Pyridopyrimidine derivatives as protein kinase inhibitors

Abstract

Compounds of the formula I ##STR00001##
in which R, R.sup.1 and R.sup.2 have the meanings indicated in claim 1, are inhibitors of Syk, and can be employed, inter alia, for the treatment of cancer, rheumatoid arthritis and/or systemic lupus.

Claims

1. Compounds of the formula I ##STR00170## in which R denotes H, A or NR.sup.4R.sup.4′, R.sup.1 denotes Ar.sup.1, Het.sup.1, CN, A or —C≡C—Ar.sup.1, R.sup.2 denotes Het.sup.2, NR.sup.3Cyc, NR.sup.3CHR.sup.3CON(R.sup.3).sub.2, NR.sup.3[C(R.sup.3).sub.2].sub.pCR.sup.3(NH.sub.2)CH.sub.2OA or NR.sup.3[C(R.sup.3).sub.2].sub.pN(R.sup.3).sub.2, Ar.sup.1 denotes phenyl, which is mono-, di- or trisubstituted by A, (CH.sub.2).sub.nHet.sup.3, [C(R.sup.3).sub.2].sub.nOR.sup.3, [C(R.sup.3).sub.2].sub.nN(R.sup.3).sub.2, NO.sub.2, CN, Hal, COOR.sup.3, CON(R.sup.3).sub.2, NR.sup.3COA, NR.sup.3SO.sub.2A, SO.sub.2N(R.sup.3).sub.2 and/or S(O).sub.mA, Het.sup.1 denotes 3,6-dihydro-2H-pyranyl, tetrahydropyridinyl, 1,3-dihydro-benzimidazolyl, pyrazolyl, chromanyl, 1,2,3,4-tetrahydro-pyrazolo[1,5-a]pyridinyl, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]-oxazinyl, 1,4-dihydro-benzo[d][1,3]oxazinyl, 4H-benzo[1,4]oxazinyl, benzimidazolyl, pyridyl, pyrimidinyl, imidazolyl, pyrazolyl, furyl,thiazolyl, triazolyl, benzotriazolyl, indolyl, indazolyl, 1,3- or 2,3-dihydro-indolyl, each of which is unsubstituted or mono-, di-, tri- or tetrasubstituted by A, CN, OH, OA, Hal, SO.sub.2NH.sub.2, (CH.sub.2).sub.nNH.sub.2, (CH.sub.2).sub.nNHA, (CH.sub.2).sub.nNA.sub.2 and/or ═O, Het.sup.2 denotes piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydropyranyl, pyrazolyl, indazolyl, azetidinyl or octahydro-benzimidazolyl, each of which is mono-, di- or trisubstituted by Hal, A, (CH.sub.2).sub.nNH.sub.2, (CH.sub.2).sub.nNHA, (CH.sub.2).sub.nNA.sub.2, (CH.sub.2).sub.nOH and/or (CH.sub.2).sub.nOA, Het.sup.3 denotes piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, imidazolidinyl, pyridyl, pyrimidinyl, imidazolyl, pyrazolyl, furyl, thiazolyl or triazolyl, each of which is unsubstituted or mono- or disubstituted by A and/or ═O, R.sup.3 denotes H or alkyl having 1, 2, 3 or 4 C-atoms, R.sup.4 and R.sup.4′ each, independently of one another, denote H or A, A denotes unbranched or branched alkyl having 1-10 C atoms, in which 1-7 H atoms may be replaced by F and/or in which one or two non-adjacent CH.sub.2 groups may be replaced by O and/or NH, or cyclic alkyl having 3-7 C atoms, Cyc denotes cyclic alkyl having 3-7 C atoms, which may be unsubstituted or monosubstituted by NH.sub.2, CN, CONH.sub.2 or OH, m denotes 0, 1 or 2, n denotes 0, 1, 2, 3 or 4, p denotes 1, 2, 3 or 4, and pharmaceutically acceptable solvates, salts, enantiomers, tautomers and stereoisomers thereof.

2. Compounds according to claim 1 in which Ar.sup.1 denotes phenyl, which is mono-, di- or trisubstituted by A, (CH.sub.2).sub.nHet.sup.3 and/or SO.sub.2NH.sub.2, and pharmaceutically acceptable solvates, salts, enantiomers, tautomers and stereoisomers thereof.

3. Compounds according to claim 1 in which Het.sup.1 denotes 3,6-dihydro-2H-pyranyl, tetrahydropyridinyl, 1,3-dihydro-benzimidazolyl, pyrazolyl, chromanyl, 1,2,3,4-tetrahydro-pyrazolo[1,5-a]pyridinyl, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]-oxazinyl, 1,4-dihydro-benzo[d][1,3]oxazinyl, 4H-benzo[1,4]oxazinyl, benzimidazolyl, benzotriazolyl, indolyl, indazolyl, 1,3- or 2,3-dihydro-indolyl, each of which is unsubstituted or mono-, di-, tri- or tetrasubstituted by A, CN, OH, OA, Hal, and/or ═O, and pharmaceutically acceptable solvates, salts, enantiomers, tautomers and stereoisomers thereof.

4. Compounds according to claim 1 in which Het.sup.2 denotes piperidinyl or octahydro-benzimidazolyl, each of which is monosubstituted by A, (CH.sub.2).sub.nOH or (CH.sub.2).sub.nOA, and pharmaceutically acceptable solvates, salts, enantiomers, tautomers and stereoisomers thereof.

5. Compounds according to claim 1 in which R denotes H, A or NR.sup.4R.sup.4′, R.sup.1 denotes Ar.sup.1, Het.sup.1, CN, A or —C≡C—Ar.sup.1, R.sup.2 denotes Het.sup.2, NR.sup.3Cyc, NR.sup.3CHR.sup.3CON(R.sup.3).sub.2, NR.sup.3[C(R.sup.3).sub.2].sub.pCR.sup.3(NH.sub.2)CH.sub.2OA or NR.sup.3[C(R.sup.3).sub.2].sub.pN(R.sup.3).sub.2, Ar.sup.1 denotes phenyl, which is mono-, di- or trisubstituted by A, (CH.sub.2).sub.nHet.sup.3 and/or SO.sub.2NH.sub.2, Het.sup.1 denotes 3,6-dihydro-2H-pyranyl, tetrahydropyridinyl, 1,3-dihydro-benzimidazolyl, pyrazolyl, chromanyl, 1,2,3,4-tetrahydro-pyrazolo[1,5-a]pyridinyl, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]-oxazinyl, 1,4-dihydro-benzo[d][1,3]oxazinyl, 4H-benzo[1,4]oxazinyl, benzimidazolyl, benzotriazolyl, indolyl, indazolyl, 1,3- or 2,3-dihydro-indolyl, each of which is unsubstituted or mono-, di-, tri- or tetrasubstituted by A, CN, OH, OA, Hal, and/or ═O, Het.sup.2 denotes piperidinyl or octahydro-benzimidazolyl, each of which is monosubstituted by A, (CH.sub.2).sub.nOH or (CH.sub.2).sub.nOA, Het.sup.3 denotes triazolyl, R.sup.3 denotes H or alkyl having 1, 2, 3 or 4 C-atoms, R.sup.4, R.sup.4′ each, independently of one another, denote H or A, A denotes unbranched or branched alkyl having 1-10 C atoms, in which 1-7 H atoms may be replaced by F and/or in which one or two non-adjacent CH.sub.2 groups may be replaced by O and/or NH, or cyclic alkyl having 3-7 C atoms, Cyc denotes cyclic alkyl having 3-7 C atoms, which may be unsubstituted or monosubstituted by NH.sub.2, CN, CONH.sub.2 or OH, m denotes 0, 1 or 2, n denotes 0, 1, 2, 3 or 4, p denotes 1, 2, 3 or 4, and pharmaceutically acceptable solvates, salts, enantiomers, tautomers and stereoisomers thereof.

6. Compounds according to claim 1, selected from the following compounds: TABLE-US-00005 Nr. name “A1” N2-((cis)-2-Amino-cyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)- pyrido[4,3-d]pyrimidine-2,5-diamine “A2” (1R,2S)-N-[8-(1-Methyl-1H-pyrazol-4-yl)-pyrido[4,3-d] pyrimidin-2-yl]-cyclohexane-1,2-diamine hydrochloride “A3” N2-(cis-2-Amino-cyclohexyl)-8-(3-[1,2,3]triazol-2-yl-phenyl)- pyrido[4,3-d]pyrimidine-2,5-diamine “A4” N2-((cis)-2-Amino-cyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)- pyrido[4,3-d]pyrimidine-2,5-diamine “A5” {1-[5-Amino-8-(1-methyl-1H-pyrazol-4-yl)-pyrido[4,3-d] pyrimidin-2-yl]-piperidin-4-yl}-methanol “A6” N2-(2-Amino-ethyl)-8-(1-methyl-1H-pyrazol-4-yl)-pyrido [4,3-d]-pyrimidine-2,5-diamine “A7” N2-(cis-2-Amino-cyclohexyl)-8-(4-tert-butyl-phenyl)-pyrido [4,3-d]pyrimidine-2,5-diamine “A8” N2-(cis-2-Amino-cyclohexyl)-8-(1-isobutyl-1H-pyrazol-4-yl)- pyrido[4,3-d]pyrimidine-2,5-diamine “A9” 5-Amino-2-(cis-2-amino-cyclohexylamino)-pyrido[4,3-d]- pyrimidine-8-carbonitrile “A10” N2-(cis-2-Amino-cyclohexyl)-8-(1H-indol-2-yl)-pyrido- [4,3-d]pyrimidine-2,5-diamine “A11” 2-((cis)-3-Methyl-octahydro-benzoimidazol-1-yl)-8-(1-methyl- 1H-pyrazol-4-yl)-pyrido[4,3-d]pyrimidin-5-ylamine “A12” N2-(cis-2-Amino-cyclohexyl)-8-methyl-pyrido- [4,3-d]pyrimidine-2,5-diamine “A13” N2-((cis)-2-Amino-cyclohexyl)-8-(4-trifluoromethoxy-phenyl)- pyrido[4,3-d]pyrimidine-2,5-diamine “A14” N2-((cis)-2-Amino-cyclohexyl)-8-(4-trifluoromethoxy-phenyl)- pyrido[4,3-d]pyrimidine-2,5-diamine “A15” {1-[5-Cyclopropylamino-8-(1-methyl-1H-pyrazol-4-yl)-pyrido- [4,3-d]pyrimidin-2-yl]-piperidin-4-yl}-methanol “A16” {1-[5-Diethylamino-8-(1-methyl-1H-pyrazol-4-yl)-pyrido [4,3-d]-pyrimidin-2-yl]-piperidin-4-yl}-methanol “A17” N2-((1R,2S)-2-Amino-cyclohexyl)-8-phenyl-pyrido[4,3-d]- pyrimidine-2,5-diamine “A18” N2-(cis-2-Amino-cyclohexyl)-8-(7-methoxy-1H-indol-2-yl)- pyrido[4,3-d]pyrimidine-2,5-diamine “A19” N2-(cis-2-Amino-cyclohexyl)-8-(5-methoxy-1H-indol-2-yl)- pyrido[4,3-d]pyrimidine-2,5-diamine “A20” N2-((R)-2-Amino-3-methoxy-propyl)-8-(1-methyl-1H-pyrazol- 4-yl)-pyrido[4,3-d]pyrimidine-2,5-diamine “A21” N2-((cis)-2-Amino-cyclohexyl)-8-m-tolyl-pyrido[4,3-d] pyrimidine-2,5-diamine “A22” N2-((cis)-2-Amino-cyclohexyl)-8-m-tolyl-pyrido[4,3-d] pyrimidine-2,5-diamine “A23” 2-[5-Amino-2-((cis)-2-amino-cyclohexylamino)-pyrido[4,3-d]- pyrimidin-8-yl]-1H-indole-5-carbonitrile “A24” N2-(cis-2-Amino-cyclohexyl)-8-(1H-indol-3-yl)-pyrido[4,3-d]- pyrimidine-2,5-diamine “A25” cis-N-[8-(1,3-Dimethyl-1H-pyrazol-4-yl)-pyrido[4,3-d] pyrimidin-2-yl]-cyclohexane-1,2-diamine “A26” (1S,2R)-N-[8-(1-Isopropyl-1H-pyrazol-4-yl)-pyrido[4,3- d]pyrimidin-2-yl]-cyclohexane-1,2-diamine “A27” (1S,2R)-N-[8-(1H-Indol-3-yl)-pyrido[4,3-d]pyrimidin-2-yl]- cyclohexane-1,2-diamine “A28” 3-[2-((1R,2S)-2-Amino-cyclohexylamino)-pyrido[4,3-d] pyrimidin-8-yl]-benzene sulfonamide “A29” (1S,2R)-N-[8-(4,4-Dimethyl-chroman-7-yl)-pyrido[4,3-d] pyrimidin-2-yl]-cyclohexane-1,2-diamine “A30” (R)-3-Methoxy-N1-(8-m-tolyl-pyrido[4,3-d]pyrimidin-2-yl)- propane-1,2-diamine “A31” (1S,2R)-N-(8-m-Tolyl-pyrido[4,3-d]pyrimidin-2-yl)- cyclohexane-1,2-diamine “A32” (R)-4-Methyl-2-(8-m-tolyl-pyrido[4,3-d]pyrimidin-2-ylamino)- pentanoic acid amide “A33” (1S,2R)-N-[8-(4,5,6,7-Tetrahydro-pyrazolo[1,5-a]pyridin-2-yl)- pyrido[4,3-d]pyrimidin-2-yl]-cyclohexane-1,2-diamine “A34” 6-[2-((1R,2S)-2-Amino-cyclohexylamino)-pyrido[4,3-d] pyrimidin-8-yl]-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one “A35” (1S,2R)-N-[8-(3-Methoxy-phenylethynyl)-pyrido[4,3-d] pyrimidin-2-yl]-cyclohexane-1,2-diamine “A36” (1S,2R)-N-[8-(1H-Benzoimidazol-5-yl)-pyrido[4,3-d] pyrimidin-2-yl]-cyclohexane-1,2-diamine “A37” 5-[2-((1R,2S)-2-Amino-cyclohexylamino)-pyrido[4,3-d] pyrimidin-8-yl]-1,3-dihydro-benzimidazol-2-one “A38” (1S,2R)-N-[8-(1,2,3,6-Tetrahydro-pyridin-4-yl)-pyrido[4,3-d]- pyrimidin-2-yl]-cyclohexane-1,2-diamine “A39” (1S,2R)-N-[8-(3,6-Dihydro-2H-pyran-4-yl)-pyrido[4,3-d] pyrimidin-2-yl]-cyclohexane-1,2-diamine “A40” (1S,2R)-N-[8-(6-Methoxy-1H-indol-3-yl)-pyrido[4,3-d] pyrimidin-2-yl]-cyclohexane-1,2-diamine “A41” (1S,2R)-N-[8-(6-Trifluoromethyl-1H-indol-3-yl)-pyrido[4,3-d]- pyrimidin-2-yl]-cyclohexane-1,2-diamine “A42” (1S,2R)-N-[8-(6-Fluoro-1H-indol-2-yl)-pyrido[4,3-d]pyrimidin- 2-yl]-cyclohexane-1,2-diamine “A43” (1S,2R)-N-[8-(6,7-Dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2- yl)-pyrido[4,3-d]pyrimidin-2-yl]-cyclohexane-1,2-diamine “A44” 3-[2-((1R,2S)-2-Amino-cyclohexylamino)-pyrido[4,3-d] pyrimidin-8-yl]-1H-indole-5-carbonitrile “A45” 3-[2-((1R,2S)-2-Amino-cyclohexylamino)-pyrido[4,3-d] pyrimidin-8-yl]-1H-indole-6-carbonitrile “A46” (1S,2R)-N-[8-(5-Fluoro-1H-indol-3-yl)-pyrido[4,3-d]pyrimidin- 2-yl]-cyclohexane-1,2-diamine “A47” (1S,2R)-N-[8-(6-Fluoro-1H-indol-3-yl)-pyrido[4,3-d]pyrimidin- 2-yl]-cyclohexane-1,2-diamine “A48” (R)-N1-[8-(1H-Indol-3-yl)-pyrido[4,3-d]pyrimidin-2-yl]-3- methoxy-propane-1,2-diamine “A49” cis-N3-[8-[6-(trifluoromethyl)-1H-indol-3-yl]pyrido[4,3-d]- pyrimidin-2-yl]tetrahydropyran-3,4-diamine “A50” cis-N4-[8-[6-(trifluoromethyl)-1H-indol-3-yl]pyrido[4,3-d]- pyrimidin-2-yl]tetrahydropyran-3,4-diamine “A51” cis-3,3-Difluoro-N1-[8-[6-(trifluoromethyl)-1H-indol-3- yl]pyrido[4,3-d]pyrimidin-2-yl]cyclohexane-1,2-diamine “A52” cis-3-Fluoro-N1-[8-[6-(trifluoromethyl)-1H-indol-3-yl]pyrido- [4,3-d]pyrimidin-2-yl]cyclohexane-1,2-diamine “A53” cis-4,4-Difluoro-N1-[8-[6-(trifluoromethyl)-1H-indol-3- yl]pyrido[4,3-d]pyrimidin-2-yl]cyclohexane-1,2-diamine “A54” cis-4-Fluoro-N1-[8-[6-(trifluoromethyl)-1H-indol-3-yl]pyrido- [4,3-d]pyrimidin-2-yl]cyclohexane-1,2-diamine “A55” cis-4,4-Difluoro-N2-[8-[6-(trifluoromethyl)-1H-indol-3- yl]pyrido[4,3-d]pyrimidin-2-yl]cyclohexane-1,2-diamine “A56” cis-4-Fluoro-N2-[8-[6-(trifluoromethyl)-1H-indol-3-yl]pyrido- [4,3-d]pyrimidin-2-yl]cyclohexane-1,2-diamine “A57” (1S,2S)-3,3-Difluoro-N2-[8-[6-(trifluoromethyl)-1H-indol-3- yl]pyrido[4,3-d]pyrimidin-2-yl]cyclohexane-1,2-diamine “A58” cis-3-Fluoro-N2-[8-[6-(trifluoromethyl)-1H-indol-3-yl]pyrido [4,3-d]pyrimidin-2-yl]cyclohexane-1,2-diamine “A59” cis-2-[[8-[6-(Trifluoromethyl)-1H-indol-3-yl]pyrido[4,3-d]- pyrimidin-2-yl]amino]cyclohexanol “A60” 3,3,3-Trifluoro-N1-[8-[6-(trifluoromethyl)-1H-indol-3- yl]pyrido[4,3-d]pyrimidin-2-yl]propane-1,2-diamine “A61” (2R)-3-Methoxy-N1-[8-[6-(trifluoromethyl)-1H-indol-3-yl]- pyrido[4,3-d]pyrimidin-2-yl]propane-1,2-diamine “A62” (2R)-4-Methyl-2-[[8-[6-(trifluoromethyl)-1H-indol-3-yl]pyrido [4,3-d]pyrimidin-2-yl]amino]pentanamide “A63” cis-N2-[8-(7-Fluoro-1H-indol-3-yl)pyrido[4,3-d]pyrimidin-2- yl]cyclohexane-1,2-diamine “A64” N2-[8-[7-(Trifluoromethyl)-1H-indol-3-yl]pyrido[4,3-d] pyrimidin-2-yl]cyclohexane-1,2-diamine “A65” (R)-2-[8-(6-Cyano-1H-indol-3-yl)-pyrido[4,3-d]pyrimidin-2-yl- amino]-4-methyl-pentanoic acid amide “A66” (1S,2R)-N-[8-(4-Methyl-1H-indol-2-yl)-pyrido[4,3-d] pyrimidin-2-yl]-cyclohexane-1,2-diamine “A67” 3-[2-((R)-2-Amino-3-methoxy-propylamino)-pyrido[4,3-d]- pyrimidin-8-yl]-1H-indole-6-carbonitrile “A68” (3R,4R)-N4-[8-(1H-Indol-3-yl)-pyrido[4,3-d]pyrimidin-2-yl]- tetrahydro-pyran-3,4-diamine “A69” 3-[2-((3R,4R)-3-Amino-tetrahydro-pyran-4-ylamino)-pyrido [4,3-d]pyrimidin-8-yl]-1H-indole-6-carbonitrile “A70”, (cis)-2-[8-(1-benzenesulfonyl-1H-indol-3-yl)-pyrido- “A71” [4,3-d]pyrimidin-2-ylamino]-cyclohexanol “A72” 3-[2-((1R,2S)-2-amino-cyclohexylamino)-pyrido[4,3-d] pyrimidin-8-yl]-1H-indole-7-carbonitrile “A73”, 3-[2-((cis)-2-hydroxy-cyclohexylamino)-pyrido[4,3-d] “A74” pyrimidin-8-yl]-1H-indole-6-carbonitrile “A75” 3-[2-((S)-5,5-difluoro-piperidin-3-ylamino)-pyrido[4,3-d] pyrimidin-8-yl]-1H-indole-6-carbonitrile “A76” (1S,2R)-N-[8-(1H-pyrrolo[2,3-c]pyridin-3-yl)-pyrido[4,3-d] pyrimidin-2-yl]-cyclohexane-1,2-diamine “A77” 3-[2-((1R,2S)-2-amino-cyclohexylamino)-pyrido[4,3-d] pyrimidin-8-yl]-1H-indole-6-carboxylic acid amide “A78”, (3-fluoro-piperidin-3-ylmethyl)-[8-(6-trifluoromethyl-1H- “A79” indol-3-yl)-pyrido[4,3-d]pyrimidin-2-yl]-amine “A80” 3-(2-cyclohexylamino-pyrido[4,3-d]pyrimidin-8-yl)-1H-indole- 6-carbonitrile “A81” (1S,2R)-N-[8-(7-fluoro-1H-indol-2-yl)-pyrido[4,3-d]pyrimidin- 2-yl]-cyclohexane-1,2-diamine “A82” (1S,2R)-N-[5-difluoromethyl-8-(6-trifluoromethyl-1H-indol-3- yl)-pyrido[4,3-d]pyrimidin-2-yl]-cyclohexane-1,2-diamine “A83” 3-[2-(2-amino-3,3,3-trifluoro-propylamino)-pyrido[4,3-d] pyrimidin-8-yl]-1H-indole-6-carbonitrile “A85” 3-[2-((cis)-2-amino-cyclohexylamino)-5-methyl-pyrido[4,3-d]- pyrimidin-8-yl]-1H-indole-6-carbonitrile “A86” 2-((cis)-2-amino-cyclohexylamino)-8-(6-trifluoromethyl-1H- indol-3-yl)-6H-pyrido[4,3-d]pyrimidin-5-one “A87” 3-[2-((1R,2S)-2-amino-cyclohexylamino)-5-difluoromethyl- pyrido[4,3-d]pyrimidin-8-yl]-1H-indole-6-carbonitrile “A88” (1S,2R)-N-[5-methyl-8-(6-trifluoromethyl-1H-indol-3-yl)- pyrido[4,3-d]pyrimidin-2-yl]-cyclohexane-1,2-diamine “A89” (1R,2S)-N-[5-methyl-8-(6-trifluoromethyl-1H-indol-3-yl)- pyrido[4,3-d]pyrimidin-2-yl]-cyclohexane-1,2-diamine “A90” 2-((1S,2R)-2-amino-cyclohexylamino)-8-(1-methyl-1H- pyrazol-4-yl)-6H-pyrido[4,3-d]pyrimidin-5-one “A91” (1R,2S)-N-[5-difluoromethyl-8-(1-methyl-1H-pyrazol-4-yl)- pyrido-[4,3-d]pyrimidin-2-yl]-cyclohexane-1,2-diamine and pharmaceutically acceptable solvates, salts, enantiomers, tautomers and stereoisomers thereof.

