WO2010017827A1 - 6-substituted 1-sulfonyl-2, 3-dihydro-indole derivatives for the treatment of proliferative diseases - Google Patents

6-substituted 1-sulfonyl-2, 3-dihydro-indole derivatives for the treatment of proliferative diseases Download PDF

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Publication number
WO2010017827A1
WO2010017827A1 PCT/EP2008/006710 EP2008006710W WO2010017827A1 WO 2010017827 A1 WO2010017827 A1 WO 2010017827A1 EP 2008006710 W EP2008006710 W EP 2008006710W WO 2010017827 A1 WO2010017827 A1 WO 2010017827A1
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alkyl
group
alkenyl
alkynyl
optionally substituted
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PCT/EP2008/006710
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French (fr)
Inventor
Bernd Janssen
Jochen Ammenn
Marcel MÜLBAIER
Jorge Alonso
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European Molecular Biology Laboratory
Elara Pharmaceuticals Gmbh
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Priority to PCT/EP2008/006710 priority Critical patent/WO2010017827A1/en
Publication of WO2010017827A1 publication Critical patent/WO2010017827A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—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
    • C07D409/12—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 linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to indoline-sulfonamide compounds according to general structural formula (I), pharmaceutical compositions comprising a compound of the invention. Further provided is the use of a compound or a composition according to the invention for the preparation of a medicament for the treatment of a proliferative disease, in particular the treatment of cancer.
  • Cancer is a disorder in which a population of cells has become, in varying degrees, unresponsive to the control mechanisms that normally govern proliferation and differentiation.
  • Therapeutic agents used in clinical cancer therapy can be categorized into several groups, including, alkylating agents, antibiotic agents, antimetabolic agents, cytostatic agents, hormonal agents, plant-derived agents and other anti-cancer agents.
  • Cancerous cells display uncontrolled growth (growth and division-rates beyond healthy cells), invasion (intrusion into and destruction of adjacent tissues), and sometimes metastasis (spread to other locations in the body via lymph or blood). Much effort has been spent to find novel anticancer agents. Cancer therapy is also being attempted by modulating the enzymatic activity of target proteins in cancer cells. For example, compounds were found which inhibit enzymes used in purine and pyrimidine synthesis such as thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyl transferase (GARPT).
  • TS thymidylate synthase
  • DHFR dihydrofolate reductase
  • GARPT glycinamide ribonucleotide formyl transferase
  • the invention provides a compound according to formula
  • R 1 is aryl or heteroaryl, substituted with at least one substituent other than hydrogen
  • R 2 is selected form the group consisting of halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyc ⁇ oalkyi, alkoxy, aryl, aralkyl, heteroaryl, -NO 2 , -CN, -NR 8 R 9 , -OR 10 , -SR 10 , -COOR 11 , -COR 10 , -CONR 8 R 9 , -CONHOR 10 , -NR 8 COR 10 , -NR 8 CONR 8 R 9 , -SO 2 NR 8 R 9 , -OOCR 1 ' and -CR 10 R 11 OH; optionally substituted;
  • R 3 is selected form the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, -NO 2 , -CN, -NR 8 R 9 , -OR 10 , -SR 10 , -COR 10 , -CONR 8 R 9 , -CONHOR 10 , -NR 8 COR 10 , -NR 8 CONR 8 R 9 , -SO 2 NR 8 R 9 , -OOCR 11 and -CR 10 R 11 OH; optionally substituted; R 4 to R 7 are each individually selected form the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, -NO 2 , -CN, -NR 12 R 13 ,
  • R 8 and R 9 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, alkylaryl and heteroaryl or together form a heteroaryl or heterocycloalkyl; optionally substituted;
  • R 10 and R 11 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and aralkyl; optionally substituted;
  • R 12 and R 1 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl and heteroaryl or together form a heteroaryl or heterocycloalkyl; optionally substituted;
  • R 14 and R 15 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and aralkyl; optionally substituted; or a pharmaceutically acceptable salt thereof; under the proviso that the compound according to formula (I) does not have a structure according to formula (II):
  • composition comprising a compound according to the invention and one or more chemotherapeutic or antiproliferative agent.
  • the invention provides the use of a compound according to the invention or a composition according to the invention for the preparation of a medicament for the treatment of a proliferative disease.
  • the invention provides a compound according to the invention and a pharmaceutical composition according to the invention, for the treatment of a proliferative disease.
  • alkyl "heteroalkyl”, “cycloalkyl”, “heterocycloalkyl”, “alicyclic system”, “aryl”, “aralkyl”, “heteroaiyl”, “heieroara ⁇ kyl”, “alkenyl”, “cycloalkenyl”, “alkynyl” and “optionally substituted” are provided.
  • alkyl refers to a saturated straight or branched carbon chain.
  • the chain comprises from 1 to 10 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 e.g. methyl, ethyl methyl, ethyl, propyl, iso-propyl, butyl, w ⁇ -butyl, tert-butyl, pentyl, hexyl, heptyl, or octyl.
  • Alkyl groups are optionally substituted.
  • heteroalkyl refers to a saturated straight or branched carbon chain.
  • the chain comprises from 1 to 9 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, 8 or 9 e.g. methyl, ethyl, propyl, /so-propyl, butyl, wo-butyl, sec-butyl, ter/-butyl, pentyl, hexyl, heptyl or octyl, which is interrupted one or more times, e.g. 1, 2, 3, 4, 5, with the same or different heteroatoms.
  • the heteroatoms are selected from O, S and N, e.g.
  • Heteroalkyl groups are optionally substituted.
  • cycloalkyl and “heterocycloalkyl”, by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl”, respectively, with preferably 3, 4, 5, 6, 7, 8, 9 or 10 atoms forming a ring, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl etc.
  • cycloalkyl and “heterocycloalkyl” are also meant to include bicyclic, tricyclic and polycyclic versions thereof.
  • heterocycloalkyl preferably refers to a saturated ring having five members of which at least one member is a N, O or S atom and which optionally contains one additional O or one additional N; a saturated ring having six members of which at least one member is a N, O or S atom and which optionally contains one additional O or one additional N or two additional N atoms; or a saturated bicyclic ring having nine or ten members of which at least one member is a N, O or S atom and which optionally contains one, two or three additional N atoms.
  • Cycloalkyl and “heterocycloalkyl” groups are optionally substituted. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule.
  • Preferred examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, spiro[3,3]heptyl, spiro[3,4]octyl, spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl, spiro[3,6]decyl, spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl, bicyclo[4.
  • heterocycloalkyl examples include l-(l,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3- piperidinyl, 4-morpholinyl, 3-morpholinyl, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro-[4,5] decyl, 1,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza-spiro[4,5] decyl, 2,6 diaza-spiro[4,5] decyl, 1,8 diaza-spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza-spiro- [5,4] decyl, 2,7 diaza-spiro- [5,4] decyl, 2,7 diaza-spiro- [5,4] decyl, 2,7 di
  • alicyclic system refers to mono, bicyclic, tricyclic or polycyclic version of a cycloalkyl or heterocycloalkyl comprising at least one double and/or triple bond.
  • an alicyclic system is not aromatic or heteroaromatic, i.e. does not have a system of conjugated double bonds/free electron pairs.
  • the number of double and/or triple bonds maximally allowed in an alicyclic system is determined by the number of ring atoms, e.g. in a ring system with up to 5 ring atoms an alicyclic system comprises up to one double bond, in a ring system with 6 ring atoms the alicyclic system comprises up to two double bonds.
  • the "cycloalkenyl" as defined below is a preferred embodiment of an alicyclic ring system.
  • Alicyclic systems are optionally substituted.
  • aryl preferably refers to an aromatic monocyclic ring containing 6 carbon atoms, an aromatic bicyclic ring system containing 10 carbon atoms or an aromatic tricyclic ring system containing 14 carbon atoms. Examples are phenyl, naphtyl or anthracenyl. The aryl group is optionally substituted.
  • aralkyl refers to an alkyl moiety, which is substituted by aryl, wherein alkyl and aryl have the meaning as outlined above.
  • An example is the benzyl radical.
  • the alkyl chain comprises from 1 to 8 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, or 8, e.g. methyl, ethyl methyl, ethyl, propyl, wo-propyl, butyl, w ⁇ -butyl, sec-butenyl, tert-butyl, pentyl, hexyl, heptyl or octyl.
  • the aralkyl group is optionally substituted at the alkyl and/or aryl part of the group.
  • heteroaryl preferably refers to a five or six-membered aromatic monocyclic ring wherein at least one of the carbon atoms are replaced by 1, 2, 3, or 4 (for the five membered ring) or 1, 2, 3, 4, or 5 (for the six membered ring) of the same or different heteroatoms, preferably selected from O, N and S; an aromatic bicyclic ring system wherein 1, 2, 3, 4, 5, or 6 carbon atoms of the 8, 9, 10, 11 or 12 carbon atoms have been replaced with the same or different heteroatoms, preferably selected from O, N and S; or an aromatic tricyclic ring system wherein 1. 2. 3, 4.
  • heteroarylkyl refers to an alkyl moiety, which is substituted by heteroaryl, wherein alkyl and heteroaryl have the meaning as outlined above.
  • An example is the 2-alklypyridinyl, 3- alkylpyridinyl, or 2-methylpyridinyl.
  • the alkyl chain comprises from 1 to 8 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, or 8, e.g.
  • heteroaralkyl group is optionally substituted at the alkyl and/or heteroaryl part of the group.
  • alkenyl and cycloalkenyl refer to olefinic unsaturated carbon atoms containing chains or rings with one or more double bonds. Examples are propenyl and cyclohexenyl.
  • the alkenyl chain comprises from 2 to 8 carbon atoms, i.e. 2, 3, 4, 5, 6, 7, or 8, e.g.
  • the term also comprises CH 2 , i.e. methenyl, if the substituent is directly bonded via the double bond.
  • the cycloalkenyl ring comprises from 3 to 14 carbon atoms, i.e. 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14, e.g.
  • alkynyl refers to unsaturated carbon atoms containing chains or rings with one or more triple bonds.
  • An example is the propargyl radical.
  • the alkynyl chain comprises from 2 to 8 carbon atoms, i.e. 2, 3, 4, 5, 6, 7, or 8, e.g. ethynyl, 1-propynyl, 2-propynyl, 1- butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, hexynyl, pentynyl, octynyl.
  • Substituciits e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 subsiiluenls which are in each instance independently selected from the group consisting of halogen, in particular F, Cl, Br or I; -R', -NO 2 , -CN, -OR 1 , -NR'R", -COOR', -CONR'R", -NR'"COR”", -NR'"C0R”", -NR'"CONR'R", -NR 55 SO 2 A, -COR'''; -SO 2 NR 5 R", -OOCR 555 , -CR'"R” 55 OH, and -E; R' and R 55 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and aral
  • R 555 and R 555 ' is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl and -NR 5 R 55 ;
  • E is selected from the group consisting of alkyl, alkenyl, cycloalkyl, alkoxy, alkoxyalkyl, heterocycloalkyl, an alicyclic system, aryl and heteroaryl; optionally substituted;
  • a compound according to the invention 55 refers to a compound according to formula I including all preferred respective embodiments of such a compound and physiological acceptable salts thereof.
  • compounds according to formula (I) are useful antiproliferative substances which can be administered to treat a proliferative disorder such as cancer.
  • R 1 is aryl, in particular phenyl, naphthalenyl or anthracenyl; or heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,- thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, l-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2-benzothienyl, lH-indazo
  • Ci C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, preferably methyl, ethyl, propyl, w ⁇ -propyl, butyl, iso-butyl, t ⁇ r/-butyl, pentyl or hexyl; alkenyl, in particular C 2 -C 6 alkenyl, e.g.
  • alkenyl preferably ethenyl, 1-propenyl, 2- propenyl, 1-wo-propenyl, 2-wo-propenyl, 1-butenyl, 2-butenyl or 3-butenyl; alkynyl, in particular C 2 -C 6 alkynyl, e.g.
  • R 3 is selected form the group consisting of hydrogen; halogen, in particular F, Cl, Br or I; alkyl, in particular C 1 -C 6 alkyl, e.g. C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, preferably methyl, ethyl, propyl, w ⁇ -propyl, butyl, iso-buty ⁇ , tert-butyl, pentyl or hexyl; alkenyl, in particular C 2 -C 6 alkenyl, e.g.
  • C 2 , C 3 , C 4 , C 5 , or C 6 alkenyl preferably ethenyl, 1-propenyl, 2-propenyl, l-wo-propenyl, 2-zso-propenyl, 1-butenyl, 2- butenyl or 3-butenyl; alkynyl, in paiticular C 2 -C 6 alkynyl, e.g.
  • R 4 to R 7 are each individually selected form the group consisting of hydrogen; halogen, in particular F, Cl, Br or I; alkyl, in particular C 1 -C 6 alkyl, e.g. Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, wo-butyl, tert-butyl, pentyl or hexyl; alkenyl, in particular C 2 -C 6 alkenyl, e.g. C 2 , C 3 , C 4 , C 5 , or C 6 alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-wo-propenyl, 2-wo-propenyl,
  • alkynyl in particular C 2 -C 6 alkynyl, e.g. C 2 , C 3 , C 4 , C 5 , or C 6 alkynyl; cycloalkyl; heterocycloalkyl; alkoxy, preferably methoxy, ethoxy or propoxy; aralkyl; cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, -NO 2 , -CN, -NR 12 R 13 , -OR 14 , -SR 14 , -COOR 15 , -COR 12 , -CONR 12 R 13 , -CONHOR 14 , -NR 12 COR 14 , -NR 12 CONR 12 R 13 , -SO 2 NR 12 R 13 , -OOCR 15 , -CR 14 R 15 OH and -R 15 OH; optionally
  • R and R is each independently selected from the group consisting of hydrogen; alkyl, in particular Ci-C 6 alkyl, e.g. C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, preferably methyl, ethyl, propyl, /so-propyl, butyl, w ⁇ -butyl, tert-butyl, pentyl or hexyl; alkenyl, in particular
  • C 2 -C 6 alkenyl e.g. C 2 , C 3 , C 4 , C 5 , or C 6 alkenyl, preferably ethenyl, 1-propenyl, 2- propenyl, 1-w ⁇ -propenyl, 2-wo-propenyl, 1-butenyl, 2-butenyl or 3-butenyl; alkynyl, in particular C 2 -C 6 alkynyl, e.g.
  • R 10 and R 11 is each independently selected from the group consisting of hydrogen; alkyl, in particular CpC 6 alkyl, e.g.
  • Ci C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, /so-butyl, terr-butyl, pentyl or hexyl; alkenyl, in particular C 2 -C 6 alkenyl, e.g.
  • alkenyl preferably ethenyl, 1-propenyl, 2- propenyl, 1 -zso-propenyl, 2-wo-propenyl, 1-butenyl, 2-butenyl or 3-butenyl; alkynyl, in particular C 2 -C 6 alkynyl, e.g.
  • R 10 and R 11 is each independently selected from Ci - C 6 alkyl, e.g.
  • Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl preferably methyl, ethyl, propyl, wo-propyl, butyl, iso- butyl, terr-butyl, pentyl or hexyl; optionally substituted;
  • R 12 and R 13 is each independently selected from the group consisting of hydrogen; alkyl, in particular C 1 -C 6 alkyl, e.g.
  • Ci C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, wo-butyl, tert-butyl, pentyl or hexyl; alkenyl, in particular C 2 -C 6 alkenyl, e.g.
  • alkenyl preferably ethenyl, 1-propenyl, 2- propenyl, 1 -wo-propenyl, 2-MO-propenyl, 1-butenyl, 2-butenyl or 3-butenyl; alkynyl, in particular C 2 -C 6 alkynyl, e.g.
  • R 14 and R 15 is each independently selected from the group consisting of hydrogen; alkyl, in particular Ci-C 6 alkyl, e.g.
  • Ci C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, preferably methyl, ethyl, propyl, w ⁇ -propyl, butyl, w ⁇ -butyl, t ⁇ r/-butyl, pentyl or hexyl; alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and aralkyi; optionally substituted; in a preferred embodiment, R 14 and R 15 are hydrogen or alkyl, in particular Cj-C 6 alkyl, e.g.
  • Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl preferably methyl, ethyl, propyl, iso- propyl, butyl, wo-butyl, tert-butyl, pentyl or hexyl; optionally substituted; or a pharmaceutically acceptable salt thereof; under the proviso that the compound according to formula (I) does not have a structure according to formula (II) :
  • Suitable pharmaceutically acceptable salts of the compound of the present invention include acid addition salts which may, for example, be formed by mixing a solution of choline or derivative thereof with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts (e.g., sodium or potassium salts); alkaline earth metal salts (e.g., calcium or magnesium salts); and salts formed with suitable organic ligands (e.g., ammonium, quaternary ammonium and amine cations formed using counteranions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl sulfonate and aryl sulfonate).
  • alkali metal salts e.g., sodium or potassium salts
  • alkaline earth metal salts e.g., calcium or magnesium salts
  • suitable organic ligands e.g., ammonium, quaternary ammonium and amine cations formed using counteranions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl sulfonate and aryl sul
  • Illustrative examples of pharmaceutically acceptable salts include but are not limited to: acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, citrate, clavulanate, cyclopentanepropionate, digluconate, dihydrochloride, dodecylsulfate, edetate, edisylate, estolate, esylate, ethanesulfonate, formate, fumarate, gluceptate, glucoheptonate, gluconate, glutamate, glycerophosphate, glycolylarsanilate, hemisulfate, heptanoate, hexanoate, hexylresorcinate
  • the neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
  • the present invention provides compounds which are in a prodrug form.
  • Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide a compound of formula (I).
  • a prodrug is an active or inactive compound that is modified chemically through in vivo physiological action, such as hydrolysis, metabolism and the like, into a compound of this invention following administration of the prodrug to a patient.
  • prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme. The suitability and techniques involved in making and using prodrugs are well known by those skilled in the art.
  • esters for example, methyl, ethyl
  • cycloalkyl for example, cyclohexyl
  • aralkyl for example, benzyl, p-methoxybenzyl
  • alkylcarbonyloxyalkyl for example, pivaloyloxymethyl
  • Amines have been masked as arylcarbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bungaard J. Med. Chem. 2503 (1989)). Also, drugs containing an acidic NH group, such as imidazole, imide, indole and the like, have been masked with N- acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)). Hydroxyl groups have been masked as esters and ethers.
  • EP 0 039 051 (Sloan and Little, Apr. 11, 1981) discloses Mannich-base hydroxamic acid prodrugs, their preparation and use.
  • Certain compounds of the present invention can exist in unsolvated forms as well as in solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
  • the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine- 125 ( 125 I) or carbon- 14 ( 14 C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the
  • R 1 is a substituent according to formula (III) or (IV):
  • P is CR 12 or N; wherein R 12 has below outlined meaning and is most preferably hydrogen;
  • Q is CR 12 or N; wherein R 12 has below outlined meaning and is most preferably hydrogen; most preferably P and Q are C;
  • Z is selected from the group consisting of O, S and NR 12 ; wherein R 12 has below outlined meaning and is most preferably hydrogen;
  • R 2 is selected form the group consisting of halogen, in particular F, Cl, Br or I; alkyl, in particular Ci-C 6 alkyl, e.g. Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, preferably methyl, ethyl, propyl, w ⁇ -propyl, butyl, wo-butyl, ter/-butyl, pentyl or hexyl; alkenyl, in particular C 2 - C 6 alkenyl, e.g.
  • alkenyl preferably ethenyl, 1-propenyl, 2-propenyl, 1-wo-propenyl, 2-/5O-propenyl, 1-butenyl, 2-butenyl or 3-butenyl; alkynyl, in particular C 2 -C 6 alkynyl, e.g.
  • R 3 is selected form the group consisting of hydrogen; halogen, in particular F, Cl, Br or I; alkyl, in particular C 1 -C 6 alkyl, e.g. C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl; alkenyl, in particular C 2 -
  • C 6 alkenyl e.g. C 2 , C 3 , C 4 , C 5 , or C 6 alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, l-/s ⁇ -propenyl, 2-w ⁇ -propenyl, 1-butenyl, 2-butenyl or 3-butenyl; alkynyl, in particular
  • C 2 -C 6 alkynyl e.g. C 2 , C 3 , C 4 , C 5 , or C 6 alkynyl; cycloalkyl; heterocycloalkyl; alkoxy, preferably methoxy, ethoxy or propoxy; aralkyl; aryl, in particular phenyl, naphthaienyi or anthracenyl; heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5- oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl,
  • R 3 is hydrogen;
  • R 4 to R 7 are each individually selected form the group consisting of hydrogen; halogen, in particular F, Cl, Br or I; alkyl, in particular Ci-C 6 alkyl, e.g.
  • C u C 2 , C 3 , C 4 , C 5 , or C 6 aikyi preferably methyl, ethyl, propyl, /s ⁇ -propyi, butyi, /s ⁇ -butyi, tert-butyl, pentyi or hexyl; alkenyl, in particular C 2 -C 6 alkenyl, e.g. C 2 , C 3 , C 4 , C 5 , or C 6 alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, l-w ⁇ -propenyl, 2-w ⁇ -propenyl, 1-butenyl, 2-butenyl or
  • alkynyl in particular C 2 -C 6 alkynyl, e.g. C 2 , C 3 , C 4 , C 5 , or C 6 alkynyl; cycloalkyl; heterocycloalkyl; alkoxy, preferably methoxy, ethoxy or propoxy; aralkyl; cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, -NO 2 , -CN, -NR 12 R 13 , -OR 14 , -SR 14 , -COOR 15 , -COR 12 , -CONR 12 R 13 , -CONHOR 14 , -NR 12 COR 14 , -NR 12 CONR 12 R 13 , -SO 2 NR 12 R 13 , -00CR 15 , -CR 14 R 15 OH and -R 15 OH; optionally substituted; most preferably, each of R 4 to
  • R" and R' is each independently selected from the group consisting of hydrogen; alkyl, in particular CpC 6 alkyl, e.g. Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, preferably methyl, ethyl, propyl, /so-propyl, butyl, zs ⁇ -butyl, tert-butyl, pentyi or hexyl; alkenyl, in particular C 2 - C 6 alkenyl, e.g.
  • alkenyl preferably ethenyl, 1-propenyl, 2-propenyl, 1-zs ⁇ -propenyl, 2-w ⁇ -propenyl, 1-butenyl, 2-butenyl or 3-butenyl; alkynyl, in particular
  • C 2 -C 6 alkynyl e.g. C 2 , C 3 , C 4 , C 5 , or C 6 alkynyl; cycloalkyl; heterocycloalkyl; alkoxy, preferably methoxy, ethoxy or propoxy; aryl, aralkyl, alkylaryl and heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl,
  • 1,3,5-triazinyl 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2- benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1 ,2,4-benzotriazinyl or together form a heteroaryl or heterocycloalkyl; optionally substituted;
  • R 10 and R 11 is each independently selected from the group consisting of hydrogen; alkyl, in particular C 1 -C 6 alkyl, e.g. Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, preferably methyl, ethyl, propyl, /s ⁇ -propyl, butyl, /s ⁇ -butyl, tert-butyl, pentyi or hexyl; alkenyl, in particular C 2 - C 6 alkenyl, e.g. C 2 , C 3 , C 4 , C 5 , or C 6 alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl,
  • alkynyl in particular C 2 -C 6 alkynyl, e.g. C 2 , C 3 , C 4 , C 5 , or C 6 alkynyl; cycloalkyl, heterocycloalkyl, aryl, heteroaryl and aralkyl; optionally substituted; most preferably, R 10 and R 11 is each independently selected from C 1 - C 6 alkyl, e.g.
  • Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl preferably methyl, ethyl, propyl, /sO-propyl, butyl, wo-butyl, tert-butyl, pentyl or hexyl; optionally substituted;
  • R 12 and R 13 is each independently selected from the group consisting of hydrogen; alkyl, in particular Ci-C 6 alkyl, e.g. Cj, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, preferably methyl, ethyl, propyl, /s ⁇ -propyl, butyl, /so-butyl, tert-butyl, pentyl or hexyl; alkenyl, in particular C 2 - C 6 alkenyl, e.g.
  • alkenyl preferably ethenyl, 1-propenyl, 2-propenyl, l-wo-propenyl, 2-wo-propenyl, 1-butenyl, 2-butenyl or 3-butenyl; alkynyl, in particular C 2 -C 6 alkynyl, e.g.
  • R 14 and R 15 is each independently selected from the group consisting of hydrogen; alkyl, in particular C 1 -C 6 alkyl, e.g. C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, preferably methyl, ethyl, propyl, /s ⁇ -propyl, butyl, w ⁇ -butyl, tert-butyl, pentyl or hexyl; alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and aralkyl; optionally substituted;
  • C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl preferably methyl, ethyl, propyl, wo-propyl, butyl, KO-butyl, tert-butyl, pentyl or hexyl; optionally substituted;
  • R 16 is selected from the group consisting of halogen, in particular F, Cl, Br or I; alkyl, in particular C 1 -C 6 alkyl, e.g.
  • C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl preferably methyl, ethyl, propyl, /so-propyl, butyl, wo-butyl, tert-butyl, pentyl or hexyl; alkenyl, in particular C 2 - C 6 alkenyl, e.g.
  • alkenyl preferably ethenyl, 1-propenyl, 2-propenyl, l-wo-propenyl, 2-wo-propenyl, 1-butenyl, 2-butenyl or 3-butenyl; alkynyl, in particular C 2 -C 6 alkynyl, e.g.
  • R 16 is selected from the group consisting of halogen, in particular Cl, Br or I; alkyl, in particular C 1 -C 6 alkyl; -OR 14 ; -SO 2 R 10 and -SR 14 , optionally substituted; wherein R 14 is alkyl, in particular C 1 - C 6 alkyl, e.g.
  • Ci C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, preferably methyl, ethyl, propyl, w ⁇ -propyl, butyl, w ⁇ -butyl, tert-butyl, pentyl or hexyl; * indicates the bond between R 1 and the compound according to formula (I).
  • R 1 is a substituent according to formula (V) or (VI):
  • R 12 to R 16 have the above indicated meanings and more preferably the following meaning: P is CR or N; wherein R has below outlined meaning and is most preferably hydrogen;
  • Q is CR 12 or N; wherein R 12 has below outlined meaning and is most preferably hydrogen; most preferably P and Q arc C;
  • Z is selected from the group consisting of O, S and NR 12 ; wherein R 12 has below outlined meaning and is most preferably hydrogen; R 2 is selected form the group consisting of halogen, in particular F, Cl, Br or I; alkyl, in particular Ci-C 6 alkyl, e.g. Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, wo-butyl, /ert-butyl, pentyl or hexyl; alkenyl, in particular C 2 - C 6 alkenyl, e.g.
  • alkenyl preferably ethenyl, 1-propenyl, 2-propenyl, 1-wo-propenyl, 2-wo-propenyl, 1-butenyl, 2-butenyl or 3-butenyl; alkynyl, in particular C 2 -C 6 alkynyl, e.g.
  • R 2 is selected form the group consisting of heteroaryl, -COOalkyl; -COR 10 ; -CONR 8 R 9 ; -CONHOR 10 ; -NR 8 COR 10 ; -NR 8 CONR 8 R 9 ; -SO 2 NR 8 R 9 ; -OOCR 11 and -CR 10 R 11 OH; optionally substituted; most preferably, R 2 is selected form the group consisting of -COOCH 3 , thiophenyl, specifically thiophene-3-yl, and alkylfuranyl, specifically 2-(Ci-C 6 )alkyl-fiiran-5-yl (i.e.
  • R 3 is selected form the group consisting of hydrogen; halogen, in particular F, Cl, Br or I; alkyl, in particular C 1 -C 6 alkyl, e.g.
  • Ci C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, wo-butyl, tert-butyl, pentyl or hexyl; alkenyl, in particular C 2 - C 6 alkenyl, e.g.
  • alkenyl preferably ethenyl, 1-propenyl, 2-propenyl, 1-wo-propenyl, 2-wo-propenyl, 1-butenyl, 2-butenyl or 3-butenyl; alkynyl, in particular C 2 -C 6 alkynyl, e.g.
  • R 3 is hydrogen
  • R 4 to R 7 are each individually selected form the group consisting of hydrogen; halogen, in particular F, Cl, Br or I; alkyl, in particular CpC 6 alkyl, e.g. C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, preferably methyl, ethyl, propyl, /so-propyl, butyl, /so-butyl, tert-butyl, pentyl or hexyl; alkenyl, in particular C 2 -C 6 alkenyl, e.g.
  • alkenyl preferably ethenyl, 1-propenyl, 2-propenyl, 1-wo-propenyl, 2-/so-propenyl, 1-butenyl, 2-butenyl or 3-butenyl; alkynyl, in particular C 2 -C 6 alkynyl, e.g.
  • each of R 4 to R 7 is hydrogen;
  • R and R is each independently selected from the group consisting of hydrogen; alkyl, in particular Ci-C 6 alkyl, e.g. Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, preferably methyl, ethyl, propyl, w ⁇ -propyl, butyl, /_? ⁇ -butyl, tert-butyl, pentyl or hexyl; alkenyl, in particular C 2 - C 6 alkenyl, e.g.
  • alkenyl preferably ethenyl, 1-propenyl, 2-propenyl, 1-w ⁇ -propenyl, 2-wo-propenyl, 1-butenyl, 2-butenyl or 3-butenyl; alkynyl, in particular
  • C 2 -C 6 alkynyl e.g. C 2 , C 3 , C 4 , C 5 , or C 6 alkynyl; cycloalkyl; heterocycloalkyl; alkoxy, preferably methoxy, ethoxy or propoxy; aryl, aralkyl, alkylaryl and heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl,
  • 1,3,5-triazinyl 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2- benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl or together form a heteroaryl or heterocycloalkyl; optionally substituted;
  • R 10 and R 11 is each independently selected from the group consisting of hydrogen; alkyl, in particular Ci-C 6 alkyl, e.g. Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, wo-butyl, tert-butyl, pentyl or hexyl; alkenyl, in particular C 2 - C 6 alkenyl, e.g. C 2 , C 3 , C 4 , C 5 , or C 6 alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl,
  • alkynyl in particular C 2 -C 6 alkynyl, e.g. C 2 , C 3 , C 4 , C 5 , or C 6 alkynyl; cycloalkyl, heterocycloalkyl, aryl, heteroaryl and aralkyl; optionally substituted; most preferably, R 10 and R 11 is each independently selected from Ci - C 6 alkyl, e.g.
  • Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl preferably methyl, ethyl, propyl, w ⁇ -propyl, butyl, w ⁇ -butyl, tert-butyl, pentyl or hexyl; optionally substituted;
  • R 12 and R 13 is each independently selected from the group consisting of hydrogen; alkyl, in particular Ci-C 6 alkyl, e.g. Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, preferably methyl, ethyl, propyl, w ⁇ -propyl, butyl, /s ⁇ -butyl, tert-butyl, pentyl or hexyl; alkenyl, in particular C 2 - C 6 alkenyl, e.g. C 2 , C 3 , C 4 , C 5 , or C 6 alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl,
  • alkynyl in particular C 2 -C 6 alkynyl, e.g. C 2 , C 3 , C 4 , C 5 , or C 6 alkynyl; cycloalkyl; heterocycloalkyl; alkoxy, preferably methoxy, ethoxy or propoxy; aryl, aralkyl and heteroaryl or together form a heteroaryl or heterocycloalkyl; optionally substituted;
  • R 14 and R 15 is each independently selected from the group consisting of hydrogen; alkyl, in particular Ci-C 6 alkyl, e.g.
  • Ci C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, wo-butyl, tert-butyl, pentyl or hexyl; alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and aralkyl; optionally substituted; in a preferred embodiment, R 14 and R 15 are hydrogen or alkyl, in particular C 1 - C 6 alkyl, e.g.
  • Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl preferably methyl, ethyl, propyl, wo-propyl, butyl, wo-butyl, ter/-butyl, pentyl or hexyl; optionally substituted; and
  • R 16 is selected from the group consisting of halogen, in particular F, Cl, Br or I; alkyl, in particular Ci-C 6 alkyl, e.g. Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, wo-butyl, tert-buty ⁇ , pentyl or hexyl; alkenyl, in particular C 2 - C 6 alkenyl, e.g.
