WO2015081280A1

WO2015081280A1 - Bromodomain ligands capable of dimerizing in an aqueous solution

Info

Publication number: WO2015081280A1
Application number: PCT/US2014/067741
Authority: WO
Inventors: Lee Daniel Arnold; Kenneth W. Foreman; Meizhong Jin; Jutta Wanner; Douglas S. Werner
Original assignee: Coferon, Inc.
Priority date: 2013-11-26
Filing date: 2014-11-26
Publication date: 2015-06-04

Abstract

Described herein are monomers capable of forming a biologically useful multimer when in contact with one, two, three or more other monomers in an aqueous media. In one aspect, such monomers may be capable of binding to another monomer in an aqueous media (e.g. in vivo) to form a multimer (e.g. a dimer). Contemplated monomers may include a ligand moiety, a linker element, and a connector element that joins the ligand moiety and the linker element. In an aqueous media, such contemplated monomers may join together via each linker element and may thus be capable of modulating one or more biomolecules substantially simultaneously, e.g., modulate two or more binding domains on a protein or on different proteins.

Description

BROMODOMAIN LIGANDS CAPABLE OF DIMERIZING IN AN AQUEOUS SOLUTION, AND METHODS OF USING SAME

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to and the benefit of U.S. Provisional Patent Application No. 61/909,240, filed on November 26, 2013, and entitled“Bromodomain Ligands Capable Of Dimerizing In An Aqueous Solution, And Methods Of Using Same” the entirety of which is incorporated by reference herein. BACKGROUND

[0002] Current drug design and drug therapies have not addressed the urgent need for therapies that interact with extended areas or multiple domains of biomolecules such as proteins. For example, few therapies exist that can modulate protein-protein interactions, e.g., by interacting, simultaneously, with two domains on a single protein or with both a domain on one protein and a domain on another protein. There is also an urgent need for such therapies that modulate fusion proteins, such as those that occur in cancer.

[0003] Signaling pathways are used by cells to generate biological responses to external or internal stimuli. A few thousand gene products control both ontogeny/development of higher organisms and sophisticated behavior by their many different cell types. These gene products can work in different combinations to achieve their goals and often do so through protein-protein interactions. Such proteins possess modular protein domains that recognize, bind, and/or modify certain motifs. For example, some proteins include tandem or repeating domains.

[0004] The BET family of bromodomain containing proteins bind to acetylated lysine residues in histones and other proteins to influence transcription, etc. Proteins in the BET family are typically characterisized by having tandem bromodomains. Exemplary protein targets having tandem bromodomains include BRD4, a member of the BET family. BRD4 is also a proto-oncogene that can be mutated via chromosomal translocation in a rare form of squamous cell carcinoma. Further, proteins having tandem bromodomains such as BRD4 may be suitable as a drug target for other indications such as acute myeloid leukemia.

Bromodomains are typically small domains having e.g., about 110 amino acids. Bromodomain modulators may be useful for various diseases or conditions, including those relating to systemic or tissue inflammation, inflammatory response to infection, malignant cell activation and proliferation, lipid metabolism, cell differentiation, and prevention and treatment of viral infections.

[0005] Current drug design and drug therapy approaches typically focus on modulating one protein domain with limited selectivity and do not address the urgent need to find drugs that are capable of modulating such tandem domains substantially simultaneously in order to further improve on specificity and potency. Although antibodies and other biological therapeutic agents may have sufficient specificity to distinguish among closely related protein surfaces, factors such as their high molecular weight prevent oral administration and cellular uptake of the antibodies. Conversely, orally active pharmaceuticals are generally too small to effectively disrupt protein-protein surface interactions, which can be much larger than the orally active pharmaceuticals. Further, previous attempts to link multiple, e.g., two, pharmacophores that each interact with, e.g., different protein domains, have focused on large covalently linked compounds assembled in organic solvents. These assemblies typically have a molecular weight too large for oral administration or effective cellular and tissue permeation. SUMMARY

[0006] Described herein, for example, are monomers capable of forming a biologically useful multimer when in contact with one, two, three or more other monomers in an aqueous media. In one aspect, such monomers may be capable of binding to another monomer in an aqueous media (e.g. in vivo) to form a multimer, (e.g., a dimer). Contemplated monomers may include a ligand moiety (e.g., a pharmacophore for the target biomolecule), a linker element, and a connector element that joins the ligand moiety and the linker element. In an aqueous media, such contemplated monomers may join together via each linker element and may thus be capable of modulating one or more biomolecules substantially simultaneously, e.g., modulate two or more binding domains on a protein or on different proteins.

[0007] In one aspect, a first monomer capable of forming a biologically useful multimer capable of modulating a protein having a first bromodomain when in contact with a second monomer in an aqueous media is provided. Such a first monomer may be represented by the formula: X¹-Y¹-Z¹ (Formula I) and pharmaceutically acceptable salts, stereoisomers, metabolites, and hydrates thereof, wherein

X¹ is a first ligand moiety capable of modulating the first bromodomain on said protein;

Y¹ is absent or is a connector moiety covalently bound to X¹ and Z¹; Z¹ is a first linker capable of binding to the second monomer; and the second monomer is represented by the formula:

X²-Y²-Z² (Formula II) and pharmaceutically acceptable salts, stereoisomers, metabolites, and hydrates thereof, wherein

X² is a second ligand moiety capable of modulating a second domain on said protein;

Y² is absent or is a connector moiety covalently bound to X² and Z²; and Z² is a second linker capable of binding to the first monomer through Z¹.

[0008] In another aspect, a therapeutic multimer compound formed from the multimerization in an aqueous media of a first monomer and a second monomer is provided. Such a first monomer may be represented by:

X¹-Y¹-Z¹ (Formula I)

and the second monomer represented by

X²-Y²-Z² (Formula II),

wherein

X¹ is a first ligand moiety capable of modulating a first bromodomain;

Y¹ is absent or is a connector moiety covalently bound to X¹ and Z¹; Z¹ is a first linker capable of binding to Z² to form the multimer;

X² is a second ligand moiety capable of modulating a second protein domain; Y² is absent or is a connector moiety covalently bound to X² and Z²; and Z² is a boronic acid or oxaborale moiety capable of binding with the Z¹ moiety of Formula I to form the multimer; and

pharmaceutically acceptable salts, stereoisomers, metabolites and hydrates thereof.

[0009] In yet another aspect, a first monomer is provided, wherein the first monomer is represented by the formula X³-Y³-Z³ (Formula III) and pharmaceutically acceptable salts, stereoisomers, metabolites and hydrates thereof, wherein

X³ is a first ligand moiety capable of modulating a bromodomain; Y³ is absent or is a connector moiety covalently bound to X³ and Z³; and Z³ is a linker capable of forming a therapeutic multimer with another monomer or other monomers of Formula III, wherein Z³ is the same for the first monomer and other monomers of the multimer.

[0010] In still another aspect, a method of treating a disease associated with a protein having tandem bromodomains in a patient in need thereof is provided. Such a disclosed method can include administering to said patient a first monomer represented by:

X¹-Y¹-Z¹ (Formula I) and pharmaceutically acceptable salts, stereoisomers, metabolites and hydrates thereof, wherein X¹ is a first ligand moiety capable of modulating a first bromodomain; and administering to said patient a second monomer represented by: X²-Y²-Z² (Formula II), wherein X² is a second ligand moiety capable of modulating a second bromodomain, wherein upon administration, said first monomer and said second monomer forms a multimer in vivo that binds to the first and the second bromodomain. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] FIG. 1 shows a screenshot of a protein X-ray crystal structure in which the structures of I-BET762 and an isoxazole pharmacophore are overlaid, according to an embodiment.

[0012] FIG. 2 shows a non-limiting set of pharmacophores (i.e., ligands) with preferred attachment points for connecting the pharmacophores to connecting moieties indicated by arrows, according to an embodiment. DETAILED DESCRIPTION

[0013] Described herein, for example, are monomers capable of forming a biologically useful multimer when in contact with one, two, three or more other monomers in an aqueous media. In one aspect, such monomers may be capable of binding to another monomer in an aqueous media (e.g., in vivo) to form a multimer, (e.g., a dimer). Contemplated monomers may include a ligand moiety (e.g., a pharmacophore moiety), a linker element, and a connector element that joins the ligand moiety and the linker element. In an aqueous media, such contemplated monomers may join together via each linker element and may thus be capable of modulating one or more biomolecules substantially simultaneously, e.g., modulate two or more binding domains on a protein or on different proteins.

[0014] For example, contemplated monomers may be separate or separatable in a solid or in an aqueous media under one set of conditions, and when placed in an aqueous media having one or more biomolecules (e.g., under a different set of conditions) can 1) form a multimer with another monomer through the linker on each monomer; and either: 2a) bind to the biomolecule in two or more locations (e.g., protein domains) through each ligand moiety of the respective monomer or 2b) bind to two or more biomolecules through each ligand moiety of the respective monomer. In an exemplary embodiment, disclosed monomers may interact with another appropriate monomer (i.e., a monomeric pair) in an aqueous media (e.g., in vivo) to form a multimer (e.g., a dimer) that can bind to two separate target biomolecule domains (e.g., protein domains). In one embodiment, the two separate target domains can be tandem domains on the same target, for example, tandem BET bromodomains.

[0015] The ligand moiety of a contemplated monomer, in some cases, may be a pharmacophore or a ligand moiety that is, e.g., capable of binding to and/or modulating a biomolecule, such as, for example, a protein, e.g, a specific protein domain, a component of a biological cell, such as a ribosome (composed of proteins and nucleic acids) or an enzyme active site (e.g., a protease, such as tryptase). In some embodiments, the linker element comprises a functional group capable of forming a chemical bond with another linker element. In some embodiments, the linker moiety may also serve as a signaling entity or“reporter,” and in some instances the assembly of two or more linkers can produce a fluorescent entity or fluorophore with properties distinct from the individual linker moiety. In another aspect, a plurality of monomers, each comprising a linker element, may react to form a multimer connected by the linker elements. In some embodiments, the multimer may be formed in vivo. In some instances, the multimer may have enhanced properties relative to the monomers that form the multimer. For example, in certain embodiments, the multimer may bind to a target with greater affinity than any of the monomers that form the multimer. Also described are methods of making the compositions and methods of administering the compositions.

[0016] In some embodiments, the first ligand moiety may be capable of binding to a bromodomain. For example, in some embodiments, X¹, X² , X³ and X⁴ of Formula I, II, III or IV may each be capable of binding to a bromodomain in a protein selected from the group consisting of BRD2 D2, BRD3 D2, BRD4 D2, BRD-t D2, yBdf1 D2, yBdf2 D2, KIAA2026, yBdf1 D1, yBdf2 D1, TAF1L D1, TAF1 D1, TAF1L D2, TAF1 D2, ZMYND8, ZMYND11, ASH1L, PBRM D3, PBRM D1, PBRM D2, PBRM D4, PBRM D5, SMARCA2, SMARCA4 ySnf2, ySth, PBRM D6, yRsc1 D2, yRsc2 D2, yRsc1 D1, yRsc2 D1, yRsc4 D1, BRWD1 D1, BRWD3 D1, PHIP D1, MLL, MLL4, BRWD2, ATAD2, ATAD2B, BRD1, BRPF1, BRPF3, BRD7, BRD9, BAZ1B, BRWD1 D2, PHIP D2, BRWD3, CREBBP, EP300 BRD8 D1, BRD8 D2, yRsc4 D2, ySpt7, BAZ1A, BAZ2A, BAZ2B, SP140, SP140L, TRIM28, TRIM24, TRIM33, TRIM66, BPTF, GCN5L2, PCAF, yGcn5, BRD2 D1, BRD3 D1, BRD4 D1, BRD-t D1 and CECR2. Reference to protein and domain names used herein are derived from Zhang Q, Chakravarty S, Ghersi D, Zeng L, Plotnikov AN, et al. (2010) Biochemical Profiling of Histone Binding Selectivity of the Yeast Bromodomain Family. PLoS ONE 5(1): e8903.

doi:10.1371/journal.pone.0008903. In some embodiments, multimers contemplated herein may be capable of binding to a tandem bromodomain. For example, in some cases, a multimer may be capable of binding to a tandem bromodomain in a protein selected from the group consisting of BRD2, BRD3, BRD4 and BRD-t.

[0017] In some embodiments, the second ligand moiety may also be capable of binding to a bromodomain. In certain embodiments, the second ligand moiety may be capable of binding to epigenetically associated domains. Non-limiting examples of epigenetically associated domains include HATs (acetyl transferases), bromodomains (acetyl readers), HDACs (deacetylases) , Methyltransferases (PRMTs , KMTs, DNMTs), Methyl readers (Chromo, Tudor, MBT, PHD, PWWP, WD40), Methyl erasers (K-specific demethylases, JmJC, MethylCytosine hydroxylase), kinases, phosphate readers (14-3-3, WD40, BRCT), phosphatases, Citruline writers (Protein arginine deiminase), SANT/MYB domain, BAH, E3 ligases, SUMO ligases, RING domain, HECT domain, and lysine biotinases.

[0018] In yet other instances, the second ligand moiety may be capable of binding to domains such as methyl transferases, ATPases, ubiquinases, histone acetyl transferases, methyl readers (PWWP, WD40), protein adaptors (extraterminal domains, MYND), and DNA binders (zinc fingers, BBOX).

[0019] In some embodiments, a plurality of monomers may assemble to form a multimer. The multimer may be used for a variety of purposes. For example, in some instances, the multimer may be used to perturb a biological system. As described in more detail below, in some embodiments, the multimer may bind to or modulate a target biomolecule, such as a protein, nucleic acid, or polysaccharide. In certain embodiments, a contemplated multimer may be used as a pharmaceutical.

[0020] Advantageously, in some embodiments, a multimer may form in vivo upon administration of suitable monomers to a subject. Also advantageously, the multimer may be capable of interacting with a relatively large target site as compared to the individual monomers that form the multimer. For example, a target may comprise, in some embodiments, two protein domains separated by a distance such that a multimer, but not a monomer, may be capable of binding to both domains essentially simultaneously. In some embodiments, contemplated multimers may bind to a target with greater affinity as compared to a monomer binding affinity alone.

[0021] In some embodiments, a contemplated multimer may advantageously exhibit enhanced properties relative to the monomers that form the multimer. As discussed above, a multimer may have improved binding properties as compared to the monomers alone. In some embodiments, a multimer may have improved signaling properties. For example, in some cases, the fluorescent properties of a multimer may be different as compared to a monomer. In some embodiments, the fluorescent brightness of a multimer at a particular wavelength may be significantly different (e.g., greater) than the fluorescent brightness at the same wavelength of the monomers that form the multimer. Advantageously, in some embodiments, a difference in signaling properties between the multimer and the monomers that form the multimer may be used to detect formation of the multimer. In some embodiments, detection of the formation of the multimer may be used to screen monomers, as discussed in more detail below. Also as discussed in more detail below, in some embodiments, the multimers may be used for imaging or as diagnostic agents.

[0022] It should be understood that a multimer, as used herein, may be a homomultimer (i.e., a multimer formed from two or more essentially identical monomers) or may be a heteromultimer (i.e., a multimer formed from two or more substantially different monomers). In some embodiments, a contemplated multimer may comprise 2 to about 10 monomers, for example, a multimer may be a dimer, a trimer, a tetramer, or a pentamer.

[0023] In some embodiments, a monomer may comprise a ligand moiety, a linker element, and a connector element that associates the ligand moiety with the linker element. In some embodiments, the linker element of a first monomer may combine with the linker element of a second monomer. In some cases, the linker element may comprise a functional group that can react with a functional group of another linker element to form a bond linking the monomers. In some embodiments, the linker element of a first monomer may be substantially the same as the linker element of a second monomer. In some embodiments, the linker element of a first monomer may be substantially different than the linker element of a second monomer.

[0024] In some cases, the ligand moiety may be a pharmacophore. In some

embodiments, the ligand moiety (e.g., a pharmacophore) may bind to a target molecule with a dissociation constant of less than 1 mM, in some embodiments less than 500 microM, in some embodiments less than 300 microM, in some embodiments less than 100 microM, in some embodiments less than 10 microM, in some embodiments less than 1 microM, in some embodiments less than 100 nM, in some embodiments less than 10 nM, and in some embodiments less than 1 nM.

[0025] In some embodiments, the IC₅₀ of the first monomer against a first target biomolecule and the IC₅₀ of the second monomer against a second target biomolecule may be greater than the apparent IC₅₀ of a combination of the monomers against the first target biomolecule and the second target biomolecule. The combination of monomers may be any suitable ratio. For example, the ratio of the first monomer to the second monomer may be between 10:1 to 1:10, in some embodiments between 5:1 and 1:5, and in some embodiments between 2:1 and 1:2. In some cases, the ratio of the first monomer to the second monomer may be essentially 1:1. In some instances, the ratio of the smaller of the IC₅₀ of the first monomer and the second monomer to the apparent IC₅₀ of the multimer may be at least 3.0. In other instances, the ratio of the smaller IC₅₀ of the first monomer or the second monomer to the apparent IC₅₀ of the multimer may be at least 10.0. In some embodiments, the ratio of the smaller IC₅₀ of the first monomer or the second monomer to the apparent IC₅₀ of the multimer may be at least 30.0.

[0026] For example, for disclosed monomers forming a heteromultimer, the apparent IC₅₀ resulting from an essentially equimolar combination of monomers against the first target biomolecule and the second target biomolecule may be, in some embodiments, at least about 3 to 10 fold lower, at least about 10 to 30 fold lower, at least about 30 fold lower, or at least about 40 to 50 fold lower than the lowest of the IC₅₀ of the second monomer against the second target biomolecule or the IC₅₀ of the first monomer against the first target biomolecule.

[0027] It will be appreciated that for monomers forming homodimers (or homo- oligomeric or homomultimeric, as described below), in aqueous solution, there may be an equilibrium between the monomeric and dimeric (or oligomeric) states with higher concentrations favoring greater extent of oligomer (e.g., dimer) formation. As the binding of monomers to the target biomolecule increases their proximity and effectively increases their local concentration on the target, the rate and extent of dimerization (oligomerization) is promoted when geometries are favorable. As a result, the occupancy of the target by favorable monomers may be nearly completely in the homodimeric (or oligomeric) state. In this manner the target, for example, may serve as a template for the dimerization (or oligomerization) of the monomers, significantly enhancing the extent and rate of dimerization.

[0028] While the affinity of the multimer for its target biomolecule(s) often cannot be measured directly due to the dynamic reversible equilibrium with its monomers in an aqueous or biological milieu, it may be possible to extract an apparent multimer-target dissociation constant from a series of experimental determinations. Exploring the effects of a matrix of monomer concentrations, monomer ratios, along with changes in concentration(s) in the target biomolecule(s), coupled with determinations of multimer-monomer dissociation constants, and in some cases additional binding competition, kinetic and biophysical methods, one can extract an estimate of the affinity of the multimeric assembly for its target(s). Through such approaches, one can demonstrate that in some embodiments, the affinity of the multimer for the target biomolecule(s) are less than 1 M, in some embodiments, less than 1 nM, in some embodiments, less than 1 pM, in some embodiments, less than 1 fM, and in some

embodiments, less than 1 aM, and in some embodiments, less than 1 zM.

[0029] Affinities of heterodimerizing monomers for the target biomolecule can be assessed through the testing of the respective monomers in appropriate assays for the target activity or biology because they do not typically self-associate. In contrast, the testing of homodimerizing monomers may not, in some embodiments, afford an affinity for the monomeric or dimeric state, but rather the observed effect (e.g. IC₅₀) is a result of the monomer-dimer dynamics and equilibrium, with the apparent binding affinity (or IC₅₀) being, e.g., a weighted measure of the monomer and dimeric inhibitory effects upon the target.

[0030] In some cases, the pH of the aqueous fluid in which the multimer forms may be between pH 1 and 9, in some embodiments, between pH 1 and 3, in some embodiments, between pH 3 and 5, in some embodiments, between pH 5 and 7, and in some embodiments, between pH 7 and 9. In some embodiments, the multimer may be stable in an aqueous solution having a pH between pH 1 and 9, in some embodiments between pH 1 and 3, in some embodiments between pH 3 and 5, in some embodiments between pH 5 and 7, and in some embodiments between pH 7 and 9. In some embodiments, the aqueous solution may have a physiologically acceptable pH.

[0031] In some embodiments, the ligand moiety may be capable of binding to a target and at least partially disrupting a biomolecule-biomolecule interaction (e.g., a protein-protein interaction). In some embodiments, the ligand moiety may be capable of binding to a target and at least partially disrupting a protein-nucleic acid interaction. In some cases, the ligand moiety may be capable of binding to a target and at least partially disrupting a protein-lipid interaction. In some cases, the ligand moiety may be capable of binding to a target and at least partially disrupting a protein-polysaccharide interaction. In some embodiments, the ligand moiety may be capable of at least partially stabilizing a biomolecule-biomolecule interaction. In certain embodiments, the ligand moiety may be capable of at least partially inhibiting a conformational change in a biomolecule target.

[0032] In some instances, the linker element may be capable of generating a signal. For example, in some embodiments, the linker element may be capable of fluorescing. In some cases, the linker element may have greater fluorescence when the monomer to which it is attached is part of a multimer as compared to when the monomer to which it is attached is not part of a multimer. In some embodiments, upon multimer formation, the fluorescent brightness of a linker element may increase by at least 2-fold, in some embodiments, by at least 5-fold, in some embodiments, by at least 10-fold, in some embodiments, by at least 50-fold, in some embodiments, by at least 100-fold, in some embodiments, by at least 1000-fold, and in some embodiments, by at least 10000-fold. In some embodiments, a linker element in a multimer may have a peak fluorescence that is red-shifted relative to the peak fluorescence of the linker element in a monomer. In other embodiments, a linker element may have a peak fluorescence that is blue-shifted relative to the peak fluorescence of a linker element in a monomer.

Monomers

[0033] In certain embodiments, a first monomer may be capable of forming a biologically useful multimer capable of modulating a protein having a bromodomain when in contact with a second monomer in an aqueous media. For example, a first monomer may be represented by the formula:

X¹-Y¹-Z¹ (Formula I) and pharmaceutically acceptable salts, stereoisomers, metabolites, and hydrates thereof, wherein X¹ is a first ligand moiety capable of binding to or modulating a bromodomain on said protein;

Y¹ is absent or is a connector moiety covalently bound to X¹ and Z¹;

Z¹ is a first linker capable of binding to the second monomer; and a second monomer may be represented by the formula:

X² is a second ligand moiety capable of binding to a second domain on said protein;

[0034] For example, when a first and second monomer capable of forming a multimer (e.g., dimer) when in contact in an aqueous solution each has a different linker, e.g., Z¹ and Z² are different, the monomers may be referred to as‘hetero’ monomers. Conversely, when a first and second monomer capable of forming a multimer (e.g., dimer) when in contact in an aqueous solution each has the same linker, e.g., Z¹ and Z² are the same, the monomers may be referred to as‘homo’ monomers.

[0035] In one embodiment, X¹ and X² are the same. In another embodiment, X¹ and X² are different.

[0036] In certain embodiments, the protein is independently selected from the group consisting of BRD2, BRD3, BRD4 and BRD-t. In another example, the second domain is a second bromodomain. For example, the second domain is a bromodomain within 50Å of the first bromodomain.

[0037] In another embodiment, a monomer may be represented by the formula:

X³-Y³-Z³ (Formula III) and pharmaceutically acceptable salts, stereoisomers, metabolites, and hydrates thereof, wherein

X³ is a ligand moiety capable of binding to a bromodomain;

Y³ is absent or is a connector moiety covalently bound to X³ and Z³;

Z³ is a linker capable of binding to one or more Z³ moieties from other X³-Y³-Z³ monomers to form a biologically useful multimer. [0038] In a certain embodiment, a first monomer is capable of forming a biologically useful multimer when in contact with a second monomer in an aqueous media, wherein the first monomer is represented by the formula:

X¹-Y¹-Z¹ (Formula I) and pharmaceutically acceptable salts, stereoisomers, metabolites, and hydrates thereof, wherein

X¹ is a first ligand moiety capable of binding to a bromodomain;

Y¹ is absent or is a connector moiety covalently bound to X¹ and Z¹; Z¹ is a first linker capable of binding to the second monomer (e.g., in-vivo); and the second monomer is represented by the formula:

X⁴-Y⁴-Z⁴ (Formula IV) and pharmaceutically acceptable salts, stereoisomers, metabolites, and hydrates thereof, wherein

X⁴ is a second ligand moiety capable of binding to a protein domain, wherein the protein domain is e.g., within about 10, 20, 30, 40, 50, 60, 70, 80 or more ǖ , e.g. within about 50 Å of the bromodomain (e.g the protein domain may be another bromodomain, or may be a different type of domain such as the NUT portion of a BRD- NUT fusion protein);

Y⁴ is absent or is a connector moiety covalently bound to X⁴ and Z⁴; and Z⁴ is a second linker capable of binding to the first monomer through Z¹.

[0039] In another certain embodiment, a first monomer may be capable of forming a biologically useful multimer when in contact with one, two, three or more monomers (e.g. a first silyl monomer and a second silyl monomer). For example, a first and second monomer may be represented by the formula:

X³-Y³-Z³ (Formula III) and pharmaceutically acceptable salts, stereoisomers, metabolites and hydrates thereof, wherein X³ is a first ligand moiety capable of binding to and modulating a first target biomolecule (e.g., bromodomain); Y³ is absent or is a connector moiety covalently bound to X³ and Z³; Z³ is linker capable of forming a therapeutic multimer (e.g., dimer) with another monomer or other monomers of Formula III, wherein Z³ is the same for the first and second monomer, as noted below. For example, when a first and second monomer capable of forming a multimer (e.g., dimer) when in contact in an aqueous solution and each monomer have the same linker, e.g., Z³, the monomers may be referred to as‘homo’ monomers.

[0040] In certain embodiments, the second bromodomain may be within 20Å of the first bromodomain. For example, in some embodiments, the maximum distance between the first ligand moiety (e.g., first bromodomain) and the second ligand moiety (e.g., second bromodomain) in the biologically useful multimer is less than about 20 Å, in some

embodiments less than 15 Å, and in some embodiments less than 10 Å.

[0041] In certain embodiments, the connector moiety may have a length of less than about 15 Å. In certain other embodiments, the connector moiety may have a length of less than about 10 Å. In still other embodiments, the connector moiety may have a length of less than about 5 Å.

[0042] In some embodiments, a monomer may be selected from the group consisting of:

,

,

acceptable salts thereof. [0043] In some embodiments, a monomer may be selected from the group consisting

and

, wherein n is 0, 1, or 2, and

pharmaceutically acceptable salts thereof.

[0044] In some embodiments, a monomer may be selected from the group consisting of:

,

and pharmaceutically acceptable salts thereof.

[0045] In some embodiments, a monomer may be selected from the group consisting of:

pharmaceutically acceptable salts thereof.

[0046] In some embodiments, a monomer may be selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

[0047] In some embodiments, a monomer may be selected from the group consisting

pharmaceutically acceptable salts thereof.

[0048] In some embodiments, a monomer may be selected from the group consisting of:

and pharmaceutically acceptable salts thereof. A) Linkers

[0049] The linker moieties Z¹, Z², Z³ and Z⁴ of Formulas I, II, III and IV may, in some embodiments, be the same or different. For example, linker moieties are independently contemplated herein.

[0050] In a certain embodiment, the first monomer is represented by the formula

[0051] X¹-Y¹-Z¹, wherein Z¹ is a first linker that, for example, may form a dimer with a second monomer, e.g., X²-Y²-Z² or X⁴-Y⁴-Z⁴, wherein, for example, Z¹ may be a diol and Z² or Z⁴ may independently be a boronic acid or oxaborole moiety. In one embodiment, Z¹ is a first linker selected from the group consisting of

wherein A₁ is (a) absent; or (b) selected from the group consisting of acyl, substituted or unsubstituted aliphatic, or substituted or unsubstituted heteroaliphatic;

A₂, independently for each occurrence, is (a) absent; or (b) selected from the group consisting of–N–, acyl, substituted or unsubstituted aliphatic, or substituted or unsubstituted heteroaliphatic, provided that at least one of A₁ and A₂ is present; or

A₁ and A₂, together with the atoms to which they are attached, form a substituted or unsubstituted 4-8 membered cycloalkyl or heterocyclic ring;

A₃ is selected from the group consisting of -NHR’, -SH, or -OH;

W is CR’ or N;

R’ is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted phenyl or naphthyl, substituted or unsubstituted heteroaryl, -NH₂, -NO₂, -SH, or -OH;

m is 1-6;

represents a single or double bond; and

R₁ is (a) absent; or (b) selected from the group consisting of hydrogen, halogen, substituted or unsubstituted aliphatic, or substituted or unsubstituted heteroaliphatic, substituted or unsubstituted phenyl or naphthyl, substituted or unsubstituted heteroaryl, -NH₂, -NO₂, -SH, or -OH;

Q₁ is (a) absent; or (b) selected from the group consisting of substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic; or

R₁ and Q₁ together with the atoms to which they are attached form a substituted or unsubstituted 4-8 membered c cloalk l or heteroc clic rin

wherein

BB, independently for each occurrence, is a 4-8 membered cycloalkyl, heterocyclic, phenyl, naphthyl, or heteroaryl moiety, wherein the cycloalkyl, heterocyclic, phenyl, naphthyl, or heteroaryl moiety is optionally substituted with one or more groups represented by R₂, wherein the two substituents comprising -OH have a 1,2 or 1,3 configuration;

each R₂ is independently selected from hydrogen, halogen, oxo, sulfonate, -NO₂, -CN, - OH, -NH₂, -SH, -COOH, -CONHR’, -CONH-SO₂-R’, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or two R₂ together with the atoms to which they are attached form a fused substituted or unsubstituted 4-6 membered cycloalkyl or heterocyclic bicyclic ring system;

A₁, independently for each occurrence, is (a) absent; or (b) selected from the group consisting of acyl, substituted or unsubstituted aliphatic, or substituted or unsubstituted heteroaliphatic;

R ;

10

wherein

BB is a substituted or unsubstituted 5- or 6-membered cycloalkyl, heterocyclic, phenyl, naphthyl, or heteroaryl moiety;

A₃, independently for each occurrence, is selected from the group consisting of–NHR’ or–OH;

R₃ and R₄ are independently selected from the group consisting of H, C_1-4alkyl, phenyl, or R₃ and R₄ taken together from a 3-6 membered ring;

R₅ and R₆ are independently selected from the group consisting of H, C_1-4alkyl optionally substituted by hydroxyl, amino, halogen, or thio; C_1-4alkoxy; halogen; -OH; -CN; - COOH; -CONHR’; or R₅ and R₆ taken together form phenyl or a 4-6 membered heterocycle; and

R’ is selected from the group consisting of hydrogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted phenyl or naphthyl, substituted or unsubstituted heteroaryl, -NH₂, -NO₂, -SH, or -OH;

w e e

A₁ is (a) absent; or (b) selected from the group consisting of acyl, substituted or unsubstituted aliphatic, or substituted or unsubstituted heteroaliphatic; A₃, independently for each occurrence, is selected from the group consisting of–NHR’ or–OH;

AR is a fused phenyl or 4-7 membered aromatic or partially aromatic heterocyclic ring, wherein AR is optionally substituted by oxo, C_1-4alkyl optionally substituted by hydroxyl, amino, halo, or thio; C_1-4alkoxy; -S- C_1-4alkyl; halogen; -OH; -CN; -COOH; -CONHR’;

wherein the two substituents comprising -OH are ortho to each other;

R₅ and R₆ are independently selected from the group consisting of H, C_1-4alkyl optionally substituted by hydroxyl, amino, halo, or thio; C_1-4alkoxy; halogen; -OH; -CN; - COOH; CONHR’; and

R’ is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted phenyl or na hth l, substituted or unsubstituted heteroaryl, -NH₂, -NO₂, -SH, or–OH;

e

) ; wherein

Q₁ is selected from the group consisting of C_1-4alkyl, alkylene, or a bond; C_1- ₆cycloalkyl; a 5-6 membered heterocyclic ring; or phenyl;

Q₂, independently for each occurrence, is selected from the group consisting of H, C_1- ₄alkyl, alkylene, or a bond; C_1-6cycloalkyl; a 5-6 membered heterocyclic ring; substituted or unsubstituted aliphatic; substituted or unsubstituted heteroaliphatic; substituted or unsubstituted phenyl or naphthyl; or substituted or unsubstituted heteroaryl;

A₃, independently for each occurrence, is selected from the group consisting of–NH₂ or -OH;

A₄, independently for each occurrence, is selected from the group consisting of -NH- NH₂; -NHOH, -NH-OR’’, or–OH;

R’’ is selected from the group consisting of H or C_1-4alkyl; and

f)

; wherein

A₅ is selected from the group consisting of–OH, -NH₂, -SH, -NHR’’’;

R’’’ is selected from -NH₂; -OH; phenoxy; heteroaryloxy; and C_1-4alkoxy; R₅ and R₆ are independently selected from the group consisting of H, C_1-4alkyl optionally substituted by hydroxyl, amino, halo, or thio; C_1-4alkoxy; halogen; -OH; -CN; - COOH; -CONHR’; or R₅ and R₆ taken together may form a 5-6 membered ring;

R’ is selected from the group consisting of hydrogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted phenyl or naphthyl, substituted or unsubstituted heteroaryl, -NH₂, -SH, or–OH.

A person of skill in the art appreciates that certain substituents may, in some embodiments, result in compounds that may have some instability and hence would be less preferred.

[0052] In some embodiments, A₁ may be selected from the group consisting of C₁- C₃alkylene optionally substituted with one, two, or three halogens, or–C(O)-.

[0053] In other embodiments, Z¹ may be , wherein R₂, independently for

each occurrence, is selected from H, C_1-4 alkyl, or two R₁ moieties taken together form a 5- or 6-membered cycloalkyl or heterocyclic ring, wherein R₃ is H, o

[0054] In certain embodiments, Z¹ may be

In some cases, Z¹ may be

A₃

A ^N

3 . For example, in some instances, Z¹ may b

[0055] In some embodiments, Z¹ may be a monosaccharide or a disaccharide. [0056] In some cases, Z¹ may be selected from the group consisting of

wherein

X is selected from O, S, CH, NR’, or when X is NR’, N may be covalently bonded to Y of Formula I;

R’ is selected from the group consisting of H, C_1-4alkyl;

R₅, R₆, and R₇ are independently selected from the group consisting of H, C_1-4alkyl optionally substituted by hydroxyl, amino, halo, or thio; C_1-4alkoxy; halogen; -OH; -CN; - COOH; -CONHR’; or a mono- or bicyclic heterocyclic optionally substituted with amino, halo, hydroxyl, oxo, or cyano; and

AA is a 5-6 membered heterocyclic ring optionally substituted by C_1-4alkyl optionally substituted by hydroxyl, amino, halo, or thio; C_1-4alkoxy; halogen; -OH; -CN; -COOH; -

CONHR’, or -S- C_1-4alkyl. For example, in some embodiments, Z¹ may be

In

some instances, Z¹ may be In certain cases, X may be nitrogen.

[0057] In some embodiments, Z¹ may be

[0058] In other embodiments, Z¹ may be

For example, in some cases, the Z¹ may be

In other instances, Z¹ may be

In some embodiments, Z¹ may be

[0059] In some cases, Z¹ may be

. For example, Z¹ may be

. In other embodiments, Z¹ may be

[0060] In some cases, Z¹ may be

. In some embodiments, Z¹ may be

[0061] In some embodiments, Z¹ may be

For example, Z¹ may be

[0062] In certain embodiments, Z¹ may be

In other embodiments, Z¹

[0063] In some embodiments, the second monomer may be X²-Y²-Z² (Formula II), wherein Z² is a boronic acid or oxaborale moiety, and wherein X² is a second ligand capable of binding to a second target biomolecule segment (e.g. a segment of a fusion protein or a bromodomain of tandem bromodomains), and Y² is absent or is a connector moiety covalently bound to X² and Z². In some instances, X¹ and X² may be the same. In other instances, X¹ and X² may be different.

[0064] In some embodiments, the second monomer may be X⁴-Y⁴-Z⁴ (Formula IV), wherein Z⁴ is a boronic acid or oxaborale moiety, and wherein X⁴ is a second ligand moiety capable of binding to a protein domain, wherein the protein domain is within e.g., about 50 ǖ of the bromodomain (e.g. a segment of a fusion protein or a second bromodomain of tandem bromodomains), and Y⁴ is absent or is a connector moiety covalently bound to X⁴ and Z⁴. For example, X¹ may be capable of binding to a first bromodomain, and X⁴ may be capble of binding to a second bromodomain, wherein the second bromodomain is within, e.g., about 50 ǖ of the first bromodomain. In some instances, X¹ and X⁴ may be the same. In other instances, X¹ and X⁴ may be different.

[0065] In some cases, the first target biomolecule and the second target biomolecule may be different. In other embodiments, the first target biomolecule and the second target biomolecule may be the same.

[0066] In some embodiments, the linker of the second monomer, for example, Z² or Z⁴

, may be selected from the group consisting of:

; wherein R₈ is selected from the group consisting of H, halogen, oxo, C_1-4alkyl optionally substituted by hydroxyl, amino, halo or thio; C_2-4alkenyl, C_1-4alkoxy; -S- C_1-4alkyl; -CN; - COOH; or–CONHR’;

A₁ is (a) absent; or (b) selected from the group consisting of acyl, substituted or unsubstituted aliphatic, or substituted or unsubstituted heteroaliphatic;

AA, independently for each occurrence, is phenyl, naphthyl, or a 5-7 membered heterocyclic or heteroaryl ring having one, two, or three heteroatoms, wherein AA is optionally substituted by one, two, or three substituents selected from the group consisting of halogen, C_1- ₄alkyl optionally substituted by hydroxyl, amino, halogen, or thio; C_2-4alkenyl, C_1-4alkoxy; -S- C_1-4alkyl; -CN; -COOH;–CONHR’; or two substituents together with the atoms to which they are attached form a fused 4-6 membered cycloalkyl or heterocyclic bicyclic ring system; and R’ is H or C_1-4alkyl.

[0067] In certain embodiments, R₈ and the substituent comprising boronic acid may be ortho to each other, and R₈ may be–CH₂NH₂. In some cases, the linker of the second

monomer ma be selected from the group consisting of:

,

[0068] In some embodiments, the linker of the second monomer may be selected from

the group consisting of:

[0069] In some cases, the linker of the second monomer may be selected from the group consisting of:

; wherein

R₈ is selected from the group consisting of H, halogen, oxo, C_1-4alkyl optionally substituted by hydroxyl, amino, halo or thio; C_2-4alkenyl, C_1-4alkoxy; -S- C_1-4alkyl; -CN; - COOH; or–CONHR’;

AA, independently for each occurrence, is a 5-7 membered heterocyclic ring having one, two, or three heteroatoms, or phenyl, wherein AA is optionally substituted by one, two, or three substituents selected from the group consisting of halo, C_1-4alkyl optionally substituted by hydroxyl, amino, halo, or thio; C_2-4alkenyl, C_1-4alkoxy; -S- C_1-4alkyl; -CN; -COOH;–

CONHR’; or two substituents together with the atoms to which they are attached form a fused 4-6 membered cycloalkyl or heterocyclic bicyclic ring system; and

R’ is H or C_1-4alkyl.

[0070] In another embodiment, a monomer may be represented by the formula:

X³-Y³-Z³ (Formula III), wherein Z³ is independently selected from the group consisting of:

O

R₄

R

a) _{3 A3} , wherein

A₃ is–OH, -SH, or -NHR’; R₃ is selected from the group consisting of H, halo, C_1-4alkyl, C_3-6cycloalkyl, and heterocycle, wherein C_1-4alkyl, C_3-6cycloalkyl, or heterocycle may be optionally substituted by one, two, or three substituents selected from the group consisting of halo, cyano, amino, or hydroxyl; and

R₄ is selected from the group consisting of H, halo, C_1-4alkyl, C_3-6cycloalkyl, and heterocycle, wherein C_1-4alkyl, C_3-6cycloalkyl, or heterocycle may be optionally substituted by one, two, or three substituents selected from the group consisting of halo, cyano, amino, or hydroxyl; or

R₃ and R₄ can be taken together with the atoms to which they are attached to form a substituted or unsubstituted phenyl, substituted or unsubstituted C_3-6cycloalkyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted saturated heterocycle;

R’ is H or C_1-4alkyl; and

b

wherein

R’ is C_1-4alkyl optionally substituted with hydroxyl; -NH₂; -OH; and C_1-4alkoxy;

R₃ is selected from the group consisting of H, halo, C_1-4alkyl, C_3-6cycloalkyl and heterocycle, wherein C_1-4alkyl, C_3-6cycloalkyl, or heterocycle may be optionally substituted by one, two, or three substituents selected from the group consisting of halo, cyano, amino, or hydroxyl;

R₄ is selected from the group consisting of H, C_1-4alkyl, C_3-6cycloalkyl and heterocycle, wherein C_1-4alkyl, C_3-6cycloalkyl, or heterocycle may be optionally substituted by one, two or three substituents selected from the group consisting of halo, cyano, amino, or hydroxyl; or R₃ and R₄ can be taken together with the atoms to which they are attached to form a substituted or unsubstituted phenyl, substituted or unsubstituted C_3-6cycloalkyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted saturated heterocycle; and

wherein Z³ is a linker moiety capable of binding to one or more X³-Y³-Z³ monomers to form a biologically useful multimer.

A person of skill in the art appreciates that certain substituents may, in some embodiments, result in compounds that may have some instability and hence would be less preferred. [0071] In another embodiment, silyl monomers are contemplated that are capable of forming a biologically useful multimer when in contact with one, two, three or more second silyl monomers in an aqueous media. The silyl monomers can be represented by Formula III above, (e.g., X³-Y³-Z³), but wherein Z³ is independently selected from the group consisting of:

wherein

R^W is absent or selected from the group consisting of -C_1-4alkyl-, -O-C_1-4alkyl-, -N(R^a)-, -N(R^a)-C_1-4alkyl-, -O-, -C(O)C_1-4alkyl-, -C(O)-O-C_1-4alkyl-, -C_2-6alkenyl-, -C_2-6alkynyl-, -C_3- ₆cycloalkyl-, -phenyl- and -heterocycle-; wherein C_1-4alkyl, R^a, R^b, C_2-6alkenyl, C_2-6alkynyl, C_3- ₆cycloalkyl, phenyl and heteroaryl may be optionally substituted by one, two, three or more substituents selected from the group consisting of C_1-4alkyl, C_1-4alkoxy, -C(O)C_1-4alkyl, -C(O)- O-C_1-4alkyl, -C(O)-NR^aR^b, halogen, cyano, hydroxyl, phenyl, R^a and R^b; or R^W and R¹ together with the silicon to which they are attached, form a 3-8 membered heterocyclic ring, wherein the 3-8 membered ring may be optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo, hydroxyl, and C_1-6alkyl;

W¹, independently for each occurrence, is (a) absent; or (b) selected from the group consisting of -C_1-4alkyl-, -O-C_1-4alkyl-, -C(O)-C_1-4alkyl-, -N(R^a)-C_1-4alkyl-, -C(O)-O-C_1-4alkyl-, -C_2-6alkenyl-, -C_2-6alkynyl-, -C_3-6cycloalkyl-, -phenyl- or -heteroaryl-; wherein C_1-4alkyl, C_2- ₆alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, R’, phenyl and heteroaryl are optionally substituted independently, for each occurrence, with one, two, three or more substituents selected from the group consisting of C_1-4alkyl, C_1-4alkoxy, -C(O)C_1-6alkyl, -C(O)-O-C_1-4alkyl, halogen, hydroxyl, nitro and cyano;

R’ is independently selected, for each occurrence, from the group consisting of hydrogen, substituted or unsubstituted aliphatic, and substituted or unsubstituted

heteroaliphatic;

Q¹ is independently selected, for each occurrence, from the group consisting of -NHR’, -SH, -OH, -O-C₁-₆alkyl, -S-C_1-6alkyl, phenoxy, -S-phenyl, heteroaryl, -O-heteroaryl, -S- heteroaryl, halogen and -O-C₁-₆alkyl-NR^aR^b; R^a and R^b are independently selected, for each occurrence, from the group consisting of hydrogen and C_1-4alkyl; wherein C_1-4alkyl may be optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo and hydroxyl; or

R^a and R^b, together with the nitrogen to which they are attached, may form a 4-7 membered heterocyclic ring, which may have an additional heteroatom selected from O, S, or N; wherein the 4-7 membered heterocyclic ring may be optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo and hydroxyl;

R¹ and R² are selected independently, for each occurrence, from the group consisting of -OH, C_1-6alkyl, -O-C_1-6alkyl, C_2-6alkenyl, C_3-6cycloalkyl, -C_1-6alkyl-NR^aR^b, phenyl and heteroaryl; wherein C_1-6alkyl, C_2-6alkenyl, C_3-6cycloalkyl, R^a, R^b, phenyl and heteroaryl, independently selected, for each occurrence, may be optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, hydroxyl, C_1-6alkyl, and phenyl; or

R¹ and R², together with the silicon to which they are attached, form a 4-7 membered heterocyclic ring, optionally containing one, two, three, or four heteroatoms selected from O, S, or N; wherein the 4-7 membered heterocyclic ring may be optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo, and hydroxyl;

BB, independently for each occurrence, is a 4-7-membered cycloalkyl, heterocyclic, phenyl, naphthyl, or heteroaryl moiety, wherein the cycloalkyl, heterocyclic, phenyl, naphthyl, or heteroaryl moiety is optionally substituted with one, two, three or more groups represented by R^BB; wherein R¹, independently for each occurrence, may be optionally bonded to BB; each R^BB is independently selected, for each occurrence, from the group consisting of hydrogen, halogen, nitro, cyano, hydroxyl, amino, thio, -COOH, -CONHR’, substituted or unsubstituted aliphatic, and substituted or unsubstituted heteroaliphatic; or two R^BB together with the atoms to which they are attached form a fused 5- or 6-membered cycloalkyl or heterocyclic bicyclic ring system; and

wherein

Q^2A is absent or selected from the group consisting of–NH-, -S-, -O-, -O-C₁-₆alkyl-, - C₁-₆alkyl-O-, -N(R’)-C₁-₆alkyl-, -C₁-6alkyl-N(R’)-, -S-C₁-₆alkyl-, -C₁-₆alkyl-S- and -O-C₁- ₆alkyl-NR^a-; or Q^2A and R¹, together with the silicon to which they are attached, form a 3-8 membered heterocyclic ring, wherein the 3-8 membered ring may be optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo, hydroxyl, and C_1-6alkyl;

W¹ and W^1A, independently for each occurrence, are (a) absent; or (b) selected from the group consisting of -O-, -C_1-4alkyl-, -O-C_1-4alkyl-, -N(R^a)-C_1-4alkyl-, -C(O)C_1-4alkyl-, -C(O)-O- C_1-4alkyl-, -C_2-6alkenyl-, -C_2-6alkynyl-, -C_3-6cycloalkyl-, -phenyl- and -heteroaryl-; wherein C_1- ₄alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, R’, phenyl and heteroaryl may be optionally substituted independently, for each occurrence, with one, two, three or more substituents selected from the group consisting of C_1-4alkyl, C_1-4alkoxy, -C(O)C_1-6alkyl, -C(O)-O-C_1-4alkyl, halogen, hydroxyl, nitro and cyano;

heteroaliphatic;

Q¹ and Q^1A are independently selected, for each occurrence, from the group consisting of -NHR’, -SH, -OH, -O-C₁-₆alkyl, -S-C_1-6alkyl, phenoxy, -S-phenyl, heteroaryl, -O-heteroaryl, -S-heteroaryl, halogen and -O-C₁-₆alkyl-NR^aR^b;

R^a and R^b are independently selected, for each occurrence, from the group consisting of hydrogen and C_1-4alkyl; wherein C_1-4alkyl may be optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo and hydroxyl; or R^a and R^b, together with the nitrogen to which they are attached, may form a 4-7 membered heterocyclic ring, which may have an additional heteroatom selected from O, S, or N; wherein the 4-7 membered heterocyclic ring may be optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo and hydroxyl;

W^2A is selected from the group consisting of N and CR^W2A.

R^W2A is selected from the group consisting of hydrogen, C_1-4alkyl, -O-C_1-4alkyl, C_2- ₆alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, phenyl and heteroaryl; wherein C_1-4alkyl, C_2-6alkenyl, C_2- ₆alkynyl, C_3-6cycloalkyl, phenyl and heteroaryl may be optionally substituted independently, for each occurrence, with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl and cyano;

BB, independently for each occurrence, is a 4-7-membered cycloalkyl, heterocyclic, phenyl, naphthyl, or heteroaryl moiety; wherein the cycloalkyl, heterocyclic, phenyl, naphthyl, or heteroaryl moiety may be optionally substituted with one, two, three or more groups represented by R^BB; wherein R¹, independently for each occurrence, may be optionally bonded to BB;

each R^BB is independently selected, for each occurrence, from the group consisting of hydrogen, halogen, nitro, cyano, hydroxyl, amino, thio, -COOH, -CONHR’, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic; or two R^BB together with the atoms to which they are attached may form a fused 5- or 6-membered cycloalkyl or heterocyclic bicyclic ring system. A person of skill in the art appreciates that certain substituents may, in some embodiments, result in compounds that may have some instability and hence would be less preferred.

[0072] As discussed above, a monomer may be capable of reacting with one or more other monomers to form a multimer. In some embodiments, a first monomer may react with a second monomer to form a dimer. In other embodiments, a first monomer may react with a second monomer and a third monomer to form a trimer. In still other embodiments, a first monomer may react with a second monomer, a third monomer, and a fourth monomer to form a tetramer. In some embodiments, each of the monomers that form a multimer may be essentially the same. In some embodiments, each of the monomers that form a multimer may be substantially different. In certain embodiments, at least some of the monomers that form a multimer may be essentially the same or may be substantially different.

[0073] In some embodiments, the linker element of a first monomer and the linker element of a second monomer may be substantially different. In other embodiments, a connector element of a first monomer and a connector element of a second monomer may be substantially different. In still other embodiments, the ligand moiety (e.g., a pharmacophore) of a first monomer and the ligand moiety (e.g., a pharmacophore) of the second monomer may be substantially different.

[0074] In some cases, formation of a multimer from a plurality of monomers may be irreversible. In some embodiments, formation of a multimer from a plurality of monomers may be reversible. For example, in some embodiments, the multimer may have an oligomer or dimer dissociation constant between 10 mM and 1 nM, in some embodiments between 1 mM and 100 nM, in some embodiments between 1 mM and 1 PM, and in some embodiments between 500 PM and 1 PM. In certain embodiments, the multimer may have a dissociation constant of less than 10 mM, in some embodiments less than 1 mM, in some embodiments less than 500 PM, in some embodiments less than 100 PM, in some embodiments less than 50 PM, in some embodiments less than 1 PM, in some embodiments less than 100 nM, and in some embodiments less than 1 nM. B) Ligands [0075] The ligand moieties X¹, X², X³ and X⁴ of Formulas I, II, III and IV may, in some embodiments, be the same or different. For example, ligand moieties are independently contemplated herein.

[0076] In one embodiment, the ligand moiety may be a pharmacophore. A

pharmacophore is typically an arrangement of the substituents of a moiety that confers biochemical or pharmacological effects. In some embodiments, identification of a

pharmacophore may be facilitated by knowing the structure of the ligand in association with a target biomolecule. In some cases, pharmacophores may be moieties derived from molecules previously known to bind to target biomolecules (e.g., proteins), fragments identified, for example, through NMR or crystallographic screening efforts, molecules that have been discovered to bind to target proteins after performing high- throughput screening of natural products libraries, previously synthesized commercial or non-commercial combinatorial compound libraries, or molecules that are discovered to bind to target proteins by screening of newly synthesized combinatorial libraries. Since most pre-existing combinatorial libraries are limited in the structural space and diversity that they encompass, newly synthesized combinatorial libraries may include molecules that are based on a variety of scaffolds.

[0077] In one embodiment, monomers that include a pharmacophore may bind to a bromodomain. Such monomers may form a multimer, as disclosed herein, that may be capable of binding to tandem bromodomains, e.g. within a BET family of bromodomains that contain tandem bromodomains in close proximity, making them capable of binding two acetylated lysine residues with greater specificity. For example, a“BET bromodomain” may refer to the bromodomains in BRD2, BRD3, BRD4 or BRD-t. A person skilled in the art may appreciate that additional pharmacophores may be discovered in the future and that the pharmacophores illustrated herein are not intended to limit in any way the claims.

[0078] In some embodiments, a ligand (e.g., a pharmacophore) may have one or more preferred attachment points for connecting the pharmacophore to the linker (e.g., with or without a connector moiety). In certain embodiments, an attachment point on a pharmacophore may be chosen so as to preserve at least some ability of the pharmacophore to bind to a bromodomain. In one embodiment, preferred attachment points may be identified using X-ray crystallography. The following description of a non-limiting exemplary method illustrates how a preferred attachment point may be identified. For example, as shown in FIG. 1, using the 3P5O structure 100 from the protein databank (PDB), a small molecule 110 (dark gray) labeled “EAM1” in the PDB file [also known as I-BET or IBET762] may be identified. The I-BET triazolo ring (indicated by white circle 120) contains two adjacent nitrogen atoms in the 3 and 4 positions and a methyl group 130 bound to the adjacent carbon at the 5 position. Together, the nitrogen atoms and methyl group constitute an acetyl lysine mimetic. The corresponding acetyl lysine mimetic in the new pharmacophore 140 (light gray) should be aligned to these elements. The final conformation and orientation of the newly aligned pharmacophore 140 in the site may be determined using a variety of approaches known to computational chemists, but can be done as simply as performing an energy minimization using a molecular mechanics forcefield. It should be noted that the alphanumeric identifiers in FIG. 1 (e.g., K141, D144, M149, etc.) correspond to amino acid residues in the 3P5O structure, where the letter of the identifier is the one-letter amino acid symbol and the number of the identifier is the position of the amino acid residue in the primary sequence of the protein. Attachment points 150 on the aligned pharmacophore which permit access to amino acid residues D96, Y139, N140, K141, D144, D145, M149, W81, or Q85 in the 3P5O structure are considered preferred attachment points for linkers. It should be apparent to those skilled in the art that overlays of the I-BET

pharmacophore with other alternate pharmacophores can be used to identify potential attachment points.

[0079] FIG. 2 provides a non-limiting set of pharmacophores (i.e., ligands) showing preferred attachment points (indicated by circled arrows) for connecting the pharmacophore to a linker.

[0080] In one embodiment, X¹ is a first ligand moiety capable of binding to a first bromodomain. In another embodiment X² is a second ligand moiety capable of binding to a second bromodomain, or to another domain, e.g., near or adjacent to the first bromodomain.

[0081] For example, the disclosed ligand moieties, X¹, X², X³ and X⁴ of Formulas I, II, III and IV may be or include bromodomain ligands as described herein. It will be appreciated that the ligands disclosed herein can be attached at any open site to a–Y-Z moiety (e.g., -Y¹-Z¹, -Y²-Z², -Y³-Z³, and -Y⁴-Z⁴) as described herein. Such embodiments described below include specific references to each attachment site. Exemplary bromodomain ligands include quinolines represented by the structures:

wherein:

X is O or S;

R¹ is C_1-6alkyl, haloC_1-6alkyl, -(CH₂)_nOR^1a, or -(CH₂)_mNR^1bR^1c; wherein R^1a is hydrogen, C_1-6alkyl or haloC_1-6alkyl; R^1b and R^1c, which may be the same or different, are hydrogen, C_1-6alkyl or haloC_1-6alkyl; and m and n, which may be the same or different, are 1, 2 or 3;

R² is R^2a, -OR^2b, or -NR^2cR^2d; wherein R^2a and R^2b are carbocyclyl, carbocyclylC_1- ₄alkyl, heterocyclyl or heterocyclylC_1-4alkyl, or R^2a is carbocyclylethenyl or

heterocyclylethenyl, wherein any of the carbocyclyl or heterocyclyl groups defined for R^2a or R^2b are optionally substituted by one or more groups independently selected from the group consisting of halogen, C_1-6alkyl, haloC_1-6alkyl, C_1-6alkoxy, haloC_1-6alkoxy, nitro, cyano, dimethylamino, benzoyl and azido; or two adjacent groups on any of the carbocyclyl or heterocyclyl groups defined for R^2a or R^2b together with the interconnecting atoms form a 5 or 6-membered ring which ring may contain 1 or 2 heteroatoms independently selected from the group consisting of O, S and N; or

R^2a and R^2b are C_1-6alkyl or haloC_1-6alkyl; and R^2c and R^2d, which may be the same or different, are carbocyclyl, carbocyclylC_1-4alkyl, heterocyclyl or heterocyclylC_1-4alkyl, wherein any of the carbocyclyl or heterocyclyl groups defined for R^2c or R^2d are optionally substituted by one or more groups independently selected from the group consisting of halogen, C_1-6alkyl, haloC_1-6alkyl, C_1-6alkoxy, haloC_1-6alkoxy, nitro, cyano and -CO₂C_1-4alkyl; or two adjacent groups on any of the carbocyclyl or heterocyclyl groups defined for R^2c and R^2d together with the interconnecting atoms form a 5 or 6-membered ring which ring may contain 1 or 2 heteroatoms independently selected from the group consisting of O, S and N; or

R^2c and R^2d are independently hydrogen, C_1-6alkyl or haloC_1-6alkyl;

R³ is C_1-6alkyl, phenyl, naphthyl, heteroaryl carbocyclyl or heterocyclyl, optionally substituted independently by one or more substitutents selected from the group consisting of halogen,–SR, -S(O)R’, -NHR’, -OR’, C_1-6alkyl, haloC_1-6alkyl, C_1-6alkoxy, haloC_1-6alkoxy, nitro and cyano;

R’ is H or C_1-6alkyl;

A is a benzene or aromatic heterocyclic ring, each of which is optionally substituted; and

n is 0, 1 or 2.

[0082] In some embodiments, compounds of Formula F or Formula G may be selected from the group consisting of:

, and

[0083] In another embodiment, exemplary bromodomain ligands include

benzodiazepines represented by the structures:

wherein:

X is phenyl, naphthyl, or heteroaryl;

R¹ is C_1-3alkyl, C_1-3alkoxy or -S- C_1-3alkyl;

R² is -NR^2aR^2a' or -OR^2b; wherein one of R^2a or R^2a’ is hydrogen, and R^2b or the other of R^2a or R^2a’ is selected from the group consisting of C_1-6alkyl, haloC_1-6alkyl, R^2cR^2c’N-C_2-6alkyl, carbocyclyl, carbocyclyloC_1-4alkyl, heterocyclyl and heterocyclylC_1-4alkyl, wherein any of the carbocyclyl or heterocyclyl groups are optionally substituted by one or more substituents selected from the group consisting of halogen, C_1-6alkyl, haloC_1-6alkyl, C_1-6alkoxy, haloC_1- ₆alkoxy, carbonyl, -CO-carbocyclyl, azido, amino, hydroxyl, nitro and cyano, wherein the– CO-carbocyclyl group may be optionally substituted by one or more substituents selected from the group consisting of halogen, C_1-6alkyl, haloC_1-6alkyl, C_1-6alkoxy, haloC_1-6alkoxy, azido, nitro and cyano; or

two adjacent groups on any of the carbocyclyl or heterocyclyl groups together with the interconnecting atoms form a 5- or 6-membered ring which ring may contain 1 or 2 heteroatoms independently selected from the group consisting of O, S and N; or R^2a and R^2a’ together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered ring which optionally contains 1 or 2 heteroatoms independently selected from the group consisting of O, S and N; wherein the 4-, 5-, 6 or 7-membered ring is optionally substituted by C_1-6alkyl, hydroxyl or amino;

R^2c and R^2c’ are independently hydrogen or C_1-6alkyl;

each R³ is independently selected from the group consisting of hydrogen, hydroxyl, thiol, sulfinyl, sulfonyl, sulfone, sulfoxide, -OR^t, -NR^tR^tt, -S(O)₂NR^tR^tt, -S(O)_wR^tR^tt (where t and tt are independently selected from H, phenyl or C_1-6alkyl, and w is 0, 1, or 2), halo, C_1- ₆alkyl, haloC_1-6alkyl, C_1-6alkoxy, haloC_1-6alkoxy, nitro, cyano, CF₃, -OCF₃, -COOR⁵, -C_1- ₄alkylamino , phenoxy, benzoxy, and C_1-4alkylOH;

XX is selected from the group consisting of a bond, NR’’’ (where R’’’ is H, C_1-6alkyl or phenyl), -O-, or S(O)_w wherein w is 0, 1 or 2, and C_1-6alkyl; (and wherein in some

embodiments XX is in the para position);

each R⁴ is hydroxyl, halo, C_1-6alkyl, hydroxyC_1-6alkyl, aminoC_1-6alkyl, haloC_1-6alkyl, C_1-6alkoxy, haloC_1-6alkoxy, acylaminoC_1-6alkyl, nitro, cyano, CF₃, -OCF₃, -COOR⁵; - OS(O)₂C_1-4alkyl, phenyl, naphthyl, phenyloxy, benzyloxy or phenylmethoxy, wherein C_1- ₆alkyl, phenyl, and naphthyl are optionally substituted by one two or three substituents selected from the group consisting of hydroxyl, halogen, amino, nitro;

R⁵ is C_1-3alkyl;

* denotes a chiral center;

m is an integer 1 to 3; and

n is an integer 1 to 5. In some embodiments, the chiral center has an S configuration. [0084] In some embodiments, compounds of Formula H or Formula I may be selected from the group consisting of:

[0085] For example, compounds of Formula F, Formula G, Formula H or Formula I may be selected from the group consisting of:

[0086] In some embodiments, exemplary bromodomain ligands include compounds represented by the structures:

Formula A1, or

wherein:

R⁴ is hydrogen, cyano or C_1-6 alkyl;

A is selected from the group consisting of:

R^x is O, NR^2a, or S; R¹ is C_1-6alkyl, C_3-6cycloalkyl, a 5 or 6 membered heterocyclyl, an aromatic group or a heteroaromatic group, wherein the aromatic group or the heteroaromatic group is optionally substituted by one to three groups selected from the group consisting of halogen, hydroxy, cyano, nitro, C_1-6alkyl, C_1-4alkoxy, haloC_1-4alkyl, haloC_1-4alkoxy, hydroxyC_1-4alkyl, C_1-4alkoxy C_1-4alkyl, C_1-4alkoxycarbonyl, C_1-4alkylsulfonyl, C_1-4alkylsulfonyloxy, C_1-4alkylsulfonyl C_1- ₄alkyl and C_1-4alkylsulfonamido;

R² is hydrogen or C_1-6alkyl;

R^2a is selected from the group consisting of H, C_1-6alkyl, C_1-6haloalkyl, (CH₂)_mcyano, (CH₂)_mOH, (CH₂)_mC_1-6alkoxy, (CH₂)_mC_1-6haloalkoxy, (CH₂)_mC_1-6haloalkyl,

(CH₂)_mC(O)NR^aR^b, (CH₂)_mNR^aR^b and (CH₂)_m C(O)CH₃, (CHR⁶)_pphenyl optionally substituted by C_1-6alkyl, C_1-6alkoxy, cyano, halo C_1-4alkoxy, haloC_1-4alkyl, (CHR⁶)_pheteroaromatic, (CHR⁶)_pheterocyclyl; wherein R^a is H, C_1-6alkyl, or heterocyclyl; wherein R^b is H or C_1-6alkyl, or

R^a and R^b together with the N to which they are attached form a 5 or 6 membered heterocyclyl;

R^2b is H, C_1-6alkyl, (CH₂)₂C_1-6alkoxy, (CH₂)₂cyano, (CH₂)_mphenyl or

(CH₂)₂heterocyclyl;

R³ is hydrogen;

R⁶ is hydrogen or C_1-6alkyl;

m is 0, 1, 2 or 3;

n is 0, 1 or 2; and

p is 0, 1 or 2.

[0087] In some embodiments, compounds of Formulae A, A1, and A2 may be selected from the group consisting of:

[0088] In another embodiment, exemplary bromodomain ligands include

tetrahydroquinolines represented by the structures:

Formula C

wherein:

A is a bond, C_1-4alkyl or–C(O)-;

X is:

i) a 6 to 10 membered aromatic group,

ii) a 5 to 10 membered heteroaromatic comprising 1, 2 or 3 heteroatoms selected from the group consisting of O, N and S, or iii)–C(O)-C_1-10alkyl;

R¹ is:

i) phenyl optionally substituted by 1 or 2 substituents independently selected from the group consisting of halogen, cyano, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, - SO₂C_1-6alkyl and -COR⁷,

ii) a 5 to 10 membered heteroaromatic comprising 1, 2 or 3 heteroatoms selected from the group consisting of O, N and S optionally substituted by 1 or 2 substituents independently selected from the group consisting of halogen, cyano, C_1-6alkyl, C_1- ₆haloalkyl, C_1-6alkoxy and -COR⁷, or

iii) C_1-6alkyl, C_0-6alkylcyano, C_0-6alkylC_1-6alkoxy, C_0-2alkylC(O)R⁷ or cyclohexyl;

R² is C_1-6alkyl;

R³ is C_1-6alkyl;

R⁴ is:

i) H, halogen, cyano, oxo, hydroxylamino, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, C_0-6hydroxyalkyl, -SO₂C_1-6alkyl, -C(O)NR⁸R⁹, -C(O)R¹⁰, -C_0-6alkyl-NR¹¹R¹², -NR⁸- C(O)-C_1-10alkyl optionally substituted with one, two, or three groups selected from oxo, hydroxyamino, hydroxyl, halogen, cyano, and nitro;

ii) -O_mC_1-6alkyl substituted by a 5 or 6 membered heterocyclyl or heteroaromatic each comprising 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O and S and wherein said hetercyclyl or heteroaromatic is optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of halogen, cyano, C_1-6alkyl, C_1-6haloalkyl and C_1-6alkoxy, wherein m is 0, 1 or 2, wherein when the heterocyclyl or heteroatomic is linked through a heteroatom and m is 1, then the heteroatom and O are not directly linked if the resultant arrangement would be unstable;

R^4a is H, halogen, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy or C_0-6hydroxyalkyl;

R⁵ is H, halogen, C_1-6alkyl or C_1-6alkoxy;

R⁶ is H, C_1-6alkyl, C_0-6alkylcyano, C_0-6alkylC_1-6alkoxy or C_0-2alkylC(O)R⁷;

R⁷ is hydroxyl, C_1-6alkoxy, -NH₂, -NHC_1-6alkyl or N(C_1-6alkyl)₂;

R⁸ and R⁹ independently are:

i) H, C_1-6alkyl, C_0-6alkylphenyl, C_0-6alkylheteroaromatic, C_3-6cycloalkyl, or ii) R⁸ and R⁹ together with the N to which they are attached form a 5 or 6 membered heterocyclyl or heteroaromatic wherein said heterocyclyl or heteroaromatic may comprise 1, 2 or 3 further heteroatoms independently selected from the group consisting of O, N and S;

R¹⁰ is hydroxyl, C_1-6alkoxy or a 5 or 6 membered heterocyclyl or heteroaromatic comprising 1, 2, 3 or 4 heteroatoms selected from the group consisting of O, N and S;

R¹¹and R¹² independently are:

i) H, C_1-6alkyl; or

ii) R¹¹ and R¹² together with the N to which they are attached form a 5 or 6 membered heterocyclyl or heteroaromatic wherein said heterocyclyl or heteroaromatic may comprise 1, 2 or 3 further heteroatoms independently selected from the group consisting of O, N and S.

[0089] In certain embodiments, compounds of Formula B or Formula C may be selected from the group consisting of:

[0090] In another embodiment, exemplary bromodomain ligands include

tetrahydroquinolines represented by the structures:

[0091]

Formula E, and

Formula E1

wherein:

R¹ is C_1-6alkyl, C_3-7cycloalkyl or benzyl;

R² is C_1-4alkyl;

R³ is C_1-4alkyl;

X is phenyl, naphthyl, or heteroaryl;

R^4a is hydrogen, C_1-4alkyl or is a group L-Y in which L is a single bond or a C_1- ₆alkylene group and Y is OH, OMe, CO₂H, CO₂C_1-6alkyl, CN, or NR⁷R⁸;

R⁷ and R⁸ are independently hydrogen, a heterocyclyl ring, C_1-6alkyl optionally substituted by hydroxyl, or a heterocyclyl ring; or

R⁷ and R⁸ combine together to form a heterocyclyl ring optionally substituted by C_1- ₆alkyl, CO₂C_1-6alkyl, NH₂, or oxo;

R^4b and R^4c are independently hydrogen, halogen, C_1-6alkyl, or C_1-6alkoxy;

R^4d is C_1-4alkyl or is a group -L-Y- in which L is a single bond or a C_1-6alkylene group and Y is -O-, -OCH₂-, -CO₂-, -CO₂C_1-6alkyl-, or–N(R⁷)-;

R⁵ is hydrogen, halogen, C_1-6alkyl, or C_1-6alkoxy;

R⁶ is hydrogen or C_1-4alkyl.

[0092] In some cases, compounds of Formula D or Formula E may be selected from the group consisting of:

[0093] For example, compounds of Formula A, Formula B, Formula C, Formula D or Formula E may be selected from the group consisting of:

[0094] In another embodiment, exemplary bromodomain ligands are represented by the structures:

, where X is O, NR⁴, or S, and R⁴ is independently selected from the group consisting of hydrogen, hydroxyl, halo, amino, thiol, C_1-6alkyl, haloC_1-6alkyl, C_1-6alkoxy, -NH-C_1-6alkyl, -S-C_1-6alkyl, haloC_1-6alkoxy, nitro, cyano, -CF₃, -OCF₃, -C(O)O-C_1-6alkyl, -C_1- ₄alkylamino , phenoxy, benzoxy, and C_1-4alkylOH;

.

[0095] In another embodiment, exemplary bromodomain ligands include heterocycles represented by the structures:

wherein:

A is independently, for each occurrence, a 4-8 membered cycloalkyl, heterocyclic, phenyl, naphthyl, or heteroaryl moiety, each optionally substituted with one, two, three or more R¹ substituents;

R¹ is selected from the group consisting of hydroxy, halogen, oxo, amino, imino, thiol, sulfanylidene, C_1-6alkyl, hydroxyC_1-6alkyl, -O-C_1-6alkyl,–NH-C_1-6alkyl, -CO₂H, -C(O)C_1- ₆alkyl,–C(O)O-C_1-6alkyl, aminoC_1-6alkyl, haloC_1-6alkyl, -C_1- ₆alkylC(O)R²

, -O-C(O)R², -NH-C(O)R², -O-C_1-6alkyl-C(O)R², -NHC_1-6alkyl-C(O)R², acylaminoC_1-6alkyl, nitro, cyano, CF₃, -OCF₃, -OS(O)₂C_1-6alkyl, phenyl, naphthyl, phenyloxy, -NH-phenyl, benzyloxy, and phenylmethoxy halogen; wherein C_1-6alkyl, phenyl, and naphthyl are optionally substituted by one two or three substituents selected from the group consisting of hydroxyl, halogen, amino, nitro, phenyl and C_1-6alkyl; or two R¹ substitutents may be taken together with the atoms to which they are attached to form a fused aliphatic or heterocyclic bicyclic ring system;

R^2c and R^2c’ are independently hydrogen or C_1-6alkyl;

B is selected from the rou consistin of: ,

,

.

[0096] In one embodiment, compounds of Formula J may be selected from the group consisting of:

wherein:

Q is independently, for each occurrence, N or CH;

V is independently, for each occurrence, O, S, NH, or a bond; and

R⁴ is independently selected from the group consisting of hydrogen, hydroxyl, halo, amino, thiol, C_1-6alkyl, haloC_1-6alkyl, C_1-6alkoxy, -NH-C_1-6alkyl, -S-C_1-6alkyl, haloC_1-6alkoxy, nitro, cyano, -CF₃, -OCF₃, -C(O)O-C_1-6alkyl, -C_1-4alkylamino , phenoxy, benzoxy, and C_1- ₄alkylOH.

[0097] For example, compounds of Formula J or Formula L may be selected from the group consisting of:

wherein:

R is independently, for each occurrence, N or CH;

V is independently, for each occurrence, a bond, O or NR⁴;

R⁴ is independently, for each occurrence, hydrogen, hydroxyl, halo, amino, -SO₂, thiol, C_1-6alkyl, haloC_1-6alkyl, C_1-6alkoxy, -NH-C_1-6alkyl, -S-C_1-6alkyl, haloC_1-6alkoxy, nitro, cyano, - CF₃, -OCF₃, -C(O)O-C_1-6alkyl, -C_1-6alkylamino , phenoxy, benzoxy, phenyl, naphthyl, heteroaryl and C_1-4alkylOH; wherein C_1-6alkyl, phenyl, and naphthyl are optionally substituted with 1, 2, 3 or more substituents selected from the group consisting of halogen, hydroxyl, amino and C_1-6alkyl; and W is independently, for each occurrence, , O, S, or NR⁴.

[0098] In another embodiment, compounds of Formula M may be selected from the group consisting of:

wherein:

B is selected from the rou consistin of: ,

,

Q is independently, for each occurrence, N or CH;

V is independently, for each occurrence, O, S, NR⁴, or a bond; and

[0099] For example, compounds of Formula J, Formula K, Formula L or Formula M may be selected from the group consisting of:

wherein:

Q is independently, for each occurrence, N or CH;

V is independently, for each occurrence, O, S, NR⁴, or a bond;

W is independently, for each occurrence, H, halogen, C_1-6alkyl, C_1-6alkoxy, -NH-C_1- ₆alkyl, or -S-C_1-6alkyl; and

R⁴ is independently selected from the group consisting of hydrogen, hydroxyl, halo, amino, thiol, C_1-6alkyl, haloC_1-6alkyl, C_1-6alkoxy, -NH-C_1-6alkyl, -S-C_1-6alkyl, haloC_1-6alkoxy, nitro, cyano, -CF₃, -OCF₃, -C(O)O-C_1-6alkyl, -C_1-4alkylamino , phenoxy, benzoxy, and C_1- ₄alkylOH. [00100] In another embodiment, exemplary bromodomain ligands include compounds represented b the structures:

Formula O, wherein:

R¹ is selected from the group consisting of hydrogen, lower alkyl, phenyl, naphthyl, aralkyl, heteroalkyl, SO₂, NH₂, NO₂, CH₃, CH₂CH₃, OCH₃, OCOCH₃, CH₂COCH₃, OH, CN, and halogen;

R² is selected from the group consisting of hydrogen, lower alkyl, aralkyl, heteroalkyl, phenyl, naphthyl, SO₂, NH₂, NH ⁺

3 , NO₂, CH₃, CH₂CH₃, OCH₃, OCOCH₃, CH₂COCH₃, OH, halogen, carboxy, and alkoxy;

X is selected from the group consisting of lower alkyl, SO₂, NH, NO₂, CH₃, CH₂CH₃, OCH₃, OCOCH₃, CH₂COCH₃, OH, carboxy, and alkoxy; and

n is an integer from 0 to 10.

[00101] For example, compounds of Formula N or Formula O may be selected from the group consistin of:

Formula O

[00102] For example, see Chemistry&Biology 13:81 (2006) and International Patent Application Publication Nos. WO2007084625 and WO2012116170, each of which is hereby incorporated by reference in its entirety.

[00103] For example, the compound may be

[00104] In some embodiments, a ligand may be selected from the group consisting of:

,

[00105] In yet another embodiment, exemplary bromodomain ligands include compounds represented by the structures: Formula P, Formula Q,

Formula

R, and Formula S

wherein:

R¹, R², R³, R⁴, R⁵, and R⁶ are independently selected from the group consisting of hydrogen, lower alkyl, phenyl, naphthyl, aralkyl, heteroaryl, SO₂, NH₂, NH ⁺

3 , NO², SO², CH³, CH₂CH₃, OCH₃, OCOCH₃, CH₂COCH₃, OCH₂CH₃, OCH(CH₃)₂, OCH₂COOH,

OCHCH₃COOH, OCH₂COCH₃, OCH₂CONH₂, OCOCH(CH₃)₂, OCH₂CH₂OH, OCH₂CH₂CH₃, O(CH₂)₃CH₃, OCHCH₃COOCH₃, OCH₂CON(CH₃)₂, NH(CH₂)₃N(CH₃)₂, NH(CH₂)₂N(CH₃)₂, NH(CH₂)₂OH, NH(CH₂)₃CH₃, NHCH₃, SH, halogen, carboxy, and alkoxy.

[00106] In some embodiments, compounds of Formula P, Formula Q, Formula R, or Formula S may be selected from the group consisting of:

where:

00107 For exam le, the com ound ma be selected from the rou consistin of:

[00108] In still another embodiment, exemplary bromodomain ligands include com ounds re resented by the structure:

Formula T,

wherein:

R¹, R², and R³ are independently selected from the group consisting of hydrogen, lower alkyl, phenyl, naphthyl, aralkyl, heteroaryl, SO NH NH ⁺

2, ₂, ₃ , NO₂, SO₂, CH₃, CH₂CH₃, OCH₃, OCOCH₃, CH₂COCH₃, OH, SH, halogen, carboxy, and alkoxy; R⁴ is selected from the group consisting of lower alkyl, phenyl, naphthyl, SO₂, NH, NO₂, CH₃, CH₂CH₃, OCH₃, OCOCH₃, CH₂COCH₃, OH, carboxy, and alkoxy.

In yet another embodiment, exemplary bromodomain ligands include compounds represented by the structures:

or a pharmaceutically acceptable salt thereof,

wherein:

X is O or N;

Y is O or N; wherein at least one of X or Y is O;

W is C or N;

R¹ is H, alkyl, alkenyl, alkynyl, aralkyl, phenyl, naphthyl, heteroaryl, halo, CN, OR^A, NR^AR^B,

N(R^A)S(O)_qR^AR^B, N(R^A)C(O)R^B, N(R^A)C(O)NR^AR^B, N(R^A)C(O)OR^A,

N(R^A)C(S)NR^AR^B, S(O)_qR^A, C(O)R^A, C(O)OR^A, OC(O)R^A, or C(O)NR^AR^B;

each R^A is independently alkyl, alkenyl, or alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; phenyl; naphthyl, heteroaryl; heterocyclic; carbocyclic; or hydrogen;

each R^B is independently alkyl, alkenyl, or alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; phenyl; naphthyl; heteroaryl; heterocyclic; carbocyclic; or hydrogen; or

R^A and R^B, together with the atoms to which each is attached, can form a

heterocycloalkyl or a heteroaryl; each of which is optionally substituted;

Ring A is cycloalkyl, phenyl, naphthyl, heterocycloalkyl, or heteroaryl;

R^C is alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, naphthyl, heterocycloalkyl, or heteroaryl, each optionally substituted with 1-5 independently selected R⁴, and when L¹ is other than a covalent bond, R^C is additionally selected from H;

R² and R³ are each independently H, halogen, alkyl, alkenyl, alkynyl, phenyl, naphthyl, aralkyl, cycloalkyl, heteroaryl, heterocycloalkyl, -OR, -SR, -CN, -N(R’)(R’’), -C(O)R, -C(S)R, -CO₂R, -C(O)N(R’)(R’’), -C(O)SR, -C(O)C(O)R, -C(O)CH₂C(O)R, -C(S)N(R’)(R’’), - C(S)OR, -S(O)R, -SO₂R, -SO₂N(R’)(R’’), -N(R’)C(O)R, -N(R’)C(O)N(R’)(R’’), - N(R')C(S)N(R')(R"), -N(R’)SO₂R, -N(R’)SO₂N(R’)(R’’), -N(R’)N(R’)(R’’), - N(R’)C(=N(R’))N(R’)(R’’), -C=NN(R’)(R’’), -C=NOR, -C(=N(R’))N(R’)(R’’), -OC(O)R, - OC(O)N(R’)(R’’), or -(CH₂)_pR^x; or

R₂ and R₃ together with the atoms to which each is attached, form an optionally substituted 3-7 membered saturated or unsaturated spiro-fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each R^x is independently halogen, alkyl, alkenyl, alkynyl, phenyl, naphthyl, aralkyl, cycloalkyl, heteroaryl, heterocycloalkyl, -OR, -SR, -CN, -N(R’)(R’’), -C(O)R, -C(S)R, -CO₂R, -C(O)N(R’)(R’’), -C(O)SR, -C(O)C(O)R, -C(O)CH₂C(O)R, -C(S)N(R’)(R’’), -C(S)OR, - S(O)R, -SO₂R, -SO₂N(R’)(R’’), -N(R’)C(O)R, -N(R’)C(O)N(R’)(R’’), -N(R’)C(S)N(R’)(R’’), -N(R’)SO₂R, -N(R’)SO₂N(R’)(R’’), -N(R’)N(R’)(R’’), -N(R’)C(=N(R’))N(R’)(R’’), - C=NN(R’)(R’’), -C=NOR, -C(=N(R’))N(R’)(R’’), -OC(O)R, -OC(O)N(R’)(R’’);

L¹ is a covalent bond or an optionally substituted bivalent C_1-6 hydrocarbon chain wherein one or two methylene units is optionally replaced by -NR’-, -N (R’)C(O)-, - C(O)N(R’)-, -N(R’)SO₂-, -SO₂N(R’)- -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO₂-; each R is independently hydrogen, alkyl, alkenyl, alkynyl, phenyl, naphthyl, aralkyl, cycloalkyl, heteroaryl, or heterocycloalkyl;

each R’ is independently -R, -C(O)R, -C(S)R, -CO₂R, -C(O)N(R)₂, -C(S)N(R)₂, - S(O)R, -SO₂R, -SO₂N(R)₂, or two R groups on the same nitrogen are taken together with their intervening atoms to form an heteroaryl or heterocycloalkyl group; each R’’ is independently - R, -C(O)R, -C(S)R, -CO₂R, -C(O)N(R)₂, -C(S)N(R)₂, -S(O)R, -SO₂R, -SO₂N(R)₂, or two R groups on the same nitrogen are taken together with their intervening atoms to form an heteroaryl or heterocycloalkyl group; or

R’ and R’’, together with the atoms to which each is attached, can form cycloalkyl, heterocycloalkyl, phenyl, naphthyl, or heteroaryl; each of which is optionally substituted; each R⁴ is independently alkyl, alkenyl, alkynyl, phenyl, naphthyl, aralkyl, cycloalkyl, heteroaryl, or heterocycloalkyl, halogen, -OR, -SR, -N(R’)(R’’), -CN, -NO₂, -C(O)R, -C(S)R, - CO₂R, -C(O)N(R’)(R’’), -C(O)SR, -C(O)C(O)R, -C(O)CH₂C(O)R, -C(S)N(R’)(R’’), -C(S)OR, -S(O)R, -SO₂R, -SO₂N(R’)(R’’), -N(R’)C(O)R, -N(R’)C(O)N(R’)(R’’), -N(R’)C(S)N(R’)(R’’), -N(R’)SO₂R, -N(R’)SO₂N(R’)(R’’), -N(R’)N(R’)(R’’), -N(R’)C(=N(R^/))N(R')(R"), - C=NN(R')(R"), -C=NOR, -C(=N(R'))N(R')(R"), -OC(O)R, or -OC(O)N(R’)(R’’);

each R⁵ is independently -R, halogen, -OR, -SR, -N(R’)(R’’), -CN, -NO₂, -C(O)R, - C(S)R, -CO₂R, -C(O)N(R’)(R’’), -C(O)SR, -C(O)C(O)R, -C(O)CH₂C(O)R, -C(S)N(R’)(R’’), - C(S)OR, -S(O)R, -SO₂R, -SO₂N(R’)(R’’), -N(R’)C(O)R, -N(R’)C(O)N(R’)(R’’), - N(R’)C(S)N(R’)(R’’), -N(R’)SO₂R, -N(R’)SO₂N(R’)(R’’), -N(R’)N(R’)(R’’), - N(R’)C(=N(R’))N(R’)(R’’), -C=NN(R’)(R’’), -C=NOR, -C(=N(R’))N(R’)(R’’), -OC(O)R, or - OC(O)N(R’)(R’’);

n is 0-5;

each q is independently 0, 1, or 2; and

p is 1-6.

[00109] In still another embodiment, exemplary bromodomain ligands include compounds represented by the structure:

wherein:

X is O or N;

Y is O or N; wherein at least one of X or Y is O;

W is C or N;

N(R^A)S(O)_qR^AR^B, N(R^A)C(O)R^B, N(R^A)C(O)NR^AR^B, N(R^A)C(O)OR^A,

N(R^A)C(S)NR^AR^B, S(O)_qR^A, C(O)R^A, C(O)OR^A, OC(O)R^A, or C(O)NR^AR^B;

each R^A is independently optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; phenyl; naphthyl; heteroaryl; heterocyclic; carbocyclic; or hydrogen;

R^A and R^B, together with the atoms to which each is attached, can form a

heterocycloalkyl or a heteroaryl; each of which is optionally substituted;

Ring A is cycloalkyl, phenyl, naphthyl, heterocycloalkyl, or heteroaryl; R^C is alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, naphthyl, heterocycloalkyl, or heteroaryl, each optionally substituted with 1-5 independently selected R⁴, and when L¹ is other than a covalent bond, R^C is additionally selected from H;

R² is H, halogen, alkyl, alkenyl, alkynyl, phenyl, naphthyl, aralkyl, cycloalkyl, heteroaryl, heterocycloalkyl, -OR, -SR, -CN, -N(R’)(R’’), -C(O)R, -C(S)R, -CO₂R, - C(O)N(R’)(R’’), -C(O)SR, -C(O)C(O)R, -C(O)CH₂C(O)R, -C(S)N(R’)(R’’), -C(S)OR, - S(O)R, -SO₂R, -SO₂N(R’)(R’’), -N(R’)C(O)R, -N(R’)C(O)N(R’)(R’’), -N(R')C(S)N(R')(R"), - N(R’)SO₂R, -N(R’)SO₂N(R’)(R’’), -N(R’)N(R’)(R’’), -N(R’)C(=N(R’))N(R’)(R’’), - C=NN(R’)(R’’), -C=NOR, -C(=N(R’))N(R’)(R’’), -OC(O)R, -OC(O)N(R’)(R’’), or -(CH₂)_pR^x;

R³ is a bond or optionally substituted alkyl; or

L¹ is a covalent bond or an optionally substituted bivalent C_1-6 hydrocarbon chain wherein one or two methylene units is optionally replaced by -NR’-, -N (R’)C(O)-, - C(O)N(R’)-, -N(R’)SO₂-, -SO₂N(R’)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO-, or -SO₂-; each R is independently hydrogen, alkyl, alkenyl, alkynyl, phenyl, naphthyl, aralkyl, cycloalkyl, heteroaryl, or heterocycloalkyl;

each R’ is independently -R, -C(O)R, -C(S)R, -CO₂R, -C(O)N(R)₂, -C(S)N(R)₂, - S(O)R, -SO₂R, -SO₂N(R)₂, or two R groups on the same nitrogen are taken together with their intervening atoms to form an heteroaryl or heterocycloalkyl group; each R’’ is independently - R, -C(O)R, -C(S)R, -CO₂R, -C(O)N(R)₂, -C(S)N(R)₂, -S(O)R, -SO₂R, -SO₂N(R)₂, or two R groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted heteroaryl or heterocycloalkyl group; or

n is 0-5;

each q is independently 0, 1, or 2; and

p is 1-6.

[00110] In yet another embodiment, compounds of Formula U, Formula V, and Formula W may be selected from the group consisting of:

It wil l be apprec iated that ea ch of these compo unds may b e connected to a–Y-Z moiety, for example, a s illustrate d for generi c structu res Formula U, Formu la V, and F ormula W a bove.

[00111 ] For example, c ompounds of Formula U, Formul a V, and Fo rmula W m ay be selecte d from the g roup consi sting of:

H

. It will be appreciated that each of these compounds may be connected to a–Y-Z moiety, for example, as illustrated for generic structures Formula U, Formula V, and Formula W above.

[00112] In some embodiments, compounds of Formula U, Formula V, and Formula W may be selected from the group consisting of:

, , , ,

It will be appreciated that each of these compounds may be connected to a–Y-Z moiety, for example, as illustrated for generic structures Formula U, Formula V, and Formula W above.

