US20090163465A1 - Pyrimidines as PLK inhibitors - Google Patents

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 claim1, 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
• This application is a continuation of U.S. application Ser. No. 11/206,703, filed on Aug. 17, 2005.
• The present invention relates to new pyrimidines of general formula (1),
• 
• wherein the groups A, W, X, Y, Z, R^a, R^b, R^c, R¹and R³have 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
• 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.
• Studies in model organisms such asSchizosaccharomyces pombe, Drosophila melanogasterorXenopus laevisas 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,Nature344: 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´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).
• 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,Cell102:279-91). 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,Cell45:145-53). 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,Cell49:559-67). 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, Science286:971-4), or by microtubuli stabilising or destabilising agents (e.g. colchicin, taxol, etoposide, vinblastine, vincristine) (Schiff and Horwitz 1980, Proc Natl Acad Sci USA77:1561-5).
• 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,Oncogene14:543-549; 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 USA100:5789-5794).
• 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.
• 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.
• 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.
• 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.
• International Patent Application WO 03/063794 describes the use of 2,4-pyrimidinediamines as inhibitors of the IgE and/or IgG receptor signal cascade.
• Antiviral 2,4,5-substituted pyrimidines, wherein the groups R^cand R^dform a heteroaromatic five-membered ring at the nitrogen of the 4-position, are known from International Patent Application WO 99/41253.
• 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.
• 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
• 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, R¹, R²and R³are 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.
• The present invention relates to compounds of general formula (1)
• 
• wherein
• W denotes N or C—R²,
• X denotes —NR^1a, O or S,
• Y denotes CH or N,
• Z denotes hydrogen, halogen, —NO₂, C_1-3alkyl, C_2-3alkenyl, C_2-3alkynyl, halogen-C_1-3alkyl, —COH, —C(═O)—C_1-3alkyl, —C(═O)—C_2-3alkenyl, —C(═O)—C_2-3alkynyl, —C(═O)C_1-3alkyl-halogen or pseudohalogen;
• A is selected from the formulae (i), (ii) or (iii)
• 
• Q₁denotes mono- or bicyclic aryl compounds;
• B¹, B², B³and B⁴in each case independently of one another denote C—R^gR^h, N—Rⁱ, O or S, while adjacent B¹-B⁴in each case do not represent —O—;
• R¹and R^1aeach independently of one another denote hydrogen or methyl,
• R²denotes a group selected from among hydrogen, halogen, —OR⁴, —C(═O)R⁴, —C(═O)NR⁴R⁵, —NR⁴R⁵, —NR⁴C(═O)R⁵, —NR⁴SO₂R⁵, —N═CR⁴R⁵, —C═NRⁱ, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR⁴R⁵and pseudohalogen, or an optionally mono- or polysubstituted group selected from among C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6-cycloalkyl, aryl, heterocyclyl and heteroaryl, while the substituent(s) may be identical or different and are selected from among halogen, —NO₂, —OR⁴, —C(═O)R⁴, —C(═O)OR⁴, —C(═O)NR⁴R⁵, —NR⁴R⁵, —NR⁴C(═O)R⁵, —NR⁴C(═O)OR⁵, —NR⁴C(═O)NR⁵R⁶, —NR⁴SO₂R⁵, —N═CR⁴R⁵, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR⁴R⁵, —NR⁴SO₂NR⁵R⁶, —OSO₂NR⁵R⁶and pseudohalogen;
• R^a, R^b, R^c, R^d, R^e, R^f, R^gand R^hin each case independently of one another denote a group selected from among hydrogen, halogen, ═O, —NO₂, —OR⁴, —C(═O)R⁴, —C(═O)OR⁴, —C(═O)NR⁴R⁵, —NR⁴R⁵, —NR⁴C(═O)R⁵, —NR⁴C(═O)OR⁵, —NR⁴C(═O)NR⁵R⁶, —NR⁴SO₂R⁵, —N═CR⁴R⁵, —C═NRⁱ, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR⁴R⁵, —NR⁴SO₂NR⁵R⁶, —OSO₂NR⁵R⁶and 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, R⁸, —NO₂, —OR⁴, —C(═O)R⁴, —C(═O)OR⁴, —C(═O)NR⁴R⁵, —NR⁴R⁵, —NR⁴C(═O)R⁵, —NR⁴C(═O)OR⁵, —NR⁴C(═O)NR⁵R⁶, —NR⁴SO₂R⁵, —N═CR⁴R⁵, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR⁴R⁵, —NR⁴SO₂NR⁵R⁶, —OSO₂NR⁵R⁶and pseudohalogen; and optionally the R^gand R^hlocated 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;
• Rⁱdenotes a group selected from among hydrogen, ═O, —OR⁴, —C(═O)R⁴, —C(═O)OR⁴, —C(═O)NR⁴R⁵, —NR⁴R⁵, —NR⁴C(═O)R⁵, —NR⁴C(═O)OR⁵, —NR⁴C(═O)NR⁵R⁶, —NR⁴SO₂R⁵, —N═CR⁴R⁵, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR⁴R⁵, —NR⁴SO₂NR⁵R⁶, —OSO₂NR⁵R⁶and pseudohalogen; or an optionally mono- or polysubstituted group selected from among C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, aryl, heterocyclyl and heteroaryl, while the substituent(s) may be identical or different and are selected from among halogen, R⁸, —NO₂, —OR⁴, —C(═O)R⁴, —C(═O)OR⁴, —C(═O)NR⁴R⁵, —NR⁴R⁵, —NR⁴C(═O)R⁵, —NR⁴C(═O)OR⁵, —NR⁴C(═O)NR⁵R⁶, —NR⁴SO₂R⁵, —N═CR⁴R⁵, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR⁴R⁵, —NR⁴SO₂NR⁵R⁶, —OSO₂NR⁵R⁶and pseudohalogen; and optionally the Rⁱgroups located at adjacent N atoms may be joined together or Rⁱwith R^gor R^hlocated 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;
• R³is selected from the formulae (iv)-(x),
• 
• R⁴, R⁵and R⁶each independently of one another denote hydrogen or a group selected from among optionally mono- or polysubstituted C_1-5-alkyl, C_2-5alkenyl, C_2-5alkynyl, C_3-10cycloalkyl, 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, —NO₂, —OR⁸, —C(═O)R⁸, —C(═O)OR⁸, —C(═O)NR⁸R⁹, —NR⁸R⁹, —NR⁸C(═O)R⁹, —NR⁸C(═O)OR⁹, —NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═O)ONR⁹R¹⁰, —NR⁸SO₂R⁹, —N═CR⁸R⁹, —SR⁸, —SOR⁸—SO₂R⁸, —SO₂NR⁸R⁹, —NR⁸SO₂NR⁹R¹⁰, —OSO₂NR⁸R⁹and 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, —NO₂, —OR⁸, —C(═O)R⁸, —C(═O)OR⁸, —C(═O)NR⁸R⁹, —NR⁸R⁹, —NR⁸C(═O)R⁹, —NR⁸C(═O)OR⁹, —NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═O)ONR⁹R¹⁰, —NR⁸SO₂R⁹, —N═CR⁸R⁹, —SR⁸, —SOR⁸, —SO₂R⁸, —SO₂NR⁸R⁹, —NR⁸SO₂NR⁹R¹⁰, —OSO₂NR⁸R⁹and pseudohalogen;
• Q₂and Q₃independently 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_2-16alkynyl, C_3-10-cycloalkyl, aryl, heterocyclyl and heteroaryl while the substituent(s) may be identical or different and are selected from among halogen, —NO₂, —OR⁸, —C(═O)R⁸, —C(═O)OR⁸, —C(═O)NR⁸R⁹, —NR⁸R⁹, —NR⁸C(═O)R⁹, —NR⁸C(═O)OR⁹, —NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═O)ONR⁹R¹⁰, —NR⁸SO₂R⁹, —N═CR⁸R⁹, —SR⁸, —SOR⁸, —SO₂R⁸, —SO₂NR⁸R⁹, —NR⁸SO₂NR⁹R¹⁰, —OSO₂NR⁸R⁹and pseudohalogen;
• R⁷denotes 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, NO₂, —OR⁸, —C(═O)R⁸, —C(═O)OR⁸, —C(═O)NR⁸R⁹, —NR⁸R⁹, —NR⁸COR⁹, —NR⁸C(═O)OR⁹, —NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═O)ONR⁹R¹⁰, —NR⁸SO₂R⁹, —N═CR⁸R⁹, —SR⁸, —SOR⁸, —SO₂R⁸, —SO₂NR⁸R⁹, —NR⁸SO₂NR⁹R¹⁰, —OSO₂NR⁸R⁹and pseudohalogen;
• R⁸, R⁹and R¹⁰each 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.
• In one aspect the invention relates to compounds of general formula (1) wherein
• W denotes C—R²and the other groups are as hereinbefore defined.
• In another aspect the invention relates to compounds of general formula (1), wherein
• X denotes —NR^1aor oxygen,
• R¹and R^1adenote hydrogen;
• R³denotes formula (iv) or (x),
• 
• and the other groups are as hereinbefore defined.
• In another aspect the invention relates to compounds of general formula (1), wherein
• Y denotes CH and
• Q₁denotes monocyclic aryl compounds and the other groups are as hereinbefore defined.
• In one aspect the invention relates to compounds of general formula (1), wherein
• R^cdenotes a group selected from among hydrogen, —F, —Cl, methyl and ethyl and the other groups are as hereinbefore defined.
• In another aspect the invention relates to compounds of general formula (1), wherein
• R^aand R^beach 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, —NO₂, —OR⁴, —C(═O)R⁴, —C(═O)OR⁴, —C(═O)NR⁴R⁵, —NR⁴R⁵, —NR⁴C(═O)R⁵, —NR⁴C(═O)OR⁵, —NR⁴C(═O)NR⁵R⁶, —NR⁴SO₂R⁵, —N═CR⁴R⁵, —SR⁴, —SOR⁵, —SO₂R⁴, —SO₂NR⁴R⁵, —NR⁴, —SO₂NR⁴R⁵, —OSO₂NR⁴R⁵and pseudohalogen
    and the other groups are as hereinbefore defined.
• In another aspect the invention also relates to compounds of general formula (1), wherein
• R^aand R^bdenote hydrogen or fluorine and the other groups are as hereinbefore defined.
• 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.
• In one aspect the invention relates to compounds of general formula (1), or the pharmaceutically active salts thereof, as pharmaceutical compositions.
• 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.
• 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.
• 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.
• 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.
• 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.
• In another aspect the invention relates to a pharmaceutical preparation containing at least one compound of general formula (1)
• 
• wherein
• W denotes N or C—R²,
• X denotes —NR^1a, O or S,
• Y denotes CH or N,
• Z denotes hydrogen, halogen, —NO₂, 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)
• 
• Q₁denotes mono- or bicyclic aryl compounds;
• B¹, B², B³and B⁴in each case independently of one another represent C—R^gR^h, N—Rⁱ, O or S, while adjacent B¹-B⁴in each case do not denote —O—;
• R¹and R^1aeach independently of one another denote hydrogen or methyl,
• R²denotes a group selected from among hydrogen, halogen, —OR⁴, —C(═O)R⁴, —C(═O)NR⁴R⁵, —NR⁴R⁵, —NR⁴C(═O)R⁵, —NR⁴SO₂R⁵, —N═CR⁴R⁵, —C═NR⁴, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR⁴R⁵and 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, —NO₂, —OR⁴, —C(═O)R⁴, —C(═O)OR⁴, —C(═O)NR⁴R⁵, —NR⁴R⁵, —NR⁴C(═O)R⁵, —NR⁴C(═O)OR⁵, —NR⁴C(═O)NR⁵R⁶, —NR⁴SO₂R⁵, —N═CR⁴R⁵, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR⁴R⁵, —NR⁴SO₂NR⁵R⁶, —OSO₂NR⁵R⁶and pseudohalogen;
• R^a, R^b, R^c, R^d, R^e, R^f, R^gand R^hin each case independently of one another denote a group selected from among hydrogen, halogen, ═O, —NO₂, —OR⁴, —C(═O)R⁴, C═O)OR⁴, —C(═O)NR⁴R⁵, —NR⁴R⁵, —NR⁴C(═O)R⁵, —NR⁴C(═O)OR⁵, —NR⁴C(═O)NR⁵R⁶, —NR⁴SO₂R⁵, —N═CR⁴R⁵, —C═NRⁱ, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR⁴R⁵, —NR⁴SO₂NR⁵R⁶, —OSO₂NR⁵R⁶and 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, R⁸, —NO₂, —OR⁴, —C(═O)R⁴, —C(═O)OR⁴, —C(═O)NR⁴R⁵, —NR⁴R⁵, —NR⁴C(═O)R⁵, —NR⁴C(═O)OR⁵—NR⁴C(═O)NR⁵R⁶, —NR⁴SO₂R⁵, —N═CR⁴R⁵, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR⁴R⁵, —NR⁴SO₂NR⁵R⁶, —OSO₂NR⁵R⁶and pseudohalogen; and optionally the R^gand R^hlocated 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;
• Rⁱdenotes a group selected from among hydrogen, ═O)—OR⁴, —C(═O)R⁴, —C(═O)OR⁴, —C(═O)NR⁴R⁵, —NR⁴R⁵, —NR⁴C(═O)R⁵, —NR⁴C(═O)OR⁵, —NR⁴C(═O)NR⁵R⁶, —NR⁴SO₂R⁵, —N═CR⁴R⁵, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR⁴R⁵, —NR⁴SO₂NR⁵R⁶, —OSO₂NR⁵R⁶or 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, R⁸, —NO₂, —OR⁴, —C(═O)R⁴, —C(═O)OR⁴, —C(═O)NR⁴R⁵, —NR⁴R⁵, —NR⁴C(═O)R⁵, —NR⁴C(═O)OR⁵, —NR⁴C(═O)NR⁵R⁶, —NR⁴SO₂R⁵, —N═CR⁴R⁵, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR⁴R⁵, —NR⁴SO₂NR⁵R⁶, —OSO₂NR⁵R⁶and pseudohalogen; and optionally the Ri groups located at adjacent N atoms may be joined together or to R^gand R^hlocated 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;
• R³is selected from the formulae (iv)-(x),
• 
• R⁴, R⁵and R⁶each 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, —NO₂, —OR⁸, —C(═O)R⁸, —C(═O)OR⁸, —C(═O)NR⁸R⁹, —NR⁸R⁹, —NR⁸C(═O)R⁹, —NR⁸C(═O)OR⁹, —NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═O)ONR⁹R¹⁰, —NR⁸SO₂R⁹, —N═CR⁸R⁹, —SR⁸, —SOR⁸, —SO₂R⁸, —SO₂NR⁸R⁹, —NR⁸SO₂NR⁹R¹⁰, —OSO₂NR⁸R⁹and 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, —NO₂, —OR⁸, —C(═O)R⁸, —C(═O)OR⁸, —C(═O)NR⁸R⁹, —NR⁸R⁹, —NR⁸C(═O)R⁹, —NR⁸C(═O)OR⁹, —NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═O)ONR⁹R¹⁰, —NR⁸SO₂R⁹, —N═CR⁸R⁹, —SR⁸, —SOR⁸, —SO₂R⁸, —SO₂NR⁸R⁹, —NR⁸SO₂NR⁹R¹⁰, —OSO₂NR⁸R⁹and pseudohalogen;
• Q₂and Q₃independently 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, —NO₂, —OR⁸, —C(═O)R⁸, —C(═O)OR⁸, —C(═O)NR⁸R⁹, —NR⁸R⁹, —NR⁸C(═O)R⁹, —NR⁸C(═O)OR⁹, —NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═O)ONR⁹R¹⁰, —NR⁸SO₂R⁹, —N═CR⁸R⁹, —SR⁸, —SOR⁸, —SO₂R⁸, —SO₂NR⁸R⁹, —NR⁸SO₂NR⁹R¹⁰, —OSO₂NR⁸R⁹and pseudohalogen;
• R⁷denotes 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, NO₂, —OR⁸, —C(═O)R⁸, —C(═O)OR⁸, —C(═O)NR⁸R⁹, —NR⁸R⁹, —NR⁸COR⁹, —NR⁸C(═O)OR⁹, —NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═O)ONR⁹R¹⁰, —NR⁸SO₂R⁹, —N═CR⁸R⁹, —SR⁸, —SOR⁸, —SO₂R⁸, —SO₂NR⁸R⁹, —NR⁸SO₂NR⁹R¹⁰, —OSO₂NR⁸R⁹and pseudohalogen;
• R⁸, R⁹and R¹⁰each 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, —NH₂, —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
• As used herein, the following definitions apply, unless stated otherwise.
• By alkyl substituents are meant in each case saturated, straight-chain or branched aliphatic hydrocarbon groups (alkyl group).
• The alkenyl substituents are in each case straight-chain or branched, unsaturated alkyl groups which have at least one double bond.
• By alkynyl substituents are meant in each case straight-chain or branched, unsaturated alkyl groups which have at least one triple bond.
• 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 —CF₃, —CHF₂, —CH₂F, —CF₂CF₃, —CHFCF₃, —CH₂CF₃, —CF₂CH₃, —CHFCH₃, —CF₂CF₂CF₃, —CF₂CH₂CH₃, —CHFCH₂CH₃and —CHFCH₂CF₃.
• Halogen relates to fluorine, chlorine, bromine and/or iodine atoms.
• By pseudohalogen are meant the following groups: —OCN, —SCN, —CF₃and —CN.
• 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.
• Aryl relates to monocyclic or bicyclic rings with 6-12 carbon atoms such as for example phenyl and naphthyl.
• 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-oxide, 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.
• 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 heterocyclyl groups are tetrahydrofuranyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, indolinyl, isoindolinyl, 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.
• The Examples that follow illustrate the present invention without restricting its scope:
Preparation of the Compounds According to the Invention:
• 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 AStep 1A
• 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.
• 
• 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
• 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.
• 
• 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 BStep 1B
• 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.
• 
• 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.
• 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.
• The combined organic extracts are dried and the solvent is distilled off. The residue is purified by chromatography or repeated crystallisation.
Step 2B
• 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.
• 
• 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
• Compounds VIII whose group R⁷denotes hydrogen may be used directly for preparing the end compounds X, while a compound VIII is reacted with a compound IX.
• Compounds VIII whose group R⁷does not denote hydrogen are converted beforehand by hydrolysis or similar methods known to the skilled man into the compounds wherein the group R⁷denotes hydrogen.
• 
• 1 equivalent of the compound VIII, 1 to 1.5 equivalents of the compound IX and 1 to 3 equivalents of a base, for example triethylamine or ethyldiisopropylamine, are stirred in a solvent, for example 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide or N-methyl-2-pyrrolidinone. At a temperature of 15 to 25° C., 1 to 1.5 equivalents of a coupling reagent, for example N,N-dicyclohexylcarbodiimide, N,N-diisopropyl-carbodiimide, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-tetrafluoroborate or 1-(3-N,N-dimethylaminopropyl)-3-ethylcarbodiimide are added. The reaction mixture is stirred for another 4 to 24 h at a temperature of 15 to 25° C. Then the solvent is distilled off and the residue is purified by chromatography.
Method CStep 1C
• 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.
• 
• 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
• 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.
• 
• 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:
• 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.
• 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:
• 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.
• 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 CDCl₃signals they are not mentioned.
Mass Spectroscopy/UV Spectrometer:
• These data are generated using an HPLC-MS apparatus (high performance liquid chromatography with mass detector) made by Agilent.
• 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 12-(2-methoxy-4-propylcarbamoyl-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine
• 
• 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% KHSO₄solution, then with 300 ml saturated aqueous NaCl solution. The organic phase is dried with MgSO₄and 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).
• Yield: 2.30 g (5.9 mmol; 27%)
• ¹H-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 27-amino-2,3-dihydro-isoindol-1-one
• 
a) 7-nitro-2,3-dihydro-isoindol-1-one
• 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.
• Yield: 960 mg (5.389 mmol, 99%)
• MS-ESI+: m/z=179 [M+H]⁺
b) 7-amino-2,3-dihydro-isoindol-1-one
• 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 (H₂pressure). The catalyst is filtered off and the solvent is eliminated in vacuo.
• Yield: 734 mg (4.958 mmol, 92%)
• MS-ESI+: m/z=149 [M+H]⁺
• The following 7-amino-2,3-dihydro-isoindol-1-one derivatives are prepared analogously to this method. A corresponding amine is used instead of ammonia:

• 	MS (ESI)
  	(M + H)+

  		163
  		177
  		191
  		231
  		219
  		233
  		207
  		234
  		274
  		195
  		213
  		231
  		209
  		245
  		188
  		187
  		206
  		233
  		233
  		202
  		206
  		191
  		205
  		227
  		223
  		193
  		225
  		243
  		221
  		255
  		192
  		255
  		178
  		192
  		211/213
  		247
  		247
  		261
  		261
  		261
  		261
  		223
  		223
  		221
  		247
  		246
  		235
  		224
  		222

Method 3Ethyl(4-amino-3-oxo-1,3-dihydro-isobenzofuran-1-yl)-acetate
• 
a) ethyl(4-amino-3-oxo-3H-isobenzofuran-1-ylidene)-acetate
• 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).
• Yield: 221 mg (0.95 mmol, 31%)
• MS-ESI+: m/z=234 [M+H]⁺
b) ethyl(4-amino-3-oxo-1,3-dihydro-isobenzofuran-1-yl)-acetate
• 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 H₂pressure and 25° C. Then the catalyst is filtered off and the solvent is eliminated in vacuo.
• Yield: 116 mg (0.49 mmol, 97%)
• MS (ESI): m/z=236 (M+H)⁺
• ¹H-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 45-amino-3H-quinazolin-4-one
• 
a) 2,6-diaminobenzamide
• 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 H₂pressure 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.
• Yield: 900 mg (5.958 mmol; 23%)
• MS (ESI): 152 (M+H)⁺
b) 5-amino-3H-quinazolin-4-one
• 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.
• Yield: 782 mg (4.852 mmol; 81%)
• MS (ESI): 162 (M+H)⁺
Method 59-amino-2,3,4,5-tetrahydro-2-benzazepin-1-one
• 
• 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 N₂, 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 H₂pressure. 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)-N⁴-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.
• Yield: 28 mg (0.160 mmol, 23%)
• MS (ESI): m/z=177 (M+H)⁺
Method 64-amino-1-methyl-1,2-dihydro-indazol-3-one
• 
a) 4-nitro-1,2-dihydro-indazol-3-one
• 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. H₂O 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.
• Yield: 1.7 g (9.5 mmol, 35%)
• MS (ESI): m/z=180 (M+H)⁺
b) 1-methyl-4-nitro-1,2-dihydro-indazol-3-one
• 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 MgSO₄, 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.
• Yield: 144 mg (0.7 mmol, 44%)
• MS (ESI): m/z=194 (M+H)⁺
• ¹H-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
• 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 MgSO₄and the solvent is eliminated in vacuo.
• Yield: 33 mg (0.2 mmol, 28%)
• MS (ESI): m/z=164 (M+H)⁺
• 4-amino-1,2-dihydro-indazol-3-one and the following compounds are prepared analogously to this method.