  • alkenyl preferably ethenyl, 1-propenyl, 2-propenyl, 1-w ⁇ -propenyl, 2-wo-propenyl, 1-butenyl, 2-butenyl or 3-butenyl; alkynyl, in particular C 2 -C 6 alkynyl, e.g.
  • R 16 is selected from the group consisting of halogen, in particular Cl, Br or I; alkyl, in particular C 1 -C 6 alkyl; -OR 14 ; -SO 2 R 10 and -SR 14 , optionally substituted; wherein R 14 is alkyl, in particular Ci - C 6 alkyl, e.g.
  • C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl preferably methyl, ethyl, propyl, iso-pioipyl, butyl, /50-butyl, ieri-hxxtyl, pentyl or hexyl.
  • R 2 is selected form the group consisting of aryl, heteroaryl, -COOR 11 , -COR 10 , -CONR 8 R 9 and -CONHOR 10 ; optionally substituted; and more preferably, R 2 is -COOR 11 or -COR 10 , optionally substituted; wherein R 11 and R 10 have above outlined meaning and are each individually preferably alkyl, in particular Ci - C 6 alkyl, e.g.
  • Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl preferably methyl, ethyl, propyl, wo-propyl, butyl, wo-butyl, tert-butyl, pentyl or hexyl.
  • R 1 is selected from the group consisting of:
  • R 2 is selected form the group consisting of halogen, in particular F, Cl, Br or I; alkyl, in particular C 1 -C 6 alkyl, e.g. C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, iso-butyl, ter/-butyl, pentyl or hexyl; alkenyl, in particular C 2 -
  • C 6 alkenyl e.g. C 2 , C 3 , C 4 , C 5 , or C 6 alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-z ' so-propenyl, 2-w ⁇ -propenyl, 1-butenyl, 2-butenyl or 3-butenyl; alkynyl, in particular C 2 -C 6 alkynyl, e.g.
  • R 2 is selected form the group consisting of -COOCH 3 , thiophenyl, specifically thiophene-3-yl, and alkylfuranyl, specifically 2-(Ci-C 6 )alkyl-furan-5-yl (i.e.
  • R 3 is selected form the group consisting of hydrogen; halogen, in particular F, Cl, Br or I; alkyl, in particular C 1 -C 6 alkyl, e.g.
  • Ci C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, preferably methyl, ethyl, propyl, /so-propyl, butyl, wo-butyl, tert-butyl, pentyl or hexyl; alkenyl, in particular C 2 - C 6 alkenyl, e.g.
  • alkenyl preferably ethenyl, 1-propenyl, 2-propenyl, 1-wo-propenyl, 2-/so-propenyl, 1-butenyl, 2-butenyl or 3-butenyl; alkynyl, in particular C 2 -C 6 alkynyl, e.g.
  • R 4 to R 7 are each individually selected form the group consisting of hydrogen; halogen, in particular F, Cl, Br or I; alkyl, in particular Cj-C 6 alkyl, e.g. C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, wo-butyl, tert-butyl, pentyl or hexyl; alkenyl, in particular C 2 -C 6 alkenyl, e.g.
  • C 2 , C 3 , C 4 , C 5 , or C 6 alkenyl preferably ethenyl, 1-propenyl, 2-propenyl, 1-wo-propenyl, 2-JSO-propenyl, 1-butenyl, 2-butenyl or
  • alkynyl in particular C 2 -C 6 alkynyl, e.g. C 2 , C 3 , C 4 , C 5 , or C 6 alkynyl; cycloalkyl; heterocycloalkyl; alkoxy, preferably methoxy, ethoxy or propoxy; aralkyl; cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, -NO 2 , -CN, -NR 12 R 13 , -OR 14 , -SR 14 , -COOR 15 , -COR 12 , -CONR 12 R 13 , -CONHOR 14 , -NR 12 COR 14 , -NR 12 CONR 12 R 13 , -SO 2 NR 12 R 13 , -OOCR 15 , -CR 14 R 15 OH and -R 15 OH; optionally substituted; most preferably, each of R 4 to
  • R 8 and R 9 is each independently selected from the group consisting of hydrogen; alkyl, in particular Ci-C 6 alkyl, e.g. C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, wo-butyl, tert-butyl, pentyl or hexyl; alkenyl, in particular C 2 - C 6 alkenyl, e.g.
  • alkenyl preferably ethenyl, 1-propenyl, 2-propenyl, 1-wo-propenyl, 2-wo-propenyl, 1-butenyl, 2-butenyl or 3-butenyl; alkynyl, in particular
  • C 2 -C 6 alkynyl e.g. C 2 , C 3 , C 4 , C 5 , or C 6 alkynyl
  • cycloalkyl e.g. C 2 , C 3 , C 4 , C 5 , or C 6 alkynyl
  • cycloalkyl heterocycloalkyl
  • alkoxy preferably methoxy, ethoxy or propoxy
  • aryl, aralkyl, alkylaryl and heteroaryl in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl,
  • 1,3,5-triazinyl 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2- benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl,
  • R 10 and R 11 is each independently selected from the group consisting of hydrogen; alkyl, in particular Cj-C 6 alkyl, e.g. C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, preferably methyl, ethyl, propyl, /so-propyl, butyl, w ⁇ -butyl, ter/-butyl, pentyl or hexyl; alkenyl, in particular C 2 - C 6 alkenyl, e.g.
  • C 2 , C 3 , C 4 , C 5 , or C 6 alkenyl preferably ethenyl, 1-propenyl, 2-propenyl, 1-zs ⁇ -propenyl, 2-/s ⁇ -propenyl, 1-butenyl, 2-butenyl or 3-butenyl; alkynyl, in particular C 2 -C 6 alkynyl, e.g. C 2 , C 3 , C 4 , C 5 , or C 6 alkynyl; cycloalkyl, heterocycloalkyl, aryl, heteroaryl and aralkyl; optionally substituted; most preferably, R 10 and R 11 is each independently selected from C 1 - Ce alkyl.
  • C 1 . C 2 , C 3 , C 4 , C 5 , or C 6 alkyl preferably methyl, ethyl, propyl, w ⁇ -propyl, butyl, w ⁇ -butyl, tert-butyl, pentyl or hexyl; optionally substituted;
  • R 12 and R 13 is each independently selected from the group consisting of hydrogen; alkyl, in particular Ci-C 6 alkyl, e.g. C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, preferably methyl, ethyl, propyl, w ⁇ -propyl, butyl, /s ⁇ -butyl, tert-butyl, pentyl or hexyl; alkenyl, in particular C 2 - C 6 alkenyl, e.g.
  • alkenyl preferably ethenyl, 1-propenyl, 2-propenyl, 1-is ⁇ -propenyl, 2-wo-propenyl, 1-butenyl, 2-butenyl or 3-butenyl; alkynyl, in particular C 2 -C 6 alkynyl, e.g.
  • R 14 and R 15 is each independently selected from the group consisting of hydrogen; alkyl, in particular C 1 -C 6 alkyl, e.g. C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, preferably methyl, ethyl, propyl, /so-propyl, butyl, /s ⁇ -butyl, tert-butyl, pentyl or hexyl; alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and aralkyl; optionally substituted; in a preferred embodiment, R 14 and R 15 are hydrogen or alkyl, in particular Ci - C 6 alkyl, e.g.
  • C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl preferably methyl, ethyl, propyl, w ⁇ -propyl, butyl, /so-butyl, terf-butyl, pentyl or hexyl; optionally substituted; and R 16 is selected from the group consisting of halogen, in particular F, Cl, Br or I; alkyl, in particular C 1 -C 6 alkyl, e.g.
  • C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl preferably methyl, ethyl, propyl, /s ⁇ -propyl, butyl, /s ⁇ -butyl, tert-butyl, pentyl or hexyl; alkenyl, in particular C 2 - C 6 alkenyl, e.g.
  • alkenyl preferably ethenyl, 1-propenyl, 2-propenyl, 1-w ⁇ -propenyl, 2-w ⁇ -propenyl, 1-butenyl, 2-butenyl or 3-butenyl; alkynyl, in particular C 2 -C 6 alkynyl, e.g.
  • R 16 is selected from the group consisting of halogen, in particular Cl, Br or I; alkyl, in particular Cj-C 6 alkyl; -OR 14 ; -SO 2 R 10 and -SR 14 , optionally substituted; wherein R 14 is alkyl, in particular C 1 - C 6 alkyl, e.g.
  • Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl preferably methyl, ethyl, propyl, w ⁇ -propyl, butyl, w ⁇ -butyl, tert-butyl, pentyl or hexyl.
  • R 3 is hydrogen or wherein R 4 through R 7 are hydrogen, or more preferably, wherein R 3 and R 4 through R 7 are hydrogen.
  • the compound according to formula (I) is a compound having a structure selected from the group consisting of:
  • the compounds having one stereochemistry can often be utilized to produce those having opposite stereochemistry (i.e., (S)) using well-known methods, for cxcix ⁇ ipiC, inversion.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to the invention and one or more chemotherapeutic or antiproliferative agent.
  • the one or more chemotherapeutic or antiproliferative agent of the pharmaceutical composition according to the invention is selected from the group consisting of ZM447439, VX- 680, anti-tumor antibodies, imatinib, the methanesulfonic acid salt of alkylating substances, anti- metabolites, antibiotics, epothilones, anti-androgens, anti-estrogens, platinum compounds, hormones and antihormones, interferons, inhibitors of cell cycle-dependent protein kinases (CDKs), imatinib, platine coordination complexes, ethyleneimenes, methylmelamines, trazines, vinca alkaloids, pyrimidine analogs, purine analoga, alkylsulfonates, folic acid analogs, anthracendiones, substituted urea, methylhydrazin derivatives, in particular acediasulfone, aclarubicine, ambazone, aminoglutethimide, CDKs
  • the invention also provides the use of a compound according to the invention or a composition according to the invention for the preparation of a medicament for the treatment of a proliferative disease.
  • the invention also provides a compound according to the invention and a pharmaceutical composition according to the invention, for the treatment of a proliferative disease.
  • Said proliferative disease may be e.g. a cancer and/or a hyperplasia.
  • Many types of cancer are known in the art all of which are characterized in a non-controlled cell division rate, i.e. a cancerous cell, e.g. in a tumour divides more frequently over the course of a defined timeframe, than a healthy cell, e.g. of the same tissue origin than the cancerous cell stems from.
  • cancerous cells and/or tissues e.g. tumours
  • the cancer involves a tumour/ neoplasm selected from the group consisting of a brain or other central nervous system tumour (e.g.
  • a respiratory tract tumour e.g. nasal cavity and middle ear, accessory sinuses, larynx, trachea, bronchus and lung, e.g. small cell lung cancer or non-small cell lung cancer
  • a skeletal system tumour e.g. bone and articular cartilage of limbs, bone articular cartilage and other sites
  • a skin tumour e.g.
  • malignant melanoma of the skin non-melanoma skin cancer, basal cell carcinoma of skin, squamous cell carcinoma of skin, mesothelioma, Kaposi's sarcoma); a tumour involving other tissues including peripheral nerves and autonomic nervous system, connective and soft tissue, retroperitoneum and peritoneum, eye and adnexa, thyroid, adrenal gland and other endocrine glands and related structures, secondary and unspecified malignant neoplasm of lymph nodes, secondary malignant neoplasm of respiratory and digestive systems and secondary malignant neoplasm of other sites and a tumour derived or affecting blood cells or the lymphatic system (e.g.
  • Hodgkin's disease Non-Hodgkin's lymphoma, Burkitt's lymphoma, AIDS-related lymphomas, malignant immunoproliferative diseases, multiple myeloma and malignant plasma cell neoplasms, lymphoid leukemia, acute or chronic myeloid leukaemia (e.g.
  • acute or chronic myeloid leukaemia acute or chronic myeloid leukaemia
  • acute or chronic lymphocytic leukemia monocytic leukemia
  • other leukemias of specified cell type leukemia of unspecified cell type
  • a malignant neoplasm of lymphoid haematopoietic or related tissues, for example, a diffuse large cell lymphoma or a T- cell lymphoma or cutaneous T-cell lymphoma).
  • Said neoplasms can be benign, potentially malignant (pre-cancer) or malignant (cancer).
  • the hyperplasia may be selected from the group consisting of congenital adrenal hyperplasia, endometrial hyperplasia, hyperplasia of the breast, focal epithelial hyperplasia (also known as Heck's disease), sebaceous hyperplasia and compensatory liver hyperplasia.
  • the cancer may also be a medullary carcinoma, an osteosarcoma, a soft-tissue sarcoma, an Ewing's sarcoma, a reticulum cell sarcoma or a Kaposi's sarcoma.
  • the cancer also called tumour herein
  • the cancer is a cancer selected from the group consisting of: a solid tumor, a hematological malignancy, a carcinoma, a neuroblastoma and a melanoma. Also included are pediatric forms of any of the cancers described herein.
  • the compounds and compositions according to the invention can be administered by various well known routes, including oral, rectal, intragastrical, intracranial and parenteral administration, e.g. intravenous, intramuscular, intranasal, intradermal, subcutaneous, and similar administration routes.
  • parenteral administration and particular intravenous administration preferably by depot injection, is preferred.
  • different pharmaceutical formulations are required and some of those may require that protective coatings are applied to the drug formulation to prevent degradation of a compound or a compositions of the invention in, for example, the digestive tract.
  • a compound or a composition of the invention is formulated as a syrup, an infusion or injection solution, a tablet, a capsule, a capslet, lozenge, a liposome, a suppository, a plaster, a band-aid, a retard capsule, a powder, or a slow release formulation.
  • the diluent is water, a buffer, a buffered salt solution or a salt solution and the carrier preferably is selected from the group consisting of cocoa butter and vitebesole.
  • Particular preferred pharmaceutical forms for the administration of a compound or a composition of the invention are forms suitable for injectionable use and include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. In all cases the final solution or dispersion form must be sterile and fluid.
  • a solution or dispersion will include a solvent or dispersion medium, containing, for example, water-buffered aqueous solutions, e.g. biocompatible buffers, ⁇ thanol, polyol, such as glycerol, propylene glycol, polyethylene glycol, suitable mixtures thereof, surfactants or vegetable oils.
  • a compound or a composition of the invention can also be formulated into liposomes, in particular for parenteral administration. Liposomes provide the advantage of increased half life in the circulation, if compared to the free drug and a prolonged more even release of the enclosed drug.
  • Sterilization of infusion or injection solutions can be accomplished by any number of art recognized techniques including but not limited to addition of preservatives like anti-bacterial or anti-fungal agents, e.g. parabene, chlorobutanol, phenol, sorbic acid or thimersal. Further, isotonic agents, such as sugars or salts, in particular sodium chloride may be incorporated in infusion or injection solutions.
  • preservatives like anti-bacterial or anti-fungal agents, e.g. parabene, chlorobutanol, phenol, sorbic acid or thimersal.
  • isotonic agents such as sugars or salts, in particular sodium chloride may be incorporated in infusion or injection solutions.
  • sterile injectable solutions containing one or several of the compounds or compositions of the invention is accomplished by incorporating the respective compound in the required amount in the appropriate solvent with various ingredients enumerated above as required followed by sterilization. To obtain a sterile powder the above solutions are vacuum- dried or freeze-dried as necessary.
  • Preferred diluents of the present invention are water, physiological acceptable buffers, physiological acceptable buffer salt solutions or salt solutions.
  • Preferred carriers are cocoa butter and vitebesole.
  • Excipients which can be used with the various pharmaceutical forms of a compound or composition of the invention can be chosen from the following non-limiting list: a) binders such as lactose, mannitol, crystalline sorbitol, dibasic phosphates, calcium phosphates, sugars, microcrystalline cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, polyvinyl pyrrolidone and the like; b) lubricants such as magnesium stearate, talc, calcium stearate, zinc stearate, stearic acid, hydrogenated vegetable oil, leucine, glycerids and sodium stearyl fumarates, c) disintegrants such as starches, croscaramellose, sodium methyl cellulose, agar, bentonite, alginic acid, carboxymethyl cellulose, polyvinyl pyrrolidone and the like.
  • binders such as lactose, mannitol, crystalline
  • the dosage of a compound of the invention in the therapeutic or prophylactic use of the invention should be in the range of about 0.1 mg to about 1 g serum per kg body weight.
