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Alkynylpyrimidines and salts thereof, pharmaceutical compositions comprising same, methods of preparing same and uses of same
8524724 Alkynylpyrimidines and salts thereof, pharmaceutical compositions comprising same, methods of preparing same and uses of same
Patent Drawings:

Inventor: Hartung, et al.
Date Issued: September 3, 2013
Application:
Filed:
Inventors:
Assignee:
Primary Examiner: Murray; Jeffrey
Assistant Examiner:
Attorney Or Agent:
U.S. Class: 514/272; 544/324; 544/325
Field Of Search:
International Class: A01N 43/54; C07D 409/00; C07D 411/00; C07D 413/00; C07D 417/00; C07D 419/00; C07D 239/02; A61K 31/505; C07D 401/00; C07D 403/00; C07D 405/00
U.S Patent Documents:
Foreign Patent Documents: WO 2005/037800; WO 2005/060969; WO 2006/082371
Other References: Vippagunta et. al. Advanced Drug Delivery Reviews 48 (2001) 3-26. cited by examiner.
Wolff et. al., "Burger's Medicinal Chemistry and Drug Discovery," 5th Ed. Part 1, pp. 975-977 (1995). cited by examiner.
Banker, et. al., Modern Pharmaceuticals, (1996) p. 596. cited by examiner.









Abstract: The invention relates to alkynylpyrimidines according to the general formula (I): ##STR00001## in which A, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are as defined in the claims, and salts, N-oxides, metabolites, solvates, tautomers and prodrugs thereof, to pharmaceutical compositions comprising said alkynylpyrimidines, to methods of preparing said alkynylpyrimidines, as well as to uses thereof for manufacturing a pharmaceutical composition for the treatment of diseases of dysregulated vascular growth or of diseases which are accompanied with dysregulated vascular growth, wherein the compounds effectively interfere with Tie2 and VEGFR2 signalling.
Claim: The invention claimed is:

1. A compound of general formula (I): ##STR00196## in which R.sup.1 is selected from the group consisting of hydrogen, halogen, nitro, cyano, --C.sub.1-C.sub.6-alkyl,--C.sub.1-C.sub.6-alkylthio, --C.sub.1-C.sub.6-haloalkyl, C.sub.3-C.sub.10-cycloalkyl, --(CH.sub.2).sub.mOR.sup.c, --(CH.sub.2).sub.mNR.sup.d1R.sup.d2, and --(CH.sub.2).sub.mC(O)R.sup.b; R.sup.2 represents hydrogen, --C(O)R.sup.b, --S(O).sub.2R.sup.b,--P(O)(OR.sup.f).sub.2, or --S(O).sub.2--(CH.sub.2).sub.2--Si(R.sup.hR.sup.kR.sup.l), or is selected from the group consisting of --C.sub.1-C.sub.6-alkyl, --C.sub.2-C.sub.6-alkenyl, --C.sub.2-C.sub.6-alkynyl, --C.sub.3-C.sub.10-cycloalkyl, aryl,heteroaryl and --C.sub.3-C.sub.10-heterocycloalkyl, wherein said residues are unsubstituted or substituted one or more times independently from each other with halogen, nitro, cyano, --C.sub.1-C.sub.6-alkyl, aryl, heteroaryl, --OR.sup.c,--NR.sup.d1R.sup.d2--C.sub.1-C.sub.6-haloalkyl, --C(O)R.sup.b, or --S(O).sub.2R.sup.b; R.sup.3 is selected from the group consisting of --C.sub.1-C.sub.6-alkyl, --C.sub.2-C.sub.6-alkenyl, --C.sub.2-C.sub.6-alkynyl, aryl, heteraryl and--C.sub.3-C.sub.10-cycloalkyl, wherein said residues are unsubstituted or substituted one or more times independently from each other with halogen, nitro, cyano, --C.sub.1-C.sub.6-alkyl, aryl, heteraryl, --OR.sup.c, --NR.sup.d1R.sup.d2,--C.sub.1-C.sub.6-haloalkyl, --C(O)R.sup.b, or --S(O).sub.2R.sup.b; R.sup.4 is selected from the group consisting of hydrogen, --OR.sup.7, --SR.sub.7and --NR.sup.7R.sup.8; R.sup.5 is selected from the group consisting of hydrogen, halogen, nitro,cyano, --C.sub.1-C.sub.6-alkyl, --C.sub.3-C.sub.10-cycloalkyl, -C.sub.1-C.sub.6-haloalkyl, --C.sub.1-C.sub.6-alkylthio, --(CH.sub.2).sub.nOR.sup.f, --(CH.sub.2).sub.nNR.sup.sC(O)R.sup.m, --(CH.sub.2).sub.nNR.sup.sS(O).sub.2R.sup.m,--(CH.sub.2).sub.nNR.sup.g1R.sup.g2, --(CH.sub.2).sub.nC(O)R.sup.n, and --(CH.sub.2).sub.nS(O).sub.2R.sup.n; R.sup.6 is selected from the group consisting of hydrogen, halogen, nitro, cyano, hydroxyl, -C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.10-cycloalkyl,--C.sub.1-C.sub.6-haloalkyl, --C.sub.1-C.sub.6-haloalkoxy, --C.sub.1-C.sub.6-alkoxy, and --C.sub.1-C.sub.6-alkylthio; R.sup.7, R.sup.8 independently from each other are selected from the group consisting of hydrogen, --C.sub.1-C.sub.6-alkyl,--C.sub.2-C.sub.6-alkenyl, --C.sub.2-C.sub.6-alkynyl, --C.sub.3-C.sub.10-cycloalkyl, --(CH.sub.2).sub.p-aryl, --(CH.sub.2).sub.p-heteroaryl and --C.sub.3-C.sub.10-heterocycloalkyl, wherein said residues are unsubstituted or substituted one or more timesindependently from each other with halogen, nitro, cyano, --C.sub.1-C.sub.6-alkyl, --C.sub.3-C.sub.10-cycloalkyl, --C.sub.3-C.sub.10-heterocycloalkyl, aryl, heteroaryl, --OR.sup.c, --NR.sup.d1R.sup.d2, --C.sub.1-C.sub.6-haloalkyl, --C(O)R.sup.b, or--S(O).sub.2R.sup.b; or R.sup.7, R.sup.8 in the context of a NR.sup.7R.sup.8 group together with the nitrogen atom to which they are attached, form a 3 to 10 membered heterocycloalkyl ring, which is optionally substituted one or more times, the same wayor differently, with C.sub.1-C.sub.6-alkyl, --NR.sup.g1R.sup.g2--OR.sup.f, --C(O)R.sup.e, --S(O).sub.2R.sup.e, or --OP(O)(OR.sup.f).sub.2; whereby the carbon backbone of this heterocycloalkyl ring can optionally be interrupted one or more times, thesame way or differently, by NH, NR.sup.a, oxygen or sulphur, and can optionally be interrupted one or more times, the same way or differently, with a --C(O)--, --S(O)--, and/or --S(O).sub.2-group, and can optionally contain one or more double bonds; R.sup.a is selected from the group consisting of hydrogen, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-heterocycloalkyl, aryl, and heteroaryl, wherein C.sub.1-C.sub.6-alkyl, and C.sub.3-C.sub.10-cycloalkyl are optionallysubstituted one or more times with hydroxyl, halogen, or C.sub.1-C.sub.6-alkoxy; R.sup.b is selected from the group consisting of --OR.sup.c, --SR.sup.c, --NR.sup.d1R.sup.d2, aryl, heteroaryl, C.sub.1-C.sub.6-alkyl, and C.sub.3-C.sub.10-cycloalkyl,wherein C.sub.1-C.sub.6-alkyl, and C.sub.3-C.sub.10-cycloalkyl are optionally substituted one or more times with hydroxyl, halogen, --NR.sup.g1R.sup.g2or C.sub.1-C.sub.6-alkoxy; R.sup.c is selected from the group consisting of hydrogen, --C(O)R.sup.e,--S(O).sub.2R.sup.e, --P(O)(OR.sup.f).sub.2, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-heterocycloalkyl, aryl, and heteroaryl, wherein C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl,C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-heterocycloalkyl, aryl, and heteroaryl are optionally substituted one or more times with halogen, aryl, --OR.sup.f, --NR.sup.d1 R.sup.d2, or --OP(O)(OR.sup.f).sub.2; R.sup.d1, R.sup.d2 independently fromeach other are selected from the group consisting of hydrogen, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-heterocycloalkyl, aryl, and heteroaryl, or a group --C(O)R.sup.e or --S(O).sub.2R.sup.e wherein C.sub.1-C.sub.6-alkyl,C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-heterocycloalkyl, aryl, and heteroaryl are optionally substituted one or more times, the same way or differently with halogen, hydroxyl, aryl, --C.sub.1-C.sub.6-alkyl, --NR.sup.g1R.sup.g2, --OR.sup.f,--C(O)R.sup.e, --S(O).sub.2R.sup.e, or --OP(O)(OR.sup.f).sub.2; or R.sup.d1 and R.sup.d2 together with the nitrogen atom to which they are attached, form a 3 to 10 membered heterocycloalkyl ring, which is optionally substituted one or more times, thesame way or differently, with C.sub.1-C.sub.6-alkyl, --NR.sup.g1R.sup.g2, --OR.sup.f, --C(O)R.sup.e, --S(O).sub.2R.sup.e, or --OP(O)(OR.sup.f).sub.2; whereby the carbon backbone of this heterocycloalkyl ring can optionally be interrupted one or moretimes, the same way or differently, by NH, NR.sup.a, oxygen or sulphur, and can optionally be interrupted one or more times, the same way or differently, with a --C(O)--, --S(O)--, and/or --S(O).sub.2-group, and can optionally contain one or more doublebonds; R.sup.e is selected from the group consisting of, --NR.sup.g1R.sup.g2, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.1-C.sub.6-alkoxy, aryl and heteroaryl; R.sup.f is selected from the group consisting of hydrogen, --C(O)R.sup.e,C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-heterocycloalkyl, aryl, and heteroaryl, wherein C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.3-C.sub.10-cycloalkyl,C.sub.3-C.sub.10-heterocycloalkyl, aryl, and heteroaryl are optionally substituted one or more times with hydroxyl, halogen, C.sub.1-C.sub.6-alkoxy, aryl, or --NR.sup.g1R.sup.g2; R.sup.g1, R.sup.g2 independently from each other are selected from thegroup consisting of hydrogen, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.10-cycloalkyl, and C.sub.3-C.sub.10-heterocycloalkyl; or R.sup.g1 and R.sup.g2 together with the nitrogen atom to which they are attached, form a 3 to 10 membered heterocycloalkyl ring,which is optionally substituted one or more times, the same way or differently, with C.sub.1-C.sub.6-alkyl, --C.sub.1-C.sub.6-alkoxy, or hydroxy; whereby the carbon backbone of this heterocycloalkyl ring can optionally be interrupted one or more times,the same way or differently, by NH, NR.sup.a, oxygen or sulphur, and can optionally be interrupted one or more times, the same way or differently, with a --C(O)--, --S(O)--, and/or --S(O).sub.2-group, and can optionally contain one or more double bonds; R.sup.h, R.sup.k,and R.sup.l independently from each other represent --C.sub.1-C.sub.6-alkyl or phenyl; R.sup.m is selected from the group consisting of C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.10-cycloalkyl and C.sub.3-C.sub.10-heterocycloalkyl; R.sup.nis selected from the group consisting of --NR.sup.g1R.sup.g2, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl, hydroxyl and C.sub.1-C.sub.6-alkoxy; R.sup.s represents hydrogen or C.sub.1-C.sub.6-alkyl A represents aryl or heteroaryl; m represent aninteger of 0, 1 or 2; n represent an integer of 0, 1 or 2; p represent an integer of 0, 1 or 2; wherein each occurrence of R.sup.a, R.sup.b, R.sup.c, R.sup.d1, R.sup.d2, R.sup.e, R.sup.f, R.sup.g1 or R.sup.g2 may be the same or different; or a saltor tautomer thereof.

