The Chks (checkpoint kinases) -, Akts (protein kinases B) and Pdks (phosphoinositide-dependent kinases) are enzyme families that play an important role in the regulation of the cell cycle and thus is an especially advantageous target for the development of small inhibitory molecules. Akts and Pdks may be involved in common signal transduction pathways. Preferential inhibitors of the Chks and Akts and/or Pdks, particularly of Pdk1 can be used for treating cancer or other diseases that cause disruptions of cell proliferation.

Pyrimidines and analogs are already described as active ingredients, such as, for example, the 2-anilino-pyrimidines as fungicides (DE-A-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).

Protein ligands and receptor tyrosine kinases that specifically regulate endothelial cell function are substantially involved in physiological as well as in disease-related angiogenesis. These ligand/receptor systems include the Vascular Endothelial Growth Factor (VEGF) and the Angiopoietin (Ang) families, and their receptors, the VEGF receptor family and the tyrosine kinase with immunoglobulin-like and epidermal growth factor homology domains (Tie) family. The members of the two families of receptor tyrosine kinases are expressed primarily on endothelial cells. The VEGF receptor family includes FIt1

(VEGF-R1), Flk1/KDR (VEGF-R2), and Flt4 (VEGF-R3). These receptors are recognized by members of the VEGF-related growth factors in that the ligands of FIt1 are VEGF and placenta growth factor (PIGF), whereas Flk1/KDR binds VEGF, VEGF-C and VEGF-D, and the ligands of Flot4 are VEGF-C and VEGF-D (Nicosia, Am. J. Pathol. 153,11-16, 1998). The second family of endothelial cell specific receptor tyrosine kinases is represented by Tie1 and Tie2 (also kown as Tek). Whereas Tie1 remains an orphan receptor, three secreted glycoprotein ligands of Tie2, Ang1, Ang2, and Ang3/Ang4 have been discovered (Davis et al., Cell 87,1161-1169, 1996; Maisonpierre et al., Science 277,55-60, 1997; Valenzuela et al, Proc. Natl. Acad. Sci. USA 96,1904-1909, 1999 ; patents: US 5,521, 073; US 5, 650, 490; US 5,814, 464). Preferential inhibitors of the angiogenesis related kinases can be used for treating cancer or other diseases that are related to angiogenesis.

The object of this invention is to provide compounds that are inhibitors of cell cycle dependent kinases, in particular Chk, Akt, Pdk, CDK (cyclin dependent kinases) and/or angiogenesis related kinases, in particular VEGF-R (vascular endothelial growth factor receptor) kinases which 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.

It has now been found that the novel compounds of general formula I

A or B in each case independently of one another represent cyano, halogen, hydrogen, hydroxy, aryl or the group-NO2,-NH2.- NR3R4, -C1-6-alkyl-NR3R4,-N(C1-6-hydroxyalkyl) 2, -NH-C (NH)-CH3,- NH (CO)-R5,-NHCOOR6,-NR7-(CO)-NR8R9,-NR7-(CS)-NR8R9,- COOR5,-CO-NR8R9, -CONH-C1-6-alkyl-COOH,-SO2-CH2, 4- bromo-1-methyl-1 H-pyrazolo-3yl or represent C1-6-alkyl optionally substituted in one or more places, the same way or differently with halogen, hydroxy, cyano or with the group-COOR5,-CONR8R9,-NH2, -NH-SO2-CH3,- <BR> <BR> <BR> NR8R9,-NH- (CO)-R5,-NR'- (CO)-NR$R9,-S02-NHR3,-0- (CO)-R5<BR> <BR> <BR> <BR> <BR> or-O-(CO)-C16-alkyl-R5, X represents an oxygen atom or the group-NH-or-NR3R4, R1 represents hydrogen, halogen, hydroxymethyl, C1-6-alkyl, cyano or the group-COOH,-COO-iso-propyl,-N02,-NH- (CO)- (CH2) 2- COOH or-NH-(CO)-(CH2) 2-COO-C16-alkyl, whereby the C1-6-alkyl can optionally be substituted in one or more places, in the same way or differently with halogen, R2 represents hydrogen or the group-NH- (CO)-aryl or C1-6-alkyl optionally substituted in one or more places, the same way or differently with cyano, hydroxy, aryl, heteroaryl, C3-6- heterocycloalkylring, which can optionally be interrupted with one or more nitrogen atoms, or substituted with the group-NR8R9,- NH- (CO)-NR8R9, -NH-(CO)-S-C1-6-alkyl, -NH-(CS)-NR8R9,-NH- (CO) O-CH2-phenyl,-NH- (CO) H, -NH (CO)-R5,-NH (CO)-OR',- (CO)-NH-NH2,- (CO)-NH-CH2- (CO)-NH2,- (CO)-NH-C_6-alkyl,- COOH,

whereby the aryl or the heteroaryl can optionally be substituted in one or more places, the same or differently with halogen, hydroxy, C1-6-alkyl, -NH2, -NH-(CO)-CH2-NH2,-NO2,-(CO)-C(CH2)-C2H5,- COOR6,-COOC (CH3) 3, or represents C3-alkinyl,

R3 and R4 in each case independently of one another represent hydrogen or C16-alkyl optionally substituted in one or more places, the same way or differently with hydroxy, phenyl or hydroxyphenyl, or R3 or R4 together form a C3-6-heterocycloalkylring containing at least one nitrogen atom and optionally can be interrupted by one or more oxygen and/or sulfur atoms and/or can be interrupted by one or more- (CO)- groups in the ring and/or optionally can contain one or more possible double bonds in the ring, whereby the 63-6- heterocycloalkylring can optionally be substituted with C16-alkyl, C16-alkyl-COOH or C,. 6-alkyl-NH2, R5 represents hydrogen, C16-alkyl, C16-alkoxy, C2-6-alkenyl, C3-6- cycloalkylring, aryl, heteroaryl, the group- (CO)-NH2 or C3-6- heterocycloalkylring that can optionally be interrupted with one or more nitrogen and/or oxygen and/or sulfur atoms and/or can be interrupted by one or more- (CO)- groups in the ring and/or optionally can contain one or more possible double bonds in the ring and C1-6-alkyl, C2-6-alkenyl, C3-6-cycloalkylring, C3-6- heterocycloalkylring defined above, aryl or heteroaryl can optionally be substituted in one or more places, the same way or differently with halogen, hydroxy, C1-6-alkyl, C1-6-alkoxy, C3-6- cycloalkyl, C3-6-heterocycloalkylring defined above, aryl, heteroaryl or with the group-NR8R9,-NO2,-NR7-(Co)-R5,-NH (CO)-C16- alkyl-NH-(CO)-C1-6-alkyl, -NR7-(CO)-NR8R9, -CO-CH3,-COOH,- CO-NR8R9,-SO2-aryl, -SH, -S-C1-6-alkyl, -SO2-NR8R9, whereby aryl itself can optionally be substituted in one or more places, the same way or differently with halogen, hydroxy, C1-6 alkyl or C »-alkoxy, R6 represents C16-alkyl, C26-alkenyl or phenyl, whereby C1-6-alkyl may optionally be substituted with 3-6- heterocycloalkylring that can optionally be interrupted with one or more nitrogen and/or oxygen and/or sulfur atoms and/or can be

interrupted by one or more- (CO)- groups in the ring and/or optionally can contain one or more possible double bonds in the ring, R7 represents hydrogen or C1-6-alkyl, R8or R9 in each case independently of one another represent hydrogen, C1-6-alkyl, C2-6-alkenyl, C3-6-cycloalkyl, aryl or heteroaryl or the group R, whereby C16-alkyl, C26-alkenyl, C36-cycloalkyl, aryl or heteroaryl can optionally be substituted in one or more places, the same way or differently with halogen, heteroaryl, hydroxy, C1-6-alkoxy, hydroxy-C16-alkoxy or the group-COOH,-N02,-NR8R9,-N (CI-6- alkyl) 2 or with a C36-heterocycloalkylring can optionally be interrupted with one or more nitrogen and/or oxygen and/or sulfur atoms and/or can be interrupted by one or more- (CO)- groups in the ring and/or optionally can contain one or more possible double bonds in the ring, or R8 and R9 together form a C36-heterocycloalkylring containing at least one nitrogen atom and optionally can be interrupted by one or more oxygen and/or sulfur atoms and/or can be interrupted by one or more- (CO)- groups in the ring and/or optionally can contain one or more possible double bonds in the ring, whereby the C3-6- heterocycloalkylring can optionally be substituted in one or more places, the same way or differently with hydroxy or the group- NR8R9,-NH (Co)-R5, hydroxy-C16-alkyl or-COOH and R represents -SO2-aryl, -SO2-heteroaryl or -SO2-NH2 or -SO2-C1-6- alkyl, whereby the aryl can be substituted with-C16-alkyl, with the following provisos: whereby if X represents-NR3R4 then R2 does not represent a substituent, whereby if A and B represent hydrogen, X represents-NH-and R2 represents C -6-alkyl,

then R'represents-NH- (CO)-CH (NH2)- (CH2) 2-COOH or-NH- (CO) -CH (NH2)- (CH2) 2-COOC2H5, whereby if A represents-(CO)-OC2H5 or hydroxy, B represents hydrogen, X represents oxygen, R'represents halogen, then R2 represents C3-alkinyl, whereby if A represents- (CO)-OC2H5 or hydroxy, B represents hydrogen, X represents-NH-, R'represents-N02, then R2 represents C3-alkinyl, whereby if A represents- (CO)-OCH3, then X represents oxygen, R'represents halogen, R2 represents C3-alkinyl and B represenst-NH2,-NHC2H40H,-N (C2H40H) 2,- NH- (CO)-CH2-0 (CO) CH3, whereby if A represents- (CO)-OCH3, then X represents-NH-, R'represents halogen, R2 represents- C2H4-imidazolyl and B represenst hydrogen-NH2, whereby if A represents-NHS02-CH3, then B represents hydrogen, X represents-NH-, R'represents halogen and R2 represents-C2H4-imidazolyl, whereby if R'represents-COO-iso-propyl, then X represents-NH-and R2 represents C3-alkinyl and A or B independently of one another represent the group-N02 or-NH- (CO)-CF3, whereby if R'represents halogen, X represents-NH-, B represents hydrogen and R2 represents C16-alkyl substituted with-NH2, then A represents-NH-(CO)-C6-cycloalkyl-NH2, whereby if R'represents halogen, X represents-NH-, B represents-S-CH3 and R2 represents imidazolyl, then A represents the group as well as all related isotopes, diastereomers, enantiomers, solvates, polymorphs or pharmaceutically acceptable salts thereof are capable of

inhibiting kinases which are involved in the regulation of the cell cycle, particulary Chks, Akt, Pdks and/or Cdks as well as angiogenesis related kinases, particulary VEGF-R kinases.

A more detailed explanation of the terms used in the claims and the description is given in the following : As used herein the singular forms"a", "and", and"the"include plural referents unless the context clearly dictates otherwise. For example compound"refers to one or more of such compounds, while"the enzyme"includes a particular enzyme as well as other family members and equivalents thereof as known to those skilled in the art.

Preferred aspects of the present invention are described in the claims. A more detailed explanation of the terms used in the claims is given in the following : "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.

"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.

"Hydroxy-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 is substituted one or more times with hydroxy.

"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.

"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.

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.

If R3 and R4 or R8 and R9 as defined in the claims, 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- (CO)- 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. In terms of this invention interrupted can mean either that the heteroatoms in addition to the carbon atoms form the ring or that the heteroatoms are substitutes for one or more carbon atoms.

"Halogen"is defined in each case as fluorine, chlorine, bromine or iodine.

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, <BR> <BR> <BR> 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,<BR> <BR> <BR> <BR> <BR> 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.

"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-in4-yl, but-2-in-1-yl, but-1-in-3-yl, etc.

The"aryl"radical in each case comprises 3-16 carbon atoms and in each case can be benzocondensed.

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

The"heteroaryl"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.

For example, there can be mentioned: Thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyi, 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.

"Heterocycloalkyl"stands for an alkyl ring that comprises 3-6 carbon atoms, which can optionally be interrupted with one or more nitrogen and/or oxygen and/or sulfur atoms and/or can be interrupted by one or more- (CO)- groups in the ring and/or optionally can contain one or more possible double bonds in the ring. In terms of this invention interrupted can mean either that the heteroatoms in

addition to the carbon atoms form the ring or that the heteroatoms are substitutes for one or more carbon atoms.

For purposes of this invention, the heterocycloalkyl radical may be a monocyclic, or bicyclic ring system, which may include fused or bridged ring systems; and additionally the nitrogen or sulfur atoms in the heterocyclyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the heterocyclyl radical may be aromatic or partially or fully saturated.

As heterocycloalkyls, there can be mentioned, e. g.: oxiranyl, oxetanyl, aziridinyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidinonyl, dioxolanyl, imidazolidinyl, imidazolidinonyl, thiazolidiononyl, pyrazolidinyl, pyrazolidinonyl, dioxanyl, piperidinyl, piperidinonyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, quinuclidinyl, oxazolidinyl, oxazolidinonyl, hydantoin, pyran, thiin, dihydroacet, etc.

As used herein,"suitable conditions"for carrying out a synthetic step are explicitly provided herein or may be discerned by reference to publications directed to methods used in synthetic organic chemistry. The reference books and treatise set forth above that detail the synthesis of reactants useful in the preparation of compounds of the present invention, will also provide suitable conditions for carrying out a synthetic step according to the present invention.

As used herein, "methods known to one of ordinary skill in the art"may be identified though various reference books and databases. Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds of the present invention, or provide references to articles that describe the preparation, include for example,"Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S. R. Sandler et a/.,"Organic Functional Group Preparations, "2nd Ed. , Academic Press, New York, 1983; H. O. House, "Modern Synthetic Reactions", 2nd Ed. , W. A. Benjamin, Inc. Menlo Park, Calif.

1972; T. L. Gilchrist,"Heterocyclic Chemistry", 2nd Ed. , John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley-Interscience, New York, 1992.

Specific and analogous reactants may also be identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line databases (the American Chemical Society, Washington, D. C. may be contacted for more details). Chemicals that are known but not commercially available in catalogs may be prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e. g., those listed above) provide custom synthesis services.

"Stable compound"and"stable structure"are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

"Mammal"includes humans and domestic animals, such as cats, dogs, swine, cattle, sheep, goats, horses, rabbits, and the like.

"Optional"or"optionally"means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example,"optionally substituted aryl"means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.

"Pharmaceutically acceptable carrier, diluent or excipient"includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.

"Pharmaceutically acceptable salt"includes both acid and base addition salts.

"Pharmaceutically acceptable acid addition salt"refers to those salts which retain the biological effectiveness and properties of the free bases, which are

not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

"Pharmaceutically acceptable base addition salt"refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2- dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like.

Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline caffeine, N-methyl-glucamine, dimethyl-glucamine, ethyl-glucamine, lysine, 1,6-hexadiamine, ethanol-amine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl-amino-methane, aminopropane diol, Sovak base, and 1-amino-2,3, 4-butanetriol.

As used herein, compounds which are"commercially available"may be obtained from standard commercial sources including Acros Organics

(Pittsburgh PA), Aldrich Chemical (Milwaukee Wl, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park UK), Avocado Research (Lancashire U. K. ), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U. K.), Chemservice Inc. (West Chester PA), Crescent Chemical Co. (Hauppauge NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester NY), Fisher Scientific Co. (Pittsburgh PA), Fisons Chemicals (Leicestershire UK), Frontier Scientific (Logan UT), ICN Biomedicals, Inc. (Costa Mesa CA), Key Organics (Cornwall U. K. ), Lancaster Synthesis (Windham NH), Maybridge Chemical Co.

Ltd. (Cornwall U. K.), Parish Chemical Co. (Orem UT), Pfaltz & Bauer, Inc.

(Waterbury CN), Polyorganix (Houston TX), Pierce Chemical Co. (Rockford IL), Riedel de Haen AG (Hannover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland OR), Trans World Chemicals, Inc.

(Rockville MD), and Wako Chemicals USA, Inc. (Richmond VA).

As used herein,"suitable conditions"for carrying out a synthetic step are explicitly provided herein or may be discerned by reference to publications directed to methods used in synthetic organic chemistry. The reference books and treatise set forth above that detail the synthesis of reactants useful in the preparation of compounds of the present invention, will also provide suitable conditions for carrying out a synthetic step according to the present invention.

As used herein, "methods known to one of ordinary skill in the art"may be identified though various reference books and databases. Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds of the present invention, or provide references to articles that describe the preparation, include for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S. R. Sandler et a/.,"Organic Functional Group Preparations,"2nd Ed. , Academic Press, New York, 1983; H. O. House, "Modern Synthetic Reactions", 2nd Ed. , W. A. Benjamin, Inc. Menlo Park, Calif.

1972; T. L. Gilchrist,"Heterocyclic Chemistry", 2nd Ed. , John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley-Interscience, New York, 1992.

Specific and analogous reactants may also be identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as

well as through on-line databases (the American Chemical Society, Washington, D. C. may be contacted for more details). Chemicals that are known but not commercially available in catalogs may be prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e. g., those listed above) provide custom synthesis services.

"Prodrugs"is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound of the invention. Thus, the term"prodrug"refers to a metabolic precursor of a compound of the invention that is pharmaceutical acceptable. A prodrug may be inactive when administered to a subject in need thereof, but is converted in vivo to an active compound of the invention. Prodrugs are typically rapidly transformed in vivo to yield the parent compound of the invention, for example, by hydrolysis in blood. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, Bundgard, H. , Design of Prodrugs (1985), pp. 7-9,21-24 (Elsevier, Amsterdam).

A discussion of prodrugs is provided in Higuchi, T., et a/.,"Pro-drugs as Novel Delivery Systems, "A. C. S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated in full by reference herein.

The term"prodrug"is also meant to include any covalently bonded carriers which release the active compound of the invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of the invention may be prepared by modifying functional groups present in the compound of the invention in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound of the invention. Prodrugs include compounds of the invention wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the compound of the invention is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate

derivatives of alcohol and amine functional groups in the compounds of the invention and the like.

"Therapeutically effective amount"refers to that amount of a compound of formula (I) which, when administered to a mammal, preferably a human, is sufficient to effect treatment, as defined below, for a disease-state alleviated by the inhibition of AKT-, PDK-, CHK-, CDK-or VEGF-R-acitivity, such as cancer.

The amount of a compound of formula (I) which constitutes a"therapeutically effective amount"will vary depending on the compound, the condition and its severity, and the age of the mammal to be treated, but can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure.

"Treating"or"treatment"as used herein covers the treatment of disease-states alleviated by the inhibition of AKT-, PDK-, CHK-, CDK-or VEGF-R-activity, such as cancer, as disclosed herein, in a mammal, preferably a human, and includes : (i) preventing the disease-state from occurring in a mammal, in particular, when such mammal is predisposed to the disease-state but has not yet been diagnosed as having it; (ii) inhibiting the disease-state, i. e.., arresting its development ; or (iii) relieving the disease-state, i. e.., causing regression of the condition.

The compounds of formula (I), or their pharmaceutical acceptable salts may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R) -or (S) -or, as (D) -or (L) -for amino acids. The present invention is meant to include all such possible isomers, as well as, their racemic and optically pure forms. Optically active (+) and (-), (R) -and (S) -, or (D) -and (L) -isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as reverse phase HPLC. When the formulae described herein contain olefinic double bonds or other centers of geometric asymmetry, unless specified otherwise, it is intended that the formulae include both E and Z geometric isomers, as well as all tautomeric

forms. In addition, all compound names herein, unless specified otherwise, are intended to include all single enantiomers, diastereomers, and mixtures thereof, as well as racemic and non-racemic mixtures.

Compounds which preferentially inhibit AKT and/or PDK kinases are the compounds of formula I in which A or B in each case independently of one another represent cyano, halogen, hydrogen, hydroxy, tetrazolyl or the group-NH2,-NR3R4, -C1-6-alkyl-NR3R4, -NH-C(NH)-CH3,-NH(CO)-R5, -NHCOOR6,- <BR> <BR> <BR> NR7-(Co)-NR8R9,-Cr 6-alkyl-COOH,-COOH,-CONH2,-CONH-<BR> <BR> <BR> <BR> <BR> C,-6-alkyl-COOH, or represent C, 6-alkyl optionally substituted in one or more places, the same way or differently with halogen, hydroxy or with the group-COOH,-CONR8R9,-NH-S02-CH3 or-NR8R9, X represents the group-NH-or-NR3R4, R1 represents cyano, hydrogen, halogen or C, 6-alkyl, whereby the C 6-alkyl can optionally be substituted in one or more places, in the same way or differently with halogen, R2 represents hydrogen or the group-NH-(CO)-aryl or -C1-6-alkyl optionally substituted in one or more places, the same way or differently with cyano, hydroxy, aryl, heteroaryl, C36- heterocycloalkylring which can be optionally be interrupted in one or more places with one or more nitrogen atoms, or substituted with the group-NR8R9,-NH-(CO)-NR8R9,-NH-(CO)-S-C 6-alkyl,- NH- (CS)-NR8R9,-NH (CO)-R5,-NH (CO)-ORS,- (CO)-NH-NH2,- (CO)-NH-CH2-(CO)-NH2, -(CO)-NH-C1-6-alkyl,-COOH whereby the aryl or the heteroaryl can optionally be substituted in one or more places, the same way or differently with hydroxy, C, 6-alkyl,-NH2,-

R3 or R4 in each case independently of one another represent hydrogen, C1-6-alkyl optionally substituted in one or more places, the same way or differently with hydroxy, phenyl or hydroxyphenyl, or R3 and R4 together form a C36-heterocycloalkylring containing at least one nitrogen atom and optionally can be interrupted by one or more oxygen and/or sulfur atoms and/or can be interrupted by one or more- (CO)- groups in the ring and/or optionally can contain one or more possible double bonds in the ring, whereby the C3-6-

heterocycloalkylring can optionally be substituted with C1-6-alkyl, C1-6-alkyl-COOH or C1-6-alkyl-NH2, R5 represents hydrogen, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, C3-6- cycloalkylring, heteroaryl, the group- (CO)-NH2 or C3-6- heterocycloalkylring that can optionally be interrupted with one or more nitrogen and/or oxygen and/or sulfur atoms and/or can be interrupted by one or more- (CO)- groups in the ring and/or optionally can contain one or more possible double bonds in the ring and C, 6-alkyl, C26-alkenyl, C36-heterocycloalkylring define above, aryl or heteroaryl can optionally be substituted in one or more places, the same way or differently with halogen, hydroxy, C1-6- alkyl, C, 6-alkoxy, C36-cycloalkyl, C36-heterocycloalkylring define above, aryl, heteroaryl or with the-NR8R9,-NO2,-NR7-(Co)-R5,- NH (CO)-C_6-alkyl-NH- (CO)-C, 6-alkyl,-NR'- (CO)-NR8R9,-CO-CH3, -COOH, -CO-NR8R9, -SO2-aryl, -SH, -S-C1-6-alkyl, -SO2-NR8R9, whereby aryl itself can optionally be substituted in one or more places, the same way or differently with halogen or hydroxy, C1-6- alkyl or C, 6-alkoxy, R7 represents hydrogen or C, 6-alkyl, R8or R9 in each case independently of one another represent hydrogen, C1-6-alkyl, aryl or heteroaryl or the group R10, whereby C1-6-alkyl, aryl or heteroaryl can optionally be substituted in one or more places, the same way or differently with halogen, heteroaryl, hydroxy, C1-6-alkoxy, hydroxy-C1-6-alkoxy or with the group- COOH,-NO2, or a C36-heterocycloalkylring can optionally be interrupted with one or more nitrogen and/or oxygen and/or sulfur atoms and/or can be interrupted by one or more- (CO)- groups in the ring and/or optionally can contain one or more possible double bonds in the ring or R8 and R9 together form a C36-heterocycloalkylring containing at least one nitrogen atom and optionally can be interrupted by one or more

oxygen and/or sulfur atoms and/or can be interrupted by one or more- (CO)- groups in the ring and/or optionally can contain one or more possible double bonds in the ring, whereby the C3-6- heterocycloalkylring can optionally be substituted in one or more places, the same way or differently with hydroxy, hydroxy-C, 6-alkyl or the group-NR8R9,-NH (Co)-R5 or-COOH and R10 represents-SO2-NH2,-SO2-C1-6-alkyl,-SO2-aryl, or -SO2- heteroaryl, whereby the aryl can be substituted with -C1-6-alkyl, as well as all related isotopes, diastereomers, enantiomers, solvates, polymorphs or pharmaceutically acceptable salts thereof.

Even more preferred are the compounds of formula 1, which inhibit preferentially AKT and/or PDK kinases in which A or B in each case independently of one another represent hydrogen, tetrazolyl or the group-N (CH3) 2,-NH- (CO)-pyrrolidinyl,-NH- (CO)- <BR> <BR> <BR> <BR> <BR> pentyl,-NH- (CO)-hexyl,-NH- (CO)-hexyl-NH2,-NH- (CO)-C3H7,-<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> NH- (CO)-CH2-phenyl,-NH- (CO)-CH2-NH2,-NH- (CO)-C2H4-NH2,-<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> NH- (CO)-CH (NH2)-CH3,-NH- (CO)-CH (NH2)-hydroxyphenyl,-NH-<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> (CO) -CH (NH2)-CH2-phenyl,-NH- (CO)-CH (NH2) -CH2-<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> hydroxyphenyl,-NH- (CO)-CH (NH- (CO)-CH3)-CH2-phenyl,-NH- (CO)-CH2-NH- (CO)-CH3,-NH- (CO)-N (C2H5) (C2H4-piperidinyl),-NH- (CO) -N (CH3) (C2H4-piperidinyl),-NH- (CO)-CH2-NH (CH3), -CH2- N (CH3) 2, -NH- (CO) NH-CH2-COOH, hydantoinyl,-CH2-COOH whereby the pyrrolidinyl can optionally be substituted with hydroxy or the group-NH2,-N (CH3) 2 or-NH- (CO)-CH3, and whereby hydantoinyl can be substituted with-CH3,-CH2- COOH, or- (CO)-thiazolidinonyl, X represents or the group-NH-, R'represents halogen and R2 represents hydrogen or the group-NH- (CO)-phenyl or-C2H4-, -C3H6-both can optionally be substituted in one or more

places, the same way or differently with cyano, hydroxy, phenyl, naphthyl, imidazolyl, thiazolyl, pyridyl, 2-oxazolinyl, piperidinyl,- NH2,-NH-CH2-thienyl,-NH-pyridinyl-NO2,-NH-thiazolyl,-S02- thienyl, -SO2-NH2, -SO2-CH3, -SO2-C3H7, pyrrolidinonyl substituted with-COOH,-NH- (CO)-NH-thienyl,-NH- (CO)-NH-phenyl,-NH- <BR> <BR> <BR> (CO)-NH-C2H5,-NH- (CO)-C (CH3) 3,-NH- (CO)-S-C2H5,-NH- (CS)-<BR> <BR> <BR> NH-C2H5,-NH- (CO)-C2H5,-NH- (CO)-thienyl,- (CO)-NH-NH2,- (CO)-NH-CH2- (CO)-NH2,- (CO)-NH-C2H5,-COOH whereby the phenyl or the imidazolyl, thiazolyl can optionally be substituted in one or more places, the same way or differently with hydroxy,- CH3,-NH- (CO)-CH2-NH2,-COOC2H5,-COOC (CH3) 3,

as well as all related isotopes, diastereomers, enantiomers, solvates, polymorphs or pharmaceutical acceptable salts thereof.

Even more preferred are compounds of general formula (I), which inhibit preferentially AKT and/or PDK kinases in which A or B in each case independently of one another represent hydrogen or the group-NH- (CO)-pyrrolidinyl,-NH- (CO)-piperidinyl,-NH- (CO)- morpholinyl,-NH- (CO)-hexyl-NH2,-NH- (CO)-CH (NH2)- hydroxyphenyl,-NH- (CO)-CH (NH2)-CH2-hydroxyphenyl, hydantoin optionally substituted with-CH3, X represents or the group-NH-, R'represents halogen and R2 represents hydrogen,-C2H4-imidazolyl or-C3H7 wich can optionally be substituted in one or more places, the same way or differently with the group-NH-CH2-thienyl,-NH- (CO)-C2H5,-NH- (CO)- C (CH3)3.

as well as all related isotopes, diastereomers, enantiomers, solvates, polymorphs or pharmaceutically acceptable salts thereof.

In particular the following compounds of general formula (I) are preferred to inhibit preferentially AKT and/or PDK kinases : N-[3-[[5-bromo-4-[[3-[[[1- (trifluoromethyl) cyclobutyl] carbonyl] amino] propyl] amino] -2- pyrimidinyl] amino] phenyl]-1-pyrrolidinecarboxamide, N-[3-[[5-bromo-4-[[3-[[1-oxo-3-(phenylsulfonyl)propyl]amino] propyl] amino] -2- pyrimidinyl] amino] phenyl]-1-pyrrolidinecarboxamide, N-[3-[[5-bromo-2-[[3-[(1-pyrrolidinylcarbonyl) amino] phenyl] amino]-4-

pyrimidinyl] amino] propyl]-2, 2-dimethyl-propanediamide, N-[3-[[4-[[3-[[(1-aminocyclopentyl)carbonyl]amino]propyl] amino] -5-bromo-2- pyrimidinyl] amino] phenyl]-1-pyrrolidinecarboxamide, N-[3-[[4-[[3-[[(1-aminocyclobutyl)carbonyl]amino]propyl]amin o]-5-iodo-2- pyrimidinyl] amino] phenyl]-1-pyrrolidinecarboxamide, N'-[3-[[5-bromo-2-[[3-[(1-pyrrolidinylcarbonyl) amino] phenyl] amino] -4- pyrimidinyl] amino] propyl]-1, 1-cyclopentanedicarboxamide, (4R)-N-[3-[[5-bromo-2-[[3-(2,5-dioxo-1-imidazolidinyl)phenyl ] amino] -4- pyrimidinyl] amino] propyl]-2-oxo-4-thiazolidinecarboxamide, (4R)-N-[3-[[5-bromo-2-[[3-(3-methyl-2,5-dioxo-1-imidazolidin yl)phenyl]amino]-4- pyrimidinyl] amino] propyl]-2-oxo-4-thiazolidinecarboxamide, 3-[3-[[5-bromo-4-[[2-(1H-imidazol-4-yl)ethyl]amino]-2-pyrimi dinyl] amino] phenyl]- 2, 4-imidazolidinedione, 3- [3- [ [5-bromo-4- [ [2- (1 H-imidazol-4-yl) ethyl] amino]-2-pyrimidinyl] amino] phenyl]- 1-methyl-2, 4-imidazolidinedione, N'-[3-[[5-bromo-4-[[2-(1H-imidazol-4-yl)ethyl]amino]-2-pyrim idinyl] amino] phenyl]- N-ethyl-N- [2- (1-piperidinyl) ethyl]-urea, N-[3-[[5-bromo-4-[[3-[(2,2-dimethyl-1-oxopropyl) amino] propyl] amino] -2- pyrimidinyl] amino] phenyl]-1-pyrrolidinecarboxamide, N-[3-[[2-[[3-[[(2S)-2-amino-3-(4-hydroxyphenyl)-1- oxopropyl] amino] phenyl] amino]-5-bromo-4-pyrimidinyl] amino] propyls-2, 2- dimethyl-propanediamide, N-[3-[[2-[[3-[[(1-aminocyclohexyl)carbonyl]amino]phenyl] amino] -5-bromo-4- pyrimidinyl] amino] propyl]-2, 2-dimethyl-propanediamide, N-[3-[[2-[[3-[[(2S)-2-amino-2-henylacetyl] amino] phenyl] amino] -5-bromo-4- pyrimidinyl] amino] propyl]-2, 2-dimethyl-propanediamide, N-[3-[[2-[[3-[[(2R)-2-amino-1-oxo-3-phenylpropyl]amino]pheny l] amino] -5-bromo- 4-pyrimid inyl] amino] propyl]-5-oxo-2-pyrrolidinecarboxamide, N-[3-[[2-[[3-[[(2R)-2-amino-1-oxo-3-phenylpropyl] amino] phenyl] amino] -5-bromo- 4-pyrimidinyl] amino] propyls-2, 2-dimethyl-propanediamide, N1-[3-[[5-bromo-2-[[3-[[(2S)-2-pyrrolidinylcarbonyl] amino] phenyl] amino] -4- pyrimidinyl] amino] propyl]- 1, 1-cyclopropanedicarboxamide, N-[3-[[5-bromo-2-[[3-(2,5-dioxo-1-imidazolidinyl)phenyl] amino] -4-

pyrimidinyl] amino] propyls-2, 2-dimethyl-propanediamide, N- (3- ( (5-bromo-4- ( (2- (1H-imidazol-4-yl) ethyl) amino) -2- pyrimidinyl) amino) phenyl)-4-morpholinecarboxamide, N- (3- ( (5-bromo-4- ( (2- (1H-imidazol-4-yl) ethyl) amino) -2- pyrimidinyl) amino) phenyl)-1-pyrrolidinecarboxamide, N-(3-((5-bromo-4-((3-((2-thienylcarbonyl) amino) propyl) amino) -2- pyrimidinyl) amino) phenyl)-1-pyrrolidinecarboxamide, N1-(3-((5-bromo-2-((3-((1-pyrrolidinylcarbonyl) amino) phenyl) amino) -4- pyrimidinyl) amino) propyl)-1, 1-cyclopropanedicarboxamide, N-(3-((5-bromo-4-((3-((1-oxopropyl) amino) propyl) amino) -2- pyrimidinyl) amino) phenyl)-1-pyrrolidinecarboxamide, N- (3- ( (5-iodo-4- ( (3- ( (2-thienylcarbonyl) amino) propyl) amino)-2-pyrimidinyl)- amino) phenyl)-1-pyrrolidinecarboxamide, N-[3-[[5-bromo-4-[[3-[[[(2S)-5-oxo-2-pyrrolidinyl]carbonyl] amino] propyl] amino]-2- pyrimidinyl] amino] phenyl]-1-pyrrolidinecarboxamide, N-[3-[[5-bromo-4-[[3-[[[(2S)-4-oxo-2-azetidinyl]carbonyl]ami no]propyl] amino] -2- pyrimidinyl] amino] phenyl]-1-pyrrolidinecarboxamide, (4R)-N-[3-[[5-bromo-2-[[3-[(1-pyrrolidinylcarbonyl) amino] phenyl] amino-4- pyrimidinyl] amino] propyl]-2-oxo-4-thiazolidinecarboxamide or N-[3-[[4-[[3-[[(1-aminocyclobutyl)carbonyl]amino]propyl] amino] -5-bromo-2- pyrimidinyl]amino]phenyl]-1-pyrrolidinecarboxamide.

