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WO2016062737A1 - Dérivé 1,3-diméthylbenzimidazolone en utilisé comme inhibiteur du bromodomaine de la protéine brpf1 - Google Patents

Dérivé 1,3-diméthylbenzimidazolone en utilisé comme inhibiteur du bromodomaine de la protéine brpf1 Download PDF

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Publication number
WO2016062737A1
WO2016062737A1 PCT/EP2015/074298 EP2015074298W WO2016062737A1 WO 2016062737 A1 WO2016062737 A1 WO 2016062737A1 EP 2015074298 W EP2015074298 W EP 2015074298W WO 2016062737 A1 WO2016062737 A1 WO 2016062737A1
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Prior art keywords
compound
formula
pharmaceutically acceptable
acceptable salt
cancer
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Inventor
Paul Bamborough
Chun-Wa Chung
Armelle LE GALL
Robert John Sheppard
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GlaxoSmithKline Intellectual Property No 2 Ltd
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GlaxoSmithKline Intellectual Property No 2 Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • the present invention relates to a novel compound, pharmaceutical compositions containing such a compound and to its use in therapy.
  • the genomes of eukaryotic organisms are highly organised within the nucleus of the cell.
  • the long strands of duplex DNA are wrapped around an octomer of histone proteins (most usually comprising two copies of histones H2A, H2B, H3 and H4) to form a
  • chromatin structure plays a critical role in regulating gene transcription, which cannot occur efficiently from highly condensed chromatin.
  • the chromatin structure is controlled by a series of post-translational
  • histone proteins notably histones H3 and H4, and most commonly within the histone tails which extend beyond the core nucleosome structure. These modifications include acetylation, methylation, phosphorylation, ubiquitinylation, SUMOylation and numerous others. These epigenetic marks are written and erased by specific enzymes, which place the tags on specific residues within the histone tail, thereby forming an epigenetic code, which is then interpreted by the cell to allow gene specific regulation of chromatin structure and thereby transcription.
  • Histone acetylation is usually associated with the activation of gene transcription, as the modification loosens the interaction of the DNA and the histone octomer by changing the electrostatics.
  • specific proteins bind to acetylated lysine residues within histones to read the epigenetic code.
  • BRPF1 (also known as peregrin or Protein Br140) is a bromodomain-containing protein that has been shown to bind to acetylated lysine residues in histone tails, including H2AK5ac, H4K12ac and H3K14ac (Poplawski et al, J. Mol. Biol., 2014 426: 1661-1676).
  • BRPF1 also contains several other domains typically found in chromatin-associated factors, including a double plant homeodomain (PHD) and zinc finger (ZnF) assembly (PZP), and a chromo/Tudor-related Pro-Trp-Trp-Pro (PWWP) domain.
  • PDD double plant homeodomain
  • ZnF zinc finger
  • PWWP chromo/Tudor-related Pro-Trp-Trp-Pro
  • BRPF1 forms a tetrameric complex with monocytic leukemia zinc-finger protein (MOZ, also known as KAT6A or MYST3) inhibitor of growth 5 (ING5) and homolog of Esa1 -associated factor (hEAF6).
  • MOZ monocytic leukemia zinc-finger protein
  • ING5 growth 5
  • hEAF6 homolog of Esa1 -associated factor
  • the BRPF1 bromodomain contributes to recruiting the MOZ complex to distinct sites of active chromatin and hence is considered to play a role in the function of MOZ in regulating transcription, hematopoiesis, leukemogenesis, and other developmental processes (Ullah et al, Mol. Cell. Biol., 2008 28: 6828-6843; Perez-Campo et al, Blood, 2009 1 13: 4866-4874).
  • Demont et al ACS Med. Chem. Lett., (2014) (dx.doi.org/10.1021/ml5002932), discloses certain 1 ,3-dimethyl benzimidazolones as potent, selective inhibitors of the BRPF1 bromodomain.
  • the compound of the invention is an inhibitor of BRPF1 bromodomain and has an improved profile with respect to known inhibitors of BRPF1 , for example in a certain aspect improved solubility and, in another aspect has been shown to possess an improved profile with respect to known inhibitors of BRPF1 , for example potency, and improved selectivity for BRPF1 over other bromodomains for example BRPF2 and BRPF3, BRD9, and the BET family of bromodomain-containing proteins.
  • a compound of formula (I) or a pharmaceuticallyacceptable salt- thereof there is provided a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically-acceptable salt thereof, and one or more pharmaceutically-acceptable excipient(s).
  • a compound of formula (I), or a pharmaceutically-acceptable salt thereof for use in therapy.
  • a compound of formula (I), or a pharmaceutically-acceptable salt thereof for the treatment of diseases or conditions for which a bromodomain inhibitor, for example a BRPF1 bromodomain inhibitor, is indicated.
  • a method of treating diseases or conditions for which a bromodomain inhibitor for example a BRPF1 bromodomain inhibitor, is indicated in a subject in need thereof which comprises administering a therapeutically-effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • a compound of formula (I), or a pharmaceutically-acceptable salt thereof in the manufacture of a medicament for the treatment of diseases or conditions for which a bromodomain inhibitor, for example a BRPF1 inhibitor, is indicated.
