EP1833823A1 - Dérivés benzazoles 2,5- et 2-6-disubstitués utiles comme des inhibiteurs de la proteine kinase - Google Patents

Dérivés benzazoles 2,5- et 2-6-disubstitués utiles comme des inhibiteurs de la proteine kinase

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Publication number
EP1833823A1
EP1833823A1 EP05824907A EP05824907A EP1833823A1 EP 1833823 A1 EP1833823 A1 EP 1833823A1 EP 05824907 A EP05824907 A EP 05824907A EP 05824907 A EP05824907 A EP 05824907A EP 1833823 A1 EP1833823 A1 EP 1833823A1
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European Patent Office
Prior art keywords
alkyl
independently represents
group
heteroaryl
aryl
Prior art date
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EP05824907A
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German (de)
English (en)
Inventor
Thomas Herz
Rolf Krauss
Michael Kubbutat
Martin Lang
Christoph SCHÄCHTELE
Stefan Tasler
Frank Totzke
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4SC AG
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4SC AG
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Priority to EP05824907A priority Critical patent/EP1833823A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine

Definitions

  • the present invention relates to benzazoles of the general formula (I) or a salt or a physiologically functional derivative or a stereoisomer thereof, for use as a medicament.
  • the compounds of the invention are exceptionally useful for the treatment of diseases associated with abnormal and hyperproliferation of cells in a mammal, especially humans. In particular, they are useful for the treatment of all forms of cancer. Furthermore a process of preparing said benzazole derivatives is disclosed.
  • Protein kinases play a central role in the regulation of cellular functions. This includes processes like cell growth and division, cell differentiation and cell death, but also many other cellular activities. Protein kinases catalyze the transfer of phosphate residues from ATP on target proteins which as a consequence of this protein kinase mediated
  • oncogenes are pathologically modified genes which in their proto- oncogenic form encode for protein kinases involved in normal, physiological regulation of cell growth and division.
  • protein kinases are key regulators of cell functions and since they can show dysregulated enzymatic activity in cells they are promising targets for the development of therapeutic agents.
  • the present invention relates to benzazole derivatives which may be useful for inhibition of protein kinases involved in diseases besides cancer, but which are especially useful as anti-tumor agents.
  • This includes monospecific protein kinase inhibitors, which preferentially inhibit one protein kinase which is causatively involved in tumor progression, but also so-called multi-target protein kinase inhibitors, which inhibit at least two different protein kinases which play a role in two or more different molecular mechanism of tumor progression.
  • such a compound could be an inhibitor of tumor angiogenesis and, in addition, also a stimulator of apoptosis.
  • multi-target protein kinase inhibitors The concept of multi-target protein kinase inhibitors is a new approach although the idea of developing "multiplex protein kinase inhibitors" has already been described by J. Adams et al., Current Opinion in Chemical Biology 6, 486-492, 2002. Therein compounds are described, which, at the same time, inhibit several protein kinases, which however all are involved in one molecular mechanism of tumor progression, namely tumor angiogenesis.
  • benzazoles are described as kinase inhibitors.
  • 2- aminobenzothiazoles are described. These compounds have also been published in Das et al., Bioorg. Med. Chem. Lett 13, 2003, 2587-2590 and in Das et al., Bioorg. Med. Chem. Lett 13, 2003, 2145-2149.
  • benzimidazolyl- and benzoxazolylacetylaminopyridylbutyrates are described as integrin antagonists.
  • WO 9940072 five-membered, benzo-condensed heterocycles used as antithrombotics of are described.
  • benzazole derivatives are a new group of protein kinase inhibitors which show differential inhibition of protein kinases, each of which can be assigned to one of the four molecular mechanism of tumor development.
  • the present invention relates to compounds of the general formula (I) or a salt or a physiologically functional derivative or a stereoisomer thereof,
  • X independently represents S, O, SO, or SO 2 ;
  • Y independently represents S, O, NR 2 , SO, or SO 2 ;
  • A independently represents ⁇ -CO-, ⁇ -CS-, ⁇ -SO-, X-SO 2 -, X-CO 2 -, X-CONR 8 -, X-NR 8 CO-, X-NR 8 CONR 9 -; X-NR 8 COO-, ⁇ -NR 8 NR 9 CO-, ⁇ -NR 8 OCO-, ⁇ -ONR 8 CO-, or ⁇ -NR 8 SO 2 -, where ⁇ - indicates the point of attachment to R 3 ;
  • R 2 independently represents H, alkyl, cycloalkyl, -COR 6 , -SOR 6 , -SO 2 R 6 , -CN, hydroxyalkyl, haloalkyl, or haloalkyloxy;
  • R J independently represents H, alkyl, cycloalkyl, aryl, or heteroaryl
  • R 4 independently represents H, -COR 6 , -CO 2 R 6 , -SOR 6 , -SO 2 R 6 , -SO 3 R 6 , -NO 2 , -CN,
  • R 5 independently represents H, alkyl, cycloalkyl, -COR 6 , -SOR 6 , -SO 2 R 6 , -CN, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, or heteroaryl;
  • R 1 6a independently represents H, alkyl, cycloalkyl, -NR 8 NR 2 R 9 , -ONR 8 R 9 ,
  • R 6 independently represents H, alkyl, cycloalkyl, -NR 8 R 9 , -NR 8 NR 2 R 9 , -ONR 8 R 9 ,
  • R 7 independently represents H, alkyl, cycloalkyl, or alkoxy
  • R 8 independently represents H, alkyl, cycloalkyl, -COR 6 , -SOR 6 , -SO 2 R 6 , haloalkyl, haloalkyloxy, aryl or heteroaryl
  • R 9 independently represents H, alkyl, cycloalkyl, -COR 6 , -SOR 6 , -SO 2 R 6 , haloalkyl, haloalkyloxy, aryl or heteroaryl
  • R 1 independently represents one of the following groups:
  • Z independently represents O, NR , or S
  • R 12 independently represents H, halogen, nitro, trifluoromethyl, alkyl, aryl, heteroaryl, -NR 8a R 9a , or -X 2 R 16 ;
  • R 8a independently represents H, alkyl, cycloalkyl, -C0R 6a , -SOR 6 , -SO 2 R 6 , haloalkyl, haloalkyloxy, aryl or heteroaryl;
  • R 9a independently represents H, alkyl, cycloalkyl, -COR 6a , -SOR 6 , -SO 2 R 6 , haloalkyl, haloalkyloxy, aryl or heteroaryl;
  • R 13 independently represents H, halogen, nitro, trifluoromethyl, alkyl, aryl, heteroaryl, -NR 8a R 9a , or -X 2 R 16 ;
  • R 14 independently represents H, halogen, nitro, trifluoro
  • R » 17 independently represents H, halogen, nitro, trifluoromethyl, alkyl, aryl, heteroaryl, -NR 8a R 9a , or -X 2 R 16 ;
  • X 2 independently represents a direct bond, -O-, -CH 2 -, -OCO-, carbonyl, -S-,
  • R 16 independently represents H, alkyl, cycloalkyl, -SOR 6 , -SO 2 R 6 , -OCH 3 , hydroxyalkyl, haloalkyl, haloalkyloxy, or one of the following groups:
  • n independently represents an integer from 1-3;
  • L is absent or represents a divalent linkage group selected from alkylen, cycloalkylen, heterocyclylen, arylen, or heteroarylen, wherein one or more of the (-CH 2 -) groups may be replaced by an oxygen or a NR 8 , and wherein one or more carbon atoms may be independently substituted by one or two substituents selected from halogen, hydroxy, alkoxy, halo- alkyloxy, phoshonooxy, or phoshonooxyalkyl;
  • X 3 independently represents -COOH, -COOalkyl, -OH, -SH, -SO 3 H, or
  • R .18 independently represents H, phosphonooxy, or phosphonooxyalkyl
  • R 19 independently represents H, alkyl, cycloalkyl, alkylamino, or alkoxy; with the proviso that the following compounds are excluded:
  • R ⁇ independently represents H, -CO 2 R", -CONHR", -CR”O, -SO 2 NR", -NR" -CO- haloalkyl, -NO 2 , -NR"-SO 2 -haloalkyl, -NR " -SO 2 -alkyl, -SO 2 -alkyl, -MT-CO-alkyl, -CN, alkyl, cycloalkyl, aminoalkyl, alkylamino, alkoxy, -OH, -SH, alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl, arylalkyl or heteroaryl;
  • R" independently represents H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl, heteroaryl or aminoalkyl;
  • an alkylene group denotes a divalent linear or branched Q-Q-alkylene, preferably a linear or branched chain of one to five carbon atoms, a linear or branched C 2 -C 6 -alkenylene or a linear or branched C 2 -C 6 -alkynylene group, which may be substituted by one or more substituents R';
  • a cycloalkylene group denotes a divalent non-aromatic ring system containing three to eight carbon atoms, preferably four to eight carbon atoms, wherein one or more of the carbon atoms in the ring may be substituted by a group E, E being O, S, SO, SO 2 , N, or NR", R" being as defined above;
  • a heterocyclylene group denotes a 3 to 8-membered divalent heterocyclic non-aromatic group which contains at least one heteroatom selected from O, N, and S, wherein the heterocyclylene group may be fused to another non-aromatic ring and may be substituted by one or more substituents R ⁇ wherein R" is as defined above;
