• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:

    公开号:ES2664499T9
    申请号:ES09756513T
    申请日:2009-11-24
    公开日:2022-01-03
    发明作者:Heinz Stadtmueller；Ioannis Sapountzis
    申请人:Ipharma H K Ltd；
    IPC主号:
    专利说明:

    [0001] Substituted pyrimidines for the treatment of diseases such as cancer
    [0002] The present invention refers to new pyrimidines of general formula ( 1a ), ( 1b ) and ( 1c )
    [0007] wherein the groups A , R 1 to R 3, W and Y have the meanings given in the claims and in the specification, to processes for preparing these pyrimidines and to their use as medicaments.
    [0008] Background of the invention
    [0009] Tumor cells that acquire the properties of invasion and metastasis require specific survival signals. These signals allow them to overcome special mechanisms of apoptosis (anoikis) that are triggered, among others, by the loss of cell adhesion. In this process, focal adhesion kinase (FAK/PTK2) is one of the essential signal molecules that, on the one hand, controls cell-matrix interactions through so-called "focal adhesions" and, on the other hand, imparts anoikis resistance. Interference with these mechanisms by inhibiting PTK2 can lead to apoptotic cell death of tumor cells and limit invasive and metastatic growth of tumors. In addition, focal adhesion kinase is of great importance for the growth, migration, and survival of tumor-associated endothelial cells. Therefore, by inhibiting PTK2, angiogenic activity can be achieved.
    [0010] Pyrimidines are generally known as kinase inhibitors. Thus, for example, International Patent Application WO 2008038011 describes pyrimidines as inhibitors of aurora kinase, these pyrimidines having, as substituents, an oxy-methyl-piperidine group in position 4 and fluorine in position 5. Documents US 2008 /255172, WO 01/64655 and WO 2006/021457 describe substituted pyrimidines and their use for the treatment of proliferative diseases. The object of the present invention is to indicate new active substances that can be used for the prevention and/or treatment of diseases characterized by excessive or abnormal cell proliferation.
    [0011] Detailed description of the invention
    [0012] It has surprisingly been found that the compounds of general formula ( 1a ), ( 1b ) and ( 1c ), in which the groups A , R 1 to R 3, W and Y have the meanings given below, act as inhibitors of specific tyrosine kinases. Therefore, the compounds according to the invention can be used, for example, to treat diseases related to the activity of specific tyrosine kinases and characterized by excessive or abnormal cell proliferation.
    [0013] In one aspect, the present invention relates to compounds of general formula ( 1a )
    [0015] where
    [0017] A designates a group, optionally substituted with one or more identical or different R1 , selected from C 3-10 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-15 aryl and 5-12 membered heteroaryl;
    [0019] R1 and R2 , each independently of the other, designate hydrogen or a group selected from Ra, Rb and Ra substituted with one or more identical or different Rc and/or Rb ;
    [0021] R3 designates a group selected from hydrogen, halogen, -OR c , -OCF 3 , -SR c , -NR c R c , -CF 3 , -CN, -OCN, -SCN, -NO, -NO 2 , alkyl C 1-3 , C 1-3 haloalkyl and C 1-3 haloalkyloxy ;
    [0023] W and Y , independently of one another, represent CH 2 , O, NR e or N-OR e ;
    [0025] each Ra is selected, independently of one another, from C 1-6 alkyl, C 3-10 cycloalkyl, C 4-16 cycloalkyl-alkyl, C 6-10 aryl, C 7-16 aryl-alkyl, heteroalkyl of 2-6 membered, 3-8 membered heterocycloalkyl, 4-14 membered heterocycloalkylalkyl, 5-12 membered heteroaryl, and 6-18 membered heteroarylalkyl;
    [0026] each Rb is a suitable group and is independently selected from =O, -OR c , C 1-3 haloalkyloxy, -OCF 3 , =S, -SR c , =NR c , =NOR c , =NNR c R c , =NN(R g )C(O)NR c R c , -NR c R c , -ONR c R c , -N(OR c )R c , -N(R g )NR c R c , halogen , -CF 3 , -CN, -NC, -OCN, -SCN, -NO, -NO 2 , =N 2 , -N 3 , -S(O)R c , -S(O)OR c , -S (O) 2 R c , -S(O) 2 OR c , -S(O)NR c R c , -S(O) 2 NR c R c , -OS(O)R c , -OS(O) 2 R c , -OS(O) 2 OR c , -OS(O)NR c R c , -OS(O) 2 NR c R c , -C(O)R c , -C(O)OR c , -C(O)SR c , -C(O)NR c R c , -C(O)N(R g )NR c R c , -C(O)N(R g )OR c , -C(NR g )NR c R c , -C(NOH)R c , -C(NOH)NR c R c , -OC(O)R c , -OC(O)OR c , -OC(O)SR c , - OC(O)NR c R c , -OC(NR g )NR c R c , -SC(O)R c , -SC(O)OR c , -SC(O)NR c R c , -SC(NR g )NR c R c , -N(R g )C(O)R c , -N[C(O)R c ] 2 , -N(0R g )C(O)R c , -N(R g )C(NR g )R c , -N(R g )N(R g )C(O)R c , -N[C(O)R c ]NR c R c , -N(R g )C( S)R c , -N(R g )S(O)R c , -N(R g )S(O)OR c , -N(R g )S(O) 2 R c , -N[S( O) 2 R c ] 2 , -N(R g )S(O) 2 OR c , -N(R g )S(O) 2 NR c R c , -N(R g )[S(O) 2 ] 2 R c , -N(R g )C(O)OR c , - N(R g )C(O)SR c , -N(R g )C(O)NR c R c , -N(R g )C(O)NR g NR c R c , -N(R g ) N(R g )C(O)NR c R c , -N(R g )C(S)NR c R c , -[N(R g )C(O)] 2 R c , -N(R g )[C(O)] 2 R c , -N{[C(O)] 2 R c } 2 , -N(R g )[C(O)] 2 OR c , -N(R g )[C (O)] 2 NR c R c , -N{[C(O)] 2 OR c } 2 , -N{[C(O)] 2 NR c R c } 2 , -[N(R g )C (O)] 2 OR c , -N(R g )C(NR g )OR c , -N(R g )C(NOH)R c , -N(R g )C(NR g )SR c and - N(R g )C(NR g )NR c R c ;
    [0028] each of Rc , independently of one another, denotes hydrogen or a group optionally substituted with one or more identical or different Rd and/or Re , selected from C 1-6 alkyl, C 3-10 cycloalkyl, C 4-11 cycloalkyl -alkyl, C 6-10 aryl, C 7-16 aryl -alkyl, 2-6 membered heteroalkyl, 3-8 membered heterocycloalkyl, 4-14 membered heterocycloalkylalkyl, 5-12 membered heteroaryl, and 6-18 membered heteroarylalkyl members;
    [0029] each of Rd is a suitable group and is independently selected from =O, -OR e , C 1-3 haloalkyloxy, -OCF 3 , =S, -SR e , =NR e , =NOR e , =NNR e R e , =NN(R g )C(O)NR e R e , -NR e R e , -ONR e R e , -N(R g )NR e R e , halogen, -CF 3 , -CN, - NC, -OCN, -SCN, -NO, -NO 2 , =N 2 , -N 3 , -S(O)R e , -S(O)OR e , -S(O) 2 R e , -S (O) 2 OR e , -S(O)NR e R e , -S(O) 2 NR e R e , -OS(O)R e , -OS(O) 2 R e , -OS(O) 2 OR e , -OS(O)NR e R e , -OS(O) 2 NR e R e , -C(O)R e , -C(O)OR e , -C(O)SR e , - C(O)NR e R e , -C(O)N(R g )NR e R e , -C(O)N(R g )OR e , -C(NR g )NR e R e , -C (NOH)R e , -C(NOH)NR e R e , -OC(O)R e , -OC(O)OR e , -OC(O)SR e , -OC(O)NR e R e , -OC(NR g )NR e R e , -SC(O)R e , -SC(O)OR e , -SC(O)NR e R e , -SC(NR g )NR e R e , -N (R g )C(O)R e , -N[C(O)R e ] 2 , -N(OR g )C(O)R e , -N(R g )C(NR g )R e , -N(R g )N(R g )C(O)R e , -N[C(O)R e ]NR e R e , -N(R g )C(S)R e , -N(R g )S(O)R e , -N(R g )S(O)OR e -N(R g )S(O) 2 R e , -N[S(O) 2 R e ] 2 , -N (R g )S(O) 2 OR e , -N(R g )S( O) 2 NR e R e , -N(R g )[S(O) 2 ] 2 R e , -N(R g )C(O)OR e , -N(R g )C(O)SR e , -N(R g )C(O)NR e R e , -N(R g )C(O)NR g NR e R e , -N(R g )N(R g )C(O)NR e R e , -N(R g )C(S)NR e R e , -[N(R g )C(O)] 2 R e , -N(R g )[C(O)] 2 R e , -N{[C(O)] 2 R e } 2 , -N(R g )[C(O)] 2 OR e , -N(R g )[C(O)] 2 NR e R e , - N{[C(O)] 2 OR e } 2 , -N{[C(O)] 2 NR e R e } 2 , -[N(R g )C(O)] 2 OR e , -N( R g )C(NR g )OR e , -N(R g )C(NOH)R e , -N(R g )C(NR g )ser and -N(R g )C(NR g )NR e R e ;
    [0030] each Re , independently of one another, designates hydrogen or a group optionally substituted with one or more Rf and/or Rg , identical or different, selected from C 1-6 alkyl, C 3-8 cycloalkyl, C 4 -cycloalkyl 11 -alkyl, C 6-10 aryl, C 7-16 aryl-alkyl, 2-6 membered heteroalkyl, 3-8 membered heterocycloalkyl, 4-14 membered heterocycloalkylalkyl, 5-12 membered heteroaryl, and 6-membered heteroarylalkyl. 18 members;
    [0031] Rf is each a suitable group and is independently selected from halogen and -CF 3 ; Y
    [0032] each of Rg , independently of one another, designates hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 4-11 cycloalkyl-alkyl, C 6-10 aryl, C 7-16 aryl-alkyl, heteroalkyl of 2 -6 membered, 3-8 membered heterocycloalkyl, 4-14 membered heterocycloalkyl, 5-12 membered heteroaryl, or 6-18 membered heteroarylalkyl; optionally in the form of the tautomers, racemates, enantiomers, diastereomers and mixtures thereof, or pharmacologically acceptable acid addition salts thereof.
    [0034] In another aspect, the invention relates to compounds of general formula ( 1b ),
    [0039] where
    [0041] A designates a group, optionally substituted with one or more identical or different R1 , selected from C 3-10 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-15 aryl and 5-12 membered heteroaryl;
    [0043] R1 and R2 , each independently of the other, designate hydrogen or a group selected from Ra, Rb and Ra substituted with one or more identical or different Rc and/or Rb ;
    [0045] R3 designates a group selected from hydrogen, halogen, -OR c , -OCF 3 , -SR c , -NR c R c , -CF 3 , -CN, -OCN, -SCN, -NO, -NO 2 , alkyl C 1-3 , C 1-3 haloalkyl and C 1-3 haloalkyloxy ;
    [0047] W and Y , independently of one another, represent CH 2 , O, NR e or N-OR e ;
    [0049] each Ra is selected, independently of one another, from C 1-6 alkyl, C 3-10 cycloalkyl, C 4-16 cycloalkyl-alkyl, C 6-10 aryl, C 7-16 aryl-alkyl, heteroalkyl of 2-6 membered, 3-8 membered heterocycloalkyl, 4-14 membered heterocycloalkylalkyl, 5-12 membered heteroaryl, and 6-18 membered heteroarylalkyl;
    [0051] each Rb is a suitable group and is independently selected from =O, -OR c , C 1-3 haloalkyloxy, -OCF 3 , =S, -SR c , =NR c , =NOR c , =NNR c R c , =NN(R g )C(O)NR c R c , -NR c R c , -ONR c R c , -N(OR c )R c , -N(R g )NR c R c , halogen , -CF 3 , -CN, -NC, -OCN, -SCN, -NO, -NO 2 , =N 2 , -N 3 , -S(O)R c , -S(O)OR c , -S (O) 2 R c , -S(O) 2 OR c , -S(O)NR c R c , -S(O) 2 NR c R c , -OS(O)R c , -OS(O) 2 R c , -OS(O) 2 OR c , -OS(O)NR c R c , -OS(O) 2 NR c R c , -C(O)R c , -C(O)OR c , -C(O)SR c , -C(O)NR c R c , -C(O)N(R g )NR c R c , -C(O)N(R g )OR c , -C(NR g )NR c R c , -C(NOH)R c , -C(NOH)NR c R c , -OC(O)R c , -OC(O)OR c , -OC(O)SR c , - OC(O)NR c R c , -OC(NR g )NR c R c , -SC(O)R c , -SC(O)OR c , -SC(O)NR c R c , -SC(NR g )NR c R c , -N(R g )C(O)R c , -N[C(O)R c ] 2 , -N(OR g )C(O)R c , -N(R g )C(NR g )R c , -N(R g )N(R g )C(O)R c , -N[C(O)R c ]NR c R c , -N(R g )C( S)R c , -N(R g )S(O)R c , -N(R g )S(O)OR c , -N(R g )S(O) 2 R c , -N[S( O) 2 R c ] 2 , -N(R g )S(O) 2 OR c , -N(R g )S(O) 2 NR c R c , -N(R g )[S(O) 2 ] 2 R c , -N(R g )C(O)OR c , - N(R g )C(O)SR c , -N(R g )C(O)NR c R c , -N(R g )C(O)NR g NR c R c , -N(R g ) N(R g )C(O)NR c R c , -N(R g )C(S)NR c R c , -[N(R g )C(O)] 2 R c , -N(R g )[C(O)] 2 R c , -N{[C(O)] 2 R c } 2 , -N(R g )[C(O)] 2 OR c , -N(R g )[C (O)] 2 NR c R c , -N{[C(O)] 2 OR c } 2 , -N{[C(O)] 2 NR c R c } 2 , -[N(R g )C (O)] 2 OR c , -N(R g )C(NR g )OR c , -N(R g )C(NOH)R c , -N(R g )C(NR g )SR c and - N(R g )C(NR g )NR c R c ;
    [0053] each of Rc , independently of one another, designates hydrogen or a group optionally substituted with one or more identical or different Rd and/or Re , selected from C1-6 alkyl, C3-10 cycloalkyl, C4-11 cycloalkyl -alkyl, C 6-10 aryl, C 7-16 aryl -alkyl, 2-6 membered heteroalkyl, 3-8 membered heterocycloalkyl, 4-14 membered heterocycloalkylalkyl, 5-12 membered heteroaryl, and 6-18 membered heteroarylalkyl members;
    [0055] each of Rd is a suitable group and is independently selected from =O, -OR e , C 1-3 haloalkyloxy, -OCF 3 , =S, -SR e , =NR e , =NOR e , =NNR e R e , =NN(R g )C(O)NR e R e , -NR e R e , -ONR e R e , -N(R g )NR e R e , halo CN, -NC, -OCN, - SCN, -NO, -NO 2 , =N 2 , -N 3 , -S(O)R e , -S(O)OR e , -S(O) 2 R e , -S(O) 2 OR e , -S(O)NR e R e , -S(O) 2 NR e R e , -OS(O)R e , -OS(O) 2 R e , -OS(O) 2 OR e , -OS (O)NR e R e , -OS(O) 2 NR e R e , -C(O)R e , -C(O)OR e , -C(O)SR e , -C(O)NR e R e , -C(O)N(R g )NR e R e , -C(O)N(R g )OR e , -C(NR g )NR e R e , -C(NOH)R e , -C(NOH)NR e R e , -OC(O)R e , -OC(O)OR e , -OC(O)SR e , -OC(O)NR e R e , -OC(NR g ) NR e R e , -SC(O)R e , -SC(O)OR e , -SC(O)NR e R e , -SC(NR g )NR e R e , -N(R g )C( O)R e , -N[C(O)R e ] 2 , -N(OR g )C(O)R e , -N(R g )C(NR g )R e , -N(R g ) N(R g )C(O)R e , -N[C(O)R e ]NR e R e , -N(R g )C(S)R e , -N(R g )S(O) R e , -N(R g )S(O)OR e -N(R g )S(O) 2 R e , -N[S(O) 2 R e ] 2 , -N(R g )S( O) 2 OR e , -N(R g )S(O) 2 NR e R e , -N(R g )[S(O) 2 ] 2 R e , -N(R g )C(O)OR e , -N(R g )C(O)SR e , -N(R g ) C(O)NR e R e , -N(R g )C(O)NR g NR e R e , -N(R g )N(R g )C(O)NR e R e , -N(R g )C(S)NR e R e , -[N(R g )C(O)] 2 R e , -N(R g )[C(O)] 2 R e , -N{[C(O )] 2 R e } 2 , -N(R g )[C(O)] 2 OR e , -N(R g )[C(O)] 2 NR e R e , -N{[C(O) ] 2 OR e } 2 , -N{[C(O)] 2 NR e R e } 2 , -[N(R g )C(O)] 2 OR e , -N(R g )C(NR g )OR e , -N(R g )C(NOH)R e , -N(R g )C(NR g )SR e and -N(R g )C(NR g )NR e R e ;
    [0057] each Re , independently of one another, designates hydrogen or a group optionally substituted with one or more Rf and/or Rg , identical or different, selected from C 1-6 alkyl, C 3-8 cycloalkyl, C 4 -cycloalkyl 11 -alkyl, C 6-10 aryl, C 7-16 aryl-alkyl, 2-6 membered heteroalkyl, 3-8 membered heterocycloalkyl, 4-14 membered heterocycloalkylalkyl, 5-12 membered heteroaryl, and 6-membered heteroarylalkyl. 18 members;
    [0058] R f is each a suitable group and is independently selected from halogen and -CF 3 ; Y
    [0059] each of Rg , independently of one another, designates hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 4-11 cycloalkyl-alkyl, C 6-10 aryl, C 7-16 aryl-alkyl, heteroalkyl of 2-6 membered, 3-8 membered heterocycloalkyl, 4-14 membered heterocycloalkyl, 5-12 membered heteroaryl or 6-18 membered heteroarylalkyl;
