WO2015081284A1 - Bivalent bromodomain ligands, and methods of using same - Google Patents

Bivalent bromodomain ligands, and methods of using same Download PDF

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Publication number
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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French (fr)
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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

Described herein are compounds capable of modulating one or more biomolecules substantially simultaneously, e.g., modulating two or more binding domains (e.g., bromodomains) on a protein or on different proteins. For example, in one aspect, a bivalent compound or a pharmaceutically acceptable salt, stereoisomer, metabolite, or hydrate thereof is provided. In another aspect, a method of treating a disease associated with a protein having tandem bromodomains in a patient in need thereof is provided. The method comprises administering to the patient the bivalent compound as described.

Description

BIVALENT BROMODOMAIN LIGANDS, AND METHODS OF USING SAME
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims priority to and the benefit of U.S. Provisional Patent Application No. 61/909,245, filed on November 26, 2013, and entitled“Bivalent Bromodomain Ligands, and Methods Of Using Same,” the entirety of which is incorporated by reference herein. BACKGROUND
[0002] Current drug design and drug therapies have not addressed the urgent need for therapies that interact with extended areas or multiple domains of biomolecules such as proteins. For example, few therapies exist that can modulate protein-protein interactions, e.g., by interacting, simultaneously, with two domains on a single protein or with both a domain on one protein and a domain on another protein. There is also an urgent need for such therapies that modulate fusion proteins, such as those that occur in cancer.
[0003] Signaling pathways are used by cells to generate biological responses to external or internal stimuli. A few thousand gene products control both ontogeny/development of higher organisms and sophisticated behavior by their many different cell types. These gene products can work in different combinations to achieve their goals and often do so through protein-protein interactions. Such proteins possess modular protein domains that recognize, bind, and/or modify certain motifs. For example, some proteins include tandem or repeating domains.
[0004] The BET family of bromodomain containing proteins bind to acetylated 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. Further, proteins having tandem bromodomains such as BRD4 may be suitable as a drug target for other indications such as acute myeloid leukemia. Bromodomains are typically small domains having e.g., about 110 amino acids. Bromodomain modulators may be useful for 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.
[0005] Current drug design and drug therapy approaches typically focus on modulating one protein domain with limited selectivity and do not address the urgent need to find drugs that are capable of modulating such tandem domains substantially simultaneously in order to further improve on specificity and potency. Although antibodies and other biological therapeutic agents may have sufficient specificity to distinguish among closely related protein surfaces, factors such as their high molecular weight prevent oral administration and cellular uptake of the antibodies. Conversely, orally active pharmaceuticals are generally too small to effectively disrupt protein-protein surface interactions, which can be much larger than the orally active pharmaceuticals. SUMMARY
[0006] Described herein, for example, are compounds capable of modulating one or more biomolecules substantially simultaneously, e.g., modulate two or more binding domains on a protein or on different proteins.
[0007] For example, in one aspect, a bivalent compound of the formula:
Figure imgf000003_0001
or a pharmaceutically acceptable salt, stereoisomer, metabolite, or hydrate thereof is provided; wherein:
Q1 is a connecting moiety covalently bound to P1 and P2, wherein Q1 is selected from the group consisting of -Si(R7)(R8)-, -Si(R7)(R8)-O-, -O-Si(R7)(R8)-, -NR’-, -N(R’)C(O)-, - C(O)N(R’)-, -N(R’)SO2-, -SO2N(R’)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO-, -SO2-, - C(=S)-, -C(=NR’)-, aliphatic, heteroaliphatic, phenyl, naphthyl, heterocyclyl, heteroaryl, or a covalently bonded combination thereof; wherein P1 and P2 are as defined below.
[0008] In another aspect, a method of treating a disease associated with a protein having tandem bromodomains in a patient in need thereof is provided. The method comprises administering to the patient the bivalent compound as described above. BRIEF DESCRIPTION OF THE DRAWINGS
[0009] 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.
[0010] FIG. 2 shows a non-limiting set of pharmacophores (i.e., ligands) with preferred attachment points for connecting the pharmacophores to connecting moieties indicated by arrows, according to an embodiment. DETAILED DESCRIPTION
[0011] 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.
[0012] Advantageously, 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. For example, 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. In some embodiments, contemplated bivlalent compounds may bind to a target with greater affinity as compared to an individual ligand moiety binding affinity alone. Also contemplated herein, in some embodiments, is a bivalent compound that, e.g., may be capable of modulating tandem bromo domains.
[0013] In an exemplary embodiment, disclosed bivalent compounds may bind to a first target biomolecule domain and a second target biomolecule domain (e.g., protein domains). In one embodiment, the first target binding domain and the second target bidning domain can be tandem domains on the same target, for example, tandem BET bromodomains. In another embodiment, 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, in some cases, may be a pharmacophore or a ligand moiety that is, e.g., capable of binding to and/or modulating a biomolecule, such as, for example, a protein, e.g, a specific protein domain, a component of a biological cell, such as a ribosome (composed of proteins and nucleic acids) or an enzyme active site (e.g., a protease, such as tryptase). 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. As described in more detail below, in some embodiments, the bivalent compound may bind to or modulate a target biomolecule, such as a protein, nucleic acid, or polysaccharide. In certain embodiments, a contemplated bivalent compound may be used as a pharmaceutical.
[0014] In some embodiments, the first ligand moiety and the second ligand moiety may be capable of binding to a bromodomain. For example, in some embodiments, 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,
ZMYND8, ZMYND11, ASH1L, PBRM D3, PBRM D1, PBRM D2, PBRM D4, PBRM D5, SMARCA2, SMARCA4 ySnf2, ySth, PBRM D6, yRsc1 D2, yRsc2 D2, yRsc1 D1, yRsc2 D1, yRsc4 D1, BRWD1 D1, BRWD3 D1, PHIP D1, MLL, MLL4, BRWD2, ATAD2, ATAD2B, BRD1, BRPF1, BRPF3, BRD7, BRD9, BAZ1B, BRWD1 D2, PHIP D2, BRWD3, CREBBP, EP300 BRD8 D1, BRD8 D2, yRsc4 D2, ySpt7, BAZ1A, BAZ2A, BAZ2B, SP140, SP140L, TRIM28, TRIM24, TRIM33, TRIM66, BPTF, GCN5L2, PCAF, yGcn5, BRD2 D1, BRD3 D1, BRD4 D1, BRD-t D1 and CECR2. Reference to protein and domain names used herein are derived from Zhang Q, Chakravarty S, Ghersi D, Zeng L, Plotnikov AN, et al. (2010)
Biochemical Profiling of Histone Binding Selectivity of the Yeast Bromodomain Family. PLoS ONE 5(1): e8903. doi:10.1371/journal.pone.0008903. In some embodiments contemplated 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.
[0015] In some cases, 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
[0016] ments, bivalent compounds of formula I are provided:
Figure imgf000006_0001
and pharmaceutically acceptable salts, stereoisomers, metabolites, and hydrates thereof, wherein:
P1 is a first ligand capable of modulating a first bromodomain;
P2 is a second ligand capable of modulating a second bromodomain; and
Q1 is a connecting moiety covalently bound to P1 and P2 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.
[0017] In some embodiments, 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). In some embodiments, identification of a pharmacophore may be facilitated by knowing the structure of the ligand in association with a target biomolecule. In some cases, pharmacophores may be moieties derived from molecules previously known to bind to target biomolecules (e.g., proteins), fragments identified, for example, through NMR or crystallographic screening efforts, molecules that have been discovered to bind to target proteins after performing high- throughput screening of natural products libraries, previously synthesized commercial or non-commercial combinatorial compound libraries, or molecules that are discovered to bind to target proteins by screening of newly synthesized combinatorial libraries. Since most pre-existing combinatorial libraries are limited in the structural space and diversity that they encompass, newly synthesized combinatorial libraries may include molecules that are based on a variety of scaffolds.
[0018] In one embodiment, 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. For example, a“BET bromodomain” may refer to the bromodomains in BRD2, BRD3, BRD4 or BRD-t. One of ordinary skill in the art will appreciate that additional pharmacophores may be discovered in the future and that the pharmacophores illustrated herein are not intended to be limiting in any way.
[0019] In some embodiments, a ligand (e.g., a pharmacophore) may have one or more preferred attachment points for connecting the pharmacophore to the connecting moiety. In certain embodiments, an attachment point on a pharmacophore may be chosen so as to preserve at least some ability of the pharmacophore to bind to a bromodomain. In one embodiment, preferred attachment points may be identified using X-ray crystallography. The following description of a non-limiting exemplary method illustrates how a preferred attachment point may be identified. For example, as shown in FIG. 1, using the 3P5O structure 100 from the protein databank (PDB), a small molecule 110 (dark gray) labeled“EAM1” in the PDB file [also known as I-BET or IBET762] may be identified. The I-BET triazolo ring (indicated by white circle 120) contains two adjacent nitrogen atoms in the 3 and 4 positions and a methyl group 130 bound to the adjacent carbon at the 5 position. Together, the nitrogen atoms and methyl group constitute an acetyl lysine mimetic. The corresponding acetyl lysine mimetic in the new pharmacophore 140 (light gray) should be aligned to these elements. The final conformation and orientation of the newly aligned pharmacophore 140 in the site may be determined using a variety of approaches known to computational chemists, but can be done as simply as performing an energy minimization using a molecular mechanics forcefield. It should be noted that the alphanumeric identifiers in FIG. 1 (e.g., K141, D144, M149, etc.) correspond to amino acid residues in the 3P5O structure, where the letter of the identifier is the one-letter amino acid symbol and the number of the identifier is the position of the amino acid residue in the primary sequence of the protein. Attachment points 150 on the aligned pharmacophore which permit access to amino acid residues D96, Y139, N140, K141, D144, D145, M149, W81, or Q85 in the 3P5O structure are considered preferred attachment points for 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.
[0020] 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. It will be appreciated that 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:
Figure imgf000008_0001
Formula G wherein:
X is O or S;
R1 is C1-6alkyl, haloC1-6alkyl, -(CH2)nOR1a, or -(CH2)mNR1bR1c; wherein R1a is hydrogen, C1-6alkyl or haloC1-6alkyl; R1b and R1c, which may be the same or different, are hydrogen, C1-6alkyl or haloC1-6alkyl; and m and n, which may be the same or different, are 1, 2 or 3;
R2 is R2a, -OR2b, or -NR2cR2d; wherein R2a and R2b are carbocyclyl, carbocyclylC1- 4alkyl, heterocyclyl or heterocyclylC1-4alkyl, or R2a is carbocyclylethenyl or
heterocyclylethenyl, wherein any of the carbocyclyl or heterocyclyl groups defined for R2a or R2b are optionally substituted by one or more groups independently selected from the group consisting of halogen, C1-6alkyl, haloC1-6alkyl, C1-6alkoxy, haloC1-6alkoxy, nitro, cyano, dimethylamino, benzoyl and azido; or two adjacent groups on any of the carbocyclyl or heterocyclyl groups defined for R2a or R2b 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
R2a and R2b are C1-6alkyl or haloC1-6alkyl; and R2c and R2d, which may be the same or different, are carbocyclyl, carbocyclylC1-4alkyl, heterocyclyl or heterocyclylC1-4alkyl, wherein any of the carbocyclyl or heterocyclyl groups defined for R2c or R2d are optionally substituted by one or more groups independently selected from the group consisting of halogen, C1-6alkyl, haloC1-6alkyl, C1-6alkoxy, haloC1-6alkoxy, nitro, cyano and -CO2C1-4alkyl; or two adjacent groups on any of the carbocyclyl or heterocyclyl groups defined for R2c and R2d 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
R2c and R2d are independently hydrogen, C1-6alkyl or haloC1-6alkyl; R3 is C1-6alkyl, phenyl, naphthyl, heteroaryl carbocyclyl or heterocyclyl, optionally substituted independently by one or more substitutents selected from the group consisting of halogen,–SR, -S(O)R’, -NHR’, -OR’, C1-6alkyl, haloC1-6alkyl, C1-6alkoxy, haloC1-6alkoxy, nitro and cyano;
R’ is H or C1-6alkyl;
* denotes a chiral center;
A is a benzene or aromatic heterocyclic ring, each of which is optionally substituted; and
n is 0, 1 or 2. In some embodiments, the chiral center has an R configuration.
[0021] In some embodiments, compounds of Formula F or Formula G may be selected from the group consisting of:
Figure imgf000009_0001
Figure imgf000010_0001
[0022] In another embodiment, exemplary bromodomain ligands include
benzodiazepines represented by the structures:
N N N
Formula I and
Figure imgf000010_0002
wherein:
X is phenyl, naphthyl, or heteroaryl;
R1 is C1-3alkyl, C1-3alkoxy or -S- C1-3alkyl;
R2 is -NR2aR2a' or -OR2b; wherein one of R2a or R2a’ is hydrogen, and R2b or the other of R2a or R2a’ is selected from the group consisting of C1-6alkyl, haloC1-6alkyl, R2cR2c’N-C2-6alkyl, carbocyclyl, carbocyclyloC1-4alkyl, heterocyclyl and heterocyclylC1-4alkyl, wherein any of the carbocyclyl or heterocyclyl groups are optionally substituted by one or more substituents selected from the group consisting of halogen, C1-6alkyl, haloC1-6alkyl, C1-6alkoxy, haloC1- 6alkoxy, carbonyl, -CO-carbocyclyl, azido, amino, hydroxyl, nitro and cyano, wherein the– CO-carbocyclyl group may be optionally substituted by one or more substituents selected from the group consisting of halogen, C1-6alkyl, haloC1-6alkyl, C1-6alkoxy, haloC1-6alkoxy, azido, nitro and cyano; or
two adjacent groups on any of the carbocyclyl or heterocyclyl groups together with the interconnecting atoms form a 5- or 6-membered ring which ring may contain 1 or 2 heteroatoms independently selected from the group consisting of O, S and N; or R2a and R2a’ together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered ring which optionally contains 1 or 2 heteroatoms independently selected from the group consisting of O, S and N; wherein the 4-, 5-, 6 or 7-membered ring is optionally substituted by C1-6alkyl, hydroxyl or amino;
R2c and R2c’ are independently hydrogen or C1-6alkyl;
each R3 is independently selected from the group consisting of hydrogen, hydroxyl, thiol, sulfinyl, sulfonyl, sulfone, sulfoxide, -ORt, -NRtRtt, -S(O)2NRtRtt, -S(O)wRtRtt (where t and tt are independently selected from H, phenyl or C1-6alkyl, and w is 0, 1, or 2), halo, C1- 6alkyl, haloC1-6alkyl, C1-6alkoxy, haloC1-6alkoxy, nitro, cyano, CF3, -OCF3, -COOR5, -C1- 4alkylamino , phenoxy, benzoxy, and C1-4alkylOH;
XX is selected from the group consisting of a bond, NR’’’ (where R’’’ is H, C1-6alkyl or phenyl), -O-, or S(O)w wherein w is 0, 1 or 2, and C1-6alkyl; (and wherein in some
embodiments XX is in the para position);
each R4 is hydroxyl, halo, C1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl, haloC1-6alkyl, C1-6alkoxy, haloC1-6alkoxy, acylaminoC1-6alkyl, nitro, cyano, CF3, -OCF3, -COOR5; - OS(O)2C1-4alkyl, phenyl, naphthyl, phenyloxy, benzyloxy or phenylmethoxy, wherein C1- 6alkyl, phenyl, and naphthyl are optionally substituted by one two or three substituents selected from the group consisting of hydroxyl, halogen, amino, nitro;
R5 is C1-3alkyl;
* denotes a chiral center;
m is an integer 1 to 3; and
n is an integer 1 to 5. In some embodiments, the chiral center has an S configuration.
[0023] In some embodiments, compounds of Formula H or Formula I may be selected from the group consisting of:
Figure imgf000012_0001
.
[0024] For example, compounds of Formula F, Formula G, Formula H or Formula I may be selected from the group consisting of: ,
Figure imgf000013_0001
[0025] In some embodiments, exemplary bromodomain ligands include compounds represented by the structures:
Formula A1, or
Figure imgf000013_0002
Formula A2,
wherein:
R4 is hydrogen, cyano or C1-6 alkyl;
A is selected from the group consisting of:
Figure imgf000013_0003
; Rx is O, NR2a, or S;
R1 is C1-6alkyl, C3-6cycloalkyl, a 5 or 6 membered heterocyclyl, an aromatic group or a heteroaromatic group, wherein the aromatic group or the heteroaromatic group is optionally substituted by one to three groups selected from the group consisting of halogen, hydroxy, cyano, nitro, C1-6alkyl, C1-4alkoxy, haloC1-4alkyl, haloC1-4alkoxy, hydroxyC1-4alkyl, C1-4alkoxy C1-4alkyl, C1-4alkoxycarbonyl, C1-4alkylsulfonyl, C1-4alkylsulfonyloxy, C1-4alkylsulfonyl C1- 4alkyl and C1-4alkylsulfonamido;
R2 is hydrogen or C1-6alkyl;
R2a is selected from the group consisting of H, C1-6alkyl, C1-6haloalkyl, (CH2)mcyano, (CH2)mOH, (CH2)mC1-6alkoxy, (CH2)mC1-6haloalkoxy, (CH2)mC1-6haloalkyl,
(CH2)mC(O)NRaRb, (CH2)mNRaRb and (CH2)m C(O)CH3, (CHR6)pphenyl optionally substituted by C1-6alkyl, C1-6alkoxy, cyano, halo C1-4alkoxy, haloC1-4alkyl, (CHR6)pheteroaromatic, (CHR6)pheterocyclyl; wherein Ra is H, C1-6alkyl, or heterocyclyl; wherein Rb is H or C1-6alkyl, or
Ra and Rb together with the N to which they are attached form a 5 or 6 membered heterocyclyl;
R2b is H, C1-6alkyl, (CH2)2C1-6alkoxy, (CH2)2cyano, (CH2)mphenyl or
(CH2)2heterocyclyl;
R3 is hydrogen;
R6 is hydrogen or C1-6alkyl;
m is 0, 1, 2 or 3;
n is 0, 1 or 2; and
p is 0, 1 or 2.
[0026] In some embodiments, compounds of Formulae A, A1, and A2 may be selected from the group consisting of:
Figure imgf000015_0001
[0027] In another embodiment, exemplary bromodomain ligands include
tetrahydroquinolines represented by the structures:
Figure imgf000015_0002
wherein:
A is a bond, C1-4alkyl or–C(O)-;
X is:
i) a 6 to 10 membered aromatic group, or
ii) a 5 to 10 membered heteroaromatic comprising 1, 2 or 3 heteroatoms selected from the group consisting of O, N and S;
R1 is: i) phenyl optionally substituted by 1 or 2 substituents independently selected from the group consisting of halogen, cyano, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, - SO2C1-6alkyl and -COR7,
ii) a 5 to 10 membered heteroaromatic comprising 1, 2 or 3 heteroatoms selected from the group consisting of O, N and S optionally substituted by 1 or 2 substituents independently selected from the group consisting of halogen, cyano, C1-6alkyl, C1- 6haloalkyl, C1-6alkoxy and -COR7, or
iii) C1-6alkyl, C0-6alkylcyano, C0-6alkylC1-6alkoxy, C0-2alkylC(O)R7 or cyclohexyl;
R2 is C1-6alkyl;
R3 is C1-6alkyl;
R4 is:
i) H, halogen, cyano, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C0-6hydroxyalkyl, -SO2C1-6alkyl, -C(O)NR8R9, -C(O)R10, -C0-6alkyl-NR11R12, or
ii) -OmC1-6alkyl substituted by a 5 or 6 membered heterocyclyl or heteroaromatic each comprising 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O and S and wherein said hetercyclyl or heteroaromatic is optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of halogen, cyano, C1-6alkyl, C1-6haloalkyl and C1-6alkoxy, wherein m is 0, 1 or 2, wherein when the heterocyclyl or heteroatomic is linked through a heteroatom and m is 1, then the heteroatom and O are not directly linked if the resultant arrangement would be unstable;
R4a is H, halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy or C0-6hydroxyalkyl;
R5 is H, halogen, C1-6alkyl or C1-6alkoxy;
R6 is H, C1-6alkyl, C0-6alkylcyano, C0-6alkylC1-6alkoxy or C0-2alkylC(O)R7;
R7 is hydroxyl, C1-6alkoxy, -NH2, -NHC1-6alkyl or N(C1-6alkyl)2;
R8 and R9 independently are:
i) H, C1-6alkyl, C0-6alkylphenyl, C0-6alkylheteroaromatic, C3-6cycloalkyl, or ii) R8 and R9 together with the N to which they are attached form a 5 or 6 membered heterocyclyl or heteroaromatic wherein said heterocyclyl or heteroaromatic may comprise 1, 2 or 3 further heteroatoms independently selected from the group consisting of O, N and S; R10 is hydroxyl, C1-6alkoxy or a 5 or 6 membered heterocyclyl or heteroaromatic comprising 1, 2, 3 or 4 heteroatoms selected from the group consisting of O, N and S;
R11and R12 independently are:
i) H, C1-6alkyl; or
ii) R11 and R12 together with the N to which they are attached form a 5 or 6 membered heterocyclyl or heteroaromatic wherein said heterocyclyl or heteroaromatic may comprise 1, 2 or 3 further heteroatoms independently selected from the group consisting of O, N and S.
[0028] In certain embodiments, compounds of Formula B or Formula C may be selected from the group consisting of:
, and
Figure imgf000017_0001
O O O .
[0029] In another embodiment, exemplary bromodomain ligands include
tetrahydroquinolines represented by the structures:
[0030]
Figure imgf000017_0002
Figure imgf000017_0003
wherein:
R1 is C1-6alkyl, C3-7cycloalkyl or benzyl;
R2 is C1-4alkyl;
R3 is C1-4alkyl;
X is phenyl, naphthyl, or heteroaryl;
R4a is hydrogen, C1-4alkyl or is a group L-Y in which L is a single bond or a C1- 6alkylene group and Y is OH, OMe, CO2H, CO2C1-6alkyl, CN, or NR7R8;
R7 and R8 are independently hydrogen, a heterocyclyl ring, C1-6alkyl optionally substituted by hydroxyl, or a heterocyclyl ring; or
R7 and R8 combine together to form a heterocyclyl ring optionally substituted by C1- 6alkyl, CO2C1-6alkyl, NH2, or oxo;
R4b and R4c are independently hydrogen, halogen, C1-6alkyl, or C1-6alkoxy;
R4d is C1-4alkyl or is a group -L-Y- in which L is a single bond or a C1-6alkylene group and Y is -O-, -OCH2-, -CO2-, -CO2C1-6alkyl-, or–N(R7)-;
R5 is hydrogen, halogen, C1-6alkyl, or C1-6alkoxy;
R6 is hydrogen or C1-4alkyl.
[0031] In some cases, compounds of Formula D or Formula E may be selected from the rou consistin of:
Figure imgf000018_0001
[0032] For example, compounds of Formula A, Formula B, Formula C, Formula D or Formula E may be selected from the group consisting of:
Figure imgf000019_0001
[0033] In another embodiment, exemplary bromodomain ligands are represented by the structures:
Figure imgf000019_0002
, where X is O, NR4, or S, and R4 is independently selected from the
Figure imgf000019_0003
group consisting of hydrogen, hydroxyl, halo, amino, thiol, C1-6alkyl, haloC1-6alkyl, C1-6alkoxy, -NH-C1-6alkyl, -S-C1-6alkyl, haloC1-6alkoxy, nitro, cyano, -CF3, -OCF3, -C(O)O-C1-6alkyl, -C1- 4alkylamino , phenoxy, benzoxy, and C1-4alkylOH;
Figure imgf000020_0001
[0034] In another embodiment, exemplary bromodomain ligands include heterocycles re resented b the structures:
Figure imgf000020_0002
wherein:
A is independently, for each occurrence, a 4-8 membered cycloalkyl, heterocyclic, phenyl, naphthyl, or heteroaryl moiety, each optionally substituted with one, two, three or more R1 substituents;
R1 is selected from the group consisting of hydroxy, halogen, oxo, amino, imino, thiol, sulfanylidene, C1-6alkyl, hydroxyC1-6alkyl, -O-C1-6alkyl,–NH-C1-6alkyl, -CO2H, -C(O)C1- 6alkyl,–C(O)O-C1-6alkyl, aminoC1-6alkyl, haloC1-6alkyl, -C1- 6alkylC(O)R2
, -O-C(O)R2, -NH-C(O)R2, -O-C1-6alkyl-C(O)R2, -NHC1-6alkyl-C(O)R2, acylaminoC1-6alkyl, nitro, cyano, CF3, -OCF3, -OS(O)2C1-6alkyl, phenyl, naphthyl, phenyloxy, -NH-phenyl, benzyloxy, and phenylmethoxy halogen; wherein C1-6alkyl, phenyl, and naphthyl are optionally substituted by one two or three substituents selected from the group consisting of hydroxyl, halogen, amino, nitro, phenyl and C1-6alkyl; or two R1 substitutents may be taken together with the atoms to which they are attached to form a fused aliphatic or heterocyclic bicyclic ring system;
R2 is -NR2aR2a' or -OR2b; wherein one of R2a or R2a’ is hydrogen, and R2b or the other of R2a or R2a’ is selected from the group consisting of C1-6alkyl, haloC1-6alkyl, R2cR2c’N-C2-6alkyl, carbocyclyl, carbocyclyloC1-4alkyl, heterocyclyl and heterocyclylC1-4alkyl, wherein any of the carbocyclyl or heterocyclyl groups are optionally substituted by one or more substituents selected from the group consisting of halogen, C1-6alkyl, haloC1-6alkyl, C1-6alkoxy, haloC1- 6alkoxy, carbonyl, -CO-carbocyclyl, azido, amino, hydroxyl, nitro and cyano, wherein the– CO-carbocyclyl group may be optionally substituted by one or more substituents selected from the group consisting of halogen, C1-6alkyl, haloC1-6alkyl, C1-6alkoxy, haloC1-6alkoxy, azido, nitro and cyano; or
two adjacent groups on any of the carbocyclyl or heterocyclyl groups together with the interconnecting atoms form a 5- or 6-membered ring which ring may contain 1 or 2 heteroatoms independently selected from the group consisting of O, S and N; or R2a and R2a’ together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered ring which optionally contains 1 or 2 heteroatoms independently selected from the group consisting of O, S and N; wherein the 4-, 5-, 6 or 7-membered ring is optionally substituted by C1-6alkyl, hydroxyl or amino;
R2c and R2c’ are independently hydrogen or C1-6alkyl;
B is selected from the rou consistin of: ,
,
Figure imgf000021_0001
.
[0035] In one embodiment, compounds of Formula J may be selected from the group consisting of:
Figure imgf000022_0001
wherein:
Q is independently, for each occurrence, N or CH;
V is independently, for each occurrence, O, S, NH, or a bond; and
R4 is independently selected from the group consisting of hydrogen, hydroxyl, halo, amino, thiol, C1-6alkyl, haloC1-6alkyl, C1-6alkoxy, -NH-C1-6alkyl, -S-C1-6alkyl, haloC1-6alkoxy, nitro, cyano, -CF3, -OCF3, -C(O)O-C1-6alkyl, -C1-4alkylamino , phenoxy, benzoxy, and C1- 4alkylOH.
[0036] For example, compounds of Formula J or Formula L may be selected from the group consisting of:
,
Figure imgf000022_0002
Figure imgf000023_0001
Figure imgf000024_0001
wherein:
R is independently, for each occurrence, N or CH;
V is independently, for each occurrence, a bond, O or NR4;
R4 is independently, for each occurrence, hydrogen, hydroxyl, halo, amino, -SO2, thiol, C1-6alkyl, haloC1-6alkyl, C1-6alkoxy, -NH-C1-6alkyl, -S-C1-6alkyl, haloC1-6alkoxy, nitro, cyano, - CF3, -OCF3, -C(O)O-C1-6alkyl, -C1-6alkylamino , phenoxy, benzoxy, phenyl, naphthyl, heteroaryl and C1-4alkylOH; wherein C1-6alkyl, phenyl, and naphthyl are optionally substituted with 1, 2, 3 or more substituents selected from the group consisting of halogen, hydroxyl, amino and C1-6alkyl; and W is independently, for each occurrence,
Figure imgf000024_0002
, O, S, or NR4.
[0037] In another embodiment, compounds of Formula M may be selected from the group consisting of:
Figure imgf000025_0001
wherein:
B is selected from the group consisting of:
Figure imgf000025_0002
Q is independently, for each occurrence, N or CH;
V is independently, for each occurrence, O, S, NR4, or a bond; and
R4 is independently selected from the group consisting of hydrogen, hydroxyl, halo, amino, thiol, C1-6alkyl, haloC1-6alkyl, C1-6alkoxy, -NH-C1-6alkyl, -S-C1-6alkyl, haloC1-6alkoxy, nitro, cyano, -CF3, -OCF3, -C(O)O-C1-6alkyl, -C1-4alkylamino , phenoxy, benzoxy, and C1- 4alkylOH.
[0038] For example, compounds of Formula J, Formula K, Formula L or Formula M may be selected from the group consisting of:
Figure imgf000026_0001
wherein:
Q is independently, for each occurrence, N or CH;
V is independently, for each occurrence, O, S, NR4, or a bond;
W is independently, for each occurrence, H, halogen, C1-6alkyl,
Figure imgf000026_0002
-NH-C1- 6alkyl, or -S-C1-6alkyl; and
R4 is independently selected from the group consisting of hydrogen, hydroxyl, halo, amino, thiol, C1-6alkyl, haloC1-6alkyl,
Figure imgf000026_0003
-NH-C1-6alkyl, -S-C1-6alkyl, haloC1-6alkoxy, nitro, cyano, -CF3, -OCF3, -C(O)O-C1-6alkyl, -C1-4alkylamino , phenoxy, benzoxy, and C1- 4alkylOH.
[0039] In another embodiment, exemplary bromodomain ligands include compounds represented by the structures:
Figure imgf000027_0001
Formula O, wherein:
R1 is selected from the group consisting of hydrogen, lower alkyl, phenyl, naphthyl, aralkyl, heteroalkyl, SO2, NH2, NO2, CH3, CH2CH3, OCH3, OCOCH3, CH2COCH3, OH, CN, and halogen;
R2 is selected from the group consisting of hydrogen, lower alkyl, aralkyl, heteroalkyl, phenyl, naphthyl, SO2, NH2, NH +
3 , NO2, CH3, CH2CH3, OCH3, OCOCH3, CH2COCH3, OH, halogen, carboxy, and alkoxy;
X is selected from the group consisting of lower alkyl, SO2, NH, NO2, CH3, CH2CH3, OCH3, OCOCH3, CH2COCH3, OH, carboxy, and alkoxy; and
n is an integer from 0 to 10.
[0040] For example, compounds of Formula N or Formula O may be selected from the group consistin of:
Figure imgf000027_0002
Formula O
Figure imgf000027_0003
Figure imgf000028_0001
[0041] For example, see Chemistry&Biology 13:81 (2006) and International Patent Application Publication Nos. WO2007084625 and WO2012116170, each of which is hereby incor orated b reference in its entiret .
,
Figure imgf000028_0002
[0043] In some embodiments, a ligand may be selected from the group consisting of:
Figure imgf000028_0003
,
Figure imgf000029_0001
[0044] In yet another embodiment, exemplary bromodomain ligands include com ounds re resented b the structures:
Figure imgf000029_0002
wherein: R1, R2, R3, R4, R5, and R6 are independently selected from the group consisting of hydrogen, lower alkyl, phenyl, naphthyl, aralkyl, heteroaryl, SO2, NH2, NH +
3 , NO2, SO2, CH3, CH2CH3, OCH3, OCOCH3, CH2COCH3, OCH2CH3, OCH(CH3)2, OCH2COOH,
OCHCH3COOH, OCH2COCH3, OCH2CONH2, OCOCH(CH3)2, OCH2CH2OH, OCH2CH2CH3, O(CH2)3CH3, OCHCH3COOCH3, OCH2CON(CH3)2, NH(CH2)3N(CH3)2, NH(CH2)2N(CH3)2, NH(CH2)2OH, NH(CH2)3CH3, NHCH3, SH, halogen, carboxy, and alkoxy.
[0045] In some embodiments, compounds of Formula P, Formula Q, Formula R, or Formula S ma be selected from the rou consistin of:
Figure imgf000030_0001
Figure imgf000031_0001
[0046] For example, the compound may be selected from the group consisting of:
,
Figure imgf000032_0001
[0047] In still another embodiment, exemplary bromodomain ligands include com ounds re resented by the structure:
Figure imgf000032_0002
Formula T,
wherein:
R1, R2, and R3 are independently selected from the group consisting of hydrogen, lower alkyl, phenyl, naphthyl, aralkyl, heteroaryl, SO2, NH2, NH +
3 , NO2, SO2, CH3, CH2CH3, OCH3, OCOCH3, CH2COCH3, OH, SH, halogen, carboxy, and alkoxy; R4 is selected from the group consisting of lower alkyl, phenyl, naphthyl, SO2, NH, NO2, CH3, CH2CH3, OCH3, OCOCH3, CH2COCH3, OH, carboxy, and alkoxy.
In yet another embodiment, exemplary bromodomain ligands include compounds represented by the structures:
Figure imgf000032_0003
Formula U and Formula V,
or a pharmaceutically acceptable salt thereof,
wherein:
X is O or N;
Y is O or N; wherein at least one of X or Y is O; W is C or N;
R1 is H, alkyl, alkenyl, alkynyl, aralkyl, phenyl, naphthyl, heteroaryl, halo, CN, ORA, NRARB,
N(RA)S(O)qRARB, N(RA)C(O)RB, N(RA)C(O)NRARB, N(RA)C(O)ORA,
N(RA)C(S)NRARB, S(O)qRA, C(O)RA, C(O)ORA, OC(O)RA, or C(O)NRARB;
each RA 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 RB 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
RA and RB, 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;
RC is alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, naphthyl, heterocycloalkyl, or heteroaryl, each optionally substituted with 1-5 independently selected R4, and when L1 is other than a covalent bond, RC is additionally selected from H;
R2 and R3 are each independently H, halogen, alkyl, alkenyl, alkynyl, phenyl, naphthyl, aralkyl, cycloalkyl, heteroaryl, heterocycloalkyl, -OR, -SR, -CN, -N(R’)(R’’), -C(O)R, -C(S)R, -CO2R, -C(O)N(R’)(R’’), -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)(R’’), - C(S)OR, -S(O)R, -SO2R, -SO2N(R’)(R’’), -N(R’)C(O)R, -N(R’)C(O)N(R’)(R’’), - N(R')C(S)N(R')(R"), -N(R’)SO2R, -N(R’)SO2N(R’)(R’’), -N(R’)N(R’)(R’’), - N(R’)C(=N(R’))N(R’)(R’’), -C=NN(R’)(R’’), -C=NOR, -C(=N(R’))N(R’)(R’’), -OC(O)R, - OC(O)N(R’)(R’’), or -(CH2)pRx; or
R2 and R3 together with the atoms to which each is attached, form an optionally substituted 3-7 membered saturated or unsaturated spiro-fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each Rx is independently halogen, alkyl, alkenyl, alkynyl, phenyl, naphthyl, aralkyl, cycloalkyl, heteroaryl, heterocycloalkyl, -OR, -SR, -CN, -N(R’)(R’’), -C(O)R, -C(S)R, -CO2R, -C(O)N(R’)(R’’), -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)(R’’), -C(S)OR, - S(O)R, -SO2R, -SO2N(R’)(R’’), -N(R’)C(O)R, -N(R’)C(O)N(R’)(R’’), -N(R’)C(S)N(R’)(R’’), -N(R’)SO2R, -N(R’)SO2N(R’)(R’’), -N(R’)N(R’)(R’’), -N(R’)C(=N(R’))N(R’)(R’’), - C=NN(R’)(R’’), -C=NOR, -C(=N(R’))N(R’)(R’’), -OC(O)R, -OC(O)N(R’)(R’’); L1 is a covalent bond or an optionally substituted bivalent C1-6 hydrocarbon chain wherein one or two methylene units is optionally replaced by -NR’-, -N (R’)C(O)-, - C(O)N(R’)-, -N(R’)SO2-, -SO2N(R’)- -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO2-; each R is independently hydrogen, alkyl, alkenyl, alkynyl, phenyl, naphthyl, aralkyl, cycloalkyl, heteroaryl, or heterocycloalkyl;
each R’ is independently -R, -C(O)R, -C(S)R, -CO2R, -C(O)N(R)2, -C(S)N(R)2, - S(O)R, -SO2R, -SO2N(R)2, or two R groups on the same nitrogen are taken together with their intervening atoms to form an heteroaryl or heterocycloalkyl group; each R’’ is independently - R, -C(O)R, -C(S)R, -CO2R, -C(O)N(R)2, -C(S)N(R)2, -S(O)R, -SO2R, -SO2N(R)2, or two R groups on the same nitrogen are taken together with their intervening atoms to form an heteroaryl or heterocycloalkyl group; or
R’ and R’’, together with the atoms to which each is attached, can form cycloalkyl, heterocycloalkyl, phenyl, naphthyl, or heteroaryl; each of which is optionally substituted; each R4 is independently alkyl, alkenyl, alkynyl, phenyl, naphthyl, aralkyl, cycloalkyl, heteroaryl, or heterocycloalkyl, halogen, -OR, -SR, -N(R’)(R’’), -CN, -NO2, -C(O)R, -C(S)R, - CO2R, -C(O)N(R’)(R’’), -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)(R’’), -C(S)OR, -S(O)R, -SO2R, -SO2N(R’)(R’’), -N(R’)C(O)R, -N(R’)C(O)N(R’)(R’’), -N(R’)C(S)N(R’)(R’’), -N(R’)SO2R, -N(R’)SO2N(R’)(R’’), -N(R’)N(R’)(R’’), -N(R’)C(=N(R/))N(R')(R"), - C=NN(R')(R"), -C=NOR, -C(=N(R'))N(R')(R"), -OC(O)R, or -OC(O)N(R’)(R’’);
each R5 is independently -R, halogen, -OR, -SR, -N(R’)(R’’), -CN, -NO2, -C(O)R, - C(S)R, -CO2R, -C(O)N(R’)(R’’), -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)(R’’), - C(S)OR, -S(O)R, -SO2R, -SO2N(R’)(R’’), -N(R’)C(O)R, -N(R’)C(O)N(R’)(R’’), - N(R’)C(S)N(R’)(R’’), -N(R’)SO2R, -N(R’)SO2N(R’)(R’’), -N(R’)N(R’)(R’’), - N(R’)C(=N(R’))N(R’)(R’’), -C=NN(R’)(R’’), -C=NOR, -C(=N(R’))N(R’)(R’’), -OC(O)R, or - OC(O)N(R’)(R’’);
n is 0-5;
each q is independently 0, 1, or 2; and
p is 1-6.
[0048] In still another embodiment, exemplary bromodomain ligands include compounds represented by the structure:
Figure imgf000035_0001
Formula W,
wherein:
X is O or N;
Y is O or N; wherein at least one of X or Y is O;
W is C or N;
R1 is H, alkyl, alkenyl, alkynyl, aralkyl, phenyl, naphthyl, heteroaryl, halo, CN, ORA, NRARB,
N(RA)S(O)qRARB, N(RA)C(O)RB, N(RA)C(O)NRARB, N(RA)C(O)ORA,
N(RA)C(S)NRARB, S(O)qRA, C(O)RA, C(O)ORA, OC(O)RA, or C(O)NRARB;
each RA 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 RB 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
RA and RB, 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;
RC is alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, naphthyl, heterocycloalkyl, or heteroaryl, each optionally substituted with 1-5 independently selected R4, and when L1 is other than a covalent bond, RC is additionally selected from H;
R2 is H, halogen, alkyl, alkenyl, alkynyl, phenyl, naphthyl, aralkyl, cycloalkyl, heteroaryl, heterocycloalkyl, -OR, -SR, -CN, -N(R’)(R’’), -C(O)R, -C(S)R, -CO2R, - C(O)N(R’)(R’’), -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)(R’’), -C(S)OR, - S(O)R, -SO2R, -SO2N(R’)(R’’), -N(R’)C(O)R, -N(R’)C(O)N(R’)(R’’), -N(R')C(S)N(R')(R"), - N(R’)SO2R, -N(R’)SO2N(R’)(R’’), -N(R’)N(R’)(R’’), -N(R’)C(=N(R’))N(R’)(R’’), - C=NN(R’)(R’’), -C=NOR, -C(=N(R’))N(R’)(R’’), -OC(O)R, -OC(O)N(R’)(R’’), or -(CH2)pRx;
R3 is a bond or optionally substituted alkyl; or R2 and R3 together with the atoms to which each is attached, form an optionally substituted 3-7 membered saturated or unsaturated spiro-fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each Rx is independently halogen, alkyl, alkenyl, alkynyl, phenyl, naphthyl, aralkyl, cycloalkyl, heteroaryl, heterocycloalkyl, -OR, -SR, -CN, -N(R’)(R’’), -C(O)R, -C(S)R, -CO2R, -C(O)N(R’)(R’’), -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)(R’’), -C(S)OR, - S(O)R, -SO2R, -SO2N(R’)(R’’), -N(R’)C(O)R, -N(R’)C(O)N(R’)(R’’), -N(R’)C(S)N(R’)(R’’), -N(R’)SO2R, -N(R’)SO2N(R’)(R’’), -N(R’)N(R’)(R’’), -N(R’)C(=N(R’))N(R’)(R’’), - C=NN(R’)(R’’), -C=NOR, -C(=N(R’))N(R’)(R’’), -OC(O)R, -OC(O)N(R’)(R’’);
L1 is a covalent bond or an optionally substituted bivalent C1-6 hydrocarbon chain wherein one or two methylene units is optionally replaced by -NR’-, -N (R’)C(O)-, - C(O)N(R’)-, -N(R’)SO2-, -SO2N(R’)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO-, or -SO2-; each R is independently hydrogen, alkyl, alkenyl, alkynyl, phenyl, naphthyl, aralkyl, cycloalkyl, heteroaryl, or heterocycloalkyl;
each R’ is independently -R, -C(O)R, -C(S)R, -CO2R, -C(O)N(R)2, -C(S)N(R)2, - S(O)R, -SO2R, -SO2N(R)2, or two R groups on the same nitrogen are taken together with their intervening atoms to form an heteroaryl or heterocycloalkyl group; each R’’ is independently - R, -C(O)R, -C(S)R, -CO2R, -C(O)N(R)2, -C(S)N(R)2, -S(O)R, -SO2R, -SO2N(R)2, or two R groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted heteroaryl or heterocycloalkyl group; or
R’ and R’’, together with the atoms to which each is attached, can form cycloalkyl, heterocycloalkyl, phenyl, naphthyl, or heteroaryl; each of which is optionally substituted; each R4 is independently alkyl, alkenyl, alkynyl, phenyl, naphthyl, aralkyl, cycloalkyl, heteroaryl, or heterocycloalkyl, halogen, -OR, -SR, -N(R’)(R’’), -CN, -NO2, -C(O)R, -C(S)R, - CO2R, -C(O)N(R’)(R’’), -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)(R’’), -C(S)OR, -S(O)R, -SO2R, -SO2N(R’)(R’’), -N(R’)C(O)R, -N(R’)C(O)N(R’)(R’’), -N(R’)C(S)N(R’)(R’’), -N(R’)SO2R, -N(R’)SO2N(R’)(R’’), -N(R’)N(R’)(R’’), -N(R’)C(=N(R/))N(R')(R"), - C=NN(R')(R"), -C=NOR, -C(=N(R'))N(R')(R"), -OC(O)R, or -OC(O)N(R’)(R’’);
each R5 is independently -R, halogen, -OR, -SR, -N(R’)(R’’), -CN, -NO2, -C(O)R, - C(S)R, -CO2R, -C(O)N(R’)(R’’), -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)(R’’), - C(S)OR, -S(O)R, -SO2R, -SO2N(R’)(R’’), -N(R’)C(O)R, -N(R’)C(O)N(R’)(R’’), - N(R’)C(S)N(R’)(R’’), -N(R’)SO2R, -N(R’)SO2N(R’)(R’’), -N(R’)N(R’)(R’’), - N(R’)C (=N(R’))N (R’)(R’’), - C=NN(R’) (R’’), -C=N OR, -C(=N (R’))N(R’ )(R’’), -OC (O)R, or - OC(O) N(R’)(R’’) ;
n is 0-5;
each q is in dependentl y 0, 1, or 2 ; and
p is 1-6.
[0049] In y et another embodimen t, compoun ds of Form ula U, Form ula V, and Formula W may be selected from the g roup consi sting of:
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
. It wi ll be apprec iated that e ach of these compo unds may b e connected to a–Y-Z moiety, for example, a s illustrate d for generi c structu res Formula U, Formu la V, and F ormula W a bove.
[0050] For example, c ompounds of Formula U, Formul a V, and Fo rmula W m ay be selecte d from the g roup consi sting of:
Figure imgf000040_0001
,
Figure imgf000041_0001
, . 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.
[0051] In some embodiments, compounds of Formula U, Formula V, and Formula W may be selected from the group consisting of:
Figure imgf000041_0002
. It will be appreciated that each of these compounds may be connected to a–Y-Z moiety, for example, as illustrated for generic structures Formula U, Formula V, and Formula W above.
[0052] In some embodiments, exemplary bromodomain ligands include compounds represented by the structures:
Figure imgf000042_0001
wherein:
Ring A is benzo, or a 5-6 membered fused heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
Ring B is a 3-7 membered saturated or partially unsaturated carbocyclic ring, phenyl, an 8-10 membered bicyclic saturated, partially unsaturated, phenyl or naphthyl ring, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
L1 is a covalent bond or an optionally substituted bivalent C1-6 hydrocarbon chain wherein one or two methylene units is optionally replaced by–NR’-, -N(R’)C(O)-, - C(O)N(R’), -N(R’)SO2-, -SO2N(R’), -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO2-;
R1 is hydrogen, halogen, optionally substituted C1-6 aliphatic, -OR, -SR, -CN, -N(R’)2, - C(O)R, -C(S)R, -CO2R, -C(O)N(R’)2, -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)2, - C(S)OR, -S(O)R, -SO2R, -SO2N(R’)2, -N(R’)C(O)R, -N(R’)C(O)N(R’)2, -N(R’)C(S)N(R’)2, - N(R’)SO2R, -N(R’)SO2N(R’)2, -N(R’)N(R’)2, -N(R’)C(=N(R’))N(R’)2, -C=NN(R’)2, -C=NOR, -C(=N(R’))N(R’)2, -OC(O)R, -OC(O)N(R’)2, or -(CH2)pRx;
p is 0-3; Rx is halogen, optionally substituted C1-6 aliphatic, -OR, -SR, -CN, -N(R’)2, -C(O)R, - C(S)R, -CO2R, -C(O)N(R’)2, -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)2, -C(S)OR, -S(O)R, -SO2R, -SO2N(R’)2, -N(R’)C(O)R, -N(R’)C(O)N(R’)2, -N(R’)C(S)N(R’)2, - N(R’)SO2R, -N(R’)SO2N(R’)2, -N(R’)N(R’)2, -N(R’)C(=N(R’))N(R’)2, -C=NN(R’)2, -C=NOR, -C(=N(R’))N(R’)2, -OC(O)R, -OC(O)N(R’)2;
R2 is hydrogen, halogen, -CN, -SR, or optionally substituted C1-6 aliphatic, or:
R1 and R2 are taken together with their intervening atoms to form an optionally substituted 3-7 membered saturated or partially unsaturated spiro-fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 7-10 membered bicyclic saturated, partially unsaturated, phenyl or naphthyl ring, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms
independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each R’ is independently -R, -C(O)R, -C(S)R, -CO2R, -C(O)N(R)2, -C(S)N(R)2, - S(O)R, -SO2R, -SO2N(R)2, or two R’ on the same nitrogen are taken together with their intervening atoms to form an optionally substituted group selected from a 4-7 membered monocyclic saturated or partially unsaturated ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 7-12 membered bicyclic saturated, partially unsaturated, or aromatic fused ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; W is , , or ;
R3 is optionally substituted C1-6 aliphatic;
X is oxygen or sulfur, or:
R3 and X are taken together with their intervening atoms to form an optionally substituted 5-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each of m and n is independently 0-4, as valency permits; and
each of R4 and R5 is independently -R, halogen, -OR, -SR, -N(R’)2, -CN, -NO2, -C(O)R, -C(S)R, -CO2R, -C(O)N(R’)2, -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)2, - C(S)OR, -S(O)R, -SO2R, -SO2N(R’)2, -N(R’)C(O)R, -N(R’)C(O)N(R’)2, -N(R’)C(S)N(R’)2, - N(R’)SO2R, -N(R’)SO2N(R’)2, -N(R’)N(R’)2, -N(R’)C(=N(R’))N(R’)2, -C=NN(R’)2, -C=NOR, -C(=N(R’))N(R’)2, -OC(O)R, or -OC(O)N(R’)2.
[0053] In another embodiment, exemplary bromodomain ligands include compounds represented b the structures:
Figure imgf000044_0001
Formula ZZ, wherein:
Ring A is benzo, or a 5-6 membered fused heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
Ring B is a 3-7 membered saturated or partially unsaturated carbocyclic ring, phenyl, an 8-10 membered bicyclic saturated, partially unsaturated, phenyl or naphthyl ring, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
L1 is a covalent bond or an optionally substituted bivalent C1-6 hydrocarbon chain wherein one or two methylene units is optionally replaced by–NR’-, -N(R’)C(O)-, - C(O)N(R’), -N(R’)SO2-, -SO2N(R’), -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO2-;
R1 is hydrogen, halogen, optionally substituted C1-6 aliphatic, -OR, -SR, -CN, -N(R’)2, - C(O)R, -C(S)R, -CO2R, -C(O)N(R’)2, -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)2, - C(S)OR, -S(O)R, -SO2R, -SO2N(R’)2, -N(R’)C(O)R, -N(R’)C(O)N(R’)2, -N(R’)C(S)N(R’)2, - N(R’)SO2R, -N(R’)SO2N(R’)2, -N(R’)N(R’)2, -N(R’)C(=N(R’))N(R’)2, -C=NN(R’)2, -C=NOR, -C(=N(R’))N(R’)2, -OC(O)R, -OC(O)N(R’)2, or -(CH2)pRx;
p is 0-3;
Rx is halogen, optionally substituted C1-6 aliphatic, -OR, -SR, -CN, -N(R’)2, -C(O)R, - C(S)R, -CO2R, -C(O)N(R’)2, -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)2, -C(S)OR, -S(O)R, -SO2R, -SO2N(R’)2, -N(R’)C(O)R, -N(R’)C(O)N(R’)2, -N(R’)C(S)N(R’)2, - N(R’)SO2R, -N(R’)SO2N(R’)2, -N(R’)N(R’)2, -N(R’)C(=N(R’))N(R’)2, -C=NN(R’)2, -C=NOR, -C(=N(R’))N(R’)2, -OC(O)R, -OC(O)N(R’)2;
R2 is a bond or optionally substituted C1-6 aliphatic, or:
R1 and R2 are taken together with their intervening atoms to form an optionally substituted 3-7 membered saturated or partially unsaturated spiro-fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 7-10 membered bicyclic saturated, partially unsaturated, phenyl, or naphthyl ring, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms
independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each R’ is independently -R, -C(O)R, -C(S)R, -CO2R, -C(O)N(R)2, -C(S)N(R)2, - S(O)R, -SO2R, -SO2N(R)2, or two R’ on the same nitrogen are taken together with their intervening atoms to form an optionally substituted group selected from a 4-7 membered monocyclic saturated or partially unsaturated ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 7-12 membered bicyclic saturated, partially unsaturated, or aromatic fused ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; W is , , or ;
R3 is optionally substituted C1-6 aliphatic;
X is oxygen or sulfur, or: R3 and X are taken together with their intervening atoms to form an optionally substituted
5-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each of m and n is independently 0-4, as valency permits; and
each of R4 and R5 is independently–R, halogen, -OR, -SR, -N(R’)2, -CN, -NO2, - C(O)R, -C(S)R, -CO2R, -C(O)N(R’)2, -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)2, - C(S)OR, -S(O)R, -SO2R, -SO2N(R’)2, -N(R’)C(O)R, -N(R’)C(O)N(R’)2, -N(R’)C(S)N(R’)2, - N(R’)SO2R, -N(R’)SO2N(R’)2, -N(R’)N(R’)2, -N(R’)C(=N(R’))N(R’)2, -C=NN(R’)2, -C=NOR, -C(=N(R’))N(R’)2, -OC(O)R, or -OC(O)N(R’)2.
[0054] For example, a compound of Formula X, Formula Y, or Formula Z may be selected from the group consisting of:
Figure imgf000046_0001
,
,
Figure imgf000047_0001
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.
[0055] In some embodiments, a compound of Formula XX, Formula YY, or Formula ZZ ma be selected from the rou consistin of:
Figure imgf000047_0002
. It will be appreciated that each of these compounds may be connected to a–Y-Z moiety, for example, as illustrated for generic structures Formula XX, Formula YY, and Formula ZZ above.
[0056] In another embodiment, exemplary bromodomain ligands include compounds represented by the structures:
Figure imgf000048_0001
Formula YYA, and
Figure imgf000048_0002
Formula ZZA,
wherein:
Ring A is benzo, or a 5-6 membered fused heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
Ring B is a 3-7 membered saturated or partially unsaturated carbocyclic ring, phenyl, an 8-10 membered bicyclic saturated, partially unsaturated, phenyl, or naphthyl ring, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
L1 is a covalent bond or an optionally substituted bivalent C1-6 hydrocarbon chain wherein one or two methylene units is optionally replaced by–NR’-, -N(R’)C(O)-, - C(O)N(R’), -N(R’)SO2-, -SO2N(R’), -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO2-;
R1 is independently hydrogen, halogen, optionally substituted C1-6 aliphatic, -OR, -SR, - CN, -N(R’)2, -C(O)R, -C(S)R, -CO2R, -C(O)N(R’)2, -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)2, -C(S)OR, -S(O)R, -SO2R, -SO2N(R’)2, -N(R’)C(O)R, -N(R’)C(O)N(R’)2, - N(R’)C(S)N(R’)2, -N(R’)SO2R, -N(R’)SO2N(R’)2, -N(R’)C(=N(R’))N(R’)2, -C=NN(R’)2, - C=NOR, -C(=N(R’))N(R’)2, -OC(O)R, -OC(O)N(R’)2, or -(CH x
2)pR ;
p is 0-3; Rx is halogen, optionally substituted C1-6 aliphatic, -OR, -SR, -CN, -N(R’)2, -C(O)R, - C(S)R, -CO2R, -C(O)N(R’)2, -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)2, -C(S)OR, -S(O)R, -SO2R, -SO2N(R’)2, -N(R’)C(O)R, -N(R’)C(O)N(R’)2, -N(R’)C(S)N(R’)2, - N(R’)SO2R, -N(R’)SO2N(R’)2, -N(R’)N(R’)2, -N(R’)C(=N(R’))N(R’)2, -C=NN(R’)2, -C=NOR, -C(=N(R’))N(R’)2, -OC(O)R, -OC(O)N(R’)2;
R2 is a bond, hydrogen, or optionally substituted C1-6 aliphatic;
each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 7-10 membered bicyclic saturated, partially unsaturated, phenyl, or naphthyl ring, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms
independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each R’ is independently -R, -C(O)R, -C(S)R, -CO2R, -C(O)N(R)2, -C(S)N(R)2, - S(O)R, -SO2R, -SO2N(R)2, or two R’ on the same nitrogen are taken together with their intervening atoms to form an optionally substituted group selected from a 4-7 membered monocyclic saturated or partially unsaturated ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 7-12 membered bicyclic saturated, partially unsaturated, or aromatic fused ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
W is C or N;
R3 is optionally substituted C1-6 aliphatic;
is a single or double bond;
each of m and n is independently 0-4, as valency permits; and
each of R4 and R5 is independently–R, halogen, -OR, -SR, -N(R’)2, -CN, -NO2, - C(O)R, -C(S)R, -CO2R, -C(O)N(R’)2, -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)2, - C(S)OR, -S(O)R, -SO2R, -SO2N(R’)2, -N(R’)C(O)R, -N(R’)C(O)N(R’)2, -N(R’)C(S)N(R’)2, - N(R’)SO2R, -N(R’)SO2N(R’)2, -N(R’)N(R’)2, -N(R’)C(=N(R’))N(R’)2, -C=NN(R’)2, -C=NOR, -C(=N(R’))N(R’)2, -OC(O)R, or -OC(O)N(R’)2.
[0057] For example, a compound of formula XXA, YYA, or ZZA may be:
Figure imgf000050_0001
[0058] wherein XX may be a bond, C1-6alkyl, -NRt- (where t is H, phenyl, or C1-6alkyl), -O-, or -S(O)w- wherein w is 0, 1, or 2;
[0059] In yet another embodiment, exemplary bromodomain ligands include com ounds re resented b the structure:
Form
Figure imgf000050_0002
AA3,
wherein:
X is selected from N and CH;
Y is CO;
R1 and R3 are each independently selected from alkoxy and hydrogen;
R2 is selected from alkoxy, alkyl, and hydrogen;
R6 and R8 are each independently selected from alkyl, alkoxy, chloride, and hydrogen; R5 and R9 are each hydrogen;
R7 is selected from amino, hydroxyl, alkoxy, and alkyl substituted with a heterocyclyl; R10 is hydrogen; or two adjacent substituents selected from R6, R7, and R8 are connected to form a heterocyclyl;
each W is independently selected from C and N, wherein if W is N, then p is 0 or 1, and if W is C, then p is 1;
for W-(R10)p, W is N and p is 1; and
for W-(R4)p, W is C, p is 1 and R4 is H, or W is N and p is 0.
[0060] For exam le, in some embodiments, a compound of Formula AA may be:
[0061]
Figure imgf000051_0001
(2-(4-(2-hydroxyethoxy)-3,5- dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one). It will be appreciated that this compound may be connected to a–Y-Z moiety, for example, as illustrated for generic structures Formula AA, Formula AA1, Formula AA2, and Formula AA3 above.
