SKBR-3 Control) SKBR-3 PLL / T-DXD) SKBR-3 Table 7: Intended Benefits of [G*]n Linker: Benefit or Function y 206 NJB0009PCT Table 8: Structure of [G*]n Linker Repeating Unit and Use With and Without Other Linkers: Linker Structure Abbreviation T able 9: Conjugation Moiety Examples with [G ]n linker according to the structure in Table 8, n 5 = 1-32, “Linker” is another linker other than [G*]n, “PL” is payload, and “R” is alkyl: Linker Abbreviation Structure O 207 NJB0009PCT Linker Abbreviation Structure O * 208 NJB0009PCT Linker Abbreviation Structure O PhS 209 NJB0009PCT Linker Abbreviation Structure Alk Li k G* PLLinker-[G*]n-PL 210 NJB0009PCT Table 10: Linker Examples to be Used in Tandem with [G*]n Linker as Either (Conjugation Motif)-[G*]n-Linker-PL or (Conjugation Motif)-Linker-[G*]n-PL; -[G*]n is linker according to the structure in Table 8, n = 1-32, and “PL” is payload: O Amino- O MC N 211 NJB0009PCT O Ami O O MC-V-A no- N H N 212 NJB0009PCT O PEG MC-A- Amino- O O N H 213 NJB0009PCT O O H O H OO PL 214 NJB0009PCT O Aryl MC-V- Amino- N . n 215 NJB0009PCT Table 11: Payloads Proposed to be attached to [G*]n-derived linkers: (ESI) m / z: Cmpd Structure [M+H]+O H2 216 NJB0009PCT (ESI) m / z: Cmpd [M+H]+Structure 217 NJB0009PCT (ESI) m / z: Cmpd [M+H]+Structure NH2 218 NJB0009PCT (ESI) m / z: Cmpd [M+H]+Structure NH2 219 NJB0009PCT (ESI) m / z: Cmpd [M+H]+Structure H 220 NJB0009PCT (ESI) m / z: Cmpd [M+H]+Structure F . conans a e : n er ayoa rucures onanng o - 72. Example 144: Synthesis of Payloads and Linker Payloads Containing G* Moiety: 5 221 NJB0009PCT Example 145: Synthesis of Payload 175 and Linker Payload PLL48: O NHFmoc O N [({N-[(9H-fluoren-9-ylmethoxy)carbonyl]glycyl}amino)methoxy]acetic acid (CAS: 1599440- 5 08-0) (47.8 mg, 0.124 mmol, 1.11 eq) under Ar. Anhydrous DMF (3.45 mL) was added to the vial to yield a solution. NMM (15 uL, 0.140 mmol, 1.25 eq) was added to the vial followed by DMTMM (62.0 mg, 0.224 mmol, 2 eq) and briefly sonicated to yield a suspension. The vial was stirred at room temperature for 0.5 h whereupon the LCMS indicated Exatecan mesylate was consumed. The crude reaction was purified via reverse phase (Teledyne Gemini (5µm C18110Å 222 NJB0009PCT 150 x 30 mm) with (5% ACN+0.05% FA) / (H2O+0.05% FA) to 95% (ACN+0.05% FA) / (H2O+0.05% FA) gradient). The product was recovered by lyophilization to obtain I-118 (86.6 mg, 96.4% yield) as off-white solid. (ESI) m / z: [M+H]+= 802.39. To an oven dried vial was added I-118 (38.0 mg, 0.047 mmol, 1 eq) and dissolved in 5 (1:4) (Morpholine: DMF) (0.668 mL) and stirred at room temperature under Ar. LCMS at 60 minutes indicated that I-118 was consumed. The crude reaction was precipitated with diethyl ether (7 mL) and the solid was obtained by centrifugation. The solid was washed with diethyl ether (1x) (7 mL) and the solid was obtained by centrifugation. This obtained solid was redissolved in (1:1) (H2O:ACN+0.05% TFA) and lyophilized to give 175 (8.2 mg, 30% yield) as 10 off-white solid. (ESI) m / z: [M+H]+= 580.16. To an oven dried vial was added 175 (30.0 mg, 0.054 mmol, 1 eq) and MC-GGFG-NH- CH2-O-CH2COOH (36.7 mg, 0.06 mmol, 1.11 eq) under Ar. Anhydrous DMF (1.65 mL) was added to the vial to yield a solution. NMM (7 uL, 0.067 mmol, 1.25 eq) was added to the vial followed by DMTMM (29.7 mg, 0.107 mmol, 2 eq) and briefly sonicated to yield a suspension. 15 The vial was stirred at room temperature for 0.5 h whereupon the LCMS indicated 175 was consumed. The crude reaction was purified via reverse (Teledyne Gemini (5µm C18110Å 150 x 30 mm) with (5% ACN) / (H2O) to 95% (ACN) / (H2O) gradient). The product was recovered by lyophilization to obtain PLL48 (18.8 mg, 29.7% yield) as off-white solid. (ESI) m / z: [M+H]+= 1178.66. 20 Example 146: Synthesis of Linker Payload PLL49: O NH2O H O , . , mg, 0.041 mmol, 1.2 eq) in anhydrous DMF under Argon at RT, NMM (0.010 mL, 0.069 mmol, 2 eq) was added. The reaction was stirred at room temperature until consumption of starting material. 223 NJB0009PCT After 1h 30 min, the reaction stalled. Another 1 eq of Malcap-Osu and 2 eq of NMM was added. LCMS after 2h 15 min showed complete consumption of 175. The crude reaction was purified via reverse phase (Teledyne Gemini (5 µm C18110 Å 150 x 30 mm) with (5% ACN) / (H2O) to 95% (ACN) / (H2O) gradient) (0.05% TFA). The product was recovered by lyophilization to obtain 5 PLL49 (18.8 mg, 71% yield) as off-white solid. (ESI) m / z: [M+H]+= 773.32. Example 147: Synthesis of Payload 176 and Linker Payload PLL50: O O H O O NNH2N NHFmoc O N O N H H H fluoren-9-ylmethoxy)carbonyl]glycyl}amino)methoxy]acetic acid (CAS: 1599440-08-0) (28.5 10 mg, 0.074 mmol, 1.11 eq) under Ar. Anhydrous DMF (2.06 mL) was added to the vial to yield a solution. NMM (9 uL, 0.0084 mmol, 1.25 eq) was added to the vial followed by DMTMM (37 mg, 0.134 mmol, 2 eq) and briefly sonicated to yield a suspension. The vial was stirred at room temperature for 0.5 h whereupon the LCMS indicated 175 was consumed. The crude reaction 224 NJB0009PCT was purified via reverse phase (Teledyne Gemini (5µm C18110Å 150 x 30 mm) with (5% ACN+0.05% TFA) / (H2O+0.05% TFA) to 95% (ACN+0.05% TFA) / (H2O+0.05% TFA) gradient). The product was recovered by lyophilization to obtain I-119 (27.4 mg, 43.4 % yield) as off-white solid. (ESI) m / z: [M+H]+= 946.92. 5 To an oven dried vial was added I-119 (27 mg, 0.029 mmol, 1 eq) and dissolved in (1:4) (Morpholine:DMF) (0.414 mL) and stirred at room temperature under Ar. LCMS at 30 minutes indicated that I-119 was consumed. The crude reaction was precipitated with diethyl ether (1 mL) and the solid was obtained by centrifugation. The solid was washed with diethyl ether (1x) (1 mL) and the solid was obtained by centrifugation. This obtained solid dried under high 10 vacuum to give 176 (21.0 mg, quant. yield) as off-white solid. (ESI) m / z: [M+H]+= 724.34. To an oven dried vial was added 176 (21.0 mg, 0.038 mmol, 1 eq) and MC-GGFG-NH- CH2-O-CH2COOH (25.7 mg, 0.042 mmol, 1.11 eq) under Ar. Anhydrous DMF (1.16 mL) was added to the vial to yield a solution. NMM (5 uL, 0.047 mmol, 1.25 eq) was added to the vial followed by DMTMM (20.8 mg, 0.075 mmol, 2 eq) and briefly sonicated to yield a suspension. 15 The vial was stirred at room temperature for 0.5 h whereupon the LCMS indicated 176 was consumed. The crude reaction was purified via reverse (Teledyne Gemini (5µm C18110Å 150 x 30 mm) with (5% ACN) / (H2O) to 95% (ACN) / (H2O) gradient). The product was recovered by lyophilization to obtain PLL50 (12.2 mg, 24% yield) as off-white solid. (ESI) m / z: [M+H]+= 1322.52. 20 Example 148: Synthesis of Linker Payload PLL51: O H O O H O H O N O N O NNH2N N O N O N N , . , g, 0.028 mmol, 1.2 eq) under Ar. Anhydrous DMF (0.7 mL) was added to the vial to yield a solution. To the vial, was added DIPEA (10 uL, 0.047 mmol, 2 eq) and was stirred at room 25 temperature for 1.25 h whereupon the LCMS indicated 176 was consumed. The crude reaction was purified via reverse (Teledyne Gemini (5µm C18110Å 150 x 30 mm) with (5% 225 NJB0009PCT ACN) / (H2O) to 95% (ACN) / (H2O) gradient). The product was recovered by lyophilization to obtain PLL51 (5.2 mg, 24% yield) as off-white solid. (ESI) m / z: [M+H]+= 917.45. Example 149: Synthesis of Payload 177 and Linker Payload PLL52: O H O O H O H O N N N NHFmoc O N O NNH2O N O N O N O H O H O H O H O H 5 To an oven dried vial was added 176 (173 mg, 0.239 mmol, 1 eq) and [({N-[(9H-fluoren- 9-ylmethoxy)carbonyl]glycyl}amino)methoxy]acetic acid (CAS: 1599440-08-0) (102 mg, 0.266 mmol, 1.11 eq) under Ar. Anhydrous DMF (1.77 mL) was added to the vial to yield a solution. 10 NMM (33 uL, 0.0299 mmol, 1.25 eq) was added to the vial followed by DMTMM (132 mg, 0.479 mmol, 2 eq) and briefly sonicated to yield a suspension. The vial was stirred at room temperature for 0.5 h whereupon the LCMS indicated 176 was consumed. The crude reaction was purified via reverse phase (Teledyne Gemini (5µm C18110Å 150 x 30 mm) with (5% ACN+0.05% TFA) / (H2O+0.05% TFA) to 95% (ACN+0.05% TFA) / (H2O+0.05% TFA) 226 NJB0009PCT gradient). The product was recovered by lyophilization to obtain I-120 (104.4 mg, 40 % yield) as off-white solid. (ESI) m / z: [M+H]+= 1090.24. To an oven dried vial was added I-120 (93 mg, 0.086 mmol, 1 eq) and dissolved in (1:4) (Morpholine:DMF) (1.22 mL) and stirred at room temperature under Ar. LCMS at 30 minutes 5 indicated that I-120 was consumed. The crude reaction was precipitated with diethyl ether (12 mL) and the solid was obtained by centrifugation. The solid was washed with diethyl ether (1x) (12 mL) and the solid was obtained by centrifugation. This obtained solid dried under high vacuum to give 177 (92.6 mg, quant. yield) as off-white solid. (ESI) m / z: [M+H]+= 868.55. To an oven dried vial was added 177 (37 mg, 0.043 mmol, 1 eq) and MC-GGFG-NH- 10 CH2-O-CH2COOH (29.3 mg, 0.043 mmol, 1.11 eq) under Ar. Anhydrous DMF (1.32 mL) was added to the vial to yield a solution. NMM (6 µL, 0.054 mmol, 1.25 eq) was added to the vial followed by DMTMM (23.7 mg, 0.086 mmol, 2 eq) and briefly sonicated to yield a suspension. The vial was stirred at room temperature for 0.5 h whereupon the LCMS indicated 177 was consumed. The crude reaction was purified via reverse (Teledyne Gemini (5µm C18110Å 150 x 15 30 mm) with (5% ACN) / (H2O) to 95% (ACN) / (H2O) gradient). The product was recovered by lyophilization to obtain PLL52 (9.4 mg, 15% yield) as off-white solid. (ESI) m / z: [M+H]+= 1466.56. Example 150: Synthesis of Linker Payload PLL53: 227 NJB0009PCT O H O H O N N NH O N O N O N2O mg, 0.015 mmol, 1.2 eq) under Ar. Anhydrous DMF (0.4 mL) was added to the vial to yield a solution. To the vial, was added DIPEA (4 µL, 0.026 mmol, 2 eq) and was stirred at room 5 temperature for 2 h whereupon the LCMS indicated 177 was consumed. The crude reaction was purified via reverse (Teledyne Gemini (5µm C18110Å 150 x 30 mm) with (5% ACN) / (H2O) to 95% (ACN) / (H2O) gradient). The product was recovered by lyophilization to obtain PLL53 (1.4 mg, 10% yield) as off-white solid. (ESI) m / z: [M+H]+= 1061.48. 