WO2015081284A1 - Ligands bromodomaines bivalents et procédés d'utilisation de ceux-ci - Google Patents

Ligands bromodomaines bivalents et procédés d'utilisation de ceux-ci Download PDF

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WO2015081284A1
WO2015081284A1 PCT/US2014/067748 US2014067748W WO2015081284A1 WO 2015081284 A1 WO2015081284 A1 WO 2015081284A1 US 2014067748 W US2014067748 W US 2014067748W WO 2015081284 A1 WO2015081284 A1 WO 2015081284A1
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alkyl
optionally substituted
group
independently
phenyl
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PCT/US2014/067748
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Lee Daniel Arnold
Kenneth W. Foreman
Meizhong Jin
Jutta Wanner
Douglas S. Werner
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Coferon, Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the BET family of bromodomain containing proteins bind to acetylated histones to influence transcription.
  • 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.
  • 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 diseases or conditions relating to systemic or tissue inflammation, inflammatory response to infection, cell activation and proliferation, lipid metabolism and prevention and treatment of viral infections.
  • a method of treating a disease associated with a protein having tandem bromodomains in a patient in need thereof comprises administering to the patient the bivalent compound as described above.
  • 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.
  • 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.
  • pharmacophores i.e., ligands
  • Described herein are compounds capable of modulating one or more biomolecules and, in some cases, modulating two or more binding domains on a protein or on different proteins.
  • the bivalent compound may be capable of interacting with a relatively large target site as compared to the individual ligands that form the bivalent compound.
  • a target may comprise, in some embodiments, two protein domains separated by a distance such that a bivalent compound, but not an individual ligand moiety, may be capable of binding to both domains essentially simultaneously.
  • contemplated bivlalent compounds may bind to a target with greater affinity as compared to an individual ligand moiety binding affinity alone.
  • a bivalent compound that, e.g., may be capable of modulating tandem bromo domains.
  • disclosed bivalent compounds may bind to a first target biomolecule domain and a second target biomolecule domain (e.g., protein domains).
  • the first target binding domain and the second target bidning domain can be tandem domains on the same target, for example, tandem BET bromodomains.
  • the first target binding domain and the second target binding domain may be located on separate biomolecules.
  • the ligand moiety of a contemplated bivalent compound 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).
  • the bivalent compound may be used for a variety of purposes. For example, in some instances, the bivalent compound may be used to perturb a biological system.
  • the bivalent compound may bind to or modulate a target biomolecule, such as a protein, nucleic acid, or polysaccharide.
  • a contemplated bivalent compound may be used as a pharmaceutical.
  • the first ligand moiety and the second ligand moiety may be capable of binding to a bromodomain.
  • the first ligand and/or the second ligand may 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,
  • dimers disclosed herein may be capable of binding to a tandem bromodomain. It will be appreciated that such tandem bromodomains may occur on the same protein or each bromodomain may occur on different proteins. In other embodiments, dimers disclosed herein may be capable of binding to one bromodomain on a first protein and to another bromodomain on a second protein. 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.
  • a bivalent compound may bind to a target biomolecule 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, in some embodiments less than 1 pM, in some embodiments less than 1 fM, in some embodiments less than 1 aM, and in some embodiments less than 1 zM.
  • Bivalent Compounds may bind to a target biomolecule 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
  • P 1 is a first ligand capable of modulating a first bromodomain
  • P 2 is a second ligand capable of modulating a second bromodomain
  • Q 1 is a connecting moiety covalently bound to P 1 and P 2 that comprises between 3 and 30 atoms, where the atoms are connected to form a cyclic or acyclic, substituted or
  • unsubstituted, branched or unbranched aliphatic moiety cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic moiety; substituted or unsubstituted phenyl or naphthyl moiety; substituted or unsubstituted heteroaryl moiety; or a combination thereof.
  • the ligand may be a pharmacophore.
  • a pharmacophore is typically an arrangement of the substituents of a moiety that confers biochemical or pharmacological effects (e.g., by targeting a bromodomain).
  • identification of a pharmacophore may be facilitated by knowing the structure of the ligand in association with a target biomolecule.
  • 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.
  • one or more of the ligands in a bivalant compound may be a pharmacophore capable of binding to a bromodomain.
  • the bivalent compound 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.
  • a“BET bromodomain” may refer to the bromodomains in BRD2, BRD3, BRD4 or BRD-t.
  • a ligand e.g., a pharmacophore
  • a ligand may have one or more preferred attachment points for connecting the pharmacophore to the connecting moiety.
  • 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.
  • 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.
  • 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 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.
  • the alphanumeric identifiers in FIG. 1 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 connecting moieties. 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.
  • FIG. 2 provides a non-limiting set of pharmacophores (i.e., ligands) showing preferred attachment points (indicated by arrows) for connecting the pharmacophore to a connecting moiety.
  • ligands i.e., ligands
  • preferred attachment points indicated by arrows
  • the ligands disclosed herein can be attached at any open site to a connector moiety as described herein. Such embodiments described below include specific references to each attachment site.
  • Exemplary bromodomain ligands include quinolines re resented b the structure:
  • X is O or S
  • R 1 is C 1-6 alkyl, haloC 1-6 alkyl, -(CH 2 ) n OR 1a , or -(CH 2 ) m NR 1b R 1c ; wherein R 1a is hydrogen, C 1-6 alkyl or haloC 1-6 alkyl; R 1b and R 1c , which may be the same or different, are hydrogen, C 1-6 alkyl or haloC 1-6 alkyl; and m and n, which may be the same or different, are 1, 2 or 3;
  • R 2 is R 2a , -OR 2b , or -NR 2c R 2d ; wherein R 2a and R 2b are carbocyclyl, carbocyclylC 1- 4 alkyl, heterocyclyl or heterocyclylC 1-4 alkyl, 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 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, 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 1-6 alkyl or haloC 1-6 alkyl; and R 2c and R 2d , which may be the same or different, are carbocyclyl, carbocyclylC 1-4 alkyl, heterocyclyl or heterocyclylC 1-4 alkyl, 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 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, nitro, cyano and -CO 2 C 1-4 alkyl; 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 1-6 alkyl or haloC 1-6 alkyl;
  • R 3 is C 1-6 alkyl, 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 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, nitro and cyano;
  • R’ is H or C 1-6 alkyl
  • A is a benzene or aromatic heterocyclic ring, each of which is optionally substituted;
  • n 0, 1 or 2.
  • the chiral center has an R configuration.
  • compounds of Formula F or Formula G may be selected from the group consisting of:
  • exemplary bromodomain ligands include
  • X is phenyl, naphthyl, or heteroaryl
  • R 1 is C 1-3 alkyl, C 1-3 alkoxy or -S- C 1-3 alkyl
  • R 2 is -NR 2a R 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 1-6 alkyl, haloC 1-6 alkyl, R 2c R 2c’ N-C 2-6 alkyl, carbocyclyl, carbocyclyloC 1-4 alkyl, heterocyclyl and heterocyclylC 1-4 alkyl, wherein any of the carbocyclyl or heterocyclyl groups are optionally substituted by one or more substituents selected from the group consisting of halogen, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1- 6 alkoxy, carbonyl, -CO-carbocyclyl, azido, amino, hydroxyl, nitro and cyano, wherein the– CO-carbocyclyl group may be optionally substituted by one or
  • R 2c and R 2c’ are independently hydrogen or C 1-6 alkyl
  • each R 3 is independently selected from the group consisting of hydrogen, hydroxyl, thiol, sulfinyl, sulfonyl, sulfone, sulfoxide, -OR t , -NR t R tt , -S(O) 2 NR t R tt , -S(O) w R t R tt (where t and tt are independently selected from H, phenyl or C 1-6 alkyl, and w is 0, 1, or 2), halo, C 1- 6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, nitro, cyano, CF 3 , -OCF 3 , -COOR 5 , -C 1- 4 alkylamino , phenoxy, benzoxy, and C 1-4 alkylOH;
  • XX is selected from the group consisting of a bond, NR’’’ (where R’’’ is H, C 1-6 alkyl or phenyl), -O-, or S(O) w wherein w is 0, 1 or 2, and C 1-6 alkyl; (and wherein in some
  • each R 4 is hydroxyl, halo, C 1-6 alkyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, acylaminoC 1-6 alkyl, nitro, cyano, CF 3 , -OCF 3 , -COOR 5 ; - OS(O) 2 C 1-4 alkyl, phenyl, naphthyl, phenyloxy, benzyloxy or phenylmethoxy, wherein C 1- 6 alkyl, phenyl, and naphthyl are optionally substituted by one two or three substituents selected from the group consisting of hydroxyl, halogen, amino, nitro;
  • R 5 is C 1-3 alkyl
  • n is an integer 1 to 3;
  • n is an integer 1 to 5.
  • the chiral center has an S configuration.
  • compounds of Formula H or Formula I may be selected from the group consisting of:
  • compounds of Formula F, Formula G, Formula H or Formula I may be selected from the group consisting of: ,
  • exemplary bromodomain ligands include compounds represented by the structures:
  • R 4 is hydrogen, cyano or C 1-6 alkyl
  • A is selected from the group consisting of:
  • R x is O, NR 2a , or S;
  • R 1 is C 1-6 alkyl, C 3-6 cycloalkyl, 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 1-6 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl, haloC 1-4 alkoxy, hydroxyC 1-4 alkyl, C 1-4 alkoxy C 1-4 alkyl, C 1-4 alkoxycarbonyl, C 1-4 alkylsulfonyl, C 1-4 alkylsulfonyloxy, C 1-4 alkylsulfonyl C 1- 4 alkyl and C 1-4 alkylsulfonamido;
  • R 2 is hydrogen or C 1-6 alkyl
  • R 2a is selected from the group consisting of H, C 1-6 alkyl, C 1-6 haloalkyl, (CH 2 ) m cyano, (CH 2 ) m OH, (CH 2 ) m C 1-6 alkoxy, (CH 2 ) m C 1-6 haloalkoxy, (CH 2 ) m C 1-6 haloalkyl,
  • 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 1-6 alkyl, (CH 2 ) 2 C 1-6 alkoxy, (CH 2 ) 2 cyano, (CH 2 ) m phenyl or
  • R 3 is hydrogen
  • R 6 is hydrogen or C 1-6 alkyl
  • n 0, 1, 2 or 3;
  • n 0, 1 or 2;
  • p 0, 1 or 2.
  • compounds of Formulae A, A1, and A2 may be selected from the group consisting of:
  • exemplary bromodomain ligands include
  • A is a bond, C 1-4 alkyl or–C(O)-;
  • X is:
  • a 5 to 10 membered heteroaromatic comprising 1, 2 or 3 heteroatoms selected from the group consisting of O, N and S;
  • R 1 is: i) phenyl optionally substituted by 1 or 2 substituents independently selected from the group consisting of halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, - SO 2 C 1-6 alkyl and -COR 7 ,
  • 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 1-6 alkyl, C 1- 6 haloalkyl, C 1-6 alkoxy and -COR 7 , or
  • R 2 is C 1-6 alkyl
  • R 3 is C 1-6 alkyl
  • R 4 is:
  • hetercyclyl 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 1-6 alkyl, C 1-6 haloalkyl and C 1-6 alkoxy, 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 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 0-6 hydroxyalkyl;
  • R 5 is H, halogen, C 1-6 alkyl or C 1-6 alkoxy
  • R 6 is H, C 1-6 alkyl, C 0-6 alkylcyano, C 0-6 alkylC 1-6 alkoxy or C 0-2 alkylC(O)R 7 ;
  • R 7 is hydroxyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl or N(C 1-6 alkyl) 2 ;
  • R 8 and R 9 independently are:
  • heterocyclyl or heteroaromatic may comprise 1, 2 or 3 further heteroatoms independently selected from the group consisting of O, N and S;
  • R 10 is hydroxyl, C 1-6 alkoxy 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;
  • R 11 and R 12 independently are:
  • R 11 and R 12 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.
  • compounds of Formula B or Formula C may be selected from the group consisting of:
  • exemplary bromodomain ligands include
  • R 1 is C 1-6 alkyl, C 3-7 cycloalkyl or benzyl
  • R 2 is C 1-4 alkyl
  • R 3 is C 1-4 alkyl
  • X is phenyl, naphthyl, or heteroaryl
  • R 4a is hydrogen, C 1-4 alkyl or is a group L-Y in which L is a single bond or a C 1- 6 alkylene group and Y is OH, OMe, CO 2 H, CO 2 C 1-6 alkyl, CN, or NR 7 R 8 ;
  • R 7 and R 8 are independently hydrogen, a heterocyclyl ring, C 1-6 alkyl optionally substituted by hydroxyl, or a heterocyclyl ring; or
  • R 7 and R 8 combine together to form a heterocyclyl ring optionally substituted by C 1- 6 alkyl, CO 2 C 1-6 alkyl, NH 2 , or oxo;
  • R 4b and R 4c are independently hydrogen, halogen, C 1-6 alkyl, or C 1-6 alkoxy;
  • R 4d is C 1-4 alkyl or is a group -L-Y- in which L is a single bond or a C 1-6 alkylene group and Y is -O-, -OCH 2 -, -CO 2 -, -CO 2 C 1-6 alkyl-, or–N(R 7 )-;
  • R 5 is hydrogen, halogen, C 1-6 alkyl, or C 1-6 alkoxy
  • R 6 is hydrogen or C 1-4 alkyl.
