CDK-inhibitory pyrimidines, their production and use as pharmaceutical agents

Abstract

This invention relates to pyrimidine derivatives of general formula I 1

Description

[0001] This invention relates to pyrimidine derivatives, their production as well as their use as medications for treating various diseases.

[0002] The CDKs (cyclin-dependent kinase) is an enzyme family that plays an important role in the regulation of the cell cycle and thus is an especially advantageous target for the development of small inhibitory molecules. Selective inhibitors of the CDKs can be used for treating cancer or other diseases that cause disruptions of cell proliferation.

[0003] Pyrimidines and analogs are already described as active ingredients, such as, for example, the 2-anilino-pyrimidines as fungicides (DE 4029650) or substituted pyrimidine derivatives for treating neurological or neurodegenerative diseases (WO 99/19305). As CDK-inhibitors, the most varied pyrimidine derivatives are described, for example bis(anilino)-pyrimidine derivatives (WO 00/12486), 2-amino-4-substituted pyrimidines (WO 01/14375), purines (WO 99/02162), 5-cyano-pyrimidines (WO 02/04429), anilinopyrimidines (WO 00/12486) and 2-hydroxy-3-N,N-dimethylaminopropoxy-pyrimidines (WO 00/39101).

[0004] The object of this invention is to provide compounds that have better properties than the inhibitors that are already known. The substances that are described here are more effective, since they already inhibit in the nanomolar range and can be distinguished from other already known CDK-inhibitors such as, e.g., olomoucine and roscovitine.

[0005] It has now been found that compounds of general formula I 2

[0006] in which

[0007] R1 stands for hydrogen, halogen, C1-C6 -alkyl, nitro, or for the group —CORs, —OCF3, —(CH2)nR5, —S—CF3 or —SO2CF3,

[0008] R2 stands for C1-C10-alkyl, C2-C10-alkenyl, C2-C10-alkinyl, or C3-C10-cycloalkyl or for C1-C10-alkyl, C2-C10-alkenyl, C2-C10-alkinyl, or C3-C10-cycloalkyl that is substituted in one or more places in the same way or differently with hydroxy, halogen, C1-C6 -alkoxy, C1-C6 -alkylthio, amino, cyano, C1-C6 -alkyl, —NH—(CH2)n-C3-C10-cycloalkyl, C3-C10-cycloalkyl, C1-C6-hydroxyalkyl, C2-C6-alkenyl, C2-C6-alkinyl, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, —NHC1-C6-alkyl, —N(C1-C6-alkyl)2, —SO(C1-C6-alkyl), —SO2(C1-C6-alkyl), C1-C6-alkanoyl, —CONR3R4, —COR5, C1-C6-alkylOAc, carboxy, aryl, heteroaryl, —(CH2)n-aryl, —(CH2)n-heteroaryl, phenyl-(CH2)n—R5, —(CH2)nPO3(R5)2 or with the group —R6 or —NR3R4, and the phenyl, C3-C10-cycloalkyl, aryl, heteroaryl, —(CH2)n-aryl and —(CH2)n-heteroaryl itself optionally can be substituted in one or more places in the same way or differently with halogen, hydroxy, C1-C6-alkyl, C1-C6-alkoxy, heteroaryl, benzoxy or with the group —CF3 or —OCF3, and the ring of the C3-C10-cycloalkyl and the C1-C10-alkyl optionally can be interrupted by one or more nitrogen, oxygen and/or sulfur atoms and/or can be interrupted by one or more ═C═O groups in the ring and/or optionally one or more possible double bonds can be contained in the ring, or

[0009] R2 stands for the group 3

[0010] X stands for oxygen or for the group —NH—, —N(C1-C3-alkyl) or for —OC3-C10-cycloalkyl, which can be substituted in one or more places in the same way or differently with a heteroaromatic compound, or

[0011] X and R2 together form a C3-C10-cycloalkyl ring, which optionally can contain one or more heteroatoms and optionally can be substituted in one or more places with hydroxy, C1-C6-alkyl, C1-C6-alkoxy or halogen,

[0012] A and B, in each case independently of one another, stand for hydrogen, hydroxy, C1-C3-alkyl, C1-C6-alkoxy or for the group —SR7, —S(O)R7, —SO2 R7, —NHSO2R7, —CH(OH)R7, —CR7(OH)—R7, C1-C6-alkylP(O)OR3OR4 or —COR7, or for 4567

[0013] A and B together form a C3-C10-cycloalkyl ring that optionally can be interrupted by one or more nitrogen, oxygen and/or sulfur atoms and/or can be interrupted by one or more ═C═O or ═SO2 groups in the ring and/or optionally one or more possible double bonds can be contained in the ring, and the C3-C10-cycloalkyl ring optionally can be substituted in one or more places in the same way or differently with hydroxy, halogen, C1-C6-alkoxy, C1-C6-alkylthio, amino, cyano, C1-C6-alkyl, C2-C6-alkenyl, C3C10-cycloalkyl, C1-C6-alkoxy-C1-C6-alkyl, —NHC1-C6-alkyl, —N(C1-C6-alkyl)2, —SO(C1-C6-alkyl), —SO2R7, C1-C6-alkanoyl, —CONR3R4, —COR5, C1-C6-alkoxyOAc, phenyl or with the group R6, whereby the phenyl itself optionally can be substituted in one or more places in the same way or differently with halogen, hydroxy, C1-C6-alkyl, C1-C6-alkoxy or with the group —CF3 or —OCF3,

[0014] R3 and R4, in each case independently of one another, stand for hydrogen, phenyl, benzyloxy, C1-C12-alkyl, C1-C6-alkoxy, C2-C4-alkenyloxy, C3-C6-cycloalkyl, hydroxy, hydroxy-C1-C6-alkyl, dihydroxy-C1-C6-alkyl, heteroaryl, heterocyclo-C3-C10-alkyl, heteroaryl-C1-C3-alkyl, C3-C6-cycloalkyl-C1-C3-alkyl that is optionally substituted with cyano, or for

[0015] C1-C6-alkyl that is optionally substituted in one or more places in the same way or differently with phenyl, pyridyl, phenyloxy, C3-C6-cycloalkyl, C1-C6-alkyl or C1-C6-alkoxy,

[0016] whereby the phenyl itself can be substituted in one or more places in the same way or differently with halogen, C1-C6-alkyl, C1-C6-alkoxy or with the group —SO2NR3R4,

[0017] or for the group —CH2)nNR3R4, —CNHNH2 or —NR3R4, or

[0018] R3 and R4 together form a C3-C10-Cycloalkyl ring that optionally can be interrupted by one or more nitrogen, oxygen and/or sulfur atoms and/or can be interrupted by one or more ═C═O groups in the ring and/or optionally one or more possible double bonds can be contained in the ring,

[0019] R5 stands for hydroxy, phenyl, C1-C6-alkyl, C3-C6-cycloalkyl, benzoxy, C1-C6-alkylthio or C1-C6-alkoxy,

[0020] R stands for a heteroaryl or C3-C10-cycloalkyl ring, whereby the ring has the above-indicated meaning,

[0021] R7 stands for halogen, hydroxy, phenyl, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkinyl, C3-C10-cycloalkyl, with the above-indicated meaning, or for the group —NR3R4, or for a C1-C10-alkyl, C2-C10-alkenyl, C2-C10-alkinyl or C3-C7-cycloalkyl that is substituted in one or more places in the same way or differently with hydroxy, C1-C6-alkoxy, halogen, phenyl, —NR3R4 or phenyl, which itself can be substituted in one or more places in the same way or differently with halogen, hydroxy, C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkyl, halo-C1-C6-alkoxy, or R7 stands for phenyl, which itself can be substituted in one or more places in the same way or differently with halogen, hydroxy, C1-C6-alkyl or C1-C6-alkoxy, halo-C1-C6-alkyl, or halo-C1-C6-alkoxy,

[0022] R3, R9 and

[0023] R10, in each case independently of one another, stand for hydrogen, hydroxy, C1-C10-alkyl, C2-C10-alkenyl, C2-C10-alkinyl, C3-C10-cycloalkyl, aryl, heteroaryl or for C1-C10-alkyl, C2-C10-alkenyl, C2-C10-alkinyl or C3-C10-cycloalkyl that is optionally substituted in one or more places in the same way or differently with hydroxy, halogen, C1-C6-alkoxy, C1-C6-alkylthio, amino, cyano, C1-C6-alkyl, —NH—(CH2)n-C3-C10-cycloalkyl, C3-C10-cycloalkyl, C1-C6-hydroxyalkyl, C2-C6-alkenyl, C2-C6-alkinyl, C1-C6-alkoxy-C1-C6-allyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, -NHC1-C6-alkyl, —N(C1-C6-allyl)2, —SO(C1-C6-alkyl), —SO2(C1-C6-alkyl), C1-C6-alkanoyl, —CONR3R4, —COR5, C1-C6-alkylOAc, carboxy, aryl, heteroaryl, —(CH2)n-aryl, —(CH2)n-heteroaryl, phenyl-(CH2)n-R5, —(CH2)nPO3(R5)2 or with the group —R6 or —NR3R4, and the phenyl, C3-C10-cycloalkyl, aryl, heteroaryl, —(CH2)n-aryl and —CH2)n-heteroaryl itself optionally can be substituted in one or more places in the same way or differently with halogen, hydroxy, C1-C6-alkyl, C1-C6-alkoxy or with the group —CF3 or —OCF3, and the ring of C3-C10-cycloalkyl and the C1-C10-alkyl optionally can be interrupted by one or more nitrogen, oxygen and/or sulfur atoms and/or can be interrupted by one or more ═C═O groups in the ring and/or optionally one or more possible double bonds can be contained in the ring, and

[0024] n stands for 0-6,

[0025] as well as isomers, diastereomers, enantiomers and salts thereof that overcome known drawbacks.

[0026] Alkyl is defined in each case as a straight-chain or branched alkyl radical, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl, octyl, nonyl and decyl.

[0027] Alkoxy is defined in each case as a straight-chain or branched alkoxy radical, such as, for example, methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, pentyloxy, isopentyloxy, or hexyloxy.

[0028] Alkylthio is defined in each case as a straight-chain or branched alkylthio radical, such as, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio or hexylthio.

[0029] Cycloalkyl is defined in general as monocyclic alkyl rings, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, but also bicyclic rings or tricyclic rings such as, for example, norbornyl, adamantanyl, etc.

[0030] The ring systems, in which optionally one or more possible double bonds can be contained in the ring, are defined as, for example, cycloalkenyls, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, or cycloheptenyl, whereby the linkage can be carried out both to the double bond and to the single bonds.

[0031] If A and B, R3 and R4, X and R2, in each case independently of one another, together form a C3-C10-cycloalkyl ring, which optionally can be interrupted by one or more heteroatoms, such as nitrogen atoms, oxygen atoms and/or sulfur atoms, and/or can be interrupted by one or more ═C═O groups in the ring and/or optionally one or more possible double bonds can be contained in the ring, however, the above-mentioned definitions are also intended to include heteroaryl radical or heterocycloalkyl and heterocycloalkenyl.

[0032] Halogen is defined in each case as fluorine, chlorine, bromine or iodine.

[0033] The alkenyl substituents in each case are straight-chain or branched, whereby, for example, the following radicals are meant: vinyl, propen-1-yl, propen-2-yl, but-1-en-1-yl, but-1-en-2-yl, but-2-en-1-yl, but-2-en-2-yl, 2-methyl-prop-2-en-1-yl, 2-methyl-prop-1-en-1-yl, but-1-en-3-yl, ethinyl, prop-1-in-1-yl, but-1-in-1-yl, but-2-in-1-yl, but-3-en-1-yl, and allyl.

[0034] Alkinyl is defined in each case as a straight-chain or branched alkinyl radical that contains 2-6, preferably 2-4 C atoms. For example, the following radicals can be mentioned: acetylene, propin-1-yl, propin-3-yl, but-1-in-1-yl, but-1-in-4-yl, but-2-in-1-yl, but-1-in-3-yl, etc.

[0035] The aryl radical in each case comprises 3-12 carbon atoms and in each case can be benzocondensed.

[0036] For example, there can be mentioned: cyclopropenyl, cyclopentadienyl, phenyl, tropyl, cyclooctadienyl, indenyl, naphthyl, azulenyl, biphenyl, fluorenyl, anthracenyl, etc.

[0037] The hetetoaryl radical in each case comprises 3-16 ring atoms, and instead of the carbon can contain one or more heteroatoms that are the same or different, such as oxygen, nitrogen or sulfur, in the ring, and can be monocyclic, bicyclic, or tricyclic and in addition in each-case can be benzocondensed.

[0038] For example, there can be mentioned:

[0039] Thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc. and benzo derivatives thereof, such as, e.g., benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, indazolyl, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc. and benzo derivatives thereof, such as, e.g., quinolyl, isoquinolyl, etc., or azocinyl, indolizinyl, purinyl, etc. and benzo derivatives thereof; or quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl, oxepinyl, etc.

[0040] Heterocycloalkyl stands for an alkyl ring that comprises 3-12 carbon atoms, which instead of the carbon contains one or more heteroatoms that are the same or different, such as, e.g., oxygen, sulfur or nitrogen.

[0041] As heterocycloalkyls, there can be mentioned, e.g.: oxiranyl, oxethanyl, aziridinyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, dioxanyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, quinuclidinyl, etc.

[0042] Heterocycloalkenyl stands for an alkyl ring that comprises 3-12 carbon atoms, which instead of the carbon contains one or more heteroatoms that are the same or different such as, e.g., oxygen, sulfur or nitrogen, and Which is partially saturated.

[0043] As heterocycloalkenyls, there can be mentioned, e.g.: pyran, thiin, dihydroacet, etc.

[0044] If an acid group is included, the physiologically compatible salts of organic and inorganic bases are suitable as salts, such as, for example, the readily soluble alkali and alkaline-earth salts, as well as N-methyl-glucamine, dimethyl-glucamine, ethyl-glucamine, lysine, 1,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl-amino-methane, aminopropane diol, Sovak base, and 1-amino-2,3,4-butanetriol.

[0045] If a basic group is included, the physiologically compatible salts of organic and inorganic acids are suitable, such as hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, i.a.

[0046] Those compounds of general formula (I) in which

[0047] R1 stands for hydrogen, halogen, C1-C6-alkyl, nitro, or for the group —COR5, —OCF3, —(CH2)nR5, —S—CF3 or —SO2CF3,

[0048] R2 stands for C1-C10-alkyl, C2-C10-alkenyl, C2-C10-alkinyl, or C3-C10-cycloalkyl or for C1-C10-alkyl, C2-C10-alkenyl, C2-C10-alkinyl, or C3-C10-cycloalkyl that is substituted in one or more places in the same way or differently with hydroxy, halogen, C1-C6-alkoxy, C1-C6-alkylthio, amino, cyano, C1-C6-alkyl, —NH—(CH2)n—C3-C10-cycloalkyl, C3-C10-cycloalkyl, C1-C6-hydroxyalkyl, C2-C6-alkenyl, C2-C6-alkinyl, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, —NHC1-C6-alkyl, —N(C1-C6-alkyl)2, —SO(C1-C6-alkyl), —SO2 (C1-C6-alkyl), C1-C6-alkanoyl, —CONR3R4, —COR5, C1-C6-alkylOAc, carboxy, aryl, heteroaryl, —(CH2)n-aryl, —(CH2)n-heteroaryl, phenyl-(CH2)n—R5, —(CH2)nPO3(R5)2 or with the group —R6 or —NR3R4, and the phenyl, C3-C10-cycloalkyl, aryl, heteroaryl, —(CH2)n-aryl and —CH2)n-heteroaryl itself optionally can be substituted in one or more places in the same way or differently with halogen, hydroxy, C1-C6-alkyl, C1-C6 alkoxy, heteroaryl, benzoxy or with the group —CF3 or —OCF3, and the ring of the C3-C10-cycloalkyl and the C1-C10-alkyl optionally can be interrupted by one/or more nitrogen, oxygen and/or sulfur atoms and/or can be interrupted by one or more ═C═O groups in the ring and/or optionally one or more possible double bonds can be contained in the ring, or

[0049] R2 stands for the group 8

[0050] X stands for oxygen or for the group —NH—, —N(C1C3-alkyl) or for —OC3-C10-cycloalkyl, which can be substituted in one or more places in the same way or differently with a heteroaromatic compound, or

[0051] X and R2 together form a C3-C10-cycloalkyl ring, which optionally can contain one or more heteroatoms and optionally can be substituted in one or more places with hydroxy, C1-C6-alkyl, C1-C6-alkoxy or halogen,

[0052] A and B, in each case independently of one another, stand for hydrogen, hydroxy, C1-C3-alkyl, C1-C6-alkoxy or for the group —S—CH3, —SO2—C2H4—OH, —CO—CH3, —S—CHF2, —S—(CH2)nCH(OH)CH2N—R3R4, —CH2P(O)OR3OR4, —S—CF3, —SO—CH3, —SO2CF3, —SO2—(CH2)n—N—R3R4, —SO2—NR3R4, —SO2R7, —CH—(OH)—CH3 or for 9101112

[0053] A and B together can form a group 13

[0054] R3 and R4, in each case independently of one another, stand for hydrogen, phenyl, benzyloxy, C1-C12-alkyl, C1-C6-alkoxy, C2-C4-alkenyloxy, C3-C6-cycloalkyl, hydroxy, hydroxy-C1-C6-allyl, dihydroxy-C1-C6-alkyl, heteroaryl, heterocyclo-C3-C10-alkyl, heteroaryl-C1-C3-alkyl, C3-C6-cycloalkyl-C1-C3-alkyl optionally substituted with cyano, or for C1-C6-alkyl that is optionally substituted in one or more places in the same way or differently with phenyl, pyridyl, phenyloxy, C3-C6-cycloalkyl, C1-C6-alkyl or C1-C6-alkoxy,

[0055] whereby the phenyl itself can be substituted in one or more places in the same way or differently with halogen, trifluoromethyl, C1-C6-alkyl, C1-C6-alkoxy or with the group —SO2NR3R4,

[0056] or for the group —(CH2)nNR3R4, —CNHNH2 or —NR3R4

[0057] or for 14

[0058] which optionally can be substituted with C1-C6-alkyl,

[0059] R5 stands for hydroxy, phenyl, C1-C6-alkyl, C3-C6-cycloalkyl, benzoxy, C1-C6-alkylthio or C1-C6-alkoxy,

[0060] R6 stands for the group 15

[0061] R7 stands for halogen, hydroxy, phenyl, C1-C6-alkyl, —C2H4OH, —NR3R4, or the group 16

[0062] R8, R9 and

[0063] R10, in each case independently of one another, stand for hydrogen, hydroxy, C1-C6-alkyl, C3-C6-cycloalkyl or for the group 17

[0064] and

[0065] n stands for 0-6,

[0066] as well as isomers, enantiomers, diastereomers, and salts thereof, are especially effective.

[0067] Those compounds of general formula I in which

[0068] R1 stands for hydrogen, halogen, C1-C3-alkyl, or for the group —(CH2)nR5,

[0069] R2 stands for —CH(CH3)—(CH2)n—R5, —CH—(CH2OH)2, —(CH2)nR7, —CH(C3H7)—(CH2)n—R5, —CH(C2H5)—(CH2)n—R5, —CH2—CN, —CH(CH3)COCH3, —CH(CH3)—C(OH)(CH3)2,—CH(CH(OH)CH3)OCH3, —CH(C2H5)CO—R5, C2-C4-alkinyl, —(CH2)n—COR5, —(CH2)n—CO—C1-C6-alkyl, —(CH2)n—C(OH)(CH3)-phenyl, —CH(CH3)—C(CH3)—R5, —CH(CH3)—C(CH3)(C2H5)—R5, —CH(OCH3)—CH2—R5, —CH2—CH(OH)—R5, —CH(OCH3)—CHR5—CH3, —CH(CH3)—CH(OH)—CH2—CH═CH2, —CH(C2H5)—CH(OH)—(CH2)n—CH3, —CH(CH3)—CH(OH)—(CH2)n—CH3, —CH(CH3)—CH(OH)—CH(CH3)2, (CH2OAC)2, —(CH2)n—R6, —(CH2)n—(CF2)n—CF3, —CH(CH2)n—R5)2, —CH(CH3)—CO—NH2, —CH(CH2OH)-phenyl, —CH(CH2OH)—CH(OH)—(CH2)nR5, —CH(CH2OH)—CH(OH)-phenyl, —CH(CH2OH)—C2H4—R5, —(CH2)n—C═C(CH3)═CH—COR5, —CH(Ph)-(CH2)n—R5, —(CH2)n—COR5, —(CH2)nPO3(R5)2, —(CH2)n—COR5, —CH((CH2)nOR5)CO—R5, —(CH2)nCONHCH((CH2)nR5)2, —(CH2)nNH—COR5, —CH(CH2)nR5—(CH2)nC3-C10-cycloalkyl, —(CH2)n—C3-C10-cycloalkyl, C3-C10-cycloalkyl; C1-C6-alkyl, C3-C10-cycloalkyl, —(CH2)n—O—(CH2)n—R5, —(CH2)n—NR3R4 that is optionally substituted in one or more places in the same way or differently with hydroxy, C1-C6-alkyl or the group —COONH(CH2)nCH3 or —NR3R4,

[0070] —CH(C3H7)—(CH2)n—OC(O)—(CH2)n—CH3, —(CH2)n—R5, —C(CH3)2—(CH2)n—R5, —C(CH2)n(CH3)—(CH2)nR5, —C(CH2)n—(CH2)nR5, —CH(t-butyl)-(CH2)n—R5, —CCH3(C3H7)—(CH2)nR5, —CH(C3H7)—(CH2)n—R5, —CH(C3H7)—COR5, —CH(C3H7)—(CH2)n—OC(O)—NH-Ph, —CH((CH2)n(C3H7))—(CH2)nR5,

[0071] —CH(C3H7)—(CH2)n—OC(O)—NH-Ph(OR5)3, —NR3R4, —NH—(CH2)n—NR3R4, R5—(CH2)n—C*H—CH(R5)—(CH2)n—R5, —(CH2)n—CO—NH—(CH2)n—CO—R5, —OC(O)NH—C1-C6-alkyl or —(CH2)n—CO—NH—(CH2)n—CH—((CH2)nR5)2,

[0072] or for C3-C10-cycloalkyl, which is substituted with the group 18

[0073] or for the group 19

[0074] X stands for oxygen or for the group —NH—, —N(C1-C3-alkyl) or 20

[0075] or

[0076] R2 stands for the group 21

[0077] or

[0078] X and R2 together form a group 22

[0079] A and B, in each case independently of one another, stand for hydrogen, hydroxy, C1-C3-alkyl, C1-C6-alkoxy or for the group —S—CH3, —SO2—C2H4—OH, —CO—CH3, —S—CHF2, —S(CH2)nCH(OH)CH2N—R3R4, —CH2PO(OC2H5)2, —S—CF3, —SO—CH3, —SO2CF3, —SO2—(CH2)n—N—R3R4, —SO2—NR3R4, —SO2R7, —CH(OH)—CH3, —COOH, —CH((CH2)nR5)2, —(CH2)nR5, —COO—C1C6-alkyl, —CONR3R4 or for 23242526

[0080] or

[0081] A and B together can form a group 27

[0082] R3 and R4, in each case independently of one another, stand for hydrogen, phenyl, benzyloxy, C1-C12-alkyl, C1-C6-alkoxy, C2-C4-alkenyloxy, C3-C6-cycloalkyl, hydroxy, hydroxy-C1-C6-alkyl, dihydroxy-C1-C6-alkyl, heteroaryl, heterocyclo-C3-C10-alkyl, heteroaryl-C1-C3-alkyl, C3-C6-cycloalkyl-C1-C3-alkyl that is optionally substituted with cyano, or for

[0083] C1-C6-alkyl that is optionally substituted in one or more places in the same way or differently with phenyl, pyridyl, phenyloxy, C3-C6-cycloalkyl, C1-C6-alkyl or C1-C6-alkoxy, whereby the phenyl itself can be substituted in one or more places in the same way or differently with halogen, trifluoromethyl, C1-C6-alkyl, C1-C6-alkoxy or with the group —SO2NR3R4,

[0084] or for the group —(CH2)nNR3R4, —CNHNH2 or —NR3R4 or for 28

[0085] which optionally can be substituted with C1-C6-alkyl,

[0086] R5 stands for hydroxy, phenyl, C1-C6-alkyl, C3-C6-cycloalkyl, benzoxy, C1-C6-alkylthio or C1-C6-alkoxy,

[0087] R6 stands for the group 29

[0088] R7 stands for halogen, hydroxy, phenyl, C1-C6-alkyl, —(CH2)nOH, —NR3R4 or the group 30

[0089] R8, R9 and

[0090] R10 stand for hydrogen, hydroxy, C1-C6-alkyl or for the group —(CH2)n—COOH, and

[0091] n stands for 0-6,

[0092] as well as isomers, diastereomers, enantiomers and salts thereof, have proven quite especially effective.