228 NJB0009PCT Example 151: Synthesis of Linker Payload PLL54: O H O N NH O N O N2O , , mg, 0.038 mmol, 2.5 eq) in anhydrous DMF under Argon at RT, NMM (0.004 mL, 0.038 mmol, 2.5 5 eq) was added followed by DMTMM (17 mg, 0.061 mmol, 4 eq). The reaction was stirred at room temperature until consumption of starting material. After 2h, the crude reaction was purified via reverse phase (Teledyne Gemini (5 µm C18110 Å 150 x 30 mm) with (5% ACN) / 229 NJB0009PCT (H2O) to 95% (ACN) / (H2O) gradient) (0.05% TFA). The product was recovered by lyophilization to obtain PLL54 (19.4 mg, 66% yield) as off-white solid. (ESI) m / z: [M+H]+= 1899.85. Example 152: Synthesis of Payload 178 and Proposed Synthesis of Linker Payload PLL73: O H O H O N N NH O N O N O N2H H H O 5 NJB0009PCT To an oven dried vial was added 177 (33 mg, 0.038 mmol, 1 eq) and [({N-[(9H-fluoren- 9-ylmethoxy)carbonyl]glycyl}amino)methoxy]acetic acid (CAS: 1599440-08-0) (16.2 mg, 0.042 mmol, 1.11 eq) under Ar. Anhydrous DMF (0.6 mL) was added to the vial to yield a solution. NMM (5 uL, 0.048 mmol, 1.25 eq) was added to the vial followed by DMTMM (21 mg, 0.076 5 mmol, 2 eq) and briefly sonicated to yield a suspension. The vial was stirred at room temperature for 0.5 h whereupon the LCMS indicated 177 was consumed. The crude reaction was purified via reverse phase (Teledyne Gemini (5µm C18110Å 150 x 30 mm) with (5% ACN+0.05% TFA) / (H2O+0.05% TFA) to 95% (ACN+0.05% TFA) / (H2O+0.05% TFA) gradient). The product was recovered by lyophilization to obtain I-121 (9.4 mg, 20% yield) as a white solid. (ESI) m / z: 10 [M+H]+ = 1234.72. To an oven dried vial was added I-121 (9 mg, 0.008 mmol, 1 eq) and dissolved in (1:4) (Morpholine:DMF) (0.095 mL) and stirred at room temperature under Ar. LCMS at 30 minutes indicated that I-121 was consumed. The crude reaction was precipitated with diethyl ether (1.5 mL) and the solid was obtained by centrifugation. The solid was washed with diethyl ether (1x) 15 (1.5 mL) and the solid was obtained by centrifugation. This obtained solid dried under high vacuum to give 178 (10 mg, quant. yield) as a white solid. (ESI) m / z: [M+H]+ = 1012.67. To an oven dried vial was added 178 (10 mg, 0.009 mmol, 1 eq) and MalCapOsu (4 mg, 0.011 mmol, 1.2 eq) under Ar. Anhydrous DMF (0.3 mL) was added to the vial to yield a solution. To the vial, was added DIPEA (3 uL, 0.019 mmol, 2 eq) and was stirred at room 20 temperature for 2 h whereupon the LCMS indicated 178 was consumed. The crude reaction was purified via reverse phase (Teledyne Gemini (5µm C18110Å 150 x 30 mm) with (5% ACN) / (H2O) to 95% (ACN) / (H2O) gradient). The product was recovered by lyophilization to obtain PLL73 (0.2 mg, impure at present) as a white solid. (ESI) m / z: [M+H]+ = 1205.68. Example 153: Synthesis of Payload 179 and Linker Payload PLL55: O AcO NNHFmoc O H oc 25 49% yieldTo an oven dried vial was added 3-butyne-1-ol (100 mg, 1.427 mmol, 1 eq) and OAc- CH2-NH-Gly-Fmoc (525 mg, 1.427 mmol, 1 eq) and suspended in Anhydrous DMF (9.51 mL) with a brief sonication under Ar. To the vial, 1M HCl etherate (2.853 mL, 2.853 mmol, 2 eq) was 231 NJB0009PCT added dropwise. The vial was stirred for 16 h at room temperature. LCMS indicated that the reaction had stalled, and the reaction was purified via reverse phase (Teledyne 100 g C18 with (5% ACN+0.05% TFA) / (H2O+0.05% TFA) to 95% (ACN+0.05% TFA) / (H2O+0.05% TFA) gradient). The product was recovered by lyophilization to obtain I-122 (239.4 mg, 44.3% yield) 5 as off-white solid. (ESI) m / z: [M+Na]+= 401.22. O O HN H NHFmoc O mmol) and I-122 (156 mg, 0.413 mmol, 0.9 eq) were added to vial under argon atmosphere. (PPh3)3CuBr (85.5 mg, 20 mol%) was added to the vial and dissolved in anhydrous 10 dichloromethane (28.7 mL). Diisopropylethylamine (1.61 mL, 9.187 mmol, 20 eq) was added to the vial and the reaction was stirred at 35°C for 16 hours sealed under argon atmosphere. The crude reaction was concentrated in vacuo and dissolved in DMF and purified via reverse phase chromatography (150 g C18 Aq) (5% ACN + 0.05% TFA) to (95% ACN+ 0.05 % TFA) / (H2O + 0.05% TFA gradient). The product was recovered by lyophilization to obtain I-123 (343.4 mg, 15 46% yield) as off-white solid. (ESI) m / z: [M+H]+= 814.48. To an oven dried vial was added I-123 (160 mg, 0.197 mmol, 1 eq) and dissolved in (1:4) (Morpholine: DMF) (2.46 mL) and stirred at room temperature under Ar. LCMS at 30 minutes 232 NJB0009PCT indicated that I-123 was consumed. The crude reaction was precipitated with diethyl ether (27 mL) and the solid was obtained by centrifugation. The solid was washed with diethyl ether (1x) (27 mL) and the solid was obtained by centrifugation. This obtained solid was redissolved in (1:1) (H2O: ACN) and lyophilized to give 179 (124 mg, 89% yield) as off-white solid. (ESI) m / z: 5 [M+H]+= 592.27. To the solution of 179 (23 mg, 0.032 mmol, 1 eq) and MalCap-Osu (12 mg, 0.038 mmol, 1.2 eq) in anhydrous DMF under Argon at RT, NMM (0.008 mL, 0.064 mmol, 2 eq) was added. The reaction was stirred at room temperature until consumption of starting material. After 1h, the crude reaction was purified via reverse phase (Teledyne Gemini (5 µm C18110 Å 150 x 30 mm) 10 with (5% ACN) / (H2O) to 95% (ACN) / (H2O) gradient) (0.05% TFA). The product was recovered by lyophilization to obtain PLL55 (12.8 mg, 51% yield) as off-white solid. (ESI) m / z: [M+H]+= 785.40. Example 154: Synthesis of Linker Payload PLL56: O O HN NH O 15 , . , CH2-O-CH2COOH (19.7 mg, 0.032 mmol, 1.11 eq) under Ar. Anhydrous DMF (0.89 mL) was added to the vial to yield a solution. NMM (4 uL, 0.036 mmol, 1.25 eq) was added to the vial 233 NJB0009PCT followed by DMTMM (15.9 mg, 0.057 mmol, 2 eq) and briefly sonicated to yield a suspension. The vial was stirred at room temperature for 0.5 h whereupon the LCMS indicated 179 was consumed. The crude reaction was purified via reverse phase (Teledyne Gemini (5µm C18110Å 150 x 30 mm) with (5% ACN) / (H2O) to 95% (ACN) / (H2O) gradient). The product was 5 recovered by lyophilization to obtain PLL56 (10.2 mg, 30% yield) as a white solid. (ESI) m / z: [M+H]+= 1190.68. Example 155: Synthesis of Payload 180 and Linker Payload PLL57: O OO OHN NH2HN NH moc - 10 9-ylmethoxy)carbonyl]glycyl}amino)methoxy]acetic acid (CAS: 1599440-08-0) (22.1 mg, 0.057 mmol, 1.11 eq) under Ar. Anhydrous DMF (0.82 mL) was added to the vial to yield a solution. NMM (7 uL, 0.065 mmol, 1.25 eq) was added to the vial followed by DMTMM (28.6 mg, 0.103 mmol, 2 eq) and briefly sonicated to yield a suspension. The vial was stirred at room temperature for 0.5 h whereupon the LCMS indicated 179 was consumed. The crude reaction was purified 234 NJB0009PCT via reverse phase (Teledyne Gemini (5µm C18110Å 150 x 30 mm) with (5% ACN+0.05% TFA) / (H2O+0.05% TFA) to 95% (ACN+0.05% TFA) / (H2O+0.05% TFA) gradient). The product was recovered by lyophilization to obtain I-124 (23.2 mg, 47 % yield) as off-white solid. (ESI) m / z: [M+H]+= 958.04. 5 To an oven dried vial was added I-124 (23 mg, 0.024 mmol, 1 eq) and dissolved in (1:4) (Morpholine: DMF) (0.303 mL) and stirred at room temperature under Ar. LCMS at 30 minutes indicated that I-124 was consumed. The crude reaction was precipitated with diethyl ether (3 mL) and the solid was obtained by centrifugation. The solid was washed with diethyl ether (1x) (3 mL) and the solid was obtained by centrifugation. This obtained solid dried under high 10 vacuum to give 180 (22 mg, quant. yield) as off-white solid. (ESI) m / z: [M+H] + = 736.43. To an oven dried vial was added 180 (22 mg, 0.030 mmol, 1 eq) and MC-GGFG-NH- CH2-O-CH2COOH (20.5 mg, 0.033 mmol, 1.11 eq) under Ar. Anhydrous DMF (0.92 mL) was added to the vial to yield a solution. NMM (4 uL, 0.037 mmol, 1.25 eq) was added to the vial followed by DMTMM (16.5 mg, 0.060 mmol, 2 eq) and briefly sonicated to yield a suspension. 15 The vial was stirred at room temperature for 0.5 h whereupon the LCMS indicated 180 was consumed. The crude reaction was purified via reverse phase (Teledyne Gemini (5µm C18110Å 150 x 30 mm) with (5% ACN) / (H2O) to 95% (ACN) / (H2O) gradient). The product was recovered by lyophilization to obtain PLL57 (9.8 mg, 25% yield) as off-white solid. (ESI) m / z: [M+H]+= 1334.53. 235 NJB0009PCT Example 156: Synthesis of Linker Payload PLL58: O H O O N NH N O N2O g, 0.015 mmol, 2.5 eq) in anhydrous DMF under Argon at RT, NMM (0.002 mL, 0.015 mmol, 2.5 5 eq) was added followed by DMTMM (6.8 mg, 0.025 mmol, 4 eq). The reaction was stirred at room temperature until consumption of starting material. After 1h, the crude reaction was purified via reverse phase (Teledyne Gemini (5 µm C18110 Å 150 x 30 mm) with (5% ACN) / (H2O) to 95% (ACN) / (H2O) gradient) (0.05% TFA). The product was recovered by lyophilization to obtain PLL59 (6 mg, 51% yield) as off-white solid. (ESI) m / z: [M+2] / 2 = 10 963.12. 236 NJB0009PCT Example 157: Synthesis of Linker Payload PLL59: 1-(9H-fluoren-9-yl)-3,6-dioxo-2,9-dio xa-4,7-diazaundecan-11-oic acid O H O N O Morpholin O HO NHFmoc H e H O Benzy O H O H O H2,Pd / H O H BnOO N O NCNNHFmoc HOO N O N NNHFmocH MeOH H 1- 5 oate (229 mg, 0.483 mmol, 1 eq) was dissolved in (1:4) morpholine / DMF (4.02 mL) under Argon and stirred at RT until consumption of starting material. LCMS after 30 min showed complete consumption of starting material. The crude reaction was purified via reverse phase chromatography (150 g C18 Aq) (5% ACN + 0.05% TFA) to (95% ACN+ 0.05 % TFA) / (H2O + 0.05% TFA gradient). The product was recovered by lyophilization to obtain I-125 (86.6 mg, 10 71% yield) as off-white solid. (ESI) m / z: [M+H]+= 253.12. To the solution of 1-(9H-fluoren-9-yl)-3,6-dioxo-2,9-dioxa-4,7-diazaundecan-11-oic acid (145 mg, 0.377 mmol, 1.11 eq) and I-125 (124 mg, 0.340 mmol, 1 eq) in anhydrous DMF under Argon at RT, NMM (0.047 mL, 0.425 mmol, 1.25 eq) was added followed by DMTMM (188 mg, 0.679 mmol, 2 eq). LCMS after 30 min showed complete consumption of I-125.The 15 crude reaction was purified via reverse phase chromatography C18 (100 g) (5% ACN + 0.05% TFA) to (95% ACN+ 0.05 % TFA) / (H2O + 0.05% TFA gradient). The product was recovered by lyophilization to obtain I-126 (171 mg, 81% yield) as off-white solid. (ESI) m / z: [M+Na]+= 641.33. To the solution of I-126 (171 mg, 0.276 mmol, 1 eq) in MeOH, 10% Pd / C (40 mol%) 20 was added and kept under Hydrogen atmosphere. LCMS after 1h 30 min showed complete consumption of I-126. The reaction mixture filtered through celite, washed with methanol. The combined solvent evaporated, and the crude dissolved in water: acetonitrile (0.05% TFA) and lyophilized to get I-127 (133.2 mg, 91% yield) as off-white solid. (ESI) m / z: [M+Na]+= 551.02. 