[00113] In some embodiments, exemplary bromodomain ligands include compounds represented by the structures: _{F l XX}

wherein:

Ring A is benzo, or a 5-6 membered fused heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

Ring B is a 3-7 membered saturated or partially unsaturated carbocyclic ring, phenyl, an 8-10 membered bicyclic saturated, partially unsaturated, phenyl or naphthyl ring, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

L¹ is a covalent bond or an optionally substituted bivalent C_1-6 hydrocarbon chain wherein one or two methylene units is optionally replaced by–NR’-, -N(R’)C(O)-, - C(O)N(R’), -N(R’)SO₂-, -SO₂N(R’), -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO₂-;

R¹ is hydrogen, halogen, optionally substituted C_1-6 aliphatic, -OR, -SR, -CN, -N(R’)₂, - C(O)R, -C(S)R, -CO₂R, -C(O)N(R’)₂, -C(O)SR, -C(O)C(O)R, -C(O)CH₂C(O)R, -C(S)N(R’)₂, - C(S)OR, -S(O)R, -SO₂R, -SO₂N(R’)₂, -N(R’)C(O)R, -N(R’)C(O)N(R’)₂, -N(R’)C(S)N(R’)₂, - N(R’)SO₂R, -N(R’)SO₂N(R’)₂, -N(R’)N(R’)₂, -N(R’)C(=N(R’))N(R’)₂, -C=NN(R’)₂, -C=NOR, -C(=N(R’))N(R’)₂, -OC(O)R, -OC(O)N(R’)₂, or -(CH₂)_pR^x;

p is 0-3; R^x is halogen, optionally substituted C_1-6 aliphatic, -OR, -SR, -CN, -N(R’)₂, -C(O)R, - C(S)R, -CO₂R, -C(O)N(R’)₂, -C(O)SR, -C(O)C(O)R, -C(O)CH₂C(O)R, -C(S)N(R’)₂, -C(S)OR, -S(O)R, -SO₂R, -SO₂N(R’)₂, -N(R’)C(O)R, -N(R’)C(O)N(R’)₂, -N(R’)C(S)N(R’)₂, - N(R’)SO₂R, -N(R’)SO₂N(R’)₂, -N(R’)N(R’)₂, -N(R’)C(=N(R’))N(R’)₂, -C=NN(R’)₂, -C=NOR, -C(=N(R’))N(R’)₂, -OC(O)R, -OC(O)N(R’)₂;

R² is hydrogen, halogen, -CN, -SR, or optionally substituted C_1-6 aliphatic, or:

R¹ and R² are taken together with their intervening atoms to form an optionally substituted 3-7 membered saturated or partially unsaturated spiro-fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each R is independently hydrogen or an optionally substituted group selected from C_1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 7-10 membered bicyclic saturated, partially unsaturated, phenyl or naphthyl ring, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms

independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each R’ is independently -R, -C(O)R, -C(S)R, -CO₂R, -C(O)N(R)₂, -C(S)N(R)₂, - S(O)R, -SO₂R, -SO₂N(R)₂, or two R’ on the same nitrogen are taken together with their intervening atoms to form an optionally substituted group selected from a 4-7 membered monocyclic saturated or partially unsaturated ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 7-12 membered bicyclic saturated, partially unsaturated, or aromatic fused ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; W is

R³ is optionally substituted C_1-6 aliphatic;

X is oxygen or sulfur, or:

R³ and X are taken together with their intervening atoms to form an optionally substituted 5-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each of m and n is independently 0-4, as valency permits; and

each of R⁴ and R⁵ is independently -R, halogen, -OR, -SR, -N(R’)₂, -CN, -NO₂, -C(O)R, -C(S)R, -CO₂R, -C(O)N(R’)₂, -C(O)SR, -C(O)C(O)R, -C(O)CH₂C(O)R, -C(S)N(R’)₂, - C(S)OR, -S(O)R, -SO₂R, -SO₂N(R’)₂, -N(R’)C(O)R, -N(R’)C(O)N(R’)₂, -N(R’)C(S)N(R’)₂, - N(R’)SO₂R, -N(R’)SO₂N(R’)₂, -N(R’)N(R’)₂, -N(R’)C(=N(R’))N(R’)₂, -C=NN(R’)₂, -C=NOR, -C(=N(R’))N(R’)₂, -OC(O)R, or -OC(O)N(R’)₂.

[00114] In another embodiment, exemplary bromodomain ligands include compounds represented by the structures:

wherein:

p is 0-3;

R^x is halogen, optionally substituted C_1-6 aliphatic, -OR, -SR, -CN, -N(R’)₂, -C(O)R, - C(S)R, -CO₂R, -C(O)N(R’)₂, -C(O)SR, -C(O)C(O)R, -C(O)CH₂C(O)R, -C(S)N(R’)₂, -C(S)OR, -S(O)R, -SO₂R, -SO₂N(R’)₂, -N(R’)C(O)R, -N(R’)C(O)N(R’)₂, -N(R’)C(S)N(R’)₂, - N(R’)SO₂R, -N(R’)SO₂N(R’)₂, -N(R’)N(R’)₂, -N(R’)C(=N(R’))N(R’)₂, -C=NN(R’)₂, -C=NOR, -C(=N(R’))N(R’)₂, -OC(O)R, -OC(O)N(R’)₂;

R² is a bond or optionally substituted C_1-6 aliphatic, or:

each R is independently hydrogen or an optionally substituted group selected from C_1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 7-10 membered bicyclic saturated, partially unsaturated, phenyl, or naphthyl ring, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms

R³ is optionally substituted C_1-6 aliphatic;

X is oxygen or sulfur, or:

R³ and X are taken together with their intervening atoms to form an optionally substituted

5-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each of m and n is independently 0-4, as valency permits; and

each of R⁴ and R⁵ is independently–R, halogen, -OR, -SR, -N(R’)₂, -CN, -NO₂, - C(O)R, -C(S)R, -CO₂R, -C(O)N(R’)₂, -C(O)SR, -C(O)C(O)R, -C(O)CH₂C(O)R, -C(S)N(R’)₂, - C(S)OR, -S(O)R, -SO₂R, -SO₂N(R’)₂, -N(R’)C(O)R, -N(R’)C(O)N(R’)₂, -N(R’)C(S)N(R’)₂, - N(R’)SO₂R, -N(R’)SO₂N(R’)₂, -N(R’)N(R’)₂, -N(R’)C(=N(R’))N(R’)₂, -C=NN(R’)₂, -C=NOR, -C(=N(R’))N(R’)₂, -OC(O)R, or -OC(O)N(R’)₂.

[00115] For example, a compound of Formula X, Formula Y, or Formula Z may be selected from the rou consistin of:

,

It will be appreciated that each of these compounds may be connected to a–Y-Z moiety, for example, as illustrated for generic structures Formula X, Formula Y, and Formula Z above.

[00116] In some embodiments, a compound of Formula XX, Formula YY, or Formula ZZ ma be selected from the rou consistin of:

be appreciated that each of these compounds may be connected to a–Y-Z moiety, for example, as illustrated for generic structures Formula XX, Formula YY, and Formula ZZ above.

[00117] In another embodiment, exemplary bromodomain ligands include compounds represented by the structures:

Formula ZZA,

wherein:

Ring B is a 3-7 membered saturated or partially unsaturated carbocyclic ring, phenyl, an 8-10 membered bicyclic saturated, partially unsaturated, phenyl, or naphthyl ring, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

R¹ is independently hydrogen, halogen, optionally substituted C_1-6 aliphatic, -OR, -SR, - CN, -N(R’)₂, -C(O)R, -C(S)R, -CO₂R, -C(O)N(R’)₂, -C(O)SR, -C(O)C(O)R, -C(O)CH₂C(O)R, -C(S)N(R’)₂, -C(S)OR, -S(O)R, -SO₂R, -SO₂N(R’)₂, -N(R’)C(O)R, -N(R’)C(O)N(R’)₂, - N(R’)C(S)N(R’)₂, -N(R’)SO₂R, -N(R’)SO₂N(R’)₂, -N(R’)C(=N(R’))N(R’)₂, -C=NN(R’)₂, - C=NOR, -C(=N(R’))N(R’)₂, -OC(O)R, -OC(O)N(R’)₂, or -(CH ^x

2)_pR ;

R² is a bond, hydrogen, or optionally substituted C_1-6 aliphatic;

each R’ is independently -R, -C(O)R, -C(S)R, -CO₂R, -C(O)N(R)₂, -C(S)N(R)₂, - S(O)R, -SO₂R, -SO₂N(R)₂, or two R’ on the same nitrogen are taken together with their intervening atoms to form an optionally substituted group selected from a 4-7 membered monocyclic saturated or partially unsaturated ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 7-12 membered bicyclic saturated, partially unsaturated, or aromatic fused ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

W is C or N;

R³ is optionally substituted C_1-6 aliphatic;

is a single or double bond;

each of m and n is independently 0-4, as valency permits; and

each of R⁴ and R⁵ is independently–R, halogen, -OR, -SR, -N(R’)₂, -CN, -NO₂, - C(O)R, -C(S)R, -CO₂R, -C(O)N(R’)₂, -C(O)SR, -C(O)C(O)R, -C(O)CH₂C(O)R, -C(S)N(R’)₂, - C(S)OR, -S(O)R, -SO₂R, -SO₂N(R’)₂, -N(R’)C(O)R, -N(R’)C(O)N(R’)₂, -N(R’)C(S)N(R’)₂, - N(R’)SO₂R, -N(R’)SO₂N(R’)₂, -N(R’)N(R’)₂, -N(R’)C(=N(R’))N(R’)₂, -C=NN(R’)₂, -C=NOR, -C(=N(R’))N(R’)₂, -OC(O)R, or -OC(O)N(R’)₂. [00118] For example, a compound of formula XXA, YYA, or ZZA may be:

[00119] wherein XX may be a bond, C_1-6alkyl, -NR^t- (where t is H, phenyl, or C_1-6alkyl), -O-, or -S(O)_w- wherein w is 0, 1, or 2;

[00120] In yet another embodiment, exemplary bromodomain ligands include compounds represented by the structure:

AA3,

wherein:

X is selected from N and CH;

Y is CO;

R¹ and R³ are each independently selected from alkoxy and hydrogen;

R² is selected from alkoxy, alkyl, and hydrogen;

R⁶ and R⁸ are each independently selected from alkyl, alkoxy, chloride, and hydrogen; R⁵ and R⁹ are each hydrogen;

R⁷ is selected from amino, hydroxyl, alkoxy, and alkyl substituted with a heterocyclyl; R¹⁰ is hydrogen; or

two adjacent substituents selected from R⁶, R⁷, and R⁸ are connected to form a heterocyclyl;

each W is independently selected from C and N, wherein if W is N, then p is 0 or 1, and if W is C, then p is 1;

for W-(R¹⁰)_p, W is N and p is 1; and

for W-(R⁴)_p, W is C, p is 1 and R⁴ is H, or W is N and p is 0.

[00121] For exam le, in some embodiments, a compound of Formula AA may be:

[00122]

(2-(4-(2-hydroxyethoxy)-3,5- dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one). It will be appreciated that this compound may be connected to a–Y-Z moiety, for example, as illustrated for generic structures Formula AA, Formula AA1, Formula AA2, and Formula AA3 above.

[00123] In still another embodiment, exemplary bromodomain ligands include compounds represented by the structures:

wherein:

Y and W are each independently selected from carbon and nitrogen;

Ra⁶ is selected from fluoride, hydrogen, C₁-C₃ alkoxy, cyclopropyloxy, SO₂R₃, SOR₃, and SR₃, wherein if Y is nitrogen then Ra⁶ is absent;

Ra⁷ is selected from hydrogen, fluoride, SO₂R₃, SOR₃, and SR₃;

Ra⁸ is selected from hydrogen, C₁-C₃ alkoxy, cyclopropyloxy, chloride, and bromide;

n is selected from 1, 2, or 3;

D is selected from O, NH, NR₁, S, or C;

Rb³ and Rb⁵ are independently selected from hydrogen and C₁-C₃ alkyl;

R ³

C and R ⁵

C are independently selected from hydrogen, C₁-C₃ alkyl, and cyclopropyl;

R ⁴

C is selected from F, Cl, Br, I, CF₃, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, NHC(O)R⁴,

R¹, R’¹, R² and R’² are independently selected from hydrogen, fluoride, C₁-C₃ alkyl, and cyclopropyl, wherein R¹ and R² and/or R’¹ and R’² may be connected to form a 3-6 membered ring;

R³ is selected from C₁-C₃ alkyl and cyclopropyl; and

R⁴ is selected from hydrogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl, phenyl, and naphthyl, provided that if Ra⁷ or Ra⁶ is fluoride, then R ⁴

C is not bromide.

[00124] In some embodiments, a compound of Formula AA, Formula AA1, Formula AA2, Formula AA3, Formula BB, or Formula CC may be selected from the group consisting of:

3-(4-sec-butylphenyl)-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one; 3-(4-bromophenyl)-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin- 4(3H)-one;

3-(4-sec-butylphenyl)-7-fluoro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)- one;

3-(4-sec-butylphenyl)-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)pyrido[4,3-d]pyrimidin- 4(3H)-one;

3-(4-sec-butylphenyl)-2-(4-(2-hydroxyethoxy)phenyl)quinazolin-4(3H)-one;

3-(4-fluorophenyl)-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;

2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-3-(4-iodophenyl)quinazolin-4(3H)-one; 3-(4-sec-butylphenyl)-6-fluoro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)- one;

3-(4-chlorophenyl)-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;

2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-3-(4-(trifluoromethyl)phenyl)quinazolin-4(3H)- one;

3-(4-sec-butylphenyl)-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-7- (methylsulfonyl)quinazolin-4(3H)-one;

3-(4-sec-butylphenyl)-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6-methoxyquinazolin- 4(3H)-one;

3-(4-sec-butylphenyl)-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-8-methoxyquinazolin- 4(3H)-one;

3-(4-sec-butylphenyl)-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6- (methylsulfonyl)quinazolin-4(3H)-one;

3-(4-bromophenyl)-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6-methoxyquinazolin-4(3H)- one;

3-(4-bromophenyl)-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-8-methoxyquinazolin-4(3H)- one;

2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-3-(4-isopropylphenyl)quinazolin-4(3H)-one; 3-(4-bromophenyl)-2-(4-(2-hydroxyethoxy)-3-methyiphenyl)quinazolin-4(3H)-one;

3-(4-bromophenyl)-8-chloro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)- one;

2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-3-(4-morpholinophenyl)quinazolin-4(3H)-one; 3-(4-tert-butylphenyl)-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one; N-(4-(2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-4-oxoquinazolin-3(4H)- yl)phenyl)acetamide;

N-(4-(2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-4-oxoquinazolin-3(4H)- yl)phenyl)isobutyramide;

methyl 4-(2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-4-oxoquinazolin-3(4H)-yl)benzoate; 3-(4-cyclohexylphenyl)-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one; N-(4-(2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-4-oxoquinazolin-3(4H)- yl)phenyl)formamide;

3-(4-aminophenyl)-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one; N-(4-(2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-4-oxoquinazolin-3(4H)- yl)phenyl)methanesulfonamide;

N-(4-(2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-4-oxoquinazolin-3(4H)- yl)phenyl)benzenesulfonamide;

N-(4-(2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-4-oxoquinazolin-3(4H)-yl)phenyl)propane- 2-sulfonamide;

3-(4-(dimethylamino)phenyl)-2-(4-(2-hydroxyethoxy)-3,5-dimethyiphenyl)quinazolin-4(3H)- one;

3-(4-sec-butylphenyl)-2-(4-(2-hydroxyethoxy)-3-methylphenyl)quinazolin-4(3H)-one;

3-(4-chlorophenyl)-2-(4-(2-hydroxyethoxy)-3-methylphenyl)quinazolin-4(3H)-one;

3-(4-sec-butylphenyl)-2-(pyridin-3-yl)quinazolin-4(3H)-one;

3-(4-chlorophenyl)-2-(quinolin-3-yl)quinazolin-4(3H)-one;

3-(4-sec-butylphenyl)-2-(5-fluoropyridin-3-yl)quinazolin-4(3H)-one;

3-(4-chlorophenyl)-2-(6-chloropyridin-3-yl)quinazolin-4(3H)-one;

3-(4-sec-butylphenyl)-2-(6-chloropyridin-3-yl)quinazolin-4(3H)-one;

3-(4-sec-butylphenyl)-2-(6-methoxypyridin-3-yl)quinazolin-4(3H)-one;

2-(6-bromopyridin-3-yl)-3-(4-chlorophenyl)quinazolin-4(3H)-one;

2-(6-bromopyridin-3-yl)-3-(4-sec-butylphenyl)quinazolin-4(3H)-one;

3-(4-chlorophenyl)-2-(6-(diethylamino)pyridin-3-yl)quinazolin-4(3H)-one;

3-(4-sec-butylphenyl)-2-(6-(diethylamino)pyridin-3-yl)quinazolin-4(3H)-one;

3-(4-sec-butylphenyl)-2-(pyrimidin-5-yl)quinazolin-4(3H)-one;

3-(4-sec-butylphenyl)-2-(6-methylpyridin-3-yl)quinazolin-4(3H)-one;

3-(4-chlorophenyl)-2-(6-methylpyridin-3-yl)quinazolin-4(3H)-one;

3-(4-chlorophenyl)-2-(6-(piperidin-1-yl)pyridin-3-yl)quinazolin-4(3H)-one;

3-(4-sec-butylphenyl)-2-(6-(piperidin-1-yl)pyridin-3-yl)quinazolin-4(3H)-one;

3-(4-chlorophenyl)-2-(6-phenoxypyridin-3-yl)quinazolin-4(3H)-one;

3-(4-sec-butylphenyl)-2-(6-fluoropyridin-3-yl)quinazolin-4(3H)-one;

3-(4-sec-butylphenyl)-2-(6-phenoxypyridin-3-yl)quinazolin-4(3H)-one;

3-(4-chlorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)quinazolin-4(3H)-one;

3-(4-sec-butylphenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)quinazolin-4(3H)-one;

3-(4-sec-butylphenyl)-2-(6-phenylpyridin-3-yl)quinazolin-4(3H)-one;

3-(4-sec-butylphenyl)-2-(5-phenylpyridin-3-yl)quinazolin-4(3H)-one; 2-(5-bromopyridin-3-yl)-3-(4-sec-butylphenyl)quinazolin-4(3H)-one;

2-(5-bromopyridin-3-yl)-3-(4-chlorophenyl)quinazolin-4(3H)-one;

3-(4-sec-butylphenyl)-2-(5-(diethylamino)pyridin-3-yl)quinazolin-4(3H)-one;

3-(4-chlorophenyl)-2-(5-phenylpyridin-3-yl)quinazolin-4(3H)-one;

3-(4-chlorophenyl)-2-(5-(diethylamino)pyridin-3-yl)quinazolin-4(3H)-one;

3-(4-cyclopentylphenyl)-2-(6-methylpyridin-3-yl)quinazolin-4(3H)-one;

3-(4-sec-butylphenyl)-2-(6-(hydroxymethyl)pyridin-3-yl)quinazolin-4(3H)-one;

2-(6-methylpyridin-3-yl)-3-(4-(methylthio)phenyl)quinazolin-4(3H)-one;

3-(4-isopropylphenyl)-2-(6-methylpyridin-3-yl)quinazolin-4(3H)-one;

N-(4-(2-(6-methylpyridin-3-yl)-4-oxoquinazolin-3(4H)-yl)phenyl)methanesulfonamide;

3-(4-sec-butylphenyl)-2-(6-(morpholinomethyl)pyridin-3-yl)quinazolin-4(3H)-one;

3-(4-cyclopropylphenyl)-2-(6-methylpyridin-3-yl)quinazolin-4(3H)-one;

3-(4-(dimethylamino)phenyl)-2-(6-methylpyridin-3-yl)quinazolin-4(3H)-one;

2-(6-chloropyridin-3-yl)-3-(4-cyclopropylphenyl)quinazolin-4(3H)-one;

3-(4-sec-butylphenyl)-2-(6-morpholinopyridin-3-yl)quinazolin-4(3H)-one;

3-(4-sec-butylphenyl)-2-(1H-indazol-5-yl)quinazolin-4(3H)-one;

3-(4-chlorophenyl)-2-(1H-indol-5-yl)quinazolin-4(3H)-one;

3-(4-sec-butylphenyl)-2-(1H-indol-5-yl)quinazolin-4(3H)-one;

3-(4-sec-butylphenyl)-2-(2-(hydroxymethyl)-1H-benzo[d]imidazol-6-yl)quinazolin-4(3H)-one; 2-(1H-indol-5-yl)-3-(4-(trifluoromethoxy)phenyl)quinazolin-4(3H)-one;

2-(1H-indol-5-yl)-3-(4-isopropylphenyl)quinazolin-4(3H)-one;

3-(4-chlorophenyl)-2-(1-(4-methoxyphenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)quinazolin- 4(3H)-one;

3-(4-chlorophenyl)-2-(1-(4-fluorophenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)quinazolin- 4(3H)-one;

3-(4-(dimethylamino)phenyl)-2-(1H-indol-5-yl)quinazolin-4(3H)-one;

3-(4-chlorophenyl)-2-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)quinazolin-4(3H)-one; 3-(4-sec-butylphenyl)-2-(2-(hydroxymethyl)-1H-indol-5-yl)quinazolin-4(3H)-one;

3-(4-chlorophenyl)-2-(1-methyl-1H-indol-5-yl)quinazolin-4(3H)-one;

3-(4-cyclopentylphenyl)-2-(1H-indol-5-yl)quinazolin-4(3H)-one;

3-(4-chlorophenyl)-2-(1H-indol-6-yl)quinazolin-4(3H)-one;

3-(4-chlorophenyl)-2-(1H-indol-7-yl)quinazolin-4(3H)-one; 3-(4-sec-butylphenyl)-2-(1H-indol-6-yl)quinazolin-4(3H)-one;

3-(4-sec-butylphenyl)-2-(1H-indol-7-yl)quinazolin-4(3H)-one;

3-(4-chlorophenyl)-2-(1H-indol-4-yl)quinazolin-4(3H)-one; and

3-(4-sec-butylphenyl)-2-(1H-indol-4-yl)quinazolin-4(3H)-one. It will be appreciated that each of these compounds may be connected to a–Y-Z moiety, for example, as illustrated for generic structures Formula AA, Formula AA1, Formula AA2, Formula AA3, Formula BB, Formula CC, and Formula DD.

[00125] In yet another embodiment, exemplary bromodomain ligands include compounds represented by the structure:

wherein:

Q and V are independently selected from CH and nitrogen;

U is selected from C=O, C=S, SO₂, S=O, SR¹, CR¹R², CR¹OR², CR¹SR²;

R¹ and R² are independently selected from hydrogen and C₁-C₆ alkyl;

Rc is selected from hydrogen, C₁-C₆ alkyl, and C₃-C₆ cycloalkyl;

Ra¹, Ra², and Ra³ are independently selected from hydrogen, C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, C₁-C₆ alkoxy, halogen, amino, amide, hydroxyl, heterocycle, and C₃-C₆ cycloalkyl, wherein Ra¹ and Ra² and/or Ra² and Ra³ may be connected to form a cycloalkyl or a heterocycle;

Rb² and Rb⁶ are independently selected from hydrogen, halogen, C₁-C₆ alkyl, C₁-C₆ alkenyl, C₃-C₆ cycloalkyl, hydroxyl, and amino; Rb³ and Rb⁵ are independently selected from hydrogen, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkyl, hydroxyl, and amino, wherein Rb² and Rb³ and/or Rb⁵ and Rb⁶ may be connected to form a cycloalkyl or a heterocycle;

represents a 3-8 membered ring system wherein: W is selected from carbon and nitrogen; Z is selected from CR⁶R⁷, NR⁸, oxygen, sulfur, -S(O)-, and -SO₂-;

said ring system being optionally fused to another ring selected from cycloalkyl, heterocycle, and phenyl, and wherein said ring system is optionally selected from rings having the

r r

R³, R⁴, and R⁵ are independently selected from hydrogen, C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkyl, phenyl, naphthyl, aryloxy, hydroxy1, amino, amide, oxo, -CN, and sulfonamide;

R⁶ and R⁷ are independently selected from hydrogen, C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, C₃-C₆ cycloalkyl, phenyl, naphthyl, halogen, hydroxyl, -CN, amino, and amido; and R⁸ is selected from hydrogen, C_1-C₆ alkyl, C₁-C₆ alkenyl, C_1-C₆ alkynyl, acyl, and C₃-C₆ cycloalkyl; and R⁹, R¹⁰, R¹¹, and R¹² are independently selected from hydrogen, C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, C₃-C₆ cycloalkyl, phenyl, naphthyl, heterocycle, hydroxyl, sulfonyl, and acyl.

[00126] In still another embodiment, exemplary bromodomain ligands include com ounds re resented b the structure:

GG,

wherein:

Q is selected from N and CRa³;

V is selected from N and CRa⁴;

W is selected from N and CH;

U is selected from C=O, C=S, SO₂, S=O, and SR¹;

X is selected from OH, SH, NH₂, S(O)H, S(O)₂H, S(O)₂NH₂, S(O)NH₂, NHAc, and NHSO₂Me;

Ra¹, Ra³, and Ra³ are independently selected from hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkyl, and halogen;

Ra² is selected from hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkyl, amino, amide, and halogen;

Rb² and Rb⁶ are independently selected from hydrogen, methyl and fluorine;

Rb³ and Rb⁵ are independently selected from hydrogen, halogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, and C₁-C₆ alkoxy; and

Rb² and Rb³ and/or Rb⁵ and Rb⁶ may be connected to form a cycloalkyl or a heterocycle, provided that at least one of Ra¹, Ra², Ra³, and Ra⁴ is not hydrogen.

[00127] In yet another embodiment, exemplary bromodomain ligands include compounds represented by the structure:

wherein:

Q is selected from N and CRa³;

V is selected from N and CRa⁴;

W is selected from N and CH;

U is selected from C=O, C=S, SO₂, S=O, and SR¹;

Rb² and Rb⁶ are independently selected from hydrogen, methyl and fluorine;

[00128] The following are hereby incorporated by reference in their entirety: Zeng et al. J. Am. Chem. Soc. (2005) 127, 2376-2377; Chung et al. J. Med. Chem. (2012) 55, 576-586; Filippakopoulos et al. Bioorg. Med. Chem. (2012) 20, 1878-1886; U.S. Patent No. 8,053,440, by Hansen; U.S. Patent Publication No. 2008/0188467, by Wong et al.; U.S. Patent Publication No. 2012/0028912; International Patent Publication Nos. WO/2010/123975, WO/2010/106436, WO/2010/079431, WO/2009/158404, and WO/2008/092231, by Hansen et al.; International Patent Publication Nos. WO/2012/075456 and WO/2012/075383, by Albrecht et al.;

International Patent Publication Nos. WO/2012/116170, WO/2007/084625, and

WO/2006/083692, by Zhou et al.

[00129] In another aspect, exemplary bromodomain ligands include fused heterocyclic systems represented by the structures: ,

wherein:

V is independently selected, for each occurrence, from the group consisting of NH, S, N(C_1-6alkyl), O, or CR⁴R⁴;

Q is independently selected, for each occurrence, from the group consisting of C(O), C(S), C(N), SO₂, or CR⁴R⁴;

U is independently selected from the group consisting of a bond, C(O), C(S), C(N), SO₂, or CR⁴R⁴

W and T are independently selected from the group consisting of NH, N(C_1-6alkyl), O, or Q;

V^C is selected from the group consisting of N, SH or CR⁴;

A is selected from the group consisting of aliphatic, cycloalkyl, heterocyclic, phenyl, naphthyl, heteroaryl or bicyclic moiety, wherein the cycloalkyl, heterocyclic, phenyl, naphthyl, heteroaryl, or bicyclic moiety is optionally substituted with one, two, three, four or more groups represented by R⁴;

R¹ is independently selected, for each occurrence, from the group consisting of hydroxyl, halo, C_1-6alkyl, hydroxyC_1-6alkyl, aminoC_1-6alkyl,

C_1-6alkoxy, haloC_1- ₆alkoxy, acylaminoC_1-6alkyl, nitro, cyano, CF₃, -OCF₃, -C(O)OC_1-6alkyl, -OS(O)₂C_1-4alkyl, phenyl, naphthyl, phenyloxy, benzyloxy, or phenylmethoxy, wherein C_1-6alkyl, phenyl, and naphthyl are optionally substituted by one two or three substituents selected from the group consisting of hydroxyl, halogen, oxo, amino, or nitro;

R² is selected from the group consisting of -O-, amino, C_1-6alkyl, -O-C_1-6alkyl-, hydroxylC_1-6alkyl, aminoC_1-6alkyl, haloC_1-6alkyl,

acylaminoC_1-6alkyl, -C(O)-, - C(O)O-, -C(O)NC_1-6alkyl-, -OS(O)₂C_1-4alkyl-, -OS(O)₂-, -S-C_1-6alkyl-, phenyl, naphthyl, phenyloxy, benzyloxy, or phenylmethoxy, wherein C_1-6alkyl, phenyl, and naphthyl are optionally substituted by one two or three substituents selected from the group consisting of hydroxyl, halogen, oxo, C_1-6alkyl, amino, or nitro;

R³ is selected from the group consisting of hydrogen or C_1-6alkyl;

R⁴ is independently selected, for each occurrence, from the group consisting of hydrogen, hydroxyl, oxo, imino, amino, halo, C_1-6alkyl, cycloalkyl, phenyl, naphthyl, heterocyclyl, -O-C_1-6alkyl, -NH-C_1-6alkyl, -N(C_1-6alkyl)C_1-6alkyl, nitro, cyano, CF₃, - OCF₃, -C(O)OC_1-6alkyl, -C(O)NHC_1-6alkyl, -C(O)NH₂ or -OS(O)₂C_1-4alkyl;

m is selected from the group consisting of 0, 1, 2, or 3;

n is selected from the group consisting of 0, 1, or 2; and

p is selected from the group consisting of 0 or 1.

[00130] For example, compounds of Formula 1, Formula 2 or Formula 5 may be selected from the group consisting of:

[00131] In a further example, compounds of Formula 1, Formula 2 or Formula 5 may be selected from the group consisting of:

- 103 - [00132] For example, compounds of Formula 3, Formula 3’ or Formula 4 may be selected from the group consisting of:

[00133] In another embodiment, bromodomain ligands include fused heterocyclic systems represented by the structures:

wherein:

V^C is selected from the group consisting of N, SH or CR⁴;

A is a ring selected from the group consisting of: phenyl, a 5-6 membered cycloalkyl, a 5-6 membered heteroaryl having 1, 2 or 3 heteroatoms each selected from S, N or O, and a 4-7 membered heterocycle having 1, 2 or 3 heteroatoms each selected from N or O;

R^A1 is R¹; or two R^A1 substituents may be taken together with the atoms to which they are attached to form phenyl, a 5-6 membered heteroaryl having 1, 2 or 3 heteroatoms each selected from S, N or O, and a 4-7 membered heterocycle having 1, 2 or 3 heteroatoms each selected from N or O;

C_1-6alkoxy, haloC_1- ₆alkoxy, acylaminoC_1-6alkyl, nitro, cyano, CF₃, -OCF₃, -C(O)OC_1-6alkyl, -OS(O)₂C_1-4alkyl, phenyl, naphthyl, phenyloxy, benzyloxy or phenylmethoxy, wherein C_1-6alkyl, phenyl, and naphthyl are optionally substituted by one two or three substituents selected from the group consisting of hydroxyl, halogen, oxo, C_1-6alkyl, amino, or nitro;

acylaminoC_1-6alkyl, -C(O)-, - C(O)O-, -C(O)NC_1-6alkyl-, -OS(O)₂C_1-4alkyl-, -OS(O)₂-, -S-C_1-6alkyl-, phenyl, naphthyl, phenyloxy, benzyloxy or phenylmethoxy, wherein C_1-6alkyl phenyl, and naphthylare optionally substituted by one two or three substituents selected from the group consisting of hydroxyl, halogen, oxo,

amino, or nitro;

R³ is selected from the group consisting of hydrogen or C_1-6alkyl;

R⁴ is independently selected, for each occurrence, selected from the group consisting of hydrogen, hydroxyl, oxo, imino, amino, halo, C_1-6alkyl, cycloalkyl, phenyl, naphthyl, heterocyclyl, -O-C_1-6alkyl, -NH-C_1-6alkyl, -N(C_1-6alkyl)C_1-6alkyl, nitro, cyano, CF₃, - OCF₃, -C(O)OC_1-6alkyl, -C(O)NHC_1-6alkyl, -C(O)NH₂ or -OS(O)₂C_1-4alkyl;

m is independently selected, for each occurrence, selected from the group consisting of 0, 1, 2, or 3;

n is selected from the group consisting of 0, 1, or 2; and

p is selected from the group consisting of 0 or 1.

[00134] For example, compounds of Formula 1a, Formula 2a or Formula 5a may be selected from the group consisting of:

. [00135] For example, compounds of Formula 3a or Formula 4a may be selected from the rou consistin of:

,

[00136] In a further embodiment, bromodomain ligands include fused heterocyclic systems represented by the structures:

1 2

wherein:

V is selected from the group consisting of a NH, S, N(C_1-6alkyl), O, or CR⁴R⁴;

Q is selected from the group consisting of a bond, C(O), C(S), C(N), SO₂, or CR⁴R⁴; A is a ring selected from the group consisting of: phenyl, a 5-6 membered cycloalkyl, a 5-6 membered heteroaryl having 1, 2 or 3 heteroatoms each selected from S, N or O, and a 4-7 membered heterocycle having 1, 2 or 3 heteroatoms each selected from N or O;

R^A1 is R¹; or two R^A1 substituents may be taken together with the atoms to which they are attached to form phenyl, a 5-6 membered heteroaryl having 1, 2 or 3 heteroatoms each selected from S, N or O, and a 4-7 membered heterocycle having 1, 2 or 3 heteroatoms each selected from N or O; R¹ is independently selected, for each occurrence, from the group consisting of hydroxyl, halo, C_1-6alkyl, hydroxyC_1-6alkyl, aminoC_1-6alkyl, haloC_1-6alkyl, C_1-6alkoxy, haloC_1- ₆alkoxy, acylaminoC_1-6alkyl, nitro, cyano, CF₃, -OCF₃, -C(O)OC_1-6alkyl, -OS(O)₂C_1- ₄alkyl, -S(C_1-4alkyl)C(O)R’, phenyl, naphthyl, phenyloxy, benzyloxy, or phenylmethoxy, wherein C_1-6alkyl, phenyl, and napththyl are optionally substituted by one two or three substituents selected from the group consisting of hydroxyl, halogen, oxo, C_1-6alkyl, amino, or nitro;

R² is selected from the group consisting of -O-, amino, C_1-6alkyl, -O-C_1-6alkyl-, hydroxylC_1-6alkyl, aminoC_1-6alkyl, haloC_1-6alkyl, haloC_1-6alkoxy, acylaminoC_1-6alkyl, -C(O)-, - C(O)O-, -C(O)NC_1-6alkyl-, -OS(O)₂C_1-4alkyl-, -OS(O)₂--S(C_1-4alkyl)C(O)R’’-, -S-C_1-6alkyl-, phenyl, naphthyl, phenyloxy, benzyloxy, or phenylmethoxy, wherein C_1-6alkyl, phenyl, and naphthyl are optionally substituted by one two or three substituents selected from the group consisting of hydroxyl, halogen, oxo, C_1-6alkyl, amino, or nitro;

R³ is selected from the group consisting of hydrogen or C_1-6alkyl;

R’ is independently selected, for each occurrence, from the group consisting of hydroxyl, amino, thio, phenyl, naphthyl, or C_1-6alkyl, wherein C_1-6alkyl, phenyl, and naphthyl are optionally substituted by one two or three substituents selected from the group consisting of hydroxyl, halogen, oxo, C_1-6alkyl, amino, or nitro;

R’’ is independently selected, for each occurrence, from the group consisting of–O-, amino, thio, phenyl, naphthyl, or C_1-6alkyl, wherein C_1-6alkyl, phenyl, and naphthyl are optionally substituted by one two or three substituents selected from the group consisting of hydroxyl, halogen, oxo, C_1-6alkyl, amino, or nitro;

m is independently selected, for each occurrence, from the group consisting of 0, 1, 2, or 3;

n is selected from the group consisting of 0, 1, or 2; and

p is selected from the group consisting of 0 or 1.

[00137] Exemplary bromodomain ligands include fused heterocyclic systems represented by the structures: _,

wherein:

L and L^X are independently selected, for each occurrence, from the group consisting of N, CH, and CR¹;

L^N1 and L^N2 are independently selected from the group consisting of CH₂, CHR¹, CR¹R¹, NH, and N(C_1-6alkyl); wherein C_1-6alkyl is optionally substituted by one two or three substituents selected from the group consisting of hydroxyl, halogen, oxo, C_1-6alkyl, amino, or nitro;

L^N3 is selected from the group consisting of O, S, NH, and N(C_1-6alkyl); wherein C_1- ₆alkyl is optionally substituted by one two or three substituents selected from the group consisting of hydroxyl, halogen, oxo, amino, or nitro; U is independently selected from the group consisting of a bond, C(O), C(S), C(N), SO₂, or CR⁴R⁴;

A is selected from the group consisting of aliphatic, cycloalkyl, heterocyclic, phenyl, naphthyl, heteroaryl, or bicyclic moiety, wherein the cycloalkyl, heterocyclic, phenyl, naphthyl, heteroaryl, or bicyclic moiety is optionally substituted with one, two, three, four or more groups represented by R⁴;

R¹ is independently selected, for each occurrence, from the group consisting of hydroxyl, halo, C_1-6alkyl, hydroxyC_1-6alkyl, aminoC_1-6alkyl, haloC_1-6alkyl, C_1-6alkoxy, haloC_1- ₆alkoxy, acylaminoC_1-6alkyl, nitro, cyano, CF₃, -OCF₃, -C(O)OC_1-6alkyl, -OS(O)₂C_1-4alkyl, phenyl, naphthyl, phenyloxy, benzyloxy, or phenylmethoxy, wherein C_1-6alkyl, phenyl, and naphthyl are optionally substituted by one two or three substituents selected from the group consisting of hydroxyl, halogen, oxo, C_1-6alkyl, amino, or nitro;

R² is selected from the group consisting of -O-, amino, C_1-6alkyl, -O-C_1-6alkyl-, hydroxylC_1-6alkyl, aminoC_1-6alkyl, haloC_1-6alkyl, haloC_1-6alkoxy, acylaminoC_1-6alkyl, -C(O)-, - C(O)O-, -C(O)NC_1-6alkyl-, -OS(O)₂C_1-4alkyl-, -OS(O)₂-, -S-C_1-6alkyl-, phenyl, naphthyl, phenyloxy, benzyloxy, or phenylmethoxy, wherein C_1-6alkyl, phenyl, and naphthyl are optionally substituted by one two or three substituents selected from the group consisting of hydroxyl, halogen, oxo, C_1-6alkyl, amino, or nitro;

R³ is selected from the group consisting of hydrogen or C_1-6alkyl; and

R⁴ is independently selected, for each occurrence, from the group consisting of hydrogen, hydroxyl, oxo, imino, amino, halo, C_1-6alkyl, cycloalkyl, phenyl, naphthyl, heterocyclyl, -O-C_1-6alkyl, -NH-C_1-6alkyl, -N(C_1-6alkyl)C_1-6alkyl, nitro, cyano, CF₃, - OCF₃, -C(O)OC_1-6alkyl, -C(O)NHC_1-6alkyl, -C(O)NH₂ or -OS(O)₂C_1-4alkyl.

[00138] For example, compounds of Formula 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 and 17 may be selected from the group consisting of:

[00139] In certain other embodiments, the ligand is one of the compounds listed in Table 1 below or a pharmaceutically acceptable salt thereof, wherein the connector attachment point may be understood to be on

TABLE 1

[00140] One of ordinary skill in the art will appreciate that certain substituents may, in some embodiments, result in compounds that may have some instability and hence would be less preferred.

[00141] In another aspect, exemplary bromodomain ligands include fused heterocyclic systems represented by the structures:

wherein

R^x is hydrogen or C₁-C₃ alkyl;

R^Y is C₁-C₃ alkyl, -(C₂-C₃ alkylenyl)-OH, or C₁-C₃ haloalkyl;

X¹ is N or CR^x1 wherein

R^x1 is hydrogen, C₂-C₆ alkenyl, C₂-C₆ alkynyl, -C(O)OR^ax1, -C(O)NR^bx1R^cx1, - C(O)R^dx1, S(O)₂R^dx1, -S(O)₂NR^bx1R^cx1, G^x1, C₁-C₆ haloalkyl, or C₁-C₆ alkyl; wherein the C₁-C₆ alkyl is optionally substituted with one substituent selected from the group consisting of OR^ax1, SR^ax1, S(O)R^dx1, S(O)₂R^dx1, NR^bx1R^cx1, - C(O)R^ax1, -C(O)OR^ax1, -C(O)NR^bx1R^cx1, -S(O)₂NR^bx1R^cx1, and G^x1; R^ax1, R^bx1, and R^cx1, at each occurrence, are each independently hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, G^a, or -(C₁-C₆ alkylenyl)-G^a;

R^dx1, at each occurrence, are each independently C₁-C₆ alkyl, C₁-C₆ haloalkyl, G^a, or -(C₁-C₆ alkylenyl)-G^a;

X² is N or CR^x2; wherein

R^x2 is hydrogen, C₂-C₆ alkenyl, C₂-C₆ alkynyl, -C(O)OR^ax2, -C(O)NR^bx2R^cx2, - C(O)R^dx2, S(O)₂R^dx2, -S(O)₂NR^bx2R^cx2, G^x2, C₁-C₆ haloalkyl, or C₁-C₆ alkyl; wherein the C₁-C₆ alkyl is optionally substituted with one substituent selected from the group consisting of OR^ax2, SR^ax2, S(O)R^dx2, S(O)₂R^dx2, NR^bx2R^cx2, - C(O)R^ax2, -C(O)OR^ax2, -C(O)NR^bx2R^cx2, -S(O)₂NR^bx2R^cx2, and G^x2; R^ax2, R^bx2, and R^cx2, at each occurrence, are each independently hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, G^b, or -(C₁-C₆ alkylenyl)-G^b;

R^dx2, at each occurrence, is independently C₁-C₆ alkyl, C₁-C₆ haloalkyl, G^b, or - (C₁-C₆ alkylenyl)-G^b;

Y¹ is N or CR^u; wherein R^u is hydrogen, C₁-C₆ alkyl, halogen, or C₁-C₆ haloalkyl; A¹ is N or CR¹, A² is N or CR², A³ is N or CR³, and A⁴ is N or CR⁴; with the proviso that zero, one, two, or three of A¹, A², A³, and A⁴ are N;

R¹, R³, and R⁴ are each independently hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl, CN, or NO₂;

R² is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl, - CN, NO₂, G^2a, -OR^2a, -OC(O)R^2d, -OC(O)NR^2bR^2c, -SR^2a, -S(O)₂R^2d, -S(O)₂NR^2bR^2c

, -C(O)R^2d, -C(O)OR^2a, -C(O)NR^2bR^2c, -NR^2bR^2c, -N(R^2e)C(O)R^2d, -N(R^2e)S(O)₂R^2d, -N(R^2e)C(O)O(R^2d), - N(R^2e)C(O)NR^2bR^2c, -N(R^2e)S(O)₂NR^2bR^2c, -(C₁-C₆ alkylenyl)-G^2a, -(C₁-C₆ alkylenyl)-OR^2a, - (C₁-C₆ alkylenyl)-OC(O)R^2d, -(C₁-C₆ alkylenyl)-OC(O)NR^2bR^2c, -(C₁-C₆ alkylenyl)-S(O)²R^2d, - (C₁-C₆

alkylenyl)-S(O)₂NR^2bR^2c, -(C₁-C₆ alkylenyl)-C(O)R^2d, -(C₁-C₆ alkylenyl)-C(O)OR^2a, -(C₁-C₆ alkylenyl)-C(O)NR^2bR^2c, -(C₁-C₆ alkylenyl)-NR^2bR^2C, -(C₁-C₆ alkylenyl)-N(R^2e)C(O)R^2d, -(C₁- C₆

alkylenyl)-N(R^2e)S(O)2R^2d, -(C₁-C₆ alkylenyl)-N(R^2e)C(O)O(R^2a), -(C₁-C₆

alkylenyl)-N(R^2e)C(O)NR^2bR^2c, -(C₁-C₆ alkylenyl)-N(R^2e)S(O)₂NR^2bR^2c, and -(C₁-C₆ alkylenyl)-CN;

R^2a, R^2b, R^2C, and R^2e, at each occurrence, are each independently hydrogen, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, G^2b, or C₁-C₆ alkyl wherein the C₁-C₆ alkyl is optionally substituted with one substituent selected from the group consisting of -OR^z1, NR^z1R^z2, -C(O)OR^z1, -C(O)NR^z1R^z2, -S(O)₂R^z1, -S(O)₂NR^z1R^z2, and G^2b;

R^2d, at each occurrence, is independently C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, G^2b, or C₁-C₆ alkyl wherein the C₁-C₆ alkyl is optionally substituted with one substituent selected from the group consisting of -OR^z1, NR^z1R^z2, -C(O)OR^z1, -C(O)NR^z1R^z2, -S(O)₂R^z1, - S(O)₂NR^z1R^z2, and G^2b;

R^z1 and R^z2, at each occurrence, are each independently hydrogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;

G^x1, G^x2, G^a, G^b, G^2a, and G^2b, at each occurrence, are each independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl, and each of which is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 of R^v;

L¹ is absent, CH₂, C(O), C(H)(OH), (CH₂)_mO, (CH₂)_mS(O)_n wherein n is 0, 1, or 2; or (CH₂)_mN(R^z) wherein R^z is hydrogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, (C₂-C₃ alkylenyl)-OH, or unsubstituted cyclopropyl; m is 0 or 1;

G¹ is C_1-C₆ alkyl, alkoxyalkyl, G^1a , or -(C₁-C₆ alkylenyl)-G^1a; wherein each G^1a is independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl, and each G^1a is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 of R^w;

R^v and R^w, at each occurrence, are each independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂- C₆ alkynyl, halogen, C₁-C₆ haloalkyl, -CN, oxo, -OR^h, -OC(O)Rⁱ -OC(O)NR^jR^k, -SR^h, - S(O)₂R^h, -S(O)₂NR^jR^k, -C(O)R^h, -C(O)-monocyclic heterocycle, -C(O)-monocyclic heteroaryl, -C(O)OR^h, -C(O)NR^jR^k, -NR^jR^k, -N(R^h)C(O)Rⁱ, -N(R^h)S(O)₂Rⁱ, -N(R^h)C(O)O(Rⁱ), - N(R^h)C(O)NR^jR^k, -(C₁-C₆ alkylenyl)-OR^h, -(C₁-C₆ alkylenyl)-OC(O)Rⁱ, -(C₁-C₆ alkylenyl)- OC(O)NR^jR^k, -(C₁-C₆ alkylenyl)-S(O)₂R^h, -(C₁-C₆ alkylenyl)-S(O)₂NR^jR^k, -(C₁-C₆ alkylenyl)- C(O)R^h, -(C₁-C₆ alkylenyl)-C(O)OR^h, -(C₁-C₆ alkylenyl)-C(O)NR^jR^k, -(C₁-C₆ alkylenyl)- NR^jR^k, -(C₁-C₆ alkylenyl)-N(R^h)C(O)Rⁱ, -(C₁-C₆ alkylenyl)-N(R^h)S(O)₂Rⁱ, -(C₁-C₆ alkylenyl)- N(R^h)C(O)O(Rⁱ), -(C₁-C₆ alkylenyl)-N(R^h)C(O)NR^jR^k, or -(C₁-C₆ alkylenyl)-CN;

R^h, R^j, R^k, at each occurrence, are each independently hydrogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; and

Rⁱ, at each occurrence, is independently C₁-C₆ alkyl or C₁-C₆ haloalkyl.

[00142] In some embodiments, exemplary bromodomain ligands include fused heterocyclic systems represented by the structures:

wherein:

R¹ is selected from the group consisting of H,–C₁-C₆ alkylene-heterocyclyl, and–C(O)- heterocyclyl, wherein heterocyclyl contains 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S and is optionally substituted by one, two, or three substituents selected from the group consisting of hydroxyl, halogen, oxo, C₁-C ₆alkyl, amino, and nitro;

R² is selected from the group consisting of H and C₁-C₆ alkyl;

R³, independently for each occurrence, is selected from the group consisting of hydrogen,–SO₂-C₁-C₆ alkyl,–NH-SO₂-C₁-C₆ alkyl,–N(C₁-C₆ alkyl)-SO₂-C₁-C₆ alkyl, and– SO₂-heterocyclyl, wherein heterocyclyl contains 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S and is optionally substituted by one, two, or three substituents selected from the group consisting of hydroxyl, halogen, oxo, C₁-C ₆alkyl, amino, and nitro;

R⁴, independently for each occurrence, is selected from the group consisting of hydrogen, hydroxyl, halogen, oxo, C₁-C ₆alkyl, amino, and nitro;

m is 1, 2, or 3; and

n is 1, 2, or 3.

[00143] In certain embodiments, R¹ is H. In certain other embodiments, R¹ is– methylene-(4-methyl-piperazinyl).

[00144] R², in certain embodiments, is methyl.

[00145] In some embodiments, R³ is selected from the group consisting of–SO₂-methyl, –NH-SO₂-ethyl, and–SO₂-pyrrolidinyl.

[00146] In certain embodiments, R⁴ is fluoro.

[00147] In another aspect, exemplary bromodomain ligands include fused heterocyclic s stems re resented b the structures:

wherein:

R¹ is optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted

heterocycloalkyl, haloalkyl, -C(O)R, -C(S)R, -CO₂R, -C(O)N(R')(R"), -C(O)SR, -C(O)C(O)R, -C(O)CH₂C(O)R, -C(S)N(R')(R"), -C(S)OR, -S(O)R, -SO₂R, -SO₂N(R')(R"), -C=NN(R')(R"), - C=NOR, or -C(=N(R'))N(R')(R");

R² is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, haloalkyl, -C(O)R, -C(S)R, -CO₂R, -C(O)N(R')(R"), - C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R')(R"), -C(S)OR, -S(O)R, -SO₂R, - SO₂N(R')(R"), -C=NN(R')(R"), -C=NOR, -C(=N(R'))N(R')(R"), or -(CH₂)_pR^x; or R¹ and R² together with the atoms to which each is attached, forms an optionally substituted 3-7 membered saturated or unsaturated ring having 0-4 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R³ is H, alkyl, alkenyl, alkynyl, aralkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, or halo, each of which is optionally substituted; or CN, OR^A, NR^AR^B, N(R^A)S(O)_qR^AR^B, N(R^A)C(O)R^B, N(R^A)C(O)NR^AR^B, N(R^A)C(O)OR^A, N(R^A)C(S)NR^AR^B, -N(R^A)S(O)_qNR^AR^B, S(O)_qR^A, C(O)R^A, C(O)OR^A, OC(O)R^A, or C(O)NR^AR^B;

each R^A is independently optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted heterocyclic;

optionally substituted carbocyclic; or hydrogen;

each R^B is independently optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted heterocyclic;

optionally substituted carbocyclic; or hydrogen; or

R^A and R^B, together with the atoms to which each is attached, can form a

heterocycloalkyl or a heteroaryl; each of which is optionally substituted;

R⁵ is halogen, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, haloalkyl, -OR, -SR, -CN, - N(R')(R"), -C(O)R, -C(S)R, -CO₂R, -C(O)N(R')(R"), -C(O)SR, -C(O)C(O)R, -C(O)CH₂C(O)R, -C(S)N(R')(R"), -C(S)OR, -S(O)R, -SO₂R, -SO₂N(R')(R"), -N(R')C(O)R, - N(R')C(O)N(R')(R"), -N(R')C(S)N(R')(R"), -N(R')SO₂R, -N(R')SO₂N(R')(R"), - N(R')N(R')(R"), -N(R')C(=N(R'))N(R')(R"), -C=NN(R')(R"), -C=NOR, -C(=N(R'))N(R')(R"), - OC(O)R, -OC(O)N(R')(R"), or -(CH₂)_pR^x;

each R^x is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, -OR, -SR, -CN, -N(R')(R"), -C(O)R, -C(S)R, -CO₂R, - C(O)N(R')(R"), -C(O)SR, -C(O)C(O)R, -C(O)CH₂C(O)R, -C(S)N(R')(R"), -C(S)OR, -S(O)R, - SO₂R, -SO₂N(R')(R"), -N(R')C(O)R, -N(R')C(O)N(R')(R"), -N(R')C(S)N(R')(R"), -N(R')SO₂R, -N(R')SO₂N(R')(R"), -N(R')N(R')(R"), -N(R')C(=N(R'))N(R')(R"), -C=NN(R')(R"), -C=NOR, - C(=N(R'))N(R')(R"), -OC(O)R, -OC(O)N(R')(R");

each R is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl;

each R' is independently -R, -C(O)R, -C(S)R, -CO₂R, -C(O)N(R)₂, -C(S)N(R)₂, -S(O)R, -SO₂R, -SO₂N(R)₂, or two R groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted heteroaryl or heterocycloalkyl group;

each R" is independently -R, -C(O)R, -C(S)R, -CO₂R, -C(O)N(R)₂, -C(S)N(R)₂, - S(O)R, -SO₂R, -SO₂N(R)₂, or two R groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted heteroaryl or heterocycloalkyl group; or R' and R", together with the atoms to which each is attached, can form a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl; each of which is optionally substituted;

each p is independently 1, 2, 3, 4, 5, or 6; and

each q is independently 0, 1, or 2.

[00148] In some embodiments, exemplary bromodomain ligands include fused heterocyclic systems represented by the structures:

wherein:

R¹ is selected from the group consisting of H and C₁-C₆ alkyl, optionally substituted by one, two, or three substituents selected from the group consisting of hydroxyl, halogen, oxo, amino, and nitro;

R² is selected from the group consisting of hydroxyl, halogen, oxo, amino, and nitro; R³ is selected from the group consisting of hydrogen and C₁-C₆ alkyl;

R⁴, independently for each occurrence, is selected from the group consisting of hydrogen, C₁-C₆ alkyl, and -C₁-C₆ alkylene-phenyl, wherein phenyl is optionally substituted by one, two, or three substituents selected from the group consisting of hydroxyl, halogen, oxo, C₁-C ₆alkyl, amino, and nitro; and

m is 0, 1, or 2.

[00149] In certain embodiments, R¹ is trifluoromethyl.

[00150] In certain embodiments, R³ is ethyl.

[00151] In certain embodiments, one R⁴ is hydrogen. In certain other embodiments, one

[00152] In some embodiments, exemplary bromodomain ligands include compounds represented by:

Formula QQ, wherein:

R¹ is selected from

and

^{O O} _;

R² is selected from

R³ is s

and

. See, for example, J. Med. Chem. (2013) 56, 3833, which is hereby incorporated by reference in its entirety.

[00153] For example, bromodomain ligands of Formula QQ may be selected from the group consisting of:

,

[00154] In some embodiments, exemplary bromodomain ligands include compounds represented by:

[00155] In some embodiments, exemplary bromodomain ligands include compounds represented by:

, and

[00156] In some embodiments, exemplary bromodomain ligands include compounds represented by:

wherein:

A is C(R⁸R⁹); Y is C(R⁶R⁷); J is C(R⁴R⁵); R¹ is hydrogen or C₁-C₃alkyl; R² is hydrogen or C₁-C₃ alkyl; R³ is heteroaryl, 9 to 12 membered bicyclic aryl, napthalen-1-yl, unsubstituted

phenyl, or X, wherein X is

wherein said heteroaryl, 9 to 12 membered bicyclic aryl, or napthalen-1-yl may be substituted with one to three substituents independently selected from the group consisting of NR¹⁶R¹⁸, halo, hydroxyl, C₁-C₃ alkyl, -O-aryl, Ci-C₃ alkylene-aryl, C₁-C₃ alkylene-O-aryl, -S-aryl, -O- C₁-C₃ alkylene-aryl, -NR¹⁶-SO₂-NR¹⁸-C₁-C₃ alkyl, -NR¹⁶- SO₂-NR¹⁸- C₁-C₃ haloalkyl, -NR¹⁶- SO₂- C₁-C₃ alkyl, -NR¹⁶-SO₂- C₁-C₃ haloalkyl, SO₂- NR¹⁶R¹⁸, SO₂- C₁-C₃ alkyl, -O- C₁-C₃ alkyl, -C(O)-O- C₁-C₃ alkyl, -C(O)-OH, -C(O)- NR¹⁶R¹⁸, -C(O)-NH(C₁-C₃ haloalkyl), -C(O)- NH(C₁-C₃ alkylene-heterocycloalkyl), - C(O)-NH(heteroaryl), -NH-C(O)- C₁-C₃ alkyl, -NH- C(O)-heteroaryl, heterocycloalkyl, -O-C₁-C₃ alkylene-heterocycloalkyl, -O-C₃-C₁₄ cycloalkyl, - O-C₁-C₃ alkylene-C₃-C₁₄ cycloalkyl, -O-C₁-C₃ alkylene-heteroaryl, or heteroaryl;

wherein X is substituted as set out in (i) or (ii):

four of R¹⁰, R¹¹, R¹², R¹³, and R¹⁴ are hydrogen, and one of R¹⁰, R¹¹, R¹², R¹³, or R¹⁴ is selected from the following groups:

R¹⁰ is NR¹⁶R¹⁸, halo, hydroxyl, C₁-C₃ alkyl, C₁-C₃ alkylene-aryl, C₁-C₃ alkylene-O-aryl, -S-aryl, -O-C₁-C₃ alkylene-aryl, -NR¹⁶-SO₂-NR¹⁸- C₁-C₃ alkyl, -NR¹⁶- SO₂-NR¹⁸- C₁-C₃ haloalkyl, -NR¹⁶-SO₂- C₁-C₃ alkyl, -NR¹⁶- SO₂- C₁-C₃ haloalkyl, SO₂- NR¹⁶R¹⁸, SO₂- C₁-C₃ alkyl, -O-C₁-C₃ alkyl, - C(O)-O- C₁-C₃ alkyl, -C(O)-OH, -C(O)- NR¹⁶R¹⁸, -C(O)-NH(C₁-C₃ haloalkyl), -C(O)-NH(C₁-C₃ alkylene-heterocycloalkyl), - C(O)- NH(heteroaryl), NH-C(O)- C₁-C₃ alkyl, NH-C(O)-heteroaryl, heterocycloalkyl, - O- C₁-C₃ alkylene-heterocycloalkyl,-O-C₃-C₁₄ cycloalkyl, -O- C₁-C₃ alkylene-C₃-C₅ cycloalkyl, C₁-C₃ alkylene-C₇-C₁₄ cycloalkyl, -O-C₁-C₃ alkylene-heteroaryl, or heteroaryl; R¹¹ is NR¹⁶R¹⁸, fluoro, iodo, bromo, hydroxyl, C₁-C₃ alkyl, -O-aryl, C₁-C₃ alkylene-aryl, C₁-C₃ alkylene-O-aryl, -S-aryl, -O-C₁-C₃ alkylene-aryl, -NR¹⁶-SO₂-NR¹⁸- C₁-C₃ alkyl, -NR¹⁶-SO₂-NR¹⁸- C₁-C₃ haloalkyl, -NR¹⁶- SO₂- C₁-C₃ alkyl, -NR¹⁶-SO₂- C₁-C₃ haloalkyl, SO₂-NR¹⁶R¹⁸, SO₂- C₁-C₃ alkyl, -O-C₁-C₃ alkyl, -C(O)-O- C₁-C₃ alkyl, -C(O)-OH, -C(O)- NR¹⁶R¹⁸, -C(O)-NH(C₁-C₃ haloalkyl), -C(O)-NH(C₁-C₃ alkylene- heterocycloalkyl), -C(O)-NH(heteroaryl), NH-C(O)- C₁-C₃ alkyl, NH- C(O)-heteroaryl, heterocycloalkyl, -O-C₁-C₃ alkylene-heterocycloalkyl,- O-C₁-C₃ alkylene-C₃-C₁₄ cycloalkyl, -O-C₁-C₃ alkylene-heteroaryl, or heteroaryl;

R¹² is NR¹⁶R¹⁸, halo, hydroxyl, C₁-C₃ alkyl, C₁-C₃ alkylene-aryl, C₁-C₃ alkylene-O-aryl, -S-aryl, -O-C₂-C₃ alkylene-aryl, -NR¹⁶-SO₂-NR¹⁸- C₁-C₃ alkyl, -NR¹⁶- SO₂-NR¹⁸- C₁-C₃ haloalkyl, -NR¹⁶-SO₂- C₁-C₃ alkyl, -NR¹⁶- SO₂- C₁-C₃ haloalkyl, SO₂- NR¹⁶R¹⁸, SO₂- C₁-C₃ alkyl, -O- C₁-C₃ alkyl, - C(O)-O- C₁-C₃ alkyl, -C(O)-OH, -C(O)- NR¹⁶R¹⁸, -C(O)-NH(C₁-C₃ haloalkyl), -C(O)-NH(C₁-C₃ alkylene-heterocycloalkyl), - C(O)- NH(heteroaryl), NH-C(O)- C₁-C₃ alkyl, NH-C(O)-heteroaryl, heterocycloalkyl, - O-C₁-C₃ alkylene-heterocycloalkyl, -O-C₃-C₁₄ cycloalkyl, -O-C₁-C₃ alkylene-C₃-C₁₄ cycloalkyl, -O-C₁-C₃ alkylene-heteroaryl, or heteroaryl;

R¹³ and R¹⁴ are NR¹⁶R¹⁸, halo, hydroxyl, C₁-C₃ alkyl, -O-aryl, C₁-C₃ alkylene- aryl, C₁-C₃ alkylene-O-aryl, -S-aryl, -O-C₁-C₃ alkylene-aryl, - NR¹⁶-SO₂-NR¹⁸- C₁-C₃ alkyl, -NR¹⁶-SO₂-NR¹⁸- C₁-C₃ haloalkyl, -NR¹⁶- SO₂- C₁-C₃ alkyl, -NR¹⁶-SO₂- C₁-C₃ haloalkyl, SO₂-NR¹⁶R¹⁸, SO₂-C₁- C₃alkyl, -O-C₁-C₃ alkyl, -C(O)-O-C₁-C₃ alkyl, -C(O)- OH, -C(O)- NR¹⁶R¹⁸, -C(O)-NH(C₁-C₃ haloalkyl), -C(O)-NH(C₁-C₃ alkylene- heterocycloalkyl), -C(O)-NH(heteroaryl), NH-C(O)- C₁-C₃ alkyl, NH- C(O)-heteroaryl, heterocycloalkyl, -O-C₁-C₃ alkylene-heterocycloalkyl, -O-C₃-C₁₄ cycloalkyl, -O-C₁-C₃ alkylene-C₃-C₁₄ cycloalkyl, -O-C₁-C₃ alkylene-heteroaryl, or heteroaryl;

wherein 5-n of R¹⁰, R¹¹, R¹², R¹³, and R¹⁴ are hydrogen, and n of R¹⁰, R¹¹, R¹², R¹³, and R¹⁴ are selected from the following groups:

NR¹⁶R¹⁸, halo, hydroxyl, C₁-C₃ alkyl, -O-aryl, C₁-C₃ alkylene-aryl, C₁-C₃ alkylene-O-aryl, -S-aryl, -0- C₁-C₃ alkylene-aryl, -NR¹⁶-SO₂-NR¹⁸- C₁-C₃ alkyl, -NR¹⁶- SO₂-NR¹⁸- C₁-C₃ haloalkyl, -NR¹⁶-SO₂- C₁-C₃ alkyl, - NR¹⁶-SO₂- C₁-C₃ haloalkyl, SO₂- NR¹⁶R¹⁸, SO₂- C₁-C₃ alkyl, -O- C₁-C₃ alkyl, -C(O)-O- C₁-C₃ alkyl, -C(O)-OH, -C(O)- NR¹⁶R¹⁸, -C(O)-NH(C₁-C₃ haloalkyl), -C(O)-NH(C₁-C₃ alkylene-heterocycloalkyl), - C(O)- NH(heteroaryl), NH-C(0)- C₁-C₃ alkyl, NH-C(O)-heteroaryl, heterocycloalkyl, - O- C₁-C₃ alkylene-heterocycloalkyl,-0-C₃-C₁₄ cycloalkyl, -O-C₁-C₃ alkylene-C₃-C₁₄ cycloalkyl, -O-C₁-C₃ alkylene-heteroaryl, or heteroaryl;

wherein n is 2, 3, 4 or 5;

wherein any of said aryl groups of -O-aryl, -S-aryl, C₁-C₃ alkylene-aryl, C₁-C₃ alkylene-O-aryl; said heterocycloalkyl; said heterocycloalkyl groups of -C(0)-NH(C₁-C₃ alkylene- heterocycloalkyl) and -O-C₁-C₃ alkylene-heterocycloalkyl; said heteroaryl and said heteroaryl groups of -C(O)-NH(heteroaryl), NH-C(O)-heteroaryl, and -O-C₁-C₃ alkylene-heteroaryl; and said cycloalkyl groups of -O-C₃-C₁₄ cycloalkyl, -O-C₁-C₃ alkylene-C₃-C₅ cycloalkyl, and -O- C₁-C₃ alkylene-C₃-C₁₄ cycloalkyl may be subsitituted with 1 to 3 subsitituents selected from the group consisting of: halo, C₁-C₃ alkyl, C₁-C₃ haloalkyl, CN, and NR¹⁶R¹⁸; R⁴ and R⁵ are each independently selected from hydrogen and C₁-C₄ alkyl; R⁶ and R⁷ are each independently selected from hydrogen and C₁-C₄ alkyl; R⁸ and R⁹ are each independently selected from hydrogen and C₁-C₄ alkyl; and R¹⁶ and R¹⁸ are each independently selected from hydrogen and C₁-C₃ alkyl. See, for example, International Patent Application Publication No.

WO/2013/158952, which is hereby incorporated by reference in its entirety.

[00157] For example, an exemplary compound of represented by Formula RR is:

.

[00158] In some embodiments, exemplary bromodomain ligands include compounds represented by:

.

[00159] In some embodiments, exemplary bromodomain ligands include compounds represented by:

.

[00160] In some embodiments, exemplary bromodomain ligands include compounds represented by:

wherein:

Ring B is absent; or a 3-7 membered saturated or partially unsaturated carbocyclic ring, phenyl, an 8-10 membered bicyclic saturated, partially unsaturated, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms

R^d and R^e taking together with their intervening atoms form an isoxazolyl optionally substituted with R₁;

R₁ is hydrogen or C_1-6 aliphatic;

R₂-R₅ are each independently hydrogen, halogen, optionally substituted C_1-6aliphatic, - OR, -SR, -CN, -N(R')₂, -C(O)R, -C(S)R, -CO₂R, -C(O)N(R')₂, -C(O)SR, -C(O)C(O)R, - C(O)CH₂C(O)R, -C(S)N(R')₂, -C(S)OR, -S(O)R, -SO₂R, -SO₂N(R')₂, -N(R')C(O)R, - N(R')C(O)N(R')₂, -N(R')C(S)N(R')₂, -N(R')SO₂R, -N(R')SO₂N(R')₂, -N(R')N(R')₂, - N(R')C(=N(R'))N(R')₂, -C=NN(R')₂, -C=NOR, -C(=N(R'))N(R')₂, -OC(O)R, -OC(O)N(R')₂, or - (CH₂)_pR^x; each of R₂ and R₃, R₂ and R₄, R₃ and R₅, or R₄ and R₅ are taken together with their intervening atoms to form CO, or an optionally substituted 3-7 membered saturated or partially unsaturated spiro-fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and X is hydrogen, SO₂, CO, a covalent bond, or an optionally substituted bivalent C_1-6hydrocarbon chain wherein one methylene unit is optionally replaced by -NR'-, - N(R')C(O)-, -C(O)N(R')-, -N(R')SO₂-, -SO₂N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)0-, -S-, -SO- or -SO₂-; or when ring B is absent, X is hydrogen or substituted C_1-6 aliphatic; and

R^x is halogen, optionally substituted C_1-6 aliphatic, -OR, -SR, -CN, -N(R')₂, -C(O)R, - C(S)R, -CO₂R, -C(O)N(R')₂, -C(O)SR, -C(O)C(O)R, -C(O)CH₂C(O)R, -C(S)N(R')₂, -C(S)OR, -S(O)R, -SO₂R, -SO₂N(R')₂, -N(R')C(O)R, -N(R')C(O)N(R')₂, -N(R')C(S)N(R')₂, -N(R')SO₂R, - N(R')SO₂N(R')₂, -N(R')N(R')₂, -N(R')C(=N(R'))N(R')₂, -C=NN(R')₂, -C=NOR, - C(=N(R'))N(R')₂, -OC(O)R, or -OC(O)N(R')₂;

each R is independently hydrogen or an optionally substituted group selected from C_1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 7-10 membered bicyclic saturated, partially unsaturated, or aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms

independently selected from nitrogen, oxygen, and sulfur, and a 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each R' is independently -R, -C(O)R, -C(S)R, -CO₂R, -C(O)N(R)₂, -C(S)N(R)₂, -S(O)R, -SO₂R, or -SO₂N(R)₂; or

two R' on the same nitrogen are taken together with their intervening atoms to form an optionally substituted group selected from a 4-7 membered monocyclic saturated or partially unsaturated ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 7-12 membered bicyclic saturated, partially unsaturated, or aromatic fused ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each of m and n is independently 0-4, as valency permits; and each of R₆ and R₇ are independently -R, halogen, (C_1-6)alkyl, halogen, (C_1-6)haloalkyl, (C_1-6)alkoxy, (C_1-6)haloalkoxy , -OR, -SR, -N(R')₂, -CN, -NO₂, -C(O)R, -C(S)R, -CO₂R, - C(O)N(R')₂, -C(O)SR, -C(O)C(O)R, -C(O)CH₂C(O)R, -C(S)N(R')₂, -C(S)OR, -S(O)R, -SO₂R, -SO₂N(R')₂, -N(R')C(O)R, -N(R')C(O)N(R')₂, -N(R')C(S)N(R')₂, -N(R')SO₂R, -N(R')SO₂N(R')₂, -N(R')N(R')₂, -N(R')C(=N(R'))N(R')₂, -C=NN(R')₂, -C=NOR, -C(=N(R'))N(R')₂, -OC(O)R, or - OC(O)N(R')₂. See, for example, International Patent Application Publication No.

WO/2013/184878, which is hereby incorporated by reference in its entirety.

[00161] For example, an exemplary compound of represented by Formula SS is:

.

[00162] In some embodiments, exemplary bromodomain ligands include compounds re resented b :

Formula TT, wherein R¹ is H, halogen, amino, -NH-C_1- ₆alkyl, -SO₂-NH₂, -SO₂-NHC_1-6alkyl, -NHSO₂-C_1-6alkyl, NO₂, C_1-6alkyl, or C_1-6alkoxy, and R² is H, acetyl, tosyl, BOC, C_1-6alkyl, -C_1-6alkyl-COOH, or -C_1-6alkyl-CONH-C_1-6alkyl. For example, in certain embodiments, R¹ is selected from Cl, Br, F, NO₂, amino, methyl, methoxy, aminomethyl, -SO₂NH-ethyl; -SO₂NH-methyl, and -NH-SO₂-methyl. In certain embodiments, R² may be methyl, -CH₂CH₂COOH, -CH₂CH₂CONHMe, -CH₂COOH, and -CH₂CONHMe.

[00163] In some embodiments, exemplary bromodomain ligands include compounds represented by:

, wherein R¹ is halo, R³ is C_1-6alkyl, amino, or–NH-C_1-6- alkyl, and X is O or S. For example, in certain embodiments, R¹ is selected from Cl and Br. In certain embodiments, R³ is selected methyl, amino, and -NH-methyl.

[00164] In some embodiments, exemplary bromodomain ligands include compounds shown in the following Table:

.

[00165] In some embodiments, exemplary bromodomain ligands include compounds represented by:

[00166] In some embodiments, exemplary bromodomain ligands include compounds represented by:

, wherein

R¹

, R²

, R³

, R⁴

, and R⁵ are independently selected from the group consisting of hydrogen, hydroxyl, amino, halo, C_1-6alkyl, cycloalkyl, phenyl, naphthyl, heterocyclyl, -O-C_1-6alkyl, -NH- C_1-6alkyl, -N(C_1-6alkyl)C_1-6alkyl, nitro, cyano, CF₃, -OCF₃, -C(O)OC_1-6alkyl, -C(O)NHC_1- ₆alkyl, -C(O)NH₂, and -OS(O)₂C_1-4alkyl.

[00167] In some embodiments, exemplary bromodomain ligands include compounds represented by:

.

[00168] In some embodiments, exemplary bromodomain ligands include compounds re resented b :

wherein:

A is phenyl or 5-6 membered heteroaryl ring;

R^1a

, R^1b

, R^1c

, R²

, R³

, R⁴

, and R⁵ are independently selected from the group consisting of hydrogen, hydroxyl, amino, halo, C_1-6alkyl, cycloalkyl, phenyl, naphthyl, heterocyclyl, -O- C_1-6alkyl, -NH-C_1-6alkyl, -N(C_1-6alkyl)C_1-6alkyl, nitro, cyano, CF₃, -OCF₃, -C(O)OC_1-6alkyl, - C(O)NHC_1-6alkyl, -C(O)NH₂, and -OS(O)₂C_1-4alkyl. See, for example, International Patent Application Publication No. WO/2014/026997, which is hereby incorporated by reference in its entirety.

[00169] In some embodiments, exemplary bromodomain ligands include compounds selected from the group consisting of TG101209, TG101348, NU7441, GW612286X, SB202190, BI-2536, Fostamatinib, SB251527, SB614067R, SB284847BT, Flavopiridol, SB409514, SB610251B, Dinaciclib, and pharmaceutically acceptable salts thereof.

[00170] In some embodiments, exemplary bromodomain ligands include compounds selected from the group consisting of SB-203580, PP-242, SCH-772984, PF-431396,

Volasertib, BI-6727, AZ-3146, GSK-2636771, Brivanib, BI-D1870, Tideglusib, and pharmaceutically acceptable salts thereof. [00171] In some embodiments, exemplary bromodomain ligands include compounds selected from the group consisting of:

,

[00172] In some embodiments, exemplary bromodomain ligands include compounds represented by the formula:

Formula WW,

wherein: R¹ is selected from

; and

R² and R³ are independently selected from H and halogen (e.g., fluoro).

[00173] In some embodiments, exemplary bromodomain ligands include compounds represented by the formula:

Formula XX,

wherein:

W is N or C-R₈;

X is N, CH or C(CH₃);

Z is N or C-R₁₄;

Y is N or C-R₅ (subject to proviso that no more than 2 of W, X, Y and Z are N);

R₁ is C₁-₄alkyl;

R₂ is H, OH, C_1-4alkyl, -N(CH₃)₂, -NH(CH₃), halo, -CF₃, -NH₂, -OC_1-4alkyl, -NHC(0)H, -NHC(0)d. ₄alkyl, -N(CH₃)C(0)Ci.4alkyl, -NHCH(CH₃)CH₂OCH₃, -N(CH₃)CH₂CH₂OCH₃, - OCH₂CH₂OCH₃, -OCH₂CH₂CH₂OH, -OCH(CH₃)CH₂OCH₃, or R₂ is a group selected from -G- CH₂CH(R₃)(R₄), -G-CH(R₃)(R₄) and -G-R₃ in which G is NH, N(CH₃), O, C(0)NH or

NHC(O);

R₃ is phenyl, pyridinyl, C_3-7cycloalkyl or a heterocycle optionally substituted by =O; and R₄ is H or C _-4 alkyl; R₅ is H, C_1-4alkyl, halo, -C–OC_1-4 alkyl, -CH₂NH₂, -OCF₃ or-SO₂CH₃;

R₆ is -NR_nR₁₂ or a group

D is CH or N;

E is N, O, CH or SO₂;

R₇, when present, is H, OH, C_1-4alkyl, -NH₂, -SO₂C_1-4alkyl, -SO₂phenyl, -SO₂benzyl, - SO₂N(CH₃)₂, -NHSO₂CH₃, -C(O)C_1-4alkyl or -C(O)phenyl;

R₈ is H, C_1-4alkyl, halo, -CF₃, CN, OH, -OC_1-4 alkyl, -OCF_3, -OCH₂phenyl or -OCH₂C_3- ₇cycloalkyl;

R₉ is H, C_1-4alkyl, -C(O)NH₂, -CO₂CH_3, -CF₃, halo, OH, -OC_1-4alkyl, -CH₂OH, - C(0)NHCH₃, - C(0)N(CH₃)₂, -CH₂OC_1-4alkyl; -CH₂OCH₂C_3-7cycloalkyl or oxo;

R₁₀ is H, C_1-4alkyl, -C(O)NH₂, -CO₂CH_3, -CF₃, halo, OH or–OC_1-4alkyl;

R₁₁ is H, C_1-4alkyl or SO₂CH₃;

R₁₂ is H, C_1-4alkyl, C_1-4alkyleneNHR₁₃, C_2-4alkyleneOH, SO₂CH₃, a heterocycle or a heterocycle comprising SO₂;

R₁₃ is H or SO₂CH₃;

R₁₄ is H, C_1-4alkyl or NHC(O)C_1-4alkyl; and

n and m are each an integer independently selected from 0, 1 and 2; or a salt thereof. See, for example, International Patent Application Publication No. WO/2014/078257, which is hereby incorporated by reference in its entirety.

[00174] For example, an exemplary compound of Formula XX is represented by the formula:

pharmaceutically acceptable salts thereof.

[00175] In some embodiments, exemplary bromodomain ligands include compounds re resented b the formula:

(Formula YY),

wherein:

W₁ is selected from N and CR₁;

W₂ is selected from N and CR₂;

W₃ is selected from N and CR₃;

W₄ is selected from N and CR₄;

each W may be the same or different from each other; A is selected from N and CH;

R₁, R₂, R₃, and R₄ are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, aryl, hydroxyl, and halogen;

two adjacent substituents selected from R₁, R₂, R₃, and Ry may be connected in a 5- or 6-membered ring to form a bicyclic carbocycle or bicyclic heterocycle;

AR1 is a group selected from the following:

AR2 is a group selected from the following:

R₅ is selected from hydrogen, alkyl, alkoxy, thioalkyl, amino, and halogen;

R₆ is selected from hydrogen, alkoxy, alkyl, aminoalkyl, and thioalkyl;

Y is selected from NH, O, and S;

W₅ is selected from N and CQ₁;

W₆ is selected from N and CQ₂;

W₇ is selected from N and CQ₃;

W₈ is selected from N and CQ₄;

W₉ is selected from N and CQ₅;

Q₁, Q₂, Q₃, Q₄, and Q₅ are independently selected from hydrogen, alkyl, halogen,—CN, —SO₂Me,—SO₂Et,—SO₂Pr,—S(O)Me,—S(O)Et,—S(O)Pr,—S(O)iPr, amide, ketone,— COOH, and ester; and

two adjacent substituents selected from R₅, R₆, Q₁, Q₂, Q₃, Q₄, Q₅, and Q₆ may be connected in a 5- or 6-membered ring to form an unsubstituted carbocycle or heterocycle. See, for example, U.S. Patent Application Publication Nos. US 2014-0140956 and US 2014- 0142102, each of which is hereby incorporated by reference in its entirety.

[00176] For example, an exemplary compound of Formula YY is represented by the formula:

and

pharmaceuticaally salts thereof.

[00177] In some embodiments, exemplary bromodomain ligands include compounds represented by the formulae:

, and

.

[00178] In some embodiments, exemplary bromodomain ligands include compounds represented by the formulae:

pharmaceutically acceptable salts thereof.

[00179] In some embodiments, exemplary bromodomain ligands include a compound represented by the formula: , and pharmaceutically acceptable salts thereof.

[00180] In some embodiments, exemplary bromodomain ligands include a compound represented by the formula:

Formula ZZ,

wherein:

W₁ is selected from N and CR₅;

W₂ is selected from N and CR₄

W₃ is selected from N and CR₃;

each W may be the same or different from each other;

R₁ is selected from a carbocycles or heterocycles; R₂ is selected from a 5~ or 6-membered monocyclic carbocycle or a 5- or 6-membered monocyclic heterocycle;

R₃, R₄, and R₅ are each independently selected from hydrogen, alkyl, -OH, -NH , thioalkyl, alkoxy, ketone, ester, carboxyiic acid, urea, carbamate, carbonate, amino, amide, halogen, carbocycle, heterocycle, sulfone, sulfoxide, sulfide, sulfonamide, and -CN;

R₃ and R₄ may be connected to form an optionally substituted 5-, 6-, or 7-membered carbocycle or heterocycle;

R₄ may be connected to B or R₂ to form a carbocycle or heterocycle;

X is selected from 0 and 5;

A is selected from -CR_XR_Y-, OG, -C(O)CR_xR_y-, -CR_xR_yCRA-, -SO₂ , -CR_xR_yCR,R_vO-, - CR„R_yCR_jR_vN- ,-CR_XR,,.CR₂R.,S-, and -CR_XR_VCR_ZR_VCR_QR_R-;

R_X, R_Y, R_Z, R_v, R_Q, and R_R are each independently selected from hydrogen, alkyl(C₁- C₈), halogen, -OH, -CF₃, amino, alkoxy (C C₈), carboxyl, -CN, sulfone, and sulfoxide, carbocycle, heterocycle, or two substituents selected from R_x, R_Y, Rz, R_V, R_Q and R_R may form an oxo or thio-oxo group, or

two substituents selected from R_S, R_Y, R_Z, Rv, R₅, and R₁ may be connected in a 5- or 6- membered ring to form a bicyc!ic carbocycle or bicyclic heterocycle;

B is selected from -(CR_aR_b)_n-, -(CR_aR_bCR_cR_d)-, -O-, -OCR_aR_b-, -CR_aR_bO-, -NH-_, - NHCR_aR_b-, - CR_aR_bNH-, -S-, -SCR_aR_b-,-CR_aR_bS-, -S(O)-, -S(O)CR_aR_b-, -CR_aR_bS(O)-, -SO₂-, - SO₂CR_aR_b-, and -CR_aR_bSO₂-;

n is selected from 0 and 1, meaning if n = 0 then 8 is absent and R₂ is connected directly to the center ring;

R_a, R_b, R_c, and R_d are each independently selected from hydrogen, alkyl(C₁-C₃), and alkoxy(C₁-C₃). See, for example, International Patent Application Publication No.

WO/2014/096965, which is hereby incorporated by reference in its entirety.

[00181] For example, an exemplary compound of Formula ZZ is represented by the formula:

, and pharmaceutically acceptable salts thereof.

[00182] In some embodiments, exemplary bromodomain ligands include a compound re resented b the formula:

Formula AAA,

wherein:

A is NH or O;

X is N or CH;

N is 0 or 1;

R¹ is–C(O)NR⁸R⁹ or–SO₂NR⁸R⁹;

R², R³, R⁴, R⁵, and R⁶ are independently selected from the group consisting of hydrogen, hydroxyl, amino, halo, C_1-6alkyl, cycloalkyl, phenyl, naphthyl, heterocyclyl, -O-C_1- ₆alkyl, -NH-C_1-6alkyl, -N(C_1-6alkyl)C_1-6alkyl, nitro, cyano, CF₃, -OCF₃, -C(O)OC_1-6alkyl, - C(O)NHC_1-6alkyl, -C(O)NH₂, and -OS(O)₂C_1-4alkyl. See, for example, International Patent Application Publication Nos. WO/2014/095774 and WO/2014/095775, each of which is hereby incorporated by reference in its entirety.

[00183] In some embodiments, exemplary bromodomain ligands include a compound represented by the formula:

Formula BBB,

wherein:

Cy₁ is an optionally substituted monocyclic ring having 1-3 heteroatoms independently selected from N and O; wherein the optional substituent is alkyl;

Cy₂ is an optionally substituted monocyclic ring having 0-2 heteroatoms; wherein the heteroatom is N and the optional substituents are selected from alkyl, halogen and alkoxy;

R₁ is selected from hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl,

cycloalkylalkyl and heterocyclylalkyl;

R₂ and R₃ are independently selected from the halogen, hydroxy or alkyl; or R₂ and R₃ combined together to form an oxo group;

alternatively, R₂ and R₃ can be taken together with the carbon atom to which they are attached to form a 3-4 membered cycloalkyl ring;

R₄ is selected from hydrogen, halogen and alkyl; and

R₅ is selected from hydrogen, halogen, alkyl and alkoxy. See, for example,

International Patent Application Publication No. WO/2014/128655, which is hereby incorporated by reference in its entirety.

[00184] For example, an exemplary compound of Formula BBB is represented by the formula:

and pharmaceutically acceptable salts thereof.

[00185] In some embodiments, exemplary bromodomain ligands include a compound represented by the formula:

Formula CCC,

wherein:

A is phenyl or a 5-6 membered heteraryl ring;

X is O or S; and

R^1a, R^1b, R², R³, R⁴, and R⁵ are independently selected from the group consisting of hydrogen, hydroxyl, amino, halo, C_1-6alkyl, cycloalkyl, phenyl, naphthyl, heterocyclyl, -O-C_1- ₆alkyl, -NH-C_1-6alkyl, -N(C_1-6alkyl)C_1-6alkyl, nitro, cyano, CF₃, -OCF₃, -C(O)OC_1-6alkyl, - C(O)NHC_1-6alkyl, -C(O)NH₂, and -OS(O)₂C_1-4alkyl. See, for example, International Patent Application Publication No. WO/2014/128067, which is hereby incorporated by reference in its entirety.

[00186] In some embodiments, exemplary bromodomain ligands include a compound represented by the formula:

wherein:

X is C or N;

Y is–C(O)OR¹²,–C(O)NR¹⁰Rⁿ, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl;

m and n are independently 0 or 1; R¹, R², R³, R⁴, and R⁵ are independently selected from the group consisting of hydrogen, hydroxyl, amino, halo, C_1-6alkyl, cycloalkyl, phenyl, naphthyl, heterocyclyl, -O-C_1- ₆alkyl, -NH-C_1-6alkyl, -N(C_1-6alkyl)C_1-6alkyl, nitro, cyano, CF₃, -OCF₃, -C(O)OC_1-6alkyl, - C(O)NHC_1-6alkyl, -C(O)NH₂, and -OS(O)₂C_1-4alkyl. See, for example, International Patent Application Publication Nos. WO/2014/128111 and WO/2014/128070, which is hereby incorporated by reference in its entirety.