[0093] The compounds according to the invention essentially inhibit cyclin-dependent kinases, upon which is based their action, for example, against cancer, such as solid tumors and leukemia; auto-immune diseases such as psoriasis, alopecia, and multiple sclerosis, chemotherapy-induced alopecia and mucositis; cardiovascular diseases such as stenoses, arterioscleroses and restenoses; infectious diseases, such as, e.g., by unicellular parasites, such as trypanosoma, toxoplasma or plasmodium, or produced by fungi; nephrological diseases, such as, e.g., glomerulonephritis, chronic neurodegenerative diseases, such as Huntington's disease, amyotropic lateral sclerosis, Parkinson's disease, AIDS dementia and Alzheimer's disease; acute neurodegenerative diseases, such as ischemias of the brain and neurotraumas; viral infections, such as, e.g., cytomegalic infections, herpes, Hepatitis B and C, and HIV diseases.

[0094] The eukaryotic cell division ensures the duplication of the genome and its distribution to the daughter cells by passing through a coordinated and regulated sequence of events. The cell cycle is divided into four successive phases: the G1 phase represents the time before the DNA replication, in which the cell grows and is sensitive to external stimuli. In the S phase, the cell replicates its DNA, and in the G2 phase, preparations are made for entry into mitosis. In mitosis (M phase), the replicated DNA separates, and cell division is completed.

[0095] The cyclin-dependent kinases (CDKs), a family of serine/threonine kinases, whose members require the binding of a cyclin (Cyc) as a regulatory subunit in order for them to activate, drive the cell through the cell cycle. Different CDK/Cyc pairs are active in the various phases of the cell cycle. CDK/Cyc pairs that are important to the basic function of the cell cycle are, for example, CDK4(6)/CycD, CDK2/CycE, CDK2/CycA, CDK1/CycA and CDK1/CycB. Some members of the CDK enzyme family have a regulatory function by influencing the activity of the above-mentioned cell cycle CDKs, while no specific function could be associated with other members of the CDK enzyme family. One of the latter, CDK5, is distinguished in that it has an atypical regulatory subunit (p35) that deviates from the cyclins, and its activity is highest in the brain.

[0096] The entry into the cell cycle and the passage through the “restriction points,” which marks the independence of a cell from further growth signals for the completion of the cell division that has begun, are controlled by the activity of the CDK4(6)/CycD and CDK2/CycE complexes. The essential substrate of these CDK complexes is the retinoblastoma protein (Rb), the product of the retinoblastoma tumor suppressor gene. Rb is a transcriptional co-repressor protein. In addition to other, still largely little understood mechanisms, Rb binds and inactivates transcription factors of the E2F type and forms transcriptional repressor complexes with histone-deacetylases (HDAC) (Zhang, H. S. et al. (2000). Exit from G1 and S Phase of the Cell Cycle is Regulated by Repressor Complexes Containing HDAC-Rb-hSWI/SNF and Rb-hSWI/SNF. Cell 101, 79-89). By the phosphorylation of Rb by CDKs, bonded E2F transcription factors are released and result in transcriptional activation of genes, whose products are required for the DNA synthesis and the progression through the S-phase. In addition, the Rb-phosphorylation brings about the breakdown of the Rb-HDAC complexes, by which additional genes are activated. The phosphorylation of Rb by CDK's is to be treated as equivalent to exceeding the “restriction points.” For the progression through the S-phase and its completion, the activity of the CDK2/CycE and CDK2/CycA complexes is necessary, e.g., the activity of the transcription factors of the E2F type is turned off by means of phosphorylation by CDK2/CycA as soon as the cells are entered into the S-phase. After replication of DNA is complete, the CDK1 in the complex with CycA or CycB controls the entry into and the passage through phases G2 and M (FIG. 1).

[0097] According to the extraordinary importance of the cell-division cycle, the passage through the cycle is strictly regulated and controlled. The enzymes that are necessary for the progression through the cycle must be activated at the correct time and are also turned off again as soon as the corresponding phase is passed. Corresponding control points (“checkpoints”) stop the progression through the cell cycle if DNA damage is detected, or the DNA replication or the creation of the spindle device is not yet completed.

[0098] The activity of the CDKs is controlled directly by various mechanisms, such as synthesis and degradation of cyclins, complexing of the CDKs with the corresponding cyclins, phosphorylation and dephosphorylation of regulatory threonine and tyrosine radicals, and the binding of natural inhibitory proteins. While the amount of protein of the CDKs in a proliferating cell is relatively constant, the amount of the individual cyclins oscillates with the passage through the cycle. Thus, for example, the expression of CycD during the early G1 phase is stimulated by growth factors, and the expression of CycE is induced after the “restriction points” are exceeded by the activation of the transcription factors of the E2F type. The cyclins themselves are degraded by the ubiquitin-mediated proteolysis. Activating and inactivating phosphorylations regulate the activities of the CDKs, for example phosphorylate CDK-activating kinases (CAKs) Thr160/161 of the CDK1, while, by contrast, the families of Wee1/Myt1 inactivate kinases CDK1 by phosphorylation of Thr14 and Tyr15. These inactivating phosphorylations can be destroyed in turn by cdc25 phosphatases. The regulation of the activity of the CDK/Cyc complexes by two families of natural CDK inhibitor proteins (CKIs), the protein products of the p21 gene family (p21, p27, p57) and the p16 gene family (p15, p16, p18, p19) is very significant. Members of the p21 family bind to cyclin complexes of CDKs 1,2,4,6, but inhibit only the complexes that contain CDK1 or CDK2. Members of the p16 family are specific inhibitors of the CDK4- and CDK6 complexes.

[0099] The plane of control point regulation lies above this complex direct regulation of the activity of the CDKs. Control points allow the cell to track the orderly sequence of the individual phases during the cell cycle. The most important control points lie at the transition from G1 to S and from G2 to M. The G1 control point ensures that the cell does not initiate any DNA synthesis unless it has proper nutrition, interacts correctly with other cells or the substrate, and its DNA is intact. The G2/M control point ensures the complete replication of DNA and the creation of the mitotic spindle before the cell enters into mitosis. The G1 control point is activated by the gene product of the p53 tumor suppressor gene. p53 is activated after detection of changes in metabolism or the genomic integrity of the cell and can trigger either a stopping of the cell cycle progression or apoptosis. In this case, the transcriptional activation of the expression of the CDK inhibitor protein p21 by p53 plays a decisive role. A second branch of the G1 control point comprises the activation of the ATM and Chk1 kinases after DNA damage by UV light or ionizing radiation and finally the phosphorylation and the subsequent proteolytic degradation of the cdc25A phosphatase (Mailand, N. et al. (2000). Rapid Destruction of Human cdc25A in Response to DNA Damage. Science 288, 1425-1429). A shutdown of the cell cycle results from this, since the inhibitory phosphorylation of the CDKs is not removed. After the G2/M control point is activated by damage of the DNA, both mechanisms are involved in a similar way in stopping the progression through the cell cycle.

[0100] The loss of the regulation of the cell cycle and the loss of function of the control points are characteristics of tumor cells. The CDK-Rb signal path is affected by mutations in over 90% of human tumor cells. These mutations, which finally result in inactivating phosphorylation of the RB, include the over-expression of D- and E-cyclins by gene amplification or chromosomal translocations, inactivating mutations or deletions of CDK inhibitors of the p 16 type, as well as increased (p27) or reduced (CycD) protein degradation. The second group of genes, which are affected by mutations in tumor cells, codes for components of the control points. Thus p53, which is essential for the G1 and G2/M control points, is the most frequently mutated gene in human tumors (about 50%). In tumor cells that express p53 without mutation, it is often inactivated because of a greatly increased protein degradation. In a similar way, the genes of other proteins that are necessary for the function of the control points are affected by mutations, for example ATM (inactivating mutations) or cdc25 phosphatases (over-expression).

[0101] Convincing experimental data indicate that CDK2/Cyc complexes occupy a decisive position during the cell cycle progression. (1) Both dominant-negative forms of CDK2, such as the transcriptional repression of the CDK2 expression by anti-sense oligonucleotides, produce a stopping of the cell cycle progression. (2) The inactivation of the CycA gene in mice is lethal. (3) The disruption of the function of the CDK2/CycA complex in cells by means of cell-permeable peptides resulted in tumor cell-selective apoptosis (Chen, Y. N. P. et al. (1999). Selective Killing of Transformed Cells by Cyclin/Cyclin-Dependent Kinase 2 Antagonists. Proc. Natl. Acad. Sci. USA 96, 4325-4329).

[0102] Changes of the cell cycle control play a role not only in carcinoses. The cell cycle is activated by a number of viruses, both by transforming viruses as well as by non-transforming viruses, to make possible the replication of viruses in the host cell. The false entry into the cell cycle of normally post-mitotic cells is associated with various neurodegenerative diseases. The mechanisms of the cell cycle regulation, their changes in diseases and a number of approaches to develop inhibitors of the cell cycle progression and especially the CDKs were already described in a detailed summary in several publications (Sielecki, T. M. et al. (2000). Cyclin-Dependent Kinase Inhibitors: Useful Targets in Cell Cycle Regulation. J. Med. Chem. 43, 1-18; Fry, D. W. & Garrett, M. D. (2000). Inhibitors of Cyclin-Dependent Kinases as Therapeutic Agents for the Treatment of Cancer. Curr. Opin. Oncol. Endo. Metab. Invest. Drugs 2, 40-59; Rosiania, G. R. & Chang, Y. T. (2000). Targeting Hyperproliferative Disorders with Cyclin-Dependent Kinase Inhibitors. Exp. Opin. Ther. Patents 10, 215-230; Meijer L. et al. (1999). Properties and Potential Applications of Chemical Inhibitors of Cyclin-Dependent Kinases. Pharmacol. Ther. 82,.279-284; Senderowicz, A. M. & Sausville, E. A. (2000). Preclinical and Clinical Development of Cyclin-Dependent Kinase Modulators. J. Natl. Cancer Inst. 92, 376-387).

[0103] To use the compounds according to the invention as pharmaceutical agents, the latter are brought into the form of a pharmaceutical preparation, which in addition to the active ingredient for enteral or parenteral administration contains suitable pharmaceutical, organic or inorganic inert carrier materials, such as, for example, water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc. The pharmaceutical preparations can be present in solid form, for example as tablets, coated tablets, suppositories, or capsules, or in liquid form, for example as solutions, suspensions, or emulsions. Moreover, they optionally contain adjuvants, such as preservatives, stabilizers, wetting agents or emulsifiers; salts for changing the osmotic pressure or buffers. These pharmaceutical preparations are also subjects of this invention.

[0104] For parenteral administration, especially injection solutions or suspensions, especially aqueous solutions of active compounds in polyhydroxyethoxylated castor oil, are suitable.

[0105] As carrier systems, surface-active adjuvants such as salts of bile acids or animal or plant phospholipids, but also mixtures thereof, as well as liposomes or their components can also be used.

[0106] For oral administration, especially tablets, coated tablets or capsules with talc and/or hydrocarbon vehicles or binders, such as, for example, lactose, corn or potato starch, are suitable. The administration can also be carried out in liquid form, such as, for example, as a juice, to which optionally a sweetener is added.

[0107] Enteral, parenteral and oral administrations are also subjects of this invention.

[0108] The dosage of the active ingredients can vary depending on the method of administration, age and weight of the patient, type and severity of the disease to be treated and similar factors. The daily dose is 0.5-1000 mg, preferably 50-200 mg, whereby the dose can be given as a single dose to be administered once or divided into two or more daily doses.

[0109] Subjects of this invention also include the use of compounds of general formula I for the production of a pharmaceutical agent for treating cancer, auto-immune diseases, cardiovascular diseases, chemotherapy agent-induced alopecia and mucositis, infectious diseases, nephrological diseases, chronic and acute neurodegenerative diseases and viral infections, whereby cancer is defined as solid tumors and leukemia; auto-immune diseases are defined as psoriasis, alopecia and multiple sclerosis; cardiovascular diseases are defined as stenoses, arterioscleroses and restenoses; infectious diseases are defined as diseases that are caused by unicellular parasites; nephrological diseases are defined as glomerulonephritis; chronic neurodegenerative diseases are defined as Huntington's disease, amyotrophic lateral sclerosis, Parkinson's disease, AIDS dementia and Alzheimer's disease; acute neurodegenerative diseases are defined as ischemias of the brain and neurotraumas; and viral infections are defined as cytomegalic infections, herpes, hepatitis B or C, and HIV diseases.

[0110] Subjects of this invention also include pharmaceutical agents for treating the above-cited diseases, which contain at least one compound according to general formula I, as well as pharmaceutical agents with suitable formulation substances and vehicles.

[0111] The compounds of general formula I according to the invention are, i.a., excellent inhibitors of the cyclin-dependent kinases, such as CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9, as well as the glycogen-synthase-kinase (GSK-3β).

[0112] If the production of the starting compounds is not described, these compounds are known or can be produced analogously to known compounds or to processes that are described here. It is also possible to perform all reactions that are described here in parallel reactors or by means of combinatory operating procedures.

[0113] The isomer mixtures can be separated into the enantiomers or E/Z isomers according to commonly used methods, such as, for example, crystallization, chromatography or salt formation.

[0114] The production of the salts is carried out in the usual way by a solution of the compound of formula I being mixed with the equivalent amount of or excess base or acid, which optionally is in solution, and the precipitate being separated or the solution being worked up in the usual way.

[0115] Production of the Compounds According to the Invention

[0116] The following examples explain the production of the compounds according to the invention, without the scope of the claimed compounds being limited to these examples.

[0117] The compounds of general formula I according to the invention can be produced according to the following general diagrams of the process: 31323334

EXAMPLE 1

Production of 5-Bromo-N2-(4-difluoromethylthiophenyl)-N4-2-propynyl-2,4-pyrimidine diamine (carried out according to process diagram 1) (compound 23).

[0118] 245 mg (1 mmol) of 2-chloro-4-2-propynylaminopyrimidine is dissolved in 2 ml of acetonitrile, and a suspension of 4-(difluoromethylthio)-aniline hydrochloride [produced from 352 mg (2 mmol) of 4-(difluoromethylthio)-aniline, 1 ml of acetonitrile and 0.5 ml of aqueous HCl (4M in dioxane)] is added at room temperature. Then, the reaction mixture is refluxed overnight under N2 atmosphere. After cooling, the mixture is filtered, the remaining solid phase is washed with H2O and dried. A yield of 328 mg (85%) of the product can be expected

35	6H 2C H	8.25(s, 1H) 7.86(d, 2H) 7.51(d, 2H) 7.38 (t, 56.8Hz, 1H)	Yield: 85% Melting point: >235° C.
	4C	4.18(m, 2H)
	H	3.16(sb, 1H)
		10.24(sb, 1H)
	NH	8.17(sb, 1H)

EXAMPLE 2

Production of 5-bromo-N-(3-(oxiranylmethoxy)phenyl)-2-(2-propynyloxy)-2-pyrimidinamine (compound 51) and carried out according to process diagram 2.

[0119] 1.55 g (4.9 mmol) of compound 20 is dissolved in 5.5 ml of epibromohydrin, and 1.38 g of K2CO3 and 65 mg of tetrabutylammonium bromide are added to it. The reaction mixture is stirred under nitrogen atmosphere at 100° C. for 1 hour. After ethyl acetate is added, the resulting precipitate is collected and recrystallized from ethanol. The product yield is 1.15 g (62%) as a white powder.

36	6H 2CH	8.45(s, 1H) 7.47(s, 1H)
		7.32(d, 1H)	Yield: 62%
		7.20(t, 1H)
		6.40(d, 1H)	Melting point:
		4.32(dd, 1H)	173° C.
		3.82(dd, 1H)
		3.3-3.4
		(m, 1H)
		2.87(t, 1H)
		2.72(dd, 1H)
	4CH	5.13(d, 2H)
		3.67(t, 1H)
	NH	9.84(sb, 1H)

[0120] Substance 40 is produced analogously to Example 2.

37	6-H 2CH	8.36(s, 1H) 7.60(d, 1H)	Chromato- graphy: H/EA 1:3 0.5% TEA
		6.91(d, 1H)
		4.28(dd, 1H)
		3.79(dd, 1H)	Yield: 38%
		3.31(m, 1H)
		2.84(dd, 1H)	Melting point:
		2.70(dd, 1H)	140-141° C.
	4CH	5.07(d, 12H)
		3.65(t, 1H)
	NH	9.65(sb, 1H)
	OH

EXAMPLE 3

Production of 1-(4-((5-bromo-4-(2-propynyloxy)-pyrimidin-2-yl)-amino)phenoxy)-3-(4-phenylpiperazin-1-yl)-2-propanol (compound 41).

[0121] 0.2 ml of a 0.5 M 4-phenylpiperazine solution in DMPU is added to a solution of 19 mg (0.05 mmol) of substance 51 in N,N′-dimethylpropylurea (DMPU). The reaction mixture is kept for 18 hours at a temperature of 80° C. After cooling, 3.5 ml of tertiary butyl methyl ether is added, and the organic phase is extracted 5 times with 1.5 ml of H2O and then evaporated in a vacuum. The remaining residue is chromatographed on 1.7 g (15 μM) of Lichrosphere Si60 (gradient: dichloromethane/hexane 1:1 to DCM and then dichloromethane/methanol 99:1 to 93:7). A product yield of 17 mg (64%) is achieved. 38

[0122] Similarly produced are also the following compounds:

No. Structure
96  39
97  40
98  41
99  42
100 43
101 44
102 45
103 46
104 47
105 48
106 49
107 50
108 51
109 52
110 53
111 54
112 55
113 56
114 57
115 58
116 59
117 60
118 61
119 62

[0123] The following compounds were similarly produced in the described examples.

No.	Structure	Name
28	63	5-Bromo-N2-(4-(2-diethylaminoethylsulfonyl)phenyl)-N4-2-pro- pynyl-2,4-pyrimidine diamine
30	64	1-(4-[5-Bromo-4-(2-propynylamino)-2-py- rimidinyl]amino-phenylthio)-3-(diethylamino)-2-pro- panol
32	65	5-Bromo-N2-(3-phenylsulfonylphenyl)-N4-2-propynyl-2,4-py- rimidine diamine
33	66	N-[4-[[5-Bromo-4-(2-propynylamino)-2-pyrimidinyl]amino]-ben- zenesulfonyl]morpholine
41	67	1-(4-((5-Bromo-4-(2-propynyloxy)-pyrimidin-2-yl)-a- mino)phenoxy)-3-(4-phenylpiperazin-1-yl)-2-propanol
57	68	N-[5-Bromo-4-((2R)-1-hydroxy-4-methyl-2-butylamino)-2-py- rimidinyl]-indazol-5-amine
58	69	4-[[5-Fluoro-4-((2R)-1-hydroxy-3-methyl-2-butylamino)-2-py- rimidinyl]amino]-benzenesulfonamide
59	70	4-[[5-Iodo-4-((2R)-1-hydroxy-3-methyl-2-butylamino)-2-py- rimidinyl]amino]-benzenesulfonamide
62	71	4-[[5-Fluoro-4-(2-propynylamino)-2-pyrimidinyl]amino]-ben- zenesulfonamide
65	72	4-[[5-Ethyl-4-(2-propynylamino)-2-pyrimidinyl]amino]-ben- zenesulfonamide
66	73	1-[4-[(5-Iodo-4-((2R)-1-hydroxy-3-methyl-2-butylamino)-2-py- rimidinyl)amino]phenyl]-ethanone
68	74	1-[4-[(5-Ethyl-4-((2R)-1-hydroxy-3-methyl-2-butylamino)-2-py- rimidinyl)amino]phenyl]-ethanone
72	75	4-[[5-Bromo-4-(2-(2-oxo-imidazolin-1-yl)ethylamine)-2-py- rimidinyl]amino]-benzenesulfonamide
73	76	4-[[5-Bromo-4-(2,2,3,3,3-pentafluoropropyloxy)-2-py- rimidinyl]amino]-benzenesulfonamide
75	77	4-[[5-Bromo-4-(1,3-bisacetoxy-2-propyloxy)-2-py- rimidinyl]amino]-benzenesulfonamide
76	78	4-[[5-Bromo-4-(1,3-dihydroxy-2-propyloxy)-2-py- rimidinyl]amino]-benzenesulfonamide
79	79	N□-(5-Bromo-2-(4-sulfamoylphenyl)amino-pyrimidin-4-yl)-L-ala- nine amide
83	80	1-[4-[(5-Bromo-4-(2-propynylamino)-2-py- rimidinyl)amino]phenyl]-ethanol

[0124] The following compounds were produced analogously to the described synthesis processes according to Diagram 1 or 2:

[0125] All NMR spectra are measured in the indicated solvent or in DMSO.

[0126] [Key to the Following Tables and Diagrams:]

[0127] Bsp.-Nr. [Beispiel Nr.]=Example No.