7. Process for the preparation of compounds of the formula I according to claim 1 and pharmaceutically acceptable salts, solvates, enantiomers, tautomers and stereoisomers thereof, comprising: a) for the preparation of compounds of the formula I, wherein R denotes NR.sup.4R.sup.4′ and R.sup.2 denotes NR.sup.3Cyc, NR.sup.3CHR.sup.3CON(R.sup.3).sub.2, NR.sup.3[C(R.sup.3).sub.2].sub.pCR.sup.3(NH.sub.2)CH.sub.2OA or NR.sup.3[C(R.sup.3).sub.2].sub.pN(R.sup.3).sub.2, reacting a compound of the formula II ##STR00171## in which R.sup.1, R.sup.4, R.sup.4′ have the meanings indicated in claim 1, with a compound of the formula III
R.sup.2—NHR.sup.3  III in which R.sup.2 and R.sup.3 have the meanings indicated in claim 1, or b) for the preparation of compounds of the formula I, wherein R denotes H, reacting a compound of the formula IV ##STR00172##  in which R.sup.2 has the meanings indicated in claim 1, with a compound of the formula V
R.sup.1-L  V in which R.sup.1 has the meaning indicated in claim 1, and L denotes a boronic acid or a boronic acid ester group, in a Suzuki-type coupling, and/or converting a base or acid of the formula I into one of its salts.

8. A medicament composition comprising at least one compound of the formula I and/or pharmaceutically acceptable salts, solvates, enantiomers, tautomers and stereoisomers thereof, including mixtures thereof in all ratios, and optionally an pharmaceutically acceptable carrier, excipient or vehicle.

9. A medicaments composition comprising at least one compound of the formula I and/or pharmaceutically acceptable salts, solvates, enantiomers, tautomers and stereoisomers thereof, including mixtures thereof in all ratios, and at least one further medicament active ingredient.

10. A kit consisting of separate packs of (a) an effective amount of a compound of the formula I and/or pharmaceutically acceptable salts, solvates, enantiomers, tautomers and stereoisomers thereof, including mixtures thereof in all ratios, and (b) an effective amount of a further medicament active ingredient.

11. A compound which is: TABLE-US-00006 “A86” 2-((cis)-2-amino-cyclohexylamino)-8-(6-trifluoromethyl-1H-indol- 3-yl)-6H-pyrido[4,3-d]pyrimidin-5-one “A90” 2-((1S,2R)-2-amino-cyclohexylamino)-8-(1-methyl-1H-pyrazol-4- yl)-6H-pyrido[4,3-d]pyrimidin-5-one or a pharmaceutically acceptable salt, solvate, enantiomer, tautomer or stereoisomer thereof.

Description

EXAMPLES

(1) General synthetic route for preparation of amino-pyridopyrimidine derivatives:

(2) ##STR00007## ##STR00008##

Preparation of intermediates

2-[1-Ethoxy-meth-(Z)-ylidene]-3-oxo-butyric acid ethyl ester

(3) ##STR00009##

(4) Ethyl acetoacetate (600 ml, 4.75 mol, 1 eq) is treated with triethyl orthoformate (780 ml, 4.74 mol, 1 eq) and acetic anhydride (900 ml, 9.52 mol, 2 eq) at rt. The resulting suspension is heated to 120° C. for 2 h and monitored by IPC. Upon completion, the reaction is cooled to rt and evaporated in vacuo. For further purification the liquid is destillated 84° C.-120° C., 0.7-0.4 mbar) to give the title compound (674 g, 72%) as a light yellow liquid;

(5) HPLC (method I): Rt 2.07 min (purity 94%); LCMS (ESI.sup.+) (method E): Rt 1.984 min, M+H.sup.+187.1 m/z.

4-Methyl-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester

(6) ##STR00010##

(7) 2-[1-Ethoxy-meth-(Z)-ylidene]-3-oxo-butyric acid ethyl ester (666 g, 3.58 mol, 1 eq) is dissolved in ethanol (3.5 L, 17 eq), TEA (515 ml, 3.7 mol, 1 eq) and S-methyl-isothiouronium sulfate (560 g, 2.01 mol, 0.6 eq) are added. Under vigorous stirring the reaction is heated to reflux for 2 h. At 0° C. 3 L water are added to the reaction mixture and the black suspension is stirred overnight at rt. The suspension is cooled to 0° C. and suctioned by vacuum. The precipitate is washed with water and dried for 14 h at 35° C. under vacuum giving 612 g (81%) of the title compound as an off-white solid;

(8) HPLC (method I): Rt 3.06 min (purity 99.9%); LCMS (ESI.sup.+) (method E): Rt 2.355 min, M+H.sup.+212.3 m/z.

4-((E)-2-Dimethylamino-vinyl)-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester

(9) ##STR00011##

(10) 4-Methyl-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (615 g, 2.9 mol, 1 eq) is suspended in DMF (2.8 L) and N,N-dimethylformamide dimethylacetal (780 ml, 2 eq) is added dropwise. The reaction is heated to reflux for 1.5 h. After completion the reaction mixture is cooled down and suspended in 9 L of an ice/water mixture. A yellow precipitate is suctioned by vacuum. The precipitate is washed with water and dried for 14 h at 40° C. A mixture of E and Z 4-(2-dimethylamino-vinyl)-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (745 g, 75%) is obtained as yellow solid; HPLC (method I): Rt 2.767 min (purity 78.3%); LCMS (ESI.sup.+) (method E): Rt 2.158 min, M+H.sup.+268.1 m/z.

2-Methylsulfanyl-6H-pyrido[4,3−d]pyrimidin-5-one

(11) ##STR00012##

(12) 4-((E)-2-Dimethylamino-vinyl)-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (316 g, 1.18 mol, 1 eq) is suspended in EtOH (3 L) and ammonium acetate (911 g, 11.82 mol, 10 eq) is added. The orange suspension is heated up to 78° C. After 20 min of reflux an almost clear red solution is obtained which starts to become a red-orange suspension after 1.5 h of reflux. HPLC shows 85% of product. The heating system is switch off and the reaction mixture is allowed to cool down. The red-orange suspension is filtered and washed with ethanol, suspended in 600 ml water and stirred for 60 min. The suspension is filtered and the precipitate is washed with water and 150 ml EtOH. The obtained red-orange crystals are dried in vacuum at 35° C. with under nitrogen flow, to give 174 g (73%) of the title compound;

(13) HPLC (method I): Rt 1.837 min (purity 95.9%); LCMS (ESI.sup.+) (method E): Rt 1.437 min, M+H.sup.+194 m/z.

8-Iodo-2-methylsulfanyl-6H-pyrido[4,3-d]pyrimidin-5-one

(14) ##STR00013##

(15) 2-Methylsulfanyl-6H-pyrido[4,3-d]pyrimidin-5-one (84 g, 0.42 mol, 1 eq) is dissolved in dry acetonitrile (2.2 L) and potassium carbonate (116 g, 0.84 mol, 2 eq) is added at rt. To the reaction mixture N-iodosuccinimide (118 g, 0.53 mol, 1.3 eq) is added in portions. The resulting suspension is heated to 75° C. for 3 h and monitored by HPLC MS. Upon completion, the reaction is cooled to rt and the precipitate is collected by suction. The precipitate is rinsed with acetonitrile, then suspended in a minimum amount of water and treated by ultra sonification. The solids are again collected by suction and dried in vacuum at 35° C. to give the title compound (115 g, 82%) as pale yellow crystals;

(16) HPLC (method A): Rt 2.48 min (purity 70.1%); LCMS (ESI.sup.+) (method G): Rt 1.687 min, M+H.sup.+319.9 m/z.

5-Chloro-8-iodo-2-methylsulfanyl-pyrido[4,3-d]pyrimidine

(17) ##STR00014##

(18) 8-Iodo-2-methylsulfanyl-6H-pyrido[4,3-d]pyrimidin-5-one (208 g, 0.63 mol, 1 eq) is suspended in acetonitrile and benzyltriethylammonium chloride (280 g, 1.23 mol, 2 eq) is added. DIPEA (137 ml, 0.81 mol, 1.3 eq) is added to the suspension, followed by slow addition of phosphorylchloride (118 ml, 1.29 mol; 204.62 mol %) within 15 min. The reaction mixture is refluxed for 14 h. The suspension is cooled to 30° C. and slowly poured into 3 L ice water. The resulting brown suspension is stirred for 20 min and filtered. The precipitate is washed with 2 L water, withdrawn by suction and dried at 35° C. under a nitrogen flow. The title compound (201 g, 88%) is obtained as a pale brown solid;

(19) HPLC (method I): Rt 3.853 min (purity 97.8%); LCMS (ESI.sup.+) (method E): Rt 2.695 min, M+H.sup.+338 m/z.

8-Iodo-2-methylsulfanyl-pyrido[4,3-d]pyrimidin-5-ylamine

(20) ##STR00015##

(21) 5-Chloro-8-iodo-2-methylsulfanyl-pyrido[4,3-d]pyrimidine (31 g, 85 mmol, 1 eq) suspended in dioxane (220 ml) is treated with an ammonia solution 32% (106 ml, 30 eq) and heated in a closed vessel at 100° C. for 15 minutes. At rt the solids are withdrawn by suction, washed with water and dried for 14 h at 35° C. under vacuum. The title compound (21.2 g, 59%) is obtained as off-white amorphous solid;

(22) HPLC (method A): Rt 2.36 min (purity 82.2%); LCMS (ESI.sup.+) (method G): Rt 1.42 min, M+H.sup.+318.9 m/z.

8-(1-Methyl-1H-pyrazol-4-yl)-2-methylsulfanyl-pyrido[4,3-d]pyrimidin-5-ylamine

(23) ##STR00016##
Process A:

(24) A microwave vial is charged with 8-iodo-2-methylsulfanyl-pyrido[4,3-d ]pyrimidin-5-ylamine (1 eq.), 1-methylpyrazole-4-boronic acid (1.50 eq.), palladium(II)-acetate (47% Pd) (5 mol %.), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (10 mol-%.), potassium carbonate (3 eq.), ethylenglycoldimethylether (1 mL/mmol.), water (0.5 ml/mmol) and is degassed for 5 min. The suspension is heated at 150° C. for 45 min under microwave irradiation and monitored via HPLC MS. Upon completion, the suspension is cooled to rt, filtered over a pad of Celite and washed with methanol. The filtrate is concentrated in vacuo. The crude material is purified by flash chromatography. The title compound (99% yield) is obtained as an orange solid.

N2-((cis)-2-Amino-cyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)-pyrido[4,3-d]-pyrimidine-2,5-diamine (“A1”)

(25) ##STR00017##

(26) 8-(1-Methyl-1H-pyrazol-4-yl)-2-methylsulfanyl-pyrido[4,3-d]pyrimidin-5-ylamine (245 mg, 0.68 mmol, 1 eq) is treated with cis-1,2-cyclohexanediamine (824 μl, 6.8 mmol, 10 eq) and stirred for 5.5 h at 150° C. The mixture is cooled to rt, diluted with acetonitrile and purified via prep. HPLC to give the title compound (180 mg, 78%) as a brown solid.

(27) One obtains the mixture of the two cis-enantiomers.

(28) The enantiomers are separated via chiral HPLC.

(29) Enantiomer 1 (the compound which eluates first from the column):

(30) HPLC (method A): Rt 2.24 min (purity 98%); LCMS (ESI+) (method G): Rt 1.243 min., MH+339.20; HCl salt: .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ [ppm] 9.35-9.23 (m, 1H), 8.60-8.37 (m, 1H), 8.34-8.21 (m, 2H), 8.08-7.97 (m, 1H), 7.29-7.03 (m, 1H), 7.00-6.86 (m, 2H), 6.52-6.43 (m, 1H), 3.98-3.90 (m, 1H), 3.86 (s, 3H), 3.19-3.13 (m, 1H), 2.55 (q, J=7.1, 2H), 1.72-1.63 (m, 2H), 1.62-1.54 (m, 2H), 1.42-1.31 (m, 2H).

(31) General synthetic route for preparation of des-amino-pyridopyrimidine derivatives:

(32) ##STR00018##

Preparation of intermediates

5-Chloro-2-methylsulfanyl-pyrido[4,3-d]pyrimidine

(33) ##STR00019##

(34) 2-Methylsulfanyl-6H-pyrido[4,3-d]pyrimidin-5-one (72 g, 0.37 mol, 1 eq) is suspended in phosphorylchloride (420 ml) and refluxed for 1.5 h. At rt the reaction mixture is evaporated in vacuo. To the residue is added 450 ml of ice water and stirred for a while. The solid is filtered by vacuum and dried for 14 h at 40° C. under vacuum. The title compound (54 g, 63%) is obtained as a light brown solid;

(35) HPLC (method A): Rt 2.57 min (purity 98.7%); LCMS (ESI.sup.+) (method G): Rt 1.95 min, M+H.sup.+212.1 m/z.

2-Methylsulfanyl-pyrido[4,3-d]pyrimidine

(36) ##STR00020##

(37) A microwave vial is charged with 5-chloro-2-methylsulfanyl-pyrido[4,3-d]-pyrimidine (1 g, 4.66 mmol, 1 eq) dissolved in MeOH (18 ml) and palladium-activated carbon (10% Pd, 452 mg, 0.42 mmol, 0.1 eq), ammonium formate (606 mg, 9.33 mmol, 2 eq) are added. The suspension is heated twice at 100° C. for 1 h under microwave irradiation and monitored by HPLC. Upon completion, the suspension is cooled to rt, filtered over a pad of Celite by suction and the solvent is removed in vacuum. The precipitate is dissolved in DCM/MeOH, absorbed on silica gel and purified by flash chromatography (n-heptane.fwdarw.n-heptane/ethyl acetate 1:3) yielding title compound (826 mg, 54%) as white solid;

(38) HPLC (method A): Rt 2.15 min (purity 100%); LCMS (ESI.sup.+) (method G): Rt 1.06 min, M+H.sup.+178.1 m/z.

8-Iodo-2-methylsulfanyl-pyrido[4,3-d]pyrimidine

(39) ##STR00021##

(40) 2-Methylsulfanyl-pyrido[4,3-d]pyrimidine (17 g, 96 mmol, 1 eq.) are suspended in N,N-dimethylformamide (340 ml, 4.37 mol, 46 eq.). Trifluoroacetic acid (9 ml, 115 mmol, 1.2 eq.) and N-iodosuccinimide (22 g, 97 mmol, 1 eq.) are added to the reaction mixture and stirred at 50° C. for 4 d. Another portion of NIS (4.3 g, 19 mmol, 0.2 eq) is added and stirring at 50° C. is continued for 3 d. Upon completion the reaction mixture is poured into water and diluted sodium thiosulphate solution is added. After 20 min the suspension turned violet. The solids are filtered by suction, washed with water. The residue is dissolved, transferred in a round bottom flask and concentrated in vacuo. The residue is further dried under vacuum to yield the title compound (30 g, 85%) as yellow solid;

(41) HPLC (method A): Rt 2.60 min (purity 100%); LCMS (ESI.sup.+) (method G): Rt 2.02 min, M+H.sup.+304 m/z.

2-Chloro-8-iodo-pyrido[4,3-d]pyrimidine

(42) ##STR00022##

(43) 8-Iodo-2-methylsulfanyl-pyrido[4,3-d]pyrimidine (2.40 g, 7.34 mmol, 1 eq.) is suspended in acetonitrile (56.00 ml). At 0° C. DCM (72 ml, 1.13 mol, 153 eq.) is added which turned the suspension in a clear solution. Sulfuryl chloride (6 ml, 73.40 mmol, 10 eq.) is added which results in an immediate precipitation. The suspension is stirred for 2 h at 0° C. The precipitate is filtered, washed with acetonitrile and dried under vacuum at 50° C. for 1 h. 2-Chloro-8-iodo-pyrido-[4,3-d]pyrimidine (1.86 g; 6.38 mmol) is obtained as an orange solid; HPLC (method A): Rt 2.45 min (purity 100%); LCMS (ESI.sup.+) (method G): Rt 1.75 min, M+H.sup.+291.9 m/z.

[(1S,2R)-2-(8-Iodo-pyrido[4,3-d]pyrimidin-2-ylamino)-cyclohexyl]-carbamic acid tea-butyl ester

(44) ##STR00023##

(45) 2-Chloro-8-iodo-pyrido[4,3-d]pyrimidine (2.26 g, 7.24 mmol, 1 eq.) is dissolved in triethylamine (1.51 ml, 10.86 mmol, 1.5 eq.) and ethanol (4.82 ml, 82.68 mmol, 11.4 eq.). ((1S,2R)-2-Amino-cyclohexyl)-carbamic acid tert-butyl ester (1.86 g, 8.69 mmol, 1.2 eq.) is added to the reaction mixture which is heated for 5 min at 120° C. in a microwave reactor. The reaction mixture is evaporated in vacuo, dissolved in ethyl acetate and sonicated. The solids (triethylammonium chloride) are withdrawn by suction. The filtrate is evaporated in vacuo. The obtained residue is suspended in acetonitrile, sonicated and filtered by suction to remove byproducts. Again, the filtrate is evaporated in vacuo. The obtained residue is dissolved in ethyl acetate and filtered over a plug of amino functionalized silica gel. The filtrate is evaporated in vacuo to give the title compound (2.17 g, 50%) as orange solid; HPLC (method A): Rt 2.49 min (purity 99.6%); LCMS (ESI.sup.+) (method G): Rt 1.95 min, M+H.sup.+470.1 m/z.

{(1S,2R)-2-[8-(1-Methyl-1H-pyrazol-4-yl)-pyrido[4,3-d]pyrimidin-2-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester

(46) ##STR00024##

(47) The Suzuki coupling is performed by reacting [(1S,2R)-2-(8-iodo-pyrido[4,3-d]pyrimidin-2-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester with 1-methylpyrazole-4-boronic acid analogously to “process A”. The title compound (41.6% yield) is obtained as yellow solid.

(1R,2S)—N-[8-(1-Methyl-1H-pyrazol-4-yl)-pyrido[4,3-d]pyrimidin-2-yl]-cyclohexane-1,2-diamine hydrochloride (“A2”)

(48) ##STR00025##

(49) {(1S,2R)-2-[8-(1-Methyl-1H-pyrazol-4-yl)-pyrido[4,3-d]pyrimidin-2-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (18.8 mg, 0.044 mmol, 1 eq.) is dissolved in ethyl acetate (1.0 ml) and HCl solution (1 N, 222 μl, 0.222 mmol, 5 eq.) are added. The reaction mixture is vigorously stirred for 4 h at 40° C. Ethyl acetate is removed by a nitrogen flow. The remaining aqueous solution is diluted with water and lyophylized to give the title compound (15 mg, 94%) as yellow solid;

(50) HPLC (method A): Rt 2.28 min (purity 100.0%); LCMS (ESI.sup.+) (method G): Rt 1.21 min, M+H.sup.+324.3 m/z;

(51) HPLC (method A): Rt 2.28 min (purity 100%); LCMS (ESI+) (Method G): Rt 1.241 min., MH+324.20; HCl salt: .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ [ppm] 9.66-9.54 (m, 1H), 9.44-9.29 (m, 1H), 9.29-9.00 (m, 1H), 8.98 (s, 1H), 8.70-8.45 (m, 1H), 8.34 (s, 1H), 8.27-8.17 (m, 2H), 4.56-4.49 (m, 1H), 3.97 (s, 3H), 3.76 (s, 1H), 2.11-1.94 (m, 2H), 1.84-1.62 (m, 4H), 1.57-1.41 (m, 2H).

