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    公开号:AU2006275160A1
    申请号:U2006275160
    申请日:2006-06-30
    公开日:2007-02-08
    发明作者:Gerhard Barnickel；Ulrich Emde；Hartmut Greiner；Werner Mederski；Frank Stieber；Frank Zenke
    申请人:Merck Patent GmbH；
    IPC主号:C07C255-22
    专利说明:
    WO 2007/014607 PCT/EP2006/006378 -1 SQUARIC ACID DERIVATIVES AS PROTEIN KINASE INHIBITORS BACKGROUND OF THE INVENTION 5 The present invention relates to compounds and to the use of compounds in which the inhibition, regulation and/or modulation of signal transduction by kinases, in particular tyrosine kinases and/or serine/threonine kinases, 10 plays a role, furthermore to pharmaceutical compositions which comprise these compounds, and to the use of the compounds for the treatment of kinase-induced diseases. The present invention relates to compounds in which the inhibition, regula 15 tion and/or modulation, in particular, of CHK1 and CHK2 kinase and of the cell volume-regulated human kinase h-sgk (human serum and glucocorti coid dependent kinase or SGK) plays a role, furthermore to pharmaceuti cal compositions which comprise these compounds, and to the use of the 20 compounds for the treatment of CHK1-, CHK2- and SGK-induced dis eases. Cell cycle checkpoints are regulatory pathways that control the sequence 25 and timing of cell cycle transitions. They ensure that important events, 25 such as DNA replication and chromosome segregation, are completed with high reliability. The control of these cell cycle checkpoints is an important determinant of the manner in which tumour cells respond to many chemo therapies and radiation. Many effective cancer therapies work by causing 30 DNA damage; however, resistance to these agents remains a considerable limitation in the treatment of cancer. There are various mechanisms of drug resistance; an important one is attributed to the prevention of cell cycle progression through the control of critical activation of a checkpoint 35 pathway that arrests the cell cycle to provide time for repair and induces WO 2007/014607 PCT/EP2006/006378 -2 the transcription of genes to facilitate repair, thereby avoiding immediate cell death. There are two of these checkpoints in the cell cycle - the G1/S checkpoint, 5 which is controlled by p53, and the G2/M checkpoint, which is monitored by the Ser/Thr kinase checkpoint kinase 1 (CHK1). By abrogating checkpoint arrests at, for example, the G2 checkpoint, it may be possible to synergistically improve tumour cell death induced by DNA damage and circumvent resistance. (Shyjan et al., U.S. Patent 10 6,723,498 (2004)). Human CHK1 plays a role in controlling cell cycle arrest by phosphorylating the phosphatase cdc25 on serine 216, which may pos sibly be involved in preventing activation of cdc2/cyclin B and initiating mitosis. (Sanchez et al., Science, 277:1497 (1997)). Inhibition of CHK1 15 should therefore enhance the action of DNA-damaging substances by ini tiating mitosis before DNA repair is complete, and thereby causing tumour cell death. An approach to the design of chemosensitisers which abrogate the G2/M 20 checkpoint consists in developing inhibitors of the key G2/M regulatory 20 kinase CHK1. The fact that this approach works has been demonstrated in a number of proof-of-concept studies (Koniaras et al., Oncogene, 2001, 20:7453; Luo et al., Neoplasia, 2001, 3:411; Busby et al., Cancer Res., 2000, 60:2108; Jackson et al., Cancer Res., 2000, 60:566). 25 A further essential checkpoint kinase that may be mentioned, which plays a crucial role in p53-dependent apoptosis, is CHK2. The inhibition of CHK2 can protect normal sensitive tissue against chemotherapeutic agents (B.-B 30 S. Zhou et al., Progress in Cell Cycle Research, Vol. 5, 413-421, 2003). It can be shown for compounds of the formula I that they inhibit the check point kinase activity. It can be shown for checkpoint kinase inhibitors that 35 they enable the cells to advance inappropriately to the metaphase of mito sis, which results in apoptosis of the cells concerned, and therefore have WO 2007/014607 PCT/EP2006/006378 -3 antiproliferative actions. The compounds of the formula I can be used for the treatment of neoplastic disease. The compounds of the formula I and salts thereof can be used against neoplastic diseases, such as carcinoma 5 of the brain, breast, ovaries, lung, intestine, prostate, skin or other tissue, 5 and against leukaemia and lymphomas, tumours of the central and periph eral nervous system and other types of tumour, such as melanoma, sar coma, fibrosarcoma and osteosarcoma. The compounds of the formula I are also suitable for the treatment of other proliferative diseases. The com 10 pounds of the formula I can also be used in combination with a broad range of DNA-damaging agents, but can also be used as individual sub stance. 15 The present invention therefore relates to the use of the compounds of the formula I for the treatment of diseases or conditions in which inhibition of CHK1 and/or CHK2 activity is advantageous. 20 Like CHK1 and CHK2, SGK belongs to the serine/threonine kinases. 20 The present invention furthermore relates to the use of the compounds of the formula I, where the inhibition, regulation and/or modulation of signal transduction of the cell volume-regulated human kinase H-SGK (human 25 serum and glucocorticoid dependent kinase or SGK) plays a role, for the treatment of SGK-induced diseases. SGKs with the isoforms SGK-1, SGK-2 and SGK-3 are a serine/threonine 30 protein kinase family (WO 02/17893). The compounds according to the invention are inhibitors of SGK-1. They may furthermore be inhibitors of SGK-2 and/or SGK-3. The present invention thus relates to the use of the compounds of the for 35 mula I which inhibit, regulate and/or modulate SGK signal transduction, to compositions which comprise these compounds, and to processes for the WO 2007/014607 PCT/EP2006/006378 -4 use thereof for the treatment of SGK-induced diseases and complaints, such as diabetes (for example diabetes mellitus, diabetic nephropathy, diabetic neuropathy, diabetic angiopathy and microangiopathy), obesity, 5 metabolic syndrome (dyslipidaemia), systemic and pulmonary hypertonia, 5 cardiovascular diseases (for example cardiac fibroses after myocardial infarction, cardiac hypertrophy and cardiac insufficiency, arteriosclerosis) and renal diseases (for example glomerulosclerosis, nephrosclerosis, nephritis, nephropathy, electrolyte excretion disorder), generally in fibroses 10 and inflammatory processes of any type (for example liver cirrhosis, pul monary fibrosis, fibrosing pancreatitis, rheumatism and arthroses, Crohn's disease, chronic bronchitis, radiation fibrosis, sclerodermatitis, cystic fibro sis, scarring, Alzheimer's disease). 15 The compounds according to the invention can also inhibit the growth of tumour cells and tumour metastases and are therefore suitable for tumour therapy. The compounds according to the invention are furthermore used for the 20 treatment of coagulopathies, such as, for example, dysfibrinogenaemia, 20 hypoproconvertinaemia, haemophilia B, Stuart-Prower defect, prothrombin complex deficiency, consumption coagulopathy, hyperfibrinolysis, immuno coagulopathy or complex coagulopathies, and also in neuronal excitability, for example epilepsy. The compounds according to the invention can also 25 be employed therapeutically in the treatment of glaucoma or a cataract. The compounds according to the invention are furthermore used in the treatment of bacterial infections and in antiinfection therapy. The com pounds according to the invention can also be employed therapeutically for 30 increasing learning ability and attention. In addition, the compounds according to the invention counter cell ageing and stress and thus increase life expectancy and fitness in the elderly. The compounds according to the invention are furthermore used in the treatment of tinnitus. 35 WO 2007/014607 PCT/E P2006/006378 -5 The identification of small compounds which inhibit, regulate and/or modu late SGK signal transduction is therefore desirable and an aim of the present invention. 5 It has been found that the compounds according to the invention and salts thereof have very valuable pharmacological properties while being well tol erated. Thus, they also exhibit SGK-inhibiting properties. 10 The present invention therefore relates to compounds according to the in vention as medicaments and/or medicament active ingredients in the treat ment and/or prophylaxis of the said diseases and to the use of compounds 15 according to the invention for the preparation of a pharmaceutical for the treatment and/or prophylaxis of the said diseases and also to a process for the treatment of the said diseases which comprises the administration of one or more compounds according to the invention to a patient in need of such an administration. 20 The host or patient may belong to any mammal species, for example a primate species, particularly humans; rodents, including mice, rats and hamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are of 25 interest for experimental investigations, where they provide a model for the treatment of a human disease. For identification of a signal transduction pathway and for detection of 30 interactions between various signal transduction pathways, various scien tists have developed suitable models or model systems, for example cell culture models (for example Khwaja et al., EMBO, 1997, 16, 2783-93) and models of transgenic animals (for example White et al., Oncogene, 2001, 35 20, 7064-7072). For the determination of certain stages in the signal trans 35 duction cascade, interacting compounds can be utilised in order to modu late the signal (for example Stephens et al., Biochemical J., 2000, 351, WO 2007/014607 PCT/EP2006/006378 -6 95-105). The compounds according to the invention can also be used as reagents for testing kinase-dependent signal transduction pathways in ani mals and/or cell culture models or in the clinical diseases mentioned in this application. 5 Measurement of the kinase activity is a technique which is well known to the person skilled in the art. Generic test systems for the determination of the kinase activity using substrates, for example histone (for example 10 Alessi et al., FEBS Lett. 1996, 399, 3, pages 333-338) or the basic myelin protein, are described in the literature (for example Campos-Gonzalez, R. and Glenney, Jr., J.R. 1992, J. Biol. Chem. 267, page 14535). 15 Various assay systems are available for identification of kinase inhibitors. In the scintillation proximity assay (Sorg et al., J. of. Biomolecular Screen ing, 2002, 7, 11-19) and the flashplate assay, the radioactive phosphoryla tion of a protein or peptide as substrate is measured using yATP. In the 20 presence of an inhibitory compound, a reduced radioactive signal, or none at all, can be detected. Furthermore, homogeneous time-resolved fluores cence resonance energy transfer (HTR-FRET) and fluorescence polarisa tion (FP) technologies are useful as assay methods (Sills et al., J. of Bio molecular Screening, 2002, 191-214). 25 Other non-radioactive ELISA assay methods use specific phospho anti bodies (phospho ABs). The phospho AB only binds the phosphorylated substrate. This binding can be detected by chemoluminescence using a second peroxidase-conjugated antisheep antibody (Ross et al., Biochem. 30 30 J., 2002, 366, 977-981). PRIOR ART 35 Other squaric acid derivatives are described as CXC chemokine receptor antagonists in WO 03/080053 Al and WO 02/083624 Al.
    WO 2007/014607 PCT/EP2006/006378 -7 WO 01/64208 discloses other squaric acid amides for the treatment of various diseases. Heterocyclic squaric acid amides are described as muscle relaxants in US 5,605,909, US 5,532,245 and US 5,466,712. 5 Substituted thiophene derivatives are described as CHK1 inhibitors in WO 2005/016909 Al. Other heterocyclic CHK1 inhibitors for combating cancer are disclosed in WO 2005/028474 A2. Aminopyrazole compounds 10 are described as CHK1 inhibitors in WO 2005/009435 Al. WO 00/62781 describes the use of medicaments comprising inhibitors of cell volume-regulated human kinase H-SGK. 15 The use of kinase inhibitors in antiinfection therapy is described by C. Doerig in Cell. Mol. Biol. Lett. Vol.8, No. 2A, 2003, 524-525. The use of kinase inhibitors in obesity is described by N.Perrotti in J. Biol. Chem. 2001, March 23; 276(12):9406-9412. 20 The following references suggest and/or describe the use of SGK inhibi tors in disease treatment: 25 1: Chung EJ, Sung YK, Farooq M, Kim Y, Im S, Tak WY, Hwang YJ, Kim YI, Han HS, Kim JC, Kim MK. Gene expression profile analysis in human hepatocellular carcinoma by cDNA microarray. Mol Cells. 2002;14:382-7. 30 2: Brickley DR, Mikosz CA, Hagan CR, Conzen SD. Ubiquitin modification of serum and glucocorticoid-induced protein kinase-1(SGK-1). J Biol Chem. 2002;277:43064-70. 35 3: Fillon S, Klingel K, Warntges S, Sauter M, Gabrysch S, Pestel S, Tan 35neur V, Waldegger S, Zipfel A, Viebahn R, Haussinger D, Broer S, Kandolf neur V, Waldegger 5, Zipfel A, Viebahn R, Haussinger D, Broer 5, Kandolf WO 2007/014607 PCT/EP2006/006378 -8 R, Lang F. Expression of the serine/threonine kinase hSGK1 in chronic viral hepatitis. Cell Physiol Biochem. 2002;12:47-54. 5 4: Brunet A, Park J, Tran H, Hu LS, Hemmings BA, Greenberg ME. Protein 5 kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a). Mol Cell Biol 2001;21:952-65 5: Mikosz CA, Brickley DR, Sharkey MS, Moran TW, Conzen SD. Gluco 10 corticoid receptor-mediated protection from apoptosis is associated with induction of the serine/threonine survival kinase gene, sgk-1. J Biol Chem. 2001;276:16649-54. 15 6: Zuo Z, Urban G, Scammell JG, Dean NM, McLean TK, Aragon I, Hon kanen RE. Ser/Thr protein phosphatase type 5 (PP5) is a negative regu lator of glucocorticoid receptor-mediated growth arrest. Biochemistry. 1999;38:8849-57. 20 7: Buse P, Tran SH, Luther E, Phu PT, Aponte GW, Firestone GL. Cell cycle and hormonal control of nuclear-cytoplasmic localisation of the serum- and glucocorticoid-inducible protein kinase, Sgk, in mammary tumour cells. A novel convergence point of anti-proliferative and prolifera 25 tive cell signalling pathways. J Biol Chem. 1999;274:7253-63. 8: M. Hertweck, C. Gobel, R. Baumeister: C.elegans SGK-1 is the critical component in the Akt/PKB Kinase complex to control stress response and 30 life span. Developmental Cell, Vol. 6, 577-588, April, 2004. SUMMARY OF THE INVENTION 35 The invention relates to compounds of the formula I WO 2007/014607 PCT/EP2006/006378 -9
    R
    2 O 0O
    R
    1 -I 5 N N-X H / R R 5 - R 3
    R
    4 in which 10 R denotes phenyl or a mono- or bicyclic saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms, where the radicals may be mono-, di-, tri-, tetra- or pentasub stituted by Hal, A, CN, Ar, Het, CONH 2 , CONHA, CONAA', 15 NHCOA, NHCOAr, NHSO 2 A, NHSO 2 Ar, =S, =NH, =NA and/or =0 (carbonyl oxygen),
    (CH
    2 )m X denotes (CH 2 )n, CHA, NH, NA or /
    -C
    20 R 1 denotes H, OH or OA,
    R
    2 denotes H, A, Hal, -CO-A, CN, COOH, COOA or CONH 2 ,
    R
    3 denotes OH, OA, NH 2 , NHA, NAA', Hal, A, CONH 2 , CONHA, CONAA', CONHAr, CONHHet, SO 2
    NH
    2 , SO 2 NHA, SO 2 NAA', 25 SO 2 NHAr, SO 2 NHHet, NHSO 2 A, NHSO 2 Ar, NHSO 2 Het, NHCOA, NHCOAr, NHCOHet or B(OH 2 ),
    R
    4 denotes H, OH or F,
    R
    5 denotes H or methyl, Ar denotes phenyl, naphthyl or biphenyl, each of which is unsub 30 stituted or mono-, di-, tri-, tetra- or pentasubstituted by A, OA, OH, SH, SA, Hal, NO 2 , CN, (CH 2 )nAr', (CH 2 )nCOOH,
    (CH
    2 )nCOOA, CHO, COA, SO 2 A, CONH 2 , SO 2
    NH
    2 , CONHA, CONAA', SO 2 NHA, SO 2 NAA', NH 2 , NHA, NAA', OCONH 2 , 35 OCONHA, OCONAA', NHCOA, NHCOOA. NACOOA,
    NHSO
    2 OA, NASO 2 OA, NHCONH 2 , NACONH 2 , NHCONHA, WO 2007/014607 PCT/E P2006/006378 - 10 NACONHA, NHCONAA',NACONAA' and/or
    NHCO(CH
    2 )nNH 2 , Ar' denotes phenyl, naphthyl or biphenyl, each of which is unsub stituted or mono-, di- or trisubstituted by A, OA, OH, SH, SA, 5 Hal, NO 2 , CN, (CH 2 )nphenyl, (CH 2 )nCOOH, (CH 2 )nCOOA, CHO, COA, SO 2 A, CONH 2 , SO 2
    NH
    2 , CONHA, CONAA',
    SO
    2 NHA, SO 2 NAA', NH 2 , NHA, NAA', OCONH 2 , OCONHA, OCONAA', NHCOA, NHCOOA, NACOOA, NHSO 2 OA, 10
    NASO
    2 OA, NHCONH 2 , NACONH 2 , NHCONHA, NACONHA, NHCONAA' and/or NACONAA', Het denotes a mono- or bicyclic saturated, unsaturated or aro matic heterocycle having 1 to 4 N, O and/or S atoms, which 15 may be mono-, di- or trisubstituted by A, OA, OH, SH, SA, Hal, NO 2 , CN, (CH 2 )nAr', (CH 2 )nCOOH, (CH 2 )nCOOA, CHO, COA, SO 2 A, CONH 2 , SO 2
    NH
    2 , CONHA, CONAA', SO 2 NHA,
    SO
    2 NAA', NH 2 , NHA, NAA', OCONH 2 , OCONHA, OCONAA', NHCOA, NHCOOA, NACOOA, NHSO 2 OA, NASO 2 OA, 20
    NHCONH
    2 , NACONH 2 , NHCONHA, NACONHA, NHCONAA', NACONAA', SO 2 A, =S, =NH, =NA and/or =0O (carbonyl oxy gen), Het 1 denotes a monocyclic saturated heterocycle having 1 to 2 N 25 and/or O atoms, which may be mono- or disubstituted by A, OA, OH, Hal and/or =0 (carbonyl oxygen), A, A' each, independently of one another, denote alkyl having 1 to 10 C atoms, in which, in addition, 1-7 H atoms may be 30 replaced by F and/or chlorine, Hal denotes F, CI, Br or I, m denotes 2, 3, 4 or 5, n denotes 0, 1 or 2, and pharmaceutically usable derivatives, solvates, salts and stereoisomers 35 thereof, including mixtures thereof in all ratios.