  • compounds of Formula D or Formula E may be selected from the rou consistin of:
  • compounds of Formula A, Formula B, Formula C, Formula D or Formula E may be selected from the group consisting of:
  • exemplary bromodomain ligands are represented by the structures:
  • exemplary bromodomain ligands include heterocycles re resented b the structures:
  • 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 R 1 substituents;
  • R 1 is selected from the group consisting of hydroxy, halogen, oxo, amino, imino, thiol, sulfanylidene, C 1-6 alkyl, hydroxyC 1-6 alkyl, -O-C 1-6 alkyl,–NH-C 1-6 alkyl, -CO 2 H, -C(O)C 1- 6 alkyl,–C(O)O-C 1-6 alkyl, aminoC 1-6 alkyl, haloC 1-6 alkyl, -C 1- 6 alkylC(O)R 2
  • R 2 is -NR 2a R 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 1-6 alkyl, haloC 1-6 alkyl, R 2c R 2c’ N-C 2-6 alkyl, carbocyclyl, carbocyclyloC 1-4 alkyl, heterocyclyl and heterocyclylC 1-4 alkyl, wherein any of the carbocyclyl or heterocyclyl groups are optionally substituted by one or more substituents selected from the group consisting of halogen, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1- 6 alkoxy, carbonyl, -CO-carbocyclyl, azido, amino, hydroxyl, nitro and cyano, wherein the– CO-carbocyclyl group may be optionally substituted by one or
  • R 2c and R 2c’ are independently hydrogen or C 1-6 alkyl
  • B is selected from the rou consistin of: ,
  • compounds of Formula J may be selected from the group consisting of:
  • Q is independently, for each occurrence, N or CH;
  • V is independently, for each occurrence, O, S, NH, or a bond
  • R 4 is independently selected from the group consisting of hydrogen, hydroxyl, halo, amino, thiol, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, -NH-C 1-6 alkyl, -S-C 1-6 alkyl, haloC 1-6 alkoxy, nitro, cyano, -CF 3 , -OCF 3 , -C(O)O-C 1-6 alkyl, -C 1-4 alkylamino , phenoxy, benzoxy, and C 1- 4 alkylOH.
  • compounds of Formula J or Formula L may be selected from the group consisting of:
  • R is independently, for each occurrence, N or CH;
  • V is independently, for each occurrence, a bond, O or NR 4 ;
  • R 4 is independently, for each occurrence, hydrogen, hydroxyl, halo, amino, -SO 2 , thiol, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, -NH-C 1-6 alkyl, -S-C 1-6 alkyl, haloC 1-6 alkoxy, nitro, cyano, - CF 3 , -OCF 3 , -C(O)O-C 1-6 alkyl, -C 1-6 alkylamino , phenoxy, benzoxy, phenyl, naphthyl, heteroaryl and C 1-4 alkylOH; wherein C 1-6 alkyl, phenyl, and naphthyl are optionally substituted with 1, 2, 3 or more substituents selected from the group consisting of halogen, hydroxyl, amino and C 1-6 alkyl; and W is independently, for each occurrence, , O, S, or NR 4 .
  • compounds of Formula M may be selected from the group consisting of:
  • B is selected from the group consisting of:
  • Q is independently, for each occurrence, N or CH;
  • V is independently, for each occurrence, O, S, NR 4 , or a bond
  • R 4 is independently selected from the group consisting of hydrogen, hydroxyl, halo, amino, thiol, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, -NH-C 1-6 alkyl, -S-C 1-6 alkyl, haloC 1-6 alkoxy, nitro, cyano, -CF 3 , -OCF 3 , -C(O)O-C 1-6 alkyl, -C 1-4 alkylamino , phenoxy, benzoxy, and C 1- 4 alkylOH.
  • compounds of Formula J, Formula K, Formula L or Formula M may be selected from the group consisting of:
  • Q is independently, for each occurrence, N or CH;
  • V is independently, for each occurrence, O, S, NR 4 , or a bond
  • W is independently, for each occurrence, H, halogen, C 1-6 alkyl, -NH-C 1- 6 alkyl, or -S-C 1-6 alkyl;
  • R 4 is independently selected from the group consisting of hydrogen, hydroxyl, halo, amino, thiol, C 1-6 alkyl, haloC 1-6 alkyl, -NH-C 1-6 alkyl, -S-C 1-6 alkyl, haloC 1-6 alkoxy, nitro, cyano, -CF 3 , -OCF 3 , -C(O)O-C 1-6 alkyl, -C 1-4 alkylamino , phenoxy, benzoxy, and C 1- 4 alkylOH.
  • exemplary bromodomain ligands include compounds represented by the structures: Formula O, wherein:
  • R 1 is selected from the group consisting of hydrogen, lower alkyl, phenyl, naphthyl, aralkyl, heteroalkyl, SO 2 , NH 2 , NO 2 , CH 3 , CH 2 CH 3 , OCH 3 , OCOCH 3 , CH 2 COCH 3 , OH, CN, and halogen;
  • R 2 is selected from the group consisting of hydrogen, lower alkyl, aralkyl, heteroalkyl, phenyl, naphthyl, SO 2 , NH 2 , NH +
  • X is selected from the group consisting of lower alkyl, SO 2 , NH, NO 2 , CH 3 , CH 2 CH 3 , OCH 3 , OCOCH 3 , CH 2 COCH 3 , OH, carboxy, and alkoxy; and
  • n is an integer from 0 to 10.
  • compounds of Formula N or Formula O may be selected from the group consistin of: Formula O
  • a ligand may be selected from the group consisting of:
  • exemplary bromodomain ligands include com ounds re resented b the structures:
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are independently selected from the group consisting of hydrogen, lower alkyl, phenyl, naphthyl, aralkyl, heteroaryl, SO 2 , NH 2 , NH +
  • compounds of Formula P, Formula Q, Formula R, or Formula S may be selected from the rou consistin of:
  • the compound may be selected from the group consisting of:
  • exemplary bromodomain ligands include com ounds re resented by the structure: Formula T,
  • R 1 , R 2 , and R 3 are independently selected from the group consisting of hydrogen, lower alkyl, phenyl, naphthyl, aralkyl, heteroaryl, SO 2 , NH 2 , NH +
  • R 4 is selected from the group consisting of lower alkyl, phenyl, naphthyl, SO 2 , NH, NO 2 , CH 3 , CH 2 CH 3 , OCH 3 , OCOCH 3 , CH 2 COCH 3 , OH, carboxy, and alkoxy.
  • exemplary bromodomain ligands include compounds represented by the structures:
  • 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;
  • R 1 is H, alkyl, alkenyl, alkynyl, aralkyl, phenyl, naphthyl, heteroaryl, halo, CN, OR A , NR A R 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 R 4 , and when L 1 is other than a covalent bond, R C is additionally selected from H;
  • R 2 and R 3 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, -CO 2 R, -C(O)N(R’)(R’’), -C(O)SR, -C(O)C(O)R, -C(O)CH 2 C(O)R, -C(S)N(R’)(R’’), - C(S)OR, -S(O)R, -SO 2 R, -SO 2 N(R’)(R’’), -N(R’)C(O)R, -N(R’)C(O)N(R’)(R’’), - N(R')C
  • R 2 and R 3 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, -CO 2 R, -C(O)N(R’)(R’’), -C(O)SR, -C(O)C(O)R, -C(O)CH 2 C(O)R, -C(S)N(R’)(R’’), -C(S)OR, - S(O)R, -SO 2 R, -SO 2 N(R’)(R’’), -N(R’)C(O)R, -N(R’)C(O)N(R’)(R’’), -N(R’)C(S)N
  • each R’ is independently -R, -C(O)R, -C(S)R, -CO 2 R, -C(O)N(R) 2 , -C(S)N(R) 2 , - S(O)R, -SO 2 R, -SO 2 N(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, -CO 2 R, -C(O)N(R) 2 , -C(S)N(R) 2 , -S(O)R, -SO 2 R, -SO 2 N(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 R 4 is independently alkyl, alkenyl, alkynyl, phenyl, naphthyl, aralkyl, cycloalkyl, heteroaryl, or heterocycloalkyl, halogen, -OR, -SR, -N(R’)(R’’), -CN, -NO 2 , -C(O)R, -C(S)R, - CO 2 R, -C(O)N(R’)(R’’), -C(O)SR, -C(O)C(O)R, -C(O)CH 2 C(O)R, -C(S)N(R’)(R’’), -C(S)OR, -S(O)R,
  • each R 5 is independently -R, halogen, -OR, -SR, -N(R’)(R’’), -CN, -NO 2 , -C(O)R, - C(S)R, -CO 2 R, -C(O)N(R’)(R’’), -C(O)SR, -C(O)C(O)R, -C(O)CH 2 C(O)R, -C(S)N(R’)(R’’), - C(S)OR, -S(O)R, -SO 2 R, -SO 2 N(R’)(R’’), -N(R’)C(O)R, -N(R’)C(O)N(R’)(R’’), - N(R’)C(S)N(R’)(R’’), -N(R’)SO 2 R, -N(R’)SO 2 N(R’)(R’’’),
  • n 0-5;
  • each q is independently 0, 1, or 2;
  • p 1-6.
  • exemplary bromodomain ligands include compounds represented by the structure: Formula W,
  • 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
  • R 1 is H, alkyl, alkenyl, alkynyl, aralkyl, phenyl, naphthyl, heteroaryl, halo, CN, OR A , NR A R 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;
  • 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 R 4 , and when L 1 is other than a covalent bond, R C is additionally selected from H;
  • R 2 is H, halogen, alkyl, alkenyl, alkynyl, phenyl, naphthyl, aralkyl, cycloalkyl, heteroaryl, heterocycloalkyl, -OR, -SR, -CN, -N(R’)(R’’), -C(O)R, -C(S)R, -CO 2 R, - C(O)N(R’)(R’’), -C(O)SR, -C(O)C(O)R, -C(O)CH 2 C(O)R, -C(S)N(R’)(R’’), -C(S)OR, - S(O)R, -SO 2 R, -SO 2 N(R’)(R’’), -N(R’)C(O)R, -N(R’)C(O)N(R’)(R’’), -N(R')C(S)N(
  • R 3 is a bond or optionally substituted alkyl; or R 2 and R 3 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, -CO 2 R, -C(O)N(R’)(R’’), -C(O)SR, -C(O)C(O)R, -C(O)CH 2 C(O)R, -C(S)N(R’)(R’’), -C(S)OR, - S(O)R, -SO 2 R, -SO 2 N(R’)(R’’), -N(R’)C(O)R, -N(R’)C(O)N(R’)(R’’), -N(R’)C(S)N
  • L 1 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’)SO 2 -, -SO 2 N(R’)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO-, or -SO 2 -; 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, -CO 2 R, -C(O)N(R) 2 , -C(S)N(R) 2 , - S(O)R, -SO 2 R, -SO 2 N(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, -CO 2 R, -C(O)N(R) 2 , -C(S)N(R) 2 , -S(O)R, -SO 2 R, -SO 2 N(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 cycloalkyl, heterocycloalkyl, phenyl, naphthyl, or heteroaryl; each of which is optionally substituted; each R 4 is independently alkyl, alkenyl, alkynyl, phenyl, naphthyl, aralkyl, cycloalkyl, heteroaryl, or heterocycloalkyl, halogen, -OR, -SR, -N(R’)(R’’), -CN, -NO 2 , -C(O)R, -C(S)R, - CO 2 R, -C(O)N(R’)(R’’), -C(O)SR, -C(O)C(O)R, -C(O)CH 2 C(O)R, -C(S)N(R’)(R’’), -C(S)OR, -S(O)R,
  • each R 5 is independently -R, halogen, -OR, -SR, -N(R’)(R’’), -CN, -NO 2 , -C(O)R, - C(S)R, -CO 2 R, -C(O)N(R’)(R’’), -C(O)SR, -C(O)C(O)R, -C(O)CH 2 C(O)R, -C(S)N(R’)(R’’), - C(S)OR, -S(O)R, -SO 2 R, -SO 2 N(R’)(R’’), -N(R’)C(O)R, -N(R’)C(O)N(R’)(R’’), - N(R’)C(S)N(R’)(R’’), -N(R’)SO 2 R, -N(R’)SO 2 N(R’)(R’’’),
  • n 0-5;
  • each q is in dependentl y 0, 1, or 2 ;
  • p 1-6.
  • compoun ds of Form ula U, Form ula V, and Formula W may be selected from the g roup consi sting of:
  • compounds of Formula U, Formula V, and Formula W may be selected from the group consisting of:
  • 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.
  • exemplary bromodomain ligands include compounds represented by the structures:
  • 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;
  • L 1 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’)SO 2 -, -SO 2 N(R’), -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO 2 -;
  • R 1 is hydrogen, halogen, optionally substituted C 1-6 aliphatic, -OR, -SR, -CN, -N(R’) 2 , - C(O)R, -C(S)R, -CO 2 R, -C(O)N(R’) 2 , -C(O)SR, -C(O)C(O)R, -C(O)CH 2 C(O)R, -C(S)N(R’) 2 , - C(S)OR, -S(O)R, -SO 2 R, -SO 2 N(R’) 2 , -N(R’)C(O)R, -N(R’)C(O)N(R’) 2 , -N(R’)C(S)N(R’) 2 , - N(R’)SO 2 R, -N(R’)SO 2 N(R’) 2 , -N(R’)N(R’) 2
  • R x is halogen, optionally substituted C 1-6 aliphatic, -OR, -SR, -CN, -N(R’) 2 , -C(O)R, - C(S)R, -CO 2 R, -C(O)N(R’) 2 , -C(O)SR, -C(O)C(O)R, -C(O)CH 2 C(O)R, -C(S)N(R’) 2 , -C(S)OR, -S(O)R, -SO 2 R, -SO 2 N(R’) 2 , -N(R’)C(O)R, -N(R’)C(O)N(R’) 2 , -N(R’)C(S)N(R’) 2 , - N(R’)SO 2 R, -N(R’)SO 2 N(R’) 2 , -N(R’)N(R’)N(R
  • R 2 is hydrogen, halogen, -CN, -SR, or optionally substituted C 1-6 aliphatic, or:
  • R 1 and R 2 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
  • each R’ is independently -R, -C(O)R, -C(S)R, -CO 2 R, -C(O)N(R) 2 , -C(S)N(R) 2 , - S(O)R, -SO 2 R, -SO 2 N(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 , , or ;
  • R 3 is optionally substituted C 1-6 aliphatic
  • X is oxygen or sulfur, or:
  • R 3 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;
  • each of R 4 and R 5 is independently -R, halogen, -OR, -SR, -N(R’) 2 , -CN, -NO 2 , -C(O)R, -C(S)R, -CO 2 R, -C(O)N(R’) 2 , -C(O)SR, -C(O)C(O)R, -C(O)CH 2 C(O)R, -C(S)N(R’) 2 , - C(S)OR, -S(O)R, -SO 2 R, -SO 2 N(R’) 2 , -N(R’)C(O)R, -N(R’)C(O)N(R’) 2 , -N(R’)C(S)N(R’) 2 , - N(R’)SO 2 R, -N(R’)SO 2 N(R’) 2 , -N(R’)N(R’)
  • exemplary bromodomain ligands include compounds represented b the structures:
  • 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;
  • L 1 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’)SO 2 -, -SO 2 N(R’), -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO 2 -;
  • R 1 is hydrogen, halogen, optionally substituted C 1-6 aliphatic, -OR, -SR, -CN, -N(R’) 2 , - C(O)R, -C(S)R, -CO 2 R, -C(O)N(R’) 2 , -C(O)SR, -C(O)C(O)R, -C(O)CH 2 C(O)R, -C(S)N(R’) 2 , - C(S)OR, -S(O)R, -SO 2 R, -SO 2 N(R’) 2 , -N(R’)C(O)R, -N(R’)C(O)N(R’) 2 , -N(R’)C(S)N(R’) 2 , - N(R’)SO 2 R, -N(R’)SO 2 N(R’) 2 , -N(R’)N(R’) 2
  • p 0-3;
  • R x is halogen, optionally substituted C 1-6 aliphatic, -OR, -SR, -CN, -N(R’) 2 , -C(O)R, - C(S)R, -CO 2 R, -C(O)N(R’) 2 , -C(O)SR, -C(O)C(O)R, -C(O)CH 2 C(O)R, -C(S)N(R’) 2 , -C(S)OR, -S(O)R, -SO 2 R, -SO 2 N(R’) 2 , -N(R’)C(O)R, -N(R’)C(O)N(R’) 2 , -N(R’)C(S)N(R’) 2 , - N(R’)SO 2 R, -N(R’)SO 2 N(R’) 2 , -N(R’)N(R’) 2 ,
  • R 2 is a bond or optionally substituted C 1-6 aliphatic, or:
  • R 1 and R 2 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
  • each R’ is independently -R, -C(O)R, -C(S)R, -CO 2 R, -C(O)N(R) 2 , -C(S)N(R) 2 , - S(O)R, -SO 2 R, -SO 2 N(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 , , or ;
  • R 3 is optionally substituted C 1-6 aliphatic
  • X is oxygen or sulfur, or: R 3 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;
  • each of R 4 and R 5 is independently–R, halogen, -OR, -SR, -N(R’) 2 , -CN, -NO 2 , - C(O)R, -C(S)R, -CO 2 R, -C(O)N(R’) 2 , -C(O)SR, -C(O)C(O)R, -C(O)CH 2 C(O)R, -C(S)N(R’) 2 , - C(S)OR, -S(O)R, -SO 2 R, -SO 2 N(R’) 2 , -N(R’)C(O)R, -N(R’)C(O)N(R’) 2 , -N(R’)C(S)N(R’) 2 , - N(R’)SO 2 R, -N(R’)SO 2 N(R’) 2 , -N(R’)N(R’) 2
  • a compound of Formula X, Formula Y, or Formula Z may be selected from the group consisting of:
  • 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.