2. The compound according to claim 1, wherein: R.sup.1 represents hydrogen; R.sup.2 represents hydrogen, --C(O)R.sup.b, --S(O).sub.2R.sup.b, --P(O)(OR.sup.f).sub.2, or --S(O).sub.2--(CH.sub.2).sub.2--Si(R.sup.hR.sup.kR.sup.l), or is selectedfrom the group consisting of --C.sub.1-C.sub.6-alkyl, --C.sub.2-C.sub.6-alkenyl, --C.sub.2-C.sub.6-alkynyl, --C.sub.3-C.sub.10-cycloalkyl, aryl, heteroaryl and --C.sub.3-C.sub.10-heterocycloalkyl, wherein said residues are unsubstituted or substitutedone or more times independently from each other with halogen, nitro, cyano, --C.sub.1-C.sub.6-alkyl, aryl, heteroaryl, --OR.sup.c, --NR.sup.d1R.sup.d2, --C.sub.1-C.sub.6-haloalkyl, --C(O)R.sup.b, or --S(O).sub.2R.sup.b; R.sup.3 is selected from thegroup consisting of --C.sub.1-C.sub.6-alkyl, --C.sub.2-C.sub.6-alkenyl, --C.sub.2-C.sub.6-alkynyl, aryl, heteraryl and --C.sub.3-C.sub.10-cycloalkyl, wherein said residues are unsubstituted or substituted one or more times independently from each otherwith halogen, nitro, cyano, --C.sub.1-C.sub.6-alkyl, aryl heteraryl, --OR.sup.c, --NR.sup.d1R.sup.d2, --C.sub.1-C.sub.6-haloalkyl, --C(O)R.sup.b, or --S(O).sub.2R.sup.b; R.sup.4 is selected from the group consisting of hydrogen, --OR.sup.7, --SR.sup.7and --NR.sup.7R.sup.8; R.sup.5 is selected from the group consisting of hydrogen, halogen, nitro, cyano, --C.sub.1-C.sub.6-alkyl, --C.sub.3-C.sub.10-cycloalkyl, --C.sub.1-C.sub.6-haloalkyl, --C.sub.1-C.sub.6-alkylthio , --(CH.sub.2).sub.nOR.sup.f,--(CH.sub.2).sub.nNR.sup.sC(O)R.sup.m, --(CH.sub.2).sub.nNR.sup.sS(O).sub.2R.sup.m, --(CH.sub.2).sub.nNR.sup.g1R.sup.g2, --(CH.sub.2).sub.nC(O)R.sup.n, and --(CH.sub.2).sub.nS(O).sub.2R.sup.n; R.sup.6 is selected from the group consisting of hydrogen,halogen, nitro, cyano, hydroxyl, --C.sub.1-C.sub.6-alkyl, --C.sub.3-C.sub.10-cycloalkyl, --C.sub.1-C.sub.6-haloalkyl, --C.sub.1-C.sub.6-haloalkoxy, --C.sub.1-C.sub.6-alkoxy, and --C.sub.1-C.sub.6-alkylthio; R.sup.7, R.sup.8 independently from each otherare selected from the group consisting of hydrogen, --C.sub.1-C.sub.6-alkyl, --C.sub.2-C.sub.6-alkenyl, --C.sub.2-C.sub.6-alkynyl, --C.sub.3-C.sub.10-cycloalkyl, --(CH.sub.2).sub.p-aryl, -(CH.sub.2).sub.p-heteroaryl and--C.sub.3-C.sub.10-heterocycloalkyl, wherein said residues are unsubstituted or substituted one or more times independently from each other with halogen, nitro, cyano, --C.sub.1-C.sub.6-alkyl, --C.sub.3-C.sub.10-cycloalkyl ,--C.sub.3-C.sub.10-heterocycloalkyl, aryl, heteroaryl, --OR.sup.c, --NR.sup.d1R.sup.d2, --C.sub.1-C.sub.6-haloalkyl, --C(O)R.sup.b, or --S(O).sub.2R.sup.b; or R.sup.7, R.sup.8 in the context of a NR.sup.7R.sup.8 group together with the nitrogen atom towhich they are attached, form a 3 to 10 membered heterocycloalkyl ring, which is optionally substituted one or more times, the same way or differently, with C.sub.1-C.sub.6-alkyl, NR.sup.g1R.sup.g2, OR.sup.f, C(O)R.sup.e, --S(O).sub.2R.sup.e, or--OP(O)(OR.sup.f).sub.2; whereby the carbon backbone of this heterocycloalkyl ring can optionally be interrupted one or more times, the same way or differently, by NH, NR.sup.a, oxygen or sulphur, and can optionally be interrupted one or more times, thesame way or differently, with a -C(O)--, --S(O)--, and/or -S(O).sub.2-group, and can optionally contain one or more double bonds; R.sup.a is selected from the group consisting of hydrogen, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.10-cycloalkyl,C.sub.3-C.sub.10-heterocycloalkyl, aryl, and heteroaryl, wherein C.sub.1-C.sub.6-alkyl, and C.sub.3-C.sub.10-cycloalkyl are optionally substituted one or more times with hydroxyl, halogen, or C.sub.1-C.sub.6-alkoxy; R.sup.b is selected from the groupconsisting of --OR.sup.c, --SR.sup.c, --NR.sup.d1R.sup.d2, aryl, heteroaryl, C.sub.1-C.sub.6-alkyl, and C.sub.3-C.sub.10-cycloalkyl, wherein C.sub.1-C.sub.6-alkyl, and C.sub.3-C.sub.10-cycloalkyl are optionally substituted one or more times withhydroxyl, halogen, --NR.sup.g1R.sup.g2or C.sub.1-C.sub.6-alkoxy; R.sup.c is selected from the group consisting of hydrogen, --C(O)R.sup.e, --S(O).sub.2R.sup.e, --P(O)(OR.sup.f).sub.2, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkylC.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-heterocycloalkyl, aryl, and heteroaryl, wherein C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-heterocycloalkyl, aryl, and heteroaryl are optionallysubstituted one or more times with halogen, aryl, --OR.sup.f, --NR.sup.d1R.sup.d2, or --OP(O)(OR.sup.f).sub.2; R.sup.d1, R.sup.d2 independently from each other are selected from the group consisting of hydrogen, C.sub.1-C.sub.6-alkyl,C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-heterocycloalkyl, aryl, and heteroaryl, or for a group --C(O)R.sup.e or --S(O).sub.2R.sup.e wherein C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-heterocycloalkyl, aryl, and heteroarylare optionally substituted one or more times, the same way or differently with halogen, hydroxy or the group aryl, --C.sub.1-C.sub.6-alkyl, --NR.sup.g1R.sup.g2, --OR.sup.f, --C(O)R.sup.e, --S(O).sub.2R.sup.e, or --OP(O)(OR.sup.f).sub.2; or R.sup.d1 andR.sup.d2 together with the nitrogen atom to which they are attached, form a 3 to 10 membered heterocycloalkyl ring, which is optionally substituted one or more times, the same way or differently, with C.sub.1-C.sub.6-alkyl, --NR.sup.g1R.sup.g2,--OR.sup.f, --C(O)R.sup.e, --S(O).sub.2R.sup.e, or --OP(O)(OR.sup.f).sub.2; whereby the carbon backbone of this heterocycloalkyl ring can optionally be interrupted one or more times, the same way or differently, by NH, NR.sup.a, oxygen or sulphur, andcan optionally be interrupted one or more times, the same way or differently, with a --C(O)--, --S(O)--, and/or --S(O).sub.2-group, and can optionally contain one or more double bonds; R.sup.e is selected from the group consisting of--NR.sup.g1R.sup.g2, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.1-C.sub.6-alkoxy, aryl and heteroaryl; R.sup.f is selected from the group consisting of hydrogen, --C(O)R.sup.e, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl,C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-heterocycloalkyl, aryl, and heteroaryl, wherein C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-heterocycloalkyl, aryl, and heteroaryl are optionallysubstituted one or more times with hydroxyl, halogen, C.sub.1-C.sub.6-alkoxy, aryl, or --NR.sup.g1R.sup.g2; R.sup.g1, R.sup.g2 independently from each other are selected from the group consisting of hydrogen, C.sub.1-C.sub.6-alkyl,C.sub.3-C.sub.10-cycloalkyl, and C.sub.3-C.sub.10-heterocycloalkyl; or R.sup.g1 and R.sup.g2 together with the nitrogen atom to which they are attached, form a 3 to 10 membered heterocycloalkyl ring, which is optionally substituted one or more times,the same way or differently, with C.sub.1-C.sub.6-alkyl, --C.sub.1-C.sub.6-alkoxy, or hydroxy; whereby the carbon backbone of this heterocycloalkyl ring can optionally be interrupted one or more times, the same way or differently, by NH, NR.sup.a,oxygen or sulphur, and can optionally be interrupted one or more times, the same way or differently, with a --C(O)--, --S(O)--, and/or --S(O).sub.2-group, and can optionally contain one or more double bonds; R.sup.h, R.sup.k, and R.sup.l independentlyfrom each other represent --C.sub.1-C.sub.6-alkyl or phenyl; R.sup.mis selected from the group consisting of C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.10-cycloalkyl and C.sub.3-C.sub.10-heterocycloalkyl; R.sup.nis selected from the group consisting of--NR.sup.g1R.sup.g2, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl, hydroxyl and C.sub.1-C.sub.6-alkoxy; R.sup.s represents hydrogen or C.sub.1-C.sub.6-alkyl A represents aryl or heteroaryl; n represent an integer of 0, 1 or 2; p represent aninteger of 0, 1 or 2; wherein each occurrence of R.sup.a, R.sup.b, R.sup.c, R.sup.d1, R.sup.d2, R.sup.e, R.sup.f, R.sup.g1 or R.sup.g2 may be the same or different; or a salt or tautomer thereof.