[0062] In still another embodiment, exemplary bromodomain ligands include com ounds re resented b the structures:
Figure imgf000051_0002
wherein:
Y and W are each independently selected from carbon and nitrogen;
Ra6 is selected from fluoride, hydrogen, C1-C3 alkoxy, cyclopropyloxy, SO2R3, SOR3, and SR3, wherein if Y is nitrogen then Ra6 is absent;
Ra7 is selected from hydrogen, fluoride, SO2R3, SOR3, and SR3; Ra8 is selected from hydrogen, C1-C3 alkoxy, cyclopropyloxy, chloride, and bromide;
n is selected from 1, 2, or 3;
D is selected from O, NH, NR1, S, or C;
Rb3 and Rb5 are independently selected from hydrogen and C1-C3 alkyl;
R 3 5
C and RC are independently selected from hydrogen, C1-C3 alkyl, and
cyclopropyl;
R 4
C is selected from F, Cl, Br, I, CF3, C1-C6 alkyl, C3-C6 cycloalkyl, NHC(O)R4,
Figure imgf000052_0001
R1, R’1, R2 and R’2 are independently selected from hydrogen, fluoride, C1-C3 alkyl, and cyclopropyl, wherein R1 and R2 and/or R’1 and R’2 may be connected to form a 3-6 membered ring;
R3 is selected from C1-C3 alkyl and cyclopropyl; and
R4 is selected from hydrogen, C1-C4 alkyl, C3-C5 cycloalkyl, phenyl, and naphthyl, provided that if Ra7 or Ra6 is fluoride, then R 4
C is not bromide.
[0063] In some embodiments, a compound of Formula AA, Formula AA1, Formula AA2, Formula AA3, Formula BB, or Formula CC may be selected from the group consisting of:
3-(4-sec-butylphenyl)-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one; 3-(4-bromophenyl)-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin- 4(3H)-one;
3-(4-sec-butylphenyl)-7-fluoro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)- one;
3-(4-sec-butylphenyl)-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)pyrido[4,3-d]pyrimidin- 4(3H)-one;
3-(4-sec-butylphenyl)-2-(4-(2-hydroxyethoxy)phenyl)quinazolin-4(3H)-one;
3-(4-fluorophenyl)-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;
2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-3-(4-iodophenyl)quinazolin-4(3H)-one;
3-(4-sec-butylphenyl)-6-fluoro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)- one;
3-(4-chlorophenyl)-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one; 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-3-(4-(trifluoromethyl)phenyl)quinazolin-4(3H)- one;
3-(4-sec-butylphenyl)-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-7- (methylsulfonyl)quinazolin-4(3H)-one;
3-(4-sec-butylphenyl)-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6-methoxyquinazolin- 4(3H)-one;
3-(4-sec-butylphenyl)-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-8-methoxyquinazolin- 4(3H)-one;
3-(4-sec-butylphenyl)-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6- (methylsulfonyl)quinazolin-4(3H)-one;
3-(4-bromophenyl)-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6-methoxyquinazolin-4(3H)- one;
3-(4-bromophenyl)-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-8-methoxyquinazolin-4(3H)- one;
2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-3-(4-isopropylphenyl)quinazolin-4(3H)-one; 3-(4-bromophenyl)-2-(4-(2-hydroxyethoxy)-3-methyiphenyl)quinazolin-4(3H)-one;
3-(4-bromophenyl)-8-chloro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)- one;
2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-3-(4-morpholinophenyl)quinazolin-4(3H)-one; 3-(4-tert-butylphenyl)-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one; N-(4-(2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-4-oxoquinazolin-3(4H)- yl)phenyl)acetamide;
N-(4-(2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-4-oxoquinazolin-3(4H)- yl)phenyl)isobutyramide;
methyl 4-(2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-4-oxoquinazolin-3(4H)-yl)benzoate; 3-(4-cyclohexylphenyl)-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one; N-(4-(2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-4-oxoquinazolin-3(4H)- yl)phenyl)formamide;
3-(4-aminophenyl)-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;
N-(4-(2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-4-oxoquinazolin-3(4H)- yl)phenyl)methanesulfonamide;
N-(4-(2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-4-oxoquinazolin-3(4H)- yl)phenyl)benzenesulfonamide; N-(4-(2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-4-oxoquinazolin-3(4H)-yl)phenyl)propane- 2-sulfonamide;
3-(4-(dimethylamino)phenyl)-2-(4-(2-hydroxyethoxy)-3,5-dimethyiphenyl)quinazolin-4(3H)- one;
3-(4-sec-butylphenyl)-2-(4-(2-hydroxyethoxy)-3-methylphenyl)quinazolin-4(3H)-one;
3-(4-chlorophenyl)-2-(4-(2-hydroxyethoxy)-3-methylphenyl)quinazolin-4(3H)-one;
3-(4-sec-butylphenyl)-2-(pyridin-3-yl)quinazolin-4(3H)-one;
3-(4-chlorophenyl)-2-(quinolin-3-yl)quinazolin-4(3H)-one;
3-(4-sec-butylphenyl)-2-(5-fluoropyridin-3-yl)quinazolin-4(3H)-one;
3-(4-chlorophenyl)-2-(6-chloropyridin-3-yl)quinazolin-4(3H)-one;
3-(4-sec-butylphenyl)-2-(6-chloropyridin-3-yl)quinazolin-4(3H)-one;
3-(4-sec-butylphenyl)-2-(6-methoxypyridin-3-yl)quinazolin-4(3H)-one;
2-(6-bromopyridin-3-yl)-3-(4-chlorophenyl)quinazolin-4(3H)-one;
2-(6-bromopyridin-3-yl)-3-(4-sec-butylphenyl)quinazolin-4(3H)-one;
3-(4-chlorophenyl)-2-(6-(diethylamino)pyridin-3-yl)quinazolin-4(3H)-one;
3-(4-sec-butylphenyl)-2-(6-(diethylamino)pyridin-3-yl)quinazolin-4(3H)-one;
3-(4-sec-butylphenyl)-2-(pyrimidin-5-yl)quinazolin-4(3H)-one;
3-(4-sec-butylphenyl)-2-(6-methylpyridin-3-yl)quinazolin-4(3H)-one;
3-(4-chlorophenyl)-2-(6-methylpyridin-3-yl)quinazolin-4(3H)-one;
3-(4-chlorophenyl)-2-(6-(piperidin-1-yl)pyridin-3-yl)quinazolin-4(3H)-one;
3-(4-sec-butylphenyl)-2-(6-(piperidin-1-yl)pyridin-3-yl)quinazolin-4(3H)-one;
3-(4-chlorophenyl)-2-(6-phenoxypyridin-3-yl)quinazolin-4(3H)-one;
3-(4-sec-butylphenyl)-2-(6-fluoropyridin-3-yl)quinazolin-4(3H)-one;
3-(4-sec-butylphenyl)-2-(6-phenoxypyridin-3-yl)quinazolin-4(3H)-one;
3-(4-chlorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)quinazolin-4(3H)-one;
3-(4-sec-butylphenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)quinazolin-4(3H)-one;
3-(4-sec-butylphenyl)-2-(6-phenylpyridin-3-yl)quinazolin-4(3H)-one;
3-(4-sec-butylphenyl)-2-(5-phenylpyridin-3-yl)quinazolin-4(3H)-one;
2-(5-bromopyridin-3-yl)-3-(4-sec-butylphenyl)quinazolin-4(3H)-one;
2-(5-bromopyridin-3-yl)-3-(4-chlorophenyl)quinazolin-4(3H)-one;
3-(4-sec-butylphenyl)-2-(5-(diethylamino)pyridin-3-yl)quinazolin-4(3H)-one;
3-(4-chlorophenyl)-2-(5-phenylpyridin-3-yl)quinazolin-4(3H)-one;
3-(4-chlorophenyl)-2-(5-(diethylamino)pyridin-3-yl)quinazolin-4(3H)-one; 3-(4-cyclopentylphenyl)-2-(6-methylpyridin-3-yl)quinazolin-4(3H)-one;
3-(4-sec-butylphenyl)-2-(6-(hydroxymethyl)pyridin-3-yl)quinazolin-4(3H)-one;
2-(6-methylpyridin-3-yl)-3-(4-(methylthio)phenyl)quinazolin-4(3H)-one;
3-(4-isopropylphenyl)-2-(6-methylpyridin-3-yl)quinazolin-4(3H)-one;
N-(4-(2-(6-methylpyridin-3-yl)-4-oxoquinazolin-3(4H)-yl)phenyl)methanesulfonamide;
3-(4-sec-butylphenyl)-2-(6-(morpholinomethyl)pyridin-3-yl)quinazolin-4(3H)-one;
3-(4-cyclopropylphenyl)-2-(6-methylpyridin-3-yl)quinazolin-4(3H)-one;
3-(4-(dimethylamino)phenyl)-2-(6-methylpyridin-3-yl)quinazolin-4(3H)-one;
2-(6-chloropyridin-3-yl)-3-(4-cyclopropylphenyl)quinazolin-4(3H)-one;
3-(4-sec-butylphenyl)-2-(6-morpholinopyridin-3-yl)quinazolin-4(3H)-one;
3-(4-sec-butylphenyl)-2-(1H-indazol-5-yl)quinazolin-4(3H)-one;
3-(4-chlorophenyl)-2-(1H-indol-5-yl)quinazolin-4(3H)-one;
3-(4-sec-butylphenyl)-2-(1H-indol-5-yl)quinazolin-4(3H)-one;
3-(4-sec-butylphenyl)-2-(2-(hydroxymethyl)-1H-benzo[d]imidazol-6-yl)quinazolin-4(3H)-one; 2-(1H-indol-5-yl)-3-(4-(trifluoromethoxy)phenyl)quinazolin-4(3H)-one;
2-(1H-indol-5-yl)-3-(4-isopropylphenyl)quinazolin-4(3H)-one;
3-(4-chlorophenyl)-2-(1-(4-methoxyphenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)quinazolin- 4(3H)-one;
3-(4-chlorophenyl)-2-(1-(4-fluorophenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)quinazolin- 4(3H)-one;
3-(4-(dimethylamino)phenyl)-2-(1H-indol-5-yl)quinazolin-4(3H)-one;
3-(4-chlorophenyl)-2-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)quinazolin-4(3H)-one; 3-(4-sec-butylphenyl)-2-(2-(hydroxymethyl)-1H-indol-5-yl)quinazolin-4(3H)-one;
3-(4-chlorophenyl)-2-(1-methyl-1H-indol-5-yl)quinazolin-4(3H)-one;
3-(4-cyclopentylphenyl)-2-(1H-indol-5-yl)quinazolin-4(3H)-one;
3-(4-chlorophenyl)-2-(1H-indol-6-yl)quinazolin-4(3H)-one;
3-(4-chlorophenyl)-2-(1H-indol-7-yl)quinazolin-4(3H)-one;
3-(4-sec-butylphenyl)-2-(1H-indol-6-yl)quinazolin-4(3H)-one;
3-(4-sec-butylphenyl)-2-(1H-indol-7-yl)quinazolin-4(3H)-one;
3-(4-chlorophenyl)-2-(1H-indol-4-yl)quinazolin-4(3H)-one; and
3-(4-sec-butylphenyl)-2-(1H-indol-4-yl)quinazolin-4(3H)-one. It will be appreciated that each of these compounds may be connected to a–Y-Z moiety, for example, as illustrated for generic structures Formula AA, Formula AA1, Formula AA2, Formula AA3, Formula BB, Formula CC, and Formula DD.
[0064] In yet another embodiment, exemplary bromodomain ligands include com ounds re resented b the structure:
Figure imgf000056_0001
wherein:
Q and V are independently selected from CH and nitrogen;
U is selected from C=O, C=S, SO2, S=O, SR1, CR1R2, CR1OR2, CR1SR2; R1 and R2 are independently selected from hydrogen and C1-C6 alkyl;
Rc is selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl;
Ra1, Ra2, and Ra3 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 alkoxy, halogen, amino, amide, hydroxyl, heterocycle, and C3-C6 cycloalkyl, wherein Ra1 and Ra2 and/or Ra2 and Ra3 may be connected to form a cycloalkyl or a heterocycle;
Rb2 and Rb6 are independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkenyl, C3-C6 cycloalkyl, hydroxyl, and amino;
Rb3 and Rb5 are independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, hydroxyl, and amino, wherein Rb2 and Rb3 and/or Rb5 and Rb6 may be conn cycloalkyl or a heterocycle;
Figure imgf000056_0002
represents a 3-8 membered ring system wherein: W is selected from carbon and nitrogen; Z is selected from CR6R7, NR8, oxygen, sulfur, -S(O)-, and -SO2-; said ring system being optionally fused to another ring selected from cycloalkyl, heterocycle, and phenyl, and wherein said ring system is optionally selected from rings having the
r r
,
Figure imgf000057_0001
R3, R4, and R5 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, phenyl, naphthyl, aryloxy, hydroxy1, amino, amide, oxo, -CN, and sulfonamide;
R6 and R7 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C3-C6 cycloalkyl, phenyl, naphthyl, halogen, hydroxyl, -CN, amino, and amido; and R8 is selected from hydrogen, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, acyl, and C3-C6 cycloalkyl; and
R9, R10, R11, and R12 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C3-C6 cycloalkyl, phenyl, naphthyl, heterocycle, hydroxyl, sulfonyl, and acyl.
[0065] In still another embodiment, exemplary bromodomain ligands include compounds represented by the structure:
Figure imgf000058_0001
Formula GG,
wherein:
Q is selected from N and CRa3;
V is selected from N and CRa4;
W is selected from N and CH;
U is selected from C=O, C=S, SO2, S=O, and SR1;
X is selected from OH, SH, NH2, S(O)H, S(O)2H, S(O)2NH2, S(O)NH2, NHAc, and NHSO2Me;
Ra1, Ra3, and Ra3 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and halogen;
Ra2 is selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, amino, amide, and halogen;
Rb2 and Rb6 are independently selected from hydrogen, methyl and fluorine;
Rb3 and Rb5 are independently selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, and C1-C6 alkoxy; and
Rb2 and Rb3 and/or Rb5 and Rb6 may be connected to form a cycloalkyl or a heterocycle, provided that at least one of Ra1, Ra2, Ra3, and Ra4 is not hydrogen.
[0066] In yet another embodiment, exemplary bromodomain ligands include compounds re resented b the structure:
Figure imgf000058_0002
ormula HH,
wherein:
Q is selected from N and CRa3;
V is selected from N and CRa4;
W is selected from N and CH; U is selected from C=O, C=S, SO2, S=O, and SR1;
X is selected from OH, SH, NH2, S(O)H, S(O)2H, S(O)2NH2, S(O)NH2, NHAc, and NHSO2Me;
Ra1, Ra3, and Ra3 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and halogen;
Ra2 is selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, amino, amide, and halogen;
Rb2 and Rb6 are independently selected from hydrogen, methyl and fluorine;
Rb3 and Rb5 are independently selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, and C1-C6 alkoxy; and
Rb2 and Rb3 and/or Rb5 and Rb6 may be connected to form a cycloalkyl or a heterocycle, provided that at least one of Ra1, Ra2, Ra3, and Ra4 is not hydrogen.
[0067] The following are hereby incorporated by reference in their entirety: Zeng et al. J. Am. Chem. Soc. (2005) 127, 2376-2377; Chung et al. J. Med. Chem. (2012) 55, 576-586; Filippakopoulos et al. Bioorg. Med. Chem. (2012) 20, 1878-1886; U.S. Patent No. 8,053,440, by Hansen; U.S. Patent Publication No. 2008/0188467, by Wong et al.; U.S. Patent Publication No. 2012/0028912; International Patent Publication Nos. WO/2010/123975, WO/2010/106436, WO/2010/079431, WO/2009/158404, and WO/2008/092231, by Hansen et al.; International Patent Publication Nos. WO/2012/075456 and WO/2012/075383, by Albrecht et al.;
International Patent Publication Nos. WO/2012/116170, WO/2007/084625, and
WO/2006/083692, by Zhou et al.
[0068] In another aspect, exemplary bromodomain ligands include fused heterocyclic systems represented by the structures:
Figure imgf000059_0001
1 2 3
, , , ,
Figure imgf000059_0002
and ; wherein:
V is independently selected, for each occurrence, from the group consisting of NH, S, N(C1-6alkyl), O, or CR4R4;
Q is independently selected, for each occurrence, from the group consisting of C(O), C(S), C(N), SO2, or CR4R4;
U is independently selected from the group consisting of a bond, C(O), C(S), C(N), SO2, or CR4R4
W and T are independently selected from the group consisting of NH, N(C1-6alkyl), O, or Q;
VC is selected from the group consisting of N, SH or CR4;
A is selected from the group consisting of aliphatic, cycloalkyl, heterocyclic, phenyl, naphthyl, heteroaryl or bicyclic moiety, wherein the cycloalkyl, heterocyclic, phenyl, naphthyl, heteroaryl, or bicyclic moiety is optionally substituted with one, two, three, four or more groups represented by R4;
R1 is independently selected, for each occurrence, from the group consisting of hydroxyl, halo, C1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl,
Figure imgf000060_0001
C1-6alkoxy, haloC1- 6alkoxy, acylaminoC1-6alkyl, nitro, cyano, CF3, -OCF3, -C(O)OC1-6alkyl, -OS(O)2C1-4alkyl, phenyl, naphthyl, phenyloxy, benzyloxy, or phenylmethoxy, wherein C1-6alkyl, phenyl, and naphthyl are optionally substituted by one two or three substituents selected from the group consisting of hydroxyl, halogen, oxo, C1-6alkyl, amino, or nitro;
R2 is selected from the group consisting of -O-, amino, C1-6alkyl, -O-C1-6alkyl-, hydroxylC1-6alkyl, aminoC1-6alkyl, haloC1-6alkyl,
Figure imgf000060_0002
acylaminoC1-6alkyl, -C(O)-, - C(O)O-, -C(O)NC1-6alkyl-, -OS(O)2C1-4alkyl-, -OS(O)2-, -S-C1-6alkyl-, phenyl, naphthyl, phenyloxy, benzyloxy, or phenylmethoxy, wherein C1-6alkyl, phenyl, and naphthyl are optionally substituted by one two or three substituents selected from the group consisting of hydroxyl, halogen, oxo, C1-6alkyl, amino, or nitro;
R3 is selected from the group consisting of hydrogen or C1-6alkyl;
R4 is independently selected, for each occurrence, from the group consisting of hydrogen, hydroxyl, oxo, imino, amino, halo, C1-6alkyl, cycloalkyl, phenyl, naphthyl, heterocyclyl, -O-C1-6alkyl, -NH-C1-6alkyl, -N(C1-6alkyl)C1-6alkyl, nitro, cyano, CF3, - OCF3, -C(O)OC1-6alkyl, -C(O)NHC1-6alkyl, -C(O)NH2 or -OS(O)2C1-4alkyl;
m is selected from the group consisting of 0, 1, 2, or 3;
n is selected from the group consisting of 0, 1, or 2; and p is selected from the group consisting of 0 or 1.
[0069] For example, compounds of Formula 1, Formula 2 or Formula 5 may be selected from the rou consistin of:
Figure imgf000061_0001
.
[0070] In a further example, compounds of Formula 1, Formula 2 or Formula 5 may be selected from the rou consistin of:
.
Figure imgf000061_0002
[0071] For example, compounds of Formula 3, Formula 3’ or Formula 4 may be selected from the group consisting of:
Figure imgf000062_0001
[0072] In another embodiment, bromodomain ligands include fused heterocyclic systems represented by the structures:
Figure imgf000062_0002
;
wherein: V is independently selected, for each occurrence, from the group consisting of NH, S, N(C1-6alkyl), O, or CR4R4;
Q is independently selected, for each occurrence, from the group consisting of C(O), C(S), C(N), SO2, or CR4R4;
W and T are independently selected from the group consisting of NH, N(C1-6alkyl), O, or Q;
VC is selected from the group consisting of N, SH or CR4;
A is a ring selected from the group consisting of: phenyl, a 5-6 membered cycloalkyl, a 5-6 membered heteroaryl having 1, 2 or 3 heteroatoms each selected from S, N or O, and a 4-7 membered heterocycle having 1, 2 or 3 heteroatoms each selected from N or O;
RA1 is R1; or two RA1 substituents may be taken together with the atoms to which they are attached to form phenyl, a 5-6 membered heteroaryl having 1, 2 or 3 heteroatoms each selected from S, N or O, and a 4-7 membered heterocycle having 1, 2 or 3 heteroatoms each selected from N or O;
R1 is independently selected, for each occurrence, from the group consisting of hydroxyl, halo, C1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl,
Figure imgf000063_0001
C1-6alkoxy, haloC1- 6alkoxy, acylaminoC1-6alkyl, nitro, cyano, CF3, -OCF3, -C(O)OC1-6alkyl, -OS(O)2C1-4alkyl, phenyl, naphthyl, phenyloxy, benzyloxy or phenylmethoxy, wherein C1-6alkyl, phenyl, and naphthyl are optionally substituted by one two or three substituents selected from the group consisting of hydroxyl, halogen, oxo, C1-6alkyl, amino, or nitro;
R2 is selected from the group consisting of -O-, amino, C1-6alkyl, -O-C1-6alkyl-, hydroxylC1-6alkyl, aminoC1-6alkyl, haloC1-6alkyl,
Figure imgf000063_0002
acylaminoC1-6alkyl, -C(O)-, - C(O)O-, -C(O)NC1-6alkyl-, -OS(O)2C1-4alkyl-, -OS(O)2-, -S-C1-6alkyl-, phenyl, naphthyl, phenyloxy, benzyloxy or phenylmethoxy, wherein C1-6alkyl phenyl, and naphthylare optionally substituted by one two or three substituents selected from the group consisting of hydroxyl, halogen, oxo,
Figure imgf000063_0003
amino, or nitro;
R3 is selected from the group consisting of hydrogen or C1-6alkyl;
R4 is independently selected, for each occurrence, selected from the group consisting of hydrogen, hydroxyl, oxo, imino, amino, halo,
Figure imgf000063_0004
cycloalkyl, phenyl, naphthyl, heterocyclyl, -O-C1-6alkyl, -NH-C1-6alkyl, -N(C1-6alkyl)C1-6alkyl, nitro, cyano, CF3, - OCF3, -C(O)OC1-6alkyl, -C(O)NHC1-6alkyl, -C(O)NH2 or -OS(O)2C1-4alkyl;
m is independently selected, for each occurrence, selected from the group consisting of 0, 1, 2, or 3; n is selected from the group consisting of 0, 1, or 2; and
p is selected from the group consisting of 0 or 1.
A person of skill in the art appreciates that certain substituents may, in some
embodiments, result in compounds that may have some instability and hence would be less preferred.
[0073] For example, compounds of Formula 1a, Formula 2a or Formula 5a may be selected from the group consisting of:
Figure imgf000064_0001
.
[0074] For example, compounds of Formula 3a or Formula 4a may be selected from the group consisting of:
,
Figure imgf000064_0002
[0075] In a further embodiment, bromodomain ligands include fused heterocyclic systems represented by the structures:
Figure imgf000065_0001
1b and 2b ;
wherein:
V is selected from the group consisting of a NH, S, N(C1-6alkyl), O, or CR4R4;
Q is selected from the group consisting of a bond, C(O), C(S), C(N), SO2, or CR4R4; A is a ring selected from the group consisting of: phenyl, a 5-6 membered cycloalkyl, a 5-6 membered heteroaryl having 1, 2 or 3 heteroatoms each selected from S, N or O, and a 4-7 membered heterocycle having 1, 2 or 3 heteroatoms each selected from N or O;
RA1 is R1; or two RA1 substituents may be taken together with the atoms to which they are attached to form phenyl, a 5-6 membered heteroaryl having 1, 2 or 3 heteroatoms each selected from S, N or O, and a 4-7 membered heterocycle having 1, 2 or 3 heteroatoms each selected from N or O;
R1 is independently selected, for each occurrence, from the group consisting of hydroxyl, halo, C1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl,
Figure imgf000065_0002
C1-6alkoxy, haloC1- 6alkoxy, acylaminoC1-6alkyl, nitro, cyano, CF3, -OCF3, -C(O)OC1-6alkyl, -OS(O)2C1- 4alkyl, -S(C1-4alkyl)C(O)R’, phenyl, naphthyl, phenyloxy, benzyloxy, or phenylmethoxy, wherein C1-6alkyl, phenyl, and napththyl are optionally substituted by one two or three substituents selected from the group consisting of hydroxyl, halogen, oxo, C1-6alkyl, amino, or nitro;
R2 is selected from the group consisting of -O-, amino, C1-6alkyl, -O-C1-6alkyl-, hydroxylC1-6alkyl, aminoC1-6alkyl, haloC1-6alkyl,
Figure imgf000065_0003
acylaminoC1-6alkyl, -C(O)-, - C(O)O-, -C(O)NC1-6alkyl-, -OS(O)2C1-4alkyl-, -OS(O)2--S(C1-4alkyl)C(O)R’’-, -S-C1-6alkyl-, phenyl, naphthyl, phenyloxy, benzyloxy, or phenylmethoxy, wherein C1-6alkyl, phenyl, and naphthyl are optionally substituted by one two or three substituents selected from the group consisting of hydroxyl, halogen, oxo,
Figure imgf000065_0004
amino, or nitro;
R3 is selected from the group consisting of hydrogen or C1-6alkyl;
R4 is independently selected, for each occurrence, from the group consisting of hydrogen, hydroxyl, oxo, imino, amino, halo, cycloalkyl, phenyl, naphthyl, heterocyclyl, -O-C1-6alkyl, -NH-C1-6alkyl, -N(C1-6alkyl)C1-6alkyl, nitro, cyano, CF3, - OCF3, -C(O)OC1-6alkyl, -C(O)NHC1-6alkyl, -C(O)NH2 or -OS(O)2C1-4alkyl; R’ is independently selected, for each occurrence, from the group consisting of hydroxyl, amino, thio, phenyl, naphthyl, or C1-6alkyl, wherein C1-6alkyl, phenyl, and naphthyl are optionally substituted by one two or three substituents selected from the group consisting of hydroxyl, halogen, oxo, C1-6alkyl, amino, or nitro;
R’’ is independently selected, for each occurrence, from the group consisting of–O-, amino, thio, phenyl, naphthyl, or C1-6alkyl, wherein C1-6alkyl, phenyl, and naphthyl are optionally substituted by one two or three substituents selected from the group consisting of hydroxyl, halogen, oxo, C1-6alkyl, amino, or nitro;
m is independently selected, for each occurrence, from the group consisting of 0, 1, 2, or 3;
n is selected from the group consisting of 0, 1, or 2; and
p is selected from the group consisting of 0 or 1.
[0076] Exemplary bromodomain ligands include fused heterocyclic systems re resented b the structures:
Figure imgf000066_0001
,
Figure imgf000067_0001
19 , and 20 ;
wherein:
L and LX are independently selected, for each occurrence, from the group consisting of N, CH, and CR1;
LN1 and LN2 are independently selected from the group consisting of CH2, CHR1, CR1R1, NH, and N(C1-6alkyl); wherein C1-6alkyl is optionally substituted by one two or three substituents selected from the group consisting of hydroxyl, halogen, oxo, C1-6alkyl, amino, or nitro;
LN3 is selected from the group consisting of O, S, NH, and N(C1-6alkyl); wherein C1- 6alkyl is optionally substituted by one two or three substituents selected from the group consisting of hydroxyl, halogen, oxo, C1-6alkyl, amino, or nitro;
U is independently selected from the group consisting of a bond, C(O), C(S), C(N), SO2, or CR4R4;
A is selected from the group consisting of aliphatic, cycloalkyl, heterocyclic, phenyl, naphthyl, heteroaryl, or bicyclic moiety, wherein the cycloalkyl, heterocyclic, phenyl, naphthyl, heteroaryl, or bicyclic moiety is optionally substituted with one, two, three, four or more groups represented by R4;
R1 is independently selected, for each occurrence, from the group consisting of hydroxyl, halo, C1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl,
Figure imgf000067_0002
C1-6alkoxy, haloC1- 6alkoxy, acylaminoC1-6alkyl, nitro, cyano, CF3, -OCF3, -C(O)OC1-6alkyl, -OS(O)2C1-4alkyl, phenyl, naphthyl, phenyloxy, benzyloxy, or phenylmethoxy, wherein C1-6alkyl, phenyl, and naphthyl are optionally substituted by one two or three substituents selected from the group consisting of hydroxyl, halogen, oxo, C1-6alkyl, amino, or nitro; R2 is selected from the group consisting of -O-, amino, C1-6alkyl, -O-C1-6alkyl-, hydroxylC1-6alkyl, aminoC1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, acylaminoC1-6alkyl, -C(O)-, - C(O)O-, -C(O)NC1-6alkyl-, -OS(O)2C1-4alkyl-, -OS(O)2-, -S-C1-6alkyl-, phenyl, naphthyl, phenyloxy, benzyloxy, or phenylmethoxy, wherein C1-6alkyl, phenyl, and naphthyl are optionally substituted by one two or three substituents selected from the group consisting of hydroxyl, halogen, oxo, C1-6alkyl, amino, or nitro;
R3 is selected from the group consisting of hydrogen or C1-6alkyl; and
R4 is independently selected, for each occurrence, from the group consisting of hydrogen, hydroxyl, oxo, imino, amino, halo, C1-6alkyl, cycloalkyl, phenyl, naphthyl, heterocyclyl, -O-C1-6alkyl, -NH-C1-6alkyl, -N(C1-6alkyl)C1-6alkyl, nitro, cyano, CF3, - OCF3, -C(O)OC1-6alkyl, -C(O)NHC1-6alkyl, -C(O)NH2 or -OS(O)2C1-4alkyl.
[0077] For example, compounds of Formula 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 and 17 may be selected from the group consisting of:
Figure imgf000068_0001
,
,
Figure imgf000069_0001
.
[0078] In certain other embodiments, the ligand is one of the compounds listed in Table 1 below or a pharmaceutically acceptable salt thereof, wherein the connector attachment point B
may be understood to be on or A. TABLE 1
Figure imgf000069_0002
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
[0079] One of ordinary skill in the art will appreciate that certain substituents may, in some embodiments, result in compounds that may have some instability and hence would be less preferred.
[0080] In another aspect, exemplary bromodomain ligands include fused heterocyclic systems represented by the structures:
Figure imgf000073_0002
Formula KK wherein
Rx is hydrogen or C1-C3 alkyl;
RY is C1-C3 alkyl, -(C2-C3 alkylenyl)-OH, or C1-C3 haloalkyl;
X1 is N or CRx1 wherein
Rx1 is hydrogen, C bx1
2-C6 alkenyl, C2-C6 alkynyl, -C(O)ORax1, -C(O)NR Rcx1, - C(O)Rdx1, S(O)2Rdx1, -S(O)2NRbx1Rcx1, Gx1, C1-C6 haloalkyl, or C1-C6 alkyl; wherein the C1-C6 alkyl is optionally substituted with one substituent selected from the group consisting of ORax1, SRax1, S(O)Rdx1, S(O)2Rdx1, NRbx1Rcx1, - C(O)Rax1, -C(O)ORax1, -C(O)NRbx1Rcx1, -S(O)2NRbx1Rcx1, and Gx1; Rax1, Rbx1, and Rcx1, at each occurrence, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, Ga, or -(C1-C6 alkylenyl)-Ga;
Rdx1, at each occurrence, are each independently C1-C6 alkyl, C1-C6 haloalkyl, Ga, or -(C1-C6 alkylenyl)-Ga;
X2 is N or CRx2; wherein
Rx2 is hydrogen, C2-C6 alkenyl, C2-C6 alkynyl, -C(O)ORax2, -C(O)NRbx2Rcx2, - C(O)Rdx2, S(O)2Rdx2, -S(O)2NRbx2Rcx2, Gx2, C1-C6 haloalkyl, or C1-C6 alkyl; wherein the C1-C6 alkyl is optionally substituted with one substituent selected from the group consisting of ORax2, SRax2, S(O)Rdx2, S(O)2Rdx2, NRbx2Rcx2, - C(O)Rax2, -C(O)ORax2, -C(O)NRbx2Rcx2, -S(O)2NRbx2Rcx2, and Gx2; Rax2, Rbx2, and Rcx2, at each occurrence, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, Gb, or -(C1-C6 alkylenyl)-Gb;
Rdx2, at each occurrence, is independently C1-C6 alkyl, C1-C6 haloalkyl, Gb, or - (C1-C6 alkylenyl)-Gb;
Y1 is N or CRu; wherein Ru is hydrogen, C1-C6 alkyl, halogen, or C1-C6 haloalkyl; A1 is N or CR1, A2 is N or CR2, A3 is N or CR3, and A4 is N or CR4; with the proviso that zero, one, two, or three of A1, A2, A3, and A4 are N;
R1, R3, and R4 are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, CN, or NO2;
R2 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, - CN, NO2, G2a, -OR2a, -OC(O)R2d, -OC(O)NR2bR2c, -SR2a, -S(O)2R2d, -S(O)2NR2bR2c
, -C(O)R2d, -C(O)OR2a, -C(O)NR2bR2c, -NR2bR2c, -N(R2e)C(O)R2d, -N(R2e)S(O)2R2d, -N(R2e)C(O)O(R2d), - N(R2e)C(O)NR2bR2c, -N(R2e)S(O)2NR2bR2c, -(C1-C6 alkylenyl)-G2a, -(C1-C6 alkylenyl)-OR2a, - (C1-C6 alkylenyl)-OC(O)R2d, -(C1-C6 alkylenyl)-OC(O)NR2bR2c, -(C1-C6 alkylenyl)-S(O)2R2d, - (C1-C6
alkylenyl)-S(O)2NR2bR2c, -(C1-C6 alkylenyl)-C(O)R2d, -(C1-C6 alkylenyl)-C(O)OR2a, -(C1-C6 alkylenyl)-C(O)NR2bR2c, -(C1-C6 alkylenyl)-NR2bR2C, -(C1-C6 alkylenyl)-N(R2e)C(O)R2d, -(C1- C6
alkylenyl)-N(R2e)S(O)2R2d, -(C1-C6 alkylenyl)-N(R2e)C(O)O(R2a), -(C1-C6
alkylenyl)-N(R2e)C(O)NR2bR2c, -(C1-C6 alkylenyl)-N(R2e)S(O)2NR2bR2c, and -(C1-C6 alkylenyl)-CN; R2a, R2b, R2C, and R2e, at each occurrence, are each independently hydrogen, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, G2b, or C1-C6 alkyl wherein the C1-C6 alkyl is optionally substituted with one substituent selected from the group consisting of -ORz1, NRz1Rz2, -C(O)ORz1, -C(O)NRz1Rz2, -S(O)2Rz1, -S(O)2NRz1Rz2, and G2b;
R2d, at each occurrence, is independently C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, G2b, or C1-C6 alkyl wherein the C1-C6 alkyl is optionally substituted with one substituent selected from the group consisting of -ORz1, NRz1Rz2, -C(O)ORz1, -C(O)NRz1Rz2, -S(O)2Rz1, - S(O)2NRz1Rz2, and G2b;
Rz1 and Rz2, at each occurrence, are each independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl;
Gx1, Gx2, Ga, Gb, G2a, and G2b, at each occurrence, are each independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl, and each of which is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 of Rv;
L1 is absent, CH2, C(O), C(H)(OH), (CH2)mO, (CH2)mS(O)n wherein n is 0, 1, or 2; or (CH2)mN(Rz) wherein Rz is hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, (C2-C3 alkylenyl)-OH, or unsubstituted cyclopropyl;
m is 0 or 1;
G1 is C1-C6 alkyl, alkoxyalkyl, G1a , or -(C1-C6 alkylenyl)-G1a; wherein each G1a is independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl, and each G1a is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 of Rw;
Rv and Rw, at each occurrence, are each independently C1-C6 alkyl, C2-C6 alkenyl, C2- C6 alkynyl, halogen, C1-C6 haloalkyl, -CN, oxo, -ORh, -OC(O)Ri -OC(O)NRjRk, -SRh, - S(O)2Rh, -S(O)2NRjRk, -C(O)Rh, -C(O)-monocyclic heterocycle, -C(O)-monocyclic heteroaryl, -C(O)ORh, -C(O)NRjRk, -NRjRk, -N(Rh)C(O)Ri, -N(Rh)S(O)2Ri, -N(Rh)C(O)O(Ri), - N(Rh)C(O)NRjRk, -(C1-C6 alkylenyl)-ORh, -(C1-C6 alkylenyl)-OC(O)Ri, -(C1-C6 alkylenyl)- OC(O)NRjRk, -(C1-C6 alkylenyl)-S(O)2Rh, -(C1-C6 alkylenyl)-S(O)2NRjRk, -(C1-C6 alkylenyl)- C(O)Rh, -(C1-C6 alkylenyl)-C(O)ORh, -(C1-C6 alkylenyl)-C(O)NRjRk, -(C1-C6 alkylenyl)- NRjRk, -(C1-C6 alkylenyl)-N(Rh)C(O)Ri, -(C1-C6 alkylenyl)-N(Rh)S(O)2Ri, -(C1-C6 alkylenyl)- N(Rh)C(O)O(Ri), -(C1-C6 alkylenyl)-N(Rh)C(O)NRjRk, or -(C1-C6 alkylenyl)-CN;
Rh, Rj, Rk, at each occurrence, are each independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; and
Ri, at each occurrence, is independently C1-C6 alkyl or C1-C6 haloalkyl. [0081] In some embodiments, exemplary bromodomain ligands include fused heterocyclic systems represented by the structures:
Figure imgf000076_0001
Formula LL,
wherein:
R1 is selected from the group consisting of H,–C1-C6 alkylene-heterocyclyl, and–C(O)- heterocyclyl, wherein heterocyclyl contains 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S and is optionally substituted by one, two, or three substituents selected from the group consisting of hydroxyl, halogen, oxo, C1-C 6alkyl, amino, and nitro;
R2 is selected from the group consisting of H and C1-C6 alkyl;
R3, independently for each occurrence, is selected from the group consisting of hydrogen,–SO2-C1-C6 alkyl,–NH-SO2-C1-C6 alkyl,–N(C1-C6 alkyl)-SO2-C1-C6 alkyl, and– SO2-heterocyclyl, wherein heterocyclyl contains 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S and is optionally substituted by one, two, or three substituents selected from the group consisting of hydroxyl, halogen, oxo, C1-C 6alkyl, amino, and nitro;
R4, independently for each occurrence, is selected from the group consisting of hydrogen, hydroxyl, halogen, oxo, C1-C 6alkyl, amino, and nitro;
m is 1, 2, or 3; and
n is 1, 2, or 3.
[0082] In certain embodiments, R1 is H. In certain other embodiments, R1 is– methylene-(4-methyl-piperazinyl).
[0083] R2, in certain embodiments, is methyl.
[0084] In some embodiments, R3 is selected from the group consisting of–SO2-methyl, –NH-SO2-ethyl, and–SO2-pyrrolidinyl.
[0085] In certain embodiments, R4 is fluoro.
[0086] In another aspect, exemplary bromodomain ligands include fused heterocyclic systems represented by the structures:
Figure imgf000077_0001
Formula MM, or
Figure imgf000077_0002
Formula NN,
wherein:
R1 is optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted
heterocycloalkyl, haloalkyl, -C(O)R, -C(S)R, -CO2R, -C(O)N(R')(R"), -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R')(R"), -C(S)OR, -S(O)R, -SO2R, -SO2N(R')(R"), -C=NN(R')(R"), - C=NOR, or -C(=N(R'))N(R')(R");
R2 is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, haloalkyl, -C(O)R, -C(S)R, -CO2R, -C(O)N(R')(R"), - C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R')(R"), -C(S)OR, -S(O)R, -SO2R, - SO2N(R')(R"), -C=NN(R')(R"), -C=NOR, -C(=N(R'))N(R')(R"), or -(CH2)pRx; or R1 and R2 together with the atoms to which each is attached, forms an optionally substituted 3-7 membered saturated or unsaturated ring having 0-4 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R3 is H, alkyl, alkenyl, alkynyl, aralkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, or halo, each of which is optionally substituted; or CN, ORA, NRARB, N(RA)S(O)qRARB, N(RA)C(O)RB, N(RA)C(O)NRARB, N(RA)C(O)ORA, N(RA)C(S)NRARB, -N(RA)S(O)qNRARB, S(O)qRA, C(O)RA, C(O)ORA, OC(O)RA, or C(O)NRARB;
each RA is independently optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted heterocyclic;
optionally substituted carbocyclic; or hydrogen;
each RB is independently optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted heterocyclic;
optionally substituted carbocyclic; or hydrogen; or
RA and RB, together with the atoms to which each is attached, can form a
heterocycloalkyl or a heteroaryl; each of which is optionally substituted;
R5 is halogen, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, haloalkyl, -OR, -SR, -CN, - N(R')(R"), -C(O)R, -C(S)R, -CO2R, -C(O)N(R')(R"), -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R')(R"), -C(S)OR, -S(O)R, -SO2R, -SO2N(R')(R"), -N(R')C(O)R, - N(R')C(O)N(R')(R"), -N(R')C(S)N(R')(R"), -N(R')SO2R, -N(R')SO2N(R')(R"), - N(R')N(R')(R"), -N(R')C(=N(R'))N(R')(R"), -C=NN(R')(R"), -C=NOR, -C(=N(R'))N(R')(R"), - OC(O)R, -OC(O)N(R')(R"), or -(CH2)pRx;
each Rx is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, -OR, -SR, -CN, -N(R')(R"), -C(O)R, -C(S)R, -CO2R, - C(O)N(R')(R"), -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R')(R"), -C(S)OR, -S(O)R, - SO2R, -SO2N(R')(R"), -N(R')C(O)R, -N(R')C(O)N(R')(R"), -N(R')C(S)N(R')(R"), -N(R')SO2R, -N(R')SO2N(R')(R"), -N(R')N(R')(R"), -N(R')C(=N(R'))N(R')(R"), -C=NN(R')(R"), -C=NOR, - C(=N(R'))N(R')(R"), -OC(O)R, -OC(O)N(R')(R");
each R is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl;
each R' is independently -R, -C(O)R, -C(S)R, -CO2R, -C(O)N(R)2, -C(S)N(R)2, -S(O)R, -SO2R, -SO2N(R)2, or two R groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted heteroaryl or heterocycloalkyl group;
each R" is independently -R, -C(O)R, -C(S)R, -CO2R, -C(O)N(R)2, -C(S)N(R)2, - S(O)R, -SO2R, -SO2N(R)2, or two R groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted heteroaryl or heterocycloalkyl group; or R' and R", together with the atoms to which each is attached, can form a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl; each of which is optionally substituted;
each p is independently 1, 2, 3, 4, 5, or 6; and
each q is independently 0, 1, or 2.
[0087] In some embodiments, exemplary bromodomain ligands include fused heteroc clic s stems re resented b the structures:
Figure imgf000079_0001
Formula PP,
wherein:
R1 is selected from the group consisting of H and C1-C6 alkyl, optionally substituted by one, two, or three substituents selected from the group consisting of hydroxyl, halogen, oxo, amino, and nitro;
R2 is selected from the group consisting of hydroxyl, halogen, oxo, amino, and nitro; R3 is selected from the group consisting of hydrogen and C1-C6 alkyl;
R4, independently for each occurrence, is selected from the group consisting of hydrogen, C1-C6 alkyl, and -C1-C6 alkylene-phenyl, wherein phenyl is optionally substituted by one, two, or three substituents selected from the group consisting of hydroxyl, halogen, oxo, C1-C 6alkyl, amino, and nitro; and
m is 0, 1, or 2.
[0088] In certain embodiments, R1 is trifluoromethyl.
[0089] In certain embodiments, R3 is ethyl. [0090] In certain embodiments, one R4 is hydrogen. In certain other embodiments, one
Figure imgf000080_0001
[0091] In some embodiments, exemplary bromodomain ligands include compounds represented by:
Figure imgf000080_0002
R2 is selected from
Figure imgf000080_0003
orated by reference in its entirety.
[0092] For example, bromodomain ligands of Formula QQ may be selected from the group consisting of:
Figure imgf000081_0001
[0093] In some embodiments, exemplary bromodomain ligands include compounds represented by:
,
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
wherein:
A is C(R8R9); Y is C(R6R7); J is C(R4R5); R1 is hydrogen or C1-C3alkyl; R2 is hydrogen or C1-C3 alkyl; R3 is heteroaryl, 9 to 12 membered bicyclic aryl, napthalen-1-yl, unsubstituted
phenyl, or X, wherein X is
Figure imgf000085_0001
wherein said heteroaryl, 9 to 12 membered bicyclic aryl, or napthalen-1-yl may be substituted with one to three substituents independently selected from the group consisting of NR16R18, halo, hydroxyl, C1-C3 alkyl, -O-aryl, Ci-C3 alkylene-aryl, C1-C3 alkylene-O-aryl, -S-aryl, -O- C1-C3 alkylene-aryl, -NR16-SO2-NR18-C1-C3 alkyl, -NR16- SO2-NR18- C1-C3 haloalkyl, -NR16- SO2- C1-C3 alkyl, -NR16-SO2- C1-C3 haloalkyl, SO2- NR16R18, SO2- C1-C3 alkyl, -O- C1-C3 alkyl, -C(O)-O- C1-C3 alkyl, -C(O)-OH, -C(O)- NR16R18, -C(O)-NH(C1-C3 haloalkyl), -C(O)- NH(C1-C3 alkylene-heterocycloalkyl), - C(O)-NH(heteroaryl), -NH-C(O)- C1-C3 alkyl, -NH- C(O)-heteroaryl, heterocycloalkyl, -O-C1-C3 alkylene-heterocycloalkyl, -O-C3-C14 cycloalkyl, - O-C1-C3 alkylene-C3-C14 cycloalkyl, -O-C1-C3 alkylene-heteroaryl, or heteroaryl;
wherein X is substituted as set out in (i) or (ii):
four of R10, R11, R12, R13, and R14 are hydrogen, and one of R10, R11, R12, R13, or R14 is selected from the following groups:
R10 is NR16R18, halo, hydroxyl, C1-C3 alkyl, C1-C3 alkylene-aryl, C1-C3 alkylene-O-aryl, -S-aryl, -O-C1-C3 alkylene-aryl, -NR16-SO2-NR18- C1-C3 alkyl, -NR16- SO2-NR18- C1-C3 haloalkyl, -NR16-SO2- C1-C3 alkyl, -NR16- SO2- C1-C3 haloalkyl, SO2- NR16R18, SO2- C1-C3 alkyl, -O-C1-C3 alkyl, - C(O)-O- C1-C3 alkyl, -C(O)-OH, -C(O)- NR16R18, -C(O)-NH(C1-C3 haloalkyl), -C(O)-NH(C1-C3 alkylene-heterocycloalkyl), - C(O)- NH(heteroaryl), NH-C(O)- C1-C3 alkyl, NH-C(O)-heteroaryl, heterocycloalkyl, - O- C1-C3 alkylene-heterocycloalkyl,-O-C3-C14 cycloalkyl, -O- C1-C3 alkylene-C3-C5 cycloalkyl, C1-C3 alkylene-C7-C14 cycloalkyl, -O-C1-C3 alkylene-heteroaryl, or heteroaryl;
R11 is NR16R18, fluoro, iodo, bromo, hydroxyl, C1-C3 alkyl, -O-aryl, C1-C3 alkylene-aryl, C1-C3 alkylene-O-aryl, -S-aryl, -O-C1-C3 alkylene-aryl, -NR16-SO2-NR18- C1-C3 alkyl, -NR16-SO2-NR18- C1-C3 haloalkyl, -NR16- SO2- C1-C3 alkyl, -NR16-SO2- C1-C3 haloalkyl, SO2-NR16R18, SO2- C1-C3 alkyl, -O-C1-C3 alkyl, -C(O)-O- C1-C3 alkyl, -C(O)-OH, -C(O)- NR16R18, -C(O)-NH(C1-C3 haloalkyl), -C(O)-NH(C1-C3 alkylene- heterocycloalkyl), -C(O)-NH(heteroaryl), NH-C(O)- C1-C3 alkyl, NH- C(O)-heteroaryl, heterocycloalkyl, -O-C1-C3 alkylene-heterocycloalkyl,- O-C1-C3 alkylene-C3-C14 cycloalkyl, -O-C1-C3 alkylene-heteroaryl, or heteroaryl;
R12 is NR16R18, halo, hydroxyl, C1-C3 alkyl, C1-C3 alkylene-aryl, C1-C3 alkylene-O-aryl, -S-aryl, -O-C2-C3 alkylene-aryl, -NR16-SO2-NR18- C1-C3 alkyl, -NR16- SO2-NR18- C1-C3 haloalkyl, -NR16-SO2- C1-C3 alkyl, -NR16- SO2- C1-C3 haloalkyl, SO2- NR16R18, SO2- C1-C3 alkyl, -O- C1-C3 alkyl, - C(O)-O- C1-C3 alkyl, -C(O)-OH, -C(O)- NR16R18, -C(O)-NH(C1-C3 haloalkyl), -C(O)-NH(C1-C3 alkylene-heterocycloalkyl), - C(O)- NH(heteroaryl), NH-C(O)- C1-C3 alkyl, NH-C(O)-heteroaryl, heterocycloalkyl, - O-C1-C3 alkylene-heterocycloalkyl, -O-C3-C14 cycloalkyl, -O-C1-C3 alkylene-C3-C14 cycloalkyl, -O-C1-C3 alkylene-heteroaryl, or heteroaryl;
R13 and R14 are NR16R18, halo, hydroxyl, C1-C3 alkyl, -O-aryl, C1-C3 alkylene- aryl, C1-C3 alkylene-O-aryl, -S-aryl, -O-C1-C3 alkylene-aryl, - NR16-SO2-NR18- C1-C3 alkyl, -NR16-SO2-NR18- C1-C3 haloalkyl, -NR16- SO2- C1-C3 alkyl, -NR16-SO2- C1-C3 haloalkyl, SO2-NR16R18, SO2-C1- C3alkyl, -O-C1-C3 alkyl, -C(O)-O-C1-C3 alkyl, -C(O)- OH, -C(O)- NR16R18, -C(O)-NH(C1-C3 haloalkyl), -C(O)-NH(C1-C3 alkylene- heterocycloalkyl), -C(O)-NH(heteroaryl), NH-C(O)- C1-C3 alkyl, NH- C(O)-heteroaryl, heterocycloalkyl, -O-C1-C3 alkylene-heterocycloalkyl, -O-C3-C14 cycloalkyl, -O-C1-C3 alkylene-C3-C14 cycloalkyl, -O-C1-C3 alkylene-heteroaryl, or heteroaryl;
wherein 5-n of R10, R11, R12, R13, and R14 are hydrogen, and n of R10, R11, R12, R13, and R14 are selected from the following groups:
NR16R18, halo, hydroxyl, C1-C3 alkyl, -O-aryl, C1-C3 alkylene-aryl, C1-C3 alkylene-O-aryl, -S-aryl, -0- C1-C3 alkylene-aryl, -NR16-SO2-NR18- C1-C3 alkyl, -NR16- SO2-NR18- C1-C3 haloalkyl, -NR16-SO2- C1-C3 alkyl, - NR16-SO2- C1-C3 haloalkyl, SO2- NR16R18, SO2- C1-C3 alkyl, -O- C1-C3 alkyl, -C(O)-O- C1-C3 alkyl, -C(O)-OH, -C(O)- NR16R18, -C(O)-NH(C1-C3 haloalkyl), -C(O)-NH(C1-C3 alkylene-heterocycloalkyl), - C(O)- NH(heteroaryl), NH-C(0)- C1-C3 alkyl, NH-C(O)-heteroaryl, heterocycloalkyl, - O- C1-C3 alkylene-heterocycloalkyl,-0-C3-C14 cycloalkyl, -O-C1-C3 alkylene-C3-C14 cycloalkyl, -O-C1-C3 alkylene-heteroaryl, or heteroaryl; wherein n is 2, 3, 4 or 5;
wherein any of said aryl groups of -O-aryl, -S-aryl, C1-C3 alkylene-aryl, C1-C3 alkylene-O-aryl; said heterocycloalkyl; said heterocycloalkyl groups of -C(0)-NH(C1-C3 alkylene- heterocycloalkyl) and -O-C1-C3 alkylene-heterocycloalkyl; said heteroaryl and said heteroaryl groups of -C(O)-NH(heteroaryl), NH-C(O)-heteroaryl, and -O-C1-C3 alkylene-heteroaryl; and said cycloalkyl groups of -O-C3-C14 cycloalkyl, -O-C1-C3 alkylene-C3-C5 cycloalkyl, and -O- C1-C3 alkylene-C3-C14 cycloalkyl may be subsitituted with 1 to 3 subsitituents selected from the group consisting of: halo, C1-C3 alkyl, C1-C3 haloalkyl, CN, and NR16R18; R4 and R5 are each independently selected from hydrogen and C1-C4 alkyl; R6 and R7 are each independently selected from hydrogen and C1-C4 alkyl; R8 and R9 are each independently selected from hydrogen and C1-C4 alkyl; and R16 and R18 are each independently selected from hydrogen and C1-C3 alkyl. See, for example, International Patent Application Publication No.
WO/2013/158952, which is hereby incorporated by reference in its entirety.
[0096] For example, an exemplary compound of represented by Formula RR is:
Figure imgf000087_0001
.
[0097] In some embodiments, exemplary bromodomain ligands include compounds represented by:
Figure imgf000088_0001
.
[0098] In some embodiments, exemplary bromodomain ligands include compounds represented by:
Figure imgf000088_0002
.
[0099] In some embodiments, exemplary bromodomain ligands include compounds represented by:
Figure imgf000089_0001
Formula SS,
wherein:
Ring B is absent; or a 3-7 membered saturated or partially unsaturated carbocyclic ring, phenyl, an 8-10 membered bicyclic saturated, partially unsaturated, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms
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;
Rd and Re taking together with their intervening atoms form an isoxazolyl optionally substituted with R1;
R1 is hydrogen or C1-6 aliphatic;
R2-R5 are each independently hydrogen, halogen, optionally substituted C1-6aliphatic, - OR, -SR, -CN, -N(R')2, -C(O)R, -C(S)R, -CO2R, -C(O)N(R')2, -C(O)SR, -C(O)C(O)R, - C(O)CH2C(O)R, -C(S)N(R')2, -C(S)OR, -S(O)R, -SO2R, -SO2N(R')2, -N(R')C(O)R, - N(R')C(O)N(R')2, -N(R')C(S)N(R')2, -N(R')SO2R, -N(R')SO2N(R')2, -N(R')N(R')2, - N(R')C(=N(R'))N(R')2, -C=NN(R')2, -C=NOR, -C(=N(R'))N(R')2, -OC(O)R, -OC(O)N(R')2, or - (CH2)pRx;
each of R2 and R3, R2 and R4, R3 and R5, or R4 and R5 are taken together with their intervening atoms to form CO, or an optionally substituted 3-7 membered saturated or partially unsaturated spiro-fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and X is hydrogen, SO2, CO, a covalent bond, or an optionally substituted bivalent
Figure imgf000090_0001
chain wherein one methylene unit is optionally replaced by -NR'-, - N(R')C(O)-, -C(O)N(R')-, -N(R')SO2-, -SO2N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)0-, -S-, -SO- or -SO2-; or when ring B is absent, X is hydrogen or substituted C1-6 aliphatic; and
Rx is halogen, optionally substituted C1-6 aliphatic, -OR, -SR, -CN, -N(R')2, -C(O)R, - C(S)R, -CO2R, -C(O)N(R')2, -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R')2, -C(S)OR, -S(O)R, -SO2R, -SO2N(R')2, -N(R')C(O)R, -N(R')C(O)N(R')2, -N(R')C(S)N(R')2, -N(R')SO2R, - N(R')SO2N(R')2, -N(R')N(R')2, -N(R')C(=N(R'))N(R')2, -C=NN(R')2, -C=NOR, - C(=N(R'))N(R')2, -OC(O)R, or -OC(O)N(R')2;
each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 7-10 membered bicyclic saturated, partially unsaturated, or aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms
independently selected from nitrogen, oxygen, and sulfur, and a 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each R' is independently -R, -C(O)R, -C(S)R, -CO2R, -C(O)N(R)2, -C(S)N(R)2, -S(O)R, -SO2R, or -SO2N(R)2; or
two R' on the same nitrogen are taken together with their intervening atoms to form an optionally substituted group selected from a 4-7 membered monocyclic saturated or partially unsaturated ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 7-12 membered bicyclic saturated, partially unsaturated, or aromatic fused ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each of m and n is independently 0-4, as valency permits; and
each of R6 and R7 are independently -R, halogen, (C1-6)alkyl, halogen, (C1-6)haloalkyl, (C1-6)alkoxy, (C1-6)haloalkoxy , -OR, -SR, -N(R')2, -CN, -NO2, -C(O)R, -C(S)R, -CO2R, - C(O)N(R')2, -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R')2, -C(S)OR, -S(O)R, -SO2R, -SO2N(R')2, -N(R')C(O)R, -N(R')C(O)N(R')2, -N(R')C(S)N(R')2, -N(R')SO2R, -N(R')SO2N(R')2, -N(R')N(R')2, -N(R')C(=N(R'))N(R')2, -C=NN(R')2, -C=NOR, -C(=N(R'))N(R')2, -OC(O)R, or - OC(O)N(R')2. See, for example, International Patent Application Publication No.
WO/2013/184878, which is hereby incorporated by reference in its entirety.
[00100] For example, an exemplary compound of represented by Formula SS is:
Figure imgf000091_0001
.
[00101] In some embodiments, exemplary bromodomain ligands include compounds re resented b :
Figure imgf000091_0002
Formula TT, wherein R1 is H, halogen, amino, -NH-C1- 6alkyl, -SO2-NH2, -SO2-NHC1-6alkyl, -NHSO2-C1-6alkyl, NO2, C1-6alkyl, or C1-6alkoxy, and R2 is H, acetyl, tosyl, BOC, C1-6alkyl, -C1-6alkyl-COOH, or -C1-6alkyl-CONH-C1-6alkyl. For example, in certain embodiments, R1 is selected from Cl, Br, F, NO2, amino, methyl, methoxy, aminomethyl, -SO2NH-ethyl; -SO2NH-methyl, and -NH-SO2-methyl. In certain embodiments, R2 may be methyl, -CH2CH2COOH, -CH2CH2CONHMe, -CH2COOH, and -CH2CONHMe.