  • a compound of the invention is administered to a subject in need thereof in an amount ranging from 1.0 to 500 mg/kg body weight, preferably ranging from 10 to 200 mg/kg body weight, preferably ranging from 50 to 150 mg/kg body weight, preferably ranging from 90 to 100 mg/kg body weight.
  • the duration of therapy with a compound of the invention will vary, depending on the severity of the disease being treated and the condition and idiosyncratic response of each individual patient.
  • the pharmaceutically effective amount of a given compound or composition will also depend on the administration route. In general the required amount will be higher, if the administration is through the gastrointestinal tract; e.g. by suppository, rectal, or by an intragastric probe, and lower if the route of administration is parenteral, e.g. intravenous.
  • a compound of the invention will be administered in ranges of 50 mg to 1 g/kg body weight, preferably 100 mg to 500 mg/kg body weight, if rectal or intragastric administration is used and in ranges of 10 to 100 mg/kg body weight, if parenteral administration is used.
  • a prophylactic administration of the biologically active blood serum or the pharmaceutical composition according to the invention may be possible.
  • the respective compound or composition of the invention is preferably administered in above outlined preferred and particular preferred doses on a daily basis. Preferably, between 0.1 mg to 1 g/kg body weight once a day, preferably 10 to 200 mg/kg body weight. This administration can be continued until the risk of developing the respective disorder has lessened. In most instances, however, a compound or composition of the invention will be administered once a disease/disorder has been diagnosed.
  • a first dose of a compound or composition of the invention is administered one, two, three or four times daily.
  • the administration is discontinued for one day, one week or one month and then repeated until the symptoms of the respective disease are no longer worsening or improving.
  • Example 1 Synthesis and analytical data of l-(4-Ethoxy-benzenesulfonyl)-2,3-dihydro- indole-6-carboxylic acid methyl ester
  • 6-Thiophene-3-yl-l-(toluene-4-sulfonyl)-2,3-dihydro-indole was synthesized starting from commercial available 6-bromo-indoline. Following general procedure A, the starting material was transformed with tosylchloride to give the sulfonamide. Following general procedure B, subsequent transformation with 3-thiophene boronic acid gave the desired product.
  • 6-(5-Methyl-furan-2-yl)-l-(toluene-4-sulfonyl)-2,3-dihydro-indole was synthesized starting from commercial available 6-bromo-indoline. Following general procedure A, the starting material was transformed with tosylchloride to give the sulfonamide. Following general procedure B, subsequent transformation with 2-methylfuran-5-boronic acid pinacolester gave the desired product.
  • tumour cells e.g. MCF7, HL60, LL2, HeLa, PC-3, A549 and A375 cells
  • Growth inhibition was tested at various concentrations in triplicate in a 10 point two fold serial dilution and cells were incubated under standard mammalian tissue culture conditions for 72 hours.
  • Cell viability was determined by measuring ATP levels in viable cells using the ATPLite kit (PerkinElmer) as described in the user manual.
  • Raw data was transformed to percentage inhibition of growth compared to DMSO- only controls (0.5% and 9% for negative and positive controls, respectively) and values were expressed as IC 50 in micromolar calculated using XLf ⁇ t (IDBS).
  • the compounds of the present invention showed the ability to inhibit the growth of various tumor cell lines indicating a broad spectrum of growth inhibitory activity.
  • the bioactivity of several exemplary indoline- sulfonamide compounds of the invention was measured using the viability assay as described above. Results obtained when using the indicated compounds on MCF-7 cells are depicted in Table 1 below.
  • Compounds with 10 ⁇ M ⁇ IC 50 ⁇ 100 ⁇ M are designated as (+); compounds with 1 ⁇ M ⁇ IC 50 ⁇ 10 ⁇ M are designated as (++) and compounds with an IC 50 ⁇ 1 ⁇ M are designated as (+++).

Abstract

The present invention relates to indoline-sulfonamide compounds according to general structural formula (I), pharmaceutical compositions comprising a compound of the invention. Further provided is the use of a compound or a composition according to the invention for the preparation of a medicament for the treatment of a proliferative disease, in particular the treatment of cancer.

Description

-SUBSTITUTED 1- SULFONYL- 2 , 3 -DIHYDRO- INDOLE DERIVATIVES FOR THE TREATMENT OF
PROLIFERATIVE DISEASES
The present invention relates to indoline-sulfonamide compounds according to general structural formula (I), pharmaceutical compositions comprising a compound of the invention. Further provided is the use of a compound or a composition according to the invention for the preparation of a medicament for the treatment of a proliferative disease, in particular the treatment of cancer.
BACKGROUND OF THE INVENTION
Cancer is a disorder in which a population of cells has become, in varying degrees, unresponsive to the control mechanisms that normally govern proliferation and differentiation. Therapeutic agents used in clinical cancer therapy can be categorized into several groups, including, alkylating agents, antibiotic agents, antimetabolic agents, cytostatic agents, hormonal agents, plant-derived agents and other anti-cancer agents.
Cancerous cells display uncontrolled growth (growth and division-rates beyond healthy cells), invasion (intrusion into and destruction of adjacent tissues), and sometimes metastasis (spread to other locations in the body via lymph or blood). Much effort has been spent to find novel anticancer agents. Cancer therapy is also being attempted by modulating the enzymatic activity of target proteins in cancer cells. For example, compounds were found which inhibit enzymes used in purine and pyrimidine synthesis such as thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyl transferase (GARPT). By inhibiting the formation of precursor purine and pyrimidine nucleotides, the formation of DNA and RNA is comprimised, which are necessary for the growth and survival of both normal cells and cancer cells. As cancer cells are rapidly dividing, they heavily rely on a sufficient supply of nucleotides to afford such rapid divisions. However, therapeutic target proteins, such as the aforementioned enzymes respond differently to treatment depending on the type of cancer and the genetic predisposition of the patient.
Thus, due to the multiple different forms of cancer, there is a need for additional pharmaceutically active substances which can be used to treat cancer. SUMMARY OF THE INVENTION
The inventors have identified novel compounds which are useful to treat a proliferative disorder such as cancer. Thus, in a first aspect, the invention provides a compound according to formula
(I):
Figure imgf000003_0001
( I ) wherein,
R1 is aryl or heteroaryl, substituted with at least one substituent other than hydrogen; R2 is selected form the group consisting of halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycϊoalkyi, alkoxy, aryl, aralkyl, heteroaryl, -NO2, -CN, -NR8R9, -OR10, -SR10, -COOR11, -COR10, -CONR8R9, -CONHOR10, -NR8COR10, -NR8CONR8R9, -SO2NR8R9, -OOCR1 ' and -CR10R11 OH; optionally substituted;
R3 is selected form the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, -NO2, -CN, -NR8R9, -OR10, -SR10, -COR10, -CONR8R9, -CONHOR10, -NR8COR10, -NR8CONR8R9, -SO2NR8R9, -OOCR11 and -CR10R11OH; optionally substituted; R4 to R7 are each individually selected form the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, -NO2, -CN, -NR12R13, -OR14, -SR14, -COOR15, -COR12, -CONR12R13, -CONHOR14, -NR12COR14, -NR12CONR12R13, -SO2NR12R13, -OOCR15, -CR14R15OH and -R15OH; optionally substituted; R4 and R5 together may form =0, =S, a cycloalkyl, a heterocycloalkyl or an alicylic system; optionally substituted; R6 and R7 together may form =0, =S, a cycloalkyl, a heterocycloalkyl or an alicylic system; optionally substituted;
R8 and R9 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, alkylaryl and heteroaryl or together form a heteroaryl or heterocycloalkyl; optionally substituted;
R10 and R11 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and aralkyl; optionally substituted; R12 and R1 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl and heteroaryl or together form a heteroaryl or heterocycloalkyl; optionally substituted;
R14 and R15 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and aralkyl; optionally substituted; or a pharmaceutically acceptable salt thereof; under the proviso that the compound according to formula (I) does not have a structure according to formula (II):
Figure imgf000004_0001
(H) wherein X is hydrogen or methyl.
Also provided is a pharmaceutical composition comprising a compound according to the invention and one or more chemotherapeutic or antiproliferative agent.
In another aspect, the invention provides the use of a compound according to the invention or a composition according to the invention for the preparation of a medicament for the treatment of a proliferative disease.
In another aspect, the invention provides a compound according to the invention and a pharmaceutical composition according to the invention, for the treatment of a proliferative disease.
DETAILED DESCRIPTION OF THE INVENTION
Before the present invention is described in detail below, it is to be understood that this invention is not limited to the particular methodology, protocols and reagents described herein as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art. Preferably, the terms used herein are defined as described in "A multilingual glossary of biotechnological terms: (IUPAC Recommendations)", Leuenberger, H.G.W, Nagel, B. and Klbl, H. eds. (1995), Helvetica Chimica Acta, CH-4010 Basel, Switzerland). Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise" and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. In the following passages different aspects of the invention are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous.
Several documents are cited throughout the text of this specification. Each of the documents cited herein (including all patents, patent applications, scientific publications, manufacturer's specifications, instructions, etc.), whether supra or infra, are hereby incorporated by reference in their entirety. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.
In the following, definitions of the terms: "alkyl", "heteroalkyl", "cycloalkyl", "heterocycloalkyl", "alicyclic system", "aryl", "aralkyl", "heteroaiyl", "heieroaraϊkyl", "alkenyl", "cycloalkenyl", "alkynyl" and "optionally substituted" are provided. These terms will in each instance of its use in the remainder of the specification have the respectively defined meaning and preferred meanings.
The term "alkyl" refers to a saturated straight or branched carbon chain. Preferably, the chain comprises from 1 to 10 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 e.g. methyl, ethyl methyl, ethyl, propyl, iso-propyl, butyl, wø-butyl, tert-butyl, pentyl, hexyl, heptyl, or octyl. Alkyl groups are optionally substituted.
The term "heteroalkyl" refers to a saturated straight or branched carbon chain. Preferably, the chain comprises from 1 to 9 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, 8 or 9 e.g. methyl, ethyl, propyl, /so-propyl, butyl, wo-butyl, sec-butyl, ter/-butyl, pentyl, hexyl, heptyl or octyl, which is interrupted one or more times, e.g. 1, 2, 3, 4, 5, with the same or different heteroatoms. Preferably the heteroatoms are selected from O, S and N, e.g. -0-CH3, -S-CH3, -CH2-O-CH3, - CH2-O-C2H5, -CH2-S-CH3, -CH2-S-C2H5, -C2H4-O-CH3, -C2H4-O-C2H5, -C2H4-S-CH3, -C2H4-S- C2H5 etc. Heteroalkyl groups are optionally substituted.
The terms "cycloalkyl" and "heterocycloalkyl", by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of "alkyl" and "heteroalkyl", respectively, with preferably 3, 4, 5, 6, 7, 8, 9 or 10 atoms forming a ring, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl etc. The terms "cycloalkyl" and "heterocycloalkyl" are also meant to include bicyclic, tricyclic and polycyclic versions thereof. If more than one cyclic ring is present such as in bicyclic, tricyclic and polycyclic versions, then these rings may also comprise one or more aryl- or heteroaryl ring. The term "heterocycloalkyl" preferably refers to a saturated ring having five members of which at least one member is a N, O or S atom and which optionally contains one additional O or one additional N; a saturated ring having six members of which at least one member is a N, O or S atom and which optionally contains one additional O or one additional N or two additional N atoms; or a saturated bicyclic ring having nine or ten members of which at least one member is a N, O or S atom and which optionally contains one, two or three additional N atoms. "Cycloalkyl" and "heterocycloalkyl" groups are optionally substituted. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Preferred examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, spiro[3,3]heptyl, spiro[3,4]octyl, spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl, spiro[3,6]decyl, spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl, bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl, octahydro-pentalenyl, octahydro- indenyl. decahvdro-azulenyl. adamantly, or decahydro-naphthalenyl. Examples of heterocycloalkyl include l-(l,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3- piperidinyl, 4-morpholinyl, 3-morpholinyl, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro-[4,5] decyl, 1,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza-spiro[4,5] decyl, 2,6 diaza-spiro[4,5] decyl, 1,8 diaza-spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza-spiro- [5,4] decyl, 2,7 diaza-spiro[5,4] decyl, 3,8 diaza-spiro[5,4] decyl, 3,7 diaza-spiro[5,4] decyl, 1- aza-7,l l-dioxo-spiro[5,5] undecyl, l,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.
The term "alicyclic system" refers to mono, bicyclic, tricyclic or polycyclic version of a cycloalkyl or heterocycloalkyl comprising at least one double and/or triple bond. However, an alicyclic system is not aromatic or heteroaromatic, i.e. does not have a system of conjugated double bonds/free electron pairs. Thus, the number of double and/or triple bonds maximally allowed in an alicyclic system is determined by the number of ring atoms, e.g. in a ring system with up to 5 ring atoms an alicyclic system comprises up to one double bond, in a ring system with 6 ring atoms the alicyclic system comprises up to two double bonds. Thus, the "cycloalkenyl" as defined below is a preferred embodiment of an alicyclic ring system. Alicyclic systems are optionally substituted.
The term "aryl" preferably refers to an aromatic monocyclic ring containing 6 carbon atoms, an aromatic bicyclic ring system containing 10 carbon atoms or an aromatic tricyclic ring system containing 14 carbon atoms. Examples are phenyl, naphtyl or anthracenyl. The aryl group is optionally substituted.
The term "aralkyl" refers to an alkyl moiety, which is substituted by aryl, wherein alkyl and aryl have the meaning as outlined above. An example is the benzyl radical. Preferably, in this context the alkyl chain comprises from 1 to 8 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, or 8, e.g. methyl, ethyl methyl, ethyl, propyl, wo-propyl, butyl, wø-butyl, sec-butenyl, tert-butyl, pentyl, hexyl, heptyl or octyl. The aralkyl group is optionally substituted at the alkyl and/or aryl part of the group.
The term "heteroaryl" preferably refers to a five or six-membered aromatic monocyclic ring wherein at least one of the carbon atoms are replaced by 1, 2, 3, or 4 (for the five membered ring) or 1, 2, 3, 4, or 5 (for the six membered ring) of the same or different heteroatoms, preferably selected from O, N and S; an aromatic bicyclic ring system wherein 1, 2, 3, 4, 5, or 6 carbon atoms of the 8, 9, 10, 11 or 12 carbon atoms have been replaced with the same or different heteroatoms, preferably selected from O, N and S; or an aromatic tricyclic ring system wherein 1. 2. 3, 4. 5, or 6 carbon atoms of the 13, 14, 15, or lό carbon aioms have been replaced with the same or different heteroatoms, preferably selected from O, N and S. Examples are oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3- triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1 -benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazoyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1- benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, 1,2,3- benzotriazinyl, or 1,2,4-benzotriazinyl.
The term "heteroaralkyl" refers to an alkyl moiety, which is substituted by heteroaryl, wherein alkyl and heteroaryl have the meaning as outlined above. An example is the 2-alklypyridinyl, 3- alkylpyridinyl, or 2-methylpyridinyl. Preferably, in this context the alkyl chain comprises from 1 to 8 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, or 8, e.g. methyl, ethyl methyl, ethyl, propyl, wo-propyl, butyl, wo-butyl, .sec-butenyl, tert-butyl, pentyl, hexyl, heptyl or octyl. The heteroaralkyl group is optionally substituted at the alkyl and/or heteroaryl part of the group.
The terms "alkenyl" and "cycloalkenyl" refer to olefinic unsaturated carbon atoms containing chains or rings with one or more double bonds. Examples are propenyl and cyclohexenyl. Preferably, the alkenyl chain comprises from 2 to 8 carbon atoms, i.e. 2, 3, 4, 5, 6, 7, or 8, e.g. ethenyl, 1 -propenyl, 2-propenyl, wo-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, wo-butenyl, sec- butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, hexenyl, heptenyl, octenyl. The term also comprises CH2, i.e. methenyl, if the substituent is directly bonded via the double bond. Preferably the cycloalkenyl ring comprises from 3 to 14 carbon atoms, i.e. 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14, e.g. cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctyl, cyclononenyl, cyclodecenyl, spiro[3,3]heptenyi, spiro[3,4]octenyl, spiro[4,3]octenyi, spiro[3,5]nonenyl, spiro[5,3]nonenyl, spiro[3,6]decenyl, spiro[6,3]decenyl, spiro[4,5]decenyl, spiro[5,4]decenyl, bicyclo[4.1.0]heptenyl, bicyclo[3.2.0]heptenyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.2]octenyl, bicyclo[5.1.0]octenyl, bicyclo[4.2.0]octenyl, hexahydro-pentalenyl, hexahydro-indenyl, octahydro-azulenyl, or octahydro-naphthalenyl.