Preffered are also compounds of general formula (I), which inhibit preferentially Chk kinases in which A or B in each case independently of one another represent hydrogen or the group-NO2,-NH2,-NR3R4,-N (C, 6-hydroxyalkyl) 2,-NH (CO) - R5, -NHCOOR6,-NR7-(CO)-NR8R9,-NR7-(CS)-NR8R9,-COOR5,- CO-NR8R9,-SO2-CH3, 4-bromo-1-methyl-1H-pyrazolo-3yl or C1-6-alkyl optionally substituted in one or more places, the same way or differently with cyano, halogen, hydroxy or the group-NH2, - NH- (CO)-R5,-S02-NHR3,-COORS,-CONR$R9,-0- (CO)-R5,-O- (CO)-C1-6-alkyl-R5,

X represents an oxygen atom or the group-NH-, R represents hydrogen, halogen, hydroxymethyl or the group- COOH,-COO-iso-propyl,-N02,-NH- (CO)- (CH2) 2-COOH or-NH- (CO)-(CH2) 2-COO-C1 6-alkyl, R2 represents C16-alkyl optionally substituted in one or more places, the same way or differently with hydroxy, imidazolyl or the group- <BR> <BR> <BR> <BR> NH2,-NH- (CO) O-CH2-phenyl,-NH- (CO) H,-NH- (CO)-phenyl,-NH-<BR> <BR> <BR> <BR> <BR> <BR> <BR> (CO)-CH2-0-phenyl,-NH- (CO)-CH2-phenyl,-NH- (CO)- CH (NH2)CH2-phenyl, -NH-(CO)-CH2-CH(CH3)-phenyl, -NH-(CO)- CH (NH2)- (CH2) 2-COOH, , whereby the phenyl can optionally be substituted in one or more places, the same or differently with halogen, C1-6-alkyl or- (CO)- C (CH2)-C2H5, or represents C3-alkinyl, R3 or R4 in each case independently of one another represent hydrogen or C16-alkyl optionally substituted in one or more places, the same way or differently with hydroxy, phenyl or hydroxyphenyl, or R3 and R4 together form a C36-heterocycloalkylring containing at least one nitrogen atom and optionally can be interrupted by one or more oxygen and/or sulfur atoms and/or can be interrupoted by one or more- (CO)- groups in the ring and/or optionally can contain one

or more possible double bonds in the ring, whereby the C3-6- heterocycloalkylring can optionally be substituted with C16-alkyl, C16-alkyl-COOH or C16-alkyl-NH2, R5 represents C1-6-alkyl, C2-6-alkenyl, C3-6-cycloalkyl or phenyl each can optionally be substituted in one or more places, the same way or differently with halogen, hydroxy, phenyl or with the group-NH2, -NH (CO)-O-C16-alkyl, whereby phenyl itself can optionally be substituted in one or more places, the same way or differently with halogen, hydroxy or C16-alkyl, R6 represents C16-alkyl, C2-6-alkenyl or phenyl, R7 represents hydrogen or C »-alkyl and Razor R9 in each case independently of one another represent hydrogen, C16-alkyl, C26-alkenyl, C36-cycloalkyl, aryl or phenyl, whereby aryl or phenyl can optionally be substituted in one or more places, the same way or differently with hydroxy or the group-N02 or-N (CI-6- alkyl) 2 or R and R9 together form a C36-heterocycloalkylring containing at least one nitrogen atom and optionally can be interrupted by one or more oxygen and/or sulfur atoms and/or can be interrupted by one or more- (CO)- groups in the ring and/or optionally can contain one or more possible double bonds in the ring, whereby the C3-6- heterocycloalkylring can optionally be substituted with the group- NH2, as well as all related isotopes, diastereomers, enantiomers, solvates, polymorphs or pharmaceutical acceptable salts thereof.

Even more preferred are those compounds of general formula (I), which inhibit preferentially Chk kinases in which A or B in each case independently of one another represent hydrogen or the group-NH-C2H4-OH,-NH-CH2-hydroxyphenyl,-NH- (CO)- pyrrolidinyl,-NH- (CO)-CH (NH2)-CH2-phenyl,-NH- (CO)-pentyl-NH2,

- NH- (CO)-hexyl-NH2,-NH- (CO)-CH2-NH2,-NH- (CO)-CH (NH2)- hydroxyphenyl,-NH- (CO)-CH2-hydroxyphenyl,-NH- (CO)-CH2- methylphenyl,-NH- (CO)-C2H4-dihydroxyphenyl,-NH- (CO)- CH (OH)-phenyl,-NH- (CO)-CH (NH2)-CH2 (OH),-NH- (CO)- C (CH3) 2NH2,-NH- (CO)-NH (C2H5),-CH20H,- (CO)-NH-cyclopropyl, - (CO)-NH-CH (CH3) 2, whereby the pyrrolidinyl can optionally be substituted with hydroxy or the group-NH2, X represents an oxygen atom or the group-NH-, R'represents halogen or hydroxymethyl and R2 represents-C2H5 optionally substituted in one or more places, the same way or differently with hydroxy, imidazolyl or represents-C3H7 or-C4H8 optionally substituted in one or more places, the same way or differently with the group-NH2,-NH- (CO) -CH (NH2)-C2H4-COOH,-NH- (CO)-phenyl,-NH- (CO)-CH2- phenyl, -NH-(CO)-CH2-CH(CH3)-phenyl, -NH-(CO)-CH2-O-phenyl, -NH-(CO)O-CH2-phenyl, -NH-(CO)-CH(NH2)CH2-phenyl, whereby the phenyl can optionally be substituted in one or more places, the same or differently with halogen,-CH3 or- (CO)- C (CH2) (C2H5), or represents C3-alkinyl,

as well as all related isotopes, diastereomers, enantiomers, solvates, polymorphs or pharmaceutical acceptable salts thereof.

In particular the following compounds for general formula (I) are preferred, which inhibit preferentially AKT and/or PDK kinases: N-[3-[[2-[[3-[[(2R)-2-amino-1-oxo-3-phenylpropyl]amino]pheny l]amino]-5-bromo- 4-pyrimidinyl] amino] propyl]-2, 2-dimethyl-propanediamide, 1-[3-[[2-[[3-[[(2R)-2-amino-1-oxo-3-phenylpropyl] amino] phenyl] amino]-5-bromo- 4-pyrimidinyl] amino]propyl]-2-oxo-3-pyrrolidinecarboxylic acid, N-[3-[[5-bromo-4-[[3-[[(5-oxo-2-pyrrolidinyl)carbonyl]amino] propyl]amino]-2- pyrimidinyl] amino] phenyl]-1-pyrrolidinecarboxamide, Pyrrolidine-1-carboxylic acid [3- (5-bromo-4- {3- [2- (2, 4-dichloro-phenyl)- acetylamino]-propylamino}-pyrimidin-2-ylamino)-phenyl]-amide , Pyrrolidine-1-carboxylic acid [3- (5-bromo-4- {3- [2- (4-bromo-phenyl)-acetylamino]- propylamino}-pyrimidin-2-ylamino)-phenyl]-amide, Pyrrolidine-1-carboxylic acid (3- {5-bromo-4- [3- (2-p-tolyl-acetylamino)- propylamino]-pyrimidin-2-ylamino}-phenyl)-amide, Pyrrolidine-1-carboxylic acid [3- (5-bromo-4- {3- [2- (2, 4-difluoro-phenyl)- acetylamino]-propylamino}-pyrimidin-2-ylamino)-phenyl]-amide , Pyrrolidine-1-carboxylic acid {3- [5-bromo-4- (3- {2- [2, 3-dichloro-4- (2-methylene- butyryl)-phenoxy]-acetylamino}-propylamino)-pyrimidin-2-ylam ino]-phenyl}- amide, Pyrrolidine-1-carboxylic acid [3-(5-bromo-4-{3-[3-(2,3-dichloro-phenyl)- butyrylamino]-propylamino}-pyrimidin-2-ylamino)-phenyl]-amid e, Pyrrolidine-1-carboxylic acid (3-{5-bromo-4-[3-(3-bromo-benzoylamino)- propylamino]-pyrimidin-2-ylamino)-phenyl)-amide, N-(3-((4-((4-aminobutyl)amino)-5-bromo-2-pyrimidinyl) amino) phenyl)-1- pyrrolidinecarboxamide, N-[3-[[2-[[3-[[(2R)-2-amino-1-oxo-3-phenylpropyl]amino]pheny l]amino]-5-bromo- 4-pyrimidinyl] amino] propyl]-2, 2-dimethyl-propanediamide, N-[3-[[(2S)-2-Amino-1-oxo-3-phenylpropyl]amino]-5-[[5-bromo- 4-(prop-2- ynyloxy) pyrimidin-2-yl] amino] phenyl] pyrrolidine-1-carboxamide, N-[3-[[(2R)-2-Amino-1-oxo-3-phenylpropyl]amino]-5-[[5-bromo- 4-(prop-2-

ynyloxy) pyrimidin-2-yl] amino] phenyl] pyrrolidine-1-carboxamide, (αR)-α-Amino-N-[3-[[5-bromo-4-(prop-2-ynyloxy)pyrimidin-2- yl]amino]-5- (hydroxymethyl) phenyl] benzenepropanamide, 2- [3- (5-Bromo-4-prop-2-ynyloxy-pyrimidine-2-ylamino)-5-hydroxymet hyl- phenylamino]-ethanol, (2R)-Amino-N- [3-hydroxymethyl-5- (4-prop-2-ynyloxy-pyrimidine-2-ylamino)- phenyl]-3-phenyl-propionamide, 3-((2R)-Amino-3-phenyl-propionylamino)-5-(5-bromo-4-prop-2-y nyloxy- pyrimidine-2-ylamino)-N-cyclopropyl-benzamide, <BR> <BR> <BR> 3- ( (2R)-Amino-3-phenyi-propionylamino)-5- (5-bromo-4-prop-2-ynyloxy-pyrimidin- 2-ylamino)-N-isopropyl-benzamide, Phenylmethyl [3-[[2-[[3-[[(ethylamino)carbonyl]amino]phenyl]amino]-5- (hydroxymethyl) pyrimidine-4-yl] amino] propyl] carbamate, Pyrrolidine-1-carboxylic acid (3-{4-[3-((2R)-amino-3-phenyl-propionylamino)- propylamino]-5-bromo-pyrimidine-2-ylamino}-phenyl)-amide, Pyrrolidine-1-carboxylic acid (3- {4- [3- ( (2S)-amino-3-phenyt-propionytamino)- propylamino]-5-bromo-pyrimidine-2-ylamino}-phenyl)-amide, <BR> <BR> <BR> 2- [3- (5-Bromo-4-prop-2-ynyloxy-pyrimidine-2-ylamino)-phenylamino] -ethanol,<BR> <BR> <BR> 1-Amino-cyclopentancarbonylic acid [3- (5-bromo-4-prop-2-ynyloxy-pyrimidine-2-<BR> <BR> <BR> ylamino)-phenyl]-amide,<BR> <BR> <BR> 1-Amino-cyclohexancarbonylic acid- [3- (5-bromo-4-prop-2-ynyloxy-pyrimidine-2- ylamino)-phenyl]-amide, <BR> <BR> <BR> (2S)-Amino-N- [3- (5-bromo-4-prop-2-ynyloxy-pyrimidine-2-ylamino)-phenyl]-3-&l t;BR> <BR> <BR> phenyl-propionamide,<BR> <BR> <BR> (2R)-Amino-N- [3- (5-bromo-4-prop-2-ynyloxy-pyrimidine-2-ylamino)-phenyl]-3-&l t;BR> <BR> <BR> phenyl-propionamide,<BR> <BR> <BR> 2- { [3- (5-Bromo-4-prop-2-ynyloxy-pyrimidine-2-ylamino)-phenylamino] -methyl)- phenol, <BR> <BR> <BR> (2R)-Amino-N- [3- (5-bromo-4-prop-2-ynyloxy-pyrimidine-2-ylamino)-phenyl]-3- (4- hydroxy-phenyl)-propionamide, <BR> <BR> <BR> N- [3- (5-Bromo-4-prop-2-ynyloxy-pyrimidine-2-ylamino)-phenyl]-3- (3, 4-dihydroxy- phenyl)-propionamide, <BR> <BR> N- [3- (5-Bromo-4-prop-2-ynyloxy-pyrimidine-2-ylamino)-phenyl]-2-hy droxy- (2S)-

phenyl-acetamide, <BR> <BR> <BR> N- [3- (5-Bromo-4-prop-2-ynyloxy-pyrimidine-2-ylamino)-phenyl]-2-hy droxy- (2R)- phenyl-acetamide, (2S)-Amino-N- [3- (5-bromo-4-prop-2-ynyloxy-pyrimidine-2-ylamino)-phenyl]-3- hydroxy-propionamide, (2R)-Amino-N- [3- (5-bromo-4-prop-2-ynyloxy-pyrimidin-2-ylamino)-phenyl]-3- hydroxy-propionamide, <BR> <BR> <BR> 2-Amino-N- [3- (5-bromo-4-prop-2-ynyloxy-pyrimidine-2-ylamino)-phenyl]-2-&l t;BR> <BR> <BR> methyl-propionamide,<BR> <BR> <BR> (2S)-Amino-N- [3- (5-bromo-4-prop-2-ynyloxy-pyrimidine-2-ylamino)-phenyl]-3- (4-<BR> <BR> <BR> hydroxy-phenyl)-propionamide, (2S)-Amino-N- [3- (5-bromo-4-prop-2-ynyloxy-pyrimidine-2-ylamino)-phenyl]-3-p- tolyl-propionamide or <BR> <BR> <BR> (2R)-Amino-N- [3- (5-bromo-4-prop-2-ynyloxy-pyrimidine-2-ylamino)-phenyl]-3-p- tolyl-propionamide.

Preferred are also the compounds of general formula (I), which inhibit preferentially AKT and VEGF-R kinases in which A or B in each case independently of one another represent halogen, hydrogen or the group-S02-CH3,-N02,-NH2,-CF3,-CH2-NH- <BR> <BR> <BR> (CO)-NH2,-CH2-pyrrolidinyl,-NH- (CO)-CH3,-NH- (CO)-hexyl-NH2,-<BR> <BR> <BR> NH- (CO)-phenyl,-NH- (CO)-pyrrolidinyl,--NH- (CO)-CH (NH2)-CH2- phenyl, NH- (CO)-OCH3,-NH- (CO)-OCH (CH3) 2,-NH- (CO)-OC2H4- morpholino,-NH- (CO)-NH-cyclopropyl,-NH- (CO)-morpholino,-NH- <BR> <BR> <BR> (CO)-NH-C2H4-morpholino,-NH- (CO)-NH-hydroxycycloalkyl,<BR> <BR> <BR> hydantoinyl, whereby the pyrrolidinyl can optionally be substituted with hydroxy or the group-NH2 and whereby the hydantoinyl can optionally be substituted with the group-CH3 or- (CO)-thiazolidinonyl, X represents the group-NH-, R'represents halogen and R2 represents-CH2-dihydroxyphenyl,-C2H4-imidazolyl, or-C3H7 optionally substituted in one or more places, the same way or differently with

as well as all related isotopes, diastereomers, enantiomers, solvates, polymorphs or pharmaceutical acceptable salts thereof.

In particular the following compounds of general formula (I) are preferred, which inhibit preferrentially AKT and VEGF-R kinases: 4-((4-((2-(1H-imidazol-4-yl)ethyl)amino)-5-iodo-2-pyrimidiny l) amino) - benzenesulfonamide, N-((3-((5-bromo-4-((2-(1H-imidazol-4-yl)ethyl) amino) -2- pyrimidinyl) amino) phenyl) methyl)-urea, 1-((3-((5-bromo-4-((2-(1 H-imidazol-4-yl) ethyl) amino) -2- pyrimidinyl) amino) phenyl) methyl)-3-pyrrolidinol, (3-((5-bromo-4-(2-(1H-imidazol-4-yl)ethyl)amino)-2-pyrimidin yl) amino) phenyl)- carbamic acid methyl ester, N2- (3-aminophenyl)-5-bromo-N4- (2- (1 H-imidazol-4-yl) ethyl)-2, 4- pyrimidinediamine, N-(3-((5-bromo-4-((2-(1H-imidazol-4-yl)ethyl) amino) -2- pyrimidinyl) amino) phenyl)-N'-cyclopropyl-urea, N-(3-((5-bromo-4-((2-(1H-imidazol-4-yl)ethyl) amino) -2- pyrimidinyl) amino) phenyl)-4-morpholinecarboxamide, (3-((5-bromo-4-((2-(1H-imidazol-4-yl)ethyl)amino)-2-pyrimidi nyl amino) phenyl)- carbamic acid 1-methylethyl ester, N-(3-((5-bromo-4-((2-(1 H-imidazol-4-yl) ethyl) amino) -2- pyrimidinyl) amino) phenyl)-methanesulfonamide,

N2- (3-amino-5- (trifluoromethyl) phenyl)-5-bromo-N4- (2- (1 H-imidazol-4-yl) ethyl)- 2,4-pyrimidinediamine, N-(3-((5-bromo-4-((2-(1H-imidazol-4-yl)ethyl) amino) -2- pyrimidinyl) amino) phenyl)-N'- (2- (4-morpholinyl) ethyl)-urea, N2- (3-amino-5-chlorophenyl)-5-bromo-N4-(2-(1H-imidazol-4-yl)eth yl)-2, 4- pyrimidinediamine, (3-((5-bromo-4-((2-(1 H-imidazol-4-yl) ethyl) amino)-2-pyrimidinyl) amino) phenyl)- carbamic acid 2- (4-morpholinyl) ethyl ester, N-(3-((5-bromo-4-((2-(1H-imidazol-4-yl)ethyl) amino) -2- pyrimidinyl) amino) phenyl)-N'- (4-hydroxycyclohexyl)-urea, N-(3-((5-bromo-4-((2-(1H-imidazol-4-yl)ethyl) amino) -2- pyrimidinyl) amino) phenyl)-acetamide, N-(3-((5-bromo-4-((2-(1H-imidazol-4-yl)ethyl) amino) -2- pyrimidinyl) amino) phenyl)-benzamide, (4R)-N-[3-[[5-bromo-2-[[3-[(1-pyrrolidinylcarbonyl) amino] phenyl] amino] -4- pyrimidins amino] propyl]-2-oxo-4-thiazolidinecarboxamide, 3-l3-[[5-bromo-4-[[2-(1 H-imidazol-4-yl) ethyl] amino]-2-pyrimidinyl] amino] phenyl]- 2, 4-imidazolidinedione, 3-[3-[[5-bromo-4-[[2-(1H-imidazol-4-yl)ethyl]amino]-2-pyrimi dinyl]amino]phenyl]- 1-methyl-2, 4-imidazolidinedione, 1-[3-[[2-[[3-[[(2R)-2-amino-1-oxo-3-phenylpropyl] amino] phenyl] amino]-5-bromo- 4-pyrimidinyl] amino] propyl]-2-oxo-3-pyrrolidinecarboxylic acid, 1-[3-[[2-[[3-[[(1-aminocyclohexyl)carbonyl] amino] phenyl] amino] -5-bromo-4- pyrimidinyl] amino] propyl]-2-oxo-3-pyrrolidinecarboxylic acid, N-[3-[[2-[[3-[[(2R)-2-amino-1-oxo-3-phenylpropyl] amino] phenyl] amino]-5-bromo- 4-pyrimidinyl] amino] propyl]-5-oxo-2-pyrrolidinecarboxamide, N-[3-[[2-[[3-[[(2R)-2-amino-1-oxo-3-phenylpropyl]amino]pheny l]amino]-5-chloro- 4-pyrimidinyl] amino] propyl]-2, 2-dimethyl-propanediamide, 3-[3-[[5-bromo-4-[[(3,4-dihydroxyphenyl)methyl]amino]-2- pyrimidinyl] amino] phenyl]-2, 4-imidazolidinedione, 3-[3-[[5-bromo-4-[[(3,4-dihydroxyphenyl)methyl] amino] -2- pyrimidinyl] amino] phenyl]-1--methyl-2,4-imidazolidinedione, (4R)-N-[3-[[5-bromo-2-[[3-(2,5-dioxo-1-imidazolidinyl)phenyl ] amino] -4-

pyrimidinyl] amino] propyl]-2-oxo-4-thiazolidinecarboxamide, N-[3-[[5-bromo-2-[[3-(2,5-dioxo-1-imidazolidinyl)phenyl]amin o]-4- pyrimidinyl] amino] propyl]-5-oxo-2-pyrrolidinecarboxamide, N-[3-[[5-bromo-2-[[3-(2,5-dioxo-1-imidazolidinyl)phenyl]amin o]-4- pyrimidinyl] amino] propyl]-2, 2-dimethyl-propanediamide, 3-[3-[[5-bromo-4-[[3-(2-oxo-1-pyrrolidinyl)propyl] amino] -2- pyrimidinyl] amino] phenyl]-2, 4-imidazolidinedione, (4R)-N- [3-[[5-bromo-2-[[3-(3-methyl-2,5-dioxo-1-imidazolidinyl)phen yl]amino]-4- pyrimidinyl] amino] propyl]-2-oxo-4-thiazolidinecarboxamide or (4R)-N-[3-[[5-bromo-2-[[3-[2,5-dioxo-3-[[(4R)-2-oxo-4-thiazo lidinyl]carbonyl]-1- imidazolidinyl] phenyl] amino]-4-pyrimidinyl] amino] propyl]-2-oxo-4- thiazolidinecarboxamide.

It has also been found that compounds of the following structure are inhibitors of kinases, particularly AKT, PDK, Chk, CDK and/or VEGF-R kinases: N- (3- ( (4- ( (3- (aminomethyl) phenyl) amino)-5-bromo-2-pyrimidinyl) amino) phenyl)- 1-pyrrolidine-carboxamide, 4-[[5-bromo-4-[[2-(1H-imidazol-5-yl)ethyl]amino]-2-pyrimidin yl]amino]-1- naphthaleneacetic acid, 5-[[5-bromo-4-[[2-(1H-imidazol-5-yl)ethyl]amino]-2-pyrimidin yl]amino]-1H-indole- 2-carboxylic acid, ethyl ester, 5-bromo-N4- [2- (1 H-imidazol-5-yl) ethyl]-N2- (2-methyl-6-quinolinyl)-2, 4- pyrimidinediamine, 4-((5-bromo-4-((2-(1H-imidazol-4-yl)ethyl)amino)-2-pyrimidin yl) amino) - benzamide, 4- ( (4- ( (2- (IH-imidazol-4-yl) ethyl) amino)-5-iodo-2-pyrimidinyl) amino) - benzenesulfonamide, 3-((5-bromo-4-((2-(1H-imidazol-4-yl)ethyl)amino)-2-pyrimidin yl) amino) - benzamide, 3- ( (5-bromo-4- ( (2- (lH-imidazol-4-yl) ethyl) amino)-2-pyrimidinyl) amino) - benzenesulfonamide, 5-((5-bromo-4-((2-(1 H-imidazol4-yl) ethyl) amino)-2-pyrimidinyl) amino) -1,3- dihydro-2H-benzimidazol-2-one,

3- ( (5-bromo-4- ( (2- (1H-imidazol-4-yl) ethyl) amino)-2-pyrimidinyl) amino)- benzoic acid methyl ester, 3-amino-5-((5-bromo-4-((2-(1H-imidazol-4-yl) ethyl) amino)-2-pyrimidinyl) amino) - benzoic acid methyl ester, N-((3-((5-bromo-4-((2-(1H-imidazol-4-yl)ethyl) amino) -2- pyrimidinyl) amino) phenyl) methyl)-methanesulfonamide, 4-((5-bromo-4-((2-(1H-imidazol-4-yl)ethyl)amino)-2-pyrimidin yl)amino)-benzoic acid methyl ester, 3-((5-bromo-4-((2-(1H-imidazol-4-yl)ethyl)amino)-2-pyrimidin yl)amino)-phenol, 5-((5-bromo-4-((2-(1H-imidazol-4-yl)ethyl)amino)-2-pyrimidin yl)amino)-1H- isoindole-1, 3 (2H)-dione, 5-bromo-N4-(2-(1 H-imidazol-4-yl) ethyl)-N2-(3-methylphenyl)-2, 4- pyrimidinediamine, N-(3-((5-bromo-4-((2-(1H-imidazol-4-yl)ethyl) amino) -2- pyrimidinyl) amino) phenyl)-methanesulfonamide, 4-((4-((2-(1H-imidazol-4-yl)ethyl)amino)-5-methyl-2-pyrimidi nyl) amino) - benzenesulfonamide, 4-((4-((2-(1H-imidazol-4-yl)ethyl)amino)-5-(trifluoromethyl) -2-pyrimidinyl)amino)- benzenesulfonamide, 4- ( (4- ( (3-aminopropyl) amino)-5-bromo-2-pyrimidinyl) amino) - benzenesulfonamide, 4-((5-bromo-4-((3-(1H-imidazol-1-yl)propyl)amino)-2-pyrimidi nyl) amino) - benzenesulfonamide, 4-((5-bromo-4-((2-(1-pyrrolidinyl) ethyl) amino)-2-pyrimid inyl) amino) - benzenesulfonamide, 4-((4-((4-aminobutyl)amino)-5-bromo-2-pyrimidinyl)amino)-ben zenesulfonamide, 4-((2-((4-(aminosulfonyl)phenyl)amino)-5-bromo-4-pyrimidinyl ) amino) -butanoic acid, 4-((4-((3-((aminocarbonyl)amino)propyl)amino)-5-bromo-2-pyri midinyl) amino) - benzenesulfonamide, 4- ( (2- ( (4- (aminosulfonyl) phenyl) amino)-5-bromo-4-pyrimidinyl) amino) -butanoic acid ethyl ester, 4-((5-bromo-4-((4-(methylamino)butyl)amino)-2-pyrimidinyl) amino) -

benzenesulfonamide, 4-((5-bromo-4-((2-(1H-imidazol-1-yl) ethyl) amino)-2-pyrimidinyl) amino) - benzenesulfonamide, 4-((5-ethyl-4-((2-(1H-imidazol-4-yl)ethyl)amino)-2-pyrimidin yl) amino) - benzenesulfonamide, 4-((4-((2-(1H-imidazol-4-yl)ethyl)amino)-2-pyrimidinyl) amino) - <BR> <BR> <BR> benzenesulfonamide,<BR> <BR> <BR> 4- ( (5-bromo-4- ( (2- (2-pyridinyl) ethyl) amino)-2-pyrimidinyl) amino)-<BR> <BR> <BR> benzenesulfonamide, 4-((5-bromo-4-((2-(1H-indol-3-yl)ethyl)amino)-2-pyrimidinyl) amino) - benzenesulfonamide, 2-((2-((4-(aminosulfonyl)phenyl)amino)-5-bromo-4-pyrimidinyl )amino- acetamide, N-(2-((2-((4-(aminosulfonyl) phenyl) amino)-5-bromo-4-pyrimid inyl) amino) ethyl)- acetamide, 3- ( (2- ( (4- (aminosulfonyl) phenyl) amino)-5-bromo-4-pyrimidinyl) amino) - propanamide, N- (4- ( (2- ( (4- (aminosulfonyl) phenyl) amino)-5-bromo-4-pyrimidinyl) amino) butyl)- acetamide, N-(3-((2-((4-(aminosulfonyl)phenyl)amino)-5-bromo-4-pyrimidi nyl) amino) propyl)- acetamide, <BR> <BR> <BR> N- (3- ( (2- ( (4- (aminosulfonyl) phenyl) amino)-5-bromo-4-pyrimidinyl) amino) propyl)- 2-furancarboxamide, <BR> <BR> <BR> N- (3- ( (2- ( (4- (aminosulfonyl) phenyl) amino)-5-bromo-4-pyrimidinyl) amino) propyl)-<BR> <BR> <BR> 1H-pyrrole-2-carboxamide, 4- ( (2- ( (4- (aminosulfonyl) phenyl) amino)-5-bromo-4-pyrimidinyl) amino) - butanamide, N- (3- ( (2- ( (4- (aminosulfonyl) phenyl) amino)-5-bromo-4-pyrimidinyl) amino) propyl)- 2-thiophenecarboxamide, 4-((4-(4-(aminomethyl)-1-piperidinyl)-5-bromo-2-pyrimidinyl) amino) - benzenesulfonamide, 4- (5-Brom-4-prop-2-ynylamino-pyrimidin-2-ylamino)-phenyl]-N, N- dimethylaminosulfonylamin,

1-Methyl-1 H-imidazol-4-sulfonsaure [4- (5-brom-4-prop-2-ynylamino-pyrimidin-2-<BR> ylamino)-phenyl]-amid, 3- (5-Bromo-4-prop-2-ynyloxy-pyrimidine-2-ylamino)-benzoic acid ethyl ester, 4- (5-Bromo-4-prop-2-ynyloxy-pyrimidine-2-ylamino)-benzoic acid ethyl ester, 2- (5-Bromo-4-prop-2-ynyloxy-pyrimidine-2-ylamino)-benzoic acid ethyl ester, 2- (5-Bromo-4-prop-2-ynyloxy-pyrimidine-2-ylamino)-phenol, 4- (5-Bromo-4-prop-2-ynyloxy-pyrimidine-2-ylamino)-benzoic acid methyl ester, 3- (5-Nitro-4-prop-2-ynylamino-pyrimidine-2-ylamino)-phenol, 2- (5-Nitro-4-prop-2-ynylamino-pyrimidine-2-ylamino)-benzoic acid ethyl ester, 3- (5-Nitro-4-prop-2-ynylamino-pyrimidine-2-ylamino)-benzoic acid ethyl ester, 4- (5-Nitro-4-prop-2-ynylamino-pyrimidine-2-ylamino)-benzoic acid ethyl ester, 4- (5-Nitro-4-prop-2-ynylamino-pyrimidine-2-ylamino)-phenol, Methyl 3-[[5-bromo-4-(prop-2-ynyloxy)pyrimidin-2-yl]amino]-5-[(2- hydroxyethyl) amino] benzoate, Methyl 3-amino-5-[[5-bromo-4-(prop-2-ynyloxy)pyrimidin-2-yl] amino] benzoate or 3- [Bis- (2-hydroxy-ethyl)-amino]-5- (5-bromo-4-prop-2-ynyloxy-pyrimidine-2- ylamino)-benzoic acid methyl ester.

