NSD2-targeted chemical degraders and compositions and methods of use thereof

Abstract

The current invention relates to nuclear receptor-binding SET domain-containing 2 (NSD2)-targeted protein degradation reagents and pharmaceutical compositions thereof and their utility as anti-cancer agents.

Description

[0001] NSD2-TARGETED CHEMICAL DEGRADERS AND COMPOSITIONS AND METHODS OF USE THEREOF FIELD OF THE INVENTION The present invention is directed to nuclear receptor-binding SET domain-containing 2 (NSD2)-targeted protein degradation ligands and pharmaceutical compositions thereof and their utility as anti-cancer agents. GOVERNMENT SUPPORT This invention was made with government support under Grant No. CA242305 awarded by the National Institutes of Health. The government has certain rights in the invention. BACKGROUND Nuclear receptor-binding SET domain-containing 2 (NSD2, also known as multiple myeloma SET domain (MMSET) and Wolf-Hirschhorn syndrome candidate 1 (WHSC1)) is a protein lysine methyltransferase that belongs to the NSD family, which also includes NSD1 and NSD3. The main function of NSD2 is the production of the bulk of H3K36me2 in diverse cell types. Dimethylation of H3K36 by both NSD1 and NSD2 recruits DNMT3a at intergenic regions to control DNA methylation and regulate development and homeostasis (Weinberg, D. N., et al., Nature, 573, 281-286, 2019). NSD2 is also required for efficient non-homologous end-joining and homologous recombination, two canonical DNA repair pathways (Shah, M. Y. et al. Oncogene, 35, 5905-5915, 2016; Zhang, J. et al., Cancer Discov., 9, 1306-1323). Structurally, NSD2 has multiple protein-protein interaction (PPI) modules with known or potential chromatin reading functions, including five PHD (plant homeodomain) and two PWWP (proline-tryptophan-tryptophan-proline) domains (Bennet, R. L. et al. Cold Spring Harb Perspect Med., 7, 2017), as well as a putative DNA-binding HMG-box (high mobility group box) domain in addition to its catalytic domain (Fig. 1). Mounting evidence suggests that these domains play important roles in NSD2 function, but the individual and / or collective roles of the NSD2 chromatin reader domains are still being elucidated. Many PWWP domains are known H3K36me2,3 reading modules that engage methyl-lysine while simultaneously interacting with nucleosomal DNA adjacent to H3K36 (Qin, S. et al. Trends Biochem. Sci., 39, 536-547, 2014; Vermeulen, M. et al. Cell 142, 967- 980, 2010). The isolated N-terminal PWWP domain of NSD2 (NSD2-PWWP1) binds H3K36 di- and trimethylated nucleosomes; this interaction presumably is mediated by a conserved aromatic cage and stabilizes NSD2 at chromatin (Sankaran, S. M. et al., J. Biol. Chem.291, 8465-8474, 2016). Mutation of the aromatic cage residues abrogates NSD2-PWWP1 binding to nucleosomal H3K36me2, but has only modest effect on global H3K36 methylation level in cells. However, H3K36 methylation has been shown to be abolished upon mutation of the second PHD domain (PHD2)(Huang, Z. et al. Cancer. Res.73, 6277-6288, 2013). Recently, a growing number of studies have linked NSD methyltransferases to a variety of diseases and cancers. For example, NSD2 is aberrantly expressed, amplified or somatically mutated in multiple types of cancer, leading to increased methylation of lysine 36 of histone 3 (H3K36) (Kuo, A. J., et al. Mol. Cell, 44, 609-620, 2011) and subsequent proliferation. In particular, the t(4;14) NSD2 translocation in multiple myeloma (MM) and the hyper-activating NSD2 E1099K mutation in a subset of pediatric acute lymphoblastic leukemia (ALL) both result in altered chromatin methylation which drives oncogenesis (Keats, J. J. et al., Blood, 101, 1520-1529, 2003; Oyer, J. A. et al., Oncogene, 38, 6710686, 2019). As such, high expression of the NSD2 protein has been demonstrated in different human cancer types, including bladder, brain, gastrointestinal, lung, liver, ovary, skin, uterus, breast, prostate and glioblastoma. (Coussens et al., J. Biol. Chem.293, 13750-13654 (2018); Ezponda et al., Oncogene 32: 2882-2890 (2013)). Notably, NSD2 is among the most frequently mutated genes in pediatric cancer genomes. The NSD2 SET domain variant, E1099K, was identified in both acute lymphoblastic leukemia tumors and cell lines with increased H3K36me2 that lack the t (4; 14) translocation. NSD2 is also among the most frequently mutated genes found in mantle cell lymphoma tumors, where both E1099K and T1150A variants are observed. The E1099K variant has also been reported in chronic lymphocytic leukemia (CLL), lung and stomach cancers. In general, NSD2 upregulation is associated with aggressive tumor behavior and poor prognosis. Due to growing occurrence of drug resistance to current traditional anticancer drugs employed in treating such cancer, there has been an ongoing need for improving such anti-cancer therapies and / or developing new treatment options, which can act via different cellular mechanisms to combat cancers. One of such new treatment options involves the NSD2 enzyme, which represents a promising target for anti-cancer therapy. SUMMARY Provided herein are compounds, which can bind to the NSD2 enzyme in the non-active site and degrade the enzyme. Thus, one aspect of the current disclosure is directed to a compound of Formula (I): A compound of Formula (I): Formula (I) or any pharmaceutically acceptable salt and / or stereoisomer thereof, wherein: Q is selected from the group consisting of R1is –cyclopropyl or -isopropyl; R1ais hydrogen or (C1-C6) alkyl; R2aand R2b, in each instance, are independently selected from hydrogen, (C1-C6) alkyl, (C1- C6) haloalkyl, (C1-C6) alkoxy, halogen, −CN, −NH2, and −OH; A is selected from the group consisting of:

[0002] ; wherein R3a, R3b R3c, R3d, R3e, R3f and R3g are each independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, halogen, −CN, −NH2, and –OH; wherein X is selected from the group consisting of -CH2-, -O-, -S-, -S(=O)-, - S(=O)2NH-, -CO(=O)-, -NH-, -C=C-, -C(=O)-, -C(=O)O-, -C(=O)NH-, -C(=O)N(CH3)-, - C(=O)HCH2C(CH3)2-, -C(=O)C(CH3)2-, -C(=O)NH-, -[(C1-C6) cycloalkyl]N[(C1-C6) alkyl]C(=O)-, and -NHC(=O)-; B is -C- or -N-; W is a bond, -C(=O)- or -N(CH3)C(=O)-; Z1and Z2are independently selected from -H, -OH, -NH2, -CN, -CF3, CD3, halogen, (C1- C6)alkyl, -O(C1-C6)alkyl, -OC(=O)(C1-C6)alkyl, -C(=O)(C1-C6)alkyl, -C(=O)O(C1-C6)alkyl, C(=O)NH(C1-C6)alkyl, -NHC(=O)(C1-C6)alkyl and (C2-C6)alkynyl; wherein G is -C(=O)-, -CH2N[(C1-C6) alkyl)]C(=O)- or -C(=O)NH-; Y is selected from the group consisting of -N[(C1-C6) alkyl)]C(=O)-, -N[(C1-C6) cycloalkyl)]C(=O)-, -N[(C1-C6) alkyl)]C(=O)O-, -CH2N[(C1-C6) alkyl)]C(=O)-, -N[(C1-C6) cycloalkyl]C(=O)-, -N[C(=O)(C1-C6) alkyl)]-, -CD2-, -NHC(=O)-, -CH=CH-, -N[C(=O) (C1-C6) alkyl]- H is selected from the group consisting of -C(CH3)2-, -CH(CH3)-, -S(=O)2-, -S(=O)-, -S-, - N[(C1-C6) alkyl]-, n, m and w are integers independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; and p and q are integers independently selected from 0, 1, 2, 3 and 4. Another aspect of the disclosure is directed to a pharmaceutical composition comprising a compound as disclosed herein or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carrier(s). Another aspect of the disclosure is directed to a method for treating a disease or condition that is treatable by inhibition of nuclear SET-domain-containing protein (NDS2), the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound, prodrug, or a pharmaceutical composition as disclosed herein. In some embodiments, the disease is cancer. DESCRIPTION OF THE DRAWINGS Fig.1 shows the NSD2 protein architecture of the three splicing isoforms NSD2-long, NSD2- short, and REIIBP. DETAILED DESCRIPTION The presently disclosed subject matter will now be described more fully hereinafter. However, many modifications and other embodiments of the presently disclosed subject matter set forth herein will come to mind to one skilled in the art to which the presently disclosed subject matter pertains having the benefit of the teachings presented in the foregoing descriptions. Therefore, it is to be understood that the presently disclosed subject matter is not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. In other words, the subject matter described herein covers all alternatives, modifications, and equivalents. In the event that one or more of the incorporated literature, patents, and similar materials differs from or contradicts this application, including but not limited to defined terms, term usage, described techniques, or the like, this application controls. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in this field. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. NSD2 (nuclear receptor-binding SET domain-containing 2) is a key player in epigenetic regulation, known for its ability to mono- and dimethylate lysine 36 of histone 3 (H3K36). This mark is associated with active transcription, and elevated levels of H3K36me2 lead to abherent activation of normally silenced genes. Consequently, NSD2 is a potent oncoprotein and has been implicated as a therapeutic target for a variety of cancers. Recent research efforts suggest that in addition to its catalytic SET domain, NSD2 contains several PWWP and PHD methyl-lysine (Kme) reader domains, which are thought to be critical in propagating H3K36me2 and recruiting NSD2 to its oncogenic genes. Various NSD2 antagonists have been prepared to date (WO2021 / 026803; WO2021 / 028854; and Dilworth, D. et al., bioRxiv, March 7, 2021). However, since drug resistance is the main limitation for cancer therapy, other treatment strategies are needed, such as compounds that block NSD2 enzymatic activity or NSD2 degraders. Thus, the disclosed compounds are NSD2 targeted compounds exhibiting potent NSD2 binding affinity while simultaneously demonstrating efficient degradation of the target protein (i.e., NSD2). Pharmaceutical compositions containing these NSD2 degraders and methods of use thereof are described further in more detail below. I. Definitions As used herein, the term “alkyl group” refers to a saturated hydrocarbon radical containing 1 to 8, 1 to 6, 1 to 4, or 5 to 8 carbons. In some embodiments, the saturated radical contains more than 8 carbons. An alkyl group is structurally similar to a noncyclic alkane compound modified by the removal of one hydrogen from the noncyclic alkane and the substitution therefore of a non-hydrogen group or radical. Alkyl group radicals can be branched or unbranched. Lower alkyl group radicals have 1 to 4 carbon atoms. Higher alkyl group radicals have 5 to 8 carbon atoms. Examples of alkyl, lower alkyl, and higher alkyl group radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec butyl, t butyl, amyl, t amyl, n-pentyl, n-hexyl, i-octyl and like radicals. As used herein, the designations “C(=O),” “CO” and “C(O)” are used to indicate a carbonyl moiety. Examples of suitable carbonyl moieties include, but are not limited to, those found in ketones and aldehydes. The term “cycloalkyl” refers to a hydrocarbon with 3-8 members or 3-7 members or 3-6 members or 3-5 members or 3-4 members and can be monocyclic or bicyclic. The ring may be saturated or may have some degree of unsaturation. Cycloalkyl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of a cycloalkyl group may be substituted by a substituent. Representative examples of cycloalkyl group include cyclopropyl, cyclopentyl, cyclohexyl, cyclobutyl, cycloheptyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, and the like. The term “aryl” refers to a hydrocarbon monocyclic, bicyclic or tricyclic aromatic ring system. Aryl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, 4, 5 or 6 atoms of each ring of an aryl group may be substituted by a substituent. Examples of aryl groups include phenyl, naphthyl, anthracenyl, fluorenyl, indenyl, azulenyl, and the like. The term “heteroaryl” refers to an aromatic 5-10 membered ring systems where the heteroatoms are selected from O, N, or S, and the remainder ring atoms being carbon (with appropriate hydrogen atoms unless otherwise indicated). Heteroaryl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of a heteroaryl group may be substituted by a substituent. Examples of heteroaryl groups include pyridyl, furanyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl, thiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, isoquinolinyl, indazolyl, and the like. As used herein, the term “alkoxy” refers to a moiety of the formula —OR a where Ra is an alkyl group as defined herein containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkoxy group is optionally substituted.’ As used therein, the term “haloalkyl” refers to an alkyl group, as defined herein, that is substituted by one or more halo atoms, as defined herein, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, —CH2CF3, —CH2CHF2, —CH2CH2F, —CHFCF3, —CHFCHF2, — CHFCH2F, —CHFCH3, —CF2CF3, —CF2CHF2, —CF2CH2F, —CF2CH3, —CH2CF2CH3, — CH2CHFCH3, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a haloalkyl group is optionally substituted. As used herein, the term “alkynyl”, used alone or as part of another group, refers to unsaturated linear or branched hydrocarbon radical that contains one triple bond. The hydrocarbon radical contains at least 2 carbon atoms, but preferably contains 3 to 20 carbon atoms. As used herein, the term “substituted” refers to a moiety (such as heteroaryl, aryl, cycloalkyl, alkyl, and / or alkenyl) wherein the moiety is bonded to one or more additional organic or inorganic substituent radicals. In some embodiments, the substituted moiety comprises 1, 2, 3, 4, or 5 additional substituent groups or radicals. Suitable organic and inorganic substituent radicals include, but are not limited to, halogen, hydroxyl, cycloalkyl, aryl, substituted aryl, heteroaryl, heterocyclic ring, substituted heterocyclic ring, amino, mono-substituted amino, di-substituted amino, acyloxy, nitro, cyano, carboxy, carboalkoxy, alkyl carboxamide, substituted alkyl carboxamide, dialkyl carboxamide, substituted dialkyl carboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl, alkoxy, substituted alkoxy or haloalkoxy radicals, wherein the terms are defined herein. Unless otherwise indicated herein, the organic substituents can comprise from 1 to 4 or from 5 to 8 carbon atoms. When a substituted moiety is bonded thereon with more than one substituent radical, then the substituent radicals may be the same or different. As used herein, the term “unsubstituted” refers to a moiety (such as heteroaryl, aryl, alkenyl, and / or alkyl) that is not bonded to one or more additional organic or inorganic substituent radical as described above, meaning that such a moiety is only substituted with hydrogens. It will be understood that the structures provided herein and any recitation of "substitution" or "substituted with" includes the implicit proviso that such structures and substitution are in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “subject” broadly refers to any animal, including but not limited to, human and non-human animals (e.g., dogs, cats, cows, horses, sheep, poultry, fish, crustaceans, etc.). As used herein, the term “patient” typically refers to a subject that is being treated for a disease or condition. As used herein, the term “effective amount” refers to the amount of a composition sufficient to effect beneficial or desired results. An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route. As used herein, the terms “administration” and “administering” refer to the act of giving a drug, prodrug, or other agent, or therapeutic treatment to a subject or in vivo, in vitro, or ex vivo cells, tissues, and organs. Exemplary routes of administration to the human body can be through space under the arachnoid membrane of the brain or spinal cord (intrathecal), the eyes (ophthalmic), mouth (oral), skin (topical or transdermal), nose (nasal), lungs (inhalant), oral mucosa (buccal), ear, rectal, vaginal, by injection (e.g., intravenously, subcutaneously, intratumorally, intraperitoneally, etc.) and the like. As used herein, the terms “co-administration” and “co-administering” refer to the administration of at least two agent(s) (e.g., NSD2 inhibitor and one or more additional therapeutics) or therapies to a subject. In some embodiments, the co-administration of two or more agents or therapies is concurrent. In other embodiments, a first agent / therapy is administered prior to a second agent / therapy. Those of skill in the art understand that the formulations and / or routes of administration of the various agents or therapies used may vary. The appropriate dosage for co-administration can be readily determined by one skilled in the art. In some embodiments, when agents or therapies are co- administered, the respective agents or therapies are administered at lower dosages than appropriate for their administration alone. Thus, co-administration is especially desirable in embodiments where the co-administration of the agents or therapies lowers the requisite dosage of a potentially harmful (e.g., toxic) agent(s), and / or when co-administration of two or more agents results in sensitization of a subject to beneficial effects of one of the agents via co-administration of the other agent. As used herein, the term “pharmaceutical composition” refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vitro, in vivo or ex vivo. The terms “pharmaceutically acceptable” or “pharmacologically acceptable,” as used herein, refer to compositions that do not substantially produce adverse reactions, e.g., toxic, allergic, or immunological reactions, when administered to a subject. As used herein, the term “pharmaceutically acceptable carrier” refers to any of the standard pharmaceutical carriers including, but not limited to, phosphate buffered saline solution, water, emulsions (e.g., such as an oil / water or water / oil emulsions), and various types of wetting agents, any and all solvents, dispersion media, coatings, sodium lauryl sulfate, isotonic and absorption delaying agents, disintegrants (e.g., potato starch or sodium starch glycolate), and the like. The compositions also can include stabilizers and preservatives. For examples of carriers, stabilizers and adjuvants, see, e.g., Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, Pa. (1975), incorporated herein by reference in its entirety. As used herein, the term “pharmaceutically acceptable salt” refers to any pharmaceutically acceptable salt (e.g., acid or base) of a compound of the present invention, which, upon administration to a subject, is capable of providing a compound of this invention or an active metabolite or residue thereof. As is known to those of skill in the art, “salts” of the compounds of the present invention may be derived from inorganic or organic acids and bases. Examples of acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic, benzenesulfonic acid, and the like. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts. As used herein, the term “inhibit”, "inhibition" or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process. As used herein, the term “treat”, “treating" or "treatment" of any disease or disorder refers to alleviating or ameliorating the disease or disorder (i.e., slowing or arresting the development of the disease or at least one of the clinical symptoms thereof); or alleviating or ameliorating at least one physical parameter or biomarker associated with the disease or disorder, including those which may not be discernible to the patient. As used herein, the term “prevent”, “preventing" or “prevention” of any disease or disorder refers to the prophylactic treatment of the disease or disorder; or delaying the onset or progression of the disease or disorder. As used herein, a subject is “in need of” a treatment if such subject would benefit biologically, medically or in quality of life from such treatment. As used herein, the term a therapeutically effective amount" of a compound of the present invention refers to an amount of the compound of the present invention that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc. As used herein, the term “anticancer agent” or antineoplastic agent, refers to a therapeutic agent that is useful for treating or controlling the growth of cancerous cells. II. Compounds Provided herein are NSD2 degraders and methods of use thereof for the treatment of disease, such as cancers and other diseases dependent on the activity of NSD2. In some embodiments, the compounds disclosed herein comprise a compound of Formula (I): Formula (I) or any pharmaceutically acceptable salt and / or stereoisomer thereof, wherein: Q is selected from the group consisting of R1is –cyclopropyl or -isopropyl; R1ais hydrogen or (C1-C6) alkyl; R2aand R2b, in each instance, are independently selected from hydrogen, (C1-C6) alkyl, (C1- C6) haloalkyl, (C1-C6) alkoxy, halogen, −CN, −NH2, and −OH; A is selected from the group consisting of:

[0003]  wherein R3a,R3bR3c, R3d, R3e, R3fand R3gare each independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, halogen, −CN, −NH2, and – OH; L1i , wherein X is selected from the group consisting of -CH2-, -O-, -S-, -S(=O)-, -S(=O)2NH-, -CO(=O)-, -NH-, -C=C-, -C(=O)-, - C(=O)O-, -C(=O)NH-, -C(=O)N(CH3)-, -C(=O)C(CH3)2-, -C(=O)NH-, -[(C1-C6) cycloalkyl]N[(C1- C6) alkyl]C(=O)-, and -NHC(=O)-; B is -C- or -N-; F is -O-, -N-, -S-, or -C-; W is a bond, -C(=O)-, -C(=O)(CH2)s, or -N(CH3)C(=O)-; Z1and Z2are independently selected from -H, -OH, -NH2, -CN, -CF3, CD3, halogen, (C1- C6)alkyl, -O(C1-C6)alkyl, -OC(=O)(C1-C6)alkyl, -C(=O)(C1-C6)alkyl, -C(=O)O(C1-C6)alkyl, C(=O)NH(C1-C6)alkyl, -NHC(=O)(C1-C6)alkyl and (C2-C6)alkynyl; L2is , wherein G is -C(=O)-, - CH2N[(C1-C6) alkyl)]C(=O)- or -C(=O)NH-; Y is selected from the group consisting of -N[(C1-C6) alkyl)]C(=O)-, -N[(C1-C6) cycloalkyl)]C(=O)-, -N[(C1-C6) alkyl)]C(=O)O-, -CH2N[(C1-C6) alkyl)]C(=O)-, -N[(C1-C6) cycloalkyl]C(=O)-, -N[C(=O)(C1-C6) alkyl)]-, -CD2-, -NHC(=O)-, -CH=CH-, -N[C(=O) (C1-C6) alkyl]- H is selected from the group consisting of -CH2-, = = S-, -N[(C1-C6) alkyl]-, -NH-, -O-, -C=C-, -OCH2CH2O-, n, m, s and w are integers independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; and p and q are integers independently selected from 0, 1, 2, 3 and 4. In some embodiments, R1ais hydrogen. In some embodiments, R1ais (C1-C6) alkyl. In some embodiments, R1is -cyclopropyl. In some embodiments, R1is -isopropyl. In some embodiments, R1a is hydrogen and R1 is -cyclopropyl.In some embodiments, comprises one of more of the following: In some embodiments, Q is selected from the group consisting of

[0004] . In some embodiments, R1ais hydrogen; R1is -cyclopropyl and Q is selected from R1ais hydrogen; R1is -cyclopropyl; Q is selected from

[0005] group; wherein R3f is -H and L1 , wherein X is -C(=O) and n is 5. In some embodiments, R1ais hydrogen; R1is -cyclopropyl; , wherein R2ais hydrogen wherein R3fis -H and L1is , wherein X is -C(=O) and n is 5. In some embodiments, R1ais (C1-C6) alkyl and R1is -cyclopropyl. In some embodiments, R1ais -CH3and R1is -cyclopropyl. In some embodiments, R1ais -CH3and R1is -cyclopropyl; Q is herein R2aand R2bare - wherein R3fis -H and wherein X is -C(=O) and n is 5.In some embodiments, Q is selected from the group consisting , wherein R2aand R2bare independently selected from the group consisting of hydrogen, (C1-C6) alkyl, and halogen. In some embodiments, . In some embodiments, i

[0006] W is -C(=O). In some embodiments, , wherein B is -C-, W is -C(=O) and Z1and Z2are -H. In some Q is wherein B is -C- and

[0007] In some embodiments, Q is In some embodiments, Q is In some embodiments, Q is and L1 is , wherein X is -C(=O) and n is an integer selected from 4, 5 and 6. In some embodiments, , wherein W is -C(=O). In some embodiments, Q is and L1is , wherein W is -C(=O) and B is -C-. In some embodiments, Q is C(=O), B is -C- and Z1and Z2are -H. In some embodiments, .In some embodiments, Q is selected from the group consisting , . In some embodiments, Q is selected from the groupconsisting wherein R2a and R2bare independently selected from the group consisting of hydrogen, (C1-C6) alkyl, and halogen. In someembodiments, Q is selected from the group consisting a wherein R2a and R2b are independently selected from the group consistingof hydrogen, (C1-C6) alkyl, and halogen . In someembodiments, wherein R3f is -H and L1 is. In some embodiments, Q A is , wherein wherein B is -C-. In someembodiments, wherein R3f is -H and L1 is , wherein B is -C- and W is -C(=O). In some embodiments, Q is , wherein B is -C-, W is -C(=O) and Z1and Z2are independently selected from -H, -OH, (C1-C6)alkyl,-O(C1-C6)alkyl, and (C2-C6)alkynyl. In In some embodiments, wherein B is -C-, W is -C(=O)and Z1 and Z2 are -H. In some embodiments, , wherein R3f is -H and L1 is . In some embodiments, , wherein n is an integerselected from 3, 4, and 5. In some embodiments, wherein R3fis -H. In some embodiments, wherein R3fis -H; and L1is , wherein wherein B is -C-. In some embodiments, Q is , wherein B is -C- and W is -C(=O)-. In some embodiments, wherein B is -C-, W is - C(=O)- and Z1and Z2are independently selected from -H, -OH, (C1-C6)alkyl, -O(C1-C6)alkyl, and(C2-C6)alkynyl. In In some embodiments, ,wherein R3fis wherein B is -C-, W is -C(=O) and Z1and Z2are -H.I In some embodiments, R1ais hydrogen; R1is -cyclopropyl; . In some embodiments, the compounds disclosed herein are compounds of Formula (II): Formula (II) or a pharmaceutically acceptable salt thereof and / or stereoisomer thereof, wherein: R2aand R2bare independently selected from hydrogen, (C1-C6) alkyl, (C1-C6) alkoxy, or halogen; A is selected from the group consisting of

[0008] wherein R3a,R3bR3c, R3d, R3e, R3fand R3gare each independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, and halogen; wherein X is selected from the group consisting of -O-, -CH2-, -C(=O)-, and -NHC(=O)-; B is -C- or -N-; W is a bond, -C(=O)- , -C(=O)(CH2)s, or -N(CH3)C(=O)-; Z1and Z2are independently selected from -H, -OH, -NH2, -CN, -CF3, CD3, halogen, (C1- C6)alkyl, -O(C1-C6)alkyl, -OC(=O)(C1-C6)alkyl, -C(=O)(C1-C6)alkyl, -C(=O)O(C1-C6)alkyl, C(=O)NH(C1-C6)alkyl, -NHC(=O)(C1-C6)alkyl and (C2-C6)alkynyl; wherein G is - C(=O)- or -C(=O)NH-; Y is selected from the group consisting of -N[(C1-C6) alkyl)]C(=O)-, -N[(C1-C6) cycloalkyl]C(=O)-, -NHC(=O)-, and -N[C(=O) (C1-C6) alkyl]-; H is selected from the group consisting of -C(CH3)2-, -CH(CH3)-, -S(=O)2-, -S(=O)-, -S-, - N[(C1-C6) alkyl]-, n, m, s and w are integers independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; and p and q are integers independently selected from 0, 1, 2, 3 and 4. In some embodiments, A is selected from the group consisting of some embodiments, A is selected from the group consisting of