[00102] In some embodiments, exemplary bromodomain ligands include compounds represented by:
Figure imgf000092_0001
, wherein R1 is halo, R3 is C1-6alkyl, amino, or–NH-C1-6- alkyl, and X is O or S. For example, in certain embodiments, R1 is selected from Cl and Br. In certain embodiments, R3 is selected methyl, amino, and -NH-methyl.
[00103] In some embodiments, exemplary bromodomain ligands include compounds shown in the following Table:
Figure imgf000092_0002
.
[00104] In some embodiments, exemplary bromodomain ligands include compounds represented by:
Figure imgf000093_0001
.
[00105] In some embodiments, exemplary bromodomain ligands include compounds represented by:
Figure imgf000093_0002
, wherein
R1
, R2
, R3
, R4
, and R5 are independently selected from the group consisting of hydrogen, hydroxyl, amino, halo, C1-6alkyl, cycloalkyl, phenyl, naphthyl, heterocyclyl, -O-C1-6alkyl, -NH- C1-6alkyl, -N(C1-6alkyl)C1-6alkyl, nitro, cyano, CF3, -OCF3, -C(O)OC1-6alkyl, -C(O)NHC1- 6alkyl, -C(O)NH2, and -OS(O)2C1-4alkyl.
[00106] In some embodiments, exemplary bromodomain ligands include compounds represented by:
Figure imgf000094_0001
.
[00107] In some embodiments, exemplary bromodomain ligands include compounds represented by:
Figure imgf000094_0002
Formula VV,
wherein:
A is phenyl or 5-6 membered heteroaryl ring;
R1a
, R1b
, R1c
, R2
, R3
, R4
, and R5 are independently selected from the group consisting of hydrogen, hydroxyl, amino, halo, C1-6alkyl, cycloalkyl, phenyl, naphthyl, heterocyclyl, -O- C1-6alkyl, -NH-C1-6alkyl, -N(C1-6alkyl)C1-6alkyl, nitro, cyano, CF3, -OCF3, -C(O)OC1-6alkyl, - C(O)NHC1-6alkyl, -C(O)NH2, and -OS(O)2C1-4alkyl. See, for example, International Patent Application Publication No. WO/2014/026997, which is hereby incorporated by reference in its entirety.
[00108] In some embodiments, exemplary bromodomain ligands include compounds selected from the group consisting of TG101209, TG101348, NU7441, GW612286X, SB202190, BI-2536, Fostamatinib, SB251527, SB614067R, SB284847BT, Flavopiridol, SB409514, SB610251B, Dinaciclib, and pharmaceutically acceptable salts thereof.
[00109] In some embodiments, exemplary bromodomain ligands include compounds selected from the group consisting of SB-203580, PP-242, SCH-772984, PF-431396,
Volasertib, BI-6727, AZ-3146, GSK-2636771, Brivanib, BI-D1870, Tideglusib, and pharmaceutically acceptable salts thereof. [00110] In some embodiments, exemplary bromodomain ligands include compounds selected from the group consisting of:
,
Figure imgf000095_0001
[00111] In some embodiments, exemplary bromodomain ligands include compounds represented by the formula:
Figure imgf000095_0002
Formula WW,
wherein: R1 is selected from
Figure imgf000096_0001
; and
R2 and R3 are independently selected from H and halogen (e.g., fluoro).
[00112] In some embodiments, exemplary bromodomain ligands include compounds represented by the formula:
Figure imgf000096_0002
Formula XX,
wherein:
W is N or C-R8;
X is N, CH or C(CH3);
Z is N or C-R14;
Y is N or C-R5 (subject to proviso that no more than 2 of W, X, Y and Z are N);
R1 is C1-4alkyl;
R2 is H, OH, C1-4alkyl, -N(CH3)2, -NH(CH3), halo, -CF3, -NH2, -OC1-4alkyl, -NHC(0)H, -NHC(0)d. 4alkyl, -N(CH3)C(0)Ci.4alkyl, -NHCH(CH3)CH2OCH3, -N(CH3)CH2CH2OCH3, - OCH2CH2OCH3, -OCH2CH2CH2OH, -OCH(CH3)CH2OCH3, or R2 is a group selected from -G- CH2CH(R3)(R4), -G-CH(R3)(R4) and -G-R3 in which G is NH, N(CH3), O, C(0)NH or
NHC(O);
R3 is phenyl, pyridinyl, C3-7cycloalkyl or a heterocycle optionally substituted by =O; and R4 is H or C -4 alkyl;
R5 is H, C1-4alkyl, halo, -C–OC1-4 alkyl, -CH2NH2, -OCF3 or-SO2CH3;
Figure imgf000097_0001
R6 is -NRnR12 or a group
D is CH or N;
E is N, O, CH or SO2;
R7, when present, is H, OH, C1-4alkyl, -NH2, -SO2C1-4alkyl, -SO2phenyl, -SO2benzyl, - SO2N(CH3)2, -NHSO2CH3, -C(O)C1-4alkyl or -C(O)phenyl;
R8 is H, C1-4alkyl, halo, -CF3, CN, OH, -OC1-4 alkyl, -OCF3, -OCH2phenyl or -OCH2C3- 7cycloalkyl;
R9 is H, C1-4alkyl, -C(O)NH2, -CO2CH3, -CF3, halo, OH, -OC1-4alkyl, -CH2OH, - C(0)NHCH3, - C(0)N(CH3)2, -CH2OC1-4alkyl; -CH2OCH2C3-7cycloalkyl or oxo;
R10 is H, C1-4alkyl, -C(O)NH2, -CO2CH3, -CF3, halo, OH or–OC1-4alkyl;
R11 is H, C1-4alkyl or SO2CH3;
R12 is H, C1-4alkyl, C1-4alkyleneNHR13, C2-4alkyleneOH, SO2CH3, a heterocycle or a heterocycle comprising SO2;
R13 is H or SO2CH3;
R14 is H, C1-4alkyl or NHC(O)C1-4alkyl; and
n and m are each an integer independently selected from 0, 1 and 2; or a salt thereof. See, for example, International Patent Application Publication No. WO/2014/078257, which is hereby incorporated by reference in its entirety.
[00113] For example, an exemplary compound of Formula XX is represented by the formula:
Figure imgf000098_0001
pharmaceutically acceptable salts thereof.
[00114] In some embodiments, exemplary bromodomain ligands include compounds re resented b the formula:
Figure imgf000098_0002
(Formula YY),
wherein:
W1 is selected from N and CR1;
W2 is selected from N and CR2;
W3 is selected from N and CR3;
W4 is selected from N and CR4;
each W may be the same or different from each other; A is selected from N and CH;
R1, R2, R3, and R4 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, aryl, hydroxyl, and halogen;
two adjacent substituents selected from R1, R2, R3, and Ry may be connected in a 5- or 6-membered ring to form a bicyclic carbocycle or bicyclic heterocycle;
AR1 is a group selected from the following:
Figure imgf000099_0001
AR2 is a group selected from the following:
Figure imgf000100_0001
R5 is selected from hydrogen, alkyl, alkoxy, thioalkyl, amino, and halogen;
R6 is selected from hydrogen, alkoxy, alkyl, aminoalkyl, and thioalkyl;
Y is selected from NH, O, and S;
W5 is selected from N and CQ1;
W6 is selected from N and CQ2;
W7 is selected from N and CQ3;
W8 is selected from N and CQ4;
W9 is selected from N and CQ5;
Q1, Q2, Q3, Q4, and Q5 are independently selected from hydrogen, alkyl, halogen,—CN, —SO2Me,—SO2Et,—SO2Pr,—S(O)Me,—S(O)Et,—S(O)Pr,—S(O)iPr, amide, ketone,— COOH, and ester; and
two adjacent substituents selected from R5, R6, Q1, Q2, Q3, Q4, Q5, and Q6 may be connected in a 5- or 6-membered ring to form an unsubstituted carbocycle or heterocycle. See, for example, U.S. Patent Application Publication Nos. US 2014-0140956 and US 2014- 0142102, each of which is hereby incorporated by reference in its entirety.
[00115] For example, an exemplary compound of Formula YY is represented by the formula:
Figure imgf000101_0001
pharmaceuticaally salts thereof.
[00116] In some embodiments, exemplary bromodomain ligands include compounds represented by the formulae:
Figure imgf000102_0001
Figure imgf000102_0002
, and
Figure imgf000103_0001
.
[00117] In some embodiments, exemplary bromodomain ligands include compounds represented by the formulae:
N O
,
Figure imgf000103_0002
,
Figure imgf000104_0001
pharmaceutically acceptable salts thereof.
[00118] In some embodiments, exemplary bromodomain ligands include a compound represented by the formula:
Figure imgf000105_0001
and pharmaceutically acceptable salts thereof.
[00119] In some embodiments, exemplary bromodomain ligands include a compound represented by the formula:
Figure imgf000105_0002
Formula ZZ,
wherein:
W1 is selected from N and CR5;
W2 is selected from N and CR4
W3 is selected from N and CR3;
each W may be the same or different from each other;
R1 is selected from a carbocycles or heterocycles; R2 is selected from a 5~ or 6-membered monocyclic carbocycle or a 5- or 6-membered monocyclic heterocycle;
R3, R4, and R5 are each independently selected from hydrogen, alkyl, -OH, -NH , thioalkyl, alkoxy, ketone, ester, carboxyiic acid, urea, carbamate, carbonate, amino, amide, halogen, carbocycle, heterocycle, sulfone, sulfoxide, sulfide, sulfonamide, and -CN;
R3 and R4 may be connected to form an optionally substituted 5-, 6-, or 7-membered carbocycle or heterocycle;
R4 may be connected to B or R2 to form a carbocycle or heterocycle;
X is selected from 0 and 5;
A is selected from -CRXRY-, OG, -C(O)CRxRy-, -CRxRyCRA-, -SO2 , -CRxRyCR,RvO-, - CR„RyCRjRvN- ,-CRXR,,.CR2R.,S-, and -CRXRVCRZRVCRQRR-;
RX, RY, RZ, Rv, RQ, and RR are each independently selected from hydrogen, alkyl(C1- C8), halogen, -OH, -CF3, amino, alkoxy (C C8), carboxyl, -CN, sulfone, and sulfoxide, carbocycle, heterocycle, or two substituents selected from Rx, RY, Rz, RV, RQ and RR may form an oxo or thio-oxo group, or
two substituents selected from RS, RY, RZ, Rv, R5, and R1 may be connected in a 5- or 6- membered ring to form a bicyc!ic carbocycle or bicyclic heterocycle;
B is selected from -(CRaRb)n-, -(CRaRbCRcRd)-, -O-, -OCRaRb-, -CRaRbO-, -NH-, - NHCRaRb-, - CRaRbNH-, -S-, -SCRaRb-,-CRaRbS-, -S(O)-, -S(O)CRaRb-, -CRaRbS(O)-, -SO2-, - SO2CRaRb-, and -CRaRbSO2-;
n is selected from 0 and 1, meaning if n = 0 then 8 is absent and R2 is connected directly to the center ring;
Ra, Rb, Rc, and Rd are each independently selected from hydrogen, alkyl(C1-C3), and alkoxy(C1-C3). See, for example, International Patent Application Publication No.
WO/2014/096965, which is hereby incorporated by reference in its entirety.
[00120] For example, an exemplary compound of Formula ZZ is represented by the formula:
Figure imgf000107_0001
, and pharmaceutically acceptable salts thereof.
[00121] In some embodiments, exemplary bromodomain ligands include a compound re resented b the formula:
Figure imgf000107_0002
Formula AAA,
wherein:
A is NH or O;
X is N or CH;
N is 0 or 1;
R1 is–C(O)NR8R9 or–SO2NR8R9;
R2, R3, R4, R5, and R6 are independently selected from the group consisting of hydrogen, hydroxyl, amino, halo, C1-6alkyl, cycloalkyl, phenyl, naphthyl, heterocyclyl, -O-C1- 6alkyl, -NH-C1-6alkyl, -N(C1-6alkyl)C1-6alkyl, nitro, cyano, CF3, -OCF3, -C(O)OC1-6alkyl, - C(O)NHC1-6alkyl, -C(O)NH2, and -OS(O)2C1-4alkyl. See, for example, International Patent Application Publication Nos. WO/2014/095774 and WO/2014/095775, each of which is hereby incorporated by reference in its entirety.
[00122] In some embodiments, exemplary bromodomain ligands include a compound represented by the formula:
Figure imgf000108_0001
Formula BBB,
wherein:
Cy1 is an optionally substituted monocyclic ring having 1-3 heteroatoms independently selected from N and O; wherein the optional substituent is alkyl;
Cy2 is an optionally substituted monocyclic ring having 0-2 heteroatoms; wherein the heteroatom is N and the optional substituents are selected from alkyl, halogen and alkoxy;
R1 is selected from hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl,
cycloalkylalkyl and heterocyclylalkyl;
R2 and R3 are independently selected from the halogen, hydroxy or alkyl; or R2 and R3 combined together to form an oxo group;
alternatively, R2 and R3 can be taken together with the carbon atom to which they are attached to form a 3-4 membered cycloalkyl ring;
R4 is selected from hydrogen, halogen and alkyl; and
R5 is selected from hydrogen, halogen, alkyl and alkoxy. See, for example,
International Patent Application Publication No. WO/2014/128655, which is hereby incorporated by reference in its entirety.
[00123] For example, an exemplary compound of Formula BBB is represented by the formula:
Figure imgf000109_0001
, and pharmaceutically acceptable salts thereof.
[00124] In some embodiments, exemplary bromodomain ligands include a compound represented by the formula:
Figure imgf000109_0002
Formula CCC,
wherein:
A is phenyl or a 5-6 membered heteraryl ring;
X is O or S; and
R1a, R1b, R2, R3, R4, and R5 are independently selected from the group consisting of hydrogen, hydroxyl, amino, halo, C1-6alkyl, cycloalkyl, phenyl, naphthyl, heterocyclyl, -O-C1- 6alkyl, -NH-C1-6alkyl, -N(C1-6alkyl)C1-6alkyl, nitro, cyano, CF3, -OCF3, -C(O)OC1-6alkyl, - C(O)NHC1-6alkyl, -C(O)NH2, and -OS(O)2C1-4alkyl. See, for example, International Patent Application Publication No. WO/2014/128067, which is hereby incorporated by reference in its entirety.
[00125] In some embodiments, exemplary bromodomain ligands include a compound represented by the formula:
Formula DDD or
Figure imgf000110_0001
Formula EEE;
wherein:
X is C or N;
Y is–C(O)OR12,–C(O)NR10Rn, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl;
m and n are independently 0 or 1;
R1, R2, R3, R4, and R5 are independently selected from the group consisting of hydrogen, hydroxyl, amino, halo, C1-6alkyl, cycloalkyl, phenyl, naphthyl, heterocyclyl, -O-C1- 6alkyl, -NH-C1-6alkyl, -N(C1-6alkyl)C1-6alkyl, nitro, cyano, CF3, -OCF3, -C(O)OC1-6alkyl, - C(O)NHC1-6alkyl, -C(O)NH2, and -OS(O)2C1-4alkyl. See, for example, International Patent Application Publication Nos. WO/2014/128111 and WO/2014/128070, which is hereby incorporated by reference in its entirety.
[00126] In some embodiments, exemplary bromodomain ligands include a compound represented by the formula:
Figure imgf000111_0001
Formula FFF;
wherein:
A is optionally substituted heteroaryl or optionally substituted heterocyclo, wherein the substituents are one or more R14, R15 or R16;
R is hydrogen, optionally substituted (C1-C6)alkyl, optionally substituted (C3- C8)cycloalkyl(C1-C6)alkyl, optionally substituted aryl(C1-C6)alkyl, optionally substituted heteroaryl(C1-C6)alkyl, optionally substituted heterocyclo(C1-C6)alkyl, optionally substituted (C1-C6)alkyl-CO-, optionally substituted aryl-CO-, optionally substituted (C3-C8)cycloalkyl- CO-, optionally substituted heteroaryl, optionally substituted heterocyclo-CO-, optionally substituted aryl-SO2-, optionally substituted (C1-C6)alkyl-SO2- , optionally substituted (C3- C8)cycloalkyl-SO2- optionally substituted heteroaryl-SO2-, optionally substituted (C1-C6)alkyl- OCO- or optionally substituted (C3-C8)cycloalkyl-OCO-;
Figure imgf000111_0002
;
X and Y are independently selected from hydrogen, optionally substituted (C1-C6)alkyl, optionally substituted (C3-C8)cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclo; Z is hydrogen, halogen, -OH, (Ci-C6)alkyl, (C1-C6)alkoxy, -NR3R4, -CONR3R4, - OCONR3R4, -NR6OCOR3, -NR6CONR3R4, -NR6SO2NR3R4 or -NR6SO2R4;
R1 is halogen, -CN, OH, -NR3R4, -CONR3R4, -COOH, -OCONR3R4, -NHOCOR7, - NHCONR7R8, -NHSO2NR7R8, optionally substituted (C1-C6)alkyl, optionally substituted (C2- C6)alkenyl, optionally substituted (C2-C6)alkynyl, optionally substituted (C1-C6)alkoxy, optionally substituted (C3-C8)cycloalkyl, optionally substituted (C3-C8)cycloalkyl-CO-, optionally substituted (C3-C8)cycloalkyl-SO2-, optionally substituted aryl (C1-C6)alkoxy, optionally substituted (C3-C8)cycloalkyl (C1-C6)alkoxy, optionally substituted heterocyclyl- CO-, optionally substituted heterocyclyl, optionally substituted (C1-C6)alkyl-SO2-, -NHSO2- optionally substituted (C1-C6)alkyl, -NHSO2-optionally substituted heterocyclo, optionally substituted (C1-C6)alkyl-NHSO2- or optionally substituted heterocyclo-NHSO2-;
R2 is H, halogen, -CN, -COOH, -CONR7R8, -NHCOR3R4, -OCONR3R4, -NHCOOR3R4, optionally substituted (C1-C6)alkyl, optionally substituted (C2-C6)alkynyl, optionally substituted (C1-C6)alkoxy, optionally substituted heteroaryl or optionally substituted heterocyclo;
R3 is hydrogen, optionally substituted (C1-C6)alkyl, optionally substituted (C3- C8)cycloalkyl, optionally substituted (C2-C6)alkenyl, optionally substituted (C2-C6)alkynyl, cyano(C1-C6)alkyl, hydroxy(C1-C6)alkyl, optionally substituted aryl, optionally substituted aryl(C1-C6)alkyl, optionally substituted aryloxy(C1-C6)alkyl, optionally substituted (C1- C6)alkyl-SO2-, optionally substituted heterocyclyl, optionally substituted heterocyclyl(C1- C6)alkyl, optionally substituted heteroaryl or optionally substituted heteroaryl(C1-C6)alkyl, R4 is hydrogen, optionally substituted (C1-C6)alkyl or optionally substituted (C3- C8)cycloalkyl;
or R3 and R4 may be taken together with the nitrogen atom to which they are attached to form an optionally substituted (C4-C8) heteroaryl or (C4-C8) heterocyclic ring;
R6 is hydrogen or optionally substituted (C1-C6)alkyl;
R7 and R8 are independently hydrogen, optionally substituted (C1-C6)alkyl, optionally substituted (C3-C8)cycloalkyl, optionally substituted (C2-C6)alkenyl, optionally substituted (C2- C6)alkynyl, cyano(C1-C6)alkyl, hydroxy(C1-C6)alkyl, optionally substituted aryl, optionally substituted aryl(C1-C6)alkyl, optionally substituted; aryloxy(C1-C6)alkyl, optionally substituted (C1-C6)alkyl-SO2-, optionally substituted heterocyclyl, optionally substituted heterocyclyl(C1-C6)alkyl, optionally substituted heteroaryl or optionally substituted heteroaryl(C1-C6)alkyl;
or R7 and R8 may be taken together with the nitrogen atom to which they are attached to form an optionally substituted (C4-C8) heteroaryl or (C4-C8) heterocyclic ring;
R12 and R13 are independently hydrogen, halogen, -CN, OH, -CONR3R4, -NHCOOR4, - NHCONR3R4, -NHCOR4, -NHSO2R7, -SO2NR3R4, -NHSO2NR3R4, -SO2R7, optionally substituted (C1-C6)alkyl, optionally substituted (C3-C8)cycloalkyl, optionally substituted (C1- C6) alkoxy, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclo;
R14 is hydrogen, optionally substituted(C1-C6)alkyl, (C1-C6)alkoxy, halogen, -CN, - NR3R4, OH, -NHOCOR7, -OCONR7R8, -NHCONR7R8 or -CF3;
R15 is hydrogen, optionally substituted(C1-C6)alkyl, (C1-C6)alkoxy, halogen, -CN, - NR3R4, OH, -NHOCOR7, -OCONR7R8, -NHCONR7R8 or -CF3;
R16 is hydrogen, optionally substituted(C1-C6)alkyl, (C1-C6)alkoxy, halogen, -CN, - NR3R4, OH, -NHOCOR7, -OCONR7R8, -NHCONR7R8 or -CF3;
with the proviso that only one of R14, R15 and R16 is hydrogen;
and/or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof. See, for example, International Patent Application Publication Nos. WO/2014/134232 and WO/2014/134267, which is hereby incorporated by reference in its entirety.
[00127] For example, an exemplary compound of Formula FFF is represented by the f rm l
Figure imgf000113_0001
, and pharmaceutically acceptable salts thereof. [00128] In some embodiments, exemplary bromodomain ligands include a compound represented by the formula:
Figure imgf000114_0001
Formula GGG;
wherein:
R1 is CD3, C1-C3 alkyl, or C1-C3 haloalkyl;
R2 is H or C1-C3 alkyl;
Y1 is N or CR3;
R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl,— C(O)R3a,—C(O)OR3a,—C(O)NR3bR3c,—C(O)N(R3b)NR3bR3c,—S(O)R3d,—S(O)2R3a,— S(O)2NR3bR3c or G1; wherein the C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl are each independently unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of G1,—C(O)R3a,—C(O)OR3a,—C(O)NR3bR3c,—S(O)R3d,—S(O)2R3a, —S(O)2NR3bR3c,—OR3a,—OC(O)R3d,—NR3bR3c, N(R3b)C(O)R3d, N(R3b)SO2R3d,
N(R3b)C(O)OR3d, N(R3b)C(O)NR3bR3c, N(R3b)SO2NR3bR3c, and N(R3b)C(NR3bR3c)ő NR3bR3c; Y2 is C(O), S(O)2, or CR4R5;
R4 is H, deuterium, C1-C6 alkyl, halogen, or C1-C6 haloalkyl; and
R5 is H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, —C(O)R5a,—C(O)OR5a,—C(O)NR5bR5c,—S(O)R5d,—S(O)2R5a,—S(O)2NR5bR5c, or G1; wherein the C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl are each independently unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of G1, —C(O)R5a,—C(O)OR5a,—C(O)NR5bR5c,—C(O)N(R5b)NR5bR5c,—S(O)R5d,—S(O)2R5a,— S(O)2NR5bR5c,—OR5a,—OC(O)R5d—NR5bR5c, N(R5b)C(O)R5d, N(R5b)SO2R5d,
N(R5b)C(O)OR5d, N(R5b)C(O)NR5bR5c, N(R5b)SO2NR5bR5c, and N(R5b)C(NR5bR5c)ő NR5bR5c;
R3a, R3b, R3c, R5a, R5b, and R5C, at each occurrence, are each independently H, C1- C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6haloalkyl, G1, or—( C1-C6alkylenyl)-G1;
R3d and R5d, at each occurrence, are each independently C1-C6 alkyl, C2-C6alkenyl, C2- C6alkynyl, C1-C6haloalkyl, G1, or—( C1-C6 alkylenyl)-G1;
G1, at each occurrence, is independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; and each G1 is optionally substituted with 1, 2, 3, 4, or 5 R1g groups;
R6 is H, C1-C6 alkyl, C2-C6alkenyl, C2-C6alkynyl, halogen, C1-C6 haloalkyl,—C(O)R6a, —C(O)OR6a,—C(O)NR6bR6c,—S(O)2R6a,—S(O)2NR6bR6c, or G2; wherein the C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl are each independently unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of G2,—C(O)R6a,—
C(O)OR6a,—C(O)NR6bR6c,—C(O)N(R6b)NR6bR6c,—S(O)R6d,—S(O)2R6a,—S(O)2NR6bR6c, —OR6a,—OC(O)R6d,—NR6bR6c, N(R6b)C(O)R6d, N(R6b)SO2R6d, N(R6b)C(O)OR6d,
N(R6b)C(O)NR6bR6c, N(R6b)SO2NR6bR6C, and N(R6b)C(NR6bR6c)ő NR6bR6c;
R6a, R6b, and R6c, at each occurrence, are each independently H, alkyl, C2-C6 alkenyl, C2-C6 alkynyl, haloalkyl, G2,—(C1-C6 alkylenyl)-G2,—(C1-C6 alkylenyl)-ORa,—(C1-C6 alkylenyl)-S(O)2Ra,—(C1-C6 alkylenyl)-S(O)2NRcRd,—(C1-C6 alkylenyl)-C(O)Ra,—(C1-C6 alkylenyl)-C(O)ORa,—(C1-C6 alkylenyl)-C(O)NRcRd,—(C1-C6 alkylenyl)-NRcRd,—(C1-C6 alkylenyl)-N(Re)C(O)Rb,—(C1-C6 alkylenyl)-N(Re)S(O)2Rb,—(C1-C6 alkylenyl)- N(Re)C(O)O(Rb),—(C1-C6 alkylenyl)-N(Re)C(O)NRcRd, or—(C1-C6 alkylenyl)- N(Re)S(O)2NRcRd;
R6d, at each occurrence, is independently alkyl, C2-C6 alkenyl, C2-C6 alkynyl, haloalkyl, G2,—(C1-C6 alkylenyl)-G2,—(C1-C6 alkylenyl)-ORa,—(C1-C6 alkylenyl)-S(O)2Ra,—(C1-C6 alkylenyl)-S(O)2NRcRd,—(C1-C6 alkylenyl)-C(O)Ra,—(C1-C6 alkylenyl)-C(O)ORa,—(C1-C6 alkylenyl)-C(O)NRcRd,—(C1-C6 alkylenyl)-NRcRd,—(C1-C6 alkylenyl)-N(Re)C(O)Rb,—(C1- C6 alkylenyl)-N(Re)S(O)2Rb,—(C1-C6 alkylenyl)-N(Re)C(O)O(Rb),—(C1-C6 alkylenyl)- N(Re)C(O)NRcRd, or—(C1-C6 alkylenyl)-N(Re)S(O)2NRcRd;
G2, at each occurrence, is independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; and each G2 is optionally substituted with 1, 2, 3, 4, or 5 R2g groups; A1 is C(R7) or N; A2 is C(R8) or N; A3 is C(R9) or N; and A4 is C(R10) or N; wherein zero, one, or two of A1, A2, A3, and A4 are N;
R7, R8, and R9, are each independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl,—CN, NO2,—ORy1,—OC(O)Ry2,—OC(O)NRy3Ry4,—SRy1,— S(O)2Ry1,—S(O)2NRy3Ry4,—C(O)Ry1,—C(O)ORy1,—C(O)NRy3Ry4,—NRy3Ry4,—
N(Ry3)C(O)Ry2,—N(Ry3)S(O)2Ry2,—N(Ry3)C(O)O(Ry2),—N(Ry3)C(O)NRy3Ry4,—
N(Ry3)S(O)2NRy3Ry4, G3,—(C1-C6 alkylenyl)-CN,—(C1-C6 alkylenyl)-ORy1,—(C1-C6 alkylenyl)-OC(O)Ry2,—(C1-C6 alkylenyl)-OC(O)NRy3Ry4,—(C1-C6 alkylenyl)-S(O)2Ry1,— (C1-C6 alkylenyl)-S(O)2NRy3Ry4,—(C1-C6 alkylenyl)-C(O)Ry1,—(C1-C6 alkylenyl)-C(O)ORy1, —(C1-C6 alkylenyl)-C(O)NRy3Ry4,—(C1-C6 alkylenyl)-NRy3Ry4,—(C1-C6 alkylenyl)- N(Ry3)C(O)Ry2,—(C1-C6 alkylenyl)-N(Ry3)S(O)2Ry2,—(C1-C6 alkylenyl)-N(Ry3)C(O)O(Ry2), —(C1-C6 alkylenyl)-N(Ry3)C(O)NRy3Ry4,—(C1-C6 alkylenyl)-N(Ry3)S(O)2NRy3Ry4,—(C1-C6 alkylenyl)-CN, or—(C1-C6 alkylenyl)-G3;
Ry1, Ry3, and Ry4, at each occurrence, are each independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, G3,—( C1-C6 alkylenyl)-G3,—( C1-C6 alkylenyl)- ORa,—( C1-C6 alkylenyl)-S(O)2Ra,—( C1-C6 alkylenyl)-S(O)2NRcRd,—( C1-C6 alkylenyl)- C(O)Ra,—( C1-C6 alkylenyl)-C(O)ORa,—( C1-C6 alkylenyl)-C(O)NRcRd,—( C1-C6 alkylenyl)-NRcRd,—( C1-C6 alkylenyl)-N(Re)C(O)Rb,—( C1-C6 alkylenyl)-N(Re)S(O)2Rb,—( C1-C6 alkylenyl)-N(Re)C(O)O(Rb),—( C1-C6 alkylenyl)-N(Re)C(O)NRcRd, or—( C1-C6 alkylenyl)-N(Re)S(O)2NRcRd;
Ry2, at each occurrence, is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1- C6 haloalkyl, G3,—(C1-C6 alkylenyl)-G3,—(C1-C6 alkylenyl)-ORa,—(C1-C6 alkylenyl)- S(O)2Ra,—(C1-C6 alkylenyl)-S(O)2NRcRd,—(C1-C6 alkylenyl)-C(O)Ra,—(C1-C6 alkylenyl)- C(O)ORa,—(C1-C6 alkylenyl)-C(O)NRcRd,—(C1-C6 alkylenyl)-NRcRd,—(C1-C6 alkylenyl)- N(Re)C(O)Rb,—(C1-C6 alkylenyl)-N(Re)S(O)2Rb,—(C1-C6 alkylenyl)-N(Re)C(O)O(Rb),— (C1-C6 alkylenyl)-N(Re)C(O)NRcRd, or—(C1-C6 alkylenyl)-N(Re)S(O)2NRcRd;
G3, at each occurrence, is independently aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocycle; and each G3 group is optionally substituted with 1, 2, 3, 4, or 5 R4g groups;
R10 is H, C1-C3 alkyl, halogen, C1-C3 haloalkyl, or—CN;
R1g, R2g, and R4g, at each occurrence, is independently selected from the group consisting of oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6haloalkyl,—CN, NO2, G2a,—ORa,—OC(O)Rb,—OC(O)NRcRd,—SRa,—S(O)2Ra,—S(O)2NRcRd,—C(O)Ra, —C(O)ORa,—C(O)NRcRd,—NRcRd,—N(Re)C(O)Rb,—N(Re)S(O)2Rb,—N(Re)C(O)O(Rb), —N(Re)C(O)NRcRd,—N(Re)S(O)2NRcRd,—(C1-C6 alkylenyl)-CN,—(C1-C6 alkylenyl)-G2a, —(C1-C6 alkylenyl)-ORa,—(C1-C6 alkylenyl)-OC(O)Rb,—( C1-C6alkylenyl)-OC(O)NRcRd,— ( C1-C6alkylenyl)-S(O)2Ra,—( C1-C6alkylenyl)-S(O)2NRcRd,—( C1-C6alkylenyl)-C(O)Ra,—( C1-C6alkylenyl)-C(O)ORa,—( C1-C6alkylenyl)-C(O)NRcRd,—( C1-C6alkylenyl)-NRcRd,—( C1-C6alkylenyl)-N(Re)C(O)Rb,—( C1-C6alkylenyl)-N(Re)S(O)2Rb,—( C1-C6alkylenyl)- N(Re)C(O)O(Rb),—( C1-C6alkylenyl)-N(Re)C(O)NRcRd,—( C1-C6alkylenyl)- N(Re)S(O)2NRcRd, or—( C1-C6alkylenyl)-CN;
Ra, Rc, Rd, and Re, at each occurrence, are each independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, G2a, or—(C1-C6 alkylenyl)-G2a;
Rb, at each occurrence, is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1- C6 haloalkyl, G2a, or—( C1-C6 alkylenyl)-G2a;
G2a, at each occurrence, are each independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; and each G2a group is optionally substituted with 1, 2, 3, 4, or 5 R3g groups;
R3g, at each occurrence, is independently oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl,—CN, NO2,—ORz1,—OC(O)Rz2,—OC(O)NRz3Rz4,— SRz1,—S(O)2Rz1,—S(O)2NRz3Rz4,—C(O) Rz1,—C(O)ORz1,—C(O)NRz3Rz4,— NRz3Rz4,—N(Rz3)C(O)Rz2,—N(Rz3)S(O)2Rz2,—N(Rz3)C(O)O(Rz2),—
N(Rz3)C(O)NRz3Rz4,—N(Rz3)S(O)2NRz3Rz4,—( C1-C6 alkylenyl)-ORz1,—( C1-C6 alkylenyl)-OC(O)Rz2,—( C1-C6 alkylenyl)-OC(O)NRz3Rz4,—( C1-C6 alkylenyl)-S(O)2Rz1, —( C1-C6 alkylenyl)-S(O)2NRz3Rz4,—( C1-C6 alkylenyl)-C(O)Rz2,—( C1-C6 alkylenyl)- C(O)ORz1,—( C1-C6 alkylenyl)-C(O)NRz3Rz4,—( C1-C6 alkylenyl)-NRz3Rz4,—( C1-C6 alkylenyl)-N(Rz3)C(O)Rz2,—( C1-C6 alkylenyl)-N(Rz3)S(O)2Rz2,—( C1-C6 alkylenyl)- N(Rz3)C(O)O(Rz2),—( C1-C6 alkylenyl)-N(Rz3)C(O)NRz3Rz4,—(C1-C6 alkylenyl)- N(Rz3)S(O)2NRz3Rz4, or—( C1-C6 alkylenyl)-CN;
Rz1, Rz3, and Rz4, at each occurrence, are each independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl; and Rz2, at each occurrence, is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl. See, for example, U.S. Patent Application Publication No. US 20140256710, which is hereby incorporated by reference in its entirety.
[00129] For example, an exemplary compound of Formula GGG is represented by the f rm l
Figure imgf000118_0001
, and pharmaceutically acceptable salts thereof.
[00130] In some embodiments, exemplary bromodomain ligands include a compound represented by the formula:
Figure imgf000118_0002
Formula HHH,
wherein:
R1 is C1-C3 alkyl or C1-C3 haloalkyl;
X—Y is—CR3ő CH—,—Nő CR4—,—CR5ő N—, or—CR6R7—CR8R9—; wherein the left ends of the moieties are attached to the NH group in the ring; A1, A2, A3, and A4 are CRx; or
one or two of A1, A2, A3, and A4 are N, and the others are CRx;
R2 is Rxa when X—Y is—CR3ő CH—,—Nő CR4—, or—CR6R7—CR8R9—; or R2 is -L-G when X—Y is—CR5ő N—, wherein L is O, N(Ry), O—C1-C6 alkylenyl, or
Figure imgf000119_0001
alkyenyl, wherein Ry is hydrogen or C1-C4 alkyl;
Rx and Rxa, at each occurrence, are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl,—CN, NO2, G,—ORx1,—OC(O)Rx2,— OC(O)NRx3Rx4,—SRx1,—S(O)2Rx1,—S(O)2NRx3Rx4,—C(O)Rx1,—C(O)ORx1,—
C(O)NRx3Rx4,—NRx3Rx4,—N(Rx5)C(O)Rx2,—N(Rx5)S(O)2Rx2,—N(Rx5)C(O)O(Rx2),— N(Rx5)C(O)NRx3Rx4,—N(Rx5)S(O)2NRx3Rx4,—(C1-C6 alkylenyl)-G,—(C1-C6 alkylenyl)- ORx1,—(C1-C6 alkylenyl)-OC(O)Rx2,—(C1-C6 alkylenyl)-OC(O)NRx3Rx4,—(C1-C6 alkylenyl)-S(O)2Rx1,—(C1-C6 alkylenyl)-S(O)2NRx3Rx4,—(C1-C6 alkylenyl)-C(O)Rx1,—(C1- C6 alkylenyl)-C(O)ORx1,—(C1-C6 alkylenyl)-C(O)NRx3Rx4,—(C1-C6 alkylenyl)-NRx3Rx4,— (C1-C6 alkylenyl)-N(Rx5)C(O)Rx2,—(C1-C6 alkylenyl)-N(Rx5)S(O)2Rx2,—(C1-C6 alkylenyl)- N(Rx5)C(O)O(Rx2),—(C1-C6 alkylenyl)-N(Rx5)C(O)NRx3Rx4,—(C1-C6 alkylenyl)- N(Rx5)S(O)2NRx3Rx4, and—(C1-C6 alkylenyl)-CN;
Rx1, Rx3, Rx4, and Rx5, at each occurrence, are each independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, G, or—C1-C6 alkylenyl-G;
Rx2, at each occurrence, is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1- C6 haloalkyl, G, or—C1-C6 alkylenyl-G;
G, at each occurrence, are each independently aryl, heteroaryl, C3-C7 heterocycle, C3-C8 cycloalkyl, or C5-C8 cycloalkenyl; and each G group is optionally substituted with 1, 2, 3, 4, or 5 Rg groups;
R3 is H,—CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl,— C(O)R3a,—C(O)OR3a,—C(O)NR3bR3c,—C(O)N(R3b)NR3bR3c,—S(O)R3d,—S(O)2R3a,— S(O)2NR3bR3c or G1; wherein the C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl are each independently unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of G1,—C(O)R3a,—C(O)OR3a,—C(O)NR3bR3c,—C(O)N(R3b)NR3bR3c, —S(O)R3d,—S(O)2R3a,—S(O)2NR3bR3c,—OR3a,—OC(O)R3d,—NR3bR3c, N(R3b)C(O)R3d, N(R3b)SO2R3d, N(R3b)C(O)OR3d, N(R3b)C(O)NR3bR3c, and N(R3b)SO2NR3bR3c; R4 is H,—CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, or C1-C6 haloalkyl; R5 is H,—CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl,— C(O)OR5a,—C(O)NR5bR5c, or G1;
R6 is H,—CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, or C1-C6 haloalkyl; R8 and R9, are each independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, or C1-C6 haloalkyl;
R7 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl,—C(O)R7a, —C(O)OR7a,—C(O)NR7bR7c,—S(O)R7d,—S(O)2R7a,—S(O)2NR7bR7c, or G1; wherein the C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl are each independently unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of G1,— C(O)R7a,—C(O)OR7a,—C(O)NR7bR7c,—C(O)N(R7b)NR7bR7c,—S(O)R7d,—S(O)2R7a,— S(O)2NR7bR7c,—OR7a,—OC(O)R7d,—NR7bR7c, N(R7b)C(O)R7d, N(R7b)SO2R7d,
N(R7b)C(O)OR7d, N(R7b)C(O)NR7bR7C, and N(R7b)SO2NR7bR7C;
R3a, R3b, R3c, R5a, R5b, R5c, R7a, R7b, and R7c, at each occurrence, are each independently H, C1-C6 alkyl, C1-C6 haloalkyl, G1,—(C1-C6 alkylenyl)-G1,—(C1-C6 alkylenyl)-ORa, or— (C1-C6 alkylenyl)-CN;
R3d and R7d, at each occurrence, are each independently C1-C6 alkyl, C1-C6 haloalkyl, G1,—(C1-C6 alkylenyl)-G1,—(C1-C6 alkylenyl)-ORa, or—(C1-C6 alkylenyl)-CN;
G1, at each occurrence, is independently aryl, heteroaryl, C3-C7 heterocycle, C3-C8 cycloalkyl, or C5-C8 cycloalkenyl; and each G1 is optionally substituted with 1, 2, 3, 4, or 5 R1g groups;
Rg and R1g, at each occurrence, are each independently selected from the group consisting of oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl,—CN, NO2, G1a,—ORa,—OC(O)Rb,—OC(O)NRcRd,—SRa,—S(O)2Ra,—S(O)2NRcRd,—C(O)Ra, —C(O)ORa,—C(O)NRcRd,—NRcRd,—N(Rc)C(O)Rb,—N(Re)S(O)2Rb,—N(Re)C(O)O(Rb), —N(Re)C(O)NRcRd,—N(Re)S(O)2NRcRd,—(C1-C6 alkylenyl)-CN,—(C1-C6 alkylenyl)-G2a, —(C1-C6 alkylenyl)-ORa,—(C1-C6 alkylenyl)-OC(O)Rb,—(C1-C6 alkylenyl)-OC(O)NRcRd,— (C1-C6 alkylenyl)-S(O)2Ra,—(C1-C6 alkylenyl)-S(O)2NRcRd,—(C1-C6 alkylenyl)-C(O)Ra,— (C1-C6 alkylenyl)-C(O)ORa,—(C1-C6 alkylenyl)-C(O)NRcRd,—(C1-C6 alkylenyl)-NRcRd,— (C1-C6 alkylenyl)-N(Rc)C(O)Rb,—(C1-C6 alkylenyl)-N(Re)S(O)2Rb,—(C1-C6 alkylenyl)- N(Re)C(O)O(Rb),—(C1-C6 alkylenyl)-N(Re)C(O)NRcRd,—(C1-C6 alkylenyl)- N(Re)S(O)2NRcRd, or—(C1-C6 alkylenyl)-CN;
Ra, Rc, Rd, and Re, at each occurrence, are each independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, G1a, or—(C1-C6 alkylenyl)-G2a;
Rb, at each occurrence, is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1- C6 haloalkyl, G2a, or—(C1-C6 alkylenyl)-G2a;
G2a, at each occurrence, are each independently aryl, heteroaryl, C3-C7 heterocycle, C3- C8 cycloalkyl, or C5-C8 cycloalkenyl; and each G2a group is optionally substituted with 1, 2, 3, 4, or 5 R2g groups;
R2g, at each occurrence, is independently oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl,—CN, NO2,—ORz1,—OC(O)Rz2,—OC(O)NRz3Rz4,—SRz1,— S(O)2Rz1,—S(O)2NRz3Rz4,—C(O)Rz1,—C(O)ORz1,—C(O)NRz3Rz4,—NRz3Rz4,—
N(Rz3)C(O)Rz2,—N(e)S(O)2Rz2,—N(Rz3)C(O)O(Rz2),—N(Rz3)C(O)NRz3Rz4,—
N(Rz3)S(O)2NRz3Rz4,—(C1-C6 alkylenyl)-ORz1,—(C1-C6 alkylenyl)-OC(O)Rz2,—(C1-C6 alkylenyl)-OC(O)NRz3Rz4,—(C1-C6 alkylenyl)-S(O)2Rz1,—(C1-C6 alkylenyl)-S(O)2NRz3Rz4, —(C1-C6 alkylenyl)-C(O)Rz1,—(C1-C6 alkylenyl)-C(O)ORz1,—(C1-C6 alkylenyl)- C(O)NRz3Rz4,—(C1-C6 alkylenyl)-NRz3Rz4,—(C1-C6 alkylenyl)-N(Rz3)C(O)Rz2,—(C1-C6 alkylenyl)-N(Rz3)S(O)2Rz2,—(C1-C6 alkylenyl)-N(Rz3)C(O)O(Rz2),—(C1-C6 alkylenyl)- N(Rz3)C(O)NRz3Rz4—, (C1-C6 alkylenyl)-N(Rz3)S(O)2NRz3Rz4, or—(C1-C6 alkylenyl)-CN; Rz1, Rz3, and Rz4, at each occurrence, are each independently H, C1-C6 alkyl, C2-C6 alkenyl, C2- C6 alkynyl, or C1-C6 haloalkyl; and
Rz2, at each occurrence, is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl. See, for example, U.S. Patent Application Publication No. US 20140256705, which is hereby incorporated by reference in its entirety.
[00131] For example, exemplary compounds of Formula HHH may be selected from the group consisting of:
Figure imgf000122_0001
, and pharmaceutically acceptable salts thereof.
[00132] In some embodiments, exemplary bromodomain ligands include a compound represented by the formula:
Figure imgf000122_0002
Formula III,
wherein:
X is N(Ra), O, or S;
Y1 and Y3, independently, are CH or N;
Y2 is CH, CRa, N, or null;
Figure imgf000122_0003
halo, OH, or null;
A is an unsubstituted or substituted 5-membered heterocyclic ring; B is aryl, CH(Ra)-aryl, C3-10cycloalkyl, CH(Ra)—C3-10cycloalkyl, heteroaryl, CH(Ra)- heteroaryl, C3-10heterocycloalkyl, or CH(Ra)—C3-10heterocycloalkyl, each unsubstituted or substituted;
G is N, O, or S;
L is null, H, or C(Rd)3;
R1 is H, halo, OH, ORa, or N(Ra)2;
Ra, independently, is H, C1-3alkyl, or benzyl;
Rb, independently, is C1-6alkyl, halo, aryl, unsubstituted or substituted CH2-aryl, unsubstituted or substituted C3-10cycloalkyl, unsubstituted or substituted
Figure imgf000123_0001
heteroaryl, unsubstituted or substituted CH2-heteroaryl, unsubstituted or substituted C3- 10heterocycloalkyl, or unsubstituted or substituted CH2—C3-10heterocycloalkyl, or CHO;
n is an integer 0, 1, 2, or 3;
Rc and Rd, each independently, are hydrogen,
Figure imgf000123_0002
unsubstituted or substituted aryl, unsubstituted or substituted CH2-aryl, unsubstituted or substituted C3-10cycloalkyl, unsubstituted or substituted CH2—C3-10cycloalkyl, heteroaryl, unsubstituted or substituted CH2- heteroaryl, unsubstituted or substituted C3-10heterocycloalkyl, or unsubstituted or substituted CH2—C3-10heterocycloalkyl;
or a pharmaceutically acceptable salt, hydrate, or solvate thereof. See, for example, U.S. Patent Application Publication No. US 20140256706, which is hereby incorporated by reference in its entirety.
[00133] For example, exemplary compounds of Formula III may be selected from the group consisting of:
Figure imgf000124_0001
and pharmaceutically acceptable salts thereof.
[00134] In some embodiments, exemplary bromodomain ligands include a compound selected from the rou consistin of:
Figure imgf000124_0002
, and pharmaceutically acceptable salts thereof, wherein R is 2-methoxyphenyl, 3-methoxyphenyl, phenyl, 2-methylphenyl, t-butyl, or benzyl.
[00135] In some embodiments, exemplary bromodomain ligands include a compound selected from the group consisting of:
Figure imgf000125_0001
, and pharmaceutically acceptable salts thereof, wherein R is 1-piperidine, 1-pyrrolidine, 4-morpholine, methoxy, methyl, or H.
[00136] In some embodiments, exemplary bromodomain ligands include a compound re resented b the formula:
Figure imgf000125_0002
Formula JJJ,
wherein:
R1 is C1-4alkyl;
R2 is C1-4alkyl, C3-7cycloalkyl, -CH2CF3, -CH2OCH3 or heterocyclyl;
R3 is C1-4alkyl, -CH2F, -CH2OH or -CH2OC(O)CH3; R4 when present is H, hydroxy, halo, cyano, -CO2H, -CONH2, -OSO2CF3, -C(O)N(R8) C1-4alkyleneOH, -C(O)N(R8)C1-4alkyleneOCH3, -C(O)N(R8)C1-4alkyleneNR6R7, - C(O)N(R8)C1-4alkyleneSO2CH3, -C(O)N(R8)C1-4alkyleneCN, -C(O)NHOH, - C(O)NHCH(CH2OH)2, -OCH2CH2OH, -B-C1-6alkyl, -B-C3-7cycloalkyl, -B-phenyl, -B- heterocyclyl or -B-heteroaromatic, wherein the C3-7cycloalkyl, phenyl, heterocyclyl or heteroaromatic ring is optionally substituted by 1 or 2 substituents independently selected from =O, C1-6alkyl, C1-6alkoxy, halo, -NH2, -CO2H, -C(O)C1-6alkyl, -C(O)NHC1-6alkyl, cyano, - CH2CH2NHCH3, -CH2CH2OH, -CH2CH2OCH3, C3-7cycloalkyl, phenyl, heterocyclyl and heteroaromatic;
R5 when present is H, halo, hydroxy or Ci-6alkoxy;
A is -NH-, -O-, -S-, -SO-, -SO2-, -N(C1-4alkyl)- or -NC(O)(CH3)-;
B is a bond, -O-, -N(R8)-, S, -SO-, -SO2-, -SO2N(R8)-, -CH2-, -C(O)-, -CO2-, - N(R8)C(O)-, -C(O)N(R8)-, -C(O)N(R8)CH2- or -C(O)N(R8)CH2CH2-;
V is phenyl, heteroaromatic or pyridone any of which may be optionally substituted by 1, 2 or 3 substituents independently selected from C1-6alkyl, fluorine, chlorine, C1-6alkoxy, hydroxy, cyclopropyl, cyano, -CO2CH3, heterocyclyl, -CO2H, -CH2NR6R7, -NR6R7, - C(O)NR6R7, -NR6C(O)R7,-CF3, -NO2, -CH2OCH3, -CH2OH, -CH(OH)CH3, -SO2CH3, - CH2heterocyclyl, -OCH2CH2NHC(O)CH3, -OCH2CH2OH, -OCH2CH2NH2, - C(O)NHheteroaromatic, -C(O)NHCH2heterocyclyl,C(O)NHCH2CH2OH, - C(O)NHCH2CH2NH2, -C(O)NHCH2CH2S02Me, -C(O)NHCH2CH(OH)CH3, -C(O)heterocyclyl and -C(O)NHheterocyclyl, wherein the heterocyclyl ring is optionally substituted by -OH;
R6, R7, R8, R9 and R10 are each independently selected from H and C1-4alkyl;
W is CH or N;
X is C or N;
Y is C or N; and
Z is CH orN. See, for example, International Patent Application Publication No.
WO/2014/140076, which is hereby incorporated by reference in its entirety.
[00137] For example, exemplary compounds of Formula JJJ may be selected from the group consisting of:
Figure imgf000127_0001
and pharmaceutically acceptable salts thereof.
[00138] In some embodiments, exemplary bromodomain ligands include compounds selected from the group consisting of:
[00139] In some embodiments, exemplary bromodomain ligands include a compound re resented b the formula:
Figure imgf000127_0002
Formula KKK,
wherein:
Y1 is N or CH;
R1 is CD3, C1-C3 alkyl, or C1-C3 haloalkyl;
R2 is H or C1-C3 alkyl;
R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, CN, - C(O)R3a, -C(O)OR3a, -C(O)NR3bR3c, -S(O)R3d, -S(O)2R3a, -S(O)2NR3bR3c, or G1; wherein the C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl are each independently unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of G1, CN, -C(O)R3a,—C(O)OR3a, -C(O)NR3bR3c, -S(O)R3d, -S(O)2R3a, -S(O)2NR3bR3c, -OR3a, - OC(O)R3d, -NR3bR3c, -N(R3b)C(O)R3d, -N(R3b)SO2R3d, -N(R3b)C(O)OR3d, - N(R3b)C(O)NR3bR3c, -N(R3b)SO2NR3bR3c, and N(R3b)C(NR3bR3c)ő NR3bR3c;
Y2 is C(O), S(O)2, or CR4R5;
R4 is H, deuterium, C1-C6 alkyl, halogen, or C1-C6 haloalkyl; and
R5 is H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -C(O)R5a, -C(O)OR5a, -C(O)NR5bR5c, -S(O)R5d, -S(O)2R5a, -S(O)2NR5bR5c, or G1; wherein the C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl are each independently unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of G1, CN, -C(O)R5a, -C(O)OR5a, -C(O)NR5bR5c, -C(O)N(R5b)NR5bR5c, -S(O)R5d, -S(O)2R5a, - S(O)2NR5bR5c, -OR5a, -OC(O)R5d, -NR5bR5c, -N(R5b)C(O)R5d, -N(R5b)SO2R5d, - N(R5b)C(O)OR5d, -N(R5b)C(O)NR5bR5c, -N(R5b)SO2NR5bR5c, and - N(R5b)C(NR5bR5c)ő NR5bR5c;
R3a, R3b, R3c, R5a, and R5b, at each occurrence, are each independently H, C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6haloalkyl, G1, or -(C1-C6alkylenyl)-G1;
R5c, at each occurrence, is each independently H, C1-C6 alkyl, C2-C6alkenyl, C2- C6alkynyl, C1-C6haloalkyl, G1, -(C1-C6 alkylenyl)-G1, -(C1-C6 alkylenyl)-CN, -(C1-C6 alkylenyl)-ORa, or -(C1-C6 alkylenyl)-C(O)ORa;
R3d, at each occurrence, is independently C1-C6 alkyl, C2-C6alkenyl, C2-C6alkynyl, C1- C6haloalkyl, G1, or -(C1-C6 alkylenyl)-G1;
R5d, at each occurrence, is independently C1-C6 alkyl, C2-C6alkenyl, C2-C6alkynyl, C1- C6haloalkyl, G1, -(C1-C6 alkylenyl)-G1, -(C1-C6 alkylenyl)-NRcRd, or -(C1-C6 alkylenyl)- N(Ra)C(O)O(Rb);
G1, at each occurrence, is independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; and each G1 is optionally substituted with 1, 2, 3, 4, or 5 R1g groups;
R6 is H, C1-C6 alkyl, C2-C6alkenyl, C2-C6alkynyl, halogen, C1-C6 haloalkyl, -C(O)R6a, - C(O)OR6a, -C(O)NR6bR6c, -S(O)2R6a, -S(O)2NR6bR6c, or G2; wherein the C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl are each independently unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of G2, CN, -C(O)R6a, -C(O)OR6a, -C(O)NR6bR6c, -C(O)N(R6b)NR6bR6c, -S(O)R6d, -S(O)2R6a,
Figure imgf000128_0001
-OR6a, -OC(O)R6d, - NR6bR6c, N(R6b)C(O)R6d, N(R6b)SO2R6d, N(R6b)C(O)OR6d, N(R6b)C(O)NR6bR6c,
Figure imgf000129_0001
R6a, R6b, and R6c, at each occurrence, are each independently H, alkyl, C2-C6 alkenyl, C2-C6 alkynyl, haloalkyl, G2, -(C1-C6 alkylenyl)-G2, -(C1-C6 alkylenyl)-ORa, -(C1-C6 alkylenyl)-S(O)2Ra, -(C1-C6 alkylenyl)-S(O)2NRcRd, -(C1-C6 alkylenyl)-C(O)Ra, -(C1-C6 alkylenyl)-C(O)ORa, -(C1-C6 alkylenyl)-C(O)NRcRd, -(C1-C6 alkylenyl)-NRcRd, -C1-C6 alkylenyl)-N(Ra)C(O)Rb, -(C1-C6 alkylenyl)-N(Ra)S(O)2Rb, -(C1-C6 alkylenyl)- N(Ra)C(O)O(Rb), -(C1-C6 alkylenyl)-N(Ra)C(O)NRcRd, or -(C1-C6 alkylenyl)- N(Ra)S(O)2NRcRd;
R6d, at each occurrence, is independently alkyl, C2-C6 alkenyl, C2-C6 alkynyl, haloalkyl, G2, -(C1-C6 alkylenyl)-G2, -(C1-C6 alkylenyl)-ORa, -(C1-C6 alkylenyl)-S(O)2Ra, -(C1-C6 alkylenyl)-S(O)2NRcRd, -(C1-C6 alkylenyl)-C(O)Ra, -(C1-C6 alkylenyl)-C(O)ORa, -(C1-C6 alkylenyl)-C(O)NRcRd, -(C1-C6 alkylenyl)-NRcRd, -(C1-C6 alkylenyl)-N(Re)C(O)Rb, -(C1-C6 alkylenyl)-N(Re)S(O)2Rb, -(C1-C6 alkylenyl)-N(Re)C(O)O(Rb), -(C1-C6 alkylenyl)- N(Re)C(O)NRcRd, or -(C1-C6 alkylenyl)-N(Re)S(O)2NRcRd;
G2, at each occurrence, is independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; and each G2 is optionally substituted with 1, 2, 3, 4, or 5 R2g groups;
A1 is C(R7) or N; A2 is C(R8) or N; A3 is C(R9) or N; and A4 is C(R10) or N; wherein zero, one, or two of A1, A2, A3, and A4 are N;
R7, R8, and R9, are each independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl,—CN, NO2,—ORy1,—OC(O)Ry2,—OC(O)NRy3Ry4,—SRy1,— S(O)2Ry1,—S(O)2NRy3Ry4,—C(O)Ry1,—C(O)ORy1,—C(O)NRy3Ry4,—NRy3Ry4,—
N(Ry3)C(O)Ry2,—N(Ry3)S(O)2Ry2,—N(Ry3)C(O)O(Ry2),—N(Ry3)C(O)NRy3Ry4,—
N(Ry3)S(O)2NRy3Ry4, G3,—(C1-C6 alkylenyl)-CN,—(C1-C6 alkylenyl)-ORy1,—(C1-C6 alkylenyl)-OC(O)Ry2,—(C1-C6 alkylenyl)-OC(O)NRy3Ry4,—(C1-C6 alkylenyl)-S(O)2Ry1,— (C1-C6 alkylenyl)-S(O)2NRy3Ry4,—(C1-C6 alkylenyl)-C(O)Ry1,—(C1-C6 alkylenyl)-C(O)ORy1, —(C1-C6 alkylenyl)-C(O)NRy3Ry4,—(C1-C6 alkylenyl)-NRy3Ry4,—(C1-C6 alkylenyl)- N(Ry3)C(O)Ry2,—(C1-C6 alkylenyl)-N(Ry3)S(O)2Ry2,—(C1-C6 alkylenyl)-N(Ry3)C(O)O(Ry2), —(C1-C6 alkylenyl)-N(Ry3)C(O)NRy3Ry4,—(C1-C6 alkylenyl)-N(Ry3)S(O)2NRy3Ry4,—(C1-C6 alkylenyl)-CN, or—(C1-C6 alkylenyl)-G3; Ry1, Ry3, and Ry4, at each occurrence, are each independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, G3,—( C1-C6 alkylenyl)-G3,—( C1-C6 alkylenyl)- ORa,—( C1-C6 alkylenyl)-S(O)2Ra,—( C1-C6 alkylenyl)-S(O)2NRcRd,—( C1-C6 alkylenyl)- C(O)Ra,—( C1-C6 alkylenyl)-C(O)ORa,—( C1-C6 alkylenyl)-C(O)NRcRd,—( C1-C6 alkylenyl)-NRcRd,—( C1-C6 alkylenyl)-N(Re)C(O)Rb,—( C1-C6 alkylenyl)-N(Re)S(O)2Rb,—( C1-C6 alkylenyl)-N(Re)C(O)O(Rb),—( C1-C6 alkylenyl)-N(Re)C(O)NRcRd, or—( C1-C6 alkylenyl)-N(Re)S(O)2NRcRd;
Ry2, at each occurrence, is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1- C6 haloalkyl, G3,—(C1-C6 alkylenyl)-G3,—(C1-C6 alkylenyl)-ORa,—(C1-C6 alkylenyl)- S(O)2Ra,—(C1-C6 alkylenyl)-S(O)2NRcRd,—(C1-C6 alkylenyl)-C(O)Ra,—(C1-C6 alkylenyl)- C(O)ORa,—(C1-C6 alkylenyl)-C(O)NRcRd,—(C1-C6 alkylenyl)-NRcRd,—(C1-C6 alkylenyl)- N(Re)C(O)Rb,—(C1-C6 alkylenyl)-N(Re)S(O)2Rb,—(C1-C6 alkylenyl)-N(Re)C(O)O(Rb),— (C1-C6 alkylenyl)-N(Re)C(O)NRcRd, or—(C1-C6 alkylenyl)-N(Re)S(O)2NRcRd;
G3, at each occurrence, is independently aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocycle; and each G3 group is optionally substituted with 1, 2, 3, 4, or 5 R4g groups;
R10 is H, C1-C3 alkyl, halogen, C1-C3 haloalkyl, or—CN;
R1g, R2g, and R4g, at each occurrence, is independently selected from the group consisting of oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6haloalkyl,—CN, NO2, G2a,—ORa,—OC(O)Rb,—OC(O)NRcRd,—SRa,—S(O)2Ra,—S(O)2NRcRd,—C(O)Ra, —C(O)ORa,—C(O)NRcRd,—NRcRd,—N(Re)C(O)Rb,—N(Re)S(O)2Rb,—N(Re)C(O)O(Rb), —N(Re)C(O)NRcRd,—N(Re)S(O)2NRcRd,—(C1-C6 alkylenyl)-CN,—(C1-C6 alkylenyl)-G2a, —(C1-C6 alkylenyl)-ORa,—(C1-C6 alkylenyl)-OC(O)Rb,—( C1-C6alkylenyl)-OC(O)NRcRd,— ( C1-C6alkylenyl)-S(O)2Ra,—( C1-C6alkylenyl)-S(O)2NRcRd,—( C1-C6alkylenyl)-C(O)Ra,—( C1-C6alkylenyl)-C(O)ORa,—( C1-C6alkylenyl)-C(O)NRcRd,—( C1-C6alkylenyl)-NRcRd,—( C1-C6alkylenyl)-N(Ra)C(O)Rb,—( C1-C6alkylenyl)-N(Ra)S(O)2Rb,—( C1-C6alkylenyl)- N(Ra)C(O)O(Rb),—( C1-C6alkylenyl)-N(Ra)C(O)NRcRd,—( C1-C6alkylenyl)- N(Ra)S(O)2NRcRd, or—( C1-C6alkylenyl)-CN;
Ra, Rc, Rd, and Re, at each occurrence, are each independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, G2a, or—(C1-C6 alkylenyl)-G2a;
Rb, at each occurrence, is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1- C6 haloalkyl, G2a, or—( C1-C6 alkylenyl)-G2a; G2a, at each occurrence, are each independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; and each G2a group is optionally substituted with 1, 2, 3, 4, or 5 R3g groups;
R3g, at each occurrence, is independently oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl,—CN, NO2,—ORz1,—OC(O)Rz2,—OC(O)NRz3Rz4,— SRz1,—S(O)2Rz1,—S(O)2NRz3Rz4,—C(O)Rz1,—C(O)ORz1,—C(O)NRz3Rz4,—NRz3Rz4,— N(Rz3)C(O)Rz2,—N(Rz3)S(O)2Rz2,—N(Rz3)C(O)O(Rz2),—N(Rz3)C(O)NRz3Rz4,—
N(Rz3)S(O)2NRz3Rz4,—( C1-C6 alkylenyl)-ORz1,—(C1-C6 alkylenyl)-OC(O)Rz2,—( C1-C6 alkylenyl)-OC(O)NRz3Rz4,—( C1-C6 alkylenyl)-S(O)2Rz1,—(C1-C6 alkylenyl)-S(O)2NRz3Rz4, —( C1-C6 alkylenyl)-C(O)Rz2,—( C1-C6 alkylenyl)-C(O)ORz1,—(C1-C6 alkylenyl)- C(O)NRz3Rz4,—( C1-C6 alkylenyl)-NRz3Rz4,—( C1-C6 alkylenyl)-N(Rz3)C(O)Rz2,—(C1-C6 alkylenyl)-N(Rz3)S(O)2Rz2,—(C1-C6 alkylenyl)-N(Rz3)C(O)O(Rz2),—( C1-C6 alkylenyl)- N(Rz3)C(O)NRz3Rz4,—(C1-C6 alkylenyl)-N(Rz3)S(O)2NRz3Rz4, or—(C1-C6 alkylenyl)-CN;
Rz1, Rz3, and Rz4, at each occurrence, are each independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl; and
Rz2, at each occurrence, is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl. See, for example, International Patent Application Publication No.
