Antibody-drug conjugates with dual PI3k / mtor inhibitors and uses thereof

Abstract

The present disclosure provides antibody-drug conjugates having a targeting antibody (Ab) conjugated to one or more compounds having the structure Y — Z, wherein Y is a linker, and Z is the dual PI3K / mTOR inhibitor Omipalisib (GSK2126458), or a derivative or analog thereof. The antibody-drug conjugates disclosed herein are useful for treating cancer and other diseases and conditions.

Description

ANTIBODY-DRUG CONJUGATES WITH DUAL PI3K / mTOR INHIBITORS ANDUSES THEREOFFIELD OF THE INVENTION

[0001] The present disclosure relates in general to the field of antibody-drug-conjugates. In one embodiment, the present disclosure provides compounds and antibody-drug conjugates carrying dual PI3K / mTOR inhibitors and uses thereof.BACKGROUND OF THE INVENTION

[0002] The phosphatidylinositol 3-kinase (PI3K) / protein kinase B (AKT) / mammalian target of rapamycin (mTOR) pathway is among the most common intracellular signaling pathways that are often abnormally activated in many human cancers and participate in different biological effects, such as cell cycle progression and cell proliferation. Activation of the PI3K / Akt / mTOR pathway mediated by molecular aberrations plays a crucial role in promoting tumor development and resistance to anticancer therapies. Therefore, this pathway is widely exploited in cancer treatment.

[0003] Initial stimulation by one of the growth factors causes activation of a cell surface receptor and phosphorylation of PI3K. Activated PI3K then phosphorylates lipids on the plasma membrane, forming second messenger phosphatidylinositol (3,4,5)-trisphosphate (PIP3). Akt, a serine / threonine kinase, is recruited to the membrane by interaction with these phosphoinositide docking sites, so that it can be fully activated. Activated Akt mediates downstream responses, including cell survival, growth, proliferation, cell migration and angiogenesis, by phosphorylating a range of intracellular proteins. The pathway is present in all cells of higher eukaryotes and is highly conserved.

[0004] PI3Ks are enzymes with unique substrate specificity, expression modes, and regulation modes. These enzymes play central roles in regulating cell metabolism, proliferation, and survival. PI3Ks are divided into several classes: class I PI3Ks comprise one regulatory subunit (p85, plOl, or p87) and four catalytic subunits: p110α, p110β, p110δ, and p110γ.

[0005] mTOR is a cytoplasmic serine / threonine kinase and a member of the PI3K-related kinase family. mTOR is a key regulator of cell metabolism, growth and survival and can respond to carcinogenic factors. The mTOR protein is at the center of the PI3K-Akt-mTOR cascade. Two different mTOR complexes have been identified: mTOR complex 1 (mTORCl) and mTOR complex 2 (mTORC2). The former regulates processes such as protein biosynthesis, while thelatter fully activates Akt kinase by phosphorylating it at Serine 473 (S473). A vital target for cancer therapy, mTOR activation occurs often in human tumors.

[0006] Dual PI3K / mTOR inhibitors show potent activity on all pl 10 isoforms and mTOR, combining multiple therapeutic effects in a single molecule. Compared with other types of PI3K pathway inhibitors, PI3K / mTOR dual inhibitors target all catalytic forms of PI3K, as well as of mTORCl and mT0RC2, and can effectively overcome the feedback inhibition observed when mTORCl inhibitors are used alone. PI3K / mTOR dual inhibitors are far more effective than those targeting only a single protein.

[0007] Antibody-drug-conjugates (ADCs) are drugs designed as a targeted therapy for treating disease. Currently, they are widely used for the management or treatment of cancer. They are complex molecules comprising an antibody linked to a biologically active cytotoxic payload or drug. Chemotherapy is a therapeutic option for cancer treatment. However, chemotherapy with its poor specificity towards tumor cells / tissues is often associated with a poor therapeutic response and substantial toxicities to normal healthy tissues. Unlike chemotherapy, antibody-drug conjugates can target and kill tumor cells without harming the healthy cells. Although ADCs are widely used to manage or cure cancer, attempts are being made to expand their use to different diseases such as atherosclerosis, bacteremia, and inflammatory diseases.

[0008] There is a need to develop improved methods of delivering dual PI3K / mTOR inhibitors to target cells using antibody-drug-conjugate technology.SUMMARY OF THE INVENTION

[0009] In one aspect, the present disclosure provides antibody-drug conjugates having a targeting antibody (Ab) conjugated to one or more compounds having the structure Y — Z, wherein Y is a linker, and Z is a dual PI3K / mTOR inhibitor, or a derivative or analog thereof. In one embodiment, the dual PI3K / mTOR inhibitor is Omipalisib (GSK2126458), or a derivative or analog thereof.

[0010] In another aspect, the present disclosure provides pharmaceutical compositions comprising an antibody-drug conjugate disclosed herein and a pharmaceutically acceptable carrier.

[0011] In another embodiment, the present disclosure provides a method of treating a disease condition in a subject in need thereof, the method comprises administering to the subject a composition comprising the antibody-drug conjugates disclosed herein. In one embodiment, the disease condition is cancer.

[0012] In one aspect, the present disclosure provides compounds having the structure Y — Z, wherein Y is a linker, and Z is a dual PI3K / mTOR inhibitor, or a derivative or analog thereof. In one embodiment, the dual PI3K / mTOR inhibitor is Omipalisib (GSK2126458), or a derivative or analog thereof.

[0013] In some embodiments of the antibody-drug conjugates and compounds provided herein, linker Y comprises an oligopeptide. In some embodiments, the oligopeptide is a dipeptide, tripeptide, or a tetrapeptide. In some embodiments, the oligopeptide is a dipeptide, e.g., Vai- Ala or Val-citrulline. In some embodiments, the oligopeptide is a tetrapeptide, e.g., Gly-Gly-Phe-Gly.

[0014] In some embodiments of the antibody-drug conjugates and compounds provided herein, Y — Z has a structure selected from Formula I thru Formula VII as follows:wherein: n is an integer from 1 to 12;R is an amino acid side chain;R1is selected from the group consisting of: H, (CH2)2N(CH3)2, (CH2)2O(CH2)2O(CH2)2OCH3, (CH2)2O(CH2)2O(CH2)2CO2H, (CH2)2O(CH2)2O(CH2)2SO3H, (CH2)2O(CH2)2O(CH2)2NH2,(CH2)2O(CH2)2O(CH2)2N(CH3)2, (CH2)2O(CH2)2O(CH2)2CONH2,(CH2)2O(CH2)2OCH(OH)CH2CO2H, and (CH2)2O(CH2)2O(CH2)2SO2CH3;R2is selected from the group consisting of: H, -C1-6alkyl, alkoxy,O(CH2)2O(CH2)2O(CH2)2CO2H, O(CH2)2O(CH2)2OCH3, O(CH2)2O(CH2)2NH2,O(CH2)2O(CH2)2NH(CH3)2, O(CH2)2O(CH2)2SO3H, O(CH2)2O(CH2)2CO2H,O(CH2)2O(CH2)2CONH2, O(CH2)2O(CH2)2SO2CH3,O(CH2)2O(CH2)2OCH2CH(OH)CH2OH, CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2OCH3,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2CO2H,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2SO2CH3, CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2N(CH3)2,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2NHCH3CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2NH2,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2SO3H, CH2N(CH3)CO(CH2)2CO2H,CH2N(CH3)CO(CH2)2NH2, and CH2N(CH3)CO(CH2)2NHCH3; andR3is selected from the group consisting of: glucamine, -NH((CH2)2O)3(CH2)2OCH3,NH(CH2)2O(CH2)2OCH2CH(OH)CH2OH, N(CH3)(CH2)2O(CH2)2OCH2CH(OH)CH2OH, NH(CH2)2O(CH2)2OCH2CH(OH)CH2OH, NHCH2CH(OH)CH2OH,NHCH2CH(OH)CH(OH)CH2OH, N(CH3)CH2CH(OH)CH2OH,N(CH3)CH2CH(OH)CH(OH)CH2OH, NH(CH2)2O(CH2)2OCH2CH(OH)CO2H,N(CH3)(CH2)2O(CH2)2OCH2CH(OH)CO2H, NH(CH2)2O(CH2)2OCH2CH(OH)CCO2H,NHCH2CH(OH)CO2H, NHCH2CH(OH)CH(OH)CO2H, N(CH3)CH2CH(OH)CO2H, andN(CH3)CH2CH(OH)CH(OH)CO2H.

[0015] In some embodiments of the antibody-drug conjugates and compounds provided herein,¥ — Z has a structure selected from Formula XI thru Formula XVII as follows:wherein: n is an integer from 1 to 12;(CH2)2O(CH2)2O(CH2)2N(CH3)2, (CH2)2O(CH2)2O(CH2)2CONH2,(CH2)2O(CH2)2OCH(OH)CH2CO2H, and (CH2)2O(CH2)2O(CH2)2SO2CH3;R2is selected from the group consisting of: H, -C1-6alkyl, alkoxy,O(CH2)2O(CH2)2O(CH2)2CO2H, O(CH2)2O(CH2)2OCH3, O(CH2)2O(CH2)2NH2,O(CH2)2O(CH2)2NH(CH3)2, O(CH2)2O(CH2)2SO3H, O(CH2)2O(CH2)2CO2H,O(CH2)2O(CH2)2CONH2, O(CH2)2O(CH2)2SO2CH3,O(CH2)2O(CH2)2OCH2CH(OH)CH2OH, CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2OCH3,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2CO2H,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2SO2CH3,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2N(CH3)2,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2NHCH3, CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2NH2, CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2SO3H, CH2N(CH3)CO(CH2)2CO2H, CH2N(CH3)CO(CH2)2NH2, and CH2N(CH3)CO(CH2)2NHCH3; andR3is selected from the group consisting of: glucamine, -NH((CH2)2O)3(CH2)2OCH3,NH(CH2)2O(CH2)2OCH2CH(OH)CH2OH, N(CH3)(CH2)2O(CH2)2OCH2CH(OH)CH2OH,NH(CH2)2O(CH2)2OCH2CH(OH)CH2OH, NHCH2CH(OH)CH2OH,NHCH2CH(OH)CH(OH)CH2OH, N(CH3)CH2CH(OH)CH2OH,N(CH3)CH2CH(OH)CH(OH)CH2OH, NH(CH2)2O(CH2)2OCH2CH(OH)CO2H,N(CH3)(CH2)2O(CH2)2OCH2CH(OH)CO2H, NH(CH2)2O(CH2)2OCH2CH(OH)CCO2H,NHCH2CH(OH)CO2H, NHCH2CH(OH)CH(OH)CO2H, N(CH3)CH2CH(OH)CO2H,N(CH3)CH2CH(OH)CH(OH)CO2H.

[0016] These and other aspects of the invention will be appreciated from the ensuing descriptions of the figures and detailed description of the invention.BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Some embodiments of the invention are herein described, by way of example only, with reference to the accompanying drawings. With specific reference now to the drawings in detail, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of embodiments of the invention. In this regard, the description taken with the drawings makes apparent to those skilled in the art how embodiments of the invention may be practiced.

[0018] Figures 1A-1D show general synthetic schemes for antibody-drug conjugates disclosed herein.

[0019] Figure 2 shows a synthetic scheme for Mal-Peg(l)-Val-Ala-PAB-Omipalisib (Coromip- 1).

[0020] Figure 3 shows the LC-MS traces of Mal-Peg(l)-Val-Ala-PAB-Omipalisib.

[0021] Figure 4 shows the H-NMR traces of Mal-Peg(l)-Val-Ala-PAB-Omipalisib.

[0022] Figure 5 shows the F-NMR traces of Mal-Peg(l)-Val-Ala-PAB-Omipalisib.

[0023] Figure 6 shows a synthetic scheme for Mal-Peg(3)-Val-Ala-PAB-Omipalisib (Coromip- 2).

[0024] Figure 7 shows the LC-MS traces of Mal-Peg(3)-Val-Ala-PAB-Omipalisib.

[0025] Figure 8 shows the H-NMR traces of Mal-Peg(3)-Val-Ala-PAB-Omipalisib.

[0026] Figure 9 shows the F-NMR traces of Mal-Peg(3)-Val-Ala-PAB-Omipalisib.

[0027] Figure 10 shows a synthetic scheme for Mal-Peg(l)-Val-Ala-PABC-Omipalisib (Coromip-3).

[0028] Figure 11 shows the LC-MS traces of Mal-Peg(l)-Val-Ala-PABC-Omipalisib.

[0029] Figure 12 shows the H-NMR traces of Mal-Peg(l)-Val-Ala-PABC-Omipalisib.

[0030] Figure 13 shows the F-NMR traces of Mal-Peg(l)-Val-Ala-PABC-Omipalisib.

[0031] Figure 14 shows a synthetic scheme for Mal-Peg(l)-Val-Cit-PAB-Omipalisib (Coromip- 4).

[0032] Figure 15 shows the LC-MS traces of Mal-Peg(l)-Val-Cit-PAB-Omipalisib.

[0033] Figure 16 shows the H-NMR traces of Mal-Peg(l)-Val-Cit-PAB-Omipalisib.

[0034] Figure 17 shows the F-NMR traces of Mal-Peg(l)-Val-Cit-PAB-Omipalisib.

[0035] Figure 18 shows a synthetic scheme for Mal-Peg(l)-Val-Cit-PABC-Omipalisib (Coromip-5).

[0036] Figure 19 shows the LC-MS traces of Mal-Peg(l)-Val-Cit-PABC-Omipalisib.

[0037] Figure 20 shows the H-NMR traces of Mal-Peg(l)-Val-Cit-PABC-Omipalisib.

[0038] Figure 21 shows the F-NMR traces of Mal-Peg(l)-Val-Cit-PABC-Omipalisib.

[0039] Figure 22 shows the effects of Omipalisib and Trastuzumab are synergistic.

[0040] Figure 23 shows the pH stability data of antibody-drug conjugates disclosed herein. The working solutions of test compounds and control compound chlorambucil were prepared in DMSO at the concentrations of 500 pM to test the stability in Buffer PBS pH 5 and pH 7. Samples are analyzed at the indicated timepoints by LC-MS / MS to assess the percentage of remaining intact compound.

[0041] Figures 24A-24B shows plasma stability (Figure 24A) and cathepsin-mediated payload release (Figure 24B) of various N-Acetylated (NAC) Linker-Payloads. Cl denotes Coromip-1; C3 denotes Coromip-3; C4 denotes Coromip-4; C5 denotes Coromip-5 and vcMMAE denotes mc-vc-PAB-MMAE.

[0042] Figure 25 shows the stability and cathepsin-mediated cleavage and cathepsin-mediated payload release kinetics of Mal-Peg(l)-Val-Cit-PABC-Peg(3)-M-Omipalisib (Coromip-81).

[0043] Figures 26A-26B: Figure 26A shows a scheme for the conjugation of Trastuzumab- Coromip-81. Figure 26B shows the MS trace and table of peaks for the Trastuzumab-Coromip- 81 with a drug-to-antibody ratio (DAR) of 7.3.

[0044] Figure 27 shows the determination of aggregate content by analytical size-exclusion chromatography (SEC) for the Trastuzumab-Coromip-81 ADC.

[0045] Figure 28 shows a synthetic scheme for Mal-Peg(l)-Val-Cit-PABC-Peg(3)-M-Omipalisib (Coromip-81).

[0046] Figure 29 shows the H-NMR traces of Intermediate 2 from the synthetic scheme depicted in Figure 28.

[0047] Figure 30 shows the MS traces of Intermediate 2 from the synthetic scheme depicted in Figure 28.

[0048] Figure 31 shows the F-NMR traces of Intermediate 4 from the synthetic scheme depicted in Figure 28.

[0049] Figure 32 shows the H-NMR traces of Intermediate 4 from the synthetic scheme depicted in Figure 28.

[0050] Figure 33 shows the MS traces of Intermediate 6 from the synthetic scheme depicted in Figure 28.

[0051] Figure 34 shows the MS traces of Intermediate 8 from the synthetic scheme depicted in Figure 28.

[0052] Figure 35 shows the H-NMR traces of Mal-Peg(l)-Val-Cit-PABC-Peg(3)-M-Omipalisib (Coromip-81).

[0053] Figure 36 shows the F-NMR traces of Mal-Peg(l)-Val-Cit-PABC-Peg(3)-M-Omipalisib.

[0054] Figure 37 shows the MS traces of Mal-Peg(l)-Val-Cit-PABC-Peg(3)-M-Omipalisib.

[0055] Figure 38 shows the HPLC traces of Mal-Peg(l)-Val-Cit-PABC-Peg(3)-M-Omipalisib.

[0056] Figure 39 shows a synthetic scheme for Mal-Peg(l)-Val-Cit-PABC-DMEA-M-Omipalisib (Coromip-67).

[0057] Figure 40 shows the F-NMR of Intermediate 5 from the synthetic scheme depicted in Figure 39.

[0058] Figure 41 shows the H-NMR of Intermediate 5 from the synthetic scheme depicted in Figure 39.

[0059] Figure 42 shows the MS of Intermediate 7 from the synthetic scheme depicted in Figure 39.

[0060] Figure 43 shows the MS of Intermediate 9 from the synthetic scheme depicted in Figure 39.

[0061] Figure 44 shows the F-NMR traces of Mal-Peg(l)-Val-Cit-PABC-DMEA-M-Omipalisib (Coromip-67).

[0062] Figure 45 shows the H-NMR traces ofMal-Peg(l)-Val-Cit-PABC-DMEA-M-Omipalisib.

[0063] Figure 46 shows the MS traces of Mal-Peg(l)-Val-Cit-PABC-DMEA-M-Omipalisib.

[0064] Figure 47 shows the HPLC traces of Mal-Peg(l)-Val-Cit-PABC-DMEA-M-Omipalisib.

[0065] Figure 48 shows a synthetic scheme for Mal-Peg(l)-Val-Cit-PABC-Methyl-Omipalisib (Coromip-68).

[0066] Figure 49 shows the LC-MS traces of Intermediate 5 from the synthetic scheme depicted in Figure 48.

[0067] Figure 50 shows the LC-MS traces of Intermediate 9 from the synthetic scheme depicted in Figure 48.

[0068] Figure 51 shows the LC-MS traces of Intermediate 10 from the synthetic scheme depicted in Figure 48.

[0069] Figure 52 shows the H-NMR traces of Mal-Peg(l)-Val-Cit-PABC-Methyl-Omipalisib (Coromip-68).

[0070] Figure 53 shows the F-NMR traces of Mal-Peg(l)-Val-Cit-PABC-Methyl-Omipalisib.

[0071] Figure 54 shows the LC-MS traces of Mal-Peg(l)-Val-Cit-PABC-Methyl-Omipalisib.DETAILED DESCRIPTION OF THE INVENTION

[0072] In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the invention. However, it will be understood by those skilled in the art that the present invention may be practiced without these specific details. In otherinstances, well-known methods, procedures, and components have not been described in detail so as not to obscure the present invention.

[0073] In order for the present disclosure to be more readily understood, certain terms and phrases are defined below and throughout the specification.

[0074] As used herein, the singular form “a”, “an” and “the” include plural references unless the context clearly dictates otherwise. For example, the term “an enzyme” or “at least one enzyme” may include a plurality of enzymes, including mixtures thereof.

[0075] The phrase “and / or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and / or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and / or” clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and / or B”, when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

[0076] As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and / or B”) can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet anotherembodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

[0077] It should also be understood that, unless clearly indicated to the contrary, in any methods claimed herein that includes more than one step or act, the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of the method are recited.

[0078] In the claims, as well as in the specification, all transitional phrases such as “comprising,” “including," “carrying,” “having,” “containing," “involving,” “holding,” “composed of,” or the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases “consisting of’ and “consisting essentially of’ shall be closed or semi-closed transitional phrases, respectively, as set forth in the M.P.E.P. § 2111.03. The open-end phrases such as “comprising” include and encompass the close-ended phrases. Comprising may be amended to the more limiting phrases “consisting essentially of’ of “consisting of’ as needed.

[0079] The definition of each expression, e.g., alkyl, Y, Z, or the like, when it occurs more than once in a structure, is intended to be independent of its definition elsewhere in the same structure.

[0080] It will be understood that “substitution" or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.

[0081] The term “substituted” means that any one or more hydrogens on the designated atom or group is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded. When the substituent by a group that is bound by a double bond, e.g. oxo (i.e., =O), then 2 hydrogens on the atom are replaced. When aromatic moieties are substituted by an oxo group, the aromatic ring is replaced by the corresponding partially unsaturated ring. For example, a pyridyl group substituted by oxo is a pyridone. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure is meant to imply a compound that is sufficiently robust to survive isolation from a reaction mixture, and subsequent formulation into an effective therapeutic agent.

[0082] A dash that is not between two letters or symbols is used to indicate a point of attachment for a substituent.

[0083] The term “saturated,” as used herein, pertains to compounds and / or groups which do not have any carbon-carbon double bonds or carbon-carbon triple bonds.

[0084] The term “unsaturated,” as used herein, pertains to compounds and / or groups which have at least one carbon-carbon double bond or carbon-carbon triple bond.

[0085] Compounds provided herein include compounds having isotopic substitutions at any position. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example, and without limitation, hydrogen isotopes include tritium and deuterium and carbon isotopes include11C,13C, and14C. Compounds provided herein also include deuteration enrichment (substitution of a hydrogen atom with deuterium) at identified positions.

[0086] The term “alkyl” means a branched or unbranched aliphatic radical containing the indicated number of carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 2-methylcyclopentyl, and 1 -cyclohexylethyl. When — C0-Cnalkyl is used in conjunction with another substituent, such as C3-C6cycloalkyl(C0-C2alkyl)- the other substituent group is bound to the group it substitutes by a single bond (C ) or by an alkylene linker having the indicated number of carbon atoms.

[0087] An “alkylene” group is a bivalent saturated alkyl radical having the indicated number of carbon atoms.

[0088] The term “alkoxy” as used herein means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.

[0089] The term “aromatic” refers to a planar or polycyclic structure characterized by a cyclically conjugated molecular moiety containing 4n+2 electrons, wherein n is the absolute value of an integer. Aromatic molecules containing fused, or joined, rings also are referred to as bicyclic aromatic rings. For example, bicyclic aromatic rings containing heteroatoms in a hydrocarbon ring structure are referred to as bicyclic heteroaryl rings.

[0090] The term “aryl,” as used herein means a cyclic hydrocarbon that is aromatic and contains only carbon ring atoms. Examples include phenyl, naphthyl, biphenyl, and anthracenyl groups. The aryl groups of this disclosure can be optionally substituted with 1, 2, 3, 4 or 5 substituents.

[0091] The term “cyano” as used herein means a — C=N group.

[0092] “Cyclolalkyl” is a saturated carbocyclic ring having the indicated number of carbon ring atoms, for example C3-C6cycloalkyl is a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group.

[0093] “Cycloalkenyl” is an unsaturated, but not aromatic, carbocyclic ring having the indicated number of carbon ring atoms, and at least on carbon-carbon double bond in the carbocyclic ring. Examples of C3-C6cycloalkenyl groups include is a cyclopropenyl, cyclobutenyl, and cyclohexenyl groups.

[0094] The term “hydrocarbon” as used herein refers to an organic compound consisting entirely of hydrogen and carbon.

[0095] The term “halo” or “halogen” means — Cl, — Br, — I or — F.

[0096] The term “heteroatom” as used herein is art-recognized and refers to an atom of any element other than carbon or hydrogen. Illustrative heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur and selenium.

[0097] “Heteroaryl” is a stable monocyclic aromatic ring having the indicated number of ring atoms which contains from 1 to 3, or, in some embodiments, from 1 to 2, heteroatoms chosen from N, O, and S, with remaining ring atoms being carbon, or a stable bicyclic or tricyclic system containing at least one 5- to 7-membered aromatic ring which contains from 1 to 3, or, in some embodiments, from 1 to 2, heteroatoms chosen from N, O, and S, with remaining ring atoms being carbon. Monocyclic heteroaryl groups typically have from 5 to 7 ring atoms. In some embodiments, bicyclic heteroaryl groups are 9- to 10-membered heteroaryl groups, that is, groups containing 9 or 10 ring atoms in which one 5- to 7-member aromatic ring is fused to a second aromatic or non-aromatic ring. When the total number of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heteroaiyl group is not more than 2. It is particularly preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1. Heteroaryl groups include, but are not limited to, oxazolyl, piperazinyl, pyranyl, pyrazinyl, pyrazolopyrimidinyl, pyrazolyl, pyridizinyl, pyridyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl, thiazolyl, thienylpyrazolyl, thiophenyl, triazolyl, benzo [djoxazolyl, benzofuranyl, benzothiazolyl, benzothiophenyl, benzoxadiazolyl, dihydrobenzodioxynyl, furanyl, imidazolyl, indolyl, and isoxazolyl.

[0098] The term “heterocycloalkyl,” means a saturated ring group usually having 4- to 7-ring atoms with 1 or 2 ring atoms independently chosen from N, O, and S: Examples of heterocycloalkyl groups includes azepines, azetidinyl, morpholinyl, thiomorpholinyl, pyranyl, oxopiperidinyl, oxopyrrolidinyl, piperazinyl, piperidinyl, pyrrolidinyl, quinicludinyl, thiomorpholinyl, tetrahydropyranyl and tetrahydrofuranyl.

[0099] The term “hydroxyl” as used herein means an — OH group.

[0100] The term “nitro” as used herein means a — NO2group.

