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:
RELATED APPLICATIONS 
       [0001]    This application is a divisional of U.S. application Ser. No. 11/206,703, filed on Aug. 17, 2005. 
     
    
       [0002]    The present invention relates to new pyrimidines of general formula (1), 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    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 
       [0003]    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. 
         [0004]    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&#39;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). 
         [0005]    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). 
         [0006]    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). 
         [0007]    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. 
         [0008]    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. 
         [0009]    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. 
         [0010]    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. 
         [0011]    International Patent Application WO 03/063794 describes the use of 2,4-pyrimidinediamines as inhibitors of the IgE and/or IgG receptor signal cascade. 
         [0012]    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. 
         [0013]    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. 
         [0014]    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 
       [0015]    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. 
         [0016]    The present invention relates to compounds of general formula (1) 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    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)   
 
         [0000]    
       
                 
         
             
             
         
       
       
         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 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  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 , —NR4C(═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), 
       
     
         [0000]    
       
                 
         
             
             
         
       
       
         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 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 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, enantiomers, diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
 
       
     
         [0036]    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. 
         [0037]    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),   
 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    and the other groups are as hereinbefore defined. 
         [0041]    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.
   
 
         [0044]    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.
   
 
         [0046]    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.
   
       
 
         [0049]    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. 
         [0050]    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.
   
 
         [0052]    In one aspect the invention relates to compounds of general formula (1), or the pharmaceutically active salts thereof, as pharmaceutical compositions. 
         [0053]    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. 
         [0054]    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. 
         [0055]    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. 
         [0056]    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. 
         [0057]    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. 
         [0058]    In another aspect the invention relates to a pharmaceutical preparation containing at least one compound of general formula (1) 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    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)   
 
         [0000]    
       
                 
         
             
             
         
       
       
         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 , —NR4C(═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 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), 
       
     
         [0000]    
       
                 
         
             
             
         
       
       
         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)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 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 
       [0077]    As used herein, the following definitions apply, unless stated otherwise. 
         [0078]    By alkyl substituents are meant in each case saturated, straight-chain or branched aliphatic hydrocarbon groups (alkyl group). 
         [0079]    The alkenyl substituents are in each case straight-chain or branched, unsaturated alkyl groups which have at least one double bond. 
         [0080]    By alkynyl substituents are meant in each case straight-chain or branched, unsaturated alkyl groups which have at least one triple bond. 
         [0081]    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 . 
         [0082]    Halogen relates to fluorine, chlorine, bromine and/or iodine atoms. 
         [0083]    By pseudohalogen are meant the following groups: —OCN, —SCN, —CF 3  and —CN. 
         [0084]    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. 
         [0085]    Aryl relates to monocyclic or bicyclic rings with 6-12 carbon atoms such as for example phenyl and naphthyl. 
         [0086]    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. 
         [0087]    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. 
         [0088]    The Examples that follow illustrate the present invention without restricting its scope: 
       Preparation of the Compounds According to the Invention: 
       [0089]    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. 
       Method A 
     Step 1A 
       [0090]    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. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0091]    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. 
       Step 2A 
       [0092]    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. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0093]    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. 
       Method B 
     Step 1B 
       [0094]    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. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0095]    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. 
         [0096]    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. 
         [0097]    The combined organic extracts are dried and the solvent is distilled off. The residue is purified by chromatography or repeated crystallisation. 
       Step 2B 
       [0098]    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. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0099]    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. 
       Step 3B 
       [0100]    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. 
         [0101]    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. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0102]    1 equivalent of the compound VIII, 1 to 1.5 equivalents 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, 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. 
       Method C 
     Step 1C 
       [0103]    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. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0104]    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. 
       Step 2C 
       [0105]    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. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0106]    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. 
       Chromatography: 
       [0107]    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. 
         [0108]    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. 
       Nuclear Magnetic Resonance (NMR) Spectroscopy: 
       [0109]    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. 
         [0110]    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. 
       Mass Spectroscopy/UV Spectrometer: 
       [0111]    These data are generated using an HPLC-MS apparatus (high performance liquid chromatography with mass detector) made by Agilent. 
         [0112]    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). 
       Method 1 
     2-(2-methoxy-4-propylcarbamoyl-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine 
       [0113]    
       
                 
         
             
             
         
       
     
         [0114]    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). 
         [0115]    Yield: 2.30 g (5.9 mmol; 27%) 
         [0116]      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) 
       Method 2 
     7-amino-2,3-dihydro-isoindol-1-one 
       [0117]    
       
                 
         
             
             
         
       
     
       a) 7-nitro-2,3-dihydro-isoindol-1-one 
       [0118]    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. 
         [0119]    Yield: 960 mg (5.389 mmol, 99%) 
         [0120]    MS-ESI+: m/z=179 [M+H] +   
       b) 7-amino-2,3-dihydro-isoindol-1-one 
       [0121]    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. 
         [0122]    Yield: 734 mg (4.958 mmol, 92%) 
         [0123]    MS-ESI+: m/z=149 [M+H] +   
         [0124]    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: 
         [0000]    
       
         
               
               
               
             
           
               
                   
                   
               
               
                   
                   
                 MS (ESI) 
               
               
                   
                   
                 (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 
       [0125]    
       
                 
         
             
             
         
       
     
       a) Ethyl (4-amino-3-oxo-3H-isobenzofuran-1-ylidene)-acetate 
       [0126]    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). 
         [0127]    Yield: 221 mg (0.95 mmol, 31%) 
         [0128]    MS-ESI+: m/z=234 [M+H]+ 
       b) Ethyl (4-amino-3-oxo-1,3-dihydro-isobenzofuran-1-yl)-acetate 
       [0129]    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. 
         [0130]    Yield: 116 mg (0.49 mmol, 97%) 
         [0131]    MS (ESI): m/z=236 (M+H) +   
         [0132]      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) 
       Method 4 
     5-amino-3H-quinazolin-4-one 
       [0133]    
       
                 
         
             
             