  • the invention relates to a compound of formula (I) which is N-(1 ,3-dimethyl-6-(2- methylpiperazin-1 -yl)-2-oxo-2,3-dihydro-1 H-benzo[d]imidazol-5-yl)-2-methoxybenzamide
  • the compound of formula (I) contains a chiral atom and hence may exist in one or more stereoisomeric forms.
  • the present invention encompasses each of the stereoisomers of the compound of formula (I), whether as individual stereoisomers or as mixtures thereof including racemic mixtures.
  • Either stereoisomer may contain less than 10% by weight, for example less than 5% by weight, less than 0.5% by weight, or less than 0.1 % by weight of the other stereoisomer.
  • Separation of enantiomers may be achieved by conventional techniques known to those skilled in the art, e.g. by fractional crystallisation or chiral chromatography, for example chiral HPLC.
  • Certain of the compounds of the invention may exist in tautomeric forms. It will be understood that the present invention encompasses all of the tautomers of the compounds of the invention whether as individual tautomers or as mixtures thereof.
  • the present invention covers the compound of formula (I) as the free base and as salts thereof, for example as a pharmaceutically-acceptable salt.
  • the invention relates to the compound of formula (I) in the form of a salt.
  • the invention relates to the compound of formula (I) in the form of a free base.
  • the invention relates to the compound of formula (I) in the form of a pharmaceutically-acceptable salt.
  • Suitable pharmaceutically acceptable salts can include acid addition salts.
  • a pharmaceutically-acceptable salt may be readily prepared by using a desired acid or base as appropriate. The resultant salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
  • a pharmaceutically acceptable acid addition salt can be formed by reaction of a compound of formula (I) with a suitable inorganic or organic acid (such as hydrobromic, hydrochloric, sulphuric, nitric, phosphoric, succinic, maleic, acetic, propionic, fumaric, citric, tartaric, lactic, benzoic, salicylic, glutamaic, aspartic, p-toluenesulfonic, benzenesulfonic, methanesulfonic, ethanesulfonic, naphthalenesulfonic such as 2-naphthalenesulfonic, or hexanoic acid), optionally in a suitable solvent such as an organic solvent, to give the salt which is usually isolated for example by crystallisation and filtration or by evaporation followed by trituration.
  • a suitable inorganic or organic acid such as hydrobromic, hydrochloric, sulphuric, nitric, phosphoric,
  • a pharmaceutically acceptable acid addition salt of a compound of formula (I) can comprise or be for example a hydrobromide, hydrochloride, sulfate, nitrate, phosphate, succinate, maleate, acetate, propionate, fumarate, citrate, tartrate, lactate, benzoate, salicylate, glutamate, aspartate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, naphthalenesulfonate (e.g. 2-naphthalenesulfonate) or hexanoate salt.
  • a hydrobromide hydrochloride, sulfate, nitrate, phosphate, succinate, maleate, acetate, propionate, fumarate, citrate, tartrate, lactate, benzoate, salicylate, glutamate, aspartate, p-toluenesulf
  • a pharmaceutically acceptable acid addition salt of a compound of formula (I) can comprise or be a hydrochloride, sulfate, maleate, fumarate, citrate, p-toluenesulfonate, benzenesulfonate or methanesulfonate salt.
  • non-pharmaceutically acceptable salts e.g. formates, oxalates and
  • trifluoroacetates may be used, for example in the isolation of the compound of formula (I), and are included within the scope of this invention.
  • the invention includes within its scope all possible stoichiometric and non- stoichiometric forms of the salts of the compound of formula (I).
  • the invention encompasses all prodrugs, of the compound of formula (I) or a pharmaceutically acceptable salt thereof, which upon administration to the recipient is capable of providing (directly or indirectly) the compound of formula (I) or a pharmaceutically acceptable salt thereof, or an active metabolite or residue thereof.
  • prodrugs of the compound of formula (I) or a pharmaceutically acceptable salt thereof, which upon administration to the recipient is capable of providing (directly or indirectly) the compound of formula (I) or a pharmaceutically acceptable salt thereof, or an active metabolite or residue thereof.
  • Such derivatives are recognizable to those skilled in the art, without undue experimentation. Reference is made to the teaching of Burger's Medicinal Chemistry and Drug Discovery, 5 th Edition, Vol 1 : Principles and Practice, which is incorporated herein by reference to the extent of teaching such derivatives.
  • the compound of formula (I) may be in crystalline or amorphous form. Furthermore, some of the crystalline forms of the compound of formula (I) may exist as polymorphs, which are included within the scope of the present invention. Polymorphic forms of the compound of formula (I) may be characterized and differentiated using a number of conventional analytical techniques, including, but not limited to, X-ray powder diffraction (XRPD) patterns, infrared (IR) spectra, Raman spectra, differential scanning calorimetry (DSC),
  • XRPD X-ray powder diffraction
  • IR infrared
  • Raman spectra Raman spectra
  • DSC differential scanning calorimetry
  • thermogravimetric analysis TGA
  • solid state nuclear magnetic resonance SSNMR
  • the compound of formula (I) or salts thereof may be made by a variety of methods. Illustrative general synthetic methods are set out below.
  • the compound of formula (I) may be prepared by deprotection of the compound of formula (II)
  • the compound of formula (II) may be prepared by reacting the compound of formula (III) with 2-methoxybenzoyl chloride in a suitable solvent, for example dichloromethane, in the presence of a suitable base, for example pyridine, at a suitable temperature, for example ambient temperature.
