WO2011161201A1 - Bisarylsulfonamides utilisés comme inhibiteurs de la kinase dans le traitement de l'inflammation et du cancer - Google Patents

Bisarylsulfonamides utilisés comme inhibiteurs de la kinase dans le traitement de l'inflammation et du cancer Download PDF

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WO2011161201A1
WO2011161201A1 PCT/EP2011/060526 EP2011060526W WO2011161201A1 WO 2011161201 A1 WO2011161201 A1 WO 2011161201A1 EP 2011060526 W EP2011060526 W EP 2011060526W WO 2011161201 A1 WO2011161201 A1 WO 2011161201A1
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hydroxy
benzoic acid
sulfonylamino
acid
chloro
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PCT/EP2011/060526
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English (en)
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Johan Angbrant
Evert Homan
Thomas LUNDBÄCK
Jessica Martinsson
Meral Sari
Mattias JÖNSSON
Katarina FÄRNEGÅRDH
Kenth Hallberg
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Kancera Ab
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P35/00—Antineoplastic agents
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/12—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings
    • C07C311/13—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings the carbon skeleton containing six-membered aromatic rings
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    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/23—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atoms of the sulfonamide groups bound to acyclic carbon atoms
    • C07C311/27—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atoms of the sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings
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    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C07C311/38—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton
    • C07C311/39—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
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    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
    • C07C311/46—Y being a hydrogen or a carbon atom
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    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
    • C07C311/47—Y being a hetero atom
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    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/64—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and sulfur atoms, not being part of thio groups, bound to the same carbon skeleton
    • C07C323/67—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and sulfur atoms, not being part of thio groups, bound to the same carbon skeleton containing sulfur atoms of sulfonamide groups, bound to the carbon skeleton
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/32—Sulfur atoms
    • C07D213/34—Sulfur atoms to which a second hetero atom is attached
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    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/26—Radicals substituted by sulfur atoms
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
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    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
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    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
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    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to novel sulfonamide derivatives, to pharmaceutical compositions comprising these derivatives, to processes for their preparation and to sulfonamide de- rivatives for use in therapy, e.g. for the treatment of inflammation and cancer.
  • Fructose-2,6-bisphosphate plays a regulatory role in glucose metabolism by relieving ATP inhibition of phosphofructokinase-1.
  • the levels of F-2,6-P 2 are regulated by the bifunctional enzyme family 6-phosphofructo-2- kinase/fructose-2,6-bisphosphate (PFKFB 1 -4).
  • PFKFB3 and PFKFB4 are of particular interest for playing a role in cancer.
  • Anti-sense treatment against PFKFB3 was shown to reduce tumor growth rate in vivo (Chesney et al, (1999) Proc. Natl. Acad. Sci. USA 96, 3047-3052)
  • siRNA treated fibroblasts Telang et al., (2006) Oncogene 25, 7225-7234.
  • IL-6 proinflammatory cytokine interleukin-6 enhances glycolysis in mouse embryonic fibroblasts and human cell lines.
  • Minchenko et al. showed increased expression of PFKFB4 mRNA in breast and colon malig- nant tumors as compared to corresponding non-malignant tissue counterparts as well as in several cancer cell lines.
  • PFKFB4 was reported to be strongly responsive to hypoxia (Minchenko et al, (2004) FEBS Lett. 576, 14-20); Minchenko et al, (2005), Biochemie 87, 1005- 1010; Bobarykina et al, (2006), Acta Biochemica Polonica 3, 789-799).
  • Telang et al. showed decreased levels of F-2,6-P 2 and lactate as well as decreased tumor growth folio w- ing siRNA silencing of PFKFB4 (Telang, S. et al, (2010) US2010/0267815 Al).
  • a drug-like compound was recently described (Clem et al (2008) Mol. Cancer Ther. 7, 110- 120, WO 2008/156783) where 3-(3-pyridinyl)-l-(4-pyridinyl)-2-propen-l-one (3PO), by computational methods, was identified as a PFKFB3 inhibitor.
  • 3PO 3-(3-pyridinyl)-l-(4-pyridinyl)-2-propen-l-one
  • 3PO 3-(3-pyridinyl)-l-(4-pyridinyl)-2-propen-l-one
  • One object of the present invention is to provide small molecule inhibitors of the kinase activities of PFKFB3 and/or PFKFB4.
  • Another object of the present invention is to provide compounds for use in the treatment of inflammation or cancer.
  • n is 0 or 1 ;
  • R 1 is selected from H; halogen; C1-C6 alkyl, optionally substituted with at least one halogen, and C1-C6 alkoxy substituted with at least one halogen;
  • R 2 and R 3 are each independently selected from H; halogen; C1-C6 alkyl; C1-C6 alkoxy; secondary or tertiary CI -C6 alkylamido; carbocyclylcarbonylamino-C0-C2 alkyl; 5- or 6- membered cyclic aminocarbonyl; C1-C6 alkylcarbonylamino; C1-C6 alkylsulfonyl; hydro xy- C0-C6 alkyl, C1-C6 alkylcarbonyl; carboxy; C1-C6 alkoxycarbonyl; cyano; nitro; carbocy- clyloxy; heterocyclyloxy; carbocyclyl-C0-C3 alkyl; carbocyclyl-C2-C3 alkenyl; heterocyclyl- C0-C3 alkyl; and heterocyclyl-C2-C3 alkenyl; wherein any alkyl is optionally substituted with at least one halogen;
  • novel compounds of formula (I) are provided wherein: n is 0 or 1 ;
  • R 1 is selected from H; halogen; C1-C6 alkyl, optionally substituted with at least one halogen; and C1-C6 alkoxy, substituted with at least one halogen;
  • R 2 and R 3 are each independently selected from H; halogen; C1-C6 alkyl; C1-C6 alkoxy; secondary or tertiary CI -C6 alkylamido; carbocyclylcarbonylamino-C0-C2 alkyl; 5- or 6- membered cyclic aminocarbonyl; C1-C6 alkylcarbonylamino; C1-C6 alkylsulfonyl; hydro xy- C0-C6 alkyl, C1-C6 alkylcarbonyl; carboxy; C1-C6 alkoxycarbonyl; cyano; carbocyclyloxy; heterocyclyloxy; carbocyclyl-C0-C3 alkyl; carbocyclyl-C2-C3 alkenyl; heterocyclyl-C0-C3 alkyl; and heterocyclyl-C2-C3 alkenyl; wherein any alkyl is optionally substituted with at least one halogen; any carbocyclyl
  • R 2 is in meta position relative to the sulfonamide bond
  • R 3 is not selected from H; halogen; C1-C6 alkyl; C1-C6 alkoxy; C1-C6 alkylcarbonylamino; C1-C6 alkylcarbonyl; carboxy; C1-C6 alkoxycarbonyl; cyano; cyclohexyl; trifluoromethyl and trifluoromethoxy; and
  • R 3 when R 3 is selected from H, F, CI, Br, methyl and tert-butyl, R 2 is not H; and with the further proviso that the compound is not selected from
  • composition comprising a compound as defined herein, and optionally at least one pharmaceutically acceptable excipient.
  • Another object of the present invention relates to inhibition of the PFKFB3 and/or PFKFB4 protein with the compound as defined herein.
  • a compound as defined herein is provided for use in the treatment of a disorder related to or mediated by the PFKFB3 protein.
  • a compound as defined herein for use in the treatment of a disorder related to or mediated by the PFKFB4 protein.
  • the present invention provides a method of treatment of cancer and inflammation, by the inhibition of PFKFB3 and/or PFKFB4, and a compound for use in such a method. This is achieved by either a single molecule inhibiting both PFKFB3 and PFKFB4 or by separate molecules with selective specificities for either PFKFB3 or PFKFB4.
  • n is 0 or 1 ;
  • R 1 is selected from H; halogen; and C1-C6 alkyl, optionally substituted with at least one halogen; and C1-C6 alkoxy substituted with at least one halogen;
  • R 2 and R 3 are each independently selected from H; halogen; C1-C6 alkyl; C1-C6 alkoxy; secondary or tertiary CI -C6 alkylamido; carbocyclylcarbonylamino-C0-C2 alkyl; 5- or 6- membered cyclic aminocarbonyl; C1-C6 alkylcarbonylamino; C1-C6 alkylsulfonyl; hydro xy- C0-C6 alkyl, C1-C6 alkylcarbonyl; carboxy; C1-C6 alkoxycarbonyl; cyano; nitro; carbocy- clyloxy; heterocyclyloxy; carbocyclyl-C0-C3 alkyl; carbocyclyl-C2-
  • one object of the invention is to provide a method for the treatment of cancer, inflammation or an inflammatory disorder in a mammal in need of such treatment by adminis- tering to said mammal a compound as defined herein.
  • the present invention provides a compound of formula (I) as defined herein above, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, inflammation or an inflammatory disorder, with the proviso that the compound is not selected from 4-(3,4-dichlorophenylsulfonamido)-2-hydroxybenzoic acid and 4-(4- ethylphenylsulfonamido)-2-hydroxybenzoic acid.
  • EphA2 Receptors The Journal of Biological Chemistry, Vol. 283, No. 43, pp. 29461-29472, Oct. 24, 2008.
  • EphA4 and EphA2 Receptors are involved in pathologies such as nerve injuries and cancer.
  • the compound 4-(4-ethylphenylsulfonamido)-2- hydroxybenzoic acid is mentioned in WO/2007/087266, which is directed to the development of new chemical entities for use in the treatment of disease, and more particularly to methods of identifying lead molecules for use in quasi-rational drug design.
  • WO/2007/087266 there is described "the provision of a method that can test literally trillions of chemical structures within a living host to find chemical structures that bind to the target (e.g., a protein or other large molecule); uses standard assaying techniques to determine which of the chemical struc- tures that bind to the target will provide the desired activity; and/or uses already known facts about the binding chemical structures to guide the construction of the small molecule lead".