The term "alkynyl" refers to unsaturated carbon atoms containing chains or rings with one or more triple bonds. An example is the propargyl radical. Preferably, the alkynyl chain comprises from 2 to 8 carbon atoms, i.e. 2, 3, 4, 5, 6, 7, or 8, e.g. ethynyl, 1-propynyl, 2-propynyl, 1- butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, hexynyl, pentynyl, octynyl.
The term "optionally substituted" in each instance if not further specified refers to between 1 and 10 Substituciits, e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 subsiiluenls which are in each instance independently selected from the group consisting of halogen, in particular F, Cl, Br or I; -R', -NO2, -CN, -OR1, -NR'R", -COOR', -CONR'R", -NR'"COR"", -NR'"C0R"", -NR'"CONR'R", -NR55SO2A, -COR'''; -SO2NR5R", -OOCR555, -CR'"R"55OH, and -E; R' and R55 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and aralkyl or together form a heteroaryl, or heterocycloalkyl;
R555 and R555' is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl and -NR5R55; E is selected from the group consisting of alkyl, alkenyl, cycloalkyl, alkoxy, alkoxyalkyl, heterocycloalkyl, an alicyclic system, aryl and heteroaryl; optionally substituted;
As used throughout the specification, the term "a compound according to the invention55 refers to a compound according to formula I including all preferred respective embodiments of such a compound and physiological acceptable salts thereof.
The inventors have surprisingly found that compounds according to formula (I) are useful antiproliferative substances which can be administered to treat a proliferative disorder such as cancer.
Thus, in a first aspect the invention provides a compound according to formula (I):
Figure imgf000009_0001
( I ) wherein, R1 is aryl, in particular phenyl, naphthalenyl or anthracenyl; or heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,- thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, l-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2-benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1- benzisoihiazoiyi, benzoiriazoiyi, quinolinyl, i&υquinυiiiiyi, 2,3-bciiZυdiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; substituted with at least one substituent other than hydrogen; preferably, R1 is a five or six-membered aromatic or heteroaromatic monocyclic ring which is substituted with at least one substituent and if R1 is, which is most preferred, a six- membered aromatic or heteroaromatic monocyclic ring then R1 is most preferably substituted with a substituent at its 4-position; R2 is selected form the group consisting of halogen, in particular F, Cl, Br or I; alkyl, in particular Ci-C6 alkyl, e.g. Ci, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, wø-propyl, butyl, iso-butyl, tør/-butyl, pentyl or hexyl; alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl, preferably ethenyl, 1-propenyl, 2- propenyl, 1-wo-propenyl, 2-wo-propenyl, 1-butenyl, 2-butenyl or 3-butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl; cycloalkyl; heterocycloalkyl; alkoxy, preferably methoxy, ethoxy or propoxy; aralkyl; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, l-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl,
2-benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; -NO2; -CN; -NR8R9; -OR10; -SR10; -COOR11, -COR10; -CONR8R9; -CONHOR10; -NR8COR10; -NR8CONR8R9; -SO2NR8R9; -OOCR11 and -CR10R11OH; optionally substituted; more preferably, R2 is selected form the group consisting of heteroaryl, -COOalkyl; -COR10; -CONR8R9; -CONHOR10; -NR8COR10; -NR8CONR8R9; -SO2NR8R9; -OOCR11 and -CR10R11OH; optionally substituted; most preferably, R2 is selected form the group consisting of -COOCH3, thiophenyl, specifically thiophene-3-yl, and alkylfuranyl, specifically 2-(C1-C6)alkyl-furan-5-yl (i.e. 2-methyl-furan-5-yl, 2- ethyl-furan-5-yl, 2-propyl-furan-5-yl, 2-/so-propyl-furan-5-yl, 2-butyl-furan-5-yl, 2- wo-butyl-furan-5-yl, 2-tert-butyl-furan-5-yl, 2-pentyl-furan-5-yl, or 2-hexyl-furan- 5-yl); optionally substituted;
R3 is selected form the group consisting of hydrogen; halogen, in particular F, Cl, Br or I; alkyl, in particular C1-C6 alkyl, e.g. C1, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, wø-propyl, butyl, iso-buty\, tert-butyl, pentyl or hexyl; alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, l-wo-propenyl, 2-zso-propenyl, 1-butenyl, 2- butenyl or 3-butenyl; alkynyl, in paiticular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl; cycloalkyl; heterocycloalkyl; alkoxy, preferably methoxy, ethoxy or propoxy; aralkyl; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3- oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl,
1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3- triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2-benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1,2- benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl,
2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4- benzotriazinyl; -NO2, -CN, -NR8R9, -OR10, -SR10, -COR10, -CONR8R9, -CONHOR10, -NR8COR10, -NR8CONR8R9, -SO2NR8R9, -OOCR11 and -CR10R11OH; optionally substituted; most preferably, R3 is hydrogen;
R4 to R7 are each individually selected form the group consisting of hydrogen; halogen, in particular F, Cl, Br or I; alkyl, in particular C1-C6 alkyl, e.g. Ci, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, wo-butyl, tert-butyl, pentyl or hexyl; alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-wo-propenyl, 2-wo-propenyl,
1-butenyl, 2-butenyl or 3-butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl; cycloalkyl; heterocycloalkyl; alkoxy, preferably methoxy, ethoxy or propoxy; aralkyl; cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, -NO2, -CN, -NR12R13, -OR14, -SR14, -COOR15, -COR12, -CONR12R13, -CONHOR14, -NR12COR14, -NR12CONR12R13, -SO2NR12R13, -OOCR15, -CR14R15OH and -R15OH; optionally substituted; preferably R4 to R7 are hydrogen; R4 and R5 together may form =0, =S, a cycloalkyl, a heterocycloalkyl or an alicylic system; optionally substituted;
R6 and R7 together may form =0, =S, a cycloalkyl, a heterocycloalkyl or an alicylic system; optionally substituted;
R and R is each independently selected from the group consisting of hydrogen; alkyl, in particular Ci-C6 alkyl, e.g. C1, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, /so-propyl, butyl, wσ-butyl, tert-butyl, pentyl or hexyl; alkenyl, in particular
C2-C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl, preferably ethenyl, 1-propenyl, 2- propenyl, 1-wø-propenyl, 2-wo-propenyl, 1-butenyl, 2-butenyl or 3-butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl; cycloalkyl; heterocycloalkyl; alkoxy, preferably methoxy, ethoxy or propoxy; aryl, aralkyl, alkylaryl and heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5- oxadiazolyl. 1 ;2-3-oxadiazoiyl, pyrrolyl, irnidazclyl, p>τazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2- benzofuranyl, indolyl, isoindolyl, benzothienyl, 2-benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl,
1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4- benzotriazinyl or together form a heteroaryl or heterocycloalkyl; optionally substituted; R10 and R11 is each independently selected from the group consisting of hydrogen; alkyl, in particular CpC6 alkyl, e.g. Ci, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, /so-butyl, terr-butyl, pentyl or hexyl; alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl, preferably ethenyl, 1-propenyl, 2- propenyl, 1 -zso-propenyl, 2-wo-propenyl, 1-butenyl, 2-butenyl or 3-butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl; cycloalkyl, heterocycloalkyl, aryl, heteroaryl and aralkyl; optionally substituted; most preferably, R10 and R11 is each independently selected from Ci - C6 alkyl, e.g. Ci, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, iso- butyl, terr-butyl, pentyl or hexyl; optionally substituted; R12 and R13 is each independently selected from the group consisting of hydrogen; alkyl, in particular C1-C6 alkyl, e.g. Ci, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, wo-butyl, tert-butyl, pentyl or hexyl; alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl, preferably ethenyl, 1-propenyl, 2- propenyl, 1 -wo-propenyl, 2-MO-propenyl, 1-butenyl, 2-butenyl or 3-butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl; cycloalkyl; heterocycloalkyl; alkoxy, preferably methoxy, εthoxy or propoxy; aryl, aralkyi and heteroaryl or together form a heteroaryl or heterocycloalkyl; optionally substituted; R14 and R15 is each independently selected from the group consisting of hydrogen; alkyl, in particular Ci-C6 alkyl, e.g. Ci, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, wø-propyl, butyl, wø-butyl, tør/-butyl, pentyl or hexyl; alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and aralkyi; optionally substituted; in a preferred embodiment, R14 and R15 are hydrogen or alkyl, in particular Cj-C6 alkyl, e.g. Ci, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso- propyl, butyl, wo-butyl, tert-butyl, pentyl or hexyl; optionally substituted; or a pharmaceutically acceptable salt thereof; under the proviso that the compound according to formula (I) does not have a structure according to formula (II) :
Figure imgf000012_0001
(H) wherein X is hydrogen or methyl.
The term "pharmaceutically acceptable salt" refers to a salt of the compound of the present invention. Suitable pharmaceutically acceptable salts of the compound of the present invention include acid addition salts which may, for example, be formed by mixing a solution of choline or derivative thereof with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compound of the invention carries an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts (e.g., sodium or potassium salts); alkaline earth metal salts (e.g., calcium or magnesium salts); and salts formed with suitable organic ligands (e.g., ammonium, quaternary ammonium and amine cations formed using counteranions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl sulfonate and aryl sulfonate). Illustrative examples of pharmaceutically acceptable salts include but are not limited to: acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, citrate, clavulanate, cyclopentanepropionate, digluconate, dihydrochloride, dodecylsulfate, edetate, edisylate, estolate, esylate, ethanesulfonate, formate, fumarate, gluceptate, glucoheptonate, gluconate, glutamate, glycerophosphate, glycolylarsanilate, hemisulfate, heptanoate, hexanoate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, lauratε, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methanesulfonate, methylsulfate, mucate, 2-naphthalenesulfonate, napsylate, nicotinate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, pectinate, persulfate, 3-phenylpropionate, phosphate/diphosphate, picrate, pivalate, polygalacturonate, propionate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide, undecanoate, valerate, and the like (see, for example, Berge, S. M., et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
In addition to salt forms, the present invention provides compounds which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide a compound of formula (I). A prodrug is an active or inactive compound that is modified chemically through in vivo physiological action, such as hydrolysis, metabolism and the like, into a compound of this invention following administration of the prodrug to a patient. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme. The suitability and techniques involved in making and using prodrugs are well known by those skilled in the art. For a general discussion of prodrugs involving esters see Svensson and Tunek Drug Metabolism Reviews 16.5 (1988) and Bundgaard Design of Prodrugs, Elsevier (1985). Examples of a masked carboxylate anion include a variety of esters, such as alkyl (for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl (for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (for example, pivaloyloxymethyl). Amines have been masked as arylcarbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bungaard J. Med. Chem. 2503 (1989)). Also, drugs containing an acidic NH group, such as imidazole, imide, indole and the like, have been masked with N- acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)). Hydroxyl groups have been masked as esters and ethers. EP 0 039 051 (Sloan and Little, Apr. 11, 1981) discloses Mannich-base hydroxamic acid prodrugs, their preparation and use.
Certain compounds of the present invention can exist in unsolvated forms as well as in solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine- 125 (125I) or carbon- 14 (14C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the
In a preferred embodiment of the compound according to the invention, R1 is a substituent according to formula (III) or (IV):
Figure imgf000014_0001
(IV) wherein
P is CR12 or N; wherein R12 has below outlined meaning and is most preferably hydrogen; Q is CR12 or N; wherein R12 has below outlined meaning and is most preferably hydrogen; most preferably P and Q are C; Z is selected from the group consisting of O, S and NR12; wherein R12 has below outlined meaning and is most preferably hydrogen;
R2 is selected form the group consisting of halogen, in particular F, Cl, Br or I; alkyl, in particular Ci-C6 alkyl, e.g. Ci, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, wø-propyl, butyl, wo-butyl, ter/-butyl, pentyl or hexyl; alkenyl, in particular C2- C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-wo-propenyl, 2-/5O-propenyl, 1-butenyl, 2-butenyl or 3-butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl; cycloalkyl; heterocycloalkyl; alkoxy, preferably rnethoxy, ethoxy or propoxy; aralkyl; aryl, in particular phenyl, naphthaienyi or anthracenyl; heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5- oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2-benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1- benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; -NO2; -CN; -NR8R9; -OR10; -SR10; -COOR11, -COR10; -CONR8R9; -CONHOR10; -NR8COR10; -NR8CONR8R9; -SO2NR8R9; -OOCR11 and -CR10R11OH; optionally substituted; more preferably, R2 is selected form the group consisting of heteroaryl, -COOalkyl; -COR10; -CONR8R9; -CONHOR10; -NR8COR10; -NR8CONR8R9; -SO2NR8R9; -OOCR11 and -CR R OH; optionally substituted, most picfciably, R is selected foini the gxoup consisting of -COOCH3, thiophenyl, specifically thiophene-3-yl, and alkylfuranyl, specifically 2-(C1-C6)alkyl-furan-5-yl (i.e. 2-methyl-furan-5-yl, 2-ethyl-furan-5-yl, 2- propyl-furan-5-yl, 2-/sø-propyl-furan-5-yl, 2-butyl-furan-5-yl, 2- wo-butyl-furan-5-yl, 2- tert-butyl-furan-5-yl, 2-pentyl-furan-5-yl, or 2-hexyl-furan-5-yl); optionally substituted;
R3 is selected form the group consisting of hydrogen; halogen, in particular F, Cl, Br or I; alkyl, in particular C1-C6 alkyl, e.g. C1, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl; alkenyl, in particular C2-
C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, l-/sø-propenyl, 2-wø-propenyl, 1-butenyl, 2-butenyl or 3-butenyl; alkynyl, in particular
C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl; cycloalkyl; heterocycloalkyl; alkoxy, preferably methoxy, ethoxy or propoxy; aralkyl; aryl, in particular phenyl, naphthaienyi or anthracenyl; heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5- oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl,
1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2-benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1- benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; -NO2, -CN,
-NR8R9, -OR10, -SR10, -COR10, -CONR8R9, -CONHOR10, -NR8COR10, -NR8CONR8R9, -SO2NR8R9, -OOCR11 and -CR10R11OH; optionally substituted; most preferably, R3 is hydrogen; R4 to R7 are each individually selected form the group consisting of hydrogen; halogen, in particular F, Cl, Br or I; alkyl, in particular Ci-C6 alkyl, e.g. Cu C2, C3, C4, C5, or C6 aikyi, preferably methyl, ethyl, propyl, /sø-propyi, butyi, /sø-butyi, tert-butyl, pentyi or hexyl; alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, l-wø-propenyl, 2-wø-propenyl, 1-butenyl, 2-butenyl or
3-butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl; cycloalkyl; heterocycloalkyl; alkoxy, preferably methoxy, ethoxy or propoxy; aralkyl; cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, -NO2, -CN, -NR12R13, -OR14, -SR14, -COOR15, -COR12, -CONR12R13, -CONHOR14, -NR12COR14, -NR12CONR12R13, -SO2NR12R13, -00CR15, -CR14R15OH and -R15OH; optionally substituted; most preferably, each of R4 to R7 is hydrogen; R4 and R5 together may form =0, =S, a cycloalkyl, a heterocycloalkyl or an alicylic system; optionally substituted; R and R7 together may form =0, =S, a cycloalkyl, a heterocycloalkyl or an alicylic system; optionally substituted;
R" and R' is each independently selected from the group consisting of hydrogen; alkyl, in particular CpC6 alkyl, e.g. Ci, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, /so-propyl, butyl, zsø-butyl, tert-butyl, pentyi or hexyl; alkenyl, in particular C2- C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-zsø-propenyl, 2-wø-propenyl, 1-butenyl, 2-butenyl or 3-butenyl; alkynyl, in particular
C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl; cycloalkyl; heterocycloalkyl; alkoxy, preferably methoxy, ethoxy or propoxy; aryl, aralkyl, alkylaryl and heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl,
1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2- benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1 ,2,4-benzotriazinyl or together form a heteroaryl or heterocycloalkyl; optionally substituted;
R10 and R11 is each independently selected from the group consisting of hydrogen; alkyl, in particular C1-C6 alkyl, e.g. Ci, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, /sø-propyl, butyl, /sø-butyl, tert-butyl, pentyi or hexyl; alkenyl, in particular C2- C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl,
1 -/so-propenyl, 2-wø-propenyl, 1-butenyl, 2-butenyl or 3-butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl; cycloalkyl, heterocycloalkyl, aryl, heteroaryl and aralkyl; optionally substituted; most preferably, R10 and R11 is each independently selected from C1 - C6 alkyl, e.g. Ci, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, /sO-propyl, butyl, wo-butyl, tert-butyl, pentyl or hexyl; optionally substituted;
R12 and R13 is each independently selected from the group consisting of hydrogen; alkyl, in particular Ci-C6 alkyl, e.g. Cj, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, /sø-propyl, butyl, /so-butyl, tert-butyl, pentyl or hexyl; alkenyl, in particular C2- C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, l-wo-propenyl, 2-wo-propenyl, 1-butenyl, 2-butenyl or 3-butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl; cycloalkyl; heterocycloalkyl; alkoxy, preferably methoxy, ethoxy or propoxy; aryl, aralkyl and heteroaryl or together form a heteroaryl or heterocycloalkyl; optionally substituted;
R14 and R15 is each independently selected from the group consisting of hydrogen; alkyl, in particular C1-C6 alkyl, e.g. C1, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, /sø-propyl, butyl, wø-butyl, tert-butyl, pentyl or hexyl; alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and aralkyl; optionally substituted;
;„ - r j i i: ÷ r» 14 j τ-» 15 i i u_.i :.. <.: i __. /-i /~< _n i in α piciciicu ciiiυυuiiiiciii, is. tuiu rv. cue nyuiυgcii υi αuyyi, in pαi ucuiαi ^1 — \_-6 αijs.yi, e.g. C1, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, KO-butyl, tert-butyl, pentyl or hexyl; optionally substituted; R16 is selected from the group consisting of halogen, in particular F, Cl, Br or I; alkyl, in particular C1-C6 alkyl, e.g. C1, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, /so-propyl, butyl, wo-butyl, tert-butyl, pentyl or hexyl; alkenyl, in particular C2- C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, l-wo-propenyl, 2-wo-propenyl, 1-butenyl, 2-butenyl or 3-butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl; -NO2; -CN; -NR12R13, in particular - NH2; -OR14, in particular -OH; -SR14; -COOR15; -SO2R10; -COR12; -CONR12R13;
-NR12COR14; -NR12CONR12R13; -SO2NR12R13; -00CR15; -CR14R15OH and -R15OH; optionally substituted; more preferably, R16 is selected from the group consisting of halogen, in particular Cl, Br or I; alkyl, in particular C1-C6 alkyl; -OR14; -SO2R10 and -SR14, optionally substituted; wherein R14 is alkyl, in particular C1 - C6 alkyl, e.g. Ci, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, wø-propyl, butyl, wø-butyl, tert-butyl, pentyl or hexyl; * indicates the bond between R1 and the compound according to formula (I).