(52) Analogous reaction gives the following compounds:

(53) TABLE-US-00003 nr. name and/or structure “A3” N2-(cis-2-Amino-cyclohexyl)-8-(3-[1,2,3]triazol-2-yl-phenyl)- pyrido[4,3-d]pyrimidine-2,5-diamine HPLC (method A): Rt 2.31 min (purity 100%); LCMS (ESI+) (method G): Rt 1.350 min., MH+ 402.20; HCl salt: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ [ppm] 9.70 (s, 1H), 9.14 (s, 1H), 8.96-8.87 (m, 1H), 8.55-8.33 (m, 3H), 8.19 (s, 1H), 8.02-8.02 (m, 1H), 7.99-7.90 (m, 2H), 7.82-7.75 (m, 1H), 7.74-7.66 (m, 2H), 3.58-3.45 (m, 2H), 1.88-1.61 (m, 4H), 1.60- 1.50 (m, 2H), 1.48-1.35 (m, 1H), 1.33-1.16 (m, 1H) “A4” N2-((cis)-2-Amino-cyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)- pyrido[4,3-d]pyrimidine-2,5-diamine Enantiomer 2 (the compound which eluates second from the column) HPLC (method A): Rt 2.27 min (purity 98%); LCMS (ESI+) (method G): Rt 1.271 min., MH+ 339.20; HCl salt: .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ [ppm] 9.35-9.23 (m, 1H), 8.60-8.37 (m, 1H), 8.34-8.21 (m, 2H), 8.08-7.97 (m, 1H), 7.29-7.03 (m, 1H), 7.00-6.86 (m, 2H), 6.52-6.43 (m, 1H), 3.98- 3.90 (m, 1H), 3.86 (s, 3H), 3.19-3.13 (m, 1H), 2.55 (q, J = 7.1, 2H), 1.72-1.63 (m, 2H), 1.62-1.54 (m, 2H), 1.42-1.31 (m, 2H) “A5” {1-[5-Amino-8-(1-methyl-1H-pyrazol-4-yl)-pyrido[4,3-d] pyrimidin-2-yl]-piperidin-4-yl}-methanol HPLC (Method J): Rt 1.82 min (purity 97%); LCMS (ESI+) (Method G): Rt 1.363 min., MH+ 340.20: .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ [ppm] 9.33 (s, 1H), 8.23 (s, 1H), 8.15 (s, 1H), 7.97 (s, 1H), 6.99 (s, 2H), 4.89-4.75 (m, 2H), 4.47 (s, 1H), 3.87 (s, 3H), 3.32-3.26 (m, 2H), 3.00 (td, J = 12.7, 2.7, 2H), 1.85-1.76 (m, 2H), 1.73 (td, J = 6.4, 3.5, 1H), 1.21-1.08 (m, 2H) “A6” N2-(2-Amino-ethyl)-8-(1-methyl-1H-pyrazol-4-yl)-pyrido[4,3-d]- pyrimidine-2,5-diamine HPLC (method A): Rt 2.20 min (purity 100%); LCMS (ESI+) (method G): Rt 1.060 min., MH+ 285.20; HCl salt: .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ [ppm] 9.73-9.57 (m, 1H), 9.05-8.76 (m, 2H), 8.68-8.59 (m, 1H), 8.33 (s, 1H), 8.15- 8.05 (m, 3H), 8.03 (s, 1H), 3.96-3.88 (m, 3H), 3.75 (q, J = 6.1, 2H), 3.18-3.10 (m, 1H), 3.10-3.03 (m, 1H) “ A7” N2-(cis-2-Amino-cyclohexyl)-8-(4-tert-butyl-phenyl)-pyrido[4,3- d]pyrimidine-2,5-diamine 0 HPLC (method J): Rt 2.236 min (purity 100%); LCMS (ESI+) (method G): Rt 1.790 min., MH+ 391.30 “A8” N2-(cis-2-Amino-cyclohexyl)-8-(1-isobutyl-1H-pyrazol-4-yl)- pyrido[4,3-d]pyrimidine-2,5-diamine HPLC (method J): Rt 1.89 min (purity 97%); LCMS (ESI+) (method G): Rt 1.526 min., MH+ 381.30; HCl salt: .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ [ppm] 9.74-9.66 (m, 1H), 9.05-8.94 (m, 2H), 8.49 (d, J = 7.3, 1H), 8.37 (s, 1H), 8.33- 8.26 (m, 1H), 8.22-8.12 (m, 3H), 8.05 (s, 1H), 4.48-4.40 (m, 1H), 4.03-3.96 (m, 2H), 3.66-3.60 (m, 1H), 2.22-2.11 (m, 1H), 2.06-1.88 (m, 2H), 1.82-1.58 (m, 4H), 1.49-1.41 (m, 2H), 0.90- 0.84 (m, 6H) “A9” 5-Amino-2-(cis2-amino-cyclohexylamino)-pyrido[4,3-d]pyrimi- dine-8-carbonitrile HPLC (method J): Rt 1.526 min (purity 56%); LCMS (ESI+) (method G): Rt 1.209 min., MH+ 284.10; formate salt: .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ [ppm] 9.39-9.28 (m, 1H), 8.38 (s, 1H), 8.32-7.90 (m, 4H), 7.89-7.78 (m, 1H), 7.78-7.54 (m, 1H), 4.15 (s, 1H), 3.41-3.36 (m, 1H), 1.88-1.71 (m, 2H), 1.68-1.51 (m, 4H), 1.42-1.31 (m, 2H) “A10” N2-(cis-2-Amino-cyclohexyl)-8-(1H-indol-2-yl)-pyrido[4,3- d]pyrimidine-2,5-diamine HPLC (method A): Rt 2.40 min (purity 100%); LCMS (ESI+) (method G): Rt 1.636 min., MH+ 374.20: .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ [ppm] 1.62 (s, 1H), 9.35 (s, 1H), 8.62 (s, 1H), 7.63-7.50 (m, 1H), 7.50-7.34 (m, 3H), 7.34-7.09 (m, 3H), 7.08-6.90 (m, 3H), 4.10-4.02 (m, 1H), 3.27-3.20 (m, 1H), 1.87-1.27 (m, 8H) “A11” 2-((cis)-3-Methyl-octahydro-benzoimidazol-1-yl)-8-(1-methyl- 1H-pyrazol-4-yl)-pyrido[4,3-d]pyrimidin-5-ylamine Enantiomer 2 (the compound which eluates second from the column) HPLC (method A): Rt 2.28 min (purity 100%); LCMS (ESI+) (method G): Rt 1.221 min., MH+ 365.20: .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ [ppm] 9.33 (d, J = 6.4, 1H), 8.48-8.25 (m, 2H), 8.24 (s, 1H), 8.09-7.95 (m, 1H), 7.09-6.91 (m, 2H), 4.79-4.68 (m, 1H), 4.27-4.16 (m, 1H), 3.89-3.83 (m, 3H), 3.34-3.27 (m, 3H), 2.36-2.24 (m, 3H), 2.20-1.89 (m, 2H), 1.73-1.50 (m, 2H), 1.48-1.19 (m, 4H) “A12” N2-(cis2-Amino-cyclohexyl)-8-methyl-pyrido- [4,3-d]pyrimidine-2,5-diamine HPLC (method A): Rt 2.24 min (purity 94%); LCMS (ESI+) (method G): Rt 1.295 min., MH+ 273.20; HCl salt “A13” N2-((cis)-2-Amino-cyclohexyl)-8-(4-trifluoromethoxy-phenyl)- pyrido[4,3-d]pyrimidine-2,5-diamine Enantiomer 1 (the compound which eluates first from the column) HPLC (method A): Rt 2.40 min (purity 99%); LCMS (ESI+) (method G): Rt 1.715 min., MH+ 419.20; HCl salt: .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ [ppm] 9.68 (s, 1H), 9.15 (s, 2H), 8.46 (d, J = 6.4, 1H), 8.05 (s, 1H), 8.04-7.95 (m, 2H), 7.83-7.75 (m, 2H), 7.46 (d, J = 8.2, 2H), 4.05-3.96 (m, 1H), 3.63- 3.56 (m, 1H), 1.93-1.77 (m, 2H), 1.72-1.50 (m, 4H), 1.45- 1.30 (m, 2H) “A14” N2-((cis)-2-Amino-cyclohexyl)-8-(4-trifluoromethoxy-phenyl)- pyrido[4,3-d]pyrimidine-2,5-diamine Enantiomer 2 (the compound which eluates second from the column) HPLC (method A): Rt 2.40 min (purity 99%); LCMS (ESI+) (method G): Rt 1.712 min., MH+ 419.20; HCl salt: .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ [ppm] 9.68 (s, 1H), 9.15 (s, 2H), 8.46 (d, J = 6.4, 1H), 8.05 (s, 1H), 8.04-7.95 (m, 2H), 7.83-7.75 (m, 2H), 7.46 (d, J = 8.2, 2H), 4.05-3.96 (m, 1H), 3.63-3.56 (m, 1H), .93-1.77 (m, 2H), 1.72-1.50 (m, 4H), 1.45- 1.30 (m, 2H) “A15” {1-[5-Cyclopropylamino-8-(1-methyl-1H-pyrazol-4-yl)-pyrido- [4,3-d]pyrimidin-2-yl]-piperidin-4-yl}-methanol HPLC (method J): Rt 1.94 min (purity 100%); LCMS (ESI+) (method G): Rt 1.515 min., MH+ 380.20; HCl salt “A16” {1-[5-Diethylamino-8-(1-methyl-1H-pyrazol-4-yl)-pyrido[4,3-d]- pyrimidin-2-yl]-piperidin-4-yl}-methanol HPLC (method J): Rt 2.03 min (purity 100%); LCMS (ESI+) (method G): Rt 1.588 min., MH+ 396.30; HCl salt “A17” N2-((1R,2S)-2-Amino-cyclohexyl)-8-phenyl-pyrido[4,3-d]- pyrimidine-2,5-diamine 0 HPLC (method A): Rt 2.32 min (purity 96%); LCMS (ESI+) (method G): Rt 1.468 min., MH+ 335.20; .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ [ppm] 9.37 (s, 1H), 8.12 (s, 1H), 7.85-7.58 (m, 2H), 7.43 (t, J = 7.6, 2H), 7.36-7.29 (m, 1H), 7.27- 7.19 (m, 1H), 7.17-7.07 (m, 4H), 3.83 (s, 1H), 3.17-3.10 (m, 1H), 1.78-1.45 (m, 6H), 1.43-1.22 (m, 2H) “A18” N2-(cis-2-Amino-cyclohexyl)-8-(7-methoxy-1H-indol-2-yl)- pyrido[4,3-d]pyrimidine-2,5-diamine HPLC (method A): Rt 2.39 min (purity 100%); LCMS (ESI+) (method G): Rt 1.669 min., MH+ 404.20; formate salt: .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ [ppm] 11.44 (s, 1H), 9.55 (s, 1H), 8.57 (s, 1H), 8.43-8.02 (m, 2H), 7.98-7.73 (m, 3H), 7.14 (d, J = 7.6, 2H), 6.95 (t, J = 7.8, 1H), 6.69 (d, J = 7.7, 1H), 4.46-4.39 (m, 1H), 3.96 (s, 3H), 3.73 (s, 1H), 2.04-1.87 (m, 2H), 1.85-1.74 (m, 2H), 1.73-1.61 (m, 2H), 1.57-1.45 (m, 2H) “A19” N2-(cis-2-Amino-cyclohexyl)-8-(5-methoxy-1H-indol-2-yl)- pyrido[4,3-d]pyrimidine-2,5-diamine HPLC (method A): Rt 2.36 min (purity 98%); LCMS (ESI+) (method G): Rt 1.591 min., MH+ 404.30; .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ [ppm] 11.80 (s, 1H), 11.52 (s, 1H), 9.35 (s, 1H), 8.58 (s, 1H), 7.63-7.53 (m, 1H), 7.48-7.35 (m, 1H), 7.32-7.16 (m, 3H), 7.03-6.92 (m, 2H), 6.74-6.65 (m, 1H), 4.09-4.01 (m, 1H), 3.76 (s, 3H), 3.24-3.19 (m, 1H), 1.88- 1.54 (m, 6H), 1.50-1.31 (m, 2H) “A20” N2-((R)-2-Amino-3-methoxy-propyl)-8-(1-methyl-1H-pyrazol- 4-yl)-pyrido[4,3-d]pyrimidine-2,5-diamine HPLC (method J): Rt 1.51 min (purity 100%); LCMS (ESI+) (method G): Rt 1.146 min., MH+ 329.20; HCl salt: .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ [ppm] 9.89-9.58 (m, 1H), 8.64-8.54 (m, 1H), 8.49-7.99 (m, 3H), 4.39-4.06 (m, 1H), 4.03-3.94 (m, 3H), 3.91-3.70 (m, 2H), 3.68-3.56 (m, 2H), 3.44-3.32 (m, 3H) “A21” N2-((cis)-2-Amino-cyclohexyl)-8-m-tolyl-pyrido[4,3-d] pyrimidine-2,5-diamine Enantiomer 1 (the compound which eluates first from the column) HPLC (method A): Rt 2.33 min (purity 98%); LCMS (ESI+) (method G): Rt 1.542 min., MH+ 349.20; HCl salt: .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ [ppm] 9.66 (s, 1H), 9.21-8.87 (m, 1H), 8.52 (s, 1H), 8.40 (d, J = 6.5, 1H), 8.01-7.92 (m, 3H), 7.50-7.42 (m, 2H), 7.34 (t, J = 7.6, 1H), 7.25-7.18 (m, 1H), 4.06-3.97 (m, 1H), 3.63-3.55 (m, 1H), 2.95-2.86 (m, 2H), 2.38 (s, 3H), 1.94-1.85 (m, 2H), 1.65-1.56 (m, 2H), 1.44-1.32 (m, 2H) “A22” N2-((cis)-2-Amino-cyclohexyl)-8-m-tolyl-pyrido[4,3-d] pyrimidine-2,5-diamine Enantiomer 2 (the compound which eluates second from the column) HPLC (method A): Rt 2.33 min (purity 99%); LCMS (ESI+) (method G): Rt 1.541 min., MH+ 349.30; HCl salt: .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ [ppm] 9.66 (s, 1H), 9.21-8.87 (m, 1H), 8.52 (s, 1H), 8.40 (d, J = 6.5, 1H), 8.01-7.92 (m, 3H), 7.50-7.42 (m, 2H), 7.34 (t, J = 7.6, 1H), 7.25-7.18 (m, 1H), 4.06-3.97 (m, 1H), 3.63-3.55 (m, 1H), 2.95-2.86 (m, 2H), 2.38 (s, 3H), 1.94-1.85 (m, 2H), 1.65-1.56 (m, 2H), 1.44-1.32 (m, 2H) “A23” 2-[5-Amino-2-((cis)-2-amino-cyclohexylamino)-pyrido[4,3-d]- pyrimidin-8-yl]-1H-indole-5-carbonitrile HPLC (method A): Rt 2.37 min (purity 100%); LCMS (ESI+) (method G): Rt 1.657 min., MH+ 399.20 .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ [ppm] 12.18 (s, 1H), 9.47-9.26 (m, 2H), 8.66-8.54 (m, 1H), 7.98-7.91 (m, 1H), 7.75-7.62 (m, 1H), 7.59-7.50 (m, 1H), 7.48-7.40 (m, 1H), 7.39-7.33 (m, 2H), 7.28-7.21 (m, 2H), 4.10-4.03 (m, 1H), 3.96 (s, 1H), 1.79-1.65 (m, 2H), 1.50-1.33 (m, 2H), 1.09-0.87 (m, 4H) “A24” N2-(cis-2-Amino-cyclohexyl)-8-(1H-indol-3-yl)-pyrido[4,3- d]pyrimidine-2,5-diamine HPLC (method J): Rt 1.93 min (purity 89%); LCMS (ESI+) (method G): Rt 1.560 min., MH+ 374.20; HCl salt: .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ [ppm] 12.94 (s, 1H), 11.49 (s, 1H), 9.66 (s, 1H), 9.01-8.90 (m, 1H), 8.43 (d, J = 6.7, 1H), 8.07 (s, 1H), 7.98-7.82 (m, 4H), 7.68-7.63 (m, 1H), 7.48 (d, J = 8.0, 1H), 7.20-7.13 (m, 1H), 7.13-7.06 (m, 1H), 4.13- 4.06 (m, 1H), 3.54-3.48 (m, 1H), 1.91-1.68 (m, 2H), 1.66-1.58 (m, 2H), 1.57-1.41 (m, 1H), 1.38-1.26 (m, 3H) “A25” cis-N-[8-(1,3-Dimethyl-1H-pyrazol-4-yl)-pyrido[4,3-d] pyrimidin-2-yl]-cyclohexane-1,2-diamine HPLC (method A): Rt 2.21 min (purity 98%); LCMS (ESI+) (method G): Rt 1.216 min., MH+ 338.20; .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ [ppm] 9.27 (s, 1H), 8.90 (s, 1H), 8.60 (s, 1H), 8.18 (s, 1H), 7.61-7.50 (m, 2H), 7.43-7.23 (m, 1H), 3.97-3.90 (m, 1H), 3.85 (s, 3H), 3.17-3.10 (m, 1H), 2.32 (s, 3H), 1.70-1.61 (m, 4H), 1.58-1.49 (m, 2H), 1.40-1.27 (m, 2H) “A26” (1S,2R)-[8-(1-Isopropyl-1H-pyrazol-4-yl)-pyrido[4,3-d]pyrimidin- 2-yl]-cyclohexane-1,2-diamine HPLC (method A): Rt 2.31 min (purity 98%); LCMS (ESI+) (method G): Rt 1.430 min., MH+ 352.20; .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ [ppm] 9.56 (s, 1H), 9.31-9.28 (m, 1H), 9.01 (s, 1H), 8.73 (s, 1H), 8.37 (s, 1H), 8.34-8.29 (m, 1H), 8.22-8.13 (m, 2H), 4.66-4.51 (m, 2H), 3.76-3.68 (m, 1H), 2.10-1.95 (m, 2H), 1.83-1.72 (m, 2H), 1.72-1.58 (m, 2H), 1.54- 1.42 (m, 8H) “A27” (1S,2R)-N-[8-(1H-Indol-3-yl)-pyrido[4,3-d]pyrimidin-2-yl]- cyclohexane-1,2-diamine 0 HPLC (method J): Rt 1.87 min (purity 100%); LCMS (ESI+) (method G): Rt 1.439 min., MH+ 359.20; .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ [ppm] 11.54 (s, 1H), 9.28 (s, 1H), 8.93 (s, 1H), 8.88 (s, 1H), 8.23-8.14 (m, 1H), 7.86 (d, J = 8.0, 1H), 7.55 (d, J = 7.7, 1H), 7.48 (d, J = 8.0, 1H), 7.21-7.14 (m, 1H), 7.13- 7.06 (m, 1H), 3.98-3.90 (m, 1H), 3.15-3.09 (m, 1H), 1.81- 1.42 (m, 6H), 1.37-1.19 (m, 2H) “A28” 3-[2-((1R,2S)-2-Amino-cyclohexylamino)-pyrido[4,3-d] pyrimidin-8-yl]-benzenesulfonamide HPLC (method A): Rt 2.27 min (purity 100%); LCMS (ESI+) (method G): Rt 1.237 min., MH+ 399.10; HCl salt “A29” (1S,2R)-N48-(4,4-Dimethyl-chroman-7-yl)-pyrido[4,3-d] pyrimidin-2-yl]-cyclohexane-1,2-diamine HPLC (method A): Rt 2.37 min (purity 100%); LCMS (ESI+) (method G): Rt 1.657 min., MH+ 404.30; HCl salt: .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ [ppm] 9.36 (s, 1H), 9.09-9.03 (m, 1H), 8.64 (s, 1H), 7.99-7.61 (m, 2H), 7.58-7.44 (m, 1H), 7.43-7.33 (m, 1H), 7.29-7.21 (m, 1H), 7.21-7.16 (m, 1H), 4.25-4.14 (m, 3H), 3.69 (s, 1H), 1.97-1.82 (m, 4H), 1.78- 1.58 (m, 4H), 1.57-1.39 (m, 2H), 1.36 (s, 6H) “A30” (R)-3-Methoxy-N1-(8-m-tolyl-pyrido[4,3-d]pyrimidin-2-yl)- propane-1,2-diamine HPLC (method A): Rt 2.29 min (purity 99%); LCMS (ESI+) (method G): Rt 1.341 min., MH+ 324.20; HCl salt: .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ [ppm] 9.52 (s, 1H), 9.33 (s, 1H), 8.88-8.77 (m, 1H), 8.72 (s, 1H), 8.22-8.16 (m, 2H), 7.65-7.60 (m, 2H), 7.46-7.39 (m, 1H), 7.31 (d, J = 7.8, 1H), 3.79-3.73 (m, 1H), 3.70-3.40 (m, 3H), 3.31 (s, 1H), 3.24 (s, 3H), 2.42 (s, 3H) “A31” (1S,2R)-N-(8-m-Tolyl-pyrido[4,3-d]pyrimidin-2-yl)-cyclohexane- 1,2-diamine HPLC (method A): Rt 2.33 min (purity 99%); LCMS (ESI+) (method G): Rt 1.478 min., MH+ 334.20; HCl salt: .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ [ppm] 9.59 (s, 1H), 9.43 (s, 1H), 8.93 (d, J = 6.5, 1H), 8.76 (s, 1H), 8.19-8.12 (m, 2H), 7.68-7.60 (m, 2H), 7.43 (t, J = 7.6, 1H), 7.35-7.30 (m, 1H), 4.15- 4.06 (m, 1H), 3.72-3.64 (m, 1H), 2.42 (s, 3H), 2.03-1.91 (m, 2H), 1.77-1.54 (m, 4H), 1.47-1.31 (m, 2H) “A32” (R)-4-Methyl-2-(8-m-tolyl-pyrido[4,3-d]pyrimidin-2-ylamino)- pentanoic acid amide HPLC (method A): Rt 2.41 min (purity 99%); LCMS (ESI+) (method G): Rt 1.696 min., MH+ 350.20; .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ [ppm] 9.33 (s, 1H), 9.01 (s, 1H), 8.63 (s, 1H), 7.94 (d, J = 8.2, 1H), 7.64-7.57 (m, 2H), 7.35 (t, J = 7.6, 1H), 7.24-7.18 (m, 1H), 7.10 (s, 1H), 6.97 (s, 1H), 4.42- 4.35 (m, 1H), 2.39 (s, 3H), 1.71-1.59 (m, 3H), 0.88 (d, J = 6.4, 3H), 0.81 (d, J = 6.3, 3H) “A33” (1S,2R)-N-[8-(4,5,6,7-Tetrahydro-pyrazolo[1,5-a]pyridin-2-yl)- pyrido[4,3-d]pyrimidin-2-yl]-cyclohexane-1,2-diamine HPLC (method A): Rt 2.28 min (purity 91%); LCMS (ESI+) (method G): Rt 1.421 min., MH+ 364.30; HCl salt “A34” 6-[2-((1R,2S)-2-Amino-cyclohexylamino)-pyrido[4,3-d] pyrimidin-8-yl]-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one HPLC (method A): Rt 2.32 min (purity 100%); LCMS (ESI+) (method G): Rt 1.473 min., MH+ 419.20; HCl salt “A35” (1S,2R)-N-[8-(3-Methoxy-phenylethynyl)-pyrido[4,3-d] pyrimidin-2-yl]-cyclohexane-1,2-diamine HPLC (method A): Rt 2.40 min (purity 98%); LCMS (ESI+) (method G): Rt 1.695 min., MH+ 374.20; HCl salt “A36” (1S,2R)-N-[8-(1H-Benzoimidazol-5-yl)-pyrido[4,3-d] pyrimidin-2-yl]-cyclohexane-1,2-diamine HPLC (method A): Rt 2.17 min (purity 88%); LCMS (ESI+) (method G): Rt 1.082 min., MH+ 360.20; HCl salt: .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ [ppm] 9.52 (s, 1H), 9.42 (s, 1H), 9.27 (s, 1H), 8.84 (s, 1H), 8.38 (s, 1H), 8.31 (s, 1H), 8.13-7.73 (m, 5H), 4.14-4.08 (m, 1H), 3.72-3.62 (m, 1H), 1.93- 1.80 (m, 2H), 1.82-1.49 (m, 4H), 1.44-1.31 (m, 2H) “A37” 5-[2-((1R,2S)-2-Amino-cyclohexylamino)-pyrido[4,3-d] pyrimidin-8-yl]-1,3-dihydro-benzimidazol-2-one 0 HPLC (method A): Rt 2.23 min (purity 99%); LCMS (ESI+) (method G): Rt 1.227 min., MH+ 376.10; HCl salt: .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ [ppm] 10.90-10.84 (m, 1H), 10.81 (s, 1H), 9.56 (s, 1H), 9.34 (s, 1H), 8.77 (s, 1H), 8.73 (s, 1H), 8.02 (d, J = 6.2, 2H), 7.54-7.50 (m, 1H), 7.39 (dd, J = 8.1, 1.7, 1H), 7.07 (d, J = 8.1, 1H), 4.19-4.09 (m, 1H), 3.83 (s, 1H), 2.00-1.84 (m, 2H), 1.75-1.53 (m, 3H), 1.48-1.36 (m, 3H) “A38” (1S,2R)-N-[8-(1,2,3,6-Tetrahydro-pyridin-4-yl)-pyrido[4,3- d]pyrimidin-2-yl]-cyclohexane-1,2-diamine HPLC (method J): Rt 1.29 min (purity 68%); LCMS (ESI+) (method G): Rt 1.140 min., MH+ 325.20; HCl salt “A39” (1S,2R)-N-[8-(3,6-Dihydro-2H-pyran-4-yl)-pyrido[4,3-d] pyrimidin-2-yl]-cyclohexane-1,2-diamine HPLC (method J): Rt 1.63 min (purity 94%); LCMS (ESI+) (method G): Rt 1.340 min., MH+ 326.20; HCl salt “A40” (1S,2R)-N-[8-(6-Methoxy-1H-indol-3-yl)-pyrido[4,3-d] pyrimidin-2-yl]-cyclohexane-1,2-diamine HPLC (method J): Rt 1.85 min (purity 64%); LCMS (ESI+) (method G): Rt 1.432 min., MH+ 389.20 “A41” (1S,2R)-N-[8-(6-Trifluoromethyl-1H-indol-3-yl)-pyrido[4,3- d]pyrimidin-2-yl]-cyclohexane-1,2-diamine no HPLC data; LCMS (ESI+) (method G): Rt 1.642 min., MH+ 427.20; .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ [ppm] 11.96-11.77 (m, 2H), 9.31 (s, 1H), 8.95 (s, 1H), 8.88 (s, 1H), 8.25 (s, 1H), 7.96 (d, J = 8.5, 1H), 7.82 (s, 1H), 7.71-7.44 (m, 2H), 7.39-7.33 (m, 1H), 3.91-3.82 (m, 1H), 3.15-3.09 (m, 1H), 1.63-1.50 (m, 4H), 1.39- 1.09 (m, 4H) “A42” (1S,2R)-N-[8-(6-Fluoro-1H-indol-2-yl)-pyrido[4,3-d] pyrimidin-2-yl]-cyclohexane-1,2-diamine HPLC (method A): Rt 2.31 min (purity 92%); LCMS (ESI+) (method G): Rt 1.376 min., MH+ 377.10; .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ [ppm] 11.94-11.23 (m, 1H), 9.80-8.56 (m, 1H), 8.40-7.60 (m, 4H), 7.57-7.07 (m, 3H), 6.93- 5.70 (m, 2H), 4.72-3.98 (m, 1H), 3.80-3.49 (m, 1H), 1.93- 0.96 (m, 8H) “A43” (1S,2R)-N-[8-(6,7-Dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)- pyrido[4,3-d]pyrimidin-2-yl]-cyclohexane-1,2-diamine HPLC (method A): Rt 2.24 min (purity 100%); LCMS (ESI+) (method G): Rt 1.264 min., MH+ 366.10; HCl salt: .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ [ppm] 9.57 (s, 1H), 9.35 (s, 1H), 9.04 (s, 1H), 9.01-8.95 (m, 1H), 8.23-8.15 (m, 2H), 7.08 (s, 1H), 4.91 (d, J = 3.1, 2H), 4.61-4.35 (m, 1H), 4.31- 4.20 (m, 2H), 4.18-4.12 (m, 2H), 3.79-3.53 (m, 1H), 2.01-1.91 (m, 2H), 1.82-1.66 (m, 4H), 1.53-1.41 (m, 2H) “A44” 3-[2-((1 R,2S)-2-Amino-cyclohexylamino)-pyrido[4,3-d] pyrimidin-8-yl]-1H-indole-5-carbonitrile HPLC (method J): Rt 1.84 min (purity 100%); LCMS (ESI+) (method G): Rt 1.379 min., MH+ 384.20 “A45” 3-[2-((1R,2S)-2-Amino-cyclohexylamino)-pyrido[4,3-d] pyrimidin-8-yl]-1H-indole-6-carbonitrile HPLC (method J): Rt 1.85 min (purity 100%); LCMS (ESI+) (method G): Rt 1.399 min., MH+ 384.30 “A46” (1S,2R)-N-[8-(5-Fluoro-1H-indol-3-yl)-pyrido[4,3-d] pyrimidin-2-yl]-cyclohexane-1,2-diamine LCMS (ESI+) (Method G): Rt 1.455 min., MH+ 377.20 “A47” (1S,2R)-N-[8-(6-Fluoro-1H-indol-3-yl)-pyrido[4,3-d] pyrimidin-2-yl]-cyclohexane-1,2-diamine 0 LCMS (ESI+) (method G): Rt 1.469 min., MH+ 377.20; .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ [ppm] 11.61 (s, 1H), 9.30 (s, 1H), 8.94-8.86 (m, 3H), 8.16-8.12 (m, 1H), 7.85-7.80 (m, 1H), 7.57 (d, J = 7.6, 1H), 7.26 (dd, J = 9.9, 2.4, 2H), 6.94 (td, J = 9.3, 2.5, 1H), 3.93-3.87 (m, 1H), 3.12-3.07 (m, 1H) 1.76-1.65 (m, 2H), 1.49-1.40 (m, 2H), 1.36-1.18 (m, 4H) “A48” (R)-N1-[8-(1H-Indol-3-yl)-pyrido[4,3-d]pyrimidin-2-yl]- 3-methoxy-propane-1,2-diamine HPLC (method J): Rt 1.68 min (purity 63%); LCMS (ESI+) (method G): Rt 1.288 min., MH+ 349.00 “A49” cis-N3-[8-[6-(trifluoromethyl)-1H-indol-3-yl]pyrido[4,3-d] pyrimidin-2-yl]tetrahydropyran-3,4-diamine orange solid, LCMS (ESI+) (Method G), Rt 1.49 min., MH+ 429.2; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ [ppm] 11.90 (s, 1H), 9.36-9.32 (m, 1H), 8.97 (s, 1H), 8.90-8.86 (m, 1H), 8.23 (s, 1H), 7.97-7.92 (m, 1H), 7.86-7.78 (m, 2H), 7.69-7.62 (m, 1H), 7.42-7.32 (m, 2H), 4.06-3.92 (m, 1H), 3.78-3.72 (m, 1H), 3.64-3.55 (m, 1H), 3.27-3.24 (m, 1H), 3.21-3.11 (m, 1H), 2.93-2.88 (m, 1H), 1.90-1.75 (m, 1H), 1.64-1.58 (m, 1H) “A50” cis-N4-[8-[6-(trifluoromethyl)-1H-indol-3-yl]pyrido[4,3-d] pyrimidin-2-yl]tetrahydropyran-3,4-diamine “A51” cis-3,3-Difluoro-N1-[8-[6-(trifluoromethyl)-1H-indol-3-yl] pyrido[4,3-d]pyrimidin-2-yl]cyclohexane-1,2-diamine “A52” cis-3-Fluoro-N1-[8-[6-(trifluoromethyl)-1H-indol-3-yl]pyrido [4,3-d]-pyrimidin-2-yl]cyclohexane-1,2-diamine “A53” cis-4,4-Difluoro-N1-[8-[6-(trifluoromethyl)-1H-indol-3-yl]pyrido [4,3-d]pyrimidin-2-yl]cyclohexane-1,2-diamine “A54” cis-4-Fluoro-N1-[8-[6-(trifluoromethyl)-1H-indol-3-yl]pyrido [4,3-d]-pyrimidin-2-yl]cyclohexane-1,2-diamine “A55” cis-4,4-Difluoro-N2-[8-[6-(trifluoromethyl)-1H-indol-3-yl] pyrido[4,3-d]pyrimidin-2-yl]cyclohexane-1,2-diamine “A56” cis-4-Fluoro-N2-[8-[6-(trifluoromethyl)-1H-indol-3-yl]pyrido [4,3-d]-pyrimidin-2-yl]cyclohexane-1,2-diamine “A57” (1S,2S)-3,3-Difluoro-N2-[8-[6-(trifluoromethyl)-1H-indol-3- yl]pyrido[4,3-d]pyrimidin-2-yl]cyclohexane-1,2-diamine 0 “A58” cis-3-Fluoro-N2-[8-[6-(trifluoromethyl)-1H-indol-3-yl]pyrido [4,3-d]-pyrimidin-2-yl]cyclohexane-1,2-diamine “A59” cis-2-[[8-[6-(Trifluoromethyl)-1H-indol-3-yl]pyrido[4,3-d] pyrimidin-2-yl]amino]cyclohexanol “A60” 3,3,3-Trifluoro-N1-[8-[6-(trifluoromethyl)-1H-indol-3-yl] pyrido[4,3-d]pyrimidin-2-yl]propane-1,2-diamine “A61” (2R)-3-Methoxy-N1-[8-[6-(trifluoromethyl)-1H-indol-3-yl] pyrido[4,3-d]pyrimidin-2-yl]propane-1,2-diamine yellow solid, HPLC: (Method J) 100%; Rt 2.003 min; LCMS (ESI+) (Method G) Rt 1.48 min, MH+ 417.1; .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ [ppm] 11.90 (s, 1H), 9.30 (s, 1H), 8.95 (s, 1H), 8.89 (s, 1H), 8.35 (s, 1H), 8.00 (d, J = 8.4, 1H), 7.94 (t, J = 5.8, 1H), 7.83 (s, 1H), 7.40-7.34 (m, 1H), 3.47-3.37 (m, 1H), 3.17 (s, 3H), 315-3.01 (m, 3H), 1.61 (s, 2H) “A62” (2R)-4-Methyl-2-[[8-[6-(trifluoromethyl)-1H-indol-3-yl]pyrido [4,3-d]-pyrimidin-2-yl]amino]pentanamide yellow solid, HPLC: (Method J) 100%; Rt 2.416 min.; LCMS (ESI+) (Method E) Rt 1.78 min, MH+ 443.2; .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ [ppm] 11.92-11.89 (m, 1H), 9.35 (s, 1H), 8.99- 8.95 (m, 2H), 8.44 (d, J = 2.6, 1H), 8.06-8.00 (m, 2H), 7.84- 7.82 (m, 1H), 7.38 (dd, J = 8.5, 1.7, 1H), 7.10 (s, 1H), 6.96 (s, 1H), 4.38-4.31 (m, 1H), 1.78-1.66 (m, 2H), 1.64-1.54 (m, 1H), 0.88 (d, J = 6.2, 3H), 0.80 (d, J = 6.3, 3H) “A63” cis-N2-[8-(7-Fluoro-1H-indol-3-yl)pyrido[4,3-d]pyrimidin-2- yl]cyclohexane-1,2-diamine orange solid; LCMS (ESI+) (Method G): Rt 1.44 min, MH+ 377.2; .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ [ppm] 12.03 (s, 1H), 9.32 (s, 1H), 8.94 (s, 1H), 8.91 (s, 1H), 8.20-8.14 (m, 1H), 7.70-7.58 (m, 2H), 7.10-6.97 (m, 2H), 4.00-3.91 (m, 1H), 3.24-3.18 (m, 1H), 1.78-1.51 (m, 6H), 1.50-1.26 (m, 4H) “A64” N2-[8-[7-(Trifluoromethyl)-1H-indol-3-yl]pyrido[4,3-d] pyrimidin-2-yl]cyclohexane-1,2-diamine “A65” (R)-2-[8-(6-Cyano-1H-indol-3-yl)-pyrido[4,3-d]pyrimidin- 2-yl-amino]-4-methyl-pentanoic acid amide yellow solid; HPLC: (Method J) 100%; Rt 2.116 min. LCMS (ESI+) (MethodG) Rt 1.58 min, MH+ 400.2); .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ [ppm] 12.10-11.98 (m, 1H), 9.35 (s, 1H), 8.98 (s, 1H), 8.92 (s, 1H), 8.43 (d, J = 2.6, 1H), 8.05-7.95 (m, 3H), 7.43-7.38 (m, 1H), 7.11 (s, 1H), 6.95 (s, 1H), 4.36-4.27 (m, 1H), 1.76-1.65 (m, 2H), 1.63-1.53 (m, 1H), 0.87 (d, J = 6.2, 3H), 0.78 (d, J = 6.3, 3H) “A66” (1S,2R)-N-[8-(4-Methyl-1H-indol-2-yl)-pyrido[4,3-d] pyrimidin-2-yl]-cyclohexane-1,2-diamine beige solid; HPLC: (Method J) 100%; Rt 2.32 min, LCMS (ESI+) (Method G): Rt 1.35 min, MH+ 373.2 “A67” 3-[2-((R)-2-Amino-3-methoxy-propylamino)-pyrido[4,3-d] pyrimidin-8-yl]-1H-indole-6-carbonitrile 0 yellow solid, HPLC: (Method J) 100%; Rt 1.706 min. LCMS (ESI+) (Method G) Rt 1.24, MH+ 374.2; *H NMR (500 MHz, DMSO-d.sub.6) δ [ppm] 12.03 (s, 1H), 9.30 (s, 1H), 8.95 (s, 1H), 8.86 (s, 1H), 8.35 (s, 1H), 8.01-7.97 (m, 1H), 7.97-7.90 (m, 3H), 7.89-7.66 (m, 1H), 7.40 (dd, J = 8.4, 1.5, 1H), 3.44-3.36 (m, 1H), 3.27-3.23 (m, 1H), 3.18 (s, 3H), 3.15-3.03 (m, 3H) “A68” (3R,4R)-N4-[8-(1H-Indol-3-yl)-pyrido[4,3-d]pyrimidin-2-yl]- tetrahydro-pyran-3,4-diamine yellow powder LCMS(ESI+) (Method G): Rt 1.26 min, MH+ 361.0 “A69” 3[2-((3R,4R)-3-Amino-tetrahydro-pyran-4-ylamino)-pyrido [4,3-d]pyrimidin-8-yl]-1H-indole-6-carbonitrile yellow solid, LCMS (ESI+) (Method G) Rt 1.25 min, MH+ 386.1; .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ [ppm] 12.14 (s, 1H), 9.47 (s, 1H), 9.41 (s, 1H), 9.05 (s, 1H), 8.93 (s, 1H), 8.47 (s, 1H), 8.34 (s, 1H), 8.07 (s, 1H), 7.97 (d, J = 8.3, 1H), 7.80 (d, J = 7.2, 1H), 7.46 (dd, J = 8.3, 1.5, 1H), 4.11-4.02 (m, 1H), 3.88-3.82 (m, 1H), 3.72-3.66 (m, 1H), 3.34-3.25 (m, 2H), 3.06 (s, 1H), 1.97- 1.84 (m, 1H), 1.73-1.64 (m, 1H)

