AU2007260040A1

AU2007260040A1 - Pyrazolopyrimidones

Info

Publication number: AU2007260040A1
Application number: AU2007260040A
Authority: AU
Inventors: Thomas Bar; Markus Boehm; Jurgen Braunger; Volker Gekeler; Andreas Lindenmaier; Thomas Maier; Matthias Vennemann; Astrid Zimmermann
Original assignee: 4SC AG
Current assignee: 4SC AG
Priority date: 2006-06-14
Filing date: 2007-06-13
Publication date: 2007-12-21
Also published as: CA2655267A1; JP2009539936A; WO2007144384A1; EP2035426A1

Description

WO 2007/144384 PCT/EP2007/055846 -1 Pyrazolopyrimidones Field of application of the invention The invention relates to pyrazolopyrimidone derivatives, which can be used in the pharmaceutical industry for the production of pharmaceutical compositions. Known technical background The US application US2004/0242596 contains pyrazolo[3,4-d]pyrimidones which are said to be useful as anti-cancer agents and to induce mitotic arrest. Description of the invention It has now been found, that the pyrazolo[1,5-c]pyrimidone derivatives, which are described in greater details below, differ from prior art compounds by unanticipated structural features and have surprising and particularly advantageous properties. Thus, for example, the compounds according to this invention can act as inhibitors of Eg5 kinesin. In more detail, it has been unexpectedly found that these derivatives are potent and highly efficacious inhibitors of cellular (hyper)proliferation and/or cell-cycle specific inducers of apoptosis in cancer cells. Therefore, these compounds can be particular useful for treating (hyper)proliferative diseases and/or disorders responsive to the induction of apoptosis, notably cancer. By having a cell-cycle specific mode of action, these derivatives should have a higher therapeutic index compared to standard chemotherapeutic drugs targeting basic cellular processes like DNA replication or interfering with basic cellular molecules like DNA. Thus, for example, the compounds according to this invention are expected to be useful in targeted cancer therapy. The invention thus relates to compounds of formula I O N -N' NA NN R2 / H R4 R 1 O N N(R5)R6 B (I) in which WO 2007/144384 PCT/EP2007/055846 -2 R1 is hydrogen or halogen, R2 is 1-4C-alkyl, A is Aryl-1-4C-alkyl, in which Aryl is phenyl, or R3- and R31-substituted phenyl, in which R3 is 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy, hydroxyl, halogen, or completely or predominantly fluorine-substituted 1-4C-alkoxy, R31 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy, R4 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or 3-7C-cycloalkyl-1-4C-alkyl, R5 is hydrogen or 1-4C-alkyl, R6 is hydrogen or 1-4C-alkyl, B is phenyl, or R7- and R71-substituted phenyl, in which R7 is 1-4C-alkyl, trifluoromethyl, cyano, 1-4C-alkoxy, halogen, carboxyl, 1-4C-alkylcarbonyl, methylenedioxy, ethylenedioxy, 1-4C-alkoxy-1-4C-alkyl, hydroxy-1-4C-alkyl, or completely or predominantly fluorine-substituted 1-4C-alkoxy, R71 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy, n is 2, 3, 4, 5 or 6, and the salts, stereoisomers and the salts of the stereoisomers of these compounds. As used herein, "alkyl" alone or as part of another group refers to both branched and straight chain saturated aliphatic hydrocarbon groups having the specified numbers of carbon atoms, such as for example: 1-4C-Alkyl is a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Examples are the butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl radicals, of which propyl, isopropyl, ethyl and methyl are more worthy to be mentioned. Halogen within the meaning of the present invention is iodine or, in particular, bromine, chlorine or fluorine. 1-4C-Alkoxy represents radicals which, in addition to the oxygen atom, contain a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are the butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy, ethoxy and methoxy radicals, of which propoxy, isopropoxy, and, particularly, ethoxy and methoxy are more worthy to be mentioned. The term "cycloalkyl" alone or as part of another group refers to a monocyclic saturated aliphatic hydrocarbon group having the specified numbers of carbon atoms, such as for example: 3-7C-Cycloalkyl stands for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, of which cyclopentyl, cyclobutyl and, in particular, cyclopropyl are more worthy to be mentioned. 3-7C-Cycloalkyl-1-4C-alkyl stands for one of the abovementioned 1-4C-alkyl radicals, which is substituted by one of the abovementioned 3-7C-cycloalkyl radicals. Examples which may be WO 2007/144384 PCT/EP2007/055846 -3 mentioned are the 3-7C-cycloalkylmethyl radicals, of which cyclopentylmethyl, cyclobutylmethyl and, in particular, cyclopropylmethyl are more worthy to be mentioned. 1-4C-Alkoxy-1-4C-alkyl represents one of the abovementioned 1-4C-alkyl radicals, which is substituted by one of the abovementioned 1-4C-alkoxy radicals. Examples which may be mentioned are the 2-isopropoxyethyl, 2-ethoxyethyl, 2-methoxyethyl and, in particular, isopropoxymethyl, ethoxymethyl and, in more particular, methoxymethyl radical. Hydroxy-1-4C-alkyl represents one of the abovementioned 1-4C-alkyl radicals, which is substituted by a hydroxyl radical. Examples which may be mentioned are the 3-hydroxypropoxy, 2-hydroxyethyl and, in particular, hydroxymethyl radical. Completely or predominantly fluorine-substituted 1-4C-alkoxy is, for example, the 2,2,3,3,3 pentafluoropropoxy, the perfluoroethoxy, the 1,2,2-trifluoroethoxy and in particular the 1,1,2,2 tetrafluoroethoxy, the 2,2,2-trifluoroethoxy, the trifluoromethoxy and the difluoromethoxy radical, of which the trifluoromethoxy and the difluoromethoxy radicals are preferred. "Predominantly" in this connection means that more than half of the hydrogen atoms of the 1-4C-alkoxy groups are replaced by fluorine atoms. 1-4C-Alkylcarbonyl is a carbonyl group, to which one of the abovementioned 1-4C-alkyl radicals is bonded. An example is the acetyl radical (CH 3 CO-). Aryl-1-4C-alkyl stands for one of the abovementioned 1-4C-alkyl radicals, which is substituted by an Aryl radical as defined below, such as e.g. the Aryl-methyl or 2-Aryl-ethyl radical, of which the Aryl methyl radical is to be emphasized. Aryl stands for phenyl, or R3- and R31-substituted phenyl. Examples of the Aryl-1-4C-alkyl radical include the phenethyl and, particularly, the benzyl radical, each of which is optionally substituted by R3 and R31 on the phenyl moiety. Suitable salts for compounds according to this invention - depending on substitution - are all acid addi tion salts or all salts with bases. Particular mention may be made of the pharmacologically and/or pharmaceutically tolerable inorganic and organic acids and bases customarily used in pharmacy. Those suitable include, but are not limited to, water-insoluble and, particularly, water-soluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulphuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl) benzoic acid, butyric acid, sulphosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulphonic acid, phenylsulphonic acid, methanesulphonic acid or 3-hydroxy-2-naphthoic acid, the acids being WO 2007/144384 PCT/EP2007/055846 -4 employed in salt preparation - depending on whether a mono- or polybasic acid is concerned and depending on which salt is desired - in an equimolar quantitative ratio or one differing therefrom. Preferred are the salts selected from hydrochlorides, mesylates, tartrates, citrates, fumarates or sulfates. On the other hand, salts with bases are - depending on substitution - also suitable. As examples of salts with bases are mentioned the lithium, sodium, potassium, calcium, aluminium, magnesium, titanium, ammonium, meglumine or guanidinium salts, here, too, the bases being employed in salt preparation in an equimolar quantitative ratio or one differing therefrom. Salts which are unsuitable for pharmaceutical uses but which can be employed, for example, for the isolation or purification of free compounds of formula I or their pharmaceutically acceptable salts, are also included. Pharmaceutically unacceptable salts, which can be obtained, for example, as process products during the preparation of the compounds according to this invention on an industrial scale, are converted into pharmaceutically acceptable salts by processes known to the person skilled in the art. According to expert's knowledge the compounds of formula I according to this invention as well as their salts may contain, e.g. when isolated in crystalline form, varying amounts of solvents. Included within the scope of the invention are therefore all solvates and in particular all hydrates of the compounds of formula I according to this invention as well as all solvates and in particular all hydrates of the salts of the compounds of formula I according to this invention. In one embodiment of this invention, salts of compounds of formula I include a salt of a compound of formula I with hydrochloric acid (hydrochloride). The substituents R3 and R31 of compounds of formula I can be attached in the ortho, meta or para position with respect to the binding position in which the Aryl ring is bonded to the 1-4C-alkyl group, whereby emphasis is given to the attachment of R3 in the meta or para position. In one embodiment R31 is hydrogen. The substituents R7 and R71 of compounds of formula I can be attached in the ortho, meta or para position with respect to the binding position in which the phenyl ring is bonded to the carbonyl group, whereby emphasis is given to the attachment of R7 in the meta or para position. In one embodiment R71 is hydrogen. In the context of this invention, hyperproliferation and analogous terms are used to describe aberrant / dysregulated cellular growth, a hallmark of diseases like cancer. This hyperproliferation might be caused by single or multiple cellular / molecular alterations in respective cells and can be, in context WO 2007/144384 PCT/EP2007/055846 -5 of a whole organism, of benign or malignant behaviour. Inhibition of cell proliferation and analogous terms is used herein to denote an ability of the compound to retard the growth of and/or kill a cell contacted with that compound as compared to cells not contacted with that compound. Most preferable this inhibition of cell proliferation is 100%, meaning that proliferation of all cells is stopped and/or cells undergo programmed cell death. In some preferred embodiments the contacted cell is a neoplastic cell. A neoplastic cell is defined as a cell with aberrant cell proliferation and/or the potential to metastasize to different tissues or organs. A benign neoplasia is described by hyperproliferation of cells, incapable of forming an aggressive, metastasizing tumor in-vivo. In contrast, a malignant neoplasia is described by cells with different cellular and biochemical abnormalities, e.g. capable of forming tumor metastasis. The aquired functional abnormalities of malignant neoplastic cells (also defined as "hallmarks of cancer") are replicative potential ("hyperproliferation"), self-sufficiency in growth signals, insensitivity to anti-growth signals, evasion from apoptosis, sustained angiogenesis and tissue invasion and metastasis. Inducer of apoptosis and analogous terms are used herein to identify a compound which executes programmed cell death in cells contacted with that compound. Apoptosis is defined by complex biochemical events within the contacted cell, such as the activation of cystein specific proteinases ("caspases") and the fragmentation of chromatin. Induction of apoptosis in cells contacted with the compound might not necessarily be coupled with inhibition of cell proliferation. Preferably, the inhibition of cell proliferation and/or induction of apoptosis is specific to cells with aberrant cell growth (hyperproliferation). Thus, compared to cells with aberrant cell growth, normal proliferating or arrested cells are less sensitive or even insensitive to the proliferation inhibiting or apoptosis inducing activity of the compound. Finally, cytotoxic is used in a more general sense to identify compounds which kill cells by various mechanisms, including the induction of apoptosis / programmed cell death in a cell cycle dependent or cell-cycle independent manner. Cell cycle specific and analogous terms are used herein to identify a compound as inducing apoptosis only in continously proliferating cells actively passing a specific phase of the cell cycle, but not in resting, non-dividing cells. Continously proliferating cells are typical for diseases like cancer and characterized by cells in all phases of the cell division cycle, namely in the G ("gap") 1, S ("DNA synthesis"), G2 and M ("mitosis") phase. Compounds according to this invention worthy to be mentioned are those compounds of formula I, in which R1 is hydrogen or halogen, R2 is 1-2C-alkyl, A is Aryl-1-2C-alkyl, in which Aryl is phenyl, or R3- and R31-substituted phenyl, in which R3 is 1-2C-alkyl, trifluoromethyl, 1-2C-alkoxy, hydroxyl, halogen, or completely or predominantly fluorine-substituted 1-2C-alkoxy, WO 2007/144384 PCT/EP2007/055846 -6 R31 is hydrogen, halogen, 1-2C-alkyl or 1-2C-alkoxy, R4 is hydrogen, 1-4C-alkyl, cyclopropyl or cyclopropyl-1-2C-alkyl, R5 is hydrogen or 1-3C-alkyl, R6 is hydrogen or 1-3C-alkyl, B is phenyl, or R7- and R71-substituted phenyl, in which R7 is 1-2C-alkyl, trifluoromethyl, cyano, 1-2C-alkoxy, halogen, carboxyl, 1-2C-alkylcarbonyl, methylenedioxy, ethylenedioxy, 1-2C-alkoxy-1-2C-alkyl, hydroxy-1-2C-alkyl, or completely or predominantly fluorine-substituted 1-2C-alkoxy, R71 is hydrogen, halogen, 1-2C-alkyl or 1-2C-alkoxy, n is 2, 3 or 4, and the salts, stereoisomers and the salts of the stereoisomers of these compounds. Compounds according to this invention more worthy to be mentioned are those compounds of formula I, in which R1 is hydrogen or halogen, R2 is methyl or ethyl, A is Arylmethyl, in which Aryl is phenyl, or R3- and R31-substituted phenyl, in which R3 is methyl, ethyl, trifluoromethyl, methoxy, ethoxy, hydroxyl, halogen, difluoromethoxy or trifluoromethoxy, R31 is hydrogen, halogen, methyl, ethyl, methoxy or ethoxy, R4 is methyl, ethyl, propyl, isopropyl, sec-butyl, cyclopropyl or cyclopropylmethyl, R5 is hydrogen, methyl, ethyl, propyl or isopropyl, R6 is hydrogen, methyl, ethyl, propyl or isopropyl, B is phenyl, or R7- and R71-substituted phenyl, in which R7 is methyl, ethyl, trifluoromethyl, cyano, methoxy, ethoxy, halogen, carboxyl, acetyl, methylenedioxy, ethylenedioxy, methoxymethyl, hydroxymethyl, difluoromethoxy or trifluoromethoxy, R71 is hydrogen, halogen, methyl, ethyl, methoxy or ethoxy, n is 2, 3 or 4, and the salts, stereoisomers and the salts of the stereoisomers of these compounds. Compounds according to this invention in particular worthy to be mentioned are those compounds of formula I, in which R1 is hydrogen, fluorine, chlorine or bromine, R2 is methyl or ethyl, A is Arylmethyl, in which Aryl is phenyl, or R3- and R31-substituted phenyl, in which R3 is methyl, ethyl, trifluoromethyl, methoxy, ethoxy, hydroxyl or halogen, R31 is hydrogen, halogen, methyl or methoxy, WO 2007/144384 PCT/EP2007/055846 -7 R4 is ethyl, propyl, isopropyl, sec-butyl, cyclopropyl or cyclopropylmethyl, R5 is hydrogen, methyl, ethyl, propyl or isopropyl, R6 is hydrogen, methyl, ethyl, propyl or isopropyl, B is phenyl, or R7- and R71-substituted phenyl, in which R7 is methyl, ethyl, trifluoromethyl, cyano, methoxy, ethoxy, halogen, carboxyl, methylenedioxy, ethylenedioxy, methoxymethyl or hydroxymethyl, R71 is hydrogen, halogen, methyl, ethyl or methoxy, n is 2, 3 or 4, and the salts, stereoisomers and the salts of the stereoisomers of these compounds. Compounds according to this invention in more particular worthy to be mentioned are those compounds of formula I, in which R1 is hydrogen, chlorine or bromine, R2 is methyl or ethyl, A is benzyl, halobenzyl (e.g. fluorobenzyl, chlorobenzyl or bromobenzyl), methylbenzyl, methylhalobenzyl, methoxybenzyl, hydroxybenzyl, dihalobenzyl (e.g. dichlorobenzyl), or dimethoxybenzyl, R4 is ethyl, propyl, isopropyl, sec-butyl, cyclopropyl or cyclopropylmethyl, R5 is hydrogen, methyl, ethyl, propyl or isopropyl, R6 is hydrogen, methyl, ethyl, propyl or isopropyl, B is phenyl, or R7- and R71-substituted phenyl, in which R7 is methyl, ethyl, trifluoromethyl, cyano, methoxy, ethoxy, halogen, carboxyl, methylenedioxy, ethylenedioxy, methoxymethyl or hydroxymethyl, R71 is hydrogen, halogen, methyl or ethyl, such as, for example, B is phenyl, methylphenyl, ethylphenyl, halophenyl, methylhalophenyl, (hydroxymethyl)phenyl, methoxyphenyl, ethoxyphenyl, trifluoromethylphenyl, halo(trifluoromethyl)phenyl, dihalophenyl, methylenedioxyphenyl, ethylenedioxyphenyl, (methoxymethyl)phenyl, methoxychlorophenyl, carboxyphenyl or cyanophenyl, n is 2, 3 or 4, and the salts, stereoisomers and the salts of the stereoisomers of these compounds. Compounds according to this invention in further more particular worthy to be mentioned are those compounds of formula I, in which R1 is hydrogen, chlorine or bromine, R2 is methyl or ethyl, A is benzyl, halobenzyl (e.g. fluorobenzyl, chlorobenzyl or bromobenzyl), methylbenzyl, methoxybenzyl or hydroxybenzyl, R4 is ethyl, propyl, isopropyl, sec-butyl or cyclopropyl, either WO 2007/144384 PCT/EP2007/055846 -8 R5 and R6 are both hydrogen, or R5 is methyl, and R6 is hydrogen, or R5 is ethyl, and R6 is hydrogen, or R5 is propyl, and R6 is hydrogen, or R5 is isopropyl, and R6 is hydrogen, or R5 and R6 are both methyl, B is phenyl, or R7- and R71-substituted phenyl, in which R7 is methyl, ethyl, trifluoromethyl, cyano, methoxy, ethoxy, halogen, carboxyl, methylenedioxy, ethylenedioxy, methoxymethyl or hydroxymethyl, R71 is hydrogen, halogen, methyl or ethyl, such as, for example, B is phenyl, methylphenyl, ethylphenyl, halophenyl, dihalophenyl, methylhalophenyl, (hydroxymethyl)phenyl, halo(trifluoromethyl)phenyl, trifluoromethylphenyl, methoxyphenyl, methylenedioxyphenyl or cyanophenyl, such as, for more detailed example, B is phenyl, 4-methylphenyl, 3-methylphenyl, 4-chlorophenyl, 4-bromophenyl, 4-fluorophenyl, 3 fluoro-4-methylphenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 3,4 dichlorophenyl or 2,3-dichlorophenyl, n is 2, 3 or 4, and the salts, stereoisomers and the salts of the stereoisomers of these compounds. Compounds according to this invention to be emphasized are those compounds of formula I, in which R1 is hydrogen, chlorine or bromine, particularly R1 is chlorine or bromine, R2 is methyl, A is benzyl, fluorobenzyl, chlorobenzyl, bromobenzyl, methylbenzyl, methoxybenzyl or hydroxybenzyl, in particular A is benzyl or fluorobenzyl (e.g. 3-fluorobenzyl or 4-fluorobenzyl), R4 is ethyl, propyl, isopropyl, sec-butyl or cyclopropyl, WO 2007/144384 PCT/EP2007/055846 -9 either R5 and R6 are both hydrogen, or R5 is methyl, and R6 is hydrogen, or R5 is ethyl, and R6 is hydrogen, or R5 and R6 are both methyl, B is phenyl, or R7- and R71-substituted phenyl, in which R7 is methyl, ethyl, trifluoromethyl, fluorine, chlorine or bromine, R71 is hydrogen, methyl, fluorine, chlorine or bromine, such as, for example, B is phenyl, methylphenyl, trifluoromethylphenyl, methoxyphenyl, halophenyl, dihalophenyl or methylhalophenyl, such as, for more detailed example, B is phenyl, methylphenyl, trifluoromethylphenyl, methoxyphenyl, fluorophenyl, chlorophenyl, bromophenyl, dichlorophenyl, difluorophenyl, methylfluorophenyl, methylchlorophenyl or methylbromophenyl, such as, for yet more detailed example, B is phenyl, 4-methylphenyl, 3-methylphenyl, 4-chlorophenyl, 4-bromophenyl, 4-fluorophenyl, 3 fluoro-4-methylphenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl or 3,4-dichlorophenyl, n is 2 or 3, and the salts, stereoisomers and the salts of the stereoisomers of these compounds. Compounds according to this invention to be more emphasized are those compounds of formula I, in which R1 is chlorine or bromine, R2 is methyl, A is benzyl or fluorobenzyl (e.g. 3-fluorobenzyl or 4-fluorobenzyl), R4 is ethyl, propyl, isopropyl, sec-butyl or cyclopropyl, either R5 and R6 are both hydrogen, or R5 and R6 are both methyl, B is phenyl, methylphenyl, trifluoromethylphenyl, methoxyphenyl, halophenyl, dihalophenyl or methylhalophenyl, such as, for example, WO 2007/144384 PCT/EP2007/055846 -10 B is methylphenyl, trifluoromethylphenyl, methoxyphenyl, fluorophenyl, chlorophenyl, bromophenyl, dichlorophenyl, difluorophenyl, methylfluorophenyl, methylchlorophenyl or methylbromophenyl, such as, for more detailed example, B is 4-methylphenyl, 3-methylphenyl, 4-chlorophenyl, 4-bromophenyl, 4-fluorophenyl, 3-fluoro-4 methylphenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl or 3,4-dichlorophenyl, n is 2 or 3, and the salts, stereoisomers and the salts of the stereoisomers of these compounds. Compounds according to this invention to be in particular emphasized are those compounds of formula I, in which R1 is chlorine or bromine, R2 is methyl, A is benzyl, 3-fluorobenzyl or 4-fluorobenzyl, R4 is ethyl, propyl, isopropyl or cyclopropyl, either R5 and R6 are both hydrogen, or R5 and R6 are both methyl, B is methylphenyl, trifluoromethylphenyl, methoxyphenyl, chlorophenyl, dichlorophenyl, bromophenyl, fluorophenyl or methylfluorophenyl, such as, for example, B is 4-methylphenyl, 3-methylphenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, 4-chlorophenyl, 4-bromophenyl, 4-fluorophenyl or 3-fluoro-4-methylphenyl, n is 2 or 3, and the salts, stereoisomers and the salts of the stereoisomers of these compounds. In a preferred embodiment, the invention relates to compounds of formula I according to the invention, in which R1 is hydrogen, chlorine or bromine, R2 is methyl, A is benzyl or fluorobenzyl, R4 is ethyl, propyl, isopropyl, sec-butyl or cyclopropyl, either R5 and R6 are both hydrogen, or R5 and R6 are both methyl, B is phenyl, methylphenyl, trifluoromethylphenyl, methoxyphenyl, halophenyl, dihalophenyl or methylhalophenyl, n is 2 or 3, WO 2007/144384 PCT/EP2007/055846 -11 and the salts, stereoisomers and the salts of the stereoisomers of these compounds. Compounds according to this invention to be in more particular emphasized are those compounds of formula I, in which R1 is chlorine or bromine, R2 is methyl, A is benzyl, R4 is ethyl or isopropyl, either R5 and R6 are both hydrogen, or R5 and R6 are both methyl, B is methylphenyl, chlorophenyl, trifluoromethylphenyl, methoxyphenyl, bromophenyl or fluorophenyl, such as, for example, B is 4-methylphenyl, 3-methylphenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, 4-chlorophenyl, 4-bromophenyl or 4-fluorophenyl, n is 3, and the salts, stereoisomers and the salts of the stereoisomers of these compounds. Compounds according to this invention to be particularly emphasized are those compounds of formula I comprising one or more of the following: R1 is chlorine or bromine; R2 is methyl; A is benzyl; R4 is ethyl or isopropyl; either R5 and R6 are both hydrogen, or R5 and R6 are both methyl; B is 4-methylphenyl, 3-methylphenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4 chlorophenyl, 4-bromophenyl or 3-fluoro-4-methylphenyl; and n is 3; and the salts, stereoisomers and the salts of the stereoisomers of these compounds. Compounds according to this invention to be in further more particular emphasized are those compounds of formula I, in which R1 is chlorine or bromine, R2 is methyl, A is benzyl, WO 2007/144384 PCT/EP2007/055846 -12 R4 is isopropyl, R5 and R6 are both hydrogen, B is methylphenyl, chlorophenyl, trifluoromethylphenyl, methoxyphenyl, bromophenyl or fluorophenyl, such as, for example, B is 4-methylphenyl, 4-chlorophenyl or 4-bromophenyl, n is 3, and the salts, stereoisomers and the salts of the stereoisomers of these compounds. The invention also relates to compounds of formula I according to the invention comprising one or more of the following: R1 is chlorine or bromine; R2 is methyl; A is benzyl; R4 is isopropyl; R5 and R6 are both hydrogen; B is 4-methylphenyl, 4-chlorophenyl or 4-bromophenyl; and n is 3; and the salts, stereoisomers and the salts of the stereoisomers of these compounds. In a further preferred embodiment, the invention relates to compounds of formula I in which R1 is hydrogen, chlorine, bromine or fluorine, R2 is methyl, A is benzyl, R4 is ethyl, isopropyl, sec-butyl, cyclopropyl or cyclobutyl, either R5 and R6 are both hydrogen, or R5 and R6 are both methyl, B is 4-methylphenyl, 3-methylphenyl, 4-fluorophenyl, 4-bromophenyl, 4-chlorophenyl, 4 methoxyphenyl, 4-trifluoromethylphenyl, 3-fluoro-4-methylphenyl, 2-fluoro-4-methylphenyl, 3,4 dichlorophenyl or 2,3-dichlorophenyl, n is 2, 3 or 4, and the salts, stereoisomers and the salts of the stereoisomers of these compounds. In a further preferred embodiment, the invention relates to compounds of formula I according to the invention, in which R1 is hydrogen, chlorine or bromine, R2 is methyl, A is benzyl, WO 2007/144384 PCT/EP2007/055846 -13 R4 is ethyl or isopropyl, either R5 and R6 are both hydrogen, or R5 and R6 are both methyl, B is 4-methylphenyl, 3-methylphenyl, 4-fluorophenyl, 4-bromophenyl, 4-chlorophenyl, 4 methoxyphenyl, n is 3, and the salts, stereoisomers and the salts of the stereoisomers of these compounds. In a further preferred embodiment, the invention relates to compounds of formula I in which R1 is chlorine, bromine or fluorine, R2 is methyl, A is benzyl, R4 is ethyl, isopropyl, sec-butyl or cyclopropyl, R5 and R6 are both hydrogen, B is 4-methylphenyl, 3-methylphenyl, 4-fluorophenyl, 4-bromophenyl, 4-chlorophenyl, 4 methoxyphenyl, 3-fluoro-4-methylphenyl, 2-fluoro-4-methylphenyl or 3,4-dichlorophenyl, n is 3 or 4, and the salts, stereoisomers and the salts of the stereoisomers of these compounds. A special interest in the compounds according to this invention refers to those compounds of formula I which are included -within the scope of this invention- by one or, when possible, by a combination of more of the following special embodiments: Another special embodiment (embodiment 1) of the compounds of formula I according to this invention refers to those compounds of formula I, in which R1 is hydrogen. Another special embodiment (embodiment 2) of the compounds of formula I according to this invention refers to those compounds of formula I, in which R1 is chlorine. Another special embodiment (embodiment 3) of the compounds of formula I according to this invention refers to those compounds of formula I, in which R1 is bromine. Another special embodiment (embodiment 3a) of the compounds of formula I according to this invention refers to those compounds of formula I, in which R1 is fluorine.

WO 2007/144384 PCT/EP2007/055846 -14 Another special embodiment (embodiment 4) of the compounds of formula I according to this invention refers to those compounds of formula I, in which R2 is methyl. Another special embodiment (embodiment 5) of the compounds of formula I according to this invention refers to those compounds of formula I, in which R1 is chlorine, and R2 is methyl. Another special embodiment (embodiment 6) of the compounds of formula I according to this invention refers to those compounds of formula I, in which R1 is bromine, and R2 is methyl. A special embodiment (embodiment 7) of the compounds of formula I according to this invention refers to those compounds of formula I, in which A is benzyl. Another special embodiment (embodiment 8) of the compounds of formula I according to this invention refers to those compounds of formula I, in which A is fluorobenzyl, such as e.g. 3-fluorobenzyl or 4-fluorobenzyl. Another special embodiment (embodiment 9) of the compounds of formula I according to this invention refers to those compounds of formula I, in which A is benzyl, halobenzyl (such as e.g. chlorobenzyl or bromobenzyl), methylbenzyl, hydroxybenzyl or methoxybenzyl. Another special embodiment (embodiment 10) of the compounds of formula I according to this invention refers to those compounds of formula I, in which R4 is ethyl. Another special embodiment (embodiment 11) of the compounds of formula I according to this invention refers to those compounds of formula I, in which R4 is isopropyl. Another special embodiment (embodiment 1 a) of the compounds of formula I according to this invention refers to those compounds of formula I, in which R1 is chlorine, and R2 is methyl, and R4 is isopropyl.

WO 2007/144384 PCT/EP2007/055846 -15 Another special embodiment (embodiment 11 b) of the compounds of formula I according to this invention refers to those compounds of formula I, in which A is benzyl, and R4 is isopropyl. Another special embodiment (embodiment 1 1c) of the compounds of formula I according to this invention refers to those compounds of formula I, in which R1 is chlorine, and R2 is methyl, and A is benzyl, and R4 is isopropyl. Another special embodiment (embodiment 12) of the compounds of formula I according to this invention refers to those compounds of formula I, in which R4 is propyl. Another special embodiment (embodiment 13) of the compounds of formula I according to this invention refers to those compounds of formula I, in which R4 is cyclopropyl. Another special embodiment (embodiment 13a) of the compounds of formula I according to this invention refers to those compounds of formula I, in which R4 is cyclobutyl. Another special embodiment (embodiment 14) of the compounds of formula I according to this invention refers to those compounds of formula I, in which R4 is sec-butyl. Another special embodiment (embodiment 15) of the compounds of formula I according to this invention refers to those compounds of formula I, in which n is 2. Another special embodiment (embodiment 16) of the compounds of formula I according to this invention refers to those compounds of formula I, in which n is 3. Another special embodiment (embodiment 17) of the compounds of formula I according to this invention refers to those compounds of formula I, in which R5 and R6 are the same and selected from hydrogen, methyl and ethyl.