WO/2014/139324, which is hereby incorporated by reference in its entirety.
[00140] For example, exemplary compounds of Formula KKK may be selected from the group consisting of:
Figure imgf000132_0001
, and pharmaceutically acceptable salts thereof.
[00141] In some embodiments, exemplary bromodomain ligands include a compound re resented b the formula:
Figure imgf000132_0002
Formula LLL,
wherein:
(i) Y2 is N and Y3 is C; or
(ii) Y2 is C and Y3 is N;
Y1 is CH or N;
L is a bond, optionally substituted Ci_6alkylene, optionally substituted deuterated Ci_6alkylene, -C(R6R7)-, -C(O)NR9-, -CH2N(R9)-, -SO2N(R9)-, -N(R9)C(O)N(R9)-, -N(R9)SO2- , -N(R9)CH2-, -OC1-4alkylene-, - C1-4alkylene-0-, -NR9C(O)-, -N(R9)SO2-, -C(O)-, -S(O)-, - SO2-, -O-, -S-, -P(O)(Ra)-, optionally substituted C2-6alkenylene, optionally substituted - CH=C(Rb)- or optionally substituted -Si(Rc)(Rc); or R6 and R7 taken together with the carbon atom to which they attach form an optionally substituted 3- to 6-membered ring having from 0- 2 heteroatoms selected from O, N or S or an oxo; Ra is optionally substituted C1-6alkyl, optionally substituted aryl or optionally substituted heteroaryl; Rb is H or C1-6alkyl; or Rb and R1 taken together with the carbon atom to which they attach form an optionally substituted 3- to 6-membered carbocyclic ring or an optionally substituted 4- to 8-membered heterocyclic ring having from 1-2 heteroatoms as ring members selected from O, N or S, wherein the nitrogen or sulfur ring atoms can be optionally oxidized; each Rc is independently C1-6alkyl or C1-6alkoxy; R9 is H, C1-4alkyl, or C1-4haloalkyl;
R1, R2, R4, R6 and R7 are each independently H, D, optionally substituted C1-6alkyl, optionally substituted C1-6alkenyl, optionally substituted C1-6alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted
heterocycloalkylalkyl, optionally substituted cycloalkylalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted -Si(Rc)(Rc) or R13 selected from halogen, -CN, -OH, -NH2, -NO2, -C(O)OH, - C(S)OH, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, - C(NH)NH2, -CH=C(R8)(R8), -OR8, -SR8, -OC(O)R8, -OC(S)R8, -P(=O)HR8, -P(=O)R8R8, - PH(=O)OR8, -P(=O)(OR8)2, -OP(=O)(OR8)2, -C(O)H, -O(CO)OR8, -C(O)R8, -C(S)R8, - C(O)OR8,
-C(S)ORs, -S(O)Rs, -S(O)2Rs, -C(O)NHRg, -C(S)NHRg, -C(O)NRgRg, -C(S)NRgRg, - S(O)2NHRg, -S(O)2NRgRg, -C(NH)NHRg, -C(NH)NRgRg, -NHC(O)Rg, -NHC(S)Rg, - NRgC(O)Rg, -NRgC(S)Rg, -NHS(O)2Rg, -NRgS(O)2Rg, -NHC(O)NHRg, -NHC(S)NHRg, - NRgC(O)NH2, -NRgC(S)NH2,
-NRgC(O)NHRg, -NRgC(S)NHRg, -NHC(O)NRgRg, -NHC(S)NRgRg, -NRgC(O)NRgRg, -NRgC(S)NRgRg, -NHS(O)2NHRg, -NRgS(O)2NH2, -NRgS(O)2NHRg, -NHS(O)2NRgRg, - NRgS(O)2NRgRg, -NHRg or -NRgRg, wherein each Rg is independently H, optionally substituted C1-6alkyl, optionally substituted C1-6alkenyl, optionally substituted C1-6alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted cycloalkylalkyl, optionally substituted arylalkyl, optionally substituted
heteroarylalkyl or optionally substituted heterocycloalkylalkyl; or two Rg groups when attached to the same carbon or nitrogen atom are taken together to form a 3- to 6-membered carbocyclic ring or 3- to 8-membered heterocyclic ring having from 1-2 heteroatoms as ring members selected from O, N or S, wherein the nitrogen or sulfur ring atoms are optionally oxidized; wherein the aliphatic or aromatic portion of Rg is optionally substituted with from 1 -3 Rh substituents independently selected from halogen, -CN, -OH, -NH2, -NO2, -CH=C(Ri)(Ri), - C(O)OH, -C(S)OH, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NHC(O)NH2, -NHC(S)NH2, - NHS(O)2NH2, -C(NH)NH2, -OR, -SRi, -OC(O)Ri, -OC(S)Ri, -P(=O)HR, -P(=O)RiRi, - PH(=O)ORi, -P(=O)(ORi)2, -OP(=O)(ORi)2, -C(O)H, -O(CO)ORi, -C(O)Ri, -C(S)Ri, -C(O)ORi, -C(S)ORi, -S(O)Ri, -S(O)2Ri, -C(O)NHRi, -C(S)NHRi, -C(O)NRiRi, -C(S)NRiRi, -S(O)2NHRi, - S(O)2NRiRi, -C(NH)NHRi, -C(NH)NRiRi, -NHC(O)Ri, -NHC(S)Ri, -NRiC(O)R, -NRC(S)Ri, - NHS(O)2Ri, -NRiS(O)2R, -NHC(O)NHR, -NHC(S)NHRi, -NRC(O)NH2, -NRiC(S)NH2, - NRiC(O)NHRi, -NRiC(S)NHRi, -ȃ ǾC(ȅ )ȃ RiRi, -NHC(S)NRiRi, -ȃ RiC(O)ȃ RiRi, - ȃ RiC(S)ȃ RiRi, -ȃ ǾS(O)2ȃ ǾRi, -ȃ RiS(O)2ȃ Ǿ2, -NRiS(O)2NHRi, -NHS(O)2NRiRi, - ȃ RiS(O)2ȃ RiRi, Ri, -NHRi or -NRiRi, wherein each Ri is independently C1-6alkyl, aryl, aryl-C1- 2alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-4alkyl, heteroaryl, heteroaryl-C1-4alkyl,
heterocycloalkyl or heterocycloalkyl-C1-4alkyl, wherein each Ri is further optionally substituted with from 1-3 Rp groups independently selected from halogen, CN, -OH, -NH2, -N(Rq)(Rq), - NO2, -C(O)OH, - C(O)NH2, -S(O)2NH2, -NHC(O)NH2, -C(NH)NH2, -P(=O)HRq , -P(=O)RqRq , -PH(=O)ORq, -P(=O)(ORq)2, -OP(=O)(ORq)2, -OC(O)Rq, -OC(S)Rq, -C(O)Rq, -C(S)Rq, - C(O)ORq, -S(O)2Rq, -C(O)NHRq, C1-6alkyl, C1-6alkoxy, halogen, C1-6haloalkyl or C1- 6haloalkoxy, wherein Rq is C1-6alkyl;
R3 is H, halogen, -CN, optionally substituted C1-6alkyl, optionally substituted deuterated C1-6alkyl,optionally substituted aryl, optionally substituted aryl-C1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl-C1-4alkyl, optionally substituted C3-6 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted C3-8 cycloalkyl-C-1-4alkyl, optionally substituted C2-6 alkynyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkyl-C1-4alkyl or RJ selected from halogen, -CN, -OH, -NH2, -NO2, - C(O)OH, -C(S)OH, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NHC(O)NH2, -NHC(S)NH2, - NHS(O)2NH2, -C(NH)NH2, -CH=C(Rk)(Rk), -ORk, -SRk, -OC(O)Rk, -OC(S)Rk, -P(=O)HRk, - P(=O)RkRk, -PH(=O)ORk, -P(=O)(ORk)2, -OP(=O)(ORk)2, -C(O)H, -O(CO)ORk, -C(O)Rk, - C(S)Rk, -C(O)ORk, -C(S)ORk, -S(O)Rk, -S(O)2Rk, -C(O)NHRk, -C(S)NHRk, -C(O)NRkRk, - C(S)NRkRk -S(O)2NHRk, -S(O)2NRkRk, -C(NH)NHRk, -C(NH)NRkRk, -NHC(O)Rk, - NHC(S)Rk, -NRkC(O)Rk, -NRkC(S)Rk, -NHS(O)2Rk, -NRkS(O)2Rk, -NHC(O)NHRk, - NHC(S)NHRk, -NRkC(O)NH2, -NRkC(S)NH2, -NRkC(O)NHRk, -NRkC(S)NHRk, - NHC(O)NRkRk -NHC(S)NRkRk, -NRkC(O)NRkRk -NRkC(S)NRkRk, -NHS(O)2NHRk, - NRkS(O)2NH2, -NRkS(O)2NHRk -NHS(O)2NRkRk, -NRkS(O)2NRkRk -NHRk or -NRkRk; or two Rk groups when attached to the same carbon or nitrogen atom are taken together to form a 3- to 6-membered carbocyclic ring or 3- to 8-membered heterocyclic ring having from 1-2 heteroatoms as ring members selected from O, N or S, wherein the nitrogen or sulfur ring atoms are optionally oxidized; wherein each Rk is independently H, C1-66alkyl or aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, cycloalkyl or
cycloalkylalkyl, wherein Rk is optionally substituted with from 1-3 Rh;
R5 is an optionally substituted 5- or 6-membered heteroaryl having from 1 to 4 heteroatoms as ring members selected from O, N or S; or an optionally substituted
heterocycloalkyl; and
is a single bond or a double bond to maintain ring A being aromatic. See, for example, International Patent Application Publication No. WO/2014/145051, which is hereby incorporated by reference in its entirety.
[00142] For example, exemplary compounds of Formula LLL may be selected from the group consisting of:
Figure imgf000136_0001
, and pharmaceutically acceptable salts thereof.
[00143] In some embodiments, exemplary bromodomain ligands include a compound represented by the formula:
Figure imgf000136_0002
Formula MMM;
wherein:
V is N or C-R2; W is N or C-R8;
X is N, CH or C(CH3);
Y is N or C-R5;
Figure imgf000137_0001
Q is N or CH;
R1 is C1-4 alkyl;
R2, when present, is H, OH, C1-4alkyl, halo, -CF3, -NH2, -OC1-4alkyl, -NHC(O)H, - NHC(O)C1-4alkyl, -N(CH3)C(O)C1-4alkyl, -NHC(O)NH2, -NHC(O)C1-4alkyleneNH2, - N(CH3)C(O)NH2, -N(CH3)C(O)C1-4alkyleneNH2, -NHC2-4alkyleneOCH3, -N(CH3)C2- 4alkyleneOCH3, -OC2-4alkyleneOCH3, -OC2-4alkyleneOH or
R2 is a group selected from -G-CH2CH(R3)(R4), -G-CH(R3)(R4) and -G-R3 in which G is NH, N(CH3), O, C(O)NH or NHC(O);
R3 is phenyl, pyridinyl, C3-7cycloalkyl or a heterocycle optionally substituted by =O; and R4 is H or C1-4 alkyl; -CF3, CN, OH, -OC1-4 alkyl, -CH2NH2, -OCF3, -SO2CH3, - C(O)NHC1-4alkyl or–CO2H;
R6 is–NR11R12 or a group
Figure imgf000137_0002
;
D is CH or N;
E is N, O, CH, or SO2;
R7, when present, is H, OH, C1-4alkyl, -NH2, -SO2C1-4alkyl, -SO2phenyl, -SO2benzyl, - SO2N(CH3)2, -NHSO2CH3, -C(O)C1-4alkyl, -C(O)phenyl;
R8, when present, is H, C1-4alkyl, halo, -CF3, CN, OH, -OC1-4alkyl, -OC2-4alkyleneOC1- 4alkyl, -OCF3 -OC1-4alkyleneF, -OC1-4alkyleneCHF2, -OC2-4alkyleneOH, -Ophenyl, -OC1- 4alkylenephenyl, -NHC3-7cycloalkyl, -NHC1-4alkyleneC3-7cycloalkyl, -OC3-7cycloalkyl, -OC1- 4alkyleneC3-7cycloalkyl, -NHC4-6heterocycle -NHC1-4alkyleneC4-6heterocycle, -OC4- 6heterocycle or -OC1-4alkyleneC4-6heterocycle wherein the C3-7cycloalkyl or the C4- 6heterocycle are each optionally substituted by one or two substituents independently selected from halo, OH, oxo, C1-4alkyl and -NH2; or R3 and R2 together with the carbon atoms to which they are attached, form a heterocycle optionally substituted by oxo;
R9 is H, C1-4alkyl, -C(O)NH2, -CO2CH3, -CF3, halo, OH, -OC1-4alkyl, -CH2OH, - C(O)NHCH3, -C(O)NH(CH3)2, -CH2OC1-4alkyl or -CH2OCH2C3-7cycloalkyl;
R10 is H, C1-4alkyl, -C(O)NH2, -CO2CH3, -CF3, halo, OH, -OC1-4alkyl or oxo;
R11 is H, C1-4alkyl or SO2CH3;
R12 is H, C1-4alkyl, C2-4alkyleneNHR13, SO2CH3, a heterocycle or a heterocycle comprising SO2; R13 is H or SO2CH3;
R14 is H or C1-4alkyl;
R15 is H, C1-4alkyl or NHC(O)C1-4alkyl;
R16 is H or C1-4alkyl; and
n and m are each an integer independently selected from 0, 1 and 2. See, for example, International Patent Application Publication No. WO/2014/140077, which is hereby incorporated by reference in its entirety.
[00144] For example, exemplary compounds of Formula MMM may be selected from the group consisting of:
Figure imgf000138_0001
, and pharmaceutically acceptable salts thereof.
[00145] In some embodiments, exemplary bromodomain ligands include a compound represented by the formula:
Figure imgf000139_0001
Formula NNN;
wherein:
represents a single bond or a double bond;
L is CR9R9a, O, S, SO, or SO2;
Cy1 is selected from phenyl or a 5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, wherein said phenyl or 5-6 membered heteroaryl of Cy1 is optionally substituted with 1, 2, 3, or 4 groups independently selected from R11;
R1 and R2 are independently selected from H, halo, CN, OH, C1-6 alkyl, C2-6 alkenyl, C2- 6 alkynyl, C1-6 haloalkyl, ORal, SRal, C(=O)Rbl, C(=O)NRc1Rd1, C(=O)ORa1, OC(=O)Rb1, OC(=O)NRc1Rd1, NRc1Rd1, NRc1C(=O)Rb1, NRc1C(=O)NRc1Rd1, NRc1C(=O)ORa1, S(=O)Rb1, S(=O)NRc1Rd1, S(=O)2Rb1, NRc1S(=O)2Rb1 and S(=O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl of R1 and R2 are optionally substituted with 1, 2, or 3 groups independently selected from halo, CN, OH, ORa1, SRa1, C(=O)Rb1, C(=O)NRc1Rd1, C(=O)ORa1, OC(=O)Rb1, OC(=O)NRc1Rd1, NRc1Rd1, NRc1C(=O)Rb1, NRc1C(=O)NRc1Rd1, NRc1C(=O)ORa1, S(=O)Rb1, S(=O)NRc1Rd1, S(=O)2Rb1, NRc1S(=O)2Rb1 and S(=O)2NRc1Rd1;
alternatively, R1 and R2 together with the carbon atom to which they are attached are combined to form a C3-7 cycloalkyl group, wherein said cycloalkyl group is optionally substituted with 1, 2, 3, or 4 groups independently selected from R20;
Cy3 is selected from phenyl, C3-7 cycloalkyl, a 5-10 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-10 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said phenyl, C3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl of Cy3 is optionally substituted with 1, 2, 3, or 4 groups independently selected from R , wherein a ring- forming nitrogen atom of said 5-10 membered heteroaryl group or a ring- forming nitrogen atom of said 4-10 membered heterocycloalkyl group is optionally oxidized;
R4 is H, C(=O)NR14aR14b, C(=O)R14a, C(=O)OR14a, or C1-6 alkyl optionally substituted by 1, 2, or 3 substituents independently selected from halo, NR14aR14b, OR14a, SR14a, CN, C(=O)R14a, C(=O)NR14aR14b, C(=O)OR14a, OC(=O)R14b, OC(=O)NR14aR14b, NR14aC(=O)R14b, NR14aC(=O)NR14aR14b, NR14aC(=O)OR14b, S(=O)R14a, S(=O)NR14aR14b, S(=O)2R14a,
NR14aS(=O)2R14b , and S(=O)2NR14aR14b;
R5 is selected from =O and =S when C N is a single bond,
alternatively, when C N is a double bond then R5 is selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, NR15aR15b, -C(=O)NR15aR15b, -C(=O)OR15a, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-10 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said alkyl, phenyl, C3-7 cycloalkyl, 5- 6 membered heteroaryl, and 4-10 membered heterocycloalkyl of R5 is optionally substituted by 1, 2, 3, or 4 groups independently selected from R15;
R6 is selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, and C1-6 haloalkyl, wherein said alkyl, alkenyl, and alkynyl of R6 are each optionally substituted by 1, 2, 3, or 4 groups independently selected R16;
alternatively, R6 is selected from C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from , O and S, wherein said C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-7 membered heterocycloalkyl of R6 are each optionally substituted by 1, 2, 3, or 4 groups independently selected R20;
R7 is selected from H, halo, CN, ORa, NRcRd, SRb, C(=O)NRcRd, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, 5-6 membered heteroaryl group, and a 4-7 membered heterocycloalkyl group of R7 are optionally substituted with 1, 2, or 3 groups independently selected from R17;
R8 is selected from H, C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 haloalkyl, halo, CN, ORa, NRcRd, SRb, and C(=O)NRcRd, wherein said C1-3 alkyl of R8 is optionally substituted with 1, 2, or 3 groups independently selected from R18;
R9 and R9a are independently selected from H, C1-3 alkyl, C1-3 haloalkyl, halo, CN, ORa, NRcRd, SRb, and C(=O)NRcRd;
R11 is independently at each occurrence selected from H, C1-3 alkyl, C1-3 haloalkyl, halo, CN, ORa, NRcRd, SRb, and C(=O)NRcRd, wherein said C1-3 alkyl is optionally substituted by OH;
R13 is independently at each occurrence selected from H, halo, CN, OH, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, OR33, SRa3, C(=O)Rb3, C(=O)NRc3Rd3, C(=O)ORa3, OC(=O)Rb3, OC(=O)NRc3Rd3, NRc3Rd3, NRc3C(=O)Rb3, NRc3C(=O)NRc3Rd3, NRc3C(=O)ORa3, S(=O)Rb3, S(=O)NRc3Rd3, S(=O)2Rb3, NRc3S(=O)2Rb3 and S(=O)2NRc3Rd3, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl of R13 is optionally substituted with 1 , 2, or 3 groups independently selected from halo, CN, OH, ORa3, SR33, C(=O)Rb3, C(=O)NRc3Rd3, C(=O)ORa3, OC(=O)Rb3, OC(=O)NRc3Rd3, NRc3Rd3, NRc3C(=O)Rb3, NRc3C(=O)NRc3Rd3, NRc3C(=O)ORa3, S(=O)Rb3, S(=O)NRc3Rd3, S(=O)2Rb3, NRc3S(=O)2Rb3 and S(=O)2NRc3Rd3;
R15 is independently at each occurrence selected from H, C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, halo, CN, ORa5, SRa5,
C(=O)Rb5, C(=O)NRc5Rd5, C(=O)ORa5, OC(=O)Rb5, OC(=O)NRc5Rd5, NRc5Rd5,
NRc5C(=O)Rb5, NRc5C(=O)NRc5Rd5, NRc5C(=O)ORa5, S(=O)Rb5, S(=O)NRc5Rd5, S(=O)2Rb5, NRc5S(=O)2Rb5, and S(=O)2NRc5Rd5, wherein said C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa5, SRa5, C(=O)Rb5, C(=O)NRc5Rd5, C(=O)ORa5, OC(=O)Rb5, OC(=O)NRc5Rd5, NRc5Rd5, NRc5C(=O)Rb5, NRc5C(=O)NRc5Rd5, NRc5C(=O)ORa5, S(=O)Rb5, S(=O)NRc5Rd5, S(=O)2Rb5, NRc5S(=O)2Rb5, S(=O)2NRc5Rd5, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl, and C3-7 cycloalkyl;
R14a and R14b are independently at each occurrence selected from H and C1-6 alkyl, wherein said C1-6 alkyl of R14a and R14b is optionally substituted with 1, 2, or 3 substituents selected from R20; or R15a and R15b together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl ring optionally substituted with 1, 2, or 3 substituents selected from R20;
R15a and R15b are independently at each occurrence selected from H and Ci_6 alkyl, wherein said C1-6 alkyl of R15a and R15b is optionally substituted with 1, 2, or 3 substituents selected from R20;
or R15a and R15b together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl ring optionally substituted with 1, 2, or 3 substituents selected from R20;
R16 is independently at each occurrence selected from halo, CN, OH, ORa6, SRa6, C(=O)Rb6, C(=O)NRc6Rd6, C(=O)ORa6, OC(=O)Rb6, OC(=O)NRc6Rd6, NRc6Rd6,
NRc6C(=O)Rb6, NRc6C(=O)NRc6Rd6, NRc6C(=O)ORa6, S(=O)Rb6, S(=O)NRc6Rd6, S(=O)2Rb6, NRc6S(=O)2Rb6 and S(=O)2NRc6Rd6, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-7 membered heterocycloalkyl of R16 are each optionally substituted by 1, 2, 3, or 4 groups independently selected R20;
R17 and R18 are independently at each occurrence selected from halo, C1-4 alkyl, CN, ORa, NRcRd, SRb, C(=O)NRcRd, C(=O)ORa, and NRcC(=O)Ra;
Ra, Rc, and Rd are independently at each occurrence selected from H, C1-6 alkyl, C(O)Re, S(=O)2Rf, C(=O)NRgRh, and phenyl optionally substituted by C1-4 alkoxy;
Rb is at each occurrence C1-6 alkyl;
Re is at each occurrence C1-4 alkyl optionally substituted by a group selected from phenyl, C1-4 alkoxy, amino, C1-4 alkylamino, and C2-8 dialkylamino;
Rf is C1-4 alkyl;
Rg and Rh are independently at each occurrence selected from H and C1-4 alkyl;
Ra1, Rb1, Rc1 and Rd1 are independently at each occurrence selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl forming Ra1, Rb1, Rc1 and Rd1 are each optionally substituted with 1, 2, or 3 substituents independently selected from R20;
Ra3, Rb3, Rc3 and Rd3 are independently at each occurrence selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, and C1-6 haloalkyl, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl forming Ra3, Rb3, Rc3 and Rd3 are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, OH, ORa4, SRa4, C(=O)Rb4,
C(=O)NRc4Rd4, C(=O)ORa4, OC(=O)RM, OC(=O)NRc4Rd4, NRc4Rd4, NRc4C(=O)Rd4,
Figure imgf000143_0001
and S(=O)2NRc4Rd4;
Ra4, Rb4, Rc4 and Rd4 are independently at each occurrence selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl forming Ra4, Rb4, Rc4 and Rd4 are each optionally substituted with 1, 2, or 3 substituents independently selected from R20;
Ra5, Rb5, Rc5 and Rd5 are independently at each occurrence selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 5-6 membered heterocycloalkyl, and C1-6 haloalkyl wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl forming Ra5, Rb5, Rc5 and Rd5 are each optionally substituted with 1, 2, or 3 substituents independently selected from R20;
or Rc5 and Rd5 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl ring optionally substituted with 1, 2, or 3 substituents
independently selected from R20;
Ra6, Rc6 and Rd6 are independently at each occurrence selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl forming Ra6, Rc6 and Rd6 are each optionally substituted with 1, 2, or 3 substituents
independently selected from R20;
alternatively, Rc6 and Rd6 together with the nitrogen atom to which they are attached form a 4-7 membered heterocycloalkyl group comprising carbon, nitrogen, and 0, 1, or 2 additional heteroatoms selected from N, O and S, wherein said 4-7 membered heterocycloalkyl group is optionally substituted with 1, 2, or 3 substituents independently selected from R20;
Rb6 is independently at each occurrence selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein said alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, 5-6 membered heteroaryl group, and 4- 7 membered heterocycloalkyl group are each optionally substituted with 1, 2, or 3 substituents independently selected from R20; and
R20 is at each occurrence independently selected from H, halo, OH, CN, amino, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino, di(C1-4 alkyl)amino, C1-4 haloalkyl, C1-4 haloalkoxy, C1-4 alkyl-C(=O)-, C1-4 alkyl-C(=O)O-, C1-4 alkyl-OC(=O)-, HOC(=O)-,
H2NC(=O)-, C1-4 alkyl-NHC(=O)-, di(C1-4 alkyl)NC(=O)-, C1-4 alkyl- C(=O)NH-, C1-4 alkyl- O-C(=O)NH-, C1-4 alkyl-S(=O)-, H2NS(=O)-, C1-4 alkyl- NHS(=O)-, di(C1-4 alkyl)NS(=O)-, C1-4 alkyl-S(=O)2-, C1-4 alkyl-S(=O)2NH-, H2NS(=O)2-, C1-4 alkyl-NHS(=O)2-, and di(C1-4 alkyl)NS(=O)2-. See, for example, International Patent Application Publication No.
WO/2014/143768, which is hereby incorporated by reference in its entirety.
[00146] For example, exemplary compounds of Formula NNN may be selected from the rou consistin of:
Figure imgf000144_0001
, and pharmaceutically acceptable salts thereof.
[00147] In some embodiments, exemplary bromodomain ligands include a compound represented by the formula:
Figure imgf000145_0001
Formula OOO,
wherein:
R1 is C1-3 alkyl;
R2 is hydrogen or C1-3 alkyl;
R3 is -C(O)- C1-3 alkyl, COOH, or -C(O)NR8R9;
R8 and R9 are chosen from one of the following groups:
(i) R8 and R9 are both H;
(ii) R8 is H and R9 is C1-3 alkylene-C(O)O-C1-3 alkyl or OH; and (iii) R8 is C1-3 alkylene-aryl and R9 is C1-3 alkylene-C(O)-C1-3 alkyl; R10 is aryl or heteroaryl, wherein R10 may be substituted with 1 to 3 substituents designated as R40, R41, and R42 and independently selected from the group consisting of:
NO2, NR20R22, halo, C1-6 alkyl, C1-6 haloalkyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, C1-3 alkylene-OH, C1-3 alkylene-C(O)OH, C1-3 alkylene-C(O)O-C1-4 alkyl, C2-3alkenylene-O-C1-3alkyl, -NHC(O)—C1-3 alkyl, -NH-SO2-C1-3 alkyl, - NH-SO2-C1-3 haloalkyl, -SO2-NH2, -C(O)-NR20R22, and -L-R12, wherein L is absent or is -C1-3alkylene-, -C2-3alkenylene-, -NH-, -NH-C1- 3alkylene-, -NR26-, -NHS(O)2-, NHS(O)2-C1-3alkylene-, -NH-C(O)—C1- 3alkylene-, -C(O)-, -C(O)-NH-C1-3alkylene-, and -O-;
R12 is selected from the group consisting of: C1-6 alkyl, C1-6 haloalkyl, C3- 10 cycloalkyl, 3 to 8 membered heterocycloalkyl, 5 to 12 membered heteroaryl, and aryl, which may be substituted with one, two, or three substituents designated R15, R16, and R17,
R15, R16, and R17 are independently selected from the group consisting of: OH, CN, halo, C1-3 alkyl, C1-3 haloalkyl, -O-C1-3 alkyl, -O-C1-3 haloalkyl, - C1-3 alkylene-OH, - C1-3 alkylene-C(O)O- C1-3 alkyl, -C(O)- C1-4 alkyl, -C(O)O C1-4 alkyl, -C(O)NH-C1-3 alkylene-NR30R32, -C(O)NR30R32, -O- C1-4 alkyl- NR30N32, -NR30R32, -NHC(O)O-C1-4 alkyl, -NH-S(O)2-C1-3 alkyl, -NH-S(O)2-C1- 3 haloalkyl, -S(O)2-C1-3 alkyl, aryl, -O-aryl, -C1-3 alkylene-aryl, C3-6 cycloalkyl, heterocycloalkyl, -C1-3 alkylene-heterocycloalkyl, -C(O)-heterocycloalkyl, 5 to 12 membered heteroaryl, and -C(O)NH-C1-3alkylene-heteroaryl, wherein said heterocycloalkyl, heteroaryl or aryl groups on R15, R16, and R17 may be independently substituted with 1 to 3 substituents selected from the group consisting of: C1-3-alkyl, C1-3-haloalkyl, -O- C1-3-alkyl, -O-C1-3-haloalkyl, halo, - NH-S(O)2- C1-3 alkyl, -NH-S(O)2- C1-3 haloalkyl, and -S(O)2-C1-3 alkyl, R26 is C1-3 alkylene-C3-6 cycloalkyl; R20 and R22 are independently selected from the group consisting of H and C1-6 alkyl; and R30 and R32 are independently selected from the group consisting of H and C1-4alkyl. See, for example, U.S. Patent Application Publication No. US 20140275079, which is hereby incorporated by reference in its entirety.
[00148] For example, exemplary compounds of Formula OOO may be selected from the rou consistin of:
Figure imgf000146_0001
, and pharmaceutically acceptable salts thereof.
[00149] In some embodiments, exemplary bromodomain ligands include a compound represented by the formula:
Figure imgf000147_0001
Formula PPP,
wherein:
X1 is H, -C(O)NR1R2, -C(O)-R1, -C(O)OR1, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -CH2OR1, -CH2R1, or -CŁN;
X2 is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted -CH2-cyloalkyl, optionally substituted - CH2-aryl, optionally substituted -CH2-heterocycloalkyl, optionally substituted -CH2-heteroaryl, optionally substituted -CH(C1-C6-alkyl)-alkyl, optionally substituted -CH(C1-C6-alkyl)- cycloalkyl, optionally substituted -CH(C1-C6-alkyl)-aryl, optionally substituted -CH(C1-C6- alkyl)-heterocycloalkyl, or optionally substituted -CH(C1-C6-alkyl)-heteroaryl;
X3 is -OR3, -CŁN, -CH2OR3, -NH-alkyl, -N(alkyl)2, -CH2N(alkyl)2, -CH2NH(alkyl), or halogen, and
R1, R2 and R3 are each independently H, C1-C12alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl optionally substituted with alkyl. See, for example, International Patent
Application Publication No. WO/2014/152029, which is hereby incorporated by reference in its entirety.
[00150] For example, exemplary compounds of Formula PPP may be selected from the group consisting of:
Figure imgf000148_0001
, and pharmaceutically acceptable salts thereof.
[00151] In some embodiments, exemplary bromodomain ligands include a compound re resented b the formula:
Figure imgf000148_0002
Formula QQQ,
wherein:
R1a and R1b are each independently C1-6alkyl, C1-6alkoxy,
Figure imgf000148_0003
C1-6hydroxyalkyl, C3-6cycloalkyl, of CH2-C3-6cycloalkyl;
R2a and R2b are each independently H or halogen; R3 is
C5-10aryl, C5-10heteroaryl, or C5-10heteroarylalkyl, each of which is optionally substituted with from 1 to 5 R20 groups; or
-S(O)2NHR4, wherein R4 is C1-6alkyl or C3-7cycloalkyl, each of which is optionally substituted with from 1 to 5 R20 groups; or
a moiety of the formula
Figure imgf000149_0001
wherein
R6 is H, OH, or halogen; and R7 and R8 are each independently C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C1-6heteroalkyl, C5-12heteroaryl; and R7 and R8 together form a C1-6 alkylidene group having a double bond with the carbon to which each of R6, R7, and R8 are bound wherein each of the
Figure imgf000149_0002
C2-6alkenyl, C2-6alkynyl, -C3-6cycloalkyl, phenyl, naphthyl, or C3-12heteroaryl groups is optionally substituted with from 1 to 5 R20 groups;
X is N-Q, or O;
Q is H, C1-3 alkyl, C1-3 haloalkyl, benzyl or substituted benzyl;
each R20 is independently C1-6alkyl, C3-6cycloalkyl,
Figure imgf000149_0003
C3-6heterocyclic, C a
5-12aryl, C5-12heteroaryl, halogen, oxo, -ORa, -C(O)Ra, -C(O)ORa, -C(O)NR Rb, - OC(O)NRaRb, -NaNb, -NRaC(O)Rb, -NRaC(O)ORb, -S(O)0-2Ra, -S(O)2NRaRb, -NRaS(O)2Rb, - N3, -CN, or–NO2, wherein each C1-6alkyl, C3-6cycloalkyl, C1-6heteroalkyl, C3-6heterocyclic, C5- 12aryl, C5-12heteroaryl is optionally substituted with one to five halogen, oxo, -ORa, -C(O)Ra, - C(O)ORa, -C(O)NRaRb, -OC(O)NRaRb, -NaNb, -NRaC(O)Rb, -NRaC(O)ORb, -S(O)0-2Ra, - S(O)2NRaRb, -NRaS(O)2Rb, -N3, -CN, or–NO2;
each Ra and Rb is independently H; or C1-6alkyl, C3-6cycloalkyl,
Figure imgf000149_0004
C3- 6heterocyclic, C5-12aryl, C5-12heteroaryl, each of which is optionally substituted with from one to five R21; or Ra and Rb together with the atoms to which they are attached form a heterocycle; and
each R21 is independently C1-6alkyl, C3-6cycloalkyl,
Figure imgf000149_0005
C3-6heterocyclic, C5-12aryl, C5-12heteroaryl, or halogen. See, for example, International Patent Application Publication No. WO/2014/160873, which is hereby incorporated by reference in its entirety. [00152] For example, exemplary compounds of Formula QQQ may be selected from the rou consistin of:
Figure imgf000150_0001
, and pharmaceutically acceptable salts thereof.
[00153] In some embodiments, exemplary bromodomain ligands include a compound selected from the group consisting of:
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
,
Figure imgf000154_0001
and pharmaceutically acceptable salts thereof.
[00154] In some embodiments, exemplary bromodomain ligands include a compound selected from the group consisting of:
Figure imgf000155_0001
,
,
Figure imgf000156_0001
, and pharmaceutically acceptable salts thereof.
[00155] In some embodiments, a bivalent compound may be selected from the group consisting of:
,
Figure imgf000157_0001
and pharmaceutically acceptable salts thereof, wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.
Connectors (Q1)
[00156] As discussed above, certain compounds contemplated herein comprise a first ligand and a second ligand covalently joined by a connector moiety. In some instances, such connector moieties do not have significant binding or other affinity towards an intended target. However, in certain embodiments, a connector may contribute to the affinity of a ligand moiety to a target.
[00157] In some instances, the connector moiety may be varied to control the spacing between two ligands. For example, in some cases, it may be desirable to adjust the spacing between two ligands so as, for instance, to achieve optimal binding of the bivalent compound to a target. In some cases, the connector moiety may be used to adjust the orientation of the ligands. In certain embodiments, the spacing and/or orientation the connector moiety relative to the ligand moiety can affect the binding affinity of the ligand moiety (e.g., a pharmacophore) to a target. In some cases, connector moieties with restricted degrees of freedom are preferred to reduce the entropic losses incurred upon the binding of a bivalent compound to its target biomolecule. In some embodiments, connector moieties with restricted degrees of freedom are preferred to promote cellular permeability of the bivalent compound.
[00158] In some embodiments, the connector moiety may be used for modular assembly of ligands. For example, in some instances, a connector moiety may comprise a functional group formed from reaction of a first and second molecule. In some cases, a series of ligand moieties may be provided, where each ligand moiety comprises a common functional group that can participate in a reaction with a compatible functional group on a connector moiety. In some embodiments, the connector moiety may comprise a spacer having a first functional group that forms a bond with a first ligand moiety and a second functional group that forms a bond with a second ligand moiety.
[00159] Contemplated connecter moieties may be any acceptable (e.g., pharmaceutically and/or chemically acceptable) bivalent linker. For instance, such connecter moieties may comprise 3 to 30 atoms, 3 to 20 atoms, 3 to 15 atoms, 3 to 10 atoms, 5 to 15 atoms, 10 to 20 atoms, 15 to 25 atoms, 20 to 30 atoms, or 10 to 30 atoms. The atoms may be connected in any suitable arrangement. For example, the atoms may be 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. In some instances, a connector moiety may include a substituted or unsubstituted C1-C10 alkylene, substituted or unsubstituted cycloalkylene, acyl, sulfone, phosphate, ester, carbamate, or amide.
[00160] In some instances, contempla oieties may include polymeric connectors, such a polyethylene glycol (e.g.,
Figure imgf000159_0001
, where n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, and X is O, S, NH, or -C(O)-) or other
pharmaceutically acceptable polymers. For example, contemplated connecter moieties may be a covalent bond or a bivalent C1-40, C1-30, C1-20, C1-10, C10-40, or C20-40, saturated or unsaturated, branched or unbranched, hydrocarbon chain, wherein one, two, or three or four methylene units of the hydrocarbon chain are optionally and independently replaced by -SiR2-, -SiR2-O-, -O- SiR2-, cyclopropylene, -NR-, -N(R)C(O)-, -C(O)N(R)-, -N(R)SO2-, -SO2N(R)-, -O-, -C(O)-, - OC(O)-, -C(O)O-, -S-, -SO-, -SO2-, -C(=S)-, -C(=NR)-, phenyl, or a mono or bicyclic heterocyclic or heteroaryl ring, where R is independently hydrogen or any suitable substituent. In certain embodiments, the connector moiety may be substituted with -SiR2- and -SiR2-O-, where -SiR2- and -SiR2-O- are covalently bonded to form -SiR2-O-SiR2-. In some
embodiments, a connector may be from about 7 atoms to about 13 atoms in length, or about 8 atoms to about 12 atoms, or about 9 atoms to about 11 atoms in length. For purposes of counting connector length when a ring is present in the connector group, the ring is counted as three atoms from one end to the other.
[00161] For example, in some embodiments, a connector moiety may be selected from the group consisting of C1-20alkylene, wherein one, two, three, or four methylene units of the hydrocarbon chain are optionally and independently replaced by -Si(R7)(R8)-, -Si(R7)(R8)-O-, - O-Si(R7)(R8)-, cyclopropylene, -NR’-, -N(R’)C(O)-, -C(O)N(R’)-, -N(R’)SO2-, -SO2N(R’)-, - O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO-, -SO2-, -C(=S)-, -C(=NR’)-, C2-6alkenylene, C2- 6alkynylene, phenyl, naphthyl, or a mono or bicyclic heterocyclic or heteroaryl ring; -NR’-C1- 15alkyl-NR’-C(O)-; -NR’-(CH2-CH2-O)s-C1-6alkyl-NR’-C(O)-; -(O-CH2-CH2)s-NR’-C(O)-; - (O-CH2-CH2)s; -S-C0-6alkyl-; -NR’-C1-6alkyl-; -N(C1-3alkyl)-C1-6alkyl-NH-C(O)-; -NH-C1- 6alkyl-N(C1-3alkyl)-C(O)-; -SO2-NR’-C0-6alkyl-; -SO2-heterocyclyl-C0-6alkyl-; -heterocyclyl- C(O)-; -heterocyclyl-C0-6alkyl-NR’-C(O)-; -NR’-C0-6alkylene-heterocyclene-C(O)-; -O-C1- 6alkylene-C(O)-; -O-C1-15alkylene-NR’-C(O)-; -O-C1-15alkylene-C(O)-NR’-; and -O-C1- 6alkylene-, wherein C1-6alkylene is optionally substituted by -OH;
wherein:
R7 and R8 are selected, independently for each occurrence, from the group consisting of -OH, C1-6alkyl, -O-C1-6alkyl, C2-6alkenyl, C3-6cycloalkyl, -C1-6alkyl- NRaRb, phenyl and heteroaryl; wherein C1-6alkyl, C2-6alkenyl, C3-6cycloalkyl, phenyl, and heteroaryl may be optionally substituted by one or more substituents independently selected from the group consisting of halogen, cyano, hydroxyl, C1-6alkyl, and phenyl; or
R7 and R8, together with the silicon to which they are attached, form a 4-7 membered heterocyclic ring, optionally containing one, two, three, or four heteroatoms independently selected from O, S, or N; wherein the 4-7 membered heterocyclic ring may be optionally substituted by one or more substituents independently selected from the group consisting of halogen, cyano, oxo, and hydroxyl;
R’ is, independently for each occurrence, selected from the group consisting of hydrogen and C1-4alkyl; wherein
Figure imgf000160_0001
may be optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo, and hydroxyl; and
s is an integer from 1-15.
[00162] In certain embodiments, a connector moiety may comprise:
a first group selected from the group consisting of:
Figure imgf000160_0002
a second group selected from the group consisting of:
Figure imgf000160_0003
Si of the first group and the Si of the second group are connected by an oxygen atom; wherein:
RW is, independently for each occurrence, absent or selected from the group consisting of -C1-4alkylene-, -O-C1-4alkylene-, -N(R’)-, -N(R’)-C1-4alkylene-, -O-, - C(O)C1-4alkylene-, -C(O)-O-C1-4alkylene-, -C2-6alkenylene-, -C2-6alkynylene-, -C3- 6cycloalkylene-, -phenylene-, and -heteroarylene-; wherein C1-4alkylene, C2-6alkenylene, C2-6alkynylene, C3-6cycloalkylene, phenylene, and heteroarylene may be optionally substituted by one, two, three, or more substituents independently selected from the group consisting of
Figure imgf000161_0001
C1-4alkoxy, -C(O)C1-4alkyl, -C(O)-O-C1-4alkyl, -C(O)- NRaRb, halogen, cyano, hydroxyl, and phenyl; or RW and R7, together with the silicon to which they are attached, form a 3-8 membered heterocyclic ring, wherein the 3-8 membered ring may be optionally substituted by one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxyl, and C1-6alkyl;
W3 is, independently for each occurrence, (a) absent; or (b) selected from the group consisting of -C1-4alkylene-, -O-C1-4alkylene-, -C(O)-C1-4alkylene-, -N(R’)-C1- 4alkylene-, -C(O)-O-C1-4alkylene-, -C2-6alkenylene-, -C2-6alkynylene-, -C3- 6cycloalkylene-, -phenylene-, and -heteroarylene-; wherein C1-4alkylene, C2-6alkenylene, C2-6alkynylene, C3-6cycloalkylene, phenylene, and heteroarylene are optionally substituted by one, two, three, or more substituents independently selected from the group consisting of
Figure imgf000161_0002
C1-4alkoxy, -C(O)C1-6alkyl, -C(O)-O-C1-4alkyl, halogen, hydroxyl, nitro, and cyano;
R7 and R8 are selected, independently for each occurrence, from the group consisting of -OH, C1-6alkyl, -O-C1-6alkyl, C2-6alkenyl, C3-6cycloalkyl, -C1-6alkyl- NRaRb, phenyl and heteroaryl; wherein C1-6alkyl, C2-6alkenyl, C3-6cycloalkyl, phenyl, and heteroaryl may be optionally substituted by one or more substituents independently selected from the group consisting of halogen, cyano, hydroxyl, C1-6alkyl, and phenyl; or
R7 and R8, together with the silicon to which they are attached, form a 4-7 membered heterocyclic ring, optionally containing one, two, three, or four heteroatoms independently selected from O, S, or N; wherein the 4-7 membered heterocyclic ring may be optionally substituted by one or more substituents independently selected from the group consisting of halogen, cyano, oxo, and hydroxyl; R’, Ra, and Rb are selected, independently for each occurrence, from the group consisting of hydrogen and C1-4alkyl; wherein C1-4alkyl may be optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo, and hydroxyl; or
Ra and Rb, together with the nitrogen to which they are attached, may form a 4-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from O, S, and N; wherein the 4-7 membered heterocyclic ring may be optionally substituted by one or more substituents independently selected from the group consisting of halogen, cyano, oxo and hydroxyl;
BB, independently for each occurrence, is a 4-7-membered cycloalkyl, heterocyclic, phenyl, naphthyl, or heteroaryl moiety, wherein the cycloalkyl, heterocyclic, phenyl, naphthyl, or heteroaryl moiety is optionally substituted with one, two, three, or more groups represented by RBB; wherein R7, independently for each occurrence, may be optionally bonded to BB; and
each RBB is selected, independently for each occurrence, from the group consisting of hydrogen, halogen, nitro, cyano, hydroxyl, amino, thio, -COOH, - CONHR’, substituted or unsubstituted aliphatic, and substituted or unsubstituted heteroaliphatic; or two RBB together with the atoms to which they are attached form a fused 5- or 6-membered cycloalkyl or heterocyclic bicyclic ring system.
[00163] For example, in some embodiments, a connector moiety may comprise:
a first group selected from the group consisting of:
Figure imgf000162_0001
a second group selected from the group consisting of: ,
Figure imgf000163_0001
f the first group and the Si of the second group are connected by an oxygen atom, and wherein R7 and R8 are as defined above.
[00164] In certain embodiments, R7 and R8 are C1-6alkyl.
[00165] In certain embodiments, the connector moiety is selected from the group consisting of:
,
Figure imgf000163_0002
[00166] In some embodiments, a contemplated connector moiety may be an optionally substituted unsaturated heteroaliphatic moiety, wherein the optionally substituted unsaturated heteroaliphatic moiety comprises at least one functional group, e.g., one, two, three, or four groups, selected from -SiR2-, -SiR2-O-, -NR-, -N(R)C(O)-, -C(O)N(R)-, -N(R)SO2-, -SO2N(R)- , -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO-, -SO2-, -C(=S)-, and -C(=NR)-, where R is independently hydrogen or any suitable substituent. The functional group may be positioned at any suitable position within the optionally substituted unsaturated heteroaliphatic moiety. In some embodiments, the optionally substituted unsaturated heteroaliphatic moiety may comprise 3 to 30 atoms, 3 to 20 atoms, 3 to 15 atoms, 3 to 10 atoms, 5 to 15 atoms, 10 to 20 atoms, 15 to 25 atoms, 20 to 30 atoms, or 10 to 30 atoms.
[00167] The optionally substituted unsaturated heteroaliphatic moiety comprises at least one unsaturated group, e.g., an alkenylene group or an alkynylene group. For example, in some embodiments, the optionally substituted unsaturated heteroaliphatic moiety may comprise 1 to 10, 1 to 3, 2 to 4, 3 to 5, 4 to 6, 5 to 7, 6 to 8, 7 to 9, or 8 to 10 unsaturated groups. For instance, the optionally substituted unsaturated heteroaliphatic moiety may contain one, two, three , four, five, six, seven, eight, nine, or ten unsaturated groups. In instances where the optionally substituted unsaturated heteroaliphatic moiety comprises a plurality of unsaturated groups, the unsaturated groups may be alkenylene groups, alkynylene groups, or a mixture thereof.
[00168] An unsaturated group may be positioned at any suitable position within the optionally substituted unsaturated heteroaliphatic moiety. For example, in some embodiments, an unsaturated group may be positioned adjacent to a ligand moiety (i.e., directly connected by a covalent bond) and/or a functional group. In other embodiments, an unsaturated group and a ligand moiety may be separated by one or more atoms. In one embodiment, the optionally substituted unsaturated heteroaliphatic moiety is directly connected to a first ligand moiety by a first unsaturated group and directly connected to a second ligand moiety by a second unsaturated group.
[00169] In some embodiments, a connector may have the following structure:
Figure imgf000164_0001
, where:
n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20;
R1 and R2 are, independently for each occurrence, selected from the group consisting of H, C1-6alkyl,
Figure imgf000164_0002
phenyl, or heteroaryl, wherein alkyl, heteroalkyl, phenyl, and heteroaryl are optionally substituted with–OH, -NH2,–SH, -COOH, -C(O)NH2, halo, phenyl, and heteroaryl; or
R1 and R2, or R2 and R2, together with the atoms to which they are attached, form a heterocyclic structure optionally substituted with–OH, -NH2,–SH, -COOH, -C(O)NH2, halo, phenyl, and heteroaryl. [00170] In some embodiments, a connector may comprise a phenyl, naphthyl, or mono or bicyclic heteroaryl ring, each optionally substituted. For example, a connector may com rise one or more of the following aryl structures:
Figure imgf000165_0001
, where R1 and R2 are the remainder of the connector. A person of skill in the art would recognize that some substitutions may be chemically less stable and hence less preferred.
[00171] In another embodiment, a connector may compose a triazole ring having the following structure:
Figure imgf000165_0002
, where R and R are the remainder of the connector. For example, a bivalent compound comprising a triazole-containing connector may have the following general structure:
. Such triazole-joined compounds may be formed, e.g., as a result of a“click” type reaction (i.e., an azide-alkyne cycloaddition). For example, a first segment of a connector having a terminal alkyne and a second segment of a connector having a terminal azide may be joined by a“click” reaction to form a single connector joined by a triazole, as shown above. In some embodiments, the first connector and the second connector each are less than or equal to 20 atoms in length, or in some embodiments each are less than or equal to 12 atoms in length.
[00172] In certain embodiments, a triazole-containing connector may be represented by - W1-(CH2-CH2-O)t-C1-6alkylene-triazolylene-C1-6alkylene-O-C1-6alkylene-. For example, the triazole-containin connector ma be re resented b :
Figure imgf000165_0003
[00173] In certain embodiments, the optionally substituted unsaturated heteroaliphatic moiety may be: , wherein:
R13 is, independently for each occurrence, selected from the groups consisting of hydrogen or any suitable substituent; and
W2 is selected from the group consisting of -SiR2-, -SiR2-O-, -O-SiR2-, -NR-, - N(R)C(O)-, -C(O)N(R)-, -N(R)SO2-, -SO2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO-, - SO2-, -C(=S)-, and -C(=NR)-, wherein R is hydrogen or any suitable substituent.
[00174] In another embodiment, a connecter moiety may maximally span from about 5Å to about 50Å, in some embodiments about 5Å to about 25Å, in some embodiments about 20Å to about 50Å, and in some embodiments about 6Å to about 15Å in length. In another embodiment, a connecter moiety may maximally span less than about 30Å, in some embodiments less than about 20Å, and in some embodiments less than about 10Å. In another embodiment, a connecter moiety may maximally span from about 1Å to about 30Å, in some embodiments about 1Å to about 20Å, in some embodiments about 1Å to about 10Å, in some embodiments about 1Å to about 5Å, in some embodiments about 20Å to about 30Å, in some embodiments about 15Å to about 25Å, in some embodiments about 10Å to about 20Å, and in some embodiments about 5Å to about 15Å, in length. For example, a connector moiety may maximally span about 1Å, about 3Å, about 5Å, about 7Å, about 9Å, about 11Å, about 13Å, about 15Å, about 17Å, about 19Å, , about 21Å, about 23Å, about 25Å, about 27Å, or about 29Å.
[00175] In certain embodiments, a connector (i.e., Q1) is selected from the group consisting of:
-W1-(C2-6alkylene-O)s-C2-6alkylene-W1-; -W1-(CH2-CH2-O)s-; and
Figure imgf000166_0002
W1-;
wherein:
W1 is, independently for each occurrence, NR’, O, or S;
R’ is, independently for each occurrence, selected from the group consisting of hydrogen and C1-4alkyl; wherein
Figure imgf000166_0003
may be optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo, and hydroxyl; and s is an integer from 1-10.
[00176] For example, in some embodiments, a connector is selected from the group consisting of: -S-(C2-6alkylene-O)s-C2-6alkylene-S-; -O-(CH2-CH2-O)s-; and -O-C1-15alkylene- O-; wherein s is an integer from 1-10.
[00177] In certain embodiments, the connector is -O-(CH2-CH2-O)s-. In certain other embodiments, the connector is selected from the group consisting of: -S-(CH2-CH2-CH2-O)s- CH2-CH2-CH2-S-; -S-(CH2-CH2-O)s-CH2-CH2-S-; and -O-(CH2)u-O-; wherein u is an integer from 1-15. For example, in some embodiments, u is 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. In some embodiments, s is 2, 3, 4, 5, 6, 7, or 8.