[00187] In some embodiments, exemplary bromodomain ligands include a compound re resented b the formula:

Formula FFF;

wherein:

A is optionally substituted heteroaryl or optionally substituted heterocyclo, wherein the substituents are one or more R¹⁴, R¹⁵ or R¹⁶;

R is hydrogen, optionally substituted (C₁-C₆)alkyl, optionally substituted (C₃- C₈)cycloalkyl(C₁-C₆)alkyl, optionally substituted aryl(C₁-C₆)alkyl, optionally substituted heteroaryl(C₁-C₆)alkyl, optionally substituted heterocyclo(C₁-C₆)alkyl, optionally substituted (C₁-C₆)alkyl-CO-, optionally substituted aryl-CO-, optionally substituted (C₃-C₈)cycloalkyl- CO-, optionally substituted heteroaryl, optionally substituted heterocyclo-CO-, optionally substituted aryl-SO₂-, optionally substituted (C₁-C₆)alkyl-SO₂- , optionally substituted (C₃- C₈)cycloalkyl-SO₂- optionally substituted heteroaryl-SO₂-, optionally substituted (C₁-C₆)alkyl- OCO- or optionally substituted (C₃-C₈)cycloalkyl-OCO-;

; X and Y are independently selected from hydrogen, optionally substituted (C₁-C₆)alkyl, optionally substituted (C₃-C₈)cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclo;

Z is hydrogen, halogen, -OH, (Ci-C₆)alkyl, (C₁-C₆)alkoxy, -NR³R⁴, -CONR³R⁴, - OCONR³R⁴, -NR⁶OCOR³, -NR⁶CONR³R⁴, -NR⁶SO₂NR³R⁴ or -NR⁶SO₂R⁴;

R¹ is halogen, -CN, OH, -NR³R⁴, -CONR³R⁴, -COOH, -OCONR³R⁴, -NHOCOR⁷, - NHCONR⁷R⁸, -NHSO₂NR⁷R⁸, optionally substituted (C₁-C₆)alkyl, optionally substituted (C₂- C₆)alkenyl, optionally substituted (C₂-C₆)alkynyl, optionally substituted (C₁-C₆)alkoxy, optionally substituted (C₃-C₈)cycloalkyl, optionally substituted (C₃-C₈)cycloalkyl-CO-, optionally substituted (C₃-C₈)cycloalkyl-SO₂-, optionally substituted aryl (C₁-C₆)alkoxy, optionally substituted (C₃-C₈)cycloalkyl (C₁-C₆)alkoxy, optionally substituted heterocyclyl- CO-, optionally substituted heterocyclyl, optionally substituted (C₁-C₆)alkyl-SO₂-, -NHSO₂- optionally substituted (C₁-C₆)alkyl, -NHSO₂-optionally substituted heterocyclo, optionally substituted (C₁-C₆)alkyl-NHSO₂- or optionally substituted heterocyclo-NHSO₂-;

R² is H, halogen, -CN, -COOH, -CONR⁷R⁸, -NHCOR³R⁴, -OCONR³R⁴, -NHCOOR³R⁴, optionally substituted (C₁-C₆)alkyl, optionally substituted (C₂-C₆)alkynyl, optionally substituted (C₁-C₆)alkoxy, optionally substituted heteroaryl or optionally substituted heterocyclo;

R³ is hydrogen, optionally substituted (C₁-C₆)alkyl, optionally substituted (C₃- C₈)cycloalkyl, optionally substituted (C₂-C₆)alkenyl, optionally substituted (C₂-C₆)alkynyl, cyano(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, optionally substituted aryl, optionally substituted aryl(C₁-C₆)alkyl, optionally substituted aryloxy(C₁-C₆)alkyl, optionally substituted (C₁- C₆)alkyl-SO₂-, optionally substituted heterocyclyl, optionally substituted heterocyclyl(C₁- C₆)alkyl, optionally substituted heteroaryl or optionally substituted heteroaryl(C₁-C₆)alkyl, R⁴ is hydrogen, optionally substituted (C₁-C₆)alkyl or optionally substituted (C₃- C₈)cycloalkyl;

or R³ and R⁴ may be taken together with the nitrogen atom to which they are attached to form an optionally substituted (C₄-C₈) heteroaryl or (C₄-C₈) heterocyclic ring;

R⁶ is hydrogen or optionally substituted (C₁-C₆)alkyl; R⁷ and R⁸ are independently hydrogen, optionally substituted (C₁-C₆)alkyl, optionally substituted (C₃-C₈)cycloalkyl, optionally substituted (C₂-C₆)alkenyl, optionally substituted (C₂- C₆)alkynyl, cyano(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, optionally substituted aryl, optionally substituted aryl(C₁-C₆)alkyl, optionally substituted;

aryloxy(C₁-C₆)alkyl, optionally substituted (C₁-C₆)alkyl-SO₂-, optionally substituted heterocyclyl, optionally substituted heterocyclyl(C₁-C₆)alkyl, optionally substituted heteroaryl or optionally substituted heteroaryl(C₁-C₆)alkyl;

or R⁷ and R⁸ may be taken together with the nitrogen atom to which they are attached to form an optionally substituted (C₄-C₈) heteroaryl or (C₄-C₈) heterocyclic ring;

R¹² and R¹³ are independently hydrogen, halogen, -CN, OH, -CONR³R⁴, -NHCOOR⁴, - NHCONR³R⁴, -NHCOR⁴, -NHSO₂R⁷, -SO₂NR³R⁴, -NHSO₂NR³R⁴, -SO₂R⁷, optionally substituted (C₁-C₆)alkyl, optionally substituted (C₃-C₈)cycloalkyl, optionally substituted (C₁- C₆) alkoxy, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclo;

R¹⁴ is hydrogen, optionally substituted(C₁-C₆)alkyl, (C₁-C₆)alkoxy, halogen, -CN, - NR³R⁴, OH, -NHOCOR⁷, -OCONR⁷R⁸, -NHCONR⁷R⁸ or -CF₃;

R¹⁵ is hydrogen, optionally substituted(C₁-C₆)alkyl, (C₁-C₆)alkoxy, halogen, -CN, - NR³R⁴, OH, -NHOCOR⁷, -OCONR⁷R⁸, -NHCONR⁷R⁸ or -CF₃;

R¹⁶ is hydrogen, optionally substituted(C₁-C₆)alkyl, (C₁-C₆)alkoxy, halogen, -CN, - NR³R⁴, OH, -NHOCOR⁷, -OCONR⁷R⁸, -NHCONR⁷R⁸ or -CF₃;

with the proviso that only one of R¹⁴, R¹⁵ and R¹⁶ is hydrogen;

and/or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof. See, for example, International Patent Application Publication Nos. WO/2014/134232 and WO/2014/134267, which is hereby incorporated by reference in its entirety.

[00188] For example, an exemplary compound of Formula FFF is represented by the formula:

and pharmaceutically acceptable salts thereof.

[00189] In some embodiments, exemplary bromodomain ligands include a compound represented by the formula:

wherein:

R₁ is CD₃, C₁-C₃ alkyl, or C₁-C₃ haloalkyl;

R₂ is H or C₁-C₃ alkyl;

Y₁ is N or CR₃;

R₃ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, C1-C6 haloalkyl,— C(O)R_3a,—C(O)OR_3a,—C(O)NR_3bR_3c,—C(O)N(R_3b)NR_3bR_3c,—S(O)R_3d,—S(O)₂R_3a,— S(O)₂NR_3bR_3c or G₁; wherein the C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl are each independently unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of G₁,—C(O)R_3a,—C(O)OR_3a,—C(O)NR_3bR_3c,—S(O)R_3d,—S(O)₂R_3a, —S(O)₂NR_3bR_3c,—OR_3a,—OC(O)R_3d,—NR_3bR_3c, N(R_3b)C(O)R_3d, N(R_3b)SO₂R_3d,

N(R_3b)C(O)OR_3d, N(R_3b)C(O)NR_3bR_3c, N(R_3b)SO₂NR_3bR_3c, and N(R_3b)C(NR_3bR_3c)ő NR_3bR_3c; Y₂ is C(O), S(O)₂, or CR₄R₅;

R₄ is H, deuterium, C₁-C₆ alkyl, halogen, or C₁-C₆ haloalkyl; and

R₅ is H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl, —C(O)R_5a,—C(O)OR_5a,—C(O)NR_5bR_5c,—S(O)R_5d,—S(O)₂R_5a,—S(O)₂NR_5bR_5c, or G₁; wherein the C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl are each independently

unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of G₁,—C(O)R_5a,—C(O)OR_5a,—C(O)NR_5bR_5c,—C(O)N(R_5b)NR_5bR_5c,—

S(O)R_5d,—S(O)₂R_5a,—S(O)₂NR_5bR_5c,—OR_5a,—OC(O)R_5d—NR_5bR_5c, N(R_5b)C(O)R_5d, N(R_5b)SO₂R_5d, N(R_5b)C(O)OR_5d, N(R_5b)C(O)NR_5bR_5c, N(R_5b)SO₂NR_5bR_5c, and

N(R_5b)C(NR_5bR_5c)ő NR_5bR_5c;

R_3a, R_3b, R_3c, R_5a, R_5b, and R_5C, at each occurrence, are each independently H, C₁- C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆haloalkyl, G₁, or—( C₁-C₆alkylenyl)-G₁;

R_3d and R_5d, at each occurrence, are each independently C₁-C₆ alkyl, C₂-C₆alkenyl, C₂- C₆alkynyl, C₁-C₆haloalkyl, G₁, or—( C₁-C₆ alkylenyl)-G₁;

G₁, at each occurrence, is independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; and each G₁ is optionally substituted with 1, 2, 3, 4, or 5 R_1g groups;

R₆ is H, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, halogen, C₁-C₆ haloalkyl,—C(O)R_6a, —C(O)OR_6a,—C(O)NR_6bR_6c,—S(O)₂R_6a,—S(O)₂NR_6bR_6c, or G₂; wherein the C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl are each independently unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of G2,—C(O)R_6a,—

C(O)OR_6a,—C(O)NR_6bR_6c,—C(O)N(R_6b)NR_6bR_6c,—S(O)R_6d,—S(O)₂R_6a,—S(O)₂NR_6bR_6c, —OR_6a,—OC(O)R_6d,—NR_6bR_6c, N(R_6b)C(O)R_6d, N(R_6b)SO₂R_6d, N(R_6b)C(O)OR_6d,

N(R_6b)C(O)NR_6bR_6c, N(R_6b)SO₂NR_6bR_6C, and N(R_6b)C(NR_6bR_6c)ő NR_6bR_6c;

R_6a, R_6b, and R_6c, at each occurrence, are each independently H, alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, haloalkyl, G₂,—(C₁-C₆ alkylenyl)-G₂,—(C₁-C₆ alkylenyl)-OR^a,—(C₁-C₆ alkylenyl)-S(O)₂R^a,—(C₁-C₆ alkylenyl)-S(O)₂NR^cR^d,—(C₁-C₆ alkylenyl)-C(O)R^a,—(C₁-C₆ alkylenyl)-C(O)OR^a,—(C₁-C₆ alkylenyl)-C(O)NR^cR^d,—(C₁-C₆ alkylenyl)-NR^cR^d,—(C₁-C₆ alkylenyl)-N(R^e)C(O)R^b,—(C₁-C₆ alkylenyl)-N(R^e)S(O)₂R^b,—(C₁-C₆ alkylenyl)- N(R^e)C(O)O(R^b),—(C₁-C₆ alkylenyl)-N(R^e)C(O)NR^cR^d, or—(C₁-C₆ alkylenyl)- N(R^e)S(O)2NR^cR^d; R_6d, at each occurrence, is independently alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, haloalkyl, G₂,—(C₁-C₆ alkylenyl)-G₂,—(C₁-C₆ alkylenyl)-OR_a,—(C₁-C₆ alkylenyl)-S(O)₂R_a,—(C₁-C₆ alkylenyl)-S(O)₂NR^cR^d,—(C₁-C₆ alkylenyl)-C(O)R^a,—(C₁-C₆ alkylenyl)-C(O)OR^a,—(C₁-C₆ alkylenyl)-C(O)NR^cR^d,—(C₁-C₆ alkylenyl)-NR^cR^d,—(C₁-C₆ alkylenyl)-N(R^e)C(O)R^b,—(C₁- C₆ alkylenyl)-N(R^e)S(O)₂R^b,—(C₁-C₆ alkylenyl)-N(R^e)C(O)O(R^b),—(C₁-C₆ alkylenyl)- N(R^e)C(O)NR^cR^d, or—(C₁-C₆ alkylenyl)-N(R^e)S(O)₂NR^cR^d;

G², at each occurrence, is independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; and each G2 is optionally substituted with 1, 2, 3, 4, or 5 R^2g groups;

A¹ is C(R⁷) or N; A² is C(R⁸) or N; A³ is C(R⁹) or N; and A⁴ is C(R¹⁰) or N; wherein zero, one, or two of A¹, A², A³, and A⁴ are N;

R₇, R₈, and R₉, are each independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl,—CN, NO₂,—OR_y1,—OC(O)R_y2,—OC(O)NR_y3R_y4,—SR_y1,— S(O)₂R_y1,—S(O)₂NR_y3R_y4,—C(O)R_y1,—C(O)OR_y1,—C(O)NR_y3R_y4,—NR_y3R_y4,—

N(R_y3)C(O)R_y2,—N(R_y3)S(O)₂R_y2,—N(R_y3)C(O)O(R_y2),—N(R_y3)C(O)NR_y3R_y4,—

N(R_y3)S(O)₂NR_y3R_y4, G₃,—(C₁-C₆ alkylenyl)-CN,—(C₁-C₆ alkylenyl)-OR_y1,—(C₁-C₆ alkylenyl)-OC(O)R_y2,—(C₁-C₆ alkylenyl)-OC(O)NR_y3R_y4,—(C₁-C₆ alkylenyl)-S(O)₂R_y1,— (C₁-C₆ alkylenyl)-S(O)₂NR_y3R_y4,—(C₁-C₆ alkylenyl)-C(O)R_y1,—(C₁-C₆ alkylenyl)-C(O)OR_y1, —(C₁-C₆ alkylenyl)-C(O)NR_y3R_y4,—(C₁-C₆ alkylenyl)-NR_y3R_y4,—(C₁-C₆ alkylenyl)- N(R_y3)C(O)R_y2,—(C₁-C₆ alkylenyl)-N(R_y3)S(O)₂R_y2,—(C₁-C₆ alkylenyl)-N(R_y3)C(O)O(R_y2), —(C₁-C₆ alkylenyl)-N(R_y3)C(O)NR_y3R_y4,—(C₁-C₆ alkylenyl)-N(R_y3)S(O)₂NR_y3R_y4,—(C₁-C₆ alkylenyl)-CN, or—(C₁-C₆ alkylenyl)-G₃;

R_y1, R_y3, and R_y4, at each occurrence, are each independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, G₃,—( C₁-C₆ alkylenyl)-G₃,—( C₁-C₆ alkylenyl)- OR^a,—( C₁-C₆ alkylenyl)-S(O)₂R^a,—( C₁-C₆ alkylenyl)-S(O)₂NR^cR^d,—( C₁-C₆ alkylenyl)- C(O)R^a,—( C₁-C₆ alkylenyl)-C(O)OR^a,—( C₁-C₆ alkylenyl)-C(O)NR^cR^d,—( C₁-C₆ alkylenyl)-NR^cR^d,—( C₁-C₆ alkylenyl)-N(R^e)C(O)R^b,—( C₁-C₆ alkylenyl)-N(R^e)S(O)₂R^b,—( C₁-C₆ alkylenyl)-N(R^e)C(O)O(R^b),—( C₁-C₆ alkylenyl)-N(R^e)C(O)NR^cR^d, or—( C₁-C₆ alkylenyl)-N(R^e)S(O)₂NR^cR^d;

R_y2, at each occurrence, is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁- C₆ haloalkyl, G₃,—(C₁-C₆ alkylenyl)-G₃,—(C₁-C₆ alkylenyl)-OR^a,—(C₁-C₆ alkylenyl)- S(O)₂R^a,—(C₁-C₆ alkylenyl)-S(O)₂NR^cR^d,—(C₁-C₆ alkylenyl)-C(O)R^a,—(C₁-C₆ alkylenyl)- C(O)OR^a,—(C₁-C₆ alkylenyl)-C(O)NR^cR^d,—(C₁-C₆ alkylenyl)-NR^cR^d,—(C₁-C₆ alkylenyl)- N(R^e)C(O)R^b,—(C₁-C₆ alkylenyl)-N(R^e)S(O)₂R^b,—(C₁-C₆ alkylenyl)-N(R^e)C(O)O(R^b),— (C₁-C₆ alkylenyl)-N(R^e)C(O)NR^cR^d, or—(C₁-C₆ alkylenyl)-N(R^e)S(O)₂NR^cR^d;

G³, at each occurrence, is independently aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocycle; and each G³ group is optionally substituted with 1, 2, 3, 4, or 5 R^4g groups;

R10 is H, C1-C3 alkyl, halogen, C1-C3 haloalkyl, or—CN;

R^1g, R^2g, and R^4g, at each occurrence, is independently selected from the group consisting of oxo, C₁-C₆ alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C₁-C₆haloalkyl,—CN, NO₂, G^2a,—OR^a,—OC(O)R^b,—OC(O)NR^cR^d,—SR^a,—S(O)₂R^a,—S(O)₂NR^cR^d,—C(O)R^a, —C(O)OR^a,—C(O)NR^cR^d,—NR^cR^d,—N(R^e)C(O)R^b,—N(R^e)S(O)₂R^b,—N(R^e)C(O)O(R^b), —N(R^e)C(O)NR^cR^d,—N(R^e)S(O)₂NR^cR^d,—(C₁-C₆ alkylenyl)-CN,—(C₁-C₆ alkylenyl)-G^2a, —(C₁-C₆ alkylenyl)-OR^a,—(C₁-C₆ alkylenyl)-OC(O)R^b,—( C₁-C₆alkylenyl)-OC(O)NR^cR^d,— ( C₁-C₆alkylenyl)-S(O)₂R^a,—( C₁-C₆alkylenyl)-S(O)₂NR^cR^d,—( C₁-C₆alkylenyl)-C(O)R^a,—( C₁-C₆alkylenyl)-C(O)OR^a,—( C₁-C₆alkylenyl)-C(O)NR^cR^d,—( C₁-C₆alkylenyl)-NR^cR^d,—( C₁-C₆alkylenyl)-N(R^e)C(O)R^b,—( C₁-C₆alkylenyl)-N(R^e)S(O)₂R^b,—( C₁-C₆alkylenyl)- N(R^e)C(O)O(R^b),—( C₁-C₆alkylenyl)-N(R^e)C(O)NR^cR^d,—( C₁-C₆alkylenyl)- N(R^e)S(O)₂NR^cR^d, or—( C₁-C₆alkylenyl)-CN;

R^a, R^c, R^d, and R^e, at each occurrence, are each independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, G^2a, or—(C₁-C₆ alkylenyl)-G^2a;

R^b, at each occurrence, is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁- C₆ haloalkyl, G^2a, or—( C₁-C₆ alkylenyl)-G^2a;

G2a, at each occurrence, are each independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; and each G^2a group is optionally substituted with 1, 2, 3, 4, or 5 R^3g groups;

R^3g, at each occurrence, is independently oxo, C₁-C₆ alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C₁-C₆ haloalkyl,—CN, NO2,—ORz1,—OC(O)Rz2,—OC(O)NRz3Rz4,— SRz1,—S(O)2Rz1,—S(O)2NRz3Rz4,—C(O) Rz1,—C(O)ORz1,—C(O)NRz3Rz4,— NRz3Rz4,—N(Rz3)C(O)Rz2,—N(Rz3)S(O)2Rz2,—N(Rz3)C(O)O(Rz2),—

N(Rz3)C(O)NRz3Rz4,—N(Rz3)S(O)2NRz3Rz4,—( C₁-C₆ alkylenyl)-ORz1,—( C₁-C₆ alkylenyl)-OC(O)Rz2,—( C₁-C₆ alkylenyl)-OC(O)NRz3Rz4,—( C₁-C₆ alkylenyl)-S(O)2Rz1, —( C₁-C₆ alkylenyl)-S(O)2NRz3Rz4,—( C₁-C₆ alkylenyl)-C(O)Rz2,—( C₁-C₆ alkylenyl)- C(O)ORz1,—( C₁-C₆ alkylenyl)-C(O)NRz3Rz4,—( C₁-C₆ alkylenyl)-NR^z3R^z4,—( C₁-C₆ alkylenyl)-N(R^z3)C(O)R^z2,—( C₁-C₆ alkylenyl)-N(R^z3)S(O)2Rz2,—( C₁-C₆ alkylenyl)- N(R^z3)C(O)O(R^z2),—( C₁-C₆ alkylenyl)-N(R^z3)C(O)NR^z3R^z4,—(C₁-C₆ alkylenyl)- N(R^z3)S(O)₂NR^z3R^z4, or—( C₁-C₆ alkylenyl)-CN;

R^z1, R^z3, and R^z4, at each occurrence, are each independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, or C₁-C₆ haloalkyl; and

R^z2, at each occurrence, is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, or C₁-C₆ haloalkyl. See, for example, U.S. Patent Application Publication No. US 20140256710, which is hereby incorporated by reference in its entirety.

[00190] For example, an exemplary compound of Formula GGG is represented by the formula:

, and pharmaceutically acceptable salts thereof.

[00191] In some embodiments, exemplary bromodomain ligands include a compound represented by the formula:

Formula HHH,

wherein:

R¹ is C₁-C₃ alkyl or C₁-C₃ haloalkyl;

X—Y is—CR³ő CH—,—Nő CR⁴—,—CR⁵ő N—, or—CR⁶R⁷—CR⁸R⁹—; wherein the left ends of the moieties are attached to the NH group in the ring;

A¹, A², A³, and A⁴ are CR^x; or

one or two of A¹, A², A³, and A⁴ are N, and the others are CR^x;

R² is R^xa when X—Y is—CR³ő CH—,—Nő CR⁴—, or—CR⁶R⁷—CR⁸R⁹—; or R² is -L-G when X—Y is—CR⁵ő N—, wherein L is O, N(R^y), O—C₁-C₆ alkylenyl, or N(R^y)—C₁-C₆ alkyenyl, wherein R^y is hydrogen or C₁-C₄ alkyl;

R^x and R^xa, at each occurrence, are each independently hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl,—CN, NO₂, G,—OR^x1,—OC(O)R^x2,— OC(O)NR^x3R^x4,—SR^x1,—S(O) ¹

2R^x1,—S(O)₂NR^x3R^x4,—C(O)R^x ,—C(O)OR^x1,—

C(O)NR^x3R^x4,—NR^x3R^x4,—N(R^x5)C(O)R^x2,—N(R^x5)S(O)₂R^x2,—N(R^x5)C(O)O(R^x2),— N(R^x5)C(O)NR^x3R^x4,—N(R^x5)S(O)₂NR^x3R^x4,—(C₁-C₆ alkylenyl)-G,—(C₁-C₆ alkylenyl)- OR^x1,—(C₁-C₆ alkylenyl)-OC(O)R^x2,—(C₁-C₆ alkylenyl)-OC(O)NR^x3R^x4,—(C₁-C₆ alkylenyl)-S(O)₂R^x1,—(C₁-C₆ alkylenyl)-S(O)₂NR^x3R^x4,—(C₁-C₆ alkylenyl)-C(O)R^x1,—(C₁- C₆ alkylenyl)-C(O)OR^x1,—(C₁-C₆ alkylenyl)-C(O)NR^x3R^x4,—(C₁-C₆ alkylenyl)-NR^x3R^x4,— (C₁-C₆ alkylenyl)-N(R^x5)C(O)R^x2,—(C₁-C₆ alkylenyl)-N(R^x5)S(O)₂R^x2,—(C₁-C₆ alkylenyl)- N(R^x5)C(O)O(R^x2),—(C₁-C₆ alkylenyl)-N(R^x5)C(O)NR^x3R^x4,—(C₁-C₆ alkylenyl)- N(R^x5)S(O)₂NR^x3R^x4, and—(C₁-C₆ alkylenyl)-CN; R^x1, R^x3, R^x4, and R^x5, at each occurrence, are each independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, G, or—C₁-C₆ alkylenyl-G;

R^x2, at each occurrence, is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁- C₆ haloalkyl, G, or—C₁-C₆ alkylenyl-G;

G, at each occurrence, are each independently aryl, heteroaryl, C₃-C₇ heterocycle, C₃-C₈ cycloalkyl, or C₅-C₈ cycloalkenyl; and each G group is optionally substituted with 1, 2, 3, 4, or 5 R^g groups;

R³ is H,—CN, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl,— C(O)R^3a,—C(O)OR^3a,—C(O)NR^3bR^3c,—C(O)N(R^3b)NR^3bR^3c,—S(O)R^3d,—S(O)₂R^3a,— S(O)₂NR^3bR^3c or G¹; wherein the C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl are each independently unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of G¹,—C(O)R^3a,—C(O)OR^3a,—C(O)NR^3bR^3c,—C(O)N(R^3b)NR^3bR^3c, —S(O)R^3d,—S(O)₂R^3a,—S(O)₂NR^3bR^3c,—OR^3a,—OC(O)R^3d,—NR^3bR^3c, N(R^3b)C(O)R^3d, N(R^3b)SO₂R^3d, N(R^3b)C(O)OR^3d, N(R^3b)C(O)NR^3bR^3c, and N(R^3b)SO₂NR^3bR^3c;

R⁴ is H,—CN, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, or C₁-C₆ haloalkyl; R⁵ is H,—CN, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl,— C(O)OR^5a,—C(O)NR^5bR^5c, or G¹;

R⁶ is H,—CN, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, or C₁-C₆ haloalkyl; R⁸ and R⁹, are each independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, or C₁-C₆ haloalkyl;

R⁷ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl,—C(O)R^7a, —C(O)OR^7a,—C(O)NR^7bR^7c,—S(O)R^7d,—S(O)₂R^7a,—S(O)₂NR^7bR^7c, or G¹; wherein the C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl are each independently unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of G¹,— C(O)R^7a,—C(O)OR^7a,—C(O)NR^7bR^7c,—C(O)N(R^7b)NR^7bR^7c,—S(O)R^7d,—S(O)₂R^7a,— S(O)₂NR^7bR^7c,—OR^7a,—OC(O)R^7d,—NR^7bR^7c, N(R^7b)C(O)R^7d, N(R^7b)SO₂R^7d,

N(R^7b)C(O)OR^7d, N(R^7b)C(O)NR^7bR^7C, and N(R^7b)SO₂NR^7bR^7C; R^3a, R^3b, R^3c, R^5a, R^5b, R^5c, R^7a, R^7b, and R^7c, at each occurrence, are each independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, G¹,—(C₁-C₆ alkylenyl)-G¹,—(C₁-C₆ alkylenyl)-OR^a, or— (C₁-C₆ alkylenyl)-CN;

R^3d and R^7d, at each occurrence, are each independently C₁-C₆ alkyl, C₁-C₆ haloalkyl, G¹,—(C₁-C₆ alkylenyl)-G¹,—(C₁-C₆ alkylenyl)-OR^a, or—(C₁-C₆ alkylenyl)-CN;

G¹, at each occurrence, is independently aryl, heteroaryl, C₃-C₇ heterocycle, C₃-C₈ cycloalkyl, or C₅-C₈ cycloalkenyl; and each G¹ is optionally substituted with 1, 2, 3, 4, or 5 R^1g groups;

R^g and R^1g, at each occurrence, are each independently selected from the group consisting of oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl,—CN, NO₂, G^1a,—OR^a,—OC(O)R^b,—OC(O)NR^cR^d,—SR^a,—S(O)₂R^a,—S(O)₂NR^cR^d,—C(O)R^a, —C(O)OR^a,—C(O)NR^cR^d,—NR^cR^d,—N(R^c)C(O)R^b,—N(R^e)S(O)₂R^b,—N(R^e)C(O)O(R^b), —N(R^e)C(O)NR^cR^d,—N(R^e)S(O)₂NR^cR^d,—(C₁-C₆ alkylenyl)-CN,—(C₁-C₆ alkylenyl)-G^2a, —(C₁-C₆ alkylenyl)-OR^a,—(C₁-C₆ alkylenyl)-OC(O)R^b,—(C₁-C₆ alkylenyl)-OC(O)NR^cR^d,— (C₁-C₆ alkylenyl)-S(O)₂R^a,—(C₁-C₆ alkylenyl)-S(O)₂NR^cR^d,—(C₁-C₆ alkylenyl)-C(O)R^a,— (C₁-C₆ alkylenyl)-C(O)OR^a,—(C₁-C₆ alkylenyl)-C(O)NR^cR^d,—(C₁-C₆ alkylenyl)-NR^cR^d,— (C₁-C₆ alkylenyl)-N(R^c)C(O)R^b,—(C₁-C₆ alkylenyl)-N(R^e)S(O)₂R^b,—(C₁-C₆ alkylenyl)- N(R^e)C(O)O(R^b),—(C₁-C₆ alkylenyl)-N(R^e)C(O)NR^cR^d,—(C₁-C₆ alkylenyl)- N(R^e)S(O)₂NR^cR^d, or—(C₁-C₆ alkylenyl)-CN;

R^a, R^c, R^d, and R^e, at each occurrence, are each independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, G^1a, or—(C₁-C₆ alkylenyl)-G^2a;

R^b, at each occurrence, is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁- C₆ haloalkyl, G^2a, or—(C₁-C₆ alkylenyl)-G^2a;

G^2a, at each occurrence, are each independently aryl, heteroaryl, C₃-C₇ heterocycle, C₃- C₈ cycloalkyl, or C₅-C₈ cycloalkenyl; and each G^2a group is optionally substituted with 1, 2, 3, 4, or 5 R^2g groups;

R^2g, at each occurrence, is independently oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl,—CN, NO₂,—OR^z1,—OC(O)R^z2,—OC(O)NR^z3R^z4,—SR^z1,— S(O)₂R^z1,—S(O)₂NR^z3R^z4,—C(O)R^z1,—C(O)OR^z1,—C(O)NR^z3R^z4,—NR^z3R^z4,—

N(R^z3)C(O)R^z2,—N(e)S(O)₂R^z2,—N(R^z3)C(O)O(R^z2),—N(R^z3)C(O)NR^z3R^z4,— N(R^z3)S(O)₂NR^z3R^z4,—(C₁-C₆ alkylenyl)-OR^z1,—(C₁-C₆ alkylenyl)-OC(O)R^z2,—(C₁-C₆ alkylenyl)-OC(O)NR^z3R^z4,—(C₁-C₆ alkylenyl)-S(O)₂R^z1,—(C₁-C₆ alkylenyl)-S(O)₂NR^z3R^z4, —(C₁-C₆ alkylenyl)-C(O)R^z1,—(C₁-C₆ alkylenyl)-C(O)OR^z1,—(C₁-C₆ alkylenyl)- C(O)NR^z3R^z4,—(C₁-C₆ alkylenyl)-NR^z3R^z4,—(C₁-C₆ alkylenyl)-N(R^z3)C(O)R^z2,—(C₁-C₆ alkylenyl)-N(R^z3)S(O)₂R^z2,—(C₁-C₆ alkylenyl)-N(R^z3)C(O)O(R^z2),—(C₁-C₆ alkylenyl)- N(R^z3)C(O)NR^z3R^z4—, (C₁-C₆ alkylenyl)-N(R^z3)S(O)₂NR^z3R^z4, or—(C₁-C₆ alkylenyl)-CN; R^z1, R^z3, and R^z4, at each occurrence, are each independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂- C₆ alkynyl, or C₁-C₆ haloalkyl; and

R^z2, at each occurrence, is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, or C₁-C₆ haloalkyl. See, for example, U.S. Patent Application Publication No. US 20140256705, which is hereby incorporated by reference in its entirety.

[00192] For example, exemplary compounds of Formula HHH may be selected from the group consisting of:

, and pharmaceutically acceptable salts thereof.

[00193] In some embodiments, exemplary bromodomain ligands include a compound represented by the formula:

Formula III,

wherein:

X is N(R^a), O, or S;

Y¹ and Y³, independently, are CH or N;

Y² is CH, CR^a, N, or null;

Z is H, halo, OH, or null;

A is an unsubstituted or substituted 5-membered heterocyclic ring;

B is aryl, CH(R^a)-aryl, C_3-10cycloalkyl, CH(R^a)—C_3-10cycloalkyl, heteroaryl, CH(R^a)- heteroaryl, C_3-10heterocycloalkyl, or CH(R^a)—C_3-10heterocycloalkyl, each unsubstituted or substituted;

G is N, O, or S;

L is null, H, or C(R^d)₃;

R¹ is H, halo, OH, OR^a, or N(R^a)₂;

R^a, independently, is H, C_1-3alkyl, or benzyl;

R^b, independently, is C_1-6alkyl, halo, aryl, unsubstituted or substituted CH₂-aryl, unsubstituted or substituted C_3-10cycloalkyl, unsubstituted or substituted CH₂—C_3-10cycloalkyl, heteroaryl, unsubstituted or substituted CH₂-heteroaryl, unsubstituted or substituted C_3- ₁₀heterocycloalkyl, or unsubstituted or substituted CH₂—C_3-10heterocycloalkyl, or CHO; n is an integer 0, 1, 2, or 3;

R^c and R^d, each independently, are hydrogen, C_1-6alkyl, unsubstituted or substituted aryl, unsubstituted or substituted CH₂-aryl, unsubstituted or substituted C_3-10cycloalkyl, unsubstituted or substituted CH₂—C_3-10cycloalkyl, heteroaryl, unsubstituted or substituted CH₂-heteroaryl, unsubstituted or substituted C_3-10heterocycloalkyl, or unsubstituted or substituted CH₂—C_3-10heterocycloalkyl;

or a pharmaceutically acceptable salt, hydrate, or solvate thereof. See, for example, U.S. Patent Application Publication No. US 20140256706, which is hereby incorporated by reference in its entirety.

[00194] For example, exemplary compounds of Formula III may be selected from the group consisting of:

, and pharmaceutically acceptable salts thereof.

[00195] In some embodiments, exemplary bromodomain ligands include a compound selected from the group consisting of:

pharmaceutically acceptable salts thereof, wherein R is 2-methoxyphenyl, 3-methoxyphenyl, phenyl, 2-methylphenyl, t-butyl, or benzyl.

[00196] In some embodiments, exemplary bromodomain ligands include a compound selected from the group consisting of:

, and pharmaceutically acceptable salts thereof, wherein R is 1-piperidine, 1-pyrrolidine, 4-morpholine, methoxy, methyl, or H.

[00197] In some embodiments, exemplary bromodomain ligands include a compound represented by the formula:

Formula JJJ,

wherein:

R₁ is C_1-4alkyl;

R₂ is C_1-4alkyl, C_3-7cycloalkyl, -CH₂CF₃, -CH₂OCH₃ or heterocyclyl;

R₃ is C_1-4alkyl, -CH₂F, -CH₂OH or -CH₂OC(O)CH₃;

R₄ when present is H, hydroxy, halo, cyano, -CO₂H, -CONH₂, -OSO₂CF₃, -C(O)N(R₈) C_1-4alkyleneOH, -C(O)N(R₈)C_1-4alkyleneOCH₃, -C(O)N(R₈)C_1-4alkyleneNR₆R₇, - C(O)N(R₈)C_1-4alkyleneSO₂CH₃, -C(O)N(R₈)C_1-4alkyleneCN, -C(O)NHOH, - C(O)NHCH(CH₂OH)₂, -OCH₂CH₂OH, -B-C_1-6alkyl, -B-C_3-7cycloalkyl, -B-phenyl, -B- heterocyclyl or -B-heteroaromatic, wherein the C_3-7cycloalkyl, phenyl, heterocyclyl or heteroaromatic ring is optionally substituted by 1 or 2 substituents independently selected from =O, C_1-6alkyl, C_1-6alkoxy, halo, -NH₂, -CO₂H, -C(O)C_1-6alkyl, -C(O)NHC_1-6alkyl, cyano, - CH₂CH₂NHCH₃, -CH₂CH₂OH, -CH₂CH₂OCH₃, C_3-7cycloalkyl, phenyl, heterocyclyl and heteroaromatic;

R₅ when present is H, halo, hydroxy or Ci-6alkoxy;

A is -NH-, -O-, -S-, -SO-, -SO₂-, -N(C_1-4alkyl)- or -NC(O)(CH₃)-;

B is a bond, -O-, -N(R₈)-, S, -SO-, -SO₂-, -SO₂N(R₈)-, -CH₂-, -C(O)-, -CO₂-, - N(R₈)C(O)-, -C(O)N(R₈)-, -C(O)N(R₈)CH₂- or -C(O)N(R₈)CH₂CH₂-;

V is phenyl, heteroaromatic or pyridone any of which may be optionally substituted by 1, 2 or 3 substituents independently selected from C_1-6alkyl, fluorine, chlorine, C_1-6alkoxy, hydroxy, cyclopropyl, cyano, -CO₂CH₃, heterocyclyl, -CO₂H, -CH₂NR₆R₇, -NR₆R₇, - C(O)NR₆R₇, -NR₆C(O)R₇,-CF₃, -NO₂, -CH₂OCH₃, -CH₂OH, -CH(OH)CH₃, -SO₂CH₃, - CH₂heterocyclyl, -OCH₂CH₂NHC(O)CH₃, -OCH₂CH₂OH, -OCH₂CH₂NH₂, - C(O)NHheteroaromatic, -C(O)NHCH₂heterocyclyl,C(O)NHCH₂CH₂OH, - C(O)NHCH₂CH₂NH₂, -C(O)NHCH₂CH₂S0₂Me, -C(O)NHCH₂CH(OH)CH₃, -C(O)heterocyclyl and -C(O)NHheterocyclyl, wherein the heterocyclyl ring is optionally substituted by -OH;

R₆, R₇, R₈, R₉ and R₁₀ are each independently selected from H and C_1-4alkyl;

W is CH or N;

X is C or N;

Y is C or N; and

Z is CH orN. See, for example, International Patent Application Publication No.

WO/2014/140076, which is hereby incorporated by reference in its entirety.

[00198] For example, exemplary compounds of Formula JJJ may be selected from the rou consistin of:

, and pharmaceutically acceptable salts thereof.

[00199] In some embodiments, exemplary bromodomain ligands include compounds selected from the group consisting of:

[00200] In some embodiments, exemplary bromodomain ligands include a compound represented by the formula:

Formula KKK,

wherein:

Y₁ is N or CH;

R₁ is CD₃, C₁-C₃ alkyl, or C₁-C₃ haloalkyl;

R₂ is H or C₁-C₃ alkyl;

R₃ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl, CN, - C(O)R_3a, -C(O)OR_3a, -C(O)NR_3bR_3c, -S(O)R_3d, -S(O)₂R_3a, -S(O)₂NR_3bR_3c, or G₁; wherein the C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl are each independently unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of G₁, CN, -C(O)R_3a,—C(O)OR_3a, -C(O)NR_3bR_3c, -S(O)R_3d, -S(O)₂R_3a, -S(O)₂NR_3bR_3c, -OR_3a, - OC(O)R_3d, -NR_3bR_3c, -N(R_3b)C(O)R_3d, -N(R_3b)SO₂R_3d, -N(R_3b)C(O)OR_3d, - N(R_3b)C(O)NR_3bR_3c, -N(R_3b)SO₂NR_3bR_3c, and N(R_3b)C(NR_3bR_3c)ő NR_3bR_3c;

Y₂ is C(O), S(O)₂, or CR₄R₅;

R₄ is H, deuterium, C₁-C₆ alkyl, halogen, or C₁-C₆ haloalkyl; and

R₅ is H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl, -C(O)R_5a, -C(O)OR_5a, -C(O)NR_5bR_5c, -S(O)R_5d, -S(O)₂R_5a, -S(O)₂NR_5bR_5c, or G₁; wherein the C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl are each independently unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of G₁, CN, -C(O)R_5a, -C(O)OR_5a, -C(O)NR_5bR_5c, -C(O)N(R_5b)NR_5bR_5c, -S(O)R_5d, -S(O)₂R_5a, - S(O)₂NR_5bR_5c, -OR_5a, -OC(O)R_5d, -NR_5bR_5c, -N(R_5b)C(O)R_5d, -N(R_5b)SO₂R_5d, - N(R_5b)C(O)OR_5d, -N(R_5b)C(O)NR_5bR_5c, -N(R_5b)SO₂NR_5bR_5c, and - N(R_5b)C(NR_5bR_5c)ő NR_5bR_5c;

R_3a, R_3b, R_3c, R_5a, and R_5b, at each occurrence, are each independently H, C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆haloalkyl, G₁, or -(C₁-C₆alkylenyl)-G₁;

R_5c, at each occurrence, is each independently H, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂- C₆alkynyl, C₁-C₆haloalkyl, G₁, -(C₁-C₆ alkylenyl)-G₁, -(C₁-C₆ alkylenyl)-CN, -(C₁-C₆ alkylenyl)-OR_a, or -(C₁-C₆ alkylenyl)-C(O)OR_a;

R_3d, at each occurrence, is independently C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁- C₆haloalkyl, G₁, or -(C₁-C₆ alkylenyl)-G₁;

R_5d, at each occurrence, is independently C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁- C₆haloalkyl, G₁, -(C₁-C₆ alkylenyl)-G₁, -(C₁-C₆ alkylenyl)-NR_cR_d, or -(C₁-C₆ alkylenyl)- N(R_a)C(O)O(R_b);

R₆ is H, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, halogen, C₁-C₆ haloalkyl, -C(O)R_6a, - C(O)OR_6a, -C(O)NR_6bR_6c, -S(O)₂R_6a, -S(O)₂NR_6bR_6c, or G₂; wherein the C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl are each independently unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of G₂, CN, -C(O)R_6a, -C(O)OR_6a, -C(O)NR_6bR_6c, -C(O)N(R_6b)NR_6bR_6c, -S(O)R_6d, -S(O)₂R_6a, -S(O)₂NR_6bR_6c, -OR_6a, -OC(O)R_6d, - NR_6bR_6c, N(R_6b)C(O)R_6d, N(R_6b)SO₂R_6d, N(R_6b)C(O)OR_6d, N(R_6b)C(O)NR_6bR_6c,

N(R_6b)SO₂NR_6bR_6C, and N(R_6b)C(NR_6bR_6c)ő NR_6bR_6c;

R_6a, R_6b, and R_6c, at each occurrence, are each independently H, alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, haloalkyl, G₂, -(C₁-C₆ alkylenyl)-G₂, -(C₁-C₆ alkylenyl)-OR^a, -(C₁-C₆ alkylenyl)-S(O)₂R^a, -(C₁-C₆ alkylenyl)-S(O)₂NR^cR^d, -(C₁-C₆ alkylenyl)-C(O)R^a, -(C₁-C₆ alkylenyl)-C(O)OR^a, -(C₁-C₆ alkylenyl)-C(O)NR^cR^d, -(C₁-C₆ alkylenyl)-NR^cR^d, -C₁-C₆ alkylenyl)-N(R^a)C(O)R^b, -(C₁-C₆ alkylenyl)-N(R^a)S(O)₂R^b, -(C₁-C₆ alkylenyl)- N(R^a)C(O)O(R^b), -(C₁-C₆ alkylenyl)-N(R^a)C(O)NR^cR^d, or -(C₁-C₆ alkylenyl)- N(R^a)S(O)₂NR^cR^d;

R_6d, at each occurrence, is independently alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, haloalkyl, G₂, -(C₁-C₆ alkylenyl)-G₂, -(C₁-C₆ alkylenyl)-OR_a, -(C₁-C₆ alkylenyl)-S(O)₂R_a, -(C₁-C₆ alkylenyl)-S(O)₂NR^cR^d, -(C₁-C₆ alkylenyl)-C(O)R^a, -(C₁-C₆ alkylenyl)-C(O)OR^a, -(C₁-C₆ alkylenyl)-C(O)NR^cR^d, -(C₁-C₆ alkylenyl)-NR^cR^d, -(C₁-C₆ alkylenyl)-N(R^e)C(O)R^b, -(C₁-C₆ alkylenyl)-N(R^e)S(O)₂R^b, -(C₁-C₆ alkylenyl)-N(R^e)C(O)O(R^b), -(C₁-C₆ alkylenyl)- N(R^e)C(O)NR^cR^d, or -(C₁-C₆ alkylenyl)-N(R^e)S(O)₂NR^cR^d;

G², at each occurrence, is independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; and each G₂ is optionally substituted with 1, 2, 3, 4, or 5 R^2g groups;

R₁₀ is H, C₁-C₃ alkyl, halogen, C₁-C₃ haloalkyl, or—CN;

R^1g, R^2g, and R^4g, at each occurrence, is independently selected from the group consisting of oxo, C₁-C₆ alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C₁-C₆haloalkyl,—CN, NO₂, G^2a,—OR^a,—OC(O)R^b,—OC(O)NR^cR^d,—SR^a,—S(O)₂R^a,—S(O)₂NR^cR^d,—C(O)R^a, —C(O)OR^a,—C(O)NR^cR^d,—NR^cR^d,—N(R^e)C(O)R^b,—N(R^e)S(O)₂R^b,—N(R^e)C(O)O(R^b), —N(R^e)C(O)NR^cR^d,—N(R^e)S(O)₂NR^cR^d,—(C₁-C₆ alkylenyl)-CN,—(C₁-C₆ alkylenyl)-G^2a, —(C₁-C₆ alkylenyl)-OR^a,—(C₁-C₆ alkylenyl)-OC(O)R^b,—( C₁-C₆alkylenyl)-OC(O)NR^cR^d,— ( C₁-C₆alkylenyl)-S(O)₂R^a,—( C₁-C₆alkylenyl)-S(O)₂NR^cR^d,—( C₁-C₆alkylenyl)-C(O)R^a,—( C₁-C₆alkylenyl)-C(O)OR^a,—( C₁-C₆alkylenyl)-C(O)NR^cR^d,—( C₁-C₆alkylenyl)-NR^cR^d,—( C₁-C₆alkylenyl)-N(R^a)C(O)R^b,—( C₁-C₆alkylenyl)-N(R^a)S(O)₂R^b,—( C₁-C₆alkylenyl)- N(R^a)C(O)O(R^b),—( C₁-C₆alkylenyl)-N(R^a)C(O)NR^cR^d,—( C₁-C₆alkylenyl)- N(R^a)S(O)₂NR^cR^d, or—( C₁-C₆alkylenyl)-CN;

G^2a, at each occurrence, are each independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; and each G^2a group is optionally substituted with 1, 2, 3, 4, or 5 R^3g groups;

R^3g, at each occurrence, is independently oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl,—CN, NO₂,—OR^z1,—OC(O)R^z2,—OC(O)NR^z3R^z4,— SR^z1,—S(O)₂R^z1,—S(O)₂NR^z3R^z4,—C(O)R^z1,—C(O)OR^z1,—C(O)NR^z3R^z4,—NR^z3R^z4,— N(R^z3)C(O)R^z2,—N(R^z3)S(O)₂R^z2,—N(R^z3)C(O)O(R^z2),—N(R^z3)C(O)NR^z3R^z4,—

N(R^z3)S(O)₂NR^z3R^z4,—( C₁-C₆ alkylenyl)-OR^z1,—(C₁-C₆ alkylenyl)-OC(O)R^z2,—( C₁-C₆ alkylenyl)-OC(O)NR^z3R^z4,—( C₁-C₆ alkylenyl)-S(O)₂R^z1,—(C₁-C₆ alkylenyl)-S(O)₂NR^z3R^z4, —( C₁-C₆ alkylenyl)-C(O)R^z2,—( C₁-C₆ alkylenyl)-C(O)OR^z1,—(C₁-C₆ alkylenyl)- C(O)NR^z3R^z4,—( C₁-C₆ alkylenyl)-NR^z3R^z4,—( C₁-C₆ alkylenyl)-N(R^z3)C(O)R^z2,—(C₁-C₆ alkylenyl)-N(R^z3)S(O)₂R^z2,—(C₁-C₆ alkylenyl)-N(R^z3)C(O)O(R^z2),—( C₁-C₆ alkylenyl)- N(R^z3)C(O)NR^z3R^z4,—(C₁-C₆ alkylenyl)-N(R^z3)S(O)₂NR^z3R^z4, or—(C₁-C₆ alkylenyl)-CN;

R^z2, at each occurrence, is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, or C₁-C₆ haloalkyl. See, for example, International Patent Application Publication No.

WO/2014/139324, which is hereby incorporated by reference in its entirety.

[00201] For example, exemplary compounds of Formula KKK may be selected from the group consisting of:

, and pharmaceutically acceptable salts thereof.

[00202] In some embodiments, exemplary bromodomain ligands include a compound represented by the formula:

Formula LLL,

wherein:

(i) Y² is N and Y³ is C; or

(ii) Y² is C and Y³ is N;

Y¹ is CH or N;

L is a bond, optionally substituted Ci_₆alkylene, optionally substituted deuterated Ci_₆alkylene, -C(R⁶R⁷)-, -C(O)NR⁹-, -CH₂N(R⁹)-, -SO₂N(R⁹)-, -N(R⁹)C(O)N(R⁹)-, -N(R⁹)SO₂- , -N(R⁹)CH₂-, -OC_1-4alkylene-, - C_1-4alkylene-0-, -NR⁹C(O)-, -N(R⁹)SO₂-, -C(O)-, -S(O)-, - SO₂-, -O-, -S-, -P(O)(R^a)-, optionally substituted C_2-6alkenylene, optionally substituted - CH=C(R^b)- or optionally substituted -Si(R^c)(R^c); or R⁶ and R⁷ taken together with the carbon atom to which they attach form an optionally substituted 3- to 6-membered ring having from 0- 2 heteroatoms selected from O, N or S or an oxo; R^a is optionally substituted C_1-6alkyl, optionally substituted aryl or optionally substituted heteroaryl; R^b is H or C_1-6alkyl; or R^b and R¹ taken together with the carbon atom to which they attach form an optionally substituted 3- to 6-membered carbocyclic ring or an optionally substituted 4- to 8-membered heterocyclic ring having from 1-2 heteroatoms as ring members selected from O, N or S, wherein the nitrogen or sulfur ring atoms can be optionally oxidized; each R^c is independently C_1-6alkyl or C_1-6alkoxy; R⁹ is H, C_1-4alkyl, or C_1-4haloalkyl;

R¹, R², R⁴, R⁶ and R⁷ are each independently H, D, optionally substituted C_1-6alkyl, optionally substituted C_1-6alkenyl, optionally substituted C_1-6alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted

heterocycloalkylalkyl, optionally substituted cycloalkylalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted -Si(R^c)(R^c) or R¹³ selected from halogen, -CN, -OH, -NH₂, -NO₂, -C(O)OH, - C(S)OH, -C(O)NH₂, -C(S)NH₂, -S(O)₂NH₂, -NHC(O)NH₂, -NHC(S)NH₂, -NHS(O)₂NH₂, - C(NH)NH₂, -CH=C(R⁸)(R⁸), -OR⁸, -SR⁸, -OC(O)R⁸, -OC(S)R⁸, -P(=O)HR⁸, -P(=O)R⁸R⁸, - PH(=O)OR⁸, -P(=O)(OR⁸)₂, -OP(=O)(OR⁸)₂, -C(O)H, -O(CO)OR⁸, -C(O)R⁸, -C(S)R⁸, - C(O)OR⁸,

-C(S)OR^s, -S(O)R^s, -S(O)₂R^s, -C(O)NHR^g, -C(S)NHR^g, -C(O)NR^gR^g, -C(S)NR^gR^g, - S(O)₂NHR^g, -S(O)₂NR^gR^g, -C(NH)NHR^g, -C(NH)NR^gR^g, -NHC(O)R^g, -NHC(S)R^g, - NR^gC(O)R^g, -NR^gC(S)R^g, -NHS(O)₂R^g, -NR^gS(O)₂R^g, -NHC(O)NHR^g, -NHC(S)NHR^g, - NR^gC(O)NH₂, -NR^gC(S)NH₂,

-NR^gC(O)NHR^g, -NR^gC(S)NHR^g, -NHC(O)NR^gR^g, -NHC(S)NR^gR^g, -NR^gC(O)NR^gR^g, -NR^gC(S)NR^gR^g, -NHS(O)₂NHR^g, -NR^gS(O)₂NH₂, -NR^gS(O)₂NHR^g, -NHS(O)₂NR^gR^g, - NR^gS(O)₂NR^gR^g, -NHR^g or -NR^gR^g, wherein each R^g is independently H, optionally substituted C_1-6alkyl, optionally substituted C_1-6alkenyl, optionally substituted C_1-6alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted cycloalkylalkyl, optionally substituted arylalkyl, optionally substituted

heteroarylalkyl or optionally substituted heterocycloalkylalkyl; or two R^g groups when attached to the same carbon or nitrogen atom are taken together to form a 3- to 6-membered carbocyclic ring or 3- to 8-membered heterocyclic ring having from 1-2 heteroatoms as ring members selected from O, N or S, wherein the nitrogen or sulfur ring atoms are optionally oxidized; wherein the aliphatic or aromatic portion of R^g is optionally substituted with from 1 -3 R^h substituents independently selected from halogen, -CN, -OH, -NH₂, -NO₂, -CH=C(Rⁱ)(Rⁱ), - C(O)OH, -C(S)OH, -C(O)NH₂, -C(S)NH₂, -S(O)₂NH₂, -NHC(O)NH₂, -NHC(S)NH₂, - NHS(O)₂NH₂, -C(NH)NH₂, -OR, -SRⁱ, -OC(O)Rⁱ, -OC(S)Rⁱ, -P(=O)HR, -P(=O)RⁱRⁱ, - PH(=O)ORⁱ, -P(=O)(ORⁱ)₂, -OP(=O)(ORⁱ)₂, -C(O)H, -O(CO)ORⁱ, -C(O)Rⁱ, -C(S)Rⁱ, -C(O)ORⁱ, -C(S)ORⁱ, -S(O)Rⁱ, -S(O)₂Rⁱ, -C(O)NHRⁱ, -C(S)NHRⁱ, -C(O)NRⁱRⁱ, -C(S)NRⁱRⁱ, -S(O)₂NHRⁱ, - S(O)₂NRⁱRⁱ, -C(NH)NHRⁱ, -C(NH)NRⁱRⁱ, -NHC(O)Rⁱ, -NHC(S)Rⁱ, -NRⁱC(O)R, -NRC(S)Rⁱ, - NHS(O)₂Rⁱ, -NRⁱS(O)₂R, -NHC(O)NHR, -NHC(S)NHRⁱ, -NRC(O)NH₂, -NRⁱC(S)NH₂, - NRⁱC(O)NHRⁱ, -NRⁱC(S)NHRⁱ, -ȃ ǾC(ȅ )ȃ RⁱRⁱ, -NHC(S)NRⁱRⁱ, -ȃ RⁱC(O)ȃ RⁱRⁱ, - ȃ RⁱC(S)ȃ RⁱRⁱ, -ȃ ǾS(O)₂ȃ ǾRⁱ, -ȃ RⁱS(O)₂ȃ Ǿ₂, -NRⁱS(O)₂NHRⁱ, -NHS(O)₂NRⁱRⁱ, - ȃ RⁱS(O)₂ȃ RⁱRⁱ, Rⁱ, -NHRⁱ or -NRⁱRⁱ, wherein each Rⁱ is independently C_1-6alkyl, aryl, aryl-C_1- ₂alkyl, C_3-6cycloalkyl, C_3-6cycloalkyl-C_1-4alkyl, heteroaryl, heteroaryl-C_1-4alkyl,

heterocycloalkyl or heterocycloalkyl-C_1-4alkyl, wherein each Rⁱ is further optionally substituted with from 1-3 R^p groups independently selected from halogen, CN, -OH, -NH₂, -N(R^q)(R^q), - NO₂, -C(O)OH, - C(O)NH₂, -S(O)₂NH₂, -NHC(O)NH₂, -C(NH)NH₂, -P(=O)HR^q , -P(=O)R^qR^q , -PH(=O)OR^q, -P(=O)(OR^q)₂, -OP(=O)(OR^q)₂, -OC(O)R^q, -OC(S)R^q, -C(O)R^q, -C(S)R^q, - C(O)OR^q, -S(O)₂R^q, -C(O)NHR^q, C_1-6alkyl, C_1-6alkoxy, halogen, C_1-6haloalkyl or C_1- ₆haloalkoxy, wherein R^q is C_1-6alkyl;

R³ is H, halogen, -CN, optionally substituted C_1-6alkyl, optionally substituted deuterated C_1-6alkyl,optionally substituted aryl, optionally substituted aryl-C_1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl-C_1-4alkyl, optionally substituted C_3-6 cycloalkyl, optionally substituted C_3-8 cycloalkenyl, optionally substituted C_3-8 cycloalkyl-C-_1-4alkyl, optionally substituted C_2-6 alkynyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkyl-C_1-4alkyl or R^J selected from halogen, -CN, -OH, -NH₂, -NO₂, - C(O)OH, -C(S)OH, -C(O)NH₂, -C(S)NH₂, -S(O)₂NH₂, -NHC(O)NH₂, -NHC(S)NH₂, - NHS(O)₂NH₂, -C(NH)NH₂, -CH=C(R^k)(R^k), -OR^k, -SR^k, -OC(O)R^k, -OC(S)R^k, -P(=O)HR^k, - P(=O)R^kR^k, -PH(=O)OR^k, -P(=O)(OR^k)₂, -OP(=O)(OR^k)₂, -C(O)H, -O(CO)OR^k, -C(O)R^k, - C(S)R^k, -C(O)OR^k, -C(S)OR^k, -S(O)R^k, -S(O)₂R^k, -C(O)NHR^k, -C(S)NHR^k, -C(O)NR^kR^k, - C(S)NR^kR^k -S(O)₂NHR^k, -S(O)₂NR^kR^k, -C(NH)NHR^k, -C(NH)NR^kR^k, -NHC(O)R^k, - NHC(S)R^k, -NR^kC(O)R^k, -NR^kC(S)R^k, -NHS(O)₂R^k, -NR^kS(O)₂R^k, -NHC(O)NHR^k, - NHC(S)NHR^k, -NR^kC(O)NH₂, -NR^kC(S)NH₂, -NR^kC(O)NHR^k, -NR^kC(S)NHR^k, - NHC(O)NR^kR^k -NHC(S)NR^kR^k, -NR^kC(O)NR^kR^k -NR^kC(S)NR^kR^k, -NHS(O)₂NHR^k, - NR^kS(O)₂NH₂, -NR^kS(O)₂NHR^k -NHS(O)₂NR^kR^k, -NR^kS(O)₂NR^kR^k -NHR^k or -NR^kR^k; or two R^k groups when attached to the same carbon or nitrogen atom are taken together to form a 3- to 6-membered carbocyclic ring or 3- to 8-membered heterocyclic ring having from 1-2 heteroatoms as ring members selected from O, N or S, wherein the nitrogen or sulfur ring atoms are optionally oxidized; wherein each R^k is independently H, C_1-66alkyl or aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, cycloalkyl or

cycloalkylalkyl, wherein R^k is optionally substituted with from 1-3 R^h;

R⁵ is an optionally substituted 5- or 6-membered heteroaryl having from 1 to 4 heteroatoms as ring members selected from O, N or S; or an optionally substituted

heterocycloalkyl; and is a single bond or a double bond to maintain ring A being aromatic. See, for example, International Patent Application Publication No. WO/2014/145051, which is hereby incorporated by reference in its entirety.

[00203] For example, exemplary compounds of Formula LLL may be selected from the group consisting of:

, and pharmaceutically acceptable salts thereof.

[00204] In some embodiments, exemplary bromodomain ligands include a compound represented by the formula:

Formula MMM;

wherein:

V is N or C-R₂;

W is N or C-R₈;

X is N, CH or C(CH₃);

Y is N or C-R₅;

Z is N or C-R₁₅;

Q is N or CH;

R₁ is C_1-4 alkyl;

R₂, when present, is H, OH, C_1-4alkyl, halo, -CF₃, -NH₂, -OC_1-4alkyl, -NHC(O)H, - NHC(O)C_1-4alkyl, -N(CH₃)C(O)C_1-4alkyl, -NHC(O)NH₂, -NHC(O)C_1-4alkyleneNH₂, - N(CH₃)C(O)NH₂, -N(CH₃)C(O)C_1-4alkyleneNH₂, -NHC_2-4alkyleneOCH₃, -N(CH₃)C_2- ₄alkyleneOCH₃, -OC_2-4alkyleneOCH₃, -OC_2-4alkyleneOH or

R₂ is a group selected from -G-CH₂CH(R₃)(R₄), -G-CH(R₃)(R₄) and -G-R₃ in which G is NH, N(CH₃), O, C(O)NH or NHC(O);

R₃ is phenyl, pyridinyl, C_3-7cycloalkyl or a heterocycle optionally substituted by =O; and R₄ is H or C_1-4 alkyl; -CF₃, CN, OH, -OC_1-4 alkyl, -CH₂NH₂, -OCF₃, -SO₂CH₃, - C(O)NHC_1-4alkyl or–CO₂H; R⁶ is–NR¹¹R¹² or a group

;

D is CH or N;

E is N, O, CH, or SO₂;

R₇, when present, is H, OH, C_1-4alkyl, -NH₂, -SO₂C_1-4alkyl, -SO₂phenyl, -SO₂benzyl, - SO₂N(CH₃)₂, -NHSO₂CH₃, -C(O)C_1-4alkyl, -C(O)phenyl;

R₈, when present, is H, C_1-4alkyl, halo, -CF₃, CN, OH, -OC_1-4alkyl, -OC_2-4alkyleneOC_1- ₄alkyl, -OCF₃ -OC_1-4alkyleneF, -OC_1-4alkyleneCHF₂, -OC_2-4alkyleneOH, -Ophenyl, -OC_1- ₄alkylenephenyl, -NHC_3-7cycloalkyl, -NHC_1-4alkyleneC_3-7cycloalkyl, -OC_3-7cycloalkyl, -OC_1- ₄alkyleneC_3-7cycloalkyl, -NHC_4-6heterocycle -NHC_1-4alkyleneC₄-₆heterocycle, -OC_4- ₆heterocycle or -OC_1-4alkyleneC₄-₆heterocycle wherein the C_3-7cycloalkyl or the C₄- ₆heterocycle are each optionally substituted by one or two substituents independently selected from halo, OH, oxo, C_1-4alkyl and -NH₂; or

R₃ and R₂ together with the carbon atoms to which they are attached, form a heterocycle optionally substituted by oxo;

R₉ is H, C_1-4alkyl, -C(O)NH₂, -CO₂CH_3, -CF₃, halo, OH, -OC_1-4alkyl, -CH₂OH, - C(O)NHCH₃, -C(O)NH(CH₃)_2, -CH₂OC_1-4alkyl or -CH₂OCH₂C_3-7cycloalkyl;

R₁₀ is H, C_1-4alkyl, -C(O)NH₂, -CO₂CH_3, -CF₃, halo, OH, -OC_1-4alkyl or oxo;

R₁₁ is H, C_1-4alkyl or SO₂CH₃;

R₁₂ is H, C_1-4alkyl, C_2-4alkyleneNHR₁₃, SO₂CH₃, a heterocycle or a heterocycle comprising SO₂; R₁₃ is H or SO₂CH₃;

R₁₄ is H or C_1-4alkyl;

R₁₅ is H, C_1-4alkyl or NHC(O)C_1-4alkyl;

R₁₆ is H or C_1-4alkyl; and

n and m are each an integer independently selected from 0, 1 and 2. See, for example, International Patent Application Publication No. WO/2014/140077, which is hereby incorporated by reference in its entirety. [00205] For example, exemplary compounds of Formula MMM may be selected from the group consisting of:

, and pharmaceutically acceptable salts thereof.

[00206] In some embodiments, exemplary bromodomain ligands include a compound represented by the formula:

Formula NNN;

wherein:

represents a single bond or a double bond;

L is CR⁹R^9a, O, S, SO, or SO₂;

Cy¹ is selected from phenyl or a 5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, wherein said phenyl or 5-6 membered heteroaryl of Cy¹ is optionally substituted with 1, 2, 3, or 4 groups independently selected from R¹¹; R¹ and R² are independently selected from H, halo, CN, OH, C_1-6 alkyl, C_2-6 alkenyl, C_2- ₆ alkynyl, C_1-6 haloalkyl, OR^al, SR^al, C(=O)R^bl, C(=O)NR^c1R^d1, C(=O)OR^a1, OC(=O)R^b1, OC(=O)NR^c1R^d1, NR^c1R^d1, NR^c1C(=O)R^b1, NR^c1C(=O)NR^c1R^d1, NR^c1C(=O)OR^a1, S(=O)R^b1, S(=O)NR^c1R^d1, S(=O)₂R^b1, NR^c1S(=O)₂R^b1 and S(=O)₂NR^c1R^d1, wherein said C_1-6 alkyl, C_2-6 alkenyl, and C_2-6 alkynyl of R¹ and R² are optionally substituted with 1, 2, or 3 groups independently selected from halo, CN, OH, OR^a1, SR^a1, C(=O)R^b1, C(=O)NR^c1R^d1, C(=O)OR^a1, OC(=O)R^b1, OC(=O)NR^c1R^d1, NR^c1R^d1, NR^c1C(=O)R^b1, NR^c1C(=O)NR^c1R^d1, NR^c1C(=O)OR^a1, S(=O)R^b1, S(=O)NR^c1R^d1, S(=O)₂R^b1, NR^c1S(=O)₂R^b1 and S(=O)₂NR^c1R^d1;

alternatively, R¹ and R² together with the carbon atom to which they are attached are combined to form a C₃-7 cycloalkyl group, wherein said cycloalkyl group is optionally substituted with 1, 2, 3, or 4 groups independently selected from R²⁰;

Cy³ is selected from phenyl, C_3-7 cycloalkyl, a 5-10 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-10 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said phenyl, C_3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl of Cy³ is optionally substituted with 1, 2, 3, or 4 groups independently selected from R , wherein a ring- forming nitrogen atom of said 5-10 membered heteroaryl group or a ring- forming nitrogen atom of said 4-10 membered heterocycloalkyl group is optionally oxidized;

R⁴ is H, C(=O)NR^14aR^14b, C(=O)R^14a, C(=O)OR^14a, or C_1-6 alkyl optionally substituted by 1, 2, or 3 substituents independently selected from halo, NR^14aR^14b, OR^14a, SR^14a, CN, C(=O)R^14a, C(=O)NR^14aR^14b, C(=O)OR^14a, OC(=O)R^14b, OC(=O)NR^14aR^14b, NR^14aC(=O)R^14b, NR^14aC(=O)NR^14aR^14b, NR^14aC(=O)OR^14b, S(=O)R^14a, S(=O)NR^14aR^14b, S(=O)₂R^14a,

NR^14aS(=O)₂R^14b , and S(=O)₂NR^14aR^14b;

R⁵ is selected from =O and =S when C N is a single bond,

alternatively, when C N is a double bond then R⁵ is selected from H, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, NR^15aR^15b, -C(=O)NR^15aR^15b, -C(=O)OR^15a, phenyl, C_3-7 cycloalkyl, 5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-10 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said alkyl, phenyl, C_3-7 cycloalkyl, 5- 6 membered heteroaryl, and 4-10 membered heterocycloalkyl of R⁵ is optionally substituted by 1, 2, 3, or 4 groups independently selected from R¹⁵;

R⁶ is selected from H, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 alkoxy, and C_1-6 haloalkyl, wherein said alkyl, alkenyl, and alkynyl of R⁶ are each optionally substituted by 1, 2, 3, or 4 groups independently selected R¹⁶;

alternatively, R⁶ is selected from C_6-10 aryl, C_3-7 cycloalkyl, 5-10 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from , O and S, wherein said C_6-10 aryl, C_3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-7 membered heterocycloalkyl of R⁶ are each optionally substituted by 1, 2, 3, or 4 groups independently selected R²⁰;

R⁷ is selected from H, halo, CN, OR^a, NR^cR^d, SR^b, C(=O)NR^cR^d, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, phenyl, C_3-7 cycloalkyl, 5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, 5-6 membered heteroaryl group, and a 4-7 membered heterocycloalkyl group of R⁷ are optionally substituted with 1, 2, or 3 groups independently selected from R¹⁷;

R⁸ is selected from H, C_1-3 alkyl, C_2-3 alkenyl, C_2-3 alkynyl, C_1-3 haloalkyl, halo, CN, OR^a, NR^cR^d, SR^b, and C(=O)NR^cR^d, wherein said C_1-3 alkyl of R⁸ is optionally substituted with 1, 2, or 3 groups independently selected from R¹⁸;

R⁹ and R^9a are independently selected from H, C_1-3 alkyl, C_1-3 haloalkyl, halo, CN, OR^a, NR^cR^d, SR^b, and C(=O)NR^cR^d;

R¹¹ is independently at each occurrence selected from H, C_1-3 alkyl, C_1-3 haloalkyl, halo, CN, OR^a, NR^cR^d, SR^b, and C(=O)NR^cR^d, wherein said C_1-3 alkyl is optionally substituted by OH;

R¹³ is independently at each occurrence selected from H, halo, CN, OH, C_1-6 alkyl, C₂-₆ alkenyl, C₂-₆ alkynyl, C_1-6 haloalkyl, OR³³, SR^a3, C(=O)R^b3, C(=O)NR^c3R^d3, C(=O)OR^a3, OC(=O)R^b3, OC(=O)NR^c3R^d3, NR^c3R^d3, NR^c3C(=O)R^b3, NR^c3C(=O)NR^c3R^d3, NR^c3C(=O)OR^a3, S(=O)R^b3, S(=O)NR^c3R^d3, S(=O)₂R^b3, NR^c3S(=O)₂R^b3 and S(=O)₂NR^c3R^d3, wherein said C_1-6 alkyl, C₂-₆ alkenyl, and C₂-₆ alkynyl of R¹³ is optionally substituted with 1 , 2, or 3 groups independently selected from halo, CN, OH, OR^a3, SR³³, C(=O)R^b3, C(=O)NR^c3R^d3, C(=O)OR^a3, OC(=O)R^b3, OC(=O)NR^c3R^d3, NR^c3R^d3, NR^c3C(=O)R^b3, NR^c3C(=O)NR^c3R^d3, NR^c3C(=O)OR^a3, S(=O)R^b3, S(=O)NR^c3R^d3, S(=O)₂R^b3, NR^c3S(=O)₂R^b3 and S(=O)₂NR^c3R^d3;

R¹⁵ is independently at each occurrence selected from H, C_1-6 alkyl, C_3-7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, halo, CN, OR^a5, SR^a5,

C(=O)R^b5, C(=O)NR^c5R^d5, C(=O)OR^a5, OC(=O)R^b5, OC(=O)NR^c5R^d5, NR^c5R^d5,

NR^c5C(=O)R^b5, NR^c5C(=O)NR^c5R^d5, NR^c5C(=O)OR^a5, S(=O)R^b5, S(=O)NR^c5R^d5, S(=O)₂R^b5, NR^c5S(=O)₂R^b5, and S(=O)₂NR^c5R^d5, wherein said C_1-6 alkyl, C_3-7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, OR^a5, SR^a5, C(=O)R^b5, C(=O)NR^c5R^d5, C(=O)OR^a5, OC(=O)R^b5, OC(=O)NR^c5R^d5, NR^c5R^d5, NR^c5C(=O)R^b5, NR^c5C(=O)NR^c5R^d5, NR^c5C(=O)OR^a5, S(=O)R^b5, S(=O)NR^c5R^d5, S(=O)₂R^b5, NR^c5S(=O)₂R^b5, S(=O)₂NR^c5R^d5, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl, and C_3-7 cycloalkyl;

R^14a and R^14b are independently at each occurrence selected from H and C_1-6 alkyl, wherein said C_1-6 alkyl of R^14a and R^14b is optionally substituted with 1, 2, or 3 substituents selected from R²⁰;

or R^15a and R^15b together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl ring optionally substituted with 1, 2, or 3 substituents selected from R²⁰;

R^15a and R^15b are independently at each occurrence selected from H and Ci_6 alkyl, wherein said C_1-6 alkyl of R^15a and R^15b is optionally substituted with 1, 2, or 3 substituents selected from R²⁰;

R¹⁶ is independently at each occurrence selected from halo, CN, OH, OR^a6, SR^a6, C(=O)R^b6, C(=O)NR^c6R^d6, C(=O)OR^a6, OC(=O)R^b6, OC(=O)NR^c6R^d6, NR^c6R^d6,

NR^c6C(=O)R^b6, NR^c6C(=O)NR^c6R^d6, NR^c6C(=O)OR^a6, S(=O)R^b6, S(=O)NR^c6R^d6, S(=O)₂R^b6, NR^c6S(=O)₂R^b6 and S(=O)₂NR^c6R^d6, C_6-10 aryl, C₃-₇ cycloalkyl, 5-10 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said C_6-10 aryl, C_3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-7 membered heterocycloalkyl of R¹⁶ are each optionally substituted by 1, 2, 3, or 4 groups independently selected R²⁰;

R¹⁷ and R¹⁸ are independently at each occurrence selected from halo, C_1-4 alkyl, CN, OR^a, NR^cR^d, SR^b, C(=O)NR^cR^d, C(=O)OR^a, and NR^cC(=O)R^a;

R^a, R^c, and R^d are independently at each occurrence selected from H, C_1-6 alkyl, C(O)R^e, S(=O)₂R^f, C(=O)NR^gR^h, and phenyl optionally substituted by C_1-4 alkoxy;

R^b is at each occurrence C_1-6 alkyl;

R^e is at each occurrence C_1-4 alkyl optionally substituted by a group selected from phenyl, C_1-4 alkoxy, amino, C_1-4 alkylamino, and C_2-8 dialkylamino;

R^f is C_1-4 alkyl;

R^g and R^h are independently at each occurrence selected from H and C_1-4 alkyl;

R^a1, R^b1, R^c1 and R^d1 are independently at each occurrence selected from H, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, and C_1-6 haloalkyl, wherein said C_1-6 alkyl, C_2-6 alkenyl, and C_2-6 alkynyl forming R^a1, R^b1, R^c1 and R^d1 are each optionally substituted with 1, 2, or 3 substituents independently selected from R²⁰;

R^a3, R^b3, R^c3 and R^d3 are independently at each occurrence selected from H, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 cycloalkyl, and C_1-6 haloalkyl, wherein said C_1-6 alkyl, C_2-6 alkenyl, and C_2-6 alkynyl forming R^a3, R^b3, R^c3 and R^d3 are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, OH, OR^a4, SR^a4, C(=O)R^b4,

C(=O)NR^c4R^d4, C(=O)OR^a4, OC(=O)R^M, OC(=O)NR^c4R^d4, NR^c4R^d4, NR^c4C(=O)R^d4,

NR^c4C(=O)NR^c4R^d4, NR^c4C(=O)OR^a4, S(=O)R^b4, S(=O)NR^c4R^d4, S(=O)₂R^b4, NR^c4S(=O)₂R^b4 and S(=O)₂NR^c4R^d4;

R^a4, R^b4, R^c4 and R^d4 are independently at each occurrence selected from H, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, and C_1-6 haloalkyl, wherein said C_1-6 alkyl, C_2-6 alkenyl, and C_2-6 alkynyl forming R^a4, R^b4, R^c4 and R^d4 are each optionally substituted with 1, 2, or 3 substituents independently selected from R²⁰; R^a5, R^b5, R^c5 and R^d5 are independently at each occurrence selected from H, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 cycloalkyl, 5-6 membered heterocycloalkyl, and C_1-6 haloalkyl wherein said C_1-6 alkyl, C_2-6 alkenyl, and C_2-6 alkynyl forming R^a5, R^b5, R^c5 and R^d5 are each optionally substituted with 1, 2, or 3 substituents independently selected from R²⁰;

or R^c5 and R^d5 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl ring optionally substituted with 1, 2, or 3 substituents

independently selected from R²⁰;

R^a6, R^c6 and R^d6 are independently at each occurrence selected from H, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, and C_1-6 haloalkyl wherein said C_1-6 alkyl, C_2-6 alkenyl, and C_2-6 alkynyl forming R^a6, R^c6 and R^d6 are each optionally substituted with 1, 2, or 3 substituents

independently selected from R²⁰;

alternatively, R^c6 and R^d6 together with the nitrogen atom to which they are attached form a 4-7 membered heterocycloalkyl group comprising carbon, nitrogen, and 0, 1, or 2 additional heteroatoms selected from N, O and S, wherein said 4-7 membered heterocycloalkyl group is optionally substituted with 1, 2, or 3 substituents independently selected from R²⁰;

R^b6 is independently at each occurrence selected from C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, phenyl, C_3-7 cycloalkyl, 5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7 membered

heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, 5-6 membered heteroaryl group, and 4- 7 membered heterocycloalkyl group are each optionally substituted with 1, 2, or 3 substituents independently selected from R²⁰; and

R²⁰ is at each occurrence independently selected from H, halo, OH, CN, amino, C_1-4 alkyl, C_1-4 alkoxy, C_1-4 alkylthio, C_1-4 alkylamino, di(C_1-4 alkyl)amino, C_1-4 haloalkyl, C_1-4 haloalkoxy, C_1-4 alkyl-C(=O)-, C_1-4 alkyl-C(=O)O-, C_1-4 alkyl-OC(=O)-, HOC(=O)-,

H₂NC(=O)-, C_1-4 alkyl-NHC(=O)-, di(C_1-4 alkyl)NC(=O)-, C_1-4 alkyl- C(=O)NH-, C_1-4 alkyl- O-C(=O)NH-, C_1-4 alkyl-S(=O)-, H₂NS(=O)-, C_1-4 alkyl- NHS(=O)-, di(C_1-4 alkyl)NS(=O)-, C_1-4 alkyl-S(=O)₂-, C_1-4 alkyl-S(=O)₂NH-, H₂NS(=O)₂-, C_1-4 alkyl-NHS(=O)₂-, and di(C_1-4 alkyl)NS(=O)₂-. See, for example, International Patent Application Publication No.

WO/2014/143768, which is hereby incorporated by reference in its entirety. [00207] For example, exemplary compounds of Formula NNN may be selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

[00208] In some embodiments, exemplary bromodomain ligands include a compound represented by the formula:

wherein:

R¹ is C_1-3 alkyl;

R² is hydrogen or C_1-3 alkyl;

R³ is -C(O)- C_1-3 alkyl, COOH, or -C(O)NR⁸R⁹;

R⁸ and R⁹ are chosen from one of the following groups:

(i) R⁸ and R⁹ are both H;

(ii) R⁸ is H and R⁹ is C_1-3 alkylene-C(O)O-C_1-3 alkyl or OH; and (iii) R⁸ is C_1-3 alkylene-aryl and R⁹ is C_1-3 alkylene-C(O)-C_1-3 alkyl;

R¹⁰ is aryl or heteroaryl, wherein R¹⁰ may be substituted with 1 to 3 substituents designated as R⁴⁰, R⁴¹, and R⁴² and independently selected from the group consisting of:

NO₂, NR²⁰R²², halo, C_1-6 alkyl, C_1-6 haloalkyl, -O-C_1-6 alkyl, -O-C_1-6 haloalkyl, C_1-3 alkylene-OH, C_1-3 alkylene-C(O)OH, C_1-3 alkylene-C(O)O-C_1-4 alkyl, C_2-3alkenylene-O-C_1-3alkyl, -NHC(O)—C_1-3 alkyl, -NH-SO₂-C_1-3 alkyl, - NH-SO₂-C_1-3 haloalkyl, -SO₂-NH₂, -C(O)-NR²⁰R²², and -L-R¹², wherein L is absent or is -C_1-3alkylene-, -C_2-3alkenylene-, -NH-, -NH-C_1- ₃alkylene-, -NR²⁶-, -NHS(O)₂-, NHS(O)₂-C_1-3alkylene-, -NH-C(O)—C_1- ₃alkylene-, -C(O)-, -C(O)-NH-C_1-3alkylene-, and -O-;

R¹² is selected from the group consisting of: C_1-6 alkyl, C_1-6 haloalkyl, C_3- ₁₀ cycloalkyl, 3 to 8 membered heterocycloalkyl, 5 to 12 membered heteroaryl, and aryl, which may be substituted with one, two, or three substituents designated R¹⁵, R¹⁶, and R¹⁷,

R¹⁵, R¹⁶, and R¹⁷ are independently selected from the group consisting of: OH, CN, halo, C_1-3 alkyl, C_1-3 haloalkyl, -O-C_1-3 alkyl, -O-C_1-3 haloalkyl, - C_1-3 alkylene-OH, - C_1-3 alkylene-C(O)O- C_1-3 alkyl, -C(O)- C_1-4 alkyl, -C(O)O C_1-4 alkyl, -C(O)NH-C_1-3 alkylene-NR³⁰R³², -C(O)NR³⁰R³², -O- C_1-4 alkyl- NR³⁰N³², -NR³⁰R³², -NHC(O)O-C_1-4 alkyl, -NH-S(O)₂-C_1-3 alkyl, -NH-S(O)₂-C_1- ₃ haloalkyl, -S(O)₂-C_1-3 alkyl, aryl, -O-aryl, -C_1-3 alkylene-aryl, C_3-6 cycloalkyl, heterocycloalkyl, -C_1-3 alkylene-heterocycloalkyl, -C(O)-heterocycloalkyl, 5 to 12 membered heteroaryl, and -C(O)NH-C_1-3alkylene-heteroaryl, wherein said heterocycloalkyl, heteroaryl or aryl groups on R¹⁵, R¹⁶, and R¹⁷ may be independently substituted with 1 to 3 substituents selected from the group consisting of: C_1-3-alkyl, C_1-3-haloalkyl, -O- C_1-3-alkyl, -O-C_1-3-haloalkyl, halo, - NH-S(O)₂- C_1-3 alkyl, -NH-S(O)₂- C_1-3 haloalkyl, and -S(O)₂-C_1-3 alkyl, R²⁶ is C_1-3 alkylene-C_3-6 cycloalkyl; R²⁰ and R²² are independently selected from the group consisting of H and C_1-6 alkyl; and R³⁰ and R³² are independently selected from the group consisting of H and C_1-4alkyl. See, for example, U.S. Patent Application Publication No. US 20140275079, which is hereby incorporated by reference in its entirety. [00209] For example, exemplary compounds of Formula OOO may be selected from the rou consistin of:

, and pharmaceutically acceptable salts thereof.

[00210] In some embodiments, exemplary bromodomain ligands include a compound represented by the formula:

Formula PPP,

wherein:

X¹ is H, -C(O)NR¹R², -C(O)-R¹, -C(O)OR¹, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -CH₂OR¹, -CH₂R¹, or -CŁN;

X² is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted -CH₂-cyloalkyl, optionally substituted - CH₂-aryl, optionally substituted -CH₂-heterocycloalkyl, optionally substituted -CH₂-heteroaryl, optionally substituted -CH(C₁-C₆-alkyl)-alkyl, optionally substituted -CH(C₁-C₆-alkyl)- cycloalkyl, optionally substituted -CH(C₁-C₆-alkyl)-aryl, optionally substituted -CH(C₁-C₆- alkyl)-heterocycloalkyl, or optionally substituted -CH(C₁-C₆-alkyl)-heteroaryl; X³ is -OR³, -CŁN, -CH₂OR³, -NH-alkyl, -N(alkyl)₂, -CH₂N(alkyl)₂, -CH₂NH(alkyl), or halogen, and

R¹, R² and R³ are each independently H, C₁-C₁₂alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl optionally substituted with alkyl. See, for example, International Patent

Application Publication No. WO/2014/152029, which is hereby incorporated by reference in its entirety.

[00211] For example, exemplary compounds of Formula PPP may be selected from the group consisting of:

, and pharmaceutically acceptable salts 10 thereof.

[00212] In some embodiments, exemplary bromodomain ligands include a compound represented by the formula:

Formula QQQ,

wherein:

R^1a and R^1b are each independently C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkyl, C_1-6haloalkoxy, C_1-6hydroxyalkyl, C_3-6cycloalkyl, of CH₂-C_3-6cycloalkyl;

R^2a and R^2b are each independently H or halogen;

R³ is

C_5-10aryl, C_5-10heteroaryl, or C_5-10heteroarylalkyl, each of which is optionally substituted with from 1 to 5 R²⁰ groups; or

-S(O)₂NHR⁴, wherein R⁴ is C_1-6alkyl or C_3-7cycloalkyl, each of which is optionally substituted with from 1 to 5 R²⁰ groups; or

a moiety of the formula

wherein

R⁶ is H, OH, or halogen; and R⁷ and R⁸ are each independently C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_1-6heteroalkyl, C_5-12heteroaryl; and R₇ and R⁸ together form a C_1-6 alkylidene group having a double bond with the carbon to which each of R⁶, R⁷, and R⁸ are bound wherein each of the C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, -C_3-6cycloalkyl, phenyl, naphthyl, or C_3-12heteroaryl groups is optionally substituted with from 1 to 5 R²⁰ groups;

X is N-Q, or O;

Q is H, C_1-3 alkyl, C_1-3 haloalkyl, benzyl or substituted benzyl; each R²⁰ is independently C_1-6alkyl, C_3-6cycloalkyl, C_1-6heteroalkyl, C_3-6heterocyclic, C_5-12aryl, C_5-12heteroaryl, halogen, oxo, -OR^a, -C(O)R^a, -C(O)OR^a, -C(O)NR^aR^b, - OC(O)NR^aR^b, -N^aN^b, -NR^aC(O)R^b, -NR^aC(O)OR^b, -S(O)_0-2R^a, -S(O)₂NR^aR^b, -NR^aS(O)₂R^b, - N₃, -CN, or–NO₂, wherein each C_1-6alkyl, C_3-6cycloalkyl, C_1-6heteroalkyl, C_3-6heterocyclic, C_5- ₁₂aryl, C_5-12heteroaryl is optionally substituted with one to five halogen, oxo, -OR^a, -C(O)R^a, - C(O)OR^a, -C(O)NR^aR^b, -OC(O)NR^aR^b, -N^aN^b, -NR^aC(O)R^b, -NR^aC(O)OR^b, -S(O)_0-2R^a, - S(O)₂NR^aR^b, -NR^aS(O)₂R^b, -N₃, -CN, or–NO₂;

each R^a and R^b is independently H; or C_1-6alkyl, C_3-6cycloalkyl, C_1-6heteroalkyl, C_3- ₆heterocyclic, C_5-12aryl, C_5-12heteroaryl, each of which is optionally substituted with from one to five R²¹; or R^a and R^b together with the atoms to which they are attached form a heterocycle; and

each R²¹ is independently C_1-6alkyl, C_3-6cycloalkyl, C_1-6heteroalkyl, C_3-6heterocyclic, C_5-12aryl, C_5-12heteroaryl, or halogen. See, for example, International Patent Application Publication No. WO/2014/160873, which is hereby incorporated by reference in its entirety.

[00213] For example, exemplary compounds of Formula QQQ may be selected from the rou consistin of:

, and pharmaceutically acceptable salts thereof.

[00214] In some embodiments, exemplary bromodomain ligands include a compound selected from the group consisting of:

,

and pharmaceutically acceptable salts thereof.

[00215] In some embodiments, exemplary bromodomain ligands include a compound selected from the group consisting of:

,

, and pharmaceutically acceptable salts thereof.

C) Connectors [00216] The connector moieties Y¹, Y², Y³, and Y⁴ of Formulas I, II, III and IV may, in some embodiments, be the same or different. For example, connector moieties are

independently contemplated herein.

[00217] In some embodiments, a monomer may comprise a connector that joins the ligand moiety with the linker element. In some instances, such connectors do not have significant binding or other affinity to an intended target. However, in certain embodiments, a connector may contribute to the affinity of a ligand moiety to a target.

[00218] In some embodiments, a connector element may be used to connect the linker element to the ligand moiety. In some instances, a connector element may be used to adjust spacing between the linker element and the ligand moiety. In some cases, the connector element may be used to adjust the orientation of the linker element and the ligand moiety. In certain embodiments, the spacing and/or orientation the linker element relative to the ligand moiety can affect the binding affinity of the ligand moiety (e.g., a pharmacophore) to a target. In some cases, connectors with restricted degrees of freedom are preferred to reduce the entropic losses incurred upon the binding of a multimer to its target biomolecule. In some embodiments, connectors with restricted degrees of freedom are preferred to promote cellular permeability of the monomer.

[00219] In some embodiments, the connector element may be used for modular assembly of monomers. For example, in some instances, a connector element may comprise a functional group formed from reaction of a first and second molecule. In some cases, a series of ligand moieties may be provided, where each ligand moiety comprises a common functional group that can participate in a reaction with a compatible functional group on a linker element. In some embodiments, the connector element may comprise a spacer having a first functional group that forms a bond with a ligand moiety and a second functional group that forms a bond with a linker element.

[00220] Contemplated connecters may be any acceptable (e.g. pharmaceutically and/or chemically acceptable) bivalent linker that, for example, does not interfere with

multimerization of the disclosed monomers. For instance, such linkers may be substituted or unsubstituted C₁-C₁₀ alkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted phenyl or naphthyl, substituted or unsubstituted heteroaryl, acyl, sulfone, phosphate, ester, carbamate, or amide. Contemplated connectors may include polymeric connectors, such a polyethylene glycol (e.g.,

, where n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, and X is C; O; S(O)_q, where q is 0, 1, or 2; NH; N- alkyl; or -C(O)-) or other pharmaceutically acceptable polymers. For example, contemplated connectors may be a covalent bond or a bivalent C_1-20 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one, two, or three or four methylene units of the hydrocarbon chain are optionally and independently replaced by cyclopropylene, -NR-, - N(R)C(O)-, -C(O)N(R)-, -N(R)SO₂-, -SO₂N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO-, - SO₂-, -C(=S)-, -C(=NR)-, phenyl, naphthyl, or a mono or bicyclic heterocycle ring, where R is H or C_1-6alkyl. In some embodiments, a connector may be from about 7 atoms to about 13 atoms in length, or about 8 atoms to about 12 atoms, or about 9 atoms to about 11 atoms in length. For purposes of counting connector length when a ring is present in the connector group, the ring is counted as three atoms from one end to the other.