[0009] and , wherein X is -CH2-. In some embodiments, A is selectedfrom the group consisting of an integer selected from 2, 3, 4, 5, 6, and 7. In some embodiments, A is selected from the group consisting of and wherein X is -CH2-; n is 3 or 4; and R2aand R2bare hydrogen. In some embodiments, A is selected from the group consisting of and . In some embodiments, A is selected from the group consisting of diments, A is selected from the group consisting of , wherein X is -CH2- or -C(=O) and n is an integer selected from 4, 5, 6, and 7. In some embodiments, A is selected from the group consisting of , wherein X is -CH2- and n is an integer selected from 4, 5, 6, and 7. In some embodiments, A is selected from the group consisting of , wherein X is -CH2- and n is 4. In some embodiments, A is selected from the group consisting of is selected from the group consisting of wherein X is -C(=O) and n is an integer selected from 4, 5, 6, and 7. In some embodiments, A is selected from the group consisting of wherein X is -C(=O) and n is 4. In such embodiments, R3fis hydrogen. In some embodiments, A is selected from the group consisting of e In some embodiments, A is selected from the group consisting of In some embodiments, A is selected from the group consisting of O) and n is an integer selected from 4, 5, 6, and 7. In some embodiments, A is selected from the group consisting of n is an integer selected from 4, 5, 6, and 7. In some embodiments, A is selected from the group consisting of , wherein X is -CH2- and n is 5. In some embodiments, A is selected from the group consisting of wherein X is -CH2- and n is 5. In some embodiments, A is selected from the group consisting of and , wherein X is -C(=O) and n is an integer selected from 4, 5, 6, and 7. In some embodiments, A is selected from the group consisting of , wherein X is --C(=O) and n is 4. In some embodiments, A is ; and wherein X is -C(=O) and n is 4. In some embodiments, A is . In some embodiments, A is . , and L2is . In some embodiments, A is , wherein G is -C(=O)NH. In some embodiments, wherein G is -C(=O)N and H is -O- or - OCH2CH2O-. In some embodiments, , wherein G is - C(=O)N; H is -O- or -OCH2CH2O-; and p and q are integers independently selected from 0, 1, 2, 3, 4 and 5. In some embodiments, A is , wherein G is -C(=O)N; 0 or 2. In some embodiments, A is , wherein G is -C(=O)N; H is -O- ; p 2; and q is 2. In some embodiments, A is , wherein G is -C(=O)N; H is -OCH2CH2O-; p is 0 or 2; and q is 0 or 2. In some embodiments, A is . In some embodiments, A is , wherein Y is selected from the group consisting of - N(CH3)C(=O)-, -N[CH(CH3)2]C(=O)-, -N[C(CH3)3]C(=O)-, -N[cyclopropyl]C(=O)-, and - N[C(=O)CH3]-. In some embodiments, A is , wherein Y is selected from the group consisting of -N(CH3)C(=O)-, -N[CH(CH3)2]C(=O)-, -N[C(CH3)3]C(=O)-, - N[cyclopropyl]C(=O)-, and -N[C(=O)CH3]-; and w is 4, 5, or 6. In some embodiments, A is , wherein Y is selected from the group consisting of -N(CH3)C(=O)-, -N[CH(CH3)2]C(=O)-, -N[C(CH3)3]C(=O)-, - N[cyclopropyl]C(=O)-, and -N[C(=O)CH3]-. In some embodiments, A is and L2is , ; 3a - ; 2 , from the group consisting of -N(CH3)C(=O)-, -N[CH(CH3)2]C(=O)-, -N[C(CH3)3]C(=O)-, - N[cyclopropyl]C(=O)-, and -N[C(=O)CH3]-; and w is 5. In some embodiments, A is ; R3ais -CH3; and L2is , wherein Y is selected from the group consisting of - N(CH3)C(=O)-, -N[CH(CH3)2]C(=O)-, -N[C(CH [cyclopropyl]C(=O)-, and - N[C(=O)CH3]-; and w is 5. In some embodiments, ; R3aand R2bare -CH3; R2ais - H; and L2 is , wherein Y is selected from the group consisting of -N(CH3)C(=O)-, - N[CH(CH3)2]C(=O)-, -N[C(CH3)3]C(=O)-, -N[cyclopropyl]C(=O)-, and -N[C(=O)CH3]-; and w is 5.In some embodiments, A , wherein Y is -N[C(CH3)3]C(=O)-; and w is 6. In some embodiments, A is , wherein G is -CH2N[(C1-C6) alkyl]C(=O)-. In some embodiments, A is , wherein G is -- , w e e p s , , , o ; s -2 1-6a y - a s -3 2-. In some embodiments, A is , wherein p is 0, 1, 2, or 3; q is 1, 2, 3 or 4; G is -CH2N[(C1-C6) alkyl]C(=O)- and H is -C(CH3)2-. In some embodiments, A is wherein p is 0; q is 4; G is -CH2N(CH3)C(=O)- and H is -

[0010] embodiments, wherein p is 3; q is 1; G is - In some embodiments, A is . In some embodiments, A is , wherein L1 is . , and L1is , wherein X is - NHC(=O) or -O-. In some embodiments, A is , wherein X is - NHC(=O) or -O-; and n is 4, 5, 6, 7 or 8. In some embodiments, and L1is

[0011] In some embodiments, A is , wherein X is selected from the group consisting of -CH2-, -O-, -S-, -S(=O)-, -S(=O)2NH-, -CO(=O)-, -NH-, -C=C-, -C(=O)O-, - C(=O)NH- and -C(=O)N(CH3)-. In some embodiments, , wherein n is 5, 6, or 7; and X is selected from the group consisting of -CH2-, -O-, -S-, -S(=O)-, - S(=O)2NH-, -CO(=O)-, -NH-, -C=C-, -C(=O)O-, -C(=O)NH- and -C(=O)N(CH3)-. In some embodiments, A is , wherein n is 7; and X is selected from the group consisting of -CH2-, -O-, -S-, -S(=O)-, and -NH-. In some embodiments, A is and L1 , wherein n is 6; and X is selected from the group consisting of -S(=O)2NH-, - CO(=O)-, -C=C-, -C(=O)N(CH3)- and -C(=O)NH-. In some embodiments, A is . In some embodiments, A is embodiments, wherein X is -O-; and n is 4, 5, 6 or 7. In some embodiments, A is , wherein X is -C(=O)NH- and n is 4, 5, 6 or 7. In some embodiments, A is selected from the group consisting of . I In some embodiments, A is selected from the group consisting of is , wherein X is -C(=O) and n is selected from the group consisting of 4, 5, 6, and 7. I selected from the group consisting of 4, 5, 6, and 7.In some embodiments, A is wherein Wis -C(=O)-. In some embodiments, A is wherein R3fis -H, and L1 , wherein W is -C(=O)- and B is -C-. In some embodiments, A is , wherein R3fis - embodiments, A is , wherein R3fis -H, and L1, wherein W is - C(=O)-, B is -C- and Z1is -H or (C1-C6)alkyl). In some embodiments, , wherein R3fis - wherein W is -C(=O)-, B is -C-, Z1is -H and Z2is selected from the group consisting of -H, -OH, -NH2, -O(C1-C6)alkyl, (C2-C6)alkynyl and (C1-C6alkyl). In such embodiments –O(C1-C6)alkyl is -OCH3or -OCH2CH3. In such embodiment, (C1-C6alkyl) is - CH3. In such embodiments, (C2-C6)alkynyl is C=CH. In some embodiments, wherein wherein W is -C(=O)-, B is -C- and Z1and Z2are (C1-C6 alkyl). In such embodiments, Z1and Z2are both - CH3. In such embodiments, Z1is -H and Z2is -CH3. In some embodiments, wherein wherein W is -C(=O)- and B is -N-. In some embodiments, , wherein R3fis -H, and L1 , wherein W is -C(=O)-, B is -N-, and R1is -H. In some embodiments, A is ,3f,1, wherein W is -C(=O)-, B is -N-, and R1and R2are both -H.In some embodiments, wherein X is -C(=O)-, -C(=O)O-, -C(=O)NH- and -C(=O)NH[(C1-C6) alkyl-. In some embodiments, and L1is , wherein X is -C(=O)-, -C(=O)O-, -C(=O)NH- and -C(=O)NH[(C1-C6) alkyl-; and n is 3, 4, or 5. In some embodiments, A is and L1 is , whereinX is -C(=O)-, -C(=O)O-, -C(=O)NH- and -C(=O)NH[(C1-C6) alkyl-; and n is 4. In such embodiments, X is -C(=O). In a particular embodiment, X is -C(=O)- and n is 5. In some embodiments, . In some embodiments, wherein G is -C(=O)-; H is -CH(CH3)- or - C(CH3)2-. In some embodiments, wherein G is -C(=O)-; H is -CH(CH3)- or -C(CH3)2-; and p+q = 4. In such embodiments, p is 2 and q is 2. In such embodiments, p is 1 and q is 3. In some embodiments, some embodiments, , embodiments, wherein p+q = 3 or 4; and H is selected from the groups consisting of -C(CH3)2-, -CH(CH3)-, -S(=O)2-, -S(=O)-, -S-, - N[(C1-C6) alkyl]-, -NH-, -O-, -C=C-, -OCH2CH2O- and . In some embodiments, A is wherein p+q = 3 or 4; and H is selected from the groups consisting of -S(=O)2-, -S(=O)-, -S-, -N[(C1-C6) alkyl]-, -NH-, -O-, -C=C- a C(=O)-, wherein p+q = 4; and H is selected from the groups consisting of -S(=O)2-, -S(=O)-, -S-, - N[(C1-C6) alkyl]-, -NH-, -O-. In some embodiments, A is ; L2is wherein p+q = 4 and p is 2 and q is 2; and H is selected from the groups consisting of -S(=O)2-, -S(=O)-, -S-, -N[(C1-C6) alkyl]-, -NH-, -O-. In some embodiments, ; and G is -C(=O)-, wherein p+q = 3; and H is - -C(=O), wherein .Preferred embodiments include the following: Embodiment 1: A compound of Formula (I): Formula (I) or any pharmaceutically acceptable salt and / or stereoisomer thereof, wherein: Q is selected from the group consisting of

[0012] R1is –cyclopropyl or -isopropyl; R1ais hydrogen or (C1-C6) alkyl; R2aand R2b, in each instance, are independently selected from hydrogen, (C1-C6) alkyl, (C1- C6) haloalkyl, (C1-C6) alkoxy, halogen, −CN, −NH2, and −OH; A is selected from the group consisting of:

[0013] , wherein R3a,R3bR3c, R3d, R3e, R3fand R3gare each independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, halogen, −CN, −NH2, and – OH; or wherein X is selected from the group consisting of -CH2-, -O-, -S-, -S(=O)-, - S(=O)2NH-, -CO(=O)-, -NH-, -C=C-, -C(=O)-, -C(=O)O-, -C(=O)NH-, -C(=O)N(CH3)-, - C(=O)C(CH3)2-, -C(=O)NH-, -[(C1-C6) cycloalkyl]N[(C1-C6) alkyl]C(=O)-, and -NHC(=O)-; B is -C- or -N-; W is a bond, -C(=O)- or -N(CH3)C(=O)-; Z1and Z2are independently selected from -H, -OH, -NH2, -CN, -CF3, CD3, halogen, (C1- C6)alkyl, -O(C1-C6)alkyl, -OC(=O)(C1-C6)alkyl, -C(=O)(C1-C6)alkyl, -C(=O)O(C1-C6)alkyl, C(=O)NH(C1-C6)alkyl, -NHC(=O)(C1-C6)alkyl and (C2-C6)alkynyl; wherein G is -C(=O)-, - CH2N[(C1-C6) alkyl)]C(=O)- or -C(=O)NH-; Y is selected from the group consisting of -N[(C1-C6) alkyl)]C(=O)-, -N[(C1-C6) cycloalkyl)]C(=O)-, -N[(C1-C6) alkyl)]C(=O)O-, -CH2N[(C1-C6) alkyl)]C(=O)-, -N[(C1-C6) cycloalkyl]C(=O)-, -N[C(=O)(C1-C6) alkyl)]-, -CD2-, -NHC(=O)-, -CH=CH-, -N[C(=O) (C1-C6) alkyl]- H is selected from the group consisting of -C(CH3)2-, -CH(CH3)-, -S(=O)2-, -S(=O)-, -S-, - n, m and w are integers independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; and p and q are integers independently selected from 0, 1, 2, 3 and 4. Embodiment 2: The compound of embodiment 1, wherein R1ais hydrogen. Embodiment 3: The compound of embodiment 1 or embodiment 2, wherein R1is cyclopropyl. Embodiment 4: The compound of any one of the preceding embodiments, wherein Q is selected from the group consisting of Embodiment 5: The compound of any one of the preceding embodiments, wherein the compound is a compound of Formula (II): Formula (II) or a pharmaceutically acceptable salt thereof and / or stereoisomer thereof, wherein: R2aand R2bare independently selected from hydrogen, (C1-C6) alkyl, (C1-C6) alkoxy, or halogen; A is selected from the group consisting of ; wherein R3a, R3b R3c, R3d, R3e, R3f and R3g are each independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, and halogen; or wherein X is selected from the group consisting of -CH2-, -O-, -S-, -S(=O)-, - S(=O)2NH-, -CO(=O)-, -NH-, -C=C-, -C(=O)-, -C(=O)O-, -C(=O)NH-, -C(=O)N(CH3)-, - C(=O)C(CH3)2-, -C(=O)CH2C(CH3)2-, -C(=O)NH-, -[(C1-C6) cycloalkyl]N[(C1-C6) alkyl]C(=O)-, and -NHC(=O)-; B is -C- or -N-; W is a bond, -C(=O)- or -N(CH3)C(=O)-; Z1and Z2are independently selected from -H, -OH, -NH2, -CN, -CF3, CD3, halogen, (C1- C6)alkyl, -O(C1-C6)alkyl, -OC(=O)(C1-C6)alkyl, -C(=O)(C1-C6)alkyl, -C(=O)O(C1-C6)alkyl, C(=O)NH(C1-C6)alkyl, -NHC(=O)(C1-C6)alkyl and (C2-C6)alkynyl; wherein G is -C(=O)- or - C(=O)NH-; Y is selected from the group consisting of -N[(C1-C6) alkyl)]C(=O)-, -N[(C1-C6) cycloalkyl]C(=O)-, -NHC(=O)-, and -N[C(=O) (C1-C6) alkyl]-; H is selected from the group consisting of -C(CH3)2-, -CH(CH3)-, -S(=O)2-, -S(=O)-, -S-, - N[(C1-C6) alkyl]-, n, m and w are integers independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; and p and q are integers independently selected from 0, 1, 2, 3 and 4. Embodiment 6: The compound of embodiment 5, wherein A is selected from the group consisting of . Embodiment 7: The compound of embodiment 6, wherein X in L1is selected from the group consisting of -CH2-,-C(=O)CH2C(CH3)2- or -C(=O)-. Embodiment 8: The compound of embodiment 6 or 7, wherein A is ; X is -CH2-, and n is an integer selected from 3, 4, 5, and 6. Embodiment 9: The compound of embodiment 7, wherein A is selected from the group consisting of ; X is -C(=O)-; and n is an integer selected from 3, 4, 5, and 6. Embodiment 10: The compound of embodiment 9, wherein A is , R3fis -H, X is -C(=O) and n is an integer selected from 4, 5 and 6. Embodiment 11: The compound of claim 6, wherein A and L2is . Embodiment 12: The compound of embodiment 11, wherein G is -C(=O)-; H is -CH(CH3)- or - C(CH3)2-; and p+q = 4. Embodiment13: The compound of embodiment 11, wherein G is -C(=O)-, H is selected from the group consisting of -S(=O)2-, -S(=O)-, -S-, -N(C1-C6 alkyl)- 4. Embodiment 14: The compound of embodiment 12 or 13, wherein p is 2 and q is 2. Embodiment 15: The compound of embodiment 12 or 13, wherein p is 1 and q is 3. Embodiment 16: The compound of embodiment 5, wherein A is or and X is -CH2.Embodiment 17: The compound of embodiment 16, wherein n is an integer selected from 2, 3 and 4. Embodiment 18: The compound of embodiment 5, wherein A is and L2is . Embodiment 19: The compound of embodiment 18, wherein G is -C(=O)NH-; H is -O- or - OCH2CH2O-; p is 1 or 2; and q is 0 or 2. Embodiment 20: The compound of embodiment 5, wherein A is and L2is . Embodiment 21: The compound of embodiment 20, wherein Y is selected from the group consisting of -N(CH3)C(=O)-, -N[CH(CH3)2]C(=O)-, -N[C(CH3)3]C(=O)-, -N[cyclopropyl]C(=O)-, and - N[C(=O)CH3]-; and w is 4, 5 or 6. Embodiment 22: The compound of embodiment 1, wherein A is , R3gis -H and L1is , wherein B is -C- or -N-; W is a bond, -C(=O)- or -N(CH3)C(=O)-; and Z1 and Z2 are independently selected from -H, -OH, (C1-C6)alkyl, and (C2-C6)alkynyl. Embodiment 23: The compound of embodiment 22, wherein W is -C(=O), B is -C-; and Z1is -H. Embodiment 24: The compound of embodiment 23, wherein Z2is -H or -CH3. Embodiment 25: The compound of embodiment 5, wherein A is and L2is . Embodiment 26: The compound of embodiment 5, wherein A is . Embodiment 27: The compound of embodiment 26, wherein X is -O- or -C(=O)NH-. Embodiment 28: The compound of embodiment 26, wherein n is 4, 5, 6 or 7. A compound of any one of Formula (I) and (II) may be selected from the compound listed in Table 1. Compounds of Formula (I) and (II) that are not listed in Table 1 are also within the scope herein. Table 1:

[0014]

[0015] The compounds described herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Separation of stereoisomers may be performed by chromatography and / or recrystallization or by the forming diastereomers and separation thereof (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981). Stereoisomers may also be obtained by stereoselective synthesis using synthetic methods known in the art. In some embodiments, the compounds disclosed herein are enantiomers having an enantiomeric excess (% ee) of at least about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 98%, or about 99.5%. In some embodiments, the compounds disclosed herein are disateremores having a diatereomeric excess (% de) of at least about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 98%, or about 99.5%. In some embodiments, the compounds disclosed herein are present as enantiomeric or diastereomeric mixtures. The methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also known as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. Active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure. In some embodiments, the compounds described herein may be formed as, and / or used as, pharmaceutically acceptable salts. The type of pharmaceutical acceptable salts, include, but are not limited to: (1) acid addition salts, formed by reacting the free base form of the compound with a pharmaceutically acceptable: inorganic acid, such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid, and the like; or with an organic acid, such as, for example, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4′-methylenebis-(3- hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, butyric acid, phenylacetic acid, phenylbutyric acid, valproic acid, and the like; (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion (e.g. lithium, sodium, potassium), an alkaline earth ion (e.g. magnesium, or calcium), or an aluminum ion. In some cases, compounds described herein may coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, N- methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. In other cases, compounds described herein may form salts with amino acids such as, but not limited to, arginine, lysine, and the like. Acceptable inorganic bases used to form salts with compounds that include an acidic proton, include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like. In some embodiments, the compounds and salts described herein include isotopically-labeled compounds. In general, isotopically-labeled compounds are identical to those recited in the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most common in nature. Examples of isotopes that can be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, for example, 2H, 3H, 13C, 14C, 15N, 18O, 17O, 35S, 18F, 36Cl, respectively. Certain isotopically-labeled compounds described herein, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Further, substitution with isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements. In some embodiments, the compounds or salts described herein is a prodrug. In some embodiments, the compounds described herein may be formed as, and / or used as, prodrugs. A “prodrug” refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. Examples, without limitation, of a prodrug would be a compound described herein, which is administered as an ester or an amide (the “prodrug”) to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid and / or amine, the active entity, once inside the cell where water-solubility is beneficial. A further example of a prodrug might be a short peptide (polyaminoacid) or amino acid (natural or unnatural) bonded to an acid group or an amine group where the peptide or amino acid is metabolized to reveal the active moiety. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound. In certain embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound. To produce a prodrug, a pharmaceutically active compound is modified such that the active compound will be regenerated upon in vivo administration. The prodrug can be designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug. In some embodiments, by virtue of knowledge of pharmacodynamic processes and drug metabolism in vivo, once a pharmaceutically active compound is determined, prodrugs of the compound are designed. (see, for example, Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392; Silverman (1992), The Organic Chemistry of Drug Design and Drug Action, Academic Press, Inc., San Diego, pages 352-401, Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985; Rooseboom et al., Pharmacological Reviews, 56:53- 102, 2004; Miller et al., J. Med. Chem. Vol. 46, no. 24, 5097-5116, 2003; Aesop Cho, “Recent Advances in Oral Prodrug Discovery”, Annual Reports in Medicinal Chemistry, Vol. 41, 395-407, 2006). In some embodiments, the compounds disclosed herein bind to NSD2 and exhibit a dissociation constant (Kd) ranging from about 1 nM to about 500 nM, from about 1 nM to about 400 nM, from about 1 nM to about 300 nM, from about 1 nM to about 200 nM, from about 1 nM to about 100 nM, from about 1 nM to about 75 nM, from about 1 nM to about 50 nM, from about 1 nM to about 25 nM, or from about 1 nM to about 10 nM. In some embodiments, the disclosed compounds exhibit a Kd of less than about 500 nM, about 400 nM, about 300 nM, about 200 nM, about 100 nM, about 75 nM, about 50 nM, about 25 nM, or less than about 10 nM. In some embodiments, the compounds disclosed herein degrade enzyme NSD2 in cells at concentrations ranging from about 1 microM to about 10 μM (i.e., at a concentration of less than about 10, about 9, about 8, about 7, about 6, about 5, about 4, about 3, about 2, or about 1 μM). In some embodiments, the compounds disclosed herein are present at a concentration that is at least 10 μM. At such concentrations the compound degrades enzyme NSD2 in such a manner that less than about 100%, about 75%, about 50%, about 25%, or less than about 10% of the enzyme remains intact after a certain time period of exposure. In some embodiments, the disclosed compounds degrade enzyme NSD2 and exhibit a DC50 (compound concentration at which 50% of the NSD2 protein is degraded) ranging from about 0.1 μM to about 5 μM, from about 0.1 μM to about 4 μM, from about 0.1 μM to about 3 μM, from about 0.1 μM to about 2 μM, from about 0.1 μM to about 1 μM, from about 0.1 μM to about 0.5 μM and from about 0.1 μM to about 0.25 μM. In some embodiments, the disclosed compounds degrade enzyme NSD2 and exhibit a DC50 (compound concentration at which 50% of the NSD2 protein is degraded) of less than about 5 μM, about 4 μM, about 3 μM, about 2 μM, about 1 μM, about 0.75 μM, about 0.50 μM, about 0.25 μM, or less than about 0.1 μM. III. Structure Activity Studies Numerous compounds disclosed herein were screened for their cellular activities. Table 1.