  • the target e.g., a protein or other large molecule
  • 4- (4-ethylphenylsulfonamido)-2-hydroxybenzoic acid is identified as an inhibitor of epidermal growth factor binding to its receptor and it is noted that such compounds have utility as treatments in oncology.
  • the present invention also provides a compound of formula (I) as defined herein above, or a pharmaceutically acceptable salt thereof, for use in therapy, with the proviso that the compound is not selected from
  • the present invention provides a novel compound of formula (I) as defined herein above, or a pharmaceutically acceptable salt thereof, with the proviso that the compound is not selected from:
  • the term “carbocyclyl” refers to a cyclic moiety containing only carbon at- oms
  • the term “heterocyclyl” refers to a cyclic moiety containing not only carbon atoms, but also at least one other atom in the ring structure, e.g. a nitrogen, sulphur or oxygen atom.
  • the terms “carbocyclyl” and “heterocyclyl” should not be construed as encompassing cyclic moieties containing an oxo group in the ring, such as in e.g. cyclohexa-2,5- dienone, cyclohexanone or 3H-pyrrol-3-one.
  • the term monocyclic refers to a cyclic moiety containing only one ring.
  • bicyclic refers to a cyclic moiety containing two rings, fused to each other.
  • any cyclyl may be carbocyclyl or heterocyclyl, saturated or unsaturated, and aromatic or non-aromatic.
  • cyclohexyl, cyclohexenyl and phenyl are all examples of monocyclic C6 carbocyclyl.
  • aromatic refers to an unsaturated cyclic (carbocyclic or heterocyclic) moiety that has an aromatic character
  • non-aromatic refers to a cyclic moiety, that may be unsaturated, but that does not have an aromatic charac- ter.
  • the two rings, fused to each other may be both saturated or both unsaturated, e.g. both aromatic.
  • the rings may also be of different degrees of saturation, and one ring may be aromatic whereas the other is non-aromatic.
  • the rings also may comprise different numbers of atoms, e.g. one ring being 5-membered and the other one being 6-membered, forming together a 9-membered bicyclic ring.
  • heterocyclyl or heterocycle or heterocyclic moiety, etc.
  • one or both of the rings may contain one or several, e.g. 1, 2, 3 or 4 heteroatoms.
  • heteroa- tom is meant N, O and S.
  • n-membered cyclic moiety as referred to herein contains n ring (or cyclic) atoms.
  • aromatic heterocyclic moieties according to the invention are pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzothiazol- yl, benzoxadiazolyl, benzimidazolyl, indazolyl, benzothiazolyl, benzo furyl, benzoxazolyl, benzothienyl, isoquinolinyl, naphthyridinyl, quinolinyl, phthalazinyl, quin
  • non-aromatic heterocycle or “non- aromatic heterocyclyl” refers to a non-aromatic cyclic group or radical containing one or more heteroatom(s) preferably selected fromN, O and S, such as a dihydropyrrolyl, dioxolanyl, dithiolanyl, imidazolidinyl, imidazolinyl, pyrrolidinyl, pyrazolidinyl, tetrahydro furyl, thiola- nyl, dihydropyranyl, dihydropyridyl, dioxanyl, dithianyl, morpholinyl, piperidyl, piperazinyl, pyranyl, tetrahydropyranyl, tetrahydropyridyl, tetrahydro -2H-thiopyranyl, and trithianyl etc.
  • heteroatom(s) preferably selected fromN, O and S, such as a dihydropyrrolyl,
  • non-aromatic heterocycles are bicyclyl radicals, also including those containing one aromatic and one non-aromatic ring, e.g. indolinyl, chromanyl, thiochromanyl, 1,2,3,4-tetrahydroisoquinolyl, etc.
  • Cn refers to a radical or moiety containing n carbon atoms.
  • Cn-Cm where m>n, refers to a radical or moiety containing n, n+1, n+2,...or m carbon atoms.
  • C1-C6 alkyl refers to an alkyl radical that may contain 1, 2, 3, 4, 5 or 6 carbon atoms.
  • CO alkyl refers to a covalent bond.
  • carbocyclyl-CO alkyl refers to carbocyclyl.
  • An alkyl moiety according to the invention having from 1-6 C may be branched or linear, e.g. selected from methyl, ethyl, n-propyl, /-propyl, n-butyl, /-butyl, sec- butyl, /er/-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3- methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl.
  • An alkenyl moiety according to the invention is a straight or branched hydrocarbyl comprising at least one double bond between any two adjacent carbon atoms, e.g. a straight or branched hydrocarbyl comprising 1 double bond.
  • halogen or “halo" means fluorine (F), chlorine (CI), bromine (Br) or iodine (I).
  • carbocyclyloxy refers to a radical of the type RO-, wherein R is a carbocyclyl moiety.
  • Phenoxy is an example of a carbocyclyloxy radical.
  • phenoxy refers to the radical
  • heterocyclyloxy refers to a radical of the type RO-, wherein R is a heterocyclyl moi- ety.
  • alkoxy refers to a radical of the type RO-, wherein R is an alkyl moiety.
  • alkoxycarbonyl refers to a radical of the type ROC(O)-, wherein R is an alkyl moiety.
  • carboxy refers to the radical HO(0)C-.
  • alkylthio refers to a radical of the type RS-, wherein R is an alkyl moiety.
  • amino refers to the radical H 2 N-.
  • hydroxy refers to the radical HO-.
  • hydroxy-C0-C6 alkyl refers to a radical selected from hydroxy (viz. hydroxy-CO alkyl) and a C1-C6 alkyl radical substituted with a hydroxy.
  • the hydroxy may be attached at any carbon atom of the alkyl radical, and the alkyl radical may be branched or linear.
  • hydroxy-Cl alkyl is hydroxymethyl.
  • cyano refers to the radical NC-.
  • alkyl substituted with at least one halogen is meant an alkyl radical of the formula C n X p H(2n+i-p)-, wherein X p refers to p independently selected halogen atoms, replacing p hydrogen atoms of the alkyl radical C n H2 n +i- at the same or different carbon atoms.
  • An example of an alkyl substituted with at least one halogen is trifluoromethyl.
  • the alkyl substituted with at least one halogen may be a moiety forming a part of another radical, such as in trifluoro- methoxy or difluoromethoxy.
  • trifluoromethyl refers to the radical CF 3 -.
  • trifluoromethoxy refers to the radical CF 3 0-.
  • difluoromethoxy refers to the radical CHF 2 0-.
  • secondary alkylamino refers to a radical of the type RHN-, wherein R is an alkyl moiety.
  • tertiary alkylamino refers to a radical of the type RR ' N-, wherein R and R ' are each an independently selected alkyl moiety.
  • carbamoyl refers to the radical NH 2 C(0)-.
  • secondary alkylamido refers to radical of the type RHNC(O)-, wherein R is an alkyl moiety.
  • tertiary alkylamido refers to a radical of the type RR ' NC(O)-, wherein R and R ' are each an independently selected alkyl moiety.
  • alkylcarbonylamino refers to a radical of the type RC(0)NH-, wherein R is an alkyl moiety.
  • carbocyclylcarbonylammo refers to a radical of the type RC(0)NH-, wherein R is a carbocyclic moiety, e.g. an aromatic carbocyclic moiety such as phenyl.
  • carbocyclylcarbonylamino-C0-C2 alkyl refers to a radical selected from carbocyclylcarbonylammo (viz. carbocyclylcarbonylamino-CO alkyl), carbocyclylcarbonylaminome- thyl (viz. carbocyclylcarbonylamino-Cl alkyl) or carbocyclylcarbonylaminoethyl (viz. carbo- cyclylcarbonylamino-C2 alkyl).
  • alkylcarbonyl refers to a radical of the type RC(O)-, wherein R is an alkyl moiety.
  • acetyl refers to an alkylcarbonyl radical of formula CH 3 C(0)-.
  • cyclic amino refers to a radical of the type RR ' N-, wherein R and R ' together with the nitrogen atom to which they are attached form a nitrogen-containing cycle.
  • a preferred 5- or 6-membered cyclic amino radical according to the invention is pyrrolidin-1- yl or piperidin- 1 -yl, respectively.
  • cyclic aminocarbonyl refers to a radical of the type RR ' N-C(O)-, wherein RR ' N- is a cyclic amino as defined herein above.
  • alkylsulfonyl refers to a radical of the type RS(0) 2 -, wherein R is an alkyl moiety.
  • alkylsulfonylamino refers to a radical of the type RS(0) 2 NH-, wherein R is an alkyl moiety.
  • nitro refers to the radical -N0 2 .
  • the present invention provides compounds of formula (I)
  • A is S, i.e. the compound may be represented by formula (la)
  • a compound of formula (la) is a compound according to formula (Iaa)
  • a compound of formula (la) is a compound according to formula (lab)
  • A is O, i.e. the compound may be represented by formula (la')
  • a compound of formula (la') is a compound according to formula (laa')
  • a compound of formula (la') is a compound according to formula (lab')
  • a compound of formula (lb) is a compound according to formula (Iba)
  • a compound of formula (lb) is a compound according to formula
  • a compound of formula (Ic) may be a compound of formula (lea) or (Icb)
  • the compound of formula (Ic) or (Ic') is a compound of formula (lea) or (lea').
  • any reference to a compound of formula (I) is meant to include a compound of any of the above formulas (la), (Iaa), (lab), (la'), (Iaa'), (lab'), (lb), (Iba), (Ibb), (Ic), (lea), (Icb), (Ic'), (lea'), and (Icb').
  • any reference to a compound of formula (la) is meant to include a compound of any of the above formulas (Iaa) and (lab); any reference to a compound of for- mula (la') is meant to include a compound of any of the above formulas (Iaa') and (lab'); any reference to a compound of formula (lb) is meant to include a compound a compound of any of the above formulas (Iba) and (Ibb), any reference to a compound of formula (Ic), is meant to include a compound of any of the above formulas (lea) and (Icb), and any reference to a compound of formula (Ic'), is meant to include a compound of any of the above formulas (lea') and (Icb').