  • a suitable solvent for example dichloromethane
  • a suitable base for example pyridine
  • the compound of formula (III) can be prepared by reduction of the compound of formula (IV), for example by hydrogenation of a solution of the compound of formula (IV) in suitable solvent, for example /so-propyl alcohol, in the presence of a suitable catalyst, for example palladium supported on carbon, at a suitable temperature, for example ambient temperature.
  • suitable solvent for example /so-propyl alcohol
  • a suitable catalyst for example palladium supported on carbon
  • the compound of formula (IV) may be prepared by reaction of a compound of formula (V) with the compound of formula (VI) in a suitable solvent, for example
  • DMSO dimethylsulfoxide
  • the compound of formula (V) may be prepared by nitration of the compound of formula (VII) by, for example, the addition of nitric acid to a solution of a compound of formula (VII) in a suitable solvent, for example acetic anhydride, at a suitable temperature, for example between -30°C and 0°C.
  • a suitable solvent for example acetic anhydride
  • the compound of formula (VII) may be prepared by dimethylation of the compound of formula (VIII) by, for example treatment of a solution of the compound of formula (VIII) in a suitable solvent, for example ⁇ , ⁇ -dimethylformamide (DMF), with excess iodomethane in the presence of a suitable base, for example sodium hydride, at a suitable temperature, for example 0°C to ambient temperature.
  • a suitable solvent for example ⁇ , ⁇ -dimethylformamide (DMF)
  • a suitable base for example sodium hydride
  • the compound of formula (VIII) may be prepared from the compound of formula (IX) by treatment with di(1 /-/-imidazol-1-yl)methanone in a suitable solvent, for example tetrahydrofuran (THF), at a suitable temperature, for example between 0°C and 5°C
  • a suitable solvent for example tetrahydrofuran (THF)
  • THF tetrahydrofuran
  • the compounds of formula (IA) and formula (IB) can be obtained from the compound of formula (I) using suitable separation techniques which are familiar to those skilled in the art, such as those described herein.
  • the compounds of formula (IA) and (IB) may be prepared by a chiral synthesis procedure.
  • the compound of formula (IA) may be prepared by the procedure set out in Scheme 1 .
  • Suitable amine protecting groups include acyl (e.g. acetyl), carbamate (e.g. 2',2',2'-trichloroethoxycarbonyl, benzyloxycarbonyl or t-butoxycarbonyl) and arylalkyl (e.g. benzyl), which may be removed by hydrolysis (e.g.
  • an acid such as hydrochloric acid in dioxane or trifluoroacetic acid in dichloromethane
  • reductively e.g. hydrogenolysis of a benzyl or benzyloxycarbonyl group or reductive removal of a 2',2',2'-trichloroethoxycarbonyl group using zinc in acetic acid
  • Other suitable amine protecting groups include trifluoroacetyl (-COCF 3 ) which may be removed by base catalysed hydrolysis.
  • the compound of formula (I) and salts thereof, in particular pharmaceutically- acceptable salts thereof, are BRPF1 bromodomain inhibitors, and thus are believed to have potential utility in the treatment of diseases or conditions for which a bromodomain inhibitor is indicated.
  • Bromodomain inhibitors are believed to be useful in the treatment of a variety of diseases or conditions related to systemic or tissue inflammation, inflammatory responses to infection or hypoxia, cellular activation and proliferation, lipid metabolism, fibrosis and in the prevention and treatment of viral infections.
  • Bromodomain inhibitors may be useful in the treatment of a wide variety of chronic autoimmune and inflammatory conditions such as rheumatoid arthritis, osteoarthritis, 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 (including atopic dermatitis), alopecia, vitiligo, bullous skin diseases, nephritis, vasculitis, atherosclerosis, Alzheimer's disease, depression, Sjogren's syndrome, sialoadenitis, central retinal vein occlusion, branched retinal vein occlusion, Irvine-Gass syndrome (post-cataract and post-surgical), retinitis pigmentosa, pars planitis, birdshot
  • Bromodomain inhibitors may be useful in the treatment of a wide variety of acute inflammatory conditions such as acute gout, nephritis including lupus ne
  • vasculitis including giant cell arteritis, Wegener's granulomatosis, Polyarteritis nodosa, Behcet's disease, Kawasaki disease, Takayasu's Arteritis, pyoderma gangrenosum, vasculitis with organ involvement and acute rejection of transplanted organs.
  • Bromodomain inhibitors may be useful in the treatment of diseases or conditions which involve inflammatory responses to infections with bacteria, viruses, fungi, parasites or their toxins, 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 and SIRS associated with viral infections such as influenza, herpes zoster, herpes simplex and coronavirus.
  • SIRS systemic inflammatory response syndrome
  • multi-organ dysfunction syndrome toxic shock syndrome
  • acute lung injury ARDS (adult respiratory distress syndrome)
  • ARDS adult respiratory distress syndrome
  • fulminant hepatitis burns
  • acute pancreatitis post-
  • Bromodomain inhibitors may be useful in the treatment of conditions associated with ischaemia-reperfusion injury such as myocardial infarction, cerebro-vascular 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.
  • Bromodomain inhibitors may be useful in the treatment of disorders of lipid metabolism via the regulation of APO-A1 such as hypercholesterolemia, atherosclerosis and Alzheimer's disease.