3. The compound according to claim 1, wherein: R.sup.1 represents hydrogen; R.sup.2 represents hydrogen, --C(O)R.sup.b, or is selected from the group consisting of --C.sub.1-C.sub.6-alkyl, --C.sub.3-C.sub.6-cycloalkyl, aryl and--C.sub.3-C.sub.6-heterocycloalkyl, wherein said residues are unsubstituted or substituted once with halogen, cyano, --C.sub.1-C.sub.6-alkyl, --OR.sup.c, --NR .sub.d1R.sup.d2, --C.sub.1-C.sub.6-haloalkyl; R.sup.3 is selected from the group consisting of--C.sub.1-C.sub.6-alkyl, --C.sub.2-C.sub.6-alkenyl, --C.sub.2-C.sub.6-alkynyl, aryl, heteraryl and --C.sub.3-C.sub.10-cycloalkyl, wherein said residues are unsubstituted or substituted one or more times independently from each other with halogen, nitro,cyano, --C.sub.1-C.sub.6-alkyl, aryl, heteraryl, --OR.sup.c, --NR.sup.d1R.sup.d2, --C.sub.1-C.sub.6-haloalkyl, --C(O)R.sup.b, or --S(O).sub.2R.sup.b; R.sup.4 is selected from the group consisting of hydrogen, --OR.sup.7, --SR.sup.7 and--NR.sup.7R.sup.8; R.sup.5 is selected from the group consisting of hydrogen, halogen, nitro, cyano, --C.sub.1-C.sub.6-alkyl, --C.sub.3-C.sub.10-cycloalkyl, --C.sub.1-C.sub.6-haloalkyl, --C.sub.1-C.sub.6-alkylthio , --(CH.sub.2)OR.sup.f,--(CH.sub.2).sub.nNR.sup.sC(O)R.sup.m, --(CH.sub.2).sub.nNR.sup.sS(O).sub.2R.sup.m, --(CH.sub.2).sub.nNR.sup.g1R.sup.g2, --(CH.sub.2).sub.nC(O)R.sup.n, and --(CH.sub.2).sub.nS(O).sub.2R.sup.n; R.sup.6 is selected from the group consisting of hydrogen,halogen, nitro, cyano, hydroxyl, --C.sub.1-C.sub.6-alkyl, --C.sub.3-C.sub.10-cycloalkyl, --C.sub.1-C.sub.6-haloalkyl, --C.sub.1-C.sub.6-haloalkoxy, --C.sub.1-C.sub.6-alkoxy, and -C.sub.1-C.sub.6-alkylthio; R.sup.7, R.sup.8 independently from each otherare selected from the group consisting of hydrogen, --C.sub.1-C.sub.6-alkyl, --C.sub.2-C.sub.6-alkenyl, --C.sub.2-C.sub.6-alkynyl, --C.sub.3-C.sub.10-cycloalkyl, --(CH.sub.2).sub.p-aryl, --(CH.sub.2).sub.p-heteroaryl and--C.sub.3-C.sub.10-heterocycloalkyl, wherein said residues are unsubstituted or substituted one or more times independently from each other with halogen, nitro, cyano, --C.sub.1-C.sub.6-alkyl, --C.sub.3-C.sub.10-cycloalkyl ,--C.sub.3-C.sub.10-heterocycloalkyl, aryl, heteroaryl, --OR.sup.c, --NR.sup.d1R.sup.d2, C.sub.1-C.sub.6-haloalkyl, --C(O)R.sup.b, or --S(O).sub.2R.sup.b; or R.sup.7, R.sup.8 in the context of a NR.sup.7R.sup.8 group together with the nitrogen atom towhich they are attached, form a 3 to 10 membered heterocycloalkyl ring, which is optionally substituted one or more times, the same way or differently, with C.sub.1-C.sub.6-alkyl, --NR.sup.g1R.sup.g2--OR.sup.f, --C(O)R.sup.e, --S(O).sub.2R.sup.e, or--OP(O)(OR.sup.f).sub.2; whereby the carbon backbone of this heterocycloalkyl ring can optionally be interrupted one or more times, the same way or differently, by NH, NR.sup.a, oxygen or sulphur, and can optionally be interrupted one or more times, thesame way or differently, with a --C(O)--, --S(O)--, and/or --S(O).sub.2-group, and can optionally contain one or more double bonds; R.sup.a is selected from the group consisting of hydrogen, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.10-cycloalkyl,C.sub.3-C.sub.10-heterocycloalkyl, aryl, and heteroaryl, wherein C.sub.1-C.sub.6-alkyl, and C.sub.3-C.sub.10-cycloalkyl are optionally substituted one or more times with hydroxyl, halogen, or C.sub.1-C.sub.6-alkoxy; R.sup.b is selected from the groupconsisting of --OR.sup.c, --SR.sup.c, --NR.sup.d1R.sup.d2 aryl, heteroaryl, C.sub.1-C.sub.6-alkyl, and C.sub.3-C.sub.10-cycloalkyl, wherein C.sub.1-C.sub.6-alkyl, and C.sub.3-C.sub.10-cycloalkyl are optionally substituted one or more times with hydroxyl,halogen, --NR.sup.g1R.sup.g2 or C.sub.1-C.sub.6-alkoxy; R.sup.c is selected from the group consisting of hydrogen, --C(O)R.sup.e, --S(O).sub.2R.sup.e, --P(O)(OR.sup.f).sub.2, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl C.sub.3-C.sub.10-cycloalkyl,C.sub.3-C.sub.10-heterocycloalkyl, aryl, and heteroaryl, wherein C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-heterocycloalkyl, aryl, and heteroaryl are optionally substituted one or more times withhalogen, aryl, --OR.sup.f, --NR.sup.d1R.sup.d2, or --OP(O)(OR.sup.f).sub.2; R.sup.d1, R.sup.d2 independently from each other are selected from the group consisting of hydrogen, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.10-cycloalkyl,C.sub.3-C.sub.10-heterocycloalkyl, aryl, and heteroaryl, or a group --C(O)R.sup.e or --S(O).sub.2R.sup.e wherein C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-heterocycloalkyl, aryl, and heteroaryl are optionally substituted one ormore times, the same way or differently with halogen, hydroxy or the group aryl, --C.sub.1-C.sub.6-alkyl, --NR.sup.g1R.sup.g2, --OR.sup.f, --C(O)R.sup.e, --S(O).sub.2R.sup.e, or --OP(O)(OR.sup.f).sub.2; or R.sup.d1 and R.sup.d2 together with thenitrogen atom to which they are attached, form a 3 to 10 membered heterocycloalkyl ring, which is optionally substituted one or more times, the same way or differently, with C.sub.1-C.sub.6-alkyl, --NR.sup.g1R.sup.g2, --OR.sup.f, --C(O)R.sup.e,--S(O).sub.2R.sup.e, or --OP(O)(OR.sup.f).sub.2; whereby the carbon backbone of this heterocycloalkyl ring can optionally be interrupted one or more times, the same way or differently, by NH, NR.sup.a, oxygen or sulphur, and can optionally beinterrupted one or more times, the same way or differently, with a --C(O)--, --S(O)--, and/or --S(O).sub.2-group, and can optionally contain one or more double bonds; R.sup.e is selected from the group consisting of --NR.sup.g1R.sup.g2,C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.1-C.sub.6-alkoxy, aryl and heteroaryl; R.sup.f is selected from the group consisting of hydrogen, --C(O)R.sup.e, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.3-C.sub.10-cycloalkyl,C.sub.3-C.sub.10-heterocycloalkyl, aryl, and heteroaryl, wherein C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-heterocycloalkyl, aryl, and heteroaryl are optionally substituted one or more times withhydroxyl, halogen, C.sub.1-C.sub.6-alkoxy, aryl, or --NR.sup.g1R.sup.g2; Rg.sup.1, Rg.sup.2 independently from each other are selected from the group consisting of hydrogen, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.10-cycloalkyl,C.sub.3-C.sub.10-heterocycloalkyl; or R.sup.g1 and R.sup.g2 together with the nitrogen atom to which they are attached, form a 3 to 10 membered heterocycloalkyl ring, which is optionally substituted one or more times, the same way or differently, withC.sub.1-C.sub.6-alkyl, --C.sub.1-C.sub.6-alkoxy, or hydroxy; whereby the carbon backbone of this heterocycloalkyl ring can optionally be interrupted one or more times, the same way or differently, by NH, NR.sup.a, oxygen or sulphur, and can optionallybe interrupted one or more times, the same way or differently, with a --C(O)--, --S(O)--, and/or --S(O).sub.2-group, and can optionally contain one or more double bonds; R.sup.mis selected from the group consisting of C.sub.1-C.sub.6-alkyl,C.sub.3-C.sub.10-cycloalkyl and C.sub.3-C.sub.10-heterocycloalkyl; R.sup.n is selected from the group consisting of --NR.sup.g1R.sup.g2, --C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl, hydroxyl and --C.sub.1-C.sub.6-alkoxy; R.sup.s representshydrogen or C.sub.1-C.sub.6-alkyl A represents aryl or heteroaryl; n represent an integer of 0, 1 or 2; P represent an integer of 0, 1 or 2; wherein each occurrence of R.sup.a , R.sup.b, R.sup.c, R.sup.d1, R.sup.d2, R.sup.e , R.sup.f, R.sup.g1 orR.sup.g2 may be the same or different; or a salt or tautomer thereof.