  • the two ring systems i.e. the 2- hydroxy benzoic acid ring and the ring containing A, are linked to each other via a linking group -NH-S(0)2-(CH) n -, referred to herein as a sulfonamide bond; wherein n is 0 or 1.
  • n is 0.
  • n is 1.
  • n is 1.
  • R 1 is selected from H; halogen; C1-C6 alkyl, optionally substituted with at least one halogen; and C1-C6 alkoxy, substituted with at least one halogen.
  • R 1 may be selected from H, F, CI, Br, CH 3 and CF 3 .
  • R 1 is selected from H; halogen, C1-C6 alkyl, e.g. C1-C3 alkyl, such as methyl, optionally substituted with at least one halogen; and C1-C6 alkoxy, substituted with at least one halogen, e.g. at least one F, such as trifluoromethoxy.
  • R 1 may be selected from H and halogen.
  • R 1 is selected from H and C1-C6 alkyl, e.g. C1-C3 alkyl, such as methyl.
  • R 1 may be H.
  • R 1 is a halogen
  • R 1 is C1-C6 alkyl.
  • R 1 is C1-C6 alkyl; and R 2 and R 3 form, together with the carbon atoms to which they are attached, a 5- or 6-membered carbocyclic or heterocyclic ring, which ring is optionally substituted with at least one R 5 .
  • A preferably is S or O, i.e. the compound is represented by formula (la) or (la'), e.g. (Iaa) or (Iaa').
  • R 2 and R 3 are each independently selected from H; halogen; C1-C6 alkyl; C1-C6 alkoxy; secondary or tertiary CI -C6 alkylamido; car- bocyclylcarbonylamino-C0-C2 alkyl; 5- or 6-membered cyclic amino carbonyl; C1-C6 alkyl- carbonylamino; C1-C6 alkylsulfonyl; hydroxy-C0-C6 alkyl, C1-C6 alkylcarbonyl; carboxy; C1-C6 alkoxycarbonyl; cyano; nitro; carbocyclyloxy; heterocyclyloxy; carbocyclyl-C0-C3 alkyl; carbocyclyl-C2-C3 alkenyl; heterocyclyl-C0-C3 alkyl; and heterocyclyl-C2-C3 alkenyl; wherein any alkyl is optionally
  • R 2 and R 3 are each independently selected from H; halogen; C1-C6 alkyl; C1-C6 alkoxy; secondary or tertiary C1-C6 alkylamido; 5- or 6-membered cyclic ami- nocarbonyl; C1-C6 alkylcarbonylamino; C1-C6 alkylsulfonyl; hydroxy; C1-C6 alkylcarbonyl; carboxy; C1-C6 alkoxycarbonyl; cyano; nitro; carbocyclyloxy; heterocyclyloxy; carbocyclyl- C0-C3 alkyl; carbocyclyl-C2-C3 alkenyl; heterocyclyl-C0-C3 alkyl; or heterocyclyl-C2-C3 alkenyl; wherein any alkyl is optionally substituted with at least one halogen; any carbocyclyl or heterocyclyl is 5- or 6-membered monocyclyl or 9- or
  • R 2 and R 3 are each independently selected from H; halogen; C1-C6 alkyl; C1-C6 alkoxy; secondary or tertiary C1-C6 alkylamido; 5- or 6-membered cyclic ami- nocarbonyl; C1-C6 alkylcarbonylamino; C1-C6 alkylsulfonyl; hydroxy; C1-C6 alkylcarbonyl; carboxy; C1-C6 alkoxycarbonyl; cyano; nitro; carbocyclyloxy; heterocyclyloxy; carbocyclyl- C0-C3 alkyl; carbocyclyl-C2-C3 alkenyl; heterocyclyl-C0-C3 alkyl; or heterocyclyl-C2-C3 alkenyl; wherein any alkyl is optionally substituted with at least one halogen; any carbocyclyl or heterocyclyl is 5- or 6-membered monocyclyl or 9- or
  • R 2 and R 3 are each independently selected from H, halogen, e.g. F, CI and Br; C1-C6 alkyl, e.g. C1-C4 alkyl; C1-C6 alkoxy, e.g. C1-C4 alkoxy; hydroxy-C0-C6 alkyl, e.g. hydroxy-C0-C4 alkyl, such as hydroxy and hydroxymethyl; C1-C6 alkylcarbonyl, e.g.
  • C1-C4 alkylcarbonyl such as acetyl; secondary or tertiary CI -C6 alkylamido, such as secondary or tertiary CI -C4 alkylamido, e.g. methylamido; carbocyclylcarbonylamino-C0-C2 alkyl, such as benzamido-C0-C2-alkyl; e.g. benzamidomethyl; 5- or 6-membered cyclic ami- nocarbonyl; such as piperidin-l-ylcarbonyl; C1-C6 alkylsulfonyl, e.g.
  • C1-C4 alkylsulfonyl such as methylsulfonyl; carboxy; C1-C6 alkoxycarbonyl, e.g. C1-C4 alkoxycarbonyl; cyano; nitro; carbocyclyloxy; heterocyclyloxy; carbocyclyl-C0-C3 alkyl, e.g. carbocyclyl; carbocy- clyl-C2-C3 alkenyl, e.g. carbocyclyl-ethenyl; heterocyclyl-C0-C3 alkyl, e.g. heterocyclyl; or heterocyclyl-C2-C3 alkenyl, e.g.
  • R 2 and R 3 are each independently selected from H, halogen, e.g. F, CI and Br; C1-C6 alkyl, e.g. C1-C4 alkyl; C1-C6 alkoxy, e.g. C1-C4 alkoxy; hydroxy, C1-C6 alkylcarbonyl, e.g.
  • C1-C4 alkylcarbonyl such as acetyl; secondary or tertiary C1-C6 alkylamido, such as secondary or tertiary CI -C4 alkylamido, e.g. methylamido; 5- or 6-membered cyclic aminocarbonyl; such as piperidin-l-ylcarbonyl; C1-C6 alkylsulfonyl, e.g. C1-C4 alkyl- sulfonyl, such as methylsulfonyl; carboxy; C1-C6 alkoxycarbonyl, e.g.
  • heterocyclyl-ethenyl wherein any alkyl is optionally substituted with at least one halogen, any carbocyclyl or heterocyclyl is 5- or 6-membered monocyclyl or 9- or 10-membered bicyclyl; and any carbocyclyl or heterocyclyl is optionally substituted with at least one R 5 .
  • any alkyl that is optionally substituted with at least one halogen may optionally be part of a radical, i.e. an alkoxy or alkylcarbonyl.
  • R 2 and R 3 may be e.g. a halogenated alkyl, a halogenated alkoxy or a halogenated alkylcarbonyl etc.
  • the number of halogen atoms attached to any one alkyl may be e.g. 1, 2 or 3 and may be independently selected from e.g. F and CI.
  • any alkyl may be substituted by 1, 2 or 3 halogens that are all fluoro, such as in trifluoromethyl, trifluoromethoxy or difluoromethoxy.
  • any carbocyclyl or heterocyclyl as being 5- or 6-membered monocyclyl or 9- or 10-membered bicyclyl also inludes the carbocyclyl and heterocylyl, respectively, when present as a moiety of a radical such as e.g. carbocyclyloxy or carbocyclyl-C2-C3 alkenyl.
  • R 2 and R 3 are each independently selected from H, halogen, e.g. F, CI and Br; C1-C6 alkyl, e.g. C1-C4 alkyl; C1-C6 alkoxy, e.g. C1-C4 alkoxy; C1-C6 alkylcar- bonyl, e.g. C1-C4 alkylcarbonyl, such as acetyl; secondary or tertiary CI -C6 alkylamido, such as secondary or tertiary CI -C4 alkylamido, e.g.
  • methylamido 5- or 6-membered cyclic aminocarbonyl; such as piperidin-l-ylcarbonyl; C1-C6 alkylcarbonylamino; such as C1-C4 al- kylcarbonylamino; C1-C6 alkylsulfonyl, e.g. C1-C4 alkylsulfonyl, such as methylsulfonyl; carbocyclyl-C0-C3 alkyl, e.g. carbocyclyl; carbocyclyl-C2-C3 alkenyl, e.g. carbocyclyl- ethenyl; heterocyclyl-C0-C3 alkyl, e.g.
  • heterocyclyl or heterocyclyl-C2-C3 alkenyl, e.g. heterocyclyl-ethenyl; wherein any alkyl is optionally substituted with at least one halogen, any carbocyclyl or heterocyclyl is 5- or 6-membered monocyclyl or 9- or 10-membered bicyclyl; and any carbocyclyl or heterocyclyl is optionally substituted with at least one R 5 .
  • R 2 and R 3 may be independently selected from H, halogen, methyl, tert-butyl, trifluoromethyl, methoxy, acetyl, methylamido, piperidinylcarbonyl, such as piperidinyl-1- carbonyl, methylsulfonyl, phenyl, phenylethenyl, benzofuryl, dihydrobenzofuryl, such as 2,3- dihydro-1 -benzofuryl, quinolyl, 1,3-benzodioxyl, thienyl, pyridyl, thiazolyl, and piperidyl, wherein any carbocyclyl or heterocyclyl is optionally substituted with at least one R 5 .
  • R 2 or R 3 is a carbocyclyl or heterocyclyl radical, or a radical comprising a carbocyclyl or heterocyclyl moiety
  • carbocyclyl or heterocyclyl radical or moiety is selected from phenyl, benzofuryl, dihydrobenzofuryl, such as 2,3-dihydro-l- benzofuryl, quinolyl, 1,3-benzodioxyl, thienyl, pyridyl, thiazolyl, and piperidyl.