In another preferred embodiment of the compound according to the invention, R1 is a substituent according to formula (V) or (VI):
Figure imgf000018_0001
(VI) wherein
* indicates the bond between R1 and the compound according to formula (I).
In this preferred embodiment, the other substituents R12 to R16 have the above indicated meanings and more preferably the following meaning: P is CR or N; wherein R has below outlined meaning and is most preferably hydrogen;
Q is CR12 or N; wherein R12 has below outlined meaning and is most preferably hydrogen; most preferably P and Q arc C;
Z is selected from the group consisting of O, S and NR12; wherein R12 has below outlined meaning and is most preferably hydrogen; R2 is selected form the group consisting of halogen, in particular F, Cl, Br or I; alkyl, in particular Ci-C6 alkyl, e.g. Ci, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, wo-butyl, /ert-butyl, pentyl or hexyl; alkenyl, in particular C2- C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-wo-propenyl, 2-wo-propenyl, 1-butenyl, 2-butenyl or 3-butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl; cycloalkyl; heterocycloalkyl; alkoxy, preferably methoxy, ethoxy or propoxy; aralkyl; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5- oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2-benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1- benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; -NO2; -CN; -NR8R9; -OR10; -SR10; -COOR11, -COR10; -CONR8R9; -CONHOR10; -NR8COR10;
-NR8CONR8R9; -SO2NR8R9; -OOCR11 and -CR10R11OH; optionally substituted; more preferably, R2 is selected form the group consisting of heteroaryl, -COOalkyl; -COR10; -CONR8R9; -CONHOR10; -NR8COR10; -NR8CONR8R9; -SO2NR8R9; -OOCR11 and -CR10R11OH; optionally substituted; most preferably, R2 is selected form the group consisting of -COOCH3, thiophenyl, specifically thiophene-3-yl, and alkylfuranyl, specifically 2-(Ci-C6)alkyl-fiiran-5-yl (i.e. 2-methyl-furan-5-yl, 2-ethyl-furan-5-yl, 2- propyl-furan-5-yl, 2-/_fo-propyl-furan-5-yl, 2-butyl-furaii-5-yl, 2- /Λo-bulyl-furan-5-yi, 2- tert-butyl-furan-5-yl, 2-pentyl-furan-5-yl, or 2-hexyl-fiiran-5-yl); optionally substituted; R3 is selected form the group consisting of hydrogen; halogen, in particular F, Cl, Br or I; alkyl, in particular C1-C6 alkyl, e.g. Ci, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, wo-butyl, tert-butyl, pentyl or hexyl; alkenyl, in particular C2- C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-wo-propenyl, 2-wo-propenyl, 1-butenyl, 2-butenyl or 3-butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl; cycloalkyl; heterocycloalkyl; alkoxy, preferably methoxy, ethoxy or propoxy; aralkyl; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5- oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2-benzothicnyl, ll-I-indazolyl, bcnziϋudάzolyl, bciizoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1- benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; -NO2, -CN, -NR8R9, -OR10, -SR10, -COR10, -CONR8R9, -CONHOR10, -NR8COR10, -NR8CONR8R9,
-SO2NR8R9, -00CR11 and -CR10R11OH; optionally substituted; most preferably, R3 is hydrogen;
R4 to R7 are each individually selected form the group consisting of hydrogen; halogen, in particular F, Cl, Br or I; alkyl, in particular CpC6 alkyl, e.g. C1, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, /so-propyl, butyl, /so-butyl, tert-butyl, pentyl or hexyl; alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-wo-propenyl, 2-/so-propenyl, 1-butenyl, 2-butenyl or 3-butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl; cycloalkyl; heterocycloalkyl; alkoxy, preferably methoxy, ethoxy or propoxy; aralkyl; cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, -NO2, -CN,
-NR12R13, -OR14, -SR14, -COOR15, -COR12, -CONR12R13, -CONHOR14, -NR12COR14,
-NR12CONR12R13, -SO2NR12R13, -00CR15, -CR14R15OH and -R15OH; optionally substituted; most preferably, each of R4 to R7 is hydrogen;
R4 and R5 together may form =0, =S, a cycloalkyl, a heterocycloalkyl or an alicylic system; optionally substituted;
R6 and R7 together may form =0, =S, a cycloalkyl, a heterocycloalkyl or an alicylic system; optionally substituted; R and R is each independently selected from the group consisting of hydrogen; alkyl, in particular Ci-C6 alkyl, e.g. Ci, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, wσ-propyl, butyl, /_?ø-butyl, tert-butyl, pentyl or hexyl; alkenyl, in particular C2- C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-wø-propenyl, 2-wo-propenyl, 1-butenyl, 2-butenyl or 3-butenyl; alkynyl, in particular
C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl; cycloalkyl; heterocycloalkyl; alkoxy, preferably methoxy, ethoxy or propoxy; aryl, aralkyl, alkylaryl and heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl,
1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2- benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl or together form a heteroaryl or heterocycloalkyl; optionally substituted;
R10 and R11 is each independently selected from the group consisting of hydrogen; alkyl, in particular Ci-C6 alkyl, e.g. Ci, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, wo-butyl, tert-butyl, pentyl or hexyl; alkenyl, in particular C2- C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl,
1-zsø-propenyl, 2-wø-propenyl, 1-butenyl, 2-butenyl or 3-butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl; cycloalkyl, heterocycloalkyl, aryl, heteroaryl and aralkyl; optionally substituted; most preferably, R10 and R11 is each independently selected from Ci - C6 alkyl, e.g. Ci, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, wø-propyl, butyl, wø-butyl, tert-butyl, pentyl or hexyl; optionally substituted;
R12 and R13 is each independently selected from the group consisting of hydrogen; alkyl, in particular Ci-C6 alkyl, e.g. Ci, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, wø-propyl, butyl, /sø-butyl, tert-butyl, pentyl or hexyl; alkenyl, in particular C2- C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl,
1-wø-propenyl, 2-wø-propenyl, 1-butenyl, 2-butenyl or 3-butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl; cycloalkyl; heterocycloalkyl; alkoxy, preferably methoxy, ethoxy or propoxy; aryl, aralkyl and heteroaryl or together form a heteroaryl or heterocycloalkyl; optionally substituted; R14 and R15 is each independently selected from the group consisting of hydrogen; alkyl, in particular Ci-C6 alkyl, e.g. Ci, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, wo-butyl, tert-butyl, pentyl or hexyl; alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and aralkyl; optionally substituted; in a preferred embodiment, R14 and R15 are hydrogen or alkyl, in particular C1 - C6 alkyl, e.g. Ci, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, wo-butyl, ter/-butyl, pentyl or hexyl; optionally substituted; and
R 16 is selected from the group consisting of halogen, in particular F, Cl, Br or I; alkyl, in particular Ci-C6 alkyl, e.g. Ci, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, wo-butyl, tert-buty\, pentyl or hexyl; alkenyl, in particular C2- C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-wø-propenyl, 2-wo-propenyl, 1-butenyl, 2-butenyl or 3-butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl; -NO2; -CN; -NR12R13, in particular -NH2; -OR14, in particular -OH; -SR14; -COOR15; -SO2R10; -COR12; -CONR12R13;
-NR12COR14; -NR12CONR12R13; -SO2NR12R13; -00CR15; -CR14R15OH and -R15OH; optionally substituted; more preferably, R16 is selected from the group consisting of halogen, in particular Cl, Br or I; alkyl, in particular C1-C6 alkyl; -OR14; -SO2R10 and -SR14, optionally substituted; wherein R14 is alkyl, in particular Ci - C6 alkyl, e.g. C1, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-pioipyl, butyl, /50-butyl, ieri-hxxtyl, pentyl or hexyl.
Also preferred is a compound according to the invention, wherein R2 is selected form the group consisting of aryl, heteroaryl, -COOR11, -COR10, -CONR8R9 and -CONHOR10; optionally substituted; and more preferably, R2 is -COOR11 or -COR10, optionally substituted; wherein R11 and R10 have above outlined meaning and are each individually preferably alkyl, in particular Ci - C6 alkyl, e.g. Ci, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, wo-butyl, tert-butyl, pentyl or hexyl.
Also preferred is a compound according to the invention, wherein R1 is selected from the group consisting of:
Figure imgf000021_0001
Figure imgf000022_0001
wherein * indicates the bond between R1 and the compound according to formula (I).
In this preferred embodiment, the other substituents have preferably the following meaning: R2 is selected form the group consisting of halogen, in particular F, Cl, Br or I; alkyl, in particular C1-C6 alkyl, e.g. C1, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, iso-butyl, ter/-butyl, pentyl or hexyl; alkenyl, in particular C2-
C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-z'so-propenyl, 2-wø-propenyl, 1-butenyl, 2-butenyl or 3-butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl; cycloalkyl; heterocycloalkyl; alkoxy, preferably methoxy, ethoxy or propoxy; aralkyl; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5- oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2-benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1- benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; -NO2; -CN; -NR8R9; -OR10; -SR10; -COOR11, -COR10; -CONR8R9; -CONHOR10; -NR8COR10; -NR8CONR8R9; -SO2NR8R9; -OOCR11 and -CR10R11OH; optionally substituted; more preferably, R2 is selected form the group consisting of heteroaryl, -COOalkyl;
-COR10; -CONR8R9; -CONHOR10; -NR8COR10; -NR8CONR8R9; -SO2NR8R9; -OOCR11 and -CR10R11OH; optionally substituted; most preferably, R2 is selected form the group consisting of -COOCH3, thiophenyl, specifically thiophene-3-yl, and alkylfuranyl, specifically 2-(Ci-C6)alkyl-furan-5-yl (i.e. 2-methyl-furan-5-yl, 2-ethyl-furan-5-yl, 2- propyl-furan-5-yl, 2-/so-propyl-furan-5-yl, 2-butyl-furan-5-yl, 2- /so-butyl-furan-5-yl, 2- tert-butyl-furan-5-yl, 2-pentyl-furan-5-yl, or 2-hexyl-furan-5-yl); optionally substituted; R3 is selected form the group consisting of hydrogen; halogen, in particular F, Cl, Br or I; alkyl, in particular C1-C6 alkyl, e.g. Ci, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, /so-propyl, butyl, wo-butyl, tert-butyl, pentyl or hexyl; alkenyl, in particular C2- C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-wo-propenyl, 2-/so-propenyl, 1-butenyl, 2-butenyl or 3-butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl; cycloalkyl; heterocycloalkyl; alkoxy, preferably methoxy, ethoxy or propoxy; aralkyl; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5- oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2-benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1- benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; -NO2, -CN, - NR8R9, -OR10, -SR10, -COR10, -CONR8R9, -CONHOR10, -NR8COR10, -NR8CONR8R9, -SO2NR8R9, -OOCR11 and -CR10R11OH; optionally substituted; most preferably, R3 is hydrogen;
R4 to R7 are each individually selected form the group consisting of hydrogen; halogen, in particular F, Cl, Br or I; alkyl, in particular Cj-C6 alkyl, e.g. C1, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, wo-butyl, tert-butyl, pentyl or hexyl; alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-wo-propenyl, 2-JSO-propenyl, 1-butenyl, 2-butenyl or
3-butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl; cycloalkyl; heterocycloalkyl; alkoxy, preferably methoxy, ethoxy or propoxy; aralkyl; cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, -NO2, -CN, -NR12R13, -OR14, -SR14, -COOR15, -COR12, -CONR12R13, -CONHOR14, -NR12COR14, -NR12CONR12R13, -SO2NR12R13, -OOCR15, -CR14R15OH and -R15OH; optionally substituted; most preferably, each of R4 to R7 is hydrogen; R4 and R5 together may form =0, =S, a cycloalkyl, a heterocycloalkyl or an alicylic system; optionally substituted; R6 and R7 together may form =0, =S, a cycloalkyl, a heterocycloalkyl or an alicylic system; optionally substituted;
R8 and R9 is each independently selected from the group consisting of hydrogen; alkyl, in particular Ci-C6 alkyl, e.g. C1, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, wo-butyl, tert-butyl, pentyl or hexyl; alkenyl, in particular C2- C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-wo-propenyl, 2-wo-propenyl, 1-butenyl, 2-butenyl or 3-butenyl; alkynyl, in particular
C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl; cycloalkyl; heterocycloalkyl; alkoxy, preferably methoxy, ethoxy or propoxy; aryl, aralkyl, alkylaryl and heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl,
1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl,
1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2- benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl,
1,2,3-benzotriazinyl, or 1 ,2,4-benzotriazinyl or together form a heteroaryl or heterocycloalkyl; optionally substituted;
R10 and R11 is each independently selected from the group consisting of hydrogen; alkyl, in particular Cj-C6 alkyl, e.g. C1, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, /so-propyl, butyl, wø-butyl, ter/-butyl, pentyl or hexyl; alkenyl, in particular C2- C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-zsø-propenyl, 2-/sø-propenyl, 1-butenyl, 2-butenyl or 3-butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl; cycloalkyl, heterocycloalkyl, aryl, heteroaryl and aralkyl; optionally substituted; most preferably, R10 and R11 is each independently selected from C1 - Ce alkyl. e.g. C1. C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, wø-propyl, butyl, wø-butyl, tert-butyl, pentyl or hexyl; optionally substituted;
R12 and R13 is each independently selected from the group consisting of hydrogen; alkyl, in particular Ci-C6 alkyl, e.g. C1, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, wø-propyl, butyl, /sø-butyl, tert-butyl, pentyl or hexyl; alkenyl, in particular C2- C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-isø-propenyl, 2-wo-propenyl, 1-butenyl, 2-butenyl or 3-butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl; cycloalkyl; heterocycloalkyl; alkoxy, preferably methoxy, ethoxy or propoxy; aryl, aralkyl and heteroaryl or together form a heteroaryl or heterocycloalkyl; optionally substituted;
R14 and R15 is each independently selected from the group consisting of hydrogen; alkyl, in particular C1-C6 alkyl, e.g. C1, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, /so-propyl, butyl, /sø-butyl, tert-butyl, pentyl or hexyl; alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and aralkyl; optionally substituted; in a preferred embodiment, R14 and R15 are hydrogen or alkyl, in particular Ci - C6 alkyl, e.g. C1, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, wø-propyl, butyl, /so-butyl, terf-butyl, pentyl or hexyl; optionally substituted; and R16 is selected from the group consisting of halogen, in particular F, Cl, Br or I; alkyl, in particular C1-C6 alkyl, e.g. C1, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, /sø-propyl, butyl, /sø-butyl, tert-butyl, pentyl or hexyl; alkenyl, in particular C2- C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-wø-propenyl, 2-wø-propenyl, 1-butenyl, 2-butenyl or 3-butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl; -NO2; -CN; -NR12R13, in particular -NH2; -OR14, in particular -OH; -SR14; -COOR15; -COR12; -CONR12R13; -NR12COR14; -NR12CONR12R13: -SO2NR12R13; -OOCR15; -SO2R10; -CR14R15OH and -R15OH; optionally substituted; more preferably, R16 is selected from the group consisting of halogen, in particular Cl, Br or I; alkyl, in particular Cj-C6 alkyl; -OR14; -SO2R10 and -SR14, optionally substituted; wherein R14 is alkyl, in particular C1 - C6 alkyl, e.g. Ci, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, wø-propyl, butyl, wø-butyl, tert-butyl, pentyl or hexyl.