[0101] As used herein, the term “administering” means providing a pharmaceutical agent or composition to a subject, and includes, but is not limited to, administering by a medical professional and self-administering.

[0102] “Carrier” means a diluent, excipient, or vehicle with which an active compound is administered. A “pharmaceutically acceptable carrier" means a substance, e.g., excipient, diluent, or vehicle, that is useful in preparing a pharmaceutical composition that is generally safe, nontoxic and neither biologically nor otherwise undesirable, and includes a carrier that is acceptable for veterinary use as well as human pharmaceutical use. A “pharmaceutically acceptable carrier” includes both one and more than one such carrier.

[0103] “Pharmaceutical compositions” means compositions comprising at least one active agent, such as the compounds provided herein, and at least one other substance, such as a carrier. Pharmaceutical compositions meet the U.S. FDA's GMP (good manufacturing practice) standards for human or non-human drugs.

[0104] “Pharmaceutically acceptable salts” include derivatives of the disclosed compounds in which the parent compound is modified by making inorganic and organic, non-toxic, acid or base addition salts thereof. The salts of the present compounds can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used, where practicable. Salts of the present compounds further include solvates and hydrates of the compounds and of the compound salts.

[0105] Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts and the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC — (CH2)n— COOH where n is 0-4, and the like. Lists of additional suitable salts may be found, e.g., in G. Steffen Paulekuhn, et al., Journal of Medicinal Chemistry 2007, 50, 6665 and Handbook of Pharmaceutically Acceptable Salts: Properties, Selection and Use, P. Heinrich Stahl and Camille G. Wermuth Editors. Wiley-VCH, 2002.

[0106] As used herein, the term “patient" or “subject" means a human or non-human animal, e.g. a companion animal such as a cat or dog, selected for treatment or therapy. In preferred embodiments, the subject is a human.

[0107] As used throughout this application, the term “pharmaceutically effective amount of a compound for pharmaceutical use" shall mean an amount of compound that exhibits the intended pharmaceutical or therapeutic or diagnostic effect when administered.

[0108] “Therapeutically effective amount” or “effective amount” refers to the amount of a compound that, when administered to a subject for treating or diagnosing or monitoring a disease, or at least one of the clinical symptoms of a disease or disorder, is sufficient to affect such treatment for the disease, disorder, or symptom. The “therapeutically effective amount” can vary depending on the compound, the disease, disorder, and / or symptoms of the disease or disorder, severity of the disease, disorder, and / or symptoms of the disease or disorder, the age of the subject to be treated, and / or the weight of the subject to be treated. An appropriate amount in any given instance can be readily apparent to those skilled in the art or capable of determination by routine experimentation.

[0109] In one aspect, the present disclosure provides antibody-drug conjugates having a targeting antibody (Ab) conjugated to one or more compounds having the structure Y — Z, wherein Y is a18linker, and Z is a dual PI3K / mTOR inhibitor, or a derivative or analog thereof. In one embodiment, the dual PI3K / mTOR inhibitor is Omipalisib (GSK2126458) with the structure below, or a derivative or analog thereof.Omipalisib

[0110] As used herein, a derivative or analog of Omipalisib refers to any closely related chemical compounds that inhibit pan PI3K isoforms and mTORl / mTOR2 proteins.

[0111] In one embodiment, the antibody-drug conjugates (ADCs) comprise antibodies engineered to utilize the capability of the antibodies (e.g., monoclonal antibodies) by combining them with cytotoxic agents. In one embodiment, an ADC comprises a monoclonal antibody (mAb) that targets a specific cancer antigen while not harming healthy cells, and a potent cytotoxic small molecular agent designed to induce target cell death after being internalized in the tumor cell and discharged. The ADC also comprises a linker stable in circulation which releases the medicinal preparation in neoplasms. The resulting ADC induces higher tumor selectivity while improving the tolerability of the drug. As opposed to standard chemotherapeutic biologies or drugs, the ADC has limited systemic exposure.

[0112] In one aspect, the present disclosure provides compounds having the structure Y — Z, wherein Y is a linker, and Z is a dual PI3K / mTOR inhibitor, or a derivative or analog thereof. In one embodiment, the dual PI3K / mTOR inhibitor is Omipalisib (GSK2126458), or a derivative or analog thereof.

[0113] In some embodiments of the antibody-drug conjugates and compounds provided herein, Y — Z has a structure selected from Formula I thru Formula VII as follows:Formula IIIFormula VF:O o o RFN N^NH HNH o=s=o“* n O O . / N^R2O' N IFormula VIFormula Vlli wherein: n is an integer from 1 to 12;R is an amino acid side chain;R1is selected from the group consisting of: H, (CH2)2N(CH3)2, (CH2)2O(CH2)2O(CH2)2OCH3, (CH2)2O(CH2)2O(CH2)2CO2H, (CH2)2O(CH2)2O(CH2)2SO3H, (CH2)2O(CH2)2O(CH2)2NH2,(CH2)2O(CH2)2O(CH2)2N(CH3)2, (CH2)2O(CH2)2O(CH2)2CONH2,(CH2)2O(CH2)2OCH(OH)CH2CO2H, and (CH2)2O(CH2)2O(CH2)2SO2CH3;R2is selected from the group consisting of: H, -C1-6alkyl, alkoxy,O(CH2)2O(CH2)2O(CH2)2CO2H, O(CH2)2O(CH2)2OCH3, O(CH2)2O(CH2)2NH2,O(CH2)2O(CH2)2NH(CH3)2, O(CH2)2O(CH2)2SO3H, O(CH2)2O(CH2)2CO2H,O(CH2)2O(CH2)2CONH2, O(CH2)2O(CH2)2SO2CH3,O(CH2)2O(CH2)2OCH2CH(OH)CH2OH, CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2OCH3,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2CO2H,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2SO2CH3,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2N(CH3)2,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2NHCH3CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2NH2,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2SO3H, CH2N(CH3)CO(CH2)2CO2H,CH2N(CH3)CO(CH2)2NH2, and CH2N(CH3)CO(CH2)2NHCH3; andR3is selected from the group consisting of: glucamine, -NH((CH2)2O)3(CH2)2OCH3,NH(CH2)2O(CH2)2OCH2CH(OH)CH2OH, N(CH3)(CH2)2O(CH2)2OCH2CH(OH)CH2OH,NH(CH2)2O(CH2)2OCH2CH(OH)CH2OH, NHCH2CH(OH)CH2OH,NHCH2CH(OH)CH(OH)CH2OH, N(CH3)CH2CH(OH)CH2OH,N(CH3)CH2CH(OH)CH(OH)CH2OH, NH(CH2)2O(CH2)2OCH2CH(OH)CO2H,N(CH3)(CH2)2O(CH2)2OCH2CH(OH)CO2H, NH(CH2)2O(CH2)2OCH2CH(OH)CCO2H,NHCH2CH(OH)CO2H, NHCH2CH(OH)CH(OH)CO2H, N(CH3)CH2CH(OH)CO2H, andN(CH3)CH2CH(OH)CH(OH)CO2H.

[0114] In some embodiments of the antibody-drug conjugates and compounds provided herein,¥ — Z has a structure selected from Formula XI thru Formula XVII as follows:Formula XIIQ QFormula XVR1is selected from the group consisting of: H, (CH2)2N(CH3)2, (CH2)2O(CH2)2O(CH2)2OCH3, (CH2)2O(CH2)2O(CH2)2CO2H, (CH2)2O(CH2)2O(CH2)2SO3H, (CH2)2O(CH2)2O(CH2)2NH2,(CH2)2O(CH2)2O(CH2)2N(CH3)2, (CH2)2O(CH2)2O(CH2)2CONH2,(CH2)2O(CH2)2OCH(OH)CH2CO2H, and (CH2)2O(CH2)2O(CH2)2SO2CH3;R2is selected from the group consisting of: H, -C1-6alkyl, alkoxy, O(CH2)2O(CH2)2O(CH2)2CO2H, O(CH2)2O(CH2)2OCH3, O(CH2)2O(CH2)2NH2, O(CH2)2O(CH2)2NH(CH3)2, O(CH2)2O(CH2)2SO3H, O(CH2)2O(CH2)2CO2H,O(CH2)2O(CH2)2CONH2, O(CH2)2O(CH2)2SO2CH3,O(CH2)2O(CH2)2OCH2CH(OH)CH2OH, CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2OCH3,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2CO2H,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2SO2CH3,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2N(CH3)2,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2NHCH3, CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2NH2, CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2SO3H, CH2N(CH3)CO(CH2)2CO2H, CH2N(CH3)CO(CH2)2NH2, and CH2N(CH3)CO(CH2)2NHCH3; andR3is selected from the group consisting of: glucamine, -NH((CH2)2O)3(CH2)2OCH3, NH(CH2)2O(CH2)2OCH2CH(OH)CH2OH, N(CH3)(CH2)2O(CH2)2OCH2CH(OH)CH2OH, NH(CH2)2O(CH2)2OCH2CH(OH)CH2OH, NHCH2CH(OH)CH2OH, NHCH2CH(OH)CH(OH)CH2OH, N(CH3)CH2CH(OH)CH2OH, N(CH3)CH2CH(OH)CH(OH)CH2OH, NH(CH2)2O(CH2)2OCH2CH(OH)CO2H, N(CH3)(CH2)2O(CH2)2OCH2CH(OH)CO2H, NH(CH2)2O(CH2)2OCH2CH(OH)CCO2H, NHCH2CH(OH)CO2H, NHCH2CH(OH)CH(OH)CO2H, N(CH3)CH2CH(OH)CO2H, N(CH3)CH2CH(OH)CH(OH)CO2H.

[0115] In some embodiments, n is an integer from one to three. In some embodiments, n is an integer from eight to twelve. In some embodiments, n is one. In some embodiments, n is two. In some embodiments, n is three. In some embodiments, n is four. In some embodiments, n is five.In some embodiments, n is six. In some embodiments, n is seven. In some embodiments, n is eight. In some embodiments, n is nine. In some embodiments, n is ten.

[0116] In some embodiments, R is the amino acid side chain of alanine, namely methyl. In some embodiments, R is the amino acid side chain of citrulline, namely CH2CH2CH2NHCONH2. In some embodiments, R2is hydrogen. In some embodiments, R2is methoxy, hi some embodiments, X is malemide. In some embodiments, X is NH2.

[0117] In one embodiment, the targeting antibody is the anti-HER2 receptor antibody Trastuzumab, or a derivative or analog thereof.

[0118] In another aspect, the present disclosure provides pharmaceutical compositions comprising an antibody-drug conjugate disclosed herein and a pharmaceutically acceptable carrier.

[0119] In another embodiment, the present disclosure provides a method of treating a disease condition in a subject in need thereof, the method comprises administering to the subject a composition comprising the antibody-drug conjugates disclosed herein. In one embodiment, the disease condition is cancer.

[0120] In some embodiments of the antibody-drug conjugates and compounds provided herein, wherein Y — Z is represented by Formula I and is a compound selected from:

[0121] In some embodiments of the antibody-drug conjugates and compounds provided herein, wherein Y — Z is represented by Formula II and is a compound selected from:(Coromip-3) and(Coromip-5).

[0122] In some embodiments of the antibody-drug conjugates and compounds provided herein, wherein Y — Z is represented by Formula HI and is a compound selected from:, o. / N"\\ 1 o‘o o I ,Coromip-106 N

[0123] In some embodiments of the antibody-drug conjugates and compounds provided herein, wherein Y — Z is represented by Formula IV and is:(Coromip 107).

[0124] In some embodiments of the antibody-drug conjugates and compounds provided herein, wherein Y — Z is represented by Formula V and is:Coromip-105 o I' HV.Dual PI3K / mT0R Inhibitors

[0125] Several dual PI3K / mTOR inhibitors are known in the art. In one embodiment, the present disclosure uses Omipalisib (GSK2126458) as an example. Omipalisib, also known as GSK2126458, is an investigational Akt inhibitor drug by Glaxo SmithKline, which dually targets direct phosphorylation of Akt by PI3Kinase and reverse phosphorylation of Akt by mTOR, thereby completely deactivating Akt. It is highly active against all PI3K isoforms and both mTOR complexes, and it is more potent than BEZ235 and GDC-0941. Its promising role as a potential therapeutic agent is shown in in vitro studies reflecting a variety of cancer types and idiopathic pulmonary fibrosis. Omipalisib has already passed human phase- 1 trials for idiopathic pulmonary fibrosis and solid tumors, documenting drug tolerance, dosing safety, clinical outcome, and drug combination effectiveness in human patients, making it a potential candidate to be tested in other diseases.

[0126] In certain embodiments, the dual PI3K / mTOR inhibitor of the present ADCs comprises a predetermined molar weight percentage from about 1% to about 10%, or about 10% to about 20%, or about 20% to about 30%, or about 30% to about 40%, or about 40% to about 50%, or about50% to about 60%, or about 60% to about 70%, or about 70% to about 80%, or about 80% to about 90%, or about 90% to about 99% such that the sum of the molar weight percentages of the components of the ADCs is 100%. The amount of dual PI3K / mTOR inhibitor of the present ADCs may also be expressed in terms of proportion to the targeting antibody. For example, the present disclosure provides a ratio of dual PI3K / mTOR inhibitor to targeting antibody of about 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4; 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10.Targeting Antibodies

[0127] In one embodiment, the targeting antibodies in the present ADCs are monoclonal antibodies. As is generally known in the art, a monoclonal antibody (mAb) is an antibody made by cloning a specific white blood cell or unique parent cell. Monoclonal antibodies possess monovalent affinity, binding only to a molecular region or part of an antigen (epitope or antigenic determinant) that is recognized by the antibody. In some embodiments, targeting antibodies in the present ADCs bind to the target protein Human Epidermal growth factor Receptor 2 (HER2), e.g., trastuzumab, or a derivative or analog thereof. As used herein, a derivative or analog of trastuzumab refers to any antibody (e.g. monoclonal) that binds to HER2.

[0128] In another embodiment, the targeting antibodies in the present ADCs are bispecific antibodies. In one embodiment, bispecific antibodies are bioengineered mAbs, increasing the therapeutic payload targets of one mAb to two epitopes. For example, bispecific antibodies are produced by combining a targeting forefront region of two different antibodies and recombining them to generate a product that can bind to a pair of contrasting targets. In another embodiment, the bispecific antibodies are BiTEs, which are antibodies that target both neoplasms and T cells or immune cells. These BiTEs operate by inducing T cells into close quarters with neoplasms to facilitate their eradication. Due to their ability to target immune cells directly, BiTEs are deemed active immunotherapy.

[0129] In another embodiment, examples of targeting antibodies in the present ADCs include, but are not limited to, antibodies that bind to target proteins such as HER2, CD180, CDH17, CD33, Trophoblast cell surface antigen 2 (TROP-2), CD19, NECTIN-4, c-MET, epithelial cell adhesion molecule (EpCAM), Prostate-Specific Membrane Antigen (PSMA), and Folate receptor alpha (FRa).

[0130] In another embodiment, examples of targeting antibodies in the present ADCs include, but are not limited to, antibodies that bind to target proteins such as Fibroblast Activation Protein(FAP), Integrin av06, asialoglycoprotein receptor 1 (ASGR1), CD13, Platelet-Derived Growth Factor Receptor beta (PDGFR-0), Cadherin-11, CD248, ANP-R, periostin, CD59, VEGFR2, ICAM-1, CD19, CD4, and CD38.

[0131] In another embodiment, targeting antibodies in the present ADCs bind to the target protein Cadherin 17 (CDH17), which may be used to treat cancers, including but not limited to, gastric cancer, pancreatic cancer, ovarian cancer, colon cancer, and colorectal cancer. Examples of anti- CDH17 antibodies that may be used in the present ADCs are described in PCT7US2025 / 032351 filed June 04, 2025, which is hereby incorporated by reference in its entirety.

[0132] In another embodiment, targeting antibodies in the present ADCs bind to the target protein CD33. Examples of an anti-CD33 antibody that may be used in the present ADCs is gemtuzumab, which may be used to treat leukemias like AML.

[0133] In another embodiment, targeting antibodies in the present ADCs bind to the target protein CD 19. Examples of anti-CD19 antibodies that may be used in the present ADCs are loncastuximab, tafasitamab, and blinatumomab, which may be used to treat leukemias like diffuse large B-cell lymphoma (DLBCL) and chronic lymphoblastic leukemia (CLL).

[0134] In another embodiment, targeting antibodies in the present ADCs bind to the target protein NECTIN-4. Examples of an anti- NECTIN-4 antibody that may be used in the present ADCs is enfortumab, which may be used to treat urothelial and bladder cancers.Linkers

[0135] In one embodiment, the present ADCs comprise one or more linkers attaching the dual PI3K / mTOR inhibitor and targeting antibodies. The linker Y is bound to one or more dual PI3K / mTOR inhibitors and one or more targeting antibodies to form the present conjugate. The linker Y can be attached to the targeting antibodies and the dual PI3K / mTOR inhibitors by functional groups independently selected from an ester bond, disulfide, amide, acylhydrazone, ether, carbamate, carbonate, or urea. Alternatively the linker can be attached to either the targeting antibodies or the dual PI3K / mTOR inhibitors by a non-cleavable group such as provided by the conjugation between a thiol and a maleimide, an azide and an alkyne. In one embodiment, the linker is independently selected from an alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of the alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups optionally is substituted with one or more groups, such as halogen, cyano, nitro, hydroxyl, carboxyl, carbamoyl, ether, alkoxy, aryloxy, amino, amide, carbamate, alkyl, alkenyl, alkynyl, aryl,arylalkyl, cycloalkyl, heteroaryl, or heterocyclyl. In some embodiments, the linker comprises polyethylene glycol (PEG), i.e., -(O-CH2-CH2)n-. In one embodiment, n can be selected from the range 1 to 12, inclusive.

[0136] In some embodiments of the antibody-drug conjugates and compounds provided herein, linker Y comprises an oligopeptide. In some embodiments, the oligopeptide is a dipeptide, tripeptide, or a tetrapeptide. In some embodiments, the oligopeptide is a dipeptide, such as Val- Ala or Val-citrulline. In some embodiments, the oligopeptide is a tetrapeptide, such as Gly-Gly- Phe-Gly.

[0137] In some embodiments, the linker comprises a cleavable functionality that is cleavable. The cleavable functionality may be hydrolyzed in vivo or may be designed to be hydrolyzed enzymatically, for example by cathepsin B. A “cleavable” linker, as used herein, refers to any linker which can be cleaved physically or chemically. Examples for physical cleavage may be cleavage by light, radioactive emission or heat, while examples for chemical cleavage include cleavage by re-dox-reactions, hydrolysis, pH-dependent cleavage or cleavage by enzymes. For example, the cleavable functionality may be a disulfide bond or a carbamate bond.

[0138] In some embodiments, the cleavable linker moiety is a hydrazone linker, a disulphide linker, or a peptide linker. In some embodiments, the peptide linker is a dipeptide linker such as valine-citrulline (Val-Cit), valine-alanine (Vai-Ala) or alanine-alanine (Ala-Ala). In some embodiments, the dipeptide linker is joined to the cytotoxic payload by the spacer unit paraaminobenzyloxycarbonyl (PABC).

[0139] In some embodiments, the peptide linker is a tripeptide linker comprising a glutamic acid- valine-citrulline (EYCit). In some embodiments, the glutamic acid-valine-citrulline (EVCit) tripeptide linker is joined to a meta-amide para-aminobenzyl carbamate (MA-PABC) group.

[0140] In another embodiment, the present ADCs comprise one or more non-cleavable linkers. Non-cleavable linkers are a significant building block of antibody-drug conjugates. They disengage their cytotoxic payload during lysosomal degradation of the antibody-drug conjugate inside the target cells or tumor environment, bypassing non-specific dispersion of the toxic preparation.

[0141] Non-cleavable linkers may have more advanced plasma stability than many cleavable linkers. Non-cleavable linkers do not seem to contain a definable payload dispersion mode, and ADCs developed with this mechanism depend on lysosomal proteolytic decomposition of theantibody after ingestion to deliver the cytotoxic medicine. Via this strategy, the non-cleavable linker transporting the medication is attached to the conjugation amino acid within the antibody. ADCs containing non-cleavable linkers are more contingent on the membrane biology of the neoplasm than cleavable linkers.

[0142] In vivo research studies have demonstrated that non-cleavable linked ADCs outperform cleavable equivalents. Antibody degradation in the lysosome after ADC ingestion is necessary for non-cleavable linkers to liberate their medical preparation. The payload derivative from non- cleavable ADCs destroys the target cells, and non-cleavable linkers may theoretically offer a superior medicinal opportunity versus cleavable linkers. With a reduced off-target toxicity compared to the cleavable ADCs, non-cleavable ADCs may offer improved stability and tolerability.

[0143] In one aspect, the present disclosure provides antibody-drug conjugates having a targeting antibody (Ab) conjugated to one or more compounds having the structure Y — Z, wherein Y is a linker, and Z is the dual PI3K / mTOR inhibitor Omipalisib (GSK2126458) or a derivative or analog thereof.

[0144] The drug-to-antibody ratio (DAR) is the average number of drugs conjugated to the antibody. In one embodiment, the DAR ranges from 1 to 10. In one embodiment, the DAR is one. In one embodiment, the DAR is two. In one embodiment, the DAR is three. In one embodiment, the DAR is four. In one embodiment, the DAR is five. In one embodiment, the DAR is six. In one embodiment, the DAR is seven. In one embodiment, the DAR is eight. In one embodiment, the DAR is nine. In one embodiment, the DAR is ten.

[0145] In one embodiment, the DAR is between zero and one inclusive. In one embodiment, theDAR is between one and two inclusive. In one embodiment, the DAR is between two and three inclusive. In one embodiment, the DAR is between three and four inclusive. In one embodiment, the DAR is between four and five inclusive. In one embodiment, the DAR is between five and six inclusive. In one embodiment, the DAR is between six and seven inclusive. In one embodiment, the DAR is between seven and eight inclusive. In one embodiment, the DAR is between eight and nine inclusive. In one embodiment, the DAR is between nine and ten inclusive.

[0146] In one embodiment, the DAR is between zero and two inclusive. In one embodiment, the DAR is between one and three inclusive. In one embodiment, the DAR is between two and four inclusive. In one embodiment, the DAR is between three and five inclusive. In one embodiment,the DAR is between four and six inclusive. In one embodiment, the DAR is between five and seven inclusive. In one embodiment, the DAR is between six and eight inclusive. In one embodiment, the DAR is between seven and nine inclusive. In one embodiment, the DAR is between eight and ten inclusive.

[0147] In one embodiment, the targeting antibody of the present ADC is a monoclonal antibody. In another embodiment, the targeting antibody of the present ADC is a bispecific antibody. In one embodiment, the targeting antibody is the anti-HER2 receptor antibody Trastuzumab, or a derivative or analog thereof.Uses of ADCs

[0148] In another embodiment, the present disclosure provides a method of treating a disease condition in a subject in need thereof, the method comprises administering to the subject a composition comprising the antibody-drug conjugates disclosed herein. In one embodiment, the disease condition is cancer. In one embodiment, the cancer is lymphoma, leukemia, or breast cancer. In another embodiment, the cancer is non-small cell lung cancer, bladder cancer, gastric cancer, colorectal cancer, pancreatic cancer, or ovarian cancer. In another embodiment, the cancer is lymphoma, leukemia, breast cancer, non-small cell lung cancer (NSCLC), urothelial cancer, bladder cancer, gastric cancer, colorectal cancer, pancreatic cancer, ovarian cancer, colon cancer, endometrial cancer, prostate cancer.

[0149] In some embodiments, uses an ADC wherein the targeting antibody binds to a target protein selected from the group consisting of HER2, CD180, CDH17, CD33, Trophoblast cell surface antigen 2 (TROP-2), CD19, NECTIN-4, c-MET, epithelial cell adhesion molecule (EpCAM), Prostate-Specific Membrane Antigen (PSMA), and Folate receptor alpha (FRa). In one embodiment, the above method uses an ADC wherein the targeting antibody is an anti-HER2 receptor antibody e.g., Trastuzumab.

[0150] In another embodiment, the disease condition to be treated is idiopathic pulmonary fibrosis, e.g., using an antibody that targets Fibroblast Activation Protein (FAP) or Integrin av06.

[0151] In another embodiment, the disease condition to be treated is liver fibrosis, nonalcoholic steatohepatitis (NASH), or nonalcoholic fatty liver disease, e.g., using an antibody that targets asialoglycoprotein receptor 1 (ASGR1) or Fibroblast Activation Protein (FAP).

[0152] In another embodiment, the disease condition to be treated is renal fibrosis or chronic kidney disease progression, e.g., using an antibody that targets CD 13 or Platelet-Derived GrowthFactor Receptor beta (PDGFR-0).

[0153] In another embodiment, the disease condition to be treated is systemic sclerosis, e.g., using an antibody that targets Cadherin-11, FAP, or CD248.

[0154] In another embodiment, the disease condition to be treated is pathologic cardiac hypertrophy or heart failure, e.g., using an antibody that targets NPPA receptor (also known as atrial natriuretic peptide receptor (ANP-R)) or periostin.

[0155] In another embodiment, the disease condition to be treated is age-related macular degeneration (AMD), e.g., using an antibody that targets CD59, VEGFR2, or ICAM-1.

[0156] In another embodiment, the disease condition to be treated is autoimmune disorder, such as lupus or rheumatoid arthritis, e.g., using an antibody that targets CD19, CD4, or CD38.