• 	MS (ESI)
  	(M + H)+

  		178
  		194
  		178

Method 78-amino-4-methyl-3,4-dihydro-2H-isoquinolin-1-one
• 
a) methyl 2-(cyanomethyl-2-methyl)-6-nitro-benzoate
• 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.
• Yield: 289 mg (1.2 mmol, 68%)
• MS (ESI): 233 (M−H)⁻
b) 8-amino-4-methyl-3,4-dihydro-2H-isoquinolin-1-one
• 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 H₂pressure and 25° C. Then the catalyst is filtered off and the solvent is eliminated in vacuo.
• Yield: 170 mg (0.8 mmol, 46%)
• MS (ESI): 177 (M+H)⁺
• 8-amino-3,4-dihydro-2H-isoquinolin-1-one and 8-amino-4,4-dimethyl-3,4-dihydro-2H-isoquinolin-1-one and the following compounds are prepared analogously to this method.

• 	MS (ESI)
  	(M + H)+

  		221
  		253
  		205

Method 87-amino-indan-1-one
• 
a) indan-4-ylamine
• 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 MgSO₄and 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 H₂pressure 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).
• Yield: 3.81 g (28.6 mmol, 12%)
• MS (ESI): 134 (M+H)⁺
• ¹H-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
• 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 MgSO₄, 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).
• Yield: 152 mg (0.9 mmol, 51%)
• MS (ESI): 176 (M+H)⁺
• ¹H-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
• 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).
• Yield: 95 mg (0.500 mmol, 60%)
• MS (ESI): 190 (M+H)⁺
d) 7-amino-indan-1-on
• 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.
• Yield: 388 mg (2.6 mmol, 100%)
• 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 9N-(7-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-acetamide
• 
• a) 2-benzyloxy-N-(7-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-acetamide
• 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).
• Yield: 910 mg (2.7 mmol, 59%)
b) N-(7-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-acetamide
• 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 H₂pressure 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).
• Yield: 210 mg (0.1 mmol, 41%)
• MS (ESI): 222 (M+H)⁺
Method 106-amino-2-ethyl-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one
• 
a) 2-amino-6-(1-aminomethyl-propoxy)-benzonitrile
• 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.
• Yield: 1.15 g (5.6 mmol, 38%)
• MS (ESI): 206 (M+H)⁺
b) 2-amino-6-(1-aminomethyl-propoxy)-benzoic acid
• 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.
• Yield: 262 mg (1.2 mmol, 21%)
• MS (ESI): 225 (M+H)⁺
c) 6-amino-2-ethyl-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one
• 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.
• Yield: 50 mg (0.2 mmol, 21%)
• MS (ESI): 207 (M+H)⁺
• The following compounds are prepared analogously to this method. 1-amino-2-butanol was replaced by a corresponding aminoalcohol or by a corresponding 1,2-diaminoethylene.

• 	MS (ESI)
  	(M + H)+

  		207
  		193
  		235
  		219
  		233
  		207
  		207
  		193
  		221
  		299
  		219
  		209
  		269
  		251
  		179
  		221
  		206
  		235
  		227
  		219
  		207
  		269
  		225
  		253
  		241
  		233

Method 116-amino-3-benzyl-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione
• 
a) methyl 2-(2-amino-6-nitro-benzoylamino)-3-phenyl-propionate
• 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).
• Yield: 1.04 g (3.03 mmol, 65%)
• MS (ESI): 344 (M+H)⁺
b) 2-(2-amino-6-nitro-benzoylamino)-3-phenyl-propionic acid
• 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.
• Yield: 636 mg (1.9 mmol, 64%)
• MS (ESI): 329 (M+H)⁺
• ¹H-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
• 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 H₂pressure 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.
• Yield: 88 mg (0.29 mmol, 24%)
• MS (ESI): 300 (M+H)⁺
d) 6-amino-3-benzyl-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione
• 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.
• Yield: 22 mg (0.08 mmol, 27%)
• MS (ESI): 282 (M+H)⁺
• The following compounds are prepared analogously to method 11.

• 	MS (ESI)
  	(M + H)+

  		192
  		206
  		206
  		218
  		220
  		220
  		232
  		232
  		234
  		234
  		234
  		246
  		246
  		246
  		248
  		248
  		248
  		250
  		265
  		265
  		268
  		277
  		278
  		278
  		282
  		283
  		283
  		288
  		296
  		192
  		298
  		298
  		300
  		300
  		300
  		307
  		316/318
  		321
  		321
  		346

Method 122-(4-carboxy-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine
• 
• 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 MgSO₄and 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.
• Yield: 330 mg (0.95 mmol, 2%)
• MS (ESI): 348 (M+H)⁺
• ¹H-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 134-(4-amino-cyclohexyl)-morpholine
• 
a) dibenzyl-(4-morpholino-4-yl-cyclohexyl)-amine
• 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.
• Yield: 6.6 g (18 mmol, 60%) cis-isomer
• • 2 g (5.4 mmol, 18%) trans-isomer.
b) trans-4-morpholino-4-yl-cyclohexylamine
• 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.
• Yield: 3.9 g (15.2 mmol, 93%)
• melting point: 312° C.
• The following compounds are prepared analogously to Method 13:

• 	MS (ESI)
  	(M + H)+

  		169
  		211
  		213
  		238

Method 142-(4-carboxy-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine
• 
a) 2-(4-benzyloxycarbonyl-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine
• 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.
• Yield: 1.03 g (2.360 mmol; 26%)
• UV max: 320 nm
• 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
• 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.
• Yield: 0.76 g (2.192 mmol; 96%)
• UV max: 288 nm
• MS (ESI): 346/348 (M−H)⁻Cl distribution
• The following compounds are prepared analogously to this process:
• 2-(4-carboxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine
• MS (ESI): 316/318 (M−H)⁻Cl distribution
• 2-[4-(4-benzyloxycarbonyl-piperazin-1-yl)-phenylamino]-4-chloro-5-trifluoromethyl-pyrimidine
• MS (ESI): 492/494 (M+H)⁺Cl distribution
• 2-[4-(4-benzyloxycarbonyl-piperazin-1-yl)-2-methoxy-phenylamino]-4-chloro-5-trifluoromethyl-pyrimidine
• MS (ESI): 522/524 (M+H)⁺Cl distribution
Method 153-pyrrolidin-1-yl-cyclobutylamine
• 
a) tert. butyl (3-benzyloxy-cyclobutyl)-carbamate
• 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).
• Yield: 5.98 g (22 mmol; 48%)
• MS (ESI): 178 (M+H-boc)⁺Boc cleaving in the mass detector
b) tert. butyl (3-hydroxy-cyclobutyl)-carbamate
• 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 H₂pressure. 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.
• Yield: 1.53 g (8.2 mmol; 82%)
• MS (ESI): 188 (M+H)⁺
c) tert. butyl (3-tosyl-cyclobutyl)-carbamate
• 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.
• Yield: 28.30 g (83 mmol; 83%)
• MS (ESI): 342 (M+H)⁺
d) tert. butyl (3-pyrrolidine-cyclobutyl)-carbamate
• 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.
• The substances that elute first are designated as follows:
• 
• Yield product A: 1 g (4.17 mmol; 4%)
• RF value (silica gel; dichloromethane:methanol:conc. aqueous ammonia=90:9:1)=0.62
• The substances that elute second are designated as follows:
• 
• Yield product C: 2.00 g (8.33 mmol; 8%)
• RF value (silica gel; dichloromethane:methanol:conc. aqueous ammonia=90:9:1)=0.53
e) (*1′,1″)-3-pyrrolidin-1-yl-cyclobutylamine
• 
• 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.
• Yield: 0.43 g (2.786 mmol; 67%)
• MS (ESI): 141 (M+H)⁺
• The following compounds are prepared analogously to this process:

• 	MS (ESI)
  	(M + H)+

  		170
  		210
  		184
  		224
  		171
  		212
  		143
  		198
  		196
  		194
  		183

(*2′,*2″)-3-pyrrolidin-1-yl-cyclobutylamine
• 
• 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.
• Yield: 0.43 g (3.09 mmol; 74%)
• MS (ESI): 141 (M+H)⁺
• The following compounds are prepared analogously to this method:

• 	MS (ESI)
  	(M + H)+

  	155
  	157
  	171
  	184
  	170
  	210
  	253
  	224
  	212
  	143
  	141
  	198
  	251
  	194
  	196
  	171
  	183

Method 162-(4-carboxy-2-bromo-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine
• 
• 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.
• Yield: 0.57 g (1.44 mmol; 46%)
• MS (ESI): 396/398 (M−H)⁺Cl/Br distribution
Method 175-amino-3-(2-fluoro-ethyl)-3H-quinazolin-4-one
• 
• 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.
• Yield: 67 mg (0.323 mmol; 10%)
• MS (ESI): 208 (M+H)⁺
Method 188-amino-2-(2-fluoro-ethyl)-3,4-dihydro-2H-isoquinolin-1-one
• 
a) 8-dibenzylamino-3,4-dihydro-2H-isoquinolin-1-one
• 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.
• Yield: 1.670 g (4.877 mmol; 54%)
• MS (ESI): 343 (M+H)⁺
b) 8-dibenzylamino-2-(2-fluoro-ethyl)-3,4-dihydro-2H-isoquinolin-1-one
• 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.
• Yield: 0.83 g (2.136 mmol; 69%)
• MS (ESI): 389 (M+H)⁺
c) 8-amino-2-(2-fluoro-ethyl)-3,4-dihydro-2H-isoquinolin-1-one
• 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 H₂pressure. Then the catalyst is filtered off and the solvent is eliminated in vacuo.
• Yield: 0.403 g (1.935 mmol; 91%)
• MS (ESI): 209 (M+H)⁺
• The following compounds are prepared analogously to this process:

• 	MS (ESI)
  	(M + H)+

  		177
  		191
  		223

Method 197-amino-5H-phenanthridin-6-one
• 
• 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 H₂pressure. 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.
• Yield: 46 mg (0.221 mmol; 94%)
• MS (ESI): 211 (M+H)⁺
Method 20C-(5-morpholin-4-ylmethyl-1H-[1,2,3]triazol-4-yl)-methylamine
• 
• 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 H₂pressure. Then the catalyst is filtered off and the solvent is eliminated in vacuo.
• Yield: 8.588 g (28.00 mmol; 28%)
• MS (ESI): 198 (M+H)⁺
Method 214-morpholin-4-ylmethyl-cyclohexylamine
• 
• 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.
• Yield: 4.22 g (9.9 mmol; 90%) (double trifluoroacetic acid salt)
• MS (ESI): 199 (M+H)⁺
• The following compounds are prepared analogously to this process:

• 	MS (ESI)
  	(M + H)+

  		157
  		157
  		183
  		169

Method 227-amino-2-(2-fluoro-ethyl)-3-methyl-2,3-dihydro-isoindol-1-one
• 
• 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 H₂pressure. 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).
• Yield: 3.83 g (18.404 mmol, 43%)
• MS (ESI): 209 (M+H)⁺
• UV max: 318 nm
• The following compounds are prepared analogously to this process, using the corresponding methyl 6-nitro-benzoate derivative:

• 	MS (ESI)
  	(M + H)+

  		163
  		177
  		203
  		223
  		225
  		239
  		207
  		217
  		221
  		227
  		241
  		253
  		252
  		278
  		237
  		245

Method 232-azetidin-1-yl-ethylamine
• 
• 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 H₂pressure. The catalyst is filtered off and the solvent is eliminated in vacuo.
• Yield: 365 mg (3.664 mmol, 48%)
• MS (ESI): 101 (M+H)⁺
• The following compounds are prepared analogously to this process:

• 	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
• 
• 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.
• Yield: 500 mg (3.995 mmol, 74%)
• MS (ESI): 126 (M+H)⁺
Method 25(R)-2-pyrrolidin-1-yl-propylamine
• 
a) (R)-2-pyrrolidin-1-yl-propionamide
• 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.
• Yield: 1.305 g (9.177 mmol, 57%)
• MS (ESI): 143 (M+H)⁺
b) (R)-2-pyrrolidin-1-yl-propylamine
• 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.
• Yield: 160 mg (1.248 mmol, 18%)
• MS (ESI): 129 (M+H)⁺
• The following compounds are prepared analogously to this process:

• 	MS (ESI)
  	(M + H)+

  		129
  		129
  		129
  		143
  		157
  		157
  		169
  		183
  		183
  		197

Method 262-chloro-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine
• 
• 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.
• Yield: 485 mg (1.250 mmol, 25%)
• MS (ESI): 389/391 (M+H)⁺; Cl distribution
• The following compounds are prepared analogously to this process. The aniline derivatives used are described in the supplements to method 2, in method 10 and in the supplements to method 10. The preparation of the 2,4-dichloropyrimidine derivatives is known from the literature or may be carried out by methods known from the literature.

• 	MS (ESI)
  	(M + H)+

  		363/365
  		355/357
  		367/369
  		349/351
  		381/383
  		333/335
  		373/375
  		447/449
  		399/401
  		366/368
  		345/347
  		385/387
  		381/383

Method 272-[2-(4-amino-3-methoxy-phenyl)-1H-imidazol-4-yl]-ethanol
• 
a) 3-methoxy-4-nitro-benzonitrile
• 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.
• Yield: 25.092 g (140.852 mmol, 94%)
• UV max: 334 nm
b) 3-methoxy-4-nitro-benzamidine
• 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.
• Yield: 14.30 g (crude product: 60% purity)
• MS (ESI): 196 (M+H)⁺
• UV max: 334 nm
c) [2-(3-methoxy-4-nitro-phenyl)-1H-imidazol-4-yl]-acetic acid
• 7 g (60% purity, 21.519 mmol) 3-methoxy-4-nitro-benzamidine are dissolved in methanol and combined with 11 ml (44 mmol) 4 N dioxanic hydrochloric acid, the solvents are eliminated in vacuo. The residue and 6.13 g (44.384 mmol) potassium carbonate are suspended in 350 ml acetonitrile and combined with 3.24 ml (22.764 mmol) ethyl 4-chloracetoacetate and 880 mg (5.301 mmol) potassium iodide. The reaction mixture is stirred for 16 h at 45° C. The reaction mixture is diluted with water and combined with 1 N sodium hydroxide solution, and extracted with ethyl acetate. The aqueous phase is adjusted to pH 1 with 1 N HCL and saturated with sodium chloride. The product is then suction filtered.
• Yield: 1.45 g (5.230 mmol, 24%)
• MS (ESI): 278 (M+H)⁺
• UV max: 294 nm
d) 2-[2-(3-methoxy-4-nitro-phenyl)-1H-imidazol-4-yl]-ethanol
• 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.
• Yield: 0.65 g (2.465 mmol, 47%)
• MS (ESI): 264 (M+H)⁺
• UV max: 298 nm
e) 2-[2-(4-amino-3-methoxy-phenyl)-1H-imidazol-4-yl]-ethanol
• 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 H₂pressure. The palladium on charcoal is suction filtered and the methanol is eliminated in vacuo.
• Yield: 87 mg (0.373 mmol, 68%)
• MS (APCI): 234 (M+H)⁺
• UV max: 314 nm
• The following compounds are prepared analogously to this process:

• 	MS (ESI)
  	(M + H)+

  		220
  		251
  		190

• [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.
• 
• MS (ESI): 251 (M+H)⁺
Method 282-methoxy-N⁴-(3-pyrrolidin-1-yl-propyl)-benzene-1,4-diamine
• 
a) (3-methoxy-4-nitro-phenyl)-(3-pyrrolidin-1-yl-propyl)-amine
• 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.
• Yield: 1.07 g (3.827 mmol; 65%)
• MS (ESI): 280 (M+H)⁺
b) 2-methoxy-N⁴-(3-pyrrolidin-1-yl-propyl)-benzene-1,4-diamine
• 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 H₂pressure. The catalyst is filtered off and the solvent is eliminated in vacuo.
• Yield: 213 mg (0.661 mmol, 92%)
• MS (ESI): 250 (M+H)⁺
• The following compounds are prepared analogously to this process:

• 	MS (ESI)
  	(M + H)+

  	236
  	307
  	333
  	333
  	347
  	333
  	240
  	240
  	222
  	208
  	262
  	222
  	236
  	168
  	250
  	250
  	307
  	307

Method 292-(4-carboxy-2-bromo-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine
• 
• 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.
• Yield: 571 mg (1.440 mmol, 46%)
• MS (ESI): 396/398 (M+H)⁺
Method 302-(4-Acryloylamino-2-methoxy-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine
• 
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
• 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.
• Yield: 606 mg (1.236 mmol, 64%)
• 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
• 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.
• Yield: 340 mg (0.625 mmol, 98%)
• MS (ESI): 545 (M+H)⁺
• The following compounds are prepared analogously to this process:

• 	MS (ESI)
  	(M + H)+

  	581
  	582
  	659
  	611

Method 31Separation of the racemic 7-amino-2-(2-fluoro-ethyl)-3-methyl-2,3-dihydro-isoindol-1-one (method 22) into the two enantiomers
• The separation is carried out by preparative chromatography under the following conditions:
• column: 280×110 mm CHIRALPAK® AD 20 μm
• Eluant: 95% acetonitrile/5% isopropanol (v/v)
• Flow rate: 570 ml/min
• Temperature: ambient temperature
• The enantiomer that elutes first is known as enantiomer 1 and in the chemical formula bears the symbol *1:
Enantiomer 1
• 
• The enantiomer that elutes second is known as enantiomer 2 and in the chemical formula bears the symbol *2:
Enantiomer 2
• 
Method 327-amino-3-ethyl-indan-1-one
• 
• 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.
• Yield: 70 mg (0.399 mmol; 29%)
• MS (ESI): 176 (M+H)⁺
• The following compounds are prepared analogously to this process:

• 	MS (ESI)		MS (ESI)
  	(M + H)+		(M + H)+

  	162		190

Method 337-amino-3,3-dimethyl-3H-isobenzofuran-1-one
• 
• 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.
• Yield: 34 mg (0.192 mmol; 32%)
• MS (ESI): 178 (M+H)⁺
• The following compounds are prepared analogously to this process:

• 	MS (ESI)		MS (ESI)
  	(M + H)+		(M + H)+

  	164		190
  	192		178
  	220

Method 347-amino-2-(2-fluoro-ethyl)-3,3-dimethyl-2,3-dihydro-isoindol-1-one
• 
a) methyl 2-(cyano-dimethyl-methyl)-6-nitro-benzoate
• 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.
• Yield: 3.11 g (12.535 mmol; 92%)
b) 3,3-dimethyl-7-nitro-2,3-dihydro-isoindol-1-oneReaction Mixture 1
• 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.
Reaction Mixture 2
• 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).
• Yield: 67 mg (0.325 mmol, 8%)
• MS (ESI): 207 (M+H)⁺
c) 3,3-dimethyl-7-amino-2,3-dihydro-isoindol-1-one
• 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 H₂pressure and ambient temperature. Then the catalyst is filtered off and the solvent is eliminated in vacuo.
• Yield: 50 mg (0.284 mmol, 93%)
• MS (ESI): 177 (M+H)⁺
d) 7-dibenzylamino-3,3-dimethyl-2,3-dihydro-isoindol-1-one
• 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.
• Yield: 67 mg (0.188 mmol; 66%)
• MS (ESI): 357 (M+H)⁺
e) 7-dibenzylamino-2-(2-fluoro-ethyl)-3,3-dimethyl-2,3-dihydro-isoindol-1-one
• 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.
• Yield: 75 mg (0.188 mmol; 100%)
• MS (ESI): 403 (M+H)⁺
f) 7-amino-2-(2-fluoro-ethyl)-3,3-dimethyl-2,3-dihydro-isoindol-1-one
• 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 H₂pressure and ambient temperature. Then the catalyst is filtered off and the solvent is eliminated in vacuo.
• Yield: 36 mg (0.162 mmol, 87%)
• MS (ESI): 223 (M+H)⁺
EXAMPLE 12-(2-methoxy-4-N-propylcarbamoyl-phenylamino)-4-(3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine
• 
• 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 C18RP-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.
• Yield: 42 mg (0.084 mmol; 33%)
• UV max: 318 nm
• MS (ESI): 501 (M+H)⁺
• ¹H-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
• 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.

• 		UV max	MS (ESI)
  #	A	[nm]	(M + 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 182-(2-methoxy-4-N-propylcarbamoyl-phenylamino)-4-(3-oxo-1,3-dihydro-isobenzofuran-4-ylamino)-5-trifluoromethyl-pyrimidine
• 
• 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 Lett2001, 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.
• Yield: 26 mg (0.051 mmol; 20%)
• UV max: 322 nm
• MS (ESI): 502 (M+H)⁺
• ¹H-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, H), 7.67-7.78 (m, 1H), 8.38-8.48 (m, 2H), 8.50 (s, 1H), 9.21 (s, 1H), 9.64 (s, 1H)
EXAMPLE 19-37
• The following compounds are prepared by analogous methods to those described in Example 1 and Example 18. 2-(2-methoxy-4-propylcarbamoyl-phenylamino)-4-chloro-5-trifluoromethylpyrimidine (method 1) is used. The corresponding aniline derivative is commercially obtainable, known from the literature or is prepared by the processes described in method 2 and 4 to 9. N-methyl-2-pyrrolidinone or N,N-dimethylacetamide is used as solvent.

