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WO2016001452A1 - Composés, destinés plus particulièrement à être utilisés dans le traitement d'une maladie ou d'une pathologie pour laquelle un inhibiteur du bromodomaine est indiqué - Google Patents

Composés, destinés plus particulièrement à être utilisés dans le traitement d'une maladie ou d'une pathologie pour laquelle un inhibiteur du bromodomaine est indiqué Download PDF

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Publication number
WO2016001452A1
WO2016001452A1 PCT/EP2015/065404 EP2015065404W WO2016001452A1 WO 2016001452 A1 WO2016001452 A1 WO 2016001452A1 EP 2015065404 W EP2015065404 W EP 2015065404W WO 2016001452 A1 WO2016001452 A1 WO 2016001452A1
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alkyl
substituted
nhc
unsubstituted
heterocycle
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Inventor
Cristina BLÁZQUEZ NEVADO
Amedeo Caflisch
Andrea Unzue Lopez
Min Xu
Jing Dong
Dimitrios SPILIOTOPOULOS
Emilie Frugier
Aymeric DOLBOIS
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Zurich Universitaet Institut fuer Medizinische Virologie
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Zurich Universitaet Institut fuer Medizinische Virologie
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to novel compounds, to pharmaceutical compositions containing such compounds and to their use in therapy.
  • long strands of DNA are packed within the nucleus in a dynamic form allowing intermittent and regulated access to genes for transcription.
  • This form is achieved by the winding of sections of DNA around octameric groups of histone proteins to form nucleosomes. Repeating nucleosomes units along the DNA strand aggregate and fold to form tightly packed chromatin. The degree of chromatin packing varies throughout the cell cycle; regulated chromatin loosening allows transcription machinery to access and transcribe selected genes.
  • Chromatin packing is influenced by a series of post-translational modifications of histone proteins and in particular of histones H3 and H4. Indeed, the post-translational acetylation of lysine residues within histone proteins has been recognized to play a critical role in the packing of chromatin and regulation of gene transcription.
  • acetylated lysines are generally recognized by a small protein domain referred to as a bromodomain. Bromodomain binding (commonly referred to as "reading") of acetylated lysines initiates the recruitment of regulatory complexes, thereby influencing chromatin structure.
  • bromodomain inhibitors Small-molecule inhibitors of selected bromodomain/histone interactions (hereafter “bromodomain inhibitors”) have been identified and show promise as future therapeutics, notably relative to cancer and inflammatory diseases. Acetylated lysines of p53, a tumor suppressor, have further been reported to associate with bromodomains.
  • CBP CREB-binding protein or CREBBP
  • CBP CREB-binding protein
  • CREB cAMP response element binding protein
  • CBP has been shown to function as a transcriptional coactivator for numerous oncogenes and tumor suppressors.
  • specific inhibition of CBP has been proposed as a treatment of obesity-linked diabetes and atherosclerosis (Tsuchida A. et al, "Nuclear receptors as targets for drug development: molecular mechanisms for regulation of obesity and insulin resistance by peroxisome proliferator-activated receptor gamma, CREB-binding protein, and adiponectin" J. Pharmacol.
  • I-BET and JQ-1 inhibitors only weakly inhibit the interaction of CBP with peptide binding partners (half maximal inhibition concentration (IC 50 ) ⁇ 50 ⁇ ). Indeed, few highly potent inhibitors of CBP have been reported to date.
  • ischemin inhibitors are reported to provide up 100% inhibition of CBP at 50 ⁇ , with CBP-inhibitor complex dissociation constant (K D ) values down to 19 ⁇ at best.
  • table 1 includes compounds with IC 50 values on CBP of 200 nM at best.
  • the Structural Genomics Consortium has published compounds I-CBP1 12 (a tetrahydro benzoxazepine derivative), with an IC 50 of 170 nM on CBP, and SGC-CBP30 (an isoxazole derivative), with an IC 50 of 69 nM on CBP, at http://www.thesgc.org/chemical- probes/epigenetics (see also Hay et al. "Discovery and Optimization of Small-Molecule Ligands for the CBP/p300 Bromodomains" J. Am. Chem. Soc, 136 (26): 9308-9319, 2014).
  • CPB inhibitors that are selective for CBP relative to other bromodomains, meaning that they bind to CBP with more potency than (have a lower K D or IC 50 than on) other bromodomains.
  • inhibitors are synthetically accessible, i.e. can be synthesized according to few, standard synthetic steps.
  • EP 1 666 473 A1 discloses broad class of carboxylic acid compounds as selective antagonists of prostoglandin D2 and indicated as useful for the treatment of diseases such as allergic diseases, systemic mastocytosis, disorders accompanied by systemic mast cell activation, anaphylactic shock, bronchoconstriction, urticarial, eczema, acne, allergic bronchial pulmonary aspergillosis, sinusitis, migraine, nasal polypus, anaphylactic vasculitis, eosinophilic syndrome, contact dermatitis, diseases accompanied by itch, inflammation, chronic obstructive pulmonary diseases, ischemic reperfusion injury, cerebrovascular accident, autoimmune disease, traumatic brain disorder, hepatopathy, graft rejection, chronic rheumatoid arthritis, pleurisy, osteroarthritis, Crohn's disease, ulcerative colitis, irritable bowel syndrome, interstitial cystitis, muscular dystrophy, polymyositis
  • WO 2012/1 16170 A1 discloses a wide range of compounds, though specific embodiments define a narrow chemical space, which are indicated as inhibitors of bromodomains. Among other important differences to the compounds of the present invention, WO 2012/1 16170 A1 does not disclose a compound comprising a substituted phenyl ring as is mandatory in the compounds of the present invention and further comprises linker moieties not corresponding to those of the present invention.
  • CBP inhibitors a novel class of compounds useful as inhibitors of the CBP/acetylated lysine interaction
  • Pharmaceutical compositions containing such compounds are further objects of the present invention.
  • a method of treating a disease or condition for which a bromodomain inhibitor is indicated is also subject of the present invention.
  • a first aspect of the present invention relates to a compound for use in the treatment of a disease or condition for which a bromodomain inhibitor is indicated characterized by a general formula (1 ),
  • a second aspect of the present invention relates to a compound, or prodrug or salt thereof, of formula (3),
  • a third aspect of the present invention relates to a method of treating a disease or condition for which a bromodomain inhibitor is indicated in a subject in need thereof which comprises administering a therapeutically effective amount of a compound, or salt or prodrug thereof, where said compound is characterized by the general formula (1 ), (2), (3), (4) or (5), particularly by the general formula (1 ), (2) or (3).
  • a fourth aspect of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of general formula (3), (4) or (5), particularly of general formula (3), and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • bromodomain inhibitor refers to a compound that inhibits the binding of a bromodomain with its cognate acetylated lysine or lysines of one or more proteins.
  • said cognate acetylated lysines are among the residues of one or more histones. More particularly, said histones are H3 or H4.
  • said bromodomain is CBP and/or EP300.
  • a CBP or EP300 bromodomain inhibitor is a compound that has a IC 50 that is less than 100 ⁇ as measured according to the IC 50 measurement method provided in the examples section hereafter, and/or a thermal shift of greater than or equal to 1 °C as measured according to the thermal shift measurement method provided in the examples section hereafter, and/or a K D of less than 50 ⁇ as measured according to the K D measurement method provided in the examples section hereafter.
  • the term "effective amount” refers to the amount of compound needed to elicit a biological or medical response within a human or within a human tissue, by a researcher or a clinician.
  • the term “therapeutically effective amount” refers to any amount of compound that will result in improved treatment, healing, prevention or amelioration of a disease or condition in a subject, or decreased advancement of a disease or condition in a subject, relative to a corresponding subject who has not received such an amount.
  • the term “parent compound” refers to all of the atoms of the general formulas (1 ), (2) and (3) provided herein having a single possible chemical identity.
  • Compounds of the present invention may be in the form of a "salt", meaning in the form of an ionic compound resulting from a neutralization reaction of an organic or inorganic acid with an organic or inorganic base.
  • salts are pharmaceutically acceptable salts.
  • suitable salts see Berge et al., J. Pharm. Sci., 66:1 -19, (1977).
  • the resultant salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
  • Compounds of the present invention may be in the form of a "prodrug", which is an inactive or less than fully active precursor form of the compound that is converted into the compound by normal metabolic processes, e.g., hydrolysis by, for example, an esterase of an ester form of the compound, and in particular of a methyl ester form of the compound, to generate a carboxylic acid.
  • Suitable prodrugs are recognizable to those skilled in the art, without undue experimentation. Nevertheless, reference is made to the teaching of Burger's Medicinal Chemistry and Drug Discovery, 5th Edition, Vol 1 : Principles and Practice.
  • substituted group refers to a chemical group in which one hydrogen atom has been replaced by a bond to a non-hydrogen atom on the parent compound.
  • alkyl refers to a saturated hydrocarbon substituent group containing 1 to 6, particularly 1 to 3 carbon atoms, that is linear or branched.
  • alkyl groups include, without limitation, methyl, ethyl, propyl, n-butyl, isobutyl, pentyl, isopentyl, neopentyl, hexyl, 2-methylpentyl, 3-methylpentyl, 2,2- methylpentyl, 2, 3-methylpentyl and the like.
  • heteroalkyl refers to a saturated hydrocarbon substituent group containing 1 to 5, particularly 1 to 3 carbon atoms, that is linear or branched, wherein at least one carbon is replaced with an oxygen or a nitrogen atom.
  • alkanol refers to an alkyl substituent group in which one or more hydrogen atom is replaced by a hydroxyl group.
  • alkanol substituent groups include, without limitation, methanol, ethanol, propanol, n-butanol, isobutanol and the like.
  • Alkanol groups as used herein may optionally include further substituent groups.
  • haloalkyi refers to an alkyl substituent group in which one or more hydrogen atom is replaced by a halogen atom.
  • this halogen atom is a CI or F.
  • haloalkyl substituent groups include, without limitation, CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, CHFCF 3 , CHFCHF 2 , CHFCH 2 F, CF 2 CF 3 , CF 2 CHF 2 , CF 2 CH 2 F and the like.
  • Haloalkyl groups as used herein may optionally include further substituent groups.
  • alkoxy refers to an oxygen-alkyl substituent group, wherein the oxygen atom is used to attach the alkoxy group to the parent compound.
  • alkoxy substituent groups include, without limitation, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, neopentoxy, n- hexoxy and the like.
  • Alkoxy groups as used herein may optionally include further substituent groups.
  • ether refers to an oxygen-alkyl or oxygen-aryl or oxygen-alkyl-aryl substituent group, wherein the oxygen atom is connected to two alkyi or two aryl groups, or to one alkyi and one aryl group, wherein these alkyi and/or aryl groups do not belong to the parent compound.
  • Ether groups as used herein may optionally include further substituent groups.
  • heterocycle refers to a saturated heterocycle or a heteroaryl substituent group.