[00178] In certain embodiments, a connector (i.e., Q1) is selected from the group consisting of:
-W1-(C3-6alkylene-O)s-C1-6alkylene-W1-;
Figure imgf000167_0001
-W1- (CH2-CH2-O)s-; and
Figure imgf000167_0002
wherein W1 is, independently for each occurrence, N, O, or S; s is an integer from 1-10; and t is an integer from 3-10. For example, in some embodiments, a connector is selected from the group consisting of: -S-(C3-6alkylene-O)s-C1- 6alkylene-S-; -S-(CH2-CH2-O)t-C1-6alkylene-S-; -O-(CH2-CH2-O)s-; and -O-C1-15alkylene-O-; wherein s is an integer from 1-10, and t is an integer from 3-10. In certain embodiments, the connector is -O-(CH2-CH2-O)s-. In certain other embodiments, the connector is selected from the group consisting of: -S-(CH2-CH2-CH2-O)s-CH2-CH2-CH2-S-; -S-(CH2-CH2-O)t-CH2-CH2- S-; and -O-(CH2)u-O-; wherein u is an integer from 1-15. For example, in some embodiments, u is 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. In some embodiments, s is 2, 3, 4, 5, 6, 7, or 8.
[00179] In one embodiment, for the benzodiazepine compounds disclosed herein, there are several possible connection regions that can contain an attachment point for the connector element: the carbonyl region, the phenyl ether region, and the chlorophenyl region. Of course, other attachments points may also be envisioned by one of ordinary skill in the art using the present disclosure. As seen below, the connector moiety may be identified as a Q1 group in benzodiazepine-connector 1 A, benzodiazepine-connector 2 B, benzodiazepine-connector 3 C, and dimethyl isoxazole-connector 4 D:
Figure imgf000168_0001
, ,
Figure imgf000168_0002
, and , where X = CH2, S, O, or NH and Q1 = connector moiety as described herein.
[00180] The synthetic route in Scheme Xa illustrates a general method for preparing benzodiazepine-connector 1 derivatives. The method involves attaching the desired substituents to the phenol core. Benzodiazepine 1 can be prepared following procedures described below. The desired Q1 group attached at the 4-position of the phenol can be installed by reacting benzodiazepine 1 with the appropriate electrophile 2 to provide 3 (benzodiazepine- connector 1 derivative). For example, Scheme Xa provides for a connector Q1, which may then be used to connect to a second ligand, thus forming a contemplated bivalent compound. It should be understood that the synthetic routes described herein are not limited to the depicted schemes, but rather may be applied, as one of ordinary skill in the art would understand, to any suitable ligand-connector pair contemplated herein.
SCHEME Xa
Figure imgf000169_0001
[00181] For example, Q1 may be selected from the group consisting of:
Figure imgf000169_0002
, wherein n is 0, 1, 2, 3, 4 or 5.
[00182] Additional examples for 2 and Q1 can be found in Table A, seen below: Table A
Figure imgf000169_0003
Figure imgf000170_0001
[00183] The following table (Table U) indicates exemplary benzodiazepine-connector 1 derivatives (e.g., 3 of Scheme Xa) that include a ligand moiety (e.g., P1) and a connector (Q1). It is understood that such derivatives can be modified to include a second ligand moiety such as provided for herein. Table U
Figure imgf000170_0002
Figure imgf000171_0001
Figure imgf000172_0001
[00184] Any free amino group seen in the Q1 examples of Table A above may be functionalized further to include additional functional groups, e.g., a benzoyl moiety.
[00185] In another embodiment, the attachment point identified in A (benzodiazepine- connector 1) may be further elaborated to incorporate not only the connector moiety (Q1), but also a second ligand (P2), as represented by: [00186]
Figure imgf000173_0001
The Q1-P2 moiety may be formed from direct attachment of Q1-P2 to the phenyl ether, or the Q1-P2 moiety may be formed from the further functionalization of any free amino group seen in the Q1 examples of Table A above to include the second ligand (P2). The synthetic route in Scheme Xb illustrates a general method for preparing benzodiazepine-connector 2 derivatives. The method involves attaching the desired substituents to the carbonyl substituent. The desired R group attached at the carbonyl substituent can be installed by reacting carboxylic acid 4 with 1-ethyl-3-(3- dimethylaminopropyl)-carbodiimide (EDC) and hydroxybenzotriazole (HOBt) then further reacting the activated ester 6 with the appropriate nucleophile, for example, amine 7, to provide 8a (benzodiazepine-connector 2 derivative). For example, Scheme Xb provides for a connector Q1, wherein Q1 is–NH-R (e.g., -NH-R of 8a).
SCHEME Xb 7
Figure imgf000173_0002
8a
[00187] le, R may be selected from the group consisting of:
Figure imgf000173_0003
Figure imgf000173_0004
, where n may be 0, 1, 2, 3,4 or 5.
[00188] In some embodiments, R may generally be represented for example, by:
Figure imgf000174_0001
where n may be 0, 1, 2, 3, 4, 5, or 6.
[00189] Additional examples for 7 and–NH-R (e.g., Q1) can be found in Table B, seen below:
Table B
Figure imgf000174_0002
Figure imgf000175_0001
Figure imgf000176_0001
[00190] The following table (Table V) contains exemplary benzodiazepine-connector 2 derivatives (e.g., 8a of Scheme Xb) that include a ligand moiety (e.g., P1) and a connector (Q1).
Table V
Figure imgf000176_0002
Figure imgf000177_0001
Figure imgf000178_0001
[00191] In another embodiment, the attachment point identified in B may be further elaborated ond ligand, as e.g.,
represented
Figure imgf000178_0002
The Q1-P2 moiety may be formed from direct attachment of Q1-P2 to the carbonyl, or the Q1-P2 moiety may be formed from the further functionalization of any free amino group seen in the–NH-R examples (i.e., Q1 examples) of Table B above to include the second ligand moiety (P2). [00192] In another embodiment, the two attachment points identified in A and B may be further elaborated to incorporate not only a connector moiety, but also a second ligand moiety.
[00193] Scheme Xc provides a synthetic procedure for making A derivatives having various connectors attached to both the benzodiazepine compound and to any of the above- identified ligands. In the scheme below, the second ligand moiety is designated by P2. Phenol 1 is converted to carboxylic acid 10 using ethyl-2-bromoacetate, followed by hydrolysis.
Following formation of 10, the general procedure outlined in Scheme Xb can be utilized in the synthesis of the benzodiazepine-connector 1 derivative 12. For example, Scheme Xc provides for a connector Q1 attached to a second ligand moiety (P2), wherein Q1 is–CH2-C(O)-R- (e.g., –CH2-C(O)-R- of 12).
SCHEME Xc
Figure imgf000179_0001
[00194] For example, R-P2 may be selected from the group consisting of:
Figure imgf000179_0002
[00195] Scheme Xd provides an exemplary synthetic procedure for making B derivatives having various connectors attached to both the benzodiazepine compound and to any of the above-identified ligands. In the scheme below, the second ligand moiety is designated by P2. Activated ester 6 is reacted with various nucleophiles to provide benzodiazepine-connector 2 derivative 8b. For example, Scheme Xd provides for a connector Q1 attached to a second ligand moiety (P2), wherein Q1 is -R- (e.g., -R- of 8b).
SCHEME Xd
Figure imgf000180_0001
[00196] For example, R-P2 (i.e., Q1-P2) may be selected from the group consisting of:
Figure imgf000180_0002
[00197] Similar to Scheme Xd, Scheme Xe provides a synthetic procedure for making B derivatives having various connectors of shorter length attached to both the benzodiazepine compound and to any of the above-identified ligands. In the scheme below, the second ligand moiety is designated by P2. Activated ester 6 is reacted with various nucleophiles to provide benzodiazepine-connector 2 derivative 8c. For example, Scheme Xe provides for a connector Q1 attached to a ligand moiety (P2), wherein Q1 is -R- (e.g., -R- of 8c).
SCHEME Xe
Figure imgf000180_0003
6
8c [00198] For example, R-P2 (i.e., Q1-P2) may be represented by the structure: , wherein n is 0, 1, 2, 3, 4, or 5, e.g. n is 1 to 5. For example, Scheme Xe provides for a connector moiety Q1.
[00199] Scheme Xf provides an additional exemplary synthetic procedure for making B derivatives having various connector moieties attached to both the benzodiazepine compound and to any of the above-identified ligands. In the scheme below, the second ligand moiety is designated by P2. Activated ester 6a is reacted with various nucleophiles to provide benzodiazepine-connector 2 derivative 8d. For example, Scheme Xf provides for a connector Q1 attached to a second ligand moiety (P2), wherein Q1 is–NHCH2-C(O)-R- (e.g.,–NHCH2- C(O)-R- of 8d).
SCHEME Xf
Figure imgf000181_0001
, wherein n is 0, 1, 2, 3, 4 or 5, e.g. n is 1 to 5. [00201] The above-identified benzodiazepine compounds may for example, attach to a connector element at one of at least two possible attachment points: e.g., the phenyl ether or the amino group. As seen below, a connector element may be identified as a Q1 group in benzodiaze ine-connector 1’ A’ and benzodiaze ine-connector 3 C:
Figure imgf000182_0001
and .
[00202] In correlation to Scheme Xa, the synthetic route in Scheme Xa’ illustrates a general method for preparing benzodiazepine-connector 1’ derivatives. The method involves attaching the desired substituents to the phenol core. The desired Q1 group attached at the 4- position of the phenol can be installed by reacting benzodiazepine 3 (see Scheme Xa’’) with the appropriate electrophile 5a to provide 4 (benzodiazepine-connector 1’ derivative). For example, Scheme Xa’ provides for a connector Q1.
Figure imgf000182_0002
[00203] For example, Q1 may be selected from the group consisting of:
Figure imgf000182_0003
.
[00204] Additional examples for 5a and Q1 can be found in Table F, seen below: Table F
Figure imgf000183_0001
Figure imgf000184_0001
[00205] The synthetic route in Scheme Xb’ illustrates a general method for preparing benzodiazepine-connector 3 derivatives. The method involves attaching the desired carbonyl substituents to the free amine. The carbonyl group can be installed by reacting amine 2 (see Scheme Xa’’) with carboxylic acid 7 to provide 6’ (benzodiazepine-connector 3 derivative).
wherein Q1 is–C(O)R (e.g.,–C(O)R of
Figure imgf000184_0002
00206 For exam le, -C(O)R (i.e., Q1) may be selected from the group consisting of:
Figure imgf000184_0003
[00207] Additional examples for 7 and–C(O)R (i.e., -Q1) can be found in Table G, seen below: Table G
Figure imgf000184_0004
[00208] The synthetic route in Scheme Xa’’ illustrates a general method for preparing benzodiazepine derivatives, for example, benzodiazepine 3, as seen in Scheme Xa’ or , benzodiazepine 2, as seen in Scheme Xb’. The starting material, benzotriazole 1, may be purchased from commercial sources or can be prepared by one of skill in the art, for example, following procedures described in J. Org. Chem. v. 55, p. 2206, 1990. Following the amide coupling of 1 with 1a (to provide 2), ammonia is used to prepare amino-substituted 4. Acid- promoted cyclization (condensation) of 4 affords benzodiazepine carbamate 5. A three step procedure is used to prepare thioamide 8: cleavage of the carbamate 5, Boc-protection of amine 6, and thiolation, utilizing P4S10 as the sulfur source. The fused triazole 9 is formed from 8 following a three step procedure: hydrazone formation, acylation and cyclization. Boc-group removal from the reaction of 9 with trifluoroacetic acid (TFA) affords the key intermediate 2, which is used to prepare benzodiazepine-connector 3 derivatives. Intermediate 2 is reacted further to prepare phenol 3, which is a key intermediate in the formation of benzodiazepine- connector 1’ derivatives. To this end, cleavage of methyl ether 2 and selective coupling of the free amine affords phenol 3. SCHEME Xa’’
1a
Figure imgf000186_0001
[00209] In a certain embodiment, for the above-identified benzodiazepine compounds, the attachment point for a connector element of benzodiazepine-connector 2 B is utilized in benzodiazepine-connector 2’’ B’’:
Figure imgf000186_0002
[00210] Scheme Xb’’ provides a synthetic procedure for making key intermediate 6b. The intermediate (+)-JQ1 may be prepared, for example, by known methods. The activated ester 6b can be prepared by reacting (+)-JQ1, e.g., with N-hydroxysuccinimide and a coupling agent such as EDC, or e.g., with EDC and HOBt. SCHEME Xb’’
Figure imgf000187_0001
[00211] It is contemplated herein that the general methods seen above in Scheme Xb and Schemes Xd-Xg can also utilize intermediate 6b, in place of intermediate 6 or 6a, in the preparation of B’ derivatives.
[00212] In one embodiment, an exemplary B’ derivative is represented by the structure:
Figure imgf000187_0002
8h
(see Scheme Xb) ,wherein R is, for example, selected from the group consisting of:
Figure imgf000187_0003
. For example, 8h provides for a connector Q1 wherein Q1 is–NH-R.
[00213] It will be appreciated that for tetrahydroquinoline compounds, the connector element may attach at one of at least two possible attachment points for example, via a terminal amino group or via a carbonyl substituent. As seen below, a connector element may be identified as a Q1 group in tetrahydoquinoline-connector 1 10A’, tetrahydoquinoline-connector 1 10B’, tetrahydroquinoline-connector 210C, and tetrahydroquinoline-connector 10D:
,
Figure imgf000188_0001
.
[00214] For example, Q1 may be as described above in connector 1 10A’ connector 1 10B’ or connector 210C.
[00215] The synthetic route in Scheme Xh illustrates a divergent procedure for preparing tetrahydroquinoline-connector 1 derivatives. The tetrahydroquinoline core is formed in a two step-process beginning with the condensation of 5, 6 and acetaldehyde to form 7 and followed by conjugate addition to acrylaldehyde to afford 8. Tetrahydroquinoline 8 is utilized in a divergent step to install varying phenyl substituents via reaction with the bromo-group to provide 9A and 9B. Following hydrolysis of the amide group, the desired Q1 group is attached at the terminal amino group by reacting the unsubstituted amines of 4A or 3 with the appropriate electrophile to provide 10A or 10B (tetrahydroquinoline-connector 1 derivative). For example, Scheme Xh provides for a connector Q1.
SCHEME Xh
Figure imgf000189_0001
.
[00216] Additional examples for W-Q1 and -Q1 can be found in Table J, seen below: Table J
Figure imgf000189_0002
[00217] The synthetic route in Scheme Xi illustrates a general method for preparing tetrahydroquinoline-connector 2 derivatives. Tetrahydroquinoline 3 is converted to phenyl- substituted 11 utilizing a Suzuki coupling, and the ester of 11 is hydrolyzed to afford carboxylic acid 2. The connecter moieties can be installed via a peptide coupling of the carboxylic acid 2 to prepare 12 (tetrahydroquinoline-connector 2 derivatives 10C). For example, Scheme Xi provides for a connector Q1, wherein Q1 is -W-R (e.g., -W-R of 12).
SCHEME Xi
Figure imgf000190_0001
[00218] For example, R may be .
[00219] The above-identified imidazoquinoline compounds may have an attachment point for a connector element via the imidazole group. As seen below, a connector element may be identified as a Q1 group in imidazoquinoline-connector 1 C, imidazoquinoline- connector 1 D, imidazoquinoline-connector 1 E, imidazoquinoline-connector 1 F, and imidazo uinoline-connector 1 G:
Figure imgf000190_0002
.
[00220] The synthetic routes in Scheme Xm and Scheme Xn provide two
complementary methods for preparing imidazoquinoline-connector 1 derivatives. In Scheme Xm, commercially available 6 is reacted with isoxazole 7 under Suzuki coupling conditions to prepare quinoline intermediate 8. The amine intermediate 9 is formed via nitration of quinoline 8 and is followed by chlorination to afford key intermediate 3. Nucleophilic aromatic substitution to install the desired Q1 group and reduction of the nitro group provides 10. In the final step, the fused imidazolidinone ring is is formed to afford 11 (imidazoquinoline-connector 1 derivative). For example, Scheme Xm provides for a connector Q1.
[00221] In Scheme Xn, commercially available diester 12 and aniline 13 are reacted to prepare the quinoline core intermediate 14. The isoxazole of 15 is installed via a Suzuki coupling. A three step procedure: hydrolysis, chlorination and amidation, provides carboxamide 4. Nucleophilic aromatic substitution is utilized to install the desired Q1 group, and formation of the imidazolidinone ring is the final step in the preparation of 18
(imidazoquinoline-connector 1 derivative). For example, Scheme Xn provides for a connector moiety Q1.
Figure imgf000191_0001
SCHEME Xn
Figure imgf000192_0001
[00223] For example, Q1 may be selected from the group consisting of:
OH NH2
, ,
O and NH2
[00224] Additional examples for NHQ1 and -Q1 that can be utilized in Scheme Xm and Scheme Xn can be found in Table M, seen below: Table M
Figure imgf000192_0003
[00225] The above-identified isoxazole compounds may have one of e.g., two possible attachment points for a connector element: the phenyl ether and the benzylic ether. As seen below, a connector element may be identified as a Q1 group in isoxazole-connector 1 E and
Figure imgf000192_0002
[00226] The synthetic route in Scheme Xt illustrates a general method for preparing isoxazole-connector 1 derivatives. The method involves attaching the desired substituents to the phenol core. The desired Q1 group attached at the meta-position of the phenol can be installed by reacting isoxazole 1t with the appropriate electrophile 2 to provide 3t (isoxazole- connector 1 derivative). For example, Scheme Xt provides for a connector moiety Q1. SCHEME Xt
Figure imgf000193_0001
[00227] Similar to Scheme Xt, Scheme Xu provides a synthetic route for preparing isoxazole-connector 2 derivatives. The method involves attaching the desired substituents to the phenol core. The desired Q1 group attached at the benzylic alcohol can be installed by reacting isoxazole 1u with the appropriate electrophile 2 to provide 3u (isoxazole-connector 2 derivative). For example, Scheme Xu provides for a connector moiety Q1. SCHME Xu
Figure imgf000193_0002
[00228] For Scheme Xt and Scheme Xu, additional examples for 2 and Q1 can be found in Table A.
[00229] Isoxazole compounds may be attached to a connector through a different attachment point, e.g., the amino group of the quinazolone core. As seen below, a connector element may be identified, e.g., as a Q1 group in isoxazole-connector G, isoxazole-connector H, isoxazole-connector I, isoxazole-connector J, isoxazole-connector K,: , and
Figure imgf000194_0001
. A) Carbonyl Region-to-Phenyl Ether Region Connections
[00230] Scheme Xr and Scheme Xr’ provide exemplary synthetic procedures for making bivalent molecules with a carbonyl region-to-phenyl ether region orientations, having a connecting moiety between the two attachment points of the A and B derivatives, 1 and 15, respectively. Intermediate 6 is converted to alcohol 15 via reaction with amine 14. The dimerization of 15 and 1 affords the bivalent molecule 16. SCHEME Xr
Figure imgf000194_0002
[00231] The bivalent molecule 16’ of Scheme Xr’ can be prepared following the general procedure outlined for 16 of Scheme Xr. SCHEME Xr’
Figure imgf000195_0001
B) Carbonyl Region-to-Carbonyl Region Connections
[00233] Scheme Xs provides a synthetic procedure for making bivalent molecules with a carbonyl region-to-carbonyl region orientation, having a connecting moiety between the two attachment points of the B derivatives, 18 and 6. Intermediate 6 is converted to amine 18 via reaction with linear amine 17. The dimerization of 18 and 6 affords the bivalent molecule 19. SCHEME Xs
Figure imgf000196_0001
[00234] In one embodiment, the bivalent molecule 19 may be capable of binding to a bromodomain or to tandem bromodomains.
[00235] Additional examples of connecting moieties that can be utilized in Scheme Xr, Scheme Xr’ and Scheme Xs can be found in Table P’, seen below: Table P’
Figure imgf000196_0002
Figure imgf000197_0001
C) Phenyl Region-to-Carbonyl Region Connections
[00236] Schemes Xt and Xu provide synthetic procedures for making bivalent molecules with a phenyl region-to-carbonyl region orientation.
Figure imgf000197_0002
SCHEME Xu
Figure imgf000198_0001
Figure imgf000198_0002
D) Phenyl Region-to-Phenyl Region Connections
[00237] Schemes Xv and Xw provide synthetic procedures for making bivalent molecules with a phenyl region-to-phenyl region orientation. SCHEME Xv
Figure imgf000198_0003
SCHEME Xw
Figure imgf000199_0001
Figure imgf000199_0002
Methods
[00238] In some embodiments, contemplated bivalent compounds may be administered to a patient in need thereof. In some embodiments, a method of administering a
pharmaceutically effective amount of a compound to a patient in need thereof is provided. In some instances, a method of modulating two or more target biomolecule domains is provided. In some embodiments, the target biomolecule may be a protein. In other embodiments, the target biomolecule may be nucleic acid.
[00239] In some instances, a method of modulating two or more target biomolecule domains is provided, e.g., two bromodomains. In some embodiments, a compound may be used to inhibit or facilitate protein-protein interactions. For example, in some cases, a compound may be capable of activating or inactivating a signaling pathway. Without wishing to be bound by any theory, a compound may bind to a target protein and affect the conformation of the target protein such that the target protein is more biologically active as compared to when the compound does not bind the target protein. In some embodiments, the compound may bind to one region (e.g., domain) of a target molecule. In some embodiments, the compound may bind to two regions of a target molecule. In some embodiments, the compound may bind to a first region of a first target molecule and a second region of a second target molecule. [00240] For example, in some embodiments, P1 and P2 of Formula I may each be capable of binding to a bromodomain in a protein selected from the group consisting of BRD2 D2, BRD3 D2, BRD4 D2, BRD-t D2, yBdf1 D2, yBdf2 D2, KIAA2026, yBdf1 D1, yBdf2 D1, TAF1L D1, TAF1 D1, TAF1L D2, TAF1 D2, ZMYND8, ZMYND11, ASH1L, PBRM D3, PBRM D1, PBRM D2, PBRM D4, PBRM D5, SMARCA2, SMARCA4 ySnf2, ySth, PBRM D6, yRsc1 D2, yRsc2 D2, yRsc1 D1, yRsc2 D1, yRsc4 D1, BRWD1 D1, BRWD3 D1, PHIP D1, MLL, MLL4, BRWD2, ATAD2, ATAD2B, BRD1, BRPF1, BRPF3, BRD7, BRD9, BAZ1B, BRWD1 D2, PHIP D2, BRWD3, CREBBP, EP300 BRD8 D1, BRD8 D2, yRsc4 D2, ySpt7, BAZ1A, BAZ2A, BAZ2B, SP140, SP140L, TRIM28, TRIM24, TRIM33, TRIM66, BPTF, GCN5L2, PCAF, yGcn5, BRD2 D1, BRD3 D1, BRD4 D1, BRD-t D1 and CECR2. Reference to protein and domain names used herein are derived from Zhang Q, Chakravarty S, Ghersi D, Zeng L, Plotnikov AN, et al. (2010) Biochemical Profiling of Histone Binding Selectivity of the Yeast Bromodomain Family. PLoS ONE 5(1): e8903.
doi:10.1371/journal.pone.0008903.
[00241] In one embodiment, compounds contemplated herein may be capable of binding to a protein having a bromodomain, wherein the protein is independently selected from the group consisting of BRD2, BRD3, BRD4 and BRD-t. In another embodiment, compounds contemplated herein may be capable of binding to a tandem bromodomain in a protein selected from the group consisting of BRD2, BRD3, BRD4 and BRD-t. For example, a contemplated bivalent compound may be capable of binding to a tandem bromodomain in a protein selected from the group consisting of BRD2, BRD3, BRD4 and BRD-t.
[00242] In one embodiment, a contemplated bivalent compound may be capable of binding to a bromodomain and a second protein domain, wherein the protein domain is within, e.g., about 40 ǖ , or about 50 ǖ , of the bromodomain.
[00243] In one embodiment, bivalent compounds contemplated herein may be capable of modulating oncology fusion proteins. For example, a bivalent compound may be capable of modulating oncology fusion proteins. Methods of modulating oncology fusion proteins include methods of modulating, e.g., BRD-NUT. In some embodiments, the oncology fusion protein (e.g., fusion gene product) is a BRD fusion product, for example, BRD3-NUT and BRD4- NUT. For example, a method of modulating a fusion protein provided, wherein the fusion protein is selected from the group consisting of BRD3-NUT and BRD4-NUT.
[00244] In one embodiment, a contemplated compound may be capable of binding to a first protein binding site and a second protein binding site, wherein the second protein binding site is, e.g. between about 5 ǖ and about 30 ǖ of the first protein binding site, or in some embodiments within about 40 ǖ of the first protein binding site.
[00245] In an embodiment, the compounds contemplated herein may be used in a method for treating diseases or conditions for which a bromodomain inhibitor is indicated, for example, a compound may be used for treating a chronic autoimmune and/or inflammatory condition in a patient in need thereof. In another embodiment, the compounds contemplated herein may be used in a method for treating cancer, such as midline carcinoma. For example, provided herein is a method of treating a disease associated with a protein having tandem bromodomains in a patient in need.
[00246] Provided herein, for example, is a use of a compound in the manufacture of a medicament for the treatment of diseases or conditions for which a bromodomain inhibitor is indicated. In another embodiment, provided herein is a use of a compound or a
pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a chronic autoimmune and/or inflammatory condition. In a further embodiment, provided herein is a use of a compound or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cancer, such as midline carcinoma or acute myeloid leukemia.
[00247] Provided herein is a method of treating a disease or condition such as systemic or tissue inflammation, inflammatory responses to infection or hypoxia, cellular activation and proliferation, lipid metabolism, fibrosis, or the prevention and treatment of viral infections in a patient in need thereof comprising administering a pharmaceutically effective amount of a contemplated bivalent compound.
[00248] For example, methods of treating chronic autoimmune and inflammatory conditions such as rheumatoid arthritis, osteoarthritis, acute gout, psoriasis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease (Crohn's disease and Ulcerative colitis), asthma, chronic obstructive airways disease, pneumonitis, myocarditis, pericarditis, myositis, eczema, dermatitis, alopecia, vitiligo, bullous skin diseases, nephritis, vasculitis, atherosclerosis, Alzheimer's disease, depression, retinitis, uveitis, scleritis, hepatitis, pancreatitis, primary biliary cirrhosis, sclerosing cholangitis, Addison's disease, hypophysitis, thyroiditis, type II diabetes, acute rejection of transplanted organs in a patient in need thereof are contemplated, comprising administering a contemplated bivalent compound.
[00249] Also contemplated herein are methods of treating acute inflammatory conditions in a patient in need thereof such as acute gout, giant cell arteritis, nephritis including lupus nephritis, vasculitis with organ involvement such as glomerulonephritis, vasculitis including giant cell arteritis, Wegener's granulomatosis, Polyarteritis nodosa, Behcet's disease, Kawasaki disease, Takayasu's Arteritis, or vasculitis with organ involvement, comprising administering a contemplated bivalent compound.
[00250] Methods of treating disorders relating to inflammatory responses to infections with bacteria, viruses, fungi, parasites or their toxins, in a patient in need thereof is
contemplated, such as sepsis, sepsis syndrome, septic shock, endotoxaemia, systemic inflammatory response syndrome (SIRS), multi-organ dysfunction syndrome, toxic shock syndrome, acute lung injury, ARDS (adult respiratory distress syndrome), acute renal failure, fulminant hepatitis, burns, acute pancreatitis, post-surgical syndromes, sarcoidosis, Herxheimer reactions, encephalitis, myelitis, meningitis, malaria, SIRS associated with viral infections such as influenza, herpes zoster, herpes simplex, coronavirus, cold sores, chickenpox, shingles, human papilloma virus, cervical neoplasia, adenovirus infections, including acute respiratory disease, human immunodeficiency virus (HIV), poxvirus infections such as cowpox and smallpox and African swine fever virus comprising administering administering a contemplated bivalent compound.
[00251] Contemplated bivalent compounds may be useful, when administered to a patient in need thereof, in the prevention or treatment of conditions associated with ischaemia- reperfusion injury in a patient need thereof such as myocardial infarction, cerebrovascular ischaemia (stroke), acute coronary syndromes, renal reperfusion injury, organ transplantation, coronary artery bypass grafting, cardio-pulmonary bypass procedures, pulmonary, renal, hepatic, gastro-intestinal or peripheral limb embolism.
[00252] Other contemplated methods of treatment that include administering disclosed compounds include treatment of disorders of lipid metabolism via the regulation of APO-A1 such as hypercholesterolemia, atherosclerosis and Alzheimer's disease, treatment of fibrotic conditions such as idiopathic pulmonary fibrosis, renal fibrosis, post-operative stricture, keloid formation, scleroderma, cardiac fibrosis, and the prevention and treatment of viral infections such as herpes virus, human papilloma virus, adenovirus, human immunodeficiency virus (HIV), and poxvirus and other DNA viruses.
[00253] Contemplated herein are methods of treating cancers, e.g., cancers such as including hematological, epithelial including lung, breast and colon carcinomas, mesenchymal, hepatic, renal and neurological tumors, comprising administering a disclosed compound to a patient in need thereof. For example, contemplated herein is a method of treating squamous cell carcinoma, midline carcinoma or leukemia such as acute myeloid leukemia in a patient in need thereof comprising administering a bivalent compound.
[00254] In an embodiment, a bivalent compound may be administered at the point of diagnosis to reduce the incidence of: SIRS, the onset of shock, multi-organ dysfunction syndrome, which includes the onset of acute lung injury, ARDS, acute renal, hepatic, and cardiac and gastro-intestinal injury.
[00255] Also contemplated herein are methods of providing contraceptive agents, or a method of providing contraception, to a male patient, comprising administering a bivalent compound.
[00256] In some embodiments, a ligand moiety (e.g., a pharmacophore) may have a molecular weight between 50 Da and 2000 Da, in some embodiments between 50 Da and 1500 Da, in some embodiments, between 50 Da and 1000 Da, and in some embodiments, between 50 Da and 500 Da. In certain embodiments, a ligand moiety may have a molecular weight of less than 2000 Da, in some embodiments, less than 1000 Da, and in some embodiments less than 500 Da.
[00257] In certain embodiments, the compound utilized by one or more of the foregoing methods is one of the generic, subgeneric, or specific compounds described herein.
[00258] Disclosed compositions may be administered to patients (animals and humans) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. It will be appreciated that the dose required for use in any particular application will vary from patient to patient, not only with the particular compound or composition selected, but also with the route of administration, the nature of the condition being treated, the age and condition of the patient, concurrent medication or special diets then being followed by the patient, and other factors which those skilled in the art will recognize, with the appropriate dosage ultimately being at the discretion of the attendant physician. For treating clinical conditions and diseases noted above, a compound may be administered orally, subcutaneously, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, and vehicles. Parenteral administration may include subcutaneous injections, intravenous or intramuscular injections, or infusion techniques.
[00259] Treatment can be continued for as long or as short a period as desired. The compositions may be administered on a regimen of, for example, one to four or more times per day. A suitable treatment period can be, for example, at least about one week, at least about two weeks, at least about one month, at least about six months, at least about 1 year, or indefinitely. A treatment period can terminate when a desired result, for example a partial or total alleviation of symptoms, is achieved.
[00260] In another aspect, pharmaceutical compositions comprising bivalent compounds as disclosed herein formulated together with a pharmaceutically acceptable carrier provided. In particular, the present disclosure provides pharmaceutical compositions bivalent compounds as disclosed herein formulated together with one or more pharmaceutically acceptable carriers. These formulations include those suitable for oral, rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) rectal, vaginal, or aerosol administration, although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used. For example, disclosed compositions may be formulated as a unit dose, and/or may be formulated for oral or subcutaneous administration.
[00261] Exemplary pharmaceutical compositions may be used in the form of a pharmaceutical preparation, for example, in solid, semisolid, or liquid form, which contains one or more of the compounds, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral, or parenteral applications. The active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease.
[00262] For preparing solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid
preformulation composition containing a homogeneous mixture of a compound, or a non-toxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
[00263] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the subject composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4)
disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
[00264] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface- active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent. Tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art.
[00265] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the subject composition, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof. [00266] Suspensions, in addition to the subject composition, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
[00267] Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.
[00268] Dosage forms for transdermal administration of a subject composition includes powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active component may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
[00269] The ointments, pastes, creams and gels may contain, in addition to a subject composition, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
[00270] Powders and sprays may contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
[00271] Compositions and compounds may alternatively be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound. A non-aqueous (e.g., fluorocarbon propellant) suspension could be used. Sonic nebulizers may be used because they minimize exposing the agent to shear, which may result in degradation of the compounds contained in the subject compositions. Ordinarily, an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars, or sugar alcohols. Aerosols generally are prepared from isotonic solutions.
[00272] Pharmaceutical compositions suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
[00273] Examples of suitable aqueous and non-aqueous carriers which may be employed in the pharmaceutical compositions include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins. Proper fluidity may be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants
[00274] In another aspect, enteral pharmaceutical formulations including a disclosed pharmaceutical composition comprising bivalent compounds, an enteric material; and a pharmaceutically acceptable carrier or excipient thereof are provided. Enteric materials refer to polymers that are substantially insoluble in the acidic environment of the stomach, and that are predominantly soluble in intestinal fluids at specific pHs. The small intestine is the part of the gastrointestinal tract (gut) between the stomach and the large intestine, and includes the duodenum, jejunum, and ileum. The pH of the duodenum is about 5.5, the pH of the jejunum is about 6.5 and the pH of the distal ileum is about 7.5. Accordingly, enteric materials are not soluble, for example, until a pH of about 5.0, of about 5.2, of about 5.4, of about 5.6, of about 5.8, of about 6.0, of about 6.2, of about 6.4, of about 6.6, of about 6.8, of about 7.0, of about 7.2, of about 7.4, of about 7.6, of about 7.8, of about 8.0, of about 8.2, of about 8.4, of about 8.6, of about 8.8, of about 9.0, of about 9.2, of about 9.4, of about 9.6, of about 9.8, or of about 10.0. Exemplary enteric materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleat, cellulose acetate butyrate, cellulose acetate propionate, copolymer of methylmethacrylic acid and methyl methacrylate, copolymer of methyl acrylate, methylmethacrylate and methacrylic acid, copolymer of methylvinyl ether and maleic anhydride (Gantrez ES series), ethyl methyacrylate-methylmethacrylate- chlorotrimethylammonium ethyl acrylate copolymer, natural resins such as zein, shellac and copal collophorium, and several commercially available enteric dispersion systems (e. g. , Eudragit L30D55, Eudragit FS30D, Eudragit L100, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric, and Aquateric). The solubility of each of the above materials is either known or is readily determinable in vitro. The foregoing is a list of possible materials, but one of skill in the art with the benefit of the disclosure would recognize that it is not comprehensive and that there are other enteric materials that may be used.
[00275] Advantageously, kits are provided containing one or more compositions. Such kits include a suitable dosage form such as those described above and instructions describing the method of using such dosage form to treat a disease or condition. The instructions would direct the consumer or medical personnel to administer the dosage form according to administration modes known to those skilled in the art. Such kits could advantageously be packaged and sold in single or multiple kit units. An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.
[00276] It may be desirable to provide a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested. Another example of such a memory aid is a calendar printed on the card, e.g., as follows“First Week, Monday, Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, . . .” etc. Other variations of memory aids will be readily apparent. A“daily dose” can be a single tablet or capsule or several pills or capsules to be taken on a given day. Also, a daily dose of a first compound can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa. The memory aid should reflect this.
[00277] Also contemplated herein are methods and compositions that include a second active agent, or administering a second active agent.
[00278] Certain terms employed in the specification, examples, and appended claims are collected here. These definitions should be read in light of the entirety of the disclosure and understood as by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art. DEFINITIONS
[00279] In some embodiments, the compounds, as described herein, may be substituted with any number of substituents or functional moieties. In general, the term“substituted” whether preceded by the term“optionally” or not, and substituents contained in formulas, refer to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent.
[00280] In some instances, when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
[00281] As used herein, the term“substituted” is contemplated to include all permissible substituents of organic and inorganic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. In some embodiments, heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms. Non-limiting examples of substituents include acyl; aliphatic; heteroaliphatic; phenyl; naphthyl; heteroaryl; arylalkyl; heteroarylalkyl; alkoxy; cycloalkoxy;
heterocyclylalkoxy; heterocyclyloxy; heterocyclyloxyalkyl; alkenyloxy; alkynyloxy; phenoxy; heteroalkoxy; heteroaryloxy; alkylthio; phenylthio; heteroalkylthio; heteroarylthio; oxo; -F; - Cl; -Br; -I; -OH; -NO2; -CN; -SCN; -SRx; -CF3; -CH2CF3; -CHCl2; -CH2OH; -CH2CH2OH; - CH2NH2; -CH2SO2CH3; -ORx, -C(O)Rx; -CO2(Rx); -C(O)N(Rx)2; -OC(O)Rx; -OCO2Rx; - OC(O)N(Rx)2; -N(Rx)2; -SORx; -S(O)2Rx; -NRxC(O)Rx; or -C(Rx)3; wherein each occurrence of Rx independently is hydrogen, aliphatic, heteroaliphatic, phenyl, naphthyl, heteroaryl, arylalkyl, or heteroarylalkyl, wherein any of the aliphatic, heteroaliphatic, arylalkyl, or heteroarylalkyl substituents described above and herein may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and wherein any of the phenyl, naphthyl, or heteroaryl substituents described above and herein may be substituted or unsubstituted. Furthermore, the compounds described herein are not intended to be limited in any manner by the permissible substituents of organic compounds. In some embodiments, combinations of substituents and variables described herein may be preferably those that result in the formation of stable compounds. The term“stable,” as used herein, refers to compounds which possess stability sufficient to allow manufacture and which maintain the integrity of the compound for a sufficient period of time to be detected and preferably for a sufficient period of time to be useful for the purposes detailed herein.
[00282] The term“acyl,” as used herein, refers to a moiety that includes a carbonyl group. In some embodiments, an acyl group may have a general formula selected from - C(O)Rx; -CO2(Rx); -C(O)N(Rx)2; -OC(O)Rx; -OCO2Rx; and -OC(O)N(Rx)2; wherein each occurrence of Rx independently includes, but is not limited to, hydrogen, aliphatic,
heteroaliphatic, phenyl, naphthyl, heteroaryl, arylalkyl, or heteroarylalkyl, wherein any of the aliphatic, heteroaliphatic, arylalkyl, or heteroarylalkyl substituents described above and herein may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and wherein any of the phenyl, naphthyl, or heteroaryl substituents described above and herein may be substituted or unsubstituted.
[00283] The term“aliphatic,” as used herein, includes both saturated and unsaturated, straight chain (i.e., unbranched), branched, acyclic, cyclic, or polycyclic aliphatic
hydrocarbons, which are optionally substituted with one or more functional groups. As will be appreciated by one of ordinary skill in the art,“aliphatic” is intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties. The term“heteroaliphatic,” as used herein, refers to aliphatic moieties that contain one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms, e.g., in place of carbon atoms.
Heteroaliphatic moieties may be branched, unbranched, cyclic or acyclic and include saturated and unsaturated heterocycles such as morpholino, pyrrolidinyl, etc.
[00284] In general, the terms“aryl,”“aromatic,”“heteroaryl,” and“heteroaromtic” as used herein, refer to stable mono- or polycyclic, heterocyclic, polycyclic, and polyheterocyclic unsaturated moieties having preferably 3-14 carbon atoms, each of which may be substituted or unsubstituted. Substituents include, but are not limited to, any of the previously mentioned substituents, i.e., the substituents recited for aliphatic moieties, or for other moieties as disclosed herein, resulting in the formation of a stable compound. In certain embodiments, aryl or aromatic refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings selected from phenyl, naphthyl, tetrahydronaphthyl, indanyl, and indenyl. In certain embodiments, the term heteroaryl, as used herein, refers to a cyclic aromatic radical having from five to ten ring atoms of which one ring atom is selected from the group consisting of S, O, and N; zero, one, or two ring atoms are additional heteroatoms independently selected from the group consisting of S, O, and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms. Heteroaryl moieties may be selected from: pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl,oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, and the like.
[00285] It will be appreciated that aryl, aromatic, heteroaryl, and heteroaromatic groups described herein can be unsubstituted or substituted, wherein substitution includes replacement of one, two, three, or more of the hydrogen atoms thereon independently with a group selected from: C1-6alkyl; phenyl; heteroaryl; benzyl; heteroarylalkyl; C1-6alkoxy; C1-6cycloalkoxy; C1- 6heterocyclylalkoxy;
Figure imgf000211_0001
heterocyclyloxyalkyl; C2-6alkenyloxy; C2- 6alkynyloxy; phenoxy; heteroalkoxy; heteroaryloxy; C1-6alkylthio; phenylthio; heteroalkylthio; heteroarylthio; oxo; -F; -Cl; -Br; -I; -OH; -NO2; -CN; -CF3; -CH2CF3; -CHCl2; -CH2OH; - CH2CH2OH; -CH2NH2; -CH2SO2CH3; -C(O)Rx; -CO2(Rx); -CON(Rx)2; -OC(O)Rx; -OCO2Rx; - OCON(Rx)2; -N(Rx)2; - S(O)2Rx; -NRx(CO)Rx, wherein each occurrence of Rx is selected from hydrogen, C1-6alkyl, aliphatic, heteroaliphatic, phenyl, or heteroaryl. Additional examples of generally applicable substituents are illustrated by the specific embodiments shown in the Examples that are described herein.
[00286] The term“heterocyclic,” as used herein, refers to an aromatic or non-aromatic, partially unsaturated or fully saturated, 3- to 10-membered ring system, which includes single rings of 3 to 8 atoms in size and bi- and tri-cyclic ring systems which may include aromatic five- or six-membered aryl or aromatic heterocyclic groups fused to a non-aromatic ring.
These heterocyclic rings include those having from one to three heteroatoms independently selected from the group consisting of oxygen, sulfur, and nitrogen, in which the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. In certain embodiments, the term heterocyclic refers to a non-aromatic 5-, 6-, or 7-membered ring or a polycyclic group wherein at least one ring atom is a heteroatom selected from the group consisting of O, S, and N (wherein the nitrogen and sulfur heteroatoms may be optionally oxidized), including, but not limited to, a bi- or tri-cyclic group, comprising fused six-membered rings having between one and three heteroatoms independently selected from the group consisting of the oxygen, sulfur, and nitrogen, wherein (i) each 5-membered ring has 0 to 2 double bonds, each 6-membered ring has 0 to 2 double bonds, and each 7-membered ring has 0 to 3 double bonds, (ii) the nitrogen and sulfur heteroatoms may be optionally oxidized, (iii) the nitrogen heteroatom may optionally be quaternized, and (iv) any of the above heterocyclic rings may be fused to an aryl or heteroaryl ring.
[00287] The term“alkenyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond, such as a straight or branched group of 2-6 or 3-4 carbon atoms, referred to herein for example as C2-6alkenyl, and C3- 4alkenyl, respectively. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, etc.
[00288] The term“alkenyloxy” used herein refers to a straight or branched alkenyl group attached to an oxygen (alkenyl-O). Exemplary alkenoxy groups include, but are not limited to, groups with an alkenyl group of 3-6 carbon atoms referred to herein as C3-6alkenyloxy.
Exemplary“alkenyloxy” groups include, but are not limited to allyloxy, butenyloxy, etc.
[00289] The term“alkoxy” as used herein refers to a straight or branched alkyl group attached to an oxygen (alkyl-O-). Exemplary alkoxy groups include, but are not limited to, groups with an alkyl group of 1-6 or 2-6 carbon atoms, referred to herein as C1-6alkoxy, and C2- C6alkoxy, respectively. Exemplary alkoxy groups include, but are not limited to methoxy, ethoxy, isopropoxy, etc.
[00290] The term“alkoxycarbonyl” as used herein refers to a straight or branched alkyl group attached to oxygen, attached to a carbonyl group (alkyl-O-C(O)-). Exemplary alkoxycarbonyl groups include, but are not limited to, alkoxycarbonyl groups of 1-6 carbon atoms, referred to herein as C1-6alkoxycarbonyl. Exemplary alkoxycarbonyl groups include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, etc.
[00291] The term“alkynyloxy” used herein refers to a straight or branched alkynyl group attached to an oxygen (alkynyl-O)). Exemplary alkynyloxy groups include, but are not limited to, propynyloxy. [00292] The term“alkyl” as used herein refers to a saturated straight or branched hydrocarbon, for example, such as a straight or branched group of 1-6, 1-4, or 1-3 carbon atoms, referred to herein as C1-6alkyl, C1-4alkyl, and C1-3alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2- methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 3-methyl-2-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2- pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.
[00293] The term“alkylene” as used herein refers to a bivalent saturated straight or branched hydrocarbon, for example, such as a straight or branched group of 1-6, 1-4, or 1-3 carbon atoms, referred to herein as -C1-6alkylene-, -C1-4alkylene-, and -C1-3alkylene-, respectively, where the alkylene has two open valences. Exemplary alkyl groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, 2-methyl-1-propylene, 2- methyl-2-propylene, 2-methyl-1-butylene, 3-methyl-1-butylene, 3-methyl-2-butylene, 2,2- dimethyl-1-propylene, 2-methyl-1-pentylene, 3-methyl-1-pentylene, 4-methyl-1-pentylene, 2- methyl-2-pentylene, 3-methyl-2-pentylene, 4-methyl-2-pentylene, 2,2-dimethyl-1-butylene, 3,3-dimethyl-1-butylene, 2-ethyl-1-butylene, butylene, isobutylene, t-butylene, pentylene, isopentylene, neopentylene, hexylene, etc.
[00294] The term“alkylcarbonyl” as used herein refers to a straight or branched alkyl group attached to a carbonyl group (alkyl-C(O)-). Exemplary alkylcarbonyl groups include, but are not limited to, alkylcarbonyl groups of 1-6 atoms, referred to herein as C1- 6alkylcarbonyl groups. Exemplary alkylcarbonyl groups include, but are not limited to, acetyl, propanoyl, isopropanoyl, butanoyl, etc.
[00295] The term“alkynyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond, such as a straight or branched group of 2-6, or 3-6 carbon atoms, referred to herein as C2-6alkynyl, and C3-6alkynyl, respectively. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, etc.
[00296] The term“carbonyl” as used herein refers to the radical -C(O)-.
[00297] The term“carboxylic acid” as used herein refers to a group of formula -CO2H.
[00298] The term“cyano” as used herein refers to the radical -CN.
[00299] The term“cycloalkoxy” as used herein refers to a cycloalkyl group attached to an oxygen (cycloalkyl-O-). [00300] The term“cycloalkyl” as used herein refers to a monocyclic saturated or partially unsaturated hydrocarbon group of for example 3-6, or 4-6 carbons, referred to herein, e.g., as C3-6cycloalkyl or C4-6cycloalkyl and derived from a cycloalkane. Exemplary cycloalkyl groups include, but are not limited to, cyclohexyl, cyclohexenyl, cyclopentyl, cyclobutyl or, cyclopropyl.
[00301] The terms“halo” or“halogen” as used herein refer to F, Cl, Br, or I.
[00302] The term“heterocyclylalkoxy” as used herein refers to a heterocyclyl- alkyl-O- group.
[00303] The term“heterocyclyloxyalkyl” refers to a heterocyclyl-O-alkyl- group.
[00304] The term“heterocyclyloxy” refers to a heterocyclyl-O- group.
[00305] The term“heteroaryloxy” refers to a heteroaryl-O- group.
[00306] The terms“hydroxy” and“hydroxyl” as used herein refers to the radical -OH.
[00307] The term“oxo” as used herein refers to the radical =O.
[00308] The term“connector” as used herein to refers to an atom or a collection of atoms optionally used to link interconnecting moieties, such as a disclosed connecting moiety (i.e., linker) and a pharmacophore. Contemplated connectors are generally hydrolytically stable.
[00309] “Treating” includes any effect, e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder and the like.
[00310] “Pharmaceutically or pharmacologically acceptable” include molecular entities and compositions that do not produce an adverse, allergic, or other untoward reaction when administered to an animal, or a human, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, general safety and purity standards as required by FDA Office of Biologics standards.
[00311] The term“pharmaceutically acceptable carrier” or“pharmaceutically acceptable excipient” as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical
administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.
[00312] The term“pharmaceutical composition” as used herein refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers. [00313] “Individual,”“patient,” or“subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans. The compounds can be administered to a mammal, such as a human, but can also be administered to other mammals such as an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like). The mammal treated is desirably a mammal in which treatment of obesity, or weight loss is desired. “Modulation” includes antagonism (e.g., inhibition), agonism, partial antagonism and/or partial agonism.
[00314] In the present specification, the term“therapeutically effective amount” means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought by the researcher, veterinarian, medical doctor, or other clinician. The compounds are administered in therapeutically effective amounts to treat a disease. Alternatively, a therapeutically effective amount of a compound is the quantity required to achieve a desired therapeutic and/or prophylactic effect, such as an amount which results in weight loss.
[00315] The term“pharmaceutically acceptable salt(s)” as used herein refers to salts of acidic or basic groups that may be present in compounds used in the present compositions. Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including but not limited to malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3- naphthoate)) salts. Compounds included in the present compositions that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. Compounds included in the present compositions that include a basic or acidic moiety may also form pharmaceutically acceptable salts with various amino acids. The compounds of the disclosure may contain both acidic and basic groups; for example, one amino and one carboxylic acid group. In such a case, the compound can exist as an acid addition salt, a zwitterion, or a base salt.
[00316] The compounds of the disclosure may contain one or more chiral centers and/or double bonds and, therefore, exist as stereoisomers, such as geometric isomers, enantiomers or diastereomers. The term“stereoisomers” when used herein comprises all geometric isomers, enantiomers or diastereomers. These compounds may be designated by the symbols“R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom.
Various stereoisomers of these compounds and mixtures thereof are encompassed by this disclosure. Stereoisomers include enantiomers and diastereomers. Mixtures of enantiomers or diastereomers may be designated“(±)” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.
[00317] The compounds of the disclosure may contain one or more chiral centers and/or double bonds and, therefore, exist as geometric isomers, enantiomers or diastereomers. The enantiomers and diastereomers may be designated by the symbols“(+),”“(-).”“R” or“S,” depending on the configuration of substituents around the stereogenic carbon atom, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. Geometric isomers, resulting from the arrangement of substituents around a carbon-carbon double bond or arrangement of substituents around a cycloalkyl or heterocyclic ring, can also exist in the compounds. The symbol denotes a bond that may be a single, double or triple bond as described herein. Substituents around a carbon-carbon double bond are designated as being in the“Z” or“E” configuration wherein the terms“Z” and“E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the“E” and“Z” isomers. Substituents around a carbon-carbon double bond alternatively can be referred to as“cis” or“trans,” where“cis” represents substituents on the same side of the double bond and“trans” represents substituents on opposite sides of the double bond. The arrangement of substituents around a carbocyclic ring can also be designated as“cis” or “trans.” The term“cis” represents substituents on the same side of the plane of the ring and the term“trans” represents substituents on opposite sides of the plane of the ring. Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated“cis/trans.”
[00318] The term“stereoisomers” when used herein comprises all geometric isomers, enantiomers or diastereomers. Various stereoisomers of these compounds and mixtures thereof are encompassed by this disclosure. [00319] Individual enantiomers and diastereomers of the compounds can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, (3) direct separation of the mixture of optical enantiomers on chiral liquid chromatographic columns or (4) kinetic resolution using stereoselective chemical or enzymatic reagents.
Racemic mixtures can also be resolved into their component enantiomers by well known methods, such as chiral-phase gas chromatography or crystallizing the compound in a chiral solvent. Stereoselective syntheses, a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or during the transformation of a pre-existing one, are well known in the art. Stereoselective syntheses encompass both enantio- and diastereoselective transformations. For examples, see Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.
[00320] The compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In one embodiment, the compound is amorphous. In one embodiment, the compound is a polymorph. In another embodiment, the compound is in a crystalline form.
[00321] Also embraced are isotopically labeled compounds which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
Examples of isotopes that can be incorporated into the compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 10B, 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively. For example, a compound may have one or more H atom replaced with deuterium.
[00322] Certain isotopically-labeled disclosed compounds (e.g., those labeled with 3H and 14C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3H) and carbon-14 (i.e., 14C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed in the Examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
[00323] The term“prodrug” refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (such as by esterase, amidase, phosphatase, oxidative and or reductive metabolism) in various locations (such as in the intestinal lumen or upon transit of the intestine, blood, or liver). Prodrugs are well known in the art (for example, see Rautio, Kumpulainen, et al, Nature Reviews Drug Discovery 2008, 7, 255). For example, if a compound or a pharmaceutically acceptable salt, hydrate, or solvate of the compound contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as (C1-8)alkyl, (C2-12)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N- (alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,
1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl,
4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(C1-C2)alkylamino(C2-C3)alkyl (such as ȕ-dimethylaminoethyl), carbamoyl-(C1-C2)alkyl, N,N-di(C1-C2)alkylcarbamoyl-(C1-C2)alkyl and piperidino-, pyrrolidino- or morpholino(C2-C3)alkyl.
[00324] Similarly, if a compound contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (C1- 6)alkanoyloxymethyl, 1-((C1-6)alkanoyloxy)ethyl, 1-methyl-1-((C1-6)alkanoyloxy)ethyl (C1- 6)alkoxycarbonyloxymethyl, N-(C1-6)alkoxycarbonylaminomethyl, succinoyl, (C1-6)alkanoyl, Į- amino(C1-4)alkanoyl, arylacyl and Į-aminoacyl, or Į-aminoacyl-Į-aminoacyl, where each D- aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH)2, -P(O)(O(C1-C6)alkyl)2 or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate).
[00325] If a compound incorporates an amine functional group, a prodrug can be formed, for example, by creation of an amide or carbamate, an N-acyloxyalkyl derivative, an
(oxodioxolenyl)methyl derivative, an N-Mannich base, imine, or enamine. In addition, a secondary amine can be metabolically cleaved to generate a bioactive primary amine, or a tertiary amine can be metabolically cleaved to generate a bioactive primary or secondary amine. For examples, see Simplício, et al., Molecules 2008, 13, 519 and references therein. INCORPORATION BY REFERENCE
[00326] All publications and patents mentioned herein, including those items listed below, are hereby incorporated by reference in their entirety for all purposes as if each individual publication or patent was specifically and individually incorporated by reference. In case of conflict, the present application, including any definitions herein, will control. EXAMPLES
[00327] The compounds described herein can be prepared in a number of ways based on the teachings contained herein and synthetic procedures known in the art. Where a particular stereochemistry is indicated for a compound, one of ordinary skill in the art would recognize that other stereoisomers of the compound may also be formed. In some cases, a starting material or intermediate used in the synthesis of a contemplated compound may have an enantiomeric excess greater than 0, e.g., greater than about 95%, greater than about 98%, greater than about 99%, or essentially 100%. For example, in some cases, a starting material or intermediate may be essentially stereoisomerically pure. However, partial or complete loss of chiral integrity may occur during the synthesis of the contemplated compound thereby reducing or eliminating the enantiomeric excess. For example, where a stereoisomerically pure starting material or intermediate is used in a synthesis of a contemplated compound, partial or complete loss of chiral integrity results in a stereoisomeric mixture. A stereoisomeric mixture may be partially or essentially completely resolved by subjecting the stereoisomeric mixture to a chiral purification technique (e.g., chiral HPLC purification). EXAMPLES 1-12:
[00328] Compounds were synthesized according to the following procedures.
Scheme 1. Synthesis of bivalent compounds
Figure imgf000220_0001
[00329] General procedure for coupling reaction
[00330] A suspension of 2-((4S)-6-(4-chlorophenyl)-8-hydroxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (1 eq.) in acetonitrile (10 mL) was charged with K2CO3 (3 eq.) and a linker precursor (2a-l) (0.5 eq.). The resulting mixture was heated at 80°C for 16 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was partitioned between DCM and H2O and separated. The aqueous layer was re-extracted with DCM and the combined organic fractions were dried over anhydrous Na2SO4, filtered and concentrated in vacuo resulting in the crude product. The crude product was purified by preparative HPLC.
[00331] Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 were synthesized using the following procedures.
[00332] 2,2'-((4S,4'S)-8,8'-(Butane-1,4-diylbis(oxy))bis(6-(4-chlorophenyl)-1-methyl- 4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine-8,4-diyl))bis(N-ethylacetamide) [Example 1] :
Figure imgf000220_0002
[00333] A suspension of 2-((4S)-6-(4-chlorophenyl)-8-hydroxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (204 mg, 0.50 mmol) in acetonitrile (10 mL) was charged with K2CO3 (82 mg, 0.6 mmol) and butane-1,4-diyl dimethanesulfonate (2a) (50 mg, 0.20 mmol). The resulting mixture was heated at 80°C for 16 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was partitioned between DCM (20 mL) and H2O (10 mL) and separated. The aqueous layer was extracted with DCM (3 X 15 mL) and the combined organic fractions were dried over anhydrous Na2SO4, filtered and concentrated in vacuo resulting in the crude product. The crude product was purified by preparative HPLC to give 40 mg (23 % yield) of the title compound as a white solid. 1H NMR (400 MHz, CD3OD): į = 7.90 (s, 2H), 7.69 (d, J = 8.9 Hz, 2H), 7.52 (d, J = 8.3 Hz, 2H), 7.42– 7.29 (m, 6H), 6.88 (d, J = 2.8 Hz, 2H), 4.59 (dd, J = 5.03, 8.91 Hz, 2H), 3.99– 4.16 (m, 4H), 3.38 - 3.23 (m, 8H), 2.62 (s, 6H), 1.93 (br. s., 4H), 1.19 (t, J = 7.4 Hz, 6H); MS (ES+): m/z = 873.35, 875.40 [M+H]+; LCMS: tR = 2.44 min.
[00334] 2,2'-((4S,4'S)-8,8'-((Oxybis(ethane-2,1-diyl))bis(oxy))bis(6-(4-chlorophenyl)- 1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine-8,4-diyl))bis(N-ethylacetamide) [Example 2]:
Figure imgf000221_0001
[00335] A suspension of 2-((4S)-6-(4-chlorophenyl)-8-hydroxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (204 mg, 0.5 mmol) in acetonitrile (10 mL) with K2CO3 (82 mg, 0.6 mmol) and oxybis(ethane-2,1-diyl)
dimethanesulfonate (2b) (50 mg, 0.2 mmol) was heated at 80°C for 16 h. After work up, the crude was purified by preparative HPLC to give 30 mg ( 17% yield) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): į = 7.45 (dd, J = 14.4, 8.6 Hz, 6H), 7.38– 7.31 (m, 4H), 6.92 (d, J = 2.7 Hz, 2H), 6.51 (d, J = 5.8 Hz, 2H), 4.68 (q, J = 6.5 Hz, 2H), 4.16 - 3.90 (m, 8H), 3.52– 3.23 (m, 8H), 2.73 (s, 6H), 1.19 (t, J = 7.3 Hz, 6H); MS (ES+): m/z = 889.15, 891.25 [M+H]+; LCMS: tR = 2.30 min.
