Abstract:
The present invention encompasses compounds of general formula (1),  
                         
wherein A, W, X, Y, Z, Ra, Rb, Rc, R1 and R3 are defined as in claim 1, which are suitable for the treatment of diseases characterised by excessive or abnormal cell proliferation, and the use thereof for preparing a pharmaceutical composition having the above-mentioned properties.

Description:
[0001]     The present invention relates to new pyrimidines of general formula (1),  
                         
 
 wherein the groups A, W, X, Y, Z, R a , R b , R c , R 1  and R 3  have the meanings given in the claims and description, the isomers thereof, processes for preparing these pyrimidines and their use as pharmaceutical compositions. 
 
       BACKGROUND TO THE INVENTION  
       [0002]     Tumour cells wholly or partly elude regulation and control by the body and are characterised by uncontrolled growth. This is due on the one hand to the loss of control proteins such as for example Rb, p16, p21 and p53 and also to the activation of so-called accelerators of the cell cycle, the cyclin-dependent kinases.  
         [0003]     Studies in model organisms such as  Schizosaccharomyces pombe, Drosophila melanogaster  or  Xenopus laevis  as well as investigations in human cells have shown that the transition from the G2 phase to mitosis is regulated by the CDK1/cyclin B kinase (Nurse 1990 , Nature  344: 503-508). This kinase, which is also known as “mitosis promoting factor” (MPF), phosphorylates and regulates a plurality of proteins, such as e.g. nuclear lamina, kinesin-like motor proteins, condensins and Golgi Matrix Proteins, which play an important part in the breakdown of the nuclear coat, in centrosome separation, the structure of the mitotic spindle apparatus, chromosome condensation and breakdown of the Golgi apparatus (Nigg. E. 2001 , Nat Rev Mol Cell Biol.  2(1):21-32). A murine cell line with a temperature-sensitive CDK-1 kinase mutant shows a rapid breakdown in CDK-1 kinase after temperature increase and a subsequent arrest in the G2/M phase (Th{acute over ( )}ng et al. 1990 , Cell.  63(2):313-24). The treatment of human tumour cells with inhibitors against CDK1/cyclin B, such as e.g. butyrolactone, leads to an arrest in the G2/M phase and subsequent apoptosis (Nishio, et al. 1996 , Anticancer Res. 16(6B):3387-95).  
         [0004]     Moreover, the protein kinase Aurora B has also been described as having an essential function during entry into mitosis. Aurora B phosphorylates histone H3 on Ser10 and thereby initiates chromosome condensation (Hsu et al. 2000 , Cell  102:279-91). A specific cell cycle arrest in the G2/M phase may, however, also be initiated e.g. by inhibition of specific phosphatases such as e.g. Cdc25C (Russell and Nurse 1986 , Cell  45:145-53). Yeasts with a defective Cdc25 gene arrest in the G2 phase, whereas overexpression of Cdc25 leads to premature entry into the mitosis phase (Russell and Nurse, 1987 , Cell  49:559-67). Moreover, an arrest in the G2/M phase may also be initiated by inhibition of specific motor proteins, the so-called kinesins such as for example Eg5 (Mayer et al. 1999 , Science  286:971-4), or by microtubuli stabilising or destabilising agents (e.g. colchicin, taxol, etoposide, vinblastine, vincristine) (Schiff and Horwitz 1980 , Proc Natl Acad Sci  USA 77:1561-5).  
         [0005]     In addition to the cyclin-dependent and Aurora kinases the so-called polo-like kinases, a small family of serine/threonine kinases, also play an important role in the regulation of the eukaryotic cell cycle. Up till now the polo-like kinases PLK-1, PLK-2, PLK-3 and PLK-4 have been described in the literature. PLK-1 in particular has been found to play a central role in the regulation of the mitosis phase. PLK-1 is responsible for the maturation of the centrosomes, for the activation of phosphatase Cdc25C, as well as for the activation of the Anaphase Promoting Complex (Glover et al. 1998 , Genes Dev.  12:3777-87; Qian et al. 2001 , Mol Biol Cell.  12:1791-9). The injection of PLK-1 antibodies leads to a G2 arrest in untransformed cells, whereas tumour cells arrest during the mitosis phase (Lane and Nigg 1996 , J. Cell Biol.  135:1701-13). Overexpression of PLK-1 has been demonstrated in various types of tumour, such as non-small-cell carcinoma of the lung, plate epithelial carcinoma, breast and colorectal carcinoma (Wolf et al. 1997 , Oncogene  14:543-549; Knecht et al. 1999 , Cancer Res.  59:2794-2797; Wolf et al. 2000 , Pathol. Res. Pract.  196:753-759; Takahashi et al. 2003 , Cancer Sci.  94:148-52). Therefore, this category of proteins also presents an interesting point of attack for therapeutic intervention in proliferative diseases (Liu and Erikson 2003 , Proc Natl Acad Sci USA  100:5789-5794).  
         [0006]     Pyrimidines are generally known as inhibitors of kinases. Thus, for example, pyrimidines are described as an active component with an anticancer activity in International Patent Application WO 00/53595, which describes the use of 2,4,5-substituted pyrimidines with a heterocyclic group in the 4-position and an anilino group in the 2 position, which in turn comprises a side chain with the length of at least one n-propyl group.  
         [0007]     Moreover, International Patent Application WO 00/39101 describes the use of 2,4,5-substituted pyrimidines as compounds with an anticancer activity which are linked in the 2- and 4-position with an aromatic or heteroaromatic ring, at least one of which comprises a side chain with the length of at least one n-propyl group.  
         [0008]     International Patent Application WO 97/19065 further proposes the use of 2,4,5-substituted pyrimidines with a 3,4-dialkoxyanilino group in position 2 as kinase inhibitors.  
         [0009]     International Patent Application WO 02/04429 describes 2,4,5-substituted pyrimidines with a cyano group in position 5 and their cell cycle inhibiting effect.  
         [0010]     International Patent Application WO 03/063794 describes the use of 2,4-pyrimidinediamines as inhibitors of the IgE and/or IgG receptor signal cascade.  
         [0011]     Antiviral 2,4,5-substituted pyrimidines, wherein the groups R c  and R d  form a heteroaromatic five-membered ring at the nitrogen of the 4-position, are known from International Patent Application WO 99/41253.  
         [0012]     2,4,5-substituted pyrimidines which carry (hetero)aryls in position 2 and 4 (WO00/27825) and also 2, 4, 5-substituted pyrimidines which carry a (hetero)aryl group functionalised with a nitrile group in position 2 or 4 (EP 0 945 443 A1) are described as having an antiviral activity.  
         [0013]     The resistance of many types of tumour demands that new drugs be developed to fight the tumours. The aim of the present invention is therefore to indicate new active substances which may be used for the prevention and/or treatment of diseases characterised by excessive or anomalous cell proliferation.  
     
    
     DETAILED DESCRIPTION OF THE INVENTION  
       [0014]     It has now been found that, surprisingly, compounds of general formula (1), wherein the groups A, W, X, Y, R a , R b , R c , R 1 , R 2  and R 3  are defined as hereinafter, act as inhibitors of specific cell cycle kinases. Thus, the compounds according to the invention may be used for example for the treatment of diseases associated with the activity of specific cell cycle kinases and characterised by excessive or anomalous cell proliferation.  
         [0015]     The present invention relates to compounds of general formula (1)  
                         
 
 wherein 
    W denotes N or C—R 2 ,     X denotes —NR 1a , O or S,     Y denotes CH or N,     Z denotes hydrogen, halogen, —NO 2 , C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, halogen-C 1-3 alkyl, —COH, —C(═O)—C 1-3 alkyl, —C(═O)—C 2-3 alkenyl, —C(═O)—C 2-3 alkynyl, —C(═O)C 1-3 alkyl-halogen or pseudohalogen;     A is selected from the formulae (i), (ii) or (iii)  
                         
    Q 1  denotes mono- or bicyclic aryl compounds,     B 1 , B 2 , B 3  and B 4  in each case independently of one another denote C—R g R h , N—R i , O or S, while adjacent B 1 -B 4  in each case do not represent —O—;     R 1  and R 1a  each independently of one another denote hydrogen or methyl,     R 2  denotes a group selected from among hydrogen, halogen, —OR 4 , —C(═O)R 4 , —C(═O)NR 4 R 5 , —NR 4 R 5 , —NR 4 C(═O)R 5 , —NR 4 SO 2 R 5 , —N═CR 4 R 5 , —C═NR i , —SR 4 , —SOR 4 , —SO 2 R 4 , —SO 2 NR 4 R 5  and pseudohalogen, or an optionally mono- or polysubstituted group selected from among C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 -cycloalkyl, aryl, heterocyclyl and heteroaryl, while the substituent(s) may be identical or different and are selected from among halogen, —NO 2 , —OR 4 , —C(═O)R 4 , —C(═O)OR 4 , —C(═O)NR 4 R 5 , —NR 4 R 5 , —NR 4 C(═O)R 5 , —NR 4 C(═O)OR 5 , —NR 4 C(═O)NR 4 R 5 , —NR 4 SO 2 R 5 , —N═CR 4 R 5 , —SR 4 , —SOR 4 , —SO 2 R 4 , —SO 2 NR 4 R 5 , —NR 4 SO 2 NR 5 R 6 , —OSO 2 NR 5 R 6  and pseudohalogen;     R a , R b , R c , R d , R e , R f , R g  and R h  in each case independently of one another denote a group selected from among hydrogen, halogen, ═O, —NO 2 , —OR 4 , —C(═O)R 4 , —C(═O)OR 4 , —C(═O)NR 4 R 5 , —NR 4 R 5 , —NR 4 C(═O)R 5 , —NR 4 C(═O)OR 5 , —NR 4 C(═O)NR 5 R 6 , —NR 4 SO 2 R 5 , —N═CR 4 R 5 , —C═NR i , —SR 4 , —SOR 4 , —SO 2 R 4 , —SO 2 NR 4 R 5 , —NR 4 SO 2 NR 5 R 6 , —OSO 2 NR 5 R 6  and pseudohalogen; or an optionally mono- or polysubstituted group selected from among C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-6 -cycloalkyl, aryl, heterocyclyl and heteroaryl, while the substituent(s) may be identical or different and are selected from among halogen, R 8 , —NO 2 , —OR 4 , —C(═O)R 4 , —C(═O)OR 4 , —C(═O)NR 4 R 5 , —NR 4 R 5 , —NR 4 C(═O)R 5 , —NR 4 C(═O)OR 5 , —NR 4 C(═O)NR 5 R 6 , NR 4 SO 2 R 5 , —N═CR 4 R 5 , —SR 4 , —SOR 4 , —SO 2 R 4 , —SO 2 NR 4 R 5 , —NR 4 SO 2 NR 5 R 6 , —OSO 2 NR 5 R 6  and pseudohalogen; and optionally the R g  and R h  located at the same or at adjacent C atoms may be attached in any combination to a common saturated or partially unsaturated 3-5-membered alkyl bridge which may contain one to two heteroatoms;     R i  denotes a group selected from among hydrogen, ═O, —OR 4 , —C(═O)R 4 , —C(═O)OR 4 , —C(═O)NR 4 R 5 , —NR 4 R 5 , —NR 4 C(═O)R 5 , —NR 4 C(═O)OR 5 , —NR 4 C(═O)NR 5 R 6 , —NR 4 SO 2 R 5 , —N═CR 4 R 5 , —SR 4 , —SOR 4 , —SO 2 R 4 , SO 2 NR 4 R 5 , —NR 4 SO 2 NR 5 R 6 , —OSO 2 NR 5 R 6  and pseudohalogen; or an optionally mono- or polysubstituted group selected from among C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, aryl, heterocyclyl and heteroaryl, while the substituent(s) may be identical or different and are selected from among halogen, R 8 , —NO 2 , —OR 4 , —C(═O)R 4 , —C(═O)OR 4 , —C(═O)NR 4 R 5 , —NR 4 R 5 , —NR 4 C(═O)R 5 , —NR 4 C(═O)OR 5 , —NR 4 C(═O)NR 5 R 6 , —NR 4 SO 2 R 5 , —N═CR 4 R 5 , —SR 4 , —SOR 4 , —SO 2 R 4 , —SO 2 NR 4 R 5 , —NR 4 SO 2 NR 5 R 6 , —OSO 2 NR 5 R 6  and pseudohalogen; and optionally the R i  groups located at adjacent N atoms may be joined together or R i  with R g  or R h  located at adjacent C atoms may be attached in any combination to a common saturated or partially unsaturated 3-5-membered alkyl bridge which may contain one to two heteroatoms;     R 3  is selected from the formulae (iv)-(x),  
                         
    R 4 , R 5  and R 6  each independently of one another denote hydrogen or a group selected from among optionally mono- or polysubstituted C 1-5 -alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-10 cycloalkyl, aryl, heterocyclyl and heteroaryl, while the substituent(s) may be identical or different and are selected from among C 3-10 -cycloalkyl, aryl, heterocyclyl, heteroaryl, halogen, —NO 2 , —OR 8 , —C(═O)R 8 , —C(═O)OR 8 , —C(═O)NR 8 R 9 , —NR 8 R 9 , —NR 8 C(═O)R 9 , —NR 8 C(═O)OR 9 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═O)ONR 9 R 10 , —NR 8 SO 2 R 9 , —N═CR 8 R 9 , —SR 8 , —SOR 8 , —SO 2 R 8 , —SO 2 NR 8 R 9 , —NR 8 SO 2 NR 9 R 10 , —OSO 2 NR 8 R 9  and pseudohalogen;     L denotes a bond or a group selected from among optionally mono- or polysubstituted C 1-16 -alkyl, C 2-16 -alkenyl, C 2-16 -alkynyl, C 3-10 cycloalkyl, aryl, heterocyclyl and heteroaryl, while the substituent(s) may be identical or different and are selected from among halogen, —NO 2 , —OR 8 , —C(═O)R 8 , —C(═O)OR 8 , —C(═O)NR 8 R 9 , —NR 8 R 9 , —NR 8 C(═O)R 9 , —NR 8 C(═O)OR 9 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═O)ONR 9 R 10 , —NR 8 SO 2 R 9 , —N═CR 8 R 9 , —SR 8 , —SOR 8 , —SO 2 R 8 , —SO 2 NR 8 R 9 , —NR 8 SO 2 NR 9 R 10 , —OSO 2 NR 8 R 9  and pseudohalogen;     Q 2  and Q 3  independently of one another denote a bond or a group selected from among optionally mono- or polysubstituted C 1-16 -alkyl, C 2-16 -alkenyl, C 2-16 -alkynyl, C 3-10 cycloalkyl, aryl, heterocyclyl and heteroaryl while the substituent(s) may be identical or different and are selected from among halogen, —NO 2 , —OR 8 , —C(═O)R 8 , —C(═O)OR 8 , —C(═O)NR 8 R 9 , —NR 8 R 9 , —NR 8 C(═O)R 9 , —NR 8 C(═O)OR 9 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═O)ONR 9 R 10 , —NR 8 SO 2 R 9 , —N═CR 8 R 9 , —SR 8 , —SOR 8 , —SO 2 R 8 , —SO 2 NR 8 R 9 , —NR 8 SO 2 NR 9 R 10 , —OSO 2 NR 8 R 9  and pseudohalogen;     R 7  denotes hydrogen or a group selected from among optionally mono- or polysubstituted C 1-16 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-10 cycloalkyl, aryl, heterocyclyl and heteroaryl, while the substituent(s) may be identical or different and are selected from among halogen, NO 2 , —OR 8 , —C(═O)R 8 , —C(═O)OR 8 , —C(═O)NR 8 R 9 , —NR 8 R 9 , —NR 8 COR 9 , —NR 8 C(═O)OR 9 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═O)ONR 9 R 10 , —NR 8 SO 2 R 9 , —N═CR 8 R 9 , —SR 8 , —SOR 8 , —SO 2 R 8 , —SO 2 NR 8 R 9 , —NR 8 SO 2 NR 9 R 10 , —OSO 2 NR 8 R 9  and pseudohalogen;     R 8 , R 9  and R 10  each independently of one another denote hydrogen or a group selected from among optionally substituted C 1-8 -alkyl, C 2-8 -alkenyl, C 2-8 -alkynyl, C 3-10 -cycloalkyl, aryl, heterocyclyl and heteroaryl, while the substituent(s) may be identical or different and are selected from among halogen, methyl, ethyl, amino, methylamino, dimethylamino, —OH and pseudohalogen; 
 
 optionally in the form of the tautomers, racemates, enantiomners, diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof. 
   
 
         [0033]     In one aspect the invention relates to compounds of general formula (1) wherein 
    W denotes C—R 2  and the other groups are as hereinbefore defined.    
 
         [0035]     In another aspect the invention relates to compounds of general formula (1), wherein 
    X denotes —NR 1a  or oxygen,     R 1  and R 1a  denote hydrogen;     R 3  denotes formula (iv) or (x),  
                         
 
 and the other groups are as hereinbefore defined. 
   
 
         [0039]     In another aspect the invention relates to compounds of general formula (1), wherein 
    Y denotes CH and     Q 1  denotes monocyclic aryl compounds 
 
 and the other groups are as hereinbefore defined. 
   
 
         [0042]     In one aspect the invention relates to compounds of general formula (1), wherein 
    R c  denotes a group selected from among hydrogen, —F, —Cl, methyl and ethyl and the other groups are as hereinbefore defined.    
 
         [0044]     In another aspect the invention relates to compounds of general formula (1), wherein 
    R a  and R b  each independently of one another denote hydrogen or fluorine; or an optionally mono- or polysubstituted group selected from among C 1-2 -alkyl, C 2 -alkenyl, C 2 -alkynyl, C 3-6 -cycloalkyl, aryl, heterocyclyl and heteroaryl, while the substituent(s) may be identical or different and are selected from among hydrogen, halogen, —NO 2 , —OR 4 , —C(═O)R 4 , —C(═O)OR 4 , —C(═O)NR 4 R 5 , —NR 4 R 5 , —NR 4 C(═O)R 5 , —NR 4 C(═O)OR 5 , —NR 4 C(═O)NR 5 R 6 , —NR 4 SO 2 R 5 , —N═CR 4 R 5 , —SR 4 , —SOR 5 , —SO 2 R 4 , —SO 2 NR 4 R 5 , —NR 4 , —SO 2 NR 4 R 5 , —OSO 2 NR 4 R 5  and pseudohalogen 
 
 and the other groups are as hereinbefore defined. 
   
 
         [0046]     In another aspect the invention also relates to compounds of general formula (1), wherein  
         [0000]     R a  and R b  denote hydrogen or fluorine and the other groups are as hereinbefore defined.  
         [0047]     The invention also includes compounds of general formula (1), wherein 
    Z denotes halogen-C 1-3 -alkyl, —COH, —C(═O)—C 1-3 -alkyl, —C(═O)—C 2-3 -alkenyl, —C(═O)—C 2-3 -alkynyl, —C(═O)C 1-3 -alkyl-halogen and pseudohalogen 
 
 and the other groups are as hereinbefore defined. 
   
 
         [0049]     In one aspect the invention relates to compounds of general formula (1), or the pharmaceutically active salts thereof, as pharmaceutical compositions.  
         [0050]     In an essential aspect the invention relates to compounds of general formula (1), or the pharmaceutically active salts thereof, for use as pharmaceutical compositions with an antiproliferative activity.  
         [0051]     Moreover the invention includes compounds of general formula (1), or the pharmaceutically active salts thereof, for use as pharmaceutical compositions with an antiproliferative activity with a selective kinase-inhibiting mechanism of activity.  
         [0052]     In one aspect the invention relates to the use of compounds of general formula (1), or the pharmaceutically active salts thereof, for preparing a pharmaceutical composition with an antiproliferative activity with a PLK inhibiting mechanism of activity.  
         [0053]     In another aspect the invention relates to pharmaceutical preparations, containing as active substance one or more compounds of general formula (I), or the physiologically acceptable salts thereof, optionally in conjunction with conventional excipients and/or carriers.  
         [0054]     In another aspect the invention relates to the use of one or more compounds of general formula (1) for preparing a pharmaceutical composition for the treatment and/or prevention of cancer, infections, inflammatory and autoimmune diseases.  
         [0055]     In another aspect the invention relates to a pharmaceutical preparation containing at least one compound of general formula (1)  
                         
 
 wherein 
    W denotes N or C—R 2 ,     X denotes —NR 1a , O or S,     Y denotes CH or N,     Z denotes hydrogen, halogen, —NO 2 , C 1-3 -alkyl, C 2-3 -alkenyl, C 2-3 -alkynyl, halogen-C 1-3 -alkyl, —COH, —C(═O)—C 1-3 -alkyl, —C(═O)—C 2-3 -alkenyl, —C(═O)—C 2-3 -alkynyl, —C(═O)C 1-3 -alkyl-halogen and pseudohalogen;     A is selected from the formulae (i), (ii) or (iii)  
                         
    Q 1  denotes mono- or bicyclic aryl compounds;     B 1 , B 2 , B 3  and B 4  in each case independently of one another represent C—R g R h , N—R i , O or S, while adjacent B 1 -B 4  in each case do not denote —O—;     R 1  and R 1a  each independently of one another denote hydrogen or methyl,     R 2  denotes a group selected from among hydrogen, halogen, —OR 4 , —C(═O)R 4 , —C(═O)NR 4 R 5 , —NR 4 R 5 , —NR 4 C(═O)R 5 , —NR 4 SO 2 R 5 , —N═CR 4 R 5 , —C═NR i , —SR 4 , —SOR 4 , —SO 2 R 4 , —SO 2 NR 4 R 5  and pseudohalogen, or an optionally mono- or polysubstituted group selected from among C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-6 -cycloalkyl, aryl, heterocyclyl and heteroaryl, while the substituent(s) may be identical or different and are selected from among halogen, —NO 2 , —OR 4 , —C(═O)R 4 , —C(═O)OR 4 , —C(═O)NR 4 R 5 , —NR 4 R 5 , —NR 4 C(═O)R 5 , —NR 4 C(═O)OR 5 , —NR 4 C(═O)NR 5 R 6 , —NR 4 SO 2 R 5 , —N═CR 4 R 5 , —SR 4 , —SOR 4 , —SO 2 R 4 , —SO 2 NR 4 R 5 , —NR 4 SO 2 NR 5 R 6 , —OSO 2 NR 5 R 6  and pseudohalogen;     R a , R b , R c , R d , R e , R f , R g  and R h  in each case independently of one another denote a group selected from among hydrogen, halogen, ═O, —NO 2 , —OR 4 , —C(═O)R 4 , —C═O)OR 4 , —C(═O)NR 4 R 5 , —NR 4 R 5 , —NR 4 C(═O)R 5 , —NR 4 C(═O)OR 5 , —NR 4 C(═O)NR 5 R 6 , —NR 4 SO 2 R 5 , —N═CR 4 R 5 , —C═NR i , —SR 4 , —SOR 4 , —SO 2 R 4 , —SO 2 NR 4 R 5 , —NR 4 SO 2 NR 5 R 6 , —OSO 2 NR 5 R 6  and pseudohalogen; or an optionally mono- or polysubstituted group selected from among C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-6 -cycloalkyl, aryl, heterocyclyl and heteroaryl, while the substituent(s) may be identical or different and are selected from among halogen, R 8 , —NO 2 , —OR 4 , —C(═O)R 4 , —C(═O)OR 4 , —C(═O)NR 4 R 5 , —NR 4 R 5 , —NR 4 C(═O)R 5 , —NR 4 C(═O)OR 5 , —NR 4 C(═O)NR 5 R 6 , —NR 4 SO 2 R 5 , —N═CR 4 R 5 , —SR 4 , —SOR 4 , —SO 2 R 4 , —SO 2 NR 4 R 5 , —NR 4 SO 2 NR 5 R 6 , —OSO 2 NR 5 R 6  and pseudohalogen; and optionally the R g  and R h  located at the same or at adjacent C atoms may be attached in any combination to a common saturated or partially unsaturated 3-5-membered alkyl bridge which may contain one to two heteroatoms;     R i  denotes a group selected from among hydrogen, ═O)—OR 4 , —C(═O)R 4 , —C(═O)OR 4 , —C(═O)NR 4 R 5 , —NR 4 R 5 , —NR 4 C(═O)R 5 , —NR 4 C(═O)OR 5 , —NR 4 C(═O)NR 5 R 6 , —NR 4 SO 2 R 5 , —N═CR 4 R 5 , —SR 4 , —SOR 4 , —SO 2 R 4 , —SO 2 NR 4 R 5 , —NR 4 SO 2 NR 5 R 6 , —OSO 2 NR 5 R 6  or an optionally mono- or polysubstituted group selected from among C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-6 -cycloalkyl, aryl, heterocyclyl and heteroaryl, while the substituent(s) may be identical or different and are selected from among halogen, R 8 , —NO 2 , —OR 4 , —C(═O)R 4 , —C(═O)OR 4 , —C(═O)NR 4 R 5 , —NR 4 R 5 , —NR 4 C(═O)R 5 , —NR 4 C(═O)OR 5 , —NR 4 C(═O)NR 5 R 6 , —NR 4 SO 2 R 5 , —N═CR 4 R 5 , —SR 4 , —SOR 4 , —SO 2 R 4 , —SO 2 NR 4 R 5 , —NR 4 SO 2 NR 5 R 6  and pseudohalogen; and optionally the Ri groups located at adjacent N atoms may be joined together or to R g  and R h  located at adjacent C atoms in any combination with a common saturated or partially unsaturated 3-5-membered alkyl bridge which may contain one to two heteroatoms;     R 3  is selected from the formulae (iv)-(x),  
                         
    R 4 , R 5  and R 6  each independently of one another denote hydrogen or a group selected from among optionally mono- or polysubstituted C 1-5 -alkyl, C 2-5 -alkenyl, C 2-5 -alkynyl, C 3-10 -cycloalkyl, aryl, heterocyclyl and heteroaryl, while the substituent(s) may be identical or different and are selected from among C 3-10 -cycloalkyl, aryl, heterocyclyl, heteroaryl, halogen, —NO 2 , —OR 8 , —C(═O)R 8 , —C(═O)OR 8 , —C(═O)NR 8 R 9 , —NR 8 R 9 , —NR 8 C(═O)R 9 , —NR 8 C(═O)OR 9 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═O)ONR 9 R 10 , —NR 8 SO 2 R 9 , —N═CR 8 R 9 , —SR 8 , —SOR 8 , —SO 2 R 8 , —SO 2 NR 8 R 9 , —NR 8 SO 2 NR 9 R 10 , —OSO 2 NR 8 R 9  and pseudohalogen;     L denotes a bond or a group selected from among optionally mono- or polysubstituted C 1-16 -alkyl, C 2-16 -alkenyl, C 2-16 -alkynyl, C 3-10 -cycloalkyl, aryl, heterocyclyl and heteroaryl, while the substituent(s) may be identical or different and are selected from among halogen, —NO 2 , —OR 8 , —C(═O)R 8 , —C(═O)OR 8 , —C(═O)NR 8 R 9 , —NR 8 R 9 , —NR 8 C(═O)R 9 , —NR 8 C(═O)OR 9 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═O)ONR 9 R 10 , —NR 8 SO 2 R 9 , —N═CR 8 R 9 , —SR 8 , —SOR 8 , —SO 2 R 8 , —SO 2 NR 8 R 9 , —NR 8 SO 2 NR 9 R 10 , —OSO 2 NR 8 R 9  and pseudohalogen;     Q 2  and Q 3  independently of one another denote a bond or a group selected from among optionally mono- or polysubstituted C 1-16 -alkyl, C 2-16 -alkenyl, C 2-16 -alkynyl, C 3-10 -cycloalkyl, aryl, heterocyclyl and heteroaryl, while the substituent(s) may be identical or different and are selected from among halogen, —NO 2 , —OR 8 , —C(═O)R 8 , —C(═O)OR 8 , —C(═O)NR 8 R 9 , —NR 8 R 9 , —NR 8 C(═O)R 9 , —NR 8 C(═O)OR 9 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═O)ONR 9 R 10 , —NR 8 SO 2 R 9 , —N═CR 8 R 9 , —SR 8 , —SOR 8 , —SO 2 R 8 , —SO 2 NR 8 R 9 , —NR 8 SO 2 NR 9 R 10 , —OSO 2 NR 8 R 9  and pseudohalogen;     R 7  denotes hydrogen or a group selected from among optionally mono- or polysubstituted C 1-16 -alkyl, C 2-16 -alkenyl, C 2-16 -alkynyl, C 3-10 -cycloalkyl, aryl, heterocyclyl and heteroaryl, while the substituent(s) may be identical or different and are selected from among halogen, NO 2 , —OR 8 , —C(═O)R 8 , —C(═O)OR 8 , —C(═O)NR 8 R 9 , —NR 8 R 9 , —NR 8 COR 9 , —NR 8 C(═O)OR 9 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═O)ONR 9 R 10 , —NR 8 SO 2 R 9 , —N═CR 8 R 9 , —SR 8 , —SOR 8 , —SO 2 R 8 , —SO 2 NR 8 R 9 , —NR 8 SO 2 NR 9 R 10 , —OSO 2 NR 8 R 9  and pseudohalogen;     R 8 , R 9  and R 10  each independently of one another denote hydrogen or a group selected from among optionally substituted C 1-8 -alkyl, C 2-8 -alkenyl, C 2-8 -alkynyl, C 3-10 -cycloalkyl, aryl, heterocyclyl and heteroaryl, while the substituent(s) may be identical or different and are selected from among halogen, —NH 2 , —OH and pseudohalogen; 
 
 optionally in the form of the tautomers, racemates, enantiomers, diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof, and 
 
 at least one other cytostatic or cytotoxic active substance, optionally in the form of the tautomers, racemates, enantiomers, diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof. 
 