WO 2007/144384 PCT/EP2007/055846 -16 Another special embodiment (embodiment 18) of the compounds of formula I according to this invention refers to those compounds of formula I, in which R5 is methyl, ethyl, propyl or isopropyl, and R6 is hydrogen. Another special embodiment (embodiment 19) of the compounds of formula I according to this invention refers to those compounds of formula I, in which R5 is methyl or ethyl, and R6 is hydrogen. Another special embodiment (embodiment 20) of the compounds of formula I according to this invention refers to those compounds of formula I, in which R5 and R6 are both hydrogen, and n is 2. Another special embodiment (embodiment 21) of the compounds of formula I according to this invention refers to those compounds of formula I, in which R5 and R6 are both methyl, and n is 2. Another special embodiment (embodiment 22) of the compounds of formula I according to this invention refers to those compounds of formula I, in which R5 and R6 are both hydrogen, and n is 3. Another special embodiment (embodiment 23) of the compounds of formula I according to this invention refers to those compounds of formula I, in which R5 and R6 are both methyl, and n is 3. Another special embodiment (embodiment 24) of the compounds of formula I according to this invention refers to those compounds of formula I, in which B is phenyl, or R7- and R71-substituted phenyl, in which R7 is fluorine, chlorine, bromine, methyl, trifluoromethyl or ethyl, R71 is hydrogen, fluorine, chlorine or methyl. Another special embodiment (embodiment 25) of the compounds of formula I according to this invention refers to those compounds of formula I, in which B is phenyl, halophenyl, dihalophenyl, cyanophenyl, halo(trifluoromethyl)phenyl, (hydroxymethyl)phenyl, (methoxymethyl)phenyl, methoxyphenyl, ethoxyphenyl, carboxyphenyl, methylphenyl, ethylphenyl, methylenedioxyphenyl, ethylenedioxyphenyl, methoxychlorophenyl, methylhalophenyl or (trifluoromethyl)phenyl. Another special embodiment (embodiment 26) of the compounds of formula I according to this invention refers to those compounds of formula I, in which WO 2007/144384 PCT/EP2007/055846 -17 B is phenyl, methylphenyl, halophenyl (e.g. chlorophenyl or bromophenyl), dihalophenyl (e.g. dichlorophenyl), methylhalophenyl (e.g. methylfluorophenyl), (hydroxymethyl)phenyl, halo(trifluoromethyl)phenyl, methylenedioxyphenyl, (trifluoromethyl)phenyl, methoxyphenyl or cyanophenyl. Another special embodiment (embodiment 27) of the compounds of formula I according to this invention refers to those compounds of formula I, in which B is methylphenyl, chlorophenyl, dichlorophenyl, bromophenyl, fluorophenyl, (trifluoromethyl)phenyl, methoxyphenyl or methylfluorophenyl. Another special embodiment (embodiment 28) of the compounds of formula I according to this invention refers to those compounds of formula I, in which B is 4-methylphenyl, 3-methylphenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4 chlorophenyl, 4-bromophenyl or 3-fluoro-4-methylphenyl. Another special embodiment (embodiment 29) of the compounds of formula I according to this invention refers to those compounds of formula I, in which B is 4-methylphenyl, 4-chlorophenyl or 4-bromophenyl. Another special embodiment (embodiment 30) of the compounds of formula I according to this invention refers to those compounds of formula I, in which B is 4-methylphenyl. Another special embodiment (embodiment 31) of the compounds of formula I according to this invention refers to those compounds which are from formula 1* as shown below. Another special embodiment (embodiment 32) of the compounds of formula I according to this invention refers to those compounds which are from formula I** as shown below. A respective another special embodiment (embodiment 33 to 92) of the compounds of formula I according to this invention refers to those compounds of formula I, in which R1 is bromine, R2 is methyl, and A, R4, n, R5 and R6 have the respective meanings indicated in Table 1 given below. Table 1: embodiment A R4 n R5 R6 33 benzyl ethyl 2 H H 34 3-fluorobenzyl ethyl 2 H H 35 4-fluorobenzyl ethyl 2 H H 36 benzyl isopropyl 2 H H 37 3-fluorobenzyl isopropyl 2 H H 38 4-fluorobenzyl isopropyl 2 H H 39 benzyl sec-butyl 2 H H WO 2007/144384 PCT/EP2007/055846 -18 embodiment A R4 n R5 R6 40 3-fluorobenzyl sec-butyl 2 H H 41 4-fluorobenzyl sec-butyl 2 H H 42 benzyl cyclopropyl 2 H H 43 3-fluorobenzyl cyclopropyl 2 H H 44 4-fluorobenzyl cyclopropyl 2 H H 45 benzyl propyl 2 H H 46 3-fluorobenzyl propyl 2 H H 47 4-fluorobenzyl propyl 2 H H 48 benzyl ethyl 3 H H 49 3-fluorobenzyl ethyl 3 H H 50 4-fluorobenzyl ethyl 3 H H 51 benzyl isopropyl 3 H H 52 3-fluorobenzyl isopropyl 3 H H 53 4-fluorobenzyl isopropyl 3 H H 54 benzyl sec-butyl 3 H H 55 3-fluorobenzyl sec-butyl 3 H H 56 4-fluorobenzyl sec-butyl 3 H H 57 benzyl cyclopropyl 3 H H 58 3-fluorobenzyl cyclopropyl 3 H H 59 4-fluorobenzyl cyclopropyl 3 H H 60 benzyl propyl 3 H H 61 3-fluorobenzyl propyl 3 H H 62 4-fluorobenzyl propyl 3 H H 63 benzyl ethyl 2 methyl methyl 64 3-fluorobenzyl ethyl 2 methyl methyl 65 4-fluorobenzyl ethyl 2 methyl methyl 66 benzyl isopropyl 2 methyl methyl 67 3-fluorobenzyl isopropyl 2 methyl methyl 68 4-fluorobenzyl isopropyl 2 methyl methyl 69 benzyl sec-butyl 2 methyl methyl 70 3-fluorobenzyl sec-butyl 2 methyl methyl 71 4-fluorobenzyl sec-butyl 2 methyl methyl 72 benzyl cyclopropyl 2 methyl methyl 73 3-fluorobenzyl cyclopropyl 2 methyl methyl 74 4-fluorobenzyl cyclopropyl 2 methyl methyl 75 benzyl propyl 2 methyl methyl 76 3-fluorobenzyl propyl 2 methyl methyl 77 4-fluorobenzyl propyl 2 methyl methyl 78 benzyl ethyl 3 methyl methyl 79 3-fluorobenzyl ethyl 3 methyl methyl 80 4-fluorobenzyl ethyl 3 methyl methyl 81 benzyl isopropyl 3 methyl methyl 82 3-fluorobenzyl isopropyl 3 methyl methyl 83 4-fluorobenzyl isopropyl 3 methyl methyl 84 benzyl sec-butyl 3 methyl methyl 85 3-fluorobenzyl sec-butyl 3 methyl methyl 86 4-fluorobenzyl sec-butyl 3 methyl methyl 87 benzyl cyclopropyl 3 methyl methyl 88 3-fluorobenzyl cyclopropyl 3 methyl methyl 89 4-fluorobenzyl cyclopropyl 3 methyl methyl 90 benzyl propyl 3 methyl methyl 91 3-fluorobenzyl propyl 3 methyl methyl 92 4-fluorobenzyl propyl 3 methyl methyl WO 2007/144384 PCT/EP2007/055846 -19 A respective another special embodiment (embodiment 93 to 152) of the compounds of formula I according to this invention refers to those compounds of formula I, in which R1 is chlorine, R2 is methyl, and A, R4, n, R5 and R6 have the respective meanings indicated in Table 2 given below. Table 2: embodiment A R4 n R5 R6 93 benzyl ethyl 2 H H 94 3-fluorobenzyl ethyl 2 H H 95 4-fluorobenzyl ethyl 2 H H 96 benzyl isopropyl 2 H H 97 3-fluorobenzyl isopropyl 2 H H 98 4-fluorobenzyl isopropyl 2 H H 99 benzyl sec-butyl 2 H H 100 3-fluorobenzyl sec-butyl 2 H H 101 4-fluorobenzyl sec-butyl 2 H H 102 benzyl cyclopropyl 2 H H 103 3-fluorobenzyl cyclopropyl 2 H H 104 4-fluorobenzyl cyclopropyl 2 H H 105 benzyl propyl 2 H H 106 3-fluorobenzyl propyl 2 H H 107 4-fluorobenzyl propyl 2 H H 108 benzyl ethyl 3 H H 109 3-fluorobenzyl ethyl 3 H H 110 4-fluorobenzyl ethyl 3 H H 111 benzyl isopropyl 3 H H 112 3-fluorobenzyl isopropyl 3 H H 113 4-fluorobenzyl isopropyl 3 H H 114 benzyl sec-butyl 3 H H 115 3-fluorobenzyl sec-butyl 3 H H 116 4-fluorobenzyl sec-butyl 3 H H 117 benzyl cyclopropyl 3 H H 118 3-fluorobenzyl cyclopropyl 3 H H 119 4-fluorobenzyl cyclopropyl 3 H H 120 benzyl propyl 3 H H 121 3-fluorobenzyl propyl 3 H H 122 4-fluorobenzyl propyl 3 H H 123 benzyl ethyl 2 methyl methyl 124 3-fluorobenzyl ethyl 2 methyl methyl 125 4-fluorobenzyl ethyl 2 methyl methyl 126 benzyl isopropyl 2 methyl methyl 127 3-fluorobenzyl isopropyl 2 methyl methyl 128 4-fluorobenzyl isopropyl 2 methyl methyl 129 benzyl sec-butyl 2 methyl methyl 130 3-fluorobenzyl sec-butyl 2 methyl methyl 131 4-fluorobenzyl sec-butyl 2 methyl methyl 132 benzyl cyclopropyl 2 methyl methyl 133 3-fluorobenzyl cyclopropyl 2 methyl methyl 134 4-fluorobenzyl cyclopropyl 2 methyl methyl 135 benzyl propyl 2 methyl methyl 136 3-fluorobenzyl propyl 2 methyl methyl 137 4-fluorobenzyl propyl 2 methyl methyl 138 benzyl ethyl 3 methyl methyl 139 3-fluorobenzyl ethyl 3 methyl methyl 140 4-fluorobenzyl ethyl 3 methyl methyl WO 2007/144384 PCT/EP2007/055846 -20 embodiment A R4 n R5 R6 141 benzyl isopropyl 3 methyl methyl 142 3-fluorobenzyl isopropyl 3 methyl methyl 143 4-fluorobenzyl isopropyl 3 methyl methyl 144 benzyl sec-butyl 3 methyl methyl 145 3-fluorobenzyl sec-butyl 3 methyl methyl 146 4-fluorobenzyl sec-butyl 3 methyl methyl 147 benzyl cyclopropyl 3 methyl methyl 148 3-fluorobenzyl cyclopropyl 3 methyl methyl 149 4-fluorobenzyl cyclopropyl 3 methyl methyl 150 benzyl propyl 3 methyl methyl 151 3-fluorobenzyl propyl 3 methyl methyl 152 4-fluorobenzyl propyl 3 methyl methyl It is to be understood that the present invention includes any or all possible combinations and subsets of the special embodiments defined hereinabove. The compounds of formula I, in which R4 is different from hydrogen, are chiral compounds having a chiral center in position 2'. Numbering: O N ,A N 7 N R2 / 6 H 3 5 R4 3 4 2' R1 O N N(R5)R6 (I) B The invention includes all conceivable stereoisomers of the compounds of this invention, like e.g. diastereomers and enantiomers, in substantially pure form as well as in any mixing ratio, including the racemates, as well as the salts thereof. In this connection, compounds of formula I worthy to be mentioned are those which have, with respect to the position 2', the same configuration as shown in formula 1*: WO 2007/144384 PCT/EP2007/055846 -21 O N-N '- N A R2 H - R4 O N N(R5)R6 (1*) B In a preferred embodiment, the invention therefore relates to compounds of formula I as described in this application, wherein said compounds have the configuration as shown in formula 1*, and the salts thereof. If, for example, in compounds of formula 1* R4 has the meaning methyl, ethyl, propyl, isopropyl, sec butyl or cyclopropyl, then the configuration - according to the rules of Cahn, Ingold and Prelog - is R in the 2' position. Further on, compounds of the formula I also worthy to be mentioned are those which have, with respect to the position 2', the same configuration as shown in formula I**: O N- N '"-N A R2 HR 4 H R1 O N N(R5)R6 B (1**) If, for example, in compounds of formula I** R4 has the meaning methyl, ethyl, propyl, isopropyl, sec butyl or cyclopropyl, then the configuration - according to the rules of Cahn, Ingold and Prelog - is S in the position 2'. In general, enantiomerically pure compounds of this invention may be prepared according to art known processes, such as e.g. via asymmetric syntheses, for example by preparation and separation of appropriate diastereoisomeric compounds/intermediates, which can be separated by known methods (e.g. by chromatographic separation or (fractional) crystallization from a suitable solvent), or by using chiral synthons or chiral reagents; by chromatographic separation of the corresponding racemate on chiral separating columns; by means of diastereomeric salt formation of the racemic compounds with optically active acids (such as e.g. those mentioned below) or bases, subsequent resolution of the salts and release of the desired compound from the salt; by derivatization of the racemic compounds with chiral auxiliary reagents, subsequent diastereomer separation and removal WO 2007/144384 PCT/EP2007/055846 - 22 of the chiral auxiliary group; by resolution via diastereomeric inclusion compounds (e.g. complexes or clathrates); by kinetic resolution of a racemate (e.g. by enzymatic resolution); by enantioselective (preferential) crystallization (or crystallization by entrainment) from a conglomerate of enantiomorphous crystals under suitable conditions; or by (fractional) crystallization from a suitable solvent in the presence of a chiral auxiliary. Thus, e.g. one possible alternative for enatiomer separation may be carried out at the stage of the compounds of formula I or of the starting compounds having a protonatable group, e.g. a free amino group, such as starting compounds of formula II as defined later. Hereby, separation of the enantiomers may be carried out, for example, by means of salt formation of the racemic compounds of formula II with optically active acids, preferably carboxylic acids, subsequent resolution of the salts and release of the desired compound from the salt. Examples of optically active carboxylic acids which may be mentioned in this connection, without being restricted thereto, are the enantiomeric forms of mandelic acid, tartaric acid, O,O'-dibenzoyltartaric acid, camphoric acid, quinic acid, glutamic acid, pyroglutamic acid, malic acid, camphorsulfonic acid, 3-bromocamphorsulfonic acid, ca-methoxyphenylacetic acid, ca-methoxy-c-trifluoromethylphenylacetic acid or 2-phenylpropionic acid or the like. Another possible alternative for enantiomer separation may be carried out by chromatographic separation of a racemic mixture of compounds of formula I or of starting compounds thereof on a chiral separating column, such as e.g. described in the following examples or analogously or similarly thereto, using the appropriate separation conditions. The enantiomers having the formula 1* and the salts thereof are part of the invention. The enantiomers having the formula I** and the salts thereof are also part of the invention. Preference is given in this connection to those compounds of formula I which have with respect to the asymmetric -C(R4)H- atom (position 2') the same absolute configuration as the compound (+)-N-(3 amino-propyl)-N-[1-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl ) propyl]-4-methyl-benzamide hydrochloride having the specific optical rotation [t]D 2 0 = + 231 o (c=0.4535, CHC 3 ), as well as the salts thereof. The invention therefore relates to compounds of formula I according to the invention, in which R4 is different from hydrogen, and which have with respect to the asymmetric -C(R4)H- atom the same absolute configuration as the compound (+)-N-(3-amino-propyl)-N-[1-(6-benzyl-3-chloro-2-methyl-7 oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl)-propyl]-4-methyl-benzamide hydrochloride having the specific optical rotation [C]D20= + 231 o (c=0.4535, CHC 3 ), as well as the salts thereof. As exemplary compounds according to this invention the following compounds of formula 1*, in which WO 2007/144384 PCT/EP2007/055846 -23 R1 is bromine, and R2 is methyl, and the salts thereof, may be mentioned by means of the substituent meanings for A, R4, n, R5, R6 and B in the Table 3 given below. As further exemplary compounds according to this invention the following compounds of formula 1*, in which R1 is chlorine, and R2 is methyl, and the salts thereof, may be mentioned by means of the substituent meanings for A, R4, n, R5, R6 and B in the Table 3 given below. As further exemplary compounds according to this invention the following compounds of formula 1*, in which R1 is hydrogen, and R2 is methyl, and the salts thereof, may be mentioned by means of the substituent meanings for A, R4, n, R5, R6 and B in the Table 3 given below. As further exemplary compounds according to this invention the following compounds of formula I**, in which R1 is bromine, and R2 is methyl, and the salts thereof, may be mentioned by means of the substituent meanings for A, R4, n, R5, R6 and B in the Table 3 given below. As further exemplary compounds according to this invention the following compounds of formula I**, in which R1 is chlorine, and R2 is methyl, and the salts thereof, may be mentioned by means of the substituent meanings for A, R4, n, R5, R6 and B in the Table 3 given below. As further exemplary compounds according to this invention the following compounds of formula I**, in which R1 is hydrogen, and R2 is methyl, and the salts thereof, may be mentioned by means of the substituent meanings for A, R4, n, R5, R6 and B in the Table 3 given below.

WO 2007/144384 PCT/EP2007/055846 - 24 Table 3: A R4 n R5 R6 B 1) benzyl ethyl 2 H H 4-methylphenyl 2) benzyl ethyl 2 H H 4-bromophenyl 3) benzyl ethyl 2 H H 4-chlorophenyl 4) benzyl ethyl 2 H H 4-methyl-3-fluorophenyl 5) benzyl ethyl 2 H H 4-fluorophenyl 6) benzyl ethyl 2 H H 4-trifluoromethylphenyl 7) benzyl ethyl 2 H H 4-methoxyphenyl 8) benzyl ethyl 3 H H 4-methylphenyl 9) benzyl ethyl 3 H H 4-bromophenyl 10) benzyl ethyl 3 H H 4-chlorophenyl 11) benzyl ethyl 3 H H 4-methyl-3-fluorophenyl 12) benzyl ethyl 3 H H 4-fluorophenyl 13) benzyl ethyl 3 H H 4-trifluoromethylphenyl 14) benzyl ethyl 3 H H 4-methoxyphenyl 15) benzyl ethyl 2 methyl methyl 4-methylphenyl 16) benzyl ethyl 2 methyl methyl 4-bromophenyl 17) benzyl ethyl 2 methyl methyl 4-chlorophenyl 18) benzyl ethyl 2 methyl methyl 4-methyl-3-fluorophenyl 19) benzyl ethyl 2 methyl methyl 4-fluorophenyl 20) benzyl ethyl 2 methyl methyl 4-trifluoromethylphenyl 21) benzyl ethyl 2 methyl methyl 4-methoxyphenyl 22) benzyl ethyl 3 methyl methyl 4-methylphenyl 23) benzyl ethyl 3 methyl methyl 4-bromophenyl 24) benzyl ethyl 3 methyl methyl 4-chlorophenyl 25) benzyl ethyl 3 methyl methyl 4-methyl-3-fluorophenyl 26) benzyl ethyl 3 methyl methyl 4-fluorophenyl 27) benzyl ethyl 3 methyl methyl 4-trifluoromethylphenyl 28) benzyl ethyl 3 methyl methyl 4-methoxyphenyl 29) 3-fluorobenzyl ethyl 2 H H 4-methylphenyl 30) 3-fluorobenzyl ethyl 2 H H 4-bromophenyl 31) 3-fluorobenzyl ethyl 2 H H 4-chlorophenyl 32) 3-fluorobenzyl ethyl 2 H H 4-methyl-3-fluorophenyl 33) 3-fluorobenzyl ethyl 2 H H 4-fluorophenyl 34) 3-fluorobenzyl ethyl 2 H H 4-trifluoromethylphenyl 35) 3-fluorobenzyl ethyl 2 H H 4-methoxyphenyl 36) 3-fluorobenzyl ethyl 3 H H 4-methylphenyl 37) 3-fluorobenzyl ethyl 3 H H 4-bromophenyl 38) 3-fluorobenzyl ethyl 3 H H 4-chlorophenyl 39) 3-fluorobenzyl ethyl 3 H H 4-methyl-3-fluorophenyl 40) 3-fluorobenzyl ethyl 3 H H 4-fluorophenyl 41) 3-fluorobenzyl ethyl 3 H H 4-trifluoromethylphenyl 42) 3-fluorobenzyl ethyl 3 H H 4-methoxyphenyl 43) 3-fluorobenzyl ethyl 2 methyl methyl 4-methylphenyl 44) 3-fluorobenzyl ethyl 2 methyl methyl 4-bromophenyl 45) 3-fluorobenzyl ethyl 2 methyl methyl 4-chlorophenyl 46) 3-fluorobenzyl ethyl 2 methyl methyl 4-methyl-3-fluorophenyl 47) 3-fluorobenzyl ethyl 2 methyl methyl 4-fluorophenyl 48) 3-fluorobenzyl ethyl 2 methyl methyl 4-trifluoromethylphenyl 49) 3-fluorobenzyl ethyl 2 methyl methyl 4-methoxyphenyl 50) 3-fluorobenzyl ethyl 3 methyl methyl 4-methylphenyl 51) 3-fluorobenzyl ethyl 3 methyl methyl 4-bromophenyl 52) 3-fluorobenzyl ethyl 3 methyl methyl 4-chlorophenyl 53) 3-fluorobenzyl ethyl 3 methyl methyl 4-methyl-3-fluorophenyl 54) 3-fluorobenzyl ethyl 3 methyl methyl 4-fluorophenyl 55) 3-fluorobenzyl ethyl 3 methyl methyl 4-trifluoromethylphenyl WO 2007/144384 PCT/EP2007/055846 - 25 A R4 n R5 R6 B 56) 3-fluorobenzyl ethyl 3 methyl methyl 4-methoxyphenyl 57) 4-fluorobenzyl ethyl 2 H H 4-methylphenyl 58) 4-fluorobenzyl ethyl 2 H H 4-bromophenyl 59) 4-fluorobenzyl ethyl 2 H H 4-chlorophenyl 60) 4-fluorobenzyl ethyl 2 H H 4-methyl-3-fluorophenyl 61) 4-fluorobenzyl ethyl 2 H H 4-fluorophenyl 62) 4-fluorobenzyl ethyl 2 H H 4-trifluoromethylphenyl 63) 4-fluorobenzyl ethyl 2 H H 4-methoxyphenyl 64) 4-fluorobenzyl ethyl 3 H H 4-methylphenyl 65) 4-fluorobenzyl ethyl 3 H H 4-bromophenyl 66) 4-fluorobenzyl ethyl 3 H H 4-chlorophenyl 67) 4-fluorobenzyl ethyl 3 H H 4-methyl-3-fluorophenyl 68) 4-fluorobenzyl ethyl 3 H H 4-fluorophenyl 69) 4-fluorobenzyl ethyl 3 H H 4-trifluoromethylphenyl 70) 4-fluorobenzyl ethyl 3 H H 4-methoxyphenyl 71) 4-fluorobenzyl ethyl 2 methyl methyl 4-methylphenyl 72) 4-fluorobenzyl ethyl 2 methyl methyl 4-bromophenyl 73) 4-fluorobenzyl ethyl 2 methyl methyl 4-chlorophenyl 74) 4-fluorobenzyl ethyl 2 methyl methyl 4-methyl-3-fluorophenyl 75) 4-fluorobenzyl ethyl 2 methyl methyl 4-fluorophenyl 76) 4-fluorobenzyl ethyl 2 methyl methyl 4-trifluoromethylphenyl 77) 4-fluorobenzyl ethyl 2 methyl methyl 4-methoxyphenyl 78) 4-fluorobenzyl ethyl 3 methyl methyl 4-methylphenyl 79) 4-fluorobenzyl ethyl 3 methyl methyl 4-bromophenyl 80) 4-fluorobenzyl ethyl 3 methyl methyl 4-chlorophenyl 81) 4-fluorobenzyl ethyl 3 methyl methyl 4-methyl-3-fluorophenyl 82) 4-fluorobenzyl ethyl 3 methyl methyl 4-fluorophenyl 83) 4-fluorobenzyl ethyl 3 methyl methyl 4-trifluoromethylphenyl 84) 4-fluorobenzyl ethyl 3 methyl methyl 4-methoxyphenyl 85) benzyl isopropyl 2 H H 4-methylphenyl 86) benzyl isopropyl 2 H H 4-bromophenyl 87) benzyl isopropyl 2 H H 4-chlorophenyl 88) benzyl isopropyl 2 H H 4-methyl-3-fluorophenyl 89) benzyl isopropyl 2 H H 4-fluorophenyl 90) benzyl isopropyl 2 H H 4-trifluoromethylphenyl 91) benzyl isopropyl 2 H H 4-methoxyphenyl 92) benzyl isopropyl 3 H H 4-methylphenyl 93) benzyl isopropyl 3 H H 4-bromophenyl 94) benzyl isopropyl 3 H H 4-chlorophenyl 95) benzyl isopropyl 3 H H 4-methyl-3-fluorophenyl 96) benzyl isopropyl 3 H H 4-fluorophenyl 97) benzyl isopropyl 3 H H 4-trifluoromethylphenyl 98) benzyl isopropyl 3 H H 4-methoxyphenyl 99) benzyl isopropyl 2 methyl methyl 4-methylphenyl 100) benzyl isopropyl 2 methyl methyl 4-bromophenyl 101) benzyl isopropyl 2 methyl methyl 4-chlorophenyl 102) benzyl isopropyl 2 methyl methyl 4-methyl-3-fluorophenyl 103) benzyl isopropyl 2 methyl methyl 4-fluorophenyl 104) benzyl isopropyl 2 methyl methyl 4-trifluoromethylphenyl 105) benzyl isopropyl 2 methyl methyl 4-methoxyphenyl 106) benzyl isopropyl 3 methyl methyl 4-methylphenyl 107) benzyl isopropyl 3 methyl methyl 4-bromophenyl 108) benzyl isopropyl 3 methyl methyl 4-chlorophenyl 109) benzyl isopropyl 3 methyl methyl 4-methyl-3-fluorophenyl 110) benzyl isopropyl 3 methyl methyl 4-fluorophenyl 111) benzyl isopropyl 3 methyl methyl 4-trifluoromethylphenyl WO 2007/144384 PCT/EP2007/055846 - 26 A R4 n R5 R6 B 112) benzyl isoproy 3 mehy mehy 4-methoxyphenyl 113) 3-fluorobenzyl isopropyl 2 H H 4-methyiphenyl 114) 3-fluorobenzyl isopropyl 2 H H 4-bromophenyl 115) 3-fluorobenzyl isopropyl 2 H H 4-chiorophenyl 116) 3-fluorobenzyl isopropyl 2 H H 4-methyl-3-fluorophenyl 117) 3-fluorobenzyl isopropyl 2 H H 4-fluorophenyl 118) 3-fluorobenzyl isopropyl 2 H H 4-trifluoromethyiphenyl 119) 3-fluorobenzyl isopropyl 2 H H 4-methoxyphenyl 120) 3-fluorobenzyl isopropyl 3 H H 4-methyiphenyl 121) 3-fluorobenzyl isopropyl 3 H H 4-bromophenyl 122) 3-fluorobenzyl isopropyl 3 H H 4-chiorophenyl 123) 3-fluorobenzyl isopropyl 3 H H 4-methyl-3-fluorophenyl 124 3-fluorobenzyl isopropyl 3 H H 4-fluorophenyl 125) 3-fluorobenzyl isopropyl 3 H H 4-trifluoromethyiphenyl 126) 3-fluorobenzyl isopropyl 3 H H 4-methoxyphenyl 127) 3-fluorobenzyl isopropyl 2 methyl methyl 4-methyiphenyl 128) 3-fluorobenzyl isopropyl 2 methyl methyl 4-bromophenyl 129) 3-fluorobenzyl isopropyl 2 methyl methyl 4-chlorophenyl 130) 3-fluorobenzyl isopropyl 2 methyl methyl 4-methyl-3-fluorophenyl 131) 3-fluorobenzyl isopropyl 2 methyl methyl 4-fluorophenyl 132) 3-fluorobenzyl isopropyl 2 methyl methyl 4-trifluoromethylphenyl 133) 3-fluorobenzyl isopropyl 2 methyl methyl 4-methoxyphenyl 134) 3-fluorobenzyl isopropyl 3 methyl methyl 4-methylphenyl 135) 3-fluorobenzyl isopropyl 3 methyl methyl 4-bromophenyl 136) 3-fluorobenzyl isopropyl 3 methyl methyl 4-chlorophenyl 137) 3-fluorobenzyl isopropyl 3 methyl methyl 4-methyl-3-fluorophenyl 138) 3-fluorobenzyl isopropyl 3 methyl methyl 4-fluorophenyl 139) 3-fluorobenzyl isopropyl 3 methyl methyl 4-trifluoromethylphenyl 140) 3-fluorobenzyl isopropyl 3 methyl methyl 4-methoxyphenyl 141) 4-fluorobenzyl isopropyl 2 H H 4-methylphenyl 142) 4-fluorobenzyl isopropyl 2 H H 4-bromophenyl 143) 4-fluorobenzyl isopropyl 2 H H 4-chlorophenyl 144) 4-fluorobenzyl isopropyl 2 H H 4-methyl-3-fluorophenl 145) 4-fluorobenzyl isopropyl 2 H H 4-fluorophenyl 146) 4-fl orobenzyl isopropyl 2 H H 4-trifluoromethylphenyl 147) 4-fluorobenzyl isopropyl 2 H H 4-methoxyphenyl 148) 4-fluorobenzyl isopropyl 3 H H 4-methylphenyl 149) 4-fluorobenzyl isopropyl 3 H H 4-bromophenyl 150) 4-fluorobenzyl isopropyl 3 H H 4-chlorophenyl 151) 4-fluorobenzyl isopropyl 3 H H 4-methyl-3-fluorophenyl 152) 4-fluorobenzyl isopropyl 3 H H 4-fluorophenyl 153) 4-fluorobenzyl isopropyl 3 H H 4-trifluoromethylphenyl 154) 4-fluorobenzyl isopropyl 3 H H 4-methoxyphenyl 155) 4-fluorobenzyl isopropyl 2 methyl methyl 4-methylphenyl 156) 4-fluorobenzyl isopropyl 2 methyl methyl 4-bromophenyl 157) 4-fluorobenzyl isopropyl 2 methyl methyl 4-chlorophenyl 158) 4-fluorobenzyl isopropyl 2 methyl methyl 4-methyl-3-fluorophenyl 159) 4-fluorobenzyl isopropyl 2 methyl methyl 4-fluorophenyl 160) 4-fluorobenzyl isopropyl 2 methyl methyl 4-trifluoromethylphenyl 161) 4-fluorobenzyl isopropyl 2 methyl methyl 4-methoxyphenyl 162) 4-fluorobenzyl isopropyl 3 methyl mety 4-methylphenyl 163) 4-fluorobenzyl isopropyl 3 methyl methyl 4-bromophenyl 164) 4-fluorobenzyl isopropyl 3 methyl methyl 4-chlorophenyl 165) 4-fluorobenzyl isopropyl 3 methyl methyl 4-methyl-3-fluorophenyl 166) 4-fluorobenzyl isopropyl 3 methyl methyl 4-fluorophenyl 167) 4-fluorobenzyl isopropyl 3 methyl methyl 4-trifluoromethylphenyl WO 2007/144384 PCT/EP2007/055846 - 27 A R4 n R5 R6 B 168) 4-fluorobenzyl isopropyl 3 methyl methyl 4-methoxyphenyl 169) benzyl cyclopropyl 2 H H 4-methylphenyl 170) benzyl cyclopropyl 2 H H 4-bromophenyl 171) benzyl cyclopropyl 2 H H 4-chlorophenyl 172) benzyl cyclopropyl 2 H H 4-methyl-3-fluorophenyl 173) benzyl cyclopropyl 2 H H 4-fluorophenyl 174) benzyl cyclopropyl 2 H H 4-trifluoromethylphenyl 175) benzyl cyclopropyl 2 H H 4-methoxyphenyl 176) benzyl cyclopropyl 3 H H 4-methylphenyl 177) benzyl cyclopropyl 3 H H 4-bromophenyl 178) benzyl cyclopropyl 3 H H 4-chlorophenyl 179) benzyl cyclopropyl 3 H H 4-methyl-3-fluorophenyl 180) benzyl cyclopropyl 3 H H 4-fluorophenyl 181) benzyl cyclopropyl 3 H H 4-trifluoromethylphenyl 182) benzyl cyclopropyl 3 H H 4-methoxyphenyl 183) benzyl cyclopropyl 2 methyl methyl 4-methylphenyl 184) benzyl cyclopropyl 2 methyl methyl 4-bromophenyl 185) benzyl cyclopropyl 2 methyl methyl 4-chlorophenyl 186) benzyl cyclopropyl 2 methyl methyl 4-methyl-3-fluorophenyl 187) benzyl cyclopropyl 2 methyl methyl 4-fluorophenyl 188) benzyl cyclopropyl 2 methyl methyl 4-trifluoromethylphenyl 189) benzyl cyclopropyl 2 methyl methyl 4-methoxyphenyl 190) benzyl cyclopropyl 3 methyl methyl 4-methylphenyl 191) benzyl cyclopropyl 3 methyl methyl 4-bromophenyl 192) benzyl cyclopropyl 3 methyl methyl 4-chlorophenyl 193) benzyl cyclopropyl 3 methyl methyl 4-methyl-3-fluorophenyl 194) benzyl cyclopropyl 3 methyl methyl 4-fluorophenyl 195) benzyl cyclopropyl 3 methyl methyl 4-trifluoromethylphenyl 196) benzyl cyclopropyl 3 methyl methyl 4-methoxyphenyl 197) 3-fluorobenzyl cyclopropyl 2 H H 4-methylphenyl 198) 3-fluorobenzyl cyclopropyl 2 H H 4-bromophenyl 199) 3-fluorobenzyl cyclopropyl 2 H H 4-chlorophenyl 200) 3-fluorobenzyl cyclopropyl 2 H H 4-methyl-3-fluorophenyl 201) 3-fluorobenzyl cyclopropyl 2 H H 4-fluorophenyl 202) 3-fluorobenzyl cyclopropyl 2 H H 4-trifluoromethylphenyl 203) 3-fluorobenzyl cyclopropyl 2 H H 4-methoxyphenyl 204) 3-fluorobenzyl cyclopropyl 3 H H 4-methylphenyl 205) 3-fluorobenzyl cyclopropyl 3 H H 4-bromophenyl 206) 3-fluorobenzyl cyclopropyl 3 H H 4-chlorophenyl 207) 3-fluorobenzyl cyclopropyl 3 H H 4-methyl-3-fluorophenyl 208) 3-fluorobenzyl cyclopropyl 3 H H 4-fluorophenyl 209) 3-fluorobenzyl cyclopropyl 3 H H 4-trifluoromethylphenyl 210) 3-fluorobenzyl cyclopropyl 3 H H 4-methoxyphenyl 211) 3-fluorobenzyl cyclopropyl 2 methyl methyl 4-methylphenyl 212) 3-fluorobenzyl cyclopropyl 2 methyl methyl 4-bromophenyl 213) 3-fluorobenzyl cyclopropyl 2 methyl methyl 4-chlorophenyl 214) 3-fluorobenzyl cyclopropyl 2 methyl methyl 4-methyl-3-fluorophenyl 215) 3-fluorobenzyl cyclopropyl 2 methyl methyl 4-fluorophenyl 216) 3-fluorobenzyl cyclopropyl 2 methyl methyl 4-trifluoromethylphenyl 217) 3-fluorobenzyl cyclopropyl 2 methyl methyl 4-methoxyphenyl 218) 3-fluorobenzyl cyclopropyl 3 methyl methyl 4-methylphenyl 219) 3-fluorobenzyl cyclopropyl 3 methyl methyl 4-bromophenyl 220) 3-fluorobenzyl cyclopropyl 3 methyl methyl 4-chlorophenyl 221) 3-fluorobenzyl cyclopropyl 3 methyl methyl 4-methyl-3-fluorophenyl 222) 3-fluorobenzyl cyclopropyl 3 methyl methyl 4-fluorophenyl 223) 3-fluorobenzyl cyclopropyl 3 methyl methyl 4-trifluoromethylphenyl WO 2007/144384 PCT/EP2007/055846 -28 A R4 n R5 R6 B 224) 3-fluorobenzyl cyclopropyl 3 methyl methyl 4-methoxyphenyl 225) 4-fluorobenzyl cyclopropyl 2 H H 4-methylphenyl 226) 4-fluorobenzyl cyclopropyl 2 H H 4-bromophenyl 227) 4-fluorobenzyl cyclopropyl 2 H H 4-chlorophenyl 228) 4-fluorobenzyl cyclopropyl 2 H H 4-methyl-3-fluorophenyl 229) 4-fluorobenzyl cyclopropyl 2 H H 4-fluorophenyl 230) 4-fluorobenzyl cyclopropyl 2 H H 4-trifluoromethylphenyl 231) 4-fluorobenzyl cyclopropyl 2 H H 4-methoxyphenyl 232) 4-fluorobenzyl cyclopropyl 3 H H 4-methylphenyl 233) 4-fluorobenzyl cyclopropyl 3 H H 4-bromophenyl 234) 4-fluorobenzyl cyclopropyl 3 H H 4-chlorophenyl 235) 4-fluorobenzyl cyclopropyl 3 H H 4-methyl-3-fluorophenyl 236) 4-fluorobenzyl cyclopropyl 3 H H 4-fluorophenyl 237) 4-fluorobenzyl cyclopropyl 3 H H 4-trifluoromethylphenyl 238) 4-fluorobenzyl cyclopropyl 3 H H 4-methoxyphenyl 239) 4-fluorobenzyl cyclopropyl 2 methyl methyl 4-methylphenyl 240) 4-fluorobenzyl cyclopropyl 2 methyl methyl 4-bromophenyl 241) 4-fluorobenzyl cyclopropyl 2 methyl methyl 4-chlorophenyl 242) 4-fluorobenzyl cyclopropyl 2 methyl methyl 4-methyl-3-fluorophenyl 243) 4-fluorobenzyl cyclopropyl 2 methyl methyl 4-fluorophenyl 244) 4-fluorobenzyl cyclopropyl 2 methyl methyl 4-trifluoromethylphenyl 245) 4-fluorobenzyl cyclopropyl 2 methyl methyl 4-methoxyphenyl 246) 4-fluorobenzyl cyclopropyl 3 methyl methyl 4-methylphenyl 247) 4-fluorobenzyl cyclopropyl 3 methyl methyl 4-bromophenyl 248) 4-fluorobenzyl cyclopropyl 3 methyl methyl 4-chlorophenyl 249) 4-fluorobenzyl cyclopropyl 3 methyl methyl 4-methyl-3-fluorophenyl 250) 4-fluorobenzyl cyclopropyl 3 methyl methyl 4-fluorophenyl 251) 4-fluorobenzyl cyclopropyl 3 methyl methyl 4-trifluoromethylphenyl 252) 4-fluorobenzyl cyclopropyl 3 methyl methyl 4-methoxyphenyl 253) benzyl sec-butyl 2 H H 4-methylphenyl 254) benzyl sec-butyl 2 H H 4-bromophenyl 255) benzyl sec-butyl 2 H H 4-chlorophenyl 256) benzyl sec-butyl 2 H H 4-methyl-3-fluorophenyl 257) benzyl sec-butyl 2 H H 4-fluorophenyl 258) benzyl sec-butyl 2 H H 4-trifluoromethylphenyl 259) benzyl sec-butyl 2 H H 4-methoxyphenyl 260) benzyl sec-butyl 3 H H 4-methylphenyl 261) benzyl sec-butyl 3 H H 4-bromophenyl 262) benzyl sec-butyl 3 H H 4-chlorophenyl 263) benzyl sec-butyl 3 H H 4-methyl-3-fluorophenyl 264) benzyl sec-butyl 3 H H 4-fluorophenyl 265) benzyl sec-butyl 3 H H 4-trifluoromethylphenyl 266) benzyl sec-butyl 3 H H 4-methoxyphenyl 267) benzyl sec-butyl 2 methyl methyl 4-methylphenyl 268) benzyl sec-butyl 2 methyl methyl 4-bromophenyl 269) benzyl sec-butyl 2 methyl methyl 4-chlorophenyl 270) benzyl sec-butyl 2 methyl methyl 4-methyl-3-fluorophenyl 271) benzyl sec-butyl 2 methyl methyl 4-fluorophenyl 272) benzyl sec-butyl 2 methyl methyl 4-trifluoromethylphenyl 273) benzyl sec-butyl 2 methyl methyl 4-methoxyphenyl 274) benzyl sec-butyl 3 methyl methyl 4-methylphenyl 275) benzyl sec-butyl 3 methyl methyl 4-bromophenyl 276) benzyl sec-butyl 3 methyl methyl 4-chlorophenyl 277) benzyl sec-butyl 3 methyl methyl 4-methyl-3-fluorophenyl 278) benzyl sec-butyl 3 methyl methyl 4-fluorophenyl 279) benzyl sec-butyl 3 methyl methyl 4-trifluoromethylphenyl WO 2007/144384 PCT/EP2007/055846 - 29 A R4 n R5 R6 B 280) benzyl sec-butyl 3 methyl methyl 4-methoxyphenyl 281) 3-fluorobenzyl sec-butyl 2 H H 4-methylphenyl 282) 3-fluorobenzyl sec-butyl 2 H H 4-bromophenyl 283) 3-fluorobenzyl sec-butyl 2 H H 4-chlorophenyl 284) 3-fluorobenzyl sec-butyl 2 H H 4-methyl-3-fluorophenyl 285) 3-fluorobenzyl sec-butyl 2 H H 4-fluorophenyl 286) 3-fluorobenzyl sec-butyl 2 H H 4-trifluoromethylphenyl 287) 3-fluorobenzyl sec-butyl 2 H H 4-methoxyphenyl 288) 3-fluorobenzyl sec-butyl 3 H H 4-methylphenyl 289) 3-fluorobenzyl sec-butyl 3 H H 4-bromophenyl 290) 3-fluorobenzyl sec-butyl 3 H H 4-chlorophenyl 291) 3-fluorobenzyl sec-butyl 3 H H 4-methyl-3-fluorophenyl 292) 3-fluorobenzyl sec-butyl 3 H H 4-fluorophenyl 293) 3-fluorobenzyl sec-butyl 3 H H 4-trifluoromethylphenyl 294) 3-fluorobenzyl sec-butyl 3 H H 4-methoxyphenyl 295) 3-fluorobenzyl sec-butyl 2 methyl methyl 4-methylphenyl 296) 3-fluorobenzyl sec-butyl 2 methyl methyl 4-bromophenyl 297) 3-fluorobenzyl sec-butyl 2 methyl methyl 4-chlorophenyl 298) 3-fluorobenzyl sec-butyl 2 methyl methyl 4-methyl-3-fluorophenyl 299) 3-fluorobenzyl sec-butyl 2 methyl methyl 4-fluorophenyl 300) 3-fluorobenzyl sec-butyl 2 methyl methyl 4-trifluoromethylphenyl 301) 3-fluorobenzyl sec-butyl 2 methyl methyl 4-methoxyphenyl 302) 3-fluorobenzyl sec-butyl 3 methyl methyl 4-methylphenyl 303) 3-fluorobenzyl sec-butyl 3 methyl methyl 4-bromophenyl 304) 3-fluorobenzyl sec-butyl 3 methyl methyl 4-chlorophenyl 305) 3-fluorobenzyl sec-butyl 3 methyl methyl 4-methyl-3-fluorophenyl 306) 3-fluorobenzyl sec-butyl 3 methyl methyl 4-fluorophenyl 307) 3-fluorobenzyl sec-butyl 3 methyl methyl 4-trifluoromethylphenyl 308) 3-fluorobenzyl sec-butyl 3 methyl methyl 4-methoxyphenyl 309) 4-fluorobenzyl sec-butyl 2 H H 4-methylphenyl 310) 4-fluorobenzyl sec-butyl 2 H H 4-bromophenyl 311) 4-fluorobenzyl sec-butyl 2 H H 4-chlorophenyl 312) 4-fluorobenzyl sec-butyl 2 H H 4-methyl-3-fluorophenyl 313) 4-fluorobenzyl sec-butyl 2 H H 4-fluorophenyl 314) 4-fluorobenzyl sec-butyl 2 H H 4-trifluoromethylphenyl 315) 4-fluorobenzyl sec-butyl 2 H H 4-methoxyphenyl 316) 4-fluorobenzyl sec-butyl 3 H H 4-methylphenyl 317) 4-fluorobenzyl sec-butyl 3 H H 4-bromophenyl 318) 4-fluorobenzyl sec-butyl 3 H H 4-chlorophenyl 319) 4-fluorobenzyl sec-butyl 3 H H 4-methyl-3-fluorophenyl 320) 4-fluorobenzyl sec-butyl 3 H H 4-fluorophenyl 321) 4-fluorobenzyl sec-butyl 3 H H 4-trifluoromethylphenyl 322) 4-fluorobenzyl sec-butyl 3 H H 4-methoxyphenyl 323) 4-fluorobenzyl sec-butyl 2 methyl methyl 4-methylphenyl 324) 4-fluorobenzyl sec-butyl 2 methyl methyl 4-bromophenyl 325) 4-fluorobenzyl sec-butyl 2 methyl methyl 4-chlorophenyl 326) 4-fluorobenzyl sec-butyl 2 methyl methyl 4-methyl-3-fluorophenyl 327) 4-fluorobenzyl sec-butyl 2 methyl methyl 4-fluorophenyl 328) 4-fluorobenzyl sec-butyl 2 methyl methyl 4-trifluoromethylphenyl 329) 4-fluorobenzyl sec-butyl 2 methyl methyl 4-methoxyphenyl 330) 4-fluorobenzyl sec-butyl 3 methyl methyl 4-methylphenyl 331) 4-fluorobenzyl sec-butyl 3 methyl methyl 4-bromophenyl 332) 4-fluorobenzyl sec-butyl 3 methyl methyl 4-chlorophenyl 333) 4-fluorobenzyl sec-butyl 3 methyl methyl 4-methyl-3-fluorophenyl 334) 4-fluorobenzyl sec-butyl 3 methyl methyl 4-fluorophenyl 335) 4-fluorobenzyl sec-butyl 3 methyl methyl 4-trifluoromethylphenyl WO 2007/144384 PCT/EP2007/055846 - 30 -A R4 n R5 R6 B 336 4-fluorobenzyl sec-butyl 3 methyl methyl 4-methoxyphenyl The compounds according to the invention can be prepared e.g. as described as follows and according to the following specified reaction steps, or, particularly, in a manner as described by way of example in the following examples, or analogously or similarly thereto according to preparation procedures or synthesis strategies known to the person skilled in the art. As shown in the synthesis route outlined in scheme 1 below, the trione compound of formula IX, in which R2 has the meanings given above (particularly, R2 is methyl), is condensed and cyclized with semicarbazide (H 2