[00221] In some embodiments, a connector may have the following structure:

, where:

n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20;

R¹ and R² are, independently for each occurrence, selected from the group consisting of H, C_1-6alkyl, C_1-6heteroalkyl, phenyl, or heteroaryl, wherein alkyl, heteroalkyl, phenyl, and heteroaryl are optionally substituted with–OH, -NH₂,–SH, -COOH, -C(O)NH₂, halo, phenyl, and heteroaryl; or

R¹ and R², or R² and R², together with the atoms to which they are attached, form a heterocyclic structure optionally substituted with–OH, -NH₂,–SH, -COOH, -C(O)NH₂, halo, phenyl, and heteroaryl.

[00222] In some embodiments, a connector may comprise a phenyl, naphthyl, or mono or bicyclic heteroaryl ring, each optionally substituted. For example, a connector may comprise one or more of the following aryl structures:

, where R¹ and R² are the remainder of the connector. A person of skill in the art would recognize that some substitutions may be chemically less stable and hence less preferred.

[00223] In another embodiment, a connector may compise a triazole ring having the followin structure:

, where R¹ and R² are the remainder of the connector. For example, a monomer comprising a triazole-containing connector may have the following general structure:

[00224]

. Such triazole-joined compounds may be formed, e.g., as a result of a“click” type reaction (i.e., an azide-alkyne cycloaddition). For example, a first segment of a connector having a terminal alkyne and a second segment of a connector having a terminal azide may be joined by a“click” reaction to form a single connector joined by a triazole, as shown above. In some embodiments, the first connector and the second connector each are less than or equal to 20 atoms in length, or in some embodiments each are less than or equal to 12 atoms in length.

[00225] In another embodiment, a connecter moiety may maximally span from about 5Å to about 50Å, in some embodiments about 5Å to about 25Å, in some embodiments about 20Å to about 50Å, and in some embodiments about 6Å to about 15Å in length. For purposes of counting connector length when a ring is present in the connector group, the ring is counted as three atoms from one end to the other. In another embodiment, a connecter moiety may maximally span from about 1Å to about 20Å, in some embodiments about 1Å to about 10Å, in some embodiments about 1Å to about 5Å, and in some embodiments about 5Å to about 15Å in length. For example, a connector moiety may maximally span about 1Å, about 3Å, about 5Å, about 7Å, about 9Å, about 11Å, about 13Å, about 15Å, about 17Å, or about 19Å.

[00226] In some embodiments, a connector may be selected from the group consisting of: -NR¹³-(CH₂-CH₂-O)_s-CH₂-CH₂-NR¹³-C(O)-; -(O-CH₂-CH₂)_t-NR¹³-C(O)-; -O-C_5- ₁₀alkyl-NR¹³-C(O)-; -heterocyclyl-C(O)-; -N(C_1-3alkyl)-C_1-6alkyl-NH-C(O)-; -NH-C_1-6alkyl- N(C_1-3alkyl)-C(O)-; -NR¹³-C_6-15alkyl-NR¹³-C(O)-; -heterocyclyl-C_0-6alkyl-NR¹³-C(O)-; and - NR¹³-C_0-6alkyl-heterocyclyl-C(O)-;

wherein, independently for each occurrence,

R¹³ is selected from the group consisting of H and C_1-6alkyl;

s is an integer from 0-10 (i.e., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10); and t is an integer from 0-10 (i.e., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10).

[00227] In certain embodiments, heterocyclyl may be a 5-7 membered heterocyclic ring comprising 1 or 2 nitrogen atoms.

[00228] In certain embodiments, R¹³ may be H. In certain other embodiments, R¹³ may be C_1-6alkyl. For example, in some embodiments, R¹³ may be methyl.

[00229] For example, in some embodiments, a connector may be selected from the group consisting of:

-NH-(CH₂-CH₂-O)_s- CH₂-CH₂-NH-C(O)-; -(O-CH₂-CH₂)_t-NH-C(O)-; -O-(CH₂)_t-NH- C(O)-; -N(CH₃)-(CH₂)₂-NH-C(O)-; -NH-(CH₂)₂-N(CH₃)-C(O); -NH-(CH₂)_u-NH-C(O)-; -O-

; wherein u is an integer from 2-15 (i.e., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15).

[00230] In certain embodiments, a connector may be selected from the group consisting of:

-NR¹³-C_6-15alkyl-NR¹³-C(O)-; -NR¹³-(CH₂-CH₂-O)_s-C_1-6alkyl-NR¹³-C(O)-; -(O-CH₂- CH₂)_s-NR¹³-C(O)-; -S-C_0-6alkyl-; -NR¹³-C_3-6alkyl-; -SO₂-NR¹³-C_0-6alkyl-; -SO₂-heterocyclyl- C_0-6alkyl-; -heterocyclyl-C(O)-; -heterocyclyl-C_0-6alkyl-NR¹³-C(O)-; -NR¹³-C_0-6alkyl- heterocyclyl-C(O)-; -O-C_1-6alkyl-C(O)-; -O-C_1-15alkyl-NR¹³-C(O)-; -O-C_1-15alkyl-C(O)-NR¹³-; and -O-C_1-6alkyl-, wherein C_1-6alkyl is optionally substituted by -OH;

wherein, independently for each occurrence, R¹³ is selected from the group consisting of H and C_1-6alkyl; and s is an integer from 1-15.

[00231] In certain embodiments, heterocyclyl may be a 5-7 membered heterocyclic ring comprising 1 or 2 nitrogen atoms.

[00232] In certain embodiments, R¹³ may be H. In certain other embodiments, R¹³ may be C_1-6alkyl. For example, in some embodiments, R¹³ may be methyl.

[00233] In certain embodiments, a connector may be selected from the group consisting of:

-NH-(CH₂-CH₂-O)_s- CH₂-CH₂-NH-C(O)-; -(O-CH₂-CH₂)_s-NH-C(O)-; -S-; -S-CH₂-; -O- (CH₂)_s-NH-C(O)-; -SO₂-NH-; -SO₂-NH-CH₂-; -N(CH₃)-(CH₂)₂-NH-C(O)-; -NH-(CH₂)₂- N(CH₃)-C(O); -NH-(CH₂)_u-NH-C(O)-; -O-CH₂-C(O)-;

.

[00234] In some embodiments, a connector may be selected from the group consisting of:

-NR¹³-(CH₂-CH₂-O)_s-C_1-6alkyl-NR¹³-C(O)-; -(O-CH₂-CH₂)_s-NR¹³-C(O)-; -S-C_0-6alkyl-; -NR¹³-C_0-6alkyl-; -SO₂-NR¹³-C_0-6alkyl-; -SO₂-heterocyclyl-C_0-6alkyl-; -heterocyclyl-C(O)-; - heterocyclyl-C_0-6alkyl-NR¹³-C(O)-; -NR¹³-C_0-6alkyl-heterocyclyl-C(O)-; -O-C_1-6alkyl-C(O)-; - O-C_1-15alkyl-NR¹³-C(O)-; and -O-C_1-6alkyl-, wherein C_1-6alkyl is optionally substituted by - OH; wherein, independently for each occurrence, s is an integer from 0-10 and R¹³ is selected from the group consisting of H and C_1-6alkyl.

[00235] In another embodiment, for the above-identified benzodiazepine compounds, there are, e.g., three possible attachment points for the connector element: the phenyl ether, the amino group, or the chloro position of the chlorophenyl ring. As seen below, the connector element may be identified as a Y group in benzodiazepine-connector 1 A, benzodiazepine- connector 2 B, and benzodiazepine-connector 3 D: Benzodiaz

B

,

where X = CH₂, S, O, or NH.

[00236] For example, Y¹, Y², Y³ and Y⁴ may be Y as described above in connector 1 A, connector 2 B, or connector 3 D.

[00237] The synthetic route in Scheme Xa illustrates a general method for preparing benzodiazepine-connector 1 derivatives. The method involves attaching the desired substituents to the phenol core. Benzodiazepine 1 can be prepared following procedures described below. The desired Y group attached at the 4-position of the phenol can be installed by reacting benzodiazepine 1 with the appropriate electrophile 2 to provide 3 (benzodiazepine- connector 1 derivative). For example, Scheme Xa provides for a connector Y (e.g. Y¹, Y², Y³ or Y⁴).

SCHEME Xa

[00238] For example, Y may be selected from the group consisting of:

, wherein n is 1, 2, 3, 4 or 5.

[00239] Additional examples for 2 and Y can be found in Table A, seen below: Table A

[00240] The following table (Table U) indicates exemplary benzodiazepine-connector 1 derivatives (e.g., 3 of Scheme Xa) that include a ligand moiety (X) and a connector (Y). It is understood that such derivatives can be modified to include a pharmacophore (Z) such as provided for herein. Table U

[00241] Any free amino group seen in the Y examples of Table A above may be functionalized further to include additional functional groups, e.g., a benzoyl moiety.

[00242] In another embodiment, the attachment point identified in A (benzodiazepine- connector 1) may be further elaborated to incorporate not only the connector moiety (Y), but also the linker Z , as re resented by:

The Y-Z moiety may be formed from direct attachment of Y-Z to the phenyl ether, or the Y-Z moiety may be formed from the further functionalization of any free amino group seen in the Y examples of Table A above to include the linker moiety (Z). Examples of Y-Z groups having a boronic acid linker (Z) can be found in Table A’’, seen below. It is clear from the linker section described above that a first monomer that has a boronic acid linker may be capable of forming a multimer with a second monomer that has a diol linker. Table A’’

[00243] The synthetic route in Scheme Xb illustrates a general method for preparing benzodiazepine-connector 2 derivatives. The method involves attaching the desired substituents to the carbonyl substituent. The desired R group attached at the carbonyl substituent can be installed by reacting carboxylic acid 4 with common coupling reagents such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and hydroxybenzotriazole (HOBt) and then further reacting the activated ester 6 with the appropriate nucleophile, for example, amine 7, to provide 8a (benzodiazepine-connector 2 derivative). For example, Scheme Xb provides for a connector Y (e.g. Y₁, Y₂, Y₃ or Y₄) wherein Y is–NH-R (e.g., -NH-R of 8a). SCHEME Xb

8a

[00244] For example, R may be selected from the group consisting of:

, where n may be 0, 1, 2, 3,4 or 5.

[00245] In some embodiments, R may generally be represented for example, by:

where n may be 0, 1, 2, 3, 4, 5, or 6.

[00246] Additional examples for 7 and–NH-R (e.g., Y) can be found in Table B, seen below: Table B

[00247] The following table (Table V) contains exemplary benzodiazepine-connector 2 derivatives (e.g., 8a of Scheme Xb) that include a ligand moiety (X) and a connector (Y). A person of skill in the art would undertand that such derivatives can be modified to include a disclosed pharmacophore Z. Table V

[00248] Any free amino group seen in the–NH-R examples (e.g., Y examples) of Table B above may be functionalized further to include additional functional groups, e.g., a benzoyl moiety.

[00249] In another embodiment, the attachment point identified in B may be further elaborated to incorporate not only a connector moiety, but also a linker, as e.g., represented by:

The connector-linker (i.e., Y-Z) moiety

may be formed from direct attachment of Y-Z to the carbonyl, or the Y-Z moiety may be formed from the further functionalization of any free amino group seen in the–NH-R examples (i.e., Y examples) of Table B above to include the linker moiety (Z). Examples of–NH-R-Z groups (e.g., Y-Z groups) having a boronic acid, diol or silanol linker (Z) can be found in Table B’’, seen below. It is clear from the linker section described above that a first monomer that has a boronic acid linker may be capable of forming a multimer with a second monomer that has a diol linker. In another embodiment, a first monomer that has a silanol linker may be capable of forming a multimer with a second monomer that has the same or different silanol linker. Table B’’

[00250] In another embodiment, the two attachment points identified in A and B may be further elaborated to incorporate not only a connector moiety, but also a linker.

[00251] Scheme Xc provides a synthetic procedure for making A derivatives having various connectors attached to both the benzodiazepine compound and to any of the above- identified linkers (Z¹, Z², Z³ and Z⁴). In the scheme below, the linker moiety is designated by Z. Phenol 1 is converted to carboxylic acid 10 using ethyl-2-bromoacetate, followed by hydrolysis. Following formation of 10, the general procedure outlined in Scheme Xb can be utilized in the synthesis of the benzodiazepine-connector 1 derivative 12. For example, Scheme Xc provides for a connector Y (e.g. Y₁, Y₂, Y₃ or Y₄) attached to a linker moiety (Z), wherein Y is –CH₂-C(O)-R- (e.g.,–CH₂-C(O)-R- of 12).

SCHEME Xc

[00252] For example, R-Z may be selected from the group consisting of:

[00253] Scheme Xd provides an exemplary synthetic procedure for making B derivatives having various connectors attached to both the benzodiazepine compound and to any of the above-identified linkers (Z¹, Z², Z³ and Z⁴). In the scheme below, the linker moiety is designated by Z. Activated ester 6 is reacted with various nucleophiles to provide

benzodiazepine-connector 2 derivative 8b. For example, Scheme Xd provides for a connector Y (e.g. Y₁, Y₂, Y₃ or Y₄) attached to a linker moiety (Z), wherein Y is–R- (e.g., -R- of 8b). SCHEME Xd

6

8b

[00254] For example, R-Z (i.e.,Y-Z) may be selected from the group consisting of:

[00255] Additional examples for Z-R-H and -R-Z that can be utilized in Scheme Xc and Scheme Xd can be found in Table C, seen below:

[00256] Similar to Scheme Xd, Scheme Xe provides a synthetic procedure for making B derivatives having various connectors of shorter length attached to both the benzodiazepine compound and to any of the above-identified linkers (Z¹, Z², Z³ and Z⁴). In the scheme below, the linker moiety is designated by Z. Activated ester 6 is reacted with various nucleophiles to provide benzodiazepine-connector 2 derivative 8c. For example, Scheme Xe provides for a connector Y (e.g. Y₁, Y₂, Y₃ or Y₄) attached to a linker moiety (Z), wherein Y is–R- (e.g., -R- of 8c).

SCHEME Xe

6

8^c

[00257] For example, R-Z (i.e.,Y-Z) may be represented by the structure: N ^Z

H ⁿ , wherein n is 0, 1, 2, 3, 4, or 5, e.g. n is 1 to 5. For example, Scheme Xe provides for a linker Y (e.g. Y₁, Y₂, Y₃ or Y₄).

[00258] Scheme Xf provides an additional exemplary synthetic procedure for making B derivatives having various connectors attached to both the benzodiazepine compound and to any of the above-identified linkers (Z¹, Z², Z³ and Z⁴). In the scheme below, the linker moiety is designated by Z. Activated ester 6a is reacted with various nucleophiles to provide benzodiazepine-connector 2 derivative 8d. For example, Scheme Xf provides for a connector Y (e.g. Y₁, Y₂, Y₃ or Y₄) attached to a linker moiety (Z), wherein Y is–NHCH₂-C(O)-R- (e.g., –NHCH₂-C(O)-R- of 8d).

SCHEME Xf

6^{a 8d}

[00259] For example, R-Z may be represented by the structure:

wherein n is 0, 1, 2, 3, 4 or 5, e.g. n is 1 to 5.

[00260] Additional examples for Z-R-H and -R-Z that can be utilized in Scheme Xe and Scheme Xf can be found in Table D, seen below: Table D

[00261] Further to Scheme Xf, Scheme Xg provides an alternative synthetic procedure for making B derivatives having various connectors attached to both the benzodiazepine compound and to any of the above-identified linkers (Z¹, Z², Z³ and Z⁴). In the scheme below, the linker moiety is designated by Z. Activated ester 6a is reacted with Boc-protected ethylenediamine and followed by Boc-removal with TFA to afford diamine 20. The terminal amino group of 20 may be reacted with a variety of electrophiles to afford benzodiazepine- connector 2 derivative 21. For example, Scheme Xg provides for a connector Y (e.g. Y₁, Y₂, Y₃ or Y₄) attached to a linker moiety (Z), wherein Y is–NHCH₂CH₂NH-R- (e.g.,–

NHCH₂CH₂NH-R- of 21). SCHEME Xg

[00262] For example, R-Z may be represented by the structure:

[00263] Additional examples for Z-R-W and R-Z that can be utilized in Scheme Xg can be found in Table E, seen below: Table E

[00264] In another embodiment, for the above-identified benzodiazepine compounds, there are, e.g., three possible attachment points for the connector element: the phenyl ether, the amino group, or the chloro position of the chlorophenyl ring. As seen below, a connector element may be identified as a Y group in benzodiazepine-connector 1’ A’, benzodiazepine- connector 3 C, and benzodiazepine-connector 4 D: Benzodiazepin

A ,

where X = CH₂, S, O, or NH.

[00265] For example, Y¹, Y², Y³ and Y⁴ may be Y as described above in connector 1’ A’ or connector 3 C.

[00266] In correlation to Scheme Xa, the synthetic route in Scheme Xa’ illustrates a general method for preparing benzodiazepine-connector 1’ derivatives. The method involves attaching the desired substituents to the phenol core. The desired Y group attached at the 4- position of the phenol can be installed by reacting benzodiazepine 3 (see Scheme Xa’’) with the appropriate electrophile 5a to provide 4 (benzodiazepine-connector 1’ derivative). For example, Scheme Xa’ provides for a connector Y (e.g. Y₁, Y₂, Y₃ or Y₄).

SCHEME Xa’

[00267] For example, Y may be selected from the group consisting of: ,

.

[00268] Additional examples for 5a and Y can be found in Table F, seen below: Table F

[00269] The synthetic route in Scheme Xb’ illustrates a general method for preparing benzodiazepine-connector 3 derivatives. The method involves attaching the desired carbonyl substituents to the free amine. The carbonyl group can be installed by reacting amine 2 (see Scheme Xa’’) with carboxylic acid 7 to provide 6’ (benzodiazepine-connector 3 derivative). For example, Scheme Xb provides for a connector Y (e.g. Y₁, Y₂, Y₃ or Y₄), wherein Y is– C(O)R (e.g.,–C(O)R of 6’).

SCHEME Xb’

6'

[00270] For example, -C(O)R (i.e., Y) may be selected from the group consisting of:

.

[00271] Additional examples for 7 and–C(O)R (i.e., -Y) can be found in Table G, seen below:

Table G

[00272] The synthetic route in Scheme Xa’’ illustrates a general method for preparing benzodiazepine derivatives, for example, benzodiazepine 3, as seen in Scheme Xa’ or , benzodiazepine 2, as seen in Scheme Xb’. The starting material, benzotriazole 1, may be purchased from commercial sources or can be prepared by one of skill in the art, for example, following procedures described in J. Org. Chem. v. 55, p. 2206, 1990. Following the amide coupling of 1 with 1a (to provide 2), ammonia is used to prepare amino-substituted 4. Acid- promoted cyclization (condensation) of 4 affords benzodiazepine carbamate 5. A three step procedure is used to prepare thioamide 8: cleavage of the carbamate 5, Boc-protection of amine 6, and thiolation, utilizing P₄S₁₀ as the sulfur source. The fused triazole 9 is formed from 8 following a three step procedure: hydrazone formation, acylation and cyclization. Boc-group removal from the reaction of 9 with trifluoroacetic acid (TFA) affords the key intermediate 2, which is used to prepare benzodiazepine-connector 3 derivatives. Intermediate 2 is reacted further to prepare phenol 3, which is a key intermediate in the formation of benzodiazepine- connector 1’ derivatives. To this end, cleavage of methyl ether 2 and selective coupling of the free amine affords phenol 3.

SCHEME Xa’’

[00273] In another embodiment, the two attachment points identified in A’ and C may be further elaborated to incorporate not only a connector moiety (Y), but also a linker (Z).

[00274] Scheme Xc’ provides a synthetic procedure for making A’ derivatives having various connectors attached to both the benzodiazepine compound and to any of the above- identified linkers (Z¹, Z², Z³ and Z⁴). In the scheme below, the linker moiety is designated by Z. Phenol 3 is converted to carboxylic acid 9 using ethyl-2-bromoacetate, followed by hydrolysis. Following formation of 9, the general procedure outlined in Scheme Xb can be utilized in the synthesis of the benzodiazepine-connector 1’ derivative 12. For example, Scheme Xc’ provides for a connector Y (e.g. Y₁, Y₂, Y₃ or Y₄) attached to a linker moiety (Z), wherein Y is –CH₂-C(O)-R- (e.g.,–CH₂-C(O)-R- of 12).

SCHEME Xc’

[00275] For example, R-Z may be selected from the group consisting of:

[00276] Scheme Xd’ provides an exemplary synthetic procedure for making C

derivatives having various connectors attached to both the benzodiazepine compound and to any of the above-identified linkers (Z¹, Z², Z³ and Z⁴). In the scheme below, the linker moiety is designated by Z. Activated ester 14 is prepared following the general procedure seen in Scheme Xc’. Benzodiazepine-connector 3 derivative 15 is afforded by reacting 14 with various nucleophiles. For example, Scheme Xd’ provides for a connector Y (e.g. Y₁, Y₂, Y₃ or Y₄) attached to a linker moiety (Z), wherein Y is–CH₂-C(O)-R- (e.g.,–CH₂-C(O)-R- of 15).

[00277] For example, R-Z may be selected from the group consisting of:

[00278] Additional examples for Z-R-H and -R-Z that can be utilized in Scheme Xc’ and Scheme Xd’ can be found in Table H, seen below:

Table H

[00279] Scheme Xe’ provides a synthetic procedure for making C derivatives having various connectors of shorter length attached to both the benzodiazepine compound and to any of the above-identified linkers (Z¹, Z², Z³ and Z⁴). In the scheme below, the linker moiety is designated by Z. Amine intermediate 2 is reacted with various electrophiles, for example, a carboxylic acid, to provide benzodiazepine-connector 3 derivative 17. For example, Scheme Xe’ provides for a connector Y (e.g. Y₁, Y₂, Y₃ or Y₄) attached to a linker moiety (Z), wherein Y is -R- (e.g., -R- of 17).

SCHEME Xe’

[00280] For example, R-Z (e.g., Y-Z) may be represented by the structure:

[00281] Further to Scheme Xe’, Scheme Xf’ provides a synthetic procedure for making C derivatives having various connectors of longer length attached to both the benzodiazepine compound and to any of the above-identified linkers (Z¹, Z², Z³ and Z⁴). In the scheme below, the linker moiety is designated by Z. Amine intermediate 2 is reacted with various carboxylic acids to provide benzodiazepine-connector 3 derivative 20. For example, Scheme Xf’ provides for a connector Y (e.g. Y₁, Y₂, Y₃ or Y₄) attached to a linker moiety (Z), wherein Y is

-C(O)CH₂-NHR- (e.g., -C(O)CH₂-NHR- of 20).

SCHEME Xf’

[00282] For example, R-Z may be represented by the structure:

O

Z .

[00283] Additional examples for Z-R-W and -R-Z that can be utilized in Scheme Xe’ and Scheme Xf’ can be found in Table I, seen below: Table I

[00284] In a certain embodiment, for the above-identified benzodiazepine compounds, the attachment point for a connector element of benzodiazepine-connector 2 B is utilized in benzodiazepine-connector 2’’ B’’:

Benzodiazepine-Connector 2''

B''

[00285] Scheme Xb’ provides a synthetic procedure for making key intermediate 6b. The intermediate (+)-JQ1 may be prepared, for example, by known methods. The activated ester 6b can be prepared by reacting (+)-JQ1 with a coupling reagent, such as EDC or HOBt. SCHEME Xb’

^6b

[00286] It is contemplated herein that the general methods seen above in Scheme Xb and Schemes Xd-Xg can also utilize intermediate 6b, in place of intermediate 6 or 6a, in the preparation of B’ derivatives.

[00287] In one embodiment, an exemplary B’ derivative is represented by the structure:

8h

(^{see Scheme Xb)} ,wherein R is, for example, selected from the group consisting of:

. For example, 8h provides for a connector Y (e.g. Y₁, Y₂, Y₃ or Y₄) wherein Y is–NH-R.

[00288] In another embodiment, an exemplary B’ derivative is represented by the structure:

, wherein R-Z is, for example,

For example, 21a provides for a connector Y (e.g. Y₁, Y₂, Y₃ or Y₄) attached to a linker moiety (Z), wherein Y is –NHCH₂CH₂NH-R-.

[00289] For example, an exemplary B’ derivative is represented by the structure:

8e ^{(see Scheme Xf)} , wherein R-Z is, for example,

wherein n is 0, 1, 2, 3, 4 or 5, e.g. n is 1 to 5. For example, 8e provides for a connector Y (e.g. Y₁, Y₂, Y₃ or Y₄) attached to a linker moiety (Z), wherein Y is–NHCH₂C(O)R-. [00290] In a certain embodiment, an exemplary B’ derivative is represented by the structure:

8f ^{(see Scheme Xe)} , wherein R-Z is, for example,

wherein n is 0, 1, 2, 3, 4 or 5, e.g. n is 1 to 5. For example, 8f provides for a connector Y (e.g. Y₁, Y₂, Y₃ or Y₄) attached to a linker moiety (Z), wherein Y is–R-.

[00291] In another embodiment, an exemplary B’ derivative is represented by the structure:

8g ^{(see Scheme Xd)}, wherein R-Z is, for example, selected from the group consisting of:

. For example, 8g provides for a connector Y (e.g. Y₁, Y₂, Y₃ or Y₄) attached to a linker moiety (Z), wherein Y is–R-.

[00292] It will be appreciated that for the above-identified tetrahydroquinoline compounds, the connector element may attach at one of at least two possible attachment points for example, via a terminal amino group or via a carbonyl substituent. As seen below, a connector element may be identified as a Y group in tetrahydoquinoline-connector 1 10A’, tetrahydoquinoline-connector 1 10B’ and tetrahydroquinoline-connector 2 10C:

[00293] For example, Y¹, Y², Y³ and Y⁴ may be Y as described above in connector 1 10A’ connector 1 10B’ or connector 210C.

[00294] The synthetic route in Scheme Xh illustrates a divergent procedure for preparing tetrahydroquinoline-connector 1 derivatives. The tetrahydroquinoline core is formed in a two step-process beginning with the condensation of 5, 6 and acetaldehyde to form 7 and followed by conjugate addition to acrylaldehyde to afford 8. Tetrahydroquinoline 8 is utilized in a divergent step to install varying phenyl substituents via reaction with the bromo-group to provide 9A and 9B. Following hydrolysis of the amide group, the desired Y group is attached at the terminal amino group by reacting the unsubstituted amines of 4A or 3 with the appropriate electrophile to provide 10A or 10B (tetrahydroquinoline-connector 1 derivative). For example, Scheme Xh provides for a connector Y (e.g. Y₁, Y₂, Y₃ or Y₄).

SCHEME Xh

O For exam le, W-Y ma be selected from the group consisting of:

.

[00295] Additional examples for W-Y and -Y can be found in Table J, seen below: Table J

[00296] The synthetic route in Scheme Xi illustrates a general method for preparing tetrahydroquinoline-connector 2 derivatives. Tetrahydroquinoline 3 is converted to phenyl- substituted 11 utilizing a Suzuki coupling, and the ester of 11 is hydrolyzed to afford carboxylic acid 2. The connecter moieties can be installed via a peptide coupling of the carboxylic acid 2 to prepare 12 (tetrahydroquinoline-connector 2 derivatives 10C). For example, Scheme Xi provides for a connector Y (e.g. Y₁, Y₂, Y₃ or Y₄), wherein Y is–W-R (e.g., -W-R of 12).

SCHEME Xi

For example, R may be selected from the group consisting of:

[00297] The synthetic route in Scheme Xj illustrates a general method for preparing tetrahydroquinoline-connector 1 derivatives having various connectors attached to both the tetrahydroquinoline compound and to any of the above-identified linkers (Z¹, Z², Z³ and Z⁴). In the scheme below, the linker moiety is designated by Z. The amino group of 4 is reacted with bromo-acetic acid to afford amide 13. The D-bromo amide 13 may be reacted with a variety of nucleophiles to afford tetrahydroquinoline-connector 1 derivative 14, following deprotection of the benzylic amine. For example, Scheme Xj provides for a connector Y (e.g. Y₁, Y₂, Y₃ or Y₄) attached to a linker moiety (Z), wherein Y is e.g,–C(O)CH₂-R- of 14.

SCHEME Xj

For example, R-Z may be selected from the group consisting of:

.

[00298] Additional examples for Z-R-H and -R-Z can be found in Table K, seen below: Table K

[00299] The synthetic route in Scheme Xk illustrates a complementary method to Scheme Xj for preparing tetrahydroquinoline-connector 1 derivatives having various connectors attached to both the tetrahydroquinoline compound and to any of the above- identified linkers (Z¹, Z², Z³ and Z⁴). In the scheme below, the linker moiety is designated by Z. Unlike Scheme Xj, Scheme Xk provides a procedure for the direct linkage of a connector moiety to the carbonyl substituent. The amino group of 4 may be reacted with a variety of electrophiles, for example, a carboxylic acid, to afford tetrahydroquinoline-connector 1 derivative 15, following deprotection of the benzylic amine. For example, Scheme Xk provides for a connector Y (e.g. Y₁, Y₂, Y₃ or Y₄) attached to a linker moiety (Z), wherein Y is–R- (e.g., -R- of 15).

SCHEME Xk

[00300] For example, R-Z may be represented by the structure:

[00301] The synthetic route in Scheme Xl illustrates an method for preparing tetrahydroquinoline-connector 1 derivatives having various connectors attached to both the tetrahydroquinoline compound and to any of the above-identified linkers (Z¹, Z², Z³ and Z⁴). In the scheme below, the linker moiety is designated by Z. A portion of a connector moiety is installed via reaction of the amino group of 4 with acid 4a. Global deprotection of 16, affords the free amine of 16, which can be reacted with a variety of electrophiles, for example, a carboxylic acid, to afford tetrahydroquinoline-connector 1 derivative 17. For example, Scheme Xl provides for a connector Y (e.g. Y₁, Y₂, Y₃ or Y₄) attached to a linker moiety (Z), wherein Y is–C(O)CH₂NHR- (e.g.,–C(O)CH₂NHR- of 17).

SCHEME Xl

[00302] For example, R-Z may be represented by the structure:

O

Z .

[00303] Additional examples for Z-R-OH and -R-Z that can be utilized in Scheme Xk and Scheme Xl can be found in Table L, seen below: Table L

[00304] The above-identified imidazoquinoline compounds may have an attachment point for a connector element via the imidazole group. As seen below, a connector element may be identified as a Y group in imidazoquinoline-connector 1 C and imidazoquinoline- connector 1 D:

[00305] For example, Y¹, Y², Y³ and Y⁴ may be Y as described above in

imidazoquinoline-connector 1 C or imidazoquinoline-connector 1 D.

[00306] The synthetic routes in Scheme Xm and Scheme Xn provide two

complementary methods for preparing imidazoquinoline-connector 1 derivatives. In Scheme Xm, commercially available 6 is reacted with isoxazole 7 under Suzuki coupling conditions to prepare quinoline intermediate 8. The amine intermediate 9 is formed via nitration of quinoline 8 and is followed by chlorination to afford key intermediate 3. Nucleophilic aromatic substitution to install the desired Y group and reduction of the nitro group provides 10. In the final step, the fused imidazolidinone ring is is formed to afford 11 (imidazoquinoline-connector 1 derivative). For example, Scheme Xm provides for a connector Y (e.g. Y₁, Y₂, Y₃ or Y₄).

[00307] In Scheme Xn, commercially available diester 12 and aniline 13 are reacted to prepare the quinoline core intermediate 14. The isoxazole of 15 is installed via a Suzuki coupling. A three step procedure: hydrolysis, chlorination and amidation, provides carboxamide 4. Nucleophilic aromatic substitution is utilized to install the desired Y group, and formation of the imidazolidinone ring is the final step in the preparation of 18

(imidazoquinoline-connector 1 derivative). For example, Scheme Xn provides for a connector Y (e.g. Y₁, Y₂, Y₃ or Y₄).

SCHEME Xm

[00308] For example, Y may be selected from the group consisting of:

SCHEME Xn

[00309] For example, Y may be selected from the group consisting of:

[00310] Additional examples for NHY and -Y that can be utilized in Scheme Xm and Scheme Xn can be found in Table M, seen below: Table M

[00311] The divergent synthetic route in Scheme Xo illustrates a general method for providing imidazoquinoline-connector 1 derivatives having various connectors attached to both the imidazoquinoline compound and to any of the above-identified linkers (Z¹, Z², Z³ and Z⁴). In the scheme below, the linker moiety is designated by Z. Utilizing key intermediate 3

(synthesis described in Scheme Xm), nucleophilic aromatic substitution allows for the installation of the desired Y-Z group. The final divergent step is cyclization to provide imidazoquinoline 11 (fused-imidazoquinoline derivative C) and 21 (fused-imidazole derivative D), respectively. For example, Scheme Xo provides for a connector Y (e.g. Y₁, Y₂, Y₃ or Y₄) attached to a linker moiety (Z).

SCHEME Xo

21

[00312] For example, -Y-Z may be selected from the group consisting of:

[00313] Additional examples for Z-Y-NH₂ and NH-Y-Z that can be utilized in Scheme Xo can be found in Table N, seen below:

Table N

[00314] The divergent synthetic route in Scheme Xq illustrates a general method for providing imidazoquinoline-connector 1 derivatives having various ethylene-substituted connectors attached to both the imidazoquinoline compound and to any of the above-identified linkers (Z¹, Z², Z³ and Z⁴). In the scheme below, the linker moiety is designated by Z. The ethylene diamine connector is installed via nucleophilic aromatic substitution. Following reduction of the nitro group to afford amino-quinoline 18, the divergent cyclization steps provide imidazoquinoline 19 (fused-imidazoquinoline) and 22 (fused-imidazole), respectively. The desired R-Z group is installed via reaction with a variety of electrophiles, for example, a carboxylic acid, to afford 20A (fused-imidazoquinoline derivative C) and 23 (fused-imidazole derivative D), respectively. For example, Scheme Xq provides for a connector Y (e.g. Y₁, Y₂, Y₃ or Y₄) attached to a linker moiety (Z), wherein Y is–CH₂CH₂NHR- (e.g.,–CH₂CH₂NHR- of 20A or 23). SCHEME Xq

[00315] For example, R-Z may be represented by the structure:

[00316] Additional examples for Z-R-OH and -R-Z that can be utilized in Scheme Xq can be found in Table O, seen below:

Table O

[00317] The above-identified isoxazole compounds may have one of e.g., two possible attachment points for a connector element: the phenyl ether and the benzylic ether. As seen below, a connector element may be identified as a Y group in isoxazole-connector 1 E and isoxazole-connector 2 F:

[00318] For example, Y , Y , Y and Y may be Y as described above in connector 1 E or connector 2 F.

[00319] The synthetic route in Scheme Xt illustrates a general method for preparing isoxazole -connector 1 derivatives. The method involves attaching the desired substituents to the phenol core. The desired Y group attached at the meta-position of the phenol can be installed by reacting isoxazole 1t with the appropriate electrophile 2 to provide 3t (isoxazole- connector 1 derivative). For example, Scheme Xt provides for a connector Y (e.g. Y¹, Y², Y³ or Y⁴). SCHEME Xt

[00320] Similar to Scheme Xt, Scheme Xu provides a synthetic route for preparing isoxazole -connector 2 derivatives. The method involves attaching the desired substituents to the phenol core. The desired Y group attached at the benzylic alcohol can be installed by reacting isoxazole 1u with the appropriate electrophile 2 to provide 3u (isoxazole-connector 2 derivative). For example, Scheme Xu provides for a connector Y (e.g. Y¹, Y², Y³ or Y⁴). 10 SCHEME Xu

[00321] For Scheme Xt and Scheme Xu, additional examples for 2 and Y can be found in Table A.

[00322] In another embodiment, the attachment points identified in E (isoxazole- connector 1) or F (isoxazole-connector 2) may be further elaborated to incorporate not only a connector moiety (Y), but also a linker (Z), as e.g., represented by:

(isoxazole-connector 1) or (isoxazole-connector 2).

For example, Z (e.g., Z¹, Z², Z³ and Z⁴) may be any of the linker moieties contemplated herein. [00323] The above-identified isoxazole compounds may connect to a connector through a different attachment point, e.g., : the amino group of the quinazolone core. As seen below, a connector element may identified e.g., as a Y group in isoxazole-connector 3 G:

[00324] In one embodiment, the attachment point identified in G may be further elaborated to incorporate not only a connector moiety (Y), but also a linker (Z), as represented by:

For example, Z (e.g., Z¹, Z², Z³ and Z⁴) may be any of the linker moieties contemplated herein.

[00325] Scheme Xv provides a synthetic procedure for making G derivatives having a connector attached to both the heterocyclic compound and to any of the above-identified linkers (Z¹, Z², Z³ and Z⁴). In the scheme below, the linker moiety is designated by Z. Starting from tri-substituted phenyl 1, the ethylene diamine substitutent (2) is attached via nucleophilic substitution. Reductive cyclization of 3 affords quinazolone 4. The isoxazole is installed utilizing a Suzuki coupling, and upon subsequent formation of 6, deprotection of the terminal amine provides 7. The desired R-Z group is installed via reaction with a variety of electrophiles, for example, a carboxylic acid, to afford 8 (isoxazole-conncetor 3 G). For example, Scheme Xv provides for a connector Y (e.g. Y₁, Y₂, Y₃ or Y₄) attached to a linker moiety (Z), wherein Y is –CH₂CH₂NHR- (e.g.,–CH₂CH₂NHR- of 8).

SCHEME Xv

[00326] For example, R-Z may be represented by the structure:

.

[00327] Additional examples for Z-R-OH or Z-R-OPG and -R-Z that can be utilized in Scheme Xv can be found in Table P, seen below:

Table P

Multimers [00328] In some embodiments, a first monomer and a second monomer may form a dimer in aqueous solution. For example, in some instances, the first monomer may form a biologically useful dimer with a second monomer in vivo.

[00329] Without wishing to be bound by any theory, it is believed that molecular self- assembly may be directed through noncovalent interactions, e.g., hydrogen bonding, metal coordination, hydrophobic forces, van der Waals forces, pi-pi interactions, electrostatic, and/or electromagnetic interactions.

[00330] Without wishing to be bound by any theory, pi-pi and pi-cation interactions can be used to drive multimerization. In addition, van der Waals and electromagnetic forces are other interactions that can help to drive multimerization. Alternatively, acid/base pairs and donor-acceptor pairs, e.g., amide and/or sulfonamide pairs, can be employed to help direct self- assembly. In other cases, use of hydrophobic interactions can be used for multimerization targeting a membrane-bound protein. Additionally, metal coordination might be used when the target itself incorporates the metal, but could also be used in other scenarios.

[00331] In one embodiment, a therapeutic multimer compound may be formed from the multimerization in an aqueous media of a first monomer X¹-Y¹-Z¹ with a second monomer X²- Y²-Z². For example, Z¹ is a first linker capable of binding to the second monomer, wherein Z² is a second linker capable of binding to the first monomer through Z¹. In a certain

embodiment, Z² is a nucleophile moiety capable of binding with the Z¹ moiety of Formula I to form the multimer. In another embodiment, the first monomer forms a biologically useful dimer with a second monomer in vivo.

[00332] In another embodiment, a therapeutic multimer compound may be formed from the multimerization in an aqueous media of a first monomer X¹-Y¹-Z¹ with a second monomer X⁴-Y⁴-Z⁴. For example, Z¹ is a first linker capable of binding to the second monomer, wherein Z⁴ is a second linker capable of binding to the first monomer through Z¹.

[00333] In certain embodiments, the multimerization may be substantially irreversible in an aqueous media. For example, the multimerization with Formula Is may be photolytically induced. In another example, Z¹ may be independently selected for each occurrence from the group consisting of Formula Ia, Ia’, Ib, Ic, Id, Ie, Ie’ and Ih and Z² may be independently selected for each occurrence from the group consisting of Formula Im, In, Io, Ip, Ir and Is; and wherein N₂ may be released during the multimerization. In some instances, the multimer may be fluorescent. [00334] It is contemplated herein that while many chemistries are in principle reversible, the extent, probability and rate of the reverse reaction will depend heavily upon a range of conditions including temperature, concentration, solvent, catalysis, and binding to the target biomolecule. The term“irreversible” typically refers to the low probability of the reverse reaction occurring to a significant extent in an aqueous media within the timeframe of associated biological, pharmacologic and metabolic events, e.g., turn-over or degradation of the target biomolecule, signal transduction responses, drug metabolism and clearance, etc. As the affinity of the“irreversible” multimeric assembly for the target biomolecule is at least an order of magnitude higher than that of its monomers, it is likely to persist on the target for a prolonged period and exhibit a very slow off-rate. Additionally, the binding of the

“irreversible” multimeric assembly by the target biomolecule may also significantly slow the dissociative reversal of the linker reaction to regenerate monomers. Also, the irreversible extrusion of a small molecule from the multimer linkage, may ensure the linker reaction cannot be revered in an aqueous or biological milieu. Thus, in general the half-life for the

“irreversible” multimeric assembly is considered e.g., comparable to, or longer than the half- life for, the associated biological processes, with the potential to provide a relatively long duration of pharmacologic action.

[00335] In some embodiments, X¹ and X² may be the same. In other cases, X¹ and X² may be different. In some embodiments, X¹ and X⁴ may be the same. In other cases, X¹ and X⁴ may be different. Methods

[00336] In some embodiments, contemplated monomers and multimers may be administered to a patient in need thereof. In some embodiments, a method of administering a pharmaceutically effective amount of a multimeric compound to a patient in need thereof is provided. In some cases, the method comprises administering to the patient thereof an amount of the first monomer and an amount of a second monomer in amounts effective such that the pharmaceutically effective amount of the resulting multimer is formed in vivo.

[00337] In some embodiments, a first monomer and a second monomer may be administered substantially sequentially. In other embodiments, the first monomer and the second monomer are administered substantially simultaneously. In some embodiments the monomers may be administered, sequentially or simultaneously, by different routes of administration or the same route of administration. In still further embodiments, a first monomer and a second monomer may be administered after forming a multimer.

[00338] In some instances, a method of modulating two or more target biomolecule domains is provided, e.g., two bromodomains. In some embodiments, a first ligand moiety (e.g., bound to a first monomer) may bind to a first bromodomain and a second ligand moiety (e.g., bound to a second monomer) may bind to a second domain. In certain embodiments, a multimer comprising the first and second ligand moieties may form prior to binding the first and second domains. In other embodiments, a multimer may form after one and/or two of the monomers bind the first and second domains.

[00339] In some embodiments, a multimer contemplated herein may be used to inhibit or facilitate protein-protein interactions. For example, in some cases, a contemplated multimer may be capable of activating or inactivating a signaling pathway. Without wishing to be bound by any theory, a multimer may bind to a target protein and affect the conformation of the target protein such that the target protein is more biologically active as compared to when the multimer does not bind the target protein. In some embodiments monomers may be chosen such that a multimer formed from the monomers binds to at least two regions of a target molecule.

[00340] In one embodiment, a contemplated multimer may be capable of binding to a bromodomain and a second protein domain, wherein the second protein domain is, e.g. between about 5 ǖ and about 30 ǖ of the bromodomain, or in some embodiments within about 40 ǖ of the bromodomain.

[00341] In one embodiment, compounds contemplated herein may be capable of modulating oncology fusion proteins. For example, a multimer may be capable of modulating oncology fusion proteins. Methods of modulating oncology fusion proteins include methods of modulating, e.g., BRD-NUT. In some embodiments, the oncology fusion protein (e.g., fusion gene product) is a BRD fusion product, for example, BRD3-NUT and BRD4-NUT. For example, a method of modulating a fusion protein provided, wherein the fusion protein is selected from the group consisting of BRD3-NUT and BRD4-NUT.

[00342] In an embodiment, the compounds contemplated herein may be used in a method for treating diseases or conditions for which a bromodomain inhibitor is indicated, for example, a compound may be used for treating a chronic autoimmune and/or inflammatory condition in a patient in need thereof. In another embodiment, the compounds contemplated herein may be used in a method for treating cancer, such as midline carcinoma. For example, provided herein is a method of treating a disease associated with a protein having tandem bromodomains in a patient in need.

[00343] Provided herein, for example, is a use of a compound in the manufacture of a medicament for the treatment of diseases or conditions for which a bromodomain inhibitor is indicated. In another embodiment, provided herein is a use of a compound or a

pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a chronic autoimmune and/or inflammatory condition. In a further embodiment, provided herein is a use of a compound or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cancer, such as midline carcinoma or acute myeloid leukemia.

[00344] Provided herein is a method of treating a disease or condition such as systemic or tissue inflammation, inflammatory responses to infection or hypoxia, cellular activation and proliferation, lipid metabolism, fibrosis, or the prevention and treatment of viral infections in a patient in need thereof comprising administering a pharmaceutically effective amount of two or more disclosed monomers, e.g. simultaneously or sequentially, or administering a contemplated multimer.

[00345] For example, methods of treating chronic autoimmune and inflammatory conditions such as rheumatoid arthritis, osteoarthritis, acute gout, psoriasis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease (Crohn's disease and Ulcerative colitis), asthma, chronic obstructive airways disease, pneumonitis, myocarditis, pericarditis, myositis, eczema, dermatitis, alopecia, vitiligo, bullous skin diseases, nephritis, vasculitis, atherosclerosis, Alzheimer's disease, depression, retinitis, uveitis, scleritis, hepatitis, pancreatitis, primary biliary cirrhosis, sclerosing cholangitis, Addison's disease, hypophysitis, thyroiditis, type II diabetes, acute rejection of transplanted organs in a patient in need thereof are contemplated, comprising administering two or more disclosed monomers, e.g. capable of forming a multimer, e.g., dimer in-vivo, or administering a contemplated multimer.

[00346] Also contemplated herein are methods of treating acute inflammatory conditions in a patient in need thereof such as acute gout, giant cell arteritis, nephritis including lupus nephritis, vasculitis with organ involvement such as glomerulonephritis, vasculitis including giant cell arteritis, Wegener's granulomatosis, Polyarteritis nodosa, Behcet's disease, Kawasaki disease, Takayasu's Arteritis, or vasculitis with organ involvement, comprising administering administering two or more disclosed monomers, e.g. capable of forming a multimer e.g., dimer in-vivo.

[00347] Methods of treating disorders relating to inflammatory responses to infections with bacteria, viruses, fungi, parasites or their toxins, in a patient in need thereof is

contemplated, such as sepsis, sepsis syndrome, septic shock, endotoxaemia, systemic inflammatory response syndrome (SIRS), multi-organ dysfunction syndrome, toxic shock syndrome, acute lung injury, ARDS (adult respiratory distress syndrome), acute renal failure, fulminant hepatitis, burns, acute pancreatitis, post-surgical syndromes, sarcoidosis, Herxheimer reactions, encephalitis, myelitis, meningitis, malaria, SIRS associated with viral infections such as influenza, herpes zoster, herpes simplex, coronavirus, cold sores, chickenpox, shingles, human papilloma virus, cervical neoplasia, adenovirus infections, including acute respiratory disease, poxvirus infections such as cowpox and smallpox and African swine fever virus comprising administering administering two or more disclosed monomers, e.g. capable of forming a multimer e.g., dimer in-vivo, or administering a contemplated multimer.

[00348] Contemplated monomers or multimers may be useful, when administered to a patient in need thereof, in the prevention or treatment of conditions associated with ischaemia- reperfusion injury in a patient need thereof such as myocardial infarction, cerebrovascular ischaemia (stroke), acute coronary syndromes, renal reperfusion injury, organ transplantation, coronary artery bypass grafting, cardio-pulmonary bypass procedures, pulmonary, renal, hepatic, gastro-intestinal or peripheral limb embolism.

[00349] Other contemplated methods of treatment that include administering disclosed compounds include treatment of disorders of lipid metabolism via the regulation of APO-A1 such as hypercholesterolemia, atherosclerosis and Alzheimer's disease, treatment of fibrotic conditions such as idiopathic pulmonary fibrosis, renal fibrosis, post-operative stricture, keloid formation, scleroderma, cardiac fibrosis, and the prevention and treatment of viral infections such as herpes virus, human papilloma virus, adenovirus, human immunodeficiency virus (HIV), and poxvirus and other DNA viruses.

[00350] Contemplated herein are methods of treating cancers, e.g., cancers such as including hematological, epithelial including lung, breast and colon carcinomas, mesenchymal, hepatic, renal and neurological tumors, comprising administering a disclosed compound to a patient in need thereof. For example, contemplated herein is a method of treating squamous cell carcinoma, midline carcinoma or leukemia such as acute myeloid leukemia in a patient in need thereof comprising administering two or more disclosed monomers such that the monomers form a multimer (e.g. dimer) in-vivo.

[00351] In an embodiment, two or more contemplated monomers that e.g., form a multimer in-vivo, or a contemplated multimer, may be administered at the point of diagnosis to reduce the incidence of: SIRS, the onset of shock, multi-organ dysfunction syndrome, which includes the onset of acute lung injury, ARDS, acute renal, hepatic, and cardiac and gastro- intestinal injury.

[00352] Also contemplated herein are methods of providing contraceptive agents, or a method of providing contraception, to a male patient, comprising administering two or more disclosed monomers, or a disclosed multimer.

[00353] In some embodiments, a ligand moiety (e.g., a pharmacophore) may have a molecular weight between 50 Da and 2000 Da, in some embodiments between 50 Da and 1500 Da, in some embodiments, between 50 Da and 1000 Da, and in some embodiments, between 50 Da and 500 Da. In certain embodiments, a ligand moiety may have a molecular weight of less than 2000 Da, in some embodiments, less than 1000 Da, and in some embodiments less than 500 Da.

[00354] In certain embodiments, the compound utilized by one or more of the foregoing methods is one of the generic, subgeneric, or specific compounds described herein.

[00355] Disclosed compositions may be administered to patients (animals and humans) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. It will be appreciated that the dose required for use in any particular application will vary from patient to patient, not only with the particular compound or composition selected, but also with the route of administration, the nature of the condition being treated, the age and condition of the patient, concurrent medication or special diets then being followed by the patient, and other factors which those skilled in the art will recognize, with the appropriate dosage ultimately being at the discretion of the attendant physician. For treating clinical conditions and diseases noted above, a compound may be administered orally, subcutaneously, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, and vehicles. Parenteral administration may include subcutaneous injections, intravenous or intramuscular injections, or infusion techniques. [00356] Treatment can be continued for as long or as short a period as desired. The compositions may be administered on a regimen of, for example, one to four or more times per day. A suitable treatment period can be, for example, at least about one week, at least about two weeks, at least about one month, at least about six months, at least about 1 year, or indefinitely. A treatment period can terminate when a desired result, for example a partial or total alleviation of symptoms, is achieved.

[00357] In another aspect, pharmaceutical compositions comprising monomers, dimers, and/or multimers as disclosed herein formulated together with a pharmaceutically acceptable carrier provided. In particular, the present disclosure provides pharmaceutical compositions comprising monomers, dimers, and/or multimers as disclosed herein formulated together with one or more pharmaceutically acceptable carriers. These formulations include those suitable for oral, rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) rectal, vaginal, or aerosol administration, although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used. For example, disclosed compositions may be formulated as a unit dose, and/or may be formulated for oral or subcutaneous administration.

[00358] Exemplary pharmaceutical compositions may be used in the form of a pharmaceutical preparation, for example, in solid, semisolid, or liquid form, which contains one or more of the compounds, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral, or parenteral applications. The active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease.

[00359] For preparing solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid

preformulation composition containing a homogeneous mixture of a compound, or a non-toxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

[00360] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the subject composition is mixed with one or more

pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4)

disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[00361] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface- active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent. Tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art.

[00362] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the subject composition, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.

[00363] Suspensions, in addition to the subject composition, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[00364] Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.

[00365] Dosage forms for transdermal administration of a subject composition includes powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active component may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.

[00366] The ointments, pastes, creams and gels may contain, in addition to a subject composition, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[00367] Powders and sprays may contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[00368] Compositions and compounds may alternatively be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound. A non-aqueous (e.g., fluorocarbon propellant) suspension could be used. Sonic nebulizers may be used because they minimize exposing the agent to shear, which may result in degradation of the compounds contained in the subject compositions. Ordinarily, an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars, or sugar alcohols. Aerosols generally are prepared from isotonic solutions.

[00369] Pharmaceutical compositions suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[00370] Examples of suitable aqueous and non-aqueous carriers which may be employed in the pharmaceutical compositions include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins. Proper fluidity may be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants

[00371] In another aspect, enteral pharmaceutical formulations including a disclosed pharmaceutical composition comprising monomers, dimers, and/or multimers, an enteric material; and a pharmaceutically acceptable carrier or excipient thereof are provided. Enteric materials refer to polymers that are substantially insoluble in the acidic environment of the stomach, and that are predominantly soluble in intestinal fluids at specific pHs. The small intestine is the part of the gastrointestinal tract (gut) between the stomach and the large intestine, and includes the duodenum, jejunum, and ileum. The pH of the duodenum is about 5.5, the pH of the jejunum is about 6.5 and the pH of the distal ileum is about 7.5.

Accordingly, enteric materials are not soluble, for example, until a pH of about 5.0, of about 5.2, of about 5.4, of about 5.6, of about 5.8, of about 6.0, of about 6.2, of about 6.4, of about 6.6, of about 6.8, of about 7.0, of about 7.2, of about 7.4, of about 7.6, of about 7.8, of about 8.0, of about 8.2, of about 8.4, of about 8.6, of about 8.8, of about 9.0, of about 9.2, of about 9.4, of about 9.6, of about 9.8, or of about 10.0. Exemplary enteric materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleat, cellulose acetate butyrate, cellulose acetate propionate, copolymer of methylmethacrylic acid and methyl methacrylate, copolymer of methyl acrylate, methylmethacrylate and methacrylic acid, copolymer of methylvinyl ether and maleic anhydride (Gantrez ES series), ethyl methyacrylate-methylmethacrylate-chlorotrimethylammonium ethyl acrylate copolymer, natural resins such as zein, shellac and copal collophorium, and several commercially available enteric dispersion systems (e. g. , Eudragit L30D55, Eudragit FS30D, Eudragit L100, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric, and Aquateric). The solubility of each of the above materials is either known or is readily determinable in vitro. The foregoing is a list of possible materials, but one of skill in the art with the benefit of the disclosure would recognize that it is not comprehensive and that there are other enteric materials that may be used.

[00372] Advantageously, kits are provided containing one or more compositions each including the same or different monomers. Such kits include a suitable dosage form such as those described above and instructions describing the method of using such dosage form to treat a disease or condition. The instructions would direct the consumer or medical personnel to administer the dosage form according to administration modes known to those skilled in the art. Such kits could advantageously be packaged and sold in single or multiple kit units. An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.

[00373] It may be desirable to provide a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested. Another example of such a memory aid is a calendar printed on the card, e.g., as follows“First Week, Monday, Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, . . .” etc. Other variations of memory aids will be readily apparent. A“daily dose” can be a single tablet or capsule or several pills or capsules to be taken on a given day. Also, a daily dose of a first compound can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa. The memory aid should reflect this.

[00374] Also contemplated herein are methods and compositions that include a second active agent, or administering a second active agent.

[00375] Certain terms employed in the specification, examples, and appended claims are collected here. These definitions should be read in light of the entirety of the disclosure and understood as by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art. DEFINITIONS

[00376] In some embodiments, the compounds, as described herein, may be substituted with any number of substituents or functional moieties. In general, the term“substituted” whether preceded by the term“optionally” or not, and substituents contained in formulas, refer to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent.

[00377] In some instances, when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.

[00378] As used herein, the term“substituted” is contemplated to include all permissible substituents of organic and inorganic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. In some embodiments, heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms. Non-limiting examples of substituents include acyl; aliphatic; heteroaliphatic; phenyl; naphthyl; heteroaryl; arylalkyl; heteroarylalkyl; alkoxy; cycloalkoxy;

heterocyclylalkoxy; heterocyclyloxy; heterocyclyloxyalkyl; alkenyloxy; alkynyloxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; oxo; -F; -Cl; - Br; -I; -OH; -NO₂; -CN; -SCN; -SR_x; -CF₃; -CH₂CF₃; -CHCl₂; -CH₂OH; -CH₂CH₂OH; - CH₂NH₂; -CH₂SO₂CH₃; -OR_x, -C(O)R_x; -CO₂(R_x); -C(O)N(R_x)₂; -OC(O)R_x; -OCO₂R_x; - OC(O)N(R_x)₂; -N(R_x)₂; -SOR_x; -S(O)₂R_x; -NR_xC(O)R_x; or -C(R_x)₃; wherein each occurrence of R_x independently is hydrogen, aliphatic, heteroaliphatic, phenyl, naphthyl, heteroaryl, arylalkyl, or heteroarylalkyl, wherein any of the aliphatic, heteroaliphatic, arylalkyl, or heteroarylalkyl substituents described above and herein may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and wherein any of the phenyl, naphthyl, or heteroaryl substituents described above and herein may be substituted or unsubstituted. Furthermore, the compounds described herein are not intended to be limited in any manner by the permissible substituents of organic compounds. In some embodiments, combinations of substituents and variables described herein may be preferably those that result in the formation of stable compounds. The term“stable,” as used herein, refers to compounds which possess stability sufficient to allow manufacture and which maintain the integrity of the compound for a sufficient period of time to be detected and preferably for a sufficient period of time to be useful for the purposes detailed herein.

[00379] The term“acyl,” as used herein, refers to a moiety that includes a carbonyl group. In some embodiments, an acyl group may have a general formula selected from - C(O)R_x; -CO₂(R_x); -C(O)N(R_x)₂; -OC(O)R_x; -OCO₂R_x; and -OC(O)N(R_x)₂; wherein each occurrence of R_x independently includes, but is not limited to, hydrogen, aliphatic,

heteroaliphatic, phenyl, naphthyl, heteroaryl, arylalkyl, or heteroarylalkyl, wherein any of the aliphatic, heteroaliphatic, arylalkyl, or heteroarylalkyl substituents described above and herein may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and wherein any of the phenyl, naphthyl, or heteroaryl substituents described above and herein may be substituted or unsubstituted. [00380] The term“aliphatic,” as used herein, includes both saturated and unsaturated, straight chain (i.e., unbranched), branched, acyclic, cyclic, or polycyclic aliphatic

hydrocarbons, which are optionally substituted with one or more functional groups. As will be appreciated by one of ordinary skill in the art,“aliphatic” is intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties. The term“heteroaliphatic,” as used herein, refers to aliphatic moieties that contain one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms, e.g., in place of carbon atoms.

Heteroaliphatic moieties may be branched, unbranched, cyclic or acyclic and include saturated and unsaturated heterocycles such as morpholino, pyrrolidinyl, etc.

[00381] In general, the terms“aryl,”“aromatic,”“heteroaryl,” and“heteroaromtic” as used herein, refer to stable mono- or polycyclic, heterocyclic, polycyclic, and polyheterocyclic unsaturated moieties having preferably 3-14 carbon atoms, each of which may be substituted or unsubstituted. Substituents include, but are not limited to, any of the previously mentioned substituents, i.e., the substituents recited for aliphatic moieties, or for other moieties as disclosed herein, resulting in the formation of a stable compound. In certain embodiments, aryl or aromatic refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings selected from phenyl, naphthyl, tetrahydronaphthyl, indanyl, and indenyl. In certain embodiments, the term heteroaryl, as used herein, refers to a cyclic aromatic radical having from five to ten ring atoms of which one ring atom is selected from the group consisting of S, O, and N; zero, one, or two ring atoms are additional heteroatoms independently selected from the group consisting of S, O, and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms. Heteroaryl moieties may be selected from: pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl,oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, and the like.

[00382] It will be appreciated that aryl, aromatic, heteroaryl, and heteroaromatic groups described herein can be unsubstituted or substituted, wherein substitution includes replacement of one, two, three, or more of the hydrogen atoms thereon independently with a group selected from: C_1-6alkyl; phenyl; heteroaryl; benzyl; heteroarylalkyl; C_1-6alkoxy; C_1-6cycloalkoxy; C_1- ₆heterocyclylalkoxy; C_1-6heterocyclyloxy; heterocyclyloxyalkyl; C_2-6alkenyloxy; C_2- ₆alkynyloxy; phenoxy; heteroalkoxy; heteroaryloxy; C_1-6alkylthio; phenylthio; heteroalkylthio; heteroarylthio; oxo; -F; -Cl; -Br; -I; -OH; -NO₂; -CN; -CF₃; -CH₂CF₃; -CHCl₂; -CH₂OH; - CH₂CH₂OH; -CH₂NH₂; -CH₂SO₂CH₃; -C(O)R_x; -CO₂(R_x); -CON(R_x)₂; -OC(O)R_x; -OCO₂R_x; - OCON(R_x)₂; -N(R_x)₂; - S(O)₂R_x; -NR_x(CO)R_x, wherein each occurrence of R_x is selected from hydrogen, C_1-6alkyl_, aliphatic, heteroaliphatic, phenyl, or heteroaryl. Additional examples of generally applicable substituents are illustrated by the specific embodiments shown in the Examples that are described herein.

[00383] The term“heterocyclic,” as used herein, refers to an aromatic or non-aromatic, partially unsaturated or fully saturated, 3- to 10-membered ring system, which includes single rings of 3 to 8 atoms in size and bi- and tri-cyclic ring systems which may include aromatic five- or six-membered aryl or aromatic heterocyclic groups fused to a non-aromatic ring.

These heterocyclic rings include those having from one to three heteroatoms independently selected from the group consisting of oxygen, sulfur, and nitrogen, in which the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. In certain embodiments, the term heterocyclic refers to a non-aromatic 5-, 6-, or 7-membered ring or a polycyclic group wherein at least one ring atom is a heteroatom selected from the group consisting of O, S, and N (wherein the nitrogen and sulfur heteroatoms may be optionally oxidized), including, but not limited to, a bi- or tri-cyclic group, comprising fused six-membered rings having between one and three heteroatoms independently selected from the group consisting of the oxygen, sulfur, and nitrogen, wherein (i) each 5-membered ring has 0 to 2 double bonds, each 6-membered ring has 0 to 2 double bonds, and each 7-membered ring has 0 to 3 double bonds, (ii) the nitrogen and sulfur heteroatoms may be optionally oxidized, (iii) the nitrogen heteroatom may optionally be quaternized, and (iv) any of the above heterocyclic rings may be fused to an aryl or heteroaryl ring.

[00384] The term“alkenyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond, such as a straight or branched group of 2-6 or 3-4 carbon atoms, referred to herein for example as C_2-6alkenyl, and C_3- ₄alkenyl, respectively. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, etc.

[00385] The term“alkenyloxy” used herein refers to a straight or branched alkenyl group attached to an oxygen (alkenyl-O). Exemplary alkenoxy groups include, but are not limited to, groups with an alkenyl group of 3-6 carbon atoms referred to herein as C_3-6alkenyloxy.

Exemplary“alkenyloxy” groups include, but are not limited to allyloxy, butenyloxy, etc. [00386] The term“alkoxy” as used herein refers to a straight or branched alkyl group attached to an oxygen (alkyl-O-). Exemplary alkoxy groups include, but are not limited to, groups with an alkyl group of 1-6 or 2-6 carbon atoms, referred to herein as C_1-6alkoxy, and C₂- C₆alkoxy, respectively. Exemplary alkoxy groups include, but are not limited to methoxy, ethoxy, isopropoxy, etc.

[00387] The term“alkoxycarbonyl” as used herein refers to a straight or branched alkyl group attached to oxygen, attached to a carbonyl group (alkyl-O-C(O)-). Exemplary alkoxycarbonyl groups include, but are not limited to, alkoxycarbonyl groups of 1-6 carbon atoms, referred to herein as C_1-6alkoxycarbonyl. Exemplary alkoxycarbonyl groups include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, etc.

[00388] The term“alkynyloxy” used herein refers to a straight or branched alkynyl group attached to an oxygen (alkynyl-O)). Exemplary alkynyloxy groups include, but are not limited to, propynyloxy.

[00389] The term“alkyl” as used herein refers to a saturated straight or branched hydrocarbon, for example, such as a straight or branched group of 1-6, 1-4, or 1-3 carbon atoms, referred to herein as C_1-6alkyl, C_1-4alkyl, and C_1-3alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2- methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 3-methyl-2-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2- pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.

[00390] The term“alkylene” as used herein refers to a bivalent saturated straight or branched hydrocarbon, for example, such as a straight or branched group of 1-6, 1-4, or 1-3 carbon atoms, referred to herein as -C_1-6alkylene-, -C_1-4alkylene-, and -C_1-3alkylene-, respectively, where the alkylene has two open valences. Exemplary alkyl groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, 2-methyl-1-propylene, 2- methyl-2-propylene, 2-methyl-1-butylene, 3-methyl-1-butylene, 3-methyl-2-butylene, 2,2- dimethyl-1-propylene, 2-methyl-1-pentylene, 3-methyl-1-pentylene, 4-methyl-1-pentylene, 2- methyl-2-pentylene, 3-methyl-2-pentylene, 4-methyl-2-pentylene, 2,2-dimethyl-1-butylene, 3,3-dimethyl-1-butylene, 2-ethyl-1-butylene, butylene, isobutylene, t-butylene, pentylene, isopentylene, neopentylene, hexylene, etc. [00391] The term“alkylcarbonyl” as used herein refers to a straight or branched alkyl group attached to a carbonyl group (alkyl-C(O)-). Exemplary alkylcarbonyl groups include, but are not limited to, alkylcarbonyl groups of 1-6 atoms, referred to herein as C_1- ₆alkylcarbonyl groups. Exemplary alkylcarbonyl groups include, but are not limited to, acetyl, propanoyl, isopropanoyl, butanoyl, etc.

[00392] The term“alkynyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond, such as a straight or branched group of 2-6, or 3-6 carbon atoms, referred to herein as C_2-6alkynyl, and C_3-6alkynyl, respectively. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, etc.

[00393] The term“carbonyl” as used herein refers to the radical -C(O)-.

[00394] The term“carboxylic acid” as used herein refers to a group of formula -CO₂H.

[00395] The term“cyano” as used herein refers to the radical -CN.

[00396] The term“cycloalkoxy” as used herein refers to a cycloalkyl group attached to an oxygen (cycloalkyl-O-).

[00397] The term“cycloalkyl” as used herein refers to a monocyclic saturated or partially unsaturated hydrocarbon group of for example 3-6, or 4-6 carbons, referred to herein, e.g., as C_3-6cycloalkyl or C_4-6cycloalkyl and derived from a cycloalkane. Exemplary cycloalkyl groups include, but are not limited to, cyclohexyl, cyclohexenyl, cyclopentyl, cyclobutyl or, cyclopropyl.

[00398] The terms“halo” or“halogen” as used herein refer to F, Cl, Br, or I.

[00399] The term“heterocyclylalkoxy” as used herein refers to a heterocyclyl- alkyl-O- group.

[00400] The term“heterocyclyloxyalkyl” refers to a heterocyclyl-O-alkyl- group.

[00401] The term“heterocyclyloxy” refers to a heterocyclyl-O- group.

[00402] The term“heteroaryloxy” refers to a heteroaryl-O- group.

[00403] The terms“hydroxy” and“hydroxyl” as used herein refers to the radical -OH.

[00404] The term“oxo” as used herein refers to the radical =O.

[00405] The term“connector” as used herein to refers to an atom or a collection of atoms optionally used to link interconnecting moieties, such as a disclosed linker and a

pharmacophore. Contemplated connectors are generally hydrolytically stable. [00406] “Treating” includes any effect, e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder and the like.

[00407] “Pharmaceutically or pharmacologically acceptable” include molecular entities and compositions that do not produce an adverse, allergic, or other untoward reaction when administered to an animal, or a human, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, general safety and purity standards as required by FDA Office of Biologics standards.

[00408] The term“pharmaceutically acceptable carrier” or“pharmaceutically acceptable excipient” as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical

administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.

[00409] The term“pharmaceutical composition” as used herein refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.

[00410] “Individual,”“patient,” or“subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans. The compounds can be administered to a mammal, such as a human, but can also be administered to other mammals such as an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like). The mammal treated is desirably a mammal in which treatment of obesity, or weight loss is desired.“Modulation” includes antagonism (e.g., inhibition), agonism, partial antagonism and/or partial agonism.

[00411] In the present specification, the term“therapeutically effective amount” means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought by the researcher, veterinarian, medical doctor, or other clinician. The compounds are administered in therapeutically effective amounts to treat a disease. Alternatively, a therapeutically effective amount of a compound is the quantity required to achieve a desired therapeutic and/or prophylactic effect, such as an amount which results in weight loss. [00412] The term“pharmaceutically acceptable salt(s)” as used herein refers to salts of acidic or basic groups that may be present in compounds used in the present compositions. Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including but not limited to malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3- naphthoate)) salts. Compounds included in the present compositions that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. Compounds included in the present compositions that include a basic or acidic moiety may also form pharmaceutically acceptable salts with various amino acids. The compounds of the disclosure may contain both acidic and basic groups; for example, one amino and one carboxylic acid group. In such a case, the compound can exist as an acid addition salt, a zwitterion, or a base salt.

[00413] The compounds of the disclosure may contain one or more chiral centers and/or double bonds and, therefore, exist as stereoisomers, such as geometric isomers, enantiomers or diastereomers. The term“stereoisomers” when used herein consist of all geometric isomers, enantiomers or diastereomers. These compounds may be designated by the symbols“R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom.

Various stereoisomers of these compounds and mixtures thereof are encompassed by this disclosure. Stereoisomers include enantiomers and diastereomers. Mixtures of enantiomers or diastereomers may be designated“(±)” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.

[00414] The compounds of the disclosure may contain one or more chiral centers and/or double bonds and, therefore, exist as geometric isomers, enantiomers or diastereomers. The enantiomers and diastereomers may be designated by the symbols“(+),”“(-).”“R” or“S,” depending on the configuration of substituents around the stereogenic carbon atom, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. Geometric isomers, resulting from the arrangement of substituents around a carbon-carbon double bond or arrangement of substituents around a cycloalkyl or heterocyclic ring, can also exist in the compounds. The symbol denotes a bond that may be a single, double or triple bond as described herein. Substituents around a carbon-carbon double bond are designated as being in the“Z” or“E” configuration wherein the terms“Z” and“E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the“E” and“Z” isomers. Substituents around a carbon-carbon double bond alternatively can be referred to as“cis” or“trans,” where“cis” represents substituents on the same side of the double bond and“trans” represents substituents on opposite sides of the double bond. The arrangement of substituents around a carbocyclic ring can also be designated as“cis” or “trans.” The term“cis” represents substituents on the same side of the plane of the ring and the term“trans” represents substituents on opposite sides of the plane of the ring. Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated“cis/trans.”

[00415] The term“stereoisomers” when used herein consist of all geometric isomers, enantiomers or diastereomers. Various stereoisomers of these compounds and mixtures thereof are encompassed by this disclosure.

[00416] Individual enantiomers and diastereomers of the compounds can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, (3) direct separation of the mixture of optical enantiomers on chiral liquid chromatographic columns or (4) kinetic resolution using stereoselective chemical or enzymatic reagents.

Racemic mixtures can also be resolved into their component enantiomers by well known methods, such as chiral-phase gas chromatography or crystallizing the compound in a chiral solvent. Stereoselective syntheses, a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or during the transformation of a pre-existing one, are well known in the art. Stereoselective syntheses encompass both enantio- and diastereoselective transformations. For examples, see Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.

[00417] The compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In one embodiment, the compound is amorphous. In one embodiment, the compound is a polymorph. In another embodiment, the compound is in a crystalline form.

[00418] Also embraced are isotopically labeled compounds which are identical to those recited herein, except 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 usually found in nature.

Examples of isotopes that can be incorporated into the compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as ¹⁰B, ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. For example, a compound may have one or more H atom replaced with deuterium.

[00419] Certain isotopically-labeled disclosed compounds (e.g., those labeled with ³H and ¹⁴C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., ²H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed in the Examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[00420] The term“prodrug” refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (such as by esterase, amidase, phosphatase, oxidative and or reductive metabolism) in various locations (such as in the intestinal lumen or upon transit of the intestine, blood, or liver). Prodrugs are well known in the art (for example, see Rautio, Kumpulainen, et al, Nature Reviews Drug Discovery 2008, 7, 255). For example, if a compound or a pharmaceutically acceptable salt, hydrate, or solvate of the compound contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as (C_1-8)alkyl, (C_2-12)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N- (alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,

1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl,

4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as ȕ-dimethylaminoethyl), carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)alkylcarbamoyl-(C₁-C₂)alkyl and piperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl.

[00421] Similarly, if a compound contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (C_1- ₆)alkanoyloxymethyl, 1-((C_1-6)alkanoyloxy)ethyl, 1-methyl-1-((C_1-6)alkanoyloxy)ethyl (C_1- ₆)alkoxycarbonyloxymethyl, N-(C_1-6)alkoxycarbonylaminomethyl, succinoyl, (C_1-6)alkanoyl, Į - amino(C_1-4)alkanoyl, arylacyl and Į -aminoacyl, or Į-aminoacyl-Į -aminoacyl, where each D- aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH)₂, -P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate).

[00422] If a compound incorporates an amine functional group, a prodrug can be formed, for example, by creation of an amide or carbamate, an N-acyloxyakyl derivative, an

(oxodioxolenyl)methyl derivative, an N-Mannich base, imine, or enamine. In addition, a secondary amine can be metabolically cleaved to generate a bioactive primary amine, or a tertiary amine can be metabolically cleaved to generate a bioactive primary or secondary amine. For examples, see Simplício, et al., Molecules 2008, 13, 519 and references therein. INCORPORATION BY REFERENCE

[00423] All publications and patents mentioned herein, including those items listed below, are hereby incorporated by reference in their entirety for all purposes as if each individual publication or patent was specifically and individually incorporated by reference. In case of conflict, the present application, including any definitions herein, will control. EXAMPLES

[00424] The compounds described herein can be prepared in a number of ways based on the teachings contained herein and synthetic procedures known in the art. Where a particular stereochemistry is indicated for a compound, one of ordinary skill in the art would recognize that other stereoisomers of the compound may also be formed. In some cases, a starting material or intermediate used in the synthesis of a contemplated compound may have an enantiomeric excess greater than 0, e.g., greater than about 95%, greater than about 98%, greater than about 99%, or essentially 100%. For example, in some cases, a starting material or intermediate may be essentially stereoisomerically pure. However, partial or complete loss of chiral integrity may occur during the synthesis of the contemplated compound thereby reducing or eliminating the enantiomeric excess. For example, where a stereoisomerically pure starting material or intermediate is used in a synthesis of a contemplated compound, partial or complete loss of chiral integrity results in a stereoisomeric mixture. A stereoisomeric mixture may be partially or essentially completely resolved by subjecting the stereoisomeric mixture to a chiral purification technique (e.g., chiral HPLC purification). EXAMPLES 1-7:

[00425] Monomers were synthesized according to the procedures described below.

[00426] S)-N-(2-((6-(4-chlorophenyl)-4-(2-(ethylamino)-2-oxoethyl)-1-methyl-4H- benzo[f][1,2,4] triazolo[4,3-a][1,4]diazepin-8-yl)oxy)ethyl)-4- ((hydroxydimethylsilyl)methyl) benzamide [Example 1]:

[00427] A solution of 4-((hydroxydimethylsilyl)methyl)benzoic acid (83 mg, 0.39 mmol) in dry DCM (15 mL) was charged with HATU (148 mg, 0.0.39 mmol), and stirred at room temperature for 10 minutes. (S)-2-(8-(3-aminopropoxy)-6-(4-chlorophenyl)-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (150 mg, 0.33 mmol) and DIPEA (0.11 mL, 0.66 mmol) were added and stirred at room temperature for 1h. The reaction mixture was partitioned between DCM and H₂O and separated. The aqueous layer was extracted with DCM and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo resulting in crude product that was purified by preparative HPLC to obtain 10 mg (4.7% yield) of the title compound as a white solid. ¹H NMR (400 MHz, CD₃OD): į = 7.71– 7.65 (m, 3H), 7.58– 7.38 (m, 5H), 7.17– 7.14 (m, 2H), 6.96– 6.91 (m, 1H), 4.21– 4.15 (m, 2H), 3.82 (s, 1H), 3.79– 3.70 (m, 2H), 3.40– 3.21 (m, 4H), 2.62 (s, 3H), 2.24 (br. s, 2H), 1.18 (t, J = 7.2 Hz, 3H), 0.04 (s, 6H); MS (ES⁺): m/z = 645.25, 647.20 [M/2]⁺; (monomer); m/z = 637.65, 639.64 [M/2]⁺ (dimer); LCMS: t_R = 2.12 min (monomer), 2.93 min (dimer).

[00428] ((S)-N-(2-((6-(4-chlorophenyl)-4-(2-(ethylamino)-2-oxoethyl)-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl)oxy)ethyl)-3-((hydroxydimethylsilyl)

[00429] A solution of 3-((hydroxydimethylsilyl)methyl)benzoic acid (83 mg, 0.39 mmol) in dry DCM (15 mL) was charged with HATU (148 mg, 0.39 mmol) and stirred at room temperature for 10 minutes. (S)-2-(8-(3-aminopropoxy)-6-(4-chlorophenyl)-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (150 mg, 0.33 mmol) and DIPEA (0.11 mL, 0.66 mmol) were added to the reaction mixture and stirred at room temperature for 1 h. The reaction mixture was partitioned between DCM (15 mL) and H₂O (10 mL) and separated. The aqueous layer was extracted with DCM and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo resulting in crude product which was purified by preparative HPLC to obtain 20 mg (9 % yield) of the title compound as a white solid. ¹H NMR (400 MHz, CD₃OD): į = 7.70 (d, J = 9.2 Hz, 1H), 7.54– 7.48 (m, 4H), 7.43– 7.37 (m, 3H), 7.29– 7.25 (m, 2H), 6.97 (d, J = 2.8 Hz, 1H), 4.61– 4.58 (m, 1H), 4.23– 3.98 (m, 2H), 3.75 (t, J = 5.2 Hz, 2H), 3.41– 3.20 (m, 4H), 2.61 (s, 3H), 2.21 (s, 2H), 1.18 (t, J = 7.2 Hz, 3H), 0.05 (s, 6H); MS (ES⁺): m/z = 645.45, 647.45 [M/2]⁺

(monomer), 636.65, 638.40 [M/2]⁺ (dimer); LCMS: t_R = 2.17 min (monomer), 2.94 min (dimer).

[00430] (S)-2-(8-(2-Aminoethoxy)-6-(4-chlorophenyl)-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (4a):

[00431] A solution of (S)-tert- butyl (2-((6-(4-chlorophenyl)-4-(2-(ethylamino)-2- oxoethyl)-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl)oxy)ethyl)carbamate (350 mg, 0.60 mmol) in DCM (10 mL) was charged with TFA (2 mL) and stirred at room temperature for 2h. The reaction mixture was then evaporated in vacuo to obtain a residue which was quenched with sat sodium bicarbonate solution (10 mL) and extracted with DCM (3 X 10 mL) to obtain 300 mg of the crude title compound as a pale yellow solid. MS (ES⁺): m/z = 453.30, 455.20 [M+H]⁺; LCMS: t_R = 1.37 min.

[00432] (S)-(tert-Butyl(2-((6-(4-chlorophenyl)-4-(2-(ethylamino)-2-oxoethyl)-1- methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl)oxy)ethyl)carbamate (3a):

[00433] A solution of (S)-2-(6-(4-chlorophenyl)-8-hydroxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (500 mg, 1.2 mmol) in acetonitrile (20 mL) was charged with K₂CO₃ (331 mg, 2.4 mmol) and 2-((tert- butoxycarbonyl)amino)ethyl methanesulfonate (438 mg, 1.8 mmol) under nitrogen atmosphere. The resulting solution was heated at 80°C for 16 h. The reaction mixture was cooled to room temperature and evaporated in vacuo. The crude product was partitioned between ethyl acetate (50 mL) and water (25 mL) and separated. The aqueous layer was extracted with ethyl acetate (3 x 20 mL). The combined organic fractions were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo resulting in a crude product which was purified by column

chromatography on silica gel (230-400 mesh), eluting with 5% methanol in DCM to obtain 350 mg (51.77 %) of the title compound as a white solid. ¹H NMR (400 MHz, CD₃OD): į = 7.54 (d, J = 8.8 Hz, 2H), 7.44– 7.18 (m, 4H), 6.96 (s, 1H), 6.39– 6.41 (m, 1H), 4.63 (t, J = 5.2 Hz, 1H), 4.08– 3.98 (m, 2H), 3.59– 3.26 (m, 6H), 2.64 (s, 3H), 1.42 (s, 9H), 1.19 (t, J = 7.2 Hz, 3H). MS (ES⁺): m/z = 553.50, 555.65 [M+H]⁺; LCMS: t_R = 2.26 min.

[00434] 2-((tert-Butoxycarbonyl)amino)ethyl methanesulfonate (2a):

[00435] A solution of tert-butyl (2-hydroxyethyl)carbamate (3 g, 18.0 mmol) in anhydrous DCM (15 mL) charged with triethylamine (5.19 mL, 37.0 mmol) stirred at 0°C for 10 min and methane sulfonyl chloride (2.09 mL, 27.0 mmol) was added, stirred at room temperature for 1 h. After the work up and purification by column chromatography, 2.8 g (62.92% yield) of the title compound was obtained as oil. ¹H NMR (400 MHz, CDCl₃): į = 4.31– 4.23 (m, 2H), 3.46 (t, J = 5.4 Hz, 2H), 3.03 (s, 6H), 1.44 (s, 9H).

[00436] (S)-N-(2-((6-(4-chlorophenyl)-4-(2-(ethylamino)-2-oxoethyl)-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl)oxy)ethyl)-4- (hydroxydimethylsilyl)benzamide [Example 3]:

[00437] A solution of 4-(hydroxydimethylsilyl)benzoic acid (20 mg, 0.100 mmol) in dry DCM (15 mL) was charged with HATU (45 mg, 0.120 mmol) and stirred at room temperature for 10 minutes. (S)-2-(8-(3-aminopropoxy)-6-(4-chlorophenyl)-1-methyl-4H- benzo[f][1,2,4]triazolo [4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (50 mg, 0.12 mmol) and DIPEA (0.03 mL, 0.12 mmol) were added to the reaction mixture and stirred at room temperature for 1 h. The reaction mixture was partitioned between DCM (10 mL) and H₂O (10 mL) and separated. The aqueous layer was extracted with DCM (3 X 10 mL) and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo resulting in crude product. The crude product of two batches was purified by preparative HPLC to obtain 35 mg (25.54% yield) of the title compound as a white solid. ¹H NMR (400 MHz, CD₃OD): į = 8.33 (d, J = 6.4 Hz, 1H), 7.82– 7.64 (m, 4H), 7.53 (d, J = 8.4 Hz, 2H), 7.45– 7.32 (m, 3H), 6.92 (d, J = 2.9 Hz, 1H), 4.62 (dd, J = 9.0, 5.2 Hz, 1H), 4.17– 4.02 (m, 2H), 3.56 (td, J = 6.7, 3.2 Hz, 2H), 3.39– 3.19 (m, 4H), 2.63 (s, 3H), 2.09 (m, 2H), 1.18 (t, J = 7.3 Hz, 3H), 0.35 (s, 6H); MS (ES⁺): m/z = 645.50, 647.40 [M+H]⁺; LCMS: t_R = 2.21 min.

[00438] ((S)-N-(3-((6-(4-chlorophenyl)-4-(2-(ethylamino)-2-oxoethyl)-1-methyl-4H- benzo[f][1,2,4] triazolo[4,3-a][1,4]diazepin-8-yl)oxy)propyl)-3- (hydroxydimethylsilyl)benzamide [Example 4]:

[00439] A solution of 3-(hydroxydimethylsilyl)benzoic acid (40 mg, 0.2 mmol) in dry DCM (15 mL) was charged with HATU (91 mg, 0.24 mmol), and stirred at room temperature for 10 minutes. (S)-2-(8-(3-aminopropoxy)-6-(4-chlorophenyl)-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (100 mg, 0.2 mmol) and DIPEA (0.06 mL, 0.4 mmol) were added and stirred at room temperature for 1h. The reaction mixture was partitioned between DCM (10 mL) and H₂O (10 mL) and separated. The aqueous layer was extracted with DCM (3 X 10 mL) and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo resulting in crude product which was purified by preparative HPLC resulting in 20 mg (15% yield) of the title compound as a white solid. ¹H NMR (400 MHz, CD₃OD): į = 8.33 (br. s, 2H), 7.97 (s, 2H), 7.78– 7.61 (m, 6H), 7.51 (d, J = 8.2 Hz, 4H), 7.43– 7.30 (m, 8H), 6.90 (d, J = 2.7 Hz, 2H), 4.60 (dd, J = 9.1, 5.3 Hz, 2H), 4.16 - 4.08 (m, 4H), 3.54 (t, J = 6.4 Hz, 4H), 3.37 -3.25 (m, 8H), 2.61 (s, 6H), 2.07 (m, 4H), 1.17 (t, J = 7.2 Hz, 6H), 0.35 (s, 12H); MS (ES⁺): m/z = 637.35, 639.25 [M/2]⁺;

LCMS: t_R = 3.02 min.

[00440] (S)-N-(3-((6-(4-chlorophenyl)-4-(2-(ethylamino)-2-oxoethyl)-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl)oxy)propyl)-3-(2-hydroxypropan-2- yl)benzamide [Example 5]:

[00441] A solution of 3-(2-hydroxypropan-2-yl)benzoic acid (74 mg, 0.4 mmol) in dry DCM (15 mL) was charged with HATU (155 mg, 0.4 mmol), stirred at room temperature for 10 min. (S)-2-(8-(3-aminopropoxy)-6-(4-chlorophenyl)-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (160 mg, 0.3 mmol) and DIPEA (0.1 mL, 0.6 mmol) were added to the reaction mixture and stirred at room temperature for 1 h. The reaction mixture was partitioned between DCM (10 mL) and H₂O (10 mL) and separated. The aqueous layer was extracted with DCM (3 X 10 mL) and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo resulting in crude product which was purified by preparative HPLC to obtain 50 mg (23 % yield) of the title compound as a white solid. ¹H NMR (400 MHz, DMSO-d₆): į = 8.51 (t, J = 5.6 Hz, 1H), 8.39 (s, 2H), 8.22 (t, J = 5.6 Hz, 1H), 7.93 (t, J = 1.9 Hz, 1H), 7.78 (d, J = 9.0 Hz, 1H), 7.67– 7.55 (m, 2H), 7.55– 7.31 (m, 5H), 6.86 (d, J = 2.8 Hz, 1H), 4.47 (dd, J = 8.3, 5.7 Hz, 1H), 4.16 – 4.02 (m, 2H), 3.40– 3.03 (m, 6H), 2.53 (s, 3H), 1.96 (m, 2H), 1.43 (s, 6H), 1.06 (t, J = 7.2 Hz, 3H); MS (ES⁺): m/z = 629.15, 631.45 [M+H]⁺; LCMS: t_R = 1.97 min.

[00442] S)-2-(8-(3-Aminopropoxy)-6-(4-chlorophenyl)-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (4b):

[00443] A solution of (S)-tert-butyl(3-((6-(4-chlorophenyl)-4-(2-(ethylamino)-2- oxoethyl)-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl)oxy)propyl)carbamate (300 mg, 0.5 mmol) in DCM (10 mL) was charged with TFA (2 mL, excess) and stirred at room temperature for 2 h. The reaction mixture was then evaporated in vacuo to obtain a residue which was quenched with sat sodium bicarbonate solution (10 mL) and extracted with DCM (3 X 10 mL) to obtain 190 mg of the crude compound as a pale yellow solid. The crude was used in the next step without further purification. ¹H NMR (400 MHz, CDCl₃): į = 7.48 (d, J = 8.2 Hz, 2H), 7.35 (t, J = 8.9 Hz, 3H), 7.19 (dd, J = 8.8, 2.9 Hz, 1H), 6.85 (d, J = 2.8 Hz, 1H), 6.40 (d, J = 7.3 Hz, 1H), 4.60 (t, J = 7.1 Hz, 1H), 4.03 (q, J = 5.6 Hz, 2H), 3.61– 3.44 (m, 1H), 3.30 (m, 3H), 2.91 (t, J = 6.8 Hz, 2H), 2.60 (s, 3H), 1.94 (t, J = 6.5 Hz, 2H), 1.18 (t, J = 7.2 Hz, 3H); MS (ES⁺): m/z = 469.20, 471.40 [M+H]⁺; LCMS: t_R = 1.47 min.

