Anthracycline derivatives and conjugates and uses thereof

Abstract

The specification relates to anthracycline compounds and conjugates thereof. The specification further relates to the use of the compounds and conjugates in treating cancer, and to processes for preparing the compounds and conjugates.

Description

ANTHRACYCLINE DERIVATIVES AND CONJUGATES AND USES THEREOF CROSS-REFERENCE TO RELATED PATENT APPLICATIONS This specification claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 518,651 (filed 10 August 2023) and U.S. Provisional Patent Application No.63 / 631,545 (filed 9 April 2024). The entire contents of the above-referenced patent applications is incorporated by reference into this specification for all purposes. FIELD This specification relates to anthracycline derivatives and to conjugates thereof, as well as to pharmaceutical compositions containing them. This specification further relates to the use of the anthracycline derivatives and conjugates in treating diseases such as cancer. This specification further relates to processes and intermediate compounds involved in the preparation of the anthracycline derivatives and conjugates thereof. BACKGROUND Anthracyclines are a class of potent chemotherapy drugs used in the treatment of cancer. The most commonly used anthracyclines include doxorubicin, daunorubicin and idarubicin. These compounds have been used in wide range of therapeutics including breast cancer, leukaemia, lymphomas, and in other solid tumours. The mechanism of action for anthracyclines primarily involves DNA intercalation, inhibition of topoisomerase II, and the generation of free radicals, ultimately leading to DNA damage and apoptosis of cancer cells. However, the clinical use of anthracyclines is often limited by their systemic toxicity and does-dependent side effects (as a result of their high potency). To mitigate the potential toxic effects of anthracyclines, various strategies have been used. Recently, targeted therapy approach has been utilized to minimize side effects of anthracyclines. One such approach is the design of anthracycline antibody-drug conjugates (ADCs). ADCs utilize the targeting capabilities of monoclonal antibodies (mAbs) to selectively deliver cytotoxic payloads (such as anthracyclines) to tumour cells. This selective delivery can increase the efficacy of the cytotoxic payloads while minimizing systemic toxicity. Several anthracycline ADCs have been investigated in preclinical and clinical settings. Doxorubicin and daunorubicin have been used in early examples of anthracycline ADCs. More recently, morpholino derivatives such as nemorubicin and its metabolite PNU-159682 have been developed and used in ADCs. These morpholino derivatives are reportedly highly potent while having reducedcardiotoxicity; however, off-target toxicity is still seen in ADCs incorporating these derivatives, as a result of their extremely high potency.There remains a need for anthracycline derivatives having attenuated potency and / or favourable lysosomal stability and / or favourable physicochemical properties, such as solubility and permeability, allowing for a wider therapeutic window and reduced side effects. The anthracycline derivatives and conjugates of the present disclosure may be used for the treatment of diseases such as cancer. SUMMARY According to one aspect, there is provided a compound of Formula (Ia): A-E-X-Y-Z or a pharmaceutically acceptable salt thereof, wherein A is:E is: (ii) a bicyclic 7-10 membered saturated heterocycle containing two nitrogen atoms and optionally an oxygen atom, wherein one nitrogen atom in the heterocycle is connected to A and the second nitrogen atom in the heterocycle is connected to X;(ii) a monocyclic 5-8 membered saturated heterocycle containing two nitrogen atoms, wherein one nitrogen atom in the heterocycle is connected to A and the second nitrogen atom in the heterocycle is connected to X, optionally wherein the heterocycle is geminally substituted on a carbon atom with two occurrences of C1-3alkyl; provided that when E is a piperazine, the piperazine is geminally substituted on a carbon atom with two occurrences of C1-3alkyl; (iii) -NR-heterocycle- wherein the heterocycle is a saturated 5-8 membered heterocycle containing a nitrogen atom which is connected to X; and wherein a carbon atom in the heterocycle connects to -NR-; or (iv) -heterocycle-NR- or -heterocycle-C(O)NH- wherein the heterocycle is a saturated 5-8 membered heterocycle containing a nitrogen atom which is connected to A; and wherein a carbon atom in the heterocycle connects to -NR- or - C(O)NH-; R is H, C1-4alkyl or C3-4cycloalkyl; X is absent, -C(O)CH2O-*, -C(O)CH2NH-*, or -Xa-(CH2)m-Xb-, wherein Xbis connected to Y; Xais - C(O)- or absent; and Xbis -C(O)NH-*, -O- or -NH-, wherein * indicates the point of attachment to Y; m is 2 or 3; Y is absent or, wherein the wavy line indicates the point of attachment to X and the asterisk-wavy line indicates the point of attachment to Z; ya and yb are each independently selected from 0, 1, 2 and 3; and Q is NH, -N(C1-3alkyl)-, S, O, - S(CH2)2NH-*, -O(CH2)2NH-* or -NH(CH2)2NH-*, wherein * indicates the point of attachment to Z; Z is H, C1-4 alkyl, -C(O)C1-4 alkyl,integer from 1 to 5; and each Rzis independently H, C1-4 alkyl, phenyl or benzyl. According to another aspect of the specification, there is provided a compound of Formula (I): A-E-X-Y-Z or a pharmaceutically acceptable salt thereof,wherein A is:E is: (i) a bicyclic 7-10 membered saturated heterocycle containing two nitrogen atoms and optionally an oxygen atom, wherein one nitrogen atom in the heterocycle is connected to A and the second nitrogen in the heterocycle is connected to X; (ii) a monocyclic 5-8 membered saturated heterocycle containing two nitrogen atoms, wherein one nitrogen atom in the heterocycle is connected to A and the second nitrogen in the heterocycle is connected to X, optionally wherein the heterocycle is geminally substituted on a carbon atom with two occurrences of C1-3 alkyl; provided that when E is a piperazine, the piperazine is geminally substituted on a carbon atom with two occurrences of C1-3 alkyl; (iii) -NR-heterocycle- wherein the heterocycle is a saturated 5-8 membered heterocycle containing a nitrogen atom which is connected to X; and wherein a carbon atom in the heterocycle connects to -NR-; or (iv) -heterocycle-NR- or -heterocycle-C(O)NH- wherein the heterocycle is a saturated 5-8 membered heterocycle containing a nitrogen atom which is connected to A; and wherein a carbon atom in the heterocycle connects to -NR- or - C(O)NH-; R is H, C1-4 alkyl or C3-4 cycloalkyl; X is absent, -C(O)CH2O-*, -C(O)CH2NH-*, or -Xa-(CH2)m-Xb-, wherein Xbis connected to Y; Xais - C(O)- or absent; and Xbis -C(O)NH-*, -O- or -NH-, wherein * indicates the point of attachment to Y; m is 2 or 3; Y is absent or, wherein the wavy line indicates the point of attachment to X and the asterisk-wavy line indicates the point of attachment to Z; and Q is NH, S, O, -S(CH2)2NH-*, -O(CH2)2NH-* or -NH(CH2)2NH-*, wherein * indicates the point of attachment to Z; Z is H, C1-4 alkyl, -C(O)C1-4 alkyl,integer from 1 to 5; and each Rzis independently H, C1-4 alkyl, phenyl or benzyl; provided that when E is -heterocycle-C(O)NH-, then X is absent or -(CH2)m-Xb-; and provided that when Z is -C(O)C1-4alkyl,absent, then Xbis not -C(O)NH-. According to another aspect, there is provided a compound of Formula (IIa): or a pharmaceutically acceptable salt thereof, wherein A is:E1is: i) -NR-; ii) a 5-10 membered saturated heterocycle containing two nitrogen atoms and optionally an oxygen atom, wherein one nitrogen atom in the heterocycle is connected to A and the second nitrogen atom in the heterocycle is connected to X1; optionally wherein theheterocycle is geminally substituted on a carbon atom with two occurrences of C1-3 alkyl; iii) -NR-heterocycle- wherein the heterocycle is a saturated 5-8 membered heterocycle containing a nitrogen atom which is connected to X1; and wherein a carbon atom in the heterocycle connects to -NR-; or iv) -heterocycle-NR- or -heterocycle-C(O)NH- wherein the heterocycle is a saturated 5-8 membered heterocycle containing a nitrogen atom which is connected to A; and wherein a carbon atom in the heterocycle connects to -NR- or -C(O)NH-; R is H, C1-4 alkyl or C3-4 cycloalkyl; X1is absent, -C(O)CH2O-*, -C(O)CH2NH-*, or -Xa-(CH2)m-Xb-, wherein Xbis connected to Y1; Xais - C(O)- or absent; Xbis -C(O)NH-*, -O- or -NH-, wherein * indicates the point of attachment to Y1; m is 2 or 3;, wherein the wavy line indicates the point of attachment to X1and the asterisk-wavy line indicates the point of attachment to Z1; ya and yb are each independently selected from 0, 1, 2 and 3; and Q is NH, -N(C1-3alkyl)-, S, O, -S-(CH2)2NH-*, -O- (CH2)2NH-* or -NH-(CH2)2NH-*, wherein * indicates the point of attachment to Z1; Z1is H, C1-4 alkyl, C(O)C1-4 alkyl,and each Rzis independently H, C1-4 alkyl, phenyl or benzyl. According to another aspect, there is provided a compound of Formula (II): A-E1-X1-Y1-Z1or a pharmaceutically acceptable salt thereof, wherein A is:E1is: i) -NR-; ii) a 5-10 membered saturated heterocycle containing two nitrogen atoms and optionally an oxygen atom, wherein one nitrogen atom in the heterocycle is connected to A and the second nitrogen in the heterocycle is connected to X1; optionally wherein the heterocycle is geminally substituted on a carbon atom with two occurrences of C1-3 alkyl; iii) -NR-heterocycle- wherein the heterocycle is a saturated 5-8 membered heterocycle containing a nitrogen atom which is connected to X1; and wherein a carbon atom in the heterocycle connects to -NR-; or iv) -heterocycle-NR- or -heterocycle-C(O)NH- wherein the heterocycle is a saturated 5-8 membered heterocycle containing a nitrogen atom which is connected to A; and wherein a carbon atom in the heterocycle connects to -NR- or -C(O)NH-; R is H, C1-4 alkyl or C3-4 cycloalkyl; X1is absent, -C(O)CH2O-*, -C(O)CH2NH-*, or -Xa-(CH2)m-Xb-, wherein Xbis connected to Y1; Xais - C(O)- or absent; Xbis -C(O)NH-*, -O- or -NH-, wherein * indicates the point of attachment to Y1; m is 2 or 3; provided that when E1is -NR- or -heterocycle-C(O)NH-, then X1is absent or -(CH2)m- Xb-; Y1is, wherein the wavy line indicates the point of attachment to X1and the asterisk-wavy line indicates the point of attachment to Z1; and Q is NH, S, O, -S-(CH2)2NH-*, -O- (CH2)2NH-* or -NH-(CH2)2NH-*, wherein * indicates the point of attachment to Z1;Z1is H, C1-4 alkyl, C(O)C1-4 alkyl,integer from 1 to 5; and each Rzis independently H, C1-4 alkyl, phenyl or benzyl. In a further aspect there is provided a pharmaceutical composition comprising a compound of Formula (Ia) or (IIa), or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. In a further aspect there is provided a pharmaceutical composition comprising a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. In a further aspect there is provided a compound of Formula (Ia) or (IIa), or a pharmaceutically acceptable salt thereof, for use in therapy. In a further aspect there is provided a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, for use in therapy. In a further aspect there is provided a compound of Formula (Ia) or (IIa), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer. In a further aspect there is provided a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer. In a further aspect there is provided the use of a compound of Formula (Ia) or (IIa), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament. In a further aspect there is provided the use of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament. In a further aspect there is provided the use of a compound of Formula (Ia) or (IIa), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer. In a further aspect there is provided the use of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer. In a further aspect there is provided a method of treating cancer in a patient comprising administering to the patient an effective amount of a compound of Formula (Ia) or (IIa), or a pharmaceutically acceptable salt thereof. In a further aspect there is provided a method of treating cancer in a patient comprising administering to the patient an effective amount of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof.In further aspects, there are provided methods and intermediates for preparing compounds of Formula (Ia) or (IIa), or a pharmaceutically acceptable salt thereof. In further aspects, there are provided methods and intermediates for preparing compounds of Formula (I) or (II), or a pharmaceutically acceptable salt thereof. According to another aspect, there is provided a compound of Formula (IIIa): A-E-X-Y-L1or a salt thereof, wherein A, E and X are as defined herein; and Y is absent or, wherein the wavy line indicates the point of attachment to X and the asterisk-wavy line indicates the point of attachment to L1; ya and yb are each independently selected from 0, 1, 2 and 3; and Q is NH, -N(C1-3alkyl)-, S, O, -S(CH2)2NH-*, - O(CH2)2NH-* or -NH(CH2)2NH-*, wherein * indicates the point of attachment to L1; and L1is a linker for connection to an antibody or antigen-binding fragment thereof. According to one aspect, there is provided a compound of Formula (III): A-E-X-Y-L1or a salt thereof, wherein A, E and X are as defined herein; and Y is absent or, wherein the wavy line indicates the point of attachment to X and the asterisk-wavy line indicates the point of attachment to L1; and Q is NH, S, O, -S(CH2)2NH-*, - O(CH2)2NH-* or -NH(CH2)2NH-*, wherein * indicates the point of attachment to L1; and L1is a linker for connection to an antibody or antigen-binding fragment thereof. According to another aspect, there is provided a compound of Formula (IVa): A-E1-X1-Y1-L1or a salt thereof,wherein A, E1and X1are as defined herein; Y1is, wherein the wavy line indicates the point of attachment to X1and the asterisk-wavy line indicates the point of attachment to L1; ya and yb are each independently selected from 0, 1, 2 and 3; and Q is NH, -N(C1-3alkyl)-, S, O, -S(CH2)2NH-*, -O(CH2)2NH-* or - NH(CH2)2NH-*, wherein * indicates the point of attachment to L1; and L1is a linker for connection to an antibody or antigen-binding fragment thereof. According to another aspect, there is provided a compound of Formula (IV): A-E1-X1-Y1-L1or a salt thereof, wherein A, E1and X1are as defined herein; Y1is, wherein the wavy line indicates the point of attachment to X1and the asterisk-wavy line indicates the point of attachment to L1; and Q is NH, S, O, -S(CH2)2NH-*, - O(CH2)2NH-* or -NH(CH2)2NH-*, wherein * indicates the point of attachment to L1; and L1is a linker for connection to an antibody or antigen-binding fragment thereof. In further aspects, there are provided methods for preparing compounds of Formula (III) or (IV), or a salt thereof. In further aspects, there are provided methods for preparing compounds of Formula (IIIa) or (IVa), or a salt thereof. According to one aspect, there is provided a conjugate of Formula (Va): (A-E-X-Y-L2)k-Ab or a pharmaceutically acceptable salt thereof, wherein each A, E and X is as defined herein, Y is absent or, wherein the wavy line indicates the point of attachment to X and the asterisk-wavy line indicates the point of attachment to L2; ya and yb are eachindependently selected from 0, 1, 2 and 3; and Q is NH, -N(C1-3alkyl)-, S, O, -S(CH2)2NH-*, - O(CH2)2NH-* or -NH(CH2)2NH-*, wherein * indicates the point of attachment to L2; each L2is a linker, k is an integer from 1 to 10, and Ab is an antibody or antigen-binding fragment thereof. According to another aspect, there is provided a conjugate of Formula (V): (A-E-X-Y-L2)k-Ab or a pharmaceutically acceptable salt thereof, wherein each A, E and X is as defined herein, Y is absent or, wherein the wavy line indicates the point of attachment to X and the asterisk-wavy line indicates the point of attachment to L2; and Q is NH, S, O, -S(CH2)2NH-*, - O(CH2)2NH-* or -NH(CH2)2NH-*, wherein * indicates the point of attachment to L2; each L2is a linker, k is an integer from 1 to 10, and Ab is an antibody or antigen-binding fragment thereof. According to another aspect, there is provided a conjugate of Formula (VIa): (A-E1-X1-Y1-L2)k-Ab or a pharmaceutically acceptable salt thereof, wherein each A, E1and X1is as defined herein, Y1is, wherein the wavy line indicates the point of attachment to X1and the asterisk-wavy line indicates the point of attachment to L2; ya and yb are each independently selected from 0, 1, 2 and 3; and Q is NH, -N(C1-3alkyl)-, S, O, -S(CH2)2NH-*, -O(CH2)2NH-* or - NH(CH2)2NH-*, wherein * indicates the point of attachment to L2; each L2is a linker, k is an integer from 1 to 10, and Ab is an antibody or antigen-binding fragment thereof. According to another aspect, there is provided a conjugate of Formula (VI):(A-E1-X1-Y1-L2)k-Ab or a pharmaceutically acceptable salt thereof, wherein each A, E1and X1is as defined herein, Y1is, wherein the wavy line indicates the point of attachment to X1and the asterisk-wavy line indicates the point of attachment to L2; and Q is NH, S, O, -S(CH2)2NH-*, - O(CH2)2NH-* or -NH(CH2)2NH-*, wherein * indicates the point of attachment to L2; each L2is a linker, k is an integer from 1 to 10, and Ab is an antibody or antigen-binding fragment thereof. In a further aspect there is provided a pharmaceutical composition comprising a conjugate of Formula (Va) or (VIa), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In a further aspect there is provided a pharmaceutical composition comprising a conjugate of Formula (V) or (VI), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In a further aspect there is provided a conjugate of Formula (Va) or (VIa), or a pharmaceutically acceptable salt thereof, for use in therapy. In a further aspect there is provided a conjugate of Formula (V) or (VI), or a pharmaceutically acceptable salt thereof, for use in therapy. In a further aspect there is provided a conjugate of Formula (Va) or (VIa), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer. In a further aspect there is provided a conjugate of Formula (V) or (VI), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer. In a further aspect there is provided the use of a conjugate of Formula (Va) or (VIa), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament. In a further aspect there is provided the use of a conjugate of Formula (V) or (VI), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament. In a further aspect there is provided the use of a conjugate of Formula (Va) or (VIa), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer. In a further aspect there is provided the use of a conjugate of Formula (V) or (VI), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.In a further aspect there is provided a method of treating cancer in a patient comprising administering to the patient an effective amount of a conjugate of Formula (Va) or (VIa), or a pharmaceutically acceptable salt thereof. In a further aspect there is provided a method of treating cancer in a patient comprising administering to the patient an effective amount of a conjugate of Formula (V) or (VI), or a pharmaceutically acceptable salt thereof. In a further aspect there is provided a method of preparing a conjugate of Formula (Va) or (VIa), or a pharmaceutically acceptable salt thereof, by reacting a compound of Formula (IIIa) or (IVa), respectively, or a salt thereof, with an antibody or an antigen-binding fragment thereof. In a further aspect there is provided a method of preparing a conjugate of Formula (V) or (VI), or a pharmaceutically acceptable salt thereof, by reacting a compound of Formula (III) or (IV), respectively, or a salt thereof, with an antibody or an antigen-binding fragment thereof. BRIEF DESCRIPTION OF THE DRAWINGS Figures 1A-1C depict results from in vitro studies described in Example 57, demonstrating inhibitory activity of payloads of the present disclosure against various cancer cell lines, compared to PNU-159682. Figures 2A-2B depict results from in vivo studies described in Example 59, demonstrating effect of anti-HER2 ADCs (ADC-1 to ADC-6) and negative control ADCs (Control ADCs 1-6) on tumour growth in xenograft models. DETAILED DESCRIPTION Definitions So that the present specification may be more readily understood, certain terms are explicitly defined below. In addition, definitions are set forth as appropriate throughout the detailed description. Where examples are provided for a definition, they are not limiting. The prefix Cx-y, where x and y are integers, indicates the numerical range of carbon atoms that are present in a group. As used herein the term “alkyl” refers to a saturated, linear or branched, hydrocarbon radical having the specified number of carbon atoms. Examples of C1-3 alkyl groups include methyl (Me), ethyl (Et), n-propyl (nPr), and i-propyl (iPr). Examples of C1-4 alkyl groups include methyl (Me), ethyl (Et), n-propyl (nPr), i-propyl (iPr), n-butyl (nBu), i-butyl (iBu), s-butyl (sBu), and t-butyl (tBu). Examples of C1-6 alk l i l d th l th l l i l b t l i-butyl, s-butyl, t-butyl, n-pentyland n-hexyl. As used herein the term “cycloalkyl” refers to a saturated, cyclic hydrocarbon radical having the specified number of carbon atoms. Examples of C3-4 cycloalkyl groups include cyclopropyl and cyclobutyl. As used herein the term “heterocycle” refers to a ring structure containing the specified number of ring atoms (referred to as “members”), wherein one or more of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur, unless otherwise defined), with the remaining ring atoms being carbon. A heterocycle may be monocyclic or multicyclic (e.g. bicyclic), unless otherwise specified. As used herein the term “bicyclic” refers to a fused, bridged or spirocyclic bicyclic ring. Certain embodiments of this specification include a heterocycle which is said to optionally contain an oxygen atom. In further embodiments said heterocycle does not contain an oxygen atom. Certain embodiments of this specification recite a saturated heterocycle that contains more than one heteroatom. In such embodiments, the heteroatoms present in the heterocycle may be non- adjacent (i.e. the heteroatoms may be separated by at least one carbon atom in the heterocycle). As used herein,refers to a ring; for example, is ring F1. As used herein the term “linker for connection to an antibody, or antigen-binding fragment thereof” refers to a group of atoms capable of forming a covalent bond to an antibody, or antigen- binding fragment thereof, through a chemical reaction. For example, the linker in the compound of Formula (III), (IIIa), (IV) or (IVa) (e.g. the compound of Formula (III) or (IV)) enables the formation of a covalent bond between said compound and an antibody or antigen-binding fragment thereof. Accordingly, an antibody-drug conjugate (ADC) derivatised from the compound of Formula (III), (IIIa), (IV) or (IVa) (e.g. the compound of Formula (III) or (IV)) may be formed, for example a conjugate of Formula (V), (Va), (VI) or (VIa) (e.g. a conjugate of Formula (V) or (VI)), or a pharmaceutically acceptable salt thereof may be formed. As used herein the term “conjugation group for conjugation to an antibody, or antigen-binding fragment thereof” refers to an atom or group of atoms capable of forming a covalent bond to an antibody, or antigen-binding fragment thereof, through a chemical reaction. The use of “ ” (referred to as a “wavy line”), “ ” (referred to as an “asterisk-wavy line”), or “ ” in formulae of this specification denotes the point of covalent attachment to a chemical moiety. indicates the point of attachment to an antibody, or antigen-binding fragment thereof.Certain embodiments of this specification include a group which is said to be “optionally substituted”. In further embodiments said group is unsubstituted. Certain embodiments in this specification include a group that can be “absent”. Where a group is absent, the groups on either side of this are linked by a direct covalent bond. For example, in some embodiments of Formula (II) or (IIa) (e.g. Formula (II)), X1is absent; in such embodiments, Formula (II) or (IIa) (e.g. Formula (II)) could be rewritten as: A-E1-Y1-Z1. As another example, in some embodiments of Formula (II) or (IIa) (e.g. Formula (II)), X1is -Xa-(CH2)m-Xb-, wherein Xais absent; in such embodiments, X1can be described as -(CH2)m-Xb-. Units, prefixes, and symbols are denoted in their International System of Units (SI) accepted form. Numeric ranges are inclusive of the numbers defining the range. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure is related. For example, the Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd ed., 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 3rd ed., 1999, Academic Press; and the Oxford Dictionary of Biochemistry and Molecular Biology, Revised, 2000, Oxford University Press, provide one of skill with a general dictionary of many of the terms used in this disclosure. Compounds of Formula (I), (Ia), (II) and (IIa) In one aspect, this specification provides a compound of Formula (Ia), or a pharmaceutically acceptable salt thereof, as defined above. In another aspect, this specification provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined above. In another aspect, this specification provides a compound of Formula (IIa), or a pharmaceutically acceptable salt thereof, as defined above. In another aspect, this specification provides a compound of Formula (II), or a pharmaceutically acceptable salt thereof, as defined above. The compounds of Formulae (I), (Ia), (II) or (IIa) (e.g. the compounds of Formula (I) and (II)), or pharmaceutically acceptable salts thereof, are anthracycline derivatives. These compounds may be useful in the treatment of cancer. The compounds may be directly administered to a patient for treating cancer. Alternatively, the compounds may be used to prepare ADCs, which may be administered to a patient for treating cancer (such as conjugates of Formula (V), (Va), (VI) or (VIa), e.g. conjugates of Formula (V) or (VI), or a pharmaceutically acceptable salt thereof, as disclosed herein). In such instances, the compounds of Formulae (I), (Ia), (II) or (IIa) (e.g. the compounds of Formulae (I) or (II)), or pharmaceutically acceptable salts thereof, may be referred to as payloads.The payloads may be released from the ADC at a target site, for example via enzymatic cleavage of a linker portion of the ADC. Compounds of Formula (I), (Ia), (II) or (IIa) (e.g. compounds of Formula (I) or (II)), or a pharmaceutically acceptable salt thereof, may have attenuated potency compared to known anthracyclines, such as PNU-159682. Compounds of Formula (I), (Ia), (II) or (IIa) (e.g. compounds of Formula (I) or (II)) may exhibit advantageous physicochemical properties (for example, lower lipophilicity, higher aqueous solubility, higher permeability and / or lower plasma protein binding), and / or favourable toxicity profiles (for example a decreased activity at hERG), and / or favourable metabolic or pharmacokinetic profiles, in comparison with known anthracyclines. Compounds of Formula (I), (Ia), (II) or (IIa) (e.g. compounds of Formula (I) or (II)) may exhibit favourable lysosomal stability. Any of these properties may result in a wider therapeutic window compared to known anthracyclines and conjugates (e.g. ADCs) thereof; thus reducing side effects. As such, the compounds of Formula (I), (Ia), (II) or (IIa) (e.g. the compounds of Formula (I) or (II)) and conjugates thereof may be especially suitable as therapeutic agents, such as for the treatment of cancer. Compounds of Formula (I) and (Ia) In one aspect, provided herein is a compound of Formula (Ia): A-E-X-Y-Z or a pharmaceutically acceptable salt thereof, wherein A is:E is: i) a bicyclic 7-10 membered saturated heterocycle containing two nitrogen atoms and optionally an oxygen atom, wherein one nitrogen atom in the heterocycle is connected to A and the second nitrogen atom in the heterocycle is connected to X;(ii) a monocyclic 5-8 membered saturated heterocycle containing two nitrogen atoms, wherein one nitrogen atom in the heterocycle is connected to A and the second nitrogen atom in the heterocycle is connected to X, optionally wherein the heterocycle is geminally substituted on a carbon atom with two occurrences of C1-3alkyl; provided that when E is a piperazine, the piperazine is geminally substituted on a carbon atom with two occurrences of C1-3alkyl;iii) -NR-heterocycle- wherein the heterocycle is a saturated 5-8 membered heterocycle containing a nitrogen atom which is connected to X; and wherein a carbon atom in the heterocycle connects to -NR-; or iv) -heterocycle-NR- or -heterocycle-C(O)NH- wherein the heterocycle is a saturated 5-8 membered heterocycle containing a nitrogen atom which is connected to A; and wherein a carbon atom in the heterocycle connects to -NR- or - C(O)NH-; R is H, C1-4alkyl or C3-4cycloalkyl; X is absent, -C(O)CH2O-*, -C(O)CH2NH-*, or -Xa-(CH2)m-Xb-, wherein Xbis connected to Y; Xais - C(O)- or absent; and Xbis -C(O)NH-*, -O- or -NH-, wherein * indicates the point of attachment to Y; m is 2 or 3; Y is absent or, wherein the wavy line indicates the point of attachment to X and the asterisk-wavy line indicates the point of attachment to Z; ya and yb are each independently selected from 0, 1, 2 and 3; and Q is NH, -N(C1-3alkyl)-, S, O, - S(CH2)2NH-*, -O(CH2)2NH-* or -NH(CH2)2NH-*, wherein * indicates the point of attachment to Z; Z is H, C1-4 alkyl, C(O)C1-4 alkyl,integer from 1 to 5; and each Rzis independently H, C1-4 alkyl, phenyl or benzyl. In another aspect, provided herein is a compound of Formula (I): A-E-X-Y-Z or a pharmaceutically acceptable salt thereof,wherein A is:E is: i) a bicyclic 7-10 membered saturated heterocycle containing two nitrogen atoms and optionally an oxygen atom, wherein one nitrogen atom in the heterocycle is connected to A and the second nitrogen in the heterocycle is connected to X; ii) a monocyclic 5-8 membered saturated heterocycle containing two nitrogen atoms, wherein one nitrogen atom in the heterocycle is connected to A and the second nitrogen in the heterocycle is connected to X, optionally wherein the heterocycle is geminally substituted on a carbon atom with two occurrences of C1-3 alkyl; provided that when E is a piperazine, the piperazine is geminally substituted on a carbon atom with two occurrences of C1-3 alkyl;iii) -NR-heterocycle- wherein the heterocycle is a saturated 5-8 membered heterocycle containing a nitrogen atom which is connected to X; and wherein a carbon atom in the heterocycle connects to -NR-; or iv) -heterocycle-NR- or -heterocycle-C(O)NH- wherein the heterocycle is a saturated 5-8 membered heterocycle containing a nitrogen atom which is connected to A; and wherein a carbon atom in the heterocycle connects to -NR- or - C(O)NH-; R is H, C1-4 alkyl or C3-4 cycloalkyl; X is absent, -C(O)CH2O-*, -C(O)CH2NH-*, or -Xa-(CH2)m-Xb-, wherein Xbis connected to Y; Xais - C(O)- or absent; Xbis -C(O)NH-*, -O- or -NH-, wherein * indicates the point of attachment to Y; m is 2 or 3; Y is absent or, wherein the wavy line indicates the point of attachment to X and the asterisk-wavy line indicates the point of attachment to Z; and Q is NH, S, O, -S(CH2)2NH-*, -O(CH2)2NH-* or -NH(CH2)2NH-*, wherein * indicates the point of attachment to Z; Z is H, C1-4alkyl, -C(O)C1-4alkyl,integer from 1 to 5; and each Rzis independently H,alkyl, phenyl or benzyl; provided that when E is -heterocycle-C(O)NH-, then X is absent or –(CH2)m-Xb-; and provided that when Z is -C(O)C1-4 alkyl,absent, then Xbis not -C(O)NH-. Unless otherwise specified, the following embodiments relate to compounds of Formula (I) or to compounds of Formula (Ia). In embodiments, A is:. In other embodiments, A is:In embodiments, E is a) a bicyclic 7-10 membered saturated heterocycle containing two nitrogen atoms and optionally an oxygen atom, wherein one nitrogen atom in the heterocycle is connected to A and the second nitrogen in the heterocycle is connected to X; b) -NR-heterocycle- wherein the heterocycle is a saturated 5-8 membered heterocycle containing a nitrogen atom which is connected to X; and wherein a carbon atom in the heterocycle connects to -NR-; or c) -heterocycle- NR- or -heterocycle-C(O)NH- wherein the heterocycle is a saturated 5-8 membered heterocycle containing a nitrogen atom which is connected to A; and wherein a carbon atom in the heterocycle connects to -NR- or -C(O)NH-. In embodiments, E is selected from:wherein Ring Eais a bicyclic 7-10 membered saturated heterocycle having the two nitrogen atoms shown and optionally an oxygen atom, and Ring Ebis a bicyclic 5-8 membered saturated heterocycle having the nitrogen atom shown; wherein the wavy line indicates the point of attachment to A and the asterisk-wavy line indicates the point of attachment to X. In embodiments, E is:wherein Ring Eais a bicyclic 7-10 membered saturated heterocycle having the two nitrogen atoms shown and optionally an oxygen atom, and the wavy line indicates the point of attachment to A and the asterisk-wavy line indicates the point of attachment to X. In embodiments, the bicyclic heterocycle of Ring Eais a bridged bicycle. In further embodiments, the bicyclic heterocycle is a 7-8 membered bridged bicycle.In embodiments, E is selected from:wherein the wavy line indicates the point of attachment to A and the asterisk-wavy line indicates the point of attachment to X. In further embodiments, E is selected from:. In further embodiments, E is selected from: .In further embodiments, E is , optionally . In embodiments, the bicyclic heterocycle of Ring Eais a spirocycle. In further embodiments, the bicyclic heterocycle is an 8-9 membered spirocycle. In embodiments in which Ring Eais a spirocycle, the two nitrogen atoms present in the heterocycle of Ring Eaare in the same ring of the spirocycle. In embodiments, E is selected from:wherein the wavy line indicates the point of attachment to A and the asterisk-wavy line indicates the point of attachment to X.In further embodiments. In embodiments in which Ring Eais a spirocycle, the two nitrogen atoms present in the heterocycle of Ring Eaare in separate rings of the spirocycle. In embodiments, E is selected from:wherein the wavy line indicates the point of attachment to A and the asterisk-wavy line indicates the point of attachment to X. In embodiments, the bicyclic heterocycle of Ring Eais a fused bicycle. In further embodiments, the bicyclic heterocycle is an 8-membered fused bicycle. In further embodiments,. In embodiments, E is , wherein Ring Ecis a monocyclic 5-8 membered saturated heterocycle having the two nitrogen atoms shown, optionally wherein the heterocycle is geminally substituted on a carbon atom with two occurrences of C1-3alkyl; provided that when E is a piperazine, the piperazine is geminally substituted on a carbon atom with two occurrences of C1-3 alkyl; and wherein the wavy line indicates the point of attachment to A and the asterisk-wavy line indicates the point of attachment to X. In embodiments, the heterocycle of Ring Ecis geminally substituted on a carbon atom with two occurrences of C1-3 alkyl. In further embodiments, the geminal substituent is geminal dimethyl. In embodiments, Ring Ecis a piperazine geminally substituted on a carbon atom with two occurrences of C1-3alkyl. In further embodiments, the geminal substituent is geminal dimethyl.In embodiments, E is selected from:and the asterisk-wavy line indicates the point of attachment to X. In further embodiments E is. In embodiments, Ring Ecis a monocyclic 5, 7 or 8 membered saturated heterocycle having the two nitrogen atoms shown, wherein the heterocycle is unsubstituted. In further embodiments, E is:wherein the wavy line indicates the point of attachment to A and the asterisk-wavy line indicates the point of attachment to X. In further embodiments E is. In embodiments, E is -NR-heterocycle- wherein the heterocycle is a saturated 5-8 membered heterocycle containing a nitrogen atom which is connected to X; and wherein a carbon atom in the heterocycle connects to -NR-. In further embodiments,, wherein ring Edis a monocyclic 5-8 membered saturated heterocycle having the nitrogen atom shown; wherein the wavy line indicates the point of attachment to A and the asterisk-wavy line indicates the point of attachment to X. In further embodiments, ring Edis a piperidine.In embodiments, E is wherein the wavy line indicates the point of attachment to A and the asterisk-wavy line indicates the point of attachment to X. In embodiments, E is -heterocycle-C(O)NH-, wherein the heterocycle is a saturated 5-8 membered heterocycle containing a nitrogen atom which is connected to A; and wherein a carbon atom in the heterocycle connects to -C(O)NH-. In further embodiments,, wherein ring Ebis a bicyclic 5-8 membered saturated heterocycle having the nitrogen atom shown; wherein the wavy line indicates the point of attachment to A and the asterisk-wavy line indicates the point of attachment to X. In further embodiments, the heterocycle is a bridged bicyclic heterocycle. In embodiments, E is:wherein the wavy line indicates the point of attachment to A and the asterisk-wavy line indicates the point of attac In further embodiments, E is:. In further mbodimen 2 O embo ts, R her Nd is eH *hment to X. . further embodiments, E is:iments, R is C3-4 cycloalkyl. In further embod C alkyl. In further embodiments, R is meth in * indicates the point of attachment to Y. In embodiments, X is -C(O)CH2NH-*, wherein * indicates the point of attachment to Y. In embodiments, X is -Xa-(CH2)m-Xb-, wherein Xais -C(O)- or absent; Xbis -C(O)NH-*, -O- * . In embodiments, R is H N N NHiments, R is cyclopropyl. In further e1-4yl. In embodiments, X is absent. Where X is absent, Formula (I) or (Ia) (e.g. Formula (I)) may be rewritten as: A-E-Y-Z. In embodiments, X is -C(O)CHO-*, w or -NH-, wherein * indicates the point of attachment to Y; and m is 2 or 3. In further embodiments, m is 2. In further embodiments Xais -C(O)- In further embodiments Xais absent (i.e. X is –(CH2)m-Xb-). Infurther embodiments, Xbis -C(O)NH-*, wherein * indicates the point of attachment to Y. In further embodiments, Xbis -O-. In further embodiments, Xbis -NH-. In embodiments, X is selected from, wherein the wavy line indicates the point of attachment to E and the asterisk-wavy line indicates the point of attachment to Y. In further embodiments, X is. In embodiments, E is -heterocycle-C(O)NH- and X is absent. In further embodiments, E is - heterocycle-C(O)NH-, X is -Xa-(CH2)m-Xb- and Xais absent (i.e. X is –(CH2)m-Xb-). In further embodiments, E is -heterocycle-C(O)NH-, X is -Xa-(CH2)m-Xb-, Xais absent and Xbis -NH- (i.e. X is – (CH2)m-NH-). In embodiments, wherein the compound is a compound of Formula (Ia), when E is - heterocycle-C(O)NH-, then X is absent or –(CH2)m-Xb-. In embodiments, Y is absent. Where Y is absent, Formula (I) or (Ia) (e.g. Formula (I)) may be rewritten as: A-E-X-Z., wherein the wavy line indicates the point of attachment to X and the asterisk-wavy line indicates the point of attachment to Z..In embodiments, Y is, for example. In further embodiments,example. In embodiments, wherein the compound is a compound of Formula (Ia), Y is:embodiments, ya or yb are each independently selected from 0, 1 and 2. In further embodiments, at least one of ya or yb is 0. In further embodiments, ya is 0 and yb is 1. In further embodiments, ya is 1 and yb is 0. In further embodiments, the total of ya and yb is no more than 3. In further embodiments, ya and yb are both 0 (i.e. Y is, optionallyIn further embodiments, ya and yb are both independently selected from 1 and 2. In embodiments, Q is NH, S or O. In further embodiments, Q is NH. In further embodiments, Q is S. In further embodiments, Q is O. In embodiments, wherein the compound is a compound of Formula (Ia), Q is -N(C1-3alkyl)-, for example -N(CH3)-. In embodiments, Q is -S-(CH2)2NH-*, -O-(CH2)2NH-* or -NH-(CH2)2NH-*, wherein * indicates the point of attachment to Z. In further embodiments, Q is -S-(CH2)2NH-*. In further embodiments, Q is -O-(CH2)2NH-*. In further embodiments, Q is -NH-(CH2)2NH-*. In embodiments, X and Y are both absent. In such embodiments, Formula (I) or (Ia) (e.g. Formula (I)) may be rewritten as: A-E-Z. In embodiments, Z is H. In embodiments, Z is C1-4 alkyl. In further embodiments, Z is methyl. In embodiments, Z is -C(O)C1-4 alkyl. In further embodiments, Z is -C(O)CH3.In embodiments,integer from 1 to 5, and each Rzis independently H, C1-4 alkyl, phenyl or benzyl. In further embodiments, n is 1. In further embodiments, RZis H. In further embodiments, n is 2, 3, 4 or 5. In further embodiments, one occurrence of RZis C1-4 alkyl, benzyl or phenyl and the remaining occurrence or occurrences of RZare H. In further embodiments, Z is:wherein n1 is 0, 1, 2, 3 or 4 and Rzis C1-4 alkyl, benzyl, or phenyl. In further embodiments, RZis C1-4 alkyl. In further embodiments, RZis methyl. In further embodiments, RZis isopropyl. In further embodiments, RZis benzyl. In further embodiments, RZis phenyl. In embodiments, Z is. In these embodiments, Z comprises amino acid residue(s). For example, when RZis H, Z could alternatively be defined as (Gly)1-5. When RZis H and n is 1, Z could alternatively be defined as Gly. Variable Z may comprise amino acid residues in instances where the compounds of Formula (I) or (Ia) (e.g. the compounds of Formula (I)) are payloads that have been released from an ADC, for example once a peptide linker portion has been cleaved. In embodiments, Z is -C(O)C1-4alkyl,absent and X is -Xa- (CH2)m-Xb-, wherein Xbis -O- or -NH-. In embodiments, Z is -C(O)C1-4 alkyl,absent and X is -Xa- (CH2)m-Xb-, wherein Xbis -NH-. In embodiments, wherein the compound is a compound of Formula (Ia), when Z is -C(O)C1-4 alkyl,absent, then Xbis not -C(O)NH-.In embodiments, the compound of Formula (I) or (Ia) (e.g. the compound of Formula (I)), or a pharmaceutically acceptable salt thereof, is selected from a compound of Table 1, or a pharmaceutically acceptable salt thereof. Table 1.In embodiments, the compound of Formula (I) or (la) (e.g. the compound of Formula (I)), or a pharmaceutically acceptable salt thereof, is selected from:or a pharmaceutically acceptable salt thereof.Compounds of Formula (II) and (IIa) In an aspect, provided herein is a compound of Formula (IIa): A-E1-X1-Y1-Z15 or a pharmaceutically acceptable salt thereof, wherein A is:E1is: i) -NR-; 10 ii) a 5-10 membered saturated heterocycle containing two nitrogen atoms and optionally an oxygen atom, wherein one nitrogen atom in the heterocycle is connected to A and the second nitrogen atom in the heterocycle is connected to X1; optionally wherein the heterocycle is geminally substituted on a carbon atom with two occurrences of C1-3alkyl; 15 iii) -NR-heterocycle- wherein the heterocycle is a saturated 5-8 membered heterocycle containing a nitrogen atom which is connected to X1; and wherein a carbon atom in the heterocycle connects to -NR-; or iv) -heterocycle-NR- or -heterocycle-C(O)NH- wherein the heterocycle is a saturated 5-8 membered heterocycle containing a nitrogen atom which is connected to A; and 20 wherein a carbon atom in the heterocycle connects to -NR- or -C(O)NH-; R is H, C1-4alkyl or C3-4cycloalkyl; 36X1is absent, -C(O)CH2O-*, -C(O)CH2NH-*, or -Xa-(CH2)m-Xb-, wherein Xbis connected to Y1; Xais - C(O)- or absent; Xbis -C(O)NH-*, -O- or -NH-, wherein * indicates the point of attachment to Y1; m is 2 or 3;, wherein the wavy line indicates the point of attachment to X1and 5 the asterisk-wavy line indicates the point of attachment to Z1; ya and yb are each independently selected from 0, 1, 2 and 3; and Q is NH, -N(C1-3alkyl)-, S, O, -S-(CH2)2NH-*, -O- (CH2)2NH-* or -NH-(CH2)2NH-*, wherein * indicates the point of attachment to Z1; Z1is H, C1-4alkyl, -C(O)C1-4alkyl,integer from 1 to 5; and each Rzis independently H, C1-4alkyl, phenyl or benzyl. 10 In another aspect, provided herein is a compound of Formula (II): A-E1-X1-Y1-Z1or a pharmaceutically acceptable salt thereof, wherein A is: 15iv) a 5-10 membered saturated heterocycle containing two nitrogen atoms and optionally an oxygen atom, wherein one nitrogen atom in the heterocycle is connected to A and the second nitrogen in the heterocycle is connected to X1; optionally wherein the 20 heterocycle is geminally substituted on a carbon atom with two occurrences of C1-3 alkyl; 37iii) -NR-heterocycle- wherein the heterocycle is a saturated 5-8 membered heterocycle containing a nitrogen atom which is connected to X1; and wherein a carbon atom in the heterocycle connects to -NR-; or iv) -heterocycle-NR- or -heterocycle-C(O)NH- wherein the heterocycle is a saturated 5-8 5 membered heterocycle containing a nitrogen atom which is connected to A; and wherein a carbon atom in the heterocycle connects to -NR- or -C(O)NH-; R is H, C1-4 alkyl or C3-4 cycloalkyl; X1is absent, -C(O)CH2O-*, -C(O)CH2NH-*, or -Xa-(CH2)m-Xb-, wherein Xbis connected to Y1; Xais - C(O)- or absent; Xbis -C(O)NH-*, -O- or -NH-, wherein * indicates the point of attachment to Y1;10 m is 2 or 3; provided that when E1is -NR- or -heterocycle-C(O)NH-, then X1is absent or –(CH2)m-, wherein the wavy line indicates the point of attachment to X1and the asterisk-wavy line indicates the point of attachment to Z1; and Q is NH, S, O, -S-(CH2)2NH-*, -O- (CH2)2NH-* or -NH-(CH2)2NH-*, wherein * indicates the point of attachment to Z1; 15 Z1is H, C1-4alkyl, -C(O)C1-4alkyl,integer from 1 to 5; and each Rzis independently H, C1-4alkyl, phenyl or benzyl. Unless otherwise specified, the following embodiments relate to compounds of Formula (II) or to compounds of Formula (IIa). 20 In embodiments, A is: 38.5 In embodiments, E1is -NR-. In embodiments, E1is a 5-10 membered saturated heterocycle containing two nitrogen atoms and optionally an oxygen atom, wherein one nitrogen atom in the heterocycle is connected to A and the second nitrogen in the heterocycle is connected to X1; optionally wherein the heterocycle is 10 geminally substituted on a carbon atom with two occurrences of C1-3 alkyl. In embodiments, E1is selected from:wherein ring Eais a bicyclic 7-10 membered saturated heterocycle having the two nitrogen atoms shown and optionally an oxygen atom, and ring Ebis a bicyclic 5-8 membered saturated heterocycle 15 having the nitrogen atom shown; wherein the wavy line indicates the point of attachment to A and the asterisk-wavy line indicates the point of attachment to X1. 39In embodiments, E1is:wherein ring Eais a bicyclic 7-10 membered saturated heterocycle having the two nitrogen atoms shown and optionally an oxygen atom, and the wavy line indicates the point of attachment to A and the asterisk-wavy line indicates the point of attachment to X1. 