 Definitions 
   
 
         [0073]     As used herein, the following definitions apply, unless stated otherwise.  
         [0074]     By alkyl substituents are meant in each case saturated, straight-chain or branched aliphatic hydrocarbon groups (alkyl group).  
         [0075]     The alkenyl substituents are in each case straight-chain or branched, unsaturated alkyl groups which have at least one double bond.  
         [0076]     By alkynyl substituents are meant in each case straight-chain or branched, unsaturated alkyl groups which have at least one triple bond.  
         [0077]     Haloalkyl refers to alkyl groups wherein one or more hydrogen atoms are replaced by halogen atoms. Haloalkyl includes both saturated alkyl groups and unsaturated alkenyl and alkynyl groups, such as for example —CF 3 , —CHF 2 , —CH 2 F, —CF 2 CF 3 , —CHFCF 3 , —CH 2 CF 3 , —CF 2 CH 3 , —CHFCH 3 , —CF 2 CF 2 CF 3 , —CF 2 CH 2 CH 3 , —CHFCH 2 CH 3  and —CHFCH 2 CF 3 .  
         [0078]     Halogen relates to fluorine, chlorine, bromine and/or iodine atoms.  
         [0079]     By pseudohalogen are meant the following groups: —OCN, —SCN, —CF 3  and —CN.  
         [0080]     By cycloalkyl is meant a mono- or bicyclic ring, while the ring system may be a saturated ring or an unsaturated, non-aromatic ring, which may optionally also contain double bonds, such as for example cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, norbornyl, norbornenyl, spiro[5.5]undecane, spiro[5.4]decane and spiro[4.4]nonane.  
         [0081]     Aryl relates to monocyclic or bicyclic rings with 6-12 carbon atoms such as for example phenyl and naphthyl.  
         [0082]     By heteroaryl are meant mono- or bicyclic rings which contain instead of one or more carbon atoms one or more identical or different heteroatoms, such as e.g. nitrogen, sulphur or oxygen atoms. Examples include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl and triazinyl. Examples of bicyclic heteroaryl groups are indolyl, isoindolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, indazolyl, isoquinolinyl, quinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl and benzotriazinyl, indolizinyl, oxazolopyridinyl, imidazopyridinyl, naphthyridinyl, indolinyl, isochromanyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl, benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, phenoxazinyl, phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl, imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl, dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, cumarinyl, isocumarinyl, chromonyl, chromanonyl, pyridinyl-N-oxid, tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl, dihydroisoquinolinonyl, dihydrocumarinyl, dihydroisocumarinyl, isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl-N-oxide, pyrimidinyl-N-oxide, pyridazinyl-N-oxide, pyrazinyl-N-oxide, quinolinyl-N-oxide, indolyl-N-oxide, indolinyl-N-oxide, isoquinolyl-N-oxide, quinazolinyl-N-oxide, quinoxalinyl-N-oxide, phthalazinyl-N-oxide, imidazolyl-N-oxide, isoxazolyl-N-oxide, oxazolyl-N-oxide, thiazolyl-N-oxide, indolizinyl-N-oxide, indazolyl-N-oxide, benzothiazolyl-N-oxide, benzimidazolyl-N-oxide, pyrrolyl-N-oxide, oxadiazolyl-N-oxide, thiadiazolyl-N-oxide, triazolyl-N-oxide, tetrazolyl-N-oxide, benzothiopyranyl-S-oxide and benzothiopyranyl-S,S-dioxide.  
         [0083]     Heterocyclyl relates to saturated or unsaturated, non-aromatic mono-, bicyclic or bridged bicyclic rings comprising 5-12 carbon atoms, which carry heteroatoms, such as nitrogen, oxygen or sulphur, instead of one or more carbon atoms. Examples of such heterocylyl groups are tetrahydrofuranyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, indolinyl, isoindoliny, morpholinyl, thiomorpholinyl, homomorpholinyl, homopiperidyl, homopiperazinyl, thiomorpholinyl-S-oxide, thiomorpholinyl-S,S-dioxide, tetrahydropyranyl, piperidinyl, tetrahydrothienyl, homopiperidinyl, homothiomorpholinyl-S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydrofuryl, dihydropyranyl, tetrahydrothienyl-S-oxide, tetrahydrothienyl-S,S-dioxide, homothiomorpholinyl-S-oxide, 2-oxa-5-azabicyclo[2.2.1]heptane, 8-oxa-3-aza-bicyclo[3.2.1]octane, 3,8-diaza-bicyclo[3.2.1]octane, 2,5-diaza-bicyclo[2.2.1]heptane, 3,8-diaza-bicyclo[3.2.1]octane, 3,9-diaza-bicyclo[4.2.1]nonane, 2,6-diaza-bicyclo[3.2.2]nonane, 2,7-diaza-spiro[3.5]nonane, 2,7-diaza-spiro[4.4]nonane, 2,8-diaza-spiro[4.5]decane, 3,9-diaza-spiro[5.5]undecane.  
         [0084]     The Examples that follow illustrate the present invention without restricting its scope:  
         [0000]     Preparation of the Compounds According to the Invention:  
         [0085]     The compounds according to the invention may be prepared according to methods of synthesis A to C described hereinafter, wherein the substituents of general formulae (I to XVI) have the meanings given hereinbefore.  
         [0000]     Method A  
         [0000]     Step 1A  
         [0086]     The intermediate compound III is prepared by substitution of a leaving group LG, for example halogen, SCN or methoxy, preferably chlorine, in a heteroaromatic system I by a nucleophile II.  
                         
 
         [0087]     1 equivalent of compound I and 1 to 1.5 equivalents of compound II are stirred in a solvent, for example 1,4-dioxane, tetrahydrofuran, ethanol, isopropanal, N,N-dimethylformamide or N,N-dimethylacetamide. At a temperature of 15 to 25° C., 2 to 2.5 equivalents of a base, for example potassium carbonate, sodium carbonate, caesium carbonate, N-ethyl-N,N-diisopropylamine or triethylamine, are added. The reaction mixture is stirred for 6 to 72 h at a temperature of 20 to 100° C. Then the solvent is distilled off and the residue is combined with water which has been adjusted to a pH of between 1-4 with an inorganic acid, for example hydrochloric acid or sulphuric acid. This mixture is extracted two to three times with an organic solvent, for example diethyl ether, ethyl acetate or dichloromethane. The combined organic extracts are dried and the solvent is distilled off. The residue is purified by chromatography.  
         [0000]     Step 2A  
         [0088]     The end compound V is prepared by substitution of a leaving group LG, for example halogen, SCN or methoxy, preferably chlorine, in a heteroaromatic system III by a nucleophile IV.  
                         
 
         [0089]     1 equivalent of the compound III and 1 to 3 equivalents of the compound IV are stirred in a solvent, for example 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide or N-methyl-2-pyrrolidinone. At a temperature of 15 to 40° C., 1 to 2 equivalents of an inorganic acid, for example sulphuric acid or hydrochloric acid, are added. The reaction mixture is stirred for another 12 to 72 h at a temperature of 20 to 100° C. Then the solvent is distilled off and the residue is purified by chromatography.  
         [0000]     Method B  
         [0000]     Step 1B  
         [0090]     The intermediate compound VII is prepared by substitution of a leaving group LG, for example halogen, SCN, methoxy, preferably chlorine, in a heteroaromatic system I by a nucleophile VI.  
                         
 
         [0091]     1 equivalent of the compound I and 1 to 1.5 equivalents of the compound VI are stirred in a solvent, for example 1,4-dioxane, tetrahydrofuran, ethanol, isopropanol, N,N-dimethylformamide or N,N-dimethylacetamide.  
         [0092]     At a temperature of 15 to 25° C., 2 to 2.5 equivalents of a base, for example potassium carbonate, sodium carbonate, caesium carbonate, potassium hydrogen phosphate, N-ethyl-N,N-diisopropylamine or triethylamine are added. The reaction mixture is stirred for 6 to 72 h more at a temperature of 20 to 120° C. The reaction mixture is combined with water, which has been adjusted to a pH of 8 to 9 with an inorganic base, for example sodium hydrogen carbonate or potassium carbonate. This mixture is extracted two to three times with an organic solvent, for example diethyl ether or ethyl acetate.  
         [0093]     The combined organic extracts are dried and the solvent is distilled off. The residue is purified by chromatography or repeated crystallisation.  
         [0000]     Step 2B  
         [0094]     The intermediate compound VIII is prepared by substituting a leaving group LG, for example halogen, SCN, methoxy, preferably chlorine, in a heteroaromatic system VII by a nucleophile IV.  
                         
 
         [0095]     1 equivalent of the compound VII and 1 to 1.5 equivalents of the compound IV are stirred in a solvent, for example 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide or N-methyl-2-pyrrolidinone. At a temperature of 15 to 40° C., 0.2 to 1 equivalent of an acid, for example sulphuric acid or hydrochloric acid, is added. The reaction mixture is stirred for another 12 to 72 h at a temperature of 20 to 100° C. The reaction mixture is stirred into water and the resulting precipitate is filtered off and dried. The precipitate may be purified by chromatography or crystallisation or used as the crude product in the next step.  
         [0000]     Step 3B  
         [0096]     Compounds VIII whose group R 7  denotes hydrogen may be used directly for preparing the end compounds X, while a compound VIII is reacted with a compound IX.  
         [0097]     Compounds VIII whose group R 7  does not denote hydrogen are converted beforehand by hydrolysis or similar methods known to the skilled man into the compounds wherein the group R 7  denotes hydrogen.  
                         
 
         [0098]     1 equivalent of the compound VIII, 1 to 1.5 equivalents of the compound IX and 1 to 3 equivalents of a base, for example triethylamine or ethyldiisopropylamine, are stirred in a solvent, for example 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide or N-methyl-2-pyrrolidinone. At a temperature of 15 to 25° C., 1 to 1.5 equivalents of a coupling reagent, for example N,N-dicyclohexylcarbodiimide, N,N-diisopropyl-carbodiimide, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-tetrafluoroborate or 1-(3-N,N-dimethylaminopropyl)-3-ethylcarbodiimide are added. The reaction mixture is stirred for another 4 to 24 h at a temperature of 15 to 25° C. Then the solvent is distilled off and the residue is purified by chromatography.  
         [0000]     Method C  
         [0000]     Step 1C  
         [0099]     The intermediate compound XI is prepared by substituting a leaving group LG, for example halogen, SCN, methoxy, preferably chlorine, at a heteroaromatic system I with a nucleophilic group IV.  
                         
 
         [0100]     1 equivalent of the compound I and 1 to 3 equivalents of a base, for example triethylamine or ethyldiisopropylamine, are stirred in a solvent, for example 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide or N,N-dimethylacetamide. At a temperature of −60 to 0° C., 0.8 to 1.5 equivalents of a compound IV are added. The reaction mixture is stirred for 6 to 72 h at a temperature of 15 to 75° C. Then the solvent is distilled off and the residue is purified by chromatography.  
         [0000]     Step 2C  
         [0101]     The end compound V is prepared by substitution of a leaving group LG, for example halogen, SCN, methoxy, preferably chlorine, at a heteroaromatic system XI by a nucleophile II.  
                         
 
         [0102]     1 equivalent of the compound XI and 1 to 1.5 equivalents of the compound II are stirred in a solvent, for example 1,4-dioxane, N,N-dimethyl-formamide, N,N-dimethylacetamide or N-methyl-2-pyrrolidinone. At a temperature of 15 to 40° C. 1 to 2 equivalents of an acid, for example sulphuric acid or hydrochloric acid, are added. The reaction mixture is stirred for another 6 to 72 h at a temperature of 20 to 100° C. Then the solvent is distilled off and the residue is purified by chromatography.  
         [0000]     Chromatography:  
         [0103]     For medium pressure chromatography (MPLC) silica gel made by Millipore (name: Granula Silica Si-60A 35-70 μm) or C-18 RP-silica gel made by Macherey Nagel (name: Polygoprep 100-50 C18) is used.  
         [0104]     For high pressure chromatography columns made by Waters (name: XTerra Prep. MS C18, 5 μM, 30*100 mm or Symmetrie C18, 5 μm, 19*100) are used.  
         [0000]     Nuclear Magnetic Resonance (NMR) Spectroscopy:  
         [0105]     The measurement is carried out in deuterised dimethylsulphoxide-d6. If other solvents are used they are explicitly mentioned in the Examples or in the methods. The measurements are given on a delta scale in ppm. Tetramethylsilane is taken as the standard. The measurements are carried out on an Avance 400 (400 MHz NMR spectrometer) made by Messrs Bruker Biospin GmbH.  
         [0106]     The NMR spectra are given purely in a descriptive capacity. Basically, only the visible molecular signals are listed. If for example molecular signals are partly or completely masked by foreign signals such as for example water signals, DMSO signals or CDCl 3  signals they are not mentioned.  
         [0000]     Mass Spectroscopy/UV Spectrometer:  
         [0107]     These data are generated using an HPLC-MS apparatus (high performance liquid chromatography with mass detector) made by Agilent.  
         [0108]     The apparatus is constructed so that a diode array detector (G1315B made by Agilent) and a mass detector (1100 LS-MSD SL; G1946D; Agilent) are connected in series downstream of the chromatography apparatus (column: Zorbax SB-C8, 3.5 μm, 2,1*50, Messrs. Agilent). The apparatus is operated with a flow of 0.6 ml/min. For a separation process a gradient is run through within 3.5 min (start of gradient: 95% water and 5% acetonitrile; end of gradient: 5% water and 95% acetonitrile; in each case 0.1% formic acid is added to the two solvents).  
         [0000]     Method 1  
       2-(2-methoxy-4-propylcarbamoyl-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine  
       [0109]    
       
                 
         
             
             
         
       
     
         [0110]     5 g (21.9 mmol) 2,4-dichloro-5-trifluoromethyl-pyrimidine are dissolved in 50 ml 1,4-dioxane and combined with 5.5 g (21.9 mmol) 4-amino-3-methoxybenzoic acid-propylamide hydrochloride (Zhuangyu Zhang, et al. 1989 , J Pharml Sci.  78(10):829-32). 7.5 ml (43.8 mmol) ethyldiisopropylamine are added to this reaction mixture and the mixture is stirred for 2 days at ambient temperature. Then the reaction mixture is diluted with 250 ml of ethyl acetate and washed first with 300 ml aqueous 10% KHSO 4  solution, then with 300 ml saturated aqueous NaCl solution. The organic phase is dried with MgSO 4  and the solvent is eliminated in vacuo. The crude product is purified by column chromatography. The carrier used is silica gel and the eluant is a mixture of cyclohexane:ethyl acetate (75:25).  
         [0111]     Yield: 2.30 g (5.9 mmol; 27%)  
         [0112]      1 H-NMR: 0.91 (t, 3H), 1.50-1.61 (m, 2H), 3.20-3.28 (m, 2H), 3.87 (s, 3H), 7.46-7.51 (m, 1H), 7.52-7.56 (m, 1H), 7.70-7.75 (m, 1H), 8.44 (t, 1H), 8.75 (s, 1H), 9.73 (s, 1H)  
         [0000]     Method 2  
       7-amino-2,3-dihydro-isoindol-1-one  
       [0113]    
       
                 
         
             
             
         
       
     
       a) 7-nitro-2,3-dihydro-isoindol-1-one  
       [0114]     1.5 g (5.473 mmol) methyl 2-bromomethyl-6-nitro-benzoate are dissolved in 20 ml N,N-dimethylformamide and combined with 15 ml of methanolic ammonia (7 mmol/ml). After 20 h at 25° C. the mixture is diluted with 100 ml of ethyl acetate and extracted 3 times with saturated sodium hydrogen carbonate solution. The organic phase is dried with magnesium sulphate and the solvent is eliminated in vacuo.  
         [0115]     Yield: 960 mg (5.389 mmol, 99%)  
         [0116]     MS-ESI+: m/z=179 [M+H] +   
       b) 7-amino-2,3-dihydro-isoindol-1-one  
       [0117]     960 mg (5.389 mmol) 7-nitro-2,3-dihydro-isoindol-1-one are dissolved in 100 ml of tetrahydrofuran and combined with 100 mg palladium on charcoal. Then the mixture is stirred for 20 h at 25° C. and 4 bar hydrogen pressure (H 2  pressure). The catalyst is filtered off and the solvent is eliminated in vacuo.  
         [0118]     Yield: 734 mg (4.958 mmol, 92%)  
         [0119]     MS-ESI+: m/z=149 [M+H] +   
         [0120]     The following 7-amino-2,3-dihydro-isoindol-1-one derivatives are prepared analogously to this method. A corresponding amine is used instead of ammonia:  
                                                                         MS (ESI)       MS (ESI)           (M + H) +         (M + H) +                                                                                        163                                 193                                             177                                 225                                             191                                 243                                             231                                 221                                             219                                 255                                             233                                 192                                             207                                 255                                             234                                 178                                             274                                 192                                             195                                 211/213                                             213                                 247                                             231                                 247                                             209                                 261                                             245                                 261                                             188                                 261                                             187                                 261                                             206                                 223                                             233                                 223                                             233                                 221                                             202                                 247                                             206                                 246                                             191                                 235                                             205                                 224                                             227                                 222                                             223                  
 
 Method 3 
 
       Ethyl (4-amino-3-oxo-1,3-dihydro-isobenzofuran-1-yl)-acetate  
       [0121]    
       
                 
         
             
             
         
       
     
       a) ethyl (4-amino-3-oxo-3H-isobenzofuran-1-ylidene)-acetate  
       [0122]     500 mg (3.1 mmol) 4-amino-isobenzofuran-1,3-dione and 1.13 g (3.1 mmol) (ethoxy-carbonylmethylene)-triphenylphosphorane are dissolved in 5 ml of tetrahydrofuran (THF) and refluxed for 3 h. Then the solvent is eliminated in vacuo. The crude product is purified by column chromatography. The carrier used is silica gel and the eluant used is a mixture of cyclohexane:ethyl acetate (75:25).  
         [0123]     Yield: 221 mg (0.95 mmol, 31%)  
         [0124]     MS-ESI+: m/z=234 [M+H] +   
       b) ethyl (4-amino-3-oxo-1,3-dihydro-isobenzofuran-1-yl)-acetate  
       [0125]     120 mg (0.51 mmol) ethyl (4-amino-3-oxo-3H-isobenzofuran-1-ylidene)-acetate are dissolved in 50 ml of methanol and combined with 50 mg palladium on activated charcoal (10% Pd). The reaction mixture is hydrogenated for 3 h at 2 bar H 2  pressure and 25° C. Then the catalyst is filtered off and the solvent is eliminated in vacuo.  
         [0126]     Yield: 116 mg (0.49 mmol, 97%)  
         [0127]     MS (ESI): m/z=236 (M+H) +   
         [0128]      1 H-NMR: 1.17 (t, 3H), 2.68-2.78 (m, 1H), 3.08-3.16 (m, 1H), 4.10 (q, 2H), 5.67-5.74 (m, 1H), 6.28 (bs, 2H), 6.61-6.70 (m, 2H), 7.30-7.38 (m, 1H)  
         [0000]     Method 4  
       5-amino-3H-quinazolin-4-one  
       [0129]    
       
                 
         
             
             
         
       
     
       a) 2,6-diaminobenzamide  
       [0130]     5 g (25.373 mmol) 2,6-dinitro-benzonitrile is combined with 20 ml of an aqueous 80% sulphuric acid and stirred for 2 h at 80° C. The reaction mixture is combined with 100 ml of tetrahydrofuran and neutralised with 10% aqueous sodium hydroxide solution. The organic phase is separated off, combined with another 100 ml of tetrahydrofuran and 200 mg palladium on charcoal and stirred for 20 h at 8 bar H 2  pressure and 25° C. The solids are filtered off. The filtrate is combined with 300 ml of ethyl acetate and extracted with saturated potassium hydrogen carbonate solution. The organic phase is separated off, dried and the solvent is eliminated in vacuo. The residue is purified by chromatography. The carrier used is silica gel and the eluant used is dichloromethane, to which 7% of a mixture of 90% methanol and 10% saturated aqueous ammonia solution are added.  
         [0131]     Yield: 900 mg (5.958 mmol; 23%)  
         [0132]     MS (ESI): 152 (M+H)+ 
       b) 5-amino-3H-quinazolin-4-one  
       [0133]     900 mg (5.958 mmol) 2,6-diaminobenzamide are dissolved in 3.6 ml N,N-dimethylacetamide and combined with 6.3 ml (57.01 mmol) trimethylorthoformate and 792 μl (8.865 mmol) 98% sulphuric acid. After 16 h at 25° C. the reaction mixture is taken up with 20 ml of methanol and the solvent is eliminated in vacuo. The residue is again taken up in 20 ml of methanol, neutralised with concentrated ammonia. The solvent is eliminated in vacuo and the residue purified by chromatography. The carrier used is silica gel and the eluant used is dichloromethane, to which 7% of a mixture of 90% methanol and 10% saturated aqueous ammonia solution are added.  
         [0134]     Yield: 782 mg (4.852 mmol; 81%)  
         [0135]     MS (ESI): 162 (M+H) +   
         [0000]     Method 5  
       9-amino-2,3,4,5-tetrahydro-2-benzazepin-1-one  
       [0136]    
       
                 
         
             
             
         
       
     
         [0137]     500 mg (1.825 mmol) 2-bromomethyl-6-nitro-methylbenzoate are heated to 100° C. in 2 ml trimethyl phosphate for 5 h. 2-(dimethylphosphonomethyl)-6-nitromethylbenzoate is obtained by evaporation under a high vacuum and used further directly. The crude product is dissolved in 24 ml of tetrahydrofuran at −70° C. under N 2 , 2.7 ml (2.7 mmol) of a 1 M lithium hexamethyldisilazide solution in tetrahydrofuran is added dropwise and then 430 mg (2.70 mmol) tert.-butyl-N-(2-oxoethyl)-carbamate in 5 ml of tetrahydrofuran are added. The reaction mixture is slowly heated to ambient temperature, combined with 5 ml of 1 M HCl and extracted with ethyl acetate. The combined organic phases are concentrated by evaporation and, by chromatography on silica gel with a mixture of cyclohexane-ethyl acetate in the ratio 95:5 to 75:25, 338 mg (1.006 mmol, 55%) of the E-/Z mixture of 2-(3-tert.-butoxycarbonylamino-prop-1-en-1-yl)-6-nitro-methylbenzoate are obtained. This E-/Z-mixture is treated for 12 h with 10 ml of a saturated methanolic potassium hydroxide solution. After acidification with aqueous 1 M HCl and extraction with ethyl acetate 302 mg (0.938 mmol, 93%) of the E-/Z mixture of 2-(3-tert.-butoxycarbonylamino-prop-1-en-1-yl)-6-nitro-methylbenzoic acid are obtained. To this are added 20 mg Raney nickel in 100 ml of methanol and the mixture is hydrogenated at 5 bar H 2  pressure. The catalyst is filtered off, the filtrate concentrated by evaporation and stirred overnight with a 1:1 mixture of trifluoroacetic acid and dichloromethane at ambient temperature. After elimination of the solvent 133 mg (0.686 mmol, 73%) 2-amino-6-(3-amino-propyl)-benzoic acid are obtained. The further reaction is carried out by dissolving in 10 ml THF and 10 ml DCM with the addition of 300 mg (1.570 mmol) N-(3-dimethylaminopropyl)-N-4-ethylcarbodiimide hydrochloride and 134 μl (0.830 mmol) N,N-diisopropyl-ethylamine and 48 h stirring at ambient temperature. The solvent is eliminated in vacuo and the crude product is purified by chromatography with C18-RP silica gel and an eluant mixture of acetonitrile and water in the ratio 5:95 to 95:5, to which 0.1% formic acid has been added.  
         [0138]     Yield: 28 mg (0.160 mmol, 23%)  
         [0139]     MS (ESI): m/z=177 (M+H) +   
         [0000]     Method 6  
       4-amino-1-methyl-1,2-dihydro-indazol-3-one  
       [0140]    
       
                 
         
             
             