• 		UV max	MS (ESI)
  #	A	[nm]	(M + H)+
  19		235	586
  20		323/226	543
  21		325	530
  22		262	514
  23		320	544
  24		318	542
  25		312	530
  26		315	529
  27		314	528
  28		317	502
  29		316	516
  30		322	529
  31		255	548
  32		320	500
  33		325	515
  34		250/286/ 318	516
  35		320	558
  36		316	514
  37		321

EXAMPLE 382-(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
• 
• 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).
• Yield: 23 mg (0.042 mmol; 33%)
• UV max: 318 nm
• MS (ESI): 545 (M+H)⁺
• ¹H-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
• The following compounds are prepared by analogous methods to those described in Example 1 and 18. 2-(2-methoxy-4-propylcarbamoyl-phenylamino)-4-chloro-5-trifluoromethylpyrimidine (method 1) is used. The corresponding aniline derivative is commercially obtainable, known from the literature or is prepared by the processes described in method 10 and 11. N-methyl-2-pyrrolidinone or N,N-dimethylacetamide is used as solvent.

• 		UV max	MS (ESI)
  #	A	[nm]	(M + H)+
  39		229/279/ 315	559
  40		282/314	545
  41		282/318	587
  42		282/314	571
  43		282/318	585
  44		318	559
  45		234/320	559
  46		282/218	603
  47		278/318	531
  48		286/314	573
  49		274/314	558
  50		318	587
  51		223/282/ 318	579
  52		318	634

EXAMPLE 532-[2-methoxy-4-(4-morpholin-4-yl-(1,4-trans-cyclohexyl)carbamoyl)-phenylamino]-4-(2-carbamoyl-3-fluoro-phenylamino)-5-trifluoromethyl-pyrimidine
• 
• 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.
• Yield: 55 mg (0.100 mmol; 57%)
• UV max: 318 nm
• MS (ESI): 555 (M+H)⁺
• ¹H-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
• The following compounds are prepared by an analogous method to that described in Example 53. The corresponding aniline is described in method 2, 7, 8, or 9 or known from the literature. The amine used to prepare the amide is commercially obtainable or is described in method 13.

• 			UV max	MS (ESI)
  #	A	R3′	[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
• The following compounds are prepared by an analogous method to that described in Example 53. 2-(4-Carboxy-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine may be prepared according to method 12 or 14. The corresponding aniline is described in the supplements to method 10. The amine used to prepare the amide is commercially obtainable or is described in method 13, in the supplements to method 13, 15 or 25.

• 			UV max	MS (ESI)
  #	A	R3′	[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
• The following compounds are prepared by an analogous method to that described in Example 53. The preparation of 2-(4-carboxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine is described in method 14. The corresponding aniline is described in method 10. The amine used to prepare the amide is commercially obtainable or is described in method 13, 15 or 25.

• 			UV max	MS (ESI)
  #	A	R3′	[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

EXAMPLES 1672-(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
• 
• 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.
• Yield: 0.59 g (0.86 mmol; 90%)
• 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 H₂pressure 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.
• Yield: 0.46 g (0.73 mmol; 85%)
• UV max: 284 nm
• MS (ESI): 558 (M+H)⁺
• ¹H-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)
EXAMPLES 1682-(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
• 
• This compound is prepared analogously to Example 167. The aniline used is described in method 10.
• Yield: 0.23 g (0.41 mmol; 91%)
• UV max: 282 nm
• MS (ESI): 570 (M+H)⁺
• ¹H-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 1692-[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
• 
• 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.
• Yield: 49 mg (0.074 mmol; 71%)
• UV max: 282 nm
• MS (ESI): 598 (M+H)⁺
• ¹H-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 1702-[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
• 
• To prepare this compound formaldehyde is used instead of acetaldehyde. Otherwise the method is as in Example 169.
• Yield: 16 mg (0.024 mmol; 28%)
• UV max: 278 nm MS (ESI): 584 (M+H)⁺
• ¹H-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
• The following Examples are prepared analogously to Example 169 and 170.
• The corresponding aniline is described in the supplements to method 10.

• 				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
• 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.

• 			UV max	MS (ESI)
  #	A	R3′	[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	755
  253			230; 318	695
  254			230; 318	70
  255			230; 318	389
  256			230; 318	652
  257			230	357
  258			230	784
  259			230	659
  260			319, 230	689
  261			322	703
  262			322	705
  263			320	719
  264			226	690
  265			226; 318	760
  266			230	635
  267			230; 318	381
  268			318	812
  269			318	652
  270			318	707
  271			318, 226	777
  272			318	659
  273			318	714
  274			315, 239	669
  275			319, 222	723
  276			318, 226	793
  277			316	620
  278			318	675
  279			318, 226	745
  280			317, 226	620
  281			318	675
  282			318, 230	745
  283			318	784
  284			318	758
  285			318	688
  286			238, 282, 314	616
  287			230, 282, 318	671
  288			230, 282, 318	741
  289			234, 282, 318	616
  290			226, 282, 318	671
  291			234, 282, 318	741
  292			234, 282, 318	648
  293			230, 282, 318	703
  294			226, 282, 318	773
  295			226, 282, 318	893
  296			226, 282, 318	727
  297			226, 282, 318	754
  298			230, 282, 318	823
  299			282, 318	669
  300			282, 318	613
  301			282, 318	641
  302			286, 318	639
  303			286, 318	627
  304			286, 318	655
  305			286, 318	667
  306			286, 318	717
  307			286, 318	689
  308			286, 318	665
  309			230, 286, 318	653
  310			230, 282, 318	715
  311			286, 322	695
  312			234, 286, 318	667
  313			230, 282, 318	639
  314			230, 282, 318	667
  315			230, 282, 318	681
  316			230, 282, 318	695
  317				679
  318			226, 284, 318	681
  319			230, 284, 318	697
  320			226, 284, 314	750
  321			230, 286, 318	669
  322			230, 282, 318	693
  323			230, 282, 314	709
  324			230, 286, 314	681
  325			226, 286, 314	762
  326			230, 282, 318	681
  327			230, 282, 314	697
  328			234, 282, 318	627
  329			226, 282, 318	767
  330			226, 282, 318	725
  331			230, 286, 318	711
  332			226, 282, 318	671
  333			234, 282, 314	718
  334			234, 282, 318	693
  335			234, 286, 318	653
  336			284, 318	706
  337			230, 282, 318	641
  338			230, 282, 314	667
  339			283, 318	655
  340			230, 286, 318	699
  341			230, 282, 318	750
  342			230, 282, 318	627
  343			250, 282, 318	667
  344			230, 282, 318	683
  345			238, 282, 314	641
  346			230, 314	692
  347			282, 318	723
  348			234, 286, 314	653
  349			286, 318	667
  350			234, 286, 314	718
  351			230, 286, 318	685

EXAMPLES 352-372
• The following compounds are prepared by an analogous process to that described in Example 53 described, prepared. 2-(4-carboxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine may after method 14 prepared are. The corresponding aniline is in method 11 described. The amine used to prepare the amide is commercially obtainable or is in method 13, 15 or 25 described.

• 			UV max	MS (ESI)
  #	A	R3′	[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
• The following Examples are prepared analogously to Example 169 and 170.
• The corresponding aniline is described in method 11.

• 			UV max	MS (ESI)
  #	A	D	[nm]	(M + H)+
  373			246	621
  374			246	611
  375			234	639
  376			238	597
  377			250	599
  378			250	585
  379			250	613
  380			250	609
  381			246	625
  382			250	599
  383			230	571
  384			246	595
  385			250	585
  386			246, 286	615

EXAMPLES 387-388
• The following compounds are prepared by an analogous process to that described in Example 53. 2-(4-Carboxy-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine may be prepared according to method 12 or 14. The corresponding aniline is described in method 4 or method 17. The amine used to prepare the amide is commercially obtainable.

• 			UV max	MS (ESI)
  #	A	R3′	[nm]	(M + H)+
  387			262, 318	569
  388			278, 318	615

EXAMPLES 389-404
• The following compounds are prepared by an analogous process to that described in Example 53. 2-(4-Carboxy-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine may be prepared according to method 12 or 14. The corresponding aniline is described in method 7, in method 18 or 19. The amine used to prepare the amide is commercially obtainable or is described in method 13.

• 			UV max	MS (ESI)
  #	A	R3′	[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 4052-[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
• 
• 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.
• Yield: 1626 mg (3.110 mmol; 94%)
• MS (ESI): 524 (M+H)⁺
• 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.
• Yield: 42 mg (0.053 mmol; 28%)
• UV max: 322 nm
• MS (ESI): 689 (M+H)⁺
• ¹H-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
• The following compounds are prepared by an analogous process to that described in Example 405.

• 		UV max	MS (ESI)
  #		[nm]	(M + H)+
  406		318	606
  407		322, 286	606

EXAMPLE 4082-[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
• 
• 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.
• Yield: 18 mg (0.022 mmol; 25%)
• UV max: 322 nm
• MS (ESI): 703 (M+H)⁺
EXAMPLES 409-491
• The following compounds are prepared by an analogous process to that described in Example 53. 2-(4-Carboxy-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine may be prepared according to method 12 or 14. The corresponding aniline is described in method 2. The amine used to prepare the amide is commercially obtainable or is described in method 13, 20 or 21.

• 			UV max	MS (ESI)
  #	A	R3′	[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, 242	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	621
  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
• 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.

• 				UV max	MS (ESI)
  #	A	R3′	R3″	[nm]	(M + H)+
  492			H	286, 322	584
  493			H	286, 322	826
  494			H	284, 322	613
  495			H	282, 322	640
  496			H	286, 320	570
  497			H	286, 322	584
  498			H	282, 322	693
  499			H	286, 322	686
  500			H	286, 326	616
  501			H	286, 326	630
  502			H	282, 325	704
  503			H	286, 326	634
  504			H	286, 326	648
  505			H	286, 322	712
  506			H	322, 286	739
  507			H	322, 286	645
  508			H	326, 286	632
  509			H	322, 286	672
  510			H	322, 284	700
  511			H	314, 286	616
  512			H	286, 322	684
  513			H	286, 322	670
  514			H	282, 322	658
  515			H	322, 286	632
  516			H	326, 286	628
  517			H	325, 286	628
  518			H	326, 286	659
  519			H	326	699
  520			H	284, 326	616
  521			H	234, 282, 314	630
  522			H	326	660
  523			H	326	657
  524			H		645
  525			H	326	627
  526			H	326	660
  527			H	326	659
  528			H	326	692
  529			H	326	644
  530			H	326	628
  531			H	322	662
  532			H	326	699
  533			H	326	602
  534			H		646
  535			H	326	666
  536			H	326	646
  537			H	326	—
  538			H	322	616
  539			H	318	630
  540			H	318	630
  541			H	274	644
  542			H	326	658
  543			H	286, 324	630
  544			H	286, 326	658
  545			H	286, 322	630
  546			H	286, 326	642
  547			H	286, 322	562
  548			H	322-326	630
  549			H	326	630
  550			H	286, 322	607
  551			H		646
  552			H		644
  553			H	326	644
  554			H	322-326	658
  555			H	322-326	658
  556			H	286, 326	658
  557			H	322-326	642
  558			H	322-326	642
  559			H	286, 322	656
  560			H	286, 322	656
  561			H	286, 322	671
  562			H	286, 322	671
  563			H	318	685
  564			H	322-326	685
  565			H	322-326	754
  566			H	322-326	672
  567			H	322	711
  568			H	322-326	711
  569			H	326	624
  570			H	326	645
  571			H	322-326	650
  572			H	286, 326	684
  573			H	286, 326	684
  574			H	326	673
  575			H	322	698
  576			H	326, 286	646
  577			H	286, 322	684
  578			H	282, 322	658
  579			H	322, 286	617
  580			H	326, 286	644
  581			H	326, 286	590
  582			H	286, 326	673
  583			H	326, 285	652
  584			H	326, 282	722
  585			H	326, 286	648
  586			H	326, 285	718
  587			H	326, 286	652
  588			H	326, 284	652
  589			H	325, 283	681
  590			H	325.3	652
  591			H	326.3	666
  592			H	325, 283	666
  593			H	325.3	648
  594			H	325, 284	648
  595			H	325, 284	677
  596			H	325, 284	648
  597			H	326, 285	662
  598			H	325, 284	662
  599			H	326, 282	720
  600				314, 283	576
  601			H	322, 286	714
  602			H	286, 322	670
  603			H	324, 285	614
  604			H	324, 284	684
  605			H	324, 285	628
  606			H	324, 284	698
  607			H	285, 322	630
  608			H	325, 284	576
  609			H	325, 284	576
  610			H	326, 286	659
  611			H	326, 286	646
  612			H	325, 285	630
  613			H	325, 284	630
  614			H	325, 285	590
  615			H	285, 325	642
  616			H	325, 285	670
  617			H	326, 286	684
  618			H	326, 286	658
  619			H	285, 324	684
  620			H	326, 286	658
  621			H	280, 320	631