Also preferred is a compound according to the invention, wherein R3 is hydrogen or wherein R4 through R7 are hydrogen, or more preferably, wherein R3 and R4 through R7 are hydrogen.
In another preferred embodiment of the compound according to the invention, the compound according to formula (I) is a compound having a structure selected from the group consisting of:
Figure imgf000025_0001
Figure imgf000026_0001
It should be noted that the general procedures shown relate to preparation of compounds having unspecified stereochemistry. However, such procedures are generally applicable to those compounds of a specific stereochemistry, e.g., where the stereochemistry about a group is (S) or
(R). In addition, the compounds having one stereochemistry (e.g., (R)) can often be utilized to produce those having opposite stereochemistry (i.e., (S)) using well-known methods, for cxcixϊipiC, inversion. v>CitG.in eompOuiϊuS o± mC present invention possess cisyminetrie c∑iruon atoms (optical centers) or asymmetric double bonds; the optical isomers, enantiomers, diastereomer, racemate, racemic mixtures and geometric isomers are all intended to be encompassed within the scope of the present invention.
In another aspect the invention provides a pharmaceutical composition comprising a compound according to the invention and one or more chemotherapeutic or antiproliferative agent.
Preferably, the one or more chemotherapeutic or antiproliferative agent of the pharmaceutical composition according to the invention is selected from the group consisting of ZM447439, VX- 680, anti-tumor antibodies, imatinib, the methanesulfonic acid salt of alkylating substances, anti- metabolites, antibiotics, epothilones, anti-androgens, anti-estrogens, platinum compounds, hormones and antihormones, interferons, inhibitors of cell cycle-dependent protein kinases (CDKs), imatinib, platine coordination complexes, ethyleneimenes, methylmelamines, trazines, vinca alkaloids, pyrimidine analogs, purine analoga, alkylsulfonates, folic acid analogs, anthracendiones, substituted urea, methylhydrazin derivatives, in particular acediasulfone, aclarubicine, ambazone, aminoglutethimide, L-asparaginase, azathioprine, bleomycin, busulfan, calcium folinate, carboplatin, carpecitabine, carmustine, chlorambucil, cis-platin, cladribine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin dapsone, daunorubicin, dibrompropamidine, diethylstilbestrole, docetaxel, doxorubicin, epirubicin, epothilone B, epothilone D, estramucin phosphate, estrogen, ethinylestradiole, etoposide, flavopiridol, floxuridine, fludarabine, fluorouracil, fluoxymesterone, fiutamide fosfestrol, furazolidone, gemcitabine, gonadotropin releasing hormone analog, hexamethylmelamine, hydroxycarbamide, hydroxymethylnitrofurantoin, hydroxyprogesteronecaproat, hydroxyurea, idarubicin, idoxuridine, ifosfamide, interferon α, irinotecan, leuprolide, lomustine, lurtotecan, mafenide sulfate olamide. mechlorethamine, medroxyprogesterone acetate, rnegastrolacetate, melphalan, mepacrine, mercaptopurine, methotrexate, metronidazole, mitomycin C, mitopodozide, mitotane, mitoxantrone, mithramycin, nalidixic acid, nifuratel, nifuroxazide, nifuralazine, nifurtimox, nimustine, ninorazole, nitrofurantoin, nitrogen mustards, oleomucin, oxolinic acid, pentamidine, pentostatin, phenazopyridine, phthalylsulfathiazole, pipobroman, prednimustine, prednisone, preussin, procarbazine, pyrimethamine, raltitrexed, salazosulfapyridine, scriflavinium chloride, semustine streptozocine, sulfacarbamide, sulfacetamide, sulfachlopyridazine, sulfadiazine, sulfadicramide, sulfadimethoxine, sulfaethidole, sulfafurazole, sulfaguanidine, sulfaguanole, sulfamethizole, sulfamethoxazole, co-trimoxazole, sulfamethoxydiazine, sulfamethoxypyridazine, sulfamoxole, sulfanilamide, sulfaperin, sulfaphenazole, sulfathiazole, sulfisomidine, tamoxifen, teniposide, tertiposide, testolactone, testosteronpropionate, thioguanine, thiotepa, tinidazole, topotecan, triaziquone, treosulfan, trimethoprim, trofosfamide, vinblastine, vincristine, vindesine, vinblastine, vinorelbine and zorubicin, or structurally related derivatives thereof
The invention also provides the use of a compound according to the invention or a composition according to the invention for the preparation of a medicament for the treatment of a proliferative disease. In another aspect, the invention also provides a compound according to the invention and a pharmaceutical composition according to the invention, for the treatment of a proliferative disease.
Said proliferative disease may be e.g. a cancer and/or a hyperplasia. Many types of cancer are known in the art all of which are characterized in a non-controlled cell division rate, i.e. a cancerous cell, e.g. in a tumour divides more frequently over the course of a defined timeframe, than a healthy cell, e.g. of the same tissue origin than the cancerous cell stems from. Thus, such cancerous cells and/or tissues (e.g. tumours) can be treated with a compound or composition of the invention. Preferably, the cancer involves a tumour/ neoplasm selected from the group consisting of a brain or other central nervous system tumour (e.g. a tumour of the meninges, spinal cord, hippocampus, cranial nerves and other parts of the central nervous system, e.g. glioblastomas); a tumour of the head and/or neck; a breast tumour; a circulatory system tumour (e.g. of the heart, mediastinum and pleura, or another intrathoracic organ, vascular tumours or tumour-associated vascular tissue); an excretory system tumour (e.g. kidney, renal pelvis, ureter, bladder, or unspecified urinary organ tumour); a gastrointestinal tract tumour (e.g. oesophagus, stomach, small intestine, colon, colorectal, rectosigmoid junction, rectum, anus or anal canal tumour), a tumours involving the liver or an intrahepatic bile duct, a gall bladder, a tumour of other/unspecified parts of the biliary tract or other digestive organs); a tumour of the oral cavity (lip, tongue, gum, floor of mouth, palate, and other parts of the mouth, parotid gland, and other parts of the salivary glands, tonsil, oropharynx, nasopharynx, pyriform sinus, hypopharynx, and other sites in the lip, oral cavity and pharynx); a reproductive system tumour (e.g. prostate, vulva, vagina, cervix uteri, corpus uteri, uterus, ovary, placenta, penis or testis); a respiratory tract tumour (e.g. nasal cavity and middle ear, accessory sinuses, larynx, trachea, bronchus and lung, e.g. small cell lung cancer or non-small cell lung cancer); a skeletal system tumour (e.g. bone and articular cartilage of limbs, bone articular cartilage and other sites); a skin tumour (e.g. malignant melanoma of the skin, non-melanoma skin cancer, basal cell carcinoma of skin, squamous cell carcinoma of skin, mesothelioma, Kaposi's sarcoma); a tumour involving other tissues including peripheral nerves and autonomic nervous system, connective and soft tissue, retroperitoneum and peritoneum, eye and adnexa, thyroid, adrenal gland and other endocrine glands and related structures, secondary and unspecified malignant neoplasm of lymph nodes, secondary malignant neoplasm of respiratory and digestive systems and secondary malignant neoplasm of other sites and a tumour derived or affecting blood cells or the lymphatic system (e.g. Hodgkin's disease, Non-Hodgkin's lymphoma, Burkitt's lymphoma, AIDS-related lymphomas, malignant immunoproliferative diseases, multiple myeloma and malignant plasma cell neoplasms, lymphoid leukemia, acute or chronic myeloid leukaemia (e.g. acute or chronic myeloid leukaemia), acute or chronic lymphocytic leukemia, monocytic leukemia, other leukemias of specified cell type, leukemia of unspecified cell type or a malignant neoplasm of lymphoid, haematopoietic or related tissues, for example, a diffuse large cell lymphoma or a T- cell lymphoma or cutaneous T-cell lymphoma). Said neoplasms can be benign, potentially malignant (pre-cancer) or malignant (cancer). The hyperplasia may be selected from the group consisting of congenital adrenal hyperplasia, endometrial hyperplasia, hyperplasia of the breast, focal epithelial hyperplasia (also known as Heck's disease), sebaceous hyperplasia and compensatory liver hyperplasia. The cancer may also be a medullary carcinoma, an osteosarcoma, a soft-tissue sarcoma, an Ewing's sarcoma, a reticulum cell sarcoma or a Kaposi's sarcoma.
Further preferred is the use according to the invention, wherein the cancer (also called tumour herein) is a cancer selected from the group consisting of: a solid tumor, a hematological malignancy, a carcinoma, a neuroblastoma and a melanoma. Also included are pediatric forms of any of the cancers described herein.
The compounds and compositions according to the invention can be administered by various well known routes, including oral, rectal, intragastrical, intracranial and parenteral administration, e.g. intravenous, intramuscular, intranasal, intradermal, subcutaneous, and similar administration routes. Parenteral administration and particular intravenous administration, preferably by depot injection, is preferred. Depending on the route of administration different pharmaceutical formulations are required and some of those may require that protective coatings are applied to the drug formulation to prevent degradation of a compound or a compositions of the invention in, for example, the digestive tract.
Thus, preferably, a compound or a composition of the invention is formulated as a syrup, an infusion or injection solution, a tablet, a capsule, a capslet, lozenge, a liposome, a suppository, a plaster, a band-aid, a retard capsule, a powder, or a slow release formulation. Preferably the diluent is water, a buffer, a buffered salt solution or a salt solution and the carrier preferably is selected from the group consisting of cocoa butter and vitebesole.
Particular preferred pharmaceutical forms for the administration of a compound or a composition of the invention are forms suitable for injectionable use and include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. In all cases the final solution or dispersion form must be sterile and fluid. Typically, such a solution or dispersion will include a solvent or dispersion medium, containing, for example, water-buffered aqueous solutions, e.g. biocompatible buffers, εthanol, polyol, such as glycerol, propylene glycol, polyethylene glycol, suitable mixtures thereof, surfactants or vegetable oils. A compound or a composition of the invention can also be formulated into liposomes, in particular for parenteral administration. Liposomes provide the advantage of increased half life in the circulation, if compared to the free drug and a prolonged more even release of the enclosed drug.
Sterilization of infusion or injection solutions can be accomplished by any number of art recognized techniques including but not limited to addition of preservatives like anti-bacterial or anti-fungal agents, e.g. parabene, chlorobutanol, phenol, sorbic acid or thimersal. Further, isotonic agents, such as sugars or salts, in particular sodium chloride may be incorporated in infusion or injection solutions.
Production of sterile injectable solutions containing one or several of the compounds or compositions of the invention is accomplished by incorporating the respective compound in the required amount in the appropriate solvent with various ingredients enumerated above as required followed by sterilization. To obtain a sterile powder the above solutions are vacuum- dried or freeze-dried as necessary. Preferred diluents of the present invention are water, physiological acceptable buffers, physiological acceptable buffer salt solutions or salt solutions. Preferred carriers are cocoa butter and vitebesole. Excipients which can be used with the various pharmaceutical forms of a compound or composition of the invention can be chosen from the following non-limiting list: a) binders such as lactose, mannitol, crystalline sorbitol, dibasic phosphates, calcium phosphates, sugars, microcrystalline cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, polyvinyl pyrrolidone and the like; b) lubricants such as magnesium stearate, talc, calcium stearate, zinc stearate, stearic acid, hydrogenated vegetable oil, leucine, glycerids and sodium stearyl fumarates, c) disintegrants such as starches, croscaramellose, sodium methyl cellulose, agar, bentonite, alginic acid, carboxymethyl cellulose, polyvinyl pyrrolidone and the like.
Other suitable excipients can be found in the Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association, which is herein incorporated by reference.
It is to be understood that depending on the severity of the disorder and the particular type which is treatable with one of the compounds or compositions of the invention, as well as on the respective patient to be treated, e.g. the general health status of the patient, etc., different doses of the respective compound are required to elicit a therapeutic or prophylactic effect. The determination of the appropriate dose lies within the discretion of the attending physician. Ii is contemplated that the dosage of a compound of the invention in the therapeutic or prophylactic use of the invention should be in the range of about 0.1 mg to about 1 g serum per kg body weight. However, in a preferred use of the present invention a compound of the invention is administered to a subject in need thereof in an amount ranging from 1.0 to 500 mg/kg body weight, preferably ranging from 10 to 200 mg/kg body weight, preferably ranging from 50 to 150 mg/kg body weight, preferably ranging from 90 to 100 mg/kg body weight. The duration of therapy with a compound of the invention will vary, depending on the severity of the disease being treated and the condition and idiosyncratic response of each individual patient.
As is known in the art, the pharmaceutically effective amount of a given compound or composition will also depend on the administration route. In general the required amount will be higher, if the administration is through the gastrointestinal tract; e.g. by suppository, rectal, or by an intragastric probe, and lower if the route of administration is parenteral, e.g. intravenous. Typically, a compound of the invention will be administered in ranges of 50 mg to 1 g/kg body weight, preferably 100 mg to 500 mg/kg body weight, if rectal or intragastric administration is used and in ranges of 10 to 100 mg/kg body weight, if parenteral administration is used.
If a person is know to be at risk of developing a disorder treatable with a compound or composition of the invention, a prophylactic administration of the biologically active blood serum or the pharmaceutical composition according to the invention may be possible. In these cases the respective compound or composition of the invention is preferably administered in above outlined preferred and particular preferred doses on a daily basis. Preferably, between 0.1 mg to 1 g/kg body weight once a day, preferably 10 to 200 mg/kg body weight. This administration can be continued until the risk of developing the respective disorder has lessened. In most instances, however, a compound or composition of the invention will be administered once a disease/disorder has been diagnosed. In these cases it is preferred that a first dose of a compound or composition of the invention is administered one, two, three or four times daily. Preferably the administration is discontinued for one day, one week or one month and then repeated until the symptoms of the respective disease are no longer worsening or improving.
Various modifications and variations of the invention will be apparent to those skilled in the art without departing from the scope of the invention. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention which are obvious to those skilled in the relevant fields are intended to be covered by the present invention.