[0157] The terms “treat”, “treatment”, or “therapy” (as well as different forms thereof) refer to either therapeutic treatment or prophylactic or preventative measures, wherein the object is to prevent or lessen the targeted pathologic condition or disorder as described herein. Thus, in some embodiments, treating may include directly affecting or curing, suppressing, inhibiting, preventing, reducing the severity of, delaying the onset of, reducing symptoms associated with the disease, disorder or condition, or a combination thereof. Thus, in some embodiments, "treating" refers to delaying progression, expediting remission, inducing remission, augmenting remission, speeding recovery, increasing efficacy of or decreasing resistance to alternative therapeutics, or a combination thereof. In some embodiments, “preventing” refers to delaying the onset of symptoms, preventing relapse to a disease, decreasing the number or frequency of relapse episodes, increasing latency between symptomatic episodes, or a combination thereof. In some embodiments, “suppressing” or “inhibiting”, refers to reducing the severity of symptoms, reducing the severity of an acute episode, reducing the number of symptoms, reducing the incidence of disease-related symptoms, reducing the latency of symptoms, ameliorating symptoms, reducing secondary symptoms, reducing secondary infections, prolonging patient survival, or a combination thereof. In the context of cancer, treatment includes an amount sufficient to effect remission, an amount effect to shrink a tumor, an amount effective to halt or slow tumor growth, an amount effective to decrease the probability of developing cancer in a patient having a known risk factor for cancer, such as a mutation associated with the risk of developing cancer.

[0158] The present disclosure also encompasses a pharmaceutical composition comprising the antibody-drug conjugates disclosed herein and a pharmaceutically acceptable carrier. Theantibody-drag conjugates disclosed herein can be formulated in a composition with a pharmaceutically acceptable carrier according to methods generally known in the art.

[0159] Compositions suitable for use in the methods disclosed herein comprise the present antibody-drag conjugates in an amount effective to achieve the intended purpose. In some embodiments, a therapeutically effective amount means an amount of the ADCs effective to prevent, alleviate or ameliorate symptoms of disease (e.g., cancer) or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art. The exact formulation, route of administration and dosage can be chosen by one of ordinary skill in the art in view of the patient's condition. The amount of a composition to be administered is dependent on, e.g. the subject being treated, the severity of the affliction, the manner of administration, the judgment of the prescribing physician, etc. Depending on the severity and responsiveness of the condition to be treated, dosing can be a single administration or a plurality of administrations, with a course of treatment lasting from several days to several weeks or until cure is affected or diminution of the disease state is achieved.

[0160] Administration of a composition comprising the present ADCs can be systemic or local. In some embodiments, it would be desirable to administer a composition of the present disclosure locally to the area in need of treatment; this may be achieved by, for example, and not by way of limitation, local infusion, by injection, by means of a catheter, or by means of an implant, said implant being of a porous, non-porous, or gelatinous material.

[0161] Throughout this application, various embodiments of the present disclosure may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

[0162] Whenever a numerical range is indicated herein, it is meant to include any cited numeral (fractional or integral) within the indicated range. The phrases “ranging / ranges between” a first indicate number and a second indicate number and “ranging / ranges from” a first indicate number“to” a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numerals therebetween.

[0163] Unless otherwise defined, all technical and / or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the invention, exemplary methods and / or materials are described below, hi case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be necessarily limiting. Each literature reference or other citation referred to herein is incorporated herein by reference in its entirety.

[0164] In the description presented herein, each of the steps of the invention and variations thereof are described. This description is not intended to be limiting and changes in the components, sequence of steps, and other variations would be understood to be within the scope of the present invention.

[0165] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements.

[0166] Various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below find experimental support in the following examples.EXAMPLE 1General Synthetic Schemes

[0167] In one embodiment, the antibody-drug conjugates disclosed herein have the following general structures:O RR2X’ •Nxn F ' IYN- o I ,F'Formula IFormula IVFormula V / N NH2N.OxNHyX = or pNH2or o o O wherein n = 1 - 12,R = any amino acid side chain, e.g. , -CH3(alanine) or -CH2CH2CH2NHCONH2(citrulline);R1is selected from the group consisting of: H, (CH2)2N(CH3)2, (CH2)2O(CH2)2O(CH2)2OCH3, (CH2)2O(CH2)2O(CH2)2CO2H, (CH2)2O(CH2)2O(CH2)2SO3H, (CH2)2O(CH2)2O(CH2)2NH2, (CH2)2O(CH2)2O(CH2)2N(CH3)2, (CH2)2O(CH2)2O(CH2)2CONH2,(CH2)2O(CH2)2OCH(OH)CH2CO2H; and (CH2)2O(CH2)2O(CH2)2SO2CH3;R2is selected from the group consisting of: H, -Ci -ealkyl, alkoxy,O(CH2)2O(CH2)2O(CH2)2CO2H, O(CH2)2O(CH2)2OCH3, O(CH2)2O(CH2)2NH2,O(CH2)2O(CH2)2NH(CH3)2, O(CH2)2O(CH2)2SO3H, O(CH2)2O(CH2)2CO2H,O(CH2)2O(CH2)2CONH2, O(CH2)2O(CH2)2SO2CH3,O(CH2)2O(CH2)2OCH2CH(OH)CH2OH, CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2OCH3,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2CO2H,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2SO2CH3,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2N(CH3)2,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2NHCH3, CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2NH2,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2SO3H, CH2N(CH3)CO(CH2)2CO2H,CH2N(CH3)CO(CH2)2NH2, and CH2N(CH3)CO(CH2)2NHCH3; andR3is selected from the group consisting of: glucamine, -NH((CH2)2O)3(CH2)2OCH3,NH(CH2)2O(CH2)2OCH2CH(OH)CH2OH, N(CH3)(CH2)2O(CH2)2OCH2CH(OH)CH2OH,NH(CH2)2O(CH2)2OCH2CH(OH)CH2OH, NHCH2CH(OH)CH2OH,NHCH2CH(OH)CH(OH)CH2OH, N(CH3)CH2CH(OH)CH2OH,N(CH3)CH2CH(OH)CH(OH)CH2OH, NH(CH2)2O(CH2)2OCH2CH(OH)CO2H,N(CH3)(CH2)2O(CH2)2OCH2CH(OH)CO2H, NH(CH2)2O(CH2)2OCH2CH(OH)CCO2H, NHCH2CH(OH)CO2H, NHCH2CH(OH)CH(OH)CO2H, N(CH3)CH2CH(OH)CO2H, and N(CH3)CH2CH(OH)CH(OH)CO2H.

[0168] Exemplary methods for preparing Omipalisib-derivatives described herein are illustrated in the following general and synthetic schemes. These schemes are given for the purpose of illustrating the invention and should not be regarded in any way as limiting the scope or the spirit of the invention. The group X will determine the appropriate method for antibody bioconjugation - cysteine coupling for X = maleimide, transglutaminase coupling for X = NH2and lysine coupling for X = NHS (activated acids).

[0169] The general synthetic route illustrated in Scheme 1 (Fig. 1A) depicts an exemplary procedure for preparing compounds of Formula I where n = 1 - 12; and R is derived from natural amino acid side chains, hi the first step, dipeptide-benzyl alcohol (1) can be reacted with Omipalisib under DEAD or DIAD, Ph3P - Mitsunobu conditions, in a polar solvent like THE, to provide compound 2. Reaction of 2 with a secondary amine base like DEA in DMF can provide key intermediate 3. Amide coupling of 3 with a variety of PEG(n)-activated acids in a polar aprotic solvent, provides compounds of Formula I. When X = N3, subsequent azide reduction with PPh3in H2O can provide compounds of Formula I, X = NH2.

[0170] The general synthetic route illustrated in Scheme 2 (Fig. IB) depicts an alternative procedure for preparing compounds of Formula I where n = 1 - 12; and R is derived from natural amino acid side chains. In the first step, dipeptide-benzyl alcohol (1) can be converted to the corresponding benzyl chloride 4 under standard conditions. Omipalisib can be alkylated with benzyl-chloride 4 under standard alkylation conditions to provide compound 2. Reaction of 2 with a secondary amine base like DEA in DMF can provide key intermediate 3. Amide coupling of 3 with a variety of PEG(n)-activated acids in a polar aprotic solvent, provides compounds of Formula I. When X = N3, subsequent azide reduction with PPh3in H2O can provide compounds of Formula I, X = NH2.

[0171] The general synthetic route illustrated in Scheme 3 (Fig. 1C) depicts an exemplary procedure for preparing compounds of Formula II where n = 1 - 12; and R is derived from natural amino acid side chains. In the first step, dipeptide-benzyl p-nitro phenyl carbonate (5) is reacted with Omipalisib in the presence of DMAP in a polar aprotic solvent to provide carbamate 6. Reaction of 6 with a secondary amine base like DEA in DMF can provide key intermediate 7.Amide coupling of 7 with a variety of PEG(n)-activated acids in a polar aprotic solvent, can provide compounds of Formula II. When X = N3, subsequent azide reduction with PPhs in H2O can provide compounds of Formula n, X = NH2.

[0172] The general synthetic route illustrated in Scheme 4 (Fig. ID) depicts an exemplary procedure for preparing compounds of Formula HI where n = 1 - 12; and R is derived from natural amino acid side chains and R1is selected from commercially available primary amines. In the first step, the nitro carbonate 8 is reacted with a selected R1NH2in the presence of base in a polar aprotic solvent like pyridine or DMF to give carbamate 9. Chloromethyl analog 10 can be obtained by reaction of 9 with formaldehyde in the presence of TMSC1 in a chlorinated solvent. The chloromethyl analog 10 can be used to alkylate Omipalisib in the presence of a tertiary amine base in a polar aprotic solvent to produce 11. Azide reduction can be carried out with PM 63 in THE to produce amine 12. Peptide coupling of amine 12 with an Fmoc-protected amino acid under standard coupling conditions can provide 13 which can be subsequently deprotected with DEA to generate amine 14. A second peptide coupling with a Fmoc-protected amino acid under standard conditions can produce dipeptide derivative 15 that is subsequently deprotected with DEA to produce dipeptide derivative 16 that can be acylated with a variety of PEG(n)-activated acids in a polar aprotic solvent to produce compounds of Formula HI. When X = N3, subsequent azide reduction with PPhs in H2O can provide compounds of Formula III, X = NH2.EXAMPLE 2Synthesis of Antibody-Drug Conjugates

[0173] Unless otherwise stated, commercially available reagents were used as supplied. All reactions requiring anhydrous conditions were conducted in a dried apparatus under an atmosphere of nitrogen or argon. Flash column chromatography was performed on Purisep flash cartridge (Silica irregular 40-60 pm, 60 A, 8 to 800 g weight, max. pressure: 300 psi) or oReversed phase C18 column (20 - 35 pm, 100 A, 4 to 330 g weight, max. pressure: 180 psi) either manually or automated using an Isco CombiFlash (Biotage IsoleraTM prime 3.3.0) system or AIRS CombiFlash Companion system. NMR chemical shift values were measured on the delta scale [proton magnetic resonance spectra were determined using Bruker Avance II 300 (300 MHz) and Bruker Avance IH 400 (400 MHz) instruments]; measurements were taken at ambient temperature unless otherwise specified; the following abbreviations have been used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd, doublet of doublets; ddd, doublet ofdoublet of doublet; dt, doublet of triplets; and bs, broad signal. In general, end products were also characterized by mass spectrometry following liquid chromatography (LC / MS). LC / MS experiments were performed using a Shimadzu LCMS-2020 with electrospray ionization in positive ion detection mode with 40ADXR pump, SIL-40ACXR autosampler, CTO-40AC column oven, M40A PDA Detector and LCMS 2020 MS detector. LC was run in one of three set ups: 1) Halo CIS column (2.0 pm 3.0x30 mm) in combination with a gradient (5-100% B in 1.2 minutes) of water and FA (0.1%) (A) and CH3CN and FA (0.1%) (B) at a flow rate of 1.5 mL / min; 2) Halo CIS column (2.0 pm 3.0 x 30 mm) in combination with a gradient (5 - 100% B in 1.2 minutes) of water and TFA (0.05%) (A) and CH3CN and TFA (0.05%)(B) at a flow rate of 1.5 mL / min ; 3) Shim-pack Scepter CIS-120 column (3.0 pm 3.0 x 33 mm) in combination with a gradient (10-95% B in 1.2 minutes) of aqueous 46 mM ammonium carbonate / ammonia buffer at pH 10 (A) and CH3CN (B) at a flow rate of 1.5 mL / min. The Column Oven (CTO-40AC) temperature was 40 °C. The injection volume was 0.5 pL. PDA (SPD-M40A) detection was in the range of 190 - 400 nm. The MS detector was configured with electrospray ionization as ionizable source; Acquisition mode: Scan; Nebulizing Gas Flow: 1.5 L / min; Drying Gas Flow: 15 L / min; Detector Voltage: 0.95-1.25 kv; DL Temperature: 250 °C; Heat Block Temperature: 250 °C; Scan Range: 90.00 - 2000.00 m / z. The reported molecular ion corresponds to the [M + H]+unless otherwise specified; for molecules with multiple isotopic patterns (Br, Cl, etc.), the reported value is the one obtained for the lowest isotope mass unless otherwise specified.Synthesis of Mal-Pes( 1 }-Val-Ala-PAB-Omipalisib (Coromip-l / PH-CQRL-MC-2024-00! C-l -0)

[0174] In one embodiment, the present disclosure provides a linker and Omipalisib having the structure(Formula I, n=l, R=Me). The reaction scheme is shown in Fig. 2.Step 1: 9 / / -fluoren-9-ylmethyl N-[(lS)-l-{[(lS)-l-({4-[(N-{2-methoxy-5-[4-(pyridazin-4- yl)quinolin-6-yl]pyridin-3-yl } 2,4-difhiorobenzenesulfonamido)methyl]phenyl } carbamoyl) ethyl]carbamoyl }-2-methylpropyl]carbamate (2a)

[0175] To a stirred solution of la (9 / / -fluoren-9-ylmethyl N-[(lS)-l-{[(lS)-l-{[4-(hydroxymethyl)phenyl] carbamoyl } ethyl] carbamoyl } -2-methylpropyl]carbamate) (612.00 mg, 1.187 mmol) in THF (30 mL) were added 2,4-difluoro-N-{2-methoxy-5-[4-(pyridazin-4- yl)quinolin-6-yl]pyridin-3-yl]benzenesulfonamide (400 mg, 0.791 mmol) and PPhg (622.65 mg, 2.373 mmol) at 0 °C under argon atmosphere. The reaction mixture was stirred at 0 °C for 10 min. Then DIAD (400.02 mg, 1.978 mmol) was added to the reaction mixture. The reaction was stirred at 25 °C for 3 h. The product-containing reaction mixture was purified by RP-Flash (Column: C1880 g Column; Mobile Phase A: water, Mobile Phase B: MeCN; Flow rate: 60 mL / min; Gradient: 2% B to 80% B in 45 min, Detector: UV 210 nm; RT = 28 min). The fractions containing desired product were combined and concentrated under reduced pressure to afford 2a (9H-fluoren-9-ylmethyl N- [( 1 S)- 1 - { [( IS)- 1 -( { 4- [(V- { 2-methoxy-5- [4-(pyridazin-4-yl)quinolin-6- yl]pyridin-3-yl } 2,4-difluorobenzenesulfonamido)methyl]phenyl } carbamoyl)ethyl]carbamoyl } -2- methylpropyl]carbamate) (576 mg, 72% yield) as a white solid. MS m / z. = 1003.25 [M + H]+.rH NMR (300 MHz, Chloroform-d) 39.43 (d, J = 5.2 Hz, 1H), 9.21 (s, 1H), 9.02 (s, 1H), 8.89 (s, 1H), 8.47 (d, J = 8.9 Hz, 1H), 8.13 (d, J = 13.0 Hz, 1H), 7.70 (d, J = 8.4 Hz, 4H), 7.53 (s, 4H), 7.48 - 7.27 (m, 8H), 7.24 - 7.09 (m, 4H), 7.08 - 6.87 (m, 2H), 5.88 (s, 1H), 4.80 (t, J = 7.3 Hz, 1H), 4.41 (s, 1H), 4.12 (s, 1H), 4.02 (s, 1H), 3.65 (s, 3H), 2.23 (s, 1H), 1.59 (d, J= 7.0 Hz, 3H), 1.00 (t, J = 8.1 Hz, 6H).Step 2: (2S)-2-amino-V- [(1 S)- 1 -( { 4-[(7V- { 2-methoxy-5- [4-(pyridazin-4-yl)quinolin-6-yl]pyridin- 3-yl } 2,4-difhiorobenzenesulfonamido)methyl]phenyl } carbamoyl)ethyl]-3-methylbutanamide (3a)

[0176] To a solution of 2a (576 mg, 0.574 mmol) in DMF (5.58 mL) was added diethylamine (0.18 mL) at 0 °C under N2 atmosphere. The resulting mixture was stirred at 25 °C for 2 h. The product-containing reaction mixture was purified by RP-Flash (Column: C1880 g Column; Mobile Phase A: water, Mobile Phase B: MeCN; Flow rate: 50 mL / min; Gradient: 2% B to 80% B in 45 min, Detector: UV 210 nm; RT = 32 min). The fractions containing desired product were combined and concentrated under reduced pressure to afford 3a ((2S)-2-amino-N-[(lS)-l- ({ 4-[(N- { 2-methoxy-5-[4-(pyridazin-4-yl)quinolin-6-yl]pyridin-3-yl } 2,4- difhiorobenzenesulfonamido)methyl]phenyl } carbamoyl)ethyl]-3-methylbutanamide) (320 mg, 71% yield) as a white solid. MS: m / z = 781.20 [M + H]+. ’H NMR (300 MHz, Chloroform-^?) 8 9.48 (dd, J = 5.1, 1.2 Hz, 1H), 9.41 (s, 1H), 9.32 (d, J= 2.1 Hz, 1H), 9.03 (d, J = 4.5 Hz, 1H), 8.31 - 8.21 (m, 2H), 8.03 (d, J = 7.8 Hz, 1H), 7.80 (s, 1H), 7.74 - 7.61 (m, 2H), 7.47 - 7.28 (m,5H), 7.22 - 6.74 (m, 4H), 4.76 (q, J = 7.2 Hz, 1H), 3.66 (s, 3H), 3.49 (s, 2H), 3.33 (s, 1H), 2.36 -2.20 (m, 2H), 1.50 (d, J = 7.2 Hz, 3H), 1.00 (d, J = 6.9 Hz, 3H), 0.85 (d, J = 6.9 Hz, 3H).Step 3: (2S)-2-{3-[2-(2,5-dioxopyrrol-l-yl)ethoxy]propanamido}-A-[(lS)-l-({4-[(A-{2- methoxy-5-[4-(pyridazin-4-yl)quinolin-6-yl]pyridin-3-yl}2,4-difluorobenzenesulfonamido) methyl]phenyl} carbamoyl) ethyl]-3-methylbutanamide (Coromip-1)

[0177] To a stirred solution of (2S)-2-amino-jV-[(15)-l-({4-[(A-{2-methoxy-5-[4-(pyridazin-4- yl)quinolin-6-yl]pyridin-3-yl } 2,4-difluorobenzenesulfonamido)methyl]phenyl ) carbamoyl)ethyl]- 3-methylbutanamide (3a) (150 mg, 0.192 mmol) in DMF (1.5 mL) were added DIEA (49.66 mg, 0.384 mmol) and 2,5-dioxopyrrolidin-l-yl 3-(2-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l- yl)ethoxy)propanoate (89.3 mg, 0.288 mmol) at 25 °C under argon atmosphere. The reaction mixture was stirred at 25 °C for 0.5 h. After completion, the product-containing reaction mixture was purified by RP-Flash (Column: C1840 g Column; Mobile Phase A: water (0.05% FA), Mobile Phase B: MeCN; Flow rate: 50 mL / min; Gradient: 2% B to 80% B in 30 min, Detector: UV 210 nm; RT = 26 min). The fractions containing desired product were combined and lyophilized overnight to afford Coromip-1 ((2S)-2-{3-[2-(2,5-dioxopyrrol-l- yl)ethoxy]propanamido } -A-[(15)- 1 -({ 4- [(IV- { 2-methoxy-5-[4-(pyridazin-4-yl)quinolin-6- yl]pyridin-3-yl } 2,4-difluorobenzenesulfonamido)methyl]phenyl } carbamoyl)ethyl]-3- methylbutanamide) - Formula 1 (n = 1; R = Me) (106.9 mg, 57% yield) as a white solid. MS m / z. = 975.80 [M + H]+. *H NMR (300 MHz, DMSO-J6) 8 9.86 (s, 1H), 9.55 (dd, J = 2.4, 1.2 Hz, 1H), 9.47 (dd, J = 5.4, 1.2 Hz, 1H), 9.05 (d, J = 4.5 Hz, 1H), 8.48 (d, J = 2.4 Hz, 1H), 8.23 (d, J = 8.7 Hz, 1H), 8.14 (d, J = 6.9 Hz, 1H), 8.04 (dd, J = 5.4, 2.4 Hz, 1H), 7.99 - 7.87 (m, 2H), 7.86 - 7.60 (m, 5H), 7.47 (d, J = 8.4 Hz, 2H), 7.30 - 7.14 (m, 3H), 6.99 (s, 2H), 4.80 (s, 2H), 4.32 (q, J = 7.0 Hz, 1H), 4.16 (dd, J= 8.7, 6.6 Hz, 1H), 3.61 (s, 3H), 3.59 - 3.40 (m, 6H), 2.47 - 2.23 (m, 2H), 1.91 (dt, J = 13.6, 6.8 Hz, 1H), 1.26 (d, J = 7.2 Hz, 3H), 0.78 (dd, J = 12.4, 6.6 Hz, 6H).Synthesis ofMal-Pes(3)-Val-Ala-PAB-Omipalisib (Coromip-2 / PH-CORL-MC-2024-001 C-2-0)

[0178] In one embodiment, the present disclosure provides a linker and Omipalisib having the structure(Formula I, n=3,R=Me). The reaction scheme is shown in Fig. 6.Step 1: (25)-2-[3-(2-{2-[2-(2,5-dioxopyrrol-l-yl)ethoxy]ethoxy}ethoxy)propanamido]-jV-[(lS)- l-({4-[(2V- { 2-methoxy-5- [4-(pyridazin-4-yl)quinolin-6-yl]pyridin-3-yl } 2,4- difhiorobenzenesulfonamido)methyl]phenyl } carbamoyl)ethyl]-3-methylbutanamide (Coromip- 2)

[0179] To a stirred solution of 3a ((2S)-2-amino-A-[(lS)-l-({4-[(A-{2-methoxy-5-[4-(pyridazin- 4-yl)quinolin-6-yl]pyridin-3-yl } 2,4-difluorobenzenesulfonamido)methyl]phenyl } carbamoyl) ethyl]-3-methylbutanamide) (170 mg, 0.218 mmol) in DMF (1.7 mL) were added 2,5- dioxopyrrolidin-l-yl 3-(2-{2-[2-(2,5-dioxopyrrol-l-yl)ethoxy]ethoxy } ethoxy )propanoate (112.75 mg, 0.283 mmol) and DIEA (56.28 mg, 0.436 mmol) at 25 °C under argon atmosphere. The reaction was stirred at 25 °C for 0.5 h. After completion, the product-containing reaction mixture was purified by RP-Flash (Column: C1840 g Column; Mobile Phase A: water (0.025% FA), Mobile Phase B: MeCN; Flow rate: 50 mL / min; Gradient: 2% B to 80% B in 30 min, Detector: UV 210 nm; RT = 31 min). The fractions containing desired product were combined and lyophilized overnight to afford Coromip-2 ((25)-2-[3-(2-{2-[2-(2,5-dioxopyrrol-l- yl)ethoxy] ethoxy } ethoxy )propanamido] -N- [( 1 S)- 1 -( { 4- [(A- { 2-methoxy-5- [4-(pyridazin-4- yl)quinolin-6-yl]pyridin-3-yl } 2,4-difluorobenzenesulfonamido)methyl]phenyl } carbamoyl)ethyl]-3-methylbutanamide) (105.3 mg, 45% yield) as a white solid. MS m / z = 1064.35 [M + H]+. 'H NMR (300 MHz, DMSO-cfe) 89.86 (s, 1H), 9.55 (dd, J = 2.4, 1.2 Hz, 1H), 9.47 (dd, J = 5.4, 1.2 Hz, 1H), 9.05 (d, J = 4.5 Hz, 1H), 8.48 (d, J = 2.4 Hz, 1H), 8.23 (d, J = 8.7 Hz, 1H), 8.16 (d, J = 6.9 Hz, 1H), 8.05 (dd, J = 5.4, 2.4 Hz, 1H), 8.00 - 7.59 (m, 7H), 7.51 - 7.43 (m, 2H), 7.30 - 7.13 (m, 3H), 7.01 (s, 2H), 4.81 (s, 2H), 4.34 (p, J = 7.2 Hz, 1H), 4.18 (dd, J = 8.7, 6.6 Hz, 1H), 3.61 (s, 3H), 3.59 - 3.38 (m, 14H), 2.48 - 2.28 (m, 2H), 1.98 - 1.92 (m, 1H), 1.26 (d, J = 7.2 Hz, 3H), 0.80 (dd, J = 11.8, 6.6 Hz, 6H).Synthesis of Mal-Pes( D-Val-Ala-PABC-Omipalisib (Coromip-3 / PH-CQRL-MC-2024-001 C-3-0}

[0180] In one embodiment, the present disclosure provides a linker and Omipalisib having the structure(Formula n, n=l, R=Me). The reaction scheme is shown in Fig. 10.Step 1: {4-[(2S)-2-[(2S)-2-{ [(9 / 7-fluoren-9-ylmethoxy)carbonyl]amino}-3- methylbutanamido]propanamido] phenyl } methyl 7V-(2,4-difluorobenzenesulfonyl)-7V- { 2- methoxy-5-[4-(pyridazin-4-yl)quinolin-6-yl]pyridin-3-yl[carbamate (6a)

[0181] To a stirred mixture of 5a ({4-[(2S)-2-[(2S)-2-{[(97f-fhioren-9- ylmethoxy)carbonyl]amino[-3-methylbutanamido]propanamido]phenyl}methyl 4-nitrophenyl carbonate) (600 mg, 0.881 mmol) and 2,4-difluoro- / V-{2-methoxy-5-[4-(pyridazin-4-yl)quinolin- 6-yl]pyridin-3-yl [benzenesulfonamide (356.45 mg, 0.705 mmol ) in DCM (6 mL) was added DMAP (129.22 mg, 1.057 mmol) at room temperature under argon atmosphere. The resulting mixture was stirred at 45 °C for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-100% EA in PE to afford 6a ({4-[(2S)-2-[(2S)-2-{ [(9H-fluoren-9-ylmethoxy)carbonyl]amino}-3- methylbutanamido] propanamidojphenyl [methyl A-(2,4-difluorobenzenesulfonyl)-A- { 2- methoxy-5-[4-(pyridazin-4-yl)quinolin-6-yl]pyridin-3-yl [carbamate) (600 mg, 45% yield, 70% Purity) as a yellow solid. MS: m / z = 1047.50 [M + H]+. 'H NMR (300 MHz, DMSO-J6) 3 10.04 (s, 1H), 9.61 (d, J = 2.1 Hz, 1H), 9.50 (m, 1H), 9.07 (m, 1H), 8.70 (m, 1H), 8.36 - 8.14 (m, 4H), 8.07 (m, 3H), 7.89 (m, 2H), 7.74 (m, 2H), 7.69 (m, 1H), 7.67 - 7.61 (m, 1H), 7.58 (m, 1H), 7.51 (m, 2H), 7.45 - 7.37 (m, 2H), 7.31 (m, 4H), 7.11 (m, 2H), 5.06 (m, 2H), 4.41 (m, 1H), 4.23 (m, 2H), 3.88 (m, 4H), 3.75 (m, 1H), 1.95 (m, 1H), 1.30 (m, 3H), 0.90 - 0.82 (m, 6H).