    [0060] optionally in the form of the tautomers, racemates, enantiomers, diastereomers and mixtures thereof, or pharmacologically acceptable acid addition salts thereof.
    [0062] In another aspect, the invention relates to compounds of general formula ( 1c ),
    [0066] where
    [0068] A designates a group, optionally substituted with one or more identical or different R1 , selected from C 3-10 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-15 aryl and 5-12 membered heteroaryl;
    [0070] R1 and R2 , each independently of the other, designate hydrogen or a group selected from Ra, Rb and Ra substituted with one or more identical or different Rc and/or Rb ;
    [0072] R3 designates a group selected from hydrogen, halogen, -OR c , -OCF 3 , -SR c , -NR c R c , -CF 3 , -CN, -OCN, -SCN, -NO, -NO 2 , alkyl C 1-3 , C 1-3 haloalkyl and C 1-3 haloalkyloxy ;
    [0074] W and Y , independently of one another, represent CH 2 , O, NR e or N-OR e ;
    [0076] each Ra is selected, independently of one another, from C 1-6 alkyl, C 3-10 cycloalkyl, C 4-16 cycloalkyl-alkyl, C 6-10 aryl, C 7-16 aryl-alkyl, heteroalkyl of 2-6 membered, 3-8 membered heterocycloalkyl, 4-14 membered heterocycloalkylalkyl, 5-12 membered heteroaryl, and 6-18 membered heteroarylalkyl;
    [0077] each Rb is a suitable group and is independently selected from =O, -OR c , C 1-3 haloalkyloxy, -OCF 3 , =S, -SR c , =NR c , =NOR c , =NNR c R c , =NN(R g )C(O)NR c R c , -NR c R c , -ONR c R c , -N(OR c )R c , -N(R g )NR c R c , halogen , -CF 3 , -CN, -NC, -OCN, -SCN, -NO, -NO 2 , =N 2 , -N 3 , -S(O)R c , -S(O)OR c , -S (O) 2 R c , -S(O) 2 OR c , -S(O)NR c R c , -S(O) 2 NR c R c , -OS(O)R c , -OS(O) 2 R c , -OS(O) 2 OR c , -OS(O)NR c R c , -OS(O) 2 NR c R c , -C(O)R c , -C(O)OR c , -C(O)SR c , -C(O)NR c R c , -C(O)N(R g )NR c R c , -C(O)N(R g )OR c , -C(NR g )NR c R c , -C(NOH)R c , -C(NOH)NR c R c , -OC(O)R c , -OC(O)OR c , -OC(O)SR c , - OC(O)NR c R c , -OC(NR g )NR c R c , -SC(O)R c , -SC(O)OR c , -SC(O)NR c R c , -SC(NR g )NR c R c , -N(R g )C(O)R c , -N[C(O)R c ] 2 , -N(OR g )C(O)R c , -N(R g )C(NR g )R c , -N(R g )N(R g )C(O)R c , -N[C(O)R c ]NR c R c , -N(R g )C( S)R c , -N(R g )S(O)R c , -N(R g )S(O)OR c , -N(R g )S(O) 2 R c , -N[S( O) 2 R c ] 2 , -N(R g )S(O) 2 O R c , -N(R g )S(O) 2 NR c R c , -N(R g )[S(O) 2 ] 2 R c , -N(R g )C(O)OR c , - N(R g )C(O)SR c , -N(R g )C(O)NR c R c , -N(R g )C(O)NR g NR c R c , -N(R g ) N(R g )C(O)NR c R c , -N(R g )C(S)NR c R c , -[N(R g )C(O)] 2 R c , -N(R g )[C(O)] 2 R c , -N{[C(O)] 2 R c } 2 , -N(R g )[C(O)] 2 OR c , -N(R g )[C (O)] 2 NR c R c , -N{[C(O)] 2 OR c } 2 , -N{[C(O)] 2 NR c R c } 2 , -[N(R g )C (O)] 2 OR c , -N(R g )C(NR g )OR c , -N(R g )C(NOH)R c , -N(R g )C(NR g )SR c and - N(R g )C(NR g )NR c R c ;
    [0079] each of Rc , independently of one another, denotes hydrogen or a group optionally substituted with one or more identical or different Rd and/or Re , selected from C 1-6 alkyl, C 3-10 cycloalkyl, C 4-11 cycloalkyl -alkyl, C 6-10 aryl, C 7-16 aryl -alkyl, 2-6 membered heteroalkyl, 3-8 membered heterocycloalkyl, 4-14 membered heterocycloalkylalkyl, 5-12 membered heteroaryl, and 6-18 membered heteroarylalkyl members;
    [0080] each of Rd is a suitable group and is independently selected from =O, -OR e , C 1-3 haloalkyloxy, -OCF 3 , =S, -SR e , =NR e , =NOR e , =NNR e R e , =NN(R g )C(O)NR e R e , -NR e R e , -ONR e R e , -N(R g )NR e R e , halogen, -CF 3 , -CN, - NC, -OCN, -SCN, -NO, -NO 2 , =N 2 , -N 3 , -S(O)R e , -S(O)OR e , -S(O) 2 R e , -S (O) 2 OR e , -S(O)NR e R e , -S(O) 2 NR e R e , -OS(O)R e , -OS(O) 2 R e , -OS(O) 2 OR e , -OS(O)NR e R e , -OS(O) 2 NR e R e , -C(O)R e , -C(O)OR e , -C(O)SR e , - C(O)NR e R e , -C(O)N(R g )NR e R e , -C(O)N(R g )OR e , -C(NR g )NR e R e , -C (NOH)R e , -C(NOH)NR e R e , -OC(O)R e , -OC(O)OR e , -OC(O)SR e , -OC(O)NR e R e , -OC(NR g )NR e R e , -SC(O)R e , -SC(O)OR e , -SC(O)NR e R e , -SC(NR g )NR e R e , -N (R g )C(O)R e , -N[C(O)R e ] 2 , -N(OR g )C(O)R e , -N(R g )C(NR g )R e , -N(R g )N(R g )C(O)R e , -N[C(O)R e ]NR e R e , -N(R g )C(S)R e , -N(R g )S(O)R e , -N(R g )S(O)OR e -N(R g )S(O) 2 R e , -N[S(O) 2 R e ] 2 , -N (R g )S(O) 2 OR e , -N(R g )S( O) 2 NR e R e , -N(R g )[S(O) 2 ] 2 R e , -N(R g )C(O)OR e , -N(R g )C(O)SR e , -N(R g )C(O)NR e R e , -N(R g )C(O)NR g NR e R e , -N(R g )N(R g )C(O)NR e R e , -N(R g )C(S)NR e R e , -[N(R g )C(O)] 2 R e , -N(R g )[C(O)] 2 R e , -N{[C(O)] 2 R e } 2 , -N(R g )[C(O)] 2 OR e , -N(R g )[C(O)] 2 NR e R e , - N{[C(O)] 2 OR e } 2 , -N{[C(O)] 2 NR e R e } 2 , -[N(R g )C(O)] 2 OR e , -N( R g )C(NR g )OR e , -N(R g )C(NOH)R e , -N(R g )C(NR g )SR e and -N(R g )C(NR g )NR e R e ; each of R e, independently of one another, designates hydrogen or a group optionally substituted with one or more R f and/or R g, identical or different, selected from C 1-6 alkyl, C 3-8 cycloalkyl, C cycloalkyl 4-11 -alkyl, C 6-10 -aryl, C 7-16 -aryl-alkyl, 2-6 membered heteroalkyl, 3-8 membered heterocycloalkyl, 4-14 membered heterocycloalkylalkyl, 5-12 membered heteroaryl, and 5-12 membered heteroarylalkyl. 6-18 members;
    [0081] each of R f is a suitable group and is independently selected from halogen and -CF 3 ; Y
    [0082] each of Rg , independently of one another, designates hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 4-11 cycloalkyl-alkyl, C 6-10 aryl, C 7-16 aryl-alkyl, heteroalkyl of 2-6 membered, 3-8 membered heterocycloalkyl, 4-14 membered heterocycloalkyl, 5-12 membered heteroaryl or 6-18 membered heteroarylalkyl;
    [0083] optionally in the form of the tautomers, racemates, enantiomers, diastereomers and mixtures thereof, or pharmacologically acceptable acid addition salts thereof.
    [0084] In another aspect, the invention relates to compounds of general formula ( 1a ), ( 1b ) or ( 1c ), where A is phenyl.
    [0085] In another aspect, the invention relates to compounds of general formula ( 1d ),
    [0089] where
    [0090] W and Y , each independently of the other, represent CH 2 , O, NR e or N-OR e , and
    [0091] R 1 designates hydrogen or a group selected from R a, R b and R a is substituted with one or more identical or different R c and/or R b,
    [0092] each R a is selected, independently of one another, from C 1-6 alkyl, C 3-10 cycloalkyl, C 4-16 cycloalkyl-alkyl, C 6-10 aryl, C 7-16 aryl-alkyl, heteroalkyl 2-6 membered, 3-8 membered heterocycloalkyl, 4-14 membered heterocycloalkylalkyl, 5-12 membered heteroaryl, and 6-18 membered heteroarylalkyl;
    [0093] each of R b is a suitable group and is independently selected from =O, -OR c , C 1-3 haloalkyloxy, -OCF 3 , =S, -SR c , =NR c , =NOR c , =NNR c R c , =NN(R g )C(O)NR c R c , -NR c R c , -ONR c R c , -N(OR c )R c , -N(R g )NR c R c , halogen, -CF 3 , -CN, -NC, -OCN, -SCN, -NO, -NO 2 , =N 2 , -N 3 , -S(O)R c , -S(O)OR c , - S(O) 2 R c , -S(O) 2 OR c , -S(O)NR c R c , -S(O) 2 NR c R c , -OS(O)R c , -OS(O ) 2 R c , -OS(O) 2 OR c , -OS(O)NR c R c , -OS(O) 2 NR c R c , -C(O)R c , -C(O)OR c , -C(OC(O)NR c R c , -C(O)N(R g )NR c R c , -C(O)N(R g )OR c , -C(NR g )NR c R c , -C(NOH)R c , -C(NOH)NR c R c , -OC(O)R c , -OC(O)OR c , -OC(O)SR c , -OC(O)NR c R c , -OC(NR g )NR c R c , -SC(O)R c , -SC(O)OR c , -SC(O)NR c R c , -SC(NR g )NR c R c , -N(R g )C(O)R c , -N[C(O)R c ] 2 , -N(OR g )C(O)R c , -N(R g )C(NR g )R c , -N(R g )N(R g )C(O)R c , -N[C(O)R c ]NR c R c , -N(R g )C(S)R c , -N(R g )S(O)R c , -N(R g )S(O)OR c , -N(R g )S(O) 2 R c , -N[S(O) 2 R c ] 2 , -N(R g )S(O) 2 OR c , - N(R g )S(O) 2 NR c R c , -N(R g )[S(O) 2 ] 2 R c , -N(R g )C(O)OR c , -N(R g )C(O)SR c , -N(R g )C(O)NR c R c , -N(R g )C(O)NR g NR c R c , -N(R g )N(R g )C(O)NR c R c , -N(R g )C(S)NR c R c , -[N(R g )C(O)] 2 R c , -N(R g )[C( O)] 2 R c , -N{[C(O)] 2 R c } 2 , -N(R g )[C(O)] 2 OR c , -N(R g )[C(O)] 2 NR c R c , -N{[C(O)] 2 OR c } 2 , -N{[C(O)] 2 NR c R c } 2 , -[N(R g )C(O)] 2 OR c , -N(R g )C(NR g )OR c , -N(R g )C(NOH)R c , -N(R g )C(NR g )SR c and -N(R g )C(NR g )NR c R c ,
    [0094] each of R c , independently of one another, designates hydrogen or a group optionally substituted with one or more R d and/or R e identical or different, selected from C 1-6 alkyl, C 3-10 cycloalkyl, C cycloalkyl 4-11 -alkyl, C 6-10 -aryl, C 7-16 -aryl-alkyl, 2-6 membered heteroalkyl, 3-8 membered heterocycloalkyl, 4-14 membered heterocycloalkylalkyl, 5-12 membered heteroaryl, and 5-12 membered heteroarylalkyl. 6-18 members;
    [0095] each R d is a suitable group and is independently selected from =O, -OR e , C 1-3 haloalkyloxy, -OCF 3 , =S, -SR e , =NR e , =NOR e , =NNR e R e , =NN(R g )C(O)NR e R e , -NR e R e , -ONR e R e , -N(R g )NR e R e , halo CN, -NC, -OCN, -SCN, -NO, -NO 2 , =N 2 , -N 3 , -S(O)R e , -S(O)OR e , -S(O) 2 R e , -S(O) 2 OR e , -S(O)NR e R e , -S(O) 2 NR e R e , -OS(O)R e , -OS(O) 2 R e , -OS(O) 2 OR e , - OS(O)NR e R e , -OS(O) 2 NR e R e , -C(O)R e , -C(O)OR e , -C(O)SR e , -C(O)NR e R e , -C(O)N(R g )NR e R e , -C(O)N(R g )OR e , -C(NR g )NR e R e , -C(NOH)R e , -C(NOH)NR e R e , -OC(O)R e , -OC(O)OR e , -OC(O)SR e , -OC(O)NR e R e , -OC(NR g )NR e R e , -SC(O)R e , -SC(O)OR e , -SC(O)NR e R e , -SC(NR g )NR e R e , -N(R g )C (O)R e , -N[C(O)R e ] 2 , -N(OR g )C(O)R e , -N(R g )C(NR g )R e , -N(R g )N(R g )C(O)R e , -N[C(O)R e ]NR e R e , -N(R g )C(S)R e , -N(R g )S(O )R e , -N(R g )S(O)OR e -N(R g )S(O) 2 R e , -N[S(O) 2 R e ] 2 , -N(R g )S (O) 2 OR e , -N(R g )S(O) 2 NR e R e , -N(R g )[S(O) 2 ] 2 R e , -N(R g )C(O)OR e , -N(R g )C(O)SR e , -N(R g ) C(O)NR e R e , -N(R g )C(O)NR g NR e R e , -N(R g )N(R g )C(O)NR e R e , -N(R g )C(S)NR e R e , -[N(R g )C(O)] 2 R e , -N(R g )[C(O)] 2 R e , -N{[C(O )] 2 R e } 2 , - N(R g )[C(O)] 2 OR e , -N(R g )[C(O)] 2 NR e R e , -N{[C(O) ] 2 OR e } 2 , -N{[C(O)] 2 NR e R e } 2 , -[N(R g )C(O)] 2 OR e , -N(R g )C(NR g )OR e , -N(R g )C(NOH)R e , -N(R g )C(NR g )SR e and -N(R g )C(NR g )NR e R e ,
    [0096] each of R e, independently of one another, designates hydrogen or a group optionally substituted with one or more R f and/or R g , identical or different, selected from C i -6 alkyl, C 3-8 cycloalkyl, cycloalkyl C 4- ii -alkyl, C 6-10 aryl, C 7-16 aryl -alkyl, 2-6 membered heteroalkyl, 3-8 membered heterocycloalkyl, 4-14 membered heterocycloalkylalkyl, 5-12 membered heteroaryl and heteroarylalkyl from 6-18 members; R f is each a suitable group and is independently selected from halogen and -CF 3 ; and each of R g, independently of one another, means hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, and
    [0097] R 1' and R 1”, each independently of the other, designates a group selected from hydrogen, halogen and -OR c , and R 2 designates hydrogen or a group selected from R a, R b and R a substituted with one or more R c and/or R b identical or different, and
    [0098] R 3 designates a group selected from hydrogen, halogen -OR c , -OCF 3 , -SR c , -NR c R c , -CF 3 , -CN, -OCN, -SCN, -NO, -NO 2 , alkyl C 1-3 , C 1-3 haloalkyl and C 1-3 haloalkyloxy ;
    [0099] optionally in the form of the tautomers, racemates, enantiomers, diastereomers and mixtures thereof, or pharmacologically acceptable acid addition salts thereof.
    [0100] In another aspect, the invention relates to compounds of general formula ( 1a ), ( 1b ), ( 1c ) or ( 1d ), where R 3 is Cl or CF 3 .
    [0101] In another aspect, the invention relates to a compound selected from the group consisting of,
    [0102]
    [0103]
    [0106] In another aspect, the invention relates to compounds, or their pharmaceutically effective salts, of general formula ( 1a ), ( 1b ), ( 1c ) or ( 1d ) for use as medicaments.
    [0108] In another aspect, the invention relates to compounds, or their pharmaceutically effective salts, of general formula ( 1a ), ( 1b ), ( 1c ) or ( 1d ) to prepare a drug with antiproliferative and/or pro-apoptotic activity.
    [0110] In another aspect, the invention relates to pharmaceutical preparations containing as active substance one or more compounds of general formula ( 1a ), ( 1b ), ( 1c ) or ( 1d ), or their physiologically acceptable salts, optionally in combination with excipients and/or conventional supports.
    [0112] In another aspect, the invention refers to the use of compounds of general formula ( 1a ), ( 1b ), ( 1c ) or ( 1d ) to prepare a medicament for the treatment and/or prevention of cancer, infections, inflammations or diseases. autoimmune.
    [0114] In another aspect, the invention relates to pharmaceutical preparations comprising a compound of general formula ( 1a ), ( 1b ), ( 1c ) or ( 1d ) and at least one additional active cytostatic or cytotoxic substance, different from formula ( 1a ), ( 1b ), ( 1c ) or ( 1d ), optionally in the form of the tautomers, the racemates, the enantiomers, the diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
    [0116] Definitions
    [0118] As used herein, the following definitions apply unless otherwise noted:
    [0119] Alkyl is made up of the subgroups of saturated hydrocarbon chains and unsaturated hydrocarbon chains, while the latter can be further subdivided into hydrocarbon chains with one double bond (alkenyl) and hydrocarbon chains with one triple bond (alkynyl). Alkenyl contains at least one double bond, alkynyl contains at least one triple bond. If a hydrocarbon chain carried at least one double bond and also at least one triple bond, by definition it would belong to the alkynyl subgroup. All the subgroups mentioned above can be further divided into straight chain (unbranched) and branched. If an alkyl is substituted, the substitution may be a mono- or poly-substitution in each occurrence, on all hydrogen-bearing carbon atoms, independently of one another. Examples of individual subgroup representatives are listed below.