  • R 2 and R 3 are each independently selected from H, halogen, e.g. F, CI, Br and I; C1-C6 alkyl, e.g. C1-C4 alkyl; C1-C6 alkoxy, e.g. C1-C4 alkoxy; hydroxy, C1-C6 alkylcarbonyl, e.g. C1-C4 alkylcarbonyl, such as acetyl; secondary or tertiary C1-C6 alkylamido, such as secondary or tertiary CI -C4 alkylamido, e.g.
  • methylamido 5- or 6-membered cyclic aminocarbonyl; such as piperidin-l-ylcarbonyl; C1-C6 alkylsulfonyl, e.g. C1-C4 al- kylsulfonyl, such as methylsulfonyl; carboxy; C1-C6 alkoxycarbonyl, e.g. C1-C4 alkoxycar- bonyl; cyano; and nitro; wherein any alkyl is optionally substituted with at least one halogen.
  • cyclic aminocarbonyl such as piperidin-l-ylcarbonyl; C1-C6 alkylsulfonyl, e.g. C1-C4 al- kylsulfonyl, such as methylsulfonyl; carboxy; C1-C6 alkoxycarbonyl, e.g. C1-C4 alkoxycar- bonyl; cyano; and nitro
  • R 2 and R 3 may be independently selected from H, halogen, e.g. F, CI, Br and I; C1-C6 alkyl, e.g. C1-C4 alkyl; C1-C6 alkoxy, e.g. C1-C4 alkoxy; C1-C6 alkylcarbonyl, e.g. C1-C4 alkylcarbonyl, such as acetyl; secondary or tertiary C1-C6 alkylamido, such as secondary or tertiary CI -C4 alkylamido, e.g.
  • halogen e.g. F, CI, Br and I
  • C1-C6 alkyl e.g. C1-C4 alkyl
  • C1-C6 alkoxy e.g. C1-C4 alkoxy
  • C1-C6 alkylcarbonyl e.g. C1-C4 alkylcarbonyl, such as
  • methylamido 5- or 6-membered cyclic aminocarbonyl; such as piperidin-l-ylcarbonyl; C1-C6 alkylsulfonyl, e.g. C1-C4 alkylsulfonyl, such as methylsulfonyl; and C1-C6 alkoxycarbonyl, e.g. C1-C4 alkoxycarbonyl; wherein any alkyl is optionally substituted with at least one halogen.
  • cyclic aminocarbonyl such as piperidin-l-ylcarbonyl
  • C1-C6 alkylsulfonyl e.g. C1-C4 alkylsulfonyl, such as methylsulfonyl
  • C1-C6 alkoxycarbonyl e.g. C1-C4 alkoxycarbonyl
  • R 2 and R 3 may be independently selected from H; C1-C6 alkyl, e.g. C1-C4 alkyl, such as methyl; halogen, e.g. F and CI; and C1-C6 alkoxy, e.g. C1-C4 alkoxy, such as methoxy, wherein any alkyl is optionally substituted with at least one halogen.
  • C1-C6 alkyl e.g. C1-C4 alkyl, such as methyl
  • halogen e.g. F and CI
  • C1-C6 alkoxy e.g. C1-C4 alkoxy, such as methoxy
  • R 2 and R 3 may be independently selected from H, F, CI, Br, I, methyl, trifluoromethyl, trifluoromethoxy and difluoromethoxy.
  • R 2 and R 3 may be independently selected from H; halogen, e.g. F and CI; and C1-C6 alkoxy, e.g. C1-C4 alkoxy, such as methoxy.
  • R 2 and R 3 are independently selected from H; C1-C6 alkyl, e.g. methyl; and halogen, e.g. F, CI, Br and I, in particular CI and Br; and carbocyclyl-C0-C3 alkyl, carbocyclyl-C2-C3 alkenyl, heterocyclyl-C0-C3 alkyl, heterocyclyl-C2-C3 alkenyl; wherein any carbocyclyl or heterocyclyl is optionally substituted with at least one R 5 and any alkyl is optionally substituted with at least one halogen.
  • halogen e.g. F, CI, Br and I, in particular CI and Br
  • carbocyclyl-C0-C3 alkyl carbocyclyl-C2-C3 alkenyl, heterocyclyl-C0-C3 alkyl, heterocyclyl-C2-C3 alkenyl
  • any carbocyclyl or heterocyclyl is optionally substituted with at
  • R 2 and R 3 are independent- ly selected from H; optionally halogenated C1-C6 alkyl, e.g. methyl; and halogen, e.g. F, CI, Br and I, in particular CI and Br.
  • R 2 is selected from H; C1-C6 alkyl, e.g. methyl; and halogen, e.g.
  • R 3 is selected from H; C1-C6 alkyl, e.g. methyl; and halogen, e.g. F, CI, Br and I, in particular CI and Br; wherein any alkyl is optionally substituted with at least one halogen.
  • R 2 is selected from a carbocyclyloxy, heterocyclyloxy, carbocyclyl- C0-C3 alkyl, carbocyclyl-C2-C3 alkenyl, heterocyclyl-C0-C3 alkyl, heterocyclyl-C2-C3 alkenyl, carbocyclyl or heterocyclyl radical as defined herein above, wherein any carbocyclyl or heterocyclyl is optionally substituted with at least one R 5 ; and R 3 is as defined herein above, and for example, is selected from H; halogen; C1-C6 alkyl; C1-C6 alkoxy; hydroxy; C1-C6 alkylcarbonyl; carboxy; C1-C6 alkoxycarbonyl; cyano; or nitro.
  • R 3 may be selected from H, halogen, C1-C6 alkyl, e.g. C1-C4 alkyl; and C1-C6 alkoxy, e.g. C1-C4 alkoxy; or H, halogen, and C1-C6 alkoxy, e.g. C1-C4 alkoxy; such as H, methoxy, F and CI.
  • R 3 is selected from halogen, e.g. R 3 is CI, or Br, e.g. R 3 is CI.
  • R 3 is selected from H; halogen; and C1-C6 alkoxy, e.g. C1-C4 alkoxy; e.g. R 3 is H, F or methoxy, in particular H.
  • R 3 is selected from H; halogen; and C1-C6 alkyl; e.g. C1-C4 alkyl, optionally substituted with at least one halogen; e.g. R 3 is selected from H, F, CI, Br, I, methyl or trifluoromethyl, in particular H.
  • R 3 is selected from H; and halogen; e.g. H, CI, Br and I, or H, CI and Br.
  • a compound of formula (I) e.g. a compound of formula (lb) wherein n is 0, neither R 2 nor R 3 is selected from 4-hydroxypyrazolo[l,5-a]-l,3,5-triazin-8-yl and 2,4- dihydroxypyrazolo[ 1 ,5-a]- 1 ,3,5-triazin-8-yl.
  • R 2 and R 3 are not selected from hydrogen, halogen, hydroxy, carboxy, unsubstituted C1-C4 alkyl, unsubstituted C3-C6 cycloalkyl, unsubstituted aryl, unsubstituted heteroaryl containing from 1 to 4 heteroatoms selected from N, O and S, and C1-C6 alkoxy that is optionally substituted with halogen.
  • R 2 is in meta position relative to the sulfonamide bond
  • R 3 is not selected from H; halogen; C1-C6 alkyl; C1-C6 alkoxy; C1-C6 alkylcarbonylamino; C1-C6 alkylcarbonyl; carboxy; C1-C6 alkoxycarbonyl; cyano; cyclohexyl; trifluoromethyl and trifluoromethoxy; and
  • R 3 when R 3 is selected from H, F, CI, Br, methyl and tert-butyl, R 2 is not H.
  • proviso (i) implies that when, in a compound of formula (lb), n is 0, and R 2 and R 3 do not together form a cycle, the compound is a compound of formula (Iba), as defined herein.
  • proviso (i) The second of the three provisos, which should be read together with proviso (i), implies that the phenyl ring of formula (Iba) is not unsubstituted and is not a monosubstituted phenyl ring carrying one sole substituent in para position selected from C1-C6 alkyl; C1-C6 alkoxy; Cl- C6 alkylcarbonylamino; C1-C6 alkylcarbonyl; carboxy; C1-C6 alkoxycarbonyl; cyano; cy- clohexyl; trifluoromethyl and trifluoromethoxy.
  • the third of the tree provisos which also should be read together with proviso (i), implies that when the phenyl ring of formula (Iba) is not substituted in para position, or is substituted in para position with F, CI, Br, methyl and tert-butyl, then R 2 is not hydrogen.
  • R 2 is in meta position relative to the sulfonamide bond
  • R 3 is not selected from H; halogen; C1-C6 alkyl; C1-C6 alkoxy; C1-C6 alkylcarbonylamino; C1-C6 alkylcarbonyl; carboxy; C1-C6 alkoxycarbonyl; cyano; cyclohexyl; trifluoromethyl and trifluoromethoxy; and
  • R 3 when R 3 is selected from H, F, CI, Br, methyl and tert-butyl, R 2 is not selected from H, and optionally halogenated C1-C6 alkyl.
  • R 2 is in meta position relative to the sulfonamide bond
  • R 3 is not selected from H; halogen; C1-C6 alkyl; C1-C6 alkoxy; C1-C6 alkylcarbonylamino; C1-C6 alkylcarbonyl; carboxy; C1-C6 alkoxycarbonyl; cyano; cyclohexyl; trifluoromethyl and trifluoromethoxy; and
  • R 3 when R 3 is selected from H, F, CI, Br, methyl and tert-butyl, R 2 is not selected from H, optionally halogenated C1-C6 alkyl and halogen.
  • R 2 is selected from halogen, e.g. F, CI and Br; C1-C6 alkyl, e.g. C1-C4 alkyl, such as methyl and tert-butyl; C1-C6 alkoxy, e.g. C1-C4 alkoxy; hydroxy-Cl-C6 alkyl, e.g. hydroxy and 1-hydroxyethyl; C1-C6 alkylcarbonyl, e.g.