Examples 70 and 71

Enantiomer 1 of (cis)-2-[8-(1-benzenesulfonyl-1H-indol-3-yl)-pyrido[4,3-d]pyrimidin-2-ylamino]-cyclohexanol (“A70”) and enantiomer 2 of (cis)-2-[8-(1-benzenesulfonyl-1H-indol-3-yl)-pyrido[4,3-d]pyrimidin-2-ylamino]-cyclohexanol (“A71”)

(54) ##STR00093##

Preparation of intermediate cis-2-(8-iodo-pyrido[4,3-d]pyrimidin-2-ylamino)-cyclohexanol

(55) ##STR00094##

(56) 2-Chloro-8-iodo-pyrido[4,3-d]pyrimidine (500.00 mg; 1.098 mmol; 1.00 eq.), cis-2-amino-cyclohexanol hydrochloride (166.47 mg; 1.098 mmol; 1.00 eq.), ethanol (2.00 ml) and triethylamine (456.55 μl; 3.294 mmol; 3.00 eq.) were taken into a microwave vessel and sealed with a septum. By microwave the reaction mixture was now heated for 10 min. to 120° C. The solvent was removed under vacuo. The product was purified by flash chromatography and gives 107 mg (26%) of the title compound as a yellow amorphous powder; HPLC (Method A) Rt 2.36 min.; HPLC MS (Method G): (M+H) 371; Rt 1.519 min.

(57) “A70” and “A71”:

(58) cis-2-(8-Iodo-pyrido[4,3-d]pyrimidin-2-ylamino)-cyclohexanol (117.30 mg; 316.86 μmol; 1.0 eq.), 1-(phenylsulfonyl)indole-3-boronic acid pinacol ester, 97% (188.00 mg; 0.476 mmol; 1.50 eq.), palladium(II) acetate (47% Pd) (3.60 mg; 16.035 μmol; 0.05 eq.), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (13.00 mg; 31.666 μmol; 0.10 eq.), potassium carbonate (129.00 mg; 0.933 mmol; 2.95 eq.), ethylene glycol dimethyl ether (3.30 ml; 31.857 mmol; 100.54 eq.) and water (1.10 ml; 61.043 mmol; 192.65 eq.) were taken into a microwave vessel, sealed with a septum and purged with nitrogen by, and heated for 45 min. to 150° C. The product was purified by flash chromatography and the enantiomers separated via SFC (Chiralpak AS-H with solvent CO.sub.2+25% MOH+0.5% DEA).

(59) “A70” elutes first from column. After evaporation of solvent, the product gives 43 mg (27%) of the title compound as a beige amorphous solid; HPLC (Method A): Rt 2.65 min.; HPLC MS (Method J): (M+H) 500.2; Rt 2.012 min.

(60) “A71” elutes second from column to give 64 mg (40%) of the title compound as a beige amorphous solid; HPLC (Method A) Rt 2.67 min.; HPLC MS (Method J): (M+H) 500.2; Rt 2.009 min.

Example 72

3-[2-((1R,2S)-2-amino-cyclohexylamino)-pyrido[4,3-d]pyrimidin-8-yl]-1H-indole-7-carbonitrile (“A72”)

(61) ##STR00095##

72.1

(62) ##STR00096##

(63) 1H-Indole-7-carbonitrile, 97% (1.00 g; 6.823 mmol; 1.000 eq.) was dissolved in toluene (20.00 ml; 188.843 mmol; 27.676 eq.). Tetra-n-butylammonium hydrogen sulfate (347.52 mg; 1.024 mmol; 0.150 eq.) was added. Sodium hydroxide solution 32% (20.00 ml; 216.016 mmol; 31.658 eq.) and 4-toluenesulfonyl chloride (1.34 ml; 10.235 mmol; 1.500 eq.) were added at 0° C. to the suspension and stirred vigorously for 14 h at rt. The reaction mixture was treated with toluene and water, the layers were separated and the organic extract was washed with saturated ammoniumchloride solution. The organic layer was dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The residue was treated with DCM and concentrated under reduced pressure to give 2 g (69%) of the title compound as a off-white solid; HPLC MS (Method J): (M+H) 297.1; (percent area) 90.4%; Rt 2.193 min.

72.2 3-bromo-1-(toluene-4-sulfonyl)-1H-indole-7-carbonitrile

(64) ##STR00097##

(65) 1-(Toluene-4-sulfonyl)-1H-indole-7-carbonitrile (1.55 g; 4.728 mmol; 1.000 eq.) was dissolved in acetonitrile (35.00 ml; 670.109 mmol; 141.724 eq.). Copper(II) bromide anhydrous (3.17 g; 14.185 mmol; 3.000 eq.) was added and the suspension was stirred at rt for 2 days and heated to reflux for 2 days. The reaction mixture was treated with 80 ml 7M aqueous ammonia solution (approx. 12.5%) and extracted with EtOAc 3×. The combined organic layers were dried over MgSO.sub.4, filtered and evaporated under reduced pressure to give 1 g (65%) of the title compound as a beige solid; HPLC MS (Method J): (M+H) 375; (percent area) 88.6%; Rt 2.431 min.

72.3 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-indole-7-carbonitrile

(66) ##STR00098##

(67) 4,4,5,5,4′,4′,5′,5′-Octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (1.01 g; 3.975 mmol; 1.300 eq.), potassium acetate (0.90 g; 9.173 mmol; 3.000 eq.) and bis(triphenylphosphine)palladium(II) chloride (15.2% Pd) (85.85 mg; 0.122 mmol; 0.040 eq.) were added in a microwave vial. 3-Bromo-1-(toluene-4-sulfonyl)-1H-indole-7-carbonitrile (1.30 g; 3.058 mmol; 1.000 eq.) in tetrahydrofuran SeccoSolv® (10.00 ml; 123.429 mmol; 40.367 eq.) was added while purging nitrogen through the suspension and the reaction mixture was heated in a microwave for 2 h at 100° C. The reaction mixture was concentrated under reduced pressure. The residue was treated with DCM/MeOH, the precipitate was filtered off and the mother liquor was concentrated under reduced pressure. This residue was purified by flash chromatography to give 497 mg (38%) of the title compound as a colorless solid; HPLC MS (Method J): (M+H) 341.1; (M+Na) 363.1; (percent area) 100%; Rt 1.95 min.

72.4 ((1S,2R)-2-{8-[7-cyano-1-(toluene-4-sulfonyl)-1H-indol-3-yl]-pyrido-[4,3-d]pyrimidin-2-ylamino}-cyclohexyl)-carbamic acid tert-butyl ester

(68) ##STR00099##

(69) In a microwave vial [(1S,2R)-2-(8-iodo-pyrido[4,3-d]pyrimidin-2-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester (200.00 mg; 0.426 mmol; 1.000 eq.), 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-indole-7-carbonitrile (215.96 mg; 0.511 mmol; 1.200 eq.), palladium(II)-acetat (47% Pd) (4.78 mg; 0.021 mmol; 0.050 eq.), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (17.49 mg; 0.043 mmol; 0.100 eq.) and potassium carbonate (173.62 mg; 1.256 mmol; 2.948 eq.) were added and suspended in ethylenglycoldimethylether (4.41 ml; 42.615 mmol; 100.000 eq.) and water (1.54 ml; 85.230 mmol; 200.000 eq.) while purging nitrogen through the suspension. The suspension was heated in a microwave for 45 min at 150° C. The reaction mixture was concentrated under reduced pressure and purified by Flash Chromatography to give a mixture of the title compound and de-tosylated product. 138 mg (24%) of the title compound were obtained as a solid; HPLC MS (Method J): (M+H) 638.3 and 484.3 (de-tosylated); Rt 2.172/1.887 min.