4. The compound according to any claim 1, wherein: R.sup.1 represents hydrogen; R.sup.2 represents hydrogen, --C(O)R.sup.b, or is selected from the group consisting of --C.sub.1-C.sub.6-alkyl, --C.sub.3-C.sub.6-cycloalkyl, aryl and--C.sub.3-C.sub.6-heterocycloalkyl, wherein said residues are unsubstituted or substituted once with halogen, cyano, --C.sub.1-C.sub.6-alkyl, --OR.sup.c, --NR.sup.d1R.sup.d2, C.sub.1-C.sub.6-haloalkyl; R.sup.3 is selected from the group consisting of--C.sub.1-C.sub.6-alkyl, phenyl and --C.sub.3-C.sub.6-cycloalkyl, wherein said residues are unsubstituted or substituted once with halogen, cyano, --C.sub.1-C.sub.6-alkyl, --OR.sup.c, --NR.sup.d1R.sup.d2, --C.sub.1-C.sub.6-haloalkyl; R.sup.4 is selectedfrom the group consisting of hydrogen, --OR.sup.7, --SR.sup.7 and --NR.sup.7R.sup.8; R.sup.5 is selected from the group consisting of hydrogen, halogen, nitro, cyano, --C.sub.1-C.sub.6-alkyl, --C.sub.3-C.sub.10-cycloalkyl, --C.sub.1-C.sub.6-haloalkyl,--C.sub.1-C.sub.6-alkylthio, --(CH.sub.2)OR.sup.f, --(CH.sub.2).sub.nNR.sup.sC(O)R.sup.m, --(CH.sub.2).sub.nNR.sup.sS(O).sub.2R.sup.m, --(CH.sub.2).sub.nNR.sup.g1R.sup.g2, --(CH.sub.2).sub.nC(O)R.sup.n, and --(CH.sub.2).sub.nS(O).sub.2R.sup.n; R.sup.6is selected from the group consisting of hydrogen, halogen, nitro, cyano, hydroxyl, --C.sub.1-C.sub.6-alkyl, --C.sub.3-C.sub.10-cycloalkyl, --C.sub.1-C.sub.6-haloalkyl, --C.sub.1-C.sub.6-haloalkoxy, --C.sub.1-C.sub.6-alkoxy, and--C.sub.1-C.sub.6-alkylthio; R.sup.7, R.sup.8 independently from each other are selected from the group consisting of hydrogen, --C.sub.1-C.sub.6-alkyl, --C.sub.2-C.sub.6-alkenyl, --C.sub.2-C.sub.6-alkynyl, --C.sub.3-C.sub.10-cycloalkyl,--(CH.sub.2).sub.p-aryl, --(CH.sub.2).sub.p-heteroaryl and --C.sub.3-C.sub.10-heterocycloalkyl, wherein said residues are unsubstituted or substituted one or more times independently from each other with halogen, nitro, cyano, --C.sub.1-C.sub.6-alkyl,--C.sub.3-C.sub.10-cycloalkyl, --C.sub.3-C.sub.10-heterocycloalkyl, aryl, heteroaryl, --OR.sup.c, --NR.sup.d1R.sup.d2, --C.sub.1-C.sub.6-haloalkyl, --C(O)R.sup.b, or --S(O).sub.2R.sup.b; or R.sup.7, R.sup.8 in the context of a NR.sup.7R.sup.8 grouptogether with the nitrogen atom to which they are attached, form a 3 to 10 membered heterocycloalkyl ring, which is optionally substituted one or more times, the same way or differently, with C.sub.1-C.sub.6-alkyl, --NR.sup.g1R.sup.g2, --OR.sup.f,--C(O)R.sup.e, --S(O).sub.2R.sup.e, or --OP(O)(OR.sup.f).sub.2; whereby the carbon backbone of this heterocycloalkyl ring can optionally be interrupted one or more times, the same way or differently, by NH, NR.sup.a, oxygen or sulphur, and canoptionally be interrupted one or more times, the same way or differently, with a --C(O)--, --S(O)--, and/or --S(O).sub.2-group, and can optionally contain one or more double bonds; R.sup.a is selected from the group consisting of hydrogen,C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-heterocycloalkyl, aryl, and heteroaryl, wherein C.sub.1-C.sub.6-alkyl, and C.sub.3-C.sub.10-cycloalkyl are optionally substituted one or more times with hydroxyl, halogen, orC.sub.1-C.sub.6-alkoxy; R.sup.b is selected from the group consisting of --OR.sup.c, --SR.sup.c, --NR.sup.d1R.sup.d2, aryl, heteroaryl, C.sub.1-C.sub.6-alkyl, and C.sub.3-C.sub.10-cycloalkyl, wherein C.sub.1-C.sub.6-alkyl, andC.sub.3-C.sub.10-cycloalkyl are optionally substituted one or more times with hydroxyl, halogen, --NR.sup.g1R.sup.g2 or C.sub.1-C.sub.6-alkoxy; R.sup.c is selected from the group consisting of hydrogen, --C(O)R.sup.e, --S(O).sub.2R.sup.e,--P(O)(OR.sup.f).sub.2, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-heterocycloalkyl, aryl, and heteroaryl, wherein C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.3-C.sub.10-cycloalkyl,C.sub.3-C.sub.10-heterocycloalkyl, aryl, and heteroaryl are optionally substituted one or more times with halogen, aryl, --OR.sup.f, ----NR.sup.d1R.sup.d2, or --OP(O)(OR.sup.f).sub.2; R.sub.d1, R.sup.d2 independently from each other are selected fromthe group consisting of hydrogen, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-heterocycloalkyl, aryl, and heteroaryl, or for a group --C(O)R.sup.e or --S(O).sub.2R.sup.e wherein C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.10-cycloalkyl,C.sub.3-C.sub.10-heterocycloalkyl, aryl, and heteroaryl are optionally substituted one or more times, the same way or differently with halogen, hydroxy or the group aryl, --C.sub.1-C.sub.6-alkyl, --NR.sup.g1R.sup.g2, --OR.sup.f, --C(O)R.sup.e,--S(O).sub.2R.sup.e, or --OP(O)(OR.sup.f).sub.2; or R.sup.d1 and R.sup.d2 together with the nitrogen atom to which they are attached, form a 3 to 10 membered heterocycloalkyl ring, which is optionally substituted one or more times, the same way ordifferently, with C.sub.1-C.sub.6-alkyl, --NR.sup.g1R.sup.g2, --OR.sup.f, --C(O)R.sup.e, --S(O).sub.2R.sup.e, or --OP(O)(OR.sup.f).sub.2; whereby the carbon backbone of this heterocycloalkyl ring can optionally be interrupted one or more times, the sameway or differently, by NH, NR.sup.a, oxygen or sulphur, and can optionally be interrupted one or more times, the same way or differently, with a --C(O)--, --S(O)--, and/or --S(O).sub.2-group, and can optionally contain one or more double bonds; R.sup.eis selected from the group consisting of --NR.sup.g1Rg.sup.g2, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.1-C.sub.6-alkoxy, aryl and heteroaryl; R.sup.f is selected from the group consisting of hydrogen, --C(O)R.sup.e,C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-heterocycloalkyl, aryl, and heteroaryl, wherein C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.3-C.sub.10-cycloalkyl,C.sub.3-C.sub.10-heterocycloalkyl, aryl, and heteroaryl are optionally substituted one or more times with hydroxyl, halogen, C.sub.1-C.sub.6-alkoxy, aryl, or --NR.sup.g1R.sup.g2; R.sup.g1, R.sup.g2 independently from each other are selected from thegroup consisting of hydrogen, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-hetero cycloalkyl; or R.sup.g1 and R.sup.g2 together with the nitrogen atom to which they are attached, form a 3 to 10 membered heterocycloalkyl ring,which is optionally substituted one or more times, the same way or differently, with C.sub.1-C.sub.6-alkyl, --C.sub.1-C.sub.6-alkoxy, or hydroxy; whereby the carbon backbone of this heterocycloalkyl ring can optionally be interrupted one or more times,the same way or differently, by NH, NR.sup.a, oxygen or sulphur, and can optionally be interrupted one or more times, the same way or differently, with a --C(O)--, --S(O)--, and/or --S(O).sub.2-group, and can optionally contain one or more double bonds; R.sup.mis selected from the group consisting of C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.10-cycloalkyl and C.sub.3-C.sub.10-heterocycloalkyl; R.sup.n is selected from the group consisting of --NR.sup.g1R.sup.g2, C.sub.1-C.sub.6-alkyl,C.sub.3-C.sub.6-cycloalkyl, hydroxyl and C.sub.1-C.sub.6-alkoxy; R.sup.S represents hydrogen or C.sub.1-C.sub.6-alkyl A represents aryl or heteroaryl; n represent an integer of 0, 1 or 2; p represent an integer of 0, 1 or 2; wherein each occurrenceof R.sup.a, R.sup.b, R.sup.c, R.sup.d1, R.sup.d2, R.sup.e , R.sup.f, R.sup.g1 or R.sup.g2 may be the same or different; or a salt or tautomer thereof.