[0016] * an IC50of >10 µM means compounds exhibit activities of 10 µM and higher; an IC50of >2 µM means compounds exhibit activities of 2 µM and higher but less than 10 µM; an IC50of >1 µM means compounds exhibit activities of 1 µM and higher but less than 2 µM; an IC50of >0.75 µM means compounds exhibit activities of 0.75 µM and higher but less than 1 µM; an IC50of >0.5 µM means compounds exhibit activities of 0.5 µM and higher but less than 0.75 µM; an IC50of >0.25 µM means compounds exhibit activities of 0.25 µM and higher but less than 0.5 µM; and an IC50of <0.25 µM means compounds exhibit activities of less than 0.25 µM. ** a DC50of >10 µM means compounds exhibit degradation activities of 10 µM and higher; a DC50of <0.5 µM means compounds exhibit degradation activities of less than 0.5 µM but higher than 0.1 µM; a DC50of <0.1 µM means compounds exhibit degradation activities of less than 0.1 µM. IV. Pharmaceutical Compositions In certain embodiments, compounds, prodrugs or salts of Formulae (I) and / or (II) disclosed herein, are combined with one or more additional agents to form pharmaceutical compositions. In some embodiments, compounds of Formulae (I) and / or (II) are already in the form of a prodrug. Pharmaceutical compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers including excipients and auxiliaries, which facilitate processing of the active compounds into preparations, which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Additional details about suitable excipients for pharmaceutical compositions described herein may be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa.1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), herein incorporated by reference for such disclosure. A pharmaceutical composition, as used herein, refers to a mixture of a compound or salt or prodrug of Formulae (I) and / or (II) with any suitable substituents and functional groups disclosed herein, with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and / or excipients. The pharmaceutical composition facilitates administration of the compound to an organism. In practicing the methods of treatment or use provided herein, therapeutically effective amounts of compounds described herein are administered in a pharmaceutical composition to a mammal having a disease, disorder, or condition to be treated. In some embodiments, the mammal is a human. A therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. The compounds or salts of Formula (I) with any suitable substituents and functional groups disclosed herein, can be used singly or in combination with one or more therapeutic agents as components of mixtures (as in combination therapy). The pharmaceutical formulations described herein can be administered to a subject by multiple administration routes, including but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration routes. Moreover, the pharmaceutical compositions described herein, which include a compound of Formula (I) and / or (II) with any suitable substituents and functional groups disclosed herein, can be formulated into any suitable dosage form, including but not limited to, aqueous oral dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, aerosols, fast melt formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees, and capsules. One may administer the compounds and / or compositions in a local rather than systemic manner, for example, via injection of the compound directly into an organ or tissue, often in a depot preparation or sustained release formulation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, one may administer the drug in a targeted drug delivery system, for example, in a liposome coated with organ-specific antibody. The liposomes will be targeted to and taken up selectively by the organ. In addition, the drug may be provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation. Pharmaceutical compositions including a compound described herein may be manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes. The pharmaceutical compositions will include at least one compound of Formula (I) disclosed herein, as an active ingredient in free-acid or free-base form, or in a pharmaceutically acceptable salt form. In some embodiments, compositions provided herein may also include one or more preservatives to inhibit microbial activity. Suitable preservatives include quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride. In some embodiments, the pharmaceutical solid dosage forms described herein can include a compound of Formulae (I) and / or (II) and one or more pharmaceutically acceptable additives such as a compatible carrier, binder, filling agent, suspending agent, flavoring agent, sweetening agent, disintegrating agent, dispersing agent, surfactant, lubricant, colorant, diluent, solubilizer, moistening agent, plasticizer, stabilizer, penetration enhancer, wetting agent, anti-foaming agent, antioxidant, preservative, or one or more combination thereof. In still other aspects, using standard coating procedures, such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000), a film coating is provided around the formulation of the compound described herein. In one embodiment, some or all of the particles of the compound described herein are coated. In another embodiment, some or all of the particles of the compound described herein are microencapsulated. In still another embodiment, the particles of the compound described herein are not microencapsulated and are uncoated. Suitable carriers for use in the solid dosage forms described herein include, but are not limited to, acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerine, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyl lactylate, carrageenan, monoglyceride, diglyceride, pregelatinized starch, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, sucrose, microcrystalline cellulose, lactose, mannitol and the like. Suitable filling agents for use in the solid dosage forms described herein include, but are not limited to, lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran, starches, pregelatinized starch, hydroxypropylmethycellulose (HPMC), hydroxypropylmethycellulose phthalate, hydroxypropylmethylcellulose acetate stearate (HPMCAS), sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like. Suitable disintegrants for use in the solid dosage forms described herein include, but are not limited to, natural starch such as corn starch or potato starch, a pregelatinized starch such as National 1551 or Amijel®, or sodium starch glycolate such as Promogel® or Explotab®, a cellulose such as a wood product, methylcrystalline cellulose, e.g., Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Tia®, and Solka-Floc®, methylcellulose, croscarmellose, or a cross-linked cellulose, such as cross-linked sodium carboxymethylcellulose (Ac- Di-Sol®), cross-linked carboxymethylcellulose, or cross-linked croscarmellose, a cross-linked starch such as sodium starch glycolate, a cross-linked polymer such as crospovidone, a cross-linked polyvinylpyrrolidone, alginate such as alginic acid or a salt of alginic acid such as sodium alginate, a clay such as Veegum® HV (magnesium aluminum silicate), a gum such as agar, guar, locust bean, Karaya, pectin, or tragacanth, sodium starch glycolate, bentonite, a natural sponge, a surfactant, a resin such as a cation-exchange resin, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in combination starch, and the like. Suitable binders in the solid dosage forms described herein include, but are not limited to, carboxymethylcellulose, methylcellulose (e.g., Methocel®), hydroxypropylmethylcellulose (e.g. Hypromellose USP Pharmacoat-603, hydroxypropylmethylcellulose acetate stearate (Aqoate HS-LF and HS), hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®), ethylcellulose (e.g., Ethocel®), and microcrystalline cellulose (e.g., Avicel®), microcrystalline dextrose, amylose, magnesium aluminum silicate, polysaccharide acids, bentonites, gelatin, polyvinylpyrrolidone / vinyl acetate copolymer, crospovidone, povidone, starch, pregelatinized starch, tragacanth, dextrin, a sugar, such as sucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab®), lactose, a natural or synthetic gum such as acacia, tragacanth, ghatti gum, mucilage of isapol husks, starch, polyvinylpyrrolidone (e.g., Povidone® CL, Kollidon® CL, Polyplasdone® XL- 10, and Povidone® K-12), larch arabogalactan, Veegum®, polyethylene glycol, waxes, sodium alginate, and the like. Suitable lubricants or glidants for use in the solid dosage forms described herein include, but are not limited to, stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumerate, alkali- metal and alkaline earth metal salts, such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearates, magnesium stearate, zinc stearate, waxes, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, a polyethylene glycol or a methoxypolyethylene glycol such as Carbowax™, PEG 4000, PEG 5000, PEG 6000, propylene glycol, sodium oleate, glyceryl behenate, glyceryl palmitostearate, glyceryl benzoate, magnesium or sodium lauryl sulfate, and the like. Suitable diluents for use in the solid dosage forms described herein include, but are not limited to, sugars (including lactose, sucrose, and dextrose), polysaccharides (including dextrates and maltodextrin), polyols (including mannitol, xylitol, and sorbitol), cyclodextrins and the like. Suitable wetting agents for use in the solid dosage forms described herein include, for example, oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, quaternary ammonium compounds (e.g., Polyquat 10®), sodium oleate, sodium lauryl sulfate, magnesium stearate, sodium docusate, triacetin, vitamin E TPGS and the like. Suitable surfactants for use in the solid dosage forms described herein include, for example, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, e.g., Pluronic® (BASF), and the like. Suitable suspending agents for use in the solid dosage forms described here include, but are not limited to, polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, polyethylene glycol, e.g., the polyethylene glycol can have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 5400 to about 7000, vinyl pyrrolidone / vinyl acetate copolymer (S630), sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, polysorbate-80, hydroxyethylcellulose, sodium alginate, gums, such as, e.g., gum tragacanth and gum acacia, guar gum, xanthans, including xanthan gum, sugars, cellulosics, such as, e.g., sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone and the like. Suitable antioxidants for use in the solid dosage forms described herein include, for example, e.g., butylated hydroxytoluene (BHT), sodium ascorbate, and tocopherol. There is considerable overlap between additives used in the solid dosage forms described herein. Thus, the above-listed additives should be taken as merely exemplary, and not limiting, of the types of additives that can be included in solid dosage forms of the pharmaceutical compositions described herein. Liquid formulation dosage forms for oral administration can be aqueous suspensions selected from the group including, but not limited to, pharmaceutically acceptable aqueous oral dispersions, emulsions, solutions, elixirs, gels, and syrups. See, e.g., Singh et al., Encyclopedia of Pharmaceutical Technology, 2nd Ed., pp.754-757 (2002). The pharmaceutical compositions described herein may include sweetening agents such as, but not limited to, acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, Bavarian cream, berry, black currant, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate, cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glyrrhizinate (MagnaSweet®), maltol, mannitol, maple, marshmallow, menthol, mint cream, mixed berry, neohesperidine DC, neotame, orange, pear, peach, peppermint, peppermint cream, Prosweet® Powder, raspberry, root beer, rum, saccharin, safrole, sorbitol, spearmint, spearmint cream, strawberry, strawberry cream, stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame, acesulfame potassium, mannitol, talin, sucralose, sorbitol, swiss cream, tagatose, tangerine, thaumatin, tutti fruitti, vanilla, walnut, watermelon, wild cherry, wintergreen, xylitol, or any combination of these flavoring ingredients, e.g., anise-menthol, cherry- anise, cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint, and mixtures thereof. Potential excipients for intranasal formulations include formulations solutions in saline, employing benzyl alcohol or other suitable preservatives, fluorocarbons, and / or other solubilizing or dispersing agents. See, for example, Ansel, H. C. et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, Sixth Ed. (1995). Preferably, these compositions and formulations are prepared with suitable nontoxic pharmaceutically acceptable ingredients. The choice of suitable carriers is highly dependent upon the exact nature of the nasal dosage form desired, e.g., solutions, suspensions, ointments, or gels. Nasal dosage forms generally contain large amounts of water in addition to the active ingredient. Minor amounts of other ingredients such as pH adjusters, emulsifiers or dispersing agents, preservatives, surfactants, gelling agents, or buffering and other stabilizing and solubilizing agents may also be present. Preferably, the nasal dosage form should be isotonic with nasal secretions. For administration by inhalation, the compounds described herein may be in a form as an aerosol, a mist or a powder. Pharmaceutical compositions described herein are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, such as, by way of example only, gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound described herein and a suitable powder base such as lactose or starch. Buccal formulations that include compounds described herein may be administered using a variety of formulations, which include, but are not limited to, U.S. Pat. Nos. 4,229,447, 4,596,795, 4,755,386, and 5,739,136. In addition, the buccal dosage forms described herein can further include a bioerodible (hydrolysable) polymeric carrier that also serves to adhere the dosage form to the buccal mucosa. The buccal dosage form is fabricated so as to erode gradually over a predetermined time period, wherein the delivery of the compound is provided essentially throughout. Buccal drug delivery avoids the disadvantages encountered with oral drug administration, e.g., slow absorption, degradation of the active agent by fluids present in the gastrointestinal tract and / or first-pass inactivation in the liver. With regard to the bioerodible (hydrolysable) polymeric carrier, virtually any such carrier can be used, so long as the desired drug release profile is not compromised, and the carrier is compatible with the compounds described herein, and any other components that may be present in the buccal dosage unit. Generally, the polymeric carrier comprises hydrophilic (water-soluble and water- swellable) polymers that adhere to the wet surface of the buccal mucosa. Examples of polymeric carriers useful herein include acrylic acid polymers and co, e.g., those known as “carbomers” (Carbopol®, which may be obtained from B.F. Goodrich, is one such polymer). Other components may also be incorporated into the buccal dosage forms described herein include, but are not limited to, disintegrants, diluents, binders, lubricants, flavoring, colorants, preservatives, and the like. For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, or gels formulated in a conventional manner. Transdermal formulations described herein may incorporate certain pharmaceutically acceptable excipients, which are conventional in the art. In some embodiments, formulations suitable for transdermal administration of compounds described herein may employ transdermal delivery devices and transdermal delivery patches and can be lipophilic emulsions or buffered, aqueous solutions, dissolved and / or dispersed in a polymer or an adhesive. Formulations suitable for intramuscular, subcutaneous, or intravenous injection may include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles including water, ethanol, polyols (propyleneglycol, polyethylene-glycol, glycerol, cremophor and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Formulations suitable for subcutaneous injection may also contain additives such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the growth of microorganisms can be ensured by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, such as aluminum monostearate and gelatin. For intravenous injections, compounds described herein may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally recognized in the field. For other parenteral injections, appropriate formulations may include aqueous or nonaqueous solutions, preferably with physiologically compatible buffers or excipients. Such excipients are generally recognized in the field. Parenteral injections may involve bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The pharmaceutical composition described herein may be in a form suitable for parenteral injection as a sterile suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents, which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. In certain embodiments, delivery systems for pharmaceutical compounds may be employed, such as, for example, liposomes and emulsions. In certain embodiments, compositions provided herein also include an mucoadhesive polymer, selected from among, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate and dextran. In some embodiments, the compounds described herein may be administered topically and are formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams or ointments. Such pharmaceutical compounds can contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives. The compounds described herein may also be formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and the like. In suppository forms of the compositions, a low-melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter is first melted. In some embodiments, the compounds of Formulae (I) and / or (II) disclosed herein are combined with other therapeutic agents, such as other anti-cancer agents, anti-allergic agents, anti- nausea agents (or anti-emetics), pain relievers, cytoprotective agents, and combinations thereof. In another embodiment, the compounds of Formulae (I) and / or (II) disclosed herein are combined with another therapeutic agent capable of inhibiting BRAF, MEK, CDK4 / 6, SHP-2, HDAC, EGFR, MET, mTOR, PI3K or AKT, or a combination thereof. Generally, an agent, such as a compound of Formula (I) disclosed herein, is administered in an amount effective for treating the disease or disorder (i.e., a therapeutically effective amount). Thus, a therapeutically effective amount can be an amount that is capable of at least partially treating, preventing or reversing a disease or disorder. The dose required to obtain an effective amount may vary depending on the agent, formulation, disease or disorder, and individual to whom the agent is administered. Determination of effective amounts may also involve in vitro assays in which varying doses of agent are administered to cells in culture and the concentration of agent effective for ameliorating some or all symptoms is determined in order to calculate the concentration required in vivo. Effective amounts may also be based in in vivo animal studies. An agent can be administered prior to, concurrently with and subsequent to the appearance of symptoms of a disease or disorder. In some embodiments, an agent is administered to a subject with a family history of the disease or disorder, or who has a phenotype that may indicate a predisposition to a disease or disorder, or who has a genotype which predisposes the subject to the disease or disorder. In some embodiments, the compositions described herein are provided as pharmaceutical and / or therapeutic compositions. The pharmaceutical and / or therapeutic compositions of the present disclosure can be administered in a number of ways depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration can be topical (including ophthalmic and to mucous membranes including vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Compositions and formulations for topical administration can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional carriers; aqueous, powder, or oily bases; thickeners; and the like can be necessary or desirable. Compositions and formulations for oral administration include powders or granules, suspensions or solutions in water or non-aqueous media, capsules, sachets or tablets. Thickeners, flavoring agents, diluents, emulsifiers, dispersing aids or binders can be desirable. Compositions and formulations for parenteral, intrathecal or intraventricular administration can include sterile aqueous solutions that can also contain buffers, diluents and other suitable additives such as, but not limited to, penetration enhancers, carrier compounds and other pharmaceutically acceptable carriers or excipients. Pharmaceutical and / or therapeutic compositions of the present disclosure include, but are not limited to, solutions, emulsions, and liposome containing formulations. These compositions can be generated from a variety of components that include, but are not limited to, preformed liquids, self-emulsifying solids and self-emulsifying semisolids. The pharmaceutical and / or therapeutic formulations, which can conveniently be presented in unit dosage form, can be prepared according to conventional techniques well known in the pharmaceutical / nutriceutical industries. Such techniques include the step of bringing into association the active ingredients with the pharmaceutical carrier(s) or excipient(s). In general the formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product. The compositions of the present disclosure can be formulated into any of many possible dosage forms such as, but not limited to, tablets, capsules, liquid syrups, soft gels, suppositories, and enemas. The compositions of the present disclosure can also be formulated as suspensions in aqueous, non-aqueous, oil-based, or mixed media. Suspensions can further contain substances that increase the viscosity of the suspension including, for example, sodium carboxymethylcellulose, sorbitol and / or dextran. The suspension can also contain stabilizers. In one embodiment of the present disclosure the pharmaceutical compositions can be formulated and used as foams. Pharmaceutical foams include formulations such as, but not limited to, emulsions, microemulsions, creams, jellies and liposomes. While basically similar in nature these formulations vary in the components and the consistency of the final product. The pharmaceutical composition described herein may be in unit dosage forms suitable for single administration of precise dosages. In unit dosage form, the formulation is divided into unit doses containing appropriate quantities of one or more compound. The unit dosage may be in the form of a package containing discrete quantities of the formulation. Non-limiting examples are packaged tablets or capsules, and powders in vials or ampoules. Aqueous suspension compositions can be packaged in single-dose non-reclosable containers. Alternatively, multiple-dose reclosable containers can be used, in which case it is typical to include a preservative in the composition. By way of example only, formulations for parenteral injection may be presented in unit dosage form, which include, but are not limited to ampoules, or in multi-dose containers, with an added preservative. Dosing and administration regimes are tailored by the clinician, or others skilled in the pharmacological arts, based upon well-known pharmacological and therapeutic considerations including, but not limited to, the desired level of therapeutic effect, and the practical level of therapeutic effect obtainable. Generally, it is advisable to follow well-known pharmacological principles for administrating chemotherapeutic agents (e.g., it is generally advisable to not change dosages by more than 50% at time and no more than every 3-4 agent half-lives). For compositions that have relatively little or no dose-related toxicity considerations, and where maximum efficacy is desired, doses in excess of the average required dose are not uncommon. This approach to dosing is commonly referred to as the “maximal dose” strategy. In certain embodiments, the compounds are administered to a subject at a dose of about 0.01 mg / kg to about 200 mg / kg, more preferably at about 0.1 mg / kg to about 100 mg / kg, even more preferably at about 0.5 mg / kg to about 50 mg / kg. When the compounds described herein are co-administered with another agent (e.g., as sensitizing agents), the effective amount may be less than when the agent is used alone. Dosing may be once per day or multiple times per day for one or more consecutive days. V. Methods of Treatment The present disclosure provides compounds and methods for binding to and / or inhibiting the activity of the NSD2 enzyme. In some embodiments, the present disclosure provides compounds and methods that degrade the NSD2 enzyme. Inhibition of NSD2 activity may be assessed and demonstrated by a wide variety of ways known in the art. Non-limiting examples include measure (a) a direct decrease in NSD2 activity; (b) a decrease in cell proliferation and / or cell viability; (c) an increase in cell differentiation; (d) a decrease in the levels of downstream targets of NSD2 activity; and (e) decrease in tumor volume and / or tumor volume growth rate. Kits and commercially available assays can be utilized for determining one or more of the above. Binding of compounds disclosed herein to the NSD2 enzyme can be determined using known methods in the arts, such as, but not limited to Surface Plasmon Resonance (SPR). The disclosure provides compounds and methods for treating a subject suffering from a disease, comprising administering a compound, prodrug or salt described herein, for example, a compound, prodrug or salt of Formulae (I) and / or (II) disclosed herein, to the subject. In some embodiments, the disease is selected from a disease associated with NSD2 expression (e.g., aberrant expression, overexpression, etc.) and / or activity (e.g., cancer). In certain embodiments, the disease is mediated by NSD2 activity and / or expression (e.g., aberrant expression, overexpression, etc.). In some embodiments, the disease or condition is treatable by inhibition of and / or degradarion of the NDS2 enzyme. In some embodiments, the method comprises treating a disease or condition that is treatable by inhibition of NDS2 by administering to a subject in need thereof a therapeutically effective amount of a compound, prodrug, or a salt thereof of Formulae (I) and / or (II) or a pharmaceutical composition as disclosed herein. In some embodiments, the disclosure provides a method for treating cancer in a subject, comprising administering a compound, prodrug or salt described herein, for example, a compound, prodrug or salt of Formulae (I) and / or (II) disclosed herein, to the subject. In some embodiments, the cancer is mediated by a NSD2 expression (e.g., aberrant expression, overexpression, etc.) and / or activity. In certain embodiments, the disclosure provides method of treating a disease in a subject, wherein the method comprises determining if the subject has an NSD2-mediated condition (e.g., cancer) and administering to the subject a therapeutically effective dose of a compound, prodrug or salt described herein, for example, a compound, prodrug or salt of Formulae (I) and / or (II) as disclosed herein. Determining whether a tumor or cancer expresses (e.g., overexpresses, aberrantly expresses, etc.) NSD2 can be undertaken by assessing the nucleotide sequence encoding NSD2 or by assessing the amino acid sequence of NSD2. Methods for detecting an NSD2 nucleotide sequence are known by those of skill in the art. These methods include, but are not limited to, polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP) assays, polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) assays, real-time PCR assays, PCR sequencing, mutant allele-specific PCR amplification (MASA) assays, direct sequencing, primer extension reactions, electrophoresis, oligonucleotide ligation assays, hybridization assays, TaqMan assays, SNP genotyping assays, high resolution melting assays and microarray analyses. Methods for detecting an NSD2 protein are known by those of skill in the art. These methods include, but are not limited to, detection using a binding agent, e.g., an antibody, specific for NSD2, protein electrophoresis and Western blotting, and direct peptide sequencing. Methods for determining whether a tumor or cancer expresses (e.g., overexpresses, aberrantly expresses, etc.) NSD2 or is mediated by NSD2 activity can use a variety of samples. In some embodiments, the sample is taken from a subject having a tumor or cancer. In some embodiments, the sample is taken from a subject having a cancer or tumor. In some embodiments, the sample is a fresh tumor / cancer sample. In some embodiments, the sample is a frozen tumor / cancer sample. In some embodiments, the sample is a formalin-fixed paraffin-embedded sample. In some embodiments, the sample is processed to a cell lysate. In some embodiments, the sample is processed to DNA or RNA. In certain embodiments, the disclosure provides a method of inhibiting NSD2 activity in a sample, comprising administering the compound or salt described herein to said sample comprising NSD2. The disclosure provides methods for treating a disease by administering a compound, prodrug, or salt of Formulae (I) and / or (II) disclosed herein, to a subject suffering from the disease, wherein the compound binds to NSD2 and / or inhibits NSD2 activity. In some embodiments, the compound covalently binds to NSD2. In some embodiments, the compound noncovalently binds to NSD2. In some embodiments, the compound degrades the NSD2 enzyme. The disclosure also relates to a method of treating a hyperproliferative disorder in a mammal that comprises administering to the mammal a therapeutically effective amount of a compound, prodrug, or salt of Formulae (I) and / or (II) with any suitable substituents and functional groups disclosed herein. In some embodiments, the method relates to the treatment of cancer such as acute myeloid leukemia, cancer in adolescents, adrenocortical carcinoma childhood, AIDS-related cancers, e.g., Lymphoma and Kaposi's Sarcoma, anal cancer, appendix cancer, astrocytomas, atypical teratoid, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumors, burkitt lymphoma, carcinoid tumor, atypical teratoid, embryonal tumors, germ cell tumor, primary lymphoma, cervical cancer, childhood cancers, chordoma, cardiac tumors, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myleoproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone, gall bladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumors (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors, pancreatic neuroendocrine tumors, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer with occult primary, midline tract carcinoma, mouth cancer multiple endocrine neoplasia syndromes, multiple myeloma / plasma cell neoplasm, mycosis fungoides, myelodysplastic syndromes, myelodysplastic / myeloproliferative neoplasms, multiple myeloma, merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma of bone and osteosarcoma, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-hodgkin lymphoma, non-small cell lung cancer (NSCLC), oral cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, stomach (gastric) cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-Cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell cancer of the renal pelvis and ureter, trophoblastic tumor, unusual cancers of childhood, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or Viral-Induced cancer. In some embodiments, the method relates to the treatment of a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin, e.g., psoriasis, restenosis, or prostate, e.g., benign prostatic hypertrophy (BPH). In some cases, the method relates to the treatment of leukemia, hematologic malignancy, solid tumor cancer, prostate cancer, e.g., castration-resistant prostate cancer, breast cancer, Ewing's sarcoma, bone sarcoma, primary bone sarcoma, T-cell prolymphocyte leukemia, glioma, glioblastoma, liver cancer, e.g., hepatocellular carcinoma, or diabetes. Subjects that can be treated with compounds of Formulae (I) and / or (II) disclosed herein, or pharmaceutically acceptable salt, ester, prodrug, stereoisomer, or enantiomer of the compounds, according to the methods of this disclosure include, for example, subjects that have been diagnosed as having acute myeloid leukemia, acute myeloid leukemia, cancer in adolescents, adrenocortical carcinoma childhood, AIDS-related cancers, e.g., Lymphoma and Kaposi's Sarcoma, anal cancer, appendix cancer, astrocytomas, atypical teratoid, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumors, burkitt lymphoma, carcinoid tumor, atypical teratoid, embryonal tumors, germ cell tumor, primary lymphoma, cervical cancer, childhood cancers, chordoma, cardiac tumors, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myleoproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone, gall bladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumors (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors, pancreatic neuroendocrine tumors, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer with occult primary, midline tract carcinoma, mouth cancer multiple endocrine neoplasia syndromes, multiple myeloma / plasma cell neoplasm, mycosis fungoides, myelodysplastic syndromes, myelodysplastic / myeloproliferative neoplasms, multiple myeloma, merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma of bone and osteosarcoma, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-hodgkin lymphoma, non-small cell lung cancer (NSCLC), oral cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, stomach (gastric) cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-Cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell cancer of the renal pelvis and ureter, trophoblastic tumor, unusual cancers of childhood, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Viral-Induced cancer, leukemia, hematologic malignancy, solid tumor cancer, prostate cancer, castration-resistant prostate cancer, breast cancer, Ewing's sarcoma, bone sarcoma, primary bone sarcoma, T-cell prolymphocyte leukemia, glioma, glioblastoma, hepatocellular carcinoma, liver cancer, or diabetes. In some embodiments, subjects that are treated with the compounds of the disclosure include subjects that have been diagnosed as having a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin, e.g., psoriasis, restenosis, or prostate, e.g., benign prostatic hypertrophy (BPH). The disclosure further provides methods of inhibiting NSD2 activity, by contacting the NSD2 with an effective amount of a compound, prodrug or salt of Formulae (I) and / or (II) disclosed herein (e.g., by contacting a cell, tissue, or organ that expresses NSD2). In some embodiments, the disclosure provides methods of inhibiting NSD2 activity in a subject including but not limited to rodents and mammals, e.g., humans, by administering to the subject an effective amount of a compound of Formulae (I) and / or (II) disclosed herein. Thus, the present disclosure is directed to methods of inhibiting NSD2 activity in an in vitro and in vivo testing environment, which a skilled artisan would be familiar with. In some embodiments, the percentage of inhibition of the NSD2 enzyme in vitro and / or in vivo is at least 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. For example, in some embodiments, the disclosure provides methods of inhibiting NSD2 activity in a cell by contacting the cell with an amount of a compound as disclosed herein sufficient to inhibit the activity. In some embodiments, the disclosure provides methods of inhibiting NSD2 activity in a tissue by contacting the tissue with an amount of a compound, prodrug or salt of Formulae (I) and / or (II) as disclosed herein, sufficient to inhibit the NSD2 activity in the tissue. In some embodiments, the disclosure provides methods of inhibiting NSD2 activity in an organism (e.g., mammal, human, etc.) by contacting the organism with an amount of a compound, prodrug or salt of Formulae (I) and / or (II) as disclosed herein, sufficient to inhibit the NSD2 activity in the organism. In some embodiments, the methods disclosed herein re directed to compounds that are able to degrade the NSD2 enzyme. For example, methods of degrading the NSD2 enzyme comprises contacting the NSD2 with an effective amount of a compound, prodrug or salt of Formulae (I) and / or (II) disclosed herein (e.g., by contacting a cell, tissue, or organ that expresses NSD2). In some embodiments, the disclosure provides methods of degarding the NSD2 enzyme in a subject including but not limited to rodents and mammals, e.g., humans, by administering to the subject an effective amount of a compound of Formulae (I) and / or (II) disclosed herein. In some embodiments, the percentage of degradation of the NSD2 enzyme is at least 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. The compositions containing the compounds or salts thereof described herein can be administered for prophylactic and / or therapeutic treatments. In therapeutic applications, the compositions are administered to a patient already suffering from a disease, in an amount sufficient to cure or at least partially arrest the symptoms of the disease. Amounts effective for this use will depend on the severity and course of the disease, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating clinician. In prophylactic applications, compositions containing the compounds or salts thereof described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a “prophylactically effective amount or dose.” In this use, the precise amounts also depend on the patient's state of health, weight, and the like. When used in a patient, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating clinician. The amount of a given agent that will correspond to such an amount will vary depending upon factors such as the particular compound, disease and its severity, the identity (e.g., weight) of the subject or host in need of treatment, but can nevertheless be determined in a manner recognized in the field according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated. In general, however, doses employed for adult human treatment will typically be in the range of about 0.02-about 5000 mg per day, in some embodiments, about 1-about 1500 mg per day. The desired dose may conveniently be presented in a single dose or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more sub-doses per day. Toxicity and therapeutic efficacy of such therapeutic regimens can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD50(the dose lethal to 50% of the population) and the ED50(the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD50and ED50. Compounds exhibiting high therapeutic indices are preferred. The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50with minimal toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. EXAMPLES General Chemistry Procedures Reactions were carried out using conventional glassware. All reagents and solvents were used as received unless otherwise stated. Reagents were of 95% purity or greater, and solvents were reagent grade unless otherwise stated. Any anhydrous solvents used were purchased as “anhydrous” grade and used without further drying. “Room” or ambient temperature varied between 20-25 °C. Analytical thin layer chromatography (TLC) was carried out using glass plates pre-coated with silica gel (Merck) impregnated with fluorescent indicator (254 nm). TLC plates were visualized by illumination with a 254 nm UV lamp. Analytical LCMS data for all compounds were acquired using an Agilent 1260 Infinity II system with the UV detector set to 254 nm. Samples were injected (<25 µL) onto an Agilent ZORBAX Eclipse Plus C18, 600 Bar, 4.6 x 50 mm, 1.8 μM column at 25 °C. Mobile phases A (H2O + 0.1% acetic acid), B (MeOH + 0.1% acetic acid), and C (99% MeCN + 1% H2O + 0.1% acetic acid) were used with a linear gradient from 10% to 100% B or C in 5 min, followed by a flush at 100% B or C for another 2 minutes with a flow rate of 1 mL / min. Low resolution mass spectra (MS) data were acquired in positive ion mode using an Agilent InfinityLab LC / MSD single quadrupole mass spectrometer with an electrospray ionization (ESI) source (see below for HRMS details). Normal phase column chromatography was performed with a Teledyne Isco CombiFlash®Rf200 using RediSep®RfSILICA columns with the UV detector set to 254 nm and 280 nm. Reverse phase column chromatography was performed with a Teledyne Isco CombiFlash®Rf200 using C18 RediSep®RfGold columns with the UV detector set to 220 nm and 254 nm. Mobile phases A (H2O + 0.1% TFA) and B (MeOH or MeCN) were used. Preparative HPLC was performed as follows unless otherwise noted: Preparative HPLC was performed using an Agilent Prep 1200 series with the UV detector set to 220 nm and 254 nm. Samples were injected onto either a Phenomenex Luna 250 x 30 mm (5 µm) C18 column, a Phenomenex Luna 250 x 50mm (10 µm) C18 column, a Phenomenex Luna 80 x 40mm (3 µm) C18 column, or a Phenomenex Luna 75 x 30 mm (5 µm) C18 column at rt. Mobile phases A (H2O + 0.1% TFA) and B (MeOH or MeCN) were used with a flow rate of 40 mL / min for the larger column and 30 mL / min for the smaller column. Analytical LCMS (at 254 nm) was used to establish the purity of targeted compounds. All compounds that were evaluated in biochemical and biophysical assays had >95% purity as determined by LCMS or NMR (spectra provided in Supplementary Note). Nuclear Magnetic Resonance Spectroscopy (NMR)1H and13C NMR spectra were obtained on a Varian 400MR at 400 MHz and 101 MHz respectively. Chemical shifts are reported in ppm and coupling constants are reported in Hz with CDCl3referenced at 7.26 (1H) and 77.1 ppm (13C), DMSO-d6referenced at 2.50 (1H) and 39.5 ppm (13C), acetone-d6referenced at 2.05 (1H) and 29.8 ppm (13C), and MeOH-d4referenced at 3.31 (1H) and 49.0 ppm (13C). All compounds that were evaluated in biochemical, biophysical and cellular assays had >95% purity as determined by1H NMR and LCMS (spectra provided in Supplementary Note). Reagents Compound 2, compound 156, Intermediates A-I (Int-A, Int-B, Int-C, Int-D, Int-E, Int-F, Int-G, Int-H, Int-I) and 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylic acid were prepared according to previously published procedures (see Hanley, R. P. et al., Discovery of a Potent and Selective Targeted NSD2 Degrader for the Reduction of H3K36me2, J. Am. Chem. Soc. 2023, 145, 14, 8176–8188; which is hereby incorporated in its entirety) and their respective spectroscopic signatures (1H NMR and LCMS) were found to be consistent with values reported therein. Abbreviations used Common Intermediates

