Pyrimidines As Plk Inhibitors

  *US07521457B2*
  US007521457B2                                 
(12)United States Patent(10)Patent No.: US 7,521,457 B2
 Stadtmueller et al. (45) Date of Patent:*Apr.  21, 2009

(54)Pyrimidines as PLK inhibitors 
    
(75)Inventors: Heinz Stadtmueller,  Gaweinstal (AT); 
  Harald Engelhardt,  Ebreichsdorf (AT); 
  Martin Steegmaier,  Vienna (AT); 
  Anke Baum,  Vienna (AT); 
  Ulrich Guertler,  Vienna (AT); 
  Andreas Schoop,  Vienna (AT); 
  Jens Juergen Quant,  Guntramsdorf (AT); 
  Flavio Solca,  Vienna (AT); 
  Rudolf Hauptmann,  Ebreichsdorf (AT); 
  Ulrich Reiser,  Vienna (AT); 
  Stephan Karl Zahn,  Vienna (AT); 
  Lars Herfurth,  Vienna (AT) 
(73)Assignee:Boehringer Ingelheim International GmbH,  Ingelheim (DE), Type: Foreign Company 
(*)Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. 
  This patent is subject to a terminal disclaimer. 
(21)Appl. No.: 11/206,703 
(22)Filed: Aug.  17, 2005 
(65)Prior Publication Data 
 US 2006/0148800 A1 Jul.  6, 2006 
(30)Foreign Application Priority Data 
 Aug.  20, 2004     (EP)   04019775
(51)Int. Cl. C07D 239/42 (20060101); C07D 239/46 (20060101); A61K 031/505 (20060101); A61K 031/506 (20060101); A61P 035/00 (20060101)
(52)U.S. Cl. 514/269; 514/275; 544/320; 544/323; 544/324
(58)Field of Search  544/323, 324, 320; 514/275, 269

 
(56)References Cited

 
 FOREIGN PATENT DOCUMENTS 
 
       WO       0012485                         3/2000      
       WO       0204429       A1                1/2002      
       WO       2004074244       A2                9/2004      
       WO       WO 20/04080980       A1       *       9/2004      

 OTHER PUBLICATIONS
  
  Cecil Textbook of Medicine, edited by Bennet, J.C., and Plum F., 20th edition, vol. 1, 1004-1010, 1996. *
  Ahmed FASEB Journal 18, 5-7, 2004. *
  Turner et al., Current Pharmaceutical Design. 2, 209-224, 1996. *
  Sugar et al., Diagn. Microbiol. Infect. Dis. 21:129-133, 1995. *
  Snyder et al., J. Med. Liban 48(4): 208-214, 2000. *
  International Preliminary Report on Patentability (Form PCT/IB/373) for corresponding PCT/EP2005/054089.
  Written Opinion of the International Searching Authority (Form PCT/ISA/237) for corresponding PCT/EP2005/054089.
 
 
     * cited by examiner
 
     Primary Examiner —Venkataraman Balasubramanian
     Art Unit — 1624
     Exemplary claim number — 1
 
(74)Attorney, Agent, or Firm — Michael P. Morris; Mary-Ellen M. Devlin; Philip I. Datlow

(57)

Abstract

The present invention encompasses compounds of general formula (1),
[see pdf for image]
wherein
A, W, X, Y, Z, Ra, Rb, Rc, R1 and R3 are defined as in claim 1, which are suitable for the treatment of diseases characterised by excessive or abnormal cell proliferation, and the use thereof for preparing a pharmaceutical composition having the above-mentioned properties.
11 Claims, Drawing Sheets, and Figures
 
 
[0001] The present invention relates to new pyrimidines of general formula (1),
[0002]  [see pdf for image]
wherein the groups A, W, X, Y, Z, Ra, Rb, Rc, R1 and R3 have the meanings given in the claims and description, the isomers thereof, processes for preparing these pyrimidines and their use as pharmaceutical compositions.

BACKGROUND TO THE INVENTION

[0003] Tumour cells wholly or partly elude regulation and control by the body and are characterised by uncontrolled growth. This is due on the one hand to the loss of control proteins such as for example Rb, p16, p21 and p53 and also to the activation of so-called accelerators of the cell cycle, the cyclin-dependent kinases.
[0004] Studies in model organisms such as Schizosaccharomyces pombe, Drosophila melanogaster or Xenopus laevis as well as investigations in human cells have shown that the transition from the G2 phase to mitosis is regulated by the CDK1/cyclin B kinase (Nurse 1990, Nature 344: 503-508). This kinase, which is also known as “mitosis promoting factor” (MPF), phosphorylates and regulates a plurality of proteins, such as e.g. nuclear lamina, kinesin-like motor proteins, condensins and Golgi Matrix Proteins, which play an important part in the breakdown of the nuclear coat, in centrosome separation, the structure of the mitotic spindle apparatus, chromosome condensation and breakdown of the Golgi apparatus (Nigg. E. 2001, Nat Rev Mol Cell Biol. 2(1):21-32). A murine cell line with a temperature-sensitive CDK-1 kinase mutant shows a rapid breakdown in CDK-1 kinase after temperature increase and a subsequent arrest in the G2/M phase (Th´ng et al. 1990, Cell. 63(2):313-24). The treatment of human tumour cells with inhibitors against CDK1/cyclin B, such as e.g. butyrolactone, leads to an arrest in the G2/M phase and subsequent apoptosis (Nishio, et al. 1996, Anticancer Res.16(6B):3387-95).
[0005] Moreover, the protein kinase Aurora B has also been described as having an essential function during entry into mitosis. Aurora B phosphorylates histone H3 on Ser10 and thereby initiates chromosome condensation (Hsu et al. 2000, Cell 102:279-91). A specific cell cycle arrest in the G2/M phase may, however, also be initiated e.g. by inhibition of specific phosphatases such as e.g. Cdc25C (Russell and Nurse 1986, Cell 45:145-53). Yeasts with a defective Cdc25 gene arrest in the G2 phase, whereas overexpression of Cdc25 leads to premature entry into the mitosis phase (Russell and Nurse, 1987, Cell 49:559-67). Moreover, an arrest in the G2/M phase may also be initiated by inhibition of specific motor proteins, the so-called kinesins such as for example Eg5 (Mayer et al. 1999, Science 286:971-4), or by microtubuli stabilising or destabilising agents (e.g. colchicin, taxol, etoposide, vinblastine, vincristine) (Schiff and Horwitz 1980, Proc Natl Acad Sci USA 77:1561-5).
[0006] In addition to the cyclin-dependent and Aurora kinases the so-called polo-like kinases, a small family of serine/threonine kinases, also play an important role in the regulation of the eukaryotic cell cycle. Up till now the polo-like kinases PLK-1, PLK-2, PLK-3 and PLK-4 have been described in the literature. PLK-1 in particular has been found to play a central role in the regulation of the mitosis phase. PLK-1 is responsible for the maturation of the centrosomes, for the activation of phosphatase Cdc25C, as well as for the activation of the Anaphase Promoting Complex (Glover et al. 1998, Genes Dev. 12:3777-87; Qian et al. 2001, Mol Biol Cell. 12:1791-9). The injection of PLK-1 antibodies leads to a G2 arrest in untransformed cells, whereas tumour cells arrest during the mitosis phase (Lane and Nigg 1996, J. Cell Biol. 135:1701-13). Overexpression of PLK-1 has been demonstrated in various types of tumour, such as non-small-cell carcinoma of the lung, plate epithelial carcinoma, breast and colorectal carcinoma (Wolf et al. 1997, Oncogene 14:543-549; Knecht et al. 1999, Cancer Res. 59:2794-2797; Wolf et al. 2000, Pathol. Res. Pract. 196:753-759; Takahashi et al. 2003, Cancer Sci. 94:148-52). Therefore, this category of proteins also presents an interesting point of attack for therapeutic intervention in proliferative diseases (Liu and Erikson 2003, Proc Natl Acad Sci USA 100:5789-5794).
[0007] Pyrimidines are generally known as inhibitors of kinases. Thus, for example, pyrimidines are described as an active component with an anticancer activity in International Patent Application WO 00/53595, which describes the use of 2,4,5-substituted pyrimidines with a heterocyclic group in the 4-position and an anilino group in the 2 position, which in turn comprises a side chain with the length of at least one n-propyl group.
[0008] Moreover, International Patent Application WO 00/39101 describes the use of 2,4,5-substituted pyrimidines as compounds with an anticancer activity which are linked in the 2- and 4-position with an aromatic or heteroaromatic ring, at least one of which comprises a side chain with the length of at least one n-propyl group.
[0009] International Patent Application WO 97/19065 further proposes the use of 2,4,5-substituted pyrimidines with a 3,4-dialkoxyanilino group in position 2 as kinase inhibitors.
[0010] International Patent Application WO 02/04429 describes 2,4,5-substituted pyrimidines with a cyano group in position 5 and their cell cycle inhibiting effect.
[0011] International Patent Application WO 03/063794 describes the use of 2,4-pyrimidinediamines as inhibitors of the IgE and/or IgG receptor signal cascade.
[0012] Antiviral 2,4,5-substituted pyrimidines, wherein the groups Rc and Rd form a heteroaromatic five-membered ring at the nitrogen of the 4-position, are known from International Patent Application WO 99/41253.
[0013] 2,4,5-substituted pyrimidines which carry (hetero)aryls in position 2 and 4 (WO00/27825) and also 2,4,5-substituted pyrimidines which carry a (hetero)aryl group functionalised with a nitrile group in position 2 or 4 (EP 0 945 443 A1) are described as having an antiviral activity.
[0014] The resistance of many types of tumour demands that new drugs be developed to fight the tumours. The aim of the present invention is therefore to indicate new active substances which may be used for the prevention and/or treatment of diseases characterised by excessive or anomalous cell proliferation.

DETAILED DESCRIPTION OF THE INVENTION

[0015] It has now been found that, surprisingly, compounds of general formula (1), wherein the groups A, W, X, Y, Ra, Rb, Rc, R1, R2 and R3 are defined as hereinafter, act as inhibitors of specific cell cycle kinases. Thus, the compounds according to the invention may be used for example for the treatment of diseases associated with the activity of specific cell cycle kinases and characterised by excessive or anomalous cell proliferation.
[0016] The present invention relates to compounds of general formula (1)
[0017]  [see pdf for image]
wherein
[0018] W denotes N or C—R2,
[0019] X denotes —NR1a, O or S,
[0020] Y denotes CH or N,
[0021] Z denotes hydrogen, halogen, —NO2, C1-3alkyl, C2-3alkenyl, C2-3alkynyl, halogen-C1-3alkyl, —COH, —C(═O)—C1-3alkyl, —C(═O)—C2-3alkenyl, —C(═O)—C2-3alkynyl, —C(═O)C1-3alkyl-halogen or pseudohalogen;
[0022] A is selected from the formulae (i), (ii) or (iii)
[0023]  [see pdf for image]
[0024] Q1 denotes mono- or bicyclic aryl compounds,
[0025] B1, B2, B3 and B4 in each case independently of one another denote C—RgRh, N—Ri, O or S, while adjacent B1-B4 in each case do not represent —O—;
[0026] R1 and R1a each independently of one another denote hydrogen or methyl,
[0027] R2 denotes 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, —SO2NR4R5 and pseudohalogen, or an optionally mono- or polysubstituted group selected from among C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6-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, —OSO2NR5R6 and pseudohalogen;
[0028] Ra, Rb, Rc, Rd, Re, Rf, Rg and Rh in 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, —OSO2NR5R6 and pseudohalogen; or an optionally mono- or polysubstituted group selected from among C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-6-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, —OSO2NR5R6 and pseudohalogen; and optionally the Rg and Rh located at the same or at adjacent C atoms may be attached in any combination to a common saturated or partially unsaturated 3-5-membered alkyl bridge which may contain one to two heteroatoms;
[0029] Ri denotes 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, —OSO2NR5R6 and pseudohalogen; or an optionally mono- or polysubstituted group selected from among C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, 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, —OSO2NR5R6 and pseudohalogen; and optionally the Ri groups located at adjacent N atoms may be joined together or Ri with Rg or Rh located at adjacent C atoms may be attached in any combination to a common saturated or partially unsaturated 3-5-membered alkyl bridge which may contain one to two heteroatoms;
[0030] R3 is selected from the formulae (iv)-(x),
[0031]  [see pdf for image]
[0032] R4, R5 and R6 each independently of one another denote hydrogen or a group selected from among optionally mono- or polysubstituted C1-5-alkyl, C2-5alkenyl, C2-5alkynyl, C3-10cycloalkyl, aryl, heterocyclyl and heteroaryl, while the substituent(s) may be identical or different and are selected from among C3-10-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, —OSO2NR8R9 and pseudohalogen;
[0033] L denotes a bond or a group selected from among optionally mono- or polysubstituted C1-16-alkyl, C2-16-alkenyl, C2-16-alkynyl, C3-10cycloalkyl, 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, —OSO2NR8R9 and pseudohalogen;
[0034] Q2 and Q3 independently of one another denote a bond or a group selected from among optionally mono- or polysubstituted C1-16-alkyl, C2-16-alkenyl, C2-16-alkynyl, C3-10cycloalkyl, 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, —OSO2NR8R9 and pseudohalogen;
[0035] R7 denotes hydrogen or a group selected from among optionally mono- or polysubstituted C1-16-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-10cycloalkyl, 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, —OSO2NR8R9 and pseudohalogen;
[0036] R8, R9 and R10 each independently of one another denote hydrogen or a group selected from among optionally substituted C1-8-alkyl, C2-8-alkenyl, C2-8-alkynyl, C3-10-cycloalkyl, aryl, heterocyclyl and heteroaryl, while the substituent(s) may be identical or different and are selected from among halogen, methyl, ethyl, amino, methylamino, dimethylamino, —OH and pseudohalogen;
optionally in the form of the tautomers, racemates, enantiomners, diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
[0037] In one aspect the invention relates to compounds of general formula (1) wherein
[0038] W denotes C—R2 and the other groups are as hereinbefore defined.
[0039] In another aspect the invention relates to compounds of general formula (1), wherein
[0040] X denotes —NR1a or oxygen,
[0041] R1 and R1a denote hydrogen;
[0042] R3 denotes formula (iv) or (x),
[0043]  [see pdf for image]
and the other groups are as hereinbefore defined.
[0044] In another aspect the invention relates to compounds of general formula (1), wherein
[0045] Y denotes CH and
[0046] Q1 denotes monocyclic aryl compounds
and the other groups are as hereinbefore defined.
[0047] In one aspect the invention relates to compounds of general formula (1), wherein
[0048] Rc denotes a group selected from among hydrogen, —F, —Cl, methyl and ethyl and the other groups are as hereinbefore defined.
[0049] In another aspect the invention relates to compounds of general formula (1), wherein
[0050] Ra and Rb each independently of one another denote hydrogen or fluorine; or an optionally mono- or polysubstituted group selected from among C1-2-alkyl, C2-alkenyl, C2-alkynyl, C3-6-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, —OSO2NR4R5 and pseudohalogen
and the other groups are as hereinbefore defined.
[0051] In another aspect the invention also relates to compounds of general formula (1), wherein

Ra and Rb denote hydrogen or fluorine and the other groups are as hereinbefore defined.

[0052] The invention also includes compounds of general formula (1), wherein
[0053] Z denotes halogen-C1-3-alkyl, —COH, —C(═O)—C1-3-alkyl, —C(═O)—C2-3-alkenyl, —C(═O)—C2-3-alkynyl, —C(═O)C1-3-alkyl-halogen and pseudohalogen
and the other groups are as hereinbefore defined.
[0054] In one aspect the invention relates to compounds of general formula (1), or the pharmaceutically active salts thereof, as pharmaceutical compositions.
[0055] 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.
[0056] 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.
[0057] 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.
[0058] 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.
[0059] 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.
[0060] In another aspect the invention relates to a pharmaceutical preparation containing at least one compound of general formula (1)
[0061]  [see pdf for image]
wherein
[0062] W denotes N or C—R2,
[0063] X denotes —NR1a, O or S,
[0064] Y denotes CH or N,
[0065] Z denotes hydrogen, halogen, —NO2, C1-3-alkyl, C2-3-alkenyl, C2-3-alkynyl, halogen-C1-3-alkyl, —COH, —C(═O)—C1-3-alkyl, —C(═O)—C2-3-alkenyl, —C(═O)—C2-3-alkynyl, —C(═O)C1-3-alkyl-halogen and pseudohalogen;
[0066] A is selected from the formulae (i), (ii) or (iii)
[0067]  [see pdf for image]
[0068] Q1 denotes mono- or bicyclic aryl compounds;
[0069] B1, B2, B3 and B4 in each case independently of one another represent C—RgRh, N—Ri, O or S, while adjacent B1-B4 in each case do not denote —O—;
[0070] R1 and R1a each independently of one another denote hydrogen or methyl,
[0071] R2 denotes 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, —SO2NR4R5 and pseudohalogen, or an optionally mono- or polysubstituted group selected from among C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-6-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, —OSO2NR5R6 and pseudohalogen;
[0072] Ra, Rb, Rc, Rd, Re, Rf, Rg and Rh in 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, —OSO2NR5R6 and pseudohalogen; or an optionally mono- or polysubstituted group selected from among C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-6-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, —OSO2NR5R6 and pseudohalogen; and optionally the Rg and Rh located at the same or at adjacent C atoms may be attached in any combination to a common saturated or partially unsaturated 3-5-membered alkyl bridge which may contain one to two heteroatoms;
[0073] Ri denotes 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, —OSO2NR5R6 or an optionally mono- or polysubstituted group selected from among C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-6-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 , —OSO2NR5R6 and pseudohalogen; and optionally the Ri groups located at adjacent N atoms may be joined together or to Rg and Rh located at adjacent C atoms in any combination with a common saturated or partially unsaturated 3-5-membered alkyl bridge which may contain one to two heteroatoms;
[0074] R3 is selected from the formulae (iv)-(x),
[0075]  [see pdf for image]
[0076] R4, R5 and R6 each independently of one another denote hydrogen or a group selected from among optionally mono- or polysubstituted C1-5-alkyl, C2-5-alkenyl, C2-5-alkynyl, C3-10-cycloalkyl, aryl, heterocyclyl and heteroaryl, while the substituent(s) may be identical or different and are selected from among C3-10-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, —OSO2NR8R9 and pseudohalogen;
[0077] L denotes a bond or a group selected from among optionally mono- or polysubstituted C1-16-alkyl, C2-16-alkenyl, C2-16-alkynyl, C3-10-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, —OSO2NR8R9 and pseudohalogen;
[0078] Q2 and Q3 independently of one another denote a bond or a group selected from among optionally mono- or polysubstituted C1-16-alkyl, C2-16-alkenyl, C2-16-alkynyl, C3-10-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, —OSO2NR8R9 and pseudohalogen;
[0079] R7 denotes hydrogen or a group selected from among optionally mono- or polysubstituted C1-16-alkyl, C2-16-alkenyl, C2-16-alkynyl, C3-10-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, —OSO2NR8R9 and pseudohalogen;
[0080] R8, R9 and R10 each independently of one another denote hydrogen or a group selected from among optionally substituted C1-8-alkyl, C2-8-alkenyl, C2-8-alkynyl, C3-10-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
[0081] As used herein, the following definitions apply, unless stated otherwise.
[0082] By alkyl substituents are meant in each case saturated, straight-chain or branched aliphatic hydrocarbon groups (alkyl group).
[0083] The alkenyl substituents are in each case straight-chain or branched, unsaturated alkyl groups which have at least one double bond.
[0084] By alkynyl substituents are meant in each case straight-chain or branched, unsaturated alkyl groups which have at least one triple bond.
[0085] 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, —CHFCH2CH3 and —CHFCH2CF3.
[0086] Halogen relates to fluorine, chlorine, bromine and/or iodine atoms.
[0087] By pseudohalogen are meant the following groups: —OCN, —SCN, —CF3 and —CN.
[0088] 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.
[0089] Aryl relates to monocyclic or bicyclic rings with 6-12 carbon atoms such as for example phenyl and naphthyl.
[0090] By heteroaryl are meant mono- or bicyclic rings which contain instead of one or more carbon atoms one or more identical or different heteroatoms, such as e.g. nitrogen, sulphur or oxygen atoms. Examples include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl and triazinyl. Examples of bicyclic heteroaryl groups are indolyl, isoindolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, indazolyl, isoquinolinyl, quinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl and benzotriazinyl, indolizinyl, oxazolopyridinyl, imidazopyridinyl, naphthyridinyl, indolinyl, isochromanyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl, benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, phenoxazinyl, phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl, imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl, dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, cumarinyl, isocumarinyl, chromonyl, chromanonyl, pyridinyl-N-oxid, tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl, dihydroisoquinolinonyl, dihydrocumarinyl, dihydroisocumarinyl, isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl-N-oxide, pyrimidinyl-N-oxide, pyridazinyl-N-oxide, pyrazinyl-N-oxide, quinolinyl-N-oxide, indolyl-N-oxide, indolinyl-N-oxide, isoquinolyl-N-oxide, quinazolinyl-N-oxide, quinoxalinyl-N-oxide, phthalazinyl-N-oxide, imidazolyl-N-oxide, isoxazolyl-N-oxide, oxazolyl-N-oxide, thiazolyl-N-oxide, indolizinyl-N-oxide, indazolyl-N-oxide, benzothiazolyl-N-oxide, benzimidazolyl-N-oxide, pyrrolyl-N-oxide, oxadiazolyl-N-oxide, thiadiazolyl-N-oxide, triazolyl-N-oxide, tetrazolyl-N-oxide, benzothiopyranyl-S-oxide and benzothiopyranyl-S,S-dioxide.
[0091] Heterocyclyl relates to saturated or unsaturated, non-aromatic mono-, bicyclic or bridged bicyclic rings comprising 5-12 carbon atoms, which carry heteroatoms, such as nitrogen, oxygen or sulphur, instead of one or more carbon atoms. Examples of such heterocylyl groups are tetrahydrofuranyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, indolinyl, isoindoliny, morpholinyl, thiomorpholinyl, homomorpholinyl, homopiperidyl, homopiperazinyl, thiomorpholinyl-S-oxide, thiomorpholinyl-S,S-dioxide, tetrahydropyranyl, piperidinyl, tetrahydrothienyl, homopiperidinyl, homothiomorpholinyl-S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydrofuryl, dihydropyranyl, tetrahydrothienyl-S-oxide, tetrahydrothienyl-S,S-dioxide, homothiomorpholinyl-S-oxide, 2-oxa-5-azabicyclo[2.2.1]heptane, 8-oxa-3-aza-bicyclo[3.2.1]octane, 3,8-diaza-bicyclo[3.2.1]octane, 2,5-diaza-bicyclo[2.2.1]heptane, 3,8-diaza-bicyclo[3.2.1]octane, 3,9-diaza-bicyclo[4.2.1]nonane, 2,6-diaza-bicyclo[3.2.2]nonane, 2,7-diaza-spiro[3.5]nonane, 2,7-diaza-spiro[4.4]nonane, 2,8-diaza-spiro[4.5]decane, 3,9-diaza-spiro[5.5]undecane.
[0092] The Examples that follow illustrate the present invention without restricting its scope:

Preparation of the Compounds According to the Invention:

[0093] The compounds according to the invention may be prepared according to methods of synthesis A to C described hereinafter, wherein the substituents of general formulae (I to XVI) have the meanings given hereinbefore.

Method A

[0094] Step 1A
[0095] 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.
[0096]  [see pdf for image]
[0097] 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.
[0098] Step 2A
[0099] 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.
[0100]  [see pdf for image]
[0101] 1 equivalent of the compound III and 1 to 3 equivalents of the compound IV are stirred in a solvent, for example 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide or N-methyl-2-pyrrolidinone. At a temperature of 15 to 40° C., 1 to 2 equivalents of an inorganic acid, for example sulphuric acid or hydrochloric acid, are added. The reaction mixture is stirred for another 12 to 72 h at a temperature of 20 to 100° C. Then the solvent is distilled off and the residue is purified by chromatography.

Method B

[0102] Step 1B
[0103] 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.
[0104]  [see pdf for image]
[0105] 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.
[0106] 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.
[0107] The combined organic extracts are dried and the solvent is distilled off. The residue is purified by chromatography or repeated crystallisation.
[0108] Step 2B
[0109] 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.
[0110]  [see pdf for image]
[0111] 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.
[0112] Step 3B
[0113] Compounds VIII whose group R7 denotes hydrogen may be used directly for preparing the end compounds X, while a compound VIII is reacted with a compound IX.
[0114] Compounds VIII whose group R7 does not denote hydrogen are converted beforehand by hydrolysis or similar methods known to the skilled man into the compounds wherein the group R7 denotes hydrogen.
[0115]  [see pdf for image]
[0116] 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 C

[0117] Step 1C
[0118] 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.
[0119]  [see pdf for image]
[0120] 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.
[0121] Step 2C
[0122] 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.
[0123]  [see pdf for image]
[0124] 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:

[0125] 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.
[0126] 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:

[0127] 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.
[0128] 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 CDCl3 signals they are not mentioned.

Mass Spectroscopy/UV Spectrometer:

[0129] These data are generated using an HPLC-MS apparatus (high performance liquid chromatography with mass detector) made by Agilent.
[0130] The apparatus is constructed so that a diode array detector (G1315B made by Agilent) and a mass detector (1100 LS-MSD SL; G1946D; Agilent) are connected in series downstream of the chromatography apparatus (column: Zorbax SB-C8, 3.5 μm, 2,1*50, Messrs. Agilent). The apparatus is operated with a flow of 0.6 ml/min. For a separation process a gradient is run through within 3.5 min (start of gradient: 95% water and 5% acetonitrile; end of gradient: 5% water and 95% acetonitrile; in each case 0.1% formic acid is added to the two solvents).

Method 1

[0131] 2-(2-methoxy-4-propylcarbamoyl-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine
[0132]  [see pdf for image]
[0133] 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% KHSO4 solution, then with 300 ml saturated aqueous NaCl solution. The organic phase is dried with MgSO4 and the solvent is eliminated in vacuo. The crude product is purified by column chromatography. The carrier used is silica gel and the eluant is a mixture of cyclohexane:ethyl acetate (75:25).
[0134] 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 2

[0135] 7-amino-2,3-dihydro-isoindol-1-one
[0136]  [see pdf for image]
a) 7-nitro-2,3-dihydro-isoindol-1-one
[0137] 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.
[0138] Yield: 960 mg (5.389 mmol, 99%) MS-ESI+: m/z=179 [M+H]+

b) 7-amino-2,3-dihydro-isoindol-1-one

[0139] 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 (H2 pressure). The catalyst is filtered off and the solvent is eliminated in vacuo.
[0140] Yield: 734 mg (4.958 mmol, 92%) MS-ESI+: m/z=149 [M+H]+
[0141] 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:
[0142] 
[00001] [TABLE-US-00001]
   
    MS (ESI)     MS (ESI)
  (M + H)+   (M + H)+
   
 
[see pdf for image]   163 [see pdf for image]   193
 
[see pdf for image]   177 [see pdf for image]   225
 
[see pdf for image]   191 [see pdf for image]   243
 
[see pdf for image]   231 [see pdf for image]   221
 
[see pdf for image]   219 [see pdf for image]   255
 
[see pdf for image]   233 [see pdf for image]   192
 
[see pdf for image]   207 [see pdf for image]   255
 
[see pdf for image]   234 [see pdf for image]   178
 
[see pdf for image]   274 [see pdf for image]   192
 
[see pdf for image]   195 [see pdf for image]   211/213
 
[see pdf for image]   213 [see pdf for image]   247
 
[see pdf for image]   231 [see pdf for image]   247
 
[see pdf for image]   209 [see pdf for image]   261
 
[see pdf for image]   245 [see pdf for image]   261
 
[see pdf for image]   188 [see pdf for image]   261
 
[see pdf for image]   187 [see pdf for image]   261
 
[see pdf for image]   206 [see pdf for image]   223
 
[see pdf for image]   233 [see pdf for image]   223
 
[see pdf for image]   233 [see pdf for image]   221
 
[see pdf for image]   202 [see pdf for image]   247
 
[see pdf for image]   206 [see pdf for image]   246
 
[see pdf for image]   191 [see pdf for image]   235
 
[see pdf for image]   205 [see pdf for image]   224
 
[see pdf for image]   227 [see pdf for image]   222
 
[see pdf for image]   223
 

Method 3
[0143] Ethyl (4-amino-3-oxo-1,3-dihydro-isobenzofuran-1-yl)-acetate
[0144]  [see pdf for image]
a) ethyl (4-amino-3-oxo-3H-isobenzofuran-1-ylidene)-acetate
[0145] 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).
[0146] 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

[0147] 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 H2 pressure and 25° C. Then the catalyst is filtered off and the solvent is eliminated in vacuo.
[0148] 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 4

[0149] 5-amino-3H-quinazolin-4-one
[0150]  [see pdf for image]
a) 2,6-diaminobenzamide
[0151] 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 H2 pressure and 25° C. The solids are filtered off. The filtrate is combined with 300 ml of ethyl acetate and extracted with saturated potassium hydrogen carbonate solution. The organic phase is separated off, dried and the solvent is eliminated in vacuo. The residue is purified by chromatography. The carrier used is silica gel and the eluant used is dichloromethane, to which 7% of a mixture of 90% methanol and 10% saturated aqueous ammonia solution are added.
[0152] Yield: 900 mg (5.958 mmol; 23%) MS (ESI): 152 (M+H)+

b) 5-amino-3H-quinazolin-4-one

[0153] 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.
[0154] Yield: 782 mg (4.852 mmol; 81%) MS (ESI): 162 (M+H)+

Method 5

[0155] 9-amino-2,3,4,5-tetrahydro-2-benzazepin-1-one
[0156]  [see pdf for image]
[0157] 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 H2 pressure. The catalyst is filtered off, the filtrate concentrated by evaporation and stirred overnight with a 1:1 mixture of trifluoroacetic acid and dichloromethane at ambient temperature. After elimination of the solvent 133 mg (0.686 mmol, 73%) 2-amino-6-(3-amino-propyl)-benzoic acid are obtained. The further reaction is carried out by dissolving in 10 ml THF and 10 ml DCM with the addition of 300 mg (1.570 mmol) N-(3-dimethylaminopropyl)-N-4-ethylcarbodiimide hydrochloride and 134 μl (0.830 mmol) N,N-diisopropyl-ethylamine and 48 h stirring at ambient temperature. The solvent is eliminated in vacuo and the crude product is purified by chromatography with C18-RP silica gel and an eluant mixture of acetonitrile and water in the ratio 5:95 to 95:5, to which 0.1% formic acid has been added.
[0158] Yield: 28 mg (0.160 mmol, 23%) MS (ESI): m/z=177 (M+H)+

Method 6

[0159] 4-amino-1-methyl-1,2-dihydro-indazol-3-one
[0160]  [see pdf for image]
a) 4-nitro-1,2-dihydro-indazol-3-one
[0161] 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.
[0162] 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

[0163] 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.
[0164] 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

[0165] 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 MgSO4 and the solvent is eliminated in vacuo.
[0166] Yield: 33 mg (0.2 mmol, 28%) MS (ESI): m/z=164 (M+H)+
[0167] 4-amino-1,2-dihydro-indazol-3-one and the following compounds are prepared analogously to this method.
[0168] 
[00002] [TABLE-US-00002]
   
    MS     MS
    (ESI)     (ESI)
    (M +     (M +
  H)+   H)+
   
 
[see pdf for image]   178 [see pdf for image]   178
 
[see pdf for image]   194
 

Method 7
[0169] 8-amino-4-methyl-3,4-dihydro-2H-isoquinolin-1-one
[0170]  [see pdf for image]
a) methyl 2-(cyanomethyl-2-methyl)-6-nitro-benzoate
[0171] 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.
[0172] Yield: 289 mg (1.2 mmol, 68%) MS (ESI): 233 (M−H)

b) 8-amino-4-methyl-3,4-dihydro-2H-isoquinolin-1-one

[0173] 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 H2 pressure and 25° C. Then the catalyst is filtered off and the solvent is eliminated in vacuo.
[0174] Yield: 170 mg (0.8 mmol, 46%) MS (ESI): 177 (M+H)+
[0175] 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.
[0176] 
[00003] [TABLE-US-00003]
   
    MS    
    (ESI)
    (M +     MS (ESI)
  H)+   (M + H)+
   
 
[see pdf for image]   221 [see pdf for image]   205
 
[see pdf for image]   253
 

Method 8
[0177] 7-amino-indan-1-one
[0178]  [see pdf for image]
a) indan-4-ylamine
[0179] 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 MgSO4 and the solvent is eliminated in vacuo. The crude product is dissolved in 250 ml of methanol and combined with 4.5 g Raney nickel. The reaction mixture is hydrogenated for 16 h at 3 bar H2 pressure and 25° C. Then the catalyst is filtered off and the solvent is eliminated in vacuo. The crude product is purified by column chromatography. The carrier used is silica gel and the eluant used is a mixture of cyclohexane:ethyl acetate (75:25).
[0180] 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

[0181] 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).
[0182] 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

[0183] 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).
[0184] Yield: 95 mg (0.500 mmol, 60%) MS (ESI): 190 (M+H)+

d) 7-amino-indan-1-on

[0185] 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.
[0186] Yield: 388 mg (2.6 mmol, 100%)
[0187] 8-amino-3,4-dihydro-2H-naphthalen-1-one is prepared analogously to this method. 1,2,3,4-tetrahydronaphthalene is used as starting material instead of indane.

Method 9

[0188] N-(7-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-acetamide
[0189]  [see pdf for image]
a) 2-benzyloxy-N-(7-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-acetamide
[0190] 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).
[0191] Yield: 910 mg (2.7 mmol, 59%)

b) N-(7-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-acetamide

[0192] 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 H2 pressure and 25° C. Then the catalyst is filtered off and the solvent is eliminated in vacuo. The crude product is purified by chromatography. The carrier used is silica gel and the eluant used is a mixture of dichloromethane:methanol (90:10).
[0193] Yield: 210 mg (0.1 mmol, 41%) MS (ESI): 222 (M+H)+

Method 10

[0194] 6-amino-2-ethyl-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one
[0195]  [see pdf for image]
a) 2-amino-6-(1-aminomethyl-propoxy)-benzonitrile
[0196] 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.
[0197] Yield: 1.15 g (5.6 mmol, 38%) MS (ESI): 206 (M+H)+

b) 2-amino-6-(1-aminomethyl-propoxy)-benzoic acid

[0198] 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.
[0199] 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

[0200] 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.
[0201] Yield: 50 mg (0.2 mmol, 21%) MS (ESI): 207 (M+H)+
[0202] 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.
[0203] 
[00004] [TABLE-US-00004]
   
    MS (ESI)     MS (ESI)
  (M + H)+   (M + H)+
   
 
[see pdf for image]   207 [see pdf for image]   251
 
[see pdf for image]   193 [see pdf for image]   179
 
[see pdf for image]   235 [see pdf for image]   221
 
[see pdf for image]   219 [see pdf for image]   206
 
[see pdf for image]   233 [see pdf for image]   235
 
[see pdf for image]   207 [see pdf for image]   227
 
[see pdf for image]   207 [see pdf for image]   219
 
[see pdf for image]   193 [see pdf for image]   207
 
[see pdf for image]   221 [see pdf for image]   269
 
[see pdf for image]   299 [see pdf for image]   225
 
[see pdf for image]   219 [see pdf for image]   253
 
[see pdf for image]   209 [see pdf for image]   241
 
[see pdf for image]   269 [see pdf for image]   233
 

Method 11
[0204] 6-amino-3-benzyl-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione
[0205]  [see pdf for image]
a) methyl 2-(2-amino-6-nitro-benzoylamino)-3-phenyl-propionate
[0206] 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).
[0207] Yield: 1.04 g (3.03 mmol, 65%) MS (ESI): 344 (M+H)+

b) 2-(2-amino-6-nitro-benzoylamino)-3-phenyl-propionic acid

[0208] 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.
[0209] Yield: 636 mg (1.9 mmol, 64%)
[0210] 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

[0211] 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 H2 pressure and 25° C. Then the catalyst is filtered off, the solvent is eliminated in vacuo and the crude product is purified by chromatography. The carrier used is C18-RP-silica gel and a gradient is run through which consists of 95% water and 5% acetonitrile at the starting point and consists of 5% water and 95% acetonitrile at the finishing point.
[0212] 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

[0213] 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.
[0214] Yield: 22 mg (0.08 mmol, 27%) MS (ESI): 282 (M+H)+
[0215] The following compounds are prepared analogously to method 11.
[0216] 
[00005] [TABLE-US-00005]
   
    MS (ESI)     MS (ESI)
  (M + H)+   (M + H)+
   
 
[see pdf for image]   192 [see pdf for image]   268
 
[see pdf for image]   206 [see pdf for image]   277
 
[see pdf for image]   206 [see pdf for image]   278
 
[see pdf for image]   218 [see pdf for image]   278
 
[see pdf for image]   220 [see pdf for image]   282
 
[see pdf for image]   220 [see pdf for image]   283
 
[see pdf for image]   232 [see pdf for image]   283
 
[see pdf for image]   232 [see pdf for image]   288
 
[see pdf for image]   234 [see pdf for image]   296
 
[see pdf for image]   234 [see pdf for image]   192
 
[see pdf for image]   234 [see pdf for image]   298
 
[see pdf for image]   246 [see pdf for image]   298
 
[see pdf for image]   246 [see pdf for image]   300
 
[see pdf for image]   246 [see pdf for image]   300
 
[see pdf for image]   248 [see pdf for image]   300
 
[see pdf for image]   248 [see pdf for image]   307
 
[see pdf for image]   248 [see pdf for image]   316/318
 
[see pdf for image]   250 [see pdf for image]   321
 
[see pdf for image]   265 [see pdf for image]   321
 
[see pdf for image]   265 [see pdf for image]   346
 

Method 12
[0217] 2-(4-carboxy-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine
[0218]  [see pdf for image]
[0219] 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 MgSO4 and the solvent is eliminated in vacuo. The crude product is suspended in 10 ml n-hexane and refluxed. The precipitate is filtered off, suspended in 48 ml of a saturated aqueous sodium hydrogen carbonate solution and heated to 65° C. for 1 h. Then the solution is crystallised at 0° C. The precipitate is filtered off, the filtrate is acidified with 1 N aqueous hydrochloric acid and combined with 100 ml of ethyl acetate. The organic phase is separated off, dried with magnesium sulphate and the solvent is eliminated in vacuo. The residue is recrystallised from ethyl acetate.
[0220] 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 13

[0221] 4-(4-amino-cyclohexyl)-morpholine
[0222]  [see pdf for image]
a) dibenzyl-(4-morpholino-4-yl-cyclohexyl)-amine
[0223] 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.
[0224] Yield: 6.6 g (18 mmol, 60%) cis-isomer
[0225] 2 g (5.4 mmol, 18%) trans-isomer.

b) trans-4-morpholino-4-yl-cyclohexylamine

[0226] 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.
[0227] Yield: 3.9 g (15.2 mmol, 93%)
[0228] melting point: 312° C.
[0229] The following compounds are prepared analogously to Method 13:
[0230] 
[00006] [TABLE-US-00006]
   
    MS (ESI)     MS (ESI)
  (M + H)+   (M + H)+
   
 
[see pdf for image]   169 [see pdf for image]   213
 
[see pdf for image]   211 [see pdf for image]   238
 

Method 14
[0231] 2-(4-carboxy-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine
[0232]  [see pdf for image]
a) 2-(4-benzyloxycarbonyl-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine
[0233] 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.
[0234] 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

[0235] 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.
[0236] Yield: 0.76 g (2.192 mmol; 96%) UV max: 288 nm MS (ESI): 346/348 (M−H)Cl distribution
[0237] The following compounds are prepared analogously to this process:

2-(4-carboxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine

[0238] MS (ESI): 316/318 (M−H)Cl distribution

2-[4-(4-benzyloxycarbonyl-piperazin-1-yl)-phenylamino]-4-chloro-5-trifluoromethyl-pyrimidine

[0239] MS (ESI): 492/494 (M+H)+Cl distribution

2-[4-(4-benzyloxycarbonyl-piperazin-1-yl)-2-methoxy-phenylamino]-4-chloro-5-trifluoromethyl-pyrimidine