  • an arylene group denotes an aromatic divalent group having five to fifteen carbon atoms, which may be substituted by one or more substituents R ⁇ and may be fused to another aromatic ring, where R" is as defined above;
  • a heteroarylene group denotes a divalent 5- or 6-membered heterocyclic group which contains at least one heteroatom selected from O, N, and S, wherein the heterocyclylene group may be fused to another aromatic ring and may be substituted by one or more substituents YC, wherein R' is as defined above;
  • a cycloalkyl group denotes a non-aromatic ring system containing three to eight carbon atoms, preferably four to eight carbon atoms, wherein one or more of the carbon atoms in the ring can be substituted by a group E, E being O, S, SO, SO 2 , N, or NR", R" being as defined above;
  • the C 3 -Cg-cycloalkyl residue may be selected from the group comprising -cyclo-C 3 H 5 , -cyclo-C 4 H 7 , -cyclo-C 5 H 9 , -cyclo-C 6 H n , -cyclo-C 7 H 13 , -cyclo-C 8 H 15 , morpholine-4-yl, piperazinyl, l-alkylpiperazine-4-yl;
  • an alkoxy group denotes an O-alkyl group, the alkyl group being as defined above; the alkoxy group is preferably a methoxy, ethoxy, isopropoxy, t-butoxy or pentoxy group;
  • an alkylthio group denotes an S-alkyl group, the alkyl group being as defined above;
  • an haloalkyl group denotes an alkyl group which is substituted by one to five halogen atoms, the alkyl group being as defined above; the haloalkyl group is preferably a -C(R 10 ) 3 , -CR 10 (R 10' ) 2 , -CR 10 (R 10> )R 10" , -C 2 (R 10 ) 5 , -CH 2 -C(R 10 ) 3 , -CH 2 -CR 1 °(R 10' )2, -CH 2 - CR 10 (R 10' )R 10" , -C 3 (R 10 ) ? , or -C 2 H 4 -C(R 10 );, wherein R 10 , R 10' , R 10" represent F, Cl, Br or I, preferably F;
  • a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group being as defined above;
  • an haloalkyloxy group denotes an alkoxy group which is substituted by one to five halogen atoms, the alkyl group being as defined above; the haloalkyloxy group is preferably a -OC(R 10 ) 3 , -OCR 10 (R 10' ) 2 , -OCR 10 (R 10> )R 10" , -OC 2 (R 10 ) 5 , -OCH 2 -C(R 10 ) 3 , -OCH 2 - CR 10 (R 10' ) 2 , -OCH 2 -CR 10 (R 10' )R 10" , -OC 3 (R 10 ) 7 or -OC 2 H 4 -C(R 10 ) 3 , wherein R 10 , R 10' , R 10" represent F, Cl, Br or I, preferably F;
  • a hydroxyalkylamino group denotes an (HO-alkyl) 2 -N- group or HO-alkyl-NH- group, the alkyl group being as defined above;
  • an alkylamino group denotes an HN-alkyl or N-dialkyl group, the alkyl group being as defined above;
  • a halogen group is fluorine, chlorine, bromine, or iodine
  • an aryl group denotes an aromatic group having five to fifteen carbon atoms, which can be substituted by one or more substituents R ⁇ where R" is as defined above; the aryl group is preferably a phenyl group, -0-C 6 H 4 - R', -Hi-C 6 H 4 - R ⁇ -P-C 6 H 4 - R ⁇ 1-naphthyl, 2-naphthyl, 1-anthracenyl or 2-anthracenyl;
  • a heteroaryl group denotes a 5- or 6-membered heterocyclic group which contains at least one heteroatom like O, N, S.
  • This heterocyclic group can be fused to another aromatic ring.
  • this group can be selected from a thiadiazole, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isooxazol-3-yl, isooxazol-4-yl, isooxazol-5-yl, l,2,4-oxadiazol-3-yl, 1,2,4- oxadiazol-5-yl, l,2,5-oxadiazol-3-yl, l,2,5-oxadiazol-4-yl, l,2,4-thi
  • the present invention also relates to compounds of the general formula (Ia) or a salt or a physiologically functional derivative or a stereoisomer thereof, formula (Ia) wherein the substituent -Y a -R la is attached to the 5- or 6-position of the benzazole;
  • X a independently represents S, O, SO, or SO 2 ;
  • Y a independently represents S, NR 2 , SO, or SO 2 ;
  • a a independently represents ⁇ CO-, ⁇ -CS-, ⁇ -S0-, «-S0 2 -, ⁇ -C0 2 -, ⁇ CONR 8 -, ⁇ -NR 8 C0-, ⁇ -NR 8 CONR 9 -; ⁇ -NR 8 COO-, ⁇ -NR 8 NR 9 CO-, ⁇ -NR 8 0C0-, ⁇ 0NR 8 CO-, or ⁇ -NR 8 SO 2 -, where ⁇ r- indicates the point of attachment to R 3 ; R la independently represents one of the following groups:
  • R u independently represents H, -NHR 8a , or one of the groups:
  • R , 13a a independently represents H, halogen, nitro, trifluoromethyl, alkyl, -NR 8a R 9a , or -X 2 R 16 ;
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 6a , R 7 , R 8 , R 8a , R 9 , R 9a , R 12 , R 13 , R 16 , or X 2 are as hereinbefore defined;
  • an alkyl group denotes a linear or branched Q-Ce-alkyl, preferably a linear or branched chain of one to five carbon atoms, a linear or branched C 2 -C 6 -alkenyl or a linear or branched C 2 -C 6 -alkinyl group, which can be substituted by one or more substituents R";
  • R ⁇ independently represents H, -CO 2 R", -CONHR", -CR O, -SO 2 NR", -NR"-CO- haloalkyl, -NO 2 , -NR"-SO 2 -haloalkyl, -NR"-SO 2 -alkyl, -SO 2 -alkyl, -NR"-CO-alkyl, -CN, alkyl, cycloalkyl, aminoalkyl, alkylamino, alkoxy, -OH, -SH, alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl, arylalkyl or heteroaryl;
  • R" independently represents H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl, heteroaryl or aminoalkyl;
  • an alkylene group denotes a divalent linear or branched CrC 6 -alkylene, preferably a linear or branched chain of one to five carbon atoms, a linear or branched C 2 -C 6 -alkenylene or a linear or branched C 2 -C 6 -alkynylene group, which may be substituted by one or more substituents R';
  • a cycloalkylene group denotes a divalent non-aromatic ring system containing three to eight carbon atoms, preferably four to eight carbon atoms, wherein one or more of the carbon atoms in the ring may be substituted by a group E, E being O, S, SO, SO 2 , N, or NR" ⁇ R" ⁇ being as defined above;
  • a heterocyclylene group denotes a 3 to 8-membered divalent heterocyclic non-aromatic group which contains at least one heteroatom selected from O, N, and S, wherein the heterocyclylene group may be fused to another non-aromatic ring and may be substituted by one or more substituents R", wherein R ⁇ is as defined above;
  • an arylene group denotes an aromatic divalent group having five to fifteen carbon atoms, which may be substituted by one or more substituents R ⁇ , and may be fused to another aromatic ring, where R ⁇ is as defined above;
  • a heteroarylene group denotes a divalent 5- or 6-membered heterocyclic group which contains at least one heteroatom selected from O, N, and S, wherein the heterocyclylene group may be fused to another aromatic ring and may be substituted by one or more substituents R ⁇ wherein R' is as defined above;
  • a cycloalkyl group denotes a non-aromatic ring system containing three to eight carbon atoms, preferably four to eight carbon atoms, wherein one or more of the carbon atoms in the ring can be substituted by a group E, E being O, S, SO, SO 2 , N, or NR", R" being as defined above;
  • the C 3 -C 8 -cycloalkyl residue may be selected from the group comprising -cyclo-C 3 H 5 , -cyclo-C 4 H 7 , -cyclo-CsHg, -cyclo-C 6 H ll5 -cyclo-C 7 H 13 , -CyCIo-CgH 15 , morpholine-4-yl, piperazinyl, l-alkylpiperazine-4-yl;
  • an alkoxy group denotes an O-alkyl group, the alkyl group being as defined above; the alkoxy group is preferably a methoxy, ethoxy, isopropoxy, t-butoxy or pentoxy group;
  • an alkylthio group denotes an S-alkyl group, the alkyl group being as defined above; an haloalkyl group denotes an alkyl group which is substituted by one to five halogen atoms, the alkyl group being as defined above; the haloalkyl group is preferably a -C(R 10 ) 3 , -CR 10 (R 10' ) 2 , -CR 10 (R 10' )R 10" , -C 2 (R 10 ) 5 , -CH 2 -C(R 10 ) 3 , -CH 2 -CR 10 (R 10> ) 2 , -CH 2 - CR 10 (R 10' )R 10" , -C 3 (R 10 ) 7 , or -C 2 H 4 -C(R 1 °) 3> wherein R 10 , R 10' , R 10" represent F, Cl, Br or I, preferably F;
  • a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group being as defined above;
  • an haloalkyloxy group denotes an alkoxy group which is substituted by one to five halogen atoms, the alkyl group being as defined above; the haloalkyloxy group is preferably a -OC(R 10 ) 3 , -OCR 10 (R 10' ) 2 , -OCR 10 (R 10' )R 10" , -OC 2 (R 10 ) 5 , -OCH 2 -C(R 10 ) 3 , -OCH 2 - CR 10 (R 10' ) 2 , -OCH 2 -CR 10 (R 10> )R 10" , -OC 3 (R 10 ) ? or -OC 2 H 4 -C(R 10 X wherein R 10 , R 10' , R 10" represent F, Cl, Br or I, preferably F;
  • a hydroxyalkylamino group denotes an (HO-alkyl) 2 -N- group or HO-alkyl-NH- group, the alkyl group being as defined above;
  • an alkylamino group denotes an HN-alkyl or N-dialkyl group, the alkyl group being as defined above;
  • a halogen group is fluorine, chlorine, bromine, or iodine
  • an aryl group denotes an aromatic group having five to fifteen carbon atoms, which can be substituted by one or more substituents R ⁇ where R" is as defined above; the aryl group is preferably a phenyl group, -0-C 6 H 4 - R ⁇ -Hi-C 6 H 4 - R ⁇ -P-C 6 H 4 - R ⁇ 1-naphthyl, 2-naphthyl, 1-anthracenyl or 2-anthracenyl;
  • a heteroaryl group denotes a 5- or 6-membered heterocyclic group which contains at least one heteroatom like O, N, S. This heterocyclic group can be fused to another aromatic ring.