[0128] Chromatographie Ausbeute=Chromatography yield

[0129] Schmp.=Melting point

[0130] Kristallisiert=Crystallized

[0131] Masse=Mass

[0132] krist. Wasser=Crystallized water

[0133] Verbindung=Compound

[0134] Hitze=Heat

	81	82	83	84
Bsp.-Nr.	37	38	39	5
6-H	8.34(s, 1H)	8.39(s, 1H)	8.30(s, 1H)	8.00(s, 1H)
2CH	12.88	9.28(s, 1H)	7.74(s, 1H)	7.52(d, 2H)
	(sb, 1H)	8.79(s, 1H)	7.44(d, 1H)	6.65(d, 2H)
	8.07(s, 1H)	7.70(d, 1H)	7.22(d, 1H)
	7.93(s, 1H)	8.04(d, 1H)	3.98(t, 2H)
	7.41(d, 1H)		3.13(t, 2H)
	7.56		2.99(s, 3H)
4CH	(dd, 1H)	4.19(d, 2H)	4.16(d, 2H)	4.09(d, 2H)
		3.22(sb, 1H)	3.28(sb, 1H)	3.09(s, 1H)
NH	4.15	10.43(sb, 1H)	10.6(1H)	9.00(s, 1H)
	(dd, 2H)	8.45(sb, 1H)	8.75(1H)	8.96(s, 1H)
	3.18(t, 1H)			7.31(t, 1H)
	9.30(sb, 1H)
	7.39(tb, 1H)
Chro-	EA + 0.5%	—	Kristallisiert	—
mato-	TEA		MeOH
graphie	10%	36%	73%	20%
Ausbeute
Schmpe.	231° C.	>235° C.	237° C.	157° C.

[0135]

	85	86	87	88
Beispiel Nr.	16	24	26	35
6-H	8.80(s, 1H)	8.30(s, 1H)	8.18(s, 1H)	8.14(s, 1H)
2CH	7.67(d, 2H)	7.94(d, 2H)	7.67(s, 1H)	8.28(s, 1H)
	7.27(d, 2H)	7.63(d, 2H)	7.54(d, 1H)	7.98(d, 1H)
	2.47(s, 3H)		7.24(t, 1H)	7.41(t, 1H)
			6.92(d, 1H)	7.25(d, 1H)
4CH	4.17(dd, 2H)	4.17(dd, 2H)	4.20(dd, 2H)	4.14(dd, 2H)
	3.75(t, 1H)	3.18(t, 1H)	3.12(sb, 1H)	3.04(sb, 1H)
NH	10.55	10.45	9.78(sb, 1H)	9.58(sb, 1H)
	(sb, 1H)	(sb, 1H)	7.95(sb, 1H)	7.46(sb, 1H)
	8.68(sb, 1H)	8.22(sb, 1H)
Chrom.	—	—	—	—
Ausbeute	94%	86%	73%	69%
Schmp.	232-234° C.	160° C.	194° C.	143° C.

[0136]

	89	90	91	92
Beispiel Nr.	27	36	34	21
6-H	8.18(s, 1H)	8.26(s, 1H)	8.25(s, 1H)	8.17(s, 1H)
2CH	8.73(s, 1H)	8.12(s, 1H)	8.16(s, 1H)	8.74(s, 1H)
	7.62(d, 1H)	7.35-	7.43(d, 1H)	7.43(d, 1H)
	7.72(t, 1H)	7.55(m, 3H)	7.52(t, 1H)	7.52(t, 1H)
	8.31(d, 1H)	8.06(d, 1H)	8.01(d, 1H)	8.08(d, 1H)
			2.78(m, 2H)	3.43(t, 2H)
			1.35(mc, 2H)	3.70(t, 2H)
			1.24(mc, 2H)
			0.80(t, 3H)
4CH	4.18(dd, 2H)		4.21(d, 2H)	4.20(dd, 2H)
	3.06(t, 1H)	4.21(d, 2H)	3.09(sb, 1H)	3.08(t, 1H)
NH	10.02(s, 1H)	3.09(sb, 1H)	10.3(sb, 1H)	9.79(s, 1H)
	7.49(sb, 1H)	9.68(sb, 1H)	8.13(sb, 1H)	7.55(tb, 1H)
OH		7.30(sb, 2H)		4.90(sb, 1H)
Chrom.	—	krist. EtOH	—	—
Aus-	69%	64%	87%	59%
beute
Schmp.	144° C.	219° C.	220° C.	192.5-193.5° C.

[0137]

	93	94	95	96
Beispiel Nr.	31	25	23	11
6-H	8.25(s, 1H)	8.14(s, 1H)	8.25(s, 1H)	8.29(s, 1H)
2CH	7.65(d, 2H)	8.01(d, 2H)	7.86(d, 2H)	7.95(d, 2H)
	7.24(d, 2H)	7.56(d, 2H)	7.51(d, 2H)	7.78(d, 2H)
	3.19(d, 21.3Hz, 2H)	2.70(s, 3H)	7.38(t, 56.8Hz, 1H)
4CH	3.95(mc, 4H)	4.15(dd, 2H)	4.18(m, 2H)	4.19(d, 2H)
	1.20(t, 6H)	3.14(t, 1H)	3.16(sb, 1H)	3.18(sb, 1H)
NH	4.17(sb, 2H)	9.69(sb, 1H)	10.24(sb, 1H)	10.40(sb, 1H)
	3.15(sb, 1H)	7.55(tb, 1H)	8.17(sb, 1H)	8.24(sb, 1H)
	10.19(sb, 1H)			7.15(sb, 2H)
	8.34(sb, 1H)
Chrom.	EA krist.	DCM/MeOH	—	krist.
Ausbeute	H/DIPE	95:5	85%	DIPE/EtOH
	23%	25%		17%
Schmp.	198° C.	217-218° C.	>235° C.	>235° C.

[0138]

	97	98	99
Beispiel Nr.	44	45	4
6-H	8.34(s, 1H)	8.34(s, 1H)	8.23n(sb, 1H)
2CH	7.93(d, 2H)	7.74(mc, 4H)	7.39(d, 2H)
	7.79(d, 2H)		6.79(d, 2H)
4CH	4.20(sb, 2H)	4.55(q, 1H)	3.52-3.71(2H)
	3.31(sb, 1H)	1.98(dq, 2H)	3.97(mc, 1H)
		0.94(t, 3H)	1.96(mc, 1H)
		3.61(s, 3H)	0.91(d, 3H)
NH	11.03(sb, 1H)	10.60(s, 1H)	0.85(d, 3H)
	9.04(sb, 1H)	7.97(d, 1H)	10.35(sb, 1H)
	7.34(sb, 2H)	7.31(db, 2H)	7.76(sb, 1H)
Chrom.	krist. EtOH	krist. EtOH	—
Ausbeute	27%	48%	52%
Schmp.	252° C.	235° C.	242-243° C.

[0139]

Beispiel	100	101	102	103
Nr.	10	15	3	19
6-H	8.27 (s,1H)	8.17 (s,1H)	7.97 (s,1H)	8.20-8.35
2H	7.80	7.60 (d,2H)	7.44 (d,2H)	(2H)
	(mc,4H)	7.24 (d,2H)	6.67 (d,2H)	7.90 (sb,1H)
		2.44 (s,3H)		7.50-7.64
				(2H)
				3.46 (t,2H)
4H		3.5-3.7 (2H)	3.50-3.65	3.70 (t,2H)
	3.66.	40.1 (mc,1H)	(4H)
	(mc,2H)	1.98 (mc,1H)	4.12 (mc,1H)	3-56-3.66
	n.obs.	0.94 (d,3H)		(4H)
	2.04	0.90 (d,3H)		4.28 (mc,1H)
NH	(mc,1H)	9.95 (sb,1H)
OH	0.97 (d,3H)	6.96 (sb,1H)	8.98 (sb,1H)
	0.94 (d,3H)	ca.4, sehr	5.97 (db,1H)
	10.40	breit	8.90 (sb,1H)	NH and OH
	(sb,1H)		4.80 (tb,2H)	sind sehr
	7.18(sb,2H)			breit
	n. obs.
Chrom.	—	—	—	Kristallisiert
				Wasser
Aus-	43%	27%	76%	52%
beute
Schmp.	252-253° C.	192-193° C.	257-258° C.	209-210° C.

[0140]

Beispiel	104	105	106	107
Nr.	9	14	55	50
6-H	8.30 (s,1H)	8.30 (s,1H)	8.11 (s,1H)	8.17 (s,1H)
2H	7.82	7.55 (d,2H)	7.87 (s,4H)	7.95 (d,2H)
	(mc,4H)	7.30 (d,2H)	2.50 (s)	7.86 (d,2H)
		2.48 (s,3H)		2.50 (s)
4H		3.54-3.68	4.19 (mc,1H)	4.17 (dd,2H)
	3.63	(4H)	3.61 (mc,4H)	3.13 (t,1H)
	(mc,4H)	4.24 (mc,1H)
NH	4.24		9.73 (s,1H)	9.81 (s,1H)
OH	(mc,1H)	10.63 (sb,1H)	6.20 (s,1H)	7.58 (t,1H)
		7.60 (sb,1H)	4.88 (t,2H)
	10.59 (b,1H)	4.4 (b)
	7.2 (sb)
	6.1 (sb)
Chrom.	Kristallisiert		Kristallisiert	—
Aus-	MeOH		MeOH/DIPE
beute	24%	91%	27%	56%
Schmp.	247-248° C.	233-234° C.	228-229° C.	241° C.

[0141]

Beispiel	108	109	110	111
Nr.	46	13	52	53
6-H	8.07s,1H)	8.00 (s,1H)	8.09 (s,1H)	8.11 (s,1H)
2H	7.91 (d,2H)	7.68 (d,2H)	7.88 (s,4H)	7.86 (s,4H)
	7.69 (d,2H)	7.18 (d,2H)		not obs.
		2.44 (s,3H)
4H	3.30 (t,2H)	3.54 (q,2h9	3.32 (t,2H)	3.62 (mc,2H)
	n.obs.(mc,1	2.53 (t,2H)	1.20 (mc,1H)	4.06 (mc,1H)
	H)	2.40-2.45	0.44 (mc,2H)	2.02 (mc,1H)
	0.45	(4H)	0.30 (mc,2H)	0.97 (d,3H)
	(mc,2H)	3.58 (t,4H)		0.92 (d,3H)
NH	0.30		9.70 (s,1H)	9.70 (s,1H)
OH	(mc,2H)	9.20 (sb,1H)	7.21 (t,1H)	6.24 (d,1H)
		6.81 (tb,1H)		4.80 (sb,1H)
	9.94 (s,1H)
	7.21 (t,1H)
	7.18 (s,2H)
Chrom.	H/EA 1:2	—	—	H/EA 1:2
Aus-	20%	28%	53%	9%
beute
Schmp.	256° C.	185-186° C.	183° C.	170° C.

[0142]

Beispiel	112	113	114	115
Nr.	1	54	12	60
6-H	7.96 (s,1H)	8.22 (s,1H)	8.03 (s,1H)	8.10 (s,1H)
2H	7.43 (d,2H)	7.93 (d,2H)	7.68 (d,2H)	7.92 (d,2H)
	6.67 (d,2H)	7.85 (d,2H)	7.19 (d,2H)	7.66 (d,2H)
			2.43 (s,3H)	not. obs.
				2.74 (t,2H)
4H	1.20 (d,3H)	4.26 (d,2H)	1.20 (d,3H)	3.61 (mc,2H)
	4.38	3.12 (sb,1H)	4.42 (mc,1H)	4.04 (mc,1H)
	(mc,1H)		3.37 (dd,1H)	2.01 (mc,1H)
	3.37 (dd,1H)		3.50 (dd,1H)	0.94 (d,3H)
	3.48 (dd,1H)		3.34 (s,3H)	0.91 (d,3H)
NH	3.28 (s,3H)	9.78 (s,1H)	9.26 (s,1H)	9.72 (s,1H)
	8.92 (sb,1H)			7.65 (s,1H)
	8.81 (sb,1H)			6.27 (d,1H)
OH		7.21 (t,1H)	6.42 (d,1H)	4.80 (sb,1H)
	6.20 (tb,1H)			4.70 (sb,1H)
Chrom.	Kristallisiert	Kristallisiert	Kristallisiert.
Aus-	EA	DIPE/MeOH	EA
beute	64%	52%	36%
Schmp.	165.5-	210° C.	91° C.	150-151° C.
	166° C.

[0143]

Beispiel	116	117	118	119
Nr.	7	17	2	18
6-H	8.32 (s,1H)	8.08 (s,1H)	7.95 (s,1H)	8.32 (s,1H)
4CH	1.22 (d,3H)	1.21 (d,3H)	3.50 (q,2H)	3.10 (m,2H)
	4.46	4.53 (mc,1H)	2.50 (t,2H)	3.52 (m,4H)
	(mc,1H)	3.41 (dd,1H)	2.40 (t,4H)	3.77-3.97
	3.40 (dd,1H)	3.51 (dd,1H)	3.59 (t,4H)	(6H)
	3.57 (dd,1H)	3.27 (s,3H)
2CH	3.28 (s,3H)	8.53 (s,1H)	7.45 (d,2H)
	7.80 (s,4H)	7.40 (d,1H)	6.66 (d,2H)	8.40 (s,1H)
		7.50 (t,1H)		7.55-7.70
		7.86 (d,1H)		(2H)
		3.40 (t,2H)		7.85 (d,1H)
		3.68 (t,2H)		3.48 (m,2H)
NH		9.65 (sb,1H)	8.94 (sb,1H)	3.70 (m,2H)
	10.79	6.47 (db,1H)	8.79 (sb,1H)
OH	(sb,1H)	4.84 (tb,1H)	6.70 (tb,1H)	11.16 (sb,1H)
	7.84 (db,1H)			10.60 (sb,1H)
	7.31 (sb,2H)			8.20 (sb,1H)
Chrom.		—	—	kristall.
Aus-	25%	10%	62%	MeOH
beute				50%
Schmp.	247° C. Zers.	201-202° C.	227.5-	245° C. Zers.
			228.5° C.

[0144]

Beispiel 120
Nr.      8 (D2O)
6-H      8.14 (s,1H)
4CH      3.06 (sb,2H)
         3.39 (t,4H)
         3.71 (sb,2H)
         3.85 (sb,2H)
         3.94 (t,2H)
2CH      8.00 (d,2H)
         7.72 (d,2H
NH
OH
Chrom.   krist. Wasser
Aus-     25%
beute
Schmp.   >275° C.

[0145]

Beispiel	121	122	123	124
Nr.	47	6	22	84
5-H	8.74 (s,1H)	8.31 (s,1H)	8.31 (s,1H)	8.47 (s,1H)
2CH	7.87 (d,2H)	7.47 (d,2H)	7.76 (d,2H)	4.48 (t,2H)
	7.74 (d,2H)	6.71 (d,2H)	7.72 (d,2H)	2.01 (mc,2H)
			2.58 (s,3H)	2.44 (mc,2H)
4CH	4.50 (t,2H)	5.04 (d,2H)	5.05 (d,2H)
	2.03 (mc,2H)	3.59 (t,1H)	2.57 (t,1H)	7.91 (d,2H)
	2.44 (mc,2H)
2NH	10.14 (s,1H)	9.02 (sb,1H)	7.47 (sb,1H)	7.85 (d,2H)
	7.21 (s,2H)	9.40 (sb,1H)		2.50 (s)
				10.19(s,1H)
Chrom.	MeOH/DCM		—	—
Aus-	1:9	66%	8%	11%
beute	4%
Schmp.	186-187° C.	146° C.	165-166° C.	152° C.

[0146]

Beispiel	125	126
Nr.	86	77
5-H	8.47 (s,1H)	8.48 (s,1H)
2CH	4.07 (mc,2H)	5.52 (m,1H)
	3.81 (mc,2H)	3.68 (d,4H)
	3.60 (mc,2H)	3.48 (mc,4H)
4CH	3.48 (mc,2H)	1.09 (t,6H)
	3.41 (t,2H)	7.84 (d,2H)
	1.07 (t,3H)
2NH	7.84 (d,2H)	7.74 (d,2H)
	7.91 (d,2H)	8.05 (vb)
	10.18 (s,1H)	3.40 (vb)
Chrom.	—	—
Aus-	2%	74%
beute
Schmp.	85° C.	132° C.

[0147]

Beispiel	127	128
Nr.	40	20
6-H	8.36 (s,1H)	8.40 (s,1H)
2CH	7.60 (d,1H)	7.23 (s,1H)
	6.91 (d,1H)	6.42 (d,1H)
	4.28 (dd,1H)	7.06 (t,1H)
	3.79 (dd,1H)	7.18 (d,1H)
	3.31 (m,1H)
	2.84 (dd,1H)
	2.70 (dd,1H)
4CH	5.07 (d,12H)	5.12 (d,2H)
	3.65 (t,1H)	3.60 (sb,1H)
NH	9.65 (sb,1H)	9.60 (sb,1H)
OH		9.21 (sb,1H)
Chrom.	H/EA 1:3	krist. DIPE
Aus-	0.5% TEA	35%
beute	38%
Schmp.	140-141° C.	174° C.

[0148]

Beispiel	129	130	131	132
Nr.	49	48	29	42
6-H	8.14 (s,1H)	8.10 (s,1H)	8.09 (s,1H)	7.87 (d,3.4,1H)
2H	7.88 (d,2H)	7.92 (d,2H)	8.50 (s,1H)	7.51 (d.2H)
	7.69 (d,2H)	7.66 (d,2H)	7.86 (d,1H)	6.66 (d,2H)
		not. obs.	7.50 (t,1H)
		2.74 (t,2H)	7.40 (d,1H)
4H	3.41 (q,2H)	3.61 (mc,2H)	3.40 (t,2H)	4.13 (dd,2H)
	2.20 (t,2H)	4.04 (mc,1H)	3.52-3.73	3.08 (t,1H)
	1.81 (q,2H)	2.01 (mc,1H)	(4H)
		0.94 (d,3H)	4.09 (mc,1H)
		0.91 (d,3H)	1.98 (mc,1H)
			0.97 (d,3H)
NH	9.64 (s,1H)	9.72 (s,1H)	0.89 (d,3H)	8.76 (s,1H)
	7.64 (t,1H)	7.65 (s,1H)	9.68 (s,1H)	7.74 (tb,1H)
OH	3.5(vb	6.27(d,1H)	6.17(d,1H)	8.88(s,1H)
		4.80 (sb,1H)	4.74 (t,1H)
		4.70 (sb,1H)	4.93 (t,1H)
Chrom.	—	krist.MeOH/DI	DCM/EA 2:1	H/EA 1:2
Aus-	9%	PE	26%	29%
beute		16%
Schmp.	262° C.	150-151° C.		163° C.

[0149]

	133	134	135	136
Beispiel	43	55	89	88
Nr.
6-H	7.93 (s, 1H)	8.11(s, 1H)	8.36(s,1H)	8.29(s, 1H)
2H	7.52(d, 2H)	7.87 (s, 4H)	7.7-7.8(5H)	7.73(d, 2H)
	6.68(d, 2H)	2.50(s)		7.57(d, 2H)
4H	3.09(s, 1H)	4.19(mc, 1H)	3.66(mc, 2H)	3.7-3.9(2H)
	4.14(d, 2H)	3.61(mc, 4H)	4.04(m, 1H)	5.19(m, 1H)
			1.99(mc, 1H)	7.2-7.4(5H)
			0.94(d, 3H)
			0.89(d, 3H)
NH	8.98(sb, 2H)	9.73(s, 1H)	11.11(sb, 1H)	10.50(s, 1H)
	7.50(s, 1H)	6.20(s, 1H)		5.029(vb)
OH		4.88(t, 2H)	7.34(sb, 2H)
			n. obs.
Chrom	H/EA 1:2	krist. MeOH/	—	—
Aus-	35%	DIPE	74%	27%
beute		27%
Schmp.	168° C.	228° C.	248° C. Zers.	159° C. Zers.

[0150]

	137	138	139	140
Beispiel	87	92	91	96
Nr.
6-H	8.09(s, 1H)	8.10(s, 1H)	8.09(s, 1H)	8.06(s, 1H)
2H	7.90(d, 2H)	7.91(d, 2H)	7.98(d, 2H)	7.88(d, 2H)
	7.82(d, 2H)	7.63(d, 2H)	7.61(d, 2H)	7.69(d, 2H)
	not. obs	2.39(d, 3H)	2.54(s, 6H)
4H	3.69(td, 2H)	1.21(d, 3H)	1.20(d, 3H)	2.41(m, 2H)
	2.84(t, 2H)	4.45(mc, 1H)	4.46(mc, 1H)	1.62(m, 4H)
	7.60(s, 1H)	3.38(dd, 1H)	3.47(dd, 1H)	2.41(m, 2H)
	6.86(s, 1H)	3.51(dd, 1H)	3.51(dd, 1H)	5.07(s, 2H)
			3.38(s, 3H)
NH	7.34(tb, 1H)	9.73(sb, 1H)	9.81(sb, 1H)	7.32(s, 5H)
	9.72(s, 1H)	7.20(q, 1H)	6.58(db, 1H)	9.64(s, 1H)
				7.16(sb, 2H)
OH	11.91(sb, 1H)	6.57(d, 1H)
Chrom.	—	H bis H/EA 1:1	H bis H/EA	—
Aus-	16%	21%	1:1	33%
beute			7%
Schmp.	210° C.	167-168° C.	105° C.	202° C.

[0151]

	141	142	143	144
Beispiel	97	98	90	85
Nr.
6-H	8.07(s, 1H)	8.10(s, 1H)		8.30(s, 1H)
2H	7.87(s, 4H)	7.86(mc, 4H)		7.95(d, 2H)
	2.50(s, 3H)	n. obs.		7.69(d, 2H)
				2.48(s, 3H)
4H	3.41(m, 2H)	3.68(t, 2H)		3.50(q, 2H)
	1.61(m, 4H)	2.68(t, 2H)		1.87(m, 2H)
	2.41(m, 2H)	4.08(q, 2H)		2.38(t, 2H)
	5.07(s, 2H)	1.17(t, §H)		4.03(q, 2H)
				1.13(t, 3H)
NH	7.32(s, 5H)	9.74(s, 1H)		10.86(s, 1H)
	9.70(s, 1H)	7.18(t, 1H)		8.28(sb, 2H)
	7.19(t, 1H)
Chrom.	—	—		—
Aus-	23%	32%		53%
beute
Schmp.	152° C.	172		184° C.