         
       
     
       a) 2,6-diaminobenzamide 
       [0134]    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. 
         [0135]    Yield: 900 mg (5.958 mmol; 23%) 
         [0136]    MS (ESI): 152 (M+H) +   
       b) 5-amino-3H-quinazolin-4-one 
       [0137]    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. 
         [0138]    Yield: 782 mg (4.852 mmol; 81%) 
         [0139]    MS (ESI): 162 (M+H) +   
       Method 5 
     9-amino-2,3,4,5-tetrahydro-2-benzazepin-1-one 
       [0140]    
       
                 
         
             
             
         
       
     
         [0141]    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. 
         [0142]    Yield: 28 mg (0.160 mmol, 23%) 
         [0143]    MS (ESI): m/z=177 (M+H) +   
       Method 6 
     4-amino-1-methyl-1.2-dihydro-indazol-3-one 
       [0144]    
       
                 
         
             
             
         
       
     
       a) 4-nitro-1,2-dihydro-indazol-3-one 
       [0145]    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. 
         [0146]    Yield: 1.7 g (9.5 mmol, 35%) 
         [0147]    MS (ESI): m/z=180 (M+H) +   
       b) 1-methyl-4-nitro-1,2-dihydro-indazol-3-one 
       [0148]    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% acetonitrileat the finishing point. 
         [0149]    Yield: 144 mg (0.7 mmol, 44%) 
         [0150]    MS (ESI): m/z=194 (M+H) +   
         [0151]      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 
       [0152]    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. 
         [0153]    Yield: 33 mg (0.2 mmol, 28%) 
         [0154]    MS (ESI): m/z=164 (M+H) +   
         [0155]    4-amino-1,2-dihydro-indazol-3-one and the following compounds are prepared analogously to this method. 
         [0000]    
       
         
               
               
               
             
           
               
                   
                   
               
               
                   
                   
                 MS (ESI) 
               
               
                   
                   
                 (M + H) +   
               
               
                   
                   
               
             
             
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 178 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 178 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 194 
               
               
                   
                   
               
             
          
         
       
     
       Method 7 
     8-amino-4-methyl-3,4-dihydro-2H-isoquinolin-1-one 
       [0156]    
       
                 
         
             
             
         
       
     
       a) Methyl 2-(cyanomethyl-2-methyl)-6-nitro-benzoate 
       [0157]    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. 
         [0158]    Yield: 289 mg (1.2 mmol, 68%) 
         [0159]    MS (ESI): 233 (M−H) −   
       b) 8-amino-4-methyl-3,4-dihydro-2H-isoquinolin-1-one 
       [0160]    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. 
         [0161]    Yield: 170 mg (0.8 mmol, 46%) 
         [0162]    MS (ESI): 177 (M+H) +   
         [0163]    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. 
         [0000]    
       
         
               
               
               
             
           
               
                   
                   
               
               
                   
                   
                 MS (ESI) 
               
               
                   
                   
                 (M + H) +   
               
               
                   
                   
               
             
             
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 221 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 205 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 253 
               
               
                   
                   
               
             
          
         
       
     
       Method 8 
     7-amino-indan-1-one 
       [0164]    
       
                 
         
             
             
         
       
     
       a) indan-4-ylamine 
       [0165]    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). 
         [0166]    Yield: 3.81 g (28.6 mmol, 12%) 
         [0167]    MS (ESI): 134 (M+H) +   
         [0168]      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 
       [0169]    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). 
         [0170]    Yield: 152 mg (0.9 mmol, 51%) 
         [0171]    MS (ESI): 176 (M+H) +   
         [0172]      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 
       [0173]    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). 
         [0174]    Yield: 95 mg (0.500 mmol, 60%) 
         [0175]    MS (ESI): 190 (M+H) +   
       d) 7-amino-indan-1-on 
       [0176]    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. 
         [0177]    Yield: 388 mg (2.6 mmol, 100%) 
         [0178]    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. 
       Method 9 
     N-(7-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-acetamide 
       [0179]    
       
                 
         
             
             
         
       
     
       a) 2-benzyloxy-N-(7-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-acetamide 
       [0180]    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). 
         [0181]    Yield: 910 mg (2.7 mmol, 59%) 
       b) N-(7-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-acetamide 
       [0182]    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). 
         [0183]    Yield: 210 mg (0.1 mmol, 41%) 
         [0184]    MS (ESI): 222 (M+H) +   
       Method 10 
     6-amino-2-ethyl-3,4-dihydro-2H-benzo[F/1,4]oxazepin-5-one 
       [0185]    
       
                 
         
             
             
         
       
     
       a) 2-amino-6-(1-aminomethyl-propoxy)-benzonitrile 
       [0186]    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. 
         [0187]    Yield: 1.15 g (5.6 mmol, 38%) 
         [0188]    MS (ESI): 206 (M+H) +   
       b) 2-amino-6-(1-aminomethyl-propoxy)-benzoic Acid 
       [0189]    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. 
         [0190]    Yield: 262 mg (1.2 mmol, 21%) 
         [0191]    MS (ESI): 225 (M+H) +   
       c) 6-amino-2-ethyl-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one 
       [0192]    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. 
         [0193]    Yield: 50 mg (0.2 mmol, 21%) 
         [0194]    MS (ESI): 207 (M+H) +   
         [0195]    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. 
         [0000]    
       
         
               
               
               
             
           
               
                   
                   
               
               
                   
                   
                 MS (ESI) 
               
               
                   
                   
                 (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 
       [0196]    
       
                 
         
             
             
         
       
     
       a) Methyl 2-(2-amino-6-nitro-benzoylamino)-3-phenyl-propionate 
       [0197]    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). 
         [0198]    Yield: 1.04 g (3.03 mmol, 65%) 
         [0199]    MS (ESI): 344 (M+H) +   
       b) 2-(2-amino-6-nitro-benzoylamino)-3-phenyl-propionic Acid 
       [0200]    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. 
         [0201]    Yield: 636 mg (1.9 mmol, 64%) 
         [0202]    MS (ESI): 329 (M+H) +   
         [0203]      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 
       [0204]    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. 
         [0205]    Yield: 88 mg (0.29 mmol, 24%) 
         [0206]    MS (ESI): 300 (M+H) +   
       d) 6-amino-3-benzyl-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione 
       [0207]    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. 
         [0208]    Yield: 22 mg (0.08 mmol, 27%) 
         [0209]    MS (ESI): 282 (M+H) +   
         [0210]    The following compounds are prepared analogously to method 11. 
         [0000]    
       