         
       
     
       a) 4-nitro-1,2-dihydro-indazol-3-one  
       [0141]     5 g (27.5 mmol) 2-amino-6-nitro-benzoic acid are combined with 22.2 ml (225.3 mmol) concentrated HCl and 45 ml (30.0 mmol) 5% aqueous sodium nitrite solution and stirred for 1 h at ambient temperature. Then the suspension is diluted with 150 ml dist. H 2 O and added dropwise to 350 ml destilliertes water which has been saturated with sulphur dioxide. Sulphur dioxide is piped through the reaction mixture for a further 30 min. Then the reaction mixture is refluxed for 30 min and then left to cool slowly to 20° C. The resulting precipitate is filtered off.  
         [0142]     Yield: 1.7 g (9.5 mmol, 35%)  
         [0143]     MS (ESI): m/z=180 (M+H) +   
       b) 1-methyl-4-nitro-1,2-dihydro-indazol-3-one  
       [0144]     306 mg (1.7 mmol) 4-nitro-1,2-dihydro-indazol-3-one are dissolved in 1 ml N,N-dimethyl-acetamide, combined with 150 μl (2.4 mmol) methyl iodide and 500 μl (2.32 mmol) of N-ethyldiisopropylamide and stirred for 2 h at ambient temperature. Then the reaction mixture is combined with 40 ml of a 1 N aqueous hydrochloric acid and extracted twice with 50 ml dichloromethane. Then the organic phase is dried with MgSO 4 , the solvent is eliminated in vacuo and the crude product is purified by chromatography. The carrier used is C18-RP-silica gel and a gradient is run through which consists of 95% water and 5% acetonitrile at the starting point and 5% water and 95% acetonitrile at the finishing point.  
         [0145]     Yield: 144 mg (0.7 mmol, 44%)  
         [0146]     MS (ESI): m/z=194 (M+H) +   
         [0147]      1 H-NMR: 3.90 (s, 3H), 7.47-7.52 (m, 1H), 7.68-7.73 (m, 1H), 7.88-7.93 (m, 1H), 10.53 (s, 1H)  
       c) 4-amino-1-methyl-1,2-dihydro-indazol-3-one  
       [0148]     140 mg (0.7 mmol) 1-methyl-4-nitro-1,2-dihydro-indazol-3-one are suspended in 6 ml of ethanol and combined with 600 mg (4.4 eq, 2.9 mmol) sodium dithionite, dissolved in 2 ml distilled water, and stirred for 15 min at 25° C. Then the reaction mixture is combined with distilled water and extracted twice with ethyl acetate. Then the organic phase is dried with MgSO 4  and the solvent is eliminated in vacuo.  
         [0149]     Yield: 33 mg (0.2 mmol, 28%)  
         [0150]     MS (ESI): m/z=164 (M+H) +   
         [0151]     4-amino-1,2-dihydro-indazol-3-one and the following compounds are prepared analogously to this method.  
                                                                         MS       MS           (ESI)       (ESI)           (M +       (M +           H) +         H) +                                                                                        178                                 178                                             194                  
 
 Method 7 
 
       8-amino-4-methyl-3,4-dihydro-2H-isoquinolin-1-one  
       [0152]    
       
                 
         
             
             
         
       
     
       a) methyl 2-(cyanomethyl-2-methyl)-6-nitro-benzoate  
       [0153]     400 mg (1.8 mmol) methyl 2-cyanomethyl-6-nitro-benzoate are dissolved in 13 ml THF, combined with 114 μl (1.8 mmol) methyl iodide and the mixture is cooled to −20° C. under a nitrogen atmosphere. Then at this temperature 250 mg (2.2 mmol) potassium-tert-butoxide are added. After 1 h the solvent is eliminated in vacuo and the crude product is purified by chromatography. The carrier used is C18-RP-silica gel and a gradient is run through which consists of 95% water and 5% acetonitrile at the starting point and 5% water and 95% acetonitrile at the finishing point.  
         [0154]     Yield: 289 mg (1.2 mmol, 68%)  
         [0155]     MS (ESI): 233 (M−H) −   
       b) 8-amino-4-methyl-3,4-dihydro-2H-isoquinolin-1-one  
       [0156]     400 mg (1.8 mmol) methyl 2-(cyanomethyl-2-methyl)-6-nitro-benzoate are dissolved in 13 ml of methanol and combined with 50 mg Raney nickel. The reaction mixture is hydrogenated for 16 h at 4 bar H 2  pressure and 25° C. Then the catalyst is filtered off and the solvent is eliminated in vacuo.  
         [0157]     Yield: 170 mg (0.8 mmol, 46%)  
         [0158]     MS (ESI): 177 (M+H) +   
         [0159]     8-amino-3,4-dihydro-2H-isoquinolin-1-one and 8-amino-4,4-dimethyl-3,4-dihydro-2H-isoquinolin-1-one and the following compounds are prepared analogously to this method.  
                                                                         MS                   (ESI)           (M +       MS (ESI)           H) +         (M + H) +                                                                                        221                                 205                                             253                  
 
 Method 8 
 
       7-amino-indan-1-one  
       [0160]    
       
                 
         
             
             
         
       
     
       a) indan-4-ylamine  
       [0161]     24 ml (349 mmol) 65% nitric acid are cooled to 0-5° C. 28 ml (518.5 mmol) of concentrated sulphuric acid are slowly added dropwise while cooling with ice. This solution is cooled to 5° C. and slowly added dropwise to 30 ml (232 mmol) indane cooled to 0-5° C., with vigorous stirring and further cooling with ice. The reaction mixture is stirred for 30 min at 0-5° C., and then heated to 25° C. for 1 h with stirring. Then the solution is added dropwise to 150 ml ice/water and stirred for 30 min. The aqueous phase is extracted three times with 200 ml diethyl ether. The combined organic phases are washed twice with 200 ml saturated sodium hydrogen carbonate solution and once with 150 ml distilled water. Then the organic phase is dried with MgSO 4  and the solvent is eliminated in vacuo. The crude product is dissolved in 250 ml of methanol and combined with 4.5 g Raney nickel. The reaction mixture is hydrogenated for 16 h at 3 bar H 2  pressure and 25° C. Then the catalyst is filtered off and the solvent is eliminated in vacuo. The crude product is purified by column chromatography. The carrier used is silica gel and the eluant used is a mixture of cyclohexane:ethyl acetate (75:25).  
         [0162]     Yield: 3.81 g (28.6 mmol, 12%)  
         [0163]     MS (ESI): 134 (M+H) +   
         [0164]      1 H-NMR: 1.90-2.00 (m, 2H), 2.61 (t, 2H), 2.76 (t, 2H), 4.73 (s, 2H), 6.33-6.38 (m, 1H), 6.39-6.45 (m, 1H), 6.76-6.83 (m, 1H)  
       b) N-indan-4-yl-acetamide  
       [0165]     226 mg (1.7 mmol) indan-4-ylamine are combined with 5 ml acetic anhydride. The suspension is stirred for 16 h at 70° C. The resulting solution is stirred into 40 ml distilled water, adjusted to pH 7 with sodium carbonate and extracted three times with 30 ml of ethyl acetate. Then the organic phase is dried with MgSO 4 , the solvent is eliminated in vacuo and the crude product is purified by chromatography. The carrier used is silica gel and the eluant used is a mixture of cyclohexane:ethyl acetate (70:30).  
         [0166]     Yield: 152 mg (0.9 mmol, 51%)  
         [0167]     MS (ESI): 176 (M+H) +   
         [0168]      1 H-NMR: 1.93-2.03 (m, 2H), 2.04 (s, 3H), 2.79 (t, 2H), 2.86 (t, 2H), 6.94-7.01 (m, 1H), 7.02-7.10 (m, 1H), 7.36-7.44 (m, 1H), 9.25 (s, 1H)  
       c) N-(3-oxo-indan-4-yl)-acetamide  
       [0169]     147 mg (0.84 mmol) N-indan-4-yl-acetamide are dissolved in 10 ml acetone and combined with 770 μl of a 15% aqueous magnesium sulphate solution. The solution is cooled to 0° C. and 397 mg (2.490 mmol) potassium permanganate are added batchwise. After 2 h the mixture is diluted with 50 ml of water, and extracted three times with 20 ml chloroform. The organic phase is dried with magnesium sulphate and the solvent is eliminated in vacuo and the crude product is purified by chromatography. The carrier used is silica gel and the eluant used is a mixture of cyclohexane:ethyl acetate (85:15).  
         [0170]     Yield: 95 mg (0.500 mmol, 60%)  
         [0171]     MS (ESI): 190 (M+H) +   
       d) 7-amino-indan-1-on  
       [0172]     500 mg (2.6 mmol) N-(3-oxo-indan-4-yl)-acetamide are dissolved in 5 ml of ethanol, combined with 5 ml 18% hydrochloric acid and stirred for 3 h at 70° C. Then the reaction mixture is stirred into 100 ml distilled water, adjusted to pH 7 with sodium carbonate and extracted three times with 30 ml of ethyl acetate. Then the organic phase is dried with magnesium sulphate and the solvent is eliminated in vacuo.  
         [0173]     Yield: 388 mg (2.6 mmol, 100%)  
         [0174]     8-amino-3,4-dihydro-2H-naphthalen-1-one is prepared analogously to this method. 1,2,3,4-tetrahydronaphthalene is used as starting material instead of indane.  
         [0000]     Method 9  
       N-(7-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-acetamide  
       [0175]    
       
                 
         
             
             
         
       
     
       a) 2-benzyloxy-N-(7-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-acetamide  
       [0176]     870 mg (4.5 mmol) 2-amino-7-nitro-2,3-dihydro-isoindol-1-one (prepared analogously to method 2) are dissolved in 82 ml dichloromethane and 64 ml THF. The solution is combined with 2.8 ml (3.3 eq, 20 mmol) benzyloxyacetyl chloride, 4.8 ml (28.0 mmol) N-ethyldiisopropyl-amine and 10 mg N,N-dimethylaminopyridine and stirred for 3 h at 25° C. Then the reaction mixture is combined with 100 ml aqueous 0.1 N hydrochloric acid and extracted three times with 50 ml of ethyl acetate. The organic phase is dried with magnesium sulphate, the solvent is eliminated in vacuo and the crude product is purified by chromatography. The carrier used is silica gel and the eluant used is a mixture of dichloromethane:methanol (95:5).  
         [0177]     Yield: 910 mg (2.7 mmol, 59%)  
       b) N-(7-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-acetamide  
       [0178]     790 mg (2.3 mmol) 2-benzyloxy-N-(7-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-acetamide are dissolved in 100 ml of methanol and combined with 80 mg palladium hydroxide. The reaction mixture is hydrogenated for 48 h at 4 bar H 2  pressure and 25° C. Then the catalyst is filtered off and the solvent is eliminated in vacuo. The crude product is purified by chromatography. The carrier used is silica gel and the eluant used is a mixture of dichloromethane:methanol (90:10).  
         [0179]     Yield: 210 mg (0.1 mmol, 41%)  
         [0180]     MS (ESI): 222 (M+H) +   
         [0000]     Method 10  
       6-amino-2-ethyl-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one  
       [0181]    
       
                 
         
             
             
         
       
     
       a) 2-amino-6-(1-aminomethyl-propoxy)-benzonitrile  
       [0182]     2.01 g (22 mmol) 1-amino-2-butanol are dissolved in 6.5 ml 1,4-dioxane, combined with 880 mg (7.8 mmol) sodium hydride and stirred for 30 min at ambient temperature. 2 g (14.7 mmol) of 2-amino-6-fluorobenzonitrile are added to this reaction mixture and it is stirred for 24 h at 50° C. Then the solvent is eliminated in vacuo and the crude product is purified by chromatography. The carrier used is silica gel and the eluant used is dichloromethane, to which 5% of a mixture of 90% methanol and 10% saturated aqueous ammonia solution has been added.  
         [0183]     Yield: 1.15 g (5.6 mmol, 38%)  
         [0184]     MS (ESI): 206 (M+H) +   
       b) 2-amino-6-(1-aminomethyl-propoxy)-benzoic acid  
       [0185]     1.15 g (5.6 mmol) 2-amino-6-(1-aminomethyl-propoxy)-benzonitrile are dissolved in 10 ml 20% ethanolic KOH and stirred for 24 h at 80° C. Then the solvent is eliminated in vacuo and the crude product is purified by chromatography. The carrier used is silica gel and the eluant used is dichloromethane, to which 12% of a mixture of 90% methanol and 10% saturated aqueous ammonia solution have been added.  
         [0186]     Yield: 262 mg (1.2 mmol, 21%)  
         [0187]     MS (ESI): 225 (M+H) +   
       c) 6-amino-2-ethyl-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one  
       [0188]     262 mg (1.2 mmol) 2-amino-6-(1-aminomethyl-propoxy)-benzoic acid are dissolved in 26 ml THF, combined with 680 mg (3.5 mmol) 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride and 0.6 ml (3.5 mmol) diisopropyl-ethylamine and stirred for 3 h at 50° C. Then the solvent is eliminated in vacuo and the crude product is purified by chromatography. The carrier used is silica gel and the eluant used is dichloromethane, to which 4% of a mixture of 90% methanol and 10% saturated aqueous ammonia solution have been added.  
         [0189]     Yield: 50 mg (0.2 mmol, 21%)  
         [0190]     MS (ESI): 207 (M+H) +   
         [0191]     The following compounds are prepared analogously to this method. 1-amino-2-butanol was replaced by a corresponding aminoalcohol or by a corresponding 1,2-diaminoethylene.  
                                                                         MS (ESI)       MS (ESI)           (M + H) +         (M + H) +                                                                                        207                                 251                                             193                                 179                                             235                                 221                                             219                                 206                                             233                                 235                                             207                                 227                                             207                                 219                                             193                                 207                                             221                                 269                                             299                                 225                                             219                                 253                                             209                                 241                                             269                                 233                  
 
 Method 11 
 
       6-amino-3-benzyl-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione  
       [0192]    
       
                 
         
             
             
         
       
     
       a) methyl 2-(2-amino-6-nitro-benzoylamino)-3-phenyl-propionate  
       [0193]     1.18 g (6.5 mmol) 2-amino-6-nitrobenzoic acid, 1.0 g (4.6 mmol) D,L-phenylalanine-methylester hydrochloride, 4.05 ml (23.2 mmol) N-ethyldiisopropylamine are combined with 2.5 ml of tetrahydrofuran. 1.71 g (5.1 mmol) O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-tetrafluoroborate are added to this reaction mixture and it is heated for 12 h to 50° C. Then the solvent is eliminated in vacuo and the crude product is purified by chromatography. The carrier used is silica gel and the eluant used is a mixture of cyclohexane:ethyl acetate (50:50).  
         [0194]     Yield: 1.04 g (3.03 mmol, 65%)  
         [0195]     MS (ESI): 344 (M+H) +   
       b) 2-(2-amino-6-nitro-benzoylamino)-3-phenyl-propionic acid  
       [0196]     1.04 g (3.03 mmol) methyl 2-(2-amino-6-nitro-benzoylamino)-3-phenyl-propionate are dissolved in 3 ml 20% ethanolic KOH and stirred for 1.5 h at 50° C. Then the solvent is eliminated in vacuo and the crude product is purified by chromatography. The carrier used is silica gel and the eluant used is dichloromethane, to which 15% of a mixture of 90% methanol and 10% saturated aqueous ammonia solution has been added.  
         [0197]     Yield: 636 mg (1.9 mmol, 64%)  
         [0198]     MS(ESI): 329 (M+H) +   
         [0199]      1 H-NMR: 2.86-2.94 (m, 1H), 3.17 (s, 1H), 3.22-3.29 (m, 1H), 4.30-4.38 (m, 1H), 6.63 (s, 2H), 6.89-6.96 (m, 1H), 6.97-7.02 (m, 1H), 7.12-7.21 (m, 2H), 7.21-7.27 (m, 2H), 7.28-7.35 (m, 2H), 8.33-8.43 (m, 1H)  
       c) 2-(2,6-diamino-benzoylamino)-3-phenyl-propionic acid  
       [0200]     410 mg (1.25 mmol) 2-(2-amino-6-nitro-benzoylamino)-3-phenyl-propionic acid are dissolved in 50 ml of methanol and combined with 40 mg palladium on charcoal (10% Pd). The reaction mixture is hydrogenated for 9 h at 5 bar H 2  pressure and 25° C. Then the catalyst is filtered off, the solvent is eliminated in vacuo and the crude product is purified by chromatography. The carrier used is C18-RP-silica gel and a gradient is run through which consists of 95% water and 5% acetonitrile at the starting point and consists of 5% water and 95% acetonitrile at the finishing point.  
         [0201]     Yield: 88 mg (0.29 mmol, 24%)  
         [0202]     MS (ESI): 300 (M+H) +   
       d) 6-amino-3-benzyl-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione  
       [0203]     88 mg (0.3 mmol) 2-(2,6-diamino-benzoylamino)-3-phenyl-propionic acid are dissolved in 2 ml THF, combined with 143 mg (0.9 mmol) 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride and 103 μl (0.6 mmol) diisopropyl-ethylamine and stirred for 17 h at 50° C. Then the solvent is eliminated in vacuo and the crude product is purified by chromatography. The carrier used is silica gel and the eluant used is dichloromethane, to which 5% of a mixture of 90% methanol and 10% saturated aqueous ammonia solution have been added.  
         [0204]     Yield: 22 mg (0.08 mmol, 27%)  
         [0205]     MS (ESI): 282 (M+H) +   
         [0206]     The following compounds are prepared analogously to to method 11.  
                                                                         MS (ESI)       MS (ESI)           (M + H) +         (M + H) +                                                                                        192                                 268                                             206                                 277                                             206                                 278                                             218                                 278                                             220                                 282                                             220                                 283                                             232                                 283                                             232                                 288                                             234                                 296                                             234                                 192                                             234                                 298                                             246                                 298                                             246                                 300                                             246                                 300                                             248                                 300                                             248                                 307                                             2458                                 316/318                                             250                                 321                                             265                                 321                                             265                                 346                  
 
 Method 12 
 
       2-(4-carboxy-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine  
       [0207]    
       
                 
         
             
             
         
       
     
         [0208]     7.36 g (44 mmol) 4-amino-3-methoxybenzoic acid are suspended in 80 ml of an aqueous phosphate buffer solution (pH 6.3) and combined with 9.5 g (44 mmol) 2,4-dichloro-5-trifluoro-methyl-pyrimidine, which is dissolved in 240 ml 1,4-dioxane. After 4 h at 100° C. the reaction mixture is crystallised at 0° C. The precipitate is filtered off, the filtrate is combined with 150 ml of ethyl acetate and washed twice with 200 ml of a saturated aqueous sodium hydrogen carbonate solution. The organic phase is dried with MgSO 4  and the solvent is eliminated in vacuo. The crude product is suspended in 10 ml n-hexane and refluxed. The precipitate is filtered off, suspended in 48 ml of a saturated aqueous sodium hydrogen carbonate solution and heated to 65° C. for 1 h. Then the solution is crystallised at 0° C. The precipitate is filtered off, the filtrate is acidified with 1 N aqueous hydrochloric acid and combined with 100 ml of ethyl acetate. The organic phase is separated off, dried with magnesium sulphate and the solvent is eliminated in vacuo. The residue is recrystallised from ethyl acetate.  
         [0209]     Yield: 330 mg (0.95 mmol, 2%)  
         [0210]     MS (ESI): 348 (M+H) +   
         [0211]      1 H-NMR: 1.55 (s, 1H), 4.01 (s, 3H), 7.61-7.64 (m, 1H), 7.79-7.85 (m, 1H), 8.34 (s, 1H), 8.59-8.63 (m, 1H), 8.66 (s, 1H)  
         [0000]     Method 13  
       4-(4-amino-cyclohexyl)-morpholine  
       [0212]    
       
                 
         
             
             
         
       
     
       a) dibenzyl-(4-morpholino-4-yl-cyclohexyl)-amine  
       [0213]     3.9 g (30 mmol) 4-dibenzylamino-cyclohexanone are dissolved in 100 ml dichloromethane and stirred with 3.9 g (45 mmol) morpholine and 9.5 g (45 mmol) sodium triacetoxyborohydride for 12 h at ambient temperature. Then water and potassium carbonate are added, the organic phase is separated off, dried and the solvent is eliminated in vacuo. The crude product is purified by column chromatography. The carrier used is silica gel and the eluant used is ethyl acetate, to which 10% of a mixture of 90% methanol and 10% saturated aqueous ammonia solution have been added. The suitable fractions are evaporated down in vacuo.  
         [0214]     Yield: 6.6 g (18 mmol, 60%) cis-isomer  
         [0215]     2 g (5.4 mmol, 18%) trans-isomer.  
       b) trans-4-morpholino-4-yl-cyclohexylamine  
       [0216]     7.2 g (16.4 mmol) trans-dibenzyl-4-morpholino-cyclohexylamine are dissolved in 100 ml of methanol and hydrogenated on 1.4 g palladium on charcoal (10% Pd) at 30-50° C. The solvent is eliminated in vacuo and the residue is crystallised from ethanol and concentrated hydrochloric acid.  
         [0217]     Yield: 3.9 g (15.2 mmol, 93%)  
         [0218]     melting point: 312° C.  
         [0219]     The following compounds are prepared analogously to Method 13:  
                                                                         MS (ESI)       MS (ESI)           (M + H) +         (M + H) +                                                                                        169                                 213                                             211                                 238                  
 
 Method 14 
 
       2-(4-carboxy-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine  
       [0220]    
       
                 
         
             
             
         
       
     
       a) 2-(4-benzyloxycarbonyl-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine  
       [0221]     2 g (9.217 mmol) 2,4-dichloro-5-trifluoromethylpyrimidine are dissolved in 4 ml dioxane and combined with 6.01 g (18.430 mmol) caesium carbonate and 2.16 g (7.363 mmol) benzyl 4-amino-3-methoxybenzoate (WO 9825901). This suspension is stirred for 30 h at 100° C. The suspension is combined with 50 ml dichloromethane and methanol and filtered to remove the insoluble constituents. The solvent is eliminated in vacuo and the residue is purified by column chromatography. The carrier used is silica gel and the eluant used is a mixture of 85% cyclohexane and 15% ethyl acetate.  
         [0222]     Yield: 1.03 g (2.360 mmol; 26%)  
         [0223]     UV max: 320 nm  
         [0224]     MS (ESI): 438/440 (M+H) + Cl distribution 436/438 (M−H) − Cl distribution  
       b) 2-(4-carboxy-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine  
       [0225]     1 g (2.284 mmol) 2-(4-benzyloxycarbonyl-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine are dissolved in 50 ml THF and combined with 100 mg palladium hydroxide. The reaction mixture is stirred for 16 h at ambient temperature and 4 bar hydrogen pressure. Then the catalyst is filtered off and the solvent is eliminated in vacuo.  
         [0226]     Yield: 0.76 g (2.192 mmol; 96%)  
         [0227]     UV max: 288 nm  
         [0228]     MS (ESI): 346/348 (M−H) − Cl distribution  
         [0229]     The following compounds are prepared analogously to this process:  
         [0000]     2-(4-carboxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine  
         [0230]     MS (ESI): 316/318 (M−H) − Cl distribution  
         [0000]     2-[4-(4-benzyloxycarbonyl-piperazin-1-yl)-phenylamino]-4-chloro-5-trifluoromethyl-pyrimidine  
         [0231]     MS (ESI): 492/494 (M+H) + Cl distribution  
         [0000]     2-[4-(4-benzyloxycarbonyl-piperazin-1-yl)-2-methoxy-phenylamino]-4-chloro-5-trifluoromethyl-pyrimidine  
         [0232]     MS (ESI): 522/524, (M+H) + Cl distribution  
         [0000]     Method 15  
       3-pyrrolidin-1-yl-cyclobutylamine  
       [0233]    
       
                 
         
             
             
         
       
     
       a) tert.butyl (3-benzyloxy-cyclobutyl)-carbamate  
       [0234]     9.28 g (45 mmol) 3-benzyloxy-cyclobutancarboxylic acid (Org. Lett. 6(11), 1853-1856, 2004) are suspended in 80 ml dry tert-butanol and combined with 5.1 g (50 mmol) triethylamine and 13.8 g (50 mmol) phosphoric acid diphenylester azide. The reaction mixture is stirred for 20 h under reflux conditions. The solvent is eliminated in vacuo and the residue is taken up in dichloromethane. The organic phase is washed three times with 2 N sodium hydroxide solution, dried with sodium sulphate and the dichloromethane is eliminated in vacuo. The crude product is recrystallised from acetonitrile (1 g crude product: 5 ml acetonitrile).  
         [0235]     Yield: 5.98 g (22 mmol; 48%)  
         [0236]     MS (ESI): 178 (M+H−boc) + Boc cleaving in the mass detector  
       b) tert.butyl (3-hydroxy-cyclobutyl)-carbamate  
       [0237]     2.77 g (10 mmol) tert.butyl (3-benzyloxy-cyclobutyl)-carbamate are suspended in 100 ml of methanol and combined with 200 mg palladium hydroxide. The reaction mixture is stirred for 5 h at 45° C. and 45 bar H 2  pressure. Then the catalyst is filtered off and the solvent is eliminated in vacuo. The residue is taken up in chloroform and washed three times with aqueous sodium hydrogen carbonate solution. The organic phase is dried with magnesium sulphate and the solvent is eliminated in vacuo.  
         [0238]     Yield: 1.53 g (8.2 mmol; 82%)  
         [0239]     MS (ESI): 188 (M+H) +   
       c) tert.butyl (3-tosyl-cyclobutyl)-carbamate  
       [0240]     18.7 g (100 mmol) tert.butyl (3-hydroxy-cyclobutyl)-carbamate and 12.1 g (120 mmol) triethylamine are placed in 500 ml chloroform. 20.5 g (105 mmol) tosyl chloride, dissolved in 150 ml chloroform, is added dropwise to this solution at 0° C. with stirring. Then the mixture is left to come up to ambient temperature and stirred for 2 h. The organic phase is washed successively with water, dilute hydrochloric acid, sodium hydrogen carbonate solution and water. The organic phase is dried with magnesium sulphate and the solvent is eliminated in vacuo.  
         [0241]     Yield: 28.30 g (83 mmol; 83%)  
         [0242]     MS (ESI): 342 (M+H) +   
       d) tert.butyl (3-pyrrolidine-cyclobutyl)-carbamate  
       [0243]     34.1 g (100 mmol) tert.butyl (3-tosyl-cyclobutyl)-carbamate are dissolved in 750 ml pyrrolidine, and combined with a catalytic amount of DMAP. The reaction mixture is refluxed for 20 h with stirring. The pyrrolidine is eliminated in vacuo, the residue is taken up in 500 ml of ethyl acetate and washed twice with saturated sodium hydrogen carbonate solution. The organic phase is dried with magnesium sulphate and the solvent is eliminated in vacuo. The crude product consists—as in all the analogous reactions—of a mixture of 2 isomeric compounds which are separated by column chromatography. The stationary phase used is silica gel and the eluant used is dichloromethane, to which 9% of a mixture of 90% methanol and 10% saturated aqueous ammonia solution have been added.  
         [0244]     The substances that elute first are designated as follows:  
                         
 
         [0245]     Yield product A: 1 g (4.17 mmol; 4%)  
         [0246]     RF value (silica gel; dichloromethane:methanol:conc. aqueous ammonia=90:9:1)=0.62  
         [0247]     The substances that elute second are designated as follows:  
                         
 
         [0248]     Yield product C, 2.00 g (8.33 mmol; 8%)  
         [0249]     RF value (silica gel; dichloromethane:methanol:conc. aqueous ammonia=90:9:1)=0.53  
       e) (*1′,*1″)-3-pyrrolidin-1-yl-cyclobutylamine  
       [0250]    
       
                 
         
             
             
         
       
     
         [0251]     1 g (4.17 mmol) tert.butyl (3-pyrrolidine-cyclobutyl)-carbamate (product A from precursor) are stirred in 20 ml of a 2 N aqueous hydrochloric acid solution for 2 h at 40° C. Then the solvent is eliminated in vacuo and the residue is recrystallised from ethanol.  
         [0252]     Yield: 0.43 g (2.786 mmol; 67%)  
         [0253]     MS (ESI): 141 (M+H) +   
         [0254]     The following compounds are prepared analogously to this process:  
                                                                         MS (ESI)       MS (ESI)           (M + H) +         (M + H) +                                                                                        170                                 143                                             210                                 198                                             184                                 196                                             224                                 194                                             171                                 183                                             212                  
 