  • saturated heterocycle refers to a saturated cyclic group wherein at least one carbon is replaced with an oxygen, a nitrogen or a sulphur atom.
  • saturated heterocycle substituent groups include, without limitation, morpholine, piperazine, pyrrolidine, thiolane, tetrahydrofuran, imidazolidine, pyrazolidine, oxazolidine, thiazolidine, piperidine, oxane groups and the like.
  • Saturated heterocycle groups as used herein may optionally include further substituent groups.
  • aryl refers to a hydrocarbon with alternating double and single bonds between the carbon atoms forming a ring structure.
  • heteroaryl refers to aryl compounds in which at least one carbon atom is replaced with an oxygen, a nitrogen or a sulphur atom.
  • aryl or hetero aryl substituent groups include, without limitation, benzene, pyridine, pyrrole, quinolone, imidazole, triazine, pyrazine, pyrimidine, pyradazine, thiazine, dioxin, tetrazole, triazole, thiadiazole, pyrazole, oxazole, thiazole, furan and the like.
  • Aryl or heteroaryl groups as used herein may optionally include further substituent groups.
  • the term "-COOH or salt thereof” refers to a carboxyl group or a salt derivative of the carboxyl group preferably selected from the group of alkali metals. .
  • any reference to the compounds of the general formula (1 ), (2), (3), (4) or (5) is to be understood as referring also to the corresponding tautomers.
  • the present invention relates to a compound for use in the treatment of a disease or condition for which a bromodomain inhibitor is indicated characterized by a general formula (1 ),
  • Ri is a C1-C3 alkyl, cyclopropane, a C1-C3 haloalkyl, halocyclopropane or -NHR 8 , wherein R 8 is a C1-C3 alkyl, cyclopropane, a C1-C3 haloalkyl or halocyclopropane; R 2 is H, F, a C1-C4 alkyl or a C1-C4 alkanol;
  • R 3 is H, F, CI, a CrC 6 alkyl, a C1-C 3 haloalkyl, a C1-C4 alkoxy, a C1-C4 alkanol, a C 2 - C 4 ether, a 3- to 6-membered saturated heterocycle, a 3- to 6-membered heteroaryl, a benzyloxy or a substituted amine of the form -NHR 8 , wherein R 8 is a C1-C 3 alkyl, cyclopropane, a C1-C 3 haloalkyl or halocyclopropane;
  • R 9 is C1-C 3 alkyl, C C 3 alkoxy, C C 3 haloalkyl, C C 3 alkanol, C 2 -C 4 ether, 3- to 6-membered heterocycle, or substituted or unsubstituted aryl, and wherein Ri 2 is -(CH 2 ) r -phenyl with r being 0, 1 or 2 and said phenyl may be substituted with one or more electron donating groups, in particular one or more electron donating groups selected from -OR1 3, with R 13 being H, a methyl group or an ethyl group;
  • A is selected from
  • R 4 is H or a methyl group
  • R 5 is H, -COOH or salt thereof, a C1-C3 alkoxyl, a C1-C3 alkyl, a C1-C3 alkyl ester, a heteroaryl, a substituted or unsubstituted Ci-C 6 alkoxyl or a sulfonic acid, a sulfonamide, particularly an S-linked sulfonamide, that may be singly substituted with a C1-C3 alkyl group or with a C 3 -C 6 cyclic alkyl; and
  • R 6 is H, - COOH or salt thereof, a C1-C 3 alkoxyl, a C1-C 3 alkyl, a C1-C 3 alkyl ester, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted Ci-C 6 alkoxyl or a sulfonic acid, a sulfonamide, particularly an S-linked sulfonamide, that may be singly substituted with a C1-C 3 alkyl group or with a C 3 -C 6 cyclic alkyl; and wherein R 7 and R1 0 being independently from each other selected from
  • n 0, 1 or 2;
  • Y is N, CH or C-Rn , with
  • R11 being a hydroxyl, a C1-C5 heteroalkyl, particularly a -(CH 2 ) p -OT 3 or a -(CH 2 ) P - N(T 3 )(T 4 ), with T 3 and T 4 being independently from each other H or C1-C 3 alkyl, and p is 0, 1 , 2, 3 ,4 or 5, a substituted or unsubstituted Ci-C 6 alkoxyl, a heteroaryl, a saturated heterocycle, -0-(CH 2 ) q -phenyl or -0-(CH 2 ) q -heterocycle, with q being 0, 1 or 2, wherein the saturated heterocycle or the -0-(CH 2 ) q - heterocycle are preferably C 3 -C 6 heterocycles, more preferably C 5 -C 6 heterocycles,
  • ⁇ - ⁇ and T 2 being independently from each other H, CH 3 or CH 2 CH 3 , particularly H, and R 7 and R1 0 having the same meaning as above.
  • the present invention relates to a compound for use in the treatment of a disease or condition for which a bromodomain inhibitor is indicated characterized by a general formula (1 ),
  • Ri is a C1-C3 alkyl, cyclopropane, a C1-C3 haloalkyl, halocyclopropane or -NHR 8 , wherein R 8 is a C1-C3 alkyl, cyclopropane, a C1-C3 haloalkyl or halocyclopropane; R 2 is H, F, a C1-C4 alkyl or a C1-C4 alkanol;
  • R 3 is H, F, CI, a C C 6 alkyl, a C C 3 haloalkyl, a C C 4 alkoxy, a C C 4 alkanol, a C 2 -
  • C 4 ether a 3- to 6-membered saturated heterocycle, a 3- to 6-membered heteroaryl, a benzyloxy or a substituted amine of the form -NHR 8 , wherein R 8 is a C1-C 3 alkyl, cyclopropane, a C1-C 3 haloalkyl or halocyclopropane;
  • R 9 is C1-C 3 alkyl, C C 3 alkoxy, C C 3 haloalkyl, C C 3 alkanol, C 2 -C 4 ether, 3- to 6-membered heterocycle, or substituted or unsubstituted aryl, and wherein Ri 2 is -(CH 2 ) r -phenyl with r being 0, 1 or 2 and said phenyl may be substituted with one or more electron donating groups, in particular one or more electron donating groups selected from -OR1 3, with R 13 being H, a methyl group or an ethyl group;
  • A is selected from
  • R 4 is H or a methyl group
  • R 5 is H, -COOH or salt thereof, a C1-C 3 alkoxyl, a C1-C 3 alkyl, a C1-C 3 alkyl ester, a heteroaryl, a substituted or unsubstituted Ci-C 6 alkoxyl or a sulfonic acid, a sulfonamide that may be singly substituted with a C1-C 3 alkyl group or with a C 3 -C 6 cyclic alkyl; and
  • R 6 is H, - COOH or salt thereof, a C1-C 3 alkoxyl, a C1-C 3 alkyl, a C1-C 3 alkyl ester, a heteroaryl, a substituted or unsubstituted Ci-C 6 alkoxyl or a sulfonic acid, a sulfonamide that may be singly substituted with a C1-C 3 alkyl group or with a C 3 -C 6 cyclic alkyl; and wherein
  • R 7 and R1 0 being independently from each other selected from
  • - n 0, 1 or 2;
  • R11 being a substituted or unsubstituted Ci-C 6 alkoxyl, a heteroaryl, -0-(CH 2 ) q -phenyl or -0-(CH 2 ) q -heterocycle, with q being 0, 1 or 2.
  • Ri is a C1-C 3 alkyl, cyclopropane, a C1-C 3 haloalkyi, halocyclopropane or -NHR 8 , wherein R 8 is a C1-C 3 alkyl, cyclopropane, a C1-C 3 haloalkyi or halocyclopropane.
  • R 2 is H, F, a C1-C4 alkyl or a C1-C4 alkanol.
  • R 3 is H, F, CI, a CrC 6 alkyl, a C1-C 3 haloalkyi, a C1-C4 alkoxy, a C1-C4 alkanol, a C 2 -C 4 ether, a 3- to 6-membered saturated heterocycle, a 3- to 6-membered heteroaryl, a benzyloxy or a substituted amine of the form -NHR 8 , wherein R 8 is a C1-C3 alkyi, cyclopropane, a C1-C3 haloalkyl or halocyclopropane.
  • R 4 is H or a methyl group.
  • R 5 is H, - COOH or salt thereof, a C C 3 alkoxyl, a C C 3 alkyi, a d- C 3 alkyi ester, a heteroaryl, a substituted or unsubstituted Ci-C 6 alkoxyl or a sulfonic acid, an S-linked sulfonamide that may be singly substituted with a C C 3 alkyi group or with a C 3 -C 6 cyclic alkyi, and preferably R 5 is H-COOH or salt thereof, C C 3 alkyi ester, in particular methylester, a tetrazole, which is preferably linked by its carbon moiety.
  • R 5 is H, -COOH or salt thereof, a C C 3 alkoxyl, a C C 3 alkyi, a C C 3 alkyi ester, a heteroaryl, a substituted or unsubstituted Ci-C 6 alkoxyl or a sulfonic acid, a sulfonamide that may be singly substituted with a C C 3 alkyi group or with a C 3 -C 6 cyclic alkyi.
  • R 6 is H, - COOH or salt thereof, a C C 3 alkoxyl, a C C 3 alkyi, a C C 3 alkyi ester, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted Ci-C 6 alkoxyl or a sulfonic acid, an S-linked sulfonamide that may be singly substituted with a C C 3 alkyi group or with a C 3 -C 6 cyclic alkyi, and preferably R 5 is H-COOH or salt thereof, C C 3 alkyi ester, in particular methylester, a tetrazole.
  • R 6 is H, - COOH or salt thereof, a C C 3 alkoxyl, a C C 3 alkyi, a C C 3 alkyi ester, a heteroaryl, a substituted or unsubstituted Ci-C 6 alkoxyl or a sulfonic acid, a sulfonamide that may be singly substituted with a C1-C3 alkyl group or with a C 3 -C 6 cyclic alkyl.
  • R 7 and Rio being independently from each other selected from
  • R 7 and R1 0 are independently from each other selected from H, CI, F or C1-C 3 alkanol, C1-C 3 alkyl, C1-C 3 haloalkyl, C1-C 3 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 4 alkyl ether, 3- to 6-membered saturated heterocycle, a 3- to 6-membered heteroaryl moiety, wherein said moieties may be substituted or unsubstituted, wherein the substituents of said substituted moieties with respect to R 4 and R 7 are selected from 3- to 6-membered heteroaryls and aryls, or 3- to 6-membered saturated heterocycles, which may also be substituted with one or more hydroxyl, amine or C1-C 3 alkoxy groups.
  • n 0, 1 or 2.