[0152]

	145	146	147	148
Beispiel	63	94	93	80
Nr.
	9.73(s, 1H)	10.91(s, 1H)	10.80(s, 1H)	10.88(s, 1H)
	8.25(s, 1H)	8.34(s, 1H)	8.30(s, 1H)	8.40(s, 1H)
	7.95(d, 2H)	7.80(s, 4H)	7.81(d, 2H)	8.29(m, 1H)
	7.67(d, 2H)	7.30(s, 2H)	7.65(d, 2H)	7.79(s, 4H)
	7.21(s, 3H)	4.35(m, 1H)	7.30(m, 8H)	7.31(s, 2H)
	4.12(s, 2H)	3.58(m, 2H)	4.95(d, 1H)	4.75(dd, 1H)
	3.12(s, 1H)	2.47(m, 2H)	4.38(m, 1H)	3.65(m, 1H)
		2.03(s, 3H)	3.59(d, 1H)	3.49(m, 1H)
		1.91(m, 2H)		2.10(m, 2H)
Aus.	61%	24%	70%	51%
beute
Schmp.	220	168	243
Masse	428(EI)	462(ES)	494(ES)	427(EI)

[0153]

	149	150
Beispiel	120	121
Nr.
	9.65(s, 1H)	9.68(s, 1H)
	8.12(s, 1H)	8.11(s, 1H)
	7.89(d, 2H)	7.93(t, 1H)
	7.65(d, 2H)	7.90(d, 2H)
	7.15(s, 2H)	7.65(d, 2H)
	6.06(d, 1H)	7.15(s, 2H)
	4.71(t, 1H)	7.07(t, 1H)
	4.18(m, 1H)	3.65(m, 2H)
	3.67(t, 1H)	3.56(s, 3H)
	0.95(s, 9H)	3.07(q, 2H)
		2.45(t, 2H)
		2.30(t, 2H)
		1.65(p, 2H)
Aus-	49%	24%
beute
Schmp.
Masse	445(EI)	516(EI)
	151	152
Beispiel	122	123
Nr.
	11.30(s, 1H)	10.79(s, 1H)
	8.11(d, 1H)	8.35(s, 1H)
	7.85(d, 2H)	8.25(S, 1H)
	7.72(d, 2H)	7.80(s, 4H)
	7.31(s, 2H)	7.30(s, 2H)
	6.71(d, 1H)	3.41(m, 2H)
	3.85(m, 8H)	2.22(t, 2H)
		1.60(m, 4H)
		1.30(m, 2H)
Aus-	80%	73%
beute
Schmp.		252
Masse	334(EI)	459(EI)

[0154]

	153	154
Beispiel	95	124
Nr.
	11.19(s, 1H)	9.62(s, 1H)
	8.37(s, 1H)	8.04(s, 1H)
	8.11(d, 1H)	7.88(m, 3H)
	7.80(s, 4H)	7.66(d, 2H)
	7.31(s, 2H)	7.13(s, 3H)
	3.91(m, 1H)	3.58(s, 3H)
	1.89(m, 4H)	3.40(m, 2H)
	1.67(m, 1H)	3.05(m, 2H)
	1.55(m, 2H)	2.25(m, 2H)
	1.34(m, 2H)	2.05(m, 2H)
	1.15(m, 1H)	1.60(m, 5H)
	1.32(m, 3H)
Aus-	29%	25%
beute
Schmp.	255
Masse	425(EI)	557(ES)
	155	156
Beispiel	125	126
Nr.
	9.62(s, 1H)	10.91(s, 1H)
	8.04(s, 1H)	8.38(s, 1H)
	7.86(d, 2H)	7.83(d, 2H)
	7.66(d, 2H)	7.77(d, 2H)
	7.12(s, 3H)	7.28(s, 2H)
	3.58(s, 3H)	7.04(d, 1H)
	3.40(m, 2H)	6.40(br, 3H)
	2.30(t, 2H)	4.35(m, 1H)
	1.60(m, 4H)	3.87(m, 1H)
	1.32(m, 2H)	3.60(d, 2H)
		3.41(dd, 1H)
		3.28(dd, 1H)
Aus-	27%	46%
beute
Schmp.	218
Masse	471(EI)	449(EI)

[0155]

	157	158
Beispiel	127	128
Nr.
	9.96(s, 1H)	9.60(s, 1H)
	8.12(s, 1H)	8.05(s, 1H)
	7.85(d, 2H)	7.90(d, 2H)
	7.69(d, 2H)	7.69(d, 2H)
	7.20(s, 2H)	7.42(d, 1H)
	6.78(d, 1H)	7.16(m, 3H)
	4.35(m, 1H)	4.57(t, 2H)
	3.48(m, 2H)	3.70(m, 1H)
	1.65(m, 7H)	3.4(m, 5H)
	1.10(m, 6H)	2.10(t, 2H)
		1.55(m, 4H)
		1.30(m, 2H)
Aus-	18%	94%
beute
Schmp.	220
Masse	485(EI)	531(ES)
	159	160
Beispiel	129	130
Nr.
	9.67(s, 1H)	9.65(s, 1H)
	8.07(s, 1H)	8.08(s, 1H)
	7.87(d, 2H)	7.87(d, 2H)
	7.75(d, 2H)	7.64(d, 2H)
	7.13(s, 2H)	7.14(s, 2H)
	6.40(d, 1H)	6.53(d, 1H)
	4.91(br, 1H) 4.62(d, 1H)
	4.23(m, 1H)	3.90(br, 1H)
	3.52(m, 2H)	3.40(br, 1H)
	1.21(d, 3H)	1.88(m, 4H)
		1.50(m, 2H)
		1.30(m, 2H)
Aus-	61%	58%
beute
Schmp.	259	262
Masse	403(EI)	443(EI)

[0156]

	161	162	163	164
Beispiel	131	132	133	134
Nr.
	9.62(s, 1H)	9.70(s, 1H)	9.69(s, 1H)	10.85(s, 1H)
	8.08(s, 1H)	8.11(s, 1H)	8.11(s, 1H)	8.31(s, 1H)
	7.92(d, 2H)	7.90(d, 2H)	7.88(d, 2H)	7.90(d, 1H)
	7.67(d, 2H)	7.60(d, 2H)	7.66(d, 2H)	7.85(d, 2H)
	7.23(s, 2H)	7.21(q, 1H)	7.15(s, 2H)	7.75(d, 2H)
	6.75(t, 1H)	5.25(d, 1H)	6.52(d, 1H)	7.54(s, 1H)
	3.22(d, 2H)	4.77(t, 1H)	4.35(dd, 1H)	3.90(m,1H)
	1.95(s, 3H)	4.02(m, 1H)	2.29(m, 1H)	3.38(t, 2H)
	1.60(m, 12H)	3.60(m,2H)	1.07(d, 3H)	2.78(br, 2H)
		2.39(d, 3H)	0.91(d, 3H)	1.50(m, 11H)
		2.02(m, 1H)
		0.95(dd, 6H)
Aus-	9%	42%	25%	64%
beute
Schmp.	229	141
Masse	491(EI)	443(EI)	444(FAB)

[0157]

	165	166
Beispiel	135	136
Nr.
	10.01(s, 1H)	9.70(s, 1H)
	8.28(s, 1H)	8.11(s, 1H)
	7.81(d, 2H)	7.90(d, 2H)
	7.71(t, 1H)	7.64(d, 2H)
	7.63(d, 2H)	7.35(t, 1H)
	7.45(br, 1H)	6.55(d, 1H)
	4.34(dt, 2H)	4.65(t, 1H)
	3.32(t, 2H)	4.45(m, 1H)
	2.71(br, 2H)	3.53(m, 1H)
		3.44(m, 6H)
		2.75(q, 2H)
		1.20(d, 3H)
Aus-	34%	53%
beute
Schmp.
Masse	570(ES)	460(ES)
	167	168
Beispiel	137	138
Nr.
	9.65(s, 1H)	9.70(s, 1H)
	9.58(s, 1H)	8.10(s, 1H)
	8.10(s, 1H)	7.89(d, 2H)
	7.85(d, 2H)	7.63(d, 2H)
	7.68(d, 2H)	7.39(t, 1H)
	7.40(m, 2H)	6.68(d, 1H)
	7.18(m, 4H)	4.34(dd, 1H)
	6.94(t, 1H)	3.36(m, 3H)
	6.75(d, 1H)	2.25(q, 2H)
	4.40(m, 3H)	2.29(m, 1H)
	2.05(m, 1H)	1.05(dd, 6H)
	0.96(dd, 6H)
Aus-	59%	57%
beute
Schmp.
Masse	549(ES)	488(ES)

[0158]

	169	170	171	172
Beispiel	139	140	141	142
Nr.
	9.82(s, 1H)	9.82(s, 1H)	9.58(s, 1H)	9.62(s, 1H)
	8.15(s, 1H)	8.08(s, 1H)	8.12(s, 1H)	8.97(s, 1H)
	7.82(d, 2H)	7.96(d, 2H)	7.83(d, 2H)	7.87(d, 2H)
	7.64(d, 2H)	7.75(t, 1H)	7.68(d, 2H)	7.67(d, 2H)
	7.39(t, 1H)	7.62(d, 2H)	7.15(s, 2H)	7.14(s, 2H)
	6.55(d, 1H)	7.30(t, 1H)	5.92(s, 1H)	6.36(d, 1H)
	4.64(t, 1H)	4.64(t, 1H)	5.28(t, 1H)	4.81(t, 1H)
	4.50(t, 1H)	4.14(m, 2H)	3.50(d, 2H)	4.32(m, 1H)
	3.65(s, 3H)	3.35(m, 2H)	1.42(s, 6H)	3.47(m, 2H)
	3.4(m, 2H)	3.16(m, 1H)		1.52(m, 3H)
	2.75(m, 2H)	2.75(q, 2H)		0.90(d, 3H)
	2.35(m, 1H)		0.86(d, 3H)
	1.00(dd, 6H)
Aus-	20%	63%	23%	8%
beute
Schmp.
Masse	502(ES)	382(ES)	415(EI)	443(EI)

[0159]

	173	174	175	176
Beispiel	143	144	145	78
Nr.
	10.6(s, 1H)	10.11(s, 1H)	11.05(s, 1H)	9.69(s, 1H)
	8.28(s, 1H)	8.45(s, 1H)	8.32(s, 1H)	8.06(s, 1H)
	8.30(m, 5H)	7.86(d, 2H)	8.08(d, 1H)	7.88(d, 2H)
	7.48(d, 1H)	7.78(d, 2H)	7.80(m, 4H)	7.63(d, 2H)
	7.20(s, 1H)	7.15(br, 2H)	7.30(br, 2H)	7.18(s, 2H)
	4.05(br, 1H)	5.32(m, 1H)	3.88(m, 1H)	7.10(t, 1H)
	3.60(br, 2H)	3.91(m, 2H)	3.65(m, 1H)	6.65(d, 1H)
	2.01(m, 1H)	3.53(m, 2H)	1.95(m, 2H)	4.47(m, 1H)
	0.90(m, 6H)	2.05(m, 2H)	1.69(m, 2H)	3.97(m, 1H)
		1.70(m, 2H)	1.35(m, 4H)	2.98(m, 2H)
				2.00(m, 4H)
				1.40(m, 8H)
				0.85(t, 3H)
Aus-	13%	47%	42%	20%
beute
Schmp.
Masse	392(EI)	428(EI)	441(EI)	541(ES)

[0160]

	177	178	179	180
Beispiel	146	147	148	149
Nr.
	11.13(s, 1H)	11.18(s, 1H)	11.15(s, 1H)	9.19(s, 1H)
	8.38(s, 1H)	8.35(s, 1H)	8.35(s, 1H)	8.30(s, 1H)
	7.92(d, 2H)	7.90(s, 4H)	7.90(d, 2H)	8.02(s, 1H)
	7.75(m, 3H)	7.62(d, 1H)	7.65(m, 3H)	7.62(m, 1H)
	4.04(m, 1H)	4.02(m, 1H)	4.01(m, 1H)	6.85(d, 1H)
	3.80(s, 3H)	3.62(m, 2H)	3.60(m, 6H)	6.05(d, 1H)
	3.65(m, 2H)	3.02(s, 3H)	2.85(m, 4H)	4.03(m, 1H)
	2.00(m, 1H)	2.00(m, 1H)	2.00(m, 1H)	3.56(m, 2H)
	0.96(d, 3H)	0.95(d, 3H)	0.95(d, 3H)	1.96(m, 1H)
	0.89(d, 3H)	0.89(d, 3H)	0.85(d, 3H)	0.97(d, 3H)
				0.90(d, 3H)
Aus-	86%	33%	79%	42%
beute
Schmp.	225	211	232	241
Masse	408(EI)	428(EI)	501(EI)	411(ES)

[0161]

	181	182	183	184
Beispiel	150	151	152	153
Nr.
	11.19(s, 1H)	10.96(s, 1H)	9.50(s, 1H)	12.90(s, 1H)
	10.80(s, 1H)	8.35(s, 1H)	8.08(s, 1H)	9.45(s, 1H)
	8.30(m, 2H)	7.95(m, 2H)	7.75(m, 5H)	8.52(s, 1H)
	7.85(d, 1H)	7.65(m, 3H)	6.17(d, 1H)	8.05(s, 1H)
	7.72(d, 1H)	4.04(m, 1H)	4.80(br, 1H)	7.82(d, 1H)
	7.20(d, 1H)	3.62(m, 2H)	4.64(br, 2H)	7.50(d, 1H)
	4.02(m, 1H)	2.00(m, 1H)	4.05(m, 1H)	7.32(t, 1H)
	3.60(m, 2H)	0.90(M, 6H)	3.94(m, 1H)	6.11(d, 1H)
	2.00(m, 1H)		3.52(m, 6H)	4.72(s, 1H)
	1.01(d, 3H)		2.01(m, 1H)	4.10(s, 1H)
	0.90(d, 3H)		0.93(dd, 6H)	3.60(m, 2H)
				2.01(m, 1H)
				0.99(d, 3H)
				0.92(d, 3H)
Aus-	27%	65%	85%	9%
beute
Schmp.				231
Masse	420(ES)	395(ES)	468(ES)	395(ES)

[0162]

	185	186	187	188
Beispiel	154	155	156	157
Nr.
	10.91(s, 1H)	11.05(s, 1H)	10.51(s, 1H)	15.5° (s, 1H)
	8.38(s, 1H)	8.34(m, 2H)	8.22(s, 1H)	9.50(s, 1H)
	7.90(d, 1H)	7.75(m, 3H)	7.71(d, 1H)	8.40(s, 1H)
	7.80(m, 4H)	7.52(t, 1H)	7.27(m, 1H)	8.11(s, 1H)
	7.05(d, 1H)	4.04(m, 1H)	6.86(m, 2H)	7.80(d, 1H)
	4.50(s, 2H)	3.85(s, 3H)	6.06(s, 2H)	7.53(d, 1H)
	4.04(m, 1H)	3.65(m, 2H)	3.96(m, 1H)	6.16(d, 1H)
	3.62(m, 2H)	2.00(m, 1H)	3.62(m, 2H)	4.78(br, 1H)
	1.96(m, 1H)	0.94(d, 3H)	1.99(m, 1H)	4.03(m, 1H)
	0.93(d, 3H)	0.85(d, 3H)	0.90(m, 6H)	3.60(m, 2H)
	0.85(d, 3H)			2.01(m, 1H)
				0.91(dd, 6H)
Aus-	90%	48%	77%	21%
beute
Schmp.	170	181	177	196
Masse	381(ES)	409(ES)	394(EI)	391(EI)

[0163]

	189	190	191	192
Beispiel	158	159*	160*	161*
Nr.
	10.80(s, 1H)	9.65	9.65	7.92(s, 1H)
	8.31(s, 1H)	(s, 1H, 1+2)	(s, 1H, 1+2)	7.84(d, 2H)
	7.97(d, 2H)	8.08	8.08	7.58(d, 2H)
	7.88(m, 3H)	(s, 1H, 1+2)	(s, 1H, 1+2)	3.72(m, 1H)
	7.52(m, 5H)	7.88	7.88	3.35(m, 2H)
	4.01(m, 1H)	(d, 2H, 1+2)	(d, 2H, 1+2)	3.10(m, 1H)
	3.62(m, 2H)	7.65	7.65	2.91(m, 2H)
	2.00(m, 1H)	(d, 2H, 1+2)	(d, 2H, 1+2)	2.00(m, 2H)
	0.91(m, 6H)	7.15	7.15	1.89(m, 2H)
		(s, 1H, 1+2)	(s, 1H, 1+2)	1.66(m, 4H)
		6.62(d, 1H, 2)	6.62(d, 1H, 2)	1.39(m, 5H)
		6.40(d, 1H, 1)	6.40(d, 1H, 1)
		4.05(m, 1H, 1)	4.05(m, 1H, 1)
		3.89(m, 1H, 2)	3.89(m, 1H, 2)
		2.30-1.20	2.30-1.20
		(m, 15H, 1+2)	(m, 15H, 1+2)
Aus-	37%	21%	14%	8%
beute
Schmp.			199	>300
Masse	469(EI)	468(EI)	468(EI)	508(EI)

[0164]

	193	194
Bsp.-Nr.	162	163*
	11.25(s, 1H)	10.95(s, 1H)
	9.40(s, 1H)	10.72(s, 1H)
	8.47(s, 1H)	9.47(br, 2H)
	8.29(s, 1H)	9.30(br, 2H)
	7.63(s, 1H)	8.32(2xs, 2H)
	7.43(d, 1H)	8.08(d, 1H)
	7.07(m, 3H)	7.88(d, 2H)
	4.06(m, 1H)	7.75(m, 6H)
	3.63(m, 2H)	7.30(br, 4H)
	1.98(m, 1H)	6.95(d, 1H)
	0.95(d, 3H)	4.12(m, 1H)
	0.85(d, 3H)	3.98(m, 1H)
		3.30(m, 1H)
		3.10(m, 1H)
		2.69(m, 2H)
		2.25(m, 2H)
		1.80(m, 18H)
		1.01(m, 4H)
		0.72(m, 4H)
Aus-	16%	33%
beute
Schmp.	195
Masse	446(ES)	480(EI)
	195	196
Bsp.-Nr.	164	165
	9.65(s, 1H)
	8.54(s, 1H)
	8.10(s, 1H)
	7.82(d, 1H)
	7.45(m, 2H)
	6.20(d, 1H)
	4.70(t, 1H)
	4.10(m, 1H)
	3.60(m, 2H)
	3.15(s, 3H)
	2.00(m, 1H)
	0.96(d, 3H)
	0.89(d, 3H)
Aus-	14%	51%
beute
Schmp.		162-164
Masse	429(ES)	462(EI)

[0165]

	197	198
Beispiel	166	167 *
Nr.
	10.90(s, 1H)	11.15(br, 1H)
	8.95(s, 1H)	10.90(s, 1H)
	7.93(m, 2H)	9.75(br, 2H)
	7.25(m, 3H)	8.35(s, 1H)
	6.30(s, 1H)	7.78(m, 4H)
	6.00(d, 1H)	7.30(br, 2H)
	4.75(tr, 1H)	4.15(m, 1H)
	4.05(m, 1H)	3.50(m, 5H)
	3.60(m, 2H)	2.85(s, 6H)
	2.00(m, 1H)	1.90(m, 8H)
	1.00(m, 6H)
Aus-	6%	16%
beute
Schmp.		256
Masse	390(ES)	512(ES)
	199	200
Beispiel	168*	169
Nr.
	11.30(br, 2H)	9.05(br, 1H)
	11.08(s, 1H)	8.85(s, 1H)
	10.92(s, 1H)	8.11(d, 1H)
	9.90(s, 1H)	7.97(s, 1H)
	9.70(s, 1H)	7.47(dd, 1H)
	8.36(2xs, 2H)	6.80(d, 1H)
	8.20(d, 1H)	5.95(d, 1H)
	7.93(d, 2H)	4.80(br, 2H)
	7.75(m, 6H)	3.90(m, 2H)
	7.35(br, 4H)	3.45(m, 6H)
	7.10(d, 1H)	2.00(m, 1H)
	4.15(m, 1H)	0.90(m, 6H)
	3.98(m, 1H)
	3.64(m, 8H)
	3.40(m, 5H)
	3.10(m, 5H)
	1.95(m, 26H)
Aus-	58%	60%
beute
Schmp.	261
Masse	538(ES)	484(ES)

[0166]

	201	202	203	204
Beispiel	170*	171	172	173
Nr.
	11.05(s, 1H)	10.45(s, 1H)	11.05(s, 1H)	8.90(s, 1H)
	10.90(s, 1H)	8.25(s, 1H)	8.35(m, 2H)	8.72(s, 1H)
	10.6(br, 2H)	8.00(br, 1H) 7.82(d, 1H)	7.95(s, 1H)
	8.35(2xs, 2H)	7.85(d, 2H)	7.65(d, 2H)	7.18(m, 1H)
	8.15(d, 1H)	7.75(d, 2H)	7.50(t, 1H)	7.05(dd, 1H)
	7.80(m, 8H)	7.45(br, 1H)	4.05(m, 1H)	6.75(d, 1H)
	7.30(br, 4H)	3.60(m, 5H)	3.62(m, 2H)	5.99(d, 1H)
	7.05(m, 1H)	3.35(m, 2H)	2.00(m, 1H)	4.74(t, 1H)
	4.25(m, 1H)	2.80(m, 2H)	0.96(d, 3H)	4.03(m, 1H)
	3:95(m, 2H)	2.41(t, 2H)	0.85(d, 3H)	3.70 .(s, 3H)
	3.65(m, 1H)	1.90(m, 2H)		3.60(m, 2H)
	3:20(m, 10H)		2.00(m, 1H)
	1.90(m, 24H)			0.90(m, 6H)
Aus-	64%	7%	65%	40%
beute
Schmp.	226	164	206	144
Masse	525(ES)	488(ES)	395(ES)	397(ES)

[0167]

	205	206
Beispiel	174*	175*
Nr.
	11.05(m, 3H)	11.15(br, 1H)
	10.48(s, 1H)	11.05(s, 2H)
	8:38(s, 2H)	10.65(br, 1H)
	7.80(m, 8H)	8.30(s, 2H)
	7.80(br, 4H)	8.13(m, 2H)
	7.10(s, 1H)	7.88(m, 8H)
	6.95(s, 1H)	7.30(br, 4H)
	4.42(m, 2H)	4.40(m, 2H)
	4.1.8(m, 2H)	4.00(br, 2H)
	3.70-2.90	3.70-2.90
	(m, 10H)	(m, 10H)
	2.40-1.60	2.40-1.40
	(m, 20H)	(m, 20H)
Aus-	95%	51%
beute
Schmp.
Masse	511(ES)	511(ES)
	207	208
Beispiel	176	177
Nr.
	8.00(s, 1H)	9.65(s, 1H)
	7.80(m, 4H)	8.08(s, 1H)
	4.48(m, 1H)	7.85(d, 2H)
	3.65(d, 2H)	7.65(d, 2H)
	1.75(m, 1H)	7.40(br, 1H)
	1.59(m, 2H)	7.15(s, 2H)
	1.01(d, 3H)	3.55(m, 2H)
	0.92(d, 3H)	2.55(m, 2H)
	2.15(m, 2H)
	1.80(m, 3H)
	1.65(m, 1H)
Aus-	3%	8%
beute
Schmp.
Masse	443(EI)	456(EI)

[0168]