EXAMPLE 622(2-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
• 
• 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.
• Yield: 33 mg (0.045 mmol; 35%)
• UV max: 314 nm
• MS (ESI): 659 (M+H)⁺
• ¹H-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 6232-(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
• 
• 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.
• Yield: 7 mg (0.011 mmol, 28%)
• MS (ESI): 639 (M+H)⁺
• UV max: 330 nm
• 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
• The following compounds are prepared by an analogous process to that described in Example 622 or 623. The corresponding aniline is described in method 27 and 28.

• 		UV max	MS (ESI)
  #	B	[nm]	(M + H)+
  624		290, 326	586
  625		290, 330	654
  626		290, 326	625
  627		326	512
  628		314	685
  629		290, 314	659
  630			659
  631		278	592
  632		314	592
  633		314	588
  634		314	602
  635		314	602
  636		314	588
  637		314	602
  638			670

EXAMPLE 639(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
• 
• 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.
• Yield: 51 mg (0.074 mmol; 85%)
• UV max: 314 nm
• MS (ESI): 616 (M+H)⁺
• ¹H-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)
EXAMPLE 640-648
• The following compounds are prepared by an analogous process to that described in Example 639.

• 		UV max	MS (ESI)
  #	D	[nm]	(M + H)+
  640		314	574
  641		310-314	628
  642		310-314	602
  643		310-314	630
  644		314	671
  645		310-314	618
  646		314	658
  647		314	588

EXAMPLES 648-659
• The following compounds are prepared by an analogous process to that described in Example 639. For the reductive amination 2-(2-methoxy-4-piperazin-1-yl-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine is used. The aniline for preparing this compound is described in method 28.

• 		UV max	MS (ESI)
  #	D	[nm]	(M + H)+
  648		286, 314	631
  649		286, 314	603
  650		282, 314	643
  651		282, 314	671
  652		286, 314	657
  653		282, 314	628
  654		286, 314	657
  655		286, 314	671
  656		282, 314	614
  657		282, 314	560
  658		234, 283, 314	694
  659		286, 314	574

EXAMPLES 660-666
• The following compounds are prepared by an analogous process to that described in Example 53. 2-(4-Carboxy-2-bromo-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine may be prepared according to method 29. The corresponding aniline is described in method 22. The amine used to prepare the amide is commercially obtainable or described in method 13.

• 			UV max	MS (ESI)
  #	A	R3′	[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
• 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 R₃′ may be synthesised analogously to Example 639 by reductive amination. An amine is used which has another protected amino function in the side chain. The protective group used may be a tert-butoxycarbonyl, benzyloxycarbonyl or benzyl group. This protective group is cleaved by a procedure familiar to the skilled man and reductive amination (analogously to Example 639) or alkylation (analogously to method 34 or WO2004052857) are the last steps in this sequence.

• 				UV max	MS (ESI)
  #	A	R3′	R3″	[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 6822-(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
• 
• 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.
• Yield: 58 mg (0.081 mmol; 70%)
• UV max: 282 nm
• MS (ESI): 645 (M+H)⁺
• ¹H-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)
EXAMPLE 683-692
• The following compounds are prepared by an analogous process to that described in Example 682.

• 		UV max	MS (ESI)
  #	E	[nm]	(M + H)+
  683		282	661
  684		282	673
  685		282	701
  686		282	645
  687		282	685
  688		282	616
  689		282	713
  690		282	630
  691		282	632
  692		282	602

EXAMPLES 693-704
• The following compounds are prepared by an analogous process to that described in Example 682. 2-(4-(2-Bromo-acetylamino)-2-methoxy-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine or 2-(4-(2-bromo-acetylamino)-2-bromo-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine or 2-[5-(2-bromo-acetylamino)-pyridin-2-ylamino]-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine, which are described in method 30, are used as educt for the nucleophilic substitution.

• 		UV max	MS (ESI)
  #	B	[nm]:	(M + H)+:
  693		282	685
  694		282	685
  695		314	659
  696		282	645
  697		282	644
  698		282	618
  699		282	602
  700		282	687
  701		322	573
  702		322	630
  703		222	650
  704		278	707

EXAMPLE 7052-(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
• 
• 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.
• Yield: 42 mg (0.067 mmol; 50%)
• UV max: 282 nm
• MS (ESI): 631 (M+H)⁺
• ¹H-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 7062-(2-methoxy-4-ureido-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine
• 
• This compound is prepared analogously to Example 705.
• UV max: 282/314 nm
• MS (ESI): 534 (M+H)⁺
• ¹H-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-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
• 
• 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.
• UV max: 282 nm
• MS (ESI): 616 (M+H)⁺
• ¹H-NMR (400 MHz, CDCl₃): 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
• Using an analogous method to that described in Example 53 a primary amine which has another protected amino function in the side chain is coupled to 2-(4-carboxy-2-methoxy-phenylamino)-4-[2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino]-5-trifluoromethyl-pyrimidine. The protective group used may be a tert-butoxycarbonyl, benzyloxycarbonyl or benzyl group. This protective group is cleaved using a procedure familiar to the skilled man and reductive amination (analogously to Example 639) or alkylation (analogously to method 34 or WO2004052857) are the final steps in this sequence.

• 		UV max	MS (ESI)
  #	R3′	[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 7962-[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
• 
• 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.
• Yield: 20 mg (0.032 mmol, 8%)
• UV max: 325 nm
• MS (ESI): 644 (M+H)⁺
• ¹H-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
• The following compounds are prepared by an analogous method to that described in Example 796:

• 		UV max	MS (ESI)
  #	R3′	[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
• The following compounds are prepared by an analogous process to that described in Example 53. The corresponding aniline is described in method 31. The amine used to prepare the amide is commercially obtainable or is described in method 13, 21 or in method 25.

• 		UV max	MS (ESI)
  #	R3′	[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
• The following compounds are prepared by an analogous process to that described in Example 53. The corresponding aniline is described in method 31. The amine used to prepare the amide is commercially obtainable, described in method 13, 15, 20, 21, 23, 24 and 25 or in J. Med. Chem. 2003, 46(5), 702-715.

• 		UV max	MS (ESI)
  #	R3′	[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
• 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.

• 		UV
  		max	MS (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
• The following compounds are prepared by an analogous process to that described in Example 53. 2-(4-carboxy-2-bromo-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine is described in method 29. The corresponding aniline is described in method 31. The amine used to prepare the amide is commercially obtainable.

• 			UV max	MS (ESI)
  	#	R3′	[nm]	(M + H)+
  	892		314	665
  	893		270	665
  	894		270	680

EXAMPLES 8952-(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
• 
• 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.
• UV max: 310 nm
• MS (ESI): 616 (M+H)⁺
• ¹H-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 8962-(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
• 
• 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.
• UV max: 282 nm
• MS (ESI): 602 (M+H)⁺
• ¹H-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
• Using a method analogous to that described in Example 53 a primary amine which has another protected amino function in the side chain is coupled to 2-(4-carboxy-2-methoxy-phenylamino)-4-[2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino]-5-trifluoromethyl-pyrimidine Enantiomer 1. The protective group used may be a tert-butoxycarbonyl, benzyloxycarbonyl or benzyl group. This protective group is cleaved using a procedure familiar to the skilled man and reductive amination (analogously to Example 639) or alkylation (analogously to method 34 or WO2004052857) are the final steps in this sequence.

• 		UV max	MS (ESI)
  #	R3′	[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
• The following compounds are prepared by a method analogous to that described in Example 796:

• 		UV max	MS (ESI)
  #	R3′	[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 9592-(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
• 
• 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:
• 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.
• The enantiomer that elutes first is referred to as Enantiomer 1 and bears the symbol *1 in the chemical formula.
Enantiomer 1
• 
• retention time: 9.96 min
• The enantiomer that elutes second is referred to as Enantiomer 2 and bears the symbol *2 in the chemical formula.
Enantiomer 2
• 
• retention time: 12.60 min
EXAMPLES 960-976
• The following compounds are prepared by an analogous method to that described in Example 53. The corresponding aniline is described in method 22. The amine used to prepare the amide is commercially obtainable or is described in method 13.

• 			UV max	MS (ESI)
  #	A	R3′	[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
• The following compounds are prepared by an analogous method to that described in Example 53. The corresponding aniline is described in method 6. The amine used to prepare the amide is described in method 13.

• 			UV max	MS (ESI)
  #	A	R3′	[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
• The following compounds are prepared by an analogous method to that described in Example 53. The corresponding aniline is described in method 32. The amine used to prepare the amide is commercially obtainable or described in method 13.

• 			UV max	MS (ESI)
  #	A	R3′	[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
• The following compounds are prepared by an analogous method to that described in Example 53. The corresponding aniline is described in method 33. The amine used to prepare the amide is commercially obtainable or described in method 13 or 21.

• 			UV max	MS (ESI)
  #	A	R3′	[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
• The following compounds are prepared by an analogous method to that described in Example 53. The corresponding aniline is described in method 10. The amine used to prepare the amide is commercially obtainable or described in method 13.

• 			UV max	MS (ESI)
  #	A	R3′	[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
• The following compounds are prepared by an analogous method to that described in Example 53. The corresponding aniline is described in method 2. The amine used to prepare the amide is described in method 13.

• 		MS (ESI)
  #	R3′	(M + H)+	salt form
  1033		701	base
  1034		645	formate
  1035		631	formate

EXAMPLE 1036(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
• 
• 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.
• UV max: 326, 286 nm
• MS (ESI): 630 (M+H)⁺
• ¹H-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 10372-(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
• 
• 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.
• UV max: 326 nm
• MS (ESI): 605 (M+H)⁺
• ¹H-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
• 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.

• 			UV max	MS (ESI)
  #	A	R3′	[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
• The following compounds are prepared by an analogous method to that described in Example 622 or 623. The corresponding aniline is described in method 28.

• 			UV max	MS (ESI)
  #	A	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
• The following compounds are prepared by an analogous method to that described in Example 622 or 623 and 53. The corresponding aniline is described in method 28. The amine used to prepare the amide is commercially obtainable or described in method 13.