  • halogen e.g. F, CI and Br
  • C1-C6 alkyl e.g. C1-C4 alkyl, such as methyl and tert-butyl
  • C1-C6 alkoxy e.g. C1-C4 alkoxy
  • hydroxy-Cl-C6 alkyl e.g. hydroxy and 1-hydroxyethyl
  • C1-C6 alkylcarbonyl e.g.
  • C1-C4 alkylcarbonyl such as acetyl; secondary or tertiary C1-C6 alkylamido, such as secondary or tertiary C1-C4 alkyl- amido, e.g. methylamido; 5- or 6-membered cyclic aminocarbonyl; such as piperidin-1- ylcarbonyl; C1-C6 alkylsulfonyl, e.g. C1-C4 alkylsulfonyl, such as methylsulfonyl; carboxy; cyano; nitro; carbocyclyloxy; heterocyclyloxy; carbocyclyl-C0-C3 alkyl, e.g.
  • carbocyclyl carbocyclyl; carbocyclyl-C2-C3 alkenyl, e.g. carbocyclyl-ethenyl; heterocyclyl-C0-C3 alkyl, e.g. heterocyclyl; or heterocyclyl-C2-C3 alkenyl, e.g. heterocyclyl-ethenyl; wherein any alkyl is optionally substituted with at least one halogen, any carbocyclyl or heterocyclyl is 5- or 6-membered monocyclyl or 9- or 10-membered bicyclyl; and any carbocyclyl or heterocyclyl is optionally substituted with at least one R 5 .
  • R 2 is selected from halogen, e.g. F, CI and Br; C1-C6 alkyl, e.g. C1-C4 alkyl; C1-C6 alkoxy, e.g. C1-C4 alkoxy; hydroxy, C1-C6 alkylcarbonyl, e.g. C1-C4 alkylcar- bonyl, such as acetyl; secondary or tertiary C1-C6 alkylamido, such as secondary or tertiary C1-C4 alkylamido, e.g.
  • halogen e.g. F, CI and Br
  • C1-C6 alkyl e.g. C1-C4 alkyl
  • C1-C6 alkoxy e.g. C1-C4 alkoxy
  • hydroxy, C1-C6 alkylcarbonyl e.g. C1-C4 alkylcar- bonyl, such as acet
  • methylamido 5- or 6-membered cyclic amino carbonyl; such as piper- idin-1 -ylcarbonyl; C1-C6 alkylsulfonyl, e.g. C1-C4 alkylsulfonyl, such as methylsulfonyl; carboxy; C1-C6 alkoxycarbonyl, e.g. C1-C4 alkoxycarbonyl; cyano; nitro; carbocyclyloxy; heterocyclyloxy; carbocyclyl-C0-C3 alkyl, e.g. carbocyclyl; carbocyclyl-C2-C3 alkenyl, e.g.
  • any alkyl is optionally substituted with at least one halogen, any carbocyclyl or heterocyclyl is 5- or 6-membered monocyclyl or 9- or 10- membered bicyclyl; and any carbocyclyl or heterocyclyl is optionally substituted with at least one R 5 .
  • R 2 is alkylcarbonyl, it is C2-C6 alkylcarbonyl.
  • R 2 may be selected from C1-C6 alkyl; e.g. C2-C6 alkyl; C1-C6 alkylcarbonyl; secondary or tertiary C1-C6 alkylamido, such as secondary or tertiary CI -C4 alkylamido, e.g. methylamido, 5- or 6-membered cyclic aminocarbonyl, such as piperidin-1 -ylcarbonyl; Cl- C6 alkylsulfonyl, e.g.
  • C1-C4 alkylsulfonyl such as methylsulfonyl; carbocyclyloxy; hetero- cyclyloxy; carbocyclyl-C0-C3 alkyl, carbocyclyl-C2-C3 alkenyl, heterocyclyl-C0-C3 alkyl or heterocyclyl-C2-C3 alkenyl; wherein any alkyl is optionally substituted with at least one halogen, any carbocyclyl or heterocyclyl is 5- or 6-membered monocyclyl or 9- or 10-membered bicyclyl; and any carbocyclyl or heterocyclyl is optionally substituted with at least one R 5 .
  • R 2 may be selected from C1-C6 alkyl e.g. C2-C6 alkyl; C1-C6 alkylcar- bonyl; carbocyclyl-C0-C3 alkyl, carbocyclyl-C2-C3 alkenyl, heterocyclyl-C0-C3 alkyl or heterocyclyl-C2-C3 alkenyl; wherein any alkyl is optionally substituted with at least one hal- ogen, any carbocyclyl or heterocyclyl is 5- or 6-membered monocyclyl or 9- or 10-membered bicyclyl; and any carbocyclyl or heterocyclyl is optionally substituted with at least one R 5 .
  • C1-C6 alkyl e.g. C2-C6 alkyl; C1-C6 alkylcar- bonyl; carbocyclyl-C0-C3 alkyl, carbocyclyl-C2-C3 alkenyl, heterocyclyl-C0-C3 al
  • R 2 may be selected from carbocyclyl-C0-C3 alkyl, e.g. carbocyclyl; carbocy- clyl-C2-C3 alkenyl, e.g. carbocyclyl-ethenyl; heterocyclyl-C0-C3 alkyl, e.g. heterocyclyl; or heterocyclyl-C2-C3 alkenyl, e.g. heterocyclyl-ethenyl; wherein any carbocyclyl or heterocyclyl is 5- or 6-membered monocyclyl or 9- or 10-membered bicyclyl; and any carbocyclyl or heterocyclyl is optionally substituted with at least one R 5 .
  • carbocyclyl-C0-C3 alkyl e.g. carbocyclyl
  • carbocy- clyl-C2-C3 alkenyl e.g. carbocyclyl-ethenyl
  • R 2 is selected from carbocyclyl-C0-C3 alkyl, e.g. carbocyclyl; carbo- cyclyl-C2-C3 alkenyl, e.g. carbocyclyl-ethenyl; or heterocyclyl-C0-C3 alkyl, e.g. heterocy- clyl; wherein any carbocyclyl or heterocyclyl is 5- or 6-membered monocyclyl or 9- or 10- membered bicyclyl; and any carbocyclyl or heterocyclyl is optionally substituted with at least one R 5 .
  • carbocyclyl-C0-C3 alkyl e.g. carbocyclyl
  • carbo- cyclyl-C2-C3 alkenyl e.g. carbocyclyl-ethenyl
  • heterocyclyl-C0-C3 alkyl e.g. heterocy- clyl
  • any carbocyclyl or heterocyclyl is
  • R 2 may be selected from bicyclic 9- or 10-membered or monocyclic 5- or 6- membered carbocyclyl; monocyclic 5- or 6-membered carbocyclyl-ethenyl; bicyclic 9- or 10- membered or monocyclic 5- or 6-membered heterocyclyl; wherein any carbocyclyl or heterocyclyl is optionally substituted with at least one R 5 .
  • R 2 may be selected from phenyl, phenylethenyl, benzofuryl, such as 2 -benzofuryl, dihydrobenzofuryl, such as 2,3-dihydro-l -benzofuryl, quinolyl, 1,3- benzodioxyl, thienyl, pyridyl, thiazolyl, lH-pyrazolyl and piperidyl, and optionally be substituted with at least one R 5 .
  • R 2 is a carbocyclyl or heterocyclyl radical or a radical containing a carbocyclyl or heterocyclyl moiety, wherein the carbocyclyl or heterocyclyl is optionally substituted with at least one R 5 , said carbocyclyl or heterocyclyl is aromatic.
  • R 2 is bicyclic 9- or 10-membered carbocyclyl or hetero- cyclyl, optionally substituted with at least one R 5
  • said carbocyclyl or heterocyclyl comprises at least one aromatic ring, e.g. at least one phenyl ring, fused to another ring which may be aromatic or non-aromatic.
  • this other ring may be a heterocyclic, non-aromatic or aromatic 5- or 6-membered ring, e.g. comprising 1-3 heteroatoms, e.g. 1 or 2 heteroatoms selected from N, O and S, e.g. N and O.
  • R 2 is selected from carbocyclyl-C0-C3 alkyl, e.g. carbocyclyl; carbo- cyclyl-C2-C3 alkenyl, e.g. carbocyclyl-ethenyl; heterocyclyl-C0-C3 alkyl, e.g. heterocyclyl; or heterocyclyl-C2-C3 alkenyl, e.g. heterocyclyl-ethenyl; wherein any carbocyclyl or heterocyclyl is 5- or 6-membered monocyclyl; and any cyclyl is optionally substituted with at least one R 5 .
  • R 2 is selected from phenyl-C0-C3 alkyl, e.g. phenyl; phenyl-C2-C3 alkenyl, e.g. phenylethenyl; heterocyclyl-C0-C3 alkyl, e.g. thienyl-C0-C3 alkyl, pyridyl-CO- C3 alkyl, thiazolyl-C0-C3 alkyl, lH-pyrazolyl-C0-C3 alkyl, and piperidyl-C0-C3 alkyl, e.g.
  • R 2 is selected from phenyl-C0-C3 alkyl, e.g. phenyl; phenyl-C2- C3 alkenyl, e.g. phenylethenyl; heterocyclyl-C0-C3 alkyl, e.g. thienyl-C0-C3 alkyl, pyridyl- C0-C3 alkyl, thiazolyl-C0-C3 alkyl, and piperidyl-C0-C3 alkyl, e.g. thienyl, pyridyl, thiazolyl and piperidyl; or heterocyclyl-C2-C3 alkenyl, e.g.
  • thienyl-C2-C3 alkenyl such as thienylethenyl, pyridylethenyl, thiazolylethenyl and piperidylethenyl; wherein any heterocyclyl is 5- or 6- membered monocyclyl; and any phenyl or heterocyclyl is optionally substituted with at least one R 5 .