  • Bromodomain inhibitors may be useful in the treatment of fibrotic conditions such as idiopathic pulmonary fibrosis, renal fibrosis, postoperative stricture, keloid scar formation, scleroderma (including morphea) and cardiac fibrosis.
  • Bromodomain inhibitors may be useful in the treatment of a variety of diseases associated with bone remodelling such as osteoporosis, osteopetrosis, pycnodysostosis, Paget's disease of bone, familial expanile osteolysis, expansile skeletal hyperphosphatasia, hyperososis corticalis deformans Juvenilis, juvenile Paget's disease and Camurati
  • Bromodomain inhibitors may be useful in the treatment of viral infections such as herpes virus, human papilloma virus, adenovirus and poxvirus and other DNA viruses.
  • Bromodomain inhibitors may be useful in the treatment of cancer, including hematological (such as leukaemia, lymphoma and multiple myeloma), epithelial including lung, breast and colon carcinomas, midline carcinomas, mesenchymal, hepatic, renal and neurological tumours.
  • Bromodomain inhibitors may be useful in the treatment of one or more cancers selected from brain cancer (gliomas), glioblastomas, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast cancer, inflammatory breast cancer, colorectal cancer, Wilm's tumor, Ewing's sarcoma, rhabdomyosarcoma, ependymoma, medulloblastoma, colon cancer, head and neck cancer, kidney cancer, lung cancer, liver cancer, melanoma, squamous cell carcinoma, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma cancer, osteosarcoma, giant cell tumor of bone, thyroid cancer,
  • cancers selected from brain cancer (gliomas), glioblastomas, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast cancer, inflammatory breast cancer, colorectal cancer, Wilm's tumor, Ewing
  • lymphoblastic T-cell leukemia chronic myelogenous leukemia, chronic lymphocytic leukemia, hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic neutrophilic leukemia, acute lymphoblastic T-cell leukemia, acute myeloid leukemia, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, megakaryoblastic leukemia, acute megakaryocytic leukemia, promyelocytic leukemia, mixed lineage leukaemia, erythroleukemia, malignant lymphoma, Hodgkins lymphoma, non- Hodgkins lymphoma, lymphoblastic T-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, vulval cancer, cervical cancer, endometrial cancer, renal cancer, me
  • the cancer is a leukaemia, for example a leukaemia selected from acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, acute myeloid leukemia and mixed lineage leukaemia (MLL).
  • MML mixed lineage leukaemia
  • the cancer is multiple myeloma.
  • the cancer is a lung cancer such as small cell lung cancer (SCLC).
  • SCLC small cell lung cancer
  • the cancer is a neuroblastoma.
  • the cancer is Burkitt's lymphoma.
  • the cancer is cervical cancer.
  • the cancer is esophageal cancer.
  • the cancer is ovarian cancer.
  • the cancer is breast cancer.
  • the cancer is colarectal cancer.
  • the disease or condition for which a bromodomain inhibitor is indicated is selected from diseases associated with systemic inflammatory response syndrome, such as sepsis, burns, pancreatitis, major trauma, haemorrhage and ischaemia.
  • diseases associated with systemic inflammatory response syndrome such as sepsis, burns, pancreatitis, major trauma, haemorrhage and ischaemia.
  • bromodomain inhibitor would 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, cardiac or gastro-intestinal injury and mortality.
  • the bromodomain inhibitor would be administered prior to surgical or other procedures associated with a high risk of sepsis, haemorrhage, extensive tissue damage, SIRS or MODS (multiple organ dysfunction syndrome).
  • the disease or condition for which a bromodomain inhibitor is indicated is sepsis, sepsis syndrome, septic shock and endotoxaemia.
  • the bromodomain inhibitor is indicated for the treatment of acute or chronic pancreatitis.
  • the bromodomain is indicated for the treatment of burns.
  • the disease or condition for which a bromodomain inhibitor is indicated is selected from herpes simplex infections and reactivations, cold sores, herpes zoster infections and reactivations, chickenpox, shingles, human papilloma virus, human immunodeficiency virus (HIV), cervical neoplasia, adenovirus infections, including acute respiratory disease, poxvirus infections such as cowpox and smallpox and African swine fever virus.
  • a bromodomain inhibitor is indicated for the treatment of Human papilloma virus infections of skin or cervical epithelia.
  • the bromodomain inhibitor is indicated for the treatment of latent HIV infection.
  • the present invention thus provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in therapy.
  • a compound of formula (IA) or a pharmaceutically acceptable salt thereof for use in therapy In one embodiment there is provided a compound of formula (I B) or a pharmaceutically acceptable salt thereof for use in therapy.
  • the present invention thus provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of any diseases or conditions for which a BRPF1 bromodomain inhibitor is indicated.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of chronic auto-immune and/or inflammatory conditions In another embodiment there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of chronic auto-immune conditions. In another embodiment there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of inflammatory conditions. In another embodiment there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of viral infections. In a further embodiment there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of cancer.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of diseases or conditions for which a BRPF1 bromodomain inhibitor is indicated.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of chronic auto-immune conditions.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of inflammatory conditions.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of viral infections.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of cancer.
  • a method of treating chronic auto-immune conditions which comprises administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • a method of treating inflammatory conditions comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • a method of treating viral infections comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • a method of treating cancer comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the subject in need thereof is a mammal, particularly a human.
  • the term "effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, or subject (e.g. a human) that is being sought, for instance, by a researcher or clinician.