  • this group can be selected from a thiadiazole, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isooxazol-3-yl, isooxazol-4-yl, isooxazol-5-yl, l,2,4-oxadiazol-3-yl, 1,2,4- oxadiazol-5-yl, l,2,5-oxadiazol-3-yl, l,2,5-oxadiazol-4-yl, l,2,4-thiadiazol-3-yl, 1,2,4- thiadiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, l,
  • the present invention also relates to compounds of the general formula (II) or a salt or a physiologically functional derivative or a stereoisomer thereof,
  • X b independently represents S, O, SO, or SO 2 ;
  • Y b independently represents S, NR 2 , SO, or SO 2 ;
  • a b independently represents 4-C0-, 4-CS-, ⁇ -SO-, 4-SO 2 -, 4-CO 2 -, 4-CONR 8 -, 4-NR 8 CO-, -(-NR 8 CONR 9 -; 4-NR 8 COO-, -(-NR 8 NR 9 CO-, 4-NR 8 OCO-, ⁇ -0NR 8 CO-, or 4-NR 8 SO 2 -, where ⁇ - indicates the point of attachment to R 3 ;
  • R 4b independently represents H, -SOR 6 , -SO 2 R 6 , -SO 3 R 6 , -NO 2 , -CN, -CF 3 , -OCH 3 , -OCF 3 , alkyl, cycloalkyl, alkoxy, -NH 2 , alkylamino, -NR 7 COR 6 , halogen, -OH, -SH, alkylthio, haloalkyl, haloalkyloxy, aryl or heteroaryl;
  • R 2 , R 3 , R 5 , R 6 , R 6a , R 7 , R 8 , R 8a , R 9 , R 9a , R 11 , R 12 , R 16 , X 2 are as hereinbefore defined;
  • an alkyl group denotes a linear or branched CrC ⁇ -alkyl, preferably a linear or branched chain of one to five carbon atoms, a linear or branched C 2 -C 6 -alkenyl or a linear or branched C 2 -C 6 -alkinyl group, which can be substituted by one or more substituents R' ;
  • IT independently represents H, -CO 2 R", -CONHR", -CR”O, -SO 2 NR", -NR" -CO- haloalkyl, -NO 2 , -NR"-SO 2 -haloalkyl, -NR"-S0 2 -alkyl, -SO 2 -alkyl, -NR"-CO-alkyl, -CN, alkyl, cycloalkyl, aminoalkyl, alkylamino, alkoxy, -OH, -SH, alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl, arylalkyl or heteroaryl;
  • R" independently represents H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl, heteroaryl or aminoalkyl;
  • an alkylene group denotes a divalent linear or branched CrC ⁇ -alkylene, preferably a linear or branched chain of one to five carbon atoms, a linear or branched C 2 -C 6 -alkenylene or a linear or branched C 2 -C ⁇ -alkynylene group, which may be substituted by one or more substituents R';
  • a cycloalkylene group denotes a divalent non-aromatic ring system containing three to eight carbon atoms, preferably four to eight carbon atoms, wherein one or more of the carbon atoms in the ring may be substituted by a group E, E being O, S, SO, SO 2 , N, or NR", R" being as defined above;
  • a heterocyclylene group denotes a 3 to 8-membered divalent heterocyclic non-aromatic group which contains at least one heteroatom selected from O, N, and S, wherein the heterocyclylene group may be fused to another non-aromatic ring and may be substituted by one or more substituents R", wherein R" is as defined above;
  • an arylene group denotes an aromatic divalent group having five to fifteen carbon atoms, which may be substituted by one or more substituents R ⁇ and may be fused to another aromatic ring, where R" is as defined above;
  • a heteroarylene group denotes a divalent 5- or 6-membered heterocyclic group which contains at least one heteroatom selected from O, N, and S, wherein the heterocyclylene group may be fused to another aromatic ring and may be substituted by one or more substituents R", wherein R ⁇ is as defined above;
  • a cycloalkyl group denotes a non-aromatic ring system containing three to eight carbon atoms, preferably four to eight carbon atoms, wherein one or more of the carbon atoms in the ring can be substituted by a group E, E being O, S, SO, SO 2 , N, or NR" ⁇ R" being as defined above;
  • the Q-Cs-cycloalkyl residue may be selected from the group comprising -CyCIo-C 3 H 5 , -cyclo-C 4 H 7 , -cyclo-C 5 H 9 , -CyCIo-C 6 H 11 , -cyclo-C 7 H
  • an alkoxy group denotes an O-alkyl group, the alkyl group being as defined above; the alkoxy group is preferably a methoxy, ethoxy, isopropoxy, t-butoxy or pentoxy group;
  • an alkylthio group denotes an S-alkyl group, the alkyl group being as defined above;
  • an haloalkyl group denotes an alkyl group which is substituted by one to five halogen atoms, the alkyl group being as defined above; the haloalkyl group is preferably a -C(R 10 )3, -CR 10 (R 10' ) 2 , -CR 10 (R 10' )R 10" , -C 2 (R 10 ) 5 , -CH 2 -C(R 10 ) 3 , -CH 2 -CR 10 (R 10' ) 2 , -CH 2 - CR 10 (R 10' )R 10" , -C 3 (R 10 ) ? , or -C 2 H 4 -C(R 10 );, , wherein R 10 , R 10' , R 10" represent F, Cl, Br or I, preferably F;
  • a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group being as defined above;
  • an haloalkyloxy group denotes an alkoxy group which is substituted by one to five halogen atoms, the alkyl group being as defined above; the haloalkyloxy group is preferably a -OC(R 10 ) 3 , -OCR 10 (R 10' ) 2 , -OCR 10 (R 10' )R 10" , -OC 2 (R 10 ) 5 , -OCH 2 -C(R 10 ) 3 , -OCH 2 - CR 1 V) 2 , -OCH 2 -CR 1 V)R 10" , -OC 3 (R 10 ) 7 or -OC 2 H4-C(R 10 ) 3> wherein R 10 , R 10' , R 10" represent F, Cl, Br or I, preferably F;
  • a hydroxyalkylamino group denotes an (HO-alkyl) 2 -N- group or HO-alkyl-NH- group, the alkyl group being as defined above;
  • an alkylamino group denotes an HN-alkyl or N-dialkyl group, the alkyl group being as defined above;
  • a halogen group is fluorine, chlorine, bromine, or iodine
  • an aryl group denotes an aromatic group having five to fifteen carbon atoms, which can be substituted by one or more substituents R ⁇ where R x is as defined above; the aryl group is preferably a phenyl group, -0-C 6 H 4 - R ⁇ -In-C 6 H 4 - R ⁇ -P-C 6 H 4 - R ⁇ 1-naphthyl, 2-naphthyl, 1-anthracenyl or 2-anthracenyl;
  • a heteroaryl group denotes a 5- or 6-membered heterocyclic group which contains at least one heteroatom like O, N, S.
  • This heterocyclic group can be fused to another aromatic ring.
  • this group can be selected from a thiadiazole, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isooxazol-3-yl, isooxazol-4-yl, isooxazol-5-yl, l,2,4-oxadiazol-3-yl, 1,2,4- oxadiazol-5-yl, l,2,5-oxadiazol-3-yl, l,2,5-oxadiazol-4-yl, l,2,4-thi
  • the invention also provides a pharmaceutical composition comprising a compound of formula (I), in free form or in the form of pharmaceutically acceptable salts and physiologically functional derivatives, together with a pharmaceutically acceptable diluent or carrier therefore.
  • physiologically functional derivative refers to compounds which are not pharmaceutically active themselves but which are transformed into their pharmaceutical active form in vivo, i.e. in the subject to which the compound is administered.
  • physiologically functional derivatives are prodrugs such as those described below in the present application.
  • Prodrugs of the compounds of the present invention include but are not limited to: esters, which are transformed in vivo into the corresponding active alcohol, esters, which are transformed in vivo into the corresponding active acid, imines, which are transformed in vivo into the corresponding amines, imines which are metabolized in vivo into the corresponding active carbonyl derivative (e.g. aldehyde or ketone), 1-carboxy-amines, which are decarboxylated in vivo into the active amine, phosphoryloxy-compounds, which are dephosporylated in vivo by phosphateases into the active alcohols, and amides which are metabolized into the corresponding active amine or acid respectively.
  • esters which are transformed in vivo into the corresponding active alcohol
  • esters which are transformed in vivo into the corresponding active acid
  • imines which are transformed in vivo into the corresponding amines
  • stereoisomer refers to compound with at least one stereogenic center, which can be R- or S-conf ⁇ gurated. It has to be understood, that in compounds with more than one stereogenic center each of which independently from each other can be R- or S-configurated.
  • stereoisomer as used herein also refers to salts of the compounds herein described with optically active acids or bases.
  • the present invention provides methods for preparing the compounds of the invention such as compounds of formula (I).
  • the compounds of formula (I), formula (Ia) and formula (II) may be obtained via various methods.