         
               
               
               
             
           
               
                   
                   
               
               
                   
                   
                 MS (ESI) 
               
               
                   
                   
                 (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 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 248 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 316/318 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 250 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 321 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 265 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 321 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 265 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 346 
               
               
                   
                   
               
             
          
         
       
     
       Method 12 
     2-(4-carboxy-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine 
       [0211]    
       
                 
         
             
             
         
       
     
         [0212]    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. 
         [0213]    Yield: 330 mg (0.95 mmol, 2%) 
         [0214]    MS (ESI): 348 (M+H) +   
         [0215]      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) 
       Method 13 
     4-(4-amino-cyclohexyl)-morpholine 
       [0216]    
       
                 
         
             
             
         
       
     
       a) dibenzyl-(4-morpholino-4-yl-cyclohexyl)-amine 
       [0217]    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. 
         [0218]    Yield: 6.6 g (18 mmol, 60%) cis-isomer 2 g (5.4 mmol, 18%) trans-isomer. 
       b) trans-4-morpholino-4-yl-cyclohexylamine 
       [0219]    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. 
         [0220]    Yield: 3.9 g (15.2 mmol, 93%) 
         [0221]    melting point: 312° C. 
         [0222]    The following compounds are prepared analogously to Method 13: 
         [0000]    
       
         
               
               
             
               
               
             
           
               
                   
                   
               
               
                   
                 MS 
               
               
                   
                 (ESI) 
               
               
                   
                 (M + H) +   
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 169 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 211 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 213 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 238 
               
               
                   
               
             
          
         
       
     
       Method 14 
     2-(4-carboxy-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine 
       [0223]    
       
                 
         
             
             
         
       
     
       a) 2-(4-benzyloxycarbonyl-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine 
       [0224]    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. 
         [0225]    Yield: 1.03 g (2.360 mmol; 26%) 
         [0226]    UV max: 320 nm 
         [0227]    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 
       [0228]    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. 
         [0229]    Yield: 0.76 g (2.192 mmol; 96%) 
         [0230]    UV max: 288 nm 
         [0231]    MS (ESI): 346/348 (M−H) − Cl distribution 
         [0232]    The following compounds are prepared analogously to this process:
   2-(4-carboxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine   
 
         [0234]    MS (ESI): 316/318 (M−H) − Cl distribution
   2-[4-(4-benzyloxycarbonyl-piperazin-1-yl)-phenylamino]-4-chloro-5-trifluoromethyl-pyrimidine   
 
         [0236]    MS (ESI): 492/494 (M+H) − Cl distribution
   2-[4-(4-benzyloxycarbonyl-piperazin-1-yl)-2-methoxy-phenylamino]-4-chloro-5-trifluoromethyl-pyrimidine   
 
         [0238]    MS (ESI): 522/524 (M+H) + Cl distribution 
       Method 15 
     3-pyrrolidin-1-yl-cyclobutylamine 
       [0239]    
       
                 
         
             
             
         
       
     
       a) Tert. Butyl (3-benzyloxy-cyclobutyl)-carbamate 
       [0240]    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). 
         [0241]    Yield: 5.98 g (22 mmol; 48%) 
         [0242]    MS (ESI): 178 (M+H-boc) + Boc cleaving in the mass detector 
       b) Tert. Butyl (3-hydroxy-cyclobutyl)-carbamate 
       [0243]    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. 
         [0244]    Yield: 1.53 g (8.2 mmol; 82%) 
         [0245]    MS (ESI): 188 (M+H) +   
       c) Tert. Butyl (3-tosyl-cyclobutyl)-carbamate 
       [0246]    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. 
         [0247]    Yield: 28.30 g (83 mmol; 83%) 
         [0248]    MS (ESI): 342 (M+H) +   
         [0249]    d) Tert. Butyl (3-pyrrolidine-cyclobutyl)-carbamate 
         [0250]    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. 
         [0251]    The substances that elute first are designated as follows: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0252]    Yield product A: 1 g (4.17 mmol; 4%) 
         [0253]    RF value (silica gel; dichloromethane:methanol:conc. aqueous ammonia=90:9:1)=0.62 
         [0254]    The substances that elute second are designated as follows: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0255]    Yield product C, 2.00 g (8.33 mmol; 8%) 
         [0256]    RF value (silica gel; dichloromethane:methanol:conc. aqueous ammonia=90:9:1)=0.53 
       e) (*1′,*1″)-3-pyrrolidin-1-yl-cyclobutylamine 
       [0257]    
       
                 
         
             
             
         
       
     
         [0258]    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. 
         [0259]    Yield: 0.43 g (2.786 mmol; 67%) 
         [0260]    MS (ESI): 141 (M+H) +   
         [0261]    The following compounds are prepared analogously to this process: 
         [0000]    
       
         
               
               
             
               
               
               
             
           
               
                   
                   
               
               
                   
                 MS 
               
               
                   
                 (ESI) 
               
               
                   
                 (M + H) +   
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 170 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 210 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 184 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 224 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 171 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 212 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 143 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 198 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 196 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 194 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 183 
               
               
                   
                   
               
             
          
         
       
     
       (*2′,*2″)-3-pyrrolidin-1-yl-cyclobutylamine 
       [0262]    
       
                 
         
             
             
         
       
     
         [0263]    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. 
         [0264]    Yield: 0.43 g (3.09 mmol; 74%) 
         [0265]    MS (ESI): 141 (M+H) +   
         [0266]    The following compounds are prepared analogously to this method: 
         [0000]    
       
         
               
               
             
               
               
               
             
           
               
                   
                   
               
               
                   
                 MS 
               
               
                   
                 (ESI) 
               
               
                   
                 (M + H) +   
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 155 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 157 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 171 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 184 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 170 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 210 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 253 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 224 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 183 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 212 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 143 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 141 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 198 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 251 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 194 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 196 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 171 
               
               
                   
                   
               
             
          
         
       
     
       Method 16 
     2-(4-carboxy-2-bromo-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine 
       [0267]    
       
                 
         
             
             
         
       