72.5 3-[2-((1R,2S)-2-amino-cyclohexylamino)-pyrido[4,3-d]pyrimidin-8-yl]-1H-indole-7-carbonitrile

(70) The solid from example 72.4 was dissolved in dichloromethane SeccoSolv® (1.50 ml; 23.489 mmol). Trifluoroacetic acid (158.04 μl; 2.051 mmol) was added and the solution was stirred at rt for 14 h. The solvent was evaporated under reduced pressure. Ethanol (8.00 ml; 137.189 mmol), tetrahydrofuran SeccoSolv® (2.00 ml; 24.686 mmol) and sodium hydroxide pellets (81.65 mg; 2.042 mmol; 20.000 eq.) were added. The solution was stirred at 50° C. for 14 h. The solvent was evaporated under reduced pressure. The residue was treated with water and filtered and dried under vacuum. This gives 86 mg of the title compound as a yellow solid; .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ [ppm] 12.41 (s, 1H), 9.30 (s, 1H), 8.94 (s, 1H), 8.89 (s, 1H), 8.23-8.14 (m, 2H), 7.68 (d, J=7.4, 1H), 7.60 (d, J=7.8, 1H), 7.24 (t, J=7.7, 1H), 3.88-3.81 (m, 1H), 3.10-3.04 (m, 1H), 1.72-1.63 (m, 2H), 1.64-1.50 (m, 4H), 1.37-1.17 (m, 2H); HPLC MS (Method J): (M+H) 384.2; (percent area) 100%; Rt 1.396 min.

Example 73

Enantiomer 1 of 3-[2-((cis)-2-hydroxy-cyclohexylamino)-pyrido[4,3-d]pyrimidin-8-yl]-1H-indole-6-carbonitrile (“A73”)

(71) ##STR00100##

73.1 Enantiomer 1 and Enantiomer 2: cis-2-(8-iodo-pyrido[4,3-d]pyrimidin-2-ylamino)-cyclohexanol

(72) ##STR00101##

(73) 2-Chloro-8-iodo-pyrido[4,3-d]pyrimidine (1.00 g; 2.556 mmol; 1.00 eq.), cis-2-amino-cyclohexanol hydrochloride (387.57 mg; 2.556 mmol; 1.00 eq.), ethanol (10.00 ml; 0.171 mol; 67.09 eq.) and triethylamine (1.06 ml; 7.668 mmol; 3.00 eq.) were taken into a microwave vessel and sealed with a septum. The reaction mixture was heated for 10 min in a microwave to 120° C. The reaction mixture was evaporated to dryness and the product purified by flash chromatography. The enantiomers were separated by chiral SFC.

(74) Enantiomer 1: The stereoisomer eluates first from column Chiralpak AS-H with solvent CO.sub.2+20% MOH+0.5% DEA; absolute configuration arbitrary; 61 mg (6%) of the title compound as a yellow amorphous powder; HPLC (Method A): (percent area) 100%; Rt 2.41 min.; HPLC MS (Method J): (M+H) 371; Rt 1.513 min.

(75) Enantiomer 2: The stereoisomer eluates second from column Chiralpak AS-H with solvent CO.sub.2+20% MOH+0.5% DEA; absolute configuration arbitrary; 62.50 mg; 0.169 mmol.

73.2 3-[2-((1R,2S)-2-hydroxy-cyclohexylamino)-pyrido[4,3-d]pyrimidin-8-yl]-1H-indole-6-carbonitrile

(76) 2-(8-Iodo-pyrido[4,3-d]pyrimidin-2-ylamino)-cyclohexanol (enantiomer 1) from example 73.1 (61.40 mg; 0.166 mmol; 1.00 eq.), 1-BOC-6-cyanoindole-3-boronic acid, pinacol ester (95.00 mg; 0.248 mmol; 1.49 eq.), palladium(II)-acetat (47% Pd) (1.90 mg; 0.008 mmol; 0.05 eq.), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (6.80 mg; 0.017 mmol; 0.10 eq.), potassium carbonate (68.00 mg; 0.492 mmol; 2.97 eq.), ethylenglycoldimethylether (2.10 ml; 20.273 mmol; 122.23 eq.) and water (0.70 ml; 38.846 mmol; 234.21 eq.) were taken into a microwave vessel, sealed with a septum and purged with nitrogen. The reaction was heated in a microwave for 45 min. to 150° C. The reaction mixture was evaporated to dryness and the product purified by flash chromatography. This gives 46 mg (70%) of the title compound as a yellow amorphous solid; .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ [ppm] 12.09 (s, 1H), 9.30 (s, 1H), 8.95 (s, 1H), 8.86 (s, 1H), 8.30 (d, J=2.6, 1H), 7.99 (s, 1H), 7.92 (d, J=8.3, 1H), 7.55-7.29 (m, 2H), 4.60 (d, J=4.0, 1H), 3.91 (s, 1H), 3.82-3.72 (m, 1H), 1.75-1.50 (m, 5H), 1.38-1.25 (m, 2H), 1.20-1.08 (m, 1H); HPLC (Method A): (percent area) 98.1%; Rt 2.43 min.; HPLC MS (Method J): (M+H) 385.1; Rt 1.599 min.

Example 74

Enantiomer 2 of 3-[2-((cis)-2-hydroxy-cyclohexylamino)-pyrido[4,3-d]pyrimidin-8-yl]-1H-indole-6-carbonitrile (“A74”)

(77) ##STR00102##

(78) 2-(8-Iodo-pyrido[4,3-d]pyrimidin-2-ylamino)-cyclohexanol (Enantiomer 2 from example 73.1 (62.50 mg; 0.169 mmol; 1.00 eq.), 1-BOC-6-cyanoindole-3-boronic acid, pinacol ester (97.00 mg; 0.253 mmol; 1.50 eq.), palladium(II)-acetat (47% Pd) (1.90 mg; 0.008 mmol; 0.05 eq.), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (6.80 mg; 0.017 mmol; 0.10 eq.), potassium carbonate (68.00 mg; 0.492 mmol; 2.91 eq.), ethylenglycoldimethylether (2.10 ml; 20.273 mmol; 120.08 eq.) and water (0.70 ml; 38.846 mmol; 230.08 eq.) were taken into a microwave vessel, sealed with a septum and purged with nitrogen. The reaction was heated in a microwave for 45 min. to 150° C. The reaction mixture was evaporated to dryness. The residue was purified by flash chromatography. This gives 22 mg (34%) of the title compound as a yellow amorphous powder; .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ [ppm] 12.18 (s, 1H), 9.37 (s, 1H), 9.06 (s, 1H), 8.86 (s, 1H), 8.35 (d, J=2.6, 1H), 8.01 (s, 1H), 7.95 (d, J=8.3, 1H), 7.87 (s, 1H), 7.47-7.38 (m, 1H), 4.62 (s, 1H), 3.96-3.87 (m, 1H), 3.84-3.75 (m, 1H), 1.81-1.46 (m, 4H), 1.40-1.05 (m, 4H);

(79) HPLC (Method A): (percent area) 100%; Rt 2.43 min.; HPLC MS (Method J): (M+H) 385.1; Rt 1.593 min.

Example 75

3-[2-((S)-5,5-difluoro-piperidin-3-ylamino)-pyrido[4,3-d]pyrimidin-8-yl]-1H-indole-6-carbonitrile (“A75”)

(80) ##STR00103##

75.1 (S)-3,3-difluoro-5-(8-iodo-pyrido[4,3-d]pyrimidin-2-ylamino)-piperidine-1-carboxylic acid benzyl ester

(81) ##STR00104##

(82) 2-Chloro-8-iodo-pyrido[4,3-d]pyrimidine (200.000 mg; 0.686 mmol; 100.00 mol %) and (S)-5-amino-3,3-difluoro-piperidine-1-carboxylic acid benzyl ester (211.463 mg; 0.686 mmol; 100.00 mol %) was added together with triethylamine (0.143 ml; 1.029 mmol; 150.00 mol %) and ethanol (600.000 μl) in a microwave vessel, closed with a septum and heated 5 min in a microwave at 120° C. Water was added and the precipitation was filtered off. The precipitation was dried in vacuo to give 310 mg (62%) of the title compound as a brown film; HPLC MS (Method H): Rt 2.54 min, MH+526.0.

75.2 (S)-5-[8-(6-cyano-1H-indol-3-yl)-pyrido[4,3-d]pyrimidin-2-ylamino]-3,3-difluoro-piperidine-1-carboxylic acid benzyl ester

(83) ##STR00105##

(84) In a microwave vessel 1-BOC-6-cyanoindole-3-boronic acid, pinacol ester (57.592 mg; 0.150 mmol; 110.00 mol %), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (S-Phos) (5.777 mg; 0.014 mmol; 10.00 mol %) and potassium carbonate (56.593 mg; 0.409 mmol; 300.00 mol %) was suspended in ethylenglycoldimethylether (5.000 ml) and water (1.000 ml). Under nitrogen palladium(II)-acetat (3.064 mg; 0.014 mmol; 10.00 mol %) was added, closed with a septum and heated by microwave (160° C., 60 min). The product was purified by flash chromatography to give 45 mg (39%) of the title compound as a yellow solid; HPLC (Method H): Rt 2.494 min.; HPLC MS (Method G): (M+H) 540.2; Rt 1.866 min.

75.3 3-[2-((S)-5,5-difluoro-piperidin-3-ylamino)-pyrido[4,3-d]pyrimidin-8-yl]-1H-indole-6-carbonitrile

(85) In a microwave-vial (S)-5-[8-(6-cyano-1H-indol-3-yl)-pyrido[4,3-d]pyrimidin-2-ylamino]-3,3-difluoro-piperidine-1-carboxylic acid benzyl ester (35.000 mg; 0.041 mmol; 42.50 mol %) and (S)-5-[8-(6-cyano-1H-indol-3-yl)-pyrido[4,3-d]pyrimidin-2-ylamino]-3,3-difluoro-piperidine-1-carboxylic acid benzyl ester (45.000 mg; 0.055 mmol; 57.50 mol %) were dissolved in dichlormethane (1.000 ml). Then trifluoroacetic acid (0.447 ml; 5.779 mmol; 6000.00 mol %) was added. The vial was capped with a septum and heated by microwave (120° C., 2 h), The solution was evaporated to dryness. The residue was purified by preparative HPLC to give 8 mg (20%) of the title compound as a yellow solid; .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ [ppm] 12.17 (s, 1H), 10.68-9.80 (m, 2H), 9.55 (s, 1H), 9.29 (s, 1H), 9.04-8.79 (m, 2H), 8.39 (d, J=2.7, 1H), 8.02 (s, 1H), 7.93 (d, J=8.3, 1H), 7.49-7.43 (m, 1H), 4.45-4.36 (m, 1H), 3.68-3.63 (m, 1H), 3.38-3.32 (m, 2H), 3.11 (t, J=11.5, 1H), 2.74-2.58 (m, 1H), 2.26-2.10 (m, 1H); HPLC MS (Method G): (M+H) 406.2; Rt 1.311 min.

Example 76

(1S,2R)—N-[8-(1H-pyrrolo[2,3-c]pyridin-3-yl)-pyrido[4,3-d]pyrimidin-2-yl]-cyclohexane-1,2-diamine (“A76”)

(86) ##STR00106##

76.1 1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-c]pyridine

(87) ##STR00107##

(88) 6-Azaindole (1.00 g; 8.296 mmol; 1.000 eq.) was suspended in toluene (22.00 ml; 207.727 mmol; 25.041 eq.) and to this suspension tetra-n-butylammonium hydrogen sulfate (422.50 mg; 1.244 mmol; 0.150 eq.) was added. At 0° C. sodium hydroxide 32% (22.00 ml; 237.618 mmol; 28.644 eq.) and 4-toluenesulfonyl chloride (1.62 ml; 12.443 mmol; 1.500 eq.) were added and the reaction stirred at RT for 14 h. The reaction mixture was diluted with toluene and water was added. Phases were separated; the organic layer was washed successively with water, saturated aqueous ammoniumchloride solution and water once again, dried over MgSO.sub.4, filtered and evaporated under reduced pressure to give 2 g (68%) of the title compound as a beige solid; HPLC MS (Method G): (M+H) 273.1; (percent area) 100%; Rt 1.489 min.

76.2 3-bromo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-c]pyridine

(89) ##STR00108##

(90) 3-Bromo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-c]pyridine (687.00 mg; 1.956 mmol; 1.000 eq.) was dissolved in acetonitrile (15.00 ml; 287.190 mmol; 113.840 eq.). Copper(II) bromide anhydrous (1.31 g; 5.865 mmol; 2.325 eq.) was added and the suspension was heated to reflux and stirred 3 days. The reaction mixture was treated with 30 ml 7M aqueous ammonia solution (approx. 12.5%) and extracted with EtOAc 3×. The organic layer was dried over MgSO.sub.4, filtered and evaporated under reduced pressure: The product was purified by Flash Chromatography to give 184 mg (21%) of the title compound as a colorless solid; HPLC MS (Method G): (M+H) 351; (percent area) 100%; Rt 1.694 min.

76.3 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-c]pyridine

(91) ##STR00109##

(92) 3-Bromo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-c]pyridine (184.00 mg; 0.524 mmol; 1.000 eq.), 4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (161.26 mg; 0.629 mmol; 1.200 eq.) and potassium acetate (103.87 mg; 1.048 mmol; 2.000 eq.) were suspended in ethylene glycol dimethyl ether (2.50 ml; 23.893 mmol; 45.607 eq.). The reaction mixture was purged with nitrogen while adding (1,1′-bis(diphenylphosphino)ferrocene) dichloropalladium(II), complex with dichloromethane (21.39 mg; 0.026 mmol; 0.050 eq.). The resulting mixture was heated for 2 h at 100° C. in the microwave. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc and water. The phases were separated and the organic layer was washed with water 2 more times. The organic layer was dried over MgSO.sub.4, filtered and evaporated under reduced pressure. This gives 216 mg (97%) of the title compound as a brown solid; HPLC MS (Method G): (M+H) 317.1; (desired product as free boronic acid); (percent area) 93.6%; Rt 1.424 min.

76.4 {(1S,2R)-2-[8-(1H-pyrrolo[2,3-c]pyridin-3-yl)-pyrido[4,3-d]pyrimidin-2-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester

(93) ##STR00110##

(94) [(1S,2R)-2-(8-Iodo-pyrido[4,3-d]pyrimidin-2-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester (192.00 mg; 0.409 mmol; 1.000 eq.), 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-c]pyridine (195.53 mg; 0.460 mmol; 1.123 eq.), palladium(II)-acetat (47% Pd) (4.59 mg; 0.020 mmol; 0.050 eq.), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (16.79 mg; 0.041 mmol; 0.100 eq.) and potassium carbonate (166.68 mg; 1.206 mmol; 2.948 eq.) were suspended in ethylenglycoldimethylether (4.24 ml; 40.910 mmol; 100.000 eq.) and water (1.47 ml; 81.821 mmol; 200.000 eq.) while purging nitrogen through the suspension. The suspension was heated for 45 min at 150° C. in the microwave. The reaction mixture was concentrated under reduced pressure. The product was purified by flash chromatography to give 98 mg (49%) of the title compound as a brown solid;

(95) HPLC MS (Method G): (M+H) 460.3; (percent area) 94.2%; Rt 1.398 min.

76.5 (1S,2R)—N-[8-(1H-pyrrolo[2,3-c]pyridin-3-yl)-pyrido[4,3-d]pyrimidin-2-yl]-cyclohexane-1,2-diamine

(96) {(1S,2R)-2-[8-(1H-Pyrrolo[2,3-c]pyridin-3-yl)-pyrido[4,3-d]pyrimidin-2-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (92.00 mg; 0.189 mmol; 1.000 eq.) was dissolved in dichloromethane (1.50 ml; 23.489 mmol; 124.553 eq.). Trifluoroacetic acid (145.29 μl; 1.886 mmol; 10.000 eq.) was added and the reaction mixture was stirred at rt for 3 days. The reaction mixture was evaporated under reduced pressure and the product was purified by preparative HPLC to give 38 mg (43%) of the title compound as a yellow solid; HPLC MS (Method G): (M+H) 360.2; (percent area) 100%; Rt 1.02 min.

Example 77

3-[2-((1R,2S)-2-amino-cyclohexylamino)-pyrido[4,3-d]pyrimidin-8-yl]-1H-indole-6-carboxylic acid amide (“A77”)

(97) ##STR00111##

77.1 1H-indole-6-carboxamide

(98) ##STR00112##

(99) A solution of 6-cyanoindole (1.000 g; 7.034 mmol; 1.00 eq.) in methanol (10.000 ml; 246.567 mmol; 35.05 eq.) was treated with hydrogen peroxide 30% (0.790 ml; 7.738 mmol; 1.10 eq.) and sodium hydroxide solution (1 N) (5.000 ml; 130.010 mmol; 18.48 eq.), then heated at 40° C. for 1 h. Hydrogen peroxide 30% (0,790 ml; 7,738 mmol; 1.10 eq.) was added and heated at 40° C. for 19 h. The reaction mixture was cooled, poured into 100 ml of ice-water and stirred for 15 min. The resulting precipitate was collected by filtration, washed with water and dried in vacuo at 40° C. to give 894 mg (79%) of the title compound as a beige crystals; HPLC MS (Method G): (M+H) 161.1; (percent area) 100%; Rt 1.185 min.

77.2 tert-butyl 6-carbamoylindole-1-carboxylate

(100) ##STR00113##

(101) 1H-Indole-6-carboxamide (876,000 mg; 5,469 mmol; 1.00 eq.) was dissolved in dichloromethane (10.000 ml; 156.594 mmol; 28.63 eq.). Di-tert-butyl dicarbonate (1.287 ml; 6.016 mmol; 1.10 eq.) and 4-(dimethylamino)pyridine (66.816 mg; 0.547 mmol; 0.10 eq.) were added and the solution was stirred at RT for 1 h. The reaction mixture was diluted with DCM and washed 3× with water. The organic layer was dried over MgSO.sub.4, filtered and concentrated under reduced pressure to give 1 g (98%) of the title compound; HPLC MS (Method G): Rt 1.19 min, MH+161.1.

77.3 tert-butyl 3-bromo-6-carbamoyl-indole-1-carboxylate

(102) ##STR00114##

(103) tert-Butyl 6-carbamoylindole-1-carboxylate (1.418 g; 5.305 mmol; 1.00 eq.) was dissolved in dichloromethane (10.000 ml; 156.594 mmol; 29.52 eq.). N-Bromo-succinimide (1.133 g; 6.365 mmol; 1.20 eq.) was added and the solution was stirred at rt for 2 h. The reaction mixture was diluted with DCM and washed 3× with water. The organic layer was dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The product was purified by Flash Chromatography to give 347 mg (19%) of the title compound as a beige solid;

(104) HPLC MS (Method G): (M+H) 339; (percent area) 100%; Rt 2.186 min.

77.4 tert-butyl 6-carbamoyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indole-1-carboxylate

(105) ##STR00115##

(106) tert-Butyl 3-bromo-6-carbamoyl-indole-1-carboxylate (498.000 mg; 2 mmol; 1 eq.), 4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (1029.764 mg; 4.055 mmol; 2.00 eq.), potassium acetat (0.380 ml; 6.082 mmol; 3.00 eq.) and bis(triphenylphosphin)-palladium(II)-chlorid (15.2% Pd) (56.927 mg; 0.081 mmol; 0.04 eq.) were added. Under nitrogen tetrahydrofuran (15.000 ml; 185.144 mmol; 91.31 eq.) was added and the reaction mixture was heated to 100° C. for 2 h in the microwave. The reaction mixture was concentrated under reduced pressure. The residue was purified by Flash Chromatography to give 176 mg (22%) of the title compound; HPLC MS (Method G): (M+H) 387.2; (22% boronic acid); (percent area) 78.13%; (22% boronic acid); Rt 2.337 min; (22% boronic acid).

77.5 {(1S,2R)-2-[8-(6-Carbamoyl-1H-indol-3-yl)-pyrido[4,3-d]pyrimidin-2-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester

(107) ##STR00116##

(108) [(1S,2R)-2-(8-Iodo-pyrido[4,3-d]pyrimidin-2-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester (50.00 mg; 0.08 mmol; 1.00 eq.), 6-carbamoyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indole-1-carboxylic acid tert-butyl ester (61.94 mg; 0.13 mmol; 1.50 eq.), palladium(II) acetate (47% Pd) for synthesis (0.94 mg; 0.00 mmol; 0.05 eq.), 2-dicyclohexylphosphino-2′-6′-dimethoxybiphenyl (3.43 mg; 0.01 mmol; 0.10 eq.) and potassium carbonate (0.01 ml; 0.25 mmol; 3.00 eq.) was dissolved in ethylene glycol dimethyl ether (2.10 ml; 20.27 mmol; 242.71 eq.) and water (0.70 ml; 38.85 mmol; 465.08 eq.). The mixture was heated to 150° C. in the microwave for 45 min, then concentrated. The precipitate was purified by Flash Chromatography to give 18 mg (44%) of the title compound as a yellow solid; HPLC MS (Method G): Rt 1.62 min;

(109) (M+H) 502.3.

77.6 3-[2-((1R,2S)-2-amino-cyclohexylamino)-pyrido[4,3-d]pyrimidin-8-yl]-1H-indole-6-carboxylic acid amide

(110) {(1S,2R)-2-[8-(6-Carbamoyl-1H-indol-3-yl)-pyrido[4,3-d]pyrimidin-2-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (17.70 mg; 0.035 mmol; 1.00 eq.) was dissolved in ethylacetat (4.00 ml; 40.858 mmol; 1176.66 eq.) and hydrochloric acid (1 N) (0.40 ml; 11.190 mmol; 322.27 eq.) and was stirred at rt for 16 h. The solvent was removed in vacuo to give 15 mg (91%) of the title compound as a yellow brown solid; HPLC MS (Method G): Rt 1.214 min; (M+H) 402.1;

(111) .sup.1H NMR (500 MHz, DMSO-d.sub.6+TFA-d.sub.1) δ [ppm] 9.68-9.55 (s, 1H), 9.48-9.28 (s, 1H), 9.06-8.93 (s, 1H), 8.56-8.33 (s, 1H), 8.24-8.09 (d, J=1.3 Hz, 1H), 7.99-7.90 (d, J=8.5 Hz, 1H), 7.84-7.72 (m, 1H), 4.38-4.27 (m, 1H), 3.74-3.61 (m, 1H), 2.01-1.93 (m, 1H), 1.91-1.71 (m, 3H), 1.66-1.38 (m, 4H).

Example 78

Enantiomer 1 of (3-fluoro-piperidin-3-ylmethyl)-[8-(6-trifluoromethyl-1H-indol-3-yl)-pyrido[4,3-d]pyrimidin-2-yl]-amine (“A78”)

(112) ##STR00117##
(given absolute configuration is arbitrary).

78.1 1-(p-tolylsulfonyl)-6-(trifluoromethyl)indole

(113) ##STR00118##

(114) 6-Trifluoromethylindole (2.082 g; 10.908 mmol; 1.00 eq.) was dissolved in toluene (30.000 ml; 283.265 mmol; 25.97 eq.). Tetra-n-butylammonium hydrogensulfat (555.541 mg; 1.636 mmol; 0.15 eq.), NaOH solution 32% (30.000 ml; 324.024 mmol; 29.71 eq.) and toluene-4-sulfonylchloride (3.183 g; 16.362 mmol; 1.50 eq.) were added at 0° C. The solution was stirred for 14 h in a thawing ice bath. The reaction mixture was diluted with toluene and water, the organic layer was washed twice with a saturated solution of ammonia and 1× with water. The organic layer was dried over MgSO.sub.4, filtered and concentrated under reduced pressure. This gives 4 g (95%) of the title compound as a brown solid; HPLC MS (Method G): (M+H) 340; Rt 2.601 min.