[0240] MS (ESI): 522/524, (M+H)+Cl distribution

Method 15

[0241] 3-pyrrolidin-1-yl-cyclobutylamine
[0242]  [see pdf for image]
a) tert.butyl (3-benzyloxy-cyclobutyl)-carbamate
[0243] 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).
[0244] 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

[0245] 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 H2 pressure. Then the catalyst is filtered off and the solvent is eliminated in vacuo. The residue is taken up in chloroform and washed three times with aqueous sodium hydrogen carbonate solution. The organic phase is dried with magnesium sulphate and the solvent is eliminated in vacuo.
[0246] Yield: 1.53 g (8.2 mmol; 82%) MS (ESI): 188 (M+H)+

c) tert.butyl (3-tosyl-cyclobutyl)-carbamate

[0247] 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.
[0248] Yield: 28.30 g (83 mmol; 83%) MS (ESI): 342 (M+H)+

d) tert.butyl (3-pyrrolidine-cyclobutyl)-carbamate

[0249] 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.
[0250] The substances that elute first are designated as follows:
[0251]  [see pdf for image]
[0252] Yield product A: 1 g (4.17 mmol; 4%)
[0253] RF value (silica gel; dichloromethane:methanol:conc. aqueous ammonia=90:9:1)=0.62
[0254] The substances that elute second are designated as follows:
[0255]  [see pdf for image]
[0256] Yield product C: 2.00 g (8.33 mmol; 8%)
[0257] RF value (silica gel; dichloromethane:methanol:conc. aqueous ammonia=90:9:1)=0.53

e) (*1′,*1″)-3-pyrrolidin-1-yl-cyclobutylamine

[0258]  [see pdf for image]
[0259] 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.
[0260] Yield: 0.43 g (2.786 mmol; 67%) MS (ESI): 141 (M+H)+
[0261] The following compounds are prepared analogously to this process:
[0262] 
[00007] [TABLE-US-00007]
   
    MS (ESI)     MS (ESI)
  (M + H)+   (M + H)+
   
 
[see pdf for image]   170 [see pdf for image]   143
 
[see pdf for image]   210 [see pdf for image]   198
 
[see pdf for image]   184 [see pdf for image]   196
 
[see pdf for image]   224 [see pdf for image]   194
 
[see pdf for image]   171 [see pdf for image]   183
 
[see pdf for image]   212
 
[0263] (*2′,*2″)-3-pyrrolidin-1-yl-cyclobutylamine
[0264]  [see pdf for image]
[0265] 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.
[0266] Yield: 0.43 g (3.09 mmol; 74%) MS (ESI): 141 (M+H)+
[0267] The following compounds are prepared analogously to this method:
[0268] 
[00008] [TABLE-US-00008]
   
    MS (ESI)     MS (ESI)
  (M + H)+   (M + H)+
   
 
[see pdf for image]   155 [see pdf for image]   212
 
[see pdf for image]   157 [see pdf for image]   143
 
[see pdf for image]   171 [see pdf for image]   141
 
[see pdf for image]   184 [see pdf for image]   198
 
[see pdf for image]   170 [see pdf for image]   251
 
[see pdf for image]   210 [see pdf for image]   194
 
[see pdf for image]   253 [see pdf for image]   196
 
[see pdf for image]   224 [see pdf for image]   171
 
[see pdf for image]   183
 

Method 16
[0269] 2-(4-carboxy-2-bromo-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine
[0270]  [see pdf for image]
[0271] 1 g (3.15 mmol) 2-(4-carboxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine are dissolved in 5 ml DMF and combined batchwise with 3.36 g (18.89 mmol) N-bromosuccinimide. The reaction mixture is stirred for 16 h at ambient temperature. The solvent is eliminated in vacuo and the residue is purified by column chromatography. The carrier used is C18-RP-silica gel and a gradient is ran through which consists of 95% water and 5% acetonitrile at the starting point and consists of 2% water and 98% acetonitrile at the finishing point. 0.1% formic acid is added in each case to both the water and to the acetonitrile.
[0272] Yield: 0.57 g (1.44 mmol; 46%) MS (ESI): 396/398 (M−H)+Cl/Br distribution

Method 17

[0273] 5-amino-3-(2-fluoro-ethyl)-3H-quinazolin-4-one
[0274]  [see pdf for image]
[0275] 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.
[0276] Yield: 67 mg (0.323 mmol; 10%) MS (ESI): 208 (M+H)+

Method 18

[0277] 8-amino-2-(2-fluoro-ethyl)-3,4-dihydro-2H-isoquinolin-1-one
[0278]  [see pdf for image]
a) 8-dibenzylamino-3,4-dihydro-2H-isoquinolin-1-one
[0279] 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.
[0280] 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

[0281] 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.
[0282] 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

[0283] 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 H2 pressure. Then the catalyst is filtered off and the solvent is eliminated in vacuo.
[0284] Yield: 0.403 g (1.935 mmol; 91%) MS (ESI): 209 (M+H)+
[0285] The following compounds are prepared analogously to this process:
[0286] 
[00009] [TABLE-US-00009]
   
    MS (ESI)     MS (ESI)
  (M + H)+   (M + H)+
   
 
[see pdf for image]   177 [see pdf for image]   223
 
[see pdf for image]   191
 

Method 19
[0287] 7-amino-5H-phenanthridin-6-one
[0288]  [see pdf for image]
[0289] 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 H2 pressure. 50 ml dichloromethane are added to the reaction solution, the mixture is treated for 5 min in the ultrasound bath and then the catalyst is filtered off. The solvent is eliminated in vacuo.
[0290] Yield: 46 mg (0.221 mmol; 94%) MS (ESI): 211 (M+H)+

Method 20

[0291] C-(5-morpholin-4-ylmethyl-1H-[1,2,3]triazol-4-yl)-methylamine
[0292]  [see pdf for image]
[0293] 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 H2 pressure. Then the catalyst is filtered off and the solvent is eliminated in vacuo.
[0294] Yield: 8.588 g (28.00 mmol; 28%) MS (ESI): 198 (M+H)+

Method 21

[0295] 4-morpholin-4-ylmethyl-cyclohexylamine
[0296]  [see pdf for image]
[0297] 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.
[0298] Yield: 4.22 g (9.9 mmol; 90%) (double trifluoroacetic acid salt) MS (ESI): 199 (M+H)+
[0299] The following compounds are prepared analogously to this process:
[0300] 
[00010] [TABLE-US-00010]
   
    MS (ESI)  
  (M + H)+
   
 
[see pdf for image]   157 [see pdf for image]   183
 
[see pdf for image]   157 [see pdf for image]   169
 

Method 22
[0301] 7-amino-2-(2-fluoro-ethyl)-3-methyl-2,3-dihydro-isoindol-1-one
[0302]  [see pdf for image]
[0303] 10 g (42.157 mmol) methyl 2-acetyl-6-nitro-benzoate (J. Org. Chem. (1952), 17, 164-76), 6.06 g (54.804 mmol) 2-fluoroethylamine and 9.32 ml (54.804 mmol) N-ethyldlisopropylamine are suspended in 25 ml of toluene and refluxed for 40 h with stirring. The reaction mixture is diluted with 400 ml of methanol and combined with 2.5 g palladium on charcoal. Then the mixture is stirred for 48 h at ambient temperature and 5 bar H2 pressure. The catalyst is filtered off and the solvent is eliminated in vacuo. The residue is taken up in dichloromethane and washed with water. The organic phase is dried with magnesium sulphate, the solvent is eliminated in vacuo and the crude product is purified by chromatography. The carrier used is silica gel and the eluant used is a mixture of cyclohexane:ethyl acetate (70:30).
[0304] Yield: 3.83 g (18.404 mmol, 43%) MS (ESI): 209 (M+H)+UV max: 318 nm
[0305] The following compounds are prepared analogously to this process, using the corresponding methyl 6-nitro-benzoate derivative:
[0306] 
[00011] [TABLE-US-00011]
   
    MS (ESI)     MS (ESI)
  (M + H)+   (M + H)+
   
 
[see pdf for image]   163 [see pdf for image]   223
 
[see pdf for image]   177 [see pdf for image]   225
 
[see pdf for image]   203 [see pdf for image]   239
 
[see pdf for image]   207 [see pdf for image]   253
 
[see pdf for image]   217 [see pdf for image]   252
 
[see pdf for image]   221 [see pdf for image]   278
 
[see pdf for image]   227 [see pdf for image]   237
 
[see pdf for image]   241 [see pdf for image]   245
 

Method 23
[0307] 2-azetidin-1-yl-ethylamine
[0308]  [see pdf for image]
[0309] 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 H2 pressure. The catalyst is filtered off and the solvent is eliminated in vacuo.
[0310] Yield: 365 mg (3.664 mmol, 48%) MS (ESI): 101 (M+H)+
[0311] The following compounds are prepared analogously to this process:
[0312] 
[00012] [TABLE-US-00012]
   
    MS (ESI)     MS (ESI)
  (M + H)+   (M + H)+
   
 
[see pdf for image]   129 [see pdf for image]   156
 
[see pdf for image]   131 [see pdf for image]   157
 
[see pdf for image]   158 [see pdf for image]   143
 
[see pdf for image]   159 [see pdf for image]   145
 
[see pdf for image]   159 [see pdf for image]   145
 
[see pdf for image]   141 [see pdf for image]   158
 
[see pdf for image]   165 [see pdf for image]   198
 
[see pdf for image]   172 [see pdf for image]   145
 

Method 24
[0313] ((S)-3-amino-pyrrolidin-1-yl)-acetonitrile
[0314]  [see pdf for image]
[0315] 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.
[0316] Yield: 500 mg (3.995 mmol, 74%) MS (ESI): 126 (M+H)+

Method 25

[0317] (R)-2-pyrrolidin-1-yl-propylamine
[0318]  [see pdf for image]
a) (R)-2-pyrrolidin-1-yl-propionamide
[0319] 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.
[0320] Yield: 1.305 g (9.177 mmol, 57%) MS (ESI): 143 (M+H)+

b) (R)-2-pyrrolidin-1-yl-propylamine

[0321] 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.
[0322] Yield: 160 mg (1.248 mmol, 18%) MS (ESI): 129 (M+H)+
[0323] The following compounds are prepared analogously to this process:
[0324] 
[00013] [TABLE-US-00013]
   
    MS (ESI)     MS (ESI)
  (M + H)+   (M + H)+
   
 
[see pdf for image]   129 [see pdf for image]   157
 
[see pdf for image]   129 [see pdf for image]   169
 
[see pdf for image]   129 [see pdf for image]   183
 
[see pdf for image]   143 [see pdf for image]   183
 
[see pdf for image]   157 [see pdf for image]   197
 

Method 26
[0325] 2-chloro-4-(2-(2-fluoro-ethyl-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine
[0326]  [see pdf for image]
[0327] 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.
[0328] Yield: 485 mg (1.250 mmol, 25%) MS (ESI): 389/391 (M+H)+; Cl distribution
[0329] 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.
[0330] 
[00014] [TABLE-US-00014]
   
    MS (ESI)     MS (ESI)
  (M + H)+   (M + H)+
   
 
[see pdf for image]   363/365 [see pdf for image]   355/357
 
[see pdf for image]   367/369 [see pdf for image]   399/401
 
[see pdf for image]   349/351 [see pdf for image]   366/368
 
[see pdf for image]   381/383 [see pdf for image]   345/347
 
[see pdf for image]   333/335 [see pdf for image]   385/387
 
[see pdf for image]   373/375 [see pdf for image]   381/383
 
[see pdf for image]   447/449
 

Method 27
[0331] 2-[2-(4-amino-3-methoxy-phenyl)-1H-imidazol-4-yl]-ethanol
[0332]  [see pdf for image]
a) 3-methoxy-4-nitro-benzonitrile
[0333] 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.
[0334] Yield: 25.092 g (140.852 mmol, 94%) UV max: 334 nm

b) 3-methoxy-4-nitro-benzamidine

[0335] 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.
[0336] 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

[0337] 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.
[0338] 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

[0339] 1.45 g (5.23 mmol) [2-(3-methoxy-4-nitro-phenyl)-1H-imidazol-4-yl]-acetic acid are dissolved in 36 ml THF and cooled to 0° C. and combined with 10 ml (18 mmol) borane-THF complex (1.8 mol/V). After 1 h the mixture is heated to 20° C. and stirred for 16 h. Water is added until the development of gas has ended. Then the mixture is extracted twice with saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic phases are combined, dried and freed from the solvent in vacuo.
[0340] 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

[0341] 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 H2 pressure. The palladium on charcoal is suction filtered and the methanol is eliminated in vacuo.
[0342] Yield: 87 mg (0.373 mmol, 68%) MS (APCI): 234 (M+H)+UV max: 314 nm
[0343] The following compounds are prepared analogously to this process:
[0344] 
[00015] [TABLE-US-00015]
   
    MS (ESI)     MS (ESI)
  (M + H)+   (M + H)+
   
 
[see pdf for image]   220 [see pdf for image]   190
 
[see pdf for image]   251
 
[0345] 2-[2-(4-amino-3-methoxy-phenyl)-thiazole-5-yl]-ethanol is prepared analogously to the processes described above. For the cyclisation, 4-amino-3-methoxy-thiobenzamide is used (analogously to J. Am. Soc. 82, 2656, 1960) instead of 3-methoxy-4-nitro-benzamidine.
[0346]  [see pdf for image]
[0347] MS (ESI): 251 (M+H)+

Method 28

[0348] 2-methoxy-N4-(3-pyrrolidin-1-yl-propyl)-benzene-1,4-diamine
[0349]  [see pdf for image]
a) (3-methoxy-4-nitro-phenyl)-(3-pyrrolidin-1-yl-propyl)-amine
[0350] 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.
[0351] 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

[0352] 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 H2 pressure. The catalyst is filtered off and the solvent is eliminated in vacuo.
[0353] Yield: 213 mg (0.661 mmol, 92%) MS (ESI): 250 (M+H)+
[0354] The following compounds are prepared analogously to this process:
[0355] 
[00016] [TABLE-US-00016]
   
    MS (ESI)     MS (ESI)
  (M + H)+   (M + H)+
   
 
[see pdf for image]   236 [see pdf for image]   208
 
[see pdf for image]   307 [see pdf for image]   262
 
[see pdf for image]   333 [see pdf for image]   222
 
[see pdf for image]   333 [see pdf for image]   236
 
[see pdf for image]   347 [see pdf for image]   168
 
[see pdf for image]   333 [see pdf for image]   250
 
[see pdf for image]   240 [see pdf for image]   250
 
[see pdf for image]   240 [see pdf for image]   307
 
[see pdf for image]   222 [see pdf for image]   307
 

Method 29
[0356] 2-(4-carboxy-2-bromo-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine
[0357]  [see pdf for image]
[0358] 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.
[0359] Yield: 571 mg (1.440 mmol, 46%) MS (ESI): 396/398 (M+H)+

Method 30

[0360] 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
[0361]  [see pdf for image]
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
[0362] 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.
[0363] 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

[0364] 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.
[0365] Yield: 340 mg (0.625 mmol, 98%) MS (ESI): 545 (M+H)+
[0366] The following compounds are prepared analogously to this process:
[0367] 
[00017] [TABLE-US-00017]
   
    MS (ESI)     MS (ESI)
  (M + H)+   (M + H)+
   
 
[see pdf for image]   581 [see pdf for image]   659
 
[see pdf for image]   582 [see pdf for image]   611
 

Method 31
[0368] Separation of the racemic 7-amino-2-(2-fluoro-ethyl)-3-methyl-2,3-dihydro-isoindol-1-one (method 22) into the two enantiomers
[0369] The separation is carried out by preparative chromatography under the following conditions:
[0370] column: 280×110 mm CHIRALPAK® AD 20 μm
[0371] Eluant: 95% acetonitrile/5% isopropanol (v/v)
[0372] Flow rate: 570 ml/min
[0373] Temperature: ambient temperature
[0374] The enantiomer that elutes first is known as enantiomer 1 and in the chemical formula bears the symbol *1:

Enantiomer 1

[0375]  [see pdf for image]
[0376] The enantiomer that elutes second is known as enantiomer 2 and in the chemical formula bears the symbol *2:

Enantiomer 2

[0377]  [see pdf for image]
Method 32
[0378] 7-amino-3-ethyl-indan-1-one
[0379]  [see pdf for image]
[0380] 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.
[0381] Yield: 70 mg (0.399 mmol; 29%) MS (ESI): 176 (M+H)+
[0382] The following compounds are prepared analogously to this process:
[0383] 
[00018] [TABLE-US-00018]
   
    MS (ESI)     MS (ESI)
  (M + H)+   (M + H)+
   
 
[see pdf for image]   162 [see pdf for image]   190
 

Method 33
[0384] 7-amino-3,3-dimethyl-3H-isobenzofuran-1-one
[0385]  [see pdf for image]
[0386] 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.
[0387] Yield: 34 mg (0.192 mmol; 32%) MS (ESI): 178 (M+H)+
[0388] The following compounds are prepared analogously to this process:
[0389] 
[00019] [TABLE-US-00019]
   
    MS     MS
    (ESI)     (ESI)
    (M +     (M +
  H)+   H)+
   
 
[see pdf for image]   164 [see pdf for image]   190
 
[see pdf for image]   192 [see pdf for image]   178
 
[see pdf for image]   220
 

Method 34
[0390] 7-amino-2-(2-fluoro-ethyl)-3,3-dimethyl-2,3-dihydro-isoindol-1-one
[0391]  [see pdf for image]
a) methyl 2-(cyano-dimethyl-methyl)-6-nitro-benzoate
[0392] 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.
[0393] Yield: 3.11 g (12.535 mmol; 92%)

b) 3,3-dimethyl-7-nitro-2,3-dihydro-isoindol-1-one

Reaction Mixture 1

[0394] 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

[0395] 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).
[0396] Yield: 67 mg (0.325 mmol, 8%) MS (ESI): 207 (M+H)+

c) 3,3-dimethyl-7-amino-2,3-dihydro-isoindol-1-one

[0397] 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 H2 pressure and ambient temperature. Then the catalyst is filtered off and the solvent is eliminated in vacuo.
[0398] Yield: 50 mg (0.284 mmol, 93%) MS (ESI): 177 (M+H)+

d) 7-dibenzylamino-3,3-dimethyl-2,3-dihydro-isoindol-1-one

[0399] 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.
[0400] 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

[0401] 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.
[0402] 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

[0403] 75 mg (0.188 mmol) 7-dibenzylamino-2-(2-fluoro-ethyl)-3,3-dimethyl-2,3-dihydro-isoindol-1-one are dissolved in 50 ml of methanol and combined with 10 mg palladium on charcoal. The mixture is hydrogenated for 16 h at 5 bar H2 pressure and ambient temperature. Then the catalyst is filtered off and the solvent is eliminated in vacuo.
[0404] Yield: 36 mg (0.162 mmol, 87%) MS (ESI): 223 (M+H)+

EXAMPLE 1

[0405] 2-(2-methoxy-4-N-propylcarbamoyl-phenylamino)-4-(3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine
[0406]  [see pdf for image]
[0407] 100 mg (0.257 mmol) 2-(2-methoxy-4-propylcarbamoyl-phenylamino)-4-chloro-5-trifluoro-methyl-pyrimidine (method 1) are dissolved in 1 ml N,N-dimethylacetamide and combined with 83 mg (0.565 mmol) 7-amino-2,3-dihydro-isoindol-1-one (method 2). 48 μl of a 4 molar solution of HCl (0.193 mmol) in 1,4-dioxane are metered into this reaction mixture. After two days at 50° C. the solvent is eliminated in vacuo. The crude product is purified by column chromatography. The carrier used is silica gel and the eluant used is dichloromethane, to which 5% of a mixture of 90% methanol and 10% saturated aqueous ammonia solution have been added. The concentrated crude product is again purified by column chromatography. The carrier used is C18-RP-silica gel and a gradient is run through which consists of 80% water and 20% acetonitrile at the starting point and 60% water and 40% acetonitrile aat the finishing point.
[0408] 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

[0409] 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.
[0410] 
[00020] [TABLE-US-00020]
 
[see pdf for image]
 
