NZ554695A

NZ554695A - Thiazolyl-dihydro indazoles

Info

Publication number: NZ554695A
Application number: NZ554695A
Authority: NZ
Inventors: Bodo Betzemeier; Trixi Brandl; Steffen Breitfelder; Ralph Brueckner; Thomas Gerstberger; Michael Gmachl; Matthias Grauert; Frank Hilberg; Christoph Hoenke; Matthias Hoffmann; Maria Impagnatiello; Dirk Kessler; Christian Klein; Bernd Krist; Udo Maier; Darryl Mcconnel; Charlotte Reither; Stefan Scheuerer; Andreas Schoop; Norbert Schweifer
Original assignee: Boehringer Ingelheim Int
Priority date: 2004-10-07
Filing date: 2005-10-05
Publication date: 2010-12-24
Also published as: AR051743A1; CN101035795A; BRPI0518169A; PL1799690T3; UY29149A1; KR20070113188A; ES2304022T3; JP2008515854A; ATE392425T1; AU2005293609B2; EP1799690A1; WO2006040281A1; EP1799690B1; CN101035795B; PE20060583A1; DE502005003777D1; PT1799690E; TW200630374A; CA2579288A1; SI1799690T1

Abstract

Disclosed is a thiazolyl-dihydro indazole derivative of formula (1), wherein the substituents are as defined in the specification. Also disclosed are intermediates useful in preparing the above compound. Also disclosed is the use of the above compound for treatin cancer.