  • terapéuticaally effective amount means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
  • the term also includes within its scope amounts effective to enhance normal physiological function.
  • a compound of formula (I) as well as pharmaceutically acceptable salts thereof may be administered alone, it is common to present the active ingredient as a pharmaceutical composition.
  • the present invention therefore provides in a further aspect a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients.
  • a pharmaceutical composition comprising a compound of formula (IA) or a pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients.
  • compositions including admixing a compound of formula (I), or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable excipients.
  • Suitable pharmaceutically acceptable excipients include the following types of excipients: carriers, diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, flavor masking agents, coloring agents, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents.
  • carriers diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, flavor masking agents, coloring agents, anti-caking agents, humectants, chelating agents, plasticizers, viscosity
  • Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically acceptable excipients in appropriate amounts for use in the invention.
  • resources that are available to the skilled artisan which describe pharmaceutically acceptable excipients and may be useful in selecting suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).
  • compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company). The pharmaceutical composition can be used in the treatment of any of the conditions described herein. Since the compound of formula (I) is intended for use in pharmaceutical
  • compositions it will be readily understood that it is preferably provided in substantially pure form, for example, at least 85% pure, especially at least 98% pure (% in a weight for weight basis).
  • Pharmaceutical compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Preferred unit dosage
  • compositions are those containing a daily dose or sub-dose, or an appropriate fraction thereof, of an active ingredient. Such unit doses may therefore be administered more than once a day.
  • Preferred unit dosage compositions are those containing a daily dose or sub- dose (for administration more than once a day), as herein above recited, or an appropriate fraction thereof, of an active ingredient.
  • compositions may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, inhaled, intranasal, topical (including buccal, sublingual or transdermal), ocular (including topical, intraocular, subconjunctival, episcleral, sub-Tenon), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route.
  • Such compositions may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the excipient(s).
  • the pharmaceutical composition is adapted for parenteral administration, particularly intravenous administration.
  • the pharmaceutical composition is adapted for oral administration.
  • pharmaceutical composition is adapted for topical administration.
  • compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water, for injections immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
  • compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
  • the active drug component can be combined with an oral, non-toxic
  • inert carrier such as ethanol, glycerol, water and the like.
  • Powders suitable for incorporating into tablets or capsules may be prepared by reducing the compound to a suitable fine size (e.g. by micronisation) and mixing with a similarly prepared pharmaceutical carrier such as an edible carbohydrate, for example, starch or mannitol. Flavouring, preservative, dispersing and colouring agent can also be present.
  • Capsules may be made by preparing a powder mixture, as described above, and filling formed gelatin sheaths. Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation.
  • a disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.
  • suitable binders, glidants, lubricants, sweetening agents, flavours, disintegrating agents and colouring agents can also be incorporated into the mixture.
  • suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include starch, methyl cellulose, agar, bentonite, xanthan gum and the like. Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets.
  • a powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or an absorption agent such as bentonite, kaolin or dicalcium phosphate.
  • a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone
  • a solution retardant such as paraffin
  • a resorption accelerator such as a quaternary salt
  • the powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen.
  • a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen.
  • the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules.
  • the granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil. The lubricated mixture is then compressed into tablets.
  • the compound of formula (I) and pharmaceutically acceptable salts thereof can also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps.
  • a clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages.
  • Oral fluids such as solutions, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound.
  • Syrups can be prepared by dissolving the compound in a suitably flavoured aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle.
  • Suspensions can be formulated by dispersing the compound in a non-toxic vehicle.
  • Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavour additive such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, and the like can also be added.
  • compositions for administration may be designed to provide a modified release profile so as to sustain or otherwise control the release of the
  • a modified release profile of the therapeutically active agent may be obtained through the design of polymeric matrices incorporating different choices and properties of biodegradable/bioerodable polymers (e.g. poly(ethylene vinyl) acetate (EVA), superhydrolyzed PVA), hydroxyalkyl cellulose (HPC), methylcellulose (MC), hydroxypropyl methyl cellulose (HPMC), polycaprolactone, poly(glycolic) acid, poly(lactic) acid, polyanhydride, of polymer molecular weights, polymer crystallinity, copolymer ratios, processing conditions, surface finish, geometry, excipient addition and polymeric coatings that will enhance drug diffusion, erosion, dissolution and osmosis.
  • dosage unit compositions for oral administration can be microencapsulated.
  • composition may be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like.
  • the compound of formula (I) and pharmaceutically acceptable salts thereof can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • Pharmaceutical compositions adapted for topical administration may be formulated as ointments, creams, suspensions, emulsions, lotions, powders, solutions, pastes, gels, foams, sprays, aerosols or oils.
  • compositions may include conventional additives which include, but are not limited to, preservatives, solvents to assist drug penetration, co-solvents, emollients, propellants, viscosity modifying agents (gelling agents), surfactants and carriers.
  • a pharmaceutical composition adapted for topical administration which comprises between 0.01 - 10%, or between 0.01 - 1 % of the compound of formula (I), or a pharmaceutically acceptable salt thereof, by weight of the composition.
  • the compositions are preferably applied as a topical ointment, cream, gel, spray or foam.
  • the active ingredient may be employed with either a paraffinic or a water-miscible ointment base.
  • the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in-oil base.
  • compositions adapted for topical administrations to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.