  • Another way to synthesize compounds of formula (I), formula (Ia) and formula (II) comprises the step of adding a R 5 to a compound of formula (IX), wherein R 1 , R 4 , X, and Y are as defined above in formula (I), formula (Ia) and formula (II), followed by reaction with an acid chloride, a carboxylic acid, a sulfonic acid chloride, or an isocyanate or vice versa.
  • the compounds of formula (XI) can be synthesized by adding a R 5 to a compound of formula (XII), wherein R 4 and X are as defined above, followed by reaction with an acid chloride, a carboxylic acid, a sulfonic acid chloride, or an isocyanate or vice versa.
  • A, X, Y, R 3 , R 4 , R 5 , R 12 , R 13 , R 14 , R 15 are as defined above for formula (I).
  • Another preferred embodiment of the invention are compounds of formula (III), wherein R 12 and R 15 are H and R 13 and R 14 independently represent O-alkyl which may be substituted.
  • a more preferred embodiment of the present invention are compounds of formula (III), wherein X independently represents S or O; Y represents NH; A independently represents -CO- or ⁇ — NHCO-, where ⁇ - indicates the point of attachment to R 3 ; R 3 is an optionally substituted aryl or heteroaryl group, R 5 , R 12 and R 15 are H; R 13 and R 14 are -O-alkyl, which may be substituted.
  • Another preferred embodiment of the invention are compounds of the formula (FV)
  • R 13 , R 14 , R 15 are as defined above for formula (I).
  • Another preferred embodiment of the invention are compounds of the formula (VI)
  • Another preferred embodiment of the invention are compounds of formula (I), where X represents S; Y represents NH; A represents -CO-; R 5 represents H.
  • Another preferred embodiment of the invention are compounds of formula (I), where X represents S; Y represents NH; A represents ⁇ — NHCO-, where ⁇ — indicates the point of attachment to R 3 ; R 5 represents H.
  • Another preferred embodiment of the invention are compounds of formula (I), where X represents O; Y represents NH; A represents -CO-; R 5 represents H.
  • Another preferred embodiment of the invention are compounds of formula (I) 5 where X represents O; Y represents NH; A represents ⁇ -NHCO-, where ⁇ - indicates the point of attachment to R 3 ; R 5 represents H.
  • Another preferred embodiment of the invention are compounds of formula (I), are compounds where X represents O; Y represents NH; A represents -CO-; R 3 represents an optionally substituted aryl or heteroaryl group; R 5 represents H.
  • a more preferred embodiment of the present invention are compounds of formula (III), wherein the -Y-R 1 substituent is attached to the 5-position of the benzazole, X independently represents S or O; Y represents NH; A independently represents -CO- or ⁇ — NHCO-, where ⁇ — indicates the point of attachment to R , R is an optionally substituted aryl or heteroaryl group, R 5 , R 12 and R 15 are H; R 13 and R 14 are -O-alkyl, which may be substituted.
  • a more preferred embodiment of the present invention are compounds of formula (III), wherein the -Y-R 1 substituent is attached to the 6-position of the benzazole, X independently represents S or O; Y represents NH; A independently represents -CO- or ⁇ -NHC0-, where ⁇ — indicates the point of attachment to R 3 , R 3 is an optionally substituted aryl or heteroaryl group, R 5 , R 12 and R 15 are H; R 13 and R 14 are -O-alkyl, which may be substituted.
  • a more preferred embodiment of the present invention are compounds of formula (III), wherein the -Y-R 1 substituent is attached to the 5-position of the benzazole, X independently represents S or O; Y represents NH; A independently represents -CO- or ⁇ -NHC0-, where ⁇ — indicates the point of attachment to R 3 , R 3 is an optionally substituted phenyl, R 5 , R 12 and R 15 are H; R 13 and R 14 are -O-alkyl, which may be substituted.
  • a more preferred embodiment of the present invention are compounds of formula (III), wherein the -Y-R 1 substituent is attached to the 6-position of the benzazole, X independently represents S or O; Y represents NH; A independently represents -CO- or ⁇ -NHCO-, where ⁇ - indicates the point of attachment to R 3 , R 3 is an optionally substituted phenylaryl or heteroaryl group, R 5 , R 12 and R 15 are H; R 13 and R 14 are -O-alkyl, which may be substituted.
  • Another preferred embodiment of the invention are compounds of formula (I), where R 3 is an optionally substituted aryl or heteroaryl group.
  • Another preferred embodiment of the invention are compounds of formula (I), where R 3 is an optionally substituted phenyl group.
  • Another preferred embodiment of the invention are compounds of formula (I), where the -Y-R 1 substituent is attached to the 5-position of the benzazole.
  • Another preferred embodiment of the invention are compounds of formula (I), where the -Y-R 1 substituent is attached to the 6-position of the benzazole.
  • Another preferred embodiment of the invention are compounds of formula (III), where R 3 is an optionally substituted aryl or heteroaryl group.
  • Another preferred embodiment of the invention are compounds of formula (III), where R 3 is an optionally substituted phenyl group.
  • Another preferred embodiment of the invention are compounds of formula (III), where the -Y-R 1 substituent is attached to the 5-position of the benzazole.
  • Another preferred embodiment of the invention are compounds of formula (III), where the -Y-R 1 substituent is attached to the 6-position of the benzazole.
  • Another preferred embodiment of the invention are compounds of formula (III), where X represents S; Y represents NH; A represents -CO-; R 5 represents H.
  • Another preferred embodiment of the invention are compounds of formula (III), where X represents S; Y represents NH; A represents ⁇ — NHCO-, where ⁇ — indicates the point of attachment to R 3 ; R 5 represents H.
  • Another preferred embodiment of the invention are compounds of formula (III), where X represents O; Y represents NH; A represents -CO-; R 5 represents H.
  • Another preferred embodiment of the invention are compounds of formula (III), where X represents O; Y represents NH; A represents ⁇ — NHCO-, where ⁇ —
  • Another preferred embodiment of the invention are compounds of formula (III), are compounds where X represents O; Y represents NH; A represents -CO-; R 3 represents an optionally substituted aryl or heteroaryl group; R 5 represents H.
  • Another preferred embodiment of the invention are compounds of formula (Ia), where X a represents S; Y a represents NH; A a represents -CO-; R 5 represents H.
  • Another preferred embodiment of the invention are compounds of formula (Ia), where X a represents S; Y a represents NH; A a represents ⁇ — NHCO-, where ⁇ - indicates the point of attachment to R 3 ; R 5 represents H.
  • Another preferred embodiment of the invention are compounds of formula (Ia), where R 3 is an optionally substituted aryl or heteroaryl group.
  • Another preferred embodiment of the invention are compounds of formula (Ia), where R is an optionally substituted phenyl group.
  • Another preferred embodiment of the invention are compounds of formula (Ia), where the -Y a -R la substituent is attached to the 5-position of the benzazole.
  • Another preferred embodiment of the invention are compounds of formula (Ia), where the -Y a -R la substituent is attached to the 6-position of the benzazole.
  • Another preferred embodiment of the invention are compounds of formula (II), where X b represents S; Y b represents NH; A b represents -CO-; R 5 represents H.
  • Another preferred embodiment of the invention are compounds of formula (II), where X b represents S; Y b represents NH; A represents ⁇ -NHCO-, where ⁇ — indicates the point ofattachment to R 3 ; R 5 represents H.
  • Another preferred embodiment of the invention are compounds of formula (II), where R 3 is an optionally substituted aryl or heteroaryl group.
  • Another preferred embodiment of the invention are compounds of formula (II), where R 3 is an optionally substituted phenyl group.
  • Another preferred embodiment of the invention are compounds of formula (II), where the -Y b - substituent is attached to the 5-position of the benzazole.
  • Another preferred embodiment of the invention are compounds of formula (II), where the -Y b - substituent is attached to the 6-position of the benzazole.
  • compositions containing one ore more compounds of the present invention and a pharmaceutical acceptable carrier or diluent are also preferred embodiments.
  • the compounds of the present invention can form salts with inorganic or organic acids or bases.
  • pharmaceutically acceptable salts comprise without limitation nontoxic inorganic or organic salts such as acetate derived from acetic acid, aconitate derived from aconitic acid, ascorbate derived from ascorbic acid, benzoate derived from benzoic acid, cinnamate derived from cinnamic acid, citrate derived from citric acid, embonate derived from embonic acid, enantate derived from heptanoic acid, formiate derived from formic acid, fumarate derived from fumaric acid, glutamate derived from glutamic acid, glycolate derived from glycolic acid, chloride derived from hydrochloric acid, bromide derived from hydrobromic acid, lactate derived from lactic acid, maleate derived from maleic acid, malonate derived from malonic acid, mandelate derived from mandelic acid, methanesulfonate derived from methan
  • Salts of phosphonoxy- and phosphonoxyalkyl groups may be those formed with alkali metal ions e.g. sodium or potassium, or those formed with alkaline earth metal ions e. g. calcium or magnesium, or those formed with zinc ions.
  • Such salts of the compounds of the present invention may be anhydrous or solvated. Such salts can be produced by methods known to someone of skill in the art and described in the prior art.
  • the compounds according to the invention and medicaments prepared therewith are generally useful for the treatment of cell proliferation disorders, for the treatment or prophylaxis of immunological diseases and conditions (as for instance inflammatory diseases, neuroimmunological diseases, autoimmune diseases or other).