    WO 2007/014607 PCT/EP2006/006378 -11 The invention also relates to the optically active forms (stereoisomers), the enantiomers, the racemates, the diastereomers, and the hydrates and sol vates of these compounds. Solvate of the compounds are taken to mean 5 adductions of inert solvent molecules onto the compounds which form owing to their mutual attractive force. Solvate are, for example, mono- or dihydrates or alcoholates. Pharmaceutically usable derivatives are taken to mean, for example, the 10 salts of the compounds according to the invention and also so-called pro drug compounds. Prodrug derivatives are taken to mean compounds of the formula I which have been modified with, for example, alkyl or acyl groups, sugars or 15 oligopeptides and which are rapidly cleaved in the organism to form the active compounds according to the invention. These also include biodegradable polymer derivatives of the compounds according to the invention, as is described, for example, in Int. J. Pharm. 115, 61-67 (1995). 20 The expression "effective amount" means the amount of a medicament or pharmaceutical active ingredient which causes a biological or medical response which is sought or aimed at, for example by a researcher or phy 25 sician, in a tissue, system, animal or human. In addition, the expression "therapeutically effective amount" means an amount which, compared with a corresponding subject who has not received this amount, has the following consequence: 30 improved treatment, healing, prevention or elimination of a disease, syn drome, condition, complaint, disorder or side effects or also the reduction in the progress of a disease, complaint or disorder. The expression "therapeutically effective amount" also encompasses the 35 amounts which are effective for increasing normal physiological function. 35 WO 2007/014607 PCT/EP2006/006378 -12 The invention also relates to the use of mixtures of the compounds of the formula I, for example mixtures of two diastereomers, for example in the ratio 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000. 5 These are particularly preferably mixtures of stereoisomeric compounds. The invention relates to the compounds of the formula I and salts thereof and to a process for the preparation of compounds of the formula I according to Claims 1-10 and pharmaceutically usable derivatives, salts, 10 solvates and stereoisomers thereof, characterised in that a compound of the formula II R2O 0 15 R 1 II N OA H R 20 in which R, R 1 and R 2 have the meanings indicated in Claim 1, and A denotes alkyl having 1-4 C atoms, is reacted with a compound of the formula III 25
    H
    2 N
    R
    3 30 3 30 in which X and R 3 have the meaning indicated in Claim 1, and/or a base or acid of the formula I is converted into one of its salts. 35 WO 2007/014607 PCT/E P200(6/006378 -13 Above and below, the radicals R, X, R 1, R and R 3 have the meanings indicated in the case of the formula I, unless expressly indicated otherwise. 5 A, A' denote alkyl, is unbranched (linear) or branched, and has 1, 2, 3, 4, 5 5, 6, 7, 8, 9 or 10 C atoms. A preferably denotes methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethyl propyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 10 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl, further preferably, for example, trifluoromethyl. A, A' very particularly preferably denotes alkyl having 1, 2, 3, 4, 5 or 6 C 15 atoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethyl or 1,1,1-trifluoro ethyl. 20 R preferably denotes phenyl or a mono- or bicyclic aromatic heterocycle 20 having 1 to 4 N, O and/or S atoms, which may be mono-, di-, tri-, tetra- or pentasubstituted by Hal, A, CN, Ar, Het, CONH 2 , CONHA, CONAA', NHCOA, NHCOAr, NHSO 2 A and/or NHSO 2 Ar. 25 In a further embodiment, R preferably denotes phenyl or a mono- or bicyclic aromatic heterocycle having 1 to 4 N and/or O atoms, which may optionally be mono-, di- or trisubstituted by A, Hal, CN, phenyl, OA, OH and/or COOA. 30 In a further embodiment, R preferably denotes phenyl, 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazo lyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 35 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or 5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4- WO 2007/014607 PCT/E P2006/006378 -14 thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-iso indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indazolyl, 1-, 5 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 5 6- or 7- benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, imidazo[4,5-c]pyridinyl, 1,2,3-triazolo[4,5-c]pyridinyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7 10 or 8-quinazolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo-1,4 oxazinyl, further preferably 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazol-4- or -5-yl or 2,1,3-benzoxadiazol-5-yl, 2,3-dihydro-2 , -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or 5-furyl, tetrahydro-2- or -3 15 furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrro lidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5 pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or -4 20 pyridyl, 1,2,3,4-tetrahydro-1-, -2-: -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4 dioxanyl, 1,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1,2,3,4-tetra hydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or-8-quinolyl, 1,2,3,4-tetrahydro-1-, -2-, 25 -3-, -4-, -5-, -6-, -7- or -8-isoquinolyl, 2-, 3-, 5-, 6-, 7- or 8- 3,4-dihydro-2H benzo-1,4-oxazinyl, further preferably 2,3-methylenedioxyphenyl, 3,4 methylenedioxyphenyl, 2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl, 3,4-(difluoromethylenedioxy)phenyl, 2,3-dihydrobenzofuran-5- or 6-yl, 2,3 30 (2-oxomethylenedioxy)phenyl or also 3,4-dihydro-2H-1,5-benzodioxepin-6 or -7-yl, furthermore preferably 2,3-dihydrobenzofuranyl or 2,3-dihydro-2 oxofuranyl, where the said radicals may be mono-, di-, tri-, tetra- or penta substituted by Hal, A, CN, Ar, Het, CONH 2 , CONHA, CONAA', NHCOA, 35 NHCOAr, NHSO 2 A, NHSO 2 Ar, =S, =NH, =NA and/or =0 (carbonyl oxy 35gen). gen).
    WO 2007/014607 PCT/EP2006/006378 -15 R particularly preferably denotes phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinoline or isoquinoline, each of which is unsubstituted or mono-, di- or trisubstituted by Hal, CN, phenyl and/or A. 5 X preferably denotes CH 2 ; CHA, such as, for example, CH(CH 3 ); or NH.
    R
    1 preferably denotes H or OH, furthermore OA.
    R
    2 preferably denotes H.
    R
    3 preferably denotes OH, OA, NH 2 , NHCOA, CONH 2 , SO 2 NHA, NHSO 2 A, 10 B(OH) 2 or SO 2
    NH
    2 , particularly preferably OH or OA. n preferably denotes 1 or 2. Ar denotes, for example, phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, 15 o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p-tert-butyl phenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p aminophenyl, o-, m- or p-(N-methylamino)phenyl, o-, m- or p-(N-methyl aminocarbonyl)phenyl, o-, m- or p-acetamidophenyl, o-, m- or p-methoxy 20 phenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-ethoxycarbonylphenyl, o-, m or p-(N,N-dimethylamino)phenyl, o-, m- or p-(N,N-dimethylaminocarbonyl) phenyl, o-, m- or p-(N-ethylamino)phenyl, o-, m- or p-(N,N-diethylamino) phenyl, o-, m- or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p chlorophenyl, o-, m- or p-(methylsulfonamido)phenyl, o-, m- or p-(methyl 25 sulfonyl)phenyl, o-, m- or p-cyanophenyl, o-, m- or p-ureidophenyl, o-, m or p-formylphenyl, o-, m- or p-acetylphenyl, o-, m- or p-aminosulfonyl phenyl, o-, m- or p-carboxyphenyl, o-, m- or p-carboxymethylphenyl, o-, m or p-carboxymethoxyphenyl, further preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 30 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino-4-chloro-, 2-amino 3-chloro-, 2-amino-4-chloro-, 2-amino-5-chloro- or 2-amino-6-chlorophenyl, 35 2-nitro-4-N,N-dimethylamino- or 3-nitro-4-N,N-dimethylaminophenyl, 2,3 diaminophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl, 2,4,6 trimethoxyphenyl, 2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-di- WO 2007/014607 PCT/EPI2006/006378 -16 chloro-4-aminophenyl, 4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl, 2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl, 3-chloro-6-meth oxyphenyl, 3-chloro-4-acetamidophenyl, 3-fluoro-4-methoxyphenyl, 3 5 amino-6-methylphenyl, 3-chloro-4-acetamidophenyl or 2,5-dimethyl-4 chlorophenyl. Ar preferably denotes phenyl which is unsubstituted or mono-, di-, tri-, tetra- or pentasubstituted by A, Hal, OA, (CH 2 )nCOOH, (CH 2 )nCOOA, 10 NHCO(CH 2 )nNH 2 and/or -O-(CH 2 )o-Het 1 . Ar particularly preferably denotes phenyl which is unsubstituted or mono or disubstituted by A, Hal, (CH 2 )nCOOH, (CH 2 )nCOOA, NHCO(CH 2 )nNH 2 and/or -O-(CH 2 )o-Het 1 . 15 Ar' preferably denotes, for example, phenyl which is unsubstituted or mono-, di- or trisubstituted by Hal. 20 Irrespective of further substitutions, Het denotes, for example, 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2, 4- or 5-imidazolyl, 1-, 3-, 4- or 5 pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, further more preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or 5-yl, 1 25 or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4 thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-iso indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indazolyl, 1-, 30 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7- benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8 35 cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo-1,4-oxazinyl, further preferably 1,3-benzodioxol-5-yl, WO 2007/014607 PCT/EP2006/006378 -17 1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazol-4- or -5-yl or 2,1,3-benzoxa diazol-5-yl. The heterocyclic radicals may also be partially or fully hydrogenated. 5 Het can thus also denote, for example, 2,3-dihydro-2-, -3-, -4- or -5-furyl, 5 2,5-dihydro-2-, -3-, -4- or 5-furyl, tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-di hydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2 or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, 10 -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or -4-pyridyl, 1,2,3,4-tetrahydro 1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-mor pholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimi 15 dinyl, 1-, 2- or 3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7 or -8-quinolyl, 1,2,3,4-tetrahydro-1-,-2-,-3-, -4-, -5-, -6-, -7- or -8-isoquinolyl, 2-, 3-, 5-, 6-, 7- or 8- 3,4-dihydro-2H-benzo-1,4-oxazinyl, further preferably 2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl, 2,3-ethylenedioxy 20 phenyl, 3,4-ethylenedioxyphenyl, 3,4-(difluoromethylenedioxy)phenyl, 2,3 dihydrobenzofuran-5- or 6-yl, 2,3-(2-oxomethylenedioxy)phenyl or also 3,4 dihydro-2H-1,5-benzodioxepin-6- or -7-yl, furthermore preferably 2,3-di hydrobenzofuranyl or 2,3-dihydro-2-oxofuranyl. 25 Het preferably denotes a mono- or bicyclic saturated, unsaturated or aro matic heterocycle having 1 to 4 N, O and/or S atoms, which may be mono-, di- or trisubstituted by A, OA, Hal and/or =0 (carbonyl oxygen). 30 Het particularly preferably denotes a mono- or bicyclic saturated, unsatu rated or aromatic heterocycle having 1 to 2 N and/or O atoms, which may be mono- or disubstituted by A and/or =0 (carbonyl oxygen), where A preferably denotes methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl or 35 trifluoromethyl.
    WO 2007/014607 PCT/EP2006/006378 -18 In a further embodiment, Het preferably denotes piperidine, piperazine, pyrrolidine, pyridine, pyrrole, indole, indazole, morpholine or isoxazole, each of which may be unsubstituted or mono- or disubstituted by A and/or 5 =0O, where A preferably denotes methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl or trifluoromethyl. Het 1 preferably denotes a monocyclic saturated heterocycle having 1 to 2 N and/or O atoms, which may be mono- or disubstituted by A and/or =0 10 (carbonyl oxygen), 4-methylpiperazinyl is particularly preferred. Throughout the invention, all radicals which occur more than once may be identical or different, i.e. are independent of one another. 15 The compounds of the formula I may have one or more chiral centres and can therefore occur in various stereoisomeric forms. The formula I encom passes all these forms. 20 Accordingly, the invention relates, in particular, to the compounds of the formula I in which at least one of the said radicals has one of the preferred meanings indicated above. Some preferred groups of compounds may be expressed by the following sub-formulae la to Ih, which conform to the 25 formula I and in which the radicals not designated in greater detail have the meaning indicated for the formula I, but in which in la X denotes (CH 2 )n, CHA or NH; 30 in Ib R 1 denotes H or OH: in Ic R 2 denotes H; 35 in Id R 3 denotes OH, OA, NH 2 , NHCOA,
    CONH
    2 , SO 2 NHA,
    NHSO
    2 A, B(OH) 2 or SO 2
    NH
    2
    ;
    WO 2007/014607 PCT/EP2006/006378 - 19 in le R 3 denotes OH or OA; in If n denotes 1 or 2; in Ig A denotes alkyl having 1 to 6 C atoms, in which, in addi tion, 1-5 H atoms may be replaced by F and/or chlorine; 10 in Ih R denotes phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyraz inyl, quinoline or isoquinoline, each of which is unsub stituted or mono-, di- or trisubstituted by Hal, CN, phenyl and/or A, 15 X denotes (CH 2 )n, CHA or NH
    R
    1 denotes H, OH or OA,
    R
    2 denotes H,
    R
    3 denotes OH, OA, NH 2 , NHCOA, CONH 2 , SO 2 NHA, 20
    NHSO
    2 A, B(OH) 2 or SO 2
    NH
    2 , A denotes alkyl having 1 to 6 C atoms, in which, in addi tion, 1-5 H atoms may be replaced by F and/or chlorine, n denotes 1 or 2,
    R
    4 denotes H, OH or F; 25 and pharmaceutically usable derivatives, salts, solvates and stereoisomers thereof, including mixtures thereof in all ratios. 30 The compounds of the formula I and also the starting materials for their preparation are, in addition, prepared by methods known per se, as described in the literature (for example in the standard works, such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic 35 Chemistry], Georg-Thieme-Verlag, Stuttgart), to be precise under reaction conditions which are known and suitable for the said reactions. Use may WO 2007/014607 PCT/EP2006/006378 - 20 also be made here of variants known per se which are not mentioned here in greater detail. If desired, the starting materials can also be formed in situ by not isolating 5 them from the reaction mixture, but instead immediately converting them further into the compounds of the formula I. Compounds of the formula I can preferably be obtained by reacting com 10 pounds of the formula II with compounds of the formula 111. The compounds of the formula II are novel, those of the formula Ill are generally known. 15 The reaction is generally carried out in an inert solvent, depending on the conditions used, the reaction time is between a few minutes and 14 days, the reaction temperature is between about 00 and 1500, normally between 20 150 and 1000, particularly preferably between 50 and 85oC. 20 Examples of suitable inert solvents are hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloro 25 form or dichloromethane; alcohols, such as methanol, ethanol, isopropa nol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether, ethylene glycol dimethyl 30 ether (diglyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide or dimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); carbon di sulfide; carboxylic acids, such as formic acid or acetic acid; nitro com 35 pounds, such as nitromethane or nitrobenzene; esters, such as ethyl ace 35tate, or mixtures of the said solvents. tate, or mixtures of the said solvents.
    WO 2007/014607 PCT/EP2006/006378 -21 Compounds of the formula I can furthermore be obtained by liberating them from one of their functional derivatives by treatment with a solvolys ing and/or hydrogenolysing agent by replacing a conventional amino-pro 5 tecting group with hydrogen by treatment with a solvolysing or hydrogeno lysing agent or liberating an amino group which is protected by a conven tional protecting group. Preferred starting materials for the solvolysis or hydrogenolysis are those 10 which otherwise conform to the formula I, but contain corresponding pro tected amino and/or hydroxyl groups instead of one or more free amino and/or hydroxyl groups, preferably those which carry an amino-protecting group instead of an H atom bonded to an N atom, in particular those which 15 carry an R'-N group, in which R' denotes an amino-protecting group, instead of an HN group, and/or those which carry a hydroxyl-protecting group instead of the H atom of a hydroxyl group, for example those which conform to the formula I, but carry a -COOR" group, in which R" denotes a 20 hydroxyl-protecting group, instead of a -COOH group. 20 It is also possible for a plurality of - identical or different - protected amino and/or hydroxyl groups to be present in the molecule of the starting mate rial. If the protecting groups present are different from one another, they 25 can in many cases be cleaved off selectively. The expression "amino-protecting group" is known in general terms and relates to groups which are suitable for protecting (blocking) an amino 30 group against chemical reactions, but which are easy to remove after the desired chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are, in particular, unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since the amino-protecting groups 35 are removed after the desired reaction (or reaction sequence), their type and size is furthermore not crucial; however, preference is given to those having 1-20, in particular 1-8, C atoms. The expression "acyl group" is to WO 2007/014607 PCT/EP2006/006378 - 22 be understood in the broadest sense in connection with the present proc ess. It encompasses acyl groups derived from aliphatic, araliphatic, aro matic or heterocyclic carboxylic acids or sulfonic acids, and, in particular, 5 alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of such acyl groups are alkanoyl, such as acetyl, propionyl, butyryl; aralkanoyl, such as phenylacetyl; aroyl, such as benzoyl or tolyl; aryloxyalkanoyl, such as POA; alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC (tert-butyloxycarbonyl), 10 2-iodoethoxycarbonyl; aralkoxycarbonyl, such as CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl, FMOC; arylsulfonyl, such as Mtr. Preferred amino-protecting groups are BOC and Mtr, furthermore CBZ, Fmoc, benzyl and acetyl. 15 The expression "hydroxyl-protecting group" is likewise known in general terms and relates to groups which are suitable for protecting a hydroxyl group against chemical reactions, but which are easy to remove after the desired chemical reaction has been carried out elsewhere in the molecule. 20 Typical of such groups are the above-mentioned unsubstituted or substi tuted aryl, aralkyl or acyl groups, furthermore also alkyl groups. The nature and size of the hydroxyl-protecting groups is not crucial since they are re moved again after the desired chemical reaction or reaction sequence; 25 preference is given to groups having 1-20, in particular 1-10, C atoms. Examples of hydroxyl-protecting groups are, inter alia, benzyl, 4-methoxy benzyl, p-nitrobenzoyl, p-toluenesulfonyl, tert-butyl and acetyl, where benzyl and tert-butyl are particularly preferred. 30 The compounds of the formula I are liberated from their functional deriva tives - depending on the protecting group used - for example using strong acids, advantageously using TFA or perchloric acid, but also using other strong inorganic acids, such as hydrochloric acid or sulfuric acid, strong 35 organic carboxylic acids, such as trichloroacetic acid, or sulfonic acids, such as benzene- or p-toluenesulfonic acid. The presence of an additional WO 2007/014607 PCT/EP2006/006378 - 23 inert solvent is possible, but is not always necessary. Suitable inert sol vents are preferably organic, for example carboxylic acids, such as acetic acid, ethers, such as tetrahydrofuran or dioxane, amides, such as DMF, halogenated hydrocarbons, such as dichloromethane, furthermore also alcohols, such as methanol, ethanol or isopropanol, and water. Mixtures of the above-mentioned solvents are furthermore suitable. TFA is preferably used in excess without addition of a further solvent, perchloric acid is pref erably used in the form of a mixture of acetic acid and 70% perchloric acid 10 in the ratio 9:1. The reaction temperatures for the cleavage are advanta geously between about 0 and about 500, preferably between 15 and 30' (room temperature). 15 The BOC, OBut and Mtr groups can, for example, preferably be cleaved off using TFA in dichloromethane or using approximately 3 to 5N HCI in dioxane at 15-300, the FMOC group can be cleaved off using an approxi mately 5 to 50% solution of dimethylamine, diethylamine or piperidine in DMF at 15-300. 20 Hydrogenolytically removable protecting groups (for example CBZ, benzyl) can be cleaved off, for example, by treatment with hydrogen in the pres ence of a catalyst (for example a noble-metal catalyst, such as palladium, 25 advantageously on a support, such as carbon). Suitable solvents here are those indicated above, in particular, for example, alcohols, such as metha nol or ethanol, or amides, such as DMF. The hydrogenolysis is generally carried out at temperatures between about 0 and 1000 and pressures be 30 tween about 1 and 200 bar, preferably at 20-30' and 1-10 bar. Hydrogen olysis of the CBZ group succeeds well, for example, on 5 to 10% Pd/C in methanol or using ammonium formate (instead of hydrogen) on Pd/C in methanol/DMF at 20-300. 35 Examples of suitable inert solvents are hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, WO 2007/014607 PCT/E P2006/006378 - 24 such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride, tri fluoromethylbenzene, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; 5 ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether, ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide, N-methyl pyrrolidone (NMP) or dimethylformamide (DMF); nitriles, such as aceto 10 nitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids, such as formic acid or acetic acid; nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate, or mixtures of the said solvents. 15 Esters can be saponified, for example, using acetic acid or using NaOH or KOH in water, water/THF or water/dioxane, at temperatures between 0 and 1000. 20 Furthermore, free amino groups can be acylated in a conventional manner using an acid chloride or anhydride or alkylated using an unsubstituted or substituted alkyl halide, or reacted with CH 3 -C(=NH)-OEt, advantageously in an inert solvent, such as dichloromethane or THF, and/or in the pres 25 ence of a base, such as triethylamine or pyridine, at temperatures between -60 and +300. Pharmaceutical salts and other forms 30 The said compounds according to the invention can be used in their final non-salt form. On the other hand, the present invention also encompasses the use of these compounds in the form of their pharmaceutically accept able salts, which can be derived from various organic and inorganic acids 35 and bases by procedures known in the art. Pharmaceutically acceptable 35 salt forms of the compounds of the formula I are for the most part prepared by conventional methods. If the compound of the formula I contains a car- WO 2007/014607 PCT/EP2006/006378 -25 boxyl group, one of its suitable salts can be formed by reacting the com pound with a suitable base to give the corresponding base-addition salt. Such bases are, for example, alkali metal hydroxides, including potassium 5 hydroxide, sodium hydroxide and lithium hydroxide; alkaline-earth metal hydroxides, such as barium hydroxide and calcium hydroxide; alkali metal alkoxides, for example potassium ethoxide and sodium propoxide; and various organic bases, such as piperidine, diethanolamine and N-methyl glutamine. The aluminium salts of the compounds of the formula I are like 10 wise included. In the case of certain compounds of the formula I, acid addition salts can be formed by treating these compounds with pharma ceutically acceptable organic and inorganic acids, for example hydrogen halides, such as hydrogen chloride, hydrogen bromide or hydrogen iodide, 15 other mineral acids and corresponding salts thereof, such as sulfate, nitrate or phosphate and the like, and alkyl- and monoarylsulfonates, such as ethanesulfonate, toluenesulfonate and benzenesulfonate, and other organic acids and corresponding salts thereof, such as acetate, trifluoro 20 acetate, tartrate, maleate, succinate, citrate, benzoate, salicylate, ascor 20 bate and the like. Accordingly, pharmaceutically acceptable acid-addition salts of the compounds of the formula I include the following: acetate, adi pate, alginate, arginate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, 25 caprylate, chloride, chlorobenzoate, citrate, cyclopentanepropionate, diglu conate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethane sulfonate, fumarate, galacterate (from mucic acid), galacturonate, gluco heptanoate, gluconate, glutamate, glycerophosphate, hemisuccinate, 30 hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydro bromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate, iso butyrate, lactate, lactobionate, malate, maleate, malonate, mandelate, metaphosphate, methanesulfonate, methylbenzoate, monohydrogenphos 35 phate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, palmo ate, pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate, phosphonate, phthalate, but this does not represent a restriction.