• 			UV max	MS (ESI)
  #	A	R3′	[nm]	(M + H)+
  1070			330	608
  1071			330	678

EXAMPLES 1072-1085
• The following compounds are prepared by an analogous method to that described in Example 1037. The corresponding aniline is described in method 28. The amine used to prepare the amide is commercially obtainable or described in method 13.

• 			UV
  			max	MS (ESI)
  #	Z	R3′	[nm]	(M + H)+
  1072			285, 320	674
  1073			326	663
  1074			306	596
  1075			326	593
  1076			262	596
  1077			326	593
  1078			318	652
  1079			325	582
  1080			319	582
  1081			302	666
  1082			322	626
  1083			318	626
  1084			286, 318	612
  1085			280, 325	572

Biological Properties
• 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.
• Such diseases include for example: viral infections (e.g. HIV and Kaposi's sarcoma); inflammatory and autoimmune diseases (e.g. colitis, arthritis, Alzheimer'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.
• 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
• 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.
• 4×10⁷Sf21 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' incubation at 27° C. and 70 rpm, 1×10⁸Sf21 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 Na₂HPO₄/l, 0.24 g KH₂PO₄/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 MgCl₂, 1 mM DTT, 5 μg/ml leupeptin, 5 μg/ml aprotinin, 100 μM NaF, 100 μM PMSF, 10 mM β-glycerolphosphate, 0.1 mM Na₃VO₄, 30 mM 4-nitrophenylphosphate) to give 1×10⁸cells/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 MgCl₂, 1 mM DTT). The protein concentration is determined by Bradford Assay.
Assay
• 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 MgCl₂, 1 mM DTT
  • 20 μl substrate solution (25 mM MOPS pH=7.0, 15 mM MgCl₂, 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 MgCl₂, 1 mM DTT)
  • 10 μl ATP solution (45 μM ATP with 1.11×10⁶Bq/ml gamma-P33-ATP).
• The reaction is started by adding the ATP solution and continued for 45 minutes at 30° C. with gentle shaking (650 rpm on an IKA Schüttler MTS2). The reaction is stopped by the addition of 125 μl of ice-cold 5% TCA per well and incubated on ice for at least 30 minutes. The precipitate is transferred by harvesting onto filter plates (96-well microtitre filter plate: UniFilter-96, GF/B; Packard; No. 6005177), then washed four times with 1% TCA and dried at 60° C. After the addition of 35 μl scintillation solution (Ready-Safe; Beckmann) per well the plate is sealed shut with sealing tape and the amount of P33 precipitated is measured with the Wallac Betacounter. The measured data are evaluated using the standard Graphpad software (Levenburg-Marquard Algorhythmus).
• 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
• 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'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
• 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.
• For PI staining, for example, 1×10⁶HeLa 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.
• 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-460), pancreas (BxPC-3), prostate (DU145)), sarcomas (e.g. SK-UT-1B), leukaemias and lymphomas (e.g. HL-60; Jurkat, THP-1) and other tumours (e.g. melanomas (BRO), gliomas (U-87MG)) and could be used for such indications. This is evidence of the broad applicability of the compounds according to the invention for the treatment of all kinds of tumour types.
• The compounds of general formula (I) may be used on their own or in conjunction with other active substances according to the invention, optionally also in conjunction with other pharmacologically active substances.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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).
• 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.
• For parenteral use, solutions of the active substances with suitable liquid carriers may be used.
• The dosage for intravenous use is from 1-1000 mg per hour, preferably between 5 and 500 mg per hour.
• 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.
• The formulation examples which follow illustrate the present invention without restricting its scope:
Examples of Pharmaceutical Formulations

• A)	Tablets	per tablet

  	active substance	100	mg
  	lactose	140	mg
  	corn starch	240	mg
  	polyvinylpyrrolidone	15	mg
  	magnesium stearate	5	mg
  		500	mg

• The finely ground active substance, lactose and some of the corn starch are mixed together. The mixture is screened, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet-granulated and dried. The granules, the remaining corn starch and the magnesium stearate are screened and mixed together. The mixture is compressed to produce tablets of suitable shape and size.

• B)	Tablets	per tablet

  	active substance	80	mg
  	lactose	55	mg
  	corn starch	190	mg
  	microcrystalline cellulose	35	mg
  	polyvinylpyrrolidone	15	mg
  	sodium-carboxymethyl starch	23	mg
  	magnesium stearate	2	mg
  		400	mg

• The finely ground active substance, some of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is screened and worked with the remaining corn starch and water to form a granulate which is dried and screened. The sodiumcarboxymethyl starch and the magnesium stearate are added and mixed in and the mixture is compressed to form tablets of a suitable size.

• C)	Ampoule solution

  	active substance	50	mg
  	sodium chloride	50	mg
  	water for inj.	5	ml

• 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.

Claims (2)

1.) A method of treatment of a disease or condition responsive to an inhibitor of PLK, said disease or condition being selected from the group consisting of: cancer, infection, inflammation and an autoimmune disease, said method comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a compound of the following formula (1):

wherein

W denotes N or C—R²,

X denotes —NR^1a, O or S,

Y denotes CH,

Z denotes —CF₃;

A is selected from one of the following formulas (i), (ii) and (iii):

Q₁denotes that (i), (ii) and (iii) are mono- or bicyclic aryl;

B¹, B², B³and B⁴each independently of one another denote C—R^gR^h, N—Rⁱ, O or S;

R¹and R^1aeach independently of one another denote hydrogen or methyl;

R²denotes one of hydrogen, halogen, —OR⁴, —C(═O)R⁴, —C(═O)NR⁴R⁵, —NR⁴R⁵, —NR⁴C(═O)R⁵, —NR⁴SO₂R⁵, —N═CR⁴R⁵, —C═NRⁱ, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR⁴R⁵, pseudohalogen, and a mono- or polysubstituted group selected from the group consisting of C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6-cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent(s) of the mono- or polysubstituted group are identical or different and are selected from the group consisting of halogen, —NO₂, —OR⁴, —C(═O)R⁴, —C(═O)OR⁴, —C(═O)NR⁴R⁵, —NR⁴R⁵, —NR⁴C(═O)R⁵, —NR⁴C(═O)OR⁵, —NR⁴C(═O)NR⁵R⁶, —NR⁴SO₂R⁵, —N═CR⁴R⁵, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR⁴R⁵, —NR⁴SO₂NR⁵R⁶, —OSO₂NR⁵R⁶and pseudohalogen;

R^a, R^b, R^c, R^d, R^e, R^f, R^gand R^heach independently of one another denote a group selected from the group consisting of hydrogen, halogen, ═O, —NO₂, —OR⁴, —C(═O)R⁴, —C(═O)OR⁴, —C(═O)NR⁴R⁵, —NR⁴R⁵, —NR⁴C(═O)R⁵—NR⁴C(═O)OR⁵, —NR⁴C(═O)NR⁵R⁶, —NR⁴SO₂R⁵, —N═CR⁴R⁵, —C═NRⁱ, —SR⁴, —SOR⁴—SO₂R⁴, —SO₂NR⁴R⁵, —NR⁴SO₂NR⁵R⁶, —OSO₂NR⁵R⁶, pseudohalogen, and an unsubstituted or mono- or polysubstituted group selected from the group consisting of C_1-6-alkyl, C_2-6-alkenyl, C_2-6-alkynyl, C_3-6-cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent(s) of the mono- or polysubstituted group are identical or different and are selected from the group consisting of halogen, R⁸, —NO₂, —OR⁴, —C(═O)R⁴, —C(═O)OR⁴, —C(═O)NR⁴R⁵, —NR⁴R⁵, —NR⁴C(═O)R⁵, —NR⁴C(═O)OR⁵, —NR⁴C(═O)NR⁵R⁶, —NR⁴SO₂R⁵, —N═CR⁴R⁵, —SR¹, —SOR⁴, —SO₂R⁴, —SO₂NR⁴R⁵, —NR⁴SO₂NR⁵R⁶, —OSO₂NR⁵R⁶and pseudohalogen; wherein R^gand R^hare optionally located at the same or at adjacent C atoms and are attached in any combination to a common saturated or partially unsaturated 3-5-membered alkyl bridge which contains one to two heteroatoms;

Rⁱdenotes a group selected from the group consisting of hydrogen, —OR⁴, —C(═O)R⁴, —C(═O)OR⁴, —C(═O)NR⁴R⁵, —NR⁴R⁵, —NR⁴C(═O)R⁵—NR⁴C(═O)OR⁵, —NR⁴C(═O)NR⁵R⁶, —NR⁴SO₂R⁵, —N═CR⁴R⁵, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR⁴R⁵, —NR⁴SO₂NR⁵R⁶, —OSO₂NR⁵R⁶, pseudohalogen and an unsubstituted or substituted mono- or polysubstituted group selected from the group consisting of C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent(s) of the mono- or polysubstituted group are identical or different and are selected from the group consisting of halogen, R⁸, —NO₂, —OR⁴, —C(═O)R⁴, —C(═O)OR⁴, —C(═O)NR⁴R⁵, —NR⁴R⁵, —NR⁴C(═O)R⁵, —NR⁴C(═O)OR⁵, —NR⁴C(═O)NR⁵R⁶, —NR⁴SO₂R⁵, —N═CR⁴R⁵, —SR⁴, —SOR⁴, —SO₂R⁴—SO₂NR⁴R⁵, —NR⁴SO₂NR⁵R⁶, —OSO₂NR⁵R⁶and pseudohalogen; wherein the Rⁱgroups located at adjacent N atoms are optionally joined together or Rⁱwith R^gor R^hlocated at adjacent C atoms are optionally attached in any combination to a common saturated or partially unsaturated 3-5-membered alkyl bridge which contains one to two heteroatoms;

R³is selected from the following formulas (iv)-(x):

R⁴, R⁵and R⁶each independently of one another denote hydrogen or an unsubstituted or mono- or polysubstituted group selected from the group consisting of C_1-5-alkyl, C_2-5alkenyl, C_2-5alkynyl, C_3-10cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent(s) of the mono- or polysubstituted group are identical or different and are selected from the group consisting of C_3-10-cycloalkyl, aryl, heterocyclyl, heteroaryl, halogen, —NO₂, —OR⁸, —C(═O)R⁸, —C(═O)OR⁸, —C(═O)NR⁸R⁹, —NR⁸R⁹, —NR⁸C(═O)R⁹, —NR⁸C(═O)OR⁹, —NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═O)ONR⁹R¹⁰, —NR⁸SO₂R⁹, —N═CR⁸R⁹, —SR⁸, —SOR⁸, —SO₂R⁸, —SO₂NR⁸R⁹, —NR⁸SO₂NR⁹R¹⁰, —OSO₂NR⁸R⁹and pseudohalogen;

L denotes a bond or an unsubstituted or mono- or polysubstituted group selected from the group consisting of C_1-16-alkyl, C_2-16-alkenyl, C_2-16-alkynyl, C_3-10-cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent(s) of the mono- or polysubstituted group are identical or different and are selected from the group consisting of halogen, —NO₂, —OR⁸, —C(═O)R⁸, —C(═O)OR⁸, —C(═O)NR⁸R⁹, —NR⁸R⁹, —NR⁸C(═O)R⁹, —NR⁸C(═O)OR⁹, —NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═O)ONR⁹R¹⁰, —NR⁸SO₂R⁹, —N═CR⁸R⁹, —SR⁸, —SOR⁸, —SO₂R⁸, —SO₂NR⁸R⁹, —NR⁸SO₂NR⁹R¹⁰, —OSO₂NR⁸R⁹and pseudohalogen;