5. The compound according to claim 1, wherein: R.sup.1 represents hydrogen; R.sup.2 represents hydrogen, --C(O)R.sup.b, or is selected from the group consisting of --C.sub.1-C.sub.6-alkyl, --C.sub.3-C.sub.6-cycloalkyl, wherein said residuesare unsubstituted or substituted once with C.sub.1-C.sub.6-alkyl, --OR.sup.c, or --NR.sup.d1R.sup.d2; R.sup.3 is selected from the group consisting of --C.sub.1-C.sub.6-alkyl, phenyl and --C.sub.3-C.sub.6-cycloalkyl, wherein said residues areunsubstituted or substituted once with halogen, --C.sub.1-C.sub.6-alkyl, --OR.sup.c, or --NR.sup.d1R.sup.d2; R.sup.4 is selected from the group consisting of hydrogen, --OR.sup.7, --SR.sup.7 and --NR.sup.7R.sup.8; R.sup.5 is selected from the groupconsisting of hydrogen, halogen, nitro, cyano, --C.sub.1-C.sub.6-alkyl, --C.sub.3-C.sub.10-cycloalkyl, --C.sub.1-C.sub.6-haloalkyl, --C.sub.1-C.sub.6-alkylthio , --(CH.sub.2)OR.sup.f, --(CH.sub.2).sub.nNR.sup.sC(O)R.sup.m,--(CH.sub.2).sub.nNR.sup.sS(O).sub.2R.sup.m, --(CH.sub.2).sub.nNR.sup.g1R.sup.g2, --(CH.sub.2).sub.nC(O)R.sup.n, and --(CH.sub.2).sub.nS(O).sub.2R.sup.n; R.sup.6 is selected from the group consisting of hydrogen, halogen, nitro, cyano, hydroxyl,---C.sub.1-C.sub.6-alkyl, --C.sub.3-C.sub.10-cycloalkyl, --C.sub.1-C.sub.6-haloalkyl, --C.sub.1-C.sub.6-haloalkoxy, --C.sub.1-C.sub.6-alkoxy, and -C.sub.1-C.sub.6-alkylthio; R.sup.7, R.sup.8 independently from each other are selected from the groupconsisting of hydrogen, --C.sub.1-C.sub.6-alkyl, --C.sub.2-C.sub.6-alkenyl, --C.sub.2-C.sub.6-alkenyl, --C.sub.3-C.sub.10-cycloalkyl, --(CH.sub.2).sub.p-aryl, --(CH.sub.2).sub.p-heteroaryl and --C.sub.3-C.sub.10-heterocycloalkyl, wherein said residuesare unsubstituted or substituted one or more times independently from each other with halogen, nitro, cyano, --C.sub.1-C.sub.6-alkyl, --C.sub.3-C.sub.10-cycloalkyl, --C.sub.3-C.sub.10-heterocycloalkyl, aryl, heteroaryl, --OR.sup.c, --NR.sub.d1R.sub.d2,--C.sub.1 -C.sub.6-haloalkyl, --C(O)R.sup.b, or --S(O).sub.2R.sup.b; or R.sup.7, R.sup.8 in the context of a NR.sup.7R.sup.8 group together with the nitrogen atom to which they are attached, form a 3 to 10 membered heterocycloalkyl ring, which isoptionally substituted one or more times, the same way or differently, with C.sub.1-C.sub.6-alkyl, --NR.sup.g1R.sup.g2, --OR.sup.f, --C(O)R.sup.e, --S(O).sub.2R.sup.e, or --OP(O)(OR.sup.f).sub.2; whereby the carbon backbone of this heterocycloalkyl ringcan optionally be interrupted one or more times, the same way or differently, by NH, NR.sup.a, oxygen or sulphur, and can optionally be interrupted one or more times, the same way or differently, with a --C(O)--,--S(O)--, and/or --S(O).sub.2-group, andcan optionally contain one or more double bonds; R.sup.a is selected from the group consisting of hydrogen, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.10-cycloalkyl, C.sub.3C.sub.10-heterocycloalkyl, aryl, and heteroaryl, wherein C.sub.1-C.sub.6-alkyl, andC.sub.3-C.sub.10-cycloalkyl are optionally substituted one or more times with hydroxyl, halogen, or C.sub.1-C.sub.6-alkoxy; R.sup.b is selected from the group consisting of --OR.sup.c, --SR.sup.c, --NR.sup.d1R.sup.d2, aryl, heteroaryl,C.sub.1-C.sub.6-alkyl, and C.sub.3-C.sub.10-cycloalkyl, wherein C.sub.1-C.sub.6-alkyl, and C.sub.3-C.sub.10-cycloalkyl are optionally substituted one or more times with hydroxyl, halogen, --NR.sup.g1R.sup.g2 or C.sub.1-C.sub.6-alkoxy; R.sup.c isselected from the group consisting of hydrogen, --C(O)R.sup.e, --S(O).sub.2R.sup.e, --P(O)(OR.sup.f).sub.2, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-heterocycloalkyl, aryl, and heteroaryl, whereinC.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-heterocycloalkyl, aryl, and heteroaryl are optionally substituted one or more times with halogen, aryl, --OR.sup.f, --NR.sup.d1R.sup.d2, or--OP(O)(OR.sup.f).sub.2; R.sup.d1, R.sup.d2 independently from each other are selected from the group consisting of hydrogen, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-heterocycloalkyl, aryl, and heteroaryl, or for a group--C(O)R.sup.e or --S(O).sub.2R.sup.e wherein C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-heterocycloalkyl, aryl, and heteroaryl are optionally substituted one or more times, the same way or differently with halogen, hydroxy orthe group aryl, --C.sub.1-C.sub.6-alkyl, --NR.sup.g1R.sup.g2OR.sup.f, --C(O)R.sup.e, --S(O).sub.2R.sup.e, or --OP(O)(OR.sup.f).sub.2; or R.sup.d1 and R.sup.d2 together with the nitrogen atom to which they are attached, form a 3 to 10 memberedheterocycloalkyl ring, which is optionally substituted one or more times, the same way or differently, with C.sub.1-C.sub.6-alkyl, --NR.sup.g1R.sup.g2--OR.sup.f, --C(O)R.sup.e, --S(O).sub.2R.sup.e, or --OP(O)(OR.sup.f).sub.2; whereby the carbon backboneof this heterocycloalkyl ring can optionally be interrupted one or more times, the same way or differently, by NH, NR.sup.a, oxygen or sulphur, and can optionally be interrupted one or more times, the same way or differently, with a --C(O)--, --S(O)--,and/or --S(O).sub.2-group, and can optionally contain one or more double bonds; R.sup.e is selected from the group consisting of --NR.sup.g1R.sup.g2, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.1-C.sub.6-alkoxy, aryl and heteroaryl; R.sup.f is selected from the group consisting of hydrogen, --C(O)R.sup.e, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-heterocycloalkyl, aryl, and heteroaryl, wherein C.sub.1-C.sub.6-alkyl,C.sub.1-C.sub.6-haloalkyl, C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-heterocycloalkyl, aryl, and heteroaryl are optionally substituted one or more times with hydroxyl, halogen, C.sub.1-C.sub.6-alkoxy, aryl, or --NR.sup.g1R.sup.g2; R.sup.g1, R.sup.g2independently from each other are selected from the group consisting of hydrogen, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-hetero cycloalkyl; or R.sup.g1and R.sup.g2 together with the nitrogen atom to which they are attached,form a 3 to 10 membered heterocycloalkyl ring, which is optionally substituted one or more times, the same way or differently, with C.sub.1-C.sub.6-alkyl, --C.sub.1-C.sub.6-alkoxy, or hydroxy; whereby the carbon backbone of this heterocycloalkyl ringcan optionally be interrupted one or more times, the same way or differently, by NH, NR.sup.a, oxygen or sulphur, and can optionally be interrupted one or more times, the same way or differently, with a --C(O)--, --S(O)--, and/or --S(O).sub.2-group, andcan optionally contain one or more double bonds; R.sup.mis selected from the group consisting of C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.10-cycloalkyl and C.sub.3-C.sub.10-heterocycloalkyl; R.sup.nis selected from the group consisting of--NR.sup.g1R.sup.g2, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl, hydroxyl and C.sub.1-C.sub.6-alkoxy; R.sup.s represents hydrogen or C.sub.1-C.sub.6-alkyl A represents aryl or heteroaryl; n represent an integer of 0, 1 or 2; p represent aninteger of 0, 1 or 2; wherein each occurrence of R.sup.a , R.sup.b, R.sup.c, R.sup.d1, R.sup.d2, R.sup.e , R.sup.f, R.sup.g1 or R.sup.g2 may be the same or different; or a salt or tautomer thereof.