     
         [0268]    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 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 is added in each case to both the water and to the acetonitrile. 
         [0269]    Yield: 0.57 g (1.44 mmol; 46%) 
         [0270]    MS (ESI): 396/398 (M−H) + Cl/Br distribution 
       Method 17 
     5-amino-3-(2-fluoro-ethyl)-3H-quinazolin-4-one 
       [0271]    
       
                 
         
             
             
         
       
     
         [0272]    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. 
         [0273]    Yield: 67 mg (0.323 mmol; 10%) 
         [0274]    MS (ESI): 208 (M+H) +   
       Method 18 
     8-amino-2-(2-fluoro-ethyl)-3,4-dihydro-2H-isoquinolin-1-one 
       [0275]    
       
                 
         
             
             
         
       
     
       a) 8-dibenzylamino-3,4-dihydro-2H-isoquinolin-1-one 
       [0276]    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. 
         [0277]    Yield: 1.670 g (4.877 mmol; 54%) 
         [0278]    MS (ESI): 343 (M+H) +   
       b) 8-dibenzylamino-2-(2-fluoro-ethyl)-3,4-dihydro-2H-isoquinolin-1-one 
       [0279]    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. 
         [0280]    Yield: 0.83 g (2.136 mmol; 69%) 
         [0281]    MS (ESI): 389 (M+H) +   
       c) 8-amino-2-(2-fluoro-ethyl)-3,4-dihydro-2H-isoquinolin-1-one 
       [0282]    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. 
         [0283]    Yield: 0.403 g (1.935 mmol; 91%) 
         [0284]    MS (ESI): 209 (M+H) +   
         [0285]    The following compounds are prepared analogously to this process: 
         [0000]    
       
         
               
               
             
               
               
               
             
           
               
                   
                   
               
               
                   
                 MS (ESI) 
               
               
                   
                 (M + H) +   
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 177 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 191 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 223 
               
               
                   
                   
               
             
          
         
       
     
       Method 19 
     7-amino-5H-phenanthridin-6-one 
       [0286]    
       
                 
         
             
             
         
       
     
         [0287]    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. 
         [0288]    Yield: 46 mg (0.221 mmol; 94%) 
         [0289]    MS (ESI): 211 (M+H) +   
       Method 20 
     C-(5-morpholin-4-ylmethyl-1H-[1,2,3]triazol-4-yl)-methylamine 
       [0290]    
       
                 
         
             
             
         
       
     
         [0291]    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. 
         [0292]    Yield: 8.588 g (28.00 mmol; 28%) 
         [0293]    MS (ESI): 198 (M+H) +   
       Method 21 
     4-morpholin-4-ylmethyl-cyclohexylamine 
       [0294]    
       
                 
         
             
             
         
       
     
         [0295]    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. 
         [0296]    Yield: 4.22 g (9.9 mmol; 90%) (double trifluoroacetic acid salt) 
         [0297]    MS (ESI): 199 (M+H) +   
         [0298]    The following compounds are prepared analogously to this process: 
         [0000]    
       
         
               
               
             
               
               
               
             
           
               
                   
                   
               
               
                   
                 MS (ESI) 
               
               
                   
                 (M + H) +   
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 157 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 157 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 183 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 169 
               
               
                   
                   
               
             
          
         
       
     
       Method 22 
     7-amino-2-(2-fluoro-ethyl)-3-methyl-2,3-dihydro-isoindol-1-one 
       [0299]    
       
                 
         
             
             
         
       
     
         [0300]    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-ethyldiisopropylamine 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). 
         [0301]    Yield: 3.83 g (18.404 mmol, 43%) 
         [0302]    MS (ESI): 209 (M+H) +   
         [0303]    UV max: 318 nm 
         [0304]    The following compounds are prepared analogously to this process, using the corresponding methyl 6-nitro-benzoate derivative: 
         [0000]    
       
         
               
               
             
               
               
               
             
           
               
                   
                   
               
               
                   
                 MS (ESI) 
               
               
                   
                 (M + H) +   
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 163 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 177 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 203 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 207 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 217 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 221 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 227 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 241 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 223 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 225 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 239 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 253 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 252 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 278 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 237 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 245 
               
               
                   
                   
               
             
          
         
       
     
       Method 23 
     2-azetidin-1-yl-ethylamine 
       [0305]    
       
                 
         
             
             
         
       
     
         [0306]    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. 
         [0307]    Yield: 365 mg (3.664 mmol, 48%) 
         [0308]    MS (ESI): 101 (M+H) +   
         [0309]    The following compounds are prepared analogously to this process: 
         [0000]    
       
         
               
               
             
               
               
               
             
           
               
                   
                   
               
               
                   
                 MS (ESI) 
               
               
                   
                 (M + H) +   
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 129 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 131 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 158 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 159 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 159 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 141 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 165 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 172 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 156 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 157 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 143 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 145 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 145 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 158 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 198 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 145 
               
               
                   
                   
               
             
          
         
       
     
       Method 24 
     ((S)-3-amino-pyrrolidin-1-yl)-acetonitrile 
       [0310]    
       
                 
         
             
             
         
       
     
         [0311]    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. 
         [0312]    Yield: 500 mg (3.995 mmol, 74%) 
         [0313]    MS (ESI): 126 (M+H) +   
       Method 25 
     (R)-2-pyrrolidin-1-yl-propylamine 
       [0314]    
       
                 
         
             
             
         
       
     
       a) (R)-2-pyrrolidin-1-yl-propionamide 
       [0315]    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. 
         [0316]    Yield: 1.305 g (9.177 mmol, 57%) 
         [0317]    MS (ESI): 143 (M+H) +   
       b) (R)-2-pyrrolidin-1-yl-propylamine 
       [0318]    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. 
         [0319]    Yield: 160 mg (1.248 mmol, 18%) 
         [0320]    MS (ESI): 129 (M+H) +   
         [0321]    The following compounds are prepared analogously to this process: 
         [0000]    
       
         
               
               
             
               
               
               
             
           
               
                   
                   
               
               
                   
                 MS (ESI) 
               
               
                   
                 (M + H) +   
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 129 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 129 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 129 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 143 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 157 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 157 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 169 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 183 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 183 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 197 
               
               
                   
                   
               
             
          
         
       
     
       Method 26 
     2-chloro-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine 
       [0322]    
       