[00336] 2,2'-((4S,4'S)-8,8'-(Hexane-1,6-diylbis(oxy))bis(6-(4-chlorophenyl)-1- methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine-8,4-diyl))bis(N-ethylacetamide)
Figure imgf000221_0002
[00337] A suspension of 2-((4S)-6-(4-chlorophenyl)-8-hydroxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (200 mg, 0.488 mmol) in acetonitrile (10 mL) with K2CO3 (202 mg, 1.4mmol) and hexane-1,6-diyl dimethanesulfonate (2c) (66.9 mg, 0.244 mmol) was heated at 80°C for 16 h. After the work up, the crude was purified by preparative HPLC to give 20 mg (9 % yield) of the title compound as a white solid. 1H NMR (400 MHz, CD3OD): į = 7.90 (d, J = 1.3 Hz, 2H), 7.70 (d, J = 9.1 Hz, 2H), 7.53 (d, J = 7.6 Hz, 4H), 7.43– 7.30 (m, 6H), 6.92– 6.84 (m, 2H), 4.61 (m, 2H), 4.12– 3.93 (m, 4H), 3.39–3.16 (m, 8H), 2.63 (s, 6H), 1.82– 1.78 (m, 4H), 1.54– 1.45 (m, 2H), 1.18 (t, J = 7.3 Hz, 6H); MS (ES+): m/z = 452.15, 454.50 [M/2]+; LCMS: tR = 2.92 min.
[00338] 2,2'-((4S,4'S)-8,8'-(((Ethane-1,2-diylbis(oxy))bis(ethane-2,1- diyl))bis(oxy))bis(6-(4-chlorophenyl)-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3- le 4]:
Figure imgf000222_0001
[00339] A suspension of 2-((4S)-6-(4-chlorophenyl)-8-hydroxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (133 mg, 0.3 mmol) in acetonitrile (10 mL) with K2CO3 (66 mg, 0.4 mmol) and (ethane-1,2-diylbis(oxy))bis(ethane- 2,1-diyl) dimethanesulfonate (2d) (50 mg, 0.1 mmol) was heated at 80°C for 16 h. After the work up, the crude was purified by preparative HPLC to give 50 mg (54% yield) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): į = 7.50– 7.30 (m, 10H), 7.28– 7.20 (m, 2H), 6.90 (dd, J = 6.5, 2.8 Hz, 2H), 6.46 (dt, J = 11.4, 6.0 Hz, 2H), 4.67 (t, J = 7.1 Hz, 2H), 4.10 (t, J = 4.5 Hz, 4H), 3.84 (d, J = 4.7 Hz, 4H), 3.70 (s, 4H), 3.61– 3.32 (m, 6H), 2.70 (s, 6H), 1.18 (t, J = 7.3 Hz, 6H). MS (ES+): m/z = 933.25, 935.15 [M+H]+; LCMS: tR = 2.29 min.
[00340] 2,2'-((4S,4'S)-8,8'-((((Oxybis(ethane-2,1-diyl))bis(oxy))bis(ethane-2,1- diyl))bis(oxy))bis(6-(4-chlorophenyl)-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3- a][1,4]diazepine-8,4-diyl))bis(N-ethylacetamide) [Example 5]:
Figure imgf000223_0001
[00341] A suspension of 2-((4S)-6-(4-chlorophenyl)-8-hydroxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (116 mg, 0.2 mmol) in acetonitrile (10 mL) with K2CO3 (41 mg, 0.3 mmol) and ((oxybis(ethane-2,1- diyl))bis(oxy))bis(ethane-2,1-diyl) dimethanesulfonate (2e) (50 mg, 0.1 mmol) was heated at 80 °C for 16 h. After the work up, the crude was purified by preparative HPLC to give 20 mg (20 % yield) of the title compound as a white solid. 1H NMR (400 MHz, CD3OD): į = 7.68 (dd, J = 9.0, 2.9 Hz, 1H), 7.52 (d, J = 8.2 Hz, 2H), 7.41– 7.30 (m, 3H), 6.98– 6.92 (m, 1H), 4.60– 4.56 (m, 1H), 4.19– 4.10 (m, 2H), 3.79 (q, J = 6.2, 4.6 Hz, 2H), 3.61 (q, J = 7.5, 6.4 Hz, 4H), 3.38– 3.25 (m, 4H), 2.62 (s, 3H), 1.18 (t, J = 7.3 Hz, 3H); MS (ES+): m/z = 977.30, 979.20 [M+H]+; LCMS: tR = 2.27 min.
[00342] 2,2'-((4S,4'S)-8,8'-(3,6,9,12-Tetraoxatetradecane-1,14-diylbis(oxy))bis(6-(4- chlorophenyl)-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine-8,4-diyl))bis(N- ethylacetamide) [Example 6]:
Figure imgf000223_0002
[00343] A suspension of 2-((4S)-6-(4-chlorophenyl)-8-hydroxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (100 mg, 0.244 mmol) in acetonitrile (10 mL) was charged with K2CO3 (99 mg, 0.7mmol) and 3,6,9,12- tetraoxatetradecane-1,14-diyl dimethanesulfonate (2f) (48 mg, 0.122 mmol) was heated at 80°C for 16 h. After the work up, the crude was purified by preparative HPLC to give 30 mg, (24.0 % yield) of the title compound as a white solid. 1H NMR (400 MHz, CD3OD): į = 7.69 (dd, J = 9.1, 2.9 Hz, 2H), 7.52 (dd, J = 8.6, 3.5 Hz, 4H), 7.45– 7.30 (m, 6H), 6.92 (dd, J = 14.3, 2.8 Hz, 2H), 4.60– 4.57 (m, 2H), 4.17 - 4.11 (, m, 4H), 3.87– 3.74 (m, 4H), 3.60 -3.55 (m, 12H), 3.31 – 3.17 (m, 8H), 2.62 (s, 6H), 1.18 (t, J = 7.3 Hz, 6H); MS (ES+): m/z = 512.50 , 514.00 [M/2]+; LCMS: tR = 2.57 min.
[00344] 2,2'-((4S,4'S)-8,8'-(3,6,9,12,15-Pentaoxaheptadecane-1,17-diylbis(oxy))bis(6- (4-chlorophenyl)-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine-8,4-diyl))bis(N- ethylacetamide) [Example 7]:
[00345] A suspension of 2-((4S)-6-(4-chlorophenyl)-8-hydroxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (187 mg, 0.456 mmol) in acetonitrile (10 mL) with K2CO3 (91 mg, 0.6 mmol) and 3,6,9,12,15-pentaoxaheptadecane- 1,17-diyl dimethanesulfonate (100 mg, 0.228 mmol) was heated at 80°C for 16 h. After the work up, the crude was purified by preparative HPLC to give 30 mg, (12 % yield) of the title compound as a white solid. 1H NMR (400 MHz, CD3OD): į = 7.69 (dd, J = 9.1, 2.9 Hz, 2H), 7.52 (dd, J = 8.6, 3.5 Hz, 4H), 7.45– 7.30 (m, 6H), 6.92 (dd, J = 14.3, 2.8 Hz, 2H), 4.60– 4.55 (m, 2H), 4.15 - 4.11 (m, 4H), 3.87– 3.74 (m, 4H), 3.65 - 3.60 (m, , 10H), 3.38– 3.17 (m, 6H), 2.62 (s, 6H), 1.65 (s, 8H), 1.18 (t, J = 7.3 Hz, 6H). MS (ES+): m/z = 534.20, 536.60 [M/2]+; LCMS: tR = 2.16 min.
[00346] 2,2'-((4S,4'S)-8,8'-(3,6,9,12,15,18,21-Heptaoxatricosane-1,23- diylbis(oxy))bis(6-(4-chlorophenyl)-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3- a][1,4]diazepine-8,4-diyl))bis(N-ethylacetamide) [Example 8]:
Figure imgf000224_0001
[00347] A suspension of 2-((4S)-6-(4-chlorophenyl)-8-hydroxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (100 mg, 0.244 mmol) in acetonitrile (10 mL) with K2CO3 (82 mg, 0.6mmol) and 3,6,9,12,15,18,21-heptaoxatricosane- 1,23-diyl dimethanesulfonate (2h) (64 mg, 0.122 mmol) was heated at 80°C for 16 h. After the work up, the crude was purified by preparative HPLC to give in 20 mg, (14 % yield) of the title compound as a white solid. 1H NMR (400 MHz, CD3OD): į = 8.32 (t, J = 5.8 Hz, 2H), 7.70 (d, J = 8.9 Hz, 2H), 7.53 (d, J = 8.0 Hz, 4H), 7.39 (dd, J = 9.4, 7.1 Hz, 6H), 6.97– 6.89 (m, 2H), 4.70 - 4.62 (m, 2H), 4.12– 4.07 (m, 4H), 3.79 (d, J = 4.7 Hz, 4H), 3.67– 3.55 (m, 22H), 3.44– 3.18 (m, 8H), 2.63 (s, 6H), 1.18 (t, J = 7.3 Hz, 6H); MS (ES+): m/z = 577.65, 579.50 [M/2]+; LCMS: tR = 2.31 min.
[00348] 2,2'-((4S,4'S)-8,8'-(Pentane-1,5-diylbis(oxy))bis(6-(4-chlorophenyl)-1- methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine-8,4-diyl))bis(N-ethylacetamide) Exam le 9 :
Figure imgf000225_0001
[00349] A suspension of 2-((4S)-6-(4-chlorophenyl)-8-hydroxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (200 mg, 0.488 mmol) in acetonitrile (10 mL) with K2CO3 (165 mg, 1.2 mmol) and pentane-1,5-diyl dimethanesulfonate (2i) (63 mg, 0.2 mmol) was heated at 80°C for 16 h. After the work up and purification by preparative HPLC, resulted in 50 mg (28% yield) of the title compound as a white solid. 1H NMR (400 MHz, CD3OD): į 7.74 (d, J = 9.2 Hz, 2H), 7.55 (d, J = 8.4 Hz, 4H), 7.41–7.36 (m, 6H), 6.90– 6.89 (m, 2H), 4.67– 4.62 (m, 2H), 4.04– 4.00 (m, 4H), 3.42– 3.20 (m, 8H), 2.71 (s, 6H), 1.84– 1.80 (m, 4H), 1.64– 1.59 (m, 4H), 1.18 (t, J = 7.3 Hz, 6H); MS (ES+): m/z = 445.20, 447.45 [M/2]+; LCMS: tR = 2.74 min.
[00350] 2,2'-(4S,4'S)-8,8'-(heptane-1,7-diylbis(oxy))bis(6-(4-chlorophenyl)-1-methyl- 4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine-8,4-diyl))bis(N-ethylacetamide) [Example 10]:
Figure imgf000225_0002
[00351] A suspension of 2-((4S)-6-(4-chlorophenyl)-8-hydroxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (282.8 mg, 0.69 mmol) in acetonitrile (10 mL) was charged with K2CO3 (140 mg, 1.04 mmol) followed by heptane-1,7- diyl dimethanesulfonate (100 mg, 0.34 mmol) and heated at 80°C for 12 h. After the completion of reaction, the solvents were concentrated in vacuo and the residue was partitioned between DCM (20 mL) and H2O (10 mL) and separated. The aqueous layer was re-extracted with DCM (3 X 15 mL) and the combined organic fractions were dried over anhydrous Na2SO4, filtered and concentrated in vacuo resulting in a crude product which was purified by preparative HPLC to afford 53 mg (17 % yield ) of the title compound as a light brown solid. 1H NMR (400 MHz, DMSO-d6): į = 8.21 (t, J = 5.5 Hz, 2H), 7.76 (d, J = 8.9 Hz, 2H), 7.54– 7.43 (m, 6H), 7.35 (dd, J = 9.0, 2.9 Hz, 2H), 6.82 (dd, J = 7.8, 2.9 Hz, 2H), 4.47 (dd, J = 8.3, 5.7 Hz, 2H), 4.10– 3.89 (m, 4H), 3.43– 3.33 (m, 4H), 3.29– 3.02 (m, 8H), 2.48– 2.41 (m, 4H), 1.66 (q, J = 6.6 Hz, 4H), 1.36 (dd, J = 13.5, 7.0 Hz, 4H), 1.23 (s, 2H), 1.06 (t, J = 7.2 Hz, 6H); MS (ES+): m/z = 915.35, 917.30 [M+H] +; LCMS: tR = 3.05 min.
[00352] 2,2'-(4S,4'S)-8,8'-(decane-1,10-diylbis(oxy)bis(6-(4-chlorophenyl)-1-methyl- 4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine-8,4-diyl))bis(N-ethylacetamide) [Example 11]:
Figure imgf000226_0001
[00353] A suspension of 2-(4S)-6-(4-chlorophenyl)-8-hydroxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (208 mg, 0.507 mmol) in acetonitrile (10 mL) was charged with K2CO3 (82 mg, 0.6 mmol) and 1,10-diiododecane (100 mg, 0.254 mmol) and the resulting mixture was heated at 80 oC for 12 h. After the completion of reaction, the reaction mixture was concentrated in vacuo and the residue was partitioned between DCM (20 mL) and H2O (10 mL) and separated. The aqueous layer was re-extracted with DCM (3 X 15 mL) and the combined organic fractions were dried over anhydrous Na2SO4, filtered and concentrated in vacuo resulting in a crude product which was purified by preparative HPLC to afford 30 mg, (12 % yield ) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6): į = 8.26– 8.15 (m, 2H), 7.78 (t, J = 8.8 Hz, 2H), 7.50– 7.31 (m, 10H), 6.89– 6.80 (m, 2H), 4.47– 4.40 (m, 2H) , 4.06 - 3.85 (m, 4H), 3.36– 3.05 (m, 8H), 2.52 (s, 6H), 1.80– 1.60 (m, 4H), 1.40– 1.21 (m, 12H), 1.06 (t, J = 7.2 Hz, 6H); MS (ES+): m/z = 958.65, 960.70 [M+H] +; LCMS: tR = 3.3 min. [00354] 2,2'-(4S,4'S)-8,8'-(dodecane-1,12-diylbis(oxy))bis(6-(4-chlorophenyl)-1- methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine-8,4-diyl)bis(N-ethylacetamide)
Figure imgf000227_0001
[00355] A suspension of 2-((4S)-6-(4-chlorophenyl)-8-hydroxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (98.5 mg, 0.47 mmol) in acetonitrile (10 mL) was charged with K2CO3 (95.2mg, 0.63 mmol) and 1,12-diiodododecane (100 mg, 0.23 mmol) and the resulting mixture was heated at 80 oC for 12 h. After the completion of reaction, the reaction mixture was concentrated in vacuo and the residue was partitioned between DCM (20 mL) and H2O (10 mL) and separated. The aqueous layer was re- extracted with DCM (3 X 15 mL) and the combined organic fractions were dried over anhydrous Na2SO4, filtered and concentrated in vacuo resulting in a crude product which was purified by preparative HPLC to afford 40 mg, (17 % yield) of the title compound as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6): į = 8.24– 8.16 (m, 2H), 7.70 (d, J = 8.7 Hz, 2H), 7.54– 7.42 (m, 8H), 7.38 (dd, J = 9.0, 3.0 Hz, 2H), 6.82 (s, 2H), 4.50 - 4.40 (m, 2H), 4.17 – 3.85 (m, 4H), 3.29– 3.03 (m, 8H), 2.55 (s, 6H), 1.70 -1.60 (m, 4H) 1.40-1.25 (m, 16H), 1.06 (t, J = 7.2, 6H); MS (ES+): m/z = 988.85, 990.00 [M+H]+; LCMS: tR = 3.76 min.
[00356] Heptane-1, 7-diyl dimethanesulfonate
[00357] General procedure for mesylation
[00358] A solution of diol (1 eq) in anhydrous DCM (10 mL) was charged with triethylamine (2 eq.) and stirred at 0°C for 10 min. Methane sulfonyl chloride (1.3 eq.) was added to the reaction mixture and the resulting solution was stirred at room temperature for 4 h. The reaction mixture was concentrated in vacuo resulting in a residue that was partitioned between DCM and H2O and separated. The aqueous layer was re-extracted with DCM and the combined organic fractions were dried over anhydrous Na2SO4, filtered and concentrated in vacuo resulting in crude product. The crude material was purified by column chromatography on silica gel. [00359] The following bis mesylates were synthesized using the general procedure highlighted above.
[00360] Butane-1,4-diyl dimethanesulfonate (2a):
Figure imgf000228_0001
[00361] A solution of butane-1,4-diol (500 mg, 5.5 mmol) in anhydrous DCM (15 mL) was charged with triethylamine (2.31 ml, 16.6 mmol) and stirred at 0°C for 10 min. Methane sulfonyl chloride (1.07 ml, 13.0 mmol) was added to the reaction mixture and stirred at room temperature for 4 h. After concentration in vacuo, the residue was partitioned between DCM (20 mL) and H2O (10 mL) and separated. The aqueous layer was re-extracted with DCM (3 x 15 mL) and the combined organic fractions were dried over anhydrous Na2SO4, filtered and concentrated in vacuo resulting in crude product. The crude material was purified by column chromatography on silica gel (100-200 mesh), eluting with 5% methanol in chloroform to afford 1 g (73.52% yield) of the title compound as an oil. 1H NMR (400 MHz, CDCl3): į = 4.32– 4.25 (m, 4H), 3.03 (s, 6H), 1.97– 1.86 (m, 4H).
[00362] 2-Oxybis(ethane-2,1-diyl) dimethanesulfonate (2b):
Figure imgf000228_0002
[00363] A solution of 2,2’-oxybis(ethan-1-ol) (500 mg, 4.0mmol) in anhydrous DCM (15 mL) was charged with triethylamine (2.31 mL, 16.6 mmol) at 0°C for 10 min. To this solution, methane sulfonyl chloride (1.07 ml, 13.0 mmol) was added and stirred at room temperature for 4 h. After the work up and purification by column chromatography on silica gel (100-200 mesh), eluting with 5% methanol in chloroform resulted in 1.01 g (82.11% yield) of the title compound was obtained as an oil. 1H NMR (400 MHz, CDCl3): į = 4.41– 4.34 (m, 4H), 3.83– 3.76 (m, 4H), 3.06 (s, 6H).
[00364] 2-Hexane-1,6-diyl dimethanesulfonate (2c):
[00365] A solution of hexane-1,6-diol (500 mg, 4.2 mmol) in anhydrous DCM (15 mL) was charged with triethylamine (1.76 ml, 12.0 mmol) at 0°C for 10 min. To this solution, methane sulfonyl chloride (0.81 ml, 10.0 mmol) was added and stirred at room temperature for 4 h. After work up and purification by column chromatography on silica gel (100-200 mesh), eluting with 5% methanol in chloroform resulted in 1.12 g (96.5% yield) of the title compound as an oil. 1H NMR (400 MHz, CDCl3): į = 4.23 (t, J = 6.4 Hz, 4H), 3.00 (s, 6H), 1.83– 1.71 (t, J = 6.4 Hz, 4H), 1.50– 1.41 (m, 4H).
[00366] (Ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl) dimethanesulfonate (2d):
Figure imgf000229_0001
[00367] A solution of triethylene glycol (500 mg, 3.3 mmol) in anhydrous DCM (15 mL) was charged with triethylamine (1.4 mL, 9.9 mmol) and stirred at 0°C for 10 min. To this solution, methane sulfonyl chloride (0.84 ml, 8.2 mmol) was added and stirred at room temperature for 4 h. After the work up and purification by column chromatography on silica gel (100-200 mesh), eluting with 5% methanol in chloroform, resulted in 980 mg (96.07% yield) of the title compound as an oil. 1H NMR (400 MHz, CDCl3): į = 4.40– 4.33 (m, 4H), 3.76 (dd, J = 5.4, 3.6 Hz, 4H), 3.67 (s, 4H), 3.06 (s, 6H).
[00368] ((Oxybis(ethane-2,1-diyl))bis(oxy))bis(ethane-2,1-diyl) dimethanesulfonate (2e):
Figure imgf000229_0002
[00369] A solution of tetraethylene glycol (500 mg, 2.5mmol) in anhydrous DCM (15 mL) was charged with triethylamine (1.07 ml, 7.7 mmol) and stirred at 0°C for 10 min.
Methane sulfonyl chloride (0.71 ml, 6.2 mmol) was added to the reaction mixture and stirred at room temperature for 4 h. After work up and purification by column chromatography on silica gel on silica gel (100-200 mesh), eluting with 5% methanol in chloroform resulted in 860 mg (95.34% yield) of the title compound as an oil. 1H NMR (400 MHz, CDCl3): į = 4.41– 4.33 (m, 4H), 3.80– 3.72 (m, 4H), 3.70– 3.60 (m, 8H), 3.07 (s, 6H).
[00370] 3,6,9,12-Tetraoxatetradecane-1,14-diyl dimethanesulfonate (2f):
Figure imgf000229_0003
[00371] A solution of pentaethylene glycol (50 mg, 0.2mmol) in anhydrous DCM (15 mL) was charged with triethylamine (0.08 ml, 0.6 mmol) and stirred at 0°C for 10 min.
Methane sulfonyl chloride (0.04 ml, 0.5mmol) was added to the reaction mixture and stirred at room temperature for 4 h. After the work up, 130 mg of crude title compound was obtained as an oil. The crude was used in the next step without further purification. 1H NMR (400 MHz, CDCl3): į = 4.38 (t, J = 3.8 Hz, 4H), 3.76 (t, J = 3.9 Hz, 4H), 3.70– 3.60 (m, 12H), 3.08 (s, 6H).
dimethanesulfonate (2g):
Figure imgf000230_0001
[00373] A solution of 3,6,9,12,15-pentaoxaheptadecane-1,17-diol (500 mg, 1.7 mmol) in anhydrous DCM (15 mL) was charged with triethylamine (0.74 ml, 5.3 mmol) and stirred at 0°C for 10 min. Methane sulfonyl chloride (0.33 ml, 4.2 mmol) was added to the reaction mixture and stirred at room temperature for 4 h. After the work up resulted in 1 g of crude title compound as an oil. The crude material was taken on to the next step without further purification. 1H NMR (400 MHz, CDCl3): į = 4.38 (t, J = 3.8, 1.3 Hz, 4H), 3.76 (t, J = 3.9, Hz, 4H), 3.70– 3.60 (m, 16H), 3.08 (q, J = 1.1 Hz, 6H).
[00374] 3,6,9,12,15,18,21-Heptaoxatricosane-1,23-diyl dimethanesulfonate (2h):
Figure imgf000230_0002
[00375] A solution of 3,6,9,12,15,18,21-heptaoxatricosane-1,23-diol (500 mg, 1.3 mmol) in anhydrous DCM (15 mL) was charged with triethylamine (0.56 ml, 4.0 mmol) and stirred at 0°C for 10 min. Methane sulfonyl chloride (0.25 ml, 3.2 mmol) was added to the reaction mixture and stirred at room temperature for 4 h. The reaction was worked up and resulted in 700 mg of crude (2h) as an oil. The crude material was used in the next step without further purification. 1H NMR (400 MHz, CDCl3): į = 4.44– 4.28 (m, 4H), 3.81– 3.71 (m, 4H), 3.64– 3.51 (m, 24 H), 3.16– 3.03 (m, 6H).
[00376] Pentane-1,5-diyl dimethanesulfonate (2i):
Figure imgf000230_0003
[00377] A solution of pentanediol (500 mg, 4.8 mmol) in anhydrous DCM (15 mL) was charged with triethylamine (2 ml, 1.4 mmol) and stirred at 0°C for 10 min. Methane sulfonyl chloride (1.2 ml, 1.2 mmol) was added to the reaction mixture and stirred at room temperature for 4 h. The reaction mixture was worked up, and resulted in 600 mg of crude 2i as an oil. 1H NMR (400 MHz, CDCl3): į = 4.24 (t, J = 6.4 Hz, 4H), 3.01 (s, 6H), 1.85– 1.78 (m, 4H), 1.60– 1.53 (m, 2H). [00378] Heptane-1, 7-diyl dimethanesulfonate (2j):
Figure imgf000231_0001
[00379] A solution of heptane-1,7-diol (500 mg, 3.7 mmol) in anhydrous DCM (15 mL) was charged with triethylamine (1.54 ml, 11.1 mmol) stirred at 0°C for 10 min. This solution was charged wtih methane sulfonyl chloride (1.26 g, 11.1 mmol) and stirred at room temperature for 4 h. The reaction mixture was concentrated in vacuo. The residue was partitioned between H2O (30 mL) and ethyl acetate (3 X 50 mL) and separated. The aqueous layer was re-extracted with ethyl acetate (2 X 20 ml) and combined organic fraction were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo resulting in crude product. The crude was purified by column chromatography on silica gel (100-200 mesh), eluting with 5% methanol in chloroform to afford 927 mg, (85 % yield) of the title compound as an oil. 1H NMR (400 MHz, DMSO-d6): į = 4.18 (t, J = 6.4 Hz, 4H), 3.15 (d, J = 0.7 Hz, 6H), 1.65 (m, 4H), 1.40– 1.28 (m, 6H).
[00380] Decane-1,10-diyl dimethanesulfonate:
Figure imgf000231_0002
[00381] A solution of Decane-1,10-diol (500 mg, 2.8 mmol) in anhydrous DCM (15 mL) was charged with triethylamine (870 mg, 8.6 mmol) stirred at 0°C for 10 min. The reaction was charged with Methane sulfonyl chloride (980.4 mg, 8.6 mmol) and stirred at room temperature for 4 h. The reaction mixture was concentrated in vacuo and residue was partitioned between H2O (30 mL) and ethyl acetate (3 X 50 mL) and separated. The aqueous layer was re-extracted with ethyl acetate (2 X 20 mL) and combined organic fraction were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo resulting in crude product. The crude was purified by column chromatography on silica gel (100-200 mesh), eluting with 5 % methanol in chloroform to afford 663 mg, (70 % yield) of the title compound as an oil. 1H NMR (400 MHz, CDCl3): į = 4.21 (t, J = 6.6 Hz, 4H), 3.00 (s, 6H), 1.67 (t, J = 7.2 Hz, 4H), 1.53– 1.26 (m, 12H).
[00382] 1, 10-Diiododecane (2k): [00383] A solution of decane-1,10-diyl dimethanesulfonate (500 mg, 1.5 mmol) in anhydrous acetone (15 mL) was charged with sodium iodide (2.24 g, 15 mmol) and refluxed for 12 h. The reaction mixture was cooled to room temperature and concentrated in vacuo and the residue was partitioned between H2O (30 mL) and ethyl acetate (3 X 50 mL) and separated. The aqueous layer was re-extracted with ethyl acetate (2 X 20 mL) and combined organic fraction were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo resulting in crude product. The crude was purified by column chromatography on silica gel (100-200 mesh), eluting with 5-10 % methanol in chloroform to afford 369 mg, (62 % yield) of the title compound as a brown solid. 1H NMR (400 MHz, DMSO-d6): į = 3.28 (dd, J = 13.3, 6.4 Hz, 4H), 1.74 (m, 4H), 1.40– 1.23 (m, 12H).
[00384] Dodecane-1,12-diyl bis(4-methylbenzenesulfonate):
Figure imgf000232_0001
[00385] A solution of Dodecane-1,12-diol (500 mg, 2.4 mmol) in anhydrous DCM (15 mL) charged with triethylamine (749 mg, 7.4 mmol) and stirred at 0°C for 10 min. The reaction was charged with p-toluene sulfonyl chloride (843.6 mg, 7.4 mmol) and stirred at room temperature for 6 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between H2O (30 ml) and ethyl acetate (3 X 50 ml) and separated. The aqueous was re-extracted with ethyl acetate (2 X 20 ml) and combined organic fractions were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo resulting in crude product. The crude was purified by column chromatography on silica gel (100-200 mesh), eluting with 5% methanol in chloroform to afford 872.2 mg (84% yield) of the title compound as an oil. 1H NMR (400 MHz, DMSO-d6): į = 7.82– 7.74 (m, 4H), 7.52– 7.44 (m, 4H), 4.00 (t, J = 6.3 Hz, 4H), 2.42 (s, 6H), 1.59– 1.47 (m, 4H), 1.26– 1.11 (m, 16H).
[00386] 1,12-Diiodododecane (2l): [00387] A solution of dodecane-1,12-diyl dimethanesulfonate (500 mg, 1.3 mmol) in anhydrous acetone (15 mL) was charged with sodium iodide (1.94 g, 13 mmol) and refluxed for 12 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between H2O (20 mL) and ethyl acetate (3 X 50 mL) and separated. The aqueous layer was re- extracted with ethyl acetate (2 X 20 ml) and combined organic fraction were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo resulting in crude product. The crude was purified by column chromatography on silica gel (100-200 mesh), eluting with 5% methanol in chloroform to afford 412 mg (70 % yield) of the title compound as brown solid. 1H NMR (400 MHz, DMSO-d6): į = 3.28 (t, J = 6.8 Hz, 4H), 1.74 (m, 4H), 1.38– 1.20 (m, 16H). EXAMPLES 13-19:
[00388] Compounds were synthesized according to the following procedures.
Scheme 2. Synthesis of bivalent compounds
Figure imgf000233_0001
[00389] General procedure for Buchwald reaction:
[00390] A suspension of (S)-2-(6-(4-bromophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (4) (1.0 eq), dithiol (5a-e) (0.5 eq), tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (20% w/w), 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (20% w/w) and DIPEA (3.0 eq) in 1,4-dioxane (20 mL/g) in sealed tube was heated to 140°C for 30 min [Biotage microwave reactor, 400W]. The reaction mixture was partitioned between DCM and H2O and separated. The aqueous layer was re-extracted with DCM (3 x 10 mL) and the combined organic fractions were dried over anhydrous Na2SO4, filtered and concentrated in vacuo resulting in a crude product which was purified by column chromatography and then by preparative HPLC.
[00391] Examples 13, 14, 15, 16, 17, 18 and 19 were synthesized using the following procedures.
[00392] 2,2'-((4S,4'S)-6,6'-((heptane-1,7-diylbis(sulfanediyl))bis(4,1- phenylene))bis(8-methoxy-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine-6,4- diyl))bis(N-ethylacetamide) [Example 13]:
Figure imgf000233_0002
[00393] A suspension of (S)-2-(6-(4-bromophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (100 mg, 0.213 mmol), heptane-1,7-dithiol (17.4 mg, 0.106 mmol),
tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (20 mg, 0.021 mmol, 18.86 mol %), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (20 mg, 0.034 mmol, 32.64 mol %) and DIPEA (82 mg, 0.634 mmol) in 1,4-dioxane (2 mL) in a sealed tube was heated to 140°C for 30 min [Biotage microwave reactor, 400W]. After work up and preparative HPLC purification resulted in 28 mg (28. % yield) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6): į = 8.21 (t, J = 5.5 Hz, 2H), 7.77 (dd, J = 9.0, 2.0 Hz, 2H), 7.46– 7.33 (m, 4H), 7.28 (d, J = 8.5 Hz, 2H), 6.87 (d, J = 2.9 Hz, 2H), 4.45 (dd, J = 8.2, 5.7 Hz, 2H), 3.78 (s, 6H), 3.43– 3.33 (m, 4H), 3.27– 2.94 (m, 12H), 2.52 (s, 6H), 1.56 (p, J = 7.5 Hz, 4H), 1.42– 1.21 (m, 6H), 1.05 (t, J = 7.2 Hz, 6H); MS (ES+): m/z = 939.55 [M+H]+; LCMS: tR = 3.13 min.
[00394] 2,2'-((4S,4'S)-6,6'-((butane-1,4-diylbis(sulfanediyl))bis(4,1-phenylene))bis(8- methoxy-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine-6,4-diyl))bis(N-
Figure imgf000234_0001
[00395] A suspension of (S)-2-(6-(4-bromophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (500 mg, 1.06 mmol), butane-1,4-dithiol (65 mg, 0.533 mmol), tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (100 mg, 0.109 mmol,10.32 mol %), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (100 mg, 0.17 mmol, 16.32 mol %) and DIPEA (411 mg, 3.18 mmol) in 1,4-dioxane (5 mL) was placed in a sealed tube and heated to 140°C for 30 min [Biotage microwave reactor, 400W]. The reaction was worked up and purified by preparative HPLC resulting in 120 mg (25.0 % yield) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6): į = 8.20 (t, J = 5.5 Hz, 2H), 7.78 (d, J = 8.9 Hz, 2H), 7.46– 7.26 (m, 8H), 6.87 (d, J = 2.8 Hz, 2H), 4.46 (dd, J = 8.3, 5.8 Hz, 2H), 3.78 (s, 6H), 3.27– 2.99 (m, 12H), 2.53 (s, 6H), 1.77– 1.66 (m, 4H), 1.13-1.01 (m, 6H); MS (ES+): m/z = 897.60 [M+H]+; LCMS: tR = 2.56 min. [00396] 2,2'-((4S,4'S)-6,6'-((hexane-1,6-diylbis(sulfanediyl))bis(4,1-phenylene))bis(8- methoxy-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine-6,4-diyl))bis(N-
Figure imgf000235_0001
[00397] A suspension of (S)-2-(6-(4-bromophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (500 mg, 1.06 mmol), hexane-1,6-dithiol (80 mg, 0.533 mmol), tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (100 mg, 0.109 mmol,10.32 mol %), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (100 mg, 0.17 mmol, 16.32 mol %) and DIPEA (411 mg, 3.18 mmol) in 1,4-dioxane (5 mL) was placed in a sealed to and heated to 140°C for 30 min [Biotage microwave reactor, 400W]. The reaction mixture was worked up and purified by preparative HPLC resulting in 125 mg (25.4 % yield) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6): į = 8.21 (q, J = 3.8, 2.7 Hz, 2H), 7.78 (d, J = 8.9 Hz, 2H), 7.50– 7.31 (m, 6H), 7.31– 7.25 (m, 4H), 6.87 (d, J = 2.9 Hz, 2H), 4.49– 4.41 (m, 2H), 3.79 (s, 6H), 3.27– 2.94 (m, 14H), 2.52 (s, 6H), 1.56 -1.43 (m, 4H), 1.43– 1.34 (m, 4H), 1.18– 1.01 (m, 8H); MS (ES+): m/z = 925.10 [M+H]+; LCMS: tR = 2.92 min.
[00398] (S)-N,N'-(ethane-1,2-diyl)bis(2-((4-((S)-4-(2-(ethylamino)-2-oxoethyl)-8- methoxy-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-
Figure imgf000235_0002
[00399] A suspension of (S)-2-(6-(4-bromophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (100 mg, 0.213 mmol), N,N'-(ethane-1,2-diyl)bis(2-mercaptoacetamide) (72 mg, 0.0.106 mmol),
tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (20 mg, 0.021 mmol, 18.86 mol %), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (20 mg, 0.034 mmol, 32.64 mol %) and DIPEA (82.5 mg, 0.639 mmol) in 1,4-dioxane (2 mL) in a sealed tube was heated to 140°C for 30 min [Biotage microwave reactor, 400W]. The reaction mixture was worked up and purified by preparative HPLC resulting in 18 mg (17.2 % yield) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6): į = 8.24 (m, 2H), 7.77 (d, J = 9.0 Hz, 2H), 7.46– 7.26 (m, 10H), 6.84 (d, J = 2.9 Hz, 2H), 4.45 (dd, J = 8.3, 5.7 Hz, 2H), 3.77 (s, 6H), 3.25– 3.02 (m, 14H), 2.54 (s, 6H), 1.05 (t, J = 7.2 Hz, 6H); MS (ES+): m/z = 983.50 [M+H]+; LCMS: tR = 1.51 min.
[00400] 2,2'-((4S,4'S)-6,6'-(((oxybis(propane-3,1-diyl))bis(sulfanediyl))bis(4,1- phenylene))bis(8-methoxy-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine-6,4- diyl))bis(N-ethylacetamide) [Example 17]:
Figure imgf000236_0001
[00401] A suspension of (S)-2-(6-(4-bromophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (50 mg, 0.106 mmol), 3,3'- oxybis(propane-1-thiol) (9 mg, 0.0533mmol),
tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (10 mg, 0.010 mmol,10 mol %), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (10 mg, 0.017 mmol, 13.32 mol % ) and DIPEA (41 mg, 0.318 mmol) in 1,4-dioxane (1 mL) in a sealed tube was heated to 140°C for 30 min [Biotage microwave reactor, 400W]. The reaction mixture was worked up and purified by preparative HPLC purification resulting in 20 mg (39 % yield) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6): į = 8.21 (t, J = 5.1 Hz, 2H), 7.77 (dd, J = 9.2, 1.9 Hz, 2H), 7.37-7.01 (m, 8H), 6.85 (q, J = 3.5, 3.1 Hz, 2H), 4.45– 4.37 (m, 2H), 3.79 (s, 6H), 3.77 (dd, J = 3.7, 2.2 Hz, 6H), 3.13– 3.01 (m, J = 28.3, 14.3, 7.7 Hz, 10H), 2.52 (s, 6H), 1.18-1.23- (m, 4H), 1.18– 1.00 (m, 6H); MS (ES+): m/z = 941.90 [M+H]+; LCMS: tR = 2.28 min.
[00402] 2,2'-((4S,4'S)-6,6'-(((oxybis(ethane-2,1-diyl))bis(sulfanediyl))bis(4,1- phenylene))bis(8-methoxy-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine-6,4- diyl))bis(N-ethylacetamide) [Example 18]:
Figure imgf000237_0001
[00403] A suspension of (S)-2-(6-(4-bromophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (100 mg, 0.213 mmol), 2,2'- oxydiethanethiol (14.6 mg, 0.106 mmol), tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (20 mg, 0.021 mmol, 0.18 eq.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (20 mg, 0.034 mmol, 0.33 eq.) and DIPEA (82.5 mg, 0.639 mmol) in 1,4-dioxane (2 mL) in a sealed tube was heated to 140°C for 30 min [Biotage microwave reactor, 400W]. The reaction mixture was worked up and purified by preparative HPLC resulting in 15 mg (15.2 % yield) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6): į = 8.25– 8.17 (m, 2H), 7.78 (d, J = 9.0 Hz, 2H), 7.46– 7.29 (m, 10H), 6.86 (d, J = 2.9 Hz, 2H), 4.45 (dd, J = 8.1, 5.6 Hz, 2H), 3.78 (s, 6H), 3.61 (t, J = 6.1 Hz, 4H), 3.14– 3.03 (m, 12H), 2.52 (s, 6H), 1.05 (t, J = 7.2 Hz, 6H); MS (ES+): m/z = 913.48 [M+H]+; LCMS: tR = 2.20 min.
[00404] 2,2'-((4S,4'S)-6,6'-((((ethane-1,2-diylbis(oxy))bis(ethane-2,1- diyl))bis(sulfanediyl))bis(4,1-phenylene))bis(8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine-6,4-diyl))bis(N-ethylacetamide) [Example 19]:
Figure imgf000237_0002
[00405] A suspension of (S)-2-(6-(4-bromophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (100 mg, 0.213 mmol), 2,2'- (ethane-1,2-diylbis(oxy))diethanethiol (19 mg, 0.106 mmol),
tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (20 mg, 0.021 mmol, 18.86 mol %), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (20 mg, 0.034 mmol, 32.64 mol %) and DIPEA (82.5 mg, 0.639 mmol) in 1,4-dioxane (2 mL) in a sealed tube was heated to 140°C for 30 min [Biotage microwave reactor, 400W]. The reaction mixture was worked up and purified by preparative HPLC resulting 20 mg (19 % yield) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6): į = 8.24– 8.13 (m, 2H), 7.77 (dd, J = 9.1, 3.3 Hz, 2H), 7.49– 7.28 (m, 12H), 6.86 (d, J = 3.0 Hz, 2H), 6.53 (s, 2H), 4.49– 4.41 (m, 2H), 3.78 (s, 6H), 3.59 (t, J = 6.5 Hz, 4H), 3.50 (s, 4H), 3.33– 3.02 (m, 8 H), 2.56 (s, 6H), 1.05 (t, J = 7.3 Hz, 6H); MS (ES+): m/z = 957.61 [M+H]+; LCMS: tR = 2.19 min. EXAMPLES 20-28:
[00406] Compounds were synthesized according to the following procedures.
Figure imgf000238_0001
[00407] Examples 20, 21, 22, 23, 24, 25, 26, 27 and 28 were synthesized using the following procedures.
[00408] N1, N8-bis (2-(5-(3, 5-dimethylisoxazol-4-yl)-2methylphenylsulfonamido) ethyl) octanediamide [Example 20]:
[00409]
Figure imgf000238_0002
[00410] N-(2-aminoethyl)-5-(3,5-dimethylisoxazol-4-yl)-2-methylbenzenesulfonamide (100 mg, 0.32 mmol) in DCM (20 mL) was charged with EDCI (122 mg, 0.64mmol) and stirred at room temperature for 10 minutes. Octanedioic acid (28 mg, 0.16 mmol), and DMAP (78 mg, 0.51 mmol) were added to the reaction mixture. The resulting solution was stirred at room temperature for 5 h. The reaction mixture was partitioned between DCM (10 mL) and H2O (15 mL) and separated. The aqueous layer was re-extracted with DCM (3 X 10 mL) and the combined organic fractions were washed with 2N acetic acid solution (2 X 5 mL), H2O (2 X 10 mL), and dried over anhydrous Na2SO4, filtered and concentrated in vacuo resulting in a crude product which was purified by preparative HPLC to afford 10 mg (8 % yield) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6): į = 7.86– 7.63 (m, 6H), 7.58– 7.40 (m, 4H), 3.10 - 3.02 (m, 4H), 2.86 - 2.80 (m, 4H), 2.58 (s, 6H), 2.40 (S, 6H), 2.22 (S, 6H), 1.94 (t, J = 7.3 Hz, 4H), 1.39 (d, J = 9.6 Hz, 4H), 1.14 (s, 4H); MS (ES+): m/z = 757.05
[M+H]+; LCMS: tR = 2.43 min.
[00411] tert-butyl(2-(5-(3,5-dimethylisoxazol-4-yl)-2methylphenylsulfonamido)ethyl)
Figure imgf000239_0001
[00412] A solution of 5-(3, 5-dimethylisoxazol-4-yl)-2-methylbenzene-1-sulfonyl chloride (300 mg, 1.05 mmol) in pyridine (15 mL) was charged with tert-butyl (2- aminoethyl)carbamate (201 mg, 1.26 mmol) and stirred at room temperature for 3 h. Crude product obtained after the work up was purified by column chromatography eluting with 5-10% methanol in DCM to afford 300 mg (69. % yield ) of the title compound as a colorless oil. MS (ES+): m/z = 432.45 [M+Na] +; LCMS: tR = 2.61 min.
[00413] N-(2-Aminoethyl)-5-(3, 5-dimethylisoxazol-4-yl)-2- e (5b):
Figure imgf000239_0002
[00414] A solution of tert-butyl (2-(5-(3, 5-dimethylisoxazol-4-yl)-2- methylphenylsulfonamido) ethyl) carbamate (250 mg, 0.61 mmol) in DCM (20 mL) and TFA (1.83 mL), was stirred at room temperature for 6 h. The reaction mixture was concentrated to dryness and dissolved in DCM (5 mL) and charged with powdered KOH (210 mg) to adjust pH ~8-9. The solution was filtered through pad of celite and the filtrate was concentrated in vacuo resulting in 150 mg (79.8% yield) of crude title compound as a yellow solid. The crude material was used in the next step without further purification. MS (ES+): m/z = 310.95 [M+H] +; LCMS: tR = 1.50 min.
[00415] 1,8-bis(4-((5-(3,5-dimethylisoxazol-4-yl)-2-methylphenyl)sulfonyl)piperazin-
Figure imgf000240_0001
[00416] A solution of 5-(3,5-dimethylisoxazol-4-yl)-2-methylbenzene-1-sulfonyl chloride (219 mg, 0.77 mmol) in DCM (10 ml) was charged with 1,8-di(piperazin-1-yl)octane- 1,8-dione (120 mg, 0.38mmol) and triethyl amine (311mg, 0.30 mmol) and stirred at room temperature for 2 h. The reaction mixture was worked up and purified by preparative HPLC resulting in 10 mg (3% yield) of (8b) BRD-B-85 as a yellow solid. H NMR (400 MHz, DMSO- d6): į = 7.65– 7.53 (m, 6H), 3.54– 3.48 (m, 8H), 3.14– 3.02 (m, 8H), 2.60 (s, 6H), 2.41 (s, 6H), 2.24 (s, 6H), 1.41– 1.35 (m, 8H), 1.31– 1.13 (m, 4H); MS (ES+): m/z = 809.05 [M+H]+; LCMS: tR = 2.91 min.
[00417] 1,2-bis(4-((5-(3,5-dimethylisoxazol-4-yl)-2-methylphenyl)sulfonyl)piperazin-
Figure imgf000240_0002
[00418] A solution of 5-(3,5-dimethylisoxazol-4-yl)-2-methylbenzene-1-sulfonyl chloride (287 mg, 1.0 mmol) in DCM (10 ml) was charged with 1,2-di(piperazin-1-yl)ethane (100 mg, 0.50 mmol) and triethyl amine (151 mg, 1.5 mmol) and stirred at room temperature for 4 h. The reaction was worked up and purified by preparative HPLC resulting in 40mg (11.3 % yield) of the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3): į = 7.78 (s, 2H), 7.46– 7.35 (m, 4H), 3.46– 3.40 (m, 4H), 3.20 - 3.00 (m, 16H), 2.61 (s, 6H), 2.41 (s, 6H), 2.27 (s, 6H); MS (ES+): m/z = 696.95 [M+H]+; LCMS: tR = 2.30 min.
[00419] N,N'-(heptane-1,7-diyl)bis(5-(3,5-dimethylisoxazol-4-yl)-2- methylbenzenesulfonamide) [Example 23]:
Figure imgf000241_0001
[00420] A solution of 5-(3, 5-dimethylisoxazol-4-yl)-2-methylbenzene-1-sulfonyl chloride (100 mg, 0.35 mmol) in pyridine (5 mL) was charged with heptane-1,7-diamine (22 mg, 0.17 mmol) and stirred at room temperature for 3 h. The reaction mixture was worked up and purified by preparative HPLC resulting in 30mg (28 % yield) of the title compound as a colorless semi solid. 1H NMR (400 MHz, CDCl3): į = 7.86 (d, J = 1.9 Hz, 2H), 7.44– 7.32 (m, 4H), 4.48 (s, 2H), 3.03– 2.93 (m, 4H), 2.68 (s, 6H), 2.42 (s, 6H), 2.28 (s, 6H), 1.55– 1.43 (m, 4H), 1.33– 1.17 (m, 6H); MS (ES+): m/z = 628.95 [M+H]+; LCMS: tR = 3.00 min.
[00421] N,N'-(nonane-1,9-diyl)bis(5-(3,5-dimethylisoxazol-4-yl)-2-
Figure imgf000241_0002
[00422] A solution of 5-(3,5-dimethylisoxazol-4-yl)-2-methylbenzene-1-sulfonyl chloride (100 mg, 0.35 mmol) in pyridine (5 ml) was charged with heptane-1,7-diamine (27 mg, 0.17 mmol) and stirred at room temperature for 6 h. The reaction mixture was worked up and purified by preparative HPLC resulting in 35mg ( 31% yield) of the title compound as an off white solid. 1H NMR (400 MHz, DMSO-d6): į = 7.76– 7.68 (m, 2H), 7.57– 7.45 (m, 4H), 2.81– 2.76 (m, 4H), 2.60 (s, 6H), 2.39 (s, 6H), 2.21 (s, 6H), 1.31-1.24 (m, 4H), 1.07– 1.03 (m, 10H); MS (ES+): m/z = 657.00 [M+H]+; LCMS: tR = 3.30 min.
[00423] N,N'-((ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))bis(5-(3,5- e) [Example 25]:
Figure imgf000241_0003
[00424] A solution of 5-(3,5-dimethylisoxazol-4-yl)-2-methylbenzene-1-sulfonyl chloride (200 mg, 0.67mmol) in pyridine (10 ml) was charged with 2,2'-(ethane-1,2- diylbis(oxy))diethanamine (51 mg, 0.33 mmol) and stirred at room temperature for 4 h. The reaction mixture was worked up and purified by preparative HPLC resulting in 65mg (30% yield) of the title compound as an off white solid. 1H NMR (400 MHz, DMSO-d6): į = 7.84 (t, J = 5.6 Hz, 2H), 7.72 (s, 2H), 7.56– 7.44 (m, 4H), 3.30– 3.20 (m, 8H), 2.96 (q, J = 11.8, 5.7 Hz, 4H), 2.59 (s, 6H), 2.39 (s, 6H), 2.21 (s, 6H); MS (ES+): m/z = 647.20 [M+H]+; LCMS: tR = 2.76 min.
[00425] N,N'-(oxybis(ethane-2,1-diyl))bis(oxy))bis(ethane-2,1-diyl))bis(5-(3,5- dimethylisoxazol-4-yl)-2-methylbenzenesulfonamide) [Example 26]:
[00426]
Figure imgf000242_0001
[00427] A solution of 5-(3,5-dimethylisoxazol-4-yl)-2-methylbenzene-1-sulfonyl chloride (200 mg, 0.69 mmol) in pyridine (10ml) was charged with 2,2'-((oxybis(ethane-2,1- diyl))bis(oxy))diethanamine (67 mg, 0.34 mmol) and stirred at room temperature for 4 h. The reaction mixture was worked up and purified by preparative HPLC resulting in 90 mg (38% yield) of the title compound as a light yellow oil. 1H NMR (400 MHz, DMSO-d6): į = 7.74– 7.70 (m, 2H), 7.50 (q, J = 15.4, 7.8 Hz, 4H), 3.37– 3.28 (m, 12H), 2.98 (t, J = 5.7 Hz, 4H), 2.59 (s, 6H), 2.38 (s, 6H), 2.20 (s, 6H); MS (ES+): m/z = 690.46[M+H]+; LCMS: tR = 2.77 min.
[00428] N,N'-(3,6,9,12-tetraoxatetradecane-1,14-diyl)bis(5-(3,5-dimethylisoxazol-4- l -2-meth lbenzenesulfonamide Exam le 27 :
Figure imgf000242_0002
[00429] A solution of 5-(3,5-dimethylisoxazol-4-yl)-2-methylbenzene-1-sulfonyl chloride (140 mg, 0.59 mmol) in pyridine (10 mL) was charged with 3,6,9,12- tetraoxatetradecane-1,14-diamine (338 mg, 0.11 mmol) and stirred at room temperature for 12 h. The reaction mixture was worked up and purified by preparative HPLC resulting in 21 mg (26.05 % yield) of the title compound as a light yellow oil. 1H NMR (400 MHz, CDCl3): į = 7.87 (d, J = 1.9 Hz, 2H), 7.42– 7.29 (m, 4H), 3.68– 3.49 (m, 16H), 3.15 (br.s., 4H), 2.68 (s, 6H), 2.41 (s, 6H), 2.28 (s, 6H); MS (ES+): m/z = 734.95 [M+H]+; LCMS: tR = 2.77 min.
[00430] 1,3-bis(4-((5-(3,5-dimethylisoxazol-4-yl)-2-methylphenyl)sulfonyl)piperazin- 1-yl)propane [Example 28]:
Figure imgf000242_0003
[00431] A solution of 5-(3,5-dimethylisoxazol-4-yl)-2-methylbenzene-1-sulfonyl chloride (285 mg, 0.35 mmol) in DCM (10 mL) was charged with 1,3-di(piperazin-1- yl)propane (37 mg, 0.175 mmol), triethyl amine (106 mg, 1.05 mmol ) and stirred at room temperature for 6 h. The reaction mixture was worked up and purified by preparative HPLC resulting in 40mg (32% yield) of the title compound as a light yellow oil. 1H NMR (400 MHz, CDCl3): į = 7.78 (d, J = 1.8 Hz, 2H), 7.46– 7.35 (m, 4H), 3.46 (d, J = 5.2 Hz, 8H), 3.20 (d, J = 5.2 Hz, 8H) 3.10 (t, J = 5.2 Hz ,2H ) 2.61 (s, 6H), 2.41 (s, 6H), 2.27 (s, 6H); MS (ES+): m/z = 710.95 [M+H]+; LCMS: tR = 1.94 min. EXAMPLE 29:
[00432] Example 29 was synthesized using the following procedure.
Figure imgf000243_0001
[00433] (S)-2-(6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-(2-(2-(2-(2-(5-(3,5-dimethylisoxazol-4- yl)-2-ethylphenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl) acetamide [Example 29]:
Figure imgf000244_0001
[00434] A suspension of (S)-2-(6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetic acid (8) (50 mg, 0.125 mmol) in DCM (1.5 mL) was charged with EDCI (35.8 mg, 0.187 mmol), 4-DMAP (22.8 mg, 0.187 mmol), and HOBt (25.2 mg, 0.187 mmol) and stirred at room temperature for 10 minutes. The reaction mixture was charged with N-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-5-(3,5- dimethylisoxazol-4-yl)-2-methylbenzenesulfonamide (7) (66 mg, 0.151 mmol) and stirred at room temperature for 15 h. The reaction mixture was partitioned between DCM (10 mL) and H2O (5 mL) and separated. The aqueous layer was re-extracted with DCM (3 x 10 mL) and the combined organic fractions were dried over anhydrous Na2SO4, filtered and concentrated in vacuo resulting in a crude product which was purified by column chromatography followed by an additional purification using preparative HPLC resulting in 25 mg (24.1 % yield) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) į = 8.29 (t, J = 5.6 Hz, 1H), 7.88 (s, 1H), 7.82– 7.71 (m, 2H), 7.57– 7.43 (m, 4H), 7.38 (dd, J = 9.0, 2.9 Hz, 1H), 6.86 (d, J = 3.0 Hz, 1H), 4.47 (dd, J = 8.5, 5.5 Hz, 1H), 3.78 (s, 3H), 3.57– 3.19 (m, 20H), 3.19– 3.10 (m, 1H), 3.00 (t, J = 5.6 Hz, 1H), 2.60 (s, 3H), 2.40 (s, 3H), 2.22 (s, 3H); MS (ES+): m/z = 820.15, 822.30 [M+H]+; LCMS: tR = 2.56 min.
[00435] N-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-5-(3,5-dimethylisoxazol-4- yl)-2-methylbenzenesulfonamide (7):
Figure imgf000244_0002
[00436] A suspension of tert-butyl (2-(2-(2-(2-(5-(3,5-dimethylisoxazol-4-yl)-2- methylphenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)carbamate (100 mg, 0.155 mmol) in 4M HCl in dioxane solution (1 mL) was stirred at room temperature for 1 h. The reaction mixture was partitioned between DCM (10 mL) and saturated solution of sodium bicarbonate (5 mL) and separated. The aqueous layer was re-extracted with DCM (3 x 1.0 mL) and the combined organic fractions were dried over anhydrous Na2SO4, filtered and concentrated in vacuo resulting in 70 mg (90% yield) of crude product. The crude material was used in the next step without further purification. MS (ES+): m/z = 442.05 [M+H]+; LCMS: tR = 1.66 min. [00437] tert-Butyl(2-(2-(2-(2-(5-(3,5-dimethylisoxazol-4-yl)-2- hoxy)ethyl)carbamate (6):
Figure imgf000245_0001
[00438] tert-butyl (2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)carbamate (61.4 mg, 0.210 mmol) was added to the solution of 5-(3,5-dimethylisoxazol-4-yl)-2-methylbenzene-1- sulfonyl chloride (50 mg, 0.175 mmol) in pyridine (10 mL/g) at room temperature and stirred for 30 min. The reaction mixture was concentrated to dryness then partitioned between DCM (10 mL) and H2O (5 mL) and separated. The aqueous layer was re-extracted with DCM (3 x 10 mL) and the combined organic fractions were dried over anhydrous Na2SO4, filtered and concentrated in vacuo resulting in 100 mg (90% yield) of crude product. The crude material was used in the next step without further purification. MS (ES+): m/z = 542.10 [M+H]+;
LCMS: tR = 3.42 min. EXAMPLES 30-32:
[00439] Examples 30, 31, and 32 were synthesized using the following procedures.
Figure imgf000245_0002
[00440] General procedure: [00441] A suspension of (S)-2-(6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetic acid (1 eq) in DCM (30 mL/g) was charged with EDCI (1.5 eq), 4-DMAP (1.5 eq), HOBt (1.5 eq) and stirred at room temperature for 10 minutes. Amine (1.5 eq.) was added to the reaction mixture. The resulting solution was stirred at room temperature for 15 h. The reaction mixture was partitioned between DCM and H2O and separated. The aqueous layer was re-extracted with DCM and the combined organic fractions were washed with 5% aqueous solution of acetic acid and saturated solution of sodium bicarbonate. Organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo resulting in a crude product which was subjected to hydrolysis using LiOH (5 eq) in methanol (3 mL/g) purified by column chromatography to afford desired compound.
[00442] 2-((S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-(2-(2-((4-((S)-4-(2-(ethylamino)-2- oxoethyl)-8-methoxy-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-6- yl)phenyl)thio)ethoxy)ethyl)acetamide [Example 30]:
Figure imgf000246_0001
[00443] A suspension of (S)-2-(6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-(2-(2-mercaptoethoxy)ethyl)acetamide (10) (69 mg, 0.138 mmol) , (S)-2-(6-(4-bromophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (3) (50 mg, 0.106 mmol), tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (10 mg, 0.0109 mmol, 10.30 mol %), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (10 mg,0.017 mmol, 16.32 mol %) and DIPEA (41 mg, 0.318 mmol) in 1,4-dioxane (1 mL) in sealed tube was heated to 140°C for 30 min [Biotage microwave reactor, 400W]. The reaction mixture was partitioned between DCM (10 mL) and H2O (5 mL) and separated. The aqueous layer was re-extracted with DCM (3 x 10 mL) and the combined organic fractions were dried over anhydrous Na2SO4, filtered and concentrated in vacuo resulting in a crude product which was purified by column
chromatography and then by preparative HPLC to resulting in 21 mg (22.3 % yield) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6): į = 8.34– 8.24 (m, 2H), 7.77 (dd, J = 8.9, 2.4 Hz, 2H), 7.57– 7.30 (m, 8H), 6.85– 6.70 (m, 2H), 4.52– 4.39 (m, 2H), 3.77 (s, 6H), 3.63 (t, J = 6.6 Hz, 2H), 3.50– 3.01 (m, 12H), 2.55 (s, 6H), 1.07 ( t, J = 7.2 Hz, 6H); MS (ES+): m/z = 887.35, 889.25 [M+H]+; LCMS: tR = 2.42 min.