    WO 2007/014607 PCT/EP2006/006378 - 26 Furthermore, the base salts of the compounds according to the invention include aluminium, ammonium, calcium, copper, iron(IIlI), iron(ll), lithium, 5 magnesium, manganese(Ill), manganese(ll), potassium, sodium and zinc salts, but this is not intended to represent a restriction. Of the above-men tioned salts, preference is given to ammonium; the alkali metal salts so dium and potassium, and the alkaline-earth metal salts calcium and mag nesium. Salts of the compounds of the formula I which are derived from 10 pharmaceutically acceptable organic non-toxic bases include salts of pri mary, secondary and tertiary amines, substituted amines, also including naturally occurring substituted amines, cyclic amines, and basic ion exchanger resins, for example arginine, betaine, caffeine, chloroprocaine, 15 choline, N,N'-dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol, 2-dimethylamino ethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethyl piperidine, glucamine, glucosamine, histidine, hydrabamine, isopropyl amine, lidocaine, lysine, meglumine, N-methyl-D-glucamine, morpholine, 20 piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethanolamine, triethylamine, trimethylamine, tripropylamine and tris (hydroxymethyl)methylamine (tromethamine), but this is not intended to represent a restriction. 25 Compounds of the present invention which contain basic nitrogen-con taining groups can be quaternised using agents such as (C 1
    -C
    4 )alkyl hal ides, for example methyl, ethyl, isopropyl and tert-butyl chloride, bromide 30 and iodide; di(C1-C 4 )alkyl sulfates, for example dimethyl, diethyl and diamyl sulfate; (C10-C 18 )alkyl halides, for example decyl, dodecyl, lauryl, myristyl and stearyl chloride, bromide and iodide; and aryl(C 1
    -C
    4 )alkyl halides, for example benzyl chloride and phenethyl bromide. Both water- and oil-solu 35 ble compounds according to the invention can be prepared using such 35salts. salts.
    WO 2007/014607 PCT/EP2006/006378 - 27 The above-mentioned pharmaceutical salts which are preferred include acetate, trifluoroacetate, besylate, citrate, fumarate, gluconate, hemisucci nate, hippurate, hydrochloride, hydrobromide, isethionate, mandelate, 5 meglumine, nitrate, oleate, phosphonate, pivalate, sodium phosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate, tosylate and trometh amine, but this is not intended to represent a restriction. The acid-addition salts of basic compounds of the formula I are prepared 10 by bringing the free base form into contact with a sufficient amount of the desired acid, causing the formation of the salt in a conventional manner. The free base can be regenerated by bringing the salt form into contact with a base and isolating the free base in a conventional manner. The free 15 base forms differ in a certain respect from the corresponding salt forms thereof with respect to certain physical properties, such as solubility in polar solvents; for the purposes of the invention, however, the salts other wise correspond to the respective free base forms thereof. 20 As mentioned, the pharmaceutically acceptable base-addition salts of the compounds of the formula I are formed with metals or amines, such as alkali metals and alkaline-earth metals or organic amines. Preferred metals are sodium, potassium, magnesium and calcium. Preferred organic 25 amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, di ethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine. The base-addition salts of acidic compounds according to the invention are 30 prepared by bringing the free acid form into contact with a sufficient amount of the desired base, causing the formation of the salt in a conven tional manner. The free acid can be regenerated by bringing the salt form into contact with an acid and isolating the free acid in a conventional man 35 ner. The free acid forms differ in a certain respect from the corresponding 35salt forms thereof with respect to certain physical properties, such as solu salt forms thereof with respect to certain physical properties, such as solu- WO 2007/014607 PCT/EP2006/006378 - 28 bility in polar solvents; for the purposes of the invention, however, the salts otherwise correspond to the respective free acid forms thereof. 5 If a compound according to the invention contains more than one group which is capable of forming pharmaceutically acceptable salts of this type, the invention also encompasses multiple salts. Typical multiple salt forms include, for example, bitartrate, diacetate, difumarate, dimeglumine, di phosphate, disodium and trihydrochloride, but this is not intended to repre 10 sent a restriction. With regard to that stated above, it can be seen that the expression "pharmaceutically acceptable salt" in the present connection is taken to 15 mean an active ingredient which comprises a compound of the formula I in the form of one of its salts, in particular if this salt form imparts improved pharmacokinetic properties on the active ingredient compared with the free form of the active ingredient or any other salt form of the active ingredient 20 used earlier. The pharmaceutically acceptable salt form of the active in 20 gredient can also provide this active ingredient for the first time with a desired pharmacokinetic property which it did not have earlier and can even have a positive influence on the pharmacodynamics of this active ingredient with respect to its therapeutic efficacy in the body. 25 The invention furthermore relates to medicaments comprising at least one compound of the formula I and/or pharmaceutically usable derivatives, sol vates and stereoisomers thereof, including mixtures thereof in all ratios, 30 and optionally excipients and/or adjuvants. Pharmaceutical formulations can be administered in the form of dosage units which comprise a predetermined amount of active ingredient per 35 dosage unit. Such a unit can comprise, for example, 0.5 mg to 1 g, prefer ably 1 mg to 700 mg, particularly preferably 5 mg to 100 mg, of a com pound according to the invention, depending on the condition treated, the WO 2007/014607 PCT/EP2006/006378 - 29 method of administration and the age, weight and condition of the patient, or pharmaceutical formulations can be administered in the form of dosage units which comprise a predetermined amount of active ingredient per 5 dosage unit. Preferred dosage unit formulations are those which comprise a daily dose or part-dose, as indicated above, or a corresponding fraction thereof of an active ingredient. Furthermore, pharmaceutical formulations of this type can be prepared using a process which is generally known in the pharmaceutical art. 10 Pharmaceutical formulations can be adapted for administration via any desired suitable method, for example by oral (including buccal or sublin gual), rectal, nasal, topical (including buccal, sublingual or transdermal), 15 vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) methods. Such formulations can be prepared using all processes known in the pharmaceutical art by, for example, combining the active ingredient with the excipient(s) or adjuvant(s). 20 Pharmaceutical formulations adapted for oral administration can be admin istered as separate units, such as, for example, capsules or tablets; pow ders or granules; solutions or suspensions in aqueous or non-aqueous liq uids; edible foams or foam foods; or oil-in-water liquid emulsions or water 25 in-oil liquid emulsions. Thus, for example, in the case of oral administration in the form of a tablet or capsule, the active-ingredient component can be combined with an oral, 30 non-toxic and pharmaceutically acceptable inert excipient, such as, for example, ethanol, glycerol, water and the like. Powders are prepared by comminuting the compound to a suitable fine size and mixing it with a pharmaceutical excipient comminuted in a similar manner, such as, for 35 example, an edible carbohydrate, such as, for example, starch or mannitol. A flavour, preservative, dispersant and dye may likewise be present.
    WO 2007/014607 PCT/EP2006/006378 - 30 Capsules are produced by preparing a powder mixture as described above and filling shaped gelatine shells therewith. Glidants and lubricants, such as, for example, highly disperse silicic acid, talc, magnesium stearate, cal 5 cium stearate or polyethylene glycol in solid form, can be added to the powder mixture before the filling operation. A disintegrant or solubiliser, such as, for example, agar-agar, calcium carbonate or sodium carbonate, may likewise be added in order to improve the availability of the medica ment after the capsule has been taken. 10 In addition, if desired or necessary, suitable binders, lubricants and disin tegrants as well as dyes can likewise be incorporated into the mixture. Suitable binders include starch, gelatine, natural sugars, such as, for 15 example, glucose or beta-lactose, sweeteners made from maize, natural and synthetic rubber, such as, for example, acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. The lubricants used in these dosage forms include sodium oleate, sodium 20 stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium 20 chloride and the like. The disintegrants include, without being restricted thereto, starch, methylcellulose, agar, bentonite, xanthan gum and the like. The tablets are formulated by, for example, preparing a powder mixture, granulating or dry-pressing the mixture, adding a lubricant and a disinteg 25 rant and pressing the entire mixture to give tablets. A powder mixture is prepared by mixing the compound comminuted in a suitable manner with a diluent or a base, as described above, and optionally with a binder, such as, for example, carboxymethylcellulose, an alginate, gelatine or polyvinyl 30 pyrrolidone, a dissolution retardant, such as, for example, paraffin, an ab sorption accelerator, such as, for example, a quaternary salt, and/or an absorbent, such as, for example, bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting it with a binder, such as, 35 for example, syrup, starch paste, acadia mucilage or solutions of cellulose 35 or polymer materials and pressing it through a sieve. As an alternative to granulation, the powder mixture can be run through a tableting machine, WO 2007/014607 PCT/EP2006/006378 -31 giving lumps of non-uniform shape which are broken up to form granules. The granules can be lubricated by addition of stearic acid, a stearate salt, talc or mineral oil in order to prevent sticking to the tablet casting moulds. The lubricated mixture is then pressed to give tablets. The compounds 5 according to the invention can also be combined with a free-flowing inert excipient and then pressed directly to give tablets without carrying out the granulation or dry-pressing steps. A transparent or opaque protective layer consisting of a shellac sealing layer, a layer of sugar or polymer material 10 and a gloss layer of wax may be present. Dyes can be added to these coatings in order to be able to differentiate between different dosage units. Oral liquids, such as, for example, solution, syrups and elixirs, can be pre 15 pared in the form of dosage units so that a given quantity comprises a pre specified amount of the compound. Syrups can be prepared by dissolving the compound in an aqueous solution with a suitable flavour, while elixirs are prepared using a non-toxic alcoholic vehicle. Suspensions can be for mulated by dispersion of the compound in a non-toxic vehicle. Solubilisers 20 and emulsifiers, such as, for example, ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavour additives, such as, for example, peppermint oil or natural sweeteners or saccharin, or other artificial sweeteners and the like, can likewise be added. 25 The dosage unit formulations for oral administration can, if desired, be en capsulated in microcapsules. The formulation can also be prepared in such a way that the release is extended or retarded, such as, for example, 30 by coating or embedding of particulate material in polymers, wax and the like. The compounds of the formula I and salts, solvates and physiologically 35 functional derivatives thereof can also be administered in the form of lipo 35 some delivery systems, such as, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be WO 2007/014607 PCT/EP2006/006378 - 32 formed from various phospholipids, such as, for example, cholesterol, stearylamine or phosphatidylcholines. 5 The compounds of the formula I and the salts, solvates and physiologically functional derivatives thereof can also be delivered using monoclonal anti bodies as individual carriers to which the compound molecules are cou pled. The compounds can also be coupled to soluble polymers as targeted medicament carriers. Such polymers may encompass polyvinylpyrrolidone, 10 pyran copolymer, polyhydroxypropylmethacrylamidophenol, polyhydroxy ethylaspartamidophenol or polyethylene oxide polylysine, substituted by palmitoyl radicals. The compounds may furthermore be coupled to a class of biodegradable polymers which are suitable for achieving controlled 15 release of a medicament, for example polylactic acid, poly-epsilon-capro lactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, poly dihydroxypyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels. 20 Pharmaceutical formulations adapted for transdermal administration can be administered as independent plasters for extended, close contact with the epidermis of the recipient. Thus, for example, the active ingredient can be delivered from the plaster by iontophoresis, as described in general 25 terms in Pharmaceutical Research, 3(6), 318 (1986). Pharmaceutical compounds adapted for topical administration can be for mulated as ointments, creams, suspensions, lotions, powders, solutions, 30 pastes, gels, sprays, aerosols or oils. For the treatment of the eye or other external tissue, for example mouth and skin, the formulations are preferably applied as topical ointment or 35 cream. In the case of formulation to give an ointment, the active ingredient 35can be employed either with a paraffinic or a water-miscible cream base. can be employed either with a paraffinic or a water-miscible cream base.