[0017] Note that these Intermediates were used to prepare the Inventive Compounds according to the procedures described below. Example 1: General Procedures General Procedure A: For the coupling of aliphatic amines or anilines with achiral carboxylic acids To a scintillation vial charged with a stirbar was added carboxylic acid (1 Eq), EDC (1.5 – 2 Eq), HOAt (1.5 – 2 Eq) and DMF or MeCN (0.5 – 4 mL). The mixture was left to stir at room temperature for 30 minutes. To the vial was then added amine / aniline (1 – 1.9 Eq) followed by triethylamine (3 – 4 Eq). The reaction was stirred at room temperature for 24 (aliphatic amines) or 48 (anilines) hours. See below for N-Boc deprotection (when relevant) and workup / purification. Following N-Boc deprotection and purification, all free aliphatic amine products were isolated as trifluoroacetate salts (unless otherwise noted). All final products were suspended in water, flash frozen and lyophilized to dryness. Workup A: The reaction was diluted with distilled water and extracted 3 times with ethyl acetate. The combined organic layers were washed once with water, twice with saturated sodium bicarbonate, once with brine, then dried over sodium sulfate, filtered and concentrated in vacuo. Workup B: The reaction was poured onto water (10x v / v w.r.t. DMF) and the precipitate collected by centrifugation. Supernatant was discarded. To the pellet was added 10 mL of water, and the pellet was re-suspended with sonication. The precipitate was again collected by centrifugation and the supernatant again discarded. The pellet briefly air-dried before being suspended in methanol / DCM and transferred to a scintillation vial where volatiles were removed in vacuo. N-Boc Deprotection: To a scintillation vial containing a stirbar and crude reaction mixture or purified N-Boc-protected amine was added TFA in DCM (10 Eq, 20% v / v). The mixture was stirred overnight. Volatiles were removed in vacuo and residual TFA was removed by co-evaporation with methanol. General Procedure B: For the coupling of aliphatic amines with chiral carboxylic acids To a scintillation vial charged with a stirbar was added carboxylic acid (1.1 Eq), TBTU (1.3 Eq) and DMF (0.5 – 2 mL). The mixture was left to stir at room temperature for 30 minutes. To the vial was then added amine salt (1 Eq) followed by DIPEA (3.3 Eq). The reaction was stirred at room temperature for 24 hours. See above for N-Boc deprotection (when relevant) and workup / purification. Following N-Boc deprotection and purification, all free aliphatic amine products were isolated as trifluoroacetate salts (unless otherwise noted). All final products were suspended in water, flash frozen and lyophilized to dryness. General Procedure C: For the reduction of nitroarenes To a round-bottom flask charged with a stirbar was added nitroarene (1 Eq) and ethyl acetate (5 – 24 mL), following which the reaction was evacuated and purged with nitrogen for three cycles. Pd / C (10% Wt) was added and the evacuation / refill cycle was repeated thrice more. A hydrogen balloon was equipped and the reaction was stirred at room temperature while monitoring by TLC. If complete consumption of starting material did not occur by 24 hours, the Pd / C was replenished and a second hydrogen balloon was equipped. Upon consumption of starting material, the reaction was filtered over celite and rinsed thoroughly with ethyl acetate. The filtrate was concentrated in vacuo. See individual reaction procedures for purification details. General Procedure D: For the hydrolysis of esters To a round-bottom flask charged with a stirbar was added ester (1 Eq) and THF or dioxane (4 – 5 mL). Next, a solution of lithium hydroxide hydrate (5 Eq) in water (1 – 2 mL) was added, and the reaction was stirred overnight with monitoring by TLC. Upon consumption of starting material the mixture was washed with 5 portions of ether (organics discarded) and the pH was adjusted to 2 with concentrated HCl. Upon addition of acid, a precipitate formed. The precipitate was collected by filtration, washed with copious amounts of water and air-dried to give product, which was used without further purification (unless otherwise noted). General Procedure E: For the substitution of alkyl tosylates / bromides with phenols / thiophenols To a scintillation vial charged with a stirbar was added alkyl tosylate / bromide (1 Eq), DMF (3 – 5 mL), phenol / thiophenol (1.2 – 1.3 Eq) and potassium carbonate (1.5 – 3 Eq). The vial was heated to 50 ºC (tosylates) or 70 ºC (bromides) and allowed to stir overnight. The reaction was allowed to cool to room temperature and was quenched with water and extracted 3 times with ethyl acetate. The combined organic fractions were washed once with 1 M NaOH, three times with water, once with brine, dried over sodium sulfate, filtered, and concentrated. See individual reaction procedures for purification details. General Procedure F: For the conversion of alcohols to sulfonate esters then displacement with Di- tert-butyl iminodicarboxylate (Step 1) To a round-bottom flask charged with a stirbar was added alcohol (1 Eq), DCM (5 – 15 mL) and triethylamine (1.8 – 2 Eq). The flask was cooled in an ice bath and sulfonyl chloride (1.4 – 1.5 Eq) was added dropwise. The reaction was allowed to come to room temperature with stirring overnight. The reaction was quenched with 1M HCl and extracted 3 times with DCM. The combined organic layers were washed once with water, once with saturated sodium bicarbonate, once with brine, dried over sodium sulfate, filtered and concentrated in vacuo. (Step 2) To the sulfonate ester was then added di-tert-butyl iminodicarbonate (1.2 Eq), Cs2CO3(1.5 Eq) and DMF (2.5 – 5 mL). The reaction was heated to 70˚C and stirred overnight. The reaction was then cooled and diluted with water. The aqueous solution was extracted three times with ethyl acetate, and the combined organic layers washed three times with water, once with brine, then dried over sodium sulfate, filtered and concentrated. See individual reaction procedures for purification details. General Procedure G: Alternative method for the coupling of carboxylic acids and anilines / alcohols) To a stirred solution of carboxylic acid (1 Eq) in DMF / MeCN (1 – 5 mL) was added DMAP (0.1 – 2 Eq) and aniline / alcohol (2 – 4 Eq). EDC / DCC (1.1 – 2 Eq) was added and the reaction was stirred at room temperature or 50ºC overnight. See individual procedures for workup / purification details. Example 2: Synthesis of N-(4-((2-(6-Amino-3,3-dimethylhexanoyl)-1,2,3,4- tetrahydroisoquinolin-6-yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (compound 53). To a stirred solution of methyl 3,3-dimethylpent-4-enoate (1.00 eq, 3.00 g, 21.1 mmol) in THF:MeOH (1:1, 60.0 mL) was added the solution of NaOH (2.50 eq, 2.11 g, 52.7 mmol) in water (20 mL) at room temperature. The resulting reaction mixture was stirred at 25oC for 16 h. Upon completion (monitored by LCMS), the reaction mixture was concentrated and diluted with water (100 mL). The aqueous layer was washed with MTBE (2 × 50 mL) and then acidified to pH~3 with 6 N HCl at 0 to 5oC. The mixture was then extracted with ethyl acetate (3 × 50 mL). Combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 3,3- dimethylpent-4-enoic acid (2.30 g, 17.8 mmol, yield 84%) as a pale-yellow gum. LCMS ESI, (+ve mode): Expected m / z for C7H13O2[M+H] 129.17, found 129.2. Next, to a stirred solution of 3,3-dimethylpent-4-enoic acid (1.00 eq, 2.30 g, 17.9 mmol) and N, O- dimethylhydroxylamine (2.00 eq, 3.50 g, 35.9 mmol) in DCM (100 mL) was added N,N- diisopropylethylamine (5.00 eq, 16 mL, 89.7 mmol) and 1-hydroxybenzotriazole hydrate (1.20 eq, 3.30 g, 21.5 mmol). The reaction mixture was stirred at room temperature for 15 minutes and then added allylamine (1.20 eq, 1.6 mL, 21.5 mmol). The resulting reaction mixture was stirred at 25oC for 16 h. Upon completion (monitored by LCMS), the reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (3 × 50 mL). The combined organic extracts were washed with brine solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford N-allyl-3,3-dimethyl-pent-4-enamide (2.8 g, 11.885 mmol, yield 66%) as light brown colored oil. LCMS ESI, (+ve mode): Expected m / z for C10H18NO [M+H] 168.25, found 168.2. Next, to a stirred solution of N-allyl-3,3-dimethyl-pent-4-enamide (1.00 eq, 2.80 g, 16.7 mmol) and 4- dimethylaminopyridine (1.50 eq, 3.07 g, 25.1 mmol) in MeCN (60.0 mL) was added Boc-anhydride (1.50 eq, 5.8 mL, 25.1 mmol). The reaction mixture was stirred at room temperature for 16 hours. Upon completion (monitored by TLC / LCMS), the reaction mixture was concentrated under reduced pressure and purified by flash column chromatography [silica gel (230-400 mesh), eluent: 0-15% ethyl acetate in petroleum ether] tert-butyl N-allyl-N-(3,3-dimethylpent-4-enoyl)carbamate (1.80 g, 6.60 mmol, yield 39%) as colorless oil. LCMS ESI, (+ve mode): Expected m / z for C10H18NO [ M- CO2tButyl+H] 168.36, found 168.2. Next, to a stirred solution of tert-butyl N-allyl-N-(3,3-dimethylpent-4-enoyl)carbamate (1.00 eq, 400 mg, 1.50 mmol)) in DCM (1.5 L) under nitrogen atmosphere was added Grubbs Catalyst 2ndGeneration (0.10 eq, 127 mg, 0.150 mmol). The reaction mixture was heated at 50oC for 16 hours. Upon completion (monitored by TLC), the reaction mixture was concentrated under reduced pressure and purified by flash column chromatography [silica gel (230-400 mesh), eluent: 10-50% ethyl acetate in petroleum ether] to afford tert-butyl 5,5-dimethyl-7-oxo-2,6-dihydroazepine-1-carboxylate (350 mg, 1.45 mmol, yield 97%) as pale-yellow gum.1LCMS ESI, (+ve mode): Expected m / z for C13H21NO3Na [M+Na] 262.31, found 262.4. Next, to a stirred solution of tert-butyl 5,5-dimethyl-7-oxo-2,6-dihydroazepine-1-carboxylate (S-223) (1.00 eq, 300 mg, 1.25 mmol) in THF:water (5:3, 16.0 mL) was added lithium hydroxide monohydrate (5.00 eq, 263 mg, 6.27 mmol) at room temperature. The resulting reaction mixture was stirred at 25oC for 16 h. Upon completion (monitored by LCMS), the reaction mixture was diluted with water (30 mL) and washed with MTBE (3 × 20 mL). The aqueous layer was acidified with potassium hydrogen sulfate (pH~5 to 6). The aqueous layer was extracted with ethyl acetate (3 × 20 mL). Combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford (E)-6-(tert-butoxycarbonylamino)-3,3-dimethyl-hex-4-enoic acid (275 mg, 1.0682 mmol, yield 85%) as pale-yellow oil. LCMS ESI, (+ve mode): Expected m / z for C13H23NO4Na [M+Na] 280.33, found 280.2. Next, to a stirred solution of (E)-6-(tert-butoxycarbonylamino)-3,3-dimethyl-hex-4-enoic acid (1.00 eq, 170 mg, 0.661 mmol) in ethyl acetate (10.0 mL) was added Pd / C (10% on dry basis) (0.711 eq, 50.0 mg, 0.470 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 25oC for 5 h under bladder hydrogen pressure. Upon completion (monitored by LCMS), the reaction mixture was filtered through celite bed [30 mL of ethyl acetate was used to rinse the solid residue on celite bed] and the filtrate was concentrated under reduced pressure to afford 6-(tert- butoxycarbonyl amino)-3,3-dimethyl-hexanoic acid (160 mg, 0.616 mmol, yield 93%) as light brown gum. LCMS ESI, (+ve mode): Expected m / z for C13H26NO4[(M-CO2tButyl)+H] 160.34, found 160.2. Next, to the stirred solution of 6-(tert-butoxycarbonylamino)-3,3-dimethyl-hexanoic acid (1.00 eq, 100 mg, 0.386 mmol) and 6-nitro-1,2,3,4-tetrahydroisoquinoline (1.20 eq, 82.0 mg, 0.463 mmol) in DMF (6.0 mL) was added 1-hydroxybenzotriazole hydrate (2.00 eq, 118 mg, 0.771 mmol) and EDC (3.00 eq, 222 mg, 1.16 mmol) at 25oC. Then reaction mixture was stirred at room temperature for 30 minute and then added 4-dimethylaminopyridine (5.00 eq, 236 mg, 1.93 mmol). The reaction mixture was stirred at 25oC for 16 h. Upon completion (monitored by LCMS), the reaction mixture was concentrated under reduced pressure and the crude material was purified by reverse phase prep HPLC purification (method: A: 0.1% formic acid in water, B: ACN, column: C18), to afford tert-butyl N- [4,4-dimethyl-6-(6-nitro-3,4-dihydro-1H-isoquinolin-2-yl)-6-oxo-hexyl]carbamate (150 mg, 0.328 mmol, yield 85%) as a pale-yellow gum. LCMS ESI, (+ve mode): Expected m / z for C17H26N3O3[(M- CO2tButyl)+H] 320.51, found 320.2. Next, to the stirred solution of tert-butyl N-[4,4-dimethyl-6-(6-nitro-3,4-dihydro-1H-isoquinolin-2- yl)-6-oxo-hexyl]carbamate (1S-226) (1.00 eq, 150 mg, 0.358 mmol) in EtOH:water (5:3, 8.0 mL) in a screw-cap vial was added iron powder (10.0 eq, 200 mg, 3.58 mmol) and ammonium chloride (10.0 eq, 191 mg, 3.58 mmol) at room temperature. The reaction mixture was heated to 70oC for 2 h. Upon completion (monitored by LCMS), the reaction mixture was diluted with water (50 mL) and then extracted with dichloromethane (3 × 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford tert-butyl N-[6-(6-amino- 3,4-dihydro-1H-isoquinolin-2-yl)-4,4-dimethyl-6-oxo-hexyl]carbamate. LCMS ESI, (+ve mode): Expected m / z for C22H36N3O3[M+H] 390.53, found 390.2. Next, to the stirred solution of Int-A (1.20 eq, 147 mg, 0.400 mmol) and tert-butyl N-[6-(6-amino-3,4- dihydro-1H-isoquinolin-2-yl)-4,4-dimethyl-6-oxo-hexyl]carbamate (1.00 eq, 130 mg, 0.334 mmol) in DMF (7.0 mL) was added 1-hydroxybenzotriazole hydrate (2.00 eq, 102 mg, 0.667 mmol) and 4- dimethylaminopyridine (6.00 eq, 245 mg, 2.00 mmol) followed by EDC (3.00 eq, 192 mg, 1.00 mmol) at room temperature. The reaction mixture was stirred at 25oC for 16 h. Upon completion (monitored by LCMS), the reaction mixture was concentrated under reduced pressure and the crude material was purified by reverse phase prep HPLC purification (method A: 0.1% formic acid in water, B: ACN, column:C18) to afford tert-butyl N-[6-[6-[[4-[[cyclopropyl-(3-oxo-4H-1,4-benzoxazine-7- carbonyl)amino]methyl]benzoyl]amino]-3,4-dihydro-1H-isoquinolin-2-yl]-4,4-dimethyl-6-oxo- hexyl]carbamate (160 mg, 0.202 mmol, yield 61%) as pale-yellow gum. LCMS ESI, (+ve mode): Expected m / z for C37H44N5O5[(M-CO2tButyl)+H] 638.88, found 638.2. Next, to a stirred solution of tert-butyl N-[6-[6-[[4-[[cyclopropyl-(3-oxo-4H-1,4-benzoxazine-7- carbonyl) amino]methyl]benzoyl]amino]-3,4-dihydro-1H-isoquinolin-2-yl]-4,4-dimethyl-6-oxo- hexyl]carbamate (1.00 eq, 160 mg, 0.217 mmol) in anhydrous DCM (3.0 mL) was added 4 M HCl in 1,4-dioxane (111 eq, 6.0 mL, 24.0 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at 25oC for 2 h. Upon completion (monitored by LCMS), the reaction mixture was concentrated under reduced pressure and the crude material was purified by reverse phase prep HPLC purification [method A: 0.1% TFA in water, B: ACN, column: XSELECT C18 (150 × 19 mm) 5 um, FLOW: 15 mL], to afford N-[[4-[[2-(6-amino-3,3-dimethyl-hexanoyl)-3,4-dihydro-1H- isoquinolin-6-yl]carbamoyl]phenyl] methyl]-N-cyclopropyl-3-oxo-4H-1,4-benzoxazine-7- carboxamide (compound 53) (125 mg, 0.1958 mmol, yield 90%) as an off-white solid.1H NMR (400 MHz, DMSO-d6): δ 10.22 (d, J = 3.20 Hz, 1H), 8.45 (s, 1H), 7.95 (d, J = 8.40 Hz, 2H), 7.68-7.53 (m, 2H), 7.45 (d, J = 7.60 Hz, 2H), 7.20-7.15 (m, 3H), 6.94 (d, J = 8.00 Hz, 1H), 4.72-4.59 (m, 6H), 3.74- 3.69 (m, 2H), 2.85-2.64 (m, 5H), 2.33-2.32 (m, 2H), 1.51-1.49 (m, 2H), 1.37-1.36 (m, 2H), 0.99 (s, 3H), 0.94 (s, 3H), 0.56-0.48 (m, 4H). LCMS ESI, (+ve mode): Expected m / z for C37H44N5O5[M+H] 638.77, found 638.2. Example 3: Synthesis of N-(4-(2-(6-Aminohexanoyl)-1,2,3,4-tetrahydroisoquinoline-6- carboxamido)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamide (compound 63) To a stirred solution of Int-A (1.00 eq, 200 mg, 0.546 mmol) and N-methoxymethanamine (1.50 eq, 50.0 mg, 0.819 mmol) in anhydrous DMF (4.0 mL) was added DIPEA (5.00 eq, 0.49 mL, 2.73 mmol) and HATU (1.20 eq, 249 mg, 0.655 mmol) at room temperature under nitrogen atmosphere. The resulting reaction mixture was stirred at 25oC for 16 h. The progress of the reaction was monitored by LCMS. After completion, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic extracts were washed with brine solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash column chromatography [silica gel (230-400 mesh), eluent: 30-50% EtOAc / petroleum ether] to afford N-cyclopropyl-N-[[4-[methoxy(methyl)carbamoyl]phenyl]methyl]-3-oxo-4H-1,4-benzoxazine-7- carboxamide (235 mg , 0.5451 mmol, 99% yield ) as an off-white solid. LCMS (ESI, +ve mode): Expected m / z for C22H24N3O5[M+H] 410.4, found 410.2. Next, to a stirred solution of N-cyclopropyl-N-[[4-[methoxy(methyl)carbamoyl]phenyl]methyl]-3- oxo-4H-1,4-benzoxazine-7-carboxamide (1.00 eq, 100 mg, 0.244 mmol) in dry THF (3.0 mL) was drop-wise added DIBAL-H (2.46 eq, 0.30 mL, 0.600 mmol) at -78oC under nitrogen atmosphere. The resulting reaction mixture was allowed to stir at -78oC for 3 h and slowly warmed to 25oC. The progress of the reaction was monitored by LCMS. After completion, the reaction mixture was quenched with water (10 mL) and extracted with EtOAc (2 × 20 mL). The combined organic extracts were washed with brine solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash column chromatography [silica gel (60-120 mesh), eluent: 30-40% EtOAc / petroleum ether] to afford N-cyclopropyl-N-[(4-formylphenyl)methyl]-3-oxo- 4H-1,4-benzoxazine-7-carboxamide (60.0 mg, 0.131 mmol, 53% yield) an colorless gum. LCMS (ESI, +ve mode): Expected m / z for C20H19N2O4 [M+H] 351.3, found 351.2. Next, to a stirred solution of N-cyclopropyl-N-[(4-formylphenyl)methyl]-3-oxo-4H-1,4-benzoxazine- 7-carboxamide (S-177) (1.00 eq, 50.0 mg, 0.143 mmol) and tert-butyl N-[6-(6-amino-3,4-dihydro-1H- isoquinolin-2-yl)-6-oxo-hexyl]carbamate (1.10 eq, 57.0 mg, 0.157 mmol) in methanol (5.0 mL) was added acetic acid (6.12 eq, 0.010 mL, 0.175 mmol) at room temperature under nitrogen atmosphere. The resulting reaction mixture was stirred at 25oC for 1 h. Biotage® MP-cyanoborohydride (18.5 eq, 100 mg, 2.64 mmol) was added to the reaction mixture and allowed to stir at 25oC for 16 h. The progress of the reaction was monitored by LCMS. After completion, the reaction mixture was diluted with ethyl acetate, filtered through celite bed and washed with ethyl acetate. Evaporated the solvent under reduced pressure to afford tert-butyl N-[6-[6-[[4-[[cyclopropyl-(3-oxo-4H-1,4-benzoxazine -7- carbonyl)amino]methyl]phenyl]methylamino]-3,4-dihydro-1H-isoquinolin-2-yl]-6-oxo-hexyl] carbamate (20.0 mg, 0.0209 mmol, 73% yield) as an colorless gum. LCMS (ESI, +ve mode): Expected m / z for C40H50N5O6[M-CO2tbutyl+H] 696.8, found 596.2. Next, to a stirred solution of tert-butyl N-[6-[6-[[4-[[cyclopropyl-(3-oxo-4H-1,4-benzoxazine-7- carbonyl) amino]methyl]phenyl]methylamino]-3,4-dihydro-1H-isoquinolin-2-yl]-6-oxo- hexyl]carbamate (1.00 eq, 100 mg, 0.144 mmol) in DCM (2.0 mL) was added HCl (4 M in 1,4- dioxane) (111 eq, 4.0 mL, 16.0 mmol) at 0oC and stirred at 25oC for 1 h. The progress of the reaction was monitored by LCMS. After completion, the reaction mixture was concentrated under reduced pressure and the crude material was purified by reverse phase prep HPLC (Method: A.0.1 % FA in water B. ACN; Column: X SELECT C18(150*19mm) 5um) to afford N-[[4-[[[2-(6-aminohexanoyl)- 3,4-dihydro-1H-isoquinolin-6-yl]amino] methyl]phenyl]methyl]-N-cyclopropyl-3-oxo-4H-1,4- benzoxazine-7-carboxamide (compound 74) (43.0 mg, 0.0716 mmol, 49% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6): δ 8.44 (s, 1H), 7.32 (d, J = 8.00 Hz, 2H), 7.23 (d, J = 7.60 Hz, 2H), 7.15 (d, J = 8.40 Hz, 1H), 7.10 (d, J = 1.60 Hz, 1H), 6.91 (d, J = 8.00 Hz, 1H), 6.84 (t, J = 6.40 Hz, 1H), 6.44 (d, J = 8.40 Hz, 1H), 6.37 (s, 1H), 6.12 (br s, 1H), 4.61-4.60 (m, 4H), 4.42 (d, J = 17.20 Hz, 1H), 4.23 (d, J = 5.60 Hz, 2H), 3.57 (t, J = 4.00 Hz, 2H), 2.71-2.67 (m, 4H), 2.56-2.61 (m, 1H), 2.50- 2.33 (m, 2H), 1.53-1.45 (m, 4H), 1.35-1.28 (m, 2H), 0.53-0.45 (m, 4H). LCMS (ESI, +ve mode): Expected m / z for C35H42N5O4[M+H] 596.7, found 596.0. Example 4: Synthesis of N-(4-((2-(4-(3-Aminopropyl)pyridin-2-yl)-1,2,3,4- tetrahydroisoquinolin-6-yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (compound 17) To a stirred solution of 2-chloro-4-iodo-pyridine (1.00 eq, 500 mg, 2.09 mmol) and tert-butyl N-prop- 2-ynylcarbamate (1.10 eq, 356 mg, 2.30 mmol) in dry THF (10.0 mL) was added triethylamine (3.00 eq, 0.87 mL, 6.26 mmol) and purged mixture with nitrogen for 5 minutes. Added copper iodide (0.100 eq, 40.0 mg, 0.209 mmol) and bis(triphenylphosphine)palladium(II) dichloride (0.0500 eq, 73.0 mg, 0.104 mmol) to mixture and stirred at 25oC for 16 h. Upon completion (monitored by LCMS), the reaction mixture was diluted with ethyl acetate (25 mL), filtered through celite bed and washed with ethyl acetate. Evaporated the solvent under reduced pressure and the crude material was purified by flash column chromatography [silica gel (230-400 mesh), eluent: 0-20% EtOAc / petroleum ether] to afford tert-butyl N-[3-(2-chloro-4-pyridyl)prop-2-ynyl]carbamate (540 mg, 1.97 mmol, 94% yield) as pale-yellow solid. LCMS (ESI, +ve mode): Expected m / z for C13H16ClN2O2[M+H] 267.7, found 267.0. To a stirred solution of tert-butyl N-[3-(2-chloro-4-pyridyl)prop-2-ynyl]carbamate (1.00 eq, 150 mg, 0.562 mmol) and 6-nitro-1,2,3,4-tetrahydroisoquinoline (1.50 eq, 150 mg, 0.844 mmol) in 1,4-dioxane (6.0 mL) in a sealed tube was added cesium carbonate (3.00 eq, 550 mg, 1.69 mmol) and purged the mixture with nitrogen for 5 minutes. Added Pd-PEPPSI™-IPent catalyst (0.05 eq, 22.0 mg, 0.0281 mmol) and the resulting reaction mixture was stirred at 90oC for 16 h. Upon completion (monitored by LCMS), the reaction mixture was diluted with water and extracted with ethyl acetate (3 × 20 mL). The combined organic extracts were washed with water and brine solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash column chromatography [silica gel (60-120 mesh), eluent: 30-50% EtOAc / petroleum ether] to afford tert- butyl N-[3-[2-(6-nitro-3,4-dihydro-1H-isoquinolin-2-yl)-4-pyridyl]prop-2-ynyl]carbamate (200 mg, 0.471 mmol, 84% yield) as pale-yellow solid. LCMS (ESI, +ve mode): Expected m / z for C22H25N4O4[M+H] 409.4, found 409.2. To a stirred solution of tert-butyl N-[3-[2-(6-nitro-3,4-dihydro-1H-isoquinolin-2-yl)-4-pyridyl]prop- 2-ynyl]carbamate (1.00 eq, 240 mg, 0.588 mmol) in methanol (12.0 mL) was added Pd / C (10 % dry basis) (1.00 eq, 0.059 mL, 0.588 mmol) at room temperature under nitrogen atmosphere. The resulting reaction mixture was stirred at 25oC for 16 h under bladder hydrogen pressure. Upon completion (monitored by LCMS), the reaction mixture was filtered through celite bed and washed with methanol (20 mL). Evaporated the solvent under reduced pressure to afford tert-butyl N-[3-[2-(6-amino-3,4- dihydro-1H-isoquinolin-2-yl)-4-pyridyl]propyl]carbamate (180 mg, 0.463 mmol, 79% yield) as an off-white solid. LCMS (ESI, +ve mode): Expected m / z for C22H31N4O2[M+H] 383.5, found 383.2. To a stirred solution of Int-A (1.00 eq, 170 mg, 0.464 mmol) and tert-butyl N-[3-[2-(6-amino-3,4- dihydro-1H-isoquinolin-2-yl)-4-pyridyl]propyl]carbamate (1.00 eq, 177 mg, 0.464 mmol) in anhydrous DMF (4.0 mL) was added DIPEA (5.00 eq, 0.40 mL, 2.32 mmol) and HATU (1.20 eq, 212 mg, 0.557 mmol) at room temperature under nitrogen atmosphere. The resulting reaction mixture was stirred at 25oC for 2 h. Upon completion (monitored by LCMS), the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic extracts were washed with water and brine solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford tert-butyl N-[3-[2-[6-[[4-[[cyclopropyl-(3-oxo-4H-1,4-benzoxazine-7- carbonyl)amino]methyl] benzoyl]amino]-3,4-dihydro-1H-isoquinolin-2-yl]-4- pyridyl]propyl]carbamate (360 mg, 0.341 mmol, 73% yield) as pale-yellow gum. LCMS (ESI, +ve mode): Expected m / z for C42H47N6O6[M+H] 731.8, found 731.2. To a stirred solution of tert-butyl N-[3-[2-[6-[[4-[[cyclopropyl-(3-oxo-4H-1,4-benzoxazine-7- carbonyl)amino]methyl]benzoyl]amino]-3,4-dihydro-1H-isoquinolin-2-yl]-4- pyridyl]propyl]carbamate (1.00 eq, 360 mg, 0.363 mmol) in DCM (3.0 mL) was added HCl (4 M in 1,4-dioxane) (1.00 eq, 6.0 mL, 0.363 mmol) at 0oC and stirred at 25oC for 1 h. Upon completion (monitored by LCMS), the reaction mixture was concentrated under reduced pressure and the crude material was purified by reverse phase prep HPLC (Method: A. 0.1 % ABC in water B. ACN; Column: X SELECT C18(150*19mm) 5um) to afford N-[[4-[[2-[4-(3-aminopropyl)-2-pyridyl]-3,4- dihydro-1H-isoquinolin-6-yl]carbamoyl] phenyl]methyl]-N-cyclopropyl-3-oxo-4H-1,4-benzoxazine- 7-carboxamide (compound 17)(100 mg, 0.157 mmol, 43% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6): δ 10.19 (br s, 1H), 8.01 (d, J = 5.20 Hz, 1H), 7.95 (d, J = 8.00 Hz, 2H), 7.65 (s, 1H), 7.57 (dd, J = 1.60, 8.40 Hz, 1H), 7.45 (d, J = 8.00 Hz, 2H), 7.23-7.16 (m, 3H), 6.93 (d, J = 8.00 Hz, 1H), 6.73-6.71 (m, 2H), 6.51 (d, J = 5.20 Hz, 1H), 4.72 (s, 2H), 4.64-4.63 (m, 4H), 3.81 (t, J = 5.60 Hz, 2H), 2.96-2.68 (m, 4H), 2.61-2.51 (m, 3H), 1.70-1.63 (m, 2H), 0.56-0.48 (m, 4H). LCMS (ESI, +ve mode): Expected m / z for C37H39N6O4[M+H] 631.7, found 631.2. Example 5: Synthesis of N-(4-((4-((6- aminohexyl)(methyl)carbamoyl)phenyl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro- 2H-benzo[b][1,4]oxazine-7-carboxamide 2,2,2-trifluoroacetate (compound 125) To a flask were added precursor (100 mg, 1 Eq, 269 µmol), THF (1 mL), and finally aqueous methanamine (418 mg, 466 µL, 40% Wt, 20 Eq, 5.38 mmol). The solution was heated to reflux until consumption of the starting material was indicated by TLC. The reaction was cooled, diluted with water, and extracted three times with dichloromethane. The combined organic extracts were washed once with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to yield tert-butyl (6-(methylamino)hexyl) carbamate (38.2 mg, 166 µmol, 61.6 %) as a residue that was used without further purification.LCMS (ESI, +ve mode): Expected m / z for [M+H]+231.21, found 231.20 Next, prepared according to General Procedure A / Workup A using Int-C (80 mg, 1 Eq, 0.16 mmol), EDC (47 mg, 1.5 Eq, 0.25 mmol), HOAt (34 mg, 