Another object of the invention are pharmaceutical composition comprising as an active ingredient at least one compound of general formula (I) or compounds disclosed hereinbefore in an therapeutically effective amount for the prevention or treatment of a disorder caused by, associated with or accompanied by disruptions of cell proliferation and/or angiogenesis together with an pharmaceutically acceptable carrier, diluent or excipient.

A further object of the invention are use of a compound of general formula (I) or compounds disclosed hereinbefore for the manufacture of a medicament for the prevention or treatment of a disorder caused by, associated with or accompanied by any abnormal kinase activity selected from Chk, Akt, Pdk, Cdk and/or VEGF-R activity as well as combinations thereof.

Preferred is the use of compounds of general formula (I), wherein the kinase is selected from PDK1, Akt1, Akt2 and/or Akt3, particularly, wherein the kinase is

selected from PDK1, Akt1, Akt2 and/or Akt3 in combination with VEGF-R or wherein the kinase is selected from Chk1 and/or Chk2.

Another objective of this invention is a method of treating a mammal having a disease-state alleviated by the inhibition of Akt, Pdk, chk and/or VEGF-R activity, wherein the method comprises administering to a mammal a therapeutically effective amount of a compound of general formula (I) or a compound disclosed hereinbefore. In particular the method is objective wherein the mammal is a human.

"Disorders"and/or"disease state"in the meaning of this invention are selected from cancer, angiofribroma, arthritis, eye diseases, auto-immune diseases, chemotherapy agent-induced alopecia and mucositis, Crohn-disease, endometriosis, fibrotic diseases, hemangioma, cardiovaskular diseases, infectious diseases, nephrological diseases, chronic und acute neurodegenerative diseases, like disruptions of nerval tissue, viral infections, to prevent restenosis of vessels, for preventing the formation of scars, preventing or treating keratoma seniles and contact dermatitis, wherein cancer stands for solide tumours, tumour-or metastasis growth, Kaposis Sarkom, Hodgkin's disease and/or leukemia, arthritis stands for rheumatoid arthritis, eyes diseases stand for diabetic retinopathy, neovaskular glaukoma, auto-immune diseases stand for psoriasis, alopecia and/or multiple sklerosis, fibrotic diseases stand for cirrhosis of the liver, mesangial cell proliferative diseases, arteriosklerosis, infectiouse diseases stand for diseases that are caused by unicellular parasites, cardiovascular diseases stand for stenosis, like stent induced restenosis, arteriosklerosis and restenosis, nephrological diseases stand for glomerulonephritis, diabetic nephropaty, malignant nephrosklerosis, thrombic mikroangiopathis syndrome, transplant rejections and glomerulopathy, chronic neurodegenerative diseases stand for Huntington's disease,

amyotrophic lateralsklerosis, Parkinsons disease, AIDS, dementia und Alzheimer's disease, acute neurodegenerative diseases stand for ischemias of the brain and neurotraumas, and viral infections stand for cytomegalic infections, herpes, hepatitis B or C and HIV.

The compounds according to the invention essentially inhibit on the one hand cell- cycle-associated kinases, particularly serin/threonine kinases, more particularly cyclin-dependent kinases (Cdks), Chks, Akts and/or Pdks or VEGF-R kinases. Preferred is the inhibition of Chks, e. g. Chk1 and/or Chk2, Akts, e. g. Akt1, Akt2 and/or Akt3 and/or Pdks, e. g. Pdk1.

On the other hand the compounds according to this invention essentially inhibit angiogenesis related kinases, particularly tyrosine kinases, more particularly VEGF-R kinases.

Of particular interest is a preferential inhibition of specific kinases. For example, the compounds of general formula (I) according to claims 2 to 5 show a preferentiality towards Akts, e. g. Akt1, Akt2 and/or Akt3 and/or Pdks, e. g. Pdk1 ; the compounds of general formula (I) according to claims 6 to 8 show a preferentiality towards Chks, e. g. Chk1 and/or Chk2 and the compounds of general formula (I) according to claims 9 and 10 show preferentiality towards Akts and VEGF-R kinases upon which is based their action, for example, against cancer, angiofribroma, arthritis, eye diseases, auto-immune diseases, chemotherapy agent-induced alopecia and mucositis, Crohn-disease, endometriosis, fibrotic diseases, hemangioma, cardiovaskular diseases, infectious diseases, nephrological diseases, chronic und acute neurodegenerative diseases, like disruptions of nerval tissue, viral infections, to prevent restenosis of vessels, for preventing the formation of scars, preventing or treating keratoma seniles and contact dermatitis. Compounds of general formula (I) according to claims 9 and 10 show the advantage in the treatment of disorders to have an inhibiting effect of two ways, in particular the cell cycle inhibition and the angiogenesis inhibition due to the preferential inhibition of AKT and VEGF compounds.

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.

The loss of the regulation of the cell cycle and the loss of function of the control points are characteristics of tumor cells.

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).

The pivotal role of VEGF and of its receptors during vascular development was exemplified in studies on targeted gene inactivation. Even the heterozygous

disruption of the VEGF gene resulted in fatal deficiencies in vascularization (Carmeliet et al., Nature 380, 435-439, 1996 ; Ferrara et al., Nature 380, 439- 442,1996). Mice carrying homozygous disruptions in either Flt1 or Flk1/KDR gene die in mid-gestation of acute vascular defects. However, the phenotypes are distinct in that Flk1/KDR knock-out mice lack both endothelial cells and a developing hematopoietic system (Shalaby et al. Nature 376,62-66, 1995), whereas FIt1 deficient mice have normal hematopoietic progenitors and endothelial cells, which fail to assemble into functional vessels (Fong et al., 376, 66-70,1995). Disruption of the FIt4 gene, whose extensive embryonic expression becomes restricted to lymphatic vessels in adults, revealed an essential role of FIt4 for the remodeling and maturation of the primary vascular networks into larger blood vessels during early development of the cardiovascular system (Dumont et al., Science 282,946-949, 1998). Consistent with the lymphatic expression of Flot4 in adults overexpression of VEGF-C in the skin of transgenic mice resulted in lymphatic, but not vascular, endothelial proliferation and vessel enlargement (Jeltsch et al., Science 276,1423-1425, 1997). Moreover, VEGF-C was reported to induce neovascularization in mouse cornea and chicken embryo chorioallantoic membrane models of angiogenesis (Cao et al., Proc. Natl. Acad. Sci. USA 95,14389-14394, 1998).

In pathological settings associated with aberrant neovascularization elevated expression of angiogenic growth factors and of their receptors has been observed. Most solid tumors express high levels of VEGF and the VEGF receptors appear predominantly in endothelial cells of vessels surrounding or penetrating the malignant tissue (Plate et al., Cancer Res. 53, 5822-5827, 1993). Interference with the VEGF/VEGF receptor system by means of VEGF- neutralizing antibodies (Kim et al., Nature 362,841-844, 1993), retroviral expression of dominant negative VEGF receptor variants (Millauer et al., Nature 367,576-579, 1994), recombinant VEGF-neutralizing receptor variants (Goldman et al., Proc. Natl. Acad. Sci. USA 95, 8795-8800, 1998), or small molecule inhibitors of VEGF receptor tyrosine kinase (Fong et al., Cancer Res.

59, 99-106, 1999 ; Wedge et al., Cancer Res. 60,970-975, 2000 ; Wood et al. Cancer Res. 60, 2178-2189, 2000), or targeting cytotoxic agents via the

VEGFNEGF receptor system (Arora et al., Cancer Res. 59,183-188, 1999; EP 0696456A2) resulted in reduced tumor growth and tumor vascularization.

However, although many tumors were inhibited by interference with the VEGF/VEGF receptor system, others were unaffected (Millauer et al., Cancer Res. 56,1615-1620, 1996). Human tumors as well as experimental tumor xenografts contain a large number of immature blood vessels that have not yet recruited periendothelial cells. The fraction of immature vessels is in the range of 40% in slow growing prostate cancer and 90% in fast growing glioblastoma. A selective obliteration of immature tumor vessels was observed upon withdrawal of VEGF by means of downregulation of VEGF transgene expression in a C6 glioblastoma xenograft model. This result is in accordance with a function of VEGF as endothelial cell survival factor. Similarly, in human prostate cancer shutting off VEGF expression as a consequence of androgen-ablation therapy led to selective apoptotic death of endothelial cells in vessels lacking periendothelial cell coverage. In contrast, the fraction of vessels which resisted VEGF withdrawal showed periendothelial cell coverage (Benjamin et al., J. Clin.

Invest. 103, 159-165,1999).

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.

For parenteral administration, especially injection solutions or suspensions, especially aqueous solutions of active compounds in polyhydroxy-ethoxylated castor oil, are suitable.

As carrier systems, surface-active adjuvants such as salts of gallic acids or animal or plant phospholipids, as well as mixtures thereof and liposomes or ingredients thereof can also be used.

For oral administration, especially tablets, coated tablets, pills or capsules with talcum and/or hydrocarbon carriers or binders, such as, for example, lactose, maize or potato starch, are suitable. The oral application can also be in a liquid form, such as, for example, as a juice, to which optionally a sweetener is added.

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

If the production of the starting compounds for the manufacture of the compounds of the invention is not described, these starting 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.

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.

The production of the salts is carried out in the usual way by a solution of the compound of formulae I-VII 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.

Inhibition of Pdk/Akt activity General remarks Compounds described herein, potently block an assay in which phosphoinositide-dependent kinase-1 (PDK-1) mediates the activation of AKT, whose activity is measured in the assay. The compounds, therefore, can be blocking the assay by inhibiting PDK-1 enzyme activity, AKT enzyme activity, or the activation of AKT by PDK-1. These compounds are expected to be therapeutical useful in cancer by inhibiting processes critical for tumor progression, including cell proliferation, survival, and tumor angiogenesis (Testa and Bellacosa 2001; Vivanco and Sawyers 2002). As described herein, compounds blocking block colony formation and/or growth of PC-3 prostate and MDA-468 breast cancer cells in soft agar, which is an in vitro measure of potential anti-tumor activity. Furthermore, the compounds described herein are expected to sensitize tumors to the effects of other chemotherapeutic agents and radiation (Page, Lin et al. 2000; Brognard, Clark et al. 2001).

PDK-1 is a Ser/Thr kinase that functions to phosphorylate and activate other Ser/Thr kinases in the AGC kinase family (Vanhaesebroeck and Alessi 2000).

The best-characterized substrate of PDK-1 is the intracellular Serine/Threonine kinase AKT, whose expression and/or activity is elevated in many cancers.

Kinase activity of serum and glucocordicoid regulated kinase (SGK), which is structurally related to AKT, can also be phosphorylated and activated by PDK-1.

Once activated in tumors, AKT promotes increase tumor cell survival, drug resistance, growth and angiogenesis. Three highly related isoforms of AKT, termed AKT1, AKT2 and AKT3 are known in humans. Activation of AKT is dependent on the activity of phosphatidylinsoitol-3 kinase (PI-3 kinase), whose activity is activated by many signaling molecules elevated in cancer cells, including growth factor receptors (e. g., epidermal growth factor (EGF) receptor, ErbB2 and IGF1-receptor) and oncogenes (e. g, Ras, BCR-abl, and Src). Other potential substrates of PDK-1 include p70 S6 kinase, p90 S6 kinase, protein

kinase C, cAMP-dependent protein kinase (PKA), PRK1, Protein kinase G and serum and glucocorticoid regulated kinase (SGK).

PDK-1-mediated phosphorylation of AKT, which is largely in an inactive form in unstimulated cells, converts the enzyme to a catalytically active form. This occurs through the phosphorylation of the activation loop domain of AKT e. g. , at Threonine-309 in AKT2 and Theonine-308 in AKT1. Phosphorylation of a homologous domain in many kinases is known to regulate their kinase activity.

One stimulus for PDK-1 mediated phosphorylation of AKT is the association PI-3 kinase products (3,4, 5) PIP3 or (3,4) PIP2 with the pleckstrin homology (PH) domain of AKT. Although AKT displays low, basal levels of activation in normal, unstimulated cells, AKT often becomes constitutively activated in tumor cells.

This occurs through the up-regulation of a variety of different signaling molecules or the presence of oncogenenic mutations commonly found in cancer cells that can promote the activation of AKT, such as PI-3 kinase, growth factor receptors (e. g. , EGFR family members), Ras, Src, and BCR-ABL activation. Loss of the tumor suppressor PTEN is another means of greatly increasing AKT activity in cancer cells (Besson, Robbins et al. 1999). PTEN mutation or down regulation of PTEN protein is found in a large number of tumors and cancer cell lines. PTEN is a phosphatase that removes the D-3 phosphate from the products of PI-3 kinase such as phosphatidylinositol 3, 4, 5-trisphosphate and phosphatidylinositol 3,4-bisphosphate (Myers, Pass et al. 1998; Stambolic, Suzuki et al. 1998). Loss of PTEN, therefore, has the effect of increasing products of PI-3 kinase and promoting constitutive activation of AKT. Cancers with highly up-regulated levels of AKT may be especially sensitive to the effects of PDK-1/AKT pathway inhibitors.

Downstream substrates of PDK-1 and/or AKT are associated with a number of cell responses including proliferation, metabolism and cell survival (Testa and Bellacosa 2001; Vivanco and Sawyers 2002). Examples of signaling molecules downstream from PDK-1 or AKT involved in these pathways include BAD, p70 S6 kinase, p21 (Waf-1/Cip-1), Forkhead transcription factors, p27 (kip-1), GSK-3-alpha/beta, TSC2 (tuberin), and ecNOS. The survival function of AKT is

particularly well-characterized cellular activity of AKT (Datta, Brunet et al. 1999). AKT functions to suppress apoptosis induced by a variety of agents, including UV radiation, chemotherateutic drugs, TFG-beta, withdrawal of survival factors, overexpression of oncogenes such as c-myc and detachment of cells from the extracellular matrix.

The ability to escape cell death, also termed apoptosis, is critical characteristic of tumor cells allowing their uncontrolled growth and invasive behavior. One trigger for apoptosis is the perturbation of the normal growth regulation resulting from oncogenic mutations or inappropriate expression signaling molecules coupled to cell proliferation. Apoptotic pathways, therefore, provide a key means of protection from the development and progression of cancer. Cancer cells, however, can escape apoptotic death by selecting for activation of signaling molecules such as AKT that turn off apoptotic signals. Some oncogenes, such as Ras, which is activated in as many as 60% of human tumors, simultaneously promote uncontrolled growth and the activation of AKT. Inhibition of AKT in HIH 3T3 cells prevents transformation of these cells through transfection with activated Ras. Furthermore, a number of studies have shown that combining expression an oncogene with an activated form of AKT greatly facilitates formation of tumors in vivo (e. g., (Holland, Celestino et al. 2000) ). Inhibitors of PDK-1, by blocking activation of AKT, are a means of promoting apoptosis in tumors cells, especially, but not necessarily limited to those over-expressing AKT activity. By blocking cell survival mechanisms, the compounds described herein could also be useful to promote sensitivity of cancer cells to radiation therapy and to treatment with a variety of chemotherapeutic agents.

Inhibitors of the PDK-1/AKT pathway are also expected to block cancer progression through inhibition of tumor-stimulated angiogenesis (Dimmeler and Zeiher 2000; Shiojima and Walsh 2002). AKT has been shown to regulate a number of responses critical for the process of angiogeneisis, including endothelial cell migration, proliferation and survival during new vessel formation, ecNOS regulation, response of endothelial cells to growth factors (including

IGF-1, agniopoetin-1 and VEGF) and the regulation of hypoxia-inducible factor-1 (HIF-1)-alpha levels.

Inhibition of the cell cycle and growth of tumor cells is yet another expected effect of compounds that block PDK-1 and/or AKT. Inhibition of PDK-1 and/or AKT activity has been shown to regulate growth of cancer cells in a number of studies. These effects may occur through PDK-1 or AKT-mediated regulation of a number of different signaling pathways important in growth regulation. For example, AKT has been shown to block nuclear localization and/or expression of the cyclin-dependent kinase inhibitors, p21 (Waf-1/Cip-1) and p27 (kip-1). Compounds blocking these effects would be expected to reduce the activity of cyclin-dependent kinases, blocking progression through the cell cycle and reducing tumor cell growth. AKT was found to inhibit Myt1, thereby acting as an initiator of mitosis in oocytes fronm the starfish Asterina pectinfera. Furthermore, PDK-1 and/or AKT regulate the expression of proteins important for cell growth through its regulation of mTOR, p70 S6 kinase and eukaryotic initiation factor 4E binding protein 1 (4E-BP1). While the mechanism of this regulation is not firmly established, it has been shown that AKT phosphorylations and reduces expression of TSC2, thereby relieving TSC-2 mediated suppression of mTOR activity. This, in turn, promotes the activation p70 S6 kinase activity and the phosphorylation and inhibition of 4E-BP1 (Inoki, Li et al. 2002; Potter, Pedraza et al. 2002). Both these effects result in increased synthesis of mRNAs encoding proteins important for cell growth. Loss of TSC2 function is associated with the disease tuberous sclerosis, which results in differentiated benign growths (harmatomas) in a wide variety of organs. PDK-1 also has been shown to have a direct role in the phosphorylation and activation p70 S6 kinase (Alessi, Kozlowski et al. 1998).

In summary, the compounds described which block PDK-1 mediated activation of AKT or PDK-1 directly may be useful therapeutic agents in cancer by blocking a number of processes required for tumor progression, including growth, tumor cell survival, and recruitment of new blood vessels. The compounds described may also enhance the anti-tumor effects of radiation or other chemotherepeutic drugs.

The compounds may also be useful for the treatment of tuberous sclerosis. Furthermore, the compounds described could be useful modulators of the immune response (Cantrell 2002) and for the treatment of autoimmune diseases such as rheumatoid arthritis and MS.

Experimental Procedures 1 Cell-based assays Materials : Prostate cancer cells (PC-3) and breast cancer cells (MDA-468) were obtained from the ATCC (Manassas, VA). Mammalian protein extraction reagent (MPER), Halt protease inhibitor cocktail, BCA protein reagent, and Supersignal Western Chemiluminescent reagent were obtained from Pierce Chemical Co. (Rockford, IL). 10% Tris-Glycine gels (1. 0mm, 15-well) and nitrocellulose (0.2 micron) were obtained from Invitrogen Life Technologies (Carlsbad, CA). Agar agar was purchased from EM Science. Polyclonal antibodies raised against phospho-AKT (Thr308, #9275), phospho-AKT (Ser473, #9271), phospho-S6-kinase (Thr389, #9205), and anti-rabbit IgG-HRP conjugate were obtained from Cell Signaling Technologies (Beverly, MA). Nitroblue tetrazolium reagent and staurosporine were purchased from Sigma Chemical Co. (St. Louis, MO). LY294002 was purchased from Cayman Chemicals (Ann Arbor, MI). All other materials were of reagent-grade quality.

Cell growth conditions: PC-3 cells were grown in F12K medium, supplemented with 7% (v/v) fetal calf serum (fcs) and 2mM glutamine. MDA-468 cells were grown in MEM-alpha, supplemented with 10% (v/v) fcs, 2mM glutamine, 1mM sodium pyruvate, 0. 1 mM non-essential amino acids, 1 OmM Hepes, and 1pg/ml insulin. All cell lines were incubated in a 37DC humidified incubator, with a 5% C02 atmosphere.

Cell-based assays using Western blot analysis : PC-3 cells were seeded into 24-well plates (Corning Costar) at 100-120,000 cells per well and allowed to grow overnight to 90% confluence. On the next day, the cells were washed once with

1. 5ml PBS, and the medium replaced with low serum (0. 1% fcs) containing growth medium (starvation medium). After a second overnight incubation, the medium was replaced with 0. 5ml/well of starvation medium. Some assays were also conducted in normal growth medium (7% fcs, PC-3, or 10% fcs, MDA-468).

Cells were treated with vehicle control (DMSO) or drug at a final DMSO concentration of 1% v/v (a 5pl addition per 0. 5ml medium), and cells were allowed to incubate for the stated times. The incubations were terminated by aspiration of the medium, washing the wells with 1. Oml PBS, and lysis in 0. 1ml MPER reagent, supplemented with protease inhibitors (Halt reagent) and phosphatase inhibitors (1mM NaF, 1mM sodium vanadate). Cell lysates were briefly centrifuged to remove insoluble debris, and aliquots were taken for protein (BCA) and Western blot analysis. For Western analysis, lysates were combined with Laemmli SDS sample buffer, boiled, and loaded onto 10% Tris-Glylcine gels, normalizing for the amount of protein loaded in each lane. Electrophoresed gels were transferred onto nitrocellulose paper, blocked with 5% milk in Tris-buffered saline containing 0. 1 % Tween-20, and incubated overnight with the primary antibody (phospho-AKT-Thr308 @ 1: 667, phospho-AKT-Ser473 @ 1: 1000, phospho-S6 kinase @ 1: 1000). Blots were washed three times with blocking buffer and incubated one hour with anti-rabbit IgG-HRP @ 1: 2000. Washed blots were developed using the Supersignal Western Chemiluminescent detection system.

Films were scanned using a Bio Rad CCD camera, and phospho-protein bands were quantitated using Bio Rad Quantity-One software.

Soft agar efficacy assays: PC-3 and MDA-468 cells were grown in soft agar over a period of 2 weeks. Culture plates (Corning 35mm x 10mm) were prepared with a bottom layer of 0.5% agar in growth medium, 2ml/well. Cells were trypsinized, dispersed into single cells with a 21-gauge needle, and seeded in a top layer of 0.3% agar/growth medium, 1. 5ml/plate, containing 4500 cells per plate. On the following day, the first vehicle or drug treatment was added, in a volume of 1. Oml of 0.3% agar/growth medium, containing 1% DMSO. Drug concentrations were adjusted to reflect the total volume of agar in the plates. The cells were allowed to grow for seven days and treated a second time (adding an additional 1 ml of 0.3% agar). Colonies were visually inspected for growth and viability every few days.

On day 12-14, nitroblue tetrazolium (0.5 mg/ml PBS) was added, 0.3 ml per plate, and the viable colonies were allowed to develop color for 1-2 days. Plates were scanned using a Bio Rad CCD camera, and the colonies were quantitated for ony number, and for total stained area, using ImagePro software.

AKT2 and PDK-1 Expression and purification pHisAKT2 was constructed by cloning AKT2 into pBlueBacHis2A (Invitrogen Corp. ) through the BamH1 and Bgl2 restriction sites, forming a fusion protein behind a 38 amino acid N-terminal His tag sequence derived from the vector. The new N-terminal sequence + first 10 residues of AKT2 is as follows : MPRGSHHHHHHGMASMTGGQQMGRDLYDDDDKDRWGSMNEVSVIKEG (AKT2 is underlined and is in bold His-6). Similarly, pHisPDK-1 was constructed by cloning PDK1 into pBlueBacHis2A (Invitrogen Corp. ) at EcoR1 cloning site, forming a fusion protein behind an N-terminal His-tag (preceding sequence of ... ICSWYHGILDMARTTSQLYD.... (PDK1 sequence underlined). The new N-terminal sequence + first 10 residues of PDK1 is as follows : MPRGSHHHHHHGMASMTGGQQMGRDLYDDDDKDRWGSELEICSWYHGILD MARTTSQLYD... (PDK1 is underlined and His-6 is in bold).

Recombinant baculovirus containing either His-tagged AKT2 or His-tagged PDK-1 cDNAs were prepared by the following method. pHisAKT2 or pHisPDK-1 were cotransfected with Bac-N-Blue (Invitrogen) viral DNA info SF-21 cells and after 3- 4 days, viral supernatant were isolated and recombinant viruses were plaque purified. His-tagged AKT2 (HisAKT-V) or His-tagged PDK-1 (HisPDK-1-V) cDNA expressing clones were selected and expanded as a stock for use in the expression of recombinant proteins described below.

To express His-tagged AKT2 and PDK-1, a 10 liter suspensions of SF-21 insect cells were infected with recombinant viruses (i. e. , either HisPDK-1-V or HisAKT2-V) and cells were harvested 3-4 days post infection and frozen. To purify recombinant His-tagged AKT2 and PDK-1, cell pellets were thawed, homogenized (in phosphate buffered saline (PBS), supplemented with 10% Triton

X-100,0. 5 M NaCI, 2 g/l NaF, 2. 5 µg/ml aprotinin, 5 pg/ml leupeptin, 1. 25 ugiml pepstatin, 0. 1% beta-mecaptoethanol, and 1 mM vanidate, 10 mM imidizole and adjusted to pH 7.6) and were purified using two sequential rounds of Ni2+ affinity chromatography followed by gel filtration. Enzymes were frozen in small aliquots and stored at-800C in 50 mM Tris-HCI, pH 7.5, 150 mM NaCI, pH 7. 5, 0.1 mM EGTA, 0.1 mM EDTA, 0. 2 uM benzamidine, 0.1% beta-mercaptoethanol and 0.25 M sucrose.

Enzyme Assays PDK-1-dependent activation and subsequent enzymatic activity of AKT2 : Purified human AKT2 activity was routinely measured in an assay in which the enzyme was first activated by PDK-1 in the presence of phosphatidylinositol4, 5-bisphosphate (PIP2). Once activated, AKT2-dependent phosphorylation of a peptide substrate was measured by scintillation proximity assay (SPA).

Phospholipid vesicles were prepared as follows : 2.2 mg each of phosphatidylcholine (Sigma Cat # P-1287) and phosphatidylserine (Sigma Cat #P-6641) were transferred to a borosilicate glass test tube and dried down under nitrogen. 1 mg of PIP2 (Biomol Cat #PH-106) was suspended in 9.5 ml of 10 mM HEPES, pH 7.5 and transferred to the dried lipids. The tube was vortexed until a milky suspension was produced. Then the tube was placed in a ice water-jacketed cup horn sonicator (Branson Instruments) and subjected to sonication for 20 min at medium power until a translucent phospholipid vesicle preparation was obtained. Aliquots of the vesicle suspension were frozen at-800C until needed.

Assays were performed in 96-well polypropylene V-bottom plates. Incubations were carried out for 2 hr at room temperature. The assay mixture contained in a volume of 60pL : 15 mM MOPS, pH 7.2, 1 mg/ml bovine serum albumin, 18 mM betaglycerolphosphate, 0.7 mM dithiothreitol, 3 mM EGTA, 10 mM MgOAc, 7.5 (M ATP, 0. 2 uCi of [y-33P] ATP, 7. 5 uM biotinylated peptide substrate (biotin-ARRRDGGGAQPFRPRAATF), 0. 5 uL of PIP2-containing phospholipid

vesicles, 60 pg of purified recombinant human PDK-1, and 172 ng of purified recombinant human AKT2. Test compounds were added from stock solutions in DMSO. The final concentration of DMSO was 2.5%. Following incubation, 10 pL of the assay mixture was transferred to a 96-well clear-bottom polystyrene plate (Wallac Isoplate) containing 0.33 mg of streptavidin-coated SPA beads (Amersham Cat. # RPNQ0007) suspended in 200 uL of phosphate-buffered saline, pH 7.4, containing 50 mM EDTA and 0. 1% Triton X-100. After brief shaking, the SPA beads were allowed to settle to the bottom of the plate overnight at room temperature. Product formation, measured in a Wallac MicroBeta scintillation counter, was proportional to the time of incubation and to the amount of PDK-1 and inactive AKT2 added. PDK-1 was added at sub-optimal levels so that the assay could sensitively detect inhibitors of AKT2 activation as well as direct AKT2 kinase inhibitors. The z'-factor for the assay was greater than 0.7.

Phosphorylation of the peptide substrate on the threonine residue was shown to be dependent upon activated AKT2 produced during the incubation. No phosphorylation was observed in the absence of ATP, Mg2+, PDK-1, AKT2, or PIP2-containing vesicles. Phosphorylation was readily observed, however, upon addition of purified activated human AKT1 (purchased from Upstate Biotechnology), independent of the presence or absence of added PDK-1 or PIP2-containing vesicles.

Direct assay of PDK-1 activity: Recombinant human PDK-1 activity was directly measured using a filter binding protocol. Incubations were performed at room temperature for 4 hr in a final volume of 60 pL containing: 50 mM Tris-HCI, pH 7.5, 0.1 mM EGTA, 0.1 mM EDTA, 0. 1% beta-mercaptoethanol, 1 mg/ml bovine serum albumin, 10 mM MgOAc, 10 uM ATP, 0. 2 uCi of [y-33P] ATP, 7.5 pM of substrate peptide (H2N-ARRRGVTTKTFCGT) and 60 ng of purified human PDK-1. The enzymatic reaction was stopped by addition of 25 mM EDTA. A portion of the reaction mixture was spotted on Whatman P81 phosphocellulose paper. The filter paper was washed 3 times with 0.75% phosphoric acid to remove unreacted [y-33P] ATP, and once with acetone. After drying, the filter-bound labeled peptide was quantitated using a Fuji Phosphoimager.

Results Compounds, which preferentially inhibit Akt/Pdk activity are shown in figure 1.

An overview of the results of the inhibition IC50 in nM are presented in the table 1 below : Table 1: Example Akt-2 inhibition IC50 (nM) 546 4 220 6 521 44 504 24 492 23 540 19 References: Alessi, D. R. , M. T. Kozlowski, et al. (1998).

"3-Phosphoinositide-dependent protein kinase 1 (PDK1) phosphorylates and activates the p70 S6 kinase in vivo and in vitro."Curr Biol 8 (2): 69-81.

Besson, A. , S. M. Robbins, et al. (1999)."PTEN/MMAC1/TEP1 in signal transduction and tumorigenesis. "Eur J Biochem 263 (3): 605-11.

Brognard, J. , A. S. Clark, et al. (2001)."Akt/protein kinase B is constitutively active in non-small cell lung cancer cells and promotes cellular survival and resistance to chemotherapy and radiation. "Cancer Res 61 (10) : 3986-97.

Cantrell, D. (2002). "Protein kinase B (Akt) regulation and function in T lymphocytes."Semin Immunol 14 (1) : 19-26.

Datta, S. R. , A. Brunet, et al. (1999)."Cellular survival : a play in three Akts." Genes Dev 13 (22): 2905-27.

Dimmeler, S. and A. M. Zeiher (2000). "Akt takes center stage in angiogenesis signaling."Circ Res 86 (1) : 4-5.

Holland, E. C. , J. Celestino, et al. (2000). "Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice. "Nat Genet 25 (1) : 55-7.

Inoki, K. , Y. Li, et al. (2002). "TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling."Nat Cell Biol 12: 12.

Myers, M. P., I. Pass, et al. (1998). "The lipid phosphatase activity of PTEN is critical for its tumor supressor function."Proc Natl Acad Sci U S A 95 (23): 13513-8.

Page, C. , H. J. Lin, et al. (2000). "Overexpression of Akt/AKT can modulate chemotherapy-induced apoptosis. "Anticancer Res 20 (1A) : 407-16.

Potter, C. J. , L. G. Pedraza, et al. (2002). "Akt regulates growth by directly phosphorylating Tsc2. "Nat Cell Biol 12: 12.

Shiojima, l. and K. Walsh (2002)."Role of Akt signaling in vascular homeostasis and angiogenesis. "Circ Res 90 (12): 1243-50.

Stambolic, V. , A. Suzuki, et al. (1998). "Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN."Cell 95 (1) : 29-39.

Testa, J. R. and A. Bellacosa (2001). "AKT plays a central role in tumorigenesis." Proc Natl Acad Sci U S A 98 (20): 10983-5. <BR> <BR> <BR> <P>Vanhaesebroeck, B. and D. R. Alessi (2000). "The P13K-PDK1 connection: more than just a road to PKB. "Biochem J 346 (Pt 3): 561-76.

Vivanco, I. and C. L. Sawyers (2002)."The phosphatidylinositol 3-Kinase AKT pathway in human cancer. "Nat Rev Cancer 2 (7) : 489-501.