  • a compound of Formula XX, Formula YY, or Formula ZZ may be selected from the rou consistin of:
  • 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.
  • exemplary bromodomain ligands include compounds represented by the structures: Formula YYA, and
  • 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;
  • L 1 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’)SO 2 -, -SO 2 N(R’), -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO 2 -;
  • R x is halogen, optionally substituted C 1-6 aliphatic, -OR, -SR, -CN, -N(R’) 2 , -C(O)R, - C(S)R, -CO 2 R, -C(O)N(R’) 2 , -C(O)SR, -C(O)C(O)R, -C(O)CH 2 C(O)R, -C(S)N(R’) 2 , -C(S)OR, -S(O)R, -SO 2 R, -SO 2 N(R’) 2 , -N(R’)C(O)R, -N(R’)C(O)N(R’) 2 , -N(R’)C(S)N(R’) 2 , - N(R’)SO 2 R, -N(R’)SO 2 N(R’) 2 , -N(R’)N(R’)N(R
  • R 2 is a bond, hydrogen, or optionally substituted C 1-6 aliphatic
  • 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
  • each R’ is independently -R, -C(O)R, -C(S)R, -CO 2 R, -C(O)N(R) 2 , -C(S)N(R) 2 , - S(O)R, -SO 2 R, -SO 2 N(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
  • R 3 is optionally substituted C 1-6 aliphatic
  • each of m and n is independently 0-4, as valency permits;
  • each of R 4 and R 5 is independently–R, halogen, -OR, -SR, -N(R’) 2 , -CN, -NO 2 , - C(O)R, -C(S)R, -CO 2 R, -C(O)N(R’) 2 , -C(O)SR, -C(O)C(O)R, -C(O)CH 2 C(O)R, -C(S)N(R’) 2 , - C(S)OR, -S(O)R, -SO 2 R, -SO 2 N(R’) 2 , -N(R’)C(O)R, -N(R’)C(O)N(R’) 2 , -N(R’)C(S)N(R’) 2 , - N(R’)SO 2 R, -N(R’)SO 2 N(R’) 2 , -N(R’)N(R’) 2
  • a compound of formula XXA, YYA, or ZZA may be:
  • XX may be a bond, C 1-6 alkyl, -NR t - (where t is H, phenyl, or C 1-6 alkyl), -O-, or -S(O) w - wherein w is 0, 1, or 2;
  • exemplary bromodomain ligands include com ounds re resented b the structure:
  • X is selected from N and CH;
  • Y is CO
  • R 1 and R 3 are each independently selected from alkoxy and hydrogen
  • R 2 is selected from alkoxy, alkyl, and hydrogen
  • R 6 and R 8 are each independently selected from alkyl, alkoxy, chloride, and hydrogen; R 5 and R 9 are each hydrogen;
  • R 7 is selected from amino, hydroxyl, alkoxy, and alkyl substituted with a heterocyclyl
  • R 10 is hydrogen; or two adjacent substituents selected from R 6 , R 7 , and R 8 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;
  • W is N and p is 1;
  • W is C, p is 1 and R 4 is H, or W is N and p is 0.
  • a compound of Formula AA may be:
  • exemplary bromodomain ligands include com ounds re resented b the structures:
  • Y and W are each independently selected from carbon and nitrogen;
  • Ra 6 is selected from fluoride, hydrogen, C 1 -C 3 alkoxy, cyclopropyloxy, SO 2 R 3 , SOR 3 , and SR 3 , wherein if Y is nitrogen then Ra 6 is absent;
  • Ra 7 is selected from hydrogen, fluoride, SO 2 R 3 , SOR 3 , and SR 3 ;
  • Ra 8 is selected from hydrogen, C 1 -C 3 alkoxy, cyclopropyloxy, chloride, and bromide;
  • n is selected from 1, 2, or 3;
  • D is selected from O, NH, NR 1 , S, or C;
  • Rb 3 and Rb 5 are independently selected from hydrogen and C 1 -C 3 alkyl
  • R C and R C are independently selected from hydrogen, C 1 -C 3 alkyl, and
  • C is selected from F, Cl, Br, I, CF 3 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, NHC(O)R 4 ,
  • R 1 , R’ 1 , R 2 and R’ 2 are independently selected from hydrogen, fluoride, C 1 -C 3 alkyl, and cyclopropyl, wherein R 1 and R 2 and/or R’ 1 and R’ 2 may be connected to form a 3-6 membered ring;
  • R 3 is selected from C 1 -C 3 alkyl and cyclopropyl
  • R 4 is selected from hydrogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl, phenyl, and naphthyl, provided that if Ra 7 or Ra 6 is fluoride, then R 4
  • C is not bromide
  • a compound of Formula AA, Formula AA1, Formula AA2, Formula AA3, Formula BB, or Formula CC may be selected from the group consisting of:
  • exemplary bromodomain ligands include com ounds re resented b the structure:
  • Q and V are independently selected from CH and nitrogen;
  • R 1 and R 2 are independently selected from hydrogen and C 1 -C 6 alkyl;
  • Rc is selected from hydrogen, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl;
  • Ra 1 , Ra 2 , and Ra 3 are independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, C 1 -C 6 alkoxy, halogen, amino, amide, hydroxyl, heterocycle, and C 3 -C 6 cycloalkyl, wherein Ra 1 and Ra 2 and/or Ra 2 and Ra 3 may be connected to form a cycloalkyl or a heterocycle;
  • Rb 2 and Rb 6 are independently selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 3 -C 6 cycloalkyl, hydroxyl, and amino;
  • Rb 3 and Rb 5 are independently selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, hydroxyl, and amino, wherein Rb 2 and Rb 3 and/or Rb 5 and Rb 6 may be conn cycloalkyl or a heterocycle; represents a 3-8 membered ring system wherein: W is selected from carbon and nitrogen; Z is selected from CR 6 R 7 , NR 8 , oxygen, sulfur, -S(O)-, and -SO 2 -; 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 3 , R 4 , and R 5 are independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, phenyl, naphthyl, aryloxy, hydroxy1, amino, amide, oxo, -CN, and sulfonamide;
  • R 6 and R 7 are independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, C 3 -C 6 cycloalkyl, phenyl, naphthyl, halogen, hydroxyl, -CN, amino, and amido; and R 8 is selected from hydrogen, C 1- C 6 alkyl, C 1 -C 6 alkenyl, C 1- C 6 alkynyl, acyl, and C 3 -C 6 cycloalkyl; and
  • R 9 , R 10 , R 11 , and R 12 are independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, C 3 -C 6 cycloalkyl, phenyl, naphthyl, heterocycle, hydroxyl, sulfonyl, and acyl.
  • exemplary bromodomain ligands include compounds represented by the structure: Formula GG,
  • Q is selected from N and CRa 3 ;
  • V is selected from N and CRa 4 ;
  • W is selected from N and CH;
  • X is selected from OH, SH, NH 2 , S(O)H, S(O) 2 H, S(O) 2 NH 2 , S(O)NH 2 , NHAc, and NHSO 2 Me;
  • Ra 1 , Ra 3 , and Ra 3 are independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, and halogen;
  • Ra 2 is selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, amino, amide, and halogen;
  • Rb 2 and Rb 6 are independently selected from hydrogen, methyl and fluorine;
  • Rb 3 and Rb 5 are independently selected from hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and C 1 -C 6 alkoxy;
  • Rb 2 and Rb 3 and/or Rb 5 and Rb 6 may be connected to form a cycloalkyl or a heterocycle, provided that at least one of Ra 1 , Ra 2 , Ra 3 , and Ra 4 is not hydrogen.
  • exemplary bromodomain ligands include compounds re resented b the structure:
  • Q is selected from N and CRa 3 ;
  • V is selected from N and CRa 4 ;
  • W is selected from N and CH;
  • X is selected from OH, SH, NH 2 , S(O)H, S(O) 2 H, S(O) 2 NH 2 , S(O)NH 2 , NHAc, and NHSO 2 Me;
  • Ra 1 , Ra 3 , and Ra 3 are independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, and halogen;
  • Ra 2 is selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, amino, amide, and halogen;
  • Rb 2 and Rb 6 are independently selected from hydrogen, methyl and fluorine;
  • Rb 3 and Rb 5 are independently selected from hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and C 1 -C 6 alkoxy;
  • Rb 2 and Rb 3 and/or Rb 5 and Rb 6 may be connected to form a cycloalkyl or a heterocycle, provided that at least one of Ra 1 , Ra 2 , Ra 3 , and Ra 4 is not hydrogen.
  • exemplary bromodomain ligands include fused heterocyclic systems represented by the structures:
  • V is independently selected, for each occurrence, from the group consisting of NH, S, N(C 1-6 alkyl), O, or CR 4 R 4 ;
  • Q is independently selected, for each occurrence, from the group consisting of C(O), C(S), C(N), SO 2 , or CR 4 R 4 ;
  • U is independently selected from the group consisting of a bond, C(O), C(S), C(N), SO 2 , or CR 4 R 4
  • W and T are independently selected from the group consisting of NH, N(C 1-6 alkyl), O, or Q;
  • V C is selected from the group consisting of N, SH or CR 4 ;
  • 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 R 4 ;
  • R 1 is independently selected, for each occurrence, from the group consisting of hydroxyl, halo, C 1-6 alkyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, C 1-6 alkoxy, haloC 1- 6 alkoxy, acylaminoC 1-6 alkyl, nitro, cyano, CF 3 , -OCF 3 , -C(O)OC 1-6 alkyl, -OS(O) 2 C 1-4 alkyl, phenyl, naphthyl, phenyloxy, benzyloxy, or phenylmethoxy, wherein C 1-6 alkyl, phenyl, and naphthyl are optionally substituted by one two or three substituents selected from the group consisting of hydroxyl, halogen, oxo, C 1-6 alkyl, amino, or nitro;
  • R 2 is selected from the group consisting of -O-, amino, C 1-6 alkyl, -O-C 1-6 alkyl-, hydroxylC 1-6 alkyl, aminoC 1-6 alkyl, haloC 1-6 alkyl, acylaminoC 1-6 alkyl, -C(O)-, - C(O)O-, -C(O)NC 1-6 alkyl-, -OS(O) 2 C 1-4 alkyl-, -OS(O) 2 -, -S-C 1-6 alkyl-, phenyl, naphthyl, phenyloxy, benzyloxy, or phenylmethoxy, wherein C 1-6 alkyl, phenyl, and naphthyl are optionally substituted by one two or three substituents selected from the group consisting of hydroxyl, halogen, oxo, C 1-6 alkyl, amino, or nitro;
  • R 3 is selected from the group consisting of hydrogen or C 1-6 alkyl
  • R 4 is independently selected, for each occurrence, from the group consisting of hydrogen, hydroxyl, oxo, imino, amino, halo, C 1-6 alkyl, cycloalkyl, phenyl, naphthyl, heterocyclyl, -O-C 1-6 alkyl, -NH-C 1-6 alkyl, -N(C 1-6 alkyl)C 1-6 alkyl, nitro, cyano, CF 3 , - OCF 3 , -C(O)OC 1-6 alkyl, -C(O)NHC 1-6 alkyl, -C(O)NH 2 or -OS(O) 2 C 1-4 alkyl;
  • n 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.