        MS
        (ESI)
      UV max   (M +
  #   A   [nm]H)+
 
  2 [see pdf for image]   322   515
 
  3 [see pdf for image]   314   529
 
  4 [see pdf for image]   285   543
 
  5 [see pdf for image]   286/310   583
 
  6 [see pdf for image]   322   571
 
  7 [see pdf for image]   285/321   585
 
  8 [see pdf for image]   285/318   559
 
  9 [see pdf for image]   285/318   586
 
  10 [see pdf for image]   281/316   626
 
  11 [see pdf for image]   284/316   545
 
  12 [see pdf for image]   325   577
 
  13 [see pdf for image]   282/318   595
 
  14 [see pdf for image]   284/322   573
 
  15 [see pdf for image]   286, 306   607
 
  16 [see pdf for image]   325
 
  17 [see pdf for image]   318/282   607
 

EXAMPLE 18

[0411] 2-(2-methoxy-4-N-propylcarbamoyl-phenylamino)-4-(3-oxo-1,3-dihydro-isobenzofuran-4-ylamino)-5-trifluoromethyl-pyrimidine
[0412]  [see pdf for image]
[0413] 100 mg (0.257 mmol) 2-(2-methoxy-4-propylcarbamoyl-phenylamino)-4-chloro-5-trifluoro-methyl-pyrimidine (method 1) are dissolved in 1 ml N,N-dimethylacetamide and combined with 46 mg (0.308 mmol) 7-amino-3H-isobenzofuran-1-one (Safdar Hayat et al., Tetrahedron Lett 2001, 42(9):1647-1649). 48 ill of a 4 molar solution of HCl (0.193 mmol) in 1,4-dioxane zudosiert metered into this reaction mixture. After 4 days at 50° C. the solvent is eliminated in vacuo. The crude product is purified by column chromatography. The carrier used is silica gel and the eluant used is dichloromethane, to which 4% of a mixture of 90% methanol and 10% saturated aqueous ammonia solution have been added.
[0414] 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, 1H), 7.67-7.78 (m, 1H), 8.38-8.48 (m, 2H), 8.50 (s, 1H), 9.21 (s, 1H), 9.64 (s, 1H)

EXAMPLES 19-37

[0415] 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.
[0416] 
[00021] [TABLE-US-00021]
 
[see pdf for image]
 
      UV max   MS (ESI)
  #   A   [nm](M + H)+
 
  19 [see pdf for image]   235   586
 
  20 [see pdf for image]   323/226   543
 
  21 [see pdf for image]   325   530
 
  22 [see pdf for image]   262   514
 
  23 [see pdf for image]   320   544
 
  24 [see pdf for image]   318   542
 
  25 [see pdf for image]   312   530
 
  26 [see pdf for image]   315   529
 
  27 [see pdf for image]   314   528
 
  28 [see pdf for image]   317   502
 
  29 [see pdf for image]   316   516
 
  30 [see pdf for image]   322   529
 
  31 [see pdf for image]   255   548
 
  32 [see pdf for image]   320   500
 
  33 [see pdf for image]   325   515
 
  34 [see pdf for image]   250/286/318   516
 
  35 [see pdf for image]   320   558
 
  36 [see pdf for image]   316   514
 
  37 [see pdf for image]   321
 

EXAMPLE 38

[0417] 2-(2-methoxy-4-N-propylcarbamoyl-phenylamino)-4-(4-methyl-5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-6-ylamino)-5-trifluoromethyl-pyrimidine
[0418]  [see pdf for image]
[0419] 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).
[0420] 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

[0421] 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.
[0422] 
[00022] [TABLE-US-00022]
 
[see pdf for image]
 
      UV max   MS (ESI)
  #   A   [nm](M + H)+
 
  39 [see pdf for image]   229/279/315   559
 
  40 [see pdf for image]   282/314   545
 
  41 [see pdf for image]   282/318   587
 
  42 [see pdf for image]   282/314   571
 
  43 [see pdf for image]   282/318   585
 
  44 [see pdf for image]   318   559
 
  45 [see pdf for image]   234/320   559
 
  46 [see pdf for image]   282/218   603
 
  47 [see pdf for image]   278/318   531
 
  48 [see pdf for image]   286/314   573
 
  49 [see pdf for image]   274/314   558
 
  50 [see pdf for image]   318   587
 
  51 [see pdf for image]   223/282/318   579
 
  52 [see pdf for image]   318   634
 

EXAMPLE 53

[0423] 2-[2-methoxy-4-(4-morpholin-4-yl-(1,4-trans-cyclohexyl)carbamoyl)-phenylamino]-4-(2-carbamoyl-3-fluoro-phenylamino)-5-trifluoromethyl-pyrimidine
[0424]  [see pdf for image]
[0425] 102 mg (0.29 mmol) 2-(4-carboxyamino-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine (method 12) are dissolved in 250 μl N-methyl-2-pyrrolidinone and combined with 47 mg (0.319 mmol) 7-amino-indan-1-one (method 8). 15 μl of a 4 M solution of HCl (0.058 mmol) in 1,4-dioxane are metered into this reaction mixture. After 16 h at 90° C. the reaction mixture is stirred into 150 ml of a aqueous 1 N hydrochloric acid. The precipitate is filtered off and dried in vacuo. 100 mg (0.174 mmol) of this precipitate, 150 μl (0.875 mmol) N-ethyldiisopropylamine, 68 mg (0.210 mmol) O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-tetrafluoroborate and 30 mg (0.163 mmol) trans-4-morpholin-4-yl-cyclohexylamine (method 13) are dissolved in 5 ml N,N-dimethylformamide. After 15 h at ambient temperature the solvent is eliminated in vacuo. The crude product is purified by column chromatography. The carrier used is silica gel and the eluant used is dichloromethane, to which 7% of a mixture of 90% methanol and 10% saturated aqueous ammonia solution have been added.
[0426] 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

[0427] 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.
[0428] 
[00023] [TABLE-US-00023]
 
[see pdf for image]
 
        UV max   ME (ESI)
  #   AR3   [nm](M + H)+
 
  54 [see pdf for image] [see pdf for image]   318   555
 
  55 [see pdf for image] [see pdf for image]   318   569
 
  56 [see pdf for image] [see pdf for image]   322   570
 
  57 [see pdf for image] [see pdf for image]   320   640
 
  58 [see pdf for image] [see pdf for image]   284, 322   556
 
  59 [see pdf for image] [see pdf for image]   282, 318   626
 
  60 [see pdf for image] [see pdf for image]   325   655
 
  61 [see pdf for image] [see pdf for image]   325   585
 
  62 [see pdf for image] [see pdf for image]   254, 286, 318   639
 
  63 [see pdf for image] [see pdf for image]   321   631
 
  64 [see pdf for image] [see pdf for image]   322   570
 
  65 [see pdf for image] [see pdf for image]   322   640
 
  66 [see pdf for image] [see pdf for image]   322   683
 
  67 [see pdf for image] [see pdf for image]   322   613
 
  68 [see pdf for image] [see pdf for image]   286, 322   654
 
  69 [see pdf for image] [see pdf for image]   286, 322   584
 
  70 [see pdf for image] [see pdf for image]   282, 322   627
 
  71 [see pdf for image] [see pdf for image]   322   670
 
  72 [see pdf for image] [see pdf for image]   286, 322   600
 
  73 [see pdf for image] [see pdf for image]   322   684
 
  74 [see pdf for image] [see pdf for image]   286, 322   614
 
  75 [see pdf for image] [see pdf for image]   322   557
 
  76 [see pdf for image] [see pdf for image]   330   732
 
  77 [see pdf for image] [see pdf for image]   325   654
 

EXAMPLES 78-140

[0429] 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.
[0430] 
[00024] [TABLE-US-00024]
 
[see pdf for image]
 
        UV max   MS (ESI)
  #   AR3   [nm](M + H)+
 
  78 [see pdf for image] [see pdf for image]   318   308
 
  79 [see pdf for image] [see pdf for image]   326   346
 
  80 [see pdf for image] [see pdf for image]   318   706
 
  81 [see pdf for image] [see pdf for image]   318   584
 
  82 [see pdf for image] [see pdf for image]   318   614
 
  83 [see pdf for image] [see pdf for image]   318   776
 
  84 [see pdf for image] [see pdf for image]   318   626
 
  85 [see pdf for image] [see pdf for image]   318   348
 
  86 [see pdf for image] [see pdf for image]   318   718
 
  87 [see pdf for image] [see pdf for image]   318   684
 
  88 [see pdf for image] [see pdf for image]   318   353
 
  89 [see pdf for image] [see pdf for image]   322   346
 
  90 [see pdf for image] [see pdf for image]   318   686
 
  91 [see pdf for image] [see pdf for image]   310   621
 
  92 [see pdf for image] [see pdf for image]   318   746
 
  93 [see pdf for image] [see pdf for image]   318   676
 
  94 [see pdf for image] [see pdf for image]   318   316
 
  95 [see pdf for image] [see pdf for image]   318   696
 
  96 [see pdf for image] [see pdf for image]   282; 310   571
 
  97 [see pdf for image] [see pdf for image]   318   614
 
  98 [see pdf for image] [see pdf for image]   318   684
 
  99 [see pdf for image] [see pdf for image]   315   559
 
  100 [see pdf for image] [see pdf for image]   314   621
 
  101 [see pdf for image] [see pdf for image]   314   676
 
  102 [see pdf for image] [see pdf for image]   318   747
 
  103 [see pdf for image] [see pdf for image]   318   656
 
  104 [see pdf for image] [see pdf for image]   318   586
 
  105 [see pdf for image] [see pdf for image]   318   (M
 
  106 [see pdf for image] [see pdf for image]   318   730
 
  107 [see pdf for image] [see pdf for image]   322   674
 
  108 [see pdf for image] [see pdf for image]   318   640
 
  109 [see pdf for image] [see pdf for image]   322   640
 
  110 [see pdf for image] [see pdf for image]   282, 318   614
 
  111 [see pdf for image] [see pdf for image]   226, 282, 318   640
 
  112 [see pdf for image] [see pdf for image]   318   614
 
  113 [see pdf for image] [see pdf for image]     626
 
  114 [see pdf for image] [see pdf for image]   318   640
 
  115 [see pdf for image] [see pdf for image]   318   640
 
  116 [see pdf for image] [see pdf for image]   318   654
 
  117 [see pdf for image] [see pdf for image]   318   668
 
  118 [see pdf for image] [see pdf for image]   318   628
 
  119 [see pdf for image] [see pdf for image]   318   600
 
  120 [see pdf for image] [see pdf for image]   318–322   614
 
  121 [see pdf for image] [see pdf for image]   318   670
 
  122 [see pdf for image] [see pdf for image]   318   654
 
  123 [see pdf for image] [see pdf for image]   318   626
 
  124 [see pdf for image] [see pdf for image]   282, 318   668
 
  125 [see pdf for image] [see pdf for image]   282, 318   642
 
  126 [see pdf for image] [see pdf for image]   282, 318   693
 
  127 [see pdf for image] [see pdf for image]   318   680
 
  128 [see pdf for image] [see pdf for image]   318   654
 
  129 [see pdf for image] [see pdf for image]   318   705
 
  130 [see pdf for image] [see pdf for image]   226, 282,318   628
 
  131 [see pdf for image] [see pdf for image]   318   668
 
  132 [see pdf for image] [see pdf for image]   318-322   642
 
  133 [see pdf for image] [see pdf for image]   318   693
 
  134 [see pdf for image] [see pdf for image]   318-322   642
 
  135 [see pdf for image] [see pdf for image]   318   682
 
  136 [see pdf for image] [see pdf for image]   318   698
 
  137 [see pdf for image] [see pdf for image]   318-322   656
 
  138 [see pdf for image] [see pdf for image]   318-322   707
 
  139 [see pdf for image] [see pdf for image]   318-322   640
 
  140 [see pdf for image] [see pdf for image]   318-322   628
 

EXAMPLES 141-166

[0431] 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.
[0432] 
[00025] [TABLE-US-00025]
 
[see pdf for image]
 
        UV max   MS (ESI)
  #   AR3   [nm](M + H)+
 
  141 [see pdf for image] [see pdf for image]   302   596
 
  142 [see pdf for image] [see pdf for image]   302   610
 
  143 [see pdf for image] [see pdf for image]   302   596
 
  144 [see pdf for image] [see pdf for image]   302   584
 
  145 [see pdf for image] [see pdf for image]   302   610
 
  146 [see pdf for image] [see pdf for image]   302   638
 
  147 [see pdf for image] [see pdf for image]   298   654
 
  148 [see pdf for image] [see pdf for image]   302   610
 
  149 [see pdf for image] [see pdf for image]   302   650
 
  150 [see pdf for image] [see pdf for image]   298-302   666
 
  151 [see pdf for image] [see pdf for image]   302   584
 
  152 [see pdf for image] [see pdf for image]   302   624
 
  153 [see pdf for image] [see pdf for image]   298-302   640
 
  154 [see pdf for image] [see pdf for image]   302   598
 
  155 [see pdf for image] [see pdf for image]   298-302   649
 
  156 [see pdf for image] [see pdf for image]   302   598
 
  157 [see pdf for image] [see pdf for image]   302   638
 
  158 [see pdf for image] [see pdf for image]   298-302   654
 
  159 [see pdf for image] [see pdf for image]   302   612
 
  160 [see pdf for image] [see pdf for image]   302   663
 
  161 [see pdf for image] [see pdf for image]   302   612
 
  162 [see pdf for image] [see pdf for image]   302   652
 
  163 [see pdf for image] [see pdf for image]   298-302   668
 
  164 [see pdf for image] [see pdf for image]   302   677
 
  165 [see pdf for image] [see pdf for image]   302   626
 
  166 [see pdf for image] [see pdf for image]   302   624
 

EXAMPLE 167

[0433] 2-(2-methoxy-4-piperazin-1-yl-phenylamino)-4-(3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-6-ylamino)-5-trifluoromethyl-pyrimidine
[0434]  [see pdf for image]
[0435] 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.
[0436] Yield: 0.59 g (0.86 mmol; 90%)
[0437] 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 H2 pressure and 20° C. for 6 h. The catalyst is filtered off and the solvent is eliminated in vacuo. The residue is purified by column chromatography. The carrier used is C18-RP-silica gel and a gradient is run through which consists at the starting point of 60% water and 40% acetonitrile and at the finishing point of 15% water and 85% acetonitrile. 10 mmol/l ammonium hydrogen carbonate and 20 mmol/l ammonia are dissolved in the water. The suitable fractions are freeze-dried. The residue is dissolved in acetonitrile and combined with 2 ml of a 1 M hydrochloric acid solution. Then the solvent is eliminated in vacuo. The substance is obtained as the dihydrochloride.
[0438] 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)

EXAMPLE 168

[0439] 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
[0440]  [see pdf for image]
[0441] This compound is prepared analogously to Example 167. The aniline used is described in method 10.
[0442] 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 169

[0443] 2-[4-(4-ethyl-piperazin-1-yl)-2-methoxy-phenylamino]-4-((S)-4-oxo-2,3,10,10a-tetrahydro-1H.4H-9-oxa-3a-aza-benzo[f]azulen-5-ylamino-5-trifluoromethyl-pyrimidine
[0444]  [see pdf for image]
[0445] 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.
[0446] 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 170

[0447] 2-[4-(4-methyl-piperazin-1-yl)-2-methoxy-phenylamino]-4-((S)-4-oxo-2,3,10,10a-tetrahydro-1H.4H-9-oxa-3a-aza-benzo[f]azulen-5-ylamino-5-trifluoromethyl-pyrimidine
[0448]  [see pdf for image]
[0449] To prepare this compound formaldehyde is used instead of acetaldehyde. Otherwise the method is as in Example 169.
[0450] 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

[0451] The following Examples are prepared analogously to Example 169 and 170. The corresponding aniline is described in the supplements to method 10.
[0452] 
[00026] [TABLE-US-00026]
 
[see pdf for image]
 
        UV max   MS (ESI)
  #   A   D   [nm](M + H)+
 
  171 [see pdf for image] [see pdf for image]   226, 282   572
 
  172 [see pdf for image] [see pdf for image]   250, 282   586
 
  173 [see pdf for image] [see pdf for image]   250, 282   596
 
  174 [see pdf for image] [see pdf for image]   250, 282   600
 
  175 [see pdf for image] [see pdf for image]   282   544
 
  176 [see pdf for image] [see pdf for image]   282   558
 
  177 [see pdf for image] [see pdf for image]   218; 282   586
 
  178 [see pdf for image] [see pdf for image]   282   582
 
  179 [see pdf for image] [see pdf for image]   226   558
 
  180 [see pdf for image] [see pdf for image]   226   572
 

EXAMPLES 181-332

[0453] The following compounds are prepared by an analogous process to that described in Example 53. 2-(4-Carboxy-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine may be obtained according to method 12 or 14. The corresponding aniline described in method 11. The amine used to prepare the amide is commercially obtainable or described in method 13, 15 and 25.
[0454] 
[00027] [TABLE-US-00027]
 
[see pdf for image]
 