  • R 2 may be selected from phenyl-C0-C3 alkyl, e.g. phenyl; phenyl-C2-C3 alkenyl, e.g. phenylethenyl; monocyclic 5- or 6-membered heterocyclyl-C0-C3 alkyl, e.g. thienyl-C0-C3 alkyl, pyridyl-C0-C3 alkyl, thiazolyl-C0-C3 alkyl, lH-pyrazolyl-C0-C3 alkyl; and piperidyl-C0-C3 alkyl, e.g.
  • thienyl pyridyl, thiazolyl, lH-pyrazolyl, and piperidyl, wherein any carbocyclyl or heterocyclyl is optionally substituted with at least one R 5 ; or from from phenyl-C0-C3 alkyl, e.g. phenyl; phenyl-C2-C3 alkenyl, e.g. phenylethenyl; monocyclic 5- or 6-membered heterocyclyl-C0-C3 alkyl, e.g.
  • R 2 may be phenyl-C0-C3 alkyl, optionally substituted with at least one R 5 .
  • R 2 may be phenyl or phenyl substituted with at least one R 5 , e.g. 1-3 R 5 as defined herein, e.g.
  • C1-C6 alkyl independently selected from halogen; C1-C6 alkyl; C1-C6 alkoxy; hydroxy-Cl- C6 alkyl; phenoxy; amino; cyano; nitro; secondary or tertiary C1-C6 alkylamino; 5- or 6- membered cyclic amino; C1-C6 alkylcarbonylamino; carbamoyl; secondary or tertiary C1-C6 alkylamido; 5- or 6-membered cyclic aminocarbonyl; C1-C6 alkoxy carbonylamino; hydroxy- C1-C6 alkyl; Cl-C6-alkylthio; trifluoromethyl; trifluoromethoxy; carboxy-Cl-C6-alkyl; Cl- C6 alkoxycarbonyl; C1-C6 alkylcarbonyl; Cl-C6-alkylsulfonyl; and C1-C6 alkyl, or from hal
  • R 2 is selected from phenyl, fluorophenyl, chlorophenyl, methylphenyl, ethylphenyl, butylphenyl, trifluoromethylphenyl, hydroxyphenyl, (hydroxymethyl)phenyl, methoxyphenyl, ethoxyphenyl, isopropoxyphenyl, butoxyphenyl, aminophenyl,
  • phenoxyphenyl cyanophenyl, (methylsulfonyl)phenyl, (ethylsulfonyl)phenyl, (methylsulfon- amido)phenyl, difluorophenyl, dichlorophenyl, (fluoro)(methyl)phenyl, (fluo- ro)(hydroxy)phenyl, (fluoro)(methoxy)phenyl, (chloro)(methoxy)phenyl, (meth- oxy)(methyl)phenyl, (hydroxy)(methoxy)phenyl, dimethoxyphenyl, (amino)(methoxy)phenyl, (hydroxy)(dimethyl)phenyl, (methoxy)(dimethyl)phenyl, trifluorophenyl, quinolinyl, ben- zo[d][l,3]dioxolyl, 2,3-dihydrobenzofuranyl, naphthalen
  • R 2 may be a radical such as phenyl, fluorophenyl, trifluoromethylphenyl, tri- fluoromethoxyphenyl, methoxyphenyl, ethoxyphenyl, phenoxyphenyl, acetylaminophenyl, methoxycarbonylaminophenyl, carbamoylphenyl, cyanophenyl, nitrophenyl, methylthio- phenyl, methylsulfonylphenylacetylphenyl, isopropoxycarbonylphenyl, hy- droxymethylphenyl, hydroxyphenyl, aminophenyl, dimethylaminophenyl, methylsulfonyla- minophenyl, difluorophenyl, (fluoro)(hydroxy)phenyl, dichlorophenyl, (hy- droxy)(methoxy)phenyl, (amino)(hydroxy)phenyl,
  • R 2 is selected from: phenyl, 3 -fluorophenyl, 4-fluorophenyl, 3- chlorophenyl, 4-chlorophenyl, 4-methylphenyl, 3-methylphenyl, 2-methylphenyl, 4- ethylphenyl, 4-butylphenyl, 3 -trifluoromethylphenyl, 4-trifluoromethylphenyl, 3- hydroxyphenyl, 2-hydroxyphenyl, 4-hydroxyphenyl, 4-(hydroxymethyl)phenyl, 3- (hydroxymethyl)phenyl, 2-(hydroxymethyl)phenyl, 2-methoxyphenyl, 4-methoxyphenyl, 3- ethoxyphenyl, 4-isopropoxyphenyl, 4-butoxyphenyl, 3 -aminophenyl, 4-aminophenyl, 2- aminophenyl, 4-(dimethylamino)phenyl, 2-nitrophenyl, 4-nitrophenyl, 4-acetylphenyl, 3- ace
  • R 2 and R 3 form, together with the carbon atoms to which they are attached, form a 5- or 6-membered carbocyclic or heterocyclic ring, which ring is optionally substituted with at least one R 5 .
  • R 2 and R 3 together with the carbon atoms to which they are attached may form a 5- or 6-membered carbocyclic or heterocyclic aromatic ring.
  • the ring formed by R 2 and R 3 is a carbocyclic aromatic ring, e.g. a benzene ring.
  • the ring formed by R 2 and R 3 is a 5- or 6-membered heterocyclic, aromatic or non-aromatic ring containing 1-4, e.g. 1, 2 or 3 heteroatoms selected from N, O and S, such as a thiadiazole, e.g. a 1,2,5-thiadiazole, an oxadiazole, e.g. a 1,2,5-oxadiazole or a tetrahydrofuran ring.
  • a thiadiazole e.g. a 1,2,5-thiadiazole
  • an oxadiazole e.g. a 1,2,5-oxadiazole or a tetrahydrofuran ring.
  • R 2 and R 3 are each independently selected from H; halogen; C1-C6 alkyl; C1-C6 alkoxy; secondary or tertiary C1-C6 alkylamido; 5- or 6-membered cyclic aminocarbonyl; C1-C6 alkylsulfonyl; hydroxy- C0-C6 alkyl, C1-C6 alkylcarbonyl; carboxy; nitro; carbocyclyl-C0-C3 alkyl; carbocyclyl-C2- C3 alkenyl; and heterocyclyl-C0-C3 alkyl; wherein any alkyl is optionally substituted with at least one halogen; any carbocyclyl or heterocyclyl is 5- or 6-membered monocyclyl or 9- or 10-membered bicyclyl; and any carbocyclyl or heterocyclyl is optionally substituted with at least one R 5 ;
  • R 2 is selected from H; halogen; C1-C6 alkyl; C1-C6 alkoxy; secondary or tertiary C1-C6 alkylamido; 5- or 6-membered cyclic aminocarbonyl; C1-C6 alkylsulfonyl; hydroxy-C0-C6 alkyl, C1-C6 alkylcarbonyl; carboxy; nitro; carbocyclyl-C0-C3 alkyl; carbo- cyclyl-C2-C3 alkenyl; and heterocyclyl-C0-C3 alkyl; wherein any alkyl is optionally substituted with at least one halogen; any carbocyclyl or heterocyclyl is 5- or 6-membered monocyclyl or 9- or 10-membered bicyclyl; and any carbocyclyl or heterocyclyl is optionally substituted with at least one R 5
  • n is 0;
  • R 2 is selected from halogen; C1-C6 alkyl; C1-C6 alkoxy; secondary or tertiary C1-C6 alkylamido; 5- or 6-membered cyclic aminocarbonyl; C1-C6 alkylsulfonyl; hydroxy- C0-C6 alkyl, C1-C6 alkylcarbonyl; carboxy; carbocyclyl-C0-C3 alkyl; carbocyclyl-C2-C3 alkenyl; and heterocyclyl-C0-C3 alkyl; wherein any alkyl is optionally substituted with at least one halogen; any carbocyclyl or heterocyclyl is 5- or 6-membered monocyclyl or 9- or 10-membered bicyclyl; and any carbocyclyl or heterocyclyl is optionally substituted with at least one R 5 ; and
  • Each R 4 which is present in a compound of formula (lb) or (Ic), is independently selected from H, halogen, monocyclic C3-C6 carbocyclyl and C1-C6 alkyl, wherein any alkyl is op- tionally substituted with at least one halogen; or from H, monocyclic C3-C6 carbocyclyl, e.g. phenyl, and C1-C6 alkyl, such as C1-C3 alkyl, e.g. methyl, wherein any alkyl is optionally substituted with at least one halogen.
  • each R 4 may be selected from H, F, tri- fluoromethyl and phenyl; or from H, trifluoromethyl and phenyl.
  • each R 4 is H.
  • R 2 and/or R 3 is a cyclic moiety or R 2 and R 3 , together with the carbon atoms to which they are attached form a cyclic moiety, such cyclic moiety may optionally be substitued with at least one R 5 , e.g. 1-3 R 5 , independently selected from halogen, e.g. F and CI; C1-C6 alkyl, e.g. C1-C4 alkyl, such as methyl, ethyl, and n-butyl; C1-C6 alkoxy, e.g.
  • C1-C4 alkoxy such as methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy; hydroxy-C0-C6 alkyl, e.g. hydro xy-C0-C2 alkyl, such as hydroxy and hydroxymethyl; phenoxy; amino; cyano; nitro; sec- ondary or tertiary CI -C6 alkylamino, e.g.
  • secondary or tertiary CI -C3 alkylamino such as dimethylamino; carbamoyl; secondary or tertiary C1-C6 alkylamido, such as dimethylcar- bamoyl and diisopropylcarbamoyl; Cl-C6-alkylthio, such as C1-C3 alkylthio, e.g. methylthio; trifluoromethyl; trifluoromethoxy; carboxy-C0-C6-alkyl, e.g. carboxy and 2-carboxyethyl; C1-C6 alkoxycarbonyl, such as C1-C3 alkoxycarbonyl, e.g.