  • compounds of Formula 1, Formula 2 or Formula 5 may be selected from the rou consistin of:
  • compounds of Formula 1, Formula 2 or Formula 5 may be selected from the rou consistin of:
  • compounds of Formula 3, Formula 3’ or Formula 4 may be selected from the group consisting of:
  • bromodomain ligands include fused heterocyclic systems represented by the structures:
  • V is independently selected, for each occurrence, from the group consisting of NH, S, N(C 1-6 alkyl), O, or CR 4 R 4 ;
  • Q is independently selected, for each occurrence, from the group consisting of C(O), C(S), C(N), SO 2 , or CR 4 R 4 ;
  • W and T are independently selected from the group consisting of NH, N(C 1-6 alkyl), O, or Q;
  • V C is selected from the group consisting of N, SH or CR 4 ;
  • 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 R 1 ; 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;
  • R 1 is independently selected, for each occurrence, from the group consisting of hydroxyl, halo, C 1-6 alkyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, C 1-6 alkoxy, haloC 1- 6 alkoxy, acylaminoC 1-6 alkyl, nitro, cyano, CF 3 , -OCF 3 , -C(O)OC 1-6 alkyl, -OS(O) 2 C 1-4 alkyl, phenyl, naphthyl, phenyloxy, benzyloxy or phenylmethoxy, wherein C 1-6 alkyl, phenyl, and naphthyl are optionally substituted by one two or three substituents selected from the group consisting of hydroxyl, halogen, oxo, C 1-6 alkyl, amino, or nitro;
  • R 2 is selected from the group consisting of -O-, amino, C 1-6 alkyl, -O-C 1-6 alkyl-, hydroxylC 1-6 alkyl, aminoC 1-6 alkyl, haloC 1-6 alkyl, acylaminoC 1-6 alkyl, -C(O)-, - C(O)O-, -C(O)NC 1-6 alkyl-, -OS(O) 2 C 1-4 alkyl-, -OS(O) 2 -, -S-C 1-6 alkyl-, phenyl, naphthyl, phenyloxy, benzyloxy or phenylmethoxy, wherein C 1-6 alkyl phenyl, and naphthylare optionally substituted by one two or three substituents selected from the group consisting of hydroxyl, halogen, oxo, amino, or nitro;
  • R 3 is selected from the group consisting of hydrogen or C 1-6 alkyl
  • R 4 is independently selected, for each occurrence, selected from the group consisting of hydrogen, hydroxyl, oxo, imino, amino, halo, cycloalkyl, phenyl, naphthyl, heterocyclyl, -O-C 1-6 alkyl, -NH-C 1-6 alkyl, -N(C 1-6 alkyl)C 1-6 alkyl, nitro, cyano, CF 3 , - OCF 3 , -C(O)OC 1-6 alkyl, -C(O)NHC 1-6 alkyl, -C(O)NH 2 or -OS(O) 2 C 1-4 alkyl;
  • n 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.
  • compounds of Formula 1a, Formula 2a or Formula 5a may be selected from the group consisting of:
  • compounds of Formula 3a or Formula 4a may be selected from the group consisting of:
  • bromodomain ligands include fused heterocyclic systems represented by the structures:
  • V is selected from the group consisting of a NH, S, N(C 1-6 alkyl), O, or CR 4 R 4 ;
  • Q is selected from the group consisting of a bond, C(O), C(S), C(N), SO 2 , or CR 4 R 4 ;
  • 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 R 1 ; 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;
  • R 1 is independently selected, for each occurrence, from the group consisting of hydroxyl, halo, C 1-6 alkyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, C 1-6 alkoxy, haloC 1- 6 alkoxy, acylaminoC 1-6 alkyl, nitro, cyano, CF 3 , -OCF 3 , -C(O)OC 1-6 alkyl, -OS(O) 2 C 1- 4 alkyl, -S(C 1-4 alkyl)C(O)R’, phenyl, naphthyl, phenyloxy, benzyloxy, or phenylmethoxy, wherein C 1-6 alkyl, phenyl, and napththyl are optionally substituted by one two or three substituents selected from the group consisting of hydroxyl, halogen, oxo, C 1-6 alkyl, amino, or nitro;
  • R 2 is selected from the group consisting of -O-, amino, C 1-6 alkyl, -O-C 1-6 alkyl-, hydroxylC 1-6 alkyl, aminoC 1-6 alkyl, haloC 1-6 alkyl, acylaminoC 1-6 alkyl, -C(O)-, - C(O)O-, -C(O)NC 1-6 alkyl-, -OS(O) 2 C 1-4 alkyl-, -OS(O) 2 --S(C 1-4 alkyl)C(O)R’’-, -S-C 1-6 alkyl-, phenyl, naphthyl, phenyloxy, benzyloxy, or phenylmethoxy, wherein C 1-6 alkyl, phenyl, and naphthyl are optionally substituted by one two or three substituents selected from the group consisting of hydroxyl, halogen, oxo, amino, or nitro;
  • R 3 is selected from the group consisting of hydrogen or C 1-6 alkyl
  • R 4 is independently selected, for each occurrence, from the group consisting of hydrogen, hydroxyl, oxo, imino, amino, halo, cycloalkyl, phenyl, naphthyl, heterocyclyl, -O-C 1-6 alkyl, -NH-C 1-6 alkyl, -N(C 1-6 alkyl)C 1-6 alkyl, nitro, cyano, CF 3 , - OCF 3 , -C(O)OC 1-6 alkyl, -C(O)NHC 1-6 alkyl, -C(O)NH 2 or -OS(O) 2 C 1-4 alkyl;
  • R’ is independently selected, for each occurrence, from the group consisting of hydroxyl, amino, thio, phenyl, naphthyl, or C 1-6 alkyl, wherein C 1-6 alkyl, phenyl, and naphthyl are optionally substituted by one two or three substituents selected from the
  • R’’ is independently selected, for each occurrence, from the group consisting of–O-, amino, thio, phenyl, naphthyl, or C 1-6 alkyl, wherein C 1-6 alkyl, phenyl, and naphthyl are optionally substituted by one two or three substituents selected from the group consisting of hydroxyl, halogen, oxo, C 1-6 alkyl, amino, or nitro;
  • n 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;
  • p is selected from the group consisting of 0 or 1.
  • Exemplary bromodomain ligands include fused heterocyclic systems re resented b the structures:
  • L and L X are independently selected, for each occurrence, from the group consisting of N, CH, and CR 1 ;
  • L N1 and L N2 are independently selected from the group consisting of CH 2 , CHR 1 , CR 1 R 1 , NH, and N(C 1-6 alkyl); wherein C 1-6 alkyl is optionally substituted by one two or three substituents selected from the group consisting of hydroxyl, halogen, oxo, C 1-6 alkyl, amino, or nitro;
  • L N3 is selected from the group consisting of O, S, NH, and N(C 1-6 alkyl); wherein C 1- 6 alkyl is optionally substituted by one two or three substituents selected from the group consisting of hydroxyl, halogen, oxo, C 1-6 alkyl, amino, or nitro;
  • U is independently selected from the group consisting of a bond, C(O), C(S), C(N), SO 2 , or CR 4 R 4 ;
  • 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 R 4 ;
  • R 1 is independently selected, for each occurrence, from the group consisting of hydroxyl, halo, C 1-6 alkyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, C 1-6 alkoxy, haloC 1- 6 alkoxy, acylaminoC 1-6 alkyl, nitro, cyano, CF 3 , -OCF 3 , -C(O)OC 1-6 alkyl, -OS(O) 2 C 1-4 alkyl, phenyl, naphthyl, phenyloxy, benzyloxy, or phenylmethoxy, wherein C 1-6 alkyl, phenyl, and naphthyl are optionally substituted by one two or three substituents selected from the group consisting of hydroxyl, halogen, oxo, C 1-6 alkyl, amino, or nitro; R 2 is selected from the group consisting of -O-, amino, C 1-6 alkyl, -O-C 1-6 al
  • R 3 is selected from the group consisting of hydrogen or C 1-6 alkyl
  • R 4 is independently selected, for each occurrence, from the group consisting of hydrogen, hydroxyl, oxo, imino, amino, halo, C 1-6 alkyl, cycloalkyl, phenyl, naphthyl, heterocyclyl, -O-C 1-6 alkyl, -NH-C 1-6 alkyl, -N(C 1-6 alkyl)C 1-6 alkyl, nitro, cyano, CF 3 , - OCF 3 , -C(O)OC 1-6 alkyl, -C(O)NHC 1-6 alkyl, -C(O)NH 2 or -OS(O) 2 C 1-4 alkyl.
  • compounds of Formula 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 and 17 may be selected from the group consisting of:
  • the ligand is one of the compounds listed in Table 1 below or a pharmaceutically acceptable salt thereof, wherein the connector attachment point B
  • exemplary bromodomain ligands include fused heterocyclic systems represented by the structures:
  • R x is hydrogen or C 1 -C 3 alkyl
  • R Y is C 1 -C 3 alkyl, -(C 2 -C 3 alkylenyl)-OH, or C 1 -C 3 haloalkyl;
  • X 1 is N or CR x1 wherein
  • R x1 is hydrogen, C bx1
  • R dx1 at each occurrence, are each independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, G a , or -(C 1 -C 6 alkylenyl)-G a ;
  • X 2 is N or CR x2 ;
  • R x2 is hydrogen, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -C(O)OR ax2 , -C(O)NR bx2 R cx2 , - C(O)R dx2 , S(O) 2 R dx2 , -S(O) 2 NR bx2 R cx2 , G x2 , C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl; wherein the C 1 -C 6 alkyl is optionally substituted with one substituent selected from the group consisting of OR ax2 , SR ax2 , S(O)R dx2 , S(O) 2 R dx2 , NR bx2 R cx2 , - C(O)R ax2 , -C(O)OR ax2 , -C(O)NR bx2 R
  • R dx2 at each occurrence, is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, G b , or - (C 1 -C 6 alkylenyl)-G b ;
  • Y 1 is N or CR u ; wherein R u is hydrogen, C 1 -C 6 alkyl, halogen, or C 1 -C 6 haloalkyl; A 1 is N or CR 1 , A 2 is N or CR 2 , A 3 is N or CR 3 , and A 4 is N or CR 4 ; with the proviso that zero, one, two, or three of A 1 , A 2 , A 3 , and A 4 are N;
  • R 1 , R 3 , and R 4 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, C 1 -C 6 haloalkyl, CN, or NO 2 ;
  • R 2 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, C 1 -C 6 haloalkyl, - CN, NO 2 , G 2a , -OR 2a , -OC(O)R 2d , -OC(O)NR 2b R 2c , -SR 2a , -S(O) 2 R 2d , -S(O) 2 NR 2b R 2c
  • R 2a , R 2b , R 2C , and R 2e are each independently hydrogen, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, G 2b , or C 1 -C 6 alkyl wherein the C 1 -C 6 alkyl is optionally substituted with one substituent selected from the group consisting of -OR z1 , NR z1 R z2 , -C(O)OR z1 , -C(O)NR z1 R z2 , -S(O) 2 R z1 ,
  • R 2d is independently C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, G 2b , or C 1 -C 6 alkyl wherein the C 1 -C 6 alkyl is optionally substituted with one substituent selected from the group consisting of -OR z1 , NR z1 R z2 , -C(O)OR z1 , -C(O)NR z1 R z2 , -S(O) 2 R z1 , - S(O) 2 NR z1 R z2 , and G 2b ;
  • R z1 and R z2 are each independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
  • G x1 , G x2 , G a , G b , G 2a , and G 2b 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 ;
  • L 1 is absent, CH 2 , C(O), C(H)(OH), (CH 2 ) m O, (CH 2 ) m S(O) n wherein n is 0, 1, or 2; or (CH 2 ) m N(R z ) wherein R z is hydrogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, (C 2 -C 3 alkylenyl)-OH, or unsubstituted cyclopropyl;
  • n 0 or 1
  • G 1 is C 1- C 6 alkyl, alkoxyalkyl, G 1a , or -(C 1 -C 6 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 are each independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 - C 6 alkynyl, halogen, C 1 -C 6 haloalkyl, -CN, oxo, -OR h , -OC(O)R i -OC(O)NR j R k , -SR h , - S(O) 2 R h , -S(O) 2 NR j R k , -C(O)R h , -C(O)-monocyclic heterocycle, -C(O)-monocyclic heteroaryl, -C(O)OR h , -C(O)NR j R k , -NR j R k , -N(R h )C(O)R i , -N(R h )S(O) 2 R i , -
  • R h , R j , R k are each independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
  • R i at each occurrence, is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl.
  • exemplary bromodomain ligands include fused heterocyclic systems represented by the structures:
  • R 1 is selected from the group consisting of H,–C 1 -C 6 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, C 1 -C 6 alkyl, amino, and nitro;
  • R 2 is selected from the group consisting of H and C 1 -C 6 alkyl
  • R 3 is selected from the group consisting of hydrogen,–SO 2 -C 1 -C 6 alkyl,–NH-SO 2 -C 1 -C 6 alkyl,–N(C 1 -C 6 alkyl)-SO 2 -C 1 -C 6 alkyl, and– SO 2 -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, C 1 -C 6 alkyl, amino, and nitro;
  • R 4 independently for each occurrence, is selected from the group consisting of hydrogen, hydroxyl, halogen, oxo, C 1 -C 6 alkyl, amino, and nitro;
  • n 1, 2, or 3;
  • n 1, 2, or 3.
  • R 1 is H. In certain other embodiments, R 1 is– methylene-(4-methyl-piperazinyl).
  • R 2 in certain embodiments, is methyl.
  • R 3 is selected from the group consisting of–SO 2 -methyl, –NH-SO 2 -ethyl, and–SO 2 -pyrrolidinyl.
  • R 4 is fluoro
  • exemplary bromodomain ligands include fused heterocyclic systems represented by the structures:
  • R 1 is optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted
  • R 3 is H, alkyl, alkenyl, alkynyl, aralkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, or halo, each of which is optionally substituted; or CN, OR A , NR A R B , N(R A )S(O) q R A R B , N(R A )C(O)R B , N(R A )C(O)NR A R B , N(R A )C(O)OR A , N(R A )C(S)NR A R B , -N(R A )S(O) q NR A R B , S(O) q R A , C(O)R A , C(O)OR A , OC(O)R A , or C(O)NR A R 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;
  • 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;
  • 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;
  • R 5 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, -CO 2 R, -C(O)N(R')(R"), -C(O)SR, -C(O)C(O)R, -C(O)CH 2 C(O)R, -C(S)N(R')(R"), -C(S)OR, -S(O)R, -SO 2 R, -SO 2 N(R')(R"), -N(R')C(O)R, - N(R')C(O)N(R')
  • 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, -CO 2 R, - C(O)N(R')(R"), -C(O)SR, -C(O)C(O)R, -C(O)CH 2 C(O)R, -C(S)N(R')(R"), -C(S)OR, -S(O)R, - SO 2 R, -SO 2 N(R')(R"), -N(R')C(O)R, -N(R')C(O
  • 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, -CO 2 R, -C(O)N(R) 2 , -C(S)N(R) 2 , -S(O)R, -SO 2 R, -SO 2 N(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, -CO 2 R, -C(O)N(R) 2 , -C(S)N(R) 2 , - S(O)R, -SO 2 R, -SO 2 N(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;
  • each q is independently 0, 1, or 2.