  • Compositions to be administered to the eye will have ophthalmically compatible pH and osmolality.
  • One or more ophthalmically acceptable pH adjusting agents and/or buffering agents can be included in a composition of the invention, including acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, and sodium lactate; and buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride.
  • Such acids, bases, and buffers can be included in an amount required to maintain pH of the composition in an ophthalmically acceptable range.
  • One or more ophthalmically acceptable salts can be included in the composition in an amount sufficient to bring osmolality of the composition into an ophthalmically acceptable range.
  • Such salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions.
  • the ocular delivery device may be designed for the controlled release of one or more therapeutic agents with multiple defined release rates and sustained dose kinetics and permeability.
  • Pharmaceutical compositions for ocular delivery also include in situ gellable aqueous composition.
  • Such a composition comprises a gelling agent in a concentration effective to promote gelling upon contact with the eye or with lacrimal fluid.
  • Suitable gelling agents include but are not limited to thermosetting polymers.
  • the term "in situ gellable” as used herein is includes not only liquids of low viscosity that form gels upon contact with the eye or with lacrimal fluid, but also includes more viscous liquids such as semi-fluid and thixotropic gels that exhibit substantially increased viscosity or gel stiffness upon administration to the eye. See, for example, Ludwig (2005) Adv. Drug Deliv. Rev.
  • Dosage forms for nasal or inhaled administration may conveniently be formulated as aerosols, solutions, suspensions, gels or dry powders.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is in a particle-size-reduced form e.g. obtained by micronisation.
  • the preferable particle size of the size-reduced (e.g. micronised) compound or salt is defined by a D 50 value of about 0.5 to about 10 microns (for example as measured using laser diffraction).
  • Aerosol formulations e.g.
  • Aerosol formulations can be presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device or inhaler.
  • the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve (metered dose inhaler) which is intended for disposal once the contents of the container have been exhausted.
  • the dosage form comprises an aerosol dispenser, it preferably contains a suitable propellant under pressure such as compressed air, carbon dioxide or an organic propellant such as a
  • HFC hydrofluorocarbon
  • Suitable HFC propellants include 1 ,1 ,1 ,2,3,3,3- heptafluoropropane and 1 ,1 ,1 ,2-tetrafluoroethane.
  • the aerosol dosage forms can also take the form of a pump-atomiser.
  • the pressurised aerosol may contain a solution or a suspension of the active compound. This may require the incorporation of additional excipients e.g. co-solvents and/or surfactants to improve the dispersion characteristics and homogeneity of suspension formulations. Solution formulations may also require the addition of co-solvents such as ethanol.
  • the pharmaceutical composition may be a dry powder inhalable composition.
  • a dry powder inhalable composition can comprise a powder base such as lactose, glucose, trehalose, mannitol or starch, the compound of formula (I) or a pharmaceutically acceptable salt thereof (preferably in particle-size-reduced form, e.g. in micronised form), and optionally a performance modifier such as L-leucine or another amino acid and/or metal salt of stearic acid such as magnesium or calcium stearate.
  • the dry powder inhalable composition comprises a dry powder blend of lactose e.g. lactose monohydrate and the compound of formula (I) or salt thereof.
  • Such compositions can be administered to the patient using a suitable device such as the DISKUS® device, marketed by
  • GlaxoSmithKline which is for example described in GB 2242134 A.
  • the compound of formula (I) and pharmaceutically acceptable salts thereof may be formulated as a fluid formulation for delivery from a fluid dispenser, for example a fluid dispenser having a dispensing nozzle or dispensing orifice through which a metered dose of the fluid formulation is dispensed upon the application of a user-applied force to a pump mechanism of the fluid dispenser.
  • a fluid dispenser for example a fluid dispenser having a dispensing nozzle or dispensing orifice through which a metered dose of the fluid formulation is dispensed upon the application of a user-applied force to a pump mechanism of the fluid dispenser.
  • Such fluid dispensers are generally provided with a reservoir of multiple metered doses of the fluid formulation, the doses being dispensable upon sequential pump actuations.
  • the dispensing nozzle or orifice may be configured for insertion into the nostrils of the user for spray dispensing of the fluid formulation into the nasal cavity.
  • a fluid dispenser of the aforementioned type is described and illustrated in WO- A-2005/04
  • each dosage unit for oral or parenteral administration preferably contains from 0.01 to 3000 mg, more preferably 0.5 to 1000 mg, of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base.
  • Each dosage unit for nasal or inhaled administration preferably contains from 0.001 to 50 mg, more preferably 0.01 to 5 mg, of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base.
  • the pharmaceutically acceptable compound of formula (I) and pharmaceutically acceptable salts thereof can be administered in a daily dose (for an adult patient) of, for example, an oral or parenteral dose of 0.01 mg to 3000 mg per day, 0.5 to 1000 mg per day or 100 mg to 2500mg per day, or a nasal or inhaled dose of 0.001 to 50 mg per day or 0.01 to 5 mg per day, of the compound of the formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base.
  • This amount may be given in a single dose per day or more usually in a number (such as two, three, four, five or six) of sub-doses per day such that the total daily dose is the same.
  • An effective amount of a salt thereof may be determined as a proportion of the effective amount of the compound of formula (I) per se.
  • Combination therapies according to the present invention thus comprise the administration of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof, and the use of at least one other therapeutically active agent.