237 NJB0009PCT O O O O Ph HN HN H O H NH2N N N NHFmoc oc 238 NJB0009PCT OOHN Ph NH O N N H N O O To the solution of 179 (127 mg, 0.180 mmol, 1 eq) and Fmoc-GGF-OH (100 mg, 0.200 5 mmol, 1.11 eq) in anhydrous DMF under Argon at RT, NMM (0.025 mL, 0.225 mmol, 1.25 eq) was added followed by DMTMM (99.6 mg, 0.360 mmol, 2 eq). LCMS after 30 min showed complete consumption of 179. The crude reaction was purified via reverse phase chromatography C18 (100 g) (5% ACN + 0.05% TFA) to (95% ACN+ 0.05 % TFA) / (H2O + 0.05% TFA gradient). The product was recovered by lyophilization to obtain I-128 (154.4 mg, 10 80% yield) as off-white solid. (ESI) m / z: [M+H]+= 1075.59. The compound I-128 (154 mg, 0.144 mmol, 1 eq) was dissolved in (1:4) morpholine: DMF (1.8 mL) under Argon and stirred at RT until consumption of starting material. LCMS after 30 min showed complete consumption of starting material. The crude reaction was precipitated with diethyl ether (15 mL) and the solid was obtained by centrifugation. The solid was washed 15 with diethyl ether (3 mL) and the solid was obtained by centrifugation. This obtained solid dissolved in 1:1 water: acetonitrile (0.05% TFA) and lyophilized to get I-129 (142.4 mg, quant. yield) as off white solid. (ESI) m / z: [M+H]+= 853.48. To the solution of I-129 (142 mg, 0.147 mmol, 1 eq) and I-127 (86.4 mg, 0.163 mmol, 1.11 eq) in anhydrous DMF under Argon at RT, NMM (0.020 mL, 0.184 mmol, 1.25 eq) was 20 added followed by DMTMM (81.5 mg, 0.295 mmol, 2 eq). The reaction was stirred at RT until consumption of starting material. After 1h, the crude reaction was purified via reverse phase 239 NJB0009PCT chromatography C18Aq (150 g) (5% ACN + 0.05% TFA) to (95% ACN+ 0.05 % TFA) / (H2O + 0.05% TFA gradient). The product was recovered by lyophilization to obtain I-130 (69.2 mg, 35% yield) as off-white solid. (ESI) m / z: [M+H]+= 1363.58. The compound I-130 (69 mg, 0.051 mmol, 1 eq) was dissolved in (1:4) morpholine: 5 DMF (0.63 mL) under Argon and stirred at RT until consumption of starting material. LCMS after 30 min showed complete consumption of starting material. The crude reaction was precipitated with diethyl ether (6 mL) and the solid was obtained by centrifugation. The solid was washed with diethyl ether (1 mL) and the solid was obtained by centrifugation. This obtained solid dissolved in 1:1 water: acetonitrile (0.05% TFA) and lyophilized to get I-131 10 (30.2 mg, 47% yield) as off white solid. (ESI) m / z: [M+H]+= 1141.96. To the solution of N-Mal-N-bis (PEG2-acid) (5 mg, 0.010 mmol, 1 eq) and I-131 (30.8 mg, 0.025 mmol, 2.4 eq) in anhydrous DMF under Argon at RT, NMM (0.003 mL, 0.026 mmol, 2.5 eq) was added followed by DMTMM (11.3 mg, 0.041 mmol, 4 eq). The reaction was stirred at room temperature until consumption of starting material. After 2h, the crude reaction was 15 purified via reverse phase (Teledyne Gemini (5 µm C18110 Å 150 x 30 mm) with (5% ACN) / (H2O) to 95% (ACN) / (H2O) gradient) (0.05% TFA). The product was recovered by lyophilization to obtain PLL59 (18.4 mg, 66% yield) as off-white solid. (ESI) m / z: [M+2] / 2 = 1368.67. Example 158: Synthesis of Payload 181 and Linker Payload PLL60: O NHFmoc oc Pro 20 77% yieldTo an oven dried vial was added propargyl alcohol (60 mg, 1.07 mmol, 1 eq) and OAc- CH2-NH-Gly-Fmoc (433.7 mg, 1.177 mmol, 1 eq) and suspended in Anhydrous DMF (7.14 mL) with a brief sonication under Ar. To the vial, 1M HCl etherate (2.141 mL, 2.141 mmol, 2 eq) was added dropwise. The vial was stirred for 4 h at room temperature. LCMS indicated that the 25 reaction had stalled, and the reaction was purified via reverse phase (Teledyne 100 g C18 with (5% ACN+0.05% TFA) / (H2O+0.05% TFA) to 95% (ACN+0.05% TFA) / (H2O+0.05% TFA) gradient). The product was recovered by lyophilization to obtain I-132 (298 mg, 76.5% yield) as off-white solid. (ESI) m / z: [M+Na]+= 387.03. 240 NJB0009PCT ONHFmocNH l) and I-132 (69.6 mg, 0.191 mmol, 1.0 eq) were added to vial under argon atmosphere. (PPh3)3CuBr (35.6 mg, 20 mol%) was added to the vial and dissolved in anhydrous 5 dichloromethane (11.94 mL). Diisopropylethylamine (0.67 mL, 3.822 mmol, 20 eq) was added to the vial and the reaction was stirred at 35°C for 2 hours sealed under argon atmosphere. The crude reaction was concentrated en vacuo and dissolved in (3 mL) (2:1) (ACN: H2O) + 0.05% 241 NJB0009PCT trifluoro acetic acid (TFA). The crude material was purified via reverse phase chromatography (100 g C18) (5% ACN + 0.05% TFA) to (95% ACN+ 0.05 % TFA) / (H2O + 0.05% TFA gradient). The product was recovered by lyophilization to obtain I-133 (54 mg, 35% yield) as off-white solid. (ESI) m / z: [M+H]+= 800.32. 5 To an oven dried vial was added I-133 (54 mg, 0.068 mmol, 1 eq) and dissolved in (1:4) (Morpholine: DMF) (0.844 mL) and stirred at room temperature under Ar. LCMS at 30 minutes indicated that I-133 was consumed. The crude reaction was precipitated with diethyl ether (8.5 mL) and the solid was obtained by centrifugation. The solid was washed with diethyl ether (1x) (8.5 mL) and the solid was obtained by centrifugation. This obtained solid was redissolved in 10 (1:1) (H2O:ACN) and lyophilized to give 181 (45 mg, quant. yield) as off-white solid. (ESI) m / z: [M+H]+= 578.14. To an oven dried vial was added 181 (17 mg, 0.029 mmol, 1 eq) and MC-GGFG-NH- CH2-O-CH2COOH (19.9 mg, 0.032 mmol, 1.11 eq) under Ar. Anhydrous DMF (0.9 mL) was added to the vial to yield a solution. NMM (4 uL, 0.036 mmol, 1.25 eq) was added to the vial 15 followed by DMTMM (16.1 mg, 0.058 mmol, 2 eq) and briefly sonicated to yield a suspension. The vial was stirred at room temperature for 0.5 h whereupon the LCMS indicated I-16 was consumed. The crude reaction was purified via reverse phase (Teledyne Gemini (5µm C18110Å 150 x 30 mm) with (5% ACN) / (H2O) to 95% (ACN) / (H2O) gradient). The product was recovered by lyophilization to obtain PLL60 (10.0 mg, 29% yield) as off-white solid. (ESI) m / z: 20 [M+H]+= 1176.52. 242 NJB0009PCT Example 159: Synthesis of Payload 182 and Linker Payload PLL61: ONH2O O H N NHFmoc NH N O N H H O n- 9-ylmethoxy)carbonyl]glycyl}amino)methoxy]acetic acid (CAS: 1599440-08-0) (21.1 mg, 0.055 5 mmol, 1.11 eq) under Ar. Anhydrous DMF (0.79 mL) was added to the vial to yield a solution. NMM (7 uL, 0.062 mmol, 1.25 eq) was added to the vial followed by DMTMM (27.4 mg, 0.099 mmol, 2 eq) and briefly sonicated to yield a suspension. The vial was stirred at room temperature for 0.5 h whereupon the LCMS indicated 181 was consumed. The crude reaction was purified via reverse phase (Teledyne Gemini (5µm C18110Å 150 x 30 mm) with (5% ACN+0.05% 10 TFA) / (H2O+0.05% TFA) to 95% (ACN+0.05% TFA) / (H2O+0.05% TFA) gradient). The product was recovered by lyophilization to obtain I-134 (17.6 mg, 38 % yield) as off-white solid. (ESI) m / z: [M+H]+= 944.62. To an oven dried vial was added I-134 (18 mg, 0.019 mmol, 1 eq) and dissolved in (1:4) (Morpholine:DMF) (0.233 mL) and stirred at room temperature under Ar. LCMS at 30 minutes 15 indicated that I-134 was consumed. The crude reaction was precipitated with diethyl ether (3 mL) and the solid was obtained by centrifugation. The solid was washed with diethyl ether (1x) (3 mL) and the solid was obtained by centrifugation. This obtained solid dried under high vacuum to give 182 (16.4 mg, quant. yield) as off-white solid. (ESI) m / z: [M+H]+= 722.36. 243 NJB0009PCT To an oven dried vial was added 182 (16 mg, 0.023mmol, 1 eq) and MalCap-Osu (8 mg, 0.027 mmol, 1.2 eq) under Ar. Anhydrous DMF (0.6 mL) was added to the vial to yield a solution. To the vial, was added DIPEA (8 uL, 0.045 mmol, 2 eq) and was stirred at room temperature for 2 h whereupon the LCMS indicated 182 was consumed. The crude reaction was 5 purified via reverse phase (Teledyne Gemini (5µm C18110Å 150 x 30 mm) with (5% ACN) / (H2O) to 95% (ACN) / (H2O) gradient). The product was recovered by lyophilization to obtain PLL61 (2.6 mg, 13% yield) as off-white solid. (ESI) m / z: [M+H]+= 915.63. 244 NJB0009PCT Example 160: Synthesis of Linker Payload PLL62: ONH2Ph O H O H NH N N N NNHFmoc 245 NJB0009PCT O H N NHFmoc O HOO Ph O HONN H O O To the solution of 181 (145 mg, 0.210 mmol, 1 eq) and Fmoc-GGF-OH (117 mg, 0.233 5 mmol, 1.11 eq) in anhydrous DMF under Argon at RT, NMM (0.029 mL, 0.262 mmol, 1.25 eq) was added followed by DMTMM (116.2 mg, 0.420 mmol, 2 eq). LCMS after 15 min showed complete consumption of 181. The crude reaction was purified via reverse phase 246 NJB0009PCT chromatography C18 (100 g) (5% ACN + 0.05% TFA) to (95% ACN+ 0.05 % TFA) / (H2O + 0.05% TFA gradient). The product was recovered by lyophilization to obtain I-135 (184.8 mg, 83% yield) as off-white solid. (ESI) m / z: [M+H]+= 1061.46. The compound I-135 (185 mg, 0.174 mmol, 1 eq) was dissolved in (1:4) morpholine: 5 DMF (1.74 mL) under Argon and stirred at RT until consumption of starting material. LCMS after 30 min showed complete consumption of starting material. The crude reaction was precipitated with diethyl ether (17 mL) and the solid was obtained by centrifugation. The solid was washed with diethyl ether (2 mL) and the solid was obtained by centrifugation. This obtained solid dissolved in 1:1 water: acetonitrile (0.05% TFA) and lyophilized to get I- 10 136(135.4 mg, 82% yield) as off white solid. (ESI) m / z: [M+H]+= 839.45. To the solution of I-136 (135 mg, 0.142 mmol, 1 eq) and I-127 (83.4 mg, 0.158 mmol, 1.11 eq) in anhydrous DMF under Argon at RT, NMM (0.020 mL, 0.178 mmol, 1.25 eq) was added followed by DMTMM (78.6 mg, 0.284 mmol, 2 eq). The reaction was stirred at RT until consumption of starting material. After 1h 30 minutes, the crude reaction was purified via 15 reverse phase chromatography C18Aq (100 g) (5% ACN + 0.05% TFA) to (95% ACN+ 0.05 % TFA) / (H2O + 0.05% TFA gradient). The product was recovered by lyophilization to obtain I-137 (91.4 mg, 48% yield) as off-white solid. (ESI) m / z: [M+H]+= 1349.66. The compound I-137 (91 mg, 0.068 mmol, 1 eq) was dissolved in (1:4) morpholine: DMF (0.85 mL) under Argon and stirred at RT until consumption of starting material. LCMS 20 after 30 min showed complete consumption of starting material. The crude reaction was precipitated with diethyl ether (6 mL) and the solid was obtained by centrifugation. The solid was washed with diethyl ether (1 mL) and the solid was obtained by centrifugation. This obtained solid dissolved in 1:1 water: acetonitrile (0.05% TFA) and lyophilized to get I-138 (45.6 mg, 54% yield) as off white solid. (ESI) m / z: [M+H]+= 1127.67. 25 To the solution of N-Mal-N-bis (PEG2-acid) (7.5 mg, 0.015 mmol, 1 eq) and I-138 (45.7 mg, 0.037 mmol, 2.4 eq) in anhydrous DMF under Argon at RT, NMM (0.004 mL, 0.038 mmol, 2.5 eq) was added followed by DMTMM (17 mg, 0.061 mmol, 4 eq). The reaction was stirred at room temperature until consumption of starting material. After 30 min, the crude reaction was purified via reverse phase (Teledyne Gemini (5 µm C18110 Å 150 x 30 mm) with 30 (5% ACN) / (H2O) to 95% (ACN) / (H2O) gradient) (0.05% TFA). The product was recovered by 247 NJB0009PCT lyophilization to obtain PLL62 (25.2 mg, 61% yield) as off-white solid. (ESI) m / z: [M+2] / 2 = 1353.84. Example 161: Synthesis of Payload 183 and 184 and Linker Payload PLL63: NH2O NJB0009PCT Camptothecin azide (ACS Med. Chem. Lett. 2019, 10, 1386-1392) (40 mg, 0.092 mmol) and propargylamine (24.7 ul, 0.367 mmol, 1.0 eq) were added to vial under argon atmosphere. (PPh3)3CuBr (17.1 mg, 20 mol%) was added to the vial and dissolved in anhydrous dichloromethane (5.74 mL). Diisopropylethylamine (0.32 mL, 1.837 mmol, 20 eq) was added to 5 the vial and the reaction was stirred at 35°C for 16 hours sealed under argon atmosphere. The crude reaction was concentrated en vacuo and dissolved in (3 mL) (2:1) (ACN: H2O) + 0.05% trifluoro acetic acid (TFA). The crude material was purified via reverse phase chromatography (100 g C18) (5% ACN + 0.05% TFA) to (95% ACN+ 0.05 % TFA) / (H2O + 0.05% TFA gradient). The product was recovered by lyophilization to obtain 183 (14.5 mg, 32% yield) as 10 off-white solid. (ESI) m / z: [M+H]+= 491.19. To an oven dried vial was added 183 (87 mg, 0.144 mmol, 1 eq) and [({N-[(9H-fluoren- 9-ylmethoxy)carbonyl]glycyl}amino)methoxy]acetic acid (CAS: 1599440-08-0) (61.4 mg, 0.160 mmol, 1.11 eq) under Ar. Anhydrous DMF (2.28 mL) was added to the vial to yield a solution. NMM (20 uL, 0.180 mmol, 1.25 eq) was added to the vial followed by DMTMM (80 mg, 0.288 15 mmol, 2 eq) and briefly sonicated to yield a suspension. The vial was stirred at room temperature for 0.5 h whereupon the LCMS indicated 183 was consumed. The crude reaction was purified via reverse phase (Teledyne Gemini (5µm C18110Å 150 x 30 mm) with (5% ACN+0.05% TFA) / (H2O+0.05% TFA) to 95% (ACN+0.05% TFA) / (H2O+0.05% TFA) gradient). The product was recovered by lyophilization to obtain I-139 (12 mg, 9.7 % yield) as off-white solid. 