    [0121] Straight chain (unbranched) or branched saturated hydrocarbon chains:
    [0123] Methyl; ethyl; n-propyl; isopropyl (1-methylethyl); n-butyl; 1-methylpropyl; isobutyl (2-methylpropyl); sec.-butyl (1-methylpropyl); tert.-butyl (1,1-dimethylethyl); n-pentyl; 1-methylbutyl; 1-ethylpropyl; isopentyl (3-methylbutyl); neopentyl (2,2-dimethyl-propyl); n-hexyl; 2,3-dimethylbutyl; 2,2-dimethylbutyl; 3,3-dimethylbutyl; 2-methyl-pentyl; 3-methylpentyl; nheptyl; 2-methylhexyl; 3-methylhexyl; 2,2-dimethylpentyl; 2,3-dimethylpentyl; 2,4-dimethylpentyl; 3,3-dimethylpentyl; 2,2,3-trimethylbutyl; 3-ethylpentyl; n-octyl; n-nonyl; n-decyl, etc.
    [0125] Straight chain (unbranched) or branched alkenyl:
    [0127] Vinyl (ethenyl); prop-1-enyl; allyl (prop-2-enyl); isopropenyl; but-1-enyl; but-2-enyl; but-3-enyl; 2-methyl-prop-2-enyl; 2-methyl-prop-1-enyl; 1-methyl-prop-2-enyl; 1-methyl-prop-1-enyl; 1-methylidenepropyl; pent-1-enyl; pent-2-enyl; pent-3-enyl; pent-4-enyl; 3-methyl-but-3-enyl; 3-methyl-but-2-enyl; 3-methyl-but-1-enyl; hex-1-enyl; hex-2-enyl; hex-3-enyl; hex-4-enyl; hex-5-enyl; 2,3-dimethyl-but-3-enyl; 2,3-dimethyl-but-2-enyl; 2-methylidene-3-methylbutyl; 2,3-dimethylbut-1-enyl; hexa-1,3-dienyl; hexa-1,4-dienyl; penta-1,4-dienyl; penta-1,3-dienyl; buta-1,3-dienyl; 2,3-dimethylbuta-1,3-diene, etc.
    [0128] Straight chain (unbranched) or branched alkynyl:
    [0130] Ethynyl; prop-1-ynyl; prop-2-ynyl; but-1-ynyl; but-2-ynyl; but-3-ynyl; 1-methyl-prop-2-ynyl, etc.
    [0132] By the terms propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., without further definition, is meant saturated hydrocarbon groups with the corresponding number of carbon atoms, all isomeric forms being included. .
    [0134] By the terms propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, etc. without further definition is meant unsaturated hydrocarbon groups with the corresponding number of carbon atoms and one double bond, all isomeric forms, ie ( Z)/ ( E) Isomers, included where appropriate.
    [0136] By the terms butadienyl, pentadienyl, hexadienyl, heptadienyl, octadienyl, nonadienyl, decadienyl, etc. without further definition is meant unsaturated hydrocarbon groups with the corresponding number of carbon atoms and two double bonds, including all isomeric forms, ie ( Z)/ ( E) isomers, where appropriate.
    [0138] By the terms propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonyl, decynyl, etc. without further definition is meant unsaturated hydrocarbon groups with the corresponding number of carbon atoms and a triple bond, all isomeric forms being included.
    [0140] By the term heteroalkyl is meant groups which can be derived from alkyl as defined above in its broadest sense if, in the hydrocarbon chains, one or more of the -CH 3 groups are replaced independently of one another by the - groups. OH, -SH or -NH 2 , one or more of the -CH 2 - groups are replaced independently of each other by -O-, -S- or -NH- groups, one or more of the groups
    [0145] are replaced by the group
    [0149] one or more of the =CH- groups are replaced by the =N- group, one or more of the =CH 2 groups are replaced by the =NH group, or one or more of the CH groups are replaced by the EN group, although in general there can be a maximum of three heteroatoms in a heteroalkyl, there must be at least one carbon atom between two oxygen atoms and between two sulfur atoms or between an oxygen atom and a sulfur atom and the group as a whole It must be chemically stable.
    [0151] It is immediately apparent from the indirect definition/derivation of alkyl that heteroalkyl is made up of the subgroups heteroatom(s)-saturated hydrocarbon chains, heteroalkenyl and heteroalkynyl, and further subdivision can be carried out into a straight (unbranched) chain and branched. If a heteroalkyl is substituted, the substitution may be a mono- or poly-substitution in each occurrence, on all hydrogen-bearing oxygen, sulfur, nitrogen and/or carbon atoms, independently of one another. The heteroalkyl itself can be attached to the molecule as a substituent either through a carbon atom or through a heteroatom.
    [0153] Typical examples are listed below:
    [0155] Dimethylaminomethyl; dimethylaminoethyl (1-dimethylaminoethyl; 2-dimethylaminoethyl); dimethylaminopropyl (1-dimethylaminopropyl, 2-dimethylaminopropyl, 3-dimethylaminopropyl); diethylaminomethyl; diethylaminoethyl (1-diethylaminoethyl, 2-diethylaminoethyl); diethylaminopropyl (1-diethylaminopropyl, 2-diethylamino-propyl, 3-diethylaminopropyl); diisopropylaminoethyl (1-diisopropylaminoethyl, 2-diisopropylaminoethyl); bis-2-methoxyethylamino; [2-(dimethylamino-ethyl)-ethyl-amino]-methyl; 3-[2-(dimethylamino-ethyl)-ethyl-amino]-propyl; hydroxymethyl; 2-hydroxyethyl; 3-hydroxypropyl; methoxy; ethoxy; propoxy; methoxymethyl; 2-methoxyethyl etc.
    [0157] Halogen denotes fluorine, chlorine, bromine and/or iodine atoms.
    [0159] Haloalkyl is derived from alkyl as defined above in its broadest sense, when one or more hydrogen atoms of the hydrocarbon chain are replaced independently of one another by halogen atoms, which may be identical or different. It is immediately evident from the indirect definition/derivation of alkyl that haloalkyl is made up of the saturated hydrocarbon chain subgroups, haloalkenyl and haloalkynyl, and further subdivision can be straight chain (unbranched) and branched. If a haloalkyl is substituted, the substitution may be mono- or poly-substitution in each occurrence, on all hydrogen-bearing carbon atoms, independently of one another.
    [0161] Typical examples include -CF 3 ; -CHF 2 ; -CH 2 F; -CF 2 CF 3 ; -CHFCF 3 ; -CH 2 CF 3 ; -CF 2 CH 3 ; -CHFCH 3 ; -CF 2 CF 2 CF 3 ; -CF 2 CH 2 CH 3 ; -CF=CF 2 ; -CCl=CH 2 ; -CBr=CH 2 ; -CUCH 2 ; -CEC-CF 3 -CHFCH 2 CH 3 ; and -CHFCH 2 CF 3 .
    [0163] Cycloalkyl is made up of the subgroups of monocyclic hydrocarbon rings, bicyclic hydrocarbon rings, and spirohydrocarbon rings, while each of the subgroups can be further subdivided into saturated and unsaturated (cycloalkenyl). The term unsaturated means that at least one double bond exists in the ring system in question, but no aromatic system is formed. In bicyclic hydrocarbon rings, two rings are joined such that they have at least two carbon atoms in common. In spirohydrocarbon rings, one carbon atom (spiroatom) is shared by two rings. If a cycloalkyl is substituted, the substitution may be mono- or poly-substitution in each occurrence, on all hydrogen-bearing carbon atoms, independently of one another. Cycloalkyl itself may be attached to the molecule as a substituent through any suitable position on the ring system.
    [0164] Typical examples of individual subgroups are listed below.
    [0166] Monocyclic saturated hydrocarbon rings:
    [0168] Cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; cycloheptyl, etc.
    [0170] Unsaturated Monocyclic Hydrocarbon Rings:
    [0172] Cycloprop-1-enyl; cycloprop-2-enyl; cyclobut-1-enyl; cyclobut-2-enyl; cyclopent-1-enyl; cyclopent-2-enyl; cyclopent-3-enyl; cyclohex-1-enyl; cyclohex-2-enyl; cyclohex-3-enyl; cyclohept-1-enyl; cyclohept-2-enyl; cyclohept-3-enyl; cyclohept-4-enyl; cyclobuta-1,3-dienyl; cyclopenta-1,4-dienyl; cyclopenta-1,3-dienyl; cyclopenta-2,4-dienyl; cyclohexa-1,3-dienyl; cyclohexa-1,5-dienyl; cyclohexa-2,4-dienyl; cyclohexa-1,4-dienyl; cyclohexa-2,5-dienyl, etc.
    [0174] Saturated and unsaturated bicyclic hydrocarbon rings:
    [0176] Bicyclo[2.2.0]hexyl; bicyclo[3.2.0]heptyl; bicyclo[3.2.1]octyl; bicyclo[2.2.2]octyl; bicyclo[4.3.0]nonyl(octahydroindenyl); bicyclo[4.4.0]decyl(decahydronaphthalene); bicyclo[2.2.1]heptyl (norbornyl); (bicyclo[2.2.1]hepta-2,5-dienyl (norborna-2,5-dienyl); bicyclo[2.2.1]hept-2-enyl (norbornenyl); bicyclo[4.1.0]heptyl (norcaranyl ); bicyclo[3.1.1]heptyl (pinanil) etc.
    [0178] Saturated and unsaturated spirohydrocarbon rings:
    [0180] Spiro[2.5]octyl, spiro[3.3]heptyl, spiro[4.5]dec-2-ene, etc.
    [0182] Cycloalkylalkyl designates the combination of the alkyl and cycloalkyl groups defined above, in each case in its broadest sense. The alkyl group as a substituent is directly attached to the molecule and, in turn, is substituted with a cycloalkyl group. Alkyl and cycloalkyl may be attached to both groups through any suitable carbon atom for this purpose. The respective alkyl and cycloalkyl subgroups are also included in the combination of the two groups.
    [0184] Aryl designates mono-, bi- or tri-cyclic carbon rings with at least one aromatic ring. If an aryl is substituted, the substitution may be mono- or poly-substitution in each case, on all hydrogen-bearing carbon atoms, independently of one another. The aryl itself may be attached to the molecule as a substituent through any suitable position on the ring system.
    [0185] Typical examples include phenyl, naphthyl, indanyl (2,3-dihydroindanyl), 1,2,3,4-tetrahydronaphthyl, and fluorenyl.
    [0187] Carbocyclic ring systems include, for example, indanyl, 1,2,3,4-tetrahydronaphthyl, and 6,7,8,9-tetrahydrobenzocycloheptyl.
    [0189] "Arylalkyl" designates the combination of alkyl and aryl groups as defined above, in each case in its broadest sense. The alkyl group as a substituent is directly attached to the molecule and, in turn, is substituted with an aryl group. Alkyl and aryl may be attached in both groups through any suitable carbon atom for this purpose. The respective alkyl and aryl subgroups are also included in the combination of the two groups.
    [0191] Typical examples include benzyl; 1-phenylethyl; 2-phenylethyl; phenylvinyl; phenylallyl, etc.
    [0193] Heteroaryl designates monocyclic aromatic rings or polycyclic rings with at least one aromatic ring which, compared to the corresponding aryl or cycloalkyl, contains one or more carbon atoms instead of one or more more identical or different heteroatoms, selected independently of each other from nitrogen, sulfur and oxygen, while the resulting group must be chemically stable. If a heteroaryl is substituted, the substitution may be a mono- or poly-substitution in each occurrence, on all hydrogen-bearing carbon and/or nitrogen atoms, independently of one another. The heteroaryl itself as a substituent can be attached to the molecule through any suitable position on the ring system, both carbon and nitrogen.
    [0195] Typical examples are listed below.
    [0197] Monocyclic heteroaryls:
    [0199] Furyl; thienyl; pyrrolyl; oxazolyl; thiazolyl; isoxazolyl; isothiazolyl; pyrazolyl; imidazolyl; triazolyl; tetrazolyl; oxadiazolyl; thiadiazolyl; pyridyl; pyrimidyl; pyridazinil; pyrazinil; triazinyl; pyridyl-W-oxide; pyrrolyl-W-oxide; pyrimidinyl-W-oxide; pyridazinyl-W-oxide; pyrazinyl-W-oxide; imidazolyl-W-oxide; isoxazolyl-W-oxide; oxazolyl-W-oxide; thiazolyl-W-oxide; oxadiazolyl-W-oxide; thiadiazolyl-W-oxide; triazolyl-W-oxide; tetrazolyl-W-oxide, etc.
    [0201] Polycyclic heteroaryls:
    [0203] indolyl; isoindolyl; benzofuryl; benzothienyl; benzoxazolyl; benzothiazolyl; benzisoxazolyl; benzisothiazolyl; benzimidazolyl; indazolyl; isoquinolinyl; quinolinyl; quinoxalinil; cinolinil; phthalazinyl; quinazolinyl; benzotriazinyl; indolizinil; oxazolopyridyl; imidazopyridyl; naphthyridinyl; indolinyl; isochromanil; chromanyl; tetrahydroisoquinolinyl; isoindolinyl; isobenzotetrahydrofuryl; isobenzotetrahydrothienyl; isobenzothienyl; benzoxazolyl; pyridopyridyl; benzotetrahydrofuryl; benzotetrahydrothienyl; purinyl; benzodioxolyl; phenoxazinil; phenothiazinil; pteridinyl; benzothiazolyl; imidazopyridyl; imidazothiazolyl; dihydrobenzisoxazinyl; benzisoxazinil; benzoxazinil; dihydrobenzisothiazinyl; benzopyranil; benzothiopyranil; coumarinil; isocoumarinil; chromonil; chromanonil; tetrahydroquinolinyl; dihydroquinolinyl; dihydroquinolinonyl; dihydroisoquinolinonyl; dihydrocoumarinyl; dihydroisocoumarinyl; isoindolinonyl; benzodioxanil; benzoxazolinonil; quinolinyl-W-oxide; indolyl-W-oxide; indolinyl-W-oxide; isoquinolyl-W-oxide; quinazolinyl-W-oxide; quinoxalinyl-W-oxide; phthalazinyl-W-oxide; indolizinyl-W-oxide; indazolyl-W-oxide; benzothiazolyl-W-oxide; benzimidazolyl-W-oxide; benzo-thiopyranyl-S-oxide and benzothiopyranyl-S,S-dioxide, etc.
    [0204] Heterobicyclic ring systems include, for example, dihydrobenzofuryl, dihydroisobenzofuryl, dihydroindolyl, dihydroisoindolyl, dihydrobenzothiophenyl, dihydroisobenzothiophenyl, dihydroindazolyl, 1,2-benzisoxazolyl, 1H-1,2-benzisoxazolyl, 1,2-benzothiazolyl, 2,3-tetrahydro-1 H-isoquinolinyl, 3,4-tetrahydro-2H-isoquinolinyl, tetrahydroquinolinyl, chromanyl, isochromanyl, isochromenyl, thiochromanil, thiochromenil, dihydro-2H-phthalazinyl, tetrahydrocinolinyl, tetrahydroquinazolinyl, tetrahydrobenzodiazepinyl, and tetrahydrobenzoxazepinyl.
    [0206] Heteroarylalkyl designates the combination of the alkyl and heteroaryl groups defined above, in each case in its broadest sense. The alkyl group as a substituent is directly attached to the molecule and, in turn, is substituted with a heteroaryl group. The attachment of alkyl and heteroaryl can be achieved on the alkyl side through any carbon atom suitable for this purpose and on the heteroaryl side via any carbon or nitrogen atom suitable for this purpose. The respective alkyl and heteroaryl subgroups are also included in the combination of the two groups.