  • the compounds of the present invention are useful for the treatment of diseases which are caused by malignant cell proliferation, such as all forms of solid tumors, leukemias and lymphomas. Therefore the compounds according to the invention and medicaments prepared therewith are generally useful for regulating cell activation, cell proliferation, cell survival, cell differentiation, cell cycle, cell maturation and cell death or to induce systemic changes in metabolism such as changes in sugar, lipid or protein metabolism.
  • cell generation poiesis including blood cell growth and generation (prohematopoietic effect) after depletion or destruction of cells, as caused by, for example, toxic agents, radiation, immunotherapy, growth defects, malnutrition, malabsorption, immune dysregulation, anemia and the like or to provide a therapeutic control of tissue generation and degradation, and therapeutic modification of cell and tissue maintenance and blood cell homeostasis.
  • diseases and conditions include but are not limited to cancer as hematological (e.g. leukemia, myeloma), or lymphomas (e.g.
  • Hodgkin's and non-Hodgkin's lymphomas or solid tumors (for example breast, prostate, liver, bladder, lung, esophageal, stomach, colorectal, genitourinary, gastrointestinal, skin, pancreatic, brain, uterine, colon, head and neck, and ovarian, melanoma, astrocytoma, small cell lung cancer, glioma, basal and squameous cell carcinoma, sarcomas as Kaposi's sarcoma and osteosarcoma).
  • solid tumors for example breast, prostate, liver, bladder, lung, esophageal, stomach, colorectal, genitourinary, gastrointestinal, skin, pancreatic, brain, uterine, colon, head and neck, and ovarian, melanoma, astrocytoma, small cell lung cancer, glioma, basal and squameous cell carcinoma, sarcomas as Kaposi's sarcom
  • benzazole derivatives as new pharmaceutically active agents, especially for the preparation of a pharmaceutical composition for the treatment of diseases which are cured or relieved by the inhibition of one or several kinases and/or phosphatases.
  • the compounds of the present invention may be used for treating and/or preventing diseases by inhibition of one ore more kinases like: Aurora A, Aurora B, EGF-R, ERBB2, IGFl-R, PDGFR, FLT3 VEGF-R2, VEGF-R3, EPHB4, Tie2, FAK and SRC.
  • kinases like: Aurora A, Aurora B, EGF-R, ERBB2, IGFl-R, PDGFR, FLT3 VEGF-R2, VEGF-R3, EPHB4, Tie2, FAK and SRC.
  • Treatment is intended to mean complete or partial healing of a disease, prevention of a disease, or alleviation of a disease or stop of progression of a given disease.
  • the compounds of the present invention can further be used for diseases that are caused by protozoal infestations in humans and animals.
  • the compounds of the present invention can further be used for viral infections or other infections caused for instance by Pneumocystis carinii.
  • the invention relates to a method of treatment or prevention of diseases which comprises the administration of an effective amount of compounds of the formula (I) or a pharmaceutically acceptable salt or physiologically functional derivative or a stereoisomer thereof.
  • the compounds of the according invention and their pharmacologically acceptable salts can be administered to animals, preferably to mammals, and in particular to humans, as therapeutics per se, as mixtures with one another or in the form of pharmaceutical preparations which allow enteral or parenteral use and which as active constituent contain an effective dose of at least one compound of the present invention or a salt thereof, in addition to customary pharmaceutically innocuous excipients and additives.
  • the compounds according to the invention for use in therapy may be administered in the form of the raw chemical compound, it is preferred to introduce the active ingredient, optionally in the form of a physiologically acceptable salt in a pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffers, diluents, and/or other customary pharmaceutical auxiliaries.
  • Such salts of the compounds may be anhydrous or solvated.
  • the invention provides medicaments comprising compounds according to the present invention, or a pharmaceutically acceptable salt or physiologically functional derivative or a stereoisomer thereof, together with one or more pharmaceutically acceptable carriers thereof, and, optionally, other therapeutic and/or prophylactic ingredients.
  • the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient thereof.
  • a medicament of the invention may be those suitable for oral, rectal, bronchial, nasal, topical, buccal, sub-lingual, transdermal, vaginal or parenteral (including cutaneous, subcutaneous, intramuscular, intraperitoneal, intravenous, intraarterial, intracerebral, intraocular injection or infusion) administration, or those in a form suitable for administration by inhalation or insufflation, including powders and liquid aerosol administration, or by sustained release systems.
  • sustained release systems include semipermeable matrices of solid hydrophobic polymers containing the compound of the invention, which matrices may be in form of shaped articles, e.g. films or microcapsules.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier can be one or more substances which may also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier is a finely divided solid which is in a mixture with the finely divided active component, hi tablets, the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • the term "preparation” is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier,- which is thus in association with it.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.
  • a low melting wax such as a mixture of fatty acid glyceride or cocoa butter
  • the active component is dispersed homogeneously therein, as by stirring.
  • the molten homogenous mixture is then poured into convenient sized moulds, allowed to cool, and thereby to solidify.
  • Compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • Liquid preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions.
  • parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution.
  • the compounds according to the present invention may thus be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative.
  • the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulation agents such as suspending, stabilising and/or dispersing agents.
  • the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
  • a suitable vehicle e.g. sterile, pyrogen-free water
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavours, stabilising and thickening agents, as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration.
  • liquid forms include solutions, suspensions, and emulsions.
  • These preparations may contain, in addition to the active component, colorants, flavours, stabilisers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • the medicament is applied topically. This reduces possible side effects and limits the necessary treatment to those areas affected.
  • the medicament is prepared in form of an ointment, a gel, a plaster, an emulsion, a lotion, a foam, a cream of a mixed phase or amphiphilic emulsion system (oil/water-water/oil mixed phase), a liposome, a transfersome, a paste or a powder.
  • an ointment a gel, a plaster, an emulsion, a lotion, a foam, a cream of a mixed phase or amphiphilic emulsion system (oil/water-water/oil mixed phase), a liposome, a transfersome, a paste or a powder.
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents.
  • compositions suitable for topical administration in the mouth include lozenges comprising the active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerine or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray.
  • the compositions may be provided in single or multi-dose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomising spray pump.
  • Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurised pack with a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • CFC chlorofluorocarbon
  • the aerosol may conveniently also contain a surfactant such as lecithin.
  • the dose of drug may be controlled by provision of a metered valve.
  • the active ingredients may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
  • a powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
  • PVP polyvinylpyrrolidone
  • the powder carrier will form a gel in the nasal cavity
  • the powder composition may be presented in unit dose form for example in capsules or cartridges of, e.g., gelatin, or blister packs from which the powder may be administered by means of an inhaler.
  • the compound In compositions intended for administration to the respiratory tract, including intranasal compositions, the compound will generally have a small particle size for example of the order of 5 microns or less. Such a particle size may be obtained by means known in the art, for example by micronization.
  • compositions adapted to give sustained release of the active ingredient may be employed.
  • the pharmaceutical preparations are preferably in unit dosage forms.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packaged tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form. Tablets or capsules for oral administration and liquids for intravenous administration and continuous infusion are preferred compositions.
  • compositions can also contain two or more compounds of the present invention or their pharmacologically acceptable salts and also other therapeutically active substances.
  • the compounds of the present invention can be used in the form of one compound alone or in combination with other active compounds - for example with medicaments already known for the treatment of the aforementioned diseases, whereby in the latter case a favorable additive, amplifying effect is noticed.
  • pharmaceutically inert inorganic or organic excipients can be used.
  • pills tablets, coated tablets and hard gelatin capsules, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts, etc.
  • Excipients for soft gelatin capsules and suppositories are, for example, fats, waxes, semi-solid and liquid polyols, natural or hardened oils etc.
  • Suitable excipients for the production of solutions and syrups are, for example, water, sucrose, invert sugar, glucose, polyols etc.
  • Suitable excipients for the production of injection solutions are, for example, water, alcohols, glycerol, polyols or vegetable oils.
  • the dose can vary within wide limits and is to be suited to the individual conditions in each individual case.
  • the appropriate dosage will vary depending on the mode of administration, the particular condition to be treated and the effect desired, hi general, however, satisfactory results are achieved at dosage rates of about 1 to 100 mg/kg animal body weight preferably 1 to 50 mg/kg.
  • Suitable dosage rates for larger mammals, for example humans, are of the order of from about 10 mg to 3 g/day, conveniently administered once, in divided doses 2 to 4 times a day, or in sustained release form.
  • Analytical LC/ESI-MS 2 x Waters 600 Multisolvent Delivery System. 50 ⁇ l Sample loop. Column, Chromolith Speed ROD RPl 8e (Merck, Darmstadt), 50 x 4.6 mm, with 2 ⁇ m prefilter (Merck). Eluent A, H 2 O + 0.1% HCO 2 H; eluent B, MeCN. Gradient, 5 % B to 100 % B within 5 min; flow, 3 ml/min. Waters LCZ single quadrupol mass spectrometer with electrospray source.
  • MS method MS8minPM-80-800-20V; positive/negative ion mode scanning, m/z 80 - 800 in 1 s; capillary, 3.5 kV; cone voltage, 20 V; multiplier voltage, 400 V; probe and desolvation gas temperature, 120° C and 350° C, respectively.
  • Waters 2487 Dual ⁇ Absorbance Detector set to 254 nm.
  • Preparative HPLC-MS Waters 600 Multisolvent Delivery System with peparative pump heads. 2000 ⁇ l or 5000 ⁇ l Sample loop. Column, Waters X-Terra RP 18, 7 ⁇ m, 19 x 150 mm with X-Terra RP 18 guard cartridge 7 ⁇ m, 19 x 10 mm; used at flow rate 20 ml/min or YMC ODS- A, 120 A, 40 x 150 mm with X-Terra RP 18 guard cartridge 7 ⁇ m, 19 x 10 mm; used at flow rate 50 ml/min. Make-up solvent: MeCN - H 2 O - HCO 2 H 80 : 20 : 0.05 (v:v:v).