[0182] 19F NMR (282 MHz, DMSO-J6) 3 -98.44 - -98.49 (m, IF), -102.28 - -102.33 (m, IF).Step 2: {4-[(2S)-2-[(2S)-2-amino-3-methylbutanamido]propanamido]phenyl[methyl N-(2,4- di fluorobenzenesulfonyl)-? / - {2-methoxy-5-[4-(pyridazin-4-yl)quinolin-6-yl]pyridin-3- yl } carbamate (7a)

[0183] A solution of 6a ({4-[(2S)-2-[(2S)-2-{ |(9W-fluoren-9-ylmethoxy)carbonyl]amino}-3- methylbutanamido] propanamido]phenyl } methyl A-(2,4-difluorobenzenesulfonyl)-A- { 2- methoxy-5-[4-(pyridazin-4-yl)quinolin-6-yl]pyridin-3-yl [carbamate) (600 mg, 0.401 mmol, 70% Purity) in DEA : DMF (6 mL, v : v = 1 : 30) was stirred at 0 °C for 45 min. The resulted productcontaining mixture was purified by reversed-phase flash chromatography with the following conditions: Column: C18 silica gel, 80 g; Mobile phase: MeCN in Water (0.1% FA), 0% to 50% gradient in 30 min; Detector, UV 254 nm. The fractions containing desired product was pooled and lyophilized overnight to afford 7a ({4-[(2S)-2-[(2S)-2-amino-3- methylbutanamido]propanamido] phenyl [methyl V-(2,4-difluorobenzenesulfonyl)-Af-{ 2- methoxy-5-[4-(pyridazin-4-yl)quinolin-6-yl]pyridin-3-yl[carbamate) (190 mg, 57.43% yield) as a white solid. MS: m / z = 825.20 [M + H]+. NMR (300 MHz, DMSO-cfe) 8 10.10 (s, 1H), 9.61 (m, 1H), 9.50 (m, 1H), 9.07 (m, 1H), 8.71 (m, 1H), 8.35 - 8.25 (m, 2H), 8.25 - 8.17 (m, 2H), 8.06 (m, 3H), 7.70 (m, 1H), 7.65 - 7.58 (m, 1H), 7.55 - 7.48 (m, 2H), 7.39 - 7.26 (m, 2H), 7.15 - 7.07 (m, 2H), 5.06 (m, 2H), 4.51 - 4.40 (m, 1H), 3.86 (s, 3H), 3.04 (m, 1H), 1.92 (m, 1H), 1.30 (m, 3H), 0.88 (m, 3H), 0.79 (m, 3H).

[0184] 19F NMR (282 MHz, DMSO) 8 -98.44 - -98.49 (m, IF), -102.28 ~ -102.33 (m, IF).Step 3: { 4-[(2S)-2- [(25)-2- { 3- [2-(2,5-dioxopyrrol- 1 -yl)ethoxy]propanamido } -3- methylbutanamido] propanamido]phenyl } methyl V-(2,4-difluorobenzenesulfonyl)-2V-{ 2- methoxy-5-[4-(pyridazin-4-yl)quinolin-6-yl]pyridin-3-yl[carbamate (Coromip-3)

[0185] To a stirred solution of 7a ({4-[(25)-2-[(25)-2-amino-3- methylbutanamido]propanamido]phenyl [methyl / V-(2,4-difluorobenzenesulfonyl)-A^-{2- methoxy-5-[4-(pyridazin-4-yl)quinolin-6-yl]pyridin-3-yl[carbamate) (150 mg, 0.182 mmol) and 2,5-dioxopyrrolidin-l-yl 3-[2-(2,5-dioxopyrrol-l-yl)ethoxy]propanoate (73.35 mg, 0.237 mmol) in DMF (1.5 mL) was added DIEA (47.01 mg, 0.364 mmol) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 30 min. After completion, the product-containing reaction mixture was purified by RP-Flash Column: (Cl 840 g Column; Mobile Phase A: water (0.025% FA), Mobile Phase B: MeCN; Flow rate: 60 mL / min; Gradient: 2% B to 60% B in 30 min, Detector: UV 210 run; RT = 26 min). The fractions containing desired product were combined and lyophilized overnight to afford Coromip-3 ({4- [(2S)-2- [(2S)-2- { 3- [2-(2,5-dioxopyrrol- 1 -yl)ethoxy]propanamido } -3-methylbutanamido] propanamidojphenyl } methyl A-(2,4-difluorobenzenesulfonyl)-A- { 2-methoxy-5-[4-(pyridazin-4-yl)quinolin-6-yl]pyridin-3-yl} carbamate) (110.1 mg, 59.36% yield) as a white solid. MS: m / 7, = 1020.15 [M + H]+. ’H NMR (300 MHz, DMSO-d6) 89.96 (s, 1H), 9.61 (m, 1H), 9.50 (m, 1H), 9.07 (m, 1H), 8.71 (m, 1H), 8.35 - 8.26 (m, 2H), 8.26 - 8.18 (m, 2H), 8.10 - 8.02 (m, 3H), 7.87 (m, 1H), 7.69 (m, 1H), 7.67 - 7.58 (m, 1H), 7.52 (m, 2H), 7.33 (m, 1H), 7.10 (m, 2H), 7.01 (s, 2H), 5.12 - 4.98 (m, 2H), 4.36 (m, 1H), 4.18 (m, 1H), 3.85 (s, 3H), 3.61 - 3.50 (m, 4H), 3.47 (m, 2H), 2.46 - 2.26 (m, 2H), 1.94 (m, 1H), 1.29 (m, 3H), 0.83 (m, 6H).

[0186] 19F NMR (282 MHz, DMSO-<Z6) 8 -98.45 - -98.50 (m, IF), -102.28 - -102.33 (m, IF).Synthesis of Mal-Pes( D-Val-Cit-PAB-Omipalisib (Coromip-4 / PH-CQRL-MC-2024-001 C-4-0}

[0187] In one embodiment, the present disclosure provides a linker and Omipalisib having the structure(Formula I, n=l, R=CH2CH2CH2NHCONH2). The reaction scheme is shown in Fig. 14.Step 1: (97 / -fluoren-9-yl)methyl ((5)- !-(((£)- l-((4-(chloromethyl)phenyl)amino)-l-oxo-5- ureidopentan-2-yl)amino)-3-methyl- 1 -oxobutan-2-yl)carbamate (4b)

[0188] To a solution of lb (9H-fluoren-9-ylmethyl N-[(lS)-l-{ [(15)-4-(carbamoylamino)-l-{ [4- (hydroxymethyl)phenyl] carbamoyl }butyl]carbamoyl }-2-methylpropyl] carbamate) (500 mg, 0.831 mmol) in NMP (5 mL) was added SOCh (118.62 mg, 0.997 mmol) at 0 °C under nitrogen atmosphere. The reaction solution was stirred at 0 °C for 1 h. The resulting mixture was concentrated under reduced pressure to afford 700 mg of (977-fluoren-9-yl)methyl ((£)- !-(((£)- 1- ((4-(chloromethyl)phenyl)amino)-l-oxo-5-ureidopentan-2-yl)amino)-3-methyl-l-oxobutan-2- yl)carbamate as a crude product. The crude product was used in the next step directly without further purification.Step 2: 9H-fluoren-9-ylmethyl A^-[(1S)-l-{[(1S)-4-(carbamoylamino)-1 -((4-[(7V-{2-methoxy-5- [4-(pyridazin-4-yl)quinolin-6-yl]pyridin-3-yl]2,4-difluorobenzenesulfonamido) methyljphenyl } carbamoyl)butyl] carbamoyl } -2-methylpropyl] carbamate (2b)

[0189] To a stirred solution of crude 4b ((9H-fluoren-9-yl)methyl ((S)-l-(((S)-l-((4- (chloromethyl)phenyl)amino)- 1 -oxo-5-ureidopentan-2-yl)amino)-3-methyl- 1 -oxobutan-2-yl)carbamate) (400 mg, 0.645 mmol, crude) and DIEA (166.73 mg, 1.290 mmol) in NMP (5 mL) were added 2,4-difluoro-7V-{ 2-methoxy-5-[4-(pyridazin-4-yl)quinolin-6-yl]pyridin-3- yl } benzenesulfonamide (195.63 mg, 0.387 mmol) and tetrabutylammonium iodide (23.82 mg, 0.065 mmol) at room temperature under nitrogen atmosphere. The reaction was stirred at 60 °C for 2 h. After completion, the reaction was cooled down to room temperature and purified by RP- Flash (Column: C1840 g Column; Mobile Phase A: water, Mobile Phase B: MeCN; Flow rate: 50 mL / min; Gradient: 2% B to 90% B in 45 min, Detector: UV 254 nm; RT = 29 min). The fractions containing desired product were combined and concentrated under reduced pressure to afford 2b (9 / / -fluoren-9-ylmethyl V-[(lS)-l-{[(lS)-4-(carbamoylamino)-l-({4-[(V-{2-methoxy- 5-[4-(pyridazin-4-yl)quinolin-6-yl]pyridin-3-yl}2,4-difluorobenzenesulfonamido)methyl] phenyl}carbamoyl)butyl]carbamoyl}-2-methylpropyl]carbamate) (280 mg, 66% yield over two steps) as a yellow solid. MS m / z = 1089.45 [M + H]+. *H NMR (300 MHz, DMSO) 8 9.99 (s, 1H), 9.54 (dd, J = 2.4, 1.3 Hz, 1H), 9.47 (dd, J = 5.4, 1.3 Hz, 1H), 9.03 (d, J = 4.5 Hz, 1H), 8.48 (d, J = 2.4 Hz, 1H), 8.24 (d, J = 8.6 Hz, 1H), 8.16 - 7.99 (m, 2H), 7.97 - 7.59 (m, 9H), 7.55 - 7.14 (m, 9H), 5.95 (s, 1H), 5.39 (s, 2H), 4.80 (s, 1H), 4.43 - 4.16 (m, 4H), 4.10 (q, J= 5.1 Hz, 1H), 3.92 (d, J= 8.1 Hz, 1H), 3.61 (s, 3H), 3.01- 2.92 (m, 2H), 2.02 - 1.90 (m, 1H), 1.79 - 1.26 (m, 4H), 0.81 (t, J = 7.8 Hz, 6H).Step 3: (2S)-2-[(2S)-2-amino-3-methylbutanamido]-5-(carbamoylamino)-A-{4-[(A-{2-methoxy- 5-[4-(pyridazin-4-yl)quinolin-6-yl]pyridin-3-yl}2,4-difluorobenzenesulfonamido) methyl]phenyl}pentanamide (3b)

[0190] To a stirred solution of 2b (9f / -fluoren-9-ylmethyl V-[(18)-l-{[(lS)-4-(carbamoylamino)- l-({4-[(N-{2-methoxy-5-[4-(pyridazin-4-yl)quinolin-6-yl]pyridin-3-yl}2,4- difluorobenzenesulfonamido)methyl]phenyl } carbamoyl)butyl]carbamoyl } -2- methylpropyl]carbamate) (280 mg, 0.257 mmol) in DMF (5 mL) was added diethylamine (0.5 mL, 3.855 mmol) at room temperature under nitrogen atmosphere. The reaction was stirred at 25 °C for 1 h. The reaction mixture was directly purified by RP-Flash (Column: C1840 g Column; Mobile Phase A: water, Mobile Phase B: MeCN; Flow rate: 50 mL / min; Gradient: 2% B to 90% B in 33 min, Detector: UV 254 nm; RT = 24 min). The fractions containing desired product were combined and concentrated under reduced pressure to afford 3b ((2S)-2-[(2S)-2-amino-3- methylbutanamido]-5-(carbamoylamino)-7V- { 4-[(N- { 2-methoxy-5-[4-(pyridazin-4-yl)quinolin-6- yl]pyridin-3-yl}2,4-difluorobenzenesulfonamido)methyl]phenyl} pentanamide) (200 mg, 89%yield) as a yellow solid. MS m / z = 865.20 [M - H]". 'H NMR (400 MHz, DMSO) 3 10.04 (s, 1H), 9.55 (dd, J = 2.4, 1.2 Hz, 1H), 9.47 (dd, J = 5.2, 1.2 Hz, 1H), 9.05 (d, J = 4.4 Hz, 1H), 8.48 (d, J = 2.4 Hz, 1H), 8.23 (d, J = 8.8 Hz, 1H), 8.15 - 8.00 (m, 2H), 7.96 (dd, J = 8.8, 2.0 Hz, 1H), 7.91 - 7.81 (m, 2H), 7.76 (td, J = 8.6, 6.0 Hz, 1H), 7.71 - 7.59 (m, 2H), 7.52 - 7.45 (m, 2H), 7.32 - 7.15 (m, 3H), 5.94 (t, J = 6.1 Hz, 1H), 5.39 (s, 2H), 4.81 (s, 2H), 4.42 (s, 1H), 4.11 (q, J = 5.3 Hz, 1H), 3.61 (s, 3H), 3.17 (d, J= 4.6 Hz, 4H), 3.02- 2.91 (m, 3H), 1.91 - 1.88 (m, 2H), 1.73 - 1.51 (m, 1H), 1.48 - 1.29 (m, 1H), 0.84 (d, J = 6.9 Hz, 3H), 0.74 (d, J= 6.8 Hz, 3H).Step 4: (2S)-5-(carbamoylamino)-2-[(2S')-2-{3-[2-(2,5-dioxopyrrol-l-yl)ethoxy] propanamido}- 3-methylbutanamido]-A-{4-[(A-{2-methoxy-5-[4-(pyridazin-4-yl)quinolin-6-yl]pyridin-3- yl }2,4-difluorobenzenesulfonamido)methyl]phenyl [pentanamide (Coromip-4)

[0191] To a stirred solution of 3b ((2S)-2-[(2S)-2-amino-3-methylbutanamido]-5- (carbamoylamino)-A-{4-[(iV-{2-methoxy-5-[4-(pyridazin-4-yl)quinolin-6-yl]pyridin-3-yl}2,4- difluorobenzenesulfonamido)methyl]phenyl} pentanamide) (200 mg, 0.231 mmol) in DMF (2 mL) were added 2,5-dioxopyrrolidin-l-yl 3-[2-(2,5-dioxopyrrol-l-yl)ethoxy]propanoate (93.05 mg, 0.300 mmol) and DIEA (59.63 mg, 0.462 mmol) at 0 °C under argon atmosphere. The reaction was stirred at 0 °C for 0.5 h. The reaction mixture was directly purified by RP-Flash (Column: C1840 g Column; Mobile Phase A: water (0.025% FA), Mobile Phase B: MeCN; Flow rate: 50 mL / min; Gradient: 2% B to 90% B in 40 min, Detector: UV 210 nm; RT = 25 min). The fractions containing desired product were combined and lyophilized to afford Coromip-4 ((2S)-5-(carbamoylamino)-2-[(2S)-2- { 3-[2-(2,5-dioxopyrrol- 1 -yl)ethoxy]propanamido }-3- methylbutanamido]-iV-{4-[(lV-{2-methoxy-5-[4-(pyridazin-4-yl)quinolin-6-yl]pyridin-3-yl}2,4- difhiorobenzenesulfonamido)methyl]phenyl} pentanamide) (102.7 mg, 41.8% yield) as a white solid. MS m / z = 1062.30 [M + H]+. 'H NMR (400 MHz, DMSO-cfe) 89.90 (d, J = 6.9 Hz, 1H), 9.60 - 9.42 (m, 2H), 9.05 (d, J = 4.4 Hz, 1H), 8.48 (d, J = 2.4 Hz, 1H), 8.23 (d, J = 8.8 Hz, 1H), 8.11 - 8.03 (m, 2H), 7.98 - 7.89 (m, 2H), 7.87 - 7.72 (m, 3H), 7.70 - 7.63 (m, 2H), 7.60 - 7.48 (m, 2H), 7.29 - 7.16 (m, 3H), 6.99 (s, 2H), 5.94 (t, J = 5.8 Hz, 1H), 5.39 (s, 2H), 4.81 (s, 2H), 4.39 - 4.11 (m, 2H), 3.68 - 3.41 (m, 9H), 3.13 - 2.86 (m, 2H), 2.47 - 2.35 (m, 1H), 2.30 - 2.13 (m, 1H), 1.91 - 1.82 (m, 1H), 1.65 (s, 2H), 1.47 - 1.27 (m, 2H), 0.80 - 0.74 (m, 6H).Synthesis of Mal-Pes( D-Val-Cit-PABC-Omipalisib (Coromiv-5 / PH-CORL-MC-2024-001C-5-Q)

[0192] In one embodiment, the present disclosure provides a linker and Omipalisib having the structure(Formula II, n=l, R=CH2CH2CH2NHCONH2). The reaction scheme is shown in Fig. 18.Step 1: {4-[(25)-5-(carbamoylamino)-2-[(25)-2-{ [(9H-fluoren-9-ylmethoxy)carbonyl]amino}-3- methylbutanamido]pentanamido]phenyl Jmethyl 7V-(2,4-difluorobenzenesulfonyl)-?V- { 2- methoxy-5-[4-(pyridazin-4-yl)quinolin-6-yl]pyridin-3-yl}carbamate (6b)

[0193] To a stirred solution of 5b ({4-[(25)-5-(carbamoylamino)-2-[(25)-2-{ [(9Ff-fluoren-9- ylmethoxy)carbonyl] amino }-3-methylbutanamido]pentanamido]phenyl Jmethyl 4-nitrophenyl carbonate) (500 mg, 0.652 mmol) and 2,4-difluoro- / V-{2-methoxy-5-[4-(pyridazin-4-yl)quinolin- 6-yl]pyridin-3-yl}benzenesulfonamide (263.69 mg, 0.522 mmol) in DCM (3 mL) and DMF (3 mL) was added DMAP (95.59 mg, 0.782 mmol) at room temperature under nitrogen atmosphere. The reaction was stirred at 45 °C for 1 h. The reaction mixture was concentrated to dryness and the residue was purified by silica gel column chromatography, eluted with 0 ~ 10% MeOH in DCM to afford 6b ({4-[(2S)-5-(carbamoylamino)-2-[(2S)-2-{[(9H-fluoren-9- ylmethoxy)carbonyl] amino } -3-methylbutanamido]pentanamido]phenyl } methyl vV-(2,4- difluorobenzenesulfonyl)-7V-{2-methoxy-5-[4-(pyridazin-4-yl)quinolin-6-yl]pyridin-3- yljcarbamate) (400 mg, 54% yield) as a white solid. MS m / z = 1133.55 [M + H]+.XH NMR (300 MHz, DMSO) 3 10.09 (s, 1H), 9.61 (dd, J = 2.4, 1.2 Hz, 1H), 9.50 (dd, J = 5.4, 1.2 Hz, 1H), 9.07 (d, J = 4.5 Hz, 1H), 8.71 (d, J = 2.3 Hz, 1H), 8.35 - 8.19 (m, 2H), 8.17 - 8.01 (m, 3H), 7.88 (d, J = 7.5 Hz, 1H), 7.79 - 7.58 (m, 3H), 7.52 (d, J = 8.4 Hz, 1H), 7.49 - 7.27 (m, 4H), 7.10 (d, J = 8.3 Hz, 1H), 5.97 (s, 1H), 5.42 (s, 2H), 5.21 - 4.90 (m, 2H), 4.40 (s, 1H), 4.31 - 4.13 (m, 3H), 3.99 - 3.89 (m, 1H), 3.85 (s, 3H),3.01 - 2.97 (m, 2H), 1.62 - 1.58 (m, 2H), 1.39 - 1.35 (m, 2H), 0.86 (t, J = 7.5 Hz, 6H).Step 2: {4-[(2S)-2-[(2S)-2-amino-3-methylbutanamido]-5-(carbamoylamino) pentanamidojphenyl } methyl A-(2,4-difluorobenzenesulfonyl)-A- { 2-methoxy-5-[4-(pyridazin-4- yl)quinolin-6-yl]pyridin-3-yl } carbamate (7b)

[0194] To a solution of 6b ({4-[(25)-5-(carbamoylamino)-2-[(25)-2-{[(977-fluoren-9- ylmethoxy)carbonyl]amino}-3-methylbutanamido]pentanamido]phenyl [methyl jV-(2, 4- difluorobenzenesulfonyl)-A-{2-methoxy-5-[4-(pyridazin-4-yl)quinolin-6-yl]pyridin-3- yljcarbamate) (400 mg, 0.353 mmol) in DMF (10 mL) was added diethylamine (1 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was directly purified by RP-Flash (Column: C1840 g Column; Mobile Phase A: water, Mobile Phase B: MeCN; Flow rate: 50 mL / min; Gradient: 2% B to 80% B in 40 min, Detector: UV 254 nm; RT = 31 min). The fractions containing desired product were combined and concentrated under reduced pressure to afford 7b ({4-[(25)-2-[(25)-2-amino-3-methylbutanamido]-5-(carbamoylamino)pentanamido]phenyl}methyl 2V-(2,4-difluorobenzenesulfonyl)-2V-{2-methoxy- 5-[4-(pyridazin-4-yl)quinolin-6-yl]pyridin-3-yl]carbamate) (200 mg, 93% yield) as a white solid. MS m / z = 911.40 [M + H]+.Step 3: {4-[(2S)-5-(carbamoylamino)-2-[(2S)-2-{ 3-[2-(2,5-dioxopyrrol-l-yl)ethoxy] propanamido}-3-methylbutanamido]pentanamido]phenyl}methyl 7V-(2,4- difluorobenzenesulfonyl)-Af-{2-methoxy-5-[4-(pyridazin-4-yl)quinolin-6-yl]pyridin-3- yl} carbamate

[0195] To a stirred solution of [4-[(25)-2-[(25)-2-amino-3-methylbutanamido]-5- (carbamoylamino) pentanamido]phenyl } methyl V-(2,4-difluorobenzenesulfonyl)-7V-{ 2-methoxy- 5-[4-(pyridazin-4-yl)quinolin-6-yl]pyridin-3-yl}carbamate (150 mg, 0.165 mmol) in DMF (1.7 mL) were added 2,5-dioxopyrrolidin-l-yl 3-[2-(2,5-dioxopyrrol-l-yl)ethoxy]propanoate (66.42 mg, 0.215 mmol) and DIEA (42.56 mg, 0.330 mmol) at 0 °C under argon atmosphere. The reaction was stirred at 0 °C for 0.5 h. The reaction mixture containing desired product was directly purified by RP-Flash (Column: C1840 g Column; Mobile Phase A: water (0.025% formic acid), Mobile Phase B: MeCN; Flow rate: 50 mL / min; Gradient: 2% B to 70% B in 30 min, Detector: UV 210 nm; RT = 25 min). The fractions containing desired product were combined and lyophilized to afford [4-[(2S)-5-(carbamoylamino)-2-[(2S)-2-{3-[2-(2,5- dioxopyrrol- 1 -yl)ethoxy]propanamido } -3-methylbutanamido]pentanamido]phenyl } methyl N- (2, 4-difluorobenzenesulfonyl)-A-{2-methoxy-5-[4-(pyridazin-4-yl)quinolin-6-yl]pyri din-3-yljcarbamate (102.6 mg, 56% yield) as a white solid. MS m / z. = 1106.30 [M + H]+. ’H NMR (400 MHz, DMSO-tZe) 8 10.00 (s, 1H), 9.54 (d, J = 1.9 Hz, 1H), 9.43 (d, J = 5.2 Hz, 1H), 9.00 (d, J = 4.4 Hz, 1H), 8.64 (d, J = 2.4 Hz, 1H), 8.26 (s, 1H), 8.21 (d, J = 8.8 Hz, 1H), 8.21 - 8.12 (m, 1H), 8.08 - 7.94 (m, 4H), 7.78 (d, J= 8.8 Hz, 1H), 7.62 (d, J = 4.4 Hz, 1H), 7.59 - 7.53 (m, 1H), 7.46 (d, J = 8.2 Hz, 2H), 7.26 (td, J = 9.2, 8.4, 2.4 Hz, 1H), 7.03 (d, J = 8.2 Hz, 2H), 6.94 (s, 2H), 5.91 (t, J = 6.0 Hz, 1H), 5.35 (s, 2H), 5.09 - 4.90 (m, 2H), 4.34 - 4.25 (m, 1H), 4.17 - 4.09 (m, 1H), 3.78 (s, 3H), 3.58 - 3.31 (m, 4H), 3.10 - 2.85 (m, 2H), 2.35 (q, J = 7.2 Hz, 1H), 2.30 - 2.15 (m, 1H), 1.94 - 1.82 (m, 1H), 1.68 - 1.45 (m, 2H), 1.29 (d, J = 7.9 Hz, 2H), 0.84 - 0.79 (m, 6H).