    WO 2007/014607 PCT/EP2006/006378 - 33 Alternatively, the active ingredient can be formulated to give a cream with an oil-in-water cream base or a water-in-oil base. 5 Pharmaceutical formulations adapted for topical application to the eye 5 include eye drops, in which the active ingredient is dissolved or suspended in a suitable carrier, in particular an aqueous solvent. Pharmaceutical formulations adapted for topical application in the mouth 10 encompass lozenges, pastilles and mouthwashes. Pharmaceutical formulations adapted for rectal administration can be ad ministered in the form of suppositories or enemas. 15 Pharmaceutical formulations adapted for nasal administration in which the carrier substance is a solid comprise a coarse powder having a particle size, for example, in the range 20-500 microns, which is administered in 20 the manner in which snuff is taken, i.e. by rapid inhalation via the nasal 20 passages from a container containing the powder held close to the nose. Suitable formulations for administration as nasal spray or nose drops with a liquid as carrier substance encompass active-ingredient solutions in water or oil. 25 Pharmaceutical formulations adapted for administration by inhalation en compass finely particulate dusts or mists, which can be generated by vari ous types of pressurised dispensers with aerosols, nebulisers or insuffla 30 tors. Pharmaceutical formulations adapted for vaginal administration can be administered as pessaries, tampons, creams, gels, pastes, foams or spray formulations. 35 WO 201)7/014607 PCT/EP2006/006378 - 34 Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions comprising antioxi dants, buffers, bacteriostatics and solutes, by means of which the formula tion is rendered isotonic with the blood of the recipient to be treated; and 5 aqueous and non-aqueous sterile suspensions, which may comprise sus pension media and thickeners. The formulations can be administered in single-dose or multidose containers, for example sealed ampoules and vials, and stored in freeze-dried (lyophilised) state, so that only the addition 10 of the sterile carrier liquid, for example water for injection purposes, imme diately before use is necessary. Injection solutions and suspensions prepared in accordance with the rec ipe can be prepared from sterile powders, granules and tablets. 15 It goes without saying that, in addition to the above particularly mentioned constituents, the formulations may also comprise other agents usual in the art with respect to the particular type of formulation; thus, for example, 20 formulations which are suitable for oral administration may comprise fla 20 vours. A therapeutically effective amount of a compound of the formula I depends on a number of factors, including, for example, the age and weight of the 25 animal, the precise condition which requires treatment, and its severity, the nature of the formulation and the method of administration, and is ultimate ly determined by the treating doctor or vet. However, an effective amount of a compound according to the invention for the treatment of neoplastic 30 growth, for example large bowel or breast carcinoma, is generally in the range from 0.1 to 100 mg/kg of body weight of the recipient (mammal) per day and particularly typically in the range from 1 to 10 mg/kg of body weight per day. Thus, the actual amount per day for an adult mammal 35 weighing 70 kg is usually between 70 and 700 mg, where this amount can be administered as an individual dose per day or more usually in a series of part-doses (such as, for example, two, three, four, five or six) per day, WO 2007/014607 PCT/EP2006/006378 - 35 so that the total daily dose is the same. An effective amount of a salt or solvate or of a physiologically functional derivative thereof can be deter mined as the fraction of the effective amount of the compound according to the invention per se. It can be assumed that similar doses are suitable 5 for the treatment of other conditions mentioned above. The invention furthermore relates to medicaments comprising at least one compound of the formula I and/or pharmaceutically usable derivatives, sol 10 vates and stereoisomers thereof, including mixtures thereof in all ratios, and at least one further medicament active ingredient. The invention also relates to a set (kit) consisting of separate packs of 15 (a) an effective amount of a compound of the formula I and/or pharma ceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and 20 (b) an effective amount of a further medicament active ingredient. The set comprises suitable containers, such as boxes, individual bottles, bags or ampoules. The set may, for example, comprise separate am poules, each containing an effective amount of a compound of the formula 25 I and/or pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and an effective amount of a further medicament active ingredient in dis solved or lyophilised form. 30 USE 1. The disclosed compounds of the formula I are particularly useful in 35 therapeutic applications relating to a CHK1-mediated disorder. As used herein, the term "CHK-1-rnediated disorder" encompasses any disorder, WO 2007/014607 PCT/EP2006/006378 - 36 disease or condition which is caused or characterised by an increase in CHK1 expression or activity, or which requires CHK1 activity. The term "CHK1-mediated disorder" also encompasses any disorder, disease or 5 condition in which inhibition of CHK1 activity is beneficial. 5 CHK1 inhibition can be used to achieve a beneficial therapeutic or pro phylactic effect, for example in patients having a proliferative disorder. Non-limiting examples of proliferative disorders include chronic inflamma 10 tory proliferative disorders, for example psoriasis and rheumatoid arthritis, proliferative ocular disorders, for example diabetic retinopathy, benign pro liferative disorders, for example haemangiomas, and cancer. As used herein, the term "cancer" relates to a cellular disorder characterised by un 15 controlled or disregulated cell proliferation, decreased cell differentiation, inappropriate ability to invade surrounding tissue, and/or ability to establish new growth at ectopic sites. The term "cancer" encompasses, but is not limited to, solid tumours and bloodborne tumours. The term "cancer" en 20 compasses diseases of skin, tissues, organs, bone, cartilage, blood and vessels. The term "cancer" furthermore encompasses primary and meta static cancer diseases. Non-limiting examples of solid tumrnours that can be treated with the dis 25 closed CHK1 inhibitors include pancreatic cancer, bladder cancer, colo rectal cancer, breast cancer, including metastatic breast cancer, prostate cancer, including androgen-dependent and androgen-independent pros tate cancer, renal cancer, including, for example, metastatic renal-cell car 30 cinoma, hepatocellular cancer, lung cancer, including, for example, non small-cell lung cancer (NSCLC), bronchioloalveolar carcinoma (BAC), and adenocarcinoma of the lung, ovarian cancer, including, for example, pro gressive epithelial or primary peritoneal cancer, cervical cancer, gastric 35 cancer, oesophageal cancer, head and neck cancer, including, for exam 35 ple, squamous cell carcinoma of the head and neck, melanoma, neuro endocrine cancer, including metastatic neuroendocrine tumours, brain WO 2007/014607 PCT/E P2006/006378 - 37 tumours, including, for example, glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma, bone cancer and soft tissue sarcoma. 5 Non-limiting examples of haematological malignancies that can be treated with the disclosed CHK1 inhibitors include acute myeloid leukaemia (AML), chronic myeloid leukaemia (CML), including accelerated CML and CML blast phase (CML-BP), acute lymphoblastic leukaemia (ALL), chronic lym 10 phocytic leukaemia (CLL), Hodgkin's disease (HD), non-Hodgkin's lym phoma (NHL), including follicular lymphoma and mantle cell lymphoma, B-cell lymphoma, T-cell lymphoma, multiple myeloma (MM), Walden strom's macroglobulinaemia, myelodysplastic syndromes (MDS), including 15 refractory anaemia (RA), refractory anaemia with ringed sideoblasts (RARS), (refractory anaemia with excess blasts (RAEB), and RAEB in transformation (RAEB-T), and myeloproliferative syndromes. 20 The disclosed compounds of the formula I are particularly suitable for the 20 treatment of cancers or cell types in which CHK1 protein or activity is up regulated, including, without limitation, rapidly proliferating cells and drug resistant cells (Shyjan et al., U.S. Patent No. 6,723,498 (2004)), as well as retinoblastomas, such as Rb-negative or inactivated cells (Gottifredi et al., 25 Mol. Cell Biol., 21:1066 (2001)), or in which the ARF 1 4 p19 locus has been inactivated or misregulated. The disclosed CHK1 inhibitors also are par ticularly suitable for the treatment of cancer types or cell types in which another checkpoint pathway has been mutated or abrogated, including, 30 without limitation, cancers types or cell types in which p53 or the p53 pathway has been inactivated or abrogated. The disclosed compounds of the formula I can be administered in combi 35 nation with other therapeutic agents, including anticancer agents. As used 35 herein, the term- "anticancer agent" relates to any agent which is adminis tered to a patient with cancer for the purposes of treating the cancer.
    WO 2007/014607 PCT/EP2006/006378 - 38 The anti-cancer treatment defined herein may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional 5 surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti- tumour agents: (i) antiproliferative/antineoplastic/DNA-damaging agents and combi nations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, 10 melphalan, chloroambucil, busulphan and nitrosoureas); antimetabolites (for example antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea and gemcitabine); antitumour antibiotics (for example anthracyclines, like adria 15 mycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mito mycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids, like vincristine, vinblastine, vindesine and vinorelbine, and taxoids, like taxol and taxotere) ; topoisomerase inhibitors (for example 20 epipodophyllotoxins, like etoposide and teniposide, amsacrine, topotecan, irinotecan and camptothecin) and cell-differentiating agents (for example all-trans-retinoic acid, 13-cis-retinoic acid and fenretinide); (ii) cytostatic agents, such as antioestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene), oestrogen receptor 25 downregulators (for example fulvestrant), antiandrogens (for example bi calutamide, flutamide, nilutamide and cyproterone acetate), LHRH antago nists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progesterones (for example megestrol acetate), aromatase inhibitors (for 30 example as anastrozole, letrozole, vorazole and exemestane) and inhibi tors of 5c-reductase, such as finasteride; (iii) agents which inhibit cancer cell invasion (for example metallo proteinase inhibitors, like marimastat, and inhibitors of urokinase plasmi 35 nogen activator receptor function); WO 2007/014607 PCT/EP2006/006378 - 39 (iv) inhibitors of growth factor function, for example such inhibitors include growth factor antibodies, growth factor receptor antibodies (for example the anti-erbb2 antibody trastuzumab [Herceptin T M ] and the anti 5 erbbl antibody cetuximab [C225]), farnesyl transferase inhibitors, tyrosine kinase inhibitors and serine/threonine kinase inhibitors, for example in hibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors, such as N-(3-chloro-4-fluorophenyl)-7-methoxy 6- (3-morpholinopropoxy) quinazolin-4-amine (gefitinib, AZD1839), N-(3 10 ethynylphenyl)-6,7-bis (2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholino propoxy)quinazolin-4-amine (CI 1033) ), for example inhibitors of the platelet-derived growth factor family and for example inhibitors of the 15 hepatocyte growth factor family; (v)antiangiogenic agents, such as those which inhibit the effects of vascu lar endothelial growth factor, (for example the anti-vascular endothelial cell growth factor antibody bevacizumab [AvastinTM], compounds such as 20 those disclosed in published international patent applications 20 WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) and compounds that work by other mechanisms (for example linomide, inhibi tors of integrin tav3 function and angiostatin); (vi) vessel-damaging agents, such as combretastatin A4 and com 25 pounds disclosed in international patent applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213; (vii) antisense therapies, for example those which are directed to the 30 targets listed above, such as ISIS 2503, an anti-Ras antisense; (viii) gene therapy approaches, including, for example, approaches for replacement of aberrant genes, such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches, 35 such as those using cytosine deaminase, thymidine kinase or a bacterial 35nitroreductase enzyme, and approaches for increasing patient tolerance to nitroreductase enzyme, and approaches for increasing patient tolerance to WO 2007/014607 PCT/EP2006/006378 -40 chemotherapy or radiotherapy, such as multi-drug resistance gene ther apy; and (ix) immunotherapy approaches, including, for example, ex-vivo and 5 in-vivo approaches for increasing the immunogenicity of patient tumour 5 cells, such as transfection with cytokines, such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches for decreasing T-cell anergy, approaches using transfected immune cells, such as cytokine-transfected dendritic cells, approaches using cytokine 10 transfected tumour cell lines, and approaches using anti-idiotypic anti bodies. The medicaments from Table 1 below are preferably, but not exclusively, 15 combined with the compounds of the formula I. Table 1. Alkylating agents Cyclophosphamide Lomustine Busulfan Procarbazine Ifosfamide Altretamine 20 Melphalan Estramustine phosphate Hexamethylmelamine Mechloroethamine Thiotepa Streptozocin chloroambucil Temozolomide Dacarbazine Semustine Carmustine 25 Platinum agents Cisplatin Carboplatin Oxaliplatin ZD-0473 (AnorMED) Spiroplatin Lobaplatin (Aetema) Carboxyphthalatoplatinum Satraplatin (Johnson Tetraplatin Matthey) Ormiplatin BBR-3464 30 Iproplatin (Hoffrnann-La Roche) SM-11355 (Sumitomo) AP-5280 (Access) Antimetabolites Azacytidine Tomudex Gemcitabine Trimetrexate 35 Capecitabine Deoxycoformycin 5-fluorouracil Fludarabine Floxuridine Pentostatin WO 2007/014607 PCT/EP2006/006378 -41 2-chlorodesoxyadenosine Raltitrexed 6-Mercaptopurine Hydroxyurea 6-Thioguanine Decitabine (SuperGen) Cytarabine Clofarabine (Bioenvision) 2-fluorodesoxycytidine Irofulven (MGI Pharrna) 5 Methotrexate DMDC (Hoffmann-La Idatrexate Roche) Ethynylcytidine (Taiho) Topoisomerase Amsacrine Rubitecan (SuperGen) inhibitors Epirubicin Exatecan mesylate Etoposide (Daiichi) 10 Teniposide or Quinamed (ChemGenex) mitoxantrone Gimatecan (Sigma- Tau) Irinotecan (CPT-11) Diflomotecan (Beaufour 7-Ethyl-10- Ipsen) hydroxycamptothecin TAS-103 (Taiho) Topotecan Elsamitrucin (Spectrum) 15 Dexrazoxanet J-107088 (Merck & Co) (TopoTarget) BNP-1350 (BioNumerik) Pixantrone (Novuspharrna) CKD-602 (Chong Kun Rebeccamycin analogue Dang) (Exelixis) KW-2170 (Kyowa Hakko) BBR-3576 (Novuspharrna) 20 Antitumour Dactinomycin (Actinomycin Amonafide antibiotics D) Azonafide