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number 554695 WO 2006/040281 1 PCT/EP2005/055021 88994pct THXAZOLYIi-DXHYDRO INDAZOLES The present invention relates to novel thiazolyldihydroindazoles of the general formula (1) where the radicals R1 to R3 have the meanings given in the claims and the description, to their isomers, to processes for preparing these thiazolyldihydroindazoles, and to the use of the latter as pharmaceuticals. Background to the invention The phosphorylation of proteins and lipids is an important cellular regulation mechanism which plays a role in many different biological processes such as cell proliferation, differentiation, apoptosis, metabolism, inflammation, immune reactions and angiogenesis. More than 500 kinases are encoded in the human genome. In general, tyrosine protein kinases are stimulated by growth factors or other mitogenic signals and phosphorylate proteins which initiate rapid signal transmissions. Serine/threonine protein kinases mostly phosphorylate proteins which crosslink and amplify intracellular signals. Lipid kinases are likewise important switching sites in intracellular signal pathways, with these sites linking various biological processes. A number of protein kinases have already proved to be suitable target mo1ecules for therapeutic intervention in a variety of indications, e.g. cancer and inflammatory and autoimmune diseases. Since a high percentage of the genes involved in the development of WO 2006/040281 2 PCT/EP2005/055021 cancer which have been identified thus far encode kinases, these enzymes are attractive target molecules for the therapy of cancer in particular. Phosphatidylinositol 3-kinases (PI3 kinases) are a subfamily of the lipid kinases and catalyse the transfer of a phosphate radical to the 3' position of the inositol ring of phosphoinositides. They play a crucial role in a large number of cellular processes such as cell growth and differentiation processes, the regulation of cytoskeletal changes and the regulation of intracellular transport processes. The PI3 kinases can be subdivided into different classes on the basis of their in-vitro specificity for particular phosphoinositide substrates. Among the members of the class I PI3 kinases, the a, (3 and 5 PI3 kinases (class IA) are principally activated by receptor tyrosine kinases (RTKs) or soluble tyrosine kinases. On the other hand, the y PI3 kinase (class IB) is principally activated by G(3y subunits which are released from heterotrimeric G proteins following activation of heptahelical receptors. As a result of these differences in the coupling to cell surface receptors, in combination with a more or less restricted expression, the 4 class I PI3 kinases inevitably have very different tasks and functions in the intact organism. Many independent findings indicate that class IA PI3 kinases are involved in uncontrolled processes of cell growth and differentiation. Thus, the first PI3 kinase activity which was detected was associated with the transforming activity of viral oncogenes such as the middle T antigen of polyoma viruses, Src tyrosine kinases or activated growth factors (Workman, Biochem Soc Trans. 2004; 32(Pt 2):393-6). Akt/PKB, which is activated directly by the lipid products of the class I WO 2006/040281 3 ' PCT/EP2005/055021 PI3 kinases and in this way transmits the signals into the cell, is found to be hyperactive in many tumours such as breast cancer and ovarian or pancreatic carcinoma. In addition, it has recently been found that the PIK3 CA gene, which encodes the pllO subunit of Pl3Ka, exhibits a high frequency of mutation in many tumour types such as colon, mammary and lung carcinomas, with some of the mutations being representatively characterized as being activating mutations (Samuels et al. , Science 2004; 304 (5670) : 554) . Detailed description of the invention It has now been found, surprisingly, that compounds of the general formula (I), in which the radicals R1 to R3 have the meanings given below, act as inhibitors of specific cell cycle kinases. Consequently, the compounds according to the invention can be used, for example, for treating diseases which are connected to the activity of specific cell cycle kinases and are characterized by excessive or anomalous cell proliferation. The present invention relates to compounds of the general formula (1) in which R1 is selected from the group consisting of -NHRC, -NHC (0) Rc, -NHC(0)0Rc, -NHC(0)NRcRc and -NHC(0)SRc; R2 is a radical which is optionally substituted by one or more R4 and which is selected from the group consisting of Ci^alkyl, C3_8cycloalkyl, 3-8-membered heterocycloalkyl, C6-ioaryl and 5-10-membered heteroaryl; I (1) R2 WO 2006/040281 4 PCT/EP2005/055021 R3 is a radical which is optionally substituted by one or more Re and/or Rf and is selected from the group consisting of C6-ioaryl and 5-10-membered heteroaryl; R4 is a radical selected from the group consisting of Ra, Rb and Ra which is substituted by one or more, identical or different, R° and/or Rb; each Ra is, independently of each other, selected from the group consisting of Ci-6alkyl, C3-8cycloalkyl, C4-ncycloalkylalkyl, C6-ioaryl, C7-i6arylalkyl, 2-6-membered heteroalkyl, 3-8-membered heterocycloalkyl, 4-14-membered heterocycloalkylalkyl, 5-10-membered heteroaryl and 6-16-membered heteroarylalkyl; each Rb is a suitable radical and in each case selected, independently of each other, from the group consisting of =0, -OR0, Ci_3haloalkyloxy, -OCF3, =S, -SRC, =NRC, =NOR°, -NRCRC, halogen, -CF3, -CN, -NC, -OCN, -SCN, -NO, -N02, =N2, -N3, -S(0)Rc, -S(0)2Rc, -S(0)20Rc, -S(0)NRcRc, -S(0)2NRcRc, -0S(0)Rc, -0S(0)2Rc, -0S(0)20Rc, -OS (0)2NRcRc, -C (0) Rc, -C (0) ORc, -C (0) NRCRC, -C (O) N (Rs) NRCR°, -C (0) N (R9) 0RC, -CN(Rg)NRcRc, -0C(0)Rc, -0C(0)0Rc, 0C(0)NRcRc, - OCN (Rg) NRCRC, -N(Rg) C (0) R°, -N (R9) C (0) Rc, -N(Rg)C(S)Rc, -N(R9)S(0)2Rc, -N(Rg)S(0)2NRcRc, -N[S(0)2]2Rc, -N(Rg)C(0)0Rc, -N(Rg)C (0)NRcRc, and -N(Rg)CN(Rg)NRcRc; each R° is, independently of each other, hydrogen or a radical which is optionally substituted by one or more, identical or different, Rd and/or Re and which is selected from the group consisting of Ci-6alkyl, C3-scycloalkyl, C4_ncycloalkylalkyl, C6-ioaryl, C7-i6arylalkyl, 2-6-membered heteroalkyl, 3-8-membered heterocycloalkyl, 4-14-membered heterocycloalkylalkyl, 5-10-membered