[00444] (S)-2-(6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-(2-(2-mercaptoethoxy)ethyl)acetamide (10):
[00445]
Figure imgf000247_0001
[00446] A suspension of (S)-2-(6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetic acid (100 mg.) in DCM (3 mL) was charged with EDCI (72.4 mg, 0.378 mmol), 4-DMAP (46 mg, 0.378 mmol), and HOBt (51mg, 0.378 mmol) and stirred at room temperature for 10 minutes. This solution was charged with (2-(2-aminoethoxy)ethyl) ethanethioate (61.7 mg,0.378 mmol) and stirred for an additional 15 h at room temperature. The reaction was worked up and purified by chromatography on silica gel resulting in 75.6 mg (60.0% yield) of crude product as white solid. The crude material was used in the next step without further purification. MS (ES+): m/z = 500.05, 502.20 [M+H]+; LCMS: tR = 2.12 min.
Scheme 6. Synthesis of Example 31
Figure imgf000248_0001
[00447] 2-((S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-(2-(2-(2-((4-((S)-4-(2-(ethylamino)-2- oxoethyl)-8-methoxy-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-6- l hen l thio ethox ethox eth l acetamide Example 31]:
Figure imgf000248_0002
[00448] A suspension of (S)-2-(6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-(2-(2-(2- mercaptoethoxy)ethoxy)ethyl)acetamide (12) (75 mg, 0.138 mmol), (S)-2-(6-(4-bromophenyl)- 8-methoxy-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (3) (50 mg, 0.106 mmol), tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (10 mg, 0.010 mmol, 10.3 mol %), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (10 mg, 0.017 mmol, 16.32 mmol %) and DIPEA (41 mg, 0.318 mmol) in 1,4-dioxane (1 mL) in sealed tube was heated to 140°C for 30 min [Biotage microwave reactor, 400W]. The reaction mixture was partitioned between DCM (10 mL) and H2O (5 mL) and separated. The aqueous layer was re- extracted with DCM (3 x 10 mL) and the combined organic fractions were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo resulting in a crude product which was purified by column chromatography and then by preparative HPLC resulting in 15 mg (15.09 % yield) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6): į = 8.21– 8.30 (m, 2H), 7.77 (dd, J = 9.1, 2.6 Hz, 2H), 7.55– 7.29 (m, 8H), 6.86 (dd, J = 6.5, 2.9 Hz, 2H), 4.46 (m, 2H), 3.78 (s, 3H), 3.72 (s, 3H), 3.61 (t, J = 6.6 Hz, 1H), 3.53 (d, J = 3.9 Hz, 2H), 3.48– 3.35 (m, 1H), 3.31– 3.02 (m, 5H), 2.56 (s, 3H), 2.52 (s, 3H), 1.05 (t, J = 7.2 Hz, 6H); MS (ES+): m/z = 931.25, 933.40 [M+H]+; LCMS: tR = 2.59 min.
[00449] (S)-2-(6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-(2-(2-(2- e (12):
Figure imgf000249_0001
[00450] A suspension of (S)-2-(6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetic acid (8) (100 mg, 0.252 mmol) in DCM (3 mL) was charged with EDCI (72.4 mg, 0.378 mmol), 4-DMAP(46 mg, 0.378 mmol), and HOBt (51mg, 0.378 mmol) and stirred at room temperature for 10 minutes. This solution was charged with (2-(2-(2-aminoethoxy)ethoxy)ethyl) ethanethioate (11) (78 mg, 0.378 mmol) and stirred at room temperature for 15 h. The reaction mixture was partitioned between DCM (10 mL) and H2O (5 mL) and separated. The aqueous layer was re-extracted with DCM (3 x 10 mL) and the combined organic fractions were washed with 5% aqueous solution of acetic acid (1x), saturated solution of sodium bicarbonate (1x), dried over anhydrous Na2SO4, filtered and concentrated in vacuo resulting in a crude product which was subjected to hydrolysis using LiOH (30.1 mg, 1.260 mmol) in methanol (3 mL). The reaction mixture was partitioned between DCM (10 mL) and 5% aqueous solution of acetic acid (5 mL) and separated. The aqueous layer was re-extracted with DCM (3 x 10 mL) and the combined organic fractions were dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by column chromatography to obtain 76 mg (54.7 % yield) of title compound as a white solid. MS (ES+): m/z = 544.10, 546.25 [M+H]+; LCMS: tR = 2.31 min.
Figure imgf000250_0001
[00451] General procedure:
[00452] A suspension of (S)-2-(6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetic acid (1 eq) in DCM (30 mL/g) was charged with EDCI (1.5 eq), 4-DMAP (1.5 eq), HOBt (1.5 eq) and stirred at room temperature for 10 minutes. Amine (1.5 eq) was added to the reaction mixture. The resulting solution was stirred at room temperature for 16 h. The reaction mixture was partitioned between DCM and H2O and separated. The aqueous layer was re-extracted with DCM and the combined organic fractions were washed with 5% aqueous solution of acetic acid and saturated solution of sodium bicarbonate. Organic layer was dried over anhydrous Na2SO4, filtered and concentrated to afford desired compound. [00453] 2-((S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-(3-(3-((4-((S)-4-(2-(ethylamino)-2- oxoethyl)-8-methoxy-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-6- e 32]:
Figure imgf000251_0001
[00454] A suspension of (S)-2-(6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-(3-(3-mercaptopropoxy)propyl)acetamide
[00455] (17) (55 mg, 0.106 mmol), (S)-2-(6-(4-bromophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (3) (50 mg, 0.106 mmol), tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (10 mg, 0.010 mmol, 10.3 mol %), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (10 mg, 0.017 mmol, 16.32 mol %) and DIPEA (41 mg, 0.318 mmol) in 1,4-dioxane (1 mL) in sealed tube was heated to 140°C for 30 min in a microwave reactor. The reaction mixture was partitioned between DCM (10 mL) and H2O (5 mL) and separated. The aqueous layer was re-extracted with DCM (3 x 10 mL) and the combined organic fractions were dried over anhydrous Na2SO4, filtered and concentrated in vacuo resulting in a crude product which was purified by column chromatography and then by preparative HPLC to obtain 50 mg (51.5 % yield) of the title compound as a white solid . 1H NMR (400 MHz, DMSO-d6): į = 8.20 (t, J = 5.5 Hz, 2H), 7.81– 7.70 (m, 2H), 7.55– 7.29 (m, 10H), 6.90– 6.78 (m, 2H), 4.46 (q, J = 6.6 Hz, 2H), 3.8 (s,6H), 3.4-3.6 (m, 4H), 3.24– 3.02 (m, 8H), 2.53 (s, 6H), 1.31– 1.14 (m, 5H), 1.12– 0.98 (m, 7H); MS (ES+): m/z = 915.55, 917.40 [M+H]+; LCMS: tR = 2.59 min.
[00456] (S)-2-(6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-(3-(3- (17):
Figure imgf000251_0002
[00457] A solution of (S)-S-(3-(3-(2-(6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetamido)propoxy)propyl) ethanethioate (16) (150 mg, 0.263 mmol) in ethanol (4.5 mL) was charged with Potassium hydroxide (44 mg, 0.789 mmol) and stirred at room temperature for 15 h. The reaction mixture was partitioned between DCM (10 mL) and H2O (5 mL) and pH of the mixture was adjusted to ~5-6 by adding 10% aqueous acetic acid solution and separated. The aqueous layer was re-extracted with DCM (3 x 10 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo resulting in 90 mg (65.2 % yield) of crude product as a white solid. Crude material was used for next step without purification. MS (ES+): m/z = 528.05, 530.20 [M+H]+; LCMS: tR = 2.10 min.
[00458] (S)-S-(3-(3-(2-(6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetamido)propoxy)propyl) ethanethioate (16):
[00459] A solution of (S)-3-(3-(2-(6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetamido)propoxy)propyl methanesulfonate (15) (200 mg, 0.38 mmol) in DMSO (6 mL) was charged with potassium thioacetate (77 mg, 0.677 mmol) the reaction mixture was heated to 71°C for 3h. The reaction mixture was partitioned between DCM (10 mL) and H2O (5 mL) and separated. The aqueous layer was re- extracted with DCM (3 x 10 mL) and the combined organic fractions were washed with 5% aqueous solution of acetic acid (1x), saturated sodium bicarbonate (1x), dried over anhydrous Na2SO4, filtered and concentrated in vacuo resulting in 150 mg (77.7% yield) of crude product as a white solid. Crude material was used in the next step without further purification. MS (ES+): m/z = 570.20, 572.30 [M+H]+; LCMS: tR = 2.85 min.
[00460] (S)-3-(3-(2-(6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetamido)propoxy)propyl
methanesulfonate (15):
Figure imgf000253_0001
[00461] A solution of (S)-2-(6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-(3-(3-hydroxypropoxy)propyl)acetamide (14) (200 mg, 0.390 mmol) in DCM (6 mL) was charged with TEA (79 mg, 0.78 mmol) the reaction mixture was cooled to 0°C. To this solution methane sulphonyl chloride (58 mg, 0.507 mmol) was added. The resulting solution was stirred at room temperature for 1 h. The reaction mixture was partitioned between DCM (10 mL), H2O (5 mL) and separated. The aqueous layer was re-extracted with DCM (3 x 10 mL) and the combined organic fractions were washed with 5% aqueous solution of acetic acid (1x), saturated solution of sodium bicarbonate (1x), dried over anhydrous Na2SO4, filtered and concentrated in vacuo resulting in 200 mg (86.9 % yield) of crude product as white solid. Crude material was used in the next step without further purification. MS (ES+): m/z = 590.15, 592.70 [M+H]+; LCMS: tR = 2.98 min.
[00462] (S)-2-(6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-(3-(3- e (14):
Figure imgf000253_0002
[00463] A suspension of (S)-2-(6-(4-chlorophenyl)-8-methoxy-1-methyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetic acid (8) (200 mg, 0.503 mmol) in DCM (6 mL) was charged with EDCI (144 mg, 0.754 mmol), 4-DMAP (92.1 mg, 0.754 mmol), and HOBt (101mg, 0.754 mmol) and stirred at room temperature for 10 minutes. The reaction was charged with 3-(3-Aminopropoxy)propan-1-ol (61.7 mg, 0.378 mmol) and stirred at room temperature 16 h. The reaction mixture was partitioned between DCM and H2O and separated the aqueous was re-extracted with DCM and the combined organic fractions were washed with 5% aqueous acetic acid (1x), sat. sodium bicarbonate (1x), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo resulting in 200 mg (71.8% yield) of crude product as a white solid. The crude material was used in the next step without further purification MS (ES+): m/z = 512.05, 514.30[M+H]+; LCMS: tR = 2.01 min. EXAMPLE 33:
[00464] This example demonstrates in vitro properties of disclosed compounds.
[00465] Inhibition of MV4-11 cell proliferation. MV4-11 cells (5000 cells in 50 μl volumes) in growth medium containing 10% FBS and 1% Pen/Strep were plated and grown overnight in 96 well plates and treated the next day with 3-fold dilutions of test compounds or with DMSO vehicle. After 72 hours of growth, 30 ul of Cell-Titer Glo reagent (Promega) was added to the wells and the plates incubated for 30 minutes. Luminescence was measured on a Spectramax M5 plate reader and GI50 values were calculated for each test compound. MV4-11 Cell Proliferation Results:
Figure imgf000254_0001
[00466] Inhibition of Myc expression. MV4-11 (ATCC® CRL9591™) cells were seeded in 96-well plates at a density of 105 cells in 100ul volume per well and grown overnight. Compounds were prepared at 1000-fold in DMSO, diluted 100x in growth medium (10%FBS in IMEM) before adding one tenth volume to the cells on the day following seeding (final concentration DMSO 0.1%). After 4 hours compound treatment, cells were collected through centrifugation at 3000 rpm for 10 min. Cell pellets were lysed with RLT buffer (Qiagen) and total RNA isolation was carried out with the RNeasy 96 kit from Qiagen (catalog No. 74182) following the manufacturer’s instructions. cDNA was made from total RNA using reverse transcription reagents from Life Technologies (catalog No. 4391852C), and used as directed. MYC mRNA level were measured by real time PCR using MYC Taqman probe (Life Technologies, catalog No. Hs00905027-ml) after normalization with GAPDH (Life
Technologies, catalog No. Hs02758991-gi). The relative MYC expression levels were then calculated through comparison to samples treated with DMSO, and EC50 were determined through four-parameter dose-response curve equation with GraphPad Prism software. Myc Inhibition Results:
Grou A > Grou B > Grou C in otenc :
Figure imgf000255_0001
EQUIVALENTS
[00467] While specific embodiments have been discussed, the above specification is illustrative and not restrictive. Many variations will become apparent to those skilled in the art upon review of this specification. The full scope of the embodiments should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.
[00468] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term“about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained.

Claims

What is claimed is:
1. A bivalent compound of the formula:
Figure imgf000256_0001
or a pharmaceutically acceptable salt, stereoisomer, metabolite, or hydrate thereof;
wherein:
Q1 is a connecting moiety covalently bound to P1 and P2, wherein Q1 is selected from the group consisting of:
-W1-(C3-6alkylene-O)s-C1-6alkylene-W1-; -W1-(CH2-CH2-O)t-C1-6alkylene-W1-; -W1- (CH2-CH2-O)s-;
Figure imgf000256_0002
an optionally substituted unsaturated heteroaliphatic moiety; -Si(R7)(R8)-; -Si(R7)(R8)-O-; -O-Si(R7)(R8)-; -NR’-; -N(R’)C(O)-; -C(O)N(R’)-; - N(R’)SO2-; -SO2N(R’)-; -O-; -C(O)-; -OC(O)-; -C(O)O-; -S-; -SO-; -SO2-; -C(=S)-; -C(=NR’)-; aliphatic, heteroaliphatic; phenyl; naphthyl; heterocyclyl; heteroaryl; and covalently bonded combinations thereof;
wherein:
W1 is, independently for each occurrence, N, O, or S;
s is an integer from 1-10;
t is an integer from 3-10;
R7 and R8 are selected, independently for each occurrence, from the group consisting of -OH, C1-6alkyl, -O-C1-6alkyl, C2-6alkenyl, C3-6cycloalkyl, -C1-6alkyl-NRaRb, phenyl and heteroaryl; wherein C1-6alkyl, C2-6alkenyl, C3-6cycloalkyl, phenyl, and heteroaryl may be optionally substituted by one or more substituents independently selected from the group consisting of halogen, cyano, hydroxyl, C1-6alkyl, and phenyl; or
R7 and R8, together with the silicon to which they are attached, form a 4-7 membered heterocyclic ring, optionally containing one, two, three, or four heteroatoms independently selected from O, S, or N; wherein the 4-7 membered heterocyclic ring may be optionally substituted by one or more substituents independently selected from the group consisting of halogen, cyano, oxo, and hydroxyl; and R’ is, independently for each occurrence, selected from the group consisting of hydrogen and C1-4alkyl; wherein
Figure imgf000257_0001
may be optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo, and hydroxyl; and wherein:
P1 is a first ligand moiety capable of modulating a first bromodomain on a protein and P2 is second ligand moiety capable of modulating a second bromodomain on the protein.
2. The bivalent compound of claim 1, wherein Q1 is selected from the group consisting of: -W1-(C3-6alkylene-O)s-C1-6alkylene-W1-;
Figure imgf000257_0002
-W1-(CH2-CH2- O)s-;
Figure imgf000257_0003
and an optionally substituted unsaturated heteroaliphatic moiety; wherein:
W1 is, independently for each occurrence, N, O, or S;
s is an integer from 1-10;
t is an integer from 3-10
3. The bivalent compound of claim 2, wherein Q1 is selected from the group consisting of: -S-(C3-6alkylene-O)s-C1-6alkylene-S-; -S-(CH2-CH2-O)t-C1-6alkylene-S-; -O-(CH2-CH2-O)s-; and -O-C1-15alkylene-O-; wherein s is an integer from 1-10, and t is an integer from 3-10.
4. The bivalent compound of claim 2, wherein Q1 is -O-(CH2-CH2-O)s-.
5. The bivalent compound of claim 2, wherein Q1 is selected from the group consisting of:
-S-(CH2-CH2-CH2-O)s-CH2-CH2-CH2-S-; -S-(CH2-CH2-O)t-CH2-CH2-S-; and -O- (CH2)u-O-; wherein u is an integer from 1-15.
6. The bivalent compound of claim 5, wherein u is 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. 7. The bivalent compound of any one of claims 1-6, wherein s is 2, 3, 4, 5, 6,
7, or 8.
8. A bivalent compound of the formula:
Figure imgf000257_0004
or a pharmaceutically acceptable salt, stereoisomer, metabolite, or hydrate thereof;
wherein: Q1 is a connecting moiety covalently bound to P1 and P2, wherein Q1 has a length of less than about 30 Å;
wherein:
P1 is a first ligand moiety capable of modulating a first bromodomain on a protein and P2 is second ligand moiety capable of modulating a second bromodomain on the protein.
9. The bivalent compound of claim 8, wherein Q1 has a length of less than about 20 Å.
10. The bivalent compound of claim 8, wherein Q1 has a length of less than about 10 Å.
11. The bivalent compound of any one of claims 1-10, wherein P1 and P2 are independently selected from the rou consistin of:
Formula I, and
Figure imgf000258_0001
wherein:
X is phenyl, naphthyl, or heteroaryl;
R1 is C1-3alkyl,
Figure imgf000258_0002
R2 is -NR2aR2a' or -OR2b; wherein one of R2a or R2a’ is hydrogen, and R2b or the other of R2a or R2a’ is selected from the group consisting of C1-6alkyl, haloC1-6alkyl, R2cR2c’N-C2-6alkyl, carbocyclyl, carbocyclyloC1-4alkyl, heterocyclyl and heterocyclylC1-4alkyl, wherein any of the carbocyclyl or heterocyclyl groups are optionally substituted by one or more substituents selected from the group consisting of halogen, C1-6alkyl, haloC1-6alkyl, C1-6alkoxy, haloC1- 6alkoxy, carbonyl, -CO-carbocyclyl, azido, amino, hydroxyl, nitro and cyano, wherein the– CO-carbocyclyl group may be optionally substituted by one or more substituents selected from the group consisting of halogen, C1-6alkyl, haloC1-6alkyl, C1-6alkoxy, haloC1-6alkoxy, azido, nitro and cyano; or
two adjacent groups on any of the carbocyclyl or heterocyclyl groups together with the interconnecting atoms form a 5- or 6-membered ring which ring may contain 1 or 2 heteroatoms independently selected from the group consisting of O, S and N; or R2a and R2a’ together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered ring which optionally contains 1 or 2 heteroatoms independently selected from the group consisting of O, S and N; wherein the 4-, 5-, 6 or 7-membered ring is optionally substituted by C1-6alkyl, hydroxyl or amino;
R2c and R2c’ are independently hydrogen or C1-6alkyl;
each R3 is independently selected from the group consisting of hydrogen, hydroxyl, thiol, sulfinyl, amino, halo, C1-6alkyl, haloC1-6alkyl, C1-6alkoxy, haloC1-6alkoxy, nitro, cyano, CF3, -OCF3, -COOR5, -C1-4alkylamino , phenoxy, benzoxy, and C1-4alkylOH;
each R4 is hydroxyl, halo, C1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl,
Figure imgf000259_0001
C1-6alkoxy,
Figure imgf000259_0002
acylaminoC1-6alkyl, nitro, cyano, CF3, -OCF3, -COOR5; - OS(O)2C1-4alkyl, phenyl, naphthyl, phenyloxy, benzyloxy or phenylmethoxy, wherein C1- 6alkyl, phenyl, and naphthyl are optionally substituted by one two or three substituents selected from the group consisting of hydroxyl, halogen, amino, nitro;
R5 is C1-3alkyl;
* denotes a chiral center;
m is an integer 1 to 3; and
n is an integer 1 to 5;
Figure imgf000259_0003
II) Formula F and Formula G wherein:
X is O or S;
R1 is C1-6alkyl, haloC1-6alkyl, -(CH2)nOR1a, or -(CH2)mNR1bR1c; wherein R1a is hydrogen, C1-6alkyl or haloC1-6alkyl; R1b and R1c, which may be the same or different, are hydrogen, C1-6alkyl or haloC1-6alkyl; and m and n, which may be the same or different, are 1, 2 or 3;
R2 is R2a, -OR2b, or -NR2cR2d; wherein R2a and R2b are carbocyclyl, carbocyclylC1- 4alkyl, heterocyclyl or heterocyclylC1-4alkyl, or R2a is carbocyclylethenyl or
heterocyclylethenyl, wherein any of the carbocyclyl or heterocyclyl groups defined for R2a or R2b are optionally substituted by one or more groups independently selected from the group consisting of halogen, C1-6alkyl, haloC1-6alkyl, C1-6alkoxy, haloC1-6alkoxy, nitro, cyano, dimethylamino, benzoyl and azido; or two adjacent groups on any of the carbocyclyl or heterocyclyl groups defined for R2a or R2b 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
R2a and R2b are C1-6alkyl or haloC1-6alkyl; and R2c and R2d, which may be the same or different, are carbocyclyl, carbocyclylC1-4alkyl, heterocyclyl or heterocyclylC1-4alkyl, wherein any of the carbocyclyl or heterocyclyl groups defined for R2c or R2d are optionally substituted by one or more groups independently selected from the group consisting of halogen, C1-6alkyl, haloC1-6alkyl, C1-6alkoxy, haloC1-6alkoxy, nitro, cyano and
Figure imgf000260_0001
or two adjacent groups on any of the carbocyclyl or heterocyclyl groups defined for R2c and R2d 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
R2c and R2d are independently hydrogen, C1-6alkyl or haloC1-6alkyl;
R3 is C1-6alkyl, phenyl, naphthyl, heteroaryl carbocyclyl or heterocyclyl, optionally substituted independently by one or more substitutents selected from the group consisting of halogen,–SR, -S(O)R’, -NHR’, -OR’, C1-6alkyl, haloC1-6alkyl, C1-6alkoxy, haloC1-6alkoxy, nitro and cyano;
R’ is H or C1-6alkyl;
A is a benzene or aromatic heterocyclic ring, each of which is optionally substituted; and
n is 0, 1 or 2; Formula A1, or
Figure imgf000261_0001
wherein:
R4 is hydrogen, cyano or C1-6 alkyl;
A is selected from the group consisting of:
Figure imgf000261_0002
Rx is O, NR2a, or S;
R1 is C1-6alkyl, C3-6cycloalkyl, a 5 or 6 membered heterocyclyl, an aromatic group or a heteroaromatic group, wherein the aromatic group or the heteroaromatic group is optionally substituted by one to three groups selected from the group consisting of halogen, hydroxy, cyano, nitro, C1-6alkyl, C1-4alkoxy,
Figure imgf000261_0003
hydroxyC1-4alkyl, C1-4alkoxy C1-4alkyl, C1-4alkoxycarbonyl,
Figure imgf000261_0004
C1- 4alkyl and C1-4alkylsulfonamido;
R2 is hydrogen or C1-6alkyl;
R2a is selected from the group consisting of H, C1-6alkyl, C1-6haloalkyl, (CH2)mcyano, (CH2)mOH, (CH2)mC1-6alkoxy, (CH2)mC1-6haloalkoxy, (CH2)mC1-6haloalkyl,
(CH2)mC(O)NRaRb, (CH2)mNRaRb and (CH2)m C(O)CH3, (CHR6)pphenyl optionally substituted by C1-6alkyl, C1-6alkoxy, cyano, halo C1-4alkoxy,
Figure imgf000261_0005
(CHR6)pheteroaromatic, (CHR6)pheterocyclyl; wherein Ra is H, C1-6alkyl, or heterocyclyl; wherein Rb is H or C1-6alkyl, or
Ra and Rb together with the N to which they are attached form a 5 or 6 membered heterocyclyl;
R2b is H, C1-6alkyl, (CH2)2C1-6alkoxy, (CH2)2cyano, (CH2)mphenyl or
(CH2)2heterocyclyl;
R3 is hydrogen;
R6 is hydrogen or C1-6alkyl;
m is 0, 1, 2 or 3;
n is 0, 1 or 2; and
p is 0, 1 or 2;
Figure imgf000262_0001
wherein:
A is a bond, C1-4alkyl or–C(O)-;
X is:
i) a 6 to 10 membered aromatic group, or
ii) a 5 to 10 membered heteroaromatic comprising 1, 2 or 3 heteroatoms selected from the group consisting of O, N and S;
R1 is:
i) phenyl optionally substituted by 1 or 2 substituents independently selected from the group consisting of halogen, cyano, C1-6alkyl,
Figure imgf000262_0002
C1-6alkoxy, - SO2C1-6alkyl and -COR7,
ii) a 5 to 10 membered heteroaromatic comprising 1, 2 or 3 heteroatoms selected from the group consisting of O, N and S optionally substituted by 1 or 2 substituents independently selected from the group consisting of halogen, cyano, C1-6alkyl, C1- 6haloalkyl, C1-6alkoxy and -COR7, or
iii) C1-6alkyl, C0-6alkylcyano, C0-6alkylC1-6alkoxy, C0-2alkylC(O)R7 or cyclohexyl; R2 is C1-6alkyl;
R3 is C1-6alkyl;
R4 is:
i) H, halogen, cyano, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C0-6hydroxyalkyl, -SO2C1-6alkyl, -C(O)NR8R9, -C(O)R10, -C0-6alkyl-NR11R12, or
ii) -OmC1-6alkyl substituted by a 5 or 6 membered heterocyclyl or heteroaromatic each comprising 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O and S and wherein said hetercyclyl or heteroaromatic is optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of halogen, cyano, C1-6alkyl, C1-6haloalkyl and C1-6alkoxy, wherein m is 0, 1 or 2, wherein when the heterocyclyl or heteroatomic is linked through a heteroatom and m is 1, then the heteroatom and O are not directly linked if the resultant arrangement would be unstable;
R4a is H, halogen, C1-6alkyl,
Figure imgf000263_0001
C1-6alkoxy or C0-6hydroxyalkyl;
R5 is H, halogen, C1-6alkyl or C1-6alkoxy;
R6 is H, C1-6alkyl, C0-6alkylcyano, C0-6alkylC1-6alkoxy or C0-2alkylC(O)R7;
R7 is hydroxyl, C1-6alkoxy, -NH2, -NHC1-6alkyl or N(C1-6alkyl)2;
R8 and R9 independently are:
i) H, C1-6alkyl, C0-6alkylphenyl, C0-6alkylheteroaromatic, C3-6cycloalkyl, or ii) R8 and R9 together with the N to which they are attached form a 5 or 6 membered heterocyclyl or heteroaromatic wherein said heterocyclyl or heteroaromatic may comprise 1, 2 or 3 further heteroatoms independently selected from the group consisting of O, N and S;
R10 is hydroxyl, C1-6alkoxy or a 5 or 6 membered heterocyclyl or heteroaromatic comprising 1, 2, 3 or 4 heteroatoms selected from the group consisting of O, N and S;
R11and R12 independently are:
i) H, C1-6alkyl; or
ii) R11 and R12 together with the N to which they are attached form a 5 or 6 membered heterocyclyl or heteroaromatic wherein said heterocyclyl or heteroaromatic may comprise 1, 2 or 3 further heteroatoms independently selected from the group consisting of O, N and S; Formula E, and
Figure imgf000264_0001
wherein:
R1 is C1-6alkyl, C3-7cycloalkyl or benzyl;
R2 is C1-4alkyl;
R3 is C1-4alkyl;
X is phenyl, naphthyl, or heteroaryl;
R4a is hydrogen, C1-4alkyl or is a group L-Y in which L is a single bond or a C1- 6alkylene group and Y is OH, OMe, CO2H, CO2C1-6alkyl, CN, or NR7R8;
R7 and R8 are independently hydrogen, a heterocyclyl ring, C1-6alkyl optionally substituted by hydroxyl, or a heterocyclyl ring; or
R7 and R8 combine together to form a heterocyclyl ring optionally substituted by C1- 6alkyl, CO2C1-6alkyl, NH2, or oxo;
R4b and R4c are independently hydrogen, halogen, C1-6alkyl, or C1-6alkoxy;
R4d is C1-4alkyl or is a group -L-Y- in which L is a single bond or a C1-6alkylene group and Y is -O-, -OCH2-, -CO2-, -CO2C1-6alkyl-, or–N(R7)-;
R5 is hydrogen, halogen, C1-6alkyl, or C1-6alkoxy;
R6 is hydrogen or C1-4alkyl; Formula L,
Figure imgf000265_0001
wherein:
A is independently, for each occurrence, a 4-8 membered cycloalkyl, heterocyclic, phenyl, naphthyl, or heteroaryl moiety, each optionally substituted with one, two, three or more R1 substituents;
R1 is selected from the group consisting of hydroxy, halogen, oxo, amino, imino, thiol, sulfanylidene, C1-6alkyl, hydroxyC1-6alkyl, -O-C1-6alkyl,–NH-C1-6alkyl, -CO2H, -C(O)C1- 6alkyl,–C(O)O-C1-6alkyl, aminoC1-6alkyl, haloC1-6alkyl, -C1- 6alkylC(O)R2
, -O-C(O)R2, -NH-C(O)R2, -O-C1-6alkyl-C(O)R2, -NHC1-6alkyl-C(O)R2, acylaminoC1-6alkyl, nitro, cyano, CF3, -OCF3, -OS(O)2C1-6alkyl, phenyl, naphthyl,
phenyloxy, -NH-phenyl, benzyloxy, and phenylmethoxy halogen; wherein C1-6alkyl, phenyl, and naphthyl are optionally substituted by one two or three substituents selected from the group consisting of hydroxyl, halogen, amino, nitro, phenyl and C1-6alkyl; or two R1 substitutents may be taken together with the atoms to which they are attached to form a fused aliphatic or heterocyclic bicyclic ring system;
R2 is -NR2aR2a' or -OR2b; wherein one of R2a or R2a’ is hydrogen, and R2b or the other of R2a or R2a’ is selected from the group consisting of C1-6alkyl, haloC1-6alkyl, R2cR2c’N-C2-6alkyl, carbocyclyl, carbocyclyloC1-4alkyl, heterocyclyl and heterocyclylC1-4alkyl, wherein any of the carbocyclyl or heterocyclyl groups are optionally substituted by one or more substituents selected from the group consisting of halogen, C1-6alkyl, haloC1-6alkyl, C1-6alkoxy, haloC1- 6alkoxy, carbonyl, -CO-carbocyclyl, azido, amino, hydroxyl, nitro and cyano, wherein the– CO-carbocyclyl group may be optionally substituted by one or more substituents selected from the group consisting of halogen, C1-6alkyl, haloC1-6alkyl, C1-6alkoxy, haloC1-6alkoxy, azido, nitro and cyano; or
two adjacent groups on any of the carbocyclyl or heterocyclyl groups together with the interconnecting atoms form a 5- or 6-membered ring which ring may contain 1 or 2 heteroatoms independently selected from the group consisting of O, S and N; or R2a and R2a’ together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered ring which optionally contains 1 or 2 heteroatoms independently selected from the group consisting of O, S and N; wherein the 4-, 5-, 6 or 7-membered ring is optionally substituted by C1-6alkyl, hydroxyl or amino;
R2c and R2c’ are independently hydrogen or C1-6alkyl;
B is selected from the group consisting of:
N N S N
Figure imgf000266_0001
R4
wherein:
B is selected from the group consisting of:
,
,
Figure imgf000267_0001
Q is independently, for each occurrence, N or CH;
V is independently, for each occurrence, O, S, NR4, or a bond; and
R4 is independently selected from the group consisting of hydrogen, hydroxyl, halo, amino, thiol, C1-6alkyl, haloC1-6alkyl,
Figure imgf000267_0002
-NH-C1-6alkyl, -S-C1-6alkyl, haloC1-6alkoxy, nitro, cyano, -CF3, -OCF3, -C(O)O-C1-6alkyl, -C1-4alkylamino , phenoxy, benzoxy, and C1- 4alkylOH;
Figure imgf000267_0003
VIII) Formula N or Formula O,
wherein:
R1 is selected from the group consisting of hydrogen, lower alkyl, phenyl, naphthyl, aralkyl, heteroalkyl, SO2, NH2, NO2, CH3, CH2CH3, OCH3, OCOCH3, CH2COCH3, OH, CN, and halogen;
R2 is selected from the group consisting of hydrogen, lower alkyl, aralkyl, heteroalkyl, phenyl, naphthyl, SO2, NH2, NH +
3 , NO2, CH3, CH2CH3, OCH3, OCOCH3, CH2COCH3, OH, halogen, carboxy, and alkoxy;
X is selected from the group consisting of lower alkyl, SO2, NH, NO2, CH3, CH2CH3, OCH3, OCOCH3, CH2COCH3, OH, carboxy, and alkoxy; and
n is an integer from 0 to 10; IX)
Formul
Figure imgf000268_0001
wherein:
R1, R2, R3, R4, R5, and R6 are independently selected from the group consisting of hydrogen, lower alkyl, phenyl, naphthyl, aralkyl, heteroaryl, SO2, NH2, NH +
3 , NO2, SO2, CH3, CH2CH3, OCH3, OCOCH3, CH2COCH3, OCH2CH3, OCH(CH3)2, OCH2COOH, OCHCH3COOH, OCH2COCH3, OCH2CONH2, OCOCH(CH3)2, OCH2CH2OH, OCH2CH2CH3, O(CH2)3CH3, OCHCH3COOCH3, OCH2CON(CH3)2, NH(CH2)3N(CH3)2, NH(CH2)2N(CH3)2, NH(CH2)2OH, NH(CH2)3CH3, NHCH3, SH, halogen, carboxy, and alkoxy;
X)
Figure imgf000268_0002
Formula T,
wherein:
R1, R2, and R3 are independently selected from the group consisting of hydrogen, lower alkyl, phenyl, naphthyl, aralkyl, heteroaryl, SO2, NH2, NH +
3 , NO2, SO2, CH3, CH2CH3, OCH3, OCOCH3, CH2COCH3, OH, SH, halogen, carboxy, and alkoxy; R4 is selected from the group consisting of lower alkyl, phenyl, naphthyl, SO2, NH, NO2, CH3, CH2CH3, OCH3, OCOCH3, CH2COCH3, OH, carboxy, and alkoxy;
XI)
Figure imgf000268_0003
Formula V,
or a pharmaceutically acceptable salt thereof,
wherein:
X is O or N; Y is O or N; wherein at least one of X or Y is O;
W is C or N;
R1 is H, alkyl, alkenyl, alkynyl, aralkyl, phenyl, naphthyl, heteroaryl, halo, CN, ORA, NRARB,
N(RA)S(O)qRARB, N(RA)C(O)RB, N(RA)C(O)NRARB, N(RA)C(O)ORA,
N(RA)C(S)NRARB, S(O)qRA, C(O)RA, C(O)ORA, OC(O)RA, or C(O)NRARB;
each RA 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 RB 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
RA and RB, 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;
RC is alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, naphthyl, heterocycloalkyl, or heteroaryl, each optionally substituted with 1-5 independently selected R4, and when L1 is other than a covalent bond, RC is additionally selected from H;
R2 and R3 are each independently H, halogen, alkyl, alkenyl, alkynyl, phenyl, naphthyl, aralkyl, cycloalkyl, heteroaryl, heterocycloalkyl, -OR, -SR, -CN, -N(R’)(R’’), -C(O)R, -C(S)R, -CO2R, -C(O)N(R’)(R’’), -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)(R’’), - C(S)OR, -S(O)R, -SO2R, -SO2N(R’)(R’’), -N(R’)C(O)R, -N(R’)C(O)N(R’)(R’’), - N(R')C(S)N(R')(R"), -N(R’)SO2R, -N(R’)SO2N(R’)(R’’), -N(R’)N(R’)(R’’), - N(R’)C(=N(R’))N(R’)(R’’), -C=NN(R’)(R’’), -C=NOR, -C(=N(R’))N(R’)(R’’), -OC(O)R, - OC(O)N(R’)(R’’), or -(CH2)pRx; or
R2 and R3 together with the atoms to which each is attached, form an optionally substituted 3-7 membered saturated or unsaturated spiro-fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each Rx is independently halogen, alkyl, alkenyl, alkynyl, phenyl, naphthyl, aralkyl, cycloalkyl, heteroaryl, heterocycloalkyl, -OR, -SR, -CN, -N(R’)(R’’), -C(O)R, -C(S)R, -CO2R, -C(O)N(R’)(R’’), -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)(R’’), -C(S)OR, - S(O)R, -SO2R, -SO2N(R’)(R’’), -N(R’)C(O)R, -N(R’)C(O)N(R’)(R’’), -N(R’)C(S)N(R’)(R’’), -N(R’)SO2R, -N(R’)SO2N(R’)(R’’), -N(R’)N(R’)(R’’), -N(R’)C(=N(R’))N(R’)(R’’), - C=NN(R’)(R’’), -C=NOR, -C(=N(R’))N(R’)(R’’), -OC(O)R, -OC(O)N(R’)(R’’);
L1 is a covalent bond or an optionally substituted bivalent C1-6 hydrocarbon chain wherein one or two methylene units is optionally replaced by -NR’-, -N (R’)C(O)-, - C(O)N(R’)-, -N(R’)SO2-, -SO2N(R’)- -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO2-; each R is independently hydrogen, alkyl, alkenyl, alkynyl, phenyl, naphthyl, aralkyl, cycloalkyl, heteroaryl, or heterocycloalkyl;
each R’ is independently -R, -C(O)R, -C(S)R, -CO2R, -C(O)N(R)2, -C(S)N(R)2, - S(O)R, -SO2R, -SO2N(R)2, or two R groups on the same nitrogen are taken together with their intervening atoms to form an heteroaryl or heterocycloalkyl group; each R’’ is independently - R, -C(O)R, -C(S)R, -CO2R, -C(O)N(R)2, -C(S)N(R)2, -S(O)R, -SO2R, -SO2N(R)2, or two R groups on the same nitrogen are taken together with their intervening atoms to form an heteroaryl or heterocycloalkyl group; or
R’ and R’’, together with the atoms to which each is attached, can form cycloalkyl, heterocycloalkyl, phenyl, naphthyl, or heteroaryl; each of which is optionally substituted; each R4 is independently alkyl, alkenyl, alkynyl, phenyl, naphthyl, aralkyl, cycloalkyl, heteroaryl, or heterocycloalkyl, halogen, -OR, -SR, -N(R’)(R’’), -CN, -NO2, -C(O)R, -C(S)R, - CO2R, -C(O)N(R’)(R’’), -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)(R’’), -C(S)OR, -S(O)R, -SO2R, -SO2N(R’)(R’’), -N(R’)C(O)R, -N(R’)C(O)N(R’)(R’’), -N(R’)C(S)N(R’)(R’’), -N(R’)SO2R, -N(R’)SO2N(R’)(R’’), -N(R’)N(R’)(R’’), -N(R’)C(=N(R/))N(R')(R"), - C=NN(R')(R"), -C=NOR, -C(=N(R'))N(R')(R"), -OC(O)R, or -OC(O)N(R’)(R’’);
each R5 is independently -R, halogen, -OR, -SR, -N(R’)(R’’), -CN, -NO2, -C(O)R, - C(S)R, -CO2R, -C(O)N(R’)(R’’), -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)(R’’), - C(S)OR, -S(O)R, -SO2R, -SO2N(R’)(R’’), -N(R’)C(O)R, -N(R’)C(O)N(R’)(R’’), - N(R’)C(S)N(R’)(R’’), -N(R’)SO2R, -N(R’)SO2N(R’)(R’’), -N(R’)N(R’)(R’’), - N(R’)C(=N(R’))N(R’)(R’’), -C=NN(R’)(R’’), -C=NOR, -C(=N(R’))N(R’)(R’’), -OC(O)R, or - OC(O)N(R’)(R’’);
n is 0-5;
each q is independently 0, 1, or 2; and
p is 1-6; XII)
Figure imgf000271_0001
Formula W,
wherein:
X is O or N;
Y is O or N; wherein at least one of X or Y is O;
W is C or N;
R1 is H, alkyl, alkenyl, alkynyl, aralkyl, phenyl, naphthyl, heteroaryl, halo, CN, ORA, NRARB,
N(RA)S(O)qRARB, N(RA)C(O)RB, N(RA)C(O)NRARB, N(RA)C(O)ORA,
N(RA)C(S)NRARB, S(O)qRA, C(O)RA, C(O)ORA, OC(O)RA, or C(O)NRARB;
each RA 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 RB 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
RA and RB, 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;
RC is alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, naphthyl, heterocycloalkyl, or heteroaryl, each optionally substituted with 1-5 independently selected R4, and when L1 is other than a covalent bond, RC is additionally selected from H;
R2 is H, halogen, alkyl, alkenyl, alkynyl, phenyl, naphthyl, aralkyl, cycloalkyl, heteroaryl, heterocycloalkyl, -OR, -SR, -CN, -N(R’)(R’’), -C(O)R, -C(S)R, -CO2R, - C(O)N(R’)(R’’), -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)(R’’), -C(S)OR, - S(O)R, -SO2R, -SO2N(R’)(R’’), -N(R’)C(O)R, -N(R’)C(O)N(R’)(R’’), -N(R')C(S)N(R')(R"), - N(R’)SO2R, -N(R’)SO2N(R’)(R’’), -N(R’)N(R’)(R’’), -N(R’)C(=N(R’))N(R’)(R’’), - C=NN(R’)(R’’), -C=NOR, -C(=N(R’))N(R’)(R’’), -OC(O)R, -OC(O)N(R’)(R’’), or -(CH2)pRx;
R3 is a bond or optionally substituted alkyl; or R2 and R3 together with the atoms to which each is attached, form an optionally substituted 3-7 membered saturated or unsaturated spiro-fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each Rx is independently halogen, alkyl, alkenyl, alkynyl, phenyl, naphthyl, aralkyl, cycloalkyl, heteroaryl, heterocycloalkyl, -OR, -SR, -CN, -N(R’)(R’’), -C(O)R, -C(S)R, -CO2R, -C(O)N(R’)(R’’), -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)(R’’), -C(S)OR, - S(O)R, -SO2R, -SO2N(R’)(R’’), -N(R’)C(O)R, -N(R’)C(O)N(R’)(R’’), -N(R’)C(S)N(R’)(R’’), -N(R’)SO2R, -N(R’)SO2N(R’)(R’’), -N(R’)N(R’)(R’’), -N(R’)C(=N(R’))N(R’)(R’’), - C=NN(R’)(R’’), -C=NOR, -C(=N(R’))N(R’)(R’’), -OC(O)R, -OC(O)N(R’)(R’’);
L1 is a covalent bond or an optionally substituted bivalent C1-6 hydrocarbon chain wherein one or two methylene units is optionally replaced by -NR’-, -N (R’)C(O)-, - C(O)N(R’)-, -N(R’)SO2-, -SO2N(R’)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO-, or -SO2-; each R is independently hydrogen, alkyl, alkenyl, alkynyl, phenyl, naphthyl, aralkyl, cycloalkyl, heteroaryl, or heterocycloalkyl;
each R’ is independently -R, -C(O)R, -C(S)R, -CO2R, -C(O)N(R)2, -C(S)N(R)2, - S(O)R, -SO2R, -SO2N(R)2, or two R groups on the same nitrogen are taken together with their intervening atoms to form an heteroaryl or heterocycloalkyl group; each R’’ is independently - R, -C(O)R, -C(S)R, -CO2R, -C(O)N(R)2, -C(S)N(R)2, -S(O)R, -SO2R, -SO2N(R)2, or two R groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted heteroaryl or heterocycloalkyl group; or
R’ and R’’, together with the atoms to which each is attached, can form cycloalkyl, heterocycloalkyl, phenyl, naphthyl, or heteroaryl; each of which is optionally substituted; each R4 is independently alkyl, alkenyl, alkynyl, phenyl, naphthyl, aralkyl, cycloalkyl, heteroaryl, or heterocycloalkyl, halogen, -OR, -SR, -N(R’)(R’’), -CN, -NO2, -C(O)R, -C(S)R, - CO2R, -C(O)N(R’)(R’’), -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)(R’’), -C(S)OR, -S(O)R, -SO2R, -SO2N(R’)(R’’), -N(R’)C(O)R, -N(R’)C(O)N(R’)(R’’), -N(R’)C(S)N(R’)(R’’), -N(R’)SO2R, -N(R’)SO2N(R’)(R’’), -N(R’)N(R’)(R’’), -N(R’)C(=N(R/))N(R')(R"), - C=NN(R')(R"), -C=NOR, -C(=N(R'))N(R')(R"), -OC(O)R, or -OC(O)N(R’)(R’’);
each R5 is independently -R, halogen, -OR, -SR, -N(R’)(R’’), -CN, -NO2, -C(O)R, - C(S)R, -CO2R, -C(O)N(R’)(R’’), -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)(R’’), - C(S)OR, -S(O)R, -SO2R, -SO2N(R’)(R’’), -N(R’)C(O)R, -N(R’)C(O)N(R’)(R’’), - N(R’)C(S)N(R’)(R’’), -N(R’)SO2R, -N(R’)SO2N(R’)(R’’), -N(R’)N(R’)(R’’), - N(R’)C(=N(R’))N(R’)(R’’), -C=NN(R’)(R’’), -C=NOR, -C(=N(R’))N(R’)(R’’), -OC(O)R, or - OC(O)N(R’)(R’’);
n is 0-5;
each q is independently 0, 1, or 2; and
p is 1-6;
XIII)
Figure imgf000273_0001
Formula XX,
Figure imgf000273_0002
Formula YY,
wherein:
Ring A is benzo, or a 5-6 membered fused heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
Ring B is a 3-7 membered saturated or partially unsaturated carbocyclic ring, phenyl, an 8-10 membered bicyclic saturated, partially unsaturated, phenyl or naphthyl ring, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
L1 is a covalent bond or an optionally substituted bivalent C1-6 hydrocarbon chain wherein one or two methylene units is optionally replaced by–NR’-, -N(R’)C(O)-, - C(O)N(R’), -N(R’)SO2-, -SO2N(R’), -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO2-;
R1 is hydrogen, halogen, optionally substituted C1-6 aliphatic, -OR, -SR, -CN, -N(R’)2, - C(O)R, -C(S)R, -CO2R, -C(O)N(R’)2, -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)2, - C(S)OR, -S(O)R, -SO2R, -SO2N(R’)2, -N(R’)C(O)R, -N(R’)C(O)N(R’)2, -N(R’)C(S)N(R’)2, - N(R’)SO2R, -N(R’)SO2N(R’)2, -N(R’)N(R’)2, -N(R’)C(=N(R’))N(R’)2, -C=NN(R’)2, -C=NOR, -C(=N(R’))N(R’)2, -OC(O)R, -OC(O)N(R’)2, or -(CH2)pRx;
p is 0-3;
Rx is halogen, optionally substituted C1-6 aliphatic, -OR, -SR, -CN, -N(R’)2, -C(O)R, - C(S)R, -CO2R, -C(O)N(R’)2, -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)2, -C(S)OR, -S(O)R, -SO2R, -SO2N(R’)2, -N(R’)C(O)R, -N(R’)C(O)N(R’)2, -N(R’)C(S)N(R’)2, - N(R’)SO2R, -N(R’)SO2N(R’)2, -N(R’)N(R’)2, -N(R’)C(=N(R’))N(R’)2, -C=NN(R’)2, -C=NOR, -C(=N(R’))N(R’)2, -OC(O)R, -OC(O)N(R’)2;
R2 is hydrogen, halogen, -CN, -SR, or optionally substituted C1-6 aliphatic, or:
R1 and R2 are taken together with their intervening atoms to form an optionally substituted 3-7 membered saturated or partially unsaturated spiro-fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 7-10 membered bicyclic saturated, partially unsaturated, phenyl or naphthyl ring, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms
independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each R’ is independently -R, -C(O)R, -C(S)R, -CO2R, -C(O)N(R)2, -C(S)N(R)2, - S(O)R, -SO2R, -SO2N(R)2, or two R’ on the same nitrogen are taken together with their intervening atoms to form an optionally substituted group selected from a 4-7 membered monocyclic saturated or partially unsaturated ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 7-12 membered bicyclic saturated, partially unsaturated, or aromatic fused ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; W is , , or ;
R3 is optionally substituted C1-6 aliphatic; X is oxygen or sulfur, or:
R3 and X are taken together with their intervening atoms to form an optionally substituted
5-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each of m and n is independently 0-4, as valency permits; and
each of R4 and R5 is independently -R, halogen, -OR, -SR, -N(R’)2, -CN, -NO2, -C(O)R, -C(S)R, -CO2R, -C(O)N(R’)2, -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)2, - C(S)OR, -S(O)R, -SO2R, -SO2N(R’)2, -N(R’)C(O)R, -N(R’)C(O)N(R’)2, -N(R’)C(S)N(R’)2, - N(R’)SO2R, -N(R’)SO2N(R’)2, -N(R’)N(R’)2, -N(R’)C(=N(R’))N(R’)2, -C=NN(R’)2, -C=NOR, -C(=N(R’))N(R’)2, -OC(O)R, or -OC(O)N(R’)2;
XIV)
Figure imgf000275_0001
Formula ZZ,
wherein:
Ring A is benzo, or a 5-6 membered fused heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
Ring B is a 3-7 membered saturated or partially unsaturated carbocyclic ring, phenyl, an 8-10 membered bicyclic saturated, partially unsaturated, phenyl or naphthyl ring, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
L1 is a covalent bond or an optionally substituted bivalent C1-6 hydrocarbon chain wherein one or two methylene units is optionally replaced by–NR’-, -N(R’)C(O)-, - C(O)N(R’), -N(R’)SO2-, -SO2N(R’), -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO2-;
R1 is hydrogen, halogen, optionally substituted C1-6 aliphatic, -OR, -SR, -CN, -N(R’)2, - C(O)R, -C(S)R, -CO2R, -C(O)N(R’)2, -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)2, - C(S)OR, -S(O)R, -SO2R, -SO2N(R’)2, -N(R’)C(O)R, -N(R’)C(O)N(R’)2, -N(R’)C(S)N(R’)2, - N(R’)SO2R, -N(R’)SO2N(R’)2, -N(R’)N(R’)2, -N(R’)C(=N(R’))N(R’)2, -C=NN(R’)2, -C=NOR, -C(=N(R’))N(R’)2, -OC(O)R, -OC(O)N(R’)2, or -(CH2)pRx;
p is 0-3;
Rx is halogen, optionally substituted C1-6 aliphatic, -OR, -SR, -CN, -N(R’)2, -C(O)R, - C(S)R, -CO2R, -C(O)N(R’)2, -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)2, -C(S)OR, -S(O)R, -SO2R, -SO2N(R’)2, -N(R’)C(O)R, -N(R’)C(O)N(R’)2, -N(R’)C(S)N(R’)2, - N(R’)SO2R, -N(R’)SO2N(R’)2, -N(R’)N(R’)2, -N(R’)C(=N(R’))N(R’)2, -C=NN(R’)2, -C=NOR, -C(=N(R’))N(R’)2, -OC(O)R, -OC(O)N(R’)2;
R2 is a bond or optionally substituted C1-6 aliphatic, or:
R1 and R2 are taken together with their intervening atoms to form an optionally substituted 3-7 membered saturated or partially unsaturated spiro-fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 7-10 membered bicyclic saturated, partially unsaturated, phenyl, or naphthyl ring, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms
independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each R’ is independently -R, -C(O)R, -C(S)R, -CO2R, -C(O)N(R)2, -C(S)N(R)2, - S(O)R, -SO2R, -SO2N(R)2, or two R’ on the same nitrogen are taken together with their intervening atoms to form an optionally substituted group selected from a 4-7 membered monocyclic saturated or partially unsaturated ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 7-12 membered bicyclic saturated, partially unsaturated, or aromatic fused ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; W is , , or ;
R3 is optionally substituted C1-6 aliphatic; X is oxygen or sulfur, or:
R3 and X are taken together with their intervening atoms to form an optionally substituted
5-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each of m and n is independently 0-4, as valency permits; and
each of R4 and R5 is independently–R, halogen, -OR, -SR, -N(R’)2, -CN, -NO2, - C(O)R, -C(S)R, -CO2R, -C(O)N(R’)2, -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)2, - C(S)OR, -S(O)R, -SO2R, -SO2N(R’)2, -N(R’)C(O)R, -N(R’)C(O)N(R’)2, -N(R’)C(S)N(R’)2, - N(R’)SO2R, -N(R’)SO2N(R’)2, -N(R’)N(R’)2, -N(R’)C(=N(R’))N(R’)2, -C=NN(R’)2, -C=NOR, -C(=N(R’))N(R’)2, -OC(O)R, or -OC(O)N(R’)2;
XV)
Figure imgf000277_0001
Formula YYA, and
Figure imgf000277_0002
Formula ZZA,
wherein:
Ring A is benzo, or a 5-6 membered fused heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
Ring B is a 3-7 membered saturated or partially unsaturated carbocyclic ring, phenyl, an 8-10 membered bicyclic saturated, partially unsaturated, phenyl, or naphthyl ring, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
L1 is a covalent bond or an optionally substituted bivalent C1-6 hydrocarbon chain wherein one or two methylene units is optionally replaced by–NR’-, -N(R’)C(O)-, - C(O)N(R’), -N(R’)SO2-, -SO2N(R’), -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO2-;
R1 is independently hydrogen, halogen, optionally substituted C1-6 aliphatic, -OR, -SR, - CN, -N(R’)2, -C(O)R, -C(S)R, -CO2R, -C(O)N(R’)2, -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)2, -C(S)OR, -S(O)R, -SO2R, -SO2N(R’)2, -N(R’)C(O)R, -N(R’)C(O)N(R’)2, - N(R’)C(S)N(R’)2, -N(R’)SO2R, -N(R’)SO2N(R’)2, -N(R’)C(=N(R’))N(R’)2, -C=NN(R’)2, - C=NOR, -C(=N(R’))N(R’)2, -OC(O)R, -OC(O)N(R’)2, or -(CH2)pRx;
p is 0-3;
Rx is halogen, optionally substituted C1-6 aliphatic, -OR, -SR, -CN, -N(R’)2, -C(O)R, - C(S)R, -CO2R, -C(O)N(R’)2, -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)2, -C(S)OR, -S(O)R, -SO2R, -SO2N(R’)2, -N(R’)C(O)R, -N(R’)C(O)N(R’)2, -N(R’)C(S)N(R’)2, - N(R’)SO2R, -N(R’)SO2N(R’)2, -N(R’)N(R’)2, -N(R’)C(=N(R’))N(R’)2, -C=NN(R’)2, -C=NOR, -C(=N(R’))N(R’)2, -OC(O)R, -OC(O)N(R’)2;
R2 is a bond, hydrogen, or optionally substituted C1-6 aliphatic;
each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 7-10 membered bicyclic saturated, partially unsaturated, phenyl, or naphthyl ring, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms
independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each R’ is independently -R, -C(O)R, -C(S)R, -CO2R, -C(O)N(R)2, -C(S)N(R)2, - S(O)R, -SO2R, -SO2N(R)2, or two R’ on the same nitrogen are taken together with their intervening atoms to form an optionally substituted group selected from a 4-7 membered monocyclic saturated or partially unsaturated ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 7-12 membered bicyclic saturated, partially unsaturated, or aromatic fused ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
W is C or N;
R3 is optionally substituted C1-6 aliphatic;
is a single or double bond;
each of m and n is independently 0-4, as valency permits; and
each of R4 and R5 is independently–R, halogen, -OR, -SR, -N(R’)2, -CN, -NO2, - C(O)R, -C(S)R, -CO2R, -C(O)N(R’)2, -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R’)2, - C(S)OR, -S(O)R, -SO2R, -SO2N(R’)2, -N(R’)C(O)R, -N(R’)C(O)N(R’)2, -N(R’)C(S)N(R’)2, - N(R’)SO2R, -N(R’)SO2N(R’)2, -N(R’)N(R’)2, -N(R’)C(=N(R’))N(R’)2, -C=NN(R’)2, -C=NOR, -C(=N(R’))N(R’)2, -OC(O)R, or -OC(O)N(R’)2;
XVI)
Formul
Figure imgf000279_0001
la AA3,
wherein:
X is selected from N and CH;
Y is CO;
R1 and R3 are each independently selected from alkoxy and hydrogen;
R2 is selected from alkoxy, alkyl, and hydrogen;
R6 and R8 are each independently selected from alkyl, alkoxy, chloride, and hydrogen; R5 and R9 are each hydrogen;
R7 is selected from amino, hydroxyl, alkoxy, and alkyl substituted with a heterocyclyl; R10 is hydrogen; or two adjacent substituents selected from R6, R7, and R8 are connected to form a heterocyclyl;
each W is independently selected from C and N, wherein if W is N, then p is 0 or 1, and if W is C, then p is 1;
for W-(R10)p, W is N and p is 1; and
for W-(R4)p, W is C, p is 1 and R4 is H, or W is N and p is 0;