[0196] _In one embodiment, the present disclosure provides a linker and Omipalisib having the structure(Formula HI, n=l, R2= H, R1= (CH2)2O(CH2)2O(CH2)2OMe, R= CH2CH2CH2NHCONH2). The reaction scheme is shown in Fig. 28.Step 1: 4-azidobenzyl (2-(2-(2-methoxyethoxy)ethoxy)ethyl)carbamate EB2503211-018.

[0197] To a solution of 4-azidobenzyl (4-nitrophenyl) carbonate (500 mg, 1.591 mmol) in DMF (5 mL) and pyridine (1 mL) were added 2-(2-(2-methoxyethoxy)ethoxy)ethan-l -amine (311.62 mg, 1.909 mmol), HOBT (107.50 mg, 0.795 mmol) and DIEA (205.64 mg, 1.591 mmol) at 25 °C under argon atmosphere. The resulting mixture was stirred at 25 °C for 3 hours. The reaction was quenched with water (50 mL), extracted with ethyl acetate (100 mL x 3). The organic layer was washed with water (50 mL x 5) and brine (50 mL). After then the organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with ethyl acetate / petroleum ether (1 ~ 90%) to afford 4-azidobenzyl (2-(2-(2- methoxyethoxy)ethoxy)ethyl)carbamate (480 mg, 89.1% yield) as a yellow oil. MS ESI calculated for C15H22N4O5 [M - H]" 337.16, found 337.10; 'H NMR (300 MHz, CDCI3) 87.40 -7.30 (m, 2H), 7.06 - 6.96 (m, 2H), 5.37 - 5.27 (m, 1H), 5.06 (s, 2H), 3.68 - 3.58 (m, 2H), 3.66 - 3.60 (m, 4H), 3.60 - 3.49 (m, 4H), 3.42 - 3.34 (m, 2H),3.39 - 3.33 (m, 3H).Step 2: 4-azidobenzyl (chloromethyl)(2-(2-(2-methoxyethoxy)ethoxy)ethyl)carbamateEB2503211-027.

[0198] To a solution of 4-azidobenzyl (2-(2-(2-methoxyethoxy)ethoxy)ethyl)carbamate (100 mg, 0.296 mmol) and (HCHO)n (17.75 mg, 0.592 mmol) in DCM (1 mL) was added TMSC1 (144.48 mg, 1.332 mmol) at 25 °C under argon atmosphere. The resulting mixture was stirred at 25 °C for 2 hours. Upon completion the mixture was filtered. The filter cake was washed with DCM (3 x 10 mL). The filtrate was concentrated under reduced pressure to afford 4-azidobenzyl (chloromethyl)(2-(2-(2-methoxyethoxy)ethoxy)ethyl)carbamate as a light yellow oil (100 mg crude). The crude product was used in the next step directly without further purification. (Note: for LCMS monitoring, the aliquot was quenched with MeOH to afford 4-azidobenzyl (2-(2-(2- methoxyethoxy)ethoxy)ethyl)(methoxymethyl)carbamate; MS ESI calculated for C17H26N4O6 [M + NH4]+400.22, found 400.15.)Step 3: 4-azidobenzyl (((2,4-difluoro- / V-(2-methoxy-5-(4-(pyridazin-4-yl)quinolin-6-yl)pyridin- 3-yl)phenyl)sulfonamido)methyl)(2-(2-(2-methoxyethoxy)ethoxy)ethyl)carbamate EB2503211- 028.

[0199] To a solution of 4-azidobenzyl (chloromethyl)(2-(2-(2- methoxyethoxy)ethoxy)ethyl)carbamate (85 mg, 0.220 mmol) in DMF (1 mL) were added 2,4- difluoro-A^(2-methoxy-5-(4-(pyridazin-4-yl)quinolin-6-yl)pyridin-3-yl)benzenesulfonamide (66.65 mg, 0.132 mmol) and DIEA (56.80 mg, 0.440 mmol) at 25 °C under argon atmosphere. The resulting mixture was stirred at 25 °C for 1 hour. The mixture was directly purified by RP- flash chromatography, eluted with 0 - 50% acetonitrile in water to afford 4-azidobenzyl (((2,4- difluoro-Af-(2-methoxy-5-(4-(pyridazin-4-yl)quinolin-6-yl)pyridin-3- yl)phenyl)sulfonamido)methyl)(2-(2-(2-methoxyethoxy)ethoxy)ethyl)carbamate (100 mg, 53.1% yield) as an off-white solid. MS ESI calculated for C41H39F2N9O8S [M + H]+856.27, found 856.30. 'H NMR (400 MHz, CDCh) 89.50 - 9.35 (m, 3H), 9.17 - 9.08 (m, 1H), 8.54 - 8.36 (m, 1H), 8.30 - 8.06 (m, 1H), 7.97 - 7.80 (m, 1H), 7.81 - 7.68 (m, 2H), 7.72 - 7.54 (m, 2H), 7.55 - 7.42(m, 1H), 7.12 - 6.92 (m, 2H), 6.90 - 6.81 (m, 1H), 6.81 - 6.73 (m, 1H), 6.70 - 6.58 (m, 1H), 5.69 - 4.40 (m, 4H), 3.83 - 3.48 (m, 12H), 3.47 - 3.28 (m, 6H).19F NMR (376 MHz, CDCI3) 8 - 100.08 - -100.16 (m, IF), -102.75 - -102.99 (m, IF).Step 4: 4-aminobenzyl (((2,4-difluoro- / V-(2-methoxy-5-(4-(pyridazin-4-yl)quinolin-6-yl)pyridin- 3-yl)phenyl)sulfonamido)methyl)(2-(2-(2-methoxyethoxy)ethoxy)ethyl)carbamate EB2503256-032

[0200] To a solution of 4-azidobenzyl (((2,4-difluoro-A-(2-methoxy-5-(4-(pyridazin-4- yl)quinolin-6-yl)pyridin-3-yl)phenyl)sulfonamido)methyl)(2-(2-(2- methoxyethoxy)ethoxy)ethyl)carbamate (90 mg, 0.105 mmol) in THF (0.3 mL) was added trimethyl phosphine (1.0M in THF, 0.04 mL, 0.038 mmol) at 0 °C under argon atmosphere. The resulting mixture was stirred at 0 °C for 3 minutes. After then the mixture was concentrated under reduced pressure to afford 4-aminobenzyl (((2,4-difluoro-7V-(2-methoxy-5-(4-(pyridazin-4- yl)quinolin-6-yl)pyridin-3-yl)phenyl)sulfonamido)methyl)(2-(2-(2- methoxyethoxy)ethoxy)ethyl)carbamate (90 mg crude), which was used in the next step directly without further purification. MS ESI calculated for C41H41F2N7O8S [M + H]+830.27, found 830.30.Step 5: (S)-4-(2-((((9 / / -fluoren-9-yl)methoxy)carbonyl)amino)-5-ureidopentanamido)benzyl (((2,4-difluoro-7V-(2-methoxy-5-(4-(pyridazin-4-yl)quinolin-6-yl)pyridin-3- yl)phenyl)sulfonamido)methyl) (2-(2-(2-methoxyethoxy)ethoxy)ethyl)carbamate EB2503211- 033.

[0201] To a solution of 4-aminobenzyl (((2,4-difluoro-A-(2-methoxy-5-(4-(pyridazin-4- yl)quinolin-6-yl)pyridin-3-yl)phenyl)sulfonamido)methyl)(2-(2-(2- methoxyethoxy)ethoxy)ethyl)carbamate (75 mg, 0.090 mmol) in DMF (1 mL) were added (5)-2- ((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-ureidopentanoic acid (53.88 mg, 0.135 mmol), HATH (51.55 mg, 0.135 mmol) and DIEA (23.36 mg, 0.180 mmol) at room temperature under argon atmosphere. The resulting mixture was stirred at 25 °C for 2 hours. The reaction was purified by 7? P- flash chromatography, eluted with 0 - 51% acetonitrile in water to afford (S)-4- (2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-ureidopentanamido)benzyl (((2,4-difluoro-A- (2-methoxy-5-(4-(pyridazin-4-yl)quinolin-6-yl)pyridin-3-yl)phenyl)sulfonamido)methyl)(2-(2- (2-methoxyethoxy)ethoxy)ethyl)carbamate (90 mg, 82.3% yield) as an off-white solid. MS ESI calculated for C62H62F2N10O12S [M + H]+1209.42, found 1209.35.Step 6: (S)-4-(2-amino-5-ureidopentanamido)benzyl (((2,4-difhioro-7V-(2-methoxy-5-(4- (pyridazin-4-yl)quinolin-6-yl)pyridin-3-yl)phenyl)sulfonamido)methyl)(2-(2-(2- methoxyethoxy)ethoxy)ethyl) carbamate EB2503256-035.

[0202] A solution of (S)-4-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5- ureidopentanamido)benzyl (((2,4-difluoro-Ar-(2-methoxy-5-(4-(pyridazin-4-yl)quinolin-6- yl)pyridin-3-yl)phenyl)sulfonamido) methyl)(2-(2-(2-methoxyethoxy)ethoxy)ethyl)carbamate (90 mg, 0.074 mmol) in DEA (0.02 mL) and DMF (0.8 mL) was stirred at 25 °C for 1 hour under argon atmosphere. Upon completion the mixture was directly purified by / ?P- flash chromatography, eluted with 0 - 51% acetonitrile in water to afford (S)-4-(2-amino-5- ureidopentanamido)benzyl (((2,4-difluoro-Ar-(2-methoxy-5-(4-(pyridazin-4-yl)quinolin-6- yl)pyridin-3-yl)phenyl)sulfonamido)methyl)(2-(2-(2-methoxyethoxy)ethoxy)ethyl) carbamate (60 mg, 81.6% yield) as an off-white solid. MS ESI calculated for C47H52F2N10O10S [M + H]+987.36, found 987.55.Step 7: 4-((S)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methylbutanamido)-5- ureidopentanamido)benzyl (((2,4-difluoro-A-(2-methoxy-5-(4-(pyridazin-4-yl)quinolin-6- yl)pyridin-3-yl)phenyl)sulfonamido)methyl)(2-(2-(2-methoxyethoxy)ethoxy)ethyl)carbamate EB2503211-037.

[0203] To a solution of (5)-4-(2-amino-5-ureidopentanamido)benzyl (((2,4-difluoro-A-(2- methoxy-5-(4-(pyridazin-4-yl)quinolin-6-yl)pyridin-3-yl)phenyl)sulfonamido)methyl)(2-(2-(2- methoxyethoxy) ethoxy)ethyl)carbamate (60 mg, 0.061 mmol) in DMF (1 mL) were added (((977-fluoren-9-yl)methoxy)carbonyl)-L-valine (30.95 mg, 0.091 mmol), HATU (34.67 mg, 0.091 mmol) and DIEA (15.71 mg, 0.122 mmol) at room temperature under argon atmosphere. The resulting mixture was stirred at 25 °C for 2 hours. Upon completion the mixture was directly purified by / ?P- flash chromatography, eluted with 0 - 51 % acetonitrile in water to afford 4-((S)- 2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methylbutanamido)-5- ureidopentanamido)benzyl (((2,4-difluoro-A-(2-methoxy-5-(4-(pyridazin-4-yl)quinolin-6- yl)pyridin-3-yl)phenyl)sulfonamido)methyl)(2-(2-(2-methoxyethoxy)ethoxy)ethyl)carbamate (70 mg, 88.0% yield) as an off-white solid. MS ESI calculated for C67H71F2N11O13S [M + H]+1308.49, found 1308.55.Step 8: 4-((5)-2-((S)-2-amino-3-methylbutanamido)-5-ureidopentanamido)benzyl (((2,4- difluoro-A^-(2-methoxy-5-(4-(pyridazin-4-yl)quinolin-6-yl)pyridin-3- yl)phenyl)sulfonamido)methyl)(2-(2-(2-methoxyethoxy)ethoxy)ethyl)carbamate EB2503211- 039.

[0204] A solution of 4-((S)-2-((S)-2-((((977-fluoren-9-yl)methoxy)carbonyl)amino)-3-methylbutanamido)-5-ureidopentanamido)benzyl (((2,4-difluoro-? / -(2-methoxy-5-(4-(pyridazin- 4-yl)quinolin-6-yl)pyridin-3-yl)phenyl)sulfonamido)methyl)(2-(2-(2- methoxyethoxy)ethoxy)ethyl)carbamate (70 mg, 0.053 mmol) in DEA (0.02 mL) and DMF (0.8 mL) was stirred at 25 °C for 1 hour under argon atmosphere. The resulting mixture was directly purified by flash chromatography, eluted with 0 - 51% acetonitrile in water to afford 4-((5)- 2-((S)-2-amino-3-methylbutanamido)-5-ureidopentanamido)benzyl (((2,4-difluoro-7V-(2- methoxy-5-(4-(pyridazin-4-yl)quinolin-6-yl)pyridin-3-yl)phenyl)sulfonamido)methyl)(2-(2-(2- methoxyethoxy)ethoxy)ethyl)carbamate (50 mg, 86.0% yield) as an off-white solid. MS ESI calculated for C52H61F2N11O11S [M + H]+1086.42, found 1086.70.Step 9: 4-((S)-2-((S)-2-(3-(2-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)ethoxy)propanamido)-3- methylbutanamido)-5-ureidopentanamido)benzyl (((2,4-difluoro-jV-(2-methoxy-5-(4-(pyridazin- 4-yl)quinolin-6-yl)pyridin-3-yl)phenyl)sulfonamido)methyl)(2-(2-(2- methoxyethoxy)ethoxy)ethyl)carbamate EB2503211-041.

[0205] To a solution of 4-((S)-2-((S)-2-amino-3-methylbutanamido)-5- ureidopentanamido)benzyl (((2,4-difluoro-A-(2-methoxy-5-(4-(pyridazin-4-yl)quinolin-6- yl)pyridin-3-yl)phenyl)sulfonamido)methyl) (2-(2-(2-methoxyethoxy)ethoxy)ethyl)carbamate (20 mg, 0.018 mmol) in DMF (0.5 mL) were added 2,5-dioxopyrrolidin-l-yl 3-(2-(2,5-dioxo- 2,5-dihydro-177-pyrrol-l-yl)ethoxy)propanoate (6.86 mg, 0.022 mmol) and DIEA (4.76 mg, 0.036 mmol) at 25 °C under argon atmosphere. The resulting mixture was stirred at 25 °C for 1 hour. The reaction mixture was purified by RP-flash chromatography, eluted with 0 - 48% acetonitrile in water to afford 4-((S)-2-((S)-2-(3-(2-(2,5-dioxo-2,5-dihydro-17 / -pyrrol-l- yl)ethoxy)propanamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl (((2,4-difluoro-vV- (2-methoxy-5-(4-(pyridazin-4-yl)quinolin-6-yl)pyridin-3-yl)phenyl)sulfonamido)methyl)(2-(2- (2-methoxyethoxy)ethoxy)ethyl)carbamate (11.2 mg, 47.4% yield) as a white solid. MS ESI calculated for C61H70F2N12O15S [M + H]+1281.48, found 1281.30. 'H NMR (400 MHz, DMSO - J6) 8 9.93 - 9.89 (m, 1H), 9.63 - 9.59 (m, 1H), 9.47 - 9.40 (m, 1H), 9.07 - 9.06 (m, 1H), 8.59 - 8.55 (m, 1H), 8.30 - 8.26 (m, 1H), 8.09 - 8.05 (m, 3H), 7.94 - 7.91 (m, 2H), 7.86 - 7.84 (m, 1H), 7.70 - 7.63 (m, 3H), 7.49 - 7.37 (m, 2H), 7.23 - 7.15 (m, 1H), 7.03 - 6.94 (m, 3H), 6.88 - 6.86 (m, 1H), 6.01 - 5.95 (s, 1H), 5.42 - 5.19 (m, 2H), 4.64 - 4.58 (m, 1H), 4.41 - 4.22 (m, 3H), 3.62 - 3.49 (m, 18H), 3.48 - 3.32 (m, 4H), 3.21 (s, 3H), 3.07 - 2.98 (m, 2H), 2.51 - 2.42 (m, 1H), 2.37 - 2.31(m, 1H), 2.09 - 1.98 (m, 1H), 1.68 - 1.51 (m, 2H), 1.49 - 1.32 (m, 2H), 0.85 - 0.80 (m, 6H).19F NMR (376 MHz, DMSO - d6) 8 -100.68 - -100.77 (m, IF), -103.70 - -103.73 (m, IF).

[0206] In one embodiment, the present disclosure provides a linker and Omipalisib having the structure(Formula HI, n=l, R2= H, R1=(CH2)2N(CH3)2, R= CH2CH2CH2NHCONH2). The reaction scheme is shown in Fig. 39.Step 1: (4-azidophenyl)methanol EB2501844-001

[0207] To a solution of (4-aminophenyl)methanol (2 g, 16.240 mmol) in HC1 (20 mL, 6 M in H2O) was added dropwise NaNCh (1.68 g, 24.360 mmol) in H2O (40 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes. NaNg (4.22 g, 64.960 mmol, 4 equiv.) in H2O (80 mL) was added to above solution at 0 °C. The resultant mixture was stirred for 2 hours at room temperature. The reaction was quenched by addition of saturated aqueous sodium bicarbonate (200 mL), extracted with ethyl acetate (200 mL x 3). The organic layer was washed with water (100 mL) and brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0 - 60% EA in PE to afford (4- azidophenyl)methanol (2.1 g, 86.7% yield) as a light yellow oil. H NMR (400 MHz, CDCI3) 3 7.42 - 7.30 (m, 2H), 7.08 - 6.97 (m, 2H), 4.65 (s, 2H).Step 2: 4-azidobenzyl (4-nitrophenyl) carbonate EB2501844-003

[0208] To a stirred mixture of (4-azidophenyl)methanol (2 g, 13.409 mmol) in DCM (30 mL) were added pyridine (2.12 g, 26.818 mmol) and 4-nitrophenyl carbonochloridate (3.24 g, 16.091 mmol) at 0 °C under argon atmosphere. The resulting mixture was stirred at room temperature for 16 hours. The reaction was quenched with H2O (50 mL), extracted with ethyl acetate (100 mL x 3). The organic layer was washed with water (100 mL) and brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated underreduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient 0% to 20% EA in PE to afford 4-azidobenzyl (4-nitrophenyl) carbonate (3.4 g, 80.6% yield) as a light yellow solid. ’H NMR (300 MHz, CDCI3) 58.32 - 8.24 (m, 2H), 7.48 - 7.41 (m, 2H), 7.41 - 7.34 (m, 2H), 7.10 - 7.03 (m, 2H), 5.26 (s, 2H).Step 3: (9H-fluoren-9-yl)methyl (2-((tert-butoxycarbonyl)amino)ethyl)(methyl)carbamateEB2501844-005

[0209] To a stirred solution of tert-butyl (2-(methylamino)ethyl)carbamate (1 g, 5.739 mmol) in THE (10 mL) and H2O (10 mL) were added NaHCOs (1.45 g, 17.217 mmol) and Fmoc-OSu (2.13 g, 6.313 mmol) at room temperature under argon atmosphere. The reaction mixture was stirred for 4 hours. Upon completion the resulting mixture was directly purified by RP-Flash chromatography, eluted with 2 - 98% acetonitrile in water to afford (9H-fluoren-9-yl)methyl (2- ((tert-butoxycarbonyl)amino)ethyl)(methyl)carbamate (2 g, 87.8% yield) as a light yellow solid. MS ESI calculated for C23H28N2O4 [M + H]+397.21, found 397.25. 'H NMR (400 MHz, DMSO) 87.91 - 7.84 (m, 2H), 7.67 - 7.63 (m, 2H), 7.42 - 7.39 (m, 2H), 7.38 - 7.31 (m, 2H), 6.86 (s, 1H), 4.34 - 4.23 (m, 3H), 3.26 - 3.20 (m, 2H), 3.05 - 2.98 (m, 2H), 2.82 (s, 3H), 1.37 - 1.34 (m, 9H). Step 4: (9H-fluoren-9-yl)methyl (2-aminoethyl)(methyl)carbamate 2,2,2-trifluoroacetic acid salt EB2501844-006

[0210] To a stirred solution of (9 / 7-fluoren-9-yl)methyl (2-((tert- butoxycarbonyl)amino)ethyl)(methyl) carbamate (2 g, 5.044 mmol) in DCM (20 mL) was added TEA (4 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to afford 9(9 / 7-fluoren-9-yl)methyl (2-aminoethyl)(methyl)carbamate 2,2,2-trifluoroacetic acid salt (2 g) as reddish brown yellow oil. MS ESI calculated for C18H20N2O2 [M + H]+297.16, found 297.20Step 5: (9H-fluoren-9-yl)methyl (2-((((4-azidobenzyl)oxy)carbonyl)amino)ethyl)(methyl) carbamate EB2501844-007

[0211] To a stirred mixture of 9(9 / / -fluoren-9-yl)methyl (2-aminoethyl)(methyl)carbamate 2,2,2- trifluoroacetic acid salt (2.22 g, 5.410 mmol) in DMF (20 mL) and pyridine (4 mL) were added 4-azidobenzyl (4-nitrophenyl) carbonate (1.7 g, 5.410 mmol), HOBT (365.49 mg, 2.705 mmol) and DIEA (699.17 mg, 5.410 mmol) at 0 °C under argon atmosphere. The resulting mixture was stirred at room temperature for 4 hours. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (3 x 150 mL). The combined organic layers were washed with brine(150 mL x 3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient 0% to 80% ethyl acetate in petroleum ether to afford (9H-fluoren-9-yl)methyl (2-((((4- azidobenzyl)oxy)carbonyl) amino)ethyl)(methyl)carbamate (1.82 g, 71.3% yield) as a light yellow oil. MS ESI calculated for C26H25N5O4 [M + Na]+494.18, found 494.20.XH NMR (300 MHz, DMSO-Je) 87.91 - 7.88 (m, 2H), 7.66 - 7.54 (m, 2H), 7.45 - 7.26 (m, 7H), 7.08 - 7.02 (m, 2H), 4.97 (s, 2H), 4.26 - 4.21 (m, 3H), 3.28 - 3.23 (m, 2H), 3.17 - 2.99 (m, 2H), 2.82 (s, 3H).Step 6: 4-azidobenzyl (2-((((97 / -fluoren-9-yl)methoxy)carbonyl)(methyl)amino)ethyl) (chloromethyl) carbamate EB2501844-008

[0212] To a stirred mixture of (9H-fluoren-9-yl)methyl (2-((((4- azidobenzyl)oxy)carbonyl)amino)ethyl) (methyl)carbamate (1.8 g, 3.817 mmol) in DCM (20 mL) were added (CthO),, (336.34 mg, 7.634 mmol) and TMSC1 (1.66 g, 15.268 mmol) at 0 °C under argon atmosphere. The resulting mixture was stirred at room temperature for 2 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford 4- azidobenzyl (2-((((977-fluoren-9-yl)methoxy) carbonyl)(methyl)amino)ethyl)(chloromethyl)carbamate (1.8 g) as a light yellow solid. (Note: for LCMS monitoring, the aliquot was quenched with MeOH to afford 4-azidobenzyl (2-((((977- fluoren-9-yl)methoxy)carbonyl)(methyl)amino)ethyl)(methoxymethyl)carbamate; MS ESI calculated for C28H29N5O5 [M + NH4]+533.25, found 533.30.)Step 7: (9H-fluoren-9-yl)methyl (2-((((4-azidobenzyl)oxy)carbonyl)(((2,4-difluoro-A-(2- methoxy- 5-(4-(pyridazin-4-yl)quinolin-6-yl)pyridin-3- yl)phenyl)sulfonamido)methyl)amino)ethyl)(methyl)carbamate EB2501844-009