Inhibition of Chk kinase activity General Remarks The compounds of this invention inhibit the cell cycle checkpoint kinases which are essential for the cellular response to DNA damage and for the coordination of the cell cycle. The DNA damage might be due to external or internal influence. These influences involve-without being limited to them-replication errors, DNA base damages, DNA strand breaks and the exposition to irradiation or cytotoxic chemicals.

The inhibition of one or more of the cell cycle checkpoint kinases is the basis for the effect of the compounds of this invention e. g. against cancer, like solid tumours or leukemia, against other hyperproliferative diseases, e. g. HIV and viral infections, like e. g. cytomegalus-infections, herpes and hepatitis B and C and HIV.

The eukaryotic cell division cycle ensures the duplication of the genome and its correct distribution to the daughter cells by running through a coordinated and regulated sequence of events. The cell cycle is divided in four successive phases: the G1 phase represents the time before the DNA replication, during which the cell is growing and susceptible for external stimuli. During the S-phase the cell replicates its DNA, and in the G2 phase the cell prepares for the entry into the mitosis. During the mitosis (M-Phase) the replicated DNA is separated and the cell division is carried out.

Corresponding to the extraordinary relevance of the cell division cycle the passage through the cycle is strictly regulated and controlled. The enzymes needed for the progression through the cycle, the cyclin-dependent kinases, have to be activated at the right moment and have to be switched off as soon as the corresponding phase is finished. Checkpoint systems arrest the progression through the cell cycle if DNA damage is detected, the DNA replication is not completed or the building of the spindel apparatus is not completed (Hartwell et

al., 1989). They do this by influencing the generation, activation or inactivation of the cyclin-dependent kinases.

Checkpoints permit the cell to track the ordered course of the individual phases of the cell cycle. The most important checkpoints are at the transition from the G1 phase into the S phase and at the transition from the G2 phase into the M phase (for a review see Dasika et al. 1999). The G1 checkpoint ensures that the cell does not start the DNA synthesis if it is not sufficiently nourished or if it does not correctly interact with other cells or with the substrate or if the DNA of the cell is not intact. The G2/M checkpoint ensures that the DNA is completely replicated and the mitotic spindle is build up before the cell enters the mitosis. The G1 checkpoint is controlled by the gene product of the tumour suppressor gene p53. p53 becomes activated after the detection of changes in the metabolism or the genomic integrity of the cell and p53 is able to initiate either a stop of the cell cycle program or apoptosis. For this the transcriptional activation of the expression CDK inhibiting protein p21 plays a crucial role.

A fundamental component of the G2/M checkpoint is the activation of the kinases ATM, Chk1 and Chk2 after a DNA damage and finally the phosphorylation and inactivation of the phosphatase Cdc25C. This results in a cell cycle arrest, as the inhibitory phosphorylation of the amino acids threonine-14 and tyrosine-15 of the cyclin dependent kinase 1 (CDK1) is not further removed by Cdc25C.

The loss of the regulation of the cell cycle and the loss of checkpoint control are characteristic features of tumour cells. p53, which is essential for the G1 checkpoint, is the gene most often mutated in human tumours (about 50 %). In tumour cells expressing unmutated p53, it is often inactivated by an enhanced proteolytic degradation or the genes of other proteins involved in the G1 checkpoint are mutated or deregulated. Examples are the inactivation of the tumour suppressor genes Rb, p16'NK4 and p19ARF or the overexpression of the oncogenes HDM-2 and cyclin D (Levine, 1997). In consequence nearly all tumour cells do not have a functional G1 checkpoint which enables the to accumulate further mutations and to escape from a DNA damage induced apoptosis. This

inactivation of the G1 checkpoint is an important factor for the genomic instability which drives the evolution of human tumours and crucially contributes to the resistance of tumour cells against chemotherapeutics and irradiation. On the other hand the inactivation of the G1 checkpoint enhances the dependence of the tumour cells on the second important barrier against the cell killing effect of DNA damages, the G2/M checkpoint, and makes the tumour cells especially vulnerable to an abrogation of the G2/M checkpoint (Hartwell und Kastan, 1994, O'Connor und Fan, 1996).

The cell cycle checkpoint kinase Chk1 is an important part of the G2/M checkpoint (Sanchez et al., 1997). Inactivation of Chk1 abrogates a DNA damage induced G2/M arrest and thereby leads to a preferred killing of the resulting checkpoint deficient cells (Takai et al., 2000, Koniaras et al., 2001, Liu et al., 2000). The inactivation of Chk1 causes that Cdc25C stays active despite of the DNA damage and is able to activate Cdk1/CycB, the main effector of the entry into the mitosis.

However, due to the persistent DNA damage the cell is not able to complete the M phase successfully and undergoes apoptosis instead ("mitotic catastrophe").

The cell cycle checkpoint kinase Chk2 is also activated by DNA damage (Matsuoka et al. 1998, Chaturvedi et al., 1999) and activated Chk2 phosphorylates and thereby inactivates Cdc25C. Cells without active Chk2 have a defect in their checkpoint response to DNA damage (Hirao et al., 2000).

The inactivation of Chk1 and Chk2 abrogates the G2/M arrest which is induced by damaged DNA and sensitises the resulting checkpoint deficient cells to the killing by DNA damaging events. As cancer cells are more sensitive towards the abrogation of the G2/M checkpoint than normal cells there is great interest in compounds, which inhibit Chk1, Chk2 or Chk1 and Chk2, as a result abrogate the G2/M checkpoint and improve the killing of cancer cells by DNA damaging events.

Such DNA damaging events can be the direct damage of the DNA by irradiation or chemotherapeutics, e. g. strandbreaks inducing compounds, DNA-alkylating compounds or topoisomerase inhibitors, the exertion of influence on the building of the mitotic spindle apparatus, hypoxic stress due to limited supply of the tumour with blood-e. g. induced by anti-angiogenic drugs-or also endogenous DNA damages resulting from the genomic instability inherent to cancer cells.

Experimental Procedure 2 Chk1 kinase assay Recombinant Chk1-His6-fusion protein, expressed in insect cells (Sf-9) and purified by Ni-NTA affinity chromatography was used as kinase. Alternatively, commercially available GST-Chk1-fusion protein (Upstate Biotechnology, Dundee, Scotland) can be used. As substrate for the kinase reaction the biotinylated peptide biotin-Arg-Ser-Gly-Leu-Tyr-Arg-Ser-Pro-Ser-Met-Pro-Glu-Asn-L eu-Asn-Arg-Pro- Arg-OH was used which can be purchased e. g. from the company Biosyntan GmbH (Berlin-Buch, Germany).

Chk1 (200 ng/measurement point) was incubated for 60 min at 22 DC in the presence of different concentrations of test compounds (0 uM and concentrations in the range 0. 001-30 uM) in 30 pi assay buffer [50 mM Hepes/NaOH pH7.5, 10 mM MgCI2, 1 mM MnCI21 0.1 mM sodium ortho-vanadate, 1.0 mM dithiothreitol, 0.5 pM adenosine-tri-phosphate (ATP), 1. 9 uM substrate peptide (Biotin-Arg-Ser-Gly-Leu-Tyr-Arg-Ser-Pro-Ser-Met-Pro-Glu-Asn- Leu-Asn- Arg-Pro-Arg-OH), 6 nCi/measurement point 33P-gamma ATP, 0.008% NP40, 1.5% (v/v) dimethylsulfoxide]. The reaction was stopped by the addition of 20 NI of a suspension of streptavidine coated PVT-SPA-beads (0.15 mg/measurement point, from Amersham Biotech) in an aqueous EDTA/ATP-solution (20 mM EDTA, 50 uM ATP, 1 % (v/v) Triton X-100 in PBS).

The resulting mixture was incubated further 16 h at 22°C to allow the binding of the biotinylated peptide to the streptavidine coated PVT-SPA-beads and to allow the sedimentation of the beads. Subsequently the amount of 33P incorporated into the substrate peptide was evaluated by scintillation measurement in a Topcount NXT (Perkin-Elmer).

Chk2 kinase assay Recombinant Chk2-His6-fusion protein, expressed in insect cells (Sf-9) and purified by Ni-NTA affinity chromatography was used as kinase. Alternatively, commercially available GST-Chk2-fusion protein (Upstate Biotechnology, Dundee, Scotland) can be used. As substrate for the kinase reaction the biotinylated peptide biotin-Arg-Ser-Gly-Leu-Tyr-Arg-Ser-Pro-Ser-Met-Pro-Glu-Asn-L eu-Asn Arg-Pro-Arg-OH was used which can be purchased e. g. from the company Biosyntan GmbH (Berlin-Buch, Germany).

Chk2 (400 ng/measurement point) was incubated for 60 min at 220C in the presence of different concentrations of test compounds (0 uM and concentrations in the range 0.001-30 uM) in 30 NI assay buffer [50 mM Hepes/NaOH pH7, 5,10 mM MgCI21 1 mM MnCI21 0.1 mM sodium ortho-vanadate, 1.0 mM dithiothreitol, 1. 5 uM adenosine-tri-phosphate (ATP), 8 uM substrate peptide (Biotin-Arg-Ser-Gly-Leu-Tyr-Arg-Ser- Pro-Ser-Met-Pro-Glu-Asn-Leu-Asn-Arg-Pro-Arg-OH), 15 nCi/measurement point 33P-gamma ATP, 0.008% NP40,1. 5% (v/v) dimethylsulfoxide]. The reaction was stopped by the addition of 20 NI of a suspension of streptavidine coated PVT-SPA-beads (0.25 mg/measurement point, from Amersham Biotech) in an aqueous EDTA/ATP-solution (20 mM EDTA, 50 uM ATP, 1 % (v/v) Triton X-100 in PBS).

The resulting mixture was incubated further 16 h at 22°C to allow the binding of the biotinylated peptide to the streptavidine coated PVT-SPA-beads and to allow the sedimentation of the beads. Subsequently the amount of 33P incorporated into the substrate peptide was evaluated by scintillation measurement in a Topcount NXT (Perkin-Elmer).

FACS-Assay Human HeLa (ATCC CCL-2) cervix adenocarcinoma cells were plate out to a density of 3000 cells/cm2 in DMEM medium containing 10% FCS in 6-well plates. After 48 h incubation the medium was exchange for DMEM medium supplemented with 10% FCS and 5 ug/ml bleomycine sulfate. After 18 h incubation the test compounds were added to final concentrations of 0. 03 uM, 0. 1 pM, 0.3 pM, 1 pM, 3 pM, 10 uM, or 30 uM. After a further incubation of 24 h or 48 h the cells were collected by trypsinisation, permeablelised and fixed in 70 % ethanol. The DNA was stained with propidium iodide and the cellular DNA-content was measured by a Fluorescence Activated Cell Scan (FACS).

The portion of cells with a cellular DNA-content corresponding to the G2 and M phases of the cell cycle was evaluated to judge the effect of the test compound on the bleomycine induced G2/M arrest of the cells.

Expression and purification of Chk1 and Chk2 The coding sequences were cloned by RT-PCR and nested PCR from commercially available polyA-RNA. The primers used for this purpose were designed according to the sequence information in Genebank (AF 016582 for Chk1, AF086904 for Chk2). In preparation for the C-terminal His6-fusion in the respective second PCRs 3'-primers were used, which removed the stop codon at the end of the coding sequence of Chk1 and Chk2 by mutation. Additional restriction sites were added to the primers (EcoRI-sites for the 5'-primers and Hindlll-sites for the 3'-primers).

The cDNAs were cloned into the vector pT7-Blue T (Novagen). To introduce the Hiss-sequence at the C-terminus of Chk1 and Chk2 EcoRl/Hindlll fragments from these pT7-Blue plasmids were cloned into the bacterial expression vector pET23a. From these pET23a-Chk1 und pET23a-Chk1 vectors DNA fragments coding for Chk1-His6 or Chk2-His6 were excised and inserted into the baculovirus-transfer-vector pVL1392.

The generated vectors were transfected into Sf-9 cells with AcNPV baculovirus genomic DNA (BaculoGold Transfection Kit, Pharmingen). The viruses produced by this procedure were plaque-purified and amplified for further infections.

Recombinant Chk1-His6-fusion protein and recombinant Chk2-His6-fusion protein were produced in Sf-9-cells. The Sf-9-cells were infected with the viruses at a MOI (Multiplicity of infectivity) = 1 and subsequently cultivated for 3 days in TNM-FH-medium. After lysis of the cells and sedimentation of the cell debris by centrifugation (20000 x g) the fusion proteins were purified from the supernatant by Ni-NTA affinity chromatography (Superflow from QIAGEN, Hilden, Germany) and dialysed into 50 mM Tris/HCI buffer (pH 7.5) containing 150 mM NaCI and 2 mM EDTA. The protein solution was shock frozen and stored at-800C.

Results Compounds, which preferentially inhibit Chk activity are shown in figure 2.

An overview of the results of the inhibition IC50 in nM are presented in the table 2 below : Table 2: Example Chk-1 IC50 (nM) 65 440 A16 300 A17 200 A18 80 699 20

References: Chaturvedi, P. et al. (1999), Oncogene 18,4047-4054.

Dasika, G. K : et al. (1999), Oncogene 18,7883-7899.

Hartwell, L. H. et al. (1989), Science 246,629-634.

Hartwell, L. H. und Kastan, M. B. (1994). Science 266, 1821-1828.

Hirao, A. et al. (2000), Science 287,1824-1827.

Jackson, J. R. et al. (2000), Cancer Res. 60,566-572.

Koniaras, K. et al. (2001), Oncogene 20,7453-7463.

Levine, A. J. (1997), Cell 88,323-331.

Liu, Q. et al. (2000), Genes Dev. 14,1448-1459.

Matsuoka, S. et al. (1998), Science 282,1893-1897.

O'Connor, P. M. , und Fan, S. (1996). Prog. Cell Cycle Res. 2, 165-173.

Sanchez, Y. et al. (1997), Science 277,1497-1501.

Takai, H. et al. (2000), Genes Dev. 14,1439-1447.

Inhibition of KDR-kinase activity KDR kinase assay Recombinant KDR-GST-fusion protein, expressed in insect cells (Sf-9) and purified by Glutathion affinity chromatography was used as kinase. Alternatively, commercially available GST-KDR-fusion protein (Proqinase, Freiburg i. Brsg., Germany) can be used. As substrate for the kinase reaction the biotinylated copolymer poly- (Glu, Tyr; 4: 1) which can be purchased e. g. from the company Cisbiointernational (Marcoule, France).

In a black low volume 384well microtiterplate (Greiner, Frickenhausen, Germany) KDR (enzyme amount depending on lot, adjusted to give an dF of about 300-400) was incubated for 20 min at 22°C in the presence of different concentrations of test compounds (0 uM and concentrations in the range 0.001- 30 uM) in 15 pi assay buffer [50 mM Hepes/NaOH pH7.0, 25 mM v) gCt2, 5 mM MnCl2, 0.5 mM sodium ortho-vanadate, 1.0 mM dithiothreitol, 1 uM adenosine-tri-phosphate (ATP), 23. 5 ug/ml substrate [biotinylated poly- (Glu, Tyr;

4: 1)], 1.5% (v/v) dimethylsulfoxide]. The reaction was stopped by the addition of 5 NI of a solution of the detection reagents [0. 3 pg/ml Eu-W1024-labeled antiphosphotyrosine antibody (PT66) (Perkin-Elmer) and 4. 125 pg/ml SA-XL- 665 (Cisbiointernational, Marcoule, France) ] in an aqueous EDTA-solution (250 mM EDTA, 0.1 % (w/v) bovine serum albumine in 100 mM HEPES/NaOH pH 7.0).

The resulting mixture was incubated further 2 h at 22°C to allow the binding of the biotinylated substrate and product to the SA-XL-665 and the EU labeled anti- phosphotyrosine antibody. Subsequently the amount of phosphate incorporated into the substrate was evaluated by resonance energy transfer measurement in a HTRF reader (Discovery, Perkin-Elmer).

The IC50 values are determined from the inhibitor concentration that is necessary to inhibit the phosphate incorporation to 50% of the uninhibited incorporation after removal of the blank reading (EDTA-stopped reaction).

Results : Compounds, which preferentially inhibit Akt and/or Pdk and the VEGF-R activity are shown in figure 3.

An overview of the results of the inhibition ! Cso in nM are presented in the table 3 below : Table 3: Example VEGFRII (KDR) ! Cso (nM) 389 330 477 740 473 400 512 1400 436 1600 535 2,6 546 4 452 9, 7 539 10, 6 395 32

Further, the invention is explained in more detail by the enclosed drawings and examples.

Figures: Figure 1: preferred compounds inhibiting preferentially Akt, Pdk kinases Figure 2: preferred compounds inhibiting preferentially Chk kinases Figure 3: preferred compounds inhibiting preferentially Akt and/or Pdk and VEGF- R kinases

The following examples demonstrate the feasability of the disclosed invention, without restricting the inventon to these disclosed examples.

Synthetic Schemes Scheme 1: O CI R-NH2, NEt3, CI HN NH 13'NWN CH3CN, r. t. NlN 2 A, 1- or R-GH, TFOH, xR R'reflux R1 r. t. (G=O, S) RI A A J@B H ; JWB Hie_ --) I-N N HCI, H20, x R2 X MeOH, reflux R

Scheme 2: H 0 w N cF ( NHz ., il eG HCI, H2O, MeOH, N ; N reflux X 2. LiOH, MeOH, THF, Et2O, reflux R' X = 0-6

Scheme 3:

Scheme 4: A in, B CI HN i A 1 Ir'- B il + X-R'-NHPG H N% HCI, H20, \ X-R'-NH 2 z R5 OH R1 2-AKT MeCN, R1 1-AKT reflux 3-AKT A B HN HATU, DIEA N),-N 0 DMF, r. t. X R'H \ R1 R5 4-AKT

Where R'= C1-6Alkyl and PG =-NHCOOR6 Scheme 4A

A A HN B HN'IJB HO HN r O pyridine, RT NAIN O I OII N N O X-R'-NHz + R OCI X-R'-N- R1 5 R1 H OR5 3-AKT 35-AKT Where R'= C1-6Alkyl Scheme 4B

Where R'= C, 6Alkyl Scheme 4C

Where R'= C1-6Alkyl Scheme 4D

Where R'= C1-6Alkyl Scheme 4E

Where R'= C1-6Alkyl Scheme 4F

Where R'= C1-6Alkyl and PG =-NHCOOR6 Scheme 5

Where R8 and R9 are as described in the claims.

Scheme 6 Where R6 is as described in the claims.

Scheme 7 ., R'0 H N 1. 6 N HCI, acetone OMe I THF, RT, o/n N N OMe-- HN"-y 31 R'O o2N O2N 10-AKT 2 H2, Pd/C, MeOH 9-AKT o, R' N H N I N II 11-AKT z O

Where R'is hydrogen or methyl.

Scheme 8 Where R5 is as described in the claims and PG =-NHCOOR6 Scheme 9 Where R'is C1-6Aklylaryl or C1-6Alkylheteroaryl.

Scheme 10 CsC03, DMF, heat PG Vs PGN-R'-R"+ HNRBR9 N-R'-N H Hz 19-AKT 20-AKT 1 9-AKT Where R'is C1-6Alkyl, R"is halogen, R8 and R9 are as described in the claims and PG =-NHCOOR6.

Scheme 11 ci ci A i MeCN. Et, N.. -., fil I/+ H2N PG /N. R'O. PG + HzN/ ci O R1 H IOI 22-AKT 21-AKT 21-AKT A A A A HCI, H O, HN HN z HATU, DIEA MeCN. reflux N N + HNR R. N"N R8 8 1 9 H T 9 R'N Ru H IOI IR1 H ici0 23-AKT 24-AKT

Where R'is C 6Alkyl ; A, B, R8, R9 are as described in the claims and PG = R6 as described in the claims.

Scheme 12

Where R'is C1-6Alkyl ; and R', A and B are as described in the claims.

Scheme 13

Where R'is C, 6Alkyl and R"is cycloalkyl ring, heteroaryl or aryl ; and R', A and B are as described in the claims.

Scheme 14 A A =NH NHz ll N [l f1 CI A HCI, H20, HNJ JUN N N N/g MeCN, reflux NHZ N non N AKT H H Y H H R1 2g_AKT R1 H R1 30-AKT 31-AKT

Where R'and A are as described in the claims.

Scheme 15

Where R'is C, 6Alkyl and R'and R5 are as described in the claims.

Examples A. Synthesis of Compounds The following Examples have been synthesized according to the above mentioned schemes.

A1 5-Bromo-4-(2-(1 H-imidazol-4-yl) xthylamino)-2-(4-pyrrolidi n-1-ylmethyl- phenylamino)-pyrimidine 1a) 5-Bromo-2, 4-dichloropyrimidine To 5-bromouracil (50 g) were sequentially added N, N-diethylaniline (60 mL) and phosphoryl chloride (120 mL), and the mixture was refluxed for 5 h. The volatiles were removed by distillation, the residue poured into ice water and the mixture extracted with methyl tert-butyl ether. The combined extracts were washed with brine, dried (Na2SO4) and filtered through Celite. Distillation of the crude product gave the title compound (63.4 g).

IH NMR (300 MHz, CDCl3) : o/ppm = 8.69 (s, 1H).

1b) 5-Bromo-4- (2- (1H-imidazol-4-yl)-ethylamino)-2-chloro-pyrimidine To a solution of 5-bromo-2, 4-dichloropyrimidine (4.56 g) and triethylamine (3 mL) in acetonitrile (20 mL) 2- (1H-imidazol-4-yl)-ethylamine (2.45 g) was added portionwise at 0 °C, and the suspension stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and brine, the aqueous phase extracted with additional ethyl acetate, the combined organic phases dried (Na2SO4) and evaporated, which gave, after chromato- graphy on silica using dichloromethane/methanol, the title compound (4.41 g).

'H NMR (300 MHz, CD30D) : o/ppm = 2.91 (t, 2H, J=7 Hz), 3.73 (t, 2H, J=7 Hz), 6.87 (s, 1 H), 7.61 (s, 1H), 8.11 (s, 1H).

1c) 4-Pyrrolidin-1-ylmethyl-phenylamine To a suspension of sodium hydride (60% in oil, 220 mg) in THF (5 mL) pyrrolidine (391 mg) was added, the mixture stirred at r. t. for 6 h, a solution of 1- bromomethyl-4-nitro-benzene (1. 08 g) in THF (8 mL) added and stirred overnight. The reaction was quenched with water and extracted with ethyl acetate, the organic phase dried (Na2SO4) and evaporated, which gave, after chromatography on silica using dichloromethane/methanol, 1- (4-nitro-benzyl)- pyrrolidine (690 mg).

'H NMR (300 MHz, CDCI3) : o/ppm = 1.84 (m, 4H), 2.58 (m, 4H), 3.77 (s, 2H), 7.61 (dbr, 2H, J=9 Hz), 8.22 (dbr, 2H, J=9 Hz).

To a solution of 1- (4-nitro-benzyl)-pyrrolidine (1. 37 g) in ethanol (66 mL) tin (Il)- chloride dihydrate (9.0 g) was added portionwise and the resulting mixture refluxed for 2 h. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution, the aqueous phase extracted with additional ethyl acetate, the combined organic phases dried (Na2SO4) and evaporated, which gave, after chromatography on silica using dichloromethane/methanol, the title compound (432 mg).

'H NMR (300 MHz, CD30D) : o/ppm = 1.85 (m, 4H), 2.65 (m, 4H), 3.61 (s, 2H), 6.72 (d, 2H, J=9 Hz), 7.11 (d, 2H, J=9 Hz). <BR> <BR> <BR> <BR> <BR> <BR> <P>1d) 5-Bromo-4- (2- (1H-imidazol-4-yl)-ethylamino)-2- (4-pyrrolidin-1-ylmethyl- phenylamino)-pyrimidine A mixture of 5-bromo-4- (2- (1H-imidazol-4-yl)-ethylamino)-2-chloro-pyrimidine (60 mg), 4-pyrrolidin-1-ylmethyl-phenylamine (35 mg) and hydrochloric acid (37% in water, 40 uL) in methanol (2 mL) was refluxed overnight. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution, the organic phase dried (Na2SO4) and evaporated, which gave, after chromatography on silica using dichloromethane/methanol, the title compound (4 mg).

'H NMR (400 MHz, CD30D) : o/ppm = 2.09 (m, 4H), 3.02 (t, 2H, J=7 Hz), 3.31 (m, 4H), 3.79 (t, 2H, J=7 Hz), 4.30 (s, 2H), 7.11 (s, 1H), 7.40 (d, 2H, J=9 Hz), 7.76 (d, 2H, J=9 Hz), 7.97 (s, 1 H), 8.19 (s, 1H).

A2 <BR> <BR> <BR> <BR> 2- (4- (Aminomethyl)-phenylamino)-4- (prop-2-ynylamino)-5-trifluoromethyl- pyrimidine 2a) 2, 4-Dichloro-5-trifluoromethyl-pyrimidine To 5-trifluoromethyluracil (25 g) were sequentially added N, N-diethylaniline (25 g) and phosphoryl chloride (94 g), and the mixture was refluxed for 18 h.

After cooling to r. t. the solution was poured onto ice (100 g), stirred for 10 min. and extracted with diethyl ether. The combined organic phases were washed with saturated aqueous sodium carbonate solution and water, dried (Na2SO4), and filtered. After removal of most of the ether, distillation of the residue at 190 °C and 860 to 300 mbar gave the title compound (5.8 g). aH NMR (300 MHz, CDC13) : o/ppm = 8.83 (s, 1H).

2b) 2-Chloro-4- (prop-2-ynylamino)-5-trifluoromethyl-pyrimidine To a solution of 2, 4-dichloro-5-trifluoromethyl-pyrimidine (3.47 g) in acetonitrile (16 mL) a solution of propargylamine (1.76 g) in acetonitrile (16 mL) was added dropwise at 0 °C, the mixture warmed to r. t. and stirred at r. t. for 48 h. The suspension was diluted with ethyl acetate, washed with brine, dried (Na2SO4). and evaporated. Purification by flash chromatography on silica using hexane/methyl tert-butyl ether gave the title compound (1.97 g).

'H NMR (400 MHz, CDC13) : o/ppm = 2.34 (t, 1H, J=1. 5Hz), 4.37 (dd, 2H, J=1.5/5 Hz), 5.53 (brs, 1H), 8.33 (s, 1H).

2c) 2- (4- (Aminomethyl)-phenylamino)-4- (prop-2-ynylamino)-5- trifluoromethyl-pyrimidine A mixture of 2-chloro-4- (prop-2-ynylamino)-5-trifluoromethyl-pyrimidine (235 mg), N- (4-aminobenzyl)-2, 2, 2-trifluoro-acetamide (410 mg) and hydrochloric acid (37% in water, 0.2 mL) in methanol (5 mL) was refluxed for 1 h. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution, the aqueous phase extracted with ethyl acetate, the combined organic phases dried (Na2SO4), concentrated, filtered through silica using dichloromethane/methanol, and the filtrate evaporated. To a solution of the residue in methanol (9 mL), tetrahydrofuran (9 mL) and diethyl ether (4. 5 mL) was added lithium hydroxide (150 mg) and the mixture was refluxed for 6 h, after which it was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted with additional ethyl acetate, the combined organic phases dried (Na2SO4) and evaporated, which gave, after chromatography on silica using dichloromethane/methanol, the title compound (120 mg).

'H NMR (300 MHz, CD30D) : o/ppm = 2.55 (t, 1H, J=1.5 Hz), 4.07 (s, 2H), 4.26 (d, 2H, J=1.5 Hz), 7.39 (d, 2H, J=8 Hz), 7.86 (d, 2H, J=8 Hz).

A3 N- (3- ( (2- ( (4- (aminosulfonyl) phenyl) amino)-5-bromo-4- pyrimidinyl) amino) propyl)-1H-pyrrole-2-carboxamide 3a) (3- ( (5-bromo-2-chloro-4-pyrimidinyl) amino) propyl)-carbamic acid tert- butyl ester To a solution of 5-bromo-2, 4-dichloro-pyrimidine (1. 4 g) in acetonitrile (10 mL) at 0°C was added triethylamine (0. 94 mL) and 3-aminopropylcarbamic acid-1,1- dimethylethyl ester (1.0 g). After removing the cooling bath the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated and to the residue water (20 mL) was added. The precipitate was collected, washed with water and ether to afford the title compound (1.8 g).

'H NMR (400 MHz, DMSO-d6) : o/ppm = 1.34 (s, 9H), 1.62 (m, 2H), 2.93 (m, 2H), 3.36 (m, 2H), 6.78 (t, 1H), 7.64 (t, 1H), 8.22 (s, 1H).

3b) 4- ( (4- ( (3-aminopropyl) amino)-5-bromo-2-pyrimidinyl) amino)- benzenesulfonamide hydrochloride To a solution of 4-aminobenzenesulfonamide (190 mg) in acetonitrile (20 mL), hydrochloric acid solution (4M in dioxane, 0.3 mL) and water (0.3 mL) was added (3-((5-bromo-2-chloro-4-pyrimidinyl) amino) propyl)-carbamic acid-1, 1-dimethylethyl ester (360 mg). The resulting mixture was refluxed overnight. The precipitate was collected and washed with acetonitrile and methanol to afford the title compound (320 mg).

'H NMR (400 MHz, DMSO-d6) : b/ppm = 1.86 (m, 2H), 2.78 (m, 2H), 3.51 (m, 2H), 7.23 (s, 2H), 7.75 (d, 2H), 7.79 (d, 2H), 7.96 (m, 3H), 8.19 (s, 1H), 10.38 (t, 1H).

3c) N-(3-((2-((4-(aminosulfonyl)phenyl)amino)-5-bromo-4- pyrimidinyl) amino) propyl)-1H-pyrrole-2-carboxamide trifluoroacetate 4-((4-((3-aminopropyl)amino)-5-bromo-2-pyrimidinyl)amino)-be nzenesulfonamide (120 mg) was suspended in dimethylformamide (5 mL). 2-Pyrrolecarboxylic acid (50 mg), 0-(7-azabenzotriazol-1-yl)-N, N, N', N'-tetramethyluronium hexafluorophosphate (180 mg), and diisopropylethylamine (0.3 mL) were added and the resulting mixture was stirred at room temperature for 15 min. Purification by HPLC chromatography using acetonitrile/water gave the title compound (65 mg).

'H NMR (400 MHz, DMSO-d6) : 5/pom = 1.78 (m, 2H), 3.27 (m, 2H), 3.44 (m, 2H), 6.03 (d, 1H), 6.71 (s, 1H), 6.80 (s, 1H), 7.14 (s, 2H), 7.42 (t, 1 H), 7.68 (d, 2H), 7.83 (d, 2H), 8.04 (t, 1 H), 8.11 (s, 1H), 9.78 (s, 1 H), 11.39 (s, 1H).

A4 N-[3-[[(2R)-2-Amino-1-oxo-3-phenylpropyl]amino]-5-[[5-bromo- 4-(prop-2- ynyloxy) pyrimidin-2-yl] amino] phenyl] pyrrolidine-1-carboxamide 4a) Methyl3-amino-5- [ [5-bromo-4- (prop-2-ynyloxy) pyrimidin 2yl] amino] benzoate A mixture of 5-bromo-2-chloro-4- (prop-2-ynyloxy) pyrimidine (15 g), methyl 3,5- diaminobenzoate (45 g) and concentrated hydrochloric acid (15 ml) in methanol (600 ml) was stirred at 65°C for 8 h. After concentration to half the volume water was added and the precipitate collected by filtration. The precipitate then was treated with sodium hydroxide solution (1 n) and dichloromethane. The organic phase then was washed with water and brine, dried (Na2SO4) and evaporated to dryness to give the title compound (13.8 g).

Mp. : 207. 5-209 °C 4b) Methyl 5-[[5-bromo-4-(prop-2-ynyloxy)pyrimidin-2-yl]amino]-3-[[(2R) -2- [ [ (1, 1-dimethylethoxy) carbonyl] amino]-l-oxo-3- phenylpropyl] amino] benzoate N-BOC-D-phenylalanine (3.3 g), 1-hydroxy-1H-benzotriazole hydrate (1. 9 g) and N- [3- (dimethylamino) propyl]-N'-ethylcarbodiimid hydrochloride (2.37 g) were stirred in DMF (30 mt) for 30 minutes. Then methyl 3-amino-5- [ [5-bromo-4- (prop-2-ynyloxy) pyrimidin-2-yl] amino] benzoate (3.88 g) were added and the mixture stirred over night. Then ethyl acetate (500 ml) was added and the reaction mixture washed subsequently with hydrochloric acid (0.1 n), saturated NaHCOs-sotution, water and brine. After drying (Na2SO4) the organic phase was evaporated and the residue subjected to column chromatography (ethyl acetate/dichloromethane) to yield 5.36 g of the title compound.