       (*2′,*2″)-3-pyrrolidin-1-yl-cyclobutylamine  
       [0255]    
       
                 
         
             
             
         
       
     
         [0256]     1 g (4.17 mmol) tert.butyl (3-pyrrolidine-cyclobutyl)-carbamate (product C from precursor) are stirred in 20 ml of a 2 N aqueous hydrochloric acid solution for 2 h at 40° C. Then the solvent is eliminated in vacuo and the residue is recrystallised from ethanol.  
         [0257]     Yield: 0.43 g (3.09 mmol; 74%)  
         [0258]     MS (ESI): 141 (M+H) +   
         [0259]     The following compounds are prepared analogously to this method:  
                                                                         MS (ESI)       MS (ESI)           (M + H) +         (M + H) +                                                                                        155                                 212                                             157                                 143                                             171                                 141                                             184                                 198                                             170                                 251                                             210                                 194                                             253                                 196                                             224                                 171                                             183                  
 
 Method 16 
 
       2-(4-carboxy-2-bromo-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine  
       [0260]    
       
                 
         
             
             
         
       
     
         [0261]     1 g (3.15 mmol) 2-(4-carboxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine are dissolved in 5 ml DMF and combined batchwise with 3.36 g (18.89 mmol) N-bromosuccinimide. The reaction mixture is stirred for 16 h at ambient temperature. The solvent is eliminated in vacuo and the residue is purified by column chromatography. The carrier used is C18-RP-silica gel and a gradient is ran through which consists of 95% water and 5% acetonitrile at the starting point and consists of 2% water and 98% acetonitrile at the finishing point. 0.1% formic acid is added in each case to both the water and to the acetonitrile.  
         [0262]     Yield: 0.57 g (1.44 mmol; 46%)  
         [0263]     MS (ESI): 396/398 (M−H) + Cl/Br distribution  
         [0000]     Method 17  
       5-amino-3-(2-fluoro-ethyl)-3H-quinazolin-4-one  
       [0264]    
       
                 
         
             
             
         
       
     
         [0265]     500 mg (3.102 mmol) 5-amino-3H-quinazolin-4-one are combined with 2 ml (15.596 mmol) 1-bromo-2-fluoroethane. 125 mg (3.125 mmol) sodium hydride are added thereto and the mixture is stirred for 5 days at ambient temperature. The reaction mixture is diluted with 100 ml of ethyl acetate and washed with 100 ml saturated aqueous sodium chloride solution. The aqueous phase is combined with 50 ml 1 N sodium hydroxide solution and extracted 5 times with ethyl acetate. The combined organic phases are dried and the solvent is eliminated in vacuo. The residue is purified by column chromatography. The carrier used is C18-RP-silica gel and a gradient is run through which consists of 95% water and 5% acetonitrile at the starting point and consists of 5% water and 95% acetonitrile at the finishing point. 0.1% formic acid is added in each case to both the water and to the acetonitrile.  
         [0266]     Yield: 67 mg (0.323 mmol; 10%)  
         [0267]     MS (ESI): 208 (M+H) +   
         [0000]     Method 18  
       8-amino-2-(2-fluoro-ethyl)-3,4-dihydro-2H-isoquinolin-1-one  
       [0268]    
       
                 
         
             
             
         
       
     
       a) 8-dibenzylamino-3,4-dihydro-2H-isoquinolin-1-one  
       [0269]     1.466 g (9.039 mmol) 8-amino-3,4-dihydro-2H-isoquinolin-1-one are dissolved in 15 ml DMF and combined with 3.226 g (23.340 mmol) potassium carbonate and with 3.808 ml (31.420 mmol) benzylbromide. This reaction mixture is stirred for 16 h at 50° C. The reaction mixture is diluted with ethyl acetate and extracted with sodium hydrogen carbonate solution. The organic phases are dried and the solvent is eliminated in vacuo.  
         [0270]     Yield: 1.670 g (4.877 mmol; 54%)  
         [0271]     MS (ESI): 343 (M+H) +   
       b) 8-dibenzylamino-2-(2-fluoro-ethyl)-3,4-dihydro-2H-isoquinolin-1-one  
       [0272]     1.06 g (3.095 mmol) 8-dibenzylamino-3,4-dihydro-2H-isoquinolin-1-one are combined with 1.5 ml (12 mmol) 1-bromo-2-fluoro-ethane and at ambient temperature 780 mg (19.50 mmol) sodium hydride are added batchwise over a period of 30 h. The reaction mixture is diluted with ethyl acetate and extracted with sodium hydrogen carbonate solution. The organic phases are dried and the solvent is eliminated in vacuo. The crude product is purified by column chromatography. The carrier used is silica gel and the eluant used is dichloromethane, to which 5% of a mixture of 90% methanol and 10% saturated aqueous ammonia solution have been added.  
         [0273]     Yield: 0.83 g (2.136 mmol; 69%)  
         [0274]     MS (ESI): 389 (M+H) +   
       c) 8-amino-2-(2-fluoro-ethyl)-3,4-dihydro-2H-isoquinolin-1-one  
       [0275]     830 mg (2.136 mmol) 8-dibenzylamino-2-(2-fluoro-ethyl)-3,4-dihydro-2H-isoquinolin-1-one are dissolved in 50 ml of methanol and combined with 80 mg palladium hydroxide. The reaction mixture is stirred for 48 h at ambient temperature and 4.5 bar H 2  pressure. Then the catalyst is filtered off and the solvent is eliminated in vacuo.  
         [0276]     Yield: 0.403 g (1.935 mmol; 91%)  
         [0277]     MS (ESI): 209 (M+H) +   
         [0278]     The following compounds are prepared analogously to this process:  
                                                                         MS (ESI)       MS (ESI)           (M + H) +         (M + H) +                                                                                        177                                 223                                             191                  
 
 Method 19 
 
       7-amino-5H-phenanthridin-6-one  
       [0279]    
       
                 
         
             
             
         
       
     
         [0280]     250 mg (1.16 mmol) methyl 2-chloro-6-nitro-benzoate, 458 mg (1.392 mmol) caesium carbonate, 211 mg (1.218 mmol) 2-nitrophenylboric acid and 18 mg (0.035 mmol) bis(tri-tert-butylphosphin)palladium(0) are placed under argon and combined with 0.8 ml dioxane. This reaction mixture is stirred for 48 h at 80° C. The reaction mixture is diluted with ethyl acetate and extracted with 1 N hydrochloric acid. The organic phase is dried and the solvent is eliminated in vacuo. The crude product is purified by column chromatography. The carrier used is C18-RP-silica gel and a gradient is run through which consists of 95% water and 5% acetonitrile at the starting point and consists of 5% water and 95% acetonitrile at the finishing point. 0.1% formic acid is added to both the water and the acetonitrile. The suitable fractions are freeze-dried. 71 mg of the intermediate product thus obtained are dissolved in 50 ml of methanol and combined with 10 mg palladium on charcoal. The reaction mixture is stirred for 48 h at ambient temperature and 4.5 bar H 2  pressure. 50 ml dichloromethane are added to the reaction solution, the mixture is treated for 5 min in the ultrasound bath and then the catalyst is filtered off. The solvent is eliminated in vacuo.  
         [0281]     Yield: 46 mg (0.221 mmol; 94%)  
         [0282]     MS (ESI): 211 (M+H) +   
         [0000]     Method 20  
       C-(5-morpholin-4-ylmethyl-1H-[1,2,3]triazol-4-yl)-methylamine  
       [0283]    
       
                 
         
             
             
         
       
     
         [0284]     18.021 g (100 mmol) 1-azido-4-morpholino-2-butyne and 19.728 g (100 mmol) dibenzylamine are dissolved in 100 ml dioxane and heated to 80° C. with stirring. After stirring for 20 h at this temperature the solvent is eliminated in vacuo and the residue is purified by column chromatography. The carrier used is silica gel and the eluant used is dichloromethane, to which 5% of a mixture of 90% methanol and 10% saturated aqueous ammonia solution have been added. The suitable fractions are combined and the solvent is eliminated in vacuo. The residue is dissolved in 480 ml of methanol and combined with 30 ml concentrated aqueous hydrochloric acid and 1 g palladium on charcoal. This reaction mixture is stirred for 5 h at 50° C. and 50 bar H 2  pressure. Then the catalyst is filtered off and the solvent is eliminated in vacuo.  
         [0285]     Yield: 8.588 g (28.00 mmol; 28%)  
         [0286]     MS (ESI): 198 (M+H) +   
         [0000]     Method 21  
       4-morpholin-4-ylmethyl-cyclohexylamine  
       [0287]    
       
                 
         
             
             
         
       
     
         [0288]     2.5 g (11 mmol) tert.butyl trans-(4-formyl-cyclohexyl)-carbamate dissolved in 25 ml dimethylacetamide are combined with 1 ml (11 mmol) morpholine and 0.7 ml acetic acid. 2.4 g (11.3 mmol) sodium triacetoxyborohydride dissolved in 12.5 ml dimethylacetamide is added to this mixture. The reaction mixture is stirred for 16 h at ambient temperature. Then the reaction mixture is added to 250 ml 10% potassium hydrogen carbonate solution and this mixture is extracted three times with 100 ml of ethyl acetate. The organic phases are combined, dried and then the solvent is eliminated in vacuo. The residue is taken up in 20 ml dichloromethane and 20 ml trifluoroacetic acid and stirred for 1 h at ambient temperature. The solvents are eliminated in vacuo.  
         [0289]     Yield: 4.22 g (9.9 mmol; 90%) (double trifluoroacetic acid salt)  
         [0290]     MS (ESI): 199 (M+H) +   
         [0291]     The following compounds are prepared analogously to this process:  
                                                                     MS (ESI)               (M + H) +                                                                                        157                                 183                                             157                                 169                  
 
 Method 22 
 
       7-amino-2-(2-fluoro-ethyl)-3-methyl-2,3-dihydro-isoindol-1-one  
       [0292]    
       
                 
         
             
             
         
       
     
         [0293]     10 g (42.157 mmol) methyl 2-acetyl-6-nitro-benzoate (J. Org. Chem. (1952), 17, 164-76), 6.06 g (54.804 mmol) 2-fluoroethylamine and 9.32 ml (54.804 mmol) N-ethyldlisopropylamine are suspended in 25 ml of toluene and refluxed for 40 h with stirring. The reaction mixture is diluted with 400 ml of methanol and combined with 2.5 g palladium on charcoal. Then the mixture is stirred for 48 h at ambient temperature and 5 bar H 2  pressure. The catalyst is filtered off and the solvent is eliminated in vacuo. The residue is taken up in dichloromethane and washed with water. The organic phase is dried with magnesium sulphate, the solvent is eliminated in vacuo and the crude product is purified by chromatography. The carrier used is silica gel and the eluant used is a mixture of cyclohexane:ethyl acetate (70:30).  
         [0294]     Yield: 3.83 g (18.404 mmol, 43%)  
         [0295]     MS (ESI): 209 (M+H) +   
         [0296]     UV max: 318 nm  
         [0297]     The following compounds are prepared analogously to this process, using the corresponding methyl 6-nitro-benzoate derivative:  
                                                                         MS (ESI)       MS (ESI)           (M + H) +         (M + H) +                                                                                        163                                 223                                             177                                 225                                             203                                 239                                             207                                 253                                             217                                 252                                             221                                 278                                             227                                 237                                             241                                 245                  
 
 Method 23 
 
       2-azetidin-1-yl-ethylamine  
       [0298]    
       
                 
         
             
             
         
       
     
         [0299]     500 μl (7.49 mmol) azetidin are dissolved in 15 ml acetonitrile, combined with 4.831 g (34.822 mmol) potassium carbonate and 445 μl (7.038 mmol) chloroacetonitrile. This reaction mixture is stirred for 20 h at ambient temperature. To this reaction mixture are added 20 ml diethyl ether, the suspension is stirred for 10 min and filtered to separate the solid constituents. The filtrate is freed from solvents in vacuo. 463 mg (4.816 mmol) of this intermediate product are dissolved in 50 ml 7 N methanolic ammonia and Raney nickel is added. The reaction mixture is stirred for 2 h at 60° C. and 20 bar H 2  pressure. The catalyst is filtered off and the solvent is eliminated in vacuo.  
         [0300]     Yield: 365 mg (3.664 mmol, 48%)  
         [0301]     MS (ESI): 101 (M+H) +   
         [0302]     The following compounds are prepared analogously to this process:  
                                                                         MS (ESI)       MS (ESI)           (M + H) +         (M + H) +                                                                                        129                                 156                                             131                                 157                                             158                                 143                                             159                                 145                                             159                                 145                                             141                                 158                                             165                                 198                                             172                                 145                  
 
 Method 24 
 
       ((S)-3-amino-pyrrolidin-1-yl)-acetonitrile  
       [0303]    
       
                 
         
             
             
         
       
     
         [0304]     1 g (5.369 mmol) (S)-3-(Boc-amino)-pyrrolidine are dissolved in 20 ml acetonitrile and combined with 4.831 g (34.822 mmol) potassium carbonate and 322 μl (5.101 mmol) chloroacetonitrile. This reaction mixture is stirred for 20 h at ambient temperature. 20 ml diethyl ether are added to this reaction mixture, the suspension is stirred for 10 min and filtered to separate off the solid constituents. The filtrate is freed from the solvents in vacuo. The intermediate product is dissolved in 2 ml dioxane and combined with 13 ml of 4 N dioxanic hydrochloric acid and stirred overnight at RT. Then the solvent is eliminated in vacuo.  
         [0305]     Yield: 500 mg (3.995 mmol, 74%)  
         [0306]     MS (ESI): 126 (M+H) +   
         [0000]     Method 25  
       (R)-2-pyrrolidin-1-yl-propylamine  
       [0307]    
       
                 
         
             
             
         
       
     
       a) (R)-2-pyrrolidin-1-yl-propionamide  
       [0308]     2 g (16.055 mmol) R-alaninamide hydrochloride, 6.67 g (16.083 mmol) potassium carbonate and 8 mg (0.048 mmol) potassium iodide are suspended in 50 ml acetonitrile and then combined with 1.921 ml (16.083 mmol) 1,4-dibromobutane. This reaction mixture is refluxed for 14 h with stirring. 100 ml 1 N hydrochloric acid and 100 ml dichloromethane are added to the reaction mixture. The organic phase is separated off and discarded. The aqueous phase is made basic with sodium hydroxide solution and extracted three times with dichloromethane. The organic phases are combined, dried and freed from the solvent in vacuo.  
         [0309]     Yield: 1.305 g (9.177 mmol, 57%)  
         [0310]     MS (ESI): 143 (M+H) +   
       b) (R)-2-pyrrolidin-1-yl-propylamine  
       [0311]     Under a nitrogen atmosphere 31.65 ml 1 M Lithiumaluminiumhydrid solution (THF) are taken and combined with 1 g (7.032 mmol) (R)-2-pyrrolidin-1-yl-propionamide, dissolved in 2 ml THF, at 0° C. The reaction mixture is stirred for 48 h at 50° C. The reaction mixture is combined with 100 ml of methanol and then with the same amount of dichloromethane while cooling with ice. Approx. 25 g silica gel are added to this mixture and the solvent is eliminated in vacuo. This silica gel applied to a suction filter which has previously been charged with approx. 75 g silica gel. The suction filter is washed batchwise with a total of 500 ml of a mixture of dichloromethane, methanol and aqueous conc. ammonia (90:9:1). The majority of the solvent is eliminated at a vacuum of 200 mbar and a sump temperature of approx. 50° C. The product is distilled at 69-71° C. and 10 mbar.  
         [0312]     Yield: 160 mg (1.248 mmol, 18%)  
         [0313]     MS (ESI): 129 (M+H) +   
         [0314]     The following compounds are prepared analogously to this process:  
                                                                         MS (ESI)       MS (ESI)           (M + H) +         (M + H) +                                                                                        129                                 157                                             129                                 169                                             129                                 183                                             143                                 183                                             157                                 197                  
 
 Method 26 
 
       2-chloro-4-(2-(2-fluoro-ethyl-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine  
       [0315]    
       
                 
         
             
             
         
       
     
         [0316]     1.1 g (5.07 mmol) 2,4-dichloro-5-trifluoromethylpyrimidin are dissolved in 1 ml dioxane and combined with 0.9 g (4.322 mmol) 7-amino-2-(2-fluoro-ethyl)-3-methyl-2,3-dihydro-isoindol-1-one (method 22) and 0.9 ml (5.257 mmol) diisopropyethylamine. This mixture is stirred for 1 h at 80° C. Then the solvent is eliminated in vacuo. The crude product is purified by column chromatography. The carrier used is C18-RP-silica gel and a gradient is run through which consists of 95% water and 5% acetonitrile at the starting point and consists of 20% water and 80% acetonitrile at the finishing point. 0.1% formic acid are added to both the water and to the acetonitrile. The suitable fractions are combined with dichloromethane, the organic phase is separated off, dried and the solvent is eliminated in vacuo.  
         [0317]     Yield: 485 mg (1.250 mmol, 25%)  
         [0318]     MS (ESI): 389/391 (M+H) + ; Cl distribution  
         [0319]     The following compounds are prepared analogously to this process. The aniline derivatives used are described in the supplements to method 2, in method 10 and in the supplements to method 10. The preparation of the 2,4-dichloropyrimidine derivatives is known from the literature or may be carried out by methods known from the literature.  
                                                                         MS (ESI)       MS (ESI)           (M + H) +         (M + H) +                                                                                        363/365                                 355/357                                             367/369                                 399/401                                             349/351                                 366/368                                             381/383                                 345/347                                             333/335                                 385/387                                             373/375                                 381/383                                             447/449                  
 
 Method 27 
 
       2-[2-(4-amino-3-methoxy-phenyl)-1H-imidazol-4-yl]-ethanol  
       [0320]    
       
                 
         
             
             
         
       
     
       a) 3-methoxy-4-nitro-benzonitrile  
       [0321]     25 g (150.504 mmol) 3-fluoro-4-nitrobenzonitrile and 25 g (462.757 mmol) sodium methoxide are dissolved in 125 ml THF at 0° C. This reaction mixture is stirred for 30 min. The reaction mixture is extracted with ethyl acetate and 1 N hydrochloric acid. The organic phase is dried with magnesium sulphate and the solvent is eliminated in vacuo.  
         [0322]     Yield: 25.092 g (140.852 mmol, 94%)  
         [0323]     UV max: 334 nm  
       b) 3-methoxy-4-nitro-benzamidine  
       [0324]     99 ml (99 mmol) lithium-bis-trimethylsilylamide solution (1 mol/l in THF) are diluted with 640 ml THF, cooled to 10° C. and combined with 8.3 g (46.591 mmol) 3-methoxy-4-nitro-benzonitrile. The reaction mixture is stirred for 10 min at 20° C. The mixture is cooled to 0° C. and combined with 80 ml 3 N hydrochloric acid. The reaction mixture is evaporated down in vacuo and extracted with water and ethyl acetate. The aqueous phase is adjusted to pH 14 with 3 N sodium hydroxide solution. The product is then suction filtered.  
         [0325]     Yield: 14.30 g (crude product: 60% purity)  
         [0326]     MS (ESI): 196 (M+H) +   
         [0327]     UV max: 334 nm  
       c) [2-(3-methoxy-4-nitro-phenyl)-1H-imidazol-4-yl]-acetic acid  
       [0328]     7 g (60% purity, 21.519 mmol) 3-methoxy-4-nitro-benzamidine are dissolved in methanol and combined with 11 ml (44 mmol) 4 N dioxanic hydrochloric acid, the solvents are eliminated in vacuo. The residue and 6.13 g (44.384 mmol) potassium carbonate are suspended in 350 ml acetonitrile and combined with 3.24 ml (22.764 mmol) ethyl 4-chloracetoacetate and 880 mg (5.301 mmol) potassium iodide. The reaction mixture is stirred for 16 h at 45° C. The reaction mixture is diluted with water and combined with 1 N sodium hydroxide solution, and extracted with ethyl acetate. The aqueous phase is adjusted to pH 1 with 1 N HCL and saturated with sodium chloride. The product is then suction filtered.  
         [0329]     Yield: 1.45 g (5.230 mmol, 24%)  
         [0330]     MS (ESI): 278 (M+H) +   
         [0331]     UV max: 294 nm  
       d) 2-[2-(3-methoxy-4-nitro-phenyl)-1H-imidazol-4-yl]-ethanol  
       [0332]     1.45 g (5.23 mmol) [2-(3-methoxy-4-nitro-phenyl)-1H-imidazol-4-yl]-acetic acid are dissolved in 36 ml THF and cooled to 0° C. and combined with 10 ml (18 mmol) borane-THF complex (1.8 mol/V). After 1 h the mixture is heated to 20° C. and stirred for 16 h. Water is added until the development of gas has ended. Then the mixture is extracted twice with saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic phases are combined, dried and freed from the solvent in vacuo.  
         [0333]     Yield: 0.65 g (2.465 mmol, 47%)  
         [0334]     MS (ESI): 264 (M+H) +   
         [0335]     UV max: 298 nm  
       e) 2-[2-(4-amino-3-methoxy-phenyl)-1H-imidazol-4-yl]-ethanol  
       [0336]     0.144 g (0.547 mmol) 2-[2-(3-methoxy-4-nitro-phenyl)-1H-imidazol-4-yl]-ethanol are dissolved in 100 ml of methanol and combined with 0.08 g (5%) palladium on charcoal. The reaction mixture is hydrogenated for 16 h at 20° C. and 4 bar H 2  pressure. The palladium on charcoal is suction filtered and the methanol is eliminated in vacuo.  
         [0337]     Yield: 87 mg (0.373 mmol, 68%)  
         [0338]     MS (APCI): 234 (M+H) +   
         [0339]     UV max: 314 nm  
         [0340]     The following compounds are prepared analogously to this process:  
                                                                         MS (ESI)       MS (ESI)           (M + H) +         (M + H) +                                                                                        220                                 190                                             251                  
 
         [0341]     2-[2-(4-amino-3-methoxy-phenyl)-thiazole-5-yl]-ethanol is prepared analogously to the processes described above. For the cyclisation, 4-amino-3-methoxy-thiobenzamide is used (analogously to J. Am. Soc. 82, 2656, 1960) instead of 3-methoxy-4-nitro-benzamidine.  
                         
 
         [0342]     MS (ESI): 251 (M+H) +   
         [0000]     Method 28  
       2-methoxy-N 4 -(3-pyrrolidin-1-yl-propyl)-benzene-1,4-diamine  
       [0343]    
       
                 
         
             
             
         
       
     
       a) (3-methoxy-4-nitro-phenyl)-(3-pyrrolidin-1-yl-propyl)-amine  
       [0344]     1 g (5.884 mmol) 4-fluoro-2-methoxy-1-nitro-benzene, 975 mg (7.369 mmol) 1-(3-aminopropyl)pyrrolidine and 1.5 ml (8.765 mmol) diisopropyethylamine are dissolved in 5 ml dioxane and stirred for 24 h at 95° C. The solvents are eliminated in vacuo and the crude product is purified by column chromatography. The carrier used is silica gel and the eluant used is dichloromethane, to which 15% of a mixture of 90% methanol and 10% saturated aqueous ammonia solution has been added.  
         [0345]     Yield: 1.07 g (3.827 mmol; 65%)  
         [0346]     MS (ESI): 280 (M+H) +   
       b) 2-methoxy-N 4 -(3-pyrrolidin-1-yl-propyl)-benzene-1,4-diamine  
       [0347]     200 mg (0.716 mmol) (3-methoxy-4-nitro-phenyl)-(3-pyrrolidin-1-yl-propyl)-amine are dissolved in 10 ml of methanol and combined with 537 μl (2.148 mmol) dioxanic hydrochloric acid and 20 mg palladium on charcoal. The reaction mixture is stirred for 1 h at ambient temperature and 5 bar H 2  pressure. The catalyst is filtered off and the solvent is eliminated in vacuo.  
         [0348]     Yield: 213 mg (0.661 mmol, 92%)  
         [0349]     MS (ESI): 250 (M+H) +   
         [0350]     The following compounds are prepared analogously to this process:  
                                                                         MS (ESI)       MS (ESI)           (M + H) +         (M + H) +                                                                                        236                                 208                                             307                                 262                                             333                                 222                                             333                                 236                                             347                                 168                                             347                                 168                                             333                                 250                                             240                                 250                                             240                                 307                                             222                                 307                  
 
 Method 29 
 
       2-(4-carboxy-2-bromo-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine  
       [0351]    
       
                 
         
             
             
         
       
     
         [0352]     1 g (3.148 mmol) 2-(4-carboxy-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine (method 12 or 14) are dissolved in 5 ml DMF and combined batchwise with 3.36 g (18.889 mmol) N-bromosuccinimide. This reaction mixture is stirred for 16 h at ambient temperature. Then the solvent is eliminated in vacuo and the residue is purified by column chromatography. The carrier used is C18-RP-silica gel and a gradient is run through which consists of 95% water and 5% acetonitrile at the starting point and consists of 2% water and 98% acetonitrile at the finishing point. 0.1% formic acid are added to both the water and to the acetonitrile.  
         [0353]     Yield: 571 mg (1.440 mmol, 46%)  
         [0354]     MS (ESI): 396/398 (M+H) +   
         [0000]     Method 30  
       2-(4-Acryloylamino-2-methoxy-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine  
       [0355]    
       
                 
         
             
             
         
       
     
       a) 4-amino-2-methoxy-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine  
       [0356]     1 g (1.925 mmol) 2-(4-carboxy-2-methoxy-phenylamino)-4-[2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino]-5-trifluoromethyl-pyrimidine (prepared analogously to Example 53) are dissolved in 2 ml of toluene and combined successively with 0.43 ml (2.503 mmol) diisopropylethylamine, with 1.8 ml tert-butanol and with 0.49 ml (2.310 mmol) diphenylphosphorylazide and heated to 80° C. for 18 h. The reaction mixture is cooled, diluted with 100 ml of ethyl acetate and washed twice with 0.5 N sodium hydroxide solution. The organic phase is dried with magnesium sulphate and the solvent is eliminated in vacuo. The residue is taken up in dichloromethane and combined with 4 M dioxanic hydrochloric acid. The mixture is stirred for 72 h at ambient temperature. It is diluted with ethyl acetate and extracted 4 times with 1 N hydrochloric acid. The aqueous phases are combined and extracted once with ethyl acetate. The aqueous phase is made basic with sodium hydroxide solution and extracted three times with ethyl acetate. The organic phases are combined, dried and the solvent is eliminated in vacuo.  
         [0357]     Yield: 606 mg (1.236 mmol, 64%)  
         [0358]     MS (ESI): 491 (M+H) +   
       b) 2-(4-Acryloylamino-2-methoxy-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine  
       [0359]     311 mg (0.634 mmol) 2-(4-amino-2-methoxy-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine are dissolved in 10 ml THF and combined with 115 μl (0.824 mmol) triethylamine and 62 μl (0.761 mmol) acrylic chloride. This mixture is stirred for 1 h at ambient temperature. Then it is diluted with ethyl acetate and extracted three times with water. The organic phase is dried with magnesium sulphate and the solvent is eliminated in vacuo.  
         [0360]     Yield: 340 mg (0.625 mmol, 98%)  
         [0361]     MS (ESI): 545 (M+H) +   
         [0362]     The following compounds are prepared analogously to this process:  
                                                                         MS (ESI)       MS (ESI)           (M + H) +         (M + H) +                                                                                        581                                 659                                             582                                 611                  
 