6. The compound according to claim 1 selected from the group consisting of : (RS)-S-(4-[4-((R)-2-Hydroxy-1-methyl-ethylamino)-5-(4-methoxy-phenyl- ethynyl)-pyrimidin-2-ylamino]-phenyl)-S-methylsulfoximide; (RS)-S-(4-[4-((R)-2-Hydroxy-1-methyl-ethylamino)-5-(phenylethynyl)-pyrimi- din-2-ylamino]-phenyl)-S-methylsulfoximide; (RS)-S-(4-[4-((R)-2-Hydroxy-1-methyl-ethylamino)-5-(2-methyl-phenylethyny- l)-pyrimidin-2-ylamino]-phenyl)-S-methylsulfoximide; (RS)-S-(4-[4-((R)-2-Hydroxy-1-methyl-ethylamino)-5-(3-methyl-phenylethyny- l)-pyrimidin-2-ylamino]-phenyl)-S-methylsulfoximide; (RS)-S-(4-[4-((R)-2-Hydroxy-1-methyl-ethylamino)-5-(4-methyl-phenylethyny-l)-pyrimidin-2-ylamino]-phenyl)-S-methylsulfoximide; (RS)-S-(4-[4-((R)-2-Hydroxy-1-methyl-ethylamino)-5-(2-methoxy-phenylethyn- yl)-pyrimidin-2-ylamino]-phenyl)-S-methylsulfoximide; (RS)-S-(4-[4-((R)-2-Hydroxy-1-methyl-ethylamino)-5-(3-methoxy-phenylethyn- yl)-pyrimidin-2-ylamino]-phenyl)-S-methylsulfoximide; (RS)-S-(4-[5-(4-Ethyl-phenylethynyl)-4-((R)-2-hydroxy-1-methyl-ethylamino-)-pyrimidin-2-ylamino]-phenyl)-S-methylsulfoximide; (RS)-S-(4-[5-(4-Fluoro-phenyl-ethynyl)-4-((R)-2-hydroxy-1-methyl-ethylami- no)-pyrimidin-2-ylamino]-phenyl)-S-methylsulfoximide; (RS)-S-(4-[5-(4-Cyano-phenyl-ethynyl)-4-((R)-2-hydroxy-1-methyl-ethylamin- o)-pyrimidin-2-ylamino]-phenyl)-S-methylsulfoximide; (RS)-S-(4-[5-(3,5-Dimethoxy-phenylethynyl)-4-((R)-2-hydroxy-1-methyl-ethy-lamino)-pyrimidin-2-ylamino]-phenyl)-S-methylsulfoximide; (RS)-S-(4-[4-((R)-2-Hydroxy-1-methyl-ethylamino)-5-(4-methoxy-2-methyl-ph- enylethynyl)-pyrimidin-2-ylamino]-phenyl)-S-methylsulfoximide; (RS)-S-(4-[5-(4-Fluoro-3-methyl-phenyl-ethynyl)-4-((R)-2-hydroxy-1-methyl- -ethylamino)-pyrimidin-2-ylamino]-phenyl)-S-methylsulfoximide; (RS)-S-(4-[4-((R)-2-Hydroxy-1-methyl-ethylamino)-5-(3-hydroxy-phenylethyn-yl)-pyrimidin-2-ylamino]-phenyl)-S-methylsulfoximide; (RS)-S-(3-[4-((R)-2-Hydroxy-1-methyl-ethylamino)-5-(3-hydroxy-phenylethyn- yl)-pyrimidin-2-ylamino]-phenyl)-N-(isopropylcarbamoyl)-S-methylsulfoximid- e; (RS)-S-(3-[4-((R)-2-Hydroxy-1-methyl-ethylamino)-5-(phenylethynyl)-pyri- midin-2-ylamino]-phenyl)-S-methylsulfoximide; (RS)-S-(3-[4-((R)-2-Hydroxy-1-methyl-ethylamino)-5-(4-methoxy-phenylethyn- yl)-pyrimidin-2-ylamino]-phenyl)-S-methylsulfoximide; (RS)-S-(3-[4-((R)-2-Hydroxy-1-methyl-ethylamino)-5-(3-hydroxy-phenylethyn- yl)-pyrimidin-2-ylamino]-phenyl)-S-methylsulfoximide; (RS)-S-(3-[4-((R)-2-Hydroxy-1-methyl-ethylamino)-5-(2-methyl-phenylethyny-l)-pyrimidin-2-ylamino]-phenyl)-S-methylsulfoximide; (RS)-S-(3-[5-(4-Fluoro-3-methyl-phenyl-ethynyl)-4-((R)-2-hydroxy-1-methyl- -ethylamino)-pyrimidin-2-ylamino]-phenyl)-S-methylsulfoximide; (RS)-S-(3-[4-((R)-2-Hydroxy-1-methyl-ethylamino)-5-(3-methoxy-phenylethyn- yl)-pyrimidin-2-ylamino]-phenyl)-S-methylsulfoximide; (RS)-S-(3-[4-((R)-2-Hydroxy-1-methyl-ethylamino)-5-(4-methyl-phenylethyny-l)-pyrimidin-2-ylamino]-phenyl)-S-methylsulfoximide; (RS)-S-(4-[5-(4-Fluoro-3-methyl-phenyl-ethynyl)-4-methylamino-pyrimidin-2- -ylamino]-phenyl)-S-methylsulfoximide; (RS)-S-(4-[4-ethylamino-5-(4-fluoro-3-methyl-phenyl-ethynyl)-pyrimidin-2--ylamino]-phenyl)-S-methylsulfoximide; (RS)-S-(4-[5-(4-methoxy-phenyl-ethynyl)-4-methylamino-pyrimidin-2-ylamino- ]-phenyl)-S-methylsulfoximide; (RS)-S-(4-[4-ethylamino-5-(4-methoxy-phenyl-ethynyl)-pyrimidin-2-ylamino]- -phenyl)-S-methylsulfoximide; (RS)-S-4-[4-((R)-2-Hydroxy-1-methyl-ethylamino)-5-(1H-indazol-6-ylethynyl- )-pyrimidin-2-ylamino]-phenyl)-S-methylsulfoximide; (RS)-S-4-[4-((R)-2-Hydroxy-1-methyl-ethylamino)-5-(1H-indazol-5-ylethynyl- )-pyrimidin-2-ylamino]-phenyl)-S-methylsulfoximide; (RS)-S-4-[4-((R)-2-Hydroxy-1-methyl-ethylamino)-5-(1H-indazol-4-ylethynyl- )-pyrimidin-2-ylamino]-phenyl)-S-methylsulfoximide; (RS)-S-4-[5-(3-Benzyloxy-phenylethynyl)-4-((R)-2-hydroxy-1-methyl-ethylam- ino)-pyrimidin-2-ylamino]-S-methylsulfoximide; (RS)-N-(Ethoxycarbonyl)-S-4-[4-((R)-2-Hydroxy-1-methyl-ethylamino)-5-(pyr- idin-3-ylethynyl)-pyrimidin-2-ylamino]-phenyl)-S-methyl-sulfoximide; (RS)-N-(Ethoxycarbonyl)-S-(4-[4((R)-2-Hydroxy-1-methyl-ethylamino)-5-(2-m-ethyl-phenylethynyl)-pyrimidin-2-ylamino]-phenyl)-S-methylsulfoximide; (RS)-N-(Ethoxycarbonyl)-S-(4-[4-((R)-2-Hydroxy-1-methyl-ethylamino)-5-(4-- methoxy-phenylethynyl)-pyrimidin-2-ylamino]-phenyl)-S-methylsulfoximide; (RS)-N-(Ethoxycarbonyl)-S-(4-[4-((R)-2-Hydroxy-1-methyl-ethylamino)-5-(ph- enylethynyl)-pyrimidin-2-ylamino]-phenyl)-S-methylsulfoximide; (RS)-N-(Ethoxycarbonyl)-S-(4-[5-(4-dimethyl-aminophenyl-ethynyl)-4((R)-2--hydroxy-1-methyl-ethylamino)-pyrimidin-2-ylamino]-phenyl)-S-methylsulfoxim- ide; (RS)-N-(Ethoxycarbonyl)-S-(4-[5-(4-cyanophenyl-ethynyl)-4-((R)-2-hydr- oxy-1-methyl-ethylamino)-pyrimidin-2-ylamino]-phenyl)-S-methylsulfoximide; (RS)-N-(Ethoxycarbonyl)-S-4-[4-((R)-2-Hydroxy-1-methyl-ethylamino)-5-(3-h- ydroxyphenyl-ethynyl)-pyrimidin-2-ylamino]-phenyl)-S-methyl-sulfoximide; (RS)-N-(Ethoxycarbonyl)-S-4-[4-((R)-2-Hydroxy-1-methyl-ethylamino)-5-(pyr-idin-2-ylethynyl)-pyrimidin-2-ylamino]-phenyl)-S-methyl-sulfoximide; (RS)-N-(Ethoxycarbonyl)-S-4-[4-((R)-2-Hydroxy-1-methyl-ethylamino)-5-(3-m- ethyl-3H-imidazol-4-yl-ethynyl)-pyrimidin-2-ylamino]-phenyl)-S-methyl-sulf- oximide; (RS)-S-(3-[5-(4-Ethoxy-phenyl-ethynyl)-4-((R)-2-hydroxy-1-methyl-- ethylamino)-pyrimidin-2-ylamino]-phenyl)-N-(isopropylcarbamoyl)-S-methylsu- lfoximide; (RS)-S-(4-[5-(4-Ethoxy-phenyl-ethynyl)-4-((R)-2-hydroxy-1-methy-l-ethylamino)-pyrimidin-2-ylamino]-phenyl)-S-methylsulfoximide; (RS)-S-(3-[5-(4-methoxy-phenylethynyl)-pyrimidin-2-ylamino]-phenyl)-S-met- hylsulfoximide; and (RS)-S-(3-[5-(3-hydroxy-phenylethynyl)-pyrimidin-2-ylamino]-phenyl)-S-met- hylsulfoximide.