20 (ESI) m / z: [M+H]+= 857.38. To an oven dried vial was added I-139 (12 mg, 0.014 mmol, 1 eq) and dissolved in (1:4) (Morpholine:DMF) (0.175 mL) and stirred at room temperature under Ar. LCMS at 30 minutes indicated that I-139 was consumed. The crude reaction was precipitated with diethyl ether (2 mL) and the solid was obtained by centrifugation. The solid was washed with diethyl ether (1x) 25 (2 mL) and the solid was obtained by centrifugation. This obtained solid was redissolved in (1:1) (H2O:ACN) and lyophilized to give 184 (10.8 mg, quant. yield) as off-white solid. (ESI) m / z: [M+H]+= 635.33. To an oven dried vial was added 184 (10.8 mg, 0.017 mmol, 1 eq) and MC-GGFG-NH- CH2-O-CH2COOH (11.6 mg, 0.019 mmol, 1.11 eq) under Ar. Anhydrous DMF (0.52 mL) was 30 added to the vial to yield a solution. NMM (2 µL, 0.021 mmol, 1.25 eq) was added to the vial followed by DMTMM (9.4 mg, 0.034 mmol, 2 eq) and briefly sonicated to yield a suspension. 249 NJB0009PCT The vial was stirred at room temperature for 0.5 h whereupon the LCMS indicated 184 was consumed. The crude reaction was purified via reverse (Teledyne Gemini (5µm C18110Å 150 x 30 mm) with (5% ACN) / (H2O) to 95% (ACN) / (H2O) gradient). The product was recovered by lyophilization to obtain PLL63 (9.4 mg, 45% yield) as off-white solid. (ESI) m / z: [M+H]+= 5 1233.51. 250 NJB0009PCT Example 162: Synthesis of Payloads 185 and 186 and Linker Payload PLL64: NH2H2N O NJB0009PCT Camptothecin azide (ACS Med. Chem. Lett. 2019, 10, 1386-1392) (131 mg, 0.302 mmol) and 4-ethynylaniline (106 mg, 0.905 mmol, 3.0 eq) were added to vial under argon atmosphere. (PPh3)3CuBr (56.2 mg, 20 mol%) was added to the vial and dissolved in anhydrous dichloromethane (18.8 mL). Diisopropylethylamine (1.06 mL, 6.036 mmol, 20 eq) was added to 5 the vial and the reaction was stirred at 35°C for 4 hours sealed under argon atmosphere. The crude reaction was concentrated en vacuo and dissolved in (3 mL) (2:1) (ACN: H2O) + 0.05% trifluoro acetic acid (TFA). The crude material was purified via reverse phase chromatography (100 g C18) (5% ACN + 0.05% TFA) to (95% ACN+ 0.05 % TFA) / (H2O + 0.05% TFA gradient). The product was recovered by lyophilization to obtain 185 (57.4 mg, 34% yield) as 10 off-white solid. (ESI) m / z: [M+H]+= 553.29. To an oven dried vial was added 185 (36 mg, 0.066 mmol, 1 eq) and [({N-[(9H-fluoren- 9-ylmethoxy)carbonyl]glycyl}amino)methoxy]acetic acid (CAS: 1599440-08-0) (28 mg, 0.073 mmol, 1.11 eq) under Ar. Anhydrous DMF (1.04 mL) was added to the vial to yield a solution. NMM (9 uL, 0.082 mmol, 1.25 eq) was added to the vial followed by DMTMM (36.5 mg, 0.132 15 mmol, 2 eq) and briefly sonicated to yield a suspension. The vial was stirred at room temperature for 0.5 h whereupon the LCMS indicated 185 was consumed. The crude reaction was purified via reverse phase (Teledyne Gemini (5µm C18110Å 150 x 30 mm) with (5% ACN+0.05% TFA) / (H2O+0.05% TFA) to 95% (ACN+0.05% TFA) / (H2O+0.05% TFA) gradient). The product was recovered by lyophilization to obtain I-140 (49 mg, 81 % yield) as off-white solid. (ESI) 20 m / z: [M+H]+= 919.61. To an oven dried vial was added I-140 (49 mg, 0.053 mmol, 1 eq) and dissolved in (1:4) (Morpholine: DMF) (0.667 mL) and stirred at room temperature under Ar. LCMS at 30 minutes indicated that I-140 was consumed. The crude reaction was precipitated with diethyl ether (7 mL) and the solid was obtained by centrifugation. The solid was washed with diethyl ether (1x) 25 (7 mL) and the solid was obtained by centrifugation. This obtained solid dried under high vacuum to give 186 (38 mg, quant. yield) as off-white solid. (ESI) m / z: [M+H]+= 692.29. To an oven dried vial was added 186 (32 mg, 0.046 mmol, 1 eq) and MC-GGFG-NH- CH2-O-CH2COOH (32 mg, 0.051 mmol, 1.11 eq) under Ar. Anhydrous DMF (1.43 mL) was added to the vial to yield a solution. NMM (0.006 mL, 0.058 mmol, 1.25 eq) was added to the 30 vial followed by DMTMM (25.6 mg, 0.092 mmol, 2 eq) and briefly sonicated to yield a suspension. The vial was stirred at room temperature for 0.5 h whereupon the LCMS indicated 252 NJB0009PCT 186 was consumed. The crude reaction was purified via reverse phase (Teledyne Gemini (5µm C18110Å 150 x 30 mm) with (5% ACN) / (H2O) to 95% (ACN) / (H2O) gradient). The product was recovered by lyophilization to obtain PLL64 (20.8 mg, 35% yield) as off-white solid. (ESI) m / z: [M+H]+= 1295.75. 253 NJB0009PCT Example 163: Synthesis of Payloads 187 and 188 and Linker Payload PLL65: NH2O NJB0009PCT Camptothecin azide (ACS Med. Chem. Lett. 2019, 10, 1386-1392) (100 mg, 0.230 mmol) and pent-4-yn-1-amine (88.9 ul, 0.919 mmol, 4.0 eq) were added to vial under argon atmosphere. (PPh3)3CuBr (42.7 mg, 20 mol%) was added to the vial and dissolved in anhydrous dichloromethane (14.3 mL). Diisopropylethylamine (0.8 mL, 4.593 mmol, 20 eq) was added to 5 the vial and the reaction was stirred at 35°C for 3 hours sealed under argon atmosphere. The crude reaction was concentrated en vacuo and dissolved in (3 mL) (2:1) (ACN: H2O) + 0.05% trifluoro acetic acid (TFA). The crude material was purified via reverse phase chromatography (100 g C18) (5% ACN + 0.05% TFA) to (95% ACN+ 0.05 % TFA) / (H2O + 0.05% TFA gradient). The product was recovered by lyophilization to obtain 187 (87.4 mg, 73.4% yield) as 10 off-white solid. (ESI) m / z: [M+H]+= 519.05. To an oven dried vial was added 187 (64 mg, 0.101 mmol, 1 eq) and [({N-[(9H-fluoren- 9-ylmethoxy)carbonyl]glycyl}amino)methoxy]acetic acid (CAS: 1599440-08-0) (43 mg, 0.112 mmol, 1.11 eq) under Ar. Anhydrous DMF (1.6 mL) was added to the vial to yield a solution. NMM (14 uL, 0.126 mmol, 1.25 eq) was added to the vial followed by DMTMM (55.7 mg, 15 0.201 mmol, 2 eq) and briefly sonicated to yield a suspension. The vial was stirred at room temperature for 0.5 h whereupon the LCMS indicated 187 was consumed. The crude reaction was purified via reverse phase (Teledyne Gemini (5µm C18110Å 150 x 30 mm) with (5% ACN+0.05% TFA) / (H2O+0.05% TFA) to 95% (ACN+0.05% TFA) / (H2O+0.05% TFA) gradient). The product was recovered by lyophilization to obtain I-144 (25.4 mg, 29 % yield) as 20 off-white solid. (ESI) m / z: [M+H]+= 885.46. To an oven dried vial was added I-144 (25 mg, 0.029 mmol, 1 eq) and dissolved in (1:4) (Morpholine: DMF) (0.359 mL) and stirred at room temperature under Ar. LCMS at 30 minutes indicated that I-144 was consumed. The crude reaction was precipitated with diethyl ether (4 mL) and the solid was obtained by centrifugation. The solid was washed with diethyl ether (1x) 25 (4 mL) and the solid was obtained by centrifugation. This obtained solid was redissolved in (1:1) (H2O: ACN) and lyophilized to give 188 (19.8 mg, quant. yield) as off-white solid. (ESI) m / z: [M+H]+= 663.33. To an oven dried vial was added 188 (10 mg, 0.015 mmol, 1 eq) and MC-GGFG-NH- CH2-O-CH2COOH (10 mg, 0.017 mmol, 1.11 eq) under Ar. Anhydrous DMF (0.47 mL) was 30 added to the vial to yield a solution. NMM (2 uL, 0.019 mmol, 1.25 eq) was added to the vial followed by DMTMM (8.4 mg, 0.03 mmol, 2 eq) and briefly sonicated to yield a suspension. 255 NJB0009PCT The vial was stirred at room temperature for 0.5 h whereupon the LCMS indicated 188 was consumed. The crude reaction was purified via reverse phase (Teledyne Gemini (5µm C18110Å 150 x 30 mm) with (5% ACN) / (H2O) to 95% (ACN) / (H2O) gradient). The product was recovered by lyophilization to obtain PLL65 (6.2 mg, 33% yield) as off-white solid. (ESI) m / z: 5 [M+H]+= 1261.67. Example 164: Synthesis of Payload 189 and Linker Payload PLL66: O H O N NH NH2NH2 , . , 9- ylmethoxy)carbonyl]glycyl}amino)methoxy]acetic acid (CAS: 1599440-08-0) (4.5 mg, 0.012 10 mmol, 1.11 eq) under Ar. Anhydrous DMF (0.17 mL) was added to the vial to yield a solution. 256 NJB0009PCT NMM (1 µL, 0.013 mmol, 1.25 eq) was added to the vial followed by DMTMM (5.8 mg, 0.021 mmol, 2 eq) and briefly sonicated to yield a suspension. The vial was stirred at room temperature for 0.5 h whereupon the LCMS indicated 188 was consumed. The crude reaction was purified via reverse phase (Teledyne Gemini (5µm C18110Å 150 x 30 mm) with (5% ACN+0.05% 5 TFA) / (H2O+0.05% TFA) to 95% (ACN+0.05% TFA) / (H2O+0.05% TFA) gradient). The product was recovered by lyophilization to obtain I-145 (4.2 mg, 39 % yield) as off-white solid. (ESI) m / z: [M+H]+= 1029.54. To an oven dried vial was added I-145 (4 mg, 0.004 mmol, 1 eq) and dissolved in (1:4) (Morpholine:DMF) (0.051 mL) and stirred at room temperature under Ar. LCMS at 30 minutes 10 indicated that I-145 was consumed. The crude reaction was precipitated with diethyl ether (1 mL) and the solid was obtained by centrifugation. The solid was washed with diethyl ether (1x) (1 mL) and the solid was obtained by centrifugation. This obtained solid was redissolved in (1:1) (H2O:ACN) and lyophilized to give 189 (5 mg, quant. yield) as off-white solid. (ESI) m / z: [M+H]+= 807.61. 15 To an oven dried vial was added 189 (5 mg, 0.006 mmol, 1 eq) and MalCap-Osu (2 mg, 0.007 mmol, 1.2 eq) under Ar. Anhydrous DMF (0.2 mL) was added to the vial to yield a solution. To the vial, was added DIPEA (2 µL, 0.012 mmol, 2 eq) and was stirred at room temperature for 2 h whereupon the LCMS indicated 189 was consumed. The crude reaction was purified via reverse phase (Teledyne Gemini (5µm C18110Å 150 x 30 mm) with (5% 20 ACN) / (H2O) to 95% (ACN) / (H2O) gradient). The product was recovered by lyophilization to obtain PLL66 (2.2 mg, 36% yield) as off-white solid. (ESI) m / z: [M+H]+= 1000.68. 