  • exemplary bromodomain ligands include fused heteroc scrap s stems re resented b the structures:
  • R 1 is selected from the group consisting of H and C 1 -C 6 alkyl, optionally substituted by one, two, or three substituents selected from the group consisting of hydroxyl, halogen, oxo, amino, and nitro;
  • R 2 is selected from the group consisting of hydroxyl, halogen, oxo, amino, and nitro;
  • R 3 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl;
  • R 4 independently for each occurrence, is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and -C 1 -C 6 alkylene-phenyl, wherein phenyl is optionally substituted by one, two, or three substituents selected from the group consisting of hydroxyl, halogen, oxo, C 1 -C 6 alkyl, amino, and nitro; and
  • n 0, 1, or 2.
  • R 1 is trifluoromethyl.
  • R 3 is ethyl.
  • one R 4 is hydrogen. In certain other embodiments, one
  • exemplary bromodomain ligands include compounds represented by:
  • R 2 is selected from
  • bromodomain ligands of Formula QQ may be selected from the group consisting of:
  • exemplary bromodomain ligands include compounds represented by:
  • A is C(R 8 R 9 ); Y is C(R 6 R 7 ); J is C(R 4 R 5 ); R 1 is hydrogen or C 1 -C 3 alkyl; R 2 is hydrogen or C 1 -C 3 alkyl; R 3 is heteroaryl, 9 to 12 membered bicyclic aryl, napthalen-1-yl, unsubstituted
  • 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 NR 16 R 18 , halo, hydroxyl, C 1 -C 3 alkyl, -O-aryl, Ci-C 3 alkylene-aryl, C 1 -C 3 alkylene-O-aryl, -S-aryl, -O- C 1 -C 3 alkylene-aryl, -NR 16 -SO 2 -NR 18 -C 1 -C 3 alkyl, -NR 16 - SO 2 -NR 18 - C 1 -C 3 haloalkyl, -NR 16 - SO 2 - C 1 -C 3 alkyl, -NR 16 -SO 2 - C 1 -C 3 haloalkyl, SO 2 - NR 16 R 18 , SO 2 - C 1 -C 3 alkyl, -O- C 1
  • R 10 , R 11 , R 12 , R 13 , and R 14 are hydrogen, and one of R 10 , R 11 , R 12 , R 13 , or R 14 is selected from the following groups:
  • R 10 is NR 16 R 18 , halo, hydroxyl, C 1 -C 3 alkyl, C 1 -C 3 alkylene-aryl, C 1 -C 3 alkylene-O-aryl, -S-aryl, -O-C 1 -C 3 alkylene-aryl, -NR 16 -SO 2 -NR 18 - C 1 -C 3 alkyl, -NR 16 - SO 2 -NR 18 - C 1 -C 3 haloalkyl, -NR 16 -SO 2 - C 1 -C 3 alkyl, -NR 16 - SO 2 - C 1 -C 3 haloalkyl, SO 2 - NR 16 R 18 , SO 2 - C 1 -C 3 alkyl, -O-C 1 -C 3 alkyl, - C(O)-O- C 1 -C 3 alkyl, -C(O)-OH, -C(O)- NR 16 R 18
  • R 11 is NR 16 R 18 , fluoro, iodo, bromo, hydroxyl, C 1 -C 3 alkyl, -O-aryl, C 1 -C 3 alkylene-aryl, C 1 -C 3 alkylene-O-aryl, -S-aryl, -O-C 1 -C 3 alkylene-aryl, -NR 16 -SO 2 -NR 18 - C 1 -C 3 alkyl, -NR 16 -SO 2 -NR 18 - C 1 -C 3 haloalkyl, -NR 16 - SO 2 - C 1 -C 3 alkyl, -NR 16 -SO 2 - C 1 -C 3 haloalkyl, SO 2 -NR 16 R 18 , SO 2 - C 1 -C 3 alkyl, -O-C 1 -C 3 alkyl, -C(O)-O- C 1 -C 3 alkyl, -C(O)
  • R 12 is NR 16 R 18 , halo, hydroxyl, C 1 -C 3 alkyl, C 1 -C 3 alkylene-aryl, C 1 -C 3 alkylene-O-aryl, -S-aryl, -O-C 2 -C 3 alkylene-aryl, -NR 16 -SO 2 -NR 18 - C 1 -C 3 alkyl, -NR 16 - SO 2 -NR 18 - C 1 -C 3 haloalkyl, -NR 16 -SO 2 - C 1 -C 3 alkyl, -NR 16 - SO 2 - C 1 -C 3 haloalkyl, SO 2 - NR 16 R 18 , SO 2 - C 1 -C 3 alkyl, -O- C 1 -C 3 alkyl, - C(O)-O- C 1 -C 3 alkyl, -C(O)-OH, -C(O)- NR 16 R 18
  • R 13 and R 14 are NR 16 R 18 , halo, hydroxyl, C 1 -C 3 alkyl, -O-aryl, C 1 -C 3 alkylene- aryl, C 1 -C 3 alkylene-O-aryl, -S-aryl, -O-C 1 -C 3 alkylene-aryl, - NR 16 -SO 2 -NR 18 - C 1 -C 3 alkyl, -NR 16 -SO 2 -NR 18 - C 1 -C 3 haloalkyl, -NR 16 - SO 2 - C 1 -C 3 alkyl, -NR 16 -SO 2 - C 1 -C 3 haloalkyl, SO 2 -NR 16 R 18 , SO 2 -C 1 - C 3 alkyl, -O-C 1 -C 3 alkyl, -C(O)-O-C 1 -C 3 alkyl, -C(O)- OH,
  • R 10 , R 11 , R 12 , R 13 , and R 14 are hydrogen, and n of R 10 , R 11 , R 12 , R 13 , and R 14 are selected from the following groups:
  • NR 16 R 18 halo, hydroxyl, C 1 -C 3 alkyl, -O-aryl, C 1 -C 3 alkylene-aryl, C 1 -C 3 alkylene-O-aryl, -S-aryl, -0- C 1 -C 3 alkylene-aryl, -NR 16 -SO 2 -NR 18 - C 1 -C 3 alkyl, -NR 16 - SO 2 -NR 18 - C 1 -C 3 haloalkyl, -NR 16 -SO 2 - C 1 -C 3 alkyl, - NR 16 -SO 2 - C 1 -C 3 haloalkyl, SO 2 - NR 16 R 18 , SO 2 - C 1 -C 3 alkyl, -O- C 1 -C 3 alkyl, -C(O)-O- C 1 -C 3 alkyl, -C(O)-OH, -C(O)- NR 16
  • an exemplary compound of represented by Formula RR is:
  • exemplary bromodomain ligands include compounds represented by:
  • exemplary bromodomain ligands include compounds represented by:
  • exemplary bromodomain ligands include compounds represented by:
  • 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 R 1 ;
  • R 1 is hydrogen or C 1-6 aliphatic
  • R 2 -R 5 are each independently hydrogen, halogen, optionally substituted C 1-6 aliphatic, - OR, -SR, -CN, -N(R') 2 , -C(O)R, -C(S)R, -CO 2 R, -C(O)N(R') 2 , -C(O)SR, -C(O)C(O)R, - C(O)CH 2 C(O)R, -C(S)N(R') 2 , -C(S)OR, -S(O)R, -SO 2 R, -SO 2 N(R') 2 , -N(R')C(O)R, - N(R')C(O)N(R') 2 , -N(R')C(S)N(R') 2 , -N(R')SO 2 R, -N(R')SO 2 N(R') 2 , -N(R')N
  • each of R 2 and R 3 , R 2 and R 4 , R 3 and R 5 , or R 4 and R 5 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, SO 2 , CO, a covalent bond, or an optionally substituted bivalent chain wherein one methylene unit is optionally replaced by -NR'-, - N(R')C(O)-, -C(O)N(R')-, -N(R')SO 2 -, -SO 2 N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)0-, -S-, -SO- or -SO 2 -; 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, -CO 2 R, -C(O)N(R') 2 , -C(O)SR, -C(O)C(O)R, -C(O)CH 2 C(O)R, -C(S)N(R') 2 , -C(S)OR, -S(O)R, -SO 2 R, -SO 2 N(R') 2 , -N(R')C(O)R, -N(R')C(O)N(R') 2 , -N(R')C(S)N(R') 2 , -N(R')SO 2 R, - N(R')SO 2 N(R') 2 , -N(R')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
  • each R' is independently -R, -C(O)R, -C(S)R, -CO 2 R, -C(O)N(R) 2 , -C(S)N(R) 2 , -S(O)R, -SO 2 R, or -SO 2 N(R) 2 ; or
  • 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;
  • each of R 6 and R 7 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, -NO 2 , -C(O)R, -C(S)R, -CO 2 R, - C(O)N(R') 2 , -C(O)SR, -C(O)C(O)R, -C(O)CH 2 C(O)R, -C(S)N(R') 2 , -C(S)OR, -S(O)R, -SO 2 R, -SO 2 N(R') 2 , -N(R')C(O)R, -N(R')C(O)N(R') 2 , -N(R')C(S
  • an exemplary compound of represented by Formula SS is:
  • exemplary bromodomain ligands include compounds re resented b :
  • Formula TT wherein R 1 is H, halogen, amino, -NH-C 1- 6 alkyl, -SO 2 -NH 2 , -SO 2 -NHC 1-6 alkyl, -NHSO 2 -C 1-6 alkyl, NO 2 , C 1-6 alkyl, or C 1-6 alkoxy, and R 2 is H, acetyl, tosyl, BOC, C 1-6 alkyl, -C 1-6 alkyl-COOH, or -C 1-6 alkyl-CONH-C 1-6 alkyl.
  • R 1 is selected from Cl, Br, F, NO 2 , amino, methyl, methoxy, aminomethyl, -SO 2 NH-ethyl; -SO 2 NH-methyl, and -NH-SO 2 -methyl.
  • R 2 may be methyl, -CH 2 CH 2 COOH, -CH 2 CH 2 CONHMe, -CH 2 COOH, and -CH 2 CONHMe.
  • exemplary bromodomain ligands include compounds represented by:
  • R 1 is halo
  • R 3 is C 1-6 alkyl, amino, or–NH-C 1-6- alkyl
  • X is O or S.
  • R 1 is selected from Cl and Br.
  • R 3 is selected methyl, amino, and -NH-methyl.
  • exemplary bromodomain ligands include compounds shown in the following Table:
  • exemplary bromodomain ligands include compounds represented by:
  • exemplary bromodomain ligands include compounds represented by:
  • R 5 are independently selected from the group consisting of hydrogen, hydroxyl, amino, halo, C 1-6 alkyl, cycloalkyl, phenyl, naphthyl, heterocyclyl, -O-C 1-6 alkyl, -NH- C 1-6 alkyl, -N(C 1-6 alkyl)C 1-6 alkyl, nitro, cyano, CF 3 , -OCF 3 , -C(O)OC 1-6 alkyl, -C(O)NHC 1- 6 alkyl, -C(O)NH 2 , and -OS(O) 2 C 1-4 alkyl.
  • exemplary bromodomain ligands include compounds represented by: .
  • exemplary bromodomain ligands include compounds represented by:
  • A is phenyl or 5-6 membered heteroaryl ring
  • R 5 are independently selected from the group consisting of hydrogen, hydroxyl, amino, halo, C 1-6 alkyl, cycloalkyl, phenyl, naphthyl, heterocyclyl, -O- C 1-6 alkyl, -NH-C 1-6 alkyl, -N(C 1-6 alkyl)C 1-6 alkyl, nitro, cyano, CF 3 , -OCF 3 , -C(O)OC 1-6 alkyl, - C(O)NHC 1-6 alkyl, -C(O)NH 2 , and -OS(O) 2 C 1-4 alkyl.
  • WO/2014/026997 which is hereby incorporated by reference in its entirety.
  • 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.
  • exemplary bromodomain ligands include compounds selected from the group consisting of SB-203580, PP-242, SCH-772984, PF-431396,
  • exemplary bromodomain ligands include compounds selected from the group consisting of:
  • exemplary bromodomain ligands include compounds represented by the formula:
  • R 1 is selected from ;
  • R 2 and R 3 are independently selected from H and halogen (e.g., fluoro).
  • exemplary bromodomain ligands include compounds represented by the formula:
  • W is N or C-R 8 ;
  • X is N, CH or C(CH 3 );
  • Z is N or C-R 14 ;
  • Y is N or C-R 5 (subject to proviso that no more than 2 of W, X, Y and Z are N);
  • R 1 is C 1 - 4 alkyl
  • R 2 is H, OH, C 1-4 alkyl, -N(CH 3 ) 2 , -NH(CH 3 ), halo, -CF 3 , -NH 2 , -OC 1-4 alkyl, -NHC(0)H, -NHC(0)d.
  • R 2 is a group selected from -G- CH 2 CH(R 3 )(R 4 ), -G-CH(R 3 )(R 4 ) and -G-R 3 in which G is NH, N(CH 3 ), O, C(0)NH or
  • R 5 is H, C 1-4 alkyl, halo, -C–OC 1-4 alkyl, -CH 2 NH 2 , -OCF 3 or-SO 2 CH 3 ;
  • R 6 is -NR n R 12 or a group
  • D is CH or N
  • E is N, O, CH or SO 2 ;
  • R 7 when present, is H, OH, C 1-4 alkyl, -NH 2 , -SO 2 C 1-4 alkyl, -SO 2 phenyl, -SO 2 benzyl, - SO 2 N(CH 3 ) 2 , -NHSO 2 CH 3 , -C(O)C 1-4 alkyl or -C(O)phenyl;
  • R 8 is H, C 1-4 alkyl, halo, -CF 3 , CN, OH, -OC 1-4 alkyl, -OCF 3, -OCH 2 phenyl or -OCH 2 C 3- 7 cycloalkyl;
  • R 9 is H, C 1-4 alkyl, -C(O)NH 2 , -CO 2 CH 3, -CF 3 , halo, OH, -OC 1-4 alkyl, -CH 2 OH, - C(0)NHCH 3 , - C(0)N(CH 3 ) 2 , -CH 2 OC 1-4 alkyl; -CH 2 OCH 2 C 3-7 cycloalkyl or oxo;
  • R 10 is H, C 1-4 alkyl, -C(O)NH 2 , -CO 2 CH 3, -CF 3 , halo, OH or–OC 1-4 alkyl;
  • R 11 is H, C 1-4 alkyl or SO 2 CH 3 ;
  • R 12 is H, C 1-4 alkyl, C 1-4 alkyleneNHR 13 , C 2-4 alkyleneOH, SO 2 CH 3 , a heterocycle or a heterocycle comprising SO 2 ;
  • R 13 is H or SO 2 CH 3 ;
  • R 14 is H, C 1-4 alkyl or NHC(O)C 1-4 alkyl
  • 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.