    [0208] By the term heterocycloalkyl is meant groups deriving from cycloalkyl as defined above if in the hydrocarbon rings one or more of the -CH 2 - groups are replaced independently of one another by -O- groups, -S- or -NH-, or one or more of the =CH- groups are replaced by the =N- group, while no more than five total heteroatoms may be present, there must be at least one carbon atom between two oxygen atoms and between two sulfur atoms or between an oxygen and a sulfur atom and the group as a whole must be chemically stable. Heteroatoms can be present simultaneously in all possible oxidation stages (sulfur ^ sulfoxide -SO-, sulfone -SO 2 -; nitrogen ^ N-oxide). From the indirect definition/derivation of cycloalkyl it is immediately apparent that heterocycloalkyl is composed of the subgroups of monocyclic hetero-rings, bicyclic hetero-rings, and spirohetero-rings, while each of the subgroups can also be subdivided into saturated and unsaturated. (heterocycloalkenyl). The term unsaturated means that at least one double bond exists in the ring system in question, but no aromatic system is formed. In bicyclic hetero-rings, two rings are joined in such a way that they have at least two atoms in common. In spirohetero-rings one carbon atom (spiroatom) is shared by two rings. If a heterocycloalkyl is substituted, the substitution may be a mono- or poly-substitution in each occurrence, on all hydrogen-bearing carbon and/or nitrogen atoms, independently of one another. Heterocycloalkyl itself as a substituent may be attached to the molecule through any suitable position of the ring system.
    [0209] Typical examples of individual subgroups are listed below.
    [0211] Monocyclic hetero rings (saturated and unsaturated):
    [0213] Tetrahydrofuryl; pyrrolidinyl; pyrrolinyl; imidazolidinyl; thiazolidinyl; imidazolinyl; pyrazolidinyl; pyrazolinyl; piperidinyl; piperazinil; oxiranil; aziridinyl; azetidinyl; 1,4-dioxanil; azepanil; diazepanil; morpholinyl; thiomorpholinil; homomorpholinyl; homopiperidinyl; homopiperazinyl; homothiomorpholinyl; thiomorpholinyl-S-oxide; thiomorpholinyl-S,Sdioxide; 1,3-dioxolanil; tetrahydropyranyl; tetrahydrothiopyranyl; [1,4]-oxazepanil; tetrahydrothienyl; homothiomorpholinyl-S,S-dioxide; oxazolidinonyl; dihydropyrazolyl; dihydropyrrolyl; dihydropyrazinyl; dihydropyridyl; dihydropyrimidinyl; dihydrofuryl; dihydropyranyl; tetrahydrothienyl-S-oxide; tetrahydrothienyl-S,S-dioxide; homothiomorpholinyl-S-oxide; 2,3-dihydroazet; 2H-pyrrolyl; 4H-pyranyl; 1,4-dihydropyridinyl, etc.
    [0215] Bicyclic hetero rings (saturated and unsaturated):
    [0217] 8-azabicyclo[3.2.1]octyl; 8-azabicyclo[5.1.0]octyl; 2-oxa-5-azabicyclo[2.2.1]heptyl; 8-oxa-3-aza-bicyclo[3.2.1]octyl; 3,8-diaza-bicyclo[3.2.1]octyl; 2,5-diaza-bicyclo-[2.2.1]heptyl; 1-aza-bicyclo[2.2.2]octyl; 3,8-diaza-bicyclo[3.2.1]octyl; 3,9-diaza-bicyclo[4.2.1]nonyl; 2,6-diaza-bicyclo[3.2.2]nonyl; hexahydro-furo[3,2-b]furyl; etc.
    [0219] Spiro-heterorings (saturated and unsaturated):
    [0221] 1,4-dioxa-spiro[4.5]decyl; 1-oxa-3,8-diaza-spiro[4.5]decyl; and 2,6-diaza-spiro[3.3]heptyl; 2,7-diazaspiro[4.4]nonyl; 2,6-diaza-spiro[3.4]octyl; 3,9-diaza-spiro[5.5]undecyl; 2,8-diaza-spiro[4.5]decyl, etc.
    [0223] Heterocycloalkylalkyl designates the combination of the alkyl and heterocycloalkyl groups defined above, in each case in its broadest sense. The alkyl group as a substituent is directly attached to the molecule and, in turn, is substituted with a heterocycloalkyl group. The bonding of the alkyl and heterocycloalkyl can be achieved on the alkyl side via any carbon atom suitable for this purpose and on the heterocycloalkyl side via any carbon or nitrogen atom suitable for this purpose. The respective alkyl and heterocycloalkyl subgroups are also included in the combination of the two groups.
    [0225] By the term "suitable substituent" is meant a substituent which, on the one hand, fits due to its valence and, on the other hand, leads to a chemically stable system.
    [0227] By "prodrug" is meant an active substance in the form of its precursor metabolite. (Prodrugs are not part of the invention). A distinction can be made between multipart carrier prodrug systems and biotransformation systems. The latter contain the active substance in a form that requires chemical or biological metabolism. The skilled person will be familiar with prodrug systems of this type (Sloan, Kenneth B.; Wasdo, Scott C. The role of prodrugs in penetration enhancement.Percutaneous Penetration Enhancers (2nd Edition) (2006).51-64; Lloyd, Andrew W. Prodrugs.Smith and Williams' Introduction to the Principles of Drug Design and Action (4th Edition) (2006), 211-232;Neervannan, Seshadri. Strategies to impact solubility and dissolution rate during drug lead optimization: salt selection and prodrug design approaches.American Pharmaceutical Review (2004), 7(5), 108,110-113). A suitable prodrug contains, for example, a substance of the general formula that is linked via an enzymatically cleavable linker (eg, carbamate, phosphate, N-glycoside, or a disulfide group) to a dissolution-enhancing substance (eg. , tetraethylene glycol, saccharides, amino acids). Carrier-prodrug systems contain the active substance as such bound to a masking group that can be cleaved by the simplest possible controllable mechanism. The role of masking groups according to the invention in compounds according to the invention is to neutralize charge in order to improve cellular uptake If the compounds according to the invention are used with a masking group, these may also additionally influence other pharmacological parameters such as, for example, bioavailability oral administration, tissue distribution, pharmacokinetics, and stability against non-specific phosphatases. the active substance may also involve a sustained release effect. In addition, modified metabolism may occur, thus resulting in increased efficacy of the active substance or organ specificity. In the case of a prodrug formulation, the masking group or a linker that attaches the masking group to the active substance is selected such that the prodrug is sufficiently hydrophilic to dissolve in blood serum, has sufficient chemical and enzymatic stability to reach the site of activity and is also sufficiently hydrophilic to ensure that it is suitable for diffusion-controlled membrane transport. Furthermore, it must allow the chemically or enzymatically induced release of the active substance within a reasonable period and, needless to say, the released ancillary components must not be toxic. However, within the scope of the invention, the compound without a mask or linker, and a mask, can be considered as a prodrug that first has to be prepared in the cell from the ingested compound by enzymatic and biochemical processes.
    [0229] list of abbreviations
    [0231] abs. absolute, anhydrous
    [0232] ac acetyl
    [0233] bn benzyl
    [0234] Boc ferc.-butyloxycarbonyl
    [0235] bu butyl
    [0236] C concentration
    [0237] cHex cyclohexane
    [0238] d day(s)
    [0239] TLC thin layer chromatography
    [0240] DCM dichloromethane
    [0241] DEA diethylamine
    [0242] DIPEA N-ethyl-N,N-diisopropylamine (Hünig's base)
    [0243] DMF N,N-dimethylformamide
    [0244] DMSO dimethyl sulfoxide
    [0245] ESI Electron Spray Ionization
    [0246] Ethyl et
    [0247] EtOH ethanol
    [0248] h hour(s)
    [0249] HATU 0-(7-azabenzotriazol-1-yl)-N, N,N', /V'-tetramethyl-uronium tetrafluorophosphate
    [0250] hex hexyl
    [0251] HPLC high performance liquid chromatography
    [0252] i iso
    [0253] IR infrared spectroscopy
    [0254] conc. concentrated
    [0255] LC liquid chromatography
    [0256] I methylate
    [0257] MeOH methanol
    [0258] min minute(s)
    [0259] MPLC medium pressure liquid chromatography
    [0260] MS mass spectrometry
    [0261] NMP N -methylpyrrolidone
    [0262] NP normal phase
    [0263] Pd 2 dba 3 tris(dibenzylideneacetone)dipalladium(0)
    [0264] Ph phenyl
    [0265] pr propyl
    [0266] py pyridine
    [0267] racemic rac
    [0268] Rf (Rf) retention factor
    [0269] inverted phase RP
    [0270] RT Ambient temperature
    [0271] TBTU 0-(benzotriazol-1-yl)-N,N, N', /V'-tetramethyl-uronium tetrafluoroborate
    [0272] Temp. temperature
    [0273] tere. tertiary
    [0274] TFA trifluoroacetic acid
    [0275] THF tetrahydrofuran
    [0276] t Ret . retention time (HPLC)
    [0277] UV ultraviolet
    [0278] X-Phos 2-dicyclohexylphosphonium-2',4',6'-triisopropyl-1,1'-biphenyl
    [0280] Characteristics and advantages of the present invention will be evident from the following detailed Examples that illustrate the fundamentals of the invention by way of example, without restricting its scope (only examples covered by the scope of the claims form part of the invention):
    [0282] Preparation of the compounds according to the invention
    [0284] general
    [0286] All reactions are carried out - unless otherwise indicated - in commercially available apparatus, using methods conventionally used in chemical laboratories.
    [0287] Air- and/or moisture-sensitive starting materials are stored under protective gas and the corresponding reactions and handling are carried out under protective gas (nitrogen or argon).
    [0289] Microwave reactions are carried out in an Initiator made by Biotage or an Explorer made by CEM in sealed vessels (preferably 2, 5 or 20 mL), preferably with stirring.
    [0291] Chromatography
    [0293] For preparative medium pressure chromatography (MPLC, normal phase) silica gel manufactured by Millipore (named: Granula Silica Si-60A 35-70 qm) or C-18 RP-silica gel (RP phase) manufactured by Macherey Nagel is used. (named: Polygoprep 100-50 C18).
    [0294] Thin-layer chromatography is carried out on prepared silica gel 60 TLC plates on glass (with F-254 fluorescence indicator) manufactured by Merck.
    [0295] Preparative high pressure chromatography (HPLC) is carried out using columns manufactured by Waters (designated: XTerra Prep. MS C18, 5 qM, 30 x 100 mm or XTerra Prep. MS C18, 5 qm, 50 x 100 mm OBD or Symmetrie C18, 5 |jm, 19 x 100 mm or Sunfire C18 OBD, 19 x 100 mm, 5 |jm or Sunfire Prep C 10 jm OBD 50 x 150 mm or X-Bridge Prep C18 5 jm OBD 19 x 50 mm), Agilent (designated: Zorbax SB-C8 5 jm PrepHT 21.2 x 50 mm) and Phenomenex (designated: Gemini C18 5 jm AXIA 21.2 x 50 mm or Gemini C18 10 jm 50 x 150 mm), analytical HPLC (reaction control) is carried out with columns manufactured by Agilent (designated: Zorbax SB-C8, 5 jm , 21.2 x 50 mm or Zorbax SB-C83.5 jm 2.1 x 50 mm) and Phenomenex (designated: Gemini C183 jm 2 x 30 mm) .
    [0297] HPLC mass spectroscopy/UV spectrometry
    [0299] Retention times/MS-ESI+ to characterize the examples are obtained using an HPLC-MS (high performance liquid chromatography with mass detector) apparatus manufactured by Agilent. Compounds eluting with the injection peak are given the retention time tRet. = 0.00.
    [0301] Method A:
    [0302] Column: Waters, Xterra MS C18, 2.5 jm, 2.1 x 30 mm, Part. N2186000592 Eluant: A: H 2 O with 0.1% HCOOH; B: acetonitrile (HPLC grade)
    [0303] Detection: MS: positive and negative mode
    [0304] Mass range: 120 - 900 m/z
    [0305] Shatterer: 120
    [0306] EMV Gain: 1; Threshold: 150; Step Size: 0.25; UV: 254nm; Bandwidth: 1 Injection: Inj. Vol. of 5 jL
    [0307] Separation: Flow rate 1.10 mL/min
    [0308] Temp. of column 40°C
    [0309] Gradient: 0.00 min: 5% solvent B
    [0310] 0.00 - 2.50 min: 5% ^ 95% solvent B
    [0311] 2.50 - 2.80 min: 95% solvent B
    [0312] 2.81 - 3.10 min: 95%^5% Solvent B
    [0314] Method B:
    [0316] Column: Waters, Xterra MS C18, 2.5 jm, 2.1 x 50 mm, Part. N2186000594 Eluant: A: H 2 O with 0.1% HCOOH; B: Acetonitrile with 0.1% HCOOH Detection: MS: positive and negative mode
    [0317] Mass range: 100 - 1200 m/z
    [0318] Shatterer: 70
    [0319] EMV Gain: Threshold: 1 mAU; Step size: 2nm; UV: 254nm as well as 230nm Injection: Standard 1 jL
    [0320] Flow rate 0.6mL/min
    [0321] Temp. of column 35°C
    [0322] Gradient: 0.00 min: 5% solvent B
    [0323] 0.00 - 2.50 min: 5% ^ 95% solvent B
    [0324] 2.50 - 4.00 min: 95% solvent B
    [0325] 4.00 - 4.50 min: 95% ^ 5% Solvent B
    [0326] 4.50 - 6.00 min: 95% solvent A
    [0328] Method C:
    [0330] Column: Waters, X-Bridge C18, 3.5 jm, 2.1 x 50 mm,
    [0331] Eluent: A: H 2 O with 10 mM NH 3 ; B: acetonitrile with 10 mM NH 3
    [0332] Detection: MS: positive and negative mode
    [0333] Mass range: 100 - 800 m/z
    [0334] Shatterer: 70
    [0335] EMV Gain: Threshold: 1 mAU; Step size: 2nm; UV: 220-320nm
    [0336] Injection: Standard 1 jL
    [0337] Flow rate 0.8mL/min
    [0338] Temp. of column 25°C
    [0339] Gradient: 0.00 min: 2% solvent B
    [0340] 0.00 - 4.00 min: 2% ^ 98% Solvent B
    [0341] 4.00 - 6.00 min: 98% solvent B
    [0343] Method D:
    [0345] Column: Waters, X-Bridge C18, 3.5 jm, 2.1 x 50 mm,
    [0346] Eluent: A: H 2 O with 0.1% HCOOH; B: Acetonitrile with 0.1% HCOOH Detection: MS: positive and negative mode
    [0347] Mass range: 100 - 800 m/z
    [0348] Shatterer: 70
    [0349] EMV Gain: Threshold: 1 mAU; Step size: 2nm; UV: 220-320nm
    [0350] Injection: Standard 1 gL
    [0351] Flow rate 0.8mL/min
    [0352] Temp. of column 35°C
    [0353] Gradient: 0.00 min: 2% solvent B
    [0354] 0.00 - 4.00 min: 2% ^ 98% Solvent B
    [0355] 4.00 - 6.00 min: 98% solvent B
    [0357] Method E:
    [0359] Column: Phenomenex Gemini C18, 3.0 gm, 2.0 x 50 mm,