ESI-MS : 624 and 626 (M+) 4c) 5-[[5-Bromo-4-(prop-2-ynyloxy)pyrimidin-2-yl]amino]-3-[[(2R) -2-[[(1,1- dimethylethoxy) carbonyl] amino]-1-oxo-3-phenylpropyl] amino] benzoic acid Methyl 5-[[5-bromo-4-(prop-2-ynyloxy)pyrimidin-2-yl]amino]-3-[[(2R) -2-[[(1, 1- dimethylethoxy) carbonyl] amino]-1-oxo-3-phenylpropyl] amino] benzoate (1.0 g)

was stirred in a mixture of tetrahydrofuran (20 ml), methanol (20 ml) and sodium hydroxide solution (2 n; 20 ml) for 48 h. After evaporation water (50 ml) was added to the residue. On neutralisation with hydrochloric acid (1 n) a precipitate formed. The precipitate was subjected to chromatography on silica gel (hexanes/ethyl acetate/methanol) to yield the title compound (450 mg).

ESI-MS : 610 and 612 (M+) 4d) 1, 1-Dimethylethoxy [(1R)-2-[[3-[[5-bromo-4-(prop-2-ynyloxy)pyrimidin-2- yl] amino]-5-[[(pyrrolidin-1-yl) carbonyl] amino] phenyl] amino]-2-oxo-1- (phenylmethyl) ethyl] carbamate 5-[[5-Bromo-4-(prop-2-ynyloxy)pyrimidin-2-yl]amino]-3-[[(2R) -2-[[(1. 1- dimethylethoxy) carbonyl] amino]-1-oxo-3-phenylpropyl] amino] benzoic acid (200 mg), diphenylphosphorylazide (0.75 ml) and triethylamine (0.67 ml) were refluxed in toluene (40 ml) for 1.5 h. Then pyrrolidine (0.26 ml) was added and the mixture refluxed for additional 2 h. After cooling the reaction mixture was diluted with ethyl acetate (50 ml) and subsequently washed with saturated NaHC03-solution, water and brine. After drying (Na2SO4) and evaporation the residue was subjected to chromatography on silica gel (hexanes/ethyl acetate) to yield the title compound (126 mg).

ESI-MS : 678 and 680 (M+) 4e) N-[3-[[(2R)-2-Amino-1-oxo-3-phenylpropyl]amino]-5-[[5-bromo- 4-(prop-2- ynyloxy) pyrimidin-2-yl] amino] phenyl] pyrrolidine-1-carboxamide 1, 1-Dimethylethoxy [ (1R)-2-[[3-[[5-bromo-4-(prop-2-ynyloxy)pyrimidin-2yl]amino]- 5-[[(pyrrolidin-1-yl) carbonyl] amino] phenyl] amino] -2-oxo-1 (phenylmethyl) ethyl] carbamate (105 mg) and sulfuric acid (0.5 ml ; 2 n) were stirred in dioxane (5 ml) at 85°C for 3.5 h. After cooling and dilution with water saturated NaHCO3- solution was added and the resulting precipitate collected by filtration yielding the title compound (76 mg).

ESI-MS : 578 and 580 (M+)

A4A Synthesis of [3-[[5-bromo-2-[[3-[(1-pyrrolidinylcarbonyl) amino] phenyl] amino]-4-pyrimidinyl] amino] propyl]-carbamic acid ethyl ester To a solution of N- (3- ( (4- ( (3-aminopropyl) amino)-5-bromo-2-pyrimidinyl) amino) phenyl)-1-pyrrolidinecarboxamide (150 mg, 0.30 mmol) in pyridine (5mL) was added ethyl chloroformate (38.5 mg, 0.35 mmol) at 0°C under N2. The resulting reaction mixture was stirred at 0°C for 1 h and then was stirred at room temperature overnight. The mixture was washed with water (3 x 50 mL). Then the reaction mixture was concentrated. Purification by HPLC chromatography using acetonitrile/water gave the title compound (10 mg).

'H NMR (400 MHz, DMSO-d6) : o/ppm = 0.79 (t, 3H), 1.38 (t, 2H), 1.48 (m, 4H), 2.65 (m, 2H), 3.00 (m, 4H), 3.19 (m, 2H), 3.59 (m, 2H), 6.78 (m, 1H), 6.85 (m, 2H), 7.57 (s, 1H), 7.82 (m, 2H), 8.23 (m, 1 H), 10.08 (s, 1H) A4B Synthesis of N-[3-[[5-bromo-4-[[3-[(propylsulfonyl)amino]propyl]amino]-2- pyrimidinyl] amino] phenyl]-1-pyrrolidinecarboxamide To a solution of N-(3-((4-((3-aminopropyl)amino)-5-bromo-2-pyrimidinyl) amino) phenyl)-1-pyrrolidinecarboxamide (150 mg, 0.30 mmol) in dichloromethane (4mL) was added DIEA (0.16 mL, 0.92 mmol) and DMAP (1.4 mg, 0.011 mmol) at 0°C, then a solution of 1-propanesulfonyl chloride (51 mg, 0.36 mmol) in dichloromethane (5mL) was added. The resulting reaction mixture was stirred at 0°C for 1 h and at room temperature overnight. The reaction mixture was concentrated. Purification by HPLC using acetonitrile/water gave the title compound (67mg).

'H NMR (400 MHz, DMSO): o/ppm = 0.82 (t, 3H), 1.61 (m, 2H), 1.76 (m, 2H), 1.79 (m, 4H), 2.80 (m, 2H), 2.90 (m, 2H), 3.31 (m, 4H), 3.51 (m, 2H), 7.09 (m, 1H), 7.18 (m, 2H), 7.89 (s, 1H), 8.11 (s, 2H), 8.50 (m, 1H), 10.31 (s, 1H)

A4C Synthesis of N-[3-[[5-bromo-4-[[3-[[(phenylamino)carbonyl] amino] propyl] amino]-2-pyrimidinyl] amino] phenyl]-1-pyrrolidinecarboxamide To a suspension of N-(3-((4-((3-aminopropyl)amino)-5-bromo-2-pyrimidinyl) amino) phenyl)-1-pyrrolidinecarboxamide (100 mg, 0.2 mmol) and DIEA (0.14mL, 0. 8mmol) in 1,4-dioxane (5mL) was added phenyl isocyanate (35 mg, 0. 3mmol).

The resulting solution was stirred overnight and concentrated. The crude residue was directly purified by prep HPLC using acetonitrile/water to give the title compound (68 mg).

'H NMR (400 MHz, DMSO-d6), 8/pom = 1.71 (m, 2H), 1.84 (m, 4H), 3.09 (m, 2H), 3.36 (m, 4H), 3.48 (m, 2H), 6.21 (t, 1H), 6.83 (t, 1H), 7.05 (m, 1H), 7.19 (m, 4H), 7.36 (m, 2H), 7.84 (br s, 1H), 7.92 (s, 1 H), 8.16 (s, 2H), 8.47 (s, 1 H), 9.71 (s, 1H).

A4D Synthesis of N-[3-[[5-bromo-4-[[3-[[(ethylamino)thioxomethyl]amino] propyl] amino]-2-pyrimidinyl] amino] phenyl]-1-pyrrolidinecarboxamide A solution of N-(3-((4-((3-aminopropyl)amino)-5-bromo-2-pyrimidinyl) amino) phenyl)-1-pyrrolidinecarboxamide (100 mg, 0.20 mmol) and DMF (5 mL) was treated with DIEA (0.1 mL, 0.6 mmol, 3eq) and ethylthioisocyanate (15 mg, 0.17 mmol, 0.9 eq). The resulting mixture was stirred at RT for 2hr. Then the crude mixture was purified by HPLC using acetonitrile/water to afford the title compound (82 mg).

'H NMR (400 MHz, DMSO-d6) : o/ppm = 1.02 (t, 3H), 1.74 (m, 2H), 1.82 (m, 4H), 3.30-3. 48 (m, 8H), 7.04-7. 16 (m, 3H), 7.37 (m, 2H), 7.88 (s, 1H), 8.08 (m, 2H).

A4E Synthesis of [3-[[5-bromo-2-[l3-[(1-pyrrolidinylcarbonyl) amino] phenyl] amino]-4-pyrimidinyl]amino]propyl]-carbamothioic acid S-ethyl ester A solution of N-(3-((4-((3-aminopropyl)amino)-5-bromo-2-pyrimidinyl) amino) phenyl)-1-pyrrolidinecarboxamide (150 mg, 0.30 mmol), DMF (1.5 mL) and dichloromethane (5 mL) was treated with DIEA (0.2 mL, 1.15 mmol, 4 eq. ) and the was treated dropwise with a solution of ethyl chlorothioformate (41 mg, 0.33 mmol, 1. 1eq) and dichloromethane (1 mL). The resulting mixture was stirred at it. for 30 mins. Then the reaction mixture was diluted with dichloromethane (30 mL), washed with water (3 x 20 mL) and concentrated. The crude product was purified by chromatography on Si02 using ethyl acetate/methanol to afford the titile compound (112 mg).

'H NMR (400 MHz, DMSO-d6) : 6/pom = 1.14 (t, 3H), 1.68 (m, 2H), 1.82 (m, 4H), 2.74 (q, 2H), 3.13 (m, 2H), 3.35 (m, 4H), 3.42 (m, 2H), 6.89 (t, 1H), 6.94 (d, 1H), 7.05 (t, 1 H), 7.23 (d, 2H), 7.86 (s, 1H), 7.95 (m, 2H), 8.12 (t, 1H), 9.06 (s, 1H).

A4F Synthesis of N-[3-[[4-[[3-[(aminosulfonyl) amino] propyl] amino] -5-bromo-2- pyrimidinyl]amino]phenyl]-1-pyrrolidinecarboxamide Chloro[[(1,1-dimethylethoxy)carbonyl]amino]-sulfane dioxide was prepared by adding chlorosulfonyl isocyanate (32 mg, 0.23 mmol, 1.0 eq. ) to a cooled solution of tert-butyl alcohol (17 mg, 0.23 mmol, 1. 0eq.) and dichloromethane (2 mL) in an ice-water bath. The resulting mixture was stirred at 0-5°C for 2-3hr.

The solution was then treated with a solution of N-(3-((4-((3- aminopropyl) amino)-5-bromo-2-pyrimidinyl) amino) phenyl)-1- pyrrolidinecarboxamide (100 mg, 0.20 mmol, 1eq.) and dichloromethane (5 mL).

DMAP (20 mg, 0.16 mmol) was then added followed by the dropwise addition of DIEA (0.1 mL, 0.57 mmol). The mixture was stirred at RT for overnight. The reaction mixture was concentrated in vacuo. The residue was dissolved in TFA

(2 mL), and purified by HPLC using acetonitrile/water to afford the title compound (30 mg).

1H NMR (400 MHz, DMSO-d6) : o/ppm = 1.76 (m, 2H), 1.82 (m, 4H), 2.92 (m, 2H), 3.36 (m, 4H), 3.45 (m, 2H), 6.48 (s, 2H), 7.04 (d, 1H), 7.14 (t, 1H), 7.21 (d, 2H), 7.82 (s, 1 H), 8.05 (m, 2H).

A5 N- (3-aminophenyl)-urea (A5) Ammonia was bubbled into a solution of 3-nitrophenylisocyanate (1.5 g, 9.1 mmol) for ten minutes. The reaction mixture was then concentrated and the resulting yellow solid was washed with ether (200 mL) to afford N- (3- nitrophenyl)-urea (1.35 g, 7.5 mmol).

A solution of N- (3-nitrophenyl)-urea (1.0 g, 5.5 mmol) and methanol (40 mL) was treated with 10% Pd/C (250 mg) and placed under H2 (45 psi) for 2 h. The mixture was then filtered through celite and concentrated to afford N- (3- aminophenyl)-urea (828 mg, 5.5 mmol).

'H NMR (400 MHz, DMSO) : o/ppm = 4.90 (s, 2H), 5.66 (s, 2H), 6.08 (dm, J = 8 Hz, 1 H), 6.43 (dm, J = 8 Hz, 1 H), 6.70 (t, J = 1.6 Hz, 1 H), 6.80 (t, J = 8 Hz, 1 H), 8.13 (s, 1H).

A 6 (3-aminophenyl)-2- (4-morpholinyl)-carbamic acid ethyl ester 6a) 2- (4-morpholinyl)- (3-nitrophenyl)-carbamic acid ethyl ester A solution of 3-nitrophenyl isocyanate (0.5 g, 3.0 mmol) and 4- (2- aminoethyl) morpholine (0.5 mL, 3.8 mmol, 1.3 equiv. ) in tetrahydrofuran (20mL) was stirred for 3 h. The reaction mixture was concentrated and purified by chromatography (Si02) using hexane/ethyl acetate to afford 2- (4-morpholinyl)- (3-nitrophenyl)-carbamic acid ethyl ester (0.5 g).

aH NMR (400 MHz, CDC13) : O/ppm = 2.52 (m, 4H), 2.58 (m, 2H), 3.39 (m, 2H), 3.76 (m, 4H), 5.35 (br s, 1 H), 7.43 (t, 1 H), 7.87 (m, 2H), 8.20 (m, 1H) 6b) (3-aminophenyl)-2- (4-morpholinyl)-carbamic acid ethyl ester A solution of 2- (4-morpholinyl)- (3-nitrophenyl)-carbamic acid ethyl ester (0.5 g, 1.7 mmol) and methanol (50 mL) was treated with 10% Pd/C (150 mg) and placed under H2 (50 psi) for 2 h. The mixture was then filtered through celite and concentrated to afford the title compound (320 mg).

H NMR (400 MHz, CDC13) : 6/pom'= 2.52 (m, 4H), 2.68 (m, 2H), 3.52 (br s, 2H), 3.74 (m, 4H), 4.31 (m, 2H), 6.39 (m, 1H), 6.58 (m, 1 H), 6.68 (br s, 1H), 6.94 (br s, 1H), 7. 09 (m, 1H). <BR> <BR> <BR> <BR> <BR> <BR> <P>A7<BR> <BR> <BR> <BR> <BR> 3- (3-Aminophenyl)-2, 4-imidazolidinedione 7a) [[(3-nitrophenyl)amino]carbonyl]aminoacetic acid methyl ester To a suspension of 3-nitrophenyl isocyanate (10 g, 61 mmol) and glycine methyl ester hydrochloride (8.4 g, 67 mmol, 1.1 equiv. ) in dichloromethane (250 mL) was added triethylamine (10 mL, 72 mmol, 1.2 equiv. ) at 0 °C. The resulting solution was stirred at room temperature overnight. The resulting dark brown solution was concentrated and triturated in water to give a light yellow suspension. The suspension was filtered and the filter cake was washed with water and air-dried to give [[[(3-nitrophenyl)amino]carbonyl]aminoacetic acid methyl ester (15 g) in quantitative yield.

'H NMR (400 MHz, DMSO-d6) : O/ppm = 3.64 (s, 3H), 3.89 (d, 2H), 6.67 (t, 1H), 7.52 (t, 1 H), 7.68 (dd, 1 H), 7.76 (dd, 1 H), 8.51 (s, 1 H), 9.38 (br s, 1 H).

7b) 3- (3-Nitrophenyl)-2, 4-imidazolidinedione A suspension of [[[(3-nitrophenyl) amino] carbonyl] aminoacetic acid methyl ester (6.9 g, 27 mmol) in 6N aqueous hydrochloride solution (40 mL) and acetone (20 mL) was stirred at reflux overnight. The resulting solution was cooled and concentrated. The resulting yellowish suspension was filtered and the filter cake was washed with water (50 mL), aqueous sodium bicarbonate solution (50 mL), and air-dried to afford the title compound (4.4 g).

'H NMR (400 MHz, DMSO-d6) : #/ppm = 4.09 (s, 2H), 7.78 (t, 1H), 7.89 (dd, 1H), 8.23 (dd, 1 H), 8.31 (d, 1 H), 8.49 (br s, 1 H).

7c) 3- (3-Aminophenyl)-2, 4-imidazolidinedione A solution of 3- (3-nitrophenyl)-2, 4-imidazolidinedione (4.4 g, 20 mmol) and methanol (100 mL) was treated with 10% Pd/C (1.0 g) and placed under H2 (40 psi) for 2 h. The mixture was then filtered through celite and concentrated to afford the title compound (3.8 g).

'H NMR (400 MHz, DMSO-d6) : o/ppm = 4.02 (s, 2H), 5.23 (br s, 2H), 6.39 (d, 1 H), 6.47 (s, 1 H), 6.54 (d, 1H), 7.06 (t, 1H), 8.19 (br s, 1H).

A8 D- [2- [ (3-Aminophenyl) amino]-2-oxo-1- (phenylmethyl) ethyl]-carbamic acid tert-butyl ester A solution of 1, 3-phenylenediamine (1.0 g, 10 mmol, 2 equiv.) and N-tert- butoxycarbonyl-D-phenylalanine hydroxysuccinimide ester (1.8 g, 5 mmol, 1 equiv. ) in acetonitrile (40 mL) was stirred overnight. The reaction mixture was concentrated and purified by chromatography (SiO2) using dichloromethane/methanol to afford the title compound (1.2 g).

'H NMR (400 MHz, CDC13) : o/ppm = 1.43 (s, 9H), 3.14 (m, 2H), 3.71 (br s, 2H), 4.48 (br s, 1H), 5.21 (br s, 1H), 6.43 (m, 1H), 6.53 (br s, 1 H), 7.04 (m, 2H), 7.29 (m, 5H), 7.74 (br s, 1 H).

A9 5-bromo-2-chloro-N- [2- (4-thiazolyl) ethyl]-4-pyrimidinamine Lithium Aluminum hydride (95%) (1.1 g, 27.5 mmol) was suspended in dry THF (20 mL) and cooled with an ice-water bath. A solution of 1, 3-thiazol4-acetonitrile (1.0 g, 8.06 mmol) in THF (10 mL) was added dropwise. The resulting mixture was stirred at room temperature overnight. To the reaction mixture was added water (1 mL), 15% NaOH (1 mL) followed by water (3 mL). The precipitate inorganic solid was filtered, then washed with ethyl acetate (100 mL). The combined organic phase was dried (Na2SO4) and concentrate in vacuo to afford 4-thiazoleethanamine as a brown oil (400 mg, 3.12 mmol). The oil (400 mg, 3.12 mmol) was dissolved in CH3CN (10 mL), treated with Et3N (0.7 mL, 97.5 mmol) and cooled with an ice-water bath. 5-Bromo-2, 4-dichloropyrimidine (800 mg, 3.51 mmol) was then added. The resulting mixture was stirred at room temperature overnight. The mixture was dried in vacuo, then purified by chromatograpy (Si02) using hexane/ethyl acetate to afford the titled compound (110 mg) 'H NMR (400 MHz, CDC13) : o/ppm = 3.13 (t, 2H), 3.86 (m, 2H), 6.74 (t, 1H), 7.11 (s, 1H), 8.12 (s, 1H), 8.83 (s, 1H) A10 [3- (2-thiazolylamino) propyl]-carbamic acid 1, 1-dimethylethyl ester To a solution of (3-bromopropyl)-carbamic acid 1, 1-dimethylethyl ester (1.2 g, 5.0 mmol) and 2-aminothiazole (1.0 g, 10 mmol, 2 equiv. ) in DMF 20 (mL) was added Cs2CO3 (2.5 g, 7.7 mmol, 1.5 equiv. ). The resulting mixture was heated at 85 °C under N2 overnight. The reaction mixture was diluted with ethyl acetate (200 mL), washed with water (3 x 200 mL), and brine (200 mL). The organic phase was dried over Na2SO4, then concentrated in vacuo to afford an oil. The crude product was purified by chromatography (Si02) using hexane/ethyl acetate to afford the title compound as a light yellow solid (300 mg).

'H NMR (400 MHz, DMSO-d6): o/ppm = 1.37 (s, 9H), 1.65 (m, 2H), 2.95 (m, 2H), 3.14 (m, 2H), 6.57 (d, 1 H), 6.83 (t, 1H), 6.98 (d, 1H), 7.46 (t, 1H) A11 N-[3-[[5-bromo-4-[[3-oxo-3-(propylamino)propyl]amino]-2- pyrimidinyl] amino] phenyl]-1-pyrrolidinecarboxamide 11a)N-[5-bromo-2-[[3-[(1-pyrrolidinylcarbonyl)amino]phenyl]a mino]-4- pyrimidinyl]-ß-alanine To a solution of 5-bromo-2, 4-dichloropyrimidine (1.0 g, 4.4 mmol, 1 equiv. ) in acetonitrile (10 mL) at 0°C was added triethylamine (0.672 mL, 4.8 mmol, 1.1 equiv. ) and H-beta-Ala-OtBu HCI (0.8 g, 4.4 mmol, 1 equiv. ). After removing the cooling bath the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and to the residue water (20 mL) was added.

The precipitate was collected, washed with water and ether to afford N- (5-bromo- 2-chloro-4-pyrimidinyl)-ß-alanine 1, 1-dimethylethyl ester (0.52 g).

To a solution of N- (5-bromo-2-chloro-4-pyrimidinyl)-0-alanine 1, 1-dimethylethyl ester (348 mg, 1.2 mmol, 1 equiv. ) in acetonitrile (10 mL) was added water (1.0 mL), 4. 0M HCI in dioxane (1.0 mL) and N- (3-aminophenyl)-1- pyrrolidinecarboxamide (520 mg, 2.5 mmol, 2.1 equiv. ). The resulting mixture was stirred at 80 °C overnight. The white suspension was filtered and washed with acetonitrile to afford the title compound (500 mg).

'H NMR (400 MHz, DMSO): o/ppm = 2.15 (t, 4H), 2.79 (t, 2H), 3.55 (t, 4H), 3.89 (m, 2H), 7.45 (m, 3H), 8.10 (s, 1 H), 8.40 (d, 2H), 8.80 (t, 1 H), 10.65 (s, 1H)

11 b) N-[3-[[5-bromo-4-[3-oxo-3-(propylamino)propyl]amino]-2-pyrim idinyl] amino] phenyl]-1-pyrrolidinecarboxamide To a solution of N-[5-bromo-2-[[3-[(1-pyrrolidinylcarbonyl) amino] phenyl] amino]-4- pyrimidinyl]-0-alanine (200 mg, 0.45 mmol) in DMF (20 mL) was added O-(7-aza- benzotriazol-1-yl)-N, N, N'N'-tetramethyluronium hexafluorophosphate (243 mg, <BR> <BR> <BR> <BR> 0.64 mmol, 1.4 equiv. ), diisopropylethylamine (0.46 mL, 2.64 mmo, 5.9 equiv.l) and propylamine (32 mg, 0.54 mmol, 1.2 equiv. ). The resulting mixture was stirred at room temperature for 20min. Purification by HPLC chromatography using acetonitrile/water gave the title compound (40mg).

1H NMR (400 MHz, DMSO-d6) : #/ppm = 0.50 (t, 3H), 1.07 (m, 2H), 1.54 (t, 4H), 2.16 (t, 2H), 2.70 (m, 2H), 3.08 (t, 4H), 3.45 (m, 2H), 6.80 (d, 1H), 6.92 (t, 1H), 7.02 (d, 1 H), 7.63 (s, 1H), 7.69 (t, 1 H), 7.91 (s, 1H), 7.96 (s, 1H), 8.39 (t, 1H), 10.13 (s, 1 H) A12 N-(3-((4-(((3-aminophenyl)methyl)amino)-5-bromo-2-pyrimidiny l) amino) phenyl)-1-pyrrolidinecarboxamide (ZK 822797/26-AKT) (SY) N-(3-((5-bromo-4-(((3-nitrophenyl)methyl)amino)-2-pyrimidiny l) amino) phenyl)-1- pyrrolidinecarboxamide (350mg, 0. 68mmol) was dissolved in methanol (5 mL) and ethyl acetate (15 mL), then tin (II) chloride dihydrate (1. 0g, 4.44 mmol) was added. The resulting mixture was heated to reflux for 2hr. The reaction mixture was diluted with ethyl acetate (100 mL), then washed with 4N NaOH (60 mL) and brine (80 mL). The organic phase was dried over Na2SO4, then concentrated in vacuo to afford the titled compound (288 mg).

'H NMR (400 MHz, DMSO-d6) : #/ppm = 1.76 (m, 4H), 3.28 (m, 4H), 4.47 (d, 2H), 4.93 (s, 2H), 6.35 (d, 1H), 6.44 (m, 2H), 6.88-7. 00 (m, 3H), 7.19 (d, 1H), 7.34 (t, 1H), 7.72 (s, 1H), 7.92 (s, 1 H), 7.97 (s, 1H), 9.05 (s, 1H)

A13 N-[3-[[5-bromo-4-[[3-[(3-thienylmethyl) amino] propyl] amino]-2- pyrimidinyl] amino] phenyl]-1-pyrrolidinecarboxamide To a solution of N-(3-((4-((3-aminopropyl)amino)-5-bromo-2-pyrimidinyl) amino) phenyl)-1-pyrrolidinecarboxamide (1.0 g, 1.97 mmol) in THF (30 mL) was added 2-thiophenecarboxaldehyde (184 mg, 1.64 mmol, 0.8 equiv. ), triethylamine (362 mg, 3.6 mmol, 1.8 equiv) and sodium triacetoxyborohydride (688 mg, 3.25 mmol, 1.6 equiv. ). The resulting mixture was stirred overnight at room temperature under N2. The reaction was quenched by satuarated sodium bicarbonate (30 mL) and was extracted with ethyl acetate (3 x 30 mL). The reaction mixture was concentrated. Purification by HPLC chromatography using acetonitrile/water gave the title compound (310 mg).

'H NMR (400 MHz, DMSO): 6/ppm = 1.81 (t, 2H), 1.87 (t, 4H), 2.88 (m, 2H), 3.32 (t, 4H), 3.54 (m, 2H), 4.30 (t, 2H), 7.04 (m, 2H), 7.17 (m, 3H), 7.59 (d, 1 H), 7.92 (s, 1H), 8.20 (s, 1 H), 8.26 (s, 1H), 8.62 (t, 1H), 8.82 (s, 2H), 10.48 (s, 1H) A14 <BR> <BR> <BR> <BR> N2- (3-amino-5- (trifluoromethyl) phenyl)-5-bromo-N4- (2- (1H-imidazol-4-<BR> <BR> <BR> <BR> <BR> <BR> <BR> yl) ethyl)-2, 4-pyrimidinediamine and N- (3- ( (5-bromo-4- ( (2- (lH-imidazol-4- yl) ethyl) amino)-2-pyrimidinyl) amino)-5- (trifluoromethyl) phenyl)- ethanimidamide To a suspension of 5- (trifluoromethyl)-1, 3-diaminobenzene (105 mg, 0.6 mmol, 1.2 equiv. ) in acetonitrile (10 mL), hydrogen chloride (4. 0M in dioxane, 0.15 mL.

0.6 mmol) and water (0.15 mL) was added 5-bromo-2-chloro-N [2- (1H-imidazol-4- yl) ethyl]-4-pyrimidine (150 mg, 0.5 mmol, 1 equiv. ). The resulting mixture was refluxed overnight. The resulting white suspension was cooled to room temperature and concentrated. The crude residue was purified by HPLC chromatography using acetonitrile/water to afford the title compounds, N2-(3- amino-5-(trifluoromethyl) phenyl)-5-bromo-N4-(2-(1H-imidazol4-yl) ethyl)-2, 4- pyrimidinediamine (50 mg) and N-(3-((5-bromo-4-((2-(1H-imidazol-4-

yl) ethyl) amino)-2-pyrimidinyl) amino)-5- (trifluoromethyl) phenyl)-ethanimidamide (22 <BR> <BR> <BR> mg).<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <P>N2- (3-amino-5- (trifluoromethyl) phenyl)-5-bromo-/V4- (2- (lH-imidazol-4- yl) ethyl)-2, 4-pyrimidinediamine :'H NMR (400 MHz, DMSO-d6) : o/ppm = 2.96 (t, 2H), 3.64 (t, 2H), 6.42 (s, 1H), 7.01 (s, 1H), 7.24 (br t, 1 H), 7.44 (d, 2H), 8.06 (s, 1 H), 8.97 (s, 1 H), 9.39 (s, 1 H).

N-(3-((5-bromo-4-((2-(1H-imidazol-4-yl)ethyl)amino)-2-pyr imidinyl)amino)-5- (trifluoromethyl) phenyl)-ethanimidamide :'H NMR (400 MHz, DMSO-d6) : o/ppm = 2.32 (s, 3H), 2.97 (m, 2H), 3.68 (m, 2H), 7.18 (s, 1H), 7.32 (m, 1H), 7.43 (s, 1H), 7.79 (s, 1 H), 8.13 (s, 1H), 8.36 (s, 1 H), 8.71 (s, 1H), 8.99 (s, 1H), 9.56 (s, 1 H), 9.92 (s, 1 H), 11.34 (s, 1 H).

A15 (4R)-N-[3-[[5-bromo-2-[[3-(2,5-dioxo-1-imidazolidinyl)phenyl ]amino]-5- pyrimidinyl] amino] propyl]-2-oxo-4-thiazolidinecarboxamide and (4R)-N- [3- [[5-bromo-2-[[3-[2,5-dioxo-3-[[(4R)-2-oxo-4-thiazolidinyl]ca rbonyl]-1- imidazolidinyl] phenyl] amino]-4-pyrimidinyl] amino] propyl]-2-oxo-4- thiazolidinecarboxamide To a solution of 3-[3-[[4-[(3-aminopropyl) amino] -5-bromo-2- pyrimidinyl] amino] phenyl-2, 4-imidazolidinedione hydrogen chloride salt (6.9 g, 13.9 mmol), (-)-2-oxo-4-thiazolidinecarboxylic acid (2.5 g, 17 mmol, 1.2 equiv. ) and N,N-diisopropylethylamine (10 mL, 57.4 mmol, 4.1 equiv. ) in dimethylformamide (150 mL) was added 0-(7-azabenzotriazol-1-yl)-N, N, N', N' tetramethyluronium hexafluorophosphate (6.5 g, 17.1 mmol, 1.2 equiv. ) at 0 °C.

The resulting solution was warmed to room temperature and stirred overnight.

The reaction mixture was concentrated under reduced pressure to remove dimethylformamide. The crude residue was triturated in water to give a suspension. The suspension was filtered and the filter cake was washed with water and air-dried (ca. 8 g). The solid was purified by HPLC chromatography using acetonitrile/water to afford the title compounds, (4R)-N-[3-[[5-bromo-2-[[3-

(2, 5-dioxo-1-imidazolidinyl) phenyl] amino]-4-pyrimidinyl] amino] propyl]-2-oxo-4- thiazolidinecarboxamide (2.8 g) and (4R)-N-[3-[[5-bromo-2-[[3-[2,5-dioxo-3-[[(4R)- 2-oxo-4-thiazolidinyl] carbonyl]-1-imidazolidinyl] phenyl] amino]-4- pyrimidinyl] amino] propyl]-2-oxo-4-thiazolidinecarboxamide (72 mg).

N-[3-[[5-bromo-2-[[3-(2,5-dioxo-1-imidazolidinyl)phenyl]a mino]-4- pyrimidinyl] amino] propyl]-2-oxo-4-thiazolidinecarboxamide :'H NMR (400 MHz, DMSO-d6) : 5/pom = 1.71 (m, 2H), 3.14 (m, 2H), 3.36 (m, 1H), 3.42 (m, 2H), 3.64 (t, 1H), 4.04 (s, 2H), 4.23 (m, 1H), 6.99 (d, 1H), 7.01 (t, 1H), 7.59 (d, 1H), 7.72 (s, 1 H), 7.81 (br s, 1 H), 8.16 (m, 2H), 8.29 (s, 1H), 8.34 (s, 1H), 9.99 (br s, 1 H).