  • combination therapies according to the present invention comprise the administration of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one other therapeutically active agent.
  • the compound(s) of formula (I) and pharmaceutically acceptable salts thereof, and the other therapeutically active agent(s) may be administered together in a single pharmaceutical composition or separately and, when administered separately this may occur simultaneously or sequentially in any order.
  • a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one other therapeutically active agent.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof, and pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, according to the invention may be used in combination with or include one or more other therapeutic agents, for example selected from antibiotics, anti-virals, glucocorticosteroids, muscarinic antagonists beta-2 agonists and Vitamin D3 analogues.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof may be used in combination with a further therapeutic agent which is suitable for the treatment of cancer.
  • further therapeutic agents are described in Cancer Principles and Practice of Oncology by V.T. Devita and S. Hellman (editors), 6 th edition (2001 ), Lippincott Williams & Wilkins Publishers. A person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the cancer involved.
  • Further therapeutic agents to be used in combination with the compound of formula (I) or a pharmaceutically acceptable salt thereof include, but are not limited to, anti-microtubule agents (such as diterpenoids and vinca alkaloids); platinum coordination complexes;
  • alkylating agents such as nitrogen mustards, oxazaphosphorines, alkylsulfonates, nitrosoureas, and triazenes
  • antibiotic agents such as anthracyclins, actinomycins and bleomycins
  • topoisomerase II inhibitors such as epipodophyllotoxins
  • antimetabolites such as purine and pyrimidine analogues and anti-folate compounds
  • topoisomerase I inhibitors such as camptothecins; hormones and hormonal analogues
  • signal transduction pathway inhibitors such as tyropsine receptor inhibitors
  • immunotherapeutic agents such as proapoptotic agents
  • epigenetic or transcriptional modulators such as histone deacetylase inhibitors
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof when administered in combination with other therapeutic agents normally administered by the inhaled, intravenous, oral or intranasal route, that the resultant pharmaceutical composition may be administered by the same routes. Alternatively the individual components of the composition may be administered by different routes.
  • One embodiment of the invention encompasses combinations comprising one or two other therapeutic agents.
  • the other therapeutic ingredient(s) may be used in the form of salts, for example as alkali metal or amine salts or as acid addition salts, or prodrugs, or as esters, for example lower alkyl esters, or as solvates, for example hydrates, to optimise the activity and/or stability and/or physical characteristics, such as solubility, of the therapeutic ingredient.
  • the therapeutic ingredients may be used in optically pure form. The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical composition and thus pharmaceutical compositions comprising a
  • the compound of formula (I) and pharmaceutically acceptable salts thereof may be prepared by the methods described below or by similar methods.
  • the following Intermediates and Examples serve to illustrate the preparation of the compound of formula (I) and pharmaceutically acceptable salts thereof, and are not to be considered as limiting the scope of the invention in any way.
  • the UPLC analysis was conducted on an Acquity UPLC BEH C18 column (50 mm x 2.1 mm, i.d. 1.7 ⁇ packing diameter) at 40'C.
  • the UV detection was a summed signal from wavelength of 210 nm to 350 nm.
  • the UPLC analysis was conducted on an Acquity UPLC BEH C18 column (50 mm x 2.1 mm, i.d. 1.7 ⁇ packing diameter) at 40'C.
  • the UV detection was a summed signal from wavelength of 210 nm to 350 nm.
  • the HPLC analysis was conducted on an XBridge C18 column (100 mm x 30 mm i.d. 5 ⁇ packing diameter) at ambient temperature.
  • A 10 mM Ammonium Bicarbonate in water adjusted to pH 10 with ammonia solution.
  • B Acetonitrile. The gradient employee was:
  • the UV detection was an averaged signal from wavelength of 210 nm to 350 nm.
  • the HPLC analysis was conducted on an XSELECT CSH C18 column (150 mm x 30 mm i.d. 5 ⁇ packing diameter) at ambient temperature.
  • A 10 mM Ammonium Bicarbonate in water adjusted to pH 10 with ammonia solution.
  • the UV detection was for a signal wavelength at 254nm.
  • the compound of formula (IA) was tested in one or more of the following assays. Expression and purification of BET and BRPF1 proteins.
  • BET proteins were produced using protocols given in the literature. 1 6H-Flag-TEV- BRPF1 (622-738) was expressed in E.coli BL21 (DE3) cells. The pellet from the E.coli culture was resuspended in buffer A (50 mM HEPES pH 7.5, 300 mM NaCI, 10 mM imidazole, and 0.5 mM TCEP) plus 0.1 mg/ml lysozyme (Sigma 92971 -50G-F) and 1 ⁇ /ml Protease Inhibitor Cocktail (Sigma P8340). Cells were lysed by sonication, on ice, and centrifuged at 100,000 x g for 90 minutes at 4 ° C. The supernatant was applied to a
  • BRPF1 protein was cleaved with rTEV protease at a ratio of 1 :200, and dialysed overnight at 4°C against buffer B (50 mM HEPES pH 7.5, 150 mM NaCI and 0.5 mM TCEP) using SnakeSkin Dialysis Tubing 3.5K MWCO (Thermo Scientific #68035).
  • Compounds were screened against 6H-Flag-Tev-BRPF1 (622-738), 6HisFlag-Tev- BRPF2 (also known as BRD1 ) (551 -673) or 6His-Flag-Tev-BRPF3 (579-706) protein in dose- response format in a TR-FRET assay measuring competition between test compound and a synthetic fluorescent ligand.