Doxorubicin (Adriamycin) Anthrapyrazole Deoxyrubicin Oxantrazole Valrubicin Losoxantrone Daunorubicin Bleomycin sulfate 25 (Daunomycin) (Blenoxan) Epirubicin Bleomycinic acid Therarubicin Bleomycin A Idarubicin Bleomycin B Rubidazon Mitomycin C Plicamycinp MEN-10755 (Menarini) 30 Porfiromycin GPX-100 (Gem 30 Cyanomorpholinodoxo- Pharmaceuticals) rubicin Mitoxantron (Novantron) Antimitotic agents Paclitaxel SB 408075 Docetaxel (GlaxoSmithKline) 35 Colchicine E7010 (Abbott) Vinblastine PG-TXL (Cell Vincristine Therapeutics) WO 2007/014607 PCT/EP2006/006378 - 42 Vinorelbine IDN 5109 (Bayer) Vindesine A 105972 (Abbott) Dolastatin 10 (NCI) A 204197 (Abbott) Rhizoxin (Fujisawa) LU 223651 (BASF) Mivobulin (Warner- D 24851 (ASTA Medica) 5 Lambert) ER-86526 (Eisai) Cemadotin (BASF) Combretastatin A4 (BMS) RPR 109881A (Aventis) Isohomohalichondrin-B TXD 258 (Aventis) (PharmaMar) Epothilone B (Novartis) ZD 6126 (AstraZeneca) T 900607 (Tularik) PEG-Paclitaxel (Enzon) T 138067 (Tularik) AZ10992 (Asahi) 10 Cryptophycin 52 (Eli Lilly) !DN-5109 (Indena) Vinflunine (Fabre) AVLB (Prescient Auristatin PE (Teikoku NeuroPharma) Hormone) Azaepothilon B (BMS) BMS 247550 (BMS) BNP- 7787 (BioNumerik) BMS 184476 (BMS) CA-4-Prodrug (OXiGENE) 15 BMS 188797 (BMS) Dolastatin-10 (NrH) Taxoprexin (Protarga) CA-4 (OXiGENE) Aromatase Aminoglutethimide Exemestan inhibitors Letrozole Atamestan (BioMedicines) Anastrazole YM-511 (Yamanouchi) Formestan 20 Thymidylate Pemetrexed (Eli Lilly) Nolatrexed (Eximias) synthase ZD-9331 (BTG) CoFactor T M (BioKeys) inhibitors DNA antagonists Trabectedin (PharmaMar) Mafosfamide (Baxter 25 Glufosfamide (Baxter International) International) Apaziquone (Spectrum Albumin + 32P (Isotope Pharmaceuticals) Solutions) 06-Benzylguanine Thymectacin (NewBiotics) (Paligent) Edotreotid (Novartis) 30 Farnesyl Arglabin (NuOncology Tipifarnib (Johnson & transferase Labs) Johnson) inhibitors lonafarnib (Schering- Perillyl alcohol (DOR Plough) BioPharma) BAY-43-9006 (Bayer) 35 Pump inhibitors CBT-1 (CBA Pharma) Zosuquidar Tariquidar (Xenova) trihydrochloride (Eli Lilly) MS-209 (Schering AG) Biricodar dicitrate (Vertex) WO 2007/014607 PCT/EPI2006/006378 -43 Histone acetyl Tacedinaline (Pfizer) Pivaloyloxymethyl butyrate transferase in- SAHA (Aton Pharma) (Titan) hibitors MS-275 (Schering AG) Depsipeptide (Fujisawa) 5 Metalloproteinase Neovastat (Aeterna Labo- CMT -3 (CollaGenex) inhibitors ratories) BMS-275291 (Celltech) Ribonucleoside Marimastat (British Bio- Tezacitabine (Aventis) reductase inhibi- tech) Didox (Molecules for tors Gallium maltolate (Titan) Health) Triapin (Vion) 10 TNF-alpha Virulizin (Lorus Therapeu- Revimid (Celgene) agonists/ tics) antagonists CDC-394 (Celgene) Endothelin-A re- Atrasentan (Abbot) YM-598 (Yamanouchi) ceptor antagonists ZD-4054 (AstraZeneca) 15 Retinoic acid re- Fenretinide (Johnson & Alitretinoin (Ligand) ceptor agonists Johnson) LGD-1550 (Ligand) Immunomodula- Interferon Dexosome therapy (Ano 20 tors Oncophage (Antigenics) sys) GMK (Progenics) Pentrix (Australian Cancer Adenocarcinoma vaccine Technology) (Biomira) JSF-154 (Tragen) CTP-37 (AVI BioPharma) Cancer vaccine (Intercell) JRX-2 (Immuno-Rx) Norelin (Biostar) PEP-005 (Peplin Biotech) BLP-25 (Biomira) 25 Synchrovax vaccines (CTL MGV (Progenics) Immuno) !3-Alethin (Dovetail) Melanoma vaccine (CTL CLL-Thera (Vasogen) Immuno) p21-RAS vaccine (Gem Vax) 30 30 Hormonal and Oestrogens Prednisone antihormonal Conjugated oestrogens Methylprednisolone agents Ethynyloestradiol Prednisolone chlorotrianisene Aminoglutethimide Idenestrol Leuprolide Hydroxyprogesterone Goserelin 35 caproate Leuporelin Medroxyprogesterone Bicalutamide Testosterone Flutamide WO 2007/014607 PCT/EP2006/006378 - 44 Testosterone propionate Octreotide Fluoxymesterone Nilutamide Methyltestosterone Mitotan Diethylstilbestrol P-04 (Novogen) Megestrol 2-methoxyoestradiol (En 5 Tamoxifen treMed) Toremofin Arzoxifen (Eli Lilly) Dexamethasone Photodynamic Talaporfin (Light Sciences) Pd-Bacteriopheophorbid agents Theralux (Theratechnolo- (Yeda) 10 gies) Lutetium-Texaphyrin 10 Motexafin-Gadolinium (Pharmacyclics) (Pharmacyclics) Hypericin Tyrosine kinase Imatinib (Novartis) Kahalide F (PharmaMar) inhibitors Leflunomide(Sugen/Phar- CEP- 701 (Cephalon) macia) CEP-751 (Cephalon) 15 ZDI839 (AstraZeneca) MLN518 (Millenium) Erlotinib (Oncogene Sci- PKC412 (Novartis) ence) Phenoxodiol O Canertjnib (Pfizer) Trastuzumab (Genentech) Squalamine (Genaera) C225 (ImClone) SU5416 (Pharmacia) rhu-Mab (Genentech) 20 SU6668 (Pharmacia) MDX-H210 (Medarex) 20 ZD4190 (AstraZeneca) 2C4 (Genentech) ZD6474 (AstraZeneca) MDX-447 (Medarex) Vatalanib (Novartis) ABX-EGF (Abgenix) PKI166 (Novartis) IMC-1C11 (ImClone) GW2016 (GlaxoSmith Kline) 25 EKB-509 (Wyeth) EKB-569 (Wyeth) Various agents SR-27897 (CCK-A inhibi- BCX-1777 (PNP inhibitor, tor, Sanofi-Synthelabo) BioCryst) Tocladesine (cyclic AMP Ranpirnase (ribonuclease agonist, Ribapharm) stimulant, Alfacell) 30 Alvocidib (CDK inhibitor, Galarubicin (RNA synthe 30 Aventis) sis inhibitor, Dong-A) CV-247 (COX-2 inhibitor, Tirapazamine (reducing Ivy Medical) agent, SRI International) P54 (COX-2 inhibitor, N-Acetylcysteine (reducing Phytopharm) agent, Zambon) CapCelI T M (CYP450 R-Flurbiprofen (NF-kappaB 35 stimulant, Bavarian Nordic) inhibitor, Encore) GCS-IOO (gal3 antagonist, 3CPA (NF-kappaB GlycoGenesys) inhibitor, Active Biotech) WO 2007/014607 PCT/EP2006/006378 - 45 G17DT immunogen (gas- Seocalcitol (vitamin D trin inhibitor, Aphton) receptor agonist, Leo) Efaproxiral (oxygenator, 131-1-TM-601 (DNA Allos Therapeutics) antagonist, PI-88 (heparanase inhibi- TransMolecular) 5 tor, Progen) Eflornithin (ODC inhibitor, Tesmilifen (histamine an- ILEX Oncology) tagonist, YM BioSciences) Minodronic acid Histamine (histamine H2 (osteoclast inhibitor, receptor agonist, Maxim) Yamanouchi) Tiazofurin (IMPDH inhibi- Indisulam (p53 stimulant, tor, Ribapharm) Eisai) 10 Cilengitide (integrin an- Aplidin (PPT inhibitor, tagonist, Merck KGaA) PharmaMar) SR-31747 (IL-1 antagonist, Rituximab (CD20 antibody, Sanofi-Synthelabo) Genentech) CCI-779 (mTOR kinase Gemtuzumab (CD33 inhibitor, Wyeth) antibody, Wyeth Ayerst) 15 Exisulind (PDE-V inhibitor, PG2 (haematopoiesis Cell Pathways) promoter, Pharmagenesis) CP-461 (PDE-V inhibitor, Immunol T M (triclosan Cell PathWays) mouthwash, Endo) AG-2037 (GART inhibitor, Triacetyluridine (uridine Pfizer) prodrug, Wellstat) WX-UK1 (plasminogen SN-4071 (sarcoma agent, 20 activator inhibitor, Wilex) Signature BioScience) PBI-1402 (PMN stimulant, TransMID-107TM ProMetic LifeSciences) (immunotoxin, KS Bortezomib (proteasome Biomedix) inhibitor, Millennium) PCK-3145 (apoptosis SRL-172 (T-cell stimulant, promoter, Procyon) 25 SR Pharma) Doranidazole (apoptosis TLK-286 (glutathione-S promoter, Pola) transferase inhibitor, Telik) CHS-828 (cytotoxic agent, PT-100 (growth factor Leo) agonist, Point Therapeu- Trans-retinic acid tics) (differentiator, NIH) Midostaurin (PKC inhibitor, MX6 (apoptosis promoter, 30 Novartis) MAXIA) Bryostatin-1 (PKC stimu- Apomine (apoptosis lant, GPC Biotech) promoter, ILEX Oncology) CDA-II (apoptosis pro- Urocidin (apoptosis moter, Everlife) promoter, Bioniche) SDX-101 (apoptosis pro- Ro-31-7453 (apoptosis 35 moter, Salmedix) promoter, La Roche) Ceflatonin (apoptosis pro- Brostallicin (apoptosis moter, ChemGenex) promoter, Pharmacia) WO 2007/014607 PCT/EP2006/006378 - 46 Alkylating agents Cyclophosphamide Lomustine Busulfan Procarbazine Ifosfamide Altretamine Melphalan Estramustine phosphate 5 Hexamethylmelamine Mechloroethamine Thiotepa Streptozocin chloroambucil Temozolomide Dacarbazine Semustine Carmustine Platinum agents Cisplatin Carboplatin 10 Oxaliplatin ZD-0473 (AnorMED) Spiroplatin Lobaplatin (Aetema) Carboxyphthalatoplatinum Satraplatin (Johnson Tetraplatin Matthey) Ormiplatin BBR-3464 Iproplatin (Hoffrnann-La Roche) 15 SM-11355 (Sumitomo) AP-5280 (Access) Antimetabolites Azacytidine Tomudex Gemcitabine Trimetrexate Capecitabine Deoxycoformycin 20 5-fluorouracil Fludarabine 20 Floxuridine Pentostatin 2-chlorodesoxyadenosine Raltitrexed 6-Mercaptopurine Hydroxyurea 6-Thioguanine Decitabine (SuperGen) Cytarabine Clofarabine (Bioenvision) 2-fluorodesoxycytidine Irofulven (MGI Pharrna) 25 Methotrexate DMDC (Hoffmann-La Idatrexate Roche) Ethynylcytidine (Taiho) Topoisomerase Amsacrine Rubitecan (SuperGen) inhibitors Epirubicin Exatecan mesylate 30 Etoposide (Daiichi) 30 Teniposide or Quinamed (ChemGenex) mitoxantrone Gimatecan (Sigma- Tau) Irinotecan (CPT-11) Diflomotecan (Beaufour 7-Ethyl-10- Ipsen) hydroxycamptothecin TAS-103 (Taiho) Topotecan Elsamitrucin (Spectrum) 35 Dexrazoxanet J-107088 (Merck & Co) (TopoTarget) BNP-1350 (BioNumerik) Pixantrone (Novuspharrna) CKD-602 (Chong Kun WO 2007/014607 PCT/EP2006/006378 -47 Rebeccamycin analogue Dang) (Exelixis) KW-2170 (Kyowa Hakko) BBR-3576 (Novuspharrna) 5 Antitumour Dactinomycin (Actinomycin Amonafide antibiotics D) Azonafide 10 Doxorubicin (Adriamycin) Anthrapyrazole Deoxyrubicin Oxantrazole Valrubicin Losoxantrone Daunorubicin Bleomycin sulfate (Daunomycin) (Blenoxan) Epirubicin Bleomycinic acid Therarubicin Bleomycin A 15 Idarubicin Bleomycin B Rubidazon Mitomycin C Plicamycinp MEN-10755 (Menarini) Porfiromycin GPX-100 (Gem Cyanomorpholinodoxo- Pharmaceuticals) rubicin 20 Mitoxantron (Novantron) Antimitotic agents Paclitaxel SB 408075 Docetaxel (GlaxoSmithKline) Colchicine E7010 (Abbott) Vinblastine PG-TXL (Cell Vincristine Therapeutics) 25 Vinorelbine IDN 5109 (Bayer) Vindesine A 105972 (Abbott) Dolastatin 10 (NCI) A 204197 (Abbott) Rhizoxin (Fujisawa) LU 223651 (BASF) Mivobulin (Warner- D 24851 (ASTA Medica) Lambert) ER-86526 (Eisai) 30 Cemadotin (BASF) Combretastatin A4 (BMS) RPR 109881A (Aventis) Isohomohalichondrin-B TXD 258 (Aventis) (PharmaMar) Epothilone B (Novartis) ZD 6126 (AstraZeneca) T 900607 (Tularik) PEG-Paclitaxel (Enzon) T 138067 (Tularik) AZ10992 (Asahi) Cryptophycin 52 (Eli Lilly) !DN-5109 (Indena) 35 Vinflunine (Fabre) AVLB (Prescient Auristatin PE (Teikoku NeuroPharma) Hormone) Azaepothilon B (BMS) WO 2007/014607 PiCT/E P2006/006378 - 48 BMS 247550 (BMS) BNP- 7787 (BioNumerik) BMS 184476 (BMS) CA-4-Prodrug (OXiGENE) BMS 188797 (BMS) Dolastatin-10 (NrH) Taxoprexin (Protarga) CA-4 (OXiGENE) 5 10 Aromatase Aminoglutethimide Exemestan 15 inhibitors Letrozole Atamestan (BioMedicines) Anastrazole YM-511 (Yamanouchi) Formestan Thymidylate Pemetrexed (Eli Lilly) Nolatrexed (Eximias) synthase ZD-9331 (BTG) CoFactor T M (BioKeys) inhibitors 20 DNA antagonists Trabectedin (PharmaMar) Mafosfamide (Baxter Glufosfamide (Baxter International) International) Apaziquone (Spectrum Albumin + 32P (Isotope Pharmaceuticals) Solutions) 06-Benzylguanine 25 Thymectacin (NewBiotics) (Paligent) Edotreotid (Novartis) Farnesyl Arglabin (NuOncology Tipifarnib (Johnson & transferase Labs) Johnson) inhibitors lonafarnib (Schering- Perillyl alcohol (DOR Plough) BioPharma) 30 BAY-43-9006 (Bayer) Pump inhibitors CBT-1 (CBA Pharma) Zosuquidar Tariquidar (Xenova) trihydrochloride (Eli Lilly) MS-209 (Schering AG) Biricodar dicitrate (Vertex) 35 Histone acetyl Tacedinaline (Pfizer) Pivaloyloxymethyl butyrate transferase SAHA (Aton Pharma) (Titan) inhibitors MS-275 (Schering AG) Depsipeptide (Fujisawa) WO 2007/014607 PCT/EP2006/006378 -49 Metalloproteinase Neovastat (Aeterna CMT -3 (CollaGenex) inhibitors Laboratories) BMS-275291 (Celltech) Ribonucleoside Marimastat (British Tezacitabine (Aventis) reductase Biotech) Didox (Molecules for 5 inhibitors Gallium maltolate (Titan) Health) Triapin (Vion) TNF-alpha Virulizin (Lorus Revimid (Celgene) agonists/ Therapeutics) antagonists CDC-394 (Celgene) 10 Endothelin-A Atrasentan (Abbot) YM-598 (Yamanouchi) receptor ZD-4054 (AstraZeneca) antagonists Retinoic acid Fenretinide (Johnson & Alitretinoin (Ligand) receptor agonists Johnson) 15 LGD-1550 (Ligand) Immuno- Interferon Dexosome therapy modulators Oncophage (Antigenics) (Anosys) GMK (Progenics) Pentrix (Australian Cancer Adenocarcinoma vaccine Technology) 20 (Biomira) JSF-154 (Tragen) CTP-37 (AVI BioPharma) Cancer vaccine (Intercell) JRX-2 (Immuno-Rx) Norelin (Biostar) PEP-005 (Peplin Biotech) BLP-25 (Biomira) Synchrovax vaccines (CTL MGV (Progenics) Immuno) !3-Alethin (Dovetail) Melanoma vaccine (CTL CLL-Thera (Vasogen) 25 Immuno) p21-RAS vaccine (GemVax) Hormonal and Oestrogens Prednisone antihormonal Conjugated oestrogens Methylprednisolone 30 agents Ethynyloestradiol Prednisolone chlorotrianisene Aminoglutethimide Idenestrol Leuprolide Hydroxyprogesterone Goserelin caproate Leuporelin Medroxyprogesterone Bicalutamide Testosterone Flutamide 35 Testosterone propionate Octreotide Fluoxymesterone Nilutamide Methyltestosterone Mitotan WO 2007/014607 PCT/EP2006/006378 - 50 Diethylstilbestrol P-04 (Novogen) Megestrol 2-methoxyoestradiol Tamoxifen (EntreMed) Toremofin Arzoxifen (Eli Lilly) Dexamethasone 5 10 Photodynamic Talaporfin (Light Sciences) Pd-Bacteriopheophorbid agents Theralux (Yeda) (Theratechnologies) Lutetium-Texaphyrin Motexafin-Gadolinium (Pharmacyclics) (Pharmacyclics) Hypericin 15 Tyrosine kinase Imatinib (Novartis) Kahalide F (PharmaMar) inhibitors Leflunomide(Sugen/Pharm CEP- 701 (Cephalon) acia) CEP-751 (Cephalon) ZDI839 (AstraZeneca) MLN518 (Millenium) Erlotinib (Oncogene PKC412 (Novartis) Science) Phenoxodiol O 20 Canertjnib (Pfizer) Trastuzumab (Genentech) Squalamine (Genaera) C225 (ImClone) SU5416 (Pharmacia) rhu-Mab (Genentech) SU6668 (Pharmacia) MDX-H210 (Medarex) ZD4190 (AstraZeneca) 2C4 (Genentech) ZD6474 (AstraZeneca) MDX-447 (Medarex) Vatalanib (Novartis) ABX-EGF (Abgenix) 25 PKI166 (Novartis) IMC-1C11 (ImClone) GW2016 (GlaxoSmithKline) EKB-509 (Wyeth) EKB-569 (Wyeth) 30 Various agents SR-27897 (CCK-A BCX-1777 (PNP inhibitor, inhibitor, Sanofi- BioCryst) Synthelabo) Ranpirnase (ribonuclease Tocladesine (cyclic AMP stimulant, Alfacell) agonist, Ribapharm) Galarubicin (RNA Alvocidib (CDK inhibitor, synthesis inhibitor, Dong Aventis) A) 35 CV-247 (COX-2 inhibitor, Tirapazamine (reducing Ivy Medical) agent, SRI International) P54 (COX-2 inhibitor, N-Acetylcysteine (reducing WO 2007/014607 PCT/E P2006/006378 -51 Phytopharm) agent, Zambon) CapCell T M (CYP450 R-Flurbiprofen (NF-kappaB stimulant, Bavarian Nordic) inhibitor, Encore) GCS-IOO (gal3 antagonist, 3CPA (NF-kappaB GlycoGenesys) inhibitor, Active Biotech) 5 G17DT immunogen Seocalcitol (vitamin D (gastrin inhibitor, Aphton) receptor agonist, Leo) Efaproxiral (oxygenator, 131-1-TM-601 (DNA Allos Therapeutics) antagonist, PI-88 (heparanase TransMolecular) inhibitor, Progen) Eflornithin (ODC inhibitor, Tesmilifen (histamine ILEX Oncology) 10 antagonist, YM Minodronic acid BioSciences) (osteoclast inhibitor, Histamine (histamine H2 Yamanouchi) receptor agonist, Maxim) Indisulam (p53 stimulant, Tiazofurin (IMPDH Eisai) inhibitor, Ribapharm) Aplidin (PPT inhibitor, 15 Cilengitide (integrin PharmaMar) antagonist, Merck KGaA) Rituximab (CD20 antibody, SR-31747 (IL-1 antagonist, Genentech) Sanofi-Synthelabo) Gemtuzumab (CD33 CCI-779 (mTOR kinase antibody, Wyeth Ayerst) inhibitor, Wyeth) PG2 (haematopoiesis Exisulind (PDE-V inhibitor, promoter, Pharmagenesis) 20 Cell Pathways) Immunol TM (triclosan CP-461 (PDE-V inhibitor, mouthwash, Endo) Cell Pathways) Triacetyluridine (uridine AG-2037 (GART inhibitor, prodrug, Wellstat) Pfizer) SN-4071 (sarcoma agent, WX-UK1 (plasminogen Signature BioScience) 25 activator inhibitor, Wilex) TransMID-107TM PBI-1402 (PMN stimulant, (immunotoxin, KS ProMetic LifeSciences) Biomedix) Bortezomib (proteasome PCK-3145 (apoptosis inhibitor, Millennium) promoter, Procyon) SRL-172 (T-cell stimulant, Doranidazole (apoptosis SR Pharma) promoter, Pola) 30 TLK-286 (glutathione-S CHS-828 (cytotoxic agent, transferase inhibitor, Telik) Leo) PT-100 (growth factor Trans-retinic acid agonist, Point (differentiator, NIH) Therapeutics) MX6 (apoptosis promoter, Midostaurin (PKC inhibitor, MAXIA) 35 Novartis) Apomine (apoptosis Bryostatin-1 (PKC promoter, ILEX Oncology) stimulant, GPC Biotech) Urocidin (apoptosis WO 2007/014607 PCT/EP2006/006378 - 52 CDA-Il (apoptosis promoter, Bioniche) promoter, Everlife) Ro-31-7453 (apoptosis SDX-101 (apoptosis promoter, La Roche) promoter, Salmedix) Brostallicin (apoptosis Ceflatonin (apoptosis promoter, Pharmacia) 5 _promoter, ChemGenex) A combined treatment of this type can be achieved with the aid of simulta neous, consecutive or separate dispensing of the individual components of 10 the treatment. Combination products of this type employ the compounds according to the invention. 