  • Y is N, CH or C-Rn , with R-n being a hydroxyl, a C1-C5 heteroalkyl, particularly a -(CH 2 ) p -OT 3 or a -(CH 2 ) P -N(T 3 )(T 4 ), with T 3 and T 4 being independently from each other H or C1-C 3 alkyl, and p is 0, 1 , 2, 3 ,4 or 5, a substituted or unsubstituted CrC 6 alkoxyl, a heteroaryl, a saturated heterocycle, -0-(CH 2 ) q -phenyl or -0-(CH 2 ) q -heterocycle, with q being 0, 1 or 2, wherein the saturated heterocycle or the -0-(CH 2 ) q -heterocycle are preferably C 3 -C 6 heterocycles, more preferably C 5 -C 6 heterocycles,
  • Y is N, CH or C-Rn , with R-n being a substituted or unsubstituted C C 6 alkoxyl, a heteroaryl, -0-(CH 2 ) q -phenyl or -0-(CH 2 ) q -heterocycle, with q being 0, 1 or 2.
  • R 6 and Y are connected forming a cyclic moiety of the formula 5'
  • the compound according to first aspect of the invention is characterized by a general formula (1 ), wherein R-i is a methyl or -NHR 8 where R 8 is a methyl, in particular R-i is a methyl; and/or R 2 is a hydrogen; and/or R 3 is H, F, a CrC 6 alkyl or a C1-C4 alkoxy, a benzyloxy or a morpholino, in particular R 3 is an ethoxy, a propoxy, a butoxy, cyclopropane, cyclopropylethoxy, benzyloxy or a morpholino, more particularly ethoxy; and/or R 4 is H or a methyl group; and/or R 5 is H, - COOH or salt thereof, a C1-C3 alkoxyl, a C1-C3 alkyl, a C1-
  • the compound according to first aspect of the invention is characterized by a general formula (1 ), wherein R-i is a methyl or -NHR 8 where R 8 is a methyl, in particular R-i is a methyl; and/or R 2 is a hydrogen; and/or R 3 is H, F, a CrC 6 alkyl or a C1-C4 alkoxy, a benzyloxy or a morpholino, in particular R 3 is an ethoxy, a propoxy, a butoxy, cyclopropane, cyclopropylethoxy, benzyloxy or a morpholino, more particularly ethoxy; and/or R 4 is H or a methyl group; and/or R 5 is H, - COOH or salt thereof, a C1-C3 alkoxyl, a C1-C3 alkyl, a C1-C3 alkyl ester, a heteroaryl, a substituted or unsubstitute
  • the compound according to first aspect of the invention is characterized by a general formula (2),
  • Ri is a C1-C3 alkyl, cyclopropane, a C1-C3 haloalkyi, halocyclopropane or -NHR 8 , wherein R 8 is a C1-C3 alkyl, cyclopropane, a C1-C3 haloalkyi or halocyclopropane;
  • R 2 is H, F, a C1-C4 alkyl or a C1-C4 alkanol
  • R 3 is H, F, CI, a CrC 6 alkyl, a C1-C 3 haloalkyi, a C1-C4 alkoxy, a C1-C4 alkanol, a C 2 -C 4 ether, a 3- to 6-membered saturated heterocycle, a 3- to 6-membered heteroaryl, a benzyloxy or a substituted amine of the form -NHR 8 , wherein R 8 is a C1-C 3 alkyl, cyclopropane, a C1-C 3 haloalkyi or halocyclopropane;
  • R 9 is C1-C 3 alkyl, C1-C 3 alkoxy, C1-C 3 haloalkyi, C1-C 3 alkanol, C 2 -C 4 ether, 3- to 6-membered heterocycle, or substituted or unsubstituted aryl, and wherein
  • R 12 is -(CH 2 ) r -phenyl with r being 0, 1 or 2 and said phenyl may be substituted with one or more electron donating groups, in particular one or more electron donating groups selected from -OR-I3, with R 13 being H, a methyl group or an ethyl group;
  • R 4 is H or a methyl group
  • R 5 being H, - COOH or salt thereof, a C1-C 3 alkoxyl, a C1-C 3 alkyl, a C1-C 3 alkyl ester, a heteroaryl, a substituted or unsubstituted Ci-C 6 alkoxyl or a sulfonic acid, a sulfonamide, particularly an S-linked sulfonamide, that may be singly substituted with a C1-C 3 alkyl group or with a C 3 -C 6 cyclic alkyl; and R 6 being H, - COOH or salt thereof, a C1-C3 alkoxyl, a C1-C3 alkyl, a C1-C3 alkyl ester, substituted or unsubstituted a heteroaryl, a substituted or unsubstituted Ci-C 6 alkoxyl or a sulfonic acid, a sulfonamide, particularly an S-linked sulfon
  • Ri is a C1-C3 alkyl, cyclopropane, a C1-C3 haloalkyl, halocyclopropane or -NHR 8 , wherein R 8 is a C1-C3 alkyl, cyclopropane, a C1-C3 haloalkyl or halocyclopropane;
  • R 2 is H, F, a C1-C4 alkyl or a C1-C4 alkanol
  • R 3 is H , F, CI, a CrC 6 alkyl, a C1-C 3 haloalkyl, a C1-C4 alkoxy, a C1-C4 alkanol, a C 2 -C 4 ether, a 3- to 6-membered saturated heterocycle, a 3- to 6-membered heteroaryl, a benzyloxy or a substituted amine of the form -NHR 8 , wherein R 8 is a C1-C 3 alkyl, cyclopropane, a C1-C 3 haloalkyl or halocyclopropane
  • R 9 is C1-C 3 alkyl, C1-C 3 alkoxy, C1-C 3 haloalkyl, C1-C 3 alkanol, C 2 -C 4 ether, 3- to 6-membered heterocycle, or substituted or unsubstituted aryl, and wherein
  • R 12 is -(CH 2 ) r -phenyl with r being 0, 1 or 2 and said phenyl may be substituted with one or more electron donating groups, in particular one or more electron donating groups selected from -OR-I3, with R 13 being H, a methyl group or an ethyl group,
  • R 4 is H or a methyl group
  • R 5 is H, - COOH or salt thereof, a C1-C 3 alkoxyl, a C1-C 3 alkyl, a C1-C 3 alkyl ester, a heteroaryl, a substituted or unsubstituted Ci-C 6 alkoxyl or a sulfonic acid, a sulfonamide that may be singly substituted with a C1-C 3 alkyl group or with a C 3 -C 6 cyclic alkyl; and
  • R 6 is H, - COOH or salt thereof, a C1-C 3 alkoxyl, a C1-C 3 alkyl, a C1-C 3 alkyl ester, a heteroaryl, a substituted or unsubstituted Ci-C 6 alkoxyl or a sulfonic acid, a sulfonamide that may be singly substituted with a C1-C3 alkyi group or with a C 3 -C 6 cyclic alkyi; and wherein n is 0, 1 or 2.
  • Ri is a C1-C3 alkyi, cyclopropane, a C1-C3 haloalkyl, halocyclopropane or -NHR 8 , wherein R 8 is a C C 3 alkyi, cyclopropane, a C C 3 haloalkyl or halocyclopropane.
  • Ri is a methyl or -NHR 8 where R 8 is a CrC 3 alkyi.
  • Ri is a methyl or -NHR 8 where R 8 is a methyl, in particular R-i is a methyl.
  • R 2 is H, F, a CrC 4 alkyi or a CrC 4 alkanol. In some embodiments, R 2 is a hydrogen, a methyl or a Ci-C 4 alkanol. In some embodiments, R 2 is a hydrogen.
  • R 3 is H, F, CI, a CrC 6 alkyi, a Ci-C 3 haloalkyl, a Ci-C 4 alkoxy, a Ci-C 4 alkanol, a C 2 -C 4 ether, a 3- to 6-membered saturated heterocycle, a 3- to 6-membered heteroaryl, a benzyloxy or a substituted amine of the form -NHR 8 , wherein R 8 is a CrC 3 alkyi, cyclopropane, a Ci-C 3 haloalkyl or halocyclopropane.
  • R 3 is H, F, a Ci-C 6 alkyi or a CrC 4 alkoxy, a benzyloxy or a morpholino, in particular R 3 is an ethoxy, a propoxy, a butoxy, cyclopropane, cyclopropylethoxy, benzyloxy or a morpholino, more particularly ethoxy.
  • R 3 is H, F, a CrC 6 alkyi or a CrC 4 alkoxy, in particular R 3 is an ethoxy.
  • R 4 is H or a methyl group.
  • R 5 is H, - COOH or salt thereof, a C1-C 3 alkoxyl, a C1-C 3 alkyi, a d- C 3 alkyi ester, a heteroaryl, a substituted or unsubstituted Ci-C 6 alkoxyl or a sulfonic acid, a sulfonamide, particularly an S-linked sulfonamide, that may be singly substituted with a C C 3 alkyi group or with a C 3 -C 6 cyclic alkyi.
  • R 5 Is is H, -COOH or salt thereof, C1-C 3 alkyi ester, in particular methylester, tetrazole, which is preferably linked by its carbon moiety, more particularly R 5 is H.
  • R 5 is H, - COOH or salt thereof, a C1-C 3 alkoxyl, a C1-C 3 alkyi, a C C 3 alkyi ester, a heteroaryl, a substituted or unsubstituted Ci-C 6 alkoxyl or a sulfonic acid, a sulfonamide that may be singly substituted with a C1-C 3 alkyi group or with a C 3 -C 6 cyclic alkyi.
  • R 5 is H-COOH or salt thereof, tetrazole, particularly a tetrazole bonded to the parent compound at the N1 position, C1-C 3 alkyi ester, in particular methylester.
  • R 6 is H, - COOH or salt thereof, a C1-C 3 alkoxyl, a C1-C 3 alkyi, a C C 3 alkyi ester, substituted or unsubstituted a heteroaryl, a substituted or unsubstituted Ci-C 6 alkoxyl or a sulfonic acid, a sulfonamide, particularly an S-linked sulfonamide, that may be singly substituted with a C1-C 3 alkyi group or with a C 3 -C 6 cyclic alkyi.
  • R 6 is H, -COOH or salt thereof, C1-C 3 alkyi ester, in particular methylester, a substituted or unsubstituted heteroaryl, a tetrazole, which is preferably linked by its carbon moiety.
  • R 6 is H, - COOH or salt thereof, a C1-C 3 alkoxyl, a C1-C 3 alkyi, a C C 3 alkyi ester, a heteroaryl, a substituted or unsubstituted Ci-C 6 alkoxyl or a sulfonic acid, a sulfonamide that may be singly substituted with a C1-C 3 alkyi group or with a C 3 -C 6 cyclic alkyi.
  • R 6 is H-COOH or salt thereof, tetrazole, particularly a tetrazole bonded to the parent compound at the N1 position, C1-C 3 alkyi ester, in particular methylester.
  • n 0, 1 or 2. In some embodiments, n is 0.