 Method 31 
 
       Separation of the racemic 7-amino-2-(2-fluoro-ethyl)-3-methyl-2,3-dihydro-isoindol-1-one (method 22) into the two enantiomers  
       [0363]     The separation is carried out by preparative chromatography under the following 1 conditions:  
         [0000]     column: 280×110 mm CHIRALPAK® AD 20 μm  
         [0000]     Eluant: 95% acetonitrile/5% isopropanol (v/v)  
         [0000]     Flow rate: 570 ml/min  
         [0000]     Temperature: ambient temperature  
         [0364]     The enantiomer that elutes first is known as enantiomer 1 and in the chemical formula bears the symbol *1: 
 
 Enantiomer 1 
                         
 
         [0365]     The enantiomer that elutes second is known as enantiomer 2 and in the chemical formula bears the symbol *2: 
 
 Enantiomer 2 
                         
 
 Method 32 
 
       7-amino-3-ethyl-indan-1-one  
       [0366]    
       
                 
         
             
             
         
       
     
         [0367]     262 mg (1.364 mmol) copper iodide are taken and heated in an argon current. Then the copper iodide is suspended in ether and cooled to −78° C. At this temperature 0.8 ml of a 3 M ethylmagnesium bromide solution (in ether) are added and the mixture is stirred for 10 min and then left to thaw to 0° C. After 15 min stirring at this temperature the mixture is cooled to −78° C. again and 200 mg (0.802 mmol) N-(3-oxo-3H-inden-4-yl)-benzamide, dissolved in 9 ml THF, are added dropwise and the mixture is stirred for 1 h at 0° C. The reaction mixture is diluted with dichloromethane and washed three times with concentrated aqueous ammonia solution. The organic phase is dried with magnesium sulphate and the solvent is eliminated in vacuo. The residue is purified by column chromatography. The carrier used is C18-RP-silica gel and a gradient is run through which consists of 98% water and 2% acetonitrile at the starting point and 2% water and 98% acetonitrile at the finishing point. 0.1% formic acid are added to both the water and to the acetonitrile. The suitable fractions are freeze-dried. This intermediate product is dissolved in 2 ml dioxane and combined with 5 ml concentrated hydrochloric acid. The reaction mixture is refluxed for 24 h with stirring. Then it is diluted with water and extracted three times with dichloromethane. The combined organic phases are again washed with water, dried and the solvent is removed. The residue is purified by column chromatography. The carrier used is silica gel and the eluant used is dichloromethane, to which 5% of a mixture of 90% methanol and 10% saturated aqueous ammonia solution have been added.  
         [0368]     Yield: 70 mg (0.399 mmol; 29%)  
         [0369]     MS (ESI): 176 (M+H) +   
         [0370]     The following compounds are prepared analogously to this process:  
                                                                         MS (ESI)       MS (ESI)           (M + H) +         (M + H) +                                                                                        162                                 190                  
 
 Method 33 
 
       7-amino-3,3-dimethyl-3H-isobenzofuran-1-one  
       [0371]    
       
                 
         
             
             
         
       
     
         [0372]     250 mg (0.609 mmol) methyl 2-dibenzylamino-benzoate are combined under argon with 0.609 ml of a 1 M lithium chloride solution (THF). This solution is cooled to—ambient temperature and slowly 0.914 ml (1.827 mmol) of a 2 M isopropyl-magnesium chloride solution are metered in. After stirring for 16 h at this temperature, 45 μl (0.609 mmol) acetone are added dropwise and the mixture is stirred for 4 h at ambient temperature. The reaction solution is combined with sodium hydrogen carbonate solution and extracted three times with dichloromethane. The combined organic phases are dried and the solvent is eliminated in vacuo. The residue is purified by column chromatography. The carrier used is C18-RP-silica gel and a gradient is run through which consists of 95% water and 5% acetonitrile at the starting point and 5% water and 95% acetonitrile at the finishing point. 0.1% formic acid are added to both the water and to the acetonitrile. The suitable fractions are freeze-dried. This intermediate product is dissolved in 50 ml of methanol combined with 10 mg palladium on charcoal and hydrogenated for 20 h at 5 bar hydrogen pressure and ambient temperature. Then the catalyst is filtered off and the solvent is eliminated in vacuo. The residue is purified by column chromatography. The carrier used is C18-RP-silica gel and a gradient is run through which consists of 95% water and 5% acetonitrile at the starting point and consists of 5% water and 95% acetonitrile at the finishing point. 0.1% formic acid are added to both the water and to the acetonitrile. The suitable fractions are freeze-dried.  
         [0373]     Yield: 34 mg (0.192 mmol; 32%)  
         [0374]     MS (ESI): 178 (M+H) +   
         [0375]     The following compounds are prepared analogously to this process:  
                                                                         MS       MS           (ESI)       (ESI)           (M +       (M +           H) +         H) +                                                                                        164                                 190                                             192                                 178                                             220                  
 
 Method 34 
 
       7-amino-2-(2-fluoro-ethyl)-3,3-dimethyl-2,3-dihydro-isoindol-1-one  
       [0376]    
       
                 
         
             
             
         
       
     
       a) methyl 2-(cyano-dimethyl-methyl)-6-nitro-benzoate  
       [0377]     3 g (13.625 mmol) methyl 2-cyanomethyl-6-nitro-benzoate (WO 9518097) are dissolved in 20 ml THF combined with 4.33 ml (68.788 mmol) iodomethane and cooled to 0° C. At this temperature 40.87 ml of a 1 M potassium-tert-butoxide solution is slowly added dropwise. The mixture is heated to ambient temperature and stirred for 16 h at this temperature. The reaction mixture is diluted with ethyl acetate and extracted three times with 1 M hydrochloric acid. The combined organic phases are dried and the solvent is eliminated in vacuo.  
         [0378]     Yield: 3.11 g (12.535 mmol; 92%)  
       b) 3,3-dimethyl-7-nitro-2,3-dihydro-isoindol-1-one  
       [0000]     Reaction Mixture 1  
         [0379]     1 g (4.028 mmol) methyl 2-(cyano-dimethyl-methyl)-6-nitro-benzoate are suspended in 20% ethanolic potassium hydroxide solution and stirred for 24 h at ambient temperature.  
         [0000]     Reaction Mixture 2  
         [0380]     1.9 g (47.577 mmol) sodium hydroxide are dissolved in 40 ml of water cooled to 0° C. and combined with 0.5 ml (28.899 mmol) bromine. reaction mixture 1 is slowly added dropwise to this solution. After 8 h the same amount of reaction mixture 1 is added again. The mixture is stirred for a further 48 h at RT. Then sodium sulphite solution is added, the mixture is stirred for 20 min and then acidified with potassium hydrogen sulphate solution. It is extracted three times with ethyl acetate. The combined organic phases are dried and the solvent is eliminated in vacuo. The residue is purified by column chromatography. The carrier used is silica gel and the eluant used is a mixture of cyclohexane:ethyl acetate (3:1).  
         [0381]     Yield: 67 mg (0.325 mmol, 8%)  
         [0382]     MS (ESI): 207 (M+H) +   
       c) 3,3-dimethyl-7-amino-2,3-dihydro-isoindol-1-one  
       [0383]     67 mg (0.325 mmol) 3,3-dimethyl-7-nitro-2,3-dihydro-isoindol-1-one are dissolved in 50 ml of methanol and combined with 10 mg palladium on charcoal. The mixture is hydrogenated for 16 h at 4 bar H 2  pressure and ambient temperature. Then the catalyst is filtered off and the solvent is eliminated in vacuo.  
         [0384]     Yield: 50 mg (0.284 mmol, 93%)  
         [0385]     MS (ESI): 177 (M+H) +   
       d) 7-dibenzylamino-3,3-dimethyl-2,3-dihydro-isoindol-1-one  
       [0386]     50 mg (0.284 mmol) 3,3-dimethyl-7-amino-2,3-dihydro-isoindol-1-one are dissolved in 0.5 ml DMF and combined with 141 mg (1.021 mmol) potassium carbonate and 10 mg (0.028 mmol) tetrabutylammonium iodide. The mixture is heated to 50° C. and 155 μl (1.277 mmol) benzylbromide are added dropwise thereto. After stirring for 16 h at this temperature the mixture is diluted with ethyl acetate and extracted three times with 1 M hydrochloric acid. The combined organic phases are dried and the solvent is eliminated in vacuo.  
         [0387]     Yield: 67 mg (0.188 mmol; 66%)  
         [0388]     MS (ESI): 357 (M+H) +   
       e) 7-dibenzylamino-2-(2-fluoro-ethyl)-3,3-dimethyl-2,3-dihydro-isoindol-1-one  
       [0389]     67 mg (0.188 mmol) 7-dibenzylamino-3,3-dimethyl-2,3-dihydro-isoindol-1-one are dissolved in 1 ml (7.877 mmol) 1-bromo-2-fluoroethane and combined with 52 mg (0.376 mmol) sodium hydride. After 4 h stirring at ambient temperature the mixture is diluted with ethyl acetate and extracted three times with 1 M hydrochloric acid. The combined organic phases are dried and the solvent is eliminated in vacuo.  
         [0390]     Yield: 75 mg (0.188 mmol; 100%)  
         [0391]     MS (ESI): 403 (M+H) +   
       f) 7-amino-2-(2-fluoro-ethyl)-3,3-dimethyl-2,3-dihydro-isoindol-1-one  
       [0392]     75 mg (0.188 mmol) 7-dibenzylamino-2-(2-fluoro-ethyl)-3,3-dimethyl-2,3-dihydro-isoindol-1-one are dissolved in 50 ml of methanol and combined with 10 mg palladium on charcoal. The mixture is hydrogenated for 16 h at 5 bar H 2  pressure and ambient temperature. Then the catalyst is filtered off and the solvent is eliminated in vacuo.  
         [0393]     Yield: 36 mg (0.162 mmol, 87%)  
         [0394]     MS (ESI): 223 (M+H) +   
       EXAMPLE 1  
     2-(2-methoxy-4-N-propylcarbamoyl-phenylamino)-4-(3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine  
       [0395]    
       
                 
         
             
             
         
       
     
         [0396]     100 mg (0.257 mmol) 2-(2-methoxy-4-propylcarbamoyl-phenylamino)-4-chloro-5-trifluoro-methyl-pyrimidine (method 1) are dissolved in 1 ml N,N-dimethylacetamide and combined with 83 mg (0.565 mmol) 7-amino-2,3-dihydro-isoindol-1-one (method 2). 48 μl of a 4 molar solution of HCl (0.193 mmol) in 1,4-dioxane are metered into this reaction mixture. After two days at 50° C. the solvent is eliminated in vacuo. The crude product is purified by column chromatography. The carrier used is silica gel and the eluant used is dichloromethane, to which 5% of a mixture of 90% methanol and 10% saturated aqueous ammonia solution have been added. The concentrated crude product is again purified by column chromatography. The carrier used is C18-RP-silica gel and a gradient is run through which consists of 80% water and 20% acetonitrile at the starting point and 60% water and 40% acetonitrile aat the finishing point.  
         [0397]     Yield: 42 mg (0.084 mmol; 33%)  
         [0398]     UV max: 318 nm  
         [0399]     MS (ESI): 501 (M+H) +   
         [0400]      1 H-NMR: 0.92 (t, 3H), 1.51-1.63 (m, 2H), 3.21-3.29 (m, 2H), 3.86 (s, 3H), 4.37 (s, 2H), 7.14-7.21 (m, 1H), 7.33 (t, 1H), 7.47-7.54 (m, 1H), 7.55-7.60 (m, 1H), 7.73-7.82 (m, 1H), 8.35-8.50 (m, 3H), 8.75 (s, 1H), 9.09 (s, 1H), 10.66 (s, 1H)  
       EXAMPLES 2-17  
       [0401]     The following compounds are prepared by an analogous method as described in Example 1. 2-(2-Methoxy-4-propylcarbamoyl-phenylamino)-4-chloro-5-trifluoromethylpyrimidine and a corresponding 7-amino-2,3-dihydro-isoindol-1-one derivative (method 2) are used. N-methyl-2-pyrrolidinone or N,N-dimethylacetamide is used as solvent.  
                                                                                                                                      MS                   (ESI)               UV max   (M +       #   A   [nm]   H) +                                          2                                 322   515               3                                 314   529               4                                 285   543               5                                 286/310   583               6                                 322   571               7                                 285/321   585               8                                 285/318   559               9                                 285/318   586               10                                 281/316   626               11                                 284/316   545               12                                 325   577               13                                 282/318   595               14                                 284/322   573               15                                 286, 306   607               16                                 325               17                                 318/282   607                  
 
       EXAMPLE 18  
     2-(2-methoxy-4-N-propylcarbamoyl-phenylamino)-4-(3-oxo-1,3-dihydro-isobenzofuran-4-ylamino)-5-trifluoromethyl-pyrimidine  
       [0402]    
       
                 
         
             
             
         
       
     
         [0403]     100 mg (0.257 mmol) 2-(2-methoxy-4-propylcarbamoyl-phenylamino)-4-chloro-5-trifluoro-methyl-pyrimidine (method 1) are dissolved in 1 ml N,N-dimethylacetamide and combined with 46 mg (0.308 mmol) 7-amino-3H-isobenzofuran-1-one (Safdar Hayat et al.,  Tetrahedron Lett  2001, 42(9):1647-1649). 48 ill of a 4 molar solution of HCl (0.193 mmol) in 1,4-dioxane zudosiert metered into this reaction mixture. After 4 days at 50° C. the solvent is eliminated in vacuo. The crude product is purified by column chromatography. The carrier used is silica gel and the eluant used is dichloromethane, to which 4% of a mixture of 90% methanol and 10% saturated aqueous ammonia solution have been added.  
         [0404]     Yield: 26 mg (0.051 mmol; 20%)  
         [0405]     UV max: 322 nm  
         [0406]     MS (ESI): 502 (M+H) +   
         [0407]      1 H-NMR: 0.92 (t, 3H), 1.51-1.63 (m, 2H), 3.22-3.28 (m, 2H), 3.86 (s, 3H), 5.42 (s, 2H), 7.24-7.30 (m, 1H), 7.44-7.55 (m, 2H), 7.55-7.60 (m, 1H), 7.67-7.78 (m, 1H), 8.38-8.48 (m, 2H), 8.50 (s, 1H), 9.21 (s, 1H), 9.64 (s, 1H)  
       EXAMPLES 19-37  
       [0408]     The following compounds are prepared by analogous methods to those described in Example 1 and Example 18. 2-(2-methoxy-4-propylcarbamoyl-phenylamino)-4-chloro-5-trifluoromethylpyrimidine (method 1) is used. The corresponding aniline derivative is commercially obtainable, known from the literature or is prepared by the processes described in method 2 and 4 to 9. N-methyl-2-pyrrolidinone or N,N-dimethylacetamide is used as solvent.  
                                                                                                                UV max   MS (ESI)       #   A   [nm]   (M + H) +                                     19                                 235   586               20                                 323/226   543               21                                 325   530               22                                 262   514               23                                 320   544               24                                 318   542               25                                 312   530               26                                 315   529               27                                 314   528               28                                 317   502               29                                 316   516               30                                 322   529               31                                 255   548               32                                 320   500               33                                 325   515               34                                 250/286/318   516               35                                 320   558               36                                 316   514               37                                 321                  
 
       EXAMPLE 38  
     2-(2-methoxy-4-N-propylcarbamoyl-phenylamino)-4-(4-methyl-5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-6-ylamino)-5-trifluoromethyl-pyrimidine  
       [0409]    
       
                 
         
             
             
         
       
     
         [0410]     50 mg (0.129 mmol) 2-(2-methoxy-4-propylcarbamoyl-phenylamino)-4-chloro-5-trifluoro-methyl-pyrimidine (method 1) are dissolved in 200 μl 1,4-dioxane and combined with 25 mg (0.13 mmol) 6-amino-4-methyl-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one (method 10). 36 μl of a 4 molar solution of HCl (0.144 mmol) in 1,4-dioxane are metered into this reaction mixture. After 4 days at 50° C. the solvent is eliminated in vacuo. The crude product is purified by column chromatography. The carrier used is silica gel and the eluant used is a mixture of dichloromethane and ethyl acetate (1:1).  
         [0411]     Yield: 23 mg (0.042 mmol; 33%)  
         [0412]     UV max: 318 nm  
         [0413]     MS (ESI): 545 (M+H) +   
         [0414]      1 H-NMR: 0.91 (t, 3H), 1.49-1.61 (m, 2H), 3.09 (s, 3H), 3.20-3.28 (m, 2H), 3.49 (t, 2H), 3.88 (s, 3H), 4.31 (t, 2H), 6.83-6.88 (m, 1H), 7.34-7.45 (m, 2H), 7.50-7.54 (m, 1H), 7.88-8.00 (m, 2H), 8.37-8.44 (m, 2H), 8.62 (s, 1H), 9.97 (s, 1H)  
       EXAMPLES 39-52  
       [0415]     The following compounds are prepared by analogous methods to those described in Example 1 and 18. 2-(2-methoxy-4-propylcarbamoyl-phenylamino)-4-chloro-5-trifluoromethylpyrimidine (method 1) is used. The corresponding aniline derivative is commercially obtainable, known from the literature or is prepared by the processes described in method 10 and 11. N-methyl-2-pyrrolidinone or N,N-dimethylacetamide is used as solvent.  
                                                                                                                UV max   MS (ESI)       #   A   [nm]   (M + H) +                                     39                                 229/279/315   559               40                                 282/314   545               41                                 282/318   587               42                                 282/314   571               43                                 282/318   585               44                                 318   559               45                                 234/320   559               46                                 282/218   603               47                                 278/318   531               48                                 286/314   573               49                                 274/314   558               50                                 318   587               51                                 223/282/318   579               52                                 318   634                  
 
       EXAMPLE 53  
     2-[2-methoxy-4-(4-morpholin-4-yl-(1,4-trans-cyclohexyl)carbamoyl)-phenylamino]-4-(2-carbamoyl-3-fluoro-phenylamino)-5-trifluoromethyl-pyrimidine  
       [0416]    
       
                 
         
             
             
         
       
     
         [0417]     102 mg (0.29 mmol) 2-(4-carboxyamino-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine (method 12) are dissolved in 250 μl N-methyl-2-pyrrolidinone and combined with 47 mg (0.319 mmol) 7-amino-indan-1-one (method 8). 15 μl of a 4 M solution of HCl (0.058 mmol) in 1,4-dioxane are metered into this reaction mixture. After 16 h at 90° C. the reaction mixture is stirred into 150 ml of a aqueous 1 N hydrochloric acid. The precipitate is filtered off and dried in vacuo. 100 mg (0.174 mmol) of this precipitate, 150 μl (0.875 mmol) N-ethyldiisopropylamine, 68 mg (0.210 mmol) O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-tetrafluoroborate and 30 mg (0.163 mmol) trans-4-morpholin-4-yl-cyclohexylamine (method 13) are dissolved in 5 ml N,N-dimethylformamide. After 15 h at ambient temperature the solvent is eliminated in vacuo. The crude product is purified by column chromatography. The carrier used is silica gel and the eluant used is dichloromethane, to which 7% of a mixture of 90% methanol and 10% saturated aqueous ammonia solution have been added.  
         [0418]     Yield: 55 mg (0.100 mmol; 57%)  
         [0419]     UV max: 318 nm  
         [0420]     MS (ESI): 555 (M+H) +   
         [0421]      1 H-NMR: 1.55-1.69 (m, 2H), 1.74-1.84 (m, 2H), 1.91-2.02 (m, 2H), 2.18 (s, 3H), 2.69-2.75 (m, 2H), 2.75-2.84 (m, 2H), 3.03-3.10 (m, 2H), 3.70-3.83 (m, 1H), 3.86 (s, 3H), 7.15-7.21 (m, 1H), 7.36-7.46 (m, 1H), 7.48-7.54 (m, 1H), 7.54-7.58 (m, 1H), 7.71-7.79 (m, 1H), 8.18-8.25 (m, 1H), 8.30-8.45 (m, 1H), 8.48 (s, 1H), 9.16 (s, 1H), 10.59 (s, 1H)  
       EXAMPLES 54-77  
       [0422]     The following compounds are prepared by an analogous method to that described in Example 53. The corresponding aniline is described in method 2, 7, 8, or 9 or known from the literature. The amine used to prepare the amide is commercially obtainable or is described in method 13.  
                                                                                                                        UV max   ME (ESI)       #   A   R 3 ′   [nm]   (M + H) +                                         54                                                               318   555               55                                                               318   569               56                                                               322   570               57                                                               320   640               58                                                               284, 322   556               59                                                               282, 318   626               60                                                               325   655               61                                                               325   585               62                                                               254, 286, 318   639               63                                                               321   631               64                                                               322   570               65                                                               322   640               66                                                               322   683               67                                                               322   613               68                                                               286, 322   654               69                                                               286, 322   584               70                                                               282, 322   627               71                                                               322   670               72                                                               286, 322   600               73                                                               322   684               74                                                               286, 322   614               75                                                               322   557               76                                                               330   732               77                                                               325   654                  
 
       EXAMPLES 78-140  
       [0423]     The following compounds are prepared by an analogous method to that described in Example 53. 2-(4-Carboxy-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine may be prepared according to method 12 or 14. The corresponding aniline is described in the supplements to method 10. The amine used to prepare the amide is commercially obtainable or is described in method 13, in the supplements to method 13, 15 or 25.  
                                                                                                                        UV max   MS (ESI)       #   A   R 3 ′   [nm]   (M + H) +                                         78                                                               318   308               79                                                               326   346               80                                                               318   706               81                                                               318   584               82                                                               318   614               83                                                               318   776               84                                                               318   626               85                                                               318   348               86                                                               318   718               87                                                               318   684               88                                                               318   353               89                                                               322   346               90                                                               318   686               91                                                               310   621               92                                                               318   746               93                                                               318   676               94                                                               318   316               95                                                               318   696               96                                                               282; 310   571               97                                                               318   614               98                                                               318   684               99                                                               315   559               100                                                               314   621               101                                                               314   676               102                                                               318   747               103                                                               318   656               104                                                               318   586               105                                                               318   (M               106                                                               318   730               107                                                               322   674               108                                                               318   640               109                                                               322   640               110                                                               282, 318   614               111                                                               226, 282, 318   640               112                                                               318   614               113                                                                   626               114                                                               318   640               115                                                               318   640               116                                                               318   654               117                                                               318   668               118                                                               318   628               119                                                               318   600               120                                                               318-322   614               121                                                               318   670               122                                                               318   654               123                                                               318   626               124                                                               282, 318   668               125                                                               282, 318   642               126                                                               282, 318   693               127                                                               318   680               128                                                               318   654               129                                                               318   705               130                                                               226, 282,318   628               131                                                               318   668               132                                                               318-322   642               133                                                               318   693               134                                                               318-322   642               135                                                               318   682               136                                                               318   698               137                                                               318-322   656               138                                                               318-322   707               139                                                               318-322   640               140                                                               318-322   628                  
 
       EXAMPLES 141-166  
       [0424]     The following compounds are prepared by an analogous method to that described in Example 53. The preparation of 2-(4-carboxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine is described in method 14. The corresponding aniline is described in method 10. The amine used to prepare the amide is commercially obtainable or is described in method 13, 15 or 25.  
                                                                                                                        UV max   MS (ESI)       #   A   R 3 ′   [nm]   (M + H) +                                         141                                                               302   596               142                                                               302   610               143                                                               302   596               144                                                               302   584               145                                                               302   610               146                                                               302   638               147                                                               298   654               148                                                               302   610               149                                                               302   650               150                                                               298-302   666               151                                                               302   584               152                                                               302   624               153                                                               298-302   640               154                                                               302   598               155                                                               298-302   649               156                                                               302   598               157                                                               302   638               158                                                               298-302   654               159                                                               302   612               160                                                               302   663               161                                                               302   612               162                                                               302   652               163                                                               298-302   668               164                                                               302   677               165                                                               302   626               166                                                               302   624                  
 
       EXAMPLE 167  
     2-(2-methoxy-4-piperazin-1-yl-phenylamino)-4-(3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-6-ylamino)-5-trifluoromethyl-pyrimidine  
       [0425]    
       
                 
         
             
             
         
       
     
         [0426]     500 mg (0.958 mmol) 2-[4-(4-benzyloxycarbonyl-piperazin-1-yl)-phenylamino]-4-chloro-5-trifluoromethyl-pyrimidine (method 14) are dissolved in 0.5 ml NMP, combined with 198 mg (0.960 mmol) 6-amino-3,3-dimethyl-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one (method 10) and with 25 μl (0.1 mmol) dioxanic hydrochloric acid. This reaction mixture is stirred for 1.5 h at 100° C. The solvent is eliminated in vacuo and the residue is purified by column chromatography. The carrier used is C18-RP-silica gel and a gradient is run through which consists of 95% water and 5% acetonitrile at the starting point and consists of 5% water and 95% acetonitrile at the finishing point. 0.1% formic acid are added to both the water and to the acetonitrile.  
         [0427]     Yield: 0.59 g (0.86 mmol; 90%)  
         [0428]     0.59 g (0.86 mmol) of the above-mentioned intermediate products are dissolved in 50 ml of dimethylformamide and combined with a quantity of distilled water such that there is no precipitation. To this solution are added 60 mg palladium on charcoal and the mixture is hydrogenated at 7 bar H 2  pressure and 20° C. for 6 h. The catalyst is filtered off and the solvent is eliminated in vacuo. The residue is purified by column chromatography. The carrier used is C18-RP-silica gel and a gradient is run through which consists at the starting point of 60% water and 40% acetonitrile and at the finishing point of 15% water and 85% acetonitrile. 10 mmol/l ammonium hydrogen carbonate and 20 mmol/l ammonia are dissolved in the water. The suitable fractions are freeze-dried. The residue is dissolved in acetonitrile and combined with 2 ml of a 1 M hydrochloric acid solution. Then the solvent is eliminated in vacuo. The substance is obtained as the dihydrochloride.  
         [0429]     Yield: 0.46 g (0.73 mmol; 85%)  
         [0430]     UV max: 284 nm  
         [0431]     MS (ESI): 558 (M+H) +   
         [0432]      1 H-NMR: 1.19 (s, 6H), 3.19-3.28 (m, 4H), 3.41-3.49 (m, 4H), 3.80 (s, 3H), 4.07 (s, 1H), 6.54-6.60 (m, 1H), 6.72-6.76 (m, 1H), 6.83-6.89 (m, 1H), 7.21-7.42 (m, 2H), 7.85-8.20 (m, 1H), 8.33-8.60 (m, 1H), 8.74 (s, 1H), 9.30-9.71 (m, 3H), 12.84 (s, 1H)  
       EXAMPLE 168  
     2-(2-methoxy-4-piperazin-1-yl-phenylamino)-4-((S)-4-oxo-2,3,10,10a-tetrahydro-1H.4H-9-oxa-3a-aza-benzo[f]azulen-5-ylamino-5-trifluoromethyl-pyrimidine  
       [0433]    
       
                 
         
             
             
         
       