257 NJB0009PCT Example 165: Synthesis of Payloads 190 and 191 and Linker Payload PLL67: NH21-amino-3-butyne O mmol, 1 eq) and 1-amino-3-butyne (0.144 mL, 1.76 mmol, 4.0 eq) were added to vial under 5 argon atmosphere. (PPh3)3CuBr (81.9 mg, 20 mol%) was added to the vial and dissolved in anhydrous dichloromethane (27.5 mL). Diisopropylethylamine (1.54 mL, 8.801 mmol, 20 eq) was added to the vial and the reaction was stirred at 35°C for 2 hours sealed under argon atmosphere. The crude reaction was concentrated in vacuo and dissolved in DMF and was purified via reverse phase chromatography (100 g C18Aq) (5% ACN + 0.05% TFA) to (95% 258 NJB0009PCT ACN+ 0.05 % TFA) / (H2O + 0.05% TFA gradient). The product was recovered by lyophilization to obtain 190 (76.8 mg, 35% yield) as off-white solid. (ESI) m / z: [M+H]+= 505.13. To an oven dried vial was added 190 (77 mg, 0.124 mmol, 1 eq) and [({N-[(9H-fluoren- 9-ylmethoxy)carbonyl]glycyl}amino)methoxy]acetic acid (CAS: 1599440-08-0) (53 mg, 0.138 5 mmol, 1.11 eq) under Ar. Anhydrous DMF (1.24 mL) was added to the vial to yield a solution. NMM (0.017 mL, 0.155 mmol, 1.25 eq) was added to the vial followed by DMTMM (68.7 mg, 0.248 mmol, 2 eq) and briefly sonicated to yield a suspension. The vial was stirred at room temperature for 15 min whereupon the LCMS indicated 190 was consumed. The crude reaction was purified via reverse phase chromatography (100 g C18) (5% ACN + 0.05% TFA) to (95% 10 ACN+ 0.05 % TFA) / (H2O + 0.05% TFA gradient). The product was recovered by lyophilization to obtain I-146 (79.8 mg, 74% yield) as off-white solid. (ESI) m / z: [M+H]+= 871.31. To an oven dried vial was added I-146 (80 mg, 0.092 mmol, 1 eq) and dissolved in (1:4) (Morpholine: DMF) (1.15 mL) and stirred at room temperature under Ar. LCMS at 30 minutes indicated that I-146 was consumed. The crude reaction was precipitated with diethyl ether (10 15 mL) and the solid was obtained by centrifugation. The solid was washed with diethyl ether (1x) (2 mL) and the solid was obtained by centrifugation. This obtained solid was redissolved in (1:1) (H2O: ACN) (0.05% TFA) and lyophilized to give 191 (43.2 mg, 62% yield) as off-white solid. (ESI) m / z: [M+H]+= 649.32. To an oven dried vial was added 191 (16 mg, 0.022 mmol, 1 eq) and MalCap-Osu (8 mg, 20 0.026 mmol, 1.2 eq) under Ar. Anhydrous DMF (0.6 mL) was added to the vial to yield a solution. To the vial, was added NMM (0.006 mL, 0.043 mmol, 2 eq) and was stirred at room temperature for 1h 30 min whereupon the LCMS indicated 191 was consumed. The crude reaction was purified via reverse phase (Teledyne Gemini (5µm C18110Å 150 x 30 mm) with (5% ACN) / (H2O) to 95% (ACN) / (H2O) gradient). The product was recovered by lyophilization 25 to obtain PLL67 (8.8 mg, 49% yield) as off-white solid. (ESI) m / z: [M+H]+= 842.41. 259 NJB0009PCT Example 166: Synthesis of Linker Payload PLL68: O H O H O H O N O N O N HN NH2 HNNNHFmocO O H O , , ylmethoxy)carbonyl]glycyl}amino)methoxy]acetic acid (CAS: 1599440-08-0) (15 mg, 0.039 5 mmol, 1.11 eq) under Argon in anhydrous DMF (0.33 mL), NMM (0.005 mL, 0.044 mmol, 1.25 eq) was added followed by DMTMM (19.4 mg, 0.070 mmol, 2 eq). The vial was stirred at room temperature for 30 min whereupon the LCMS indicated 191 was consumed. The crude reaction 260 NJB0009PCT was purified via reverse phase chromatography (50 g C18Aq) (5% ACN + 0.05% TFA) to (95% ACN+ 0.05 % TFA) / (H2O + 0.05% TFA gradient). The product was recovered by lyophilization to obtain I-147 (30.2 mg, 85% yield) as off-white solid. (ESI) m / z: [M+H]+= 1015.70. The compound I-147 (30 mg, 0.030 mmol, 1 eq) was dissolved in (1:4) (Morpholine: 5 DMF) (0.37 mL) and stirred at room temperature under Argon. LCMS at 30 minutes indicated that I-147 was consumed. The crude reaction was precipitated with diethyl ether (3 mL) and the solid was obtained by centrifugation. The solid was washed with diethyl ether (1x) (1 mL) and the solid was obtained by centrifugation. This obtained solid was redissolved in (1:1) (H2O: ACN) (0.05% TFA) and lyophilized to give I-148 (20.4 mg, 76% yield) as off-white solid. (ESI) 10 m / z: [M+H]+= 793.47. To the solution of N-Mal-N-bis (PEG2-acid) (4.4 mg, 0.009 mmol, 1 eq) and I-148 (20.4 mg, 0.023 mmol, 2.5 eq) in anhydrous DMF under Argon at RT, NMM (0.002 mL, 0.023 mmol, 2.5 eq) was added followed by DMTMM (10 mg, 0.036 mmol, 4 eq). The reaction was stirred at room temperature until consumption of starting material. After 50 min, the crude 15 reaction was purified via reverse phase (Teledyne Gemini (5 µm C18110 Å 150 x 30 mm) with (5% ACN) / (H2O) to 95% (ACN) / (H2O) gradient) (0.05% TFA). The product was recovered by lyophilization to obtain PL68 (6.6 mg, 36% yield) as off-white solid. (ESI) m / z: [M+2] / 2 = 1019.55. Example 167: Proposed Synthesis of PLL74 261 NJB0009PCT ONH2NH O 262 NJB0009PCT Example 168: Synthesis of Payloads 192 and 193 and Linker Payload PLL69: NH2N O NJB0009PCT Camptothecin azide (ACS Med. Chem. Lett. 2019, 10, 1386-1392) (59 mg, 0.135 mmol) and 5-ethynylpyridin-2-amine (64 mg, 0.538 mmol, 4.0 eq) were added to vial under argon atmosphere. (PPh3)3CuBr (25 mg, 20 mol%) was added to the vial and dissolved in anhydrous dichloromethane (8.4 mL). Diisopropylethylamine (0.47 mL, 2.69 mmol, 20 eq) was added to 5 the vial and the reaction was stirred at 35°C for 3 hours sealed under argon atmosphere. The crude reaction was concentrated in vacuo and dissolved in (3 mL) (2:1) (ACN: H2O) + 0.05% trifluoro acetic acid (TFA). The crude material was purified via reverse phase chromatography (50 g C18) (5% ACN + 0.05% TFA) to (95% ACN+ 0.05 % TFA) / (H2O + 0.05% TFA gradient). The product was recovered by lyophilization to obtain 192 (22.7 mg, 33% yield) as off-white 10 solid. (ESI) m / z: [M+H]+= 554.26. To the solution of compound 192 (71 mg, 0.128 mmol, 1 eq) and [({N-[(9H-fluoren-9- ylmethoxy)carbonyl]glycyl}amino)methoxy]acetic acid (CAS: 1599440-08-0) (54.7 mg, 0.142 mmol, 1.11 eq) under Argon in anhydrous DMF (0.95 mL), NMM (0.018 mL, 0.160 mmol, 1.25 eq) was added followed by DMTMM (71 mg, 0.257 mmol, 2 eq). The vial was stirred at room 15 temperature for overnight whereupon the LCMS indicated over 83% product formation. The crude reaction was purified via reverse phase chromatography (100 g C18) (5% ACN + 0.05% FA) to (95% ACN+ 0.05 % FA) / (H2O + 0.05% FA gradient). The product was recovered by lyophilization to obtain I-149 (67.2 mg, 57% yield) as off-white solid. (ESI) m / z: [M+H]+= 920.51. 20 The compound I-149 (67 mg, 0.073 mmol, 1 eq) was dissolved in (1:4) (Morpholine: DMF) (1.04 mL) and stirred at room temperature under Argon. LCMS at 30 minutes indicated that I-149 was consumed. The crude reaction was precipitated with diethyl ether (10 mL) and the solid was obtained by centrifugation. The solid was washed with diethyl ether (1x) (5 mL) and the solid was obtained by centrifugation. This obtained solid was kept in high vacuum overnight 25 to give 193 (41.4 mg, 98% yield) as off-white solid. (ESI) m / z: [M+H]+= 698.37. To an oven dried vial was added 193 (38 mg, 0.055 mmol, 1 eq) and MC-GGFG-NH- CH2-O-CH2COOH (37.7 mg, 0.061 mmol, 1.11 eq) under Ar. Anhydrous DMF (1.70 mL) was added to the vial to yield a solution. NMM (0.008 mL, 0.069 mmol, 1.25 eq) was added to the vial followed by DMTMM (30.5 mg, 0.110 mmol, 2 eq) and briefly sonicated to yield a 30 suspension. The vial was stirred at room temperature for 10 min whereupon the LCMS indicated 193 was consumed. The crude reaction was purified via reverse phase (Teledyne Gemini (5µm 264 NJB0009PCT C18 110Å 150 x 30 mm) with (5% ACN) / (H2O) to 95% (ACN) / (H2O) gradient). The product was recovered by lyophilization to obtain PLL69 (22 mg, 31% yield) as off-white solid. (ESI) m / z: [M+H]+= 1296.89. Example 169: Proposed Synthesis of Linker Payload PLL75: 5 NHFmoc NH2O HN H O O M NOO Example 170: Proposed Synthesis of Linker Payload PLL76: 265 NJB0009PCT H O N NHFmoc O N O O 266 NJB0009PCT F F O NJB0009PCT Example 172: Synthesis of Linker Payload PLL70: O NH O O CH2COOH (6.1 mg, 0.01 mmol, 1.11 eq) under Argon in anhydrous DMF (0.28 mL), NMM 5 (0.001 mL, 0.011 mmol, 1.25 eq) was added followed by DMTMM (5 mg, 0.018 mmol, 2 eq). The reaction mixture was stirred at room temperature for 15 min whereupon the LCMS indicated I-104 was consumed. The crude reaction was purified via reverse phase (Teledyne Gemini (5µm C18110Å 150 x 30 mm) with (5% ACN) / (H2O) to 95% (ACN) / (H2O) gradient). The product was recovered by lyophilization to obtain PLL70 (4.6 mg, 44% yield) as off-white solid. (ESI) 10 m / z: [M+H]+= 1155.73. 268 NJB0009PCT Example 173: Synthesis of Linker Payload PLL71: ONH2N O H (3.2 mg, 0.0051 mmol, 1.11 eq) under Argon in anhydrous DMF (0.14 mL), NMM (0.001 mL, 5 0.006 mmol, 1.25 eq) was added followed by DMTMM (2.6 mg, 0.009 mmol, 2 eq). The reaction mixture was stirred at room temperature for 15 min whereupon the LCMS indicated I- 93 was consumed. The crude reaction was purified via reverse phase (Teledyne Gemini (5µm C18110Å 150 x 30 mm) with (5% ACN) / (H2O) to 95% (ACN) / (H2O) gradient). The product was recovered by lyophilization to obtain PLL71 (1.2 mg, 21% yield) as off-white solid. (ESI) 10 m / z: [M+H]+= 1194.63. 269 NJB0009PCT Example 174: Synthesis of Linker Payload PLL72: O H O N NH2 NH NHFmocn- 9-ylmethoxy)carbonyl]glycyl}amino)methoxy]acetic acid (CAS: 1599440-08-0) (83.2 mg, 0.216 5 mmol, 1.11 eq) under Ar. Anhydrous DMF (1.44 mL) was added to the vial to yield a solution. NMM (27 uL, 0.244 mmol, 1.25 eq) was added to the vial followed by DMTMM (108 mg, 0.390 mmol, 2 eq) and briefly sonicated to yield a suspension. The vial was stirred at room temperature for 0.5 h whereupon the LCMS indicated 15 was consumed. The crude reaction was purified via reverse phase (Teledyne Gemini (5µm C18110Å 150 x 30 mm) with (5% ACN+0.05% 10 TFA) / (H2O+0.05% TFA) to 95% (ACN+0.05% TFA) / (H2O+0.05% TFA) gradient). The product was recovered by lyophilization to obtain I-150 (57.4 mg, 37 % yield) as off-white solid. (ESI) m / z: [M+H]+= 794.46. To an oven dried vial was added I-150 (57 mg, 0.072 mmol, 1 eq) and dissolved in (1:4) (Morpholine:DMF) (1.03mL) and stirred at room temperature under Ar. LCMS at 20 minutes 270 NJB0009PCT indicated that I-150 was consumed. The crude reaction was precipitated with diethyl ether (10 mL) and the solid was obtained by centrifugation. The solid was washed with diethyl ether (1x) (10 mL) and the solid was obtained by centrifugation. This obtained solid was redissolved in (1:1) (H2O:ACN) and lyophilized to give I-151 (35.8 mg, 87% yield) as off-white solid. (ESI) 5 m / z: [M+H]+= 572.33. To an oven dried vial was added I-151 (38 mg, 0.066 mmol, 1 eq) and MC-GGFG-NH- CH2-O-CH2COOH (45.3 mg, 0.073 mmol, 1.11 eq) under Ar. Anhydrous DMF (2.04 mL) was added to the vial to yield a solution. NMM (9 uL, 0.083 mmol, 1.25 eq) was added to the vial followed by DMTMM (36.6 mg, 0.132 mmol, 2 eq) and briefly sonicated to yield a suspension. 