1.5 Eq, 0.25 mmol), DMF (0.5 mL), tert- butyl (6-(methylamino)hexyl) carbamate (38 mg, 1 Eq, 0.16 mmol) and triethylamine (50 mg, 69 µL, 3 Eq, 0.49 mmol). Following N-Boc deprotection, the product was purified by reverse phase chromatography (10-100% methanol in water + 0.1% TFA) and lyophilized to yield N-(4-((4-((6- aminohexyl)(methyl)carbamoyl)phenyl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide 2,2,2-trifluoroacetate (compound 125) (35.9 mg, 50.4 µmol, 31 %) as a white solid.1H NMR (400 MHz, MeOH-d4) δ 7.95 (d, J = 8.2 Hz, 2H), 7.83 (d, J = 8.1 Hz, 2H), 7.49 (d, J = 7.7 Hz, 2H), 7.43 (d, J = 7.7 Hz, 2H), 7.20 (dd, J = 8.0, 1.7 Hz, 1H), 7.17 (d, J = 1.7 Hz, 1H), 6.96 (d, J = 8.0 Hz, 1H), 4.82 (s, 2H), 4.61 (s, 2H), 3.56 (s, 1H), 3.36 (d, J = 6.9 Hz, 1H), 3.05 (d, J = 16.0 Hz, 3H), 2.93 (d, J = 7.3 Hz, 1H), 2.84 (s, 2H), 1.65 (d, J = 43.1 Hz, 4H), 1.47 (s, 2H), 1.22 (s, 2H), 0.64 (d, J = 6.7 Hz, 2H), 0.55 (s, 2H). LCMS (ESI, +ve mode): Expected m / z for [M+H]+598.30, found 598.25 Example 6: Synthesis of N-(4-((4-((6-amino-N- methylhexanamido)methyl)phenyl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide 2,2,2-trifluoroacetate (compound 40) Prepared according to General Procedure A / Workup A using 6-((tert-butoxycarbonyl)amino)hexanoic acid (100 mg, 1 Eq, 432 µmol), EDC (124 mg, 1.5 Eq, 649 µmol), HOAt (88.3 mg, 1.5 Eq, 649 µmol), DMF (1.5 mL), 4-((methylamino)methyl)aniline (58.9 mg, 1 Eq, 432 µmol) and triethylamine (175 mg, 0.24 mL, 4 Eq, 1.73 mmol). The product was purified by normal phase chromatography (0-10% MeOH in DCM) to give tert-butyl (6-((4-aminobenzyl)(methyl)amino)-6-oxohexyl)carbamate (52.2 mg, 149 µmol, 34.5 %). LCMS (ESI, +ve mode): Expected m / z for [C19H32N3O3+] [M+H] 350.24, found 350.2; [C19H31N3NaO3+] [M+Na] 372.23, found 372.3; [C14H24N3O+] [M-Boc+H] 250.19, found 250.2 Next, prepared according to General Procedure A / Workup A using (Int-A) (54.7 mg, 1 Eq, 149 μmol), EDC (42.9 mg, 1.5 Eq, 224 μmol), HOAt (30.5 mg, 1.5 Eq, 224 μmol), DMF (2 mL) (52.2 mg, 1 Eq, 149 μmol) and triethylamine (60.5 mg, 83 μL, 4 Eq, 597 μmol). Following N-Boc deprotection, the product was purified by reverse phase chromatography (10-100% methanol in water + 0.1% TFA) to give N-(4-((4-((6-amino-N-methylhexanamido)methyl)phenyl)carbamoyl)benzyl)-N-cyclopropyl-3- oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide 2,2,2-trifluoroacetate (compound 40) (79.56 mg, 111.8 μmol, 74.8 %).1H NMR (400 MHz, MeOH-d4) δ 7.93 (dd, J = 8.2, 3.3 Hz, 2H), 7.79 – 7.58 (m, 2H), 7.47 (d, J = 7.9 Hz, 2H), 7.31 – 7.06 (m, 4H), 6.95 (d, J = 8.0 Hz, 1H), 4.80 (s, 2H), 4.65 – 4.53 (m, 4H), 3.03 – 2.86 (m, 5H), 2.81 (s, 1H), 2.53 – 2.41 (m, 2H), 1.77 – 1.56 (m, 4H), 1.55 – 1.29 (m, 2H), 0.63 (s, 2H), 0.54 (s, 2H). LCMS (ESI, +ve mode): Expected m / z for [C34H40N5O5+] [M+H] 598.30, found 598.3. Example 7: Synthesis of N-(4-((4-(4-aminobutoxy)phenyl)carbamoyl)benzyl)-N-cyclopropyl-3- oxo-3,4-dihydro-2H-benzo[b][1,4] oxazine-7-carboxamide 2,2,2-trifluoroacetate (compound 200). Prepared using Intermediate A according to above-described procedures to afford compound 200 (8.04 mg, 12.5 µmol, 11 %) as a white solid (8.04 mg, 12.5 µmol, 11 %).LCMS (ESI, +ve mode): Expected m / z for [C30H33N4O5+] [M+H] 529.2, found 529.2 Example 8: Synthesis of N-(4-((4-((5-aminopentyl)oxy)phenyl)carbamoyl)benzyl)-N- cyclopropyl-3-oxo-3,4-dihydro-2H-benzo [b][1,4]oxazine-7-carboxamide 2,2,2-trifluoroacetate (compound 201). Prepared using Intermediate A according to above-described procedures to afford compound 201 (287 mg, 437 μmol, 79.3 %) as a white solid. LCMS (ESI, +ve mode): Expected m / z for [C31H35N4O5+] [M+H] 543.3, found 543.2. Example 9: Synthesis of N-(4-((4-((6-aminohexyl)oxy)phenyl)carbamoyl)benzyl)-N-cyclopropyl- 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide 2,2,2-trifluoroacetate (compound 203). Prepared using Intermediate A according to above-described procedures to afford compound 203 (114 mg, 170 µmol, 64 %) as a white solid. LCMS (ESI, +ve mode): Expected m / z for [C32H37N4O5+] [M+H] 557.3, found 557.3. Example 10: Synthesis of N-(4-((4-((7-aminoheptyl)oxy)phenyl)carbamoyl)benzyl)-N- cyclopropyl-3-oxo-3,4-dihydro-2H-benzo [b][1,4]oxazine-7-carboxamide 2,2,2-trifluoroacetate (compound 204). Prepared using Intermediate A according to above-described procedures to afford compound 204 (6 mg, 9 μmol, 20 %). LCMS (ESI, +ve mode): Expected m / z for [C33H39N4O5+] [M+H] 571.29, found 571.25 Example 11: Synthesis of N-(4-((4-((8-aminooctyl)oxy)phenyl)carbamoyl)benzyl)-N- cyclopropyl-3-oxo-3,4-dihydro-2H-benzo [b][1,4]oxazine-7-carboxamide 2,2,2-trifluoroacetate (Compound 205). Prepared using Intermediate A according to above-described procedures to afford compound 205 (71.56 mg, 102.4 µmol, 21.61 %) as a white solid. LCMS (ESI, +ve mode): Expected m / z for [C34H41N4O5+] [M+H] 585.3, found 585.3. Example 12: Synthesis of N-(4-((4-((3-(2-aminoethoxy)propyl)carbamoyl)phenyl) carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide 2,2,2-trifluoroacetate (compound 91). Prepared using Intermediate C according to above-described procedures to afford compound 91 (29.3 mg, 41.9 μmol, 28.6 %). LCMS (ESI, +ve mode): Expected m / z for [C32H36N5O6+] [M+H] 586.27, found 586.20. Example 13: Synthesis of N-(4-((4-((2-(2- aminoethoxy)ethoxy)carbamoyl)phenyl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro- 2H-benzo[b][1,4]oxazine-7-carboxamide 2,2,2-trifluoroacetate (compound 206). Prepared using Intermediate C according to above-described procedures to afford compound 206 (50.64 mg, 72.17 µmol, 23.4 %) as a white solid. LCMS (ESI, +ve mode): Expected m / z for [C31H34N5O7+] [M+H] 588.2, found 588.2. Example 14: Synthesis of N-(4-((4-((2-(2- (aminooxy)ethoxy)ethyl)carbamoyl)phenyl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide 2,2,2-trifluoroacetate (compound 207). Prepared using Intermediate C according to above-described procedures to afford compound 207 (0.99 mg, 1.4 µmol, 3.3 %) as a white solid. LCMS (ESI, +ve mode): Expected m / z for [C31H34N5O7+] [M+H] 588.2, found 588.2 Example 15: Synthesis of 3-(4-((N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamido)methyl)benzamido) benzoic acid (Int-I) Prepared according to General Procedure D using methyl precursor (239 mg, 1 Eq, 478 µmol), THF (5 mL), lithium hydroxide hydrate (100 mg, 5 Eq, 2.39 mmol) and water (1.25 mL) to give (Int-I) (191.6 mg, 394.6 µmol, 82.5 %) as a white solid. LCMS (ESI, +ve mode): Expected m / z for [C27H24N3O6+] [M+H] 486.2, found 486.2; [C27H23N3NaO6+] [M+Na] 508.15, found 508.1 Example 16: Synthesis of N-(4-((3-((4-aminobutyl)carbamoyl)phenyl)carbamoyl)benzyl)-N- cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide 2,2,2-trifluoroacetate (compound 208). Prepared using Intermediate I according to above-described procedures to afford compound 208 (3.66 mg, 5.47 µmol, 4.42 %) as a red solid. LCMS (ESI, +ve mode): Expected m / z for [C31H34N5O5+] [M+H] 556.3, found 556.2 Example 17: Synthesis of N-(4-((3-((5-aminopentyl)carbamoyl)phenyl)carbamoyl)benzyl)-N- cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide 2,2,2-trifluoroacetate (compound 209). Prepared using Intermediate I according to above-described procedures to afford compound 209 (27.49 mg, 40.21 µmol, 39.0 %) as a white solid. LCMS (ESI, +ve mode): Expected m / z for [C32H36N5O5+] [M+H] 570.3, found 570.3 Example 18: Synthesis of N-(4-((3-((6-aminohexyl)carbamoyl)phenyl)carbamoyl)benzyl)-N- cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide 2,2,2-trifluoroacetate (compound 210). Prepared using Intermediate I according to above-described procedures to afford compound 210 (58.5 mg, 83.8 µmol, 81 %) as a white solid. LCMS (ESI, +ve mode): Expected m / z for [C33H38N5O5+] [M+H] 584.29, found 584.25 Example 19: Synthesis of N-(4-((3-((7-aminoheptyl)carbamoyl)phenyl)carbamoyl)benzyl)-N- cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide 2,2,2-trifluoroacetate (compound 211). Prepared using Intermediate I according to above-described procedures to afford compound 211(6.24 mg, 8.77 µmol, 7.09 %) as a white solid. LCMS (ESI, +ve mode): Expected m / z for [C34H40N5O5+] [M+H] 598.3, found 598.3 Example 20: Synthesis of N-(4-((3-(4-aminobutoxy)phenyl)carbamoyl)benzyl)-N-cyclopropyl-3- oxo-3,4-dihydro-2H-benzo[b][1,4] oxazine-7-carboxamide 2,2,2-trifluoroacetate (compound 212). Prepared using Intermediate A according to above-described procedures to afford compound 212 (6.65 mg, 10.3 µmol, 8.7 %) as a white solid. LCMS (ESI, +ve mode): Expected m / z for [C30H33N4O5+] [M+H] 529.2, found 529.3 Example 21: Synthesis of N-(4-((3-((5-aminopentyl)oxy)phenyl)carbamoyl)benzyl)-N- cyclopropyl-3-oxo-3,4-dihydro-2H-benzo [b][1,4]oxazine-7-carboxamide 2,2,2-trifluoroacetate (compound 213). Prepared using Intermediate A according to above-described procedures to afford compound 213(6.18 mg, 9.41 µmol, 9.4 %) as a white solid. LCMS (ESI, +ve mode): Expected m / z for [C31H35N4O5+] [M+H] 543.3, found 543.2 Example 22: Synthesis of N-(4-((3-((6-aminohexyl)oxy)phenyl)carbamoyl)benzyl)-N- cyclopropyl-3-oxo-3,4-dihydro-2H-benzo [b][1,4]oxazine-7-carboxamide 2,2,2-trifluoroacetate (Compound 214). Prepared using Intermediate A according to above-described procedures to afford compound 214 (6.95 mg, 10.4 µmol, 11 %) as a white solid. LCMS (ESI, +ve mode): Expected m / z for [C32H37N4O5+] [M+H] 557.3, found 557.3 Example 23: Synthesis of N-(4-((3-((7-aminoheptyl)oxy)phenyl)carbamoyl)benzyl)-N- cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[ b][1,4]oxazine-7-carboxamide 2,2,2-trifluoroacetate (compound 215). Prepared using Intermediate I according to above-described procedures to afford compound 215 (44.6 mg, 65.1 µmol, 80 %). LCMS (ESI, +ve mode): Expected m / z for [C33H39N4O5+] [M+H] 571.29, found 571.2 Example 24: Synthesis of N-(4-((4-((7-aminoheptyl)thio)phenyl)carbamoyl)benzyl)-N- cyclopropyl-3-oxo-3,4-dihydro-2H-benzo [b][1,4]oxazine-7-carboxamide 2,2,2-trifluoroacetate (compound 81). Prepared using Intermediate A according to above-described procedures to afford compound 81(16.51 mg, 23.56 µmol, 14.63 %) as a white solid. LCMS (ESI, +ve mode): Expected m / z for [C33H39N4O4S+] [M+H] 587.3, found 587.2 Example 25: Synthesis of N-(4-((4-((7-aminoheptyl)sulfinyl)phenyl)carbamoyl)benzyl)-N- cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide 2,2,2-trifluoroacetate (compound 89). Prepared using Intermediate A according to above-described procedures to afford compound 89 (5.83 mg, 8.13 µmol, 12 %) as a white solid. LCMS (ESI, +ve mode): Expected m / z for [C33H39N4O5S+] [M+H] 603.3, found 603.2 Example 26: Synthesis of N-(4-((4-(N-(6-aminohexyl)sulfamoyl)phenyl)carbamoyl)benzyl)-N- cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide 2,2,2-trifluoroacetate (Compound 217). Prepared using Intermediate A according to above-described procedures to afford compound 217 (52.01 mg, 1 Eq, 142.0 (60 mg, 82 μmol, 58 %). LCMS (ESI, +ve mode): Expected m / z for [C32H38N5O6S+] [M+H] 620.2, found 620.2 Example 27: Synthesis of N-(4-((4-(8-aminooctyl)phenyl)carbamoyl)benzyl)-N-cyclopropyl-3- oxo-3,4-dihydro-2H-benzo[b][1,4] oxazine-7-carboxamide 2,2,2-trifluoroacetate (Compound 218). Prepared using Intermediate A according to above-described procedures to afford compound 218 (73.65 mg, 107.9 µmol, 34.05 %) as a white solid. LCMS (ESI, +ve mode): Expected m / z for [C34H41N4O4+] [M+H] 569.7, found 569.3. Example 28: Synthesis of 6-aminohexyl 4-(4-((N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamido)methyl) benzamido)benzoate 2,2,2-trifluoroacetate (Compound 219). Prepared using Intermediate C according to above-described procedures to afford compound 219 (5.12 mg, 7.33 µmol, 5.1 %) as a white solid. LCMS (ESI, +ve mode): Expected m / z for [C33H37N4O6+] [M+H] 585.3, found 585.2 Example 29: Synthesis of N-(4-((4-((7-aminoheptyl)amino)phenyl)carbamoyl)benzyl)-N- cyclopropyl-3-oxo-3,4-dihydro-2H-benzo [b][1,4]oxazine-7-carboxamide 2,2,2-trifluoroacetate (compound 21). Prepared using Intermediate A according to above-described procedures to afford compound 21 (106.65 mg, 155.98 µmol, 71.74 %) as an off-white solid. LCMS (ESI, +ve mode): Expected m / z for [C33H40N5O4+] [M+H] 570.3, found 570.3 Example 30: Synthesis of N-(4-((4-(8-aminooct-1-yn-1-yl)phenyl)carbamoyl)benzyl)-N- cyclopropyl-3-oxo-3,4-dihydro-2H-benzo [b][1,4]oxazine-7-carboxamide 2,2,2-trifluoroacetate (compound 87). Prepared using Intermediate A according to above-described procedures to afford compound 87 (28.84 mg, 42.49 µmol, 58.5 %) as a white solid following lyophilization. LCMS (ESI, +ve mode): Expected m / z for [M+H]+565.28, found 565.20 Example 31: Synthesis of N-(4-((4-(1-(5-aminopentyl)-1H-1,2,3-triazol-4- yl)phenyl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamide 2,2,2-trifluoroacetate (compound 90). Prepared using Intermediate A according to above-described procedures to afford compound 90 (7.42 mg, 10.5 µmol, 49 %) as a white solid. LCMS (ESI, +ve mode): Expected m / z for [M+H] 594.28, found 594.20 Example 32: Synthesis of N-(4-((4-(5-(5-aminopentyl)-1,3,4-oxadiazol-2- yl)phenyl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamide 2,2,2-trifluoroacetate (compound 29). Prepared using Intermediate A according to above-described procedures to afford compound 29 (142.6 mg, 209.2 µmol, 140 %) as a clear resin. LCMS (ESI, +ve mode): Expected m / z for [C33H35N6O5+] [M+H] 595.27, found 595.2 Example 33: Synthesis of N-(4-((2-(6-aminohexyl)benzofuran-5-yl)carbamoyl)benzyl)-N- cyclopropyl-3-oxo-3,4-dihydro-2H-benzo [b][1,4]oxazine-7-carboxamide 2,2,2-trifluoroacetate (compound 86). Prepared using a modified Intermediate A according to above-described procedures to afford compound 86 (31.44 mg, 45.26 µmol, 38 %) as a white solid. LCMS (ESI, +ve mode): Expected m / z for [M+H]+581.28, found 581.20 Example 34: Synthesis of N-(4-((2-(6-aminohexyl)isoindolin-5-yl)carbamoyl)benzyl)-N- cyclopropyl-3-oxo-3,4-dihydro-2H-benzo [b][1,4]oxazine-7-carboxamide bis(2,2,2- trifluoroacetate) (Compound 220). Prepared using a modified Intermediate D according to above- described procedures to afford compound 220 (33.4 mg, 41.2 µmol, 49 %) as a white solid. LCMS (ESI, +ve mode): Expected m / z for [M+H]+582.31, found 582.25; expected m / z for [M+2H]2+291.66, found 291.80. Example 35: Synthesis of N-(4-((2-(6-aminohexanoyl)isoindolin-5-yl)carbamoyl)benzyl)-N- cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide 2,2,2-trifluoroacetate (Compound 221). Prepared using a modified Intermediate D according to above-described procedures to afford compound 221 (55 mg, 77 µmol, 92 %) as a white solid. LCMS (ESI, +ve mode): Expected m / z for [C34H38N5O5+] [M+H] 596.29, found 596.20 Example 36: Synthesis of N-(4-((2-(5-aminopentanoyl)isoindolin-5-yl)carbamoyl)benzyl)-N- cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide 2,2,2-trifluoroacetate (Compound 223). Prepared using a modified Intermediate D according to above-described procedures to afford compound 223 (50.53 mg, 72.63 µmol, 87 %) as a white solid. LCMS (ESI, +ve mode): Expected m / z for [C33H36N5O5+] [M+H] 582.3, found 582.2 Example 37: Synthesis of N-(4-((2-(7-aminoheptanoyl)isoindolin-5-yl)carbamoyl)benzyl)-N- cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide 2,2,2-trifluoroacetate (Compound 224). Prepared using a modified Intermediate D according to above-described procedures to afford compound 224 (7.99 mg, 11.0 µmol, 37.8 %) as a white solid. LCMS (ESI, +ve mode): Expected m / z for [C35H40N5O5+] [M+H] 610.3, found 610.3 Example 38: Synthesis of N-(4-((2-(5-aminopentanoyl)-1,2,3,4-tetrahydroisoquinolin-6- yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamide 2,2,2-trifluoroacetate (Compound 225). Prepared using Intermediate D according to above-described procedures to afford compound 225 (41.08 mg, 57.88 µmol, 55 %) as a white solid. LCMS (ESI, +ve mode): Expected m / z for [C34H38N5O5+] [M+H] 596.3, found 596.2 Example 39: Synthesis of N-(4-((2-(7-aminoheptanoyl)-1,2,3,4-tetrahydroisoquinolin-6- yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamide 2,2,2-trifluoroacetate (compound 80). Prepared using Intermediate D according to above-described procedures to afford compound 80 (30.40 mg, 41.20 µmol, 50 %) as a white solid. LCMS (ESI, +ve mode): Expected m / z for [C36H42N5O5+] [M+H] 624.3, found 624.3 Example 40: Synthesis of N-(4-((3-(5-aminopentanoyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7- yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamide 2,2,2-trifluoroacetate (compound 24). Prepared using a modified Intermediate D according to above-described procedures to afford compound 24 (25 mg, 35 μmol, 57 %) as a white solid. LCMS (ESI, +ve mode): Expected m / z for [C35H40N5O5+] [M+H] 610.3, found 610. Example 41: Synthesis of N-(4-((3-(6-aminohexanoyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7- yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamide 2,2,2-trifluoroacetate (compound 25). Prepared using a modified Intermediate D according to above-described procedures to afford compound 25 (25.45 mg, 34.50 μmol, 57 %) as a white solid. LCMS (ESI, +ve mode): Expected m / z for [C36H42N5O5+] [M+H] 624.32, found 624.3 Example 42: Synthesis of N-(4-((3-(7-aminoheptanoyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7- yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamide 2,2,2-trifluoroacetate (compound 26). Prepared using a modified Intermediate D according to above-described procedures to afford compound 26 (21.36 mg, 28.41 μmol, 47 %) as a white solid. LCMS (ESI, +ve mode): Expected m / z for [C37H44N5O5+] [M+H] 638.33, found 638.3 Example 43: Synthesis of N-(4-((1-(5-aminopentanoyl)-1,2,3,4-tetrahydroquinolin-6- yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamide 2,2,2-trifluoroacetate (compound 27). Prepared using a modified Intermediate D according to above-described procedures to afford compound 27 (11.99 mg, 16.89 μmol, 37 %) as a white solid. LCMS (ESI, +ve mode): Expected m / z for [C34H38N5O5+] [M+H] 596.29, found 596.2 Example 44: Synthesis of N-(4-((1-(6-aminohexanoyl)-1,2,3,4-tetrahydroquinolin-6- yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamide 2,2,2-trifluoroacetate (compound 28). Prepared using a modified Intermediate D according to above-described procedures to afford compound 28 (12.27 mg, 16.95 μmol, 37 %) as a white solid. LCMS (ESI, +ve mode): Expected m / z for [C35H40N5O5+] [M+H] 610.30, found 610.3 Example 45: Synthesis of N-(4-((2-(5-aminopentanoyl)-1,2,3,4-tetrahydroisoquinolin-7- yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamide 2,2,2-trifluoroacetate (compound 31). Prepared using a modified Intermediate D according to above-described procedures to afford compound 31 (44.97 mg, 63.36 μmol, 72 %) as a white solid. LCMS (ESI, +ve mode): Expected m / z for [C34H38N5O5+] [M+H] 596.29, found 596.2 Example 46: Synthesis of N-(4-((2-(6-aminohexanoyl)-1,2,3,4-tetrahydroisoquinolin-7- yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamide 2,2,2-trifluoroacetate (Compound 226). Prepared using a modified Intermediate D according to above-described procedures to afford compound 226 (45 mg, 62 µmol, 85 %) as a white solid. LCMS (ESI, +ve mode): Expected m / z for [C35H40N5O5+] [M+H] 610.3, found 610.3 Example 47: Synthesis of N-(4-((2-(7-aminoheptanoyl)-1,2,3,4-tetrahydroisoquinolin-7- yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamide 2,2,2-trifluoroacetate (compound 157). Prepared using a modified Intermediate D according to above-described procedures to afford compound 157 (29.88 mg, 40.50 µmol, 58 %) as a white solid. LCMS (ESI, +ve mode): Expected m / z for [C36H42N5O5+] [M+H] 624.3, found 624.3 Example 48: Synthesis of N-(4-((1-(5-aminopentanoyl)-1,2,3,4-tetrahydroquinolin-7- yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamide 2,2,2-trifluoroacetate (compound 33). Prepared using a modified Intermediate D according to above-described procedures to afford compound 33 (36.6 mg, 51.6 μmol, 59 %) as a white solid. LCMS (ESI, +ve mode): Expected m / z for [C34H38N5O5+] [M+H] 596.29, found 596.2 Example 49: Synthesis of N-(4-((2-(6-aminohexanoyl)-1,2,3,4-tetrahydroisoquinolin-7- yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamide 2,2,2-trifluoroacetate (Compound 227). Prepared using Intermediate A according to above-described procedures to afford compound 227 (3.05 mg, 4.21 µmol, 5.1 %) as a white solid. LCMS (ESI, +ve mode): Expected m / z for [C35H40N5O5+] [M+H] 610.3, found 610.3 Example 50: Synthesis of N-(4-((1-(7-aminoheptanoyl)-1,2,3,4-tetrahydroquinolin-7- yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamide 2,2,2-trifluoroacetate (Compound 228). Prepared using Intermediate A according to above-described procedures to afford compound 228 (2.97 mg, 4.03 µmol, 4.5 %) as a white solid. LCMS (ESI, +ve mode): Expected m / z for [C36H42N5O5+] [M+H] 624.3, found 624.3 Example 51: Synthesis of N-(4-((2-(6-aminohexyl)-1,2,3,4-tetrahydroisoquinolin-6- yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamide bis(2,2,2-trifluoroacetate) (compound 37). Prepared using Intermediate D according to above-described procedures to afford compound 37 (34.6 mg, 42.0 μmol, 31.2 %).1LCMS (ESI, +ve mode): Expected m / z for [C35H43N5O4+] [M+2] 597.33, found 597.3 Example 52: Synthesis of N-(4-((4-((6-amino-N- isopropylhexanamido)methyl)phenyl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide 2,2,2-trifluoroacetate (compound 150). Prepared using Intermediate A according to above-described procedures to afford compound 150 (67.29 mg, 90.96 μmol, 27.1 %). LCMS (ESI, +ve mode): Expected m / z for [C36H44N5O5+] [M+H] 626.33, found 626.3 Example 53: Synthesis of N-(4-((4-((6-aminohexanamido)methyl)phenyl)carbamoyl)benzyl)-N- cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide 2,2,2-trifluoroacetate (compound 32). Prepared using a modified Intermediate C according to above-described procedures to afford compound 32 (38.08 mg, 54.58 μmol, 90 %) as a white solid. LCMS (ESI, +ve mode): Expected m / z for [C33H38N5O5+] [M+H] 584.29, found 584.2 Example 54: Synthesis of N-(4-((4-((N-(6- aminohexyl)acetamido)methyl)phenyl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro- 2H-benzo[b][1,4]oxazine-7-carboxamide 2,2,2-trifluoroacetate (compound 65). Prepared using Intermediate C according to above-described procedures to afford compound 65 (63.02 mg, 86.83 μmol, 66.6 %). LCMS (ESI, +ve mode): Expected m / z for [C35H42N5O5+] [M+H] 612.32, found 612.2 Example 55: Synthesis of N-(4-((2-(6-aminohexanoyl)-1,2,3,4-tetrahydroisoquinolin-6- yl)carbamoyl)-3-methylbenzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamide 2,2,2-trifluoroacetate (compound 101). Prepared using a modified Intermediate D according to above-described procedures to afford compound 101 (45.51 mg, 61.69 μmol, 68 %) as a white solid. LCMS (ESI, +ve mode): Expected m / z for [C36H42N5O5+] [M+H] 624.32, found 624.3 Example 56: Synthesis of N-(4-((2-(6-aminohexanoyl)-1,2,3,4-tetrahydroisoquinolin-6- yl)carbamoyl)-3-fluorobenzyl)-N-cyclo propyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamide 2,2,2-trifluoroacetate (compound 154). Prepared using a modified Intermediate D according to above-described procedures to afford compound 154 (80.5 mg, 109 μmol, 68.2 %) as a white solid. LCMS (ESI, +ve mode): Expected m / z for [C35H39FN5O5+] [M+H] 628.29, found 628.2 Example 57: Synthesis of N-(4-((2-(6-aminohexanoyl)-7-fluoro-1,2,3,4-tetrahydroisoquinolin-6- yl)carbamoyl)benzyl)-N-cyclo propyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamide 2,2,2-trifluoroacetate (compound 102). Prepared using a modified Intermediate D according to above-described procedures to afford compound 102 (36.1 mg, 48.7 μmol, 54 %). LCMS (ESI, +ve mode): Expected m / z for [C35H39FN5O5+] [M+H] 628.29, found 628.3 Example 58: Synthesis of N-((6-((2-(6-aminohexanoyl)-1,2,3,4-tetrahydroisoquinolin-6- yl)carbamoyl)pyridin-3-yl)methyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine- 7-carboxamide bis(2,2,2-trifluoroacetate) (compound 69). Prepared using Intermediate D according to above-described procedures to afford compound 69 (22.6 mg, 26.9 μmol, 69 %) as a white solid. LCMS (ESI, +ve mode): Expected m / z for [C34H39N6O5+] [M+H] 611.3, found 611.2 Example 59: Synthesis of N-((5-((2-(6-aminohexanoyl)-1,2,3,4-tetrahydroisoquinolin-6- yl)carbamoyl)pyridin-2-yl)methyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine- 7-carboxamide bis(2,2,2-trifluoroacetate) (compound 149). Prepared using Intermediate D according to above-described procedures to afford compound 149 (12.58 mg, 15.00 μmol, 52 %). LCMS (ESI, +ve mode): Expected m / z for [C34H39N6O5+] [M+H] 611.3, found 611.3 Example 60: Synthesis of N-(4-((6-(6-aminohexanoyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2- yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamide bis(2,2,2-trifluoroacetate) (compound 109). Prepared using Intermediate D according to above-described procedures to afford compound 109 (51.88 mg, 61.85 μmol, 65 %). LCMS (ESI, +ve mode): Expected m / z for [C34H39N6O5+] [M+H] 611.3, found 611.3 Example 61: Synthesis of N-(4-(4-((6-amino-N-methylhexanamido)methyl)benzamido)benzyl)- N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide 2,2,2- trifluoroacetate (compound 68). Prepared using a modified Intermediate A according to above- described procedures to afford compound 68 (89.1 mg, 125 μmol, 51.3 %) as a white solid. LCMS (ESI, +ve mode): Expected m / z for [C34H40N5O5+] [M+H] 598.30, found 598.3 Example 62: Synthesis of N-(4-((4-(2-(5-Aminopentyl)oxazol-4-yl)phenyl)carbamoyl)benzyl)-N- cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (compound 14). Prepared using Intermediate A according to above-described procedures to afford compound 14 (45.0 mg, 0.0754 mmol, 35% yield) as an off-white solid. LCMS (ESI, +ve mode): Expected m / z for C34H36N5O5 [M+H] 594.6, found 594.2. Example 63: Synthesis of