5 In embodiments, the bicyclic heterocycle of Ring Eais a bridged bicycle. In further embodiments, the bicyclic heterocycle is a 7-8 membered bridged bicycle. In embodiments, E1is selected from:wherein the wavy line indicates the point of attachment to A and the asterisk-wavy line indicates 10 the point of attachment to X1. In further embodiments, E1is selected from:. further embodiments, E1is selected from:. In embodiments, the bicyclic heterocycle of Ring Eais a spirocycle. In further embodiments, the 15 bicyclic heterocycle is an 8-9 membered spirocycle. In embodiments in which Ring Eais a spirocycle, the two nitrogen atoms present in the heterocycle of Ring Eaare in the same ring of the spirocycle. In embodiments, E1is selected from: 40wherein the wavy line indicates the point of attachment to A and the asterisk-wavy line indicates the point of attachment to X1. In further embodiments,. 5 In embodiments in which Ring Eais a spirocycle, the two nitrogen atoms present in the heterocycle of Ring Eaare in separate rings of the spirocycle. In embodiments, E1is selected from:wherein the wavy line indicates the point of attachment to A and the asterisk-wavy line indicates the point of attachment to X1. 10 In embodiments, the bicyclic heterocycle of Ring Eais a fused bicycle. In further embodiments, the bicyclic heterocycle is an 8-membered fused bicycle. In further embodiments,. In further embodiments,. In embodiments, E1is, wherein ring Ecis a monocyclic 5-8 membered saturated heterocycle having the two nitrogen atoms shown, optionally wherein the heterocycle is geminally 41substituted on a carbon atom with two occurrences of C1-3 alkyl; and the wavy line indicates the point of attachment to A and the asterisk-wavy line indicates the point of attachment to X1. In embodiments, the heterocycle of Ring Ecis geminally substituted on a carbon atom with two occurrences of C1-3 alkyl. In further embodiments, the geminal substituent is geminal dimethyl. 5 In embodiments, Ring Ecis a piperazine geminally substituted on a carbon atom with two occurrences of C1-3 alkyl. In further embodiments, the geminal substituent is geminal dimethyl. In embodiments, E1is selected from:, wherein the wavy line indicates the point of attachment to A and the asterisk-wavy line indicates the point of attachment to X1. 10 In embodiments, Ring Ecis a monocyclic 5 to 8 membered saturated heterocycle having the two nitrogen atoms shown, wherein the heterocycle is unsubstituted. In further embodiments E1iswherein the wavy line indicates the point of attachment to A and the asterisk-wavy line indicates the point of attachment to X1. In further embodiments, E1is:wherein the wavy line indicates the point of attachment to A and the asterisk-wavy 15 line indicates the point of attachment to X1. In further embodiments, E1is unsubstituted piperazine. In embodiments, E1is -NR-heterocycle- wherein the heterocycle is a saturated 5-8 membered heterocycle containing a nitrogen atom which is connected to X1; and wherein a carbon atom in the heterocycle connects to -NR-. In embodiments, E1is, wherein ring Edis a monocyclic 5-8 membered saturated 20 heterocycle having the nitrogen atom shown; wherein the wavy line indicates the point of 42attachment to A and the asterisk-wavy line indicates the point of attachment to X1. In further embodiments, ring Edis a piperidine. 1In embodiments E is wherein the wavy line indicates the point of attachment to A and the asterisk-wavy line indicates the point of attachment to X1. 5 In embodiments, E1is -heterocycle-C(O)NH-, wherein the heterocycle is a saturated 5-8 membered heterocycle containing a nitrogen atom which is connected to A; and wherein a carbon atom in the heterocycle connects to -C(O)NH-. In further embodiments,wherein ring Ebis a bicyclic 5-8 membered saturated heterocycle having the nitrogen atom shown; wherein the 10 wavy line indicates the point of attachment to A and the asterisk-wavy line indicates the point of attachment to X1. In further embodiments, the heterocycle is a bridged bicyclic heterocycle. In embodiments, E1is:wherein the wavy line indicates the point of attachment tand the asterisk-wavy line indicates the point of attachment to X1. In further embodiments, E is:. In further embodiments, E is:. 15 In embodiments, R is H. In further embodiments, R is C3-4 cycloalkyl. In further embodiments, R is cyclopropyl. In further embodiments, R is C1-4 alkyl. In further embodiments, R is methyl. In embodiments, X1is absent. Where X1is absent, Formula (II) or (IIa) (e.g. Formula (II)) may be rewritten as: A-E1-Y1-Z1. In embodiments, X1is -C(O)CH2O-*, wherein * indicates the point of 20 attachment to Y1. In embodiments, X1is -C(O)CH2NH-*, wherein * indicates the point of attachment to Y1. 43In embodiments, X1is -Xa-(CH2)m-Xb-, wherein Xais -C(O)- or absent; Xbis -C(O)NH-*, -O- or -NH-, wherein * indicates the point of attachment to Y; and m is 2 or 3. In further embodiments, m is 2. In further embodiments, Xais -C(O)-. In further embodiments, Xais absent (i.e. X1is -(CH2)m-Xb-). In further embodiments, Xbis -C(O)NH-*, wherein * indicates the point of attachment to Y1. In further 5 embodiments, Xbis -NH-. In embodiments, X1is selected fromwherein the wavy line indicates the point of attachment to E1and the asterisk-wavy line indicates the point of attachment to Y1. In further embodiments, X1is. In embodiments, E1is -NH- and X1is absent. In further embodiments, E1is -NH-, X1is -Xa-(CH2)m-Xb- 10 and Xais absent (i.e. X1is -(CH2)m-Xb-). In further embodiments, E1is -NH-, X1is -Xa-(CH2)m-Xb-, Xais absent and Xbis -NH- (i.e. X1is -(CH2)m-NH-). In embodiments, E1is -heterocycle-C(O)NH- and X1is absent. In further embodiments, E1is - heterocycle-C(O)NH-, X1is -Xa-(CH2)m-Xb- and Xais absent (i.e. X1is -(CH2)m-Xb-). In further embodiments, E1is -heterocycle-C(O)NH-, X1is -Xa-(CH2)m-Xb-, Xais absent and Xbis -NH- (i.e. X1is -15 (CH2)m-NH-). In embodiments, wherein the compound is a compound of Formula (IIa), when E1is - NR- or -heterocycle-C(O)NH-, then X1is absent or -(CH2)m-Xb-. In compounds of Formula, wherein the wavy line indicates the point of attachment to X1and the asterisk-wavy line indicates the point of attachment to Z1. In embodiments,example. In further embodiments, 20. 44. 5 In compounds of Formula, wherein the wavy line indicates the point of attachment to X1and the asterisk-wavy line indicates the point of attachment to Z1. In further embodiments, Y1is:. In further embodiments, yaand ybare each independently selected from 0, 1 and 2. In further embodiments, at least one of ya or yb is 0. In further embodiments, ya is 0 and yb is 1. In further embodiments, ya is 1 and yb is 0. In further 10 embodiments, the total of ya and yb is no more than 3. In further embodiments, ya and yb are both 0 (i.e. Y1isIn further embodiments, ya and yb are both independently selected from 1 and 2. In further embodiments of a compound of Formula (IIa), Y1is as described in relation to a compound of Formula (II). In embodiments, Q is NH, S or O. In further embodiments, Q is NH. In further embodiments, Q is S. 15 In further embodiments, Q is O. In embodiments, Q is -S-(CH2)2NH-*, -O-(CH2)2NH-* or -NH-(CH2)2NH-*, wherein * indicates the point of attachment to Z1. In further embodiments, Q is -S-(CH2)2NH-*. In further embodiments, Q is -O-(CH2)2NH-*. In further embodiments, Q is -NH-(CH2)2NH-*. 45In embodiments, wherein the compound is a compound of Formula (IIa), Q is -N(C1-3alkyl)-, for example -N(CH3)-. In embodiments, Z1is H. In embodiments, Z1is C1-4alkyl. In further embodiments, Z1is methyl. In embodiments, Z1is -C(O)C1-54alkyl. In further embodiments, Z1is -C(O)CH3. In embodiments,integer from 1 to 5, and each Rzis independently H, C1-4alkyl, phenyl or benzyl. In further embodiments, n is 1. In further embodiments, RZis H. In further embodiments, n is 2, 3, 4 or 5. In further embodiments, one occurrence of RZis C1-4 alkyl, benzyl or phenyl and the remaining occurrence or occurrences of RZare H. In further embodiments, Z1is: 10wherein n1 is 0, 1, 2, 3 or 4 and Rzis C1-4 alkyl, benzyl, or phenyl. In further embodiments, RZis C1-4 alkyl. In further embodiments, RZis methyl. In further embodiments, RZis isopropyl. In further embodiments, RZis benzyl. In further embodiments, RZis phenyl. In embodiments,. For example, when RZis H, Z1could alternatively be defined as (Gly)1-5. When RZis H and n is 1, Z115 could alternatively be defined as Gly. Variable Z1may comprise amino acid residues in instances where the compounds of Formula (II) or (IIa) (e.g. Formula (II)) are payloads that have been released from an ADC, for example once a peptide linker portion has been cleaved. In embodiments, the compound of Formula (IIa), or a pharmaceutically acceptable salt thereof, is 20 selected from a compound of Table 2 or Table 2A, or a pharmaceutically acceptable salt thereof. In embodiments, the compound of Formula (II), or a pharmaceutically acceptable salt thereof, is selected from a compound of Table 2, or a pharmaceutically acceptable salt thereof. 25 46Table 2.Table 2A.In embodiments, the compound of Formula (II) or (IIa) (e.g. the compound of Formula (II)), or a pharmaceutically acceptable salt thereof, is selected from:or a pharmaceutically acceptable salt thereof. In further aspects, there are provided methods for preparing compounds of Formula (I), (Ia), (II) or (IIa) (e.g. compounds of Formula (I) or (II)), or a pharmaceutically acceptable salt thereof; and intermediates in said methods. The method may be any method as described herein, for example as described in General Procedures and / or reaction schemes herein. The intermediate may be an Intermediate Compound disclosed herein. The Intermediate Compound may be in a salt form, for example a specific salt form described herein. The Intermediate Compound may be in a non-salt form (i.e. as a free base). Compounds of Formula (III), (IIIa), (IV) and (IVa) In one aspect, provided herein is a compound of Formula (IIIa): A-E-X-Y-L1or a salt thereof, wherein A, E and X are as defined herein; and Y is absent or, wherein the wavy line indicates the point of attachment to X and the asterisk-wavy line indicates the point of attachment to L1; ya and yb are each independently selected from 0, 1, 2 and 3; and Q is NH, -N(C1-3alkyl)-, S, O, -S(CH2)2NH-*, - O(CH2)2NH-* or -NH(CH2)2NH-*, wherein * indicates the point of attachment to L1; and L1is a linker for connection to an antibody or antigen-binding fragment thereof. In another aspect, there is provided a compound of Formula (III): A-E-X-Y-L1or a salt thereof, wherein A, E and X are as defined herein; and Y is absent or, wherein the wavy line indicates the point of attachment to X and the asterisk-wavy line indicates the point of attachment to L1; and Q is NH, S, O, -S(CH2)2NH-*, - O(CH2)2NH-* or -NH(CH2)2NH-*, wherein * indicates the point of attachment to L1; and L1is a linker for connection to an antibody or antigen-binding fragment thereof.In another aspect, there is provided a compound of Formula (IVa): A-E1-X1-Y1-L1or a salt thereof, wherein A, E1and X1are as defined herein; Y1is, wherein the wavy line indicates the point of attachment to X1and the asterisk-wavy line indicates the point of attachment to L1; ya and yb are each independently selected from 0, 1, 2 and 3; and Q is NH, -N(C1-3alkyl)-, S, O, -S(CH2)2NH-*, -O(CH2)2NH-* or - NH(CH2)2NH-*, wherein * indicates the point of attachment to L1; and L1is a linker for connection to an antibody or antigen-binding fragment thereof. In another aspect, this specification provides a compound of Formula (IV): A-E1-X1-Y1-L1or a salt thereof, wherein A, E1and X1are as defined herein; Y1is, wherein the wavy line indicates the point of attachment to X1and the asterisk-wavy line indicates the point of attachment to L1; and Q is NH, S, O, -S(CH2)2NH-*, - O(CH2)2NH-* or -NH(CH2)2NH-*, wherein * indicates the point of attachment to L1; and L1is a linker for connection to an antibody or antigen-binding fragment thereof. The compounds of Formulae (III), (IIIa), (IV) and (IVa) (e.g. the compounds of Formulae (III) and (IV)), or salts thereof, may be referred to “linker payloads”. These compounds comprise a payload portion (derived from the compounds of Formula (I), (Ia), (II) or (IIa), e.g. compounds of Formula (I) or (II)), respectively, connected to a linker portion. The linker portion enables the connection of the payload(s) to an antibody, or antigen-binding fragment thereof, through covalent bond(s) to form an ADC (such as a conjugate of Formula (V), (Va), (VI) or (VIa), e.g. a conjugate of Formula (V) or (VI), or a pharmaceutically acceptable salt thereof, as disclosed herein). The payload(s) may be released from the ADC at a target site, for example via enzymatic cleavage of the linker portion, to provide compounds of Formula (I), (Ia), (II) or (IIa). Compounds of Formula (I), (Ia), (II) or (IIa) may exhibit advantageous properties, as described above.As an example, the payload-linker may be conjugated to an anti-HER2 monoclonal antibody to obtain an anti-HER2 ADC that is effective in treating cancer, such as HER2 positive cancer. The compound of Formula (III), (IIIa), (IV) or (IVa) (e.g. the compound of Formula (III) or (IV)) may be in a salt form, for example a pharmaceutically acceptable salt. Variable A in a compound of Formula (IIIa) or (IVa) may be as described herein, for example, as described in relation to a compound of Formula (Ia) or (IIa). Variable A in a compound of Formula (III) or (IV) may be as described herein, for example, as described in relation to a compound of Formula (I) or (II). Variables E and X in a compound of Formula (IIIa) may be as described herein, for example, as described in relation to a compound of Formula (Ia). Variable Y in a compound of Formula (IIIa) may be as described in relation to a compound of Formula (Ia), but wherein an asterisk-wavy line or an asterisk (*) indicates the point of attachment to L1. Variables E and X in a compound of Formula (III) may be as described herein, for example, as described in relation to a compound of Formula (I). Variable Y in a compound of Formula (III) may be as described in relation to a compound of Formula (I), but wherein an asterisk-wavy line or an asterisk (*) indicates the point of attachment to L1. Variables E1and X1in a compound of Formula (IVa) may be as described herein, for example, as described in relation to a compound of Formula (IIa). Variable Y1in a compound of Formula (IVa) may be as described in relation to a compound of Formula (IIa), but wherein an asterisk-wavy line or an asterisk (*) indicates the point of attachment to L1. Variables E1and X1in a compound of Formula (IV) may be as described herein, for example, as described in relation to a compound of Formula (II). Variable Y1in a compound of Formula (IV) may be as described in relation to a compound of Formula (II), but wherein an asterisk-wavy line or an asterisk (*) indicates the point of attachment to L1. In a compound of Formula (III), (IIIa), (IV) or (IVa) (e.g. a compound of Formula (III) or (IV)), the linker L1contains a reactive moiety through which the compound may be connected to an antibody or antigen-binding fragment thereof. For example, L1may comprise a reactive moiety which reacts with a site in the antibody or antigen-binding fragment thereof, to form a covalent bond between the linker and the antibody or antigen-binding fragment thereof. The reactive moiety in the linker L1may be an electrophilic group, capable of reacting with a nucleophilic group within the antibody, or antigen-binding fragment thereof. Nucleophilic groupson antibodies include side chain thiol groups (e.g. cysteine), side chain amine groups (e.g. lysine), N-terminal amine groups, and sugar hydroxyl or amino groups where the antibody is glycosylated. Electrophilic groups on the linker include, but are not limited to: (i) active esters such as NHS esters, HOBt esters, haloformates, and acid halides; (ii) alkyl and benzyl halides such as haloacetamides; (iii) aldehydes, ketones, carboxyl, and maleimide groups. The antibody or antigen- binding fragment thereof may contain reducible interchain disulfides, such as cysteine bridges. Such antibodies or antigen fragments may be treated with a reducing agent, such as dithiothreitol, so that each disulfide forms two reactive thiol nucleotides that can react with linkers. Additional nucleophilic groups can be introduced into antibodies through the reaction of lysines with 2- iminothiolane resulting in conversion of an amine into a thiol. Reactive thiol groups may be introduced into the antibody, or antigen-binding fragment thereof, for example by preparing mutant antibodies comprising one or more non-native cysteine amino acid residues. The reactive moiety in the linker may be a nucleophilic group, capable of reacting with an electrophilic group within the antibody, or antigen-binding fragment thereof. Electrophilic groups on an antibody include, but are not limited to, aldehyde and ketone carbonyl groups. Nucleophilic groups on a linker include, but are not limited to, hydrazide, oxime, amino, hydroxyl, hydrazine, thiosemicarbazone, hydrazine carboxylate, and arylhydrazide. The reactive moiety in the linker may be a substrate for an enzyme, where the enzyme catalyses conjugation of the reactive moiety to the antibody or antigen-binding fragment thereof. The enzyme may be a transpeptidase, for example sortase A. Sortase A, originally derived from the bacterium Staphylococcus aureus, exhibits high specificity in cross-linking. Sortase A may catalyze the reaction of an amine, e.g. an alkyl amine, in the linker with the antibody or antigen-binding fragment thereof. The linker L1may be cleavable by enzymatic activity, hydrolysis, or other metabolic conditions. In embodiments the linker is cleavable by enzymatic activity, such as a protease or glucuronidase. For example, the linker may be peptide- or glucuronide-based. The cleavage of the linker may be such that the released payload contains a portion of the cleaved linker. For example, if the linker is (Gly)5, then the released payload may contain 1, 2, 3, 4 or 5 glycine residues, depending on the point of enzymatic cleavage. Cleavage of the linker L1, in a compound of Formula (III) or (IIIa) (e.g. a compound of Formula (III)), may lead to the release of a payload which is a compound of Formula (I) or (Ia), respectively (e.g. a compound of Formula (I)). Cleavage of the linker L1, in a compound of Formula (IV) or (IVa) (e.g. a compound of Formula (IV)), may lead to the release of a payload which is a compound of Formula (II) or (IIa), respectively (e.g. a compound of Formula (II)).The linker may be a non-cleavable linker. ADCs containing non-cleavable linkers may rely on degradation of the antibody, or antigen-binding fragment thereof, in order to release the payloadlinker.The linker may be stable extracellularly, such that the ADC remains intact until it reaches the target cell. The linker may be cleaved once inside the target cell.Suitable linkers are known in the art; for example, as disclosed in Bargh et al, Chem. Soc. Rev., 2019, 48, 4391-4374 or Su et al, Acta Pharm. Sin. B, 2021, 11, 3889-3907 (incorporated herein by reference in their entirety).In embodiments, L1is:CH2-NH-, wherein LA1is O, S or NH, and * indicates the point of attachment to Y in a compound of Formula (III) or (Illa) or the point of attachment to Y1in a compound of Formula (IV) or (IVa); each RZ1is independently H, C1.4 alkyl, phenyl or benzyl; q is 3, 4 or 5;the asterisk-wavy line indicates the point of attachment to G1; b is an integer from 1 to 5; c is an integer from 5 to 15; d is an integer from 1 to 10; dl and cl are each independently 1 or 2; and G1is a conjugation group for conjugation to an antibody or antigen-binding fragment thereof.In embodiments, Lwherein LAis absent or is selected from *-CH2-NH-, and *-C(O)-CH2-LA1-CH2-NH-, wherein LA1is O, S or NH, and * indicates the point of attachment to Y in a compound of Formula (III) or (Illa) (e.g. a compound of Formula (III)) or the point of attachment to Y1in a compound of Formula (IV) or (IVa) (e.g. a compound of Formula (IV)); each RZ1is independently H, CM alkyl, phenyl or benzyl; q is 3, 4 or 5; LBis selected from -(CH2)b- and, wherein the asterisk-wavy line indicates the point of attachment to G1; b is an integer from 1 to 5; c is an integer from 5 to 15; and G1is a conjugation group forconjugation to an antibody or antigen-binding fragment thereof; provided that, for a compound ofFormula (III), when Y is absent, then Xbis not -C(O)NH-.In further embodiments, LAis absent or *-CH2-NH-.In further embodiments, L1is:. In further embodiments, q is 3. In further embodiments, q is 4. In further embodiments, q is 5. In further embodiments, b is 2. In further embodiments, c is 7. In further embodiments, RZ1is H. In further embodiments, one occurrence of RZ1is Ci-4 alkyl, benzyl or phenyl and the remaining occurrences of RZ1are H. In further embodiments, L1is:wherein RZ1is CMalkyl, benzyl, or phenyl and ql is2, 3 or 4, optionally wherein ql is 3. In further embodiments, RZ1is CMalkyl. In further embodiments, RZ1is methyl. In further embodiments, RZ1is isopropyl. In further embodiments, RZ1is benzyl. In further embodiments, RZ1is phenyl.In further embodiments, I_Bis -(CH2)b-. In further embodiments, LBis. In embodiments, b is 2. In embodiments, c is 7.In further embodiments, LBis. In embodiments, d is 1. In other embodiments, d is 2.In further embodiments, L1is selected from:or a salt thereof.In further embodiments, LMS:salt thereof.In embodiments, L1is a group of Formula (L-IA):wherein Ring F1is a saturated bicyclic ring having 6, 7 , or 8 carbon atoms and optionally 1 or 2 oxygen atoms, Ring F2is a saturated bicyclic ring having the 2 nitrogen atoms shown, 4, 5, 6, 7 or 8 carbon atoms and optionally 1 oxygen atom, and Ring F3is a saturated bicyclic ring having the 1 nitrogen atom shown, 5, 6, 7 or 8 carbon atoms and optionally 1 oxygen atom,R1is CM alkyl,X2is (CH2)n3, wherein n3 is 0, 1, 2 or 3,Y2is (CH2)n4, wherein n4 is 0, 1, 2, 3 or 4,wherein n5 is 1, 2, 3, 4 or 5, n5A is an integer from 1 to 10, n5B is 1 or 2, and the asterisk-wavy line indicates the point of attachment to G1, m2 is an integer from 5 to 17, p is 1 or 0, pl is 0 or 1, andG1is a conjugation group for conjugation to an antibody or antigen-binding fragment thereof.In embodiments, L1is a group of Formula (L-l):wherein E2is (CH2)n2, wherein n2 is 0, 1, 2 or 3,wherein Ring F1is a saturated bicyclic ring having 6, 7, or 8 carbon atoms and optionally 1 or 2 oxygen atoms, Ring F2is a saturated bicyclic ring having the 2 nitrogen atoms shown, 4, 5, 6, 7 or 8 carbon atoms and optionally 1 oxygen atom, and Ring F3is a saturated bicyclic ring having the 1 nitrogen atom shown, 5, 6, 7 or 8 carbon atoms and optionally 1 oxygen atom,R1is Ci-4 alkyl,X2is (CH2)n3, wherein n3 is 0, 1, 2 or 3,Y2is (CH2)n4, wherein n4 is 0, 1, 2, 3 or 4,Z2is (CH2)n5, wherein n5 is 1, 2, 3, 4 or 5, m2 is an integer from 5 to 17, p is 1 or 0, pl is 0 or 1, andG1is a conjugation group for conjugation to an antibody or antigen-binding fragment thereof; provided that, for a compound of Formula (III), when Y is absent, then Xbis not -C(O)NH-. In further embodiments of a compound of Formula (L-IA) or (L-l), Q2is12 or 13. In further embodiments, R1is CH3. In further embodiments, E2is CH2. In further embodiments, X2is CH2. In further embodiments, Y2is (CH2)2. In further embodiments, Z2is (CH2)2. In further embodiments, p is 1. In further embodiments, pl is 0. In further embodiments, pl is 1. In| ‘■J* further embodiments of a compound of Formula ( L-l A), Z2isn5A. In further embodiments, n5B is 2. In further embodiments, n5A is 1.In further embodiments, L1is selected from:In embodiments, L1is a group of Formula (L-ll I) :wherein E3is (CH2)n6, wherein n6 is 0, 1, 2 or 3; R1Ais CM alkyl or H,wherein n7 and n9 are 0, 1, 2 or 3, n8 is 1, 2 or3, and Q3is O or NRA, wherein RAis H, CMalkyl or C3-4cycloalkyl, and wherein the asterisk-wavy line indicates the point of attachment to the (C=O) moiety;Y3is O or NRB, wherein RBis H, Ci~4alkyl or C3-4cycloalkyl,Z3is (CH2)nio or, wherein nlO is 0, 1, 2, 3, 4 or 5, nlOA is an integer from 1 to 10, nlOB is 1 or 2, and the asterisk-wavy line indicates the point of attachment to G1, m3 is an integer from 2 to 17; p2 is 1 or 0; q2 is 1 or 0; p3 is 0 or 1; andG1is a conjugation group for conjugation to an antibody or antigen-binding fragment thereof.In further embodiments, m3 is 9, 10, 11, 12 or 13. In further embodiments, R1Ais CH3. In furtherfurther embodiments, E3is CH2.In further embodiments, X4is CH2. In further embodiments, Y3is O. In further embodiments, Z3is (CH2)nio. In further embodiments, Z3is (CH2)2. In further embodiments, Z3is absent (i.e. Z3is(CH2)nl0, where nlO is 0). In further embodiments, Z3is. In further embodiments, nlOB is 2. In further embodiments, nlOA is 1. In further embodiments, p2 is 1. In further embodiments, q2 is 1. In further embodiments, p2 is 0. In further embodiments, p3 is 1. In further embodiments, p3 is 0. In further embodiments, L1is:In embodiments, L1is selected from the moieties of Table 3:In embodiments G1is selected from:wherein X3is CH or N, h is 0 or 1, Hal is Cl, Br or I, RKis H or CH3, and RLis Cv6alkyl.In embodiments G1is selected from:wherein X3is CH or N, h is 0 or 1, Hal is Cl, Br or I, RKis H or CH3, and RLis Ci-6alkyl. In embodiments G1is selected from:wherein X3is CH or N, h is 0 or 1, Hal is Cl, Br or I, RKis H or CH3, and RLis Ci-6alkylIn further embodiments, G1is selected fromIn further embodiments,further embodiments, G1is. In further embodiments, G1isIn further embodiments, G1isIn some embodiments, -In embodiments L1is selected from:or a salt thereof.In further embodiments, L1is:salt thereof.In embodiments, L1is selected from the moieties of Table 4:In embodiments, for a compound of Formula (III) or (Illa), when Y is absent, then Xbis not -C(O)NH-.In embodiments, the compound of Formula (III) or (Illa) (e.g. the compound of Formula (III)), or a salt thereof, is selected from a compound of Table 5A, or a salt thereof:In embodiments, the compound of Formula (IVa), or a salt thereof, is selected from a compound of Table 5B or Table 5C, or a salt thereof. In embodiments, the compound of Formula (IV), or a salt thereof, is selected from a compound of Table 5B, or a salt thereof.A compound of Formula (III), (Illa), (IV) or (IVa) (e.g. a compound of Formula (III) or (IV)), or a salt thereof, may be prepared by reacting (i.e. conjugating) a compound of Formula (I), (la), (II) or (Ila) (e.g. a compound of Formula (I) or (II)) or a derivative thereof, or a salt thereof, with a precursor toL1. The precursor to L1contains a second reactive moiety which reacts with the compound of Formula (I), (la), (II) or (Ila) (e.g. the compound of Formula (I) or (II)) or derivative thereof. For example, compound LP1 or LP2 may be prepared by reacting compound P20 or P8, respectively, or a salt thereof, with compound LI, or a salt thereof (see example section for LI structure).Conjugates of Formula (V), (Va), (VI) and (Via)In one aspect, provided herein is a conjugate of Formula (Va):(A-E-X-Y-L2)k-Abor a pharmaceutically acceptable salt thereof, wherein each A, E and X is as defined herein; Y is absent, wherein the wavy line indicates the point of attachment to X and the asterisk-wavy line indicates the point of attachment to L2; ya and yb are each independently selected from 0, 1, 2 and 3; and Q is NH, -N (Ci-3al kyl)-, S, O, -S(CH2)2NH-*, - O(CH2)2NH-* or -NH(CH2)2NH-*, wherein * indicates the point of attachment to L2; each L2is a linker; k is an integer from 1 to 10; and Ab is an antibody or antigen-binding fragment thereof.In another aspect, provided herein is a conjugate of Formula (V):(A-E-X-Y-L2)k-Ab or a pharmaceutically acceptable salt thereof, wherein each A, E and X is as defined herein; Y is absent, wherein the wavy line indicates the point of attachment to X and the asterisk-wavy line indicates the point of attachment to L2; and Q is NH, S, O, -S(CH2)2NH-*, - O(CH2)2NH-* or -NH(CH2)2NH-*, wherein * indicates the point of attachment to I2; each L2is a linker; k is an integer from 1 to 10; and Ab is an antibody or antigen-binding fragment thereof.In another aspect, provided herein is a conjugate of Formula (Via):(A-E1-X1-Y1~L2)k~Ab or a pharmaceutically acceptable salt thereof, wherein each A, E1and X1is as defined herein; Y1is, wherein the wavy line indicates the point of attachment to X1and the asterisk-wavy line indicates the point of attachment to L2; ya and yb are each independently selected from 0, 1, 2 and 3; and Q is NH, -N(Ci_3alkyl)-, S, O, -S(CH2)2NH-*, -O(CH2)2NH-* or -NH(CH2)2NH-*, wherein * indicates the point of attachment to L2; each L2is a linker; k is an integer from 1 to 10; and Ab is an antibody or antigen-binding fragment thereof.In another aspect, provided herein is a conjugate of Formula (VI):(A-E1-X1-Y1-L2)k-Abor a pharmaceutically acceptable salt thereof, wherein each A, E1and X1is as defined herein; Y1is, wherein the wavy line indicates the point of attachment to X1and the asterisk- wavy line indicates the point of attachment to L2; and Q is NH, S, 0, -S(CH2)2NH-*, -O(CH2)2NH-* or - NH(CH2)2NH-*, wherein * indicates the point of attachment to L2; each L2is a linker; k is an integer from 1 to 10; and Ab is an antibody or antigen-binding fragment thereof.The conjugates of Formula (V), (Va), (VI) and (Via) (e.g. the conjugates of Formula (V) and (VI) may alternatively be referred to as the compounds of Formula (V), (Va), (VI) and (Via) (e.g. compounds of Formula (V) and (VI). The conjugates of Formula (V), (Va), (VI) and (Via) may also be referred to as ADCs. A conjugate of Formula (V), (Va), (VI) and (Via) (e.g. a conjugate of Formula (V) or (VI)), or a pharmaceutically acceptable salt thereof, may undergo cleavage to release a compound of Formula (I), (la), (II) or (Ila) (e.g. a compound of Formula (I) or (II)), respectively. Compounds of Formula (I), (la), (II) or (Ila), and the conjugates of Formula (V), (Va), (VI) and (Via), may exhibit advantageous properties, as described above, which may result in a wider therapeutic window.Variable A in a conjugate of Formula (Va) or (Via) may be as described herein, for example, as described in relation to a compound of Formula (la) or (Ila). Variable A in a conjugate of Formula (V) or (VI) may be as described herein, for example, as described in relation to a compound of Formula (I) or (II).Variables E and X in a conjugate of Formula (Va) may be as described herein, for example, as described in relation to a compound of Formula (la). Variable Y in a conjugate of Formula (Va) may be as described in relation to a compound of Formula (la), but wherein an asterisk-wavy line or an asterisk (*) indicates the point of attachment to L2.Variables E and X in a conjugate of Formula (V) may be as described herein, for example, as described in relation to a compound of Formula (I). Variable Y in a conjugate of Formula (V) may be as described in relation to a compound of Formula (I), but wherein an asterisk-wavy line or an asterisk (*) indicates the point of attachment to L2.Variables E1and X1in a conjugate of Formula (Via) may be as described herein, for example, as described in relation to a compound of Formula (Ila). Variable Y1in a conjugate of Formula (Via) may be as described in relation to a compound of Formula (Ila), but wherein an asterisk-wavy line or an asterisk (*) indicates the point of attachment to L2.Variables E1and X1in a conjugate of Formula (VI) may be as described herein, for example, as described in relation to a compound of Formula (II). Variable Y1in a conjugate of Formula (VI) may be as described in relation to a compound of Formula (II), but wherein an asterisk-wavy line or an asterisk (*) indicates the point of attachment to L2.In a conjugate of Formula (V), (Va), (VI) or (Via) (e.g. a conjugate of Formula (V) or (VI)), the linker L2may be cleavable by enzymatic activity, hydrolysis, or other metabolic conditions. In embodiments the linker is cleavable by enzymatic activity, such as protease or glucuronidase. For example, the linker may be peptide- or glucuronide-based. The cleavage of the linker may be such that the released payload contains a portion of the cleaved linker. For example, if the linker is (Gly)5, then the released payload may contain 1, 2, 3, 4 or 5 glycine residues, depending on the point of enzymatic cleavage. Cleavage of the linker L2, in a conjugate of Formula (Va), may lead to the release of a payload which is a compound of Formula (la). Cleavage of the linker L2, in a compound of Formula (V), may lead to the release of a payload which is a compound of Formula (I). Cleavage of the linker, L2, in a conjugate of Formula (Via), may lead to the release of a payload which is a compound of Formula (Ila). Cleavage of the linker, L2, in a conjugate of Formula (VI), may lead to the release of a payload which is a compound of Formula (II).The linker may be a non-cleavable linker. ADCs containing non-cleavable linkers rely on degradation of the antibody, or antigen-binding fragment thereof, in order to release the payloadlinker.The linker may be stable extracellularly, such that the ADC remains intact until it reaches the target cell. The linker may be cleaved once inside the target cell.Suitable linkers are known in the art; for example, as disclosed in Bargh et al, Chem. Soc. Rev., 2019, 48, 4391-4374 or Su et al, Acta Pharm. Sin. B, 2021, 11, 3889-3907 (incorporated herein by reference in their entirety).In embodiments, L2is:, wherein LAis absent or is selected from *-CH2-NH-, and *-C(O)-CH2-LA1-CH2-NH-, wherein LA1is O, S or NH, and * indicates the point of attachment to Y in a conjugate of Formula (V) or (Va) or the point of attachment to Y1in a conjugate of Formula (VI) or (Via); each RZ1is independently H, C1.4 alkyl, phenyl or benzyl; q is 3, 4 or 5; LBis selected from - (CH2)b-,, wherein the asterisk-wavy line indicates the point of attachment to G2; b is an integer from 1 to 5; c is an integer from 5 to 15; d is an integer from 1 to 10; dl and cl are each independently 1 or 2; and G2is a conjugation group conjugated to the antibody or antigen-binding fragment thereof, whereinindicates the point of attachment to the antibody or antigen-binding fragment thereof.In embodiments,wherein LAis absent or is selected from *-CH2-NH-, and *-C(O)-CH2-LA1-CH2-NH-, wherein LA1is O, S or NH, and * indicates the point of attachment to Y in a conjugate of Formula (V) or (Va) (e.g. a compound of Formula (V)) or the point of attachment to Y1in a conjugate of Formula (VI) or (Via) (e.g. a compound of Formula (VI)); each RZ1is independently H, Ci.4alkyl, phenyl or benzyl; q is 3, 4 or 5; LBis selected from — (CH2)b- and, wherein the asterisk-wavy line indicates the point of attachment to G2; b is an integer from 1 to 5; c is an integer from 5 to 15; and G2is a conjugation group conjugated to the antibody or antigen-binding fragment thereof, whereinindicates the point of attachment to the antibody or antigen-binding fragment thereof; provided that, for a conjugate of Formula (V), when Y is absent, then Xbis not -C(O)NH-.In further embodiments, LAis absent or *-CH2-NH-.In further embodiments, L2is:further embodiments, q is 3. In further embodiments, q is 4. In further embodiments, q is 5. In further embodiments, b is 2. In further embodiments, c is 7. In further embodiments, RZ1is H. In further embodiments, one occurrence ofRZ1is CM alkyl, benzyl or phenyl and the remaining occurrences of RZ1are H. In further embodiments, Lwherein RZ1is Ci.4alkyl, benzyl, or phenyl andql is 2, 3 or 4, optionally wherein ql is 3. In further embodiments, RZ1is Ci.4alkyl. In further embodiments, RZ1is methyl. In further embodiments, RZ1is isopropyl. In further embodiments, RZ1is benzyl. In further embodiments, RZ1is phenyl.In further embodiments, LBis — (CH2)b-- In further embodiments, LBisIn further embodiments, LBis. In embodiments, d is 1. In other embodiments, d is 2.In embodiments, L2is selected from:or a pharmaceutically acceptable salt thereof, whereinindicates the point of attachment to the antibody or antigen-binding fragment thereof.In embodiments, L2is:pharmaceutically acceptable salt thereof, wherein indicates the point of attachment to the antibody or antigen-binding fragment thereof.In embodiments, L2is a group of Formula (L-ll A):wherein Ring F1is a saturated bicyclic ring having 6, 7, or 8 carbon atoms and optionally 1 or 2 oxygen atoms, Ring F2is a saturated bicyclic ring having the 2 nitrogen atoms shown, 4, 5, 6, 7 or 8 carbon atoms and optionally 1 oxygen atom, and Ring F3is a saturated bicyclic ring having the 1 nitrogen atom shown, 5, 6, 7 or 8 carbon atoms and optionally 1 oxygen atom,R1is Ci-4 alkyl,X2is (CH2)n3, wherein n3 is 0, 1, 2 or 3,Y2is (CH2)n4, wherein n4 is 0, 1, 2, 3 or 4,or 2, and the asterisk-wavy line indicates the point of attachment to G2, m2 is an integer from 5 to 17, p is 1 or 0, pl is 0 or 1, andG2is a conjugation group conjugated to the antibody or antigen-binding fragment thereof, wherein indicates the point of attachment to the antibody or antigen-binding fragment thereof.In embodiments, L2is a group of Formula (L-ll):(HI), wherein E2is (CH2)n2, wherein n2 is 0, 1, 2 or 3,wherein Ring F1is a saturated bicyclic ring having 6, 7, or 8 carbon atoms and optionally 1 or 2 oxygen atoms, Ring F2is a saturated bicyclic ring having the 2 nitrogen atoms shown, 4, 5, 6, 7 or 8 carbon atoms and optionally 1 oxygen atom, and Ring F3is a saturated bicyclic ring having the 1 nitrogen atom shown, 5, 6, 7 or 8 carbon atoms and optionally 1 oxygen atom,R1is Ci-4 alkyl,X2is (CH2)n3, wherein n3 is 0, 1, 2 or 3,Y2is (CH2)n4, wherein n4 is 0, 1, 2, 3 or 4,Z2is (CH2)n5, wherein n5 is 1, 2, 3, 4 or 5, m2 is an integer from 5 to 17, p is 1 or 0, pl is 0 or 1, andG2is a conjugation group conjugated to the antibody or antigen-binding fragment thereof, wherein indicates the point of attachment to the antibody or antigen-binding fragment thereof; provided that, for a conjugate of Formula (V), when Y is absent, then Xbis not -C(O)NH-.In further embodiments of Formula (L-IIA) or (L-ll ), Q2is12 or 13. In further embodiments, R1is CH3. In further embodiments, E2is CH2. In further embodiments, X2is CH2. In further embodiments, Y2is (CH2)2. In further embodiments, Z2is (CH2)2. In further embodiments, p is 1. In further embodiments, pl is 0. In further embodiments, pl is 1. In further embodiments of Formulafurther embodiments, n5A is 1.In further embodiments, L2is selected from:wherein indicates the point of attachment to the antibody or antigen-binding fragment thereof.In embodiments, L2is a group of Formula (L-IV):wherein E3is (CH2)n6, wherein n6 is 0, 1, 2 or 3, R1Ais C1-4alkyl or H;3, and Q3is O or NRA, wherein RAis H, C1-4 alkyl or C3-4 cycloalkyl, and wherein the asterisk-wavy line indicates the point of attachment to the (C=O) moiety; Y3is O or NRB, wherein RBis H, C1-4 alkyl or C3-4 cycloalkyl, Z3is (CH2)n10 or, wherein n10 is 0, 1, 2, 3, 4 or 5, n10A is an integer from 1 to 10, n10B is 1 or 2, and the asterisk-wavy line indicates the point of attachment to G2, m3 is an integer from 2 to 17, p2 is 1 or 0, q2 is 1 or 0, p3 is 0 or 1, and G2is a conjugation group conjugated to the antibody or antigen-binding fragment thereof, wherein indicates the point of attachment to the antibody or antigen-binding fragment thereof.In further embodiments, m3 is 9, 10, 11, 12 or 13. In further embodiments, R1Ais CH3. In furtherfurther embodiments, E3is CH2.In further embodiments, X4is CH2. In further embodiments, Y3is O. In further embodiments, Z3is(CH2)nio. In further embodiments, Z3is (CH2)2. In further embodiments, Z3is absent (i.e. Z3is(CH2)n10, where nlO is 0). In further embodiments, Z3isembodiments, nlOB is 2. In further embodiments, nlOA is 1. In further embodiments, p2 is 1. In further embodiments, q2 is 1. In further embodiments, p2 is 0. In further embodiments, p3 is 1. In further embodiments, p3 is 0. In further embodiments, L2is:In embodiments, L2is selected from a moiety of Table 6:In embodiments, G2is selected from:wherein RKis H or CH3, RLis Cv6alkyl, and -x'1!indicates the point of attachment to the antibody, or antigen-binding fragment thereof.In embodiments, G2is selected from:wherein RKis H or CH3, RLis Cv6alkyl, andindicates the point of attachment to the antibody, or antigen-binding fragment thereof.In embodiments, G2is selected from:wherein RKis H or CH3, RLis Ci_6alkyl, andindicates the point of attachment to the antibody, or antigen-binding fragment thereof.In further embodiments, G2is selected from:In further embodiments,further embodiments, G2isfurther embodiments, G2is In embodiments, G2is (i.e. G2a bond).In embodiments, -LB-G2, -Z2-G2or -Z3-G2is:In embodiments, L2is selected from:or a pharmaceutically acceptable salt thereof, whereinindicates the point of attachment to the antibody or antigen-binding fragment thereof.In embodiments, L2is:or a pharmaceutically acceptable salt thereof, wherein -x"' indicates the point of attachment to the antibody or antigen-binding fragment thereof.In embodiments, L2is selected from a moiety of Table 7:In embodiments, for a conjugate of Formula (V) or (Va), when Y is absent, then Xbis not -C(O)NH-. In embodiments, the conjugate of Formula (V) or (Va) (e.g. the conjugate of Formula (V)), or a pharmaceutically acceptable salt thereof, is selected from a conjugate of Table 8A:or a pharmaceutically acceptable salt thereof, wherein Ab is an antibody or antigen-binding fragment thereof and k is an integer from 1 to 10.In embodiments, the conjugate of Formula (VI) or (Via) (e.g. the conjugate of Formula (VI)), or a pharmaceutically acceptable salt thereof, is selected from a conjugate of Table 8B:or a pharmaceutically acceptable salt thereof, wherein Ab is an antibody or antigen-binding fragment thereof and k is an integer from 1 to 10.In embodiments, the conjugate of Formula (Via) or a pharmaceutically acceptable salt thereof, is selected from a conjugate of Table 8C:or a pharmaceutically acceptable salt thereof, wherein Ab is an antibody or antigen-binding fragment thereof and k is an integer from 1 to 10.In embodiments, k is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. In further embodiments k is an integer from 2 to10. In further embodiments k is an integer from 2 to 8. In further embodiments k is 4. In further embodiments k is 8.The present specification is intended to include all isotopes of atoms occurring in the present compounds and conjugates. Isotopes will be understood to include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include13C and14C. Isotopes of nitrogen include15N.The compounds disclosed herein may contain one or more chiral centres. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e. as individual enantiomers, diastereoisomers, or as a stereoisomerically enriched mixture. All such stereoisomer (and enriched) mixtures are included within the scope of the embodiments, unless otherwise stated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like.Unless stereochemistry is explicitly indicated in a chemical structure or chemical name, the chemical structure or chemical name is intended to embrace all possible stereoisomers, diastereoisomers, conformers, rotamers and tautomers of the compound depicted. For example, acompound containing a chiral carbon atom is intended to embrace both the (R) enantiomer and the (S) enantiomer, as well as mixtures of the enantiomers, including racemic mixtures; and a compound containing two chiral carbons is intended to embrace all enantiomers and diastereoisomers including (R,R), (S,S), (R,S) and (S,R). In cases where compounds may exist in tautomeric forms (e.g. keto / enol), whether existing in equilibrium or predominantly in one form, depiction of one tautomer is intended to encompass the other tautomer.The compounds disclosed herein may be prepared, used or supplied in amorphous form, crystalline form, or semicrystalline form and any given compound disclosed herein may be capable of being formed into more than one crystalline / polymorphic form, including hydrated (e.g. hemi hydrate, a mono hydrate, a di hydrate, a tri hydrate or other stoichiometry of hydrate) and / or solvated forms. It is to be understood that the present specification encompasses any and all such solid forms of the compound disclosed herein.The compounds disclosed herein may be prepared as a co-crystal solid form. It is to be understood present specification encompasses any and all such co-crystals of a compound disclosed herein.A suitable pharmaceutically acceptable salt of a compound disclosed herein (e.g. a compound of Formula (I), (II), (III) or (IV) or a conjugate of Formula (V) or (VI)) is, for example, an acid addition salt. An acid addition salt may be formed by bringing the compound into contact with a suitable inorganic or organic acid under conditions known to the skilled person. An acid addition salt may for example be formed using an inorganic acid selected from hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid. An acid addition salt may also be formed using an organic acid selected from trifluoroacetic acid, citric acid, maleic acid, oxalic acid, acetic acid, formic acid, benzoic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, methanesulfonic acid, benzenesulfonic acid and para-toluenesulfonic acid.A suitable pharmaceutically acceptable salt of a compound disclosed herein (e.g. a compound of Formula (I), (II), (III) or (IV) or a conjugate of Formula (V) or (VI)) is, for example, a base addition salt. A base addition salt may be formed by bringing the compound into contact with a suitable inorganic or organic base under conditions known to the skilled person. A base addition salt may for example be an alkali metal salt (such as a sodium, potassium, or lithium salt) or an alkaline earth metal salt (such as a calcium salt), which may be formed using an alkali metal or alkaline earth metal hydroxide or alkoxide (e.g., an ethoxide or methoxide). A base addition salt may also be formed using a suitably basic organic amine (e.g., a choline or meglumine salt).A further suitable pharmaceutically acceptable salt of a compound of Formula (I) or (II) or a conjugate of Formula (V) or (VI) is, for example, a salt formed within a patient's body after administration of a compound of Formula (I) or (II) or a conjugate of Formula (V) or (VI) to the patient. A further suitable pharmaceutically acceptable salt of a compound of Formula (la) or (Ila) or a conjugate of Formula (Va) or (Via) is, for example, a salt formed within a patient's body after administration of a compound of Formula (la) or (Ila) or a conjugate of Formula (Va) or (Via) to the patient.ConjugationA conjugate of Formula (V) or (VI), or a pharmaceutically acceptable salt thereof, may be prepared by reacting (i.e. conjugating) a compound of Formula (III) or (IV), or a salt thereof, with an antibody or an antigen-binding fragment thereof. In some embodiments, a compound of Formula (III) or (IV) contains moiety G1and a conjugate of Formula (V) or (VI) contains moiety G2, as described above. Upon conjugation, a moiety G1is converted to moiety G2where G2has a point of attachment to the antibody or antigen-binding fragment thereof.A conjugate of Formula (Va) or (Via), or a pharmaceutically acceptable salt thereof, may be prepared by reacting (i.e. conjugating) a compound of Formula (Illa) or (IVa), or a salt thereof, with an antibody or an antigen-binding fragment thereof. In some embodiments, a compound of Formula (Illa) or (IVa) contains moiety G1and a conjugate of Formula (Va) or (Via) contains moiety G2, as described above. Upon conjugation, a moiety G1is converted to moiety G2where G2has a point of attachment to the antibody or antigen-binding fragment thereof.Examples of G1and G2include, but are not limited to, the following moieties set out in Table 9, wherein X3is CH or N, h is 0 or 1, RKis H or CH3, Hal is Cl, Br or I, RLis Ci.6alkyl. " indicates the point of attachment to the antibody, or antigen-binding fragment thereof.Table 9. Exemplary G1and G2moieties.A further example of G1and G2is set out in Table 9A. For the example of Table 9A, sortase A enzyme may be used to effect the conjugation to the antibody or antigen-binding fragment thereof. Table 9A:Antibody or antigen-binding fragment thereofAs used herein, the term "antibody" refers to an immunoglobulin molecule that specifically binds to, or is immunologically reactive with, a particular antigen.In embodiments the antibody is isolated or recombinant. "Isolated", when used herein refers to a polypeptide, e.g., an antibody, that has been identified and separated and / or recovered from a cell or cell culture from which it was expressed. Ordinarily, an isolated antibody will be prepared by at least one purification step. Thus, an "isolated antibody" refers to an antibody which is substantially free of other antibodies having different antigenic specificities.In embodiments the antibody comprises at least two "light chains" (LC) and two "heavy chains" (HC). The light chains and heavy chains of such antibodies are polypeptides consisting of several domains. Each heavy chain comprises a heavy chain variable region (abbreviated herein as "VH") and a heavy chain constant region (abbreviated herein as "CH"). The heavy chain constant region comprises the heavy chain constant domains CHI, CH2 and CH3 (antibody classes IgA, IgD, and IgG) and optionally the heavy chain constant domain CH4 (antibody classes IgE and IgM). Each light chain comprises a light chain variable domain (abbreviated herein as "VL") and a light chain constant domain (abbreviated herein as "CL").In embodiments the antibody is a full-length antibody. An "intact" or "full-length" antibody, as used herein, refers to an antibody having two heavy (H) chain polypeptides and two light (L) chain polypeptides interconnected by disulfide bonds.A "variable region" of an antibody refers to the variable region of the antibody light chain or the variable region of the antibody heavy chain, either alone or in combination. The variable regions VH and VL can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs) (also known as hypervariable regions), interspersed with regions that are more conserved, termed framework regions (FRs). In embodiments each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The VH or VL chain of the antibody can further include all or part of a heavy or light chain constant region.Binding between an antibody and its target antigen or epitope is mediated by the CDRs. The term "epitope" refers to a target protein region (e.g. polypeptide) capable of binding to (e.g. being bound by) an antibody or antigen-binding fragment of the disclosure. The CDRs are the main determinants of antigen specificity. There are at least two techniques for determining CDRs: (1) an approach based on cross-species sequence variability (i.e., Kabat et al. Sequences of Proteins of Immunological Interest,(5th ed., 1991, National Institutes of Health, Bethesda Md.)); and (2) an approach based on crystallographic studies of antigen-antibody complexes (Al-lazikani et al. (1997) J. Molec. Biol. 273:927-948)). In addition, combinations of these two approaches are sometimes used in the art to determine CDRs.The "constant domains" (or "constant regions") of the heavy chain and of the light chain are not involved directly in binding of an antibody to a target, but exhibit various effector functions. The constant regions of the antibodies can mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system.There are five major classes of heavy chain constant region, classified as IgA, IgG, IgD, IgE and IgM, each with characteristic effector functions designated by isotype. Ig molecules interact with multiple classes of cellular receptors. For example, IgG molecules interact with three classes of Fey receptors (FcyR) specific for the IgG class of antibody, namely FcyRI, FcyRII, and FcyRIII. Binding of antibody to Fc receptors on cell surfaces triggers a number of important and diverse biological responses including engulfment and destruction of antibody-coated particles, clearance of immune complexes, lysis of antibody-coated target cells by killer cells (called antibody-dependent cell- mediated cytotoxicity, or ADCC), release of inflammatory mediators, placental transfer and control of immunoglobulin production. The important sequences for the binding of IgG to the FcyR receptors have been reported to be located in the CH2 and CH3 domains.In embodiments the antibody or antigen-binding fragment thereof is an IgG isotype. The antibody or antigen-binding fragment thereof can be any IgG subclass, for example IgGl, lgG2, lgG3, or lgG4 isotype. In embodiments the antibody or antigen-binding fragment thereof is based on an IgGl isotype.The terms "Fc region", "Fc part" and "Fc" are used interchangeably herein and refer to the portion of a native immunoglobulin that is formed by two Fc chains. Each "Fc chain" comprises a constant domain CH2 and a constant domain CH3. Each Fc chain may also comprise a hinge region. A native Fc region is homodimeric. In embodiments the Fc region may be heterodimeric because it may contain modifications to enforce Fc heterodimerisation. The Fc region contains the carbohydrate moiety and binding sites for complement and Fc receptors (including the FcRn receptor), and has no antigen binding activity. Fc can refer to this region in isolation, or this region in the context of an antibody, antibody fragment, or Fc fusion protein. Polymorphisms have been found in a number of Fc domain sites, including but not limited to EU positions 270, 272, 312, 315, 356, and 358, resulting in minor variations between sequences. As a result, every naturally occurring IgG Fc region is referred to as a "wild type IgG Fc domain" or "WT IgG Fc domain" (i.e., any allele). Human IgGl, lgG2, lgG3, and lgG4 heavy chain sequences can be obtained in a variety of sequence databases, including the UniProt database (www.uniprot.org) under accession numbers P01857(IGHG1_HUMAN), P01859 (IGHG2_HUMAN), P01860 (IGHG3_HUMAN), and P01861 (IGHG4_HUMAN) respectively.In embodiments the antibody of the disclosure is a monoclonal antibody. A "monoclonal antibody" (mAb) refers to a homogeneous antibody population involved in the highly specific recognition and binding of a single antigenic determinant, or epitope. This is in contrast to polyclonal antibodies that typically include different antibodies directed against different antigenic determinants. The term "monoclonal antibody" can encompass both full-length monoclonal antibodies as well as antibody fragments (such as Fab, Fab1, F(ab')2, Fv), single chain (scFv) mutants, fusion proteins comprising an antibody portion, and any other modified immunoglobulin molecule comprising an antigen recognition site. Furthermore, "monoclonal antibody" refers to such antibodies made in any number of ways including, but not limited to, hybridoma, phage selection, recombinant expression, and transgenic animals. In embodiments the antibody of the disclosure is an isolated monoclonal antibody. In further embodiments the antibody is a fully human monoclonal antibody.In embodiments the antibody of the disclosure is a full-length antibody described above. Alternatively, the antibody can be an antigen-binding fragment. The term "antigen-binding fragment" as used herein incudes any naturally-occurring or artificially-constructed configuration of an antigen-binding polypeptide comprising one, two or three light chain CDRs, and / or one, two or three heavy chain CDRs, wherein the polypeptide is capable of binding to the antigen.In embodiments the antigen-binding fragment of the disclosure is a Fab fragment. The antibody according to the disclosure can also be a Fab', an Fv, an scFv, an Fd, a V NAR domain, an IgNAR, an intrabody, an IgG CH2, a minibody, a single-domain antibody, an Fcab, an scFv-Fc, F(ab')2, a di-scFv, a bi-specific T-cell engager (BITE), a F(ab')3, a tetrabody, a triabody, a diabody, a DVD-lg, an (scFv)2, a mAb2 or a DARPin.The terms "Fab fragment" and "Fab" are used interchangeably herein and contain a single light chain (e.g. a constant domain CL and a VL) and a single heavy chain (e.g. a constant domain CHI and a VH). The heavy chain of a Fab fragment is not capable of forming a disulfide bond with another heavy chain.A "Fab1fragment" contains a single light chain and a single heavy chain but in addition to the CHI and the VH, a "Fab' fragment" contains the region of the heavy chain between the CHI and CH2 domains that is required for the formation of an inter-chain disulfide bond. Thus, two "Fab1fragments" can associate via the formation of a disulfide bond to form a F(ab')2 molecule.A "F(ab')2 fragment" contains two light chains and two heavy chains. Each chain includes a portion of the constant region necessary for the formation of an inter-chain disulfide bond between two heavy chains.An "Fv fragment" contains only the variable regions of the heavy and light chain. It contains no constant regions.A "single-domain antibody" is an antibody fragment containing a single antibody domain unit (e.g., VH or VL).A "single-chain Fv" ("scFv") is antibody fragment containing the VH and VL domain of an antibody, linked together to form a single chain. A polypeptide linker is commonly used to connect the VH and VL domains of the scFv.A "tandem scFv", also known as a TandAb, is a single-chain Fv molecule formed by covalent bonding of two scFvs in a tandem orientation with a flexible peptide linker.A "bi-specific T cell engager" (BiTE) is a fusion protein consisting of two single-chain variable fragments (scFvs) on a single peptide chain. One of the scFvs binds to T cells via the CD3 receptor, and the other to a tumour cell antigen.A "diabody" is a small bivalent and bispecific antibody fragment comprising a heavy chain variable domain (VH) connected to a light chain variable domain (VL) on the same polypeptide chain (VH- VL) connected by a peptide linker that is too short to allow pairing between the two domains on the same chain (Kipriyanov, Int. J. Cancer 77 (1998), 763-772). This forces pairing with the complementary domains of another chain and promotes the assembly of a dimeric molecule with two functional antigen binding sites.A "DARPin" is a bispecific ankyrin repeat molecule. DARPins are derived from natural ankyrin proteins, which can be found in the human genome and are one of the most abundant types of binding proteins. A DARPin library module is defined by natural ankyrin repeat protein sequences, using 229 ankyrin repeats for the initial design and another 2200 for subsequent refinement. The modules serve as building blocks for the DARPin libraries. The library modules resemble human genome sequences. A DARPin is composed of 4 to 6 modules. Because each module is approx. 3.5 kDa, the size of an average DARPin is 16-21 kDa. Selection of binders is done by ribosome display, which is completely cell-free and is described in He M. and Taussig MJ., Biochem Soc Trans. 2007, Nov;35(Pt 5):962-5.In embodiments the antibody or antigen-binding fragment thereof can be further modified to contain additional chemical moieties not normally part of the protein. Those derivatised moieties can improve the solubility, the biological half-life or absorption of the protein. The moieties can also reduce or eliminate any desirable side effects of the proteins and the like. An overview for those moieties can be found in Remington's Pharmaceutical Sciences, 2nd ed., Ed. Lloyd V. Allen, Jr. (2012).Pharmaceutical CompositionsThe term "pharmaceutical composition" refers to a preparation which is in such form as to permit the biological activity of the active ingredient, and which contains no additional components which are unacceptably toxic to a patient to which the composition would be administered. Such compositions can be sterile. A pharmaceutical composition according to the present specification comprises a compound of Formula (I), (la), (II) or (Ila), or a pharmaceutically acceptable salt thereof, or a conjugate of Formula (V), (Va), (VI) or (Via), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In embodiments, a pharmaceutical composition comprises a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, or a conjugate of Formula (V) or (VI), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.In embodiments there is provided a pharmaceutical composition comprising a conjugate of Formula (V), (Va), (VI) or (Via) (e.g. a conjugate of Formula (V) or (VI)), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, carrier, buffer or stabilizer. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient. The precise nature of the carrier or other material will depend on the route of administration, which may be oral, or by injection, e.g. cutaneous, subcutaneous, or intravenous.In embodiments there is provided a pharmaceutical composition comprising a conjugate of Formula (V), (Va), (VI) or (Via) (e.g. a conjugate of Formula (V) or (VI)), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable, non-toxic, sterile carrier. In further embodiments the carrier is a physiological saline, non-toxic buffer, or preservative. Suitable formulations for use in the therapeutic methods disclosed herein are described in Remington's Pharmaceutical Sciences, 2nd ed., Ed. Lloyd V. Allen, Jr. (2012), the contents of which are incorporated by reference.Examples of suitable excipients include one or more of water, saline, phosphate buffered saline, dextrose, glycerol and ethanol, as well as any combination thereof. In embodiments there isprovided a pharmaceutical composition comprising a conjugate of Formula (V), (Va), (VI) or (Via) (e.g. a conjugate of Formula (V) or (VI)), or a pharmaceutically acceptable salt thereof, and one or more isotonic agents. In further embodiments the one or more isotonic agents are selected from a sugar, a polyalcohol and sodium chloride.In embodiments there is provided a pharmaceutical composition comprising a conjugate of Formula (V), (Va), (VI) or (Via) (e.g. a conjugate of Formula (V) or (VI)), or a pharmaceutically acceptable salt thereof, contained within one or more formulations selected from a capsule, a tablet, an aqueous suspension, a solution, a nasal aerosol, and a lyophilized powder which can be reconstituted to make a suspension or solution before use.In embodiments there is provided a pharmaceutical composition comprising a conjugate of Formula (V), (Va), (VI) or (Via) (e.g. a conjugate of Formula (V) or (VI)), or a pharmaceutically acceptable salt thereof, a buffer, a surfactant and / or a stabilizer agent. In further embodiments the buffer is an acetate, phosphate or citrate buffer. In further embodiments the surfactant is polysorbate. In further embodiments the stabilizer agent is human albumin.The pharmaceutical composition comprising a conjugate of Formula (V), (Va), (VI) or (Via) (e.g. a conjugate of Formula (V) or (VI)), or a pharmaceutically acceptable salt thereof, can be administered to a patient by any appropriate systemic or local route of administration. For example, administration may be oral, buccal, sublingual, ophthalmic, intranasal, intratracheal, pulmonary, topical, transdermal, urogenital, rectal, subcutaneous, intravenous, intra-arterial, intraperitoneal, intramuscular, intracranial, intrathecal, epidural, intraventricular or intratumoural.The pharmaceutical composition comprising a conjugate of Formula (V), (Va), (VI) or (Via) (e.g. a conjugate of Formula (V) or (VI)), or a pharmaceutically acceptable salt thereof, can be formulated for administration by any appropriate means, for example by epidermal or transdermal patches, ointments, lotions, creams, or gels; by nebulizers, vaporizers, or inhalers; by injection or infusion; or in the form of capsules, tablets, liquid solutions or suspensions in water or non-aqueous media, drops, suppositories, enemas, sprays, or powders. The most suitable route for administration in any given case will depend on the physical and mental condition of the subject, the nature and severity of the disease, and the desired properties of the formulation.Pharmaceutical compositions comprising a conjugate of Formula (V), (Va), (VI) or (Via) (e.g. a conjugate of Formula (V) or (VI)), or a pharmaceutically acceptable salt thereof, for oral administration may be in tablet, capsule, powder or liquid form. A tablet may comprise a solid carrier or an adjuvant. Liquid pharmaceutical compositions generally comprise a liquid carrier suchas water, petroleum, animal or vegetable oils, mineral oil or synthetic oil. Physiological saline solution, dextrose or other saccharide solution or glycols such as ethylene glycol, propylene glycol or polyethylene glycol may be included. A capsule may comprise a solid carrier such a gelatin.For intravenous, cutaneous or subcutaneous injection, or injection at the site of affliction, the conjugate of Formula (V), (Va), (VI) or (Via) (e.g. the conjugate of Formula (V) or (VI)), or a pharmaceutically acceptable salt thereof, will be in the form of a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability. Those of relevant skill in the art are well able to prepare suitable solutions using, for example, isotonic vehicles such as Sodium Chloride Injection, Ringer's Injection, Lactated Ringer's Injection. Preservatives, stabilizers, buffers, antioxidants and / or other additives may be included, as required.A pharmaceutical composition comprising a compound of Formula (I), (la), (II) or (Ila) (e.g. a compound of Formula (I) or (II)), or a pharmaceutically acceptable salt thereof may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing). Such compositions may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, pharmaceutical compositions comprising a compound of Formula (I), (la), (II) or (Ila) (e.g. a compound of Formula (I) or (II)), or a pharmaceutically acceptable salt thereof, intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and / or preservative agents. An effective amount of the compound of Formula (I), (la), (II) or (Ila) (e.g. the compound of Formula (I) or (II)), or a pharmaceutically acceptable salt thereof, will normally be present in the composition.TherapyIn one aspect there is provided a compound of Formula (I), (la), (II) or (Ila) (e.g. a compound of Formula (I) or (II)), or a pharmaceutically acceptable salt thereof, for use in therapy.In one aspect there is provided a compound of Formula (I), (la), (II) or (Ila) (e.g. a compound of Formula (I) or (II)), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.In one aspect there is provided a conjugate of Formula (V), (Va), (VI) or (Via) (e.g. a conjugate of Formula (V) or (VI)), or a pharmaceutically acceptable salt thereof, for use in therapy.In one aspect there is provided a conjugate of Formula (V), (Va), (VI) or (Via) (e.g. a conjugate of Formula (V) or (VI)), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.Where "cancer" is mentioned, this includes both non-metastatic cancer and also metastatic cancer, such that treating cancer involves treatment of both primary tumours and also tumour metastases.The term "therapy" is intended to have its normal meaning of dealing with a disease in order to entirely or partially relieve one, some or all of its symptoms, or to correct or compensate for the underlying pathology. The term "therapy" also includes "prophylaxis" unless there are specific indications to the contrary. The terms "therapeutic" and "therapeutically" should be interpreted in a corresponding manner.The term "prophylaxis" is intended to have its normal meaning and includes primary prophylaxis to prevent the development of the disease and secondary prophylaxis whereby the disease has already developed and the patient is temporarily or permanently protected against exacerbation or worsening of the disease or the development of new symptoms associated with the disease.The term "treatment" is used synonymously with "therapy". Similarly, the term "treat" can be regarded as "applying therapy" where "therapy" is as defined herein.In embodiments there is provided a conjugate of Formula (V), (Va), (VI) or (Via) (e.g. a conjugate of Formula (V) or (VI)), or a pharmaceutically acceptable salt thereof, for use in the treatment of HER2 positive cancer.In one aspect there is provided the use of a conjugate of Formula (V), (Va), (VI) or (Via) (e.g. a conjugate of Formula (V) or (VI)), or a pharmaceutically acceptable salt thereof, as described herein, in the manufacture of a medicament, such as a medicament for the treatment of cancer.In one aspect there is provided the use of a compound of Formula (I), (la), (II) or (Ila) (e.g. a compound of Formula (I) or (II)), or a pharmaceutically acceptable salt thereof, as described herein, in the manufacture of a medicament, such as a medicament for the treatment of cancer.In one aspect there is provided a method of treating cancer in a patient comprising administering to the patient an effective amount of a conjugate of Formula (V), (Va), (VI) or (Via) (e.g. a conjugate of Formula (V) or (VI)), or a pharmaceutically acceptable salt thereof.In one aspect there is provided a method of treating cancer in a patient comprising administering to the patient an effective amount of a compound of Formula (I), (la), (II) or (Ila) (e.g. a compound of Formula (I) or (II)), or a pharmaceutically acceptable salt thereof.Terms such as "treating" or "treatment" refer to both (1) therapeutic measures that cure, slow down, lessen symptoms of, and / or halt progression of a diagnosed pathologic condition or disorder and (2) prophylactic or preventative measures that prevent and / or slow the development of a targeted pathologic condition or disorder. Thus, those in need of treatment include those already with the disorder; those prone to have the disorder; and those in whom the disorder is to be prevented. In certain aspects, a patient is successfully "treated" for cancer according to the methods of the present disclosure if the patient shows, e.g., total, partial, or transient remission of a certain type of cancer.The term "effective amount" means an amount of an active ingredient which is sufficient enough to significantly and positively modify the symptoms and / or conditions to be treated (e.g., provide a positive clinical response). The effective amount of an active ingredient for use in a pharmaceutical composition will vary with the particular condition being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular active ingredient(s) being employed, the particular pharmaceutically acceptable excipient(s) / carrier(s) utilized, and like factors within the knowledge and expertise of the attending physician.The term "patient" refers to any animal (e.g., a mammal), including, but not limited to humans, non-human primates, rodents, and the like, which is to be the recipient of a particular treatment. In embodiments the term "patient" refers to a human subject.In embodiments there is provided a method of treating cancer in a patient comprising administering to the patient an effective amount of a conjugate of Formula (V), (Va), (VI) or (Via) (e.g. a conjugate of Formula (V) or (VI)), or a pharmaceutically acceptable salt thereof, wherein the cancer is a HER2 positive cancer.In embodiments there is provided a conjugate of Formula (V), (Va), (VI) or (Via) (e.g. a conjugate of Formula (V) or (VI)), or a pharmaceutically acceptable salt thereof, and an additional anti-tumour substance for the conjoint treatment of cancer.In embodiments there is provided a combination for use in the treatment of cancer comprising a conjugate of Formula (V), (Va), (VI) or (Via) (e.g. a conjugate of the Formula (V) or (VI)), or a pharmaceutically acceptable salt thereof and an additional anti-tumour agent.In embodiments there is provided a conjugate of Formula (V), (Va), (VI) or (Via) (e.g. a conjugate of the Formula (V) or (VI)), or a pharmaceutically acceptable salt thereof, in combination with an additional anti-tumour agent.Herein, where the term "conjoint treatment" is used in reference to a combination treatment, it is to be understood that this may refer to simultaneous, separate or sequential administration. In one aspect, "conjoint treatment" refers to simultaneous administration. In another aspect, "conjoint treatment" refers to separate administration. In a further aspect, "conjoint treatment" refers to sequential administration.In embodiments there is provided a method of treating cancer in a patient comprising administering to the patient an effective amount of a conjugate of Formula (V), (Va), (VI) or (Via) (e.g. a conjugate of Formula (V) or (VI)), or a pharmaceutically acceptable salt thereof, and simultaneously, separately or sequentially administering at least one additional anti-tumour substance to said patient, where the amounts of the conjugate of Formula (V), (Va), (VI) or (Via) (e.g. a conjugate of Formula (V) or (VI)), or pharmaceutically acceptable salt thereof, and the additional anti-tumour substance are jointly effective in producing an anti-cancer effect.In embodiments there is provided a compound of Formula (I), (la), (II) or (Ila) (e.g. a compound of Formula (I) or (II)), or a pharmaceutically acceptable salt thereof, and an additional anti-tumour substance for the conjoint treatment of cancer.In embodiments there is provided a combination for use in the treatment of cancer comprising a compound of Formula (I), (la), (II) or (Ila) (e.g. a compound of Formula (I) or (II)), or a pharmaceutically acceptable salt thereof and an additional anti-tumour agent.In embodiments there is provided a compound of Formula (I), (la), (II) or (Ila) (e.g. a compound of Formula (I) or (II)), or a pharmaceutically acceptable salt thereof, in combination with an additional anti-tumour agent.In embodiments there is provided a method of treating cancer in a patient comprising administering to the patient an effective amount of a compound of Formula (I), (la), (II) or (Ila) (e.g. a compound of Formula (I) or (II)), or a pharmaceutically acceptable salt thereof, and simultaneously, separately or sequentially administering at least one additional anti-tumour substance to said patient, where the amounts of the compound of Formula (I), (la), (II) or (Ila) (e.g. the compound of Formula (I) or (II)), or pharmaceutically acceptable salt thereof, and the additional anti-tumour substance are jointly effective in producing an anti-cancer effect.EXAMPLESThe specification will now be illustrated by the following non-limiting Examples.General InformationReagents and solvents (all anhydrous HPLC-grade), including PNU-159682 carboxylic acid (CAS No.: 1204819-92-0), were obtained from commercial suppliers and used without any further purification unless otherwise stated. All reagents were weighed and handled in air unless otherwise stated. Brine refers to a saturated solution of NaCI. Concentration under reduced pressure refers to the use of a rotary evaporator.AbbreviationsACN acetonitrileBoc tert-butyloxycarbonylDBU l,8-diazabicyclo(5.4.0)undec-7-eneDCM dichloromethaneDEA diethylamineDIC diisopropylcarbodiimideDMF dimethylformamideDMSO dimethylsulfoxide1DMA dimethylacetamideDIEA, DIPEA N,N-diisopropylethylamineEDC l-ethyl-3-(3-dimethylaminopropyl)carbodiimideFA formic acidFmoc 9-fluorenylmethyloxycarbonylFmoc-OSu N-(9H-fluorenylmethoxycarbonyloxy)succinimideHATU hexafluorophosphate azabenzotriazole tetramethyl uroniumHFIP hexafluoro-2-propanolHOBt hydroxybenzotriazoleInt Intermediate compound mAb monoclonal antibodyMTBE methyl tert-butyl etherNMI 1-methylimidazole1In the context of NMR characterisation in the below examples, "DMSO" refers to c / 6-DMSO.[ethyl cyano(hydroxyimino)acetato-O2]tri-l-pyrrolidinylphosphoniumPyOxim hexafluorophosphateRT, rt room temperatureTBAF tetra-n-butylammonium fluorideTBS tert-butyldimethylsilylTCFH chloro-N,N,N',N'-tetra-methylformamidinium hexa-fluorophosphateTEA triethylamineTEA trifluoroacetic acidTLC thin layer chromatographyTCEP tris(2-carboxyethyl)phosphine hydrochlorideTHF tetrahydrofuranPAYLOAD SYNTHESISGeneral procedure I: Synthesis of amide by the coupling reaction of acid with amine using PyOxim or HATU((2S,4S)-2,5,12-trihydroxy-7-methoxy-4-(((lS,3R,4aS,9S,9aR,10aS)-9-methoxy-l-methyloctahydro- lH-pyrano[4',3':4,5]oxazolo[2,3-c][l,4]oxazin-3-yl)oxy)-6,ll-dioxo-l,2,3,4,6,ll- hexahydrotetracene-2-carboxylic acid (CAS No.: 1204819-92-0; "PNU-159682 carboxylic acid") was added to a solution of DIEA (5 eq) and mono-protected diamine (2-3 eq) in DMA / MeCN (v / v: 1 / 3) at 25 °C under nitrogen. PyOxim (2 eq) / or HATU (2 eq) was added. The resulting mixture was stirred at 25 °C for a few hours. The solvent was removed under reduced pressure. The crude product was purified by flash C18 chromatography using 0 to 100% MeCN in water (5%NH4HCO3) to afford the product.General procedure II: deprotection of Boc-amineMethod A: Boc protected amine was dissolved in 1,4-dioxane, then HCI solution (4 M in dioxane) was added in one portion at 0 °C under nitrogen. The resulting mixture was stirred at 25 °C for a few hours until the reaction was completed, and then concentrated to remove the solvent. The crude product was purified by preparative HPLC using MeCN / water (containing 0.01% NH4HCO3) to afford the product.Method B: TFA (40 mL) was added to Boc protected amine (~ 8.0 mmol) in DCM (60 ml) under nitrogen. The resulting mixture was stirred at 25 °C for a few hours. The solvent was removed under reduced pressure. The crude product was purified by flash C18 chromatography using elution gradient 0 to 100% MeCN in water (0.1% NH4HCO3) to afford the product.General procedure III: deprotection of Fmoc-amine: A DCM solution of DBU (15.2 mg / mL) (0. 45 eq) was added dropwise to Fmoc protected amine in a mixture of DCM and acetonitrile (v / v: 1 / 1) under nitrogen. The resulting mixture was stirred at 0 °C for a few hours until the reaction was completed. The reaction mixture was quenched with 0.1% NH4HCO3. The solvent was removed under reduced pressure. The crude product was purified by combi-flash or preparative HPLC (YMC- Actus Triant C18 Column, 20 x 250 mm, 5pm; Mobile Phase A: Water (lOmmol / L NH4HC03+0.1%NH3H20), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient: 40% B to 54% B in 10 min) to afford the product.Step 1 - Intermediate Compound 1: (9H-fluoren-9-yl)methyl 3,6-diazabicyclo[3.1.1]heptane-6- carboxylate, HCI saltHCIFmoc tert-Butyl 3,6-diazabicyclo[3.1.1]heptane-3-carboxylate (500 mg, 2.52 mmol) was added to a solution of N,N-diisopropylethylamine (978 mg, 7.57 mmol) and N-(9H-fluoren-2- ylmethoxycarbonyloxyjsuccinimide (936 mg, 2.77 mmol) in DCM (10 mL). The resulting mixture was stirred at 25 °C for 2 hours. The reaction mixture was quenched with water. The organic layer was separated, the aq solution was extracted with DCM. The combined organic solution was dried over Na2SO4, and concentrated to afford the crude intermediate. The crude intermediate was treated with HCI solution (4 M in dioxane) according to General Procedure II, Method A to affordIntermediate Compound 1 (800 mg, 99 %) as a white solid.NMR (400 MHz, DMSO) 6 1.22 - 1.37 (m, 3H), 1.93 - 2.09 (m, 1H), 2.58 - 2.71 (m, 1H), 2.75 - 2.91 (m, 1H), 3.08 - 3.22 (m, 1H), 3.28 (d, J = 12.6 Hz, 1H), 4.12 - 4.47 (m, 4H), 7.35 (qd, J = 1.2, 7.3 Hz, 2H), 7.40 - 7.47 (m, 2H), 7.68 (dd, J = 7.4, 22.5 Hz, 2H), 7.86 - 7.94 (m, 2H). ES+[M+H]+: 321.Step 2 - Intermediate Compound 2: (9H-fluoren-9-yl)methyl 3-((2S,4S)-2,5,12-trihydroxy-7- methoxy-4-(((lS,3R,4aS,9S,9aR, 10aS)-9-methoxy-l-methyloctahydro-lH- pyrano[4',3':4,5]oxazolo[2,3-c][l,4]oxazin-3-yl)oxy)-6,ll-dioxo-l,2,3,4,6,ll-hexahydrotetracene-2- carbonyl)-3,6-diazabicyclo- [3.1.1]heptane-6-carboxylateGeneral Procedure I was followed using the PNU-159682 carboxylic acid (CAS No. 1204819-92-0; 150 mg, 0.24 mmol), DIEA (0.209 mL, 1.20 mmol) and Intermediate compound 1 (191 mg, 0.60 mmol) and PyOxim (244 mg, 0.48 mmol) to synthesize Intermediate compound 2 (110 mg, 49.5 %) as a red solid. ES+[M+1]: 930.Step 3 - Compound P1: (8S,10S)-8-(3,6-diazabicyclo[3.1.1]heptane-3-carbonyl)-6,8,11-trihydroxy-1- methoxy-10-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo [2,3-c][1,4]oxazin-3-yl)oxy)-7,8,9,10-tetrahydrotetracene-5,12-dioneGeneral procedure II was followed using DCM solution of DBU (15.2 mg / mL) (0.53 mL, ~0.05mmol) and Intermediate Compound 2 (100 mg, 0.11 mmol) to afford Compound P1 (15.00 mg, 19.71 %) as a red solid.1H NMR (300 MHz, CDCl3) δ 1.41 (t, J = 6.4 Hz, 3H), 1.62-1.71 (m, 1H),1.76-1.79 (m, 2H), 1.90-2.03 (m, 1H), 2.38 – 2.60 (m, 1H), 2.70-2.85 (m, 4H), 3.10 (t, J = 18.5 Hz, 1H), 3.39 (d, J = 6.6 Hz, 1H), 3.48 (s, 3H), 3.54 – 3.64 (m, 2H), 3.77 (dd, J = 13.7, 21.1 Hz, 2H), 3.93 (m, 3H), 3.95-4.09 (m, 5H), 4.220-4.26 (m, 1H), 4.36 (s, 1H), 4.50 (d, J = 1.9 Hz, 1H), 4.66 (d, J = 12.9 Hz, 1H), 4.73 (s, 1H), 4.91 (d, J = 7.6 Hz, 1H), 5.39 (s, 1H), 5.58 (d, J = 5.1 Hz, 1H) 7.42 (d, J = 8.5 Hz, 1H), 7.80 (t, J = 8.1 Hz, 1H), 8.06 (d, J = 7.7 Hz, 1H), 13.38 (s, 1H), 13.97 (d, J = 4.1 Hz, 1H). ES+[M+1] = 708.15. Example 2: Synthesis of Compound P2Step 1 - Intermediate Compound 3: 3-((9H-fluoren-9-yl)methyl) 6-(tert-butyl) 3,6- diazabicyclo[3.1.1]heptane-3,6-dicarboxylateN-(9H-Fluoren-2-ylmethoxycarbonyloxy)succinimide (3.40 g, 10.09 mmol) was added to a mixture of tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (2 g, 10.09 mmol) and DIEA (3.52 mL, 20.17 mmol) in DCM (60 mL) under nitrogen. The resulting mixture was stirred at 25 °C for 2 hours. The reaction mixture was diluted with DCM (300 mL), and washed sequentially with water (3 x 250 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford Intermediate Compound 3 (3.50 g, yield: 83 %) as a yellow solid.1H NMR (400 MHz, DMSO) δ 1.29 – 1.34 (m, 9H), 2.44 (s, 2H), 3.81 (dd, J = 2.8, 12.2 Hz, 2H), 3.99 (s, 1H), 4.06 (s, 2H), 4.23 – 4.31 (m, 2H), 4.40 (t, J = 8.7 Hz, 2H), 7.33 – 7.35 (m, 2H), 7.43 (s, 2H), 7.66 (d, J = 7.5 Hz, 2H), 7.91 (d, J = 7.5 Hz, 2H). ES+[M+23]: 443. Step 2 - Intermediate Compound 4: (9H-fluoren-9-yl)methyl 3,6-diazabicyclo[3.1.1]heptane-3- carboxylate, TFA saltGeneral Procedure II, Method B was followed using Intermediate Compound 3 (3.4 g, 8.09 mmol) in DCM (60 mL) to afford Intermediate Compound 4 (2.300 g, yield: 89 %) as a pale yellow solid.1H NMR (400 MHz, DMSO) δ 1.75 (dd, J = 5.7, 10.5 Hz, 1H), 2.76 – 2.87 (m, 1H), 3.68 – 3.78 (m, 3H), 3.82 (dd, J = 2.1, 12.7 Hz, 1H), 4.28 – 4.48 (m, 5H), 7.31 – 7.40 (m, 2H), 7.40 – 7.48 (m, 2H), 7.69 (dd, J = 2.2, 7.4 Hz, 2H), 7.92 (d, J = 7.5 Hz, 2H). ES+(M+1 = 321). Step 3 – Intermediate Compound 5: (9H-fluoren-9-yl)methyl 6-((2S,4S)-2,5,12-trihydroxy-7- methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H- pyrano[4’,3’:4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracene-2- carbonyl)-3,6-diazabicyclo[3.1.1]heptane-3-carboxylateGeneral Procedure I was followed using PyOxim (652 mg, 1.27 mmol), the PNU-159682 carboxylic acid (CAS No.1204819-92-0; 400 mg, 0.64 mmol), Intermediate Compound 4 (511 mg, 1.59 mmol) and DIEA (0.557 mL, 3.19 mmol) in DMA (8 mL) to afford Intermediate Compound 5 (500 mg, yield: 84 %) as a red solid.NMR (400 MHz, DMSO) δ 1.27 (dd, J = 4.0, 6.6 Hz, 3H), 1.54 (dd, J = 8.8, 17.9 Hz, 2H), 1.63 – 1.75 (m, 3H), 2.25 (d, J = 6.0 Hz, 1H), 2.30 – 2.39 (m, 2H), 2.63 – 2.69 (m, 3H), 2.85 – 3.12 (m, 4H), 3.32 (d, J = 2.4 Hz, 2H), 3.50 (d, J = 7.9 Hz, 2H), 3.61 – 3.71 (m, 3H), 3.98 (s, 3H), 4.24 – 4.37 (m, 6H), 4.89 (s, 1H), 5.23 (d, J = 5.0 Hz, 2H), 5.33 (d, J = 10.0 Hz, 1H), 7.32 – 7.37 (m, 3H), 7.39 – 7.44 (m, 3H), 7.67 (d, J = 7.7 Hz, 2H), 7.86 – 7.92 (m, 4H), 13.17 (s, 1H), 14.00 (s, 1H). ES+(M+1 = 930). Step 4 - Compound P2: (8S,10S)-8-(3,6-diazabicyclo[3.1.1]heptane-6-carbonyl)-6,8,11-trihydroxy-1- methoxy-10-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H- pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-7,8,9,10-tetrahydrotetracene-5,12-dioneGeneral Procedure III was followed using DCM solution of DBU（15.2 mg / mL in DCM）(0.354 mL, ~0.35 mmol) and Intermediate Compound 5 (470 mg, 0.51 mmol) to afford Compound P2 (59.0 mg, yield: 16.50 %) as a red solid.1HNMR (400 MHz, CDCl3) δ 1.38-1.47 (m, 3H), 1.70-1.88 (m, 2H), 1.93-2.10 (m, 1H), 2.30 – 2.58 (m, 2H), 2.70 – 2.86 (m, 3H), 3.06 – 3.17 (m, 2H), 3.27 – 3.43 (m, 3H), 3.48 (s, 3H), 3.53 – 3.64 (m, 3H), 3.92 – 4.11 (m, 6H), 4.47 (dd, J = 6.3, 17.4 Hz, 2H), 4.69 (d, J = 23.4 Hz, 2H), 4.83 – 4.90 (m, 1H), 5.31 (d, J = 18.9 Hz, 1H), 5.45 – 5.55 (m, 1H), 7.39 (dd, J = 5.0, 8.6 Hz, 1H), 7.74 – 7.85 (m, 1H), 8.03 (dd, J = 2.6, 7.7 Hz, 1H), 13.91 (s, 1H). ES+(M+1 = 708).Example 3: Synthesis of Compound P2aCompound P2a: (8S,10S)-8-(6-acetyl-3,6-diazabicyclo[3.1.1] heptane-3-carbonyl)-6,8,11-trihydroxy- 1-methoxy-10-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5] oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-7,8,9,10-tetrahydrotetracene-5,12-dioneGeneral Procedure I was followed using 1-(3,6-diazabicyclo[3.1.1]heptan-6-yl)ethan-1-one (53.6 mg, 0.38 mmol), the PNU-159682 carboxylic acid (CAS No.1204819-92-0; 120 mg, 0.19 mmol), HATU (145 mg, 0.38 mmol) and DIEA (0.100 mL, 0.57 mmol) to afford Compound P2a (23.00 mg, 16.04 %) as a red solid.1H NMR (300 MHz, DMSO) δ 1.16 – 1.30 (m, 3H), 1.54 (t, J = 10.2 Hz, 1H), 1.70 (s, 2H), 2.02 (d, J = 3.3 Hz, 3H), 2.65 (d, J = 8.5 Hz, 2H), 2.91 (dd, J = 9.9, 18.9 Hz, 3H), 2.93 – 3.02 (m, 2H), 3.05 – 3.14 (m, 3H), 3.52 (d, J = 6.1 Hz, 1H), 3.66 (d, J = 10.0 Hz, 1H),3.68 - 3.75 (m, 4H), 3.92 (dd, J = 9.2, 15.0 Hz, 1H), 4.00 (s, 3H), 4.24 (s, 1H), 4.35 (d, J = 17.8 Hz, 1H), 4.59 (s, 1H), 4.88 (s, 1H), 4.99 (s, 1H), 5.07 (s, 1H), 5.24 (s, 1H), 5.26 – 5.38 (m, 2H), 7.68 (q, J = 4.3, 4.9 Hz, 1H), 7.93 (d, J = 4.8 Hz, 2H), 13.28 (s, 1H), 14.06 (s, 1H). ES+(M+1= 750).Example 4: Synthesis of Compound P2b:Step 1 – Intermediate Compound 6: tert-butyl 3-(2-hydroxyacetyl)-3,6-diazabicyclo[3.1.1]heptane- 6-carboxylate General Procedure I was followed using tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (1 g, 5.04 mmol), 2-hydroxyacetic acid (1.918 g, 25.22 mmol), HATU (4.79 g, 12.61 mmol) and N,N- Diisopropylethylamine (3.26 g, 25.22 mmol) in DMA (20 mL) to afford Intermediate Compound 6 (1.000 g, 77 %) as a yellow solid.NMR (400 MHz, DMSO) δ 1.36 (s, 9H), 2.42 – 2.50 (m, 1H), 3.34 (s, 1H), 3.36 (d, J = 1.2 Hz, 1H), 3.46 (d, J = 11.2 Hz, 1H), 3.75 – 3.91 (m, 1H), 3.97 – 4.20 (m, 4H), 4.57 (s, 1H). ES+(M+1 = 257).Step 2 – Intermediate Compound 7: 1-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-2-hydroxyethan-1-one, HCl saltGeneral Procedure II, Method A was followed using Intermediate Compound 6 (1g, 3.90 mmol) to afford Intermediate Compound 7 (0.600 g, 85 %) as a yellow solid.1H NMR (400 MHz, DMSO) δ 1.67 – 1.82 (m, 1H), 2.84 (m, 1H), 3.72 – 3.95 (m, 2H), 4.00 – 4.10 (m, 1H), 4.19 (d, J = 15.7 Hz, 1H), 4.33 (d, J = 5.7 Hz, 1H), 4.79 (s, 3H), 10.21 (s, 1H). ES+(M+1 = 157). Step 3 – Compound P2b: (8S,10S)-6,8,11-trihydroxy-8-(3-(2-hydroxyacetyl)-3,6- diazabicyclo[3.1.1]heptane-6-carbonyl)-1-methoxy-10-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1- methyloctahydro-1H-pyrano[4',3':4,5] oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-7,8,9,10- tetrahydrotetracene-5,12-dioneGeneral Procedure I was followed using the PNU-159682 carboxylic acid (CAS No.1204819-92-0; 150 mg, 0.24 mmol), Intermediate Compound 7 (112 mg, 0.72 mmol), PyOxim (244 mg, 0.48 mmol) and N,N-diisopropylethylamine (154 mg, 1.20 mmol) to afford Compound P2b (40.0 mg, 21.86 %) as a red solid.1HNMR (400 MHz, DMSO) δ 1.15-1.25 (m, 3H), 1.53-1.58 (m, 1H), 1.70 (b, 2H), 2.01 – 2.41 (m, 3H), 2.57 – 2.78 (m, 3H), 2.85 – 2.98 (m, 1H), 3.04-3.10 (m, 1H), 3.32 (s, 3H), 3.46 – 3.76 (m, 4H), 3.79 – 4.20 (m, 9H), 4.21 – 4.26 (m, 1H), 4.36 (d, J = 24.6 Hz, 1H), 4.47 – 4.64 (m, 2H), 4.79-5.06 (m, 2H), 5.20 – 5.52 (m, 2H), 7.66 (m, 1H), 7.88 – 7.95 (m, 2H), 13.26 (s, 1H), 14.04 (s, 1H). ES+(M+1 = 766).Example 5: Synthesis of Compound P3Step 1 – Intermediate Compound 8: 2-((9H-fluoren-9-yl)methyl) 5-(tert-butyl) (1R,4R)-2,5- diazabicyclo[2.2.2]octane-2,5-dicarboxylatetert-Butyl (1R,4R)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (500 mg, 2.36 mmol) was added to a mixture of N-(9H-fluoren-2-ylmethoxycarbonyloxy)succinimide (794 mg, 2.36 mmol) and DIEA (1.234 mL, 7.07 mmol) in DCM (10 mL) under nitrogen. The resulting mixture was stirred at 25 °C for 2 hours. The reaction mixture was diluted with DCM (100 mL), and washed sequentially with water ( 2 x 80 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford Intermediate Compound 8 (1100 mg, 99 %) as a yellow solid.1H NMR (300 MHz, DMSO) δ 1.41 (d, J = 3.3 Hz, 9H), 1.74 (dt, J = 10.2, 20.1 Hz, 5H), 3.25 – 3.32 (m, 1H), 3.35 – 3.43 (m, 1H), 4.07 (d, J = 23.5 Hz, 2H), 4.28 (d, J = 6.0 Hz, 1H), 4.39 (dd, J = 3.7, 6.5 Hz, 2H), 5.76 (s, 1H), 7.30 – 7.47 (m, 4H), 7.64 (t, J = 6.6 Hz, 2H), 7.90 (dd, J = 1.6, 7.4 Hz, 2H). ES+(M+23 = 457.3). Step 2 – Intermediate Compound 9: (9H-fluoren-9-yl)methyl (1R,4R)-2,5-diazabicyclo[2.2.2]octane- 2-carboxylate, HCl saltGeneral Procedure II, Method A was followed using Intermediate Compound 8 (1.5 g, 3.45 mmol) to afford Intermediate Compound 9 (0.900 g, 70.3 %) as a white solid.1H NMR (300 MHz, DMSO) δ 1.18 – 1.33 (m, 1H), 1.74 – 1.82 (m, 3H), 2.08 (d, J = 13.6 Hz, 1H), 3.17 – 3.44 (m, 4H), 3.60 – 3.83 (m, 2H), 4.25 – 4.48 (m, 3H), 7.28 – 7.46 (m, 4H), 7.56 – 7.76 (m, 2H), 7.91 (d, J = 7.4 Hz, 2H). ES+(M+1 = 335.2).Step 3 – Intermediate Compound 10: (9H-fluoren-9-yl)methyl (1R,4R)-5-((2S,4S)-2,5,12-trihydroxy- 7-methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyran’[4’,3’:4,5]oxazolo [2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracene-2-carbonyl)-2,5- diazabicyclo[2.2.2]octane-2-carboxylateGeneral Procedure I was followed using PyOxim (326 mg, 0.64 mmol), the PNU-159682 carboxylic acid (CAS No.1204819-92-0; 200 mg, 0.32 mmol) and Intermediate Compound 9 (266 mg, 0.80 mmol) and DIEA (0.278 mL, 1.59 mmol) to afford Intermediate Compound 10 (175 mg, 58.2 %) as a red solid. NMR (400 MHz, DMSO) δ 1.21 – 1.29 (m, 3H), 1.67 (d, J = 5.8 Hz, 2H), 1.78 (s, 1H), 1.82 – 1.89 (m, 2H), 1.95 – 2.06 (m, 2H), 2.08 (s, 1H), 2.70 (s, 2H), 2.78 (d, J = 17.3 Hz, 1H), 3.37 (s, 3H), 3.41 – 3.57 (m, 4H), 3.62 – 3.72 (m, 1H), 3.79 (d, J = 10.8 Hz, 1H), 3.88 – 4.01 (m, 5H), 4.01 – 4.06 (m, 1H), 4.09 – 4.16 (m, 2H), 4.20 – 4.31 (m, 3H), 4.34 – 4.46 (m, 2H), 5.10 – 5.20 (m, 2H), 5.25 – 5.33 (m, 1H), 6.14 (s, 1H), 7.31 – 7.41 (m, 4H), 7.46 – 7.67 (m, 5H), 7.81 – 7.93 (m, 2H), 13.27 (s, 1H), 14.00 (s, 1H). ES+(M+1 = 944). Step 4 – Compound P3: (8S,10S)-8-((1R,4R)-2,5-diazabicyclo[2.2.2] octane-2-carbonyl)-6,8,11- trihydroxy-1-methoxy-10-(((1S,3R,4aS,-9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H- pyran’[4’,3’:4,5]oxazolo[2,3-c][1,4] oxazin-3-yl)oxy)-7,8,9, 10-tetrahydrotetracene-5,12-dioneGeneral Procedure III was followed using DCM solution of DBU (15.2 mg / mL in DCM) (0.828 mL, 0.08 mmol) and Intermediate Compound 10 (156 mg 017 mmol) to afford Compound P3 (26.0mg, 21.80 %) as a red solid.1H NMR (300 MHz, CDCl3) δ 0.85（s, 1H), 1.41-1.48(m, 3H), 1.70- 1.91(m, 2H), 1.92-2.05(m,3H),2.13 – 2.66 (m, 4H), 2.81 (s, 2H), 3.00-3.10 (m,1H), 3.21 – 3.74 (m, 10H), 3.74 – 4.29 (m, 7H), 4.49 (s, 1H), 4.73 (s, 1H), 4.89 (d, J = 16.5 Hz, 1H), 5.07 (s, 1H), 5.38 (s, 1H), 5.57 (s, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.81 (t, J = 8.1 Hz, 1H), 8.06 (s, 1H), 13.96 (s, 1H). ES+(M+1 = 722). Example 6: Synthesis of Compound P4Step 1 – Intermediate Compound 11: 2-((9H-fluoren-9-yl)methyl) 5-(tert-butyl) (1S,4S)-2,5- diazabicyclo[2.2.2]octane-2,5-dicarboxylatetert-Butyl (1S,4S)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (500 mg, 2.36 mmol) was added to a solution of N-(9H-fluoren-2-ylmethoxycarbonyloxy)succinimide (794 mg, 2.36 mmol) and DIEA (0.411 mL, 2.36 mmol) in DCM (15 mL) at RT. The resulting mixture was stirred at RT for 2 hours. The reaction mixture was diluted with DCM (100 mL), and washed sequentially with water (2 x 100 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford Intermediate Compound 11 (1100 mg, 99 %) as a yellow solid.1HNMR (300 MHz, DMSO) δ 0.95 (d, J = 6.4 Hz, 1H), 1.41 (d, J = 3.7 Hz, 9H), 1.59 – 1.90 (m, 5H), 3.29 (d, J = 5.3 Hz, 1H), 4.07 (d, J = 23.9 Hz, 2H), 4.28 – 4.30(m, 1H), 4.34 – 4.49 (m, 2H), 5.77 (s, 1H), 7.29 – 7.47 (m, 4H), 7.64 (t, J = 6.5 Hz, 2H), 7.85 – 7.95 (m, 2H). ES+(M+23 = 457).Step 2 - Intermediate Compound 12: (9H-fluoren-9-yl)methyl (1S,4S)-2,5-diazabicyclo[2.2.2]octane- 2-carboxylate, HCl saltGeneral Procedure II, Method A was followed using Intermediate Compound 11 (800 mg, 1.84 mmol) to afford Intermediate Compound 12 (1050 mg, 97%) as a pale yellow solid.1H NMR (400 MHz, DMSO) δ 1.22 – 1.33 (m, 1H), 1.64 – 1.85 (m, 3H), 2.03 – 2.14 (m, 1H), 3.17 – 3.32 (m, 2H), 3.33 – 3.47 (m, 2H), 3.67 – 3.82 (m, 2H), 4.24 – 4.51 (m, 3H), 7.35 – 7.39(m, 2H), 7.43 (t, J = 7.4 Hz, 2H), 7.60 – 7.70 (m, 2H), 7.91 (d, J = 7.5 Hz, 2H). ES+(M+1 = 335). Step 3 - Intermediate Compound 13: (9H-fluoren-9-yl)methyl (1S,4S)-5-((2S,4S)-2,5,12-trihydroxy-7- methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo- [2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracene-2-carbonyl)-2,5- diazabicyclo[2.2.2]octane-2-carboxylateGeneral Procedure I was followed using HATU (136 mg, 0.36 mmol), the PNU-159682 carboxylic acid (CAS No.1204819-92-0; 150 mg, 0.24 mmol), DIEA (0.209 mL, 1.20 mmol) and Intermediate Compound 12 (160 mg, 0.48 mmol) to afford Intermediate Compound 13 (160 mg, 70.9 %) as a red solid.1H NMR (400 MHz, DMSO) δ 1.18 – 1.32 (m, 3H), 1.68 (d, J = 7.8 Hz, 3H), 1.77 (s, 2H), 2.08 (s, 2H), 2.65 (d, J = 18.6 Hz, 2H), 2.77 – 2.87 (m, 1H), 3.15 – 3.32 (m, 4H), 3.35 – 3.43 (m, 3H), 3.47 – 3.59 (m, 2H), 3.65 (d, J = 7.3 Hz, 1H), 3.85-3.96 (m, 2H), 3.99 (s, 3H), 4.16 (s, 1H), 4.19 – 4.32 (m, 2H), 4.34 – 4.50 (m, 3H), 4.58 (dd, J = 2.1, 16.0 Hz, 1H), 4.95 – 5.15 (m, 2H), 5.27 (t, J = 4.4 Hz, 1H), 5.95 (d, J = 1.9 Hz, 1H), 7.28 – 7.39 (m, 3H), 7.39 – 7.46 (m, 2H), 7.63 – 7.67 (m, 2H), 7.87 – 7.94 (m, 4H), 13.32 (s, 1H), 14.02 – 14.11 (m, 1H). ES+(M+1 = 944).Step 4 - Compound P4: (8S,10S)-8-((1S,4S)-2,5-diazabicyclo[2.2.2]octane-2-carbonyl)-6,8,11- trihydroxy-1-methoxy-10-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H- pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-7,8,9,10-tetrahydrotetracene-5,12-dioneGeneral Procedure III was followed using DBU (0.012 mL, 0.08 mmol) and Intermediate Compound 13 (150 mg, 0.16 mmol) to afford Compound P4 (15.00 mg, 13.08 %) as a red solid.1H NMR (300 MHz, CDCl3) δ 1.42 (d, J = 6.4 Hz, 3H), 1.72 - 2.19 (m, 9H), 2.36 - 2.49 (m, 1H), 2.62-2.68 (m, 1H), 2.74 - 2.87 (m, 2H), 3.00-3.08 (m, 1H), 3.12 - 3.25 (m, 1H), 3.30 (s, 1H), 3.33 - 3.47 (m, 3H), 3.53 - 3.66 (m, 2H), 3.70-3.75 (m, 1H), 3.87 - 4.01 (m, 1H), 4.00 - 4.19 (m, 5H), 4.24 (s, 1H), 4.49 (d, J = 1.8 Hz, 1H), 4.74 (d, J = 1.9 Hz, 1H), 4.86 (s, 1H), 4.96 (s, 1H), 5.39 (s, 1H), 5.58 (t, J = 5.3 Hz, 1H), 7.42 (d, J = 8.5 Hz, 1H), 7.80 (t, J = 8.1 Hz, 1H), 8.02 - 8.11 (m, 1H), 13.98 (s, 1H). ES+(M+1 = 722). Example 7: Synthesis of Compound P5Step 1 - Intermediate Compound 14 ((9H-fluoren-9-yl)methyl) 5-(tert-butyl) (3aR,6aS)- tetrahydropyrrolo[3,4-c]pyrrole-2,5(1H,3H)-dicarboxylate(9H-Fluoren-9-yl)methyl (2,5-dioxopyrrolidin-1-yl) carbonate (1.748 g, 5.18 mmol) was added to tert-butyl (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (1g, 4.71 mmol) and DIEA (2.468 mL, 14.13 mmol) in DCM (15 mL) at 25°C under nitrogen. The resulting mixture was stirred at 25 °C for 2 hours. The reaction mixture was diluted with DCM (300 mL), and washed sequentially with water (3 x 250 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford Intermediate Compound 14 (1.500 g, 73.3 %) as a pale yellow oil.1H NMR (400 MHz, DMSO) δ 1.39 (s, 9H), 2.81 (s, 2H), 3.03 - 3.15 (m, 4H), 3.39 -3.54 (m, 4H), 5.76 (s, 1H), 6.28 (s, 2H), 7.30 - 7.38 (m, 2H), 7.38 - 7.46 (m, 2H), 7.81 - 7.92 (m, 4H). ES+(M+1 = 435). Step 2 - Compound 15 (9H-fluoren-9-yl)methyl (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)- carboxylate, HCl saltGeneral Procedure II, Method A was followed using Intermediate Compound 14 (1.4 g, 3.22 mmol) to afford Intermediate Compound 15 (1.000 g, 93 %) as a pale yellow solid.1H NMR (400 MHz, DMSO) δ 1.27 - 1.32 (m, 3H), 3.00 (s, 2H), 3.02 - 3.17 (m, 2H), 3.32 -3.43 (m, 4H), 4.24 - 4.34 (m, 3H), 7.31 - 7.39 (m, 2H), 7.39 - 7.48 (m, 2H), 7.61 - 7.70 (m, 2H), 7.89 - 7.94 (m, 2H). ES+(M+1 = 335). Step 3 - Intermediate Compound 16: (9H-fluoren-9-yl)methyl (3aR,6aS)-5-((2S,4S)-2,5,12- trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H- pyrano[4',3':4,5]oxazolo [2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracene-2- carbonyl) hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylateGeneral Procedure I was followed using HATU (136 mg, 0.36 mmol), the PNU-159682 carboxylic acid (CAS No.1204819-92-0; 150 mg, 0.24 mmol), DIEA (0.209 mL, 1.20 mmol) and Intermediate Compound 15 (160 mg, 0.48 mmol) to afford Intermediate Compound 16 ((130 mg, 57.6 %) as a red solid.1H NMR (400 MHz, DMSO) δ 1.18 – 1.34 (m, 3H), 2.58 – 2.68 (m, 2H), 2.79 (s, 1H), 2.86 (s, 1H), 2.90 – 2.95 (m, 1H), 3.17 (s, 10H), 3.26 – 3.34 (m, 5H), 3.36 (d, J = 8.7 Hz, 2H), 3.69 (q, J = 9.2,10.5 Hz, 2H), 3.91 – 4.14 (m, 7H), 4.18 – 4.30 (m, 2H), 4.55 – 4.73 (m, 1H), 5.77 (s, 1H), 6.28 (s, 2H), 7.31 – 7.45 (m, 5H), 7.81 – 7.91 (m, 6H). ES+(M+1 = 944). Step 4 – Compound P5: (8S,10S)-6,8,11-trihydroxy-1-methoxy-10-(((1S,3R,4aS,9S,9aR,10aS)-9- methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-8-((3aR,6aS)- octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-7,8,9,10-tetrahydrotetracene-5,12-dioneGeneral Procedure III was followed using Intermediate Compound 16 (120 mg, 0.13 mmol) to afford Compound P5 (13.00 mg, 14.17 %) as a red solid.NMR (400 MHz, CDCl3) δ 1.41 (d, J = 6.3 Hz, 3H), 1.91 – 2.09 (m, 4H), 2.43 (d, J = 14.8 Hz, 1H), 2.61 (d, J = 15.3 Hz, 1H), 2.73 – 3.08 (m, 7H), 3.20 (s, 2H), 3.36 – 3.44 (m, 2H), 3.48 (s, 3H), 3.56 – 3.63 (m, 2H), 3.83 (s, 1H), 3.90 – 3.98 (m, 2H), 4.09 (d, J = 16.7 Hz, 6H), 4.49 (s, 1H), 4.73 (s, 1H), 5.36 (s, 1H), 5.57 (s, 1H), 7.41 (d, J = 8.5 Hz, 1H), 7.80 (t, J = 8.1 Hz, 1H), 8.05 (d, J = 7.7 Hz, 1H), 13.97 (s, 1H). ES+(M+1 = 722). Example 8: Synthesis of Compound P6Steps 1, 2 – Intermediate Compound 18: (9H-fluoren-9-yl)methyl 2,7-diazaspiro[3.5]nonane-7- carboxylate, HCl salt(9H-Fluoren-9-yl)methyl carbonochloridate (1.257 g, 4.86 mmol) was added to a mixture of tert- butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (1 g, 4.42 mmol) and K2CO3 (1.832 g, 13.26 mmol) in DCM (50 mL) under air. The resulting mixture was stirred at 25 °C for 3 hours. The reaction mixture was filtered. The filtration was evaporated to afford the di-protected Intermediate Compound 17 as a crude product (1.3 g). The crude Intermediate Compound 17 was treated with HCl solution in dioxane 4M (30 mL) according to General Procedure II, Method A to afford Intermediate Compound 18 as crude product ((1.200 g, 70.6 %) as a yellow oil. ES+(M+1 = 349). Step 3 - Intermediate Compound 19: (9H-fluoren-9-yl)methyl 2-((2S,4S)-2,5,12-trihydroxy-7- methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H- pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracene-2- carbonyl)-2,7-diazaspiro[3.5]nonane-7-carboxylateGeneral Procedure I was followed using the PNU-159682 carboxylic acid (CAS No.1204819-92-0; 200 mg, 0.32 mmol), PyOxim (244 mg, 0.48 mmol), DIEA (0.278 mL, 1.59 mmol) and Intermediate Compound 18 (222 mg, 0.64 mmol) to afford Intermediate Compound 19 (100 mg, 32.8 %) as a red solid. ES+(M+1 = 958). Step 4 - Compound P6 (8S,10S)-6,8,11-trihydroxy-1-methoxy-10-(((1S,3R,4aS,9S,9aR,10aS)-9- methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-8-(2,7- diazaspiro[3.5]nonane-2-carbonyl)-7,8,9,10-tetrahydrotetracene-5,12-dioneGeneral Procedure III was followed u Osing O O Inte O OrHHme d OdO sOia oHl Ote id N C . Oo Nmpo NM N Ou RHnd 19 (100 mg, 0.10 mmol) to afford Compound P6 (19.00 mg, 24.74 %) as a reO (300 MHz, CDCl3) δ 1.42 (d, J = 6.3 Hz, 3H), 1.73 – 1.87 (m, 3H), 1.95 (s, 4H), 2.05 (s, 1H), 2.36 (d, J = 13.2 Hz, 1H), 2.58 (d, J = 15.0 Hz, 1H), 2.80 (d, J = 18.3 Hz, 2H), 2.97 (s, 2H), 3.16 – 3.26 (m, 3H), 3.31 (s, 1H), 3.41 (dd, J = 6.6, 13.2 Hz, 2H), 3.49 (s, 3H), 3.60 (d, J = 11.7 Hz, 2H), 3.84 (s, 2H), 3.94 (t, J = 9.3 Hz, 2H), 4.06 (d, J = 10.5 Hz, 2H), 4.11 (s, 3H), 4.22 – 4.35 (m, 2H), 4.50 (d, J = 1.8 Hz, 1H), 4.63 (s, 1H), 4.73 (s, 1H), 5.33 (s, 1H), 5.52 (t, J = 5.4 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.80 (t, J = 8.1 Hz, 1H), 8.07 (d, J = 7.8 Hz, 1H), 13.35 (s, 1H), 13.96 (s, 1H). ES+(M+1 = 736). Example 9: Synthesis of Compound P7Step 1, 2 - Intermediate Compound 21: (9H-fluoren-9-yl)methyl 2,2-dimethylpiperazine-1- carboxylate, HCl saltK2CO3(1.935 g, 14.00 mmol) was added to a mixture of tert-butyl 3,3-dimethylpiperazine-1- carboxylate (1 g, 4.67 mmol) and (9H-fluoren-9-yl)methyl carbonochloridate (1.328 g, 5.13 mmol) in DCM (3 mL). The resulting mixture was stirred at 25 °C for 3 hours. The reaction mixture was filtered through celite The solvent was removed under reduced pressure to afford the di-protectedIntermediate Compound 20. The intermediate was treated with HCl in dioxane according to General Procedure II, Method A to afford Intermediate Compound 21 (1.300 g, 83 %) as a white solid.1H NMR (400 MHz, DMSO) δ 0.98 (s, 6H), 1.12 – 1.20 (m, 1H), 2.86 – 2.93 (m, 2H), 3.00 – 3.06 (m, 2H), 3.43 – 3.47 (m, 2H), 4.29 (s, 1H), 4.58 (d, J = 4.9 Hz, 2H), 7.33 (dd, J = 1.3, 7.5 Hz, 2H), 7.40 – 7.44 (m, 2H), 7.65 (d, J = 7.6 Hz, 2H), 7.89 (d, J = 7.2 Hz, 2H). ES+(M+1 = 337). Step 3 - Intermediate Compound 22 (9H-fluoren-9-yl)methyl 2,2-dimethyl-4-((2S,4S)-2,5,12- trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H- pyrano[4',3':4,5]oxazolo [2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracene-2- carbonyl)- piperazine-1-carboxylateGeneral Procedure I was followed using PyOxim (306 mg, 0.60 mmol), the PNU-159682 carboxylic acid (CAS No.: 1204819-92-0; 150 mg, 0.24 mmol), Intermediate Compound 21121 mg, 0.36 mmol) and DIEA (0.209 mL, 1.20 mmol) to afford Intermediate Compound 22 (170 mg, 75 %) as a red solid. NMR (400 MHz, DMSO) δ 0.93 (s, 3H), 0.98 – 1.05 (m, 3H), 1.19 – 1.27 (m, 3H), 1.63 – 1.72 (m, 2H), 2.05 – 2.21 (m, 2H), 2.62 – 2.70 (m, 3H), 2.85 – 2.89 (m, 3H), 3.30 (d, J = 8.5 Hz, 5H), 3.48 – 3.56 (m, 4H), 3.68 (dd, J = 8.5, 11.9 Hz, 2H), 3.83 – 3.97 (m, 5H), 4.18 – 4.30 (m, 3H), 4.60 (d, J = 2.1 Hz, 1H), 5.00 (d, J = 8.7 Hz, 1H), 5.25 (d, J = 5.5 Hz, 1H), 5.74 (s, 1H), 7.32 – 7.35 (m, 3H), 7.63 (d, J = 6.8 Hz, 3H), 7.88 (dd, J = 3.3, 7.2 Hz, 5H). ES+(M+1 = 946).Step 4 - Compound P7 (8S,10S)-8-(3,3-dimethylpiperazine-1-carbonyl)-6,8,11-trihydroxy-1-methoxy- 10-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo[2,3- c][1,4]oxazin-3-yl)oxy)-7,8,9,10-tetrahydrotetracene-5,12-dioneGeneral Procedure III was followed using DCM solution of DBU (15.2 mg / mL in DCM) (0.07 mL, 0.08 mmol) and Intermediate Compound 22 (160 mg, 0.17 mmol) in DCM (4 mL) / MeCN (1.000 mL) to afford Compound P7 (21.00 mg, 17.16 %) as a red solid.NMR (400 MHz, DMSO) δ 0.80 – 1.06 (m, 7H), 1.24 (d, J = 6.3 Hz, 4H), 1.65 – 1.70 (m, 2H), 2.11 – 2.17 (m, 1H), 2.64 (d, J = 8.7 Hz, 2H), 2.84 (d, J = 17.8 Hz, 2H), 3.06 – 3.22 (m, 2H), 3.38 (d, J = 6.3 Hz, 3H), 3.47 – 3.54 (m, 2H), 3.67 (s, 1H), 3.81 (s, 1H), 3.93 (d, J = 2.0 Hz, 1H), 3.94 – 4.07 (m, 6H), 4.24 (d, J = 2.2 Hz, 1H), 4.60 (d, J = 2.1 Hz, 1H), 5.00 – 5.04 (m, 1H), 5.24 – 5.27 (m, 1H), 5.88 (s, 1H), 7.65 – 7.69 (m, 1H), 7.91 – 7.96 (m, 2H), 13.91 – 14.20 (m, 1H). ES+(M+1 = 724). Example 9A: Synthesis of Compound P7aStep 1 - Intermediate Compound 23: tert-butyl 4-acetyl-3,3-dimethylpiperazine-1-carboxylateAcetic anhydride (5.00 g, 48.99 mmol) was added dropwise to a solution of tert-butyl 3,3- dimethylpiperazine-1-carboxylate (5 g, 23.33 mmol) and DIEA (20.37 mL, 116.65 mmol) in DCM (110 mL) under nitrogen. The resulting mixture was stirred at 25 °C for 4 hours. The reaction mixture was quenched with saturated brine (100 mL), extracted with DCM (2 x 75 mL), the organic layer was dried over Na2SO4, filtered and evaporated to afford Intermediate Compound 23 (5.20 g, 87 %) as a white solid.NMR (300 MHz, CDCl3) δ 1.48 (d, J = 2.6 Hz, 15H), 2.24 (s, 3H), 3.32 – 3.66 (m, 6H). ES+(M+1= 257). Step 2 - Intermediate Compound 24: 1-(2,2-dimethylpiperazin-1-yl)ethan-1-one, HCl saltGeneral Procedure II, Method A was followed using HCl in dioxane (4 M) (29.3 mL, 117.2 mmol) and Intermediate Compound 23 (5 g, 19.50 mmol) to afford Intermediate Compound 24 as a pure solid material (3 g HCl salt).1HNMR (300 MHz, DMSO) δ 1.46 (s, 6H), 2.00 (s, 3H), 3.03 (t, J = 5.1 Hz, 2H), 3.07 – 3.24 (m, 2H), 3.51 – 3.69 (m, 2H). ES+(M+1 = 157). Step 3 - Compound P7a: (8S,10S)-8-(4-acetyl-3,3-dimethylpiperazine-1-carbonyl)-6,8,11-trihydroxy- 1-methoxy-10-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H- pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-7,8,9,10-tetrahydrotetracene-5,12-dioneGeneral Procedure I was followed using DIEA (0.139 mL, 0.80 mmol), Intermediate Compound 24 (49.8 mg, 0.32 mmol), HATU (121 mg, 0.32 mmol) and the PNU-159682 carboxylic acid (CAS No. 1204819-92-0; 100 mg, 0.16 mmol) to afford Compound P7a (22.01 mg, 18.04 %) as a red solid.1H NMR (400 MHz, CDCl3) δ 1.39 (d, J = 6.4 Hz, 3H), 1.58 (d, J = 12.9 Hz, 6H), 1.70 – 1.81 (m, 1H), 1.92 – 2.03 (m, 1H), 2.13 (s, 3H), 2.47 (dd, J = 4.0, 15.3 Hz, 1H), 2.63 – 2.86 (m, 3H), 2.96 (dd, J = 10.6, 19.3 Hz, 1H), 3.38 – 3.42 (m, 1H), 3.47 (s, 4H), 3.54 – 3.63 (m, 1H), 3.66 – 3.79 (m, 4H), 3.88 – 4.13 (m, 7H), 4.27 (dd, J = 13.5, 22.8 Hz, 1H), 4.48 (d, J = 1.9 Hz, 1H), 4.72 (d, J = 1.9 Hz, 1H), 5.00 (s, 1H), 5.36 (d, J = 4.7 Hz, 1H), 5.52 – 5.59 (m, 1H), 7.40 (d, J = 8.5 Hz, 1H), 7.75 – 7.83 (m, 1H), 8.04 (d, J = 7.6 Hz, 1H), 13.33 (d, J = 10.4 Hz, 1H), 13.92 (d, J = 4.7 Hz, 1H). ES+(M+1 = 766). Example 10: Synthesis of Compound P8Step 1 - Compound P8: (8S,10S)-6,8,11-trihydroxy-1-methoxy-10-(((1S,3R,4aS,9S,9aR,10aS)-9- methoxy-1-methyloctahydro-1H-pyrano[4’,3’:4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-8-(5,8- diazaspiro[3.5]nonane-8-carbonyl)-7,8,9,10-tetrahydrotetracene-5,12-dioneGeneral Procedure I was followed using HATU (273 mg, 0.72 mmol), the PNU-159682 carboxylic acid (CAS No.1204819-92-0; 300 mg, 0.48 mmol), DIEA (0.417 mL, 2.39 mmol) and 5,8- diazaspiro[3.5]nonane (121 mg, 0.96 mmol) to afford Compound P8 (50.0 mg, 14.22 %) as a red solid.1H NMR (300 MHz, CDCl3) δ 1.28 (s, 1H), 1.41 (d, J = 6.3 Hz, 3H), 1.77 (dt, J = 6.0, 15.0 Hz, 1H), 1.86 (s, 4H), 1.98 (dt, J = 5.7, 15.0 Hz, 1H), 2.47 (d, J = 15.3 Hz, 1H), 2.65 – 2.87 (m, 2H), 2.95 (d, J = 7.5 Hz, 3H), 3.03 (s, 1H), 3.39 (q, J = 6.3 Hz, 1H), 3.48 (s, 3H), 3.59 (dt, J = 3.6, 11.7 Hz, 1H), 3.87 –4.01 (m, 1H), 4.09 (d, J = 16.5 Hz, 5H), 4.50 (d, J = 1.8 Hz, 1H), 4.74 (d, J = 1.8 Hz, 1H), 4.97 (s, 1H), 5.39 (s, 1H), 5.57 (s, 1H), 7.42 (dd, J = 1.2, 8.7 Hz, 1H), 7.81 (t, J = 8.1 Hz, 1H), 8.06 (dd, J = 1.2, 7.8 Hz, 1H), 13.36 (s, 1H), 13.97 (s, 1H). ES+(M+1 = 736). Example 11: Synthesis of Compound P9Step 1 – Intermediate Compound 25: 2-((9H-fluoren-9-yl)methyl) 6-(tert-butyl) 2,6- diazaspiro[3.3]heptane-2,6-dicarboxylatetert-Butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (1 g, 5.04 mmol) was added to a mixture of N- (9H-fluoren-2-ylmethoxycarbonyloxy)succinimide (1.701 g, 5.04 mmol) and DIEA (2.64 mL, 15.13 mmol) in DCM (30 mL) at RT. The resulting mixture was stirred at RT for 2 hours. The reaction mixture was diluted with DCM (20 mL), and washed with water (3 x 40 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford Intermediate Compound 25 (1.700 g, 80 %) as a yellow solid. NMR (400 MHz, DMSO) δ 1.37 (s, 9H), 3.30 (s, 8H), 3.75 – 3.83 (m, 3H), 7.37 (s, 4H), 7.65 (s, 1H), 7.85 (s, 3H). ES+(M+23 = 443). Step 2 – Intermediate Compound 26: (9H-fluoren-9-yl)methyl 2,6-diazaspiro[3.3]heptane-2- carboxylate, TFA saltGeneral Procedure II, Method B was followed using TFA (15 ml, 194.70 mmol), Intermediate Compound 25 (1.6 g, 3.80 mmol) in DCM (20 mL) to afford Intermediate Compound 26 (1.100 g, 90 %) as a pale yellow solid.1HNMR (400 MHz, DMSO) δ 1.19 – 1.32 (m, 2H), 4.06 – 4.14 (m, 5H), 4.19 – 4.27 (m, 1H), 4.29 (d, J = 6.1 Hz, 2H), 7.28 – 7.39 (m, 2H), 7.39 – 7.49 (m, 2H), 7.64 (d, J = 7.4 Hz, 2H), 7.91 (d, J = 7.5 Hz, 2H). ES+(M+1 = 321). Step 3 – Intermediate Compound 27: (9H-fluoren-9-yl)methyl 6-((2S,4S)-2,5,12-trihydroxy-7- methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4’,3’:4,5]oxazolo [2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracene-2-carbonyl)-2,6- diazaspiro[3.3]heptane-2-carboxylateGeneral Procedure I was followed using HATU (136 mg, 0.36 mmol), the PNU-159682 carboxylic acid (CAS No.1204819-92-0; 150 mg, 0.24 mmol), DIEA (0.209 mL, 1.20 mmol) and Intermediate Compound 26 (153 mg, 0.48 mmol) to afford Intermediate Compound 27 (130 mg, 58.5 %) as a red solid.1H NMR (300 MHz, DMSO) δ 1.15 – 1.32 (m, 3H), 1.67 (t, J = 5.9 Hz, 1H), 2.18 (d, J = 14.6 Hz, 1H), 2.21 – 2.34 (m, 1H), 2.65 (d, J = 15.4 Hz, 2H), 2.91 (d, J = 18.3 Hz, 1H), 3.09 (d, J = 18.1 Hz, 1H), 3.36 (s, 1H), 3.51 (d, J = 11.6 Hz, 1H), 3.66 (d, J = 8.4 Hz, 1H), 4.02 (d, J = 19.0 Hz, 10H), 4.21 – 4.33 (m, 4H), 4.53 (d, J = 10.8 Hz, 1H), 4.56 – 4.64 (m, 2H), 4.99 (s, 1H), 5.26 (d, J = 4.1 Hz, 2H), 5.76 (s, 5H), 7.39 (dtd, J = 1.2, 7.4, 25.2 Hz, 4H), 7.64 (d, J = 7.2 Hz, 3H), 7.80 – 7.95 (m, 4H), 13.28 (s, 1H), 14.06 (s, 1H). ES+(M+1 = 930). Step 4 – Compound P9: (8S,10S)-6,8,11-trihydroxy-1-methoxy-10-(((1S,3R,4aS,9S,9aR,10aS)-9- methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-8-(2,6- diazaspiro[3.3]heptane-2-carbonyl)-7,8,9,10-tetrahydrotetracene-5,12-dioneGeneral Procedure III was followed using DBU (9.73 µl, 0.06 mmol) and Intermediate Compound 27 (120 mg, 0.13 mmol) to afford Compound P9 (11.00 mg, 12.05 %) as a red solid.1H NMR (400 MHz, CDCl3) δ 1.43 (d, J = 6.5 Hz, 3H), 1.74 - 1.79 (m, 1H), 1.97 - 2.03 (m, 1H), 2.31 - 2.39 (m, 1H), 2.52 (d, J = 14.3 Hz, 1H), 2.73 - 2.88 (m, 2H), 3.15 (d, J = 19.0 Hz, 1H), 3.27 - 3.36 (m, 1H), 3.41 (d, J = 6.7 Hz, 1H), 3.48 (d, J = 1.4 Hz, 3H), 3.57- 3.65 (m, 1H), 3.92 - 4.16 (m, 10H), 4.23 (s, 2H), 4.50 (d, J = 1.9 Hz, 1H), 4.64 - 4.78 (m, 4H), 5.33 (s, 1H), 5.53 (t, J = 5.3 Hz, 1H), 7.41 (d, J = 8.5 Hz, 1H), 7.76 - 7.85 (m, 1H), 8.02 - 8.10 (m, 1H), 13.35 (s, 1H), 13.96 (s, 1H). ES+(M+1 = 708). Example 12: Synthesis of Compound P9aStep 1 - Intermediate Compound 28: tert-butyl 6-acetyl-2,6-diazaspiro[3.3]heptane-2-carboxylateAc2O (0.714 mL, 7.57 mmol) was added to a solution of tert-butyl 2,6-diazaspiro[3.3]heptane-2- carboxylate (1g, 5.04 mmol) and DIEA (4.40 mL, 25.22 mmol) in DCM (15 mL) / DMA (1.5 mL) at 0°C under nitrogen. The resulting mixture was stirred at 25 °C for 2 hours. The reaction mixture was quenched with water (25 mL), extracted with DCM (3 x 20 mL), the organic layer was dried over Na2SO4, filtered and evaporated to afford crude Intermediate Compound 28 (1.000 g, 83 %) as a pale yellow oil.1H NMR (400 MHz, DMSO) δ 1.37 (s, 9H), 1.72 (s, 3H), 3.95 (d, J = 12.4 Hz, 6H), 4.21 (s, 2H). m / z (ES+), [M+H]+= 241.Step 2 - Intermediate Compound 29: 1-(2,6-diazaspiro [3.3]heptan-2-yl)ethan-1-one, TFA saltGeneral Procedure II, Method B was followed using Intermediate Compound 28 (900 mg, 3.75 mmol) and TFA (5 mL) / DCM (5.00 mL) to afford Intermediate Compound 29 (450 mg, 86 %) as a pale yellow solid.NMR (400 MHz, DMSO) δ 1.72 (s, 3H), 1.96 (s, 1H), 3.97 (d, J = 5.9 Hz, 2H), 4.10 (t, J = 6.2 Hz, 4H), 4.25 (s, 2H). m / z (ES+), [M+H]+ = 141. Step 3 - Compound P9a (8S,10S)-8-(6-acetyl-2,6-diazaspiro[3.3]heptane-2-carbonyl)-6,8,11- trihydroxy-1-methoxy-10-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H- pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-7,8,9,10-tetrahydrotetracene-5,12-dione ., . , . , , . , . , . , , . , , . (dd, J = 5.3, 15.3 Hz, 1H), 2.35 (d, J = 15.0 Hz, 1H), 2.53 (d, J = 15.1 Hz, 1H), 2.68 – 2.87 (m, 2H), 3.13 (dd, J = 5.4, 19.1 Hz, 1H), 3.27 – 3.42 (m, 2H), 3.46 (s, 3H), 3.58 (d, J = 11.7 Hz, 1H), 3.87 – 4.12 (m, 6H), 4.11-4.19 (m, 2H), 4.20-4.25 (m, 2H), 4.28-4.32 (m, 2H), 4.70 – 4.82 (m, 4H), 5.32 (s, 1H), 5.51 (s, 1H), 7.40 (d, J = 8.5 Hz, 1H), 7.79 (d, J = 8.1 Hz, 1H), 8.04 (d, J = 7.7 Hz, 1H), 13.33 (d, J = 5.3 Hz, 1H), 13.94 (s, 1H). [M+H]+= 750.Example 13: Synthesis of Compound P10Step 1 - Intermediate Compound 30: 8-((9H-fluoren-9-yl)methyl) 3-(tert-butyl) 3,8- diazabicyclo[3.2.1]octane-3,8-dicarboxylateN-(9H-Fluoren-2-ylmethoxycarbonyloxy)succinimide (1.589 g, 4.71 mmol) was added to tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (1 g, 4.71 mmol) and DIEA (1.645 mL, 9.42 mmol) in DCM (20 mL) under nitrogen. The resulting mixture was stirred at 25 °C for 3 hours. The reaction mixture was diluted with DCM (50 mL), and washed with water (2 x 50 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford afford Intermediate Compound 30 (1.700 g, 83 %) as a yellow solid. ES+(M+1 = 435). Step 2 - Intermediate Compound 31: (9H-fluoren-9-yl)methyl 3,8-diazabicyclo[3.2.1]octane-8- carboxylate, HCl saltGeneral Procedure II, Method A was followed using HCl (5 mL, 4 M in dioxane) and Intermediate Compound 30 (1.6 g, 3.68 mmol) in 1,4-dioxane (10 mL) to afford Intermediate Compound 31 (0.950 g, 77 %) as a yellow solid.NMR (400 MHz, DMSO) δ 1.78 – 2.08 (m, 4H), 2.50 (s, 1H), 2.86 (s, 2H), 3.05 (d, J = 12.4 Hz, 2H), 4.17 (d, J = 43.1 Hz, 1H), 4.31 (t, J = 6.2 Hz, 1H), 4.47 (s, 2H), 7.35(td, J = 1.2, 7.4 Hz, 2H), 7.43 (td, J = 1.2, 7.5 Hz, 2H), 7.64 (d, J = 7.5 Hz, 2H), 7.91 (d, J = 7.6 Hz, 2H). ES+(M+1 = 335). Step 3 - Intermediate Compound 32: (9H-fluoren-9-yl)methyl 3-((2S,4S)-2,5,12-trihydroxy-7- methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo [2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracene-2-carbonyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylateGeneral Procedure I was followed using PyOxim (733 mg, 1.43 mmol), the PNU-159682 carboxylic acid (CAS No.1204819-92-0; 450 mg, 0.72 mmol), Intermediate Compound 31 (599 mg, 1.79 mmol) and DIEA (0.626 mL, 3.59 mmol) to afford Intermediate Compound 32 (550 mg, 81%) as a red solid. NMR (400 MHz, DMSO) δ 1.24 (s, 3H), 1.66 – 1.72 (m, 4H), 1.88 (d, J = 31.5 Hz, 2H), 2.17 (d, J = 44.7 Hz, 2H), 2.67 (dd, J = 5.9, 16.4 Hz, 4H), 3.39 (d, J = 6.6 Hz, 2H), 3.48 – 3.55 (m, 1H), 3.62 – 3.72 (m, 2H), 3.94 (d, J = 6.3 Hz, 3H), 3.99 (s, 5H), 4.01 – 4.06 (m, 2H), 4.22 – 4.31 (m, 3H), 4.50 (d, J = 24.1 Hz, 2H), 4.61 (d, J = 2.0 Hz, 2H), 5.25 – 5.29 (m, 1H), 5.85 (s, 1H), 7.32 – 7.42 (m, 4H), 7.64 (d, J = 6.0 Hz, 3H), 7.91 (d, J = 7.1 Hz, 4H), 13.32 (s, 1H), 14.04 (s, 1H). ES+(M+1 = 944). Step 4 - Compound P10: (8S,10S)-8-(3,8-diazabicyclo[3.2.1]octane-3-carbonyl)-6,8,11-trihydroxy-1- methoxy-10-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H- pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-7,8,9,10-tetrahydrotetracene-5,12-dioneGeneral Procedure III was followed using DCM solution of DBU (15.2 mg / mL in DCM) (3.86 mL, 0.39 mmol) and Intermediate Compound 32 (520 mg, 0.55 mmol) in DCM (24 mL) / MeCN (6.00 mL) to afford Compound P10 (130 mg, 32.7 %) as a red solid.1H NMR (400 MHz, CDCl3) δ 1.42 (d, J = 6.4 Hz, 3H), 1.70 – 1.83 (m, 4H), 1.99 (s, 3H), 2.43 (dd, J = 4.0, 15.3 Hz, 1H), 2.63 – 3.12 (m, 5H), 3.48 (s, 6H), 3.55 – 3.68 (m, 3H), 3.90 – 4.00 (m, 1H), 4.02 – 4.13 (m, 5H), 4.28 – 4.40 (m, 1H), 4.47 – 4.61 (m, 2H), 4.74 (d, J = 1.7 Hz, 1H), 4.87 (s, 1H), 5.38 (dd, J = 2.3, 4.1 Hz, 1H), 5.56 (s, 1H), 7.42 (dd, J = 1.1, 8.6 Hz, 1H), 7.76 – 7.85 (m, 1H), 8.03 – 8.09 (m, 1H), 13.36 (s, 1H), 13.95 (s, 1H). ES+(M+1 = 722). Example 14: Synthesis of Compound P11Steps 1, 2 - Intermediate Compound 34: (9H-fluoren-9-yl)methyl 3,8-diazabicyclo[3.2.1]octane-3- carboxylate, HCl salt K2CO3 (1758 mg, 12.72 mmol) was added to a solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8- carboxylate (900 mg, 4.24 mmol) and (9H-fluoren-9-yl)methyl carbonochloridate (1206 mg, 4.66 mmol) in DCM (30 mL). The resulting mixture was stirred at 25 °C for 3 hours. The reaction mixture was filtered through celite. The solution was washed with water, dried over Na2SO4, then concentrated to afford the di-protected Intermediate Compound 33 as a a yellow oil. The yellow oil was redissolved in EtOH (10 mL), then HCl in EtOH / 4M (15 mL, 60.00 mmol) was added. The resulting mixture was stirred at 25 °C for 3 hours. The solvent was removed under reduced pressure to afford Intermediate Compound 34 (1200 mg, 85 %) as a yellow solid. ES+( [M+H]+ = 335.Step 3 - Intermediate Compound 35: (9H-fluoren-9-yl)methyl 8-((2S,4S)-2,5,12-trihydroxy-7- methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo [2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracene-2-carbonyl)-3,8- diazabicyclo[3.2.1]octane-3-carboxylateGeneral Procedure I was followed using PyOxim (244 mg, 0.48 mmol), the PNU-159682 carboxylic acid (CAS No.1204819-92-0; 150 mg, 0.24 mmol), Intermediate Compound 34 (200 mg, 0.60 mmol) and DIEA (0.209 mL, 1.20 mmol) to afford Intermediate Compound 35 (140 mg, 62.1 %) as a red solid. NMR (400 MHz, DMSO) δ 1.24 (dd, J = 3.3, 6.8 Hz, 3H), 1.49 – 1.62 (m, 2H), 1.69 (d, J = 5.7 Hz, 2H), 1.74 – 1.82 (m, 2H), 1.82 – 1.93 (m, 2H), 2.05 – 2.17 (m, 2H), 2.56 (s, 1H), 2.60 – 2.71 (m, 4H), 2.88 (dd, J = 8.3, 12.8 Hz, 2H), 3.39 (d, J = 6.2 Hz, 2H), 3.47 – 3.59 (m, 2H), 3.62 – 3.72 (m, 2H), 3.93 (d, J = 6.0 Hz, 1H), 3.98 (s, 3H), 3.99 – 4.08 (m, 2H), 4.25 (dd, J = 4.7, 9.9 Hz, 2H), 4.59 (d, J = 2.1 Hz, 1H), 4.97 (d, J = 22.6 Hz, 2H), 5.26 (d, J = 7.3 Hz, 1H), 6.28 (s, 2H), 7.35 (d, J = 1.3 Hz, 2H), 7.43 (dd, J = 1.2, 7.4 Hz, 2H), 7.64 (dd, J = 4.8, 9.1 Hz, 2H), 7.89 (dd, J = 3.4, 7.7 Hz, 5H). ES+(M+1 = 945). Step 4 - Compound P11: (8S,10S)-8-(3,8-diazabicyclo[3.2.1]octane-8-carbonyl)-6,8,11-trihydroxy-1- methoxy-10-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H- pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-7,8,9,10-tetrahydrotetracene-5,12-dioneGeneral Procedure III was followed using DCM solution of DBU (15.2 mg / mL in DCM) (0.828 mL, 0.08 mmol) and Intermediate Compound 35 (130 mg, 0.14 mmol) in DCM (8.00 mL) / MeCN (2 mL) to afford Compound P11 (22.00 mg, 22.13 %) as a red solid.1H NMR (400 MHz, CDCl3) δ 1.42 (d, J = 6.7 Hz, 3H), 1.72 – 1.83 (m, 1H), 1.98 (s, 6H), 2.47 (d, J = 16.8 Hz, 1H), 2.64 – 2.96 (m, 6H), 3.19 (d, J = 31.9 Hz, 2H), 3.31 – 3.44 (m, 2H), 3.48 (s, 3H), 3.57 – 3.64 (m, 1H), 3.88 – 4.00 (m, 1H), 4.11 (s, 5H), 4.50 (s, 1H), 4.80 (d, J = 53.4 Hz, 4H), 5.38 (s, 1H), 5.56 (s, 1H), 7.41 (d, J = 8.5 Hz, 1H), 7.76 – 7.84 (m, 1H), 8.06 (d, J = 7.6 Hz, 1H), 13.36 (s, 1H), 13.98 (s, 1H). ES+(M+1 = 722). Example 15: Synthesis of Compound P12Step 1 - Intermediate Compound 36: 2-((9H-fluoren-9-yl)methyl) 5-(tert-butyl) (1R,4R)-2,5- diazabicyclo[2.2.1]heptane-2,5-dicarboxylatetert-Butyl (1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (1g, 5.04 mmol) was added to a solution of DIEA (2.64 mL, 15.13 mmol) and N-(9H-Fluoren-2-ylmethoxycarbonyloxy)succinimide (1.701 g, 5.04 mmol) in DCM (20 mL) at RT. The resulting mixture was stirred at RT for 2 hours. The reaction mixture was diluted with DCM (200 mL), and washed with water (3 x 200 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford Intermediate Compound 36 (2.300 g, 92 %) as a yellow solid.1H NMR (300 MHz, DMSO) δ 0.96 (dd, J = 6.9, 2.0 Hz, 6H), 1.40 (d, J = 4.1 Hz, 9H), 1.77 (s, 2H), 2.98 (pd, J = 6.4, 1.2 Hz, 1H), 4.27 (d, J = 22.4 Hz, 1H), 6.29 (s, 2H), 7.38 (dtd, J = 21.9, 7.4, 1.3 Hz, 4H), 7.8–7.91 (m, 3H). ES+(M+23 = 443).Step 2 - Intermediate Compound 37: (9H-fluoren-9-yl)methyl (1R,4R)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate, HCl saltGeneral Procedure II, Method A was followed using 4 N HCL in 1,4-dioxane (10 ml, 40.00 mmol), and Intermediate Compound 36 (2 g, 4.76 mmol) in DCM (10 mL) to afford crude product Intermediate Compound 37 (2.200 g, 99 %) as a yellow solid.NMR (300 MHz, DMSO) δ 1.29 (dd, J = 10.6, 6.7 Hz, 4H), 1.71–2.05 (m, 1H), 2.91–3.27 (m, 2H), 3.29–3.81 (m, 3H), 4.15–4.6 (m, 3H), 5.77 (s, 1H), 7.26–7.48 (m, 2H), 7.66 (d, J = 7.4 Hz, 1H), 7.91 (d, J = 7.4 Hz, 1H), 9.30 (d, J = 60.3 Hz, 1H), 9.86 (s, 1H). ES+(M+1 = 321). Step 3 - Intermediate Compound 38 (9H-fluoren-9-yl)methyl (1R,4R)-5-((2S,4S)-2,5,12-trihydroxy-7- methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo [2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracene-2-carbonyl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylateGeneral Procedure I was followed using PyOxim (293 mg, 0.57 mmol), the PNU-159682 carboxylic acid (CAS No.1204819-92-0; 180 mg, 0.29 mmol), Intermediate Compound 37 (230 mg, 0.72 mmol) and DIEA (0.250 mL, 1.43 mmol) to afford Intermediate Compound 38 (160 mg, 60.0 %) as a red solid. NMR (400 MHz, DMSO) δ 1.20 – 1.29 (m, 3H), 1.66 (d, J = 10.1 Hz, 2H), 1.77 – 1.92 (m, 2H), 2.01 (dd, J = 8.5, 12.7 Hz, 2H), 2.10 – 2.40 (m, 2H), 2.61 – 2.70 (m, 2H), 2.73 – 3.02 (m, 3H), 3.17 (d, J = 11.3 Hz, 1H), 3.38 (dd, J = 5.7, 12.7 Hz, 5H), 3.45 – 3.57 (m, 2H), 3.63 – 3.71 (m, 2H), 3.94 – 4.00 (m, 4H), 4.01 – 4.11 (m, 1H), 4.14 (d, J = 10.4 Hz, 1H), 4.22 – 4.29 (m, 2H), 4.31 – 4.37 (m, 2H), 4.61 (dd, J = 2.0, 8.6 Hz, 1H), 5.52 (s, 1H), 7.26 – 7.45 (m, 6H), 7.54 – 7.66 (m, 2H), 7.81 – 7.96 (m, 3H), 13.27 (s, 1H), 13.89 (s, 1H). ES+(M+1 = 930).Step 4 - Compound P12: (8S,10S)-8-((1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)-6,8,11- trihydroxy-1-methoxy-10-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H- pyrano[4',3':4,5]oxazolo [2,3-c][1,4]oxazin-3-yl)oxy)-7,8,9,10-tetrahydrotetracene-5,12-dioneGeneral Procedure III was followed using DCM solution of DBU (15.2 mg / mL in DCM) (1.131 mL, 0.11 mmol) and Intermediate Compound 38 (150 mg, 0.16 mmol) in DCM (8 mL) / MeCN (2.000 mL) to afford Compound P12 (42.0 mg, 36.8 %) as a red solid.NMR (400 MHz, CDCl3) δ 1.42 (dd, J = 4.3, 6.5 Hz, 3H), 1.72 – 1.91 (m, 4H), 1.97 – 2.04 (m, 1H), 2.29 – 2.40 (m, 1H), 2.60 – 2.70 (m, 1H), 2.72 – 2.87 (m, 2H), 3.08 – 3.25 (m, 3H), 3.33 – 3.46 (m, 3H), 3.48 (s, 3H), 3.55 – 3.65 (m, 2H), 3.79 – 4.00 (m, 3H), 4.07 (d, J = 7.1 Hz, 1H), 4.11 (d, J = 4.8 Hz, 3H), 4.47 – 4.52 (m, 1H), 4.68 – 4.76 (m, 1H), 4.81 (s, 1H), 5.35 (s, 1H), 5.47 (s, 1H), 5.50 – 5.60 (m, 1H), 7.41 (d, J = 8.5 Hz, 1H), 7.76 – 7.87 (m, 1H), 8.06 (d, J = 7.7 Hz, 1H), 13.34 (s, 1H), 13.98 (s, 1H). ES+(M+1 = 708). Example 16: Synthesis of Compound P13Step 1 - Intermediate Compound 39: 2-((9H-fluoren-9-yl)methyl) 5-(tert-butyl) (1S,4S)-2,5- diazabicyclo[2.2.1]heptane-2,5-dicarboxylateDIEA (0.881 mL, 5.04 mmol) was added to a solution of tert-butyl (1S,4S)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (500 mg, 2.52 mmol) and N-(9H-Fluoren-2- ylmethoxycarbonyloxy)succinimide (851 mg, 2.52 mmol) in DCM (20 mL) under nitrogen. The resulting mixture was stirred at 25 °C for 3 hours. The reaction mixture was diluted with DCM (25 mL), and washed with water (2 x 25 mL). The bottom layer was dried over Na2SO4, filtered and evaporated to afford crude product Intermediate Compound 39 (800 mg, 75 %) as a yellow solid. NMR (400 MHz, DMSO) δ 1.40 (s, 11H), 2.61 – 3.03 (m, 4H), 3.07 – 3.22 (m, 3H), 4.12 – 4.44 (m, 2H), 7.25 – 7.47 (m, 4H), 7.59 – 7.74 (m, 1H), 7.78 – 7.95 (m, 3H). ES+(M+23 = 443). Step 2 - Intermediate Compound 40: (9H-fluoren-9-yl)methyl (1S,4S)-2,5-diazabicyclo [2.2.1]heptane-2-carboxylate, HCl saltGeneral Procedure II, Method A was followed using 4N HCL in 1,4-dioxane (1.40 mL, 5.64 mmol), and Intermediate Compound 39 (790 mg, 1.88 mmol) in DCM (10 mL) to afford Intermediate Compound 40 (550 mg, 91 %) as a yellow solid.NMR (400 MHz, DMSO) δ 1.88 – 2.00 (m, 1H), 2.27 (t, J = 8.0 Hz, 2H), 2.74 – 2.81 (m, 2H), 3.26 – 3.29 (m, 2H), 3.60 (dd, J = 5.2, 17.3 Hz, 2H), 4.03 – 4.11 (m, 1H), 4.24 – 4.28 (m, 2H), 7.30 – 7.37 (m, 2H), 7.42 (t, J = 7.4 Hz, 2H), 7.75 (t, J = 7.8 Hz, 2H), 7.90 (d, J = 7.5 Hz, 2H). ES+(M+1 = 321). Step 3 - Intermediate Compound 41: (9H-fluoren-9-yl)methyl (1S,4S)-5-((2S,4S)-2,5,12-trihydroxy-7- methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo [2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracene-2-carbonyl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylateGeneral Procedure I was followed using PyOxim (326 mg, 0.64 mmol), the PNU-159682 carboxylic acid (CAS No.1204819-92-0; 200 mg, 0.32 mmol), Intermediate Compound 40 (255 mg, 0.80 mmol) and DIEA (0.278 mL, 1.59 mmol) to afford Intermediate Compound 41 (200 mg, 67.5 %) as ared solid.1H NMR (400 MHz, DMSO) δ 1.20 – 1.27 (m, 3H), 1.60 – 2.01 (m, 6H), 2.55 – 2.65 (m, 2H), 2.87 (d, J = 17.7 Hz, 1H), 2.98 – 3.03 (m, 1H), 3.08 – 3.21 (m, 2H), 3.31 (s, 3H), 3.89 – 4.11 (m, 6H), 4.21 – 4.31 (m, 3H), 4.35 (dd, J = 6.8, 16.4 Hz, 2H), 4.42 (s, 1H), 4.57 – 4.63 (m, 1H), 5.00 – 5.09 (m, 1H), 5.19 – 5.40 (m, 2H), 5.41 – 5.55 (m, 1H), 5.77 (s, 3H), 7.29 – 7.36 (m, 2H), 7.36 – 7.43 (m, 2H), 7.63 (dd, J = 7.2, 10.2 Hz, 3H), 7.85 – 7.93 (m, 4H), 13.21 (s, 1H), 14.05 (s, 1H). ES+(M+23 = 952). Step 4 - Compound P13: (8S,10S)-8-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)-6,8,11- trihydroxy-1-methoxy-10-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H- pyrano[4',3':4,5]oxazolo [2,3-c][1,4]oxazin-3-yl)oxy)-7,8,9,10-tetrahydrotetracene-5,12-dioneGeneral Procedure III was followed using DCM solution of DBU (15.2 mg / mL in DCM) (0.969 mL, 0.10 mmol) and Intermediate Compound 41 (180 mg, 0.19 mmol) in DCM (12 mL) / MeCN (3.00 mL) to afford Compound P13 (33.0 mg, 24.09 %) as a red solid.1H NMR (400 MHz, CDCl3) δ 1.37 – 1.45 (m, 3H), 1.76 – 2.01 (m, 4H), 2.48 – 2.63 (m, 2H), 2.74 – 2.85 (m, 2H), 3.01 (d, J = 5.0 Hz, 1H), 3.13 – 3.27 (m, 2H), 3.48 (s, 6H), 3.55 – 3.67 (m, 2H), 3.90 – 3.98 (m, 3H), 3.99 – 4.14 (m, 5H), 4.49 (d, J = 1.8 Hz, 1H), 4.72 – 4.91 (m, 2H), 5.29 – 5.41 (m, 2H), 5.51 – 5.60 (m, 1H), 7.36 – 7.45 (m, 1H), 7.75 – 7.84 (m, 1H), 8.00 – 8.09 (m, 1H), 13.38 (s, 1H), 13.96 (d, J = 9.8 Hz, 1H). ES+(M+1 = 708).Example 17: Synthesis of Compound P14Step 1a and 1b - Intermediate Compound 43: (9H-fluoren-9-yl)methyl 5-oxa-2,8- diazaspiro[3.5]nonane-8-carboxylate, HCl salttert-Butyl 5-oxa-2,8-diazaspiro[3.5]nonane-2-carboxylate (500 mg, 2.19 mmol) was added to a solution of N,N-diisopropylethylamine (849 mg, 6.57 mmol) and N-(9H-fluoren-2- ylmethoxycarbonyloxy)succinimide (813 mg, 2.41 mmol) in DCM (8 mL). The resulting mixture was stirred at 25 °C for 2 hours. The reaction mixture was quenched with water. The organic layer was separated, dried over Na2SO4. The solvent was removed under reduced pressure. The crude di- protected product Intermediate Compound 42 was treated with 4 N HCl solution in dioxane according to General Procedure II, Method A to afford Intermediate Compound 43 (650 mg, 85 %) as a yellow solid.1H NMR (400 MHz, DMSO) δ3.11 – 3.83 (m, 9H), 4.12-4.51 (m, 3H), 7.36 (t, J = 7.7 Hz, 2H), 7.40 – 7.49 (m, 2H), 7.65 (t, J = 6.5 Hz, 2H), 7.92 (d, J = 7.6 Hz, 2H), 9.26 (br,2H). Step 3 - Intermediate Compound 44: (9H-fluoren-9-yl)methyl 2-((2S,4S)-2,5,12-trihydroxy-7- methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H- pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracene-2- carbonyl)-5-oxa-2,8-diazaspiro[3.5]nonane-8-carboxylateGeneral Procedure I was followed using the PNU-159682 carboxylic acid (CAS No.1204819-92-0; 200 mg, 0.32 mmol), Intermediate Compound 43 (279 mg, 0.80 mmol), N,N-diisopropylethylamine (206 mg, 1.59 mmol) and PyOxim (326 mg, 0.64 mmol) in DMA (2 mL) and MeCN (4 mL) to afford Intermediate Compound 44 (150 mg, 49.0 %) as a red solid.1H NMR (400 MHz, DMSO) δ 1.25 (d, J = 6.8 Hz, 2H), 1.67 (s, 2H), 2.12 – 2.37 (m, 2H), 2.57 – 3.02 (m, 4H), 3.27 – 3.32 (m, 2H), 3.36 (s, 20H), 3.61 – 3.95 (m, 4H), 4.05 – 4.65 (m, 4H), 4.95 – 5.40 (m, 2H), 6.10 (s, 1H), 7.32 – 7.68 (m, 5H), 7.79 – 7.98 (m, 4H). m / z (ES+), [M+H]+ = 960. Step 4 - Compound P14: (8S,10S)-6,8,11-trihydroxy-1-methoxy-10-(((1S,3R,4aS,9S,9aR,10aS)-9- methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo [2,3-c][1,4]oxazin-3-yl)oxy)-8-(5-oxa-2,8- diazaspiro[3.5]nonane-2-carbonyl)-7,8,9,10-tetrahydrotetracene-5,12-dioneGeneral Procedure III was followed using Intermediate Compound 44 (130 mg, 0.14 mmol) and DCM solution of DBU (15.2mg / mL in DCM) (0.746 mL, ~0.07mmol) in DCM (1.5 mL) and MeCN (0.5 mL) to afford Compound P14 (20.00 mg, 20.02 %) as a red solid.NMR (300 MHz, DMSO) δ 1.17 (d, J = 6.7 Hz, 1H), 1.25 (d, J = 6.7 Hz, 4H), 1.67 (s, 2H), 2.28 (s, 1H), 2.65 (d, J = 15.2 Hz, 3H), 2.79 (s, 1H), 2.92 (d, J = 17.6 Hz, 1H), 3.13 (s, 1H), 3.52 (d, J = 4.6 Hz, 4H), 3.59–3.80 (m, 4H), 3.94 (d, J = 8.4 Hz, 2H), 4.00 (s, 3H), 4.07 – 4.43 (m, 5H), 4.59 (s, 1H), 4.98 (s, 1H), 5.25 (d, J = 4.4 Hz, 1H), 5.31–5.39 (m, 1H), 7.67 (t, J = 4.9 Hz, 1H), 7.93 (d, J = 4.7 Hz, 2H). m / z (ES+), [M+H]+ = 738.Example 18: Synthesis of Compound P15Steps 1-2 - Intermediate Compound 46: (9H-fluoren-9-yl)methyl 5-oxa-2,8-diazaspiro[3.5]nonane- 2-carboxylate, HCl salttert-Butyl 5-oxa-2,8-diazaspiro[3.5]nonane-8-carboxylate (700 mg, 3.07 mmol) was added to a solution of N-(9H-fluoren-2-ylmethoxycarbonyloxy)succinimide (1138 mg, 3.37 mmol) and N,N- diisopropylethylamine (1189 mg, 9.20 mmol) in DCM (15 mL) under air. The resulting mixture was stirred at 25 °C for 2 hours. The mixture was diluted with 50 ml of DCM, and washed with water (50 mL). The organic phase was isolated and dried over Na2SO4, then evaporated under reduced pressure. The crude di-protected product Intermediate Compound 45 was treated with HCl solution (4N in 1,4-dioxane) (10 mL) according to General Procedure II, Method A to afford Intermediate Compound 46 (1000 mg, 76 %) as a yellow solid.1H NMR (300 MHz, DMSO) δ 3.09 (d, J = 19.2 Hz, 2H), 3.33 (s, 2H), 3.65 – 4.41 (m, 9H), 7.35 (td, J = 1.2, 7.4 Hz, 2H), 7.40 – 7.48 (m, 2H), 7.65 (d, J = 7.4 Hz, 2H), 7.91 (d, J = 7.4 Hz, 2H), 9.49 (s, 2H). ES+(M+1= 351). Step 3 - Intermediate Compound 47: (9H-fluoren-9-yl)methyl 8-((2S,4S)-2,5,12-trihydroxy-7- methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo [2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracene-2-carbonyl)-5-oxa-2,8- diazaspiro[3.5]nonane-2-carboxylateGeneral Procedure I was followed using HATU (136 mg, 0.36 mmol), the PNU-159682 carboxylic acid (CAS No.1204819-92-0; 150 mg, 0.24 mmol), N,N-diisopropylethylamine (154 mg, 1.20 mmol), Intermediate Compound 46 (209 mg, 0.60 mmol) to afford Intermediate Compound 47 ( (130 mg, 56.7 %) as a red solid.NMR (300 MHz, DMSO) δ 1.25 (d, J = 6.7 Hz, 3H), 1.66 (s, 1H), 2.17 (s, 1H), 2.59 – 2.68 (m, 2H), 2.90 (s, 1H), 3.31 (s, 5H), 3.39 - 4.06 (m, 20H), 4.24 (s, 1H), 4.59 (s, 1H), 5.07 (s, 1H), 5.26 (s, 1H), 5.77 (s, 3H), 6.09 (s, 1H), 7.39 (d, J = 7.7 Hz, 5H), 7.62 (s, 2H), 7.78 – 7.95 (m, 4H). ES+(M+1 = 960). Step 4 - Compound P15: (8S,10S)-6,8,11-trihydroxy-1-methoxy-10-(((1S,3R,4aS,9S,9aR,10aS)-9- methoxy-1-methyloctahydro-1H-pyrano[4’,3’:4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-8-(5-oxa-2,8- diazaspiro[3.5]nonane-8-carbonyl)-7,8,9,10-tetrahydrotetracene-5,12-dioneGeneral Procedure III was followed using DBU (7.85 µl, 0.05 mmol) and Intermediate Compound 47 (100 mg, 0.10 mmol) in DCM (2 mL) / MeCN (0.5 mL) to afford Compound P15 (15.00 mg, 19.52 %) as a red solid. ES+(M+1 = 738).Example 19: Synthesis of Compound P15aStep 1 – Intermediate Compound 48: tert-butyl 2-acetyl-5-oxa-2,8-diazaspiro[3.5]nonane-8- carboxylateAc2O (0.248 mL, 2.63 mmol) was added to a solution of tert-butyl 5-oxa-2,8-diazaspiro[3.5]nonane- 8-carboxylate (400 mg, 1.75 mmol) and DIEA (1.530 mL, 8.76 mmol) in DCM (15 mL) at 25°C under nitrogen. The resulting mixture was stirred at 25 °C for 2 hours. The reaction mixture was diluted with DCM (75 mL), and washed with water (3 x 50 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford Intermediate Compound 48 (420 mg, 89%) as a yellow solid.1H NMR (400 MHz, DMSO) δ 1.42 (s, 9H), 1.79 (s, 3H), 3.26 – 3.33 (m, 2H), 3.47 (d, J = 16.4 Hz, 2H), 3.52 – 3.62 (m, 2H), 3.62 – 3.71 (m, 2H), 3.96 (s, 2H). m / z (ES+), [M+H]+ = 271. Step 2 – Intermediate Compound 49: 1-(5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)ethan-1-one, HCl saltGeneral Procedure II, Method A was followed using Intermediate Compound 48 (410 mg, 1.52 mmol) to afford Intermediate Compound 49 (210 mg, 81 %) as a yellow solid.1H NMR (400 MHz, DMSO) δ 1.77 (s, 3H), 2.97 – 3.08 (m, 2H), 3.22 – 3.34 (m, 2H), 3.65 (d, J = 10.6 Hz, 1H), 3.79 – 3.88 (m, 2H), 3.99 (dd, J = 3.5, 10.0 Hz, 2H), 4.20 – 4.27 (m, 1H). m / z (ES+), [M+H]+= 171. Step 3 – Compound P15a: (8S,10S)-8-(2-acetyl-5-oxa-2,8-diazaspiro[3.5]nonane-8-carbonyl)-6,8,11- trihydroxy-1-methoxy-10-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H- pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-7,8,9,10-tetrahydrotetracene-5,12-dioneGeneral Procedure I was followed using HATU (158 mg, 0.41 mmol), the PNU-159682 carboxylic acid (CAS No.1204819-92-0; 130 mg, 0.21 mmol), DIEA (0.181 mL, 1.04 mmol) and Intermediate Compound 49 (70.5 mg, 0.41 mmol) in DMA (1.5 mL) to afford Compound P15a (46.0 mg, 28.5 %) as a red solid.1H NMR (400 MHz, CDCl3) δ 1.42 (d, J = 6.4 Hz, 3H), 1.75 (s, 3H), 1.93 (s, 4H), 2.44 (dd, J = 4.2, 15.3 Hz, 1H), 2.65 – 3.01 (m, 4H), 3.48 (d, J = 2.3 Hz, 5H), 3.58 – 3.80 (m, 3H), 3.84 – 4.19 (m, 12H), 4.49 (d, J = 2.0 Hz, 1H), 4.69 – 4.76 (m, 1H), 5.11 (d, J = 63.0 Hz, 1H), 5.40 (s, 1H), 5.57 (d, J = 5.0 Hz, 1H), 7.43 (dd, J = 1.1, 8.6 Hz, 1H), 7.77 – 7.85 (m, 1H), 8.03 – 8.09 (m, 1H), 13.37 (s, 1H), 13.94 (d, J = 6.4 Hz, 1H). m / z (ES+), [M+H]+= 780. Example 20: Synthesis of Compound P16Step 1 - Compound P16: (8S,10S)-6,8,11-trihydroxy-1-methoxy-10-(((1S,3R,4aS,9S,9aR,10aS)-9- methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-8-(2-oxa-5,8- diazaspiro[3.5]nonane-8-carbonyl)-7,8,9,10-tetrahydrotetracene-5,12-dioneGeneral Procedure I was followed using HATU (91 mg, 0.24 mmol), the PNU-159682 carboxylic acid (CAS No.1204819-92-0; 100 mg, 0.16 mmol), DIEA (0.139 mL, 0.80 mmol) and 2-oxa-5,8- diazaspiro[3.5]nonane (71.5 mg, 0.56 mmol) to afford Compound P16 (30.0 mg, 25.5 %) as a red solid.1H NMR (300 MHz, CDCl3) δ 1.41 (d, J = 6.4 Hz, 3H), 1.70 - 1.81 (m, 1H), 1.92 - 2.07 (m, 1H), 2.40 - 2.50 (m, 1H), 2.67 - 2.86 (m, 3H), 2.90-3.02 (m, 3H), 3.40 (q, J = 6.4 Hz, 2H), 3.48 (s, 4H), 3.55 - 3.70 (m, 2H), 3.81 - 4.10 (m, 6H), 4.12 (s, 3H), 4.49 (d, J = 1.9 Hz, 1H), 4.51 - 4.67 (m, 3H), 4.73 (d, J = 1.9 Hz, 2H), 5.15 (s, 1H), 5.40 (s, 1H), 5.57 (t, J = 5.2 Hz, 1H), 7.38 - 7.47 (m, 1H), 7.81 (t, J = 8.1 Hz, 1H), 8.07 (dd, J = 1.1, 7.7 Hz, 1H), 13.37 (s, 1H), 13.96 (s, 1H). ES+(M+1 = 738). Example 21: Synthesis of Compound P17Step 1 - Compound P17: (8S,10S)-6,8,11-trihydroxy-1-methoxy-10-(((1S,3R,4aS,9S,9aR,10aS)-9- methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-8-(4,7- diazaspiro[2.5]octane-7-carbonyl)-7,8,9,10-tetrahydrotetracene-5,12-dioneGeneral Procedure I was followed using HATU (91 mg, 0.24 mmol), the PNU-159682 carboxylic acid (CAS No.1204819-92-0; 100 mg, 0.16 mmol), DIEA (0.139 mL, 0.80 mmol) and 4,7- diazaspiro[2.5]octane (35.7 mg, 0.32 mmol) to afford Compound P17 (22.00 mg, 19.13 %) as a red solid.1H NMR (400 MHz, CDCl3) δ 0.80-0.85 (m, 4H), 1.29 (d, J = 11.8 Hz, 1H), 1.42 (d, J = 6.4 Hz, 3H), 1.76 (t, J = 7.8 Hz, 1H), 1.95 – 1.99 (m, 1H), 2.40 - 2.50 (m, 1H), 2.64 – 2.87 (m, 3H), 2.98 (d, J = 18.5 Hz, 1H), 3.10 (s, 2H), 3.48 (s, 5H), 3.56 – 3.66 (m, 2H), 3.82 – 3.99 (m, 2H), 4.01 – 4.26 (m, 7H), 4.50 (d, J = 2.0 Hz, 1H), 4.74 (d, J = 1.8 Hz, 1H), 4.96 (s, 1H), 5.39 (s, 1H), 5.57 (t, J = 5.2 Hz, 1H), 7.42 (d, J = 8.5 Hz, 1H), 7.81 (t, J = 8.1 Hz, 1H), 8.03 - 8.10 (m, 1H), 13.36 (s, 1H), 13.96 (s, 1H). ES+(M+1 = 722). Example 22: Synthesis of Compound P18Step 1 – Compound P18: (8S,10S)-8-(1,5-diazocane-1-carbonyl)-6,8,11-trihydroxy-1-methoxy-10- (((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo [2,3- c][1,4]oxazin-3-yl)oxy)-7,8,9,10-tetrahydrotetracene-5,12-dioneGeneral Procedure I was followed using HATU (145 mg, 0.38 mmol), the PNU-159682 carboxylic acid (CAS No.1204819-92-0; 120 mg, 0.19 mmol), DIEA (0.167 mL, 0.96 mmol) and 1,5-diazocane dihydrobromide (79 mg, 0.29 mmol) in DMA (3 mL) to afford Compound P18 (32.0 mg, 23.12 %) as a red solid. NMR (400 MHz, CDCl3) δ 1.28 (s, 1H), 1.41 (d, J = 6.4 Hz, 3H), 1.76 – 2.05 (m, 7H), 20 2.48 – 2.82 (m, 4H), 2.88 – 3.19 (m, 5H), 3.38 – 3.64 (m, 8H), 3.89 – 3.99 (m, 2H), 4.05-4.14 (m, 6H),4.50 (d, J = 2.0 Hz, 1H), 4.74 (d, J = 1.6Hz, 1H), 5.37 (s, 1H), 5.52 – 5.59 (m, 1H), 7.41 (dd, J = 1.2, 8.8 Hz, 1H), 7.76 – 7.84 (m, 1H), 8.05 (dd, J = 1.2, 7.7 Hz, 1H), 13.96 (s, 1H). ES+(M+1 = 724). Example 23: Synthesis of Compound P19Step 1 - Compound P19: (8S,10S)-8-(6,6-dimethyl-1,4-diazepane-1-carbonyl)-6,8,11-trihydroxy-1- methoxy-10-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H- pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-7,8,9,10-tetrahydrotetracene-5,12-dioneGeneral Procedure I was followed using HATU (145 mg, 0.38 mmol), the PNU-159682 carboxylic acid (CAS No.1204819-92-0; 120 mg, 0.19 mmol), DIEA (0.167 mL, 0.96 mmol) and 6,6-dimethyl- 1,4-diazepane dihydrochloride (77 mg, 0.38 mmol) to afford Compound P19 (10.50 mg, 7.44 %) as a red solid. NMR (400 MHz, CDCl3) δ 0.86 – 0.90 (m, 1H), 0.98 – 1.04 (m, 5H), 1.04 – 1.10 (m, 1H), 1.28 (s, 1H), 1.41 (d, J = 6.4 Hz, 3H), 1.74 – 1.81 (m, 1H), 1.98 – 2.02 (m, 1H), 2.46 – 2.54 (m, 1H), 2.62 – 2.85 (m, 5H), 2.99 (s, 1H), 3.03-3.11 (br, 2H), 3.30 (d, J = 13.6 Hz, 1H), 3.40 (d, J = 6.4 Hz, 1H), 3.48 (s, 4H), 3.53 – 3.63 (m, 2H), 3.70 – 3.86 (m, 2H), 3.91 – 3.96 (m, 1H), 4.12 (s, 6H), 4.50 (d, J = 1.9 Hz, 1H), 4.74 (d, J = 1.6 Hz, 1H), 5.00 (s, 1H), 5.36 (s, 1H), 5.54 (s, 1H), 7.39 – 7.45 (m, 1H), 7.76 – 7.85 (m, 1H), 8.06 (dd, J = 1.2, 7.6 Hz, 1H), 13.38 (s, 1H), 13.95 (s, 1H). ES+(M+1 = 738). 