10 The vial was stirred at room temperature for 0.5 h whereupon the LCMS indicated I-151 was consumed. The crude reaction was purified via reverse phase (Teledyne Gemini (5µm C18110Å 150 x 30 mm) with (5% ACN) / (H2O) to 95% (ACN) / (H2O) gradient). The product was recovered by lyophilization to obtain PLL72 (18.4 mg, 34% yield) as off-white solid. (ESI) m / z: [M+H]+= 1170.11. 15 Example 175: Preparation of G* Containing ADC’s: Drug to Antibody Ratio (DAR) by RP-LC / MS was determined by analytical liquid chromatography-mass spectrometry (LC-MS), employing a Waters Acquity Ultra Performance LC system and a Synapt high-definition mass spectrometer. 15 µg of ADC was injected over a PLRP-S column (1000 Å, 8 µm, 2.1 x 50 mm) against a 25 – 45 % gradient (ACN + 0.1 % 20 formic acid; 0.35 mL / min flow). Monomeric purity was found via size exclusion chromatography, employed on an Agilent 1260 HPLC. 20 µg of ADC was injected over a TSKgelG3000SWXL column against a 100 % PBS gradient (0.8 mL / min flow). The T-PLL crude ADC solution was dialyzed against 1X-PBS buffer, pH-7.4 using 0.5ml dialysis cassette generation 2 at room temperature for 5-6 h followed up overnight at cold room with continuous 25 stirring using magnetic stirrer to remove free payload, buffer additives, and TCEP. The final solution was filtered using 0.2 µm syringe filter. Final analysis was performed on an aliquoted sample of the filtered ADC. Bioconjugates were reduced with dithiothreitol (0.5 M; 1 µL / 10 µg ADC) and allowed to incubate at 37 ℃ x 30 min. Reduced light chain and heavy chain charge envelopes were deconvoluted and reduced light chain and heavy chain species were identified 30 and quantified. 271 NJB0009PCT Table 13: Synthesis of ADC-Conjugates T-PLL48 – T-PLL72: Co- Payload DAR (Drug to Monomeric Concentration Conjugates Solvent Example 176: Cytotoxicity Assay: 5 Protocol: Day 1: 2,000 cells / well were plated and incubated at 37°C overnight. Day 2: Payload / ADC / vehicle control dilutions were made in respective media and added to cells. Volume added: 50uL to each well. Starting treatment concentration was 1 mM for free 272 NJB0009PCT payloads / 1 µM for ADC’s / 10% for vehicle control and then diluted 10-fold down for a total of 11 treatment dilutions. Each concentration was analyzed in triplicates. Media-only wells were used as a control to calculate percent viability. Day 5: Cell titer glow reagent (volume: 50uL) was added to each well, the plate was 5 shaken for 5 mins and the luminescence was recorded. Drug Treatment Time: 72 hours. Data Analysis: Percent viability was calculated by dividing the luminescence signal obtained for each treated well by the untreated well (media-only control) and multiplying by 100. Data was next transformed using X= Log (x) and then analyzed with nonlinear regression (curve fit), Dose Response inhibition – log (inhibitor) vs response (3 parameters) using PRISM software to 10 determine the IC50value. The results of cytotoxicity of SKBR-3 cell line (human breast cancer) and are provided in Tables 14 and 15. Table 14: In Vitro Cytotoxicity Assay of Payloads 175 through 197: Payload IC50 (nM) IC50 (nM) (DXD Control) Normalized IC5o (PL SKBR-3 (1599440-33-1) SKBR-3 IC50 / DXD IC50) 273 NJB0009PCT Table 15: In Vitro Cytotoxicity Assay of ADCs T-PLL48 – TPLL72: IC50 (pM) IC5O (pM) (T-DXD Normalized IC5o (T- Conjugates SKBR-3 Control) SKBR-3 PLL / T-DXD) SKBR-3 Example 177: In Vivo Efficacy Testing of ADCs (T-PLL): 5 FIG. 6 illustrates the results of in vivo efficacy testing of ADCs (T-PLL) versus control. dT / dC % Analysis: Measures anti-tumor effect as a percentage of relative median tumor volume (RTV) for the ‘Treated’ group divided by the RTV for the ‘control’ group on any given day. Compounds with a dT / dC % > 40% are inactive, a dT / dC % of 10-40% are ‘Active’ and those with a dT / dC lower than 10% are ‘Highly Active’. 274 NJB0009PCT RTV = Tumor volume at Day x / Tumor volume at Day 0 dT / dC % = 100*(median RTV ‘treated’ group / median RTV ‘control group’) Highly Active = dT / dC %< 10% Active = 10% < dT / dC % < 40% 5 Not Active = dT / dC % > 40% Table 16: In Vivo Efficacy of T-PLL’s: In Vivo Efficacy of T-PLL’s T-PLL# Efficac Result 275 NJB0009PCT In Vivo Efficacy of T-PLL’s T-PLL# Efficacy Result Example 178: In V Histopathological evaluation of lung tissue was conducted to evaluate the histopathological features and extent of interstitial lung disease in murine lungs, including 5 inflammation, fibrosis, alveolar damage, and architectural distortion consistent with previous reports using similar models (Moeller et al., 2008; Tashiro et al., 2017). In a previous study, mice were administered with Trastuzumab-DXD and novel PLL ADCs at escalating doses of 50 mg / kg, 100 mg / kg, and 200 mg / kg to evaluate systemic tolerability and Maximum Tolerance Dose (MTD), Mice treated with 50 mg / kg and 100 mg / kg showed no significant adverse effects 10 or mortality. However, dosing at 200mg / kg resulted in 100% mortality, indicating that this dose exceeds the tolerable limit. Based on these findings, the MTD in mice is estimated to be in between 100 mg / kg and 200 mg / kg for Trastuzumab-DXD and novel PLL ADCs. Accordingly, 100mg / kg was selected as a dose for further evaluation of ILD (Interstitial Lung Disease) in follow-up studies. 15 All Procedures involving the care and use of animals in the study were reviewed and approved by the Stony Brook University Institutional Animal Care and Use Committee (Protocol # IACUC2021-00074) prior to conduct. During the study, the care and use of animals was conducted in accordance with the principles outlined in the Guide for the Care and Use of Laboratory Animals, 8th Edition, 2010 (National Research Council). The animals were kept in a 20 controlled environment (targeted ranges: temperature 21 ± 3°C, humidity 30-70%, 60 air changes per hour), with a 12-hour light / dark cycle, and under barrier (quarantine) conditions. Temperature and relative humidity were monitored continuously. All animals were subjected to the same environmental conditions. A standard certified commercial rodent diet (Pico Lab Protein Rodent Diet 20) and tap water were provided to the animals ad libitum. Supportive care 25 in the form of a high fat diet (Bacon Softies™) was available to provide for animals exhibiting body weight loss. 276 NJB0009PCT As previously described (Morzon et al., 2023) specific pathogen-free female Balb / C mice aged 8–10 weeks were purchased from Taconic biosciences, USA and delivered to the Division of Laboratory Animal Resources, (DLAR), at Stony Brook University 7 days prior to dosing, allowing availability of animals for the study and the animals to become accustomed to the 5 laboratory environment. Mice were randomized into treatment and control groups based on the Body weights, and dosing was initiated (Day 0). Trastuzumab, Trastuzumab-DXD, and novel PLL ADCs were administered intravenously to the mice at a volume of (5 mL / kg) at a dose of (100 mg / kg) Q3D for 2 weeks. As a vehicle, 1 X PBS (pH = 7.0), or HBS buffer (10 mM Histidine, 10% Trehalose, 0.02% Polysorbate 20, and pH 5.5) were administered at the same 10 volume as the ADCs. Two weeks after the last dose, Lungs were harvested and processed for paraffin embedding, followed by staining with hematoxylin and eosin (H&E), digitally scanned on a GT450 scanner (Leica Biosystems, Inc) creating whole slide images (WSIs), and evaluated by a senior board-certified research pathologist. WSIs were reviewed in their entirety in a blinded fashion. 15 Most commonly, histopathological parameters presented in interstitial lung disease, (ILD), Granuloma, a tiny cluster of white blood cells formed as a reaction to infections, inflammation, irritants or foreign objects. Inflammation and structural integrity of Peribronchial, Peribronchiolar, alveolar, and intravascular regions of lung (Habiel & Hogaboam, 2014) were assessed and scored based on severity (Broncano. J, 2015). 20 In addition, Mononuclear infiltration, an accumulation of mononuclear cells, like lymphocytes and monocytes, in lungs, often in response to inflammation were assessed and scored based on severity (sara Szabo et, al. 2010). Lymphoid hyperplasia, a condition in which the lymph nodes enlarge due to an increase in the number of lymphocytes (white blood cells) within them were assessed and scored based on severity (Likui. F, 2019). Fibrosis, a process in 25 which excessive fibrous connective tissue (scarring) develops in lungs was assessed and scored (Thomas AW, 2012). Perivascular edema, a condition where fluid accumulates around blood vessels, causing swelling was assessed and scored based on severity (Philpott, H.T et al. 2022). Pulmonary Microthrombi, an aggregation of platelets in lungs was assessed and scored based on severity (Andrew SW, 2012). Fibrinous deposition, an abnormal accumulation of fibrin 30 in the lung tissue and Pulmonary Hemorrhage (Reddy & Lakshmi, 2015) were assessed and scored based on severity. 277 NJB0009PCT The whole slide images were semi-quantitatively scored based on visual assessment of stained histological samples. Interstitial fibrosis, congestion, and macrophage infiltration were also assessed and scored based on severity (Ogger, PP. et. al, 2020). All scoring was performed based on the guidelines described in the National Toxicology program (NTP, 2019). The severity 5 Score (Ashcroft et al., 1988) is the scale used to evaluate ILD parameters. It ranges from 0 to 3, with 0 indicating normal tissue (<5% lung tissue affected), a score 1 indicating mild effect (5% - 33% lung tissue affected), a score of 2 indicating moderate effect (34% - 66% lung tissue affected), and a score of 3 indicated severe affect (> 66% lung tissue affected). Mice subjected to ILD induction with Trastuzumab, Trastuzumab deruxtecan (T-DXD), 10 and novel PLL ADCs exhibited varied levels of disruption of normal alveolar architecture, fibrosis, and infiltration of inflammatory cells, predominantly lymphocytes. The mice dosed with T-DXD showed moderate to severe fibrosis. In contrast, minimal changes were observed in novel T-PLL’s. These findings confirm the successful establishment of an ILD phenotype and provide a foundation for evaluating therapeutic interventions. Based on the negative and positive 15 control IHC of murine lung sections results the score for novel linker payloads are provided in Tables 18 and 19 below. A composite score in histopathological studies (reported below in Table 18 and Table 19) is a summation of the individual severity scoring (see above) across twelve parameters (1. Granuloma, 2. Lymphocytic infiltration, 3. Lymphoid hyperplasia, 4. Perivascular edema, 5. 20 Intravasular, 6. Alveolar, 7. Microthrombi, 8. Hemorrhage, 9. Peribronchiolar & Peri bronchial, 10. Interalveolar interstitial intravascular fibrinous deposition, and 11. Fibrosis) to ...