  • Eluent A H 2 O + 0.1% HCO 2 H
  • eluent B MeCN.
  • Injection volume 500 ⁇ l - 2000 ⁇ l depending on sample.
  • Waters ZQ single quadrupol mass spectrometer with electrospray source Positive or negative ion mode scanning m/z 80 - 800 in 1 s; capillary, 3.5 kV or 3.0 kV; cone voltage, 20 V; multiplier voltage, 400 V; probe and desolvation gas temperature, 120° C and 350° C 5 respectively.
  • Waters Fraction Collector II with mass-triggered fraction collection. Waters 996 photo diode array detector.
  • Step 1 A solution of cyanogen bromide (3.50 g, 33 mmol; caution: highly toxic! Waste disposal: addition of excess NaOCl to a basic aqueous solution of cyanogen bromide) in tetrahydrofuran (3 mL) was added to a solution of 2-amino-5-nitrophenol (4.62 g, 30 mmol) in tetrahydrofuran (20 mL). After stirring for 1 day at r.t., a precipitate had formed which was dissolved by addition of water (5 mL). After stirring further 3 days at r.t., water (10 mL) was added and NaOH was added until the mixture turned basic.
  • Step 2 Benzoyl chloride (1.17 mL, 10.0 mmol) was added to a suspension of 2-amino-6- nitrobenzoxazole (1.50 g, 8.37 mmol) in pyridine (10 mL). After stirring for 24 h at 80 0 C, the solution was poured into water (250 mL). The mixture was stirred overnight at r.t. and the resulting precipitate was separated by filtration. N-(6-Nitrobenzoxazol-2-yi)benzarnide (2.08 g, 7.32 mmol, 88 %) was thus obtained as a yellow solid.
  • Step 3 To a solution of N-(6-nitrobenzoxazol-2-yl)benzamide (2.03 g, 7.17 mmol) in dimethylformamide (60 mL), palladium on charcoal (1.52 g, 10 % Pd, 1.43 mmol Pd) was added and the air was replaced with hydrogen (1 bar). The mixture was stirred for 2 h at 6O 0 C and then overnight at r.t. The palladium was removed by filtration through a pad of celite. After concentration to 20 mL, water was added and the resulting precipitate was separated by filtration to obtain N-(6-aminobenzoxazol-2-yl)benzamide (0.823 g, 3.25 mmol, 45 %) as a brown solid.
  • Step 1 To a suspension of 2-amino-6-nitrobenzothiazole (Sigma Aldrich, 2.93 g, 15 mmol) in pyridine (20 mL), benzoyl chloride (1.74 mL, 15 mmol) was added. After stirring overnight at r.t., additional benzoyl chloride (1.74 mL, 15 mmol) was added and the mixture was stirred at 6O 0 C . After completion of the reaction, the mixture was poured into water (250 mL) and stirred overnight at r.t..
  • Step 2 A mixture of iV-(6-nitrobenzothiazol-2-yl)benzamide (3.77 g, 12.6 mmol), palladium on charcoal (2 g, 10 % Pd, 1.88 mmol Pd), dimethyl formamide (80 mL) and ethyl acetate (20 mL) was hydrogenated (1 bar) for 2 h at 60°C. The palladium was removed by filtration through a pad of celite. After concentration to 20 mL, water was added and the resulting precipitate was separated by filtration to obtain iV-(6-aminobenzothiazol-2-yl)- benzamide (3.15 g, 11.7 mmol, 93 %) as a grey solid.
  • Step 1 To a mixture of 2-amino-6-nitrobenzothiazole (Sigma Aldrich, 1.95 g, 10 mmol) and pyridine (40 mL), benzoyl chloride (2.1 mL, 18 mmol) was added. After stirring for 5 h at 80°C, water (10 mL) was added. The mixture was stirred for 0.5 h at r.t., then methanol (30 mL) and water (50 mL) were added. The precipitated iV-(6-nitrobenzothiazol-2-yl)- isonicotinamide was separated by filtration.
  • Step 1 N-(6-Aminobenzothiazol-2-yl)nicotinamide.
  • Step 1 A mixture of 2-amino-6-nitrobenzothiazole (0.976 g, 5 mmol), nicotinoyl chloride hydrochloride (1.07 g, 6 mmol), triethylamine (1.9 ml, 13.8 mmol), DMAP (catalytic amount) and dioxane (50 mL) was heated to reflux for 7 h. After addition of nicotinoyl chloride hydrochloride (0.89 g, 5 mmol) and triethylamine (1.8 mL, 12.5 mmol), heating was continued for 5 h.
  • N-(6- ⁇ itrobenzothiazol-2-yl)nicotinamide (0.50 g, 1.67 mmol) was dissolved in " dimethylsulfoxide (50 mL) by warming. After addition of palladium on charcoal (0.089 g, 10 % Pd, 0.08 mmol Pd), the mixture was hydrogenated for 5.5 h at 80°C. The palladium was removed by hot filtration through a pad of silica. After removal of the solvent, N-(6- aminobenzothiazol-2-yl)nicotinamide (0.45 g, 1.67 mmol, 100 %) was obtained as a brownish solid.
  • Step 3 A mixture of 2-amino-5-nitrobenzothiazole (1.52 g, 7.8 mmol), benzoyl chloride (1.36 mL, 11.7 mmol) and pyridine (15 mL) was heated to 6O 0 C for 24 h. The mixture was poured into water (250 mL), and the resulting precipitate was separated by filtration to yield 7V-(5-nitrobenzothiazol-2-yl)benzamide (1.83 g, 6.12 mmol, 78 %) as a yellow solid.
  • Step 4 A mixture of N-(5-nitrobenzothiazol-2-yl)benzamide (1.79 g, 6.00 mmol) and palladium on charcoal (0.95 g, 10 % Pd, 0.9 mmol Pd) in dimethylformamide (40 mL) was hydrogenated (1 bar) for 2 h at 100°C. The palladium was removed by filtration through a pad of celite and the filtrate was concentrated to a small volume. Upon addition of water (200 mL), a precipitate formed which was separated by filtration. There was thus obtained iV-(5-aminobenzothiazol-2-yl)benzamide (1.39 g, 5.14 mmol, 86 %) as a grey solid.
  • Step 3 In a 1 1 Schlenk flask filled with argon, methyl 4-benzyloxy-5-methoxy-2-nitroben- zoate (11.60 g, 36.6 mmol) and palladium on charcoal (1.17 g, 10 % Pd, 1.1 mmol Pd) were combined and tetrahydrofuran (250 mL) was added. The argon was replaced with hydrogen (1 bar), and the mixture was vigorously stirred at r.t. until completion of the reaction.
  • Step 4 A mixture of formamide (29 mL), ammonium formate (3.41 g, 54 mmol) and methyl 2-amino-4-hydroxy-5-methoxybenzoate (6.56 g, 36.0 mmol) was heated to 140°C for 4 h. After cooling to r.t., water (75 mL) was added. After stirring for 1 h, the precipitated 7-hydroxy-6-methoxy-3,4-dihydroquinazolin-4-one was filtered off, washed with water and dried (grey solid, 5.86 g, 30.5 mmol, 85 %).
  • Step 5 A mixture of 7-hydroxy-6-methoxy-3,4-dihydroquinazolin-4-one (5.86 g, 30.5 mmol) and acetic anhydride (21.5 mL, 229 mmol) in pyridine (4.9 mL, 61 mmol) was heated to 100°C for 4 h. After cooling to r.t., ice water (200 mL) was added and the mixture was vigorously stirred for 1 h. The precipitated 7-acetoxy-6-methoxy-3,4- dihydroquinazolin-4-one was filtered off, washed with water and dried (grey solid, 6.64 g,
  • Step 6 7-Acetoxy-6-methoxy-3,4-dihydroquinazolin-4-one (2.34 g, 10.0 mmol) was converted into 4-chloro-7-hydroxy-6-methoxyquinazoline (1.22 g, 5.79 mmol, 58 %) as described in WO 04/043472, page 32.
  • Di-tert-butyl azodicarboxylate (0.478 g, 2.08 mmol) was added portionwise to a mixture of 4-chloro-7-hydroxy-6-methoxyquinazoline (0.350 g, 1.66 mmol), 3-(4-methyl- piperazin-l-yl)-propan-l-ol (Intermediate 9, 0.276 g, 1.74 mmol), and triphenylphosphine (0.544 g, 2.08 mmol) in dichloromethane (20 mL) at r.t.. If necessary, further alcohol was added.
  • Step 1 Methyl isovanillate (2.73 g, 15 mmol) was converted into methyl 3-benzyloxy-4- methoxybenzoate (3.91 g, 14.4 mmol, 96 %) in analogy to the preparation of Intermediate 7, Step 1.
  • 3-Bromopro- panol (2.62 mL, 30 mmol) was added slowly and the mixture was stirred overnight at r.t. After heating to 80°C for 2 h and cooling to r.t., the mixture was filtered and the filter cake was thoroughly washed with toluene. After removal of the solvent, the residue was subjected to distillation (b.p., 18O 0 C / 2 mbar) to obtain a colourless oil (4.08 g, 25.8 mmol, 86 %).