  • the compound according to first aspect of the invention is characterized by a general formula (2), wherein R-i is a methyl or -NHR 8 where R 8 is a C1-C 3 alkyi; and/or R 2 is a hydrogen, a methyl or a C1-C4 alkanol; and/or R 3 is H, F, a CrC 6 alkyi or a C1-C4 alkoxy, a benzyloxy or a morpholino, in particular R 3 is an ethoxy, a propoxy, a butoxy, cyclopropane, cyclopropylethoxy, benzyloxy or a morpholino, more particularly ethoxy; and/or R 4 is H or a methyl group; and/or R 5 is H, -COOH or salt thereof, C1-C3 alkyl ester, in particular methylester; or tetrazole, which is preferably linked by its carbon moiety, more particularly R 5
  • the compound according to first aspect of the invention is characterized by a general formula (2), wherein R-i is a methyl or -NHR 8 where R 8 is a C1-C 3 alkyl; R 2 is a hydrogen, a methyl or a C1-C4 alkanol; R 3 is H, F, a CrC 6 alkyl or a C1-C4 alkoxy, a benzyloxy or a morpholino, in particular R 3 is an ethoxy, a propoxy, a butoxy, cyclopropane, cyclopropylethoxy, benzyloxy or a morpholino, more particularly ethoxy; R 4 is H or a methyl group; R 5 is H-COOH or salt thereof, tetrazole, particularly a tetrazole bonded to the parent compound at the N1 position, C1-C 3 alkyl ester, in particular methylester; R 6 is H-COOH or salt
  • the compound according to first aspect of the invention is characterized by a general formula (2), wherein R-i is a methyl or -NHR 8 where R 8 is a methyl, in particular R-i is a methyl; and/or R 2 is a hydrogen; and/or R 3 is H, F, a CrC 6 alkyl or a C1-C4 alkoxy, in particular R 3 is an ethoxy; and/or R 4 is H or a methyl group; and/or R 5 is H, -COOH or salt thereof, C1-C 3 alkyl ester, in particular methylester, a tetrazole, which is preferably linked by its carbon moiety, more particularly R 5 is H; and/or R 6 is H, -COOH or salt thereof, C1-C 3 alkyl ester, in particular methylester, a substituted or unsubstituted heteroaryl, tetrazole, which is preferably linked by its carbon moiety; and/
  • the compound according to first aspect of the invention is characterized general formula (3) or (4),
  • Ri is a C1-C 3 alkyl, cyclopropane, a C1-C 3 haloalkyi, halocyclopropane or -NHR 8 , wherein R 8 is a C1-C 3 alkyl, cyclopropane, a C1-C 3 haloalkyi or halocyclopropane;
  • R 2 is H, F, a C C 4 alkyl or a C C 4 alkanol
  • R 3 is H , F, CI, a CrC 6 alkyl, a C1-C 3 haloalkyi, a C1-C4 alkoxy, a C1-C4 alkanol, a C 2 -C 4 ether, a 3- to 6-membered saturated heterocycle, a 3- to 6-membered heteroaryl, a benzyloxy or a substituted amine of the form -NHR 8 , wherein R 8 is a C1-C 3 alkyl, cyclopropane, a C1-C 3 haloalkyi or halocyclopropane;
  • R 5 being H, - COOH or salt thereof, a C1-C3 alkoxyl, a C1-C3 alkyl, a C1-C3 alkyl ester, a heteroaryl, a substituted or unsubstituted Ci-C 6 alkoxyl or a sulfonic acid, a sulfonamide, particularly an S-linked sulfonamide, that may be singly substituted with a C1-C3 alkyl group or with a C 3 -C 6 cyclic alkyl; and
  • R 6 being H, -COOH or salt thereof, a C1-C 3 alkoxyl, a C1-C 3 alkyl, a C1-C 3 alkyl ester, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted Ci-C 6 alkoxyl or a sulfonic acid, a sulfonamide, particularly an S-linked sulfonamide, that may be singly substituted with a C1-C 3 alkyl group or with a C 3 -C 6 cyclic alkyl; and wherein
  • R 7 and R1 0 being independently from each other selected from H, Br, CI, F, N0 2 or substituted or unsubstituted C1-C 3 alkanol, C1-C 3 alkyl, C1-C 3 haloalkyl, substituted or unsubstituted C1-C 3 alkoxy, C 3 -C 6 cycloalkyi, C 2 -C 4 alkyl ether, 3- to 6-membered saturated heterocycle, a 3- to 6-membered heteroaryl moiety, wherein said moieties may be substituted or unsubstituted, wherein the substituents of said substituted moieties with respect to R 4 and R 7 are selected from 3- to 6-membered heteroaryls and aryls, or 3- to 6- membered saturated heterocycles, which may also be substituted with one or more hydroxyl, amine or C1-C 3 alkoxy groups;
  • n 0, 1 or 2;
  • Y is N, CH or C-Rn , with Rn being a hydroxyl, a C1-C5 heteroalkyl, particularly a -(CH 2 ) p -OT 3 or a -(CH 2 )p-N(T 3 )(T4), with T 3 and T 4 being independently from each other H or C1-C 3 alkyl, and p is 0, 1 , 2, 3 ,4 or 5, a substituted or unsubstituted Ci-C 6 alkoxyl, a heteroaryl, a saturated heterocycle, -0-(CH 2 ) q -phenyl or -0-(CH 2 ) q -heterocycle, with q being 0, 1 or 2, wherein the saturated heterocycle or the -0-(CH 2 ) q -heterocycle are preferably C 3 -C 6 heterocycles, more preferably C 5 -C 6 heterocycles, or
  • the compound according to first aspect of the invention is characterized by a general formula (3), wherein is a C1-C3 alkyl, cyclopropane, a C1-C3 haloalkyi, halocyclopropane or -NHR 8 , wherein R 8 is a C1-C3 alkyl, cyclopropane, a C1-C3 haloalkyi or halocyclopropane; R 2 is H, F, a C1-C4 alkyl or a C1-C4 alkanol; R 3 is H, F, CI, a Ci-C 6 alkyl, a C1-C3 haloalkyi, a C1-C4 alkoxy, a C1-C4 alkanol, a C 2 -C 4 ether, a 3- to 6- membered saturated heterocycle, a 3- to 6-membered heteroaryl, a benzyloxy or a substituted
  • Ri is a C1-C 3 alkyl, cyclopropane, a C1-C 3 haloalkyi, halocyclopropane or -NHR 8 , wherein R 8 is a C1-C 3 alkyl, cyclopropane, a C1-C 3 haloalkyi or halocyclopropane.
  • Ri is a methyl or -NHR 8 where R 8 is a C1-C 3 .
  • Ri is a methyl or -NHR 8 where R 8 is a methyl, in particular R-i is a methly.
  • R 2 is H, F, a C1-C4 alkyl or a C1-C4 alkanol. In some embodiments, R 2 is a hydrogen, a methyl or a C1-C4 alkanol. In some embodiments, R 2 is a hydrogen.
  • R 3 is H, F, CI, a CrC 6 alkyl, a C1-C3 haloalkyi, a C1-C4 alkoxy, a C1-C4 alkanol, a C 2 -C 4 ether, a 3- to 6-membered saturated heterocycle, a 3- to 6-membered heteroaryl, a benzyloxy or a substituted amine of the form -NHR 8 , wherein R 8 is a C1-C 3 alkyl, cyclopropane, a C1-C 3 haloalkyi or halocyclopropane.
  • R 3 is H, F, a Ci-C 6 alkyl or a C1-C4 alkoxy, a benzyloxy or a morpholino, in particular R 3 is an ethoxy, a propoxy, a butoxy, cyclopropane, cyclopropylethoxy, benzyloxy or a morpholino, more particularly ethoxy. In some embodiments, R 3 is ethoxy, a propoxy, a butoxy, cyclopropane, cyclopropylethoxy, benzyloxy or a morpholino, more particularly ethoxy.
  • R 5 is H, -COOH or salt thereof, a C1-C 3 alkoxyl, a C1-C 3 alkyl, a C1-C 3 alkyl ester, a heteroaryl, a substituted or unsubstituted Ci-C 6 alkoxyl or a sulfonic acid, an S- linked sulfonamide that may be singly substituted with a C1-C3 alkyl group or with a C 3 -C 6 cyclic alky.
  • R 5 is H, - COOH or salt thereof, a C1-C 3 alkoxyl, a C1-C 3 alkyl, a d- C 3 alkyl ester, a heteroaryl, a substituted or unsubstituted Ci-C 6 alkoxyl or a sulfonic acid, a sulfonamide that may be singly substituted with a C1-C 3 alkyl group or with a C 3 -C 6 cyclic alkyl.
  • R 5 is H-COOH or salt thereof, tetrazole, particularly a tetrazole bonded to the parent compound at the N1 position, C1-C 3 alkyl ester, in particular methylester.
  • R 6 is H, -COOH or salt thereof, a C1-C 3 alkoxyl, a C1-C 3 alkyl, a C1-C 3 alkyl ester, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted Ci-C 6 alkoxyl or a sulfonic acid, an S-linked sulfonamide that may be singly substituted with a C1-C 3 alkyl group or with a C 3 -C 6 cyclic alky.
  • R 6 is H, - COOH or salt thereof, a C1-C 3 alkoxyl, a C1-C 3 alkyl, a C C 3 alkyl ester, a heteroaryl, a substituted or unsubstituted Ci-C 6 alkoxyl or a sulfonic acid, a sulfonamide that may be singly substituted with a C1-C 3 alkyl group or with a C 3 -C 6 cyclic alkyl.
  • R 6 is H-COOH or salt thereof, tetrazole, particularly a tetrazole bonded to the parent compound at the N1 position, C1-C 3 alkyl ester, in particular methylester.
  • n 0, 1 or 2. In some embodiments, n is 0.
  • R 7 and R1 0 being independently from each other selected from H, CI, F or C1-C 3 alkanol, C1-C 3 alkyl, C1-C 3 haloalkyl, C1-C 3 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 4 alkyl ether, 3- to 6-membered saturated heterocycle, a 3- to 6-membered heteroaryl moiety, wherein said moieties may be substituted or unsubstituted, wherein the substituents of said substituted moieties with respect to R 4 and R 7 are selected from 3- to 6-membered heteroaryls and aryls, or 3- to 6-membered saturated heterocycles, which may also be substituted with one or more hydroxyl, amine or C1-C 3 alkoxy groups.
  • R 7 is pyridine, furan, CH 2 OH, CH 2 OCH 3 or CH 2 -0-tetrahydropyran, in particular pyridine and furan, more particularly furan.
  • R 7 is pyridine, furan, CH 2 OH, CH 2 OCH 3 or CH 2 -0-tetrahydropyran, more particularly furan.
  • R1 0 is H or methyl, in particular H.