The following examples are merely illustrative of the present invention and should not be construed to limit the scope of the invention as indicated by the appended claims in any way.
EXAMPLES
General methods of preparation and analysis of indoline-sulfonamides
All reactions involving air or moisture sensitive reagents were performed under an argon or nitrogen atmosphere using standard Schlenk techniques. Unless otherwise stated, chemicals and solvents were of reagent grade and used as obtained from commercial sources without further purification. Water was deionized. The reactions were monitored by analytical HPLC-MS or by thin-layer chromatography (TLC) analysis using silica gel (Merck 60-F2S4) plates. Compounds were visualized by UV irradiation and/or spraying with literature known stains followed by charring at 150 °C (Seebach stain: 2.5 g Molybdatophosphoric acid, 1.0 g Cer(IV)-sulfate, 6 ml cone. Sulfuric acid, 94 ml Water; Ninhydrin stain: 3.0 g Ninhydrin, 30 ml glacial acetic acid, 970 ml ethanol). Column chromatography was performed on silica gel (Merck, Silica Gel 60, 40- 63 μm).
Analytical HPLC-MS method:
Products were measured on HPLC/MS using a Waters X-bridge Ci8-column, 5 μm particle size,
4.6 x 150 mm (diameter x length) at a flow rate of 1.75 mL/min with a linear gradient (water to acetonitrile, 0.2% formic acid as modifier) from initially 99:1 to 1 :99 over 9.10 min, then hold for 1.80 min. Mass signals were measured using a Waters 3100 Mass detector.
General procedure A: Coupling of sulfonic acid chlorides to indolines
Figure imgf000032_0001
0.5 mmol of the Indoline were dissolved in a mixture of 2.5 mL dry dichloromethane and 0.5 mL dry pyridine under a nitrogen atmosphere. 0.6 mmol of the sulfonic acid chloride were added. The mixture was stirred at room temperature in a sealed tube for 6.5 h. Thereafter solvent was evaporated under vacuum. The crude product was purified by preparative HPLC-MS to give the corresponding sulfonamide.
General procedure B: Coupling of boronic acids (esters) to (6-bromo-indoline)- sulfonamides (Suzuki reaction)
✓(hetero)-aryl Boronic acid or ester "*"
Figure imgf000032_0002
Figure imgf000032_0003
0.5 mmol of the (6-Bromo-indoline)-sulfonamide was dissolved under nitrogen atmosphere in methanol. 0.05 mmol of [l,r-bis(diphenylphosphino)-ferrocene]dichloro-palladium(II), 1:1 complex with dichloromethane and 0.5 mmol of the corresponding boronic acid (or the boronic acid pinacol ester) were added. 675 μL of a 2 molar potassium carbonate solution were added. This mixture was stirred in a sealed tube in a microwave (CEM) at 90°C (150 W max.) for 30 minutes. After cooling to room temperature the reaction was stopped by addition of 5 mL water. This mixture was extracted three times with dichloromethane. The combined organic layers were dried with anhydrous sodium sulfate and the solvent was removed under vacuum. The crude product was purified by preparative HPLC-MS.
Example 1: Synthesis and analytical data of l-(4-Ethoxy-benzenesulfonyl)-2,3-dihydro- indole-6-carboxylic acid methyl ester
Figure imgf000033_0001
l-(4-Ethoxy-benzenesulfonyl)-2,3-dihydro-indole-6-carboxylic acid methyl ester was synthesized starting from commercial available indoline-6-carboxylic acid methylester following the general procedure A using commercial available 4-ethoxy-benzene sulfonylchloride. ESI+, m/z+l=362, found; IH-NMR (CDClS): δ(ppm)=8.25 (s, IH), 7.8.-7.65 (m, 3H), 7.15 (d, J=2Hz; 1H); 6.90 (d; J=3Hz; 2H), 4,10-3=90 (m, 7H), 2,95 (t, J=2Hz, 2H), 1.40 (t, J=2Hz, 3H)
Example 2: Synthesis and analytical data of 6-Thiophene-3-yl-l-(toluene-4-sulfonyl)-2,3- dihydro-indole
Figure imgf000033_0002
6-Thiophene-3-yl-l-(toluene-4-sulfonyl)-2,3-dihydro-indole was synthesized starting from commercial available 6-bromo-indoline. Following general procedure A, the starting material was transformed with tosylchloride to give the sulfonamide. Following general procedure B, subsequent transformation with 3-thiophene boronic acid gave the desired product. ESI+, m/z+l=356, found; IHNMR (CDC13): δ(ppm)=7.90 (s, IH), 7,70 (d, J=3Hz, 2H), 7.50 (s, IH), 7.40-7.05 (m, 2H), 7.30-7.10 (m, 4H), 3.95 (t, J=2Hz, 2H), 2.90 (t, J=2Hz, 2H), 2.35 (s, 3H)
Example 3: Synthesis and analytical data of 6-(5-Methyl-furan-2-yl)-l-(toluene-4-sulfonyl)- 2,3-dihydro-indole
Figure imgf000033_0003
6-(5-Methyl-furan-2-yl)-l-(toluene-4-sulfonyl)-2,3-dihydro-indole was synthesized starting from commercial available 6-bromo-indoline. Following general procedure A, the starting material was transformed with tosylchloride to give the sulfonamide. Following general procedure B, subsequent transformation with 2-methylfuran-5-boronic acid pinacolester gave the desired product.
ESI+, m/z+l=354, found; IHNMR (CDC13): δ(ppm)=7.90 (s, IH), 7,70 (m, 2H), 7.35-7.15 (m, 3H), 7.05 (m, IH), 6.60 (s, IH), 6.10 (s, IH), 3.95 (m, 2H), 2.85 (m, 2H), 2.50-2.30 (m, 6H)
Assay method to determine tumor cell viability
Preferred compounds were analyzed for their ability to inhibit growth of tumour cells (e.g. MCF7, HL60, LL2, HeLa, PC-3, A549 and A375 cells) in vitro. Growth inhibition was tested at various concentrations in triplicate in a 10 point two fold serial dilution and cells were incubated under standard mammalian tissue culture conditions for 72 hours. Cell viability was determined by measuring ATP levels in viable cells using the ATPLite kit (PerkinElmer) as described in the user manual. Raw data was transformed to percentage inhibition of growth compared to DMSO- only controls (0.5% and 9% for negative and positive controls, respectively) and values were expressed as IC50 in micromolar calculated using XLfϊt (IDBS). The compounds of the present invention showed the ability to inhibit the growth of various tumor cell lines indicating a broad spectrum of growth inhibitory activity. The bioactivity of several exemplary indoline- sulfonamide compounds of the invention was measured using the viability assay as described above. Results obtained when using the indicated compounds on MCF-7 cells are depicted in Table 1 below. Compounds with 10 μM < IC50 < 100 μM are designated as (+); compounds with 1 μM < IC50 < 10 μM are designated as (++) and compounds with an IC50 < 1 μM are designated as (+++).
Figure imgf000034_0001
Figure imgf000035_0001

Claims

A compound according to formula (I)
Figure imgf000036_0001
wherein,
R1 is aryl or heteroaryl, substituted with at least one substituent other than hydrogen;
R2 is selected form the group consisting of halogen, alkyl, alkenyl, alkynyl, cycloalkyl, hεterocycloalkyl, alkoxy, aryl, aralkyl, heieroaryi, -NO2, -CN, -NR"R', -OR'", -SR10, -COOR11, -COR10, -CONR8R9, -CONHOR10, -NR8COR10, -NR8CONR8R9, -SO2NR8R9, -OOCR11 and -CR10R11OH; optionally substituted;
R3 is selected form the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, -NO2, -CN, -NR8R9, -OR10, -SR10, -COR10, -CONR8R9, -CONHOR10, -NR8COR10, -NR8CONR8R9, -SO2NR8R9, -OOCR11 and -CR10R11OH; optionally substituted;
R4 to R7 are each individually selected form the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, -NO2, -CN, -NR12R13, -OR14, -SR14, -COOR15, -COR12, -CONR12R13, -CONHOR14, -NR12COR14, -NR12CONR12R13, -SO2NR12R13, -OOCR15, -CR14R15OH and -R15OH; optionally substituted;
R4 and R5 together may form =0, =S, a cycloalkyl, a heterocycloalkyl or an alicylic system; optionally substituted;
R6 and R7 together may form =0, =S, a cycloalkyl, a heterocycloalkyl or an alicylic system; optionally substituted;
R and R is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, alkylaryl and heteroaryl or together form a heteroaryl or heterocycloalkyl; optionally substituted;
R10 and R11 is each independently selected from the group consisting of hydrogen, alkyl alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and aralkyl; optionally substituted; R12 and R13 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl and heteroaryl or together form a heteroaryl or heterocycloalkyl; optionally substituted;
R14 and R15 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and aralkyl; optionally substituted; or a pharmaceutically acceptable salt thereof; under the proviso that the compound according to formula (I) does not have a structure according to formula (II):
Figure imgf000037_0001
(H) wherein X is hydrogen or methyl.
2. Compound according to claim 1, wherein R1 is a substituent according to formula (III) or (IV):
Figure imgf000037_0002
(IV) wherein
P is CR12 or N;
Q is CR12 or N; z is selected from the group consisting of O, S and NR12;
R 16 is selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, -NO2, -CN, -NR12R13, -OR14, -SR14, -COOR15, -COR12, -CONR12R13, -NR12COR14, -NR12CONR12R13, -SO2NR12R13, -SO2R10, -00CR15, -CR14R15OH and -R15OH; optionally substituted; indicates the bond between R1 and the compound according to formula (I).
Compound according to claim 1 or 2, wherein
R1 is a substituent according to formula (V) or (VI):
Figure imgf000038_0001
wherein
P is CR12 or N;
Q is CR12 or N;
Z is selected from the group consisting of O, S and NR12;
R16 is selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, -NO2, -CN, -NR12R13, -OR14, -SR14, -COOR15, -COR12, -CONR12R13, -NR12COR14, -NR12CONR12R13, -SO2NR12R13, -SO2R10, -OOCR15, -CR14R15OH and -R15OH; optionally substituted;
* indicates the bond between R1 and the compound according to formula (I).
Compound according to any of claims 1 - 3, wherein
R2 is selected form the group consisting of aryl, heteroaryl, -COOR11, -COR10,
-CONR > 88 DR9* and -CONHOR 110";. optionally substituted;
Compound according to any of claims 1-4, wherein R1 is selected from the group consisting of:
Figure imgf000038_0002
wherein
* indicates the bond between R1 and the compound according to formula (I).
6. Compound according to any of claims 1-5, wherein R3 is hydrogen.
7. Compound according to any of claims 1-6, wherein R3 and R4 through R7 are hydrogen.
8. Compound according to any of claims 1-7, wherein the compound according to formula (I)
Figure imgf000039_0001
9. Compound according to any of claims 1-8, wherein the compound is an optical isomer, an enantiomer, a diastereomer, a racemate, a racemic mixture or a geometric isomer.
10. Pharmaceutical composition comprising a compound according to any of claims 1-9 and one or more chemotherapeutic or anti-proliferative agent.
11. Pharmaceutical composition according to claim 10, wherein the one or more chemotherapeutic or antiproliferative agent is selected from the group consisting of ZM447439, VX-680, anti-tumor antibodies, imatinib, the methanεsulfonic acid salt of alkylating substances, anti-metabolites, antibiotics, epothilones, anti-androgens, anti- estrogens, platinum compounds, hormones and antihormones, interferons, inhibitors of cell cycle-dependent protein kinases (CDKs), imatinib, platine coordination complexes, ethyleneimenes, methylmelamines, trazines, vinca alkaloids, pyrimidine analogs, purine analoga, alkylsulfonates, folic acid analogs, anthracendiones, substituted urea, methylhydrazin derivatives, in particular acediasulfone, aclarubicine, ambazone, aminoglutethimide, L-asparaginase, azathioprine, bleomycin, busulfan, calcium folinate, carboplatin, carpecitabine, carmustine, chlorambucil, cis-platin, cladribine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin dapsone, daunorubicin, dibrompropamidine, diethylstilbestrole, docetaxel, doxorubicin, epirubicin, epothilone B, epothilone D, estramucin phosphate, estrogen, ethinylestradiole, etoposide, flavopiridol, floxuridine, fludarabine, fluorouracil, fiuoxymesterone, flutamide fosfestrol, furazolidone, gemcitabine, gonadotropin releasing hormone analog, hεxarncthylnielamine, hydroxycarbamide, hydroxymethylnitrofurantoin, hydroxyprogesteronecaproat, hydroxyurea, idarubicin, idoxuridine, ifosfamide, interferon α, irinotecan, leuprolide, lomustine, lurtotecan, mafenide sulfate olamide, mechlorethamine, medroxyprogesterone acetate, megastrolacetate, melphalan, mepacrine, mercaptopurine, methotrexate, metronidazole, mitomycin C, mitopodozide, mitotane, mitoxantrone, mithramycin, nalidixic acid, nifuratel, nifuroxazide, nifuralazine, nifurtimox, nimustine, ninorazole, nitrofurantoin, nitrogen mustards, oleomucin, oxolinic acid, pentamidine, pentostatin, phenazopyridine, phthalylsulfathiazole, pipobroman, prednimustine, prednisone, preussin, procarbazine, pyrimethamine, raltitrexed, salazosulfapyridine, scriflavinium chloride, semustine streptozocine, sulfacarbamide, sulfacetamide, sulfachlopyridazine, sulfadiazine, sulfadicramide, sulfadimethoxine, sulfaethidole, sulfafurazole, sulfaguanidine, sulfaguanole, sulfamethizole, sulfamethoxazole, co-trimoxazole, sulfamethoxydiazine, sulfamethoxypyridazine, sulfamoxole, sulfanilamide, sulfaperin, sulfaphenazole, sulfathiazole, sulfisomidine, tamoxifen, teniposide, tertiposide, testolactone, testosteronpropionate, thioguanine, thiotepa, tinidazole, topotecan, triaziquone, treosulfan, trimethoprim, trofosfamide, vinblastine, vincristine, vindesine, vinblastine, vinorelbine and zorubicin, or structurally related derivatives thereof.
12. Use of a compound according to any of claims 1-9 or a composition according to claim 10 or 11 for the preparation of a medicament for the treatment of a proliferative disease.
13. Use according to claim 12, wherein the proliferative disease is cancer and/or a hyperplasia.
14. Use according to claim 13, wherein the cancer is a tumour selected from the group consisting of a central nervous system tumour, a prostate rumour, a head tumour, a neck tumour, a breast tumour, a circulatory system tumour, an excretory system tumour, a gastrointestinal tract tumour, a tumour involving the liver or intrahepatic bile ducts, a tumour in the oral cavity, a reproductive system tumour, a respiratory tract tumour, a skeletal system tumour, a skin tumour, a tumour involving a tissues such as peripheral nerves, autonomic nervous system, connective tissue, adipose tissue, retroperitoneum, peritoneum, eye, adnexa, thyroid, an endocrine gland and a tumour of a lymph node.
15. Use according to claim 13, wherein the cancer is selected from the group consisting of a glioblastoma, a malignant melanoma of the skin, a non-melanoma skin cancer, a basal cell carcinoma of skin, a squamous cell carcinoma of skin, a mesothelioma, a Kaposi's sarcoma, Hodgkin's disease, a Non-Hodgkin's lymphoma, a Burkitt's lymphoma, an AIDS- related lymphoma, a multiple myeloma, a malignant plasma cell neoplasm, a lymphoid leukemia, an acute or chronic myeloid leukaemia, an acute or chronic lymphocytic leukemia, a monocytic leukemia, a diffuse large cell lymphoma, a T-cell lymphoma, a cutaneous T-cell lymphoma, a congenital adrenal hyperplasia, an endometrial hyperplasia, a hyperplasia of the breast, a focal epithelial hyperplasia, a sebaceous hyperplasia, a compensatory liver hyperplasia, a medullary carcinoma, an osteosarcoma, a soft-tissue sarcoma, an Ewing's sarcoma, a reticulum cell sarcoma and a Kaposi's sarcoma.
16. Compound according to any of claims 1 - 9 or pharmaceutical composition according to any of claims 10 or 11, for the treatment of a proliferative disease.
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