        UV max   MS (ESI)
  #   AR3   [nm](M + H)+
 
  181 [see pdf for image] [see pdf for image]   318, 282,234   380
 
  182 [see pdf for image] [see pdf for image]   238   639
 
  183 [see pdf for image] [see pdf for image]   234; 318   709
 
  184 [see pdf for image] [see pdf for image]   318, 282, 248   558
 
  185 [see pdf for image] [see pdf for image]   318, 280   613
 
  186 [see pdf for image] [see pdf for image]   316, 282, 234   342
 
  187 [see pdf for image] [see pdf for image]   318, 284, 238   307
 
  188 [see pdf for image] [see pdf for image]   318, 282, 242   342
 
  189 [see pdf for image] [see pdf for image]   314, 282, 242   600
 
  190 [see pdf for image] [see pdf for image]   318, 282, 234   328
 
  191 [see pdf for image] [see pdf for image]   318   363
 
  192 [see pdf for image] [see pdf for image]   318, 230   650
 
  193 [see pdf for image] [see pdf for image]   314   634
 
  194 [see pdf for image] [see pdf for image]   318   634
 
  195 [see pdf for image] [see pdf for image]   318   671
 
  196 [see pdf for image] [see pdf for image]   318, 230   380
 
  197 [see pdf for image] [see pdf for image]   314, 282, 250   558
 
  198 [see pdf for image] [see pdf for image]   319   705
 
  199 [see pdf for image] [see pdf for image]   318, 226   775
 
  200 [see pdf for image] [see pdf for image]   318   634
 
  201 [see pdf for image] [see pdf for image]   314   634
 
  202 [see pdf for image] [see pdf for image]   230; 318   584
 
  203 [see pdf for image] [see pdf for image]   317   572
 
  204 [see pdf for image] [see pdf for image]   318, 230   697
 
  205 [see pdf for image] [see pdf for image]   318, 234   544
 
  206 [see pdf for image] [see pdf for image]   318   669
 
  207 [see pdf for image] [see pdf for image]   318, 230   650
 
  208 [see pdf for image] [see pdf for image]   317   627
 
  209 [see pdf for image] [see pdf for image]   318, 230   599
 
  210 [see pdf for image] [see pdf for image]   318, 230   705
 
  211 [see pdf for image] [see pdf for image]   230; 322   653
 
  212 [see pdf for image] [see pdf for image]   230; 322   655
 
  213 [see pdf for image] [see pdf for image]   230; 318   669
 
  214 [see pdf for image] [see pdf for image]   230, 282, 314   634
 
  215 [see pdf for image] [see pdf for image]   318   655
 
  216 [see pdf for image] [see pdf for image]   318, 234   725
 
  217 [see pdf for image] [see pdf for image]   314, 235   586
 
  218 [see pdf for image] [see pdf for image]   318, 230   641
 
  219 [see pdf for image] [see pdf for image]   318, 226   711
 
  220 [see pdf for image] [see pdf for image]   318, 230   640
 
  221 [see pdf for image] [see pdf for image]   318   765
 
  222 [see pdf for image] [see pdf for image]   318   600
 
  223 [see pdf for image] [see pdf for image]   315   673
 
  224 [see pdf for image] [see pdf for image]   319, 226   728
 
  225 [see pdf for image] [see pdf for image]   318, 226   798
 
  226 [see pdf for image] [see pdf for image]   318, 234   655
 
  227 [see pdf for image] [see pdf for image]   230; 322   653
 
  228 [see pdf for image] [see pdf for image]   230; 318   682
 
  229 [see pdf for image] [see pdf for image]   234; 318   639
 
  230 [see pdf for image] [see pdf for image]   318, 226   695
 
  231 [see pdf for image] [see pdf for image]   234, 282, 318   598
 
  232 [see pdf for image] [see pdf for image]   230, 282, 318   653
 
  233 [see pdf for image] [see pdf for image]   234, 282, 318   723
 
  234 [see pdf for image] [see pdf for image]   318, 222   673
 
  235 [see pdf for image] [see pdf for image]   318   725
 
  236 [see pdf for image] [see pdf for image]   318, 282, 226   798
 
  237 [see pdf for image] [see pdf for image]   230; 318   641
 
  238 [see pdf for image] [see pdf for image]   230; 318   711
 
  239 [see pdf for image] [see pdf for image]   234; 318   586
 
  240 [see pdf for image] [see pdf for image]   318, 226   745
 
  241 [see pdf for image] [see pdf for image]   322   703
 
  242 [see pdf for image] [see pdf for image]   320, 226   732
 
  243 [see pdf for image] [see pdf for image]   321, 221   694
 
  244 [see pdf for image] [see pdf for image]   230, 282, 318   652
 
  245 [see pdf for image] [see pdf for image]   234, 282, 318   707
 
  246 [see pdf for image] [see pdf for image]   230, 282, 318   777
 
  247 [see pdf for image] [see pdf for image]   230, 282, 318   630
 
  248 [see pdf for image] [see pdf for image]   234, 282, 318   685
 
  249 [see pdf for image] [see pdf for image]   234, 282, 318   755
 
  250 [see pdf for image] [see pdf for image]   230, 282, 318   630
 
  251 [see pdf for image] [see pdf for image]   230, 282, 318   685
 
  252 [see pdf for image] [see pdf for image]   230, 282, 318   755
 
  253 [see pdf for image] [see pdf for image]   230; 318   695
 
  254 [see pdf for image] [see pdf for image]   230; 318   70
 
  255 [see pdf for image] [see pdf for image]   230; 318   389
 
  256 [see pdf for image] [see pdf for image]   230; 318   652
 
  257 [see pdf for image] [see pdf for image]   230   357
 
  258 [see pdf for image] [see pdf for image]   230   784
 
  259 [see pdf for image] [see pdf for image]   230   659
 
  260 [see pdf for image] [see pdf for image]   319, 230   689
 
  261 [see pdf for image] [see pdf for image]   322   703
 
  262 [see pdf for image] [see pdf for image]   322   705
 
  263 [see pdf for image] [see pdf for image]   320   719
 
  264 [see pdf for image] [see pdf for image]   226   690
 
  265 [see pdf for image] [see pdf for image]   226; 318   760
 
  266 [see pdf for image] [see pdf for image]   230   635
 
  267 [see pdf for image] [see pdf for image]   230; 318   381
 
  268 [see pdf for image] [see pdf for image]   318   812
 
  269 [see pdf for image] [see pdf for image]   318   652
 
  270 [see pdf for image] [see pdf for image]   318   707
 
  271 [see pdf for image] [see pdf for image]   318, 226   777
 
  272 [see pdf for image] [see pdf for image]   318   659
 
  273 [see pdf for image] [see pdf for image]   318   714
 
  274 [see pdf for image] [see pdf for image]   315, 239   669
 
  275 [see pdf for image] [see pdf for image]   319, 222   723
 
  276 [see pdf for image] [see pdf for image]   318, 226   793
 
  277 [see pdf for image] [see pdf for image]   316   620
 
  278 [see pdf for image] [see pdf for image]   318   675
 
  279 [see pdf for image] [see pdf for image]   318, 226   745
 
  280 [see pdf for image] [see pdf for image]   317, 226   620
 
  281 [see pdf for image] [see pdf for image]   318   675
 
  282 [see pdf for image] [see pdf for image]   318, 230   745
 
  283 [see pdf for image] [see pdf for image]   318   784
 
  284 [see pdf for image] [see pdf for image]   318   758
 
  285 [see pdf for image] [see pdf for image]   318   688
 
  286 [see pdf for image] [see pdf for image]   238, 282, 314   616
 
  287 [see pdf for image] [see pdf for image]   230, 282, 318   671
 
  288 [see pdf for image] [see pdf for image]   230, 282, 318   741
 
  289 [see pdf for image] [see pdf for image]   234, 282, 318   616
 
  290 [see pdf for image] [see pdf for image]   226, 282, 318   671
 
  291 [see pdf for image] [see pdf for image]   234, 282, 318   741
 
  292 [see pdf for image] [see pdf for image]   234, 282, 318   648
 
  293 [see pdf for image] [see pdf for image]   230, 282, 318   703
 
  294 [see pdf for image] [see pdf for image]   226, 282, 318   773
 
  295 [see pdf for image] [see pdf for image]   226, 282, 318   893
 
  296 [see pdf for image] [see pdf for image]   226, 282, 318   727
 
  297 [see pdf for image] [see pdf for image]   226, 282, 318   754
 
  298 [see pdf for image] [see pdf for image]   230, 282, 318   823
 
  299 [see pdf for image] [see pdf for image]   282, 318   669
 
  300 [see pdf for image] [see pdf for image]   282, 318   613
 
  301 [see pdf for image] [see pdf for image]   282, 318   641
 
  302 [see pdf for image] [see pdf for image]   286, 318   639
 
  303 [see pdf for image] [see pdf for image]   286, 318   627
 
  304 [see pdf for image] [see pdf for image]   286, 318   655
 
  305 [see pdf for image] [see pdf for image]   286, 318   667
 
  306 [see pdf for image] [see pdf for image]   286, 318   717
 
  307 [see pdf for image] [see pdf for image]   286, 318   689
 
  308 [see pdf for image] [see pdf for image]   286, 318   665
 
  309 [see pdf for image] [see pdf for image]   230, 286, 318   653
 
  310 [see pdf for image] [see pdf for image]   230, 282, 318   715
 
  311 [see pdf for image] [see pdf for image]   286, 322   695
 
  312 [see pdf for image] [see pdf for image]   234, 286, 318   667
 
  313 [see pdf for image] [see pdf for image]   230, 282, 318   639
 
  314 [see pdf for image] [see pdf for image]   230, 282, 318   667
 
  315 [see pdf for image] [see pdf for image]   230, 282, 318   681
 
  316 [see pdf for image] [see pdf for image]   230, 282, 318   695
 
  317 [see pdf for image] [see pdf for image]     679
 
  318 [see pdf for image] [see pdf for image]   226, 284, 318   681
 
  319 [see pdf for image] [see pdf for image]   230, 284, 318   697
 
  320 [see pdf for image] [see pdf for image]   226, 284, 314   750
 
  321 [see pdf for image] [see pdf for image]   230, 286, 318   669
 
  322 [see pdf for image] [see pdf for image]   230, 282, 318   693
 
  323 [see pdf for image] [see pdf for image]   230, 282, 314   709
 
  324 [see pdf for image] [see pdf for image]   230, 286, 314   681
 
  325 [see pdf for image] [see pdf for image]   226, 286, 314   762
 
  326 [see pdf for image] [see pdf for image]   230, 282, 318   681
 
  327 [see pdf for image] [see pdf for image]   230, 282, 314   697
 
  328 [see pdf for image] [see pdf for image]   234, 282, 318   627
 
  329 [see pdf for image] [see pdf for image]   226, 282, 318   767
 
  330 [see pdf for image] [see pdf for image]   226, 282, 318   725
 
  331 [see pdf for image] [see pdf for image]   230, 286, 318   711
 
  332 [see pdf for image] [see pdf for image]   226, 282, 318   671
 
  333 [see pdf for image] [see pdf for image]   234, 282, 314   718
 
  334 [see pdf for image] [see pdf for image]   234, 282, 318   693
 
  335 [see pdf for image] [see pdf for image]   234, 286, 318   653
 
  336 [see pdf for image] [see pdf for image]   284, 318   706
 
  337 [see pdf for image] [see pdf for image]   230, 282, 318   641
 
  338 [see pdf for image] [see pdf for image]   230, 282, 314   667
 
  339 [see pdf for image] [see pdf for image]   283, 318   655
 
  340 [see pdf for image] [see pdf for image]   230, 286, 318   699
 
  341 [see pdf for image] [see pdf for image]   230, 282, 318   750
 
  342 [see pdf for image] [see pdf for image]   230, 282, 318   627
 
  343 [see pdf for image] [see pdf for image]   250, 282, 318   667
 
  344 [see pdf for image] [see pdf for image]   230, 282, 318   683
 
  345 [see pdf for image] [see pdf for image]   238, 282, 314   641
 
  346 [see pdf for image] [see pdf for image]   230, 314   692
 
  347 [see pdf for image] [see pdf for image]   282, 318   723
 
  348 [see pdf for image] [see pdf for image]   234, 286, 314   653
 
  349 [see pdf for image] [see pdf for image]   286, 318   667
 
  350 [see pdf for image] [see pdf for image]   234, 286, 314   718
 
  351 [see pdf for image] [see pdf for image]   230, 286, 318   685
 

EXAMPLES 352-372

[0455] 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.
[0456] 
[00028] [TABLE-US-00028]
 
[see pdf for image]
 
        UV max   MS (ESI)
  #   AR3   [nm](M + H)+
 
  352 [see pdf for image] [see pdf for image]   222, 302   688
 
  353 [see pdf for image] [see pdf for image]   246, 298   663
 
  354 [see pdf for image] [see pdf for image]   234, 298   679
 
  355 [see pdf for image] [see pdf for image]   234, 302   623
 
  356 [see pdf for image] [see pdf for image]   298   611
 
  357 [see pdf for image] [see pdf for image]   246, 302   676
 
  358 [see pdf for image] [see pdf for image]     651
 
  359 [see pdf for image] [see pdf for image]     667
 
  360 [see pdf for image] [see pdf for image]   246, 302   611
 
  361 [see pdf for image] [see pdf for image]   298   662
 
  362 [see pdf for image] [see pdf for image]     637
 
  363 [see pdf for image] [see pdf for image]   234, 298   653
 
  364 [see pdf for image] [see pdf for image]   226, 302   597
 
  365 [see pdf for image] [see pdf for image]   302   637
 
  366 [see pdf for image] [see pdf for image]   246, 302   625
 
  367 [see pdf for image] [see pdf for image]   302   695
 
  368 [see pdf for image] [see pdf for image]   302   711
 
  369 [see pdf for image] [see pdf for image]   302   669
 
  370 [see pdf for image] [see pdf for image]   302   720
 
  371 [see pdf for image] [see pdf for image]   300   693
 
  372 [see pdf for image] [see pdf for image]   242, 302   655
 

EXAMPLES 373-386

[0457] The following Examples are prepared analogously to Example 169 and 170 The corresponding aniline is described in method 11.
[0458] 
[00029] [TABLE-US-00029]
 
[see pdf for image]
 
        UV max   MS (ESI)
  #   A   D   [nm](M + H)+
 
  373 [see pdf for image] [see pdf for image]   246   621
 
  374 [see pdf for image] [see pdf for image]   246   611
 
  375 [see pdf for image] [see pdf for image]   234   639
 
  376 [see pdf for image] [see pdf for image]   238   597
 
  377 [see pdf for image] [see pdf for image]   250   599
 
  378 [see pdf for image] [see pdf for image]   250   585
 
  379 [see pdf for image] [see pdf for image]   250   613
 
  380 [see pdf for image] [see pdf for image]   250   609
 
  381 [see pdf for image] [see pdf for image]   246   625
 
  382 [see pdf for image] [see pdf for image]   250   599
 
  383 [see pdf for image] [see pdf for image]   230   571
 
  384 [see pdf for image] [see pdf for image]   246   595
 
  385 [see pdf for image] [see pdf for image]   250   585
 
  386 [see pdf for image] [see pdf for image]   246, 286   615
 

EXAMPLES 387-388

[0459] 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.
[0460] 
[00030] [TABLE-US-00030]
 
[see pdf for image]
 
        UV max   MS (ESI)
  #   AR3   [nm](M + H)+
 
  387 [see pdf for image] [see pdf for image]   262, 318   569
 
  388 [see pdf for image] [see pdf for image]   278, 318   615
 

EXAMPLES 389-404

[0461] 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.
[0462] 
[00031] [TABLE-US-00031]
 
[see pdf for image]
 
        UV max   MS (ESI)
  #   AR3   [nm](M + H)+
 
  389 [see pdf for image] [see pdf for image]   284, 322   668
 
  390 [see pdf for image] [see pdf for image]   230, 285,325   698
 
  391 [see pdf for image] [see pdf for image]   280, 325   730
 
  392 [see pdf for image] [see pdf for image]   230, 285,325   682
 
  393 [see pdf for image] [see pdf for image]   285, 325   630
 
  394 [see pdf for image] [see pdf for image]   284, 322   686
 
  395 [see pdf for image] [see pdf for image]   285, 325   616
 
  396 [see pdf for image] [see pdf for image]   285, 322   654
 
  397 [see pdf for image] [see pdf for image]   285, 325   584
 
  398 [see pdf for image] [see pdf for image]   285, 325   598
 
  399 [see pdf for image] [see pdf for image]   285, 325   668
 
  400 [see pdf for image] [see pdf for image]   285, 325   598
 
  401 [see pdf for image] [see pdf for image]   285, 325   612
 
  402 [see pdf for image] [see pdf for image]   285, 322   700
 
  403 [see pdf for image] [see pdf for image]   285, 322   630
 
  404 [see pdf for image] [see pdf for image]   262   688
 

EXAMPLE 405

[0463] 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
[0464]  [see pdf for image]
[0465] 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.
[0466] Yield: 1626 mg (3.110 mmol; 94%) MS (ESI): 524 (M+H)+
[0467] 100 mg (0.191 mmol) of this precipitate, 240 μl (1.402 mmol) N-ethyldiisopropylamine, 89 mg (0.279 mmol) O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-tetrafluoroborate and 76 mg (0.267 mmol) tert-butyl 4-amino-[1,4′]bipiperidinyl-1′-carboxylate are dissolved in 3 ml N,N-dimethylformamide. After 15 h at 20° C. the solvent is eliminated in vacuo. The residue is taken up in 20 ml dichloromethane and 5 ml of methanol and filtered through aluminium oxide. The aluminium oxide is washed several times with a mixture of dichloromethane and methanol (4:1). The solvent of the combined fractions is eliminated in vacuo. The residue is dissolved in 5 ml dichloromethane and combined with 5 ml trifluoroacetic acid. This mixture is stirred for 3 h at 20° C. and then the solvent is eliminated in vacuo. The crude product is purified by column chromatography. The carrier material used is C18-RP-silica gel and a gradient is run through which consists of 90% water and 10% acetonitrile at the starting point and 5% water and 95% acetonitrile at the finishing point. 0.1% formic acid are added both to the water and to the acetonitrile. The suitable fractions are combined with 500 μl of a 1 N hydrochloric acid and freeze-dried. The product is obtained as the trihydrochloride.
[0468] 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

[0469] The following compounds are prepared by an analogous process to that described in Example 405.
[0470] 
[00032] [TABLE-US-00032]
 
      UV max   MS (ESI)
  #     [nm](M + H)+
 
  406 [see pdf for image]   318   606
 
  407 [see pdf for image]   322, 286   606
 

EXAMPLE 408

[0471] 2-[2-methoxy-4-(1′-methyl-[1,4′]bipiperidinyl-4-ylcarbamoyl)-phenylamino]-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine
[0472]  [see pdf for image]
[0473] 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.
[0474] Yield: 18 mg (0.022 mmol; 25%) UV max: 322 nm MS (ESI): 703 (M+H)+

EXAMPLES 409-491

[0475] 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.
[0476] 
[00033] [TABLE-US-00033]
 
[see pdf for image]
 
        UV max   MS (ESI)
  #   AR3   [nm](M + H)+
 
  409 [see pdf for image] [see pdf for image]   285, 320   584
 
  410 [see pdf for image] [see pdf for image]   322   716
 
  411 [see pdf for image] [see pdf for image]   326   703
 
  412 [see pdf for image] [see pdf for image]     558
 
  413 [see pdf for image] [see pdf for image]   282, 318   699
 
  414 [see pdf for image] [see pdf for image]   322, 286   668
 
  415 [see pdf for image] [see pdf for image]   322.3   724
 
  416 [see pdf for image] [see pdf for image]   322.3   362
 
  417 [see pdf for image] [see pdf for image]   322, 286   738
 
  418 [see pdf for image] [see pdf for image]   322, 286   738
 
  419 [see pdf for image] [see pdf for image]   282, 314   738
 
  420 [see pdf for image] [see pdf for image]   286, 314   738
 
  421 [see pdf for image] [see pdf for image]   286, 318   700
 
  422 [see pdf for image] [see pdf for image]   286, 322   698
 
  423 [see pdf for image] [see pdf for image]   286, 318   700
 
  424 [see pdf for image] [see pdf for image]   286, 322   712
 
  425 [see pdf for image] [see pdf for image]   286, 322   724
 
  426 [see pdf for image] [see pdf for image]   322, 286   672
 
  427 [see pdf for image] [see pdf for image]   282, 322   723
 
  428 [see pdf for image] [see pdf for image]   322, 285   602
 
  429 [see pdf for image] [see pdf for image]   326.3   616
 
  430 [see pdf for image] [see pdf for image]   322, 286   616
 
  431 [see pdf for image] [see pdf for image]   318, 286   645
 
  432 [see pdf for image] [see pdf for image]   321, 284   632
 
  433 [see pdf for image] [see pdf for image]   322, 286   618
 
  434 [see pdf for image] [see pdf for image]   318, 282   690
 
  435 [see pdf for image] [see pdf for image]   322, 282   708
 
  436 [see pdf for image] [see pdf for image]   322, 286   686
 
  437 [see pdf for image] [see pdf for image]   322, 284   722
 
  438 [see pdf for image] [see pdf for image]   322, 282   658
 
  439 [see pdf for image] [see pdf for image]   322, 285   547
 
  440 [see pdf for image] [see pdf for image]   322, 286   602
 
  441 [see pdf for image] [see pdf for image]   286.3   565
 
  442 [see pdf for image] [see pdf for image]   322, 286   620
 
  443 [see pdf for image] [see pdf for image]   322, 284   686
 
  444 [see pdf for image] [see pdf for image]   326.3   634
 
  445 [see pdf for image] [see pdf for image]   326, 286   634
 
  446 [see pdf for image] [see pdf for image]   322, 284   676
 
  447 [see pdf for image] [see pdf for image]   322.3   663
 
  448 [see pdf for image] [see pdf for image]   325.3   650
 
  449 [see pdf for image] [see pdf for image]   325.3   635
 
  450 [see pdf for image] [see pdf for image]   322, 282   620
 
  451 [see pdf for image] [see pdf for image]   322, 282   704
 
  452 [see pdf for image] [see pdf for image]   322, 282   665
 
  453 [see pdf for image] [see pdf for image]   326, 282   595
 
  454 [see pdf for image] [see pdf for image]   322, 284   677
 
  455 [see pdf for image] [see pdf for image]   322.3   664
 
  456 [see pdf for image] [see pdf for image]   326, 286   594
 
  457 [see pdf for image] [see pdf for image]   322, 282   743
 
  458 [see pdf for image] [see pdf for image]   326, 286   638
 
  459 [see pdf for image] [see pdf for image]   326, 283   681
 
  460 [see pdf for image] [see pdf for image]   318, 284   681
 
  461 [see pdf for image] [see pdf for image]   318, 286   627
 
  462 [see pdf for image] [see pdf for image]   322, 286   627
 
  463 [see pdf for image] [see pdf for image]   326, 286   648
 
  464 [see pdf for image] [see pdf for image]   322, 286   611
 
  465 [see pdf for image] [see pdf for image]   322, 286   723
 
  466 [see pdf for image] [see pdf for image]   322, 282   710
 
  467 [see pdf for image] [see pdf for image]   326, 286   654
 
  468 [see pdf for image] [see pdf for image]   326, 286   654
 
  469 [see pdf for image] [see pdf for image]   322, 284   683
 
  470 [see pdf for image] [see pdf for image]   326, 286   640
 
  471 [see pdf for image] [see pdf for image]   318, 283   710
 
  472 [see pdf for image] [see pdf for image]   326, 286   654
 
  473 [see pdf for image] [see pdf for image]   326, 286   654
 
  474 [see pdf for image] [see pdf for image]   321, 285   683
 
  475 [see pdf for image] [see pdf for image]   326, 286   630
 
  476 [see pdf for image] [see pdf for image]   322, 286   682
 
  477 [see pdf for image] [see pdf for image]   318, 286   612
 
  478 [see pdf for image] [see pdf for image]   318.3   606
 
  479 [see pdf for image] [see pdf for image]   322, 286   566
 
  480 [see pdf for image] [see pdf for image]   322, 286   621
 
  481 [see pdf for image] [see pdf for image]   318, 286   649
 
  482 [see pdf for image] [see pdf for image]   322, 286   606
 
  483 [see pdf for image] [see pdf for image]   326, 286   652
 
  484 [see pdf for image] [see pdf for image]   326, 286   648
 
  485 [see pdf for image] [see pdf for image]   322, 284   704
 
  486 [see pdf for image] [see pdf for image]   326, 286   634
 
  487 [see pdf for image] [see pdf for image]   322, 285   689
 
  488 [see pdf for image] [see pdf for image]   322, 285   703
 
  489 [see pdf for image] [see pdf for image]   322   698
 
  490 [see pdf for image] [see pdf for image]   322, 286   619
 
  491 [see pdf for image] [see pdf for image]   322, 286   689
 

EXAMPLES 492-621

[0477] The following compounds are prepared by an analogous process to that described in Example 53. 2-(4-carboxy-2-methoxy-phenylamino)-4-chloro-5-trifluoromethylpyrimidine may be prepared according to method 12 or 14. The corresponding aniline is described in method 22. The amine used to prepare the amide is commercially obtainable, described in method 13, 15, 20, 21, 23, 24 and 25 or in J. Med. Chem. 2003, 46(5), 702-715.
[0478] 
[00034] [TABLE-US-00034]
 