                 
         
             
             
         
       
     
         [0323]    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. 
         [0324]    Yield: 485 mg (1.250 mmol, 25%) 
         [0325]    MS (ESI): 389/391 (M+H) + ; Cl distribution 
         [0326]    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. 
         [0000]    
       
         
               
               
             
               
               
               
             
           
               
                   
                   
               
               
                   
                 MS (ESI) 
               
               
                   
                 (M + H) +   
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 363/365 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 367/369 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 349/351 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 381/383 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 333/335 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 373/375 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 447/449 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 355/357 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 399/401 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 366/368 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 345/347 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 385/387 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 381/383 
               
               
                   
                   
               
             
          
         
       
     
       Method 27 
     2-[2-(4-amino-3-methoxy-phenyl)-1H-imidazol-4-yl]-ethanol 
       [0327]    
       
                 
         
             
             
         
       
     
       a) 3-methoxy-4-nitro-benzonitrile 
       [0328]    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. 
         [0329]    Yield: 25.092 g (140.852 mmol, 94%) 
         [0330]    UV max: 334 nm 
       b) 3-methoxy-4-nitro-benzamidine 
       [0331]    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. 
         [0332]    Yield: 14.30 g (crude product: 60% purity) 
         [0333]    MS (ESI): 196 (M+H) +   
         [0334]    UV max: 334 nm 
       c) [2-(3-methoxy-4-nitro-phenyl)-1H-imidazol-4-yl]-acetic Acid 
       [0335]    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 NHCL and saturated with sodium chloride. The product is then suction filtered. 
         [0336]    Yield: 1.45 g (5.230 mmol, 24%) 
         [0337]    MS (ESI): 278 (M+H) +   
         [0338]    UV max: 294 nm 
       d) 2-[2-(3-methoxy-4-nitro-phenyl)-1H-imidazol-4-yl]-ethanol 
       [0339]    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/l). 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. 
         [0340]    Yield: 0.65 g (2.465 mmol, 47%) 
         [0341]    MS (ESI): 264 (M+H) +   
         [0342]    UV max: 298 nm 
       e) 2-[2-(4-amino-3-methoxy-phenyl)-1H-imidazol-4-yl]-ethanol 
       [0343]    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. 
         [0344]    Yield: 87 mg (0.373 mmol, 68%) 
         [0345]    MS (APCI): 234 (M+H) +   
         [0346]    UV max: 314 nm 
         [0347]    The following compounds are prepared analogously to this process: 
         [0000]    
       
         
               
               
             
               
               
               
             
           
               
                   
                   
               
               
                   
                 MS (ESI) 
               
               
                   
                 (M + H) +   
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 220 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 251 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 190 
               
               
                   
                   
               
             
          
         
       
     
         [0348]    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. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0349]    MS (ESI): 251 (M+H) +   
       Method 28 
     2-methoxy-N 4 -(3-pyrrolidin-1-yl-propyl)-benzene-1,4-diamine 
       [0350]    
       
                 
         
             
             
         
       
     
       a) (3-methoxy-4-nitro-phenyl)-(3-pyrrolidin-1-yl-propyl)-amine 
       [0351]    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. 
         [0352]    Yield: 1.07 g (3.827 mmol; 65%) 
         [0353]    MS (ESI): 280 (M+H) +   
       b) 2-methoxy-N 4 -(3-pyrrolidin-1-yl-propyl)-benzene-1,4-diamine 
       [0354]    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. 
         [0355]    Yield: 213 mg (0.661 mmol, 92%) 
         [0356]    MS (ESI): 250 (M+H) +   
         [0357]    The following compounds are prepared analogously to this process: 
         [0000]    
       
         
               
               
             
               
               
             
           
               
                   
                   
               
               
                   
                 MS 
               
               
                   
                 (ESI) 
               
               
                   
                 (M + 
               
               
                   
                 H) +   
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 236 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 307 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 333 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 333 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 347 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 333 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 240 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 240 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 222 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 208 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 262 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 222 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 236 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 168 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 250 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 250 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 307 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 307 
               
               
                   
               
             
          
         
       
     
       Method 29 
     2-(4-carboxy-2-bromo-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine 
       [0358]    
       
                 
         
             
             
         
       
     
         [0359]    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. 
         [0360]    Yield: 571 mg (1.440 mmol, 46%) 
         [0361]    MS (ESI): 396/398 (M+H) +   
       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 
       [0362]    
       
                 
         
             
             
         
       
     
       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 
       [0363]    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. 
         [0364]    Yield: 606 mg (1.236 mmol, 64%) 
         [0365]    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 
       [0366]    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. 
         [0367]    Yield: 340 mg (0.625 mmol, 98%) 
         [0368]    MS (ESI): 545 (M+H) +   
         [0369]    The following compounds are prepared analogously to this process: 
         [0000]    
       
         
               
               
             
               
               
             
           
               
                   
                   
               
               
                   
                 MS 
               
               
                   
                 (ESI) 
               
               
                   
                 (M + H) +   
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 581 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 582 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 659 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 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 
       [0370]    The separation is carried out by preparative chromatography under the following conditions: 
         [0000]    column: 280×110 mm CHIRALPAK® AD 20 μm
 
Eluant: 95% acetonitrile/5% isopropanol (v/v)
 
Flow rate: 570 ml/min
 
Temperature: ambient temperature
 
         [0371]    The enantiomer that elutes first is known as enantiomer 1 and in the chemical formula bears the symbol *1: 
       Enantiomer 1 
       [0372]    
       
                 
         
             
             
         
       
     
         [0373]    The enantiomer that elutes second is known as enantiomer 2 and in the chemical formula bears the symbol *2: 
       Enantiomer 2 
       [0374]    
       
                 
         
             
             
         
       
     
       Method 32 
     7-amino-3-ethyl-indan-1-one 
       [0375]    
       
                 
         
             
             
         
       
     
         [0376]    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. 
         [0377]    Yield: 70 mg (0.399 mmol; 29%) 
         [0378]    MS (ESI): 176 (M+H) +   
         [0379]    The following compounds are prepared analogously to this process: 
         [0000]    
       
         
               
               
             
               
               
               
             
           
               
                   
                   
               
               