     
         [0434]     This compound is prepared analogously to Example 167. The aniline used is described in method 10.  
         [0435]     Yield: 0.23 g (0.41 mmol; 91%)  
         [0436]     UV max: 282 nm  
         [0437]     MS (ESI): 570 (M+H) +   
         [0438]      1 H-NMR: 1.53-1.71 (m, 1H), 1.79-2.06 (m, 3H), 3.15-3.32 (m, 4H), 3.32-3.55 (m, 5H), 3.58-3.72 (m, 1H), 3.72-3.94 (m, 4H), 4.00-4.23 (m, 2H), 6.48-6.61 (m, 1H), 6.68-6.77 (m, 1H), 6.83-7.00 (m, 1H), 7.19-7.50 (m, 2H), 7.78-8.10 (m, 1H), 8.23-8.60 (m, 1H), 9.18-9.64 (m, 3H), 10.54-10.86 (m, 1H)  
       EXAMPLE 169  
     2-[4-(4-ethyl-piperazin-1-yl)-2-methoxy-phenylamino]-4-((S)-4-oxo-2,3,10,10a-tetrahydro-1H.4H-9-oxa-3a-aza-benzo[f]azulen-5-ylamino-5-trifluoromethyl-pyrimidine  
       [0439]    
       
                 
         
             
             
         
       
     
         [0440]     60 mg (0.11 mmol) 2-(2-methoxy-4-piperazin-1-yl-phenylamino)-4-((S)-4-oxo-2,3,10,10a-tetrahydro-1H.4H-9-oxa-3a-aza-benzo[f]azulen-5-ylamino-5-trifluoromethyl-pyrimidine (Example 168) are dissolved in 300 μl dimethylformamide and combined with 12 μl (0.21 mmol) acetaldehyde and 47 mg (0.21 mmol) sodium triacetoxyborohydride. This reaction mixture is stirred at 20° C. for 20 h. The solvent is eliminated in vacuo and the residue is purified by column chromatography. The carrier used is C18-RP-silica gel and a gradient is run through which consists of 95% water and 5% acetonitrile at the starting point and 50% water and 50% acetonitrile at the finishing point. 0.1% formic acid are added to both the water and to the acetonitrile. The suitable fractions are combined with 500 μl of a 1 N hydrochloric acid and freeze-dried. The product is obtained as the dihydrochloride.  
         [0441]     Yield: 49 mg (0.074 mmol; 71%)  
         [0442]     UV max: 282 nm  
         [0443]     MS (ESI): 598 (M+H) +   
         [0444]      1 H-NMR: 1.23-1.37 (m, 3H), 1.57-1.72 (m, 1H), 1.80-2.06 (m, 3H), 3.02-3.27 (m, 6H), 3.34-3.48 (m, 1H), 3.48-3.71 (m, 3H), 3.71-3.94 (m, 7H), 6.48-6.61 (m, 1H), 6.68-6.79 (m, 1H), 6.84-6.97 (m, 1H), 7.18-7.43 (m, 2H), 7.78-8.08 (m, 1H), 8.26-8.53 (m, 1H), 9.14-9.44 (m, 1H), 10.49-10.74 (m, 1H), 10.80-11.08 (m, 1H)  
       EXAMPLE 170  
     2-[4-(4-methyl-piperazin-1-yl)-2-methoxy-phenylamino]-4-((S)-4-oxo-2,3,10,10a-tetrahydro-1H.4H-9-oxa-3a-aza-benzo[f]azulen-5-ylamino-5-trifluoromethyl-pyrimidine  
       [0445]    
       
                 
         
             
             
         
       
     
         [0446]     To prepare this compound formaldehyde is used instead of acetaldehyde. Otherwise the method is as in Example 169.  
         [0447]     Yield: 16 mg (0.024 mmol; 28%)  
         [0448]     UV max: 278 nm  
         [0449]     MS (ESI): 584 (M+H) +   
         [0450]      1 H-NMR: 1.58-1.71 (m, 1H), 1.81-2.06 (m, 3H), 2.78-2.88 (m, 3H), 3.00-3.23 (m, 4H), 4.03-4.21 (m, 2H), 6.48-6.59 (m, 1H), 6.69-6.78 (m, 1H), 6.80-6.91 (m, 1H), 7.17-7.44 (m, 2H), 7.92-8.15 (m, 1H), 8.34 (s, 1H), 8.86-9.04 (m, 1H), 10.38-10.64 (m, 2H)  
       EXAMPLES 171-180  
       [0451]     The following Examples are prepared analogously to to Example 169 and 170. The corresponding aniline is described in the supplements to method 10.  
                                                                                                                        UV max   MS (ESI)       #   A   D   [nm]   (M + H) +                                         171                                                               226, 282   572               172                                                               250, 282   586               173                                                               250, 282   596               174                                                               250, 282   600               175                                                               282   544               176                                                               282   558               177                                                               218; 282   586               178                                                               282   582               179                                                               226   558               180                                                               226   572                  
 
       EXAMPLES 181-332  
       [0452]     The following compounds are prepared by an analogous process to that described in Example 53. 2-(4-Carboxy-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine may be obtained according to method 12 or 14. The corresponding aniline described in method 11. The amine used to prepare the amide is commercially obtainable or described in method 13, 15 and 25.  
                                                                                                                        UV max   MS (ESI)       #   A   R 3 ′   [nm]   (M + H) +                                         181                                                               318, 282,   380               182                                                               238   639               183                                                               234; 318   709               184                                                               318, 282, 248   558               185                                                               318, 280   613               186                                                               316, 282, 234   342               187                                                               318, 284, 238   307               188                                                               318, 282, 242   342               189                                                               314, 282, 242   600               190                                                               318, 282, 234   328               191                                                               318   363               192                                                               318, 230   650               193                                                               314   634               194                                                               318   634               195                                                               318   671               196                                                               318, 230   380               197                                                               314, 282, 250   558               198                                                               319   705               199                                                               318, 226   775               200                                                               318   634               201                                                               314   634               202                                                               230; 318   584               203                                                               317   572               204                                                               318, 230   697               205                                                               318, 234   544               206                                                               318   669               207                                                               318, 230   650               208                                                               317   627               209                                                               318, 230   599               210                                                               318, 230   705               211                                                               230; 322   653               212                                                               230; 322   655               213                                                               230; 318   669               214                                                               230, 282, 314   634               215                                                               318   655               216                                                               318, 234   725               217                                                               314, 235   586               218                                                               318, 230   641               219                                                               318, 226   711               220                                                               318, 230   640               221                                                               318   765               222                                                               318   600               223                                                               315   673               224                                                               319, 226   728               225                                                               318, 226   798               226                                                               318, 234   655               227                                                               230; 322   653               228                                                               230; 318   682               229                                                               234; 318   639               230                                                               318, 226   695               231                                                               234, 282, 318   598               232                                                               230, 282, 318   653               233                                                               234, 282, 318   723               234                                                               318, 222   673               235                                                               318   725               236                                                               318, 282, 226   798               237                                                               230; 318   641               238                                                               230; 318   711               239                                                               234; 318   586               240                                                               318, 226   745               241                                                               322   703               242                                                               320, 226   732               243                                                               321, 221   694               244                                                               230, 282, 318   652               245                                                               234, 282, 318   707               246                                                               230, 282, 318   777               247                                                               230, 282, 318   630               248                                                               234, 282, 318   685               249                                                               234, 282, 318   755               250                                                               230, 282, 318   630               251                                                               230, 282, 318   685               252                                                               230, 282, 318   755               253                                                               230; 318   695               254                                                               230; 318   70               255                                                               230; 318   389               256                                                               230; 318   652               257                                                               230   357               258                                                               230   784               259                                                               230   659               260                                                               319, 230   689               261                                                               322   703               262                                                               322   705               263                                                               320   719               264                                                               226   690               265                                                               226; 318   760               266                                                               230   635               267                                                               230; 318   381               268                                                               318   812               269                                                               318   652               270                                                               318   707               271                                                               318, 226   777               272                                                               318   659               273                                                               318   714               274                                                               315, 239   669               275                                                               319, 222   723               276                                                               318, 226   793               277                                                               316   620               278                                                               318   675               279                                                               318, 226   745               280                                                               317, 226   620               281                                                               318   675               282                                                               318, 230   745               283                                                               318   784               284                                                               318   758               285                                                               318   688               286                                                               238, 282, 314   616               287                                                               230, 282, 318   671               288                                                               230, 282, 318   741               289                                                               234, 282, 318   616               290                                                               226, 282, 318   671               291                                                               234, 282, 318   741               292                                                               234, 282, 318   648               293                                                               230, 282, 318   703               294                                                               226, 282, 318   773               295                                                               226, 282, 318   893               296                                                               226, 282, 318   727               297                                                               226, 282, 318   754               298                                                               230, 282, 318   823               299                                                               282, 318   669               300                                                               282, 318   613               301                                                               282, 318   641               302                                                               286, 318   639               303                                                               286, 318   627               304                                                               286, 318   655               305                                                               286, 318   667               306                                                               286, 318   717               307                                                               286, 318   689               308                                                               286, 318   665               309                                                               230, 286, 318   653               310                                                               230, 282, 318   715               311                                                               286, 322   695               312                                                               234, 286, 318   667               313                                                               230, 282, 318   639               314                                                               230, 282, 318   667               315                                                               230, 282, 318   681               316                                                               230, 282, 318   695               317                                                                   679               318                                                               226, 284, 318   681               319                                                               230, 284, 318   697               320                                                               226, 284, 314   750               321                                                               230, 286, 318   669               322                                                               230, 282, 318   693               323                                                               230, 282, 314   709               324                                                               230, 286, 314   681               325                                                               226, 286, 314   762               326                                                               230, 282, 318   681               327                                                               230, 282, 314   697               328                                                               234, 282, 318   627               329                                                               226, 282, 318   767               330                                                               226, 282, 318   725               331                                                               230, 286, 318   711               332                                                               226, 282, 318   671               333                                                               234, 282, 314   718               334                                                               234, 282, 318   693               335                                                               234, 286, 318   653               336                                                               284, 318   706               337                                                               230, 282, 318   641               338                                                               230, 282, 314   667               339                                                               283, 318   655               340                                                               230, 286, 318   699               341                                                               230, 282, 318   750               342                                                               230, 282, 318   627               343                                                               250, 282, 318   667               344                                                               230, 282, 318   683               345                                                               238, 282, 314   641               346                                                               230, 314   692               347                                                               282, 318   723               348                                                               234, 286, 314   653               349                                                               286, 318   667               350                                                               234, 286, 314   718               351                                                               230, 286, 318   685                  
 
       EXAMPLES 352-372  
       [0453]     The following compounds are prepared by an analogous process to that described in Example 53 described, prepared. 2-(4-carboxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine may after method 14 prepared are. The corresponding aniline is in method 11 described. The amine used to prepare the amide is commercially obtainable or is in method 13, 15 or 25 described.  
                                                                                                                        UV max   MS (ESI)       #   A   R 3 ′   [nm]   (M + H) +                                         352                                                               222, 302   688               353                                                               246, 298   663               354                                                               234, 298   679               355                                                               234, 302   623               356                                                               298   611               357                                                               246, 302   676               358                                                                   651               359                                                                   667               360                                                               246, 302   611               361                                                               298   662               362                                                                   637               363                                                               234, 298   653               364                                                               226, 302   597               365                                                               302   637               366                                                               246, 302   625               367                                                               302   695               368                                                               302   711               369                                                               302   669               370                                                               302   720               371                                                               300   693               372                                                               242, 302   655                  
 
       EXAMPLES 373-386  
       [0454]     The following Examples are prepared analogously to Example 169 and 170 The corresponding aniline is described in method 11.  
                                                                                                                        UV max   MS (ESI)       #   A   D   [nm]   (M + H) +                                         373                                                               246   621               374                                                               246   611               375                                                               234   639               376                                                               238   597               377                                                               250   599               378                                                               250   585               379                                                               250   613               380                                                               250   609               381                                                               246   625               382                                                               250   599               383                                                               230   571               384                                                               246   595               385                                                               250   585               386                                                               246, 286   615                  
 
       EXAMPLES 387-388  
       [0455]     The following compounds are prepared by an analogous process to that described in Example 53. 2-(4-Carboxy-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine may be prepared according to method 12 or 14. The corresponding aniline is described in method 4 or method 17. The amine used to prepare the amide is commercially obtainable.  
                                                                                                                        UV max   MS (ESI)       #   A   R 3 ′   [nm]   (M + H) +                                         387                                                               262, 318   569               388                                                               278, 318   615                  
 
       EXAMPLES 389-404  
       [0456]     The following compounds are prepared by an analogous process to that described in Example 53. 2-(4-Carboxy-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine may be prepared according to method 12 or 14. The corresponding aniline is described in method 7, in method 18 or 19. The amine used to prepare the amide is commercially obtainable or is described in method 13.  
                                                                                                                        UV max   MS (ESI)       #   A   R 3 ′   [nm]   (M + H) +                                         389                                                               284, 322   668               390                                                               230, 285, 325   698               391                                                               280, 325   730               392                                                               230, 285, 325   682               393                                                               285, 325   630               394                                                               284, 322   686               395                                                               285, 325   616               396                                                               285, 322   654               397                                                               285, 325   584               398                                                               285, 325   598               399                                                               285, 325   668               400                                                               285, 325   598               401                                                               285, 325   612               402                                                               285, 322   700               403                                                               285, 322   630               404                                                               262   688                  
 
       EXAMPLE 405  
     2-[4-([1,4′]bipiperidinyl-4-ylcarbamoyl)-2-methoxy-phenylamino]-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine  
       [0457]    
       
                 
         
             
             
         
       
     
         [0458]     1150 mg (3.308 mmol) 2-(4-carboxy-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine (method 12 or 14) are dissolved in 2,5 ml N-methyl-2-pyrrolidinone and combined with 883 mg (4.161 mmol) 7-amino-2-(2,2-difluoro-ethyl)-2,3-dihydro-isoindol-1-one (method 2). 115 μl of a 4 M solution of HCl (0.460 mmol) in 1,4-dioxane are metered into this reaction mixture. After 16 h at 90° C. the reaction mixture is stirred into 150 ml of an aqueous 1 N hydrochloric acid. The precipitate is filtered off and dried in vacuo.  
         [0459]     Yield: 1626 mg (3.110 mmol; 94%)  
         [0460]     MS (ESI): 524 (M+H) +   
         [0461]     100 mg (0.191 mmol) of this precipitate, 240 μl (1.402 mmol) N-ethyldiisopropylamine, 89 mg (0.279 mmol) O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-tetrafluoroborate and 76 mg (0.267 mmol) tert-butyl 4-amino-[1,4′]bipiperidinyl-1′-carboxylate are dissolved in 3 ml N,N-dimethylformamide. After 15 h at 20° C. the solvent is eliminated in vacuo. The residue is taken up in 20 ml dichloromethane and 5 ml of methanol and filtered through aluminium oxide. The aluminium oxide is washed several times with a mixture of dichloromethane and methanol (4:1). The solvent of the combined fractions is eliminated in vacuo. The residue is dissolved in 5 ml dichloromethane and combined with 5 ml trifluoroacetic acid. This mixture is stirred for 3 h at 20° C. and then the solvent is eliminated in vacuo. The crude product is purified by column chromatography. The carrier material used is C18-RP-silica gel and a gradient is run through which consists of 90% water and 10% acetonitrile at the starting point and 5% water and 95% acetonitrile at the finishing point. 0.1% formic acid are added both to the water and to the acetonitrile. The suitable fractions are combined with 500 μl of a 1 N hydrochloric acid and freeze-dried. The product is obtained as the trihydrochloride.  
         [0462]     Yield: 42 mg (0.053 mmol; 28%)  
         [0463]     UV max: 322 nm  
         [0464]     MS (ESI): 689 (M+H) +   
         [0465]      1 H-NMR: 1.92-2.19 (m, 6H), 2.28-2.37 (m, 2H), 2.86-3.00 (m, 2H), 3.07-3.19 (m, 3H), 3.84-4.18 (m, 7H), 4.59 (s, 2H), 6.15-6.47 (m, 1H), 7.23-7.28 (m, 1H), 7.35-7.43 (m, 1H), 7.54-7.64 (m, 2H), 7.75-7.82 (m, 1H), 8.40-8.64 (m, 3H), 8.90-9.01 (m, 1H), 9.10-9.25 (m, 2H), 10.40-10.47 (m, 1H), 10.91-11.27 (m, 1H)  
       EXAMPLES 406-407  
       [0466]     The following compounds are prepared by an analogous process to that described in Example 405.  
                                                   UV max   MS (ESI)       #       [nm]   (M + H) +                                         406                                 318   606               407                                 322, 286   606                  
 
       EXAMPLE 408  
     2-[2-methoxy-4-(1′-methyl-[1,4′]bipiperidinyl-4-ylcarbamoyl)-phenylamino]-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine  
       [0467]    
       
                 
         
             
             
         
       
     
         [0468]     70 mg (0.087 mmol) 2-[4-([1,4′]bipiperidinyl-4-ylcarbamoyl)-2-methoxy-phenylamino]4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine (Example 405) are dissolved in 3 ml of methanol, and combined with 8.5 μl (0.508 mmol) acetic acid and with 8 μl (0.107 mmol) of a 37% aqueous formaldehyde solution. Then at 20° C. 7.0 mg (0.112 mmol) sodium cyanoborohydride are added. This mixture is stirred for 16 h at 20° C. The solvent is eliminated in vacuo and the crude product is purified by column chromatography. The carrier material used is C18-RP-silica gel and a gradient is run through which consists at the starting point of 95% water and 5% acetonitrile and at the finishing point of 5% water and 95% acetonitrile. 0.1% formic acid are added both to the water and to the acetonitrile. The suitable fractions are combined with 500 μl of a 1 N hydrochloric acid and freeze-dried. The product is obtained as the trihydrochloride.  
         [0469]     Yield: 18 mg (0.022 mmol; 25%)  
         [0470]     UV max: 322 nm  
         [0471]     MS (ESI): 703 (M+H) +   
       EXAMPLES 409-491  
       [0472]     The following compounds are prepared by an analogous process to that described in Example 53. 2-(4-Carboxy-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine may be prepared according to method 12 or 14. The corresponding aniline is described in method 2. The amine used to prepare the amide is commercially obtainable or is described in method 13, 20 or 21.  
                                                                                                                        UV max   MS (ESI)       #   A   R 3 ′   [nm]   (M + H) +                                         409                                                               285, 320   584               410                                                               322   716               411                                                               326   703               412                                                                   558               413                                                               282, 318   699               414                                                               322, 286   668               415                                                               322.3   724               416                                                               322.3   362               417                                                               322, 286   738               418                                                               322, 286   738               419                                                               282, 314   738               420                                                               286, 314   738               421                                                               286, 318   700               422                                                               286, 322   698               423                                                               286, 318   700               424                                                               286, 322   712               425                                                               286, 322   724               426                                                               322, 286   672               427                                                               282, 322   723               428                                                               322, 285   602               429                                                               326.3   616               430                                                               322, 286   616               431                                                               318, 286   645               432                                                               321, 284   632               433                                                               322, 286   618               434                                                               318, 282   690               435                                                               322, 282   708               436                                                               322, 286   686               437                                                               322, 284   722               438                                                               322, 282   658               439                                                               322, 285   547               440                                                               322, 286   602               441                                                               286.3   565               442                                                               322, 286   620               443                                                               322, 284   686               444                                                               326.3   634               445                                                               326, 286   634               446                                                               322, 284   676               447                                                               322.3   663               448                                                               325.3   650               449                                                               325.3   635               450                                                               322, 282   620               451                                                               322, 282   704               452                                                               322, 282   665               453                                                               326, 282   595               454                                                               322, 284   677               455                                                               322.3   664               456                                                               326, 286   594               457                                                               322, 282   743               458                                                               326, 286   638               459                                                               326, 283   681               460                                                               318, 284   681               461                                                               318, 286   627               462                                                               322, 286   627               463                                                               326, 286   648               464                                                               322, 286   611               465                                                               322, 286   723               466                                                               322, 282   710               467                                                               326, 286   654               468                                                               326, 286   654               469                                                               322, 284   683               470                                                               326, 286   640               471                                                               318, 283   710               472                                                               326, 286   654               473                                                               326, 286   654               474                                                               321, 285   683               475                                                               326, 286   630               476                                                               322, 286   682               477                                                               318, 286   612               478                                                               318.3   606               479                                                               322, 286   566               480                                                               322, 286   621               481                                                               318, 286   649               482                                                               322, 286   606               483                                                               326, 286   652               484                                                               326, 286   648               485                                                               322, 284   704               486                                                               326, 286   634               487                                                               322, 285   689               488                                                               322, 285   703               489                                                               322   698               490                                                               322, 286   619               491                                                               322, 286   689                  
 
       EXAMPLES 492-621  
       [0473]     The following compounds are prepared by an analogous process to that described in Example 53. 2-(4-carboxy-2-methoxy-phenylamino)-4-chloro-5-trifluoromethylpyrimidine may be prepared according to method 12 or 14. The corresponding aniline is described in method 22. The amine used to prepare the amide is commercially obtainable, described in method 13, 15, 20, 21, 23, 24 and 25 or in J. Med. Chem. 2003, 46(5), 702-715.  
                                                                                                                                UV max   MS (ESI)       #   A   R 3 ′   R 3 ″   [nm]   (M + H) +                                             492                                                               H   286, 322   584               493                                                               H   286, 322   826               494                                                               H   284, 322   613               495                                                               H   282, 322   640               496                                                               H   286, 320   570               497                                                               H   286, 322   584               498                                                               H   282, 322   693               499                                                               H   286, 322   686               500                                                               H   286, 326   616               501                                                               H   286, 326   630               502                                                               H   282, 325   704               503                                                               H   286, 326   634               504                                                               H   286, 326   648               505                                                               H   286, 322   712               506                                                               H   322, 286   739               507                                                               H   322, 286   645               508                                                               H   326, 286   632               509                                                               H   322, 286   672               510                                                               H   322, 284   700               511                                                               H   314, 286   616               512                                                               H   286, 322   684               513                                                               H   286, 322   670               514                                                               H   282, 322   658               515                                                               H   322, 286   632               516                                                               H   326, 286   628               517                                                               H   325, 286   628               518                                                               H   326, 286   659               519                                                               H   326   699               520                                                               H   284, 326   616               521                                                               H   234, 282, 314   630               522                                                               H   326   660               523                                                               H   326   657               524                                                               H       645               525                                                               H   326   627               526                                                               H   326   660               527                                                               H   326   659               528                                                               H   326   692               529                                                               H   326   644               530                                                               H   326   628               531                                                               H   322   662               532                                                               H   326   699               533                                                               H   326   602               534                                                               H       646               535                                                               H   326   666               536                                                               H   326   646               537                                                               H   326   —               538                                                               H   322   616               539                                                               H   318   630               540                                                               H   318   630               541                                                               H   274   644               542                                                               H   326   658               543                                                               H   286, 324   630               544                                                               H   286, 326   658               545                                                               H   286, 322   630               546                                                               H   286, 326   642               547                                                               H   286, 322   562               548                                                               H   322-326   630               549                                                               H   326   630               550                                                               H   286, 322   607               551                                                               H       646               552                                                               H       644               553                                                               H   326   644               554                                                               H   322-326   658               555                                                               H   322-326   658               556                                                               H   286, 326   658               557                                                               H   322-326   642               558                                                               H   322-326   642               559                                                               H   286, 322   656               560                                                               H   286, 322   656               561                                                               H   286, 322   671               562                                                               H   286, 322   671               563                                                               H   318   685               564                                                               H   322-326   685               565                                                               H   322-326   754               566                                                               H   322-326   672               567                                                               H   322   711               568                                                               H   322-326   711               569                                                               H   326   624               570                                                               H   326   645               571                                                               H   322-326   650               572                                                               H   286, 326   684               573                                                               H   286, 326   684               574                                                               H   326   673               575                                                               H   322   698               576                                                               H   326, 286   646               577                                                               H   286, 322   684               578                                                               H   282, 322   658               579                                                               H   322, 286   617               580                                                               H   326, 286   644               581                                                               H   326, 286   590               582                                                               H   286, 326   673               583                                                               H   326, 285   652               584                                                               H   326, 282   722               585                                                               H   326, 286   648               586                                                               H   326, 285   718               587                                                               H   326, 286   652               588                                                               H   326, 284   652               589                                                               H   325, 283   681               590                                                               H   325.3   652               591                                                               H   326.3   666               592                                                               H   325, 283   666               593                                                               H   325.3   648               594                                                               H   325, 284   648               595                                                               H   325, 284   677               596                                                               H   325, 284   648               597                                                               H   326, 285   662               598                                                               H   325, 284   662               599                                                               H   326, 282   720               600                                                                                             314, 283   576               601                                                               H   322, 286   714               602                                                               H   286, 322   670               603                                                               H   324, 285   614               604                                                               H   324, 284   684               605                                                               H   324, 285   628               606                                                               H   324, 284   698               607                                                               H   285, 322   630               608                                                               H   325, 284   576               609                                                               H   325, 284   576               610                                                               H   326, 286   659               611                                                               H   326, 286   646               612                                                               H   325, 285   630               613                                                               H   325, 284   630               614                                                               H   325, 285   590               615                                                               H   285, 325   642               616                                                               H   325, 285   670               617                                                               H   326, 286   684               618                                                               H   326, 286   658               619                                                               H   285, 324   684               620                                                               H   326, 286   658               621                                                               H   280, 320   631                  
 
       EXAMPLE 622  
     2-(2-methoxy-4-[2-(2-pyrrolidin-1-yl-ethylcarbamoyl)-ethylamino]-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine  
       [0474]    
       
                 
         
             
             
         
       
     
         [0475]     73 mg (0.193 mmol) 3-(4-amino-3-methoxy-phenylamino)-N-(2-pyrrolidin-1-yl-ethyl)-propionamide hydrochloride (method 28) are dissolved in 3 ml 2-butanol and combined with 50 mg (0.129 mmol) 2-chloro-4-(2-(2-fluorethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine (method 26). This reaction mixture is stirred for 16 h at 100° C. The solvent is eliminated in vacuo and the residue is purified by column chromatography. The carrier material used is C18-RP-silica gel and a gradient is run through which consists at the starting point of 90% water and 10% acetonitrile and at the finishing point of 55% water and 45% acetonitrile. 0.1% formic acid are added both to the water and to the acetonitrile. The suitable fractions are combined with 500 μl of a 1 M aqueous hydrochloric acid and freeze-dried. The product is obtained as the dihydrochloride.  
         [0476]     Yield: 33 mg (0.045 mmol; 35%)  
         [0477]     UV max: 314 nm  
         [0478]     MS (ESI): 659 (M+H) +   
         [0479]      1 H-NMR: 1.35-1.48 (m, 3H), 1.64-1.78 (m, 4H), 2.37-2.46 (m, 2H), 3.48-3.75 (m, 4H), 3.97-4.14 (m, 1H), 4.50-4.78 (m, 3H), 5.55-5.71 (m, 1H), 6.14-6.42 (m, 2H), 6.96-7.32 (m, 3H), 7.86-7.98 (m, 1H), 8.32 (s, 1H), 8.84 (s, 1H), 10.41 (s, 1H)  
       EXAMPLE 623  
     2-(2-fluoro-ethyl)-7-(2-{4-[4-(2-hydroxy-ethyl)-1H-imidazol-2-yl]-2-methoxy-phenylamine}-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine  
       [0480]    
       
                 
         
             
             
         
       