N-(4-((2-(6-Aminohexyl)-1H-indol-5-yl)carbamoyl)benzyl)-N- cyclopropyl-3-oxo-3,4-dihydro-2H-benzo [b][1,4]oxazine-7-carboxamide (compound 71). Prepared using Intermediate A according to above-described procedures to afford compound 71 (15.0 mg, 0.0256 mmol, 20% yield) as an off-white solid. LCMS (ESI, +ve mode): Expected m / z for C34H38N5O4[M+H] 580.7, found 580.2. Example 64: Synthesis of N-(4-((2-(5-Aminopentanamido)-2,3-dihydro-1H-inden-5- yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamide (compound 7). Prepared using Intermediate A according to above-described procedures to afford compound 7 (35.0 mg, 0.0585 mmol, yield 54%) as an off-white solid. LCMS: ESI, (+ve mode) expected m / z for C34H38N5O5[M+H] 596.69, found 596.2 Example 65: Synthesis of N-(4-((2-(6-Aminohexyl)quinolin-6-yl)carbamoyl)benzyl)-N- cyclopropyl-3-oxo-3,4-dihydro-2H-benzo [b][1,4]oxazine-7-carboxamide (compound 19). Prepared using Intermediate A according to above-described procedures to afford compound 19 (50.0 mg, 0.0844 mmol, 38.90% yield) as an off-white solid. LCMS (ESI, +ve mode): Expected m / z for C35H38N5O4[M+H] 592.7, found 592.3. Example 66: Synthesis of N-(4-((3-(6-Aminohexyl)isoquinolin-7-yl)carbamoyl)benzyl)-N- cyclopropyl-3-oxo-3,4-dihydro-2H-benzo [b][1,4]oxazine-7-carboxamide (compound 59). Prepared using Intermediate A according to above-described procedures to afford compound 59 (8.5 mg, 0.0144 mmol, 10% yield) as an off-white solid. LCMS (ESI, +ve mode): Expected m / z for C35H38N5O4[M+H] 592.7, found: 592.2. Example 67: Synthesis of N-(4-((3-(6-Aminohexyl)-4-oxo-3,4-dihydroquinazolin-7- yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamide (compound 52). Prepared using Intermediate A according to above-described procedures to afford compound 52 (13.0 mg, 0.0213 mmol, 43% yield) as light yellow solid. LCMS (ESI, +ve mode): Expected m / z for C34H37N6O5[M+H] 609.69, found 609.2. Example 68: Synthesis of N-(4-((2-(7-Aminoheptanoyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin- 7-yl)carbamoyl)benzyl)-N-cyclo propyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamide (compound 78). Prepared using a modified Intermediate D according to above- described procedures to afford compound 78 (40.0 mg, 0.0625 mmol, 38% yield) as an off-white solid. LCMS (ESI, +ve mode): Expected m / z for C37H44N5O5[M+H] 638.77, found 638.2. Example 69: Synthesis of N-(4-((2-(6-Aminohexyl)-3-oxo-1,2,3,4-tetrahydroisoquinolin-6- yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamide (compound 62). Prepared using Intermediate A according to above-described procedures to afford compound 62 (13.0 mg, 0.0212 mmol, yield 50%) as an off-white solid. LCMS ESI, (+ve mode) expected m / z for C35H40N5O5[M+H] 610.71, found 610.2. Example 70: Synthesis of N-(4-((4-((6-amino-N- cyclopropylhexanamido)methyl)phenyl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro- 2H-benzo[b][1,4]oxazine-7-carboxamide (compound 144). Prepared using Intermediate A according to above-described procedures to afford compound 144 (108 mg, 0.172 mmol, yield 33%) as an off-white solid. LCMS (ESI, +ve mode): Expected m / z for C36H42N5O5[M+H] 624.74, found 624.3. Example 71: Synthesis of N-(4-((4-((6-Amino-N-(tert- butyl)hexanamido)methyl)phenyl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (compound 128). Prepared using Intermediate A according to above-described procedures to afford compound 128 (81.0 mg, 0.126 mmol, 42.52% yield) as an off- white solid. LCMS (ESI, +ve mode): Expected m / z for C37H46N5O5[M+H] 640.78, found 640.3. Example 72: Synthesis of N-((3-((2-(6-aminohexanoyl)-1,2,3,4-tetrahydroisoquinolin-6- yl)carbamoyl)bicyclo[1.1.1]pentan-1-yl)methyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (compound 99). Prepared using a modified Intermediate A according to above-described procedures to afford compound 99 (65 mg, 0.1078 mmol, 68 % yield) as an off-white solid. LCMS (ESI, +ve mode) expected m / z for C34H42N5O5[M+H] 600.72, found 600.2. Example 73: Synthesis of N-((4-((2-(6-Aminohexanoyl)-1,2,3,4-tetrahydroisoquinolin-6- yl)carbamoyl)bicyclo[2.2.2]octan-1-yl)methyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (compound 93). Prepared using a modified Intermediate A according to above-described procedures to afford compound 93 (20.0 mg, 0.031 mmol, 38% yield) as an off-white solid. LCMS (ESI, +ve mode): Expected m / z for C37H48N5O5[M+H] 642.8, found 642.4. Example 74: Synthesis of N-((5-((2-(6-Aminohexanoyl)-1,2,3,4-tetrahydroisoquinolin-6- yl)carbamoyl)thiophen-2-yl)methyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (compound 72). Prepared using a modified Intermediate D according to above-described procedures to afford compound 72 (30.0 mg, 0.0484 mmol, 38% yield) as an off-white solid. LCMS (ESI, +ve mode): Expected m / z for C33H38N5O5S [M+H] 616.7, found 616.2. Example 75: Synthesis of N-(4-(N-(2-(6-Aminohexanoyl)-1,2,3,4-tetrahydroisoquinolin-6- yl)sulfamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamide (compound 98). Prepared using a modified Intermediate D according to above- described procedures to afford compound 98 (46.0 mg, 0.0706 mmol, 8.78% yield) as an off-white solid.1LCMS (ESI, +ve mode): Expected m / z for C34H40N5O6S [M+H] 646.77, found 646. Example 76: Synthesis of N-(4-(((2-(6-Aminohexanoyl)-1,2,3,4-tetrahydroisoquinolin-6- yl)amino)methyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamide (compound 74). Prepared using a modified Intermediate D according to above- described procedures to afford compound 74 (43.0 mg, 0.0716 mmol, 49% yield) as an off-white solid. LCMS (ESI, +ve mode): Expected m / z for C35H42N5O4[M+H] 596.7, found 596.0. Example 77: Synthesis of N-(4-(1-((2-(6-Aminohexanoyl)-1,2,3,4-tetrahydroisoquinolin-6- yl)amino)-2,2,2-trifluoroethyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (compound 130). Prepared using a modified Intermediate D according to above-described procedures to afford compound 130 (10.0 mg, 0.0148 mmol, 09% yield) as an off-white solid. LCMS (ESI, +ve mode): Expected m / z for C36H41F3N5O4 [M+H] 664.7, found 664.3. Example 78: Synthesis of N-(4-(3-((2-(6-Aminohexanoyl)-1,2,3,4-tetrahydroisoquinolin-6- yl)amino)oxetan-3-yl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamide (compound 116). Prepared using a modified Intermediate D according to above- described procedures to afford compound 116 (45.0 mg, 0.0703 mmol, 40% yield) as pale-yellow solid. LCMS (ESI, +ve mode): Expected m / z for C37H44N5O5[M+H] 638.7, found 637.8. Example 79: Synthesis of (R)-N-(1-(4-((2-(6-Aminohexanoyl)-1,2,3,4-tetrahydroisoquinolin-6- yl)carbamoyl)phenyl)ethyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamide hydrochloride (compound 110). Prepared using a modified Intermediate D according to above-described procedures to afford compound 110 (25.0 mg, 0.0399 mmol, 96% yield) as an off- white solid. LCMS (ESI, +ve mode): Expected m / z for C36H42N505 [M+H] 624.7, found 624.0. Example 80: Synthesis of (S)-N-(1-(4-((2-(6-Aminohexanoyl)-1,2,3,4-tetrahydroisoquinolin-6- yl)carbamoyl)phenyl)ethyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamide hydrochloride (compound 111). Prepared using Intermediate D according to above- described procedures to afford compound 111 (22.0 mg, 0.0351 mmol, 85% yield) as an off-white solid. LCMS (ESI, +ve mode): Expected m / z for C36H42N5O5[M+H] 624.7, found 624.0. Example 81: Synthesis of N-(4-((2-(6-Aminohexanoyl)-5-methyl-1,2,3,4-tetrahydroisoquinolin- 6-yl)carbamoyl)benzyl)-N-cyclo propyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamide (compound 112). Prepared using a modified Intermediate D according to above- described procedures to afford compound 112 (35.0 mg, 0.0561 mmol, 23% yield) as an off-white solid. LCMS (ESI, +ve mode): Expected m / z for C36H42N5O5[M+H] 624.7, found 624.2. Example 82: Synthesis of N-(4-((4-((6-Amino-N-methylhexanamido)methyl)phenyl)carbamoyl)- 3-methylbenzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (compound 140). Prepared using a modified Intermediate A according to above-described procedures to afford compound 140 (35.0 mg, 0.0571 mmol, 33.87% yield) as pale yellow solid. LCMS (ESI, +ve mode): Expected m / z for C35H42N5O5[M+H] 612.7, found 612.3. Example 83: Synthesis of N-(4-((4-((6-Amino-N-methylhexanamido)methyl)-2- methylphenyl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamide (compound 145). Prepared using a modified Intermediate A according to above- described procedures to afford compound 145 (32.0 mg, 0.0523 mmol, 34% yield) as an off-white solid. LCMS (ESI, +ve mode): Expected m / z for C35H42N5O5[M+H] 612.7, found 612.3. Example 84: Synthesis of N-(4-((2-(6-Amino-5,5-dimethylhexanoyl)-1,2,3,4- tetrahydroisoquinolin-6-yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (compound 16). Prepared using Intermediate A according to above-described procedures to afford compound 16 (150 mg, 0.233 mmol, 52% yield) as off-white solid. LCMS (ESI, +ve mode): Expected m / z for C37H44N5O5[M+H] 638.7, found 638.4. Example 85: Synthesis of N-(4-((2-(6-Amino-6-methylheptanoyl)-1,2,3,4-tetrahydroisoquinolin- 6-yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamide (compound 20). Prepared using Intermediate A according to above-described procedures to afford compound 20 (53.0 mg, 0.0829 mmol, 76.496% yield) as an off-white solid. LCMS (ESI, +ve mode): Expected m / z for C37H44N5O5[M+H] 638.77, found 638.2. Example 86: Synthesis of (R)-N-(4-((2-(6-Amino-3-methylhexanoyl)-1,2,3,4- tetrahydroisoquinolin-6-yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (compound 134). Prepared using Intermediate D according to above-described procedures to afford compound 134 (60.0 mg, 0.0953 mmol, 18% yield) as an off- white solid. LCMS (ESI, +ve mode): Expected m / z for C36H42N5O5[M+H] 624.74, found 624.5. Example 87: Synthesis of (S)-N-(4-((2-(6-Amino-3-methylhexanoyl)-1,2,3,4- tetrahydroisoquinolin-6-yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (compound 135). Prepared using Intermediate D according to above-described procedures to afford compound 135 (56.0 mg, 0.0895 mmol, 18% yield) as an off- white solid. LCMS (ESI, +ve mode): Expected m / z for C36H42N5O5[M+H] 624.74, found 624.5. Example 88: Synthesis of (S)-N-(4-((2-(6-Amino-5-methylhexanoyl)-1,2,3,4- tetrahydroisoquinolin-6-yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (compound 138). Prepared using Intermediate D according to above-described procedures to afford compound 138 (72.0 mg, 0.115 mmol, 26% yield) as an off- white solid. LCMS (ESI, +ve mode): Expected m / z for C36H42N5O5[M+H] 624.74, found 624.5. Example 89: Synthesis of (R)-N-(4-((2-(6-Amino-5-methylhexanoyl)-1,2,3,4- tetrahydroisoquinolin-6-yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (compound 127). Prepared using Intermediate D according to above-described procedures to afford compound 127 (86.0 mg, 0.138 mmol, 24% yield) as an off- white solid. LCMS (ESI, +ve mode): Expected m / z for C36H42N5O5[M+H] 624.74, found 624.3. Example 90: Synthesis of (S)-N-(4-((2-(6-Aminoheptanoyl)-1,2,3,4-tetrahydroisoquinolin-6- yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamide (compound 113). Prepared using Intermediate A according to above-described procedures to afford compound 113 (21.0 mg, 0.0335 mmol, 49% yield) as an off-white solid. LCMS (ESI, +ve mode): Expected m / z for C36H42N5O5[M+H] 624.74, found 624.2. Example 91: Synthesis of N-(4-((4-((6-Amino-N,2,2- trimethylhexanamido)methyl)phenyl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (compound 148). Prepared using a modified Intermediate A according to above-described procedures to afford compound 148 (19.0 mg, 0.0303 mmol, 9.17% yield) as an off-white solid. LCMS (ESI, +ve mode): Expected m / z for C36H44N5O5[MS+H] 626.76, found 626.5. Example 92: Synthesis of N-(4-((4-((6-Amino-N,3,3- trimethylhexanamido)methyl)phenyl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (compound 100). Prepared using Intermediate A according to above-described procedures to afford compound 100 (62.0 mg, 0.0988 mmol, 71% yield) as an off- white solid. LCMS (ESI, +ve mode): Expected m / z for C36H44N5O5[M+H] 626.76, found 626.2. Example 93: Synthesis of N-(4-((4-((6-Amino-N,4,4- trimethylhexanamido)methyl)phenyl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (compound 146). Prepared using Intermediate A according to above-described procedures to afford compound 146 (70.0 mg, 0.1114 mmol, 62% yield) as an off- white solid. LCMS (ESI, +ve mode): Expected m / z for C36H44N5O5[M+H] 626.7, found 626.3. Example 94: Synthesis of N-(4-((4-((6-Amino-N,5,5- trimethylhexanamido)methyl)phenyl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo -3,4-dihydro- 2H-benzo[b][1,4]oxazine-7-carboxamide (compound 129). Prepared using a modified Intermediate A according to above-described procedures to afford compound 129 (50.0 mg, 0.0784 mmol, 51% yield) as an off-white solid. LCMS (ESI, +ve mode): Expected m / z for C36H44N5O5[M+H] 626.7, found 626.3. Example 95: Synthesis of (Z)-N-(4-((2-(6-Aminohex-4-enoyl)-1,2,3,4-tetrahydroisoquinolin-6- yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamide (compound 56). Prepared using Intermediate A according to above-described procedures to afford compound 56 (45.0 mg, 0.074 mmol, 52% yield) as an off-white solid. LCMS (ESI, +ve mode): Expected m / z for C35H38N5O5[M+H] 608.7, found 608.2. Example 96: Synthesis of (E)-N-(4-((2-(6-Aminohex-4-enoyl)-1,2,3,4-tetrahydroisoquinolin-6- yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamide (compound 55). Prepared using Intermediate A according to above-described procedures to afford compound 55 (60.0 mg, 0.0987 mmol, 78% yield) as a white solid. LCMS (ESI, +ve mode): Expected m / z for C35H38N5O5[M+H] 608.7, found 608.2. Example 97: Synthesis of N-(4-((2-(3-((1R,2R)-2-(Aminomethyl)cyclopropyl)propanoyl)-1,2,3,4- tetrahydroisoquinolin-6-yl) carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (compound 97). Prepared using Intermediate A according to above-described procedures to afford compound 97 (28.0 mg, 0.0449 mmol, 53% yield) as an off- white solid. LCMS (ESI, +ve mode): Expected m / z for C36H40N5O5[M+H] 622.73, found 622.2. Example 98: Synthesis of N-(4-((2-(3-((1S,2R)-2-(Aminomethyl)cyclopropyl)propanoyl)-1,2,3,4- tetrahydroisoquinolin-6-yl) carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (compound 94). Prepared using Intermediate A according to above-described procedures to afford compound 94 (35.0 mg, 0.0558 mmol, 34% yield) as an off- white solid. LCMS (ESI, +ve mode): Expected m / z for C36H40N5O5[M+H] 622.7, found 622.2. Example 99: Synthesis of N-(4-((2-(2-(3-Aminopropoxy)acetyl)-1,2,3,4-tetrahydroisoquinolin-6- yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamide (compound 48). Prepared using Intermediate A according to above-described procedures to afford compound 48 (90.0 mg, 0.147 mmol, 52% yield) as an off-white solid. LCMS (ESI, +ve mode): Expected m / z for C34H38N5O6[M+H] 612.6, found 612.2. Example 100: Synthesis of N-(4-((2-(3-(2-Aminoethoxy)propanoyl)-1,2,3,4- tetrahydroisoquinolin-6-yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (compound 61). Prepared using Intermediate A according to above-described procedures to afford compound 61 (78.0 mg, 0.128 mmol, 60% yield) as an off-white solid. LCMS (ESI, +ve mode): Expected m / z for C34H38N5O6[M+H] 612.70, found 612.2. Example 101: Synthesis of N-(4-((2-(3-((2-Aminoethyl)amino)propanoyl)-1,2,3,4- tetrahydroisoquinolin-6-yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (compound 45). Prepared using Intermediate A according to above-described procedures to afford compound 45 (30.0 mg, 0.0484 mmol, 39% yield) as an off- white solid. Analytical data: LCMS (ESI, +ve mode): Expected m / z for C34H39N6O5[M+H] 611.7, found 611.3. Example 102: Synthesis of N-(4-((2-(3-((2-Aminoethyl)(methyl)amino)propanoyl)-1,2,3,4- tetrahydroisoquinolin-6-yl)carbamoyl) benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (compound 60). Prepared using Intermediate A according to above-described procedures to afford compound 60 (45.0 mg, 0.0712 mmol, 26% yield) as an off- white solid. LCMS (ESI, +ve mode): Expected m / z for C35H41N6O5[M+H] 625.7, found 625.2. Example 103: Synthesis of N-(4-((2-(3-((2-aminoethyl)thio)propanoyl)-1,2,3,4- tetrahydroisoquinolin-6-yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (compound 49). Prepared using Intermediate A according to above-described procedures to afford compound 49 (50.0 mg, 0.0793 mmol, 36% yield) as an off- white solid. LCMS (ESI, +ve mode): Expected m / z for C34H38N5O5S [M+H] 628.7, found 628.2. Example 104: Synthesis of N-(4-((2-(3-((2-aminoethyl)sulfinyl)propanoyl)-1,2,3,4- tetrahydroisoquinolin-6-yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (compound 43). Prepared using Intermediate A according to above-described procedures to afford compound 43 (14.76 mg, 0.022 mmol, 09% yield) as an off- white solid. LCMS (ESI, +ve mode): Expected m / z for C34H38N5O6S [M+H] 644.75, found 644.2. Example 105: Synthesis of N-(4-((2-(3-((2-Aminoethyl)sulfonyl)propanoyl)-1,2,3,4- tetrahydroisoquinolin-6-yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (compound 44). Prepared using Intermediate A according to above-described procedures to afford compound 44 (35.46 mg, 0.0532 mmol, 34% yield) as off-white solid. LCMS (ESI, +ve mode): Expected m / z for C34H38N5O7S [M+H] 660.75, found 660.2. Example 106: Synthesis of 4-Aminobutyl6-(4-((N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamido)methyl) benzamido)-3,4-dihydroisoquinoline-2(1H)- carboxylate (compound 11). Prepared using Intermediate A according to above-described procedures to afford compound 11 (46.0 mg, 0.0751 mmol, yield 47%) as an off-white solid. LCMS ESI, (+ve mode): Expected m / z for C34H38N5O6[M+H] 612.69 found 612.2. Example 107: Synthesis of N-(4-((2-((4-aminobutyl)carbamoyl)-1,2,3,4-tetrahydroisoquinolin-6- yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamide (Compound 10). Prepared using Intermediate A according to above-described procedures to afford compound 10 (25.0 mg, 0.0409 mmol, yield 37%) as an off-white solid. LCMS ESI, (+ve mode): Expected m / z for C34H39N6O5[M+H] 611.7, found 611.4. Example 108: Synthesis of N-(4-((2-((4-Aminobutyl)(methyl)carbamoyl)-1,2,3,4- tetrahydroisoquinolin-6-yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (Compound 51). Prepared using Intermediate D according to above-described procedures to afford compound 51 (40.0 mg, 0.0627 mmol, 53.51% yield) as an off- white solid. LCMS (ESI, +ve mode): Expected m / z for C35H41N6O5 [M+H] 625.73, found 625.2. Example 109: Synthesis of 4-((N-Cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamido)methyl)benzoic acid (Intermediate A) To a stirred solution of methyl 4-formylbenzoate (1.00 eq, 10.00 g, 60.9 mmol) and cyclopropylamine (1.20 eq, 5.2 mL, 73.1 mmol) in methanol (100 mL) was added acetic acid (0.143 eq, 0.50 mL, 8.73 mmol) at room temperature under nitrogen atmosphere. The resulting reaction mixture was stirred at 25oC for 5 h. NaBH4(2.00 eq, 4.61 g, 122 mmol) was added (portion wise) at 0oC and allowed to stir at 25oC for 3 h. The progress of the reaction was monitored by LCMS. After completion, the reaction mixture was diluted with ice water (300 mL) and extracted with ethyl acetate (3 × 250 mL). The combined organic extracts were washed with water and brine solution, dried over anhydrous sodium sulfate, filtered and evaporated the solvent under reduced pressure. The crude material was purified by flash column chromatography [silica gel (230-400 mesh), eluent: 0-30% EtOAc / petroleum ether] to afford methyl 4-[(cyclopropylamino)methyl]benzoate. LCMS (ESI, +ve mode) expected m / z for C12H16NO2[M+H] 206.26, found 206.2. Next, to a stirred solution of 3-oxo-4H-1,4-benzoxazine-7-carboxylic acid (1.00 eq, 3.00 g, 15.5 mmol) and methyl 4-[(cyclopropylamino)methyl]benzoate (1.00 eq, 3.19 g, 15.5 mmol) in anhydrous DMF (40.0 mL) was added N,N-diisopropylethylamine (5.00 eq, 14 mL, 77.7 mmol) and HATU (1.20 eq, 7.09 g, 18.6 mmol) at 25oC under nitrogen atmosphere. The resulting reaction mixture was stirred at 25oC for 16 h. The progress of the reaction was monitored by LC-MS. After completion, the reaction mixture was diluted with water (250 mL), the resulting solid was filtered and washed with water, dried under vacuum to afford methyl 4-[[cyclopropyl-(3-oxo-4H-1,4-benzoxazine-7- carbonyl)amino]methyl] benzoate. LCMS (ESI, +ve mode) expected m / z for C21H21N2O5[M+H] 381.39, found 381.2. Next, to a stirred solution of methyl 4-[[cyclopropyl-(3-oxo-4H-1,4-benzoxazine-7- carbonyl)amino]methyl] benzoate (1.00 eq, 4.00 g, 10.5 mmol) in THF (40.0 mL), methanol (10.0 mL) and water (50.0 mL) was added lithium hydroxide monohydrate (5.00 eq, 2.21 g, 52.6 mmol) at room temperature. The resulting reaction mixture was stirred at 25oC for 5 h. The progress of the reaction was monitored by LC-MS. After completion, the solvent was partially removed under reduced pressure and adjusted the pH (2~3) of the mixture with 1.5 N HCl at 0-5oC. The resulting solid was filtered and washed with water, dried under vacuum to afford 4-[[cyclopropyl-(3-oxo-4H-1,4- benzoxazine-7-carbonyl)amino]methyl]benzoic acid (Int-A) (3.60 g, 9.48 mmol, 90% yield) as off- white solid.1H NMR (400 MHz, DMSO-d6): δ 12.87 (br s, 1H), 10.87 (s, 1H), 7.94 (d , J = 8.40 Hz, 2H), 7.43 (d, J = 8.00 Hz, 2H), 7.20-7.15 (m, 2H), 6.93 (d, J = 8.00 Hz, 1H), 4.71 (s, 2H), 4.62 (s, 2H), 2.79 (br s, 1H), 0.55-0.47 (m, 4H). LCMS (ESI, +ve mode) expected m / z for C20H19N2O5[M+H] 367.37, found 367.2. Example 110: Synthesis of N-(4-((4-((2-(2- Aminoethoxy)ethyl)carbamoyl)phenyl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro- 2H-benzo[b][1,4]oxazine-7-carboxamide (229). Prepared using Intermediate A according to above- described procedures to afford compound 229 (80.0 mg, 0.132 mmol, 93% yield) as pale-yellow solid. LCMS (ESI, +ve mode) expected m / z for C31H34N5O6[M+H] 572.6, found 572.2. Example 111: Synthesis of N-(4-((4-((6-Aminohexyl)carbamoyl)phenyl)carbamoyl)benzyl)-N- cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (Compound 2). Prepared using Intermediate A according to above-described procedures to afford compound 2 (30.0 mg, 0.0513 mmol, 18% yield) as an off-white solid. LCMS (ESI, +ve mode) expected m / z for C33H38N5O5[M+H] 584.6, found 584.2. Example 112: Synthesis of N-(4-((2-((4-Aminobutyl)carbamoyl)-1,2,3,4-tetrahydroisoquinolin- 7-yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamide (Compound 3). Prepared using Intermediate A according to above-described procedures to afford compound 3 (54.0 mg, 0.0882 mmol, 62% yield) as an off-white solid. LCMS ESI, (+ve mode) expected m / z for C34H39N6O5[M+H] 611.7 found 611.2. Example 113: Synthesis of N-(4-((2-((4-Aminobutyl)(methyl)carbamoyl)-1,2,3,4- tetrahydroisoquinolin-7-yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (Compound 4). Prepared using Intermediate A according to above-described procedures to afford compound 4 (50.0 mg, 0.0796 mmol, 59% yield) as an off-white solid. LCMS ESI, (+ve mode) expected m / z for C35H41N6O5[M+H] 625.73 found 625.2. Example 114: Synthesis of 4-Aminobutyl7-(4-((N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamido)methyl) benzamido)-3,4-dihydroisoquinoline-2(1H)- carboxylate (Compound 8). Prepared using Intermediate A according to above-described procedures to afford compound 8 (22.0 mg, 0.0358 mmol, 37% yield) as an off-white solid. LCMS ESI, (+ve mode) expected m / z for C34H38N5O6[M+H] 612.69 found 612.2. Example 115: Synthesis of N-(4-((2-(6-Amino-2,2-dimethylhexanoyl)-1,2,3,4- tetrahydroisoquinolin-6-yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (Compound 9). Prepared using Intermediate A according to above-described procedures to afford compound 9 (8.00 mg, 0.012 mmol, yield 11%) as an off-white solid. LCMS ESI, (+ve mode) expected m / z for C37H44N5O5[M+H] 638.77, found 638.2. Example 116: Synthesis of N-(4-((2-(6-Aminohexyl)-1-oxo-2,3,4,5-tetrahydro-1H- benzo[c]azepin-7-yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (Compound 12). Prepared using Intermediate A according to above-described procedures to afford compound 12 (35.0 mg, 0.0561 mmol, yield 51%) as an off- white solid. LCMS (ESI, +ve mode) expected m / z for C36H42N5O5[M+H] 624.74, found 624.2. Example 117: Synthesis of N-(4-((4-(6-(5-Aminopentyl)pyridin-2-yl)phenyl)carbamoyl)benzyl)- N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (Compound 15). Prepared using Intermediate A according to above-described procedures to afford compound 15 (80 mg, 0.132 mmol, yield 32%) as an off-white solid. LCMS (ESI, +ve mode) expected m / z for C36H38N5O4[M+H] 604.7, found 604.2. Example 118: Synthesis of N-(4-((2-(6-Aminohexyl)-3-oxo-2,3,4,5-tetrahydro-1H- benzo[c]azepin-7-yl)carbamoyl)benzyl)-N-cyclo propyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (Compound 46). Prepared using Intermediate A according to above-described procedures to afford compound 46 (40.0 mg, 0.0630 mmol, 35% yield) as an off- white solid. LCMS (ESI, +ve mode) expected m / z for C36H42N5O5[M+H] 624.7, found 624.2. Example 119: Synthesis of N-(4-((3-(5-Aminopentyl)-4-oxo-2,3,4,5-tetrahydro-1H- benzo[d]azepin-7-yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (Compound 47). Prepared using Intermediate A according to above-described procedures to afford compound 47(15.0 mg, 0.0244 mmol, 25% yield) as an off-white solid. LCMS (ESI, +ve mode) expected m / z for C35H40N5O5 [M+H] 610.7, found 610.2. Example 120: Synthesis of N-(4-((4-(5-(5-Aminopentyl)oxazol-2-yl)phenyl)carbamoyl)benzyl)- N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (Compound 50). Prepared using Intermediate A according to above-described procedures to afford compound 50 (1.1 mg, 0.00176 mmol, 06% yield) as an off-white solid. LCMS (ESI, +ve mode) expected m / z for C34H36N5O5[M+H] 594.6, found 594.2. Example 121: Synthesis of