N-C(O)-NHNH

2 *HCI) to give the corresponding pyrazolopyrimidone compounds of formula VIII. Said cyclocondensation reaction can be carried out as it is habitual for the skilled person or as described in the following examples or analogously or similarly thereto, in the presence of a suitable base (e.g. sodium carbonate) in a suitable solvent, for example water, at elevated temperature. Compounds of formula IX, in which R2 has the meanings given above, particularly methyl, are known or can be prepared according to known procedures or as described in the following examples, or analogously or similarly thereto. Thus, e.g. compounds of formula IX can be obtained from corresponding compounds of formula X by alkaline hydrolysis Compounds of formula X are known or can be obtained according to known procedures. Compounds of formula VIII are benzylated with compounds of formula A-X1, in which A has the meanings given above and X1 is a suitable leaving group (e.g. halogen or the like), in a standard manner or as described exemplarily in the following examples to give corresponding compounds of formula VII. Compounds of formula VII, in which R2 and A have the meanings given above, are halogenated using a suitable halogenating reagent under appropriate conditions to obtain corresponding compounds of formula VI, in which R2 and A have the meanings given above and R1 is halogen, in particular fluorine or, in more particular, chlorine or bromine. Said halogenation reaction can be carried out according to customary procedures or as described in the following examples, or analogously or similarly thereto. Thus, chlorination or bromination reaction can be carried out using an appropriate electrophilic chlorinating or brominating reagent, e.g. N-chlorosuccinimide (NCS) or N-bromosuccinimide (e.g. NBS / AIBN), respectively, under conditions customary for the skilled person or as described in the following examples.

WO 2007/144384 PCT/EP2007/055846 - 31 Reaction scheme 1: 0 0 0 O o O ,t NH2 0 0 0 H2N N NH A-X1 S R2 R2 0 CH 3 R2 OH 3 COH 3 benzylation H (X) (IX) (ViII) O O N I/ NN /J oxidation N- N N A halogenation N N NA oxidation SR2CH 3 R CH 3 H R1 (VII) (VI) O 0 N-ANJ A R4-M N- N NA oxidation R2 / R2 R4 H addition R1 R1 R OH 0 (V) (IV) 0 H2N. N(R5)R6 0 R2 /N H R R4 H/ N N R4 reductive R4 R1 amination R1 I (I)O HN N(R5)R6 (iIm) (in) 1. B-C(O)-X2, benzoylation 2. When R1 = H, optionally halogenation (e.g. bromination) 3. If necessary, removal of temporary protecting groups O R2 / R4 R14 0 N N(R5)R6 B (1) WO 2007/144384 PCT/EP2007/055846 - 32 Fluorination reaction may be carried out using a suitable electrophilic fluorinating reagent, such as e.g. 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis-(tetrafluoroborate) (Selectfluor I) or 1 methyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis-(tetrafluoroborate) (Selectfluor II) or the like, under appropriate conditions. Using appropriate conditions, said halogenation reaction is carried out largely regioselectively to obtain halogenation on the pyrazole moiety of the pyrazolopyrimidone scaffold, i.e. the 3-position of the pyrazolopyrimidone scaffold. The methyl group attached to the pyrimidone moiety of the pyrazolopyrimidone of compounds of formula VI, in which R1 is halogen and A and R2 have the meanings given above, is oxidized under suitable conditions to obtain corresponding compounds of formula V. Said oxidation is carried out in a manner habitual for the skilled person or as described in the following examples using a suitable oxidation reagent, e.g. selenium dioxide, to give largely regioselectively the 5-formyl derivative of formula V. Compounds of formula V, in which R1 is halogen and A and R2 have the meanings given above, are reacted in a nucleophilic addition reaction with compounds of formula R4-M, in which R4 is different from hydrogen and has the meanings given above and M is a suitable metal or metal complex, to give corresponding compounds of formula IV. Said nucleophilic addition reaction can be obtained using organomagnesium halides (Grignard reagents) of formula R4-Mg-X (X = Halogen) with or without further additives (e.g. LiCI or alkyl lithium reagents). Advantageously said reaction is carried out in the presence of alkyl lithium reagents, e.g. methyl lithium, forming in situ more reactive organomagnesium reagents, e.g. lithium trialkyl magnesiates such as R4Me 2 MgLi from 2 equiv. LiMe and 1 equiv. R4-Mg-X. The nucleophilic addition reaction can be carried out in a manner customary for the skilled person or as described in the following examples. When compounds of formula V, in which R1 is bromine, are reacted with Grignard reagents in said nucleophilic addition reaction, debromination of the 3-bromo substituent can be obtained depending on the reaction conditions to give corresponding compounds of formula IV, in which R1 is hydrogen. Said debromination is performed as described in the following examples. Alcohols of formula IV, in which R1 is hydrogen, fluorine or chlorine and A, R2 and R4 have the meanings given above, are converted into the corresponding ketones of formula III by oxidation reaction using an appropriate oxidation reagent, such as e.g. NMO (N-methylmorpholine-N-oxide) / TPAP (tetrapropylammonium perruthenate) or the like, under conditions known for the skilled person or as described in the following examples.

WO 2007/144384 PCT/EP2007/055846 - 33 Compounds of formula III, in which R1 is hydrogen, fluorine or chlorine and A, R2 and R4 have the meanings given above, are subjected to a reductive amination reaction with amines of formula H 2

N

(CH

2 )n-N(R5)R6, in which n has the meanings indicated above and R5 and R6 stand for a suitable temporary protective group PG1 or for the meanings given above with the exception that R5 and R6 are not hydrogen, to afford corresponding compounds of formula II in a manner which is habitual for the skilled person or which is described in the following examples. In more detail, in a first step of the reductive amination reaction the reaction partners are reacted in the presence of a suitable Lewis acid, e.g. a suitable titanium reagent like titanium(IV)isopropoxide, to give the corresponding imine compounds, which are reduced in a second step, such as with the aid of a suitable reducing reagent, e.g. a suitable hydride like a borohydride (e.g. NaCNBH 3 , NaBH 4 or Na(OAc) 3 BH) or the like, Raney Ni or in the presence of hydrogen/transition metal catalyst (e.g. H 2 /Pd). PG1 stands for a suitable temporary protective group for the amino group, for example tert butoxycarbonyl, benzyloxycarbonyl or 4-methoxy-benzyloxycarbonyl or one of those art-known protective groups mentioned in "Protective Groups in Organic Synthesis" by T. Greene and P. Wuts (John Wiley & Sons, Inc. 1999, 3 rd Ed.) or in "Protecting Groups (Thieme Foundations Organic Chemistry Series N Group" by P. Kocienski (Thieme Medical Publishers, 2000). Compounds of formula II, in which R1 is hydrogen, fluorine or chlorine and A, n, R2 and R4 have the meanings given above and R5 and R6 stand for a suitable temporary protective group PG1 as defined above or for the meanings given above with the exception that R5 and R6 are not hydrogen, are benzoylated with compounds of formula B-C(O)-X2, in which B has the meanings given above and X2 is a suitable leaving group (e.g. chlorine), to give corresponding compounds of formula I. Compounds of formula I, in which R1 is hydrogen and A, n, B, R2 and R4 have the meanings given above and R5 and R6 stand for a suitable temporary protective group PG1 as defined above or for the meanings given above with the exception that R5 and R6 are not hydrogen, can be halogenated, particularly brominated, using a suitable halogenating reagent (for bromination e.g. NBS) under appropriate conditions to obtain corresponding further compounds of formula I, in which R1 is halogen. Said halogenation reaction can be carried out according to customary procedures, such as those mentioned above, or as described in the following examples, or analogously or similarly thereto. Compounds of formula I, in which R1, A, n, B, R2 and R4 have the meanings given above and R5 and R6 stand for a suitable temporary protective group PG1 as defined above, are deprotected by removal of said protecting group PG1 in a manner known to the person skilled in the art or as described in the following examples to give corresponding deprotected compounds of formula I. Compounds of formula I, in which R5 and R6 are 1-4C-alkyl, e.g. methyl, and in which R1, A, n, B, R2 and R4 have the meanings given above, can be obtained by the methods described above, starting from compounds of formula I, in which R5 and R6 are 1-4C-alkyl, e.g. methyl, and in which R1, A, n, WO 2007/144384 PCT/EP2007/055846 - 34 B, R2 and R4 have the meanings given above. Alternatively, compounds of formula I, in which R5 and R6 are 1-4C-alkyl, e.g. methyl, and in which R1, A, n, B, R2 and R4 have the meanings given above, can be obtained by alkylation, e.g. methylation, of compounds of formula I, in which R5 and R6 are hydrogen. Alternatively, these compounds of formula I, in which R5 and R6 are 1-4C-alkyl, e.g. methyl, can be obtained by any other method that is known to the person skilled in the art. The invention therefore relates to a process for preparing a compound as described in this application, comprising at least one of the steps (i) benzoylation of a compound of formula II, with the meanings of R1, R2, A, R4, R5 and R6 as indicated for the compounds according to the invention, or with at least one of R5 and R6 being part of a protective group, O O NN AA N ,A NA R2 R 4 R2 R 4 H H R4 R4 RHN N(R5)R6 R O N N(R5)R6 B (II) (I) (ii) halogenation of a compound of formula I wherein R1 = H to give a compound of formula I wherein R1 = halogen, or O O N-. , N A N_ N , NA R2R4 R2 R4 R4 R4 R1 O N N(R5)R6 OR~ N N(R5)R6 B B (I) R1 = H (I) R1 = halogen (iii) optionally the removal of protecting groups represented by at least one of R5 and R6 as indicated under (i). Optionally, compounds of the formula I can be converted into their salts, or, optionally, salts of the compounds of the formula I can be converted into the free compounds. Corresponding processes are customary for the skilled person. When one of the final steps or purification is carried out under the presence of an inorganic or organic acid (e.g. hydrochloric, trifluoroacetic, acetic or formic acid or the like), the compounds of formula I may be obtained - depending on their individual chemical nature and the individual nature of the acid used - as free base or containing said acid in an stoechiometric or non-stoechiometric quantity. The amount of the acid contained can be determined according to art-known procedures, e.g. by titration.

WO 2007/144384 PCT/EP2007/055846 - 35 It is moreover known to the person skilled in the art that if there are a number of reactive centers on a starting or intermediate compound it may be necessary to block one or more reactive centers temporarily by protective groups in order to allow a reaction to proceed specifically at the desired reaction center. A detailed description for the use of a large number of proven protective groups is found, for example, in "Protective Groups in Organic Synthesis" by T. Greene and P. Wuts (John Wiley & Sons, Inc. 1999, 3 rd Ed.) or in "Protecting Groups (Thieme Foundations Organic Chemistry Series N Group" by P. Kocienski (Thieme Medical Publishers, 2000). The substances according to the invention are isolated and purified in a manner known per se, for example by distilling off the solvent under reduced pressure and recrystallizing the residue obtained from a suitable solvent or subjecting it to one of the customary purification methods, such as, for example, column chromatography on a suitable support material. Salts can be obtained by dissolving the free compound in a suitable solvent (e.g. a ketone, such as acetone, methyl ethyl ketone or methyl isobutyl ketone, an ether, such as diethyl ether, tetrahydrofuran or dioxane, a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a low-molecular-weight aliphatic alcohol, such as methanol, ethanol or isopropanol) which contains the desired acid or base, or to which the desired acid or base is then added. The salts can be obtained by filtering, reprecipitating, precipitating with a nonsolvent for the addition salt or by evaporating the solvent. Salts obtained can be converted into the free compounds, which can in turn be converted into salts, by alkalization or by acidification. In this manner, pharmacologically and/or pharmaceutically unacceptable salts can be converted into pharmacologically and/or pharmaceutically acceptable salts. Suitably, the conversions mentioned in this invention can be carried out analogously or similarly to methods which are familiar per se to the person skilled in the art. The person skilled in the art may know on the basis of his/her knowledge and on the basis of those synthesis routes, which are shown and described within the description of this invention, how to find other possible synthesis routes for compounds according to this invention. All these other possible synthesis routes are also part of this invention. The present invention also relates to intermediates (including their salts, stereosiomers as well as salts of these stereoisomers), methods and processes useful in synthesizing compounds according to this invention. Having described the invention in detail, the scope of the present invention is not limited only to those described characteristics or embodiments. As will be apparent to persons skilled in the art, modifications, analogies, variations, derivatizations, homologisations and adaptations to the described invention can be made on the base of art-known knowledge and/or, particularly, on the base of the WO 2007/144384 PCT/EP2007/055846 - 36 disclosure (e.g. the explicite, implicite or inherent disclosure) of the present invention without departing from the spirit and scope of this invention as defined by the appended claims. The following examples illustrate the invention in greater detail without restricting it. Likewise, further compounds according to this invention, of which the preparation is not explicitly described, can be prepared in an analogous or similar manner or in a manner familiar per se to the person skilled in the art using customary process techniques. Any or all of the compounds of formula I according to the present invention which are mentioned as final compounds in the following examples, as well as the salts, stereoisomers and salts of the stereoisomers thereof, are a preferred subject of the present invention. In the examples, m.p. stands for melting point, h for hour(s), min for minutes, conc. for concentrated, calc. for calculated, fnd. for found, EF for elemental formula, MS for mass spectrometry, M for molecular ion in mass spectrometry, TFA for trifluoroacetic acid, and other abbreviations have their meanings customary per se to the skilled person. Further on, according to common practice in stereochemistry, the term "(RS)" characterizes a racemate comprising the one enantiomer having the configuration R and the other enantiomer having the configuration S; each of these enantiomers and their salts in pure form as well as their mixtures including the racemic mixtures is part of this invention.

WO 2007/144384 PCT/EP2007/055846 - 37 Examples Final compounds 1. N-(3-Amino-propyl)-N-[(RS)-1l-(6-benzyl-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5 c]pyrimidin-5-yl)-propyl]-4-methyl-benzamide hydrochloride 150 mg {3-[[1-(6-Benzyl-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl)-propyl]-(1-p-tolyl carbonyl)-amino]-propyl}-carbamic acid tert-butyl ester (0.26 mmol) are solved in 1 ml diethylether. 10 ml HCI in diethylether (ca. 4 N) are added and the suspension is stirred 1 h at ambient temperature. Afterwards the suspension is evaporated, the colorless solid is washed twice with diethylether and dried in vacuo. By this method 120 mg (91%) of a colorless solid are obtained. M.p.: 235-250 0C (decomposition). MS: m/z (MH') = 472.1. 2. N-(3-Amino-propyl)-N-[(RS)-1l-(6-benzyl-3-bromo-2-methyl-7-oxo-6,7-dihydro pyrazolo[1,5-c]pyrimidin-5-yl)-propyl]-4-methyl-benzamide hydrochloride 150 mg {3-[[1-(6-Benzyl-3-bromo-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl)-propyl]-(1 p-tolyl-carbonyl)-amino]-propyl}-carbamic acid tert butyl ester (0.26 mmol) are solved in 1 ml diethylether, 4 ml HCI in diethylether (ca. 4N) are added and the mixture is stirred 1 h at ambient temperature. Afterwards the suspension is evaporated, the colorless solid is washed twice with diethylether and dried in vacuo. By this method 135 mg (88%) of a colorless solid are obtained. M.p.: > 190 0C (decomposition). MS: m/z (MH') = 550.0, 552.0. 3. N-(3-Amino-propyl)-N-[(RS)-1 -(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro pyrazolo[1,5-c]pyrimidin-5-yl)-2-methyl-propyl]-3-methyl-benzamide; isolated as trifluoroacetate salt 0.144 g (1.0 eq) {3-[[1-(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1 ,5-c]pyrimidin-5-yl)-2 methyl-propyl]-(1-m-tolyl-carbonyl)-amino]-propyl}-carbamic acid tert-butyl ester is dissolved in 8 mL dichloromethane and treated with 2 mL trifluoro acetic acid. After stirring 2 hours at ambient temperature the solvent is removed. Addition of diethylether results in a white slurry that is filtered. The precipitate is washed with diethylether and yields after drying 0.108 g (73%) of the title compound as a trifluoroacetate. M.p. 162 oC. MS: m/z (MH ) = 520.1, 522.1.

WO 2007/144384 PCT/EP2007/055846 - 38 4. N-(3-Amino-propyl)-N-[(RS)-1 -(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro pyrazolo[1,5-c]pyrimidin-5-yl)-2-methyl-propyl]-4-fluoro-benzamide; isolated as trifluoroacetate salt 0.090 g (1.0 eq) (3-{[1-(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1 ,5-c]pyrimidin-5-yl)-2 methyl-propyl]-[1-(4-fluoro-phenyl)-carbonyl]-amino}-propyl)-carbamic acid tert-butyl ester is dissolved in 6 mL dichloromethane and treated with 1.5 mL trifluoro acetic acid. After stirring 2 hours at ambient temperature the solvent is removed. Addition of diethylether results in a white slurry that is filtered. The precipitate is washed with diethylether and yields after drying 0.068 g (75%) of the title compound as a trifluoroacetate. M.p. 182 oC. MS: m/z (MH') = 524.1, 526.1. 5. N-(3-Amino-propyl)-N-[(RS)-1 -(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro pyrazolo[1,5-c]pyrimidin-5-yl)-2-methyl-propyl]-4-methoxy-benzamide; isolated as trifluoroacetate salt 0.014 g (1.0 eq) (3-{[1-(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1 ,5-c]pyrimidin-5-yl)-2 methyl-propyl]-[1-(4-methoxy-phenyl)-carbonyl]-amino}-propyl)-carbamic acid tert-butyl ester is dissolved in 0.8 mL dichloromethane and treated with 0.2 mL trifluoro acetic acid. After stirring 2 hours at ambient temperature the solvent is removed. Addition of diethylether results in a white slurry that is filtered. The precipitate is washed with diethylether and yields after drying 0.007 g (48%) of the title compound as a trifluoroacetate. M.p. 149 oC. MS: m/z (MH ) = 536.1, 538.1. 6. N-(3-Amino-propyl)-N-[(RS)-1 -(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro pyrazolo[1,5-c]pyrimidin-5-yl)-2-methyl-propyl]-4-bromo-benzamide; isolated as trifluoroacetate salt 0.153 g (1.0 eq) (3-{[1-(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl)-2 methyl-propyl]-[1-(4-bromo-phenyl)-carbonyl]-amino}-propyl)-carbamic acid tert-butyl ester is dissolved in 10 mL dichloromethane and treated with 2.5 mL trifluoro acetic acid. After stirring 2 hours at ambient temperature the solvent is removed. Addition of diethylether results in a white slurry that is filtered. The precipitate is washed with diethylether and yields after drying 0.086 g (55%) of the title compound as a trifluoroacetate. M.p. 204-205 0C (decomposition). MS: m/z (MH+) = 584.0, 585.9, 587.9.

WO 2007/144384 PCT/EP2007/055846 - 39 7. N-(3-Amino-propyl)-N-[(RS)-1 -(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro pyrazolo[1,5-c]pyrimidin-5-yl)-2-methyl-propyl]-4-chloro-benzamide; isolated as trifluoroacetate salt 0.130 g (1.0 eq) (3-{[1-(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl)-2 methyl-propyl]-[1-(4-chloro-phenyl)-carbonyl]-amino}-propyl)-carbamic acid tert-butyl ester is dissolved in 8 mL dichloromethane and treated with 2 mL trifluoro acetic acid. After stirring 2 hours at ambient temperature the solvent is removed. Addition of diethylether results in a white slurry that is filtered. The precipitate is washed with diethylether and yields after drying 0.075 g (56%) of the title compound as a trifluoroacetate. M.p. 199-201 0C (decomposition). MS: m/z (MH') = 540.0, 542.0, 544.0. 8. N-(3-Amino-propyl)-N-[(RS)-1 -(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro pyrazolo[1,5-c]pyrimidin-5-yl)-2-methyl-propyl]-4-methyl-benzamide hydrochloride 0.129 g (1.0 eq) {3-[[1-(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1 ,5-c]pyrimidin-5-yl)-2 methyl-propyl]-(1-p-tolyl-carbonyl)-amino]-propyl}-carbamic acid tert-butyl ester (compound A8) is dissolved in 20 mL of a 1 M solution of hydrochloric acid in diethylether at ambient temperature. After stirring for 16 hours the precipitate is filtered off and washed with diethylether. This yields after drying 0.083 g (71%) of the title compound as a hydrochloride salt. M.p. 183 oC. MS: m/z (MH ) = 520.0, 522.1. Separation of enantiomers: 8a. (+)-N-(3-Amino-propyl)-N-[1-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5 c]pyrimidin-5-yl)-2-methyl-propyl]-4-methyl-benzamide hydrochloride (assumed (R)-isomer) and 8b. (-)-N-(3-Amino-propyl)-N-[1-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5 c]pyrimidin-5-yl)-2-methyl-propyl]-4-methyl-benzamide hydrochloride (assumed (S)-isomer) 1.79 g of racemic N-(3-Amino-propyl)-N-[(RS)-1l-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro pyrazolo[1,5-c]pyrimidin-5-yl)-2-methyl-propyl]-4-methyl-benzamide hydrochloride are separated into its enantiomers by preparative HPLC (column: CHIRALPAK AD 10 pm, 250 x 20 mm; mobile phase: n-Heptane / ethanol / diethylamine 80:20:0.1 (v/v/v); flow rate: 30 ml/min; detection: UV 230 nm; temperature: 25 oC). The enantiomers elute at 7.49 min and 13.95 min. Both isomers are isolated by solving in dichloromethane and treatment with 4M solution of HCI in dioxane. After stirring for 6 hours at ambient temperature, the solvent is removed. Addition of diethylether results in a white slurry that is filtered. The precipitate is washed with diethylether and dried in vacuo.

WO 2007/144384 PCT/EP2007/055846 - 40 The HCl-salt of the first eluting enantiomer (t = 7.49 min, > 99.5 % ee, 94 % purity, 556 mg, example 8a) has an optical rotation of [0t]D 2 0 = +225 0 (c = 1.02, dichloromethane), a melting point of 203-263 0C (decomposition) and MS: m/z (MH*) = 519.8, 521.9. The HCI-salt of the second eluting enantiomer (t = 13.95 min, > 98 % ee, > 99 % purity, 870 mg, example 8b) has an optical rotation of [Ca]D 2 0 = -205 0 (c = 0.725, dichloromethane), a melting point of 206-233 0C (decomposition) and MS: m/z (MH ) = 520.1, 522.0. The absolute stereochemistry of (+)-N-(3-Amino-propyl)-N-[1-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7 dihydro-pyrazolo[1,5-c]pyrimidin-5-yl)-2-methyl-propyl]-4-methyl-benzamide hydrochloride (8a) is tentatively assigned to the enantiomer with the R-configuration (+)-N-(3-Amino-propyl)-N-[(R)-1-(6 benzyl -3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl )-2-methyl-propyl]-4-methyl benzamide hydrochloride. Consequently, the S-configuration is assigned to the (-)-enantiomer. Furthermore, a variety of salts of compound 8, 8a and 8b is prepared: 8c. N-(3-Amino-propyl)-N-[(S)-1-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5 c]pyrimidin-5-yl)-2-methyl-propyl]-4-methyl-benzamide phosphate 100 mg of (-)-N-(3-Amino-propyl)-N-[(S)-1-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5 c]pyrimidin-5-yl)-2-methyl-propyl]-4-methyl-benzamide (example 8b) are suspended in 1 mL ethanol and heated at reflux until the amine is completely dissolved. 13.1 pL phosphoric acid (85% in water, 1.0 eq) are added and the mixture is stirred for 5 minutes without heating anymore. Evaporation of the solvent and subsequent addition of diethylether yielded (after 30 min ultrasonification) in a white slurry that is filtered and washed with several portions of diethylether. The colorless solid is dried in vacuo to yield 63 mg (53%) of the title compound. There are slight impurities of diethylether and diethylammonium phosphate. M.p.: foaming at 123 0C, melting 160-205 0C (decomposition). MS: m/z (MH ) = 519.9, 522.1. 8d. N-(3-Amino-propyl)-N-[(S)-1-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5 c]pyrimidin-5-yl)-2-methyl-propyl]-4-methyl-benzamide semi fumarate 100 mg of (-)-N-(3-Amino-propyl)-N-[(S)-1-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5 c]pyrimidin-5-yl)-2-methyl-propyl]-4-methyl-benzamide (example 8b) and 22.3 mg of fumaric acid (1.0 eq) are suspended in 1 mL ethanol and heated at reflux for 2 minutes. The mixture is stirred for 5 minutes without heating anymore. Evaporation of the solvent and subsequent addition of diethylether yielded in a white slurry that is filtered and washed with several portions of diethylether. The colorless solid is dried in vacuo to yield 61 mg (55%) of the title compound. There are slight impurities of diethylether and diethylammonium fumarate. The semi fumarate is elucidated by NMR spectroscopy. M.p.: sinter from 140 0C on, melting 195-215 oC (decomposition). MS: m/z (MH ) = 519.9, 522.1.