Claims

NJB0009PCT CLAIMS 1. A compound of Formula (II), or a pharmaceutically acceptable salt thereof, O O O N I)5 R3is H, optionally substituted C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, or halogen; R4is H, optionally substituted C1-6 alkyl, C1-6 haloalkyl, HO-(C1-4 alkyl)-, H2N-(C1-4 alkyl)-, or Y4-Y3-Y2-Y1-; and each X1, X2, X3, and X4individually is N or CR5with the proviso that no more than two of X1, X2, X3, and X4are N; each R5independently is H, optionally substituted C1-6alkyl, C1-610 haloalkyl, C1-6 alkoxy, halogen, optionally substituted C2-6 alkynyl, hydroxyl, amino, mono-C1-6 alkylamine, di-C1-6alkylamine, COOH, HO-(C1-4alkyl)-, H2N-(C1-4alkyl)-, B(OH)2, or Y4-Y3- Y2-Y1-; Y1is a bond, aryl, heteroaryl, or C1-4 alkyl; Y2is a bond, O, S, N, or NH, wherein when Y2is N then N forms an optionally 15 substituted C5-C7heterocyclic with Y4; Y3is a bond or C=O; and Y4is H, hydroxyl, amino, mono-C1-6 alkylamine, di-C1-6 alkylamine, optionally substituted C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-C6alkanoyl, C1-6alkylthio, COOH, optionally substituted C3-C8cycloalkyl, optionally substituted C4-C8cycloalkenyl, optionally 20 substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C7 heterocyclic, or an amino acid; or Y4together with Y2form an optionally substituted C5-C7heterocyclic; wherein each optionally substituted group of R3, R4, R5, Y2, and Y4independently is optionally substituted with 1 or 2 substituents, wherein each substituent independently is 25 hydroxyl, amino, COOH, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-C6alkanoyl, C1-6alkylthio, cyano, halogen, nitro, mono-C1-6 alkylamine, di-C1-6 alkylamine, C3-C8 cycloalkyl, C4-C8 293NJB0009PCT cycloalkenyl, aryl, heteroaryl, C3-C7heterocyclic, C2-6alkenyl, C2-6alkynyl, H(C=O)-, HO-(C1-2alkyl)-, H2N-(C1-2 alkyl)-, HO-(C1-2 alkyl)-(C=O)-, H2N-(C1-2 alkyl)-(C=O)-, HO-(C1-2 alkyl)- (C=O)-NH-, H2N-(C1-2 alkyl)-(C=O)-NH-, H2N-(C1-2 alkyl)-(C=O)-NH-(C1-2 alkyl)-O-, or B(OH)2. 5 2. The compound of claim 1, wherein the compound comprises an aryl amine or heteroaryl amine moiety.

3. The compound of claim 1, wherein the compound comprises an aniline moiety.

4. The compound of any one of claims 1-3, wherein R3is H or halogen, specifically R3is F. 10 5. The compound of any one of claims 1-4, wherein each of X1, X2, X3, and X4is CR5.

6. The compound of any one of claims 1-4, wherein one of X1, X2, X3, and X4is N, and the remainder are CR5; or X1and X4are N and the remainder are CR5.

7. The compound of any one of claims 1-6, wherein each optionally substituted aryl or optionally substituted heteroaryl of R1, R2, and Y4independently is substituted with amino or 15 H2N-(C1-2 alkyl)-(C=O)-NH-.

8. The compound of any one of claims 1-6, wherein Y1is aryl or heteroaryl; Y2is a bond; Y3is a bond; and Y4is amino (-NH2).

9. The compound of any one of claims 1-6, wherein Y4-Y3-Y2-Y1- is HO-(C1-4 alkyl)-, H2N-(C1-4 alkyl)-, HO-(C1-2 alkyl)-(C=O)-NH-, H2N-(C1-2 alkyl)-(C=O)-NH-, H2N-(C1-2 alkyl)- 20 (C=O)-NH-(C1-2alkyl)-O-, or H2N-(C1-2alkyl)-(C=O)-NH-(C1-2alkyl)-O-(C1-2alkyl)-.

10. The compound of any one of claims 1-9, wherein R4is H, optionally substituted C1-6alkyl, HO-(C1-4 alkyl)-, H2N-(C1-4 alkyl)-, or Y4-Y3-Y2-Y1-.

10. The compound of claim 1, wherein R3is H or halogen, specifically R3is F; R4is H or optionally substituted C1-6alkyl; each of X1, X2, X3, and X4is CR5; and each R5independently is25 H, optionally substituted C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, halogen, optionally substituted C2- 6 alkynyl, hydroxyl, amino, mono-C1-6 alkylamine, di-C1-6 alkylamine, COOH, HO-(C1-4 alkyl)-, H2N-(C1-4alkyl)-, B(OH)2, or Y4-Y3-Y2-Y1-.

11. The compound of claim 10, wherein one, two, or three of X1, X2, X3, and X4is CH, specifically three, and the fourth is CR5where R5is optionally substituted C1-6 alkyl, C1-6 30 haloalkyl, C1-6alkoxy, halogen, optionally substituted C2-6alkynyl, hydroxyl, amino, mono-C1-6294NJB0009PCT alkylamine, di-C1-6alkylamine, COOH, HO-(C1-4alkyl)-, H2N-(C1-4alkyl)-, B(OH)2, or Y4-Y3- Y2-Y1-.

12. The compound of claim 1, wherein R3is H or halogen, specifically R3is F; R4is H or optionally substituted C1-6alkyl; one or two of X1, X2, X3, and X4is N and the remainder are 5 CR5; and each R5independently is H, optionally substituted C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, halogen, optionally substituted C2-6 alkynyl, hydroxyl, amino, mono-C1-6 alkylamine, di-C1-6 alkylamine, COOH, HO-(C1-4alkyl)-, H2N-(C1-4alkyl)-, B(OH)2, or Y4-Y3-Y2-Y1-.

13. The compound of claim 12, wherein one or two of X1, X2, X3, and X4is N and the remainder are CR5wherein one of the R5is not H but is optionally substituted C1-6 alkyl, C1-6 10 haloalkyl, C1-6alkoxy, halogen, optionally substituted C2-6alkynyl, hydroxyl, amino, mono-C1-6alkylamine, di-C1-6alkylamine, COOH, HO-(C1-4alkyl)-, H2N-(C1-4alkyl)-, B(OH)2, or Y4-Y3- Y2-Y1-.

14. The compound of claim 1, wherein R3is H or halogen, specifically R3is F; R4is H or optionally substituted C1-6alkyl; each of X1, X2, X3, and X4is CR5; and each R5independently is15 H, optionally substituted C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, halogen, optionally substituted C2- 6 alkynyl, hydroxyl, amino, mono-C1-6 alkylamine, di-C1-6 alkylamine, COOH, HO-(C1-4 alkyl)-, H2N-(C1-4alkyl)-, B(OH)2, or Y4-Y3-Y2-Y1-; further wherein one of R5is amino, HO-(C1-4alkyl)- , H2N-(C1-4 alkyl)-, HO-(C1-2 alkyl)-(C=O)-NH-, H2N-(C1-2 alkyl)-(C=O)-NH-, H2N-(C1-2 alkyl)- (C=O)-NH-(C1-2 alkyl)-O-(C1-2 alkyl)-, B(OH)2, or phenyl substituted with amino, HO-(C1-4 20 alkyl)-, H2N-(C1-4alkyl)-, HO-(C1-2alkyl)-(C=O)-NH-, H2N-(C1-2alkyl)-(C=O)-NH-, H2N-(C1-2alkyl)-(C=O)-NH-(C1-2alkyl)-O-(C1-2alkyl)-, or B(OH)2.

15. The compound of claim 1-6, wherein R4, R5, or Y4terminates with a hydroxyl, amino, aryl amine, or heteroaryl amine moiety.

16. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, R1N O O 25 95NJB0009PCT wherein each of R1and R2independently is H, optionally substituted C1-6 alkyl, C1-6 haloalkyl, C2- C6 alkanoyl, COOH, optionally substituted aryl, optionally substituted heteroaryl, HO-(C1-4 alkyl)-, or H2N-(C1-4alkyl)-; 5 or R2is H and R1is Y4-Y3-Y2-Y1-; Y1is a bond, aryl, heteroaryl, or C1-4alkyl; Y2is a bond, O, S, N, or NH, wherein when Y2is N then each of R1and R2independently is (Y4-Y3)2-N-Y1-, or the N forms an optionally substituted C5-C7 heterocyclic with Y4; 10 Y3is a bond or C=O; and Y4is H, hydroxyl, amino, mono-C1-6alkylamine, di-C1-6alkylamine, optionally substituted C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C2-C6 alkanoyl, C1-6 alkylthio, COOH, optionally substituted C3-C8 cycloalkyl, optionally substituted C4-C8 cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C7heterocyclic, or an 15 amino acid; or Y4together with Y2form an optionally substituted C5-C7 heterocyclic; R3is H, optionally substituted C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, or halogen; and each X1, X2, X3, and X4individually is N or CR5with the proviso that no more than two of X1, X2, X3, and X4are N; each R5independently is H, optionally substituted C1-6 alkyl, C1-6 20 haloalkyl, C1-6alkoxy, halogen, optionally substituted C2-6alkynyl, hydroxyl, amino, mono-C1-6alkylamine, di-C1-6alkylamine, COOH, HO-(C1-4alkyl)-, H2N-(C1-4alkyl)-, B(OH)2, or Y4-Y3- Y2-Y1-; wherein each optionally substituted group of R1, R2, R3, R5, Y2, and Y4independently is optionally substituted with 1 or 2 substituents, wherein each substituent independently is 25 hydroxyl, amino, COOH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C2-C6 alkanoyl, C1-6 alkylthio, cyano, halogen, nitro, mono-C1-6 alkylamine, di-C1-6 alkylamine, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, aryl, heteroaryl, C3-C7heterocyclic, C2-6alkenyl, C2-6alkynyl, H(C=O)-, HO-(C1-2alkyl)-, H2N-(C1-2 alkyl)-, HO-(C1-2 alkyl)-(C=O)-, H2N-(C1-2 alkyl)-(C=O)-, HO-(C1-2 alkyl)- (C=O)-NH-, H2N-(C1-2 alkyl)-(C=O)-NH-, H2N-(C1-2 alkyl)-(C=O)-NH-(C1-2 alkyl)-O-, or 30 B(OH)2. 296NJB0009PCT 17. The compound of claim 16, wherein the compound comprises an aryl amine or heteroaryl amine moiety, specifically an aniline moiety.

18. The compound of claim 16 or 17, wherein R3is H or halogen, specifically R3is F.

19. The compound of any one of claims 16-18, wherein R2is H. 5 20. The compound of any one of claims 16-19, wherein each of X1, X2, X3, and X4is CR5.

21. The compound of any one of claims 16-19, wherein one of X1, X2, X3, and X4is N, and the remainder are CR5; or X1and X4are N and the remainder are CR5.

22. The compound of any one of claims 16-21, wherein each optionally substituted aryl 10 or optionally substituted heteroaryl of R1, R2, and Y4independently is substituted with amino or H2N-(C1-2alkyl)-(C=O)-NH-.

23. The compound of any one of claims 16-21, wherein Y1is aryl or heteroaryl; Y2is a bond; Y3is a bond; and Y4is amino (-NH2).

24. The compound of any one of claims 16-21, wherein Y4-Y3-Y2-Y1- is HO-(C1-4alkyl)-,15 H2N-(C1-4 alkyl)-, HO-(C1-2 alkyl)-(C=O)-NH-, H2N-(C1-2 alkyl)-(C=O)-NH-, H2N-(C1-2 alkyl)- (C=O)-NH-(C1-2 alkyl)-O-, or H2N-(C1-2 alkyl)-(C=O)-NH-(C1-2 alkyl)-O-(C1-2 alkyl)-.

25. The compound of any one of claims 16-21, wherein R2is optionally substituted C1-6alkyl, HO-(C1-4 alkyl)-, H2N-(C1-4 alkyl)-, or Y4-Y3-Y2-Y1-.

26. The compound of claim 16, wherein R1is optionally substituted C1-6 alkyl, C1-6 20 haloalkyl, C2-C6alkanoyl, COOH, optionally substituted aryl, optionally substituted heteroaryl, HO-(C1-4alkyl)-, H2N-(C1-4alkyl)-, or Y4-Y3-Y2-Y1-; R2is H; R3is H or halogen, specifically R3is F; each of X1, X2, X3, and X4is CR5; optionally further wherein R1is substituted C1-6 alkyl or substituted aryl specifically phenyl, wherein the substitution is hydroxyl, amino, or H2N-(C1-2alkyl)-(C=O)-NH-; and R5is 25 H.

27. The compound of claim 16, wherein R1is optionally substituted C1-6 alkyl, C1-6 haloalkyl, C2-C6alkanoyl, COOH, optionally substituted aryl, optionally substituted heteroaryl, HO-(C1-4 alkyl)-, H2N-(C1-4 alkyl)-, or Y4-Y3-Y2-Y1-; R2is H; R3is H or halogen, specifically R3is F; one of X1, X2, X3, and X4is N and the remainder are CR5; 297NJB0009PCT optionally further wherein R1is substituted C1-6alkyl or substituted aryl specifically phenyl, wherein the substitution is hydroxyl, amino, or H2N-(C1-2 alkyl)-(C=O)-NH-; and R5is H.

28. A compound of Formula (A) or Formula (B) 5 PL*-L-RXFormula (A) (PL*-L)m-Ab Formula (B) wherein L is a linking group; PL* is a structure of Formula (I) or Formula (II) of any one of claims 1-27 or a structure 10 found in Table 1, covalently attached to L through one of R1, R2, R4, or R5; RXis a reactive group suitable for forming a covalent bond to an antibody or antibody fragment; Ab is an antibody or antibody fragment; and m is 1, 2, 3, 4, 5, 6, 7, or 8. 15 29. The compound of claim 28, wherein PL* comprises an aryl amine or heteroaryl amine moiety covalently attached to L through the amine group.

30. The compound of claim 29, wherein the linking group is cleavable.

31. The compound of claim 28, wherein L, the linking group, is a bond or a group containing 1 to about 250 non-hydrogen atoms including C, N, O, S, halogen, or a combination 20 thereof; further wherein L can optionally include one or more groups including an ether, thioether, amide, carbonyl, ester, carbonate, carbamate, urea, one or more repeat structures of the formula O H N ng rom 1 to 32; specifically an integer from 2 to 32; and more 25 specifically n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, or 32; or a combination thereof.

32. The compound of claim 31, wherein L comprises an ethylene glycol unit, specifically about 2 to about 25 repeating ethylene glycol units, more specifically about 5 to about 10 repeating ethylene glycol units; an amino acid unit, specifically 1 to about 12 amino acid units, 298NJB0009PCT more specifically about 2 to about 10 amino acid units, and yet more specifically about 4 to about 8 amino acid units; or a combination thereof.

33. The compound of claim 32, wherein the amino acid groups of L, each amino acid unit can be arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, asparagine, 5 glutamine, cysteine, selenocysteine, glycine, proline, alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, tryptophan, or citrulline (Cit).

34. The compound of any one of claims 28-33, wherein RXis an alkyne, amine, aminooxy (-O-NH2), azide, dibromopyridazinedione, 2,5-dioxopyrrolidin-1-yl formate, a disulfide, dithiophenolmaleimide, a haloacetamide, hydrazino, N-hydroxysuccinimide ester, O 10 maleimide, a monosulfone, a pentafluorophenyl ester, thio .

35. The compound of any one of claims 28-33, whble 2.

36. A pharmaceutical formulation comprising, the compound of any one of claims 1-35 and a pharmaceutically acceptable excipient.

37. A method of treating a proliferative disease including a cancer, comprising 15 administering to a patient in need thereof the compound of any one of claims 1-35 or the pharmaceutical formulation of claim 36.

38. A compound as reported in Table 1, Table 2, Table 3, Table 4, Table 9, Table 10, Table 11, Table 12, or Table 13.

39. A compound comprising one or more repeat structures of the formula O H N 20ng rom 1 to 32; specifically an integer from 2 to 32; and more specifically n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, or 32.

40. The compound of claim 39, as reported in Table 8, Table 9, or Table 10 wherein the 25 payload (PL) is a compound reported in Table 11. 299NJB0009PCT 41. The compound of claim 39, according to Formula (III) OHL1ONN PLXFormula (III) whereiPL is a drug payload; 5 L1is a bond or a linking group; L2is a bond or a linking group; RXis a reactive group suitable for forming a covalent bond to an antibody or antibody fragment; and n is an integer from 1 to 32, specifically 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 10 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, or 32.

42. The compound of claim 41, wherein PL is a compound reported in Table 11.

43. The compound of claim 41, wherein L1is a bond linked to PL via a NH group.

44. The compound of claim 41, wherein L1is a group containing 1 to about 250 non- hydrogen atoms including C, N, O, S, halogen, or a combination thereof; further wherein L1can 15 optionally include one or more groups including an ether, thioether, amide, carbonyl, ester, carbonate, carbamate, urea, or a combination thereof.

45. The compound of claim 41, wherein L1comprises an ethylene glycol unit, specifically about 2 to about 25 repeating ethylene glycol units, more specifically about 5 to about 10 repeating ethylene glycol units; an amino acid unit, specifically 1 to about 12 amino 20 acid units, more specifically about 2 to about 10 amino acid units, and yet more specifically about 4 to about 8 amino acid units; or a combination thereof.

46. The compound of claim 45, wherein the amino acid groups of L2, each amino acid unit can be arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine, cysteine, selenocysteine, glycine, proline, alanine, valine, isoleucine, leucine, 25 methionine, phenylalanine, tyrosine, tryptophan, or citrulline (Cit).

47. The compound of claim 41, wherein L2is a group containing 1 to about 250 non- hydrogen atoms including C, N, O, S, halogen, or a combination thereof; further wherein L2can optionally include one or more groups including an ether, thioether, amide, carbonyl, ester, carbonate, carbamate, urea, or a combination thereof. 300NJB0009PCT 48. The compound of claim 41, wherein L2comprises an ethylene glycol unit, specifically about 2 to about 25 repeating ethylene glycol units, more specifically about 5 to about 10 repeating ethylene glycol units; an amino acid unit, specifically 1 to about 12 amino acid units, more specifically about 2 to about 10 amino acid units, and yet more specifically 5 about 4 to about 8 amino acid units; or a combination thereof.

49. The compound of claim 48, wherein the amino acid groups of L2, each amino acid unit can be arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine, cysteine, selenocysteine, glycine, proline, alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, tryptophan, or citrulline (Cit). 10 50. The compound of any one of claims 41-49, wherein RXis an alkyne, amine, aminooxy (-O-NH2), azide, dibromopyridazinedione, 2,5-dioxopyrrolidin-1-yl formate, a disulfide, dithiophenolmaleimide, a haloacetamide, hydrazino, N-hydroxysuccinimide ester, O maleimide, a monosulfone, a pentafluorophenyl ester, thio .

51. A payload-linker compound reported in Table 115 52. A compound of Formula (IV) OHb Formula (IV) wherein PL is a drug payload; L1is a bond or a linking group; 20 L2is a bond or a linking group; Ab is an antibody or antibody fragment; n is an integer from 1 to 32, specifically 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, or 32; and m is 1, 2, 3, 4, 5, 6, 7, or 8. 301NJB0009PCT 53. The compound of claim 52, wherein PL is a compound reported in Table 11 or Table 1.

54. The compound of claim 52, wherein L1is a bond linked to PL via a NH group.

55. The compound of claim 52, wherein L1is a group containing 1 to about 250 non- 5 hydrogen atoms including C, N, O, S, halogen, or a combination thereof; further wherein L1can optionally include one or more groups including an ether, thioether, amide, carbonyl, ester, carbonate, carbamate, urea, or a combination thereof.

56. The compound of claim 52, wherein L1comprises an ethylene glycol unit, specifically about 2 to about 25 repeating ethylene glycol units, more specifically about 5 to 10 about 10 repeating ethylene glycol units; an amino acid unit, specifically 1 to about 12 amino acid units, more specifically about 2 to about 10 amino acid units, and yet more specifically about 4 to about 8 amino acid units; or a combination thereof.

57. The compound of claim 52, wherein the amino acid groups of L2, each amino acid unit can be arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, asparagine, 15 glutamine, cysteine, selenocysteine, glycine, proline, alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, tryptophan, or citrulline (Cit).

58. The compound of claim 52, wherein L2is a group containing 1 to about 250 non- hydrogen atoms including C, N, O, S, halogen, or a combination thereof; further wherein L2can optionally include one or more groups including an ether, thioether, amide, carbonyl, ester, 20 carbonate, carbamate, urea, or a combination thereof.

59. The compound of claim 52, wherein L2comprises an ethylene glycol unit, specifically about 2 to about 25 repeating ethylene glycol units, more specifically about 5 to about 10 repeating ethylene glycol units; an amino acid unit, specifically 1 to about 12 amino acid units, more specifically about 2 to about 10 amino acid units, and yet more specifically 25 about 4 to about 8 amino acid units; or a combination thereof.

60. The compound of claim 59, wherein the amino acid groups of L2, each amino acid unit can be arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine, cysteine, selenocysteine, glycine, proline, alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, tryptophan, or citrulline (Cit). 30 61. A conjugate as reported in Table 13. 302

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