78.2 3-bromo-1-(toluene-4-sulfonyl)-6-trifluoromethyl-1H-indole

(115) ##STR00119##

(116) 1-(Toluene-4-sulfonyl)-6-trifluoromethyl-1H-indole (3.646 g; 10.745 mmol; 1.00 eq.) was dissolved in acetonitril (50.000 ml; 957.299 mmol; 89.10 eq.) and Cu(II) Br (7.200 g; 32.234 mmol; 3.00 eq.) was added. The solution was stirred at rt for 5 days. The mixture was diluted with 60 ml 7M ammonia (approx. 12.5%) and extracted with ethyl acetate and the organic layer was washed with water, dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The precipitate was suspended in DCM/MeOH and filtered and dried for 14 h to give 3 g (68%) of the title compound as an off-white solid; HPLC (Method G): Rt 2.81 min.

78.3 Enantiomer 1 and Enantiomer 2 of 3-fluoro-3-[(8-iodo-pyrido[4,3-d]pyrimidin-2-ylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester

(117) ##STR00120##

(118) 2-Chloro-8-iodo-pyrido[4,3-d]pyrimidine (962.95 mg; 2.045 mmol; 1.000 eq.) was dissolved in triethylamine (0.43 ml; 3.068 mmol; 1.500 eq.) and ethanol (2.00 ml; 34.297 mmol; 16.771 eq.), Then 3-aminomethyl-3-fluoro-piperidine-1-carboxylic acid tert-butyl ester (535.56 mg; 2.045 mmol; 1.000 eq.) was added and the reaction mixture was heated to 120° C. for 5 minutes in the microwave. The reaction mixture was poured into water and filtered. The precipitate was purified by flash chromatography to give 169 mg racemate as yellow solid; HPLC MS (Method G): Rt 1.83 min, MH+488.1. The enantiomers were separated by chiral SFC (column: ChiralCel OJ-H, eluent: CO.sub.2, methanol (20%), wave length: 220 nm, flow: 5 ml/min.

(119) 78.3.1 Enantiomer 1: (S)-3-fluoro-3-[(8-iodo-pyrido[4,3-d]pyrimidin-2-ylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (81.80 mg; 0.168 mmol), this stereoisomere eluates first from column Chiralcel OJ-H with solvent system CO.sub.2+20% methanol; absolute configuration arbitrary. 78.3.2 Enantiomer 2: (R)-3-fluoro-3-[(8-iodo-pyrido[4,3-d]pyrimidin-2-ylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (64.50 mg; 0.132 mmol) brown solid, the stereoisomer eluates second from column Chiralcel OJ-H with solvent system CO.sub.2+20% methanol; absolute configuration arbitrary.

78.4 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-6-trifluoromethyl-1H-indole

(120) ##STR00121##

(121) 4,4,5,5,4′,4′,5′,5′-Octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (2.42 g; 9.549 mmol; 1.300 eq.), potassium acetate (2.16 g; 22.035 mmol; 3.000 eq.) and bis(triphenylphosphine)palladium(II) chloride (15.2% Pd) (206.23 mg; 0.294 mmol; 0.040 eq.) were added and dissolved in tetrahydrofuran (15.00 ml; 185.144 mmol; 25.206 eq.) while purging the suspension with nitrogen. 3-Bromo-1-(toluene-4-sulfonyl)-6-trifluoromethyl-1H-indole (3.07 g; 7.345 mmol; 1.000 eq.) was added and the reaction mixture was heated to 100° C. for 2 h in the microwave. The reaction mixture was concentrated under reduced pressure. The residue was purified by Flash Chromatography to give 1 g (31%) of the title compound as a white solid; HPLC MS(Method G): (M+H) 466.1/384.1; (pinacole ester/free boronic acid); (percent area) 63.8/36.2%; Rt 2.946/2.312 min.

78.5 Enantiomer 1 of 3-fluoro-3-({8-[1-(toluene-4-sulfonyl)-6-trifluoromethyl-1H-indol-3-yl]-pyrido[4,3-d]pyrimidin-2-ylamino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester

(122) ##STR00122##
(Given absolute configuration is arbitrary).

(123) (S)-3-Fluoro-3-[(8-iodo-pyrido[4,3-d]pyrimidin-2-ylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester from example 78.3.1 (81.80 mg; 0.168 mmol; 1.000 eq.), 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-6-trifluoromethyl-1H-indole (93.73 mg; 0.201 mmol; 1.200 eq.), palladium(II) acetate (47% Pd) (1.88 mg; 0.008 mmol; 0.050 eq.), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (6.89 mg; 0.017 mmol; 0.100 eq.) and potassium carbonate (68.39 mg; 0.495 mmol; 2.948 eq.) were added and suspended in ethylene glycol dimethyl ether (2.13 ml; 20.534 mmol; 122.328 eq.) and water (0.71 ml; 39.346 mmol; 234.400 eq.) while purging nitrogen through the mixture. The reaction mixture was heated for 45 min at 150° C. in the microwave. The mixture was concentrated under reduced pressure and purified by Flash Chromatography to give 68 mg (29%) of the title compound as mixture with the detosylated compound as a green solid; LC/MS(Method G): Rt 2.427 min; (M+H) 699.3 and for the detosylated compound Rt 2.08 min, MH+545.3).

78.6 Enantiomer 1 of (3-fluoro-piperidin-3-ylmethyl)-{8-[1-(toluene-4-sulfonyl)-6-trifluoromethyl-1H-indol-3-yl]-pyrido[4,3-d]pyrimidin-2-yl}-amine

(124) ##STR00123##

(125) Example 78.5 (68 mg) was dissolved in dichloromethane (500.00 μl; 7.830 mmol; 160.586 eq.) and trifluoroacetic acid (37.56 μl; 0.488 mmol; 10.000 eq.) was added and the solution was stirred at rt for 14 h. Trifluoroacetic acid (20.00 μl; 0.260 mmol; 5.324 eq.) was added and stirred for 14 h. The solvent was evaporated under reduced pressure to give 56 mg (90%) of the title compound as a yellow solid; LC/MS (Method G): Rt 1.857 min; (M+H) 599.2.

78.7 Enantiomer 1 of (3-fluoro-piperidin-3-ylmethyl)-[8-(6-trifluoromethyl-1H-indol-3-yl)-pyrido[4,3-d]pyrimidin-2-yl]-amine

(126) ##STR00124##

(127) Example 78.6 (56 mg) was dissolved in ethanol (4.00 ml; 68.594 mmol), then tetrahydrofuran (1.00 ml; 12.343 mmol) and sodium hydroxide pellets (35.02 mg; 0.876 mmol; 20.000 eq.) were added. The solution was heated to 50° C. for 14 h. The solvent was evaporated under reduced pressure. The residue was treated with water, filtered, and washed with water. The precipitate was suspended in diethyl ether and extracted with 1N HCl 2 times. The solvent of the combined aqueous layers was removed under vacuo to give the title compound as a orange solid; .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ [ppm] 12.35 (s, 1H), 9.57 (s, 1H), 9.56-9.49 (m, 1H), 9.33 (s, 1H), 9.28-9.19 (m, 1H), 8.92 (s, 1H), 8.63 (q, J=11.3, 1H), 8.46 (d, J=2.8, 1H), 8.02 (d, J=8.5, 1H), 7.91 (s, 1H), 7.46-7.42 (m, 1H), 3.81-3.65 (m, 2H), 3.37-3.28 (m, 1H), 3.20-3.11 (m, 1H), 3.09-2.94 (m, 1H), 2.71 (q, J=11.9, 1H), 1.99-1.53 (m, 4H); LC/MS (Method G): (percent area) 100%; Rt 1.496 min; (M+H) 445.2.

Example 79

Enantiomer 2 of (3-fluoro-piperidin-3-ylmethyl)-[8-(6-trifluoromethyl-1H-indol-3-yl)-pyrido[4,3-d]pyrimidin-2-yl]-amine (“A79”)

(128) ##STR00125##
(given absolute configuration is arbitrary).

79.1 Enantiomer 2 of 3-fluoro-3-({8-[1-(toluene-4-sulfonyl)-6-trifluoromethyl-1H-indol-3-yl]-pyrido[4,3-d]pyrimidin-2-ylamino}-methyl)-piperidine-1-carboxylic acid tea-butyl ester

(129) ##STR00126##

(130) Example 78.3.2 (enantiomer 2; 64.50 mg), 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-6-trifluoromethyl-1H-indole (73.90 mg; 0.159 mmol; 1.200 eq.), palladium(II) acetate (47% Pd) (1.49 mg; 0.007 mmol; 0.050 eq.), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (5.43 mg; 0.013 mmol; 0.100 eq.) and potassium carbonate (0.02 ml; 0.390 mmol; 2.948 eq.) were added and suspended in ethylene glycol dimethyl ether (1.68 ml; 16.191 mmol; 122.328 eq.) and water (0.56 ml; 31.025 mmol; 234.400 eq.) while purging nitrogen through the suspension. The reaction mixture was heated for 45 min at 150° C. in the microwave. The reaction mixture was concentrated under reduced pressure. The residue was purified by Flash Chromatography to give 62 mg (34%) of the title compound as a mixture with the detosylated product as a green solid; LC/MS(Method G): Rt 2.425 min; (M+H) 699.3.

79.2 Enantiomer 2 of (3-fluoro-piperidin-3-ylmethyl)-{8-[1-(toluene-4-sulfonyl)-6-trifluoromethyl-1H-indol-3-yl]-pyrido[4,3-d]pyrimidin-2-yl}-amine

(131) ##STR00127##

(132) Example 79.1 (62 mg) was dissolved in dichloromethane (500.00 μl; 7.830 mmol; 171.672 eq.). Trifluoroacetic acid (35.14 μl; 0.456 mmol; 10.000 eq.) was added and the solution was stirred at rt for 2 days. The solvent was evaporated under reduced pressure to give 48 mg (86%) of the title compound as mixture with the detosylated product as a yellow green solid; LC/MS (Method G): Rt 1.867 min; (M+H) 599.2.

79.2 Enantiomer 2 of (3-fluoro-piperidin-3-ylmethyl)-[8-(6-trifluoromethyl-1H-indol-3-yl)-pyrido[4,3-d]pyrimidin-2-yl]-amine

(133) 48 mg example 79.2 was dissolved in ethanol (4.00 ml; 68.594 mmol) and tetrahydrofuran (1.00 ml; 12.343 mmol) and sodium hydroxide pellets (31.24 mg; 0.781 mmol; 20.000 eq.) were added. The solution was heated to 50° C. for 14 h. The solvent was evaporated under reduced pressure. The residue suspended in water, filtered and washed with water. The precipitate was dissolved in diethyl ether and extracted with 1N HCl 2 times. The solvent of the combined aqueous layers were removed under vacuo to give 44 mg (234%) of the title compound as an orange solid; .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ [ppm] 12.27-12.21 (m, 1H), 9.54 (s, 1H), 9.38-9.25 (m, 2H), 9.14-8.96 (m, 1H), 8.92 (s, 1H), 8.57 (q, J=11.2, 1H), 8.42 (d, J=2.7, 1H), 8.01 (d, J=8.5, 1H), 7.90 (s, 1H), 7.47-7.41 (m, 1H), 3.83-3.65 (m, 2H), 3.35-3.26 (m, 1H), 3.15 (d, J=12.4, 1H), 3.08-2.90 (m, 1H), 2.68 (q, J=12.0, 1H), 1.90-1.52 (m, 4H); LC/MS (Method G): (percent area) 100%; Rt 1.499 min; (M+H) 445.2.

Example 80

3-(2-cyclohexylamino-pyrido[4,3-d]pyrimidin-8-yl)-1H-indole-6-carbonitrile (“A80”)

(134) ##STR00128##

80.1 cyclohexyl-(8-iodo-pyrido[4,3-d]pyrimidin-2-yl)-amine

(135) ##STR00129##

(136) 8-Iodo-2-methylsulfanyl-pyrido[4,3-d]pyrimidine (378.00 mg; 1.25 mmol; 1.00 eq.) and cyclohexylamine (1.42 ml; 12.47 mmol; 10.00 eq.) were heated at 120° C. for 2 h. The solvent was removed in vacuo and the precipitate purified by flash chromatography to give 97 mg (19%) of the title compound as a white yellow solid; HPLC MS (Method G): Rt 1.79 min; (M+H) 355.1.

80.2 3-(2-cyclohexylamino-pyrido[4,3-d]pyrimidin-8-yl)-1H-indole-6-carbonitrile

(137) Cyclohexyl-(8-iodo-pyrido[4,3-d]pyrimidin-2-yl)-amine (116 mg; 1 eq.), 1-BOC-6-cyanoindole-3-boronic acid, pinacol ester (180.43 mg; 0.49 mmol; 1.50 eq.), palladium(II) acetate (47% Pd) (3.67 mg; 0.02 mmol; 0.05 eq.), potassium carbonate (0.06 ml; 0.98 mmol; 3.00 eq.) and dicyclohexyl-(2′,6′-dimethoxybiphenyl-2-yl)-phosphane (13.41 mg; 0.03 mmol; 0.10 eq.) were dissolved in ethylene glycol dimethyl ether (7.50 ml; 48.27 mmol; 147.76 eq.) and water (2.50 ml; 88.79 mmol; 271.81 eq.). The mixture was heated in the microwave to 150° C. for 45 minutes. The solvent was removed under vacuo and the precipitate purified by flash chromatography to give 98 mg (81%) of the title compound as a yellow beige solid; HPLC MS (Method G): Rt 1.79 min; (M+H) 369.2,

(138) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ [ppm] 12.13-12.09 (m, 1H), 9.32-9.25 (s, 1H), 8.97-8.92 (s, 1H), 8.87-8.83 (s, 1H), 8.35-8.30 (d, J=2.7 Hz, 1H), 8.07-7.86 (m, 3H), 7.43-7.36 (m, 1H), 3.73-3.62 (m, 1H), 1.93-1.87 (m, 2H), 1.77-1.64 (m, 2H), 1.64-1.52 (m, 1H), 1.41-1.06 (m, 6H).

Example 81

(1S,2R)—N-[8-(7-fluoro-1H-indol-2-yl)-pyrido[4,3-d]pyrimidin-2-yl]-cyclohexane-1,2-diamine (“A81”)

(139) ##STR00130##

81.1 tert-butyl N-[(1S,2R)-2-[[8-(7-fluoro-1H-indol-2-yl)pyrido[4,3-d]pyrimidin-2-yl]amino]cyclohexyl]carbamate

(140) ##STR00131##

(141) [(1S,2R)-2-(8-Iodo-pyrido[4,3-d]pyrimidin-2-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester (100.000 mg; 0.213 mmol; 1.00 eq.), N—(BOC)-7-fluoroindole-2-boronic acid (89.195 mg; 0.320 mmol; 1.50 eq.), palladium(II)-acetat (47% Pd) (2.392 mg; 0.011 mmol; 0.05 eq.), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (8.747 mg; 0.021 mmol; 0.10 eq.) and potassium carbonate (88.343 mg; 0.639 mmol; 3.00 eq.) were added into a 5 ml microwave vessel. Ethylenglycoldimethylether (2.500 ml; 24.134 mmol; 113.27 eq.) and water (0.800 ml; 44.395 mmol; 208.36 eq.) were added and the suspension was purged with nitrogen. The reaction mixture was heated in the microwave at 130° C. for 45 min. N—(BOC)-7-fluoroindole-2-boronic acid (89.195 mg; 0.320 mmol; 1.50 eq.), palladium(II)-acetat (47% Pd) (2.392 mg; 0.011 mmol; 0.05 eq.) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (8.747 mg; 0.021 mmol; 0.10 eq.) were added and heated in the microwave for further 30 min. at 150° C. The reaction mixture was diluted with DMF, filtered with an Anatop 25 inorganic membrane filter and the solution was purified by preparative HPLC to give 10 mg (10%) of the title compound; HPLC MS (Method G): (M+H) 477.3; (percent area) 100%; Rt 2.148 min.

81.2 (1S,2R)—N-[8-(7-fluoro-1H-indol-2-yl)-pyrido[4,3-d]pyrimidin-2-yl]-cyclohexane-1,2-diamine

(142) tert-Butyl N-[(1S,2R)-2-[[8-(7-fluoro-1H-indol-2-yl)pyrido[4,3-d]pyrimidin-2-yl]amino]cyclohexyl]carbamate (10.000 mg; 20.984 μmol; 1.00 eq.) was suspended in ethylacetat (300.000 μl; 3.064 mmol; 146.03 eq.). Hydrochloric acid (1 N) (209.843 μl; 209.843 μmol; 10.00 eq.) was added. The mixture was stirred at RT for 21 h and stirred at 50° C. for 3 h. The solvent was removed under vacuo to give 9 mg (98%) of the title compound as a yellow solid; HPLC (Method J): (percent area) 93.35%; Rt 2.31 min.; HPLC MS (Method G): (M+H) 377.3; Rt 1.303 min.

Example 82

(1S,2R)—N-[5-difluoromethyl-8-(6-trifluoromethyl-1H-indol-3-yl)-pyrido[4,3-d]pyrimidin-2-yl]-cyclohexane-1,2-diamine (“A82”)

(143) ##STR00132##

82.1 5-difluoromethyl-2-methylsulfanyl-pyrido[4,3-d]pyrimidine

(144) ##STR00133##

(145) 2-Methylsulfanyl-pyrido[4,3-d]pyrimidine (184.32 mg; 1.040 mmol; 1.000 eq.) was dissolved in dichloromethane (4.00 ml; 62.637 mmol; 60.228 eq.). Water (1.60 ml) and bis(((difluoromethyl)sulfinyl)oxy)zinc (530.00 mg; 1.793 mmol; 1.724 eq.) were added at rt. The reaction mixture was cooled down in an ice bath and trifluoroacetic acid (80.12 μl; 1.040 mmol; 1.000 eq.) was added followed by slow addition of tert-Butyl hydroperoxide, 70% aqueous solution (743.86 μl; 5.200 mmol; 5.000 eq.). The reaction mixture was allowed to warm to rt and stirred for 14 h. tert-Butyl hydroperoxide, 70% aqueous solution (743.86 μl; 5.200 mmol; 5.000 eq.) was added and it was stirred for 14 h again. The reaction was partitioned between DCM and saturated sodium bicarbonate solution. The organic layer was separated and the aqueous layer was extracted with DCM one more time. The combined organic layers were dried over MgSO.sub.4 and concentrated under reduced pressure. The precipitate was purified by flash chromatography to give 23 mg (10%) of the title compound as a white solid; LC/MS (Method G): (percent area) 100%; Rt 1.765 min; (M+H) 228.

82.2 5-difluoromethyl-8-iodo-2-methylsulfanyl-pyrido[4,3-d]pyrimidine

(146) ##STR00134##

(147) 5-Difluoromethyl-2-methylsulfanyl-pyrido[4,3-d]pyrimidine (23.00 mg; 0.101 mmol; 1.000 eq.) was dissolved in dry N,N-dimethylformamide (500.00 μl; 0.006 mol; 63.528 eq.). Trifluoroacetic acid (9.36 μl; 0.121 mmol; 1.200 eq.) and N-iodosuccinimide (27.33 mg; 0.121 mmol; 1.200 eq.) were added and the reaction mixture was stirred at 50° C. for 3 days. The reaction was treated with water and 0.1 N sodiumthiosulfate solution and stirred for about 20 minutes while cooling down to room temperature. The precipitate was filtered off and washed with water. This wet cake was treated with DCM and evaporated under reduced pressure to give 25 mg (70%) of the title compound as a yellow solid; LC/MS (Method G): (percent area) 100%; Rt 2.238 min; (M+H) 353.9.

82.3 [(1S,2R)-2-(5-difluoromethyl-8-iodo-pyrido[4,3-d]pyrimidin-2-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester

(148) ##STR00135##

(149) To the solution of 2-chloro-5-difluoromethyl-8-iodo-pyrido[4,3-d]pyrimidine (24.00 mg; 0.070 mmol; 1.000 eq.) in acetonitrile, triethylamin (107.17 μl; 0.773 mmol; 11.000 eq.) and ethanol (46.79 μl; 0.802 mmol; 11.417 eq.) were added and treated with ((1S,2R)-2-amino-cyclohexyl)-carbamic acid tert-butyl ester (15.81 mg; 0.074 mmol; 1.050 eq.). The reaction mixture was heated in the microwave at 120° C. for 5 min. The reaction mixture was evaporated under reduced pressure. The residue was treated with water and filtered to give 21 mg (58%) of the title compound as a yellow solid; LC/MS (Method G): (percent area) 100%; Rt 2.459 min; (M+H) 520.1.

82.4 ((1S,2R)-2-{5-difluoromethyl-8-[1-(toluene-4-sulfonyl)-6-trifluoromethyl-1H-indol-3-yl]-pyrido[4,3-d]pyrimidin-2-ylamino}-cyclohexyl)-carbamic acid tert-butyl ester

(150) ##STR00136##

(151) [(1S,2R)-2-(5-difluoromethyl-8-iodo-pyrido[4,3-d]pyrimidin-2-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester (21.00 mg; 0.040 mmol; 1.000 eq.), 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-6-trifluoromethyl-1H-indole (22.58 mg; 0.049 mmol; 1.200 eq.), palladium(II)-acetat (47% Pd) (0.45 mg; 0.002 mmol; 0.050 eq.), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (1.66 mg; 0.004 mmol; 0.100 eq.) and potassium carbonate (16.48 mg; 0.119 mmol; 2.948 eq.) were added and suspended in ethylenglycoldimethylether (0.42 ml; 4.044 mmol; 100.000 eq.) and water (0.15 ml; 8.087 mmol; 200.000 eq.) while purging nitrogen through the suspension. The suspension was heated in the microwave for 45 min at 150° C. The reaction mixture was concentrated under reduced pressure and the precipitate purified by flash chromatography to give 10 mg (33%) of the title compound as a yellow solid; LC/MS (Method G): (percent area) 100%; Rt 2.882 min; (M+H) 753.3 and 5 mg of the detosylated compound as a yellow solid; LC/MS (Method G): (percent area) 100%; Rt 2.509 min; (M+H) 577.2.