(4R)-N-[3-[[5-bromo-2-[[3-[2,5-dioxo-3-[[(4R)-2-oxo-4-thi azolidinyl]carbonyl]- 1-imidazolidinyl] phenyl] amino]-4-pyrimidinyl] amino] propyl]-2-oxo-4- thiazolidinecarboxamide :'H NMR (400 MHz, DMSO-d6) : 6/pom = 1.64 (m, 2H), 3.12 (m, 2H), 3,38 (m, 4H), 3.79 (m, 2H), 4.02 (s, 2H), 5.04 (d, 2H), 5.12 (d, 2H), 6.94 (d, 1 H), 7.34 (t, 1H), 7.56 (d, 1H), 7.69 (s, 1H), 8.08 (s, 1H), 8.18 (s, 1 H), 8.26 (s, 1 H), 8.37 (s, 1 H), 9.79 (br s, 1 H).

Scheme 16

Where R', R2 and R5 are as described in the claims.

Scheme 17

Where R', R2 and R5 are as described in the claims.

Scheme 18 Where R is C1-C4 Alkyl and R', R2 and R5 are as described in the claims.

Scheme 19

Where R', R2 and R5 are as described in the claims. R8 and R9 are as described in the claims but not representing -R10 Schema 19a

NH, 3, Br O/vZ [ r Y I I Br /O rno, c' uH, N i N J N i N NaOH l CH OH Nr i'YN HO O N9jN NH NaB NH "m fl ! Fit Ci Me0 C \ NH Me C \ NOH \ OH !"" I y D- (N-BOC)-Phe HOBt/EDC CICO=Et/NaBH, Br Br N>N - Br Non \ YIN NH NH A ° \ MeOzC N \ \ OH H I HOH CN H HN 'H NaOH/CH, OH BOC Br OV'OV' N N N N 1. ClCO2Et/NaBH, NH > NH 2. HxSO, I Dioxane HOOC4H) 0 HOH, CAN 0 HOOC \ H H I HOHrC \ H I \ NH, 1. (PhO) 2PON | BOC NEt^ ! uene t 2. Pyrrolidine \ Ov O \ N N NIYN HrSO,/Dioxane NU NU I'k 0 N-'N \ N \ N N \ N \ GN NAN G H NAN H' (\/NH= I/ BOC Scheme 20 cocu O 0 0 y coci 0 0 i-PrOH H, N- (CH,),-z N N 0 m-Nitroaniline Cl Ci t C) o) Non O cl ci y ho Nlg T NtN NYO TBSCI/ImidazoZe NYN O NYN O N, fN 0 HN N02 I/I/ O, HNOoNH2 N N H H NN O \ I H H FeiSO, I NH, OH NN O Et-NCO N iN O NN 0 HO I/I/ zou i ) j0 NN'O \ 1 Y'Nx'O \ NYN O HCI l EtOH Nr N'"O T-Yo H'N IN 1

The following Examples have been synthesized according to the above mentioned schemes.

A16 N-[3-[[(2R)-2-Amino-1-oxo-3-phenylpropyl]amino]-5-[[5-bromo- 4-(prop-2- ynyloxy) pyrimidin-2-yl] amino] phenyl] pyrrolidine-1-carboxamide 16a) Methyl 3-amino-5- [ [5-bromo-4- (prop-2-ynyloxy) pyrimidin-2-yl] amino] benzoate A mixture of 5-bromo-2-chloro-4- (prop-2-ynyloxy) pyrimidine (15 g), methyl 3,5- diaminobenzoate (45 g) and concentrated hydrochloric acid (15 ml) in methanol (600 ml) was stirred at 65°C for 8 h. After concentration to half the volume water was added and the precipitate collected by filtration. The precipitate then was treated with sodium hydroxide solution (1 n) and dichloromethane. The organic phase then was washed with water and brine, dried (Na2SO4) and evaporated to dryness to give the title compound (13.8 g).

Mp.: 207. 5-209 OC 16b) Methyl 5-[[5-bromo-4-(prop-2-ynyloxy)pyrimidin-2-yl]amino]-3-[[ (2R) -2- [ [ (1, 1-dimethylethoxy) carbonyl] amino]-1-oxo-3-phenylpropyl] amino] benzoate N-BOC-D-phenylalanine (3.3 g), 1-hydroxy-1H-benzotriazole hydrate (1. 9 g) and N- [3- (dimethylamino) propyl]-/V-ethylcarbodiimid hydrochloride (2.37 g) were stirred in DMF (30 ml) for 30 minutes. Then methyl 3-amino-5- [ [5-bromo-4- (prop-2-ynyloxy) pyrimidin-2-yl] amino] benzoate (3.88 g) were added and the mixture stirred over night. Then ethyl acetate (500 ml) was added and the reaction mixture washed subsequently with hydrochloric acid (0.1 n), saturated NaHC03-solution, water and brine. After drying (Na2SO4) the organic phase was evaporated and the residue subjected to column chromatography (ethyl acetate/dichloromethane) to yield 5.36 g of the title compound.

ESI-MS : 624 and 626 (M+)

16c) 5-[[5-Bromo-4-(prop-2-ynyloxy)pyrimidin-2-yl]amino]-3-[[(2R) -2-[[(1,1- <BR> <BR> <BR> <BR> dimethylethoxy) carbonyl] amino]-1-oxo-3-phenylpropyl] amino] benzoic acid Methyl5-[[5-bromo-4-(prop-2-ynyloxy)pyrimidin-2-yl]amino]-3- [[(2R)-2-[[(1, 1- dimethylethoxy) carbonyl] amino]-1-oxo-3-phenylpropyl] amino] benzoate (1.0 g) was stirred in a mixture of tetrahydrofuran (20 ml), methanol (20 ml) and sodium hydroxide solution (2 n; 20 ml) for 48 h. After evaporation water (50 ml) was added to the residue. On neutralisation with hydrochloric acid (1 n) a precipitate formed. The precipitate was subjected to chromatography on silica gel (hexanes/ethyl acetate/methanol) to yield the title compound (450 mg).

ESI-MS : 610 and 612 (M+) 16d) 1, 1-Dimethylethoxy [(1R)-2-[[3-[[5-bromo-4-(prop-2-ynyloxy)pyrimidin- 2-yl] amino]-5-[l (pyrrolidi n-1-yl) ca rbonyl] ami no] phenyl] amino]-2-oxo-1- (phenylmethyl) ethyl] carbamate 5-[[5-Bromo-4-(prop-2-ynyloxy)pyrimidin-2-yl]amino]-3-[[(2R) -2-[[(1, 1- dimethylethoxy) carbonyl] amino]-1-oxo-3-phenylpropyl] amino] benzoic acid (200 mg), diphenylphosphorylazide (0.75 ml) and triethylamine (0.67 ml) were refluxed in toluene (40 ml) for 1.5 h. Then pyrrolidine (0.26 ml) was added and the mixture refluxed for additional 2 h. After cooling the reaction mixture was diluted with ethyl acetate (50 ml) and subsequently washed with saturated NaHCOs-sotution, water and brine. After drying (Na2SO4) and evaporation the residue was subjected to chromatography on silica gel (hexanes/ethyl acetate) to yield the title compound (126 mg).

ESI-MS : 678 and 680 (M+) 16e) N-[3-[[(2R)-2-Amino-1-oxo-3-phenylpropyl]amino]-5-[[5-bromo- 4-(prop-2- ynyloxy) pyrimidin-2-yl] amino] phenyl] pyrrolidine-1-carboxamide 1, 1-Dimethylethoxy [ (1R)-2-[[3-[[5-bromo-4-(prop-2-ynyloxy) pyrimidin-2- yl] amino]-5- [ [ (pyrrolidin-1-yl) carbonyl] amino] phenyl] amino]-2-oxo-1- (phenylmethyl) ethyl] carbamate (105 mg) and sulfuric acid (0.5 ml ; 2 n) were stirred in dioxane (5 ml) at 85°C for 3.5 h. After cooling and dilution with water saturated NaHC03-solution was added and the resulting precipitate collected by filtration yielding the title compound (76 mg).

ESI-MS : 578 and 580 (M+) A17 (αR)-α-Amino-N-[3-[[5-bromo-4-(prop-2-ynyloxy)pyrimidin-2- yl]amino]-5- (hydroxymethyl) phenyl] benzenepropanamide 17a) 1, 1-Dimethylethoxy [(1R)-2-[[3-[[5-bromo-4-(prop-2-ynyloxy)pyrimidin- 2-yl] amino]-5- (hydroxymethyl) phenyl] amino]-2-oxo-1- (phenylmethyl) ethyl] carbamate To a mixture of 5-[[5-bromo-4-(prop-2-ynyloxy)pyrimidin-2-yl]amino]-3-[[(2R) -2- [ [ (1, 1-dimethylethoxy) carbonyl] amino]-1-oxo-3-phenylpropyl] amino] benzoic acid (100 mg) and triethylamine (25 ut) in tetrahydrofuran (2 ml) was added ethyl chloroformiate (16 NI) at-10°C. After stirring for 15 minutes at 0°C sodium borohydride (19 mg) and methanol (1.6 ml) were added and stirring continued over night at room temperature. After dilution with water the reaction mixture was extracted with ethyl acetate and the organic layer subsequently washed with saturated NaHCOs-sotution and brine. After drying (Na2SO4) and evaporation the residue was subjected to chromatography on silica gel (hexanes/ethyl acetate) to yield the title compound (40 mg).

ESI-MS : 596 and 598 (M+) 17b) (aR)-a-Amino-N- [3- [ [5-bromo-4- (prop-2-ynyloxy) pyrimidin-2-yl] amino]- 5- (hydroxymethyl) phenyl] benzenepropanamide 1, 1-Dimethylethoxy [ (1R)-2-[[3-[[5-bromo-4-(prop-2-ynyloxy)pyrimidin-2-yl] amino] -5-(hydroxymethyl)phenyl]amino]-2-oxo-1-(phenylmethyl)ehtyl] carbamate (22mg) and sulfuric acid (0.3 ml ; 2 n) were stirred in dioxane (3 ml) at 100°C for 2.5 h. After cooling and dilution with water saturated NaHCOs-sotution was added and the resulting preticipate collected by filtration yielding the title compound (10 mg).

A18 3-[[5-Bromo-4-(prop-2-ynyloxy)pyrimidin-2-yl]amino]-5-[(2-hy droxyethyl) amino] benzenemethanol 18a) Methyl3-[[5-bromo-4-(prop-2-ynyloxy)pyrimidin-2-yl]amino]-[( 2hydroxy ethyl) amino] benzoate Methyl3-amino-5-[[5-bromo-4-(prop-2-ynyloxy)pyrimidin-2-yl] amino] benzoate (2 g), glycolaldehyde dimer (0.7 g), sodium cyanoborohydride (0. 49 g) and acetic acid (0.3 ml) were stirred in methanol (100 ml) for 24 h. After evaporation halfconcentrated NaHCOs-sotution and ethyl acetate were added to the residue.

The organic layer then was washed with water and brine, dried (Na2SO4), filtered and evaporated. The residue was chromatographed on silica gel (dichloromethane/methanol) to yield the title compound (1.1 g).

ESI-MS : 421 and 423 (M+) Mp.: 179-179. 5°C 18b) 3- [ [5-Bromo-4- (prop-2-ynyloxy) pyrimidin-2-yl] amino]-5- [ (2- hydroxyethyl) amino] benzoic acid Methyl3-[[5-bromo-4-(prop-2-ynyloxy)pyrimidin-2-yl]amino]-5- [(2- hydroxyethyl) amino] benzoate (350 mg) in a mixture of tetrahydrofuran (6 ml) and sodium hydroxide solution (2 n; 6 ml) was stirred for 48 h at room temperature.

After evaporation the residue was diluted with water and acidified until the product precipitated. Filtration and drying yielded the title compound (340 mg).

MS: 406 and 408 (M+) 18c) 2- [3- (5-Bromo-4-prop-2-ynyloxy-pyrimidin-2-ylamino)-5-hydroxymeth yl- phenylamino]-ethanol To a mixture of 3- [ [5-bromo-4- (prop-2-ynyloxy) pyrimidin-2-yl] amino]-5- [ (2 hydroxyethyl) amino] benzoic acid and triethylamine (57 pl) in tetrahydrofuran (4 ml) was added ethyl chloroformiate (37 uI) at-10°C. After stirring for 15 minutes at 0°C sodium borohydride (44 mg) and methanol (3.6 ml) were added and stirring continued over night at room temperature. After dilution with water the reaction mixture was extracted with ethyl acetate and the organic layer

subsequently washed with saturated NaHCOs-sotution and brine. After drying (Na2SO4) and evaporation the residue was subjected to chromatography on silica gel (hexanes/ethyl acetate) to yield the title compound (59 mg).

CL-MIS : 393 and 395 (M+) A19 Phenylmethyl[3-[[2-[[3-[[(ethylamino)carbonyl]amino]phenyl]a mino]-5- (hyd roxymethyl) pyrimidin4-yl] amino] propyl] carbamate 19a) 1-Methylethyl 2, 4-dichloropyrimidine-5-carboxylate To a precooled solution (-40°C) of 2, 4-dichloropyrimidine-5-carbonyl chloride (5 ml) in tetrahydrofuran (20 ml) isopropanol (2.6 ml) was added dropwise. Then the reaction mixture was allowed to come to room temperature and stirred for 2h. After evaporation the residue was chromatographed on silica gel (dichloromethane/ethyl acetate) to yield the title compound (8.2 g).

1H NMR (300 MHz, CD03) : a/ppm = 1.40 (d, 6H, J = 7 Hz), 5.31 (m, 1 H), 9.0 (s, 1H) 19b) 1-Methylethyl2-chloro-4-[[3-[[(phenylmethoxy)carbonyl]amino] propyl] amino] pyrimidine-5-carboxylate To a solution of 1-methylethyl 2, 4-dichloropyrimidine-5-carboxylate (4.7 g) and ethyldiisopropylamine (3.4 ml) in acetonitrile (250 ml) phenylmethyl [3- aminopropyl] carbamate (4.2 g) was added at 0°C. Subsequently the reaction mixture was stirred over night at room temperature. After evaporation the residue was chromatographed on silica gel (dichloromethane/isopropanol) to yield the title compound (5.9 g).

ESI-MS : 407 and 409 (M+) 19c) 1-Methylethyl2-[(3-nitrophenyl)amino]-4-[[3-[[(phenylmethoxy ) carbonyl] amino] propyl] amino] pyrimidine-5-carboxylate 1-Methylethyl2-chloro-4-[[3-[[(phenylmethoxy)carbonyl] amino] propyl] amino] pyrimidine-5-carboxylate (3 g) and 3-nitroaniline (1 g) were added to a mixture of dioxane (150 ml) and hydrochloric acid in dioxane (4 n; 25 ml). After

stirring at 85°C for 3.5 h the reaction mixture was poured into halfconcentrated NaHCO3-solution. The title compound precipitated and was isolated by filtration (3.5 g).

ESI-MS : 509 (M+) 19d) Phenylmethyl [3-[[5-(hydroxymethyl)-2-[(3-nitrophenyl) amino] pyrimidin-4-yl]amino]propyl]carbamate To a solution of 1-Methylethyl 2-[(3-nitrophenyl)amino]-4-[[3-[[(phenylmethoxy) carbonyl] amino] propyl] amino] pyrimidine-5-carboxylate (1.7 g) in tetrahydrofuran (100 ml) LiAIH4 (410 mg) was added in portions at 0°C. After 6h at 0°C the reaction was quenched by addition of saturated ammonium chloride solution. Ethyl acetate was added and the mixture filtered. After evaporation of the filtrate the residue was partitioned between water and dichloromethane. The organic layer was washed with brine, dried (Na2SO4), filtered and evaporated.

Chromatography of the residue on silica gel (dichloromethane/methanol)) yielded the title compound (650 mg).

ESI-MS : 453 (M+) 19e) Phenylmethyl [3-[[5-[[[(1,1-dimethylethyl)dimethylsilyl] oxy] methyl]-2- [ (3-nitrophenyl)amino]pyrimidin-4-yl]amino]propyl]carbamate A DMF solution (5 ml) of phenylmethyl [3- [ [5- (hydroxymethyl)-2- [ (3- nitrophenyl) amino] pyrimidin4-yl] amino] propyl] carbamate (250 mg), chloro (1,1- dimethylethyl) dimethylsilane (190 mg) and 1H-imidazole (170 mg) was stirred at room temperature (48 h). After addition of ice water the mixture was extracted with ethyl acetate. The organic layer was washed with water, brine, dried (Na2SO4), filtered and evaporated. Trituration of the residue with diethyl ether yielded the title compound (300 mg).

ESI-MS : 567 (M+) 19f) Phenylmethyl[3-[[2-[(3-aminophenyl)amino]-5-[[[(1,1-dimethyl ethyl) dimethylsilyl] oxy] methyl] pyrimidin-4-yl] amino] propyl] carbamate Phenylmethyl[3-[[5-[[[(1,1-dimethylethyl)dimethylsilyl]oxy]m ethyl]-2-[(3- nitrophenyl) amino] pyrimidin-4-yl] amino] propyl] carbamate (244 mg), dissolved in

ethanol (30ml), was slowly added to a mixture of FeS04 heptahydrate (1.25 g), concentrated ammonia solution (25%; 1.25 ml) and water (5 ml). After refluxing for 3 h the mixture was filtered and the filter cake washed with ethyl acetate.

The filtrate was washed with water and brine, dried (Na2SO4), filtered and evaporated to yield the crude title compound (230 mg), which was used in the next step without further purification.

19g) Phenylmethyl [3-[[5-[[[(1,1-dimethylethyl)_dimethylsilyl] oxy] methyl]-2- [[3-[[(ethylamino)carbonyl] amino] phenyl] amino] pyrimidin-4- yl] amino] propyl] carbamate To a solution of phenylmethyl [3-[[2-[(3-aminophenyl)amino]-5-[[[(1, 1- dimethylethyl) dimethylsilyl] oxy] methyl] pyrimidin-4-yl] amino] propyl] carbamate (225 mg) in acetonitrile (5 ml) ethyl isocyanate (33 µl) was added and the mixture stirred for 18 h at room temperature. Then 5 drops of ammonia solution (25%) were added and the precipitated title compound isolated by filtration (158 mg).

ESI-MS : 608 (M+) 19h) Phenylmethyl [3-[[2-[[3-[[(ethylamino)carbonyl]amino]phenyl]amino]-5- (hydroxymethyl) pyrimidin-4-yl] amino] propyl] carbamate Phenylmethyl [3-[[5-[[[(1,1-dimethylethyl)dimethylsilyl] oxy] methyl]-2- [ [3- [[(ethylamino) carbonyl] amino] phenyl] amino] pyrimidin-4- yl] amino] propyl] carbamate (145 mg) were stirred in a mixture of ethanol (10 ml) and hydrochloric acid (4 n; 1 ml) for 3 h at room temperature. Then halfconcentrated NaHCOs-sotution and ethyl acetate were added.

The organic phase was washed with water and brine, dried (Na2SO4), filtered and evaporated to yield the title compound (120 mg).

ESI-MS : 494 (M+)

20A <BR> <BR> <BR> <BR> <BR> 1-(4-{5-Bromo-4-[2-(3H-imidazol-4-yl)-ethylamino]-pyrimidi n-2-ylamino}-<BR> <BR> <BR> <BR> <BR> <BR> phenyl)-3-cyclopropyl-thiourea 20a) 2,2, 2-TrifluoroN- (4-nitro-phenyl)-acetamide 4-Nitroaniline (50 g) was dissolved in pyridine (500 ml) and cooled to 0°C.

Trifluoroacetic acid anhydride (52.2 ml) was added slowly at 0°C and allowed to stir at room temperature overnight. The pyridine was distilled off under reduced pressure and the solid partitioned between ethyl acetate and water. The organic phase was seperated, dried over magnesium sulfate and the solvent was removed. The crude product was recrystallized from diisopropyl ether to yield 82 g (97 %) of 2,2, 2-Trifluoro-N- (4-nitro-phenyl)-acetamide which was directly used without purification in the next step.

20b) 2,2, 2-TrifluoroN- (4-amino-phenyl)-acetamide 2,2, 2-Trifluoro-N- (4-nitro-phenyl)-acetamide (30 g) was dissolved in ethyl acetate (500 ml) and Pd/C (10%, 3 g) was added. After hydrogenation (1 bar, room temperature) for 3 h the catalyst was filtered off and the solvent was removed under reduced pressure. The crude product was recrystallized from diisopropyl ether to yield 20.6 g (79%) of 2,2, 2-TrifluoroN- (4-amino-phenyl)- acetamide. ESI-MS : 205.

20c) N- (4- 5-Bromo-4- [2- (3H-imidazol-4-yl)-ethylamino]-pyrimidin- 2ylamino}-phenyl)-trifluoro acetamide 5-Bromo-4- [2- (1 H-imidazol-4-yl)-ethylamino-2-chloro pyrimidine (5g, prepared according to procedure 1b) was dissolved in acetonitrile (100ml), 2,2, 2-TrifluoroN- (4-amino-phenyl)-acetamide (3.37 g) and a solution of HCI in dioxane (4 M, 10 ml) were added and the reaction mixture was heated under reflux overnight. The reaction was cooled to room temperature and the precipitate was filtered and washed with acetonitrile. Yield of N- (4- {5-Bromo-4- [2- (3H-imidazol-4-yl)- ethylamino]-pyrimidin-2-ylaminoFphenyl)-trifluoro acetamide: 7.6 g (90 %). ESI- MS: 471.

20d) N2- (4-Amino-phenyl)-5-bromo-N4- [2- (3H-imidazol-4-yl)-ethyl]-pyrim idine-2, 4-diamine N- (4- {5-Bromo-4- [2- (3H-imidazol-4-yl)-ethylamino]-pyrimidin-2-ylamino}-phenyl)- trifluor acetamide (1g, 1.9 mmole) was dissolved in THF (10 ml), MeOH (10 ml) and water (5 ml) and LiOH (455 mg) was added in one portion at room temperature. The reaction mixture was stirred at room temperature for two days, the solvent removed under reduced pressure. The residue was dissolved in ethyl acetate and water and extracted with ethyl acetate (3x). The combined organic layers were combined and dried over magnesium sulfate. After evaporation of the solvent one obtains 350 mg of N2- (4-Amino-phenyl)-5- bromo-N4- [2- (3H-imidazol-4-yl)-ethyl]-pyrimidine-2, 4-diamine. ESI-MS : 375.

20e) 1- {5-Bromo4-[2-(3H-imidazol-4-yl)-ethylamino]-pyrimidin-2- ylamino}-phenyl)-3-cyclopropyl-thiourea Cyclopropyl amine (0.275 mmole) was dissolved in THF (2 ml) and thiocarbonyl diimidazole (0.28 mmole) was added. The reaction was stirred at room temperature overnight and N2- (4-Amino-phenyl)-5-bromo-N4- [2- (3H-imidazol-4- yl)-ethyl]-pyrimidine-2, 4-diamine (0.26 mmole) was added as a solution in THF (3 ml) and DMF (1ml) and the reaction was stirred overnight. After removal of the solvents under reduced pressure the crude product was purified by flashmaster chromatography (dichloromethane : MeOH 9: 1) to yield 12.5 mg of 1- (4- {5-Bromo-4- [2- (3H-imidazol-4-yl)-ethylamino]-pyrimidin-2-ylamino}-phenyl)- 3-cyclopropyl-thiourea. ESI-MS : 474.

Scheme 21 Scheme 22 H 0 Hz xi N derivative \"j Propinyl Jl,, derivative prepared in analogy to Br ber 21d C/I \ H H H H yn ß N N /H H H han y han HN I'S Han N N IJ I/ H ^ Br Br H Br 26 25 24

The following Examples have been synthesized according to the above mentioned schemes.

A21 <BR> <BR> <BR> <BR> <BR> 1- (4- 5-Bromo-4- [2- (3H-imidazol-4-yl)-ethylamino]-pyrimidin-2-ylamino}-<BR&g t; <BR> <BR> <BR> <BR> <BR> phenyl)-3-cyclopropyl-thiourea 21a) 2,2, 2-TrifluoroN- (4-nitro-phenyl)-acetamide 4-Nitroaniline (50 g) was dissolved in pyridine (500 ml) and cooled to 0°C.

Trifluoroacetic acid anhydride (52.2 ml) was added slowly at 0°C and allowed to stir at room temperature overnight. The pyridine was distilled off under reduced pressure and the solid partitioned between ethyl acetate and water. The organic phase was seperated, dried over magnesium sulfate and the solvent was removed. The crude product was recrystallized from diisopropyl ether to yield 82 g (97 %) of 2, 2, 2-Trifluoro-N- (4-nitro-phenyl)-acetamide which was directly used without purification in the next step.

21b) 2,2, 2-TrifluoroN- (4-amino-phenyl)-acetamide 2, 2, 2-Trifluoro-N- (4-nitro-phenyl)-acetamide (30 g) was dissolved in ethyl acetate (500 ml) and Pd/C (10%, 3 g) was added. After hydrogenation (1bar, room temperature) for 3 h the catalyst was filtered off and the solvent was removed under reduced pressure. The crude product was recrystallized from diisopropyl ether to yield 20.6 g (79%) of 2, 2, 2-TrifluoroN- (4-amino-phenyl)- acetamide. ESI-MS : 205.

21c) Ng445-Bromo4-[2-(3H-imidazol4-yl)-ethylamino]-pyrimidin-2-yl amino}- phenyl)-trifluoro acetamide 5-Bromo-4- [2- (1 H-imidazol-4-yl)-ethylamino-2-chloro pyrimidine (5g, prepared according to procedure 1b) was dissolved in acetonitrile (100ml), 2,2, 2-TrifluoroN- (4-amino-phenyl)-acetamide (3.37 g) and a solution of HCI in dioxane (4 M, 10 ml) were added and the reaction mixture was heated under reflux overnight. The reaction was cooled to room temperature and the precipitate was filtered and washed with acetonitrile. Yield of N- (4- {5-Bromo-4- [2- (3H-imidazol-4-yl)- ethylamino]-pyrimidin-2-ylaminoFphenyl)-trifluoro acetamide: 7.6 g (90 %). ESI- MS : 471.

21d) N2- (4-Amino-phenyl)-5-bromo-N4- [2- (3H-imidazol-4-yl)-ethyl]- pyrimidine-2, 4-diamine N- (4- {5-Bromo-4- [2- (3H-imidazol-4-yl)-ethylamino]-pyrimidin-2-ylamino}-phenyl)- trifluor acetamide (1g, 1.9 mmole) was dissolved in THF (10 ml), MeOH (10 ml) and water (5 ml) and LiOH (455 mg) was added in one portion at room temperature. The reaction mixture was stirred at room temperature for two days, the solvent removed under reduced pressure. The residue was dissolved in ethyl acetate and water and extracted with ethyl acetate (3x). The combined organic layers were combined and dried over magnesium sulfate. After evaporation of the solvent one obtains 350 mg of N2- (4-Amino-phenyl)-5- bromo-N4- [2- (3H-imidazol-4-yl)-ethyl]-pyrimidine-2, 4-diamine. ESI-MS : 375. <BR> <BR> <BR> <BR> <BR> <BR> <P>21e) 1-(445-Bromo-4-12q3H-imidazol4-yl)-ethylamino]-pyrimidin-2-y lamino}- phenyl)-3-cyclopropyl-thiourea Cyclopropyl amine (0.275 mmole) was dissolved in THF (2 ml) and thiocarbonyl diimidazole (0.28 mmole) was added. The reaction was stirred at room temperature overnight and N2- (4-Amino-phenyl)-5-bromo-N4- [2- (3H-imidazol-4- yl)-ethyl]-pyrimidine-2, 4-diamine (0.26 mmole) was added as a solution in THF (3 ml) and DMF (1ml) and the reaction was stirred overnight. After removal of the solvents under reduced pressure the crude product was purified by flashmaster chromatography (dichloromethane : MeOH 9: 1) to yield 12.5 mg of 1- (4- {5-Bromo-4- [2- (3H-imidazol-4-yl)-ethylamino]-pyrimidin-2-ylamino}-phenyl)- 3-cyclopropyl-thiourea. ESI-MS : 474.

A21A 1- (4- {5-Bromo-4- [2- (3-imidazol-4-yl)-ethylamino]-pyrimidin-2-ylamino}- phenyl)-3-cyclopropyl-urea Cyclopropyl amine (0.275 mmole) was dissolved in THF (2 ml) and carbonyl diimidazole (0.28 mmole) was added. The reaction was stirred at room temperature overnight and N2- (4-Amino-phenyl)-5-bromo-N4- [2- (3H-imidazol-4- yl)-ethyl]-pyrimidine-2, 4-diamine (0.26 mmole, prepared according to procedure 21) was added as a solution in THF (3 ml) and DMF (1ml) and the reaction was

stirred overnight, After removal of the solvents under reduced pressure the crude product was purified by flashmaster chromatography (dichloromethane : MeOH 9: 1) to yield 23 mg (19 %) of 1- (4- {5-Bromo-4- [2- (3-imidazol-4-yl)- ethylamino]-pyrimidin-2-ylamino}-phenyl)-3-cyclopropyl-urea. ESI-MS : 458.

A22 5-Bromo-N2- (4-butylamino-phenyl)- N4- [2- (3H-imidazol-4-yl)-ethyl]- pyrimidine-2, 4-diamine N2- (4-Amino-phenyl)-5-bromo-N4- [2- (3H-imidazol-4-yl)-ethyl]-pyrimidine-2, 4- diamine (1 g, 2.6 mmole, prepared according to procedure 21) was dissolved in MeOH (10 ml), butanal (0.261 ml, 2.9 mmole) was added at room temperature and the reaction mixture was stirred at room temperature for 20 minutes.

Sodium cyanoborohydride (266 mg, 3.6 mmole) was added and the reaction mixture was stirred at room temperature overnight. After extraction with ethylacetate/bicarbonate solution (3x) the combined organic layers were washed with saturated NaCI-solution, dried over magnesium sulfate and evaporated. The crude product was purified by flashmaster chromatography (dichloromethane : MeOH 95: 5) to provide 5-Bromo-N2- (4-butylamino-phenyl)- N4- [2- (3H-imidazol-4-yl)-ethyl]-pyrimidine-2, 4-diamine (130 mg). ESI-MS : 431.

A23 N- (4- 5-Bromo-4- [2- (3H-imidazol-4-yl)-ethylamino]-pyrimidin-2-ylamino}- phenyl)-4-methanesulfonyl-3-nitro-benzamide 23a) 4-Methylsulfanyl-3-nitro-benzoic acid 4-Chloro-3-nitrobenzoic acid (10 g) were suspended in ethanol (50 ml) and water (50 ml) and sodium bicarbonate (4.16 g) was added in portions. The reaction mixture was heated at reflux for 5 minutes and NaSMe (6.95 g) was added in one portion at this temperature. The reaction was stirred under reflux for further 3 hours and then cooled to ambient temperature. The precipitate was collected by filtration to provide 4-Methylsulfanyl-3-nitro-benzoic acid (11 g, quantitative). This

material was used without further purification for the following step (procedure 23b) 23b) 4-Methanesulfonyl-3-nitro-benzoic acid 4-Methylsulfanyl-3-nitro-benzoic acid (1 g, 4.69 mmole) was dissolved in methanol (25 ml) and cooled to 5°C. A solution of Oxone (E) (5.8 g) in water (20 ml) was added portionwise at the same temperature. The reaction mixture was allowed to stir overnight at ambient temperature, methanol was removed under reduced pressure. The suspension was diluted with water and the solid was filtered off and dried in vacuum to provide 4-Methanesulfonyl-3-nitro-benzoic acid in 89% yield (960 mg). ESI-MS : 246.

23c) N- (4- 5-Bromo-4- [2- (3H-imidazol-4-yl)-ethylamino]-pyrimidin-2- ylamino}-phenyl)-4-methanesulfonyl-3-nitro-benzamide 4-Methanesulfonyl-3-nitro-benzoic acid (72 mg, 0. 29mmole) was dissolved in DMA (3 ml) and thionyl chloride (0.29 mmole) was added at ambient temperature. After the mixture was stirred for 5 minutes N2- (4-Amino-phenyl)-5- bromo-N4- [2- (3H-imidazol-4-yl)-ethyl]-pyrimidine-2, 4-diamine (100 mg, 0.26 mmole, prepared according to procedure 21) was added and the reaction was allowed to stir overnight. After extraction with bicarbonate solution and ethyl acetate (3x) the combined organic layers were dried over magnesium sulfate and the solvent was removed under reduced pressure. The crude product was purified by flashmaster chromatography on silica gel to provide 37 mg of N- (4- {5-Bromo-4- [2- (3H-imidazol-4-yl)-ethylamino]-pyrimidin-2-ylamino}-phenyl)- 4- methanesulfonyl-3-nitro-benzamide (23 % yield). ESI-MS : 602.