[0213] To a stirred mixture of 4-azidobenzyl (2-((((9W-fluorcn-9- yl)methoxy)carbonyl)(methyl)amino)ethyl) (chloromethyl)carbamate (1.8 g, 3.462 mmol) in DMF (20 mL) were added 2,4-difluoro-7V-(2-methoxy-5-(4-(pyridazin-4-yl)quinolin-6- yl)pyridin-3-yl)benzenesulfonamide (1.40 g, 2.770 mmol) and DIEA (894.80 mg, 6.924 mmol) at 0 °C under argon atmosphere. The resulting mixture was stirred at room temperature for 16 hours. Upon completion the resulting mixture was directly purified by 7?P-Flash chromatography, eluted with 2 - 85% acetonitrile in water (0.05% TEA) to afford (9H-fluoren-9- yl)methyl (2-((((4-azidobenzyl)oxy)carbonyl)(((2,4-difluoro-A-(2-methoxy-5-(4-(pyridazin-4- yl)quinolin-6-yl)pyridin-3-yl)phenyl)sulfonamido)methyl)amino)ethyl)(methyl)carbamate (1.6 g,46.7% yield) as a light yellow solid. MS ESI calculated for C52H42F2N10O7S [M + H]+989.30, found 989.40.Step 8: 4-azidobenzyl (((2,4-difluoro-AA-(2-methoxy-5-(4-(pyridazin-4-yl)quinolin-6-yl)pyridin- 3-yl) phenyl)sulfonamido)methyl)(2-(methylamino)ethyl)carbamate EB2501844-010

[0214] To a stirred mixture of (9H-fluoren-9-yl)methyl (2-((((4- azidobenzyl)oxy)carbonyl)(((2,4-difluoro-A-(2-methoxy-5-(4-(pyridazin-4-yl)quinolin-6- yl)pyridin-3-yl)phenyl)sulfonamido)methyl)amino)ethyl)(methyl)carbamate (1.4 g, 1.416 mmol) in DMF (20 mL) was added diethylamine (DEA, 517.65 mg, 7.080 mmol) at 0 °C under argon atmosphere. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was purified by 7?P-Flash chromatography, eluted with 2 - 60% acetonitrile in water (0.05% TFA) to afford 4-azidobenzyl (((2,4-difluoro-7V-(2-methoxy-5-(4-(pyridazin-4- yl)quinolin-6-yl) pyridin-3-yl)phenyl)sulfonamido)methyl)(2-(methylamino)ethyl)carbamate (850 mg, 78.3% yield) as a light yellow solid. MS ESI calculated for C37H32F2N10O5S [M + H]+767.23, found 767.15.Step 9: 4-azidobenzyl (((2,4-difluoro-Af-(2-methoxy-5-(4-(pyridazin-4-yl)quinolin-6-yl)pyridin- 3-yl) phenyl)sulfonamido)methyl)(2-(dimethylamino)ethyl)carbamate EB2501844-013

[0215] To a solution of 4-azidobenzyl (((2,4-difluoro-7V-(2-methoxy-5-(4-(pyridazin-4- yl)quinolin-6-yl)pyridin-3-yl)phenyl)sulfonamido)methyl)(2-(methylamino)ethyl)carbamate (830 mg, 1.082 mmol) in 1,2-dichloroethane (15 mL) were added formaldehyde solution (114.19 mg, 1.407 mmol, 37% wt in H2O) and EtsN (328.61 mg, 3.246 mmol) at room temperature. The resulting mixture was stirred at room temperature for 0.5 hours. Then sodium cyanoborohydride (204.06 mg, 3.246 mmol) was added to the above solution at 0 °C. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by 7?P-Flash chromatography, eluted with 2 - 50% acetonitrile in water (0.05% TEA) to afford 4-azidobenzyl (((2,4-difluoro-A- (2-methoxy-5-(4-(pyridazin-4-yl)quinolin-6-yl)pyridin-3-yl)phenyl)sulfonamido)methyl)(2- (dimethylamino)ethyl)carbamate (450 mg, 53.2% yield) as a light yellow solid. MS ESI calculated for C38H34F2N10O5S [M + H]+781.25, found 781.30. H NMR (400 MHz, DMSO - d6) 89.65 - 9.42 (m, 3H), 9.10 - 9.08 (m, 1H), 8.63 - 8.38 (m, 1H), 8.29 - 8.22 (m, 1H), 8.12 - 7.91 (m, 3H), 7.81 - 7.63 (m, 4H), 7.22 - 7.18 (m, 1H), 6.90 - 6.84 (m, 2H), 6.79 - 6.62 (m, 1H), 6.56 - 6.53 (m, 1H), 5.26 (s, 2H), 4.63 - 4.47 (m, 2H), 3.71 - 3.33 (m, 6H), 2.91 - 2.85 (m, 6H).19FNMR (376 MHz, DMSO - d6) 8 -100.30 - -101.53 (m, IF), -103.41, - -103.78 (m, IF).Step 10: 4-aminobenzyl (((2,4-difluoro-A-(2-methoxy-5-(4-(pyridazin-4-yl)quinolin-6-yl) pyridin-3-yl)phenyl)sulfonamido)methyl)(2-(dimethylamino)ethyl)carbamate EB2501844-016

[0216] To a stirred mixture of 4-azidobenzyl (((2,4-difluoro-Af-(2-methoxy-5-(4-(pyridazin-4- yl)quinolin-6-yl)pyridin-3-yl)phenyl)sulfonamido)methyl)(2-(dimethylamino)ethyl)carbamate (180 mg, 0.231 mmol) in THF (2 mL) were added trimethylphosphine (1.0 M in THF, 737.70 uL, 0.739 mmol) at 0 °C under argon atmosphere. The resulting mixture was stirred at 0 °C for 5 minutes. The reaction mixture was concentrated under reduced pressure to afford 4-aminobenzyl (((2,4-difluoro-Ar-(2-methoxy-5-(4-(pyridazin-4-yl) quinolin-6-yl)pyridin-3- yl)phenyl)sulfonamido)methyl)(2-(dimethylamino)ethyl)carbamate (180 mg) as a light yellow solid. The crude was used in the next step without further purification. MS ESI calculated for C38H36F2N8O5S [M + H]+755.26, found 755.25Step 11: (5)-4-(2-((((9 / 7-fluoren-9-yl)methoxy)carbonyl)amino)-5-ureidopentanamido)benzyl (((2,4-difluoro-7V-(2-methoxy-5-(4-(pyridazin-4-yl)quinolin-6-yl)pyridin-3- yl)phenyl)sulfonamido)methyl)(2-(dimethylamino)ethyl)carbamate EB2501844-018

[0217] To a stirred mixture of (5)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5- ureidopentanoic acid (142.16 mg, 0.357 mmol) in DMF (3 mL) were added HATU (136.01 mg, 0.357 mmol) and DIEA (92.46 mg, 0.714 mmol) at room temperature under argon atmosphere. The resulting mixture was stirred for 10 minutes. Then 4-aminobenzyl (((2,4-difhioro-2V-(2- methoxy-5-(4-(pyridazin-4-yl) quinolin-6-yl)pyridin-3-yl)phenyl)sulfonamido)methyl)(2- (dimethylamino)ethyl)carbamate (180 mg, 0.238 mmol) was added to the above solution. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was purified by RP-Flash chromatography, eluted with 2 - 70% methanol in 5 mM aq. NH4HCO3) to afford (S)-4-(2-((((977-fluoren-9-yl)methoxy)carbonyl) amino)-5-ureidopentanamido)benzyl (((2,4- difluoro-Af-(2-methoxy-5-(4-(pyridazin-4-yl) quinolin-6-yl)pyridin-3- yl)phenyl)sulfonamido)methyl)(2-(dimethylamino)ethyl)carbamate (80 mg, 29.5% yield) as a light yellow solid. MS ESI calculated for C59H57F2N11O9S [M + H]+1134.41, found 1134.55.Step 12: (S)-4-(2-amino-5-ureidopentanamido)benzyl (((2,4-difluoro- / V-(2-methoxy-5- (4- (pyridazin-4-yl)quinolin-6-yl)pyridin-3-yl)phenyl)sulfonamido)methyl)(2- (dimethylamino)ethyl)carbamate 2,2,2-trifluoroacetic acid salt EB2501844-020

[0218] To a stirred mixture of (S)-4-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5- ureidopentanamido) benzyl (((2,4-difluoro-jV-(2-methoxy-5-(4-(pyridazin-4-yl)quinolin-6- yl)pyridin-3-yl)phenyl) sulfonamido)methyl)(2-(dimethylamino)ethyl)carbamate (80 mg, 0.071 mmol) in DMF (1 mL) was added DEA (25.79 mg, 0.355 mmol) at 0 °C under argon atmosphere. The resulting mixture was stirred at room temperature for 1 hour. Upon completion the mixture was purified by 7?P-Flash chromatography, eluted with 2 - 60% acetonitrile in water (0.05% TEA) to afford (S)-4-(2-amino-5-ureidopentanamido)benzyl (((2,4-difluoro-7V-(2- methoxy-5-(4-(pyridazin-4-yl) quinolin-6-yl)pyridin-3-yl)phenyl)sulfonamido)methyl)(2- (dimethylamino)ethyl)carbamate 2,2,2-trifluoroacetic acid salt (60 mg, 93.2% yield) as a light yellow solid. MS ESI calculated for C44H47F2N11O7S [M + H]+912.34, found 912.40.Step 13: 4-((S)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methylbutanamido)- 5- ureidopentanamido)benzyl (((2,4-difluoro-Ar-(2-methoxy-5-(4-(pyridazin-4-yl)quinolin-6-yl) pyridin-3-yl)phenyl)sulfonamido)methyl)(2-(dimethylamino)ethyl)carbamate EB2501844-021

[0219] To a stirred mixture of (((9 / / -fluoren-9-yl)methoxy)carbonyl)-A-valine (26.79 mg, 0.079 mmol, 1.2 equiv.) in DMF (1 mL) were added HATU (30.02 mg, 0.079 mmol, 1.2 equiv.) and DIEA (25.51 mg, 0.198 mmol, 3 equiv.) at room temperature under argon atmosphere. The resulting mixture was stirred for 10 minutes. Then (5)-4-(2-amino-5-ureidopentanamido)benzyl (((2,4-difluoro-A-(2-methoxy-5-(4-(pyridazin-4-yl)quinolin-6-yl)pyridin-3- yl)phenyl)sulfonamido)methyl)(2-(dimethylamino)ethyl)carbamate 2,2,2-trifluoroacetic acid salt (60 mg, 0.066 mmol, 1.0 equiv.) was added to the above solution. The resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was purified by 7?P-Flash chromatography, eluted with 2 - 70% methanol in water (0.05% TFA) to afford 4-((S)-2-((S)-2- ((((977-fluoren-9-yl)methoxy)carbonyl) amino)-3-methylbutanamido)-5- ureidopentanamido)benzyl (((2,4-difluoro-A-(2-methoxy-5- (4-(pyridazin-4-yl)quinolin-6- yl)pyridin-3-yl)phenyl)sulfonamido)methyl)(2-(dimethylamino)ethyl) carbamate (70 mg, 86.2% yield) as a light yellow solid. MS ESI calculated for C64H66F2N12O10S [M + H]+1233.48, found 1233.40.Step 14: 4-((S)-2-((S)-2-amino-3-methylbutanamido)-5-ureidopentanamido)benzyl (((2,4- difluoro-A-(2-methoxy-5-(4-(pyridazin-4-yl)quinolin-6-yl)pyridin-3- yl)phenyl)sulfonamido)methyl)(2-(dimethylamino)ethyl)carbamate 2,2,2-trifluoroacetic acid saltEB2501844-022

[0220] To a stirred mixture of 4-((5)-2-((S)-2-((((97 / -fluoren-9-yl)methoxy)carbonyl)amino) -3- methylbutanamido)-5-ureidopentanamido)benzyl (((2,4-difluoro-A-(2-methoxy-5-(4- (pyridazin- 4-yl)quinolin-6-yl)pyridin-3-yl)phenyl)sulfonamido)methyl)(2-(dimethylamino)ethyl) carbamate (70 mg, 0.057 mmol) in DMF (1 mL) was added DEA (20.76 mg, 0.285 mmol) at 0 °C under argon atmosphere. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was purified by RP-Flash chromatography, eluted with 2 - 50% acetonitrile in water (0.05% TEA) to afford 4-((S)-2-((S)-2-amino-3-methylbutanamido)-5-ureidopentanamido) benzyl (((2,4-difluoro-A-(2-methoxy-5-(4-(pyridazin-4-yl)quinolin-6-yl)pyridin-3-yl) phenyl)sulfonamido)methyl)(2-(dimethylamino)ethyl)carbamate 2,2,2-trifluoroacetic acid salt (50 mg, 87.1% yield) as a light yellow solid. MS ESI calculated for C49H56F2N12O8S [M + H]+1011.41, found 1011.40.Step 15: 4-((S)-2-((S)-2-(3-(2-(2,5-dioxo-2,5-dihydro- 1 / 7-pyrrol- 1 -yl)ethoxy)propanamido)-3- methylbutanamido)-5-ureidopentanamido)benzyl (((2,4-difluoro-7V-(2-methoxy-5-(4-(pyridazin- 4-yl) quinolin-6-yl)pyridin-3-yl)phenyl)sulfonamido)methyl)(2-(dimethylamino)ethyl)carbamateEB2501844-024

[0221] To a stirred mixture of 4-((S)-2-((S)-2-amino-3-methylbutanamido)-5- ureidopentanamido)benzyl (((2,4-difluoro-A-(2-methoxy-5-(4-(pyridazin-4-yl)quinolin-6- yl)pyridin-3-yl)phenyl)sulfonamido) methyl)(2-(dimethylamino)ethyl)carbamate (50 mg, 0.049 mmol) in DMF (1 mL) were added DIEA (19.17 mg, 0.147 mmol) and 2,5-dioxopyrrolidin-l-yl3-(2-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)ethoxy)propanoate (23.01 mg, 0.074 mmol) at 0 °C under argon atmosphere. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was purified by Prep-HPLC with the follow conditions: Column: Xselect CSH Prep Column, 30 x 150 mm, 5pm; Mobile Phase A: water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 8% B to 38% B in lOmin; Wave Length: UV 254 nm / 220 nm; RT: 9.53 min. The product-containing fractions were pooled and lyophilized overnight to afford4-((5)-2-((S)-2-(3-(2-(2,5-dioxo-2,5-dihydro- 177-pyrroL 1 -yl)ethoxy)propanamido)-3- methylbutanamido)-5-ureidopentanamido)benzyl (((2,4-difluoro-7V-(2-methoxy-5-(4-(pyridazin- 4-yl)quinolin-6-yl) pyridin-3-yl)phenyl)sulfonamido)methyl)(2-(dimethylamino)ethyl)carbamate (32 mg, 53.6% yield) as an off-white solid. MS ESI calculated for C58H65F2N13O12S [M + H]+1206.46, found 1206.45. ’H NMR (400 MHz, DMSO - d6) 39.91 - 9.78 (m, 1H), 9.60 - 9.53 (m, 1H), 9.48 - 9.39 (m, 1H), 9.08 - 9.03 (m, 1H), 8.57 - 8.45 (m, 1H), 8.32 - 8.23 (m, 1H), 8.13 -8.01 (m, 3H), 8.01 - 7.95 (m, 1H), 7.92 - 7.80 (m, 2H), 7.72 - 7.59 (m, 3H), 7.45 - 7.31 (m, 2H), 7.21 - 7.12 (m, 1H), 7.01 (s, 2H), 6.98 - 6.82 (m, 2H), 6.01 - 5.94 (s, 1H), 5.42 (s, 2H), 5.33 - 5.07 (m, 2H), 4.68 - 4.59 (m, 1H), 4.40 - 4.15 (m, 3H), 3.62 - 3.50 (m, 6H), 3.49 - 3.39 (m, 3H), 3.03 - 2.88 (m, 2H), 2.47 - 2.38 (m, 2H), 2.36 - 2.28 (m, 1H), 2.24 - 2.14 (m, 6H), 2.01 - 1.89 (m, 1H), 1.66 - 1.51 (m, 2H), 1.47 - 1.29 (m, 2H), 0.87 - 0.77 (m, 6H).19F NMR (376 MHz, DMSO - de) 8 -100.67 - -100.76 (m, IF), -103.74 - -103.79 (m, IF).Synthesis ofMal-Peg( 1 PVal-Cit-PABC-Methyl-Omipalisib ( Coromiv-68 / PH-CORL-MC-2Q25- 005-1-0}

[0222] In one embodiment, the present disclosure provides a linker and Omipalisib having the structure(Formula IH, n=l, R2= H,R1= H, R= CH2CH2CH2NHCONH2). The reaction scheme is shown in Fig. 48Step 1: (((4-azidobenzyl)oxy)carbonyl)glycine EB2501844-027

[0223] To a stirred mixture of 4-azidobenzyl (4-nitrophenyl) carbonate (800 mg, 2.546 mmol) in MeCN (10 mL) were added 2-aminoacetic acid (210.21 mg, 2.801 mmol) and sodium bicarbonate (5.09 mL, 5.092 mmol, 1 M in H2O) at 0 °C under argon atmosphere. The resulting mixture was stirred at room temperature for 16 hours. The reaction was quenched with water (30 mL) and extracted with EA (80 mL). The pH of aqueous phase was adjusted to 3 with 1 N aq. HC1 and extracted with EA (3 x 80 mL). The organic layers were combined, washed with brine (3 x 80 mL), dried over anhydrous Na2SC>4 and filtered. The filtrate was concentrated under reduced pressure to afford (((4-azidobenzyl)oxy)carbonyl)glycine (540 mg, crude Product) as a light yellow solid. MS ESI calculated for C10H10N4O4 [M + NH4]"1" 268.10, found 268.15.Step 2: ((((4-azidobenzyl)oxy)carbonyl)amino)methyl acetate EB2501844-028

[0224] To a stirred mixture of (((4-azidobenzyl)oxy)carbonyl)glycine (540 mg, 2.158 mmol) in THE (10 mL) were added Pb(OAc)4 (1913.85 mg, 4.316 mmol) and Cu(OAc)2(0.22 mL, 0.216 mmol) at room temperature under argon atmosphere. The resulting mixture was stirred at 40 °C for 1 hour. The reaction was quenched with water (50 mL) and extracted with EA (3 x 100 mL).The organic layers were combined, washed with brine (3 x 100 mL), dried over anhydrous NaiSCh and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient 0% to 20% MeOH in DCM to afford ((((4-azidobenzyl)oxy)carbonyl)amino)methyl acetate (400 mg, 70.1% yield over two steps) as a light yellow solid. MS ESI calculated for C11H12N4O4 [M + NH4]+282.12, found 282.15.]H NMR (400 MHz, CDCI3) 87.36 - 7.34 (m, 2H), 7.09 - 6.98 (m, 2H), 5.90 (s, 1H), 5.25 - 5.06 (m, 4H), 2.07 (s, 3H)Step 3: 4-azidobenzyl (chloromethyl)carbamate EB2501844-029

[0225] To a stirred mixture of ((((4-azidobenzyl)oxy)carbonyl)amino)methyl acetate (400 mg, 1.514 mmol) in DCM (8 mL) were added chlorotrimethylsilane (0.82 g, 7.570 mmol) at 0 °C under argon atmosphere. The resulting mixture was stirred at room temperature for 1 hour. The solid that precipitated was filtered out. The filtrate was concentrated under reduced pressure to afford 4-azidobenzyl (chloromethyl)carbamate (400 mg, crude) as a light yellow solid. (Note: For LCMS analysis, aliquot was quenched with MeOH to afford 4-azidobenzyl (methoxymethyl)carbamate; MS ESI calculated for C10H12N4O3 [M - H]" 235.09, found 235.15.)Step 4: 4-azidobenzyl (((2,4-difluoro-A / -(2-methoxy-5-(4-(pyridazin-4-yl)quinolin-6-yl)pyridin- 3-yl) phenyl)sulfonamido)methyl)carbamate EB2501844-030

[0226] To a stirred mixture of 4-azidobenzyl (chloromethyl)carbamate (400 mg, 1.662 mmol) in DMF (20 mL) were added 2,4-difluoro-AL(2-methoxy-5-(4-(pyridazin-4-yl)quinolin-6- yl)pyridin-3-yl) benzenesulfonamide (0.76 g, 1.496 mmol) and DIEA (429.66 mg, 3.324 mmol) at 0 °C under argon atmosphere. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was directly purified by RP-Flash chromatography, eluted with 2 - 85% acetonitrile in water (0.05% TEA) to afford 4-azidobenzyl (((2,4-difluoro-A-(2-methoxy-5- (4-(pyridazin-4-yl)quinolin-6-yl) pyridin-3-yl)phenyl)sulfonamido)methyl)carbamate (320 mg, 27.1% yield) as a light yellow solid. MS ESI calculated for C34H25F2N9O5S [M + H]+710.17, found 710.15.Step 5: 4-aminobenzyl (((2,4-difluoro- / V-(2-methoxy-5-(4-(pyridazin-4-yl)quinolin-6-yl)pyridin-3-yl) phenyl)sulfonamido)methyl)carbamate EB2501844-031

[0227] Step 5: To a stirred mixture of 4-azidobenzyl (((2,4-difluoro-A-(2-methoxy-5-(4- (pyridazin-4-yl) quinolin-6-yl)pyridin-3-yl)phenyl)sulfonamido)methyl)carbamate (100 mg,0.141 mmol) in THF (2 mL) was added trimethylphosphine (1.0 M in THF, 737.70 uL, 0.739 mmol) at 0 °C under argon atmosphere. The resulting mixture was stirred at 0 °C for 5 minutes. The resulting mixture was concentrated under reduced pressure to afford 4-aminobenzyl (((2,4- difluoro-N-(2-methoxy-5-(4- (pyridazin-4-yl)quinolin-6-yl)pyridin-3- yl)phenyl)sulfonamido)methyl)carbamate (100 mg, crude) as a light yellow solid. The crude was used in the next step without further purification. MS ESI calculated for C34H27F2N7O5S [M + H]+684.18, found 684.15.Step 6: (S)-4-(2-(( / er / -butoxycarbonyl)amino)-5-ureidopentanamido)benzyl (((2,4-difluoro-7V- (2-methoxy-5-(4-(pyridazin-4-yl)quinolin-6-yl)pyridin-3- yl)phenyl)sulfonamido)methyl)carbamate EB2501844-032

[0228] To a stirred mixture of (S)-2-((tert-butoxycarbonyl)amino)-5-ureidopentanoic acid (72.48 mg, 0.264 mmol) in DMF (3 mL) were added HATU (100.11 mg, 0.264 mmol,) and D1EA (68.06 mg, 0.528 mmol) at room temperature under argon atmosphere. The resulted mixture was stirred for 10 minutes. Then 4-aminobenzyl (((2,4-difluoro-jV-(2-methoxy-5-(4-(pyridazin-4- yl)quinolin-6-yl)pyridin-3-yl) phenyl)sulfonamido)methyl)carbamate (120 mg, 0.176 mmol) was added to the above solution. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was directly purified by 7?P-Flash chromatography, eluted with 2 - 70% methanol in water (0.05% TFA) to afford (S)-4-(2-((teri-butoxycarbonyl)amino)-5- ureidopentanamido)benzyl(((2,4-difluoro-N-(2-methoxy-5-(4-(pyridazin-4-yl)quinolin-6- yl)pyridin-3-yl)phenyl)sulfonamido)methyl)carbamate (130 mg, 78.7% yield) as a light yellow solid. MS ESI calculated for C45H46F2N10O9S [M + H]+941.32, found 941.30.Step 7: (5)-4-(2-amino-5-ureidopentanamido)benzyl (((2,4-difluoro-A-(2-methoxy-5-(4- (pyridazin-4-yl)quinolin-6-yl)pyridin-3-yl)phenyl)sulfonamido)methyl)carbamate 2,2,2- trifluoroacetic acid salt EB2501844-033

[0229] To a stirred mixture of (S')-4-(2-((tert-butoxycarbonyl)amino)-5- ureidopentanamido)benzyl (((2,4-difluoro-A-(2-methoxy-5-(4-(pyridazin-4-yl)quinolin-6- yl)pyridin-3-yl)phenyl)sulfonamido)methyl)carbamate (120 mg, 0.128 mmol) in DCM (2 mL) was added TFA (0.4 mL, 0.020 mmol) at 0 °C under argon atmosphere. The resulting mixture was stirred at room temperature for 1 hour. The mixture reaction was diluted with toluene and concentrated under reduced pressure to afford (5)-4-(2-amino-5-ureidopentanamido)benzyl (((2,4-difluoro-A-(2-methoxy-5-(4-(pyridazin-4-yl) quinolin-6-yl) pyridin-3-yl)phenyl)sulfonamido)methyl)carbamate 2,2,2-trifluoroacetic acid salt (120 mg, crude) as a reddish brown yellow oil, which was used through. MS ESI calculated for C40H38F2N10O7S [M + H]+841.27, found 841.20.Step 8: 4-((S)-2-((S)-2-((terFbutoxycarbonyl)amino)-3-methylbutanamido)-5- ureidopentanamido) benzyl (((2,4-difluoro-7V-(2-methoxy-5-(4-(pyridazin-4-yl)quinolin-6- yl)pyridin-3-yl)phenyl) sulfonamido)methyl)carbamate EB2501844-034