[00444] (S)-(tert-Butyl(3-((6-(4-chlorophenyl)-4-(2-(ethylamino)-2-oxoethyl)-1- methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl)oxy)propyl)carbamate (3b):

[00445] A solution of (S)-2-(6-(4-chlorophenyl)-8-hydroxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (250 mg, 0.6 mmol) in acetonitrile (20 mL) was charged with K₂CO₃ (248 mg, 1.8 mmol) and 3-((tert- butoxycarbonyl)amino)propyl methanesulfonate (154 mg, 0.6 mmol). The reaction mixture was heated at 80°C for 16 h. The reaction mixture was cooled to room temperature and evaporated in vacuo. The crude product was partitioned between ethyl acetate (50 mL) and water (25 mL) and separated. The aqueous layer was extracted with ethyl acetate (3 x 20 mL). The combined organic fractions were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo resulting in a crude product which was purified by column chromatography on silica gel (230- 400 mesh), eluting with 5% methanol in DCM to obtain 300 mg (86% yield) of title compound as a white solid. ¹H NMR (400 MHz, CD₃OD): į = 7.71 (d, J = 9.2 Hz, 1H), 7.54 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.37 (dd, J = 8.8, 2.8 Hz, 1H), 6.92 (d, J = 2.4 Hz, 1H), 4.63 – 4.60 (m, 1H), 4.07– 4.00 (m, 2H), 3.41 - 3.18 (m, 6H), 2.63 (s, 3H), 1.97 - 1.89 (m, 2H), 1.40 (s, 9H), 1.18 ( t, J = 7.2 Hz, 3H); MS (ES⁺): m/z = 567.30, 569.25 [M+H]⁺; LCMS: t_R = 2.69 min.

[00446] 3-((tert-Butoxycarbonyl)amino)propyl methanesulfonate (2b):

[00447] A solution of tert-butyl (43-hydroxypropyl)carbamate (500 mg, 2.8 mmol) in anhydrous DCM (15 mL) was charged with triethylamine (0.79 mL, 5.7 mmol) and stirred at 0°C for 10 min. Methane sulfonyl chloride (0.28 mL, 3.7 mmol) was added to the reaction mixture and stirred at room temperature for 1 h. After the work up and purification by column chromatography, 700 mg of crude title compound was obtained as oil. ¹H NMR (400 MHz, CDCl₃): į = 4.30 (t, J = 6.1, Hz, 2H), 3.58 (t, J = 6.4 Hz, 2H), 3.14 (s, 3H), 2.81 (m, 2H), 2.10 – 1.88 (m, 2H), 1.38 (t, J = 7.3 Hz, 9H).

[00448] (S)-N-(4-((6-(4-chlorophenyl)-4-(2-(ethylamino)-2-oxoethyl)-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl)oxy)butyl)-4- (hydroxydimethylsilyl)benzamide [Example 6]:

[00449] A solution of 4-(hydroxydimethylsilyl)benzoic acid (40 mg, 0.2 mmol) in dry DCM (15 mL) was charged with HATU (91 mg, 0.24 mmol) and stirred at room temperature for 10 minutes. (S)-2-(8-(3-aminopropoxy)-6-(4-chlorophenyl)-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (100 mg, 0.2 mmol) and DIPEA (0.06 mL, 0.4 mmol) were added to the reaction mixture and stirred at room temperature for 1 h. The reaction mixture was partitioned between DCM (10 mL) and H₂O (10 mL) and separated. The aqueous layer was extracted with DCM (3 X 10 mL) and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo resulting in crude product which waspurified by preparative HPLC to obtain 20 mg (14% yield) of the title compound as a white solid. ¹H NMR (400 MHz, CD₃OD): į = 7.83– 7.62 (m, 3H), 7.56– 7.50 (m, 3H), 7.44– 7.31 (m, 3H), 6.91 (d, J = 2.8 Hz, 1H), 4.60 (m, 1H), 4.04 (dt, J = 9.3, 5.8 Hz, 2H), 3.48– 3.19 (m, 7H), 2.62 (t, J = 2.2 Hz, 3H), 1.84– 1.79 ( m, 4H), 1.18 (t, J = 7.3 Hz, 3H), 0.34 (s, 6H); MS (ES⁺): m/z = 659.45, 661.45 [M+H]⁺

(monomer), 650.65, 652.50 [M/2]⁺ (dimer); LCMS: t_R = 2.28 min (monomer), 3.30 min (dimer).

[00450] ((S)-N-(4-((6-(4-chlorophenyl)-4-(2-(ethylamino)-2-oxoethyl)-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl)oxy)butyl)-3- (hydroxydimethylsilyl)benzamide [Example 7]:

[00451] A solution of 3-(hydroxydimethylsilyl)benzoic acid (40 mg, 0.2 mmol) in dry DCM (15 mL) was charged with HATU (91 mg, 0.24 mmol), stirred at room temperature for 10 min. (S)-2-(8-(3-aminopropoxy)-6-(4-chlorophenyl)-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (100 mg, 0.2 mmol) and DIPEA (0.06 mL, 0.4 mmol) were added to the reaction mixture and stirred at room temperature for 1 h. After the work up, the crude reaction mixture was purified by preparative HPLC, to obtain 20 mg (14 % yield) of the title compound as a white solid. ¹H NMR (400 MHz, CD₃OD): į = 8.46 (t, J = 5.3 Hz, 1H), 8.33 (d, J = 5.9 Hz, 1H), 7.97 (s, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.67 (t, J = 7.4 Hz, 2H), 7.51 (d, J = 7.8 Hz, 2H), 7.44– 7.31 (m, 4H), 6.89 (d, J = 2.6 Hz, 1H), 4.61 (dd, J = 9.0, 5.4 Hz, 1H), 4.04– 3.92 (m, 2H), 3.42– 3.19 (m, 5H), 2.61 (s, 3H), 1.88– 1.76 (m, 4H), 1.18 (t, J = 7.3 Hz, 3H), 0.36 (s, 6H); MS (ES⁺): m/z = 651.35, 653.15 [M /2]⁺ (dimer); LCMS: t_R = 3.40 min (monomer).

[00452] ((S)-2-(8-(4-Aminobutoxy)-6-(4-chlorophenyl)-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (4c):

[00453] A solution of (S)-tert-butyl(4-((6-(4-chlorophenyl)-4-(2-(ethylamino)-2- oxoethyl)-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl)oxy)butyl)carbamate (500 mg, 0.8 mmol) in DCM (10 mL) was charged with TFA (2 mL) and stirred at room temperature for 2 h. After the work up obtained 260 mg of the crude title compound as a pale yellow solid. No further purification was done on this compound and was taken on to the next step without further purification. ¹H NMR (400 MHz, CDCl₃): į = 7.48 (d, J = 8.1 Hz, 2H), 7.35 (t, J = 9.1 Hz, 3H), 7.17 (dd, J = 9.1, 2.8 Hz, 1H), 6.83 (d, J = 2.8 Hz, 1H), 6.43 (t, J = 5.3 Hz, 1H), 4.59 (t, J = 7.1 Hz, 1H), 3.94 (q, J = 6.2 Hz, 2H), 3.55– 3.22 (m, 5H), 2.80 (t, J = 7.2 Hz, 2H), 2.60 (s, 3H), 1.87– 1.76 (m, 2H), 1.61– 1.70 (m, 2H), 1.18 (t, J = 7.2 Hz, 3H); MS (ES⁺): m/z = 481.25, 483.10 [M+H]⁺; LCMS: t_R = 1.54 min.

[00454] (S)-(tert-Butyl(4-((6-(4-chlorophenyl)-4-(2-(ethylamino)-2-oxoethyl)-1- methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl)oxy)butyl)carbamate (3c):

[00455] A solution of (S)-2-(6-(4-chlorophenyl)-8-hydroxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (250 mg, 1.2 mmol) in acetonitrile (20 mL) was charged with K₂CO₃ (496 mg, 3.6 mmol) and 4-((tert- butoxycarbonyl)amino)butyl methanesulfonate (326 mg, 1.2 mmol). The reaction mixture was heated at 80 °C for 16 h. After the work up, the crude was purified by column chromatography on silica gel (230-400 mesh) eluting with 5% methanol in DCM to obtain 500 mg (70.% of yield) of the title compound as a white solid. ¹H NMR (400 MHz, CD₃OD): į = 7.70 (d, J = 9.0 Hz, 1H), 7.54 (d, J = 8.3 Hz, 2H), 7.41 (d, J = 8.8 Hz, 2H), 7.36 (dd, J = 8.8, 2.4 Hz, 1H), 6.90 (d, J = 2.8 Hz, 1H), 4.62 (dd, J = 9.0, 5.3 Hz, 1H), 4.09– 3.94 (m, 2H), 3.42– 3.21 (m, 4H), 3.09– 3.06 (m, 2H), 2.63 (s, 3H), 1.80– 1.75 (m, 2H), 1.65–1.58 (m, 2H), 1.42 (s, 9H), 1.18 (t, J = 7.3 Hz, 3H); MS (ES⁺): m/z = 581.35, 583.30 [M+H]⁺; LCMS: t_R = 2.79 min.

[00456] 4-((tert-Butoxycarbonyl)amino)butyl methanesulfonate (2c):

[00457] A solution of tert -butyl (4-hydroxybutyl)carbamate (4.5 g, 23.80 mmol) in anhydrous DCM (15 mL) charged with triethylamine (6.6 mL, 47.61 mmol) was stirred at 0°C for 10 min. To this solution, methane sulfonyl chloride (2.4 mL, 30.95 mmol) was added. The resulting solution was stirred at room temperature for 1 h. The reaction mixture was partitioned between DCM (25 mL) and water (25 mL) and separated. The aqueous was re-extracted with DCM (3 x 20 mL). The combined organic fractions were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo resulting in a crude product. Crude material was purified by column chromatography on silica gel (230-400 mesh), eluting with 5% methanol in DCM to afford 3.8 g (62.7 % yield) of the title compound as an oil. ¹H NMR (400 MHz, CDCl₃): į = 4.24 (t, J = 6.4, Hz, 2H), 3.16-3.13 (m, 3H), 3.00 (s, 2H), 1.81-1.74 (m, 2H), 1.66– 1.56 (m, 2H), 1.43 (s, 9H).

[00458] EXAMPLES 8 and 9:

[00459] Monomers were synthesized according to the procedures described below. Scheme 2: Synthesis of Examples 8 and 9

[00460] (S)-5-((6-(4-Chlorophenyl)-4-(2-(ethyl amino)-2-oxoethyl)-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl)oxy)-N-(3-(hydroxydimethylsilyl)phenyl) pentanamide [Example 8]:

[00461] A solution of (S)-N-(3-bromophenyl)-5-((6-(4-chlorophenyl)-4-(2-(ethylamino)- 2-oxoethyl)-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl)oxy)pentanamide (250 mg, 0.38 mmol), 1,2-diethoxy-1,1,2,2-tetramethyldisilane (159 mg, 0.77 mmol), 2-(di- tert-butylphosphino)biphenyl (50 mg, , palladium dichloride (50 mg, 0.282mmol, 74mol%) and DIPEA (299 mg, 2.32 mmol) in NMP (2.5 mL) was heated to 60°C for 2 h. The reaction mixture was partitioned between DCM (15 mL) and H₂O (15 mL) and separated. The aqueous layer was extracted with DCM (3 X 2.5 mL) and the combined organic fractions were washed with 5 % aqueous acetic acid (7.5 mL), H₂O (7.5 mL), and separated. The combined organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo resulting in a crude product which was purified by column chromatography on silica gel (100-200 mesh) eluting with 1% methanol in DCM followed by preparative HPLC to afford 25 mg (10 % yield) of the title compound as a white solid. ¹H NMR (400 MHz, DMSO-d₆): į = 9.85 (s, 1H), 8.26– 8.18 (m, 1H), 7.81 - 7.61 (m, 3H), 7.55– 7.42 (m, 4H), 7.37 (dt, J = 7.3, 3.5 Hz, 1H), 7.32– 7.13 (m, 2H), 6.86 (t, J = 3.2 Hz, 1H), 4.47– 4.41 (m, 1H), 4.03 (m, 1H), 3.31– 3.01 (m, 4H), 2.69 (s, 1H), 2.52 (s, 3H), 2.34 (d, J = 6.7 Hz, 2H), 2.17 (t, J = 8.1 Hz, 1H), 1.96– 1.83 (m, 1H), 1.76– 1.69 (m, 4H), 1.11 (t, 3H), 0.2 (S, 6H); MS (ES⁺): m/z = 659.25, 661.30 [M+H]⁺;

LCMS: t_R = 2.25 min (monomer) and 3.93 min (Dimer).

[00462] (S)-N-(3-bromophenyl)-5-((6-(4-chlorophenyl)-4-(2-(ethyl amino)-2- oxoethyl)-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl)oxy)pentanamide (7a):

[00463] A solution of (S)-5-((6-(4-chlorophenyl)-4-(2-(ethyl amino)-2-oxoethyl)-1- methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl)oxy)pentanoic acid (200 mg, 0.39 mmol) in DCM (10 mL) was charged with EDCI (112 mg, 0.58 mmol), DMAP (95 mg, 0.78 mmol), and stirred at room temperature for 10 minutes. 3-Bromo aniline (67 mg, 0.39 mmol) was added to the reaction mixture and the resulting solution was stirred at room temperature for 3 h. The reaction mixture was partitioned between DCM (15 mL) and H₂O (15 mL) and separated. The aqueous layer was extracted with DCM (3 X 15 mL) and the combined organic fractions were washed with dil. acetic acid and brine (2 X 25 mL) and dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to afford 260 mg of the crude product. The crude material was used in the next step without further purification. MS (ES⁺): m/z = 663.10, 665.10 [M+H] ⁺; LCMS: t_R = 2.65 min.

[00464] (S)-5-((6-(4-Chlorophenyl)-4-(2-(ethyl amino)-2-oxoethyl)-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl)oxy)-N-(4-(hydroxydimethylsilyl)phenyl) pentanamide [Example 9]:

[00465] A solution of (S)-N-(4-bromophenyl)-5-((6-(4-chlorophenyl)-4-(2-(ethylamino)- 2-oxoethyl)-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl)oxy)pentanamide (250 mg, 0.38 mmol), 1,2-diethoxy-1,1,2,2-tetramethyldisilane (159mg, 0.77 mmol), 2-(di-tert- butylphosphino)biphenyl (50 mg, 0.167 mmol, 43.94 mol%), palladium dichloride (50 mg, 0.282 mmol, 74 mol%) and DIPEA (299 mg, 2.32 mmol) in NMP (2.5 mL) was heated to 60°C for 2 h. The reaction mixture was partitioned between DCM (15 mL) and H₂O (15 mL) and separated. The aqueous layer was extracted with DCM (3 X 2.5 mL) and the combined organic fractions were washed with 5% aqueous acetic acid (7.5 mL) and H₂O (7.5 mL). The combined organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo resulting in a crude product which was purified by column chromatography on silica gel (100- 200 mesh) eluting with 1% methanol in DCM followed by preparative HPLC to afford 38.2 mg (15% yield) of the title compound as a white solid. ¹H NMR (400 MHz, DMSO-d₆): į = 9.88 (s, 1H), 8.21 (t, J = 5.4 Hz, 1H), 7.76 (d, J = 9.0 Hz, 1H), 7.60– 7.33 (m, 9H), 6.86 (d, J = 2.8 Hz, 1H), 5.78 (s, 1H), 4.47 (dd, J = 8.3, 5.8 Hz, 1H), 4.06 (q, J = 5.5 Hz, 1H), 3.99 (dt, J = 10.1, 5.2 Hz, 1H), 3.28– 3.03 (m, 4H), 2.52 (s, 3H), 2.39– 2.31 (m, 2H), 1.76– 1.67 (m, 4H), 1.06 (t, J = 7.2 Hz, 3H), 0.21 (s, 6H); MS (ES⁺): m/z = 659.30, 661.20 [M+H]⁺ ; LCMS: t_R = 2.23 min (monomer) and 3.61min (dimer).

[00466] (S)-N-(4-bromophenyl)-5-((6-(4-chlorophenyl)-4-(2-(ethyl amino)-2- oxoethyl)-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl)oxy)pentanamide (7b):

[00467]

[00468] A solution of (S)-5-((6-(4-chlorophenyl)-4-(2-(ethylamino)-2-oxoethyl)-1- methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl)oxy)pentanoic acid (200 mg, 0.39 mmol) in DCM (10 mL) was charged with EDCI (112 mg, 0.58 mmol), DMAP (95 mg, 0.78 mmol), and stirred at room temperature for 10 minutes. 4-Bromo aniline (67 mg, 0.39 mmol) was added to the reaction mixture and the resulting solution was stirred at room temperature for 3 h. The reaction mixture was partitioned between DCM (15 mL) and H₂O (15 mL) and separated. The aqueous layer was extracted with DCM (3 X 15 mL) and the combined organic fractions were washed with dil. acetic acid (2 X 25 mL) and brine (2 X 25 mL) and dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to obtain 260 mg of the crude product. The crude material was used in the next step without further purification. MS (ES⁺): m/z = 663.30, 665.05 [M+H] ⁺; LCMS: t_R = 2.61 min.

[00469] (S)-5-((6-(4-Chlorophenyl)-4-(2-(ethylamino)-2-oxoethyl)-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl)oxy)pentanoic acid (6):

[00470] A solution of (S)-ethyl 5-((6-(4-chlorophenyl)-4-(2-(ethylamino)-2-oxoethyl)-1- methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8- yl)oxy)pentanoate (640 mg, 1.1 mmol) in mixture of 1:1 ethanol and H₂O (20 mL) was charged with sodium hydroxide (237 mg, 5.9 mmol) and stirred at room temperature for 3 h. The reaction mixture was evaporated under reduced pressure to obtain a residue which was dissolved in H₂O (20 mL) and charged with aq. HCl (1.2 mL) to adjust the pH to ~ 1-2. The reaction mixture was partitioned between ethyl acetate (100 mL) and H₂O (100 mL) and separated. The aqueous layer was extracted with ethyl acetate (3 X 50 mL) and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to afford 546 mg (90 % yield) of the crude product as a white solid. The crude material was used in the next step without further purification. MS (ES⁺): m/z = 510.20, 512.25 [M+H] ⁺; LCMS: t_R = 1.91 min.

[00471] (S)-Ethyl 5-((6-(4-chlorophenyl)-4-(2-(ethylamino)-2-oxoethyl)-1-methyl- 4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8- yl)oxy)pentanoate (5):

[00472] A solution of (S)-2-(6-(4-chlorophenyl)-8-hydroxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (550 mg, 1.34 mmol) in acetonitrile (11 mL) was charged with potassium carbonate (546 mg, 4.02 mmol), ethyl 5- bromopentanoate (281 mg, 1.34 mmol) and stirred at 90°C for 15 h. The reaction mixture was evaporated under reduced pressure to obtain a residue which was dissolved in DCM (100 mL) then partitioned between DCM (100 mL) and H₂O (100 mL) and separated. The aqueous layer was extracted with DCM (3 X 50 mL) and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to afford 651 mg (90 % yield) of the title compound as a white solid. MS (ES⁺): m/z = 538.20, 540.25 [M+H] ⁺; LCMS: t_R = 2.43 min. EXAMPLES 10-13:

[00473] Monomers were synthesized according to the procedures described below. Scheme 3: Synthesis of Examples 10, 11, 12, and 13

[00474] (S)-2-(6-(4-Chlorophenyl)-8-(3-(hydroxydimethylsilyl)phenyl)-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide [Example 10]:

[00475] A solution of (S)-2-(8-(3-bromophenyl)-6-(4-chlorophenyl)-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (400mg, 0.72 mmol), 1,2- diethoxy-1,1,2,2-tetramethyldisilane (225 mg, 1.0 mmol), 2-(di-tert-butylphosphino)biphenyl (40 mg, 0.134 mmol, 18 mol%), palladium dichloride (40 mg, 0.225 mmol, 31 mol%) and DIPEA (564 mg, 4.3 mmol) in NMP (4 mL) were heated to 50°C for 2 h. The reaction mixture was partitioned between DCM (15 mL) and H₂O (15 mL) and separated. The aqueous layer was extracted with DCM (3 X 100 mL) and the combined organic fractions were washed with 5% aqueous acetic acid (3 X 25 mL) and H₂O (3 X 25 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo resulting in a crude product which was purified by column chromatography on silica gel (100-200 mesh) eluting with 10% ethyl acetate in n-hexane followed by preparative HPLC to obtain 198 mg (50% yield) of the title compound as an off white solid. ¹H NMR (400 MHz, DMSO-d₆): į = 8.23 (t, J = 5.5 Hz, 1H), 8.07 (dd, J = 8.5, 2.2 Hz, 1H), 7.94 (s, 1H), 7.82– 7.78 (m, 1), 7.70– 7.37 (m, 8H), 5.98 (s, 1H), 4.56 (dd, J = 8.1, 5.9 Hz, 1H), 3.35– 3.28 (m, 2H), 3.28– 3.06 (m, 2H), 2.59 (s, 3H), 1.12– 1.01 (m, 3H), 0.26 (s, 6H); MS (ES⁺): m/z = 544.20, 546.15 [M+H] ⁺; LCMS: t_R = 2.31 min.

[00476] (S)-2-(8-(3-Bromophenyl)-6-(4-chlorophenyl)-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N- ethylacetamide [Example 11]:

[00477] A suspension of (S)-6-(4-chlorophenyl)-4-(2-(ethyl amino)-2-oxoethyl)-1- methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl trifluoromethanesulfonate (500 mg, 0.92 mmol), 3-bromophenylboronic acid (220 mg, 1.1 mmol), tetrakis (100 mg, 0.086 mmol, 9.4 mol%) and sodium carbonate (291 mg, 2.7 mmol) in 1,4-dioxane (10 mL), H₂O (2 mL) and reaction mixture was stirred at 80°C for 40 min in microwave. The reaction mixture was filtered through a pad of celite and the filtrate was diluted with DCM (20 mL) and the organic layer was concentrated in vacuo resulting in a crude product which was purified by column chromatography on silica gel (100-200 mesh) eluting with 2% methanol in DCM to afford 405 mg (80 % yield) of the title compound as a white solid. ¹H NMR (400 MHz, DMSO-d₆): į = 8.23 (t, J = 5.5 Hz, 1H), 8.12 (dd, J = 8.6, 2.2 Hz, 1H), 7.99– 7.90 (m, 2H), 7.75– 7.66 (m, 2H), 7.65– 7.38 (m, 5H), 4.55 (dd, J = 8.1, 6.0 Hz, 1H), 3.38 (m, J = 7.0 Hz, 2H), 3.29– 3.02 (m, 3H), 2.60 (s, 3H), 1.07 (dd, J = 8.3, 6.9 Hz, 3H); MS (ES⁺): m/z = 548.00, 550.25 [M+H] ⁺; LCMS: t_R = 2.83 min.

[00478] (S)-2-(6-(4-Chlorophenyl)-8-(4-(hydroxydimethylsilyl)phenyl)-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide [Example 12]:

[00479] A solution of (S)-2-(8-(4-bromophenyl)-6-(4-chlorophenyl)-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (400 mg, 0.72 mmol), 1,2- diethoxy-1,1,2,2-tetramethyldisilane (225 mg, 1.0 mmol), 2-(di-tert-butylphosphino)biphenyl (40 mg, 0.134 mmol, 18 mol%), palladium dichloride (40 mg, 0.225 mmol, 31 mol%) and DIPEA (564 mg, 4.3 mmol) in NMP (4 mL) was heated at 50°C for 2 h. The reaction mixture was partitioned between DCM (15 mL) and H₂O (15 mL) and separated. The aqueous layer was extracted with DCM (3 X 100 mL) and the combined organic fractions were washed with 5 % aqueous acetic acid (3 X 25 mL), H₂O (3 X 25 mL), and the combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo resulting in a crude product which was purified by column chromatography on silica gel (100-200 mesh) eluting with 10% ethyl acetate in n-hexane followed by preparative HPLC to obtain 39 mg (10 % yield) of the title compound as an off white solid. ¹H NMR (400 MHz, DMSO-d₆): į = 8.23 (dd, J = 8.5 Hz, 1H), 8.07 (dd, J = 8.5, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.71– 7.44 (m, 8H), 6.54 (s, 1H), 5.98 (s, 1H), 4.56 (dd, J = 8.2, 5.9 Hz, 1H), 3.10– 3.40 (m, 4H), 2.59 (s, 3H), 1.07 (t, J = 7.2 Hz, 3H), 0.21 (s, 6H); MS (ES⁺): m/z = 544.15, 546.15 [M+H]⁺; LCMS: t_R = 2.28 min.

[00480] (S)-2-(8-(4-Bromophenyl)-6-(4-chlorophenyl)-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide [Example 13]:

[00481] A suspension of (S)-6-(4-chlorophenyl)-4-(2-(ethyl amino)-2-oxoethyl)-1- methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl trifluoromethanesulfonate (500 mg, 0.92 mmol), 4-bromophenyl)boronic acid (220 mg, 1.1 mmol), tetrakis (100 mg, 0.086 mmol, 9.4 mol%) and sodium carbonate (291 mg, 2.7 mmol) in 1,4-dioxane (10 mL), H₂O (2 mL) and reaction mixture was stirred at 80° for 40 min [Biotage microwave reactor, 400W]. The reaction mixture was filtered through a pad of celite and the filtrate solution was diluted with DCM (20 mL) and the organic layer was concentrated in vacuo resulting in a crude product which was purified by column chromatography on silica gel (100-200 mesh) eluting with 2% methanol in DCM to afford 420 mg (83 % yield) of the title compound as a white solid. ¹H NMR (400 MHz, DMSO-d₆): į 8.23 (t, J = 5.6 Hz, 1H), 8.11 (dd, J = 8.5, 2.3 Hz, 1H), 7.95 (d, J = 8.5 Hz, 1H), 7.66 (dd, J = 7.7, 1.9 Hz, 4H), 7.58– 7.45 (m, 4H), 4.54 (dd, J = 8.2, 5.9 Hz, 1H), 3.34– 3.03 (m, 4H), 2.60 (d, J = 3.6 Hz, 3H), 1.13– 1.02 (m, 3H); MS (ES⁺): m/z = 548.00, 549.95 [M+H] ⁺; LCMS: t_R = 2.81 min. EXAMPLE 14:

[00482] Example 14 was synthesized according to the procedure described below.

Scheme 4: Synthesis of Example 14

[00483] (S)-N-ethyl-2-(6-(4-(((hydroxydimethylsilyl)methyl)thio)phenyl)-8-methoxy- 1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetamide [Example 14]:

[00484] A solution of ((S)-N-ethyl-2-(6-(4-mercaptophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetamide (300 mg, 0.71 mmol) in DCM (10 mL), was charged with (chloromethyl)dimethylsilanol (160 mg, 1.0 mmol) and DIPEA (0.24 mL, 1.4 mmol) and stirred at 0°C for 1 h. Reaction mixture was partitioned between DCM (10 mL) and H₂O (10 mL) and separated. The aqueous layer was extracted with DCM (3 X 10 mL) and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered and

concentrated in vacuo resulting in a crude product. The crude product was purified by preparative HPLC to afford 20 mg (5.5 % yield) of the title compound as a white solid. ¹H NMR (400 MHz, DMSO-d₆): į = 8.21 (t, J = 5.5 Hz, 1H), 7.78 (d, J = 9.0 Hz, 1H), 7.46– 7.33 (m, 3H), 7.33– 7.26 (m, 1H), 6.86 (d, J = 2.9 Hz, 1H), 5.94 (d, J = 1.1 Hz, 1H), 4.44 (dd, J = 8.4, 5.7 Hz, 1H), 3.79 (s, 3H), 3.28– 3.02 (m, 4H), 2.53 (s, 3H), 2.21 (d, J = 1.7 Hz, 1H), 1.06 (td, J = 7.2, 0.9 Hz, 3H), 0.14 (d, J = 0.9 Hz, 6H); MS (ES⁺): m/z = 510.40 [M+H]⁺; LCMS: t_R = 2.06 min.

[00485] ((S)-N-ethyl-2-(6-(4-mercaptophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetamide (11):

[00486] A suspension of (S)-2-(6-(4-bromophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (500 mg, 1.1 mmol), potassium thioacetate (251 mg, 2.2 mmol),

tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (100 mg, 0.096 mmol, 8.78 mol%), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (20 mg, 0.034 mmol, 3.09 mol%) and DIPEA (100 mg, 20 % w/w) in 1,4-dioxane (10 mL) in sealed tube was heated to 140°C for 40 min [Biotage microwave reactor, 400W]. The reaction mixture was diluted with methanol (10 mL) and KOH (123 mg, 2.2 mmol) and stirred at room temperature for 1 h. The solvent was evaporated in vacuo and the residue was acidified with acetic acid (5 mL) and partitioned between DCM (10 mL) and H₂O (10 mL) and separated. The aqueous layer was extracted with DCM (3 x 10 mL) and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to afford 600 mg of crude title compound as oil which was used in the next step without further purification. MS (ES⁺): m/z = 422.25 [M+H]⁺; LCMS: t_R= 2.02 min. EXAMPLE 15:

[00487] Example 15 was synthesized according to the procedure described below.

Scheme 5: Synthesis of Example 15

[00488] ((S)-2-(6-(4-Chlorophenyl)-8-((hydroxydimethylsilyl)methoxy)-1-methyl- 4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide [Example 15]:

[00489] A solution of (S)-2-(6-(4-chlorophenyl)-8-hydroxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (400 mg, 0.97 mmol) in acetonitrile (20 mL) was charged with potassium carbonate (401 mg, 2.9 mmol),

(chloromethyl)dimethylsilanol (164 mg, 1.0 mmol) and stirred at 90°C for 15 h. The reaction mixture was then evaporated under reduced pressure to obtain a residue which was dissolved in DCM (100 mL) The reaction mixture was partitioned between DCM (100 mL) and H₂O (100 mL) and separated. The aqueous layer was extracted with DCM (3 X 50 mL) and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo resulting in a crude product. The crude product was purified by prep HPLC to afford 100 mg (20% yield) of title compound as white solid. ¹H NMR (400 MHz, CD₃OD): į = 7.85 (d, J = 9.0 Hz, 1H), 7.51– 7.31 (m, 4H), 7.38– 7.31 (m, 1H), 6.81 (d, J = 3.0 Hz, 3H), 4.58 (m, 1H), 3.64– 3.44 (m, 2H), 3.37 - 3.15 (m, 4H), 2.55 (s, 3H), 1.08 (t, J = 7.2 Hz, 3H), 0.21 (d, J = 6.6 Hz, 3H), 0.15 (d, J = 1.1 Hz, 3H). MS (ES⁺): m/z = 498.35, 500.25 [M+ H]⁺; LCMS: t_R = 2.00 min. EXAMPLES 16-23:

[00490] Monomers were synthesized according to the procedures described below.

[00491] (4-(5-(3,5-Dimethylisoxazol-4-yl)-2- methylphenylsulfonamido)phenyl)boronic acid [Example 16]:

[00492] A solution of 5-(3,5-dimethylisoxazol-4-yl)-2-methyl-N-(4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl)benzenesulfonamide (200 mg, 0.42 mmol) in conc. HCl (20 mL) was heated and stirred at 90 °C for 12 h. The reaction mixture was concentrated in vacuo resulting in crude product which was neutralized by sodium bicarbonate solution (~20 mL) and product was extracted with ethyl acetate (3 X 20 mL). The crude product was purified by preparative HPLC purification to afford 10 mg (6.0 % Yield) of the title compound as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): į = 10.61 (s, 1H), 7.76 (s, 1H), 7.61 (d, J = 8.4 Hz, 2H), 7.53 - 7.46 (m, 2H), 7.06 (d, J = 8.0 Hz, 2H), 2.63 (s, 3H), 2.30 (s, 3H), 2.12 (s, 3H); MS (ES⁺): m/z = 387.25, 388.30, 389.15, 390.30 [M+H] ⁺; LCMS: t_R = 2.13 min.

[00493] 5-(3,5-dimethylisoxazol-4-yl)-2-methyl-N-(4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)benzene sulfonamide

[00494] A solution of 5-(3,5-dimethylisoxazol-4-yl)-2-methylbenzene-1-sulfonyl chloride B (200 mg, 0.70 mmol) in pyridine (10 mL) was charged with 4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)aniline (153.6 mg, 0.70 mmol) and stirred at room temperature for 4 h. The reaction mixture was evaporated under reduced pressure to obtain a residue which was dissolved in DCM (50 mL). The reaction mixture was partitioned between DCM (50 mL) and H₂O (2 X 150 mL) and separated. The aqueous layer was extracted with DCM (3 x 50 mL) and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo resulting in 210 mg (42.68 % yield) of crude product as a yellow solid. The crude material was used in the next step without further purification. MS (ES⁺): m/z = 469.37, 470.50, 471.65, 472.45 [M+H]⁺; LCMS: t_R = 3.25 min.

[00495] (2-(3-(3,5-Dimethylisoxazol-4-yl)phenylsulfonamido)methyl)phenyl)boronic acid [Example 17]:

[00496] A solution of 5-(3,5-dimethylisoxazol-4-yl)-2-methylbenzene-1-sulfonyl chloride B (100 mg, 0.70 mmol) in pyridine (10 mL) was charged with 2-(amino

methyl)phenyl) boronic acid (52.1 mg, 0.35 mmol) and stirred at room temperature for 2 h. The reaction mixture was evaporated under reduced pressure to obtain a residue which was dissolved in DCM (50 mL). The reaction mixture was partitioned between DCM (50 mL) and H₂O (2 X 150 mL) and separated. The aqueous layer was extracted with DCM (3 x 50 mL) and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo resulting in a crude compound which was purified by preparative HPLC resulted in 15 mg (14.5 % yield) of the title compound as a white solid. ¹H NMR (400 MHz, DMSO-d₆): į = 8.18 - 8.06 (m, 3H), 7.71 (s, 1H), 7.57– 7.41 (m, 3H), 7.35 -7.20 (m, 2H), 7.19 -7.15 (m, 1H), 4.23 (s, 2H), 2.61 (s, 3H), 2.39 (s, 3H), 2.20 (s, 3H); MS (ES⁺): m/z = 400.95, 401.25, 402.30, 403.50, 404.30 [M+H]⁺; LCMS: t_R = 2.35 min.

[00497] (2-(Amino methyl) phenyl) boronic acid:

[00498] A solution of (2-cyanophenyl) boronic acid (300 mg, 2.0 mmol) in 20 mL of methanol was charged with Raney nickel (100 mg, 10 % w/w). The reaction was stirred at room temperature for 4 h under hydrogen pressure ~ 50 psi. Reaction mixture was filtered through pad of Celite and the solution was concentrated in vacuo resulting in 150 mg (48.7 % yield) of title compound as a white solid. MS (ES+): m/z = 152.20, 153.40, 154.35, 155.65 [M+H]⁺; LCMS: t_R = 0.76 min.

[00499] (4-(5-(3,5-dimethylisoxazol-4-yl)-2- ethylphenylsulfonamido)methyl)phenyl)boronic acid [Example 18]:

[00500] A solution of 5-(3,5-dimethylisoxazol-4-yl)-2-methylbenzene-1-sulfonyl chloride B (100 mg, 0.70 mmol) in pyridine (10 ml) was charged with 4-(amino methyl) phenyl) boronic acid (52.1 mg, 0.35 mmol) and stirred at room temperature for 2 h. The reaction mixture was evaporated under reduced pressure to obtain a residue which was dissolved in DCM (50 mL). The reaction mixture was partitioned between DCM (50 mL) and H₂O (2 X 150 mL) and separated. The aqueous layer was extracted with DCM (2 x 50 mL) and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo resulting in a crude compound which was purified by preparative HPLC to obtain 20 mg (14.28 % yield) of the title compound as an off white solid. ¹H NMR (400 MHz, DMSO- d₆): į = 8.24 (t, J = 7.2 Hz, 1H), 8.06 (s, 2H), 7.56– 7.41 (m, 5H), 6.50 (br. s, 2H), 4.23 (d, J = 6.2 Hz, 2H), 2.61 (s, 3H), 2.39 (s, 3H), 2.20 (s, 3H); MS (ES⁺): m/z = 400.95

,401.25,402.25,403.50.404.35[M+H]⁺; LCMS: t_R = 2.18 min.

[00501] 4-(Amino methyl) phenyl) boronic acid

[00502] A solution of (4-cyanophenyl) boronic acid (300 mg, 2.0 mmol) in 20 mL of methanol was charged with Raney nickel (100 mg, 10 % w/w). The reaction was stirred at room temperature for 4 h under hydrogen pressure (~ 50 psi.). Reaction mixture was filtered through pad of Celite and the solution was concentrated in vacuo resulting in 200mg (38.9% yield) of the title compound as a white solid. MS (ES+): m/z = 152.25,153.20,154.35,155.50 [M+H]⁺; LCMS: t_R = 0.60 min.

[00503] (2-(5-(3,5-Dimethylisoxazol-4-yl)-2- methylphenylsulfonamido)phenyl)boronic acid [Example 19]:

[00504] A solution of 5-(3,5-dimethylisoxazol-4-yl)-2-methylbenzene-1-sulfonyl chloride B (416 mg, 0.45 mmol) in pyridine (10 ml) was charged with 2-aminophenyl) boronic acid (200 mg, 1.45 mmol) and stirred at room temperature for 3 h The reaction mixture was evaporated under reduced pressure to obtain a residue which was dissolved in DCM (50 mL). The reaction mixture was partitioned between DCM (50 mL) and H₂O (2 X 150 mL) and separated. The aqueous layer was extracted with DCM (3 x 50 mL) and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo resulting in ,the crude product which was purified by preparative HPLC to obtain 25 mg (4.4 % yield) of the title compound as an off white solid. ¹H NMR (400 MHz, DMSO-d₆): į = 10.31 (s, 1H), 9.06 (s, 1H), 7.85– 7.70 (m, 2H), 7.58– 7.46 (m, 2H), 7.40– 7.23 (m, 2H), 6.99 (t, J = 7.3 Hz, 1H), 2.50 (s, 3H), 2.30 (s, 3H), 2.12 (s, 3H); MS (ES⁺): m/z = 386.85, 387.20, 388.50, 389.65 [M+H]⁺; LCMS: t_R = 2.51 min.

[00505] N-(3, 4-dihydroxybenzyl)-3-(3, 5-dimethylisoxazol-4-yl) benzene sulfonamide [Example 20]:

[00506] A solution of 5-(3,5-dimethylisoxazol-4-yl)-2-methylbenzene-1-sulfonyl chloride B (100 mg, 0.35 mmol) in pyridine (10 ml) was charged with 4-(amino

methyl)benzene-1,2-diol (48.1 mg, 0.35 mmol) and stirred at room temperature for 3.5 h The reaction mixture was evaporated under reduced pressure to obtain a residue which was dissolved in DCM (50 mL). The reaction mixture was partitioned between DCM (50 mL) and H₂O (2 X 150 mL) and separated. The aqueous layer was extracted with DCM (2 x 50 mL) and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo resulting the crude was purified by preparative HPLC to obtain 20 mg (14.7 % yield) of the title compound as an off white solid. ¹H NMR (400 MHz, DMSO- d₆): į = 8.8 (s, 1H), 8.73 (s, 1H), 8.23 (br. s, 1H), 7.70 (s, 1H), 7.53– 7.42 (m, 2H), 6.64– 6.44 (m, 3H), 4.03 (d, J = 6.0 Hz, 2H), 2.61 (s, 3H), 2.38 (s, 3H), 2.20 (s, 3H); MS (ES⁺): m/z = 388.95

[M+H]⁺;LCMS: t_R = 2.13 min.

[00507] (3-(3-(3,5-Dimethylisoxazol-4-yl)phenylsulfonamido)methyl)phenyl)boronic acid [Example 21]:

[00508] A solution of 5-(3,5-dimethylisoxazol-4-yl)-2-methylbenzene-1-sulfonyl chloride B (188 mg, 0.66 mmol) in pyridine (10 ml) was charged with 3-(amino methyl) phenyl) boronic acid (100 mg, 0.66 mmol) and stirred at room temperature for 8 h. The reaction mixture was evaporated under reduced pressure to obtain a residue which was dissolved in DCM (50 mL). The reaction mixture was partitioned between DCM (50 mL) and H₂O (2 X 150 mL) and separated. The aqueous layer was extracted with DCM (3 x 50 mL) and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo resulting in a the crude compound which was purified by preparative HPLC to obtain 26 mg (10 % yield) of the title compound as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): į = 8.32 (t, J = 6.2 Hz, 1H), 8.02 (s, 1H), 7.71– 7.58 (m, 2H), 7.52– 7.39 (m, 2H), 7.26– 7.14 (m, 2H), 4.07 (d, J = 6.1 Hz, 2H), 2.60 (s, 3H), 2.39 (s, 3H), 2.20 (s, 3H); MS (ES⁺): m/z =

401.25,402.35,403.25,404.85,405.25 [M+H]⁺; LCMS: t_R = 2.2 min.

[00509] N-(3,4-dihydroxyphenyl)-5-(3,5-dimethylisoxazol-4-yl)-2- methylbenzenesulfonamide [Example 22]:

[00510] To a stirred solution of N-(3,4-dimethoxyphenyl)-5-(3,5-dimethylisoxazol-4-yl)- 2-methylbenzenesulfonamide (190 mg, 0.47 mmol) in DCM (20 mL) was added boron tri bromide (472 mg, 1.8 mmol) at 0°C and reaction mixture was stirred at room temperature for 3 h. The reaction mixture was quenched using cold H₂O (10 mL) and solids obtained were filtered to get crude product. The crude material was purified by preparative HPLC to obtain 10 mg (5.8 % yield) of the title compound as a grey solid. ¹H NMR (400 MHz, DMSO- d₆): į = 9.83 (s, 1H), 8.98 (s, 1H), 8.69 (s, 1H), 7.58 (s, 1H), 7.47– 7.44 (m, 2H), 6.54– 6.51 (m, 2H), 6.32 (d, J = 8.4 HZ, 1H) 2.60 (s, 3H), 2.26 (s, 3H), 2.09 (s,3H); MS (ES⁺): m/z = 375.05 [M+H]⁺; LCMS: t_R = 2.0 min.

[00511] N-(3,4-dimethoxyphenyl)-5-(3,5-dimethylisoxazol-4-yl)-2- methylbenzenesulfonamide

[00512] A solution of 5-(3,5-dimethylisoxazol-4-yl)-2-methylbenzene-1-sulfonyl chloride B (200 mg, 0.70 mmol) in DCM (10 mL) was charged with 3,4-dimethoxyaniline (107 mg, 0.70 mmol), triethyl amine (212 mg, 2.1 mmol) and stirred at room temperature for 5 h The reaction mixture was evaporated under reduced pressure to obtain a residue which was dissolved in DCM (50 mL). The reaction mixture was partitioned between DCM (50 mL) and H₂O (2 X 150 mL) and separated. The aqueous layer was extracted with DCM (2 x 50 mL) and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo resulting in a up, obtained 197 mg (70 % yield) of the title compound as a white solid. The crude was used in the next step without further purification.

[00513] N-(2, 3-Dihydroxybenzyl)-5-(3, 5-dimethylisoxazol-4-yl)-2- methylbenzenesulfonamide [Example 23]:

[00514] A solution of 5-(3,5-dimethylisoxazol-4-yl)-2-methylbenzene-1-sulfonyl chloride B (100 mg, 0.35 mmol) in pyridine (10 ml) was charged with 3-(amino

methyl)benzene-1,2-diol (48 mg, 0.35 mmol) and stirred at room temperature for 4 h The reaction mixture was evaporated under reduced pressure to obtain a residue which was dissolved in DCM (50 mL). The reaction mixture was partitioned between DCM (50 mL) and H₂O (2 X 150 mL) and separated. The aqueous layer was extracted with DCM (3 x 50 mL) and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo resulting in a crude product was purified by preparative HPLC to obtain 20mg (14.7 % yield) of the title compound as a white solid. ¹H NMR (400 MHz, DMSO- d₆): į = 9.22 (s, 1H), 8.34 (s, 1H), 8.01 (q, J = 7.8, 7.0 Hz, 1H), 7.70 (d, J = 2.2 Hz, 1H), 7.53– 7.42 (m, 2H), 6.64– 6.44 (m, 3H), 4.03 (d, J = 6.0 Hz, 2H), 2.61 (s, 3H), 2.38 (s, 3H), 2.20 (s, 3H); MS (ES⁺): m/z = 389.65 [M+H]⁺; LCMS: t_R = 2.2 min. EXAMPLES 24 and 25:

[00515] Monomers were synthesized according to the procedures described below. Scheme 7: Synthesis of Examples 24 and 25

[00516] (4-((4-((5-(3, 5-Dimethylisoxazol-4-yl)-2-methylphenyl) sulfonyl) piperazin- 1-yl) methyl) phenyl) boronic acid [Example 24]:

[00517] A solution of 3, 5-dimethyl-4-(4-methyl-3-(piperazin-1-ylsulfonyl) phenyl) isoxazole (100 mg, 0.29 mmol) in acetonitrile (3 mL) was charged with sodium bi carbonate (60 mg, 0.72 mmol), (4-(bromomethyl) phenyl) boronic acid (63 mg, 0.29 mmol) and stirred at 90°C for 15 h. The reaction mixture was evaporated under reduced pressure to obtain a residue which was dissolved in ethyl acetate (50 mL). The reaction mixture was partitioned between ethyl acetate (50 mL) and H₂O (100 mL) and separated. The aqueous layer was extracted with ethyl acetate (2 X 50 mL)) and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo resulting in a crude product which was purified by column chromatography on silica gel (100-200 mesh) eluting with 2% methanol in DCM followed by preparative HPLC to obtain 28 mg (20.0 % yield) of the title compound as a white solid. ¹H NMR (400 MHz, DMSO- d₆): į 7.84 (s, 1H), 7.73– 7.71 (m, 2H), 7.56– 7.56 (m, 2H), 7.48– 7.46 (m, 2H), 4.36 (s, 2H), 3.48– 3.36(m, 4H), 2.66 (s, 3H), 2.42 (s, 3H), 2.47– 2.25 (m, 3H); MS (ES⁺): m/z = 470.05,471.65,472.35,473.45,474.85 [M+H] ⁺; LCMS: t_R = 1.79 min.

[00518] (3-((4-((5-(3, 5-Dimethylisoxazol-4-yl)-2-methylphenyl) sulphonyl) piperazin-1-yl) methyl) phenyl) boronic acid [Example 25]:

[00519] A solution of 3, 5-dimethyl-4-(4-methyl-3-(piperazin-1-ylsulfonyl) phenyl) isoxazole (100 mg, 0.29 mmol) in acetonitrile (3 mL) was charged with sodium bi carbonate (60 mg, 0.72 mmol), (3-(bromomethyl) phenyl) boronic acid (63 mg, 0.29 mmol) and stirred at 90 °C for 15 h. The reaction mixture was then evaporated under reduced pressure to obtain a residue which was re-dissolved in ethyl acetate (50 mL). The reaction mixture was partitioned between ethyl acetate (50 mL) and H₂O (100 mL) and separated. The aqueous layer was extracted with ethyl acetate (2 x 50 mL)) and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo resulting in a crude product which was purified by column chromatography on silica gel (100-200 mesh) eluting with 2% methanol in DCM followed by preparative HPLC to obtain 42 mg (30 % yield) of the title compound as a white solid. ¹H NMR (400 MHz, DMSO- d₆): į = 7.99 (s, 1H), 7.76– 7.51 (m, 3H), 7.33– 7.20 (m, 2H), 3.59– 3.23 (m, 4H), 3.21– 3.01 (m, 4H),, 2.59 (s, 3H), 2.47– 2.33 (m, 6H), 2.22 (s, 3H); MS (ES⁺): m/z = 470.10, 471.20, 472.50, 473.25 [M+H] ⁺; LCMS: t_R = 1.80 min.

[00520] 3, 5-Dimethyl-4-(4-methyl-3-(piperazin-1-ylsulfonyl) phenyl) isoxazole (16):

[00521] A stirred solution of 4-(3-((4-(tert-butoxymethyl) piperazin-1-yl) sulphonyl)-4- methylphenyl)-3,5-dimethylisoxazole (1) (700 mg, 1.55 mmol) in DCM (10 mL) was charged with 4.0 M solution of HCl in dioxane (3.5 mL) and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was concentrated in vacuo to obtain 431 mg (80 % yield) of crude product as an oil. The crude material was used in the next step without further purification.

[00522] 4-(3-((4-(tert-Butoxymethyl) piperazin-1-yl) sulphonyl)-4-methylphenyl)- 3,5-dimethylisoxazole (15):

[00523] A solution of 5-(3,5-dimethylisoxazol-4-yl)-2-methylbenzene-1-sulfonyl chloride B (500 mg, 1.75 mmol) in pyridine (5 mL) was charged with 1-(tert- butoxymethyl)piperazine (326 mg, 1.75 mmol) and stirred at rt for 2 h. The pH was adjusted to ~1-2 using 1N HCl and product was extracted using ethyl acetate (3 X 15 mL). The reaction mixture was concentrated in vacuo resulting in a crude product which was purified by column chromatography on silica gel to obtain 711 mg (90 % yield) of the title compound as a white solid. The crude material was used in the next step without further purification. EXAMPLES 26 and 27:

[00524] Monomers were synthesized according to the procedures described below.

[00525] N-(2-(2-((4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetamido)ethyl)-3-(2-hydroxypropan-2- yl)benzamide [Example 26]:

[00526] A solution of 3-(2-hydroxypropan-2-yl)benzoic acid (43 mg, 0.24 mmol) in DCM (10 mL) was charged with EDCI (64 mg, 0.33 mmol), HOBt (44 mg, 0.33 mmol), DMAP (40 mg, 0.33 mmol), and stirred at room temperature for 10 minutes. The mixture was charged with N-(2-aminoethyl)-2-((4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetamide (19) (100 mg, 0.22 mmol) and stirred at room temperature for 6 h. The reaction mixture was partitioned between DCM (15 mL) and H₂O (15 mL) and separated. The aqueous layer was extracted with DCM (3 X 15 mL) and the combined organic fractions were washed with dilute acetic acid (2 X 25ml) and brine (2 X 25ml) and dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to obtain 35 mg (25.5 % yield) of the title compound as a white solid. ¹H NMR (400 MHz, DMSO-d₆): į = 8.51– 8.40 (m, 2H), 7.95 (s, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.56 - 7.30 (m, 6H), 6.83 (d, J = 2.4 Hz, 1H), 5.10 (s, 1H), 4.49 (dd, J = 8.3, 5.5 Hz, 1H), 3.79 (s, 3H), 3.37-3.20 (m, 4H), 3.17 (dd, J = 14.6, 5.4 Hz, 1H), 2.53 (s, 3H), 1.42 (s, 6H), 1.23 (s, 1H); MS (ES⁺): m/z = 601.15, 603.35 [M+H] ⁺; LCMS: t_R = 2.0 min.

[00527] N-(4-(2-((4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetamido)butyl)-3-(2-hydroxypropan-2- yl)benzamide [Example 27]:

[00528] A solution of 3-(2-hydroxypropan-2-yl)benzoic acid (42 mg, 0.23 mmol) in DCM (10 mL) was charged with EDCI (60.1 mg, 0.31 mmol), HOBt (42.1 mg, 0.31 mmol), DMAP (37.8 mg, 0.31 mmol), and stirred at room temperature for 10 minutes. The reaction mixture was charged with N-(4-aminobutyl)-2-((4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl- 4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetamide (100mg, 0.21 mmol) and stirred at room temperature for 6 h. The reaction mixture was partitioned between DCM (15 mL) and H₂O (15 mL) and separated. The aqueous layer was extracted with DCM (3 X 15 mL) and the combined organic fractions were washed with dil. acetic acid (2 X 25 mL) and brine (2 X 25 mL) and dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo resulting in crude product which was purified by preparative HPLC to obtain 36 mg (27 % yield) of the title compound as a white solid. ¹H NMR (400 MHz, DMSO-d6): į = 8.42 (s, 1H), 8.24 (s, 1H), 7.88 (s, 1H), 7.75 (d, J = 9.1 Hz, 1H), 7.61 (dd, J = 14.0, 7.7 Hz, 2H), 7.51– 7.31 (m, 6H), 6.85 (s, 1H), 4.49 (t, J = 6.9 Hz, 1H), 3.76 (s, 3H), 3.31– 3.02 (m, 7H), 2.54 (s, 3H), 1.59– 1.42 (m, 4H), 1.39 (s, 6H); MS (ES⁺): m/z = 629.20, 631.35 [M+H] ⁺; LCMS: t_R = 2.0 min. EXAMPLES 28 and 29:

[00529] Monomers were synthesized according to the procedures described below. Scheme 9: Synthesis of Examples 28 and 29

[00530] (S)-N-ethyl-2-(8-methoxy-1-methyl-6-(4-((trimethylsilyl)ethynyl)phenyl)- 4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetamide (S)-N-ethyl-2-(6-(4- ethynylphenyl)-8-methoxy-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4- yl)acetamide [Example 28]:

[00531] A solution of (S)-2-(6-(4-bromophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (300 mg, 0.64 mmol) in dry DMF (10 mL) was charged with bis(triphenylphosphine)palladium(II) dichloride (60 mg, 0.08 mmol), triethyl amine (0.26 mL, 1.92 mmol), ethynyltrimethylsilane (0.27mL, 1.92mmol), and stirred at 60 ⁰C for 4 h. The reaction mixture was partitioned between ethyl acetate (15 mL) and H₂O (15 mL) and separated. The aqueous layer was extracted with ethyl acetate (3 X 15 mL) and the combined organic fractions were washed with brine (2 X 25ml) and dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo resulting in a crude product which was purified by preparative HPLC to to obtain 25mg (8.06 % yield ) of the title compound as a brown solid. ¹H NMR (400 MHz, DMSO-d₆): į = 8.23– 8.21 (m, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.51 - 7.48 (m, 4H), 7.37 (dd, J = 9.0, 3.0 Hz, 1H), 6.85 (d, J = 2.8 Hz, 1H), 4.36 (s, 1H), 3.26 - 3.18 (m, 1H), 3.14 - 3.05 (m, 3H), 2.53 (s, 3H), 1.06 (t, J = 7.4 Hz, 3H); MS (ES⁺): m/z = 486.20 [M+H] ⁺; LCMS: t_R = 2.81 min. [00532] (S)-N-ethyl-2-(6-(4-ethynylphenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetamide [Example 29]:

[00533] A solution of (S)-N-ethyl-2-(8-methoxy-1-methyl-6-(4- ((trimethylsilyl)ethynyl)phenyl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetamide (290 mg, 0.59 mmol) in methanol (10 mL) was charged with K₂CO₃ (247 mg, 1.79 mmol) and stirred at 0 ^oC for 2 h. The reaction mixture was concentrated in vacuo then the reaction mixture was partitioned between ethyl acetate (20 mL) and H₂O (10 mL) and separated. The aqueous layer was extracted with ethyl acetate (3 X 15 mL) and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo resulting in a crude product which was purified by preparative HPLC to obtain 30 mg (12.19 % yield ) of the title compound as a yellow solid. ¹H NMR (400 MHz, ACN-d): į = 7.56 (d, J = 9.2 Hz, 1H), 7.53 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 7.28 (dd, J = 9.0, 3.0 Hz, 1H), 6.89 (d, J = 3.2 Hz, 1H), 6.75 (br. s, 1H), 4.51 (t, J = 7.0 Hz, 1H), 3.77 (s, 3H), 3.31– 3.01 (m, 4H), 2.51 (s, 3H), 1.11 (t, J = 7.4 Hz, 3H), 0.23 (s, 9H); MS (ES⁺): m/z = 414.10 [M+H] ⁺; LCMS: t_R =1.98 min. EXAMPLE 30:

[00534] Example 30 was synthesized according to the procedure described below.

Scheme 10: Synthesis of Example 30

[00535] (S)-N-ethyl-2-(8-methoxy-6-(4-((2-methoxyethyl)thio)phenyl)-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetamide [Example 30]:

[00536] A solution of (S)-2-(6-(4-bromophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (100 mg, 0.220 mmol) in dioxane (3 mL) was charged with DIPEA (0.15 mL, 0.881 mmol),

tris(dibenzylideneacetone)dipalladium(0) (20 mg, 0.0354 mmol, 0.17 eq, 17.7mol%) , Xphos (20 mg, 0.0417 mmol, 0.20 eq, 18.95 mol%%) and resulting solution was stirred at 140°C for 30 min [Biotoage microwave reactor, 400W] The reaction mixture was concentrated in vacuo and the residue was partitioned between DCM (10 mL) and H₂O (5 mL) and separated. The aqueous layer was extracted with DCM (3 X 10 mL) and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo resulting in a crude product which was purified by column chromatography on silica gel (230-400 mesh), eluting with 3% methanol in chloroform to obtain 18 mg (17.14 % yield) of (S)-N-ethyl-2-(8-methoxy-6-(4-((2- methoxyethyl)thio)phenyl)-1-methyl-4H-benzo[f][1,2,4]triazolo [4,3-a][1,4]diazepin-4- yl)acetamide as a white solid. ¹H NMR (400 MHz, DMSO-d₆): į = 8.20 (br. s, 1H), 7.78 (d, J = 9.0 Hz, 1H), 7.47– 7.30 (m, 5H), 6.88 (s, 1H), 4.45 (dd, J = 8.4, 5.7 Hz, 1H), 3.80 (s, 3H), 3.53 (t, J = 6.4 Hz, 2H), 3.35 (s, 3H), 3.21– 3.02 (m, 6H), 2.53 (s, 3H), 1.06 (t, J = 7.2 Hz, 3H); MS (ES⁺): m/z = 479.59 [M+H]⁺; LCMS: t_R = 2.13 min. EXAMPLES 31-35:

[00537] Monomers were synthesized according to the procedures described below. Scheme 11: Synthesis of Examples 31 to 35

[00538] (4-((2-(2-(2-(2-((4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetamido)ethoxy)ethoxy)ethyl) carbamoyl)phenyl)boronic acid [Example 31]:

[00539]

[00540] A solution of 4-boronobenzoic acid (23.6 mg, 0.14 mmol) in 1:1 mixture of DCM: DMF (10 mL) were charged with EDCI (40 mg, 0.21 mmol), DMAP (34.7 mg, 0.28 mmol), and stirred at room temperature for 10 min. N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2- ((4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin- 4-yl)acetamide (75 mg, 0.14 mmol) was added to the reaction mixture. The resulting solution was stirred at room temperature for 15 h. The reaction mixture was partitioned between DCM (10 mL) and H₂O (10 mL) and separated. The aqueous layer was re-extracted with DCM (3 X 10 mL) and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo resulting in a crude compound which was purified by preparative HPLC to afford 10 mg (10.5% yield) of the title compound as a white solid.¹H NMR (400 MHz, DMSO-d₆): į = 8.50 (t, J = 5.6 Hz, 1H), 8.30 (t, J = 5.7 Hz, 1H), 8.07 (s, 1H), 7.87– 7.75 (m, 4H), 7.50 (q, J = 8.6 Hz, 3H), 7.38 (dd, J = 9.1, 2.9 Hz, 2H), 6.87 (d, J = 3.0 Hz, 1H), 4.49 (dd, J = 8.3, 5.7 Hz, 1H), 3.79 (s, 3H), 3.58– 3.34 (m, 10H), 3.34– 3.11 (m, 4H), 2.55 (s, 3H); MS (ES⁺): m/z = 673.95, 674.80, 675.85, 676.95, 677.85 [M+H]⁺; LCMS: t_R = 1.87 min.

[00541] 2-((4S)-8-(2-(2-aminoethoxy)ethoxy)-6-(4-chlorophenyl)-1-methyl-4H-N-(2- (2-(2-aminoethoxy)ethoxy)ethyl)-2-((4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetamide (21):

[00542] A solution of tert-butyl (2-(2-(2-(2-((4S)-6-(4-chlorophenyl)-8-methoxy-1- methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4- yl)acetamido)ethoxy)ethoxy)ethyl)carbamate (1.2 g, 0.52 mmol) in DCM (25 mL) was charged with TFA (3.6 mL) and stirred at room temperature for 12 h. The reaction mixture was then evaporated under reduced pressure to obtain a residue which was re-dissolved in DCM (10 mL) and powdered KOH was added to adjust pH ~ 8-9. The solution was filtered through a pad of Celite and the filtrate was concentrated in vacuo to obtain crude compound which was purified by column chromatography, eluting with 7 % methanol in chloroform to afford 0.35 g (35 % yield) of the title compound as a light yellow solid. MS (ES⁺): m/z = 548.95, 550.90 [M+Na]⁺; LCMS: t_R = 1.67 min.

[00543] tert-butyl (2-(2-(2-(2-((4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetamido)ethoxy)ethoxy)ethyl)carbamate (20):

[00544] A solution of 2-((4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetic acid (1 g, 2.5 mmol) in DCM (50 mL) were charged with EDCI (0.71 g, 3.0 mmol), DMAP (0.3 g, 3.7 mmol), and stirred at room temperature for 10 min. tert-butyl (2-(2-(2-aminoethoxy)ethoxy)ethyl)carbamate (0.62 g, 2.5 mmol) was added to the reaction mixture. The resulting solution was stirred at room temperature for 15 h. The reaction mixture was partitioned between DCM (10 mL) and H₂O (15 mL) and separated. The aqueous layer was extracted with DCM (3 X 20 mL) and the combined organic fractions were dried over anhydrous Na₂SO₄, concentrated in vacuo resulting in a crude compound which was purified by column chromatography, eluting with 4% methanol in chloroform to afford 1.2 g (75.9 % yield) of the title compound as an off white solid. MS (ES⁺): m/z = 627.30, 629.00 [M+H]⁺; LCMS: t_R = 2.37 min.

[00545] Examples 32 through 35 were synthesized in an analagous way to Example 31 above.

[00546] N-(1-((4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-2-oxo-6,9,12,15-tetraoxa-3- azaheptadecan-17-yl)-3,4-dihydroxybenzamide [Example 32]:

[00547] ¹H NMR (400 MHz, CD₃OD): į = 7.70 (d, J = 9.0 Hz, 1H), 7.55 (d, J = 8.4 Hz, 2H), 7.45– 7.35 (m, 3H), 7.30– 7.24 (m, 2H), 6.90 (d, J = 2.9 Hz, 1H), 6.77 (d, J = 8.2 Hz, 1H), 4.86 (s, 1H), 3.82 (s, 3H), 3.67– 3.22 (m, 22H), 2.63 (s, 3H); MS (ES⁺): m/z = 751.15, 753.20 [M+H] ⁺; LCMS: t_R = 1.99 min.

[00548] N-(1-((4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-2-oxo-6,9,12-trioxa-3-azatetradecan-14- yl)-2,3-dihydroxybenzamide [Example 33]:

[00549] A solution of 2, 3-dihydroxybenzoic acid (27 mg, 0.17 mmol) in DCM, (20 mL) were charged with EDCI (50 mg, 0.26 mmol), DMAP (25.6 mg, 0.21 mmol), and stirred at room temperature for 10 min. N-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-2-((4S)-6-(4- chlorophenyl)-8-methoxy-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4- yl)acetamide (100 mg, 0.17 mmol) was added to the reaction mixture. After work up and purification by preparative HPLC, 10 mg (8.1 % yield) of the title compound was obtained as a white solid. ¹H NMR (400 MHz, CD₃OD): į = 7.70 (d, J = 8.0 Hz, 1H ), 7.54 (d, J = 8.3 Hz, 1H), 7.40 (d, J = 8.3 Hz, 1H), 7.25– 7.35 (m, 2H), 7.20 (d, J = 8.0 Hz, 1H), 6.80– 6.90 (m, 2H), 6.60– 6.70 (m,1H), 4.76 (s, 1H), 3.82 (s, 3H), 3.68– 3.60 (m, 10H), 3.56 (t, J = 5.3 Hz, 2H), 3.42 (q, J = 5.0, 4.2 Hz, 2H), 3.31 (d, J = 3.5 Hz, 2H), 2.62 (s, 3H), 1.31 (d, J = 11.6 Hz, 4H); MS (ES⁺): m/z = 707.05, 709.20 [M+H] ⁺; LCMS: t_R = 2.14 min.

[00550] N-(2-(2-(2-(2-((4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetamido)ethoxy)ethoxy)ethyl)-3,4- dihydroxybenzamide [Example 34]:

[00551] A solution of 3, 4-dihydroxybenzoic acid (73 mg, 0.47 mmol) in DMF (5 mL) was charged with EDCI (54 mg, 0.28 mmol), DIPEA (49 mg, 0.38 mmol), HOBt (38 mg, 0.28 mmol) and stirred at rt for 10 min. N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2-((4S)-6-(4- chlorophenyl)-8-methoxy-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4- yl)acetamide (100 mg, 0.19 mmol) was added to the reaction mixture. The resulting solution was stirred at room temperature for 15 h. The reaction mixture was partitioned between DCM (25 mL) and H₂O (10 mL) and separated. The aqueous layer was re-extracted with DCM (3 X 10 mL) and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo resulting in a crude compound which was purified by preparative HPLC to afford 20 mg (16 % yield) of the title compound as an off white solid.¹H NMR (400 MHz, CD₃OD): į = 7.71 (d, J = 9.6 Hz, 1H), 7.55 (d, J = 8.4 Hz, 2H), 7.38 (dd, J = 10.8 Hz, 2.8 Hz, 3H), 7.24 (s, 1H), 7.19– 7.16 (m, 1H), 6.93 (d, J = 2.8 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 4.68 (dd, J = 8.0, 5.6 Hz, 1H), 3.83 (s, 3H), 3.65 - 3.59 (m, 8H), 3.53– 3.50 (m, 3H), 3.44– 3.39 (m, 3H), 2.70 (s, 3H); MS (ES⁺): m/z = 663.20, 665.25 [M+H] ⁺; LCMS: t_R = 2.38 min. [00552] N-(1-((4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-2-oxo-6,9,12-trioxa-3-azatetradecan-14- yl)-3,4-dihydroxybenzamide [Example 35]:

[00553] A solution of 3, 4-dihydroxybenzoic acid (67.5 mg, 0.43 mmol) in DMF (5 mL) was charged with EDCI (50 mg, 0.26 mmol), DIPEA (45.2 mg, 0.26 mmol), HOBt (35.5 mg, 0.26 mmol) and stirred at room temperature for 10 min. N-(1-((4S)-6-(4-chlorophenyl)-8- methoxy-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-2-oxo-6,9,12-trioxa-3- azatetradecan-14-yl)-3,4-dihydroxybenzamide (100 mg, 0.17 mmol) was added to the reaction mixture. After work up and purification by preparative HPLC, 10 mg (8 % yield) of the title compound was obtained as an off white solid. ¹H NMR (400 MHz, CD₃OD): į = 7.70 (dd, J = 8.8, 1.8 Hz, 1H), 7.54 (dd, J = 8.4, 1.5 Hz, 2H), 7.47– 7.32 (m, 3H), 7.26 (s, 1H), 7.22– 7.09 (m, 2H), 6.90 (s, 1H), 6.76 (dd, J = 8.3, 1.1 Hz, 1H), 4.66– 4.55 (m, 1H), 3.82 (s, 3H), 3.69– 3.60 (m, 12H), 3.58– 3.48 (m, 4H), 3.44– 3.38 (m, 2H), 2.63 (s, 3H); MS (ES⁺): m/z = 707.05, 709.25 [M+H] ⁺; LCMS: t_R = 1.98 min. EXAMPLES 36-43:

[00554] Monomers were synthesized according to the procedures described below. Scheme 12: Synthesis of Examples 36 to 43

[00555] (4-((2-(2-(((4S)-6-(4-chlorophenyl)-4-(2-(ethylamino)-2-oxoethyl)-1-methyl- 4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8- yl)oxy)ethoxy)ethyl)carbamoyl)phenyl)boronic acid [Example 36]:

[00556] A solution of N-(2-(2-(((4S)-6-(4-chlorophenyl)-4-(2-(ethylamino)-2-oxoethyl)- 1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl)oxy)ethoxy)ethyl)-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (120 mg, 0.16 mmol) in methanol (5 mL) and H₂O (3 mL) was charged with silica (300 mg) and KHF₂ (51 mg, 0.66 mmol) stirred for 3h reaction at room temperature, filtered the reaction mass and washed with 10 mL of ethyl acetate, separated two layer, organic layer dried over sodium sulfate, concentrated to get 90 mg crude product, purified by preparative HPLC to afford 10 mg (9 % yield) of the title compound as a white solid.¹H NMR (400 MHz, DMSO- d₆): į = 8.47 (t, J = 5.6 Hz, 1H), 8.19 (t, J = 5.6 Hz, 1H), 7.85– 7.69 (m, 3H), 7.69– 7.54 (m, 2H), 7.52– 7.42 (m, 3H), 7.36 (dd, J = 9.0, 3.0 Hz, 1H), 6.86 (d, J = 2.9 Hz, 1H), 4.47 (dd, J = 8.2, 5.8 Hz, 1H), 4.22– 4.03 (m, 2H), 3.81– 3.69 (m, 3H), 3.56 (t, J = 6.0 Hz, 2H), 3.40 (q, J = 6.4, 6.0 Hz, 2H), 3.09 - 2.85 (m, 4H), 2.53 (s, 3H), 1.08– 1.00 (m, 3H); MS (ES⁺): m/z = 645.00, 647.05 [M+H] ⁺; LCMS: t_R = 1.80 min.

[00557] N-(2-(2-(((4S)-6-(4-chlorophenyl)-4-(2-(ethylamino)-2-oxoethyl)-1-methyl- 4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl)oxy)ethoxy)ethyl)-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

[00558] A solution of 2-((4S)-6-(4-chlorophenyl)-8-hydroxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (79 mg, 0.19 mmol) in acetonitrile (15 mL) was charged with potassium carbonate (80 mg, 0.58 mmol) and 2-(2-(4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamido)ethoxy)ethyl methanesulfonate (80 mg, 0.19 mmol) under nitrogen atmosphere. The resulting solution was heated at 80 °C for 8 h. The reaction mixture was cooled to room temperature, concentrated in vacuo and diluted with H₂O (15 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic fractions were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo resulting in a crude product 120 mg (85 % yield) of title compound as an off white solid which was used as such for next step. Characterized by LCMS only. MS (ES⁺): m/z = 727.05, 729.10 [M+H]⁺; LCMS: t_R = 2.55 min. [00559] 2-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamido)ethoxy)ethyl methanesulfonate

[00560] A solution of N-(2-(2-hydroxyethoxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (130 mg, 0.29 mmol) in DCM (20 mL) was charged with TEA (78 mg, 0.77 mmol) at 0⁰C and stirred for 5 min. Then to this solution was added

methanesulfonyl chloride (35 mg, 0.37 mmol) and the reaction mixture was stirred at the same temperature for 1h. Then 1N HCl aq. solution (15 mL) was added to reaction mixture. The organic layer was then separated, dried over anhydrous sodium sulfate, concentrated in vacuo resulting in a crude product which was purified by column chromatography, eluting with 2% methanol in dichloromethane to afford 80 mg (57 % yield) of title compound as a light yellow solid. MS (ES⁺): m/z = 413.95 [M+H] ⁺; LCMS: t_R = 2.43 min. [00561] N-(2-(2-hydroxyethoxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- l benzamide

[00562] A solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (200 mg, 0.80 mmol) in DCM (20 mL) was charged with EDCI (228 mg, 1.2 mmol), DMAP (117 mg, 0.96 mmol), and stirred for 10 min at room temperature. To this solution, 2-(2- aminoethoxy)ethanol (158 mg, 1.5 mmol) was added. The resulting solution was stirred for 15 h at room temperature. The reaction mixture was partitioned between DCM (10 mL) and H₂O (10 mL) and separated. The aqueous layer was extracted with DCM (3 X 10 mL) and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo resulting in 130 mg (48.8 % yield) of the crude title compound as a light yellow solid which was used in the next step without further purification. MS (ES⁺): m/z = 357.95 [M+Na] ⁺; LCMS: t_R = 2.03 min.

[00563] Examples 37 through 43 were synthesized acording to a similar procedure used for the synthesis of Example 36 above

[00564] (3-((2-(2-(((4S)-6-(4-chlorophenyl)-4-(2-(ethylamino)-2-oxoethyl)-1-methyl- 4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8- yl)oxy)ethoxy)ethyl)carbamoyl)phenyl)boronic acid [Example 37]:

[00565] ¹H NMR (400 MHz, CD₃OD): į = 7.80-7.66 (m, 4H), 7.53 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.8 Hz, 4H), 6.94 (s, 1H), 4.68 - 4.65 (m, 1H), 4.19– 4.17 (m, 2H), 3.85 - 3.82 (m, 2H), 3.71 - 3.68 (m, 3H), 3.57 - 3.55 (m, 2H), 3.40 - 3.26 (m, 4H), 2.69 (s, 3H), 1.18 (t, J = 7.2 Hz, 3H); MS (ES⁺): m/z = 645.20, 647.35 [M+H] ⁺; LCMS: t_R = 2.35 min. [00566] (4-((2-(2-(2-(((4S)-6-(4-chlorophenyl)-4-(2-(ethylamino)-2-oxoethyl)-1- methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl)oxy)ethoxy)ethoxy)ethyl) carbamoyl)phenyl)boronic acid [Example 38]:

[00567] ¹H NMR (400 MHz, DMSO- d₆): į = 8.41 (s, 1H), 8.24– 8.12 (m, 2H), 7.93– 7.71 (m, 3H), 7.54– 7.42 (m, 6H), 6.87 (d, J = 3.0 Hz, 1H), 4.21– 4.00 (m, 5H), 3.80– 3.67 (m, 2H), 3.60– 3.43 (m, 5H), 3.40 - 3.32 (m, 2H), 3.28– 3.08 (m, 3H), 2.55 (s, 3H), 1.07 (t, J = 7.2 Hz, 3H); MS (ES⁺): m/z = 689.05, 691.15 [M+H]⁺; LCMS: t_R = 1.85 min.

[00568] (3-((2-(2-(2-(((4S)-6-(4-chlorophenyl)-4-(2-(ethylamino)-2-oxoethyl)-1- methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl)oxy)ethoxy)ethoxy)ethyl) carbamoyl)phenyl)boronic acid [Example 39]:

[00569] ¹H NMR (400 MHz, DMSO- d₆): į = 8.56– 8.45 (m, 1H), 8.29– 8.18 (m, 2H), 7.87– 7.72 (m, 4H), 7.71– 7.56 (m, 2H), 7.54– 7.42 (m, 2H), 6.87 (d, J = 3.0 Hz, 1H), 4.59– 3.98 (m, 5H), 3.79– 3.67 (m, 2H), 3.63– 3.47 (m, 5H), 3.43 -3.89 (m, 2H), 3.35– 3.11 (m, 3H), 2.52 (s, 3H), 1.03 (t, J = 7.3 Hz, 3H); MS (ES+): m/z = 689.05, 691.10 [M+H] ⁺; LCMS: t_R = 1.83 min.

[00570] 4-((2-(2-(2-(2-(((4S)-6-(4-chlorophenyl)-4-(2-(ethylamino)-2-oxoethyl)-1- methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl)oxy)ethoxy)ethoxy) ethoxy)ethyl) carbamoyl) phenyl)boronic acid [Example 40]:

[00571] ¹H NMR (400 MHz, DMSO-d₆): į = 7.87– 7.72 (m, 5H), 7.55– 7.36 (m, 5H), 6.88 (s, 1H), 4.49 (dd, J = 8.2, 5.7 Hz, 1H), 4.22– 4.01 (m, 2H), 3.77– 3.39 (m, 14H), 3.29– 3.10 (m, 4H), 2.54 (s, 3H), 1.05 (t, J = 7.2 Hz, 3H); MS (ES⁺): m/z = 733.05, 735.15[M+H] ⁺; LCMS: t_R = 1.82 min.

[00572] (3-((2-(2-(2-(2-(((4S)-6-(4-chlorophenyl)-4-(2-(ethylamino)-2-oxoethyl)-1- methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8- yl)oxy)ethoxy)ethoxy)ethoxy)ethyl) carbamoyl)phenyl)boronic acid [Example 41]:

[00573] ¹H NMR (400 MHz, DMSO-d₆): į = 8.22 (s, 1H), 7.93– 7.71 (m, 3H), 7.56– 7.38 (m, 6H), 6.82 (s, 1H), 4.50 (dd, J = 8.3, 5.8 Hz, 1H), 4.18– 4.02 (m, 2H), 3.72– 3.19 (m, 14H), 3.20-3.15 (m, 4H), 2.55 (s, 3H), 1.05 (t, J = 7.4 Hz, 3H); MS (ES⁺): m/z = 733.00, 735.05 [M+H] ⁺; LCMS: t_R = 1.85 min. [00574] (4-((7-(((4S)-6-(4-chlorophenyl)-4-(2-(ethylamino)-2-oxoethyl)-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl)oxy)heptyl)carbamoyl)phenyl)boronic acid [Example 42]:

[00575] ¹H NMR (400 MHz, CD₃OD): į = 7.80– 7.65 (m, 5H), 7.57– 7.49 (m, 2H), 7.45– 7.29 (m, 3H), 6.88 (s, 1H), 4.62 (dd, J = 9.0, 5.2 Hz, 1H), 4.16 - 3.99 (m, 2H), 3.44– 3.18 (m, 6H), 2.63 (s, 3H), 1.82 - 1.77 (m, 2H), 1.69– 1.61 (m, 2H), 1.56– 1.22 (m, 6H), 1.18 (t, J = 7.3 Hz, 3H); MS (ES⁺): m/z = 671.15, 673.30 [M+H] ⁺ LCMS: t_R = 2.30 min.

[00576] (4-((6-(((4S)-6-(4-chlorophenyl)-4-(2-(ethylamino)-2-oxoethyl)-1-methyl-4H- benzo[f][1,2,4] triazolo[4,3-a][1,4]diazepin-8-yl)oxy)hexyl)carbamoyl)phenyl)boronic acid [Example 43]:

1H NMR (400 MHz, CD₃OD): į = 7.80 - 7.72 (m, 5H), 7.57– 7.49 (m, 2H), 7.45– 7.27 (m, 3H), 6.88 (d, J = 2.9 Hz, 1H), 4.62 (dd, J = 9.1, 5.2 Hz, 1H), 4.00– 3.98(m, 2H), 3.44– 3.18 (m, 6H), 2.63 (s, 3H), 1.82 - 1.75 (m, 2H), 1.69– 1.60 (m, 2H), 1.58– 1.38 (m, 4H), 1.18 (t, J = 7.3 Hz, 3H); MS (ES⁺): m/z = 657.20, 659.05 [M+H] ⁺; LCMS: t_R = 2.18 min. EXAMPLES 44-49:

[00577] Monomers were synthesized according to the procedures described below. Scheme 13: Synthesis of Examples 44 to 49

[00578] N-(2-(2-(((4S)-6-(4-chlorophenyl)-4-(2-(ethylamino)-2-oxoethyl)-1-methyl- 4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl)oxy)ethoxy)ethyl)-3,4- dihydroxybenzamide [Example 44]:

[00579] A solution of 3, 4-dihydroxybenzoic acid (58 mg, 0.37 mmol) in DMF (2.5 mL) was charged with EDCI (43 mg, 0.22 mmol), HOBt(30 mg, 0.22 mmol), DIPEA(38 mg, 0.30 mmol), and stirred at room temperature for 10 min. To this solution, 2-((4S)-8-(2-(2- aminoethoxy)ethoxy)-6-(4-chlorophenyl)-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3- a][1,4]diazepin-4-yl)-N-ethylacetamide (75 mg, 0.16 mmol) were added. The resulting solution was stirred at room temperature for 16 h. The reaction mixture was partitioned between DCM (10 mL) and H₂O (10 mL) and separated. The aqueous layer was re-extracted with DCM (3 X 15 mL) and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo resulting in a crude product which was purified by preparative HPLC to afford corresponding 10 mg (10.5 % yield) of the title compound as a white solid. ¹H NMR (400 MHz, CD₃OD): į = 7.65 (d, J = 9.2 Hz, 1H), 7.51 (d, J = 8.4 Hz, 2H), 7.40– 7.35 (m, 3H), 7.21 (s, 1H), 7.15– 7.13 (m, 1H), 6.91 (s, 1H) , 6.73 (d, J = 8.4 Hz, 1H), 4.68 (dd, J = 8.2, 5.6 Hz, 1H), 4.18– 4.14 (m, 2H), 3.84 - 3.82 (m, 2H), 3.68 (t, J = 5.2 Hz, 2H), 3.54– 3.50 (m, 2H), 3.39– 3.20 (m, 4H), 2.69 (s, 3H), 1.18 (t, J = 8.0 Hz, 3H); MS (ES⁺): m/z = 633.10, 635.15 [M+H] ⁺; LCMS: t_R = 1.80 min. [00580] Benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide

[00581] A solution of tert-butyl (2-(2-(((4S)-6-(4-chlorophenyl)-4-(2-(ethylamino)-2- oxoethyl)-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8- yl)oxy)ethoxy)ethyl)carbamate(0.2 g, 0.33mmol) in DCM (25 mL) was charged with TFA (2 mL) and stirred for 3 h at room temperature. The reaction mixture was then evaporated under reduced pressure to obtain a residue which was re-dissolved in DCM (20 mL) and powdered KOH was added to adjust pH ~ 8-9 and the solution was filtered through a pad of Celite and the filtrate was concentrated in vacuo resulting in a crude product 0.15 g (90.3 % yield) of title compound was obtained as a light yellow solid. The crude product was used in the next step without further purification. MS (ES⁺): m/z = 497.15, 499.35 [M+H] ⁺; LCMS: t_R = 1.46 min. [00582] tert-Butyl(2-(2-(((4S)-6-(4-chlorophenyl)-4-(2-(ethylamino)-2-oxoethyl)-1- methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl)oxy)ethoxy)ethyl)carbamate

[00583] A solution of 2-((4S)-6-(4-chlorophenyl)-8-hydroxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (185 mg, 0.45 mmol) in acetonitrile (10 mL) was charged with potassium carbonate (186 mg, 1.3 mmol) and 2-(2-((tert- butoxycarbonyl)amino)ethoxy)ethyl methanesulfonate (140 mg, 0.49 mmol) under nitrogen atmosphere. The resulting solution was heated at 80 °C for 8 h. The reaction mixture was cooled to room temperature, concentrated in vacuo, diluted with H₂O (15 mL) and extracted with ethyl acetate (3 X 20 mL). The combined organic fractions were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo resulting in a crude product which was purified by column chromatography, eluting with 5% methanol in dichloromethane to afford 200 mg (74 % yield) of pure N-Boc protected analogue as an off white solid. MS (ES⁺): m/z = 597.30, 599.45 [M+H] ⁺; LCMS: t_R = 2.36 min.

[00584] Examples 45 to 49 were synthesized according to analagous procedures to the synthesis of Example 44.

[00585] N-(2-(2-(2-(((4S)-6-(4-chlorophenyl)-4-(2-(ethylamino)-2-oxoethyl)-1- methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl)oxy)ethoxy)ethoxy)ethyl)-3,4- dihydroxybenzamide [Example 45]:

[00586] ¹H NMR (400 MHz, CD₃OD): į = 7.67 (d, J = 8.4 Hz, 1H) , 7.53 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H) 7.39 - 7.33 (m, 1H), 7.24 (s, 1H), 7.16 (d, J = 8.4, 1H), 6.92 (s, 1H), 6.72 (d, J = 8.4 Hz, 1H), 4.84 (m, 1H), 4.12– 4.09 (m, 2H), 3.85– 3.79 (m, 2H), 3.68– 3.61 (m, 6H), 3.52– 3.50 (m, 3H), 3.41– 3.31 (s, 3H), 2.72 (s, 3H), 1.18 (t, J = 7.2 Hz, 3H); MS (ES⁺): m/z = 677.15, 677.35 [M+H] ⁺;LCMS: t_R = 1.83 min. [00587] N-(17-(((4S)-6-(4-chlorophenyl)-4-(2-(ethylamino)-2-oxoethyl)-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl)oxy)-3,6,9,12,15-pentaoxaheptadecyl)-3,4- dihydroxybenzamide [Example 46]:

[00588] ¹H NMR (400 MHz, CD₃OD): į = 7.68 (d, J = 9.0 Hz, 1H), 7.58– 7.49 (m, 2H), 7.45– 7.33 (m, 3H), 7.27 (d, J = 2.2 Hz, 1H), 7.20 (dd, J = 8.3, 2.2 Hz, 1H), 6.92 (d, J = 2.8 Hz, 1H), 6.77 (d, J = 8.3 Hz, 1H), 4.67– 4.55 (m, 1H), 4.20– 4.06 (m, 2H), 3.81 (t, J = 4.5 Hz, 2H), 3.68– 3.47 (m, 18H), 3.44– 3.32 (m, 2H), 3.31– 3.19 (m, 4H), 2.63 (s, 3H), 1.18 (t, J = 7.3 Hz, 3H); MS (ES⁺): m/z = 809.50, 811.45 [M+H] ; LCMS: t_R = 1.90 min.

[00589] N-(20-(((4S)-6-(4-chlorophenyl)-4-(2-(ethylamino)-2-oxoethyl)-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl)oxy)-3,6,9,12,15,18-hexaoxaicosyl)-2,3- dihydroxybenzamide [Example 47]:

[00590] ¹H NMR (400 MHz, CD₃OD): į = 7.75– 7.63 (m, 1H), 7.58– 7.49 (m, 2H), 7.45– 7.32 (m, 3H), 7.30– 7.19 (m, 1H), 6.98– 6.87 (m, 2H), 6.75– 6.63 (m, 1H), 4.67– 4.55 (m, 1H), 4.20– 4.06 (m, 2H), 3.85– 3.75 (m, 2H), 3.69– 3.48 (m, 22H), 3.46– 3.32 (m, 2H), 3.32– 3.16 (m, 4H), 2.63 (d, J = 2.2 Hz, 3H), 1.18 (t, J = 7.2 Hz, 3H); MS (ES⁺): m/z = 853.15, 855.05 [M+H] ⁺; LCMS: t_R = 2.19 min.

[00591] N-(2-(2-(2-(2-(((4S)-6-(4-chlorophenyl)-4-(2-(ethylamino)-2-oxoethyl)-1- methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8- yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)-3,4-dihydroxybenzamide [Example 48]:

[00592] A solution of 3, 4-dihydroxybenzoic acid (59 mg, 0.38 mmol) in DMF (5 mL) was charged with EDCI (44 mg, 0.23 mmol), HOBt(24 mg, 0.18 mmol), DIPEA(39 mg, 0.30 mmol), and stirred at room temperature for 10 min. To this solution, 22-((4S)-8-(2-(2-(2-(2- aminoethoxy)ethoxy)ethoxy)ethoxy)-6-(4-chlorophenyl)-1-methyl-4H- enzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (90 mg, 0.15 mmol) were added. After the work up and preparative HPLC purification, 8 mg (7.2 % yield) of the title compound was obtained as an off white solid. ¹H NMR (400 MHz, CD₃OD): į = 7.66 (d, J = 9.0 Hz, 1H), 7.56– 7.48 (m, 2H), 7.44– 7.39 (m, 2H), 7.36– 7.23 (m, 2H), 7.19 (dd, J = 8.2, 2.3 Hz, 1H), 6.89 (d, J = 2.9 Hz, 1H), 6.75 (d, J = 8.3 Hz, 1H), 4.63 (dd, J = 9.1, 5.3 Hz, 1H), 4.18– 4.09 (m, 2H), 3.78 (t, J = 4.5 Hz, 2H), 3.62– 3.57 (m, 10H), 3.50 (t, J = 5.4 Hz, 2H), 3.45– 3.21 (m, 4H), 2.63 (s, 3H), 1.18 (t, J = 7.3 Hz, 3H); MS (ES⁺): m/z = 721.15, 723.20 [M+H] ⁺; LCMS: t_R = 1.90 min. [00593] N-(2-(2-(2-(((4S)-6-(4-chlorophenyl)-4-(2-(ethylamino)-2-oxoethyl)-1- methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl)oxy)ethoxy)ethoxy)ethyl)-2,3- dihydroxybenzamide [Example 49]:

[00594] ¹H NMR (400 MHz, DMSO-d₆): į = 7.74 (d, J = 9.0 Hz, 1H), 7.52– 7.42 (m, 4H), 7.35 (dd, J = 9.0, 2.9 Hz, 1H), 7.27– 7.20 (m, 1H), 6.92– 6.80 (m, 2H), 6.64 (t, J = 7.7 Hz, 1H), 4.51 (dd, J = 8.3, 5.7 Hz, 1H), 4.14– 3.97 (m, 2H), 3.57– 3.53 (m, 8H), 3.41 (t, J = 5.7 Hz, 2H), 3.28 - 3.11 (m, 4H), 2.54 (s, 3H), 1.04 (t, J = 7.2 Hz, 3H); MS (ES⁺): m/z = 677.15, 679.25 [M+H]⁺; LCMS: t_R = 2.09 min.