[see pdf for image]
 
          UV max   MS (ESI)
  #   AR3R3   [nm](M + H)+
 
  492 [see pdf for image] [see pdf for image]   H   286, 322   584
 
  493 [see pdf for image] [see pdf for image]   H   286, 322   826
 
  494 [see pdf for image] [see pdf for image]   H   284, 322   613
 
  495 [see pdf for image] [see pdf for image]   H   282, 322   640
 
  496 [see pdf for image] [see pdf for image]   H   286, 320   570
 
  497 [see pdf for image] [see pdf for image]   H   286, 322   584
 
  498 [see pdf for image] [see pdf for image]   H   282, 322   693
 
  499 [see pdf for image] [see pdf for image]   H   286, 322   686
 
  500 [see pdf for image] [see pdf for image]   H   286, 326   616
 
  501 [see pdf for image] [see pdf for image]   H   286, 326   630
 
  502 [see pdf for image] [see pdf for image]   H   282, 325   704
 
  503 [see pdf for image] [see pdf for image]   H   286, 326   634
 
  504 [see pdf for image] [see pdf for image]   H   286, 326   648
 
  505 [see pdf for image] [see pdf for image]   H   286, 322   712
 
  506 [see pdf for image] [see pdf for image]   H   322, 286   739
 
  507 [see pdf for image] [see pdf for image]   H   322, 286   645
 
  508 [see pdf for image] [see pdf for image]   H   326, 286   632
 
  509 [see pdf for image] [see pdf for image]   H   322, 286   672
 
  510 [see pdf for image] [see pdf for image]   H   322, 284   700
 
  511 [see pdf for image] [see pdf for image]   H   314, 286   616
 
  512 [see pdf for image] [see pdf for image]   H   286, 322   684
 
  513 [see pdf for image] [see pdf for image]   H   286, 322   670
 
  514 [see pdf for image] [see pdf for image]   H   282, 322   658
 
  515 [see pdf for image] [see pdf for image]   H   322, 286   632
 
  516 [see pdf for image] [see pdf for image]   H   326, 286   628
 
  517 [see pdf for image] [see pdf for image]   H   325, 286   628
 
  518 [see pdf for image] [see pdf for image]   H   326, 286   659
 
  519 [see pdf for image] [see pdf for image]   H   326   699
 
  520 [see pdf for image] [see pdf for image]   H   284, 326   616
 
  521 [see pdf for image] [see pdf for image]   H   234, 282,314   630
 
  522 [see pdf for image] [see pdf for image]   H   326   660
 
  523 [see pdf for image] [see pdf for image]   H   326   657
 
  524 [see pdf for image] [see pdf for image]   H     645
 
  525 [see pdf for image] [see pdf for image]   H   326   627
 
  526 [see pdf for image] [see pdf for image]   H   326   660
 
  527 [see pdf for image] [see pdf for image]   H   326   659
 
  528 [see pdf for image] [see pdf for image]   H   326   692
 
  529 [see pdf for image] [see pdf for image]   H   326   644
 
  530 [see pdf for image] [see pdf for image]   H   326   628
 
  531 [see pdf for image] [see pdf for image]   H   322   662
 
  532 [see pdf for image] [see pdf for image]   H   326   699
 
  533 [see pdf for image] [see pdf for image]   H   326   602
 
  534 [see pdf for image] [see pdf for image]   H     646
 
  535 [see pdf for image] [see pdf for image]   H   326   666
 
  536 [see pdf for image] [see pdf for image]   H   326   646
 
  537 [see pdf for image] [see pdf for image]   H   326   —
 
  538 [see pdf for image] [see pdf for image]   H   322   616
 
  539 [see pdf for image] [see pdf for image]   H   318   630
 
  540 [see pdf for image] [see pdf for image]   H   318   630
 
  541 [see pdf for image] [see pdf for image]   H   274   644
 
  542 [see pdf for image] [see pdf for image]   H   326   658
 
  543 [see pdf for image] [see pdf for image]   H   286, 324   630
 
  544 [see pdf for image] [see pdf for image]   H   286, 326   658
 
  545 [see pdf for image] [see pdf for image]   H   286, 322   630
 
  546 [see pdf for image] [see pdf for image]   H   286, 326   642
 
  547 [see pdf for image] [see pdf for image]   H   286, 322   562
 
  548 [see pdf for image] [see pdf for image]   H   322-326   630
 
  549 [see pdf for image] [see pdf for image]   H   326   630
 
  550 [see pdf for image] [see pdf for image]   H   286, 322   607
 
  551 [see pdf for image] [see pdf for image]   H     646
 
  552 [see pdf for image] [see pdf for image]   H     644
 
  553 [see pdf for image] [see pdf for image]   H   326   644
 
  554 [see pdf for image] [see pdf for image]   H   322-326   658
 
  555 [see pdf for image] [see pdf for image]   H   322-326   658
 
  556 [see pdf for image] [see pdf for image]   H   286, 326   658
 
  557 [see pdf for image] [see pdf for image]   H   322-326   642
 
  558 [see pdf for image] [see pdf for image]   H   322-326   642
 
  559 [see pdf for image] [see pdf for image]   H   286, 322   656
 
  560 [see pdf for image] [see pdf for image]   H   286, 322   656
 
  561 [see pdf for image] [see pdf for image]   H   286, 322   671
 
  562 [see pdf for image] [see pdf for image]   H   286, 322   671
 
  563 [see pdf for image] [see pdf for image]   H   318   685
 
  564 [see pdf for image] [see pdf for image]   H   322-326   685
 
  565 [see pdf for image] [see pdf for image]   H   322-326   754
 
  566 [see pdf for image] [see pdf for image]   H   322-326   672
 
  567 [see pdf for image] [see pdf for image]   H   322   711
 
  568 [see pdf for image] [see pdf for image]   H   322-326   711
 
  569 [see pdf for image] [see pdf for image]   H   326   624
 
  570 [see pdf for image] [see pdf for image]   H   326   645
 
  571 [see pdf for image] [see pdf for image]   H   322-326   650
 
  572 [see pdf for image] [see pdf for image]   H   286, 326   684
 
  573 [see pdf for image] [see pdf for image]   H   286, 326   684
 
  574 [see pdf for image] [see pdf for image]   H   326   673
 
  575 [see pdf for image] [see pdf for image]   H   322   698
 
  576 [see pdf for image] [see pdf for image]   H   326, 286   646
 
  577 [see pdf for image] [see pdf for image]   H   286, 322   684
 
  578 [see pdf for image] [see pdf for image]   H   282, 322   658
 
  579 [see pdf for image] [see pdf for image]   H   322, 286   617
 
  580 [see pdf for image] [see pdf for image]   H   326, 286   644
 
  581 [see pdf for image] [see pdf for image]   H   326, 286   590
 
  582 [see pdf for image] [see pdf for image]   H   286, 326   673
 
  583 [see pdf for image] [see pdf for image]   H   326, 285   652
 
  584 [see pdf for image] [see pdf for image]   H   326, 282   722
 
  585 [see pdf for image] [see pdf for image]   H   326, 286   648
 
  586 [see pdf for image] [see pdf for image]   H   326, 285   718
 
  587 [see pdf for image] [see pdf for image]   H   326, 286   652
 
  588 [see pdf for image] [see pdf for image]   H   326, 284   652
 
  589 [see pdf for image] [see pdf for image]   H   325, 283   681
 
  590 [see pdf for image] [see pdf for image]   H   325.3   652
 
  591 [see pdf for image] [see pdf for image]   H   326.3   666
 
  592 [see pdf for image] [see pdf for image]   H   325, 283   666
 
  593 [see pdf for image] [see pdf for image]   H   325.3   648
 
  594 [see pdf for image] [see pdf for image]   H   325, 284   648
 
  595 [see pdf for image] [see pdf for image]   H   325, 284   677
 
  596 [see pdf for image] [see pdf for image]   H   325, 284   648
 
  597 [see pdf for image] [see pdf for image]   H   326, 285   662
 
  598 [see pdf for image] [see pdf for image]   H   325, 284   662
 
  599 [see pdf for image] [see pdf for image]   H   326, 282   720
 
  600 [see pdf for image] [see pdf for image] [see pdf for image]   314, 283   576
 
  601 [see pdf for image] [see pdf for image]   H   322, 286   714
 
  602 [see pdf for image] [see pdf for image]   H   286, 322   670
 
  603 [see pdf for image] [see pdf for image]   H   324, 285   614
 
  604 [see pdf for image] [see pdf for image]   H   324, 284   684
 
  605 [see pdf for image] [see pdf for image]   H   324, 285   628
 
  606 [see pdf for image] [see pdf for image]   H   324, 284   698
 
  607 [see pdf for image] [see pdf for image]   H   285, 322   630
 
  608 [see pdf for image] [see pdf for image]   H   325, 284   576
 
  609 [see pdf for image] [see pdf for image]   H   325, 284   576
 
  610 [see pdf for image] [see pdf for image]   H   326, 286   659
 
  611 [see pdf for image] [see pdf for image]   H   326, 286   646
 
  612 [see pdf for image] [see pdf for image]   H   325, 285   630
 
  613 [see pdf for image] [see pdf for image]   H   325, 284   630
 
  614 [see pdf for image] [see pdf for image]   H   325, 285   590
 
  615 [see pdf for image] [see pdf for image]   H   285, 325   642
 
  616 [see pdf for image] [see pdf for image]   H   325, 285   670
 
  617 [see pdf for image] [see pdf for image]   H   326, 286   684
 
  618 [see pdf for image] [see pdf for image]   H   326, 286   658
 
  619 [see pdf for image] [see pdf for image]   H   285, 324   684
 
  620 [see pdf for image] [see pdf for image]   H   326, 286   658
 
  621 [see pdf for image] [see pdf for image]   H   280, 320   631
 

EXAMPLE 622

[0479] 2-(2-methoxy-4-[2-(2-pyrrolidin-1-yl-ethylcarbamoyl)-ethylamino]-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine
[0480]  [see pdf for image]
[0481] 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.
[0482] 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 623

[0483] 2-(2-fluoro-ethyl)-7-(2-{4-[4-(2-hydroxy-ethyl)-1H-imidazol-2-yl]-2-methoxy-phenylamine}-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine
[0484]  [see pdf for image]
[0485] 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.
[0486] 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

[0487] 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.
[0488] 
[00035] [TABLE-US-00035]
 
[see pdf for image]
 
      UV max   MS (ESI)
  #   B   [nm](M + H)+
 
  624 [see pdf for image]   290, 326   586
 
  625 [see pdf for image]   290, 330   654
 
  626 [see pdf for image]   290, 326   625
 
  627 [see pdf for image]   326   512
 
  628 [see pdf for image]   314   685
 
  629 [see pdf for image]   290, 314   659
 
  630 [see pdf for image]     659
 
  631 [see pdf for image]   278   592
 
  632 [see pdf for image]   314   592
 
  633 [see pdf for image]   314   588
 
  634 [see pdf for image]   314   602
 
  635 [see pdf for image]   314   602
 
  636 [see pdf for image]   314   588
 
  637 [see pdf for image]   314   602
 
  638 [see pdf for image]     670
 

EXAMPLE 639

[0489] 2-(4-(4-isopropyl-[1,4]diazepin-1-yl)-2-methoxy-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine
[0490]  [see pdf for image]
[0491] 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.
[0492] 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)

EXAMPLES 640-648

[0493] The following compounds are prepared by an analogous process to that described in Example 639.
[0494] 
[00036] [TABLE-US-00036]
 
[see pdf for image]
 
        UV max   MS (ESI)
    #   D   [nm](M + H)+
   
    640 [see pdf for image]   314   574
   
    641 [see pdf for image]   310-314   628
   
    642 [see pdf for image]   310-314   602
   
    643 [see pdf for image]   310-314   630
   
    644 [see pdf for image]   314   671
   
    645 [see pdf for image]   310-314   618
   
    646 [see pdf for image]   314   658
   
    647 [see pdf for image]   314   588
   

EXAMPLES 648-659

[0495] 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.
[0496] 
[00037] [TABLE-US-00037]
 
[see pdf for image]
 
      UV max   MS (ESI)
  #   D   [nm](M + H)+
 
  648 [see pdf for image]   286, 314   631
 
  649 [see pdf for image]   286, 314   603
 
  650 [see pdf for image]   282, 314   643
 
  651 [see pdf for image]   282, 314   671
 
  652 [see pdf for image]   286, 314   657
 
  653 [see pdf for image]   282, 314   628
 
  654 [see pdf for image]   286, 314   657
 
  655 [see pdf for image]   286, 314   671
 
  656 [see pdf for image]   282, 314   614
 
  657 [see pdf for image]   282, 314   560
 
  658 [see pdf for image]   234, 283, 314   694
 
  659 [see pdf for image]   286, 314   574
 

EXAMPLES 660-666

[0497] 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.
[0498] 
[00038] [TABLE-US-00038]
 
[see pdf for image]
 
        UV max   MS (ESI)
  #   AR3   [nm](M + H)+
 
  660 [see pdf for image] [see pdf for image]   314   678/680
 
  661 [see pdf for image] [see pdf for image]   314   626/628
 
  662 [see pdf for image] [see pdf for image]   314   626/628
 
  663 [see pdf for image] [see pdf for image]   286   609/611
 
  664 [see pdf for image] [see pdf for image]   314   734/736
 
  665 [see pdf for image] [see pdf for image]   314   693/695
 
  666 [see pdf for image] [see pdf for image]   286   678/680
 

EXAMPLES 667-681

[0499] 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.
[0500] 
[00039] [TABLE-US-00039]
 
[see pdf for image]
 
          UV max   MS (ESI)
  #   AR3R3   [nm](M + H)+
 
  667 [see pdf for image] [see pdf for image]   H   314   586
 
  668 [see pdf for image] [see pdf for image]   H   314   586
 
  669 [see pdf for image] [see pdf for image]   H   314   586
 
  670 [see pdf for image] [see pdf for image]   H   314   642
 
  671 [see pdf for image] [see pdf for image]   H   314   616
 
  672 [see pdf for image] [see pdf for image]   H   290   600
 
  673 [see pdf for image] [see pdf for image]   H   290   709
 
  674 [see pdf for image] [see pdf for image]   H   314   600
 
  675 [see pdf for image] [see pdf for image]   H   314   586
 
  676 [see pdf for image] [see pdf for image] [see pdf for image]   286   574
 
  677 [see pdf for image] [see pdf for image]   H   286   572
 
  678 [see pdf for image] [see pdf for image]   H   290   682
 
  679 [see pdf for image] [see pdf for image]   H   314   642
 
  680 [see pdf for image] [see pdf for image]   H   290   656
 
  681 [see pdf for image] [see pdf for image]   H   314   615
 

EXAMPLE 682

[0501] 2-(2-methoxy-4-[3-(4-methyl-piperazin-1-yl)-propionylamino]-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine
[0502]  [see pdf for image]
[0503] 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.
[0504] 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)

EXAMPLES 683-692

[0505] The following compounds are prepared by an analogous process to that described in Example 682.
[0506] 
[00040] [TABLE-US-00040]
 
[see pdf for image]
 
        UV max   MS (ESI)
    #   E   [nm](M + H)+
   
    683 [see pdf for image]   282   661
   
    684 [see pdf for image]   282   673
   
    685 [see pdf for image]   282   701
   
    686 [see pdf for image]   282   645
   
    687 [see pdf for image]   282   685
   
    688 [see pdf for image]   282   616
   
    689 [see pdf for image]   282   713
   
    690 [see pdf for image]   282   630
   
    691 [see pdf for image]   282   632
   
    692 [see pdf for image]   282   602
   

EXAMPLES 693-704

[0507] 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.
[0508] 
[00041] [TABLE-US-00041]
 
[see pdf for image]
 
      UV max   MS (ESI)
  #   B   [nm](M + H)+
 
  693 [see pdf for image]   282   685
 
  694 [see pdf for image]   282   685
 
  695 [see pdf for image]   314   659
 
  696 [see pdf for image]   282   645
 
  697 [see pdf for image]   282   644
 
  698 [see pdf for image]   282   618
 
  699 [see pdf for image]   282   602
 
  700 [see pdf for image]   282   687
 
  701 [see pdf for image]   322   573
 
  702 [see pdf for image]   322   630
 
  703 [see pdf for image]   222   650
 
  704 [see pdf for image]   278   707
 

EXAMPLE 705

[0509] 2-(2-methoxy-4-[3-(3-pyrrolidin-1-yl-ethyl)-ureido]-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine
[0510]  [see pdf for image]
[0511] 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.
[0512] 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 706

[0513] 2-(2-methoxy-4-ureido-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine
[0514]  [see pdf for image]
[0515] This compound is prepared analogously to Example 705.
[0516] 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

[0517] 2-(2-methoxy-4-[(1-methyl-piperidin-4-carbonyl)-amino]-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine
[0518]  [see pdf for image]
[0519] 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.
[0520] 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

[0521] Using an analogous method to that described in Example 53 a primary amine which has another protected amino function in the side chain is coupled to 2-(4-carboxy-2-methoxy-phenylamino)-4-[2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino]-5-trifluoromethyl-pyrimidine. The protective group used may be a tert-butoxycarbonyl, benzyloxycarbonyl or benzyl group. This protective group is cleaved using a procedure familiar to the skilled man and reductive amination (analogously to Example 639) or alkylation (analogously to method 34 or WO2004052857) are the final steps in this sequence.
[0522] 
[00042] [TABLE-US-00042]
 
[see pdf for image]
 