N-(4-((3-(5-Aminopentyl)-2-oxo-2,3,4,5-tetrahydro-1H- benzo[d]azepin-7-yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (Compound 54). Prepared using Intermediate A according to above-described procedures to afford compound 54 (50.0 mg, 0.0815 mmol, 64% yield) as an off- white solid. LCMS (ESI, +ve mode) expected m / z for C35H40N5O5[M+H] 610.71, found 610.2. Example 122: Synthesis of N-(4-((4-((3-(4-Aminobutyl)-2-oxopyridin-1(2H)- yl)methyl)phenyl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (Compound 57). Prepared using Intermediate A according to above-described procedures to afford compound 57 (44.0 mg, 0.0706 mmol, 42% yield) as an off- white solid. LCMS (ESI, +ve mode): Expected m / z for C36H38N5O5[M+H] 620.71, found 620.2. Example 122.5: Synthesis of N-(4-((4-(4-(7-Aminoheptyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4- triazol-1-yl)phenyl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (Compound 58). Prepared using Intermediate A according to above-described procedures to afford compound 58 (60.0 mg, 0.0918 mmol, 31% yield) as an off- white solid. LCMS (ESI, +ve mode): Expected m / z for C36H42N7O5[M+H] 652.75, found 652.2. Example 123: Synthesis of N-(4-((3-(6-Aminohex-1-yn-1-yl)isoquinolin-7-yl)carbamoyl)benzyl)- N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (Compound 159). Prepared using Intermediate A according to above-described procedures to afford compound 159 (5.0 mg, 0.00849 mmol, 12.17% yield) as an off-white solid. LCMS (ESI, +ve mode): Expected m / z for C35H34N5O4[M+H] 588.67, found 588.2. Example 124: Synthesis of N-(4-((2-(6-Aminohexyl)-1,3-dioxoisoindolin-5- yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamide (Compound 70). Prepared using Intermediate A according to above-described procedures to afford compound 70 (30.0 mg, 0.0491 mmol, 35% yield) as an off-white solid. LCMS (ESI, +ve mode) expected m / z for C34H36N5O6[M+H] 610.6, found 610.2. Example 125: Synthesis of N-(4-((4-(3-(7-Aminoheptyl)-2-oxo-2,3-dihydro-1H-imidazol-1- yl)phenyl)carbamoyl)benzyl)-N-cyclo propyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamide (Compound 73). Prepared using Intermediate A according to above-described procedures to afford compound 73 (10.0 mg, 0.0157 mmol, 19% yield) as off-white solid. LCMS (ESI, +ve mode) expected m / z for C36H41N6O5[M+H] 637.7, found 637.3. Example 126: Synthesis of N-(4-((2-(4-(3-Aminopropyl)pyrimidin-2-yl)-1,2,3,4- tetrahydroisoquinolin-6-yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (Compound 75). Prepared using Intermediate A according to above-described procedures to afford compound 75 (2.0 mg, 0.00310 mmol, 05% yield) as an off- white solid. LCMS (ESI, +ve mode) expected m / z for C36H38N7O4[M+H] 632.7, found 632.2. Example 127: Synthesis of N-(4-((2-(6-Aminohexyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7- yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamide (Compound 79). Prepared using Intermediate A according to above-described procedures to afford compound 79 (11.0 mg, 0.018 mmol, 25% yield) as an off-white solid. [mixture of rotamers were observed] LCMS (ESI, +ve mode) expected m / z for C36H44N5O4[M+H] 610.76, found 610.2. Example 128: Synthesis of 4-Aminobutyl(4-(4-((N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamido)methyl)benzamido)benzyl)(methyl)carbamate (Compound 95). Prepared using Intermediate A according to above-described procedures to afford compound 95 (35.0 mg, 0.0582 mmol, 37% yield) as an off-white solid. LCMS (ESI, +ve mode) expected m / z for C33H38N5O6[M+H] 600.6, found 600.2. Example 129: Synthesis of N-(4-((2-(5-(2-Aminoethyl)pyridin-2-yl)-1,2,3,4- tetrahydroisoquinolin-6-yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (Compound 96). Prepared using Intermediate A according to above-described procedures to afford compound 96 (20 mg, 0.0318 mmol, 28% yield) as an off-white solid. LCMS (ESI, +ve mode) expected m / z for C36H37N6O4[M+H] 617.7, found 617.0. Example 130: Synthesis of N-(4-((4-((2-(1-(3-Aminopropyl)cyclopropyl)-N- methylacetamido)methyl)phenyl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (compound 115). Prepared using Intermediate A according to above-described procedures to afford compound 115 (20.0 mg, 0.0320 mmol, 29% yield) as an off- white solid. LCMS (ESI, +ve mode) expected m / z for C36H42N5O5[M+H] 624.7, found 624.2. Example 131: Synthesis of N-(4-((2-(6-Amino-4-methylhexanoyl)-1,2,3,4-tetrahydroisoquinolin- 6-yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamide (Compound 117). Prepared using Intermediate D according to above-described procedures to afford compound 117 (10.0 mg, 0.016 mmol, 12% yield) as an off-white solid. LCMS (ESI, +ve mode) expected m / z for C36H42N5O5[M+H] 624.7, found 624.3. Example 132: Synthesis of N-(4-((4-(((4-(3-Aminopropyl)pyridin-2- yl)(methyl)amino)methyl)phenyl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (Compound 118). Prepared using Intermediate A according to above-described procedures to afford compound (32.0 mg, 0.0514 mmol, 9.99% yield) as an off-white solid. LCMS (ESI, +ve mode): Expected m / z for C36H39N6O4[M+H] 619.72, found 619.3. Example 133: Synthesis of N-(4-((4-((6-Amino-N,6- dimethylheptanamido)methyl)phenyl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (Compound 131). Prepared using a variant of Intermediate C according to above-described procedures to afford compound 131 (3.5 mg, 0.00533 mmol, 02% yield) as an off-white solid. [mixture of rotamers were observed] LCMS (ESI, +ve mode) expected m / z for C36H44N5O5[M+H] 626.7, found 626.3. Example 134: Synthesis of N-(4-((4-((6-Amino-5,5- dimethylhexyl)carbamoyl)phenyl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (Compound 132). Prepared using Intermediate C according to above-described procedures to afford compound 132 (50.0 mg, 0.0812 mmol, 72% yield) as an off- white solid. LCMS (ESI, +ve mode) expected m / z for C35H42N5O5[M+H] 612.7, found 612.3. Example 135: Synthesis of N-(4-((4-((6-Amino-2,2- dimethylhexyl)carbamoyl)phenyl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (Compound 133). Prepared using Intermediate C according to above-described procedures to afford compound 133 (50.0 mg, 0.0809 mmol, 47% yield) as an off- white solid. LCMS (ESI, +ve mode) expected m / z for C35H42N5O5[M+H] 612.7, found 612.2. Example 136: Synthesis of N-(4-((4-((6-Amino-6- methylheptyl)carbamoyl)phenyl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (Compound 136). Prepared using Intermediate C according to above-described procedures to afford compound 136 (35.0 mg, 0.0572 mmol, 51% yield) as an off- white solid. LCMS (ESI, +ve mode) expected m / z for C35H42N5O5[M+H] 612.73, found 612.3. Example 137: Synthesis of N-(4-((4-((7-Amino-2-methylheptan-2- yl)carbamoyl)phenyl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (Compound 137). Prepared using Intermediate A according to above-described procedures to afford compound 137 (5.0 mg, 0.00780 mmol, 7% yield) as an off- white solid. LCMS (ESI, +ve mode) expected m / z for C35H42N5O5[M+H] 612.73, found 612.2. Example 138: Synthesis of N-(4-((4-(1-(6-Amino-N- methylhexanamido)cyclopropyl)phenyl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro- 2H-benzo[b][1,4]oxazine-7-carboxamide (Compound 139). Prepared using Intermediate A according to above-described procedures to afford compound 139 (66.0 mg, 0.105 mmol, 20.96% yield) as an off-white solid. LCMS (ESI, +ve mode): Expected m / z for C36H42N5O5[M+H] 624.74, found 624.4. Example 139: Synthesis of N-(4-((4-((6-Aminohexyl)carbamoyl)phenyl)carbamoyl)-3- methylbenzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (Compound 141). Prepared using a variant of Intermediate A according to above-described procedures to afford compound 141 (20.0 mg, 0.0328 mmol, 12.73% yield) as an off-white solid. LCMS (ESI, +ve mode): Expected m / z for C34H40N5O5[M+H] 598.7, found 598.4. Example 140: Synthesis of N-(4-((2-(4-Aminobutyl)-1-oxo-1,2,3,4-tetrahydropyrazino[1,2- a]indol-8-yl)carbamoyl)-3-methylbenzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (Compound 142). Prepared using a variant of Intermediate A according to above-described procedures to afford compound 142 (10.0 mg, 0.0156 mmol, 19.16% yield) as an off-white solid. LCMS (ESI, +ve mode): Expected m / z for C36H39N6O5[M+H] 635.7, found 635.4. Example 141: Synthesis of N-(4-((4-((6-Aminohexyl)carbamoyl)-2- methylphenyl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamide (Compound 143). Prepared using a variant of Intermediate C according to above- described procedures to afford compound 143 (7.0 mg, 0.0117 mmol, 16% yield) as an off-white solid. LCMS (ESI, +ve mode) expected m / z for C34H40N5O5[M+H] 598.7, found 598.3 Example 142: Synthesis of N-(4-((4-((6-Amino-4,4- dimethylhexyl)carbamoyl)phenyl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (Compound 144). Prepared using Intermediate C according to above-described procedures to afford compound 144 (23.0 mg, 0.0376 mmol, 33.43% yield) as an off-white solid. LCMS (ESI, +ve mode): Expected m / z for C35H42N5O5[M+H] 612.73, found 612.3. Example 143: Synthesis of N-(4-((4-((6-Amino-3,3-dimethylhexyl)carbamoyl) phenyl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamide (Compound 147). Prepared using Intermediate C according to above-described procedures to afford compound 147 (21.0 mg, 0.0342 mmol, 54.53% yield) as an off-white solid. LCMS (ESI, +ve mode): Expected m / z for C35H42N5O5[M+H] 612.73, found 612.3. Example 144: General procedures for aldehyde-containing compounds General Procedure A: For the protection of the aldehyde with ethane-1,2-diol To a scintillation vial charged with a stirbar was added formylbenzoate / formylnicotinate / formylpicolinate (1.0 Eq) and toluene (2.0 mL). A solution of PTSA / Bi(OTf)3(0.02-0.1 Eq), ethane- 1,2-diol(2.0-5.0 Eq) in toluene (1.0 mL) was added drop-wise. The reaction was stirred at 23-150°C for 3-24 hours. Workup / Purification A: After completion of the reaction, the reaction mixture was poured in to water and was extracted with EtOAc (3 x 50 mL). The organic layers were combined and washed with brine once (50 ml), dried over sodium sulfate, filtered, and concentrated in vacuo to provide the crude compound. The resulting crude compound was purified by normal phase flash column chromatography (0-100% EtOAc in Hexane). The pure product was collected and concentrated. Workup / Purification B: After completion of the reaction, the reaction mixture was concentrated with a steady nitrogen blow. The resulting crude product was purified by normal phase flash chromatography (0-100% EtOAc in Hexane). The pure product was collected and concentrated in vacuo. General Procedure B: For the hydrolysis of esters To a scintillation vial charged with a stirbar was added the benzoate (1.0 Eq) in THF (1.0 mL). LiOH⋅H2O (2.0 Eq) was dissolved in H2O (1.0 mL) and the solution was added drop-wise into the scintillation vial. The reaction was stirred at 23°C for 2-3 hours. The reaction mixture was quenched with 1M HCl (PH was adjusted to 4-6) and was extracted with DCM (3 x 30 mL). The organic layers were combined and washed with brine once (50 ml), dried over sodium sulfate, filtered, and concentrated in vacuo to provide the pure compound as a white / off-white solid, which was used without further purification. General Procedure C: For the coupling of aliphatic amines or with achiral carboxylic acids To a scintillation vial charged with a stirbar was added carboxylic acid (1.0 Eq), HATU (1.3-1.5 Eq), DIPEA (3.0-7.0 Eq) and DMF (0.5-2.0 mL). The mixture was left to stir at room temperature for 10- 60 minutes. To the vial was then added the amine (1.0 Eq). The reaction was stirred at 23°C for 3-24 hours. See below for workup / purification. Workup / Purification A: After completion of the reaction, the reaction mixture was poured in to ice cold water, separated solid was filtered and dried to get the pure product as white / off-white solids. Workup / Purification B: After completion of the reaction, the reaction mixture was concentrated with a steady nitrogen blow. The resulting crude product was purified by reverse phase flash chromatography (ACN in neutral H2O). The pure product was collected and concentrated in vacuo. General Procedure D: For the deprotecton of dioxolane To a scintillation vial charged with a stirbar was added the dioxolane (1.0 Eq), followed by formic acid (0.4 – 1.5 mL). The reaction was allowed to stir at 23°C for 2-24 hours. See below for workup / purification. Workup / Purification A: After completion of the reaction, the reaction mixture was poured in to water, and the product was extracted with DCM (3 x 50 mL). The organic layers were combined and washed with NaHCO3 once (30 ml), dried over sodium sulfate, filtered, and concentrated in vacuo to provide the crude compound. The crude compound was purified by prep-HPLC (ACN in H2O + 0.1% formic acid). The pure fractions were collected, suspended in water, flash frozen and lyophilized to dryness to yield product as yellow / off-white / white solids. Workup / Purification B: After completion of the reaction, the reaction mixture was concentrated with a steady nitrogen blow. The resulting crude product was purified by prep-HPLC (ACN in H2O + 0.05% trifluoroacetic acid ). The pure fractions were collected, suspended in water, flash frozen and lyophilized to dryness to yield product as yellow / off-white / white solids. Example 145: Synthesis of N-cyclopropyl-N-(4-((2-(4-formylbenzoyl)-1,2,3,4- tetrahydroisoquinolin-6-yl) carbamoyl) benzyl)-3-oxo-3,4-dihydro-2H-benzo[b] [1,4] oxazine- 7-carboxamide (Compound 167). 4-(1,3-dioxolan-2-yl)benzoic acid was prepared according to General Procedure A / Workup B using (methyl 4-formylbenzoate) (100.0 mg, 1.0 Eq, 609.2 µmol), ethane-1,2-diol (189.1 mg, 170.0 µL, 5.0 Eq, 3.046 mmol), 4-methylbenzenesulfonic acid (11.7 mg, 90% Wt, 0.1 Eq, 60.92 µmol), and Toluene (3.0 mL). The product was purified by normal phase chromatography (0-100% EtOAc in Hexane) to give methyl 4-(1,3-dioxolan-2-yl)benzoate (94.3 mg, 453 μmol, 74.3 %) as a clear oil. The dioxolane protected ester is used right away. Prepared according to General Procedure B using 4-(1,3-dioxolan- 2-yl)benzoate (94.3 mg, 453 μmol, 74.3 %), lithium hydroxide (54.2 mg, 5 Eq, 2.26 mmol), THF (1 mL), and H2O (1 mL). Following General Procedure B the product was worked up to provide 4-(1,3- dioxolan-2-yl)benzoic acid (76.7 mg, 395 μmol, 64.8 % over 2 steps) as an off-white solid. LCMS (ESI, +ve mode): Expected m / z for [C10H10O4+] [M+H] 195.1, found 195.2. Next, the final compound as prepared according to General Procedure C / Workup A using 4-(1,3- dioxolan-2-yl) benzoic acid (0.05 g, 0.25 mmol, 1.0 Eq), DMF (0.5 mL), HATU (0.14 g, 0.38 mmol, 1.5 Eq), N-ethyl-N-isopropylpropan-2-amine (0.100 g, 0.77 mmol, 3.0 Eq), and N-cyclopropyl-3-oxo- N-(4-((1,2,3,4-tetrahydroisoquinolin-6-yl) carbamoyl) benzyl)-3,4-dihydro-2H-benzo[b] [1,4] oxazine-7-carboxamide (0.127 g, 0.25 mmol, 1.0 Eq). The reaction mixture was stirred at 23°C for 3 hours. Using General Procedure C / Workup A, N-(4-((2-(4-(1,3-dioxolan-2-yl) benzoyl)-1,2,3,4- tetrahydroisoquinolin-6-yl) carbamoyl) benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b] [1,4] oxazine-7-carboxamide (0.05 g, 29%) was obtained as an off-white solid. The intermediate is used right away. Following General Procedure D / Workup A, N-(4-((2-(4-(1,3-dioxolan-2-yl) benzoyl)- 1,2,3,4-tetrahydroisoquinolin-6-yl) carbamoyl) benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b] [1,4] oxazine-7-carboxamide (0.05 g, 1.0 Eq) was dissolved in formic acid (0.5 mL) and allowed to stir at 23°C for 8 hours. The product was purified by prep-HPLC (5-100% ACN in H2O + 0.1% formic acid) to give N-cyclopropyl-N-(4-((2-(4-formylbenzoyl)-1,2,3,4-tetrahydroisoquinolin- 6-yl) carbamoyl) benzyl)-3-oxo-3,4-dihydro-2H-benzo[b] [1,4] oxazine-7-carboxamide (UNC10415667) (17 mg, 27.06 μmol, 10.7% over 2 steps) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.63 (s, 1H), 10.09 (s, 1H), 9.98 (s, 1H), 7.99 (d, J=7.6 Hz, 2H), 7.94 (d, J=8.0 Hz, 2H), 7.65 (d, J= 7.6 Hz, 3H), 7.57 (d, J= 7.6 Hz, 1H),7.43 (d, J=8.0 Hz, 2H), 7.15 (d, J= 8.0 Hz, 2H), 7.10 (s, 1H), 6.94 (d, J= 8 Hz, 1H), 4.71 (s, 2H), 4.65 (s, 2H), 4.59 (s, 2H), 3.68 (s, 2H), 2.79 (s 2H), 2.78 (t, J= 4.0 Hz, 1H), 1.27 (d, J= 12.8 Hz, 2H), 0.57 (d, J= 6.8 Hz, 2H). LCMS (ESI, +ve mode): Expected m / z for [C37H32N4O6+] [M+H] 629.2, found 629.2. N-cyclopropyl-N-(4-((2-(4-formyl-3-methylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-6- yl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (Compound 169) was prepared analogous to the above procedure to afford compound 169 (3.97 mg, 6.18 μmol, 5.11% over 2 steps) as an off-white solid.1H NMR (500 MHz, MeOD) δ 10.31 (s, 1H), 7.93 (d, J = 7.7 Hz, 3H), 7.75 – 7.33 (m, 6H), 7.26 (t, J = 8.7 Hz, 1H), 7.22 – 7.14 (m, 2H), 6.96 (d, J = 8.1 Hz, 1H), 4.82 (s, 2H), 4.62 (s, 2H), 4.57 (d, J = 10.3 Hz, 2H), 3.78 (d, 2H), 2.95 (d, 2H), 2.82 (s, 1H), 2.72 (d, J = 6.3 Hz, 2H), 2.43 (s, 1H), 0.72 – 0.47 (m, 4H). LCMS (ESI, +ve mode): Expected m / z for [C38H34N4O6+] [M+H] 643.2, found 643.3. N-cyclopropyl-N-(4-((2-(4-formyl-2-methylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-6- yl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (Compound 172) was prepared analogous to the above procedure to afford compound 172 (15.45 mg, 24.04 μmol, 29.8% over 2 steps) as a white solid.1H NMR (500 MHz, MeOD) δ 10.01 (s, 1H), 7.93 (dd, J = 8.2, 2.7 Hz, 2H), 7.89 – 7.82 (m, 2H), 7.60 – 7.39 (m, 5H), 7.29 – 7.13 (m, 3H), 6.99 – 6.90 (m, 1H), 5.03 (d, J = 17.1 Hz, 1H), 4.83 (s, 2H), 4.62 (s, 2H), 4.38 (d, 1H), 4.04 (d, 1H), 3.51 (d, J = 3.6 Hz, 1H), 3.03 (d, J = 6.8 Hz, 1H), 2.82 (s, 2H), 2.40 (s, 1H), 2.34 – 2.19 (m, 2H), 0.77 – 0.38 (m, 4H). LCMS (ESI, +ve mode): Expected m / z for [C38H34N4O6+] [M+H] 643.2, found 643.3. N-cyclopropyl-N-(4-((2-(3-formylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-6-yl) carbamoyl) benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (Compound 164) was prepared analogous to the above procedure to afford compound 171 (20.0 mg, 31.84 μmol, 4.20% over 2 steps) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H), 10.08 (s, 1H), 9.98 (s, 1H), 8.01 (d, J=1.2 Hz, 1H), 7.99-7.93 (m, 3H), 7.78 (d, J=7.6 Hz, 1H), 7.70 (t, J= 7.2 Hz, 1H), 7.64 (s, 1H), 7.56 (d, J= 8.0 Hz, 1H),7.44 (d, J=8.0 Hz, 2H), 7.17-7.10 (m, 3H), 6.95 (d, J= 8.0 Hz, 1H), 4.71 (s, 2H), 4.68 (s, 2H), 4.59 (s, 2H), 3.71 (s, 2H), 2.89 (t, J= 5.6 Hz, 2H), 2.79-2.76 (m, 1H), 0.58-0.54 (m, 2H), 0.52 (d, J= 2.8 Hz, 2H). LCMS (ESI, +ve mode): Expected m / z for [C37H32N4O6+] [M+H] 629.2, found 629.0 N-cyclopropyl-N-(4-((2-(4-formyl-3-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-6- yl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (Compound 170) was prepared analogous to the above procedure to afford compound 168 (16.99 mg, 25.79 μmol, 12.81% over 2 steps) as a white solid.1H NMR (500 MHz, MeOD) δ 10.45 (s, 1H), 7.93 (d, J = 7.8 Hz, 2H), 7.87 (dd, J = 7.9, 2.9 Hz, 1H), 7.65 – 7.42 (m, 4H), 7.30 – 7.00 (m, 5H), 6.96 (d, J = 8.1 Hz, 1H), 4.82 (s, 2H), 4.62 (s, 2H), 4.58 (s, 1H), 3.99 (d, 3H), 3.74 (dd, 2H), 2.95 (dt, 2H), 2.82 (s, 1H), 2.03 (s, 0H), 0.73 – 0.43 (m, 4H). LCMS (ESI, +ve mode): Expected m / z for [C38H34N4O7+] [M+H] 659.2, found 659.2 N-cyclopropyl-N-(4-((2-(2-(4-formylphenyl) acetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl) carbamoyl) benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (Compound 163) was prepared analogous to the above procedure to afford the compound (10.0 mg, 15.57 μmol, 7.83% over 2 steps) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.60 (s, 1H), 9.99 (s, 1H), 9.95 (s, 1H), 7.94 (d, J=8.0 Hz, 2H), 7.84 (d, J=8.0 Hz, 2H), 7.61 (s, 1H), 7.55 (d, J= 8.0 Hz, 1H), 7.49 (d, J= 8.0 Hz, 2H),7.43 (d, J=8.0 Hz, 2H), 7.16-7.11 (m, 3H), 6.95 (d, J= 8.0 Hz, 1H), 4.71 (s, 2H), 4.65 (s, 2H), 4.59 (s, 2H), 3.94 (s, 2H), 3.74 (s 2H), 2.82-2.78 (m, 3H), 0.58 (d, J= 6.0 Hz, 2H),0.52 (s, 2H). LCMS (ESI, +ve mode): Expected m / z for [C38H34N4O6+] [M+H] 643.2, found 643.2. Example 146: Synthesis of N-cyclopropyl-N-(4-((2-(4-formyl-3-hydroxybenzoyl)-1,2,3,4- tetrahydroisoquinolin-6-yl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamide (Compound 171) Prepared according to General Procedure C / Workup A using 4-formyl-3-hydroxybenzoic acid (8.36 mg, 1 Eq, 50.3 μmol), HATU (24.9 mg, 1.3 Eq, 65.4 μmol), N-ethyl-N-isopropylpropan-2-amine (45.5 mg, 61.4 μL, 7 Eq, 352 μmol), DMF (1.0 mL), and N-cyclopropyl-3-oxo-N-(4-((1,2,3,4- tetrahydroisoquinolin-6-yl)carbamoyl)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (25.0 mg, 1 Eq, 50.3 μmol). The reaction mixture was stirred at 23°C for 24 hours. Using General Procedure C / Workup B, the crude product was obtained. The crude product was purified by prep- HPLC (5-100% ACN in H2O + 0.05% TFA) to give N-cyclopropyl-N-(4-((2-(4-formyl-3- hydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)carbamoyl)benzyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (UNC12151) (0.65 mg, 1.0 μmol, 2.0 %) as a white solid.1H NMR (400 MHz, MeOD) δ 7.94 (d, J = 8.0 Hz, 2H), 7.62 – 7.42 (m, 5H), 7.27 – 7.14 (m, 3H), 7.00 – 6.85 (m, 3H), 4.83 (s, 2H), 4.62 (s, 2H), 4.60 (s, 1H), 3.82 (d, 2H), 2.91 (t, 3H), 2.01 (s, 1H), 0.74 – 0.46 (m, 4H). LCMS (ESI, +ve mode): Expected m / z for [C37H32N4O7+] [M+H] 645.2, found 645.3. Example 147: Synthesis of N-(4-((2-(4-acetylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-6- yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamide (Compound 168) To a scintillation vial was added 4-acetylbenzoic acid (12.9 mg, 1.3 Eq, 78.5 μmol), N-cyclopropyl- 3-oxo-N-(4-((1,2,3,4-tetrahydroisoquinolin-6-yl)carbamoyl)benzyl)-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (30.0 mg, 1 Eq, 60.4 μmol), EDC (23.2 mg, 2 Eq, 121 μmol), DMAP (14.8 mg, 2 Eq, 121 μmol), and DMF (1.0 mL). The reaction mixture was stirred at 23°C for 24 hours. The next compound was prepared using General Procedure C / Workup B, the crude product was obtained. The crude product was purified by prep-HPLC (5-100% ACN in H2O + 0.05% TFA) to give N-(4-((2-(4-acetylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)carbamoyl)benzyl)-N- cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (22.85 mg, 35.55 μmol, 58.8 %) as a white solid.1H NMR (500 MHz, DMSO) δ 10.87 (s, 1H), 10.19 (s, 0H), 8.04 (d, 2H), 7.94 (d, J = 7.7 Hz, 2H), 7.66 (s, 1H), 7.63 – 7.41 (m, 5H), 7.25 (d, J = 8.4 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.14 (s, 1H), 6.92 (d, J = 8.0 Hz, 1H), 4.74 (d, 3H), 4.61 (s, 2H), 4.49 (s, 1H), 3.87 (s, 1H), 3.52 (s, 1H), 2.96 – 2.73 (m, 3H), 2.62 (s, 3H), 0.60 – 0.40 (m, 4H). LCMS (ESI, +ve mode): Expected m / z for [C38H34N4O6+] [M+H] 643.2, found 643.3. Example 148: Synthesis of N-cyclopropyl-N-(4-((2-(2-(3-formylphenyl) acetyl)-1,2,3,4- tetrahydroisoquinolin-6-yl) carbamoyl) benzyl)-3-oxo-3,4-dihydro-2H-benzo[b] [1,4] oxazine-7- carboxamide (Compound 165) Prepared according to General Procedure C / Workup A using 2-(3-formylphenyl) acetic acid (0.05 g, 0.30 mmol, 1.0 Eq), DMF (1.0 mL) at 23°C, HATU (0.17 g, 0.45 mmol, 1.5 Eq), N-ethyl-N- isopropylpropan-2-amine (0.15 mL, 0.91 mmol, 3.0 Eq), and N-cyclopropyl-3-oxo-N-(4-((1,2,3,4- tetrahydroisoquinolin-6-yl) carbamoyl) benzyl)-3,4-dihydro-2H-benzo[b] [1,4] oxazine-7- carboxamide (0.060 g, 0.12 mmol, 0.4 Eq). The reaction mixture was stirred at 23°C for 4 hours. The reaction was poured in to water and was extracted with 10 % MeOH in DCM (3 x 50 mL). The organic layers were combined and washed with brine once (30 ml), dried over sodium sulfate, filtered, and concentrated to get the crude compound. The crude product was purified by prep-HPLC (5-100% ACN in H2O + 0.1% formic acid) to give N-cyclopropyl-N-(4-((2-(2-(3-formylphenyl) acetyl)- 1,2,3,4-tetrahydroisoquinolin-6-yl) carbamoyl) benzyl)-3-oxo-3,4-dihydro-2H-benzo[b] [1,4] oxazine-7-carboxamide (8.0 mg, 12.46 μmol, 5.0%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.62 (d, J= 5.2 Hz, 1H), 10.0 (s, 1H), 9.95 (s, 1H), 7.94 (d, J=8.4 Hz, 2H), 7.78 (d, J=8.4 Hz, 2H), 7.61-7.53 (m, 4H), 7.43 (d, J= 8.4 Hz, 2H), 7.17-7.10 (m, 3H), 6.96-6.94 (m, 1H), 4.71 (s, 2H), 4.65 (s, 2H), 4.59 (s, 2H), 3.94 (s, 2H), 3.76 (s 2H), 2.82-2.76 (m, 3H), 0.58 (d, J= 4.4 Hz, 2H),0.52 (s, 2H). LCMS (ESI, +ve mode): Expected m / z for [C38H34N4O6+] [M+H] 643.2, found 643.0 Example 149: Synthesis of N-cyclopropyl-N-(4-((2-(5-formylfuran-2-carbonyl)-1,2,3,4- tetrahydroisoquinolin-6-yl) carbamoyl) benzyl)-3-oxo-3,4-dihydro-2H-benzo[b] [1,4] oxazine-7- carboxamide (Compound 166) Prepared according to General Procedure C / Workup A using 5-formylfuran-2-carboxylic acid (0.021 g, 0.15 mmol, 1.5 Eq), DMF (1.0 mL), HATU (0.057 g, 0.15 mmol, 1.5 Eq), N-ethyl-N- isopropylpropan-2-amine (0.051 g, 0.30 mmol, 3.0 Eq), and N-cyclopropyl-3-oxo-N-(4-((1,2,3,4- tetrahydroisoquinolin-6-yl) carbamoyl) benzyl)-3,4-dihydro-2H-benzo[b] [1,4] oxazine-7- carboxamide (0.060 g, 0.12 mmol, 0.4 Eq). The reaction mixture was stirred at 23°C for 1 hour. The reaction was poured in to water to give the solid as the crude product. The crude product was purified by prep-HPLC (5-100% ACN in H2O + 0.1% formic acid) to give N-cyclopropyl-N-(4-((2-(5- formylfuran-2-carbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl) carbamoyl) benzyl)-3-oxo-3,4-dihydro- 2H-benzo[b] [1,4] oxazine-7-carboxamide (15.0 mg, 24.26 μmol, 24.0%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.62 (s, 1H), 9.99 (s, 1H), 9.74 (s, 1H), 7.94 (d, J=8.0 Hz, 2H), 7.66 (s, 1H), 7.60-7.56 (m, 2H), 7.44 (d, J= 8.4 Hz, 2H), 7.20-7.14 (m, 3H), 7.11 (s, 1H), 6.95 (d, J=8.0 Hz, 1H), 4.79 (s, 2H), 4.65 (s, 2H), 4.71 (s, 2H), 4.59 (s, 2H), 3.89 (t, J= 5.6 Hz, 2H), 2.95 (t, J= 5.6 Hz, 2H), 2.78 (d, J= 3.2 Hz, 1H), 0.58 (d, J= 6.0 Hz, 2H), 0.52 (s, 2H). LCMS (ESI, +ve mode): Expected m / z for [C35H30N4O7+] [M+H] 619.2, found 619.0.