WO 2007/144384 PCT/EP2007/055846 - 41 8e. N-(3-Amino-propyl)-N-[(S)-1-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5 c] pyrimidin-5-yl)-2-methyl-propyl]-4-methyl-benzamide sulfate 100 mg of (-)-N-(3-Amino-propyl)-N-[(S)-1-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5 c]pyrimidin-5-yl)-2-methyl-propyl]-4-methyl-benzamide (example 8b) are suspended in 1 mL ethanol and heated at reflux until the amine is completely dissolved. 10.2 pL sulfuric acid (1.0 eq) are added and the mixture is stirred for 5 minutes without heating anymore. Evaporation of the solvent and subsequent addition of diethylether yielded in a white slurry (after 15 min ultrasonification) that is filtered and washed with several portions of diethylether. The colorless solid is dried in vacuo to yield 73 mg (62%) of the title compound. There are slight impurities of diethylether and diethylammonium sulfate. M.p.: foaming at 130 0C, melting 198-209 0C (decomposition). MS: m/z (MH') = 519.9, 522.1. 8f. N-(3-Amino-propyl)-N-[(S)-1-(6-benzyl-3-ch Ioro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5 c]pyrimidin-5-yl)-2-methyl-propyl]-4-methyl-benzamide sesqui citrate 100 mg of (-)-N-(3-Amino-propyl)-N-[(S)-1-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5 c]pyrimidin-5-yl)-2-methyl-propyl]-4-methyl-benzamide (example 8b) and 37 mg of citric acid (1.0 eq) are suspended in 1 mL ethanol and heated at reflux for 2 minutes. The mixture is stirred for 5 minutes without heating anymore. Evaporation of the solvent and subsequent addition of diethylether yielded (after 15 min ultrasonification) in a white slurry that is filtered and washed with several portions of diethylether. The colorless solid is dried in vacuo to yield 85 mg (55%) of the title compound. There are slight impurities of diethylether and diethylammonium citrate. The sesqui citrate is elucidated by NMR spectroscopy. M.p.: sinter from 110 C on, melting 160-191 0C (decomposition). MS: m/z (MH ) = 520.0, 522.0. 8g. N-(3-Amino-propyl)-N-[(S)-1-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5 c]pyrimidin-5-yl)-2-methyl-propyl]-4-methyl-benzamide (D)-tartrate 100 mg of (-)-N-(3-Amino-propyl)-N-[(S)-1-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5 c]pyrimidin-5-yl)-2-methyl-propyl]-4-methyl-benzamide (example 8b) and 29 mg of D-tartaric acid (1.0 eq) are suspended in 1 mL ethanol and heated at reflux for 2 minutes. The mixture is stirred for 5 minutes without heating anymore. Evaporation of the solvent and subsequent addition of diethylether yielded (after 20 min ultrasonification) in a white slurry that is filtered and washed with several portions of diethylether. The colorless solid is dried in vacuo to yield 98 mg (76%) of the title compound. There are slight impurities of diethylether and diethylammonium tartrate. The mono tartrate is elucidated by NMR spectroscopy. M.p.: foaming at 100 oC, melting 162-176 0C (decomposition). MS: m/z (MH ) = 519.9, 522.0.

WO 2007/144384 PCT/EP2007/055846 - 42 8h. N-(3-Amino-propyl)-N-[(S)-1-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5 c]pyrimidin-5-yl)-2-methyl-propyl]-4-methyl-benzamide mesylate 100 mg of (-)-N-(3-Amino-propyl)-N-[(S)-1-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5 c]pyrimidin-5-yl)-2-methyl-propyl]-4-methyl-benzamide (example 8b) are suspended in 1 mL ethanol and heated at reflux until the amine is completely dissolved. 12.5 pL methane sulfonic acid (1.0 eq) are added and the mixture is stirred for 5 minutes without heating anymore. Evaporation of the solvent and subsequent addition of diethylether yielded in a white slurry (after 15 min ultrasonification) that is filtered and washed with several portions of diethylether. The colorless solid is dried in vacuo to yield 63 mg (53%) of the title compound. There are slight impurities of diethylether and diethylammonium mesylate. The mono mesylate is elucidated by NMR spectroscopy. M.p.: melting 150-214 0C (decomposition). MS: m/z (MH') = 520.0, 522.0. 8i. N-(3-Amino-propyl)-N-[(S)-1-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5 c]pyrimidin-5-yl)-2-methyl-propyl]-4-methyl-benzamide benzoate 50 mg of (-)-N-(3-Amino-propyl)-N-[(S)-1-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5 c]pyrimidin-5-yl)-2-methyl-propyl]-4-methyl-benzamide (example 8b) are suspended in 1 mL ethanol and heated at reflux until the amine is completely dissolved. 11.8 mg benzoic acid (1.0 eq) are added and the mixture is stirred for 5 minutes without heating anymore. Evaporation of the solvent and subsequent addition of diethylether yielded in a white slurry (after 10 min ultrasonification) that is filtered and washed with several portions of diethylether. The colorless solid is dried in vacuo to yield 29 mg (47%) of the title compound. There are slight impurities of diethylether and diethylammonium benzoate. The mono benzoate is elucidated by NMR spectroscopy. M.p.: sinter from 145 0C, melting 160-175 oC (decomposition). MS: m/z (MH ) = 520.0, 522.0. 8j. N-(3-Amino-propyl)-N-[(R)-1 -(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5 c]pyrimidin-5-yl)-2-methyl-propyl]-4-methyl-benzamide mesylate 60 mg of (-)-N-(3-Amino-propyl)-N-[(R)-1-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5 c]pyrimidin-5-yl)-2-methyl-propyl]-4-methyl-benzamide (example 8a) are suspended in 1 mL ethanol and heated at reflux until the amine is completely dissolved. 7.5 pL methane sulfonic acid (1.0 eq) are added and the mixture is stirred for 5 minutes without heating anymore. Evaporation of the solvent and subsequent addition of diethylether yielded in a white slurry (after 10 min ultrasonification) that is filtered and washed with several portions of diethylether. The colorless solid is dried in vacuo to yield 63 mg (89%) of the title compound. The mono mesylate is elucidated by NMR spectroscopy. M.p.: foaming at 125 oC, melting 190-198 0C (decomposition). MS: m/z (MH ) = 519.9, 521.9.

WO 2007/144384 PCT/EP2007/055846 - 43 8k. N-(3-Amino-propyl)-N-[(R)-1 -(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5 c]pyrimidin-5-yl)-2-methyl-propyl]-4-methyl-benzamide fumarate 59 mg of (-)-N-(3-Amino-propyl)-N-[(R)-1-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5 c]pyrimidin-5-yl)-2-methyl-propyl]-4-methyl-benzamide (example 8a) and 13.2 mg of fumaric acid (1.0 eq) are suspended in 1 mL ethanol and heated at reflux for 2 minutes. The mixture is stirred for 5 minutes without heating anymore. Evaporation of the solvent and subsequent addition of diethylether yielded in a white slurry that is filtered and washed with several portions of diethylether. The colorless solid is dried in vacuo to yield 73 mg (quant.) of the title compound. The mono fumarate is elucidated by NMR spectroscopy. M.p.: sinter from 165 0C on, melting 190-200 oC (decomposition). MS: m/z (MH') = 520.0, 522.0. 81. N-(3-Amino-propyl)-N-[(R)-1 -(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5 c]pyrimidin-5-yl)-2-methyl-propyl]-4-methyl-benzamide tosylate 58 mg of (-)-N-(3-Amino-propyl)-N-[(R)-1-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5 c]pyrimidin-5-yl)-2-methyl-propyl]-4-methyl-benzamide (example 8a) and 21.2 mg of p-toluenesulfonic acid monohydrate (1.0 eq) are suspended in 1 mL ethanol and heated at reflux for 2 minutes. The mixture is stirred for another 5 minutes without heating anymore. Evaporation of the solvent and subsequent addition of diethylether yielded in a white slurry that is filtered and washed with several portions of diethylether. The colorless solid is dried in vacuo to yield 65 mg (85%) of the title compound. The mono tosylate is elucidated by NMR spectroscopy. M.p.: sinter from 160 0C on, melting 170-175 oC (decomposition). MS: m/z (MH ) = 519.9, 522.0. 9. N-(3-Amino-propyl)-N-[(RS)-1 -(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-d i hyd ro pyrazolo[1,5-c]pyrimidin-5-yl)-propyl]-4-methyl-benzamide hydrochloride {3-[[(RS)-1-(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl)-propyl]-(4 methyl-benzoyl)-amino]-propyl}-carbamic acid tert-butyl ester (5.00 g, 8.2 mmol) is treated with HCI/diethylether (4N, 100 mL), stirred for lh at ambient temperature, the solvents are evaporated and the residue is washed with diethylether. 3.90 g (87 %) of the title compuond are obtained as colorless solid with m.p. 201-203 oC. MS: m/z (MH+) = 506.0, 508.1. Separation of enantiomers: WO 2007/144384 PCT/EP2007/055846 - 44 N-(3-Amino-propyl)-N-[(R)-1-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5 yl)-propyl]-4-methyl-benzamide hydrochloride and N-(3-Amino-propyl)-N-[(S)-1-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5 yl)-propyl]-4-methyl-benzamide hydrochloride The separation of the enantiomers of racemic N-(3-amino-propyl)-N-[(RS)-1l-(6-benzyl-3-chloro-2 methyl-7-oxo-6,7-dihydro-pyrazolo[1 ,5-c]pyrimidin-5-yl)-propyl]-4-methyl-benzamide hydrochloride is performed by preparative chromatography: 250 x 20 mm CHIRALPAK AD-H 5pM, 0.7 ml/min of ethanol + 0.1% diethylamine at 40 oC: The enantiomers elute at 6.59 and 15.38 min. Both enantiomers are isolated by mixing with 1N HCI in diethylether and stirring in this mixture. The mixture is evaporated and the residue is dissolved in a mixture of water and acetonitrile and lyophilized. The first eluting enantiomer (6.59 min, example 9a) has a MH' of 506.1 (ee = 97.9%) and at Na 589nm at 200C in CHCI 3 (0.4535 g/100ml) [C]D 2 0 = + 226 °. Thus, enantiomerically pure (+)-N-(3 Amino-propyl)-N-[1-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl ) propyl]-4-methyl-benzamide hydrochloride has [C]D 2 0 = + 231 0 (c=0.4535, CHCI 3 ). The second eluting enantiomer (15.38 min, example 9b) has a MH of 506.0 (ee = 99.7%). The absolute stereochemistry of the (+)-isomer (9a) is tentatively assigned to the enantiomer with the R-configuration. Consequently, the S-configuration is assigned to the (-)-enantiomer (9b). 10. N-(3-Amino-propyl)-N-[(RS)-1l-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro pyrazolo[1,5-c]pyrimidin-5-yl)-2-methyl-propyl]-4-trifluoromethyl-benzamide trifluoroacetate 81 mg of (3-{[(RS)-1-6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1 ,5-c]pyrimidin-5-yl)-2 methyl-propyl]-[1-(4-trifluoromethyl-phenyl)-carbonyl]-amino}-propyl)-carbamic acid tert-butyl ester (compound A1 0) are dissolved in 4 mL dichloromethane and 1.5 mL trifluoroacetic acid. After stirring this mixture for 2 hours at ambient temperature the solvent is removed. Addition of diethylether results in a white slurry that is filtered. The precipitate is washed with diethylether and dried in vacuo. By this method 64 mg (78%) of the title compound are obtained as colorless solid. M.p.: 218 oC. MS: m/z (MH ) = 574.0, 575.9. Using similar procedures to those described herein above but with suitable choice of the starting materials, which are mentioned below, the following compounds of formula I (especially in form of their hydrochloride salts) may be prepared: N-(3-Amino-propyl)-N-[(RS)-1-(6-benzyl-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl ) propyl]-3-methyl-benzamide N-(3-Amino-propyl)-N-[(RS)-1-(6-benzyl-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl ) propyl]-4-fluoro-benzamide WO 2007/144384 PCT/EP2007/055846 - 45 N-(3-Amino-propyl)-N-[(RS)-1-(6-benzyl-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl) propyl]-4-methoxy-benzamide N-(3-Amino-propyl)-N-[(RS)-1-(6-benzyl-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl) propyl]-4-bromo-benzamide N-(3-Amino-propyl)-N-[(RS)-1-(6-benzyl-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl) propyl]-4-chloro-benzamide N-(3-Amino-propyl)-N-[(RS)-1-(6-benzyl-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl) propyl]-4-trifluoromethyl-benzamide N-(3-Amino-propyl)-N-[(RS)-1-(6-benzyl-3-bromo-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin 5-yl)-propyl]-3-methyl-benzamide N-(3-Amino-propyl)-N-[(RS)-1-(6-benzyl-3-bromo-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin 5-yl)-propyl]-4-fluoro-benzamide N-(3-Amino-propyl)-N-[(RS)-1-(6-benzyl-3-bromo-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin 5-yl)-propyl]-4-methoxy-benzamide N-(3-Amino-propyl)-N-[(RS)-1-(6-benzyl-3-bromo-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin 5-yl)-propyl]-4-bromo-benzamide N-(3-Amino-propyl)-N-[(RS)-1-(6-benzyl-3-bromo-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin 5-yl)-propyl]-4-chloro-benzamide N-(3-Amino-propyl)-N-[(RS)-1-(6-benzyl-3-bromo-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin 5-yl)-propyl]-4-trifluoromethyl-benzamide N-(3-Amino-propyl)-N-[(RS)-1-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin 5-yl)-propyl]-3-methyl-benzamide N-(3-Amino-propyl)-N-[(RS)-1-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin 5-yl)-propyl]-4-fluoro-benzamide N-(3-Amino-propyl)-N-[(RS)-1-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin 5-yl)-propyl]-4-methoxy-benzamide N-(3-Am ino-propyl)-N-[(RS)-1 -(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1, 5-c]pyrimidin 5-yl)-propyl]-4-bromo-benzamide N-(3-Amino-propyl)-N-[(RS)-1-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin 5-yl)-propyl]-4-chloro-benzamide N-(3-Amino-propyl)-N-[(RS)-1-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin 5-yl)-propyl]-4-trifluoromethyl-benzamide N-(3-Amino-propyl)-N-[(RS)-1-(6-benzyl-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl)-2 methyl-propyl]-4-methyl-benzamide N-(3-Amino-propyl)-N-[(RS)-1-(6-benzyl-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl)-2 methyl-propyl]-3-methyl-benzamide N-(3-Amino-propyl)-N-[(RS)-1-(6-benzyl-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl)-2 methyl-propyl]-4-fluoro-benzamide WO 2007/144384 PCT/EP2007/055846 - 46 N-(3-Am ino-propyl )-N-[(RS)-1 -(6-benzyl-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1 ,5-c]pyrimidin-5-y )-2 methyl-propyl]-4-methoxy-benzamide N-(3-Am ino-propyl)-N-[(RS)-1 -(6-benzyl-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1 ,5-c]pyrimidin-5-y )-2 methyl-propyl]-4-bromo-benzamide N-(3-Am ino-propyl)-N-[(RS)-1 -(6-benzyl-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1 ,5-c]pyrimidin-5-y )-2 methyl-propyl]-4-chloro-benzamide N-(3-Am ino-propyl)-N-[(RS)-1 -(6-benzyl-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1 ,5-c]pyrimidin-5-y )-2 methyl-propyl]-4-trifluoromethyl-benzamide N-(3-Am ino-propyl)-N-[(RS)-1 -(6-benzyl-3-bromo-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-cipyrimidin 5-yI )-2-methyl-propyl]-4-methyl-benzamide N-(3-Am ino-propyl)-N-[(RS)-1 -(6-benzyl-3-bromo-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-cipyrimidin 5-yI )-2-methyl-propyl]-3-methyl-benzamide N-(3-Am ino-propyl)-N-[(RS)-1 -(6-benzyl-3-bromo-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-cipyrimidin 5-yI )-2-methyl-propyl]-4-fluoro-benzamide N-(3-Am ino-propyl)-N-[(RS)-1 -(6-benzyl-3-bromo-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-cipyrimidin 5-yI )-2-m ethyl -pro pyl]-4-m ethoxy-be nza mid e N-(3-Am ino-propyl)-N-[(RS)-1 -(6-benzyl-3-bromo-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-cipyrimidin 5-yI )-2-m ethyl -pro pyl]-4-bro mo-be nza mid e N-(3-Am ino-propyl)-N-[(RS)-1 -(6-benzyl-3-bromo-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-cipyrimidin 5-yI )-2-m ethyl -pro pyl]-4-chlIoro-be nza mid e N-(3-Am ino-propyl)-N-[(RS)-1 -(6-benzyl-3-bromo-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-cipyrimidin 5-yI )-2-m ethyl -pro pyl]-4-trifl uo ro meth yl-be nza mid e N-(3-Am ino-propyl)-N-[(RS)-1 -(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-cipyrimidin 5-yI )-2-methyl-butyl]-4-methyl-benzamide N-(3-Am ino-propyl)-N-[(RS)-1 -(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-cipyrimidin 5-yI )-2-methyl-butyl]-3-methyl-benzamide N-(3-Am ino-propyl)-N-[(RS)-1 -(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-cipyrimidin 5-yI )-2-methyl-butyl]-4-fluoro-benzamide N-(3-Am ino-propyl)-N-[(RS)-1 -(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-cipyrimidin 5-yI )-2-methyl-butyl]-4-methoxy-benzamide N-(3-Am ino-propyl)-N-[(RS)-1 -(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-cipyrimidin 5-yI )-2-methyl-butyl]-4-bromo-benzamide N-(3-Am ino-propyl)-N-[(RS)-1 -(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-cipyrimidin 5-yI )-2-methyl-butyl]-4-chloro-benzamide N-(3-Am ino-propyl)-N-[(RS)-1 -(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-cipyrimidin 5-yI )-2-methyl-butyl]-4-trifl uoromethyl-benzamide WO 2007/144384 PCT/EP2007/055846 - 47 11. N-[(RS)-(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl) methyl-propyl]-N-(3-dimethylamino-propyl)-4-methyl-benzamide A solution of 89 mg (1.0 eq) 6-Benzyl-3-chloro-5-[(RS)-l-(3-dimethylamino-propylamino)-2-methyl propyl]-2-methyl-6H-pyrazolo[1,5-c]pyrimidin-7-one (compound Al l), 87 pL (3.0 eq) triethylamine and 33 pL (1.2 eq) 4-methylbenzoyl chloride in 2 mL dichloromethane is stirred for 16 hours at ambient temperature. The product is extracted between dichloromethane and a saturated NaHCO 3 -solution, the organic phase is dried over magnesium sulfate and the crude product is purified by preparative HPLC. 20 mg (17%) of the title compound is isolated by means of lyophilization. M.p.: sinter at 71-72 0C and melting at 88-91 oC. MS: m/z (MH') = 548.1, 550.2. Using similar procedures to those described for Example 11 but with suitable choice of the starting materials, which are mentioned below, and the appropriate benzoic acid derivatives the following compounds of formula I may be prepared: N-[(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl )-methyl-propyl]-N-(3 dimethylamino-propyl)-3-methyl-benzamide N-[(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl )-methyl-propyl]-N-(3 dimethylamino-propyl)-4-fluoro-benzamide N-[(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl )-methyl-propyl]-N-(3 dimethylamino-propyl)-4-methoxy-benzamide N-[(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl )-methyl-propyl]-N-(3 dimethylamino-propyl)-4-bromo-benzamide N-[(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl )-methyl-propyl]-N-(3 dimethylamino-propyl)-4-chloro-benzamide N-[(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl)-methyl-propyl]-N-(3 dimethylamino-propyl)-4-trifluoromethyl-benzamide 12. N-(4-Amino-butyl)-N-[(RS)-1l-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5 c]pyrimidin-5-yl)-2-methyl-propyl]-4-methyl-benzamide trifluoroacetate 126 mg of {4-[[(RS)-1-(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1 ,5-c]pyrimidin-5-yl)-2 methyl-propyl]-(1-p-tolyl-carbonyl)-amino]-butyl}-carbamic acid tert-butyl ester (compound A12) are dissolved in 4 mL dichloromethane and 1 mL trifluoroacetic acid. After stirring this mixture for 2 hours at ambient temperature the solvent is removed. Addition of diethylether results in a white slurry that is filtered. The precipitate is washed with diethylether and dried in vacuo. By this method 85 mg (66%) of the title compound are obtained as colorless foam. M.p.: 179-182 oC. MS: m/z (MH ) = 534.1, 536.1.

WO 2007/144384 PCT/EP2007/055846 - 48 13. N-(2-Amino-ethyl)-N-[(RS)-1l-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5 c]pyrimidin-5-yl)-2-methyl-propyl]-4-methyl-benzamide 164 mg of {2-[[(RS)-1-(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1 ,5-c]pyrimidin-5-yl)-2 methyl-propyl]-(1-p-tolyl-carbonyl)-amino]-ethyl}-carbamic acid tert-butyl ester (compound A13) are dissolved in 4 mL dichloromethane and 1 mL trifluoroacetic acid. After stirring this mixture for 1 hour at ambient temperature the solvent is removed. Addition of dichloromethane and basification with saturated aqueous NaHCO 3 -solution followed by extraction of the aqueous phase with dichloromethane results after drying over magnesium sulfate and evaporation of the solvent in 145 mg (quant.) of the title compound. M.p.: 119-120 oC. MS: m/z (MH') = 506.1, 507.9. 14. N-(2-Amino-ethyl)-N-[(RS)-1l-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5 c]pyrimidin-5-yl)-2-methyl-propyl]-4-methyl-benzamide trifluoroacetate 125 mg of {2-[[(RS)-1-(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1 ,5-c]pyrimidin-5-yl)-2 methyl-propyl]-(1-p-tolyl-carbonyl)-amino]-ethyl}-carbamic acid tert-butyl ester (compound A13) are dissolved in 4 mL dichloromethane and 1 mL trifluoroacetic acid. After stirring this mixture for 2 hours at ambient temperature the solvent is removed. Addition of diethylether results in a white slurry that is filtered. The precipitate is washed with diethylether and dried in vacuo. By this method 70 mg (55%) of the title compound are obtained as colorless solid. M.p.: 173-174 oC. MS: m/z (MH') = 506.0, 508.0. 15. N-[(RS)-(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl) methyl-propyl]-N-(2-dimethylamino-ethyl)-4-methyl-benzamide A mixture of 70 mg N-(2-Amino-ethyl)-N-[(RS)-1l-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro pyrazolo[1,5-c]pyrimidin-5-yl)-2-methyl-propyl]-4-methyl-benzamide (compound 13), 33 pL formalin and 52 pL formic acid is heated for 8 hours at 100 0C. After cooling, the crude product is purified by silica gel flash chromatography using a gradient of dichloromethane and methanol from 100:0 to 90:10. This yielded 35 mg (46%) of the title compound as colorless solid. M.p.: 94-95 oC. MS: m/z (MH ) = 534.0, 536.0. 16. N-(3-Amino-propyl)-N-[(RS)-1l-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo [1,5-c]pyrimidin-5-yl)-1l-cyclobutyl-methyl]-4-methyl-benzamide trifluoroacetate 159 mg of {3-[[(RS)-1l-(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl)-l cyclobutyl-methyl]-(1-p-tolyl-carbonyl)-amino]-propyl}-carbamic acid tert-butyl ester (compound A14) are dissolved in 4 mL dichloromethane and 1 mL trifluoroacetic acid. After stirring this mixture for 1 hour at ambient temperature the solvent is removed. Addition of diethylether results in a white slurry WO 2007/144384 PCT/EP2007/055846 - 49 that is filtered. The precipitate is washed with diethylether and dried in vacuo. By this method 140 mg (87%) of the title compound are obtained as colorless solid. M.p.: sinter at 158-179 0C and melting at 180-185 oC. MS: m/z (MH') = 532.0, 534.1. 17. N-(3-Amino-propyl)-N-[(RS)-1l-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro pyrazolo[1,5-c]pyrimidin-5-yl)-2-methyl-butyl]-4-methyl-benzamide trifluoroacetate 60 mg of {3-[[(RS)-1-(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1 ,5-c]pyrimidin-5-yl)-2 methyl-butyl]-(1-p-tolyl-carbonyl)-amino]-propyl}-carbamic acid tert-butyl ester (compound A15) are dissolved in 4 mL dichloromethane and 1 mL trifluoroacetic acid. After stirring this mixture for 1.5 hours at ambient temperature the solvent is removed. Addition of diethylether results in a white slurry that is filtered. The precipitate is washed with diethylether and dried in vacuo. By this method 43 mg (70%) of the title compound are obtained as colorless solid. M.p.: 179-182 oC. MS: m/z (MH ) = 534.0, 535.8. 18. N-(3-Amino-propyl)-N-[(RS)-1l-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro pyrazolo[1,5-c]pyrimidin-5-yl)-1l-cyclopropyl-methyl]-4-methyl-benzamide hydrochloride 80 mg of {3-[[(RS)-1-(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1 ,5-c]pyrimidin-5-yl )-1 cyclopropyl-methyl]-(1-p-tolyl-carbonyl)-amino]-propyl}-carbamic acid tert-butyl ester (compound A16) dissolved in 4 mL dichloromethane and 1 mL trifluoroacetic acid. After stirring this mixture for 2 hours at ambient temperature the solvent is removed. The residue is dissolved in dichloromethane and treated with saturated aqueous NaHCO 3 -solution. Extraction of the aqueous layer followed by drying over MgSO4 results in the free base of the title compound. The solvent is evaporated and the residue is treated with 1M HCI in diethylether. The precipitate is filtered, washed with diethylether and dried in vacuo. This afforded 18 mg (26%) of the title compound as colorless solid. M.p.: 156-158 oC. MS: m/z (MH ) = 518.0, 520.1. 19. N-(3-Amino-propyl)-N-[(RS)-1l-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro pyrazolo[1,5-c]pyrimidin-5-yl)-1l-cyclopropyl-methyl]-4-bromo-benzamide trifluoroacetate 34 mg of (3-{[(RS)-1-(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1 ,5-c]pyrimidin-5-yl )-1 cyclopropyl-methyl]-[1-(4-bromo-phenyl)-carbonyl]-amino}-propyl)-carbamic acid tert-butyl ester (compound A17) are dissolved in 4 mL dichloromethane and 1 mL trifluoroacetic acid. After stirring this mixture for 2 hours at ambient temperature the solvent is removed. Addition of diethylether results in a white slurry that is filtered. The precipitate is washed with diethylether and dried in vacuo. By this method 21 mg (60%) of the title compound are obtained as colorless solid. M.p.: 178-180 0C (decomposition). MS: m/z (MH ) = 581.9, and also MH++2 and MH++4.

WO 2007/144384 PCT/EP2007/055846 - 50 20. N-(3-Amino-propyl)-N-[(RS)-1 -(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro pyrazolo[1,5-c]pyrimidin-5-yl)-2-methyl-propyl]-3-fluoro-4-methyl-benzamide trifluoroacetate 104 mg of (3-{[(RS)-1-(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1 ,5-c]pyrimidin-5-yl)-2 methyl-propyl]-[1-(3-fluoro-4-methyl-phenyl)-carbonyl]-amino}-propyl)-carbamic acid tert-butyl ester (compound A18) are dissolved in 4 mL dichloromethane and 1 mL trifluoroacetic acid. After stirring this mixture for 1.5 hours at ambient temperature the solvent is removed. Addition of diethylether results in a white slurry that is filtered. The precipitate is washed with diethylether and dried in vacuo. By this method 61 mg (57%) of the title compound are obtained as pale yellow solid. M.p.: 140-158 0C (decomposition). MS: m/z (MH') = 537.9, 540.0. 21. N-(3-Amino-propyl)-N-[(RS)-1 -(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro pyrazolo[1,5-c]pyrimidin-5-yl)-2-methyl-propyl]-2-fluoro-4-methyl-benzamide trifluoroacetate 83 mg of (3-{[(RS)-1-(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1 ,5-c]pyrimidin-5-yl)-2 methyl-propyl]-[1-(2-fluoro-4-methyl-phenyl)-carbonyl]-amino}-propyl)-carbamic acid tert-butyl ester (compound A19) are dissolved in 4 mL dichloromethane and 1 mL trifluoroacetic acid. After stirring this mixture for 2 hours at ambient temperature the solvent is removed. Addition of diethylether results in a white slurry that is filtered. The precipitate is washed with diethylether and dried in vacuo. By this method 39 mg (46%) of the title compound are obtained as colorless powder. M.p.: sinter 178-181 0C and melting at 182-192 oC. MS: m/z (MH') = 538.0, 539.9. 22. N-(3-Amino-propyl)-N-[(RS)-1 -(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro pyrazolo[1,5-c]pyrimidin-5-yl)-2-methyl-propyl]-3,4-dichloro-benzamide trifluoroacetate 88 mg of (3-{[(RS)-1-(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1 ,5-c]pyrimidin-5-yl)-2 methyl-propyl]-[1-(3,4-dichloro-phenyl)-carbonyl]-amino}-propyl)-carbamic acid tert-butyl ester (compound A20) are dissolved in 2 mL dichloromethane and 0.5 mL trifluoroacetic acid. After stirring this mixture for 1 hour at ambient temperature the solvent is removed. Addition of diethylether results in a white slurry that is filtered. The precipitate is washed with diethylether and dried in vacuo. By this method 37 mg (41%) of the title compound are obtained as colorless solid. M.p.: 184-185 oC. MS: m/z (MH') = 573.8, 575.9, 577.8. 23. N-(3-Amino-propyl)-N-[(RS)-1 -(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro pyrazolo[1,5-c]pyrimidin-5-yl)-2-methyl-propyl]-2,3-dichloro-benzamide trifluoroacetate 67 mg of (3-{[(RS)-1-(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1 5-c]pyrimidin-5-yl )-2 methyl-propyl]-[1-(2,3-dichloro-phenyl)-carbonyl]-amino}-propyl)-carbamic acid tert-butyl ester (compound A21) are dissolved in 2 mL dichloromethane and 0.5 mL trifluoroacetic acid. After stirring this mixture for 1 hour at ambient temperature the solvent is removed. Addition of diethylether results WO 2007/144384 PCT/EP2007/055846 - 51 in a white slurry that is filtered. The precipitate is washed with diethylether and dried in vacuo. By this method 31 mg (46%) of the title compound are obtained as colorless solid. M.p.: 187-188 oC. MS: m/z (MH') = 573.9, 576.0, 577.8. 24. N-(3-Amino-propyl)-N-[(RS)-1l-(6-benzyl-3-bromo-2-methyl-7-oxo-6,7-dihydro pyrazolo[1,5-c]pyrimidin-5-yl)-2-methyl-propyl]-4-methyl-benzamide hydrochloride 87 mg of {3-[[(RS)-1-(6-Benzyl-3-bromo-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1 ,5-c]pyrimidin-5-yl)-2 methyl-propyl]-(4-methyl-benzoyl)-amino]-propyl}-carbamic acid tert-butyl ester (compound A22) are dissolved in 4 M HCI in dioxane. After stirring this mixture for 3 hour at ambient temperature the solvent is removed. By this method 78 mg (quant.) of the title compound are obtained as colorless solid. MS: m/z (MH ) = 563.9, 566.0. 25. N-(3-Amino-propyl)-N-[(RS)-1 -(6-benzyl-3-fluoro-2-methyl-7-oxo-6,7-dihydro pyrazolo[1,5-c]pyrimidin-5-yl)-2-methyl-propyl]-4-methyl-benzamide hydrochloride 155 mg of {3-[[(RS)-1-(6-Benzyl-3-fluoro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1 ,5-c]pyrimidin-5-yl)-2 methyl-propyl]-(1-p-tolyl-carbonyl)-amino]-propyl}-carbamic acid tert-butyl ester (compound A24) are dissolved in 2 mL dioxane and treated with 4 M HCI in dioxane (3 mL). After stirring this mixture for 3 hour at ambient temperature the solvent is removed. By this method 80 mg (57%) of the title compound are obtained as colorless solid. MS: m/z (MH ) = 504.0.