      UV max   MS (ESI)
  #R3   [nm](M + H)+
 
  708 [see pdf for image]   285, 322   706
 
  709 [see pdf for image]   285, 322   656
 
  710 [see pdf for image]   285, 322   630
 
  711 [see pdf for image]   322, 286   644
 
  712 [see pdf for image]   325, 286   699
 
  713 [see pdf for image]   282, 318   644
 
  714 [see pdf for image]   326   685
 
  715 [see pdf for image]   326   658
 
  716 [see pdf for image]   326   699
 
  717 [see pdf for image]   326   630
 
  718 [see pdf for image]   326   644
 
  719 [see pdf for image]   322   644
 
  720 [see pdf for image]   326   656
 
  721 [see pdf for image]   326   678
 
  722 [see pdf for image]   314   630
 
  723 [see pdf for image]   322   641
 
  724 [see pdf for image]   326   712
 
  725 [see pdf for image]   326   642
 
  726 [see pdf for image]   322   642
 
  727 [see pdf for image]   318   672
 
  728 [see pdf for image]   301   686
 
  729 [see pdf for image]   326   588
 
  730 [see pdf for image]   326   642
 
  731 [see pdf for image]   326   670
 
  732 [see pdf for image]   326   642
 
  733 [see pdf for image]   326   630
 
  734 [see pdf for image]   326   699
 
  735 [see pdf for image]   310   616
 
  736 [see pdf for image]   326   656
 
  737 [see pdf for image]   322   630
 
  738 [see pdf for image]   326   656
 
  739 [see pdf for image]   326   656
 
  740 [see pdf for image]   266   652
 
  741 [see pdf for image]   326   629
 
  742 [see pdf for image]   326   671
 
  743 [see pdf for image]   326   630
 
  744 [see pdf for image]   326   642
 
  745 [see pdf for image]   326   602
 
  746 [see pdf for image]   326   628
 
  747 [see pdf for image]   326   616
 
  748 [see pdf for image]   326   602
 
  749 [see pdf for image]   322   652
 
  750 [see pdf for image]   326   646
 
  751 [see pdf for image]   326   672
 
  752 [see pdf for image]   326   616
 
  753 [see pdf for image]   326   616
 
  754 [see pdf for image]   326   685
 
  755 [see pdf for image]   322   616
 
  756 [see pdf for image]   318   713
 
  757 [see pdf for image]   286, 322   588
 
  758 [see pdf for image]   226, 286,322   602
 
  759 [see pdf for image]   322-326   656
 
  760 [see pdf for image]   322-326   699
 
  761 [see pdf for image]   322-326   670
 
  762 [see pdf for image]   322-326   699
 
  763 [see pdf for image]   322   713
 
  764 [see pdf for image]   326   685
 
  765 [see pdf for image]   322   684
 
  766 [see pdf for image]   326   642
 
  767 [see pdf for image]   322-326   656
 
  768 [see pdf for image]   322-326   685
 
  769 [see pdf for image]   322-326   630
 
  770 [see pdf for image]   286, 322   670
 
  771 [see pdf for image]   286, 322   670
 
  772 [see pdf for image]   322-326   644
 
  773 [see pdf for image]   322   684
 
  774 [see pdf for image]   322-326   658
 
  775 [see pdf for image]   322   686
 
  776 [see pdf for image]   322-326   727
 
  777 [see pdf for image]   322-326   674
 
  778 [see pdf for image]   322-326   684
 
  796 [see pdf for image]   322-326   698
 
  780 [see pdf for image]   286, 322   630
 
  781 [see pdf for image]   282, 314   616
 
  782 [see pdf for image]   322, 286   686
 
  783 [see pdf for image]   326   684
 
  784 [see pdf for image]   324, 286   656
 
  785 [see pdf for image]   326, 286   685
 
  786 [see pdf for image]   322, 286   715
 
  787 [see pdf for image]   322, 286   673
 
  788 [see pdf for image]   285, 322   616
 
  789 [see pdf for image]   285, 322   630
 
  790 [see pdf for image]   285, 322   686
 
  791 [see pdf for image]   285, 322   686
 
  792 [see pdf for image]   326   644
 
  793 [see pdf for image]   322   630
 
  794 [see pdf for image]   326   631
 
  795 [see pdf for image]   326   660
 

EXAMPLE 796

[0523] 2-[2-methoxy-4-(2-methyl-2-pyrrolidin-1-yl-propylcarbamoyl)-phenylamino]-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine
[0524]  [see pdf for image]
[0525] 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.
[0526] 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

[0527] The following compounds are prepared by an analogous method to that described in Example 796:
[0528] 
[00043] [TABLE-US-00043]
 
[see pdf for image]
 
      UV max   MS (ESI)
  #R3   [nm](M + H)+
 
  797 [see pdf for image]   285, 325   642
 
  798 [see pdf for image]   284, 325   642
 
  799 [see pdf for image]   325, 285   644
 
  800 [see pdf for image]   325, 285   644
 
  801 [see pdf for image]   325, 285   644
 
  802 [see pdf for image]   325, 285   656
 
  803 [see pdf for image]   325, 285   658
 
  804 [see pdf for image]   325, 284   658
 
  805 [see pdf for image]   326, 286   670
 
  806 [see pdf for image]   324, 285   670
 

EXAMPLES 807-821

[0529] The following compounds are prepared by an analogous process to that described in Example 53. The corresponding aniline is described in method 31. The amine used to prepare the amide is commercially obtainable or is described in method 13, 21 or in method 25.
[0530] 
[00044] [TABLE-US-00044]
 
[see pdf for image]
 
      UV max   MS (ESI)
  #R3   [nm](M + H)+
 
  807 [see pdf for image]   286, 322   686
 
  808 [see pdf for image]   286, 322   616
 
  809 [see pdf for image]   286, 322   630
 
  810 [see pdf for image]   286, 322   616
 
  811 [see pdf for image]   286, 322   712
 
  812 [see pdf for image]   322, 286   684
 
  813 [see pdf for image]     689
 
  814 [see pdf for image]   278   689
 
  815 [see pdf for image]   322   630
 
  816 [see pdf for image]   286, 326   645
 
  817 [see pdf for image]   285, 322   659
 
  818 [see pdf for image]   285, 322   616
 
  819 [see pdf for image]   285, 322   630
 
  820 [see pdf for image]     630
 
  821 [see pdf for image]   322, 286   630
 

EXAMPLES 822-885

[0531] 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.
[0532] 
[00045] [TABLE-US-00045]
 
[see pdf for image]
 
      UV max   MS (ESI)
  #R3   [nm](M + H)+
 
  822 [see pdf for image]   286, 322   686
 
  823 [see pdf for image]   325, 284   616
 
  824 [see pdf for image]   286, 326   630
 
  825 [see pdf for image]   286, 322   616
 
  826 [see pdf for image]   286, 318   712
 
  827 [see pdf for image]   286, 322   684
 
  828 [see pdf for image]   326   645
 
  829 [see pdf for image]   316   689
 
  830 [see pdf for image]   322   689
 
  831 [see pdf for image]     616
 
  832 [see pdf for image]   318   630
 
  833 [see pdf for image]   326   588
 
  834 [see pdf for image]   322   630
 
  835 [see pdf for image]   286, 322   630
 
  836 [see pdf for image]     658
 
  837 [see pdf for image]   322-326   602
 
  838 [see pdf for image]   322-326   616
 
  839 [see pdf for image]   322   616
 
  840 [see pdf for image]   322-326   616
 
  841 [see pdf for image]   322-326   630
 
  842 [see pdf for image]   322-326   630
 
  843 [see pdf for image]   286, 322   644
 
  844 [see pdf for image]   286, 322   642
 
  845 [see pdf for image]   286, 322   642
 
  846 [see pdf for image]   286, 322   656
 
  847 [see pdf for image]   282, 318   630
 
  848 [see pdf for image]   282, 322   630
 
  849 [see pdf for image]   286, 318   671
 
  850 [see pdf for image]   286, 322   630
 
  851 [see pdf for image]   286, 322   630
 
  852 [see pdf for image]   286, 322   644
 
  853 [see pdf for image]   322-326   672
 
  854 [see pdf for image]   322   672
 
  855 [see pdf for image]   286, 322   725
 
  856 [see pdf for image]   286, 322   725
 
  857 [see pdf for image]   322-326   685
 
  858 [see pdf for image]   286, 322   713
 
  859 [see pdf for image]   286, 322   713
 
  860 [see pdf for image]   286, 322   644
 
  861 [see pdf for image]   286, 322   644
 
  862 [see pdf for image]   318-322   645
 
  863 [see pdf for image]   286, 322   658
 
  864 [see pdf for image]   286, 322   699
 
  865 [see pdf for image]   286, 322   699
 
  866 [see pdf for image]   326   709
 
  867 [see pdf for image]   322   697
 
  868 [see pdf for image]   322   697
 
  869 [see pdf for image]   318   695
 
  870 [see pdf for image]   290.3   693
 
  871 [see pdf for image]   322   695
 
  872 [see pdf for image]   286, 322   753
 
  873 [see pdf for image]   286, 326   642
 
  874 [see pdf for image]   286, 322   645
 
  875 [see pdf for image]   322, 286   659
 
  876 [see pdf for image]   282, 322   684
 
  877 [see pdf for image]   324, 284   646
 
  878 [see pdf for image]   286, 322   670
 
  879 [see pdf for image]   325, 284   630
 
  880 [see pdf for image]   322, 286   630
 
  881 [see pdf for image]   322, 286   684
 
  882 [see pdf for image]   325, 286   670
 
  883 [see pdf for image]   322, 286   646
 
  884 [see pdf for image]   326, 286   644
 
  885 [see pdf for image]   325, 285   630
 

EXAMPLES 886-891

[0533] 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.
[0534] 
[00046] [TABLE-US-00046]
 
[see pdf for image]
 
        MS
        (ESI)
      UV max   (M +
  #   B   [nm]H)+
 
  886 [see pdf for image]   314   685
 
  887 [see pdf for image]   314   685
 
  888 [see pdf for image]   286, 310   685
 
  889 [see pdf for image]   282, 314   699
 
  890 [see pdf for image]   338   656
 
  891 [see pdf for image]   314   588
 

EXAMPLES 892-894

[0535] 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.
[0536] 
[00047] [TABLE-US-00047]
 
[see pdf for image]
 
        UV max   MS (ESI)
    #R3   [nm](M + H)+
   
    892 [see pdf for image]   314   665
   
    893 [see pdf for image]   270   665
   
    894 [see pdf for image]   270   680
   

EXAMPLE 895

[0537] 2-(2-methoxy-4-[(1-methyl-piperidin-4-carbonyl)-amino]-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine
Enantiomer 1
[0538]  [see pdf for image]
[0539] Starting from 2-(4-amino-2-methoxy-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine enantiomer 1 (analogously to method 30) the above-mentioned product is prepared by an amide linking method familiar to the skilled man (cf. also Example 1032). It is obtained as the dihydrochloride.
[0540] UV max 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 896

[0541] 2-(2-methoxy-4-(2-pyrrolidin-1-yl-acetylamino)-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine
Enantiomer 1
[0542]  [see pdf for image]
[0543] 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.
[0544] 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

[0545] 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.
[0546] 
[00048] [TABLE-US-00048]
 
[see pdf for image]
 
      UV max   MS (ESI)
  #R3   [nm](M + H)+
 
  897 [see pdf for image]     672
 
  898 [see pdf for image]   322   644
 
  899 [see pdf for image]   326   630
 
  900 [see pdf for image]   326   630
 
  901 [see pdf for image]   322   644
 
  902 [see pdf for image]   322   642
 
  903 [see pdf for image]   322   658
 
  904 [see pdf for image]   326   615
 
  905 [see pdf for image]   322   656
 
  906 [see pdf for image]   326   658
 
  907 [see pdf for image]   326   644
 
  908 [see pdf for image]   322   644
 
  909 [see pdf for image]   322   670
 
  910 [see pdf for image]   306   686
 
  911 [see pdf for image]   326   630
 
  912 [see pdf for image]     666
 
  913 [see pdf for image]   286, 322   656
 
  914 [see pdf for image]   286, 322   656
 
  915 [see pdf for image]   286, 318   670
 
  916 [see pdf for image]   286, 322   713
 
  917 [see pdf for image]   286, 322   670
 
  918 [see pdf for image]   286.3   713
 
  919 [see pdf for image]   286, 322   642
 
  920 [see pdf for image]   286, 322   672
 
  921 [see pdf for image]   286, 322   672
 
  922 [see pdf for image]   286, 322   644
 
  923 [see pdf for image]   286, 322   670
 
  924 [see pdf for image]   286, 322   700
 
  925 [see pdf for image]   286, 322   700
 
  926 [see pdf for image]   286, 322   670
 
  927 [see pdf for image]   326   713
 
  928 [see pdf for image]   322-326   700
 
  929 [see pdf for image]   322-326   644
 
  930 [see pdf for image]   322   658
 
  931 [see pdf for image]   322-326   713
 
  932 [see pdf for image]   322   700
 
  933 [see pdf for image]   322-326   644
 
  934 [see pdf for image]   322   658
 
  935 [see pdf for image]   322-326   714
 
  936 [see pdf for image]   322   714
 
  937 [see pdf for image]   322   662
 
  938 [see pdf for image]   322-326   662
 
  939 [see pdf for image]     676
 
  940 [see pdf for image]   322-326   680
 
  941 [see pdf for image]   286, 322   648
 
  942 [see pdf for image]   230, 286, 318   662
 
  943 [see pdf for image]   284, 324   668
 
  944 [see pdf for image]   282, 322   670
 
  945 [see pdf for image]   282, 322   696
 
  946 [see pdf for image]   228, 284, 322   642
 
  947 [see pdf for image]   226, 286, 322   672
 
  948 [see pdf for image]   286, 322   644
 
  949 [see pdf for image]   324, 284   644
 
  950 [see pdf for image]   285, 322   616
 
  951 [see pdf for image]   285, 325   630
 
  952 [see pdf for image]   285, 325   616
 

EXAMPLES 953-958

[0547] The following compounds are prepared by a method analogous to that described in Example 796:
[0548] 
[00049] [TABLE-US-00049]
 
[see pdf for image]
 
      UV max   MS (ESI)
  #R3   [nm](M + H)+
 
  953 [see pdf for image]   326, 286   658
 
  954 [see pdf for image]   325, 285   670
 
  955 [see pdf for image]   325, 285   670
 
  956 [see pdf for image]   325, 284   644
 
  957 [see pdf for image]   325, 284   658
 
  958 [see pdf for image]   325, 285   672
 

EXAMPLE 959

[0549] 2-(2-methoxy-4-(2-pyrrolidin-1-yl-ethylcarbamoyl)-phenylamino)-4-(2-(2-fluoro-ethyl)-1-ethyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine
[0550]  [see pdf for image]
[0551] 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:
[0552] column: 250×4.6 mm CHIRALPAKADH®
[0553] eluant: 25 ethanol/75 methanol (v/v) (0.03% triethylamine is added to each solvent)
[0554] flow rate: 0.5 ml/min
[0555] temperature: 20° C.
[0556] The enantiomer that elutes first is referred to as Enantiomer 1 and bears the symbol *1 in the chemical formula.

Enantiomer 1

[0557]  [see pdf for image]
[0558] retention time: 9.96 min
[0559] The enantiomer that elutes second is referred to as Enantiomer 2 and bears the symbol *2 in the chemical formula.

Enantiomer 2

[0560]  [see pdf for image]
[0561] retention time: 12.60 min

EXAMPLES 960-976

[0562] 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.
[0563] 
[00050] [TABLE-US-00050]
 
[see pdf for image]
 
        UV max   MS (ESI)
  #   AR3   [nm](M + H)+
 
  960 [see pdf for image] [see pdf for image]   280, 320   654
 
  961 [see pdf for image] [see pdf for image]   282, 318
 
  962 [see pdf for image] [see pdf for image]   286, 322   680
 
  963 [see pdf for image] [see pdf for image]   286, 326   630
 
  964 [see pdf for image] [see pdf for image]   286, 326   644
 
  965 [see pdf for image] [see pdf for image]   286, 326   630
 
  966 [see pdf for image] [see pdf for image]   286, 326   659
 
  967 [see pdf for image] [see pdf for image]   286, 326   630
 
  968 [see pdf for image] [see pdf for image]   286, 322   644
 
  969 [see pdf for image] [see pdf for image]   286, 326   644
 
  970 [see pdf for image] [see pdf for image]   286, 326   644
 
  971 [see pdf for image] [see pdf for image]   286, 326   714
 
  972 [see pdf for image] [see pdf for image]   286, 322   632
 
  973 [see pdf for image] [see pdf for image]   286, 326   646
 
  974 [see pdf for image] [see pdf for image]   286, 326   660
 
  975 [see pdf for image] [see pdf for image]   282, 326   685
 
  976 [see pdf for image] [see pdf for image]   282, 326   659
 

EXAMPLES 977-980

[0564] 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.
[0565] 
[00051] [TABLE-US-00051]
 
[see pdf for image]
 
        UV max   MS (ESI)
  #   AR3   [nm](M + H)+
 
  977 [see pdf for image] [see pdf for image]   234, 282,318   655
 
  978 [see pdf for image] [see pdf for image]   226, 282,318   655
 
  979 [see pdf for image] [see pdf for image]   222, 282,318   641
 
  980 [see pdf for image] [see pdf for image]   230, 282,671   671
 

EXAMPLES 981-999

[0566] The following compounds are prepared by an analogous method to that described in Example 53. The corresponding aniline is described in method 32. The amine used to prepare the amide is commercially obtainable or described in method 13.
[0567] 
[00052] [TABLE-US-00052]
 
[see pdf for image]
 
        UV max   MS (ESI)
  #   AR3   [nm](M + H)+
 
  981 [see pdf for image] [see pdf for image]   318   612
 
  982 [see pdf for image] [see pdf for image]   318   583
 
  983 [see pdf for image] [see pdf for image]   322   599
 
  984 [see pdf for image] [see pdf for image]     639
 
  985 [see pdf for image] [see pdf for image]   286   706
 
  986 [see pdf for image] [see pdf for image]   322   597
 
  987 [see pdf for image] [see pdf for image]   318   679
 
  988 [see pdf for image] [see pdf for image]   286   653
 
  989 [see pdf for image] [see pdf for image]   322   611
 
  990 [see pdf for image] [see pdf for image]   322   583
 
  991 [see pdf for image] [see pdf for image]   318   625
 
  992 [see pdf for image] [see pdf for image]   318   597
 
  993 [see pdf for image] [see pdf for image]   318   598
 
  994 [see pdf for image] [see pdf for image]   318   569
 
  995 [see pdf for image] [see pdf for image]   322   585
 
  996 [see pdf for image] [see pdf for image]   286   639
 
  997 [see pdf for image] [see pdf for image]   318   626
 
  998 [see pdf for image] [see pdf for image]   318   599
 
  999 [see pdf for image] [see pdf for image]   318   318
 

EXAMPLES 1000-1024

[0568] 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.
[0569] 
[00053] [TABLE-US-00053]
 
[see pdf for image]
 
        UV max   MS (ESI)
  #   AR3   [nm](M + H)+
 
  1000 [see pdf for image] [see pdf for image]   282, 322   614
 
  1001 [see pdf for image] [see pdf for image]   282, 322   841
 
  1002 [see pdf for image] [see pdf for image]   282, 326   571
 
  1003 [see pdf for image] [see pdf for image]   280, 322   655
 
  1004 [see pdf for image] [see pdf for image]   280, 325   655
 
  1005 [see pdf for image] [see pdf for image]   280, 322   669
 
  1006 [see pdf for image] [see pdf for image]   280, 325   599
 
  1007 [see pdf for image] [see pdf for image]   282, 327   613
 
  1008 [see pdf for image] [see pdf for image]   280, 322   697
 
  1009 [see pdf for image] [see pdf for image]   282, 325   627
 
  1010 [see pdf for image] [see pdf for image]   283, 328   641
 
  1011 [see pdf for image] [see pdf for image]   280, 325   585
 
  1012 [see pdf for image] [see pdf for image]   280, 325   599
 
  1013 [see pdf for image] [see pdf for image]   326, 283   585
 
  1014 [see pdf for image] [see pdf for image]   282, 327   599
 
  1015 [see pdf for image] [see pdf for image]   322-326   597
 
  1016 [see pdf for image] [see pdf for image]   326   611
 
  1017 [see pdf for image] [see pdf for image]   280, 325   585
 
  1018 [see pdf for image] [see pdf for image]   280, 325   614
 
  1019 [see pdf for image] [see pdf for image]   280, 325   585
 
  1020 [see pdf for image] [see pdf for image]   280, 322   599
 
  1021 [see pdf for image] [see pdf for image]   280, 325   641
 
  1022 [see pdf for image] [see pdf for image]   280, 325   599
 
  1023 [see pdf for image] [see pdf for image]   280, 325   585
 
  1024 [see pdf for image] [see pdf for image]   280, 322   653
 

EXAMPLES 1025-1032

[0570] 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.
[0571] 
[00054] [TABLE-US-00054]
 
[see pdf for image]
 
        UV max   MS (ESI)
  #   AR3   [nm](M + H)+
 
  1025 [see pdf for image] [see pdf for image]   318   648
 
  1026 [see pdf for image] [see pdf for image]   318   359
 
  1027 [see pdf for image] [see pdf for image]   322   662
 
  1028 [see pdf for image] [see pdf for image]   322   662
 
  1029 [see pdf for image] [see pdf for image]   322   664
 
  1030 [see pdf for image] [see pdf for image]   226, 318   678
 
  1031 [see pdf for image] [see pdf for image]   226, 318   691
 
  1032 [see pdf for image] [see pdf for image]   322   648
 

EXAMPLES 1033-1035

[0572] 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.
[0573] 
[00055] [TABLE-US-00055]
 