  • exemplary bromodomain ligands include compounds re resented b the formula:
  • W 1 is selected from N and CR 1 ;
  • W 2 is selected from N and CR 2 ;
  • W 3 is selected from N and CR 3 ;
  • W 4 is selected from N and CR 4 ;
  • each W may be the same or different from each other;
  • A is selected from N and CH;
  • R 1 , R 2 , R 3 , and R 4 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, aryl, hydroxyl, and halogen;
  • R 1 , R 2 , R 3 , 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:
  • R 5 is selected from hydrogen, alkyl, alkoxy, thioalkyl, amino, and halogen;
  • R 6 is selected from hydrogen, alkoxy, alkyl, aminoalkyl, and thioalkyl
  • Y is selected from NH, O, and S;
  • W 5 is selected from N and CQ 1 ;
  • W 6 is selected from N and CQ 2 ;
  • W 7 is selected from N and CQ 3 ;
  • W 8 is selected from N and CQ 4 ;
  • W 9 is selected from N and CQ 5 ;
  • Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 are independently selected from hydrogen, alkyl, halogen,—CN, —SO 2 Me,—SO 2 Et,—SO 2 Pr,—S(O)Me,—S(O)Et,—S(O)Pr,—S(O)iPr, amide, ketone,— COOH, and ester; and
  • R 5 , R 6 , Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , and Q 6 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.
  • exemplary bromodomain ligands include compounds represented by the formulae:
  • exemplary bromodomain ligands include compounds represented by the formulae:
  • exemplary bromodomain ligands include a compound represented by the formula:
  • exemplary bromodomain ligands include a compound represented by the formula:
  • W 1 is selected from N and CR 5 ;
  • W 2 is selected from N and CR 4
  • W 3 is selected from N and CR 3 ;
  • each W may be the same or different from each other;
  • R 1 is selected from a carbocycles or heterocycles
  • R 2 is selected from a 5 ⁇ or 6-membered monocyclic carbocycle or a 5- or 6-membered monocyclic heterocycle
  • R 3 , R 4 , and R 5 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;
  • R 3 and R 4 may be connected to form an optionally substituted 5-, 6-, or 7-membered carbocycle or heterocycle;
  • R 4 may be connected to B or R 2 to form a carbocycle or heterocycle
  • X is selected from 0 and 5;
  • A is selected from -CR X R Y -, OG, -C(O)CR x R y -, -CR x R y CRA-, -SO 2 , -CR x R y CR,R v O-, - CRNaseR y CR j R v N- ,-CR X R,,.CR 2 R.,S-, and -CR X R V CR Z R V CR Q R R- ;
  • R X , R Y , R Z , R v , R Q , and R R are each independently selected from hydrogen, alkyl(C 1 - C 8 ), halogen, -OH, -CF 3 , amino, alkoxy (C C 8 ), 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
  • R S , R Y , R Z , Rv, R 5 , and R 1 may be connected in a 5- or 6- membered ring to form a bicyc!ic carbocycle or bicyclic heterocycle;
  • B is selected from -(CR a R b ) n -, -(CR a R b CR c R d )-, -O-, -OCR a R b -, -CR a R b O-, -NH- , - NHCR a R b -, - CR a R b NH-, -S-, -SCR a R b -,-CR a R b S-, -S(O)-, -S(O)CR a R b -, -CR a R b S(O)-, -SO 2 -, - SO 2 CR a R b -, and -CR a R b SO 2 -;
  • R a , R b , R c , and R d are each independently selected from hydrogen, alkyl(C 1 -C 3 ), and alkoxy(C 1 -C 3 ). See, for example, International Patent Application Publication No.
  • exemplary bromodomain ligands include a compound re resented b the formula:
  • A is NH or O
  • X is N or CH
  • N is 0 or 1
  • R 1 is–C(O)NR 8 R 9 or–SO 2 NR 8 R 9 ;
  • R 2 , R 3 , R 4 , R 5 , and R 6 are independently selected from the group consisting of hydrogen, hydroxyl, amino, halo, C 1-6 alkyl, cycloalkyl, phenyl, naphthyl, heterocyclyl, -O-C 1- 6 alkyl, -NH-C 1-6 alkyl, -N(C 1-6 alkyl)C 1-6 alkyl, nitro, cyano, CF 3 , -OCF 3 , -C(O)OC 1-6 alkyl, - C(O)NHC 1-6 alkyl, -C(O)NH 2 , and -OS(O) 2 C 1-4 alkyl.
  • WO/2014/095774 and WO/2014/095775 each of which is hereby incorporated by reference in its entirety.
  • exemplary bromodomain ligands include a compound represented by the formula:
  • Cy 1 is an optionally substituted monocyclic ring having 1-3 heteroatoms independently selected from N and O; wherein the optional substituent is alkyl;
  • Cy 2 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;
  • R 1 is selected from hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl,
  • R 2 and R 3 are independently selected from the halogen, hydroxy or alkyl; or R 2 and R 3 combined together to form an oxo group;
  • R 2 and R 3 can be taken together with the carbon atom to which they are attached to form a 3-4 membered cycloalkyl ring;
  • R 4 is selected from hydrogen, halogen and alkyl
  • R 5 is selected from hydrogen, halogen, alkyl and alkoxy. See, for example,
  • an exemplary compound of Formula BBB is represented by the formula:
  • exemplary bromodomain ligands include a compound represented by the formula:
  • A is phenyl or a 5-6 membered heteraryl ring
  • X is O or S
  • R 1a , R 1b , R 2 , R 3 , R 4 , and R 5 are independently selected from the group consisting of hydrogen, hydroxyl, amino, halo, C 1-6 alkyl, cycloalkyl, phenyl, naphthyl, heterocyclyl, -O-C 1- 6 alkyl, -NH-C 1-6 alkyl, -N(C 1-6 alkyl)C 1-6 alkyl, nitro, cyano, CF 3 , -OCF 3 , -C(O)OC 1-6 alkyl, - C(O)NHC 1-6 alkyl, -C(O)NH 2 , and -OS(O) 2 C 1-4 alkyl.
  • WO/2014/128067 which is hereby incorporated by reference in its entirety.
  • exemplary bromodomain ligands include a compound represented by the formula:
  • X is C or N
  • Y is–C(O)OR 12 ,–C(O)NR 10 R n , phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl;
  • n and n are independently 0 or 1;
  • R 1 , R 2 , R 3 , R 4 , and R 5 are independently selected from the group consisting of hydrogen, hydroxyl, amino, halo, C 1-6 alkyl, cycloalkyl, phenyl, naphthyl, heterocyclyl, -O-C 1- 6 alkyl, -NH-C 1-6 alkyl, -N(C 1-6 alkyl)C 1-6 alkyl, nitro, cyano, CF 3 , -OCF 3 , -C(O)OC 1-6 alkyl, - C(O)NHC 1-6 alkyl, -C(O)NH 2 , and -OS(O) 2 C 1-4 alkyl.
  • WO/2014/128111 and WO/2014/128070 which is hereby incorporated by reference in its entirety.
  • exemplary bromodomain ligands include a compound represented by the formula:
  • A is optionally substituted heteroaryl or optionally substituted heterocyclo, wherein the substituents are one or more R 14 , R 15 or R 16 ;
  • R is hydrogen, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 3 - C 8 )cycloalkyl(C 1 -C 6 )alkyl, optionally substituted aryl(C 1 -C 6 )alkyl, optionally substituted heteroaryl(C 1 -C 6 )alkyl, optionally substituted heterocyclo(C 1 -C 6 )alkyl, optionally substituted (C 1 -C 6 )alkyl-CO-, optionally substituted aryl-CO-, optionally substituted (C 3 -C 8 )cycloalkyl- CO-, optionally substituted heteroaryl, optionally substituted heterocyclo-CO-, optionally substituted aryl-SO 2 -, optionally substituted (C 1 -C 6 )alkyl-SO 2 - , optionally substituted (C 3 - C 8 )cycloalkyl-SO 2 - optionally substituted heteroaryl-SO 2
  • X and Y are independently selected from hydrogen, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 8 )cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclo;
  • Z is hydrogen, halogen, -OH, (Ci-C 6 )alkyl, (C 1 -C 6 )alkoxy, -NR 3 R 4 , -CONR 3 R 4 , - OCONR 3 R 4 , -NR 6 OCOR 3 , -NR 6 CONR 3 R 4 , -NR 6 SO 2 NR 3 R 4 or -NR 6 SO 2 R 4 ;
  • R 1 is halogen, -CN, OH, -NR 3 R 4 , -CONR 3 R 4 , -COOH, -OCONR 3 R 4 , -NHOCOR 7 , - NHCONR 7 R 8 , -NHSO 2 NR 7 R 8 , optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 2 - C 6 )alkenyl, optionally substituted (C 2 -C 6 )alkynyl, optionally substituted (C 1 -C 6 )alkoxy, optionally substituted (C 3 -C 8 )cycloalkyl, optionally substituted (C 3 -C 8 )cycloalkyl-CO-, optionally substituted (C 3 -C 8 )cycloalkyl-SO 2 -, optionally substituted aryl (C 1 -C 6 )alkoxy, optionally substituted (C 3 -C 8 )cycloalkyl (C 1
  • R 2 is H, halogen, -CN, -COOH, -CONR 7 R 8 , -NHCOR 3 R 4 , -OCONR 3 R 4 , -NHCOOR 3 R 4 , optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 2 -C 6 )alkynyl, optionally substituted (C 1 -C 6 )alkoxy, optionally substituted heteroaryl or optionally substituted heterocyclo;
  • R 3 is hydrogen, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 3 - C 8 )cycloalkyl, optionally substituted (C 2 -C 6 )alkenyl, optionally substituted (C 2 -C 6 )alkynyl, cyano(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, optionally substituted aryl, optionally substituted aryl(C 1 -C 6 )alkyl, optionally substituted aryloxy(C 1 -C 6 )alkyl, optionally substituted (C 1 - C 6 )alkyl-SO 2 -, optionally substituted heterocyclyl, optionally substituted heterocyclyl(C 1 - C 6 )alkyl, optionally substituted heteroaryl or optionally substituted heteroaryl(C 1 -C 6 )alkyl, R 4 is hydrogen, optionally substituted (C 1 -C 6
  • R 3 and R 4 may be taken together with the nitrogen atom to which they are attached to form an optionally substituted (C 4 -C 8 ) heteroaryl or (C 4 -C 8 ) heterocyclic ring;
  • R 6 is hydrogen or optionally substituted (C 1 -C 6 )alkyl
  • R 7 and R 8 are independently hydrogen, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 8 )cycloalkyl, optionally substituted (C 2 -C 6 )alkenyl, optionally substituted (C 2 - C 6 )alkynyl, cyano(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, optionally substituted aryl, optionally substituted aryl(C 1 -C 6 )alkyl, optionally substituted; aryloxy(C 1 -C 6 )alkyl, optionally substituted (C 1 -C 6 )alkyl-SO 2 -, optionally substituted heterocyclyl, optionally substituted heterocyclyl(C 1 -C 6 )alkyl, optionally substituted heteroaryl or optionally substituted heteroaryl(C 1 -C 6 )alkyl;
  • R 7 and R 8 may be taken together with the nitrogen atom to which they are attached to form an optionally substituted (C 4 -C 8 ) heteroaryl or (C 4 -C 8 ) heterocyclic ring;
  • R 12 and R 13 are independently hydrogen, halogen, -CN, OH, -CONR 3 R 4 , -NHCOOR 4 , - NHCONR 3 R 4 , -NHCOR 4 , -NHSO 2 R 7 , -SO 2 NR 3 R 4 , -NHSO 2 NR 3 R 4 , -SO 2 R 7 , optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 8 )cycloalkyl, optionally substituted (C 1 - C 6 ) alkoxy, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclo;
  • R 14 is hydrogen, optionally substituted(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halogen, -CN, - NR 3 R 4 , OH, -NHOCOR 7 , -OCONR 7 R 8 , -NHCONR 7 R 8 or -CF 3 ;
  • R 15 is hydrogen, optionally substituted(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halogen, -CN, - NR 3 R 4 , OH, -NHOCOR 7 , -OCONR 7 R 8 , -NHCONR 7 R 8 or -CF 3 ;
  • R 16 is hydrogen, optionally substituted(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halogen, -CN, - NR 3 R 4 , OH, -NHOCOR 7 , -OCONR 7 R 8 , -NHCONR 7 R 8 or -CF 3 ;
  • an exemplary compound of Formula FFF is represented by the f rm l
  • exemplary bromodomain ligands include a compound represented by the formula:
  • R 1 is CD 3 , C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl
  • R 2 is H or C 1 -C 3 alkyl
  • Y 1 is N or CR 3 ;
  • R 3 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, C1-C6 haloalkyl,— C(O)R 3a ,—C(O)OR 3a ,—C(O)NR 3b R 3c ,—C(O)N(R 3b )NR 3b R 3c ,—S(O)R 3d ,—S(O) 2 R 3a ,— S(O) 2 NR 3b R 3c or G 1 ; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl are each independently unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of G 1 ,—C(O)R 3a ,—C(O)OR 3a ,—C(O)NR 3b R 3c ,—S(O)R 3d