  • C1-C6 alkylcarbonyl such as C1-C3 alkylcarbonyl, e.g. acetyl; C1-C6- alkylsulfonyl; and C1-C6 alkylsulfonylamino, such as C1-C3 alkylsulfonylamino, e.g. me- thylsulfonylamino.
  • R 2 and R 3 when either of R 2 and R 3 is a cyclic moiety or R 2 and R 3 , together with the carbon atoms to which they are attached form a cyclic moiety, such cyclic moiety may optionally be substitued with at least one R 5 , e.g. 1-3 R 5 , independently selected from halogen, e.g. F and CI; C1-C6 alkyl, e.g. C1-C3 alkyl, such as methyl and ethyl; C1-C6 alkoxy, e.g.
  • R 5 e.g. 1-3 R 5 , independently selected from halogen, e.g. F and CI; C1-C6 alkyl, e.g. C1-C3 alkyl, such as methyl and ethyl; C1-C6 alkoxy, e.g.
  • C1-C3 alkoxy such as methoxy and ethoxy; hydroxy; phenoxy; amino; cyano; nitro; secondary or tertiary C1-C6 alkylamino, e.g. secondary or tertiary C1-C3 alkylamino, such as dimethylamino; carbamoyl; secondary or tertiary C1-C6 alkylamido; hydroxy-Cl-C6 alkyl, e.g. hydroxymethyl-; Cl-C6-alkylthio, such as C1-C3 alkylthio, e.g.
  • each R 5 is independently selected from halogen, e.g. F and CI; C1-C6 alkyl, e.g. C1-C4 alkyl, such as methyl, ethyl, and n-butyl; C1-C6 alkoxy, e.g. C1-C4 alkoxy, such as methoxy, ethoxy, isopropoxy and n-butoxy; hydroxy-C0-C6 alkyl, e.g. hydroxy-CO- C2 alkyl, such as hydroxy and hydroxymethyl; amino; secondary or tertiary CI -C6 alkylamino, e.g.
  • halogen e.g. F and CI
  • C1-C6 alkyl e.g. C1-C4 alkyl, such as methyl, ethyl, and n-butyl
  • C1-C6 alkoxy e.g. C1-C4 alkoxy, such as meth
  • C1-C6 alkylcar- bonylamino such as dimethylamino; C1-C6 alkylcar- bonylamino; e.g. C1-C3 alkylcarbonylamino, such as acetylamino, Cl-C6-alkylthio, such as C1-C3 alkylthio, e.g. methylthio; C1-C6 alkoxycarbonyl, such as C1-C3 alkoxycarbonyl, e.g. methoxycarbonyl and isopropoxycarbonyl; C1-C6 alkylcarbonyl, such as C1-C3 alkylcarbonyl, e.g.
  • C1-C6 alkylsulfonylamino such as C1-C3 alkylsulfonylamino, e.g. methylsulfonylamino and ethylsulfonylamino.
  • each R 5 is independently selected from halogen, e.g. F and CI; C1-C6 alkyl, e.g. C1-C3 alkyl, such as methyl and ethyl; C1-C6 alkoxy, e.g. C1-C3 alkoxy, such as methoxy and ethoxy; hydroxy; amino; secondary or tertiary C1-C6 alkylamino, e.g. secondary or tertiary C1-C3 alkylamino, such as dimethylamino; C1-C6 alkylcarbonylamino; e.g.
  • halogen e.g. F and CI
  • C1-C6 alkyl e.g. C1-C3 alkyl, such as methyl and ethyl
  • C1-C6 alkoxy e.g. C1-C3 alkoxy, such as methoxy and ethoxy
  • hydroxy amino
  • C1-C3 alkylcarbonylamino such as acetylamino, hydroxy-Cl-C6 alkyl, such as. hydroxy-Cl-C3 alkyl, e.g. hydroxymethyl; Cl-C6-alkylthio, such as C1-C3 alkylthio, e.g. methylthio; C1-C6 alkoxycarbonyl, such as C1-C3 alkoxycarbonyl, e.g. isopropoxycarbonyl; C1-C6 alkylcarbonyl, such as C1-C3 alkylcarbonyl, e.g.
  • the present invention provides a compound for use in therapy, selected from:
  • the compound for use in therapy is a compound selected from
  • the present invention provides novel compounds of formula (I), wherein A, R 1 , R 3 , R 4 and R 5 are as defined herein above, and R 2 is a radical as defined herein above, selected from C1-C6 alkyl; C1-C6 alkylcarbonyl; carbocyclyl-C0-C3 alkyl, carbocy- clyl-C2-C3 alkenyl, heterocyclyl-C0-C3 alkyl or heterocyclyl-C2-C3 alkenyl; or selected from within any of the subgroups within these groups as defmied herein above with respect to R 2 , wherein any carbocyclyl or heterocyclyl is 5- or 6-membered monocyclyl or 9- or 10- membered bicyclyl, and any cyclyl is optionally substituted with at least one R 5 ; or R 2 and R 3 form, together with the carbon atoms to which they are attached, a 5- or 6-member
  • R 2 is selected from C1-C6 alkyl; C1-C6 alkylcarbonyl; carbocyclyl-C0-C3 alkyl, carbocyclyl- C2-C3 alkenyl, heterocyclyl-C0-C3 alkyl or heterocyclyl-C2-C3 alkenyl; wherein any carbocyclyl or heterocyclyl is 5- or 6-membered monocyclyl or 9- or 10-membered bicyclyl; and any carbocyclyl or heterocyclyl is optionally substituted with at least one R 5 .
  • R 2 is selected from CI -C6 alkyl; carbocyclyl-C0-C3 alkyl, car- bocyclyl-C2-C3 alkenyl, heterocyclyl-C0-C3 alkyl or heterocyclyl-C2-C3 alkenyl; wherein any carbocyclyl or heterocyclyl is 5- or 6-membered monocyclyl or 9- or 10-membered bicyclyl; and any carbocyclyl or heterocyclyl is optionally substituted with at least one R 5 .
  • R 2 when R 2 is an alkyl radical, said alkyl radical is selected from C2-C6 alkyl, e.g. C2-C4 alkyl.
  • R 2 may be selected from C2-C6 alkyl; carbocyclyl-C0-C3 alkyl, carbocyclyl- C2-C3 alkenyl, heterocyclyl-C0-C3 alkyl or heterocyclyl-C2-C3 alkenyl; wherein any carbocyclyl or heterocyclyl is 5- or 6-membered monocyclyl or 9- or 10-membered bicyclyl; and any carbocyclyl or heterocyclyl is optionally substituted with at least one R 5 .
  • R 2 is selected from carbocyclyl-C0-C3 alkyl, carbocyclyl-C2-C3 alkenyl, heterocyclyl-C0-C3 alkyl or heterocyclyl-C2-C3 alkenyl; wherein any carbocyclyl or heterocyclyl is 5- or 6-membered monocyclyl or 9- or 10-membered bicyclyl; and any carbocyclyl or heterocyclyl is optionally substituted with at least one R 5 .
  • novel compound of formula (I) is a compound selected from
  • the novel compound of the invention is a compound selected from
  • the present invention also provides novel compounds.
  • the present invention provides a compound.
  • Examples of pharmaceutically acceptable salts of the compounds of the invention include those derived from mineral acids, such as hydrochloric, hydrobromic, phosphoric, metaphos- phoric, nitric and sulphuric acids, and organic acids, such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, and arylsulphonic acids.
  • mineral acids such as hydrochloric, hydrobromic, phosphoric, metaphos- phoric, nitric and sulphuric acids
  • organic acids such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, and arylsulphonic acids.
  • any optical isomer or diastereomer of the inventive compounds are comprised within the scope of the invention, as well as any mixture, racemic or not, of any such isomers.
  • the compounds of the present invention may act as inhibitors of the PFKFB3 and/or PFKFB4 protein.
  • the compounds of the above formula can exhibit a PFKFB3 and/or PFKFB4 inhibiting activity corresponding to an IC 50 of from about 50 nM to about 15 ⁇ (e.g., from about 50 nM to about 13 ⁇ , from about 50 nM to about 10 ⁇ , from about 50 nM to about 500 nM, from about 50 nM to about 100 nM) or a lower concentration as tested in an conventional assay as will be described below.
  • an IC 50 of from about 50 nM to about 15 ⁇ (e.g., from about 50 nM to about 13 ⁇ , from about 50 nM to about 10 ⁇ , from about 50 nM to about 500 nM, from about 50 nM to about 100 nM) or a lower concentration as tested in an conventional assay as will be described below.
  • the compounds described herein can be used, e.g., for the treatment or prevention of cancer and inflammation, and/or in treatment of disorders related to cancer and inflammation.
  • tumors with elevated glucose uptake compared to normal nontumor tissues identified by for example PET studies.
  • These tumors include, but are not limited to breast cancer, lung cancer, prostate cancer, colorectal cancers, haematological cancers and malignant melanoma.
  • the present invention relates to a method for the treatment or prophylaxis of a disease, disorder, or condition related to undesired activity of PFKFB3 and/or PFKFB4.
  • the method includes administering to a subject (e.g., a subject in need thereof, e.g., a mammal; e.g., a human; e.g., a human having, identified as having, at risk of having, or identified as being at risk of having one or more of the diseases or disorders described herein) an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.
  • this invention relates to a method for the treatment or prophylaxis of cancer, which includes administering to a subject (e.g., a subject in need of such treatment as described herein) an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.
  • the invention in another aspect, relates to a method for the treatment or prophylaxis (e.g., treatment) of inflammation, which includes administering to a subject (e.g., a subject in need of such treatment as described herein) an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.
  • the subject can be a subject in need of treatment of inflammation (e.g., a subject identified as being in need of such treatment as described herein). Identifying a subject in need of such treatment can be in the judgment of a subject or a health care professional and can be subjective (e.g. opinion) or objective (e.g. measurable by a test or diagnostic method).
  • the subject can be a mammal. In certain embodiments, the subject is a human.