Q₂and Q₃each independently of one another denote a bond or an unsubstituted or mono- or polysubstituted group selected from the group consisting of C_1-16-alkyl, C_2-16-alkenyl, C_2-16-alkynyl, C_3-10-cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent(s) of the mono- or polysubstituted group are identical or different and are selected from the group consisting of halogen, —NO₂, —OR⁸, —C(═O)R⁸, —C(═O)OR⁸, —C(═O)NR⁸R⁹, —NR⁸R⁹, —NR⁸C(═O)R⁹, —NR⁸C(═O)OR⁹, —NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═O)ONR⁹R¹⁰, —NR⁸SO₂R⁹, —N═CR⁸R⁹, —SR⁸, —SOR⁸, —SO₂R⁸, —SO₂NR⁸R⁹, —NR⁸SO₂NR⁹R¹⁰, —OSO₂NR⁸R⁹and pseudohalogen;

R⁷denotes hydrogen or an unsubstituted or mono- or polysubstituted group selected from the group consisting of C_1-16-alkyl, C_2-16-alkenyl, C_2-16-alkynyl, C_3-10-cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent(s) of the mono- or polysubstituted group are identical or different and are selected from the group consisting of halogen, NO₂, —OR⁸, —C(═O)R⁸, —C(═O)OR⁸, —C(═O)NR⁸R⁹, —NR⁸R⁹, —NR⁸COR⁹, —NR⁸C(═O)OR⁹, —NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═O)ONR⁹R¹⁰, —NR⁸SO₂R⁹, —N═CR⁸R⁹, —SR⁸, —SOR⁸, —SO₂R⁸, —SO₂NR⁸R⁹, —NR⁸SO₂NR⁹R¹⁰, —OSO₂NR⁸R⁹and pseudohalogen; and

R⁸, R⁹and R¹⁰each independently of one another denote hydrogen or a substituted or unsubstituted group selected from the group consisting of C_1-8-alkyl, C_2-8-alkenyl, C_2-8-alkynyl, C_3-10-cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent(s) of the substituted group are identical or different and are selected from the group consisting of halogen, methyl, ethyl, amino, methylamino, dimethylamino, —OH and pseudohalogen;

or a pharmacologically acceptable acid addition salt thereof

in an excipient or carrier.

2.) A method of prevention of a disease or condition responsive to an inhibitor of PLK, said disease or condition being selected from the group consisting of: infection, and inflammation; said method comprising administering a therapeutically effective amount of a pharmaceutical composition-comprising the compound the following formula (1):

wherein

W denotes N or C—R²,

X denotes —NR^1a, O or S,

Y denotes CH,

Z denotes —CF₃;

A is selected from one of the following formulas (i), (ii) and (iii):

Q₁denotes that (i), (ii) and (iii) are mono- or bicyclic aryl;

B¹, B², B³and B⁴each independently of one another denote C—R^gR^h, N—Rⁱ, O or S;

R¹and R^1aeach independently of one another denote hydrogen or methyl;

R²denotes one of hydrogen, halogen, —OR⁴, —C(═O)R⁴, —C(═O)NR⁴R⁵, —NR⁴R⁵, —NR⁴C(═O)R⁵, —NR⁴SO₂R⁵, —N═CR⁴R⁵, —C═NR⁴, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR⁴R⁵, pseudohalogen, and a mono- or polysubstituted group selected from the group consisting of C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6-cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent(s) of the mono- or polysubstituted group are identical or different and are selected from the group consisting of halogen, —NO₂, —OR⁴, —C(═O)R⁴, —C(═O)OR⁴, —C(═O)NR⁴R⁵, —NR⁴R⁵, —NR⁴C(═O)R⁵, —NR⁴C(═O)OR⁵, —NR⁴C(═O)NR⁵R⁶, —NR⁴SO₂R⁵, —N═CR⁴R⁵, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR⁴R⁵, —NR⁴SO₂NR⁵R⁶, —OSO₂NR⁵R⁶and pseudohalogen;

R^a, R^b, R^c, R^d, R^e, R^f, R^gand R^heach independently of one another denote a group selected from the group consisting of hydrogen, halogen, ═O, —NO₂, —OR⁴, —C(═O)R⁴, —C(═O)OR⁴, —C(═O)NR⁴R⁵, —NR⁴R⁵, —NR⁴C(═O)R⁵, —NR⁴C(═O)OR⁵, —NR⁴C(═O)NR⁵R⁶, —NR⁴SO₂R⁵—N═CR⁴R⁵, —C═NR⁴, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR⁴R⁵, —NR⁴SO₂NR⁵R⁶, —OSO₂NR⁵R⁶, pseudohalogen, and an unsubstituted or mono- or polysubstituted group selected from the group consisting of C_1-6-alkyl, C_2-6-alkenyl, C_2-6-alkynyl, C_3-6-cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent(s) of the mono- or polysubstituted group are identical or different and are selected from the group consisting of halogen, R⁸, —NO₂, —OR⁴, —C(═O)R⁴, —C(═O)OR⁴, —C(═O)NR⁴R⁵, —NR⁴R⁵, —NR⁴C(═O)R⁵, —NR⁴C(═O)OR⁵, —NR⁴C(═O)NR⁵R⁶, —NR⁴SO₂R⁵, —N═CR⁴R⁵, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR⁴R⁵, —NR⁴SO₂NR⁵R⁶, —OSO₂NR⁵R⁶and pseudohalogen; wherein R^gand R^hare optionally located at the same or at adjacent C atoms and are attached in any combination to a common saturated or partially unsaturated 3-5-membered alkyl bridge which contains one to two heteroatoms;

Rⁱdenotes a group selected from the group consisting of hydrogen, —OR⁴, —C(═O)R⁴, —C(═O)OR⁴, —C(═O)NR⁴R⁵, —NR⁴R⁵, —NR⁴C(═O)R⁵, —NR⁴C(═O)OR⁵, —NR⁴C(═O)NR⁵R⁶, —NR⁴SO₂R⁵, —N═CR⁴R⁵, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR⁴R⁵, —NR⁴SO₂NR⁵R⁶, —OSO₂NR⁵R⁶, pseudohalogen and an unsubstituted or substituted mono- or polysubstituted group selected from the group consisting of C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent(s) of the mono- or polysubstituted group are identical or different and are selected from the group consisting of halogen, R⁸, —NO₂, —OR⁴, —C(═O)R⁴, —C(═O)OR⁴, —C(═O)NR⁴R⁵, —NR⁴R⁵, —NR⁴C(═O)R⁵, —NR⁴C(═O)OR⁵, —NR⁴C(═O)NR⁵R⁶, —NR⁴SO₂R⁵, —N═CR⁴R⁵, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR⁴R⁵, —NR⁴SO₂NR⁵R⁶, —OSO₂NR⁵R⁶and pseudohalogen; wherein the Rⁱgroups located at adjacent N atoms are optionally joined together or Rⁱwith R^gor R^hlocated at adjacent C atoms are optionally attached in any combination to a common saturated or partially unsaturated 3-5-membered alkyl bridge which contains one to two heteroatoms;

R³is selected from the following formulas (iv)-(x):

R⁴, R⁵and R⁶each independently of one another denote hydrogen or an unsubstituted or mono- or polysubstituted group selected from the group consisting of C_1-5-alkyl, C_2-5alkenyl, C_2-5alkynyl, C_3-10-cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent(s) of the mono- or polysubstituted group are identical or different and are selected from the group consisting of C_3-10-cycloalkyl, aryl, heterocyclyl, heteroaryl, halogen, —NO₂, —OR⁸, —C(═O)R⁸, —C(═O)OR⁸, —C(═O)NR⁸R⁹, —NR⁸R⁹, —NR⁸C(═O)R⁹, —NR⁸C(═O)OR⁹, —NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═O)ONR⁹R¹⁰, —NR⁸SO₂R⁹, —N═CR⁸R⁹, —SR⁸, —SOR⁸, —SO₂R⁸, —SO₂NR⁸R⁹, —NR⁸SO₂NR⁹R¹⁰, —OSO₂NR⁸R⁹and pseudohalogen;

L denotes a bond or an unsubstituted or mono- or polysubstituted group selected from the group consisting of C_1-16-alkyl, C_2-16-alkenyl, C_2-16-alkynyl, C_3-10-cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent(s) of the mono- or polysubstituted group are identical or different and are selected from the group consisting of halogen, —NO₂, —OR⁸, —C(═O)R⁸, —C(═O)OR⁸, —C(═O)NR⁸R⁹, —NR⁸R⁹, —NR⁸C(═O)R⁹, —NR⁸C(═O)OR⁹, —NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═O)ONR⁹R¹⁰, —NR⁸SO₂R⁹, —N═CR⁸R⁹, —SR⁸, —SOR⁸, —SO₂R⁸, —SO₂NR⁸R⁹, —NR⁸SO₂NR⁹R¹⁰, —OSO₂NR⁸R⁹and pseudohalogen;

Q₂and Q₃each independently of one another denote a bond or an unsubstituted or mono- or polysubstituted group selected from the group consisting of C_1-16-alkyl, C_2-16-alkenyl, C_2-16-alkynyl, C_3-10-cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent(s) of the mono- or polysubstituted group are identical or different and are selected from the group consisting of halogen, —NO₂, —OR⁸, —C(═O)R⁸, —C(═O)OR⁸, —C(═O)NR⁸R⁹, —NR⁸R⁹, —NR⁸C(═O)R⁹, —NR⁸C(═O)OR⁹, —NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═O)ONR⁹R¹⁰, —NR⁸SO₂R⁹, —N═CR⁸R⁹, —SR⁸, —SOR⁸, —SO₂R⁸, —SO₂NR⁸R⁹, —NR⁸SO₂NR⁹R¹⁰, —OSO₂NR⁸R⁹and pseudohalogen;

R⁷denotes hydrogen or an unsubstituted or mono- or polysubstituted group selected from the group consisting of C_1-16-alkyl, C_2-16-alkenyl, C_2-16-alkynyl, C_3-10-cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent(s) of the mono- or polysubstituted group are identical or different and are selected from the group consisting of halogen, NO₂, —OR⁸, —C(═O)R⁸, —C(═O)OR⁸, —C(═O)NR⁸R⁹, —NR⁸R⁹, —NR⁸COR⁹, —NR⁸C(═O)OR⁹, —NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═O)ONR⁹R¹⁰, —NR⁸SO₂R⁹, —N═CR⁸R⁹, —SR⁸, —SOR⁸, —SO₂R⁸, —SO₂NR⁸R⁹, —NR⁸SO₂NR⁹R¹⁰, —OSO₂NR⁸R⁹and pseudohalogen; and

R⁸, R⁹and R¹⁰each independently of one another denote hydrogen or a substituted or unsubstituted group selected from the group consisting of C_1-8-alkyl, C_2-8-alkenyl, C_2-8-alkynyl, C_3-10-cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent(s) of the substituted group are identical or different and are selected from the group consisting of halogen, methyl, ethyl, amino, methylamino, dimethylamino, —OH and pseudohalogen;

or a pharmacologically acceptable acid addition salt thereof

in an excipient or carrier.