WO 2007/144384 PCT/EP2007/055846 - 52 Starting materials: Some of the compounds in this section have an optionally substituted benzoyl group, which may be designated in the systematic name as phenyl-carbonyl group or alternatively, as a phenyl-methanoyl group. A special substituted phenyl group in this connection is the m-tolyl group (3-methyl-phenyl) or the p-tolyl group (4-methyl-phenyl). Al. {3-[[(RS)-l -(6-Benzyl-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl)-propyl] (4-methyl-benzoyl)-amino]-propyl}-carbamic acid tert-butyl ester 393 mg {3-[(RS)-1-(6-Benzyl-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1 ,5-c]pyrimidin-5-yl)-propylamino] propyl}-carbamic acid tert-butyl ester (0.87 mmol) (compound B1) are solved in 5 ml dichlormethane, afterwards 0.37 ml triethylamine (2.61 mmol) and 161 mg 4-Methyl-benzoyl chloride (1.04 mmol) are added and the reaction mixture is stirred 4 h at ambient temperature. The product is extracted between CH 2 0 2 and saturated NaHCO 3 -solution, the organic phase is dried over sodium sulphate and the crude product is purified by silica gel flash chromatography. By this method 377 mg (77%) of a colorless solid are obtained. A2. {3-[[(RS)-1 -(6-Benzyl-3-bromo-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl) propyl]-(4-methyl-benzoyl)-amino]-propyl}-carbamic acid tert-butyl ester 220 mg {3-[[(RS)-1-(6-Benzyl-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1 ,5-c]pyrimidin-5-yl)-propyl]-(1-p tolyl-carbonyl)-amino]-propyl}-carbamic acid tert-butyl ester (0.38 mmol) (compound Al) are solved in 2ml dichloromethane. 70 mg N-Bromo-succinimide (0.39 mmol) are added and the reaction mixture is stirred 4 h at ambient temperature. The product is extracted between CH 2 0 2 and saturated NaHCO 3 solution. The organic layer is dried over sodium sulfate. The solvents are evaporated and the crude product is purified by silica gel flash chromatography. By this method 170 mg ( 69 %) of a colorless solid are obtained. M.p.: 95-97 oC. A3. {3-[[(RS)-1 -(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl) 2-methyl-propyl]-(1-m-tolyl-carbonyl)-amino]-propyl}-carbamic acid tert-butyl ester 0.300 g (1.0 eq) {3-[(RS)-1-(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1 ,5-c]pyrimidin-5 yl)-2-methyl-propylamino]-propyl}-carbamic acid tert-butyl ester (compound B3), 0.095 mL (1.2 eq) m toluoyl chloride and 0.248 mL (3.0 eq) triethylamine are dissolved in 3 mL dichloromethane and stirred for 48 hours at ambient temperature. After addition of 10 mL dichloromethane and 10 mL saturated aqueous sodium hydrogen carbonate solution the phases are separated and the aqueous phase is extracted with dichloromethane. The combined organic phase is dried over magnesium sulfate and the solvent is evaporated in vacuo. Purification of the crude product by silica gel flash chromatography using n-hexane and ethyl acetate in a mixture of 3:2 povides a mixture of starting material and the title compound. A second silica gel flash chromatography using a gradient of n-hexane, ethyl acetate and WO 2007/144384 PCT/EP2007/055846 - 53 acetic acid from 39:59:2 to 0:100:0 yields 0.151 g (41%) of the title compound as a white solid. Furthermore 0.105 g (35%) of the starting material is recovered. M.p. 83.9 oC. MS: m/z (MH') = 619.9, 621.9. A4. (3-{[(RS)-1 -(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl) 2-methyl-propyl]-[1-(4-fluoro-phenyl)-carbonyl]-amino}-propyl)-carbamic acid tert-butyl ester 0.300 g (1.0 eq) {3-[(RS)-1-(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1 ,5-c]pyrimidin-5 yl)-2-methyl-propylamino]-propyl}-carbamic acid tert-butyl ester (compound B3), 0.085 mL (1.2 eq) 4 fluorobenzoyl chloride and 0.248 mL (3.0 eq) triethylamine are dissolved in 3 mL dichloromethane and stirred for 48 hours at ambient temperature. After addition of 10 mL dichloromethane and 10 mL saturated aqueous sodium hydrogen carbonate solution the phases are separated and the aqueous phase is extracted with dichloromethane. The combined organic phase is dried over magnesium sulfate and the solvent is evaporated in vacuo. Purification of the crude product by silica gel flash chromatography using gradient of n-hexane, ethyl acetate and acetic acid from 59:39:2 to 0:100:0 provides the title compound with some impurities and the pure starting material (0.190 g, 63%). A second silica gel flash chromatography using a gradient of n-hexane and ethyl acetate from 100:0 to 50:50 yields 0.096 g (26%) of the title compound as a white solid. M.p. 143.0 0C (foam). MS: m/z (MH ) = 623.9, 625.9. A5. (3-{[(RS)-1 -(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl) 2-methyl-propyl]-[1-(4-methoxy-phenyl)-carbonyl]-amino}-propyl)-carbamic acid tert-butyl ester 0.300 g (1.0 eq) {3-[(RS)-1-(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1 ,5-c]pyrimidin-5 yl)-2-methyl-propylamino]-propyl}-carbamic acid tert-butyl ester (compound B3), 0.122 g (1.2 eq) p anisoyl chloride and 0.248 mL (3.0 eq) triethylamine are dissolved in 3 mL dichloromethane and stirred for 48 hours at ambient temperature. After addition of 10 mL dichloromethane and 10 mL saturated aqueous sodium hydrogen carbonate solution the phases are separated and the aqueous phase is extracted with dichloromethane. The combined organic phase is dried over magnesium sulfate and the solvent is evaporated in vacuo. Purification of the crude product by silica gel flash chromatography using of n-hexane, ethyl acetate and acetic acid in a mixture of 39:59:2 yields 0.018 g (5%) of the title compound as a white solid. M.p. 115.7 0C (decomposition). MS: m/z (MH ) = 635.9, 637.9. A6. (3-{[(RS)-1 -(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl) 2-methyl-propyl]-[1-(4-bromo-phenyl)-carbonyl]-amino}-propyl)-carbamic acid tert-butyl ester 0.300 g (1.0 eq) {3-[(RS)-1-(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1 ,5-c]pyrimidin-5 yl)-2-methyl-propylamino]-propyl}-carbamic acid tert-butyl ester (compound B3), 0.158 mg (1.2 eq) p bromobenzoyl chloride and 0.248 mL (3.0 eq) triethylamine are dissolved in 3 mL dichloromethane WO 2007/144384 PCT/EP2007/055846 - 54 and stirred for 48 hours at ambient temperature. After addition of 10 mL dichloromethane and 10 mL saturated aqueous sodium hydrogen carbonate solution the phases are separated and the aqueous phase is extracted with dichloromethane. The combined organic phase is dried over magnesium sulfate and the solvent is evaporated in vacuo. Purification of the crude product by silica gel flash chromatography using n-hexane and ethyl acetate in a mixture of 3:2 povides a mixture of starting material and the title compound. A second silica gel flash chromatography using a gradient of n hexane, ethyl acetate and acetic acid from 39:59:2 to 0:100:0 yields 0.159 g (39%) of the title compound as a white solid. Furthermore 0.180 g (60%) of the starting material are recovered. M.p. 96 0C (foam). MS: m/z (MH') = 683.8, 685.8, 687.8. A7. (3-{[(RS)-1 -(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl) 2-methyl-propyl]-[1-(4-chloro-phenyl)-carbonyl]-amino}-propyl)-carbamic acid tert-butyl ester 0.300 g (1.0 eq) {3-[(RS)-1-(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1 ,5-c]pyrimidin-5 yl)-2-methyl-propylamino]-propyl}-carbamic acid tert-butyl ester (compound B3), 0.092 mL (1.2 eq) 4 chlorobenzoyl chloride and 0.248 mL (3.0 eq) triethylamine are dissolved in 3 mL dichloromethane and stirred for 48 hours at ambient temperature. After addition of 10 mL dichloromethane and 10 mL saturated aqueous sodium hydrogen carbonate solution the phases are separated and the aqueous phase is extracted with dichloromethane. The combined organic phase is dried over magnesium sulfate and the solvent is evaporated in vacuo. Purification of the crude product by silica gel flash chromatography using n-hexane and ethyl acetate in a mixture of 3:2 povides a mixture of starting material and the title compound. A second silica gel flash chromatography using a gradient of n hexane, ethyl acetate and acetic acid from 39:59:2 to 0:100:0 yields 0.160 g (42%) of the title compound as a white solid. Furthermore 0.170 g (57%) of the starting material is recovered. M.p. 93 0C (foam). MS: m/z (MH ) = 639.9, 641.8, MH +4. A8. {3-[[(RS)-1 -(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl) 2-methyl-propyl]-(1-p-tolyl-carbonyl)-amino]-propyl}-carbamic acid tert-butyl ester 0.405 g (1.0 eq) {3-[(RS)-1-(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1 5-c]pyrimidin-5 yl)-2-methyl-propylamino]-propyl}-carbamic acid tert-butyl ester (compound B3), 0.336 mL (1.2 eq) 4 methylbenzoyl chloride and 0.128 mL (3.0 eq) triethylamine are dissolved in 4 mL dichloromethane and stirred for 16 hours at ambient temperature. After addition of 10 mL dichloromethane and 10 mL saturated aqueous sodium hydrogen carbonate solution the phases are separated and the aqueous phase is extracted with dichloromethane. The combined organic phase is dried over magnesium sulfate and the solvent is evaporated in vacuo. Purification of the crude product by silica gel flash chromatography using a gradient of n-hexane, ethyl acetate and acetic acid from 39:59:2 to 0:100:0 yield 0.145 g (29%) of the title compound as a white solid. Furthermore 0.259 g (64%) of the starting material are recovered. M.p. 92-94 oC, sinter 82 oC.

WO 2007/144384 PCT/EP2007/055846 - 55 MS: m/z (MH') = 619.9, MH++2. A9. {3-[[(RS)-l -(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl) propyl]-(4-methyl-benzoyl)-amino]-propyl}-carbamic acid tert-butyl ester {3-[1-(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl)-propylamino] propyl}-carbamic acid tert-butyl ester (4.00 g, 8.2 mmol) (compound B2) is dissolved in dichlormethane (40 mL), treated with triethylamine (3.6 mL, 24.6 mmol) and 4-methylbenzoyl chloride (1.30 mL, 9.8 mmol) and stirred 15 h at ambient temperature. It is diluted with dichlormethane, washed with aqueous NaHCO 3 -solution and the organic phase is dried. After evaporation, the residue is purified by chromatography. 4.5 g (90 %) of a colorless solid of m.p. 80-82 0C is obtained. Al 0. (3-{[(RS)-l -(6-Benzyl-3-ch loro-2-methyl-7-oxo-6,7-d i hyd ro-pyrazolo[1,5-c] pyrimidin-5-yl) 2-methyl-propyl]-[1-(4-trifl uoro methyl-phenyl)-carbonyl]-amino}-propyl)-carbamic acid tert butyl ester A solution of 200 mg (1.0 eq) {3-[(RS)-1l-(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5 c]pyrimidin-5-yl)-2-methyl-propylamino]-propyl}-carbamic acid tert-butyl ester (compound B3), 88 pL (1.5 eq) 4-(trifluoromethyl)-benzoyl chloride with catalytic amount of DMAP in 10 mL pyridine is heated for 16 hours at 70 0C. Evaporation of the pyridine followed by two times coevaporation with toluene results in the crude product. This material is purified by silica gel flash chromatography using a gradient of n-hexane and ethyl acetate from 100:0 to 50:50. By this method 102 mg (38%) of the title compound are obtained as a colorless solid. M.p.: 106-108 oC. MS: m/z (MH ) = 673.9, 675.8. The following compounds may be prepared by benzoylation reaction of compound B1 with the appropriate benzoic acid derivative analogously or similarly as described for compounds Al and A3 to A9: {3-[[(RS)-1-(6-Benzyl-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl)-propyl]-(3-methyl benzoyl)-amino]-propyl}-carbamic acid tert-butyl ester {3-[[(RS)-1-(6-Benzyl-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl)-propyl]-(4-fluoro benzoyl)-amino]-propyl}-carbamic acid tert-butyl ester {3-[[(RS)-1-(6-Benzyl-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl)-propyl]-(4-methoxy benzoyl)-amino]-propyl}-carbamic acid tert-butyl ester {3-[[(RS)-1-(6-Benzyl-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl)-propyl]-(4-bromo benzoyl)-amino]-propyl}-carbamic acid tert-butyl ester {3-[[(RS)-1-(6-Benzyl-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl)-propyl]-(4-chloro benzoyl)-amino]-propyl}-carbamic acid tert-butyl ester {3-[[(RS)-1-(6-Benzyl-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl)-propyl]-(4 trifluoromethyl-benzoyl)-amino]-propyl}-carbamic acid tert-butyl ester WO 2007/144384 PCT/EP2007/055846 - 56 The following compounds may be prepared by bromination of the appropriate compounds mentioned afore analogously or similarly as described for compound A2: {3-[[(RS)-1-(6-Benzyl-3-bromo-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl)-propyl]-(3 methyl-benzoyl)-amino]-propyl}-carbamic acid tert-butyl ester {3-I[[(RS)-1-(6-Benzyl-3-bromo-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl)-propyl]-(4 fluoro-benzoyl)-amino]-propyl}-carbamic acid tert-butyl ester {3-[[(RS)-1-(6-Benzyl-3-bromo-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl)-propyl]-(4 methoxy-benzoyl)-amino]-propyl}-carbamic acid tert-butyl ester {3-[[(RS)-1-(6-Benzyl-3-bromo-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl)-propyl]-(4 bromo-benzoyl)-amino]-propyl}-carbamic acid tert-butyl ester {3-[[(RS)-1-(6-Benzyl-3-bromo-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl)-propyl]-(4 chloro-benzoyl)-amino]-propyl}-carbamic acid tert-butyl ester {3-[[(RS)-1-(6-Benzyl-3-bromo-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl)-propyl]-(4 trifluoromethyl-benzoyl)-amino]-propyl}-carbamic acid tert-butyl ester The following compounds may be prepared by benzoylation reaction of compound B2 with the appropriate benzoic acid derivative analogously or similarly as described for compounds Al and A3 to A9: {3-[[(RS)-1-(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl)-propyl]-(3 methyl-benzoyl)-amino]-propyl}-carbamic acid tert-butyl ester {3-[[(RS)-1-(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl)-propyl]-(4 fluoro-benzoyl)-amino]-propyl}-carbamic acid tert-butyl ester {3-[[(RS)-1-(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl)-propyl]-(4 methoxy-benzoyl)-amino]-propyl}-carbamic acid tert-butyl ester {3-[[(RS)-1-(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl)-propyl]-(4 bromo-benzoyl)-amino]-propyl}-carbamic acid tert-butyl ester {3-[[(RS)-1-(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl)-propyl]-(4 chloro-benzoyl)-amino]-propyl}-carbamic acid tert-butyl ester {3-[[(RS)-1-(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl)-propyl]-(4 trifluoromethyl-benzoyl)-amino]-propyl}-carbamic acid tert-butyl ester The following compounds may be prepared by benzoylation reaction of compound B4 with the appropriate benzoic acid derivative analogously or similarly as described for compounds Al and A3 to A9: {3-[[(RS)- 1-(6-Benzyl-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl)-2-methyl-propyl]-(1-p tolyl-carbonyl)-amino]-propyl}-carbamic acid tert-butyl ester {3-[[(RS)-1-(6-Benzyl-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl )-2-methyl-propyl]-(1-m tolyl-carbonyl)-amino]-propyl}-carbamic acid tert-butyl ester (3-{[(RS)-1-(6-Benzyl-2-methyl-7-oxo-6,7-dihydro-pyrazollo[1,5-c]pyrimidin-5-yl)-2-methyl-propyi]-[1-(4 fluoro-phenyl)-carbonyl]-amino}-propyl)-carbamic acid tert-butyl ester WO 2007/144384 PCT/EP2007/055846 - 57 (3-{[(RS)-1-(6-Benzyl-2-methyl-7-oxo-6,7-dihyd ro-pyrazolo[1,5-c]pyrimidin-5-yl )-2-methyl-propyl]-[1-(4 methoxy-phenyl)-carbonyl]-amino}-propyl)-carbamic acid tert-butyl ester (3-{[(RS)-1-(6-Benzyl-2-methyl-7-oxo-6,7-dihydro-pyrazo lo[1,5-c]pyrimidin-5-yl )-2-methyl-propyl]-[1-(4 bromo-phenyl)-carbonyl]-amino}-propyl)-carbamic acid tert-butyl ester (3-{[(RS)-1-(6-Benzyl-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl )-2-methyl-propyl]-[1-(4 chloro-phenyl)-carbonyl]-amino}-propyl)-carbamic acid tert-butyl ester (3-{[(RS)-1-(6-Benzyl-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl )-2-methyl-propyl]-[1-(4 trifluoromethyl-phenyl)-carbonyl]-amino}-propyl)-carbamic acid tert-butyl ester The following compounds may be prepared by bromination of the appropriate compounds mentioned afore analogously or similarly as described for compound A2: {3-[[(RS)-1-(6-Benzyl-3-bromo-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl)-2-methyl propyl]-(1-p-tolyl-carbonyl)-amino]-propyl}-carbamic acid tert-butyl ester {3-[[(RS)-1-(6-Benzyl-3-bromo-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl)-2-methyl propyl]-(1-m-tolyl-carbonyl)-amino]-propyl}-carbamic acid tert-butyl ester (3-{[(RS)-1-(6-Benzyl-3-bromo-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl)-2-methyl propyl]-[1-(4-fluoro-phenyl)-carbonyl]-amino}-propyl)-carbamic acid tert-butyl ester (3-{[(RS)-1-(6-Benzyl-3-bromo-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl)-2-methyl propyl]-[1-(4-methoxy-phenyl)-carbonyl]-amino}-propyl)-carbamic acid tert-butyl ester (3-{[(RS)-1-(6-Benzyl-3-bromo-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl)-2-methyl propyl]-[1-(4-bromo-phenyl)-carbonyl]-amino}-propyl)-carbamic acid tert-butyl ester (3-{[(RS)-1-(6-Benzyl-3-bromo-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl)-2-methyl propyl]-[1-(4-chloro-phenyl)-carbonyl]-amino}-propyl)-carbamic acid tert-butyl ester (3-{[(RS)-1-(6-Benzyl-3-bro mo-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl )-2-methyl propyl]-[1-(4-trifluoromethyl-phenyl)-carbonyl]-amino}-propyl)-carbamic acid tert-butyl ester The following compounds may be prepared by benzoylation reaction of compound B5 with the appropriate benzoic acid derivative analogously or similarly as described for compounds Al and A3 to A9: {3-[[(RS)-1-(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl)-2-methyl butyl]-(1-p-tolyl-carbonyl)-amino]-propyl}-carbamic acid tert-butyl ester {3-[[(RS)-1-(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl)-2-methyl butyl]-(1-m-tolyl-carbonyl)-amino]-propyl}-carbamic acid tert-butyl ester (3-{[(RS)-1-(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl)-2-methyl butyl]-[1-(4-fluoro-phenyl)-carbonyl]-amino}-propyl)-carbamic acid tert-butyl ester (3-{[(RS)-1-(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl)-2-methyl butyl]-[1-(4-methoxy-phenyl)-carbonyl]-amino}-propyl)-carbamic acid tert-butyl ester (3-{[(RS)-1-(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl)-2-methyl butyl]-[1-(4-bromo-phenyl)-carbonyl]-amino}-propyl)-carbamic acid tert-butyl ester WO 2007/144384 PCT/EP2007/055846 - 58 (3-{[(RS)-1-(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl)-2-methyl butyl]-[1-(4-chloro-phenyl)-carbonyl]-amino}-propyl)-carbamic acid tert-butyl ester (3-{[(RS)-1-(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl)-2-methyl butyl]-[1-(4-trifluoromethyl-phenyl)-carbonyl]-amino}-propyl)-carbamic acid tert-butyl ester All. 6-Benzyl-3-chloro-5-[(RS)-1-(3-dimethylamino-propylamino)-2-methyl-propyl]-2-methyl 6H-pyrazolo[1,5-c]pyrimidin-7-one A suspension of 544 mg (1.0 eq) of 6-Benzyl-3-chloro-2-methyl-5-(2-methyl-propanoyl)-6H pyrazolo[1,5-c]pyrimidin-7-one (compound C3) and 742 pL N 1 ,Nl-dimethylpropane-1,3-diamine (2.5 eq) in 1.5 mL Ti(O'Pr) 4 is heated for 16 hours at 50 0C. This crude mixture with the imine as main product is dissolved in 5 mL glacial acetic acid and treated with 400 mg (6.6 eq) NaBH 4 . This mixture is stirred for 16 hours at ambient temperature to give the crude mixture containing the title compound. The solution is treated with 2 M aqueous NaOH-solution to an pH of 12 and extracted with 1-butanol. Purification by silica gel flash chromatography using a gradient of dichloromethane, methanol and triethylamine from 89:9:2 to 79:19:2 resulted in 105 mg (15%) of the title compound as a colorless oil. MS: m/z (MH') = 430.1, 432.2. The following compounds may be prepared by reductive amination reaction of the appropriate compound C1 to C6 with N ,N -dimethyl-propane-1,3-diamine (Me 2

N-(CH

2

)

3

-NH

2 ) analogously or similarly as described for compounds B1 to B3. 6-Benzyl-5-[(RS)-1 -(3-dimethylamino-propylamino)-propyl]-2-methyl-6H-pyrazolo[1,5-c]pyrimidin-7 one 6-Benzyl-3-chloro-5-[(RS)-1 -(3-dimethylamino-propylamino)-propyl]-2-methyl-6H-pyrazolo[1,5 c]pyrimidin-7-one 6-Benzyl-5-[(RS)-1 -(3-dimethylamino-propylamino)-2-methyl-propyl]-2-methyl-6H-pyrazolo[1,5 c]pyrimidin-7-one 6-Benzyl-5-[(RS)-1 -(3-dimethylamino-propylamino)-2-methyl-butyl]-2-methyl-6H-pyrazolo[1,5 c]pyrimidin-7-one 6-Benzyl-3-chloro-5-[(RS)-1 -(3-dimethylamino-propylamino)-2-methyl-butyl]-2-methyl-6H-pyrazolo[1,5 c]pyrimidin-7-one A12. {4-[[(RS)-1 -(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl) 2-methyl-propyl]-(1-p-tolyl-carbonyl)-amino]-butyl}-carbamic acid tert-butyl ester A solution of 180 mg (1.0 eq) {4-[(RS)-1l-(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5 c]pyrimidin-5-yl)-2-methyl-propylamino]-butyl}-carbamic acid tert-butyl ester (compound B6), 175 pL (1.5 eq) 4-methyl benzoyl chloride and 145 pL (3.7 eq) triethylamine in 3.5 mL dichloromethane is stirred for 3 days at ambient temperature. After addition of 10 mL dichloromethane and 10 mL saturated aqueous NaHCO 3 -solution, the phases are separated and the aqueous phase is extracted three times with dichloromethane. The combined organic phase is dried over magnesium sulfate and the solvent is evaporated in vacuo. Purification of the crude product by silica gel flash chromatography WO 2007/144384 PCT/EP2007/055846 - 59 using a gradient of n-hexane and ethyl acetate from 100:0 to 50:50 yielded 127 mg (71%) of the title compound as a colorless solid. M.p.: 82-84 oC. MS: m/z (MNa') = 656.2, and also MNa +2. Al 3. {2-[[(RS)-1 -(6-Benzyl-3-cho ro-2-methyl-7-oxo-6,7-d i hydro-pyrazo lo[1,5-c]pyrimidin-5-yi) 2-methyl-propyl]-(1-p-tolyl-carbonyl)-amino]-ethyl}-carbamic acid tert-butyl ester A solution of 200 mg (1.0 eq) {2-[(RS)-1l-(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5 c]pyrimidin-5-yl)-2-methyl-propylamino]-ethyl}-carbamic acid tert-butyl ester (compound B7), 205 pL (3.8 eq) 4-methyl benzoyl chloride and 171 pL (3.0 eq) triethylamine in 4 mL dichloromethane is stirred for 62 hours at ambient temperature. After addition of 10 mL of dichloromethane and 10 mL saturated aqueous NaHCO 3 -solution the phases are separated and the aqueous phase is extracted three times with dichloromethane. The combined organic phase is dried over magnesium sulfate and the solvent is evaporated in vacuo. Purification of the crude product by silica gel flash chromatography using a gradient of n-hexane, ethyl acetate and acetic acid from 39:59:2 to 0:100:0 yielded 125 mg (50%) of the title compound as a colorless solid. M.p.: 119-120 oC. MS: m/z (MH ) = 605.9, 608.0. A14. {3-[[(RS)-l -(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl) 1-cyclobutyl-methyl]-(1-p-tolyl-carbonyl)-amino]-propyl}-carbamic acid tert-butyl ester A solution of 300 mg (1.0 eq) (3-{[(RS)-1-(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5 c]pyrimidin-5-yl)-1l-cyclobutyl-methyl]-amino}-propyl)-carbamic acid tert-butyl ester (compound B8), 115 pL (1.5 eq) 4-methyl benzoyl chloride and 241 pL (3.0 eq) triethylamine in 6 mL dichloromethane is stirred for 2 days at ambient temperature. After addition of 10 mL of dichloromethane and 10 mL saturated aqueous NaHCO 3 -solution the phases are separated and the aqueous phase is extracted three times with dichloromethane. The combined organic phase is dried over magnesium sulfate and the solvent is evaporated in vacuo. Purification of the crude product by silica gel flash chromatography using a gradient of n-hexane and ethyl acetate from 100:0 to 50:50 yielded 194 mg (53%) of the title compound as a colorless foam. Furthermore 76 mg (25%) of the starting material is recovered. M.p.: 108-111 oC. MS: m/z (MH ) = 631.8, 633.8. Al 5. {3-[[(RS)-1 -(6-Benzyl-3-cho ro-2-methyl-7-oxo-6,7-d i hydro-pyrazo lo[1,5-c]pyrimidin-5-yi) 2-methyl-butyl]-(1-p-tolyl-carbonyl)-amino]-propyl}-carbamic acid tert-butyl ester A solution of 260 mg (1.0 eq) {3-[(RS)-1-(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro pyrazolo[1,5c]pyrimidin-5-yl)-2-methyl-butylamino]-propyl}-carbamic acid tert-butyl ester (compound B5), 100 pL (1.5 eq) 4-methyl benzoyl chloride and 208 pL (3.0 eq) triethylamine in 5 mL dichloromethane is stirred for 16 hours at ambient temperature. After addition of 10 mL of WO 2007/144384 PCT/EP2007/055846 - 60 dichloromethane and 10 mL saturated aqueous NaHCO 3 -solution the phases are separated and the aqueous phase is extracted three times with dichloromethane. The combined organic phase is dried over magnesium sulfate and the solvent is evaporated in vacuo. Purification of the crude product by silica gel flash chromatography using a gradient of n-hexane, ethyl acetate and acetic acid from 39:59:2 to 0:100:0 yielded 81 mg (26%) of the title compound as a pale yellow foam. Furthermore 147 mg (57%) of the starting material is recovered. M.p.: 67-68 oC. MS: m/z (MH') = 633.9, 635.8. Al 6. {3-[[(RS)-1 -(6-Benzyl-3-cho ro-2-methyl-7-oxo-6,7-d i hydro-pyrazo lo[1,5-c]pyrimidin-5-yi) 1-cyclopropyl-methyl]-(1-p-tolyl-carbonyl)-amino]-propyl}-carbamic acid tert-butyl ester A solution of 257 mg (1.0 eq) (3-{[(RS)-1-(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5 c]pyrimidin-5-yl)-1l-cyclopropyl-methyl]-amino}-propyl)-carbamic acid tert-butyl ester (compound B9), 135 pL (2.0 eq) 4-methyl benzoyl chloride and 212 pL (3.0 eq) triethylamine in 5 mL dichloromethane is stirred for 3 days at ambient temperature. After addition of 10 mL of dichloromethane and 10 mL saturated aqueous NaHCO 3 -solution the phases are separated and the aqueous phase is extracted three times with dichloromethane. The combined organic phase is dried over magnesium sulfate and the solvent is evaporated in vacuo. Purification of the crude product by silica gel flash chromatography using a gradient of n-hexane, ethyl acetate and acetic acid from 39:59:2 to 0:100:0 yielded 90 mg (29%) of the title compound as a colorless foam. Furthermore 73 mg (29%) of the starting material is recovered. M.p.: 85-87 oC. MS: m/z (MH ) = 617.9, 619.9. Al 7. (3-{[(RS)-l -(6-Benzyl-3-ch loro-2-methyl-7-oxo-6,7-d i hyd ro-pyrazolo[1,5-c] pyrimidin-5-yl) 1-cyclopropyl-methyl]-[1-(4-bromo-phenyl)-carbonyl]-amino}-propyl)-carbamic acid tert-butyl ester A solution of 196 mg (1.0 eq) (3-{[(RS)-1l-(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5 c]pyrimidin-5-yl)-1l-cyclopropyl-methyl]-amino}-propyl)-carbamic acid tert-butyl ester (compound B9), 105 mg (1.2 eq) 4-bromo benzoyl chloride and 166 pL (3.0 eq) triethylamine in 4 mL dichloromethane is stirred for 3 days at ambient temperature. After addition of 10 mL of dichloromethane and 10 mL saturated aqueous NaHCO 3 -solution the phases are separated and the aqueous phase is extracted three times with dichloromethane. The combined organic phase is dried over magnesium sulfate and the solvent is evaporated in vacuo. Purification of the crude product by silica gel flash chromatography using a gradient of n-hexane and ethyl acetate from 100:0 to 50:50 yielded 50 mg (18%) of the title compound as a colorless foam. M.p.: 120-122 oC. MS: m/z (MH ) = 681.8, 683.6, 685.4.

WO 2007/144384 PCT/EP2007/055846 - 61 Al 8. (3-{[(RS)-1l-(6-Benzyl-3-ch loro-2-methyl-7-oxo-6,7-d i hyd ro-pyrazolo[1,5-c] pyrimidin-5-yl) 2-methyl-propyl]-[1-(3-fluoro-4-methyl-phenyl)-carbonyl]-amino}-propyl)-carbamic acid tert butyl ester A solution of 330 mg (1.0 eq) {3-[(RS)-1l-(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5 c]pyrimidin-5-yl)-2-methyl-propylamino]-propyl}-carbamic acid tert-butyl ester (compound B3), 171 mg (1.5 eq) 3-fluoro-4-methyl benzoyl chloride and 274 pL (3.0 eq) triethylamine in 8 mL dichloromethane is stirred for 3 days at ambient temperature. After addition of 10 mL of dichloromethane and 10 mL saturated aqueous NaHCO 3 -solution the phases are separated and the aqueous phase is extracted three times with dichloromethane. The combined organic phase is dried over magnesium sulfate and the solvent is evaporated in vacuo. Purification of the crude product by silica gel flash chromatography using a gradient of n-hexane, ethyl acetate and acetic acid from 59:39:2 to 0:100:0 yielded 115 mg (27%) of the title compound as a pale yellow foam. Furthermore 122 mg (37%) of the starting material is recovered. M.p.: 88-91 oC. MS: m/z (MH') = 637.8, 639.8. Al 9. (3-{[(RS)-l -(6-Benzyl-3-ch loro-2-methyl-7-oxo-6,7-d i hyd ro-pyrazolo[1,5-c] pyrimidin-5-yl) 2-methyl-propyl]-[1-(2-fluoro-4-methyl-phenyl)-carbonyl]-amino}-propyl)-carbamic acid tert butyl ester A solution of 277 mg (1.0 eq) {3-[(RS)-1l-(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5 c]pyrimidin-5-yl)-2-methyl-propylamino]-propyl}-carbamic acid tert-butyl ester (compound B3), 142 mg (1.5 eq) 2-fluoro-4-methyl benzoyl chloride and 229 pL (3.0 eq) triethylamine in 7 mL dichloromethane is stirred for 2 days at ambient temperature. After addition of 10 mL of dichloromethane and 10 mL saturated aqueous NaHCO 3 -solution the phases are separated and the aqueous phase is extracted three times with dichloromethane. The combined organic phase is dried over magnesium sulfate and the solvent is evaporated in vacuo. Purification of the crude product by silica gel flash chromatography using a gradient of n-hexane, ethyl acetate and acetic acid from 59:39:2 to 0:100:0 yielded 100 mg (28%) of the title compound as a colorless foam. Furthermore 100 mg (36%) of the starting material is recovered. M.p.: sinter at 100 0C and melting at 110-112 oC. MS: m/z (MH ) = 637.9, 639.9. A20. (3-{[(RS)-1 -(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl) 2-methyl-propyl]-[1-(3,4-dichloro-phenyl)-carbonyl]-amino}-propyl)-carbamic acid tert-butyl ester A solution of 259 mg (1.0 eq) {3-[(RS)-1l-(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5 c]pyrimidin-5-yl)-2-methyl-propylamino]-propyl}-carbamic acid tert-butyl ester (compound B3), 129 mg (1.2 eq) 3,4-dichloro benzoyl chloride and 214 pL (3.0 eq) triethylamine in 6 mL dichloromethane is stirred for 3 days at ambient temperature. After addition of 10 mL of dichloromethane and 10 mL WO 2007/144384 PCT/EP2007/055846 - 62 saturated aqueous NaHCO 3 -solution the phases are separated and the aqueous phase is extracted three times with dichloromethane. The combined organic phase is dried over magnesium sulfate and the solvent is evaporated in vacuo. Purification of the crude product by silica gel flash chromatography using a gradient of n-hexane and ethyl acetate from 100:0 to 50:50 yielded 88 mg (22%) of the title compound as a colorless foam. M.p.: 104-107 oC. MS: m/z (MH') = 673.6, 675.7, 677.8. A21. (3-{[(RS)-1 -(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl) 2-methyl-propyl]-[1-(2,3-dichloro-phenyl)-carbonyl]-amino}-propyl)-carbamic acid tert-butyl ester A solution of 300 mg (1.0 eq) {3-[(RS)-1l-(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5 c]pyrimidin-5-yl)-2-methyl-propylamino]-propyl}-carbamic acid tert-butyl ester (compound B3), 143 mg (1.2 eq) 2,3-dichloro benzoyl chloride and 249 pL (3.0 eq) triethylamine in 7 mL dichloromethane is stirred for 3 days at ambient temperature. After addition of 10 mL of dichloromethane and 10 mL saturated aqueous NaHCO 3 -solution the phases are separated and the aqueous phase is extracted three times with dichloromethane. The combined organic phase is dried over magnesium sulfate and the solvent is evaporated in vacuo. Purification of the crude product by silica gel flash chromatography using a gradient of n-hexane, ethyl acetate and acetic acid from 39:59:2 to 0:100:0 yielded 67 mg (17%) of the title compound as a colorless solid. Furthermore 164 mg (55%) of the starting material is recovered. M.p.: 109-110 oC. MS: m/z (MH ) = 673.8, 676.0, 677.9. A22. {3-[[(RS)-1 -(6-Benzyl-3-bromo-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl) 2-methyl-propyl]-(4-methyl-benzoyl)-amino]-propyl}-carbamic acid tert-butyl ester 0.10 g of {3-[(RS)-1-(6-Benzyl-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1 ,5-c]pyrimidin-5-yl)-2-methyl propylamino]-propyl}-carbamic acid tert-butyl ester (compound A23) are dissolved in 3 mL DMF. After adding 36.3 mg (1.2 eq) NBS at 0 0C the mixture is stirred for 16 hours at ambient temperature. Addition of water followed by extraction of the aqueous phase with dichloromethane yielded after drying over magnesium sulfate and evaporation of the solvent the crude product. The residue is purified by flash chromatography using n-hexane / ethylacetate in a ratio of 2:1 and yielded 90 mg (80%) of the title compound as colorless oil. A23. {3-[(RS)-1 -(6-Benzyl-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl)-2-methyl propylamino]-propyl}-carbamic acid tert-butyl ester A solution of 151 mg {3-[(RS)-1l-(6-Benzyl-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl)-2 methyl-propylamino]-propyl)-carbamic acid tert butyl ester (1.0 eq) (compound B4), 55 mg (1.5 eq) p methyl benzoyl chloride and 132 pL (3.0 eq) triethylamine in 5 mL dichloromethane is stirred for 1 WO 2007/144384 PCT/EP2007/055846 - 63 days at ambient temperature and for 1 day at 40 0C. After addition of 10 mL of dichloromethane and 10 mL saturated aqueous NaHCO 3 -solution the phases are separated and the aqueous phase is extracted three times with dichloromethane. The combined organic phase is dried over magnesium sulfate and the solvent is evaporated in vacuo. Purification of the crude product by silica gel flash chromatography using a ratio of n-hexane, ethyl acetate and acetic acid 66:32:2 yielded 105 mg (80%) of the title compound with impurities of acetic acid. A24. {3-[[(RS)-1 -(6-Benzyl-3-fluoro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl) 2-methyl-propyl]-(1-p-tolyl-carbonyl)-amino]-propyl}-carbamic acid tert-butyl ester A solution of 155 mg (1.0 eq) {3-[(RS)-1l-(6-Benzyl-3-fluoro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5 c]pyrimidin-5-yl)-2-methyl-propylamino]-propyl}-carbamic acid tert-butyl ester (compound B10), 62 pL (1.5 eq) p-tolyl benzoyl chloride and 137 pL (3.0 eq) triethylamine in 6 mL tetrahydrofurane is stirred for 3 days at ambient temperature. The solvent is evaporated in vacuo. Purification of the crude product by silica gel flash chromatography using a ratio of n-hexane, ethyl acetate and acetic acid 66:32:2 yielded 150 mg (78%) of the title compound with impurities of acetic acid. B1. {3-[(RS)-1 -(6-Benzyl-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl) propylamino]-propyl}-carbamic acid tert-butyl ester 437 mg 6-Benzyl-2-methyl-5-propionyl-6H-pyrazolo[1,5-c]pyrimidin-7-one (1.48 mmol) (compound C1) and 516 mg (3-Amino-propyl)-carbamic acid tert-butyl ester (2.96 mmol) are dissolved in 4 ml THF. 1.9 ml Ti(O'Pr) 4 (4.44 mmol) are added and the reaction mixture is stirred 14 h at ambient temperature. Afterwards 4 ml ethanol and 412 mg NaCNBH 3 (5.92 mmol) are added and the mixture is stirred 2 h at ambient temperature. After adding water the inorganic salts are filtrated, washed with ethanole and the filtrate is evaporated. The residue is suspended in dichloromethane, dried over sodium sulphate and filtrated. After removing the solvents the crude product is purified by silica gel flash chromatography. By this method 540 mg (80 %) of a colorless solid is obtained. M.p.: 72-74 oC. B2. {3-[(RS)-1 -(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl) propylamino]-propyl}-carbamic acid tert-butyl ester 6-Benzyl-3-chloro-2-methyl-5-propionyl-6H-pyrazolo[1,5-c]pyrimidin-7-one (3.70 g, 11.2 mmol) (compound C2) and N-Boc-1,3-diaminopropane (2.60 g, 14.6 mmol) are dissolved in THF (28 mL), treated with Ti(O'Pr) 4 (6.40 g, 22.4 mmol) and stirred for 14h at ambient temperature. Then ethanol (28 mL) and NaCNBH 3 (1.40 g, 22.4 mmol) are added and it is stirred for 2 h at ambient temperature. After adding of water it is filtered and the filtrate is evaporated. The residue is purified by silica gel flash chromatography. A colorless solid of m.p. 73-75 0C is obtained.