[see pdf for image]
 
      MS (ESI)  
  #R3(M + H)+   salt form
 
  1033 [see pdf for image]   701   base
 
  1034 [see pdf for image]   645   formate
 
  1035 [see pdf for image]   631   formate
 

EXAMPLE 1036

[0574] 2-(2-methoxy-4-(2-pyrrolidin-1-yl-ethylcarbamoyl)-phenalamino)-4-(2-(2-fluoro-ethyl)-1,1-dimethyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine
[0575]  [see pdf for image]
[0576] 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.
[0577] 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 1037

[0578] 2-(2-methoxy-4-[2-(4-methyl-piperazin-1-yl)-ethylcarbamoyl]-phenylamino)-4-(2-(2-fluoro-ethyl)-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-acetyl-pyrimidine
[0579]  [see pdf for image]
[0580] 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.
[0581] 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

[0582] The following compounds are prepared by an analogous method to that described in Example 1037. The aniline used is described in method 28.
[0583] The amine used to prepare the amide is commercially obtainable or described in method 13.
[0584] 
[00056] [TABLE-US-00056]
 
[see pdf for image]
 
        UV max   MS (ESI)
  #   AR3   [nm](M + H)+
 
  1038 [see pdf for image] [see pdf for image]   326   660
 
  1039 [see pdf for image] [see pdf for image]   326   646
 
  1040 [see pdf for image] [see pdf for image]   328   576
 
  1041 [see pdf for image] [see pdf for image]   318   672
 
  1042 [see pdf for image] [see pdf for image]   326   605
 
  1043 [see pdf for image] [see pdf for image]   330   590
 
  1044 [see pdf for image] [see pdf for image]   318   663
 
  1045 [see pdf for image] [see pdf for image]   330   604
 
  1046 [see pdf for image] [see pdf for image]   326   686
 
  1047 [see pdf for image] [see pdf for image]   326   604
 
  1048 [see pdf for image] [see pdf for image]   330   590
 
  1049 [see pdf for image] [see pdf for image]   326   713
 
  1050 [see pdf for image] [see pdf for image]   330   590
 
  1051 [see pdf for image] [see pdf for image]   250   614
 
  1052 [see pdf for image] [see pdf for image]   334-338   600
 
  1053 [see pdf for image] [see pdf for image]   334-338   614
 
  1054 [see pdf for image] [see pdf for image]   338   600
 
  1055 [see pdf for image] [see pdf for image]   338   670
 
  1056 [see pdf for image] [see pdf for image]   334   696
 
  1057 [see pdf for image] [see pdf for image]   330   622
 
  1058 [see pdf for image] [see pdf for image]   327   340
 
  1059 [see pdf for image] [see pdf for image]   330   608
 
  1060 [see pdf for image] [see pdf for image]   330   632
 

EXAMPLES 1061-1069

[0585] 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.
[0586] 
[00057] [TABLE-US-00057]
 
[see pdf for image]
 
        UV max   MS (ESI)
  #   A   B   [nm](M + H)+
 
  1061 [see pdf for image] [see pdf for image]   254, 316   552
 
  1062 [see pdf for image] [see pdf for image]   254, 314   548
 
  1063 [see pdf for image] [see pdf for image]   250   598
 
  1064 [see pdf for image] [see pdf for image]   254, 318   588
 
  1065 [see pdf for image] [see pdf for image]   250   518
 
  1066 [see pdf for image] [see pdf for image]   252, 318   606
 
  1067 [see pdf for image] [see pdf for image]   250, 310   566
 
  1068 [see pdf for image] [see pdf for image]   254, 318   552
 
  1069 [see pdf for image] [see pdf for image]   262; 314-318   566
 

EXAMPLES 1070-1071

[0587] 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.
[0588] 
[00058] [TABLE-US-00058]
 
[see pdf for image]
 
        UV max   MS (ESI)
  #   AR3   [nm](M + H)+
 
  1070 [see pdf for image] [see pdf for image]   330   608
 
  1071 [see pdf for image] [see pdf for image]   330   678
 

EXAMPLES 1072-1085

[0589] 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.
[0590] 
[00059] [TABLE-US-00059]
 
[see pdf for image]
 
        UV  
        max   MS (ESI)
  #   ZR3   [nm](M + H)+
 
  1072 [see pdf for image] [see pdf for image]   285,320   674
 
  1073 [see pdf for image] [see pdf for image]   326   663
 
  1074 [see pdf for image] [see pdf for image]   306   596
 
  1075 [see pdf for image] [see pdf for image]   326   593
 
  1076 [see pdf for image] [see pdf for image]   262   596
 
  1077 [see pdf for image] [see pdf for image]   326   593
 
  1078 [see pdf for image] [see pdf for image]   318   652
 
  1079 [see pdf for image] [see pdf for image]   325   582
 
  1080 [see pdf for image] [see pdf for image]   319   582
 
  1081 [see pdf for image] [see pdf for image]   302   666
 
  1082 [see pdf for image] [see pdf for image]   322   626
 
  1083 [see pdf for image] [see pdf for image]   318   626
 
  1084 [see pdf for image] [see pdf for image]   286,318   612
 
  1085 [see pdf for image] [see pdf for image]   280,325   572
 

Biological Properties
[0591] 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.
[0592] 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 tmours; skin diseases (e.g. psoriasis); bone diseases; cardiovascular diseases (e.g. restenosis and hypertrophy). They are also useful for protecting proliferating cells (e.g. hair, intestinal, blood and progenitor cells) from DNA damage caused by radiation, UV treatment and/or cytostatic treatment (Davis et al., 2001). The new compounds may be used for the prevention, short- or long-term treatment of the above-mentioned diseases, also in combination with other active substances used for the same indications, e.g. cytostatics, steroids or antibodies.
[0593] 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

[0594] 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.
[0595] 4×107 Sf21 cells (Spodoptera frugiperda) in 200 ml of Sf-900 II Serum free insect cell medium (Life Technologies) are seeded in a spinner flask. After 72 hours' incubation at 27° C. and 70 rpm, 1×108 Sf21 cells are seeded in a total of 180 ml medium in a new spinner flask. After another 24 hours, 20 ml of recombinant Baculovirus stock suspension are added and the cells are cultivated for 72 hours at 27° C. at 70 rpm. 3 hours before harvesting, okadaic acid is added (Calbiochem, final concentration 0.1 μM) and the suspension is incubated further. The cell number is determined, the cells are removed by centrifuging (5 minutes, 4° C., 800 rpm) and washed 1× with PBS (8 g NaCl/l, 0.2 g KCl/l, 1.44 g 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 1×108 cells/17.5 ml. The cells are lysed for 30 minutes on ice. After removal of the cell debris by centrifugation (4000 rpm, 5 minutes) the clear supernatant is combined with glutathione sepharose beads (1 ml resuspended and washed beads per 50 ml of supernatant) and the mixture is incubated for 30 minutes at 4° C. on a rotating board. Then the beads are washed with lysing buffer and the recombinant protein is eluted from the beads with 1 ml eluting buffer/ml resuspended beads (eluting buffer: 100 mM Tris/HCl pH=8.0, 120 mM-NaCl, 20 mM reduced glutathione-(Sigma-G-4251), 10 mM MgCl2, 1 mM DTT). The protein concentration is determined by Bradford Assay.

Assay

[0596] The following components are combined in a well of a 96-well round-bottomed dish (Greiner bio-one, PS Microtitre plate No. 650101):
[0597] 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
[0598] 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)
[0599] 20 μl enzyme dilution (1:100 dilution of the enzyme stock in 25 mM MOPS pH=7.0, 15 mM MgCl2, 1 mM DTT)
[0600] 10 μl ATP solution (45 μM ATP with 1.11×106 Bq/ml gamma-P33-ATP).
[0601] 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).
[0602] 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

[0603] 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

[0604] 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.
[0605] For PI staining, for example, ×106 HeLa S3 cells are seeded onto a 75 cm2 cell culture flask, and after 24 h either 0.1% DMSO is added as control or the substance is added in various concentrations (in 0.1% DMSO). The cells are incubated for 24 h with the substance or with DMSO before the cells are washed 2× with PBS and then detached with trypsin/EDTA. The cells are centrifuged (1000 rpm, 5 min, 4° C.), and the cell pellet is washed 2× with PBS before the cells are resuspended in 0.1 ml PBS. Then the cells are fixed with 80% ethanol for 16 hours at 4° C. or alternatively for 2 hours at −20° C. The fixed cells are centrifuged (1000 rpm, 5 min, 4° C.), washed with PBS and then centrifuged again. The cell pellet is resuspended in 2 ml 0.25% Triton X-100 in PBS, and incubated on ice for 5 min before 5 ml PBS are added and the mixture is centrifuged again. The cell pellet is resuspended in 350 μl PI staining solution (0.1 mg/ml RNase A (Sigma, No. R-4875), 10 μg/ml prodium iodide (Sigma, No. P-4864) in 1×PBS). The cells are incubated for 20 min in the dark with the staining buffer before being transferred into sample measuring containers for the FACS scan. The DNA measurement is carried out in a Becton Dickinson FACS Analyzer, with an argon laser (500 mW, emission 488 nm), and the DNA Cell Quest Programme (BD). The logarithmic PI fluorescence is determined with a band-pass filter (BP 585/42). The cell populations in the individual cell cycle phases are quantified using the ModFit LT Programme made by Becton Dickinson.
[0606] The compounds according to the invention are also tested accordingly for other tumour cells. For example, these compounds are effective on carcinomas of all kinds of tissue (e.g. breast (MCF7); colon (HCT116), head and neck (FaDu), lung (NCI-H460), pancreas (BxPC-3), prostate (DU145)), sarcomas (e.g. SK-UT-1B), leukaemias and lymphomas (e.g. HL-60; Jurkat, THP-1) and other tumours (e.g. melanomas (BRO), gliomas (U-87MG)) and could be used for such indications. This is evidence of the broad applicability of the compounds according to the invention for the treatment of all kinds of tumour types. The compounds of general formula (I) may be used on their own or in conjunction with other active substances according to the invention, optionally also in conjunction with other pharmacologically active substances.
[0607] Suitable preparations include for example tablets, capsules, suppositories, solutions, particularly solutions for injection (s.c., i.v., i.m.) and infussion, elixirs, emulsions or dispersible powders. The content of the pharmaceutically active compound(s) should be in the range from 0.1 to 90 wt.-%, preferably 0.5 to 50 wt.-% of the composition as a whole, i.e. in amounts which are sufficient to achieve the dosage range specified below. The doses specified may, if necessary, be given several times a day.
[0608] 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.
[0609] 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.
[0610] 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.
[0611] 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.
[0612] 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.

[0613] 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).
[0614] 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.
[0615] 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.

[0616] 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.
[0617] The formulation examples which follow illustrate the present invention without restricting its scope:

Examples of Pharmaceutical Formulations

[0618] 
[00060] [TABLE-US-00060]
   
    A) Tablets   per tablet
   
    active substance   100 mg
    lactose   140 mg
    corn starch   240 mg
    polyvinylpyrrolidone    15 mg
    magnesium stearate    5 mg
      500 mg
   
[0619] 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.
[0620] 
[00061] [TABLE-US-00061]
   
    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 
   
[0621] 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.
[0622] 
[00062] [TABLE-US-00062]
   
    C) Ampoule solution
   
 
    active substance   50   mg
    sodium chloride   50   mg
    water for inj.   5   ml
   
[0623] 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.
(57)

Claims

1. A compound of the following formula (1):
[see pdf for image]
wherein
W denotes N or C—R2,
X denotes —NR1a, O or S,
Y denotes CH,
Z denotes —CF3;
A is selected from one of the following formulas (i), (ii) and (iii):
[see pdf for image]
Q1 denotes that (i), (ii) and (iii) are mono- or bicyclic aryl;
B1, B2, B3 and B4 each independently of one another denote C—RgRh, N—Ri, O or S;
R1 and R1a each independently of one another denote hydrogen or methyl;
R2 denotes 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 C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6-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, —OSO2NR5R6 and pseudohalogen;
Ra, Rb, Rc, Rd, Re, Rf, Rg and Rh each 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 C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-6-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, —OSO2NR5R6 and pseudohalogen; wherein Rg and Rh are 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;
Ri denotes 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 C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, 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, —OSO2NR5R6 and pseudohalogen; wherein the Ri groups located at adjacent N atoms are optionally joined together or Ri with Rg or Rh located 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;
R3 is selected from the following formulas (iv)-(x):
[see pdf for image]
R4, R5 and R6 each independently of one another denote hydrogen or an unsubstituted or mono- or polysubstituted group selected from the group consisting of C1-5-alkyl, C2-5alkenyl, C2-5alkynyl, C3-10cycloalkyl, 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 C3-10-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, —OSO2NR8R9 and pseudohalogen;
L denotes a bond or an unsubstituted or mono- or polysubstituted group selected from the group consisting of C1-16-alkyl, C2-16-alkenyl, C2-16-alkynyl, C3-10-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, —OSO2NR8R9 and pseudohalogen;
Q2 and Q3 each independently of one another denote a bond or an unsubstituted or mono- or polysubstituted group selected from the group consisting of C1-16-alkyl, C2-16-alkenyl, C2-16-alkynyl, C3-10-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, —OSO2NR8R9 and pseudohalogen;
R7 denotes hydrogen or an unsubstituted or mono- or polysubstituted group selected from the group consisting of C1-16-alkyl, C2-16-alkenyl, C2-16-alkynyl, C3-10-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, —OSO2NR8R9 and pseudohalogen; and
R8, R9 and R10 each independently of one another denote hydrogen or a substituted or unsubstituted group selected from the group consisting of C1-8-alkyl, C2-8-alkenyl, C2-8-alkynyl, C3-10-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.
2. The compound according to claim 1, wherein:
W denotes C—R2.
3. The compound according to claim 1, wherein:
X denotes —NR1a or oxygen;
R1 and R1a denote hydrogen; and
R3 denotes one of the following formulas (iv) and (x):
[see pdf for image]
4. The compound according to claim 1, wherein:
Y denotes CH; and
Q1 denotes monocyclic aryl compounds.
5. The compound according to claim 1, wherein:
Rc denotes a group selected from the group consisting of hydrogen, —F, —Cl, methyl and ethyl.
6. The compound according to claim 1, wherein:
Ra and Rb each independently of one another denote one of hydrogen, fluorine and a mono- or polysubstituted group selected from the group consisting of C1-2alkyl, C2alkenyl, C2alkynyl, C3-6cycloalkyl, 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 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, —OSO2NR4R5 and pseudohalogen.
7. The compound according to claim 1, wherein:
Ra and Rb each independently of one another denote hydrogen or fluorine.
8. A pharmaceutical composition comprising the compound of claim 1, or a pharmaceutically active salt thereof, and an excipient or a carrier, wherein the composition has an antiproliferative activity, a selective, kinase-inhibiting mechanism of activity, or a PLK-inhibiting mechanism of activity.
9. A method of preparing a pharmaceutical composition, comprising:
forming a compound of the following formula (1):
[see pdf for image]
wherein
W denotes N or C—R2,
X denotes —NR1a, O or S,
Y denotes CH,
Z denotes —CF3;
A is selected from one of the following formulas (i), (ii) and (iii):
[see pdf for image]
Q1 denotes that (i), (ii) and (iii) are mono- or bicyclic aryl;
B1, B2, B3 and B4 each independently denote C—RgRh, N—Ri, O or S;
R1 and R1a each independently denote hydrogen or methyl;
R2 denotes 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 C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6-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, —OSO2NR5R6 and pseudohalogen;
Ra, Rb, Rc, Rd, Re, Rf, Rg and Rh each 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 C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl , C3-6-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, —OSO2NR5R6 and pseudohalogen; wherein Rg and Rh are 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;
Ri denotes 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 C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, 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, —OSO2NR5R6 and pseudohalogen; wherein the Ri groups located at adjacent N atoms are optionally joined together or Ri with Rg or Rh located 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;
R3 is selected from the following formulas (iv)-(x):
[see pdf for image]
R4, R5 and R6 each independently of one another denote hydrogen or an unsubstituted or mono- or polysubstituted group selected from the group consisting of C1-5-alkyl, C2-5alkenyl, C2-5alkynyl, C3-10cycloalkyl, 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 C3-10-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, —OSO2NR8R9 and pseudohalogen;
L denotes a bond or an unsubstituted or mono- or polysubstituted group selected from the group consisting of C1-16alkyl, C2-16alkenyl, C2-16alkynyl, C3-10cycloalkyl, 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 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, —OSO2NR8R9 and pseudohalogen;
Q2 and Q3 each independently of one another denote a bond or an unsubstituted or mono- or polysubstituted group selected from the group consisting of C1-16alkyl, C2-16alkenyl, C2-16-alkynyl, C3-10cycloalkyl, 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 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, —OSO2NR8R9 and pseudohalogen;
R7 hydrogen or an unsubstituted or mono- or polysubstituted group selected from the group consisting of C1-16alkyl, C2-16alkenyl, C2-16alkynyl, C3-10cycloalkyl, 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 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, —OSO2NR8R9 and pseudohalogen; and
R8, R9 and R10 each independently of one another denote hydrogen or a substituted or unsubstituted group selected from the group consisting of C1-8-alkyl, C2-8-alkenyl, C2-8-alkynyl, C3-10-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 and
combining the compound with at least one cytostatic or cytotoxic active substance.
10. The pharmaceutical composition of claim 8, further comprising a cytostatic or cytotoxic active substance.
11. A compound of the following formula (1):
[see pdf for image]
wherein
W denotes N or C—R2,
X denotes O or S,
Y denotes CH,
Z denotes one of hydrogen, halogen, —NO2, C1-3alkyl, C2-3alkenyl, C2-3alkynyl, halogen-C1-3alkyl, —C(═O)H, —C(═O)—C1-3alkyl, —C(═O)—C2-3alkenyl, —C(═O)—C2-3alkynyl, —C(═O)C1-3alkyl-halogen and pseudohalogen;
A is selected from one of the following formulas (i), (ii) and (iii):
[see pdf for image]
with the proviso that when A is (i), Z is not halogen;
Q1 denotes that (i), (ii) and (iii) are mono- or bicyclic aryl;
B1, B2, B3 and B4 each independently of one another denote C—RgRh, —N—Ri, O or S;
R1 and R1a each independently of one another denote hydrogen or methyl;
R2 denotes 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 C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6-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, —OSO2NR5R6 and pseudohalogen;
Ra, Rb, Rc, Rd, Re, Rf, Rg and Rh each 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 C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-6-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, —OSO2NR5R6 and pseudohalogen; wherein Rg and Rh are 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;
Ri denotes 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 C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, 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, —OSO2NR5R6 and pseudohalogen; wherein the Ri groups located at adjacent N atoms are optionally joined together or Ri with Rg or Rh located 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 hetero atoms;
R3 is selected from the following formulas (iv) (x):
[see pdf for image]
R4, R5 and R6 each independently of one another denote hydrogen or an unsubstituted or mono- or polysubstituted group selected from the group consisting of C1-5-alkyl, C2-5alkenyl, C2-5alkynyl, C3-10-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 C3-10cycloalkyl, 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, —OSO2NR8R9 and pseudohalogen;
L denotes a bond or an unsubstituted or mono- or polysubstituted group selected from the group consisting of C1-16-alkyl, C2-16-alkenyl, C2-16-alkynyl, C3-10-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, —OSO2NR8R9 and pseudohalogen;
Q2 and Q3 each independently of one another denote a bond or an unsubstituted or mono—or polysubstituted group selected from the group consisting of C1-16-alkyl, C2-16-alkenyl, C2-16-alkynyl, C3-10-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, —OSO2NR8R9 and pseudohalogen;
R7 hydrogen or an unsubstituted or mono- or polysubstituted group selected from the group consisting of C1-16-alkyl, C2-16-alkenyl, C2-16-alkynyl, C3-10-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, —OSO2NR8R9 and pseudohalogen; and
R8, R9and R10 each independently of one another denote hydrogen or a substituted or unsubstituted group selected from the group consisting of C1-8-alkyl, C2-8-alkenyl, C2-8-alkynyl, C3-10-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.
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