     
         [0481]     0.07 g (0.3 mmol) 2-[2-(4-amino-3-methoxy-phenyl)-1H-imidazol-4-yl]-ethanol (method 27) are suspended in 2 ml dioxane and brought into solution in the ultrasound bath at 50° C. 0.8 ml (3.20 mmol) 4 N dioxanic hydrochloric acid are added. The dioxane is eliminated in vacuo, combined with 0.096 g (0,247 mmol) 7-(2-chloro-5-trifluoromethyl-pyrimidine-4-ylamine)-2-(2-fluoro-ethyl)-3-methyl-2,3-dihydro-isoindol-1-one and suspended in butanol. The mixture is stirred for 16 h at 100° C. The crude product is purified by column chromatography. The carrier material used is C18-RP-silica gel. A gradient is run through which consists at the starting point of 75% water and 25% acetonitrile and at the finishing point of 30% water and 70% acetonitrile. 0.1% ammonia is added to the water. 23 mg of this intermediate product and 0.018 g (0.094 mmol) p-toluenesulphonyl chloride are suspended in 0.9 ml of tetrahydrofuran and 0.02 ml (0.139 mmol) triethylamine and combined with 0.007 g (0.057 mmol) 4-dimethylamino-pyridine. This reaction mixture is stirred for 16 h at 20° C. Then it is combined with 0.36 ml (5.064 mmol) pyrrolidine and stirred for 16 h at 60° C. The crude product is purified by column chromatography. The carrier material used is C18-RP-silica gel. A gradient is run through which consists of 90% water and 10% acetonitrile at the starting point and of 60% water and 40% acetonitrile at the finishing point. 0.1% formic acid is added to the water.  
         [0482]     Yield: 7 mg (0.011 mmol, 28%)  
         [0483]     MS (ESI): 639 (M+H) +   
         [0484]     UV max: 330 nm  
         [0485]     NMR: 1.42-1.46 (m, 3H), 1.78-2.08 (m, 6H), 2.29 (s, 1H), 3.95-4.16 (m, 4H), 4.52-4.78 (m, 3H), 7.09-7.13 (m, 1H), 7.24-7.28 (m, 1H), 7.46-7.50 (m, 1H), 7.52-7.58 (m, 2H), 7.64-7.67 (m, 1H), 7.82-7.88 (m, 1H), 8.02-8.13 (m, 2H), 8.50-8.60 (m, 2H), 9.20-9.23 (m, 1H), 10.52-10,82 (m, 2H).  
       EXAMPLES 624-638  
       [0486]     The following compounds are prepared by an analogous process to that described in Example 622 or 623. The corresponding aniline is described in method 27 and 28.  
                                                                                                                UV max   MS (ESI)       #   B   [nm]   (M + H) +                                     624                                 290, 326   586               625                                 290, 330   654               626                                 290, 326   625               627                                 326   512               628                                 314   685               629                                 290, 314   659               630                                     659               631                                 278   592               632                                 314   592               633                                 314   588               634                                 314   602               635                                 314   602               636                                 314   588               637                                 314   602               638                                     670                  
 
       EXAMPLE 639  
     2-(4-(4-isopropyl-[1,4]diazepin-1-yl)-2-methoxy-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine  
       [0487]    
       
                 
         
             
             
         
       
     
         [0488]     50 mg (0.087 mmol) 2-(4-(4-[1,4]diazepan-1-yl)-2-methoxy-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine (method from Example 622, aniline from method 28) are dissolved in 0.5 ml dimethylacetamide and combined with 13 μl (0.174 mmol) acetone. 37 mg (0.175 mmol) sodium triacetoxyborohydride are added to this reaction mixture. After 16 h at 20° C. the solvent is eliminated in vacuo. The residue is purified by column chromatography. The carrier material used is C18-RP-silica gel and within 15 min a gradient is run through which consists of 95% water and 5% acetonitrile at the starting point and 5% water and 95% acetonitrile at the finishing point. 0.1% formic acid are added both to the water and to the acetonitrile. The suitable fractions are combined with 500 μl of a 1 M aqueous hydrochloric acid and freeze-dried. The product is obtained as the dihydrochloride.  
         [0489]     Yield: 51 mg (0.074 mmol; 85%)  
         [0490]     UV max: 314 nm  
         [0491]     MS (ESI): 616 (M+H) +   
         [0492]      1 H-NMR: 1.23-1.35 (m, 6H), 1.35-1.51 (m, 3H), 2.16-2.29 (m, 1H), 2.95-3.05 (m, 1H), 3.12-3.23 (m, 1H), 3.42-3.66 (m, 6H), 3.78 (s, 3H), 3.83-4.00 (m, 2H), 4.00-4.16 (m, 1H), 4.50-4.79 (m, 3H), 6.32-6.63 (m, 2H), 7.08-8.59 (m, 4H), 9.24-9.76 (m, 1H), 10.67 (s, 2H)  
       EXAMPLES 640-648  
       [0493]     The following compounds are prepared by an analogous process to that described in Example 639.  
                                                                                                                        UV max   MS (ESI)           #   D   [nm]   (M + H) +                                                 640                                 314   574                       641                                 310-314   628                       642                                 310-314   602                       643                                 310-314   630                       644                                 314   671                       645                                 310-314   618                       646                                 314   658                       647                                 314   588                      
 
       EXAMPLES 648-659  
       [0494]     The following compounds are prepared by an analogous process to that described in Example 639. For the reductive amination 2-(2-methoxy-4-piperazin-1-yl-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine is used. The aniline for preparing this compound is described in method 28.  
                                                                                                                UV max   MS (ESI)       #   D   [nm]   (M + H) +                                     648                                 286, 314   631               649                                 286, 314   603               650                                 282, 314   643               651                                 282, 314   671               652                                 286, 314   657               653                                 282, 314   628               654                                 286, 314   657               655                                 286, 314   671               656                                 282, 314   614               657                                 282, 314   560               658                                 234, 283, 314   694               659                                 286, 314   574                  
 
       EXAMPLES 660-666  
       [0495]     The following compounds are prepared by an analogous process to that described in Example 53. 2-(4-Carboxy-2-bromo-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine may be prepared according to method 29. The corresponding aniline is described in method 22. The amine used to prepare the amide is commercially obtainable or described in method 13.  
                                                                                                                        UV max   MS (ESI)       #   A   R 3 ′   [nm]   (M + H) +                                         660                                                               314   678/680               661                                                               314   626/628               662                                                               314   626/628               663                                                               286   609/611               664                                                               314   734/736               665                                                               314   693/695               666                                                               286   678/680                  
 
       EXAMPLES 667-681  
       [0496]     The following compounds are prepared by an analogous process to that described in Example 53. 2-(4-Carboxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine may be prepared according to method 14. The corresponding aniline is described in method 22. The amine used to prepare the amide is commercially obtainable or described in method 13. In addition, the group R 3 ′ may be synthesised analogously to Example 639 by reductive amination. An amine is used which has another protected amino function in the side chain. The protective group used may be a tert-butoxycarbonyl, benzyloxycarbonyl or benzyl group. This protective group is cleaved by a procedure familiar to the skilled man and reductive amination (analogously to Example 639) or alkylation (analogously to method 34 or WO2004052857) are the last steps in this sequence.  
                                                                                                                                UV max   MS (ESI)       #   A   R 3 ′   R 3 ″   [nm]   (M + H) +                                             667                                                               H   314   586               668                                                               H   314   586               669                                                               H   314   586               670                                                               H   314   642               671                                                               H   314   616               672                                                               H   290   600               673                                                               H   290   709               674                                                               H   314   600               675                                                               H   314   586               676                                                                                             286   574               677                                                               H   286   572               678                                                               H   290   682               679                                                               H   314   642               680                                                               H   290   656               681                                                               H   314   615                  
 
       EXAMPLE 682  
     2-(2-methoxy-4-[3-(4-methyl-piperazin-1-yl)-propionylamino]-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine  
       [0497]    
       
                 
         
             
             
         
       
     
         [0498]     63 mg (0.116 mmol) 2-(4-acryloylamino-2-methoxy-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine (method 30) are dissolved in 1 ml of methanol and combined with 70 mg (0.699 mmol) N-methyl-piperazine. After stirring for 48 h at 20° C. the solvent is eliminated in vacuo. The residue is purified by column chromatography. The carrier material used is C18-RP-silica gel and a gradient is run through within 20 min which consists of 95% water and 5% acetonitrile at the starting point and of 2% water and 98% acetonitrile at the finishing point. 0.1% formic acid are added both to the water and to the acetonitrile. The suitable fractions are combined with 500 μl of a 1 M aqueous hydrochloric acid and freeze-dried. The product is obtained as the dihydrochloride.  
         [0499]     Yield: 58 mg (0.081 mmol; 70%)  
         [0500]     UV max: 282 nm  
         [0501]     MS (ESI): 645 (M+H) +   
         [0502]      1 H-NMR: 1.42 (d, 3H), 2.18 (s, 3H), 2.29-2.43 (m, 4H), 2.65-2.70 (m, 2H), 3.50-3.62 (m, 1H), 3.72 (s, 3H), 4.00-4.12 (m, 1H), 4.52-4.76 (m, 3H), 7.12-7.17 (m, 1H), 7.12-7.42 (m 4H), 7.51 (s, 1H), 8.17 (s, 1H), 8.38 (s, 1H), 9.08 (s, 1H), 10.18 (s, 1H), 10.46 (s, 1H)  
       EXAMPLES 683-692  
       [0503]     The following compounds are prepared by an analogous process to that described in Example 682.  
                                                                                                                        UV max   MS (ESI)           #   E   [nm]   (M + H) +                                                 683                                 282   661                       684                                 282   673                       685                                 282   701                       686                                 282   645                       687                                 282   685                       688                                 282   616                       689                                 282   713                       690                                 282   630                       691                                 282   632                       692                                 282   602                      
 
       EXAMPLES 693-704  
       [0504]     The following compounds are prepared by an analogous process to that described in Example 682. 2-(4-(2-Bromo-acetylamino)-2-methoxy-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine or 2-(4-(2-bromo-acetylamino)-2-bromo-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine or 2-[5-(2-bromo-acetylamino)-pyridin-2-ylamino]-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine, which are described in method 30, are used as educt for the nucleophilic substitution.  
                                                                                                                UV max   MS (ESI)       #   B   [nm]   (M + H) +                                     693                                 282   685               694                                 282   685               695                                 314   659               696                                 282   645               697                                 282   644               698                                 282   618               699                                 282   602               700                                 282   687               701                                 322   573               702                                 322   630               703                                 222   650               704                                 278   707                  
 
       EXAMPLE 705  
     2-(2-methoxy-4-[3-(3-pyrrolidin-1-yl-ethyl)-ureido]-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine  
       [0505]    
       
                 
         
             
             
         
       
     
         [0506]     70 mg (0.135 mmol) 2-(4-carboxy-2-methoxy-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine (analogously to Example 53) are dissolved in 2 ml of toluene and combined with 190 μl (1.348 mmol) triethylamine and 60 μl (0.270 mmol) diphenylphosphorylazide. This reaction mixture is stirred for 48 h at 20° C. Then the temperature of the suspension is adjusted to 95° C. for 2 h, whereupon a clear brown solution is formed. Then 31 mg (0.270 mmol) 1-(2-aminoethyl)-pyrrolidine are added and the mixture is again stirred for 1 h at 95° C. The solvent is eliminated in vacuo. The residue is purified by column chromatography. The carrier used is C18-RP-silica gel and within 15 min a gradient is run through which consists of 95% water and 5% acetonitrile at the starting point and consists of 2% water and 98% acetonitrile at the finishing point. 0.1% formic acid are added to both the water and to the acetonitrile. The suitable fractions are made basic with 5 M sodium hydroxide solution and extracted 4 times with 50 ml dichloromethane. The combined organic phases are dried and the solvent is eliminated in vacuo.  
         [0507]     Yield: 42 mg (0.067 mmol; 50%)  
         [0508]     UV max: 282 nm  
         [0509]     MS (ESI): 631 (M+H) +   
         [0510]      1 H-NMR: 1.42-1.48 (m, 3H), 1.69-1.79 (m, 4H), 3.22-3.28 (m, 2H), 3.49-3.62 (m, 1H), 3.70 (s, 3H), 3.99-4.12 (m, 1H), 4.53-4.76 (m, 3H), 6.17 (s, 1H), 6.84-6.91 (m, 1H), 7.15-7.33 (m, 3H), 7.40 (s, 1H), 8.36 (s, 1H), 8.76 (s, 1H), 9.01 (s, 1H), 10.44 (s, 1H)  
       EXAMPLE 706  
     2-(2-methoxy-4-ureido-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine  
       [0511]    
       
                 
         
             
             
         
       
     
         [0512]     This compound is prepared analogously to Example 705.  
         [0513]     UV max: 282/314 nm  
         [0514]     MS (ESI): 534 (M+H) +   
         [0515]      1 H-NMR: 1.42 (d, 3H), 3.48-3.64 (m, 1H), 3.69 (s, 3H), 3.98-4.13 (m, 1H), 4.50-4.77 (m, 3H), 5.89 (s, 2H), 6.94 (d, 1H), 7.16-7.30 (m, 2H), 7.36 (s, 1H), 8.33-8.41 (m, 2H), 8.38 (s, 1H), 8.73 (s, 1H), 9.00 (s, 1H), 10.44 (s, 1H)  
       EXAMPLE 707  
     2-(2-methoxy-4-[(1-methyl-piperidin-4-carbonyl)-amino]-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine  
       [0516]    
       
                 
         
             
             
         
       
     
         [0517]     Starting from 2-(4-amino-2-methoxy-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine (method 30) the above-mentioned product is prepared using an amide linking method familiar to the skilled man (cf. also Example 53 or 1032). The substance is obtained as a free base.  
         [0518]     UV max: 282 nm  
         [0519]     MS (ESI): 616 (M+H) +   
         [0520]      1 H-NMR (400 MHz, CDCl 3 ): 1.51 (d, 3H), 2.25-2.32 (m, 1H), 2.36 (s, 3H), 3.00-3.07 (m, 2H), 3.53-3.65 (m, 1H), 3.92 (s, 3H), 4.13-4.27 (m, 1H), 4.56-4.77 (m, 3H), 6.84 (d, 1H), 7.07 (d, 1H), 7.44 (s, 1H), 7.47-7.54 (m, 1H), 7.57 (s, 1H), 7.62 (s, 1H), 8.16-8.24 (m, 1H), 8.39 (s, 1H), 8.60-8.68 (m, 1H), 10.42 (s, 1H)  
       EXAMPLES 708-795  
       [0521]     Using an analogous method to that described in Example 53 a primary amine which has another protected amino function in the side chain is coupled to 2-(4-carboxy-2-methoxy-phenylamino)-4-[2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino]-5-trifluoromethyl-pyrimidine. The protective group used may be a tert-butoxycarbonyl, benzyloxycarbonyl or benzyl group. This protective group is cleaved using a procedure familiar to the skilled man and reductive amination (analogously to Example 639) or alkylation (analogously to method 34 or WO2004052857) are the final steps in this sequence.  
                                                                                                                UV max   MS (ESI)       #   R 3 ′   [nm]   (M + H) +                                     708                                 285, 322   706               709                                 285, 322   656               710                                 285, 322   630               711                                 322, 286   644               712                                 325, 286   699               713                                 282, 318   644               714                                 326   685               715                                 326   658               716                                 326   699               717                                 326   630               718                                 326   644               719                                 322   644               720                                 326   656               721                                 326   678               722                                 314   630               723                                 322   641               724                                 326   712               725                                 326   642               726                                 322   642               727                                 318   672               728                                 301   686               729                                 326   588               730                                 326   642               731                                 326   670               732                                 326   642               733                                 326   630               734                                 326   699               735                                 310   616               736                                 326   656               737                                 322   630               738                                 326   656               739                                 326   656               740                                 266   652               741                                 326   629               742                                 326   671               743                                 326   630               744                                 326   642               745                                 326   602               746                                 326   628               747                                 326   616               748                                 326   602               749                                 322   652               750                                 326   646               751                                 326   672               752                                 326   616               753                                 326   616               754                                 326   685               755                                 322   616               756                                 318   713               757                                 286, 322   588               758                                 226, 286, 322   602               759                                 322-326   656               760                                 322-326   699               761                                 322-326   670               762                                 322-326   699               763                                 322   713               764                                 326   685               765                                 322   684               766                                 326   642               767                                 322-326   656               768                                 322-326   685               769                                 322-326   630               770                                 286, 322   670               771                                 286, 322   670               772                                 322-326   644               773                                 322   684               774                                 322-326   658               775                                 322   686               776                                 322-326   727               777                                 322-326   674               778                                 322-326   684               796                                 322-326   698               780                                 286, 322   630               781                                 282, 314   616               782                                 322, 286   686               783                                 326   684               784                                 324, 286   656               785                                 326, 286   685               786                                 322, 286   715               787                                 322, 286   673               788                                 285, 322   616               789                                 285, 322   630               790                                 285, 322   686               791                                 285, 322   686               792                                 326   644               793                                 322   630               794                                 326   631               795                                 326   660                  
 
       EXAMPLE 796  
     2-[2-methoxy-4-(2-methyl-2-pyrrolidin-1-yl-propylcarbamoyl)-phenylamino]-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine  
       [0522]    
       
                 
         
             
             
         
       
     
         [0523]     200 mg (0.385 mmol) 2-(4-carboxy-2-methoxy-phenylamino)-4-[2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino]-5-trifluoromethyl-pyrimidine (analogously to Example 53) are dissolved in 1 ml of dimethylformamide cooled to 0° C. and combined with 520 μl (3.038 mmol) diisopropylethylamine and 160 mg (0.498 mmol) O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-tetrafluoroborate. This solution is slowly added dropwise after 10 min to 56 μl (0.539 mmol) 1,2-diamino-2-methylpropane, which is dissolved in 300 μl dimethylformamide. The reaction mixture is stirred for 24 h at 20° C. and then the solvent is eliminated in vacuo. The residue is purified by column chromatography. The carrier used is C18-RP-silica gel and within 15 min a gradient is run through which consists at the starting point of 90% water and 10% acetonitrile and at the finishing point of 50% water and 50% acetonitrile. 0.1% formic acid are added to both the water and to the acetonitrile. The suitable fractions are freeze-dried. This intermediate product is combined with 70 mg (0.515 mmol) potassium carbonate and with 84 mg (0.506 mmol) potassium iodide and suspended in 2 ml acetonitrile. 20 μl (0.170 mmol) 1,4-dibromobutane are added to this mixture and it is stirred under reflux conditions for 16 h. Then the solvents are solvent eliminated in vacuo and the residue is purified by column chromatography. The carrier used is C18-RP-silica gel and within 15 min a gradient is run through which consists at the starting point of 90% water and 10% acetonitrile and at the finishing point of 50% water and 50% acetonitrile. 0.1% formic acid are added to both the water and to the acetonitrile. The suitable fractions are combined with 0.5 ml 1 N hydrochloric acid and freeze-dried. The product is obtained as the dihydrochloride.  
         [0524]     Yield: 20-mg (0.032 mmol, 8%)  
         [0525]     UV max: 325 nm  
         [0526]     MS (ESI): 644 (M+H) +   
         [0527]      1 H-NMR (400 MHz): 1.30-1.47 (m, 9H), 1.85-2.01 (m, 4H), 3.20-3.31 (m, 2H), 3.91 (s, 3H), 3.99-4.15 (m, 1H), 4.51-4.78 (m, 3H), 7.23-7.29 (m, 1H), 7.39-7.47 (m, 1H), 7.63-7.69 (m, 1H), 7.73-7.77 (m, 1H), 7.79-7.87 (m, 1H), 8.40-8.59 (m, 2H), 8.75-8.82 (m, 1H), 9.16-9.21 (m, 1H), 10.50-10.63 (m, 2H)  
       EXAMPLES 797-806  
       [0528]     The following compounds are prepared by an analogous method to that described in Example 796:  
                                                                                                                UV max   MS (ESI)       #   R 3 ′   [nm]   (M + H) +                                     797                                 285, 325   642               798                                 284, 325   642               799                                 325, 285   644               800                                 325, 285   644               801                                 325, 285   644               802                                 325, 285   656               803                                 325, 285   658               804                                 325, 284   658               805                                 326, 286   670               806                                 324, 285   670                  
 
       EXAMPLES 807-821  
       [0529]     The following compounds are prepared by an analogous process to that described in Example 53. The corresponding aniline is described in method 31. The amine used to prepare the amide is commercially obtainable or is described in method 13, 21 or in method 25.  
                                                                                                                UV max   MS (ESI)       #   R 3 ′   [nm]   (M + H) +                                     807                                 286, 322   686               808                                 286, 322   616               809                                 286, 322   630               810                                 286, 322   616               811                                 286, 322   712               812                                 322, 286   684               813                                     689               814                                 278   689               815                                 322   630               816                                 286, 326   645               817                                 285, 322   659               818                                 285, 322   616               819                                 285, 322   630               820                                     630               821                                 322, 286   630                  
 
       EXAMPLES 822-885  
       [0530]     The following compounds are prepared by an analogous process to that described in Example 53. The corresponding aniline is described in method 31. The amine used to prepare the amide is commercially obtainable, described in method 13, 15, 20, 21, 23, 24 and 25 or in J. Med. Chem. 2003, 46(5), 702-715.  
                                                                                                                UV max   MS (ESI)       #   R 3 ′   [nm]   (M + H) +                                     822                                 286, 322   686               823                                 325, 284   616               824                                 286, 326   630               825                                 286, 322   616               826                                 286, 318   712               827                                 286, 322   684               828                                 326   645               829                                 316   689               830                                 322   689               831                                     616               832                                 318   630               833                                 326   588               834                                 322   630               835                                 286, 322   630               836                                     658               837                                 322-326   602               838                                 322-326   616               839                                 322   616               840                                 322-326   616               841                                 322-326   630               842                                 322-326   630               843                                 286, 322   644               844                                 286, 322   642               845                                 286, 322   642               846                                 286, 322   656               847                                 282, 318   630               848                                 282, 322   630               849                                 286, 318   671               850                                 286, 322   630               851                                 286, 322   630               852                                 286, 322   644               853                                 322-326   672               854                                 322   672               855                                 286, 322   725               856                                 286, 322   725               857                                 322-326   685               858                                 286, 322   713               859                                 286, 322   713               860                                 286, 322   644               861                                 286, 322   644               862                                 318-322   645               863                                 286, 322   658               864                                 286, 322   699               865                                 286, 322   699               866                                 326   709               867                                 322   697               868                                 322   697               869                                 318   695               870                                 290.3   693               871                                 322   695               872                                 286, 322   753               873                                 286, 326   642               874                                 286, 322   645               875                                 322, 286   659               876                                 282, 322   684               877                                 324, 284   646               878                                 286, 322   670               879                                 325, 284   630               880                                 322, 286   630               881                                 322, 286   684               882                                 325, 286   670               883                                 322, 286   646               884                                 326, 286   644               885                                 325, 285   630                  
 
       EXAMPLES 886-891  
       [0531]     The following compounds are prepared by an analogous process to that described in Example 622 or 623. The corresponding aniline is described in method 27 or 28.  
                                                                                                                    MS                   (ESI)               UV max   (M +       #   B   [nm]   H) +                                     886                                 314   685               887                                 314   685               888                                 286, 310   685               889                                 282, 314   699               890                                 338   656               891                                 314   588                  
 
       EXAMPLES 892-894  
       [0532]     The following compounds are prepared by an analogous process to that described in Example 53. 2-(4-carboxy-2-bromo-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine is described in method 29. The corresponding aniline is described in method 31. The amine used to prepare the amide is commercially obtainable.  
                                                                                                                        UV max   MS (ESI)           #   R 3 ′   [nm]   (M + H) +                                                 892                                 314   665                       893                                 270   665                       894                                 270   680                      
 
       EXAMPLE 895  
     2-(2-methoxy-4-[(1-methyl-piperidin-4-carbonyl)-amino]-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine  
       [0533]     Enantiomer 1 
                         
 
         [0534]     Starting from 2-(4-amino-2-methoxy-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine enantiomer 1 (analogously to method 30) the above-mentioned product is prepared by an amide linking method familiar to the skilled man (cf. also Example 1032). It is obtained as the dihydrochloride.  
         [0535]     UV max 310 nm  
         [0536]     MS (ESI): 616 (M+H) +   
         [0537]      1 H-NMR (500 MHz): 1.42 (d, 3H), 1.69-1.77 (m, 2H), 1.77-1.84 (m, 2H), 1.94-2.03 (m, 2H), 2.23 (s, 3H), 2.29-2.38 (m, 1H), 2.86-2.93 (m, 2H), 3.72 (s, 3H), 4.00-4.12 (m, 1H), 4.52-4.75 (m, 3H), 7.16 (d, 3H), 7.18-7.24 (m, 1H), 7.32-7.41 (m, 1H), 7.57 (s, 1H), 8.18 (s, 1H), 8.38 (s, 1H), 9.07 (s, 1H), 9.95 (s, 1H), 10.46 (s, 1H)  
       EXAMPLE 896  
     2-(2-methoxy-4-(2-pyrrolidin-1-yl-acetylamino)-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine  
       [0538]     Enantiomer 1 
                         
 
         [0539]     Starting from 2-(4-amino-2-methoxy-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine Enantiomer 1 (analogously to method 30) the above-mentioned product is prepared by an amide linking method familiar to the skilled man (cf. also Example 1032). It is obtained as the dihydrochloride.  
         [0540]     UV max: 282 nm  
         [0541]     MS (ESI): 602 (M+H) +   
         [0542]      1 H-NMR (500 MHz): 1.43 (d, 3H), 1.87-2.00 (m, 2H), 2.00-2.10 (m, 2H), 3.12-3.22 (m, 2H), 3.74 (s, 3H), 4.00-4.13 (m, 1H), 4.28-4.32 (m, 2H), 4.53-4.76 (m, 3H), 7.19-7.49 (m, 4H), 7.51 (s, 1H), 8.41 (s, 1H), 9.26 (s, 1H), 10.20-10.31 (m, 1H), 10.54 (s, 1H), 10.86 (s, 1H)  
       EXAMPLES 897-952  
       [0543]     Using a method analogous to that described in Example 53 a primary amine which has another protected amino function in the side chain is coupled to 2-(4-carboxy-2-methoxy-phenylamino)-4-[2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino]-5-trifluoromethyl-pyrimidine Enantiomer 1. The protective group used may be a tert-butoxycarbonyl, benzyloxycarbonyl or benzyl group. This protective group is cleaved using a procedure familiar to the skilled man and reductive amination (analogously to Example 639) or alkylation (analogously to method 34 or WO2004052857) are the final steps in this sequence.  
                                                                                                                UV max   MS (ESI)       #   R 3 ′   [nm]   (M + H) +                                     897                                     672               898                                 322   644               899                                 326   630               900                                 326   630               901                                 322   644               902                                 322   642               903                                 322   658               904                                 326   615               905                                 322   656               906                                 326   658               907                                 326   644               908                                 322   644               909                                 322   670               910                                 306   686               911                                 326   630               912                                     666               913                                 286, 322   656               914                                 286, 322   656               915                                 286, 318   670               916                                 286, 322   713               917                                 286, 322   670               918                                 286.3   713               919                                 286, 322   642               920                                 286, 322   672               921                                 286, 322   672               922                                 286, 322   644               923                                 286, 322   670               924                                 286, 322   700               925                                 286, 322   700               926                                 286, 322   670               927                                 326   713               928                                 322-326   700               929                                 322-326   644               930                                 322   658               931                                 322-326   713               932                                 322   700               933                                 322-326   644               934                                 322   658               935                                 322-326   714               936                                 322   714               937                                 322   662               938                                 322-326   662               939                                     676               940                                 322-326   680               941                                 286, 322   648               942                                 230, 286, 318   662               943                                 284, 324   668               944                                 282, 322   670               945                                 282, 322   696               946                                 228, 284, 322   642               947                                 226, 286, 322   672               948                                 286, 322   644               949                                 324, 284   644               950                                 285, 322   616               951                                 285, 325   630               952                                 285, 325   616                  
 
       EXAMPLES 953-958  
       [0544]     The following compounds are prepared by a method analogous to that described in Example 796:  
                                                                                                                UV max   MS (ESI)       #   R 3 ′   [nm]   (M + H) +                                     953                                 326, 286   658               954                                 325, 285   670               955                                 325, 285   670               956                                 325, 284   644               957                                 325, 284   658               958                                 325, 285   672                  
 
       EXAMPLE 959  
     2-(2-methoxy-4-(2-pyrrolidin-1-yl-ethylcarbamoyl)-phenylamino)-4-(2-(2-fluoro-ethyl)-1-ethyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine  
       [0545]    
       
                 
         
             
             
         
       
     
         [0546]     The racemic synthesis of the above-mentioned compound is carried out using by a method analogous to that described in Example 53. The corresponding aniline is described in method 22. The two enantiomers are isolated by preparative chromatography:  
         [0000]     column: 250×4.6 mm CHIRALPAKADH® 
         [0000]     eluant: 25 ethanol/75 methanol (v/v) (0.03% triethylamine is added to each solvent)  
         [0000]     flow rate: 0.5 ml/min  
         [0000]     temperature: 20° C.  
         [0547]     The enantiomer that elutes first is referred to as Enantiomer 1 and bears the symbol *1 in the chemical formula. 
 