  • Y is N, CH or C-Rn with R-n being a hydroxyl, a C1-C5 heteroalkyl, particularly a -(CH 2 ) p -OT 3 or a -(CH 2 ) P -N(T 3 )(T 4 ), with T 3 and T 4 being independently from each other H or C1-C 3 alkyl, and p is 0, 1 , 2, 3 ,4 or 5, a substituted or unsubstituted CrC 6 alkoxyl, a saturated heterocycle, -0-(CH 2 ) q -phenyl or -0-(CH 2 ) q -heterocycle, wherein the saturated heterocycle or the -0-(CH 2 ) q -heterocycle are preferably C 3 -C 6 heterocycles, more preferably C 5 -C 6 heterocycles, and q is 0, 1 or 2, wherein said phenyl and said heterocycle of R-11 may optionally be substituted with one or
  • Y is N, CH or C-Rn with R-n being a hydroxyl, a substituted or unsubstituted Ci-C 6 alkoxyl, a saturated heterocycle, -0-(CH 2 ) q -phenyl or -0-(CH 2 ) q - heterocycle, and q is 0, 1 or 2, wherein the saturated heterocycle or the -0-(CH 2 ) q - heterocycle are preferably C 3 -C 6 heterocycles, more preferably C 5 -C 6 heterocycles, wherein said phenyl and said heterocycle of Rn is substituted with one or more methoxy or hydroxy groups, wherein preferably Y is CH, -0-(CH 2 ) q -heterocycle or hydroxyl.
  • Y is N, CH or C-Rn, with R-n being a substituted or unsubstituted C C 6 alkoxyl, a heteroaryl, -0-(CH 2 ) q -phenyl or -0-(CH 2 ) q -heterocycle, with q being 0, 1 or 2.
  • Y is N, CH or C-Rn with R-n being a substituted or unsubstituted CrC 6 alkoxyl, a heteroaryl, in particular morpholino or piperazine bonded via a N atom, -0-(CH 2 ) q - phenyl or -0-(CH 2 ) q -heterocycle, morpholino, piperazine or pyridine and q is 0, 1 or 2, wherein said phenyl and said heterocycle of Rn may optionally be substituted with one or more methoxy or hydroxy groups, wherein preferably Y is CH.
  • Y is N, CH or C-Rn with R-n being a substituted or unsubstituted CrC 6 alkoxyl, a heteroaryl, in particular morpholino or piperazine bonded via a N atom, -0-(CH 2 ) q - phenyl or -0-(CH 2 ) q -heterocycle, morpholino, piperazine or pyridine and q is 0, 1 or 2, wherein said phenyl and said heterocycle of Rn is substituted with one or more methoxy or hydroxy groups, wherein preferably Y is CH.
  • the compound according to first aspect of the invention is characterized by a general formula (3a) or (4a)
  • Ri is a methyl or -NHR 8 where R 8 is a CrC 3 ; and/or R 2 is a hydrogen, a methyl or a CrC 4 alkanol; and/or R 3 is H, F, a CrC 6 alkyl or a CrC 4 alkoxy, a benzyloxy or a morpholino, in particular R 3 is an ethoxy, a propoxy, a butoxy, cyclopropane, cyclopropylethoxy, benzyloxy or a morpholino, more particularly ethoxy; and/or R 5 is H , -COOH or salt thereof, a C1-C3 alkoxyl, a C1-C3 alkyi, a C1-C3 alkyi ester, a heteroaryl, a substituted or unsubstituted Ci-C 6 alkoxyl or a sulfonic acid, an S-linked sulfonamide that may be singly substituted with
  • the compound according to first aspect of the invention is characterized by a general formula (3a), wherein R-i is a methyl or -N H R 8 where R 8 is a C C 3 ; R 2 is a hydrogen, a methyl or a C C 4 alkanol; R 3 is H , F, a Ci-C 6 alkyi or a C C 4 alkoxy, a benzyloxy or a morpholino, in particular R 3 is an ethoxy, a propoxy, a butoxy, cyclopropane, cyclopropylethoxy, benzyloxy or a morpholino, more particularly ethoxy; R 5 is H , -COOH or salt thereof, a C1-C 3 alkoxyl, a C1-C 3 alkyi, a C1-C 3 alkyi ester, a heteroaryl, a substituted or unsubstituted Ci-C 6 alkoxyl or a sul
  • the compound according to first aspect of the invention is characterized by a general formula (3a) or (4a), particularly of formula (3a), Ri is a methyl or -N H R 8 where R 8 is a methyl, in particular R-i is a methyl; and/or R 2 is a hydrogen; and/or R 3 is ethoxy, a propoxy, a butoxy, cyclopropane, cyclopropylethoxy, benzyloxy or a morpholino, more particularly ethoxy; and/or R 5 is H , -COOH or salt thereof, a C1-C3 alkoxyl, a C1-C3 alkyl, a C1-C3 alkyl ester, a heteroaryl, a substituted or unsubstituted Ci-C 6 alkoxyl or a sulfonic acid, an S-linked sulfonamide that may be singly substituted with a C1-C3 alkyl group or with
  • the compound according to first aspect of the invention is characterized by a general formula (3a), wherein R-i is a methyl or -N H R 8 where R 8 is a methyl, in particular Ri is a methyl; R 2 is a hydrogen; R 3 is ethoxy, a propoxy, a butoxy, cyclopropane, cyclopropylethoxy, benzyloxy or a morpholino, more particularly ethoxy; R 5 is - COOH or salt thereof, a C1-C 3 alkyl ester, a sulfonic acid, a sulfonamide that may be singly substituted with a C1-C 3 alkyl group or with a C 3 -C 6 cyclic alkyl, or a 5-membered heteroaryl, in particular H , -COOH or salt thereof, tetrazole, particularly a tetrazole bonded to the parent compound at the N1 position, C1-C3
  • R 5 and R 6 may be dependent on the selection of X.
  • a preferred embodiment for R-i is a methyl.
  • a preferred embodiment for R 2 is a H.
  • Preferred embodiments for R 3 are an ethoxy, a propoxy, a butoxy, cyclopropane, cyclopropylethoxy, benzyloxy or a morpholino, more particularly ethoxy.
  • Preferred embodiments for R 4 are H or a methyl group.
  • a preferred embodiment for R 5 is H
  • R 6 are -COOH or salt thereof, a C C 3 alkyl ester, an S-linked sulfonamide that may be singly substituted with a C C 3 alkyl group or with a C 3 -C 6 cyclic alkyl or a substituted or unsubstituted heteroaryl, more preferred a C C 3 alkyl ester, particularly -COOH or salt thereof, a methylester, a tetrazole, particularly linked by its carbon moiety (C- tetrazole).
  • (C- tetrazole) Preferred embodiments for the substituted or unsubstituted heteroaryl of R 6 are 3-hydroxy- isoxazole bound via C4 (a') or C5 (a"), 4-alkyl-3-hydroxy-isoxazole bound via C5, where said alkyi (depicted with R) is a C1-C3 alkyi, 5-alkyl-3-hydroxy-isoxazole bound via C4, where said alkyi (depicted with R) is a C C 3 alkyi, 1 ,2,5-oxadiazol-3(2H)-one bound via C4 (d') or 1 ,2,5- oxadiazol-3-ol bound via C4 (d"), 1 ,2,5-thiadiazol-3(2H)-one bound via C4 (e') or 1 ,2,5- thiadiazol-3-ol bound via C4 (e"), 1 ,2,5-oxadiazole-3(2H)-thione bound via C4
  • Preferred embodiments for R 7 are H, N0 2 , C 2 -C 4 alkyl ether, heteroaryl, particularly pyridine and furan, more particularly furan, a 3- to 6-membered saturated heterocycle, particularly tetrazole, a substituted or unsubstituted C1-C3 alkoxy, particularly a the -0-(CH 2 ) q - heterocycle with q being 0, 1 or 2.
  • Preferred embodiments for R 7 are H, Br, furan, in particular H.
  • Preferred embodiments for Y are CH or C-Rn, with R-n being a hydroxyl, a saturated heterocycle, a substituted or unsubstituted Ci-C 6 alkoxyl, -0-(CH 2 ) q -heterocycle, with q being 0, 1 or 2, more preferred is Y being CH or C-Rn, with R-n being H, a hydroxyl or -0-(CH 2 ) q - heterocycle, with q being 0, 1 or 2.
  • each of R 6 and R 7 is a tetrazole, particularly one of R 6 or R 7 is a tetrazole connected by its carbon moiety,
  • R 6 is a tetrazole connected by its carbon moiety and R 7 is a tetrazole connected by its nitrogen moiety;
  • each of R 6 and R 7 is a tetrazole, which are both connected by their carbon moiety
  • R 6 is a tetrazole, particularly a tetrazole connected by its carbon moiety, and R 7 is furan,
  • R 6 is -COOH or salt thereof, a Ci-C 3 alkyl ester and R 7 is a tetrazole, particularly a tetrazole connected by its carbon moiety,
  • R 6 is a tetrazole, particularly a tetrazole connected by its carbon moiety
  • R 7 is -O- (CH 2 ) q -heterocycle, with q being 0, 1 or 2
  • R 6 is a tetrazole, particularly a tetrazole connected by its carbon moiety, and Y is C- R-i-i, with Rn being H, a hydroxyl or -0-(CH 2 ) q -heterocycle, with q being 0, 1 or 2.
  • a second aspect of the present invention relates to a compound, or prodrug or salt thereof, of formula (3) (4) or (5),
  • Ri is a C 1 -C3 alkyl, cyclopropane, a C 1 -C3 haloalkyl, halocyclopropane or -NHR 8 , wherein R 8 is a C 1 -C3 alkyl, cyclopropane, a C 1 -C3 haloalkyl or halocyclopropane; R 2 is H, F, a C 1 -C4 alkyl or a C 1 -C4 alkanol;
  • R 3 is H, F, CI, a CrC 6 alkyl, a C 1 -C 3 haloalkyl, a C 1 -C4 alkoxy, a C 1 -C4 alkanol, a C 2 - C 4 ether, a 3- to 6-membered saturated heterocycle, a 3- to 6-membered heteroaryl, a benzyloxy or a substituted amine of the form -NHR 8 , wherein R 8 is a C 1 -C 3 alkyl, cyclopropane, a C 1 -C 3 haloalkyl or halocyclopropane;
  • R 9 is C 1 -C 3 alkyl, C C 3 alkoxy, C C 3 haloalkyl, C C 3 alkanol, C 2 -C 4 ether, 3- to 6-membered heterocycle, or substituted or unsubstituted aryl, and wherein Ri 2 is -(CH 2 ) r -phenyl with r being 0, 1 or 2 and said phenyl may be substituted with one or more electron donating groups, in particular one or more electron donating groups selected from -OR1 3, with R 13 being H, a methyl group or an ethyl group;
  • R 5 being H, -COOH or salt thereof, a C 1 -C 3 alkoxyl, a C 1 -C 3 alkyl, a C 1 -C 3 alkyl ester, a heteroaryl, a substituted or unsubstituted Ci-C 6 alkoxyl or a sulfonic acid, a sulfonamide, particularly an S-linked sulfonamide, that may be singly substituted with a C 1 -C 3 alkyl group or with a C 3 -C 6 cyclic alkyl; and
  • R 6 being H, -COOH or salt thereof, a C 1 -C 3 alkoxyl, a C 1 -C 3 alkyl, a C 1 -C 3 alkyl ester, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted Ci-C 6 alkoxyl or a sulfonic acid, a sulfonamide, particularly an S-linked sulfonamide, that may be singly substituted with a C 1 -C 3 alkyl group or with a C 3 -C 6 cyclic alkyl; and wherein R 7 and R 10 being independently from each other selected from
  • - n 0, 1 or 2;
  • - Y being N , CH or C-Rn , with R-n being a hydroxyl, a CrC 5 heteroalkyl, particularly a -(CH 2 ) p -OT 3 or a -(CH 2 ) P -N(T 3 )(T 4 ), with T 3 and T 4 being independently from each other H or C C 3 alkyl, and p is 0, 1 , 2, 3 ,4 or 5, a substituted or unsubstituted Ci-C 6 alkoxyl, a heteroaryl, a saturated heterocycle, -0-(CH 2 ) q -phenyl or -0-(CH 2 ) q -heterocycle, with q being 0, 1 or 2, wherein the saturated heterocycle or the -0-(CH 2 ) q -heterocycle are preferably C 3 -C 6 heterocycles, more preferably C 5 -C 6 heterocycles, and
  • ⁇ and T 2 being independently from each other H, CH 3 or CH 2 CH 3 , particularly H.