2. The present compounds are suitable as pharmaceutical active 15 ingredients for mammals, in particular for humans, in the treatment of SGK-induced diseases. The invention thus relates to the use of compounds according to Claim 1, 20 and pharmaceutically usable derivatives, solvates and stereoisomers 20 thereof, including mixtures thereof in all ratios, for the preparation of a medicament for the treatment of diseases in which the inhibition, regulation and/or modulation of kinase signal transduction plays a role. Preference is given to the use of compounds according to Claim 1, and 25 pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, for the preparation of a medicament for the treatment of diseases which are influenced by inhibition of SGKs by the compounds according to 30 Claim 1. The present invention encompasses the use of the compounds according to Claim 1 according to the invention and/or physiologically acceptable 35 salts and solvates thereof for the preparation of a medicament for the treatment or prevention of diabetes (for example diabetes mellitus, diabetic treatment or prevention of diabetes (for example diabetes mellitus, diabetic WO 2007/014607 PCT/EP2006/006378 - 53 nephropathy, diabetic neuropathy, diabetic angiopathy and microangiopa thy), obesity, metabolic syndrome (dyslipidaemia), systemic and pulmo nary hypertonia, cardiovascular diseases (for example cardiac fibroses 5 after myocardial infarction, cardiac hypertrophy and cardiac insufficiency, 5 arteriosclerosis) and renal diseases (for example glomerulosclerosis, nephrosclerosis, nephritis, nephropathy, electrolyte excretion disorder), generally in fibroses and inflammatory processes of any type (for example liver cirrhosis, pulmonary fibrosis, fibrosing pancreatitis, rheumatism and 10 arthroses, Crohn's disease, chronic bronchitis, radiation fibrosis, sclero dermatitis, cystic fibrosis, scarring, Alzheimer's disease). The compounds according to the invention can also inhibit the growth of cancer, tumour cells and tumour metastases and are therefore suitable for 15 tumour therapy. The compounds according to the invention are furthermore used for the treatment of coagulopathies, such as, for example, dysfibrinogenaemia, hypoproconvertinaemia, haemophilia B, Stuart-Prower defect, prothrombin 20 complex deficiency, consumption coagulopathy, hyperfibrinolysis, immuno 20 coagulopathy or complex coagulopathies, and also in neuronal excitability, for example epilepsy. The compounds according to the invention can also be employed therapeutically in the treatment of glaucoma or a cataract. The compounds according to the invention are furthermore used in the 25 treatment of bacterial infections and in antiinfection therapy. The com pounds according to the invention can also be employed therapeutically for increasing learning ability and attention. 30 Preference is given to the use of compounds according to Claim 1, and pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, for the preparation of a medicament for the treatment or prevention of diabetes, obesity, metabolic syndrome 35 (dyslipidaemia), systemic and pulmonary hypertonia, cardiovascular dis eases and renal diseases, generally in fibroses and inflammatory proces ses of any type, cancer, tumour cells, tumour metastases, coagulopathies, WO 2007/014607 PCT/EP2006/006378 - 54 neuronal excitability, glaucoma, cataract, bacterial infections and in anti infection therapy, for increasing learning ability and attention, and for the treatment and prophylaxis of cell ageing and stress. 5 Diabetes is preferably diabetes mellitus, diabetic nephropathy, diabetic neuropathy, diabetic angiopathy and microangiopathy. Cardiovascular diseases are preferably cardiac fibroses after myocardial 10 infarction, cardiac hypertrophy, cardiac insufficiency and arteriosclerosis. Renal diseases are preferably glomerulosclerosis, nephrosclerosis, neph ritis, nephropathy and electrolyte excretion disorder. 15 Fibroses and inflammatory processes are preferably liver cirrhosis, pulmo nary fibrosis, fibrosing pancreatitis, rheumatism and arthroses, Crohn's disease, chronic bronchitis, radiation fibrosis, sclerodermatitis, cystic fibro sis, scarring, Alzheimer's disease. 20 ASSAYS The compounds of the formula I described in the examples can be tested for a kinase-inhibiting action by the assays described below. Other assays 25 are known from the literature and can readily be performed by the person skilled in the art (see, for example, Dhanabal et al., Cancer Res. 59:189 197; Xin et al., J. Biol. Chem. 274:9116-9121; Sheu et al., Anticancer Res. 18:4435-4441; Ausprunk et al., Dev. Biol. 38:237-248; Gimbrone et al., J. 30 Natl. Cancer Inst. 52:413-427; Nicosia et al., In Vitro 18:538- 549). 30 Measurement of the CHK1 kinase activity 35 CHK1 kinase is expressed for the purposes of protein production in insect cells (Sf21; S. frugiperda) and subsequent purification by affinity chromato- WO 2007/014607 PCT/EP2006/006378 -55 graphy as fusion protein with glutathione S-transferase in a baculovirus expression vector. The cultivation, infection and digestion of the cells as well as the purification of the fusion protein by column chromatography are carried out in accordance with manufacturer-oriented generic working in 5 structions. The kinase activity is measured using various available measurement systems. In the scintillation proximity method (Sorg et al., J. of. Biomolecu 10 lar Screening, 2002, 7, 11-19), the flashplate method or the filter binding 10 test, the radioactive phosphorylation of a protein or peptide as substrate is measured using radioactively labelled ATP (y 32P-ATP, (y 33P-ATP). In the case of the presence of an inhibitory compound, a reduced radioactive signal, or none at all, can be detected. Furthermore, homogeneous time 15 resolved fluorescence resonance energy transfer (HTR-FRET) and fluores cence polarisation (FP) technologies are useful as assay methods (Sills et al., J. of Biomolecular Screening, 2002, 191-214). Other non-radioactive ELISA assay methods use specific phospho anti 20 bodies (phospho ABs). The phospho antibody only binds the phosphor ylated substrate. This binding can be detected by chemiluminescence using a second peroxidase-conjugated antibody (Ross et al., 2002, Bio chem. J.). 25 Flashplate method (CHK1): The test plates used are 384-well streptavidin-coated Flashplates PlusR from Perkin Elmer (Cat.No. SMP410A001PK). The assay plate is equili brated with 75 pl of assay buffer per well 30 min before commencement of 30 the experiment. The buffer is sucked out before commencement of the experiment, and the components of the kinase reaction described below are pipetted onto the plate. CHK1 kinase, a biotinylated substrate peptide (for example CHKtide: 35 KKKVSRSGLYRSPSMPENLNRPR), is incubated with radioactively labelled ATP in the presence and absence of test substances at 30' Cel- WO 2007/014607 PICT/EP2006/006378 - 56 sius and a total volume of 50 pl. The reaction is terminated using 25 pI of a 0.2 M EDTA solution. After incubation for 30 min at room temperature, the supernatants are filtered off with suction, and the wells are washed three times with 100 pl of 0.9% NaCI solution each time. The measurement of 5 the bound radioactivity is carried out by means of a scintillation measuring instrument (Topcount NXT, Perkin-Elmer). The full value used is the inhibitor-free kinase reaction. This should be ap proximately in the range 3000-4000 cpm. The pharmacological zero value 10 used is staurosporin in a final concentration of 0.1 pM. The inhibitory values (IC50) are determined using the program RS1_MTS 0. Kinase reaction conditions per well: 15 5-20 mU of CHK1 kinase 0.15 pg of CHKtide (KKKVSRSGLYRSPSMPENLNRPR) 8 pM of ATP, cold 0,2 pCi of y 33 P-ATP 20 50 pl total volume (1-fold assay buffer reaction conditions) 20 Solutions used: - assay buffer: 50 mM Tris 25 0.1 mM Titriplex VI (EGTA 10 mM magnesium acetate 0.1% mercaptoethanol 0.02% Brij35 30 pH= 7.5 (to be set using hydrochloric acid) Bovine serum albumin (final concentration 0.1%) is not added until just before use. 35 - stop solution: 0.2 M Titriplexill (EDTA) WO 2007/014607 PCT/EP2006/006378 - 57 - y 3 3 P-ATP (Perkin-Elmer) - CHK1 kinase preparations: specific activity > 50 U/mg - CHKtide solution: biotinylated peptide substrate (Biotrend) stored as 5 stock solution (concentration 0.15 mg/ml). Filter binding method (CHK1): 10 5-20 mU of CHK1 kinase (diluted in 20 mM MOPS pH7.5, 1 mM EDTA, 0.1% P1-mercaptoethanol, 0.01% Brij-35, 5% glycerol, 1 mg/ml of BSA) are incubated for 30 min at room temperature in the presence of 30-200 pM CHKtide in 25.5 pl in 1-fold reaction buffer (8 mM MOPS pH7, 0.2 mM 15 EDTA, 10 mM magnesium acetate, 0.02 mM y 33 P-ATP [500-1000 cpm/ pmol]). The reaction is stopped using 5 pl of 0.5 M ortho-phosphoric acid and filtered through P81 filter plates. After the filter plates have been washed a number of times, the bound radioactivity is determined in a scin 20 tillation counter. Measurement of the CHK2 kinase activity Filter binding method (CHK2): 25 5-20 mU of CHK2 kinase (diluted in 20 mM MOPS pH7.5, 1 mM EDTA, 0.1% 13-mercaptoethanol, 0.01% Brij-35, 5% glycerol, 1 mg/ml of BSA) are incubated for 30 min at room temperature in the presence of 30-200 pM CHKtide (KKKVSRSGLYRSPSMPENLNRPR) in 25.5 pl in 1-fold reaction 30 buffer (8 mM MOPS pH7, 0.2 mM EDTA, 10 mM magnesium acetate, 0.02 mM y 33 P-ATP [500-1000 cpm/pmol]). The reaction is stopped using 5 pl of 0.5 M ortho-phosphoric acid and filtered through P81 filter plates. After the filter plates have been washed a number of times, the bound radioactivity is determined in a scintillation counter. 35 WO 2007/014607 PCT/EP2006/006378 - 58 The inhibition of SGK1 protein kinase can be determined in the filter bind ing method (analogously to CHK1, CHK2). 5 Above and below, all temperatures are indicated inoC. In the following 5 examples, "conventional work-up" means: if necessary, water is added, the pH is adjusted, if necessary, to values between 2 and 10, depending on the constitution of the end product, the mixture is extracted with ethyl ace tate or dichloromethane, the phases are separated, the organic phase is 10 dried over sodium sulfate and evaporated, and the product is purified by chromatography on silica gel and/or by crystallisation. Rf values on silica gel; eluent: ethyl acetate/methanol 9:1. Mass spectrometry (MS): El (electron impact ionisation) M 15 FAB (fast atom bombardment) (M+H) ESI (electrospray ionisation) (M+H) (unless indicated otherwise) APCI-MS (atmospheric pressure chemical ionisation - mass spectrometry) 20 (M+H) . Example 1 The preparation of 3-(3-hydroxybenzylamino)-4-(4-hydroxy-3-pyridin-2-yl 25 phenylamino)cyclobut-3-ene-1,2-dione ("Al") is carried out analogously to the following scheme 30 35 WO 2007/014607 PCTI/EP2006/006378 - 59 ONa Br CHO 1. 10_ OHC N Br
    CO
    2 H 2 N0 2 3. HO 5 5 2. N N 3 4 4. 10 OH 0 0 5- O /OEt NH 2 SH ri NH 5. HO NH 6 6 nitrite in water at 45-55oC by the method of Paul E. Fanta Organic Synthe ses 1952, 32, pages 95-96, to give 2-nitrobut-2-enal sodium salt 2.. 25 n-butyllithium in tetrahydrofuran by the method of Eric Pasquinet et al. J.Chem.Soc. Perkin Trans 1 1998, 22, pages 3807-3812, to give 1-pyridin 2-ylpropan-2-one 4. 1.3 1.35 g (9.98 mmol) of 2 are dissolved in 15 ml of water, 6 ml of 30 10% sodium hydroxide solution are added, and 1.39 g (10 mmol) of 4 (dis solved in 5 ml of ethanol) are added dropwise with stirring. After stirring at room temperature for 18 h, 1.4 g (65%) is subjected to conventional work up, giving 4-nitro-2-pyridin-2-ylphenol 5; MS-FAB (M+H ) = 217. 35 1.4 1.3 g (6.0 mmol) of 5 are dissolved in 15 ml of methanol and treated with hydrogen gas over Pd/C (5%). When the uptake of hydrogen WO 2007/014607 PCT/EP2006/006378 - 60 is complete, the mixture is subjected to conventional work-up, giving 1.0 g (93%) of 4-amino-2-pyridin-2-ylphenol 6; MS-FAB (M+H ) = 187. 