	209	210	211	212
Beispiel	178	179	180	181
Nr.
	9.49(s, 1H)	9.61(s, 1H)	9.65(s, 1H)	9.71(s, 1H)
	8.25(s, 1H)	8.08(s, 1H)	8.11(s, 1H)	8.06(s, 1H)
	7.80(m, 4H)	7.88(d, 2H)	7.81(s, 2H)	7.90(d, 2H)
	7.32(br, 2H)	7.65(d, 2H)	7.63(d, 2H)	7.61(d, 2H)
	4.03(m, 2H)	7.60(t, 1H)	7.15(s, 2H)	7.37(t, 1H)
	3.75(m, 1H)	7.15(s, 2H)	6.64(d, 1H)	6.56(d, 1H)
	3.35(m, 2H)	3.45(m, 2H)	4.28(m, 3H)	4.66(m, 2H)
	1.80(m, 2H)	2.40(t, 2H)	2.00(m, 1H)	3.90(m, 1H)
	1.40(m, 2H)	2.20(s, 6H)	1.98(s, 3H)	3.39(m, 3H)
		1.75(t, 2H)	0.98(d, 3H)	2.78(q, 2H)
			0.93(d, 3H)	1.96(m, 4H)
				1.56(m, 2H)
				1.29(m, 2H)
Aus-	17%	9%	27%	24%
beute
Schmp.
Masse	427(EI)	428(EI)	472(ES)	486(ES)

[0169]

	213	214	215	216
Beispiel	182	183	184	185
Nr.
	9.68 (s, 1H)	10.97 (s, 1H)	11.06 (s, 1H)	11.01 (s, 1H)
	9.47 (s, 1H)	8.30 (s, 1H)	8.04 (m, 1H)	8.38 (s, 1H)
	8.10 (s, 1H)	8.02 (d, 1H)	7.82 (m, 2H)	7.82 (s, 4H)
	7.81 (d, 2H)	7.81 (m, 4H)	7.70 (m, 2H)	7.40 (d, 1H)
	7.67 (d, 2H)	7.30 (s, 2H)	7.30 (s, 2H)	7.32 (s, 2H)
	7.14 (s, 2H)	4.14 (m, 1H)	6.72 (m, 1H)	4.20 (m, 1H)
	6.76 (m, 3H)	1.80 (m, 12H)	3.75 (m, 5H)	3:70 (m, 2H)
	4.47 (m, 2H)		1.88 (m, 2H)	0.97 (s, 9H)
	4.30 (m, 1H)		1.48 (m, 2H)
	3.65 (s, 6H)
	3.54 (s, 3H)
	1.99 (m, 1H)
	0.98 (d, 3H)
	0.92 (d, 3H)
Aus-	57%	78%	26%	76%
beute
Schmp.
Masse	639 (ES)	439 (EI)	348 (EI)	445 (EI)

[0170]

	217	218	219	220
Beispiel	186	187	188	189
Nr.
	9.71 (s, 1H)	7.75 (s, 1H)	10.60 (s, 1H)	11.19 (s, 1H)
	8.11 (s, 1H)	7.65 (d, 2H)	8.29 (s, 1H)	8.03 (d, 1H)
	7.90 (d, 2H)	7.58 (d, 2H)	7.79 (d, 2H)	7.88 (d, 2H)
	7.70 (d, 2H)	5.82 (s, 1H)	7.71 (d, 2H)	7.78 (d, 2H)
	7.12 (s, 2H)	4.25 (s, 2H)	7.28 (s, 2H)	7.31 (s, 2H)
	6.75 (d, 1H)	3.40 (t, 2H)	6.60 (s, 1H)	6.58 (d, 1H)
	4.45 (m, 1H)	2.82 (t, 2H)	3.58 (s, 2H)	3.60 (m, 4H)
	2.25 (m, 6H)	2.06 (s, 3H)	2.10 (m, 2H)	1.20 (m, 6H)
	1.90 (m, 2H)		1.78 (m, 2H)
			1.55 (m, 4H)
Aus-	16%	7%	61%	35%
beute
Schmp.
Masse	440 (ES)	480 (ES)	443 (EI)	321 (EI)

[0171]

	221	222	223	224
Beispiel	190	191*	192*	193
Nr.
	10.61 (s, 1H)	9.67 (s, 1H)	9.63 (s, 1H)	10.61 (s, 1H)
	8.28 (s, 1H)	8.08 (s, 1H)	8.06 (s, 1H)	8.28 (s, 1H)
	7.82 (d, 2H)	7.88 (d, 2H)	7.85 (d, 2H)	7.78 (m, 4H)
	7.73 (d, 2H)	7.65 (d, 2H)	7.65 (d, 2H)	7.45 (d, 1H)
	7.53 (br, 1H)	7.11 (s, 2H)	7.15 (s, 2H)	7.20 (s, 2H)
	7.25 (s, 2H)	6.35 (d, 1H)	6.55 (d, 1H)	4.30 (br, 2H)
	4.25 (m, 1H)	4.10 (m, 1H)	3.95 (m, 1H)	3.53 (m, 2H)
	2.59 (br, 1H)	3.62 (m, 4H)	3.58 (m, 4H)	1.21 (d, 3H)
	2.21 (br, 1H)	2.45 (m, 4H)	2.50 (m, 4H)
	1.94 (m, 1H)	2.19 (m, 4H)	1.96 (m, 1H)
	1.40 (m, 7H)	1.88 (m, 4H)	1.50 (m, 4H)
		1.65 (m, 4H)	1.30 (m, 4H)
Aus-	63%	15%	17%	57%
beute
Schmp.
Masse	437 (EI)	511 (ES)	511 (EI)	403 (EI)

[0172]

	225	226	227	228
Beispiel	194	195	196	197
Nr.
	9.89 (s, 1H)	10.98 (s, 1H)	10.39 (s, 1H)	10.85 (s, 1H)
	8.21 (s, 1H)	8.51 (br, 1H)	8.30 (s, 1H)	8.71 (d, 1H)
	7.82 (d, 2H)	8.29 (s, 1H)	8.04 (d, 2H)	8.31 (s, 1H)
	7.65 (m, 3H)	7.81 (m, 4H)	7.70 (d, 2H)	7.72 (d, 2H)
	7.17 (br, 2H)	7.29 (br, 2H)	7.21 (br, 2H)	7.55 (d, 2H)
	4.30 (m, 2H)	3.45 (m, 4H)	6.55 (s, 1H)	7.30 (m, 6H)
		1.68 (m, 2H)	3.49 (s, 1H)	5.41 (m, 1H)
		1.45 (m, 2H)	2.32 (m, 2H)	3.49 (m, 2H)
			1.85 (m, 2H)	2.11 (m, 2H)
			1.60 (m, 5H)
			1.29 (m, 1H)
Aus-	26%	56%	12%	61%
beute
Schmp.
Masse	476 (EI)	417 (EI)	450 (EI)	479 (EI)

[0173]

	229	230	231	232
Beispiel	198	199	200	201
Nr.
	11.01 (s, 1H)	11.01 (s, 1H)		9.16 (s, 1H)
	8.32 (s, 1H)	8.32 (s, 1H)		8.07 (s, 1H)
	8.10 (d, 1H)	8.10 (d, 1H)		7.89 (d, 2H)
	7.80 (m, 4H)	7.80 (m, 4H)		7.67 (d, 2H)
	7.30 (br, 2H)	7.30 (br, 2H)		7.15 (s, 2H)
	3.70 (m, 1H)	3.70 (m, 1H)		6.45 (d, 1H)
	1.80 (m, 5H)	1.80 (m, 5H)		4.35 (s, 2H)
	1.48 (m, 1H)	1.48 (m, 1H)		3.97 (m, 1H)
	1.29 (m, 2H)	1.29 (m, 2H)		3.40 (m, 4H)
	1.07 (m, 1H)	1.07 (m, 1H)		2.85 (m, 1H)
	0.83 (d, 3H)	0.83 (d, 3H)		2.55 (m, 1H)
				1.82 (m, 2H)
				1.61 (m, 6H)
Aus-	4%	4%	7%	2%
beute
Schmp.
Masse	439 (EI)	439 (EI)	515 (ES)	515 (ES)

[0174]

	233	234	235	236
Beispiel	202	203 *	204 *	205
Nr.
	10.21 (s, 1H)		9.66 (s, 1H)	9.73 (s, 1H)
	8.18 (s, 1H)		8.08 (s, 1H)	8.11 (s, 1H)
	8.10 (d, 2H)		7.90 (d, 2H)	7.82 (d, 2H)
	7.92 (d, 2H)		7.69 (d, 2H)	7.65 (d, 2H)
	6.39 (d, 1H)		7.15 (s, 2H)	7.12 (s, 2H)
	4.80 (br, 1H)		6.53 (d, 1H)	6.80 (d, 1H)
	4.05 (m, 1H)		3.93 (m, 1H)	4.67 (m, 1H)
	3.62 (m, 2H)		2.05 (m, 5H)	3.13 (m, 1H)
	2.00 (m, 1H)		1.51 (m, 2H)	2.86 (m, 3H)
	0.99 (d, 3H)		1.15 (m, 2H)	2.18 (m, 2H)
	0.92 (d, 3H)		0.42 (m, 2H)
			0.25 (m, 2H)
Aus-	10%	2%	2%	16%
beute
Schmp.
Masse	483 (ES)	480 (EI)	480 (EI)	430 (ES)

[0175]

	237	238	239	240
Beispiel	206	207	208	209
Nr.
	9.75 (s, 1H)	10.98 (s, 1H)	11.00 (s, 1H)	9.55 (s, 1H)
	8.19 (s, 1H)	8.50 (d, 2H)	8.31 (s, 1H)	8.08 (s, 1H)
	7.75 (d, 2H)	8.31 (s, 1H)	7.74 (m, 5H)	7.80 (d, 2H)
	7.18 (d, 2H)	7.97 (d, 2H)	7.21 (d, 1H)	7.60 (d, 2H)
	7.17 (s, 2H)	7.78 (d, 2H)	6.80 (d, 1H)	6.58 (br, 4H)
	6.68 (d, 1H)	7.57 (d, 1H)	4.00 (m, 1H)	6.20 (d, 1H)
	5.35 (t, 1H)	7.00 (t, 1H)	3.62 (m, 2H)	4.80 (br, 1H)
	4.71 (m, 1H)	4.01 (m, 1H)	1.95 (m, 1H)	4.04 (m, 1H)
	3.91 (m, 2H)	3.62 (m, 2H)	0.98 (d, 3H)	3.60 (m, 2H)
	3.65 (s, 3H)	1.97 (m, 1H)	0.90 (d, 3H)	2.00 (m, 1H)
		0.98 (d, 3H)		0.99 (d, 3H)
		0.92 (d, 3H)		0.92 (d, 3H)
Aus-	5%	55%	44%	77%
beute
Schmp.	223	248	228	231
Masse	446 (ES)	507 (EI)	514 (EI)

[0176]

	241	242	243	244
Beispiel	210	211	212	71
Nr.
	10.03 (s, 1H)	10.90 (s, 1H)	9.18 (s, 1H)	9.66 (s, 1H)
	8.38 (s, 1H)	8.40 (m, 1H)	9.05 (s, 1H)	8.08 (s, 1H)
	8.14 (s, 1H)	8.30 (s, 1H)	7.98 (s, 1H)	7.88 (d, 2H)
	7.81 (d, 2H)	7.88 (d, 2H)	7.18 (m, 2H)	7.63 (m, 3H)
	7.60 (d, 1H)	7.73 (d, 2H)	6.98 (m, 2H)	7.28 (t, 1H)
	7.30 (m, 7H)	7.38 (br, 1H)	6.31 (m, 1H)	7.11 (s, 2H)
	4.99 (s, 2H)	3.45 (m, 4H)	4.45 (t, 1H)	6.88 (s, 1H)
	3.42 (m, 2H)	2.38 (s, 3H)	3.47 (m, 4H)	3.65 (m, 2H)
	2.97 (m, 2H)	1.62 (m, 2H)	1.63 (m, 2H)	2.88 (t, 2H)
	1.58 (m, 2H)	1.45 (m, 2H)	1.48 (m, 2H)
	1.30 (m, 4H)
Aus-	86%	22%	41%	77%
beute
Schmp.
Masse	528 (CI)	429 (EI)	352 (EI)	437 (EI)

[0177]

	245	246	247	248
Beispiel	213	61	214	215
Nr.
	12.40 (br, 1H)	12.41 (br, 1H)	8.03 (s, 1H)	9.55 (s, 1H)
	11.10 (s, 1H)	11.11 (s, 1H)	7.76 (m, 4h)	8.10 (s, 1H)
	8.08 (d, 2H)	8.10 (d, 1H)	3.70 (s, 2H)	7.80 (d, 2H)
	7.79 (m, 4H)	7.80 (m, 5H)	1.92 (m, 4H)	7.68 (d, 2H)
	7.30 (s, 2H)	7.30 (s, 2H)	0.92 (m, 6H)	7.15 (s, 2H)
	4.04 (m, 1H)	4.08 (m, 1H)	(in MeOD)	5.82 (s, 1H)
	3.60 (m, 2H)	3.63 (m, 2H)		3.74 (d, 1H)
	2.07 (s, 3H)	2.50 (m, 2H)		3.52 (d, 1H)
	2.00 (m, 1H)	2.01 (m, 1H)		2.72 (m, 1H)
	0.97 (d, 3H)	1.15 (t, 3H)		1.35 (s, 3H)
	0.90 (d, 3H)	0.99 (d, 3H)		0.97 (d, 3H)
		0.92 (d, 3H)		0.91 (d, 3H)
Aus-	49%	25%	2%	9%
beute
Schmp.
Masse	365 (EI)	379 (EI)	443 (ES)	444 (ES)

[0178]

	249	250	251	252
Beispiel	216	217	218	219
Nr.
	10.88 (s, 1H)	10.88 (s, 1H)	11.01 (s, 1H)	11.11 (s, 1H)
	8.36 (s, 1H)	8.36 (s, 1H)	8.52 (br, 1H)	8.53 (m, 1H)
	8.03 (d, 1H)	8.03 (d, 1H)	8.29 (s, 1H)	8.36 (s, 1H)
	7.79 (m, 4H)	7.79 (m, 4H)	7.78 (m, 4H)	7.80 (m, 4H)
	7.28 (br, 2H)	7.28 (br, 2H)	7.32 (s, 2H)	7.31 (s, 2H)
	4.65 (m, 1H)	4.65 (m, 1H)	3.39 (m, 2H)	3.71 (m, 2H)
	3.89 (m, 2H)	3.89 (m, 2H)	1.70 (m, 6H)	2.65 (m, 2H)
		3.71 (m, 2H)	1.15 (m, 3H)
		2.19 (m, 2H)	0.96 (m, 2H)
Aus-	65%	34%	58%	88%
beute
Schmp.	239	239	238	280
Masse	439 (EI)	413 (EI)	439 (EI)	416 (EI)

[0179]

	253	254	255	256
Beispiel	74	56	220	221
Nr.
	9.67 (s, 1H)	9.70 (s, 1H)	8.92 (m, 1H)	9.66 (s, 1H)
		8.11 (s, 1H)	8.81 (m, 1H)	8.08 (s, 1H)
		7.88 (m, 4H)	7.96 (s, 1H)	7.83 (d, 2H)
		6.25 (d, 1H)	7.43 (d, 2H)	7.68 (d, 2H)
		4.81 (m, 1H)	6.67 (d, 2H)	7.22 (t, 1H)
		4.05 (m, 1H)	6.20 (m, 1H)	7.11 (s, 2H)
		3.61 (m, 2H)	4.38 (m, 1H)	3.95 (m, 4H)
		2.01 (m, 1H)	3.48 (m, 1H)	3.48 (m, 2H)
		0.97 (d, 3H)	3.37 (m, 1H)	1.79 (m, 4H)
		0.92 (d, 3H)	1.20 (d, 3H)	1.18 (t, 6H)
Aus-	7%	17%	65%	19%
beute
Schmp.	285	158	166
Masse	457 (EI)	392 (EI)	354 (EI)	522 (ES)

[0180]

	257	258	259	260
Beispiel	222	223	224	225
Nr.
	9.81 (s, 1H)	9.71 (s, 1H)	9.70 (s, 1H)	10.29 (s, 1H)
	9.08 (s, 1H)	8.13 (s, 1H)	8.08 (s, 1H)	8.83 (m, 2H)
	8.68 (s, 1H)	7.89 (d, 2H)	7.88 (d, 2H)	8.51 (m, 1H)
	8.35 (m, 1H)	7.66 (d, 2H)	7.65 (d, 2H)	8.26 (s, 1H)
	8.20 (s, 1H)	7.31 (t, 1H)	7.25 (m, 3H)	7.93 (d, 2H)
	8.02 (t, 1H)	7.14 (s, 2H)	6.11 (m, 1H)	7.60 (d, 2H)
	7.63 (m, 5H)	3.98 (m, 2H)	3.40 (m, 5H)	7.51 (d, 2H)
	7.17 (s, 2H)	3.69 (s, 3H)		7.25 (br, 2H)
	7.03 (s, 1H)	3.64 (s, 3H)		4.90 (d, 2H)
	4.82 (d, 2H)
Aus-	54%	23%	7%	43
beute
Schmp.	300	300		243
Masse	501 (EI)	465 (EI)		434 (EI)

[0181]

	261	262	263	264
Beispiel	226	227	228	229
Nr.
	10.38 (s, 1H)	10.30 (s, 1H)	10.52 (s, 1H)	10.88 (s, 1H)
	8.52 (br, 1H)	8.78 (m, 1H)	8.66 (m, 1H)	8.92 (m, 1H)
	8.23 (s, 1H)	8.36 (m, 3H)	8.28 (s, 1H)	8.33 (s, 1H)
	7.72 (m, 4H)	7.81 (m, 2H)	7.63 (m, 4H)	7.72 (d, 2H)
	7.36 (m, 1H)	7.60 (m, 4H)	7.26 (m, 6H)	7.62 (d, 2H)
	7.22 (s, 2H)	7.22 (br, 2H) 4.63 (d, 2H)	7.30 (m, 4H)
	7.03 (m, 1H)	4.94 (d, 2H)		6.89 (d, 2H)
	6.95 (m, 1H)			4.62 (d, 2H)
	4.80 (d, 2H)			3.70 (s, 3H)
Aus-	47%	41%	88%	89%
beute
Schmp.	229	287	259	233
Masse	440 (CI)	434 (EI)	451 (EI)	463 (EI)

[0182]

            265
BeispielNr. 230
            10.45 (s, 1H)
            8.20 (s, 1H)
            3.05 (m, 1H)
            7.79 (m, 4H)
            7.21 (s, 2H)
            3.50 (m, 2H)
            1.83 (m, 2H)
            1.56 (m, 2H)
Ausbeute    58%
Schmp.      >300
Masse       466 (ES)

[0183]

	266	267	268	269
Beispiel	231	232	233	234
Nr.
	10.3 (s, 1H)	9.28 (s, 1H)	10.48 (s, 1H)	9.63 (s, 1H)
	8.34 (tr, 1H)	8.0 (s, 1H)	8.25 (s, 1H)	8.12 (s, 1H)
	8.2 (s, 1H)	7.73 (d, 2H)	7.85 (m, 4H)	7.65 (m, 4H)
	7.9 (m, 4H)	7.63 (tr, 1H)	7.25 (m, 1H)	7.42 (d, 2H)
	4.3 (q, 2H)	7.18 (d, 2H)	7.15 (s, 1H)	7.35 (tr, 2H)
	4.2 (m, 2H)	5.0 (m, 1H)	5.1 (m, 1H)	7.21 (m, 1H)
	3.23 (tr, 1H)	4.3 (s, 2H)	3.58 (m, 4H)	7.16 (s, 1H)
	1.32 (tr, 3H)	4.14 (m, 2H)		5.35 (m, 1H)
		3.11 (tr, 1H)		1.55 (d, 3H)
Aus-	85%	35%	33%	25%
beute
Schmp.
Masse	330 (EI)	288 (EI)	389 (CI)	448 (ESI)

[0184]

	270	271	272	273
Beispiel-	235	236	237	238
Nr.
Schmp.
[° C.]
Masse	486 (ES)	516 (ES)	504 (ES)	488 (ES)

[0185]

	274	275	276	277
Beispiel-	239	240	241	242
Nr.
Schmp.
[° C.]
Masse	536 (ES)	502 (ES)	484 (ES)	551 (ES)

[0186]

	278	279	280
Beispiel-	243	244	245
Nr.
Schmp.
[° C.]
Masse	516 (ES)	514 (ES)	433 (ES)

[0187]

	281	282	283	284
Beispiel-	246	247	248	249
Nr.
Schmp.			205	>300
[° C.]
Masse	446 (ES)	415 (EI)	504 (ES)	431 (ES)

[0188]

	285	286	287	288
Beispiel-	250	251	252	253
Nr.
Schmp.	113	231	187
[° C.]
Masse	488 (ES)	446 (ES)	433 (ES)

[0189]

	289	290
Nr.	254	255
Sch,p.
[° C.]
Masse	399 (ES)	444 (ES)
	291	292
Nr.	256	257
Schmp.
[° C.]
Masse	474 (ES)	486 (ES)

[0190] Compounds Nos. 159, 160, 161, 163, 167, 168, 170, 174, 175, 191, 192, 203 and 204 that are identified with *) can be produced by the process variants that are described under Example No. 292.

EXAMPLE 258

Production of 4-(5-bromo-4-morpholin-4-yl-pyrimidin-2-ylamino)-phenylsulfonamide

[0191] 293

[0192] 202 mg (0.60 mmol) of the compound of Example No. 122 is mixed with 1 ml of water and 0.2 g (1.2 mmol) of bromine and stirred at room temperature. After 24 hours, 0.2 g (1.2 mmol) of bromine is added again, and it is stirred for another 24 hours at room temperature. The solvent is evaporated by means of underpressure, and the remaining residue is purified by chromatography (Flashmaster II, DCM/MeOH 7:3). 17 mg (0.04 mmol,7%) of the product is obtained as a white solid.