  • Example 1 iV-[6-(6,7-Dimethoxyquinazolin-4-ylamino)benzoxazol-2-yl]benzamide was prepared by heating a mixture of N-(6-aminobenzoxazol-2-yl)benzamide (IM I 5 30 mg, 0.118 mmol) and 4-chloro-6,7-dimethoxyquinazoline (Fluorochem, 26.5 mg, 0.118 mmol) in ethanol (3 mL) to 80°C for 2 h. The resulting precipitate was separated by filtration, washed with ethanol and dried (yellow solid, 38 mg, 85 ⁇ mol, 72 %).
  • Example 3 N-[6-(6,7-Dimethoxyquinazolin-4-ylamino)benzothiazol-2-yl]isonicotinamide was prepared by heating a mixture of N-(6-aminobenzothiazol-2-yl)isonicotinamide (Intermediate 3, 50 mg, 0.185 mmol) and 4-chloro-6,7-dimethoxyquinazoline (Fluorochem, 42 mg, 0.185 mmol in ethanol (3 mL) to 80°C for 2 h. The resulting precipitate was separated by filtration, washed with ethanol and dried (yellow solid, 82 mg, 0.179 mmol, 97 %).
  • Example 4 N-[6-(6,7-Dimethoxyquinazolin-4-ylamino)benzothiazol-2-yl]nicotinamide was prepared by heating a mixture of N-(6-aminobenzothiazol-2-yl)nicotinamide (IM 4, 30 mg, 0.111 mmol) and 4-chloro-6,7-dimethoxyquinazoline (Fluorochem, 25 mg, 0.111 mmol) in ethanol (3 mL) to 80°C for 2 h. The resulting precipitate was separated by filtration, washed with ethanol and dried (yellow solid, 44 mg, 96 ⁇ mol, 87 %).
  • Example 5 N-(6- ⁇ 6-Methoxy-7-[3-(4-methylpiperazin-l-yl)propoxy]quinazolin-4-yl- amino ⁇ benzothiazol-2-yl)benzamide was prepared by heating a mixture of N-(6-amino- benzothiazol-2-yl)benzamide (IM 2, 30 mg, 0.111 mmol), 4-chloro-6-methoxy-7-[3-(4- methylpiperazin-l-yl)propoxy]quinazoline (Intermediate 7, 39 mg, 0.111 mmol), ethyldiisopropylamine (40 ⁇ L, 0.222 mmol), and HCl (84 ⁇ L, 4 M solution in dioxane, 0.333 mmol) in r ⁇ -butanol (3 mL) to HO 0 C for 2 h.
  • Example 7 N-[6-(Purin-6-ylamino)benzothiazol-2-yl]benzamide was prepared by heating a mixture of iV-(6-aminobenzothiazol-2-yl)benzamide (IM 2, 50 mg, 0.186 mmol) and 6- chloropurine (29 mg, 0.186 mmol) in ethanol (3 ml) to 80°C for 4 h. The resulting precipitate was separated by filtration and washed with ethanol (69 mg, 0.178 mmol, 96 %).
  • Example 8 N-[6-(Purin-6-ylamino)benzothiazol-2-yl]benzamide was prepared by heating a mixture of iV-(6-aminobenzothiazol-2-yl)benzamide (IM 2, 50 mg, 0.186
  • Example 10 N-[5-(6,7-Dimethoxyquinazolin-4-ylamino)benzothiazol-2-yl]benzamide was prepared by heating a mixture of N-(5-aminobenzothiazol-2-yl)benzamide (IM; 5, 30 mg, 0.111 mmol) and 4-chloro-6,7-dimethoxyquinazoline (Fluorochem, 25 mg, 0.111 mmol) in ethylene glycol (0.7 mL) to 100 0 C for 2 h. Brine (25 mL) and saturated sodium hydrogencarbonate solution (25 mL) were added and the product was extracted with chloroform (3 x 40 mL).
  • IM N-(5-aminobenzothiazol-2-yl)benzamide
  • Fluorochem 4-chloro-6,7-dimethoxyquinazoline
  • Example 11 N-[5-(Purin-6-ylamino)benzothiazol-2-yl]benzamide was prepared by heating a mixture of iV-(5-aminobenzothiazol-2-yl)benzamide (IM 5, 50 mg, 0.186 mmol) and 6-chloropurine (29 mg, 0.186 mmol) in ethanol (3 ml) to 80°C for 4 h. The resulting precipitate was separated by filtration and washed with ethanol (68 mg, 0.174 mmol, 94 %).
  • Example 12 N- ⁇ 5-[4-(4-Methylpiperazin-l-yl)pyrimidin-2-ylamino]benzothia2ol-2-yl ⁇ benza ⁇ iide was prepared by heating a mixture of N-(5-aminobenzothiazol-2-yl)benzamide (IM 5, 50 mg, 0.186 mmol) and 2-chloro-4-(4-methylpiperazinl-yl)pyrimidine (IM 10, 40 mg, 0.186 mmol) in ethanol (3 mL) to 80°C for 4 days.
  • IM 5 N-(5-aminobenzothiazol-2-yl)benzamide
  • 2-chloro-4-(4-methylpiperazinl-yl)pyrimidine IM 10, 40 mg, 0.186 mmol
  • N- ⁇ 5 - [4-(5 -Methylpyrazol-3 -ylamino)pyrimidin-2-ylamino]benzothiazol-2-yl ⁇ benzamide was prepared by heating a mixture of iV-(5-aminobenzothiazol-2-yl)benzamide (IM 5, 35 mg, 0.13 mmol) and (2-cUoropyrimidin-4-yl)-(5-methylpyrazol-3-yl)amine (IM 11, 30 mg, 0.143 mmol) in ethanol (3 mL) to 80°C for 9 h. The precipitate was separated by filtration, washed with ethanol and dried (32 mg, 72 ⁇ mol, 56 %).
  • Example 15 N-(6- ⁇ 6-Methoxy-7-[3-(4-methyl-piperazin-l-yl)-propoxy]-quinazolin-4- ylamino ⁇ -benzooxazol-2-yl)-benzamide was prepared by reaction of intermediate 1 (0.138 mM) with intermediate 7 (0.138 mM) in butanol (3 mL) under acidic katalysis (3.0 eq., 0.105 mL, 4 M HCl in Dioxane) at 110 °C. The reaction was finished after 5 h. After cooling the reaction was partitioned between saturated aqueous NaHCO 3 solution and ethyl acetate.
  • Example 16 N-(5- ⁇ 7-Methoxy-6-[3-(4-methyl-piperazin-l-yl)-propoxy]-quinazolin-4- ylamino ⁇ -benzothiazol-2-yl)-benzamide was prepared by heating a mixture of 7V-(5- aminobenzothiazol-2-yl)benzamide (IM 5, 35 mg, 0.13 mmol), 4-chloro-7-methoxy-6-[3- (4-methylpiperazin-l-yl)propoxy]quinazoline (IM 8, 46 mg, 0.13 mmol) and 4 M HCl in dioxane (0.09 mL, 0.39 mmol) in / ⁇ -butanol (3 mL) to 110°C for 5 h.
  • 7V-(5- aminobenzothiazol-2-yl)benzamide IM 5, 35 mg, 0.13 mmol
  • Example 17 N-(5 - ⁇ 6-Methoxy-7- [3 -(4-methyl-piperazin- 1 -yl)-propoxy] -quinazolin-4- ylamino ⁇ -benzothiazol-2-yl)-benzamide was prepared according to the procedure described for example 15 from intermediate 5 and intermediate 7.
  • Example 18 3-Chloro-N-(6- ⁇ 6-methoxy-7-[3-(4-methyl-piperazin-l-yl)-propoxy]- quinazolin-4-ylamino ⁇ -benzothiazol-2-yl)-benzamide was prepared by reaction of intermediate 12 (30 mg, 58 ⁇ mol) with 3-chloro-benzoyl chloride (8 ⁇ L, 63 ⁇ mol) in a mixture of pyridine and DMF (1:1, 4 mL total) in the presence of triethylamine (100 ⁇ L, 0.71 mmol) at 60 °C. The reaction was controlled several times, if necessary further acid chloride was added.
  • Example 19 3 -Chloro-N-(5 - ⁇ 6-methoxy-7- [3 -(4-methyl-piperazin- 1 -yl)-propoxy] - quinazolin-4-ylamino ⁇ -benzothiazol-2-yl)-benzamide was prepared following the procedure described for example 18 starting from intermediate 13.
  • Example 20 l-(4-Chloro-3-trifluoromethyl-phenyl)-3-(6- ⁇ 6-methoxy-7-[3-(4-methyl- piperazin-l-yl)-propoxy]-quinazolin-4-ylamino ⁇ -benzothiazol-2-yl)-urea was prepared by reaction of intermediate 12 (58 ⁇ mol, 30 mg) with l-chloro-4-isocyanato-2- trifluoromethyl-benzene (13 mg, 58 ⁇ mol) in dichloromethane in the presence of triethylamine (5 drops). The product was purified by prep. HPLC (5 mg, 15% yield).
  • Example 21 l-(4-Chloro-3-trifluoromethyl-phenyl)-3-(5- ⁇ 6-methoxy-7-[3-(4-methyl- piperazin- 1 -yl)-propoxy] -quinazolin-4-ylamino ⁇ -benzothiazol-2-yl)-urea was prepared according to the procedure described for example 20 starting from intermediate 13.
  • Example 22 l-(2-Methoxy-5-methyl-phenyl)-3-(6- ⁇ 6-methoxy-7-[3-(4-methyl-piperazin- l-yl)-propoxy]-quinazolin-4-ylamino ⁇ -benzothiazol-2-yl)-urea was prepared according to the procedure described for example 20 starting from intermediate 12 and 2-isocyanato-l- methoxy-4-methyl-benzene.