[0230] To a stirred mixture of (terZ-butoxy carbonyl)- A- valine (37.21 mg, 0.172 mmol) in DMF (3 mL) were added HATU (65.12 mg, 0.172 mmol) and DIEA (55.33 mg, 0.429 mmol) at room temperature under argon atmosphere. The resulting mixture was stirred for 10 minutes. Then (5)- 4-(2-amino-5-ureidopentanamido)benzyl (((2,4-difluoro- / V-(2-methoxy-5-(4-(pyridazin-4-yl) quinolin-6-yl)pyridin-3-yl)phenyl)sulfonamido)methyl)carbamate 2,2,2-trifluoroacetic acid (120 mg, 0.143 mmol) was added to the above solution. The resulting mixture was stirred at room temperature for 2 hours. Upon completion the mixture was directly purified by 7?P-Flash chromatography, eluted with 2 - 70% methanol in water (0.05% TFA) to afford 4-((S)-2-((S)-2- ((ZerZ-butoxycarbonyl)amino)-3-methylbutanamido)-5-ureidopentanamido)benzyl (((2,4- difluoro-AA(2-methoxy-5-(4-(pyridazin-4-yl)quinolin-6-yl)pyridin-3- yl)phenyl)sulfonamido)methyl)carbamate (110 mg, 74.1% yield) as a light yellow solid. MS ESI calculated for C50H55F2N11O10S [M + H]+1040.39, found 1040.45Step 9: 4-((S)-2-((S)-2-amino-3-methylbutanamido)-5-ureidopentanamido)benzyl (((2,4- difluoro-A-(2-methoxy-5-(4-(pyridazin-4-yl)quinolin-6-yl)pyridin-3- yl)phenyl)sulfonamido)methyl)carbamate 2,2,2-trifluoroacetic acid salt EB2501844-035

[0231] To a stirred mixture of 4-((S)-2-((S)-2-((tert-butoxycarbonyl)amino)-3- methylbutanamido)-5- ureidopentanamido)benzyl (((2,4-difluoro-A-(2-methoxy-5-(4-(pyridazin- 4-yl)quinolin-6-yl)pyridine -3-yl)phenyl)sulfonamido)methyl)carbamate (100 mg, 0.096 mmol) in DCM (2 mL) was added TFA (0.4 mL) at 0 °C under argon atmosphere. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was diluted with toluene and concentrated under reduced pressure. The residue was purified by 7?P-Flash chromatography, eluted with 2 - 50% acetonitrile in water (0.05% TFA) to afford 4-((S)-2-((S)-2-amino-3- methylbutanamido)-5-ureidopentanamido)benzyl (((2,4-difluoro-A-(2-methoxy-5-(4-(pyridazin- 4-yl)quinolin-6-yl)pyridin-3-yl)phenyl)sulfonamido)methyl)carbamate 2,2,2-trifluoroacetic acid salt (50 mg, 55.3% yield) as a light yellow solid. MS ESI calculated for C45H47F2N11O8S [M +H]+940.34, found 940.30.Step 10: 4-((5)-2-((5)-2-(3-(2-(2,5-dioxo-2,5-dihydro-177-pyrrol-l-yl)ethoxy)propanamido)-3- methylbutanamido)-5-ureidopentanamido)benzyl (((2,4-difluoro-vV-(2-methoxy-5-(4-(pyridazin- 4-yl) quinolin-6-yl)pyridin-3-yl)phenyl)sulfonamido)methyl)carbamate EB2501844-034

[0232] To a stirred mixture of 4-((5)-2-((S)-2-amino-3-methylbutanamido)-5- ureidopentanamido)benzyl (((2,4-difluoro-Ar-(2-methoxy-5-(4-(pyridazin-4-yl)quinolin-6- yl)pyridin-3-yl)phenyl)sulfonamido)methyl)carbamate 2,2,2-trifhioroacetic acid salt (50 mg, 0.053 mmol) in DMF (1 mL) were added DIEA (20.62 mg, 0.159 mmol) and 2,5- dioxopyrrolidin-l-yl 3-(2-(2,5-dioxo-2,5-dihydro- lH-pyrrol-l-yl)ethoxy)propanoate (24.75 mg, 0.080 mmol) at 0 °C under argon atmosphere. The resulting mixture was stirred at room temperature for 2 hours. Upon completion the resulting mixture was directly purified by Prep- HPLC with the follow conditions: Column: Xselect CSH Prep Column, 30 x 150 mm, 5pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 23% B to 53% B in lObmin; Wave Length: UV 254 nm / 220 nm; RT: 8.67 min. The productcontaining fractions were pooled and lyophilized overnight to afford 4-((S)-2-((5)-2-(3-(2-(2,5- dioxo-2,5-dihydro-l W-pyrrol- l-yl)ethoxy)propanamido)-3-rnethylbutanamido)-5- ureidopentanamido)benzyl (((2,4-difluoro-Af-(2-methoxy-5-(4-(pyridazin-4-yl)quinolin-6-yl) pyridin-3-yl)phenyl)sulfonamido)methyl)carbamate (25 mg, 41.4% yield) as an off-white solid. MS ESI calculated for C54H56F2N12O12S [M + H]+1135.39, found 1135.30.1H NMR (400 MHz, DMSO - <fe) 8 9.90 (s, 1H), 9.57 - 9.52 (m, 1H), 9.47 - 9.43 (m, 1H), 9.09 - 9.04 (m, 1H), 8.57 (s, 1H), 8.30 - 8.24 (m, 1H), 8.11 - 8.06 (m, 2H), 8.04 - 7.99 (m, 2H), 7.92 - 7.89 (m, 2H), 7.87 - 7.82 (m, 1H), 7.74 - 7.57 (m, 3H), 7.50 - 7.41 (m, 2H), 7.22 - 7.14 (m, 1H), 7.11 - 7.04 (m, 2H), 7.00 (s, 2H), 6.00 - 5.92 (m, 1H), 5.41 (s, 2H), 4.76 (s, 2H), 4.39 - 4.31 (m, 1H), 4.23 - 4.16 (m, 1H), 3.64 - 3.56 (m, 3H), 3.54 - 3.49 (m, 3H), 3.49 - 3.42 (m, 2H), 3.01 - 2.88 (m, 2H), 2.47 - 2.38 (m, 1H), 2.35 - 2.27 (m, 1H), 1.98 - 1.91 (m, 1H), 1.72 - 1.61 (m, 1H), 1.60 - 1.51 (m, 1H), 1.47 - 1.29 (m, 1H), 0.88 - 0.75 (m, 6H).19F NMR (376 MHz, DMSO - d6) 8 -101.08 - -101.11 (m, IF), -103.47 - -103.50 (m, IF)EXAMPLE 3Synergistic Effects of Omipalisib and Trastuzumab

[0233] In one embodiment, the ADCs presented herein are useful for treating HER2-high tumors. It has been reported that HER2-high tumors are more sensitive to PI3K / mTOR inhibition. PI3K / mTOR inhibition is effective clinically, albeit with a very narrow therapeutic index (TI). Following the ADC constructs described herein, conjugating dual PI3K / mTOR inhibitors to clinically validated mAbs offers new therapeutic opportunities.

[0234] Figure 22 shows that there are synergistic effects between the dual PI3K / mTOR inhibitor Omipalisib and the anti-HER2 receptor antibody Trastuzumab. BT474 or SKBR3 cells were plated in a 96 microwell plate and treated with drug (Agent 1, Omipalisib; Agent 2, Trastuzumab) at the indicated concentration. Cell viability was measured 96 hours later using cell-titre gio. Therapeutic synergy, additivity and antagonism was measured using Loewe or HAS synergy. Synergy between Trastuzumab and Omipalisib is driven by multi-inhibition of compensatory pathways such as MAPK when Trastuzumab is administered, and inhibition of PI3K / mTOR pathways when Omipalisib is administered. This multifacted inhibition of multiple pathways is synergistic.EXAMPLE 4Treatment for Acute Myelogenous Leukemia

[0235] In another embodiment, the ADCs presented herein are useful for treating acute myelogenous leukemia (AML) or CD 180+ AML. It has been reported that AML tumors are more sensitive to PI3K / mTOR inhibition than most other tumor types, and AML with MLL (mixed- lineage leukemia) fusions exhibit increased sensitivity to dual PI3K / mTOR inhibition. CD 180+ cells are enriched in MLL fusion tumors. Omipalisib is also known to reduce mitochondria biogenesis in AML. Thus, following the ADC constructs described herein, conjugating dual PI3K / mTOR inhibitors to clinically validated mAbs offers new therapeutic opportunities for AML or CD 180+ AML.EXAMPLE 5Antibody-Drug Conjugates With Improved Stability, Release and SolubilityMATERIALS AND METHODS: pH Stability Assay

[0236] 100 pL of pre-warmed (37°C) PBS, pH 5 or 7.4, was spiked with NAc-Cys-Linker-Payload at a final concentration of 5 pM (1% DMSO). The samples were incubated at 37°C on EppendorfThermomixer Confort plate shaker at 150 rpm. Samples were removed at 0-, 30- , 60-, 120-, and 480-hour time-points and diluted 1:6 in cold quenching solution (acetonitrile containing internal standards (IS, 100 nM Tolbutamide, 500 nM Labetalol and 2 pM Ketoprofen)). Proteins were precipitated by vortexing for 1 minute followed by centrifugation at 3,220 g for 30 minutes at 4°C. Supernatant was diluted 1:1 or 1:2 in water for LC-MS / MS preparation. The assay was performed in duplicate. LC-MS / MS was performed using Shimadzu LC 30AD coupled to Triple QuadTM 6500+ instrument with an ESI interface (positive MRM) to quantify abundance of Linker-Payload. 5 pL of diluted samples were injected on to XSelect Hss T32.5pm (2.1x50 mm) Column operating at 40°C. Mobile phase A and B were 0.1 % formic acid in water and 0.1 % formic acid in acetonitrile, respectively, with an elution rate of 1.0 mL / min. The analyte of interest peak areas was normalized to internal standards and the fraction of Linker-Payload remaining was calculated with respect to time point 0-hour.Human Plasma Stability Assay (37° C)

[0237] 800 pL of pre-warmed (37°C) human plasma, pH 7.54, was spiked with NAc-Cys-Linker- Payload at a final concentration of 5 pM (0.5 % DMSO). The plasma samples were incubated at 37°C water bath with shaking at approximately 60 rpm. 50 pL aliquots of the incubated plasma samples were removed at 0-, 2-, 4-, 6-, 18-, and 24-hour time-points and quenched with 300 pL of room temperature quenching solution (acetonitrile containing internal standards (IS, 100 nM Tolbutamide, 500 nM Labetalol and 2 pM Ketoprofen)). Proteins were precipitated by vortexing for 5 minutes followed by centrifugation at 3,220 g for 30 minutes at 4°C. Supernatant was diluted 1:1 or 1 :2 in water for LC-MS / MS preparation. The assay was performed in duplicate. LC-MS / MS was performed using Shimadzu LC_40D XS coupled to Triple QuadTM 6500+ instrument with an ESI interface (positive MRM) to quantify abundance of Linker-Payload. 3 pL of diluted samples were injected on to XSelect Hss T3 2.5pm (2.1x50 mm) Column operating at 40°C. Mobile phase A and B were 0.1 % formic acid in water and 0.1 % formic acid in acetonitrile, respectively. Elution rate for Cl-NAC, C2-NAC, C3-NAC, and Vedotin-NAC are 3, 3, 0.65, and 1 mL / min, respectively. The analyte of interest peak areas were normalized to internal standards and the fraction of Linker-Payload remaining was calculated with respect to payload only sample.Cathepsin-Mediated Release Assay:

[0238] In 67% dimethyl sulfoxide (DMSO), and 27 % dimethylacetamide (DMAC), 5.3 mMLinker-Payload was mixed with 2.5 molar-excess of N-Acetylcysteine amide (NAC) and 6.25molar-excess Tris(2-chloroethyl) phosphate (TCEP). Reference standards containing MMAE or Omipalisib payload were created in the same manner. The above Linker-payload and reference standard mixtures were diluted 20-fold in 74 mM MES buffer, 0.7 mM sodium acetate buffer, 1.05 mM dithiothreitol (DTT), and 0.01 mM EDTA at pH 5.0. Treated samples contained 5 pg / mL of cathepsin B (374 U / mgP) while the untreated samples and reference standards did not. Treated and untreated samples were incubated at 37 °C for 2 hours before flash-frozen and stored at -80 °C. Upon thawing, samples were diluted 1:50 in 80% acetonitrile. LC-MS / MS was performed using Acquity UHPLC (Waters) coupled to a QTRAP 6500 mass spectrometer (SCIEX) to quantify payload release. Two micro-liters of diluted samples were injected on to XSelect Hss T3 2.5pm (2.1x150 mm) operating at 45°C. Mobile phase A and B were 0.1 % formic acid in water and 0.1 % formic acid in acetonitrile, respectively, with a total run time of 15 minutes. LCMS peaks were integrated using Sciex’s Multiquant software for quantitation. The percentage of free payload detected is the fraction of MMAE or Omipalisib detected in the treated or untreated linker-payload samples to the MMAE or Omipalisib in the reference standards, relative quantitation.Assays for Cathepsin-Mediated Cleavage and Pay load Release Kinetics

[0239] Linker-Payload at a final concentration of 5 pM in 100 mM citrate buffer, 5 mM L- Cysteine, 1% DMSO, pH 5.5 were treated with 25 pg / mL Cathepsin B from human liver. Nontreated (NT) samples did not contain Cathepsin B. The assay was performed in duplicate. Vials were incubated at 37 °C at 60 rpm in a water bath. Aliquots were taken from the reaction samples at 0, 15, 30, 60 and 120 minutes. The reaction was stopped by diluting aliquot (1:9) in cold acetonitrile containing internal standards (IS, 40-200 nM labetalol, 200 nM imipramine, 80 nM tolbutamide and / or 40-2000 nM ketoprofen). Samples were vortexed for 1 minute and centrifuged at 4°C at 3220 g for 30 minutes. Aliquots of the supernatant were diluted by a certain amount of ultra-pure water and used for LC-MS / MS analysis. LC-MS / MS was performed using Shimadzu LC coupled to Triple QuadTM 5500+ or 6500+ instrument with an ESI interface (positive MRM) to quantify abundance of Linker-Payload. 3 or 5 pL of diluted samples were injected on to XSelect Hss T32.5pm (2.1x50 mm) Column XP coupled with preguard column operating at 40°C. Mobile phase A and B were 0.1 % formic acid in water and 0.1 % formic acid in acetonitrile, respectively, with an elution rate of 0.65 or 1.0 mL / min. All calculations were carried out using Microsoft Excel. The remaining percentages of payload linker and conversion percentage of the payload at each time point were estimated by determining the peak area ratios from extraction chromatograms.RESULTS

[0240] Figure 23 shows the pH stability data of various antibody-drug conjugates disclosed herein. Figure 24 shows plasma stability and cathepsin-mediated payload release of various antibody-drug conjugates. Figure 25 shows the stability and cathepsin-mediated cleavage and cathepsin-mediated payload release kinetics of Coromip-81.EXAMPLE 6Analysis of Antibody-Drug ConjugatesMATERIALS AND METHODS:Conjugation Methods of Antibody to Linker-Payload:Method A:

[0241] To a solution of antibody in buffer (1 x PBS buffer, pH = -7.3) was added TCEP hydrochloride salt (x eq., 1 mM in sterile water) at 25 °C and the mixture was warmed to 37 °C and agitated for 1.5 h in an orbital shaker with gentle (800 rpm) shaking. The reduced antibody solution was removed from incubation and allowed to cool to 25 °C. To this mixture was added linker-payload (x eq., 10 mM in DMSO) and the resulting solution was shaken at 25 °C for 1.5-2 h. The conjugation reaction was quenched with cysteine (10 mM aq., 2 eq. to linker-payload) and a small aliquot is used for SEC-MS, RP-MS and SEC-UV analysis. The remaining mixture was stored at -80 °C before purification.Method B:

[0242] To a solution of antibody in buffer (1 x PBS buffer, pH = -7.3) was added TCEP hydrochloride salt (x eq., 1 mM in sterile water) at 25 °C and the mixture was warmed to 37 °C and agitated for 1.5 h in an orbital shaker with gentle (800 rpm) shaking. The reduced antibody solution was removed from incubation and allowed to cool to 25 °C. To this mixture were x followed by the addition of linker-payload (x eq., 10 mM in DMSO) and the resulting solution was shaken at 25 °C for 1.5-2 h. The conjugation reaction was quenched with cysteine (10 mM aq., 2 eq. to linker-payload) and a small aliquot is used for SEC-MS, RP-MS and SEC-UV analysis. The remaining mixture was stored at -80 °C before purification.Method C:

[0243] To a solution of antibody in buffer (1 x PBS buffer, pH = -7.3) was added TCEP hydrochloride salt (x eq., 1 mM in sterile water) at 25 °C and the mixture was warmed to 37 °Cand agitated for 1.5 h in an orbital shaker with gentle (800 rpm) shaking. The reduced antibody solution was removed from incubation and allowed to cool to 25 °C. To this mixture were addedDMSO (10% of total volume), 1,3-Propanediol (30 - 50% of total volume) and Tween 80 (0.01% of total volume), followed by the addition of linker-payload (x eq., 10 mM in DMSO) and the resulting solution was shaken at 25 °C for 1.5-2 h. The conjugation reaction was quenched with cysteine (10 mM aq., 2 eq. to linker-payload) and a small aliquot is used for SEC-MS, RP-MS and SEC-UV analysis. The remaining mixture was stored at -80 °C before purification.Purification Methods:Method A;

[0244] The crude ADC was thawed and the purification was carried out as below.1. The reaction solution was added to an ultrafiltration tube (Volume: 15 mL, Aperture: 30 kDa, Manufacturer: Sartorius).2. Buffer (14 mL, 25 mM Histidine, 9% Sucrose, pH = 5.5) was added to centrifuge (Manufacturer: Eppendorf, Instrument Model: Centrifuge 5804R, Centrifugal Force: 2934 ref, Centrifuge Speed: 4000 trap) at 15 °C for 30 min to leave -0.4 mL.3. The process of step 2 was repeated for additional 2-3 times to afford the ADC product.Method B (optional}:

[0245] If needed, the crude ADC was further purified by SEC-HPLC with the following conditions: Column: Superdex 200 Increase 10 / 300 GL; Mobile phase: 25 mM Histidine, 150 mM NaCl, pH 5.5; Flow rate: 0.75 mL / min; Column equilibration: 3 column volumes (CV) of mobile phase. The fractions containing desired ADC product were pooled and buffer exchanged with buffer (14 mL, 25 mM Histidine, 9% Sucrose, pH = 5.5) to afford the final pure ADC.Analysis of ADCDetermination of Average Drug Loading and Drug Distribution of the ADC1. An analytical SEC-MS method was used to determine the drug loading and the drug load distribution of the ADC. Column: AdvanceBio SEC 200A (2.1 x 50 mm, 1.9 pm); The mobile phase was 100 mM NH4AC water solution. Species of different DAR were separated using a salt gradient and detected by UV absorbance at 280 nm. The average DAR and distribution profile were determined by peak area percentage of each species.2. RPLC-MS method also was used to determine the Drug-to-Antibody Ratio / DAR. Column: Agilent PLRP-S 1000A (50 x 2.1 mm, 8.0 pm); The mobile phase A is H2O + 0.1% FA and mobile phase B is ACN + 0.1% FA.Determination of Aggregate Content by Analytical SEC

[0246] The SEC method was used to determine product purity and aggregate content. The test samples are diluted with the mobile phase (150 mM Phosphate buffered solution, pH 6.8) at the concentration of 2 mg / rnL and injected onto the Yarra SEC-2000 (7.8*300mm,3pm) column at 1 mL / min for 20 min. The aggregate and monomer species in the crude ADC preparation are reported as the percent of the total area for all protein-related peaks.Other methods

[0247] HIC, Free Payload and Free Cys-Linker-Payload were also tested by LC-MS.ADC Formulation and Storage

[0248] The purified ADC material was formulated using standard formulation excipients (25 mM Histidine, 9% Sucrose, pH = 5.5). The formulated ADC solution was frozen at -80 °C for longterm storage.RESULTS

[0249] The data and results of the analysis for various antibody-drug conjugates disclosed herein are presented in the TABLE below.

[0250] Figure 26A shows a scheme for the conjugation of the antibody Trastuzumab to Coromip- 81. Figure 26B shows the MS trace and table of peaks for the Trastuzumab-Coromip-81 ADC and shows that it has a drug-to-antibody ratio (DAR) of 7.3. Figure 27 shows the determination of aggregate content by analytical size-exclusion chromatography (SEC) for the Trastuzumab- Coromip-81 ADC.^ :*8)?3419 :*8)?3419 5,4@B8)3*A9 ()*+,-. DK,,*9 ;:59 ;:59 5,4@B8)3*9 ()*+,-. 5,6)78,-,49:;<9=0>, :>3@*8A9 <3*B,*8-08)3*A9 D<E / 9F>329 / 0123049 <3*I@608)3*9 LM9 OAQ. ;STU FTE<. F5 / . :66-,608)3*9 :66-,608)3*9FOW.>)*9 0*49 / @-8X)B08)3*9 / 012304 >6 >6C>( GH F>329GH D)>,A9J- FMNMO9 / -3R0*,4)32 STH STH FV.>)*9R,0+H R,0+H <3*I@608)3*9 S,8J34^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^"^^^^^^^^^^#^^^^^#^^^^^^^^^^^^^^^^^^^^^^^^^^!^^$^^^^^^ ^^^^^^^%^&^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^''^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^#^^^^^^^^^^^^^^^^'^^^^^^^^^^^^^^^^^^^^^%^^^^^^^^^^^^^^^

Claims

WHAT IS CLAIMED IS:A compound having the structure Y — Z, wherein Y is a linker, and Z is the dual PI3K / mTOR inhibitor Omipalisib (GSK2126458), or a derivative or analog thereof.

2. The compound of claim 1, wherein Z is the dual PI3K / mTOR inhibitor Omipalisib (GSK2126458).

3. The compound of claim 2, wherein linker Y comprises an oligopeptide.

4. The compound of claim 3, wherein the oligopeptide is a dipeptide, a tripeptide, or a tetrapeptide.

5. The compound of claim 4, wherein the dipeptide is Vai- Ala or Val-citrulline.

6. The compound of claim 4, wherein the tetrapeptide is Gly-Gly-Phe-Gly.

7. The compound of claim 2, wherein Y — Z is represented by Formula I:Fwherein: n is an integer from 1 to 12;R is an amino acid side chain;X = or NH2or o ; andR2is selected from the group consisting of: H, -C1-6alkyl, alkoxy,O(CH2)2O(CH2)2O(CH2)2CO2H, O(CH2)2O(CH2)2OCH3, O(CH2)2O(CH2)2NH2,O(CH2)2O(CH2)2NH(CH3)2, O(CH2)2O(CH2)2SO3H, O(CH2)2O(CH2)2CO2H,O(CH2)2O(CH2)2CONH2, O(CH2)2O(CH2)2SO2CH3,O(CH2)2O(CH2)2OCH2CH(OH)CH2OH, CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2OCH3,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2CO2H,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2SO2CH3,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2N(CH3)2,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2NHCH3CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2NH2,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2SO3H, CH2N(CH3)CO(CH2)2CO2H,CH2N(CH3)CO(CH2)2NH2, and CH2N(CH3)CO(CH2)2NHCH3.

8. The compound of claim 2, wherein Y — Z is represented by Formula II:R2is selected from the group consisting of: H, -C1-6alkyl, alkoxy,O(CH2)2O(CH2)2O(CH2)2CO2H, O(CH2)2O(CH2)2OCH3, O(CH2)2O(CH2)2NH2,O(CH2)2O(CH2)2NH(CH3)2, O(CH2)2O(CH2)2SO3H, O(CH2)2O(CH2)2CO2H,O(CH2)2O(CH2)2CONH2, O(CH2)2O(CH2)2SO2CH3,O(CH2)2O(CH2)2OCH2CH(OH)CH2OH, CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2OCH3,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2CO2H,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2SO2CH3,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2N(CH3)2,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2NHCH3CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2NH2,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2SO3H, CH2N(CH3)CO(CH2)2CO2H,CH2N(CH3)CO(CH2)2NH2, and CH2N(CH3)CO(CH2)2NHCH3.

9. The compound of claim 2, wherein Y — Z is represented by Formula III:FFormula III wherein: n is an integer from 1 to 12;R is an amino acid side chain;R1is selected from the group consisting of: H, (CH2)2N(CH3)2, (CH2)2O(CH2)2O(CH2)2OCH3, (CH2)2O(CH2)2O(CH2)2CO2H, (CH2)2O(CH2)2O(CH2)2SO3H, (CH2)2O(CH2)2O(CH2)2NH2, (CH2)2O(CH2)2O(CH2)2N(CH3)2, (CH2)2O(CH2)2O(CH2)2CONH2,(CH2)2O(CH2)2OCH(OH)CH2CO2H; and (CH2)2O(CH2)2O(CH2)2SO2CH3; andR2is selected from the group consisting of: H, -Ci -ealkyl, alkoxy,O(CH2)2O(CH2)2O(CH2)2CO2H, O(CH2)2O(CH2)2OCH3, O(CH2)2O(CH2)2NH2,O(CH2)2O(CH2)2NH(CH3)2, O(CH2)2O(CH2)2SO3H, O(CH2)2O(CH2)2CO2H,O(CH2)2O(CH2)2CONH2, O(CH2)2O(CH2)2SO2CH3,O(CH2)2O(CH2)2OCH2CH(OH)CH2OH, CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2OCH3,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2CO2H,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2SO2CH3,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2N(CH3)2,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2NHCH3CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2NH2,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2SO3H, CH2N(CH3)CO(CH2)2CO2H,CH2N(CH3)CO(CH2)2NH2, and CH2N(CH3)CO(CH2)2NHCH3.