  • One embodiment of the second aspect of the present invention relates to a compound, or prodrug or salt thereof, of formula (3), wherein R- ⁇ is a C C 3 alkyl, cyclopropane, a C C 3 haloalkyl, halocyclopropane or -NHR 8 , wherein R 8 is a C C 3 alkyl, cyclopropane, a C C 3 haloalkyl or halocyclopropane; R 2 is H, F, a Ci-C 4 alkyl or a Ci-C 4 alkanol; R 3 is H, F, CI, a Ci-C 6 alkyl, a C C 3 haloalkyl, a Ci-C 4 alkoxy, a C1-C4 alkanol, a C 2 -C 4 ether, a 3- to 6- membered saturated heterocycle, a 3- to 6-membered heteroaryl, a benzyloxy or a substituted amine of
  • Ri is a C1-C 3 alkyi, cyclopropane, a C1-C 3 haloalkyi, halocyclopropane or -NHR 8 , wherein R 8 is a C1-C 3 alkyi, cyclopropane, a C1-C 3 haloalkyi or halocyclopropane.
  • Ri is a methyl or -NHR 8 where R 8 is a C1-C 3 .
  • Ri is a methyl or -NHR 8 where R 8 is a methyl, in particular R-i is a methy.
  • R 2 is H, F, a C1-C4 alkyi or a C1-C4 alkanol. In some embodiments, R 2 is a hydrogen, a methyl or a C1-C4 alkanol. In some embodiments, R 2 is a hydrogen.
  • R 3 is H, F, CI, a CrC 6 alkyi, a C1-C 3 haloalkyi, a C1-C4 alkoxy, a C1-C4 alkanol, a C 2 -C 4 ether, a 3- to 6-membered saturated heterocyde, a 3- to 6-membered heteroaryl, a benzyloxy or a substituted amine of the form -NHR 8 , wherein R 8 is a C1-C 3 alkyi, cyclopropane, a C1-C 3 haloalkyi or halocyclopropane.
  • R 3 is H, F, a Ci-C 6 alkyi or a C1-C4 alkoxy, a benzyloxy or a morpholino, in particular R 3 is an ethoxy, a propoxy, a butoxy, cyclopropane, cyclopropylethoxy, benzyloxy or a morpholino, more particularly ethoxy. In some embodiments, R 3 is ethoxy, a propoxy, a butoxy, cyclopropane, cyclopropylethoxy, benzyloxy or a morpholino, more particularly ethoxy.
  • R 5 is H, -COOH or salt thereof, a C C 3 alkoxyl, a C C 3 alkyl, a C C 3 alkyl ester, a heteroaryl, a substituted or unsubstituted Ci-C 6 alkoxyl or a sulfonic acid, a sulfonamide, particularly an S-linked sulfonamide, that may be singly substituted with a C C 3 alkyl group or with a C 3 -C 6 cyclic alkyl
  • R 5 is H, - COOH or salt thereof, a C C 3 alkoxyl, a C C 3 alkyl, a C C 3 alkyl ester, a heteroaryl, a substituted or unsubstituted Ci-C 6 alkoxyl or a sulfonic acid, a sulfonamide that may be singly substituted with a C C 3 alkyl group or with a C 3 -C 6 cyclic alkyl.
  • R 5 is H-COOH or salt thereof, tetrazole, particularly a tetrazole bonded to the parent compound at the N1 position, C C 3 alkyl ester, in particular methylester.
  • R 6 is H, -COOH or salt thereof, a C C 3 alkoxyl, a C C 3 alkyl, a C C 3 alkyl ester, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted Ci-C 6 alkoxyl or a sulfonic acid, a sulfonamide, particularly an S-linked sulfonamide, that may be singly substituted with a C C 3 alkyl group or with a C 3 -C 6 cyclic alkyl.
  • R 6 is H, - COOH or salt thereof, a C C 3 alkoxyl, a C C 3 alkyl, a C C 3 alkyl ester, a heteroaryl, a substituted or unsubstituted Ci-C 6 alkoxyl or a sulfonic acid, a sulfonamide that may be singly substituted with a C1-C3 alkyl group or with a C 3 -C 6 cyclic alkyl.
  • R 6 is H-COOH or salt thereof, tetrazole, particularly a tetrazole bonded to the parent compound at the N1 position, C1-C3 alkyl ester, in particular methylester.
  • n 0, 1 or 2. In some embodiments, n is 0.
  • R 7 and Rio being independently from each other selected from H, Br, CI, F, N0 2 or a substituted or unsubstituted C1-C3 alkanol, C C 3 alkyl, C C 3 haloalkyl, substituted or unsubstituted C C 3 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 4 alkyl ether, 3- to 6- membered saturated heterocycle, a 3- to 6-membered heteroaryl moiety, wherein said moieties may be substituted or unsubstituted, wherein the substituents of said substituted moieties with respect to R 4 and R 7 are selected from 3- to 6-membered heteroaryls and aryls, or 3- to 6-membered saturated heterocycles, which may also be substituted with one or more hydroxyl, amine or C C 3 alkoxy groups.
  • R 7 and Rio being independently from each other selected from H, CI, F or Ci-C 3 alkanol, C C 3 alkyl, C C 3 haloalkyl, C C 3 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 4 alkyl ether, 3- to 6-membered saturated heterocycle, a 3- to 6-membered heteroaryl moiety, wherein said moieties may be substituted or unsubstituted, wherein the substituents of said substituted moieties with respect to R 4 and R 7 are selected from 3- to 6-membered heteroaryls and aryls, or 3- to 6-membered saturated heterocycles, which may also be substituted with one or more hydroxyl, amine or C C 3 alkoxy groups.
  • R 7 is pyridine, furan, CH 2 OH, CH 2 OCH 3 or CH 2 -0-tetrahydropyran, in particular pyridine and furan, more particularly furan.
  • R 7 is pyridine, furan, CH 2 OH, CH 2 OCH 3 or CH 2 -0-tetrahydropyran, more particularly furan.
  • Rio is H or methyl, in particular H.
  • Y is N, CH or C-Rn , with R-n being a hydroxyl, a CrC 5 heteroalkyl, particularly a -(CH 2 ) p -OT 3 or a -(CH 2 ) P -N(T 3 )(T 4 ), with T 3 and T 4 being independently from each other H or C C 3 alkyl, and p is 0, 1 , 2, 3 ,4 or 5, a substituted or unsubstituted CrC 6 alkoxyl, a heteroaryl, a saturated heterocycle, -0-(CH 2 ) q -phenyl or -0-(CH 2 ) q -heterocycle, with q being 0, 1 or 2, wherein the saturated heterocycle or the -0-(CH 2 ) q -heterocycle are preferably C 3 -C 6 heterocycles, more preferably C 5 -C 6 heterocycles, and in case of formula (5) T-i and T 2 being independently from each other H
  • Y is N, CH or C-Rn , with R-n being a substituted or unsubstituted C C 6 alkoxyl, a heteroaryl, -0-(CH 2 ) q -phenyl or -0-(CH 2 ) q -heterocycle, with q being 0, 1 or 2.
  • Y is N, CH or C-Rn with R-n being a substituted or unsubstituted CrC 6 alkoxyl, a heteroaryl, in particular morpholino or piperazine bonded via a N atom, -0-(CH 2 ) q - phenyl or -0-(CH 2 ) q -heterocycle, morpholino, piperazine or pyridine and q is 0, 1 or 2, wherein said phenyl and said heterocycle of Rn may optionally be substituted with one or more methoxy or hydroxy groups, wherein preferably Y is CH.
  • Y is N, CH or C-Rn with R-n being a substituted or unsubstituted CrC 6 alkoxyl, a heteroaryl, in particular morpholino or piperazine bonded via a N atom, -0-(CH 2 ) q - phenyl or -0-(CH 2 ) q -heterocycle, morpholino, piperazine or pyridine and q is 0, 1 or 2, wherein said phenyl and said heterocycle of Rn is substituted with one or more methoxy or hydroxy groups, wherein preferably Y is CH.