 Enantiomer 1 
                         
 
 retention time: 9.96 min 
 
         [0548]     The enantiomer that elutes second is referred to as Enantiomer 2 and bears the symbol *2 in the chemical formula. 
 
 Enantiomer 2 
                         
 
 retention time: 12.60 min 
 
       EXAMPLES 960-976  
       [0549]     The following compounds are prepared by an analogous method to that described in Example 53. The corresponding aniline is described in method 22. The amine used to prepare the amide is commercially obtainable or is described in method 13.  
                                                                                                                        UV max   MS (ESI)       #   A   R 3 ′   [nm]   (M + H) +                                         960                                                               280, 320   654               961                                                               282, 318               962                                                               286, 322   680               963                                                               286, 326   630               964                                                               286, 326   644               965                                                               286, 326   630               966                                                               286, 326   659               967                                                               286, 326   630               968                                                               286, 322   644               969                                                               286, 326   644               970                                                               286, 326   644               971                                                               286, 326   714               972                                                               286, 322   632               973                                                               286, 326   646               974                                                               286, 326   660               975                                                               282, 326   685               976                                                               282, 326   659                  
 
       EXAMPLES 977-980  
       [0550]     The following compounds are prepared by an analogous method to that described in Example 53. The corresponding aniline is described in method 6. The amine used to prepare the amide is described in method 13.  
                                                                                                                        UV max   MS (ESI)       #   A   R 3 ′   [nm]   (M + H) +                                         977                                                               234, 282, 318   655               978                                                               226, 282, 318   655               979                                                               222, 282, 318   641               980                                                               230, 282, 671   671                  
 
       EXAMPLES 981-999  
       [0551]     The following compounds are prepared by an analogous method to that described in Example 53. The corresponding aniline is described in method 32. The amine used to prepare the amide is commercially obtainable or described in method 13.  
                                                                                                                        UV max   MS (ESI)       #   A   R 3 ′   [nm]   (M + H) +                                         981                                                               318   612               982                                                               318   583               983                                                               322   599               984                                                                   639               985                                                               286   706               986                                                               322   597               987                                                               318   679               988                                                               286   653               989                                                               322   611               990                                                               322   583               991                                                               318   625               992                                                               318   597               993                                                               318   598               994                                                               318   569               995                                                               322   585               996                                                               286   639               997                                                               318   626               998                                                               318   599               999                                                               318   318                  
 
       EXAMPLES 1000-1024  
       [0552]     The following compounds are prepared by an analogous method to that described in Example 53. The corresponding aniline is described in method 33. The amine used to prepare the amide is commercially obtainable or described in method 13 or 21.  
                                                                                                                        UV max   MS (ESI)       #   A   R 3 ′   [nm]   (M + H) +                                         1000                                                               282, 322   614               1001                                                               282, 322   841               1002                                                               282, 326   571               1003                                                               280, 322   655               1004                                                               280, 325   655               1005                                                               280, 322   669               1006                                                               280, 325   599               1007                                                               282, 327   613               1008                                                               280, 322   697               1009                                                               282, 325   627               1010                                                               283, 328   641               1011                                                               280, 325   585               1012                                                               280, 325   599               1013                                                               326, 283   585               1014                                                               282, 327   599               1015                                                               322-326   597               1016                                                               326   611               1017                                                               280, 325   585               1018                                                               280, 325   614               1019                                                               280, 325   585               1020                                                               280, 322   599               1021                                                               280, 325   641               1022                                                               280, 325   599               1023                                                               280, 325   585               1024                                                               280, 322   653                  
 
       EXAMPLES 1025-1032  
       [0553]     The following compounds are prepared by an analogous method to that described in Example 53. The corresponding aniline is described in method 10. The amine used to prepare the amide is commercially obtainable or described in method 13.  
                                                                                                                        UV max   MS (ESI)       #   A   R 3 ′   [nm]   (M + H) +                                         1025                                                               318   648               1026                                                               318   359               1027                                                               322   662               1028                                                               322   662               1029                                                               322   664               1030                                                               226, 318   678               1031                                                               226, 318   691               1032                                                               322   648                  
 
       EXAMPLES 1033-1035  
       [0554]     The following compounds are prepared by an analogous method to that described in Example 53. The corresponding aniline is described in method 2. The amine used to prepare the amide is described in method 13.  
                                                                                                                MS (ESI)           #   R 3 ′   (M + H) +     salt form                                   1033                                 701   base               1034                                 645   formate               1035                                 631   formate                  
 
       EXAMPLE 1036  
     2-(2-methoxy-4-(2-pyrrolidin-1-yl-ethylcarbamoyl)-phenalamino)-4-(2-(2-fluoro-ethyl)-1,1-dimethyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine  
       [0555]    
       
                 
         
             
             
         
       
     
         [0556]     The above-mentioned compound is prepared by a method analogous to that described in Example 53. The corresponding aniline is described in method 34. The amine used to prepare the amide is commercially obtainable. The substance is obtained as the dihydrochloride.  
         [0557]     UV max: 326, 286 nm  
         [0558]     MS (ESI): 630 (M+H) +   
         [0559]      1 H-NMR (400 MHz): 1.44-1.50 (m, 6H), 1.84-1.95 (m, 2H), 1.98-2.07 (m, 2H), 3.02-3.12 (m, 2H), 3.62-3.70 (m, 4H), 3.71-3.76 (m, 1H), 3.77-3.81 (m, 1H), 3.89 (s, 3H), 4.57-4.61 (m, 1H), 4.69-4.73 (m, 1H), 7.27-7.31 (m, 1H), 7.39-7.45 (m, 1H), 7.55-7.59 (m, 1H), 7.63-7.66 (m, 1H), 7.84-7.88 (m, 1H), 8.44-8.55 (m, 2H), 8.77-8.82 (m, 1H), 9.11-9.15 (m, 1H), 9.91-10.03 (m, 1H), 10.51-10.55 (m, 1H)  
       EXAMPLE 1037  
     2-(2-methoxy-4-[2-(4-methyl-piperazin-1-yl)-ethylcarbamoyl]-phenylamino)-4-(2-(2-fluoro-ethyl)-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-acetyl-pyrimidine  
       [0560]    
       
                 
         
             
             
         
       
     
         [0561]     50 mg (0.104 mmol) 2-(4-carboxy-2-methoxy-phenylamino)-4-(2-(2-fluoro-ethyl)-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-acetyl-pyrimidine (prepared by an analogous process to that described in Example 622 or 623) are dissolved in 0.5 ml of dimethylformamide and combined with 72 μl (0.520 mmol) and 34 mg (0.104 mmol) O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-tetrafluoroborate. After stirring for 20 min at 20° C., 23 mg (0.156 mmol) 2-(4-methylpiperazin-1-yl)-ethylamine are added. The reaction is completed after 2 h at 20° C. Then the solvent is eliminated in vacuo and the residue is purified by column chromatography. The carrier used is C18-RP-silica gel and a gradient is run through within 20 min which consists of 95% water and 5% acetonitrile at the starting point and consists of 5% water and 95% acetonitrile at the finishing point. 0.1% formic acid are added to both the water and to the acetonitrile. The suitable fractions are combined with 500 μl of a 1 M aqueous hydrochloric acid and freeze-dried. The product is obtained as the trihydrochloride.  
         [0562]     UV max: 326 nm  
         [0563]     MS (ESI): 605 (M+H) +   
         [0564]      1 H-NMR (500 MHz): 2.53-2.58 (m, 3H), 2.80-2.92 (m, 3H), 3.62-3.88 (m, 9H), 3.88-4.01 (m, 4H), 4.54 (s, 2H), 4.58-4.66 (m, 1H), 4.69-4.77 (m, 1H), 7.14-7.32 (m, 1H), 7.32-7.50 (m, 1H), 7.50-7.59 (m, 1H), 7.63-7.75 (m, 1H), 7.78-8.01 (m, 1H), 8.29-8.60 (m, 1H), 8.73-8.99 (m, 2H), 9.03-9.18 (m, 1H), 12.31-12.41 (m, 1H)  
       EXAMPLES 1038-1060  
       [0565]     The following compounds are prepared by an analogous method to that described in Example 1037. The aniline used is described in method 28.  
         [0566]     The amine used to prepare the amide is commercially obtainable or described in method 13.  
                                                                                                                        UV max   MS (ESI)       #   A   R 3 ′   [nm]   (M + H) +                                         1038                                                               326   660               1039                                                               326   646               1040                                                               328   576               1041                                                               318   672               1042                                                               326   605               1043                                                               330   590               1044                                                               318   663               1045                                                               330   604               1046                                                               326   686               1047                                                               326   604               1048                                                               330   590               1049                                                               326   713               1050                                                               330   590               1051                                                               250   614               1052                                                               334-338   600               1053                                                               334-338   614               1054                                                               338   600               1055                                                               338   670               1056                                                               334   696               1057                                                               330   622               1058                                                               327   340               1059                                                               330   608               1060                                                               330   632                  
 
       EXAMPLES 1061-1069  
       [0567]     The following compounds are prepared by an analogous method to that described in Example 622 or 623. The corresponding aniline is described in method 28.  
                                                                                                                        UV max   MS (ESI)       #   A   R 3 ′   [nm]   (M + H) +                                         1061                                                               254, 316   552               1062                                                               254, 314   548               1063                                                               250   598               1064                                                               254, 318   588               1065                                                               250   518               1066                                                               252, 318   606               1067                                                               250, 310   566               1068                                                               254, 318   552               1069                                                               262; 314-318   566                  
 
       EXAMPLES 1070-1071  
       [0568]     The following compounds are prepared by an analogous method to that described in Example 622 or 623 and 53. The corresponding aniline is described in method 28. The amine used to prepare the amide is commercially obtainable or described in method 13.  
                                                                                                                        UV max   MS (ESI)       #   A   R 3 ′   [nm]   (M + H) +                                         1070                                                               330   608               1071                                                               330   678                  
 
       EXAMPLES 1072-1085  
       [0569]     The following compounds are prepared by an analogous method to that described in Example 1037. The corresponding aniline is described in method 28. The amine used to prepare the amide is commercially obtainable or described in method 13.  
                                                                                                                        UV                       max   MS (ESI)       #   Z   R 3 ′   [nm]   (M + H) +                                         1072                                                               285, 320   674               1073                                                               326   663               1074                                                               306   596               1075                                                               326   593               1076                                                               262   596               1077                                                               326   593               1078                                                               318   652               1079                                                               325   582               1080                                                               319   582               1081                                                               302   666               1082                                                               322   626               1083                                                               318   626               1084                                                               286, 318   612               1085                                                               280, 325   572                  
 
 Biological Properties 
 
         [0570]     As demonstrated by DNA staining followed by FACS analysis, the inhibition of proliferation brought about by the compounds according to the invention is mediated above all by the arrest of the cells in the G2/M phase of the cell cycle. The cells arrest, depending on the type of cell used, for a specific length of time in this cell cycle phase before programmed cell death is initiated. An arrest in the G2/M phase of the cell cycle may be initiated e.g. by the inhibition of specific cell cycle kinases. On the basis of their biological properties the compounds of general formula I according to the invention, their isomers and the physiologically acceptable salts thereof are suitable for treating diseases characterised by excessive or anomalous cell proliferation.  
         [0571]     Such diseases include for example: viral infections (e.g. HIV and Kaposi&#39;s sarcoma); inflammatory and autoimmune diseases (e.g. colitis, arthritis, Alzheimer&#39;s disease, glomerulonephritis and wound healing); bacterial, fungal and/or parasitic infections; leukaemias, lymphomas and solid tmours; skin diseases (e.g. psoriasis); bone diseases; cardiovascular diseases (e.g. restenosis and hypertrophy). They are also useful for protecting proliferating cells (e.g. hair, intestinal, blood and progenitor cells) from DNA damage caused by radiation, UV treatment and/or cytostatic treatment (Davis et al., 2001). The new compounds may be used for the prevention, short- or long-term treatment of the above-mentioned diseases, also in combination with other active substances used for the same indications, e.g. cytostatics, steroids or antibodies.  
         [0572]     The activity of the compounds according to the invention on various kinases, for example on serine-threonine kinase PLK-1, was determined by in vitro kinase assays with recombinantly produced protein. In this assay the compounds exhibit a good to very good effect on PLK1, i.e. for example an IC50 value of less than 1 μmol/L, usually less than 0.1 μmol/L.  
         [0000]     Example PLK-1 Kinaseassay  
         [0573]     Recombinant human PLK1 enzyme linked to GST at its N-terminal end is isolated from insect cells infected with baculovirus (Sf21). Purification is carried out by affinity chromatography on glutathione sepharose columns.  
         [0574]     4×10 7  Sf21 cells ( Spodoptera frugiperda ) in 200 ml of Sf-900 II Serum free insect cell medium (Life Technologies) are seeded in a spinner flask. After 72 hours&#39; incubation at 27° C. and 70 rpm, 1×10 8  Sf21 cells are seeded in a total of 180 ml medium in a new spinner flask. After another 24 hours, 20 ml of recombinant Baculovirus stock suspension are added and the cells are cultivated for 72 hours at 27° C. at 70 rpm. 3 hours before harvesting, okadaic acid is added (Calbiochem, final concentration 0.1 μM) and the suspension is incubated further. The cell number is determined, the cells are removed by centrifuging (5 minutes, 4° C., 800 rpm) and washed 1× with PBS (8 g NaCl/l, 0.2 g KCl/l, 1.44 g Na 2 HPO 4 /l, 0.24 g KH 2 PO 4 /l). After centrifuging again the pellet is flash-frozen in liquid nitrogen. Then the pellet is quickly thawed and resuspended in ice-cold lysing buffer (50 mM HEPES pH 7.5, 10 mM MgCl 2 , 1 mM DTT, 5 μg/ml leupeptin, 5 μg/ml aprotinin, 100 μM NaF, 100 μM PMSF, 10 mM β-glycerolphosphate, 0.1 mM Na 3 VO 4 , 30 mM 4-nitrophenylphosphate) to give 1×10 8  cells/17.5 ml. The cells are lysed for 30 minutes on ice. After removal of the cell debris by centrifugation (4000 rpm, 5 minutes) the clear supernatant is combined with glutathione sepharose beads (1 ml resuspended and washed beads per 50 ml of supernatant) and the mixture is incubated for 30 minutes at 4° C. on a rotating board. Then the beads are washed with lysing buffer and the recombinant protein is eluted from the beads with 1 ml eluting buffer/ml resuspended beads (eluting buffer: 100 mM Tris/HCl pH=8.0, 120 mM-NaCl, 20 mM reduced glutathione-(Sigma-G-4251), 10 mM MgCl 2 , 1 mM DTT). The protein concentration is determined by Bradford Assay.  
         [0000]     Assay  
         [0575]     The following components are combined in a well of a 96-well round-bottomed dish (Greiner bio-one, PS Microtitre plate No. 650101):  
         [0576]     10 μl of the compound to be tested in variable concentrations (e.g. beginning at 300 μM, and dilution to 1:3) in 6% DMSO, 0.5 mg/ml casein (Sigma C-5890), 60 mM β-glycerophosphate, 25 mM MOPS pH=7.0, 5 mM EGTA, 15 mM MgCl 2 , 1 mM DTT  
         [0577]     20 μl substrate solution (25 mM MOPS pH=7.0, 15 mM MgCl 2 , 1 mM DTT, 2.5 mM EGTA, 30 mM β-glycerophosphate, 0.25 mg/ml casein)  
         [0578]     20 μl enzyme dilution (1:100 dilution of the enzyme stock in 25 mM MOPS pH=7.0, 15 mM MgCl 2 , 1 mM DTT)  
         [0579]     10 μl ATP solution (45 μM ATP with 1.11×10 6  Bq/ml gamma-P33-ATP).  
         [0580]     The reaction is started by adding the ATP solution and continued for 45 minutes at 30° C. with gentle shaking (650 rpm on an IKA Schüttler MTS2). The reaction is stopped by the addition of 125 μl of ice-cold 5% TCA per well and incubated on ice for at least 30 minutes. The precipitate is transferred by harvesting onto filter plates (96-well microtitre filter plate: UniFilter-96, GF/B; Packard; No. 6005177), then washed four times with 1% TCA and dried at 60° C. After the addition of 35 μl scintillation solution (Ready-Safe; Beckmann) per well the plate is sealed shut with sealing tape and the amount of P33 precipitated is measured with the Wallac Betacounter. The measured data are evaluated using the standard Graphpad software (Levenburg-Marquard Algorhythmus).  
         [0581]     The anti-proliferative activity of the compounds according to the invention is determined in the cytotoxicity test on cultivated human tumour cells and/or in a FACS analysis, for example on HeLa S3 cells. In both test methods the compounds exhibit good to very good activity, i.e. for example an EC50 value in the HeLa S3 cytotoxicity test of less than 5 μmol/L, generally less than 1 μmol/L.  
         [0000]     Measurement of Cytotoxicity on Cultivated Human Tumour Cells  
         [0582]     To measure cytotoxicity on cultivated human tumour cells, cells of cervical carcinoma tumour cell line HeLa S3 (obtained from American Type Culture Collection (ATCC)) are cultivated in Ham&#39;s F12 Medium (Life Technologies) and 10% foetal calf serum (Life Technologies) and harvested in the log growth phase. Then the HeLa S3 cells are placed in 96-well plates (Costar) at a density of 1000 cells per well and incubated overnight in an incubator (at 37° C. and 5% CO2), while on each plate 6 wells are filled with medium alone (3 wells as the medium control, 3 wells for incubation with reduced AlamarBlue reagent). The active substances are added to the cells in various concentrations (dissolved in DMSO; DMSO final concentration: 0.1%) (in each case as a triple measurement). After 72 hours incubation 20 μl AlamarBlue reagent (AccuMed International) are added to each well, and the cells are incubated for a further 5-7 hours. As a control, 20 μl reduced AlamarBlue reagent is added to each of 3 wells (AlamarBlue reagent, which is autoclaved for 30 min). After incubation the colour change of the AlamarBlue reagent in the individual wells is determined in a Perkin Elmer fluorescence spectrophotometer (excitation 530 nm, emission 590 nm, slits 15, integrate time 0.1). The amount of AlamarBlue reagent reacted represents the metabolic activity of the cells. The relative cell activity is calculated as a percentage of the control (HeLa S3 cells without inhibitor) and the active substance concentration which inhibits the cell activity by 50% (IC50) is derived. The values are calculated from the average of three individual measurements—with correction of the dummy value (medium control).  
         [0000]     FACS Analysis  
         [0583]     Propidium iodide (PI) binds stoichiometrically to double-stranded DNA, and is thus suitable for determining the proportion of cells in the G1, S, and G2/M phase of the cell cycle on the basis of the cellular DNA content. Cells in the G0 and G1 phase have a diploid DNA content (2N), whereas cells in the G2 or mitosis phase have a 4N DNA content.  
         [0584]     For PI staining, for example, ×10 6  HeLa S3 cells are seeded onto a 75 cm2 cell culture flask, and after 24 h either 0.1% DMSO is added as control or the substance is added in various concentrations (in 0.1% DMSO). The cells are incubated for 24 h with the substance or with DMSO before the cells are washed 2× with PBS and then detached with trypsin/EDTA. The cells are centrifuged (1000 rpm, 5 min, 4° C.), and the cell pellet is washed 2× with PBS before the cells are resuspended in 0.1 ml PBS. Then the cells are fixed with 80% ethanol for 16 hours at 4° C. or alternatively for 2 hours at −20° C. The fixed cells are centrifuged (1000 rpm, 5 min, 4° C.), washed with PBS and then centrifuged again. The cell pellet is resuspended in 2 ml 0.25% Triton X-100 in PBS, and incubated on ice for 5 min before 5 ml PBS are added and the mixture is centrifuged again. The cell pellet is resuspended in 350 μl PI staining solution (0.1 mg/ml RNase A (Sigma, No. R-4875), 10 μg/ml prodium iodide (Sigma, No. P-4864) in 1×PBS). The cells are incubated for 20 min in the dark with the staining buffer before being transferred into sample measuring containers for the FACS scan. The DNA measurement is carried out in a Becton Dickinson FACS Analyzer, with an argon laser (500 mW, emission 488 nm), and the DNA Cell Quest Programme (BD). The logarithmic PI fluorescence is determined with a band-pass filter (BP 585/42). The cell populations in the individual cell cycle phases are quantified using the ModFit LT Programme made by Becton Dickinson.  
         [0585]     The compounds according to the invention are also tested accordingly for other tumour cells. For example, these compounds are effective on carcinomas of all kinds of tissue (e.g. breast (MCF7); colon (HCT116), head and neck (FaDu), lung (NCI-H460), pancreas (BxPC-3), prostate (DU145)), sarcomas (e.g. SK-UT-1B), leukaemias and lymphomas (e.g. HL-60; Jurkat, THP-1) and other tumours (e.g. melanomas (BRO), gliomas (U-87MG)) and could be used for such indications. This is evidence of the broad applicability of the compounds according to the invention for the treatment of all kinds of tumour types. The compounds of general formula (I) may be used on their own or in conjunction with other active substances according to the invention, optionally also in conjunction with other pharmacologically active substances.  
         [0586]     Suitable preparations include for example tablets, capsules, suppositories, solutions, particularly solutions for injection (s.c., i.v., i.m.) and infussion, elixirs, emulsions or dispersible powders. The content of the pharmaceutically active compound(s) should be in the range from 0.1 to 90 wt.-%, preferably 0.5 to 50 wt.-% of the composition as a whole, i.e. in amounts which are sufficient to achieve the dosage range specified below. The doses specified may, if necessary, be given several times a day.  
         [0587]     Suitable tablets may be obtained, for example, by mixing the active substance(s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets may also comprise several layers.  
         [0588]     Coated tablets may be prepared accordingly by coating cores produced analogously to the tablets with substances normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or prevent incompatibilities the core may also consist of a number of layers. Similarly the tablet coating may consist of a number or layers to achieve delayed release, possibly using the excipients mentioned above for the tablets.  
         [0589]     Syrups or elixirs containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. a flavouring such as vanillin or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.  
         [0590]     Solutions for injection and infusion are prepared in the usual way, e.g. with the addition of isotonic agents, preservatives such as p-hydroxybenzoates, or stabilisers such as alkali metal salts of ethylenediamine tetraacetic acid, optionally using emulsifiers and/or dispersants, whilst if water is used as the diluent, for example, organic solvents may optionally be used as solvating agents or dissolving-aids, and transferred into injection vials or ampoules or infusion bottles.  
         [0591]     Capsules containing one or more active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatine capsules.  
         [0000]     Suitable suppositories may be made for example by mixing with carriers provided for this purpose, such as neutral fats or polyethyleneglycol or the derivatives thereof.  
         [0592]     Excipients which may be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. groundnut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk), synthetic mineral powders (e.g. highly dispersed silicic acid and silicates), sugars (e.g. cane sugar, lactose and glucose) emulsifiers (e.g. lignin, spent sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulphate).  
         [0593]     The preparations are administered by the usual methods, preferably by oral or transdermal route, most preferably by oral route. For oral administration the tablets may, of course contain, apart from the abovementioned carriers, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatine and the like. Moreover, lubricants such as magnesium stearate, sodium lauryl sulphate and talc may be used at the same time for the tabletting process. In the case of aqueous suspensions the active substances may be combined with various flavour enhancers or colourings in addition to the excipients mentioned above.  
         [0594]     For parenteral use, solutions of the active substances with suitable liquid carriers may be used.  
         [0000]     The dosage for intravenous use is from 1-1000 mg per hour, preferably between 5 and 500 mg per hour.  
         [0595]     However, it may sometimes be necessary to depart from the amounts specified, depending on the body weight, the route of administration, the individual response to the drug, the nature of its formulation and the time or interval over which the drug is administered. Thus, in some cases it may be sufficient to use less than the minimum dose given above, whereas in other cases the upper limit may have to be exceeded. When administering large amounts it may be advisable to divide them up into a number of smaller doses spread over the day.  
         [0596]     The formulation examples which follow illustrate the present invention without restricting its scope:  
         [0597]     Examples of Pharmaceutical Formulations  
                                                   A) Tablets   per tablet                           active substance   100 mg           lactose   140 mg           corn starch   240 mg           polyvinylpyrrolidone    15 mg           magnesium stearate    5 mg               500 mg                      
 
         [0598]     The finely ground active substance, lactose and some of the corn starch are mixed together. The mixture is screened, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet-granulated and dried. The granules, the remaining corn starch and the magnesium stearate are screened and mixed together. The mixture is compressed to produce tablets of suitable shape and size.  
                                                   B) Tablets   per tablet                           active substance   80 mg           lactose   55 mg           corn starch   190 mg            microcrystalline cellulose   35 mg           polyvinylpyrrolidone   15 mg           sodium-carboxymethyl starch   23 mg           magnesium stearate    2 mg               400 mg                       
 
         [0599]     The finely ground active substance, some of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is screened and worked with the remaining corn starch and water to form a granulate which is dried and screened. The sodiumcarboxymethyl starch and the magnesium stearate are added and mixed in and the mixture is compressed to form tablets of a suitable size.  
                                                                 C) Ampoule solution                                        active substance   50   mg           sodium chloride   50   mg           water for inj.   5   ml                      
 
         [0600]     The active substance is dissolved in water at its own pH or optionally at pH 5.5 to 6.5 and sodium chloride is added to make it isotonic. The solution obtained is filtered free from pyrogens and the filtrate is transferred under aseptic conditions into ampoules which are then sterilised and sealed by fusion. The ampoules contain 5 mg, 25 mg and 50 mg of active substance.