  • N(R 3b )C(O)OR 3d N(R 3b )C(O)NR 3b R 3c , N(R 3b )SO 2 NR 3b R 3c , and N(R 3b )C(NR 3b R 3c ) ⁇ NR 3b R 3c ;
  • Y 2 is C(O), S(O) 2 , or CR 4 R 5 ;
  • R 4 is H, deuterium, C 1 -C 6 alkyl, halogen, or C 1 -C 6 haloalkyl
  • R 5 is H, deuterium, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, C 1 -C 6 haloalkyl, —C(O)R 5a ,—C(O)OR 5a ,—C(O)NR 5b R 5c ,—S(O)R 5d ,—S(O) 2 R 5a ,—S(O) 2 NR 5b R 5c , or G 1 ; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl are each independently unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of G 1 , —C(O)R 5a ,—C(O)OR 5a ,—C(O)NR 5b R 5c ,—C(O)N(R 5b )NR 5b R 5c
  • N(R 5b )C(O)OR 5d N(R 5b )C(O)NR 5b R 5c , N(R 5b )SO 2 NR 5b R 5c , and N(R 5b )C(NR 5b R 5c ) ⁇ NR 5b R 5c ;
  • R 3a , R 3b , R 3c , R 5a , R 5b , and R 5C are each independently H, C 1 - C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, G 1 , or—( C 1 -C 6 alkylenyl)-G 1 ;
  • R 3d and R 5d are each independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 - C 6 alkynyl, C 1 -C 6 haloalkyl, G 1 , or—( C 1 -C 6 alkylenyl)-G 1 ;
  • G 1 at each occurrence, is independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; and each G 1 is optionally substituted with 1, 2, 3, 4, or 5 R 1g groups;
  • R 6 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, C 1 -C 6 haloalkyl,—C(O)R 6a , —C(O)OR 6a ,—C(O)NR 6b R 6c ,—S(O) 2 R 6a ,—S(O) 2 NR 6b R 6c , or G 2 ; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl are each independently unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of G2,—C(O)R 6a ,—
  • R 6a , R 6b , and R 6c are each independently H, alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, haloalkyl, G 2 ,—(C 1 -C 6 alkylenyl)-G 2 ,—(C 1 -C 6 alkylenyl)-OR a ,—(C 1 -C 6 alkylenyl)-S(O) 2 R a ,—(C 1 -C 6 alkylenyl)-S(O) 2 NR c R d ,—(C 1 -C 6 alkylenyl)-C(O)R a ,—(C 1 -C 6 alkylenyl)-C(O)OR a ,—(C 1 -C 6 alkylenyl)-C(O)NR c R d ,—(C 1 -C 6 alkylenyl)-C(O)-C
  • R 6d is independently alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, haloalkyl, G 2 ,—(C 1 -C 6 alkylenyl)-G 2 ,—(C 1 -C 6 alkylenyl)-OR a ,—(C 1 -C 6 alkylenyl)-S(O) 2 R a ,—(C 1 -C 6 alkylenyl)-S(O) 2 NR c R d ,—(C 1 -C 6 alkylenyl)-C(O)R a ,—(C 1 -C 6 alkylenyl)-C(O)OR a ,—(C 1 -C 6 alkylenyl)-C(O)NR c R d ,—(C 1 -C 6 alkylenyl)-NR c R d ,—(C 1 -C 6 alkylen
  • G 2 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;
  • a 1 is C(R 7 ) or N;
  • a 2 is C(R 8 ) or N;
  • a 3 is C(R 9 ) or N;
  • a 4 is C(R 10 ) or N; wherein zero, one, or two of A 1 , A 2 , A 3 , and A 4 are N;
  • R 7 , R 8 , and R 9 are each independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, C 1 -C 6 haloalkyl,—CN, NO 2 ,—OR y1 ,—OC(O)R y2 ,—OC(O)NR y3 R y4 ,—SR y1 ,— S(O) 2 R y1 ,—S(O) 2 NR y3 R y4 ,—C(O)R y1 ,—C(O)OR y1 ,—C(O)NR y3 R y4 ,—NR y3 R y4 ,—NR y3 R y4 ,—NR y3 R y4 ,—NR y3 R y4 ,—NR y3 R y4 ,—NR y3 R y4 ,—NR y3 R y4
  • R y1 , R y3 , and R y4 are each independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, G 3 ,—( C 1 -C 6 alkylenyl)-G 3 ,—( C 1 -C 6 alkylenyl)- OR a ,—( C 1 -C 6 alkylenyl)-S(O) 2 R a ,—( C 1 -C 6 alkylenyl)-S(O) 2 NR c R d ,—( C 1 -C 6 alkylenyl)- C(O)R a ,—( C 1 -C 6 alkylenyl)-C(O)OR a ,—( C 1 -C 6 alkylenyl)-C(O)NR c R d ,—
  • R y2 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 - C 6 haloalkyl, G 3 ,—(C 1 -C 6 alkylenyl)-G 3 ,—(C 1 -C 6 alkylenyl)-OR a ,—(C 1 -C 6 alkylenyl)- S(O) 2 R a ,—(C 1 -C 6 alkylenyl)-S(O) 2 NR c R d ,—(C 1 -C 6 alkylenyl)-C(O)R a ,—(C 1 -C 6 alkylenyl)- C(O)OR a ,—(C 1 -C 6 alkylenyl)-C(O)NR c R d ,—(C 1 -C 6 alkylenyl)-NR
  • G 3 is independently aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocycle; and each G 3 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, C 1 -C 6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C 1 -C 6 haloalkyl,—CN, NO 2 , G 2a ,—OR a ,—OC(O)R b ,—OC(O)NR c R d ,—SR a ,—S(O) 2 R a ,—S(O) 2 NR c R d ,—C(O)R a , —C(O)OR a ,—C(O)NR c R d ,—NR c R d ,—N(R e )C(O)R b ,—N(R e )S(O) 2 R b ,—N(R e )C(O)O(R b ), —N(R
  • R a , R c , R d , and R e are each independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, G 2a , or—(C 1 -C 6 alkylenyl)-G 2a ;
  • R b at each occurrence, is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 - C 6 haloalkyl, G 2a , or—( C 1 -C 6 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 is independently oxo, C 1 -C 6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C 1 -C 6 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)O(Rz2),—
  • R z1 , R z3 , and R z4 at each occurrence, are each independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 haloalkyl; and R z2 , at each occurrence, is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 haloalkyl. See, for example, U.S. Patent Application Publication No. US 20140256710, which is hereby incorporated by reference in its entirety.
  • an exemplary compound of Formula GGG is represented by the f rm l
  • exemplary bromodomain ligands include a compound represented by the formula:
  • R 1 is C 1 -C 3 alkyl or C 1 -C 3 haloalkyl
  • X—Y is—CR 3 ⁇ CH—,—N ⁇ CR 4 —,—CR 5 ⁇ N—, or—CR 6 R 7 —CR 8 R 9 —; wherein the left ends of the moieties are attached to the NH group in the ring; A 1 , A 2 , A 3 , and A 4 are CR x ; or
  • a 1 , A 2 , A 3 , and A 4 are N, and the others are CR x ;
  • R 2 is R xa when X—Y is—CR 3 ⁇ CH—,—N ⁇ CR 4 —, or—CR 6 R 7 —CR 8 R 9 —; or R 2 is -L-G when X—Y is—CR 5 ⁇ N—, wherein L is O, N(R y ), O—C 1 -C 6 alkylenyl, or alkyenyl, wherein R y is hydrogen or C 1 -C 4 alkyl;
  • R x and R xa are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, C 1 -C 6 haloalkyl,—CN, NO 2 , G,—OR x1 ,—OC(O)R x2 ,— OC(O)NR x3 R x4 ,—SR x1 ,—S(O) 2 R x1 ,—S(O) 2 NR x3 R x4 ,—C(O)R x1 ,—C(O)OR x1 ,—
  • R x1 , R x3 , R x4 , and R x5 are each independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, G, or—C 1 -C 6 alkylenyl-G;
  • R x2 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 - C 6 haloalkyl, G, or—C 1 -C 6 alkylenyl-G;
  • G at each occurrence, are each independently aryl, heteroaryl, C 3 -C 7 heterocycle, C 3 -C 8 cycloalkyl, or C 5 -C 8 cycloalkenyl; and each G group is optionally substituted with 1, 2, 3, 4, or 5 R g groups;
  • R 3 is H,—CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, C 1 -C 6 haloalkyl,— C(O)R 3a ,—C(O)OR 3a ,—C(O)NR 3b R 3c ,—C(O)N(R 3b )NR 3b R 3c ,—S(O)R 3d ,—S(O) 2 R 3a ,— S(O) 2 NR 3b R 3c or G 1 ; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl are each independently unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of G 1 ,—C(O)R 3a ,—C(O)OR 3a ,—C(O)NR 3b R 3c ,—C(O
  • R 6 is H,—CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, or C 1 -C 6 haloalkyl;
  • R 8 and R 9 are each independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, or C 1 -C 6 haloalkyl;
  • R 7 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, C 1 -C 6 haloalkyl,—C(O)R 7a , —C(O)OR 7a ,—C(O)NR 7b R 7c ,—S(O)R 7d ,—S(O) 2 R 7a ,—S(O) 2 NR 7b R 7c , or G 1 ; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl are each independently unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of G 1 ,— C(O)R 7a ,—C(O)OR 7a ,—C(O)NR 7b R 7c ,—C(O)N(R 7b )NR 7b R 7c ,—S(O
  • R 3a , R 3b , R 3c , R 5a , R 5b , R 5c , R 7a , R 7b , and R 7c are each independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, G 1 ,—(C 1 -C 6 alkylenyl)-G 1 ,—(C 1 -C 6 alkylenyl)-OR a , or— (C 1 -C 6 alkylenyl)-CN;
  • R 3d and R 7d are each independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, G 1 ,—(C 1 -C 6 alkylenyl)-G 1 ,—(C 1 -C 6 alkylenyl)-OR a , or—(C 1 -C 6 alkylenyl)-CN;
  • G 1 at each occurrence, is independently aryl, heteroaryl, C 3 -C 7 heterocycle, C 3 -C 8 cycloalkyl, or C 5 -C 8 cycloalkenyl; and each G 1 is optionally substituted with 1, 2, 3, 4, or 5 R 1g groups;
  • R g and R 1g are each independently selected from the group consisting of oxo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, C 1 -C 6 haloalkyl,—CN, NO 2 , G 1a ,—OR a ,—OC(O)R b ,—OC(O)NR c R d ,—SR a ,—S(O) 2 R a ,—S(O) 2 NR c R d ,—C(O)R a , —C(O)OR a ,—C(O)NR c R d ,—NR c R d ,—N(R c )C(O)R b ,—N(R e )S(O) 2 R b ,—N(R e )C(O)O(R b ), —N(R e )N(O
  • R a , R c , R d , and R e are each independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, G 1a , or—(C 1 -C 6 alkylenyl)-G 2a ;
  • R b at each occurrence, is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 - C 6 haloalkyl, G 2a , or—(C 1 -C 6 alkylenyl)-G 2a ;
  • G 2a at each occurrence, are each independently aryl, heteroaryl, C 3 -C 7 heterocycle, C 3 - C 8 cycloalkyl, or C 5 -C 8 cycloalkenyl; and each G 2a group is optionally substituted with 1, 2, 3, 4, or 5 R 2g groups;
  • R 2g is independently oxo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, C 1 -C 6 haloalkyl,—CN, NO 2 ,—OR z1 ,—OC(O)R z2 ,—OC(O)NR z3 R z4 ,—SR z1 ,— S(O) 2 R z1 ,—S(O) 2 NR z3 R z4 ,—C(O)R z1 ,—C(O)OR z1 ,—C(O)NR z3 R z4 ,—NR z3 R z4 ,—NR z3 R z4 ,—NR z3 R z4 ,—NR z3 R z4 ,—
  • R z2 at each occurrence, is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 haloalkyl. See, for example, U.S. Patent Application Publication No. US 20140256705, which is hereby incorporated by reference in its entirety.
  • exemplary compounds of Formula HHH may be selected from the group consisting of:
  • exemplary bromodomain ligands include a compound represented by the formula:
  • X is N(R a ), O, or S;
  • Y 1 and Y 3 independently, are CH or N;
  • Y 2 is CH, CR a , N, or null; halo, OH, or null;
  • A is an unsubstituted or substituted 5-membered heterocyclic ring
  • B is aryl, CH(R a )-aryl, C 3-10 cycloalkyl, CH(R a )—C 3-10 cycloalkyl, heteroaryl, CH(R a )- heteroaryl, C 3-10 heterocycloalkyl, or CH(R a )—C 3-10 heterocycloalkyl, each unsubstituted or substituted;
  • G is N, O, or S
  • L is null, H, or C(R d ) 3 ;
  • R 1 is H, halo, OH, OR a , or N(R a ) 2 ;
  • R a independently, is H, C 1-3 alkyl, or benzyl
  • R b independently, is C 1-6 alkyl, halo, aryl, unsubstituted or substituted CH 2 -aryl, unsubstituted or substituted C 3-10 cycloalkyl, unsubstituted or substituted
  • heteroaryl unsubstituted or substituted CH 2 -heteroaryl, unsubstituted or substituted C 3- 10 heterocycloalkyl, or unsubstituted or substituted CH 2 —C 3-10 heterocycloalkyl, or CHO;
  • n is an integer 0, 1, 2, or 3;
  • R c and R d are hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted CH 2 -aryl, unsubstituted or substituted C 3-10 cycloalkyl, unsubstituted or substituted CH 2 —C 3-10 cycloalkyl, heteroaryl, unsubstituted or substituted CH 2 - heteroaryl, unsubstituted or substituted C 3-10 heterocycloalkyl, or unsubstituted or substituted CH 2 —C 3-10 heterocycloalkyl;
  • exemplary compounds of Formula III may be selected from the group consisting of:
  • exemplary bromodomain ligands include a compound selected from the rou consistin of:
  • R is 2-methoxyphenyl, 3-methoxyphenyl, phenyl, 2-methylphenyl, t-butyl, or benzyl.
  • exemplary bromodomain ligands include a compound selected from the group consisting of:
  • R is 1-piperidine, 1-pyrrolidine, 4-morpholine, methoxy, methyl, or H.