Claims

1. THAT WHICH IS CLAIMED IS:

1. A compound of Formula (I):Formula (I) or any pharmaceutically acceptable salt and / or stereoisomer thereof, wherein: Q is selected from the group consisting ofR1is –cyclopropyl or -isopropyl; R1a is hydrogen or (C1-C6) alkyl; R2aand R2b, in each instance, are independently selected from hydrogen, (C1-C6) alkyl, (C1- C6) haloalkyl, (C1-C6) alkoxy, halogen, −CN, −NH2, and −OH; A is selected from the group consisting of:wherein R3a,R3bR3c, R3d, R3e, R3fand R3gare each independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, halogen, −CN, −NH2, and – OH;orwherein X is selected from the group consisting of -CH2-, -O-, -S-, -S(=O)-, - S(=O)2NH-, -CO(=O)-, -NH-, -C=C-, -C(=O)-, -C(=O)O-, -C(=O)NH-, -C(=O)N(CH3)-, - C(=O)C(CH3)2-, -C(=O)NH-, -[(C1-C6) cycloalkyl]N[(C1-C6) alkyl]C(=O)-, and -NHC(=O)-; B is -C- or -N-; W is a bond, -C(=O)- or -N(CH3)C(=O)-; Z1and Z2are independently selected from -H, -OH, -NH2, -CN, -CF3, CD3, halogen, (C1- C6)alkyl, -O(C1-C6)alkyl, -OC(=O)(C1-C6)alkyl, -C(=O)(C1-C6)alkyl, -C(=O)O(C1-C6)alkyl, C(=O)NH(C1-C6)alkyl, -NHC(=O)(C1-C6)alkyl and (C2-C6)alkynyl;wherein G is -C(=O)-, - CH2N[(C1-C6) alkyl)]C(=O)- or -C(=O)NH-; Y is selected from the group consisting of -N[(C1-C6) alkyl)]C(=O)-, -N[(C1-C6) cycloalkyl)]C(=O)-, -N[(C1-C6) alkyl)]C(=O)O-, -CH2N[(C1-C6) alkyl)]C(=O)-, -N[(C1-C6) cycloalkyl]C(=O)-, -N[C(=O)(C1-C6) alkyl)]-, -CD2-, -NHC(=O)-, -CH=CH-, -N[C(=O) (C1-C6) alkyl]-H is selec N[(C1-C6) alkyl]-,n, m and w are integers independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; and p and q are integers independently selected from 0, 1, 2, 3 and 4.

2. The compound of claim 1, wherein R1ais hydrogen.

3. The compound of claim 1 or claim 2, wherein R1is cyclopropyl.

4. The compound of any one of the preceding claims, wherein Q is selected from the group consisting of5. The compound of any one of the preceding claims, wherein the compound is a compound of Formula (II):Formula (II) or a pharmaceutically acceptable salt thereof and / or stereoisomer thereof, wherein: R2aand R2bare independently selected from hydrogen, (C1-C6) alkyl, (C1-C6) alkoxy, or halogen; A is selected from the group consisting of; wherein R3a,R3bR3c, R3d, R3e, R3fand R3gare each independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, and halogen; orwherein X is selected from the group consisting of -CH2-, -O-, -S-, -S(=O)-, - S(=O)2NH-, -CO(=O)-, -NH-, -C=C-, -C(=O)-, -C(=O)O-, -C(=O)NH-, -C(=O)N(CH3)-, - C(=O)C(CH3)2-, -C(=O)CH2C(CH3)2-, -C(=O)NH-, -[(C1-C6) cycloalkyl]N[(C1-C6) alkyl]C(=O)-, and -NHC(=O)-; B is -C- or -N-; W is a bond, -C(=O)- or -N(CH3)C(=O)-;Z1and Z2are independently selected from -H, -OH, -NH2, -CN, -CF3, CD3, halogen, (C1- C6)alkyl, -O(C1-C6)alkyl, -OC(=O)(C1-C6)alkyl, -C(=O)(C1-C6)alkyl, -C(=O)O(C1-C6)alkyl, C(=O)NH(C1-C6)alkyl, -NHC(=O)(C1-C6)alkyl and (C2-C6)alkynyl;wherein G is -C(=O)- or - C(=O)NH-; Y is selected from the group consisting of -N[(C1-C6) alkyl)]C(=O)-, -N[(C1-C6) cycloalkyl]C(=O)-, -NHC(=O)-, and -N[C(=O) (C1-C6) alkyl]-; H is selected from the group consisting of -C(CH3)2-, -CH(CH3)-, -S(=O)2-, -S(=O)-, -S-, - N[(C1-C6) alkyl]-,n, m and w are integers independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; and p and q are integers independently selected from 0, 1, 2, 3 and 4.

6. The compound of claim 5, wherein A is selected from the group consisting of.

7. The compound of claim 6, wherein X in L1is selected from the group consisting of -CH2-,- C(=O)CH2C(CH3)2- or -C(=O)-.

8. The compound of claim 6 or 7, wherein A is; X is -CH2-, and n is an integer selected from 3, 4, 5, and 6.

9. The compound of claim 7, wherein A is selected from the group consisting of; X is -C(=O)-; and n is an integer selected from 3, 4, 5, and 6.

10. The compound of claim 9, wherein A isis -H, X is -C(=O) and n is an integer selected from 4, 5 and 6.

11. The compound of claim 6, wherein.

12. The compound of claim 11, wherein G is -C(=O)-; H is -CH(CH3)- or -C(CH3)2-; and p+q = 4.

13. The compound of claim 11, wherein G is -C(=O)-, H is selected from the group consisting of - S(=O)2-, -S(=O)-, -S-, -N(C1-C6 alkyl)-,14. The compound of claim 12 or 13, wherein p is 2 and q is 2.

15. The compound of claim 12 or 13, wherein p is 1 and q is 3.

16. The compound of claim 5, wherein A isand X is -CH2.

17. The compound of claim 16, wherein n is an integer selected from 2, 3 and 4.

18. The compound of claim 5, wherein A is.

19. The compound of claim 18, wherein G is -C(=O)NH-; H is -O- or -OCH2CH2O-; p is 1 or 2; and q is 0 or 2.

20. The compound of claim 5, wherein A is.

21. The compound of claim 20, wherein Y is selected from the group consisting of -N(CH3)C(=O)-, - N[CH(CH3)2]C(=O)-, -N[C(CH3)3]C(=O)-, -N[cyclopropyl]C(=O)-, and -N[C(=O)CH3]-; and w is 4, 5 or 6.

22. The compound of claim 1, wherein, wherein B is -C- or -N-; W is a bond, -C(=O)- or -N(CH3)C(=O)-; and Z1and Z2are independently selected from -H, -OH, (C1-C6)alkyl, and (C2-C6)alkynyl.

23. The compound of claim 22, wherein W is -C(=O), B is -C-; and Z1is -H.

24. The compound of claim 23, wherein Z2is -H or -CH3.

25. The compound of claim 5, wherein A is.

26. The compound of claim 5, wherein A is.

27. The compound of claim 26, wherein X is -O- or -C(=O)NH-.

28. The compound of claim 26, wherein n is 4, 5, 6 or 7.

29. A pharmaceutical composition comprising a compound according to any one of the preceding claims or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carrier(s).

30. The pharmaceutical composition of claim 29, wherein the compound is a prodrug.

31. A method for treating a disease or condition that is treatable by inhibition of nuclear SET- domain-containing protein (NDS2), the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of the preceding claims or a pharmaceutical composition of claim 29.

32. The method of claim 31, wherein the disease is cancer.

33. The method of claim 32, wherein the cancer is selected from breast cancer, cervical cancer, skin cancer, ovarian cancer, gastric cancer, prostate cancer, pancreatic cancer, lung cancer, hepatocellular carcinoma, head and neck cancer, peripheral nerve sheath tumor, osteosarcoma, multiple myeloma, neuroblastoma, leukemia, non-Hodgkin’s lymphoma, and pulmonary arterial hypertension.

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