    [0360] Eluent: A: H 2 O with 10 mM NH 3 ; B: acetonitrile with 10 nM NH 3
    [0361] Detection: MS: positive and negative mode
    [0362] Mass range: 100 - 800 m/z
    [0363] Shatterer: 70
    [0364] EMV Gain: Threshold: 1 mAU; Step size: 2nm; UV: 220-320nm
    [0365] Injection: Standard 1 gL
    [0366] Flow rate 1.0mL/min
    [0367] Temp. of column 35°C
    [0368] Gradient: 0.00 min: 2% solvent B
    [0369] 0.00 - 3.50 min: 2% ^ 98% Solvent B
    [0370] 3.50 - 6.00 min: 98% solvent B
    [0372] Method F:
    [0374] Column: Phenomenex Gemini C18, 3.0 gm, 2.0 x 50 mm,
    [0375] Eluent: A: H 2 O with 0.1% HCOOH; B: acetonitrile with 0.1% HCOOH
    [0376] Detection: MS: positive and negative mode
    [0377] Mass range: 100 - 800 m/z
    [0378] Shatterer: 70
    [0379] EMV Gain: Threshold: 1 mAU; Step size: 2nm; UV: 220-320nm
    [0380] Injection: Standard 1 gL
    [0381] Flow rate 1.0mL/min
    [0382] Temp. of column 35°C
    [0383] Gradient: 0.00 min: 2% solvent B
    [0384] 0.00 - 3.50 min: 2% ^ 98% Solvent B
    [0385] 3.50 - 6.00 min: 95% solvent B
    [0387] The compounds according to the invention are prepared by the synthetic methods described below, in which the substituents of the general formulas have the meanings specified hereinabove. These methods are intended to illustrate the invention without restricting its content or limiting the scope of the compounds claimed in these Examples. When the preparation of the starting compounds is not described, they may be obtained commercially or may be prepared analogously to known compounds or methods described herein. Substances described in the literature are prepared according to published methods of synthesis.
    [0389] Reaction Scheme A
    [0391]
    [0393] Example compounds of type (1) are prepared from 2,4-dichloro-pyrimidines A-1 by nucleophilic aromatic substitution of chlorine at position 4 of the pyrimidine with a phenol OR 2 , a thiophenol SR 2 or by coupling of benzylmetal halides HalMetR 2 and later exchange of the second chlorine by means of an amine A-NH 2 . Alternatively, from 2,4-dichloropyrimidines A-1 , it is possible to carry out the exchange in position 2 of the pyrimidine with amines A-NH 2 and subsequent substitution of the chlorine in position 4 of the pyrimidine with a phenol OR 2 , a thiophenol SR 2 or by coupling benzylmeta1HalMetR 2 halides. As an alternative to conventional nucleophilic substitutions, the transition metal-catalyzed reaction of A-NH 2 with corresponding 2-chloropyrimidines A-2. R 1 and R 2 are each suitable groups to arrive at example compounds.
    [0394] Nucleophilic aromatic substitutions at A-1, A-2 and A-3 are carried out using methods known from the literature (eg WO2008/040951) in common solvents such as, for example, THF, DCM, NMP, DMSO, toluene or DMF using a base such as, for example, DIPEA, pyridine, LiOH, Cs 2 CO 3 or KOfBu, an acid such as, for example, HCl, or a Lewis acid such as, for example, ZnCl 2 . The alcohols OR 2 , the sulfides SR 2 , the organometallic compounds HalMetR 2 and the amines A-NH 2 used are commercially available or are synthesized by methods known in the literature. The 2-amino-4-oxopyrimidines, 2-amino-4-thiopyrimidines or 2-amino-4-carbapyrimidines of type (1), which can be directly obtained by these reaction methods, can be further modified at R1 and R2 at a point suitable in the manner known from the literature or analogously to the literature to form further derivatives of type (1). Thus, for example, the R1 and R2 groups of directly accessible 2-amino-4-oxo-pyrimidines, 2-amino-4-thiopyrimidines or 2-amino-4-carbapyrimidines of type (1), consisting of a carboxylic acid, sulfonic acid, halogen- or amino-substituted aryl or heteroaryl can be converted by substitution (on the heteroaryl itself), alkylation, acylation, animation or addition reactions.
    [0396] starting materials
    [0398] When their preparation is not described, the starting materials are commercially available, known from the literature or easily obtainable by those skilled in the art, using general methods, for example 4-amino-2-chloro-5-methoxybenzoic acid, 4-amino-2-fluoro-5-methoxy-benzoic acid (WO2008/040951),
    [0399] 4-(4-chloro-5-trifluoromethyl-pyrimidin-2-ylamino)-benzoic acid (WO 2007003596)
    [0400] 4-(4-chloro-5-trifluoromethyl-pyrimidin-2-ylamino)-3-methoxy-benzoic acid,
    [0401] 4-(4-chloro-5-trifluoromethyl-pyrimidin-2-ylamino)-2-chloro-5-methoxy-benzoic acid,
    [0402] 4-(4-chloro-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methoxy-benzoic acid, (analogous to WO 2007003596)
    [0403] 7- amino-2-methyl-2,3-dihydro-isoindol-1-one (WO2005/016894)
    [0404] 4-benzylamino-3-fluoro-piperidine-1-carboxylate tert.-butyl, (J. Med. Chem. (1999), 42 (12), 2087-2104) 8-amino-2-methyl-3,4 -dihydro-isoquinolin-1-one (WO2005/016894)
    [0405] Benzyl (3S,4S)-4-ferc.-butoxycarbonylamino-3-hydroxy-piperidine-1-carboxylate and
    [0406] Benzyl (3R,4R)-4-fert.-butoxycarbonylamino-3-hydroxy-piperidine-1-carboxylate (WO 2004/058144)
    [0407] 7-hydroxy-2-methyl-2,3-dihydro-isoindol-1-one
    [0412] 7-Amino-2-methyl-2,3-dihydro-isoindol-1-one (5 g) is suspended in a mixture of ice (12.6 g) and H 2 SO 4 conc. (8.62g). An aqueous solution of sodium nitrite (2.5 molar, 16 mL) is added dropwise, so that the temperature does not rise above 0°C, and the solution is stirred for 15 min at this temperature. H 2 O (60 mL) is then added and the solution is heated at 80°C for 30 min. For work-up, combine with 10% NaCl solution (100 mL) and extract twice with 100 mL CH 2 Cl 2 . The combined organic phases are dried over magnesium sulfate, the desiccant is filtered off and the solvent is removed in vacuo. Final purification is carried out by preparative HPLC.
    [0414] (R)-7-hydroxy-2,3-dimethyl-2,3-dihydro-isoindol-1-one and (S)-7-hydroxy-2,3-dimethyl-2,3-dihydro-isoindol-1- one
    [0415] a) 2-methyl-3-methylene-7-nitro-2.3-dihydro-isoindol-1-one
    [0420] Ethyl 2-acetyl-6-nitrobenzoate (11.12 g) is suspended in a mixture of MeOH (70 mL) and MgSO4. Methylamine (2 molar in THF, 28.13 mL) is added dropwise and the solution is stirred for 15 min at this temperature. It is then preheated at 70°C for 18 h. The solvent is removed in vacuo, the residue is taken up in dichloromethane (100 mL), washed with sodium chloride solution (10%), dried over magnesium sulfate, filtered off from the desiccant, and the solvent is removed. empty For purification, it is recrystallized from toluene (250 mL).
    [0421] b) 7-amino-2.3-dimethyl-2.3-dihydro-isoindol-1-one
    [0424] Suspend 2-methyl-3-methylene-7-nitro-2,3-dihydro-isoindol-1-one (13.96 g) in THF and mix with a spatula tip of Pd(5%)/C and hydrogenated under pressure of H 2 (3 bar). For work-up, the catalyst is filtered off and the solvent is removed in vacuo.
    [0425] c) 7-hydroxy-2.3-dimethyl-2.3-dihydro-isoindol-1-one
    [0429] 7-amino-2,3-dimethyl- 2,3 -dihydro-isoindol- 1 -one (11.45 g) is suspended in a mixture of ice (27 g) and conc. (9.70 mL) and cooled to -10°C. Aqueous sodium nitrite solution (2.5 molar, 31.18 mL) is added dropwise, so that the temperature does not rise above 0°C, and the solution is stirred for 15 min at this temperature. H 2 O (135 mL) is then added and the solution is heated at 80°C for 15 min. For work-up, 10% NaCl solution (100 mL) is added and extracted twice with 100 mL CH 2 Cl 2 . The organic phase is extracted with NaOH solution (0.2 molar) and then the aqueous phase is acidified (conc. aq. HCl) and re-extracted with CH 2 Cl 2 . The organic phase is dried over magnesium sulfate, the desiccant is filtered off and the solvent is removed in vacuo.
    [0430] d) (R)-7-hydroxy-2.3-dimethyl-2.3-dihydro-isoindol-1 -one and (S)-7-hydroxy-2.3-dimethyl-2.3-dihydro-isoindol-1 -one
    [0435] The two enantiomers are separated by chromatography of the racemate through a chirally modified column (CHIRALCEL® OD-I, n-heptane/CH2Cl250/50).
    [0437] 7-h¡drox¡-2,3,3-trimet¡l-2,3-d¡h¡dro-¡so¡ndol-1-one
    [0438] a) 2-(3-methoxy-phenyl)-2-methyl-propionitrile
    [0443] NaH (14.13 g, 60%) is suspended in THF (400 mL) and cooled to 0°C. (3-Methoxyphenyl)-acetonitrile (20 g) is dissolved in THF (20 mL) and added dropwise. After 30 min at this temperature, add methyl iodide (19.46 mL) in THF (20 mL). After 16 h at 0°C, the reaction mixture is combined with H 2 O and extracted 3 times with CH 2 Cl 2 . The combined organic phases are dried over magnesium sulfate, the desiccant is filtered off and the solvent is removed in vacuo. The residue is used in the next reaction step without any further purification.
    [0445] b) 2-(3-methoxyphenyl)-2-methyl-propionic acid
    [0450] 2-(3-Methoxy-phenyl)-2-methyl-propionitrile (28.55 g, 80%) is dissolved in ethylene glycol, combined with KOH (14.48 g) and heated to 150°C. After 18 h, the reaction mixture is taken up in aqueous NaCl solution (10%) and extracted 3 times with CH 2 Cl 2 and EtOAc. The aqueous phase is then acidified with HCl (1 molar, aqueous) and extracted with EtOAc. The resulting organic phase is extracted a further 3 times with HCl (1 molar, aqueous), dried over magnesium sulfate, filtered from the desiccant, and the solvent is removed in vacuo. The residue is used in the next reaction step without further purification.
    [0451] c) 1-(1-isocyanato- 1-methylethyl)-3-methoxybenzene
    [0453] 2-(3-Methoxy-phenyl)-2-methyl-propionic acid (24.40 g) is dissolved in toluene (120 mL) and cooled to 02C. Triethylamine (16.61 mL) and diphenylphosphorylazide (24.37 g) are added. After 0.5h the mixture is heated to 110°C. After 3 h the reaction mixture is diluted with EtOAc, cooled to 0°C, extracted with NaHCÜ3 solution and NaCl solution (H 2 O, 10%), dried over magnesium sulfate, filtered off of the desiccant and the solvent is removed in vacuo. The residue is used in the next reaction step without any further purification.
    [0454] d) 7-methoxy-3.3-dimethyl-2.3-dihydro-isoindol-1-one and 7-methoxy-3.3-dimethyl-2.3-dihydro-isoindol-1-one
    [0458] FeCl3 (40.00 g) is suspended in dichloroethane (10 mL) and cooled to 0°C. 1-(1-Isocyanato-1-methylethyl)-3-methoxybenzene (21.40 g, dissolved in 10 mL dichloroethane) is added dropwise. After 1.5 h, H 2 O is added and the mixture is stirred for 15 min. After the addition of CH 2 Cl 2 , the aqueous phase is separated and discarded. The organic phase is extracted with aqueous tartaric acid solution, dried over magnesium sulfate, filtered off from the desiccant and the solvent is removed in vacuo. The two regioisomers are separated using a silica gel column (cHex/EtOAc 20:80 to 0:100).
    [0459] e) 7-methoxy-2.3.3-trimethyl-2. 3-dihydro-isoindol-1-one
    [0463] 7-Methoxy-3,3-dimethyl-2,3-dihydro-isoindol-1-one (3.16 g) is dissolved in THF (50 mL) and NaH (7.88 g) is added batchwise. After 5 min, methyl iodide (7.18 mL) is added. After 18 h at 0°C, the reaction mixture is combined with H 2 O/AcCN as well as Isolute and purified by RP HPLC.
    [0464] f) 7-hydroxy-2.3.3-trimethyl-2.3-dihydro-isoindol-1-one
    [0468] Dissolve 7-methoxy-2,3,3-trimethyl-2,3-dihydro-isoindol-1-one (0.18 g) in CH 2 Cl 2 (4.5 mL) and cool to -78°C . After addition of BBr3 (1 molar in CH 2 Cl 2 , 2.92 mL) the reaction mixture is allowed to warm to -10°C within 3 h. For work-up, it is diluted with CH 2 Cl 2 and extracted with NaCl solution (H 2 O, 10%). The organic phase is dried over magnesium sulfate, the desiccant is filtered off and the solvent is removed in vacuo. The residue is used in the next reaction step without any further purification.
    [0469] (3R,4R)-3-methoxy-1-methyl-piperidin-4-ylamine
    [0470] a) ( 3R,'4R)-4-sterol. benzyl butoxycarbonylamino-3-methoxy-piperidine-1-carboxylate
    [0473] Benzyl (3S,4S)-4-ferc.-butoxycarbon¡lam¡no-3-h¡drox¡-p¡per¡n-1-carboxylate (5.00 g) is dissolved in THF (6 mL) and combined with 30 mL of semi-concentrated aqueous NaOH solution, benzyltriethylammonium chloride, as well as dimethyl sulfate (2.26 mL). After 22 h, H 2 O (200 mL) is added and the mixture is extracted with EtOAc (150 mL). The organic phase is dried over magnesium sulfate, filtered off from the desiccant and the solvent removed in vacuo. Purification is carried out using a silica gel column (cHex/EtOAc 65/35).
    [0474] b) ((3R,4R)-3-methoxy¡-p¡per¡d¡n-4-¡l)-ferc.-but¡carbamate
    [0479] Benzyl (3R,4R)-4-fert-butoxycarbonlamno-3-methoxy-pperdina-1-carboxylate (2.88 g) is given dissolved in ethanol and combined with a spatula tip of Pd/C and hydrogenated under H 2 pressure (4 bar). After 18 h, the catalyst is filtered off and the solvent is removed in vacuo. The residue is used in the next reaction step without any further purification.
    [0480] c) tert-butyl ((3R,4R)-3-methoxy¡-1-methyl-p¡per¡n-4-¡l)-carbamate
    [0485] Fert-butyl ((3R,4R)-3-methoxy-p¡per¡d¡n-4-¡l)carbamate (2.88 g) is dissolved with formaldehyde (1.79 mL , 37% solution in H 2 O) and acetic acid (100 pL) in DMF. Na(OAc)3BH (12.59 g) is then added. After 20 h, the reaction mixture is combined with aqueous NaHCO3 solution (saturated with NaCl) and extracted 5 times with EtOAc. The combined organic phase is dried over magnesium sulfate, the desiccant is filtered off and the solvent is removed in vacuo. The residue is used in the next reaction step without any further purification.
    [0486] d) (3R.4R)-3-methoxy¡-1 -methyl-piperidin-4-ylamine