7. A method of preparing a compound of general formula (I) according to claim 1, said method comprising the step of allowing an intermediate compound of general formula 6: ##STR00197## in which X stands for Br or I and R.sup.1, R.sup.2, R.sup.3and R.sup.4 are as defined in claim 1, to undergo a transition metal mediated coupling reaction with a compound of formula 5: ##STR00198## in which A, R.sup.5 and R.sup.6 are as defined in clam 1, thereby providing a compound of general formula I:##STR00199## in which R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, and A are defined as in claim 1.

8. A method of preparing a compound of general formula (I) according to claim 1, said method comprising the step of allowing an intermediate compound of general formula 6: ##STR00200## in which X stands for Br or I and R.sup.1, R.sup.2, R.sup.3and R.sup.4 are as defined in claim 1, to undergo a transition metal mediated coupling reaction with a compound of formula 5': ##STR00201## in which R stands for C1-C6 alkyl, preferably methyl, and A, R.sup.5 and R.sup.6 are as defined in claim 1,thereby providing a compound of general formula I: ##STR00202## in which R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, and A are as defined in claim 1.

9. A method of preparing a compound of general formula (Ib) according to claim 1, said method comprising the step of allowing a compound of general formula Ia: ##STR00203## in which R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6, R.sup.7 and A areas defined in claim 1, to react in the presence of an oxidizing agent, such as meta-chloroperbenzoic acid, with an amine of general formula 9: ##STR00204## in which R.sup.7 and R.sup.8 are as defined in claim 1, thereby providing a compound of generalformula Ib: ##STR00205## in which R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6, R.sup.7, R.sup.8 and A are as defined in claim 1.

10. A pharmaceutical composition which comprises a compound of general formula (I) according to claim 1, or a pharmaceutically acceptable salt or a tautomer of said compound, and a pharmaceutically acceptable diluent or carrier.

11. A method of treating a tumor and/or metastases thereof comprising administering an effective amount of a compound of general formula (I) according to claim 1.

12. The method according to claim 11, wherein said tumor and/or metastases thereof is a breast, colon, renal, ovarian, prostate, head, neck, pancreas, GI tract, thyroid, lung or brain tumor, melanoma, or metastases thereof.

13. A method of treating a disease selected from chronic myelogeneous leukaemia, acute myelogenous leukaemia, acute lymphatic leukaemia, acute lymphocytic leukaemia, chronic lymphocytic leukaemia, chronic lymphatic leukaemia, and other myeloidprecursor hyperplasias comprising administering an effective amount of a compound of general formula (I) according to claim 1.
Description:
 
 
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