  • Example , 23 l-(6- ⁇ 6-Methoxy-7-[3-(4-methyl-piperazin-l-yl)-propoxy]-quinazolin-4- ylamino ⁇ -benzothiazol-2-yl)-3-(2-methoxy-phenyl)-urea was prepared according to the procedure described for example 20 starting from intermediate 12 and l-isocyanato-2- methoxy-benzene.
  • Example 24 1 - ⁇ 6- [6-(2-Hydroxy-ethylamino)-pyrimidin-4-ylamino] -benzothiazol-2-yl ⁇ - 3-(2-methoxy-5-methyl-phenyl)-urea was prepared by heating a mixture of IM 14 (100 mg, 0.227 mmol) and 3-aminoethanol (1 mL) at 85°C for 3 h. The product was precipitated by the addition of water (47 mg, 45 %).
  • Example 25 l- ⁇ 6-[6-(3-Hydroxy-propylamino)-pyrimidin-4-ylamino]-benzothiazol-2- yl ⁇ -3-(2-methoxy-5-methyl-phenyl)-urea was prepared by heating a mixture of IM 14 (100 mg, 0.227 mmol) and 3-aminopropanol (1 mL) at 85°C for 3 h. The product was precipitated by the addition of water (42 mg, 39 %).
  • Protein Kinase Assay The effect of the benzazole derivatives was tested on recombinant, human protein kinases. All protein kinases were expressed in Sf9 insect cells as human recombinant GST-fusion proteins or as His-tagged proteins by means of the baculovirus expression system. Protein kinases were purified by affinity chromatography using either GSH-agarose or Ni-NTH- agarose. The purity and identity of each was checked by SDS-P AGE/silver staining and by western blot analysis with specific antibodies.
  • a proprietary protein kinase assay ( 33 PanQinase ® Activity Assay) was used for measuring the kinase activity. All kinase assays were performed in 96-well FlashPlatesTM in a 50 ⁇ l reaction volume. The assay for all enzymes contained 60 mM HEPES-NaOH, pH 7.5, 3 mM MgCl 2 , 3 mM MnCl 2 , 3 ⁇ M Na-orthovanadate, 1.2 mM DTT, 50 ⁇ g/ml PEG 2000O and 1 ⁇ M [ ⁇ - 33 P]-ATP (approx. 5x10 5 cpm per well).
  • reaction cocktails were incubated at 30 0 C for 80 minutes.
  • the reaction was stopped with 50 ⁇ l of 2% (v/v) H 3 PO 4 , plates were aspirated and washed two times with 200 ⁇ l of 0.9% (w/v) NaCl.
  • Incorporation of 33 Pi was determined with a microplate scintillation counter. All assays were performed with a BeckmanCoulter/ Sagian robotic system.
  • RTKs receptor tyrosine kinases
  • Sigmoidal inhibitor curves based on relative inhibition compared with phosphorylation levels under high control conditions were generated which allowed the determination of IC 50 values for each test compound.
  • Endoreduplication is detectable in cells as DNA-content higher then 4 n.
  • HT29 colon-carcinoma cells were treated with test compounds at different concentrations for 3 days. On day 5 cells were harvested and fixed in methanol.
  • RNAse A and PL Incorporated PI was detected by FACS measuring fluorescence emission at 650 nm upon excitation at 488 nm.
  • HT-29 colon-carcinoma cells were seeded on day 1 and on day 2 test compounds at different concentrations were added. Cells were incubated with test compounds for 1 hour. Subsequently, Calyculin A was added for 30 min.
  • DELFIA®- detection PerkinElmer
  • HisH3-pS10 lysates were transferred to a microtiterplate and incubated with detecting antibody directed against HisH3-pS10 and Europium-labelled secondary anti-IgG-antibody. Emission at 615 nm was measured upon excitation at 340 nm and the percentage of inhibition was calculated for each concentration of the test compounds relative to controls without inhibitor. Mean values of HisH3-pS10 percentage were plotted versus compound concentration for calculation of ICs O -values.
  • the following examples show ICs 0 values lower than 500 nM on at least one kinase selected from Aurora A, Aurora B, EGF-R, ERBB2, PDGFR, IGFl-R, VEGF-R2, VEGF- R3, EPHB4, Tie2, and SRC or display a beneficial activity profile by inhibiting at least two kinases from at least two different molecular mechanisms of tumor progression with IC 50 values lower than 500 nM: 1, 2, 5, 6, 9, 11, 15, 17, 18, 20, 21, 22.
  • the compounds of the present invention show IC 50 values lower than 10 ⁇ M in the Cellular Receptor Tyrosine Kinase Assays and / or the Cellular Aurora-B Kinase Assays.

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Abstract

La présente invention concerne des composés ayant les formules générales (I), (Ia) et (II) et leurs sels et dérivés physiologiquement fonctionnels, dans lesquels les substituants Y sont fixés sur la position 5 ou 6 du benzazole.
EP05824907A 2004-12-27 2005-12-22 Dérivés benzazoles 2,5- et 2-6-disubstitués utiles comme des inhibiteurs de la proteine kinase Withdrawn EP1833823A1 (fr)

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EP04030819A EP1674466A1 (fr) 2004-12-27 2004-12-27 Derives benzazoles 2,5- et 2-6-disubstitues utiles comme des inhibiteurs de la proteine kinase
EP05824907A EP1833823A1 (fr) 2004-12-27 2005-12-22 Dérivés benzazoles 2,5- et 2-6-disubstitués utiles comme des inhibiteurs de la proteine kinase
PCT/EP2005/013922 WO2006069740A1 (fr) 2004-12-27 2005-12-22 Analogues du benzazole disubstitues en 2,5 et 2,6 utiles en tant qu’inhibiteurs de la proteine kinase

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EP2152700B1 (fr) 2007-05-21 2013-12-11 Novartis AG Inhibiteurs du csf-1r, compositions et procédés d'utilisation
FR2922550B1 (fr) * 2007-10-19 2009-11-27 Sanofi Aventis Nouveaux derives de 6-aryl/heteroalkyloxy benzothiazole et benzimidazole, application comme medicaments, compositions pharmaceutiques et nouvelle utilisation notamment comme inhibiteurs de cmet
FR2933982A1 (fr) * 2008-07-18 2010-01-22 Sanofi Aventis Nouveaux derives imidazo°1,2-a!pyrimidine, leur procede de preparation, leur application a titre de medicaments, compositions pharmaceutiques et nouvelle utilisation notamment comme inhibiteurs de met
FR2933981A1 (fr) * 2008-07-18 2010-01-22 Sanofi Aventis NOUVEAUX DERIVES IMIDAZO°1,2-a!PYRIDINE, LEUR PROCEDE DE PREPARATION, LEUR APPLICATION A TITRE DE MEDICAMENTS, COMPOSITIONS PHARMACEUTIQUES ET NOUVELLE UTILISATION NOTAMMENT COMME INHIBITEURS DE MET
FR2933980B1 (fr) * 2008-07-18 2011-07-29 Sanofi Aventis Nouveaux derives triazolo°4,3-a!pyridine, leur procede de preparation, leur application a titre de medicaments, compositions pharmaceutiques et nouvelle utilisation notamment comme inhibiteurs de met
WO2010010435A2 (fr) * 2008-07-22 2010-01-28 Glenmark Pharmaceutical S.A. Dérivés oxazole et thiazole fusionnés en tant que modulateurs de trpm8
WO2011033094A1 (fr) 2009-09-18 2011-03-24 4Sc Ag Calendrier de l'administration de dérivés de benzazole dans le traitement de leucémies
PL2730564T3 (pl) 2010-11-19 2018-09-28 Ligand Pharmaceuticals Inc. Heterocykliczne aminy i ich zastosowania
WO2013174735A1 (fr) 2012-05-21 2013-11-28 Bayer Pharma Aktiengesellschaft Benzothienopyrimidines substituées
TW201412740A (zh) * 2012-09-20 2014-04-01 Bayer Pharma AG 經取代之吡咯并嘧啶胺基苯并噻唑酮
US10807983B2 (en) 2015-03-16 2020-10-20 Ligand Pharmaceuticals, Inc. Imidazo-fused heterocycles and uses thereof
KR20180088113A (ko) * 2017-01-26 2018-08-03 한미약품 주식회사 이미다조피리다진 화합물

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9900752D0 (en) * 1999-01-15 1999-03-03 Angiogene Pharm Ltd Benzimidazole vascular damaging agents
US7238813B2 (en) * 2000-11-29 2007-07-03 Smithkline Beecham Corporation Chemical compounds
MXPA04008458A (es) * 2002-03-01 2004-12-06 Smithkline Beecham Corp Diamino pirimidinas y su uso como inhibidores de angiogenesis.
EA007987B1 (ru) * 2002-03-29 2007-02-27 Чирон Корпорейшн Замещённые бензазолы и их применение в качестве ингибиторов киназы raf
US7531553B2 (en) * 2003-03-21 2009-05-12 Amgen Inc. Heterocyclic compounds and methods of use
SI2392565T1 (sl) * 2003-09-26 2014-05-30 Exelixis, Inc. c-Met modulatorji in postopki uporabe
AU2005207946A1 (en) * 2004-01-23 2005-08-11 Amgen Inc. Quinoline quinazoline pyridine and pyrimidine counds and their use in the treatment of inflammation angiogenesis and cancer

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2006069740A1 *

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UA92730C2 (ru) 2010-12-10
MX2007007897A (es) 2008-01-11
BRPI0519479A2 (pt) 2009-02-03
CA2592509A1 (fr) 2006-07-06
AU2005321517B2 (en) 2011-09-29
JP2008525361A (ja) 2008-07-17

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