EXAMPLES 50-53:

[00595] Monomers were synthesized according to the procedures described below. Scheme 14: Synthesis of Examples 50 to 53

[00596] 2-((4R)-6-(4-Chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-(2,3-dihydroxy-3- methylbutyl)acetamide [Example 50]:

[00597] A solution of 2-((4R)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-(3-methylbut-2-en-1-yl)acetamide (60 mg, 0.12 mmol) in mixture of 2:1 THF:H₂O (15 mL) was charged with NMO (16.6 mg, 0.14 mmol), osmium tetroxide (33 mg, 0.13 mmol), and the resulting solution was stirred at room temperature for 2h. The reaction mixture was concentrated in vacuo and aqueous layer was extracted with ethyl acetate (3 X 20 mL) and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo resulting in a crude compound which was purified by column chromatography on silica gel (100-200 mesh), eluting with 10 % methanol in dichloromethane to afford 20 mg (31.25 % yield) of the title compound as an off white solid. ¹H NMR (400 MHz, DMSO- d₆): į = 8.11 (s, 1H), 7.79 (d, J = 8.9 Hz, 1H), 7.58– 7.44 (m, 4H), 7.38 (dd, J = 8.6, 3.1 Hz, 1H), 6.87 (d, J = 3.4 Hz, 1H), 4.71 (dd, J = 14.3, 5.2 Hz, 1H), 4.52– 4.41 (m, 1H), 4.28 (d, J = 10.7 Hz, 1H), 3.79 (s, 3H), 3.60– 3.51 (m, 1H), 3.28 (q, J = 7.5, 5.9 Hz, 2H), 3.22– 3.17 (m, 1H), 2.88– 2.60 (m, 1H), 2.56 (s, 3H), 1.16– 1.01 (m, 6H); MS (ES⁺): m/z = 498.05, 500.10[M+H] ⁺;LCMS: t_R = 1.86 min.

[00598] 2-((4R)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-(3-methylbut-2-en-1-yl)acetamide

[00599] A solution of 22-((4R)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetic acid (0.163 g, 0.4 mmol) in DCM (15 mL) was charged with EDCI (0.117 g, 0.6 mmol), DMAP (0.06 g, 0.49 mmol), and stirred at room temperature for 10 min. 3-Methylbut-2-en-1-amine hydrochloride (0.5 g, 0.4 mmol) was added to the reaction mixture. The resulting solution was stirred at room temperature for 15 h. The reaction mixture was partitioned between DCM (15 mL) and H₂O (10 mL) and separated. The aqueous layer was re-extracted with DCM (3 X 15 mL) and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The resulting crude compound was purified by column chromatography on silica gel (100-200 mesh), eluting with 5 % methanol in dichloromethane to afford 70 mg (36.8 % yield) of the title compound as an off white solid.¹H NMR (400 MHz, DMSO- d₆): į = 8.27 (, s, 1H), 7.79 (d, J = 9.0 Hz, 1H), 7.50– 7.44 (m, 4H), 7.38 (dd, J = 8.9, 3.0 Hz, 1H), 6.86 (s, 1H), 5.18 (t, J = 7.0 Hz, 1H), 4.47 (dd, J = 8.5, 5.6 Hz, 1H), 3.81 (s, 3H), 3.33– 3.20 (m, 2H), 3.14– 3.05 (m, 2H), 2.53 (s, 3H), 1.67 (d, J = 24.3 Hz, 6H); MS (ES⁺): m/z = 464.05, 466.20 [M+H]⁺; LCMS: t_R = 2.49 min.

[00600] 2-((4R)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-(3,4-dihydroxy-4- methylpentyl)acetamide [Example 52]:

[00601] A solution of 2-((4R)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-(4-methylpent-3-en-1-yl)acetamide (120 mg, 0.41 mmol) in THF:H₂O, 2:1 (15 mL) was charged with NMO (53 mg, 0.46 mmol), followed by osmium tetroxide (107 mg, 0.42 mmol). The resulting solution was stirred at room temperature for 2h. The reaction mixture was concentrated in vacuo. The aqueous layer was extracted with ethyl acetate (3 X 20 mL) and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo resulting in a crude compound which was purified by preparative HPLC to afford 25 mg (11.9 % yield) of the title compound as an off white solid.¹H NMR (400 MHz, CD₃OD): į = 7.75 (dd, J = 8.9, 3.1 Hz, 1H), 7.61– 7.53 (m, 2H), 7.46– 7.36 (m, 3H), 6.95 (d, J = 2.9 Hz, 1H), 4.68–4.55 (dd, J = 8.0, 4.1 Hz, 1H), 3.84 (s, 3H), 3.48– 3.18 (m, 5H), 2.72 (s, 3H), 1.95– 1.83 (m, 1H), 1.61– 1.53 (m, 1H), 1.37– 1.22 (m, 3H), 1.22– 1.13 (m, 3H); MS (ES+): m/z = 534.00, 536.05 [M+Na] ⁺; LCMS: t_R = 1.85 min. [00602] 2-((4R)-6-(4-Chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-(4-methylpent-3-en-1-yl)acetamide

[00603] A solution of 22-((4R)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetic acid (0.199 g, 0.5 mmol) in DCM (15 mL) was charged with EDCI (0.143 g, 0.75 mmol), DMAP (0.073 g, 0.60 mmol), and stirred at room temperature for 10 min. 4-Methylpent-3-en-1-amine (0.5 g, 0.5 mmol) was added to the reaction mixture. The resulting solution was stirred at room temperature for 15 h. The reaction mixture was partitioned between DCM (15 mL) and H₂O (10 mL) and separated. The aqueous layer was re-extracted with DCM (3 X 15 mL) and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo resulting in a crude compound which was purified by preparative HPLC to afford 200 mg (83.6 % yield) of the title compound as an off white solid. ¹H NMR (400 MHz, CD₃OD): į = 7.76 (d, J = 9.0 Hz, 1H), 7.63– 7.53 (m, 2H), 7.45– 7.37 (m, 3H), 6.95 (d, J = 2.7 Hz, 1H), 5.17 (t, J = 7.2 Hz, 1H), 4.68 (dd, J = 8.7, 5.5 Hz, 1H), 3.84 (s, 3H), 3.40– 3.18 (m, 4H), 2.72 (s, 3H), 2.25– 2.21 (m, 2H), 1.71 (s, 3H), 1.65 (s, 3H); MS (ES⁺): m/z = 478.10, 480.30 [M+H]⁺; LCMS: t_R = 2.60 min. EXAMPLES 54-58:

[00604] Monomers were synthesized according to the procedures described below. Scheme 15: Synthesis of Examples 54 through 56

[00605] 2-((4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-1-(4-(3- (hydroxydimethylsilyl)benzoyl)piperazin-1-yl)ethanone [Example 54]:

[00606] A solution of 3-(hydroxydimethylsilyl)benzoic acid (50 mg, 0.25 mmol) in DCM (15 mL) was charged with EDCI (73 mg, 0.38 mmol), HOBt (51 mg, 0.38 mmol), DMAP (46 mg, 0.38 mmol), and stirred at room temperature for 10 minutes. 2-((4S)-6-(4- chlorophenyl)-8-methoxy-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-1- (piperazin-1-yl)ethanone (144 mg, 0.25 mmol) was added to the reaction mixture. The resulting solution was stirred at room temperature for 15 h. The reaction mixture was partitioned between DCM (10 mL) and H₂O (10 mL) and separated. The aqueous layer was extracted with DCM (3 x 10 mL) and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to give a crude product which was purified by preparative HPLC to afford in 40 mg (24% yield) of the title compound as an off white solid. ¹H NMR (400 MHz, CD₃OD): į = 7.70 (dd, J = 12.6, 6.8 Hz, 2H), 7.62– 7.57 (m, 1H), 7.56– 7.45 (m, 4H), 7.38 (dd, J = 10.7, 7.5 Hz, 2H), 6.90 (d, J = 2.9 Hz, 1H), 4.68 (t, J = 6.9 Hz, 1H), 3.81 (s, 3H), 3.70 (s, 1H), 3.60– 3.49 (m, 8H), 3.35 (s, 1H), 2.63 (s, 3H), 0.39 (s, 6H); MS (ES⁺): m/z 643.10, 645.15 [M+H] ⁺ (monomer), LCMS: t_R = 2.25 min(monomer),, MS (ES⁺): m/z 1267.30 , 1269.20[M+H] ⁺ (dimer); LCMS: t_R = 3.44 min (dimer).

[00607] 2-((4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo 1,2,4 triazolo 4,3-a][1,4]diazepin-4-yl)-1-(piperazin-1-yl)ethanone [Example 55]:

[00608] A solution of tert-butyl 4-(2-((4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetyl)piperazine-1-carboxylate (0.6 g, 1.0 mmol) in DCM (25 mL) was charged with TFA (1.8 mL) and stirred for at room temperature for 8 h. The reaction mixture was then evaporated under reduced pressure to obtain a residue which was dissolved in DCM (10 mL) and powdered KOH was added to adjust pH to ~ 8-9. The solution was filtered through a pad of Celite and the filtrate was concentrated in vacuo to give a crude product which was purified by column chromatography on silica gel, eluting with 6% methanol in chloroform to afford 0.40 g (81 % yield) of title compound as an off white solid. ¹H NMR (400 MHz, CD₃OD): į = 7.71 (dd, J = 9.0, 2.0 Hz, 1H), 7.55 (d, J = 8.4 Hz, 2H), 7.56– 7.48 (m, 3H), 6.89 (d, J = 2.9 Hz, 1H), 4.71– 4.62 (m, 1H), 3.83– 3.48 (m, 9H), 3.05 (td, J = 6.6, 3.9 Hz, 1H), 2.97– 2.85 (m, 2H), 2.85– 2.78 (m, 1H), 2.69 (t, J = 5.3 Hz, 1H), 2.62 (s, 3H); MS (ES⁺): m/z 465.10, 467.15 [M+H]⁺; LCMS: t_R = 1.75 min.

[00609] tert-Butyl 4-(2-((4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetyl)piperazine-1-carboxylate (23):

[00610] A solution of 2-((4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetic acid (500 mg, 1.20 mmol) in DCM (25 mL) was charged with EDCI (361 mg, 1.80 mmol), DMAP (184 mg, 1.50 mmol), and stirred at room temperature for 10 minutes. tert-Butyl piperazine-1-carboxylate (258 mg, 1.3 mmol) was added to the reaction mixture. The resulting solution was stirred at room temperature for 15 h. The reaction mixture was partitioned between DCM (10 mL) and H₂O (10 mL) and separated. The aqueous layer was re-extracted with DCM (3 x 10 mL) and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to give a crude product 600 mg ( 84% yield) of the title compound as an off white solid. The crude material was used in the next step without further purification. MS (ES⁺): m/z 565.00, 567.30 [M+H]⁺; LCMS: t_R = 2.73 min.

[00611] 2-((4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-1-(4-(4- (hydroxydimethylsilyl)benzoyl)piperazin-1-yl)ethanone [Example 56]:

[00612] ¹H NMR (400 MHz, CD₃OD): į = 7.72 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 7.1 Hz, 2H), 7.52 (d, J = 8.3 Hz, 2H), 7.47– 7.32 (m, 5H), 6.90 (d, J = 2.7 Hz, 1H), 4.68 (d, J = 8.8 Hz, 1H), 3.90 (d, J = 16.5 Hz, 1H), 3.81 (s, 3H), 3.40-3.70 (m, 10H), 2.63 (d, J = 3.0 Hz, 3H), 1.36 – 1.27 (m, 1H), 0.39 (s, 6H); MS (ES⁺): m/z 1268.00 , 1270.15 [M+H] ⁺(dimer); LCMS: t_R = 3.28 min (dimer)

[00613] 2-((4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-1-(4-(3-(hydroxydimethylsilyl)benzoyl)- 1,4-diazepan-1-yl)ethanone [Example 57]:

[00614] 1H NMR (400 MHz, CD₃OD): į = 7.71 (d, J = 8.9 Hz, 1H), 7.62– 7.49 (m, 3H), 7.46 (s, 1H), 7.37 (dd, J = 11.7, 6.1 Hz, 3H), 7.28 (d, J = 8.3 Hz, 1H), 6.89 (d, J = 3.3 Hz, 1H), 4.71 (s, 1H), 4.01– 3.85 (m, 2H), 3.85– 3.78 (m, 3H), 3.67 (tt, J = 15.6, 8.3 Hz, 4H), 3.44 (s, 1H), 2.63 (d, J = 3.1 Hz, 3H), 2.12 (d, J = 7.7 Hz, 1H), 1.97 (m, 1H), 1.83 (m, 1H), 1.56 (d, J = 7.2 Hz, 1H), 0.20– 0.36 (m, 6H); MS (ES⁺): m/z 657.10, 659.30 [M+H]⁺ (monomer); LCMS: t_R = 2.25 min (monomer); MS (ES⁺): m/z 1295.25, 1297.40 [M+H]⁺ (dimer); LCMS: t_R = 3.79 min(dimer).

[00615] 2-((4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-1-(4-(4-(hydroxydimethylsilyl)benzoyl)- 1,4-diazepan-1-yl)ethanone [Example 58]:

[00616] ¹H NMR (400 MHz, CD₃OD): į = 7.772– 7.70 (m, 1H), 7.59– 7.49 (m, 4H), 7.42– 7.30 (m, 5H), 6.90 (bs, 1H), 4.69– 4.72 (m, 1H), 3.99– 3.89 (m, 2H), 3.82– 3.79 (m, 5H), 3.72– 3.47 (m, 8H), 2.63 (s, 3H), 0.33– 0.24 (s, 6H); MS (ES⁺): m/z 643.15 , 645.35 [M+H]⁺ (monomer); LCMS: t_R = 2.25 min (monomer); (ES⁺): m/z 1295.50 , 1297.20 [M+H]⁺ (dimer); LCMS: t_R = 3.67 min(dimer). EXAMPLE 59:

[00617] Example 59 was synthesized according to the procedure described below. Scheme 17: Synthesis of Example 59

[00618] N-(2-(2-((6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)ethyl)-3- (hydroxydimethylsilyl)benzamide [Example 59]:

[00619] A solution of 3-(hydroxydimethylsilyl)benzoic acid (66 mg, 0.25 mmol) in DCM (15mL) was charged with EDCI (97 mg, 0.50 mmol), HOBt (45 mg, 0.33 mmol), DMAP (49 mg, 0.42 mmol), and stirred at room temperature for 10 minutes. N-(2-aminoethyl)-2-((6S)- 4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6- yl)acetamide (150 mg, 0.33 mmol) was added to the reaction mixture. The resulting solution was stirred at room temperature for 15 h. The reaction mixture was partitioned between DCM (10 mL) and H₂O (10 mL) and separated. The aqueous layer was extracted with DCM (3 x 10 mL) and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to give a crude product which was purified by preparative HPLC to afford 35 mg (16 % yield) of the title compound.¹H NMR (400 MHz, CD₃CN): į = 7.89 (d, J = 30.0 Hz, 1H), 7.80– 7.53 (m, 5H), 7.43– 7.20 (m, 6H), 4.51 (t, J = 7.0 Hz, 1H), 3.46 (q, J = 7.3, 6.0 Hz, 4H), 3.29 (dd, J = 7.3, 3.9 Hz, 4H), 2.64 (d, J = 51.4 Hz, 3H), 2.53 (d, J = 1.8 Hz, 3H), 2.34 (s, 4H), 1.95 (dq, J = 4.5, 2.2 Hz, 4H), 1.50 (s, 2H), 0.35 (s, 6H); MS (ES⁺): m/z 1223.30 , 1225.50 [M+H]⁺ (dimer), LCMS: t_R = 3.93 min(dimer). [00620] N-(2-aminoethyl)-2-((6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide (29):

[00621] A solution of tert-butyl (2-(2-((6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H- thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)ethyl)carbamate (0.25 g, 0.46 mmol) in DCM (20 mL) was charged with TFA (1.25 mL) and stirred for at room temperature for 8 h. The reaction mixture was then evaporated under reduced pressure to obtain a residue which was dissolved in DCM (10 mL) and powdered KOH was added to adjust pH to ~ 8-9. The solution was filtered through a pad of Celite and the filtrate was concentrated in vacuo resulting in a crude product which was purified by column chromatography on silica gel, eluting with 5% methanol in dichloromethane to afford 0.15 g (73 % yield) of title compound. MS (ES⁺): m/z 443.35, 445.60 [M+H]⁺; LCMS: t_R = 1.62 min.

[00622] tert-Butyl (2-(2-((6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)ethyl)carbamate (28):

[00623] A solution of 2-((6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid (200 mg, 0.50 mmol) in DCM (20 mL) was charged with EDCI (143 mg, 0.75 mmol), DMAP (73.2 mg, 0.60 mmol), and stirred at room temperature for 10 minutes. tert-butyl (2-aminoethyl)carbamate (80 mg, 0.50 mmol) was added to the reaction mixture. The resulting solution was stirred at room temperature for 15 h. The reaction mixture was partitioned between DCM (15 mL) and H₂O (10 mL) and separated. The aqueous layer was extracted with DCM (3 x 10 mL) and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to give a crude product 250 mg (92% yield) of the title compound. The crude product was used in the next step without any further purification. MS (ES⁺): m/z 543.10, 545.40 [M+H]⁺; LCMS: t_R = 2.44 min. EXAMPLE 60:

[00624] Example 60 was synthesized according to the procedure described below.

[00625] N-(2-(2-((4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-methylacetamido)ethyl)-3- (hydroxydimethylsilyl)benzamide. [Example 60]:

[00626] A solution of 3-(hydroxydimethylsilyl)benzoic acid (95 mg, 0.48 mmol) in DCM (15mL) was charged with EDCI (139 mg, 0.50 mmol),HOBt(98 mg, 0.72 mmol), DMAP (71 mg, 0.58 mmol), and stirred at room temperature for 10 minutes. (S)-2-(6-(4- Chlorophenyl)-8-methoxy-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetic acid (220 mg, 0.48 mmol) was added to the reaction mixture. The resulting solution was stirred at room temperature for 15 h. The reaction mixture was partitioned between DCM (10 mL) and H₂O (10 mL) and separated. The aqueous layer was re-extracted with DCM (3 x 10 mL) and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo resulting in a crude product which was purified by preparative HPLC to afford in 40 mg (13 % yield) of the title compound as an off white solid.¹H NMR (400 MHz, CDCl₃): į = 7.4– 7.6 (m, 5H), 7.3– 7.4 (m, 5H), 6.99 (dd, J = 5.4, 1.4 Hz, 1H), 4.52 (m, 1H), 3.90 (d, J = 1.5 Hz, 3H), 3.4– 3.8 (m, 5H), 3.00– 3.38 (m, 5H), 2.99 (s, 3H) 2.00 (s, 1H), 1.45– 1.35 (m, 1H), 0.36 (s, 6H); MS (ES⁺): m/z 1245.30, 1247.45 [M+H]⁺ (dimer); LCMS: t_R = 3.34 min(dimer).

[00627] N-(2-aminoethyl)-2-((4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-methylacetamide (31):

[00628] A solution of tert-butyl (2-(2-((4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-methylacetamido)ethyl)carbamate (0.20 g, 0.52 mmol) in DCM (20 mL) was charged with TFA (1.45 mL) and stirred for 8h at room temperature. The reaction mixture was then evaporated under reduced pressure to obtain a residue which was re-dissolved in DCM (10 mL) and powdered KOH was added to adjust pH ~ 8-9. The solution was filtered through a pad of Celite bed and the filtrate concentrated in vacuo to give a crude product which was purified by column chromatography on silica gel, eluting with 4 % methanol in dichloromethane to afford 0.22 g (92 % yield) desired product. MS (ES⁺): m/z 453.25, 455.15 [M+H] ⁺; LCMS: t_R = 1.56 min.

[00629] tert-Butyl (2-(2-((4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-methylacetamido)ethyl)carbamate (30):

[00630] A solution of 2-((6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid (227 mg, 0.57 mmol) in DCM (15 mL) was charged with EDCI (164 mg, 0.86 mmol), HOBt (116 mg, 0.86 mmol) DMAP (84 mg, 0.68 mmol), and stirred at room temperature for 10 minutes. tert-Butyl (2- (methylamino)ethyl)carbamate (100 mg, 0.57 mmol) was added to the reaction mixture. The resulting solution was stirred at room temperature for 15 h. The reaction mixture was partitioned between DCM (20 mL) and H₂O (10 mL) and separated. The aqueous layer was re- extracted with DCM (3 x 10 mL) and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to give a crude product 290 mg (91% yield) of the title compound. MS (ES+): m/z 553.10, 555.30 [M+H] ⁺; LCMS: t_R = 2.41 min. EXAMPLE 61:

[00631] Example 61 was synthesized according to the procedure described below.

[00632] N-(2-(2-((4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetamido)ethyl)-3- (hydroxydimethylsilyl)-N-methylbenzamide [Example 61]:

[00633] A solution of 2-((6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid (282 mg, 0.71 mmol) in DCM (15mL) was charged with EDCI (204 mg, 1.0 mmol), HOBt (144 mg, 1.0 mmol), DMAP (104 mg, 0.85 mmol), and stirred at room temperature for 10 minutes. To this solution, N-(2-aminoethyl)-3- (hydroxydimethylsilyl)-N-methylbenzamide (180 mg, 0.71 mmol) was added. The resulting solution was stirred at room temperature for overnight. The reaction mixture was partitioned between DCM and H₂O and separated. The aqueous layer was re-extracted with DCM (3 x 10 mL) and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to provide a crude product which was purified by preparative HPLC to afford in 50 mg, 11 % yield of the title compound as a off white solid.¹H NMR (400 MHz, CD₃OD): į = 7.93 (d, J = 4.5 Hz, 1H), 7.81– 7.53 (m, 3H), 7.49– 7.25 (m, 1H), 6.88– 6.82 (m, 4H), 6.82– 6.75 (m, 1H), 4.62 (q, J = 6.5 Hz, 1H), 3.92 (q, J = 9.5 Hz, 1H), 3.82 (s, 3H), 3.4-3.64 (m, 6H), 2.61 (d, J = 1.7 Hz, 3H), 0.31– 0.18 (m, 6H); MS (ES⁺): m/z 1267.25, 1269.10 [M+Na]⁺ (dimer); LCMS: t_R = 3.84 min(dimer).

[00634] N-(2-aminoethyl)-3-(hydroxydimethylsilyl)-N-methylbenzamide (33):

[00635] A solution of tert-butyl (2-(3-(hydroxydimethylsilyl)-N- methylbenzamido)ethyl)carbamate (0.26 g, 0.73 mmol) in DCM (20 mL) was charged with TFA (1.3 mL) and stirred for at room temperature for 8 h. The reaction mixture was then evaporated under reduced pressure to obtain a residue which was re-dissolved in DCM (10 mL) and powdered KOH was added to adjust pH ~ 8-9 and filtered through a pad of Celite and the filtrate concentrated in vacuo resulting in a crude product which was purified by column chromatography on silica gel, eluting with 4 % methanol in dichloromethane to afford in 0.18 g (96.7 % yield) of title compound as an off white solid. MS (ES⁺): m/z 487.30, 489.40 [M+H]⁺; LCMS: t_R = 1.44 min.

[00636] tert-Butyl (2-(3-(hydroxydimethylsilyl)-N-methylbenzamido)

ethyl)carbamate (32):

[00637] A solution of 3-(hydroxydimethylsilyl)benzoic acid (133 mg, 0.76 mmol) in DCM (15 mL) was charged with EDCI (246 mg, 1.2 mmol), HOBt (174 mg, 1.2 mmol), DMAP (126 mg, 1.0 mmol), and stirred at room temperature for 10 minutes. tert-Butyl (2- (methylamino)ethyl)carbamate (150 mg, 0.76 mmol) was added in the reaction mixture. The resulting solution was stirred at room temperature for 15h. The reaction mixture was partitioned between DCM (10 mL) and H₂O (10 mL) and separated. The aqueous layer was re-extracted with DCM (3 x 10 mL) and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to give a crude product 260 mg (86% yield) of the title compound which was used for the next step without any further purifications. MS (ES⁺): m/z 687.20, 689.10 [M+H]⁺ (dimer); LCMS: t_R = 3.18 min(dimer). EXAMPLES 62-65: [00638] Monomers were synthesized according to the procedures described below. Scheme 20: Synthesis of Examples 62 to 65

[00639] 2-((S)-6-(4-Chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-(1-(3- (hydroxydimethylsilyl)benzoyl)pyrrolidin-3-yl)acetamide [Example 62]:

A solution of (S)-2-(6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3- a][1,4]diazepin-4-yl)acetic acid (232 mg, 0.58 mmol) in DCM (15 mL) was charged with EDCI (168 mg, 0.88 mmol), HOBt (79 mg, 0.58 mmol), DMAP (86 mg, 0.70 mmol), and stirred at room temperature for 10 minutes.(3-aminopyrrolidin-1-yl)(3- (hydroxydimethylsilyl)phenyl)methanone (155 mg, 0.58 mmol) was added to the reaction mixture. The resulting solution was stirred at room temperature for 15h. The reaction mixture was partitioned between DCM (10 mL) and H₂O (10 mL) and separated. The aqueous layer was re-extracted with DCM (3 x 10 mL) and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to give a crude product which was purified by preparative HPLC to afford in 40 mg (10 % yield) of the title compound.¹H NMR (400 MHz, DMSO-d₆): į = 8.56 (dd, J = 17.5, 6.6 Hz, 1H), 7.83– 7.71 (m, 1H), 7.69– 7.59 (m, 2H), 7.59– 7.29 (m, 7H), 6.90– 6.81 (m, 1H), 4.50 (dd, J = 8.8, 5.5 Hz, 1H), 4.39 (ddt, J = 17.9, 12.3, 5.9 Hz, 1H), 4.22 (d, J = 8.2 Hz, 1H), 3.81– 3.63 (m, 5H), 3.58 (d, J = 7.2 Hz, 1H), 3.32 (s, 3H), 3.17 (q, J = 11.3, 8.0 Hz, 1H), 3.09 (s, 1H), 2.54 (s, 3H), 2.09 (dd, J = 15.9, 9.5 Hz, 1H), 1.91 (s, 1H), 1.82 (t, J = 8.1 Hz, 1H), 0.32 (s, 6H); MS (ES+): m/z 1291.15, 1293.25 [M+Na]⁺ (dimer); LCMS: t_R = 3.30 min (dimer).

[00640] The following compounds were synthesized analogously to the procedure described for synthesis of [Example 62] above:

[00641] 2-((S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-(1-(4- (hydroxydimethylsilyl)benzoyl)pyrrolidin-3-yl)acetamide [Example 63]:

[00642] (13.7% Yield). ¹H NMR (400 MHz, DMSO-d₆): į = 8.60– 8.50 (m, 1H), 7.83 – 7.69 (m, 1H), 7.48–7.35 (m, , 10H), 6.90– 6.81 (m, 1H), 4.50 (t, J = 7.0 Hz, 1H), 4.46– 4.33 (m, 1H), 4.25– 4.15 (m, 1H), 3.81– 3.63 (m, 5H), 3.62– 3.50 (m, 2H), 3.29– 3.18 (m, 4H), 3.12 (q, J = 13.9, 11.2 Hz, 1H), 2.54 (s, 3H), 2.19– 2.05 (m, 1H), 1.97– 1.88 (m, 1H), 1.83 (s, 1H), 0.33 (s, 6H); MS (ES⁺): m/z 1269.50, 1271.60 [M+H]⁺ (dimer); LCMS: t_R = 3.28 min (dimer).

[00643] 2-((S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-((1-(3- (hydroxydimethylsilyl)benzoyl)pyrrolidin-3-yl)methyl)acetamide [Example 64]:

[00644] Yield: 6%. ¹H NMR (400 MHz, DMSO-d₆): į = 8.39 (dt, J = 13.1, 6.2 Hz, 1H), 8.30 (d, J = 6.5 Hz, 1H), 7.78 (d, J = 8.6 Hz, 1H), 7.64– 7.33 (m, 9H), 6.88 (s, 1H), 6.82 (s, 1H), 4.46-4.40 (m, 1H), 4.09 (q, J = 5.4 Hz, 1H), 3.77 (s, 3H), 3.60–3.50 (m, , 2H), 3.42– 3.30 (m, 2H), 3.16– 3.05 (m, , 2H), 2.45– 2.35 (m, 3H), 2.29 (s, 1H), 1.98 (s, 1H), 1.90 (s, 1H), 1.65 (q, J = 9.2 Hz, 1H), 0.30– 0.25 (m, 6H); MS (ES⁺): m/z 1295.70, 1297.10 [M+H]⁺ (dimer), LCMS: t_R = 3.33 min (dimer).

[00645] 2-((S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-((1-(4- (hydroxydimethylsilyl)benzoyl)pyrrolidin-3-yl)methyl)acetamide [Example 65]:

[00646] Yield: 6.1 %. ¹H NMR (400 MHz, DMSO-d₆): į = 8.47– 8.25 (m, 1H), 7.78 (d, J = 8.7 Hz, 1H), 7.62– 7.33 (m, 9H), 6.91 (d, J = 14.9 Hz, 1H), 4.48– 4.40 (m, 1H), 3.78 (d, J = 3.3 Hz, 3H), 3.60– 3.47 (m, 2H), 3.43 (d, J = 7.3 Hz, 2H), 3.28– 3.02 (m, 4H), 2.53 (s, 3H), 1.99 (s, 1H), 1.91 (s, 1H), 1.65–1.60 (m, 2H), 1.17 (t, J = 11.3 Hz, 1H), 0.32 (t, J = 6.2 Hz, 6H). MS (ES⁺): m/z 1296.05, 1298.15 [M+H]⁺ (dimer), LCMS: t_R = 3.27 min (dimer).

[00647] (3-Aminopyrrolidin-1-yl)(3-(hydroxydimethylsilyl)phenyl)methanone (37a):

[00648] A solution of tert-butyl (1-(3-(hydroxydimethylsilyl)benzoyl)pyrrolidin-3- yl)carbamate (0.31g, 0.85 mmol) in DCM (15 mL) was charged with TFA (1.25 mL) and stirred for at room temperature for 3 h. The reaction mixture was then evaporated under reduced pressure to obtain a residue which was re-dissolved in DCM (10 mL) and powdered KOH was added to adjust pH to ~ 8-9 and the solution was filtered through a pad Celite and the filtrate was concentrated in vacuo to give a crude product 0.155 g (69% yield) of the title compound as an off white semi solid was obtained. This crude material was used as such for next step without purification. MS (ES⁺): m/z 511.35, 513.60 [M+H]⁺ (dimer), LCMS: t_R = 1.35 min(dimer).

[00649] tert-butyl (1-(3-(hydroxydimethylsilyl)benzoyl)pyrrolidin-3-yl)carbamate (36a):

[00650] A solution of 3-(hydroxydimethylsilyl)benzoic acid (200 mg, 1.0 mmol) in DCM (15 mL) was charged with EDCI (292 mg, 1.5 mmol), HOBt (137 mg, 1.0 mmol), DMAP (149 mg, 1.2 mmol), and stirred at room temperature for 10 minutes. tert-Butyl pyrrolidin-3-ylcarbamate (189.7 mg, 1.0 mmol) was added to the reaction mixture. The resulting solution was stirred at room temperature for 15 h. The reaction mixture was partitioned between DCM (10 mL) and H₂O (10 mL) and separated. The aqueous layer was re- extracted with DCM (3 x 15 mL) and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo resulting in a crude product 310 mg (83.5% yield) of the title compound as an off white semi solid. This crude product was taken on to the next step without purification. MS (ES⁺): m/z 711.45, 713.60 [M+H]⁺ (dimer); LCMS: t_R = 2.99 min(dimer).

[00651] 3-(hydroxydimethylsilyl)benzoic acid (35a):

[00652] A solution methyl 3-(hydroxydimethylsilyl)benzoate (3.10 g, 14 mmol) in 2:1 mixture of THF:H₂O (60 mL) was charged with LiOH (1.06 g, 44 mmol). The resulting solution was stirred for 6h at room temperature. The reaction mixture was concentrated in vacuo and acidified with saturated KHSO₄ solution up to adjust pH ~ 3. The aqueous layer was extracted with ethyl acetate (3 x 50 mL) and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to give a crude product. The crude product was stirred in n-pentane (50 mL) for 10 min and the solid product was filtered and dried get 1.80 g (62.2% yield) of title compound as an off white solid. ¹H NMR (400 MHz, CD₃OD): į = 8.21 (s, 1H), 8.02 (d, J = 7.7 Hz, 1H), 7.77– 7.65 (m, 1H), 7.47 (d, J = 7.6 Hz, 1H), 0.38 (s, 6H); MS (ES-): m/z 195.18 [M-1]- [00653] Methyl 3-(hydroxydimethylsilyl)benzoate (34a):

[00654] A suspension of methyl 3-bromobenzoate (5g, 23 mmol) in NMP (50 mL) was degassed under argon and charged with DIPEA (28.7 g, 130 mmol), PdCl₂(0.411 g, 04.6 mmol), DTBPBP (1.38 g, 130 mmol) and the reaction mixture was heated to 51°C for 30 min then 1,2-diethoxy-1,1-2,2-tetarmethyl silane (17.9 g, 130 mmol) was added and the reaction mixture was stirred for 5 h. The reaction mixture was cooled to room temperature and diluted with acetonitrile (100 mL) and was added 2-dimethylaminoethanethiol HCl (6.55 g, 46 mmol) and 2M acetic acid (25 mL) solution and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water (50 mL), and product was extracted in ethyl acetate (3 x 50 mL). All combined organic fraction were dried over Na₂SO_4, filtered and concentrated in vacuo to give a crude product which was purified by column chromatography (eluent:7% ethyl acetate in n-hexane) to obtain 3.1 g (63% yield) of title compound as light yellow solid. ¹H NMR (400 MHz, CDCl₃): į = 8.26 (d, J = 1.9 Hz, 3H), 8.06 (dq, J = 8.1, 1.5 Hz, 1H), 7.82– 7.75 (m, 2H), 7.46 (t, J = 7.5 Hz, 1H), 3.92 (s, 3H), 0.44 (m, 6H).

[00655] (3-aminopyrrolidin-1-yl)(4-(hydroxydimethylsilyl)phenyl)methanone (37b):

[00656] Yield: 71.4%. MS (ES⁺): m/z 511.25, 513.40 [M+H]⁺(dimer); LCMS: t_R = 1.37 min (dimer).

[00657] (3-(aminomethyl)pyrrolidin-1-yl)(3-(hydroxydimethylsilyl)

phenyl)methanone (37c):

[00658] Yield: 63%. MS (ES⁺): m/z 539.10, 541.30 [M+H]⁺; LCMS: t_R = 1.41 min (dimer).

[00659] (3-(aminomethyl)pyrrolidin-1-yl)(4-(hydroxydimethylsilyl)

phenyl)methanone (37d):

[00660] Yield: 58%. MS (ES⁺): m/z 539.00, 541.10 [M+H]⁺ (dimer); LCMS: t_R = 1.44 min (dimer).

[00661] tert-Butyl (1-(4-(hydroxydimethylsilyl)benzoyl)pyrrolidin-3-yl)carbamate (36b):

[00662] Yield: 80.8%. MS (ES⁺): m/z 711.35, 713.25 [M+H]⁺ (dimer); LCMS: t_R = 3.01 min(dimer).

[00663] tert-Butyl ((1-(3-(hydroxydimethylsilyl)benzoyl)pyrrolidin-3- yl)methyl)carbamate (36c):

[00664] Yield: 85.19%, MS (ES⁺): m/z 739.10, 741.40 [M+H]⁺ (dimer), LCMS: t_R = 3.04 min (dimer).

[00665] tert-Butyl ((1-(4-(hydroxydimethylsilyl)benzoyl)pyrrolidin-3- yl)methyl)carbamate (36d):

[00666] Yield: 85.19%. MS (ES⁺): m/z 739.10, 741.55 [M+H] ⁺ (dimer); LCMS: t_R = 3.02 min(dimer).

[00667] 4-(Hydroxydimethylsilyl)benzoic acid (35b):

[00668] A solution methyl 4-(hydroxydimethylsilyl) benzoate (2.50 g, 11 mmol) in the mixture of 2:1, THF: H₂O (37.5 mL) was charged with LiOH (0.85 g, 35 mmol). The resulting solution was stirred for 6h at room temperature. The reaction mixture was concentrated in vacuo and acidified with saturated KHSO₄ solution to adjust the pH ~ 3. The aqueous layer was extracted with ethyl acetate (3 x 50 mL) and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo resulting in a crude product which was stirred in n-pentane (50 mL) for 10 min, filtered off and dried the product to get 1.68 g (72% yield) of the title compound as an off white solid. ¹H NMR (400 MHz, CD₃OD): į = 8.2 (dd, J = 15.8, 7.6 Hz, 2H), 7.66 (dd, J = 15.8, 7.6 Hz, 2H), 0.38 (s, 6H).

[00669] Methyl 4-(hydroxydimethylsilyl)benzoate (34b):

[00670] A suspension of methyl 4-bromobenzoate (5 g, 23 mmol) in NMP (50 mL) was degassed under argon and charged with DIPEA (28.7 g, 130 mmol), PdCl₂ (0.411 g, 04.6 mmol), DTBPBP (1.38 g, 130 mmol) and the reaction mixture was heated to 51°C for 30 min then 1,2-diethoxy-1,1-2,2-tetarmethyl silane (17.9 g, 130 mmol) was added and the reaction mixture was stirred for 5 h. The reaction mixture was cooled to room temperature and diluted with acetonitrile (100 mL) and was added 2-dimethylaminoethanethiol HCl (6.55 g, 46 mmol) and 2M acetic acid (25 mL) solution and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water (50 mL), and product was extracted in ethyl acetate (3 x 50 mL). All combined organic fraction were dried over Na₂SO_4, filtered and concentrated in vacuo resulting in a crude product which was purified by column

chromatography(eluent: 7% ethyl acetate in n-hexane) to provide 2.5 g (51% yield) of title compound as light yellow solid. ¹H NMR (400 MHz, CDCl₃): į = 7.70– 7.63 (m, 2H), 7.33– 7.26 (m, 2H), 5.30 (s, 1H), 3.92 (s, 3H), 0.42 (s, 6H). EXAMPLES 66-69:

[00671] Monomers were synthesized according to the procedures described below. Scheme 21: Synthesis of Examples 66 to 69

[00672] N-(1-(2-((S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetyl)pyrrolidin-3-yl)-3- (hydroxydimethylsilyl)benzamide [Example 66]:

[00673] A solution of 3-(hydroxydimethylsilyl)benzoic acid (63 mg, 0.32 mmol) in DCM (15mL) was charged with EDCI (92.6 mg, 0.88 mmol), HOBt (43.6 mg, 0.58 mmol), DMAP (47.3 mg, 0.38 mmol), and stirred at room temperature for 10 minutes. 1-(3- aminopyrrolidin-1-yl)-2-((S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)ethanone (150 mg, 0.32 mmol) was added to the reaction mixture. After work up and preparative HPLC purification, 40 mg (19% yield) of the title compound was obtained as white solid. ¹H NMR (400 MHz, DMSO-d₆): į = 8.60 (d, J =, 7.0 Hz, 1H), 8.04– 7.96 (m, 1H), 7.89 (d, J = 8.8 Hz, 2H), 7.79 (dd, J = 9.0, 3.0 Hz, 1H), 7.68 (t, J = 6.2 Hz, 1H), 7.58– 7.33 (m, 6H), 6.86 (dd, J = 10.4, 2.9 Hz, 1H), 4.52–4.40 (m, , 1H), 4.11– 4.00 (m, 1H), 3.89 (t, J = 9.1 Hz, 1H), 3.82– 3.75 (m, 4H), 3.71– 3.57 (m, 1H), 3.55– 3.33 (m, 1H), 3.27 (d, J = 6.1 Hz, 2H), 2.56– 2.51 (m, 3H), 2.46 (s, 1H), 2.28 (s, 1H), 2.19– 2.05 (m, 1H), 2.02– 1.92 (m, 1H), 0.35 (s, 6H); MS (ES⁺): m/z 1269.10, 1271.40

[M+H]⁺ (dimer); LCMS: t_R = 2.71 min(dimer).

[00674] 1-(3-aminopyrrolidin-1-yl)-2-((S)-6-(4-chlorophenyl)-8-methoxy-1-methyl- 4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)ethanone (41):

[00675] A solution of tert-butyl (1-(2-((S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetyl)pyrrolidin-3-yl)carbamate (0.25 g, 0.44 mmol) in DCM (15 mL) was charged with TFA (1.25 mL) and stirred for 3 h at room temperature. Work up and preparative HPLC purification resulted in 0.15 g (73 % yield) of the title compound as an off white semi solid. MS (ES⁺): m/z 465.10, 467.25 [M+H]⁺; LCMS: t_R = 1.53 min.

[00676] tert-Butyl (1-(2-((S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetyl)pyrrolidin-3-yl)carbamate (40):

[00677] A solution of (S)-2-(6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetic acid (200 mg, 0.5 mmol) in DCM (15 mL) was charged with EDCI (144.6 mg, 0.75 mmol), DMAP (73.9 mg, 0.6 mmol), and stirred at room temperature for 10 minutes. To this solution, tert-butyl pyrrolidin-3-ylcarbamate (93.9 mg, 0.5 mmol) was added. After work up the reaction resulted in 0.25 g (88 % yield) of title compound was obtained as an off white semi solid. MS (ES⁺): m/z 565.10, 567.15 [M+H]⁺, LCMS: t_R = 2.35 min. [00678] The following compounds were synthesized analogously to the procedure described above in Scheme 21:

[00679] N-(1-(2-((S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetyl)pyrrolidin-3-yl)-4- (hydroxydimethylsilyl)benzamide [Example 67]:

[00680] Yield: 10 %. ¹H NMR (400 MHz, DMSO-d₆): į = 8.61 (dd, J = 6.4, 3.7 Hz, 1H), 8.54 (d, J = 6.7 Hz, 1H), 8.25 (s, 1H), 7.89– 7.76 (m, 4H), 7.64 (dt, J = 7.7, 3.7 Hz, 4H), 7.57– 7.34 (m, 1H), 6.87 (dd, J = 6.6, 2.9 Hz, 1H), 6.65 (s, 1H), 6.28 (s, 1H), 4.52– 4.42 (m, 1H), 4.03 (dt, J = 11.2, 6.0 Hz, 1H), 3.94– 3.82 (m, 2H), 3.79 (s, 3H), 3.70– 3.56 (m, 2H), 3.45 (d, J = 5.8 Hz, 2H), 3.40– 3.24 (m, 2H), 2.54 (s, 3H), 2.32– 2.22 (m, 2H), 2.20– 2.05 (m, 1H), 0.35 (s, 2H), 0.26 (s, 4H); MS (ES⁺): m/z 635.50, 637.20 [M/2]⁺ (dimer mass: 1268.39);

LCMS: t_R = 3.51 min (dimer).

[00681] N-((1-(2-((S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetyl)pyrrolidin-3-yl)methyl)-3- (hydroxydimethylsilyl)benzamide [Example 68]:

[00682] Yield: 21%. ¹H NMR (400 MHz, DMSO-d₆): į = 8.63 (td, J = 12.7, 11.7, 7.0 Hz, 1H), 8.01 (d, J = 3.6 Hz, 1H), 7.91– 7.74 (m, 2H), 7.70– 7.61 (m, 1H), 7.56– 7.33 (m, 6H), 6.86 (td, J = 3.6, 2.7, 1.5 Hz, 1H), 4.56– 4.47 (m, 1H), 3.87– 3.75 (m, 4H), 3.68 (p, J = 8.6 Hz, 1H), 3.57– 3.34 (m, 3H), 3.28 (t, J = 9.7 Hz, 1H), 3.08-2.95 (m, , 1H), 2.65– 2.37 (m, 1H), 2.07 (dq, J = 12.1, 6.3 Hz, 1H), 1.96 (dt, J = 12.6, 6.8 Hz, 1H), 1.78 (dq, J = 15.1, 8.1 Hz, 1H), 1.65 (dt, J = 12.4, 8.0 Hz, 1H), 0.37– 0.25 (m, 6H); MS (ES⁺): m/z 1296.10, 1298.35 [M+H]⁺ (dimer); LCMS: t_R = 2.72 min(dimer). [00683] N-((1-(2-((S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetyl)pyrrolidin-3-yl)methyl)-4- (hydroxydimethylsilyl)benzamide [Example 69]:

MR (400 MHz, DMSO- d₆): į = 7.76 (dd, J = 18.4, 5.8 Hz,

3H), 7.59 (d, J = 8.9 Hz, 2H), 7.50– 7.33 (m, 6H), 6.81 (d, J = 4.3 Hz, 1H), 4.5– 4.55(m,1H), 3.81 (d, J = 1.4 Hz, 4H), 3.68 (p, J = 8.6 Hz, 1H), 3.57– 3.34 (m, 3H), 3.28 (t, J = 9.7 Hz, 1H), 3.08–2.95 (m, , 1H), 2.53 (s, 3H), 0.32– 0.21 (m, 6H); MS (ES⁺): m/z 657.45, 659.45 [M+H]⁺ (monomer); LCMS: t_R = 2.27 min, 649.55, 651.10 [M/2]⁺(dimer); LCMS: t_R = 3.04 min.

[00685] 1-(3-(aminomethyl)pyrrolidin-1-yl)-2-((S)-6-(4-chlorophenyl)-8-methoxy-1- methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)ethanone (39):

[00686] A solution of tert-butyl (1-(2-((S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetyl)pyrrolidin-3-yl)carbamate (0.29 g, 0.50 mmol) in DCM (15 mL) was charged with TFA (1.45 mL) and stirred for 3 h at room temperature. After working up reaction, resulted in 0.14 g (58.5 % yield) of title compound as an off white semi solid. MS (ES⁺): m/z 479.35, 481.15 [M+H]⁺; LCMS: t_R = 1.53 min.

[00687] tert-Butyl ((1-(2-((S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetyl)pyrrolidin-3-yl)methyl)carbamate (38):

[00688] A solution of (S)-2-(6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetic acid (200 mg, 0.5 mmol) in DCM (15 mL) was charged with EDCI (144.6 mg, 0.75 mmol), DMAP (73.9 mg, 0.6 mmol), and stirred for 10 min at room temperature. This solution was charged with tert-butyl (pyrrolidin-3- ylmethyl)carbamate (101 mg, 0.5 mmol) and after work up obtained 0.29 g (99 % yield) of title compound as an off white semi solid. MS (ES+): m/z 579.40, 580.15 [M+H]⁺; LCMS: t_R = 2.38 min. EXAMPLES 70-73:

[00689] Monomers were synthesized according to the procedures described below.

[00690] (S)-2-(6-(4-chlorophenyl)-8-(4-((hydroxydimethylsilyl)methyl)phenyl)-1- methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide [Example 70]:

[00691] A solution of (S)-2-(8-(4-(bromomethyl)phenyl)-6-(4-chlorophenyl)-1-methyl- 4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (180 mg, 0.31 mmol.) , 1,2-diethoxy-1,1,2,2-tetramethyldisilane (395 mg , 1.9 mmol), 2-(di-tert- butylphosphino)biphenyl (18 mg, 0.06 mmol, 0.2 eq, 20 mol%, ), Palladium dichloride (5.6 mg, 0.031 mmol, 0.1 eq, 10 mol%) and DIPEA (247 mg, 1.9 mmol) in NMP (5 mL) was heated to 50°C for 2 h .The reaction mixture was partitioned between DCM (20 mL) and H₂O (10 mL) and separated. The aqueous layer was extracted with DCM (3 x 20 mL) and the combined organic fractions were washed with 5% aqueous acetic acid (3 x 10 ml) and then with water (3 x 10 mL). Organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo to give a crude product which was purified by preparative HPLC to afford 14 mg (8% yield) of the title compound as off white solid.¹H NMR (400 MHz, DMSO- d₆): į = 8.23 (t, J = 5.5 Hz, 1H), 8.06 (dd, J = 8.5, 2.2 Hz, 1H), 7.90 (d, J = 8.5 Hz, 1H), 7.61– 7.45 (m, 7H), 7.17– 7.10 (m, 2H), 4.54 (dd, J = 8.2, 6.0 Hz, 1H), 3.37– 3.02 (m, 7H), 2.60 (s, 3H), 2.11 (s, 2H), 1.07 (t, J = 7.2 Hz, 3H), -0.05 (s,6H); MS (ES⁺): m/z 558.10, 560.45

[M+H]⁺; LCMS: t_R = 2.42 min.

[00692] (S)-2-(6-(4-Chlorophenyl)-8-(4-(hydroxymethyl)phenyl)-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide [Example 71]:

[00693] A suspension of (S)-6-(4-chlorophenyl)-4-(2-(ethyl amino)-2-oxoethyl)-1- methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl trifluoromethanesulfonate (500 mg, 0.92 mmol) (3-(hydroxymethyl) phenyl) boronic acid (139 mg, 0.92 mmol), tetrakis (100 mg, , 0.86 mmol, 9.4 mol%) and sodium carbonate (291 mg, 2.7 mmol) in 1,4-dioxane (10 mL), H₂O (2 mL) and reaction mixture was stirred at 80°C for 40 min [Biotage microwave reactor, 400W]. The reaction mixture was filtered through a pad of Celite and the filtrate solution was diluted with DCM (20 mL) and the organic layer was concentrated in vacuo resulting in a crude product which was purified by column chromatography on silica gel (100-200 mesh) eluting with 3% methanol in DCM to afford 391 mg (85% yield) of the title compound as a white solid. ¹H NMR (400 MHz, DMSO-d₆): į = 8.23 (t, J = 5.5 Hz, 1H), 8.09 (dd, J = 8.6, 2.1 Hz, 1H), 7.93 (d, J = 8.5 Hz, 1H), 7.69– 7.59 (m, 3H), 7.59– 7.45 (m, 4H), 7.41 (d, J = 7.9 Hz, 2H), 5.24 (s, 1H), 4.54 (d, J = 9.4 Hz, 2H), 3.31– 3.04 (m, 5H), 2.60 (s, 3H), 1.07 (t, J = 7.2 Hz, 3H). MS (ES⁺): m/z = 500.10, 502.10 [M+H] ⁺; LCMS: t_R = 1.89 min.

[00694] (S)-2-(8-(4-(bromomethyl)phenyl)-6-(4-chlorophenyl)-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (42a):

[00695] A solution of (S)-2-(6-(4-chlorophenyl)-8-(4-(hydroxymethyl)phenyl)-1- methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide(320 mg, 0.64 mmol) in DCM (50 mL) was charged with phosphorus tribromide (0.173 mg, 0.64 mmol) at 0°C and the reaction mixture were stirred at 0°C under nitrogen atmosphere for 1 h. The reaction mixture was partitioned between DCM and H₂O (25 mL) and separated. The aqueous layer was extracted with DCM (3 x 20 mL) and the combined organic fractions were washed with saturated solution of sodium bicarbonate (3 X 20 mL) and then with H₂O (3 X 20 mL). The combined organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo resulting in a crude product which was purified by column chromatography on silica gel, eluting with 4 % methanol in dichloromethane to afford 180 mg (50% yield) of the titled compound. ¹H NMR (400 MHz, CD₃OD): į = 8.13 (dd, J = 8.8, 2.4 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.70(d, J = 2 Hz, 1H ), 7.62– 7.52 (m, 7H), 7.43 (d, J = 8.8, 2H), 4.75 (dd, J = 8.2, 6.0 Hz, 1H), 4.60(s,2H), 3.46– 3.40 (m, 1H), 3.31– 3.23 (m, 2H), 2.79 (s, 3H), 1.19 (t, J = 7.2 Hz, 3H); MS (ES⁺): m/z 562.15, 564.45 [M+H ⁺; LCMS: t_R = 2.64 min.

[00696] (S)-6-(4-chlorophenyl)-4-(2-(ethyl amino)-2-oxoethyl)-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl trifluoromethanesulfonate (8):

[00697] A suspension of (S)-2-(6-(4-chlorophenyl)-8-hydroxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (1.5 g, 3.6 mmol) in DCM (100 mL) was charged with 4-DMAP (1.34 g, 11 mmol ) and the reaction mixture was cooled to 0 - 5°C followed by addition of triflic anhydride (2.06 g, 7.3 mmol) at same temperature. The reaction mixture was stirred at room temperature for 2 h then the reaction mixture was partitioned between DCM and H₂O and separated. The aqueous layer was extracted with DCM (3 x 10 mL) and the combined organic fractions were washed with 5% aqueous solution of acetic acid and saturated solution of sodium bicarbonate. The combined organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo resulting in a crude product which was purified by column chromatography on silica gel (100-200 mesh), eluting with 5% methanol in dichloromethane to afford 1.2 g (60 % yield) of the title compound. ¹H NMR (400 MHz, CD₃OD): į = 7.99 (d, J = 8.8 Hz, 1H), 7.87 (dd, J = 8.8 2.8 Hz, 1H), 7.55– 7.50 (m, 3H), 7.42 (dd, J = 6.4,1.6 Hz 2H), 4.75 (dd, J = 8.2, 6.0 Hz, 1H), 3.45– 3.39 (m, 1H),3.31– 3.24 (m, 2H), 2.68 (s, 3H), 1.18 (t, J = 7.2 Hz, 3H). MS (ES⁺): m/z 542.20, 544.15 [M+H] ⁺; LCMS: t_R = 2.42 min.

[00698] (4-(Hydroxymethyl) phenyl) boronic acid:

[00699] A solution of (4-formylphenyl)boronic acid (1.5 g, 11 mmol.) in methanol (40 mL), was charged with sodiumborohydride (0.38 g, 11 mmol) at 0⁰C and the reaction mixture was stirred for 1 h. The reaction mixture was concentrated in vacuo resulting in a crude product was dissolved in water and cooled to 0-5°C and 5% aqueous acetic acid solution was added up to pH=~5. Precipitated solid was collected by filtration and dried to afford 1.2 (80 % yield) the titled compound.¹H NMR (400 MHz, CD₃OD) į 7.72 (d, J = 7.2 Hz, 1H), 7.59 (d, J = 7.6 Hz, 2H), 7.35– 7.30 (m, 2H), 4.60 (s, 2H); MS (ES+): m/z 542.15 , 544.35 [M+H] ⁺; LCMS: t_R = 2.42 min.

[00700] (S)-2-(6-(4-Chlorophenyl)-8-(3-(hydroxymethyl)phenyl)-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide [Example 72]:

[00701] A suspension of (S)-6-(4-chlorophenyl)-4-(2-(ethyl amino)-2-oxoethyl)-1- methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl trifluoromethanesulfonate (500 mg, 0.92 mmol) (3-(hydroxymethyl) phenyl) boronic acid (139mg, 0.92 mmol), tetrakis (100 mg, 0.86 mmol, 9.4 mol%) and sodium carbonate (291 mg, 2.7 mmol) in 1,4-dioxane (10 mL), H₂O (2 mL )and reaction mixture was stirred at 80 °C for 40 min [Biotage microwave reactor, 400W]. The reaction mixture was filtered through a pad of Celite and the filtrate solution was diluted with DCM (20 mL) and the organic layer was concentrated in vacuo resulting in a crude product which was purified by column chromatography on silica gel (100-200 mesh) eluting with 3% methanol in DCM to afford 368 mg (80% yield) of the title compound as a white solid. ¹H NMR (400 MHz, DMSO-d₆): į = 8.24 (t, J = 5.5 Hz, 1H), 8.08 (dd, J = 8.5, 2.1 Hz, 1H), 7.95 (d, J = 8.5 Hz, 1H), 7.64– 7.33 (m, 9H), 5.22 (d, J = 5.5 Hz, 1H), 4.58– 4.45 (m, 2H), 4.15 - 4.10 (m, 1H), 3.34– 3.02 (m, 4H), 2.61 (S, 3H), 1.11– 1.03 (m, 3H); MS (ES⁺): m/z = 500.05 , 502.15 [M+H] ⁺; LCMS: t_R = 1.95 min.

[00702] The following compound was synthesized according to Scheme 22 above:

[00703] (S)-2-(6-(4-chlorophenyl)-8-(4-((hydroxydimethylsilyl)methyl)phenyl)-1- methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide [Example 73]:

[00704] ¹H NMR (400 MHz, DMSO- d₆): į = 8.23 (t, J = 5.5 Hz, 1H), 8.04 (dd, J = 8.5, 2.1 Hz, 1H), 7.93 (d, J = 8.5 Hz, 1H), 7.59– 7.44 (m, 5H), 7.39– 7.25 (m, 3H), 7.08 (d, J = 7.4 Hz, 1H), 5.54 (s, 1H), 4.55 (dd, J = 8.4, 5.7 Hz, 1H), 3.32– 3.04 (m, 4H), 2.60 (s, 3H), 2.13 (s, 2H), 1.25 (d, J = 15.2 Hz, 3H), 1.07 (t, J = 7.2 Hz, 3H), 0.05– 0.06 (m, 6H); MS (ES⁺): m/z 558.30, 560.40 [M+H]⁺; LCMS: t_R = 2.39 min. EXAMPLES 74-76:

[00705] Monomers were synthesized according to the procedures described below. Scheme 23: Synthesis of Examples 74 to 76

[00706] Following a general procedure, all below compounds have been synthesized and characterized.

[00707] (S)-2-(6-(4-Chlorophenyl)-8-methoxy-1-methyl-4H-benzo[f][1,2,4] triazolo

[4,3-a][1,4]diazepin-4-yl)-N-(3,4-dihydroxyphenyl)acetamide [Example 74]:

[00708] A suspension of (S)-2-(6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetic acid (50 mg, 0.125 mmol) in DCM (5.0 mL) was charged with EDCI (36 mg, 0.188 mmol), 4-DMAP (23 mg, 0.188 mmol), and HOBt (25 mg, 0.188 mmol) and stirred at room temperature for 10 min. 4-aminobenzene-1,2-diol (23 mg, 0.188 mmol) was added to the reaction mixture. The resulting solution was stirred at room temperature for 15 h. The reaction mixture was partitioned between DCM (15 mL) and H₂O (15 mL) and separated. The aqueous layer was extracted with DCM ( 3 X 10 mL) and the combined organic fractions were washed with 5% aqueous solution of acetic acid and saturated solution of sodium bicarbonate. The organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo resulting in a crude product which was purified by silica gel column chromatography eluting with 0-10 % methanol in DCM to afford 20 mg (32% yield) of the title compound as a white solid. ¹H NMR (400 MHz, DMSO-d₆): į = 9.96 (s, 1H), 8.93 (s, 1H), 8.58 (s, 1H), 7.80 (d, J = 8.9 Hz, 1H), 7.57– 7.44 (m, 4H), 7.39 (dd, J = 9.0, 2.9 Hz, 1H), 7.16 (d, J = 2.4 Hz, 1H), 6.93– 6.80 (m, 2H), 6.63 (d, J = 8.5 Hz, 1H), 4.54 (dd, J = 8.3, 5.8 Hz, 1H), 3.79 (s, 3H), 3.45 (dd, J = 15.2, 8.4 Hz, 2H), 2.54 (s, 3H); MS (ES⁺): m/z = 504.05 , 506.10 [M+H] ⁺; LCMS: t_R = 2.12 min.

[00709] ((S)-(4-(2-(6-(4-Chlorophenyl)-8-methoxy-1-methyl-4H-benzo[f][1,2,4] triazolo[4,3-a][1,4]diazepin-4-yl)acetamido)phenyl)boronic acid [Example 75]:

[00710] A suspension of (S)-2-(6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetic acid (50 mg, 0.125 mmol) in DCM (1.5 mL) was charged with EDCI (36 mg, 0.188 mmol), 4-DMAP (23 mg, 0.188 mmol), and HOBt (25 mg, 0.188 mmol) and stirred at room temperature for 10 min. To this solution, (4- aminophenyl) boronic acid (25.7 mg, 0.188 mmol) was added. The resulting solution was stirred at room temperature for 15 h. The reaction mixture was partitioned between DCM (15 mL) and H₂O (15 mL) and separated. The aqueous layer was extracted with DCM (3 X 10 mL) and the combined organic fractions were washed with 5% aqueous solution of acetic acid and saturated solution of sodium bicarbonate. The organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo resulting in a crude product which was purified by silica gel column chromatography eluting with 0 to 10 % methanol in DCM to afford 20 mg of the desired compound (31 % yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): į = 10.35 (s, 1H), 7.90 (s, 1H), 7.81 (d, J = 9.0 Hz, 1H), 7.76– 7.69 (m, 2H), 7.62– 7.36 (m, 6H), 6.89 (d, J = 2.9 Hz, 1H), 4.57 (dd, J = 8.1, 6.0 Hz, 1H), 3.80 (s, 3H), 3.59– 3.38 (m, 2H), 2.55 (s, 3H); MS (ES⁺): m/z = 515.00, 516.10, 517.00, 518.15 [M+H]⁺; LCMS: t_R = 2.15 min.

[00711] (S)-(3-(2-(6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-benzo[f][1,2,4] triazolo[4,3-a][1,4]diazepin-4-yl)acetamido)phenyl)boronic acid [Example 76]:

1H NMR (400 MHz, DMSO-d₆): į = 10.24 (s, 1H), 8.04– 7.88 (m, 2H), 7.81 (d, J = 8.9 Hz, 2H), 7.74– 7.67 (m, 1H), 7.61– 7.22 (m, 6H), 6.89 (d, J = 2.9 Hz, 1H), 4.58 (m, 1H), 3.78 (s, 3H), 3.57– 3.37 (m, 2H), 2.54 (s, 3H); MS (ES⁺): m/z = 515.10, 516.00, 517.15, 517.00

[M+H]⁺; LCMS: t_R = 2.32 min. EXAMPLES 77-80:

[00712] Monomers were synthesized according to the procedures described below.

[00713] General procedure for triflate synthesis: (S)-6-(4-Chlorophenyl)-4-(2-(ethyl amino)-2-oxoethyl)-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl trifluoromethanesulfonate (8):

[00714] A suspension of (S)-2-(6-(4-chlorophenyl)-8-hydroxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (4.0 g, 9.7 mmol ) in DCM (120 mL) was charged with 4-DMAP (3.55 g, 29.1 mmol) and the reaction mixture was cooled to 0°C followed by addition of triflic anhydride (4.13 g, 14.6 mmol) at same temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was partitioned between DCM and H₂O and separated. The aqueous layer was extracted with DCM (3 X 100 mL) and the combined organic fractions were washed with 5% aqueous solution of acetic acid and saturated solution of sodium bicarbonate. Organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo to give the title compound (4.6 g, 88 % yield) as a white solid. MS (ES⁺): m/z = 542.20, 544.35 [M+H]⁺; LCMS: t_R = 2.40 min.

[00715] (S)-2-(6-(4-chlorophenyl)-8-(3,4-dihydroxyphenyl)-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide [Example 77]:

[00716] A suspension of (S)-6-(4-chlorophenyl)-4-(2-(ethyl amino)-2-oxoethyl)-1- methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl trifluoromethanesulfonate (100 mg, 0.184 mmol), (3,4-dihydroxyphenyl)boronic acid (42.6 mg, 0.276 mmol), dichloro{1,1'- Bis(diphenylphosphino)ferrocene}-palladium.DCM adduct (20 mg, 0.024 mmol, 13.31 mol %) and sodium carbonate (39 mg, 0.369 mmol) in 1,4-dioxane (6.0 mL) and H₂O (1.5 mL) in a sealed microwave reaction tube under nitrogen atmosphere was heated to 140°C for 30 min in a MW. The reaction mixture was partitioned between DCM (50 mL) and H₂O (10 mL) and separated. The aqueous layer was extracted with DCM (3 X 20 mL) and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered and concentrated to give a crude product which was purified by column chromatography on silica gel eluting with 5 to 15 % methanol in DCM and then purified by preparative HPLC to give 20 mg (22% yield) of the title compound as a white solid. ¹H NMR (400 MHz, DMSO-d₆): į = į 9.17 (br.s, 2H), 8.22 (t, J = 5.5 Hz, 1H), 7.94 (dd, J = 8.6, 2.1 Hz, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.58– 7.42 (m, 5H), 7.04– 6.92 (m, 2H), 6.81 (d, J = 8.2 Hz, 1H), 4.53 (dd, J = 8.1, 6.0 Hz, 1H), 3.32– 3.02 (m, 4H), 2.59 (s, 3H), 1.06 (t, J = 7.2 Hz, 3H); MS (ES⁺): m/z = 502.10, 504.25 [M+H]⁺; LCMS: t_R = 1.951 min.

[00717] (S)-(3-(6-(4-chlorophenyl)-4-(2-(ethyl amino)-2-oxoethyl)-1-methyl-4H- benzo[f][1,2,4] triazolo[4,3-a][1,4]diazepin-8-yl)phenyl)boronic acid [Example 78]:

[00718] A suspension of (S)-6-(4-chlorophenyl)-4-(2-(ethylamino)-2-oxoethyl)-1- methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl trifluoromethanesulfonate (100 mg, 0.184 mmol), 1,3-phenylenediboronic acid (61 mg, 0.368 mmol), dichloro{1,1'- Bis(diphenylphosphino)

ferrocene}-palladium.DCM adduct (20 mg, 0.024 mmol, 13.31 mol%) and sodium carbonate (39 mg, 0.369 mmol) in 1,4-dioxane (6.0 mL) and H₂O (1.5 mL) in a sealed microwave reaction tube under nitrogen atmosphere was heated to 140°C for 30 min [Biotage microwave reactor, 400W]. The reaction mixture was partitioned between DCM (50 mL) and H₂O (10 mL) and separated. The aqueous layer was extracted with DCM (3 X 20 mL) and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered, and concentrated to give a crude product which was purified by column chromatography on silica gel eluting with 0 to 10 % methanol in DCM and then purified by preparative HPLC to give 10 mg (11% yield) of the title compound as a white solid. ¹H NMR (400 MHz, DMSO-d₆): į = 8.22 - 8.10 (m, 2H), 8.09 (d, J = 7.4 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.83– 7.61 (m, 3H), 7.60– 7.40 (m, 4H), 4.56 (dd, J = 8.4, 5.6 Hz, 1H), 3.25 (d, J = 8.9 Hz, 2H), 3.21– 3.06 (m, 2H), 2.76– 2.52 (m, 3H), 1.07 (t, J = 7.2 Hz, 3H); MS (ES⁺): m/z = 513.00, 514.10, 515.00, 516.15 [M+H]⁺; LCMS: t_R = 2.10 min.

[00719] (S)-(4-(6-(4-chlorophenyl)-4-(2-(ethylamino)-2-oxoethyl)-1-methyl-4H- benzo[f][1,2,4] triazolo[4,3-a][1,4]diazepin-8-yl)phenyl) boronic acid [Example 79]:

[00720] ¹H NMR (400 MHz, DMSO-d₆): į = 8.23– 8.14 (m, 2H), 8.12 (d, J = 5.2 Hz, 1H), 7.94 (d, J = 8.5 Hz, 1H), 7.87 (d, J = 7.7 Hz, 1H), 7.70– 7.63 (m, 2H), 7.59– 7.45 (m, 4H), 4.55 (dd, J = 8.1, 5.9 Hz, 1H), 3.31– 3.04 (m, 4H), 2.61 (s, 3H), 1.07 (t, J = 7.2 Hz, 3H); MS (ES⁺): m/z = 513.10, 514.00, 515.10, 516.00 [M+H]+; LCMS: t_R = 2.057 min.

[00721] (S)-2-(6-(4-chlorophenyl)-8-(6,7-dihydroxynaphthalen-2-yl)-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide [Example 80]:

[00722] A solution of (S)-2-(6-(4-bromophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (150 mg, 0.320 mmol) in DCM (3 mL) was charged with boron tribromide (172 mg, 0.689 mmol) at 0°C and the resulting solution was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo and the residue was poured into a cold solution of saturated aq. solution of sodium bicarbonate and the precipitated crude product was filtered and dried. The crude product was purified by preparative HPLC to give 15 mg (16 % yield) of the title compound as a white solid. ¹H NMR (400 MHz, DMSO-d₆): į = 9.65 (s, 1H), 8.24 (t, J = 5.4 Hz, 1H), 8.16 (dd, J = 8.5, 2.2 Hz, 1H), 7.94 (dd, J = 5.2, 3.3 Hz, 1H), 7.72– 7.62 (m, 2H), 7.61– 7.43 (m, 4H), 7.20 (s, 1H), 7.15 (s, 1H), 4.57 (dd, J = 8.3, 5.7 Hz, 1H), 3.33– 3.03 (m, 4H), 2.62 (s, 3H), 1.08 (t, J = 7.1 Hz, 3H); MS (ES⁺): m/z = 552.35, 554.15 [M+H]⁺; LCMS: t_R = 2.22 min.

[00723] (S)-2-(6-(4-chlorophenyl)-8-(6,7-dimethoxynaphthalen-2-yl)-1-methyl-4H- benzo[f][1,2,4] triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide:

[00724] A suspension of (S)-6-(4-chlorophenyl)-4-(2-(ethylamino)-2-oxoethyl)-1- methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl trifluoromethanesulfonate (200 mg, 0.369 mmol), 2-(6,7-dimethoxynaphthalen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (231.9 mg, 0.738 mmol), dichloro{1,1'-Bis(diphenylphosphino)ferrocene}-palladium.DCM adduct (40 mg, 0.048 mmol, 13.56 mol%) and sodium carbonate (78.2 mg, 0.738 mmol) in 1,4- dioxane (9 mL), H₂O (3 mL) in a sealed microwave reaction tube under nitrogen atmosphere was heated to 140°C for 30 min [Bitoage microwave reactor, 400W]. The reaction mixture was partitioned between DCM (50 mL) and H₂O (10 mL) and separated. The aqueous layer was extracted with DCM (3 X 20 mL) and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered, and concentrated to give a crude product which was purified by column chromatography silica gel eluting with 0 to 5 % methanol in DCM to give 150 mg (70 % yield) of the title compound as a white solid. MS (ES⁺): m/z = 580.25, 582.40 [M+H]⁺; LCMS: t_R = 2.77 min. EXAMPLES 81-84:

[00725] Monomers were synthesized according to the procedures described below.

[00726] (S)-2-(6-(4-chlorophenyl)-1-methyl-8-(phenylthio)-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide [Example 81]:

[00727] A suspension of (S)-6-(4-chlorophenyl)-4-(2-(ethyl amino)-2-oxoethyl)-1- methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl trifluoromethanesulfonate (50 mg, 0.092 mmol), thiophenol (20 mg, 0.184 mmol),

tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (10 mg, 0.0096 mmol, 10.5 mol%), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (10 mg, 0.0017 mmol, 18.78 mol%) and DIPEA (36 mg, 0.276 mmol) in 1,4-dioxane (1 mL) in a sealed microwave reaction tube under nitrogen atmosphere was heated to 140°C for 30 min [Biotage microwave reactor, 400W]. The reaction mixture was partitioned between DCM (50 mL) and H₂O (10 mL) and separated. The aqueous layer was extracted with DCM (3 X 20 mL) and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo to give a crude product which was purified by column chromatography on silica gel eluting with 5 to 15 % methanol in DCM to give 15 mg (33% yield) of the title compound as a white solid. ¹H NMR (400 MHz, DMSO-d₆): į = 8.19 (t, J = 5.5 Hz, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.61 (dd, J = 8.6, 2.2 Hz, 1H), 7.52– 7.33 (m, 9H), 7.00 (d, J = 2.2 Hz, 1H), 4.48 (dd, J = 8.4, 5.8 Hz, 1H), 3.28– 3.02 (m, 4H), 2.54 (s, 3H), 1.05 (t, J = 7.2 Hz, 3H); MS (ES⁺): m/z = 502.10, 504.25 [M+H]⁺; LCMS: t_R = 2.83 min.

[00728] (S)-(3-((6-(4-chlorophenyl)-4-(2-(ethylamino)-2-oxoethyl)-1-methyl-4H- benzo[f][1,2,4] triazolo[4,3-a][1,4]diazepin-8-yl)thio)phenyl)boronic acid [Example 82]:

[00729] ¹H NMR (400 MHz, DMSO-d₆): į = 8.25– 8.12 (m, 2H), 7.95– 7.88 (m, 1H), 7.85– 7.73 (m, 2H), 7.60– 7.49 (m, 2H), 7.45– 7.31 (m, 5H), 4.48 (dd, J = 8.4, 5.7 Hz, 1H), 3.27– 3.00 (m, 4H), 2.53 (s, 3H), 1.13 (t, J = 7.12 Hz, 3H); MS (ES⁺): m/z = 545.15, 546.20, 547.15, 547.20 [M+H]⁺; LCMS: t_R = 2.28 min. [00730] (S)-(4-((6-(4-chlorophenyl)-4-(2-(ethylamino)-2-oxoethyl)-1-methyl-4H- benzo[f][1,2,4] triazolo[4,3-a][1,4]diazepin-8-yl)thio)phenyl)boronic acid [Example 83]:

[00731] ¹H NMR (400 MHz, DMSO-d₆): į = 8.22– 8.10 (m, 3H), 7.80 (t, J = 8.4 Hz, 3H), 7.63 (dd, J = 8.5, 2.2 Hz, 1H), 7.50– 7.32 (m, 4H), 7.13 (d, J = 2.2 Hz, 1H), 4.50 (dd, J = 8.3, 5.8 Hz, 1H), 3.29– 3.01 (m, 4H), 2.55 (s, 3H), 1.05 (t, J = 7.1 Hz, 3H); MS (ES⁺): m/z = 545.10, 546.00, 547.10, 548.00 [M+H]⁺; LCMS: t_R = 2.23 min.

[00732] (S)-(6-(4-chlorophenyl)-4-(2-(ethylamino)-2-oxoethyl)-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl)boronic acid [Example 84]:

[00733] A suspension of (S)-6-(4-chlorophenyl)-4-(2-(ethylamino)-2-oxoethyl)-1- methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl trifluoromethanesulfonate (264 mg, 0.488 mmol), bispinacolato diborane (247 mg, 0.977 mmol), dichloro{1,1'- bis(diphenylphosphino)ferrocene}-palladium.DCM adduct (53 mg, 0.649 mmol, 13.29 mol% ) and potassium acetate (143 mg, 1.46 mmol) in 1,4-dioxane (3 mL) in a sealed microwave reaction tube under nitrogen atmosphere was heated to 140°C for 30 min [Biotage microwave reactor, 400W]. The reaction mixture was partitioned between DCM (40 mL) and H₂O (10 mL) and separated. The aqueous layer was extracted with DCM (3 X 20 mL) and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered, and concentrated to give a crude product which was purified by preparative HPLC. ¹H NMR (400 MHz, DMSO-d₆): į = 8.38 (s, 1H), 8.25– 8.11 (m, 4H), 7.81 (dd, J = 6.4, 2.9 Hz, 1H), 7.56– 7.43 (m, 2H), 4.44 (dd, J = 8.5, 5.5 Hz, 1H), 3.30– 3.03 (m, 4H), 2.57 (s, 3H), 1.06 (t, J = 7.2 Hz, 3H); MS (ES⁺): m/z = 437.10, 438.20, 439.10, 440.20 [M+H]⁺; LCMS: t_R = 1.85min. EXAMPLES 85 and 86:

[00734] Monomers were synthesized according to the procedures described below.

[00735] (S)-(3-((4-(4-(2-(ethylamino)-2-oxoethyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)phenyl)thio)phenyl)boronic acid [Example 85]:

[00736] A suspension of (S)-2-(6-(4-bromophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (100 mg, 0.213 mmol), (3- mercaptophenyl)boronic acid (65.5 mg, 0.426 mmol), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (20 mg, 0.019 mmol, 9 mol %), 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene (20 mg, 0.0345 mol, 16 mol %) and DIPEA (82.5 mg, 0.639 mmol) in 1,4- dioxane (2 mL) in a sealed microwave reaction tube under nitrogen atmosphere was heated to 140°C for 30 min [Biotage microwave reactor, 400W]. The reaction mixture was partitioned between DCM (50 mL) and H₂O (10 mL) and separated. The aqueous layer was extracted with DCM (3 X 10 mL) and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo to give a crude product which was purified by column chromatography on silica gel eluting with 5 to 20 % methanol in DCM to give 12 mg (10% yield) of the title compound as a white solid. ¹H NMR (400 MHz, DMSO-d₆): į = 8.17 (t, J = 4.4 Hz, 1H), 7.87– 7.73 (m, 2H), 7.49– 7.28 (m, 5H), 7.22 (d, J = 7.6 Hz, 2H), 6.88 (d, J = 3.2 Hz, 1H), 4.45 (dd, J = 8.5, 5.6 Hz, 1H), 3.78 (s, 3H), 3.26– 2.99 (m, 4H), 2.54 (s, 3H), 1.04 (t, J = 7.3 Hz, 3H); MS (ES⁺): m/z = 541.00, 542.10, 543.00, 544.20 [M+H]⁺; HPLC: t_R = 2.04 min.

[00737] (S)-(4-((4-(4-(2-(ethylamino)-2-oxoethyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)phenyl)thio)phenyl)boronic acid [Example 86]:

[00738] ¹H NMR (400 MHz, DMSO-d₆): į = 8.16 (t, J = 5.4 Hz, 1H), 7.77 (d, J = 8.0 Hz, 2H), 7.54– 7.27 (m, 4H), 7.26– 7.18 (m, 2H), 7.13 (s, 1H), 6.90 (d, J = 3.1 Hz, 1H), 4.08 (d, J = 5.7 Hz, 1H), 3.78 (s, 3H), 3.14-3.05 (m, 4H), 2.55 (s, 3H), 1.03 (t, J = 7.4 Hz, 3H); MS (ES⁺): m/z = 541.00, 542.10, 543.00, 544.20 [M+H]⁺; LCMS: t_R = 2.01 min. EXAMPLES 87-89:

[00739] Monomers were synthesized according to the procedures described below. Scheme 27: Synthesis of Examples 87 to 89

[00740] (S)-(4-(((4-(4-(2-(ethylamino)-2-oxoethyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)phenyl)thio)methyl)phenyl)boronic acid [Example 87]:

[00741] A suspension of (S)-2-(6-(4-bromophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (100 mg, 0.213 mmol), potassium thioacetate (48.65 mg, 0.426 mmol), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (20 mg, 0.019 mmol, 9.07 mol%), 4,5-bis(diphenylphosphino)-9,9- dimethyl- xanthene (20 mg, 0.034 mmol, 16 mol %) and DIPEA (82.5 mg, 0.639 mmol) in 1,4- dioxane (2 mL) in a sealed microwave reaction tube under nitrogen atmosphere was heated to 140°C for 30 min [Biotage microwave reactor, 400W] The reaction mixture was partitioned between DCM (10 mL) and H₂O (5 mL) and separated. The aqueous layer was extracted with DCM (3 X 10 mL) and the combined organic fractions were washed with 5% aqueous solution of acetic acid, dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo resulting in a crude product which was then charged with KOH (35.8 mg, 0.639 mmol) in methanol (3 mL) at room temperature for 3 h. The reaction mixture was partitioned between DCM (10 mL) and H₂O (5 mL) and separated. The aqueous layer was extracted with DCM (3 X 10 mL) and the combined organic fractions were washed with 5% aqueous solution of acetic acid, dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo resulting in a crude product which was dissolved in acetonitrile (5 mL) and charged with sodium bicarbonate (53.6 mg, 0.63 mmol) and (4-(bromomethyl)phenyl)boronic acid and stirred at room temperature for 2 h. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo and purified by preparative HPLC to obtain 10 mg (8 % yield) of the title compound as a white solid. ¹H NMR (400 MHz, DMSO-d₆): į = 8.19 (t, J = 5.5 Hz, 1H), 7.98 (s, 2H), 7.77 (d, J = 8.9 Hz, 1H), 7.68 (d, J = 7.8 Hz, 2H), 7.44– 7.29 (m, 6H), 6.84 (d, J = 3.0 Hz, 1H), 4.44 (dd, J = 8.3, 5.8 Hz, 1H), 4.29 (s, 2H), 3.78 (s, 3H), 3.29– 3.02 (m, 4H), 2.55 (s, 3H), 1.06 (t, J = 7.2 Hz, 3H); MS (ES⁺): m/z = 555.10, 556.00, 557.10, 558.00 [M+H]⁺; LCMS: t_R = 2.13 min.

[00742] (S)-(3-(((4-(4-(2-(ethylamino)-2-oxoethyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)phenyl)thio)methyl)phenyl)boronic acid [Example 88]:

[00743] ¹H NMR (400 MHz, DMSO-d₆): į = 8.22– 8.18 (m, 1H), 8.03 (s, 2H), 7.83– 7.73 (m, 3H), 7.45– 7.23 (m, 7H), 6.84 (s, 1H), 4.44 (dd, J = 8.3, 5.8 Hz, 1H), 4.28 (s, 2H), 3.78 (s, 3H), 3.27– 3.04 (m, 4H), 2.50 (s, 3H), 1.06 (t, J = 7.2 Hz, 3H); MS (ES+): m/z = 555.10, 556.15, 557.00, 558.10 [M+H]⁺; LCMS: t_R = 2.16 min.

[00744] (S)-(2-(((4-(4-(2-(ethylamino)-2-oxoethyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)phenyl)thio)methyl)phenyl)boronic acid

[00745] ¹H NMR (400 MHz, DMSO-d₆): į = 8.22 - 8.17 (m, 3H), 7.77 (d, J = 9.1 Hz, 1H), 7.51 - 7.14 (m, 9H), 6.88 (m, 1H), 4.46– 4.40 (m, 3H), 3.79 (s, 3H), 3.24– 3.12 (m, 4H), 2.54 (s, 3H), 1.06 (t, J = 6.6 Hz, 3H); MS (ES+): m/z = 555.00, 556.15, 557.00, 558.15

[M+H]⁺; LCMS: t_R = 2.00 min EXAMPLE 90:

[00746] Example 90 was synthesized according to the procedure described below. Scheme 28: Synthesis of Example 90

[00747] (S,E)-N-ethyl-2-(6-(4-(2-(hydroxydimethylsilyl)vinyl)phenyl)-8-methoxy-1- methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetamide (Monomer)

[

[00748] A suspension of (S)-2-(6-(4-bromophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (1.5 g, 3.2 mmol), ethoxy dimethyl vinyl silane (1.25 g, 9.61 mmol), dichloro bis(tri-O-toluyl phosphine)palladium (300 mg, 0.381 mmol,11.9 mol%) and TEA (972 mg, 9.61 mmol) in DMF (7.5 mL) in a sealed microwave reaction tube under nitrogen atmosphere was heated at 100°C for 60 min [Biotage microwave reactor, 400W]. The reaction mixture was partitioned between DCM (100 mL) and H₂O (50 mL) and separated. The aqueous layer extracted with DCM (3 X 150 mL ) and the combined organic fractions were washed with H₂O (3 X 150 mL ) and dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo to give a crude product, which was stirred in mixture of diethyl ether (300 mL) and hexane (200 mL). The solid was filtered and purified by preparative HPLC to give 240 mg (15% yield) of the title compound as a white solid. ¹H NMR (400 MHz, CDCl₃): į = 7.55 (d, J = 9.0 Hz, 1H), 7.57– 7.44 (m, 4H), 7.19– 7.16 (dd, J = 9.1, 2.9 Hz, 2H), 7.02– 6.99- (dd, J = 19.3, 10.7 Hz, 1H), 6.84 (dd, J = 7.8, 3.4 Hz, 1H), 6.53– 6.49 (dd, J = 19.3, 10.8 Hz, 1H), 4.47 (t, J = 8.3 Hz, 1H), 3.78 (s, 3H), 3.16– 3.05 (m, 4H), 2.54 (s, 3H), 1.07 (t, J = 7.1 Hz, 3H), 0.25 (s, 6H); MS (ES⁺): m/z = 490.14 [M+H]⁺ (monomer); LCMS: t_R = 1.89 min (monomer), MS (ES⁺): m/z = 481.10 [M /2]⁺ 961.40

[M+H]⁺ (dimer); LCMS: t_R = 3.47 min (dimer). EXAMPLES 91 and 92:

[00749] Monomers were synthesized according to the procedures described below.

[00750] (S)-N-ethyl-2-(6-(4-(2-(hydroxydimethylsilyl)ethyl)phenyl)-8-methoxy-1- methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetamide [Example 91]:

[00751] A solution of (S,E)-N-ethyl-2-(6-(4-(2-(hydroxydimethylsilyl)vinyl)phenyl)-8- methoxy-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetamide (50 mg, 0.102 mmol), CuCl₂ (10 mg, 0.074 mmol, 72.54 mol %) in toluene (5 mL) was charged with hydrazine hydrate (250 mg, 5.0 mmol) at room temperature and the reaction mixture was stirred for 2 h. The reaction mixture was filtered through pad of celite and filtrate was partitioned between DCM (10 mL) and H₂O (5 mL) and separated. The aqueous layer was extracted with DCM (3 X 10 mL) and the combined organic fractions were washed with H₂O (3 X 10 mL) and dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo resulting in a crude product which was purified by preparative HPLC to obtain 20 mg (39 % yield) of the title compound. ¹H NMR (400 MHz, DMSO-d₆) į = 8.23 - 8.20 (m, 1H), 7.83– 7.73 (m, 1H), 7.53– 7.39 (m, 3H), 7.23– 7.19 (m, 2H), 6.82 (dd, J = 10.6, 2.9 Hz, 1H), 4.44 (m, 1H), 3.77 (s, 3H), 3.27– 3.01 (m, 5H), 2.69– 2.50 (m, 2H), 2.50 (s, 3H), 1.26– 0.95 (m, 3H), 0.93– 0.76 (m, 2H), 0.11 (s, 3H), 0.03 (s, 3H); MS (ES+): m/z = 492.15 [M+H]⁺ (monomer); LCMS: t_R = 1.89 min (monomer); MS (ES+): m/z = 484.00 [M+1/2]⁺ (dimer); LCMS: t_R = 3.84 min (dimer).

[00752] (S)-N-ethyl-2-(6-(4-ethylphenyl)-8-methoxy-1-methyl-4H-benzo

[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetamide [Example 92]:

[00753] Product was isolated form preparative HPLC of crude (S)-N-ethyl-2-(6-(4-(2- (hydroxydimethylsilyl)ethyl)phenyl)-8-methoxy-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3- a][1,4]diazepin-4-yl)acetamide as byproduct formed while reaction was in progress. The crude material was purified by preparative HPLC, to obtained 10 mg (23.80 % yield) of the title compound as a white solid. ¹H NMR (400 MHz, DMSO-d₆): į = 8.18 (t, J = 5.6 Hz, 1H), 7.78 (d, J = 8.9 Hz, 1H), 7.46– 7.33 (m, 3H), 7.28– 7.19 (m, 2H), 6.85 (d, J = 2.9 Hz, 1H), 4.46 (dd, J = 8.2, 5.8 Hz, 1H), 3.79 (s, 3H), 3.31– 3.01 (m, 4H), 2.63 (q, J = 7.6 Hz, 2H), 2.53 (s, 3H), 1.17 (t, J = 7.5 Hz, 3H), 1.06 (t, J = 7.2 Hz, 3H); MS (ES⁺): m/z = 418.40 [M+H]⁺;

LCMS: t_R = 2.142 min. EXAMPLE 93:

[00754] Example 93 was synthesized according to the procedure described below.