A 24 [4- (5-Bromo-4-prop-2-ynylamino-pyrimidin-2-ylamino)-phenyl]-car bamic acid butyl ester N2- (4-Amino-phenyl)-5-bromo-N4-prop-2-ynyl-pyrimidine-2, 4-diamine (0.31 mmol, prepared in analogy to procedure 21) was dissolved in THF (20 ml), triethyl amine (0.33 mmole) and butyl chloroformate (0.33 mmole) were added

at room temperature and the reaction was stirred at this temperature until the starting material disappeared (TLC, 3h). The reaction was poured into water and [4- (5-Bromo-4-prop-2-ynylamino-pyrimidin-2-ylamino)-phenyl]-car bamic acid butyl ester was isolated by filtration. Yield : 91 mg (70 %). ESI-MS : 419.

A25 1-Allyl-3- [4- (5-bromo-4-prop-2-ynylamino-pyrimidin-2-ylamino)-phenyl]- thiourea N2- (4-Amino-phenyl)-5-bromo-N4-prop-2-ynyl-pyrimidine-2, 4-diamine (100 mg, 0.3 mmole, prepared in analogy procedure 21) was dissolved in acetonitrile (10 ml) and allyl isothiocyanate (1 ml) was added at room temperature. The reaction mixture was heated under reflux for 3 hours, the solvent removed under reduced pressure and 1-Allyl-3- [4- (5-bromo-4-prop-2-ynylamino-pyrimidin-2- ylamino)-phenyl]-thiourea was crystallized from acetone/ethyl acetate/ hexanes. Yield 37 mg. ESI-MS : 418.

A26 1- [4- (5-Bromo-4-prop-2-ynylamino-pyrimidin-2-ylamino)-phenyl]-3-e thyl- urea N2- (4-Amino-phenyl)-5-bromo-N4-prop-2-ynyl-pyrimidine-2, 4-diamine (100 mg, 0.3 mmole, prepared in analogy to procedure 21) was dissolved in acetonitrile (10 ml) and ethyl isocyanate (0.5 ml) was added at room temperature. The reaction mixture was heated under reflux for 5 hours and then cooled to room temperature and stirred overnight. The solid was filtered off and dried under high vaccum to provide 47 mg of 1- [4- (5-Bromo-4-prop-2-ynylamino-pyrimidin-2- ylamino)-phenyl]-3-ethyl-urea. ESI-MS : 390.

A27 1-Methyl-1H-imidazole-4-sulfonic acid [4- (5-bromo-4-prop-2-ynylamino- pyrimidin-2-ylamino)-phenyl]-amide N2- (4-Amino-phenyl)-5-bromo-N4-prop-2-ynyl-pyrimidine-2, 4-diamine (100 mg, 0.3 mmole, prepared in analogy to procedure 21) was dissolved in acetonitrile (10 ml) and triethylamine (1 ml) and 1-Methyl-1 H-imidazole-4-sulfonyl chloride (120 mg, 0.66 mmole) was added at room temperature. The reaction mixture was stirred under reflux for 5 hours, the solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel (ethyl acetate: hexanes 1: 1). Yield 41 mg of 1-Methyl-1 H-imidazole- 4-sulfonic acid [4- (5-bromo-4-prop-2-ynylamino-pyrimidin-2-ylamino)-phenyl]- amide. ESI-MS : 463.