20Example 24: Synthesis of Compound P20Step 1 – Intermediate Compound 50: (3R,3aS,6R,6aS)-hexahydrofuro[3,2-b]furan-3,6-diyl bis(4- methylbenzenesulfonate)Ts-Cl (32.6 g, 171.07 mmol) was added to a solution of (3R,3aR,6R,6aR)-hexahydrofuro[3,2-b]furan- 3,6-diol (“isomannide”, 10 g, 68.43 mmol) and pyridine(27 g, 5 eq ) in DCM (400 mL). The solution was stirred for overnight at room temperature. The reaction mixture was diluted with DCM (200 mL), and washed sequentially with 0.1M HCl (2 x 500 mL), saturated brine (500 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography to afford Intermediate Compound 50 (8.50 g, 27.3 %) as a white solid.NMR (300 MHz, DMSO-d6) δ 2.42 (s, 6H), 3.51 – 3.61 (m, 2H), 3.74 – 3.84 (m, 2H), 4.34 -4.41 (m, 2H), 4.88 – 4.98 (m, 2H), 7.48 (d, 4H), 7.77- 7.85 (m, 4H). ES+(M+1 = 455). Step 2 - Intermediate Compound 51: (3S,3aR,6S,6aR)-3,6-diazidohexahydrofuro[3,2-b]furanSodium azide (3.43 g, 52.80 mmol) was added to a solution of Intermediate Compound 50 (4 g, 8.80 mmol) in DMF (80 mL). The solution was stirred for 3 hours at 140 °C. The reaction mixturewas diluted with water (200 mL), and extracted with EA (3 x 200 mL). The combined organic solution was washed with water (2 x 300 mL), and brine (2 x 300 mL), The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product Intermediate Compound 51 (1.4 g, 81%) as a yellow oil.1H NMR (300 MHz, DMSO-d6) δ 3.82-3.89 (m, 4H), 4.2-4.28(m, 2H), 4.58 (s, 2H). Step 3 - Intermediate Compound 52: (3S,3aR,6S,6aR)-hexahydrofuro[3,2-b]furan-3,6-diaminePd-C (0.076 g, 0.71 mmol) was added to Intermediate Compound 51 (1.4 g 7.14 mmol) in ethyl acetate (20 mL) and methanol (1 mL). The mixture was stirred for overnight hours 25 °C under H2. The reaction mixture was filtered through silica, and washed with EA (3 x 40 mL). The solvent was removed under reduced pressure to afford Intermediate Compound 52 (0.600 g, 58.3 %) as a yellow soild.1H NMR (300 MHz, DMSO-d6) δ 3.20-3.26 (m, 4H), 3.65 – 3.73 (m, 2H), 4.24 (s, 2H). ES+( M+1 = 145). Step 4 - Compound P20: (3S,3aR,6S,6aR)-hexahydrofuro[3,2-b]furan-3,6-diamine (161 mg, 1.12 mmol) to afford (2S,4S)-N-((3S,3aR,6S,6aR)-6-aminohexahydrofuro[3,2-b]furan-3-yl)-2,5,12- trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H- pyrano[4',3'':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracene-2- carboxamideGeneral Procedure I was followed using HATU (182 mg, 0.48 mmol), the PNU-159682 carboxylic acid (CAS No.1204819-92-0; 200 mg, 0.32 mmol), DIEA (0.278 mL, 1.59 mmol) and Intermediate Compound 52 (161 mg, 1.12 mmol) to afford Compound P20 (30.0 mg, 12.49 %) as a red solid.1HNMR (400 MHz, CDCl3) δ 1.40 (d, J = 6.5 Hz, 3H), 1.69-1.80 (m, 2H), 1.99-2.13 (m, 1H), 2.33-2.52 (m, 2H), 2.72-2.89 (m, 2H), 3.18-3.33 (m, 2H), 3.36-3.43 (m, 1H), 3.48 (s, 3H), 3.56-3.83 (m, 4H), 3.85- 4.03 (m, 4H), 4.12 (s, 4H), 4.38-4.56 (m, 3H), 4.70 (dd, J = 2.9, 25.8 Hz, 2H), 5.15 (s, 1H), 5.31-5.55 (m, 2H), 7.31-7.45 (m, 2H), 7.76-7.85 (m, 1H), 8.06 (dd, J = 1.1, 7.7 Hz, 1H), 13.32 (s, 1H), 13.95 (s, 1H). ES+(M+1 = 754). Example 25: Synthesis of Compound P21Step 1 – Intermediate Compound 53: (3R,3aS,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl 4- methylbenzenesulfonateTs-Cl (13.04 g, 68.43 mmol) was added to (3R,3aR,6R,6aR)-hexahydrofuro[3,2-b]furan-3,6-diol (“isomannide”, 10 g, 68.43 mmol) and pyridine (13.77 mL, 171.07 mmol) in DCM (200 mL). The solution was stirred for overnight at room temperature. The reaction mixture was diluted with DCM (200 mL), and washed sequentially with 0.1M HCl (2 x 200 mL) and saturated brine (2 x 200 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product.The crude product was purified by flash silica chromatography using 0 to 70% EtOAc in petroleum ether to afford Intermediate Compound 53 (14.50 g, 35.4 %) as a white solid.1H NMR (300 MHz, DMSO-d6) δ 2.43 (s, 3H), 3.32 (t, 1H), 3.53 - 3.61 (m, 1H), 3.73 - 3.84 (m, 2H), 4.03 - 4.14 (m, 1H), 4.23 (t, 1H), 4.39 (t, 1H), 4.80 - 5.05 (m, 2H), 7.49 (d, 2H), 7.78 -7.87 (m, 2H). m / z (ES+), [M+NH4]+= 318. Step 2 - Intermediate Compound 54: (3R,3aS,6R,6aS)-6-((tert- butyldimethylsilyl)oxy)hexahydrofuro[3,2-b]furan-3-yl 4-methylbenzenesulfonateTBS-Cl (3.76 g, 24.97 mmol) was added to a solution of Intermediate Compound 53 (5 g, 16.65 mmol) and 1H-imidazole (2.267 g, 33.30 mmol) in DCM (100 mL). The solution was stirred for overnight at room temperature. The reaction mixture was diluted with DCM (100 mL), and washed with saturated water (2 x 100 mL) and brine (2 x 100 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford Intermediate Compound 54 as crude product.1H NMR (300 MHz, DMSO-d6) δ 0.05 (s, 6H), 0.85 (s, 9H), 2.43 (s, 3H), 3.35-.341（m, 2H), 3.51 - 3.54 (m, 1H), 3.72 - 3.84 (m, 2H), 4.21 - 4.32 (m, 2H), 4.34 -4.41 (m, 1H), 4.85-4.95 (m, 1H), 7.45 - 7.52 (m, 2H), 7.77- 7.87 (m, 2H). m / z (ES+), [M+Na]+= 437.10. Step 3 – Intermediate Compound 55: (((3R,3aS,6S,6aR)-6-azidohexahydrofuro[3,2-b]furan-3- yl)oxy)(tert-butyl)dimethylsilaneSodium azide (2.59 g, 39.80 mmol) was added to Intermediate Compound 54 (5.5 g, 13.27 mmol) in DMF (110 mL). The solution was stirred for 3 hours at 140°C. The reaction mixture was diluted with water (250 mL), and extracted with ethyl acetate (3 x 150 mL). The combined organic solution was washed with water (2 x 200 mL), and brine (2 x 200 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford Intermediate Compound 55 as crude product.1HNMR (300 MHz, DMSO-d6) δ 0.08 (s, 6H), 0.87 (s, 9H), 3.41-3.48 (m, 1H), 3.66 -3.73 (m, 1H), 3.80-3.93 (m, 2H), 4.13 (d, 1H), 4.31 (q, 1H), 4.5- 4.42 (m, 1H), 4.47 (t, 1H).Step 4 – Intermediate Compound 56: (3S,3aR,6R,6aS)-6-((tert-butyldimethylsilyl)oxy)hexahydrofuro [3,2-b]furan-3-aminePd / C (1.3 g) was added to Intermediate Compound 55 (700 mg, 2.45 mmol) in EtOAc (10 mL) / MeOH (0.500 mL) at 25°C under H2. The resulting mixture was stirred at 25 °C for 16 hours under H2. The reaction mixture was filtered through celite. The solvent was removed under reduced pressure to afford Intermediate Compound 56 as crude product (600 mg, 94 %) as a yellow oil.1H NMR (400 MHz, DMSO) δ 0.07 (s, 6H), 0.87 (s, 9H), 1.66 (s, 2H), 3.22 - 3.28 (m, 1H), 3.30 – 3.40 (m, 1H), 3.48-3.56 (m, 1H), 3.62 - 3.70 (m, 1H), 3.70 - 3.78 (m, 1H), 4.12 (d, J = 4.3 Hz, 1H), 4.19 -4.35 (m, 1H), 4.39 (t, J = 4.5 Hz, 1H). m / z (ES+), [M+H]+= 260. Step 5 – Intermediate Compound 57: (2S,4S)-N-((3S,3aR,6R,6aS)-6-((tert- butyldimethylsilyl)oxy)hexahydrofuro[3,2-b]furan-3-yl)-2,5,12-trihydroxy-7-methoxy-4- (((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo[2,3- c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracene-2-carboxamideGeneral Procedure I was followed using HATU (182 mg, 0.48 mmol), the PNU-159682 carboxylic acid (CAS No.1204819-92-0; 200 mg, 0.32 mmol), DIEA (0.278 mL, 1.59 mmol) and Intermediate Compound 56 to afford Intermediate Compound 57 (220 mg, 79 %) as a red solid.1HNMR (400 MHz, DMSO) δ 0.06 - 0.09 (m, 6H), 0.87 (d, J = 6.5 Hz, 12H), 1.21 (d, J = 6.5 Hz, 3H), 1.65 - 1.71 (m, 1H), 2.15 (d, J = 14.6 Hz, 1H), 2.23 - 2.29 (m, 1H), 2.63- 2.71 (m, 1H), 2.95 (d, J = 8.7 Hz, 1H), 3.32 (s, 2H), 3.34 (s, 2H), 3.34-3.38 (m, 1H), 3.38 -3.56 (m, 3H), 3.60 -3.71 (m, 2H), 3.71 - 3.82 (m, 2H), 3.89 - 3.96 (m,2H), 4.10 - 4.18 (m, 2H), 4.24 (d, J = 2.2 Hz, 1H), 4.27 - 4.31 (m, 1H), 4.37 - 4.39 (m, 1H), 4.46 (t, J = 4.9 Hz, 1H), 4.59 (d, J = 2.2 Hz, 1H), 4.94 - 5.01 (m, 1H), 5.24 (t, J = 4.8 Hz, 1H), 5.33 (s, 1H), 7.59 - 7.66 (m, 1H), 7.83-7.94 (m, 2H), 7.99 (d, J = 7.5 Hz, 1H). m / z (ES+), [M+H]+= 869.Step 6 – Compound P21: (2S,4S)-2,5,12-trihydroxy-N-((3S,3aR,6R,6aR)-6- hydroxyhexahydrofuro[3,2-b]furan-3-yl)-7-methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1- methyloctahydro-1H-pyrano[4',3':4,5] oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11- hexahydrotetracene-2-carboxamideTBAF (57.2 mg, 0.22 mmol) was added to a solution of Intermediate Compound 57 (190 mg, 0.22 mmol) in DCM (8 mL) at 25°C under nitrogen. The resulting mixture was stirred at 25 °C for 3 hours. The reaction mixture was quenched with 0.01% NH4HCO3(2 mL). The solvent was removed under reduced pressure. The crude product was purified by preparative HPLC to afford Compound P21 (30.0 mg, 18.18 %) as a red solid.NMR (300 MHz, CDCl3) δ 1.40 (d, J = 6.5 Hz, 3H), 1.68 - 1.83 (m, 1H), 1.99 - 2.14 (m, 1H), 2.31-2.53 (m, 2H), 2.60 (d, J = 6.8 Hz, 1H), 2.71 - 2.91 (m, 2H), 3.24 (d, J = 7.6 Hz, 2H), 3.42 (q, J = 6.3 Hz, 1H), 3.49 (s, 3H), 3.52- 3.75 (m, 2H), 3.84- 4.06 (m, 4H), 4.06-4.16 (m, 5H), 4.29 - 4.43 (m, 1H), 4.50 (t, J = 3.0 Hz, 2H), 4.56-4.62 (m, 1H), 4.66 (t, J = 5.0 Hz, 1H), 4.73 (d, J = 1.9 Hz, 1H), 5.16 (s, 1H), 5.35 (s, 1H), 5.52 (t, J = 5.6 Hz, 1H), 7.34 -7.47 (m, 2H), 7.81 (t, J = 8.1 Hz, 1H), 8.02 - 8.10 (m, 1H), 13.31 (s, 1H), 13.95 (s, 1H). m / z (ES+), [M+H]+= 755.Example 26: Synthesis of Compound P22Step 1 - Intermediate Compound 53: (3R,3aS,6R,-6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl 4- methylbenzenesulfonate4-Toluenesulfonyl chloride (137 g, 718.48 mmol) was added to a solution of pyridine (135.4 g, 1710.66 mmol), and (3R,3aR,6R,6aR)-hexahydrofuro[3,2-b]furan-3,6-diol (“isomannide”; 100 g, 684.26 mmol) in DCM (1000 mL) under nitrogen. The resulting mixture was stirred at 25 °C for 16 hours. The reaction mixture was diluted with DCM (1000 mL), and washed sequentially with 1N HCl (1000 mL) and saturated brine (1000 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography (elution gradient 40 to 40% THF in petroleum ether) to afford Intermediate Compound 53 (70 g, 34.1 %) as a white solid.1H NMR (400 MHz, Chloroform-d) δ 7.86 – 7.82 (m, 2H), 7.36 (d, J = 8.1 Hz, 2H), 4.94-4.84 (m, 1H), 4.49 (t, J = 4.9 Hz, 1H), 4.41 (t, J = 5.0 Hz, 1H), 4.31 – 4.25 (m, 1H), 4.01 (dd, J = 9.3, 6.6 Hz, 1H), 3.95 (dd, J = 9.2, 6.5 Hz, 1H), 3.79 (d, J = 2.0 Hz, 1H), 3.70 (d, J = 3.1 Hz, 1H), 3.57 – 3.51 (m, 1H), 2.46 (s, 3H). ES+(M+1 = 301). Step 2 - Intermediate Compound 54: (3R,3aS,6R,6aS)-6-((tert- butyldimethylsilyl)oxy)hexahydrofuro[3,2-b]furan-3-yl-4-methylbenzenesulfonateTBS-Cl (38.64g, 256.38mmol) was added to a solution of imidazole (31.74 g, 466.16 mmol) and Intermediate Compound 53 (70 g, 333.08 mmol) in DMA (220 ml) under nitrogen. The resulting mixture was stirred at 25 °C for 2 hours. The crude product was purified by flash silica chromatography (elution gradient 20 to 25% THF in petroleum ether) to afford Intermediate Compound 54 (76 g, 79 %) as a white solid.1HNMR (300 MHz, DMSO) δ 3.65 (d, J = 3.1 Hz, 3H), 3.83 (dd, J = 10.5, 2.5 Hz, 1H), 3.93 (ddd, J = 15.0, 9.9, 5.2 Hz, 2H), 4.13 (s, 1H), 4.18 – 4.34 (m, 3H), 4.53 – 4.63 (m, 1H), 4.64 (d, J = 4.4 Hz, 1H), 7.34 (td, J = 7.4, 1.2 Hz, 2H), 7.43 (td, J = 7.5, 1.2 Hz, 2H), 7.50 – 7.67 (m, 1H), 7.72 (d, J = 7.4 Hz, 2H), 7.90 (d, J = 7.4 Hz, 2H), 8.33 (d, J = 6.9 Hz, 1H), 8.45 (s, 2H). ES+(M+1) = 415.Step 3 – Intermediate Compound 58: 2-((3S,3aR,6R,6aS)-6-((tert-butyldimethyl- silyl)oxy)hexahydrofuro-[3,2-b]furan-3-yl)isoindoline-1,3-dionePhthalimide potassium (44.7 g, 241.20 mmol) was added to a solution of 18-Crown-6 (6.38 g, 24.12 mmol) and Intermediate Compound 54 (50 g, 120.60 mmol) in DMF (500 mL) under nitrogen. The resulting mixture was stirred at 140 °C for 8 hours. When the mixture was cooled to RT, water (150 ml) was added, and filtered, then washed the cake with H2O (50ml). The filter cake was dried under vacuum to afford Intermediate Compound 58 (40 g, 85%) as a white solid.1H NMR (300 MHz, DMSO-d6) δ 7.76 (p, J = 1.8 Hz, 4H), 4.81 (dd, J = 4.9, 1.9 Hz, 1H), 4.56 – 4.45 (m, 2H), 4.25-4.18 (m, 1H), 4.12-4.04 (m, 1H), 3.86 – 3.80 (m, 1H), 3.69-3.62 (m, 1H), 3.54 – 3.42 (m, 1H), 0.79 (s, 9H), 0.00 (d, J = 2.6 Hz, 6H). ES+(M+1 = 390). Step 4 – Intermediate Compound 59: (3S,3aR,6R,6aS)-6-((tert- butyldimethylsilyl)oxy)hexahydrofuro[3,2-b]furan-3-amineIntermediate Compound 58 (40 g, 102.69 mmol) was added to a solution of hydrazine hydrate (32.1 g, 513.45 mmol) in EtOH (260 mL) under nitrogen. The resulting mixture was stirred at 80 °C for 2 hours. When the mixture was cooled, the mixture was filtrated, washed with EtOH (260 ml). The solvent was removed under reduced pressure to afford Intermediate Compound 59 (22.00 g, 83 %) as a white solid.NMR (400 MHz, DMSO) δ 0.07 (d, J = 3.1 Hz, 6H), 0.83 – 0.90 (m, 1H), 0.87 (s, 9H), 1.94 (s, 2H), 3.26 (dt, J = 4.6, 1.5 Hz, 1H), 3.35 (dd, J = 8.3, 7.1 Hz, 1H), 3.53 (dd, J = 8.6, 1.6 Hz, 1H), 3.66 (dd, J = 8.3, 6.1 Hz, 1H), 3.75 (dd, J = 8.6, 4.4 Hz, 1H), 4.13 (d, J = 4.3 Hz, 1H), 4.21-4.30 (m, 1H), 4.39 (t, J = 4.5 Hz, 1H). ES+(M+1 = 260).Step 5 – Intermediate Compound 60: benzyl ((3S,3aR,6R,6aS)-6-((tert-butyldimethylsilyl)- oxy)hexahydrofuro[3,2-b]furan-3-yl)carbamateDIEA (40.4 mL, 231.28 mmol) was added to a solution of N-(benzyloxycarbonyloxy)succinimide (23.06 g, 92.51 mmol) and Intermediate Compound 59 (20 g, 77.09 mmol), in DCM (200 mL) under nitrogen. The resulting mixture was stirred at RT for 2 hours. The solvent was removed under reduced pressure.The crude product was purified by flash silica chromatography (elution gradient 0 to 100% THF in petroleum ether) to afford Intermediate Compound 60 (22.00 g, 72.5 %) as a white solid.1H NMR (400 MHz, DMSO) δ 0.03 – 0.11 (m, 6H), 0.86 (d, J = 7.6 Hz, 9H), 3.43 (dd, J = 8.6, 6.4 Hz, 1H), 3.65 – 3.76 (m, 2H), 3.73 – 3.87 (m, 1H), 3.87 – 3.94 (m, 1H), 4.23 – 4.35 (m, 2H), 4.40 (q, J = 6.0, 5.4 Hz, 1H), 5.04 (s, 2H), 7.28 – 7.39 (m, 5H), 7.62 (d, J = 6.4 Hz, 1H). ES+(M+1 =394). Step 6 – Intermediate Compound 61: benzyl ((3S,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan- 3-yl)carbamateIntermediate Compound 60 (20 g, 50.82 mmol) was added to HCl solution in 1,4-dioxane (200 mL). The resulting mixture was stirred at 25 °C for 6 hours. The solvent was removed under reduced pressure to afford Intermediate Compound 61 (13.0 g, 92 %) as a white solid.1H NMR (400 MHz, DMSO) δ 3.35 (t, J = 8.1 Hz, 1H), 3.65 – 3.85 (m, 3H), 3.81 – 3.94 (m, 2H), 4.09 (ddd, J = 7.8, 6.6, 4.6 Hz, 1H), 4.19 – 4.43 (m, 3H), 5.03 (s, 2H), 7.35 – 7.39 (m, 5H), 7.64 (d, J = 6.6 Hz, 1H). ES+(M+1 =280). Step 7 – Intermediate Compound 62: (3R,3aS,6S,6aR)-6- (((benzyloxy)carbonyl)amino)hexahydrofuro[3,2-b]furan-3-yl trifluoromethanesulfonateTrifluoromethanesulfonic anhydride (18.18 g, 64.45 mmol) was added to a solution of DIEA (22.51 mL, 128.90 mmol) and Intermediate Compound 61 (12 g 4297 mmol) in DCM (150 mL) at 0°C overa period of 5 minutes under nitrogen. The resulting mixture was stirred at 0 °C for 1 hour. The solvent was removed under reduced pressure to afford Intermediate Compound 62 (11.00 g, 62.2 %) as a yellow oil.NMR (400 MHz, DMSO) δ 3.73 (dd, J = 9.5, 2.6 Hz, 1H), 3.82-3.87 (m, 2H), 4.05 (d, J = 11.9 Hz, 1H), 4.54 (dd, J = 4.0, 1.6 Hz, 1H), 4.72 (d, J = 4.0 Hz, 1H), 5.04 (d, J = 3.6 Hz, 2H), 5.76 (s, 1H), 7.27 – 7.46 (m, 6H), 7.69 (d, J = 6.0 Hz, 1H). ES+(M+1 =412). Step 8 – Intermediate Compound 63: tert-butyl 3-((3S,3aR,6S,6aR)-6- (((benzyloxy)carbonyl)amino)hexahydrofuro[3,2-b]furan-3-yl)-3,6-diazabicyclo[3.1.1]heptane-6- carboxylatetert-Butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (24.10 g, 121.55 mmol) was added to a solution of Intermediate Compound 62 (10 g, 24.31 mmol) in 1,4-dioxane (100 mL). The resulting mixture was stirred at 100 °C for 2 hours. The solvent was removed under reduced pressure. The crude product was purified by flash silica chromatography (elution gradient 0 to 100% THF in petroleum ether) to afford Intermediate Compound 63 (8.00 g, 71.6 %) as a yellow oil.1H NMR (400 MHz, DMSO) δ 1.38 (s, 9H), 1.47 (d, J = 8.0 Hz, 1H), 1.70 – 1.83 (m, 3H), 2.29 (q, J = 6.4 Hz, 1H), 3.04 – 3.11 (m, 1H), 3.55 – 3.75 (m, 5H), 3.85 – 3.96 (m, 4H), 4.30 – 4.43 (m, 1H), 4.51 (d, J = 5.2 Hz, 1H), 5.02 (s, 2H), 7.25-7.40 (m, 5H). ES+(M+1 =460). Step 9 – Intermediate Compound 64: tert-butyl 3-((3S,3aR,6S,6aR)-6-aminohexahydrofuro[3,2- b]furan-3-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylatePd-C (1.853 g, (10% w / w)) was added to a solution of Intermediate Compound 63 (8 g, 17.41 mmol) in MeOH (160 mL) under hydrogen. The resulting mixture was stirred at 25 °C for another 2 hours. The reaction mixture was filtered through a celite pad. The solvent was removed under reduced pressure to afford Intermediate Compound 64 (5.30 g, 94 %) as a yellow oil.1H NMR (400 MHz, DMSO) δ 1.36 (s, 1H), 1.39 (s, 9H), 1.49 (d, J = 7.9 Hz, 1H), 2.22 – 2.38 (m, 1H), 2.51 (br, 3H), 2.55 – 2.91 (m 1H) 303 (td J = 5620 Hz 1H) 318 (s 1H) 323 340 (m 1H), 3.44 (dd, J = 8.8,2.0 Hz, 1H), 3.64 (td, J = 9.4, 4.5 Hz, 1H), 3.72 (dd, J = 8.8, 4.4 Hz, 1H), 3.85 (dd, J = 9.6, 6.0 Hz, 1H), 3.95 (d, J = 6.1 Hz, 2H), 4.14 (d, J = 4.8 Hz, 1H), 4.54 (dd, J = 4.8, 2.0 Hz, 1H). ES+(M+1 =326). Step 10 – Intermediate Compound 65: tert-butyl 3-((3S,3aR,6S,6aR)-6-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)hexahydrofuro[3,2-b]furan-3-yl)-3,6-diazabicyclo[3.1.1]heptane-6- carboxylateA mixture of N-(9H-fluoren-2-ylmethoxycarbonyloxy)succinimide (6.74 g, 19.97 mmol) was added to a solution of DIEA (8.05 mL, 46.10 mmol) and Intermediate Compound 64 (5 g, 15.37 mmol) in CH2Cl2(80 mL) under nitrogen was stirred at 25 °C for 16 hours. The solvent was removed under reduced pressure. The crude product was purified by flash silica chromatography (elution gradient 30 to 60% THF in petroleum ether ) to afford Intermediate Compound 65 (6.00 g, 71.3 %) as a yellow oil.1H NMR (400 MHz, DMSO) δ 1.39 (s, 9H), 1.48 (d, J = 8.0 Hz, 1H), 1.71 – 1.82 (m, 2H), 2.30 (q, J = 6.6 Hz, 1H), 2.56 – 2.86 (m, 1H), 3.09 (d, J = 6.8 Hz, 1H), 3.33 (s, 1H), 3.56 – 3.72 (m, 2H), 3.76 – 3.93 (m, 2H), 3.95 (d, J = 6.0 Hz, 2H), 4.22 (t, J = 6.8 Hz, 1H), 4.31 – 4.39 (m, 2H), 4.53 (s, 1H), 5.76 (s, 2H), 7.29 – 7.38 (m, 2H), 7.38 – 7.46 (m, 2H), 7.63 (d, J = 6.4 Hz, 1H), 7.71 (d, J = 7.6 Hz, 2H), 7.90 (d, J = 7.6 Hz, 2H). ES+(M+1 =548). Step 11 – Intermediate Compound 66: (9H-fluoren-9-yl)methyl ((3S,3aR,6S,6aR)-6-(piperazin-1- yl)hexahydrofuro[3,2-b]furan-3-yl)carbamate, HCl saltGeneral Procedure II, Method A was followed using HCl solution (4 M in dioxane) and Intermediate Compound 65 (5.7 g, 10.41 mmol) in 1,4-dioxane (100 mL) to afford Intermediate Compound 66 (4.40 g, 97 %) as a white solid.1H NMR (300 MHz, DMSO) δ 1.96 (s, 6H), 3.57 (s, 6H), 3.88 (d, J = 8.4 Hz, 1H), 4.22 (t, J = 6.8 Hz, 1H), 4.31-4.36 (m, 5H), 4.48 (s, 1H), 7.32 – 7.46 (m, 4H), 7.71 (d, J = 7.6 Hz, 3H), 7.86 – 7.94 (m, 2H). ES+(M+1 =448).Step 12 – Intermediate Compound 67: (9H-fluoren-9-yl)methyl ((3S,3aR,6S,6aR)-6-(6-((2S,4S)- 2,5,12-trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H- pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracene-2- carbonyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)hexahydrofuro[3,2-b]furan-3-yl)carbamateGeneral Procedure I was followed using Intermediate Compound 66 (224 mg, 0.46 mmol), DIEA (0.484 mL, 2.77 mmol), HATU (228 mg, 0.60 mmol) and the PNU-159682 carboxylic acid (CAS No. 1204819-92-0; 290 mg, 0.46 mmol) to afford Intermediate Compound 67 (160 mg, 32.8 %) as a red solid.1H NMR (400 MHz, DMSO) δ 1.20 – 1.35 (m, 5H), 1.51-1.56 (m, 1H), 1.70-1.76 (m, 9H), 1.92 (s, 1H), 3.00-3.05 (m, 11H), 3.52 (s, 1H), 3.82 – 3.93 (m, 3H), 4.00 (s, 3H), 4.10 (s, 1H), 4.23 (s, 2H), 4.32 (d, J = 7.2 Hz, 2H), 4.59 (s, 1H), 4.89 (s, 1H), 5.25 (s, 1H), 5.77 (s, 2H), 6.69 (s, 1H), 7.33 (t, J = 7.6 Hz, 2H), 7.42 (t, J = 7.6 Hz, 2H), 7.70 (d, J = 8.0 Hz, 4H), 7.87-7.92 (m, 4H), 8.17 (s, 1H), 13.26 (s, 1H), 14.06 (s, 1H). ES+(M+1 =1056.4). Step 13 - Compound P22: (8S,10S)-8-(3-((3S,3aR,6S,6aR)-6-aminohexahydrofuro[3,2-b]furan-3-yl)- 3,6-diazabicyclo[3.1.1]heptane-6-carbonyl)-6,8,11-trihydroxy-1-methoxy-10- (((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo[2,3- c][1,4]oxazin-3-yl)oxy)-7,8,9,10-tetrahydrotetracene-5,12-dioneGeneral Procedure III was followed using DBU (0.021 mL, 0.14 mmol) and Intermediate Compound 67 (150 mg, 0.14 mmol) in DCM (5 mL) and MeCN (1.250 mL) to afford Compound P22 (15.00 mg, 12.66 %) as a red solid.1H NMR (300 MHz, DMSO) δ 1.15 – 1.29 (m, 3H), 1.69 (s, 2H), 1.87 (t, J = 9.2Hz, 1H), 2.10 – 2.35 (m, 2H), 2.42 (s, 1H), 2.66 (d, J = 13.3 Hz, 2H), 2.78 – 2.94 (m, 2H), 2.98 (d, J = 5.5 Hz, 2H), 3.01 – 3.18 (m, 4H), 3.47 – 3.56 (m, 3H), 3.67 (t, J = 6.1 Hz, 3H), 3.67 – 3.93 (m, 3H), 3.93 – 4.08 (m, 6H),4.10 – 4.22 (m, 1H), 4.24 (d, J = 2.3 Hz, 3H), 4.59 (d, J = 2.3 Hz, 2H), 4.81 (s, 1H), 5.01 – 5.08 (m, 1H), 5.15 (s, 1H), 5.26 (d, J = 4.1 Hz, 1H), 7.57 – 7.72 (m, 1H), 7.92 (t, J = 6.8 Hz, 2H). ES+(M+1 =835). Example 27: Synthesis of Compound P23Step 1 – Intermediate Compound 68: (3R,3aS,6R,6aS)hexahydrofuro[3,2-b]furan-3,6-diyl bis(4- methylbenzenesulfonate)4-Toluenesulfonyl chloride (130 g, 684.27 mmol) was added to a solution of pyridine (110 mL, 1368.53 mmol) and (3R,3aR,6R,6aR)-hexahydrofuro[3,2-b]furan-3,6-diol (“isomannide”; 20 g, 136.85 mmol) in DCM (500 mL) at 25°C under nitrogen. The resulting mixture was stirred at 25 °C for 16 hours. The reaction mixture was quenched with water (300 mL), extracted with DCM (3 x 500 mL). Combined extracts were washed with 0.1N HCl (3 x 500 ml) and then with H2O and washed with dilute NaHCO3 and saturated aqueons NaCl. The organic layer was dried over Na2SO4, filtered and evaporated to afford crude Intermediate Compound 68 (60.0 g, 96 %) as a white solid. (m,18-Crown-6 (3.49 g, 13.20 mmol) was added to a solution of Intermediate Compound 68 (30 g, 66.01 mmol) and potassium 1,3-dioxoisoindolin-2-ide (26.9 g, 145.21 mmol) in DMF (500 mL) under nitrogen. The resulting mixture was stirred at 140 °C for 16 hours. The mixture was combined and washed with water (3 x 500 mL), dry the filter cake to afford Intermediate Compound 69 (15.00 g, 56.2 %) as a yellow solid.1H NMR (400 MHz, DMSO) δ 3.93 (dd, J = 6.0, 9.6 Hz, 2H), 4.27 (dd, J = 7.6, 9.2 Hz, 2H), 4.69 (dd, J = 6.0, 7.6 Hz, 2H), 5.19 (s, 2H), 7.81 – 7.92 (m, 8H). ES+(M+1 = 405).Step 3 – Intermediate Compound 70: (3S,3aR,6S,6aR)-hexahydrofuro[3,2-b]furan-3,6-diamineHydrazine monohydrate (12.75 mL, 210.20 mmol) was added to a solution of Intermediate Compound 69 (17 g, 42.04 mmol) in EtOH (350 mL) under nitrogen. The resulting mixture was stirred at 80 °C for 2 hours. The reaction mixture was filtered, and wash the filter cake with EtOH (2 x 150 mL). The filtrate was evaporated to dryness to afford Intermediate Compound 70 (3.50 g, 57.7 %) as a yellow solid.1H NMR (400 MHHz, DMSO) δ 3.25 (dd, J = 2.0, 4.4 Hz, 2H), 3.43 (dd, J = 2.0, 8.7 Hz, 2H), 3.69 (dd, J = 4.5, 8.7 Hz, 2H), 4.25 (s, 2H). ES+( M+1 = 145). Step 4 – Intermediate Compound 71: (9H-fluoren-9-yl)methyl ((3S,3aR,6S,6aR)-6- aminohexahydrofuro[3,2-b]furan-3-yl)carbamateN-(9H-Fluoren-2-ylmethoxycarbonyloxy)su2Ncc ( OiSn) Him H Oide ( NS (H)1F.9m8o9c g, 5.90 mmol) was added slowly to a solution of Intermediate Compound 70 (1.7 g, 11.79 mmol) and DIEA (4.12 mL, 23.58 mmol) in THF (100 mL) under nitrogen. The resulting mixture was stirred at 25 °C for 2 hours. The solvent was removed under reduced pressure. The crude product was purified by flash C18-flash chromatography, elution gradient 5 to 100% MeCN in water. Pure fractions were evaporated to dryness to afford Intermediate Compound 71 (1.200 g, 27.8 %) as a yellow solid.1H NMR (300 MHz, DMSO) δ 3.38 – 3.48 (m, 3H), 3.55 (dd, J = 6.4, 8.4 Hz, 1H), 3.66 – 3.91 (m, 3H), 4.15 – 4.53 (m, 4H), 7.28 – 7.47 (m, 5H), 7.52 – 7.75 (m, 1H), 7.75 – 7.96 (m, 4H). ES+(M+1 = 367). Step 5 – Intermediate Compound 72: 4-((1R,4R)-5-(tert-butoxycarbonyl)-2,5- diazabicyclo[2.2.2]octan-2-yl)-4-oxobutanoic acidSuccinic anhydride (236 mg, 2.36 mmol) was added to a solution of tert-butyl (1R,4R)-2,5-diaza- bicyclo[2.2.2]octane-2-carboxylate (500 mg, 2.36 mmol) in DCM (6 mL) under nitrogen. The resulting mixture was stirred at RT for 2 hours. The solvent was removed under reduced pressure. The crude product was purified by flash C18-flash chromatography, elution gradient 0 to 100% MeCN in water. Pure fractions were evaporated to afford Intermediate Compound 72 (650 mg, 88%) as a white solid.1H NMR (400 MHz, DMSO) δ 1.41 (d, J = 2.5 Hz, 9H), 1.65 – 1.93 (m, 4H), 2.32 – 2.51 (m, 4H), 3.30 – 3.47 (m, 3H), 3.47 – 3.73 (m, 2H), 4.11 – 4.19 (m, 1H), 11.56 (s, 1H). ES+(M+1 = 313). Step 6 – Intermediate Compound 73: tert-butyl (1R,4R)-5-(4-(((3S,3aR,6S,6aR)-6-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-hexahydrofuro[3,2-b]furan-3-yl)amino)-4-oxobutanoyl)-2,5- diazabicyclo[2.2.2]octane-2-carboxylateGeneral Procedure I was followed using DIEA (0.572 mL, 3.27 mmol), Intermediate Compound 72 (511 mg, 1.64 mmol), Intermediate Compound 71 (400 mg, 1.09 mmol) and HATU (830 mg, 2.18 mmol) to afford Intermediate Compound 73 (130 mg, 18.02 %) as a yellow solid.1H NMR (400 MHz, DMSO) δ 1.41 (d, J = 2.6 Hz, 9H), 1.68 – 1.87 (m, 4H), 2.30 – 2.50 (m, 4H), 3.34 – 3.43 (m, 3H), 3.53 – 3.62 (m, 2H), 3.62 – 3.69 (m, 1H), 3.78 – 3.92 (m, 3H), 4.07 – 4.18 (m, 2H), 4.18 – 4.26 (m, 1H), 4.30 – 4.40 (m, 3H), 4.43 (d, J = 3.8 Hz, 1H), 4.53 (d, J = 13.0 Hz, 1H), 7.30 – 7.39 (m, 2H), 7.39 – 7.47 (m, 2H), 7.71 (d, J = 7.3 Hz, 3H), 7.81 – 7.93 (m, 2H), 8.14 (d, J = 7.0 Hz, 1H). ES+(M+1 = 661). Step 7 – Intermediate Compound 74: (9H-fluoren-9-yl)methyl ((3S,3aR,6S,6aR)-6-(4-((1R,4R)-2,5- diazabicyclo[2.2.2]octan-2-yl)-4-oxobutanamido) hexahydrofuro[3,2-b]furan-3-yl)carbamate, HCl saltGeneral Procedure II, Method A was followed using 4N HCl in dioxane (3 mL, 98.74 mmol) and Intermediate Compound 73 (130 mg, 0.20 mmol) to afford Intermediate Compound 74 (100 mg, 91 %) as a yellow solid.NMR (400 MHz, DMSO) δ 1.73 – 1.84 (m, 4H), 2.06 (s, 1H), 2.33 – 2.43 (m, 4H), 2.53 – 265 (m 2H) 318 331 (m 2H) 333 (s 1H) 337 352 (m 3H), 3.68 (d, J = 2.9Hz, 1H), 3.76 (d, J = 5.7 Hz, 2H), 3.80 – 3.88 (m, 4H), 4.09 (s, 1H), 4.17 – 4.26 (m, 2H), 7.33 – 7.36 (m, 2H), 7.43 (s, 2H), 7.71 (d, J = 7.3 Hz, 4H), 7.90 (d, J = 7.5 Hz, 2H). ES+(M+1 = 561). Step 8 – Intermediate Compound 75: (9H-fluoren-9-yl)methyl ((3S,3aR,6S,6aR)-6-(4-oxo-4-((1R,4R)- 5-((2S,4S)-2,5,12-trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro- 1H-pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11- hexahydrotetracene-2-carbonyl)-2,5-diazabicyclo[2.2.2]octan-2-yl)butanamido)-hexahydrofuro[3,2- b]furan-3-yl)carbamateGeneral Procedure I was followed using PyOxim (212 mg, 0.41 mmol), the PNU-159682 carboxylic acid (CAS No.1204819-92-0; 130 mg, 0.21 mmol), Intermediate Compound 74 (174 mg, 0.31 mmol) and DIEA (0.181 mL, 1.04 mmol) in DMA (3 mL) to afford Intermediate Compound 75 (140 mg, 57.8 %) as a red solid.1H NMR (400 MHz, DMSO) δ 1.14 – 1.27 (m, 3H), 1.58 – 1.87 (m, 7H), 1.91 – 2.27 (m, 2H), 2.30 – 2.43 (m, 3H), 2.59 – 2.94 (m, 3H), 2.98 – 3.06 (m, 3H), 3.34 – 3.62 (m, 11H), 3.63 – 3.77 (m, 3H), 3.80 – 4.16 (m, 8H), 4.18 – 4.45 (m, 4H), 4.47 – 4.77 (m, 2H), 4.94 – 5.32 (m, 2H), 6.29 (s, 1H), 7.28 – 7.46 (m, 4H), 7.59 – 7.73 (m, 2H), 7.82 – 7.94 (m, 5H), 8.06 – 8.17 (m, 1H), 8.34 – 8.49 (m, 1H). ES+(M+1 = 1170). Step 9 – Compound P23: N-((3S,3aR,6S,6aR)-6-aminohexahydrofuro[3,2-b]furan-3-yl)-4-oxo-4- ((1R,4R)-5-((2S,4S)-2,5,12-trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1- methyloctahydro-1H-pyrano[4',3':4,5]oxazolo-[2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11- hexahydrotetracene-2-carbonyl)-2,5-diazabicyclo[2.2.2]octan-2-yl)butanamideGeneral Procedure III was followed using a DCM solution of DBU (15.2 mg / mL in DCM) (0.779 mL, 0.08 mmol) and Intermediate Compound 75 (130 mg, 0.11 mmol) in DCM (6 mL) / MeCN (1.5 mL) to afford Compound P23 (38.0 mg, 36.1 %) as a red solid.1H NMR (400 MHz, CDCl3) δ 1.36 – 1.47 (m,3H), 1.73 – 1.89 (m, 3H), 1.93 – 2.05 (m, 2H), 2.19 (d, J = 12.4 Hz, 1H), 2.40 – 2.49 (m, 1H), 2.53 – 2.65 (m, 3H), 2.70 – 2.77 (m, 1H), 2.78 – 2.86 (m, 1H), 2.95 – 3.08 (m, 1H), 3.33 – 3.43 (m, 2H), 3.48 (d, J = 1.2 Hz, 3H), 3.54 – 3.86 (m, 7H), 3.94 (s, 4H), 4.11 (d, J = 2.4 Hz, 6H), 4.49 (d, J = 1.9 Hz, 2H), 4.60 (s, 1H), 4.73 (s, 1H), 4.76 – 4.86 (m, 1H), 4.90 – 5.02 (m, 1H), 5.26 (s, 1H), 5.38 (s, 1H), 5.56 (s, 1H), 6.34 – 6.38 (m, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.80 (dd, J = 6.8, 9.6 Hz, 1H), 8.06 (d, J = 7.6 Hz, 1H), 13.40 (s, 1H), 13.97 (s, 1H). ES+(M+1 = 948). Example 28: Synthesis of Compound P24Step 1 – Intermediate Compound 76: tert-butyl 3-(4-(benzyloxy)-4-oxobutanoyl)-3,6- diazabicyclo[3.1.1]heptane-6-carboxylateGeneral Procedure I was followed using tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (4.57 g, 23.05 mmol), 4-(benzyloxy)-4-oxobutanoic acid (4 g, 19.21 mmol), HATU (14.61 g, 38.42 mmol) and DIEA (10.07 mL, 57.63 mmol) in MeCN (150 mL) to afford Intermediate Compound 76 (6.00 g, 80 %) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 1.44 (s, 9H), 2.49 – 2.65 (m, 1H), 2.66 – 2.76 (m, 2H), 2.78 – 2.91 (m, 1H), 3.51 (dd, J = 4.0, 11.8 Hz, 2H), 4.02 (d, J = 13.2 Hz, 1H), 4.08 – 4.28 (m, 3H), 5.08 – 5.22 (m, 2H), 7.32 – 7.46 (m, 5H). ES+(M+1= 389). Step 2 - Intermediate Compound 77: (4-(6-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.1.1]heptan-3- yl)-4-oxobutanoic acidPd-C (3.29 g, 3.09 mmol) was added to a solution of Intermediate Compound 76(6 g, 15.45 mmol) in THF (100 mL) under hydrogen. The resulting mixture was stirred at 25 °C for 2 hours under hydrogen. The reaction mixture was filtered through a celite pad. The solvent was removed under reduced pressure. Intermediate Compound 77 was obtained as crude material (4.30 g, 93 %, white solid).1H NMR (400 MHz, DMSO) δ 1.23-1.39 (m, 10H), 2.42 – 2.47 (m, 4H), 3.19 – 3.43 (m, 2H), 3.55 (d, J = 11.2 Hz, 1H), 3.81 (dd, J = 2.5, 13.2 Hz, 1H), 3.98 (s, 1H), 4.09 (d, J = 6.2 Hz, 2H), 12.03 (s, 1H). ES+(M+1 = 299. Step 3 - Intermediate Compound 78: tert-butyl 3-(4-(((3S,3aR,6S,6aR)-6-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)hexahydrofuro[3,2-b]furan-3-yl)amino)-4-oxobutanoyl)-3,6- diazabicyclo[3.1.1]heptane-6-carboxylateGeneral Procedure I was followed using Intermediate Compound 71 (500 mg, 1.36 mmol), Intermediate Compound 77 (400 mg, 1.34 mmol), HATU (1020 mg, 2.68 mmol) and DIEA (0.703 mL, 4.02 mmol) in MeCN (5 mL) to afford Intermediate Compound 78 (500 mg, 57.7 %) as a yellow solid.1H NMR (400 MHz, DMSO) δ 1.35 (s, 10H), 2.29 – 2.40 (m, 2H), 2.48 (d, J = 8.8 Hz, 3H), 3.28 (d, J = 13.2 Hz, 1H), 3.51 – 3.70 (m, 3H), 3.77 – 3.94 (m, 4H), 4.03 – 4.12 (m, 3H), 4.22 (t, J = 6.8 Hz, 1H), 4.31 – 4.48 (m, 4H), 7.34 (td, J = 1.2, 7.6 Hz, 2H), 7.42 (t, J = 7.6 Hz, 2H), 7.71 (d, J = 7.2 Hz, 3H), 7.90 (d, J = 7.6Hz, 2H), 8.16 (d, J = 6.9 Hz, 1H). ES+(M+1 = 647).Step 4 - Intermediate Compound 79: (9H-fluoren-9-yl)methyl ((3S,3aR,6S,6aR)-6-(4-(3,6- diazabicyclo[3.1.1]heptan-3-yl)-4-oxobutanamido)hexahydrofuro[3,2-b]furan-3-yl)carbamate, HCl saltGeneral Procedure II, Method A was followed using HCl in dioxane（4M）(2 ml, 8.00 mmol) and Intermediate Compound 78 (470 mg, 0.73 mmol) in DCM (5 mL) to afford Intermediate Compound 79 (380 mg, 96 %) as a yellow solid.1H NMR (400 MHz, DMSO) δ 1.09 – 1.30 (m, 1H), 1.64 – 1.81 (m, 1H), 2.31 – 2.45 (m, 2H), 2.58 – 2.68 (m, 1H), 2.82 (dt, J = 6.5, 12.5 Hz, 1H), 3.59 – 3.72 (m, 2H), 3.75 – 3.92 (m, 3H), 3.97 (d, J = 2.9 Hz, 2H), 4.09 (s, 1H), 4.22 (dd, J = 7.7, 11.2 Hz, 1H), 4.32-4.39 (m, 6H), 4.46 (d, J = 4.1 Hz, 1H), 7.34 (td, J = 1.2, 7.6 Hz, 2H), 7.43 (t, J = 7.6 Hz, 2H), 7.71 (d, J = 7.4 Hz, 3H), 7.90 (d, J = 7.5 Hz, 2H), 8.14 – 8.35 (m, 2H). ES+(M+1 = 547). Step 5 - Intermediate Compound 80: (9H-fluoren-9-yl)methyl ((3S,3aR,6S,6aR)-6-(4-oxo-4-(6- ((2S,4S)-2,5,12-trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro- 1H-pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11- hexahydrotetracene-2-carbonyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)butanamido)- hexahydrofuro[3,2-b]furan-3-yl)carbamateGeneral Procedure I was followed using Intermediate Compound 79 (131 mg, 0.24 mmol), the PNU-159682 carboxylic acid (CAS No.1204819-92-0; 100 mg, 0.16 mmol), PyOxim (122 mg, 0.24 mmol) and DIEA (0.083 mL, 0.48 mmol) in DMA (5 mL) to afford Intermediate Compound 80 (120mg, 65.1 %) as a red solid.1H NMR (400 MHz, DMSO) δ 1.11 – 1.33 (m, 4H), 1.50-1.56 (m, 1H), 1.71- 1.82 (m, 20 H), 1.98 - 2.27 (m, 1H), 2.32-2.42 (m, 3H), 2.60 - 2.81 (m, 2H), 3.41-3.53 (m, 1H), 3.56 - 3.68 (m, 3H), 3.80 -3.93 (m, 2H), 3.99 (s, 3H), 4.04 - 4.15 (m, 1H), 4.23 (d, J = 5.2 Hz, 1H), 4.28 - 4.49 (m, 4H), 4.58 (s, 1H), 4.86 - 4.95 (m, 1H), 5.26 - 5.31 (m, 2H), 7.32 - 7.45 (m, 4H), 7.69 (t, J = 10.4 Hz, 4H), 7.90 (dd, J = 6.0, 12.4 Hz, 4H), 8.08 - 8.26 (m, 1H), 13.24 (s, 1H), 14.04 (s, 1H). ES+(M+1 = 1156). Step 6 – Compound P24: N-((3S,3aR,6S,6aR)-6-aminohexahydrofuro[3,2-b]furan-3-yl)-4-oxo-4-(6- ((2S,4S)-2,5,12-trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro- 1H-pyrano[4',3':4,5] oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11- hexahydrotetracene-2-carbonyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)butanamideGeneral Procedure III was followed using DBU (0.014 mL, 0.10 mmol) and Intermediate Compound 80 (110 mg, 0.10 mmol) in DCM (5 mL) and MeCN (1.25 mL) to afford Compound P24 (20.00 mg, 22.51 %) as a red solid.1H NMR (400 MHz, DMSO-d6) δ 1.19 – 1.30 (m, 4H), 1.53 (dd, J = 8.8, 16.4 Hz, 1H), 1.70 (s, 2H), 2.05 – 2.21 (m, 1H), 2.31 – 2.39 (m, 4H), 2.65 (s, 4H), 2.85 – 3.00 (m, 2H), 3.31 – 3.32 (m, 5H), 3.37 (s, 1H), 3.40 – 3.47 (m, 4H), 3.73 – 3.83 (m, 2H), 3.83 – 3.99 (m, 3H), 4.00 (s, 5H), 4.25 (dd, J = 3.6, 6.8 Hz, 2H), 4.40 (d, J = 4.0 Hz, 2H), 4.89 (s, 1H), 4.99 (s, 1H), 5.09 (s, 1H), 5.22 – 5.37 (m, 2H), 7.64 – 7.71 (m, 1H), 7.94 (dd, J = 1.6, 4.0 Hz, 2H), 8.09 – 8.18 (m, 1H). ES+(M+1 = 934).Example 29: Synthesis of Compound P25Steps 1, 2 - Intermediate Compound 82: (9H-fluoren-9-yl) methyl (2-(((3S,3aR,6S,6aR)-6-((tert- butoxycarbonyl) amino) hexahydrofuro[3,2-b] furan-3-yl) amino)-2-oxoethyl) carbamate2,5-Dioxopyrrolidin-1-yl (((9H-fluoren-9-yl) methoxy) carbonyl) glycinate (1 g, 2.54 mmol) was added to a mixture of Intermediate Compound 70 (0.731 g, 5.07 mmol) and DIEA (1.329 mL, 7.61 mmol) in DCM (15 mL) at RT. The resulting mixture was stirred at RT for 1 hour (to afford Intermediate Compound 81). Then (Boc)2O (2.94 mL, 12.68 mmol) was added. The resulting mixture was stirred at RT for 2 hours. The reaction mixture was quenched with water (50 mL), extracted with DCM (2 x 30 mL), and washed with water (50 mL) and 0.5N HCl (50 mL). The combined organic layer was dried over Na2SO4, filtered and evaporated to afford oil mixture. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford Intermediate Compound 82 (0.527 g, 39.7 %) as a white solid.1H NMR (300 MHz, DMSO) δ 1.39 (s, 9H), 3.54 – 3.62 (m, 3H), 3.85 (dd, J = 8.4, 4.2 Hz, 3H), 4.05 (m, J = 14.2, 7.0 Hz, 2H), 4.20 – 4.32 (m, 3H), 4.32 – 4.50 (m, 2H), 7.18 – 7.57 (m, 6H), 7.72 (d, J = 7.5 Hz, 2H), 7.90 (d, J = 7.4 Hz, 2H), 8.16 (d, J = 7.1 Hz, 1H). ES+(M+1 = 524).Step 3 - Intermediate Compound 83: (9H-fluoren-9-yl)methyl (2-(((3S,3aR,6S,6aR)-6- aminohexahydrofuro[3,2-b]furan-3-yl)amino)-2-oxoethyl)carbamate, HCl saltGeneral Procedure II, Method A was followed using Intermediate Compound 82 (520 mg, 0.99 mmol) and HCl solution (4 N, in 1,4-dioxane, 5 mL) to afford Intermediate Compound 83 (410 mg, 90 %) as a white solid.NMR (300 MHz, DMSO) δ 3.65 (d, J = 3.1 Hz, 3H), 3.83 (dd, J = 10.5, 2.5 Hz, 1H), 3.93 (ddd, J = 15.0, 9.9, 5.2 Hz, 2H), 4.13 (s, 1H), 4.18 – 4.34 (m, 3H), 4.53 – 4.63 (m, 1H), 4.64 (d, J = 4.4 Hz, 1H), 7.34 (td, J = 7.4, 1.2 Hz, 2H), 7.43 (td, J = 7.5, 1.2 Hz, 2H), 7.50 – 7.67 (m, 1H), 7.72 (d, J = 7.4 Hz, 2H), 7.90 (d, J = 7.4 Hz, 2H), 8.33 (d, J = 6.9 Hz, 1H), 8.45 (s, 2H). ES+(M+1 = 424). Step 4 - Intermediate Compound 84: (9H-fluoren-9-yl) methyl (2-oxo-2-(((3S,3aR,6S,6aR)-6-((2S,4S)- 2,5,12-trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano [4',3':4,5] oxazolo [2,3-c] [1,4] oxazin-3-yl) oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracene-2- carboxamido) hexahydrofuro[3,2-b] furan-3-yl) amino) ethyl) carbamateGeneral Procedure I was followed using HATU (227 mg, 0.60 mmol), the PNU-159682 carboxylic acid (CAS No.1204819-92-0; 250 mg, 0.40 mmol), DIEA (0.348 mL, 1.99 mmol) and Intermediate Compound 83 (238 mg, 0.52 mmol) to afford Intermediate Compound 84 (280 mg, 68.0 %) as a red solid.1H NMR (300 MHz, DMSO) δ 1.07 (d, J = 6.9 Hz, 3H), 1.20 (d, J = 6.3 Hz, 5H), 1.41 (s, 3H), 1.76 (s, 1H), 1.92 (s, 2H), 3.60 (s, 5H), 4.00 (s, 5H), 4.22 – 4.34 (m, 7H), 4.60 (s, 2H), 7.31-7.42 (m, 8H), 7.72 (d, J = 7.6 Hz, 4H), 7.92 (dd, J = 12.3, 6.1 Hz, 7H), 13.28 (s, 2H), 14.08 (s, 2H). ES+(M+1 = 1033).Step 5 – Compound P25: (2S,4S)-N-((3S,3aR,6S,6aR)-6-(2-aminoacetamido) hexahydrofuro[3,2-b] furan-3-yl)-2,5,12-trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1- methyloctahydro-1H-pyrano [4',3':4,5] oxazolo[2,3-c] [1,4] oxazin-3-yl) oxy)-6,11-dioxo-1,2,3,4,6,11- hexahydrotetracene-2-carboxamideGeneral Procedure III was followed using a DCM solution of DBU (1.344 mL, 0.13 mmol) (15.2 mg / mL in MeCN) and Intermediate Compound 84 (250 mg, 0.24 mmol) in DCM (2mL) / MeCN (0.5 mL) to afford Compound P25 (50.0 mg, 25.5 %) as a red solid.NMR (400 MHz, CDCl3) δ 1.34-1.46 (m, 3H), 1.75 (m, J = 15.2, 6.0 Hz, 3H), 2.04 (m, J = 15.2, 5.6 Hz, 1H), 2.36 (dd, J = 14.8, 3.6 Hz, 1H), 2.47 (d, J = 14.8 Hz, 1H), 2.66 – 2.89 (m, 2H), 3.06 – 3.34 (m, 3H), 3.41 (d, J = 5.6 Hz, 3H), 3.48 (s, 2H), 3.56 – 3.72 (m, 2H), 3.85 (d, J = 9.6 Hz, 2H), 3.89 – 4.08 (m, 4H), 4.12 (s, 4H), 4.44 – 4.57 (m, 3H), 4.63 (s, 1H), 4.73 (d, J = 2.0 Hz, 1H), 5.15 (s, 1H), 5.35 (s, 1H), 5.52 (t, J = 5.6 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.80 (t, J = 8.0 Hz, 1H), 8.06 (d, J = 7.6 Hz, 1H), 13.34 (s, 1H), 13.94 (s, 1H). ES+(M+1 = 811).Example 30: Synthesis of Compound P26Steps 1 and 2 – Intermediate Compound 86: (9H-fluoren-9-yl)methyl (2-((2-(((3S,3aR,6S,6aR)-6- ((tert-butoxycarbonyl)amino)hexahydrofuro[3,2-b]furan-3-yl)amino)-2-oxoethyl)amino)-2- oxoethyl)carbamate(((9H-Fluoren-9-yl)methoxy)carbonyl)glycylglycine (1 g, 2.82 mmol) was added to 1- methylimidazole (0.232 g, 2.82 mmol) and Intermediate Compound 70(0.814 g, 5.64 mmol) in DMF (8 mL) at 25°C under nitrogen. The mixture was cooled to 0 °C. A solution of chloro-N,N,N',N'- tetramethylformamidinium hexafluorophosphate (0.950 g, 3.39 mmol) in DMF(2 mL) and added dropwise. The resulting mixture was then stirred at 25 °C for 4 hours (to afford Intermediate Compound 85). Di-tert-butyl dicarbonate (3.08 g, 14.11 mmol) was introduced in one portion under nitrogen. The resulting mixture was stirred at 25 °C for another 2 hours. The reaction mixture was poured into water (20 mL), extracted with EtOAc (3 x 25 mL). The combined organic solution was washed with water (2 x 50mL), dried over Na2SO4, filtered and evaporated to afford brown oil. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% MeOH in DCM. Pure fractions were evaporated to dryness to afford Intermediate Compound 86 (0.900 g, 54.9 %) as a yellow oil.NMR (400 MHz, DMSO) δ 1.32-1.38 (br, 9H), 3.55 – 3.74 (m, 7H), 3.80 –3.89 (m, 3H), 4.09 (d, J = 6.8 Hz, 1H), 4.18 – 4.29 (m, 1H), 4.31 (d, J = 8.0 Hz, 1H), 4.37 (d, J = 4.2 Hz, 1H), 4.43 (d, J = 4.0 Hz, 1H), 7.24 (d, J = 6.0 Hz, 1H), 7.30 – 7.36 (m, 2H), 7.36 – 7.43 (m, 2H), 7.44 (d, J = 1.2 Hz, 1H), 7.63 (t, J = 6.0 Hz, 1H), 7.73 (d, J = 7.6Hz, 2H), 7.82 – 7.93 (m, 2H), 8.10 (t, J = 5.6 Hz, 2H). ES+(M+1 = 581). Step 3 - Intermediate Compound 87: (9H-fluoren-9-yl)methyl (2-((2-(((3S,3aR,6S,6aR)-6- aminohexahydrofuro[3,2-b]furan-3-yl)amino)-2-oxoethyl)amino)-2-oxoethyl)carbamate, HCl saltGeneral Procedure II, Method A was followed using Intermediate Compound 86 (900 mg, 1.55 mmol) and 4 M HCl in 1.4-dioxane (10 mL) to afford Intermediate Compound 87 (750 mg, 94 %) as a pale yellow solid.1HNMR (400 MHz, DMSO) δ 3.63 – 3.66 (m, 3H), 3.72 (d, J = 6.0 Hz, 2H), 3.86 – 3.98 (m, 3H), 4.13 (s, 1H), 4.17 – 4.34 (m, 3H), 4.59 (d, J = 4.4 Hz, 1H), 4.66 (d, J = 4.4 Hz, 1H), 7.34 (t, 2H), 7.38 – 7.47 (m, 2H), 7.60 – 7.76 (m, 3H), 7.90 (d, J = 7.6 Hz, 2H), 8.15 (t, J = 5.6 Hz, 1H), 8.27 (d, J = 6.8 Hz, 1H), 8.51 (s, 2H). ES+(M+1 = 481). Step 4 - Intermediate Compound 88: (9H-fluoren-9-yl)methyl (2-oxo-2-((2-oxo-2-(((3S,3aR,6S,6aR)- 6-((2S,4R)-2,5,12-trihydroxy-7-methoxy-4-(((1R,3S,4aR,9R,9aS,10aR)-9-methoxy-1- methyloctahydro-1H-pyrano-[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11- hexahydrotetracene-2-carboxamido)hexahydro-furo[3,2-b]furan- 3yl)amino)ethyl)amino)ethyl)carbamateGeneral Procedure I was followed using HATU (136 mg, 0.36 mmol), the PNU-159682 carboxylic acid (CAS No.1204819-92-0; 150 mg, 0.24 mmol), DIEA (0.209 mL, 1.20 mmol) and Intermediate Compound 87 (161 mg, 0.31 mmol) to afford Intermediate Compound 88 (200 mg, 77 %) as a red solid.1H NMR (400 MHz, DMSO) δ 1.14 – 1.26 (m, 3H), 1.67 (s, 1H), 2.10-2.15 (m, 1H), 2.24 – 2.33(m, 1H), 2.63 (t, J = 9.2 Hz, 1H), 2.68 (s, 1H), 2.90 (s, 1H), 2.97 (d, J = 12.0 Hz, 1H), 3.33 – 3.41 (m, 4H), 3.47 – 3.55 (m, 1H), 3.62 – 3.72 (m, 5H), 3.72 (s, 1H), 3.85 – 3.96 (m, 3H), 3.99 (s, 3H), 4.10 – 4.26 (m, 5H), 4.26 – 4.34 (m, 2H), 4.46 (d, J = 4.4 Hz, 1H), 4.50 – 4.55 (m, 1H), 4.59 (d, J = 2.2 Hz, 1H), 4.99 (d, J = 5.2 Hz, 1H), 5.24 (t, J = 4.8 Hz, 1H), 5.37 (s, 1H), 5.77 (s, 1H), 7.28 – 7.37 (m, 2H), 7.41 (t, J = 7.6 Hz, 2H), 7.59 – 7.67 (m, 2H), 7.71 (q, J = 7.6, 4.8 Hz, 2H), 7.88 (t, J = 7.2 Hz, 4H), 8.12 (q, J = 6.4, 5.6 Hz, 2H). ES+(M+1 = 1090). Step 5 – Compound P26: (2S,4S)-N-((3S,3aR,6S,6aR)-6-(2-(2- aminoacetamido)acetamido)hexahydrofuro[3,2-b]furan-3-yl)-2,5,12-trihydroxy-7-methoxy-4- (((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo[2,3- c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracene-2-carboxamideGeneral Procedure III was followed using a DCM solution of DBU (15.2 mg / mL in MeCN) (1.286 mL, 0.13 mmol) and Intermediate Compound 88 (200 mg, 0.18 mmol) in DCM (4 mL) / MeCN (1 mL) to afford Compound P26 (12.00 mg, 7.54 %) as a red solid.NMR (400 MHz, CDCl3) δ 1.38 (t, J = 6.0 Hz, 3H), 1.98 – 2.09 (m, 2H), 2.28 – 2.50 (m, 2H), 2.71 – 2.88 (m, 2H), 3.24 (s, 2H), 3.38 – 3.72 (m, 7H), 3.77 – 4.25 (m, 11H), 4.49 (d, J = 2.0 Hz, 3H), 4.58 – 4.77 (m, 2H), 5.29 – 5.54 (m, 1H), 7.32 – 7.48 (m, 2H), 7.79 (t, J = 8.0 Hz, 1H), 7.94 – 8.08 (m, 1H), 13.89 (s, 1H). ES+(M+1 = 868).Example 31: Synthesis of Compound P27Steps 1,–2 - Intermediate Compound 90: (9H-fluoren-9-yl)methyl (2-((2-((2-(((3S,3aR,6S,6aR)-6- ((tert-butoxycarbonyl)amino)hexahydrofuro[3,2-b]furan-3-yl)amino)-2-oxoethyl)amino)-2- oxoethyl)amino)-2-oxoethyl)carbamate(((9H-Fluoren-9-yl)methoxy)carbonyl)glycylglycylglycine (1 g, 2.43 mmol) was added to 1- methylimidazole (0.200 g, 2.43 mmol) and (3S,3aR,6S,6aR)-hexahydrofuro[3,2-b]furan-3,6-diamine (0.701 g, 4.86 mmol) was dissolved in DMF (15 mL) at 25°C under nitrogen. Chloro-N,N,N',N'-tetra- methylformamidinium hexafluorophosphate (0.818 g, 2.92 mmol) in DMF was added into above mixture dropwised at 0 °C. Then the resulting mixture was stirred at 25 °C for 4 hours. After the reaction finished (affording Intermediate Compound 89), then di-t-butyl dicarbonate (2.65 g, 12.15 mmol) was introduced in one portion under nitrogen. The resulting mixture was stirred at 25 °C for another 2 hours. The reaction mixture was poured into icy water (100 mL), extracted with EtOAc (3 x 50 mL), washed with water(2 x 100mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford a brown oil. The crude product was purified by flash silica chromatography,elution gradient 0 to 20% MeOH in DCM. Pure fractions were evaporated to dryness to afford Intermediate Compound 90 (1.000 g, 64.5 %) as a yellow oil.1H NMR (400 MHz, DMSO) δ 1.38 (s, 9H), 2.91 (d, J = 8.7 Hz, 1H), 3.54 – 3.63 (m, 2H), 3.65 – 3.72 (m, 5H), 3.74 (d, J = 5.6 Hz, 2H), 4.07 (d, J = 7.6 Hz, 1H), 4.20 – 4.27 (m, 1H), 4.30 (d, J = 7.6 Hz, 2H), 4.37 (d, J = 4.2 Hz, 1H), 4.42 (d, J = 4.2 Hz, 1H), 7.24 (d, J = 5.9 Hz, 1H), 7.30 – 7.38 (m, 2H), 7.38 – 7.47 (m, 2H), 7.55 – 7.65 (m, 2H), 7.72 (d, J = 7.4 Hz, 2H), 7.90 (d, J = 7.5 Hz, 2H), 8.05 – 8.15 (m, 2H), 8.20 (t, J = 5.7 Hz, 1H). ES+(M+1 = 638). Step 3 - Intermediate Compound 91: (9H-fluoren-9-yl)methyl (2-((2-((2-(((3S,3aR,6S,6aR)-6- aminohexahydrofuro[3,2-b]furan-3-yl)amino)-2-oxoethyl)amino)-2-oxo-ethyl)amino)-2- oxoethyl)carbamate, HCl saltGeneral Procedure II, Method A was followed using Intermediate Compound 90 (1.1 g, 1.72 mmol) and HCl solution (4N in 1.4-dioxane, 12 mL) to afford Intermediate Compound 91 (0.900 g, 97 %) as a yellow solid. (HCl salt).1HNMR (400 MHz, DMSO) δ 2.91 (d, J = 15.0 Hz, 1H), 3.65 – 3.78 (m, 7H), 3.83 – 3.98 (m, 6H), 4.08 – 4.16 (m, 1H), 4.29 (d, J = 6.3 Hz, 2H), 4.58 – 4.64 (m, 1H), 4.69 (d, J = 4.3 Hz, 1H), 7.29 – 7.38 (m, 2H), 7.42 (t, J = 7.4 Hz, 2H), 7.60 – 7.67 (m, 1H), 7.70 – 7.76 (m, 2H), 7.90 (d, J = 7.5 Hz, 2H), 8.21 (s, 1H), 8.29 (d, J = 6.3 Hz, 2H), 8.65 (s, 1H). ES+(M+1 = 538). Step 4 - Intermediate Compound 92: (9H-fluoren-9-yl)methyl (2-oxo-2-((2-oxo-2-((2-oxo-2- (((3S,3aR,6S,6aR)-6-((2S,4S)-2,5,12-trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1- methyloctahydro-1H-pyrano[4',3':-4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11- hexahydro-tetracene-2-carboxamido)hexahydrofuro[3,2-b]furan-3- yl)amino)ethyl)amino)ethyl)amino)ethyl)carbamateGeneral Procedure I was followed using HATU (136 mg, 0.36 mmol), the PNU-159682 carboxylic acid (CAS No.1204819-92-0; 150 mg, 0.24 mmol), DIEA (0.209 mL, 1.20 mmol) and Intermediate Compound 91 (178 mg, 0.31 mmol) to afford Intermediate Compound 92 (140 mg, 51.1%) as a red solid.1H NMR (400 MHz, DMSO) δ 1.17 – 1.26 (m, 3H), 1.67 (s, 2H), 2.15 (d, J = 14.5 Hz, 1H), 2.27 (s, 1H), 2.64 (d, J = 8.3 Hz, 1H), 2.92 (s, 1H), 3.00 (d, J = 15.2 Hz, 1H), 3.30 – 3.33 (m, 6H), 3.38 (d, J = 6.4 Hz, 1H), 3.51 (d, J = 11.9 Hz, 1H), 3.59 – 3.77 (m, 8H), 3.87 (s, 1H), 3.94 (d, J = 6.4 Hz, 2H), 4.00 (s, 3H), 4.13 (d, J = 17.5 Hz, 3H), 4.18 – 4.26 (m, 2H), 4.29 (d, J = 7.0 Hz, 2H), 4.46 (d, J = 4.2 Hz, 1H), 4.52 (d, J = 4.1 Hz, 1H), 4.59 (d, J = 2.2 Hz, 1H), 5.01 (s, 1H), 5.25 (s, 1H), 5.38 (s, 1H), 7.32 (t, J = 7.5 Hz, 2H), 7.40 (q, J = 7.3 Hz, 2H), 7.59 (d, J = 6.0 Hz, 1H), 7.67-7.74 (m, 3H), 7.82 – 7.95 (m, 4H), 8.12 (t, J = 7.2 Hz, 3H), 8.19 (d, J = 6.0 Hz, 1H). ES+(M+1 = 1147). Step 5 – Compound P27: (2S,4S)-N-((3S,3aR,6S,6aR)-6-(2-(2-(2-aminoacet-amido)acetamido)- acetamido)hexahydro-furo[3,2-b]furan-3-yl)-2,5,12-trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,- 9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano-[4',3':4,5]oxazolo-[2,3-c][1,4]oxazin-3-yl)oxy)- 6,11-dioxo-1,2,3,4,6,11-hexahydrotetracene-2-carboxamideGeneral Procedure III was followed using a DCM solution of DBU (15.2 mg / mL in MeCN) (0.856 mL, 0.13 mmol) and Intermediate Compound 92 (140 mg, 0.12 mmol) in DCM (8 mL) / MeCN (2 mL) to afford Compound P27 (26.0 mg, 23.03 %) as a red solid.NMR (400 MHz, DMSO) δ1.09 – 1.30 (m, 4H), 1.62-1.72 (br, 2H), 2.09 – 2.37 (m, 3H), 2.61 – 2.71 (m, 2H), 3.00 (q, J = 18.3 Hz, 2H), 3.29 (s, 1H), 3.62 – 3.78 (m, 10H), 3.85 – 3.98 (m, 5H), 4.01 (d, J = 6.6 Hz, 3H), 4.07 – 4.26 (m, 5H), 4.43 – 4.65 (m, 4H), 4.95-5.06 (br, 1H), 5.25 (s, 1H), 5.40 (s, 1H), 7.68 (d, J = 4.6 Hz, 1H), 7.90 – 7.98 (m, 2H), 8.01 – 8.54 (m, 5H). ES+(M+1 = 925).Example 32: Synthesis of Compound P28Step 1 – Intermediate Compound 94: tert-butyl 8-((3S,3aR,6S,6aR)-6- (((benzyloxy)carbonyl)amino)hexahydrofuro[3,2-b]furan-3-yl)-3,8-diazabicyclo[3.2.1]octane-3- carboxylatetert-Butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (3.87 g, 18.23 mmol) was added to (3R,3aS,6S,6aR)-6-(((benzyloxy)carbonyl)amino)hexahydrofuro[3,2-b]furan-3-yl trifluoromethanesulfonate (1.5 g, 3.65 mmol) in 1,4-dioxane (25mL) at 100°C under nitrogen. The resulting mixture was stirred at 100 °C for 2 hours. The reaction mixture was quenched with water (25 mL), extracted with EtOAc (3 x 50 mL), the organic layer was dried over Na2SO4, filtered and evaporated to afford pale yellow liquid. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% THF in petroleum ether. Pure fractions were evaporated to dryness to afford Intermediate Compound 94 (1.500 g, 87 %) as a pale yellow liquid. NMR (300 MHz, DMSO) δ 1.39 (s, 9H), 1.46 (d, J = 7.4 Hz, 2H), 1.74 – 1.80 (m, 1H), 1.84 (d, J = 8.8Hz, 1H), 2.79 – 3.01 (m, 3H), 3.06 (s, 1H), 3.36 – 3.70 (m, 5H), 3.75 – 3.89 (m, 2H), 3.99 (dd, J = 8.9, 6.2 Hz, 1H), 4.32 (d, J = 5.0 Hz, 1H), 4.45 (d, J = 3.9 Hz, 1H), 5.03 (s, 2H), 7.26 – 7.44 (m, 5H), 7.60 (d, J = 6.3 Hz, 1H). ES+(M+1 =474). Step 2 - Intermediate Compound 95: tert-butyl 8-((3S,3aR,6S,6aR)-6-aminohexahydrofuro[3,2- b]furan-3-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylatePd-C (112 mg, 0.11 mmol) was added to Intermediate Compound 94 (500 mg, 1.06 mmol) in MeOH (20 mL) under hydrogen. The resulting mixture was stirred at 25 °C for 5 hours. The reaction mixture was filtered through celite. The filtrate was evaporated to dryness to afford Intermediate Compound 95 (300 mg,83.71%).1H NMR (300 MHz, DMSO) δ 1.39 (s, 9H), 1.46 (d, J = 7.3 Hz, 2H), 1.66 (s, 1H), 1.84 (s, 1H), 2.74 – 2.91 (m, 2H), 2.99 (s, 1H), 3.06 (s, 1H), 3.21 (dd, J = 18.7, 4.3 Hz, 1H), 3.36 – 3.41 (m, 2H), 3.44 – 3.59 (m, 3H), 3.72 (dd, J = 8.8, 4.3 Hz, 1H), 3.94 (dd, J = 8.9, 6.2 Hz, 1H), 4.11 (d, J = 4.9 Hz, 1H), 4.47 (dd, J = 5.0, 2.5 Hz, 1H). ES+(M+1 = 340). Step 3 - Intermediate Compound 96: tert-butyl 8-((3S,3aR,6S,6aR)-6-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-hexahydrofuro[3,2-b]furan-3-yl)-3,8-diazabicyclo[3.2.1]octane-3- carboxylate(9H-fluoren-9-yl)methyl (2,5-dioxopyrrolidin-1-yl) carbonate (477 mg, 1.41 mmol) was added to DIEA (0.617 mL, 3.54 mmol) and Intermediate Compound 95 (400 mg, 1.18 mmol) in DCM (20 mL) at 25°C under nitrogen. The resulting mixture was stirred at 25 °C for 1 hour. The reaction mixture was quenched with water (20 mL), extracted with DCM (2 x 20 mL), the organic layer was dried over Na2SO4, filtered and evaporated to afford pale yellow liquid. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% THF in petroleum ether. Pure fractions were evaporated to dryness to afford Intermediate Compound 96 (600 mg, 76.92%) as a paleyellow liquid.1H NMR (300 MHz, DMSO) δ 1.39 (s, 9H), 1.47 (d, J = 7.6 Hz, 2H), 1.84 (s, 2H), 2.76 – 3.13 (m, 4H), 3.41 (t, J = 8.2 Hz, 2H), 3.49 – 3.70 (m, 3H), 3.80 (d, J = 8.9 Hz, 2H), 3.94 – 4.01 (m, 1H), 4.23 (d, J = 6.7 Hz, 1H), 4.34 (d, J = 7.4 Hz, 2H), 4.46 (s, 1H), 7.28 – 7.48 (m, 4H), 7.61 (d, J = 6.1 Hz, 1H), 7.71 (d, J = 7.4 Hz, 2H), 7.90 (d, J = 7.5 Hz, 2H). ES+( M+1 =562), Step 4 - Intermediate Compound 97: (9H-fluoren-9-yl)methyl ((3S,3aR,6S,6aR)-6-(3,8- diazabicyclo[3.2.1]octan-8-yl)hexahydrofuro[3,2-b]furan-3-yl)carbamate, HCl saltIntermediate Compound 96 (200 mg, 0.36 mmol) was added to HCl-1,4-dioxane (5 mL) at 25°C under nitrogen. The resulting mixture was stirred at 25 °C for 1 hour. The filtrate was evaporated to dryness to afford Intermediate Compound 97 (170 mg, 96 %) as a pale yellow solid.1H NMR (300 MHz, DMSO) δ 2.20 (s, 2H), 3.31 (s, 1H), 3.49 (dd, J = 8.2, 3.8 Hz, 1H), 3.57 (s, 5H), 3.71 (dt, J = 9.9, 7.0 Hz, 3H), 3.90 (d, J = 2.5 Hz, 4H), 4.23 (d, J = 7.0 Hz, 2H), 4.35 (d, J = 6.2 Hz, 2H), 4.48 (s, 1H), 7.29 – 7.48 (m, 4H), 7.71 (d, J = 8.1 Hz, 3H), 7.90 (d, J = 7.4 Hz, 2H). ES+(M+1 = 462). Step 5 - Intermediate Compound 98: (9H-fluoren-9-yl)-methyl ((3S,3aR,6S,6aR)-6-(3-((2S,4S)-2,5,12- trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H- pyrano[4',3':4,5]-oxazolo-[2,3-c]-[1,4]-oxazin-3-yl)-oxy)-6,11-dioxo-1,2,3,4,6,11- hexahydrotetracene-2-carbonyl)-3,8-diazabicyclo-[3.2.1]-octan-8-yl)-hexahydrofuro-[3,2-b]-furan-3- yl)-carbamateHATU (218 mg, 0.57 mmol) was added to the PNU-159682 carboxylic acid (CAS No.1204819-92-0; 180 mg, 0.29 mmol) in DMA (3 mL) under nitrogen. The resulting mixture 1 was stirred at RT for 10 minutes. DIEA (0.250 mL, 1.43 mmol) was added to Intermediate Compound 97 (199 mg, 0.43 mmol) in DMA (3.00 mL) under nitrogen. The resulting mixture 2 was stirred at RT for 10 minutes. After that, the mixture 1 and the mixture 2 was mixed, stirring at RT for 2 hours. The crude productwas purified by C18-flash chromatography, elution gradient 0 to 100% MeCN in water (NH4HCO3). Pure fractions were evaporated to dryness to afford Intermediate Compound 98 (210 mg, 68.4 %) as a red solid.1H NMR (400 MHz, DMSO) δ 1.18 – 1.28 (m, 3H), 1.35 – 1.80 (m, 4H), 1.80 – 2.43 (m, 4H), 2.57 – 2.72 (m, 2H), 2.89 (d, J = 26.8 Hz, 3H), 3.09 (d, J = 15.3 Hz, 2H), 3.32 (s, 3H), 3.36 – 3.55 (m, 7H), 3.56 – 3.75 (m, 3H), 3.77 – 3.89 (m, 2H), 3.93 – 4.03 (m, 5H), 4.05 (d, J = 7.1 Hz, 1H), 4.13 – 4.27 (m, 2H), 4.34 (s, 2H), 4.49 (s, 1H), 4.52 – 4.75 (m, 2H), 4.75 – 5.55 (m, 1H), 6.28 (s, 1H), 7.31 – 7.37 (m, 2H), 7.38 – 7.44 (m, 2H), 7.60 (s, 1H), 7.70 (s, 1H), 7.80 – 7.95 (m, 6H). ES+(M+1 = 1071). Step 6 – Compound P28: (8S,10S)-8-(8-((3S,3aR,6S,6aR)-6-aminohexahydro-furo[3,2-b]-furan-3-yl)- 3,8-diazabicyclo[3.2.1]-octane-3-carbonyl)-6,8,11-trihydroxy-1-methoxy-10- (((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano-[4',3':4,5]-oxazolo-[2,3-c]- [1,4]-oxazin-3-yl)-oxy)-7,8,9,10-tetrahydrotetracene-5,12-dione1.066 mL of DCM solution of DBU (15.2 mg / mL in DCM) (0.11 mmol) was added to Intermediate Compound 98 (190 mg, 0.18 mmol) in DCM (8 mL) / MeCN (2.000 mL) at 0°C under nitrogen. The resulting mixture was stirred at 0 °C for 1 hour. The reaction mixture was quenched with 0.1% NH4HCO3 (1.5 mL). The solvent was removed under reduced pressure. The crude product was purified by flash C18-flash chromatography, elution gradient 0 to 100% MeCN in water. Pure fractions were evaporated to dryness to afford crude product (150 mg). The crude product was purified by preparative HPLC Column: Xselect CSH Prep C18 OBD, 30*150mm, 5um; Mobile Phase A: Water (10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 30% B to 41% B in 10 min; Wavelength: 254nm / 220nm; RT1(min): 8.63. Fractions containing the desired compound were evaporated to dryness to afford Compound P28 (59.0 mg, 39.2 %) as a red solid.1H NMR (400 MHz, DMSO) δ 1.24 (d, J = 6.2 Hz, 4H), 1.39 (s, 1H), 1.63 – 1.71 (m, 2H), 1.81 (s, 3H), 2.17 (d, J = 18.5 Hz, 1H), 2.43 (s, 1H), 2.58 – 2.92 (m, 6H), 3.11 (s, 1H), 3.25 (d, J = 4.3 Hz, 3H), 3.27 – 3.31 (m, 3H), 3.46 – 3.53 (m, 2H), 3.63 – 3.75 (m, 2H), 3.80-4.10 (m, 7H), 4.13 (d, J = 5.3 Hz, 1H), 4.24 (d, J = 2.2 Hz, 1H), 4.49 (s, 2H), 4.55 – 4.67 (m, 2H), 4.86-4.95 (m, 1H), 5.25 (d, J = 11.3 Hz, 1H), 5.83 (d, J = 24.5 Hz, 1H), 7.61 – 7.69 (m, 1H), 7.91 (d, J = 5.2 Hz, 2H). ES+(M+1 = 849).Example 33: Synthesis of Compound P29Step 1 - Intermediate Compound 99: tert-butyl (1S,4S)-5-((3S,3aR,6S,-6aR)-6- (((benzyloxy)carbonyl)amino)hexahydrofuro[3,2-b]furan-3-yl)-2,5-diazabicyclo[2.2.2]-octane-2- carboxylate(3R,3aS,6S,6aR)-6-(((benzyloxy)carbonyl)amino)hexahydrofuro[3,2-b]furan-3-yl trifluoromethanesulfonate (1.5 g, 3.65 mmol) and tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.2]-octane- 2-carboxylate (2.322 g, 10.94 mmol) in 1,4-dioxane (20 mL) under nitrogen. The resulting mixture was stirred at 100 °C for 2 hours. The solvent was removed under reduced pressure. The reaction mixture was quenched with water (10 mL), extracted with EtOAc (2 x 50 mL), the combined organic layer was dried over Na2SO4, filtered and evaporated to afford residue. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% MeOH in DCM. Pure fractions were evaporated to dryness to afford Intermediate Compound 99 (1.190 g, 68.9 %) as a yellow solid.1H NMR (300 MHz, DMSO) δ 1.40 (d, J = 3.7 Hz, 8H), 1.53 (d, J = 12.5 Hz, 1H), 1.69 (s, 1H), 1.90 (d, J = 12.6 Hz, 1H), 2.78 – 2.95 (m, 3H), 3.08 (s, 1H), 3.21 (t, J = 9.3 Hz, 1H), 3.34 (s, 2H), 3.37 – 3.56 (m, 2H), 3.65 (d, J = 8.4 Hz, 1H), 3.82 (dd, J = 9.0, 4.8 Hz, 2H), 4.30 (d, J = 4.8 Hz, 1H), 4.45 (d, J = 4.8 Hz, 1H), 5.03 (s, 2H), 7.35 (d, J = 4.8 Hz, 4H), 7.39 (d, J = 8.2 Hz, 1H), 7.60 (d, J = 6.2 Hz, 1H). ES+(M+1 =474),Step 2 - Intermediate Compound 100: tert-butyl (1S,4S)-5-((3S,3aR,6S,6aR)-6- aminohexahydrofuro[3,2-b]furan-3-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylateIntermediate Compound 99 (850 mg, 1.79 mmol) in MeOH (8mL) under hydrogen. The resulting mixture was stirred at RT for 1 hour. The solvent was removed under reduced pressure to afford Intermediate Compound 100 (600 mg, 98%) as a yellow oil.1H NMR (300 MHz, DMSO) δ 1.40 (d, J = 3.8 Hz, 9H), 1.48 – 1.58 (m, 1H), 1.67 (d, J = 13.6 Hz, 2H), 1.91 (d, J = 8.1 Hz, 1H), 2.78 – 2.91 (m, 3H), 3.04 – 3.09 (m, 1H), 3.15 – 3.28 (m, 3H), 3.35 – 3.57 (m, 4H), 3.74 (dd, J = 8.7, 4.5 Hz, 1H), 3.79 – 3.94 (m, 2H), 4.09 (d, J = 4.8 Hz, 1H), 4.41 – 4.49 (m, 1H). ES+(M+1 = 340). Step 3 - Intermediate Compound 101: tert-butyl (1S,4S)-5-((3S,3aR,6S,6aR)-6-((((9H-fluoren-9-yl) methoxy) carbonyl) amino) hexahydrofuro [3,2-b] furan-3-yl)-2,5-diazabicyclo [2.2.2] octane-2- carboxylateN-(9H-Fluoren-2-ylmethoxycarbonyloxy) succinimide (806 mg, 2.39 mmol) was added to Intermediate Compound 100 (595mg, 1.75 mmol) and DIEA (0.839 mL, 4.80 mmol) in DCM (5 mL) under hydrogen. The resulting mixture was stirred at RT for 1 hour. The reaction mixture was acidified with 0.5M HCl. The reaction mixture was quenched with water (5 mL), extracted with EtOAc (2 x 5 mL), the combined organic layer was dried over Na2SO4, filtered and evaporated to afford residue.The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford Intermediate Compound 101 (930 mg, 94 %) as a white solid.1H NMR (300 MHz, DMSO) δ 1.13 – 1.21 (t, J = 7.1 Hz, 1H), 1.40 (br, J = 3.6 Hz, 9H), 1.52 (s, 1H), 1.69 (s, 2H), 1.91 (d, J = 11.7 Hz, 1H), 2.00 (s, 1H), 2.80 (dd, J = 14.8, 25.0 Hz, 3H), 3.03 – 3.25 (m, 2H), 3.39 – 3.67 (m, 3H), 3.79 – 3.95 (m, 4H), 4.02 (t, J =7.2 Hz, 1H), 4.19 – 4.37 (m, 3H), 4.44 (s, 1H), 7.29 – 7.47 (m, 4H), 7.60 (s, 1H), 7.70 (d, J = 7.4 Hz, 2H), 7.90 (d, J = 7.4 Hz, 2H). ES+(M+1 = 562). Step 4 - Intermediate Compound 102: (9H-fluoren-9-yl)methyl ((3S,3aR,6S,6aR)-6-((1S,4S)-2,5- diazabicyclo[2.2.2]octan-2-yl)hexahydrofuro[3,2-b]furan-3-yl)carbamate hydrochlorideIntermediate Compound 101 (920 mg, 1.64 mmol) in HCl [4 M in dioxane] (10 mL). The resulting mixture was stirred at rt for 1 hour. The solvent was removed under reduced pressure to afford Intermediate Compound 102 (800 mg, 98 %) as a yellow solid.1H NMR (300 MHz, DMSO) δ 1.82 (d, J = 12.8 Hz, 3H), 2.11 (s, 1H), 3.36 (s, 2H), 3.74 (s, 4H), 3.90 (s, 3H), 4.13 (s, 1H), 4.24 (d, J = 6.4 Hz, 1H), 4.34 (s, 2H), 4.45 (s, 1H), 5.76 (s, 4H), 7.30 – 7.48 (m, 5H), 7.70 (d, J = 7.6 Hz, 2H), 7.90 (d, J = 7.6 Hz, 2H). ES+(M+1 = 462). Step 5 - Intermediate Compound 103: (9H-fluoren-9-yl)methyl ((3S,3aR,6S,6aR)-6-((1S,4S)-5- ((2S,4S)-2,5,12-trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,9aR,-10aS)-9-methoxy-1-methyloctahydro- 1H-pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11- hexahydrotetracene-2-carbonyl)-2,5-diazabicyclo[2.2.2]octan-2-yl)-hexahydrofuro[3,2-b]furan-3- yl)carbamateThe PNU-159682 carboxylic acid (CAS No.1204819-92-0; 200 mg, 0.32 mmol) was added to Intermediate Compound 102 (735 mg, 1.59 mmol), N,N-Diisopropylethylamine (124 mg, 0.96 mmol) and O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (158 mg, 0.41 mmol) in DMA (4 mL). The resulting mixture was stirred at 25 °C for 2 hours. The crude product was purified by C18-flash chromatography, elution gradient 0 to 100% MeCN in water.Pure fractions were evaporated to dryness to afford Intermediate Compound 103 (230 mg, 67.4 %) as a red solid.1H NMR (400 MHz, DMSO) δ 1.23 (d, J = 7.0 Hz, 3H), 1.45 – 2.00 (m, 3H), 2.21 – 2.37 (m, 1H), 2.50 (s, 4H), 2.52 (s, 7H), 2.61 – 2.92 (m, 3H), 3.11 (s, 2H), 3.30-3.33 (m, 9H), 3.36 – 3.53 (m, 4H), 3.54 – 3.96 (m, 3H), 4.00 (s, 3H), 4.09 – 4.63 (m, 4H), 4.69 – 5.13 (m, 2H), 5.26 (s, 1H), 5.85 (s, 1H), 7.34-7.42 (m, 4H), 7.54 – 7.74 (m, 3H), 7.81 – 7.99 (m, 4H). ES+(M+1 =1072). Step 6 – Compound P29: (8S,10S)-8-((1S,4S)-5-((3S,3aR,6S,6aR)-6-aminohexahydrofuro[3,2-b]furan- 3-yl)-2,5-diazabicyclo[2.2.2]octane-2-carbonyl)-6,8,11-trihydroxy-1-methoxy-10- (((1S,3R,4aS,9S,9aR,-10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo[2,3- c][1,4]oxazin-3-yl)oxy)-7,8,9,10-tetrahydrotetracene-5,12-dione1,8-Diazabicyclo[5.4.0]undec-7-ene (1.309 mL, 0.13 mmol) (15.2mg / mL) in DCM was added to Intermediate Compound 103 (200 mg, 0.19 mmol) in DMA (1 mL), DCM (4 mL) and MeCN (1 mL). The resulting mixture was stirred at 25 °C for 1 hour. The reaction mixture was quenched with 0.1% NH4HCO3 (1 mL), The solvent was removed under reduced pressure. The crude product was purified by flash C18-flash chromatography, elution gradient 0 to 70% MeCN in water. Pure fractions were evaporated to dryness to afford crude product (100 mg, crude). The crude product was further purified by preparative HPLC (Column: YMC-Actus Triant C18 ExRs Column, 30*150 mm, 5μm; Mobile Phase A: Water (10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 30% B to 45% B in 10 min; Wavelength: 254nm / 220nm; RT1(min): 8.38). Fractions containing the desired compound were freeze dried directly to dryness to afford Compound P29 (7.30 mg, 4.61 %) as a red solid.1H NMR (400 MHz, DMSO) δ 0.85 (m, 1H) (impurity), 1.19 – 1.29 (m, 5H), 1.32 – 1.58 (m, 2H), 1.60 – 1.79 (m, 4H), 1.81 – 2.14 (m, 3H), 2.60 – 2.80 (m, 4H), 2.82 – 3.17 (m, 5H), 3.25 (d, J = 6.1 Hz, 3H), 3.45 – 3.56 (m, 3H), 3.63 – 3.79 (m, 2H), 3.81 – 3.96 (m, 4H), 4.00 (s, 3H), 4.09 (m, 1H), 4.24 (d, J = 2.0 Hz, 1H), 4.35 – 4.52 (m, 1H), 4.60 (d, J = 2.0 Hz, 1H), 4.67 – 4.88 (m, 1H), 4.93 – 5.11 (m, 1H), 5.28 (d, J = 16.4 Hz, 1H), 5.50 – 5.89 (m, 1H), 7.63 – 7.77 (m, 1H), 7.78 – 8.00 (m, 2H). ES+(M+1 =849.5).Example 34: Synthesis of Compound P30Steps 1, 2 - Intermediate Compound A-110: (9H-fluoren-9-yl)methyl ((3S,3aR,6S,6aR)-6-((tert- butoxycarbonyl)amino)hexahydrofuro[3,2-b]furan-3-yl)(methyl)carbamateFormaldehyde (340 mg, 4.30 mmol), in 150 mL round bottom flask was added to tert-butyl ((3S,3aR,6S,6aR)-6-aminohexahydrofuro[3,2-b]furan-3-yl)carbamate (CAS No.1932199-27-3; 700 mg, 2.87 mmol) in MeOH (20 mL) at 25°C under nitrogen. The resulting mixture was stirred at 25 °C for 2 hours. Then NaBH4 (650 mg, 17.19 mmol) was added, the resulting mixture was stirred at 25 °C for 1 hour. The reaction mixture was acidified with 1M HCl to pH (7~6). Then the reaction mixture was acidified with saturated NaHCO3to pH (9~8). N-(9H-Fluoren-2- ylmethoxycarbonyloxy)succinimide (1.45 g, 4.30 mmol) in THF (20.00 mL) was added to the mixture, the resulting mixture was stirred at 25 °C for 1 hour. The solvent was removed under reduced pressure. The reaction mixture was quenched with water (50 mL), extracted with DCM (3 x 100 mL), the organic layer was dried over Na2SO4, filtered and evaporated to afford pale yellow oil. The crude product was purified by flash C18-flash chromatography, elution gradient 0 to 100% MeCN in water. Pure fractions were evaporated to dryness to afford Intermediate Compound A- 110 (590 mg, 42.8 %) as a white solid.1H NMR (400 MHz, DMSO) δ 1.39 (s, 9H), 2.71 (s, 3H), 3.51 - 3.62 (m, 1H), 3.63 - 3.90 (m, 4H), 4.26 – 4.42 (m, 5H), 4.47 (s, 1H), 7.18 (d, J = 6.4 Hz, 1H), 7.30 - 7.39 (m, 2H), 7.42 (t, J = 7.4 Hz, 2H), 7.62 – 7.68 (m, 2H), 7.87 – 7.93 (m, 2H). ES+(M+1 = 481), HPLC purity: 90%. Step 3: Intermediate Compound A-111: (9H-fluoren-9-yl)methyl ((3S,3aR,6S,6aR)-6- aminohexahydrofuro[3,2-b]furan-3-yl)(methyl)carbamateIntermediate Compound A-110 (440 mg, 0.92 mmol) was added to DCM (3 mL) / HCl in dioxane (4N) (3.00 mL) at 25°C under nitrogen. The resulting mixture was stirred at 25 °C for 1 hour. The solvent was removed under reduced pressure to afford crude Intermediate Compound A-111 (300 mg, 86 %) as a pale yellow solid.1H NMR (400 MHz, DMSO) δ 2.75 (s, 3H), 3.66 – 3.98 (m, 5H), 4.28 – 4.42 (m, 4H), 4.62 – 4.73 (m, 2H), 7.31 – 7.39 (m, 2H), 7.43 (t, J = 7.4 Hz, 2H), 7.65 (d, J = 7.4 Hz, 2H), 7.91 (d, J = 7.5 Hz, 2H). (2 exchangeable protons not seen). ES+(M+1 = 381), HPLC purity: 95%. Step 4 - Intermediate Compound A-112: (9H-fluoren-9-yl) methyl((3S,3aR,6S,6aR)-6-((2S,4S)-2,5,12- trihydroxy-7-methoxy-4-(((1S,3R,-4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H- pyrano[4',3':4,5]-oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracene-2- carboxamido)-hexahydrofuro[3,2-b]furan-3-yl)carbamateIntermediate Compound A-111 (218 mg, 0.57 mmol) was added to the PNU-159682 carboxylic acid (CAS No.1204819-92-0; 300 mg, 0.48 mmol), HATU (364 mg, 0.96 mmol) and DIEA (0.417 mL, 2.39 mmol) in DMA (5 mL) at 25°C under nitrogen. The resulting mixture was stirred at 25 °C for 2 hours. The crude product was purified by flash C18-flash chromatography, elution gradient 0 to 100% MeCN in water. Pure fractions were evaporated to dryness to afford Intermediate Compound A- 112 (430 mg, 91 %) as a red solid.1H NMR (400 MHz, DMSO) δ 1.18 – 1.25 (m, 3H), 1.60 – 1.78 (m, 2H), 2.08 (s, 2H), 2.13 – 2.21 (m, 1H), 2.26 (t, J = 7.6 Hz, 1H), 2.59 – 2.79 (m, 5H), 2.92 – 3.03 (m, 2H), 3.39 (d, J = 6.6 Hz, 1H), 3.47 - 3.56 (m, 1H), 3.60 - 3.76 (m, 3H), 3.88 – 4.01 (m, 6H), 4.13 – 4.33 (m, 4H), 4.33 – 4.46 (m, 3H), 4.47 – 4.62 (m, 3H), 4.98 (s, 1H), 5.21 – 5.28 (m, 1H), 5.33 – 5.37 (m, 1H), 7.30 – 7.38 (m, 2H), 7.43 (t, J = 7.5 Hz, 2H), 7.59 – 7.69 (m, 3H), 7.83 – 7.93 (m, 4H), 8.05 (d, J = 7.6 Hz, 1H), 13.22 (br, 1H), 14.01 (br, 1H). ES+(M+1 = 990), HPLC purity: 90%.Step 5 – Compound P30: (2S,4S)-2,5,12-trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9- methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo-[2,3-c][1,4]oxazin-3-yl)oxy)-N- ((3S,3aR,6S,6aR)-6-(methylamino)hexahydrofuro[3,2-b]furan-3-yl)-6,11-dioxo-1,2,3,4,6,11- hexahydrotetracene-2-carboxamideDBU (0.053 mL, 0.35 mmol) was added to Intermediate Compound A-112 (350 mg, 0.35 mmol) in DMA (5 mL) at 0°C under nitrogen. The resulting mixture was stirred at 0 °C for 30 minutes. The crude product was purified by preparative HPLC (Column: Xbridge Prep C18 OBD, 30*150 mm, 5μm; Mobile Phase A: Water(10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 24% B to 45% B in 8 min; Wavelength: 254nm / 220nm; RT1(min): 7.35) and MeCN as eluents. Fractions containing the desired compound were freeze dried directly to dryness to afford Compound P30 (88 mg, 32.4 %) as a red solid.1H NMR (400 MHz, DMSO) δ 1.20 (d, J = 6.5 Hz, 3H), 1.59 – 1.76 (m, 2H), 2.05 – 2.19 (m, 1H), 2.27 (s, 4H), 2.60 – 2.73 (m, 2H), 2.90 – 3.03 (m, 3H), 3.30 – 3.32 (m, 3H ), 3.37 – 3.42 (m, 2H), 3.49 – 3.69 (m, 4H), 3.77 - 3.82 (m, 1H), 3.87 – 3.96 (m, 2H), 3.99 (s, 3H), 4.09 – 4.17 (m, 2H), 4.23 (d, J = 2.2 Hz, 1H), 4.35 – 4.45 (m, 2H), 4.59 (d, J = 2.2 Hz, 1H), 4.96 – 5.03 (m, 1H), 5.24 (t, J = 4.7 Hz, 1H), 5.37 (s, 1H), 7.66 (p, J = 3.8 Hz, 1H), 7.87 – 7.97 (m, 2H), 8.04 (d, J = 7.6 Hz, 1H).2 exchangeable proton not seen. ES+(M+1 = 768), HPLC purity: 99%.Example 35: Synthesis of Compound P31Step 1 – Intermediate Compound A-113: benzyl ((3S,3aR,6S,6aR)-6-cyanohexahydrofuro[3,2- b]furan-3-yl)carbamateKCN (3.56 g, 54.70 mmol) was added to Intermediate Compound 62 (15 g, 36.47 mmol) and 18- Crown-6 (15.42 g, 58.34 mmol) in THF (100 mL) at 0°C. The resulting mixture was stirred at 0 °C for 4 hours. The reaction mixture was diluted with DCM (500 mL), and washed sequentially with water (500 mL x 1) and saturated brine (500 mL x 1). The aqueous layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash C18-flash chromatography, elution gradient 60 to 60% MeCN in water. Pure fractions were evaporated to dryness to afford Intermediate Compound A-113 (10.50 g, 100 %) as a yellow oil.1H NMR 1H NMR (300 MHz, DMSO) δ 3.32 (s, 1H), 3.42-3.51 (m, 1H), 3.63 – 3.71 (m, 1H), 3.83 – 4.03 (m, 4H),4.51 (d, J = 4.6 Hz, 1H), 4.88 (dd, J = 2.2, 4.6 Hz, 1H), 5.04 (s, 2H), 7.35 (d, J = 4.8 Hz, 5H), 7.69 (d, J = 6.0 Hz, 1H). ES+(M+1 = 289.111), HPLC purity: 99.1%. Step 2 - Intermediate Compound A-114: benzyl ((3S,3aR,6S,6aR)-6- (aminomethyl)hexahydrofuro[3,2-b]furan-3-yl)carbamateBorane-tetrahydrofuran complex (156 mL, 156.09 mmol) was added to Intermediate Compound A-113 (9 g, 31.22 mmol) in THF (100 mL) at 0°C over a period of 10 minutes under nitrogen. The resulting mixture was stirred at 25 °C for 2 hours. The reaction mixture was quenched with MeOH (100 mL) in ice bath. The solvent was removed under reduced pressure, which afforded Intermediate Compound A-114 (9.00 g, 99 %) as a yellow oil.1H NMR (300 MHz, DMSO) δ 1.47 – 1.75 (m, 1H), 2.67 – 2.88 (m, 2H), 3.53 – 3.72 (m, 2H), 3.79 – 3.99 (m, 3H), 4.20 – 4.51(m, 2H), 5.03 (s, 2H), 7.36 (s, 5H), 7.67 (s, 1H), 7.90 (s, 2H). ES+( M+1 =292), HPLC purity: 93%. Step 3 - Intermediate Compound A-115: benzyl ((3S,3aR,6S,6aR)-6-(((((9H-fluoren-9- yl)methoxy)carbonyl)amino)methyl)hexahydrofuro-[3,2-b]furan-3-yl)carbamateN-(9H-Fluoren-2-ylmethoxycarbonyloxy)succinimide (9.23 g, 27.37 mmol) was added to Intermediate Compound A-114 (8g, 27.37 mmol) in MeCN (50 mL) under nitrogen. The resulting mixture was stirred at 25 °C for 2 hours. The solvent was removed under reduced pressure. The crude product was purified by flash C18-flash chromatography, elution gradient 50 to 50% MeCN in water. Pure fractions were evaporated to dryness to afford Intermediate Compound A-115 (14.00 g, 99 %) as a white solid.1H NMR 1H NMR (300 MHz, DMSO) δ 2.83 – 3.01 (m, J = 6.7 Hz, 2H), 3.33 (d, J = 2.0 Hz, 1H), 3.53 (td, J = 2.9, 8.4 Hz, 2H), 3.75 (dd, J = 5.9, 8.9 Hz, 1H), 3.85 (d, J = 7.9 Hz, 2H), 4.21 (t, J = 6.8 Hz, 1H), 4.29 – 4.38 (m, 4H), 5.02 (s, 2H), 7.29 – 7.37 (m, 8H), 7.41 (t, J = 7.3 Hz, 2H), 7.48 (t, J = 5.9 Hz, 1H), 7.68 (d, J = 7.4 Hz, 2H), 7.89 (d, J = 7.5 Hz, 2H). ES+( M+1 = 514), HPLC purity: 99%. Step 4 – Intermediate Compound A-116: (9H-fluoren-9-yl)methyl (((3S,3aR,6S,6aR)-6- aminohexahydrofuro-[3,2-b]furan-3-yl)methyl)carbamate, HCl saltPd-C (6.98 g, 13.12 mmol) was added to 0.01M HCl (3.887 mL, 0.04 mmol) and Intermediate Compound A-115 (13.5 g, 26.24 mmol) in EtOH (40 mL) under hydrogen. The resulting mixture was stirred at 25 °C for 2 hours. The reaction mixture was filtered through celite. The solvent was removed under reduced pressure and afforded Intermediate Compound A-116 (9.50 g, 95 %) as a yellow solid. NMR (400 MHz, DMSO) δ 2.89 – 2.97 (m, 1H), 3.02 (dt, J = 6.9, 13.9 Hz, 1H), 3.54 (dd, J = 4.0, 9.0 Hz, 1H), 3.63 (dd, J = 3.1, 5.2 Hz, 1H), 3.74 (dd, J = 3.0, 10.4 Hz, 1H), 3.81 (dd, J = 6.1, 9.0 Hz, 1H), 3.92 (dd, J = 5.1, 10.4 Hz, 1H), 4.22 (t, J = 6.8 Hz, 1H), 4.31 – 4.38 (m, 2H), 4.51 (s, 2H), 7.34 (td, J = 1.2, 7.5 Hz, 2H), 7.42 (t, J = 7.4 Hz, 2H), 7.54 (t, J = 5.9 Hz, 1H), 7.68 (d, J = 7.4 Hz, 2H), 7.90 (d, J = 7.5 Hz, 2H), 8.30 (s, 3H). ES+(M+1 = 380), HPLC purity: 98%. Step 5 - Intermediate Compound A-117: (9H-fluoren-9-yl)methyl (((3S,3aR,6S,6aR)-6-((2S,4S)- 2,5,12-trihydroxy-7-methoxy-4-(((1S,3R,4aS,-9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H- pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxa-zin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracene-2- carboxamido)hexahydro-furo[3,2-b]furan-3-yl)methyl)carbamateIntermediate Compound A-116 (182 mg, 0.48 mmol) was added to the PNU-159682 carboxylic acid (CAS No.1204819-92-0; 300 mg, 0.48 mmol), HATU (273 mg, 0.72 mmol) and DIEA (0.250 mL, 1.43 mmol) in DMA (10 mL) under nitrogen. The resulting mixture was stirred at 15 °C for 2 hours. The crude product was purified by flash C18-flash chromatography, elution gradient 5 to 100% MeCN in water. Pure fractions were evaporated to dryness to afford Intermediate Compound A-117 (240 mg, 50.7 %) as a red solid.1H NMR (400 MHz, DMSO) δ 1.17 – 1.32 (m, 5H), 1.42 – 1.56 (m, 3H), 1.63 – 1.79 (m, 3H), 2.08 (s, 3H), 2.22 – 2.37 (m, 4H), 2.86 – 3.10 (m, 3H), 3.44 – 3.71 (m, 4H), 3.78 (dd, J = 5.9, 8.9 Hz, 1H), 4.23 (s, 2H), 4.32 – 4.50 (m, 5H), 4.58 (d, J = 2.3 Hz, 1H), 5.02 (s, 2H), 5.20 – 5.43 (m, 2H), 5.77 (s, 4H), 7.29 – 7.36 (m, 3H), 7.42 (t, J = 7.5 Hz, 2H), 7.51 (t, J = 5.9 Hz, 1H), 7.61 – 7.73 (m, 4H), 7.84 – 7.97 (m, 6H), 8.07 (d, J = 7.7 Hz, 1H). ES+(M+1 = 990.45 ), HPLC purity: 89%.Step 6 - Compound P31: (2S,4S)-N-((3S,3aR,6S,6aR)-6-(aminomethyl)hexa-hydrofuro[3,2-b]furan-3- yl)-2,5,12-trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H- pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracene-2- carboxamideDBU (0.043 mL, 0.28 mmol) was added to Intermediate Compound A-117 (280 mg, 0.28 mmol) in DCM (10 mL) and MeCN (2.500 mL) under nitrogen. The resulting mixture was stirred at 0 °C for 1 hour. The reaction mixture was adjusted to pH=7 with 0.1M HCl aqueous solution. Then the solvent was removed under reduced pressure. The crude product was purified by preparative HPLC (Column: Xbridge Prep C18 OBD, 19*250mm, 5um; Mobile Phase A: Water (10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient: 27% B to 40% B in 10 min; Wavelength: 254nm / 220nm; RT1(min): 8.72). Fractions containing the desired compound were freeze dried directly to dryness to afford Compound P31 (74.7 mg, 34.4 %) as a red solid.1H NMR (400 MHz, DMSO) δ 1.09 – 1.25 (m, 3H), 1.67 – 1.72 (m, 2H), 2.06 – 2.16 (m, 2H), 2.21 – 2.28 (m, 1H), 2.40 – 2.46 (m, 2H), 2.66 – 2.74 (m, 2H), 3.33 – 3.43 (m, 4H), 3.46 – 3.71 (m, 5H), 3.76 – 3.82 (m, 1H), 3.86 – 3.97 (m, 3H), 3.96 (s, 3H), 3.99 (s, 2H), 4.12 (s, 1H), 4.35 – 4.45 (m, 1H), 4.48 (d, J = 4.4 Hz, 1H), 4.58 (d, J = 2.0 Hz, 1H), 4.99 (s, 1H), 5.24 (t, J = 4.8 Hz, 1H), 5.38 (s, 1H), 7.65 (t, J = 4.8 Hz, 1H), 7.91 (d, J = 4.8 Hz, 2H), 8.01 (d, J = 7.6 Hz, 1H), 8.12 – 9.01 (m, 1H). ES+(M+1 = 768.45), HPLC purity: 95.3%Example 36: Synthesis of Compound P32Step 1 – Intermediate Compound A-118: (9H-fluoren-9-yl)methyl (((3S,3aR,6S,6aR)-6- (tritylamino)hexahydrofuro[3,2-b]furan-3-yl)methyl)carbamateIntermediate Compound A-116 (300 mg, 0.79 mmol) was added to Triphenylmethyl chloride (264 mg, 0.95 mmol) and N,N-Diisopropylethylamine (306 mg, 2.37 mmol) in THF (5 mL) at 25°C under nitrogen. The resulting mixture was stirred at 25 °C for 2 hours. The reaction mixture was diluted with DCM (20 mL), and washed sequentially with water (20 mLx3), The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The product Intermediate Compound A- 118 was used in the next step directly without further purification. Step 2 - Intermediate Compound A-119: (3S,3aR,6S,6aR)-6-(aminomethyl)-N- tritylhexahydrofuro[3,2-b]furan-3-amineIntermediate Compound A-118 (491 mg, 0.79 mmol) was added to Diethylamine (3 mL, 0.79 mmol) in THF (5 mL) at 25°C under nitrogen. The resulting mixture was stirred at 25 °C for 2 hours. The solvent was removed by distillation under vacuum. The crude product was purified by flash C18-flash chromatography, elution gradient 0 to 100% water (NH4CO3) in MeCN. Pure fractions were evaporated to dryness to afford Intermediate Compound A-119 (120 mg, 38.0 %) as a white solid. NMR (300 MHz, DMSO) δ 2.30 - 2.36 (m, 1H), 2.40 - 2.46 (m, 1H), 3.50 - 3.59 (m, 4H), 3.67 - 3.83 (m, 1H), 4.22 - 4.43 (m, 2H), 7.16 - 7.49 (m, 15H). ES+( M+23 = 423.25), HPLC purity: 82.5%. Step 3 - Intermediate Compound A-120: (2S,4S)-2,5,12-trihydroxy-7-methoxy-4- (((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo[2,3- c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-N-(((3S,3aR,6S,6aR)-6-(tritylamino)hexahydrofuro[3,2-b]furan-3- yl)methyl)-1,2,3,4,6,11-hexahydrotetracene-2-carboxamideThe PNU-159682 carboxylic acid (CAS No.1204819-92-0; 120 mg, 0.19 mmol) was added to Intermediate Compound A-119 (115 mg, 0.29 mmol), N,N-Diisopropylethylamine (124 mg, 0.96 mmol) and O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (145 mg, 0.38 mmol) in DMA (3 mL) at 25°C under nitrogen. The resulting mixture was stirred at 25 °C for 1 hour. The crude product was purified by flash C18-flash chromatography, elution gradient 0 to 100% water (NH4CO3) in MeCN. Pure fractions were evaporated to dryness to afford Intermediate Compound A-120 (100 mg, 51.8 %) as a red solid. Step 4 - Compound P32: (2S,4S)-N-(((3S,3aR,6S,6aR)-6-aminohexahydrofuro[3,2-b]furan-3- yl)methyl)-2,5,12-trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro- 1H-pyrano-[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11- hexahydrotetracene-2-carboxamideIntermediate Compound A-120 (100 mg, 0.10 mmol) was added to 1,1,1,3,3,3-Hexafluoro-2- propanol (2 mL, 0.10 mmol) in DCM (5 mL) at 25°C under nitrogen. The resulting mixture was stirred at 25 °C for 1 hour. The reaction system was dried with nitrogen gas flow. The crude product was purified by preparative HPLC (Column: Xselect CSH Prep Phenyl-Hexyl OBD column, 19*250mm, 5um; Mobile Phase A: Water (10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient: 27% B to 37% B in 15 min; Wavelength: 254nm / 220nm; RT1(min): 13.48) and MeCN as eluents. Fractions containing the desired compound were freeze dried directly to dryness to afford Compound P32 (41.8 mg, 55.0 %) as a red solid.1H NMR (400 MHz, DMSO-d6) δ 1.22 (d, J = 6.6 Hz, 3H), 1.63 – 1.70 (m, 2H), 2.16 (d, J = 13.8 Hz, 1H), 2.25 – 2.30 (m, 1H), 2.37 (s, 1H), 2.61 – 2.72 (m, 2H), 2.93 – 3.03 (m, 2H), 3.10 – 3.15 (m, 2H), 3.36 – 3.44 (m, 6H), 3.50 – 3.55 (m, 3H), 3.69 – 3.74 (m, 3H), 3.91 – 3.96 (m, 2H), 4.00 (s, 3H), 4.12 – 4.17 (m 2H), 4.24 (d, J = 2.1 Hz, 1H), 4.38 – 4.42 (m, 1H), 4.59 (d, J = 2.2 Hz, 1H), 5.00 – 5.10 (m, 1H), 5.23 – 5.28 (m, 1H), 5.37 (s, 1H), 7.64 – 7.69 (m, 1H), 7.93 (d, J = 4.8 Hz, 2H), 8.23 – 8.34 (m, 1H).2H were exchanged. ES+( M+1 = 768.40), HPLC purity: 90.0%. Example 37: Synthesis of Compound P33Step 1 - Intermediate Compound A-121: (3R,3aS,6R,6aS)-hexahydrofuro[3,2-b]furan-3,6-diyl bis(trifluoromethanesulfonate)To a 5 L flask, trifluoromethanesulfonic anhydride (93 g, 328.45 mmol) was added dropwise to (3R,3aR,6R,6aR)-hexahydrofuro[3,2-b]furan-3,6-diol (“isomannide”, CAS No.641-74-7; 20 g, 136.85 mmol) and Pyridine (26.0 g, 328.45 mmol) in DCM (600 mL) at 0°C under nitrogen. The resulting mixture was stirred at rt for 16 hours. The reaction mixture was acidified with 2M HCl adjusted to pH=3. The reaction mixture was diluted with DCM (100 mL) and washed sequentially with water (500 mL x 3) and saturated brine (500 mL x 1). The organic layer was dried over Na2SO4, filtered and evaporated to afford Intermediate Compound A-121 (55.0 g, 98 %) as a yellow solid.NMR (500 MHz, CDCl3) δ 4.16 (d, J = 5.5 Hz, 4H), 4.76 – 4.80 (m, 2H), 5.19 – 5.27 (m, 2H). Step 2, 3 - Intermediate Compound A-122: ((3S,3aR,6S,6aR)-hexahydrofuro[3,2-b]furan-3,6- diyl)dimethanamineIn a 150 mL round bottom flask, was added to Intermediate Compound A-121 (4.6 g, 11.21 mmol) and 18-Crown-6 (6.22 g, 23.55 mmol) in THF (10 mL) at 0°C under N2. To the reaction mixture was added KCN (1.533 g, 23.55 mmol). The resulting mixture was stirred at rt for 2 hours. The solvent was removed under reduced pressure. The crude product was purified by flash silica chromatography, elution gradient 0 to 70% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford crude product Intermediate Compound A-121-A, and used in the next step directly without further purification. In a 150 mL round bottom flask was added Intermediate Compound A-121-A from previous reaction and dissolved in THF (10 mL). To the reaction mixture was added borane-methyl sulfide complex in THF (22.43 mL, 224.25 mmol) at 0°C under air. The resulting mixture was stirred at rt for 16 hours. The reaction mixture was quenched with MeOH (20 mL). The solvent was removed under reduced pressure. The product was purified by using protecting group then deprotecting it. The reaction mixture was filtered through celite. The solvent was removed under reduced pressure to afford crude Intermediate Compound A-122(120 mg, 77 %) as a pale yellow oil.1H NMR (400 MHz, MeOD) δ 2.34 – 2.46 (m, 2H), 2.67 – 2.93 (m, 4H), 3.61 – 3.69 (m, 2H), 4.01 – 4.05 (m, 2H), 4.40 – 4.50 (m, 2H). ES+(M+1) = 173. Step 6 - Compound P33: (2S,4S)-N-(((3S,3aR,6S,6aR)-6-(aminomethyl)-hexahy-drofuro[3,2-b]furan- 3-yl)methyl)-2,5,12-trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,-9aR,-10aS)-9-methoxy-1- methyloctahydro-1H-pyrano[4',3':4,5]oxazolo-[2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11- hexahydrotetracene-2-carboxamideTo a 50 mL round bottom flask, Intermediate Compound A-122 (82 mg, 0.48 mmol) was added to the PNU-159682 carboxylic acid (CAS No.1204819-92-0; 100 mg, 0.16 mmol), HATU (121 mg, 0.32 mmol) and DIEA (0.139 mL, 0.80 mmol) in DMA (2 mL) at 25°C under nitrogen. The resulting mixture was stirred at 25 °C for 2 hours. The crude product was purified by preparative HPLC (Column: Xbridge Prep C18 OBD, 30*150 mm, 5μm; Mobile Phase A: Water(10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 22% B to 43% B in 8 min; Wavelength: 254nm / 220nm; RT1(min): 6.98) and MeCN as eluents. Fractions containing the desired compound were freeze dried directly to dryness to afford Compound P33 (7.00 mg, 5.62 %) as a red solid.1H NMR (400 MHz, CDCl3) δ 1.40 (d, J = 6.4 Hz, 3H), 1.72 – 1.79 (m, 2H), 2.00 – 2.06 (m, 1H), 2.34 – 2.55 (m, 5H), 2.72 – 2.88 (m, 4H), 3.15 – 3.28 (m, 3H), 3.35 – 3.43 (m, 3H), 3.56 – 3.72 (m, 4H), 3.91 – 4.07 (m, 5H), 4.11 (d, J = 7.5 Hz, 4H), 4.43 (s, 1H), 4.49 (d, J = 2.0 Hz, 1H), 4.59 (s, 1H), 4.73 (d, J = 2.0 Hz, 1H), 5.12 (s, 1H), 5.31 (s, 1H), 5.50 (t, J = 5.6 Hz, 1H), 7.39 (d, J = 8.6 Hz, 1H), 7.47 (s, 1H), 7.79 (t, J = 8.1 Hz, 1H), 7.95 – 8.07 (m, 1H), 13.91 (s, 1H). ES+(M+1) = 782.Example 38: Synthesis of Compound P34Step 1 - Intermediate Compound A-123: Dibenzyl (((3S,3aR,6S,6aR)-hexahydrofuro[3,2-b]furan-3,6- diyl)bis(methylene))dicarbamateIn a round bottom flask, N-(Benzyloxycarbonyloxy)succinimide (5.59 g, 22.43 mmol) was added to DIEA (5.88 mL, 33.64 mmol) and Intermediate Compound A-122 (1.9 g, 11 mmol) in THF (10 mL) at 25°C under air. The resulting mixture was stirred at rt for 16 hours. The solvent was removed under reduced pressure. The crude product was purified by flash C18-flash chromatography, elution gradient 5 to 100% water (0.1% FA) in MeCN. Pure fractions were evaporated to dryness to afford Intermediate Compound A-123 (0.400 g, 8.10 %) as a yellow solid.1H NMR (400 MHz, DMSO) δ 2.17 – 2.31 (m, 2H), 2.81 – 3.08 (m, 4H), 3.41 – 3.51 (m, 2H), 3.68 – 3.79 (m, 2H), 4.28 (s, 2H), 5.02 (s, 4H), 7.27 – 7.42 (m, 10H), 7.46 (t, J = 5.8 Hz, 2H). ES+( M+1 = 441.15). Step 2 - Intermediate Compound A-124: Benzyl (((3S,3aR,6S,6aR)-6- (aminomethyl)hexahydrofuro[3,2-b]furan-3-yl)methyl)carbamateIn a round bottom flask, Intermediate Compound A-123 (8 g, 18.16 mmol) was added to dioxane (30 mL) / as stirred at 25 °C for 5hours. The solvent was removed by blowing N2 gently. The crude product was purified by flash C18- flash chromatography, elution gradient 0 to 100% MeCN in water (0.1%NH4HCO3). Pure fractions were evaporated to dryness to afford Intermediate Compound A-124 (1.800 g, 32.4 %) as a pale- yellow oil.1H NMR (400 MHz, DMSO) δ 1.71 – 1.82 (m, 2H), 2.15 (s, 1H), 2.25 (s, 1H), 2.41 - 2.49 (m, 1H), 2.54 – 2.68 (m, 1H), 2.84 - 3.04 (m, 2H), 3.43 - 3.55 (m, 2H), 3.67 – 3.90 (m, 4H), 5.02 (s, 2H), 7.27 - 7.41 (m, 5H), 7.46 (d, J = 5.9 Hz, 1H). ES+(M+1 =307) HPLC purity: 90%. Step 3 - Intermediate Compound A-125: Benzyl (((3S,3aR,6S,6aR)-6- ((methylamino)methyl)hexahydrofuro[3,2-b]furan-3-yl)methyl)carbamateIn a round bottom flask, methyl trifluoromethanesulfonate (0.321 g, 1.96 mmol) was added to Intermediate Compound A-124 (1g, 3.26 mmol) in HFIP (10 mL) at 25°C under nitrogen. The resulting mixture was stirred at 25 °C for 1 hour. The reaction mixture was quenched by a solution of 1 N HCl and then the solvent was removed under reduced pressure. The crude product was purified by flash C18-flash chromatography, elution gradient 0 to 100% MeCN in water (0.1%NH4HCO3). Pure fractions were evaporated to dryness to afford Intermediate Compound A- 125 (0.210 g, 20.08 %) as a pale yellow oil.1H NMR (400 MHz, DMSO) δ 1.74 – 1.79 (m, 1H), 2.22 (s, 1H), 2.26 (s, 3H), 2.28 – 2.37 (m, 1H), 2.38 - 2.48 (m, 1H), 2.84 - 3.04 (m, 2H), 3.43 – 3.66 (m, 3H), 3.69 - 3.83 (m, 2H), 4.21 – 4.41 (m, 2H), 5.02 (d, J = 5.2 Hz, 2H), 7.27 - 7.41 (m, 5H), 7.44 (t, J = 5.9 Hz, 1H). ES+(M+1 =321) HPLC purity: 90%. Step 4 - Intermediate Compound A-126: 1-((3S,3aR,6S,6aR)-6-(aminomethyl)hexahydrofuro[3,2- b]furan-3-yl)-N-methylmethanamineIn a round bottom flask, Intermediate Compound A-125 (200 mg, 0.62 mmol) was added to dioxane (1 mL) / HCl(12N) (5.00 mL) at 25°C under nitrogen. The resulting mixture was stirred at 25 °C for 5 hours. The solvent was removed under reduced pressure to afford crude Intermediate Compound A126 (150 mg 93 %) as a yellow solid1H NMR (400 MHz DMSO) δ 2.45 (d, J = 6.5 Hz,2H), 2.66 – 2.76 (m, 2H), 2.80 - 2.94 (m, 4H), 3.64 - 3.71 (m, 3H), 3.83 – 4.00 (m, 4H), 4.45 – 4.55 (m, 3H), 8.16 - 8.31 (m, 5H). ES+(M+1 =187) HPLC purity: 80%. Step 5 - Compound P34: (2S,4S)-2,5,12-trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9- methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-N- (((3S,3aR,6S,6aR)-6-((methylamino)methyl)hexahydrofuro[3,2-b]furan-3-yl)methyl)-6,11-dioxo- 1,2,3,4,6,11-hexahydrotetracene-2-carboxamideIn a round bottom flask, Intermediate Compound A-126 (89 mg, 0.48 mmol) was added to PNU- 159682 carboxylic acid (CAS No.1204819-92-0, 150 mg, 0.24 mmol), HATU (182 mg, 0.48 mmol) and DIEA (0.209 mL, 1.20 mmol) in DMSO (5 mL) at 25°C under nitrogen. The resulting mixture was stirred at 25 °C for 1 hour. The crude product was purified by preparative HPLC (Column: Kinetex EVO C18 Column, 25*250mm, 5um; Mobile Phase A: Water (10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient: 30% B to 38% B in 15 min; Wavelength: 254nm / 220nm; RT1(min): 12.62) and MeCN as eluents. Fractions containing the desired compound were freeze dried directly to dryness to afford Compound P34 as a red solid (28 mg, 13%)1H NMR (400 MHz, DMSO) δ 1.22 (s, 3H), 1.60 – 1.80 (m, 2H), 2.13 – 2.18 (m, 1H), 2.23 – 2.35 (m, 1H), 2.40 (s, 1H), 2.55 – 2.59 (m, 2H), 2.66 – 2.72 (m, 1H), 2.81 – 3.23 (m, 6H), 3.32 (s, 3H), 3.51 – 3.61 (m, 3H), 3.68- 3.78 (m, 2H), 3.80 – 3.94 (m, 2H), 3.96 (s, 1H), 4.00 (s, 3H), 4.15 (d, J = 6.8 Hz, 1H), 4.24 (s, 1H), 4.31 (d, J = 4.8 Hz, 1H), 4.44 (d, J = 5.2 Hz, 1H), 4.59 (d, J = 2.0 Hz, 1H), 5.03 (d, J = 5.2 Hz, 1H), 5.26 (d, J = 4.8 Hz, 1H), 5.40 (s, 1H), 7.68 (t, J= 4.8 Hz, 1H), 7.94 (d, J = 4.8 Hz, 2H), 8.30 (t, J = 6.0 Hz, 1H), 13.28 (s, 1H), 14.08 (s, 1H). ES+(M+1 =796) HPLC purity: 79%.LINKER PAYLOAD SYNTHESIS General procedure for Linker Payload synthesis To an appropriate size round bottom flask, a Linker (1.0 eq) is added in anhydrous DMF and cooled to 0^ C. To the solution is added HATU (1.0 eq), and DIPEA (3 eq) followed by a Payload (0.95 eq). The reaction mixture is warmed to room temperature and stirred for 1 hr. LCMS is used to confirm formation of the desired Linker-Payload. The reaction mixture is diluted with acetonitrile (1 mL) and purified via reverse phase purification by using acetonitrile and water (2 mmol HCOONH4) as mobile phase. Obtained fractions are lyophilized to afford the Linker-Payload. Protection and de-protection steps are utilized as necessary. The linker may be loaded onto a resin prior to the coupling with the payload, followed by cleavage of the resin after coupling. Example 39: Synthesis of Linker-Payload Compound LP1Synthesis of Linker Compound L1: (3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1- yl)propanoyl)glycylglycylglycylglycylglycine Resin loading: A peptide synthesizer glass vessel (Chemglass, 250-mL) adapted with an N2 (g) flow inlet and a medium size frit filter was charged with 2-chlorotrityl chloride resin (1.4 g, 1.54 mmol, 1.1 mmol / g commercial loading capacity, Chem-Impex International). The resin was swollen by agitation with a flow of N2(g) for 1.5 hours with 20 mL of anhydrous DMF and for 30 minutes with 27 mL ofDMF / DCM (3:1). N-Fmoc-Gly-Gly-Gly-Gly-OH (1.36 eq., 0.98 g, 2.09 mmol) was dissolved in 31 mL of anhydrous EtOAC / DMSO / DMF (20:6:5) and 1.88 mL of DIPEA (1.39 g, 7 eq, 10.78 mmol). The reaction was run for 15 hours and the resin was washed with DMF (4 x 5 min x 25 mL) and DCM (4 x 5 min x 25 mL). Resin capping: The resin was capped with 15 mL of 17:2:1 DCM:MeOH:DIPEA solution (2 x 10 min x 15 mL) and then washed with DCM (3 x 3 min x 12 mL) followed by DMF (3 x 3 min x 15 mL). Fmoc-removal: The Fmoc-removal was performed using in 1:4 piperidine / DMF solution (1 x 10 min x 15 mL and 1 x 5 min x 15 mL). Coupling: The resin was washed with DMF (5 x 5 min x 15 mL) and coupled to N-Fmoc-Gly-OH, assuming resin loading of 1.1 mmol / g. The coupling cocktail containing N-Fmoc-Gly-OH (2.29 g, 5 eq, 7.7 mmol), HOBt (1.18 g, 5 eq, 7.7 mmol), HATU (2.87 g, 4.9 eq, 7.55 mmol) and DIPEA (1.61 mL, 6 eq, 9.24 mmol) dissolved in 12 mL of DMF was pre-activated for 5 mins prior to addition to the resin. The coupling reaction was run for 30 min and the completion of the reaction was monitored using Ninhydrin stain. Upon completion, the coupling solution was drained and the resin-immobilized Fmoc-Gly-Gly-Gly-Gly-Gly-OH (Intermediate compound 93) was washed with DMF (5 x 5 min x 15 mL). Fmoc Removal: Resin-immobalized Fmoc-Gly-Gly-Gly-Gly-Gly-OH (Intermediate compound 93) was subjected to Fmoc-removal. The Fmoc-removal was performed using 1:4 piperidine / DMF solution (2 x 5 min 15 mL). The resin was washed with DMF (5 x 3 min x 15 mL) prior to coupling to the next carboxylic acid. Coupling and resin cleavage: The resin (0.49 mmol, assuming 1.1 mmol / g loading capacity) was coupled to 3-(2,5-dioxo-2,5- dihydro-1H-pyrrol-1-yl)propanoic acid. The coupling cocktail containing 3-(2,5-dioxo-2,5-dihydro- 1H-pyrrol-1-yl)propanoic acid (174 mg, 2.1 eq, 1.03 mmol), HOBt (278 mg, 3.7 eq, 1.81 mmol), HATU (373 mg, 2 eq, 0.98 mmol) and DIPEA (0.342 mL, 4 eq, 1.96 mmol) dissolved in 3.5 mL of DMF was pre-activated for 5 mins prior to addition to the resin. The coupling reaction was run for 30 min and the completion of the reaction was monitored using Ninhydrin stain. Upon completion, thecoupling solution was drained and the resin was washed with DMF (5 x 5 min x 8 mL) and DCM (5 x 3 min x 8 mL). Cleavage of the peptide from the resin was carried out with a 4:1 solution of DCM / HFIP (2 x 10 min x 10 mL) and the resin was washed with DCM (3 x 3 min x 5 mL). The solvent was removed in vacuo to give Linker Compound L1 as a white solid (50 mg, 0.110 mmol) in 22% yield (calculated from based on the commercial solid phase loading capacity). ES [M-H]- 453.3 m / z. Synthesis of Linker-Payload LP1: To a 25 ml round bottom flask, Linker Compound L1 (50 mg, 1.0 eq) was added in anhydrous DMF (1 mL) and cooled to 0^ C. To the solution was added HATU (42 mg, 1.0 eq), and DIPEA (3 eq) followed by Compound P20 (80 mg, 0.95 eq). The reaction mixture was warmed to room temperature and stirred for 1 hrs. LCMS showed formation of desired product. The reaction mixture was diluted with acetonitrile (1 mL) and purified via reverse phase purification by using acetonitrile and water (2 mmol HCOONH4) as mobile phase. Obtained fractions were lyophilized to afford Linker-Payload Compound LP1 as a red solid (20 mg, 15% yield) ES [M+H]+: 1191.1 m / z. Example 40: Synthesis of Linker-Payload LP2To a 25 ml round bottom flask, Linker Compound L1 (50 mg, 1.0 eq) was added in anhydrous DMF (1 mL) and cooled to 0^ C. To the solution was added HATU (42 mg, 1.0 eq), and DIPEA (3 eq) followed by Compound P8 (77 mg, 0.95 eq). The reaction mixture was warmed to room temperature and stirred for 1 hrs. LCMS showed formation of desired product. The reaction mixture was diluted with acetonitrile (1 mL) and purified via reverse phase purification by using acetonitrile and water (2 mmol HCOONH4) as mobile phase. Obtained fractions were lyophilized to afford Linker-Payload Compound LP2 as a red solid (31 mg, 24% yield) ES [M+H]+: 1172.08 m / z.Example 41: Synthesis of Linker-Payload LP6Synthesis of Intermediate compound 104: (9H-fluoren-9-yl)methyl ((S)-1-((2-(((3S,3aR,6S,6aR)-6- ((tert-butoxycarbonyl)amino)hexahydrofuro[3,2-b]furan-3-yl)amino)-2-oxoethyl)amino)-1-oxo-3- phenylpropan-2-yl)carbamateTo a 500 mL round bottom flask, chloro-N,N,N’,N’-tetramethylformamidinium hexafluorophosphate (15.15 g, 53.99 mmol) was added to (((9H-fluoren-9-yl)methoxy)carbonyl)-L- phenylalanylglycine (20 g, 45.00 mmol), (3S,3aR,6S,6aR)-hexahydrofuro[3,2-b]furan-3,6-diamine (Intermediate Compound 52, 9.73 g, 67.49 mmol) and 1-methylimidazole (7.39 g, 89.99 mmol) inDMA (250 mL) under nitrogen. The resulting mixture was stirred at 15 °C for 3 hours. The reaction mixture was diluted with EtOAc (500 mL) and washed sequentially with water (200 mL x 2). (Boc)2O (20.89 mL, 89.99 mmol) was add to the organic layer. The resulting mixture was stirred at 15 °C for 2 hours. The solvent was removed under reduced pressure. The reaction mixture was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford Intermediate Compound 104 (12.00 g, 39.8 % for 2 steps) as a yellow solid. ES M+1 = 671.1H NMR (400 MHz, DMSO) δ 1.39 (s, 9H), 2.71 – 2.85 (m, 1H), 2.99 – 3.08 (m, 1H), 3.55 – 3.64 (m, 2H), 3.65 – 3.81 (m, 2H), 3.81 – 3.89 (m, 3H), 3.98 – 4.07 (m, 1H), 4.07 – 4.20 (m, 4H), 4.20 – 4.28 (m, 1H), 4.38 (d, J = 4.4 Hz, 1H), 4.43 (d, J = 4.4 Hz, 1H), 7.22 – 7.35 (m, 7H), 7.37 – 7.46 (m, 2H), 7.61 – 7.73 (m, 3H), 7.88 (d, J = 7.6 Hz, 2H), 8.08 (d, J = 7.0 Hz, 1H), 8.26 – 8.33 (m, 1H). Synthesis of Intermediate compound 105: tert-butyl ((3S,3aR,6S,6aR)-6-(2-((S)-2-amino-3- phenylpropanamido)acetamido)hexahydrofuro[3,2-b]furan-3-yl)carbamateTo a 500 mL round bottom flask, dimethylamine (35 mL, 178.90 mmol) was added to Intermediate Compound 104 (12 g, 17.89 mmol) in DCM (100 mL) / THF (50 mL) under nitrogen. The resulting mixture was stirred at RT for 1 hour. The solvent was removed under reduced pressure to afford Intermediate Compound 105 (7.00 g, 87%) as a yellow oil. No further purification was carried out as sufficiently clean for next steps. ES M+1 = 449.1H NMR (400 MHz, DMSO) δ 1.39 (s, 9H), 2.55 – 2.64 (m, 1H), 2.93 – 3.03 (m, 1H), 3.41 – 3.50 (m, 1H), 3.56 – 3.63 (m, 2H), 3.71 (d, J = 5.2 Hz, 2H), 3.80 – 3.89 (m, 3H), 4.10 (s, 1H), 4.36 (d, J = 4.0 Hz, 1H), 4.42 (d, J = 4.0 Hz, 1H), 7.23 – 7.27 (m, 3H), 7.35 (d, J = 1.2 Hz, 1H), 7.42 (d, J = 1.2 Hz, 1H), 7.82 – 7.93 (m, 4H), 8.16 – 8.20 (m, 1H). Synthesis of Intermediate compound 106: tert-butyl ((3S,3aR,6S,6aR)-6-((S)-11-benzyl-1-(9H- fluoren-9-yl)-3,6,9,12-tetraoxo-2-oxa-4,7,10,13-tetraazapentadecan-15-amido)hexahydrofuro[3,2- b]furan-3-yl)carbamateTo a 500 mL round bottom flask, Intermediate Compound 105 (7 g, 15.61 mmol) was added to (((9H-fluoren-9-yl)methoxy)carbonyl)glycylglycine (8.30 g, 23.41 mmol), HATU (8.90 g, 23.41 mmol) and DIEA (8.18 mL, 46.82 mmol) in DMA (20 mL) / DCM (100 mL) under nitrogen. The resulting mixture was stirred at 15 °C for 2 hours. The solvent was removed under reduced pressure. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% MeOH in DCM. Pure fractions were evaporated to dryness to afford Intermediate Compound 106 (9.50 g, 78 %) as a yellow solid. ES+(M+1 = 785).1H NMR (400 MHz, DMSO) δ 1.38 (s, 9H), 2.99 – 3.08 (m, 1H), 3.09 – 3.20 (m, 1H), 3.58 – 3.66 (m, 6H), 3.69 – 3.77 (m, 2H), 3.81 – 3.87 (m, 3H), 4.08 (d, J = 6.6 Hz, 1H), 4.16 – 4.33 (m, 3H), 4.36 – 4.45 (m, 2H), 4.45 – 4.53 (m, 1H), 7.25 (d, J = 6.0 Hz, 4H), 7.28 – 7.37 (m, 2H), 7.38 – 7.46 (m, 2H), 7.56 – 7.64 (m, 1H), 7.72 (d, J = 7.6 Hz, 2H), 7.90 (d, J = 7.6 Hz, 2H), 8.00 – 8.08 (m, 2H), 8.17 (d, J = 8.0 Hz, 1H), 8.25 – 8.32 (m, 1H). Synthesis of Intermediate compound 107: tert-butyl ((3S,3aR,6S,6aR)-6-(2-((S)-2-(2-(2- aminoacetamido)acetamido)-3-phenylpropanamido)acetamido)-hexahydrofuro[3,2-b]furan-3- yl)carbamateTo a 500 mL round bottom flask, dimethylamine (40 mL, 121.04 mmol) was added to Intermediate Compound 106 (9.5 g, 12.10 mmol) in THF (40 mL) / DCM (120 mL) under nitrogen. The resulting mixture was stirred at 15 °C for 1 hour. The solvent was removed under reduced pressure to afford Intermediate Compound 107 (6.00 g, 88 %) as a yellow solid. No further purification was carried out as sufficiently clean for next steps. ES+M+1 = 563.1H NMR (400 MHz, DMSO) δ 1.39 (s, 9H), 2.73 – 2.83 (m, 1H), 3.08 (s, 2H), 3.30 (s, 2H), 3.58 – 3.64 (m, 3H), 3.64 – 3.69 (m, 2H), 3.81 – 3.88 (m, 4H), 4.09 (d, J = 6.8 Hz, 1H), 4.34 – 4.47 (m, 2H), 7.26 (d, J = 6.0 Hz, 5H), 7.82 – 7.92 (m, 1H), 8.07 (d, J = 7.2 Hz, 1H), 8.23 (s, 1H), 8.26 – 8.37 (m, 2H). Synthesis of Intermediate compound 108: tert-butyl ((3S,3aR,6S,6aR)-6-((S)-5-benzyl-15-(2,5-dioxo- 2,5-dihydro-1H-pyrrol-1-yl)-4,7,10,13-tetraoxo-3,6,9,12- tetraazapentadecanamido)hexahydrofuro[3,2-b]furan-3-yl)carbamateTo a 500 mL round bottom flask, DIEA (3.73 mL, 21.33 mmol) was added to Intermediate compound 107 (6 g, 10.66 mmol) and 2,5-dioxopyrrolidin-1-yl 3-(2,5-dioxo-2,5-dihydro-1H-pyrrol- 1-yl)propanoate (3.41 g, 12.80 mmol) in DMA (40 mL) / MeCN (40.0 mL) under nitrogen. The resulting mixture was stirred at 15 °C for 2 hours. Solvent was removed under reduced pressure.The crude product was purified by flash C18-flash chromatography, elution gradient 0 to 100% MeCN in water (0.1% FA). Pure fractions were evaporated to dryness to afford Intermediate compound 108 (4.50 g, 59.1 %) as a yellow solid. ES+M+1 = 714.1H NMR (400 MHz, DMSO) δ 1.39 (s, 9H), 2.38 – 2.46 (m, 2H), 2.75 – 2.85 (m, 1H), 2.99 – 3.08 (m, 1H), 3.56 – 3.63 (m, 5H), 3.66 (d, J = 5.6 Hz, 3H), 3.70 – 3.78 (m, 2H), 3.81 – 3.87 (m, 3H), 4.09 (d, J = 7.2 Hz, 1H), 4.37 (d, J = 4.0 Hz, 1H), 4.42 (d, J = 4.0 Hz, 1H), 4.44 – 4.51 (m, 1H), 7.00 (s, 2H), 7.16 – 7.22 (m, 1H), 7.22 – 7.29 (m, 5H), 8.01 – 8.09 (m, 2H), 8.09 – 8.20 (m, 1H), 8.22 – 8.33 (m, 2H). Synthesis of Intermediate compound 109: (S)-N-(2-(((3S,3aR,6S,6aR)-6-aminohexahydrofuro[3,2- b]furan-3-yl)amino)-2-oxoethyl)-2-(2-(2-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1- yl)propanamido)acetamido)-acetamido)-3-phenylpropanamideTo a 500 mL round bottom flask, 12M HCl (25 mL, 100.00 mmol) was added to Intermediate compound 108 (4.5 g, 6.30 mmol) in 4M HCl- EtOH (60 mL) under nitrogen. The resulting mixture was stirred at 15 °C for 1 hour. The solvent was removed under reduced pressure. The crude product was purified by flash C18-flash chromatography, elution gradient 0 to 100% MeCN in water (0.1% NH4HCO3). Pure fractions were evaporated to dryness to afford Intermediate compound 109 (3.50 g, 90 %) as a yellow solid. ES+M+1 = 6141H NMR (400 MHz, DMSO) δ 2.36 – 2.46 (m, 2H), 2.78 – 2.90 (m, 1H), 2.99 – 3.10 (m, 1H), 3.50 – 3.71 (m, 8H), 3.71 – 3.81 (m, 2H), 3.82 – 3.98 (m, 3H), 4.12 (s, 1H), 4.37 – 4.47 (m, 1H), 4.61 (d, J = 4.4 Hz, 1H), 4.69 (d, J = 4.4 Hz, 1H), 7.13 – 7.22 (m, 1H), 7.25 (d, J = 4.0 Hz, 4H), 8.10 – 8.18 (m, 1H), 8.19 – 8.26 (m, 2H), 8.32 – 8.41 (m, 2H), 8.60 – 8.66 (m, 2H). Synthesis of Compound LP6 : (2S,4S)-N-((3S,3aR,6S,6aR)-6-((S)-5-benzyl-15-(2,5-dioxo-2,5-dihydro- 1H-pyrrol-1-yl)-4,7,10,13-tetraoxo-3,6,9,12-tetraazapentadecanamido)hexahydrofuro-[3,2-b]furan- 3-yl)-2,5,12-trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H- pyrano[4’3’:45]oxazolo[23c]