                   
                 MS (ESI) 
               
               
                   
                 (M + H) +   
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 162 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 190 
               
               
                   
                   
               
             
          
         
       
     
       Method 33 
     7-amino-3,3-dimethyl-3H-isobenzofuran-1-one 
       [0380]    
       
                 
         
             
             
         
       
     
         [0381]    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. 
         [0382]    Yield: 34 mg (0.192 mmol; 32%) 
         [0383]    MS (ESI): 178 (M+H) +   
         [0384]    The following compounds are prepared analogously to this process: 
         [0000]    
       
         
               
               
             
               
               
               
             
           
               
                   
                   
               
               
                   
                 MS (ESI) 
               
               
                   
                 (M + H) +   
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 164 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 192 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 220 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 190 
               
               
                   
                   
               
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 178 
               
               
                   
                   
               
             
          
         
       
     
       Method 34 
     7-amino-2-(2-fluoro-ethyl)-3,3-dimethyl-2,3-dihydro-isoindol-1-one 
       [0385]    
       
                 
         
             
             
         
       
     
       a) Methyl 2-(cyano-dimethyl-methyl)-6-nitro-benzoate 
       [0386]    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. 
         [0387]    Yield: 3.11 g (12.535 mmol; 92%) 
       b) 3,3-dimethyl-7-nitro-2,3-dihydro-isoindol-1-one 
       [0388]    Reaction Mixture 1 
         [0389]    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. 
         [0390]    Reaction Mixture 2 
         [0391]    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). 
         [0392]    Yield: 67 mg (0.325 mmol, 8%) 
         [0393]    MS (ESI): 207 (M+H) +   
       c) 3,3-dimethyl-7-amino-2,3-dihydro-isoindol-1-one 
       [0394]    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. 
         [0395]    Yield: 50 mg (0.284 mmol, 93%) 
         [0396]    MS (ESI): 177 (M+H) +   
       d) 7-dibenzylamino-3,3-dimethyl-2,3-dihydro-isoindol-1-one 
       [0397]    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. 
         [0398]    Yield: 67 mg (0.188 mmol; 66%) 
         [0399]    MS (ESI): 357 (M+H) +   
       e) 7-dibenzylamino-2-(2-fluoro-ethyl)-3,3-dimethyl-2,3-dihydro-isoindol-1-one 
       [0400]    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. 
         [0401]    Yield: 75 mg (0.188 mmol; 100%) 
         [0402]    MS (ESI): 403 (M+H) +   
       f) 7-amino-2-(2-fluoro-ethyl)-3,3-dimethyl-2,3-dihydro-isoindol-1-one 
       [0403]    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. 
         [0404]    Yield: 36 mg (0.162 mmol, 87%) 
         [0405]    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 
       [0406]    
       
                 
         
             
             
         
       
     
         [0407]    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 at the finishing point. 
         [0408]    Yield: 42 mg (0.084 mmol; 33%) 
         [0409]    UV max: 318 nm 
         [0410]    MS (ESI): 501 (M+H) +   
         [0411]      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 
       [0412]    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. 
         [0000]    
       
         
               
             
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                 MS 
               
               
                   
                   
                   
                 (ESI) 
               
               
                   
                   
                 UX 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 
       [0413]    
       
                 
         
             
             
         
       
     
         [0414]    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 μl 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. 
         [0415]    Yield: 26 mg (0.051 mmol; 20%) 
         [0416]    UV max: 322 nm 
         [0417]    MS (ESI): 502 (M+H) +   
         [0418]      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 
       [0419]    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. 
         [0000]    
       
         
               
             
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                 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 
       [0420]    
       
                 
         
             
             
         
       
     
         [0421]    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). 
         [0422]    Yield: 23 mg (0.042 mmol; 33%) 
         [0423]    UV max: 318 nm 
         [0424]    MS (ESI): 545 (M+H) +   
         [0425]      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 
       [0426]    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. 
         [0000]    
       
         
               
             
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                 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 
       [0427]    
       
                 
         
             
             
         
       
     
         [0428]    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-ethyldiisopropyl-amine, 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. 
         [0429]    Yield: 55 mg (0.100 mmol; 57%) 
         [0430]    UV max: 318 nm 
         [0431]    MS (ESI): 555 (M+H) +   
         [0432]      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 
       [0433]    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. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                 UV max 
                 MS (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 
       [0434]    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. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                 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 
       [0435]    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. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                 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 
       [0436]    
       
                 
         
             
             
         
       
     
         [0437]    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. 
         [0438]    Yield: 0.59 g (0.86 mmol; 90%) 
         [0439]    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. 
         [0440]    Yield: 0.46 g (0.73 mmol; 85%) 
         [0441]    UV max: 284 nm 
         [0442]    MS (ESI): 558 (M+H) +   
         [0443]      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 
       [0444]    
       
                 
         
             
             
         
       
     
         [0445]    This compound is prepared analogously to Example 167. The aniline used is described in method 10. 
         [0446]    Yield: 0.23 g (0.41 mmol; 91%) 
         [0447]    UV max: 282 nm 
         [0448]    MS (ESI): 570 (M+H) +   
         [0449]      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 
       [0450]    
       
                 
         
             
             
         
       
     
         [0451]    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. 
         [0452]    Yield: 49 mg (0.074 mmol; 71%) 
         [0453]    UV max: 282 nm 
         [0454]    MS (ESI): 598 (M+H) +   
         [0455]      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 
       [0456]    
       
                 
         
             
             
         
       
     
         [0457]    To prepare this compound formaldehyde is used instead of acetaldehyde. Otherwise the method is as in Example 169. 
         [0458]    Yield: 16 mg (0.024 mmol; 28%) 
         [0459]    UV max: 278 nm 
         [0460]    MS (ESI): 584 (M+H) +   
         [0461]      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 
       [0462]    The following Examples are prepared analogously to Example 169 and 170. 
         [0463]    The corresponding aniline is described in the supplements to method 10. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                 MS 
               
               
                   
                   
                   
                   
                 (ESI) 
               
               
                   
                   
                   
                 UV max 
                 (M + 
               
               
                 # 
                 A 
                 D 
                 [nm] 
                 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 
       [0464]    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 is described in method 11. The amine used to prepare the amide is commercially obtainable or described in method 13, 15 and 25. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                 UV max 
                 MS (ESI) 
               