	294	295	296	297
Beispiel-Nr.	259	260	261	262
Schmp.			205-207	202-203
[° C,]
Masse	MS (ES) 452,			428 (ES)
	454 (M+ H,
	100%)

[0193]

Beispiel-
Nr.	Verbindung	ESI-MS
263	298	434
264	299	434
265	300	477
266	301	477
267	302	552
268	303	552
269	304

[0194] Analogously to the process for the production of intermediate products that is described under Example 6.0, following compounds were also produced:

Beispiel-	270	271	272
Nr.
	305	306	307
Ausbeute	47%	90%
Masse	ESI:	ESI:	ESI:
	MH+ 480	MH+ 432	MH+ 446 (18%)
	(100%) (100%)
	478 (97%)	430 (94%)
	115 (30%)	157 (43%)

[0195] Analogously to production example 1, the following compounds were also produced:

	308	309
Beispiel-	273	274
Nr.
Aus-	61%	44%
beute
Masse	EI:	EI:
	M+ 463 (4%)	M+ 403 (24%)
	277 (8%)	358 (100%)
	105 (100%)	277 (52%)
	310	311
Beispiel-	277	278
Nr.
Aus-	81%	58%
beute
Masse	EI:	ESI:
	M+ 431 (5%)	MH+ 444
	372 (100%)	(100%)
	291 (46%)	442 (97%)
		115 (20%)
	312	313
Beispiel-	281	282
Nr.
Aus-	55%	43%
beute
Masse	ESI:	ESI:
	MH+ 444	MH+ 446
	(100%)	(100%)
	442 (97%)	444 (95%)
	214 (12%)	346 (5%)
	314	315
Beispiel-	285	286
Nr.
Aus-	51%	46%
beute
Masse	ESI:	ESI:
	MH+ 520	MH+ 520
	(100%)	(100%)
	518 (97%)	518 (97%)
	115 (27%)	115 (23%)
		316	317
	Beispiel-	275	276
	Nr.
	Aus-	42%	68%
	beute
	Masse	ESI:	EI:
		MH+ 418	M+ 401 (33%)
		100%	372 (100%)
		416 (94%)	344 (38%)
		346 (8%)
		318	319
	Beispiel-	279	280
	Nr.
	Aus-	˜20%	30%
	beute
	Masse	ESI:	ESI:
		MH+ 494	MH+ 418
		(75%)	100%)
		346 (18%)	416 (97%)
		214 (55%)	310 (27%)
		320	321
	Beispiel-	283	284
	Nr.
	Aus-	˜18%	35%
	beute
	Masse	ESI:	ESI:
		MH+ 416	MH+ 446
		(100%)	(100%)
		414 (96%)	444 (90%)
		317 (4%)
		322	323
	Beispiel-	287	288
	Nr.
	Aus-	47%	61%
	beute
	Masse	ESI:	ESI:
		MH+ 432	MH+ 446
		(100%)	(100%)
		430 (95%)	444 (93%)
		346 (5%)	115 (31%)

[0196] According to the production variants below, the following compounds are also synthesized: 324

[0197] 30 mg (0.0678 mmol) of compound No. 278 is dissolved in 1 ml of methanol/tetrahydrofuran 1:1. After adding ≈10 mg of sodium borohydride, stirring is continued for 2 hours. Then, it is quenched with ≈3-4 drops of glacial acetic acid while being cooled, and it is concentrated by evaporation. Below, the crude product is taken up with a little water, suctioned off, rewashed with acetonitrile and dried in a vacuum at 60° C. Yield: 21 mg (70% of theory) of the desired compound.

	325	326
Beispiel-	289	290
Nr.
Aus-	52%	70%
beute
Masse	EI:	ESI:
	M+ 465 (5%)	MH+ 446
	358 (40%)	(100%)
	207 (31%)	444 (93%)
		117 (20%)

EXAMPLE 291

Production of the Oxime Ether-Pyrimidine Compounds of General Formula I

[0198] The production of the oxime ether is carried out according to the following general reaction diagram: 327

[0199] R8 and R9 have the meanings that are indicated in general formula I.

PRODUCTION OF EXAMPLE 291

[0200] 328

[0201] 50 mg (0.12 mmol) of compound No. 283, 34 mg of hydroxylammonium chloride and 150 mg of pulverized KOH are reflexed for 2 hours in 2 ml of ethanol. Then, it is poured onto ice water and acidified with glacial acetic acid, extracted 3 times with dichloromethane/isopropanol 4:1, dried with magnesium sulfate and concentrated by evaporation. The residue is suspended with acetonitrile, suctioned off and dried at 60° C.

[0202] Yield: 28 mg (54% of theory) of the desired compound. Mass ESI: MH+429 (29%) 371 (61%) 289 (91%)

[0203] Similarly produced were also the following compounds:

	329	330	331
Beispiel-Nr.	292	293	294
Ausbeute	34%	36%	40%
Masse	ESI:	ESI:	ESI:
	MH+ 443 (95%)	MH+ 485 (92%)	MH+ 487 (91%)
	445 (99%)	487 (99%)	489 (89%)
	373 (32%)		373 (32%)

EXAMPLE 295

Reduced Amination

[0204] 332

[0205] 50 mg (0.12 mmol) of compound No. 283 and 7.5 mg (0.132 mmol) of cyclopropylamine are dissolved in 2 ml of 1,2-dichloroethane. After 9.1 mg (0.144 mmol) of sodium cyanoborohydride is added, it is allowed to stir for 12 more hours. Then, it is diluted with dichloromethane/isopropanol 4:1, washed 2× with water, dried with magnesium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with dichloromethane/methanol 95:5. Yield: 18 mg (33% of theory) of the desired compound.

      333
Aus-  33%
beute
Masse ESI:
      MH+ 457
      (98%)
      455 (93%)
      249 (55%)

[0206] Produced similarly are also compounds Nos. 159, 160, 161, 163, 167, 168, 170, 174, 175, 191, 192, 203, and 204.

EXAMPLES 296 AND 297

[0207] Produced similarly to Example 1 are also the following two compounds:

	334	335
Beispiel	296	297
Ausbeute	46%	47%
Masse	ESI:	ESI:
	MH+ 432 (30%)	MH+ 446 (45%)
	434 (31%)	448 (49%)
	123 (100%)	123 (90%)

Production of Sulfonamides of General Formula I

[0208] 336

[0209] 0.2 mmol of sulfonic acid fluoride is introduced into the reactor of a synthesizer. 1.0 ml of solvent, preferably 2-butanol, is added. 0.2 ml (0.2 mmol) of DMAP—dissolved in a solvent, for example DMSO or 2-butanol—and 0.2 ml (0.2 mmol) of the amine, dissolved in 2-butanol, are added in succession via a pipette. The reaction mixture is then stirred for 20 hours at 80° C. After the reaction is completed, the crude product is pipetted off, and the reactor is rewashed with 1.0 ml of THF. The solution of the crude product is then concentrated by evaporation and purified by HPLC.

[0210] The compounds below were produced:

[0211] [Key to subsequent tables:]

[0212] Beispiel-Nr.=Example No.

[0213] Verbindung=Compound

[0214] Molgewicht=Molecular Weight

[0215] Schmelzpunkt=Melting point

[0216] und=and

Beispiel-
Nr.	Verbindung	Molgewicht	ESI-MS
298	337	526,4968	526/528
299	338	562,5298	562/564
300	339	624,6006	624/626
301	340	501,4471	501/503
302	341	538,4682	538/540
303	342	588,4465	588/590
304	343	528,5126	528/530
305	344	542,5394	542/544
306	345	556,5662	556/558
307	346	570,593	570/572
308	347	510,4106	510/512
309	348	588,4465	588/590
310	349	548,503	548/550
311	350	555,4949	555/557
312	351	500,459	500/502
313	352	514,4858	514/516
314	353	515,4739	515/517
315	354	557,5543	557/559
316	355	470,3896	470/472
317	356	551,5069	551/553
318	357	534,4762	534/536
319	358	568,9213	568/570
320	359	524,4374	524/526
321	360	534,4839	543/545
322	361	488,4044	488/490
323	362	526,4776	526/528
324	363	564,502	564/566
325	364	527,4849	527/529
326	365	541,5117	541/543
327	366	538,4395	538/540
328	367	541,5117	541/543
329	368	521,4375	521/523
330	369	538,4395	538/540
331	370	521,4375	521/523
332	371	550,4752	550/552
333	372	550,4752	550/552
334	373	613,5551	613/615
335	374	534,4762	534/536
336	375	512,47	512/514
337	376	548,503	548/550
338	377	610,5738	610/612
339	378	487,4203	487/489
340	379	524,4414	524/526
341	380	574,4197	574/576
342	381	514,4858	516/514
343	382	528,5126	528/530
344	383	542,5394	542/544
345	384	556,5662	556/558
346	385	496,3838	496/498
347	386	574,4197	574/576
348	387	534,4762	534/536
349	388	541,4681	541/543
350	389	486,4322	486/488
351	390	500,459	500/502
352	391	501,4471	501/503
353	392	543,5275	543/545
354	393	456,3628	456/458
355	394	537,4801	537/539
356	395	520,4494	520/522
357	396	554,8945	554/556
358	397	510,4106	510/512
359	398	529,4571	529/531
360	399	474,3776	474/476
361	400	512,4508	541/514
362	401	550,4752	550/552
363	402	513,4581	513/515
364	403	527,4849	527/529
365	404	524,4127	524/526
366	405	527,4849	527/529
367	406	507,4107	507/509
368	407	524,4127	524/526
369	408	507,4107	507/509
370	409	536,4484	536,538
371	410	536,4484	536/538
372	411	599,5283	599/601
373	412	520,4494	520/522
374	413	512,47	512/514
375	414	548,503	548/550
376	415	610,5738	610/612
377	416	524,4414	524/526
378	417	574,4197	574/576
379	418	514,4858	514/516
380	419	528,5126	528/530
381	420	542,5394	542/544
382	421	496,3838	496/498
383	422	574/4197	574/576
384	423	534,4762	534/536
385	424	541,4681	541/543
386	425	486,4322	486/488
387	426	500,459	500/502
388	427	501,4471	501/503
389	428	543,5275	543/545
390	429	537,4801	537/539
391	430	520,4494	520/522
392	431	554,8945	554/556
393	432	510,4106	510/512
394	433	529,4571	529/531
395	434	474,3776	474/476
396	435	512,4508	512/514
397	436	513,4581	513/515
398	437	527,4849	527/529
399	438	524,4127	524/526
400	439	527,4849	527/529
401	440	507,4107	507/509
402	441	524,4127	524,526
403	442	507,4107	507/509
404	443	536,4484	526/538
405	444	536,4484	536/538
406	445	599,5283	599/601
407	446	520,4494	520/522
408	447	529,4419	529/531
409	448	534,4762	534/536
410	449	596,547	596/598
411	450	473,3935	473/475
412	451	510,4146	510/512
413	452	560,3929	560/562
414	453	500,549	500/502
415	454	514,4858	514/516
416	455	528,5126	528/530
417	456	482,357	482/484
418	457	560,3929	560/562
419	458	520,4494	520/522
420	459	527,4413	527/529
421	460	472,4054	472/474
422	461	486,4322	486/488
423	462	487,4203	487/489
424	463	529/5007	529/531
425	464	523,4532	523/525
426	465	506,4226	506/508
427	466	540,8677	540/542
428	467	496,3838	496/498
429	468	515,4303	515/517
430	469	460,3508	460/462
431	470	498,424	498/500
432	471	499,4313	499/501
433	472	513,4581	513/515
434	473	510,3859	510/512
435	474	513,4581	513/515
436	475	493,3839	493/495
437	476	510,3859	510/512
438	477	493,3839	493/495
439	478	522,4216	522/524
440	479	522,4216	522/524
441	480	585,5015	585/587
442	481	506,4226	506/508
443	482	515,4151	515/517
444	483	416,30	416/418

Production of the Pyrimidine-Sulfonyl Fluorides of General Formula I

[0217] The production of the pyrimidine-sulfonic acid fluorides is carried out analogously to the production of the sulfonic acid amides. 484

			Schmelzpunkt
			[° C.]
Beispiel-Nr.	Verbindwig	Molgewicht	und ESI-MS
445	485	405.25	217-220 405/407
446	486	419.27	196-202 419/421
447	487	419.27	165-196 419/421
448	488	433.30	198-204 433/435
449	489	433.30	144-149 433/435
450	490	447.33	219-222 447/449

[0218] Similarly produced to the above-described examples were also the following para-compounds:

		Molekular-
Beispiel-Nr.	Verbindung	gewicht	ESI-MS
451	491	498.4432	498/500
452	492	534.4762	534/536
453	493	596.547	596/598
454	494	473.3935	473/475
455	495	510.4146	510/512
456	496	560.3929	560/562
457	497	500.459	500/502
458	498	514.4858	514/516
459	499	528.5126	528/530
460	500	542.5394	542/544
461	501	560.3929	560/562
462	502	520.4494	520/522
463	503	527.4413	527/529
464	504	472.4054	472/474
465	505	486.4322	486/488
466	506	529.5007	529/531
467	507	442.336	442/444
468	508	523.4532	523/525
469	509	506.4226	506/508
470	510	540.8677	540/542
471	511	496.3838	496/498
472	512	515.4303	515/517
473	513	460.3508	460/462
474	514	498.424	498/500
475	515	536.4484	536/538
476	516	499.4313	499/501
477	517	513.4581	513/515
478	518	510.3859	510/512
479	519	513.4581	513/515
480	520	493.3839	493/495
481	521	510.3859	510/512
482	522	493.3839	493/495
483	523	522.4216	522/524
484	524	522.4216	522/524
485	525	585.5015	585/587
486	526	506.4226	506/508
487	527	515.4151	515/517
488	528	512.47	512/514
489	529	548.503	548/550
490	530	610.5738	610/612
491	531	487.4203	487/489
492	532	524.4414	524/526
493	533	574.4197	574/576
494	534	514.4858	516/514
495	535	528.5126	528/530
496	536	542.5394	542/544
497	537	556.5662	556/558
498	538	496.3838	496/498
499	539	574.4197	574/576
500	540	534.4762	534/536
501	541	541.4681	541/543
502	542	486.4322	486/488
503	543	500.459	500/502
504	544	501.4471	501/503
505	545	543.5275	543/545
506	546	456.3628	456/458
507	547	537.4801	537/539
508	548	520.4494	520/522
509	549	566.4742
510	550	554.8945	554/556
511	551	510.4106	510/512
512	552	529.4571	529/531
513	553	474.3776	474/476
514	554	512.4508	512/514
515	555	550.4752	550/552
516	556	513.4581	513/515
517	557	527.4849	527/529
518	558	524.4127	524/526
519	559	527.4849	527/529
520	560	507.4107	507/509
521	561	524.4127	524/526
522	562	507.4107	507/509
523	563	536.4484	536/538
524	564	536.4484	536/538
525	565	599.5283	599/601
526	566	520.4494	520/522
527	567	529.4419	529/531

Separation of Diastereomer Mixtures of the Compounds According to the Invention

SEPARATION IN THE EXAMPLE OF THE DIASTEREOMER MIXTURE OF COMPOUND NO. 275

[0219] 568

[0220] The diastereomer mixture was separated in the two corresponding racemates (A and B) by means of HPLC. Conditions:

Column:          Kromasil C18 (5 μm) 150 × 4.6 mm
Eluant:          25% acetonitrile/water with 1 ml of NH3/1;
Flow:            1.0 ml/min
Detection:       PDA 300 nm
Retention times: Racemate A - 11.6 minutes
                 Racemate B - 12.4 minutes

[0221]

	569	570
NMR	DMSO-d6:	DMSO-d6:
	9.68, s, 1 H	9.68, s, 1 H
	8.12, s, 1 H	8.11, s, 1 H
	7.87, d, 2 H	7.85, d, 2 H
	7.70, d, 2 H	7.69, d, 2 H
	7.14, s, 2 H	7.16, s, 2 H
	6.15, d, 1 H	6.35, d, 1 H
	5.01, d, 1 H	4.90, d, 1 H
	4.10, m, 1 H	4.08, m, 1 H
	3.80, m, 1 H	3.80, m, 1 H
	1.22, d, 3 H	1.18, d, 3 H
	1.1, d, 3 H	1.12, d, 3 H

[0222] Below, racemates A and B in each case were separated by means of chiral HPLC. Conditions:

Column:          Chiralpak AD (10 μm) 250 × 4.6 mm
Eluant:          Hexane/ethanol 80:20
Flow:            1.0 ml/min
Detection:       PDA 300 nm
Retention times: Enantiomer A1 - 16.6 minutes
                 Enantiomer A2 - 19.6 minutes
                 Enantiomer B1 - 16.0 minutes
                 Enantiomer B2 - 17.8 minutes

[0223] Production of the intermediate stages preferably used for the synthesis of the compounds of general formula I according to the invention.

EXAMPLE 1.0

Production of N-(2-cholor-5-fluoro-4-pyrimidinyl)-N-2-propynylamine

[0224] 11.1 g (66 mmol) of 2,4-dichloro-5-fluoropyrimidine is dissolved in 60 ml of acetonitrile, and 10.2 ml (73 mmol) of triethylamine and 6.0 ml (86 mmol) of propynylamine are added. The reaction mixture is stirred overnight at room temperature and then poured into water. The mixture is extracted by means of ethyl acetate, the combined organic phases are dried on MgSO2, and the solvent is evaporated by means of underpressure. After the remaining material is recrystallized with diisopropyl ether/hexane, the yield is 10.6 g (87% of theory) of the product.

571
	5-H	8.18 (3.3 Hz, 1H)	Solvent: DMSO
	4CH	4.14 (dd, 2H)	Yield: 87%
		3.20 (t, 1H)	Melting point: 96° C.
	NH	8.65 (tb, 1H)

[0225] The 4-(diaminocyclohexyl) derivatives that are described below are synthesized via reductive aminations of the described keto derivative with use of triacetoxy borohydride (Abdel-Magid, Carson, Harris, Maryanoff, Sha, J. Org. Chem. 1996, 61, 3849). The keto derivative is obtained by TPAP oxidation (Griffith, Ley, Aldrichimica Acta 1990, 23, 13) of the corresponding alcohol.

[0226] Similarly produced are also the following intermediate compounds:

[0227] [Key to subsequent tables:]

[0228] Beispiel-Nr.=Example No.

[0229] Losemittel=Solvent

[0230] Ausbeute=Yield

[0231] Schmp.=Melting point

[0232] Masse=Mass

[0233] Chrom. Ausbeute=Chromatography yield

	572	573	574	575
Beispiel-Nr.	1.1	1.2	1.3	1.4
Lösemittel	CDCl3	DMSO	DMSO	DMSO
5-H	7.87 (s, 1H)	8.34 (s, 1H)	8.24 (s, 1H)	8.23 (s, 1H)
4CH	4.32 (dd, 2H)	4.48 (q, 1H)	3.59 (td, 2H) 3.21 (t, 2H)
	2.30 (t, 1H)	1.93 (dq, 2H)	2.78 (t, 2H)	1.10 (mc, 1H)
		0.92 (t, 3H)	7.57 (s, 1H)	0.42 (mc, 2H)
5CH	2.03 (s, 3H)	3.66 (s, 3H)	6.85 (s, 1H)	0.37 (mc, 2H)
			7.90 (tb, 1H) 7.84 (t, 1H)
NH	4.91 (sb, 1H)	7.69 (d, 1H)	11.92 (sb, 1H)
Ausbeute	80%	42%	33%	74%
Schmp.	121-121.5° C.	73° C.	90° C.	98° C.
	576	577	578	579
Beispiel-Nr.	1.5	1.6	1.7	1.8
Lösemittel	DMSO	DMSO	DMSO	DMSO
6-H	8.26 (s, 1H)	8.26 (s, 1H)	8.27 (s, 1H)	8.37 (s, 1H)
4CH	3.59 (mc, 2H)	3.58 (mc, 2H)	3.58 (sb, 4H)	4.40 (m, 1H)
	3.90 (mc, 1H)	3.97 (mc, 1H)	4.14 (mc, 1H)	3.49 (dd, 1H)
	1.98 (mc, 1H)	1.96 (mc, 1H)		3.33 (dd, 1H)
	0.94 (d, 3H)	0.92 (d, 3H)		3.26 (s, 3H)
	0.86 (d, 3H)	0.84 (d, 3H)		1.15 (d, 3H)
OH	4.67 (mb, 1H)	4.74 (t, 1H)	4.78 (sb, 2H)
NH	6.75 (sb, 1H)	6.87 (d, 1H)	6.73 (sb, 1H)	7.29 (d, 1H)
Ausbeute	82%	91%	41%	74%
Schmp.	113-114° C.	121-122° C.	155-156° C.	Öl
	580	581
	Beispiel-Nr.	1.9	1.10
	Lömittel	DMSO	DMSO
	6-H	8.24 (s, 1H)	8.36 (s, 1H)
	4CH	3.49 (q, 2H)	4.14 (d, 2H)
		2.50 (t, 2H)	3.18 (t, 1H)
		2.42 (t, 4H)
		3.56 (t, 4H)
	OH
	NH	7.57 (sb, 1H)	8.40 (s, 1H)
	Ausbeute	31%	73
	Schmp.	118-119° C.	103-104° C.
	582	583	584	585
Beispiel-Nr.	1.11	1.12	1.13	1.14
Lösemittel	DMSO	DMSO	DMSO	DMSO
6-H	8.30 (s, 1H)	8.32 (s, 1H)	8.29 (s, 1H)	8.24 (s, 1H)
	4.46 (dq, 1H)	5.04 (q, 1H)	3.7-3.9 (2H)	4.25 (m, 1H)
	1.38 (d, 3H)	2.39 (m, 2H)	5.19 (m, 1H)	3.48 (m, 2H)
			7.2-7.4 (5H)
NH	7.60 (sb, 1H)	4.31 (q, 1H)	7.72 (d, 1H)	1.86 (m, 2H)
			5.09 (t, 1H)
OH	7.29 (sb, 1H)	4.40 (t, 1H)		2.43 (m, 2H)
	7.21 (d, 1H)	8.13 (d, 1H)		2.03 (s, 3H)
				7.13 (d, 1H)
				4.88 (t, 1H)
Ausbeute	87%	63%	99%	78%
Schmp.	234° C. Zers.	210° C. Zers.	152-153° C.	130° C.
	586	587	588
	Beispiel-Nr.	1.15	1.16	1.17
	Lösemittel	DMSO	DMSO	DMSO
	6-H	8.20 (s, 1H)	8.21 (s, 1H)	8.22 (s, 1H)
		3.55 (m, 2H)	3.33 (q, 2H)	3.39 (q, 2H)
		4.22 (m, 1H)	1.53 (m, 4H)	2.26 (t, 2H)
		5.03 (m, 2H)	1.28 (m, 2H)	1.79 (q, 2H)
		7.1-7.4 (5H)	2.29 (t, 2H)
	NH	6.53 (d, 1H)	7.74 (t, 1H)	7.78 (t, 1H)
		5.93 (d, 1H)		12.11 (sb, 1H)
	Ausbeute	93%	99%	11%
	Schmp.	Öl	Öl	Öl
	589	590	591
	Beispiel-Nr.	1.18	1.19	1.20
	Ausbeute	86%	64%	87%
	Masse	ESI:	ESI:	Cl:
		MH+ 297 (2%)	MH+ 311 (2%)	M+ 354 (100%)
		266 (22%)	248 (20%)	352 (72%)
		234 (30%)	236 (18%)	308 (54%)
	592	593	594
	Beispiel-Nr.	1.21	1.22	1.23
	Ausbeute	26%	˜20%	89%
	Masse	EI:	NMR, CDCl3	EI:
		M+ 327 (10%)	8.16 (s, 1H)	M+ 265 (15%)
		222 (36%)	6.55 (s, 1H)	236 (100%)
		105 (100%)	4.43 (d, 2H)	209 (18%)
			1.29 (s, 9H)
	595	596	597
Beispiel-Nr.	1.24	1.25	1.26
Ausbeute	75%	70%	83%
Masse	Cl:	Cl	ESI:
	M+ 384	M+ 384 (100%)	319 3%
	(100%)	212 (21%)	278 100%
	212 (21%)	91 (7%)	220 68%
	91 (7%)
	598
	Beispiel-Nr.	1.27
	Ausbeute	98%
	Masse	ESI:
		MH+296 (90%)
		298 (100%)
		210 (12%)

EXAMPLE 2.0

Production of 5-Bromo-2-chloro-4-(4,4,4-trifluorobutoxy)pyrimidine

[0234] 3.19 g (14 mmol) of 5-bromo-2,4-dichloropyrimidine is mixed with 8.06 g (63 mmol) of 4,4,4-trifluorobutanol, and 0.74 ml (8.4 mmol) of trifluoromethanesulfonic acid is slowly added to it. The reaction mixture is stirred overnight at room temperature and then poured into water. The mixture is extracted by means of ethyl acetate, the combined organic phases are dried on MgSO2, and the solvent is evaporated by means of underpressure. The product is always contaminated with varying amounts of 2,4-bisalkoxypyrimidine. The remaining material is therefore purified by means of gradient chromatography with silica gel as a carrier medium (eluant: hexane and hexane/ethyl acetate at a 9:1 ratio). This process results in a yield of 1.70 g (38%) and also yields 1.93 g (34%) of 5-bromo-2,4-bis-(4,4,4-trifluorobutoxy)pyrimidine (starting compound).