    [0487] tert-Butyl (3R!4R)-3-methoxy-1-methyl-piperidin-4-yl)-carbamate (3.01 g) is combined with HCl (4 molar in dioxane, 25 mL). After 1 h, the reaction mixture is freed from solvent in vacuo and used in the next step without any further purification.
    [0488] tert-butyl (3R,4S)-4-amino-3-fluoro-piperidine-1-carboxylate
    [0493] tert.-Butyl (3R,4S)-4-benzylamino-3-fluoro-piperidine-1-carboxylate (2.13 g) is suspended in THF and mixed with a spatula tip of Pd(OH )2 and mixed. hydrogenate under pressure of H 2 (7 bars). For work-up, the catalyst is filtered off and the solvent is removed in vacuo and the residue is used in the next step without further purification.
    [0495] Example 1: 2-Chloro-4-[5-chloro-4-(2-methyl-3-oxo-2,3-dihydro-1 H -isoindol-4-yloxy)-pyrimidin-2-ylamino]-5- benzyl methoxybenzoate
    [0497] a) 7-(2,5-dichloro-pyrimidin-4-yloxy)-2-methyl-2,3-dihydro-isoindol-1-one
    [0502] 2,4,5-trichloropyrimidine (0.20 g) and 7-hydroxy-2-methyl-2,3-dihydro-isoindol-1-one are dissolved in DCM (10 mL), cooled to 0°C and Combine with cesium carbonate (0.75 g). The cooling bath is removed and the mixture is stirred for 16 h. For work-up, the mixture is combined with 10% NaCl solution (100 mL) and extracted three times with 75 mL of ethyl acetate. The combined organic phases are dried over magnesium sulfate, the desiccant is filtered off and the solvent is removed in vacuo.
    [0503] b) 2-chloro-4-[5-chloro-4-(2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yloxy)-pyrimidin-2-ylamino1-5-methoxy-benzoate benzyl
    [0508] 7-(2,5-dichloro-pyrimidin-4-yloxy)-2-methyl-2,3-dihydro-isoindol-1-one (0.10 g), 4-amino-2-chloro-5-methoxy- Benzyl benzoate (0.28 g), Pd2dba3 (18 mg), X-Phos (37 mg), and Cs2CO3 are weighed into a microwave vial and flushed with argon. Toluene (1 mL) and NMP (50 pL) are then added, argon flushing is performed again, and the mixture is stirred for 5 min at 150°C in the microwave. For work-up, the mixture is diluted with ACN (20 mL) and combined with Isolute (Separtis GmbH). The solvent is removed in vacuo and then purified by preparative HPLC. (IC 50 = 53 nmol)
    [0510] Example 2: 2-chloro-4-[5-chloro-4-(2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yloxy)-pyrimidin-2-ylamino]-5-methoxy -W-(1-methyl-piperidin-4-yl)-benzamide
    [0511] a) 2-chloro-4-[5-chloro-4-(2-methyl-3-oxo-2,3-dihydro-1 H-isoindol-4-yloxy)-pyrimidin-2-ylamino]-5- methoxy-benzoic
    [0513] 2-chloro-4-[5-chloro-4-(2-methyl-3-oxo-2,3-dihydro-1 H-isoindol-4-yloxy)-pyrimidin-2-ylamino]-5-methoxy-benzoate of benzyl (75 mg) is dissolved in THF (150 mL), Pd(OH) 2 (0.01 g) is added and the mixture is stirred for 2 h under H 2 gas. For work-up, the mixture is diluted with ACN (20 mL) and Isolute is added. The solvent is filtered off from the catalyst and the solvent is removed in vacuo.
    [0514] b) 2-chloro-4-[5-chloro-4-(2-methyl-3-oxo-2,3-dihydro-1 H-isoindol-4-yloxy)-pyrimidin-2-ylamino]-5-methoxy -N-(1-methyl-piperidin-4-yl)-benzamide
    [0516] mg), TBTU (60
    [0517] methylpiperidin-4-amine (18 mg) and the reaction mixture is stirred for another 20 min. The reaction mixture is purified by HPLC without treatment. (IC 50 = 1 nmol).
    [0518] The following compounds 3 to 215 are synthesized analogously, with the corresponding 2-chloropyrimidines as educts:
    [0519] Table 1: Examples 3-215
    [0522]
    [0523]
    [0524]
    [0525]
    [0526]
    [0527]
    [0528]
    [0529]
    [0530]
    [0531]
    [0532]
    [0533]
    [0534]
    [0535]
    [0536]
    [0537]
    [0538]
    [0539]
    [0540]
    [0541]
    [0542]
    [0543]
    [0544]
    [0545]
    [0546]
    [0547]
    [0548]
    [0549]
    [0550]
    [0551]
    [0552]
    [0553]
    [0554]
    [0555]
    [0556]
    [0557]
    [0558]
    [0559]
    [0560]
    [0561]
    [0562]
    [0563]
    [0564]
    [0565]
    [0566] The following Examples describe the biological activity of the compounds according to the invention without restricting the invention to these Examples.
    [0568] PTK2 enzyme assay
    [0570] This assay uses the active PTK2 enzyme (Invitrogen Code PV3832) and poly-Glu-Tyr (4:1, Sigma P-0275) as the kinase substrate. Kinase activity is detected by substrate phosphorylation in a DELFIA™ assay. The phosphorylated substrate is detected with the europium-labeled phosphotyrosine antibody PY20 (Perkin Elmer, N2: AD0038).
    [0571] In order to determine concentration-activity curves with PTK2 inhibitors, compounds are serially diluted in 10% DMSO/H2O and 10 pL of each dilution is dispensed per well into a 96-well microtiter plate. (clear U-shaped base plate, Greiner #650101) (inhibitors are tested in duplicate) and mixed with 10 pL/well PTK2 kinase (0.01 pg/well). PTK2 kinase is therefore diluted in advance according to the kinase dilution buffer (20 mM TRIS/HCl pH 7.5, 0.1 mM EDTA, 0.1 mM EGTA, 0.286 mM sodium orthovanadate, 10% glycerol). with the addition of freshly prepared BSA (fraction V 1 mg/mL) and DTT (1 mM)). Test compound and PTK2 kinase are preincubated for 1 h at RT and shaken at 500 rpm. Next, 20 pL of ATP mix (30 mM TRIS/HCl pH 7.5, 0.02% Brij, 0.2 mM sodium orthovanadate, 10 mM magnesium acetate, 0.1 mM EGTA, 1x Cocktail) is added. Phosphatase Inhibitors 1 (Sigma, #: P2850), 50 pM ATP (Sigma, #: A3377; 15 mM stock solution)). The reaction is initiated by the addition of 10 pL/well poly(Glu,Tyr) substrate (25 pg/well poly(Glu,Tyr), 0.05 pg/well biotinylated poly(Glu,Tyr) dissolved in TRIS /250 mM HCl pH 7.5, 9 mM dTT) - final concentration of DMSO is 2%. After 1 h of kinase reaction (plates are shaken at 500 rpm), the reaction is stopped by the addition of 12 pL/well of 100 mM EDTA, pH 8. And shaken for another 5 min at room temperature (500 U/min).
    [0573] 55 pL of the reaction mixture are transferred to a streptavidin plate (Strepta Wel1High Bind (clear, 96 wells) manufactured by Roche, No.: 11989685001) and incubated for 1 h at RT (shaking at 500 rpm). The microtiter plate is then washed three times with 200 pL/well of D-PBS (Invitrogen, #:14190). 100 pL of anti-phosphotyrosine PY20 DELFIA Eu-N1 diluted 1:2000 is then added (Perkin Elmer, N°: AD0038, 1:2000 diluted in DELFIA assay buffer (Perkin Elmer, N°: 1244-111)) and incubate for 1 h at RT (agitation at 500 rpm). The plate is then washed three times with 200 pL/well of DELFIA wash buffer (Perkin Elmer, N°: 1244 114), 200 pL/well of booster solution (Perkin Elmer, N°: 1244-105) is added. ) and the whole is incubated for 10 min at RT (agitation at 300 rpm).
    [0574] The time-delayed europium fluorescence is then measured in a microtiter plate reader (Victor, Perkin Elmer). The positive control consists of wells that contain solvent (2% DMSO in assay buffer) and show uninhibited kinase activity. Wells containing assay buffer instead of enzyme act as a control for background kinase activity.
    [0575] IC 50 values are determined from concentration-activity analyzes by iterative calculation using a sigmoidal curve analysis algorithm (FIFTY, based on GraphPAD Prism Version 3.03) with a variable Hill coefficient.
    [0577] soft agar assay
    [0579] This cellular assay is used to determine the influence of PTK2 inhibitors on the growth of PC-3 prostate carcinoma cells in soft agar ('anchorage-independent growth'). After an incubation time of two weeks, cell vitality is demonstrated by Alamar blue (resazurin) staining. PC-3 cells (ATCC CRL-1435) are grown in cell culture flasks (175 cm2) with Kaighn's F12 medium (Gibco, #: 21127) that has been supplemented with 10% fetal calf serum (Invitrogen , No.: 16000-044). Cultures are incubated in the 37°C, 5% CO 2 incubator and run twice weekly. Assay I is carried out in microtiter plates (Greiner, N°: 655 185) and consists of a lower layer composed of 90 pL of medium with 1.2% agarose (Invitrogen, 40 mL of 4% agarose gel 1x liquid, N°: 18300-012), followed by a layer of cells in 60 pL of medium and 0.3% agarose and finally an upper layer comprising 30 pL of medium containing the test compounds (without the addition of agarose). To prepare the lower layer, 4% agarose is decocted with 10x D-PBS (Gibco, #: 14200) and H 2 O and thus pre-diluted in 3% agarose in 1x D-PBS. The latter is adjusted with culture medium (Kaighn's F12/10% FCS) and FCS to a final dilution of 1.2% agarose in Kaighn's F12 medium with 10% FCS. Each well of a microtiter plate is supplied with 90 pL of the suspension for the lower layer and cooled at RT for 1 h. For the cell layer, PC-3 cells are separated using trypsin (Gibco, 0.05%; #: 25300), counted and seeded in 60 pL of Kaighn's F12 (10% FCS) with the addition 0.3% agarose (37°C). After cooling at RT for 1 h, test compounds (30 pL of serial dilutions) are added for 4-fold measurements. The concentration of test compounds generally covers an assay range of between 10 pM and 0.3 nM. Compounds (stock solution: 10 mM in 100% DMSO) were pre-diluted in Kaighn's F12 medium 6% DMSO, to obtain a final concentration of 1% DMSO. Cells are incubated at 37°C and 5% CO 2 in a steam saturated atmosphere for 14 days. The metabolic activity of living cells is then demonstrated with Alamar blue dye (AbD Serotec, No: BUFO 12B). To do this, 18 pL/well of Alamar blue suspension is added and the whole is incubated for approx. 8 h in the 37°C incubator. The positive control consists of empty wells that are filled with a mixture of 18 pL of autoclaved reduced Alamar blue and 180 pL of Kaighn's F12 medium (FCS al 10%). The fluorescence intensity is determined by means of a fluorescence spectrometer (SpectraMAX GeminiXS, Molecular Devices). The excitation wavelength is 530nm, the emission wavelength is 590nm.
    [0581] EC 50 values are determined from concentration-activity analysis by iterative calculation using a sigmoidal curve analysis algorithm (FIFTY, based on GraphPAD Prism Version 3.03) with a variable Hill coefficient.
    [0583] Phospho-PTK2 assay (pY397)
    [0585] This cellular assay is used to determine the influence of PTK2 inhibitors on the state of PTK2 phosphorylation at tyrosine 397 (pY397).
    [0586] PC-3 cells (prostate carcinoma, ATCC CRL-1435) are cultured in cell culture flasks (175 cm2) with Kaighn's F12 medium (Gibco, #: 21127) with the addition of 10% fetal calf serum ( Invitrogen, No: 16000-044). Cultures are incubated in the 37°C, 5% CO 2 incubator and run twice weekly.
    [0587] For the assay, 2 x 104 cells per well/90pL of medium are seeded in 96-well microtiter plates (Costar, N°: 3598) and incubated overnight in the 37°C incubator and 5% CO. 2 . Test compounds (10 pL serial dilution) are added the following day. The concentration of test compounds usually covers a range from 50 pM to 0.8 nM. Test compounds (stock solution: 10 mM in 100% DMSO) are diluted in medium/10% DMSO medium such that the final concentration is 1% DMSO. The cells are then incubated in the 37°C, 5% CO 2 incubator for 2 h. The culture supernatant is then removed and the cells are fixed with 150 pL of 4% formaldehyde in D-PBS for 20 min at RT. The cell lawn is washed five times with 200 pL of 0.1% Triton X-100 in D-PBS for 5 min each and then incubated for 90 min with blocking buffer (5% skimmed milk powder ( Maresi Fixmilch) in TBST (25 mM Tris/HCl, pH 8.0, 150 mM NaCl, 0.05% Tween 20.) The blocking buffer is replaced by 50 pL of the first anti-phospho PTK2 rabbit monoclonal antibody [ pY397] (Invitrogen/Biosource, No: 44-625G), which is diluted 1:200 in blocking buffer For control purposes, alternatively a PTK2 [total] antibody (mouse monoclonal clone 4.47, Upstate, N°: 05-537), diluted 1:400 in blocking buffer. This incubation is carried out at 4°C overnight. The cell lawn is then washed five times with 100 pL of 0.1% Tween in D-PBS for 5 min in each case and 50 pL/well of a second antibody is added In order to detect bound phospho-PTK2 [Y397] antibody, a goat anti-rabbit antibody is used. a that is coupled with horseradish peroxidase (Dako, #: P0448; 1:500 dilution in blocking buffer). In order to detect bound [total] PTK2 antibodies, a rabbit anti-mouse antibody is used, which is also coupled with horseradish peroxidase (Dako, No: PO161; 1:1000 dilution in blocking buffer). This incubation is carried out for 1 h at RT with gentle shaking. The cell lawn is again washed five times with 100 pL of 0.1% Tween in D-PBS for 5 min each. Peroxidase staining is carried out by adding 100 pL of staining solution (1:1 mixture of TMB peroxidase substrate (KPL, No: 50-76-02) and peroxidase B solution (H 2 O 2 ) (KPL, N°: 50-65-02). The development of the spot takes place for 10 - 30 min in the dark. The reaction is stopped by the addition of 100 pL/well of a 1M phosphoric acid solution. Absorption is determined photometrically at 450 nm with an absorption measuring device (VICTOR3 PerkinElmer) Inhibition of anti-phospho PTK2 immune staining [Y397] is used to determine EC 50 values. -PTK2 [total] is for control purposes and should remain constant under the influence of the inhibitor EC 50 values are determined from concentration-activity analyzes by iterative calculation with the aid of a sigmoidal curve analysis algorithm (FIFTY, based on GraphPAD Prism Version 3.03) with a coefficient of Variable Hill.
    [0588] The substances of the present invention are PTK2-kinase inhibitors. In view of their biological properties, the new compounds of the general formulas (1a)-(1d) and their physiologically acceptable salts are suitable for the treatment of diseases characterized by excessive or abnormal proliferation.