WO 2007/144384 PCT/EP2007/055846 - 64 B3. {3-[(RS)-1 -(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-d i hydro-pyrazolo[1,5-c] pyrimidin-5-yl) 2-methyl-propylamino]-propyl}-carbamic acid tert-butyl ester 1.10 g (1.0 eq) of 6-Benzyl-3-chloro-2-methyl-5-(2-methyl-propanoyl)-6H-pyrazolo[1 ,5-c]pyrimidin-7 one (compound C3) are dissolved in 15 ml tetrahydrofurane. 1.39 g (2.5 eq) tert-butyl-N-(3 aminopropyl)carbamate and 2.86 mL (3.0 eq) titanium(IV)isopropoxide are added and this mixture is stirred for 72 hours at reflux. After cooling the mixture is treated with an aqueous citric acid solution and stirred for another 15 min at ambient temperature. Addition of dichloromethane and filtration of the mixture yield a two-phase system. The two phases are separated and the aqueous phase is extracted with dichloromethane. The combined organic phase is dried over magnesium sulfate and the solvent is removed in vacuo. This yields the crude mixture of the corresponding imine. This mixture of the crude imine is dissolved in 20 mL acetic acid. 0.61 g (5.0 eq) sodium borohydride are added. The reaction mixture is stirred for 1 hour at ambient temperature. After addition of water the mixture is extracted with etyhl acetate. The combined organic phase is once washed with saturated aqueous sodium hydrogencarbonate solution. The organic phase is dried over magnesium sulfate and the solvent is evaporated in vacuo. The crude product is purified by silica gel flash chromatography using a gradient of n-hexane and ethyl acetate from 100:0 to 50:50. This yields 0.62 g (39%) of the title compound as a white foam. M.p. 51-53 0C (foam). MS: m/z (MH') = 501.9, 504.0. B4. {3-[(RS)-1 -(6-Benzyl-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl)-2-methyl propylamino]-propyl}-carbamic acid tert-butyl ester The title compound may be prepared by reductive amination reaction of compound C4 with N-Boc-1,3 diaminopropane analogously or similarly as described for compounds B1 to B3. B5. {3-[(RS)-1 -(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl) 2-methyl-butylamino]-propyl}-carbamic acid tert-butyl ester 0.70 g (1.0 eq) of 6-Benzyl-3-chloro-2-methyl-5-(2-methyl-butanoyl)-6H-pyrazolo[1,5-c]pyrimidin-7-one (compound C5) are dissolved in 40 mL tetrahydrofurane. 1.36 g (4.0 eq) tert-butyl-N-(3 aminopropyl)carbamate and 3.50 mL (6.0 eq) titanium(IV)isopropoxide are added and this mixture is stirred in a sealed tube for 72 hours at reflux. After cooling, the mixture is treated with an aqueous solution of citric acid and stirred for another 15 min at ambient temperature. Addition of dichloromethane and filtration of the mixture yielded a two-phase system. The phases are separated and the aqueous phase is extracted with dichloromethane. The combined organic phase is dried over magnesium sulfate and the solvent is removed in vacuo. This yielded the crude mixture of the corresponding imine. The mixture of the crude imine is dissolved in 12 mL acetic acid. 0.37 g (5.0 eq) sodium borohydride are added and the mixture is stirred for 16 hours at ambient temperature. The solvent is evaporated and the residue is partitioned between saturated aqueous NaHCO 3 -solution and dichloromethane. After phase separation, the aqueous phase is extracted three times with dichloromethane. The WO 2007/144384 PCT/EP2007/055846 - 65 combined organic phase is dried over magnesium sulfate and the solvent is evaporated in vacuo. The crude product is purified by silica gel flash chromatography using a gradient of n-hexane and ethyl acetate from 100:0 to 50:50. This yielded 0.34 g (34%) of the title compound as colorless foam. M.p.: 64-65 oC. MS: m/z (MH') = 516.0, 518.0. B6. {4-[(RS)-1 -(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl) 2-methyl-propylamino]-butyl}-carbamic acid tert-butyl ester 1.87 g (1.0 eq) of 6-Benzyl-3-chloro-2-methyl-5-(2-methyl-propanoyl)-6H-pyrazolo[1 ,5-c]pyrimidin-7 one (compound C3) are dissolved in 23 mL tetrahydrofurane. 2.56 g (2.5 eq) tert-butyl-N-(3 aminobutyl)carbamate and 4.86 mL (3.0 eq) titanium(IV)isopropoxide are added and this mixture is stirred in a sealed tube for 72 hours at 80 oC. After cooling, the mixture is treated with an aqueous solution of citric acid and stirred for another 15 min at ambient temperature. Addition of dichloromethane and filtration of the mixture yielded a two-phase system. The phases are separated and the aqueous phase is extracted with dichloromethane. The combined organic phase is dried over magnesium sulfate and the solvent is removed in vacuo. This yielded the crude mixture of the corresponding imine. The mixture of the crude imine is dissolved in 35 mL acetic acid. 1.05 g (5.0 eq) sodium borohydride are added and the mixture is stirred for 1 hour at ambient temperature. The solvent is evaporated and the residue is partitioned between saturated aqueous NaHCO 3 -solution and dichloromethane. After phase separation the aqueous phase is extracted three times with dichloromethane. The combined organic phase is dried over magnesium sulfate and the solvent is evaporated in vacuo. The crude product is purified by silica gel flash chromatography using a gradient of n-hexane and ethyl acetate from 100:0 to 50:50. This yielded 0.44 g (16%) of the title compound as colorless foam. M.p.: 63-65 oC. MS: m/z (MH ) = 516.0, 518.0. B7. {2-[(RS)-1 -(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl) 2-methyl-propylamino]-ethyl}-carbamic acid tert-butyl ester 0.61 g (1.0 eq) of 6-Benzyl-3-chloro-2-methyl-5-(2-methyl-propanoyl)-6H-pyrazolo[1 ,5-c]pyrimidin-7 one (compound C3) are dissolved in 8 mL tetrahydrofurane. 0.71 g (2.5 eq) tert-butyl-N-(3 aminoethyl)carbamate and 1.58 mL (3.0 eq) titanium(IV)isopropoxide are added and this mixture is stirred in a sealed tube for 72 hours at 80 oC. After cooling, the mixture is treated with an aqueous solution of citric acid and stirred for another 15 min at ambient temperature. Addition of dichloromethane and filtration of the mixture yielded a two-phase system. The phases are separated and the aqueous phase is extracted with dichloromethane. The combined organic phase is dried over magnesium sulfate and the solvent is removed in vacuo. This yielded the crude mixture of the corresponding imine. The mixture of the crude imine is dissolved in 11 mL acetic acid. 0.33 g (5.0 eq) sodium borohydride are added and the mixture is stirred for 1 hour at ambient temperature. The solvent is evaporated and WO 2007/144384 PCT/EP2007/055846 - 66 the residue is partitioned between saturated aqueous NaHCO 3 -solution and dichloromethane. After phase separation, the aqueous phase is extracted three times with dichloromethane. The combined organic phase is dried over magnesium sulfate and the solvent is evaporated in vacuo. The crude product is purified by silica gel flash chromatography using a gradient of n-hexane and ethyl acetate from 100:0 to 50:50. This yielded 0.21 g (25%) of the title compound as colorless foam. M.p.: 73-75 oC. MS: m/z (MH*) = 487.9, 490.0. B8. (3-{[(RS)-1 -(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl) 1-cyclobutyl-methyl]-amino}-propyl)-carbamic acid tert-butyl ester 0.63 g (1.0 eq) of 6-Benzyl-3-chloro-5-(1-cyclobutyl-carbonyl )-2-methyl-6H-pyrazolo[1 ,5-c]pyrimidin-7 one (compound C6) are dissolved in 4 mL tetrahydrofurane. 0.54 g (2.5 eq) tert-butyl-N-(3 aminopropyl)carbamate and 1.10 mL (3.0 eq) titanium(IV)isopropoxide are added and this mixture is stirred in a sealed tube for 72 hours at 80 oC. After cooling, the mixture is treated with an aqueous solution of citric acid and stirred for another 15 min at ambient temperature. Addition of dichloromethane and filtration of the mixture yielded a two-phase system. The phases are separated and the aqueous phase is extracted with dichloromethane. The combined organic phase is dried over magnesium sulfate and the solvent is removed in vacuo. This yielded the crude mixture of the corresponding imine. This mixture of the crude imine is dissolved in 8 mL acetic acid. 0.23 g (5.0 eq) sodium borohydride is added and the mixture is stirred for 1 hour at ambient temperature. The solvent is evaporated and the residue is partitioned between saturated aqueous NaHCO 3 -solution and dichloromethane. After phase separation, the aqueous phase is extracted three times with dichloromethane. The combined organic phase is dried over magnesium sulfate and the solvent is evaporated in vacuo. The crude product is purified by silica gel flash chromatography using a gradient of n-hexane and ethyl acetate from 100:0 to 50:50. This yielded 0.50 g (79%) of the title compound as colorless foam. M.p.: 73-75 oC. MS: m/z (MH ) = 514.0, 516.0. B9. (3-{[(RS)-1 -(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl) 1-cyclopropyl-methyl]-amino}-propyl)-carbamic acid tert-butyl ester 1.81 g (1.0 eq) of 6-Benzyl-3-chloro-5-(1-cyclopropyl-carbonyl )-2-methyl-6H-pyrazolo[1,5-c]pyrimidin 7-one (compound C7) are dissolved in 20 mL tetrahydrofurane. 2.31 g (2.5 eq) tert-butyl-N-(3 aminopropyl)carbamate and 4.70 mL (3.0 eq) titanium(IV)isopropoxide are added and this mixture is stirred in a sealed tube for 5 days at 80 oC. After cooling, the mixture is treated with an aqueous solution of citric acid and stirred for another 15 min at ambient temperature. Addition of dichloromethane and filtration of the mixture yielded a two-phase system. The phases are separated and the aqueous phase is extracted with dichloromethane. The combined organic phase is dried over magnesium sulfate and the solvent is removed in vacuo. This yielded the crude mixture of the corresponding imine.

WO 2007/144384 PCT/EP2007/055846 - 67 This mixture of the crude imine is dissolved in 30 mL acetic acid. 1.0 g (5.0 eq) sodium borohydride are added and the mixture is stirred for 2 hours at ambient temperature. The sovent is evaporated and the residue is partitioned between saturated aqueous NaHCO 3 -solution and dichloromethane. After phase separation, the aqueous phase is extracted three times with dichloromethane. The combined organic phase is dried over magnesium sulfate and the solvent is evaporated in vacuo. The crude product is purified by silica gel flash chromatography using a gradient of n-hexane and ethyl acetate from 100:0 to 50:50. This yielded 0.26 g of a mixture containing the title compound. This mixture was used for the further synthetic pathway. M.p.: 74-76 oC. MS: m/z (MH') = 500.0, 502.0 (analytical data measured with recovered pure starting material from A16). B10. {3-[(RS)-1 -(6-Benzyl-3-fluoro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1 ,5-c]pyrimidin-5-yI) 2-methyl-propylamino]-propyl}-carbamic acid tert-butyl ester 0.55 g (1.0 eq) of 6-Benzyl-3-chloro-2-methyl-5-(2-methyl-propanoyl)-6H-pyrazolo[1 ,5-c]pyrimidin-7 one (compound C8) are dissolved in 7 mL tetrahydrofurane. 0.74 g (2.5 eq) tert-butyl-N-(3 aminoetyl)carbamate and 1.51 mL (3.0 eq) titanium(IV)isopropoxide are added and this mixture is stirred in a sealed tube for 72 hours at 80 oC. After cooling, the mixture is treated with an aqueous solution of citric acid and stirred for another 15 min at ambient temperature. Addition of dichloromethane and filtration of the mixture yielded a two-phase system. The phases are separated and the aqueous phase is extracted with dichloromethane. The combined organic phase is dried over magnesium sulfate and the solvent is removed in vacuo. This yielded the crude mixture of the corresponding imine. The mixture of the crude imine is dissolved in 12 mL acetic acid. 0.33 g (5.0 eq) sodium borohydride are added and the mixture is stirred for 90 minutes at ambient temperature. The solvent is evaporated and the residue is partitioned between saturated aqueous NaHCO 3 -solution and dichloromethane. After phase separation, the aqueous phase is extracted three times with dichloromethane. The combined organic phase is dried over magnesium sulfate and the solvent is evaporated in vacuo. The crude product is purified by silica gel flash chromatography using a cyclohexane ethyl acetate in a 2:1 mixture. This yielded 0.16 g (19%) of the title compound as colorless solid. C1. 6-Benzyl-2-methyl-5-propionyl-6H-pyrazolo[1,5-c]pyrimidin-7-one 770 mg 6-Benzyl-5-((RS)-1l-hydroxy-propyl)-2-methyl-6H-pyrazolo[1,5-c]pyrimidin-7-one (2.59 mmol) (compound D1) are dissolved in 15 ml dichloromethane, 1.5 g molecular sieve (4 A, 500 mg/mmol Substrat) and 1060 mg NMO ( 7.8 mmol) are added and the reaction mixture is stirred 2 h at ambient temperature. Afterwards TPAP ( 100 mg, 0.26 mmol) are added and the mixture is stirred 14 h at ambient temperature. The reaction mixture is filtrated over silica gel, washed with etylacetate and evaporated. The residue is purified by silica gel flash chromatography. By this method 452 mg ( 59 %) of a yellow solid are obtained. M.p.: 128-130 oC.

WO 2007/144384 PCT/EP2007/055846 - 68 C2. 6-Benzyl-3-chloro-2-methyl-5-propionyl-6H-pyrazolo[1,5-c]pyrimidin-7-one 6-Benzyl-3-chloro-5-((RS)-1l-hydroxy-propyl)-2-methyl-6H-pyrazolo[1,5-c]pyrimidin-7-one (6.00 g, 18.0 mmol) (compound D2) is dissolved in CH 2 0 2 (90 mL) and treated with molecular sieve (4A, 9.00 g) and NMO (7.30 g, 54.0 mmol) and stirred for 2h at ambient temperature. To the mixture is added TPAP (633 mg, 1.8 mmol) and it is stirred for 14 h at ambient temperature. The mixture is filtered and evaporated. The residue is purified by silica gel flash chromatography. The title compound is obtained as 3.80 g of a yellow solid with m.p. 128 oC. C3. 6-Benzyl-3-ch loro-2-methyl-5-(2-methyl-propanoyl)-6H-pyrazo lo[1 5-c]pyrimidin-7-one 1.61 g (1.0 eq) of 6-Benzyl-3-chloro-5-((RS)-1 -hydroxy-2-methyl-propyl)-2-methyl-6H-pyrazolo[1,5 c]pyrimidin-7-one (compound D3) are dissolved in 60 mL of dichloromethane at room temperature. To this mixture are added 7 g (1,5 g/mmol) of mol sieves 4 A and 2.53 g (4.0 eq) N-methylmorpholine-N oxide. After 30 min stirring at ambient temperature 0.33 g (0.2 eq) tetrapropylammonium perruthenate is added. After 16 hours the reaction mixture is filtered through silica gel and washed out with ethyl acetate. The solvent is removed in vacuo. Flash chromatography using a gradient of n-hexane and ethyl acetate from 100:0 to 50:50 yields 1.09 g (68%) of the title compound as a white solid. M.p. 146.7 oC. MS: m/z (MH') = 344.1, 346.1. C4. 6-Benzyl-2-methyl-5-(2-methyl-propanoyl)-6H-pyrazolo[1,5-c]pyrimidin-7-one The title compound may be prepared by oxidation of compound D4 analogously or similarly as described for compounds C1 to C3. C5. 6-Benzyl-3-chloro-2-methyl-5-(2-methyl-butanoyl)-6H-pyrazolo[1 ,5-c]pyrimidin-7-one 1.12 g (1.0 eq) of 6-Benzyl-3-chloro-5-((RS)-1l-hydroxy-2-methyl-butyl)-2-methyl-6H-pyrazolo[1,5 c]pyrimidin-7-one (compound D5) are dissolved in 50 mL of dichloromethane at ambient temperature. 4.6 g (1.5 g/mmol) of mol sieves 4 A and 1.68 g (4.0 eq) N-methylmorpholine-N-oxide are added to this mixture. After 30 min stirring at ambient temperature 0.22 g (0.2 eq) tetrapropylammonium perruthenate are added. After 16 hours the reaction mixture is filtered through silica gel using ethyl acetate as eluent. The solvent is removed in vacuo. Flash chromatography using a gradient of n hexane and ethyl acetate from 100:0 to 50:50 yielded 0.78 g (70%) of the title compound as a colorless solid. M.p.: 122-123 oC. MS: m/z (MH ) = 358.1, 360.1. C6. 6-Benzyl-3-chloro-5-(1-cyclobutyl-carbonyl)-2-methyl-6H-pyrazolo[1,5-c]pyrimidin-7-one A suspension of 0.63 g (1.0 eq) of 6-Benzyl-3-chloro-5-((RS)-1-cyclobutyl-1-hydroxy-methyl)-2-methyl 6H-pyrazolo[1,5-c]pyrimidin-7-one (compound D6), 2,2,6,6-tetramethylpiperidinyloxy (TEMPO) and 1.29 g iodobenzene diacetate in 4 mL dichloromethane is stirred for 2 days at ambient temperature.

WO 2007/144384 PCT/EP2007/055846 - 69 This mixture is treated with aqueous Na 2

S

2 0 3 -solution (1M) and dichloromethane. Phase separation and extraction of the aqueous layer with dichloromethane resulted after drying over magnesium sulfate and evaporation of the solvent in vacuo in the crude product. Silica gel flash chromatography with a ratio of n-hexane and ethyl acetate 3:7 yielded 0.63 g (quant.) of the title compound as a colorless solid. M.p.: 96-97 oC. MS: m/z (MH') = 356.1, 358.1. C7. 6-Benzyl-3-chloro-5-(1-cyclopropyl-carbonyl)-2-methyl-6H-pyrazolo[1 ,5-c]pyrimidin-7 one 0.33 g (1.0 eq) of 6-Benzyl-3-chloro-5-(1-cyclopropyl-(RS)-1l-hydroxy-methyl)-2-methyl-6H pyrazolo[1,5-c]pyrimidin-7-one (compound D7) are dissolved in 15 mL of dichloromethane at ambient temperature. 1.43 g (1.5 g/mmol) of mol sieves 4 A and 0.51 g (4.0 eq) N-methylmorpholine-N-oxide are added to this mixture. After 30 min stirring at ambient temperature 67 mg (0.2 eq) tetrapropylammonium perruthenate are added. After 16 hours the reaction mixture is filtered through silica gel with ethyl acetate as eluent. The solvent is removed in vacuo. Flash chromatography using a gradient of n-hexane and ethyl acetate from 100:0 to 30:70 yielded 0.23 g (68%) of the title compound as a colorless solid. M.p.: 151-152 oC. MS: m/z (MH ) = 342.2, 344.2. C8. 6-Benzyl-3-fluoro-2-methyl-5-(2-methyl-propanoyl)-6H-pyrazo lo[1 5-c]pyrimidin-7-one A suspension of 0.55 g (1.0 eq) of 6-Benzyl-3-fluoro-5-(1-hydroxy-2-methyl-propyl)-2-methyl-6H pyrazolo[1,5-c]pyrimidin-7-one (compound D8), 55 mg (0.22 eq) 2,2,6,6-tetramethylpiperidinyloxy (TEMPO) and 1.21 g (2.2 eq) iodobenzene diacetate in 10 mL dichloromethane is stirred for 3 days at ambient temperature. After addition of 25 mg (0.1 eq) TEMPO the mixture is stirred for another 2 days at ambient temperature. This mixture is treated with aqueous Na 2

S

2 0 3 -solution (1M) and dichloromethane. Phase separation and extraction of the aqueous layer with dichloromethane resulted after drying over sodium sulfate and evaporation of the solvent in vacuo in the crude product. Silica gel flash chromatography with a ratio of cyclohexane and ethyl acetate of 3:2 yielded 0.55 g (quant.) of the title compound as a yellow solid. D1. 6-Benzyl-5-((RS)-1 -hydroxy-propyl)-2-methyl-6H-pyrazolo[1,5-c]pyrimidin-7-one To a solution of 7.2 ml MeLi (11.5 mmol, 1.6 M in Et 2 0) in THF (20 ml), 2.3 ml EtMgBr (6.9 mmol, 3 M in Et 2 0) are added at - 78 oC. The solution is stirred 1 h at - 780C. 1 g 6-Benzyl-3-bromo-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidine-5-carbaldehyde (2.89 mmol) (compound El) diluted in 4 ml DMPU and 10 ml THF are added dropwise under argon atmosphere. Afterwards the reaction mixture is stirred 2 h at - 780C and 3 h at -30 oC. The reaction mixture is quenched with aqueous NH 4 CI-solution and then warmed up to ambient temperature. The product is extracted between ethylacetate and water. The organic phase is dried over sodium WO 2007/144384 PCT/EP2007/055846 - 70 sulphate. After evaporating the solvents the crude product is purified by silica gel flash chromatography. By this method 352 mg (42%) of the title compound are obtained. M.p.: 190-191 oC. D2. 6-Benzyl-3-chloro-5-((RS)-1l-hydroxy-propyl)-2-methyl-6H-pyrazolo[1,5-c]pyrimidin-7-one To a mixture of THF (4 mL) and MeLi (1.25 mL, 2.0 mmol, 1.6 M in Et 2 0) are added at -78 0C EtMgBr (0.48 mL, 1.2 mmol, 3.0 M in Et 2 0), the solution is stirred 1 h at this temperature and 6-benzyl-3 chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidine-5-carbaldehyde (compound E2) is added. The mixture is stirred for 6h at - 70 0C and then the mixture is hydrolyzed with aqueous NH 4 0C solution and stirred at ambient temperature. After adding water the mixture is extracted with ethylacetate, the organic phase is dried and evaporated. The residue is purified by silica gel flash chromatography. 201 mg are obtained with a melting point of 80-82 oC. D3. 6-Benzyl-3-chloro-5-((RS)-1l-hydroxy-2-methyl-propyl)-2-methyl-6H-pyrazolo[1,5 c]pyrimidin-7-one 25 mL of methyllithium (2.0 eq, 1.6 M solution in diethylether) and 24 mL of isopropylmagnesium bromide (1.2 eq, -1M solution in tetrahydrofurane) are added to 200 mL dry tetrahydrofurane at 780C. After one hour at -780C 6g (1.0 eq) of 6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro pyrazolo[1,5-c]pyrimidine-5-carbaldehyde (compound E2) is added. After stirring this mixture for an additional 2 hours, a saturated aqueous solution of ammonium chloride is added. At ambient temperature the mixture is extracted with ethyl acetate and the combined organic phase is dried over magnesium sulfate. After filtration the solvent is evaporated under vacuo. The crude product is crystallized from ethyl acetate. This yields 2.83 g of the title compound. Flash chromatography of the mother liquor using a gradient of n-hexane and ethyl acetate from 100:0 to 50:50 yields another 1.15 g of the title compound (together 58% yield) as a white solid. M.p. 72.9 oC. MS: m/z (MH') = 345.9, 347.9. D4. 6-Benzyl-5-((RS)-1 -hydroxy-2-methyl-propyl)-2-methyl-6H-pyrazolo[1,5-c]pyrimidin-7 one The title compound may be prepared from compound El analogously or similarly as described for compound D1. D5. 6-Benzyl-3-chloro-5-((RS)-1l-hydroxy-2-methyl-butyl)-2-methyl-6H-pyrazolo[1,5 c]pyrimidin-7-one 12.5 mL of methyllithium (2.0 eq, 1.6 M solution in diethylether) and 12 mL of sec-butylmagnesium bromide (1.2 eq, -1M solution in tetrahydrofurane) are added to 100 mL dry tetrahydrofurane at 780C. After one hour at -780C 3.0 g (1.0 eq) of 6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro pyrazolo[1,5-c]pyrimidine-5-carbaldehyde (compound E2) are added. After stirring this mixture for an additional 2.5 hours, a saturated aqueous solution of ammonium chloride is added. The mixture is extracted with ethyl acetate and the combined organic phase is dried over magnesium sulfate. After WO 2007/144384 PCT/EP2007/055846 - 71 filtration, the solvent is evaporated in vacuo. Silica gel flash chromatography using a gradient of n hexane and ethyl acetate from 100:0 to 50:50 yielded 1.2 g (33%) of the title compound as colorless foam. M.p.: 72-73 oC. MS: m/z (MH') = 360.2, 362.2. D6. 6-Benzyl-3-chloro-5-((RS)-1l-cyclobutyl-1 -hydroxy-methyl)-2-methyl-6H-pyrazolo[1,5 c]pyrimidin-7-one 1.0 mL (3.0 eq) Cyclobutylbromide and 0.24 g (3.0 eq) magnesium (Grignard) are dissolved in 20 mL diethylether. The grignard reaction is started with iodine and heating of the suspension to reflux. After 90 minutes at reflux a solution of 1.0 g (1.0 eq) of 6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro pyrazolo[1,5-c]pyrimidine-5-carbaldehyde (compound E2) in 15 mL THF is added dropwise. After stirring for 16 hours at ambient temperature the reaction is stopped with ammonium chloride. Extraction of the aqueous phase with ethyl acetate resulted after drying over magnesium sulfate and evaporation of the solvent in vacuo in the crude product. Silica gel flash chromatography using a gradient of n-hexane and ethyl acetate from 100:0 to 50:50 yielded 0.20 g (17%) of the title compound as a colorless solid. M.p.: 188-193 0C (decomposition). MS: m/z (MH ) = 358.1, 360.0. D7. 6-Benzyl-3-chloro-5-(1 -cyclopropyl-(RS)-1 -hydroxy-methyl)-2-methyl-6H-pyrazolo[1,5 c]pyrimidin-7-one 1.0 g (1.0 eq) of 6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidine-5 carbaldehyde (compound E2) are dissolved in 30 mL THF and at 0 0C 16.5 mL (2.5 eq, 0.5 M in THF) cyclopropylmagnesiumbromide are added dropwise. After stirring for 3 days at ambient temperature the mixture is treated with a saturated aqueous solution of ammonium chloride. Extraction of the water phase with dichloromethane resulted after drying over magnesium sulfate and evaporation of the solvent in vacuo the crude product. Silica gel flash chromatography using a gradient of n-hexane and ethyl acetate from 100:0 to 50:50 yielded 0.56 g (49%) of the title compound as a colorless solid. M.p.: 119-120 oC. MS: m/z (MH ) = 344.1, 346.1. D8. 6-Benzyl-3-fluoro-5-(1 -hydroxy-2-methyl-propyl)-2-methyl-6H-pyrazolo[1,5-c]pyrimidin 7-one 3.2 mL of methyllithium (2.0 eq, 1.6 M solution in diethylether) and 3 mL of isopropylmagnesium bromide (1.2 eq, -1M solution in tetrahydrofurane) are added to 25 mL dry tetrahydrofurane at -780C. After one hour at -780C 0.6 g (1.0 eq) of 6-Benzyl-3-fluoro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5 c]pyrimidine-5-carbaldehyde (compound E3) are added. After stirring this mixture for an additional 3 hours the reaction is quenched by treatment with a 10% aqueous ammonium chloride solution. The mixture is extracted with diethylether and the combined organic phase is dried over magnesium WO 2007/144384 PCT/EP2007/055846 - 72 sulfate. After filtration, the solvent is evaporated in vacuo. Silica gel flash chromatography using a ratio of n-hexane and ethyl acetate of 1:1 yielded 0.23 g (27%) of the title compound as slightly yellow solid. El. 6-Benzyl-3-bromo-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidine-5-carbaldehyde 6-Benzyl-3-bromo-2,5-dimethyl-6H-pyrazolo[1,5-c]pyrimidin-7-one (24.0 g, 72.2 mmol) (compound F1) are dissolved in 350 ml dioxane. 24 g selendioxide are added and the reaction mixture is heated to reflux for 12 h. Afterwards the reaction mixture is filtered, the residue is washed with diethylether and the filtrate is evaporated. By this method 22.7 g (90 %) of the title compound are obtained. M.p.: 187 189 oC. E2. 6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidine-5-carbaldehyde 2.29 g (1.0 eq) of 6-Benzyl-3-chloro-2,5-dimethyl-6H-pyrazolo[1,5-c]pyrimidin-7-one (compound F2) are dissolved in 40 mL dioxane and treated with 2.64 g (3.0 eq) selenium dioxide. This mixture is heated at reflux for 5 hours. After filtration off the inorganic salts, the filtrate is evaporated in vacuo. This residue is purified by silica gel flash chromatography using cyclohexane and ethyl acetate in a mixture of 2:1 to yield 2.10 g (88%) of the title compound. M.p. 187-188 oC. E3. 6-Benzyl-3-fluoro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidine-5-carbaldehyde A solution of 6.75 g (1.0 eq) of 6-Benzyl-3(4)-fluoro-2,5-dimethyl-6H-pyrazolo[1,5-c]pyrimidin-7-one (compound F3) in 125 mL dioxane is treated with 10.55 g (3.0 eq) selenium dioxide. The mixture is heated for 7 days at reflux. This mixture is filtered, the solution is concentrated and washed three times with diethylether. The mother liquor is purified using flash chromatography (ethylacetate as eluent). This resulted in 0.60 g (8%) of the title compound. Fl. 6-Benzyl-3-bromo-2,5-dimethyl-6H-pyrazolo[1,5-c]pyrimidin-7-one 32 g (126 mmol) of the 6-Benzyl-2,5-dimethyl-6H-pyrazolo[1,5-c]pyrimidin-7-one (compound G1) are dissolved in 300 ml CC0014. 22.5 g (126 mmol) NBS and 2.1 g (12.6 mmol) AIBN are added to the solution, it is stirred at ambient temperature for 18 h. Afterwards the solution is diluted with dichloromethane and washed with saturated aqueous NaHCO 3 solution. The organic phase is dried over sodium sulphate and the solvents are evaporated. The crude product is purified by silica gel flash chromatography. By this method 24.1 g (58 %) of the title compound are obtained.