599

5-H 4C H 5C H-

8.74(s, 1H) Chromatography: H to H/EA 9:1 4.48(t, 2H) Yield: 38% 2.00(mc, 2H)Melting point: 66.5-67.5°2.44(mc, 2H)

[0235] Similarly produced are also the following compounds:

		600	601
	Beispiel-	2.1	2.2
	Nr.
		CDCl3	DMSO
	5-H	8.49(s, 1H)	8.75(s, 1H)
	4CH	5.10(d, 2H)	4.05(mc, 2H)
			3.79(mc, 2H)
			3.60(mc, 2H)
	5CH	2.59(t, 1H)	3.48(mc, 2H)
			3.40(t, 2H)
			1.07(t, 3H)
	Chrom.	H to	DCM to DCM/
		H/EA 4:1	MeOH 95:5
	Ausbeute	78%	11%
	Schmp.	55° C.	OI

[0236] Analogously to process examples 1 and 2, the following intermediate products are also produced:

	602	603
Beispiel	1-2.1	1-2.2
-Nr.
Löse	DMSO	DMSO
Mittel
	8.26(s, 1H)	8.26(s, 1H)
	6.65(d, 1H)	6.65(d, 1H)
	4.70(t, 1H)	4.70(t, 1H)
	4.10(dt, 1H)	4.10(dt, 1H)
	3.65(at, 2H)	3.65(at, 2H)
	0.90(s, 9H)	0.90(s, 9H)
Aus-	49%	70%
beute
Masse	309(EI)	309(EI)
	604	605
Beispiel	1-2.5	1-2.6
-Nr.
Löse-	DMSO	DM30
mittel
	8.15(s, 1H)	8.22(s, 1H)
	7.25(t, 1H)	4.82(t, 1H)
	3.16(s, 2H)	4.49(br, 1H)
	1.90(s, 3H)	3.85(m, 1H)
	1.61(q, 6H)	3.76(m, 1H)
	1.41(s, 6H)	3.54(m, 1H)
		3.40(m, 1H)
		1.93(m, 3H)
		1.80(m, 1H)
Aus-	70%	75%
beute
Masse	357(EI)	293(EI)
	606	607
Beispiel	1-2.9	1-2.10
-Nr.
Löse-	DMSO	DMSO
mittel
	8.38(s, 1H)	8.22(s, 1H)
	4.81(br, 1H)	7.05(d, 1H)
	3.96(m, 2H)	4.82(t, 1H)
	3.72(m, 1H)	4.18(m, 1H)
	3.30(m, 2H)	3.42(m, 2H)
	1.81(m, 2H)	1.15(d, 3H)
	1.48(m, 2H)
Aus-	19%	71%
beute
Masse	292(EI)	266(EI)
	608	609
Beispiel	1-2.13	1-2.14
-Nr.
Löse-	DMSO	DMSO
mittel
	8.41(s, 1H)	8.25(s, 1H)
	8.11(s, 1H)	4.53(m, 1H)
	4.28(t, 2H)	3.88(m, 2H)
		3.70(dd, 1H)
		3.62(dd, 1H)
		2.16(m, 1H)
		2.02(m, 1H)
		7.56(d, 1H)
Aus-	46%	72%
beute
Masse	390(FAB)	277(EI)
	610	611
Beispiel	1-2.17	1-2.18
-Nr.
Löse-	DMSO	DMSO
mittel
	8.21(s, 1H)	8.35(t, 1H)
	7.22(d, 1H)	8.19(s, 1H)
	3.88(m, 1H)	3.40(m, 2H)
	1.70(m, 4H)	2.97(p, 1H)
	1.50(m, 2H)	2.22(m, 4H)
	1.28(m, 1H)	2.08(dd, 1H)
	1.01(m, 2H)	1.70(m, 6H)
	0.82(d, 3H)
Aus-	22%	32%
beute
Masse	303(EI)	320(EI)
	612	613
Beispiel	1-2.21	1-2.22
-Nr.
Löse-	DMSO	DM30
mittel
	8.25(s, 1H)	8.25(s, 1H)
	8.08(d, 1H)	7.38(d, 1H)
	7.35(m, 5H)	4.44(m, 1H)
	5.30(m, 1H)	2.60(m, 2H)
	4.81(t, 1H)	2.24(m, 2H)
	3.45(m, 2H)	2.07(m, 2H)
	2.05(m, 2H)	1.90(m, 2H)
Aus-	97%	58%
beute
Masse	343(EI)	304(ES)
	614	615
Beispiel	1-2.25	1-2.26
-Nr.
Löse-	DMSO	DMSO
mittel
		8.22(s, 1H)
		7.21(d, 1H)
		3.82(m, 1H)
		2.45(m, 4H)
		2.22(m, 1H)
		1.78(m, 8H)
		1.45(m, 6H)
Aus-	n.b.	26%
beute
Masse	344(EI)	374(EI)
	616	617
Beispiel	1-2.29	1-2.30
-Nr.
Löse-	DMSO	DMSO
mittel
	8.22(s, 2H)	8.21(s, 1H)
	7.28(d, 1H)	7.18(d, 1H)
	7.10(d, 1H)	4.62(s, 1H)
	4.00(m, 1H)	4.20(m, 1H)
	3.85(m, 1H)	3.95(m, 1H)
	2.19(s, 6H)	2.75(dd, 1H)
	2.17(s, 6H)	2.50(m, 2H)
	2.15(m, 1H)	2.31(dd, 1H)
	2.00(m, 1H)	2.15(s, 1H)
	1.82(m, 8H)	2.00(m, 1H)
	1.50(m, 6H)	1.82(m, 4H)
	1.25(m, 2H)	1.55(m, 5H)
Aus-	13%	35%
beute
Masse	334(EI)	374(EI)
	618	619
Beispiel	1-2.33	1-2.34
-Nr.
Löse-	DMSO	CDCl3
mittel
	8.50(s, 1H)	8.08(s, 1H)
	4.10(m, 2H)	6.04(m, 1H)
	3.72(m, 1H)	5.71(br, 1H)
	3.30(m, 2H)	4.48(d, 2H)
	1.75(m, 2H)	3.71(s, 3H)
	1.35(m, 2H)	2.25(s, 3H)
Aus-	3%	30%
beute
Masse	291(EI)	300(ES)
	620	621
Beispiel	1-2.37	1-2.38
-Nr.
Löse-	CDCl3	CDCl3
mittel
	8.14(s, 1H)	8.20(s, 1H)
	5.41(m, 1H)	7.71(m, 1H)
	4.49(m, 1H)	7.30(m, 6H)
	2.44(m, 6H)	4.97(s, 2H)
	1.79(m, 2H)	3.00(m, 2H)
		1.40(m, 8H)
Aus-	58%	77%
beute
Masse	304(ES)	427(ES)
	622	623
Beispiel	1-2.41	1-2.42
-Nr.
Löse-	DMSO	DMSO
mittel
	8.19(s, 1H)	8.21(s, 1H)
	7.21(d, 1H)	7.03(d, 1H)
	4.03(m, 1H)	4.83(t, 1H)
	1.60(m, 12H)	4.13(m, 1H)
		3.47(m, 2H)
		1.12(d, 3H)
Aus-	73%	61%
beute
Masse	303(EI)	267(EI)
	624	625
Beispiel	1-2.45	1-2.46
-Nr.
Löse-	DMSO	DMSO
mittel
	8.36(s, 1H)	8.26(s, 1H)
	6.56(s, 1H)	8.06(d, 1H)
	3.81(s, 1H)	7.30(m, 5H)
	2.28(m, 2H)	5.29(m, 1H)
	1.83(m, 2H)	4.81(t, 1H)
	1.58(m, 6H)	3.42(m, 2H)
		2.10(m, 2H)
Aus-	84%	97%
beute
Masse	314(EI)	343(EI)
	626	627
Beispiel	1-2.49	1-2.50
-Nr.
Löse-	DMSO	DMSO
mittel
	8.29(s, 1H)	8.18(s, 1H)
	6.05(s, 1H)	7.25(d, 1H)
	5.18(m, 1H)	4.15(m, 1H)
	3.54(s, 2H)	2.40(m, 6H)
	1.92(m, 2H)	1.50(m, 4H)
	1.76(m, 2H)	1.17(d, 3H)
		0.90(dd, 6H)
Aus-	16%.	52%
beute
Masse	308(EI)	350(EI)
	628	629
Beispiel	1-2.53	1-2.54
-Nr.
Löse-	DMSO	DMSO
mittel
	8.22(s, 1H)	7.75(s, 1H)
	7.65(t, 1H)	6.55(d, 1H)
	7.30(m, 6H)	4.54(m, 1
	5.01(s, 2H)
	3.38(m, 2H)
	3.04(m, 2H)
	1.68(m, 2H)
Aus-	77%	50%
beute
Masse	398(EI)	229(EI)
	630	631
Beispiel	1-2.3	1-2.4
-Nr.
Löse-	DMSO	DMSO
Mittel
	8.29(s, 1H)	8.28(s, 1H)
	6.32(s, 1H)	7.09(d, 1H)
	4.89(t, 3H)	5.05(d, 1H)
	3.74(d, 6H)	3.95(m, 1H)
		3.60(m, 5H)
		1.30(s, 3H)
		1.28(s, 3H)
Aus-	16%	92%
beute
Masse	314(EI)	354(EI)
	632	633
Beispiel	1-2.7	1-2.8
-Nr.
Löse-	DMSO	DMSO
mittel
	8.28(s, 1H)	8.22(s, 1H)
	6.29(s, 1H)	7.23(d, 1H)
	5.31(t, 1H)	4.60(d, 1H)
	3.39(d, 2H)	3.85(m, 1H)
	1.39(s, 6H)	3.35(m, 1H)
		1.80(m, 4H)
		1.53(m, 2H)
		1.20(m, 2H)
Aus-	46%	24%
beute
Masse	281(EI)	305(EI)
	634	635
Beispiel	1-2.11	1-2.12
-Nr.
Löse-	DMSO	DMSO
mittel
	8.21(s, 1H)	8.31(s, 1H)
	7.06(d, 1H)	7.32(d, 1H)
	4.81(t, 1H)	4.35(s, 1H)
	4.22(m, 1H)	3.68(s, 3H)
	3.47(m, 2H)	2.32(m, 1H)
	1.51(m, 2H)	0.90(dd, 6H)
	1.37(m, 1H)
	0.88(m, 6H)
Aus-	99%	77%
beute
Masse	308(EI)	322(ES)
	636	637
Beispiel	1-2.15	1-2.16
-Nr.
Löse-	DMSO	DMSO
mittel
	8.19(s, 1H)	8.19(s, 1H)
	7.65(t, 1H)	7.30(d, 1H)
	3.18(t, 2H)	3.65(m, 1H)
	1.62(m, 6H)	1.68(m, 5H)
	1.16(m, 3H)	1.25(m, 4H)
	0.90(m, 2H)	0.78(d, 3H)
Aus-	68%	31%
beute
Masse	303(EI)	305(EI)
	638	639
Beispiel	1-2.19	1-2.20
-Nr.
Löse-	DMSO	DMSO
mittel
	8.21(s, 1H)	8.20(s, 1H)
	7.81(t, 1H)	7.71(t, 1H)
	3.41(dd, 2H)	4.45(br, 1H)
	2.31(m, 10H)	3.40(m, 4H)
	2.13(s, 3H)	1.60(m, 2H)
	1.70(p, 2H)	1.44(m, 2H)
Aus-	28%	98%
beute
Masse	349(EI)	281(EI)
	640	641
Beispiel	1-2.23	1-2.24
-Nr.
Löse-	DMSO	DMSO
mittel
	8.20(s, 1H)	8.21(s, 1H)
	7.28(d, 1H)	7.24(d, 1H)
	4.19(m, 1H)	7.02(t, 1H)
	2.40(m, 6H)	4.40(m, 1H)
	1.50(m, 4H)	3.92(m, 1H)
	1.15(d, 3H)	2.95(q, 2H)
	0.91(t, 6H)	1.95(m, 2H)
		1.82(m, 2H)
		1.59(m, 2H)
		1.3(m, 6H)
		0.82(t, 3H)
Aus-	52%	70%
beute
Masse	348(EI)
	642	643
Beispiel	1-2.27	1-2.28
-Nr.
Löse-	DMSO	DMSO
mittel
	8.25(s, 1H)	8.22(s, 1H)
	6.87(d, 1H)	7.28(d, 1H)
	4.02(m, 1H)	3.85(m, 1H)
	2.45(m, 4H)	2.19(s, 6H)
	2.22(m, 1H)	2.15(m, 1H)
	1.78(m, 8H)	1.82(m, 4H)
	1.45(m, 6H)	1.50(m, 2H)
		1.25(m, 2H)
Aus-	23%	51%
beute
Masse	374(EI)	334(EI)
	644	645
Beispiel	1-2.31	1-2.32
-Nr.
Löse-	DMSO	DMSO
mittel
	8.21(s, 1H)	8.71(s, 1H)
	7.22(d, 1H)	5.32(m, 1H)
	4.65(s, 1H)	3.82(m, 2H)
	4.15(m, 1H)	3.55(m, 2H)
	3.85(m, 1H)	2.00(m, 2H)
	2.78(m, 1H)	1.70(m, 2H)
	2.60(m, 1H)
	2.38(dd, 1H)
	1.95(m, 3H)
	1.80(m, 2H)
	1.52(m, 3H)
	1.20(m, 2H)
Aus-	21%	40%
beute
Masse	374(EI)	292(EI)
	646	647
Beispiel	1-2.35	1-2.36
-Nr.
Löse-	DMSO	CDCl3
mittel
	8.23(s, 1H)	8.11(s, 2H, 1+2)
	7.27(d, 1H)	5.55(m, 1H, 1)
	7.04(t, 1H)	5.29(m, 1H, 2)
	4.46(m, 1H)	4.25(m, 1H, 1)
	3.95(m, 1H)	3.98(m, 1H, 2)
	2.94(m, 2H)	3.72(m, 8H, 1+2)
	1.92(m, 4H)	2.65(m, 8H, 1+2)
	1.62(m, 2H)	1.70
	1.32(m, 6H)	(m, 18H, 1+2)
	0.84(t, 3H)
Aus-	70%	66%
beute
Masse	405(ES)	375(ES)
	648	649
Beispiel	1-2.39	1-2.40
-Nr.
Löse-	DMSO	DMSO
mittel
	8.22(s, 1H)	8.22(s, 1H)
	6.35(s, 1H)	7.12(d, 1H)
	5.19(t, 1H)	4.10(m, 1H)
	3.54(d, 2H)	2.20(m, 1H)
	2.00(m, 2H)	1.89(m, 1H)
	1.75(m, 4H)	1.35(m, 8H)
	1.53(m, 2H)
Aus-	48%	60%
beute
Masse	308(EI)	301(EI)
	650	651
Beispiel	1-2.43	1-2.44
-Nr.
Löse-	DMSO	DMSO
mittel
	8.28(s, 1H)	8.41(s, 1H)
	3.62(q, 4H)	8.15(t, 1H)
	1.18(t, 6H)	4.21(td, 2H)
Aus-	13%	21%
beute
Masse	265(EI)	339(EI)
	652	653
Beispiel	1-2.47	1-2.48
-Nr.
Löse-	DMSO	DMSO
mittel
	8.32(t, 1H)	8.15(s, 1H)
	8.15(s, 1H)	7.06(d, 1H)
	3.40(m, 2H)	4.65(br, 1H)
	2.34(m, 2H)	3.79(m, 1H)
	2.18(s, 6H)	3.52(m, 1H)
	1.69(m, 2H)	1.86(m, 2H)
		1.61(m, 2H)
		1.25(m, 4H)
Aus-	22%	53%
beute
Masse	294(EI)	307(EI)
	654	655
Beispiel	1-2.51	1-2.52
-Nr.
Löse-	DMSO	DMSO
mittel
	8.29(s, 1H)	8.38(s, 1H)
	6.18(s, 1H)	7.28(d, 1H)
	5.15(t, 1H)	5.28(t, 1H)
	3.70(m, 1H)	4.65(m, 1H)
	3.49(m, 1H)	3.86(m, 2H)
	2.60(m, 1H)	3.65(s, 3H)
	0.92(d, 3H)
	0.83(d, 3H)
Aus-	27%	63%
beute
Masse	308(EI)	309(EI)
	656
Beispiel	1-2.55
-Nr.
Löse-	DMSO
mittel
	8.18(s, 1H)
	7.69(t, 1H)
	4.32(br, 1H)
	3.35(m, 4H)
	1.40(m, 6H)
Aus-	43%
beute
Masse	295(EI)

EXAMPLE 3.0

Production of Amines

[0237] 657

[0238] 4.5 g (20 mmol) of 2-bromobutyraldehyde diethyl acetyl (Pfaltz-Bauer Company) and 5.2 g (80 mmol) of sodium azide are stirred for 5 days in 15 ml of DMF at 100° C. Then, it is poured onto cold dilute sodium bicarbonate solution, extracted 3× with ether, the organic phase is dried with magnesium sulfate and concentrated by evaporation: raw yield 1.87 g (50% of theory).

[0239] 936 mg of the crude product is dissolved in 50 ml of methanol, mixed with palladium on carbon (10%) and stirred for 12 hours under H2 atmosphere. After the catalyst is filtered off and after concentration by evaporation, 457 mg (57% of theory) of the desired amine remains.

	658	659	660	661
Beispiel-	3.0	3.1	3.2	3.3
Nr.
Ausbeute	50%	57%	50%	71%
NMR	4,38(d, 1H)	4,19(d, 1H)	4, 38(d, 1H)	4,25(d, 1H)
CDCl3	3,72(m, 2H)	3,68(m, 2H)	3,58(m, 2H)	3,5(m, 1H)
	3,6(m, 2H)	3,52(m, 2H)	3,5(m, 1H)	3,42(s, 3H)
	3,25(m, 1H)	2,7(m, 1H)	3,49(s, 3H)	3,41(s, 3H)
	1,7(m, 1H)	1,60(m, 1H)	3,43(s, 3H)	3,40(m, 1H)
	1,46(m, 1H)	1,25(m, 1H)	3,39(s, 3H)	3,08(m, 1H)
	1,25(trtr, 6H)	1,2(trtr, 6H)
	1,0(tr, 3H)	0,95(tr, 3H)

EXAMPLE 4.0

Production of the Free Aldehydes

[0240] 662

[0241] 148 mg (0.5 mmol) of intermediate product compound 1.18 is dissolved in 1 ml of glacial acetic acid. At room temperature, 0.5 ml of 1N hydrochloric acid is added, and it is stirred for 12 hours. For working-up, it is poured onto ice water and carefully neutralized with pulverized sodium bicarbonate. Then, it is extracted 3× with ethyl acetate, the organic phase is dried with magnesium sulfate and concentrated by evaporation, crude product 104 mg (83% of theory) of the aldehyde of compound 4.0. The crude product can be used without further purification.

	663	664	665	666
Beispiel	4.1	4.0	4.2	4.3
-Nr.
Aus-	82%	83%	89%	79%
beute
Masse	ESI:	ESI:	ESI:	ESI:
	MH+ 278	MH+ 250	MH+ 266	MH+ 294
	(39%)	(9%)	(8%)	(10%)
	210(100%)

EXAMPLE 5.0

Production of Ketones

[0242] 667

[0243] 100 mg (0.356 mmol) of compound 6.0 and 126 mg of N-methylmorpholine-N-oxide are dissolved in 5 ml of dichloromethane and stirred for 10 minutes with pulverized molecular sieve (4 A). Then, 6 mg of tetrapropylammonium perruthenate is added, and it is stirred for 4 more hours at room temperature. After concentration by evaporation, it is chromatographed on silica gel (hexane/ethyl acetate 4:1>2:1). Yield: 75 mg (76% of theory) of the ketone of compound 5.0.

         668
Beispiel 5.0
-Nr.
Aus-     76%
beute
Masse    ESI:
         MH+ 280
         (100%)
         200(37%)
         156(30%)

EXAMPLE 6.0

[0244] Production of Alcohols 669

[0245] 265 mg (1 mmol) of compound 4.2 is dissolved in 20 ml of tetrahydrofuran. While being cooled in an ice bath, 5 equivalents of methylmagnesium bromide (3 molar solution in ether) is added in portions. Then, it is stirred for 3 more hours at room temperature and then quenched with water while being cooled. Then, it is mixed with ammonium chloride solution, extracted 3× with ethyl acetate, the organic phase is dried with magnesium sulfate and concentrated by evaporation. Flash chromatography (hexane/ethyl acetate 2:1) yields 213 mg (76% of theory) of the alcohol of compound 6.0. 670

[0246] ESI:MH+ 282 (100%) 276 (5%)

[0247] Similarly produced are also the following intermediate products:

	671	672	673
Beispiel	6.1	6.2	6.3
-Nr.
Aus-	46%	32%	39%
beute
Masse	EI:	ESI:	ESI:
	M+ 267(3%)	MH+ 308	MH+ 296
	223(100%)	(100%)	(100%)
	132(27%)	306(71%)	294(73%)
		268(31%)	217(4%)
	674	675
Beispiel	6.4	6.5
-Nr.
Aus-	36%	50%
beute
Masse	EI	ESI:
	M+ 281	MH+ 310
	(3%)	(100%)
	223(100%)	308(87%)
	114(38%)	298(9%)
	676	677	678
Beispiel	6.6	6.7	6.8
-Nr.
Aus-	40%	20%	35%
beute
Masse	EI:	CI:	ESI:
	M+ 358	M+ 310 (100%)	MH+ 294
	(100%)	308 (84%)	(28%)
	356(97%)	130(54%)	296(36%)
	277(29%)		210(100%)
	679	680
Beispiel	6.9	6.10
-Nr.
Aus-	29%	67%
beute
Masse	ESI:	ESI:
	MH+ 308	MH+ 310(87%)
	(28%)	312(100%)
	310	123(24%)
	(38%)
	210
	(100%)

[0248] Subjects of this invention are thus also compounds of general formula Ia 681

[0249] in which

[0250] D stands for halogen, and X, R1, and R2 have the meanings that are indicated in general formula (I).

[0251] Those intermediate products of general formula Ia, in which D stands for chlorine and X, R1 and R2 have the meanings that are indicated in the general formula, are especially valuable.