82.5 (1S,2R)—N-{5-fifluoromethyl-8-[1-(toluene-4-sulfonyl)-6-trifluoromethyl-1H-indol-3-yl]-pyrido[4,3-d]pyrimidin-2-yl}-cyclohexane-1,2-diamine trifluoroacetate

(152) ##STR00137##

(153) From Example 82.4 ((1S,2R)-2-{5-difluoromethyl-8-[1-(toluene-4-sulfonyl)-6-trifluoromethyl-1H-indol-3-yl]-pyrido[4,3-d]pyrimidin-2-ylamino}-cyclohexyl)-carbamic acid tert-butyl ester (9.80 mg; 0.013 mmol; 1.000 eq.) and {(1S,2R)-2-[5-difluoromethyl-8-(6-trifluoromethyl-1H-indol-3-yl)-pyrido[4,3-d]pyrimidin-2-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (4.70 mg; 0.008 mmol; 0.608 eq.) were dissolved in dichloromethane (300.00 μl; 2.302 mmol). Trifluoroacetic acid (10.33 μl; 0.134 mmol; 10.000 eq.) was added and the resulting solution was stirred at rt for 14 h. The solvent was evaporated under reduced pressure to give 17 mg of the title compound as a mixture with the detosylated form as an orange solid; LC/MS (Method G): Rt 2.361 min; (M+H) 631.2.

82.6 (1S,2R)—N-[5-difluoromethyl-8-(6-trifluoromethyl-1H-indol-3-yl)-pyrido[4,3-d]pyrimidin-2-yl]-cyclohexane-1,2-diamine

(154) From example 82.5 17 mg were dissolved in ethanol (2.40 ml; 41.157 mmol; 3168.352 eq.) and tetrahydrofuran (0.70 ml; 8.640 mmol; 665.137 eq.). Sodium hydroxide pellets (18.26 mg; 0.457 mmol; 35.145 eq.) were added and the solution was stirred at 50° C. for 2.5 h. The reaction mixture was concentrated under reduced pressure. The residue was treated with water and filtered to give 6 mg (97%) of the title compound as a yellow solid; LC/MS (Method G): (percent area) 100%; Rt 2.006 min; (M+H) 477.2;

(155) .sup.1H NMR (700 MHz, DMSO-d.sub.6) δ [ppm] 12.41-11.86 (s, 1H), 9.78-9.27 (s, 1H), 8.97-8.80 (s, 1H), 8.48-8.25 (s, 1H), 8.07-7.72 (m, 3H), 7.50-7.26 (m, 2H), 3.86-3.79 (d, J=8.5 Hz, 1H), 3.12-2.96 (m, 1H), 1.74-1.06 (m, 8H).

Example 83

3-[2-(2-amino-3,3,3-trifluoro-propylamino)-pyrido[4,3-d]pyrimidin-8-yl]-1H-indole-6-carbonitrile (“A83”)

(156) ##STR00138##

83.1 3,3,3-trifluoro-N1-(8-iodo-pyrido[4,3-d]pyrimidin-2-yl)-propane-1,2-diamine

(157) ##STR00139##

(158) 2-Chloro-8-iodo-pyrido[4,3-d]pyrimidine (941.76 mg; 2.00 mmol; 1.00 eq.), 3,3,3-trifluoro-propane-1,2-diamine hydrochloride (2) (422.14 mg; 2.10 mmol; 1.05 eq.), 1,4-dioxane (9.00 ml; 105.22 mmol; 52.61 eq.) and triethylamine (1.16 ml; 8.40 mmol; 4.20 eq.) were combined and heated in the microwave on 120° C. for 10 min. The solvent was removed in vacuo and the precipitate purified by flash chromatography to give 77 mg (6%) of the title compound as a yellow brown solid; HPLC MS (Method G): Rt 1.19 min; (M+H) 384.

83.2 3-[2-(2-amino-3,3,3-trifluoro-propylamino)-pyrido[4,3-d]pyrimidin-8-yl]-1H-indole-6-carbonitrile

(159) 3,3,3-Trifluoro-N1-(8-iodo-pyrido[4,3-d]pyrimidin-2-yl)-propane-1,2-diamine (77.00 mg; 0.11 mmol; 1.00 eq.), 1-BOC-6-cyanoindole-3-boronic acid, pinacol ester (63.39 mg; 0.17 mmol; 1.50 eq.), palladium(II) acetate (47% Pd) (1.80 mg; 0.01 mmol; 0.07 eq.), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (6.60 mg; 0.02 mmol; 0.14 eq.), potassium carbonate (0.02 ml; 0.36 mmol; 3.11 eq.), ethylene glycol dimethyl ether (1.78 ml; 17.21 mmol; 150.00 eq.) and water (0.62 ml; 34.43 mmol; 300.00 eq.) were heated in the microwave for 45 min on 150° C. 1-BOC-6-cyanoindole-3-boronic acid, pinacol ester (63.39 mg (63.4 mg), 1.8 mg palladium(II)acetate and 6.6 mg 2-dicyclohexylphosphino-2′,6′-dimethoxy biphenyl were added to the mixture. The mixture was heated in the microwave for 45 min to 150° C. The solvent was removed in vacuo and the precipitate purified by reversed phase to give 13 mg of the title compound as a yellow solid; HPLC MS (Method G): (percent area) 100%; Rt 1.32 min; (M+H) 398.2;

(160) .sup.1H NMR (500 MHz, DMSO-d.sub.6+TFA-d.sub.1) δ [ppm] 9.69 (s, 1H), 9.54-9.47 (m, 1H), 9.02-8.93 (m, 1H), 8.43 (s, 1H), 8.11-8.05 (m, 1H), 7.94 (d, J=8.37 Hz, 1H), 7.51 (s, 1H), 4.48-4.34 (m, 1H), 4.04 (d, J=18.84 Hz, 1H), 3.73 (d, J=23.64 Hz, 1H).

Example 85

3-[2-((cis)-2-amino-cyclohexylamino)-5-methyl-pyrido[4,3-d]pyrimidin-8-yl]-1H-indole-6-carbonitrile (“A85”)

(161) ##STR00140##

85.1 3-(2-methylsulfanyl-5-oxo-5,6-dihydro-pyrido[4,3-d]pyrimidin-8-yl)-1H-indole-6-carbonitrile

(162) ##STR00141##

(163) In a microwave vessel 8-iodo-2-methylsulfanyl-6H-pyrido[4,3-d]pyrimidin-5-one (1000.000 mg; 3.134 mmol; 100.00 mol %), 1-BOC-6-cyanoindole-3-boronic acid, pinacol ester (1201.976 mg; 3.134 mmol; 100.00 mol %) and tripotassium phosphate trihydrate (1995.463 mg; 9.401 mmol; 300.00 mol %) were suspended in tetrahydrofuran (35.000 ml) and water (5.000 ml). Under nitrogen [2-(2-aminophenyl)phenyl]-[dicyclohexyl-[2-(2,4,6-triisopropylphenyl)-phenyl]phosphaniumyl]palladium chloride (246.552 mg; 0.313 mmol; 10.00 mol %) were added and heated in the microwave (150° C., 45 min). Under nitrogen 1-BOC-6-cyanoindole-3-boronic acid, pinacol ester (1000.000 mg; 2.607 mmol; 83.20 mol %) were added and heated in the microwave (150° C., 45 min). The solvent was removed in vacuo and the residue dissolved in DCM and water and extracted to give 220 mg (14%) of the title compound as a yellow solid; HPLC (Method J): (percent area) 64.2%; Rt 2.357 min.; LC/MS (Method G): Rt 1.766 min; (M+H) 334.1.

85.2 3-(5-chloro-2-methylsulfanyl-pyrido[4,3-d]pyrimidin-8-yl)-1H-indole-6-carbonitrile

(164) ##STR00142##

(165) Phosphorylchlorid (5.000 ml; 55.435 mmol; 13084.36 mol %) was added to 3-(2-methylsulfanyl-5-oxo-5,6-dihydro-pyrido[4,3-d]pyrimidin-8-yl)-1H-indole-6-carbonitrile (220.000 mg; 0.424 mmol; 100.00 mol %). The suspension was stirred at 110° C. for 3 h. The solvent was removed in vacuo, toluene added and removed in vacuo. The residue was suspended in a saturated NaHCO.sub.3-solution/ice mixture and filtered to give 220 mg (110%) of the title compound as a brown powder; HPLC (Method J): (percent area) 74.3%; Rt 3.014 min.; LC/MS (Method G): Rt 2.258 min; (M+H) 352.

85.3 3-(5-methyl-2-methylsulfanyl-pyrido[4,3-d]pyrimidin-8-yl)-1H-indole-6-carbonitrile

(166) ##STR00143##

(167) 3-(5-Chloro-2-methylsulfanyl-pyrido[4,3-d]pyrimidin-8-yl)-1H-indole-6-carbonitrile (220.000 mg; 0.465 mmol; 100.00 mol %), trimethylboroxine, 50 wt % solution in THF (116.652 mg; 0.465 mmol; 100.00 mol %), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (19.664 mg; 0.046 mmol; 10.00 mol %) and cesiumfluoride (141.155 mg; 0.929 mmol; 200.00 mol %) were added in a microwave vessel (2.5 ml). 1,4-Dioxane (5,000 ml) was added. Under nitrogen palladium(II)-acetat (10.431 mg; 0.046 mmol; 10.00 mol %) was added. The vessel was closed with a septum and heated in the microwave (150° C., 45 min), The product was purified by flash chromatography to give 20 mg of the title compound as a yellow solid; LC/MS (Method G): Rt 1.622 min; (M+H) 332.1.

85.4 3-[2-((cis)-2-amino-cyclohexylamino)-5-methyl-pyrido[4,3-d]pyrimidin-8-yl]-1H-indole-6-carbonitrile

(168) 3-(5-Methyl-2-methylsulfanyl-pyrido[4,3-d]pyrimidin-8-yl)-1H-indole-6-carbonitrile (20.000 mg; 0.050 mmol; 100.00 mol %) in cis-1,2-cyclohexanediamine (0.061 ml; 0.503 mmol; 1000.00 mol %) was stirred at 100° C. over night. The mixture was dissolved in DMSO and was purified by preparative HPLC. The desired fractions were combined, NaHCO.sub.3 was added until pH8 was reached and ACN was removed by vacuo. The aqueous layer was extracted with DCM. The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness to give 6 mg of the title compound as a yellow solid; HPLC (Method J): (percent area) 100%; Rt 1.857 min.; LC/MS (Method G): Rt 1.438 min; (M+H) 398.3;

(169) 1H NMR (400 MHz, CD.sub.2Cl.sub.2) δ [ppm] 9.28 (s, 1H), 9.03 (s, 1H), 8.72 (s, 1H), 8.04 (s, 1H), 7.89 (d, J=8.73 Hz, 1H), 7.81 (s, 1H), 7.37 (d, J=8.48 Hz, 1H), 6.15 (s, 1H), 3.89 (s, 1H), 3.09 (s, 1H), 2.86 (s, 3H), 1.93-0.97 (m, 8H).

Example 86

2-((cis)-2-amino-cyclohexylamino)-8-(6-trifluoromethyl-1H-indol-3-yl)-6H-pyrido[4,3-d]pyrimidin-5-one (“A86”)

(170) ##STR00144##

86.1 2-methylsulfanyl-8-[1-(toluene-4-sulfonyl)-6-trifluoromethyl-1H-indol-3-yl]-6H-pyrido[4,3-d]pyrimidin-5-one

(171) ##STR00145##

(172) 8-Iodo-2-methylsulfanyl-6H-pyrido[4,3-d]pyrimidin-5-one (1.303 g; 4.083 mmol; 95.00 mol %), 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-6-trifluoromethyl-1H-indole (2.000 g; 4.298 mmol; 100.00 mol %) and tripotassium phosphate hydrate (3.126 g; 12.895 mmol; 300.00 mol %) were suspended in 1,4-dioxane (80.000 ml) and water (20.000 ml). Under nitrogen [2-(2-aminophenyl)phenyl]-[dicyclohexyl-[2-(2,4,6-triisopropyl-phenyl)phenyl]phosphaniumyl]palladium chloride (0.169 g; 0.215 mmol; 5.00 mol %) was added and stirred at 100° C. for 2 h and was allowed to cool to rt for 14 h. The dioxane was removed in vacuo. The aqueous layer was diluted with water and extracted with DCM. The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness to give 2 g (49%) of the title compound as a yellow solid; LC/MS (Method G): Rt 2.528 min; (M+H) 531.2.

86.2 2-((cis)-2-amino-cyclohexylamino)-8-[1-(toluene-4-sulfonyl)-6-trifluoromethyl-1H-indol-3-yl]-6H-pyrido[4,3-d]pyrimidin-5-one

(173) ##STR00146##

(174) 2-Methylsulfanyl-8-[1-(toluene-4-sulfonyl)-6-trifluoromethyl-1H-indol-3-yl]-6H-pyrido[4,3-d]pyrimidin-5-one (200.000 mg; 0.193 mmol; 100.00 mol %) and cis-1,2-cyclohexanediamine (0.234 ml; 1.930 mmol; 1000.00 mol %) was stirred at 100° C. for 14 h. The mixture was diluted with water and extracted with DCM. The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to residue. The residue was purified by flash chromatography and was purified a second time by flash chromatography (basic alumina) to give 28 mg (24%) of the title compound as a yellow solid; HPLC (Method J): (percent area) 100%; Rt 2.734 min.; LC/MS (Method G): Rt 2.165 min; (M+H) 597.2.

86.3 2-((cis)-2-amino-cyclohexylamino)-8-(6-trifluoromethyl-1H-indol-3-yl)-6H-pyrido[4,3-d]pyrimidin-5-one

(175) 2-((cis)-2-Amino-cyclohexylamino)-8-[1-(toluene-4-sulfonyl)-6-trifluoromethyl-1H-indol-3-yl]-6H-pyrido[4,3-d]pyrimidin-5-one (28.000 mg; 0.047 mmol; 100.00 mol %) was dissolved in tetrahydrofuran (3.000 ml) and ethanol (1.000 ml). Sodium hydroxide pellets (37.542 mg; 0.939 mmol; 2000.00 mol %) were added to the suspension. The solution was stirred at rt for 14 h and the solvent was evaporated. The residue was dissolved in DCM and water. The organic phase was extracted with water, the aqueous phase with DCM. The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness. The residue was purified by preparative HPLC. The fractions containing the product were combined. NaHCO.sub.3 was added until pH8 was reached. ACN was evaporated and the aqueous layer was extracted twice with DCM. The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and evaporated to 7 mg (35%) of the title compound as a yellow solid; HPLC (Method J): (percent area) 100%; Rt 2.303 min.; LC/MS (Method G): Rt 2.573 min; (M+H) 443.1.

Example 87

3-[2-((1R,2S)-2-amino-cyclohexylamino)-5-difluoromethyl-pyrido[4,3-d]-pyrimidin-8-yl]-1H-indole-6-carbonitrile (“A87”)

(176) ##STR00147##

87.1 5-methyl-2-methylsulfanyl-pyrido[4,3-d]pyrimidine

(177) ##STR00148##

(178) 5-Chloro-2-methylsulfanyl-pyrido[4,3-d]pyrimidine (500.000 mg; 2.135 mmol; 100.00 mol %), trimethylboroxine, 50 wt % solution in THF (536.130 mg; 2.135 mmol; 100.00 mol %), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (90.375 mg; 0.214 mmol; 10.00 mol %) and cesiumfluoride (648.745 mg; 4.271 mmol; 200.00 mol %) were added together in a microwave vessel. 1,4-Dioxane (20,000 ml) was added. Under nitrogen palladium(II)-acetat (47.941 mg; 0.214 mmol; 10.00 mol %) was added. The vessel was closed with a septum and heated by microwave (150° C., 30 min). The reaction mixture was purified by flash chromatography to give 240 mg (56%) of the title compound as a yellow solid; HPLC (Method J): (percent area) 95.7%; Rt 1.395 min.; HPLC MS (Method G): (M+H) 192.1; Rt 0.94 min.

87.2 2-methylsulfanyl-pyrido[4,3-d]pyrimidine-5-carbaldehyde

(179) ##STR00149##

(180) 5-Methyl-2-methylsulfanyl-pyrido[4,3-d]pyrimidine (240.00 mg; 1.201 mmol; 1.000 eq.) was dissolved in 1,4-dioxane (4.00 ml; 46.762 mmol). Selenium dioxide (150.57 mg; 1.357 mmol; 1.130 eq.) was added and the reaction mixture was refluxed for 3.5 h. After cooling down to room temperature the reaction mixture was filtered and the mother liquor was evaporated under reduced pressure (brown solid). The residue was purified by flash chromatography to give 142 mg (58%) of the title compound as a beige solid; LC/MS (Method G): (percent area) 100%; Rt 1.121 min; (M+H) 206.1.

87.3 5-difluoromethyl-2-methylsulfanyl-pyrido[4,3-d]pyrimidine

(181) ##STR00150##

(182) 2-Methylsulfanyl-pyrido[4,3-d]pyrimidine-5-carbaldehyde (142.00 mg; 0.692 mmol; 1.000 eq.) was dissolved in dichlormethan (5.68 ml) and diethylamino sulfur trifluoride (304.71 μl; 2.076 mmol; 3.000 eq.) was added through a septum under nitrogen atmosphere. The solution was stirred at rt for 14 h. The reaction mixture was diluted with saturated NaHCO.sub.3 solution (80 ml) and extracted with DCM three times. The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography to give 112 mg (71%) of the title compound as a beige solid; LC/MS (Method G): (percent area) 100%; Rt 1.8 min.; (M+H) 228.1.

87.4 5-difluoromethyl-8-iodo-2-methylsulfanyl-pyrido[4,3-d]pyrimidine

(183) ##STR00151##

(184) 5-Difluoromethyl-2-methylsulfanyl-pyrido[4,3-d]pyrimidine (27.00 mg; 0.119 mmol; 0.194 eq.) was dissolved in N,N-dimethylformamide (3.00 ml; 0.039 mol). Trifluoroacetic acid (56.55 μl; 0.734 mmol; 1.200 eq.) and N-iodosuccinimide (192.67 mg; 0.856 mmol; 1.400 eq.) were added and the reaction mixture was stirred at 50° C. for 3 days. Trifluoroacetic acid (28.28 μl; 0,367 mmol; 0,600 eq.) and N-lodosuccinimide for synthesis (96.33 mg; 0.428 mmol; 0.700 eq.) were added again and it was stirred for another 4 days. The reaction was treated with water and 0.1 N sodiumthiosulfate solution and stirred for about 20 minutes while cooling down to room temperature. The precipitate was filtered off and washed with water and DCM. This gives 197 mg (85%) of the title compound as a yellow solid; LC/MS (Method G): (percent area) 93.5%; Rt 2.291 min.; (M+H) 354.

87.5 2-chloro-5-difluoromethyl-8-iodo-pyrido[4,3-d]pyrimidine

(185) ##STR00152##

(186) 5-Difluoromethyl-8-iodo-2-methylsulfanyl-pyrido[4,3-d]pyrimidine (197.00 mg; 0.522 mmol; 1.000 eq.) was dissolved in acetonitrile (10.94 ml). After cooling to 0° C. dichloromethane (14.26 ml) and sulfuryl chloride (421.56 μl; 5.216 mmol; 10.000 eq.) were added and it was stirred for 3 h at this temperature. DCM was evaporated and the resulting solution was used in next reaction step without any purification. Yield: 178 mg (100%) of the title compound as a yellow solution; LC/MS (Method G): (percent area) 100%; Rt 2.037 min.; (M+H) 341.9.

87.6 [(1S,2R)-2-(5-difluoromethyl-8-iodo-pyrido[4,3-d]pyrimidin-2-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester

(187) ##STR00153##

(188) To the solution of 2-chloro-5-difluoromethyl-8-iodo-pyrido[4,3-d]pyrimidine (178.12 mg; 0.522 mmol; 1.000 eq.) in acetonitrile (10 ml), N-ethyldiisopropyl-amine (975.74 μl; 5.738 mmol; 11.000 eq.) and ethanol (347.27 μl; 5.955 mmol) were added and ((1S,2R)-2-amino-cyclohexyl)-carbamic acid tert-butyl ester (117.37 mg; 0.548 mmol; 1.050 eq.) was added. The reaction mixture was heated by microwave at 120° C. for 5 min. The reaction mixture was evaporated under reduced pressure. The residue was washed with water and dried in vacuo to give 233 mg (77%) of the title compound as a brown solid; LC/MS (Method G): (percent area) 89.4%; Rt 2.503 min.; (M+H) 520.2.

87.7 {(1S,2R)-2-[8-(6-cyano-1H-indol-3-yl)-5-difluoromethyl-pyrido[4,3-d]pyrimidin-2-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester

(189) ##STR00154##

(190) [(1S,2R)-2-(5-Difluoromethyl-8-iodo-pyrido[4,3-d]pyrimidin-2-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester (96.00 mg; 0.185 mmol; 1.000 eq.), 1-BOC-6-cyanoindole-3-boronic acid pinacol ester (81.68 mg; 0.222 mmol; 1.200 eq.), palladium(II)-acetat (47% Pd) (2.08 mg; 0.009 mmol; 0.050 eq.), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (7.59 mg; 0.018 mmol; 0.100 eq.) and potassium carbonate (75.31 mg; 0.545 mmol; 2.948 eq.) were suspended in ethylenglycoldimethylether (1.91 ml; 18.485 mmol; 100.000 eq.) and water (0.67 ml; 36.971 mmol; 200.000 eq.) while purging nitrogen through the suspension. The suspension was heated by microwave for 45 min at 150° C. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography to give 65 mg (66%) of the title compound as a yellow solid; LC/MS (Method G): (percent area) 100%; Rt 2.395 min; (M+H) 534.3.

87.8 3-[2-((1R,2S)-2-amino-cyclohexylamino)-5-difluoromethyl-pyrido-[4,3-d]pyrimidin-8-yl]-1H-indole-6-carbonitrile

(191) {(1S,2R)-2-[8-(6-Cyano-1H-indol-3-yl)-5-difluoromethyl-pyrido[4,3-d]pyrimidin-2-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (65.00 mg; 0.122 mmol; 1.000 eq.) was suspended in dichloromethane (0.95 ml; 14.876 mmol). Trifluoroacetic acid (93.85 μl; 1.218 mmol; 10.000 eq.) was added. The reaction mixture was stirred at rt for 14 h. The reaction mixture was treated with saturated NaHCO.sub.3 solution and DCM and phases were separated. The aqueous layer was extracted with DCM 1 more time. The combined organic extracts were dried over Na.sub.2SO.sub.4 and evaporated under reduced pressure to give 46 mg (87%) of the title compound as a yellow solid; LC/MS (Method G): (percent area) 100%; Rt 1.971 min.; (M+H) 434.2;

(192) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ [ppm] 12.19 (s, 1H), 9.52 (s, 1H), 8.90 (s, 1H), 8.39 (s, 1H), 8.04-7.93 (m, 2H), 7.87 (d, J=7.60 Hz, 1H), 7.55-7.29 (m, 2H), 3.88-3.78 (m, 1H), 3.15-2.99 (m, 1H), 1.93-1.10 (m, 8H).