  • the compound according to second aspect of the invention is characterized by a general formula (3a) or (4a),
  • R-i is a methyl or -NHR 8 where R 8 is a CrC 3 ;
  • R 2 is a hydrogen, a methyl or a CrC 4 alkanol
  • R 3 is H, F, a CrC 6 alkyl or a Ci-C 4 alkoxy, a benzyloxy or a morpholino, in particular R 3 is an ethoxy, a propoxy, a butoxy, cyclopropane, cyclopropylethoxy, benzyloxy or a morpholino, more particularly ethoxy; and/or
  • - R 5 is H, -COOH or salt thereof, a C C 3 alkoxyl, a C C 3 alkyl, a C C 3 alkyl ester, a heteroaryl, a substituted or unsubstituted Ci-C 6 alkoxyl or a sulfonic acid, an S-linked sulfonamide that may be singly substituted with a C C 3 alkyl group or with a C 3 -C 6 cyclic alky; and/or
  • R 6 is H, -COOH or salt thereof, a C C 3 alkoxyl, a C C 3 alkyl, a C C 3 alkyl ester, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted Ci-C 6 alkoxyl or a sulfonic acid, an S-linked sulfonamide that may be singly substituted with a C C 3 alkyl group or with a C 3 -C 6 cyclic alky; and/or
  • R-io is H or methyl, in particular H
  • R 7 is pyridine, furan, CH 2 OH, CH 2 OCH 3 or CH 2 -0-tetrahydropyran, more particularly furan; and/or Y is N , CH or C-Rn with R-n being a hydroxyl, a substituted or unsubstituted CrC 6 alkoxyl, , a saturated heterocycle, -0-(CH 2 ) q -phenyl or -0-(CH 2 ) q -heterocycle, wherein the saturated heterocycle or the -0-(CH 2 ) q -heterocycle are preferably C 3 -C 6 heterocycles, more preferably C 5 -C 6 heterocycles, and q is 0, 1 or 2, wherein said phenyl and said heterocycle of Rn may optionally be substituted with one or more methoxy or hydroxy groups, wherein preferably Y is CH ; and/or
  • the compound according to second aspect of the invention is characterized by a general formula (3a) or (4a), particularly of formula (3a), wherein R-i is a methyl or -N H R 8 where R 8 is a methyl, in particular R-i is a methyl; and/or R 2 is a hydrogen; and/or R 3 is ethoxy, a propoxy, a butoxy, cyclopropane, cyclopropylethoxy, benzyloxy or a morpholino, more particularly ethoxy; and/or R 5 is H , -COOH or salt thereof, a C C 3 alkoxyl, a Ci-C 3 alkyi, a C C 3 alkyi ester, a heteroaryl, a substituted or unsubstituted Ci-C 6 alkoxyl or a sulfonic acid, an S-linked sulfonamide that may be singly substituted with a C C 3 alkyi group or with a C 3
  • the compound according to second aspect of the invention is characterized by a general formula (3a), wherein R-i is a methyl or -N H R 8 where R 8 is a C C 3 ; R2 is a hydrogen, a methyl or a C1-C4 alkanol; R 3 is H , F, a Ci-C 6 alkyi or a C1-C4 alkoxy, a benzyloxy or a morpholino, in particular R 3 is an ethoxy, a propoxy, a butoxy, cyclopropane, cyclopropylethoxy, benzyloxy or a morpholino, more particularly ethoxy; R 5 is H, -COOH or salt thereof, a C1-C3 alkoxyl, a C1-C3 alkyi, a C1-C3 alkyi ester, a heteroaryl, a substituted or unsubstituted Ci-C 6 alkoxyl or a
  • the compound according to first aspect of the invention is characterized by a general formula (3a), wherein R-i is a methyl or -NHR 8 where R 8 is a methyl, in particular R- ⁇ is a methyl; R 2 is a hydrogen; R 3 is ethoxy, a propoxy, a butoxy, cyclopropane, cyclopropylethoxy, benzyloxy or a morpholino, more particularly ethoxy; R 5 is - COOH or salt thereof, a C1-C 3 alkyi ester, a sulfonic acid, a sulfonamide that may be singly substituted with a C1-C 3 alkyi group or with a C 3 -C 6 cyclic alkyi, or a 5-membered heteroaryl, in particular H, -COOH or salt thereof, tetrazole, particularly a tetrazole bonded to the parent compound at the N 1 position, C1-C
  • a preferred embodiment for R-i is a methyl.
  • a preferred embodiment for R 2 is a H.
  • Preferred embodiments for R 3 are an ethoxy, a propoxy, a butoxy, cyclopropane, cyclopropylethoxy, benzyloxy or a morpholino, more particularly ethoxy.
  • Preferred embodiments for R 4 are H or a methyl group.
  • a preferred embodiment for R 5 is H
  • R 6 are -COOH or salt thereof, a C1-C3 alkyl ester, an S-linked sulfonamide that may be singly substituted with a C1-C3 alkyl group or with a C 3 -C 6 cyclic alkyl or a substituted or unsubstituted heteroaryl, more preferred a C1-C3 alkyl ester, particularly -COOH or salt thereof, a methylester, a tetrazole, particularly linked by its carbon moiety (C- tetrazole).
  • Preferred embodiments for the substituted or unsubstituted heteroaryl of R 6 are 3-hydroxy- isoxazole bound via C4 (a') or C5 (a"), 4-alkyl-3-hydroxy-isoxazole bound via C5, where said alkyl (depicted with R) is a C1-C3 alkyl, 5-alkyl-3-hydroxy-isoxazole bound via C4, where said alkyl (depicted with R) is a C C 3 alkyl, 1 ,2,5-oxadiazol-3(2H)-one bound via C4 (d') or 1 ,2,5- oxadiazol-3-ol bound via C4 (d"), 1 ,2,5-thiadiazol-3(2H)-one bound via C4 (e') or 1 ,2,5- thiadiazol-3-ol bound via C4 (e"), 1 ,2,5-oxadiazole-3(2H)-thione bound via C4 (f) or 1 ,2,5-
  • R 5 and R 6 may be dependent on the selection of X. References is made to the respective section under the first aspect of the invention.
  • Compound 50 Methyl (£)-4-((3-acetylphenyl)amino)-4-oxobut-2-enoate
  • a disease or condition for which a bromodomain inhibitor is indicated wherein said disease or condition is cancer, an autoimmune disease or alzheimer's disease, in particular leukemia and more particularly an acute myeloid leukemia.
  • said bromodomain is CBP or EP300.
  • a third aspect of the present invention relates to a method of treating a disease or condition for which a bromodomain inhibitor is indicated in a subject in need thereof which comprises administering a therapeutically effective amount of a compound, or salt or prodrug thereof, where said compound is characterized by the general formula (1 ), (2), (3), (4) or (5), particularly by by the general formula (1 ), (2) or (3).
  • a fourth aspect of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of general formula (3), (4) or (5), particularly (3), and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the pharmaceutical preparation further comprises at least one pharmaceutically acceptable carrier.
  • the invention relates to pharmaceutical preparations comprising at least one compound mentioned hereinbefore as active ingredient, which can be used especially in the treatment of the diseases mentioned.
  • the pharmaceutical preparations may be used in particular for a method for treatment of cancer.
  • the pharmaceutical preparations are for enteral administration, such as nasal, buccal, rectal or, especially, oral administration, and for parenteral administration, such as intravenous, intramuscular or subcutaneous administration, to mammals, in particular humans, are especially preferred.
  • the dosage of the active ingredient depends upon the disease to be treated and upon the species, its age, weight, and individual condition, the individual pharmacokinetic data, and the mode of administration.
  • the pharmaceutical preparations comprise from approximately 1 % to approximately 95% active ingredient.
  • Unit dose forms are, for example, coated and uncoated tablets, ampoules, vials, suppositories, or capsules. Further dosage forms are, for example, ointments, creams, pastes, foams, tinctures, lipsticks, drops, sprays, dispersions, etc.
  • the pharmaceutical preparations of the present invention are prepared in a manner known per se, for example by means of conventional mixing, granulating, coating, dissolving or lyophilizing processes.
  • the pharmaceutical preparations are in form of solutions of the active ingredient, and also suspensions or dispersions, especially isotonic aqueous solutions, dispersions or suspensions which, for example in the case of lyophilized preparations comprising the active ingredient alone or together with a carrier, for example mannitol, can be made up before use.
  • suspensions or dispersions especially isotonic aqueous solutions, dispersions or suspensions which, for example in the case of lyophilized preparations comprising the active ingredient alone or together with a carrier, for example mannitol, can be made up before use.
  • the pharmaceutical preparations may be sterilized and/or may comprise excipients, for example preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, salts for regulating osmotic pressure and/or buffers and are prepared in a manner known per se, for example by means of conventional dissolving and lyophilizing processes.
  • the said solutions or suspensions may comprise viscosity-increasing agents, typically sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone, or gelatins, or also solubilizers, e.g. Tween 80® (polyoxyethylene(20)sorbitan mono-oleate).
  • the pharmaceutical preparation comprises suspensions in oil, which comprise as the oil component a vegetable, synthetic- or semi-synthetic oils customary for injection purposes.
  • the pharmaceutical preparation comprises liquid fatty acid esters that contain as the acid component a long-chained fatty acid having from 8 to 22, especially from 12 to 22, carbon atoms.
  • the alcohol component of these fatty acid esters has a maximum of 6 carbon atoms and is monovalent or polyvalent, for example a mono-, di- or trivalent, alcohol, especially glycol and glycerol.
  • the pharmaceutical preparation comprises a mixture of fatty acid esters, vegetable oils such as, without being limited to, cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil and groundnut oil.
  • Suitable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations, and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and also binders, such as starches, for example corn, wheat, rice or potato starch, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone, and/or, if desired, disintegrators, such as the above-mentioned starches, also carboxymethyl starch, crosslinked polyvinyl pyrrolidone, alginic acid or a salt thereof, such as sodium alginate.
  • Additional excipients are especially flow conditioners and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol, or derivatives thereof.
  • Tablet cores can be provided with suitable, optionally enteric, coatings through the use of, inter alia, concentrated sugar solutions which may comprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable organic solvents or solvent mixtures, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropyl- methylcellulose phthalate. Dyes or pigments may be added to the tablets or tablet coatings, for example for identification purposes or to indicate different doses of active ingredient.
  • the pharmaceutical preparation is suitable for oral administration also include hard capsules consisting of gelatin, and soft, sealed capsules consisting of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the hard capsules may contain the active ingredient in the form of granules, for example in admixture with fillers, such as corn starch, binders, and/or glidants, such as talc or magnesium stearate, and optionally stabilizers.
  • the active ingredient is preferably dissolved or suspended in suitable liquid excipients, such as fatty oils, paraffin oil or liquid polyethylene glycols or fatty acid esters of ethylene or propylene glycol, to which stabilizers and detergents, for example of the polyoxy ethylene sorbitan fatty acid ester type, may also be added.
  • suitable liquid excipients such as fatty oils, paraffin oil or liquid polyethylene glycols or fatty acid esters of ethylene or propylene glycol, to which stabilizers and detergents, for example of the polyoxy ethylene sorbitan fatty acid ester type, may also be added.
  • the pharmaceutical preparation is suitable for rectal administration and is, for example, a suppository that consist of a combination of the active ingredient and a suppository base.
  • Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.
  • the pharmaceutical preparation is suitable for parenteral administration.
  • Aqueous solutions of an active ingredient in water-soluble form or aqueous injection suspensions that contain viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and, if desired, stabilizers, are especially suitable.
  • the active ingredient can also be in the form of a lyophilizate and can be made into a solution before parenteral administration by the addition of suitable solvents. Solutions such as are used, for example, for parenteral administration can also be employed as infusion solutions.
  • a further aspect of the invention relates to a compound according to any of the claims or a pharmaceutical preparation according to the claims for use in a method of treatment of disease.
  • the compounds of the general formula (1 ) have valuable pharmacological properties.
  • a further aspect relates to a bromodomain inhibitor comprising a compound according to the first or second aspect of the invention, in particular for use in the treatment of a disease or condition for which a bromodomain inhibitor is indicated, wherein said disease or condition is cancer, an autoimmune disease or alzheimer's disease, in particular leukemia and more particularly an acute myeloid leukemia.
  • the said bromodomain is CBP or EP300.