    [0590] Such diseases include, for example: viral infections (eg, HIV and Kaposi's sarcoma); inflammatory and autoimmune diseases (eg, colitis, arthritis, Alzheimer's disease, glomerulonephritis, and scarring); bacterial, fungal and/or parasitic infections; leukemias, lymphomas, and solid tumors (eg, carcinomas and sarcomas), skin diseases (eg, psoriasis); hyperplasia-based diseases characterized by an increase in the number of cells (eg, fibroblasts, hepatocytes, bone and bone marrow cells, cartilage or smooth muscle cells, or epithelial cells (eg, endometrial hyperplasia)); bone diseases and cardiovascular diseases (eg, restenosis and hypertrophy).
    [0592] For example, the following cancers can be treated with compounds according to the invention, without limitation:
    [0593] brain tumors such as, for example, acoustic neuroma, astrocytomas such as fibrillary, protoplasmic, gemistocytic, anaplastic, pilocytic astrocytomas, glioblastoma, gliosarcoma, pleomorphic xanthoastrocytoma, subependymal large cell giant cell astrocytoma, and infantile desmoplastic astrocytoma; brain lymphomas, brain metastases, pituitary tumor such as prolactinoma, pituitary incidentaloma, HGH (human growth hormone) producing adenoma and corticotrophic adenoma, craniopharyngiomas, medulloblastoma, meningeoma and oligodendroglioma; nerve tumors such as, for example, tumors of the vegetative nervous system such as neuroblastoma, ganglioneuroma, paraganglioma (pheochromocytoma, chromaffinoma) and tumor of the glomus-caroticum, tumors in the peripheral nervous system such as amputation neuroma, neurofibroma, neurinoma (neurilemoma, Schwannoma) and malignant Schwannoma, as well as tumors of the central nervous system such as brain and bone marrow tumors; intestinal cancer such as, for example, carcinoma of the rectum, colon, anus, and duodenum; eyelid tumors (basaloma or adenocarcinoma of the eyelid apparatus); retinoblastoma; pancreatic carcinoma; bladder carcinoma; lung tumors (bronchial carcinoma - small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC) such as, for example, epithelial spindle cell carcinomas, adenocarcinomas (acinar, parietal, bronchiolar-alveolar) and carcinoma large cell bronchial (giant cell carcinoma, clear cell carcinoma)); breast cancer such as ductal, lobular, mucinous or tubular carcinoma, Paget's carcinoma; non-Hodgkin's lymphomas (NHL B-lymphatic or T-lymphatic) such as, for example, hairy cell leukemia, Burkitt's lymphoma or mucosis fungoides; Hodgkin's disease; uterine cancer (carcinoma of the corpus or endometrial carcinoma); CUP syndrome (cancer of unknown primary); ovarian cancer (ovarian carcinoma - mucinous or serous cystoma, endometriodal tumors, clear cell tumor, Brenner tumor); gallbladder cancer; bile duct cancer such as, for example, Klatskin's tumor; testicular cancer (germ or non-germ cell tumors); laryngeal cancer such as, for example, supraglottal, glottal, and subglottal tumors of the vocal cords; bone cancer such as, for example, osteochondroma, chondroma, chondroblastoma, chondromyxoid fibroma, chondrosarcoma, osteoma, osteoid osteoma, osteoblastoma, osteosarcoma, non-ossifying bone fibroma, osteofibroma, desmoplastic bone fibroma, bone fibrosarcoma, malignant fibrous histiocytoma, osteoclastoma or tumor giant cell tumors, Ewing's sarcoma and plasmacytoma, head and neck tumors (HNO tumors) such as, for example, tumors of the lips. and oral cavity (carcinoma of the lips, tongue, oral cavity), nasopharyngeal carcinoma (tumors of the nose, lymphoepithelioma), pharyngeal carcinoma, oropharyngeal carcinomas, carcinomas of the tonsils (tonsil malignant) and (base of) tongue, hypopharyngeal carcinoma, laryngeal carcinoma (cancer of the larynx), paranasal sinus and nasal cavity tumors, salivary gland and ear tumors; liver cell carcinoma (hepatocellular carcinoma (HCC); leukemias such as, for example, acute leukemias such as acute lymphoblastic/lymphoblastic leukemia (ALL), acute myeloid leukemia (AML); chronic lymphatic leukemia (CLL), chronic myeloid leukemia (CML ); stomach cancer (papillary, tubular or mucinous adenocarcinoma, adenosquamous, squamous or undifferentiated carcinoma; malignant melanomas such as, for example, superficial spreading melanoma (SSM), nodular (NMM), lentigo-maligna (LMM), acral- lentiginous (ALM) or amelanotic (AMM); renal cancer such as, for example, renal cell carcinoma (hypernephroma or Grawitz tumor); esophageal cancer, penile cancer, prostate cancer, vaginal cancer or vaginal carcinoma, carcinomas thyroid such as, for example, papillary, follicular, medullary or anaplastic thyroid carcinoma, carcinoma of the thymus (thymoma), cancer of the urethra (carcinoma of the urethra, urothelial carcinoma) and cancer of the vulva.
    [0595] The new compounds can be used for the prevention, short-term or long-term treatment of the above-mentioned diseases, optionally also in combination with radiotherapy or other "state of the art" compounds such as, e.g. eg, cytostatic or cytotoxic substances, inhibitors of cell proliferation, antiangiogenic substances, steroids or antibodies.
    [0597] The compounds of the general formulas (1a)-(1d) can be used alone or in combination with other active substances according to the invention, optionally also in combination with other pharmacologically active substances.
    [0599] Chemotherapeutic agents that can be administered in combination with the compounds according to the invention include, but are not limited to, hormones, hormone analogs, and antihormones (eg, tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproterone acetate, finasteride, buserelin acetate, fludrocortisone, fluoxymesterone, medroxyprogesterone, octreotide), aromatase inhibitors (eg, anastrozole, letrozole, liarozole, vorozole, exemestane, atamestane), agonists and antagonists of LHRH (eg, goserelin acetate, luprolide), growth factor inhibitors (growth factors such as, for example, “platelet-derived growth factor” and “hepatocyte growth factor”, inhibitors are, for example, "growth factor" antibodies, "growth factor receptor" antibodies, and tyrosine kinase inhibitors such as, for example, gefi tinib, lapatinib, and trastuzumab), signal transduction inhibitors (eg. imatinib and sorafenib), antimetabolites (eg, antifolates such as methotrexate, premetrexed, and raltitrexed, pyrimidine analogs such as 5-fluorouracil, capecitabine, and gemcitabine, purine and adenosine analogs such as mercaptopurine, thioguanine, cladribine, and pentostatin, cytarabine, fludarabine), antitumor antibiotics (eg, anthracyclines such as doxorubicin, daunorubicin, and idarubicin, mitomycin-C, bleomycin, dactinomycin, plicamycin, streptozocin); platinum derivatives (eg, cisplatin, oxaliplatin, carboplatin); alkylating agents (eg, estramustine, mechlorethamine, melphalan, chlorambucil, busulfan, dacarbazine, cyclophosphamide, ifosfamide, temozolomide, nitrosoureas such as, eg, carmustine and lomustine, thiotepa); antimitotic agents (eg, Vinca alkaloids such as, for example, vinblastine, vindesine, vinorelbine, and vincristine; and taxanes such as paclitaxel, docetaxel); topoisomerase inhibitors (eg, epipodophyllotoxins such as, for example, etoposide and etopophos, teniposide, amsacrine, topotecan, irinotecan, mitoxantron) and various chemotherapeutic agents such as amifostine, anagrelid, clodronat, filgrastin, interferon alfa, leucovorin, rituximab , procarbazine, levamisole, mesna, mitotane, pamidronate, and porfi'mer.
    [0600] Suitable preparations include, for example, tablets, capsules, suppositories, solutions - particularly solutions for injection (s.c., i.v., i.m.) and infusion - elixirs, emulsions or dispersible powders. The content of the pharmaceutically active compound(s) should be in the range of 0.1 to 90% by weight, preferably 0.5 to 50% by weight of the composition as a whole, i.e. in amounts sufficient to reach the dosage range specified below. The specified doses can, if necessary, be administered several times a day.
    [0602] Suitable tablets can 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 gelatin, lubricants such as magnesium stearate or talc and/or release retarding agents such as carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate. Tablets can also comprise several layers.
    [0604] Coated tablets can be prepared accordingly by coating cores produced analogously to tablets with substances normally used for tablet coatings, eg colidone 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 of layers to achieve delayed release, possibly using the excipients mentioned above for tablets.
    [0606] Syrups or elixirs containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharin, cyclamate, glycerol or sugar and a flavor enhancer, e.g. eg, a flavoring such as vanillin or orange extract. They may also contain suspending or thickening aids such as sodium carboxymethylcellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.
    [0608] 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 stabilizers such as alkali metal salts of ethylenediaminetetraacetic acid, optionally using emulsifiers and/or dispersants, while if water is used as a diluent, for example, the Organic solvents can optionally be used as solvating agents or solvents, and can be transferred to injection vials or ampoules or infusion bottles.
    [0610] Capsules containing one or more active substances or combinations of active substances can be prepared, for example, by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatin capsules.
    [0612] Suitable suppositories can be prepared, for example, by mixing with carriers provided for this purpose, such as neutral fats or polyethylene glycol or their derivatives.
    [0614] Excipients that can be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (eg, petroleum fractions), vegetable oils (eg, peanut or sesame oil), mono- or polyfunctional (eg ethanol or glycerol), supports such as, for example, natural mineral powders (eg kaolins, clays, talc, chalk), synthetic mineral powders (eg silicic acid highly disperse and silicates), sugars (eg, cane sugar, lactose, and glucose), emulsifiers (eg, lignin, spent sulfite liquors, methylcellulose, starch, and polyvinylpyrrolidone), and lubricants (eg, magnesium stearate, talc, stearic acid and sodium lauryl sulfate).
    [0616] The preparations are administered by the usual methods, preferably orally or transdermally, most preferably orally. For oral administration, tablets may of course contain, in addition to the carriers mentioned above, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatin and the like. Also, lubricants such as magnesium stearate, sodium lauryl sulfate and talc can be used at the same time for the tabletting process. In the case of aqueous suspensions, the active substances can be combined with various flavor enhancers or colorants, in addition to the excipients mentioned above.
    [0618] For parenteral use, solutions of the active substances with suitable liquid carriers can be used.
    [0620] The dosage for intravenous use is 1-1000 mg per hour, preferably between 5 and 500 mg per hour.
    [0622] However, it may sometimes be necessary to deviate from the specified amounts, depending on body weight, the route of administration, the individual's response to the drug, the nature of its formulation, and the time or interval at which the drug is administered. Therefore, in some cases it may be sufficient to use less than the minimum dose indicated above, while in other cases it may be necessary to exceed the limit higher. When administering large amounts, it may be advisable to divide them into several smaller doses spread throughout the day.
    [0624] The following formulation examples illustrate the present invention without restricting its scope:
    [0626] Examples of pharmaceutical formulations
    [0628] A) Tablets_______________________________________per tablet
    [0630] active substance according to formula (1) 100 mg
    [0631] lactose 140mg
    [0632] corn starch 240mg
    [0633] polyvinylpyrrolidone 15 mg
    [0634] magnesium stearate 5mg
    [0636] 500mg
    [0638] The finely ground active substance, lactose and some of the corn starch are mixed. The mixture is sieved, 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. The mixture is compressed to produce tablets of suitable size and shape.
    [0640] B) Tablets_______________________________________per tablet
    [0642] active substance according to formula (1) 80 mg
    [0643] lactose 55mg
    [0644] corn starch 190mg
    [0645] microcrystalline cellulose 35mg
    [0646] polyvinylpyrrolidone 15 mg
    [0647] sodium carboxymethyl starch 23 mg
    [0648] magnesium stearate 2mg
    [0650] 400mg
    [0652] The finely ground active substance, some of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed, the mixture is sieved and worked up with the remaining corn starch and water to form a granulate which is dried and sieved. The sodium carboxymethyl starch and magnesium stearate are added and mixed, and the mixture is compressed to form tablets of a suitable size.
    [0654] C) Ampoule solution
    [0656] active substance according to formula (1) 50 mg
    [0657] sodium chloride 50mg
    [0658] water for injection 5ml
    [0660] 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 obtained solution is non-pyrogenically filtered and the filtrate is transferred under aseptic conditions to ampoules which are then sterilized and sealed by melting. The ampoules contain 5 mg, 25 mg and 50 mg of active substance.
    权利要求:
    Claims (26)
    [1]