  • exemplary bromodomain ligands include a compound re resented b the formula:
  • R 1 is C 1-4 alkyl
  • R 2 is C 1-4 alkyl, C 3-7 cycloalkyl, -CH 2 CF 3 , -CH 2 OCH 3 or heterocyclyl;
  • R 3 is C 1-4 alkyl, -CH 2 F, -CH 2 OH or -CH 2 OC(O)CH 3 ;
  • R 4 when present is H, hydroxy, halo, cyano, -CO 2 H, -CONH 2 , -OSO 2 CF 3 , -C(O)N(R 8 ) C 1-4 alkyleneOH, -C(O)N(R 8 )C 1-4 alkyleneOCH 3 , -C(O)N(R 8 )C 1-4 alkyleneNR 6 R 7 , - C(O)N(R 8 )C 1-4 alkyleneSO 2 CH 3 , -C(O)N(R 8 )C 1-4 alkyleneCN, -C(O)NHOH, - C(O)NHCH(CH 2 OH) 2 , -OCH 2 CH 2 OH, -B-C 1-6 alkyl, -B-C 3-7 cycloalkyl, -B
  • R 5 when present is H, halo, hydroxy or Ci-6alkoxy
  • A is -NH-, -O-, -S-, -SO-, -SO 2 -, -N(C 1-4 alkyl)- or -NC(O)(CH 3 )-;
  • B is a bond, -O-, -N(R 8 )-, S, -SO-, -SO 2 -, -SO 2 N(R 8 )-, -CH 2 -, -C(O)-, -CO 2 -, - N(R 8 )C(O)-, -C(O)N(R 8 )-, -C(O)N(R 8 )CH 2 - or -C(O)N(R 8 )CH 2 CH 2 -;
  • V is phenyl, heteroaromatic or pyridone any of which may be optionally substituted by 1, 2 or 3 substituents independently selected from C 1-6 alkyl, fluorine, chlorine, C 1-6 alkoxy, hydroxy, cyclopropyl, cyano, -CO 2 CH 3 , heterocyclyl, -CO 2 H, -CH 2 NR 6 R 7 , -NR 6 R 7 , - C(O)NR 6 R 7 , -NR 6 C(O)R 7 ,-CF 3 , -NO 2 , -CH 2 OCH 3 , -CH 2 OH, -CH(OH)CH 3 , -SO 2 CH 3 , - CH 2 heterocyclyl, -OCH 2 CH 2 NHC(O)CH 3 , -OCH 2 CH 2 OH, -OCH 2 CH 2 NH 2 , - C(O)NHheteroaromatic, -C(O)NHCH 2 heterocyclyl,C
  • R 6 , R 7 , R 8 , R 9 and R 10 are each independently selected from H and C 1-4 alkyl;
  • W is CH or N
  • X is C or N
  • Y is C or N
  • Z is CH orN. See, for example, International Patent Application Publication No.
  • exemplary compounds of Formula JJJ may be selected from the group consisting of:
  • exemplary bromodomain ligands include compounds selected from the group consisting of:
  • exemplary bromodomain ligands include a compound re resented b the formula:
  • Y 1 is N or CH
  • R 1 is CD 3 , C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl
  • R 2 is H or C 1 -C 3 alkyl
  • R 3 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, C 1 -C 6 haloalkyl, CN, - C(O)R 3a , -C(O)OR 3a , -C(O)NR 3b R 3c , -S(O)R 3d , -S(O) 2 R 3a , -S(O) 2 NR 3b R 3c , or G 1 ; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl are each independently unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of G 1 , CN, -C(O)R 3a ,—C(O)OR 3a , -C(O)NR 3b R 3c , -S(O)R 3d ,
  • Y 2 is C(O), S(O) 2 , or CR 4 R 5 ;
  • R 4 is H, deuterium, C 1 -C 6 alkyl, halogen, or C 1 -C 6 haloalkyl
  • R 5 is H, deuterium, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, C 1 -C 6 haloalkyl, -C(O)R 5a , -C(O)OR 5a , -C(O)NR 5b R 5c , -S(O)R 5d , -S(O) 2 R 5a , -S(O) 2 NR 5b R 5c , or G 1 ; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl are each independently unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of G 1 , CN, -C(O)R 5a , -C(O)OR 5a , -C(O)NR 5b R 5c , -C(O)N(R
  • R 3a , R 3b , R 3c , R 5a , and R 5b are each independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, G 1 , or -(C 1 -C 6 alkylenyl)-G 1 ;
  • R 5c is each independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 - C 6 alkynyl, C 1 -C 6 haloalkyl, G 1 , -(C 1 -C 6 alkylenyl)-G 1 , -(C 1 -C 6 alkylenyl)-CN, -(C 1 -C 6 alkylenyl)-OR a , or -(C 1 -C 6 alkylenyl)-C(O)OR a ;
  • R 3d is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 - C 6 haloalkyl, G 1 , or -(C 1 -C 6 alkylenyl)-G 1 ;
  • R 5d is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 - C 6 haloalkyl, G 1 , -(C 1 -C 6 alkylenyl)-G 1 , -(C 1 -C 6 alkylenyl)-NR c R d , or -(C 1 -C 6 alkylenyl)- N(R a )C(O)O(R b );
  • G 1 at each occurrence, is independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; and each G 1 is optionally substituted with 1, 2, 3, 4, or 5 R 1g groups;
  • R 6 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, C 1 -C 6 haloalkyl, -C(O)R 6a , - C(O)OR 6a , -C(O)NR 6b R 6c , -S(O) 2 R 6a , -S(O) 2 NR 6b R 6c , or G 2 ; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl are each independently unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of G 2 , CN, -C(O)R 6a , -C(O)OR 6a , -C(O)NR 6b R 6c , -C(O)N(R 6b )NR 6b R 6c , -S
  • R 6a , R 6b , and R 6c are each independently H, alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, haloalkyl, G 2 , -(C 1 -C 6 alkylenyl)-G 2 , -(C 1 -C 6 alkylenyl)-OR a , -(C 1 -C 6 alkylenyl)-S(O) 2 R a , -(C 1 -C 6 alkylenyl)-S(O) 2 NR c R d , -(C 1 -C 6 alkylenyl)-C(O)R a , -(C 1 -C 6 alkylenyl)-C(O)OR a , -(C 1 -C 6 alkylenyl)-C(O)NR c R d , -(C 1 -C 6
  • R 6d is independently alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, haloalkyl, G 2 , -(C 1 -C 6 alkylenyl)-G 2 , -(C 1 -C 6 alkylenyl)-OR a , -(C 1 -C 6 alkylenyl)-S(O) 2 R a , -(C 1 -C 6 alkylenyl)-S(O) 2 NR c R d , -(C 1 -C 6 alkylenyl)-C(O)R a , -(C 1 -C 6 alkylenyl)-C(O)OR a , -(C 1 -C 6 alkylenyl)-C(O)NR c R d , -(C 1 -C 6 alkylenyl)-NR c R d , -(C
  • G 2 at each occurrence, is independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; and each G 2 is optionally substituted with 1, 2, 3, 4, or 5 R 2g groups;
  • a 1 is C(R 7 ) or N;
  • a 2 is C(R 8 ) or N;
  • a 3 is C(R 9 ) or N; and
  • a 4 is C(R 10 ) or N; wherein zero, one, or two of A 1 , A 2 , A 3 , and A 4 are N;
  • R 7 , R 8 , and R 9 are each independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, C 1 -C 6 haloalkyl,—CN, NO 2 ,—OR y1 ,—OC(O)R y2 ,—OC(O)NR y3 R y4 ,—SR y1 ,— S(O) 2 R y1 ,—S(O) 2 NR y3 R y4 ,—C(O)R y1 ,—C(O)OR y1 ,—C(O)NR y3 R y4 ,—NR y3 R y4 ,—NR y3 R y4 ,—NR y3 R y4 ,—NR y3 R y4 ,—NR y3 R y4 ,—NR y3 R y4 ,—NR y3 R y4
  • R y2 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 - C 6 haloalkyl, G 3 ,—(C 1 -C 6 alkylenyl)-G 3 ,—(C 1 -C 6 alkylenyl)-OR a ,—(C 1 -C 6 alkylenyl)- S(O) 2 R a ,—(C 1 -C 6 alkylenyl)-S(O) 2 NR c R d ,—(C 1 -C 6 alkylenyl)-C(O)R a ,—(C 1 -C 6 alkylenyl)- C(O)OR a ,—(C 1 -C 6 alkylenyl)-C(O)NR c R d ,—(C 1 -C 6 alkylenyl)-NR
  • G 3 is independently aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocycle; and each G 3 group is optionally substituted with 1, 2, 3, 4, or 5 R 4g groups;
  • R 10 is H, C 1 -C 3 alkyl, halogen, C 1 -C 3 haloalkyl, or—CN;
  • R 1g , R 2g , and R 4g at each occurrence, is independently selected from the group consisting of oxo, C 1 -C 6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C 1 -C 6 haloalkyl,—CN, NO 2 , G 2a ,—OR a ,—OC(O)R b ,—OC(O)NR c R d ,—SR a ,—S(O) 2 R a ,—S(O) 2 NR c R d ,—C(O)R a , —C(O)OR a ,—C(O)NR c R d ,—NR c R d ,—N(R e )C(O)R b ,—N(R e )S(O) 2 R b ,—N(R e )C(O)O(R b ), —N(R
  • R a , R c , R d , and R e are each independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, G 2a , or—(C 1 -C 6 alkylenyl)-G 2a ;
  • R b at each occurrence, is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 - C 6 haloalkyl, G 2a , or—( C 1 -C 6 alkylenyl)-G 2a ;
  • 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 is independently oxo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, C 1 -C 6 haloalkyl,—CN, NO 2 ,—OR z1 ,—OC(O)R z2 ,—OC(O)NR z3 R z4 ,— SR z1 ,—S(O) 2 R z1 ,—S(O) 2 NR z3 R z4 ,—C(O)R z1 ,—C(O)OR z1 ,—C(O)NR z3 R z4 ,—NR z3 R z4 ,— N(R z3 )C(O)R z2 ,—N(R z3 )S(O) 2 R z2 ,—N(R z3 )C(O)O(R z2 ),—N(R z3 )
  • R z1 , R z3 , and R z4 are each independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 haloalkyl;
  • R z2 at each occurrence, is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 haloalkyl. See, for example, International Patent Application Publication No.
  • exemplary compounds of Formula KKK may be selected from the group consisting of:
  • exemplary bromodomain ligands include a compound re resented b the formula:
  • Y 1 is CH or N
  • R 1 , R 2 , R 4 , R 6 and R 7 are each independently H, D, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkenyl, optionally substituted C 1-6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted

Abstract

La présente invention concerne des composés capables de moduler une ou plusieurs biomolécules sensiblement simultanément, par exemple moduler au moins deux domaines de liaisons (par exemple des bromodomaines) sur une protéine ou sur différentes protéines. Dans un aspect, par exemple, on décrit un composé bivalent, ou son sel pharmaceutiquement acceptable, son stéréoisomère, son métabolite ou son hydrate. Dans un autre aspect, on décrit une méthode de traitement d'une maladie associée à une protéine présentant des bromodomaines tandem chez un patient qui en a besoin. La méthode consiste à administrer au patient le composé bivalent de l'invention.
PCT/US2014/067748 2013-11-26 2014-11-26 Ligands bromodomaines bivalents et procédés d'utilisation de ceux-ci WO2015081284A1 (fr)

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US9951074B2 (en) 2014-08-08 2018-04-24 Dana-Farber Cancer Institute, Inc. Dihydropteridinone derivatives and uses thereof
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US10308653B2 (en) 2014-08-08 2019-06-04 Dana-Farber Cancer Institute, Inc. Diazepane derivatives and uses thereof
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US10793571B2 (en) 2014-01-31 2020-10-06 Dana-Farber Cancer Institute, Inc. Uses of diazepane derivatives
US10881668B2 (en) 2015-09-11 2021-01-05 Dana-Farber Cancer Institute, Inc. Acetamide thienotriazolodiazepines and uses thereof
US10913752B2 (en) 2015-11-25 2021-02-09 Dana-Farber Cancer Institute, Inc. Bivalent bromodomain inhibitors and uses thereof
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WO2021065980A1 (fr) 2019-09-30 2021-04-08 協和キリン株式会社 Agent de dégradation de bet
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US10676484B2 (en) 2010-05-14 2020-06-09 Dana-Farber Cancer Institute, Inc. Compositions and methods for treating leukemia
US9789120B2 (en) 2010-05-14 2017-10-17 Dana-Farber Cancer Institute, Inc. Male contraceptive compositions and methods of use
US9975896B2 (en) 2013-07-25 2018-05-22 Dana-Farber Cancer Institute, Inc. Inhibitors of transcription factors and uses thereof
US11446309B2 (en) 2013-11-08 2022-09-20 Dana-Farber Cancer Institute, Inc. Combination therapy for cancer using bromodomain and extra-terminal (BET) protein inhibitors
US10150756B2 (en) 2014-01-31 2018-12-11 Dana-Farber Cancer Institute, Inc. Diaminopyrimidine benzenesulfone derivatives and uses thereof
US10730860B2 (en) 2014-01-31 2020-08-04 Dana-Farber Cancer Institute, Inc. Diaminopyrimidine benzenesulfone derivatives and uses thereof
US10793571B2 (en) 2014-01-31 2020-10-06 Dana-Farber Cancer Institute, Inc. Uses of diazepane derivatives
US10925881B2 (en) 2014-02-28 2021-02-23 Tensha Therapeutics, Inc. Treatment of conditions associated with hyperinsulinaemia
US10308653B2 (en) 2014-08-08 2019-06-04 Dana-Farber Cancer Institute, Inc. Diazepane derivatives and uses thereof
US9951074B2 (en) 2014-08-08 2018-04-24 Dana-Farber Cancer Institute, Inc. Dihydropteridinone derivatives and uses thereof
US10124009B2 (en) 2014-10-27 2018-11-13 Tensha Therapeutics, Inc. Bromodomain inhibitors
US10702527B2 (en) 2015-06-12 2020-07-07 Dana-Farber Cancer Institute, Inc. Combination therapy of transcription inhibitors and kinase inhibitors
US11306105B2 (en) 2015-09-11 2022-04-19 Dana-Farber Cancer Institute, Inc. Cyano thienotriazolodiazepines and uses thereof
US11406645B2 (en) 2015-09-11 2022-08-09 Dana-Farber Cancer Institute, Inc. Acetamide thienotriazolodiazepines and uses thereof
US10881668B2 (en) 2015-09-11 2021-01-05 Dana-Farber Cancer Institute, Inc. Acetamide thienotriazolodiazepines and uses thereof
US10913752B2 (en) 2015-11-25 2021-02-09 Dana-Farber Cancer Institute, Inc. Bivalent bromodomain inhibitors and uses thereof
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US11629152B2 (en) 2018-03-30 2023-04-18 Kyowa Kirin Co., Ltd. Compound with anticancer activity
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