[0252] Another subject of this invention are also those compounds that fall under industrial property right DE 4029650, whose action is in the fungicide range and which are not described as CDK inhibitors, however, and also their use for treating cancer is not described.

No.	Structure	Name
5	682	4-[[5-Bromo-4-(2-propynylamino)-2- pyrimidinyl]amino]-phenol
6	683	4-[[5-Bromo-4-(2-propynyloxy)-2- pyrimidinyl]amino]-phenol
16	684	5-Bromo-N2-(4-methylthiophenyl)-N4-2- propynyl-2,4-pyrimidine diamine
22	685	1-[4-[(5-Bromo-4-(2-propynyloxy)-2- pyrimidinyl)amino]phenyl]-ethanone
23	686	5-Bromo-N2-(4-difluoromethylthiophenyl)-N4-2- propynyl-2,4-pyrimidine diamine
24	687	5-Bromo-N4-2-propynyl-N2-(4- trifluoromethylthiophenyl)-2,4-pyrimidine diamine
35	688	5-Bromo-N4-2-propynyl-N2-(3- trifluoromethylthiophenyl)-2,4-pyrimidine diamine
37	689	N-[5-Bromo-4-(2-propynylamino)-2-pyrimidinyl]- indazol-5-amine
38	690	N-[5-Bromo-4-(2-propynylamino)-2-pyrimidinyl]- benzothiazole-5-amine
42	691	4-[[5-Fluoro-4-(2-propynyloxy)-2-pyrimidinyl]amino]- phenol
43	692	4-[[5-Chloro-4-(2-propynyloxy)-2-pyrimidinyl]amino]- phenol
50	693	1-[4-[(5-Bromo-4-(2-propynylamino)-2- pyrimidinyl)amino]phenyl]-ethanone
54	694	1-[4-[(5-Iodo-4-(2-propynylamino)-2- pyrimidinyl)amino]phenyl]-ethanone
70	695	1-[4-[(5-Ethyl-4-(2-propynylamino)-2- pyrimidinyl)amino]phenyl]-ethanone
81	696	1-[4-[(5-Bromo-4-(2-propynylamino)-2- pyrimidinyl)aminolphenyl]-ethanol
82	697	1-[4-[(5-Bromo-4-(2-propynyloxy)-2- pyrimidinyl)amino]phenyl]-ethanol

[0253] The invention thus relates in addition to pharmaceutical agents that comprise a compound of general formula I

[0254] in which

[0255] R1 stands for halogen or C1-C3-alkyl

[0256] X stands for oxygen or —NH,

[0257] A stands for hydrogen

[0258] B stands for hydroxy, —CO-alkyl-R7, —S—CHF2, —S—(CH2)nCH(OH)CH2N—R3R4, —S—CF3, or —CH—(OH)—CH3, or

[0259] A and B, independently of one another, can form a group 698

[0260] R2, R3, R4, R7 and R8 have the meanings that are indicated in general formula I, as well as isomers, diastereomers, enantiomers and salts thereof.

[0261] The agents according to the invention can also be used for treating cancer, auto-immune diseases, cardiovascular diseases, chemotherapy agent-induced alopecia and mucositis, infectious diseases, nephrological diseases, chronic and acute neurodegenerative diseases and viral infections, whereby cancer is defined as solid tumors and leukemia; auto-immune diseases are defined as psoriasis, alopecia and multiple sclerosis; cardiovascular diseases are defined as stenoses, arterioscleroses and restenoses; infectious diseases are defined as diseases that are caused by unicellular parasites; nephrological diseases are defined as glomerulonephritis; chronic neurodegenerative diseases are defined as Huntington's disease, amyotrophic lateral sclerosis, Parkinson's disease, AIDS dementia and Alzheimer's disease; acute neurodegenerative diseases are defined as ischemias of the brain and neurotraumas; and viral infections are defined as cytomegalic infections, herpes, hepatitis B or C, and HIV diseases.

[0262] The following examples describe the biological action of the compounds according to the invention without limiting the invention to these examples.

EXAMPLE 1

[0263] CDK2/CycE Kinase Assay

[0264] Recombinant CDK2- and CycE-GST-fusion proteins, purified from baculovirus-infected insect cells (Sf9), were obtained by Dr. Dieter Marmé, Klinik für Tumorbiologie [Clinic for Tumor Biology], Freiburg. Histone IIIS, which was used as a kinase substrate, was purchased by the Sigma Company.

[0265] CDK2/CycE (50 ng/measuring point) was incubated for 15 minutes at 22° C. in the presence of various concentrations of test substances (0 μm, as well as within the range of 0.01-100 μm) in assay buffer [50 mmol of tris/HCl pH 8.0, 10 mmol of MgCl2, 0.1 mmol of Na ortho-vanadate, 1.0 mmol of dithiothreitol, 0.5. μm of adenosine triphosphate (ATP), 10 μg/measuring point of histone IIIS, 0.2 μCi/measuring point of 33P-gamma ATP, 0.05% NP40, 12.5% dimethyl sulfoxide]. The reaction was stopped by adding EDTA solution (250 mmol, pH 8.0, 14 μl/measuring point).

[0266] From each reaction batch, 10 μl was applied to P30 filter strips (Wallac Company), and non-incorporated 33P-ATP was removed by subjecting the filter strips to three washing cycles for 10 minutes each in 0.5% phosphoric acid. After the filter strips were dried for one hour at 70° C., the filter strips were covered with scintillator strips (MeltiLex™ A, Wallac Company) and baked for one hour at 90° C. The amount of incorporated 33P (substrate phosphorylation) was determined by scintillation measurement in a gamma-radiation measuring device (Wallac).

EXAMPLE 2

[0267] Proliferation Assay Cultivated human tumor cells (as indicated) were flattened out at a density of 5000 cells/measuring point in a 96-hole multititer plate in 200 μl of the corresponding growth medium. After 24 hours, the cells of one plate (zero-point plate) were colored with crystal violet (see below), while the medium of the other plates was replaced by fresh culture medium (200 μl), to which the test substances were added at various concentrations (0 μm, as well as in the range of 0.01-30 μm; the final concentration of the solvent dimethyl sulfoxide was 0.5%). The cells were incubated for 4 days in the presence of test substances. The cell proliferation was determined by coloring the cells with crystal violet: the cells were fixed by adding 20 μl/measuring point of a 11% glutaric aldehyde solution for 15 minutes at room temperature. After three washing cycles of the fixed cells with water, the plates were dried at room temperature. The cells were colored by adding 100 μl/measuring point of a 0.1% crystal violet solution (pH was set at 3 by adding acetic acid). After three washing cycles of the colored cells with water, the plates were dried at room temperature. The dye was dissolved by adding 100 μl/measuring point of a 10% acetic acid solution. The extinction was determined by photometry at a wavelength of 595 nm. The change of cell growth, in percent, was calculated by standardization of the measured values to the extinction values of the zero-point plate (=0%) and the extinction of the untreated (0 μm) cells (=100%).

[0268] The results of Examples 1 and 2 are cited in the following tables.

[0269] [Key to Subsequent Tables:]

[0270] Beispiel Nummer=Example Number

	Inhibition
Beispiel	IC50 [nM]	Proliferation IC50 [μM]	Sw
Nummer	CDK2/CycE	MCF7	H460	HCT116	DU145	(g/l)
22	40	1.2	1.5	1.5	1.5	0.003
37	70	4				0.006
6	70	4	6			0.008
40	20	1	3	3	9	0.002
51	70	8
20	60	4
21	400	2
1	300	8
2	700
16	300	3
24	400	5
26	300	3
35	120	>10
23	180	3
11	6	0.2	0.5	0.3	0.2
38	80	>10
34	1800
10	4	0.2	0.5	0.5	0.5
12	400	4
25	70	1.2	1.5	1.1	1.2	0.017
9	7	0.9		3	3
7	6	0.7	1.5	1.2	0.5	0.028
31	800	7				0.0023
14	200	3				0.013
18	2000					0.039
3	200	8				0.039
19	800	>10				0.041
13	2000	>10
17	1000	>10				0.04
4	40	8				0.042
15	300	>10				0.024
8	<10	4				0.007
43	200	6				0.04
36	30	0.4	0.6	0.5	0.6	0.018
27	>10000
42	2000					0.043
39	300					0.0016
44	8	1.2	0.4	0.4	0.3	0.005
45	10	2	1.7	1.2	0.5	0.0094
50	150
5	90	10				0.043
46	7	2				0.0069
52	200	0.2	1.6	1.2	2	0.0005
53	300	1.6				0.026
54	100	1.1				0.0015
47	12	0.7	1.8	1.3	0.9
56	80	4				0.023
49	50	>10				0.044
48	4	0.2	1	0.4	0.3	0.042
96	400					0.0005
98	2000
85	2000					0.001
84	400					0.0005
86	3000
87	250	0.8				0.003
22	40	1.2	1.5	1.5	1.5	0.003
37	70	4				0.006
6	70	4	6			0.008
16	300	3
24	400	5
35	120	>10
23	180	3
38	80	>10
43	200	6				0.04
42	2000					0.043
50	150
5	90	10				0.043
54	100	1.1				0.0015

[0271] Proof of Superiority of the Compounds According to the Invention Compared to the Known Compounds

[0272] To prove the superiority of the compounds according to the invention compared to the known compounds, the compounds according to the invention were compared to known reference compounds and structurally-similar known compounds in the enzyme test. The result is cited in the following table:

[0273] [Key to the following tables:]

[0274] Beispiel-Nr.=Example No.

[0275] Löslichkeit (g/l)=Solubility (g/l)

[0276] Beispiel 11 aus WO01/14375 (Seite 38)=Example 11 from WO01/14375 (page 38)

			CDK2/		Löslish-
			CycE	MCF-7	keit
Beispiel-Nr.	R2	A	IC50 [nM]	IC50 [μM]	(g/l)
699	CH(C3H7—CH2OH—	—SO2—N—(CH2)2—OH	4	0.2	0.042
Nr. 48
700	CH(CH2OH)2	SO2NH2	7	0.9	0.009
Nr. 9
701	Propargyl—NH—	SO2NH2	6	0.2
Nr. 11
702			7000	30
Olomoucine
703			1500	8
Roscovitine
704			1800	6
Kenpaullone
705			90	1.2
Alsterpaullone
706			10	2
Purvalanol A
Beispiel 11 aus			190
WO01/14375
(Seite 38)
707

[0277] It can be seen from the results of the table that both in the enzyme test and in the cell test, the compounds according to the invention have significantly higher activities in the enzyme and in the MCF-7 cells than the compounds that are known from the prior art. The compounds according to the invention are thus far superior to the known compounds.

Claims

1. A compound of formula I

2. A compound of claim 1 wherein R1 stands for hydrogen, halogen, C1-C6-alkyl, nitro, or for the group —COR5, —OCF3, —(CH2)nR5, —S—CF3 or —SO2CF3, R2 stands for C1-C10-alkyl, C2-C10-alkenyl, C2-C10-alkinyl, or C3-C10-cycloalkyl or for C1-C10-alkyl, C2-C10-alkenyl, C2-C10-alkinyl, or C3-C10-cycloalkyl that is substituted in one or more places in the same way or differently with hydroxy, halogen, C1-C6-alkoxy, C1-C6-alkylthio, amino, cyano, C1-C6-alkyl, —NH—(CH2)n—C3-C10-cycloalkyl, C3-C10-cycloalkyl, C1-C6-hydroxyalkyl, C2-C6-alkenyl, C2-C6-alkinyl, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, —NHC1-C6-alkyl, —N(C1-C6-alkyl)2, —SO(C1-C6-alkyl), —SO2 (C1-C6-alkyl), C1-C6-alkanoyl, —CONR3R4, —COR5, C1-C6-alkylOAc, carboxy, aryl, heteroaryl, —(CH2)n-aryl, —(CH2)n-heteroaryl, phenyl-(CH2)n-R5, —(CH2)nPO3(R5)2 or with the group —R6 or —NR3R4, and the phenyl, C3-C10-cycloalkyl, aryl, heteroaryl, —(CH2)n-aryl and —(CH2)n-heteroaryl itself optionally can be substituted in one or more places in the same way or differently with halogen, hydroxy, C1-C6-alkyl, C1-C6-alkoxy, heteroaryl, benzoxy or with the group —CF3 or —OCF3, and the ring of the C3-C10-cycloalkyl and the C1-C10-alkyl optionally can be interrupted by one or more nitrogen, oxygen and/or sulfur atoms and/or can be interrupted by one or more ═C═O groups in the ring and/or optionally one or more possible double bonds can be contained in the ring, or R2 stands for the group 714X stands for oxygen or for the group —NH—, —N(C1-C3-alkyl)- or for —OC3-C10-cycloalkylene, which can be substituted in one or more places in the same way or differently with a heteroaromatic compound, or X and R2 together form a C3-C10-cycloalkyl ring, which optionally can contain one or more heteroatoms and optionally can be substituted in one or more places with hydroxy, C1-C6-alkyl, C1-C6-alkoxy or halogen, A and B, in each case independently of one another, stand for hydrogen, hydroxy, C1-C3-alkyl, C1-C6-alkoxy or for the group —S—CH3, —SO2—C2H4—OH, —CO—CH3, —S—CHF2, —S—(CH2)nCH(OH)CH2N—R3R4, —CH2P(O)OR3OR4, —S—CF3, —SO—CH3, —SO2CF3, —SO2—(CH2)n—N—R3R4, —SO2—NR3R4, —SO2R7, —CH—(OH)—CH3 or for 715716717718or A and B together can form a group 719R3 and R4, in each case independently of one another, stand for hydrogen, phenyl, benzyloxy, C1-C12-alkyl, C1-C6-alkoxy, C2-C4-alkenyloxy, C3-C6-cycloalkyl, hydroxy, hydroxy-C1-C6-alkyl, dihydroxy-C1-C6-alkyl, heteroaryl, heterocyclo-C3-C10-alkyl, heteroaryl-C1-C3-alkyl, C3-C6-cycloalkyl-C1-C3-alkyl optionally substituted with cyano, or for C1-C6-alkyl that is optionally substituted in one or more places in the same way or differently with phenyl, pyridyl, phenyloxy, C3-C6-cycloalkyl, C1-C6-alkyl or C1-C6-alkoxy, wherein the phenyl itself can be substituted in one or more places in the same way or differently with halogen, trifluoromethyl, C1-C6-alkyl, C1-C6-alkoxy or with the group —SO2NR3R4, or for the group —(CH2)nNR3R4, —CNHNH2 or —NR3R4 or for 720or which optionally can be substituted with C1-C6-alkyl, R5 stands for hydroxy, phenyl, C1-C6-alkyl, C3-C6-cycloalkyl, benzoxy, C1-C6-alkylthio or C1-C6-alkoxy, R6 stands for the group 721R7 stands for halogen, hydroxy, phenyl, C1-C6-alkyl, —C2H4OH, —NR3R4, or the group 722R8, R9 and R10, in each case independently of one another, stand for hydrogen, hydroxy, C1-C6-alkyl, C3-C6-cycloalkyl or for the group 723and n stands for 0-6.

3. A compound according to claim 1, wherein R1 stands for hydrogen, halogen, C1-C3-alkyl, or for the group —(CH2)nR5, R2 stands for —CH(CH3)—(CH2)n—R5, —CH—(CH2OH)2, —(CH2)nR7, —CH(C3H7)—(CH2)n—R5, —CH(C2H5)—(CH2)n—R5, —CH2—CN, —CH(CH3)COCH3, —CH(CH3)—C(OH)(CH3)2, —CH(CH(OH)CH3)OCH3, —CH(C2H5)CO—R5, C2-C4-alkinyl, —(CH2)n—COR5, —(CH2)n—CO—C1-C6-alkyl, —(CH2)n—C(OH)(CH3)-phenyl, —CH(CH3)—C(CH3)—R5, —CH(CH3)—C(CH3)(C2H5)—R5, —CH(OCH3)—CH2—R5, —CH2—CH(OH)—R5, —CH(OCH3)—CHR5—CH3, —CH(CH3)—CH(OH)—CH2—CH═CH2, —CH(C2H5)—CH(OH)—(CH2)n—CH3, —CH(CH3)—CH(OH)—(CH2)n—CH3, —CH(CH3)—CH(OH)—CH(CH3)2, CH2(OAc)2, —(CH2)nR6, —(CH2)n—(CF2)n—CF3, —CH((CH2)n—R5)2, —CH(CH3)—CO—NH2, —CH(CH2OH)-phenyl, —CH(CH2OH)—CH(OH)—(CH2)nR5, —CH(CH2OH)—CH(OH)-phenyl, —CH(CH2OH)—C2H4—R5, —(CH2)n—C≡C—C(CH3)═CH—COR5, —CH(Ph)-(CH2)n—R5, —(CH2)n—COR5, —(CH2)nPO3(R5)2, —(CH2)n—COR5, —CH((CH2)nOR5)CO—R5, —(CH2)nCONHCH((CH2)nR5)2, —(CH2)nNH—COR5, —CH(CH2)nR5—(CH2)nC3C10-cycloalkyl, —(CH2)n—C3-C10-cycloalkyl, C3-C10-cycloalkyl, C1-C6-alkyl, C3-C10-cycloalkyl, —(CH2)n—O—(CH2)n-R5, or —(CH2)n—NR3R4 that is optionally substituted in one or more places in the same way or differently with hydroxy, C1-C6-alkyl or the group —COONH(CH2)nCH3 or —NR3R4, —CH(C3H7)—(CH2)n—OC(O)—(CH2)n—CH3, —(CH2)n—R5, —C(CH3)2—(CH2)n—R5, —C(CH2)n(CH3)—(CH2)nR5, —C(CH2)n—(CH2)nR5, —CH(t-butyl)-(CH2)n—R5, —CCH3(C3H7)—(CH2)nR5, —CH(C3H7)—(CH2)n—R5, —CH(C3H7)—COR5, —CH(C3H7)—(CH2)n—OC(O)—NH-Ph, —CH((CH2)n(C3H7))—(CH2)nR5, —CH(C3H7)—(CH2)n—OC(O)—NH-Ph(OR5)3, —NR3R4, —NH—(CH2)n—NR3R4, R5—(CH2)n—C*H—CH(R5)—(CH2)n—R5, —(CH2)n—CO—NH—(CH2)n—CO—R5, —OC(O)NH—C1-C6-alkyl or —(CH2)n—CO—NH—(CH2)n—CH—((CH2)nR5)2, or for C3-C10-cycloalkyl, which is substituted with the group 724725X stands for oxygen or for the group —NH—, —N(C1-C3-alkyl) or 726or R2 stands for the group 727or X and R2 together form a group 728A and B, in each case independently of one another, stand for hydrogen, hydroxy, C1-C3-alkyl, C1-C6-alkoxy or for the group —S—CH3, —SO2—C2H4—OH, —CO—CH3, —S—CHF2, —S(CH2)nCH(OH)CH2N—R3R4, —CH2PO(OC2H5)2, —S—CF3, —SO—CH3, —SO2CF3, —SO2—(CH2)n—N—R3R4, —SO2—NR3R4, —SO2R7, —CH(OH)—CH3, —COOH, —CH((CH2)nR5)2, —(CH2)nR5, —COO—C1-C6-alkyl, —CONR3R4 or for 729730731732A and B together can form a group 733R3 and R4, in each case independently of one another, stand for hydrogen, phenyl, benzyloxy, C1-C12-alkyl, C1-C6-alkoxy, C2-C4-alkenyloxy, C3-C6-cycloalkyl, hydroxy, hydroxy-C1-C6-alkyl, dihydroxy-C1-C6-alkyl, heteroaryl, heterocyclo-C3-C10-alkyl, heteroaryl-C1-C3-alkyl, C3-C6-cycloalkyl-C1-C3-alkyl that is optionally substituted with cyano, or for C1-C6-alkyl that is optionally substituted in one or more places in the same way or differently with phenyl, pyridyl, phenyloxy, C3-C6-cycloalkyl, C1-C6-alkyl or C1-C6-alkoxy, wherein the phenyl itself can be substituted in one or more places in the same way or differently with halogen, trifluoromethyl, C1-C6-alkyl, C1-C6-alkoxy or with the group —SO2NR3R4, or for the group —(CH2)nNR3R4, —CNHNH2 or —NR3R4 or for 734which optionally can be substituted with C1-C6-alkyl, R5 stands for hydroxy, phenyl, C1-C6-alkyl, C3-C6-cycloalkyl, benzoxy, C1-C6-alkylthio or C1-C6-alkoxy, R6 stands for the group 735R7 stands for halogen, hydroxy, phenyl, C1-C6-alkyl, —(CH2)nOH, —NR3R4 or the group 736R8, R9 and R10 stand for hydrogen, hydroxy, C1-C6-alkyl or for the group —(CH2)n—COOH, and n stands for 0-6 thereof.

4. A process for producing a compound of general formula I according to claim 1, by reacting a compound of formula Ia

5. A process according to claim 4, wherein D stands for chlorine.

6. A composition comprising a compound of claim 1, wherein R1 stands for halogen or C1-C3-alkyl, X stands for oxygen or —NH—, A stands for hydrogen, B stands for hydroxy, —CO-alkyl-R7, —S—CHF2, —S—(CH2)nCH(OH)CH2N—R3R4, —S—CF3, or —CH—(OH)—CH3, or A and B, independently of one another, can form a group 738and a pharmaceutically acceptable carrier.

7. A method of treating cancer, an auto-immune disease, a chemotherapy agent-induced alopecia or mucositis, a cardiovascular disease, an infectious disease, a nephrological disease, a chronic or an acute neurodegenerative disease or a viral infection comprising administering an effective amount of a compound according to claim 1.

8. A method according to claim 7, for treating a solid tumor, or leukemia; psoriasis, alopecia, or multiple sclerosis; stenoses, arterioscleroses, or restenoses; a unicellular parasite; glomerulonephritis; Huntington's disease, amyotrophic lateral sclerosis, Parkinson's disease, AIDS dementia or Alzheimer's disease; an ischemia of the brain, or a neurotrauma; a cytomegalic infection, herpes, hepatitis B or C, or HIV.

9. A pharmaceutical agent comprising at least one compound according to claim 1.

10. A method for treating cancer, an auto-immune disease, a cardiovascular disease, an infectious disease, a nephrological disease, a neurodegenerative disease or a viral infection comprising administering an effective amount of a compound according to claim 1 to a patient in need thereof.

11. A composition comprising a compound according to claim 1 and at least one suitable formulation substance and/or vehicle.

12. A method of inhibiting cyclin-dependent kinase comprising administering an effective amount of a compound according to claim 1.

13. A method according to claim 12, wherein the kinase is CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 or CDK9.

14. A method of inhibiting the glycogen-synthase-kinase (GSK-3β) comprising administering an effective amount of a compound according to claim 1.

15. A method of claim 1 comprising enterally, parenterally or orally administering an effective amount of the compound according to claim 1.

16. A preparation for enteral, parenteral and oral administration comprising an agent according to claim 6.

17. A compound according to claim 1, in the form of an isomer, a diastereomer or an enantiomer.