[0014] oxazin3yl)oxy)611dioxo1234611hexahydrotetracene-2- carboxaTo a 250 mL round bottom flask, HATU (1.091 g, 2.87 mmol) was added to PNU-159682 carboxylic acid (CAS No.1204819-92-0; 1.5 g, 2.39 mmol) in DMA (40 mL) under nitrogen. The resulting mixture 1 was stirred at 15 °C for 10 minutes. DIEA (2.087 mL, 11.95 mmol) was added to Intermediate compound 109 (1.467 g, 2.39 mmol) in DMSO (20.00 mL) under nitrogen. The resulting mixture 2 was stirred at 15 °C for 10 minutes. After that, the mixture 2 was added to the mixture 1, then stirring at 15 °C for 2 hours. The reaction mixture was quenched with 10 mM NH4Cl (12 mL). The crude product was purified by flash C18-flash chromatography, elution gradient 0 to 100% MeCN in water. Pure fractions were evaporated to dryness to afford crude product (2.3 g, crude). The crude product was purified by preparative HPLC Column: XBridge Prep Shield RP18 OBD Column, 19*250 mm, 5μm; Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient: isocratic 15% B in 2 min, 30% B to 40% B in 20 min; Wave Length: 254nm / 220nm; RT1(min): 19.2. Fractions containing the desired compound were freeze dried directly to dryness to afford Linker-Payload Compound LP6 (0.640 g, 21.89 %) as a red solid. ES+(M+1 = 1223),1H NMR (400 MHz, DMSO) δ 1.20 (d, J = 6.4 Hz, 3H), 1.62 – 1.74 (m, 2H), 2.10 – 2.17 (m, 1H), 2.24 – 2.33 (m, 1H), 2.37 – 2.46 (m, 2H), 2.59 – 2.74 (m, 2H), 2.75 – 2.85 (m, 1H), 2.92 – 3.08 (m, 3H), 3.27 – 3.33 (m, 3H), 3.47 – 3.81 (m, 13H), 3.85 – 3.97 (m, 3H), 4.00 (s, 3H), 4.10 – 4.19 (m, 3H), 4.23 (d, J = 2.0 Hz, 1H), 4.43 – 4.54 (m, 3H), 4.59 (d, J = 2.0 Hz, 1H), 4.98 – 5.04 (m, 1H), 5.22 – 5.32 (m, 1H), 5.38 (s, 1H), 6.99 (s, 2H), 7.16 – 7.21 (m, 1H), 7.26 (d, J = 5.5 Hz, 4H), 7.64 – 7.70 (m, 1H), 7.93 (d, J = 4.8 Hz, 2H), 8.03 – 8.17 (m, 4H), 8.22 – 8.33 (m, 2H), 13.26 (s, 1H), 14.07 (s, 1H).Example 42: Synthesis of Compound LP3Step 1 - Intermediate Compound 110: tert-butyl ((3S,3aR,6S,6aR)-6-(1-(9H-fluoren-9-yl)-3,6,9- trioxo-2-oxa-4,7,10-triazadodecan-12-amido)hexahydrofuro[3,2-b]furan-3-yl)carbamateIn a 500 mL round bottom flask, a mixture of (((9H-fluoren-9- yl)methoxy)carbonyl)glycylglycylglycine (11.2 g, 27.22 mmol) was added to tert-butyl ((3S,3aR,6S,6aR)-6-aminohexahydrofuro[3,2-b]furan-3-yl)carbamate (9.98 g, 40.83 mmol), O-(7- Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (15.53 g, 40.83 mmol) and N,N-diisopropylethylamine (10.56 g, 81.67 mmol) in DMA (300 mL) was stirred at 25 °C for 3 hours. The crude product was purified by flash C18-flash chromatography, elution gradient 0 to 100% MeCN in water to afford Intermediate Compound 110 (9.20 g, 53.0 %) as a white solid.1H NMR (400 MHz, DMSO) δ 1.38 (s, 9H), 3.54 – 3.62 (m, 2H), 3.68 (dd, J = 5.9, 10.6 Hz, 3H), 3.73 (d, J = 5.6 Hz, 2H), 3.80 – 3.88 (m, 3H), 4.08 (s, 1H), 4.19 – 4.27 (m, 1H), 4.30 (d, J = 6.9 Hz, 2H), 4.36 (d, J = 4.2 Hz, 1H), 4.42 (d, J = 4.1 Hz, 1H), 7.23 (s, 1H), 7.30 – 7.37 (m, 2H), 7.39 – 7.46 (m, 2H), 7.58 (t, J = 6.0 Hz, 1H), 7.72 (d, J = 7.4 Hz, 2H), 7.90 (d, J = 7.5 Hz, 2H), 8.04 – 8.14 (m, 2H), 8.16 – 8.22 (m, 1H). ES+(M+1 = 638.35).Step 2 & 3 - Intermediate Compound 112: tert-butyl ((3S,3aR,6S,6aR)-6-(1-(9H-fluoren-9-yl)- 3,30,33,36-tetraoxo-2,7,10,13,16,19,22,25,28-nonaoxa-4,31,34,37-tetraazanonatriacontan-39- amido)hexahydrofuro[3,2-b]furan-3-yl)carbamateIn a 500 mL round bottom flask, Intermediate Compound 110 (9.2 g, 14.43 mmol) was added to diethylamine (31.7 g, 432.81 mmol) in THF (500 mL) and water (10 mL). The resulting mixture was stirred at 25 °C for 2 hours. The solvent was removed under reduced pressure to get crude product (Int 111). The crude product was washed with MTBE (3 x 100 mL) and dried with nitrogen flow. The above crude product was added to O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (8.23 g, 21.64 mmol), DIEA (10.08 mL, 57.71 mmol) and 1-(9H-fluoren-9-yl)-3- oxo-2,7,10,13,16,19,22,25,28-nonaoxa-4-azatriacontan-30-oic acid (18.75 g, 28.85 mmol) in DMA (100 mL). The resulting mixture was stirred at 25 °C for 2 hours. The crude product was purified by flash C18-flash chromatography, elution gradient 0 to 100% MeCN in water to afford Intermediate Compound 112 (7.30 g, 48.3 %).1H NMR (400 MHz, DMSO) δ 1.39 (s, 9H), 3.38 – 3.43 (m, 2H), 3.50 (br, 24H), 3.52 (s, 4H), 3.58 (s, 2H), 3.67 – 3.74 (m, 4H), 3.77 – 3.87 (m, 4H), 3.93 (s, 2H), 4.05 – 4.14 (m, 2H), 4.21 (t, J = 6.8 Hz, 1H), 4.29 (d, J = 6.9 Hz, 3H), 4.34 – 4.43 (m, 2H), 7.23 (s, 1H), 7.42 (t, J = 7.4 Hz, 3H), 7.70 (d, J = 7.5 Hz, 3H), 7.90 (d, J = 7.3 Hz, 4H), 8.02 – 8.13 (m, 2H), 8.24 (t, J = 5.7 Hz, 1H). ES+( M+1 = 1047.65). Step 4 & 5 - Intermediate Compound 114: tert-butyl ((3S,3aR,6S,6aR)-6-(39-(2,5-dioxo-2,5-dihydro- 1H-pyrrol-1-yl)-4,7,10,37-tetraoxo-12,15,18,21,24,27,30,33-octaoxa-3,6,9,36- tetraazanonatriacontanamido)hexahydrofuro-[3,2-b]furan-3-yl)carbamateIn a 500 mL round bottom flask, Intermediate Compound 112 (7.3 g, 6.97 mmol) was added to diethylamine (20 ml, 193.33 mmol) in THF (80 mL) at 0°C. The resulting mixture was stirred at 25 °C for 2 hours. The solvent was removed under reduced pressure. The reaction mixture was diluted with DCM (150 mL). The solvent was removed under reduced pressure. The above crude product (Int 113) was added to 2,5-dioxopyrrolidin-1-yl 3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanoate (2.60 g, 9.76 mmol) in THF (200 mL) at 0°C. The resulting mixture was stirred at 25 °C for 2 hours. The crude product was purified by flash C18-flash chromatography, elution gradient 0 to 70%MeCN in water(0.1%FA). Pure fractions were evaporated to dryness to afford Intermediate Compound 114 (5.00 g, 73.5 %) as a yellow oil.1H NMR (400 MHz, DMSO) δ 1.39 (s, 9H), 2.33 (t, J = 7.3 Hz, 2H), 3.11 – 3.17 (m, 2H), 3.47 – 3.55 (m, 22H), 3.56 – 3.65 (m, 7H), 3.67 – 3.74 (m, 4H), 3.78 – 3.87 (m, 5H), 3.94 (s, 2H), 4.08 (s, 1H), 4.34 – 4.42 (m, 2H), 5.77 (s, 1H), 7.01 (s, 1H), 7.23 (s, 1H), 7.90 (t, J = 5.9 Hz, 1H), 8.00 – 8.13 (m, 3H), 8.24 (t, J = 5.6 Hz, 1H). ES+( M+1 = 976.60). Step 6 & 7 - Compound LP3: (2S,4S)-N-((3S,3aR,6S,6aR)-6-(39-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1- yl)-4,7,10,37-tetraoxo-12,15,18,21,24,27,30,33-octaoxa-3,6,9,36- tetraazanonatriacontanamido)hexahydrofuro[3,2-b]furan-3-yl)-2,5,12-trihydroxy-7-methoxy-4- (((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano-[4',3':4,5]oxazolo[2,3- c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracene-2-carboxamideIn a 500 mL round bottom flask, Intermediate Compound 114 (3.08 g, 3.15 mmol) was added to hydrochloric acid solution (20 ml, 80.00 mmol) (4mol / L in EtOH) at 0°C. The resulting mixture was stirred at 25 °C for 2 hours. The reaction mixture was diluted with DCM (30 mL) and removed under reduced pressure to give crude Intermediate Compound 115. The crude Intermediate Compound 115 was added to the PNU-159682 carboxylic acid (CAS No.: 1204819-92-0; 1.1 g, 1.75 mmol), O-(7- Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluoro-phosphate (1.000 g, 2.63 mmol) and N,N-diisopropylethylamine (0.680 g, 5.26 mmol) in DMA (30 mL) at 0°C under nitrogen. The resulting mixture was stirred at 25 °C for 3 hours. The reaction mixture was quenched with saturated NH4Cl 10mM in water (8mL). The crude product was purified by flash C18-flash chromatography and preparative HPLC elution gradient 0 to 80% MeCN in water to afford Compound LP3 (0.530 g, 20.36 %) as a red solid.1H NMR (400 MHz, DMSO) δ 1.20 (d, J = 6.4 Hz, 3H), 1.68 (br, 2H), 2.15 (d, J = 14.0 Hz, 1H), 2.25 – 2.37 (m, 2H), 2.60 – 2.73 (m, 1H), 2.92 – 3.06 (m, 2H), 3.10 – 3.19 (m, 2H), 3.31 (s, 4H), 3.46 – 3.54 (m, 26H), 3.55 – 3.64 (m, 8H), 3.65 – 3.75 (m, 6H), 3.80 (d, J = 5.8 Hz, 2H), 3.85 – 3.96 (m, 5H), 4.00 (s, 3H), 4.08 – 4.19 (m, 3H), 4.23 (d, J = 2.2 Hz, 1H), 4.41 – 4.54 (m, 2H), 4.58 (d, J = 2.2 Hz, 1H), 4.98 – 5.09 (m, 1H), 5.19 – 5.30 (m, 1H), 5.37 (s, 1H), 7.00 (s, 2H), 7.62 – 7.72 (m, 1H), 7.87 – 7.95 (m, 3H), 8.01 (t, J = 5.5 Hz, 1H), 8.05 – 8.16 (m, 3H), 8.23 (t, J = 57 Hz 1H) 1325 (s 1H) 1406 (s 1H) ES+(M+1 = 148595)Example 43: Synthesis of Compound LP4Step 1 - Intermediate Compound 111-A: tert-butyl ((3S,3aR,6S,6aR)-6-(1-(9H-fluoren-9-yl)- 3,6,9,12,15-pentaoxo-2-oxa-4,7,10,13,16-pentaazaoctadecan-18-amido)hexahydrofuro[3,2- b]furan-3-yl)carbamateIn a 250 mL round bottom flask, tert-butyl ((3S,3aR,6S,6aR)-6-aminohexahydrofuro[3,2-b]furan-3- yl)carbamate (2.301 g, 9.42 mmol) was added to (((9H-fluoren-9- yl)methoxy)carbonyl)glycylglycylglycylglycyl-glycine CAS No. : 132742-00-8 (3.3 g, 6.28 mmol), HATU (4.78 g, 12.56 mmol) and DIEA (3.29 mL, 18.84 mmol) in DMSO (20 mL) at 25°C under nitrogen. The resulting mixture was stirred at 25 °C for 2 hours The crude product was purified by flash C18-flash chromatography, elution gradient 0 to 100% MeCN in neutral water. Pure fractionswere evaporated to dryness to afford Intermediate Compound 111-A (4.10 g, 87 %) as a pale yellow solid. ES+(M+1) = 752.NMR (400 MHz, DMSO) δ 1.39 (d, J = 4.2 Hz, 9H), 3.55 – 3.61 (m, 2H), 3.63 – 3.88 (m, 15H), 4.08 (s, 1H), 4.19 – 4.33 (m, 3H), 7.24 (s, 1H), 7.34 (t, J = 7.4 Hz, 2H), 7.42 (t, J = 7.4 Hz, 2H), 7.59 (t, J = 6.1 Hz, 1H), 7.72 (d, J = 7.5 Hz, 2H), 7.90 (d, J = 7.6 Hz, 2H), 8.04 – 8.22 (m, 5H). Step 2 - Intermediate Compound 111: tert-butyl ((3S,3aR,6S,6aR)-6-(14-amino-4,7,10,13-tetraoxo- 3,6,9,12-tetraazatetradecanamido)hexahydrofuro[3,2-b]furan-3-yl)carbamateIn a 250 mL flask, diethylamine (3.89 g, 53.21 mmol) was added to Intermediate Compound 111-A (4g, 5.32 mmol) in THF (50 mL) / water (10 mL) at 25°C under nitrogen. The resulting mixture was stirred at 25 °C for 1 hour. The solvent was removed under reduced pressure. The dried solid was titurated with MTBE (2 x 100 mL) and filtered to afford crude Intermediate Compound 111 (2.300 g, 82 %) as a pare yellow solid.1H NMR (400 MHz, DMSO) δ 1.39 (d, J = 3.1 Hz, 9H), 3.50 – 3.63 (m, 3H), 3.64 – 3.94 (m, 14H), 4.07 (d, J = 6.8 Hz, 1H), 7.25 (d, J = 5.9 Hz, 1H), 8.05 – 8.12 (m, 2H), 8.21 (t, J = 5.8 Hz, 2H). ES+(M+1 = 530), HPLC purity: 92.9%. Step 3 - Intermediate Compound 116: tert-butyl ((3S,3aR,6S,6aR)-6-(1-(9H-fluoren-9-yl)- 3,30,33,36,39,42-hexaoxo-2,7,10,13,16,19,-22,25,28-nonaoxa-4,31,34,37,40,43- hexaazapentatetracontan-45-amido)hexahydrofuro-[3,2-b]furan-3-yl)carbamateIn a 250 mL round flask, Intermediate Compound 111 (1 g, 1.89 mmol) was added to 1-(9H-fluoren- 9-yl)-3-oxo-2,7,10,13,16,19,22,25,28-nonaoxa-4-azatriacontan-30-oic acid (1.227 g, 1.89 mmol), HATU (1.436 g, 3.78 mmol) and DIEA (0.989 mL, 5.67 mmol) in DMSO (15 mL) at 25°C under nitrogen. The resulting mixture was stirred at 25 °C for 3 hours. The crude product was purified by flash C18-flash chromatography, elution gradient 0 to 100% MeCN in water. Pure fractions were evaporated to dryness to afford Intermediate Compound 116 (1.200 g, 54.7 %) as a yellow solid.1H NMR (400 MHz, DMSO) δ 1.39 (s, 9H), 3.08 (q, J = 6.0 Hz, 2H), 3.39 (t, J = 6.1 Hz, 5H), 3.48 – 3.53 (m, 23H), 3.58 (d, J = 2.9 Hz, 2H), 3.60 – 3.64 (m, 3H), 3.68 – 3.87 (m, 14H), 3.94 (s, 2H), 4.08 (d, J =6.8 Hz, 1H), 4.34 – 4.45 (m, 2H), 7.30 – 7.46 (m, 4H), 7.81 – 7.96 (m, 5H), 8.05 – 8.16 (m, 2H), 8.16 – 8.25 (m, 3H). ES+( M+1 = 1161). Step 4 - Intermediate Compound 117: tert-butyl ((3S,3aR,6S,6aR)-6-(41-amino-4,7,10,13,16- pentaoxo-18,21,24,27,30,33,36,39-octaoxa-3,6,9,12,15- pentaazahentetracontanamido)hexahydrofuro[3,2-b]furan-3-yl)carbamateIn a 250 mL round flask, diethylamine (0.630 g, 8.61 mmol) was added to Intermediate Compound 116 (1 g, 0.86 mmol) in MeCN (10 mL) / water (10.00 mL) at 25°C under nitrogen. The resulting mixture was stirred at 25 °C for...