1.5 0.91 g (5.37 mmol) of 3,4-diethoxy-3-cyclobutene-1,2-dione are 5 dissolved in 20 ml of ethanol, 1.0 g (5.37 mmol) of 6 is added, and the 5 mixture is stirred at 75oC for 20 h. The mixture is then subjected to con ventional work-up, giving 1.2 g (72%) of 3-ethoxy-4-(4-hydroxy-3-pyridin-2 ylphenlamino)cyclobut-3-ene-1,2-dione 7; MS-FAB (M+H) = 311, melting point 209-210 0 C. 10 1.6 150 mg (0.48 mmol) of 7 are dissolved in 5 ml of ethanol, 89.3 mg (1.0 mmol) of 3-aminomethylphenol are added, and the mixture is stirred at 75 0 C for 48 h. The mixture is then subjected to conventional work-up, giving 166 mg (89%) of 3-(3-hydroxybenzylamino)-4-(4-hydroxy-3-pyridin 15 2-ylphenylamino)cyclobut-3-ene-1,2-dione ("Al"), m.p. 271-272°; MS-FAB (M+H ) = 388; 1 H-NMR: DMSO-d 6 , 8 [pm] 13.816 (1H, s); 9.608 (1H, b); 9.5481 (1H, b); 8.651 20 (1H, d); 8.223 (1H, b), 8.03-8.15 (1H, m); 8.066 (1H, t); 7.91 (1H, b), 7.470 (1H, t); 7.16-7.23 (2H, m); 6.925 (1H, d); 6.76-6.82 (2H, m); 6.791 (1H, s); 6.714 (1H, d); 4.739 (2H, s). Example 2 25 The following compounds are obtained analogously to Example 1 No. Name M.p. [oC] MS-FAB [M+H] 30 "A2" 3-(3-Hydroxybenzylamino)-4-(4-hydroxy-3- 246-247 30 phenylphenylamino)cyclobut-3-ene-1,2 dione 35 WO 2007/014607 PCT/EP2006/006378 -61 "A3" 3-(4-Hyd roxy-3-pyrid in-2-ylphenylamino)-4- 298-290 [(R)-1-phenylethylamino]cyclobut-3-ene-1,2 dione 0 0 5 OHO 5 HO N N N H H 10 "A4" 3-(4-Hydroxy-3-pyridin-2-ylphenylamino)-4- 263-264 [(R)-1l-(3-methoxyphenyl)ethylamino] cyclobut-3-ene-1,2-dione "AS" 3-(4-Hydroxy-3-pyridin-2-ylphenylamino)-4- 284-285 15 [(R)-1-(3-hydroxyphenyl)ethylamino]cyclo but-3-ene-1,2-dione "A6" 3-(3-Pyridin-2-ylphenylamino)-4-[(R)-1l-(3- 264-265 hydroxyphenyl)ethylamino]cyclobut-3-ene 1,2-dione 20 "A7" 3-(4-Methoxy-3-pyridin-2-ylphenylamino)-4 [(R)-1l-(3-hydroxyphenyl)ethylamino] cyclobut-3-ene-1,2-dione "A8" 3-(3-Hydroxybenzylamino)-4-(4-hydroxy-3 25 pyrimidin-2-ylphenylamino)cyclobut-3-ene 1,2-dione "A9" 3-(4-Hydroxy-3-pyridin-2-ylphenylamino)-4 [(R)-1 -(3-hydroxyphenyl)-2-methyl-propyl 30 amino]cyclobut-3-ene-1,2-dione "A1 0" 3-(4-Hydroxy-3-pyridin-2-ylphenylamino)-4- 402 [(S)-l -(3-hydroxyphenyl)ethylamino]cyclobut 3-ene-1,2-dione 35 WO 2007/014607 PCT/EP2006/006378 - 62 "Al l" 3-(3-Aminobenzylamino)-4-(4-hydroxy-3 pyridin-2-ylphenylamino)cyclobut-3-ene-1,2 dione 5 "A12" 3-(3-Aminosulfonylbenzylamino)-4-(4 5 hyd roxy-3-pyridin-2-ylphenylamino)cyclobut 3-ene-1,2-dione "Al 3" 3-(4-Hydroxy-3-pyrimidin-2-ylphenylamino) 4-[(R)-1 -(3-hydroxyphenyl)ethylamino] 10 cyclobut-3-ene-1,2-dione "A14" 3-[N'-(3-Hydroxyphenyl)hydrazino]-4-(4 hydroxy-3-pyrimidin-2-ylphenylamino) cyclobut-3-ene-1,2-dione 15 HO H N N-N 20 H H "OH 20// "A1 5" 3-[N'-(3-Hydroxyphenyl)hydrazino]-4-(4 hydroxy-3-pyridin-2-ylphenylamino)cyclobut 25 3-ene-1,2-dione "A1 6" 3-(4-Hydroxy-3-pyridin-2-ylphenylamino)-4 [(R)-l -(3-aminophenyl)ethylamino]cyclobut 3-ene-1,2-dione "A17" 3-(3-Aminobenzylamino)-4-(4-hydroxy-3 30 30 pyrimidin-2-ylphenylamino)cyclobut-3-ene 1,2-dione "A1 8" 3-(3-Aminosulfonylbenzylamino)-4-(4 hydroxy-3-pyrimidin-2-ylphenylamino) 35 cyclobut-3-ene-1,2-dione WO 2007/014607 PCT/EP2006/006378 - 63 "A1 9" 3-(3-Hydroxybenzylamino)-4-(4-hydroxy-3 pyrazin-2-ylphenylamino)cyclobut-3-ene-1,2 dione 5 "A20" 3-(4-Hydroxy-3-pyrazin-2-ylphenylamino)-4 [(R)-l -(3-hydroxyphenyl)ethylamino]cyclo but-3-ene-1,2-dione "A21" 3-(3-Hydroxybenzylamino)-4-(4-hydroxy-3 pyridin-2-ylphenylamino)cyclobut-3-ene-1,2 10 dione "A22" 3-(3-Hydroxybenzylamino)-4-(4-hydroxy-3 pyridin-3-ylphenylamino)cyclobut-3-ene-1,2 dione 15 "A23" 3-(3-Hydroxybenzylamino)-4-(4-hydroxy-3 pyridin-4-ylphenylamino)cyclobut-3-ene-1,2 dione "A24" 3-(3-Hydroxybenzylamino)-4-(4-hydroxy-3 20 pyrimidin-2-ylphenylamino)cyclobut-3-ene 1,2-dione "A25" 3-(3-Hydroxybenzylamino)-4-(4-hydroxy-3 pyrazin-2-ylphenylamino)cyclobut-3-ene-1,2 dione 25 25 "A26" 3-(3-Hyd roxybenzylamino)-4-(4-hydroxy-3 pyrimidin-4-ylphenylamino)cyclobut-3-ene 1,2-dione "A27" 3-(3-Hydroxybenzylamino)-4-(4-hydroxy-3 30 pyridazin-3-ylphenylamino)cyclobut-3-ene 1,2-dione "A28" 3-(3-Hydroxybenzylamino)-4-[4-hydroxy-3 (6-fluoropyridin-2-yl)phenylamino]cyclobut-3 35 ene-1,2-dione WO 2007/014607 PCT/EPI2006/006378 - 64 "A29" 3-(3-Hydroxybenzylamino)-4-[4-hydroxy-3 (6-chloropyridin-2-yl)phenylamino]cyclobut 3-ene-1,2-dione 5 "A30" 3-(3-Hydroxybenzylamino)-4-(4-hydroxy-3 5 quinolin-2-ylphenylamino)cyclobut-3-ene 1,2-dione "A31" 3-(3-Hydroxybenzylamino)-4-[4-hydroxy-3 (5-cyanopyridin-2-yl)phenylamino]cyclobut-3 10 ene-1,2-dione "A32" 3-(3-Hyd roxybenzylamino)-4-(4-hydroxy-3 isoquinolin-1 -ylphenylamino)cyclobut-3-ene 1,2-dione 15 "A33" 3-(3-Hydroxybenzylamino)-4-[4-hydroxy-3 (3-phenylpyridin-2-yl)phenylamino]cyclobut 3-ene-1,2-dione "A34" 3-(3-Hydroxybenzylamino)-4-[4-hydroxy-3 20 (4-chloropyridin-2-yl)phenylamino]cyclobut 3-ene-1,2-dione "A35" 3-(4-Hydroxy-3-pyridin-3-ylphenylamino)-4 [(R)-1l-(3-hydroxyphenyl)ethylamino] cyclobut-3-ene-1,2-dione 25 25 "A36" 3-(4-Hydroxy-3-pyridin-3-ylphenylamino)-4 [(S)-1l-(3-hydroxyphenyl)ethylamino]cyclobut 3-ene-1,2-dione "A37" 3-(4-Hydroxy-3-pyridin-4-ylphenylamino)-4 30 [(R)-1l-(3-hydroxyphenyl)ethylamino] cyclobut-3-ene-1,2-dione "A38" 3-(4-Hydroxy-3-pyridin-4-ylphenylamino)-4 [(S)-1-(3-hydroxyphenyl)ethylamino]cyclobut 35 3-ene-1,2-dione WO 2007/014607 PCT/EP2006/006378 - 65 "A39" 3-(4-Hydroxy-3-pyrimidin-2-ylphenylamino) 4-[(S)-1 -(3-hydroxyphenyl)ethylamino] cyclobut-3-ene-1,2-dione 5 "A40" 3-(4-Hydroxy-3-pyrazin-2-ylphenylamino)-4 5 [(S)-1 -(3-hydroxyphenyl)ethylamino]cyclobut 3-ene-1,2-dione "A41" 3-(4-Hydroxy-3-pyrimidin-4-ylphenylamino) 4-[(R)-1 -(3-hydroxyphenyl)ethylamino] 10 cyclobut-3-ene-1,2-dione "A42" 3-(4-Hydroxy-3-pyrimidin-4-ylphenylamino) 4-[(S)-1 -(3-hydroxyphenyl)ethylamino] cyclobut-3-ene-1,2-dione 15 "A43" 3-(4-Hydroxy-3-pyridazin-3-ylphenylamino) 4-[(R)-1 -(3-hydroxyphenyl)ethylamino] cyclobut-3-ene-1,2-dione "A44" 3-(4-Hydroxy-3-pyridazin-3-ylphenylamino) 20 4-[(S)-1-(3-hydroxyphenyl)ethylamino] cyclobut-3-ene-1,2-dione "A45" 3-[4-Hydroxy-3-(6-fluoropyridin-2-yl)phenyl amino]-4-[(S)-1 -(3-hydroxyphenyl)ethyl amino]cyclobut-3-ene-1,2-dione 25 25 "A46" 3-[4-Hydroxy-3-(6-fluoropyridin-2-yl)phenyl amino]-4-[(R)-1 -(3-hydroxyphenyl)ethyl amino]cyclobut-3-ene-1,2-dione "A47" 3-[4-Hydroxy-3-(6-chloropyridin-2-yl)phenyl 30 amino]-4-[(S)-1-(3-hydroxyphenyl)ethyl amino]cyclobut-3-ene-1,2-dione "A48" 3-[4-Hydroxy-3-(6-chloropyridin-2-yl)phenyl amino]-4-[(R)-1 -(3-hydroxyphenyl)ethyl 35 amino]cyclobut-3-ene-1,2-dione WO 2007/014607 PCT/EP2006/006378 - 66 "A49" 3-(4-Hydroxy-3-quinolin-2-ylphenylamino)-4 [(S)-1l-(3-hydroxyphenyl)ethylamino]cyclobut 3-ene-1,2-dione 5 "A50" 3-(4-Hydroxy-3-quinolin-2-ylphenylamino)-4 5 [(R)-1l-(3-hydroxyphenyl)ethylamino] cyclobut-3-ene-1,2-dione "A51" 3-[4-Hydroxy-3-(5-cyanopyridin-2-yl)phenyl amino]-4-[(S)-1 -(3-hydroxyphenyl)ethyl 10 amino]cyclobut-3-ene-1,2-dione "A52" 3-[4-Hydroxy-3-(5-cyanopyridin-2-yl)phenyl amino]-4-[(R)-1 -(3-hydroxyphenyl)ethyl amino]cyclobut-3-ene-1,2-dione 15 "A53" 3-(4-Hydroxy-3-isoquinolin-1 -yl phenylamino)-4-[(S)-1 -(3-hydroxyphenyl) ethylamino]cyclobut-3-ene-1,2-dione "A54" 3-(4-Hydroxy-3-isoquinolin-1-yl 20 phenylamino)-4-[(R)-1l-(3-hydroxyphenyl) ethylamino]cyclobut-3-ene-1,2-dione "A55" 3-[4-Hydroxy-3-(3-phenylpyridin-2-yl)phenyl amino]-4-[(S)-1 -(3-hydroxyphenyl)ethyl amino]cyclobut-3-ene-1,2-dione 25 25 "A56" 3-[4-Hydroxy-3-(3-phenylpyridin-2-yl)phenyl amino]-4-[(R)-1l-(3-hydroxyphenyl)ethyl amino]cyclobut-3-ene-1,2-dione "A57" 3-[4-Hydroxy-3-(4-chloropyridin-2-yl)phenyl 30 amino]-4-[(S)-1 -(3-hydroxyphenyl)ethyl amino]cyclobut-3-ene-1,2-dione "A58" 3-[4-Hydroxy-3-(4-chloropyridin-2-yl)phenyl amino]-4-[(R)-1 -(3-hydroxyphenyl)ethyl 35 amino]cyclobut-3-ene-1,2-dione WO 2007/014607 PCT/EP2006/006378 -67 "A59" 3-(4-Hydroxy-3-pyridin-2-ylphenylamino)-4 [(S)-1l-(3-methoxyphenyl)ethylamino] cyclobut-3-ene-1,2-dione 5 "A60" 3-[2-(3-Hydroxyphenyl)ethylamino]-4-(4- 402 hydroxy-3-pyridin-2-ylphenylamino)cyclobut 3-ene-1,2-dione 1 H-NMR: DMSO-d 6 , 8 [pm] 13.786 (1H, s); 9.613 (1H, b); 9.313 (1H, b); 8.643 10 (1H, d); 8.226 (1H, b); 8.12-8.15 (1H, m); 8.070 (1H, dt); 7.555 (1H, b), 7.463 (1H, t); 7.183 (1H, dd); 7.105 (1H,t); 6.908 (1H, d); 6.66-6.71 (2H, m); 6.625 (1H, d); 3.821 (1H, m); 2.815 (1H, t). "A61" 3-(3,4-Dihydroxybenzylamino)-4-(4-hydroxy- 404 15 3-pyridin-2-ylphenylamino)cyclobut-3-ene 1,2-dione 1 H-NMR: DMSO-d 6 , 6 [pm] 13.798 (1H, s); 9.553 (1H, b); 8.980 (1H, b); 8.894 (1H, b); 8.640 (1H, d); 8.224 (1H, b); 8.09-8.13 (1H, m); 8.056 (1H, dt); 20 7.822 (1H, b); 7.460 (1H, dt); 7.192 (1H, dd); 6.909 (1H, d); 6.764 (1H, d); 6.721 (1H, d); 6.635 (1H, dd); 4.625 (2H, d). "A62" 3-(4-Fluoro-3-methoxybenzylamino)-4-(4- 420 hydroxy-3-pyridin-2-ylphenylamino)cyclobut 25 3-ene-1,2-dione "A63" 3-(3,5-Dihydroxybenzylamino)-4-(4-hydroxy- 404 3-pyridin-2-ylphenylamino)cyclobut-3-ene 1,2-dione H-NMR: 30 DMSO-d 6 , 8 [pm] 13.80 (2H, sb) 9.605 (1H, s); 9.29 (1H, b); 8.656 (1H, d); 8.203 (1H, b); 8.07-8.15 (2H, m); 7.876 (1H, b); 7.493 (1H, t); 7.219 (1H, dd); 6.928 (1H, d); 6.219 (2H, d); 6.140 (1H, s); 4.621 (2H, d). "A64" 3-(3-Acetamidobenzylamino)-4-(4-hydroxy-3- 429 35 pyridin-2-ylphenylamino)cyclobut-3-ene-1,2 dione WO 2007/014607 PCT/EP2006/006378 -68 "A65" 3-(4-Fluoro-3-hydroxybenzylamino)-4-(4- 406 hydroxy-3-pyridin-2-ylphenylamino)cyclobut 3-ene-1,2-dione 5 "A66" 3-(3-Aminocarbonylbenzylamino)-4-(4- 415 5 hydroxy-3-pyridin-2-ylphenylamino)cyclobut 3-ene-1,2-dione "A67" 3-(3-Methylaminosulfonylbenzylamino)-4-(4- 465 hydroxy-3-pyridin-2-ylphenylamino)cyclobut 10 3-ene-1,2-dione "A68" 3-[(3-Hydroxybenzyl)methylamino]-4-(4- 402 hydroxy-3-pyridin-2-ylphenylamino)cyclobut 3-ene-1,2-dione 15 "A69" 3-(3-Methylsulfonylaminobenzylamino)-4-(4 hydroxy-3-pyridin-2-ylphenylamino)cyclobut 3-ene-1,2-dione "A70" 3-(3-Methoxybenzylamino)-4-(4-hydroxy-3 20 pyridin-2-ylphenylamino)cyclobut-3-ene-1,2 dione "A71" o o HO N N H 25 N H H B / / - OH "A72" 3-(3-Hydroxybenzylamino)-4-(3-imidazol-1- 391 yl-4-methoxyphenylamino)cyclobut-3-ene 30 1,2-dione "A73" 3-(3-Hydroxybenzylamino)-4-(4-hydroxy-3- 376 pyrrol-1 -ylphenylamino)cyclobut-3-ene-1,2 dione 35 WO 2007/014607 PCT/EP2006/006378 - 69 "A74" 3-(3-Hydroxybenzylamino)-4-(3-imidazol-1- 377 yl-4-hydroxyphenylamino)cyclobut-3-ene 1,2-dione "A75" 3-(3-Hydroxybenzylamino)-4-(4-hydroxy-3- 377 5 pyrazol-1-ylphenylamino)cyclobut-3-ene-1,2 dione "A76" 3-(4-Hydroxy-3-pyrazol-1 -ylphenylamino)-4- 405 [(R)-l1-(3-methoxyphenyl)ethylamino]cyclo 10 but-3-ene-1,2-dione Pharmacological data 15 Affinity to receptors Table 1 Compound CHK1-IC 50 [M] No. 20 "Al" +++ "A2" + "A3" + "A4" + 25 "A5" +++ "A6" + "A10" + "A12" ++ "A23"' ++ 30 "A59" + "A60" ++ "A61" +++ "A62" + 35 "A63" +++ 35"A64" I "A64" + + WO 2007/0 14607 PCT/E I'2006I006378 - 70 'lA65' ++ "A66" ++ "A67" ++ "A6811 ++ 5"A72f' + "A73" + "A74"v + "A75" ++ 10 flA7611 ++ + IC 5 >lpM ++ IC 50 <1 pM 15 ... IC 50 <l100nM 20 25 30 35 WO 2007/014607 PCT/EP2006/006378 -71 The following examples relate to medicaments: 5 Example A: Injection vials A solution of 100 g of an active ingredient of the formula I and 5 g of di sodium hydrogenphosphate in 3 I of bidistilled water is adjusted to pH 6.5 using 2 N hydrochloric acid, sterile filtered, transferred into injection vials, 10 lyophilised under sterile conditions and sealed under sterile conditions. Each injection vial contains 5 mg of active ingredient. Example B: Suppositories 15 A mixture of 20 g of an active ingredient of the formula I with 100 g of soya lecithin and 1400 g of cocoa butter is melted, poured into moulds and allowed to cool. Each suppository contains 20 mg of active ingredient. 20 Example C: Solution A solution is prepared from 1 g of an active ingredient of the formula I, 9.38 g of NaH 2
    PO
    4 - 2 H 2 0, 28.48 g of Na 2
    HPO
    4 • 12 H 2 0 and 0.1 g of benzalkonium chloride in 940 ml of bidistilled water. The pH is adjusted to 6.8, and the solution is made up to 1 I and sterilised by irradiation. This 25 solution can be used in the form of eye drops. Example D: Ointment 500 mg of an active ingredient of the formula I are mixed with 99.5 g of 30 Vaseline under aseptic conditions. Example E: Tablets A mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 35 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is 35 WO 2007/014607 PCT/EP2006/006378 - 72 pressed to give tablets in a conventional manner in such a way that each tablet contains 10 mg of active ingredient. Example F: Dragees 5 Tablets are pressed analogously to Example E and subsequently coated in a conventional manner with a coating of sucrose, potato starch, talc, traga canth and dye. 10 Example G: Capsules 2 kg of active ingredient of the formula I are introduced into hard gelatine capsules in a conventional manner in such a way that each capsule con tains 20 mg of the active ingredient. 15 Example H: Ampoules A solution of 1 kg of active ingredient of the formula I in 60 I of bidistilled water is sterile filtered, transferred into ampoules, lyophilised under sterile 20 conditions and sealed under sterile conditions. Each ampoule contains 20 10 mg of active ingredient. 25 30 35
    权利要求:
    Claims (19)
    [1] 1. Compounds of the formula I 5 R20 0 N N-X H/I R R5
    [2] 10-- R R4 10 / in which R denotes phenyl or a mono- or bicyclic saturated, unsatu rated or aromatic heterocycle having 1 to 4 N, O and/or 15 S atoms, where the radicals may be mono-, di-, tri-, tetra- or pentasubstituted by Hal, A, CN, Ar, Het, CONH 2 , CONHA, CONAA', NHCOA, NHCOAr, NHSO 2 A, NHSO 2 Ar, =S, =NH, =NA and/or =0 (carbonyl 20 oxygen), (CH 2 )m X denotes (CH 2 )n, CHA, NH, NA or / -C R 1 denotes H, OH or OA, 25 R 2 denotes H, A, Hal, -CO-A, CN, COOH, COOA or CONH 2 , R 3 denotes OH, OA, NH 2 , NHA, NAA', Hal, A, CONH 2 , CONHA, CONAA', CONHAr, CONHHet, SO 2 NH 2 , 30 SO 2 NHA, SO 2 NAA', SO 2 NHAr, SO 2 NHHet, NHSO 2 A, NHSO 2 Ar, NHSO 2 Het, NHCOA, NHCOAr, NHCOHet or B(OH 2 ), R 4 denotes H, OH or F, 35 R 5 denotes H or methyl, WO 2007/014607 PCT/EP2006/006378 - 74 Ar denotes phenyl, naphthyl or biphenyl, each of which is unsubstituted or mono-, di-, tri-, tetra- or pentasubsti tuted by A, OA, OH, SH, SA, Hal, NO 2 , CN, (CH 2 )nAr', 5 (CH 2 )nCOOH, (CH 2 )nCOOA, CHO, COA, SO 2 A, CONH 2 , 5 SO 2 NH 2 , CONHA, CONAA', SO 2 NHA, SO 2 NAA', NH 2 , NHA, NAA', OCONH 2 , OCONHA, OCONAA', NHCOA, NHCOOA, NACOOA, NHSO 2 OA, NASO 2 0OA, NHCONH 2 , NACONH 2 , NHCONHA, NACONHA, 10 NHCONAA',NACONAA' and/or NHCO(CH 2 )nNH 2 , Ar' denotes phenyl, naphthyl or biphenyl, each of which is unsubstituted or mono-, di- or trisubstituted by A, OA, OH, SH, SA, Hal, NO 2 , CN, (CH 2 )nphenyl, (CH 2 )nCOOH, 15 (CH 2 )nCOOA, CHO, COA, SO 2 A, CONH 2 , SO 2 NH 2 , CONHA, CONAA', SO 2 NHA, SO 2 NAA', NH 2 , NHA, NAA', OCONH 2 , OCONHA, OCONAA', NHCOA, NHCOOA, NACOOA, NHSO 2 OA, NASO 2 OA, 20 NHCONH 2 , NACONH 2 , NHCONHA, NACONHA, 20 NHCONAA' and/or NACONAA', Het denotes a mono- or bicyclic saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms, which may be mono-, di- or trisubstituted by A, OA, OH, 25 SH, SA, Hal, NO 2 , CN, (CH 2 )nAr', (CH 2 )nCOOH, (CH 2 )nCOOA, CHO, COA, SO 2 A, CONH 2 , SO 2 NH 2 , CONHA, CONAA', SO 2 NHA, SO 2 NAA', NH 2 , NHA, NAA', OCONH 2 , OCONHA, OCONAA', NHCOA, 30 NHCOOA, NACOOA, NHSO 2 OA, NASO 2 OA, NHCONH 2 , NACONH 2 , NHCONHA, NACONHA, NHCONAA', NACONAA', SO 2 A, =S, =NH, =NA and/or =0 (carbonyl oxygen), 35 Het denotes a monocyclic saturated heterocycle having 1 to 35 2 N and/or O atoms, which may be mono- or disubsti tuted by A, OA, OH, Hal and/or =0 (carbonyl oxygen), WO 2007/014607 PCT/EP2006/006378 - 75 A, A' each, independently of one another, denote alkyl having 1 to 10 C atoms, in which, in addition, 1-7 H atoms may be replaced by F and/or chlorine, Hal denotes F, CI, Br or I, 5 m denotes 2, 3, 4 or 5, n denotes 0, 1 or 2, and pharmaceutically usable derivatives, solvates, salts and stereo isomers thereof, including mixtures thereof in all ratios. 10 2. Compounds according to Claim 1 in which X denotes (CH 2 )n, CHA or NH, and pharmaceutically usable derivatives, solvates, salts and stereo 15 isomers thereof, including mixtures thereof in all ratios. 3. Compounds according to Claim 1 or 2 in which R 1 denotes H or OH. 20 and pharmaceutically usable derivatives, solvates, salts and stereo 20 isomers thereof, including mixtures thereof in all ratios. 4. Compounds according to one or more of Claims 1-3 in which R 2 denotes H, 25 and pharmaceutically usable derivatives, solvates, salts and stereo isomers thereof, including mixtures thereof in all ratios. 5. Compounds according to one or more of Claims 1-4 in which 30 R 3 denotes OH, OA, NH 2 , NHCOA, CONH 2 , SO 2 NHA, NHSO 2 A, B(OH) 2 or SO 2 NH 2 , and pharmaceutically usable derivatives, solvates, salts and stereo isomers thereof, including mixtures thereof in all ratios. 35 6. Compounds according to one or more of Claims 1-5 in which R 3 denotes OH or OA, WO 2007/0 1 4607 PCT/E P2006/006378 - 76 and pharmaceutically usable derivatives, solvates, salts and stereo isomers thereof, including mixtures thereof in all ratios. 7. Compounds according to one or more of Claims 1-6 in which 5 n denotes 1 or 2, and pharmaceutically usable derivatives, solvates, salts and stereo isomers thereof, including mixtures thereof in all ratios. 10 8. Compounds according to one or more of Claims 1-7 in which A denotes alkyl having 1 to 6 C atoms, in which, in addi tion, 1-5 H atoms may be replaced by F and/or chlorine, and pharmaceutically usable derivatives, solvates, salts and stereo 15 isomers thereof, including mixtures thereof in all ratios. 