               
                 # 
                 A 
                 R 3 ′ 
                 [nm] 
                 (M + H) +   
               
               
                   
               
             
          
           
               
                 181 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 318, 282, 234 
                 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 
                 318 
               
               
                   
               
               
                 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 
       [0465]    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. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                 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 
       [0466]    The following Examples are prepared analogously to Example 169 and 170. 
         [0467]    The corresponding aniline is described in method 11. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                 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 
       [0468]    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. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                 UV max 
                 MS (ESI) 
               
               
                 # 
                 A 
                 R 3 ′ 
                 [nm] 
                 (M + H) +   
               
               
                   
               
               
                 387 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 262, 318 
                 569 
               
               
                   
               
               
                 388 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 278, 318 
                 615 
               
               
                   
               
             
          
         
       
     
       EXAMPLES 389-404 
       [0469]    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. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                 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 
       [0470]    
       
                 
         
             
             
         
       
     
         [0471]    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. 
         [0472]    Yield: 1626 mg (3.110 mmol; 94%) 
         [0473]    MS (ESI): 524 (M+H) +   
         [0474]    100 mg (0.191 mmol) of this precipitate, 240 μl (1.402 mmol) N-ethyldiisopropyl-amine, 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. 
         [0475]    Yield: 42 mg (0.053 mmol; 28%) 
         [0476]    UV max: 322 nm 
         [0477]    MS (ESI): 689 (M+H) +   
         [0478]      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 
       [0479]    The following compounds are prepared by an analogous process to that described in Example 405. 
         [0000]    
       
         
               
               
               
               
             
           
               
                   
               
               
                   
                   
                 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 
       [0480]    
       
                 
         
             
             
         
       
     
         [0481]    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. 
         [0482]    Yield: 18 mg (0.022 mmol; 25%) 
         [0483]    UV max: 322 nm 
         [0484]    MS (ESI): 703 (M+H) +   
       EXAMPLES 409-491 
       [0485]    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. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                 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 
       [0486]    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 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. 
         [0000]    
       
         
               
             
               
               
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                 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 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
               
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                   
                 UV max 
                 MS (ESI) 
               
               
                 # 
                 A 
                 R 3 ′ 
                 R 3 ″ 
                 [nm] 
                 (M + H) +   
               
               
                   
               
             
             
               
                 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 
       [0487]    
       
                 
         
             
             
         
       
     
         [0488]    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. 
         [0489]    Yield: 33 mg (0.045 mmol; 35%) 
         [0490]    UV max: 314 nm 
         [0491]    MS (ESI): 659 (M+H) +   
         [0492]      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 
       [0493]    
       
                 
         
             
             
         
       
     
         [0494]    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. 
         [0495]    Yield: 7 mg (0.011 mmol, 28%) 
         [0496]    MS (ESI): 639 (M+H) +   
         [0497]    UV max: 330 nm 
         [0498]    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 
       [0499]    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. 
         [0000]    
       
         
               
             
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                 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 
       [0500]    
       
                 
         
             
             
         
       
     
         [0501]    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. 
         [0502]    Yield: 51 mg (0.074 mmol; 85%) 
         [0503]    UV max: 314 nm 
         [0504]    MS (ESI): 616 (M+H) +   
         [0505]      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 
       [0506]    The following compounds are prepared by an analogous process to that described in Example 639. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                 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 
       [0507]    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. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                 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 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 282, 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 
       [0508]    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. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                 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 
       [0509]    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. 
         [0000]    
       
         
               
             
               
               
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                 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 
       [0510]    
       
                 
         
             
             
         
       
     
         [0511]    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. 
         [0512]    Yield: 58 mg (0.081 mmol; 70%) 
         [0513]    UV max: 282 nm 
         [0514]    MS (ESI): 645 (M+H) +   
         [0515]      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 
       [0516]    The following compounds are prepared by an analogous process to that described in Example 682. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                 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 
       [0517]    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. 
         [0000]    
       
         
               
             
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                 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 
       [0518]    
       
                 
         
             
             
         
       
     
         [0519]    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. 
         [0520]    Yield: 42 mg (0.067 mmol; 50%) 
         [0521]    UV max: 282 nm 
         [0522]    MS (ESI): 631 (M+H) +   
         [0523]      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 
       [0524]    
       
                 
         
             
             
         
       
     
         [0525]    This compound is prepared analogously to Example 705. 
         [0526]    UV max: 282/314 nm 
         [0527]    MS (ESI): 534 (M+H) +   
         [0528]      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 
       [0529]    
       
                 
         
             
             
         
       
     
         [0530]    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. 
         [0531]    UV max: 282 nm 
         [0532]    MS (ESI): 616 (M+H) +   
         [0533]      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 
       [0534]    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. 
         [0000]    
       
         
               
             
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                 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 
       [0535]    
       
                 
         
             
             
         
       
     
         [0536]    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. 
         [0537]    Yield: 20 mg (0.032 mmol, 8%) 
         [0538]    UV max: 325 nm 
         [0539]    MS (ESI): 644 (M+H) +   
         [0540]      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 
       [0541]    The following compounds are prepared by an analogous method to that described in Example 796: 
         [0000]    
       
         
               
             
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                 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 
       [0542]    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. 
         [0000]    
       
         
               
             
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                 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 
       [0543]    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. 
         [0000]    
       
         
               
             
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                 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 
       [0544]    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. 
         [0000]    
       
         
               
             
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                 UV 
                 MS 
               
               
                   
                   
                 max 
                 (ESI) 
               
               
                 # 
                 B 
                 [nm] 
                 (M + H) +   
               
               
                   
               
               
                 886 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 314 
                 685 
               
               
                   
               
               
                 887 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 314 
                 685 
               
               
                   
               
               
                 888 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                  286, 310 
                 685 
               
               
                   
               
               
                 889 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                  282, 314 
                 699 
               
               
                   
               
               
                 890 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 338 
                 656 
               
               
                   
               
               
                 891 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 314 
                 588 
               
               
                   
               
             
          
         
       
     
       EXAMPLES 892-894 
       [0545]    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. 
         [0000]    
       