  • High-resolution electrospray ionization mass spectrometry was performed on a Finnigan MAT 900 (Thermo Finnigan, San Jose, CA, USA) double-focusing magnetic sector mass spectrometer. Ten spectra were acquired. A mass accuracy ⁇ 2 ppm was obtained in the peak matching acquisition mode by using a solution containing 2 ⁇ _ PEG200, 2 ⁇ _ PPG450, and 1 .5 mg NaOAc (all obtained from Sigma-Aldrich, Buchs, Switzerland) dissolved in 100 mL MeOH (HPLC Supra grade, Scharlau, E-Barcelona) as internal standard.
  • Dimethyl 5- ⁇ methoxymethyl)isophthalate To a solution of dimethyl 5- (hydroxymethyl)isophthalate (150 mg, 0.669 mmol) in DMF (1.50 mL) NaH (53.5 mg, 1.34 mmol) was added and stirred at 25 °C for 30 minutes. Methyl iodide (83.3 ⁇ _, 1.34 mmol) was added and the reaction mixture stirred for 3 hours at 25 °C. The reaction was quenched by addition of 1 M HCI solution and extracted with EtOAc three times. The combined organic phases were dried over MgS0 4 and concentrated under reduced pressure.
  • Methyl 5-acetyl-2ethoxybenzoate White solid; Yield: 88 %; mp 50-53 °C; MS (ESI), m/z: calcd for Ci 2 H 14 Na0 4 + , 245.1 ; found, 244.9.
  • Methyl 4-bromo-3-formylbenzoate was prepared using the reported procedure. White solid; Yield: 90%; mp 66-70 °C.
  • alkyl chlorides products 1 -(4-isobutoxy-3-nitrophenyl)ethan-1 -one and 1 -(4-(cyclopropylmethoxy)-3- nitrophenyl)ethan-1 -one
  • the alkyl chloride (2.0 eq) was first stirred in DMF (0.30 M) in the presence of Nal (2.0 eq) for 30 min.
  • the phenol (1 .0 eq) and K 2 C0 3 (4.0 eq) were then added and the same procedure as the one described above was followed.
  • 1 -(3-amino-4-ethoxyphenyl)ethan-1 -one To a stirred solution of 1 -(4-ethoxy-3- nitrophenyl)ethan-1 -one (10 g, 48 mmol) in EtOAc (230 ml_), was added Pd/C (2.6 g, 2.4 mmol, 10 % w. Pd) portionwise and pyridine (390 ⁇ _, 0.48 mmol). Nitrogen gas was bubbled in the flask and through the mixture and two balloons of H 2 were added. The reaction was stirred for 7 hours at 25°C, it was filtered over a short pad of Celite ® and washed with MeOH. The filtrate was evaporated to afford the desired aniline as a brown solid in pure form (8.44 g, 47 mmol, 98 % yield. Mp 83-85 °C.
  • 1 - ⁇ 3-Amino-4-morpholinophenyl)ethan-1 -one A solution of 1 -(4-Bromo-3- nitrophenyl)ethanone (500 mg, 2.05 mmol) in isopropanol (5.00 ml_) was heated at 1 10 °C for 3 h. SnCI 2 .2H 2 0 (1 .80 g, 7.98 mmol) was then added and heated at 1 10 °C for 5 h. The reaction mixture was concentrated under reduced pressure and the pH was basified to pH 5 by the addition of a 5 M NaOH solution. The resulting precipitate was filtered off and washed with EtOAc.
  • 3-Amino-4-ethoxy-W-methylbenzamide To a solution of 3-amino-4-ethoxybenzoic acid (66, 100 mg, 0.552 mmol) in DMF (1.80 ml_), methylamine hydrochloride (150 mg, 2.22 mmol), HOBt (89.4 mg, 0.662 mmol), EDC.HCI (1.104 mmol, 212 mg) and DIPEA (385 ⁇ _, 2.21 mmol) were added. The solution was stirred at 55 °C for 12 h, it was concentrated and purified by flash column chromatography (5 % MeOH in DCM) affording the desired amide as a white solid in pure form (75.0 mg, 0.384 mmol, 70 % yield). Mp 142-145 °C; MS (ESI), m/z: calcd for Ci 0 H 15 N 2 O 2 + , 195.1 128; found, 195.1 129.
  • Ci 9 H 20 N 2 NaO 5 + 379.1264; found, 379.1262.
  • Methyl 3-((5-acetyl-2-ethoxyphenyl)carbamoyl)-5-(benzyloxy)benzoate White solid Yield: 51 %; mp 141 -142 °C.
  • Methyl 6-((5-acetyl-2-ethoxyphenyl)carbamoyl)picolinate White solid; Yield: 92 %;
  • the reaction mixture was stirred at 25 °C for 3 hours, it was concentrated, redissolved in EtOAc and extracted with 1 M NaHC0 3 solution.
  • the EtOAc phase was dried over MgS0 4 and concentrated under reduced pressure.
  • the obtained residue was purified by flash column chromatography (9 % MeOH, 1 % Et 3 N and 90 % DCM) obtaining the desired product together with Et 3 N.HCI, which was removed by dissolving the product in EtOAc and extracting it with 1 M NaHC0 3 .
  • the EtOAc phase was once again dried over MgS0 4 and concentrated under reduced pressure to afford the desired piperazine in pure form as a yellow solid in 60% yield, mp 122-127 °C.
  • N-(5-acetyl-2-ethoxyphenyl)-3-(2H-tetrazol-5-y)benzamide (27): Yellow solid; Yield: 97 %; mp 238-239 °C N-(5-acetyl-2-ethoxyphenyl)-3-(furan-3-yl)-5-(2H-tetrazol-5-yl)benzamide (48) Brown solid; Yield: 66 %; 265-267 °C. Methyl 3-((5-acetyl-2- ethoxyphenyl)carbamoyl)-5-hydroxybenzoate:
  • the pH of the reaction mixture was brought to 1 by the addition of a 1 M HCI solution. It was then concentrated, redissolved in EtOH (0.1 M) and PTSA (0.1 eq) was added. The solution was stirred at 25 °C for 5 h and concentrated. Upon the addition of 1 M HCI solution, the final product precipitated. It was filtered out and washed with 1 M HCI solution and Et 2 0 affording the desired alcohol in pure form.
  • reaction mixture was diluted with water and extracted with hexane.
  • the aqueous phase was then brought to pH 3-4 by addition of a 10% citric acid solution. It was then extracted with EtOAc three times, the combined organic phases were dried over MgS0 4 and evaporated under reduced pressure obtaining the final product 16 in pure form.
  • Proteins for thermal shift assays were purified as described previously (Filippakopoulos et al., 2012. Cell. 149(1 ): 214-231 ). Plasmids bearing the His-tagged bromodomain constructs in the following table were kindly provided by the Structural Genomics Consortium. His- tagged bromodomains were expressed in Escherichia coii BL21 (DE3) cells upon induction with 0.1 mM isopropyl thio-beta-D-galactoside (IPTG) for 16 h at 18°C.
  • IPTG isopropyl thio-beta-D-galactoside
  • TR-FRET assays were carried out in duplicate at BPS Bioscience using a recombinant CBP bromodomain (BPS catalogue #31 128) and the BET Ligand (BPS catalogue #33000) as provided in the CREBBP TR-FRET Assay Kit (BPS catalogue #32619).
  • BPS catalogue #31 1278 a recombinant CBP bromodomain
  • BPS catalogue #33000 the BET Ligand
  • BPS catalogue #32619 BPS catalogue #32619
  • a 10 mM solution of the compound under investigation in DMSO was prepared and shipped to BPS Bioscience, where it was tested at 10 concentrations over the range listed in the table below. Each compound solution was then diluted in water to obtain a 10% DMSO solution.
  • the TR-FRET data was analyzed using Graphpad Prism software.
  • the IC 50 value corresponds to the concentration causing a half-maximal percent activity.
  • K D determinations by means of BROMOscan technology was carried out at DiscoveRx.
  • Escherichia coii derived from BL21 strain was used as host to grow T7 phage strains displaying the correspondinging bromodomain.
  • Escherichia coii, grown to log-phase were infected with T7 phage (from a frozen stock, being the multiplicity of infection 0.4) and incubated while shaking at 32 °C for 90-150 minutes, until lysis. To remove cell debris, lysates were centrifuged at 5,000 x g and filtered (0.2 ⁇ ).
  • Affinity resins were obtained by treating streptavidin-coated magnetic beads with biotinylated acetylated peptide ligands for 30 minutes at 25 °C. These beads were then blocked with excess of biotin and washed with blocking buffer (SeaBlock (Pierce), 1 % BSA, 0.05 % Tween 20, 1 mM DTT) removing the unbound ligand and reducing non-specific phage binding.
  • blocking buffer SeaBlock (Pierce), 1 % BSA, 0.05 % Tween 20, 1 mM DTT
  • test compounds were prepared as 50 mM in pure DMSO and diluted to 5 mM with monoethyl gycol (100X concentrated in respect to the top screening concentration, 50 ⁇ ). During the assay, a DMSO and MEG final concentration of 0.1 % and 0.9 %, respectively, were used. The assays were carried out in polystyrene 96-well plates in a final volume of 0.135 ml_.
  • HL-60, ML2 and OCI-AML2 cells obtained from Dr. Nathan Luedtke, Chemistry Department, University of Zurich
  • Kasumi-1 cells obtained from Dr. Juerg Schwaller, Department of Biomedicine, University Hospital Basel
  • MOLM-13 cells obtained from Dr. Nathan Luedtke, Chemistry Department, University of Zurich
  • RPMI medium supplemented with 20 % (v/v) fetal bovine serum.
  • All the media were additionally supplemented with 100 units/mL of penicillin, 100 ⁇ g/mL of streptomycin, 4.5 g/L glucose, 0.1 1 g/L sodium pyruvate and 2mM glutamine and the cells were grown at 37 °C in 5 % C0 2 atmosphere with 80 % relative humidity.
  • Gl 50 ( ⁇ ) values calculated as the intercept at 50 % growth inhibition between two drug concentrations (50 and 25 ⁇ ). NA indicates that no Gl 50 value could be obtained. A dash indicates that no experiment was performed.

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Abstract

L'invention concerne un composé destiné à être utilisé dans le traitement d'une maladie ou d'une pathologie pour ce dernier étant caractérisé par une formule générale (1) et un composé selon la formule (3).
PCT/EP2015/065404 2014-07-04 2015-07-06 Composés, destinés plus particulièrement à être utilisés dans le traitement d'une maladie ou d'une pathologie pour laquelle un inhibiteur du bromodomaine est indiqué Ceased WO2016001452A1 (fr)

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Publication number Priority date Publication date Assignee Title
US12485169B2 (en) 2018-11-23 2025-12-02 Grey Wolf Therapeutics Limited Compounds

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US12485169B2 (en) 2018-11-23 2025-12-02 Grey Wolf Therapeutics Limited Compounds

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