WO 2007/144384 PCT/EP2007/055846 - 73 F2. 6-Benzyl-3-chloro-2,5-dimethyl-6H-pyrazolo[1,5-c]pyrimidin-7-one 2.83 g (1.0 eq) 6-Benzyl-2,5-dimethyl-6H-pyrazolo[1,5-c]pyrimidin-7-one (compound G1) are dissolved in 35 mL tetrachloromethane and treated with 1.50 g (1.0 eq) N-chlorosuccinimide for 5 hours at reflux. The reaction mixture is diluted with dichloromethane and washed with saturated aqueous sodium hydrogen carbonate solution. Drying of the organic phase over sodium sulfate and evaporation of the solvent yields the crude product. The residue is purified by silica gel flash chromatography using cyclohexane and ethyl acetate in a mixture of 2:1 to yield 2.70 g (84%) of the title compound. M.p. 140-142 oC. F3. 6-Benzyl-3(4)-fluoro-2,5-dimethyl-6H-pyrazolo[1,5-c]pyrimidin-7-one 14.7 g of 6-Benzyl-2,5-dimethyl-6H-pyrazolo[1,5-c]pyrimidin-7-one (1.0 eq, compound G1) are dissolved in 300 mL acetonitrile and treated at 0 0C with 22.6 g Selectfluor (1.1 eq). After stirring for 1 hour at this temperature, the solvent is removed in vacuo, the residue is dissolved in dichloromethane and neutralized with a saturated aqueous hydrogen carbonate solution. The aqueous phase is extracted with dichloromethane and the combined organic layer is dried over magnesium sulfate. After evaporation of the solvent, the oily residue is crystallized from diethylether. The crystals are further purified using flash chromatography (cyclohexane / ethylacetate = 1.5:1). This yielded 2.67 g (17%) of the title compound as a colorless solid. G1. 6-Benzyl-2,5-dimethyl-6H-pyrazolo[1,5-c]pyrimidin-7-one 2.30 g (1.0 eq) 2,5-dimethyl-6H-pyrazolo[1,5-c]pyrimidin-7-one (compound H1) are dissolved in 35 mL N,N-dimethylformamide (DMF). 2.20 g (1.1 eq) potassium carbonate and 1.9 mL benzyl bromide are added. The mixture is stirred at ambient temperature for 14 hours. After addition of water the aqueous phase is extracted with dichloromethane. The combined organic phase is dried over sodium sulfate and the solvent is evaporated in vacuo. The residue is washed with diethylether and yield 3.35 g (94%) of the title compound. H1. 2,5-Dimethyl-6H-pyrazolo[1,5-c]pyrimidin-7-one 2.30 g (1.0 eq) semicarbazide hydrochloride are dissolved in 40 mL water. After addition of 1.10 g (0.5 eq) of a saturated aqueous solution of sodium carbonate and 2.90 g (1.0 eq) of heptane-2,4,6-trione (compound 11), the mixture is heated for 1 hour at 1000C. Extraction of the mixture with dichloromethane yields after evaporation of the solvent in vacuo 2.6 g (79%) of the title compound. M.p. 205-208 oC. 11. Heptane-2,4,6-trione 50.0 g 2,6-Dimethyl-y-pyrone are dissolved in 250 mL ethanol and treated with 50 mL of a 16 M aqueous solution of sodium hydroxide. This mixture is heated for 5 hours at 600C and for another 1 hour at 1000C. The residue is filtered off and washed with diethylether. This residue is now dissolved in water and put in 500 mL of a 3 M aqueous solution of hydrochloric acid. The aqueous phase is WO 2007/144384 PCT/EP2007/055846 - 74 extracted with diethylether. The combined organic phase is dried over sodium sulfate and the solvent is evaporated in vacuo. This yields 31.6 g (55%) of the title compound. M.p. 43-45 oC.

WO 2007/144384 PCT/EP2007/055846 - 75 Commercial utility The compounds of formula I, 1* and I**, and their pharmacologically and/or pharmaceutically acceptable salts (= the compounds according to the present invention) have valuable pharmacological and/or pharmaceutical properties which can make them commercially applicable. Thus, for example, the compounds according to this invention can act as inhibitors of the mitotic kinesin Eg5 and these compounds are expected to be commercially applicable in the therapy of diseases responsive to the inhibition of this kinesin, such as e.g. those diseases mentioned below. Also, for example, the compounds according to this invention can display cell-cycle dependent, anti-proliferative and/or apoptosis inducing activity. The mitotic kinesin Eg5 is an enzyme essential for the assembly and function of the bipolar mitotic spindle. Eg5 plays essential roles during all phases of mitosis. Drugs that perturb mitosis have proven clinically effective in the treatment of many cancers. Despite the diverse array of essential spindle proteins that could be exploited as targets for the discovery of novel cancer therapies, all spindle targeted therapeutics in clinical use today act on only one protein, tubulin. Surprisingly, kinesin Eg5 expression is most abundant in proliferating human tissues, whereas it is absent from most postmitotic cells, such as e.g. human central nervous system neurons, consistent with an exclusive or almost confined role for Eg5 in cell proliferation. In contrary to drugs that directly interfere with microtubule dynamic instability, Eg5 kinesin inhibitors are expected not to disrupt microtubule-based cellular processes, e.g. neuronal transport, that are unrelated to proliferation. During mitosis, Eg5 is essentially involved in organizing microtubules into a bipolar structure that forms the mitotic spindle. Experimental perturbation of Eg5 function causes a characteristic malformation or dysfunction of the mitotic spindle, frequently resulting in cell cycle arrest and cell death. The compounds according to this invention can be used to modulate mitotic spindle formation, thus causing prolonged cell cycle arrest in mitosis, which is frequently followed by apoptosis. By "modulate" herein is meant altering mitotic spindle formation, including increasing and decreasing spindle formation. By "mitotic spindle formation" herein is meant organization of microtubules into bipolar structures by mitotic kinesins. By "dysfunction of the mitotic spindle" herein is meant mitotic arrest and monopolar spindle formation. "Malformation of the mitotic spindle" encompasses the splaying of mitotic spindle poles, or otherwise causing morphological perturbation of the mitotic spindle. Further on, these compounds can be useful in the treatment of benign or malignant neoplasia. A "neoplasia" is defined by cells displaying aberrant cell proliferation and/or survival and/or a block in differentiation. A "benign neoplasia" is described by hyperproliferation of cells, incapable of forming an aggressive, metastasizing tumor in-vivo. In contrast, a "malignant neoplasia" is described by cells with multiple cellular and biochemical abnormalities, capable of forming a systemic disease, for example forming tumor metastasis in distant organs.

WO 2007/144384 PCT/EP2007/055846 - 76 Various diseases are caused aberrant cell proliferation ("hyperproliferation") as well as evasion from apoptosis. These diseases include e.g. benign hyperplasia like that of the prostate ("BPH") or colon epithelium, psoriasis, glomerulonephritis or osteoarthritis. Most importantly these diseases include malignant neoplasia commonly described as cancer and characterized by tumor cells finally metastasizing into distinct organs or tissues. Malignant neoplasia include solid and hematological tumors. Solid tumors are exemplified by tumors of the breast, bladder, bone, brain, central and peripheral nervous system, colon, endocrine glands (e.g. thyroid and adrenal cortex), esophagus, endometrium, germ cells, head and neck, kidney, liver, lung, larynx and hypopharynx, mesothelioma, sarcoma, ovary, pancreas, prostate, rectum, renal, small intestine, soft tissue, testis, stomach, skin, ureter, vagina and vulva. Malignant neoplasia include inherited cancers exemplified by retinoblastoma and Wilms tumor. In addition, malignant neoplasia include primary tumors in said organs and corresponding secondary tumors in distant organs ("tumor metastases"). Hematological tumors are exemplified by aggressive and indolent forms of leukemia and lymphoma, namely non-Hodgkins disease, chronic and acute myeloid leukemia (CML / AML), acute lymphoblastic leukemia (ALL), Hodgkins disease, multiple myeloma and T-cell lymphoma. Also included are myelodysplastic syndrome, plasma cell neoplasia, paraneoplastic syndromes, cancers of unknown primary site as well as AIDS related malignancies. The invention therefore relates to a use of the compounds according to the invention in the manufacture of pharmaceutical compositions, a method of treatment or a combination according to the invention, in which the cancer to be treated is selected from the group consisting of cancer of the breast, bladder, bone, brain, central and peripheral nervous system, colon, endocrine glands, esophagus, endometrium, germ cells, head and neck, kidney, liver, lung, larynx and hypopharynx, mesothelioma, sarcoma, ovary, pancreas, prostate, rectum, renal, small intestine, soft tissue, testis, stomach, skin, ureter, vagina and vulva; inherited cancers, retinomblastoma and Wilms tumor; leukemia, lymphoma, non-Hodgkins disease, chronic and acute myeloid leukaemia, acute lymphoblastic leukemia, Hodgkins disease, multiple myeloma and T-cell lymphoma; myelodysplastic syndrome, plasma cell neoplasia, paraneoplastic syndromes, cancers of unknown primary site and AIDS related malignancies. It is to be noted that a cancer disease as well as a malignant neoplasia does not necessarily require the formation of metastases in distant organs. Certain tumors exert devastating effects on the primary organ itself through their aggressive growth properties. These can lead to the destruction of the tissue and organ structure finally resulting in failure of the assigned organ function. Neoplastic cell proliferation might affect normal cell behaviour and organ function. For example the formation of new blood vessels, a process described as neovascularization, is induced by tumors or tumor metastases. Compounds according to this invention can be commercially applicable for the treatment of pathophysiological relevant processes caused by benign or neoplastic cell proliferation, WO 2007/144384 PCT/EP2007/055846 - 77 such as but not limited to neovascularization by unphysiological proliferation of vascular endothelial cells. Drug resistance is of particular importance for the frequent failure of standard cancer therapeutics. This drug resistance is caused by various cellular and molelcular mechanisms like overexpression of drug efflux pumps or mutation within the cellular target protein. The commercial applicability of the compounds according to this invention is not limited to 1 st line treatment of patients. Patients with resistance to defined cancer chemotherapeutics or target specific anti-cancer drugs ( 2 nd or 3 rd line treatment) can be also amenable for treatment with the compounds according to this invention. Due to their cellular anti-proliferative properties, compounds according to the present invention may be also commercially usable for treatment of diseases associated with cell cycle and cell proliferation, such as, besides cancer discussed above, for example, fibroproliferative and differentiative disorders, psoriasis, rheumatoid arthritis, atherosclerosis, hyperplasia, restenosis, cardiac hypertrophy, (auto)immune disorders, fungal disorders, bone diseases, or acute or chronic inflammation. Thus, the invention relates to compounds according to the invention for use in the treatment of diseases. Compounds according to the present invention can be commercially applicable for treatment, prevention or amelioration of the diseases of benign and malignant behavior as described before, such as e.g. benign or malignant neoplasia, particularly cancer (such as e.g. any of those cancer diseases described above), especially a cancer that is susceptible to Eg5 inhibition. In the context of their properties, functions and usabilities mentioned herein, the compounds according to the present invention are expected to be distinguished by valuable and desirable effects related therewith, such as e.g. by low toxicity, superior bioavailability in general (such as e.g. good enteral absorption), superior therapeutic window, absence of significant side effects, and/or further beneficial effects related with their therapeutic and pharmaceutical suitability. The invention further includes a method for treating (hyper)proliferative diseases and/or disorders responsive to the induction of apoptosis, particularly those diseases, disorders, conditions or illnesses mentioned above, in mammals, including humans, suffering therefrom comprising administering to said mammals in need thereof a pharmacologically and/or pharmaceutically active and therapeutically effective and tolerable amount of one or more of the compounds according to this invention. The present invention further includes a method useful to modulate apoptosis and/or aberrant cell growth in the therapy of benign or malignant neoplastic diseases, such as e.g. cancer, comprising administering to a subject in need of such therapy a pharmacologically and/or pharmaceutically active and therapeutically effective and tolerable amount of one or more of the compounds according to this invention.

WO 2007/144384 PCT/EP2007/055846 - 78 The invention further includes a method for modulating, particularly inhibiting, Eg5 activity in cells comprising administering a pharmacologically and/or pharmaceutically active and therapeutically effective and tolerable amount of one or more of the compounds according to this invention to a patient in need of such modulation, particularly inhibition. The present invention further includes a method to modulate the mitotic spindle, i.e., for example, altering mitotic spindle formation, including decreasing spindle formation, or increasing or decreasing spindle pole separation causing malformation of the mitotic spindle poles, comprising administering a pharmacologically and/or pharmaceutically active and therapeutically effective and tolerable amount of one or more of the compounds according to this invention to a patient in need of such modulation. The present invention further includes a method to inhibit mitosis in cells comprising administering a pharmacologically and/or pharmaceutically active and therapeutically effective and tolerable amount of one or more of the compounds according to this invention to a patient in need of such inhibition. The present invention further includes a method for treating, preventing or ameliorating diseases and/or disorders associated with Eg5 kinesin activity, such as, for example, (hyper)proliferative diseases and/or disorders responsive to induction of apoptosis, for example, benign neoplasia or malignant neoplasia, e.g. cancer, in a mammal comprising administering a pharmacologically and/or pharmaceutically active and therapeutically effective and tolerable amount of one or more compounds according to the present invention to said mammal in need thereof. The present invention further relates to the use of the compounds according to this invention for the production of pharmaceutical compositions which are employed for the treatment, prophylaxis and/or amelioration of one or more of the illnesses mentioned. The present invention further relates to the use of the compounds according to this invention for the production of pharmaceutical compositions which can be used in the treatment, prevention or amelioration of (hyper)proliferative diseases of benign or malignant behaviour and/or disorders responsive to the induction of apoptosis in a mammal, such as, for example, benign or malignant neoplasia, e.g. cancer. The present invention further relates to the use of the compounds according to this invention for the production of pharmaceutical compositions which can be used use in the treatment, prevention or amelioration of disorders responsive to arresting of aberrant cell growth and/or induction of apoptosis. The present invention further relates to the use of the compounds according to this invention for the production of pharmaceutical compositions for treating, preventing or ameliorating benign or malignant neoplasia, particularly cancer, such as e.g. any of those cancer diseases described above.

WO 2007/144384 PCT/EP2007/055846 - 79 The present invention further relates to pharmaceutical compositions comprising one or more of the compounds according to this invention and a pharmaceutically acceptable carrier or diluent. The present invention further relates to pharmaceutical compositions made by combining one or more of the compounds according to this invention and a pharmaceutically acceptable carrier or diluent. The present invention further relates to pharmaceutical compositions comprising one or more of the compounds according to this invention and pharmaceutically acceptable auxiliaries and/or excipients. The present invention also relates to pharmaceutical compositions for treating (hyper)proliferative diseases and/or disorders responsive to induction of apoptosis, which include benign neoplasia and malignant neoplasia, including cancer, comprising a compound according to this invention. The present invention further relates to combinations comprising one or more of the compounds according to this invention and pharmaceutically acceptable auxiliaries, excipients and/or vehicles, e.g. for treating, preventing or ameliorating benign or malignant neoplasia, particularly cancer, such as e.g. any of those cancer diseases described above. The present invention further relates to a combination comprising a compound according to this invention and a pharmaceutically acceptable excipient, carrier and/or diluent, e.g. for treating, preventing or ameliorating benign or malignant neoplasia, particularly cancer, such as e.g. any of those cancer diseases described above. The present invention further relates to a composition consisting essentially of a therapeutically effective and tolerable amount of one or more compounds according to this invention together with the usual pharmaceutically acceptable vehicles, diluents and/or excipients for use in therapy, e.g. for treating, preventing or ameliorating hyperproliferative diseases, such as e.g. cancer, and/or disorders responsive to induction of apoptosis. The present invention further relates to compounds according to this invention for use in therapy, such as, for example, in the treatment, prevention or amelioration of (hyper)proliferative diseases of benign or malignant behaviour and/or disorders responsive to the induction of apoptosis, such as e.g. those diseases mentioned herein, particularly cancer. The present invention further relates to compounds according to this invention having anti-proliferative and/or apoptosis inducing activity. The present invention further relates to compounds according to this invention having Eg5 inhibiting properties.

WO 2007/144384 PCT/EP2007/055846 - 80 The present invention further relates to pharmaceutical compositions according to this invention having Eg5 inhibiting properties. The present invention further relates to pharmaceutical compositions according to this invention having anti-proliferative activity. The present invention further relates to pharmaceutical compositions according to this invention having apoptosis inducing activity. The invention further relates to the use of a pharmaceutical composition comprising one or more of the compounds according to this invention as sole active ingredient(s) and a pharmaceutically acceptable carrier or diluent in the manufacture of pharmaceutical products for the treatment and/or prophylaxis of the illnesses mentioned above. Additionally, the invention relates to an article of manufacture, which comprises packaging material and a pharmaceutical agent contained within said packaging material, wherein the pharmaceutical agent is therapeutically effective inhibiting Eg5 and/or inhibiting cellular (hyper)proliferation and/or inducing apoptosis, ameliorating the symptoms of a Eg5 mediated disease and/or a (hyper)proliferative disease and/or a disorder responsive to the induction of apoptosis, and wherein the packaging material comprises a label or package insert which indicates that the pharmaceutical agent is useful for preventing or treating a Eg5 mediated disease and/or a (hyper)proliferative disease and/or a disorder responsive to the induction of apoptosis, and wherein said pharmaceutical agent comprises one or more compounds according to the invention. The packaging material, label and package insert otherwise parallel or resemble what is generally regarded as standard packaging material, labels and package inserts for pharmaceuticals having related utilities. The pharmaceutical compositions according to this invention are prepared by processes which are known per se and familiar to the person skilled in the art. As pharmaceutical compositions, the compounds of the invention (= active compounds) are either employed as such, or preferably in combination with suitable pharmaceutical auxiliaries and/or excipients, e.g. in the form of tablets, coated tablets, dragees, pills, cachets, granules, capsules, caplets, suppositories, patches (e.g. as TTS), emulsions (such as e.g. micro-emulsions or lipid emulsions), suspensions (such as e.g. nano suspensions), gels, solubilisates or solutions (e.g. sterile solutions), or encapsuled in liposomes or as beta-cyclodextrine inclusion complexes or the like, the active compound content advantageously being between 0.1 and 95% and where, by the appropriate choice of the auxiliaries and/or excipients, a pharmaceutical administration form (e.g. a delayed release form or an enteric form) exactly suited to the active compound and/or to the desired onset of action can be achieved.

WO 2007/144384 PCT/EP2007/055846 - 81 The person skilled in the art is familiar with auxiliaries, vehicles, excipients, diluents, carriers or adjuvants which are suitable for the desired pharmaceutical formulations, preparations or compositions on account of his/her expert knowledge. In addition to solvents, gel formers, ointment bases and other active compound excipients, for example antioxidants, dispersants, emulsifiers, pre servatives, solubilizers (such as e.g. polyoxyethylenglyceroltriricinoleat 35, PEG 400, Tween 80, Solutol HS15 or the like), colorants, complexing agents, permeation promoters, stabilizers, fillers, binders, thickeners, disintegrating agents, buffers, pH regulators (e.g. to obtain neutral, alkaline or acidic formulations), polymers, lubricants, coating agents, propellants, tonicity adjusting agents, surfactants, flavorings, sweeteners or dyes, can be used. In particular, auxiliaries and/or excipients of a type appropriate to the desired formulation and the desired mode of administration are used. The administration of the compounds, pharmaceutical compositions or combinations according to the invention may be performed in any of the generally accepted modes of administration available in the art. Illustrative examples of suitable modes of administration include intravenous, oral, nasal, parenteral, topical, transdermal and rectal delivery. Oral and intravenous delivery are preferred. For the treatment of dermatoses, the compounds of the invention can be in particular administered in the form of those pharmaceutical compositions which are suitable for topical application. For the production of the pharmaceutical compositions, the compounds of the invention (= active compounds) are preferably mixed with suitable pharmaceutical auxiliaries and further processed to give suitable pharmaceutical formulations. Suitable pharmaceutical formulations are, for example, powders, emulsions, suspensions, sprays, oils, ointments, fatty ointments, creams, lotions, pastes, gels or solutions. The pharmaceutical compositions according to the invention can be prepared by processes known per se. The dosage of the compounds of the invention (= active compounds) is carried out in the order of magnitude customary for Eg5 inhibitors, inhibitors for cellular (hyper)proliferation or apoptosis inducers. Topical application forms (such as ointments) for the treatment of dermatoses thus contain the active compounds in a concentration of, for example, 0.1-99%. The customary dose in the case of systemic therapy (p.o.) may be between 0.03 and 60 mg/kg per day, (i. v.) may be between 0.03 and 60 mg/kg/h. In another embodiment, the customary dose in the case of systemic therapy (p.o.) is between 0.3 and 30 mg/kg per day, (i. v.) is between 0.3 and 30 mg/kg/h. The choice of the optimal dosage regime and duration of medication, particularly the optimal dose and manner of administration of the active compounds necessary in each case can be determined by a person skilled in the art on the basis of his/her expert knowledge. Depending upon the particular disease, to be treated or prevented, additional therapeutic active agents, which are normally administered to treat or prevent that disease, may optionally be coadministered with the compounds according to this invention. As used herein, additional therapeutic WO 2007/144384 PCT/EP2007/055846 - 82 agents that are normally administered to treat or prevent a particular disease are known as appropriate for the disease being treated. For example, compounds according to this invention may be combined with one or more standard therapeutic agents used for treatment of the diseases as mentioned before. In one particular embodiment, compounds according to this invention may be combined with one or more art-known anti-cancer agents, such as e.g. with one or more chemotherapeutic and/or target specific anti-cancer agents as described below. Examples of known chemotherapeutic anti-cancer agents frequently used in combination therapy include, but not are limited to (i) alkylating/carbamylating agents such as Cyclophosphamid (Endoxan®), Ifosfamid (Holoxan®), Thiotepa (Thiotepa Lederle®), Melphalan (Alkeran®), or chloroethylnitrosourea (BCNU); (ii) platinum derivatives like cis-platin (Platinex® BMS), oxaliplatin, satraplatin or carboplatin (Cabroplat® BMS); (iii) antimitotic agents / tubulin inhibitors such as vinca alkaloids (vincristine, vinblastine, vinorelbine), taxanes such as Paclitaxel (Taxol®), Docetaxel (Taxotere®) and analogs as well as new formulations and conjugates thereof, epothilones such as Epothilone B (Patupilone®), Azaepothilone (Ixabepilone®) or ZK-EPO, a fully synthetic epothilone B analog; (iv) topoisomerase inhibitors such as anthracyclines (exemplified by Doxorubicin / Adriblastin®), epipodophyllotoxines (examplified by Etoposide / Etopophos®) and camptothecin and camptothecin analogs (exemplified by Irinotecan / Camptosar® or Topotecan / Hycamtin®); (v) pyrimidine antagonists such as 5-fluorouracil (5-FU), Capecitabine (Xeloda®), Arabinosylcytosine / Cytarabin (Alexan®) or Gemcitabine (Gemzar®); (vi) purin antagonists such as 6-mercaptopurine (Puri-Nethol®), 6-thioguanine or fludarabine (Fludara®) and finally (vii) folic acid antagonists such as methotrexate (Farmitrexat®) or premetrexed (Alimta®). Examples of target specific anti-cancer drug classes used in experimental or standard cancer therapy include but are not limited to (i) kinase inhibitors such as e.g. Imatinib (Glivec®), ZD-1839 / Gefitinib (Iressa®), Bay43-9006 (Sorafenib), SU11248 / Sunitinib (Sutent®) or OSI-774 / Erlotinib (Tarceva®); (ii) proteasome inhibitors such as PS-341 / Bortezumib (Velcade®); (iii) histone deacetylase inhibitors like SAHA, PXD101, MS275, MGCD0103, Depsipeptide / FK228, NVP-LBH589, NVP-LAQ824, Valproic acid (VPA) and butyrates (iv) heat shock protein 90 inhibitors like 17-allylaminogeldanamycin (17-AAG); (v) vascular targeting agents (VTAs) like combretastin A4 phosphate or AVE8062 / AC7700 and anti-angiogenic drugs like the VEGF antibodies, such as Bevacizumab (Avastin®), or KDR tyrosine kinase inhibitors such as PTK787 / ZK222584 (Vatalanib); (vi) monoclonal antibodies such as Trastuzumab (Herceptin®) or Rituximab (MabThera / Rituxan®) or Alemtuzumab (Campath®) or Tositumab (Bexxar®) or C225/ Cetuximab (Erbitux®) or Avastin (see above) as well as mutants and conjugates of monoclonal antibodies, e.g. Gemtuzumab ozogamicin (Mylotarg®) or Ibritumomab tiuxetan (Zevalin®), and antibody fragments; (vii) oligonucleotide based therapeutics like G-3139 / Oblimersen (Genasense®); (viii) Toll-like receptor / TLR 9 agonists like Promune®, TLR 7 agonists WO 2007/144384 PCT/EP2007/055846 - 83 like Imiquimod (Aldara®) or Isatoribine and analogues thereof, or TLR 7/8 agonists like Resiquimod as well as immunostimulatory RNA as TLR 7/8 agonists; (ix) protease inhibitors (x) hormonal therapeutics such as anti-estrogens (e.g. Tamoxifen or Raloxifen), anti-androgens (e.g. Flutamide or Casodex), LHRH analogs (e.g. Leuprolide, Goserelin or Triptorelin) and aromatase inhibitors. Other known target specific anti-cancer agents which may be used for combination therapy include bleomycin, retinoids such as all-trans retinoic acid (ATRA), DNA methyltransferase inhibitors such as the 2-deoxycytidine derivative Decitabine (Dacogen®) and 5-azacytidine, alanosine, cytokines such as interleukin-2, interferons such as interferon cx2 or interferon-y, death receptor agonists, such as TRAIL, DR4/5 agonistic antibodies, FasL and TNF-R agonists. As exemplary anti-cancer agents, which may be useful in the combination therapy according to the present invention, any of the following drugs may be mentioned, without being restricted thereto, 5 FU, actinomycin D, ABARELIX, ABCIXIMAB, ACLARUBICIN, ADAPALENE, ALEMTUZUMAB, ALTRETAMINE, AMINOGLUTETHIMIDE, AMIPRILOSE, AMRUBICIN, ANASTROZOLE, ANCITABINE, ARTEMISININ, AZATHIOPRINE, BASILIXIMAB, BENDAMUSTINE, BEVACIZUMAB, BEXXAR, BICALUTAMIDE, BLEOMYCIN, BORTEZOMIB, BROXURIDINE, BUSULFAN, CAMPATH, CAPECITABINE, CARBOPLATIN, CARBOQUONE, CARMUSTINE, CETRORELIX, CHLORAM BUCIL, CHLORMETHINE, CISPLATIN, CLADRIBINE, CLOMIFENE, CYCLOPHOSPHAMIDE, DACARBAZINE, DACLIZUMAB, DACTINOMYCIN, DAUNORUBICIN, DECITABINE, DESLORELIN, DEXRAZOXANE, DOCETAXEL, DOXIFLURIDINE, DOXORUBICIN, DROLOXIFENE, DROSTANOLONE, EDELFOSINE, EFLORNITHINE, EMITEFUR, EPIRUBICIN, EPITIOSTANOL, EPTAPLATIN, ERBITUX, ERLOTINIB, ESTRAMUSTINE, ETOPOSIDE, EXEMESTANE, FADROZOLE, FINASTERIDE, FLOXURIDINE, FLUCYTOSINE, FLUDARABINE, FLUOROURACIL, FLUTAMIDE, FORMESTANE, FOSCARNET, FOSFESTROL, FOTEMUSTINE, FULVESTRANT, GEFITINIB, GENASENSE, GEMCITABINE, GLIVEC, GOSERELIN, GUSPERIMUS, HERCEPTIN, IDARUBICIN, IDOXURIDINE, IFOSFAMIDE, IMATINIB, IMPROSULFAN, INFLIXIMAB, IRINOTECAN, IXABEPILONE, LANREOTIDE, LETROZOLE, LEUPRORELIN, LOBAPLATIN, LOMUSTINE, LUPROLIDE, MELPHALAN, MERCAPTOPURINE, METHOTREXATE, METUREDEPA, MIBOPLATIN, MIFEPRISTONE, MILTEFOSINE, MIRIMOSTIM, MITOGUAZONE, MITOLACTOL, MITOMYCIN, MITOXANTRONE, MIZORIBINE, MOTEXAFIN, MYLOTARG, NARTOGRASTIM, NEBAZUMAB, NEDAPLATIN, NILUTAMIDE, NIMUSTINE, OCTREOTIDE, ORMELOXIFENE, OXALI PLATIN, PACLITAXEL, PALIVIZUMAB, PATUPILONE, PEGASPARGASE, PEGFILGRASTIM, PEMETREXED, PENTETREOTIDE, PENTOSTATIN, PERFOSFAMIDE, PIPOSULFAN, PIRARUBICIN, PLICAMYCIN, PREDNIMUSTINE, PROCARBAZINE, PROPAGERMANIUM, PROSPIDIUM CHLORIDE, RALOXIFEN, RALTITREXED, RANIMUSTINE, RANPIRNASE, RASBURICASE, RAZOXANE, RITUXIMAB, RIFAMPICIN, RITROSULFAN, ROMURTIDE, RUBOXISTAURIN, SARGRAMOSTIM, SATRAPLATIN, SIROLIMUS, SOBUZOXANE, SORAFENIB, SPIROMUSTINE, STREPTOZOCIN, SUNITINIB, TAMOXIFEN, TASONERMIN, TEGAFUR, TEMOPORFIN, TEMOZOLOMIDE, TENIPOSIDE, TESTOLACTONE, THIOTEPA, THYMALFASIN, WO 2007/144384 PCT/EP2007/055846 - 84 TIAMIPRINE, TOPOTECAN, TOREMIFENE, TRAIL, TRASTUZUMAB, TREOSULFAN, TRIAZIQUONE, TRIMETREXATE, TRIPTORELIN, TROFOSFAMIDE, UREDEPA, VALRUBICIN, VATALANIB, VERTEPORFIN, VINBLASTINE, VINCRISTINE, VINDESINE, VINORELBINE, VOROZOLE and ZEVALIN. The anti-cancer agents mentioned herein above as combination partners of the compounds according to this invention are meant to include pharmaceutically acceptable derivatives thereof, such as e.g. their pharmaceutically acceptable salts. The person skilled in the art is aware on the base of his/her expert knowledge of the kind, total daily dosage(s) and administration form(s) of the additional therapeutic agent(s) coadministered. Said total daily dosage(s) can vary within a wide range. In practicing the present invention, the compounds according to this invention may be administered in combination therapy separately, sequentially, simultaneously, concurrently or chronologically staggered (such as e.g. as combined unit dosage forms, as separate unit dosage forms, as adjacent discrete unit dosage forms, as fixed or non-fixed combinations, as kit-of-parts or as admixtures) with one or more standard therapeutics (chemotherapeutic and/or target specific anti-cancer agents), in particular art-known anti-cancer agents, such as any of e.g. those mentioned above. In this context, the present invention further relates to a combination comprising a first active ingredient, which is at least one compound according to this invention, and a second active ingredient, which is at least one art-known anti-cancer agent, such as e.g. one or more of those mentioned herein above, for separate, sequential, simultaneous, concurrent or chronologically staggered use in therapy, such as e.g. in therapy of any of those diseases mentioned herein. The term "combination" according to this invention may be present as a fixed combination, a non-fixed combination or a kit-of-parts. A "fixed combination" is defined as a combination wherein the said first active ingredient and the said second active ingredient are present together in one unit dosage or in a single entity. One example of a "fixed combination" is a pharmaceutical composition wherein the said first active ingredient and the said second active ingredient are present in admixture for simultaneous administration, such as in a formulation. Another example of a "fixed combination" is a pharmaceutical combination wherein the said first active ingredient and the said second active ingredient are present in one unit without being in admixture. A "kit-of-parts" is defined as a combination wherein the said first active ingredient and the said second active ingredient are present in more than one unit. One example of a "kit-of-parts" is a combination WO 2007/144384 PCT/EP2007/055846 - 85 wherein the said first active ingredient and the said second active ingredient are present separately. The components of the may be administered separately, sequentially, simultaneously, concurrently or chronologically staggered. The present invention further relates to a pharmaceutical composition comprising a first active ingredient, which is at least one compound according to this invention, and a second active ingredient, which is at least one art-known anti-cancer agent, such as e.g. one or more of those mentioned herein above, and, optionally, a pharmaceutically acceptable carrier or diluent, for separate, sequential, simultaneous, concurrent or chronologically staggered use in therapy. The present invention further relates to a combination product comprising a.) at least one compound according to this invention formulated with a pharmaceutically acceptable carrier or diluent, and b.) at least one art-known anti-cancer agent, such as e.g. one or more of those mentioned herein above, formulated with a pharmaceutically acceptable carrier or diluent. The present invention further relates to a kit-of-parts comprising a preparation of a first active ingredient, which is a compound according to this invention, and a pharmaceutically acceptable carrier or diluent; a preparation of a second active ingredient, which is an art-known anti-cancer agent, such as one of those mentioned above, and a pharmaceutically acceptable carrier or diluent; for simultaneous, concurrent, sequential, separate or chronologically staggered use in therapy. Optionally, said kit comprises instructions for its use in therapy, e.g. to treat (hyper)proliferative diseases and/or disorders responsive to the induction of apoptosis, such as e.g. cancer, more precisely, any of those cancer diseases described above. The present invention further relates to a combined preparation comprising at least one compound according to this invention and at least one art-known anti-cancer agent for simultaneous, concurrent, sequential or separate administration. The present invention further relates to combinations, compositions, formulations, preparations or kits according to the present invention having Eg5 inhibitory activity and/or anti-proliferative and/or apoptosis inducing properties. In addition, the present invention further relates to a method for treating in combination therapy (hyper)proliferative diseases and/or disorders responsive to the induction of apoptosis, such as e.g. cancer, in a patient comprising administering a combination, composition, formulation, preparation or kit as described herein to said patient in need thereof.