Scheme 30: Synthesis of Example 93

[00755] (S,E)-N-ethyl-2-(6-(4-(3-hydroxy-3-methylbut-1-en-1-yl)phenyl)-8-methoxy- 1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetamide [Example 93]:

[00756] A suspension of (S)-2-(6-(4-bromophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (250 mg , 0.533 mmol) , 2- methylbut-3-en-2-ol (137 mg, 1.60 mmol), dichloro bis(tri-O-toluyl phosphine)palladium (50 mg, 0.63 mmol, 11.93 mol %) and TEA (161 mg, 1.60 mmol) in DMF (5 mL) in a sealed microwave reaction tube under nitrogen atmosphere was heated at 100°C for 60 min [Biotage microwave reactor, 400W]. The reaction mixture was partitioned between DCM (10 mL), H₂O (5 mL) and separated. The aqueous layer was extracted with DCM (3 X 10 mL) and the combined organic fractions were washed with H₂O (3 X 10 mL) and dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo resulting in a crude product which was stirred in mixture of diethyl ether (30 mL) and hexane (20 mL). The solid was filtered and purified by preparative HPLC to give 70 mg (27.7 % yield) of the title compound the title compound as a white solid. ¹H NMR (400 MHz, DMSO-d₆): į = 8.21 (t, J = 5.6 Hz, 1H), 7.78 (d, J = 8.9 Hz, 1H), 7.49– 7.33 (m, 5H), 6.85 (d, J = 2.9 Hz, 1H), 6.59– 6.48 (m, 2H), 4.74 (s, 1H), 4.46 (dd, J = 8.4, 5.7 Hz, 1H), 3.78 (s, 3H), 3.29– 3.03 (m, 4H), 2.53 (s, 3H), 1.26 (s, 6H), 1.07 (t, J = 7.2 Hz, 3H); MS (ES⁺): m/z = 474.25 [M+H]⁺; LCMS: t_R = 1.75 min. EXAMPLE 94:

[00757] Example 94 was synthesized according to the procedure described below. Scheme 31: Synthesis of Example 94

[00758] 2-((4S)-6-(4-chlorophenyl)-8-(2-hydroxy-3-(3- (hydroxydimethylsilyl)propoxy)propoxy)-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3- a][1,4]diazepin-4-yl)-N-ethylacetamide (Monomer) [Example 94]:

[00759] A suspension of (S)-2-(6-(4-chlorophenyl)-8-hydroxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (100 mg, 0.243 mmol), ethoxydimethyl(3-(oxiran-2-ylmethoxy)propyl)silane (160 mg, 0.731 mmol) and potassium carbonate (33.5 mg, 0.243 mmol) in isopropyl alcohol (3 mL) was heated to 81°C for 12 h. The reaction mixture was partitioned between DCM (10 mL) and H₂O (5 mL) and separated. The aqueous layer was extracted with DCM (3 X 10 mL) and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo resulting in a crude product which was purified by SFC to obtain 20 mg (13 % yield) of the title compound. ¹H NMR (400 MHz, DMSO-d₆): į = 8.21 (t, J =, 5.8 Hz, 1H), 7.81– 7.72 (m, 1H), 7.55– 7.42 (m, 5H), 7.38 (dd, J = 9.0, 2.8 Hz, 1H), 6.95 (m, 1H), 5.27 (s, 1H), 5.09 (d, J = 4.9 Hz, 1H), 4.47 (dd, J = 8.4, 5.8 Hz,1H), 4.08– 3.84 (m, 3H), 3.45– 3.32 (m, 4H), 3.28– 3.03 (m, 4H), 2.53 (s, 3H), 1.48– 1.38 (m, 2H), 1.06 (t, J = 7.2 Hz, 3H), 0.56– 0.41 (m, 2H), 0.03 (s, 6H); MS (ES⁺): m/z = 600.05, 602.20 [M+H]⁺ (monomer); LCMS: t_R = 1.93 min (monomer); MS (ES⁺): m/z = 590.25, 592.15 [M/2]⁺ (dimer); LCMS: t_R = 3.09 min (dimer). EXAMPLES 95-98:

[00760] Monomers were synthesized according to the procedures described below. Scheme 32: Synthesis of Examples 95 to 98

[00761] (S)-N-(2-(2-(6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetamido)ethyl)-3- ((hydroxydimethylsilyl)methyl)benzamide (Monomer) [Example 95]:

[00762] A suspension of 3-((hydroxydimethylsilyl)methyl)benzoic acid (47.9 mg ,0.227 mmol.) in DCM (3 mL) was charged with EDCI (65.2 mg, 0.340 mmol), 4-DMAP (41.53 mg, 0.340 mmol), HOBt(45.9 mg , 0.340 mmol) and stirred at room temperature for 10 minutes. This solution was charged with (S)-N-(2-aminoethyl)-2-(6-(4-chlorophenyl)-8-methoxy-1- methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetamide (100 mg, 0.227 mmol) and stirred at room temperature for 15 h. The reaction mixture was partitioned between DCM (10 mL) and H₂O (5 mL) and separated. The aqueous layer was extracted with DCM (3 X 10 mL) and the combined organic fractions were washed with 5% aqueous solution of acetic acid, saturated solution of sodium bicarbonate, dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo resulting in a crude product which was purified by preparative HPLC to give 20 mg (14 % yield) of the title compound. ¹H NMR (400 MHz, DMSO-d₆): į = 8.39– 8.35 (m, 2H), 7.78 (dd, J = 9.0, 2.8 Hz, 1H), 7.57– 7.15 (m, 9H), 6.83 (dd, J = 4.8, 2.7 Hz, 1H), 5.56 (s, 1H), 4.49 (dd, J = 8.6, 5.7 Hz, 1H), 3.78 (s, 3H), 3.43– 3.22 (m, 4H), 2.53 (s, 3H), 2.10 (d, J = 11.1 Hz, 2H), 1.09 (t, J = 7.0 Hz, 2H), 0.07 (s, 6H); MS (ES⁺): m/z = 631.20, 633.35 [M+H]⁺ (monomer); LCMS: t_R = 2.13 min (monomer); MS (ES⁺): m/z = 1244.10, 1246.25 [M+H]⁺ (dimer); LCMS: t_R = 3.25 min.

[00763] (S)-N-(3-(2-(6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetamido)propyl)-3- ((hydroxydimethylsilyl)methyl)benzamide [Example 96]:

[00764] ¹H NMR (400 MHz, DMSO-d₆): į = 8.38 - 8.30 (m, 1H), 7.79– 7.70 (m, 1H), 7.55– 7.23 (m, 9H), 4.45 (dd, J = 8.6, 5.7 Hz, 1H), 3.77 (s, 3H), 3.31– 3.07 (m, 6H), 2.52 (s, 3H), 2.12 (s, 2H), 1.70– 1.62 (m, 2H), 0.88 (s, 6H); MS (ES⁺): m/z = 645.15, 647.30 [M+H]⁺; LCMS: t_R = 2.24 min.

[00765] (S)-N-(2-(2-(6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetamido)ethyl)-4- ((hydroxydimethylsilyl)methyl)benzamide [Example 97]:

[00766] ¹H NMR (400 MHz, DMSO-d₆) į = 8.37-8.21 (m, 2H), 7.79 (d, J = 9.0 Hz, 1H), 7.70 (dd, J = 8.2, 6.1 Hz, 2H), 7.54– 7.34 (m, 5H), 7.10 (dd, J = 8.2, 6.6 Hz, 2H), 6.85 (d, J = 2.9 Hz, 1H), 4.49 (dd, J = 8.5, 5.6 Hz, 1H), 3.79 (s, 3H), 3.43– 3.12 (m, 4H), 2.53 (s, 3H), 2.24 – 2.14 (m,2H), 0.8 (s, 6H); MS (ES⁺): m/z = 631.10, 633.20 [M+H]⁺; LCMS: t_R = 2.28 min.

[00767] (S)-N-(3-(2-(6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetamido)propyl)-4- ((hydroxydimethylsilyl)methyl)benzamide [Example 98]:

[00768] ¹H NMR (400 MHz, DMSO-d₆): į = 8.30– 8.24 (m, 2H), 7.78 (d, J = 8.9 Hz, 1H), 7.75– 7.65 (m, 2H), 7.56– 7.33 (m, 5H), 7.12 (d, J = 7.9 Hz, 2H), 6.87 (d, J = 2.9 Hz, 1H), 4.48 (dd, J = 8.8, 5.4 Hz, 1H), 3.78 (s, 3H), 3.43– 3.19 (m, 6H), 2.53 (s, 3H), 2.15-2.10 (m, 2H), 1.77– 1.70 (m, 2H), 0.98 (s, 6H); MS (ES⁺): m/z = 645.20, 647.40 [M+H]⁺; LCMS: t_R = 2.29 min.

[00769] 3-((hydroxydimethylsilyl) methyl) benzoic acid (47):

[00770] A solution of benzyl 3-((hydroxydimethylsilyl) methyl) benzoate (4.0 g, 13 mmol) in ethanol (80 mL) was charged with (10%) Pd/C (800 mg, 20% w/w). The reaction mixture was stirred at room temperature under hydrogen atmosphere for 5 h. The reaction mixture was filtered through pad of celite and the filtrate was concentrated in vacuo resulting in a crude product which was purified by column chromatography to obtain 1.80 g (64.5 % Yield) of title compound as a white solid. ¹H NMR (400 MHz, DMSO-d₆): į = 12.79 (s, 1H), 7.63 (m, 1H), 7.38– 7.16 (m, 2H), 2.15 (m, 2H), 0.03 (m, 6H).

[00771] Benzyl 3-((hydroxydimethylsilyl) methyl) benzoate (46):

[00772] A solution of benzyl 3-(bromomethyl)benzoate (5.0 g, 16.3 mmol) , 1,2- diethoxy-1,1,2,2-tetramethyldisilane (10.2 g , 49.1 mmol), 2-(di-tert-butylphosphino)biphenyl (500 mg, 1.67 mmol), palladium dichloride (500 mg, 2.81 mmol, 17.29 mol %) and DIPEA (6.2 g, 49.1 mmol) in NMP (50 mL) was heated at 50°C for 2 h . The reaction mixture was partitioned between DCM (200 mL) and H₂O (75 mL) and separated. The aqueous layer was extracted with DCM (3 X 100 mL) and the combined organic fractions were washed with 5% aqueous acetic acid (3 X 50 mL), H₂O (3 X 50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo resulting in a crude product which was purified by column chromatography on silica gel [eluting with 30% ethyl acetate in n-hexane] to give 4.0 g (81.7 % Yield) of the title compound as a colorless oil. ¹H NMR (400 MHz, CDCl₃): į = 7.84– 7.76 (m, 3H), 7.48– 7.22 (m, 6H), 5.35 (s, 2H), 2.23 (s, 2H), 0.27 (s, 6H)

[00773] Benzyl 3-(bromomethyl) benzoate (45):

[00774] A solution of benzyl 3-(hydroxymethyl) benzoate (8.0 g, 33 mmol) in DCM (80 mL) was charged with phosphorus tribromide (8.90 g, 33 mmol) at 0°C and the reaction mixture were stirred at 0°C under nitrogen atmosphere for 1 h. The reaction mixture was partitioned between DCM (200 mL) and H₂O (75 mL) and separated. The aqueous layer was extracted with DCM (3 X 80 mL) and the combined organic fractions were washed with saturated solution of sodium bicarbonate (3 X 80 mL), H₂O (3 X 80 mL),dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo resulting in 5.0 g (50 % yield) of crude product. The crude material was used in the next step without further purification.

[00775] Benzyl 3-(hydroxymethyl) benzoate (44)

[00776] A solution of 3-(hydroxymethyl) benzoic acid (7.0 g, 46 mmol) in DMF (70 mL), methanol (21 mL) and H₂O (21 mL) was charged with cesium carbonate (4.80 g, 23 mmol) and the reaction mixture was stirred at room temperature for 10 min. The reaction mixture was charged with benzyl bromide (5.05 g, 46 mmol) and stirred at room temperature for 2 h. The reaction mixture was partitioned between DCM (200 mL) and H₂O (75 mL) and separated. The aqueous layer was extracted with DCM (3 X 80 mL) and the combined organic fractions were washed with saturated solution of sodium bicarbonate (3 X 80 mL), H₂O (3 X 80 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo resulting in a crude product which was purified by column chromatography on silica gel [eluting with 5% methanol in chloroform] to give 8.0 g (72.0 % Yield) of title compound as a white solid. ¹H NMR (400 MHz, CDCl₃): į = 8.09– 7.97 (m, 2H), 7.58 (d, J = 7.6 Hz, 1H), 7.49– 7.28 (m, 6H), 5.37 (s, 2H), 4.78 (s, 2H). EXAMPLES 99 and 100: [00777] Monomers were synthesized according to the procedures described below.

[00778] (S)-2-(6-(4-chlorophenyl)-8-(2-(3-(hydroxydimethylsilyl)phenyl)-2- oxoethoxy)-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N- ethylacetamide [Example 99]:

[00779] A solution of (S)-2-(8-(2-(3-bromophenyl)-2-oxoethoxy)-6-(4-chlorophenyl)-1- methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (250 mg, 0.41 mmol) , 1,2-diethoxy-1,1,2,2-tetramethyldisilane (253 mg, 1.23 mmol), 2-(di-tert- butylphosphino)biphenyl (25 mg, 0.837 mmol, 20.4 mol%), palladium dichloride (25 mg, 0.14 mmol, 34 mol %) and DIPEA (159 mg, 1.23 mmol) in NMP (2.5 mL) was heated to 60°C for 2 h. The reaction mixture was partitioned between DCM (20 mL) and H₂O (10 mL) and separated. The aqueous layer was extracted with DCM (3 X 25 mL) and the combined organic fractions were washed with 5% aqueous acetic acid (7.5 mL), H₂O (7.5 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo resulting in a crude product which was purified by column chromatography on silica gel eluting with 5 to 20 % methanol in DCM and then by preparative HPLC to give 20 mg (8.0 % yield) of the title compound. ¹H NMR (400 MHz, DMSO-d₆): į = 8.22 (t, J = 5.6 Hz, 1H), 8.11 (d, J = 12.2 Hz, 1H), 7.96–7.82 (m, 1H), 7.92– 7.74 (m, 2H), 7.59– 7.34 (m, 5H), 6.91 (d, J = 3.0 Hz, 1H), 6.53 (s, 1H), 6.08 (s, 1H), 5.81– 5.63 (m, 2H), 4.47 (dd, J = 8.5, 5.6 Hz, 1H), 3.29– 3.02 (m, 3H), 2.54 (s, 3H), 1.11– 1.05 (m, 3H), 0.28 (s, 6H); MS (ES⁺): m/z = 602.15, 604.05 [M+H]⁺; LCMS: t_R = 2.20 min.

[00780] (S)-2-(8-(2-(3-bromophenyl)-2-oxoethoxy)-6-(4-chlorophenyl)-1-methyl-4H- benzo[f][1,2,4] triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (48a):

[00781] A solution of (S)-2-(6-(4-chlorophenyl)-8-hydroxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (250 mg, 0.609 mmol) in THF (5 mL) was charged with potassium carbonate (168 mg, 0.121 mmol) and the reaction mixture was stirred at room temperature for 10 min. 2-bromo-1-(3-bromophenyl)ethanone (254 mg, 0.919 mmol) was added to the reaction mixture at rt and stirred for 15 h. The reaction mixture was partitioned between DCM (20 mL) and H₂O (10 mL) and separated. The aqueous layer was extracted with DCM (3 X 5 mL) and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo resulting in a crude product which was purified by column chromatography on silica gel [eluting with 20% ethyl acetate in n-hexane ]to give 300 mg (81 % yield) of the title compound as a white solid. MS (ES⁺): m/z = 606.35, 608.40 [M+H]⁺; LCMS: t_R = 2.53 min.

[00782] (S)-2-(6-(4-chlorophenyl)-8-(2-(4-(hydroxydimethylsilyl)phenyl)-2- oxoethoxy)-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N- ethylacetamide [Example 100]:

[00783] ¹H NMR (400 MHz, CD₃CN): į = 7.95– 7.84 (m, 2H), 7.80– 7.67 (m, 2H), 7.58 (dd, J = 8.9, 1.4 Hz, 1H), 7.51– 7.41 (m, 2H), 7.33– 7.20 (m, 3H), 7.16 (br.s, 1H), 6.95 (s, 1H), 5.48 (s, 2H), 4.51 (s, 1H), 3.35– 3.11 (m, 4H), 2.54 (s, 3H), 1.10 (t, J = 7.3 Hz, 3H), 0.33 (s, 6H); MS (ES⁺): m/z = 602.15, 604.10 [M+H]⁺; LCMS: t_R = 2.19 min. EXAMPLES 101 and 102:

[00784] Monomers were synthesized according to the procedures described below. Scheme 34: Synthesis of Example 101 to 102

[00785] (S)-N-ethyl-2-(6-(4-((hydroxydimethylsilyl)methoxy)phenyl)-8-methoxy-1- methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetamide [Example 101]:

[00786] A solution of (S)-N-ethyl-2-(6-(4-hydroxyphenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetamide (150 mg, 0.369mmol) in acetone (7.5 mL) was charged with potassium carbonate (152.9 mg, 1.10 mmol) and chloromethyl dimethyl ethoxy silane (112.9 mg, 0.739 mmol) at room temperature then heated to 56°C for 2 h. The reaction mixture was cooled to room temperature and partitioned between DCM (10 mL) and H₂O (5 mL) and separated. The aqueous layer was extracted with DCM (3 X 5 mL) and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo resulting in a crude product which was purified by preparative HPLC to obtain 35.0 mg (19% yield) of the title compound. ¹H NMR (400 MHz, DMSO-d₆): į = 8.20 (t, J = 5.4 Hz, 1H), 7.76 (dd, J = 8.9, 1.8 Hz, 1H), 7.47– 7.32 (m, 3H), 7.01– 6.93 (m, 2H), 6.85 (t, J = 2.2 Hz, 1H), 4.42 (dd, J = 8.2, 6.0 Hz, 1H), 3.76 (s, 3H), 3.64 (s, 2H), 3.25– 3.01 (m, 4H), 2.54 (s, 3H), 1.05 (t, J = 7.2 Hz, 3H), 0.18 (s, 6H); MS (ES⁺): m/z = 969.05 [M+H]⁺; LCMS: t_R = 2.90 min.

[00787] (S)-N-ethyl-2-(6-(4-hydroxyphenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetamide [Example 102]:

[00788] A solution of (S)-N-ethyl-2-(8-methoxy-1-methyl-6-(4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetamide (400 mg, 0.776 mmol) in THF (8 mL) was added hydrogen peroxide (30% aqueous solution) (1.46 mL, 3.88 mmol) at room temperature and stirred for 2 h. The reaction mixture was partitioned between DCM (20 mL) and H₂O (10 mL) and separated. The aqueous layer was extracted with DCM (3 X 50 mL) and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo resulting in a crude product which was purified by column chromatography to give 250 mg (79 % yield) of the title compound. MS (ES⁺): m/z = 406.15 [M+H]⁺; LCMS: t_R = 1.39 min.

[00789] (S)-N-ethyl-2-(8-methoxy-1-methyl-6-(4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetamide (49):

[00790] A suspension of (S)-2-(6-(4-bromophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (500 mg, 1.06 mmol), bispinacolato diborane (542 mg, 2.13 mmol), dichloro{1,1'-bis(diphenylphosphino)ferrocene}- palladium.DCM adduct (100 mg, 0.122 mmol, 5.7 mol %) and potassium acetate (312 mg, 3.18 mmol) in 1,4-dioxane (5 mL) under nitrogen atmosphere in a sealed microwave tube was heated to 140°C for 30 min [Biotage microwave reactor, 400W]. The reaction mixture was partitioned between DCM (30 mL) and H₂O (15 mL) and separated. The aqueous layer was extracted with DCM (3 X 50 mL) and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo resulting in a crude product which was purified by column chromatography on silica gel [eluting with 5% methanol in chloroform] to give 437 mg (80 % yield) of the title compound as a white solid. MS (ES⁺): m/z = 516.20 [M+H]⁺; LCMS: t_R = 2.34 min. EXAMPLE 103:

[00791] Example 103 was synthesized according to the procedure described below.

[00792] (S)-N-ethyl-2-(8-methoxy-1-methyl-6-(4-vinylphenyl)-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetamide [Example 103]:

[00793] A suspension of (S)-2-(6-(4-bromophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (150 mg, 0.320 mmol) , Vinyl boronic acid pinacol ester (78.5 mg, 0.510 mmol), palladium tetrakis (30 mg, 20% w/w) and sodium carbonate(101.0 mg, 0.96 mmol) in 1,4-dioxane (1.5 mL) and H₂O (0.5 mL). After work up and preparative HPLC purification 50 mg (37.8 % yield) of the title compound was obtained as a white solid. ¹H NMR (400 MHz, CD₃CN) į = 7.62– 7.45 (m, 5H), 7.30 (dd, J = 9.0, 2.9 Hz, 1H), 6.95 (d, J = 2.9 Hz, 1H), 6.87– 6.75 (m, 2H), 5.90 (d, J = 17.6 Hz, 1H), 5.36 (d, J = 11.0 Hz, 1H), 4.53 (dd, J = 7.7, 6.3 Hz, 1H), 3.80 (s, 3H), 3.35– 3.13 (m, 4H), 2.54 (s, 3H), 1.14 (t, J = 7.2 Hz, 3H); MS (ES+): m/z = 416.15 [M+H]⁺; LCMS: t_R = 2.063 min. EXAMPLE 104:

[00794] Example 104 was synthesized according to the procedure described below. Scheme 35: S nthesis of Exam le 104

[00795] ((S,E)-2-(6-(4-chlorophenyl)-8-(2-(hydroxydimethylsilyl)vinyl)-1-methyl- 4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide [Example 104]:

[00796] A suspension of (S)-6-(4-chlorophenyl)-4-(2-(ethylamino)-2-oxoethyl)-1- methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl trifluoromethanesulfonate (2.1 g, 3.87 mmol) , Ethoxy dimethyl vinyl silane (1.51 g, 11.61 mmol), dichloro bis(tri-O-toluyl phosphine)palladium (420 mg, 0.534 mmol, 13.8mol%) and TEA (1.17 g, 11.61 mmol) in DMF (7.5 mL) under nitrogen atmosphere in a sealed microwave reaction tube was heated at 100°C for 60 min [Biotage microwave reactor, 400W]. The reaction mixture was partitioned between DCM (200 mL) and H₂O (100 mL) and separated. The aqueous layer was extracted with DCM (3 X 210 mL) and the combined organic fractions were washed with H₂O (3 X 210 mL) and dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo resulting in a crude product which was stirred in mixture of diethyl ether (300 mL) and hexane (200 mL). Solid was filtered and purified by preparative HPLC to give 250 mg (13.0 % yield) of the title compound as a white solid. ¹H NMR (700 MHz, DMSO-d₆): G 8.20 (t, J = 5.53 Hz, 1H), 7.97 (dd, J = 1.77, 8.40 Hz, 1H), 7.83 (d, J = 8.85 Hz, 1H), 7.43– 7.56 (m, 5H), 7.03 (d, J = 19.02 Hz, 1H), 6.60 (d, J = 19.02 Hz, 1H), 5.69 (s, 1H), 4.49 (dd, J = 5.75, 8.40 Hz, 1H), 3.25 (dd, J = 8.40, 14.60 Hz, 1H), 3.05– 3.20 (m, 3H), 2.58 (s, 3H), 1.08 (t, J = 7.30 Hz, 3H), 0.16 (d, J = 4.87 Hz, 6H); MS (ES⁺): m/z = 494.10, 496.25 [M+H]⁺; LCMS: t_R = 1.9 min. EXAMPLE 105:

[00797] Example 105 was synthesized according to the procedure described below. Scheme 36: Synthesis of Example 105

[00798] (S,E)-2-(6-(4-chlorophenyl)-8-(3-hydroxy-3-methylbut-1-en-1-yl)-1-methyl- 4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide [Example 105]:

[00799] A suspension of (S)-6-(4-chlorophenyl)-4-(2-(ethylamino)-2-oxoethyl)-1- methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl trifluoromethanesulfonate (250 mg , 0.461 mmol.), 2-methylbut-3-en-2-ol (119 mg, 1.38 mmol), dichloro bis(tri-O-toluyl phosphine)palladium (50 mg, 0.0636 mmol, 13.79 mol %) and TEA (139 mg,1.38 mmol) in DMF (5 mL) under nitrogen atmosphere in a sealed microwave reaction tube was heated at 100°C for 60 min [Biotage microwave reactor, 400W]. The reaction mixture was partitioned between DCM (10 mL) and H₂O (5 mL) and separated. The aqueous layer was extracted with DCM (3 X 10 mL) and the combined organic fractions were washed with H₂O (3 X 10 mL) and dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo resulting in a crude product which was stirred in mixture of diethyl ether (30 mL) and hexane (20 mL). The solid which formed was filtered and purified by preparative HPLC to obtain 40 mg (18. % yield) of the title compound. ¹H NMR (400 MHz, DMSO-d₆): į = 8.22– 8.10 (m, 1H), 7.88– 7.66 (m, 2H), 7.50– 7.32 (m, 4H), 6.59– 6.48 (m, 2H), 4.48– 4.45 (m, 1H), 3.33– 3.10 (m, 5H), 2.50 (s, 3H), 2.34– 2.23 (m, 1H), 1.12 (s, 6H), 1.04 (t, J = 7.2 Hz, 3H); MS (ES⁺): m/z = 478.05, 480.10 [M+H]⁺; LCMS: t_R = 1.87 min. EXAMPLES 106-108:

[00800] Monomers were synthesized according to the procedures described below.

[00801] (S,E)-2-(6-(4-(2-(hydroxydimethylsilyl)vinyl)phenyl)-8-methoxy-1-methyl- 4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetamide [Example 106]:

[00802] A suspension of (S)-2-(6-(4-bromophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetamide (700 mg,1.58 mmol), ethoxy dimethyl vinyl silane (621 mg, 4.76 mmol), dichloro bis(tri-O-toluyl phosphine)palladium (140 mg, 0.178 mmol, 11.27 mol %) and TEA (481 mg, 4.76 mmol) in DMF (2.1 mL) under nitrogen atmosphere in a sealed microwave reaction tube was heated at 100°C for 60 min [Biotage microwave reactor, 400W]. The reaction mixture was partitioned between DCM (70 mL) and H₂O (50 mL) and separated. The aqueous layer was extracted with DCM (3 X 70 mL) and the combined organic fractions were washed with H₂O (3 X 70 mL) and dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo resulting in a crude product which was stirred in mixture of diethyl ether (150 mL) and hexane (100 mL). The solid which formed was filtered and purified by preparative HPLC to give 105 mg (13 % yield) of the title compound. ¹H NMR (400 MHz, CDCl₃): į = 7.56– 7.47 (m, 3H), 7.47– 7.26 (m, 3H), 7.19 (dd, J = 8.9, 2.9 Hz, 1H), 7.00 (dd, J = 19.2, 8.3 Hz, 1H), 6.89 (d, J = 2.9 Hz, 1H), 6.52 (dd, J = 19.3, 8.5 Hz, 1H), 5.48– 5.38 (m, 1H), 4.64– 4.55 (m, 1H), 3.84 (s, 3H), 3.56– 3.42 (m, 3H), 2.62 (s, 3H), 0.29 (s, 6H); MS (ES⁺): m/z = 462.15 [M+H]⁺; LCMS: t_R = 1.80 min.

[00803] (S)-2-(8-methoxy-1-methyl-6-(4-vinylphenyl)-4H-benzo[f][1,2,4]triazolo[4,3- a][1,4]diazepin-4-yl)acetamide [Example 107]:

[00804] Product was isolated form preparative HPLC of crude (S,E)-2-(6-(4-(2- (hydroxydimethylsilyl)vinyl)phenyl)-8-methoxy-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3- a][1,4]diazepin-4-yl)acetamide as byproduct formed while reaction was In progress. Purification by preparative HPLC, 61 mg (10 % yield) of the title compound as a white solid was obtained.¹H NMR (400 MHz, CDCl₃) į = 7.56– 7.47 (m, 2H), 7.43– 7.32 (m, 3H), 7.31– 7.16 (m, 1H), 6.91 (d, J = 2.9 Hz, 1H), 6.79– 6.67 (m, 1H), 6.47 (s, 1H), 5.81 (dd, J = 17.6, 0.8 Hz, 1H), 5.46 (s, 1H), 5.33 (dd, J = 10.9, 0.8 Hz, 1H), 4.59 (t, J = 7.0 Hz, 1H), 3.80 (s, 3H), 3.56 - 3.38 (m, 4H), 2.62 (s, 3H) ; MS (ES+): m/z = 388.20 [M+H]⁺; LCMS: t_R = 1.81 min.

[00805] (S)-2-(6-(4-bromophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetamide [Example 108]:

[00806] A suspension of (S)-2-(6-(4-bromophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetic acid (850 mg, 1.92 mmol) in DCM (25 mL) was charged with EDCI (738 mg, 3.85 mmol), 4-DMAP (703 mg, 5.76 mmol), HOBt (259 mg, 1.92 mmol) and stirred at room temperature for 10 minutes. The reaction mixture was charged with ammonia gas for 2 h and stirred at room temperature for 14 h. The reaction mixture was partitioned between DCM (70 mL) and H₂O (50 mL) and separated. The aqueous layer was extracted with DCM (3 X 70 mL) and the combined organic fractions were washed with H₂O (3 X 70 mL) and dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo resulting in a crude product which was then purified by a preparative HPLC to give 750 mg (88 % yield) of the title compound. ¹H NMR (400 MHz, DMSO-d₆): į = 7.79 (d, J = 8.9 Hz, 1H), 7.68– 7.59 (m, 3H), 7.50– 7.42 (m, 2H), 7.38 (dd, J = 9.0, 2.9 Hz, 1H), 7.01– 6.96 (m, 1H), 6.87 (d, J = 2.9 Hz, 1H), 4.45 (dd, J = 8.2, 5.8 Hz, 1H), 3.79 (s, 3H), 3.34– 3.10 (m, 2H), 2.53 (s, 3H); MS (ES⁺): m/z = 440.01, 442.05 [M+H]⁺; LCMS: t_R = 1.85 min. EXAMPLES 109-112:

[00807] Monomers were synthesized according to the procedures described below. Scheme 38: Synthesis of Examples 109 to 112 ^N

[00808] (S,E)-2-(6-(4-chlorophenyl)-8-(2-(hydroxydimethylsilyl)vinyl)-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetamide [Example 109]:

[00809] A suspension of (S)-4-(2-amino-2-oxoethyl)-6-(4-chlorophenyl)-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl trifluoromethanesulfonate (1.40 g, 2.70 mmol) , Ethoxy dimethyl vinyl silane (1.06 g, 8.1 mmol), dichloro bis(tri-O-toluyl

phosphine)palladium (280 mg, 0.356 mmol, 25 mol%) and TEA (819 mg, 8.10 mmol) in DMF (6 mL) under nitrogen atmosphere in a sealed microwave reaction tube was heated at 100°C for 60 min Biotoage microwave reactor, 400W]. The reaction mixture was partitioned between DCM (150 mL) and H₂O (75 mL) and separated. The aqueous layer was extracted with DCM (3 X 75 mL) and the combined organic fractions were washed with H₂O (3 X 75 mL) and dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo resulting in a crude product. The crude product was stirred in mixture of diethyl ether (180 mL) and hexane (120 mL) and the solid was filtered off and purified by preparative HPLC to obtain 180 mg (15 % yield) of the title compound as a white solid. ¹H NMR (400 MHz, DMSO-d₆): į = 7.96 (d, J = 8.5 Hz, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.63 (brs, 1H), 753– 7.40 (m, 5H), 7.00 (d, J = 19.6 Hz, 1H), 6.94 (brs, 1H), 6.58 (d, J = 19.6 Hz, 1H), 5.68 (brs, 1H), 4.46 (t, J = 6.9 Hz, 1H), 3.21-3.10 (m, 2H), 2.57 (s, 3H), 0.14 (s, 6H); MS (ES⁺): m/z = 466.15, 468.05 [M+H]⁺; LCMS: t_R = 1.88 min.

[00810] (S)-2-(6-(4-chlorophenyl)-1-methyl-8-vinyl-4H-benzo[f][1,2,4]triazolo[4,3- a][1,4]diazepin-4-yl)acetamide [Example 110]:

[00811] Product was isolated form preparative HPLC of crude (S,E)-2-(6-(4- chlorophenyl)-8-(2-(hydroxydimethylsilyl)vinyl)-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3- a][1,4]diazepin-4-yl)acetamide [Example 109] formed as a byproduct. Purification by preparative HPLC, 61 mg (6% yield) of the title compoun as a white solid was obtained. ¹H NMR (400 MHz, DMSO-d₆): į = 7.95 (dd, J = 8.6, 2.0 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 3.4 Hz, 1H), 7.53– 7.48 (m, 5H), 6.99 (d, J = 3.3 Hz, 1H), 6.82 (dd, J = 17.6, 11.0 Hz, 1H), 5.94 (d, J = 17.6 Hz, 1H), 5.39 (d, J = 11.0 Hz, 1H), 4.46 (dd, J = 8.3, 5.6 Hz, 1H), 3.31– 3.10 (m, 2H), 2.57 (s, 3H); MS (ES⁺): m/z = 392.05, 394.15 [M+H]⁺; LCMS: t_R = 1.97 min.

[00812] (S)-4-(2-amino-2-oxoethyl)-6-(4-chlorophenyl)-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl trifluoromethanesulfonate (51):

[00813] A suspension of (S)-2-(6-(4-chlorophenyl)-8-hydroxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl) acetamide (1.84 g, 4.71 mmol) in DCM (40 mL) was charged with 4-DMAP (1.72 g, 14.1 mmol) and the reaction mixture was cooled to 0- 5°C followed by addition of triflic anhydride (1.99 g, 7.06 mmol) at same temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with H₂O (40 mL) and separated. The aqueous layer was re-extracted with DCM (3 x 20 mL) and the combined organic fractions were washed with 5% aqueous solution of acetic acid and saturated solution of sodium bicarbonate. The organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to obtain 1.45 g (60.0 % yield) of the desired product as a white solid. ¹H NMR (400 MHz, DMSO-d₆): į = 8.12-7.95 (m, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.71– 7.63 (m, 2H), 7.56–7.42 (m, 4H), 6.95 (s, 1H), 4.46 (m, 1H), 3.18– 3.34 (m, 2H), 2.56 (s, 3H); MS (ES⁺): m/z = 513.15, 515.05 [M+H]⁺; LCMS: t_R = 1.65 min.

[00814] (S)-2-(6-(4-chlorophenyl)-8-hydroxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetamide [Example 111]:

[00815] (S)-2-(6-(4-Chlorophenyl)-8-methoxy-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3- a][1,4]diazepin-4-yl)-N-acetamide (2.60 g, 6.56 mmol) in DCM (100 mL) was charged with boron tribromide (5.74 g, 2.29 mmol) at -20 °C and the reaction mixture was stirred for 15 h at room temperature. The reaction mixture was concentrated in vacuo to get residue which was poured over a solution of ice cold saturated sodium bicarbonate with vigorous stirring. The reaction mixture was stirred for an additional 6 h at room temperature. The precipitate was filtered and dried in vacuo at 50 °C to obtain 1.87 g (85% yield) of the title compound as a white solid. ¹H NMR (400 MHz, DMSO-d₆): į = 10.18(s, 1H), 7.78– 7.65 (m, 2H), 7.55– 7.40 (m, 4H), 7.16 (dd, J = 8.8, 2.8 Hz, 1H), 6.90 (s, 1H), 6.65 (s,1H) 4.46 (dd, J = 8.4, 5.8 Hz, 1H), 3.28– 3.10 (m, 2H), 2.54 (s, 3H); MS (ES⁺): m/z = 382.25, 384.15 [M+H]⁺; LCMS: t_R = 1.51 min.

[00816] (S)-2-(6-(4-bromophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetamide [Example 112]:

[00817] A suspension of (S)-2-(6-(4-bromophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetic acid (3 g, 7.55 mmol) in DCM (90 mL) was charged with EDCI (2.89 g, 15.1 mmol), 4-DMAP (2.76 g, 22.6 mmol), HOBt (259 mg, 1.92 mmol) and stirred at room temperature for 10 min. This solution was charged with ammonia gas and stirred under an ammonia atmosphere for 2 h and then the reaction mixture was stirred at room temperature for 14 h. The reaction mixture was partitioned between DCM (75 mL) and H₂O (50 mL) and separated. The aqueous layer was extracted with DCM (3 X 50 mL) and the combined organic fractions were washed with H₂O (3 X 50 mL) and dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo resulting in a crude solid product. The crude was further stirred in diethyl ether (90 mL) and the solid was filtered to obtain 2.68 g (90 % yield) of the title compound as a white solid. ¹H NMR (400 MHz, DMSO-d₆): į = 7.79 (d, J = 8.9 Hz, 1H), 7.68– 7.59 (m, 3H), 7.50– 7.42 (m, 2H), 7.38 (dd, J = 9.0, 2.9 Hz, 1H), 7.01 (brs, 1H), 6.87 (d, J = 2.9 Hz, 1H), 4.45 (dd, J = 8.2, 5.8 Hz, 1H), 3.79 (s, 3H), 3.34– 3.10 (m, 2H), 2.53 (s, 3H); MS (ES⁺): m/z = 440.15, 442.05 [M+H]⁺; LCMS: t_R = 1.85 min. EXAMPLE 113:

[00818] Example 113 was synthesized according to the procedure described below. Scheme 39: S nthesis of Exam le 113

[00819] (S,E)-2-(6-(4-Chlorophenyl)-8-(3-hydroxy-3-methylbut-1-en-1-yl)-1-methyl- 4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide [Example 113]:

[00820] A suspension of (S)-6-(4-chlorophenyl)-4-(2-(ethylamino)-2-oxoethyl)-1- methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl trifluoromethanesulfonate (250 mg, 0.461 mmol), 2-methylbut-3-en-2-ol (119 mg, 1.38 mmol), dichloro bis(tri-o-toluyl phosphine)palladium (50 mg, 0.063 mmol, 13.79 mol%) and TEA (139 mg, 1.38 mmol) in DMF (2.5 mL) in sealed tube was heated to 100°C for 60 min[biotage microwave

reactor,400W]. The reaction mixture was partitioned between DCM (10 mL) and H₂O (5 mL) and separated. The aqueous layer was extracted with DCM (3 X 10 mL) and the combined organic fractions were washed with H₂O (3 X 10 mL) and dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo resulting in a crude solid which was stirred in diethyl ether (30 mL) and hexane (20 mL). The solid was filtered and purified by preparative HPLC to obtain 40 mg (19 % yield) of the title compound the title compound as a white solid. ¹H NMR (400 MHz, DMSO-d₆): į = 8.22 (m, 1H), 7.88– 7.66 (m, 2H), 6.59– 6.48 (m, 1H), 4.48– 4.45 (m, 1H), 3.33– 3.10 (m, 5H), 2.50 (s,1H), 2.34– 2.23 (m, 1H), 1.12 (s,6H), 1.04 (t, J = 7.2 Hz, 3H); MS (ES⁺): m/z = 478.20, 480.05 [M+H]⁺; LCMS: t_R = 1.87 min. EXAMPLE 114:

[00821] Example 114 was synthesized according to the procedure described below. (S)-2-(6-(4-Chlorophenyl)-8-hydroxy-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3- a][1,4]diazepin-4-yl)-N-ethylacetamide [Example 114]:

[00822] (S)-2-(6-(4-Chlorophenyl)-8-methoxy-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3- a][1,4]diazepin-4-yl)-N-ethylacetamide (WO 2011054553) (5.0 g, 11.79 mmol) in DCM (150 mL) was charged with Boron tribromide (10.34 g, 41.28 mmol) at -20 °C and the reaction mixture was stirred for 15 h at room temperature. The reaction mixture was concentrated in vacuo to get residue which was poured over ice cold saturated solution of sodium bicarbonate with vigorous stirring and the reaction mixture was stirred for 6 h at room temperature. The precipitated product was filtered and dried in vacuo at 50⁰C 4.10 g (85% yield) to obtain the title compound as a white solid.¹H NMR (400 MHz, DMSO-d₆): į = 10.17 (s, 1H), 8.19 (t, J = 5.3 Hz, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.50 (s, 3H), 7.16 (dd, J = 8.8, 2.8 Hz, 1H), 6.71 (d, J = 2.8 Hz, 1H), 4.46 (dd, J = 8.4, 5.8 Hz, 1H), 3.28– 3.03 (m, 4H), 2.54 (s, 3H), 1.06 (t, J = 7.2 Hz, 3H); MS (ES⁺): m/z = 410.25, 412.15 [M+H]⁺; LCMS: t_R = 1.72 min. EXAMPLE 115:

[00823] Example 115 was synthesized according to the procedure described below.

[00824] 1-(3-(Aminomethyl)pyrrolidin-1-yl)-2-((S)-6-(4-chlorophenyl)-8-methoxy-1- methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)ethanone [Example 115]:

[00825] A solution of tert-butyl ((1-(2-((S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetyl)pyrrolidin-3-yl)methyl)carbamate (0.075 g, 0.12 mmol) in THF (5 mL) was charged with 4M HCl in 1,4-dioxane (5 mL) and stirred at room temperature for 3 h. The reaction mixture was partitioned between DCM (10 mL) and H₂O (15 mL) and separated. The aqueous layer was neutralized with saturated NaHCO₃ solution to adjust pH to ~ 8 and extracted with DCM (3 X 10 mL). The combined organic fractions were dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo resulting in 20 mg (32 % yield ) of the title compound the title compound as an off white solid product. ¹H NMR (400 MHz, DMSO-d₆): į = 7.80 (d, J = 9.2 Hz, 1H), 7.51– 7.43 (m, 4H), 7.38 (dd, J = 9.2, 2.8 Hz, 1H), 6.87 (d, J = 2.4 Hz, 1H), 4.52 (t, J = 6.8 Hz, 1H), 3.79 (s, 3H), 3.68– 3.58 (m, 1H), 3.48– 3.22 (m, 4H), 3.02– 2.95 (m, 1H), 2.68– 2.53 (m, 2H), 2.52 (s, 3H), 2.33– 1.91 (m, 2H), 1.70– 1.54 (m, 2H); MS (ES⁺): m/z = 479.40, 481.40 [M+H] ⁺; LCMS: t_R = 1.99 min.

[00826] tert-Butyl ((1-(2-((S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetyl)pyrrolidin-3-yl)methyl)carbamate (38):

[00827] A solution of (S)-2-(6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetic acid (0.075 g , 0.18 mmol) in DCM (10 mL) were charged with EDCI (0.054 g, 0.28 mmol), DMAP (0.027 g, 0.22 mmol), and stirred at room temperature for 10 min. To this solution, tert-butyl (pyrrolidin-3-ylmethyl)carbamate (0.041 g, 0.20 mmol) was added and the resulting solution was stirred at room temperature for 4 h. The reaction mixture was partitioned between DCM (15 mL) and H₂O (10 mL) and separated. The aqueous layer was extracted with DCM (3 x 15 mL) and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo resulting in a crude compound which was purified by column chromatography on silica gel (100-200 mesh) eluting with 5% methanol in chloroform to give 0.075 g (69 % yield) of the title compound as an off white solid. MS (ES⁺): m/z = 579.30, 581.40 [M+H] ⁺; LCMS: t_R = 1.70 min. EXAMPLE 116:

[00828] Example 116 was synthesized according to the procedure described below. Scheme 41: Synthesis of Example 116

[00829] 1-(3-aminopyrrolidin-1-yl)-2-((S)-6-(4-chlorophenyl)-8-methoxy-1-methyl- 4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)ethanone [Example 116]:

[00830] A solution of tert-butyl (1-(2-((S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetyl)pyrrolidin-3-yl)carbamate (0.20 g, 0.35 mmol) in THF (10 mL) was charged with 4M HCl in 1,4-dioxane (10 mL) and stirred at room temperature for 3 h. The reaction mixture was evaporated under reduced pressure to obtain a residue which was stirred in 10 mL diethyl ether for 10 min and the solid was filtered off and dried to get 100 mg (61% Yield) of the title compound as a white solid. ¹H NMR (400 MHz, CD₃OD): į = 7.73 (dd, J = 9.0, 2.5 Hz, 1H), 7.54 (t, J = 6.7 Hz, 2H), 7.46– 7.35 (m, 3H), 6.92 (d, J = 3.4 Hz, 1H), 4.68 (t, J = 7.2 Hz, 1H), 4.03– 3.87 (m, 1H), 3.83 (d, J = 2.4 Hz, 3H), 3.72 – 3.40 (m, 4H), 3.35 (d, J = 2.2 Hz, 1H), 3.24 (d, J = 11.5 Hz, 1H), 2.64 (d, J = 2.5 Hz, 3H), 2.25– 2.15 (m, 1H), 1.91– 1.78 (m, 1H); MS (ES⁺): m/z = 465.25, 467.15 [M+H]⁺; LCMS: t_R = 1.99 min. [00831] tert-Butyl (1-(2-((S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetyl)pyrrolidin-3-yl)carbamate (40):

[00832] A solution of (S)-2-(6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetic acid (0.15 g , 0.37 mmol) in DCM (15 mL) were charged with EDCI (0.108 g, 0.56 mmol), DMAP (0.055 g, 0.45 mmol), and stirred at room temperature for 10 min. To this solution, tert-butyl pyrrolidin-3-ylcarbamate (0.077 g, 0.41 mmol) was added and the resulting solution was stirred at room temperature for 4 h. The reaction mixture was partitioned between DCM (15 mL) and H₂O (10 mL) and separated. The aqueous layer was extracted with DCM (3 X 15 mL) and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo resulting in a crude compound which was purified by column chromatography on silica gel (100-200 mesh), eluting with 5% methanol in chloroform to give 0.20 g (98 % yield) of the title compound as an off white solid. MS (ES⁺): m/z = 565.40, 567.40 [M+H]⁺; LCMS: t_R = 2.49 min. EXAMPLE 117:

[00833] Example 117 was synthesized according to the procedure described below.

[00834] (S)-2-(2-(6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetamido)acetic acid [Example 117]:

[00835] A solution of (S)-methyl 2-(2-(6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetamido)acetate (0.125 g, 0.26 mmol) in THF (5 mL) was charged with 4M HCl in 1,4-dioxane (5 mL) and stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuo. The residue was stirred in 10 mL of diethyl ether for 10 min and the solid was filtered off and dried to get 100 mg crude product. The crude was purified by SFC to get 20 mg (17% yield) of the title compound as a white solid compound. ¹H NMR (400 MHz, DMSO-d₆): į = 7.78 (d, J = 9.2 Hz, 1H), 7.56 (d, J = 8.4, 2H), 7.46 (d, J = 8.8, 2H), 7.37 (dd, J = 9.0, 2.6 Hz, 1H), 6.86 (d, J = 2.4 Hz, 1H), 4.46 (m, 1H), 3.78 (s, 3H), 3.38– 3.36 (m, 2H), 3.25– 3.15 (m, 2H), 2.53 (s, 3H); MS (ES⁺): m/z = 454.25, 456.30 [M+H]⁺ ; LCMS: t_R = 1.72 min.

[00836] (S)-Methyl 2-(2-(6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetamido)acetate (52):

[00837] A solution of (S)-2-(6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetic acid (0.15 g, 0.37 mmol) in DCM (15 mL) were charged with EDCI (0.108 g, 0.56 mmol), and DMAP (0.055 g, 0.45 mmol) and stirred at room temperature for 10 min. The solution was charged with methyl 2-aminoacetate hydrochloride (0.052 g, 0.41 mmol) was added and the resulting solution was stirred at room temperature for 4 h. The reaction mixture was partitioned between DCM (15 mL) and H₂O (10 mL) and separated. The aqueous layer was extracted with DCM (3 X 15 mL) and the combined organic fractions were dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo resulting in a crude compound which was purified by column chromatography on silica gel (100-200 mesh) eluting with 3% methanol in chloroform to give 0.125 g (71 % yield) of the title compound as off white solid. MS (ES⁺): m/z = 468.25, 470.35 [M+H] ⁺; LCMS: t_R = 2.14 min. EXAMPLE 118:

[00838] This example demonstrates in vitro properties of disclosed compounds.

[00839] Inhibition of MV4-11 cell proliferation. MV4-11 cells (5000 cells in 50 l volumes) in growth medium containing 10% FBS and 1% Pen/Strep were plated and grown overnight in 96 well plates and treated the next day with 3-fold dilutions of test compounds or with DMSO vehicle. After 72 hours of growth, 30 ul of Cell-Titer Glo reagent (Promega) was added to the wells and the plates incubated for 30 minutes. Luminescence was measured on a Spectramax M5 plate reader and GI₅₀ values were calculated for each test compound. The results are shown in Table 2 below. Table 2. MV4-11 Cell Proliferation Results

[00840] Inhibition of Myc expression. MV4-11 (ATCC® CRL9591™) cells were seeded in 96-well plates at a density of 105 cells in 100ul volume per well and grown overnight. Compounds were prepared at 1000-fold in DMSO, diluted 100x in growth medium (10%FBS in IMEM) before adding one tenth volume to the cells on the day following seeding (final concentration DMSO 0.1%). After 4 hours compound treatment, cells were collected through centrifugation at 3000 rpm for 10 min. Cell pellets were lysed with RLT buffer (Qiagen) and total RNA isolation was carried out with the RNeasy 96 kit from Qiagen (catalog No. 74182) following the manufacturer’s instructions. cDNA was made from total RNA using reverse transcription reagents from Life Technologies (catalog No. 4391852C), and used as directed. MYC mRNA level were measured by real time PCR using MYC Taqman probe (Life Technologies, catalog No. Hs00905027-ml) after normalization with GAPDH (Life

Technologies, catalog No. Hs02758991-gi). The relative MYC expression levels were then calculated through comparison to samples treated with DMSO, and EC50 were determined through four-parameter dose-response curve equation with GraphPad Prism software. The results are shown in Table 3 below. Table 3. Myc Inhibition Results

Grou A > Grou B > Grou C in otenc :

EXAMPLE 119:

[00841] This example demonstrates the synergistic effect of certain contemplated combinations of monomers, defined as >10% Excess over Bliss (EoB) in n>2 experiments. The results are shown in Table 4 below. The structures of certain monomers used in the EoB experiments are shown in Table 5 below.

[00842] MV4-11 (ATCC CRL9591) cells were seeded in 384-well tissue culture treated plates (Corning #3570): 5x10³ cells in 45 l growth medium (10% FBS in IMEM) per well. After overnight growth, cells were dosed as follows. Compounds were prepared at 1000x in DMSO, and then diluted 100-fold in growth medium before adding one-tenth volume (5 l) to the cells. In all cases final DMSO concentration was 0.2%. After 72 hours compound treatment, cell growth was measured with the CellTiter-Glo Luminescent Cell Viability Assay (Promega #G7353). To calculate Excess over Bliss, cells were treated either with compounds alone (A or B) or in a matrix combination of both compounds A and B. Cell growth was normalized to a DMSO-only control, and fractional inhibition was calculated with 0 indicating no inhibition as compared to the DMSO control, and 1 indicating 100% growth inhibition. Bliss additivity, the expected fractional inhibition of the combination A and B, was calculated using the equation, c = x + y– (x*y), where x and y are the fractional inhibition of cell growth induced by compounds A and B alone, respectively. Excess over Bliss was determined as z– c where the Bliss value c was subtracted from the experimentally determined fractional inhibition value z. An Excess over Bliss value of zero indicated compound additivity; a value above zero indicated synergy; a value below zero indicated antagonism. [00843] Table 4. Excess Over Bliss Results

[00844] Table 5.

Example No. Compound Structure

EQUIVALENTS

[00845] While specific embodiments have been discussed, the above specification is illustrative and not restrictive. Many variations will become apparent to those skilled in the art upon review of this specification. The full scope of the embodiments should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

[00846] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term“about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained.

Claims

1 1. A first monomer capable of forming a biologically useful multimer capable of

2 modulating a protein having a first bromodomain when in contact with a second monomer in an 3 aqueous media, wherein the first monomer is represented by the formula:

4 X¹-Y¹-Z¹ (Formula I) and pharmaceutically acceptable salts, stereoisomers, metabolites, 5 and hydrates thereof, wherein

6 X¹ is a first ligand moiety capable of modulating the first bromodomain on said 7 protein;

8 Y¹ is a connector moiety covalently bound to X¹ and Z¹;

9 Z¹ is a first linker capable of binding to the second monomer; and

10 the second monomer is represented by the formula:

11 X²-Y²-Z² (Formula II) and pharmaceutically acceptable salts, stereoisomers,

12 metabolites, and hydrates thereof, wherein

13 X² is a second ligand moiety capable of modulating a second domain on said 14 protein;

15 Y² is absent or is a connector moiety covalently bound to X² and Z²; and 16 Z² is a second linker capable of binding to the first monomer through Z¹, 17 wherein

18 Y¹ is selected from the group consisting of:

19 C_1-20alkylene, wherein one, two, or three or four methylene units of the

20 hydrocarbon chain are optionally and independently replaced by cyclopropylene, - 21 NR^1Y-, -N(R^1Y)C(O)-, -C(O)N(R^1Y)-, -N(R^1Y)SO₂-, -SO₂N(R^1Y)-, -O-, -C(O)-, -OC(O)-, 22 -C(O)O-, -S-, -SO-, -SO₂-, -C(=S)-, -C(=NR^1Y)-, phenyl, naphthyl, or a mono or23 bicyclic heterocycle ring; -NR^1Y-C_1-15alkyl-NR^1Y-C(O)-; -NR^1Y-(CH₂-CH₂-O)_s-C_1-24 ₆alkyl-NR^1Y-C(O)-; -(O-CH₂-CH₂)_s-NR^1Y-C(O)-; -S-C_0-6alkyl-; -NR^1Y-C_1-6alkyl-; -25 N(C_1-3alkyl)-C_1-6alkyl-NH-C(O)-; -NH-C_1-6alkyl-N(C_1-3alkyl)-C(O)-; -SO₂-NR^1Y-C_0-26 ₆alkyl-; -SO₂-heterocyclyl-C_0-6alkyl-; -heterocyclyl-C(O)-; -heterocyclyl-C_0-6alkyl-27 NR^1Y-C(O)-; -NR^1Y-C_0-6alkylene-heterocyclene-C(O)-; -O-C_1-6alkylene-C(O)-; -O-C_1- 28 ₁₅alkylene-NR^1Y-C(O)-; -O-C_1-15alkylene-C(O)-NR^1Y-; and -O-C_1-6alkylene-, wherein 29 C_1-6alkylene is optionally substituted by -OH;

30 wherein, independently for each occurrence,

31 R^1Y is selected from the group consisting of H and C_1-6alkyl; and

32 s is an integer from 1-15..

1 2. The first monomer of claim 1, wherein heterocyclyl is a 5-7 membered heterocyclic ring 2 comprising 1 or 2 nitrogen atoms.

1 3. The first monomer of claim 1 or 2, wherein R¹³ is H.

1 4. The first monomer of claim 1 or 2, wherein R¹³ is C_1-6alkyl.

1 5. The first monomer of claim 4, wherein R¹³ is methyl.

1 6. The first monomer of claim 1, wherein Y¹ is selected from the group consisting of: 2 -NH-(CH₂-CH₂-O)_s- CH₂-CH₂-NH-C(O)-; -(O-CH₂-CH₂)_t-NH-C(O)-; -O-(CH₂)_t-NH- 3 C(O)-; -N(CH₃)-(CH₂)₂-NH-C(O)-; -NH-(CH₂)₂-N(CH₃)-C(O); -NH-(CH₂)_u-NH-C(O)-; -O-

4 CH₂-C(O

;

5

; wherein u is an integer from 6-15.

1 ng a biologically useful multimer capable of

8 Y¹ is a connector moiety covalently bound to X¹ and Z¹; 9 Z¹ is a first linker comprising a silanol and capable of binding to the second 10 monomer; and

11 the second monomer is represented by the formula:

12 X²-Y²-Z² (Formula II) and pharmaceutically acceptable salts, stereoisomers,

13 metabolites, and hydrates thereof, wherein

14 X² is a second ligand moiety capable of modulating a second domain on said 15 protein;

16 Y² is absent or is a connector moiety covalently bound to X² and Z²; and 17 Z² is a second linker capable of binding to the first monomer through Z¹, 18 wherein

19 Y¹ is selected from the group consisting of:

20 C_1-20alkylene, wherein one, two, or three or four methylene units of the

21 hydrocarbon chain are optionally and independently replaced by cyclopropylene, - 22 NR^1Y-, -N(R^1Y)C(O)-, -C(O)N(R^1Y)-, -N(R^1Y)SO₂-, -SO₂N(R^1Y)-, -O-, -C(O)-, -OC(O)-, 23 -C(O)O-, -S-, -SO-, -SO₂-, -C(=S)-, -C(=NR^1Y)-, phenyl, naphthyl, or a mono or24 bicyclic heterocycle ring; -NR^1Y-C_1-15alkyl-NR^1Y-C(O)-; -NR^1Y-(CH₂-CH₂-O)_s-C_1-25 ^Y

6alkyl-NR^1Y-C(O)-; -(O-CH₂-CH₂)_s-NR¹ -C(O)-; -S-C_0-6alkyl-; -NR^1Y-C_1-6alkyl-; -26 N(C_1-3alkyl)-C_1-6alkyl-NH-C(O)-; -NH-C_1-6alkyl-N(C_1-3alkyl)-C(O)-; -SO ^Y

2-NR¹ -C_0-27 ₆alkyl-; -SO₂-heterocyclyl-C_0-6alkyl-; -heterocyclyl-C(O)-; -heterocyclyl-C_0-6alkyl-28 NR^1Y-C(O)-; -NR^1Y-C_0-6alkylene-heterocyclene-C(O)-; -O-C_1-6alkylene-C(O)-; -O-C_1- 29 ₁₅alkylene-NR^1Y-C(O)-; -O-C_1-15alkylene-C(O)-NR^1Y-; and -O-C_1-6alkylene-, wherein 30 C_1-6alkylene is optionally substituted by -OH;

31 wherein, independently for each occurrence,

32 R^1Y is selected from the group consisting of H and C_1-6alkyl; and

33 s is an integer from 1-15..

1 8. The first monomer of claim 7, wherein heterocyclyl is a 5-7 membered heterocyclic ring 2 comprising 1 or 2 nitrogen atoms.

1 9. The first monomer of claim 7 or 8, wherein R¹³ is H.

1 10. The first monomer of claim 7 or 8, wherein R¹³ is C_1-6alkyl.

1 11. The first monomer of claim 10, wherein R¹³ is methyl.

1 12. The first monomer of claim 7, wherein Y¹ is selected from the group consisting of: 2 -NH-(CH₂-CH₂-O)_s- CH₂-CH₂-NH-C(O)-; -(O-CH₂-CH₂)_s-NH-C(O)-; -S-; -S-CH₂-; -O- 3 (CH₂)_s-NH-C(O)-; -SO₂-NH-; -SO₂-NH-CH₂-; -N(CH₃)-(CH₂)₂-NH-C(O)-; -NH-(CH₂)₂- 4 N(CH₃)-C(O); -NH-(CH₂)_u-NH-C(O)-; -O-CH₂-C(O)-;

5

6 wherein u is an integer from 6-15.

1 13. The first monomer of any one of claims 1-21, wherein the second bromodomain is 2 within 20Å of the first bromodomain.

1 14. A first monomer capable of forming a biologically useful multimer capable of

8 Y¹ is absent or is a connector moiety covalently bound to X¹ and Z¹;

9 Z¹ is a first linker capable of binding to the second monomer; and

10 the second monomer is represented by the formula:

12 metabolites, and hydrates thereof, wherein

13 X² is a second ligand moiety capable of modulating a second domain on said 14 protein; 15 Y² is absent or is a connector moiety covalently bound to X² and Z²; and 16 Z² is a second linker capable of binding to the first monomer through Z¹;

17 wherein the maximum distance between the first ligand moiety and the second ligand moiety in18 the biologically useful multimer is less than about 20 Å.

1 15. The first monomer of claim 14, wherein the connector moiety has a length of less than 2 about 15 Å.

1 16. The first monomer of claim 14, wherein the connector moiety has a length of less than 2 about 10 Å.

1 17. The first monomer of claim 14, wherein the connector moiety has a length of less than 2 about 5 Å.

1 18. The first monomer of any one of claims 14-17, wherein Y¹ is selected from the group 2 consisting of:

3 -NR¹³-(CH₂-CH₂-O)_s-C_1-6alkyl-NR¹³-C(O)-; -(O-CH₂-CH₂)_s-NR¹³-C(O)-; -S-C_0-6alkyl-; 4 -NR¹³-C_0-6alkyl-; -SO₂-NR¹³-C_0-6alkyl-; -SO₂-heterocyclyl-C_0-6alkyl-; -heterocyclyl-C(O)-; - 5 heterocyclyl-C_0-6alkyl-NR¹³-C(O)-; -NR¹³-C_0-6alkyl-heterocyclyl-C(O)-; -O-C_1-6alkyl-C(O)-; - 6 O-C_1-15alkyl-NR¹³-C(O)-; and -O-C_1-6alkyl-, wherein C_1-6alkyl is optionally substituted by - 7 OH; wherein, independently for each occurrence, s is an integer from 0-10 and R¹³ is selected 8 from the group consisting of H and C_1-6alkyl.

1 19. The first monomer of any one of claims 1-18, wherein the protein is independently 2 selected from the group consisting of BRD2, BRD3, BRD4 and BRD-t.

1 20. The monomer of any one of claims 1-18, wherein the protein is a fusion gene product 2 selected from BRD4-NUT or BRD3-NUT.

1 21. The first monomer of any one of claims 1-18, wherein the second domain is a second 2 bromodomain.

1 22. The first monomer of any one of claims 1-21, wherein X¹ and X² are independently 2 selected from the group consisting of:

3

4 wherein:

5 X is phenyl, naphthyl, or heteroaryl;

6 R¹ is C_1-3alkyl, C_1-3alkoxy or -S- C_1-3alkyl;

7 R² is -NR^2aR^2a' or -OR^2b; wherein one of R^2a or R^2a’ is hydrogen, and R^2b or the other of 8 R^2a or R^2a’ is selected from the group consisting of C_1-6alkyl, haloC ^2c

1_-6alkyl, R R^2c’N-C_2-6alkyl, 9 carbocyclyl, carbocyclyloC_1-4alkyl, heterocyclyl and heterocyclylC_1-4alkyl, wherein any of the 10 carbocyclyl or heterocyclyl groups are optionally substituted by one or more substituents11 selected from the group consisting of halogen, C_1-6alkyl, haloC_1-6alkyl, C_1-6alkoxy, haloC_1-12 ₆alkoxy, carbonyl, -CO-carbocyclyl, azido, amino, hydroxyl, nitro and cyano, wherein the– 13 CO-carbocyclyl group may be optionally substituted by one or more substituents selected from 14 the group consisting of halogen, C_1-6alkyl, haloC_1-6alkyl, C_1-6alkoxy, haloC_1-6alkoxy, azido, 15 nitro and cyano; or

16 two adjacent groups on any of the carbocyclyl or heterocyclyl groups together with the 17 interconnecting atoms form a 5- or 6-membered ring which ring may contain 1 or 2

18 heteroatoms independently selected from the group consisting of O, S and N; or R^2a and R^2a’ 19 together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered ring which 20 optionally contains 1 or 2 heteroatoms independently selected from the group consisting of O, 21 S and N; wherein the 4-, 5-, 6 or 7-membered ring is optionally substituted by C_1-6alkyl, 22 hydroxyl or amino;

23 R^2c and R^2c’ are independently hydrogen or C_1-6alkyl;

24 each R³ is independently selected from the group consisting of hydrogen, hydroxyl, 25 thiol, sulfinyl, amino, halo, C_1-6alkyl, haloC_1-6alkyl, C_1-6alkoxy, haloC_1-6alkoxy, nitro, cyano, 26 CF₃, -OCF₃, -COOR⁵, -C_1-4alkylamino , phenoxy, benzoxy, and C_1-4alkylOH;

27 each R⁴ is hydroxyl, halo, C_1-6alkyl, hydroxyC_1-6alkyl, aminoC_1-6alkyl, haloC_1-6alkyl,28 C_1-6alkoxy, haloC_1-6alkoxy, acylaminoC_1-6alkyl, nitro, cyano, CF₃, -OCF₃, -COOR⁵; - 9 OS(O)₂C_{1 4}a y , p e y , ap t y , p e yloxy, benzyloxy or phenylmethoxy, wherein C_1- 30 ₆alkyl, phenyl, and naphthyl are optionally substituted by one two or three substituents selected 31 from the group consisting of hydroxyl, halogen, amino, nitro;

32 R⁵ is C_1-3alkyl;

33 * denotes a chiral center;

34 m is an integer 1 to 3; and

35 n is an integer 1 to 5;

36 II)

37 wherein:

38 X is O or S;

39 R¹ is C_1-6alkyl, haloC_1-6alkyl, -(CH₂)_nOR^1a, or -(CH₂)_mNR^1bR^1c; wherein R^1a is 40 hydrogen, C_1-6alkyl or haloC_1-6alkyl; R^1b and R^1c, which may be the same or different, are 41 hydrogen, C_1-6alkyl or haloC_1-6alkyl; and m and n, which may be the same or different, are 1, 2 42 or 3;

43 R² is R^2a, -OR^2b, or -NR^2cR^2d; wherein R^2a and R^2b are carbocyclyl, carbocyclylC_1- 44 ₄alkyl, heterocyclyl or heterocyclylC ^a

1_-4alkyl, or R² is carbocyclylethenyl or

45 heterocyclylethenyl, wherein any of the carbocyclyl or heterocyclyl groups defined for R^2a or 46 R^2b are optionally substituted by one or more groups independently selected from the group 47 consisting of halogen, C_1-6alkyl, haloC_1-6alkyl, C_1-6alkoxy, haloC_1-6alkoxy, nitro, cyano, 48 dimethylamino, benzoyl and azido; or two adjacent groups on any of the carbocyclyl or 49 heterocyclyl groups defined for R^2a or R^2b together with the interconnecting atoms form a 5 or 50 6-membered ring which ring may contain 1 or 2 heteroatoms independently selected from the 51 group consisting of O, S and N; or

52 R^2a and R^2b are C_1-6alkyl or haloC ^2c

1_-6alkyl; and R and R^2d, which may be the same or 53 different, are carbocyclyl, carbocyclylC_1-4alkyl, heterocyclyl or heterocyclylC_1-4alkyl, wherein 54 any of the carbocyclyl or heterocyclyl groups defined for R^2c or R^2d are optionally substituted 55 by one or more groups independently selected from the group consisting of halogen, C_1-6alkyl, 56 haloC_1-6alkyl, C_1-6alkoxy, haloC_1-6alkoxy, nitro, cyano and -CO₂C_1-4alkyl; or two adjacent 57 groups on any of the carbocyclyl or heterocyclyl groups defined for R^2c and R^2d together with 58 the interconnecting atoms form a 5 or 6-membered ring which ring may contain 1 or 2 59 heteroatoms independently selected from the group consisting of O, S and N; or

60 R^2c and R^2d are independently hydrogen, C_1-6alkyl or haloC_1-6alkyl;

61 R³ is C_1-6alkyl, phenyl, naphthyl, heteroaryl carbocyclyl or heterocyclyl, optionally 62 substituted independently by one or more substitutents selected from the group consisting of 63 halogen,–SR, -S(O)R’, -NHR’, -OR’, C_1-6alkyl, haloC_1-6alkyl, C_1-6alkoxy, haloC_1-6alkoxy, 64 nitro and cyano;

65 R’ is H or C_1-6alkyl;

66 A is a benzene or aromatic heterocyclic ring, each of which is optionally substituted; 67 and

68 n is 0, 1 or 2;

69

70

71 wherein:

72 R⁴ is hydrogen, cyano or C_1-6 alkyl;

73 A is selected from the group consisting of: 74

75 R^x is O, NR^2a, or S;

76 R¹ is C_1-6alkyl, C_3-6cycloalkyl, a 5 or 6 membered heterocyclyl, an aromatic group or a 77 heteroaromatic group, wherein the aromatic group or the heteroaromatic group is optionally 78 substituted by one to three groups selected from the group consisting of halogen, hydroxy, 79 cyano, nitro, C_1-6alkyl, C_1-4alkoxy, haloC_1-4alkyl, haloC_1-4alkoxy, hydroxyC_1-4alkyl, C_1-4alkoxy80 C_1-4alkyl, C_1-4alkoxycarbonyl, C_1-4alkylsulfonyl, C_1-4alkylsulfonyloxy, C_1-4alkylsulfonyl C_1- 81 ₄alkyl and C_1-4alkylsulfonamido;

82 R² is hydrogen or C_1-6alkyl;

83 R^2a is selected from the group consisting of H, C_1-6alkyl, C_1-6haloalkyl, (CH₂)_mcyano, 84 (CH₂)_mOH, (CH₂)_mC_1-6alkoxy, (CH₂)_mC_1-6haloalkoxy, (CH₂)_mC_1-6haloalkyl,

85 (CH₂)_mC(O)NR^aR^b, (CH₂)_mNR^aR^b and (CH₂)_m C(O)CH₃, (CHR⁶)_pphenyl optionally substituted 86 by C_1-6alkyl, C_1-6alkoxy, cyano, halo C_1-4alkoxy, haloC_1-4alkyl, (CHR⁶)_pheteroaromatic, 87 (CHR⁶)_pheterocyclyl; wherein R^a is H, C_1-6alkyl, or heterocyclyl; wherein R^b is H or C_1-6alkyl, 88 or

89 R^a and R^b together with the N to which they are attached form a 5 or 6 membered 90 heterocyclyl;

91 R^2b is H, C_1-6alkyl, (CH₂)₂C_1-6alkoxy, (CH₂)₂cyano, (CH₂)_mphenyl or

92 (CH₂)₂heterocyclyl;

93 R³ is hydrogen;

94 R⁶ is hydrogen or C_1-6alkyl;

95 m is 0, 1, 2 or 3;

96 n is 0, 1 or 2; and 97 p is 0, 1 or 2;

98 IV)

99 wherein:

100 A is a bond, C_1-4alkyl or–C(O)-;

101 X is:

102 i) a 6 to 10 membered aromatic group, or

103 ii) a 5 to 10 membered heteroaromatic comprising 1, 2 or 3 heteroatoms selected 104 from the group consisting of O, N and S;

105 R¹ is:

106 i) phenyl optionally substituted by 1 or 2 substituents independently selected107 from the group consisting of halogen, cyano, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, - 108 SO₂C_1-6alkyl and -COR⁷,

109 ii) a 5 to 10 membered heteroaromatic comprising 1, 2 or 3 heteroatoms selected 110 from the group consisting of O, N and S optionally substituted by 1 or 2 substituents111 independently selected from the group consisting of halogen, cyano, C_1-6alkyl, C_1- 112 ₆haloalkyl, C_1-6alkoxy and -COR⁷, or

113 iii) C_1-6alkyl, C_0-6alkylcyano, C_0-6alkylC_1-6alkoxy, C_0-2alkylC(O)R⁷ or

114 cyclohexyl;

115 R² is C_1-6alkyl;

116 R³ is C_1-6alkyl;

117 R⁴ is:

118 i) H, halogen, cyano, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, C_0-6hydroxyalkyl, - 119 SO₂C_1-6alkyl, -C(O)NR⁸R⁹, -C(O)R¹⁰, -C_0-6alkyl-NR¹¹R¹², or 120 ii) -O_mC_1-6alkyl substituted by a 5 or 6 membered heterocyclyl or heteroaromatic 121 each comprising 1 , 2, 3 or 4 heteroatoms independently selected from the group 122 consisting of N, O and S and wherein said hetercyclyl or heteroaromatic is optionally 123 substituted by 1, 2 or 3 groups independently selected from the group consisting of 124 halogen, cyano, C_1-6alkyl, C_1-6haloalkyl and C_1-6alkoxy, wherein m is 0, 1 or 2, wherein 125 when the heterocyclyl or heteroatomic is linked through a heteroatom and m is 1, then 126 the heteroatom and O are not directly linked if the resultant arrangement would be 127 unstable;

128 R^4a is H, halogen, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy or C_0-6hydroxyalkyl;

129 R⁵ is H, halogen, C_1-6alkyl or C_1-6alkoxy;

130 R⁶ is H, C_1-6alkyl, C_0-6alkylcyano, C_0-6alkylC_1-6alkoxy or C_0-2alkylC(O)R⁷;

131 R⁷ is hydroxyl, C_1-6alkoxy, -NH₂, -NHC_1-6alkyl or N(C_1-6alkyl)₂;

132 R⁸ and R⁹ independently are:

133 i) H, C_1-6alkyl, C_0-6alkylphenyl, C_0-6alkylheteroaromatic, C_3-6cycloalkyl, or 134 ii) R⁸ and R⁹ together with the N to which they are attached form a 5 or 6 135 membered heterocyclyl or heteroaromatic wherein said heterocyclyl or heteroaromatic 136 may comprise 1, 2 or 3 further heteroatoms independently selected from the group 137 consisting of O, N and S;

138 R¹⁰ is hydroxyl, C_1-6alkoxy or a 5 or 6 membered heterocyclyl or heteroaromatic 139 comprising 1, 2, 3 or 4 heteroatoms selected from the group consisting of O, N and S;

140 R¹¹and R¹² independently are:

141 i) H, C_1-6alkyl; or

142 ii) R¹¹ and R¹² together with the N to which they are attached form a 5 or 6 143 membered heterocyclyl or heteroaromatic wherein said heterocyclyl or heteroaromatic 144 may comprise 1, 2 or 3 further heteroatoms independently selected from the group 145 consisting of O, N and S; 146

147

148 wherein:

149 R¹ is C_1-6alkyl, C_3-7cycloalkyl or benzyl;

150 R² is C_1-4alkyl;

151 R³ is C_1-4alkyl;

152 X is phenyl, naphthyl, or heteroaryl;

153 R^4a is hydrogen, C_1-4alkyl or is a group L-Y in which L is a single bond or a C_1- 154 ₆alkylene group and Y is OH, OMe, CO₂H, CO₂C_1-6alkyl, CN, or NR⁷R⁸;

155 R⁷ and R⁸ are independently hydrogen, a heterocyclyl ring, C_1-6alkyl optionally 156 substituted by hydroxyl, or a heterocyclyl ring; or

157 R⁷ and R⁸ combine together to form a heterocyclyl ring optionally substituted by C_1- 158 ₆alkyl, CO₂C_1-6alkyl, NH₂, or oxo;

159 R^4b and R^4c are independently hydrogen, halogen, C_1-6alkyl, or C_1-6alkoxy;

160 R^4d is C_1-4alkyl or is a group -L-Y- in which L is a single bond or a C_1-6alkylene group 161 and Y is -O-, -OCH₂-, -CO₂-, -CO₂C_1-6alkyl-, or–N(R⁷)-;

162 R⁵ is hydrogen, halogen, C_1-6alkyl, or C_1-6alkoxy;

163 R⁶ is hydrogen or C_1-4alkyl; 164

₁₆₅

166 wherein:

167 A is independently, for each occurrence, a 4-8 membered cycloalkyl, heterocyclic, 168 phenyl, naphthyl, or heteroaryl moiety, each optionally substituted with one, two, three or more 169 R¹ substituents;

170 R¹ is selected from the group consisting of hydroxy, halogen, oxo, amino, imino, thiol,171 sulfanylidene, C_1-6alkyl, hydroxyC_1-6alkyl, -O-C_1-6alkyl,–NH-C_1-6alkyl, -CO₂H, -C(O)C_1-172 ₆alkyl,–C(O)O-C_1-6alkyl, aminoC_1-6alkyl, haloC_1-6alkyl, -C_1- 173 ₆alkylC(O)R²

, -O-C(O)R², -NH-C(O)R², -O-C_1-6alkyl-C(O)R², -NHC_1-6alkyl-C(O)R²,

174 acylaminoC_1-6alkyl, nitro, cyano, CF₃, -OCF₃, -OS(O)₂C_1-6alkyl, phenyl, naphthyl,

175 phenyloxy, -NH-phenyl, benzyloxy, and phenylmethoxy halogen; wherein C_1-6alkyl, phenyl, 176 and naphthyl are optionally substituted by one two or three substituents selected from the group 177 consisting of hydroxyl, halogen, amino, nitro, phenyl and C_1-6alkyl; or two R¹ substitutents may 178 be taken together with the atoms to which they are attached to form a fused aliphatic or 179 heterocyclic bicyclic ring system;

180 R² is -NR^2aR^2a' or -OR^2b; wherein one of R^2a or R^2a’ is hydrogen, and R^2b or the other of 181 R^2a or R^2a’ is selected from the group consisting of C_1-6alkyl, haloC_1-6alkyl, R^2cR^2c’N-C_2-6alkyl, 182 carbocyclyl, carbocyclyloC_1-4alkyl, heterocyclyl and heterocyclylC_1-4alkyl, wherein any of the 183 carbocyclyl or heterocyclyl groups are optionally substituted by one or more substituents184 selected from the group consisting of halogen, C_1-6alkyl, haloC_1-6alkyl, C_1-6alkoxy, haloC_1-185 ₆alkoxy, carbonyl, -CO-carbocyclyl, azido, amino, hydroxyl, nitro and cyano, wherein the– 186 CO-carbocyclyl group may be optionally substituted by one or more substituents selected from 187 the group consisting of halogen, C_1-6alkyl, haloC_1-6alkyl, C_1-6alkoxy, haloC_1-6alkoxy, azido, 188 nitro and cyano; or 89 two adjace t g oups o a y o t e carbocyclyl or heterocyclyl groups together with the 190 interconnecting atoms form a 5- or 6-membered ring which ring may contain 1 or 2

191 heteroatoms independently selected from the group consisting of O, S and N; or R^2a and R^2a’ 192 together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered ring which 193 optionally contains 1 or 2 heteroatoms independently selected from the group consisting of O, 194 S and N; wherein the 4-, 5-, 6 or 7-membered ring is optionally substituted by C_1-6alkyl, 195 hydroxyl or amino;

196 R^2c and R^2c’ are independently hydrogen or C_1-6alkyl;

197 B is selected from the group consisting of:

198

199

, and

200

201 wherein:

202 B is selected from the group consisting of:

203

204 Q is independently, for each occurrence, N or CH;

205 V is independently, for each occurrence, O, S, NR⁴, or a bond; and

206 R⁴ is independently selected from the group consisting of hydrogen, hydroxyl, halo, 207 amino, thiol, C_1-6alkyl, haloC_1-6alkyl, C_1-6alkoxy, -NH-C_1-6alkyl, -S-C_1-6alkyl, haloC_1-6alkoxy,208 nitro, cyano, -CF₃, -OCF₃, -C(O)O-C_1-6alkyl, -C_1-4alkylamino , phenoxy, benzoxy, and C_1- 209 ₄alkylOH;

210

211 wherein:

212 R¹ is selected from the group consisting of hydrogen, lower alkyl, phenyl, naphthyl, 213 aralkyl, heteroalkyl, SO₂, NH₂, NO₂, CH₃, CH₂CH₃, OCH₃, OCOCH₃, CH₂COCH₃, OH, CN, 214 and halogen;

215 R² is selected from the group consisting of hydrogen, lower alkyl, aralkyl, heteroalkyl, 216 phenyl, naphthyl, SO ⁺

2, NH₂, NH₃ , NO₂, CH₃, CH₂CH₃, OCH₃, OCOCH₃, CH₂COCH₃, OH, 217 halogen, carboxy, and alkoxy;

218 X is selected from the group consisting of lower alkyl, SO₂, NH, NO₂, CH₃, CH₂CH₃, 219 OCH₃, OCOCH₃, CH₂COCH₃, OH, carboxy, and alkoxy; and

220 n is an integer from 0 to 10; 221

222

223 wherein:

224 R¹, R², R³, R⁴, R⁵, and R⁶ are independently selected from the group consisting of hydrogen, 225 lower alkyl, phenyl, naphthyl, aralkyl, heteroaryl, SO₂, NH₂, NH ⁺

3 , NO², SO², CH³, CH₂CH₃, 226 OCH₃, OCOCH₃, CH₂COCH₃, OCH₂CH₃, OCH(CH₃)₂, OCH₂COOH, OCHCH₃COOH, 227 OCH₂COCH₃, OCH₂CONH₂, OCOCH(CH₃)₂, OCH₂CH₂OH, OCH₂CH₂CH₃, O(CH₂)₃CH₃, 228 OCHCH₃COOCH₃, OCH₂CON(CH₃)₂, NH(CH₂)₃N(CH₃)₂, NH(CH₂)₂N(CH₃)₂, NH(CH₂)₂OH, 229 NH(CH₂)₃CH₃, NHCH₃, SH, halogen, carboxy, and alkoxy;

230 X

231 wherein:

232 R¹, R², and R³ are independently selected from the group consisting of hydrogen, lower 233 alkyl, phenyl, naphthyl, aralkyl, heteroaryl, SO₂, NH₂, NH ⁺

3 , NO₂, SO₂, CH₃, CH₂CH₃, OCH₃, 234 OCOCH₃, CH₂COCH₃, OH, SH, halogen, carboxy, and alkoxy; R⁴ is selected from the group 235 consisting of lower alkyl, phenyl, naphthyl, SO₂, NH, NO₂, CH₃, CH₂CH₃, OCH₃, OCOCH₃, 236 CH₂COCH₃, OH, carboxy, and alkoxy;

237

238 or a pharmaceutically acceptable salt thereof, 239 wherein :

240 X is O or N;

241 Y is O or N; wherein at least one of X or Y is O;

242 W is C or N;

243 R¹ is H, alkyl, alkenyl, alkynyl, aralkyl, phenyl, naphthyl, heteroaryl, halo, CN, OR^A, 244 NR^AR^B,

245 N(R^A)S(O)_qR^AR^B, N(R^A)C(O)R^B, N(R^A)C(O)NR^AR^B, N(R^A)C(O)OR^A,

246 N(R^A)C(S)NR^AR^B, S(O)_qR^A, C(O)R^A, C(O)OR^A, OC(O)R^A, or C(O)NR^AR^B;

247 each R^A is independently alkyl, alkenyl, or alkynyl, each containing 0, 1, 2, or 3 248 heteroatoms selected from O, S, or N; phenyl; naphthyl, heteroaryl; heterocyclic; carbocyclic; 249 or hydrogen;

250 each R^B is independently alkyl, alkenyl, or alkynyl, each containing 0, 1, 2, or 3 251 heteroatoms selected from O, S, or N; phenyl; naphthyl; heteroaryl; heterocyclic; carbocyclic; 252 or hydrogen; or

253 R^A and R^B, together with the atoms to which each is attached, can form a

254 heterocycloalkyl or a heteroaryl; each of which is optionally substituted;

255 Ring A is cycloalkyl, phenyl, naphthyl, heterocycloalkyl, or heteroaryl;

256 R^C is alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, naphthyl, heterocycloalkyl, or 257 heteroaryl, each optionally substituted with 1-5 independently selected R⁴, and when L¹ is other 258 than a covalent bond, R^C is additionally selected from H;

259 R² and R³ are each independently H, halogen, alkyl, alkenyl, alkynyl, phenyl, naphthyl, 260 aralkyl, cycloalkyl, heteroaryl, heterocycloalkyl, -OR, -SR, -CN, -N(R’)(R’’), -C(O)R, -C(S)R,261 -CO₂R, -C(O)N(R’)(R’’), -C(O)SR, -C(O)C(O)R, -C(O)CH₂C(O)R, -C(S)N(R’)(R’’), -262 C(S)OR, -S(O)R, -SO₂R, -SO₂N(R’)(R’’), -N(R’)C(O)R, -N(R’)C(O)N(R’)(R’’), -263 N(R')C(S)N(R')(R"), -N(R’)SO₂R, -N(R’)SO₂N(R’)(R’’), -N(R’)N(R’)(R’’), -264 N(R’)C(=N(R’))N(R’)(R’’), -C=NN(R’)(R’’), -C=NOR, -C(=N(R’))N(R’)(R’’), -OC(O)R, - 265 OC(O)N(R’)(R’’), or -(CH₂)_pR^x; or 266 R₂ and R₃ together with the atoms to which each is attached, form an optionally 267 substituted 3-7 membered saturated or unsaturated spiro-fused ring having 0-3 heteroatoms 268 independently selected from nitrogen, oxygen, or sulfur;

269 each R^x is independently halogen, alkyl, alkenyl, alkynyl, phenyl, naphthyl, aralkyl, 270 cycloalkyl, heteroaryl, heterocycloalkyl, -OR, -SR, -CN, -N(R’)(R’’), -C(O)R, -C(S)R, -CO₂R,271 -C(O)N(R’)(R’’), -C(O)SR, -C(O)C(O)R, -C(O)CH₂C(O)R, -C(S)N(R’)(R’’), -C(S)OR, - 272 S(O)R, -SO₂R, -SO₂N(R’)(R’’), -N(R’)C(O)R, -N(R’)C(O)N(R’)(R’’), -N(R’)C(S)N(R’)(R’’),273 -N(R’)SO₂R, -N(R’)SO₂N(R’)(R’’), -N(R’)N(R’)(R’’), -N(R’)C(=N(R’))N(R’)(R’’), - 274 C=NN(R’)(R’’), -C=NOR, -C(=N(R’))N(R’)(R’’), -OC(O)R, -OC(O)N(R’)(R’’);

275 L¹ is a covalent bond or an optionally substituted bivalent C_1-6 hydrocarbon chain276 wherein one or two methylene units is optionally replaced by -NR’-, -N (R’)C(O)-, - 277 C(O)N(R’)-, -N(R’)SO₂-, -SO₂N(R’)- -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO₂-; 278 each R is independently hydrogen, alkyl, alkenyl, alkynyl, phenyl, naphthyl, aralkyl, 279 cycloalkyl, heteroaryl, or heterocycloalkyl;

280 each R’ is independently -R, -C(O)R, -C(S)R, -CO₂R, -C(O)N(R)₂, -C(S)N(R)₂, - 281 S(O)R, -SO₂R, -SO₂N(R)₂, or two R groups on the same nitrogen are taken together with their282 intervening atoms to form an heteroaryl or heterocycloalkyl group; each R’’ is independently - 283 R, -C(O)R, -C(S)R, -CO₂R, -C(O)N(R)₂, -C(S)N(R)₂, -S(O)R, -SO₂R, -SO₂N(R)₂, or two R 284 groups on the same nitrogen are taken together with their intervening atoms to form an 285 heteroaryl or heterocycloalkyl group; or

286 R’ and R’’, together with the atoms to which each is attached, can form cycloalkyl, 287 heterocycloalkyl, phenyl, naphthyl, or heteroaryl; each of which is optionally substituted; 288 each R⁴ is independently alkyl, alkenyl, alkynyl, phenyl, naphthyl, aralkyl, cycloalkyl,289 heteroaryl, or heterocycloalkyl, halogen, -OR, -SR, -N(R’)(R’’), -CN, -NO₂, -C(O)R, -C(S)R, - 290 CO₂R, -C(O)N(R’)(R’’), -C(O)SR, -C(O)C(O)R, -C(O)CH₂C(O)R, -C(S)N(R’)(R’’), -C(S)OR, 291 -S(O)R, -SO₂R, -SO₂N(R’)(R’’), -N(R’)C(O)R, -N(R’)C(O)N(R’)(R’’), -N(R’)C(S)N(R’)(R’’),292 -N(R’)SO₂R, -N(R’)SO₂N(R’)(R’’), -N(R’)N(R’)(R’’), -N(R’)C(=N(R^/))N(R')(R"), - 293 C=NN(R')(R"), -C=NOR, -C(=N(R'))N(R')(R"), -OC(O)R, or -OC(O)N(R’)(R’’);