  • Compounds were titrated from 10 mM in 100% DMSO and 100 nl_ transferred to a low volume black 384 well micro titre plate using a Labcyte Echo 555.
  • a Thermo Scientific Multidrop Combi was used to dispense 5 ⁇ _ of 4 nM BRPF1 , 20 nM BRPF2 or 40 nM BRPF3 protein respectively in an assay buffer of 50 mM HEPES, 150 mM NaCI, 5% glycerol, 1 mM DTT and 1 mM CHAPS, pH 7.4, and in the presence of the appropriate fluorescent ligand concentration ( ⁇ K d concentration for the interaction between protein and ligand).
  • the bromodomain protein :fluorescent ligand interaction was detected using TR-FRET following a 5 ⁇ _ addition of either 3 nM Lanthascreen Elite Tb-anti His antibody (Invitrogen PV5863) for the Alexa 488 ligands, or 3 nM europium chelate labelled anti-6His antibody (Perkin Elmer, W1024, AD01 1 1 ) for the Alexa 647 ligand, in assay buffer.
  • TR-FRET Time resolved fluorescence energy transfer
  • Alexa Fluor 488 labelled ligand Alexa Fluor 488 labelled ligand Alexa Fluor 647 labelled ligand 100 (ligand binding to BRPF2) 200 (ligand binding to BRPF3) 400 nM nM nM
  • a Thermo Scientific Multidrop Combi was used to dispense 5 ⁇ _ of 20 nM protein in an assay buffer of 50 mM HEPES, 150 mM NaCI, 5% glycerol, 1 mM DTT and 1 mM CHAPS, pH 7.4, and in the presence of 100 nM fluorescent ligand ( ⁇ K d concentration for the interaction between BRD4 BD1 and ligand).
  • the compound of formula (IA) was tested in all of the BRPF1 , BRPF2, BRPF3, BRD4 BD1 , and BRD4 BD2 TR-FRET assays described above and were found to have a plC 50 as shown in the table below:-
  • HEK293 cells (8 x 10 5 ) were plated in each well of a 6-well plate and co-transfected with Histone H3.3-HaloTag (NM_002107) and NanoLuc-BRPF1 isoform 1 (P55201 -1 ) bromodomain amino acids 625-735 or isoform 2 (P55201 -2) bromodomain amino acids 625- 741 .
  • Isoform 2 has an insertion S660 -> SEVTELD in the bromodomain. Twenty hours post- transfection cells were collected, washed with PBS, and exchanged into media containing phenol red-free DMEM and 4% FBS in the absence (control sample) or the presence
  • NanoBRET furimazine substrate (Promega) was added to both control and experimental samples at a final concentration of 10 ⁇ . Readings were performed within 5 minutes using the CLARIOstar (BMG) equipped with 450/80 nm bandpass and 610 nm longpass filters with a 0.5 sec reading setting. A corrected BRET ratio was calculated and is defined as the ratio of the emission at 610 nm/450 nm for experimental samples (i.e. those treated with NanoBRET fluorescent ligand) subtracted by the emission at 610 nm/450 nm for control samples (not treated with NanoBRET fluorescent ligand). BRET ratios are expressed as milliBRET units (mBU), where 1 mBU corresponds to the corrected BRET ratio multiplied by 1000.
  • mBU milliBRET units
  • the compound of formula (IA) was tested in the BRPF1 isoform 1 , and isoform 2 assays described above and were found to have a plC 50 as shown in the table below:
  • Solubility was determined by precipitation of 10 mM DMSO stock concentration to 5% DMSO pH7.4 phosphate buffered saline, with quantification by ChemiLuminescent Nitrogen Detection.

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Abstract

L'invention concerne un nouveau composé benzoimidazolyle, des compositions pharmaceutiques contenant un tel composé et son utilisation en thérapie.
PCT/EP2015/074298 2014-10-23 2015-10-21 Dérivé 1,3-diméthylbenzimidazolone en utilisé comme inhibiteur du bromodomaine de la protéine brpf1 Ceased WO2016062737A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB1418828.8 2014-10-23
GBGB1418828.8A GB201418828D0 (en) 2014-10-23 2014-10-23 Nowel compound

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WO2016062737A1 true WO2016062737A1 (fr) 2016-04-28

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PCT/EP2015/074298 Ceased WO2016062737A1 (fr) 2014-10-23 2015-10-21 Dérivé 1,3-diméthylbenzimidazolone en utilisé comme inhibiteur du bromodomaine de la protéine brpf1

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GB (1) GB201418828D0 (fr)
WO (1) WO2016062737A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116425721A (zh) * 2022-12-19 2023-07-14 艾立康药业股份有限公司 作为mat2a抑制剂的双环类化合物

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DEMON, E. H. ET AL., ACS MEDICINAL CHEMISTRY LETTERS, vol. 5, 10 September 2014 (2014-09-10), pages 1190 - 1195, XP002750623 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116425721A (zh) * 2022-12-19 2023-07-14 艾立康药业股份有限公司 作为mat2a抑制剂的双环类化合物
CN116425721B (zh) * 2022-12-19 2024-02-02 艾立康药业股份有限公司 作为mat2a抑制剂的双环类化合物

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