Example 88

(1S,2R)—N-[5-methyl-8-(6-trifluoromethyl-1H-indol-3-yl)-pyrido[4,3-d]pyrimidin-2-yl]-cyclohexane-1,2-diamine (“A88”)

(193) ##STR00155##

88.1 5-chloro-2-methylsulfanyl-8-[1-(toluene-4-sulfonyl)-6-trifluoromethyl-1H-indol-3-yl]-pyrido[4,3-d]pyrimidine

(194) ##STR00156##

(195) 2-Methylsulfanyl-8-[1-(toluene-4-sulfonyl)-6-trifluoromethyl-1H-indol-3-yl]-6H-pyrido[4,3-d]pyrimidin-5-one (1.970 g; 1.901 mmol; 100.00 mol %) and phosphorylchloride (5.000 ml; 55.435 mmol; 2915.89 mol %) was added. The suspension was stirred at 110° C. for 4 h and then the solution was stirred at rt for 14 h. The solution was evaporated to dryness. Toluene was added and removed again by vacuo. The residue was suspended in a saturated NaHCO.sub.3-solution/ice mixture. The aqueous phase was extracted twice with DCM. The organic layers were combined, dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness. The residue was purified by flash chromatography to give 710 mg (43%) of the title compound as a yellow solid; HPLC (Method J): (percent area) 63.6%; Rt 3.871 min.; LC/MS (Method G): Rt 2.887 min.; (M+H) 549.1.

88.2 5-methyl-2-methylsulfanyl-8-[1-(toluene-4-sulfonyl)-6-trifluoromethyl-1H-indol-3-yl]-pyrido[4,3-d]pyrimidine

(196) ##STR00157##

(197) 5-Chloro-2-methylsulfanyl-8-[1-(toluene-4-sulfonyl)-6-trifluoromethyl-1H-indol-3-yl]-pyrido[4,3-d]pyrimidine (710.000 mg; 0.823 mmol; 100.00 mol %), trimethylboroxine, 50 wt % solution in THF (206.512 mg; 0.823 mmol; 100.00 mol %), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (34.812 mg; 0.082 mmol; 10.00 mol %) and cesiumfluoride (249.891 mg; 1.645 mmol; 200.00 mol %) were given together. 1,4-Dioxane (20.000 ml) was added. Under nitrogen palladium(II)-acetat (18.466 mg; 0.082 mmol; 10.00 mol %) was added. The vessel was closed with a septum and heated by microwave (150° C., 45 min). The solvent was removed in vacuo and the precipitate purified by flash chromatography to give 384 mg (63%) of the title compound as a yellow solid; HPLC (Method J): (percent area) 70.9%; Rt 3.234 min.; LC/MS (Method G): Rt 2.506 min; (M+H) 529.

88.3 (cis)-N-{5-methyl-8-[1-(toluene-4-sulfonyl)-6-trifluoromethyl-1H-indol-3-yl]-pyrido[4,3-d]pyrimidin-2-yl}-cyclohexane-1,2-diamine

(198) ##STR00158##

(199) In a 10 ml-flask charged with 5-methyl-2-methylsulfanyl-8-[1-(toluene-4-sulfonyl)-6-trifluoromethyl-1H-indol-3-yl]-pyrido[4,3-d]pyrimidine (364.00 mg; 0.49 mmol; 1.00 eq.) cis-1,2-cyclohexanediamine (0.59 ml; 4.88 mmol; 10.00 eq.) was added and stirred at 100° C. for 3 h. The reaction was diluted with DCM. The organic layer was extracted with water and the aqueous layer was extracted with DCM. The combined organic layers were dried over Na.sub.2SO.sub.4 and filtered and the solvent removed in vacuo. The precipitate purified by flash chromatography to give 145 mg (50%) of the title compound as a yellow liquid; HPLC: (purity) 100%; Rt 2.551 min.; LC/MS: Rt 1.792 min; (M+H) 595.2.

88.4 ((cis)-2-{5-methyl-8-[1-(toluene-4-sulfonyl)-6-trifluoromethyl-1H-indol-3-yl]-pyrido[4,3-d]pyrimidin-2-ylamino}-cyclohexyl)-carbamic acid tert-butyl ester

(200) ##STR00159##

(201) (1R,2S)—N-{5-Methyl-8-[1-(toluene-4-sulfonyl)-6-trifluoromethyl-1H-indol-3-yl]-pyrido[4,3-d]pyrimidin-2-yl}-cyclohexane-1,2-diamine (145.00 mg; 0.24 mmol; 1.00 eq.), DMAP (0.06 g; 0.49 mmol; 2.00 eq.) and di-tert-butyldicarbonat (0.11 g; 0.51 mmol; 2.10 eq.) was dissolved in tetrahydrofuran (25.00 ml). The reaction mixture was stirred by rt over 3 days. The crude product was evaporated under vacuo an extracted with water/DCM. Then the crude product was dried over Na.sub.2SO.sub.4 and filtered and the solvent removed in vacuo. The residue was purified twice by flash chromatography to give 44 mg (26%) of the title compound as a yellow solid; LC/MS (Chromolith Speed Rod RP18e, 50-4.6 mm; ACN+0.1% TFA, water+0.1% TFA): (percent area)100%; Rt 2.597 min.; (M+H) 695.3.

88.5 Enantiomer 1: (1S,2R)—N-{5-methyl-8-[1-(toluene-4-sulfonyl)-6-trifluoromethyl-1H-indol-3-yl]-pyrido[4,3-d]pyrimidin-2-yl}-cyclohexane-1,2-diamine and enantiomer 2: (1R,2S)—N-{5-methyl-8-[1-(toluene-4-sulfonyl)-6-trifluoromethyl-1H-indol-3-yl]-pyrido[4,3-d]pyrimidin-2-yl}-cyclohexane-1,2-diamine

(202) ##STR00160##

(203) ((cis)-2-{5-Methyl-8-[1-(toluene-4-sulfonyl)-6-trifluoromethyl-1H-indol-3-yl]-pyrido[4,3-d]pyrimidin-2-ylamino}-cyclohexyl)-carbamic acid tert-butyl ester (44.000 mg; 0.063 mmol; 100.00 mol %) was separated in both enantiomers with a chiral column.

(204) 88.5.1 Enantiomer 1 elutes first from chiral column and gives 15 mg; HPLC (Chiralpk AD-H; 25% IP0.5% DEA): (percent area) 100%; Rt 3.23 min. Absolute configuration arbitrary: ((1S,2R)-2-{5-methyl-8-[1-(toluene-4-sulfonyl)-6-trifluoromethyl-1H-indol-3-yl]-pyrido[4,3-d]pyrimidin-2-ylamino}-cyclohexyl)-carbamic acid tert-butyl ester.

(205) 88.5.2 Enantiomer 2: Gives 18 mg (41%) of the title compound; HPLC (Chiralpk AD-H; 25% IP0.5% DEA): (percent area) 100%; Rt 8.57 min. Absolute configuration arbitrary: ((1R,2S)-2-{5-methyl-8-[1-(toluene-4-sulfonyl)-6-trifluoromethyl-1H-indol-3-yl]-pyrido[4,3-d]pyrimidin-2-ylamino}-cyclohexyl)-carbamic acid tert-butyl ester.

88.6 (1S,2R)—N-{5-methyl-8-[1-(toluene-4-sulfonyl)-6-trifluoromethyl-1H-indol-3-yl]-pyrido[4,3-d]pyrimidin-2-yl}-cyclohexane-1,2-diamine trifluoroacetate

(206) ##STR00161##

(207) Enantiomer 1 from example 88.5.1 (15.000 mg; 0.022 mmol; 100.00 mol %) was dissolved in dichloromethane (1.000 ml) and trifluoroacetic acid (0.016 ml; 0.216 mmol; 1000.00 mol %). The solution was stirred at rt for 5.5 h and the solvent removed in vacuo to give 33 mg (216%) of the title compound as a yellow oil; HPLC (Method J): (percent area) 100%; Rt 2.536 min.; LC/MS (Method G): Rt 2.256 min; (M+H) 595.3.

88.7 (1S,2R)—N-[5-methyl-8-(6-trifluoromethyl-1H-indol-3-yl)-pyrido[4,3-d]pyrimidin-2-yl]-cyclohexane-1,2-diamine

(208) (1S,2R)—N-{5-Methyl-8-[1-(toluene-4-sulfonyl)-6-trifluoromethyl-1H-indol-3-yl]-pyrido[4,3-d]pyrimidin-2-yl}-cyclohexane-1,2-diamine trifluoroacetate from example 88.6 (33.000 mg; 0.047 mmol; 100.00 mol %) was dissolved in tetrahydrofuran (3.000 ml) and ethanol (1.000 ml). Then sodium hydroxide pellets (0.017 ml; 0.931 mmol; 2000.00 mol %) were added. The solution was stirred for 4 h and the solvent removed in vacuo. The residue was dissolved in DCM and water. The organic layer was washed with water, the aqueous layer was washed with DCM. The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness to give 5 mg of the title compound as a yellow solid; LC/MS (Method H): Rt 1.473 min; (M+H) 441.2.

Example 89

(1R,2S)—N-[5-methyl-8-(6-trifluoromethyl-1H-indol-3-yl)-pyrido[4,3-d]pyrimidin-2-yl]-cyclohexane-1,2-diamine (“A89”)

(209) ##STR00162##

89.1 (1R,2S)—N-{5-methyl-8-[1-(toluene-4-sulfonyl)-6-trifluoromethyl-1H-indol-3-yl]-pyrido[4,3-d]pyrimidin-2-yl}-cyclohexane-1,2-diamine trifluoroacetate

(210) ##STR00163##

(211) Enantiomer 2 from example 88.5.2 (18.000 mg; 0.026 mmol; 100.00 mol %) was dissolved in dichloromethane (1.000 ml) and trifluoroacetic acid (0.020 ml; 0.259 mmol; 1000.00 mol %). The solution was stirred at rt for 5.5 h and the solvent removed in vacuo to give 25 mg (131%) of the title compound; HPLC (Method J): (percent area) 96.4%; Rt 2.529 min.; LC/MS (Method G): Rt 2.246 min; (M+H) 595.3.

89.2 (1R,2S)—N-[5-methyl-8-(6-trifluoromethyl-1H-indol-3-yl)-pyrido[4,3-d]pyrimidin-2-yl]-cyclohexane-1,2-diamine

(212) (1R,2S)—N-{5-methyl-8-[1-(toluene-4-sulfonyl)-6-trifluoromethyl-1H-indol-3-yl]-pyrido[4,3-d]pyrimidin-2-yl}-cyclohexane-1,2-diamine trifluoroacetate (25.000 mg; 0.034 mmol; 100.00 mol %) was dissolved in tetrahydrofuran (3.000 ml) and ethanol (1.000 ml). Then sodium hydroxide pellets (0.013 ml; 0.680 mmol; 2000.00 mol %) were added. The solution was stirred at rt for 4 h and the solvent removed in vacuo. The residue was dissolved in DCM and water. The organic layer was washed with water, the aqueous layer was washed with DCM. The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness to give 4 mg (27%) of the title compound; HPLC (Method J): (percent area) 17.5/82.5%; Rt 2.095/2.129 min; (double peak/double peak); LC/MS (Method G): Rt 1.39 min; (M+H) 441.2.

Example 90

2-((1S,2R)-2-amino-cyclohexylamino)-8-(1-methyl-1H-pyrazol-4-yl)-6H-pyrido[4,3-d]pyrimidin-5-one (“A90”)

(213) ##STR00164##

90.1 8-(1-methyl-1H-pyrazol-4-yl)-2-methylsulfanyl-6H-pyrido[4,3-d]pyrimidin-5-one

(214) ##STR00165##

(215) 8-Iodo-2-methylsulfanyl-6H-pyrido[4,3-d]pyrimidin-5-one (2.00 g; 6.27 mmol; 1.00 eq.), 1-methylpyrazole-4-boronic acid pinacolester (1.56 g; 7.52 mmol; 1.20 eq.), tripotassium phosphate trihydrate (3.99 g; 18.80 mmol; 3.00 eq.), Xphos Pd—Cl precat (246.55 mg; 0.31 mmol; 0.05 eq.), 1,4-dioxane (80.00 ml; 935.25 mmol; 149.23 eq.) and water (20.00 ml; 1109.88 mmol; 177.09 eq.) were combined and heated to 120° C. for 4 h. 1-Methylpyrazole-4-boronic acid pinacolester (1.56 g; 7.52 mmol; 1.20 eq.) was added and heated for 14 h. 1-Methylpyrazole-4-boronic acid pinacolester (1.56 g; 7.52 mmol; 1.20 eq.) and Xphos Pd—Cl precat (246.55 mg; 0.31 mmol; 0.05 eq.) were added and heated 1.5 h. 1-Methylpyrazole-4-boronic acid pinacolester (1.56 g; 7.52 mmol; 1.20 eq.) and Xphos Pd—Cl precat (246.55 mg; 0.31 mmol; 0.05 eq.) were added and heated 1.5 h. Ethyl acetate and water were added and filtered. The solvent was removed in vacuo to give crude 1947 mg (114%) of the title compound as a brown solid; HPLC MS (Method G): Rt 1.61 min; (M+H) 274.1.

90.2 2-((1R,2S)-2-amino-cyclohexylamino)-8-(1-methyl-1H-pyrazol-4-yl)-6H-pyrido[4,3-d]pyrimidin-5-one

(216) ##STR00166##

(217) 8-(1-Methyl-1H-pyrazol-4-yl)-2-methylsulfanyl-6H-pyrido[4,3-d]pyrimidin-5-one (crude example 90.1; 100.00 mg; 0.37 mmol; 1.00 eq.) and cis-1,2-diamino-cyclohexane (222.02 μl; 1.83 mmol; 5.00 eq.) were heated to 150° C. for 24 h. After cooling down, water was added to the mixture and filtered. The residue gives 60 mg (45%) of the title compound as a brown solid; HPLC MS (Method G): (percent area) 94.11%; Rt 1.62 min; (M+H) 340.2.

90.3 {(1R,2S)-2-[8-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5,6-dihydro-pyrido-[4,3-d]pyrimidin-2-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester

(218) ##STR00167##

(219) 2-((1R,2S)-2-Amino-cyclohexylamino)-8-(1-methyl-1H-pyrazol-4-yl)-6H-pyrido[4,3-d]pyrimidin-5-one (example 90.2; 59.70 mg; 0.17 mmol; 1.00 eq.) was dissolved in tetrahydrofuran (900.00 μl; 11.11 mmol; 67.10 eq.), triethylamine (34.42 μl; 0.25 mmol; 1.50 eq.) and di-tert-butyl dicarbonate (38.96 μl; 0.18 mmol; 1.10 eq.) in tetrahydrofuran (150.00 μl; 1.85 mmol; 11.18 eq.) was added. The mixture was stirred for 14 h. Di-tert-butyl dicarbonate (0.04 ml; 0.18 mmol; 1.10 eq.) and triethylamine (0.03 ml; 0.25 mmol; 1.50 eq.) were added and the reaction stirred for 14 h. Di-tert-butyl dicarbonate (0.04 ml; 0.18 mmol; 1.10 eq.) and triethylamine (0.03 ml; 0.25 mmol; 1.50 eq.) were added. Di-tert-butyl dicarbonate (0.04 ml; 0.18 mmol; 1.10 eq.) and 4-(dimethylamino)pyridine (DMAP) (5.00 mg; 0.04 mmol; 0.25 eq.) were added. The mixture was washed two times with water and one time with brine and then dried over magnesium sulfate. The solvent was removed in vacuo to give 83 mg (114%) of the title compound as a brown solid.

90.4 2-((1S,2R)-2-amino-cyclohexylamino)-8-(1-methyl-1H-pyrazol-4-yl)-6H-pyrido[4,3-d]pyrimidin-5-one

(220) {(1R,2S)-2-[8-(1-Methyl-1H-pyrazol-4-yl)-5-oxo-5,6-dihydro-pyrido[4,3-d]pyrimidin-2-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (example 90.3; 83.10 mg; 0.19 mmol; 1.00 eq.), ethylacetat (10.00 ml; 102.15 mmol; 540.24 eq.) and hydrochloric acid (1 N) (1.89 ml; 1.89 mmol; 10.00 eq.) were given into an vial and heated for 2 h at 50° C. Hydrochloric acid (1 N) (1928.55 mg; 1.89 mmol; 10.00 eq.) and 2 mL ethyl acetate was added and stirred for 14 h. Ethyl acetate and water were added and the organic layer was washed three times with water, then the combined water layer were brought to alkaline pH and extracted with ethyl acetate. The combined organic layers were evaporated to dryness and the residue purified by reverse phase HPLC to give 5 mg of the title compound as a colorless solid; HPLC (Method J): (percent area) 100%; Rt 2.31 min.; LC/MS (Method H): Rt 49 min.; (M+H) 340.1.

Example 91

(1R,2S)—N-[5-difluoromethyl-8-(1-methyl-1H-pyrazol-4-yl)-pyrido-[4,3-d]pyrimidin-2-yl]-cyclohexane-1,2-diamine (“A91”)

(221) ##STR00168##

91.1 {(1S,2R)-2-[5-difluoromethyl-8-(1-methyl-1H-pyrazol-4-yl)-pyrido-[4,3-d]pyrimidin-2-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester

(222) ##STR00169##

(223) [(1S,2R)-2-(5-Difluoromethyl-8-iodo-pyrido[4,3-d]pyrimidin-2-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester (66.00 mg; 0.086 mmol; 1.000 eq.), 1-methylpyrazole-4-boronic acid pinacolester (21.42 mg; 0.103 mmol; 1.200 eq.), palladium(II)-acetat (47% Pd) (0.96 mg; 0.004 mmol; 0.050 eq.), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (3.52 mg; 0.009 mmol; 0.100 eq.) and potassium carbonate (34.95 mg; 0.253 mmol; 2.948 eq.) were added and suspended in ethylenglycoldimethylether (0.89 ml; 8.578 mmol; 100.000 eq.) and water (0.31 ml; 17.157 mmol; 200.000 eq.) while purging nitrogen through the suspension. The suspension was heated in the microwave for 45 min at 150° C. The solvent was removed in vacuo and the residue was purified by flash chromatography to give 33 mg (81%) of the title compound; LC/MS (Method G): 100%; Rt 2.299 min.; (M+H) 474.3.

91.2 (1R,2S)—N-[5-difluoromethyl-8-(1-methyl-1H-pyrazol-4-yl)-pyrido[4,3-d]pyrimidin-2-yl]-cyclohexane-1,2-diamine

(224) {(1S,2R)-2-[5-Difluoromethyl-8-(1-methyl-1H-pyrazol-4-yl)-pyrido[4,3-d]pyrimidin-2-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (33.00 mg; 0.070 mmol; 1.000 eq.) was dissolved in ethylacetat (1.57 ml). Hydrochloric acid (1 N) (348.45 μl; 0.348 mmol; 5.000 eq.) was added and stirred at rt for 14 h and 3 days at 50° C. The solvent was removed in vacuo to give 28 mg (99%) of the title compound as an orange solid; LC/MS (Method G): (percent area) 100%; Rt 1.573 min.; (M+H) 374.2;

(225) .sup.1H NMR (500 MHz, DMSO+CF.sub.3SO.sub.3D) δ [ppm] 3.81-3.72 (m, 1H), 2.02-1.92 (m, 2H), 1.92-1.86 (s, 3H), 1.83-1.59 (m, 4H), 1.57-1.34 (m, 2H), 4.46-4.38 (m, 1H), 9.76-9.44 (s, 1H), 9.06-8.80 (s, 1H), 8.59-8.48 (s, 1H), 8.39-8.21 (s, 1H), 7.56-6.98 (t, J=53.5 Hz, 1H).

(226) Pharmacological Data

(227) TABLE-US-00004 TABLE 1 Syk inhibition of some representative compounds of the formula I Compound IC.sub.50 SYK No. (enzyme assay) “A1” A “A2”  B “A3”  B “A4”  C “A5”  C “A6”  C “A7”  C “A8”  B “A9”  C “A10” A “A11” C “A12” “A13” “A14” B “A15” “A16” “A17” B “A18” A “A19” A “A20” B “A21” C “A22” A “A23” B “A24” A “A25” C “A26” C “A27” A “A28” “A29” C “A30” C  A31” B  A32” C  A33” C “A34” “A35” B “A36” C “A37” C “A38” “A39” “A40” A “A41” A “A42” C “A43” C “A44” B “A45” A “A46” A “A47” “A48” “A49” A “A50” “A61” C “A62” A “A63” A “A65” A “A66” C “A67” C “A68” A “A69” B “A72” A “A76” A “A77” A “A79” C “A80” C “A81” B “A82” A “A85” B “A87” A “A88” C “A89” A “A91” B IC.sub.50: <0.1 μM = A; 0.1-1 μM = B; 1-50 μM = C
The following examples relate to medicaments:

Example A

Injection Vials

(228) A solution of 100 g of an active ingredient of the formula I and 5 g of disodium hydrogenphosphate in 3 I of bidistilled water is adjusted to pH 6.5 using 2 N hydrochloric acid, sterile filtered, transferred into injection vials, lyophilised under sterile conditions and sealed under sterile conditions.

(229) Each injection vial contains 5 mg of active ingredient.

Example B

Suppositories

(230) A mixture of 20 g of an active ingredient of the formula I with 100 g of soya lecithin and 1400 g of cocoa butter is melted, poured into moulds and allowed to cool. Each suppository contains 20 mg of active ingredient.

Example C

Solution

(231) A solution is prepared from 1 g of an active ingredient of the formula I, 9.38 g of NaH.sub.2PO.sub.4.2 H.sub.2O, 28.48 g of Na.sub.2HPO.sub.4.12 H.sub.2O and 0.1 g of benzalkonium chloride in 940 ml of bidistilled water. The pH is adjusted to 6.8, and the solution is made up to 1 I and sterilised by irradiation. This solution can be used in the form of eye drops.

Example D

Ointment

(232) 500 mg of an active ingredient of the formula I are mixed with 99.5 g of Vaseline under aseptic conditions.

Example E

Tablets

(233) A mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is pressed in a conventional manner to give tablets in such a way that each tablet contains 10 mg of active ingredient.

Example F

Dragees

(234) Tablets are pressed analogously to Example E and subsequently coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and dye.

Example G

Capsules

(235) 2 kg of active ingredient of the formula I are introduced into hard gelatine capsules in a conventional manner in such a way that each capsule contains 20 mg of the active ingredient.

Example H

Ampoules

(236) A solution of 1 kg of active ingredient of the formula I in 60 I of bidistilled water is sterile filtered, transferred into ampoules, lyophilised under sterile conditions and sealed under sterile conditions. Each ampoule contains 10 mg of active ingredient.