10. The compound of claim 2, wherein Y — Z is represented by Formula IV:Formula IV wherein: n is an integer from 1 to 12;R is an amino acid side chain; oR1is selected from the group consisting of: H, (CH2)2N(CH3)2, (CH2)2O(CH2)2O(CH2)2OCH3, (CH2)2O(CH2)2O(CH2)2CO2H, (CH2)2O(CH2)2O(CH2)2SO3H, (CH2)2O(CH2)2O(CH2)2NH2,(CH2)2O(CH2)2O(CH2)2N(CH3)2, (CH2)2O(CH2)2O(CH2)2CONH2,(CH2)2O(CH2)2OCH(OH)CH2CO2H; and (CH2)2O(CH2)2O(CH2)2SO2CH3;R2is selected from the group consisting of: H, -C1-6alkyl, alkoxy,O(CH2)2O(CH2)2O(CH2)2CO2H, O(CH2)2O(CH2)2OCH3, O(CH2)2O(CH2)2NH2,O(CH2)2O(CH2)2NH(CH3)2, O(CH2)2O(CH2)2SO3H, O(CH2)2O(CH2)2CO2H,O(CH2)2O(CH2)2CONH2, O(CH2)2O(CH2)2SO2CH3,O(CH2)2O(CH2)2OCH2CH(OH)CH2OH, CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2OCH3,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2CO2H,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2SO2CH3,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2N(CH3)2,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2NHCH3CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2NH2,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2SO3H, CH2N(CH3)CO(CH2)2CO2H,CH2N(CH3)CO(CH2)2NH2, and CH2N(CH3)CO(CH2)2NHCH3; andR3is selected from the group consisting of: glucamine, -NH((CH2)2O)3(CH2)2OCH3,NH(CH2)2O(CH2)2OCH2CH(OH)CH2OH, N(CH3)(CH2)2O(CH2)2OCH2CH(OH)CH2OH,NH(CH2)2O(CH2)2OCH2CH(OH)CH2OH, NHCH2CH(OH)CH2OH,NHCH2CH(OH)CH(OH)CH2OH, N(CH3)CH2CH(OH)CH2OH,N(CH3)CH2CH(OH)CH(OH)CH2OH, NH(CH2)2O(CH2)2OCH2CH(OH)CO2H,N(CH3)(CH2)2O(CH2)2OCH2CH(OH)CO2H, NH(CH2)2O(CH2)2OCH2CH(OH)CCO2H,NHCH2CH(OH)CO2H, NHCH2CH(OH)CH(OH)CO2H, N(CH3)CH2CH(OH)CO2H, andN(CH3)CH2CH(OH)CH(OH)CO2H.

11. The compound of claim 2, wherein Y — Z is represented by Formula V:Formula V wherein: n is an integer from 1 to 12;R is an amino acid side chain; x = or H NH2or oR2is selected from the group consisting of: H, -C1-6alkyl, alkoxy,O(CH2)2O(CH2)2O(CH2)2CO2H, O(CH2)2O(CH2)2OCH3, O(CH2)2O(CH2)2NH2,O(CH2)2O(CH2)2NH(CH3)2, O(CH2)2O(CH2)2SO3H, O(CH2)2O(CH2)2CO2H,O(CH2)2O(CH2)2CONH2, O(CH2)2O(CH2)2SO2CH3,O(CH2)2O(CH2)2OCH2CH(OH)CH2OH, CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2OCH3,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2CO2H,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2SO2CH3,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2N(CH3)2,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2NHCH3CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2NH2,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2SO3H, CH2N(CH3)CO(CH2)2CO2H,CH2N(CH3)CO(CH2)2NH2, and CH2N(CH3)CO(CH2)2NHCH3; andR3is selected from the group consisting of: glucamine, -NH((CH2)2O)3(CH2)2OCH3,NH(CH2)2O(CH2)2OCH2CH(OH)CH2OH, N(CH3)(CH2)2O(CH2)2OCH2CH(OH)CH2OH, NH(CH2)2O(CH2)2OCH2CH(OH)CH2OH, NHCH2CH(OH)CH2OH,NHCH2CH(OH)CH(OH)CH2OH, N(CH3)CH2CH(OH)CH2OH,N(CH3)CH2CH(OH)CH(OH)CH2OH, NH(CH2)2O(CH2)2OCH2CH(OH)CO2H,N(CH3)(CH2)2O(CH2)2OCH2CH(OH)CO2H, NH(CH2)2O(CH2)2OCH2CH(OH)CCO2H,NHCH2CH(OH)CO2H, NHCH2CH(OH)CH(OH)CO2H, N(CH3)CH2CH(OH)CO2H, andN(CH3)CH2CH(OH)CH(OH)CO2H.

12. The compound of claim 2, wherein Y — Z is represented by Formula VI:Formula VI wherein: n is an integer from 1 to 12;R is an amino acid side chain;H2N.R2is selected from the group consisting of: H, -C1-6alkyl, alkoxy,O(CH2)2O(CH2)2O(CH2)2CO2H, O(CH2)2O(CH2)2OCH3, O(CH2)2O(CH2)2NH2,O(CH2)2O(CH2)2NH(CH3)2, O(CH2)2O(CH2)2SO3H, O(CH2)2O(CH2)2CO2H,O(CH2)2O(CH2)2CONH2, O(CH2)2O(CH2)2SO2CH3,O(CH2)2O(CH2)2OCH2CH(OH)CH2OH, CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2OCH3,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2CO2H,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2SO2CH3,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2N(CH3)2,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2NHCH3CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2NH2,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2SO3H, CH2N(CH3)CO(CH2)2CO2H,CH2N(CH3)CO(CH2)2NH2, and CH2N(CH3)CO(CH2)2NHCH3.R3is selected from the group consisting of: glucamine, -NH((CH2)2O)3(CH2)2OCH3,NH(CH2)2O(CH2)2OCH2CH(OH)CH2OH, N(CH3)(CH2)2O(CH2)2OCH2CH(OH)CH2OH,NH(CH2)2O(CH2)2OCH2CH(OH)CH2OH, NHCH2CH(OH)CH2OH,NHCH2CH(OH)CH(OH)CH2OH, N(CH3)CH2CH(OH)CH2OH,N(CH3)CH2CH(OH)CH(OH)CH2OH, NH(CH2)2O(CH2)2OCH2CH(OH)CO2H,N(CH3)(CH2)2O(CH2)2OCH2CH(OH)CO2H, NH(CH2)2O(CH2)2OCH2CH(OH)CCO2H,NHCH2CH(OH)CO2H, NHCH2CH(OH)CH(OH)CO2H, N(CH3)CH2CH(OH)CO2H, and N(CH3)CH2CH(OH)CH(OH)CO2H.

13. The compound of claim 2, wherein Y — Z is represented by Formula VII:Formula VII wherein: n is an integer from 1 to 12;R is an amino acid side chain;R1is selected from the group consisting of: H, (CH2)2N(CH3)2, (CH2)2O(CH2)2O(CH2)2OCH3, (CH2)2O(CH2)2O(CH2)2CO2H, (CH2)2O(CH2)2O(CH2)2SO3H, (CH2)2O(CH2)2O(CH2)2NH2, (CH2)2O(CH2)2O(CH2)2N(CH3)2, (CH2)2O(CH2)2O(CH2)2CONH2,(CH2)2O(CH2)2OCH(OH)CH2CO2H, and (CH2)2O(CH2)2O(CH2)2SO2CH3;R2is selected from the group consisting of: H, -C1-6alkyl, alkoxy,O(CH2)2O(CH2)2O(CH2)2CO2H, O(CH2)2O(CH2)2OCH3, O(CH2)2O(CH2)2NH2,O(CH2)2O(CH2)2NH(CH3)2, O(CH2)2O(CH2)2SO3H, O(CH2)2O(CH2)2CO2H,O(CH2)2O(CH2)2CONH2, O(CH2)2O(CH2)2SO2CH3,O(CH2)2O(CH2)2OCH2CH(OH)CH2OH, CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2OCH3,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2CO2H,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2SO2CH3,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2N(CH3)2,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2NHCH3CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2NH2,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2SO3H, CH2N(CH3)CO(CH2)2CO2H,CH2N(CH3)CO(CH2)2NH2, and CH2N(CH3)CO(CH2)2NHCH3; andR3is selected from the group consisting of: glucamine, -NH((CH2)2O)3(CH2)2OCH3,NH(CH2)2O(CH2)2OCH2CH(OH)CH2OH, N(CH3)(CH2)2O(CH2)2OCH2CH(OH)CH2OH,NH(CH2)2O(CH2)2OCH2CH(OH)CH2OH, NHCH2CH(OH)CH2OH,NHCH2CH(OH)CH(OH)CH2OH, N(CH3)CH2CH(OH)CH2OH,N(CH3)CH2CH(OH)CH(OH)CH2OH, NH(CH2)2O(CH2)2OCH2CH(OH)CO2H,N(CH3)(CH2)2O(CH2)2OCH2CH(OH)CO2H, NH(CH2)2O(CH2)2OCH2CH(OH)CCO2H,NHCH2CH(OH)CO2H, NHCH2CH(OH)CH(OH)CO2H, N(CH3)CH2CH(OH)CO2H, andN(CH3)CH2CH(OH)CH(OH)CO2H.

14. The compound of claim 2, wherein Y — Z is represented by Formula XI:Formula XI wherein: n is an integer from 1 to 12;R2is selected from the group consisting of: H, -C1-6alkyl, alkoxy,O(CH2)2O(CH2)2O(CH2)2CO2H, O(CH2)2O(CH2)2OCH3, O(CH2)2O(CH2)2NH2,O(CH2)2O(CH2)2NH(CH3)2, O(CH2)2O(CH2)2SO3H, O(CH2)2O(CH2)2CO2H,O(CH2)2O(CH2)2CONH2, O(CH2)2O(CH2)2SO2CH3,O(CH2)2O(CH2)2OCH2CH(OH)CH2OH, CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2OCH3,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2CO2H,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2SO2CH3,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2N(CH3)2,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2NHCH3, CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2NH2,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2SO3H, CH2N(CH3)CO(CH2)2CO2H,CH2N(CH3)CO(CH2)2NH2, and CH2N(CH3)CO(CH2)2NHCH3.

15. The compound of claim 2, wherein Y — Z is represented by Formula XII:Formula XII wherein: n is an integer from 1 to 12;R2is selected from the group consisting of: H, -Ci -ealkyl, alkoxy,O(CH2)2O(CH2)2O(CH2)2CO2H, O(CH2)2O(CH2)2OCH3, O(CH2)2O(CH2)2NH2,O(CH2)2O(CH2)2NH(CH3)2, O(CH2)2O(CH2)2SO3H, O(CH2)2O(CH2)2CO2H,O(CH2)2O(CH2)2CONH2, O(CH2)2O(CH2)2SO2CH3,O(CH2)2O(CH2)2OCH2CH(OH)CH2OH, CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2OCH3,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2CO2H,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2SO2CH3,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2N(CH3)2,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2NHCH3, CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2NH2,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2SO3H, CH2N(CH3)CO(CH2)2CO2H,CH2N(CH3)CO(CH2)2NH2, and CH2N(CH3)CO(CH2)2NHCH3.

16. The compound of claim 2, wherein Y — Z is represented by Formula XIII:Q owherein: n is an integer from 1 to 12;H2N.•NHyR1is selected from the group consisting of: H, (CH2)2N(CH3)2, (CH2)2O(CH2)2O(CH2)2OCH3, (CH2)2O(CH2)2O(CH2)2CO2H, (CH2)2O(CH2)2O(CH2)2SO3H, (CH2)2O(CH2)2O(CH2)2NH2,(CH2)2O(CH2)2O(CH2)2N(CH3)2, (CH2)2O(CH2)2O(CH2)2CONH2,(CH2)2O(CH2)2OCH(OH)CH2CO2H; and (CH2)2O(CH2)2O(CH2)2SO2CH3; andR2is selected from the group consisting of: H, -C1-6alkyl, alkoxy,O(CH2)2O(CH2)2O(CH2)2CO2H, O(CH2)2O(CH2)2OCH3, O(CH2)2O(CH2)2NH2,O(CH2)2O(CH2)2NH(CH3)2, O(CH2)2O(CH2)2SO3H, O(CH2)2O(CH2)2CO2H,O(CH2)2O(CH2)2CONH2, O(CH2)2O(CH2)2SO2CH3,O(CH2)2O(CH2)2OCH2CH(OH)CH2OH, CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2OCH3,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2CO2H,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2SO2CH3,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2N(CH3)2,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2NHCH3, CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2NH2,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2SO3H, CH2N(CH3)CO(CH2)2CO2H,CH2N(CH3)CO(CH2)2NH2, and CH2N(CH3)CO(CH2)2NHCH3.

17. The compound of claim 2, wherein Y — Z is represented by Formula XIV:FR: ;OO IO Q F T N^ ^O^AH NH NH NHNH 7 NH R10=^=0Ti ' I n O O OR2V o II N / Formula XIV wherein: n is an integer from 1 to 12;QR1is selected from the group consisting of: H, (CH2)2N(CH3)2, (CH2)2O(CH2)2O(CH2)2OCH3, (CH2)2O(CH2)2O(CH2)2CO2H, (CH2)2O(CH2)2O(CH2)2SO3H, (CH2)2O(CH2)2O(CH2)2NH2,(CH2)2O(CH2)2O(CH2)2N(CH3)2, (CH2)2O(CH2)2O(CH2)2CONH2,(CH2)2O(CH2)2OCH(OH)CH2CO2H; and (CH2)2O(CH2)2O(CH2)2SO2CH3;R2is selected from the group consisting of: H, -C1-6alkyl, alkoxy,O(CH2)2O(CH2)2O(CH2)2CO2H, O(CH2)2O(CH2)2OCH3, O(CH2)2O(CH2)2NH2,O(CH2)2O(CH2)2NH(CH3)2, O(CH2)2O(CH2)2SO3H, O(CH2)2O(CH2)2CO2H,O(CH2)2O(CH2)2CONH2, O(CH2)2O(CH2)2SO2CH3,O(CH2)2O(CH2)2OCH2CH(OH)CH2OH, CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2OCH3,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2CO2H,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2SO2CH3,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2N(CH3)2,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2NHCH3, CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2NH2,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2SO3H, CH2N(CH3)CO(CH2)2CO2H,CH2N(CH3)CO(CH2)2NH2, and CH2N(CH3)CO(CH2)2NHCH3; andR3is selected from the group consisting of: glucamine, -NH((CH2)2O)3(CH2)2OCH3,NH(CH2)2O(CH2)2OCH2CH(OH)CH2OH, N(CH3)(CH2)2O(CH2)2OCH2CH(OH)CH2OH,NH(CH2)2O(CH2)2OCH2CH(OH)CH2OH, NHCH2CH(OH)CH2OH,NHCH2CH(OH)CH(OH)CH2OH, N(CH3)CH2CH(OH)CH2OH,N(CH3)CH2CH(OH)CH(OH)CH2OH, NH(CH2)2O(CH2)2OCH2CH(OH)CO2H,N(CH3)(CH2)2O(CH2)2OCH2CH(OH)CO2H, NH(CH2)2O(CH2)2OCH2CH(OH)CCO2H,NHCH2CH(OH)CO2H, NHCH2CH(OH)CH(OH)CO2H, N(CH3)CH2CH(OH)CO2H, andN(CH3)CH2CH(OH)CH(OH)CO2H.

18. The compound of claim 2, wherein Y — Z is represented by Formula XV:Formula XV wherein: n is an integer from 1 to 12; oR2is selected from the group consisting of: H, -C1-6alkyl, alkoxy,O(CH2)2O(CH2)2O(CH2)2CO2H, O(CH2)2O(CH2)2OCH3, O(CH2)2O(CH2)2NH2,O(CH2)2O(CH2)2NH(CH3)2, O(CH2)2O(CH2)2SO3H, O(CH2)2O(CH2)2CO2H,O(CH2)2O(CH2)2CONH2, O(CH2)2O(CH2)2SO2CH3,O(CH2)2O(CH2)2OCH2CH(OH)CH2OH, CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2OCH3,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2CO2H,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2SO2CH3,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2N(CH3)2,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2NHCH3, CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2NH2,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2SO3H, CH2N(CH3)CO(CH2)2CO2H,CH2N(CH3)CO(CH2)2NH2, and CH2N(CH3)CO(CH2)2NHCH3; andR3is selected from the group consisting of: glucamine, -NH((CH2)2O)3(CH2)2OCH3, NH(CH2)2O(CH2)2OCH2CH(OH)CH2OH, N(CH3)(CH2)2O(CH2)2OCH2CH(OH)CH2OH,NH(CH2)2O(CH2)2OCH2CH(OH)CH2OH, NHCH2CH(OH)CH2OH,NHCH2CH(OH)CH(OH)CH2OH, N(CH3)CH2CH(OH)CH2OH,N(CH3)CH2CH(OH)CH(OH)CH2OH, NH(CH2)2O(CH2)2OCH2CH(OH)CO2H,N(CH3)(CH2)2O(CH2)2OCH2CH(OH)CO2H, NH(CH2)2O(CH2)2OCH2CH(OH)CCO2H,NHCH2CH(OH)CO2H, NHCH2CH(OH)CH(OH)CO2H, N(CH3)CH2CH(OH)CO2H,N(CH3)CH2CH(OH)CH(OH)CO2H.

19. The compound of claim 2, wherein Y — Z is represented by Formula XVI:Formula XVI wherein: n is an integer from 1 to 12;R2is selected from the group consisting of: H, -C1-6alkyl, alkoxy,O(CH2)2O(CH2)2O(CH2)2CO2H, O(CH2)2O(CH2)2OCH3, O(CH2)2O(CH2)2NH2,O(CH2)2O(CH2)2NH(CH3)2, O(CH2)2O(CH2)2SO3H, O(CH2)2O(CH2)2CO2H,O(CH2)2O(CH2)2CONH2, O(CH2)2O(CH2)2SO2CH3,O(CH2)2O(CH2)2OCH2CH(OH)CH2OH, CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2OCH3,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2CO2H,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2SO2CH3,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2N(CH3)2,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2NHCH3, CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2NH2,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2SO3H, CH2N(CH3)CO(CH2)2CO2H,CH2N(CH3)CO(CH2)2NH2, and CH2N(CH3)CO(CH2)2NHCH3; andR3is selected from the group consisting of: glucamine, -NH((CH2)2O)3(CH2)2OCH3,NH(CH2)2O(CH2)2OCH2CH(OH)CH2OH, N(CH3)(CH2)2O(CH2)2OCH2CH(OH)CH2OH,NH(CH2)2O(CH2)2OCH2CH(OH)CH2OH, NHCH2CH(OH)CH2OH,NHCH2CH(OH)CH(OH)CH2OH, N(CH3)CH2CH(OH)CH2OH,N(CH3)CH2CH(OH)CH(OH)CH2OH, NH(CH2)2O(CH2)2OCH2CH(OH)CO2H,N(CH3)(CH2)2O(CH2)2OCH2CH(OH)CO2H, NH(CH2)2O(CH2)2OCH2CH(OH)CCO2H,NHCH2CH(OH)CO2H, NHCH2CH(OH)CH(OH)CO2H, N(CH3)CH2CH(OH)CO2H,N(CH3)CH2CH(OH)CH(OH)CO2H.

20. The compound of claim 2, wherein Y — Z is represented by Formula XVII:Formula XVII wherein: n is an integer from 1 to 12;R1is selected from the group consisting of: H, (CH2)2N(CH3)2, (CH2)2O(CH2)2O(CH2)2OCH3, (CH2)2O(CH2)2O(CH2)2CO2H, (CH2)2O(CH2)2O(CH2)2SO3H, (CH2)2O(CH2)2O(CH2)2NH2,(CH2)2O(CH2)2O(CH2)2N(CH3)2, (CH2)2O(CH2)2O(CH2)2CONH2,(CH2)2O(CH2)2OCH(OH)CH2CO2H, and (CH2)2O(CH2)2O(CH2)2SO2CH3;R2is selected from the group consisting of: H, -C1-6alkyl, alkoxy, O(CH2)2O(CH2)2O(CH2)2CO2H, O(CH2)2O(CH2)2OCH3, O(CH2)2O(CH2)2NH2,O(CH2)2O(CH2)2NH(CH3)2, O(CH2)2O(CH2)2SO3H, O(CH2)2O(CH2)2CO2H,O(CH2)2O(CH2)2CONH2, O(CH2)2O(CH2)2SO2CH3,O(CH2)2O(CH2)2OCH2CH(OH)CH2OH, CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2OCH3,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2CO2H,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2SO2CH3,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2N(CH3)2,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2NHCH3, CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2NH2,CH2N(CH3)CO(CH2)2O(CH2)2O(CH2)2SO3H, CH2N(CH3)CO(CH2)2CO2H,CH2N(CH3)CO(CH2)2NH2, and CH2N(CH3)CO(CH2)2NHCH3; andR3is selected from the group consisting of: glucamine, -NH((CH2)2O)3(CH2)2OCH3,NH(CH2)2O(CH2)2OCH2CH(OH)CH2OH, N(CH3)(CH2)2O(CH2)2OCH2CH(OH)CH2OH,NH(CH2)2O(CH2)2OCH2CH(OH)CH2OH, NHCH2CH(OH)CH2OH,NHCH2CH(OH)CH(OH)CH2OH, N(CH3)CH2CH(OH)CH2OH,N(CH3)CH2CH(OH)CH(OH)CH2OH, NH(CH2)2O(CH2)2OCH2CH(OH)CO2H,N(CH3)(CH2)2O(CH2)2OCH2CH(OH)CO2H, NH(CH2)2O(CH2)2OCH2CH(OH)CCO2H9NHCH2CH(OH)CO2H, NHCH2CH(OH)CH(OH)CO2H, N(CH3)CH2CH(OH)CO2H,N(CH3)CH2CH(OH)CH(OH)CO2H.

21. The compound of claim 7, wherein Y — Z is represented by Formula I and is a compound selected from:,22. The compound of claim 8, wherein Y — Z is a represented by Formula H and is a compound selected from:(Coromip-3) and23. The compound of claim 9, wherein Y — Z is a represented by Formula HI and is a compound selected from:(Coromip-67),26. The compound of any one of claims 7-20, wherein n is an integer from 1 to 3.

27. The compound of any one of claims 7-13, wherein R is -CH3or -CH2CH2CH2NHCONH2.

28. The compound of any one of claims 7-20, wherein R2is H or methoxy.

29. An antibody-drug conjugate comprising a targeting antibody (Ab) conjugated to one or more compounds according to any one of claims 1-25.

30. The antibody-drug conjugate of claim 29, wherein the targeting antibody is a monoclonal antibody or a bispecific antibody.

31. The antibody-drug conjugate of claim 30, wherein the targeting antibody is an antibody that binds to a target protein selected from the the group consisting of HER2, CD 180, CDH17, CD33, Trophoblast cell surface antigen 2 (TROP-2), CD19, NECTIN-4, c-MET, epithelial cell adhesion molecule (EpCAM), Prostate-Specific Membrane Antigen (PSMA), and Folate receptor alpha (FRa).

32. The antibody-drug conjugate of claim 31, wherein the anti-HER2 antibody is Trastuzumab.

33. The antibody-drug conjugate of claim 30, wherein the targeting antibody is an antibody that binds to a target protein selected from the group consisting of Fibroblast Activation Protein (FAP), Integrin av06, asialoglycoprotein receptor 1 (ASGR1), CD13, Platelet- Derived Growth Factor Receptor beta (PDGFR-0), Cadherin-11, CD248, ANP-R, periostin, CD59, VEGFR2, ICAM-1, CD19, CD4, and CD38.

34. The antibody-drug conjugate of claim 29 having a drug-to-antibody ratio (DAR) ranging from 1 to 10.

35. The antibody-drug conjugate of claim 34 having a DAR of 8.

36. A pharmaceutical composition comprising the antibody-drug conjugate of claim 29 and a pharmaceutically acceptable carrier.

37. A method of treating a disease condition in a subject in need thereof, the method comprises administering to the subject a pharmaceutical composition according to claim 36.

38. The method of claim 37, wherein the disease condition is cancer.

39. The method of claim 38, wherein the cancer is selected from lymphoma, leukemia, breast cancer, non-small cell lung cancer (NSCLC), urothelial cancer, bladder cancer, gastric cancer, colorectal cancer, pancreatic cancer, ovarian cancer, colon cancer, endometrial cancer, and prostate cancer.

40. The method of claim 37, wherein the disease condition is idiopathic pulmonary fibrosis.

41. The method of claim 37, wherein the disease condition is liver fibrosis, nonalcoholic steatohepatitis (NASH), or nonalcoholic fatty liver disease.

42. The method of claim 37, wherein the disease condition is renal fibrosis or chronic kidney disease progression.

43. The method of claim 37, wherein the disease condition is systemic sclerosis.

44. The method of claim 37, wherein the disease condition is pathologic cardiac hypertrophy or heart failure.

45. The method of claim 37, wherein the disease condition is age-related macular degeneration (AMD).

46. The method of claim 37, wherein the disease condition is an autoimmune disorder.

47. The method of claim 46, wherein the autoimmune disorder is lupus or rheumatoid arthritis.

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