  • this invention relates to the use of a compound of formula I (e.g., as a medicament) or in the manufacture of a medicament containing a compound of formula I for the treatment or prophylaxis (e.g., treatment) of a disease, disorder, or condition related to unde- sired activity of PFKFB3 and/or PFKFB4 as described herein.
  • a compound of formula I e.g., as a medicament
  • prophylaxis e.g., treatment
  • the invention relates to a compound (including a pharmaceutically acceptable salt thereof) of any of the formulae delineated herein (e.g., a compound having formula I, (or subgenera thereof), including the specific compounds described herein); or a composition or formulation (e.g., a pharmaceutical composition or formulation) comprising a compound (including a pharmaceutically acceptable salt thereof) of any of the formulae delineated herein (e.g., a compound having formula I (or subgenera thereof), including the specific compounds described herein).
  • the composition or formulation can further include a pharmaceutically acceptable adjuvant, carrier or diluent. Any such compound can be used in the methods described herein.
  • the compound of the present invention may be administered in combination with at least one other therapeutically active compound.
  • compounds of the present invention may be used or administered in combination with one or more additional drugs useful in the treatment of inflammation or cancer.
  • the components may be in the same formu- lation or in separate formulations for administration simultaneously or at different times.
  • the compounds of the present invention may also be used or administered in combination with other treatment such as irradiation for the treatment of cancer.
  • the dose administered to a mammal, particularly a human, in the context of the present invention should be sufficient to affect a therapeutic response in the mammal over a reasonable time frame.
  • dosage will depend upon a variety of factors including the purpose of the treatment, the potency of the specific compound, the age, condition and body weight of the patient, as well as the stage/severity of the disease.
  • the dose will also be determined by the route (administration form) timing and frequency of administration.
  • One object of the present invention is to provide a pharmaceutical composition comprising a compound according to formula (I), and optionally at least one pharmaceutically acceptable excipient.
  • the pharmaceutically acceptable excipient may be e.g.
  • the pharmaceutically acceptable carrier may be one that is chemically inert to the active compounds and that has no detrimental side effects or toxicity under the conditions of use.
  • Pharmaceutical formulations are found e.g. in Remington: The Science and Practice of Pharmacy, 19th ed., Mack Printing Company, Easton, Pennsylvania (1995).
  • compositions are usually prepared by mixing the active substance, i.e. a compound of the invention, or a pharmaceutically acceptable salt thereof, with conventional pharmaceutical excipients.
  • the formulations can be further prepared by known methods such as granulation, compression, microencapsulation, spray coating, etc.
  • the formulations may be prepared by conventional methods in the dosage form of tablets, capsules, granules, powders, syrups, suspensions, suppositories or injections.
  • Liquid formulations may be prepared by dissolving or suspending the active substance in water or other suitable vehicles. Tablets and granules may be coated in a conventional manner.
  • the compounds of the invention are formulated into pharmaceutical formulations for oral, rectal, parenteral or other mode of administration.
  • These pharmaceutical preparations are a further object of the invention.
  • the amount of active compounds is between 0.1-95% by weight of the preparation, preferably between 0.2-20% by weight in preparations for parenteral use and preferably between 1 and 50% by weight in preparations for oral administration.
  • the dose level and frequency of dosage of the specific compound will vary depending on a variety of factors including the potency of the specific compound employed, the metabolic stability and length of action of that compound, the patient's age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the condition to be treated, and the patient undergoing therapy.
  • the daily dosage may, for example, range from about 0.001 mg to about 100 mg per kilo of body weight, administered singly or multiply in doses, e.g. from about 0.01 mg to about 25 mg each. Normally, such a dosage is given orally but parenteral administration may also be chosen.
  • the compound selected may be mixed with solid, powdered ingredients, such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes.
  • solid, powdered ingredients such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes.
  • disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes.
  • Soft gelatine capsules may be prepared with capsules containing a mixture of the active compound or compounds of the invention, vegetable oil, fat, or other suitable vehicle for soft gelatine capsules.
  • Hard gelatine capsules may contain granules of the active compound.
  • Hard gelatine capsules may also contain the active compound in combination with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatine.
  • Dosage units for rectal administration may be prepared (i) in the form of suppositories which contain the active substance mixed with a neutral fat base; (ii) in the form of a gelatine rectal capsule which contains the active substance in a mixture with a vegetable oil, paraffin oil or other suitable vehicle for gelatine rectal capsules; (iii) in the form of a ready-made micro enema; or (iv) in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.
  • Liquid preparations for oral administration may be prepared in the form of syrups or suspensions, e.g. solutions or suspensions containing from 0.2% to 20% by weight of the active ingredient and the remainder consisting of sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethyl cellulose or other thickening agent.
  • Liquid preparations for oral administration may also be prepared in the form of a dry powder to be reconstituted with a suitable solvent prior to use.
  • Solutions for parenteral administration may be prepared as a solution of a compound of the invention in a pharmaceutically acceptable solvent, preferably in a concentration from 0.1% to 10% by weight. These solutions may also contain stabilizing ingredients and/or buffering ingredients and are dispensed into unit doses in the form of ampoules or vials. Solutions for parenteral administration may also be prepared as a dry preparation to be reconstituted with a suitable solvent extemporaneously before use.
  • the compounds of the invention may be prepared according to known methods for those skilled in the art.
  • the sulfone amides were prepared from aryl sulfonyl chlorides and anilines following any of the three methods illustrated in Scheme 1.
  • the sulfonyl chlorides of substituted aryls and anilines were allowed to react at room temperature or 50-60 °C until the sulfone amide coupling reactions were completed.
  • methyl 4-aminosalicylate was used as starting material, the sulfone amide coupling was followed by alkaline hydrolysis at 50 °C.
  • Preparative HPLC/MS was performed on a Waters/Micromass Platform ZQ system and preparative HPLC/UV was performed on a Gilson system in accordance to the experimental de- tails specified in the examples.
  • Analytical HPLC/MS was performed using an Agilent
  • Hewlett-Packard 5971A/5972A mass selective detector using EI Preparative flash chromatography was performed on Merck silica gel 60 (230-400 mesh). The compounds were named using ACD Name 6.0 or ISIS Draw 2.4. Microwave reactions were performed with a Personal Chemistry Smith Creator or Optimizer using 0.5-2 mL or 2-5 mL Smith Process Vials fitted with aluminum caps and septa. Accurate masses were measured using an Agilent MSD-TOF connected to an Agilent 1100 HPLC system. During the analyses the calibration was checked by two masses and automatically corrected when needed. Spectra were acquired in positive electrospray mode. The acquired mass range was m/z 100-1100. Profile detection of the mass peaks was used. Intermediate 1
  • Chlorosulfonic acid (52 ⁇ ,, 0.77 mmol) was added to a solution of 2,5-dichloro-3-methyl- thiophene (125 mg, 0.75 mmol) in CH 2 C1 2 . After 1 h of stirring at room temperature another portion of chlorosulfonic acid (52 ⁇ ,, 0.77 mmol) was added. Complete conversion to the intermediate sulfonic acid was observed after stirring at room temperature over night.
  • the product was prepared from 4-amino salicylic acid (1.16 g, 7.6 mmol) and 5- bromothiophene-2-sulfonyl chloride (1.0 g, 3.8 mmol) as described in Example 1 19. 0.64 g of the title compound was obtained as light brown solid (45%).

Abstract

L'invention porte sur un composé de formule (I) utilisé dans le traitement du cancer et des maladies inflammatoires. L'invention se rapporte aussi à une composition pharmaceutique renfermant le composé.
PCT/EP2011/060526 2010-06-22 2011-06-22 Bisarylsulfonamides utilisés comme inhibiteurs de la kinase dans le traitement de l'inflammation et du cancer WO2011161201A1 (fr)

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WO2013093095A1 (fr) * 2011-12-22 2013-06-27 Kancera Ab Bisarylsulfonamides utiles dans le traitement d'inflammations et de cancer
WO2016180537A1 (fr) * 2015-05-13 2016-11-17 Selvita S.A. Dérivés de quinoxaline substitués
ITUA20161994A1 (it) * 2016-03-24 2017-09-24 Azienda Ospedaliera Univ Senese Uso degli inibitori ddx3 come agenti anti-iperproliferativi
US10000449B2 (en) 2011-12-22 2018-06-19 Kancera Ab Bisarylsulfonamides useful in the treatment of inflammation and cancer
CN109824910A (zh) * 2019-03-06 2019-05-31 北京工业大学 一种基于三头吡唑配体的镍的金属有机骨架材料和制备方法及其应用
US10647675B2 (en) 2015-09-18 2020-05-12 Kaken Pharmaceutical Co., Ltd. Biaryl derivative and medicine containing same

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JP2015506925A (ja) * 2011-12-22 2015-03-05 カンセラ・アクチエボラグ 炎症および癌の処置において有用なビスアリールスルホンアミド
WO2013093095A1 (fr) * 2011-12-22 2013-06-27 Kancera Ab Bisarylsulfonamides utiles dans le traitement d'inflammations et de cancer
US10000449B2 (en) 2011-12-22 2018-06-19 Kancera Ab Bisarylsulfonamides useful in the treatment of inflammation and cancer
WO2016180537A1 (fr) * 2015-05-13 2016-11-17 Selvita S.A. Dérivés de quinoxaline substitués
US10647675B2 (en) 2015-09-18 2020-05-12 Kaken Pharmaceutical Co., Ltd. Biaryl derivative and medicine containing same
WO2017162834A1 (fr) * 2016-03-24 2017-09-28 Azienda Ospedaliera Universitaria Senese Utilisation d'inhibiteurs de ddx3 en tant qu'agents antiprolifératifs
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JP2019509313A (ja) * 2016-03-24 2019-04-04 アジエンダ・オスペダリエラ・ウニベルシタリア・セネーゼ 抗増殖剤としてのｄｄｘ３阻害剤の使用
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