Claims

CLAIMS1. A compound of Formula (la):A-E-X-Y-Z or a pharmaceutically acceptable salt thereof, wherein A is:E is:(i) a bicyclic 7-10 membered saturated heterocycle containing two nitrogen atoms and optionally an oxygen atom, wherein one nitrogen atom in the heterocycle is connected to A and the second nitrogen atom in the heterocycle is connected to X;(ii) a monocyclic 5-8 membered saturated heterocycle containing two nitrogen atoms, wherein one nitrogen atom in the heterocycle is connected to A and the second nitrogen atom in the heterocycle is connected to X, optionally wherein the heterocycle is geminally substituted on a carbon atom with two occurrences of C1-3 alkyl; provided that when E is a piperazine, the piperazine is geminally substituted on a carbon atom with two occurrences of C1-3 alkyl;(iii) -NR-heterocycle- wherein the heterocycle is a saturated 5-8 membered heterocycle containing a nitrogen atom which is connected to X; and wherein a carbon atom in the heterocycle connects to -NR-; or(iv) -heterocycle-NR- or -heterocycle-C(O)NH- wherein the heterocycle is a saturated 5-8 membered heterocycle containing a nitrogen atom which is connected to A; and wherein a carbon atom in the heterocycle connects to -NR- or - C(O)NH-;R is H, C1-4 alkyl or C3-4 cycloalkyl;X is absent, -C(O)CH2O-*, -C(O)CH2NH-*, or -Xa-(CH2)m-Xb-, wherein Xbis connected to Y; Xais - C(O)- or absent; and Xbis -C(O)NH-*, -O- or -NH-, wherein * indicates the point of attachment to Y; m is 2 or 3;Y is absent or, wherein the wavy line indicates the point of attachment to X and the asterisk-wavy line indicates the point of attachment to Z; ya and yb are each independently selected from 0, 1, 2 and 3; and Q is NH, -N(C1-3alkyl)-, S, O, -S(CH2)2NH-*, - O(CH2)2NH-* or -NH(CH2)2NH-*, wherein * indicates the point of attachment to Z; Z is H, C1-4alkyl, -C(O)C1-4alkyl,integer from 1 to 5; and each Rzis independently H, C1-4 alkyl, phenyl or benzyl.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A is:.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein E is selected from:wherein ring Eais a bicyclic 7-10 membered saturated heterocycle having the two nitrogen atoms shown and optionally an oxygen atom, and ring Ebis a bicyclic 5-8 membered saturated heterocycle having the nitrogen atom shown; wherein the wavy line indicates the point of attachment to A and the asterisk-wavy line indicates the point of attachment to X.

4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein the bicyclic heterocycle is a bridged bicycle; optionally a 7-8 membered bridged bicycle.

5. The compound of claim 3 or 4, or a pharmaceutically acceptable salt thereof, wherein E is:

6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein E is selected from:wherein the wavy line indicates the point of attachment to A and the asterisk-wavy line indicates the point of attachment to X.

7. The compound of any of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R is H.

8. The compound of any of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein X is absent.

9. The compound of any of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein X is -Xa-(CH2)m-Xb-.

10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein m is 2 and / or wherein Xbis -NH- or -C(O)NH-*, wherein * indicates the point of attachment to Y.

11. The compound of any of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein X is selected from:wherein the wavy line indicates the point of attachment to E and the asterisk-wavy line indicates the point of attachment to Y.

12. The compound of any of claims 1 to 11, or a pharmaceutically acceptable salt thereof, whereinY is absent.

13. The compound of any of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein14. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein Y is15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein Y is16. The compound of any of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein Q is NH.

17. The compound of any of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein Z is H.

18. The compound of any of claims 1 to 16, or a pharmaceutically acceptable salt thereof, whereininteger from 1 to 5, and each Rzis independently H, Ci-4alkyl, phenyl or benzyl.

19. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein Rzis H.

20. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein Z is:wherein nl is 0, 1, 2, 3 or 4 and Rzis C1-4 alkyl, benzyl, or phenyl.

21. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from a compound of Table 1, or a pharmaceutically acceptable salt thereof.

22. A compound of Formula (Ila):A-EW-Z1or a pharmaceutically acceptable salt thereof, wherein A is:iv) -NR-; ii) a 5-10 membered saturated heterocycle containing two nitrogen atoms and optionally an oxygen atom, wherein one nitrogen atom in the heterocycle is connected to A and the second nitrogen atom in the heterocycle is connected to X1; optionally wherein the heterocycle is geminally substituted on a carbon atom with two occurrences of C1-3 alkyl; iv) -NR-heterocycle- wherein the heterocycle is a saturated 5-8 membered heterocycle containing a nitrogen atom which is connected to X1; and wherein a carbon atom in the heterocycle connects to -NR-; oriv) -heterocycle-NR- or -heterocycle-C(O)NH- wherein the heterocycle is a saturated 5-8 membered heterocycle containing a nitrogen atom which is connected to A; and wherein a carbon atom in the heterocycle connects to -NR- or -C(O)NH-;R is H, Ci-4 alkyl or C3-4 cycloalkyl;X1is absent, -C(O)CH2O-*, -C(O)CH2NH-*, or -Xa-(CH2)m-Xb-, wherein Xbis connected to Y1; Xais - C(O)- or absent; Xbis -C(O)NH-*, -O- or -NH-, wherein * indicates the point of attachment to Y1; m is 2 or 3;, wherein the wavy line indicates the point of attachment to X1and the asterisk-wavy line indicates the point of attachment to Z1; ya and yb are each independently selected from 0, 1, 2 and 3; and Q. is NH, -N(Ci-3alkyl)-, S, O, -S-fCHzhNH-*, -O- (CHzhNH-* or -NH-fCI-bhNH-*, wherein * indicates the point of attachment to Z1;Z1is H, C 1-4 alkyl, -C(O)Ci-4alkyl,integer from 1 to 5; and each Rzis independently H, C1-4 alkyl, phenyl or benzyl.

23. The compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein A is:

24. The compound of claim 22 or 23, or a pharmaceutically acceptable salt thereof, wherein E1is - NR-.

25. The compound of claim 22 or 23, or a pharmaceutically acceptable salt thereof, wherein E1is selected from:wherein ring Eais a bicyclic 7-10 membered saturated heterocycle having the two nitrogen atoms shown and optionally an oxygen atom, and ring Ebis a bicyclic 5-8 membered saturated heterocycle having the nitrogen atom shown; wherein the wavy line indicates the point of attachment to A and the asterisk-wavy line indicates the point of attachment to X1; optionally wherein E1is:

26. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein the bicyclic heterocycle is a bridged bicycle; optionally a 7-8 membered bridged bicycle.

27. The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein E1is selected from:wherein the wavy line indicates the point of attachment to A and the asterisk-wavy line indicates the point of attachment to X1.

28. The compound of any of claims 22 to 26, or a pharmaceutically acceptable salt thereof, wherein R is H.

29. The compound of any of claims 22 to 28, or a pharmaceutically acceptable salt thereof, wherein X1is absent.

30. The compound of any of claims 22 to 28, or a pharmaceutically acceptable salt thereof, wherein X1is -Xa-(CH2)m-Xb-.

31. The compound of claim 30, or a pharmaceutically acceptable salt thereof, wherein m is 2 and / or wherein Xbis -NH- or -C(O)NH-*, wherein * indicates the point of attachment to Y1.

32. The compound of any of claims 22 to 28, or a pharmaceutically acceptable salt thereof, wherein X1is selected from:wherein the wavy line indicates the point of attachment to E1and the asterisk-wavy line indicates the point of attachment to Y1.

33. The compound of any of claims 22 to 32, or a pharmaceutically acceptable salt thereof, wherein34. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein Y1is35. The compound of any of claims 22 to 34, or a pharmaceutically acceptable salt thereof, wherein Q. is NH.

36. The compound of any of claims 22 to 35, or a pharmaceutically acceptable salt thereof, wherein Z1is H.

37. The compound of any of claims 22 to 35, or a pharmaceutically acceptable salt thereof, whereininteger from 1 to 5, and each Rzis independently H, Ci-4alkyl, phenyl or benzyl.

38. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein Rzis H.

39. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein Z1is:wherein nl is 0, 1, 2, 3 or 4 and Rzis C1-4 alkyl, benzyl, or phenyl.

40. The compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from a compound of Table 2 or Table 2A, or a pharmaceutically acceptable salt thereof.

41. A compound of Formula (Illa):A-E-X-Y-L1or a salt thereof, wherein A, E and X are as defined in any of claims 1 to 11; andY is absent or, wherein the wavy line indicates the point of attachment toX and the asterisk-wavy line indicates the point of attachment to L1; ya and yb are each independently selected from 0, 1, 2 and 3; and Q. is NH, -N(Ci-3alkyl)-, S, O, -SfCHzhNH-*, - OfCHzhNH-* or -NH(CH2hNH-*, wherein * indicates the point of attachment to L1; and L1is a linker for connection to an antibody or antigen-binding fragment thereof.The compound of claim 41, or a salt thereof, wherein Y is absent.

43. The compound of claim 41, or a salt thereof, wherein Y is44. The compound of claim 41 or 43, or a salt thereof, wherein Q. is NH.

45. The compound of any of claims 41 to 44, or a salt thereof, wherein L1is:>wherein LAis absent or is selected from *-CH2-NH-, and *-C(O)-CH2-LA1-CH2-NH-, wherein LA1is O, S or NH, and * indicates the point of attachment to Y; each RZ1is independently H, C1-4 alkyl, phenyl or benzyl;q is 3, 4 or 5;LBis selected from -(CHz)b-,, wherein the asterisk-wavy line indicates the point of attachment to G1; b is an integer from 1 to 5; c is an integer from 5 to 15; d is an integer from 1 to 10; dl and cl are each independently 1 or 2; andG1is a conjugation group for conjugation to an antibody or antigen-binding fragment thereof.

46. The compound of any of claims 41 to 44, or a salt thereof, wherein L1is a group of Formula(L-IA):R1is Ci-4 alkyl,X2is (CHjjna, wherein n3 is 0, 1, 2 or 3,Y2is (CH2)n4, wherein n4 is 0, 1, 2, 3 or 4,Z2is (CHjjns or, wherein n5 is 1, 2, 3, 4 or 5, n5A is an integer from 1 to 10, n5B is 1 or 2, and the asterisk-wavy line indicates the point of attachment to G1, m2 is an integer from 5 to 17, p is 1 or 0,pl is 0 or 1, andG1is a conjugation group for conjugation to an antibody or antigen-binding fragment thereof.

47. The compound of any of claims 41 to 44, or a salt thereof, wherein L1is a group of Formula(L-lll):wherein E3is (CH2)n6, wherein n6 is 0, 1, 2 or 3,R1Ais Ci-4 alkyl or H,wherein n7 and n9 are 0, 1, 2 or 3, n8 is 1, 2 or 3, and Q3is O or NRA, wherein RAis H, Ci-4alkyl or C3-4 cycloalkyl, and wherein the asterisk-wavy line indicates the point of attachment to the (C=O) moiety;Y3is O or NRB, wherein RBis H, C1-4 alkyl or C3-4 cycloalkyl,Z3is (CH2)nio or, wherein nlO is 0, 1, 2, 3, 4 or 5, nlOA is an integer from 1 to 10, nlOB is 1 or 2, and the asterisk-wavy line indicates the point of attachment to G1, m3 is an integer from 2 to 17, p2 is 1 or 0, q2 is 1 or 0, p3 is 0 or 1, andG1is a conjugation group for conjugation to an antibody or antigen-binding fragment thereof.

48. A compound of Formula (IVa):A-EW-L1or a salt thereof, wherein A, E1and X1are as defined in any of claims 22 to 32;Y1is, wherein the wavy line indicates the point of attachment to X1and the asterisk-wavy line indicates the point of attachment to L1; ya and yb are each independently selected from 0, 1, 2 and 3; and Q is NH, -N(Ci.3alkyl)-, S, O, -S(CH2)2NH-*, -O(CH2)2NH-* or - NH(CH2)2NH-*, wherein * indicates the point of attachment to L1; and L1is a linker for connection to an antibody or antigen-binding fragment thereof.

49. The compound of claim 48, or a salt thereof, wherein Y1is50. The compound of claim 48 or 49, or a salt thereof, wherein Q. is NH.

51. The compound of any of claims 48 to 50, or a salt thereof, wherein L1is:CH2-NH-, wherein LA1is O, S or NH, and * indicates the point of attachment to Y1; each RZ1is independently H, Ci-4alkyl, phenyl or benzyl; q is 3, 4 or 5;LBis selected from -(CH2)b-,, wherein the asterisk-wavy line indicates the point of attachment to G1; b is an integer from 1 to 5; c is an integer from 5 to 15; d is an integer from 1 to 10; dl and cl are each independently 1 or 2; andG1is a conjugation group for conjugation to an antibody or antigen-binding fragment thereof.

52. The compound of any of claims 48 to 50, or a salt thereof, wherein L1is a group of Formula (L-IA):R1is Ci-4 alkyl,X2is (CH2)n3, wherein n3 is 0, 1, 2 or 3,Y2is (CH2)n4, wherein n4 is 0, 1, 2, 3 or 4,, wherein n5 is 1, 2, 3, 4 or 5, n5A is an integer from 1 to 10, n5B is1 or 2, and the asterisk-wavy line indicates the point of attachment to G1, m2 is an integer from 5 to 17, p is 1 or 0, pl is 0 or 1, andG1is a conjugation group for conjugation to an antibody or antigen-binding fragment thereof.

53. The compound of any of claims 48 to 50, or a salt thereof, wherein L1is a group of Formula(L-lll), wherein E3is (CH2)n6, wherein n6 is 0, 1, 2 or 3,R1Ais C1-4 alkyl or H,wherein n7 and n9 are 0, 1, 2 or 3, n8 is 1, 2 or 3, and Q3is O or NRA, wherein RAis H, C1-4 alkyl or C3-4 cycloalkyl, and wherein the asterisk-wavy line indicates the point of attachment to the (C=O) moiety;Y3is O or NRB, wherein RBis H, Ci-4alkyl or C3-4 cycloalkyl,Z3is (CH2)nio or;wherein nlO is 0, 1, 2, 3, 4 or 5, nlOA is an integer from 1 to 10, nlOB is 1 or 2, and the asterisk-wavy line indicates the point of attachment to G1, m3 is an integer from 2 to 17, p2 is l or O, q2 is 1 or 0, p3 is 0 or 1, andG1is a conjugation group for conjugation to an antibody or antigen-binding fragment thereof.

54. The compound of any of claims 41 to 44 and 48 to 50, or a salt thereof, wherein L1is selected from the moieties of Table 3 or Table 4.

55. The compound of any of claims 45 to 47 and 51 to 54, or a salt thereof, wherein G1is selected from:wherein X3is CH or N, h is 0 or 1, Hal is Cl, Br or I, RKis H or CH3, and RLis Ci.g alkyl.

56. The compound of claim 41, or a salt thereof, wherein the compound is selected from a compound of Table 5A, or a salt thereof.

57. The compound of claim 48, or a salt thereof, wherein the compound is selected from a compound of Table 5B or Table 5C, or a salt thereof.

58. A conjugate of Formula (Va): (A-E-X-Y-L2)k-Ab or a pharmaceutically acceptable salt thereof, wherein each A, E and X is as defined in any of claims 1 to 11,Y is absent or, wherein the wavy line indicates the point of attachment toX and the asterisk-wavy line indicates the point of attachment to L2; ya and yb are each independently selected from 0, 1, 2 and 3; and Q. is NH, -N(Ci-3alkyl)-, S, O, -S(CH2)?NH-*, - OfCHzhNH-* or -NHfCHzhNH-*, wherein * indicates the point of attachment to L2; each L2is a linker, k is an integer from 1 to 10, andAb is an antibody or antigen-binding fragment thereof.

59. The conjugate of claim 58, or a pharmaceutically acceptable salt thereof, wherein Y is absent.

60. The conjugate of claim 58, or a pharmaceutically acceptable salt thereof, wherein Y is61. The conjugate of claim 58 or 60, or a pharmaceutically acceptable salt thereof, wherein Q. is NH.

62. The conjugate of any of claims 58 to 61, or a pharmaceutically acceptable salt thereof, wherein L2is:, wherein LAis absent or is selected from *-CH2-NH-, and *-C(O)-CH2-LA1-CH2-NH-, wherein LA1is O, S or NH, and * indicates the point of attachment to Y; each RZ1is independently H, C1-4 alkyl, phenyl or benzyl; q is 3, 4 or 5;LBis selected from -(Cl-bjb-,, wherein the asterisk-wavy line indicates the point of attachment to G2; b is an integer from 1 to 5; c is an integer from 5 to 15; d is an integer from 1 to 10; dl and cl are each independently 1 or 2; andG2is a conjugation group conjugated to the antibody or antigen-binding fragment thereof, wherein s'* indicates the point of attachment to the antibody or antigen-binding fragment thereof.

63. The conjugate of any of claims 58 to 61, or a pharmaceutically acceptable salt thereof, wherein L2is a group of Formula (L-IIA):1 or 2, and the asterisk-wavy line indicates the point of attachment to G2, m2 is an integer from 5 to 17, p is 1 or 0, pl is 0 or 1, andG2is a conjugation group conjugated to the antibody or antigen-binding fragment thereof, wherein indicates the point of attachment to the antibody or antigen-binding fragment thereof.

64. The conjugate of any of claims 58 to 61, or a pharmaceutically acceptable salt thereof, wherein L2is a group of Formula (L-IV):(L-IV)wherein E3is (CH2)n6, wherein n6 is 0, 1, 2 or 3,R1Ais Ci-4 alkyl or H,wherein n7 and n9 are 0, 1, 2 or 3, n8 is 1, 2 or 3, and Q3is O or NRA, wherein RAis H, Ci-4alkyl or C3-4 cycloalkyl, and wherein the asterisk-wavy line indicates the point of attachment to the (C=O) moiety;Y3is O or NRB, wherein RBis H, C1-4 alkyl or C3-4 cycloalkyl,Z3is (CH2)nio or;wherein nlO is 0, 1, 2, 3, 4 or 5, nlOA is an integer from 1 to 10, nlOB is 1 or 2, and the asterisk-wavy line indicates the point of attachment to G2, m3 is an integer from 2 to 17, p2 is 1 or 0, q2 is 1 or 0, p3 is 0 or 1, andG2is a conjugation group conjugated to the antibody or antigen-binding fragment thereof, wherein indicates the point of attachment to the antibody or antigen-binding fragment thereof.A conjugate of Formula (Via)(A-E1-X1-Y1-L2)k-Ab or a pharmaceutically acceptable salt thereof, wherein each A, E1and X1is as defined in any of claims 22 to 32,Y1is, wherein the wavy line indicates the point of attachment to X1and the asterisk-wavy line indicates the point of attachment to L2; ya and yb are each independentlyselected from 0, 1, 2 and 3; and Q is NH, -N(C1-3alkyl)-, S, O, -S(CH2)2NH-*, -O(CH2)2NH-* or - NH(CH2)2NH-*, wherein * indicates the point of attachment to L2; each L2is a linker, k is an integer from 1 to 10, and Ab is an antibody or antigen-binding fragment thereof.

66. The conjugate of claim 65, or a pharmaceutically acceptable salt thereof, wherein Y1is.

67. The conjugate of claim 65 or 66, or a pharmaceutically acceptable salt thereof, wherein Q is NH.

68. The conjugate of any of claims 65 to 67, or a pharmaceutically acceptable salt thereof, wherein L2is:, wherein LAis absent or is selected from *-CH2-NH-, and *-C(O)-CH2-LA1- CH2-NH-, wherein LA1is O, S or NH, and * indicates the point of attachment to Y1; each Rz1is independently H, C1-4 alkyl, phenyl or benzyl; q is 3, 4 or 5; LBis selected from –(CH2)b-,, wherein the asterisk-wavy line indicates the point of attachment to G2; b is an integer from 1 to 5; c is an integer from 5 to 15; d is an integer from 1 to 10; d1 and c1 are each independently 1 or 2; and G2is a conjugation group conjugated to the antibody or antigen-binding fragment thereof, wherein indicates the point of attachment to the antibody or antigen-binding fragment thereof.

69. The conjugate of any of claims 65 to 67, or a pharmaceutically acceptable salt thereof, wherein L2is a group of Formula (L-IIA):R1is C1-4alkyl, X2is (CH2)n3, wherein n3 is 0, 1, 2 or 3, Y2is (CH2)n4, wherein n4 is 0, 1, 2, 3 or 4,wherein n5 is 1, 2, 3, 4 or 5, n5A is an integer from 1 to 10, n5B is 1 or 2, and the asterisk-wavy line indicates the point of attachment to G2, m2 is an integer from 5 to 17, p is 1 or 0, p1 is 0 or 1, and G2is a conjugation group conjugated to the antibody or antigen-binding fragment thereof, wherein indicates the point of attachment to the antibody or antigen-binding fragment thereof.

70. The conjugate of any of claims 65 to 67, or a pharmaceutically acceptable salt thereof, wherein L2is a group of Formula (L-IV):, ,, wherein n7 and n9 are 0, 1, 2 or 3, n8 is 1, 2 or 3, and Q3is O or NRA, wherein RAis H, C1-4alkyl or C3-4cycloalkyl, and wherein the asterisk-wavy line indicates the point of attachment to the (C=O) moiety; Y3is O or NRB, wherein RBis H, C1-4 alkyl or C3-4 cycloalkyl, Z3is (CH2)n10or, wherein n10 is 0, 1, 2, 3, 4 or 5, n10A is an integer from 1 to 10, n10B is 1 or 2, and the asterisk-wavy line indicates the point of attachment to G2, m3 is an integer from 2 to 17, p2 is 1 or 0, q2 is 1 or 0, p3 is 0 or 1, and G2is a conjugation group conjugated to the antibody or antigen-binding fragment thereof, wherein indicates the point of attachment to the antibody or antigen-binding fragment thereof.

71. The conjugate of any of any of claims 58 to 61 or 65 to 67, or a pharmaceutically acceptable salt thereof, wherein L2is selected from a moiety of Table 6 or Table 7.

72. The conjugate of any of claims 62 to 64 and 68 to 71, or a pharmaceutically acceptable salt thereof, wherein G2is selected from:wherein RKis H or CH3, RLis C1-6 alkyl, andindicates the point of attachment to the antibody or antigen-binding fragment thereof.

73. The conjugate of claim 58, or a pharmaceutically acceptable salt thereof, which is selected from a conjugate of Table 8A, or a pharmaceutically acceptable salt thereof.

74. The conjugate of claim 65, or a pharmaceutically acceptable salt thereof, which is selected from a conjugate of Table 8B or Table 8C, or a pharmaceutically acceptable salt thereof.

75. A pharmaceutical composition comprising a compound according to any of claims 1 to 40 or a conjugate of any of claims 58 to 74, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

76. A compound according to any of claims 1 to 40 or a conjugate according to any of claims 58 to 74, or a pharmaceutically acceptable salt thereof, for use in therapy.

77. A compound according to any of claims 1 to 40 or a conjugate according to any of claims 58 to 74, or a pharmaceutically acceptable salt thereof for use in treating cancer.

78. Use of a compound according to any of claims 1 to 40 or a conjugate according to any of claims 58 to 74, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer. 5 79. A method of treating cancer in a patient comprising administering to the patient a compound according to any of claims 1 to 40 or a conjugate according to any of claims 58 to 74, or a pharmaceutically acceptable salt thereof. 10 80. A pharmaceutical composition according to claim 75 for use in therapy.

81. A pharmaceutical composition according to claim 75 for use in treating cancer.

82. A method of treating cancer in a patient comprising administering to the patient a composition according to claim 75, or a pharmaceutically acceptable salt thereof.

Images