         
               
             
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                 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 Enantiomer 1 
       [0546]    
       
                 
         
             
             
         
       
     
         [0547]    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. 
         [0548]    UV max: 310 nm 
         [0549]    MS (ESI): 616 (M+H) +   
         [0550]      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 Enantiomer 1 
       [0551]    
       
                 
         
             
             
         
       
     
         [0552]    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. 
         [0553]    UV max: 282 nm 
         [0554]    MS (ESI): 602 (M+H) +   
         [0555]      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 
       [0556]    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. 
         [0000]    
       
         
               
             
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                 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 
       [0557]    The following compounds are prepared by a method analogous to that described in Example 796: 
         [0000]    
       
         
               
             
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                 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 
       [0558]    
       
                 
         
             
             
         
       
     
         [0559]    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®
 
eluant: 25 ethanol/75 methanol (v/v) (0.03% triethylamine is added to each solvent)
 
flow rate: 0.5 ml/min
 
temperature: 20° C.
 
         [0560]    The enantiomer that elutes first is referred to as Enantiomer 1 and bears the symbol *1 in the chemical formula. 
       Enantiomer 1 
       [0561]    
       
                 
         
             
             
         
       
     
         [0000]    retention time: 9.96 min 
         [0562]    The enantiomer that elutes second is referred to as Enantiomer 2 and bears the symbol *2 in the chemical formula. 
       Enantiomer 2 
       [0563]    
       
                 
         
             
             
         
       
     
         [0000]    retention time: 12.60 min 
       EXAMPLES 960-976 
       [0564]    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. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                 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 
       [0565]    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. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                 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, 314 
                 671 
               
               
                   
               
             
          
         
       
     
       EXAMPLES 981-999 
       [0566]    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. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                 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 
       [0567]    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. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                 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 
       [0568]    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. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                 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 
       [0569]    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. 
         [0000]    
       
         
               
             
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                 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)-phenylamino)-4-(2-(2-fluoro-ethyl)-1,1-dimethyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine 
       [0570]    
       
                 
         
             
             
         
       
     
         [0571]    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. 
         [0572]    UV max: 326, 286 nm 
         [0573]    MS (ESI): 630 (M+H) +   
         [0574]      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 
       [0575]    
       
                 
         
             
             
         
       
     
         [0576]    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. 
         [0577]    UV max: 326 nm 
         [0578]    MS (ESI): 605 (M+H) +   
         [0579]      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 
       [0580]    The following compounds are prepared by an analogous method to that described in Example 1037. The aniline used is described in method 28. The amine used to prepare the amide is commercially obtainable or described in method 13. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                 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 
       [0581]    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. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                 UV max 
                 MS (ESI) 
               
               
                 # 
                 A 
                 B 
                 [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 
       [0582]    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. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                 UV max 
                 MS (ESI) 
               
               
                 # 
                 A 
                 R 3 ′ 
                 [nm] 
                 (M + H) +   
               
               
                   
               
               
                 1070 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 330 
                 608 
               
               
                   
               
               
                 1071 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 330 
                 678 
               
               
                   
               
             
          
         
       
     
       EXAMPLES 1072-1085 
       [0583]    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. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                 MS 
               
               
                   
                   
                   
                   
                 (ESI) 
               
               
                   
                   
                   
                 UV max 
                 (M + 
               
               
                 # 
                 Z 
                 R 3 ′ 
                 [nm] 
                 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 
       [0584]    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. 
         [0585]    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 tumours; 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. 
         [0586]    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. 
       Example PLK-1 Kinaseassay 
       [0587]    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. 
         [0588]    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 PO4/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. 
       Assay 
       [0589]    The following components are combined in a well of a 96-well round-bottomed dish (Greiner bio-one, PS Microtitre plate No. 650101):
       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   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)   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)   10 μl ATP solution (45 μM ATP with 1.11×10 6  Bq/ml gamma-P33-ATP).       
 
         [0594]    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 3511 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). 
         [0595]    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. 
       Measurement of Cytotoxicity on Cultivated Human Tumour Cells 
       [0596]    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). 
       FACS Analysis 
       [0597]    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. 
         [0598]    For PI staining, for example, 1×10 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. 
         [0599]    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. 
         [0600]    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. 
         [0601]    Suitable preparations include for example tablets, capsules, suppositories, solutions, particularly solutions for injection (s.c., i.v., i.m.) and infusion, 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. 
         [0602]    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. 
         [0603]    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. 
         [0604]    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. 
         [0605]    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. 
         [0606]    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. 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. 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). 
         [0607]    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. 
         [0608]    For parenteral use, solutions of the active substances with suitable liquid carriers may be used. 
         [0609]    The dosage for intravenous use is from 1-1000 mg per hour, preferably between 5 and 500 mg per hour. 
         [0610]    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. 
         [0611]    The formulation examples which follow illustrate the present invention without restricting its scope: 
       Examples of Pharmaceutical Formulations 
       [0612]      
         [0000]    
       
         
               
               
               
               
             
           
               
                   
                   
               
               
                   
                 A) 
                 Tablets 
                 per tablet 
               
               
                   
                   
               
             
             
               
                   
                   
                 active substance 
                 100 mg 
               
               
                   
                   
                 lactose 
                 140 mg 
               
               
                   
                   
                 corn starch 
                 240 mg 
               
               
                   
                   
                 polyvinylpyrrolidone 
                  15 mg 
               
               
                   
                   
                 magnesium stearate 
                  5 mg 
               
               
                   
                   
                   
                 500 mg 
               
               
                   
                   
               
             
          
         
       
     
         [0613]    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. 
         [0000]    
       
         
               
               
               
               
             
           
               
                   
                   
               
               
                   
                 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  
               
               
                   
                   
               
             
          
         
       
     
         [0614]    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. 
         [0000]    
       
         
               
               
               
             
               
               
               
               
               
             
           
               
                   
                   
               
               
                   
                 C) 
                 Ampoule solution 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                   
                 active substance 
                 50 
                 mg 
               
               
                   
                   
                 sodium chloride 
                 50 
                 mg 
               
               
                   
                   
                 water for inj. 
                 5 
                 ml 
               
               
                   
                   
               
             
          
         
       
     
         [0615]    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.