294 each R⁵ is independently -R, halogen, -OR, -SR, -N(R’)(R’’), -CN, -NO₂, -C(O)R, -295 C(S)R, -CO₂R, -C(O)N(R’)(R’’), -C(O)SR, -C(O)C(O)R, -C(O)CH₂C(O)R, -C(S)N(R’)(R’’), -296 C(S)OR, -S(O)R, -SO₂R, -SO₂N(R’)(R’’), -N(R’)C(O)R, -N(R’)C(O)N(R’)(R’’), - 297 N(R’)C(S)N(R’)(R’’), -N(R’)SO₂R, -N(R’)SO₂N(R’)(R’’), -N(R’)N(R’)(R’’), -298 N(R’)C(=N(R’))N(R’)(R’’), -C=NN(R’)(R’’), -C=NOR, -C(=N(R’))N(R’)(R’’), -OC(O)R, or - 299 OC(O)N(R’)(R’’);

300 n is 0-5;

301 each q is independently 0, 1, or 2; and

302 p is 1-6;

303

304 wherein:

305 X is O or N;

306 Y is O or N; wherein at least one of X or Y is O;

307 W is C or N;

308 R¹ is H, alkyl, alkenyl, alkynyl, aralkyl, phenyl, naphthyl, heteroaryl, halo, CN, OR^A, 309 NR^AR^B,

310 N(R^A)S(O) ^A

qR^AR^B, N(R^A)C(O)R^B, N(R^A)C(O)NR R^B, N(R^A)C(O)OR^A,

311 N(R^A)C(S)NR^AR^B, S(O)_qR^A, C(O)R^A, C(O)OR^A, OC(O)R^A, or C(O)NR^AR^B;

312 each R^A is independently optionally substituted alkyl, optionally substituted alkenyl or 313 optionally substituted alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or 314 N; phenyl; naphthyl; heteroaryl; heterocyclic; carbocyclic; or hydrogen;

315 each R^B is independently alkyl, alkenyl, or alkynyl, each containing 0, 1, 2, or 3 316 heteroatoms selected from O, S, or N; phenyl; naphthyl; heteroaryl; heterocyclic; carbocyclic; 317 or hydrogen; or

318 R^A and R^B, together with the atoms to which each is attached, can form a

319 heterocycloalkyl or a heteroaryl; each of which is optionally substituted;

320 Ring A is cycloalkyl, phenyl, naphthyl, heterocycloalkyl, or heteroaryl; 321 R^C is alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, naphthyl, heterocycloalkyl, or 322 heteroaryl, each optionally substituted with 1-5 independently selected R⁴, and when L¹ is other 323 than a covalent bond, R^C is additionally selected from H;

324 R² is H, halogen, alkyl, alkenyl, alkynyl, phenyl, naphthyl, aralkyl, cycloalkyl,325 heteroaryl, heterocycloalkyl, -OR, -SR, -CN, -N(R’)(R’’), -C(O)R, -C(S)R, -CO₂R, -326 C(O)N(R’)(R’’), -C(O)SR, -C(O)C(O)R, -C(O)CH₂C(O)R, -C(S)N(R’)(R’’), -C(S)OR, -327 S(O)R, -SO₂R, -SO₂N(R’)(R’’), -N(R’)C(O)R, -N(R’)C(O)N(R’)(R’’), -N(R')C(S)N(R')(R"), -328 N(R’)SO₂R, -N(R’)SO₂N(R’)(R’’), -N(R’)N(R’)(R’’), -N(R’)C(=N(R’))N(R’)(R’’), - 329 C=NN(R’)(R’’), -C=NOR, -C(=N(R’))N(R’)(R’’), -OC(O)R, -OC(O)N(R’)(R’’), or -(CH ^x

2)_pR ; 330 R³ is a bond or optionally substituted alkyl; or

331 R₂ and R₃ together with the atoms to which each is attached, form an optionally 332 substituted 3-7 membered saturated or unsaturated spiro-fused ring having 0-3 heteroatoms 333 independently selected from nitrogen, oxygen, or sulfur;

334 each R^x is independently halogen, alkyl, alkenyl, alkynyl, phenyl, naphthyl, aralkyl, 335 cycloalkyl, heteroaryl, heterocycloalkyl, -OR, -SR, -CN, -N(R’)(R’’), -C(O)R, -C(S)R, -CO₂R,336 -C(O)N(R’)(R’’), -C(O)SR, -C(O)C(O)R, -C(O)CH₂C(O)R, -C(S)N(R’)(R’’), -C(S)OR, - 337 S(O)R, -SO₂R, -SO₂N(R’)(R’’), -N(R’)C(O)R, -N(R’)C(O)N(R’)(R’’), -N(R’)C(S)N(R’)(R’’),338 -N(R’)SO₂R, -N(R’)SO₂N(R’)(R’’), -N(R’)N(R’)(R’’), -N(R’)C(=N(R’))N(R’)(R’’), - 339 C=NN(R’)(R’’), -C=NOR, -C(=N(R’))N(R’)(R’’), -OC(O)R, -OC(O)N(R’)(R’’);

340 L¹ is a covalent bond or an optionally substituted bivalent C_1-6 hydrocarbon chain341 wherein one or two methylene units is optionally replaced by -NR’-, -N (R’)C(O)-, - 342 C(O)N(R’)-, -N(R’)SO₂-, -SO₂N(R’)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO-, or -SO₂-; 343 each R is independently hydrogen, alkyl, alkenyl, alkynyl, phenyl, naphthyl, aralkyl, 344 cycloalkyl, heteroaryl, or heterocycloalkyl;

345 each R’ is independently -R, -C(O)R, -C(S)R, -CO₂R, -C(O)N(R)₂, -C(S)N(R)₂, - 346 S(O)R, -SO₂R, -SO₂N(R)₂, or two R groups on the same nitrogen are taken together with their347 intervening atoms to form an heteroaryl or heterocycloalkyl group; each R’’ is independently - 348 R, -C(O)R, -C(S)R, -CO₂R, -C(O)N(R)₂, -C(S)N(R)₂, -S(O)R, -SO₂R, -SO₂N(R)₂, or two R 349 groups on the same nitrogen are taken together with their intervening atoms to form an 350 optionally substituted heteroaryl or heterocycloalkyl group; or 351 R’ and R’’, together with the atoms to which each is attached, can form cycloalkyl, 352 heterocycloalkyl, phenyl, naphthyl, or heteroaryl; each of which is optionally substituted; 353 each R⁴ is independently alkyl, alkenyl, alkynyl, phenyl, naphthyl, aralkyl, cycloalkyl,354 heteroaryl, or heterocycloalkyl, halogen, -OR, -SR, -N(R’)(R’’), -CN, -NO₂, -C(O)R, -C(S)R, - 355 CO₂R, -C(O)N(R’)(R’’), -C(O)SR, -C(O)C(O)R, -C(O)CH₂C(O)R, -C(S)N(R’)(R’’), -C(S)OR, 356 -S(O)R, -SO₂R, -SO₂N(R’)(R’’), -N(R’)C(O)R, -N(R’)C(O)N(R’)(R’’), -N(R’)C(S)N(R’)(R’’),357 -N(R’)SO₂R, -N(R’)SO₂N(R’)(R’’), -N(R’)N(R’)(R’’), -N(R’)C(=N(R^/))N(R')(R"), - 358 C=NN(R')(R"), -C=NOR, -C(=N(R'))N(R')(R"), -OC(O)R, or -OC(O)N(R’)(R’’);

359 each R⁵ is independently -R, halogen, -OR, -SR, -N(R’)(R’’), -CN, -NO₂, -C(O)R, -360 C(S)R, -CO₂R, -C(O)N(R’)(R’’), -C(O)SR, -C(O)C(O)R, -C(O)CH₂C(O)R, -C(S)N(R’)(R’’), -361 C(S)OR, -S(O)R, -SO₂R, -SO₂N(R’)(R’’), -N(R’)C(O)R, -N(R’)C(O)N(R’)(R’’), -362 N(R’)C(S)N(R’)(R’’), -N(R’)SO₂R, -N(R’)SO₂N(R’)(R’’), -N(R’)N(R’)(R’’), -363 N(R’)C(=N(R’))N(R’)(R’’), -C=NN(R’)(R’’), -C=NOR, -C(=N(R’))N(R’)(R’’), -OC(O)R, or - 364 OC(O)N(R’)(R’’);

365 n is 0-5;

366 each q is independently 0, 1, or 2; and

367 p is 1-6;

368

369

370 wherein:

371 Ring A is benzo, or a 5-6 membered fused heteroaryl ring having 1-3 heteroatoms 372 independently selected from nitrogen, oxygen, or sulfur; 373 Ring B is a 3-7 membered saturated or partially unsaturated carbocyclic ring, phenyl, an 374 8-10 membered bicyclic saturated, partially unsaturated, phenyl or naphthyl ring, a 4-7

375 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms

376 independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic 377 heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and 378 sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-4 379 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered 380 bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, 381 and sulfur;

382 L¹ is a covalent bond or an optionally substituted bivalent C_1-6 hydrocarbon chain383 wherein one or two methylene units is optionally replaced by–NR’-, -N(R’)C(O)-, - 384 C(O)N(R’), -N(R’)SO₂-, -SO₂N(R’), -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO₂-;

385 R¹ is hydrogen, halogen, optionally substituted C_1-6 aliphatic, -OR, -SR, -CN, -N(R’)₂, -386 C(O)R, -C(S)R, -CO₂R, -C(O)N(R’)₂, -C(O)SR, -C(O)C(O)R, -C(O)CH₂C(O)R, -C(S)N(R’)₂, -387 C(S)OR, -S(O)R, -SO₂R, -SO₂N(R’)₂, -N(R’)C(O)R, -N(R’)C(O)N(R’)₂, -N(R’)C(S)N(R’)₂, - 388 N(R’)SO₂R, -N(R’)SO₂N(R’)₂, -N(R’)N(R’)₂, -N(R’)C(=N(R’))N(R’)₂, -C=NN(R’)₂, -C=NOR, 389 -C(=N(R’))N(R’)₂, -OC(O)R, -OC(O)N(R’)₂, or -(CH₂)_pR^x;

390 p is 0-3;

391 R^x is halogen, optionally substituted C_1-6 aliphatic, -OR, -SR, -CN, -N(R’)₂, -C(O)R, - 392 C(S)R, -CO₂R, -C(O)N(R’)₂, -C(O)SR, -C(O)C(O)R, -C(O)CH₂C(O)R, -C(S)N(R’)₂, -C(S)OR,393 -S(O)R, -SO₂R, -SO₂N(R’)₂, -N(R’)C(O)R, -N(R’)C(O)N(R’)₂, -N(R’)C(S)N(R’)₂, - 394 N(R’)SO₂R, -N(R’)SO₂N(R’)₂, -N(R’)N(R’)₂, -N(R’)C(=N(R’))N(R’)₂, -C=NN(R’)₂, -C=NOR, 395 -C(=N(R’))N(R’)₂, -OC(O)R, -OC(O)N(R’)₂;

396 R² is hydrogen, halogen, -CN, -SR, or optionally substituted C_1-6 aliphatic, or:

397 R¹ and R² are taken together with their intervening atoms to form an optionally

398 substituted 3-7 membered saturated or partially unsaturated spiro-fused ring having 0-2 399 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

400 each R is independently hydrogen or an optionally substituted group selected from C_1-6 401 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 7-10 402 membered bicyclic saturated, partially unsaturated, phenyl or naphthyl ring, a 5-6 membered 403 monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, 404 oxygen, and sulfur, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 405 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered 406 bicyclic saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms

407 independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic 408 heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and 409 sulfur;

410 each R’ is independently -R, -C(O)R, -C(S)R, -CO₂R, -C(O)N(R)₂, -C(S)N(R)₂, - 411 S(O)R, -SO₂R, -SO₂N(R)₂, or two R’ on the same nitrogen are taken together with their 412 intervening atoms to form an optionally substituted group selected from a 4-7 membered 413 monocyclic saturated or partially unsaturated ring having 1-2 heteroatoms independently 414 selected from nitrogen, oxygen, and sulfur, or a 7-12 membered bicyclic saturated, partially 415 unsaturated, or aromatic fused ring having 1-3 heteroatoms independently selected from 416 nitrogen, oxygen, and sulfur; 417

418 R³ is optionally substituted C_1-6 aliphatic;

419 X is oxygen or sulfur, or:

420 R³ and X are taken together with their intervening atoms to form an optionally

421 substituted

422 5-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, 423 oxygen, or sulfur;

424 each of m and n is independently 0-4, as valency permits; and

425 each of R⁴ and R⁵ is independently -R, halogen, -OR, -SR, -N(R’)₂, -CN, -NO₂, -C(O)R,426 -C(S)R, -CO₂R, -C(O)N(R’)₂, -C(O)SR, -C(O)C(O)R, -C(O)CH₂C(O)R, -C(S)N(R’)₂, -427 C(S)OR, -S(O)R, -SO₂R, -SO₂N(R’)₂, -N(R’)C(O)R, -N(R’)C(O)N(R’)₂, -N(R’)C(S)N(R’)₂, - 428 N(R’)SO₂R, -N(R’)SO₂N(R’)₂, -N(R’)N(R’)₂, -N(R’)C(=N(R’))N(R’)₂, -C=NN(R’)₂, -C=NOR, 429 -C(=N(R’))N(R’)₂, -OC(O)R, or -OC(O)N(R’)₂; ₄₃₀

431 wherein:

432 Ring A is benzo, or a 5-6 membered fused heteroaryl ring having 1-3 heteroatoms 433 independently selected from nitrogen, oxygen, or sulfur;

434 Ring B is a 3-7 membered saturated or partially unsaturated carbocyclic ring, phenyl, an 435 8-10 membered bicyclic saturated, partially unsaturated, phenyl or naphthyl ring, a 4-7

436 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms

437 independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic 438 heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and 439 sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-4 440 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered 441 bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, 442 and sulfur;

443 L¹ is a covalent bond or an optionally substituted bivalent C_1-6 hydrocarbon chain444 wherein one or two methylene units is optionally replaced by–NR’-, -N(R’)C(O)-, - 445 C(O)N(R’), -N(R’)SO₂-, -SO₂N(R’), -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO₂-;

446 R¹ is hydrogen, halogen, optionally substituted C_1-6 aliphatic, -OR, -SR, -CN, -N(R’)₂, -447 C(O)R, -C(S)R, -CO₂R, -C(O)N(R’)₂, -C(O)SR, -C(O)C(O)R, -C(O)CH₂C(O)R, -C(S)N(R’)₂, -448 C(S)OR, -S(O)R, -SO₂R, -SO₂N(R’)₂, -N(R’)C(O)R, -N(R’)C(O)N(R’)₂, -N(R’)C(S)N(R’)₂, - 449 N(R’)SO₂R, -N(R’)SO₂N(R’)₂, -N(R’)N(R’)₂, -N(R’)C(=N(R’))N(R’)₂, -C=NN(R’)₂, -C=NOR, 450 -C(=N(R’))N(R’)₂, -OC(O)R, -OC(O)N(R’)₂, or -(CH₂)_pR^x;

451 p is 0-3;

452 R^x is halogen, optionally substituted C_1-6 aliphatic, -OR, -SR, -CN, -N(R’)₂, -C(O)R, - 453 C(S)R, -CO₂R, -C(O)N(R’)₂, -C(O)SR, -C(O)C(O)R, -C(O)CH₂C(O)R, -C(S)N(R’)₂, -C(S)OR,454 -S(O)R, -SO₂R, -SO₂N(R’)₂, -N(R’)C(O)R, -N(R’)C(O)N(R’)₂, -N(R’)C(S)N(R’)₂, - 455 N(R’)SO₂R, -N(R’)SO₂N(R’)₂, -N(R’)N(R’)₂, -N(R’)C(=N(R’))N(R’)₂, -C=NN(R’)₂, -C=NOR, 456 -C(=N(R’))N(R’)₂, -OC(O)R, -OC(O)N(R’)₂; 457 R² is a bond or optionally substituted C_1-6 aliphatic, or:

458 R¹ and R² are taken together with their intervening atoms to form an optionally 459 substituted 3-7 membered saturated or partially unsaturated spiro-fused ring having 0-2 460 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

461 each R is independently hydrogen or an optionally substituted group selected from C_1-6 462 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 7-10 463 membered bicyclic saturated, partially unsaturated, phenyl, or naphthyl ring, a 5-6 membered 464 monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, 465 oxygen, and sulfur, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 466 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered 467 bicyclic saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms

468 independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic 469 heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and 470 sulfur;

471 each R’ is independently -R, -C(O)R, -C(S)R, -CO₂R, -C(O)N(R)₂, -C(S)N(R)₂, - 472 S(O)R, -SO₂R, -SO₂N(R)₂, or two R’ on the same nitrogen are taken together with their 473 intervening atoms to form an optionally substituted group selected from a 4-7 membered 474 monocyclic saturated or partially unsaturated ring having 1-2 heteroatoms independently 475 selected from nitrogen, oxygen, and sulfur, or a 7-12 membered bicyclic saturated, partially 476 unsaturated, or aromatic fused ring having 1-3 heteroatoms independently selected from 477 nitrogen, oxygen, and sulfur; 478

479 R³ is optionally substituted C_1-6 aliphatic;

480 X is oxygen or sulfur, or:

481 R³ and X are taken together with their intervening atoms to form an optionally 482 substituted

483 5-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, 484 oxygen, or sulfur;

485 each of m and n is independently 0-4, as valency permits; and 486 each of R⁴ and R⁵ is independently–R, halogen, -OR, -SR, -N(R’)₂, -CN, -NO₂, -487 C(O)R, -C(S)R, -CO₂R, -C(O)N(R’)₂, -C(O)SR, -C(O)C(O)R, -C(O)CH₂C(O)R, -C(S)N(R’)₂, -488 C(S)OR, -S(O)R, -SO₂R, -SO₂N(R’)₂, -N(R’)C(O)R, -N(R’)C(O)N(R’)₂, -N(R’)C(S)N(R’)₂, - 489 N(R’)SO₂R, -N(R’)SO₂N(R’)₂, -N(R’)N(R’)₂, -N(R’)C(=N(R’))N(R’)₂, -C=NN(R’)₂, -C=NOR, 490 -C(=N(R’))N(R’)₂, -OC(O)R, or -OC(O)N(R’)₂;

491

492

493 wherein:

494 Ring A is benzo, or a 5-6 membered fused heteroaryl ring having 1-3 heteroatoms 495 independently selected from nitrogen, oxygen, or sulfur;

496 Ring B is a 3-7 membered saturated or partially unsaturated carbocyclic ring, phenyl, an 497 8-10 membered bicyclic saturated, partially unsaturated, phenyl, or naphthyl ring, a 4-7 498 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms

499 independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic 500 heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and 501 sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-4 502 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered 503 bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, 504 and sulfur;

505 L¹ is a covalent bond or an optionally substituted bivalent C_1-6 hydrocarbon chain506 wherein one or two methylene units is optionally replaced by–NR’-, -N(R’)C(O)-, - 507 C(O)N(R’), -N(R’)SO₂-, -SO₂N(R’), -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO₂-; 508 R¹ is independently hydrogen, halogen, optionally substituted C_1-6 aliphatic, -OR, -SR, - 509 CN, -N(R’)₂, -C(O)R, -C(S)R, -CO₂R, -C(O)N(R’)₂, -C(O)SR, -C(O)C(O)R, -C(O)CH₂C(O)R,510 -C(S)N(R’)₂, -C(S)OR, -S(O)R, -SO₂R, -SO₂N(R’)₂, -N(R’)C(O)R, -N(R’)C(O)N(R’)₂, -511 N(R’)C(S)N(R’)₂, -N(R’)SO₂R, -N(R’)SO₂N(R’)₂, -N(R’)C(=N(R’))N(R’)₂, -C=NN(R’)₂, - 512 C=NOR, -C(=N(R’))N(R’)₂, -OC(O)R, -OC(O)N(R’)₂, or -(CH₂)_pR^x;

513 p is 0-3;

514 R^x is halogen, optionally substituted C_1-6 aliphatic, -OR, -SR, -CN, -N(R’)₂, -C(O)R, - 515 C(S)R, -CO₂R, -C(O)N(R’)₂, -C(O)SR, -C(O)C(O)R, -C(O)CH₂C(O)R, -C(S)N(R’)₂, -C(S)OR,516 -S(O)R, -SO₂R, -SO₂N(R’)₂, -N(R’)C(O)R, -N(R’)C(O)N(R’)₂, -N(R’)C(S)N(R’)₂, - 517 N(R’)SO₂R, -N(R’)SO₂N(R’)₂, -N(R’)N(R’)₂, -N(R’)C(=N(R’))N(R’)₂, -C=NN(R’)₂, -C=NOR, 518 -C(=N(R’))N(R’)₂, -OC(O)R, -OC(O)N(R’)₂;

519 R² is a bond, hydrogen, or optionally substituted C_1-6 aliphatic;

520 each R is independently hydrogen or an optionally substituted group selected from C_1-6 521 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 7-10 522 membered bicyclic saturated, partially unsaturated, phenyl, or naphthyl ring, a 5-6 membered 523 monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, 524 oxygen, and sulfur, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 525 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered 526 bicyclic saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms

527 independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic 528 heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and 529 sulfur;

530 each R’ is independently -R, -C(O)R, -C(S)R, -CO₂R, -C(O)N(R)₂, -C(S)N(R)₂, - 531 S(O)R, -SO₂R, -SO₂N(R)₂, or two R’ on the same nitrogen are taken together with their 532 intervening atoms to form an optionally substituted group selected from a 4-7 membered 533 monocyclic saturated or partially unsaturated ring having 1-2 heteroatoms independently 534 selected from nitrogen, oxygen, and sulfur, or a 7-12 membered bicyclic saturated, partially 535 unsaturated, or aromatic fused ring having 1-3 heteroatoms independently selected from 536 nitrogen, oxygen, and sulfur;

537 W is C or N;

538 R³ is optionally substituted C_1-6 aliphatic; 539 is a single or double bond;

540 each of m and n is independently 0-4, as valency permits; and

541 each of R⁴ and R⁵ is independently–R, halogen, -OR, -SR, -N(R’)₂, -CN, -NO₂, -542 C(O)R, -C(S)R, -CO₂R, -C(O)N(R’)₂, -C(O)SR, -C(O)C(O)R, -C(O)CH₂C(O)R, -C(S)N(R’)₂, -543 C(S)OR, -S(O)R, -SO₂R, -SO₂N(R’)₂, -N(R’)C(O)R, -N(R’)C(O)N(R’)₂, -N(R’)C(S)N(R’)₂, - 544 N(R’)SO₂R, -N(R’)SO₂N(R’)₂, -N(R’)N(R’)₂, -N(R’)C(=N(R’))N(R’)₂, -C=NN(R’)₂, -C=NOR, 545 -C(=N(R’))N(R’)₂, -OC(O)R, or -OC(O)N(R’)₂;

546

547

548

549

550 wherein:

551 X is selected from N and CH;

552 Y is CO;

553 R¹ and R³ are each independently selected from alkoxy and hydrogen;

554 R² is selected from alkoxy, alkyl, and hydrogen;

555 R⁶ and R⁸ are each independently selected from alkyl, alkoxy, chloride, and hydrogen; 556 R⁵ and R⁹ are each hydrogen;

557 R⁷ is selected from amino, hydroxyl, alkoxy, and alkyl substituted with a heterocyclyl; 558 R¹⁰ is hydrogen; or 559 two adjacent substituents selected from R⁶, R⁷, and R⁸ are connected to form a 560 heterocyclyl;

561 each W is independently selected from C and N, wherein if W is N, then p is 0 or 1, and 562 if W is C, then p is 1;

563 for W-(R¹⁰)_p, W is N and p is 1; and

564 for W-(R⁴)_p, W is C, p is 1 and R⁴ is H, or W is N and p is 0;

565

566

567 wherein:

568 Y and W are each independently selected from carbon and nitrogen;

569 Ra⁶ is selected from fluoride, hydrogen, C₁-C₃ alkoxy, cyclopropyloxy, SO₂R₃, 570 SOR₃, and SR₃, wherein if Y is nitrogen then Ra⁶ is absent;

571 Ra⁷ is selected from hydrogen, fluoride, SO₂R₃, SOR₃, and SR₃;

572 Ra⁸ is selected from hydrogen, C₁-C₃ alkoxy, cyclopropyloxy, chloride, and

573 bromide;

574 n is selected from 1, 2, or 3;

575 D is selected from O, NH, NR₁, S, or C;

576 Rb³ and Rb⁵ are independently selected from hydrogen and C₁-C₃ alkyl;

577 R ³

C and R ⁵

C are independently selected from hydrogen, C₁-C₃ alkyl, and 578 cyclopropyl;

579 R ⁴

₅₈₀ NHSO₂R⁴, C(O)OR⁴, and

581 R¹, R’¹, R² and R’² are independently selected from hydrogen, fluoride, C₁-C₃ alkyl, and 582 cyclopropyl, wherein R¹ and R² and/or R’¹ and R’² may be connected to form a 3-6 membered 583 ring;

584 R³ is selected from C₁-C₃ alkyl and cyclopropyl; and

585 R⁴ is selected from hydrogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl, phenyl, and naphthyl, 586 provided that if Ra⁷ or Ra⁶ is fluoride, then R ⁴

C is not bromide;

587

588

589 wherein:

590 Q and V are independently selected from CH and nitrogen;

591 U is selected from C=O, C=S, SO₂, S=O, SR¹, CR¹R², CR¹OR², CR¹SR²;

592 R¹ and R² are independently selected from hydrogen and C₁-C₆ alkyl;

593 Rc is selected from hydrogen, C₁-C₆ alkyl, and C₃-C₆ cycloalkyl;

594 Ra¹, Ra², and Ra³ are independently selected from hydrogen, C₁-C₆ alkyl, C₁-C₆ 595 alkenyl, C₁-C₆ alkynyl, C₁-C₆ alkoxy, halogen, amino, amide, hydroxyl, heterocycle, and C₃-C₆ 596 cycloalkyl, wherein Ra¹ and Ra² and/or Ra² and Ra³ may be connected to form a cycloalkyl or 597 a heterocycle; 598 Rb² and Rb⁶ are independently selected from hydrogen, halogen, C₁-C₆ alkyl, C₁-C₆ 599 alkenyl, C₃-C₆ cycloalkyl, hydroxyl, and amino;

600 Rb³ and Rb⁵ are independently selected from hydrogen, halogen, C₁-C₆ alkyl, C₁-C₆ 601 alkoxy, C kyl, hydroxyl, and amino, wherein Rb² and Rb³ and/or Rb⁵

3-C₆ cycloal and Rb⁶ may 602 be connected to form a cycloalkyl or a heterocycle;

603

represents a 3-8 membered ring system wherein: W is selected from 604 carbon and nitrogen; Z is selected from CR⁶R⁷, NR⁸, oxygen, sulfur, -S(O)-, and -SO₂-;

605 said ring system being optionally fused to another ring selected from cycloalkyl, heterocycle, 606 and phenyl, and wherein said ring system is optionally selected from rings having the

607 structures:

₆₀₈

609

610

611

612 R³, R⁴, and R⁵ are independently selected from hydrogen, C₁-C₆ alkyl, C₁-C₆ alkenyl, 613 C₁-C₆ alkynyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkyl, phenyl, naphthyl, phenoxy, hydroxy1, amino, 614 amide, oxo, -CN, and sulfonamide;

615 R⁶ and R⁷ are independently selected from hydrogen, C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ 616 alkynyl, C₃-C₆ cycloalkyl, phenyl, naphthyl, halogen, hydroxyl, -CN, amino, and amido; and 617 R⁸ is selected from hydrogen, C_1-C₆ alkyl, C₁-C₆ alkenyl, C_1-C₆ alkynyl, acyl, and C₃-C₆ 618 cycloalkyl; and

619 R⁹, R¹⁰, R¹¹, and R¹² are independently selected from hydrogen, C₁-C₆ alkyl, C₁-C₆ 620 alkenyl, C₁-C₆ alkynyl, C₃-C₆ cycloalkyl, phenyl, naphthyl, heterocycle, hydroxyl, sulfonyl, 621 and acyl;

622

623

624 wherein:

625 Q is selected from N and CRa³;

626 V is selected from N and CRa⁴;

627 W is selected from N and CH;

628 U is selected from C=O, C=S, SO₂, S=O, and SR¹;

629 X is selected from OH, SH, NH₂, S(O)H, S(O)₂H, S(O)₂NH₂, S(O)NH₂, NHAc, and 630 NHSO₂Me;

631 Ra¹, Ra³, and Ra³ are independently selected from hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, 632 C₃-C₆ cycloalkyl, and halogen;

633 Ra² is selected from hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkyl, amino, 634 amide, and halogen;

635 Rb² and Rb⁶ are independently selected from hydrogen, methyl and fluorine;

636 Rb³ and Rb⁵ are independently selected from hydrogen, halogen, C₁-C₆ alkyl, C₃-C₆ 637 cycloalkyl, and C₁-C₆ alkoxy; and

638 Rb² and Rb³ and/or Rb⁵ and Rb⁶ may be connected to form a cycloalkyl or a heterocycle, 639 provided that at least one of Ra¹, Ra², Ra³, and Ra⁴ is not hydrogen; 640 XX)

641 wherein:

642 Q is selected from N and CRa³;

643 V is selected from N and CRa⁴;

644 W is selected from N and CH;

645 U is selected from C=O, C=S, SO₂, S=O, and SR¹;

646 X is selected from OH, SH, NH₂, S(O)H, S(O)₂H, S(O)₂NH₂, S(O)NH₂, NHAc, and 647 NHSO₂Me;

648 Ra¹, Ra³, and Ra³ are independently selected from hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, 649 C₃-C₆ cycloalkyl, and halogen;

650 Ra² is selected from hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkyl, amino, 651 amide, and halogen;

652 Rb² and Rb⁶ are independently selected from hydrogen, methyl and fluorine;

653 Rb³ and Rb⁵ are independently selected from hydrogen, halogen, C₁-C₆ alkyl, C₃-C₆ 654 cycloalkyl, and C₁-C₆ alkoxy; and

655 Rb² and Rb³ and/or Rb⁵ and Rb⁶ may be connected to form a cycloalkyl or a heterocycle, 656 provided that at least one of Ra¹, Ra², Ra³, and Ra⁴ is not hydrogen;

657

658

659 wherein:

660 V is independently selected, for each occurrence, from the group consisting of 661 NH, S, N(C_1-6alkyl), O, or CR⁴R⁴;

662 Q is independently selected, for each occurrence, from the group consisting of 663 C(O), C(S), C(N), SO ⁴

2, or CR R⁴;

664 U is independently selected from the group consisting of a bond, C(O), C(S), 665 C(N), SO₂, or CR⁴R⁴ 666 W and T are independently selected from the group consisting of NH, N(C_1- 667 ₆alkyl), O, or Q;

668 V^C is selected from the group consisting of N, SH or CR⁴;

669 A is selected from the group consisting of aliphatic, cycloalkyl, heterocyclic, 670 phenyl, naphthyl, heteroaryl or bicyclic moiety, wherein the cycloalkyl, heterocyclic, 671 phenyl, naphthyl, heteroaryl, or bicyclic moiety is optionally substituted with one, two, 672 three, four or more groups represented by R⁴;

673 R¹ is independently selected, for each occurrence, from the group consisting of 674 hydroxyl, halo, C_1-6alkyl, hydroxyC_1-6alkyl, aminoC_1-6alkyl, haloC_1-6alkyl, C_1-6alkoxy,675 haloC_1-6alkoxy, acylaminoC_1-6alkyl, nitro, cyano, CF₃, -OCF₃, -C(O)OC_1- 676 ₆alkyl, -OS(O)₂C_1-4alkyl, phenyl, naphthyl, phenyloxy, benzyloxy, or phenylmethoxy, 677 wherein C_1-6alkyl, phenyl, and naphthyl are optionally substituted by one two or three 678 substituents selected from the group consisting of hydroxyl, halogen, oxo, C_1-6alkyl, 679 amino, or nitro;

680 R² is selected from the group consisting of -O-, amino, C_1-6alkyl, -O-C_1-6alkyl-,681 hydroxylC_1-6alkyl, aminoC_1-6alkyl, haloC_1-6alkyl, haloC_1-6alkoxy, acylaminoC_1-6alkyl, - 682 C(O)-, -C(O)O-, -C(O)NC_1-6alkyl-, -OS(O)₂C_1-4alkyl-, -OS(O)₂-, -S-C_1-6alkyl-, phenyl, 683 naphthyl, phenyloxy, benzyloxy, or phenylmethoxy, wherein C_1-6alkyl, phenyl, and 684 naphthyl are optionally substituted by one two or three substituents selected from the 685 group consisting of hydroxyl, halogen, oxo, C_1-6alkyl, amino, or nitro;

686 R³ is selected from the group consisting of hydrogen or C_1-6alkyl;

687 R⁴ is independently selected, for each occurrence, from the group consisting of 688 hydrogen, hydroxyl, oxo, imino, amino, halo, C_1-6alkyl, cycloalkyl, phenyl, naphthyl,689 heterocyclyl, -O-C_1-6alkyl, -NH-C_1-6alkyl, -N(C_1-6alkyl)C_1-6alkyl, nitro, cyano, CF₃, - 690 OCF₃, -C(O)OC_1-6alkyl, -C(O)NHC_1-6alkyl, -C(O)NH₂ or -OS(O)₂C_1-4alkyl;

691 m is selected from the group consisting of 0, 1, 2, or 3;

692 n is selected from the group consisting of 0, 1, or 2; and

693 p is selected from the group consisting of 0 or 1;

694

695

696 wherein:

697 V is independently selected, for each occurrence, from the group consisting of NH, S, 698 N(C_1-6alkyl), O, or CR⁴R⁴; 699 Q is independently selected, for each occurrence, from the group consisting of C(O), 700 C(S), C(N), SO₂, or CR⁴R⁴;

701 U is independently selected from the group consisting of a bond, C(O), C(S), C(N), 702 SO₂, or CR⁴R⁴ 703 W and T are independently selected from the group consisting of NH, N(C_1-6alkyl), O, 704 or Q;

705 V^C is selected from the group consisting of N, SH or CR⁴;

706 A is selected from the group consisting of aliphatic, cycloalkyl, heterocyclic, phenyl, 707 naphthyl, heteroaryl or bicyclic moiety, wherein the cycloalkyl, heterocyclic, phenyl, naphthyl, 708 heteroaryl, or bicyclic moiety is optionally substituted with one, two, three, four or more groups 709 represented by R⁴;

710 R¹ is independently selected, for each occurrence, from the group consisting of711 hydroxyl, halo, C_1-6alkyl, hydroxyC_1-6alkyl, aminoC_1-6alkyl, haloC_1-6alkyl, C_1-6alkoxy, haloC_1- 712 ₆alkoxy, acylaminoC_1-6alkyl, nitro, cyano, CF₃, -OCF₃, -C(O)OC_1-6alkyl, -OS(O)₂C_1-4alkyl, 713 phenyl, naphthyl, phenyloxy, benzyloxy, or phenylmethoxy, wherein C_1-6alkyl, phenyl, and 714 naphthyl are optionally substituted by one two or three substituents selected from the group 715 consisting of hydroxyl, halogen, oxo, C_1-6alkyl, amino, or nitro;

716 R² is selected from the group consisting of -O-, amino, C_1-6alkyl, -O-C_1-6alkyl-,717 hydroxylC_1-6alkyl, aminoC_1-6alkyl, haloC_1-6alkyl, haloC_1-6alkoxy, acylaminoC_1-6alkyl, -C(O)-, - 718 C(O)O-, -C(O)NC_1-6alkyl-, -OS(O)₂C_1-4alkyl-, -OS(O)₂-, -S-C_1-6alkyl-, phenyl, naphthyl, 719 phenyloxy, benzyloxy, or phenylmethoxy, wherein C_1-6alkyl, phenyl, and naphthyl are

720 optionally substituted by one two or three substituents selected from the group consisting of 721 hydroxyl, halogen, oxo, C_1-6alkyl, amino, or nitro;

722 R³ is selected from the group consisting of hydrogen or C_1-6alkyl;

723 R⁴ is independently selected, for each occurrence, from the group consisting of

724 hydrogen, hydroxyl, oxo, imino, amino, halo, C_1-6alkyl, cycloalkyl, phenyl, naphthyl,

725 heterocyclyl, -O-C_1-6alkyl, -NH-C_1-6alkyl, -N(C_1-6alkyl)C_1-6alkyl, nitro, cyano, CF₃, - 726 OCF₃, -C(O)OC_1-6alkyl, -C(O)NHC_1-6alkyl, -C(O)NH₂ or -OS(O)₂C_1-4alkyl;

727 m is selected from the group consisting of 0, 1, 2, or 3;

728 n is selected from the group consisting of 0, 1, or 2; and 729 p is selected from the group consisting of 0 or 1;

730

731 wherein:

732 V is selected from the group consisting of a NH, S, N(C_1-6alkyl), O, or CR⁴R⁴;

733 Q is selected from the group consisting of a bond, C(O), C(S), C(N), SO₂, or CR⁴R⁴; 734 A is a ring selected from the group consisting of: phenyl, a 5-6 membered cycloalkyl, a 735 5-6 membered heteroaryl having 1, 2 or 3 heteroatoms each selected from S, N or O, and a 4-7 736 membered heterocycle having 1, 2 or 3 heteroatoms each selected from N or O;

737 R^A1 is R¹; or two R^A1 substituents may be taken together with the atoms to which they 738 are attached to form phenyl, a 5-6 membered heteroaryl having 1, 2 or 3 heteroatoms each 739 selected from S, N or O, and a 4-7 membered heterocycle having 1, 2 or 3 heteroatoms each 740 selected from N or O;

741 R¹ is independently selected, for each occurrence, from the group consisting of742 hydroxyl, halo, C_1-6alkyl, hydroxyC_1-6alkyl, aminoC_1-6alkyl, haloC_1-6alkyl, C_1-6alkoxy, haloC_1-743 ₆alkoxy, acylaminoC_1-6alkyl, nitro, cyano, CF₃, -OCF₃, -C(O)OC_1-6alkyl, -OS(O)₂C_1- 744 ₄alkyl, -S(C_1-4alkyl)C(O)R’, phenyl, naphthyl, phenyloxy, benzyloxy, or phenylmethoxy, 745 wherein C_1-6alkyl, phenyl, and napththyl are optionally substituted by one two or three 746 substituents selected from the group consisting of hydroxyl, halogen, oxo, C_1-6alkyl, amino, or 747 nitro;

748 R² is selected from the group consisting of -O-, amino, C_1-6alkyl, -O-C_1-6alkyl-,749 hydroxylC_1-6alkyl, aminoC_1-6alkyl, haloC_1-6alkyl, haloC_1-6alkoxy, acylaminoC_1-6alkyl, -C(O)-, - 750 C(O)O-, -C(O)NC_1-6alkyl-, -OS(O)₂C_1-4alkyl-, -OS(O)₂--S(C_1-4alkyl)C(O)R’’-, -S-C_1-6alkyl-, 751 phenyl, naphthyl, phenyloxy, benzyloxy, or phenylmethoxy, wherein C_1-6alkyl, phenyl, and 752 naphthyl are optionally substituted by one two or three substituents selected from the group 753 consisting of hydroxyl, halogen, oxo, C_1-6alkyl, amino, or nitro;

754 R³ is selected from the group consisting of hydrogen or C_1-6alkyl; 755 R⁴ is independently selected, for each occurrence, from the group consisting of 756 hydrogen, hydroxyl, oxo, imino, amino, halo, C_1-6alkyl, cycloalkyl, phenyl, naphthyl,

757 heterocyclyl, -O-C_1-6alkyl, -NH-C_1-6alkyl, -N(C_1-6alkyl)C_1-6alkyl, nitro, cyano, CF₃, - 758 OCF₃, -C(O)OC_1-6alkyl, -C(O)NHC_1-6alkyl, -C(O)NH₂ or -OS(O)₂C_1-4alkyl;

759 R’ is independently selected, for each occurrence, from the group consisting of 760 hydroxyl, amino, thio, phenyl, naphthyl, or C_1-6alkyl, wherein C_1-6alkyl, phenyl, and naphthyl 761 are optionally substituted by one two or three substituents selected from the group consisting of 762 hydroxyl, halogen, oxo, C_1-6alkyl, amino, or nitro;

763 R’’ is independently selected, for each occurrence, from the group consisting of–O-, 764 amino, thio, phenyl, naphthyl, or C_1-6alkyl, wherein C_1-6alkyl, phenyl, and naphthyl are 765 optionally substituted by one two or three substituents selected from the group consisting of 766 hydroxyl, halogen, oxo, C_1-6alkyl, amino, or nitro;

767 m is independently selected, for each occurrence, from the group consisting of 0, 1, 2, 768 or 3;

769 n is selected from the group consisting of 0, 1, or 2; and

770 p is selected from the group consisting of 0 or 1; R²

₇₇₁ 2 A

7₇₂

_, 773

₇₇₄

775 wherein:

776 L and L^X are independently selected, for each occurrence, from the group consisting of 777 N, CH, and CR¹;

778 L^N1 and L^N2 are independently selected from the group consisting of CH₂, CHR¹, 779 CR¹R¹, NH, and N(C_1-6alkyl); wherein C_1-6alkyl is optionally substituted by one two or three 780 substituents selected from the group consisting of hydroxyl, halogen, oxo, C_1-6alkyl, amino, or 781 nitro;

782 L^N3 is selected from the group consisting of O, S, NH, and N(C_1-6alkyl); wherein C_1- 783 ₆alkyl is optionally substituted by one two or three substituents selected from the group 784 consisting of hydroxyl, halogen, oxo, C_1-6alkyl, amino, or nitro;

785 U is independently selected from the group consisting of a bond, C(O), C(S), C(N), 786 SO₂, or CR⁴R⁴;

787 A is selected from the group consisting of aliphatic, cycloalkyl, heterocyclic, phenyl, 788 naphthyl, heteroaryl, or bicyclic moiety, wherein the cycloalkyl, heterocyclic, phenyl, naphthyl, 789 heteroaryl, or bicyclic moiety is optionally substituted with one, two, three, four or more groups 790 represented by R⁴;

791 R¹ is independently selected, for each occurrence, from the group consisting of792 hydroxyl, halo, C_1-6alkyl, hydroxyC_1-6alkyl, aminoC_1-6alkyl, haloC_1-6alkyl, C_1-6alkoxy, haloC_1- 793 ₆alkoxy, acylaminoC_1-6alkyl, nitro, cyano, CF₃, -OCF₃, -C(O)OC_1-6alkyl, -OS(O)₂C_1-4alkyl, 794 phenyl, naphthyl, phenyloxy, benzyloxy, or phenylmethoxy, wherein C_1-6alkyl, phenyl, and 795 naphthyl are optionally substituted by one two or three substituents selected from the group 796 consisting of hydroxyl, halogen, oxo, C_1-6alkyl, amino, or nitro;

797 R² is selected from the group consisting of -O-, amino, C_1-6alkyl, -O-C_1-6alkyl-,798 hydroxylC_1-6alkyl, aminoC_1-6alkyl, haloC_1-6alkyl, haloC_1-6alkoxy, acylaminoC_1-6alkyl, -C(O)-, - 799 C(O)O-, -C(O)NC_1-6alkyl-, -OS(O)₂C_1-4alkyl-, -OS(O)₂-, -S-C_1-6alkyl-, phenyl, naphthyl, 800 phenyloxy, benzyloxy, or phenylmethoxy, wherein C_1-6alkyl, phenyl, and naphthyl are 801 optionally substituted by one two or three substituents selected from the group consisting of 802 hydroxyl, halogen, oxo, C_1-6alkyl, amino, or nitro;

803 R³ is selected from the group consisting of hydrogen or C_1-6alkyl; and

804 R⁴ is independently selected, for each occurrence, from the group consisting of 805 hydrogen, hydroxyl, oxo, imino, amino, halo, C_1-6alkyl, cycloalkyl, phenyl, naphthyl,

806 heterocyclyl, -O-C_1-6alkyl, -NH-C_1-6alkyl, -N(C_1-6alkyl)C_1-6alkyl, nitro, cyano, CF₃, - 807 OCF₃, -C(O)OC_1-6alkyl, -C(O)NHC_1-6alkyl, -C(O)NH₂ or -OS(O)₂C_1-4alkyl;

808 XXV)

809 wherein

810 R^x is hydrogen or C₁-C₃ alkyl;

811 R^Y is C₁-C₃ alkyl, -(C₂-C₃ alkylenyl)-OH, or C₁-C₃ haloalkyl;

812 X¹ is N or CR^x1 wherein

813 R^x1 is hydrogen, C₂-C₆ alkenyl, C ^ax1

2-C₆ alkynyl, -C(O)OR , -C(O)NR^bx1R^cx1, - 814 C(O)R^dx1, S(O)₂R^dx1, -S(O)₂NR^bx1R^cx1, G^x1, C₁-C₆ haloalkyl, or C₁-C₆ alkyl; 815 wherein the C₁-C₆ alkyl is optionally substituted with one substituent selected816 from the group consisting of OR^ax1, SR^ax1, S(O)R^dx1, S(O) ^cx1

2R^dx1, NR^bx1R , - 817 C(O)R^ax1, -C(O)OR^ax1, -C(O)NR^bx1R^cx1, -S(O) R^cx1

2NR^bx1 , and G^x1; 818 R^ax1, R^bx1, and R^cx1, at each occurrence, are each independently hydrogen, C₁-C₆ 819 alkyl, C₁-C₆ haloalkyl, G^a, or -(C₁-C₆ alkylenyl)-G^a;

820 R^dx1, at each occurrence, are each independently C₁-C₆ alkyl, C₁-C₆ haloalkyl, 821 G^a, or -(C₁-C₆ alkylenyl)-G^a;

822 X² is N or CR^x2; wherein

823 R^x2 is hydrogen, C ²

2-C₆ alkenyl, C₂-C₆ alkynyl, -C(O)OR^ax2, -C(O)NR^bx R^cx2, - 824 C(O)R^dx2, S(O)₂R^dx2, -S(O)₂NR^bx2R^cx2, G^x2, C₁-C₆ haloalkyl, or C₁-C₆ alkyl; 825 wherein the C₁-C₆ alkyl is optionally substituted with one substituent selected826 from the group consisting of OR^ax2, SR^ax2, S(O)R^dx2, S(O) ^cx2

2R^dx2, NR^bx2R , - 827 C(O)R^ax2, -C(O)OR^ax2, -C(O)NR^bx2R^cx2, -S(O)₂NR^bx2R^cx2, and G^x2;

828 R^ax2, R^bx2, and R^cx2, at each occurrence, are each independently hydrogen, C₁-C₆ 829 alkyl, C₁-C₆ haloalkyl, G^b, or -(C₁-C₆ alkylenyl)-G^b;

830 R^dx2, at each occurrence, is independently C₁-C₆ alkyl, C₁-C₆ haloalkyl, G^b, or - 831 (C₁-C₆ alkylenyl)-G^b;

832 Y¹ is N or CR^u; wherein R^u is hydrogen, C₁-C₆ alkyl, halogen, or C₁-C₆ haloalkyl; 833 A¹ is N or CR¹, A² is N or CR², A³ is N or CR³, and A⁴ is N or CR⁴; with the proviso 834 that zero, one, two, or three of A¹, A², A³, and A⁴ are N;

835 R¹, R³, and R⁴ are each independently hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ 836 alkynyl, halogen, C₁-C₆ haloalkyl, CN, or NO₂;

837 R² is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl, - 838 CN, NO₂, G^2a, -OR^2a, -OC(O)R^2d, -OC(O)NR^2bR^2c, -SR^2a, -S(O)₂R^2d, -S(O)₂NR^2bR^2c

, -C(O)R^2d,839 -C(O)OR^2a, -C(O)NR^2bR^2c, -NR^2bR^2c, -N(R^2e)C(O)R^2d, -N(R^2e)S(O)₂R^2d, -N(R^2e)C(O)O(R^2d), -840 N(R^2e)C(O)NR^2bR^2c, -N(R^2e)S(O)₂NR^2bR^2c, -(C₁-C₆ alkylenyl)-G^2a, -(C₁-C₆ alkylenyl)-OR^2a, -841 (C₁-C₆ alkylenyl)-OC(O)R^2d, -(C₁-C₆ alkylenyl)-OC(O)NR^2bR^2c, -(C₁-C₆ alkylenyl)-S(O)²R^2d, - 842 (C₁-C₆

843 alkylenyl)-S(O)₂NR^2bR^2c, -(C₁-C₆ alkylenyl)-C(O)R^2d, -(C₁-C₆ alkylenyl)-C(O)OR^2a, -(C₁-C₆844 alkylenyl)-C(O)NR^2bR^2c, -(C₁-C₆ alkylenyl)-NR^2bR^2C, -(C₁-C₆ alkylenyl)-N(R^2e)C(O)R^2d, -(C₁- 845 C₆

846 alkylenyl)-N(R^2e)S(O)2R^2d, -(C ^2a

1-C₆ alkylenyl)-N(R^2e)C(O)O(R ), -(C₁-C₆

847 alkylenyl)-N(R^2e)C(O)NR^2bR^2c, -(C₁-C₆ alkylenyl)-N(R^2e)S(O)₂NR^2bR^2c, and -(C₁-C₆

848 alkylenyl)-CN;

849 R^2a, R^2b, R^2C, and R^2e, at each occurrence, are each independently hydrogen, C₂-C₆ 850 alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, G^2b, or C₁-C₆ alkyl wherein the C₁-C₆ alkyl is 851 optionally substituted with one substituent selected from the group consisting of -OR^z1, 852 NR^z1R^z2, -C(O)OR^z1, -C(O)NR^z1R^z2, -S(O)₂R^z1, -S(O) ²

2NR^z1R^z , and G^2b;

853 R^2d, at each occurrence, is independently C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, 854 G^2b, or C₁-C₆ alkyl wherein the C₁-C₆ alkyl is optionally substituted with one substituent855 selected from the group consisting of -OR^z1, NR^z1R^z2, -C(O)OR^z1, -C(O)NR^z1R^z2, -S(O)₂R^z1, - 856 S(O)₂NR^z1R^z2, and G^2b;

857 R^z1 and R^z2, at each occurrence, are each independently hydrogen, C₁-C₆ alkyl, or C₁-C₆ 858 haloalkyl;

859 G^x1, G^x2, G^a, G^b, G^2a, and G^2b, at each occurrence, are each independently aryl, 860 heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl, and each of which is independently 861 unsubstituted or substituted with 1 , 2, 3, 4, or 5 of R^v;

862 L¹ is absent, CH₂, C(O), C(H)(OH), (CH₂)_mO, (CH₂)_mS(O)_n wherein n is 0, 1, or 2; or 863 (CH₂)_mN(R^z) wherein R^z is hydrogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, (C₂-C₃ alkylenyl)-OH, or 864 unsubstituted cyclopropyl;

865 m is 0 or 1;

866 G¹ is C_1-C₆ alkyl, alkoxyalkyl, G^1a , or -(C₁-C₆ alkylenyl)-G^1a; wherein each G^1a is 867 independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl, and each G^1a is 868 independently unsubstituted or substituted with 1, 2, 3, 4, or 5 of R^w;

869 R^v and R^w, at each occurrence, are each independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-870 C₆ alkynyl, halogen, C₁-C₆ haloalkyl, -CN, oxo, -OR^h, -OC(O)Rⁱ -OC(O)NR^jR^k, -SR^h, - 871 S(O)₂R^h, -S(O)₂NR^jR^k, -C(O)R^h, -C(O)-monocyclic heterocycle, -C(O)-monocyclic heteroaryl,872 -C(O)OR^h, -C(O)NR^jR^k, -NR^jR^k, -N(R^h)C(O)Rⁱ, -N(R^h)S(O)₂Rⁱ, -N(R^h)C(O)O(Rⁱ), -873 N(R^h)C(O)NR^jR^k, -(C₁-C₆ alkylenyl)-OR^h, -(C₁-C₆ alkylenyl)-OC(O)Rⁱ, -(C₁-C₆ alkylenyl)-874 OC(O)NR^jR^k, -(C₁-C₆ alkylenyl)-S(O)₂R^h, -(C₁-C₆ alkylenyl)-S(O)₂NR^jR^k, -(C₁-C₆ alkylenyl)-875 C(O)R^h, -(C₁-C₆ alkylenyl)-C(O)OR^h, -(C₁-C₆ alkylenyl)-C(O)NR^jR^k, -(C₁-C₆ alkylenyl)-876 NR^jR^k, -(C₁-C₆ alkylenyl)-N(R^h)C(O)Rⁱ, -(C₁-C₆ alkylenyl)-N(R^h)S(O)₂Rⁱ, -(C₁-C₆ alkylenyl)- 877 N(R^h)C(O)O(Rⁱ), -(C₁-C₆ alkylenyl)-N(R^h)C(O)NR^jR^k, or -(C₁-C₆ alkylenyl)-CN;

878 R^h, R^j, R^k, at each occurrence, are each independently hydrogen, C₁-C₆ alkyl, or C₁-C₆ 879 haloalkyl; and

880 Rⁱ, at each occurrence, is independently C₁-C₆ alkyl or C₁-C₆ haloalkyl; and

881

882

883 wherein:

884 R¹ is optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally 885 substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally 886 substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted

887 heterocycloalkyl, haloalkyl, -C(O)R, -C(S)R, -CO₂R, -C(O)N(R')(R"), -C(O)SR, -C(O)C(O)R,888 -C(O)CH₂C(O)R, -C(S)N(R')(R"), -C(S)OR, -S(O)R, -SO₂R, -SO₂N(R')(R"), -C=NN(R')(R"), - 889 C=NOR, or -C(=N(R'))N(R')(R");

890 R² is H, optionally substituted alkyl, optionally substituted alkenyl, optionally

891 substituted alkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally 892 substituted heteroarylalkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl,893 optionally substituted heterocycloalkyl, haloalkyl, -C(O)R, -C(S)R, -CO₂R, -C(O)N(R')(R"), -894 C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R')(R"), -C(S)OR, -S(O)R, -SO₂R, - 895 SO₂N(R')(R"), -C=NN(R')(R"), -C=NOR, -C(=N(R'))N(R')(R"), or -(CH₂)_pR^x; or R¹ and R² 896 together with the atoms to which each is attached, forms an optionally substituted 3-7

897 membered saturated or unsaturated ring having 0-4 additional heteroatoms independently 898 selected from nitrogen, oxygen, or sulfur;

899 R³ is H, alkyl, alkenyl, alkynyl, aralkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, 900 or halo, each of which is optionally substituted; or CN, OR^A, NR^AR^B, N(R^A)S(O) ^A qR R^B, 901 N(R^A)C(O)R^B, N(R^A)C(O)NR^AR^B, N(R^A)C(O)OR^A, N(R^A)C(S)NR^AR^B, -N(R^A)S(O)_qNR^AR^B, 902 S(O)_qR^A, C(O)R^A, C(O)OR^A, OC(O)R^A, or C(O)NR^AR^B;

903 each R^A is independently optionally substituted alkyl, optionally substituted alkenyl or 904 optionally substituted alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or 905 N; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted

906 heterocyclic;

907 optionally substituted carbocyclic; or hydrogen;

908 each R^B is independently optionally substituted alkyl, optionally substituted alkenyl or 909 optionally substituted alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or 910 N; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted

911 heterocyclic;

912 optionally substituted carbocyclic; or hydrogen; or

913 R^A and R^B, together with the atoms to which each is attached, can form a

914 heterocycloalkyl or a heteroaryl; each of which is optionally substituted;

915 R⁵ is halogen, optionally substituted alkenyl, optionally substituted alkynyl, optionally 916 substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally917 substituted heteroaryl, optionally substituted heterocycloalkyl, haloalkyl, -OR, -SR, -CN, - 918 N(R')(R"), -C(O)R, -C(S)R, -CO₂R, -C(O)N(R')(R"), -C(O)SR, -C(O)C(O)R, -C(O)CH₂C(O)R,919 -C(S)N(R')(R"), -C(S)OR, -S(O)R, -SO₂R, -SO₂N(R')(R"), -N(R')C(O)R, -920 N(R')C(O)N(R')(R"), -N(R')C(S)N(R')(R"), -N(R')SO₂R, -N(R')SO₂N(R')(R"), -921 N(R')N(R')(R"), -N(R')C(=N(R'))N(R')(R"), -C=NN(R')(R"), -C=NOR, -C(=N(R'))N(R')(R"), - 922 OC(O)R, -OC(O)N(R')(R"), or -(CH₂)_pR^x;

923 each R^x is independently hydrogen, halogen, optionally substituted alkyl, optionally 924 substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally 925 substituted aralkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl,926 optionally substituted heterocycloalkyl, -OR, -SR, -CN, -N(R')(R"), -C(O)R, -C(S)R, -CO₂R, -927 C(O)N(R')(R"), -C(O)SR, -C(O)C(O)R, -C(O)CH₂C(O)R, -C(S)N(R')(R"), -C(S)OR, -S(O)R, - 928 SO₂R, -SO₂N(R')(R"), -N(R')C(O)R, -N(R')C(O)N(R')(R"), -N(R')C(S)N(R')(R"), -N(R')SO₂R,929 -N(R')SO₂N(R')(R"), -N(R')N(R')(R"), -N(R')C(=N(R'))N(R')(R"), -C=NN(R')(R"), -C=NOR, - 930 C(=N(R'))N(R')(R"), -OC(O)R, -OC(O)N(R')(R");

931 each R is independently hydrogen, optionally substituted alkyl, optionally substituted 932 alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted 933 aralkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, or optionally 934 substituted heterocycloalkyl;

935 each R' is independently -R, -C(O)R, -C(S)R, -CO₂R, -C(O)N(R)₂, -C(S)N(R)₂, -S(O)R, 936 -SO₂R, -SO₂N(R)₂, or two R groups on the same nitrogen are taken together with their 937 intervening atoms to form an optionally substituted heteroaryl or heterocycloalkyl group;

938 each R" is independently -R, -C(O)R, -C(S)R, -CO₂R, -C(O)N(R)₂, -C(S)N(R)₂, - 939 S(O)R, -SO₂R, -SO₂N(R)₂, or two R groups on the same nitrogen are taken together with their 940 intervening atoms to form an optionally substituted heteroaryl or heterocycloalkyl group; or 941 R' and R", together with the atoms to which each is attached, can form a cycloalkyl, a 942 heterocycloalkyl, an aryl, or a heteroaryl; each of which is optionally substituted;

943 each p is independently 1, 2, 3, 4, 5, or 6; and

944 each q is independently 0, 1, or 2.

1 23. The first monomer of any one of claims 1-22, wherein X¹ and X² are each

2 independently selected from the group consisting of:

3

4

5

1 24. The first monomer of any one of claims 1-22, wherein X¹ and X² are each selected 2 independently from the group consisting of: 3

4

1 25. The first monomer of any one of claims 1-22, wherein X¹ and X² are each selected 2 independently from the group consisting of:

3

1 26. The first monomer of any one of claims 1-25, wherein X¹ and X² are the same.

1 27. The first monomer of any one of claims 1-25, wherein X¹ and X² are different.

1 28. The first monomer of any one of claims 1-27 wherein the first monomer forms a 2 biologically useful dimer with a second monomer in vivo.

1 29. The first monomer of any one of claims 1-28, wherein Z¹ is selected from the group 2 consisting of:

3

4 wherein

5 A₁ is (a) absent; or (b) selected from the group consisting of acyl, substituted or 6 unsubstituted aliphatic, or substituted or unsubstituted heteroaliphatic; 7 A₂, independently for each occurrence, is (a) absent; or (b) selected from the 8 group consisting of–N–, acyl, substituted or unsubstituted aliphatic, or substituted or 9 unsubstituted heteroaliphatic, provided that at least one of A₁ and A₂ is present; or 10 A₁ and A₂, together with the atoms to which they are attached, form a

11 substituted or unsubstituted 4-8 membered cycloalkyl or heterocyclic ring;

12 A₃ is selected from the group consisting of -NHR’, -SH, or -OH;

13 W is CR’ or N;

14 R’ is selected from the group consisting of hydrogen, halogen, substituted or 15 unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, substituted or16 unsubstituted phenyl or naphthyl, substituted or unsubstituted heteroaryl, -NH₂, -NO₂, - 17 SH, or -OH;

18 m is 1-6;

19 represents a single or double bond; and

20 R₁ is (a) absent; or (b) selected from the group consisting of hydrogen, halogen, 21 substituted or unsubstituted aliphatic, or substituted or unsubstituted heteroaliphatic, 22 substituted or unsubstituted phenyl or naphthyl, substituted or unsubstituted heteroaryl, 23 -NH₂, -NO₂, -SH, or -OH;

24 Q₁ is (a) absent; or (b) selected from the group consisting of substituted or 25 unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic; or

26 R₁ and Q₁ together with the atoms to which they are attached form a substituted 27 or unsubstituted 4-8 membered cycloalkyl or heterocyclic ring;

28 b , wherein

29 BB, independently for each occurrence, is a 4-8 membered cycloalkyl,

30 heterocyclic, phenyl, naphthyl, or heteroaryl moiety, wherein the cycloalkyl,

31 heterocyclic, phenyl, naphthyl, or heteroaryl moiety is optionally substituted with one or 32 more groups represented by R₂, wherein the two substituents comprising -OH have a 33 1,2 or 1,3 configuration; 34 each R₂ is independently selected from hydrogen, halogen, oxo, sulfonate, -NO₂, 35 -CN, -OH, -NH₂, -SH, -COOH, -CONHR’, -CONH-SO₂-R’, substituted or

36 unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, or two R₂ together 37 with the atoms to which they are attached form a fused substituted or unsubstituted 4-6 38 membered cycloalkyl or heterocyclic bicyclic ring system;

39 A₁, independently for each occurrence, is (a) absent; or (b) selected from the 40 group consisting of acyl, substituted or unsubstituted aliphatic, or substituted or 41 unsubstituted heteroaliphatic;

42 R’ is selected from the group consisting of hydrogen, halogen, substituted or 43 unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, substituted or44 unsubstituted phenyl or naphthyl, substituted or unsubstituted heteroaryl, -NH₂, -NO₂, - 45 SH, or -OH;

46

47 wherein

48 BB is a substituted or unsubstituted 5- or 6-membered cycloalkyl, heterocyclic, 49 phenyl or naphthyl, or heteroaryl moiety;

50 A₃, independently for each occurrence, is selected from the group consisting of– 51 NHR’ or–OH;

52 R₃ and R₄ are independently selected from the group consisting of H, C_1-4alkyl, 53 phenyl, or R₃ and R₄ taken together from a 3-6 membered ring;

54 R₅ and R₆ are independently selected from the group consisting of H, C_1-4alkyl55 optionally substituted by hydroxyl, amino, halogen, or thio; C_1-4alkoxy; halogen; -OH; - 56 CN; -COOH; -CONHR’; or R₅ and R₆ taken together form phenyl or a 4-6 membered 57 heterocycle; and

58 R’ is selected from the group consisting of hydrogen, substituted or

59 unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, substituted or60 unsubstituted phenyl or naphthyl, substituted or unsubstituted heteroaryl, -NH₂, -NO₂, - 61 SH, or -OH; 62

63 wherein

64 A₁ is (a) absent; or (b) selected from the group consisting of acyl, substituted or 65 unsubstituted aliphatic, or substituted or unsubstituted heteroaliphatic;

66 A₃, independently for each occurrence, is selected from the group consisting of– 67 NHR’ or–OH;

68 AR is a fused phenyl or 4-7 membered aromatic or partially aromatic

69 heterocyclic ring, wherein AR is optionally substituted by oxo, C_1-4alkyl optionally70 substituted by hydroxyl, amino, halo, or thio; C_1-4alkoxy; -S- C_1-4alkyl; halogen; -OH; - 71 CN; -COOH; -CONHR’; wherein the two substituents comprising -OH are ortho to 72 each other;

73 R₅ and R₆ are independently selected from the group consisting of H, C_1-4alkyl74 optionally substituted by hydroxyl, amino, halo, or thio; C_1-4alkoxy; halogen; -OH; - 75 CN; -COOH; CONHR’; and

76 R’ is selected from the group consisting of hydrogen, halogen, substituted or 77 unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, substituted or78 unsubstituted phenyl or naphthyl, substituted or unsubstituted heteroaryl, -NH₂, -NO₂, - 79 SH, or–OH;

80 ; wherein

81 Q₁ is selected from the group consisting of C_1-4alkyl, alkylene, or a bond; C_1- 82 ₆cycloalkyl; a 5-6 membered heterocyclic ring; or phenyl;

83 Q₂, independently for each occurrence, is selected from the group consisting of 84 H, C_1-4alkyl, alkylene, or a bond; C_1-6cycloalkyl; a 5-6 membered heterocyclic ring; 85 substituted or unsubstituted aliphatic; substituted or unsubstituted heteroaliphatic; 86 substituted or unsubstituted phenyl or naphthyl; or substituted or unsubstituted 87 heteroaryl;

88 A₃, independently for each occurrence, is selected from the group consisting of– 89 NH₂ or -OH;

90 A₄, independently for each occurrence, is selected from the group consisting of - 91 NH-NH₂; -NHOH, -NH-OR’’, or–OH;

92 R’’ is selected from the group consisting of H or C_1-4alkyl; and

93 f ; wherein

94 A₅ is selected from the group consisting of–OH, -NH₂, -SH, -NHR’’’;

95 R’’’ is selected from -NH₂; -OH; phenoxy; and C_1-4alkoxy;

96 R₅ and R₆ are independently selected from the group consisting of H, C_1-4alkyl 97 optionally substituted by hydroxyl, amino, halo, or thio; C_1-4alkoxy; halogen; -OH; - 98 CN; -COOH; -CONHR’; or R₅ and R₆ taken together may form a 5-6 membered ring; 99 R’ is selected from the group consisting of hydrogen, substituted or

100 unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, substituted or 101 unsubstituted phenyl or naphthyl, substituted or unsubstituted heteroaryl, -NH₂, -SH, or 102 –OH; and

103 the second monomer has a boronic acid or oxaborole moiety capable of binding with the Z₁ 104 moiety of Formula I to form the multimer.

1 30. The first monomer of claim 29, wherein Z² of the second monomer is selected from the 2 group consisting of: 3

4

; wherein

5 R₈ is selected from the group consisting of H, halogen, oxo, C_1-4alkyl optionally 6 substituted by hydroxyl, amino, halo or thio; C_2-4alkenyl, C_1-4alkoxy; -S- C_1-4alkyl; -CN; - 7 COOH; or–CONHR’;

8 A₁ is (a) absent; or (b) selected from the group consisting of acyl, substituted or 9 unsubstituted aliphatic, or substituted or unsubstituted heteroaliphatic;

10 Q is selected from the group consisting of substituted or unsubstituted aliphatic, or 11 substituted or unsubstituted heteroaliphatic;

12 AA, independently for each occurrence, is phenyl, naphthyl, or a 5-7 membered 13 heterocyclic or heteroaryl ring having one, two, or three heteroatoms, wherein AA is optionally14 substituted by one, two, or three substituents selected from the group consisting of halogen, C_1- 15 ₄alkyl optionally substituted by hydroxyl, amino, halogen, or thio; C_2-4alkenyl, C_1-4alkoxy; -S- 16 C_1-4alkyl; -CN; -COOH;–CONHR’; or two substituents together with the atoms to which they 17 are attached form a fused 4-6 membered cycloalkyl or heterocyclic bicyclic ring system; and 18 R’ is H or C_1-4alkyl.

1 31. The first monomer of any one of claims 1-28, wherein Z¹ and Z² are independently 2 selected from the group consisting of:

3

4 wherein

5 R^W is absent or selected from the group consisting of -C_1-4alkyl-, -O-C_1-4alkyl-, - 6 N(R^a)-, -N(R^a)-C_1-4alkyl-, -O-, -C(O)C_1-4alkyl-, -C(O)-O-C_1-4alkyl-, -C_2-6alkenyl-, -C_2- 7 ₆alkynyl-, -C_3-6cycloalkyl-, -phenyl- and -heterocycle-; wherein C ^a

1_-4alkyl, R , R^b, C_2- 8 ₆alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, phenyl and heteroaryl may be optionally 9 substituted by one, two, three or more substituents selected from the group consisting of 10 C_1-4alkyl, C_1-4alkoxy, -C(O)C_1-4alkyl, -C(O)-O-C_1-4alkyl, -C(O)-NR^aR^b, halogen, cyano, 11 hydroxyl, phenyl, R^a and R^b; or R^W and R¹ together with the silicon to which they are 12 attached, form a 3-8 membered heterocyclic ring, wherein the 3-8 membered ring may 13 be optionally substituted by one or more substituents selected from the group consisting 14 of halogen, cyano, oxo, hydroxyl, and C_1-6alkyl;

15 W¹, independently for each occurrence, is (a) absent; or (b) selected from the16 group consisting of -C_1-4alkyl-, -O-C_1-4alkyl-, -C(O)-C_1-4alkyl-, -N(R^a)-C_1-4alkyl-, -17 C(O)-O-C_1-4alkyl-, -C_2-6alkenyl-, -C_2-6alkynyl-, -C_3-6cycloalkyl-, -phenyl- or - 18 heteroaryl-; wherein C_1-4alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, R’, phenyl and 19 heteroaryl are optionally substituted independently, for each occurrence, with one, two,20 three or more substituents selected from the group consisting of C_1-4alkyl, C_1-4alkoxy, - 21 C(O)C_1-6alkyl, -C(O)-O-C_1-4alkyl, halogen, hydroxyl, nitro and cyano;

22 R’ is independently selected, for each occurrence, from the group consisting of 23 hydrogen, substituted or unsubstituted aliphatic, and substituted or unsubstituted 24 heteroaliphatic;

25 Q¹ is independently selected, for each occurrence, from the group consisting of -26 NHR’, -SH, -OH, -O-C₁-₆alkyl, -S-C_1-6alkyl, phenoxy, -S-phenyl, heteroaryl, -O- 27 heteroaryl, -S-heteroaryl, halogen and -O-C ^b

1-₆alkyl-NR^aR ;

28 R^a and R^b are independently selected, for each occurrence, from the group 29 consisting of hydrogen and C_1-4alkyl; wherein C_1-4alkyl may be optionally substituted 30 by one or more substituents selected from the group consisting of halogen, cyano, oxo 31 and hydroxyl; or

32 R^a and R^b, together with the nitrogen to which they are attached, may form a 4-7 33 membered heterocyclic ring, which may have an additional heteroatom selected from 34 O, S, or N; wherein the 4-7 membered heterocyclic ring may be optionally substituted 35 by one or more substituents selected from the group consisting of halogen, cyano, oxo 36 and hydroxyl;

37 R¹ and R² are selected independently, for each occurrence, from the group38 consisting of -OH, C_1-6alkyl, -O-C_1-6alkyl, C_2-6alkenyl, C_3-6cycloalkyl, -C_1-6alkyl- 39 NR^aR^b, phenyl and heteroaryl; wherein C_1-6alkyl, C_2-6alkenyl, C_3-6cycloalkyl, R^a, R^b, 40 phenyl and heteroaryl, independently selected, for each occurrence, may be optionally 41 substituted by one or more substituents selected from the group consisting of halogen, 42 cyano, hydroxyl, C_1-6alkyl, and phenyl; or

43 R¹ and R², together with the silicon to which they are attached, form a 4-7 44 membered heterocyclic ring, optionally containing one, two, three, or four heteroatoms 45 selected from O, S, or N; wherein the 4-7 membered heterocyclic ring may be

46 optionally substituted by one or more substituents selected from the group consisting of 47 halogen, cyano, oxo, and hydroxyl;

48 BB, independently for each occurrence, is a 4-7-membered cycloalkyl, 49 heterocyclic, phenyl, naphthyl, or heteroaryl moiety, wherein the cycloalkyl,

50 heterocyclic, phenyl, naphthyl, or heteroaryl moiety is optionally substituted with one, 51 two, three or more groups represented by R^BB; wherein R¹, independently for each 52 occurrence, may be optionally bonded to BB;

53 each R^BB is independently selected, for each occurrence, from the group54 consisting of hydrogen, halogen, nitro, cyano, hydroxyl, amino, thio, -COOH, - 55 CONHR’, substituted or unsubstituted aliphatic, and substituted or unsubstituted 56 heteroaliphatic; or two R^BB together with the atoms to which they are attached form a 57 fused 5- or 6-membered cycloalkyl or heterocyclic bicyclic ring system; and

58

59 ,

60

61 wherein 62 Q^2A is absent or selected from the group consisting of–NH-, -S-, -O-, -O-C₁- 63 ₆alkyl-, -C₁-₆alkyl-O-, -N(R’)-C₁-₆alkyl-, -C₁-6alkyl-N(R’)-, -S-C₁-₆alkyl-, -C₁-₆alkyl-S- 64 and -O-C₁-₆alkyl-NR^a-; or Q^2A and R¹, together with the silicon to which they are 65 attached, form a 3-8 membered heterocyclic ring, wherein the 3-8 membered ring may 66 be optionally substituted by one or more substituents selected from the group consisting 67 of halogen, cyano, oxo, hydroxyl, and C_1-6alkyl;

68 W¹ and W^1A, independently for each occurrence, are (a) absent; or (b) selected69 from the group consisting of -O-, -C_1-4alkyl-, -O-C_1-4alkyl-, -N(R^a)-C_1-4alkyl-, -C(O)C_1-70 ₄alkyl-, -C(O)-O-C_1-4alkyl-, -C_2-6alkenyl-, -C_2-6alkynyl-, -C_3-6cycloalkyl-, -phenyl- and - 71 heteroaryl-; wherein C_1-4alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, R’, phenyl and 72 heteroaryl may be optionally substituted independently, for each occurrence, with one,73 two, three or more substituents selected from the group consisting of C_1-4alkyl, C_1- 74 ₄alkoxy, -C(O)C_1-6alkyl, -C(O)-O-C_1-4alkyl, halogen, hydroxyl, nitro and cyano;

75 R’ is independently selected, for each occurrence, from the group consisting of 76 hydrogen, substituted or unsubstituted aliphatic, and substituted or unsubstituted 77 heteroaliphatic;

78 Q¹ and Q^1A are independently selected, for each occurrence, from the group 79 consisting of -NHR’, -SH, -OH, -O-C₁-₆alkyl, -S-C_1-6alkyl, phenoxy, -S-phenyl, 80 heteroaryl, -O-heteroaryl, -S-heteroaryl, halogen and -O-C₁-₆alkyl-NR^aR^b;

81 R^a and R^b are independently selected, for each occurrence, from the group 82 consisting of hydrogen and C_1-4alkyl; wherein C_1-4alkyl may be optionally substituted 83 by one or more substituents selected from the group consisting of halogen, cyano, oxo 84 and hydroxyl; or

85 R^a and R^b, together with the nitrogen to which they are attached, may form a 4-7 86 membered heterocyclic ring, which may have an additional heteroatom selected from 87 O, S, or N; wherein the 4-7 membered heterocyclic ring may be optionally substituted 88 by one or more substituents selected from the group consisting of halogen, cyano, oxo 89 and hydroxyl;

90 R¹ and R² are selected independently, for each occurrence, from the group91 consisting of -OH, C_1-6alkyl, -O-C_1-6alkyl, C_2-6alkenyl, C_3-6cycloalkyl, -C_1-6alkyl- 92 NR^aR^b, phenyl and heteroaryl; wherein C_1-6alkyl, C_2-6alkenyl, C_3-6cycloalkyl, R^a, R^b, 93 phenyl and heteroaryl, independently selected, for each occurrence, may be optionally 94 substituted by one or more substituents selected from the group consisting of halogen, 95 cyano, hydroxyl, C_1-6alkyl, and phenyl; or

96 R¹ and R², together with the silicon to which they are attached, form a 4-7 97 membered heterocyclic ring, optionally containing one, two, three, or four heteroatoms 98 selected from O, S, or N; wherein the 4-7 membered heterocyclic ring may be

99 optionally substituted by one or more substituents selected from the group consisting of 100 halogen, cyano, oxo, and hydroxyl;

101 W^2A is selected from the group consisting of N and CR^W2A.

102 R^W2A is selected from the group consisting of hydrogen, C_1-4alkyl, -O-C_1-4alkyl,103 C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, phenyl and heteroaryl; wherein C_1-4alkyl, C_2- 104 ₆alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, phenyl and heteroaryl may be optionally

105 substituted independently, for each occurrence, with one, two, three or more

106 substituents selected from the group consisting of halogen, hydroxyl and cyano;

107 BB, independently for each occurrence, is a 4-7-membered cycloalkyl, 108 heterocyclic, phenyl, naphthyl, or heteroaryl moiety; wherein the cycloalkyl,

109 heterocyclic, phenyl, naphthyl, or heteroaryl moiety may be optionally substituted with 110 one, two, three or more groups represented by R^BB; wherein R¹, independently for each 111 occurrence, may be optionally bonded to BB;

112 each R^BB is independently selected, for each occurrence, from the group113 consisting of hydrogen, halogen, nitro, cyano, hydroxyl, amino, thio, -COOH, - 114 CONHR’, substituted or unsubstituted aliphatic, substituted or unsubstituted

115 heteroaliphatic; or two R^BB together with the atoms to which they are attached may 116 form a fused 5- or 6-membered cycloalkyl or heterocyclic bicyclic ring system.

1 32. The first monomer of claim 31, wherein Z¹ and Z² are the same.

1 33. The first monomer of any one of claims 1-32, wherein the aqueous fluid has a

2 physiologically acceptable pH.

1 34. The first monomer of any one of claims 1-33, wherein Y¹ and Y² are the same.

1 35. The first monomer of any one of claims 1-33, wherein Y¹ and Y² are different.

36. A first monomer selected from the group consisting of:

wherein n is 0, 1, or 2,

,

,

, , , ,

,

, , ,

,

N

N , ,

,

,

,

, and pharmaceutically acceptable salts thereof.

37. A first monomer capable of forming a biologically useful multimer capable of modulating a protein having a first bromodomain when in contact with a second monomer in an aqueous media, wherein the first monomer is represented by the formula:

Y¹ is absent or is a connector moiety covalently bound to X¹ and Z¹;

Z¹ is a first linker capable of binding to the second monomer; and the second monomer is represented by the formula:

Y² is absent or is a connector moiety covalently bound to X² and Z²; and Z² is a second linker capable of binding to the first monomer through Z¹, wherein X¹ selected from the group consisting of:

I)

wherein

R^x is hydrogen or C₁-C₃ alkyl;

R^Y is C₁-C₃ alkyl, -(C₂-C₃ alkylenyl)-OH, or C₁-C₃ haloalkyl;

X¹ is N or CR^x1 wherein

R^x1 is hydrogen, C₂-C₆ alkenyl, C₂-C₆ alkynyl, -C(O)OR^ax1, -C(O)NR^bx1R^cx1, - C(O)R^dx1, S(O) ¹

2R^dx1, -S(O)₂NR^bx1R^cx1, G^x , C₁-C₆ haloalkyl, or C₁-C₆ alkyl; wherein the C₁-C₆ alkyl is optionally substituted with one substituent selected from the group consisting of OR^ax1, SR^ax1, S(O)R^dx1, S(O)₂R^dx1, NR^bx1R^cx1, - C(O)R^ax1, -C(O)OR^ax1, -C(O)NR^bx1R^cx1, -S(O)₂NR^bx1R^cx1, and G^x1; R^ax1, R^bx1, and R^cx1, at each occurrence, are each independently hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, G^a, or -(C₁-C₆ alkylenyl)-G^a;

X² is N or CR^x2; wherein

R^x2 is hydrogen, C ²

2-C₆ alkenyl, C₂-C₆ alkynyl, -C(O)OR^ax2, -C(O)NR^bx R^cx2, - C(O)R^dx2, S(O) ^cx2

2R^dx2, -S(O)₂NR^bx2R , G^x2, C₁-C₆ haloalkyl, or C₁-C₆ alkyl; wherein the C₁-C₆ alkyl is optionally substituted with one substituent selected from the group consisting of OR^ax2, SR^ax2, S(O)R^dx2, S(O)₂R^dx2, NR^bx2R^cx2, - C(O)R^ax2, -C(O)OR^ax2, -C(O)NR^bx2R^cx2, -S(O) ^cx2

2NR^bx2R , and G^x2;

R^ax2, R^bx2, and R^cx2, at each occurrence, are each independently hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, G^b, or -(C₁-C₆ alkylenyl)-G^b;

R^dx2, at each occurrence, is independently C₁-C₆ alkyl, C₁-C₆ haloalkyl, G^b, or - (C₁-C₆ alkylenyl)-G^b; Y¹ is N or CR^u; wherein R^u is hydrogen, C₁-C₆ alkyl, halogen, or C₁-C₆ haloalkyl; A¹ is N or CR¹, A² is N or CR², A³ is N or CR³, and A⁴ is N or CR⁴; with the proviso that zero, one, two, or three of A¹, A², A³, and A⁴ are N;

R² is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl, - CN, NO₂, G^2a, -OR^2a, -OC(O)R^2d, -OC(O)NR^2bR^2c, -SR^2a, -S(O) ^2c

2R^2d, -S(O)₂NR^2bR _, -C(O)R^2d, -C(O)OR^2a, -C(O)NR^2bR^2c, -NR^2bR^2c, -N(R^2e)C(O)R^2d, -N(R^2e)S(O) ^e

2R^2d, -N(R² )C(O)O(R^2d), - N(R^2e)C(O)NR^2bR^2c, -N(R^2e)S(O)₂NR^2bR^2c, -(C₁-C₆ alkylenyl)-G^2a, -(C ^2a

1-C₆ alkylenyl)-OR , - (C₁-C₆ alkylenyl)-OC(O)R^2d, -(C₁-C₆ alkylenyl)-OC(O)NR^2bR^2c, -(C₁-C₆ alkylenyl)-S(O)²R^2d, - (C₁-C₆

R^2a, R^2b, R^2C, and R^2e, at each occurrence, are each independently hydrogen, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, G^2b, or C₁-C₆ alkyl wherein the C₁-C₆ alkyl is optionally substituted with one substituent selected from the group consisting of -OR^z1, NR^z1R^z2, -C(O)OR^z1, -C(O)NR^z1R^z2, -S(O)₂R^z1, -S(O) ^2b

2NR^z1R^z2, and G ;

G^x1, G^x2, G^a, G^b, G^2a, and G^2b, at each occurrence, are each independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl, and each of which is independently unsubstituted or substituted with 1 , 2, 3, 4, or 5 of R^v;

Rⁱ, at each occurrence, is independently C₁-C₆ alkyl or C₁-C₆ haloalkyl; and

wherein:

optionally substituted carbocyclic; or hydrogen;

optionally substituted carbocyclic; or hydrogen; or

R^A and R^B, together with the atoms to which each is attached, can form a

heterocycloalkyl or a heteroaryl; each of which is optionally substituted;

each p is independently 1, 2, 3, 4, 5, or 6; and

each q is independently 0, 1, or 2.

38. A compound selected from the group consisting of:

, and pharmaceutically acceptable salts thereof.

39. A pharmaceutically acceptable composition comprising a first monomer of any one of claims 1-38 and a pharmaceutically acceptable carrier.

40. A therapeutic multimer compound formed from the multimerization in an aqueous media of a first monomer represented by:

X¹-Y¹-Z¹ (Formula I)

and a second monomer represented by

X²-Y²-Z² (Formula II),

wherein

X¹ is a first ligand moiety capable of modulating a first bromodomain;

Y¹ is a connector moiety covalently bound to X¹ and Z¹;

Z¹ is a first linker capable of binding to Z² to form the multimer; X² is a second ligand moiety capable of modulating a second protein domain; Y² is absent or is a connector moiety covalently bound to X² and Z²; and Z² is a second linker moiety capable of binding with the Z¹ moiety of Formula I to form the multimer; wherein

Y¹ is selected from the group consisting of:

-NR¹³-(CH₂-CH₂-O)_s-CH₂-CH₂-NR¹³-C(O)-; -(O-CH₂-CH₂)_t-NR¹³-C(O)-; -O- C_5-10alkyl-NR¹³-C(O)-; -heterocyclyl-C(O)-; -N(C_1-3alkyl)-C_1-6alkyl-NH-C(O)-; -NH-C_1-6alkyl-N(C ¹³

1_-3alkyl)-C(O)-; -NR¹³-C_6-15alkyl-NR -C(O)-; -heterocyclyl- C_0-6alkyl-NR¹³-C(O)-; -NR¹³-C_0-6alkyl-heterocyclyl-C(O)-;

wherein, independently for each occurrence,

R¹³ is selected from the group consisting of H and C_1-6alkyl;

s is an integer from 4-10; and

t is an integer from 5-10; and

41. A therapeutic multimer compound formed from the multimerization in an aqueous media of a first monomer represented by:

X¹-Y¹-Z¹ (Formula I)

and a second monomer represented by

X²-Y²-Z² (Formula II),

wherein

X¹ is a first ligand moiety capable of modulating a first bromodomain;

Y¹ is a connector moiety covalently bound to X¹ and Z¹;

Z¹ is a first linker capable of binding to Z² to form the multimer; X² is a second ligand moiety capable of modulating a second protein domain; Y² is absent or is a connector moiety covalently bound to X² and Z²; and Z² is a second linker moiety capable of binding with the Z¹ moiety of Formula I to form the multimer; wherein Y¹ is selected from the group consisting of:

-NR¹³-C_6-15alkyl-NR¹³-C(O)-; -NR¹³-(CH₂-CH₂-O)_s-C_1-6alkyl-NR¹³-C(O)-; -(O- CH₂-CH₂)_s-NR¹³-C(O)-; -S-C_0-6alkyl-; -NR¹³-C_3-6alkyl-; -SO₂-NR¹³-C_0-6alkyl-; - SO₂-heterocyclyl-C_0-6alkyl-; -heterocyclyl-C(O)-; -heterocyclyl-C_0-6alkyl-NR¹³- C(O)-; -NR¹³-C_0-6alkyl-heterocyclyl-C(O)-; -O-C_1-6alkyl-C(O)-; -O-C_1-15alkyl- NR¹³-C(O)-; -O-C_1-15alkyl-C(O)-NR¹³-; and -O-C_1-6alkyl-, wherein C_1-6alkyl is optionally substituted by -OH;

wherein, independently for each occurrence,

R¹³ is selected from the group consisting of H and C_1-6alkyl; and s is an integer from 1-15; and

42. A therapeutic multimer compound formed from the multimerization in an aqueous media of a first monomer represented by:

X¹-Y¹-Z¹ (Formula I)

and a second monomer represented by

X²-Y²-Z² (Formula II),

wherein

X¹ is a first ligand moiety capable of modulating a first bromodomain;

Y¹ is absent or is a connector moiety covalently bound to X¹ and Z¹;

Z¹ is a first linker capable of binding to Z² to form the multimer; X² is a second ligand moiety capable of modulating a second protein domain; Y² is absent or is a connector moiety covalently bound to X² and Z²; and Z² is a second linker moiety capable of binding with the Z¹ moiety of Formula I to form the multimer;

wherein the maximum distance between the first ligand moiety and the second ligand moiety in the therapeutic multimer is less than about 20 Å; and

43. The therapeutic multimer compound of any one of claims 40-42, wherein X¹ and X² are each independently selected from the group consisting of:

44. The therapeutic multimer compound of any one of claims 40-42, wherein X¹ and X² are each independently selected from the group consisting of:

45. The therapeutic multimer compound of any one of claims 40-42, wherein X¹ and X² are each independently selected from the group consisting of:

46. A pharmaceutically acceptable composition comprising a therapeutic multimer of any one of claims 40-45 and a pharmaceutically acceptable carrier.

47. A method of treating a disease associated with a protein having tandem bromodomains in a patient in need thereof comprising:

administering to said patient a first monomer of any one of claims 1-38; and administering to said patient a second monomer represented by:

X²-Y²-Z² (Formula II), wherein

X² is a second ligand moiety capable of modulating a second bromodomain, Y² is absent or is a connector moiety covalently bound to X² and Z²; and Z² is a second linker capable of binding to the first monomer through Z¹; wherein upon administration, said first monomer and said second monomer form a multimer in vivo that binds to the first and the second bromodomain.

48. The method of claim 47, wherein the disease is acute myeloid leukemia or midline carcinoma.