Figure imgf000280_0001
wherein:
Y and W are each independently selected from carbon and nitrogen;
Ra6 is selected from fluoride, hydrogen, C1-C3 alkoxy, cyclopropyloxy, SO2R3, SOR3, and SR3, wherein if Y is nitrogen then Ra6 is absent;
Ra7 is selected from hydrogen, fluoride, SO2R3, SOR3, and SR3;
Ra8 is selected from hydrogen, C1-C3 alkoxy, cyclopropyloxy, chloride, and bromide;
n is selected from 1, 2, or 3;
D is selected from O, NH, NR1, S, or C;
Rb3 and Rb5 are independently selected from hydrogen and C1-C3 alkyl; R 3
C and R 5
C are independently selected from hydrogen, C1-C3 alkyl, and
cyclopropyl;
R 4
C is selected from F, Cl, Br, I, CF3, C1-C6 alkyl, C3-C6 cycloalkyl, NHC(O)R4,
NHSO2R4, C(O)OR4, and
Figure imgf000280_0002
; R1, R’1, R2 and R’2 are independently selected from hydrogen, fluoride, C1-C3 alkyl, and cyclopropyl, wherein R1 and R2 and/or R’1 and R’2 may be connected to form a 3-6 membered ring;
R3 is selected from C1-C3 alkyl and cyclopropyl; and
R4 is selected from hydrogen, C1-C4 alkyl, C3-C5 cycloalkyl, phenyl, and naphthyl, rovided that if Ra7 or Ra6 is fluoride, then R 4
C is not bromide;
Figure imgf000281_0001
wherein:
Q and V are independently selected from CH and nitrogen;
U is selected from C=O, C=S, SO2, S=O, SR1, CR1R2, CR1OR2, CR1SR2; R1 and R2 are independently selected from hydrogen and C1-C6 alkyl;
Rc is selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl;
Ra1, Ra2, and Ra3 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 alkoxy, halogen, amino, amide, hydroxyl, heterocycle, and C3-C6 cycloalkyl, wherein Ra1 and Ra2 and/or Ra2 and Ra3 may be connected to form a cycloalkyl or a heterocycle;
Rb2 and Rb6 are independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkenyl, C3-C6 cycloalkyl, hydroxyl, and amino;
Rb3 and Rb5 are independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, hydroxyl, and amino, wherein Rb2 and Rb3 and/or Rb5 and Rb6 may be connected to form a cycloalkyl or a heterocycle;
Figure imgf000282_0001
represents a 3-8 membered ring system wherein: W is selected from carbon and nitrogen; Z is selected from CR6R7, NR8, oxygen, sulfur, -S(O)-, and -SO2-;
said ring system being optionally fused to another ring selected from cycloalkyl, heterocycle, and phenyl, and wherein said ring system is optionally selected from rings having the structures:
Figure imgf000282_0002
, , , , , and ; R3, R4, and R5 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, phenyl, naphthyl, phenoxy, hydroxy1, amino, amide, oxo, -CN, and sulfonamide;
R6 and R7 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C3-C6 cycloalkyl, phenyl, naphthyl, halogen, hydroxyl, -CN, amino, and amido; and R8 is selected from hydrogen, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, acyl, and C3-C6 cycloalkyl; and
R9, R10, R11, and R12 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C3-C6 cycloalkyl, phenyl, naphthyl, heterocycle, hydroxyl, sulfonyl, and acyl; XIX)
Figure imgf000283_0001
Formula GG,
wherein:
Q is selected from N and CRa3;
V is selected from N and CRa4;
W is selected from N and CH;
U is selected from C=O, C=S, SO2, S=O, and SR1;
X is selected from OH, SH, NH2, S(O)H, S(O)2H, S(O)2NH2, S(O)NH2, NHAc, and NHSO2Me;
Ra1, Ra3, and Ra3 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and halogen;
Ra2 is selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, amino, amide, and halogen;
Rb2 and Rb6 are independently selected from hydrogen, methyl and fluorine;
Rb3 and Rb5 are independently selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, and C1-C6 alkoxy; and
Rb2 and Rb3 and/or Rb5 and Rb6 may be connected to form a cycloalkyl or a heterocycle, provided that at least one of Ra1, Ra2, Ra3, and Ra4 is not hydrogen;
XX)
Figure imgf000283_0002
Formula HH,
wherein:
Q is selected from N and CRa3;
V is selected from N and CRa4;
W is selected from N and CH;
U is selected from C=O, C=S, SO2, S=O, and SR1; X is selected from OH, SH, NH2, S(O)H, S(O)2H, S(O)2NH2, S(O)NH2, NHAc, and NHSO2Me;
Ra1, Ra3, and Ra3 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and halogen;
Ra2 is selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, amino, amide, and halogen;
Rb2 and Rb6 are independently selected from hydrogen, methyl and fluorine;
Rb3 and Rb5 are independently selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, and C1-C6 alkoxy; and
Rb2 and Rb3 and/or Rb5 and Rb6 may be connected to form a cycloalkyl or a heterocycle, provided that at least one of Ra1, Ra2, Ra3, and Ra4 is not hydrogen;
,
Figure imgf000284_0001
wherein:
V is independently selected, for each occurrence, from the group consisting of NH, S, N(C1-6alkyl), O, or CR4R4;
Q is independently selected, for each occurrence, from the group consisting of C(O), C(S), C(N), SO2, or CR4R4;
U is independently selected from the group consisting of a bond, C(O), C(S), C(N), SO2, or CR4R4
W and T are independently selected from the group consisting of NH, N(C1- 6alkyl), O, or Q;
VC is selected from the group consisting of N, SH or CR4;
A is selected from the group consisting of aliphatic, cycloalkyl, heterocyclic, phenyl, naphthyl, heteroaryl or bicyclic moiety, wherein the cycloalkyl, heterocyclic, phenyl, naphthyl, heteroaryl, or bicyclic moiety is optionally substituted with one, two, three, four or more groups represented by R4;
R1 is independently selected, for each occurrence, from the group consisting of hydroxyl, halo, C1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl,
Figure imgf000285_0001
haloC1-6alkoxy, acylaminoC1-6alkyl, nitro, cyano, CF3, -OCF3, -C(O)OC1- 6alkyl, -OS(O)2C1-4alkyl, phenyl, naphthyl, phenyloxy, benzyloxy, or phenylmethoxy, wherein C1-6alkyl, phenyl, and naphthyl are optionally substituted by one two or three substituents selected from the group consisting of hydroxyl, halogen, oxo,
Figure imgf000285_0002
amino, or nitro;
R2 is selected from the group consisting of -O-, amino, C1-6alkyl, -O-C1-6alkyl-, hydroxylC1-6alkyl, aminoC1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, acylaminoC1-6alkyl, - C(O)-, -C(O)O-, -C(O)NC1-6alkyl-, -OS(O)2C1-4alkyl-, -OS(O)2-, -S-C1-6alkyl-, phenyl, naphthyl, phenyloxy, benzyloxy, or phenylmethoxy, wherein C1-6alkyl, phenyl, and naphthyl are optionally substituted by one two or three substituents selected from the group consisting of hydroxyl, halogen, oxo, C1-6alkyl, amino, or nitro;
R3 is selected from the group consisting of hydrogen or C1-6alkyl;
R4 is independently selected, for each occurrence, from the group consisting of hydrogen, hydroxyl, oxo, imino, amino, halo,
Figure imgf000285_0003
cycloalkyl, phenyl, naphthyl, heterocyclyl, -O-C1-6alkyl, -NH-C1-6alkyl, -N(C1-6alkyl)C1-6alkyl, nitro, cyano, CF3, - OCF3, -C(O)OC1-6alkyl, -C(O)NHC1-6alkyl, -C(O)NH2 or -OS(O)2C1-4alkyl;
m is selected from the group consisting of 0, 1, 2, or 3;
n is selected from the group consisting of 0, 1, or 2; and p is selected from the group consisting of 0 or 1;
Figure imgf000285_0004
wherein:
V is independently selected, for each occurrence, from the group consisting of NH, S, N(C1-6alkyl), O, or CR4R4;
Q is independently selected, for each occurrence, from the group consisting of C(O), C(S), C(N), SO2, or CR4R4;
U is independently selected from the group consisting of a bond, C(O), C(S), C(N), SO2, or CR4R4
W and T are independently selected from the group consisting of NH, N(C1-6alkyl), O, or Q;
VC is selected from the group consisting of N, SH or CR4;
A is selected from the group consisting of aliphatic, cycloalkyl, heterocyclic, phenyl, naphthyl, heteroaryl or bicyclic moiety, wherein the cycloalkyl, heterocyclic, phenyl, naphthyl, heteroaryl, or bicyclic moiety is optionally substituted with one, two, three, four or more groups represented by R4;
R1 is independently selected, for each occurrence, from the group consisting of hydroxyl, halo, C1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl,
Figure imgf000286_0001
C1-6alkoxy, haloC1- 6alkoxy, acylaminoC1-6alkyl, nitro, cyano, CF3, -OCF3, -C(O)OC1-6alkyl, -OS(O)2C1-4alkyl, phenyl, naphthyl, phenyloxy, benzyloxy, or phenylmethoxy, wherein C1-6alkyl, phenyl, and naphthyl are optionally substituted by one two or three substituents selected from the group consisting of hydroxyl, halogen, oxo, C1-6alkyl, amino, or nitro;
R2 is selected from the group consisting of -O-, amino, C1-6alkyl, -O-C1-6alkyl-, hydroxylC1-6alkyl, aminoC1-6alkyl, haloC1-6alkyl,
Figure imgf000286_0002
acylaminoC1-6alkyl, -C(O)-, - C(O)O-, -C(O)NC1-6alkyl-, -OS(O)2C1-4alkyl-, -OS(O)2-, -S-C1-6alkyl-, phenyl, naphthyl, phenyloxy, benzyloxy, or phenylmethoxy, wherein C1-6alkyl, phenyl, and naphthyl are optionally substituted by one two or three substituents selected from the group consisting of hydroxyl, halogen, oxo, C1-6alkyl, amino, or nitro;
R3 is selected from the group consisting of hydrogen or C1-6alkyl;
R4 is independently selected, for each occurrence, from the group consisting of hydrogen, hydroxyl, oxo, imino, amino, halo, C1-6alkyl, cycloalkyl, phenyl, naphthyl, heterocyclyl, -O-C1-6alkyl, -NH-C1-6alkyl, -N(C1-6alkyl)C1-6alkyl, nitro, cyano, CF3, - OCF3, -C(O)OC1-6alkyl, -C(O)NHC1-6alkyl, -C(O)NH2 or -OS(O)2C1-4alkyl;
m is selected from the group consisting of 0, 1, 2, or 3;
n is selected from the group consisting of 0, 1, or 2; and p is selected from the group consisting of 0 or 1;
Figure imgf000287_0001
XXIII) 1b and 2b ;
wherein:
V is selected from the group consisting of a NH, S, N(C1-6alkyl), O, or CR4R4;
Q is selected from the group consisting of a bond, C(O), C(S), C(N), SO2, or CR4R4; A is a ring selected from the group consisting of: phenyl, a 5-6 membered cycloalkyl, a 5-6 membered heteroaryl having 1, 2 or 3 heteroatoms each selected from S, N or O, and a 4-7 membered heterocycle having 1, 2 or 3 heteroatoms each selected from N or O;
RA1 is R1; or two RA1 substituents may be taken together with the atoms to which they are attached to form phenyl, a 5-6 membered heteroaryl having 1, 2 or 3 heteroatoms each selected from S, N or O, and a 4-7 membered heterocycle having 1, 2 or 3 heteroatoms each selected from N or O;
R1 is independently selected, for each occurrence, from the group consisting of hydroxyl, halo, C1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl, haloC1-6alkyl, C1-6alkoxy, haloC1- 6alkoxy, acylaminoC1-6alkyl, nitro, cyano, CF3, -OCF3, -C(O)OC1-6alkyl, -OS(O)2C1- 4alkyl, -S(C1-4alkyl)C(O)R’, phenyl, naphthyl, phenyloxy, benzyloxy, or phenylmethoxy, wherein C1-6alkyl, phenyl, and napththyl are optionally substituted by one two or three substituents selected from the group consisting of hydroxyl, halogen, oxo, C1-6alkyl, amino, or nitro;
R2 is selected from the group consisting of -O-, amino, C1-6alkyl, -O-C1-6alkyl-, hydroxylC1-6alkyl, aminoC1-6alkyl, haloC1-6alkyl,
Figure imgf000287_0002
acylaminoC1-6alkyl, -C(O)-, - C(O)O-, -C(O)NC1-6alkyl-, -OS(O)2C1-4alkyl-, -OS(O)2--S(C1-4alkyl)C(O)R’’-, -S-C1-6alkyl-, phenyl, naphthyl, phenyloxy, benzyloxy, or phenylmethoxy, wherein C1-6alkyl, phenyl, and naphthyl are optionally substituted by one two or three substituents selected from the group consisting of hydroxyl, halogen, oxo, C1-6alkyl, amino, or nitro;
R3 is selected from the group consisting of hydrogen or C1-6alkyl;
R4 is independently selected, for each occurrence, from the group consisting of hydrogen, hydroxyl, oxo, imino, amino, halo, C1-6alkyl, cycloalkyl, phenyl, naphthyl, heterocyclyl, -O-C1-6alkyl, -NH-C1-6alkyl, -N(C1-6alkyl)C1-6alkyl, nitro, cyano, CF3, - OCF3, -C(O)OC1-6alkyl, -C(O)NHC1-6alkyl, -C(O)NH2 or -OS(O)2C1-4alkyl;
R’ is independently selected, for each occurrence, from the group consisting of hydroxyl, amino, thio, phenyl, naphthyl, or C1-6alkyl, wherein C1-6alkyl, phenyl, and naphthyl are optionally substituted by one two or three substituents selected from the group consisting of hydroxyl, halogen, oxo, C1-6alkyl, amino, or nitro;
R’’ is independently selected, for each occurrence, from the group consisting of–O-, amino, thio, phenyl, naphthyl, or C1-6alkyl, wherein C1-6alkyl, phenyl, and naphthyl are optionally substituted by one two or three substituents selected from the group consisting of hydroxyl, halogen, oxo, C1-6alkyl, amino, or nitro;
m is independently selected, for each occurrence, from the group consisting of 0, 1, 2, or 3;
n is selected from the group consisting of 0, 1, or 2; and
is selected from the rou consistin of 0 or 1;
Figure imgf000288_0001
, ,
Figure imgf000289_0001
19 , and 20 ;
wherein:
L and LX are independently selected, for each occurrence, from the group consisting of N, CH, and CR1;
LN1 and LN2 are independently selected from the group consisting of CH2, CHR1, CR1R1, NH, and N(C1-6alkyl); wherein C1-6alkyl is optionally substituted by one two or three substituents selected from the group consisting of hydroxyl, halogen, oxo, C1-6alkyl, amino, or nitro;
LN3 is selected from the group consisting of O, S, NH, and N(C1-6alkyl); wherein C1- 6alkyl is optionally substituted by one two or three substituents selected from the group consisting of hydroxyl, halogen, oxo, C1-6alkyl, amino, or nitro;
U is independently selected from the group consisting of a bond, C(O), C(S), C(N), SO2, or CR4R4;
A is selected from the group consisting of aliphatic, cycloalkyl, heterocyclic, phenyl, naphthyl, heteroaryl, or bicyclic moiety, wherein the cycloalkyl, heterocyclic, phenyl, naphthyl, heteroaryl, or bicyclic moiety is optionally substituted with one, two, three, four or more groups represented by R4;
R1 is independently selected, for each occurrence, from the group consisting of hydroxyl, halo, C1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl,
Figure imgf000289_0002
C1-6alkoxy, haloC1- 6alkoxy, acylaminoC1-6alkyl, nitro, cyano, CF3, -OCF3, -C(O)OC1-6alkyl, -OS(O)2C1-4alkyl, phenyl, naphthyl, phenyloxy, benzyloxy, or phenylmethoxy, wherein C1-6alkyl, phenyl, and naphthyl are optionally substituted by one two or three substituents selected from the group consisting of hydroxyl, halogen, oxo, C1-6alkyl, amino, or nitro; R2 is selected from the group consisting of -O-, amino, C1-6alkyl, -O-C1-6alkyl-, hydroxylC1-6alkyl, aminoC1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, acylaminoC1-6alkyl, -C(O)-, - C(O)O-, -C(O)NC1-6alkyl-, -OS(O)2C1-4alkyl-, -OS(O)2-, -S-C1-6alkyl-, phenyl, naphthyl, phenyloxy, benzyloxy, or phenylmethoxy, wherein C1-6alkyl, phenyl, and naphthyl are optionally substituted by one two or three substituents selected from the group consisting of hydroxyl, halogen, oxo, C1-6alkyl, amino, or nitro;
R3 is selected from the group consisting of hydrogen or C1-6alkyl; and
R4 is independently selected, for each occurrence, from the group consisting of hydrogen, hydroxyl, oxo, imino, amino, halo, C1-6alkyl, cycloalkyl, phenyl, naphthyl, heterocyclyl, -O-C1-6alkyl, -NH-C1-6alkyl, -N(C1-6alkyl)C1-6alkyl, nitro, cyano, CF3, - OCF3, -C(O)OC1-6alkyl, -C(O)NHC1-6alkyl, -C(O)NH2 or -OS(O)2C1-4alkyl; and
XXV)
Figure imgf000290_0001
Formula KK wherein
Rx is hydrogen or C1-C3 alkyl;
RY is C1-C3 alkyl, -(C2-C3 alkylenyl)-OH, or C1-C3 haloalkyl;
X1 is N or CRx1 wherein
Rx1 is hydrogen, C2-C6 alkenyl, C2-C6 alkynyl, -C(O)ORax1, -C(O)NRbx1Rcx1, - C(O)Rdx1, S(O)2Rdx1, -S(O)2NRbx1Rcx1, Gx1, C1-C6 haloalkyl, or C1-C6 alkyl; wherein the C1-C6 alkyl is optionally substituted with one substituent selected from the group consisting of ORax1, SRax1, S(O)Rdx1, S(O)2Rdx1, NRbx1Rcx1, - C(O)Rax1, -C(O)ORax1, -C(O)NRbx1Rcx1, -S(O)2NRbx1Rcx1, and Gx1; Rax1, Rbx1, and Rcx1, at each occurrence, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, Ga, or -(C1-C6 alkylenyl)-Ga;
Rdx1, at each occurrence, are each independently C1-C6 alkyl, C1-C6 haloalkyl, Ga, or -(C1-C6 alkylenyl)-Ga; X2 is N or CRx2; wherein
Rx2 is hydrogen, C2-C6 alkenyl, C2-C6 alkynyl, -C(O)ORax2, -C(O)NRbx2Rcx2, - C(O)Rdx2, S(O)2Rdx2, -S(O)2NRbx2Rcx2, Gx2, C1-C6 haloalkyl, or C1-C6 alkyl; wherein the C1-C6 alkyl is optionally substituted with one substituent selected from the group consisting of ORax2, SRax2, S(O)Rdx2, S(O)2Rdx2, NRbx2Rcx2, - C(O)Rax2, -C(O)ORax2, -C(O)NRbx2Rcx2, -S(O)2NRbx2Rcx2, and Gx2; Rax2, Rbx2, and Rcx2, at each occurrence, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, Gb, or -(C1-C6 alkylenyl)-Gb;
Rdx2, at each occurrence, is independently C1-C6 alkyl, C1-C6 haloalkyl, Gb, or - (C1-C6 alkylenyl)-Gb;
Y1 is N or CRu; wherein Ru is hydrogen, C1-C6 alkyl, halogen, or C1-C6 haloalkyl; A1 is N or CR1, A2 is N or CR2, A3 is N or CR3, and A4 is N or CR4; with the proviso that zero, one, two, or three of A1, A2, A3, and A4 are N;
R1, R3, and R4 are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, CN, or NO2;
R2 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, - CN, NO2, G2a, -OR2a, -OC(O)R2d, -OC(O)NR2bR2c, -SR2a, -S(O)2R2d, -S(O)2NR2bR2c
, -C(O)R2d, -C(O)OR2a, -C(O)NR2bR2c, -NR2bR2c, -N(R2e)C(O)R2d, -N(R2e)S(O)2R2d, -N(R2e)C(O)O(R2d), - N(R2e)C(O)NR2bR2c, -N(R2e)S(O)2NR2bR2c, -(C1-C6 alkylenyl)-G2a, -(C1-C6 alkylenyl)-OR2a, - (C1-C6 alkylenyl)-OC(O)R2d, -(C1-C6 alkylenyl)-OC(O)NR2bR2c, -(C1-C6 alkylenyl)-S(O)2R2d, - (C1-C6
alkylenyl)-S(O)2NR2bR2c, -(C1-C6 alkylenyl)-C(O)R2d, -(C1-C6 alkylenyl)-C(O)OR2a, -(C1-C6 alkylenyl)-C(O)NR2bR2c, -(C1-C6 alkylenyl)-NR2bR2C, -(C1-C6 alkylenyl)-N(R2e)C(O)R2d, -(C1- C6
alkylenyl)-N(R2e)S(O)2R2d, -(C1-C6 alkylenyl)-N(R2e)C(O)O(R2a), -(C1-C6
alkylenyl)-N(R2e)C(O)NR2bR2c, -(C1-C6 alkylenyl)-N(R2e)S(O)2NR2bR2c, and -(C1-C6 alkylenyl)-CN;
R2a, R2b, R2C, and R2e, at each occurrence, are each independently hydrogen, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, G2b, or C1-C6 alkyl wherein the C1-C6 alkyl is optionally substituted with one substituent selected from the group consisting of -ORz1, NRz1Rz2, -C(O)ORz1, -C(O)NRz1Rz2, -S(O)2Rz1, -S(O)2NRz1Rz2, and G2b;
R2d, at each occurrence, is independently C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, G2b, or C1-C6 alkyl wherein the C1-C6 alkyl is optionally substituted with one substituent selected from the group consisting of -ORz1, NRz1Rz2, -C(O)ORz1, -C(O)NRz1Rz2, -S(O)2Rz1, - S(O)2NRz1Rz2, and G2b;
Rz1 and Rz2, at each occurrence, are each independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl;
Gx1, Gx2, Ga, Gb, G2a, and G2b, at each occurrence, are each independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl, and each of which is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 of Rv;
L1 is absent, CH2, C(O), C(H)(OH), (CH2)mO, (CH2)mS(O)n wherein n is 0, 1, or 2; or (CH2)mN(Rz) wherein Rz is hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, (C2-C3 alkylenyl)-OH, or unsubstituted cyclopropyl;
m is 0 or 1;
G1 is C1-C6 alkyl, alkoxyalkyl, G1a , or -(C1-C6 alkylenyl)-G1a; wherein each G1a is independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl, and each G1a is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 of Rw;
Rv and Rw, at each occurrence, are each independently C1-C6 alkyl, C2-C6 alkenyl, C2- C6 alkynyl, halogen, C1-C6 haloalkyl, -CN, oxo, -ORh, -OC(O)Ri -OC(O)NRjRk, -SRh, - S(O)2Rh, -S(O)2NRjRk, -C(O)Rh, -C(O)-monocyclic heterocycle, -C(O)-monocyclic heteroaryl, -C(O)ORh, -C(O)NRjRk, -NRjRk, -N(Rh)C(O)Ri, -N(Rh)S(O)2Ri, -N(Rh)C(O)O(Ri), - N(Rh)C(O)NRjRk, -(C1-C6 alkylenyl)-ORh, -(C1-C6 alkylenyl)-OC(O)Ri, -(C1-C6 alkylenyl)- OC(O)NRjRk, -(C1-C6 alkylenyl)-S(O)2Rh, -(C1-C6 alkylenyl)-S(O)2NRjRk, -(C1-C6 alkylenyl)- C(O)Rh, -(C1-C6 alkylenyl)-C(O)ORh, -(C1-C6 alkylenyl)-C(O)NRjRk, -(C1-C6 alkylenyl)- NRjRk, -(C1-C6 alkylenyl)-N(Rh)C(O)Ri, -(C1-C6 alkylenyl)-N(Rh)S(O)2Ri, -(C1-C6 alkylenyl)- N(Rh)C(O)O(Ri), -(C1-C6 alkylenyl)-N(Rh)C(O)NRjRk, or -(C1-C6 alkylenyl)-CN;
Rh, Rj, Rk, at each occurrence, are each independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; and
Ri, at each occurrence, is independently C1-C6 alkyl or C1-C6 haloalkyl; and
XXVI)
Figure imgf000293_0001
Formula MM,
or
Figure imgf000293_0002
Formula NN,
wherein:
R1 is optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted
heterocycloalkyl, haloalkyl, -C(O)R, -C(S)R, -CO2R, -C(O)N(R')(R"), -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R')(R"), -C(S)OR, -S(O)R, -SO2R, -SO2N(R')(R"), -C=NN(R')(R"), - C=NOR, or -C(=N(R'))N(R')(R");
R2 is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, haloalkyl, -C(O)R, -C(S)R, -CO2R, -C(O)N(R')(R"), - C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R')(R"), -C(S)OR, -S(O)R, -SO2R, - SO2N(R')(R"), -C=NN(R')(R"), -C=NOR, -C(=N(R'))N(R')(R"), or -(CH2)pRx; or R1 and R2 together with the atoms to which each is attached, forms an optionally substituted 3-7 membered saturated or unsaturated ring having 0-4 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R3 is H, alkyl, alkenyl, alkynyl, aralkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, or halo, each of which is optionally substituted; or CN, ORA, NRARB, N(RA)S(O)qRARB, N(RA)C(O)RB, N(RA)C(O)NRARB, N(RA)C(O)ORA, N(RA)C(S)NRARB, -N(RA)S(O)qNRARB, S(O)qRA, C(O)RA, C(O)ORA, OC(O)RA, or C(O)NRARB;
each RA is independently optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted heterocyclic;
optionally substituted carbocyclic; or hydrogen;
each RB is independently optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted heterocyclic;
optionally substituted carbocyclic; or hydrogen; or
RA and RB, together with the atoms to which each is attached, can form a
heterocycloalkyl or a heteroaryl; each of which is optionally substituted;
R5 is halogen, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, haloalkyl, -OR, -SR, -CN, - N(R')(R"), -C(O)R, -C(S)R, -CO2R, -C(O)N(R')(R"), -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R')(R"), -C(S)OR, -S(O)R, -SO2R, -SO2N(R')(R"), -N(R')C(O)R, - N(R')C(O)N(R')(R"), -N(R')C(S)N(R')(R"), -N(R')SO2R, -N(R')SO2N(R')(R"), - N(R')N(R')(R"), -N(R')C(=N(R'))N(R')(R"), -C=NN(R')(R"), -C=NOR, -C(=N(R'))N(R')(R"), - OC(O)R, -OC(O)N(R')(R"), or -(CH2)pRx;
each Rx is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, -OR, -SR, -CN, -N(R')(R"), -C(O)R, -C(S)R, -CO2R, - C(O)N(R')(R"), -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R')(R"), -C(S)OR, -S(O)R, - SO2R, -SO2N(R')(R"), -N(R')C(O)R, -N(R')C(O)N(R')(R"), -N(R')C(S)N(R')(R"), -N(R')SO2R, -N(R')SO2N(R')(R"), -N(R')N(R')(R"), -N(R')C(=N(R'))N(R')(R"), -C=NN(R')(R"), -C=NOR, - C(=N(R'))N(R')(R"), -OC(O)R, -OC(O)N(R')(R");
each R is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl;
each R' is independently -R, -C(O)R, -C(S)R, -CO2R, -C(O)N(R)2, -C(S)N(R)2, -S(O)R, -SO2R, -SO2N(R)2, or two R groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted heteroaryl or heterocycloalkyl group;
each R" is independently -R, -C(O)R, -C(S)R, -CO2R, -C(O)N(R)2, -C(S)N(R)2, - S(O)R, -SO2R, -SO2N(R)2, or two R groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted heteroaryl or heterocycloalkyl group; or R' and R", together with the atoms to which each is attached, can form a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl; each of which is optionally substituted;
each p is independently 1, 2, 3, 4, 5, or 6; and
each q is independently 0, 1, or 2.
12. The bivalent compound of any one of claims 1-11, wherein P1 and P2 are the same.
13. The bivalent compound of any one of claims 1-11, wherein P1 and P2 are different.
14. The bivalent compound of any one of claims 1-13, wherein P1 and P2 are each inde endentl selected from the rou consistin of:
Figure imgf000295_0001
15. The bivalent compound of any one of claims 1-13, wherein P1 and P2 are each independently selected from the group consisting of:
Figure imgf000296_0001
16. The bivalent compound of any one of claims 1-13, wherein P1 and P2 are each independently selected from the group consisting of:
Figure imgf000296_0002
18. The bivalent compound of any one of claims 1-13, wherein P1 and P2 are each independently selected from the group consisting of:
Figure imgf000297_0001
19. The bivalent compound of any one of claims 1-13, wherein P1 and P2 are each inde endentl selected from the rou consistin of:
Figure imgf000297_0002
20. The bivalent compound of any one of claims 1-19, wherein the first bromodomain and the second bromodomain are each independently associated with a protein selected from the group consisting of BRD2, BRD3, BRD4 and BRD-t.
21. The bivalent compound of claim 20, wherein the protein is a fusion gene product selected from BRD4-NUT or BRD3-NUT.
22. A bivalent compound selected from the group consisting of:
,
Figure imgf000298_0001
and pharmaceutically acceptable salts thereof, wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.
23. A bivalent com ound of the formula:
Figure imgf000299_0001
or a pharmaceutically acceptable salt, stereoisomer, metabolite, or hydrate thereof;
wherein:
Q1 is a connecting moiety covalently bound to P1 and P2, wherein Q1 is selected from the group consisting of -Si(R7)(R8)-, -Si(R7)(R8)-O-, -O-Si(R7)(R8)-, -NR’-, -N(R’)C(O)-, - C(O)N(R’)-, -N(R’)SO2-, -SO2N(R’)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO-, -SO2-, - C(=S)-, -C(=NR’)-, aliphatic, heteroaliphatic, phenyl, naphthyl, heterocyclyl, heteroaryl, and covalently bonded combinations thereof;
wherein:
R7 and R8 are selected, independently for each occurrence, from the group consisting of -OH, C1-6alkyl, -O-C1-6alkyl, C2-6alkenyl, C3-6cycloalkyl, -C1-6alkyl- NRaRb, phenyl and heteroaryl; wherein C1-6alkyl, C2-6alkenyl, C3-6cycloalkyl, phenyl, and heteroaryl may be optionally substituted by one or more substituents independently selected from the group consisting of halogen, cyano, hydroxyl, C1-6alkyl, and phenyl; or
R7 and R8, together with the silicon to which they are attached, form a 4-7 membered heterocyclic ring, optionally containing one, two, three, or four heteroatoms independently selected from O, S, or N; wherein the 4-7 membered heterocyclic ring may be optionally substituted by one or more substituents independently selected from the group consisting of halogen, cyano, oxo, and hydroxyl; and
R’ is, independently for each occurrence, selected from the group consisting of hydrogen and C1-4alkyl; wherein C1-4alkyl may be optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo, and hydroxyl wherein:
P1 and P2 are independently selected from the group consisting of:
I)
Figure imgf000300_0001
Formula KK wherein
Rx is hydrogen or C1-C3 alkyl;
RY is C1-C3 alkyl, -(C2-C3 alkylenyl)-OH, or C1-C3 haloalkyl;
X1 is N or CRx1 wherein
Rx1 is hydrogen, C2-C6 alkenyl, C2-C6 alkynyl, -C(O)ORax1, -C(O)NRbx1Rcx1, - C(O)Rdx1, S(O)2Rdx1, -S(O)2NRbx1Rcx1, Gx1, C1-C6 haloalkyl, or C1-C6 alkyl; wherein the C1-C6 alkyl is optionally substituted with one substituent selected from the group consisting of ORax1, SRax1, S(O)Rdx1, S(O)2Rdx1, NRbx1Rcx1, - C(O)Rax1, -C(O)ORax1, -C(O)NRbx1Rcx1, -S(O)2NRbx1Rcx1, and Gx1; Rax1, Rbx1, and Rcx1, at each occurrence, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, Ga, or -(C1-C6 alkylenyl)-Ga;
Rdx1, at each occurrence, are each independently C1-C6 alkyl, C1-C6 haloalkyl, Ga, or -(C1-C6 alkylenyl)-Ga;
X2 is N or CRx2; wherein
Rx2 is hydrogen, C2-C6 alkenyl, C2-C6 alkynyl, -C(O)ORax2, -C(O)NRbx2Rcx2, - C(O)Rdx2, S(O)2Rdx2, -S(O)2NRbx2Rcx2, Gx2, C1-C6 haloalkyl, or C1-C6 alkyl; wherein the C1-C6 alkyl is optionally substituted with one substituent selected from the group consisting of ORax2, SRax2, S(O)Rdx2, S(O)2Rdx2, NRbx2Rcx2, - C(O)Rax2, -C(O)ORax2, -C(O)NRbx2Rcx2, -S(O)2NRbx2Rcx2, and Gx2; Rax2, Rbx2, and Rcx2, at each occurrence, are each independently hydrogen, C1-C6 alkyl, C b
1-C6 haloalkyl, Gb, or -(C1-C6 alkylenyl)-G ;
Rdx2, at each occurrence, is independently C1-C6 alkyl, C1-C6 haloalkyl, Gb, or - (C1-C6 alkylenyl)-Gb;
Y1 is N or CRu; wherein Ru is hydrogen, C1-C6 alkyl, halogen, or C1-C6 haloalkyl; A1 is N or CR1, A2 is N or CR2, A3 is N or CR3, and A4 is N or CR4; with the proviso that zero, one, two, or three of A1, A2, A3, and A4 are N;
R1, R3, and R4 are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, CN, or NO2;
R2 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, - CN, NO2, G2a, -OR2a, -OC(O)R2d, -OC(O)NR2bR2c, -SR2a, -S(O)2R2d, -S(O)2NR2bR2c
, -C(O)R2d, -C(O)OR2a, -C(O)NR2bR2c, -NR2bR2c, -N(R2e)C(O)R2d, -N(R2e)S(O)2R2d, -N(R2e)C(O)O(R2d), - N(R2e)C(O)NR2bR2c, -N(R2e)S(O)2NR2bR2c, -(C1-C6 alkylenyl)-G2a, -(C1-C6 alkylenyl)-OR2a, - (C1-C6 alkylenyl)-OC(O)R2d, -(C1-C6 alkylenyl)-OC(O)NR2bR2c, -(C1-C6 alkylenyl)-S(O)2R2d, - (C1-C6
alkylenyl)-S(O)2NR2bR2c, -(C1-C6 alkylenyl)-C(O)R2d, -(C1-C6 alkylenyl)-C(O)OR2a, -(C1-C6 alkylenyl)-C(O)NR2bR2c, -(C1-C6 alkylenyl)-NR2bR2C, -(C1-C6 alkylenyl)-N(R2e)C(O)R2d, -(C1- C6
alkylenyl)-N(R2e)S(O)2R2d, -(C1-C6 alkylenyl)-N(R2e)C(O)O(R2a), -(C1-C6
alkylenyl)-N(R2e)C(O)NR2bR2c, -(C1-C6 alkylenyl)-N(R2e)S(O)2NR2bR2c, and -(C1-C6 alkylenyl)-CN;
R2a, R2b, R2C, and R2e, at each occurrence, are each independently hydrogen, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, G2b, or C1-C6 alkyl wherein the C1-C6 alkyl is optionally substituted with one substituent selected from the group consisting of -ORz1, NRz1Rz2, -C(O)ORz1, -C(O)NRz1Rz2, -S(O)2Rz1, -S(O)2NRz1Rz2, and G2b;
R2d, at each occurrence, is independently C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, G2b, or C1-C6 alkyl wherein the C1-C6 alkyl is optionally substituted with one substituent selected from the group consisting of -ORz1, NRz1Rz2, -C(O)ORz1, -C(O)NRz1Rz2, -S(O)2Rz1, - S(O)2NRz1Rz2, and G2b;
Rz1 and Rz2, at each occurrence, are each independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl;
Gx1, Gx2, Ga, Gb, G2a, and G2b, at each occurrence, are each independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl, and each of which is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 of Rv;
L1 is absent, CH2, C(O), C(H)(OH), (CH2)mO, (CH2)mS(O)n wherein n is 0, 1, or 2; or (CH2)mN(Rz) wherein Rz is hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, (C2-C3 alkylenyl)-OH, or unsubstituted cyclopropyl;
m is 0 or 1; G1 is C1-C6 alkyl, alkoxyalkyl, G1a , or -(C1-C6 alkylenyl)-G1a; wherein each G1a is independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl, and each G1a is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 of Rw;
Rv and Rw, at each occurrence, are each independently C1-C6 alkyl, C2-C6 alkenyl, C2- C6 alkynyl, halogen, C1-C6 haloalkyl, -CN, oxo, -ORh, -OC(O)Ri -OC(O)NRjRk, -SRh, - S(O)2Rh, -S(O)2NRjRk, -C(O)Rh, -C(O)-monocyclic heterocycle, -C(O)-monocyclic heteroaryl, -C(O)ORh, -C(O)NRjRk, -NRjRk, -N(Rh)C(O)Ri, -N(Rh)S(O)2Ri, -N(Rh)C(O)O(Ri), - N(Rh)C(O)NRjRk, -(C1-C6 alkylenyl)-ORh, -(C1-C6 alkylenyl)-OC(O)Ri, -(C1-C6 alkylenyl)- OC(O)NRjRk, -(C1-C6 alkylenyl)-S(O)2Rh, -(C1-C6 alkylenyl)-S(O)2NRjRk, -(C1-C6 alkylenyl)- C(O)Rh, -(C1-C6 alkylenyl)-C(O)ORh, -(C1-C6 alkylenyl)-C(O)NRjRk, -(C1-C6 alkylenyl)- NRjRk, -(C1-C6 alkylenyl)-N(Rh)C(O)Ri, -(C1-C6 alkylenyl)-N(Rh)S(O)2Ri, -(C1-C6 alkylenyl)- N(Rh)C(O)O(Ri), -(C1-C6 alkylenyl)-N(Rh)C(O)NRjRk, or -(C1-C6 alkylenyl)-CN;
Rh, Rj, Rk, at each occurrence, are each independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; and
a MM, or
Figure imgf000302_0001
wherein:
R1 is optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, haloalkyl, -C(O)R, -C(S)R, -CO2R, -C(O)N(R')(R"), -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R')(R"), -C(S)OR, -S(O)R, -SO2R, -SO2N(R')(R"), -C=NN(R')(R"), - C=NOR, or -C(=N(R'))N(R')(R");
R2 is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, haloalkyl, -C(O)R, -C(S)R, -CO2R, -C(O)N(R')(R"), - C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R')(R"), -C(S)OR, -S(O)R, -SO2R, - SO2N(R')(R"), -C=NN(R')(R"), -C=NOR, -C(=N(R'))N(R')(R"), or -(CH2)pRx; or R1 and R2 together with the atoms to which each is attached, forms an optionally substituted 3-7 membered saturated or unsaturated ring having 0-4 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R3 is H, alkyl, alkenyl, alkynyl, aralkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, or halo, each of which is optionally substituted; or CN, ORA, NRARB, N(RA)S(O)qRARB, N(RA)C(O)RB, N(RA)C(O)NRARB, N(RA)C(O)ORA, N(RA)C(S)NRARB, -N(RA)S(O)qNRARB, S(O)qRA, C(O)RA, C(O)ORA, OC(O)RA, or C(O)NRARB;
each RA is independently optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted heterocyclic;
optionally substituted carbocyclic; or hydrogen;
each RB is independently optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted heterocyclic;
optionally substituted carbocyclic; or hydrogen; or
RA and RB, together with the atoms to which each is attached, can form a
heterocycloalkyl or a heteroaryl; each of which is optionally substituted;
R5 is halogen, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, haloalkyl, -OR, -SR, -CN, - N(R')(R"), -C(O)R, -C(S)R, -CO2R, -C(O)N(R')(R"), -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R')(R"), -C(S)OR, -S(O)R, -SO2R, -SO2N(R')(R"), -N(R')C(O)R, - N(R')C(O)N(R')(R"), -N(R')C(S)N(R')(R"), -N(R')SO2R, -N(R')SO2N(R')(R"), - N(R')N(R')(R"), -N(R')C(=N(R'))N(R')(R"), -C=NN(R')(R"), -C=NOR, -C(=N(R'))N(R')(R"), - OC(O)R, -OC(O)N(R')(R"), or -(CH2)pRx;
each Rx is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, -OR, -SR, -CN, -N(R')(R"), -C(O)R, -C(S)R, -CO2R, - C(O)N(R')(R"), -C(O)SR, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)N(R')(R"), -C(S)OR, -S(O)R, - SO2R, -SO2N(R')(R"), -N(R')C(O)R, -N(R')C(O)N(R')(R"), -N(R')C(S)N(R')(R"), -N(R')SO2R, -N(R')SO2N(R')(R"), -N(R')N(R')(R"), -N(R')C(=N(R'))N(R')(R"), -C=NN(R')(R"), -C=NOR, - C(=N(R'))N(R')(R"), -OC(O)R, -OC(O)N(R')(R");
each R is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl;
each R' is independently -R, -C(O)R, -C(S)R, -CO2R, -C(O)N(R)2, -C(S)N(R)2, -S(O)R, -SO2R, -SO2N(R)2, or two R groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted heteroaryl or heterocycloalkyl group;
each R" is independently -R, -C(O)R, -C(S)R, -CO2R, -C(O)N(R)2, -C(S)N(R)2, - S(O)R, -SO2R, -SO2N(R)2, or two R groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted heteroaryl or heterocycloalkyl group; or R' and R", together with the atoms to which each is attached, can form a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl; each of which is optionally substituted;
each p is independently 1, 2, 3, 4, 5, or 6; and
each q is independently 0, 1, or 2.
24. A bivalent com ound of the formula:
Figure imgf000304_0001
or a pharmaceutically acceptable salt, stereoisomer, metabolite, or hydrate thereof;
wherein:
Q1 is a connecting moiety covalently bound to P1 and P2, wherein Q1 is selected from the group consisting of -Si(R7)(R8)-, -Si(R7)(R8)-O-, -O-Si(R7)(R8)-, -NR’-, -N(R’)C(O)-, - C(O)N(R’)-, -N(R’)SO2-, -SO2N(R’)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO-, -SO2-, - C(=S)-, -C(=NR’)-, aliphatic, heteroaliphatic, phenyl, naphthyl, heterocyclyl, heteroaryl, and covalently bonded combinations thereof;
wherein:
R7 and R8 are selected, independently for each occurrence, from the group consisting of -OH, C1-6alkyl, -O-C1-6alkyl, C2-6alkenyl, C3-6cycloalkyl, -C1-6alkyl- NRaRb, phenyl and heteroaryl; wherein C1-6alkyl, C2-6alkenyl, C3-6cycloalkyl, phenyl, and heteroaryl may be optionally substituted by one or more substituents independently selected from the group consisting of halogen, cyano, hydroxyl, C1-6alkyl, and phenyl; or
R7 and R8, together with the silicon to which they are attached, form a 4-7 membered heterocyclic ring, optionally containing one, two, three, or four heteroatoms independently selected from O, S, or N; wherein the 4-7 membered heterocyclic ring may be optionally substituted by one or more substituents independently selected from the group consisting of halogen, cyano, oxo, and hydroxyl; and
R’ is, independently for each occurrence, selected from the group consisting of hydrogen and C1-4alkyl; wherein
Figure imgf000305_0001
may be optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo, and hydroxyl wherein:
P1 is selected from the group consisting of:
and
Figure imgf000306_0001
wherein:
V is N or C-R2;
W is N or C-R8;
X is N, CH or C(CH3);
Y is N or C-R5;
Z is N or C-R15; Q is N or CH;
R1 is C1-4 alkyl;
R2, when present, is H, OH, C1-4alkyl, halo, -CF3, -NH2, -OC1-4alkyl, - NHC(O)H, -NHC(O)C1-4alkyl, -N(CH3)C(O)C1-4alkyl, -NHC(O)NH2, -NHC(O)C1- 4alkyleneNH2, -N(CH3)C(O)NH2, -N(CH3)C(O)C1-4alkyleneNH2, -NHC2- 4alkyleneOCH3, -N(CH3)C2-4alkyleneOCH3, -OC2-4alkyleneOCH3, -OC2-4alkyleneOH or
R2 is a group selected from -G-CH2CH(R3)(R4), -G-CH(R3)(R4) and -G-R3 in which G is NH, N(CH3), O, C(O)NH or NHC(O);
R3 is phenyl, pyridinyl, C3-7cycloalkyl or a heterocycle optionally substituted by =O; and R4 is H or C1-4 alkyl; -CF3, CN, OH, -OC1-4 alkyl, -CH2NH2, -OCF3, -SO2CH3, -C(O)NHC1-4alkyl or–CO2H;
R6 is–NR11R12 or a group
Figure imgf000307_0001
;
D is CH or N;
E is N, O, CH, or SO2;
R7, when present, is H, OH, C1-4alkyl, -NH2, -SO2C1-4alkyl, -SO2phenyl, - SO2benzyl, -SO2N(CH3)2, -NHSO2CH3, -C(O)C1-4alkyl, -C(O)phenyl;
R8, when present, is H, C1-4alkyl, halo, -CF3, CN, OH, -OC1-4alkyl, -OC2- 4alkyleneOC1-4alkyl, -OCF3 -OC1-4alkyleneF, -OC1-4alkyleneCHF2, -OC2-4alkyleneOH, -Ophenyl, -OC1-4alkylenephenyl, -NHC3-7cycloalkyl, -NHC1-4alkyleneC3-7cycloalkyl, - OC3-7cycloalkyl, -OC1-4alkyleneC3-7cycloalkyl, -NHC4-6heterocycle -NHC1- 4alkyleneC4-6heterocycle, -OC4-6heterocycle or -OC1-4alkyleneC4-6heterocycle wherein the C3-7cycloalkyl or the C4-6heterocycle are each optionally substituted by one or two substituents independently selected from halo, OH, oxo, C1-4alkyl and -NH2; or
R3 and R2 together with the carbon atoms to which they are attached, form a heterocycle optionally substituted by oxo; R9 is H, C1-4alkyl, -C(O)NH2, -CO2CH3, -CF3, halo, OH, -OC1-4alkyl, -CH2OH, - C(O)NHCH3, -C(O)NH(CH3)2, -CH2OC1-4alkyl or -CH2OCH2C3-7cycloalkyl;
R10 is H, C1-4alkyl, -C(O)NH2, -CO2CH3, -CF3, halo, OH, -OC1-4alkyl or oxo; R11 is H, C1-4alkyl or SO2CH3;
R12 is H, C1-4alkyl, C2-4alkyleneNHR13, SO2CH3, a heterocycle or a heterocycle comprising SO2; R13 is H or SO2CH3;
R14 is H or C1-4alkyl;
R15 is H, C1-4alkyl or NHC(O)C1-4alkyl;
R16 is H or C1-4alkyl; and
n and m are each an integer independently selected from 0, 1 and 2; and P2 is selected from the group consisting of:
Figure imgf000308_0001
, wherein:
R1 is C1-4alkyl;
R2 is C1-4alkyl, C3-7cycloalkyl, -CH2CF3, -CH2OCH3 or heterocyclyl;
R3 is C1-4alkyl, -CH2F, -CH2OH or -CH2OC(O)CH3;
R4 when present is H, hydroxy, halo, cyano, -CO2H, -CONH2, -OSO2CF3, - C(O)N(R8) C1-4alkyleneOH, -C(O)N(R8)C1-4alkyleneOCH3, -C(O)N(R8)C1- 4alkyleneNR6R7, -C(O)N(R8)C1-4alkyleneSO2CH3, -C(O)N(R8)C1-4alkyleneCN, - C(O)NHOH, -C(O)NHCH(CH2OH)2, -OCH2CH2OH, -B-C1-6alkyl, -B-C3-7cycloalkyl, - B-phenyl, -B-heterocyclyl or -B-heteroaromatic, wherein the C3-7cycloalkyl, phenyl, heterocyclyl or heteroaromatic ring is optionally substituted by 1 or 2 substituents independently selected from =O, C1-6alkyl, C1-6alkoxy, halo, -NH2, -CO2H, -C(O)C1- 6alkyl, -C(O)NHC1-6alkyl, cyano, -CH2CH2NHCH3, -CH2CH2OH, -CH2CH2OCH3, C3- 7cycloalkyl, phenyl, heterocyclyl and heteroaromatic;
R5 when present is H, halo, hydroxy or Ci-6alkoxy;
A is -NH-, -O-, -S-, -SO-, -SO2-, -N(C1-4alkyl)- or -NC(O)(CH3)-;
B is a bond, -O-, -N(R8)-, S, -SO-, -SO2-, -SO2N(R8)-, -CH2-, -C(O)-, -CO2-, - N(R8)C(O)-, -C(O)N(R8)-, -C(O)N(R8)CH2- or -C(O)N(R8)CH2CH2-;
V is phenyl, heteroaromatic or pyridone any of which may be optionally substituted by 1, 2 or 3 substituents independently selected from C1-6alkyl, fluorine, chlorine, C1-6alkoxy, hydroxy, cyclopropyl, cyano, -CO2CH3, heterocyclyl, -CO2H, - CH2NR6R7, -NR6R7, -C(O)NR6R7, -NR6C(O)R7,-CF3, -NO2, -CH2OCH3, -CH2OH, - CH(OH)CH3, -SO2CH3, -CH2heterocyclyl, -OCH2CH2NHC(O)CH3, -OCH2CH2OH, - OCH2CH2NH2, -C(O)NHheteroaromatic, -C(O)NHCH2heterocyclyl,
C(O)NHCH2CH2OH, -C(O)NHCH2CH2NH2, -C(O)NHCH2CH2S02Me, - C(O)NHCH2CH(OH)CH3, -C(O)heterocyclyl and -C(O)NHheterocyclyl, wherein the heterocyclyl ring is optionally substituted by -OH;
R6, R7, R8, R9 and R10 are each independently selected from H and C1-4alkyl; W is CH or N;
X is C or N;
Y is C or N; and
Z is CH orN; or
P2 is selected from
Figure imgf000309_0001
wherein:
Q is selected from N and CRa3;
V is selected from N and CRa4; W is selected from N and CH;
U is selected from C=O, C=S, SO2, S=O, and SR1;
X is selected from OH, SH, NH2, S(O)H, S(O)2H, S(O)2NH2, S(O)NH2, NHAc, and NHSO2Me;
Ra1, Ra3, and Ra3 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and halogen;
Ra2 is selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, amino, amide, and halogen;
Rb2 and Rb6 are independently selected from hydrogen, methyl and fluorine; Rb3 and Rb5 are independently selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, and C1-C6 alkoxy; and
Rb2 and Rb3 and/or Rb5 and Rb6 may be connected to form a cycloalkyl or a heterocycle, provided that at least one of Ra1, Ra2, Ra3, and Ra4 is not hydrogen.
25. The bivalent compound of any one of claims 1, 8-21, 23, and 24, wherein Q1 is selected from the group consisting of:
C1-20alkylene, wherein one, two, or three or four methylene units of the hydrocarbon chain are optionally and independently replaced by -Si(R7)(R8)-, -Si(R7)(R8)-O-, -O-Si(R7)(R8)- , cyclopropylene, -NR’-, -N(R’)C(O)-, -C(O)N(R’)-, -N(R’)SO2-, -SO2N(R’)-, -O-, -C(O)-, - OC(O)-, -C(O)O-, -S-, -SO-, -SO2-, -C(=S)-, -C(=NR’)-, C2-6alkenylene, C2-6alkynylene, phenyl, naphthyl, or a mono or bicyclic heterocyclic or heteroaryl ring; -NR’-C1-15alkyl-NR’- C(O)-; -NR’-(CH2-CH2-O)s-C1-6alkyl-NR’-C(O)-; -(O-CH2-CH2)s-NR’-C(O)-; -(O-CH2-CH2)s; -S-C0-6alkyl-; -NR’-C1-6alkyl-; -N(C1-3alkyl)-C1-6alkyl-NH-C(O)-; -NH-C1-6alkyl-N(C1-3alkyl)- C(O)-; -SO2-NR’-C0-6alkyl-; -SO2-heterocyclyl-C0-6alkyl-; -heterocyclyl-C(O)-; -heterocyclyl- C0-6alkyl-NR’-C(O)-; -NR’-C0-6alkylene-heterocyclene-C(O)-; -O-C1-6alkylene-C(O)-; -O-C1- 15alkylene-NR’-C(O)-; -O-C1-15alkylene-C(O)-NR’-; and -O-C1-6alkylene-, wherein C1- 6alkylene is optionally substituted by -OH;
wherein:
R7 and R8 are selected, independently for each occurrence, from the group consisting of -OH, C1-6alkyl, -O-C1-6alkyl, C2-6alkenyl, C3-6cycloalkyl, -C1-6alkyl- NRaRb, phenyl and heteroaryl; wherein C1-6alkyl, C2-6alkenyl, C3-6cycloalkyl, phenyl, and heteroaryl may be optionally substituted by one or more substituents independently selected from the group consisting of halogen, cyano, hydroxyl, C1-6alkyl, and phenyl; or
R7 and R8, together with the silicon to which they are attached, form a 4-7 membered heterocyclic ring, optionally containing one, two, three, or four heteroatoms independently selected from O, S, or N; wherein the 4-7 membered heterocyclic ring may be optionally substituted by one or more substituents independently selected from the group consisting of halogen, cyano, oxo, and hydroxyl;
R’ is, independently for each occurrence, selected from the group consisting of hydrogen and C1-4alkyl; wherein
Figure imgf000311_0001
may be optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo, and hydroxyl; and
s is an integer from 1-15.
26. The bivalent compound of claim 25, wherein Q1 comprises:
a first group selected from the group consisting of:
Figure imgf000311_0002
a second group selected from the group consisting of:
, ,
Figure imgf000311_0003
, and ; wherein the Si of the first group and the Si of the second group are connected by an oxygen atom;
wherein:
RW is, independently for each occurrence, absent or selected from the group consisting of
Figure imgf000311_0004
-O-C1-4alkylene-, -N(R’)-, -N(R’)-C1-4alkylene-, -O-, - C(O)C1-4alkylene-, -C(O)-O-C1-4alkylene-, -C2-6alkenylene-, -C2-6alkynylene-, -C3- 6cycloalkylene-, -phenylene-, and -heteroarylene-; wherein
Figure imgf000311_0005
C2-6alkenylene, C2-6alkynylene, C3-6cycloalkylene, phenylene, and heteroarylene may be optionally substituted by one, two, three, or more substituents independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, -C(O)C1-4alkyl, -C(O)-O-C1-4alkyl, -C(O)- NRaRb, halogen, cyano, hydroxyl, and phenyl; or RW and R7, together with the silicon to which they are attached, form a 3-8 membered heterocyclic ring, wherein the 3-8 membered ring may be optionally substituted by one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxyl, and C1-6alkyl;
W3 is, independently for each occurrence, (a) absent; or (b) selected from the group consisting of -C1-4alkylene-, -O-C1-4alkylene-, -C(O)-C1-4alkylene-, -N(R’)-C1- 4alkylene-, -C(O)-O-C1-4alkylene-, -C2-6alkenylene-, -C2-6alkynylene-, -C3- 6cycloalkylene-, -phenylene-, and -heteroarylene-; wherein C1-4alkylene, C2-6alkenylene, C2-6alkynylene, C3-6cycloalkylene, phenylene, and heteroarylene are optionally substituted by one, two, three, or more substituents independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, -C(O)C1-6alkyl, -C(O)-O-C1-4alkyl, halogen, hydroxyl, nitro, and cyano;
R7 and R8 are selected, independently for each occurrence, from the group consisting of -OH, C1-6alkyl, -O-C1-6alkyl, C2-6alkenyl, C3-6cycloalkyl, -C1-6alkyl- NRaRb, phenyl and heteroaryl; wherein C1-6alkyl, C2-6alkenyl, C3-6cycloalkyl, phenyl, and heteroaryl may be optionally substituted by one or more substituents independently selected from the group consisting of halogen, cyano, hydroxyl, C1-6alkyl, and phenyl; or
R7 and R8, together with the silicon to which they are attached, form a 4-7 membered heterocyclic ring, optionally containing one, two, three, or four heteroatoms independently selected from O, S, or N; wherein the 4-7 membered heterocyclic ring may be optionally substituted by one or more substituents independently selected from the group consisting of halogen, cyano, oxo, and hydroxyl;
R’, Ra, and Rb are selected, independently for each occurrence, from the group consisting of hydrogen and C1-4alkyl; wherein C1-4alkyl may be optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo, and hydroxyl; or
Ra and Rb, together with the nitrogen to which they are attached, may form a 4-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from O, S, and N; wherein the 4-7 membered heterocyclic ring may be optionally substituted by one or more substituents independently selected from the group consisting of halogen, cyano, oxo and hydroxyl; BB, independently for each occurrence, is a 4-7-membered cycloalkyl, heterocyclic, phenyl, naphthyl, or heteroaryl moiety, wherein the cycloalkyl, heterocyclic, phenyl, naphthyl, or heteroaryl moiety is optionally substituted with one, two, three, or more groups represented by RBB; wherein R7, independently for each occurrence, may be optionally bonded to BB; and
each RBB is selected, independently for each occurrence, from the group consisting of hydrogen, halogen, nitro, cyano, hydroxyl, amino, thio, -COOH, - CONHR’, substituted or unsubstituted aliphatic, and substituted or unsubstituted heteroaliphatic; or two RBB together with the atoms to which they are attached form a fused 5- or 6-membered cycloalkyl or heterocyclic bicyclic ring system.
27. The bivalent compound of claim 26, wherein Q1 comprises:
a first group selected from the group consisting of:
Figure imgf000313_0001
a second group selected from the group consisting of:
,
Figure imgf000313_0002
28. The bivalent compound of claim 26 or 27, wherein R7 and R8 are C1-6alkyl.
29. The bivalent compound of any one of claims 25-28, wherein Q1 is selected from the group consisting of:
,
Figure imgf000314_0001
30. The bivalent compound of any one of claims 1, 11-21, and 23-25, wherein Q1 comprises a triazolyl group.
31. The bivalent compound of claim 30, wherein Q1 is -W1-(CH2-CH2-O)s-C1-6alkylene- triazolylene-C1-6alkylene-O-C1-6alkylene-.
32. The bivalent com ound of claim 31, wherein Q1 has the following structure:
Figure imgf000314_0002
, wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
33. A method of treating a disease associated with a protein having tandem bromodomains in a patient in need thereof comprising:
administering to the patient the bivalent compound of any one of claims 1-32.
34. The method of claim 33, wherein the disease is acute myeloid leukemia or midline carcinoma.
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