    [2]
    2. A compound of general formula (1b),

    [3]
    3. A compound of general formula (1c),

    [4]
    4. A compound according to one of claims 1 to 3, wherein A is phenyl.
    [5]
    5. A compound of general formula (1d) according to claim 3,

    [6]
    6. A compound according to one of claims 1 to 5, wherein R3 is Cl or CF3 .
    [7]
    7. A compound selected from

    [8]
    8. A compound according to claim 7 of the formula

    [9]
    9. A compound according to claim 7 of the formula

    [10]
    10. A compound according to claim 7 of the formula

    [11]
    11. A compound according to claim 7 of the formula

    [12]
    12. A compound according to claim 7 of the formula

    [13]
    13. A compound according to claim 7 of the formula

    [14]
    14. A compound according to claim 7 of the formula

    [15]
    15. A compound according to claim 7 of the formula

    [16]
    16. A compound according to claim 7 of the formula

    [17]
    17. A compound according to claim 7 of the formula

    [18]
    18. A compound according to claim 7 of the formula

    [19]
    19. A compound according to claim 7 of the formula

    [20]
    20. A compound according to claim 7 of the formula

    [21]
    21. A compound according to claim 7 of the formula

    [22]
    22. A compound - or pharmaceutically effective salts thereof - according to one of claims 1 to 21 for use as a medicament.
    [23]
    23. A compound - or pharmaceutically effective salts thereof - according to one of claims 1 to 21 for preparing a medicament with anti-proliferative and/or pro-apoptotic activity.
    [24]
    24. Pharmaceutical preparation, containing as active substance one or more compounds of general formulas (1a), (1b), (1c) or (1d) according to one of claims 1 to 21 or physiologically acceptable salts thereof , optionally in combination with conventional excipients and/or carriers.
    [25]
    25. Use of a compound of general formula (1a), (1b), (1c) or (1d) according to one of claims 1 to 21 to prepare a pharmaceutical composition for the treatment and/or prevention of cancer, infections, inflammations and autoimmune diseases.
    [26]
    26. Pharmaceutical preparation, comprising a compound of general formula (1a), (1b), (1c) or (1d) according to one of claims 1 to 21 and at least one active cytostatic or cytotoxic substance different from the formula (1a), (1b), (1c) or (1d), optionally in the form of tautomers, racemates, enantiomers, diastereomers and mixtures thereof, or pharmacologically acceptable acid addition salts thereof .
    类似技术:
    公开号 | 公开日 | 专利标题
    US9676762B2|2017-06-13|Pyrimidine compounds containing seven-membered fused ring systems
    US8785464B2|2014-07-22|Pyrimidine derivatives that inhibit FAK/PTK2
    US8461147B2|2013-06-11|Diaminopyridines for the treatment of diseases which are characterised by excessive or anomal cell proliferation
    US8377943B2|2013-02-19|2,4-diaminopyrimidine derivates as PTK2-inhibitors for the treatment of abnormal cell growth
    EP2435411B1|2014-10-29|2,4-diaminopyrimidines for the treatment of diseases characterised by excessive or abnormal cell proliferation
    US20130165439A1|2013-06-27|Chemical compounds
    WO2010106097A1|2010-09-23|Substituted pyrimidines for the treatment of cancer
    JP5651110B2|2015-01-07|New compounds
    EP2134723A1|2009-12-23|9h- purine derivatives and their use in the treatment of proliferative diseases
    BRPI0922801B1|2021-12-21|PYRIMIDINE COMPOUNDS, THEIR USE AND PHARMACEUTICAL PREPARATION INCLUDING THEM
    同族专利:
    公开号 | 公开日
    AR074210A1|2010-12-29|
    US20110288071A1|2011-11-24|
    BRPI0922801A2|2020-08-04|
    WO2010058032A2|2010-05-27|
    CA2744351A1|2010-05-27|
    EA201100794A1|2012-01-30|
    US9676762B2|2017-06-13|
    KR101710058B1|2017-02-24|
    HK1160841A1|2012-08-17|
    WO2010058032A3|2010-07-15|
    CA2744351C|2017-07-04|
    ECSP11011079A|2011-06-30|
    IL212814A|2018-05-31|
    AP2011005706A0|2011-06-30|
    EP2367800B1|2018-02-28|
    UY32259A|2010-06-30|
    CN104478865B|2017-09-22|
    US20160362404A1|2016-12-15|
    JP5622740B2|2014-11-12|
    EP2367800B9|2021-10-20|
    US8846689B2|2014-09-30|
    CL2011001215A1|2011-09-30|
    CN102292322B|2015-11-25|
    NZ592925A|2013-04-26|
    AP2960A|2014-08-31|
    IL212814D0|2011-07-31|
    AU2009317170B2|2015-05-28|
    MX2011005420A|2011-06-16|
    US20140371205A1|2014-12-18|
    MA32811B1|2011-11-01|
    AU2009317170A1|2010-05-27|
    US20150376141A1|2015-12-31|
    EA021997B1|2015-10-30|
    CN102292322A|2011-12-21|
    MY176944A|2020-08-27|
    JP2012509864A|2012-04-26|
    CO6511283A2|2012-08-31|
    EP2367800A2|2011-09-28|
    CN104478865A|2015-04-01|
    ES2664499T3|2018-04-19|
    TW201026682A|2010-07-16|
    TWI491605B|2015-07-11|
    TN2011000259A1|2012-12-17|
    MX337116B|2016-02-12|
    KR20110084551A|2011-07-25|
    PE20120034A1|2012-02-19|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    GB9705361D0|1997-03-14|1997-04-30|Celltech Therapeutics Ltd|Chemical compounds|
    ES2274634T3|1998-08-29|2007-05-16|Astrazeneca Ab|PIRIMIDINE COMPOUNDS.|
    US6906067B2|1999-12-28|2005-06-14|Bristol-Myers Squibb Company|N-heterocyclic inhibitors of TNF-α expression|
    GB0004890D0|2000-03-01|2000-04-19|Astrazeneca Uk Ltd|Chemical compounds|
    GB0004886D0|2000-03-01|2000-04-19|Astrazeneca Uk Ltd|Chemical compounds|
    GB0004888D0|2000-03-01|2000-04-19|Astrazeneca Uk Ltd|Chemical compounds|
    GB0016877D0|2000-07-11|2000-08-30|Astrazeneca Ab|Chemical compounds|
    EP2332924A1|2001-10-17|2011-06-15|Boehringer Ingelheim Pharma GmbH & Co. KG|Pyrimidine derivates, medicaments comprising them, their use and process of their preparation|
    MY141867A|2002-06-20|2010-07-16|Vertex Pharma|Substituted pyrimidines useful as protein kinase inhibitors|
    EA200500721A1|2002-11-28|2005-12-29|Шеринг Акциенгезельшафт|Pyrimidines inhibiting CHK, PDK and ACT, THEIR RECEIVING AND USING AS MEDICINES|
    CL2004000306A1|2003-02-20|2005-04-08|Tibotec Pharm Ltd|COMPOUNDS DERIVED FROM PYRIMIDINE REPLACED WITH INDANO; PROCESS FOR PREPARATION; PHARMACEUTICAL COMPOSITION THAT UNDERSTANDS IT; PHARMACEUTICAL COMBINATION; AND ITS USE FOR THE TREATMENT OR PROFILAXIS OF AN INFECTIOUS DISEASE.|
    ES2325440T3|2003-02-20|2009-09-04|Smithkline Beecham Corporation|PIRIMIDINE COMPOUNDS.|
    GB0305929D0|2003-03-14|2003-04-23|Novartis Ag|Organic compounds|
    US7504396B2|2003-06-24|2009-03-17|Amgen Inc.|Substituted heterocyclic compounds and methods of use|
    KR100904570B1|2003-08-15|2009-06-25|노파르티스 아게|2,4-pyrimidinediamines useful in the treatment of neoplastic diseases, inflammatory and immune system disorders|
    EP1598343A1|2004-05-19|2005-11-23|Boehringer Ingelheim International GmbH|2-Arylaminopyrimidine derivatives as PLK inhibitors|
    US7521457B2|2004-08-20|2009-04-21|Boehringer Ingelheim International Gmbh|Pyrimidines as PLK inhibitors|
    GB0419160D0|2004-08-27|2004-09-29|Novartis Ag|Organic compounds|
    ES2371924T3|2004-09-30|2012-01-11|Tibotec Pharmaceuticals|PYRIMIDINES 5-CARBO OR HETEROCICLO- SUBSTITUTES THAT INHIBIT HIV.|
    WO2006076646A2|2005-01-14|2006-07-20|Neurogen Corporation|Heteroaryl substituted quinolin-4-ylamine analogues|
    US20070032514A1|2005-07-01|2007-02-08|Zahn Stephan K|2,4-diamino-pyrimidines as aurora inhibitors|
    EP1934200A1|2005-09-15|2008-06-25|Merck & Co., Inc.|Tyrosine kinase inhibitors|
    EP1968950A4|2005-12-19|2010-04-28|Genentech Inc|Pyrimidine kinase inhibitors|
    FR2896503B1|2006-01-23|2012-07-13|Aventis Pharma Sa|NOVEL CYCLIC UREA SULFUR DERIVATIVES, THEIR PREPARATION AND THEIR PHARMACEUTICAL USE AS INHIBITORS OF KINASES|
    US7569561B2|2006-02-22|2009-08-04|Boehringer Ingelheim International Gmbh|2,4-diaminopyrimidines useful for treating cell proliferation diseases|
    EP2007752B1|2006-03-31|2010-08-18|Janssen Pharmaceutica NV|Benzoimidazol-2-yl pyrimidines and pyrazines as modulators of the histamine h4 receptor|
    GB0619343D0|2006-09-30|2006-11-08|Vernalis R & D Ltd|New chemical compounds|
    WO2008040951A1|2006-10-03|2008-04-10|Astrazeneca Ab|Compounds|
    EP2089384B1|2006-12-13|2015-08-05|F. Hoffmann-La Roche AG|2--4-phenoxy-or phenylamino-pyrimidine derivatives as non-nucleoside reverse transcriptase inhibitors|
    US20100144732A1|2006-12-19|2010-06-10|Krueger Elaine B|Pyrimidine kinase inhibitors|
    CA2702647C|2007-01-31|2016-03-22|Ym Biosciences Australia Pty Ltd|Thiopyrimidine-based compounds and uses thereof|
    DK2154967T5|2007-04-16|2014-11-17|Hutchison Medipharma Entpr Ltd|Pyriminderivater|
    CA2718858A1|2008-03-20|2009-09-24|Boehringer Ingelheim International Gmbh|Selective synthesis of substituted pyrimidines|
    CA2727455C|2008-06-27|2019-02-12|Avila Therapeutics, Inc.|Heteroaryl compounds and uses thereof|
    AR074210A1|2008-11-24|2010-12-29|Boehringer Ingelheim Int|PIRIMIDINE DERIVATIVES AS INHIBITORS OF PTK2-QUINASA|
    AR074209A1|2008-11-24|2010-12-29|Boehringer Ingelheim Int|USEFUL PYRIMIDINE DERIVATIVES FOR CANCER TREATMENT|
    US9908884B2|2009-05-05|2018-03-06|Dana-Farber Cancer Institute, Inc.|EGFR inhibitors and methods of treating disorders|AR074209A1|2008-11-24|2010-12-29|Boehringer Ingelheim Int|USEFUL PYRIMIDINE DERIVATIVES FOR CANCER TREATMENT|
    AR074210A1|2008-11-24|2010-12-29|Boehringer Ingelheim Int|PIRIMIDINE DERIVATIVES AS INHIBITORS OF PTK2-QUINASA|
    US8933227B2|2009-08-14|2015-01-13|Boehringer Ingelheim International Gmbh|Selective synthesis of functionalized pyrimidines|
    US8729265B2|2009-08-14|2014-05-20|Boehringer Ingelheim International Gmbh|Regioselective preparation of 2-amino-5-trifluoromethylpyrimidine derivatives|
    US20120244141A1|2010-09-28|2012-09-27|Boehringer Ingelheim International Gmbh|Stratification of cancer patients for susceptibility to therapy with PTK2 inhibitors|
    ES2691673T3|2011-02-17|2018-11-28|Cancer Therapeutics Crc Pty Limited|Fak inhibitors|
    CN103534240B|2011-02-17|2015-12-09|癌症疗法Crc私人有限公司|Selectivity Fak inhibitor|
    JPWO2013146963A1|2012-03-28|2015-12-14|武田薬品工業株式会社|Heterocyclic compounds|
    PT3043784T|2013-09-09|2019-08-02|Peloton Therapeutics Inc|Aryl ethers and uses thereof|
    US10512626B2|2015-03-11|2019-12-24|Peloton Therapeautics, Inc.|Compositions for use in treating glioblastoma|
    US10278942B2|2015-03-11|2019-05-07|Peloton Therapeutics, Inc.|Compositions for use in treating pulmonary arterial hypertension|
    EP3268362B1|2015-03-11|2021-10-20|Peloton Therapeutics, Inc.|Substituted pyridines and uses thereof|
    US10807948B2|2015-03-11|2020-10-20|Peloton Therapeutics, Inc.|Aromatic compounds and uses thereof|
    WO2016168510A1|2015-04-17|2016-10-20|Peloton Therapeutics, Inc.|Combination therapy of a hif-2-alpha inhibitor and an immunotherapeutic agent and uses thereof|
    US20170066778A1|2015-09-04|2017-03-09|Aunova Medchem LLC|Solubility for target compounds|
    WO2021098679A1|2019-11-18|2021-05-27|应世生物科技有限公司|Use of fak inhibitor in preparation of drug for treating tumors having nras mutation|
    TW202133852A|2019-11-28|2021-09-16|大陸商應世生物科技（南京）有限公司|Use of bi853520 in the treatment of cancer|
    WO2021155764A1|2020-02-05|2021-08-12|应世生物科技有限公司|Combination of bi853520 with chemotherapeutic drugs|
    WO2022028367A1|2020-08-03|2022-02-10|应世生物科技有限公司|Solid form of compound|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    EP08169807|2008-11-24|
    EP08169807|2008-11-24|
    EP09169654|2009-09-07|
    EP09169654|2009-09-07|
    PCT/EP2009/065768|WO2010058032A2|2008-11-24|2009-11-24|New compounds|
    [返回顶部]