WO 2007/144384 PCT/EP2007/055846 - 86 In addition, the present invention further relates to a method for treating (hyper)proliferative diseases of benign or malignant behaviour and/or disorders responsive to the induction of apoptosis, such as e.g. cancer, in a patient comprising administering in combination therapy separately, simultaneously, concurrently, sequentially or chronologically staggered a pharmaceutically active and therapeutically effective and tolerable amount of a pharmaceutical composition, which comprises a compound according to this invention and a pharmaceutically acceptable carrier or diluent, and a pharmaceutically active and therapeutically effective and tolerable amount of one or more art-known anti-cancer agents, such as e.g. one or more of those mentioned herein, to said patient in need thereof. In further addition, the present invention relates to a method for treating, preventing or ameliorating (hyper)proliferative diseases and/or disorders responsive to induction of apoptosis, such as, for example, benign or malignant neoplasia, e.g. cancer, particularly any of those cancer diseases mentioned herein, in a patient comprising administering separately, simultaneously, concurrently, sequentially or chronologically staggered to said patient in need thereof an amount of a first active compound, which is a compound according to the present invention, and an amount of at least one second active compound, said at least one second active compound being a standard therapeutic agent, particularly at least one art-known anti-cancer agent, such as e.g. one or more of those chemotherapeutic and target-specific anti-cancer agents mentioned herein, wherein the amounts of the first active compound and said second active compound result in a therapeutic effect. In yet further addition, the present invention relates to a method for treating, preventing or ameliorating (hyper)proliferative diseases and/or disorders responsive to induction of apoptosis, such as e.g. benign or malignant neoplasia, e.g. cancer, particularly any of those cancer diseases mentioned herein, in a patient comprising administering a combination according to the present invention. In addition, the present invention further relates to the use of a composition, combination, formulation, preparation or kit according to this invention in the manufacture of a pharmaceutical product, such as e.g. a commercial package or a medicament, for treating, preventing or ameliorating (hyper)proliferative diseases, such as e.g. cancer, and/or disorders responsive to the induction of apoptosis, particularly those diseases mentioned herein, such as e.g. malignant or benign neoplasia. The present invention further relates to a commercial package comprising one or more compounds of the present invention together with instructions for simultaneous, concurrent, sequential or separate use with one or more chemotherapeutic and/or target specific anti-cancer agents, such as e.g. any of those mentioned herein. The present invention further relates to a commercial package consisting essentially of one or more compounds of the present invention as sole active ingredient together with instructions for WO 2007/144384 PCT/EP2007/055846 - 87 simultaneous, concurrent, sequential or separate use with one or more chemotherapeutic and/or target specific anti-cancer agents, such as e.g. any of those mentioned herein. The present invention further relates to a commercial package comprising one or more chemotherapeutic and/or target specific anti-cancer agents, such as e.g. any of those mentioned herein, together with instructions for simultaneous, concurrent, sequential or separate use with one or more compounds according to the present invention. The compositions, combinations, preparations, formulations, kits or packages mentioned in the context of the combination therapy according to this invention may also include more than one of the compounds according to this invention and/or more than one of the art-known anti-cancer agents mentioned. The first and second active ingredient of a combination or kit-of-parts according to this invention may be provided as separate formulations (i.e. independently of one another), which are subsequently brought together for simultaneous, concurrent, sequential, separate or chronologically staggered use in combination therapy; or packaged and presented together as separate components of a combination pack for simultaneous, concurrent, sequential, separate or chronologically staggered use in combination therapy. The type of pharmaceutical formulation of the first and second active ingredient of a combination or kit-of-parts according to this invention can be similar, i.e. both ingredients are formulated in separate tablets or capsules, or can be different, i.e. suited for different administration forms, such as e.g. one active ingredient is formulated as tablet or capsule and the other is formulated for e.g. intravenous administration. The amounts of the first and second active ingredients of the combinations, compositions or kits according to this invention may together comprise a therapeutically effective amount for the treatment, prophylaxis or amelioration of a (hyper)proliferative diseases and/or a disorder responsive to the induction of apoptosis, particularly one of those diseases mentioned herein, such as e.g. malignant or benign neoplasia, especially cancer, like any of those cancer diseases mentioned herein. In addition, compounds according to the present invention can be used in the pre- or post-surgical treatment of cancer. In further addition, compounds of the present invention can be used in combination with radiation therapy. A combination according to this invention can refer to a composition comprising both the compound(s) according to this invention and the other active anti-cancer agent(s) in a fixed combination (fixed unit WO 2007/144384 PCT/EP2007/055846 - 88 dosage form), or a medicament pack comprising the two or more active ingredients as discrete separate dosage forms (non-fixed combination). In case of a medicament pack comprising the two or more active ingredients, the active ingredients are preferably packed into blister cards which are suited for improving compliance. Each blister card preferably contains the medicaments to be taken on one day of treatment. If the medicaments are to be taken at different times of day, the medicaments can be disposed in different sections on the blister card according to the different ranges of times of day at which the medicaments are to be taken (for example morning and evening or morning, midday and evening). The blister cavities for the medicaments to be taken together at a particular time of day are accommodated in the respective range of times of day. The various times of day are, of course, also put on the blister in a clearly visible way. It is also possible, of course, for example to indicate a period in which the medicaments are to be taken, for example stating the times. The daily sections may represent one line of the blister card, and the times of day are then identified in chronological sequence in this column. Medicaments which must be taken together at a particular time of day are placed together at the appropriate time on the blister card, preferably a narrow distance apart, allowing them to be pushed out of the blister easily, and having the effect that removal of the dosage form from the blister is not forgotten.

WO 2007/144384 PCT/EP2007/055846 - 89 Biological Investigations The ATPase activity of Eg5 kinesin motor domains (Cytoskeleton, cat. No. EG01) can be used to monitor the effects of modulating agents. The test compounds are dissolved as 10 mM solutions in dimethylsulfoxide (DMSO). 2 pl of appropriate DMSO dilutions of the test compounds are added to each well of a 96 well flat bottom plate. Each compound dilution is tested as triplicates. The reagents are added and the final reaction of the standard assay contains 15 mM Pipes, pH 6.8, 5.0 mM MgCI 2 , 0.5 mM KCI, 1 mM EGTA, 0.1 mg/ml BSA, 1 pM Paclitaxel, 250 nM preformed microtubules (Cytoskeleton, cat. No. MT001), 300 pM ATP, and Eg5 protein (50 ng) in a reaction volume of 100 pl. The controls include buffer wells with ATP and 2% DMSO. Reactions are started by the addition of ATP, incubated at room temperature for 30 min., and terminated by removing 20 pl of the reaction volume and adding it to 80 pl of 1 M perchloric acid, followed by the addition of 80 pl Malachite green reagent. Malachite green reagent is prepared by mixing a solution of 4.2 g ammonium molybdate in 100 ml 4 N HCI with a solution of 0.135 g Malachite green in 300 ml H 2 0. The reactions are incubated for a further 20 min. and then read at 615 nm. The corresponding IC50 values of the compounds for Eg5 inhibition are determined from the concentration-effect curves. Representative inhibitory values [measured as -log IC50 (mol/1)] determined in the aforementioned assay follow from the following table A, in which the numbers of the compounds correspond to the numbers of the examples. Table A Inhibition of Eg5 activity Compound -log IC50 [mol/I] 2 to9, 9a, 10 and The inhibitory values of these listed 11 compounds are all - 6.6 The anti-proliferative / cytotoxic activity of the compounds described herein can be tested on subclones of RKO human colon adenocarcinoma cells (Schmidt et al., Oncogene 19, 2423-2429; 2000) using the Alamar Blue cell viability assay (described in O'Brien et al. Eur J Biochem 267, 5421 5426, 2000). The compounds are dissolved as 10 mM solutions in DMSO and subsequently diluted in semi-logarithmic steps. DMSO dilutions are further diluted 1:100 into Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal calf serum to a final concentration twice as much as the final concentration in the test. RKO subclones are seeded into 96 well flat bottom plates at a density of 4000 cells per well in a volume of 50 pl per well. 24 hours after seeding the 50 pl each of the compound dilutions in DMEM medium are added into each well of the 96 well plate. Each compound dilution is tested as triplicates. Wells containing untreated control cells are filled with 50 pl DMEM medium containing 1% DMSO. The cells are then incubated with the substances for 72 hours at 370C WO 2007/144384 PCT/EP2007/055846 -90 in a humidified atmosphere containing 5% carbon dioxide. To determine the viability of the cells, 10 pl of an Alamar Blue solution (Biosource) are added and the fluorescence is measured at an extinction of 544 nm and an emission of 590 nm. For the calculation of the cell viability the emission value from untreated cells is set as 100% viability and the emission rates of treated cells are set in relation to the values of untreated cells. Viabilities are expressed as % values. The Graphpad Prism program is used for the calculation of EC 50 values for anti-proliferative / cytotoxic activity out of the obtained dose response curves. To determine the cell cycle specific mode of action, subclones of RKO colon adenocarcinoma cells (RKOp27 as described by Schmidt et al. in Oncogene 19, 2423-2429; 2000) are seeded into 96 well flat bottom plates at a density of 16000 cells per well in a volume of 50 pl per well in DMEM growth medium with 10% FCS containing 10 pM Ponasterone A. 24 hours after seeding the 50 pl each of the compound dilutions in DMEM medium are added into each well of the 96-well plate. Each compound dilution is tested as triplicates. Wells containing untreated control cells are filled with 50 pl DMEM medium containing 1% DMSO. The cells are then incubated with the substances for 72 hours at 370C in a humidified atmosphere containing 5% carbon dioxide. To determine the viability of the cells, 10 pl of an Alamar Blue solution (Biosource) are added and the fluorescence is measured at an extinction of 544 nm and an emission of 590 nm. For the calculation of the cell viability the emission value from untreated cells is set as 100% viability and the emission rates of treated cells are set in relation to the values of untreated cells. Viabilities are expressed as % values. The Graphpad Prism program is used for the calculation of EC 50 values out of the obtained dose-response curves. Viability is compared of proliferating cells grown in the absence of the inducer Ponasterone A, versus viability of cells arrested by the expression of ectopic p27Kip1 induced by Ponasterone A. Representative values for anti-proliferation / cytotoxicity [measured as -log EC 50 (mol/1)] determined in the aforementioned assays follow from the following table B, in which the numbers of the compounds correspond to the numbers of the examples. Table B Anti-proliferative I cytotoxic activity on RKO colon cancer cells Examples -log EC5o [mol/I] -log E 50 [mo/ 2, 3, 4, 5, 6, 7, 8, 8a, 9a, 13, RKO p27 uninduced 14, 17, 18, 19,20,21,22,24 (proliferating) > 7.0 -log EC 50 [mol/I] RKO p27 uninduced 1, 9, 10, 11, 12, 15, 16, 23 (proliferating) < 7.0 but > 6.0 WO 2007/144384 PCT/EP2007/055846 -91 The value of -log EC 50 [mol/I] RKO p27 induced (arrested) was below the minimum determined by the assay specification (<: 5.0, < 5.5 or < 6.0). The induction of apoptosis can be measured by using a Cell death detection ELISA (Roche Biochemicals, Mannheim, Germany). NCI-H460 non-small cell lung cancer cells are seeded into 96 well flat bottom plates at a density of 10000 cells per well in a volume of 50 pl RPMI medium (containing 10% fetal calf serum) per well. The compounds are dissolved as 10 mM solutions in DMSO and subsequently diluted in semi-logarithmic steps. DMSO dilutions are further diluted 1:100 into RPMI medium (containing 10% fetal calf serum) to a final concentration twice as much as the final concentration in the test. 24 hours after seeding the 50 pl each of the compound dilutions in RPMI medium are added into each well of the 96 Well plate. Each compound dilution is tested at least as duplicates. Wells containing untreated control cells are filled with 50 pl RPMI medium containing 1% DMSO. The cells are then incubated with the substances for 24 hours at 370C in a humidified atmosphere containing 5% carbon dioxide. As a positive control for the induction of apoptosis, cells are treated with 50 pM Cisplatin (Gry Pharmaceuticals, Kirchzarten, Germany). Medium is then removed and the cells are lysed in 200 pl lysis buffer. After centrifugation as described by the manufacturer, 10 pl of cell lysate is processed as described in the protocol. The degree of apoptosis is calculated as follows: The absorbance at 405 nm obtained with lysates from cells treated with 50 pM cisplatin is set as 100 cpu (cisplatin units), while an absorbance at 405 nm of 0.0 is set as 0.0 cpu. The degree of apoptosis is expressed as cpu in relation to the value of 100 cpu reached with the lysates obtained from cells treated with 50 pM cisplatin. Experimental perturbation of Eg5 function causes a characteristic malformation of the mitotic spindle, which can be examined by confocal laser scanning microscopy. HeLa cervical cancer cells are grown overnight on glass cover slips (Nunc T M Lab-Tek T M Chamber Slides) in 1800 pl DMEM medium containing 10% fetal calf serum. The test compounds are dissolved as 10 mM solutions in DMSO. Appropriate DMSO dilutions of the test compounds are further diluted 1:20 into DMEM medium containing 10% fetal calf serum to a final concentration ten times as much as the final concentration in the test. 24 hours after seeding, 200 pl of the compound dilutions in DMEM medium are added into each well of the cover slip. As a control, 200 pl DMEM medium containing 5% DMSO are added. 24 hours after incubation with the test compounds, the cells are washed with PBS, and fixed with 3.7% formaldehyde in H 2 0 for 20 min. at 37 0 C. Subsequently, cells are washed with PBS and incubated with 0,1% Triton X-100 in a buffer containing 1.471 mM KH 2

PO

4 , 8.504 mM Na 2

HPO

4 , 137 mM NaCI, 1.325 mM CaC 2 , 2.685 mM KCI, 0.542 mM MgCI 2 , pH 7.2 for 15 min. at room temperature. For saturation of non-specific binding, cells are incubated in 2% BSA/10% FCS in PBS (= blocking buffer) for 30 min. at room temperature prior to incubation with anti-alpha tubulin monoclonal antibodies (Sigma, #T5168; 1:1000), followed by Cy3-conjugated rabbit anti-mouse IgG (H+L) antibody (Jackson Immuno Research; 1:1000). All antibody incubations are performed for one hour at 37 oC in blocking buffer, and cells are washed three times in PBS between different incubations. DNA is counterstained with Hoechst 33342 (0.1 pg/ml). Coverslips are mounted in Vectashield (Vector Laboratories, WO 2007/144384 PCT/EP2007/055846 - 92 Burlingame, CA) and examined with a Leica TCS SP2 confocal laser scanning microscope fitted with appropriate filters (Leica Microsystems, Bensheim, Germany). Some of the compounds according to this invention may be efficacious against p-glycoprotein mediated multidrug-resistent tumour cell lines (e.g. HCT-15), that can be measured as follows: All cell lines used are cultured at standard conditions in a tissue culture incubator at 370C, 5% CO2 and 95% humidity. At day 1, cells are detached with Trypsin / EDTA and pelleted by centrifugation. Cells are resuspended at the appropriate density in culture medium, seeded into 96well microtiter plates and incubated over night in a tissue culture incubator at 37 0 C, 5% CO 2 and 95% humidity. Stock solution of all compounds to be tested are dissolved at 10mM in DMSO and at day 2 added to the microtiter plates in the desired dilutions. The final DMSO concentration in the microtiter plates is kept at 0.5 %. Control cells are treated with culture medium including a final concentration of 0.5% DMSO only. The microtiter plates are incubated with the compounds in a tissue culture incubator at 37 0 C, 5% CO 2 and 95% humidity for further 72 hours. To determine the viability of the cells at day 5, an Alamar Blue solution (Biosource) is added at 1/10 culture volume to the microtiter plates. The cells are incubated in a tissue culture incubator at 37 0 C, 5% CO 2 and 95% humidity for additional 1-6 hours and the fluorescence is measured at an extinction of 544 nm and an emission of 590 nm. For the calculation of the cell viability the emission value from untreated cells is set as 100% viability and the emission rates of treated cells are set in relation to the values of untreated cells. Viabilities are expressed as % values. The Graphpad Prism program is used for the calculation of EC 50 values out of the obtained dose response curves.

Claims

1. Compounds of formula I O N N,' NA NN R2 / H R4 R1 R1 O N N(R5)R6 n B (I) in which R1 is hydrogen or halogen, R2 is 1-4C-alkyl, A is Aryl-1-4C-alkyl, in which Aryl is phenyl, or R3- and R31-substituted phenyl, in which R3 is 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy, hydroxyl, halogen, or completely or predominantly fluorine-substituted 1-4C-alkoxy, R31 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy, R4 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or 3-7C-cycloalkyl-1-4C-alkyl, R5 is hydrogen or 1-4C-alkyl, R6 is hydrogen or 1-4C-alkyl, B is phenyl, or R7- and R71-substituted phenyl, in which R7 is 1-4C-alkyl, trifluoromethyl, cyano, 1-4C-alkoxy, halogen, carboxyl, 1-4C-alkylcarbonyl, methylenedioxy, ethylenedioxy, 1-4C-alkoxy-1-4C-alkyl, hydroxy-1-4C-alkyl, or completely or predominantly fluorine-substituted 1-4C-alkoxy, R71 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy, n is 2, 3, 4, 5 or 6, and the salts, stereoisomers and the salts of the stereoisomers of these compounds.

2. Compounds of formula I according to claim 1, in which R1 is hydrogen or halogen, R2 is methyl or ethyl, A is Arylmethyl, in which Aryl is phenyl, or R3- and R31-substituted phenyl, in which R3 is methyl, ethyl, trifluoromethyl, methoxy, ethoxy, hydroxyl, halogen, difluoromethoxy or trifluoromethoxy, R31 is hydrogen, halogen, methyl, ethyl, methoxy or ethoxy, R4 is methyl, ethyl, propyl, isopropyl, sec-butyl, cyclopropyl or cyclopropylmethyl, WO 2007/144384 PCT/EP2007/055846 - 94 R5 is hydrogen, methyl, ethyl, propyl or isopropyl, R6 is hydrogen, methyl, ethyl, propyl or isopropyl, B is phenyl, or R7- and R71-substituted phenyl, in which R7 is methyl, ethyl, trifluoromethyl, cyano, methoxy, ethoxy, halogen, carboxyl, acetyl, methylenedioxy, ethylenedioxy, methoxymethyl, hydroxymethyl, difluoromethoxy or trifluoromethoxy, R71 is hydrogen, halogen, methyl, ethyl, methoxy or ethoxy, n is 2, 3 or 4, and the salts, stereoisomers and the salts of the stereoisomers of these compounds.

3. Compounds of formula I according to claim 1, in which R1 is hydrogen, chlorine or bromine, R2 is methyl or ethyl, A is benzyl, halobenzyl (e.g. fluorobenzyl, chlorobenzyl or bromobenzyl), methylbenzyl, methoxybenzyl or hydroxybenzyl, R4 is ethyl, propyl, isopropyl, sec-butyl or cyclopropyl, either R5 and R6 are both hydrogen, or R5 is methyl, and R6 is hydrogen, or R5 is ethyl, and R6 is hydrogen, or R5 is propyl, and R6 is hydrogen, or R5 is isopropyl, and R6 is hydrogen, or R5 and R6 are both methyl, B is phenyl, or R7- and R71-substituted phenyl, in which R7 is methyl, ethyl, trifluoromethyl, cyano, methoxy, ethoxy, halogen, carboxyl, methylenedioxy, ethylenedioxy, methoxymethyl or hydroxymethyl, R71 is hydrogen, halogen, methyl or ethyl, n is 2 or 3, and the salts, stereoisomers and the salts of the stereoisomers of these compounds. WO 2007/144384 PCT/EP2007/055846 -95

4. Compounds of formula I according to any of the preceding claims comprising one or more of the following: R1 is chlorine or bromine; R2 is methyl; A is benzyl; R4 is ethyl or isopropyl; either R5 and R6 are both hydrogen, or R5 and R6 are both methyl; B is 4-methylphenyl, 3-methylphenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4 chlorophenyl, 4-bromophenyl or 3-fluoro-4-methylphenyl; and n is 3; and the salts, stereoisomers and the salts of the stereoisomers of these compounds.

5. Compounds of formula I according to claim 1, in which R1 is hydrogen, chlorine, bromine or fluorine, R2 is methyl, A is benzyl, R4 is ethyl, isopropyl, sec-butyl, cyclopropyl or cyclobutyl, either R5 and R6 are both hydrogen, or R5 and R6 are both methyl, B is 4-methylphenyl, 3-methylphenyl, 4-fluorophenyl, 4-bromophenyl, 4-chlorophenyl, 4 methoxyphenyl, 4-trifluoromethylphenyl, 3-fluoro-4-methylphenyl, 2-fluoro-4-methylphenyl, 3,4 dichlorophenyl or 2,3-dichlorophenyl, n is 2, 3 or 4, and the salts, stereoisomers and the salts of the stereoisomers of these compounds.

6. Compounds of formula I according to claim 1, in which R1 is chlorine, bromine or fluorine, R2 is methyl, A is benzyl, R4 is ethyl, isopropyl, sec-butyl or cyclopropyl, R5 and R6 are both hydrogen, B is 4-methylphenyl, 3-methylphenyl, 4-fluorophenyl, 4-bromophenyl, 4-chlorophenyl, 4 methoxyphenyl, 3-fluoro-4-methylphenyl, 2-fluoro-4-methylphenyl or 3,4-dichlorophenyl n is 3 or 4, and the salts, stereoisomers and the salts of the stereoisomers of these compounds. WO 2007/144384 PCT/EP2007/055846 -96

7. Compounds of formula I according to any of the preceding claims, wherein said compounds have the configuration as shown in formula 1* O /N NA R2 H -R4 O N N(R5)R6 (1*) B and the salts thereof.

8. Compounds of formula I, selected from: (1) N-(3-Amin o-pro pyl)-N-[(RS)-1-(6-benzyl-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1 5-c]pyrimidin-5 yl)-propyl]-4-methyl-benzamide, (2) N-(3-Amin o-pro pyl)-N-[(RS)-1-(6-benzyl-3-bro mo-2-methyl -7-oxo-6,7-dihydro-pyrazolo[1 5 c]pyrimidin-5-yl)-propyl]-4-methyl-benzamide, (3) N-(3-Amin o-pro pyl)-N-[(RS)-1-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1 5 c]pyrimidin-5-yl)-2-methyl-propyl]-3-methyl-benzamide, (4) N-(3-Amin o-pro pyl)-N-[(RS)-1-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1 5 c]pyrimid i n-5-yl)-2-methyl-propyl]-4-fluoro-benzamide, (5) N-(3-Amin o-pro pyl)-N-[(RS)-1-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1 5 c]pyrimidin-5-yl)-2-methyl-propyl]-4-methoxy-benzamide, (6) N-(3-Amin o-pro pyl)-N-[(RS)-1-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1 5 c]pyrimidin-5-yl)-2-methyl-propyl]-4-bromo-benzamide, (7) N-(3-Amin o-pro pyl)-N-[(RS)-1-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1 5 c]pyrimidin-5-yl)-2-methyl-propyl]-4-chloro-benzamide, (8) N-(3-Amin o-propyl )-N-[(RS)-1-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1 5 c]pyrimidin-5-yl)-2-methyl-propyl]-4-methyl-benzamide, (9) N-(3-Amin o-pro pyl)-N-[(RS)-1-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1 5 c]pyrimidin-5-yl)-propyl]-4-methyl-benzamide, (10) N-(3-Amin o-pro pyl)-N-[(RS)-1-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5 c]pyrimidin-5-yl)-2-methyl-propyl]-4-trifluoromethyl-benzamide, (11) N-[(RS)-(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl)-methyl propyl]-N-(3-dimethylamino-propyl)-4-methyl-benzamide, (12) N-(4-Amin o-butyl)-N-[(RS)-1-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1 5 c]pyrimidin-5-yl)-2-methyl-propyl]-4-methyl-benzamide, (13) N-(2-Amin o-ethyl)-N-[(RS)-1-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5 c]pyrimidin-5-yl)-2-methyl-propyl]-4-methyl-benzamide, WO 2007/144384 PCT/EP2007/055846 -97 (14) N-(2-Amin o-ethyl)-N-[(RS)-1-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1 5 c]pyrimidin-5-yl)-2-methyl-propyl]-4-methyl-benzamide, (15) N-[(RS)-(6-Benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5-c]pyrimidin-5-yl)-methyl propyl]-N-(2-dimethylamino-ethyl)-4-methyl-benzamide, (16) N-(3-Amin o-pro pyl)-N-[(RS)-1-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo [1,5 c]pyrimidin-5-yl)-1l-cyclobutyl-methyl]-4-methyl-benzamide, (17) N-(3-Amin o-pro pyl)-N-[(RS)-1-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5 c]pyrimidin-5-yl)-2-methyl-butyl]-4-methyl-benzamide, (18) N-(3-Amin o-pro pyl)-N-[(RS)-1-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5 c]pyrimidin-5-yl)-1l-cyclopropyl-methyl]-4-methyl-benzamide, (19) N-(3-Amin o-pro pyl)-N-[(RS)-1-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5 c]pyrimidin-5-yl)-1l-cyclopropyl-methyl]-4-bromo-benzamide, (20) N-(3-Amin o-propyl )-N-[(RS)-1-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1 5 c]pyrimidin-5-yl)-2-methyl-propyl]-3-fluoro-4-methyl-benzamide, (21) N-(3-Amin o-pro pyl)-N-[(RS)-1-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1,5 c]pyrimidin-5-yl)-2-methyl-propyl]-2-fluoro-4-methyl-benzamide, (22) N-(3-Amin o-pro pyl)-N-[(RS)-1-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1 5 c]pyrimidin-5-yl)-2-methyl-propyl]-3,4-dichloro-benzamide, (23) N-(3-Amin o-pro pyl)-N-[(RS)-1-(6-benzyl-3-chloro-2-methyl-7-oxo-6,7-dihydro-pyrazolo[1 5 c]pyrimidin-5-yl)-2-methyl-propyl]-2,3-dichloro-benzamide, (24) N-(3-Amin o-pro pyl)-N-[(RS)-1-(6-benzyl-3-bro mo-2-methyl -7-oxo-6,7-dihydro-pyrazolo[1 5 c]pyrimidin-5-yl)-2-methyl-propyl]-4-methyl-benzamide, (25) N-(3-Amin o-pro pyl)-N-[(RS)-1-(6-benzyl-3-fl uo ro-2-methyl -7-oxo-6,7-dihydro-pyrazolo[1 5 c]pyrimidin-5-yl)-2-methyl-propyl]-4-methyl-benzamide, and the salts, stereoisomers and the salts of the stereoisomers of these compounds.

9. Process for preparing a compound according to any of claims 1 to 8, comprising at least one of the steps (i) benzoylation of a compound of formula II, with the meanings of R1, R2, A, R4, R5 and R6 as indicated for the compounds according to any of claims 1 to 8, or with at least one of R5 and R6 being part of a protective group, O O NN NA N NJ N A R2 NR2 /R 4 H H R4 R4 RHN N(R5)R6 R O N+ N(R5)R6 B (II) (I) (ii) halogenation of a compound of formula I wherein R1 = H to give a compound of formula I wherein R1 = halogen, or WO 2007/144384 PCT/EP2007/055846 -98 O O R2 R e R2 R4 R4 O N N(R5)R6 R ONN(R5)R6 " On ( -N N(R5)R6 B B (I) RI = H (I) RI = halogen (iii) optionally the removal of protecting groups represented by at least one of R5 and R6 as indicated under (i).

10. Compounds according to any of the claims 1 to 8 for use in the treatment of diseases.

11. A pharmaceutical composition comprising one or more compounds according to any of the claims 1 to 8 together with customary pharmaceutical auxiliaries and/or excipients.

12. Use of the compounds according to any of the claims 1 to 8 in the manufacture of pharmaceutical compositions for treating (hyper)proliferative diseases and/or disorders responsive to induction of apoptosis, such as, for example, benign and/or malignant neoplasia, e.g. cancer.

13. Pharmaceutical composition for treating (hyper)proliferative diseases and/or disorders responsive to induction of apoptosis, which include benign neoplasia and malignant neoplasia, including cancer, comprising a compound according to any of claims 1 to 8.

14. A method for treating, preventing or ameliorating (hyper)proliferative diseases and/or disorders responsive to induction of apoptosis, such as, for example, benign or malignant neoplasia, e.g. cancer, in a mammal comprising administering a therapeutically effective and tolerable amount of one or more compounds according to any of the claims 1 to 8 to said mammal in need thereof.

15. A method for modulating Eg5 kinesin activity comprising administering a therapeutically effective and tolerable amount of one or more compounds according to any of the claims 1 to 8 to a mammal in need of said modulation.

16. A combination comprising a first active ingredient, which is at least one compound according to any of the claims 1 to 8, and a second active ingredient, which is at least one anti-cancer agent selected from the group consisting of chemotherapeutic anti-cancer agents and target-specific anti-cancer agents, for separate, sequential, simultaneous, concurrent or chronologically staggered use in therapy, such as e.g. therapy of (hyper)proliferative diseases of benign or malignant behaviour and/or disorders WO 2007/144384 PCT/EP2007/055846 - 99 responsive to the induction of apoptosis, such as, for example, benign or malignant neoplasia, e.g. cancer.

17. A method for treating, preventing or ameliorating hyperproliferative diseases and/or disorders responsive to induction of apoptosis, such as, for example, benign or malignant neoplasia, e.g. cancer, in a patient comprising administering separately, simultaneously, concurrently, sequentially or chronologically staggered to said patient in need thereof an amount of a first active compound, which is a compound according to any of the claims 1 to 8, and an amount of at least one second active compound, said second active compound being an anti cancer agent selected from the group consisting of chemotherapeutic anti-cancer agents and target specific anti-cancer agents, wherein the amounts of the first active compound and said second active compound result in a therapeutic effect.

18. The combination or method according to claim 16 or 17, in which said chemotherapeutic anti cancer agents are selected from (i) alkylating/carbamylating agents including Cyclophosphamid, Ifosfamid, Thiotepa, Melphalan and chloroethylnitrosourea; (ii) platinum derivatives including cis platin, oxaliplatin, satraplatin and carboplatin; (iii) antimitotic agents / tubulin inhibitors including vinca alkaloids, such as e.g. vincristine, vinblastine or vinorelbine, taxanes, such as e.g. Paclitaxel, Docetaxel and analogs as well as formulations and conjugates thereof, and epothilones, such as e.g. Epothilone B, Azaepothilone or ZK-EPO; (iv) topoisomerase inhibitors including anthracyclines, such as e.g. Doxorubicin, epipodophyllotoxines, such as e.g. Etoposide, and camptothecin and camptothecin analogs, such as e.g. Irinotecan or Topotecan; (v) pyrimidine antagonists including 5 fluorouracil, Capecitabine, Arabinosylcytosine / Cytarabin and Gemcitabine; (vi) purin antagonists including 6-mercaptopurine, 6-thioguanine and fludarabine; and (vii) folic acid antagonists including methotrexate and pemetrexed.

19. The combination or method according to claim 16, 17 or 18, in which said target-specific anti cancer agents are selected from (i) kinase inhibitors including Imatinib, ZD-1839 / Gefitinib, BAY43 9006 / Sorafenib, SU11248 / Sunitinib and OSI-774 / Erlotinib; (ii) proteasome inhibitors including PS 341 / Bortezomib; (iii) histone deacetylase inhibitors including SAHA, PXD101, MS275, MGCD0103, Depsipeptide / FK228, NVP-LBH589, NVP-LAQ824, Valproic acid (VPA) and butyrates; (iv) heat shock protein 90 inhibitors including 17-allylaminogeldanamycin (17-AAG); (v) vascular targeting agents (VAT) including combretastatin A4 phosphate and AVE8062 / AC7700, and anti-angiogenic drugs including VEGF antibodies, such as e.g. Bevacizumab, and KDR tyrosine kinase inhibitors, such as e.g. PTK787 / ZK222584 (Vatalanib); (vi) monoclonal antibodies including Trastuzumab, Rituximab, Alemtuzumab, Tositumab, Cetuximab and Bevacizumab as well as mutants and conjugates of monoclonal antibodies, such as e.g. Gemtuzumab ozogamicin or Ibritumomab tiuxetan, and antibody fragments; (vii) oligonucleotide based therapeutics including G-3139 / Oblimersen; (viii) Toll-like receptor / TLR 9 agonists including Promune®, TLR 7 agonists including Imiquimod and WO 2007/144384 PCT/EP2007/055846 - 100 Isatoribine and analogues thereof, or TLR 7/8 agonists including Resiquimod as well as immunostimulatory RNA as TLR 7/8 agonists; (ix) protease inhibitors; (x) hormonal therapeutics including anti-estrogens, such as e.g. Tamoxifen or Raloxifen, anti-androgens, such as e.g. Flutamide or Casodex, LHRH analogs, such as e.g. Luprolide, Goserelin or Triptorelin, and aromatase inhibitors; bleomycin; retinoids including all-trans retinoic acid (ATRA); DNA methyltransferase inhibitors including the 2-deoxycytidine derivative Decitabine and 5-azacytidine; alanosine; cytokines including interleukin-2; interferons including interferon cx2 and interferon-y; and death receptor agonists including TRAIL, DR4/5 agonistic antibodies, FasL and TNF-R agonists.

20. The use, method or combination according to any of the claims 12, 14, 16 and 17, in which said cancer is selected from the group consisting of cancer of the breast, bladder, bone, brain, central and peripheral nervous system, colon, endocrine glands, esophagus, endometrium, germ cells, head and neck, kidney, liver, lung, larynx and hypopharynx, mesothelioma, sarcoma, ovary, pancreas, prostate, rectum, renal, small intestine, soft tissue, testis, stomach, skin, ureter, vagina and vulva; inherited cancers, retinomblastoma and Wilms tumor; leukemia, lymphoma, non-Hodgkins disease, chronic and acute myeloid leukaemia, acute lymphoblastic leukemia, Hodgkins disease, multiple myeloma and T-cell lymphoma; myelodysplastic syndrome, plasma cell neoplasia, paraneoplastic syndromes, cancers of unknown primary site and AIDS related malignancies.