9. Compounds according to one or more of Claims 1-8 in which in which 20 R denotes phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyraz 20 inyl, quinoline or isoquinoline, each of which is unsub stituted or mono-, di- or trisubstituted by Hal, CN, phenyl and/or A, X denotes (CH 2 )n, CHA or NH 25 R denotes H, OH or OA, R 2 denotes H, R 3 denotes OH, OA, NH 2 , NHCOA, CONH 2 , SO 2 NHA, NHSO 2 A, B(OH) 2 or SO 2 NH 2 , 30 A denotes alkyl having 1 to 6 C atoms, in which, in addi tion, 1-5 H atoms may be replaced by F and/or chlorine, n denotes 1 or 2, R 4 denotes H, OH or F, 35 and pharmaceutically usable derivatives, solvates, salts and stereo 35isomers thereof, including mixtures thereof in all ratios. isomers thereof, including mixtures thereof in all ratios. WO 2007/014607 PCT/E P2006/006378 - 77 10. Compounds according to Claim 1, selected from the group "Al" 3-(3-Hydroxybenzylamino)-4-(4-hydroxy-3-pyridin-2-yl 5 phenylamino)cyclobut-3-ene-1,2-dione "A2" 3-(3-Hydroxybenzylamino)-4-(4-hydroxy-3-phenylphenyl amino)cyclobut-3-ene-1,2-dione "A3" 3-(4-Hydroxy-3-pyridin-2-ylphenylamino)-4-[(R)-1 -phenyl ethylamino]cyclobut-3-ene-1,2-dione 10 0 o HO N N N H H 15 "A4" 3-(4-Hydroxy-3-pyridin-2-ylphenylamino)-4-[(R)-1 -(3-meth oxyphenyl)ethylamino]cyclobut-3-ene-1,2-dione "A5" 3-(4-Hydroxy-3-pyridin-2-ylphenylamino)-4-[(R)-1 -(3 20 hydroxyphenyl)ethylamino]cyclobut-3-ene-1,2-dione 20 "A6" 3-(3-Pyridin-2-ylphenylamino)-4-[(R)-1 -(3-hydroxyphenyl) ethylamino]cyclobut-3-ene-1,2-dione "A7" 3-(4-Methoxy-3-pyridin-2-ylphenylamino)-4-[(R)-1-(3 hydroxyphenyl)ethylamino]cyclobut-3-ene-1,2-dione 25 "A8" 3-(3-Hydroxybenzylamino)-4-(4-hydroxy-3-pyrimidin-2-yl phenylamino)cyclobut-3-ene-1,2-dione "A9" 3-(4-Hydroxy-3-pyridin-2-ylphenylamino)-4-[(R)-1 -(3 hydroxyphenyl)-2-methylpropylamino]cyclobut-3-ene-1,2 30 dione "A1 0" 3-(4-Hydroxy-3-pyridin-2-ylphenylamino)-4-[(S)-1 -(3 hydroxyphenyl)ethylamino]cyclobut-3-ene-1,2-dione "A11" 3-(3-Aminobenzylamino)-4-(4-hydroxy-3-pyridin-2-yl 35 phenylamino)cyclobut-3-ene-l1,2-dione WO 2007/014607 PCT/EP2006/006378 - 78 "A12" 3-(3-Aminosulfonylbenzylamino)-4-(4-hydroxy-3-pyridin-2 ylphenylamino)cyclobut-3-ene-1,2-dione "A1 3" 3-(4-Hydroxy-3-pyrimidin-2-ylphenylamino)-4-[(R)-l -(3 5 hydroxyphenyl)ethylamino]cyclobut-3-ene-1,2-dione "A14" 3-[N'-(3-Hydroxyphenyl)hydrazino]-4-(4-hydroxy-3 pyrimidin-2-ylphenylamino)cyclobut-3-ene-l1,2-dione O O 10 HO ON N NN N H H OH N 15 "A1 5" 3-[N'-(3-Hydroxyphenyl)hydrazino]-4-(4-hydroxy-3-pyridin 2-ylphenylamino)cyclobut-3-ene-1,2-dione "A16" 3-(4-Hydroxy-3-pyridin-2-ylphenylamino)-4-[(R)-l-(3 aminophenyl)ethylamino]cyclobut-3-ene-1,2-dione 20 "A17" 3-(3-Aminobenzylamino)-4-(4-hydroxy-3-pyrimidin-2-yl phenylamino)cyclobut-3-ene-1,2-dione "A1 8" 3-(3-Aminosulfonylbenzylamino)-4-(4-hydroxy-3-pyrimidin 2-ylphenylamino)cyclobut-3-ene-1,2-dione 25 "A1 9" 3-(3-Hydroxybenzylamino)-4-(4-hydroxy-3-pyrazin-2-yl phenylamino)cyclobut-3-ene-1,2-dione "A20" 3-(4-Hydroxy-3-pyrazin-2-ylphenylamino)-4-[(R)--(3 hydroxyphenyl)ethylamino]cyclobut-3-ene-1,2-dione "A21" 3-(3-Hydroxybenzylamino)-4-(4-hydroxy-3-pyridin-2-yl 30 phenylamino)cyclobut-3-ene-1,2-dione "A22" 3-(3-Hydroxybenzylamino)-4-(4-hydroxy-3-pyridin-3-yl phenylamino)cyclobut-3-ene-1,2-dione "A23" 3-(3-Hydroxybenzylamino)-4-(4-hydroxy-3-pyridin-4-yl 35 phenylamino)cyclobut-3-ene-1,2-dione WO 2007/014607 PCT/EP2006/006378 - 79 "A24" 3-(3-Hydroxybenzylamino)-4-(4-hydroxy-3-pyrimidin-2-yl phenylamino)cyclobut-3-ene-1,2-dione "A25" 3-(3-Hydroxybenzylamino)-4-(4-hydroxy-3-pyrazin-2-yl 5 phenylamino)cyclobut-3-ene-1,2-dione "A26" 3-(3-Hydroxybenzylamino)-4-(4-hydroxy-3-pyrimidin-4-yl phenylamino)cyclobut-3-ene-1,2-dione "A27" 3-(3-Hydroxybenzylamino)-4-(4-hydroxy-3-pyridazin-3-yl phenylamino)cyclobut-3-ene-1,2-dione 10 "A28" 3-(3-Hydroxybenzylamino)-4-[4-hydroxy-3-(6-fluoropyridin 2-yl)phenylamino]cyclobut-3-ene-1,2-dione "A29" 3-(3-Hydroxybenzylamino)-4-[4-hydroxy-3-(6 chloropyridin-2-yl)phenylamino]cyclobut-3-ene-1,2-dione 15 "A30" 3-(3-Hydroxybenzylamino)-4-(4-hydroxy-3-quinolin-2-yl phenylamino)cyclobut-3-ene-1,2-dione "A31" 3-(3-Hydroxybenzylamino)-4-[4-hydroxy-3-(5-cyanopyridin 2-yl)phenylamino]cyclobut-3-ene-1,2-dione 20 "A32" 3-(3-Hydroxybenzylamino)-4-(4-hydroxy-3-isoquinolin-1 -yl phenylamino)cyclobut-3-ene-1,2-dione "A33" 3-(3-Hydroxybenzylamino)-4-[4-hydroxy-3-(3-phenyl pyridin-2-yl)phenylamino]cyclobut-3-ene-1,2-dione "A34" 3-(3-Hydroxybenzylamino)-4-[4-hydroxy-3-(4-chloro 25 pyridin-2-yl)phenylamino]cyclobut-3-ene-1,2-dione "A35" 3-(4-Hydroxy-3-pyridin-3-ylphenylamino)-4-[(R)-1l-(3 hydroxyphenyl)ethylamino]cyclobut-3-ene-1,2-dione "A36" 3-(4-Hydroxy-3-pyridin-3-ylphenylamino)-4-[(S)-1-(3 30 hydroxyphenyl)ethylamino]cyclobut-3-ene-1,2-dione "A37" 3-(4-Hydroxy-3-pyridin-4-ylphenylamino)-4-[(R)-1-(3 hydroxyphenyl)ethylamino]cyclobut-3-ene-1,2-dione "A38" 3-(4-Hydroxy-3-pyridin-4-ylphenylamino)-4-[(S)-1-(3 35 hydroxyphenyl)ethylamino]cyclobut-3-ene-1,2-dione WO 2007/014607 PCT/EP2006/006378 - 80 "A39" 3-(4-Hydroxy-3-pyrimidin-2-ylphenylamino)-4-[(S)-1-(3 hydroxyphenyl)ethylamino]cyclobut-3-ene-1,2-dione "A40" 3-(4-Hydroxy-3-pyrazin-2-ylphenylamino)-4-[(S)-1l-(3 5 hydroxyphenyl)ethylamino]cyclobut-3-ene-1,2-dione "A41" 3-(4-Hydroxy-3-pyrimidin-4-ylphenylamino)-4-[(R)-1l-(3 hydroxyphenyl)ethylamino]cyclobut-3-ene-1,2-dione "A42" 3-(4-Hydroxy-3-pyrimidin-4-ylphenylamino)-4-[(S)-l1-(3 hydroxyphenyl)ethylamino]cyclobut-3-ene-1,2-dione 10 "A43" 3-(4-Hydroxy-3-pyridazin-3-ylphenylamino)-4-[(R)-1-(3 hydroxyphenyl)ethylamino]cyclobut-3-ene-1,2-dione "A44" 3-(4-Hydroxy-3-pyridazin-3-ylphenylamino)-4-[(S)-l1-(3 hydroxyphenyl)ethylamino]cyclobut-3-ene-1,2-dione 15 "A45" 3-[4-Hydroxy-3-(6-fluoropyridin-2-yl)phenylamino]-4-[(S)-1 (3-hydroxyphenyl)ethylamino]cyclobut-3-ene-1,2-dione "A46" 3-[4-Hydroxy-3-(6-fluoropyridin-2-yl)phenylamino]-4-[(R)-1 (3-hydroxyphenyl)ethylamino]cyclobut-3-ene-1,2-dione 20 "A47" 3-[4-Hydroxy-3-(6-chloropyridin-2-yl)phenylamino]-4-[(S) 1-(3-hydroxyphenyl)ethylamino]cyclobut-3-ene-1,2-dione "A48" 3-[4-Hydroxy-3-(6-chloropyridin-2-yl)phenylamino]-4-[(R) 1-(3-hydroxyphenyl)ethylamino]cyclobut-3-ene-1,2-dione "A49" 3-(4-Hydroxy-3-quinolin-2-ylphenylamino)-4-[(S)-1-(3 25 hydroxyphenyl)ethylamino]cyclobut-3-ene-1,2-dione "A50" 3-(4-Hydroxy-3-quinolin-2-ylphenylamino)-4-[(R)-l1-(3 hydroxyphenyl)ethylamino]cyclobut-3-ene-1,2-dione "A51" 3-[4-Hydroxy-3-(5-cyanopyridin-2-yl)phenylamino]-4-[(S) 30 1-(3-hydroxyphenyl)ethylamino]cyclobut-3-ene-1,2-dione "A52" 3-[4-Hydroxy-3-(5-cyanopyridin-2-yl)phenylamino]-4-[(R) 1-(3-hydroxyphenyl)ethylamino]cyclobut-3-ene-1,2-dione "A53" 3-(4-Hydroxy-3-isoquinolin-1 -ylphenylamino)-4-[(S)-1 -(3 35 hydroxyphenyl)ethylamino]cyclobut-3-ene-1,2-dione WO 2007/014607 PCT/EPI2006/006378 -81 "A54" 3-(4-Hydroxy-3-isoquinolin-1 -ylphenylamino)-4-[(R)-1-(3 hydroxyphenyl)ethylamino]cyclobut-3-ene-1,2-dione "A55" 3-[4-Hydroxy-3-(3-phenylpyridin-2-yl)phenylamino]-4-[(S) 51 -(3-hydroxyphenyl)ethylamino]cyclobut-3-ene-1,2-dione "A56" 3-[4-Hydroxy-3-(3-phenylpyridin-2-yl)phenylamino]-4-[(R) 1-(3-hydroxyphenyl)ethylamino]cyclobut-3-ene-1,2-dione "A57" 3-[4-Hydroxy-3-(4-chloropyridin-2-yl)phenylamino]-4-[(S) 1-(3-hydroxyphenyl)ethylamino]cyclobut-3-ene-1,2-dione 10 "A58" 3-[4-Hydroxy-3-(4-chloropyridin-2-yl)phenylamino]-4-[(R) 1-(3-hydroxyphenyl)ethylamino]cyclobut-3-ene-1,2-dione "A59" 3-(4-Hydroxy-3-pyridin-2-ylphenylamino)-4-[(S)-l1-(3 methoxyphenyl)ethylamino]cyclobut-3-ene-1,2-dione 15 "A60" 3-[2-(3-Hydroxyphenyl)ethylamino]-4-(4-hydroxy-3-pyridin 2-ylphenylamino)cyclobut-3-ene-1,2-dione "A61" 3-(3,4-Dihydroxybenzylamino)-4-(4-hydroxy-3-pyridin-2-yl phenylamino)cyclobut-3-ene-1,2-dione 20 "A62" 3-(4-Fluoro-3-methoxybenzylamino)-4-(4-hydroxy-3 pyridin-2-ylphenylamino)cyclobut-3-ene-1,2-dione "A63" 3-(3,5-Dihydroxybenzylamino)-4-(4-hydroxy-3-pyridin-2-yl phenylamino)cyclobut-3-ene-1,2-dione "A64" 3-(3-Acetamidobenzylamino)-4-(4-hydroxy-3-pyridin-2-yl 25 phenylamino)cyclobut-3-ene-1,2-dione "A65" 3-(4-Fluoro-3-hydroxybenzylamino)-4-(4-hydroxy-3 pyridin-2-ylphenylamino)cyclobut-3-ene-1,2-dione "A66" 3-(3-Aminocarbonylbenzylamino)-4-(4-hydroxy-3-pyridin 30 2-ylphenylamino)cyclobut-3-ene-1,2-dione "A67" 3-(3-Methylaminosulfonylbenzylamino)-4-(4-hydroxy-3 pyridin-2-ylphenylamino)cyclobut-3-ene-1,2-dione "A68" 3-[(3-Hydroxybenzyl)methylamino]-4-(4-hydroxy-3-pyridin 35 2-ylphenylamino)cyclobut-3-ene-1,2-dione WO 2007/014607 PCT/EP2006/006378 - 82 "A69" 3-(3-Methylsulfonylaminobenzylamino)-4-(4-hydroxy-3 pyridin-2-ylphenylamino)cyclobut-3-ene-1,2-dione "A70" 3-(3-Methoxybenzylamino)-4-(4-hydroxy-3-pyridin-2-yl 5 phenylamino)cyclobut-3-ene-1,2-dione "A71" o 0o HO O N N O N H H BOH 10 "A72" 3-(3-Hydroxybenzylamino)-4-(3-imidazol-1 -yl-4-methoxy phenylamino)cyclobut-3-ene-1,2-dione "A73" 3-(3-Hydroxybenzylamino)-4-(4-hydroxy-3-pyrrol-1-yl 15 phenylamino)cyclobut-3-ene-1,2-dione "A74" 3-(3-Hydroxybenzylamino)-4-(3-imidazol-1 -yl-4-hydroxy phenylamino)cyclobut-3-ene-1,2-dione "A75" 3-(3-Hydroxybenzylamino)-4-(4-hydroxy-3-pyrazol-1 -yl 20 phenylamino)cyclobut-3-ene-1,2-dione "A76" 3-(4-Hydroxy-3-pyrazol-1 -ylphenylamino)-4-[(R)-1-(3 methoxyphenyl)ethylamino]cyclobut-3-ene-1,2-dione and pharmaceutically usable derivatives, solvates, salts and stereo 25 25 isomers thereof, including mixtures thereof in all ratios.
    [3] 11. Process for the preparation of compounds of the formula I according to Claims 1-10 and pharmaceutically usable derivatives, salts, sol 30 vates and stereoisomers thereof, characterised in that a compound of the formula II 35 WO 2007/014607 PCT/EP2006/006378 - 83 R20 0 R 1 it II N OA H 5 R in which R, R 1 and R 2 have the meanings indicated in Claim 1, and A denotes alkyl having 1-4 C atoms, 10 is reacted with a compound of the formula III 15 H 2 NX IR3 II 15 in which X and R have the meaning indicated in Claim 1, 20 and/or a base or acid of the formula I is converted into one of its salts.
    [4] 12. Medicament comprising at least one compound of the formula I 25 according to Claim 1 and/or pharmaceutically usable derivatives, salts, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and optionally excipients and/or adjuvants.
    [5] 13. Use of compounds of the formula I according to Claim 1, 30 30 and pharmaceutically usable derivatives, salts, solvates, tautomers and stereoisomers thereof, including mixtures thereof in all ratios, for the preparation of a medicament for the treatment of diseases in which the inhibition, regulation and/or modulation of kinase signal 35 transduction plays a role. WO 2007/014607 PCT/EP2006/006378 - 84 14. Use according to Claim 13, where the kinases are selected from the group of the serine / threonine kinases. 5 15. Use according to Claim 14, where the serine / threonine kinases are CHK1 and CHK2.
    [6] 16. Use according to Claim 15 of compounds of the formula I according to Claim 1 and pharmaceutically usable derivatives, salts, solvates, 10 tautomers and stereoisomers thereof, including mixtures thereof in all ratios, for the preparation of a medicament for the treatment of a disease which is influenced by inhibition of the CHK1 and/or CHK2 kinase by 15 the compounds of the formula I according to Claim 1.
    [7] 17. Use according to Claim 16, where the disease to be treated is a proliferative disorder. 20
    [8] 18. Use according to Claim 17, where the proliferative disorder is a can cer.
    [9] 19. Use according to Claim 18, where a checkpoint pathway in the can 25 cer has been mutated or upregulated.
    [10] 20. Use according to Claim 19, where the compound of the formula I is administered in combination with another therapeutic agent. 30
    [11] 21. Use according to Claim 20, where the compound of the formula I and the other therapeutic agent are administered as part of the same pharmaceutical composition. 35
    [12] 22. Use according to Claim 21, where the compound of the formula I and the other therapeutic agent are administered as separate pharma- WO 2007/014607 PCT/EP2006/006378 - 85 ceutical compositions and the compound of the formula I is adminis tered before, at the same time as or after the administration of the other substance. 5
    [13] 23. Use according to Claim 22, where the other therapeutic agent is an anticancer agent.
    [14] 24. Use according to Claim 13, where the kinase is SGK. 10
    [15] 25. Use according to Claim 24 of compounds of the formula I according to Claim 1, and pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, for the 15 preparation of a medicament for the treatment of diseases which are influenced by inhibition of SGKs by the compounds according to Claim 1.
    [16] 26. Use according to Claim 25 of compounds according to Claim 1, and 20 20 pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, for the preparation of a medicament for the treatment or prevention of diabetes, obesity, metabolic syndrome (dyslipidaemia), systemic and pulmonary hyper 25 tonia, cardiovascular diseases and renal diseases, generally in fibro ses and inflammatory processes of any type, cancer, tumour cells, tumour metastases, coagulopathies, neuronal excitability, glaucoma, cataract, bacterial infections and in antiinfection therapy, for increas 30 ing learning ability and attention, and for the treatment and prophy laxis of cell ageing and stress, and for the treatment of tinnitus.
    [17] 27. Use according to Claim 26, where diabetes is diabetes mellitus, dia betic nephropathy, diabetic neuropathy, diabetic angiopathy and 35oangiopathy. microangiopathy. WO 2007/014607 PCT/EP2006/006378 - 86 28. Use according to Claim 26, where cardiovascular diseases are car diac fibroses after myocardial infarction, cardiac hypertrophy, cardiac insufficiency and arteriosclerosis. 5
    [18] 29. Use according to Claim 26, where renal diseases are glomerulo sclerosis, nephrosclerosis, nephritis, nephropathy and electrolyte excretion disorder. 10 30. Use according to Claim 26, where fibroses and inflammatory proc esses are liver cirrhosis, pulmonary fibrosis, fibrosing pancreatitis, rheumatism and arthroses, Crohn's disease, chronic bronchitis, radiation fibrosis, sclerodermatitis, cystic fibrosis, scarring and Alz 15 heimer's disease.
    [19] 31. Set (kit) consisting of separate packs of (a) an effective amount of a compound according to Claim 1 and/or pharmaceutically usable derivatives, solvates and stereo 20 isomers thereof, including mixtures thereof in all ratios, and (b) an effective amount of a further medicament active ingredi ent. 25 30 35
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    同族专利:
    公开号 | 公开日
    US20080312244A1|2008-12-18|
    WO2007014607A1|2007-02-08|
    JP2009502820A|2009-01-29|
    AR057696A1|2007-12-12|
    CA2616682A1|2007-02-08|
    DE102005035741A1|2007-02-08|
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    法律状态:
    2008-05-22| DA3| Amendments made section 104|Free format text: THE NATURE OF THE AMENDMENT IS: AMEND THE INVENTION TITLE TO READ SQUADRIC ACID DERIVATIVES AS PROTEIN KINASE INHIBITORS |
    2010-08-05| MK1| Application lapsed section 142(2)(a) - no request for examination in relevant period|
    优先权:
    申请号 | 申请日 | 专利标题
    DE102005035741A|DE102005035741A1|2005-07-29|2005-07-29|Square acid derivatives|
    DE102005035741.5||2005-07-29||
    PCT/EP2006/006378|WO2007014607A1|2005-07-29|2006-06-30|Quadratic acid derivatives in the form of a protein kinase inhibitors|
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