The following examples were prepared in analogy to the compounds described above. Example Structure ESI-MS Mol-Weight ^'nor UN NON zu F F 29 °H f HN-311 N'kN OH Br 30"0- . Nb 349 HAN Ber Bu 31 Br I HN N'-'N Bf IBr Non ber 33 0 Y 367 NON UN Br /ou bu 33 ° HN non un Br 34 OH nu 349 HNI NON Ber riz j0" UN NN 0--Q 377 Br non o 377 HN 37 OH zou Br N'ka 3 9 HNI Non Han Ber H fez N non 361 un Ber H Br 3g H F N F 415 NON N-\ N !" Br 40 NH2 1 319 HNI NON 'N Bu Br 41 u N F 429 F F HN N_ \ N NJS3/\ H \ Br 42 ° N F 592 BER F NX 463 HN v OII 45 NN N \/ F Br 43 Br bu 43 Ni 347 I HNs N/f E NON zu N 44 or N 463 i Nu N HAN r / NON 45 Ber 361 zon I N\/N HIRN N 46 N 439 NON Han, a NEZ 47 Br oh 0 nu, NHz In H N 48 Br I \ in 48 426 Non N HN NH N 49 Br 'vim 49 N zu N H 50 Br 50 Br N N 459 N N 459 fly \) non N H Han N 51 N N 417 N N 417 NyN N IN H Han 52 ber 52 r n NON N H HN n 53 Br N CL CI/A_ ci Ei3 Br NHZ HN n N l 54 S 395 n Hlln non HNI'N N 395 NN un 55 i 370 N N HIYN X H N N H 56 Br N 387 ft T NN NyN 57 Br /nez ru NON I N\ N HIYN 58 N 387 NyN ""0 59 or 59 ber N 385 NON HIYN 60 Br N 403 I N, N 403 HYMN HAN N 61 Br gv 384 I "dz Zur N N N 62 ber Non HAN N NHZ T H Non NON N HAN Nez N 64 l H 443 _ 65 N sc N \X) 441 64 ber N 443 "y-s NON H Han 65 Br N N 441 Non N HIYN N 66 Br N N 459 II I N/N N HN Han 67 Br H N y 458 N_rN N H HNJaN N zu 68 Br H N N 445 NON N Zu HAZAN 0 ""519 in | S1 9 NON N HAN HNI I NHz N-' 70 N N 440 N rN N Y H HN N Nez N 71 H F 7 1 /I F 471 han, a HN-v HZ NH Br H bu 72 NHi I 375 HN NN N===\ I nu OH bu 73/NHz nia 308 7X 308 N 'N N " 74 H F F NON N F 443 o HN N"k'N !" Br 75 F H /I"F 404 Non HAN- Non N /^1\ F F F F F 76 jj N F 485 ! \ F F HN-" HN ' N''N N HNJ : : R BER H Bu Dur NHZ 389 Han \ t" Br N H Br 78 nui 347 HNI 80 H Br F 499 F 499 HN HN' N'IN N N ^ I\/NH H Br 80 0 N F 418 NON '/C\ F Ho_ v N'\ N I F H F F 81 F HAN non I00 zoll F ZU FF 82 322 Han HAN NON zu F F HE F F F 83 F N 432 I I. F HAN HAN N " F 84 0 84, p non HN Ber Ber Ou Bu N-N ber Br Y-O Blr 86 O. 0 _ _ N 286 285, 262 Non NHZ yins OH 87 0 H 344 343, 385 N NON NU / 88 oN,. o 42g 428, 249 J'N Br W Nv i YNH NHz nu N 1 HONH 344 343, 385 ))) H NON NON 90 90I 0. +. 0 286 285, 262 NlS N % N y N NON NU HO" ho 91 0 u 358 357, 412 HN'0 H fly NON NU 92 311 310, 355 H IZ-1 NEZ N N NON / 93 356 355, 352 o Nu 11. NHz in O HN\ ^/N _ 94 v 422 421, 377 NH NON HAN N lu F H HN \ N F 95 \ ol 508 508, 532 \ NN O I/ H H N. N 0 HN) ! _ 96 OXO HFt H g6 0 oH \ 0% o 467 466, 452 f T Non ! ! i. %- 97 Br i 97 422 421, 249 98 Br IY H HN \ N 98 Br Q O gg No¢ N 378 377, 197 NN HN \ NH= 0 Q O 99 Br 'S79 578, 468 N N NHZ H HN \ N Y N N H \ C) NYNH 100 OH H H 347 346, 35 CHO N N in O HN N. 115 101 Br /o 453 452, 469 NyN rOH HN \ N\ Oh 102 ber Q O 102 B Ir/ 102 (Jqz 466 465, 302 'V -OH HAN N Hein N 103 Q O 103 418 417, 47 NON NU H Han N 0 HA HO 104 Br 550 549, 43 'V N\ N 1'nu2 NEO ERR /O/ N ° I H 105 552 551, 45 NyN NH2 NON 'NHZ H' HN N H N °II 106 Br H _ NNHz 435 434, 34 NON HN ONyNH \NNH Y 0 1076r' 478 477, 27 o"Y" N\/N OH zozo O'NH 108 Br NH. H H rl)--N 582 581, 52 N N 0 H HN Ny 0 N 0 109 B NHZ 109 I4N Hs 582 581, 52 N ! H ! Non 0 IN U 110 i. JL, 320 319, 161 NN NON V Br 111 HN OH 364 363, 214 HAN N NON V Or bu 112 112 0 531 530, 42 HN N oh HN\/O N 8ruz bu 113 i o 545 544, 447 HN N-Y HN O N \-N Bu ole bu 114 je ; 431 430304 HO NHZ NON Br 115 445 444, 331 Nu2 ber Non - 8r O Br 116 } il 438 437, 339 HN v N H I X Ss Ou Br 117 i 426 425, 284 H I N"N H OH Wv Br 118 o HNJAN NH, 467 466, 337 H ION N Bu Br 119 0 119 NX 467 466, 337 1"L N \ N Ber Br zoo 120 t 503 502, 367 "A T Non Vu Br zon Blr 121/H- HN 426 425, 284 ZU Vu Or bu 122 i o X U 468 467. 33 i"t JL COOH Vu Br 123. , NH= 483 482, 34 HN an NHz N \N 0 oh Br zu oH 484 483, 33 HO HO Ber B \r 125 0 125 HNANX 454 453, 30 )" /II OH Non Bf 126 0 w 126 0 454 453, 30 jyo N (tA N N - Br 127. 407 406, 24 HN N OH H NH, N N Vu Br po 128/o HN'AN OH 482 481, 31 H I N'kan Ber Br 129 < 407 406, 24 HN H Y OH 'NHz N-N NN V. Br 130 I, o 130 0 NH2 405 404, 27 HO Lia kr-l0 Br zu 131 1 0 NH, 483 482, 34 HAZAN NII \ N NON O Oh zu 132 NHz 481 480, 37 HN N I'kan N \N O Br 133 481 480, 37 ill Han N Ho _an N"\ N _ Br 134 134 1 N 361 360, 214 un NN - N Br 135 H F Xz NCW 415 414, 184 HN- ° NON HAN Bu Ber N HNv 429 428, 211 /I N HN N-N HAN Ber 1373 H Br 137 ° "f YF 592 591, 308 H F F Han 0 NI N'YF H F /NaF OH ! H 8r 138 138 NH2 333 332, 204 HN NON zu H \ Br 139 I NHz JLJJ 319 318, 177 HO NON Y NHz 140 nu Br 140/nu= 375 374, 244 HN I-rl H nu N !" Bu 141 F N-V--F 471 470, 251 o HN N'N NH N H Br 142 H. __ H F 404 403, 285 N'kN N-\ N NON ZU 143 0 ) if N F 485 484, 278 H Ho Han NU NH Ber Br 144. XoNH2 i) J 308 307, 278 HAN N F rj" FF F F 145 F- H F N 443 442, 237 ° HN N _ I-r-l-H Br N ! 389 388. 271 HAN NU (//I. NH zon H Br 147 NH2 347 346, 230 H N NON N bu Br 148 H F- N F 499 498, 305 W Nw Han Han Non ZON 149 0 ! H 149 ° F 418 417, 312 N4N F HAN HN zizi N F H F F 0 H 0 I'l'400 399, 395 un HAN non N F H FCS 151/I NHz nu2 322 321, 305 HN Non N N F H 152 H F 152 H F /N F 432 431, 339 0 F HAN Han NN F H F% CF 153 F F 153/ 153 391 390, 235 HO NON V - or IBr 154 NH2 336 335, 331 HN Non N NEZ F H 155 HO 155 Ho _- 349 348, 199 i HN N"N I 0 Br 156 o 0 377 376, 209 han HAN non or Br 157 OH 349 348, 199 HN Non ou Br 158 ° 376, 209 i ° 377 Han NON O Br 159 9 HN 377 376, 209 HN N-N 0 Br 160, 405 404, 262 un HN N'-N Br Br 161 OH 435 434, 336 HN N"N 0 H Br 6 Br 162 °II Nlk 376 375, 224 i ! J" HN N) % N HO) o Br 163"o i 163 321 320, 145 HN NON zou Br 164 HN \ I Nw° 350 349, 143 N/t N NON zou Br 165 OH 377 376, 209 HN Non N-N Br O Bf 166 N 0 391 390, 235 HN4f HAN V 8r IBr 167 0 oH 377 376, 209 HN HAN Or bu 168 HN 391 390, 235 H \/\/\ NON V.-. Br Br 169 404 403, 278 N JK N N N HAN zu O Br 170 O _ 0 377 376, 209 HN N"kN 0 Br 171, oH 338 337, 300 HN N"kN Ou FF 172 OH HNJO"'0 363 362, 182 Han Non Br 173 : :-o HN v HN 482 481, 348 HN I N 'N 'OH Br 174 NHZ HNX ° 390 389, 251 HN NON Br 175 335 334, 172 OH HN N-N zu Br 176 HN" 349 348, 199 HO OH N N V. Br 177 Br ! j) 367 366, 645 N"N ci N-\ N N N - Bu 178 oH 350 349, 187 HN NHZ N-N v. Br 179 724 723, 236 ci a 0 HAN cl v Ber H CI O Br 180 OH 533 532, 190 o HN N N N \ Br 181 Br 181/ O4Br 716 715, 194 bu 0 0 HN N N"kN H Ber bu Br 182 0" ci 537 536, 211 HN Nj----q HAN ci NON bu ber 183 385 384. 24 HAN \// N \_N N NH X BER Ber 184 zu 474 473. 401 HN Non v-i N--, N Br \\NH 185 Ho ", aNyN 458 457. 334 HN HN"-- , nu J. i _ HAN Br IjggHH 186 oC \ 506 505. 375 o HN NON Irl-H N-\ N ber NH 187 N VN 474 473. 376 un HNI Non nu ly-l-H bu Ber 188oT N yN 502 501. 387 zozo HN,, a HAN NU ly-l-H ZON Br bu N NO 189 < ° 490 489. 375 o Han Nu I/ ,. NH ber Br Br 190 F N 433 432. 238 TY" HAN HAN COOH H Br 191 N N N y N-o 464 463. 377 o HN Non N--"OH COOH BER Bu 192/N'NOOH 470 469. 337 0 HNI NN - COOH ! H 8r 1QQHHo 572 571. 458 o HNja 0 0 NoX N I//I,. NH H H Bu Br 10/1HH y 500 499. 414 o Han Han I/ _ . NH H H Br 195 r", 195 8r 431 430. 352 HN N N I, _NH zon H 6r 196 H H NN 476 475. 417 Han s N ill N N -NH Br N bu H H H 603 602. 562 HN- S U. HN I S I N I NN N=\ eH Br Ber H 198 H H N N 474 473. 401 s N""N N\ NH Bu H Br H 199 H H - Ny N 462 461. 39 s N N\ Bu H _N "200Hz 200 '0 602 601. 44 Y° O O "aN N'\ N N HAN Oh Bu Br 201 H'o 674 673. 614 'all 0 Han 0 Han NH NH j N Br H 202 H H 522 521. 42 Han N"-N N==\ NH _N Bu 203 Q 556 555. 521 ONH NEZ HN HN XN v A _N 204 Br H N N 443 i\ N// 443 NON H HN N 205 ° HNe NH2 401 HO NN N==\ NH H bu H 206 HN I °H 388 H N l)-l N N NeH~¢N/> N'-.'N Bu H ber 's : NHZ 485 Han N eH _ . H I 208 O NHz 401 HN HAN LU NH N Br H 209 0 v Zu 486 , aNYN") HAN HAN NON NU BRU bu H 210 s- HN S. z non N NJ N O I N brd N-v Nl H Br 211 HN't NH2 387 H , ill N - Br 212. . H NN BU H 212 H Ber 212 H HN \ N HAN NN N=\ NH N Bu H 213 H rrY 416 o HAN BRU NH N Br H 214 I/I 416 JL N o S 1-0 H Nu N .- OH Br 215 cl, 9 431 HNNH- i H Bu H N N Bu H 216 H 9 N-S-CH3 465 11 HN HN NN N NI,, N N IN N Br H 217/ oH 402 HAN 9 H N NJ Br H 218 0 /I o. cH3 416 HN N N N NON H Ber zoo 219 416 HN H NHZ JL NH /N Br H 220 HN470 t H V-J N BER L 221 0 Ji N NH 430 HNI 9 N N H N Br H 222/O NHz 430 Han N H Ber ber H 223 222 Nl-l 426 9 N/) ~ HN N'\ N H H Br 2240 'oh Han HN" H C") Bu H 225, oh Il 416 225 0 H Non N-N N Bu 226 O 416 I HN \ OH A H 1- HAN N N N N Br H 227 cl, HN'6 372 HN ! H Riz N N Br H 228 N 471 OH HN I H N'I', N N> i Bu H 229 OH 229 H HN H NN N In Non Bu H ber N 457 HNI H N"N, r\ Ber N-N ber H 231 o H N 427 ruz HN 1 N In BER 232 Br JLJi cl 444 HN N N itch NN N3 N CH3 NU Br H 233 0 431 HN N0'CH HN N O N N H NN N=\ NH Zozo Bu H i H H HN N N H H N N N7=\ NH N 235 HN N 463 n ° ° HNI N-N H Br 236ho c 3 431 Han 0 N N NH Br H bu H ° 402 ) H Han N Ber 238 HH Br H 238 H H NN 418 HAN NON N Br H Br H 239 \ I 373 I HN NHz N'-'N N"N rr\ Ber Br 240 0 OH 417 HN NH 2 HN \ NHz Z N'u N Bu H 241 456 HN N N H H N N NN H Bu H zon ber H 242 4$6 HN N N O H U ! H y N N N==7\ NH Erz zoo 243 HUI f JL NN H CH3 eH Br a ~ N Hz Z NN-N I _ \ N/v''Nl Br H 245 H H NN 390 H N 0 HAN non Bu H Br 246 0 cl 459 HN-N-OCH- t H NN N==\ NH Bu H zoo 247 492 t H H H H N N N==\ NH N Br 248 0 I'579 HN"'"N H N N O N'N 0 N N OH Br J ! J JJ 581 HN-N-N 249 Ja Jt 492 eH 11 H0 N"N 0 HH \/OH Bu B r 544 H N NN < N N Bu 251 I o JL iL A 447 II 447 251 H N Ja N) t Nt) 447 JL. L/ N ill N H0 N N H2 Bu H zoo 252 0 448 HNN N N'' OH N NH3C CH 3 NOH Br H 253 Ho 0 Oh 418 HN \ H In if Ber" Br 254 o 418 HN-0 451 I H N-N N B ru Bu" HN N N 255 I 484 HJ H N NN H C) i H L J Ir H BRU 256 - 256-N-CH3 401 N NOW N N= NH zu Bru 257 H 0 N-N 0 -H NN O N Bu H 258 H3 258 CH3 58 H 482 HN \ I F F H " NN> Bu H 259 NHz HN F 441 zu FI N FUN if N N Br H 260 0 HN , CH3 443 NN fr\ I _ \ Ber" Bu 261 0 NJ 529 N N ~ N N N N N- Bu H 262 Br H 486 H N N N N, Q NAOH Un Ber ber 500 N 9 N < H 263 C_, OH Bu H i H 264 N 500 HN4N XO H 264, N HX NH run Bu H H H N N N H CH 3H eHt c3 H !) j t NH CH, 266 N-N N. N 426 N H H Bu H Bu 267 0 Han" HAN HAN H NH 268 Br H 268 NEZ 483 COX/--I w N-ill H N H N 269 Br H 0 HNJAN N 383 Nli"N H 0 Non NON C3 H cl3 Cl," N, CH3 401 HN N-\ N N=1 HN Bu H bu L" 492 HN N N H H N N N==\ NH Ber Br H 272 0 r 9 N sNH 272 HN ; N N) 486 9NA NH ) Hz NU zon 273 273 OH 500 N HN, AN 0 H 275 H N 0~ S 530 eH N Br H Ir 274 NHz A HNa N Ili, N N==\ L'AN N H N Bu H 1 H HN N O H 9 N= NH ZU Bu H 276 II 484 ! Hz H .NJ NN N=\ ) H ! Zon B H C 3 277 552 t H NN O _ \i II NN'N H H H Ber 278 H HN N N H HN-NN NN AN H NH Bu H 279 F 0 488 / 488 H N H N'I N _ \ N N J 9 H N L" 280 ^ 392 H N H N' 281 0 NH N H 281 468 H H N JL H e H 282 0 Bu H 282 ru 420 -282 NH H i L. NH N J/N J 283 0 CH, zoo I/ 433 J N N N) 448 eH _ N N H2 N"N bu 2 4 448 JL JL Ji s HN"N-N\ JL N H NON If N Bu H 285 0 498 JL H 498 Oh N Bu H OH 286 H N Ja N Jt N ~~ N3 541 _ 286 0 HN"NN--N H H H ! J H H NN N= NH N Br H 287 o HN NN_, N 527 HN N N H H N-N N==\ NH B r H Br H 288 0 HNI1 543 HO Nez H HO Zu NH N Br H 289 0, O,', OH HN'v 514 N N H H N-N N==\ Br H r Zoo 2 0 N HN N N I 291 0 N-\ N S-1 Br CHg Br v CH3 291 I o 467 H nu N N O (ii NN 0 CL 292 o 292, H X 511 HN-v'NN 511 ! Hz N"-N 0 lui. Nro- Br X Bu 293 H NJa N) t N>3 481 zoo 481 kf)'N 2 Non NHZ Bu Leu N NH2 295 0 NON F Hz H 295 zoo H nu N N N ! Hz Un H N Br"H 296 I o Wo N9 N H2 N)-, N H 0 NON H H I NNH2 Br H HN 297 0 297". o Jt J. ! t 415 415 HN H CH3 N"N N==\ Br H L N 298 477 H / N N N= hei Bu H Br H 299 o eHA HN, AN , CH 3 3 t H N'N N=\ NH ZU Sr H 300 HNJa N) t N) 467 HN N N N)"N H LD L/ BU Br 301 IL 474 302 HNJaN H 484 Non Bu H NN Bu 3 2 zozo H H NV HNN-N\ N, cl Bu 303 / 500 303 JL JL A/ oo HN-N-N HN H 2 500 NN oHN , Jk ZON ber H N 484 JL H 484 N"N n-N CH 305 N) % N, 43 481 eH Br 305 481 N XI NN rN-" LU zozo Ber Br H zu 559 H/H N N N d3C NN Jl/j N N-N dsC Br H H'g N 307 503 HNNN J H N H N Br tOH Br H H bu 308 \ I 496 NN H N ,- (-,-H Bu H Ber OH 309 0 I/ 527 H N H N 1 H N"N 0 Br 310 zoo H N ? 544 NN O eNN) 9O Br H L" H 572 . A. i A HN H N NN O Non Br N L"" O-CH, 312 o\\ CH3 N N, CH3 513 Ho'' Han Nu N Bu H Br 3 13 H N XH NX 543 HN NN3 5 3 JL H \y N N 0 f H S/ Bu zoo 5 3 Br H H i hay N N 0 Hz Br S 315 479 H NHJ N N 0 I t H \ CH3 NN" H H \L/ 316 o 315 JL H 539 9 H H Jt NN 0 N It, N H0 N Ber 317 (% 538 HNNN eN NN 0 bu H 3H H Bu 318 539 J H N N"N 0 N"'N MHz Nu Br N HN-N""-N J JL N"N 0 539 L N v./ NJ O In Hz Br N 320 0 II 604 HN v _N'N ) Hz N N 0 CH 1 3 Br 3C CH3 321 > o HN v NN 719 ,'I-H D N N 0 N"N 0 HsCW Br H H NH/ 322 H3C H/0 '322. o 538 H N aN rA 538 H Hic N-N 0 bu Br" 323 o 537 H N N N N N-"-C/N H H Ber NHZ Bu zoo 504 H N H N ! H H N"N 0., Bu Zoo ! H H B r H H H N N'k ND H -N i H'" N"N 0 L'L i/=N H H N/i Br H H NH / Z zoo HN'v'NN 630 N"I-, N H 0 Non NN 0 BrH Br NHZ / 327 H N J3 N) t N ? 530 327 0 530 HN H N N) 465 NEZ N O Non HH _ J Br N H 328 0 zoo J H NV N N 0 J, H \ NN 0 329 0 H H \LJ/ l-lu N N 0 I NN 0 bu HIC B r 330 I o HN-' _NN 593 N"N H0 A H \7 N"N 0 Ber 331 OH IH, 559 HN_Nv'N-- Nez NN 0 NN O 'H H S/ bu 332 0 33 557 HN \ HN'i NN s Br H 0 Bu zoo II 499 HN "N N J JL N"N 0 I 0 " CI zoo 483 N)"N H 0 N N O H H F 335 \ I 490 r l H N JLJL H 0 I eHNs Hot ce N'-N 0 H nez H H eH HN O 337 0 580 Bu NHZ 337 non l H N NN 0 338 0 MHz Br NHz i. 1 JJ. 580 HNN-N J JL N'N 0 338 I j 592 eN HJS3 N N O HNN N < HH I W Br < 340 H') ( ! J H N N N O Ir-H H ! Hz 3 0 475 H Nt. J N f"N 0 N' N C H3 Bu NN 0 SNNCH, L H 341 505 J H N t Hz I (J N"N 0 Bu 342 0 zoo H nu u I] N N O O Br H H 343 0 489 Br 343 HN. Ni'N H 0 343 HN <NAN ? 489 eH 3 NNCH3 Br 344 0 551 Br"" 344 o ) t J JJ 551 HN-NN j JL H N 0, NC 551 N-N eH H 345 (j 586 N-N N N O eH HNX 346 0 S po 591 H nu ) Hz NN 0 I 347 \ o I 519 I J H N JL N O O HHOH bu Br SN-N-OH Br " zoo 491 HN H N JL H \ NN 0 N)-, N H 0 Br H H 349 B r 349 JL H N N M N 484 HN N H NON Bu N N bu H erz zu NJN w N N Ber H zozo 433 N)-I, NN NON Non ! NNH2 Br H 352/O 9 420 HN \ N N Nllk, N H N B r H Bu H zu I'481 HNNN X ß t HN N N N_ \ N/ !/N \ NH2 Br H 3 4 473 i. i A HNNN\ HN H N NON N Br HNnNH 355 0 500 HN, AN N HNI H N. N J H N /_ N N : =\ N Ber H 356 N CH3 423 HAN H N"N N I N-N Ber H 3 7 481 O N NH/N Hazy Non N Ber 358 0 557 HNNN j NN HN N N CH3 I 359 C 3 bu 359 I/ 699 H N H N NJN O Br I NN/S\ Br Br H H 360 HN N N J H N ! Hz N'-'N ITIH H S Bu Br 361 588 J H N N N O 360 bF NX | 621 H H S p 362 362 0 H nez N N O Zozo NN H \ Br Br 363 466 HAN Oh N WON \/SS Br H 364 H CH 3 Bu .- H 364 H CH, 364 469 eH HAN NN N Ber Example Structure ESI-MS Mol- Weight 365 I o HN HN 448 N/WNIH3C CH3 3KH TBr H erz 366 CH3 N' 401 NH N Bu H ber H 367 0 J N. N N, CH3 444 HO NN N==\ eHA Zu ber H L CH HN 401 HN 4U1 NTN N=\ eHA Ber" Br H 369 I o HN \ HN'I 484 N N N V= 'NH N-Y t LJ) Br H CH3 370 0 HN \ HN'I 502 NN S \. N Br CH3 Br CH 371 0 HN 538 N N H NN N-YY Br H 0 372 I o HN-v _NN 484 H NN N NNCH3 BrH 373 0 373 0 YjO. 481 N NN NJ BER bu H 374 0 N ." 4 viz NON N ber H i OH 375 H tOH -N N, Ho H CH3 513 9 Nu NH N BrH zoo HNNN 558 N Ili, N H0 . I-H H H Ber 377 o L ji jJ HN 570 N 111, NN= : \ CH N-11, -- CH3 Blr zozo zozo N"N H N ) Hz NN N-\ Br 379.- o fuzz un HN" NN N=\ HN H L" Br H 380 o H N'C'N Nfj 461 Non NON NNHZ Br HH3C CH3 381 0-0 fuzz HN H 483 N. \ N N=\ NH Bu H bu 382 I o 382 NAN 529 ! Hz NON NN S Br 9 H HX __ po N Je H H N Ber J N 384 o cH, HN-"H-- 3 HN H 3 513 385 HN XNX 491 N N N==\ NH Bu H Br H zozo 491 HAN N N ill N HH N N OH N 386 zozo Nu HAN N H N Bu L 387 o HN' N-v N C 472 H NN N CH3 eH-N Bu 388 0 HNJAN 495 N-'--nu NN N-N Ho zoo '" a H 1 H \ - (J N zoo HN'aN"kN 434 H i H t) NH Ber ber H 391 o HN I NNN 541 H H NN -N Bu 392 Q N fTi O'_N-v-NH 429 b S r 429 N SU erz 393 393 0 : N.. o- N 541 O N I NIH N H N/ N'NH J (N Bu H 394 « erz HN-6 I H NN 456 if Bu H bu H 395"3 N N-N,-\ Xi eH Zu if N"'CN Br H NN, r\ 396 0 HNJAN 579 NN 0 Si'su H H HO 397 I o N 9s, 516 NN S- H H N Bu zozo HN NN 487 H Bu H zizi 399 o 399 0 HN N NH2 485 HNI H N-N N H N N Bu H 400 ? HN-"N\ H 527 H 9 N, 1 H Non BU Zozo w I 419 H nez Non BER Bu H L" zozo Han \ N Bu H Ih HNHz bu Br" 403 o I . HN-v _N 'CH3 407 9 H 2 I, N"."NH2 Bu 404 0 HNI 504 j N OI eH H H CH3 IY 470 405 - , N N 470 o HN N4N N=\ eH B r H bu 406 I o HNJAN N 520 Nill H0 N s 2 eN\N) (N CH Bu Br""H 407 I o H HN 521 N"-N 0 I il Y N N S CH, Br" H H bu 408 w Y fl 487 H n N)"N N NN NJ Ber" ZOZO Ber 409 I o "NNH, t-)' NN Br" Bu Bu H 461 HN N 1 H NHZ Non H NH2 J Bu Br H o HN \ N' 4$4 J. N H N N O eNa Br H OH 412 I o HN \ HN 512 ! H LV N N 0 bu r 413 I o HN 539 NHz NN 0 Br H H 0 414 0 498 HN_ v _N' I I N-CH, eH 0 /oh Br H zozo HN NN_CH 376 NN 0 NHz Br Br zozo HN-v-N'N-CH 482 N 'N O' eH N Br H i/OH 417 _ < J 419 IN N N /O Bu H Br zozo H H-y 437 N 'N O NHz H Br zozo 419 v'N' 450 I N 0H3 N N /O NOH Br H OH 420 o HN"AN'N 3 433 NON eHNNH2 Bu 421 C3 421 HNXN4O 552 N, I,- NH 0 J, H. H H H Br 422 N 373 HN N O H NON FI H 423 0 N 423 o r", HN' HAN Non 1--H Br 424 oh -N 0 nr' Han H NN N In if NON Br H 425 o H 579 NN 0 I Bu bu 426 I o H N N) No 581 N I' N H-'0 N N OH IYK H H L" - Br 427 0 HN HN 544 NIt, N H0 C H 3 N'---'N bu ber N"J-N Hd3c 559 NN baC S-N Ber Br 429' o'I HN N'j N) ) 503 ! H I L Bu zoo HN NN 527 H N-"N 0 N-N Br H O 431 I o HN 544 N N O NN 0 NNO Br H 432 in 0 HN 1-1 N) Nrj JL." 572 N'-"N 0 Br H H N 0-CH3 po N Ili-, N H0 N N O N-N 0 SNN NN 3 Zozo 434 o H N I'N H 0CH3 555 I N NYDN"'N H H N B r cl, HNN""N 555 eH N 0CH3 I Bru H 4 H H O 436 I o HN'QN'kNo 558 Oh NN 0 Y"N"-N"rN NN O W I NN I vN Br H H O 437 0 HN 558 N N O NN 0 NHZ Br 438 I o HNN 560 NN 0 CH , 3 N N CH3 439 I o eHN HJX t H H H Br 440 I o 440 o HN'HN 557 JL NN-Nv H H Br H H 441 I o 'HN 585 I Hz NN 0 NN S CH3 Br H H 442 0 442 o I I' HN_ v _NN CH3 587 Hz NON H H s Ber Br eHN v N) X3 HN NN 589 H NN O ""NH 5 Br H H-NH 1 (O H70 444 I o eH 530 H N"N 0 Bu H H H N zozo H HN 544 JL H NN 0 ZOZO Ber H zozo HNJAN 544 ! H" AH HN H H H O Bu 447 I o NHZ 577 N N N ci Non H H s Br H H 448 I o HN NN 532 ) Hz NN 0 H H Br H H-I (p 449 zozo I I' HN NN 530 H N-"N 0 I Bu N Bu 450, o HN 543 NN 0 NNO Bray ber 451 0 HN NN 515 H N"N 0 I Hic B'-H, C 452 I o H HN 562 JL N N O ! NaOH N""'N "" zoo H 515 N-'N 0. BU Ber"" zozo HNI'A-NIND N"N H 0 557 Br H H FF 455 1- HNI'A"NIND H 515 HN-0 N"'NA2 CH, Y-- ber 456 N H N 571 NN 0 S"3 CH S Br o , C CHH s 4 7 NN 0 I J H 9NmN9Nto I) AH H Zozo po HN N H 517 N) IIN 0 9NN) % 459 NJ. N H N 531 N'N 0 r-NN'CH- Bu cl zozo N) IIN H 0 531 I NN 0 N''N CH, Br""H, CCH, ber N'N H N 531 H" c7 H H 0 Ber NN O I J ^ NN 0 Br""CH, Br""CH, 463 o k NN H N 531 N''N Br H H Bu zoo HN H N 531 NN O y I B'r H H V _ 4M o HNNN) i H \J 501 NN \JO I "" bu H 645 eNAN) 97 Br H H I C'a ci ci HN. H N 569 9 H H Sr H H 468 o 469r o 468 HNgN NX A""561 Br H H 469 T" 469 H N) 583 H HNI Non 470 Br H F 470 H N'CL N) O ND NN H N 561 N N F Br H H bu H HN H N 629 H 629 N"-"N NN H H 0 ! H H H 546 ""2 ZOO BU 0 ber H H O 473'' eNH H 54 __. _ HH-CH Br zoo k NN H NO O 546 473 HAJa N N>g 517 NN 0 0 eNN4CH Br HC CH, po HNJaN) Nfj H 489 NON 0 . HiHCH3 Bu 476 0 ""-504 H 504 N po Br H H LLL111 z 477 II HN'NY, Ni) H 505 I II Br"" Bu zoo Han'N-N N'N 0 NNN II NHz L H HH3C CH3p 479 i'' HNN H 1'S ""NH,' H H NH \/O, CHa n zozo If A H N 539 NN 0 Bu 481 H Br NH2 0 NN 0 NN = II NHz Br H H NHz O 482 II N 0 658 BU NN'0 658 Br H H NHz 483 N), N H 518 483 H 518 \ N " 0 0 g H H ! z 484 \ o HN OH 490 Non 0 nu2 Br H H NAH 485 ber NI./N' N 0 9HNNV N H HN H O I \ NOOr N H CH3 486 oI' H 530 9 H Br Bu""0 N 490 NHZ 1 jfY J"490 0 NJ NH 0 NH H NON ZON Br 488 o N H N 529 NN zu Br 0 489 HN-aN'o D HN \ NN 504 I H Br"0 NN O Br H H0 Br H H O eNt_ Br""0 Br H 0. N-N HO O H 0 H _k N'-"-'-'N HNN NN Br H.'JO O/I H 0 f H 0 492 o H 544 "N-/544 N I,, N H H N N ° (f zozo NN H N 544 4tNNtNH2 ,)---H H ber HN HNJ NN OI 521 495 O N<, a H 546 Ne Hß Br 495 H, C CH NN 0 546 I-r--, N Ber non 0 ber H J 496 fri o N H o H 573 Or H H H H Bu 497 o'I eHN HNJ9NH2 NN 0 0 H ho HHNHz 498 o'I HN'a H 0 578 N N 0 N"I'N H, HHNHz 1 499 H N>g 530 499from "f"\3 530 Ne 4 Nn _ N'-"-"kN S Bu 500 a 0 HN 544 501 eH HN) 4 NN O Brus NH 0NH N H2 Hz BrH O N NH O NH 532 H N+HN ß NN N ber H 502 7 ? o N N O O HN eH OH 503. t o H 552 H N Ho o H2 a"CCH, zozo zizi NIyN NH 596 N) IIN 0 H H2 Br H, C CH, 505 ) 9 HNJAN Nu "'u 612 NN a O NNOH BrH HNH, 506 1 zoo /,, oH HNNN t-C HN H N I 562 N -N \OJ O I, NNNHZ Br H Fh3C CH3 507 H 560 t, H0 N"N 0 Br NNro Br "U° 508 0 Han'a N)"N 594 h) ! j H Bu Ber 509 0 'O NNNHZ NN 6 o 510 0 "H. CCH, zozo 510 0 Bu H NN NHz 11---, N Bu H 511 CH, nez ZU Br" 0 N ONH 0 NH H NAIN Itch Ber non N ber" 513 0 " , NHz Ber Ber" Non 0 N Ber" oh I NH 533 I nu N N O/O O NNOH Br""H, CCH, o 512 t CXNHz H NN OII OIf H N N'k No Br hl (V) h1 516 N xi N NH HN 592 N/ N J NH1 N H zoo HNI'aN'ZNC] If H vu 545 BrH H N BER 518 1 518 J. H H J Br Ha N v N. NHZ 518pic 519 o i"\-'462 L 519 o IO 504 NN 0 )"H 504 ""s zoo HN \ NNH 487 V c o Han 0 0 ber HN N-p N% wN H NHb 5U2 NN 6 o NNNHz Br H HHC CH, 522 i oII HN NNH 548 NN O"O O 522 g 548 Sr H H NH= BrH HNH, 523 OH NHZ hic ONNH ONH 534 "JL J If Br Br" 524 r o H H 574 N N C NHz Br H, C CH, jNNNH, Br""H. CCH, 525 r oII HN \ NxN I eH \JJJ 544 NN O tir N-N JULAjJ Br H HNH H H HN H NH 58O Zozo N ill N H NH6 0 580 l H vJ 530 HH L1 NHZ Br zozo Ber 527 0 HN_AN H 530 L "LJ Bu Ber HNI \ HN I 544 NN 0 H 544 eHN HN) tjNH Bu ber 529 HN \ HN I 544 9 H H ß H Bu 530 r o aH2 596 o N--N 0 Br H, C CH, N'N 0 N"'N H0 518 N''N"JJO eHN 2 Au 3 3 532 HNJaN'o j W z g 614 N"-N 0 F F F 533 OH 5 3 612 H HNI H nu NN HO 534 1 H 534 NyCH3 638 HNNO ° ) H N*N 0 0 I/ NNNHz Br H , C CW, 5 5 HAN N N), o"c, 548 Il H Br H Hs 5r H S HNNN) HN v'NN I NIIJINH 0 586 NN xNCH "" (Jo 537 II HN'QN 0 N3 LAH N-IJINH 0 606 I NNSCH Br H HHN'Y CH, 0 0 Zizi HNNN) NOCH, FI- hasch3 iso HN-AN'NH ill o ? H 0 H Br H H 540 HN N'NH 540 A NHz 532 NNNHz Br H HHyC CH, 541 in 0 H H N N NI) H Br""NH, Br H H NN ! S. CHy Br H H NH= 542'' HN NxN CH, N) IIN H 0s 592 W x S X BrH 0 O 543 i I' 543 1 :) N N (Hs 562 Br H Clip 544 i'' HNNO HNI- NN NuCHy "ru 545rio 545 HNJ :)'N'o NN O NNNCHy CH ? CHU cl, ?. HN N N 562 - " Ls' Br H H 111---S 547 0 0 H O H NNO Br H H S 548 No fi) HN'AN'J"O 517 H CL, H CH, BU HIC 549 0 N HN I H-'O 486 i H N'N 0 0 'sx F"''H, CCHj 550 C3 N HN I NO 489 1 H NN Bru 0 Br H O N \ HNNO 518 N N H O'' N--) NHZ BrH 0 552 0 Ber"0 552 Non N ^NaOH 1 H NN NY OH 462 zu N HN-O 547 eHN HNgOH NN O O 554 0 ZU HN I N0 560 1 H N 0 0 I J . _ 5 5 5 N 1> H 5 7 4 SJNX N' 555tua cl 3 N N O O Ber NN 0 0 Br H HiC CHC'H H H4f ru' Br C''CHj 556 fuzz 556 A H 560 1 H ? ? eHN, N9NH2 H Br CH433CCH3 557 ,. o /I, S. NHz Ho'fla 373 N"N N=\ NH CHN cl H 558 /I NHz 400 HAN N-N 9 NNH2 Bu 559 HzN. ° ___ N S NH N7 451 N r jan Br H 560 2 s Os 440 o'' erz N N Br 561 101 ISI-N H2 561 ° i I NH 562 \ z 414 Bru ' Bu H 5 429 / NHz 429 Han non N^ ^'oh BrH 0 563 o I p NH z HN 443 NN NH2 Ici Br" Br 564 lot rY'"NH2 Han NON 'OCH, L"5 N II OCH3 Br H O 565 HNXONH2 428 N-"-N H NN H H N +NsCH Bu ber o . NNN N Bu H 567 HzN_SO o 0"aNH N---\ 387 ) ! NH N ZU ! H CH, a 568 Hf N 9 / HN \ I 359 H N H N N H H S-NH2 j0"'k 448 HN 448 H N LU Bu H N H 570 H2N ; S _ Ne NH T NH/N 486 NON W N H 571 00 _-- ; 400 N ill N Non N II NHz Br H O 572 ° fY Han 428 NON NN II CH3 Br H O 573 ° HN 0 414 un eH 0 Ir I' BRU Bu 574 iNH, HN 0 456 N)"N H y-N yCH3 LYS ber ho 575 11 s HN- NN 0 f J. A 0t H2 442 "" 576 9 fY-'NH, Br NN 0 576 1. Han \ 577 N1)"N 0 NHz Br H H I 577 ° i ONHz 493 HN1 493 ver, 0H ' !' ?" BrH H 578 It 11 NH2 H° 428 HAN NON 579 N,, S B rH 0 579 ° fY"NH, Han 0 510 1 N-11N 0 H H 580 It Han Non NON Br NH2 S Hz 416 415. 29 N HNI 582 Bf Hz Br 582 482 481. 40 583 iN/I NHz bu 583 HNN N-N HNI \ B. 0 584J Br O 584 518 517. 47 585 0 585 ° ^ . N N 463 462. 39 "" HNI ' N B,. 1 bu H 586 B fOf 504 43 . i/ Y-Ci 587 0 489 488. 43 Bf N N & 588 j, . i0 475 474. 40 HNt 589 0 589j H Br 589/°II\II ^ HN'N \ 436 435. 32 hub HAN & N//O\ H & 590 590 t Ng 463 462. 35 H NN H N & O 591 HNN 509 508. 42 HZ OU I B H//H ou 592 ^ t 0 464 463. 33 1"6 N'l"N N Ber 0 593 0 550. 46 HNN 551 HAN OU N 59N N y H 6 594/°IIII ^ HN'H \ 496 495. 42 'I//) HAN NHz H I Br/ 595 437 536. 43 \ \ 596 l 596 498 497. 40 W B' Hz 597 jQII 597 HN No 450 449. 35 HNI NON Ou N) IN Bu 598 0 ) HN N 514 513. 39 han-' ""r Y N '"OH ef OH zu 599 599 HN Ng 489 488. 43 HN N) % N HAN I"L7 600 je .., K. 462 461. 36 , N, 6 oh 601 Oh ")'0 510 509. 45 9 NX NN N' N N I H Bi 602 HNN\ 431 430. 31 HNb NON HAN NN ) H Br H 8r 603 ° ^ '0 496 495. 42 /I) I HN N"N WNHm zu 604 0 604 °IIIIII HN) No 468 467. 37 Ho'b I HN NAN Ht B'\- Br/ 605 X 605 HN NC) 417 416. 28 HN'6 NN 8r Su bu 606 ° ^ 606 HN NX 482 481. 40 H. NON Ber zu H I I" 607 ° ^ i0 452 451. 32 NON N)"N Sf OHt 608} er OH 608 QI' HN--\ 458 457. 33 HN NON HN 0 BER 609 je NO 496 495. 42 HN \ iN I N 9 H4 610 je 610 HN Ng 458 457. 37 Ber NN / 611 R 611/P HN-'N, 462 461. 36 /1tl/I H non a. Ly H Br 612 RRR//I ^ 612 KN NO 418 417. 31 HNt N NO Bf" Br N KN, 6 HN Ng 551 550. 46 Hub i H zu N N N r" I/\ o 614 ° 482 481-40 NN N' N N I H Br/ 615 No 558 557. 49 en 616 0 Br O O 517 516. 49 HH \ "X) Br 617 HN No Y'0 483 482. 38 N Xi Han Ber N H Br 618 HNb L 469 468. 36 HN B, 9 HN X N I H Br/ 619 A HNN-\ 436 435. 32 N-N NON un Ber Br Btr 620 H r'r 287 386. 30 Null Niez Y N 621 ber & 443 442. 36 Non N H Nô un 622 I N HN 453 452. 40 N"N N N Bu t Br 623. j- A 434 433. 40 NAN 9 N/N Ber Bu 624 rv HN I '460 459. 43 N,-kN f N oh Ber bu 625 \ N 446 445. 41 HN'CRN N'kan . 0 !" Br bu 626 \ N 626 Ly 407 406. 33 NON \%'N\/\ t" Br 627 w N 627 HNm 434 433. 35 NI-'N NON zozo Bf0 628 w N 436. 35 Han 437 Nlk, O !" Br 629 w N HN 492 491. 43 630't H N-'N H Bu ber 630-'N min \ " & H 631 \ N/ Cira 631 522 521. 46 N'ka N 'N N H Br 632 \ NI 632 Lu 467 466. 42 N9HN X Zanzi TAU buzz 633 \ N HN 469 468. 40 Ne XJ30 J Ber bu 634 \ NI HN /'485 484. 40 N"kN '" Ber Bu/ ou /O 635 \ N, HN/V 499 498. 42 Non H Br \ O/ 636 \ N 636 L7 469 468. 40 N N OH N/ 7 bu Br ,, t, N 637 420 420. 35 HN Non N 0 BER H Br 638 \ N /485 484. 40 HN ' Oh N OH I1--H---y I I 639 rv 639 No 481 480. 45 N-'N N Ber Bu/ 640w N N'kN N N-\ N In Br H Br 641 I N J. J Ly 467 466. 42 N'kN NON Ber '" 642 642N- 642 Ly 439 438. 37 NON NON Ber " Br- "643. jryo HN//506 505. 46 BOF N I H f"y') Bf Y 644, 644 LY 388 387. 28 NON N ! han Bu 645 0 HN 453 452. 40 NON ZON Br H I/ 646 N HN 467 466. 42 1 N Ber bu Br 647 1 nô HN- 461 460. 42 NeNH X) OH I-r, H H Br jg48j'o en 503 502. 46 N-N IN ber/ /I 649 N 649 I/489 488. 43 Non N9H-X f Ber ! H 650fj HN/506 505. 46 N''N Y NH IBr N N/ H 651 N HN/389 388. 31 NON '-r'No Br 652YN uN 522 521. 46 9 N X zon H Br 0-- 653jYN HN 653 HNJCCNO 522 521. 46 NN N N illNN L"'° bu Br HN 453 452. 40 eHNSv Y N \ IBr H I/ 655 y-Y) HN 529 528. 50 NON NH Bu I \ 656 han han 488 487. 49 NON r--, H son B'k 657rY"' 5 ; 445 44442 Non Bu Sur 658N--\ 658 HN-454 453. 39 NN N N OH Br ITf HN/440 439. 36 NON N-Y'S Bu ber 69 \ 407 406. 33 Non NAOH Br ber NN 466 465. 35 HNI IN OH N 662 ° HN r I \ 532 531. 46 HN Ex fi) B." & 663 je 663 NAN 500 499. 37 /nui/ zu NON Ifs H Br O 664 iL 568 567. 53 HN HAN Ne _ Sur Br H Nw 665 JL HN Y Y [ 665 HNt 513 512. 45 HNI \ N' N L"' bu 666 HN \ HHt NH, 539 538. 49 Mon Non 6N N. 8 667 JR 525 524. 46 HAN H & 668 H Br HN N 4AS3 t 486 485. 38 H~ \ NON Ber H Br 669 Jl ß C1 513 512. 41 NON N- N N-N NEZ Ber 0 bu O 670 670 I4N 516 515. 41 Non N'I, ION zu 671 671 t 571 570. 49 HAN H N N N Ber bu 672 ° HN i \ 559 558. 48 /NHz/ HAN 673 0 t ~N OH Bu 673, J HN r I \ NH/546 545. 48 JE Non ber N I han 674 ° : 4 ; 514 513. 39 HN zu N N-lu lu0 675 0 675 ° _ , NH 601 600. 52 HNI HN' H zu HN NH, 546 545. 48 HO HNI zon Br 677 0 iHN NH2 622 621. 49 H N OH OH "oh 0 H Br 678 HN NH2 548 547. 45 xi H Ber ! H Br 679 0 IHN 564 563. 45 NHz t HNI NON Ber 680 0 680 ° 680 j ? HN NH2 % 578 577. 48 HNI6 N NON I/ zizi Borzoi zu HN 587 586. 49 HNI HN ZON ! HZ Ber OH Bu OH 682 ° HNI 548 547. 45 Nah HN N 'N OH OH H Br Br 683 HN NH, 500 499. 41 HN HAN NHz N ou 684 bu 684 5 : 5 n 31 564 563. 45 , neo H, b N nazi NaOH Br H H 685 0 HN 481 480. 37 HNjb HNI Non N N H Br 686 jet HIN-NH, 546 545. 48 Non HNI NHZ ber H 687 9 H 3 HIN 518 517. 43 HN-b NON oh 9 H93 688 tJ 532 531. 46 Han) 6 Non N \ Br 689 0 689 HN 502 501. 38 NH,/ HNI NON N OH OH 690 H HN NH, 508 507. 39 HN HNI Non iso Itch Bu 691 ° 691 JbJX 508 507. 43 / HN' NAN lu 692j' 692 tA 512 511. 42 zizi HNI NON Y N T o 1 vu Bu 693 °-_ __ IHN 585 584. 52 Zizi HAN- N'N N OH Br 694 ° 694,, 532 531. 46 Zizi HAN- Non N \ Br H I/ HN NH2 496 495. 42 /nui HN N)"N N Br 696 Br lX HN 510 509. 45 HAN HN- N I \ BER Br 697 A HN NH= i 533 532. 44 'i HAN- N$HN t3 , H bu 698 698 NH, 486 485. 38 HNI HN (NOH L" Br 699 N < <\1 No 622 621. 37 N H4 0 N cri 0 CRI 700 _ N-,/632 631. 37 NH N 0 0 Non 701 N-X 701r NNH 567 566. 51 (r N N NEZ 702 p N 589 588. 48 nez H O Br HNS wF H 1 N H F 703 & _ G 720 719. 47 Hum \, \ N 0 a 0 704 v 581 580-53 0 ou Nu Nu NH /N /IBr 705 \ N, 618 617. 35 HN 0 N H NF-\-N_ H Bu Example Structure ESI-MS Mol- Weight 706 Br H N N 4 3 N N N H HNI N 707 0 702 NH, 402 HN 9 N== NH t" 9 NXT 708 \ oh 1 H In N N N V'N 709 Bu 709 \ NH 402 HAN BER N N Zon sur H Ber 710 N N 487 nia 0 HAN N H + 2 388 H Br 711 HAN H N N N N N ! H Br H Br 712 H /N N° 415 HAN H ! N N N==\ /H ! H Br 713 N NHZ / if-, H un HN ' 713 H N ^ \. \N H "UU //H Br non / 417 Br 714 N I N / / 'N OH Ber 715 0 0 N'N,-N XI HN NH= Ber Nez N N 716 0 H 11 N-S- H in Han H H ! t I i ° HN L" NN r-\ N"N N> H - ber fl 717/ 551, N HAN N'\ N ° H Ber Br H N Br 718 o 718 0 HNI H N' N I N I-r-, H N N Br bu 719/I o 417 HN N NH- JL NU H Ber H Br 720 471 H N N N H NN N I NH 9\N. HN--'\ NU H Br 721 0 N NH2 431 /NHZ HAN H HNI NN N Ber /^v-/w ! H Br ! '432 722 HN NHz f Nv Han NU . NH ber Br H Br 723 H 426 c'o HN N N NN H Br ber OH HNe 403 HAN HN" , N O ber Br 725 ou han 0 417 HN N N H N H 726 ? N ,- Br 726 ? o HN oi OH 417 H N N N // N N Br bu 373 373 H H . N N H bu 7 471 OH OH HAN N"L"N N NN NO Ber" 729 OH f) H Han H N_ \ N N 730 0 H N 0 458 Bu H N"N N /> Il HAN BER 731 Br N N H Br 731 i I o 428 !" ! H I > 428 ! H Br 732 o 445 HN N N H I N,-N N N---N H ! H Br 733 0 HN N 0 HN"'AN 0 ! N"kN H N==\ ! H Br B r 734 JX 3 ° HN-N N HO S N Nt\ NH "roh Br H Br 735 H 463 s 463 0 0 HN N-N H Ber Br y 432 w Han HN- HNia AN H Nu /'^vJ_/w Ber H Br 737 H H N 4 8 HAN NON Bu H 738 738 HN \ I NH 373 H N \_ N N in ! H BER Bu Ber /418 HN \ NHZ HN NH2 H Br N, _N Br H 740 458 HN N N ! H H N'N N--\ NU . N H Br H Br 741 I o 0 HO ! Nez 488 N''N N=\ NH Br ber '42 ? o HN ! NJI\N/409 H I N N NN Bu Br 743 0 HN 417 Nu2 N N N kf-- N Zu bu y 390 Han 0 HN HAN NON Br ber H 745 o HN No' 459 H N'N N==\ zon Br 746 zozo I HN N--NCI 459 je H H NN N=\ NH Ber zoo Zozo / 581 HN H NJ N i N O N'N OH Br 748 f \ a _ "N N 583 H H 583 \ N- ! H H \/ Br 749 o __ 543 9\H HJ N I ! H H \/ Bu 750/I Q- Ber H. No 448 N'kN H I/ \/NH N Br Br 751, O- HN \, N'N 450 NaOH N N N (OH H Br Br 752 HO 0 OH 419 HAN H H N'IN N /> Bu H Bu H 753 "H 452 Han I" N Br H 754 OH 754 oh N N I HO 9 N N BRU bu H L 755 o HN \ N_ _N 485 Eh N N N ber zon H Br 756/ Q-N 403 HN I 756 \_N N= | NH H Br Br 757-H o H"K HN N OH 460 N N gk 482 N N H Br 758 HNI 482 F HN F H 79 IINFN In N N H Bu 759'.. Z 441 F 441 HAN NN F N ! H Ber N N Ber bu 760 HN N 443 nui \ N 761 NN N H Br 761 Br 529 ! H H H H NON N N Bu H HN N N 487 4 7 NU OH W i^ H N Br Br 763 OH N 501 HN \ NO JE NU NU Ber ) H Br bu 764 HN H N 485 N N N NH it w Br zu bu 765/I o HN N N 485 H 0 i" . NH X N\ N Ber 765 N-N\ HO'AN H N"'N N nu Ber 766 N-N H Bu 767 N 446 HN N N N==\ NNH H Br 768 - 483 NI-N 0 Non ^ /'/N H H N Br 769 0 o HN \ H-_N l 383 N"N H NHZ N !" 770 H c 403 HN 7 * NH H Ber Br bu 771 HN N N 493 H H N\N N NH ber Br zoo HN N N > 487 \ /H N'kN N ==7\ Oh Ber 8r ber ,.,/oh 0 oh JE HN v _NO I H , nu PH Br 774 H Bu 774 NHz 407 w HN CI NII-t-N N==\ s j N V H bu N i" eNz NI= ! H Br Br 776 0 486 H N'i N NI-N HN\ ire-H Bu 777 0 778 552 NN 0 N-0 N N p Br NNN H H H ex 778/p ber 779 F H N 485 Br nu TH ° N H Br 779 w 489 H N H N Zu NH ber 780- H Br . JL" Vu j H fD o JL iL A/ 469 N \_N N NH H N 0 f H Ber nu Han \ N NN N , nu zu N H Bu " "l \ 421 L il O'_NNH N "NU Br N H HN I 433 H N HNHz Br 784 0 L iL A HLD 449 ."0 N IT Br 785 o HN-OIN N 499 NON Oh N-, aOH COOH Br OH 786 0 HN HNHN 541 N/-N N- ! H Ber Br 787 \ N HN NN 527 HH NAN N= NH ber H ber 788 i I o Nez HH Zozo N'IN IN N ^ (\. NH Br bu H89 I o., oH ! H H HN N N H H NN IN N'5KN N Bu ber Ber 790 jai 0 504 HN'-"N N ; H NHZ /O Bu 791 0 467 467 H N N N N"kN 0 11 S ! H Ho C ! cl 792/o \ 512 1" H XH H o NIo_ Bu I rH Ber non HNiaN'kNC) 482 H N NHz N N H2 I I", IH Br 794 o NN HNNN 395 non N NHZ HNNN 795 \ I 521 /\ H N N N~ X N H N Br bu 540 ! Hz N"N NON I Y _N N (NHZ Br H I/, ii0 797 0 415 HNiaN,-k ,-It H i NU N Br Br o 477 , " N 11-0 {Y N=\ Bu Br ber 799 t N'-N H N==\ Nu ! H Br bu 800 O HN v _NN 467 HAN A JL"L/ Y'J'N N H Br Br'' '801. o L j ! [j HN) NXNX 474 N N N HJt 485 N-0--OH Bu 802 i o \ 485 H nez N N N Ber t H Br 803, I o J J/i 501 HNiaN"K NC) 501 xi N"'N OH NH H Br bu HN4/I O 486 NN r-N N'\ N JN 8 N. N Bu ber 805 C) N 483 f f) ONNH r t H H NkN N f ON If-l-H Br ber HN/N_ _N J 561 VH Ni'N O \ I NN/N H H N Ber 807 0 HN N-_N 505 H N"N 0 H H B r ber N ItN JL H LD 498 Non N X a I OH 809 o A H 1 NN 0 Ber H H 0 Br 810 w O HN I NN 546 ) H N"N 0 nain H 0 H H N Br H 811 812 ß. ° »/515 ! H \ N""'-' Ho 0 812 0 O-N 515 HN H 814 N===-\ HN" Bu H bu H 1 0 Br NI A No 544 N"N H NN 0 Bu ber 814 0 HN N N 1 \/H " Non H H Ber S Br'-S 815 zozo HN N'k No 479 H \/ N N /O I/ S H H !""\lu/ zu HN N N HAN'D -ON N--N NHZ Bu ber-- 817-. o HN/N--N 538 H N- N 0 I N- 1)), H H Br ber-- 539 HN N N i" Non \ I N- Ber N Ber N 0 819 I \ o 539 1" Non N- _N O - N Hz 0 820 1" H nez i N\ IN NNN O Ber 0 bu O 821 0 H N/N N 719 H NN O i 1 H H H ' Bu-nu \-1\ (O zu 0__ 0 HN I/N-_N 538 H Ni _N O HH N bu Br 823 o HN-aN'KN) 537 H N)''N 0 N/'N O Br 824 ber 824 o 504 HN , NC 504 H N)-'N H \ HH/N\ bu Br 825-'Zz 0 HN N N 581 N)-N H 0 N-N o \ I-N ZON BU NEZ 826 0 Han 630 I N N/./N/w Ber Br NHz \/ N-N Br NH, \ A \ N J0N/3 530 827 t 9 NX J 530 N-----' H Ber N NHZ ber N 465 82$/O- 465 H NJ N N O S H H 829 o 557 AL A \ 557 HN N N \V/H N N O "830 c bu 830 o _ HN v N 593 H 831 0 N-- N I""L Ber 831 O ou 560 HN H N 0 NN"w//O I/NN S 557 Bu o 557 H N N Ber-- N _,, N <""H ICH Bu 833 833 0 HN \ I NN 5OO N'kN H 0 N N 0 If-, H H ci 834/I o zu HN N N OH N"kN 0 zu N N 0 X H H J F F 835 0 X N z N"N 0 S MHz Con 836 con HN H N N"-"-N OH OH Br NHZ 837 I 580 NN H 0 Non MHz Bu NHZ 838 ! H H t . HAN No 592 H N' :"k N 0 N N Fion BU HAN Br HN 8 I \ iI HNJaN 566 1" N N N 'N O _ Br NH, NHZ zu 840 I \ 475 475 NN 0 H ! H H Ber 505 Bu 841 o JL" HN/NN H N- _N O \ I NN \/O\ oh H Br 842 r 0 . J/ 544 N/N W H N)"N 0 0 NNNH, N i _N O O \ 843 -- 489 Br H NJ--'N 0 ! H H Br zu , 1 551 MHz Ber 844 I 551 HN/N N, 1 H 843 A o \/ Br Br 845 0 II 586 "H N $ N N Ber Hz Br NHz S 846 ! 591 HN H N N-\ N VO zu NN 0 847 847 zu HN N N I Oh Ni _N 0 0 HHOH bu Br 848 0 N/491 HN H N-J Oh H BER bu Br zu han N H HNN JL" N"N H N N H H N L" 850 r H N 850 N 482 Nana O'N-v'NH/ N Ber H bu 851 I o HN/N-_N 433 N'55KN H Ni _N N-N NHZ bu Br zu If-,-H N BER iL NN"-' Bu ! H Br H H Non I/N \ I NHz Zu Br 854 zu ^ 474 N"kN H \V/H NN N ! H ! H holz \ I 501 H H !"\/ ."o\ - N"'N N : ==\ Nu Br ber 425 Han H C, qu . Br H Br 857 482 Zizi O'-N v-NH/ H N Ber t H Br bu 858 . 5 557 HN-H N Zu Irks H Ber Bu ber" zu 699 HN N N H NN 0/Br B S 699 H H S Br Br Br 860. . k,, o 621 H Non Non , IH H Bu Br 5 8 HN H N N i O N l)-IH H s 0 Br 862 bu 621 o HN I/N 621 NJ 0 Vu N i O Ber Src bu f H H"-s Br 863 0 468 HO PU N'\ N HN non 1-f-H Br 864 H Cl, 471 Han o H N NN I ber H N N BrH NN rT\ -JN Br 865 865 HNJaOH 283 N'\ N OH Br 866 oH N--N 0 N'\ N p I-r,-H Br 867 0 405 Han non Bu Ber 0 377 Han zoo HN', a JkJ 377 NN Br t§ 5 B HN/JS ° 377 Br 869 No JkJ T 419 Han NON NON Br ber N 0 f 419 HN \ I O Non N-N Bu ber Ber 871 N 0 403 Han N"kN HO Bu Br H 872 N 0 1 439 0 HN', a NI-N Br "873pro Br NyNJ 433 Han'a N-\ N NN BER ber H H 874 N N ! T n T 1 q HN'ia f aN' 0 539 han N I I_ N Bu H 875 H H °, N N° 555 HN \ S/ N N N HN H///\NH N 876 HN \ I N 398 ! H)-) HN 398 NSNx 342 HN Ber H Br H 8770, 0- H N 342 NyN 1N'H 0 0 878 o, N.. o N, 342 INI I IN NON Nu ozon N 879 0, N.. o- /N\/t 342 N>fN NH o I i 0 0 880 o,, N.. o- N 314 N-N NtN OH 881 0\ N,. o- _ rn", 314 Non Cry NON HA