heteroaryl and 6-16-membered heteroarylalkyl, WO 2006/040281 5 PCT/EP2005/055021 each Rd is, independently of each other, hydrogen or a radical which is optionally substituted by one or more, identical or different, Re and/or Rf and which is selected from the group consisting of Ci-6alkyl, C3-8cycloalkyl, C4-ncycloalkylalkyl, C6-ioaryl, C7-i6arylalkyl, 2-6-membered heteroalkyl, 3-8-membered heterocycloalkyl, 4-14-membered heterocycloalkylalkyl, 5-10-membered heteroaryl and 6-16-membered heteroarylalkyl, each Re is a suitable radical and in each case selected, independently of each other, from the group consisting of =0, -ORf, Ci_3haloalkyloxy, -OCF3, =S, -SRf, =NRf, =NORf, -NRfRf, halogen, -CF3, -CN, -NC, -OCN, -SCN, -NO, -N02, =N2, -N3, - S (0) Rf, -S(0)2Rf, -S (0) 2ORf, -S (0) NRfRf, -S (0) 2NRfRf, -OS (0) Rf, -OS (0) 2Rf, -0S(0)20Rf, -OS (0) 2NRfRf, -C (0) Rf, -C (0) 0Rf, -C(0)NRfRf, - CN (R9) NRf Rf, -0C(0)Rf, -0C (0) 0Rf, -0C(0)NRfRf, -OCN (Rg) NRfRf, -N (Rg) C (0) Rf, -N(Rg)C(S)Rf, -N(Rg)S(0)2Rf, -N (R9) C (O) 0Rf, -N (R9) C (0) NRfRf, and -N (R9) CN (R9) NRfRf; each Rf is, independently of each other, hydrogen or a radical which is optionally substituted by one or more, identical or different, Rg and which is selected from the group consisting of Ci-6alkyl, C3_8cycloalkyl, C4-ncycloalkylalkyl, C6-ioaryl, C7-i6arylalkyl, 2-6-membered heteroalkyl, 3-8-membered heterocycloalkyl, 4-14-membered heterocycloalkylalkyl, 5-10-membered heteroaryl and 6-16-membered heteroarylalkyl, each R9 is, independently of each other, hydrogen, Ci_6alkyl, C3_8cycloalkyl, C4_ncycloalkylalkyl, C6-ioaryl, C7-i6arylalkyl, 2-6-membered heteroalkyl, 3-8-membered heterocycloalkyl, 4-14-membered heterocycloalkylalkyl, 5-10-membered heteroaryl and 6-16-membered heteroarylalkyl, where appropriate in the form of their tautomers, their WO 2006/040281 6 PCT/EP2005/055021 racemates, their enantiomers, their diastereomers and their mixtures, as well as, where appropriate, their pharmacologically harmless acid addition salts. One aspect of the invention relates to compounds of the general formula (1) where R3 is a radical which is selected from the group consisting of phenyl, furyl, pyridyl, pyrimidinyl and pyrazinyl, where appropriate substituted by one or more R4. Another aspect of the invention relates to compounds of the general formula (1) where R3 is pyridyl. Another aspect of the invention relates to compounds of the general formula (1) where R1 is -NHC(0)Rc. Another aspect of the invention relates to compounds of the general formula (1) where R1 is -NHC(0)CH3. One aspect of the invention relates to compounds of formula (A) where X is -CH3, -OR4 or -SR4, and Y is phenyl, 5-10-membered heteroaryl or the group -C(0)0, and Ry is hydrogen, -NO2 or Ci_6alkyl and R4 is defined as above. Another aspect of the invention relates to compounds of the general formula (A) where R4 is -Chalky 1. Another aspect of the invention relates to the use of compounds of the formula (A) as synthesis (A) O O WO 2006/040281 7 PCT/EP2005/055021 intermediates. One aspect of the invention relates to compounds of the general formula (1) , or their pharmaceutically active salts, as pharmaceuticals. One aspect of the invention relates to the use of compounds of the general formula (1), or their pharmaceutically active salts, for producing a pharmaceutical having an antiproliferative effect. One aspect of the invention relates to a pharmaceutical composition which comprises, as the active compound, one or more compounds of the general formula (1) or their physiologically tolerated salts, where appropriate in combination with customary auxiliary substances and/or carrier substances. Another aspect of the invention relates to the use of compounds of the general formula (1) for producing a pharmaceutical for treating and/or preventing cancer. One aspect of the invention relates to a pharmaceutical preparation which comprises a compound of the general formula (1) and at least one further cytostatic or cytotoxic active substance which differs from formula (1) , where appropriate in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, as well as, where appropriate, their pharmacologically harmless acid addition salts. DEFINITIONS As used herein, the! following definitions apply unless otherwise described. Alkyl substituents are in each case to be understood as being saturated, unsaturated, straight-chain or branched aliphatic hydrocarbon radicals (alkyl WO 2006/040281 8 PCT/EP2005/055021 radicals) and comprise both saturated alkyl radicals and unsaturated alkenyl and alkynyl radicals. Alkenyl substituents are in each case straight-chain or branched, unsaturated alkyl radicals which possess at least one double bond. Alkynyl substituents are in each case to be understood as being straight-chain or branched, unsaturated alkyl radicals which possess at least one triple bond. Heteroalkyl represents straight-chain or branched aliphatic hydrocarbon chains which are interrupted by from 1 to 3 heteroatoms, with it being possible for each of the available carbon and nitrogen atoms in the heteroalkyl chain to be optionally substituted, in each case independently of each other, and with the heteroatoms being selected, in each case independently of each other, from the group consisting of O, N and S (e.g. dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, diethylaminomethyl, diethylamino-ethyl, diethylaminopropyl, 2-diisopropylaminoethyl, bis-2-methoxyethylamino, [2-(dimethylaminoethyl)- ethylamino]methyl, 3-[2-(dimethylaminoethyl)ethyl- amino]propyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxy-propyl, methoxy, ethoxy, propoxy, methoxymethyl and 2-methoxyethyl). Haloalkyl refers to alkyl radicals in which one or more hydrogen atom(s) has/have been replaced by halogen atoms. Haloalkyl includes both saturated alkyl radicals and unsaturated alkenyl and alkynyl radicals, such as -cf3, -chf2, -ch2f, -cf2cf3,-chfcf3, -ch2cf3, -cf2ch3, -chfch3, -cf2cf2cf3, -cf2ch2ch3, -cf=cf2, -cci=ch2, -CBr=CH2, -CI=CH2/ -C=C-CF3, -CHFCH2CH3 and -CHFCH2CF3. Halogen refers to fluorine, chlorine, bromine and/or iodine atoms. Cycloalkyl is to be understood as being a monocyclic or WO 2006/040281 9 PCT/EP2005/055021 bicyclic ring where the ring system can be a saturated ring, or else an unsaturated, nonaromatic ring, which can, where appropriate, also contain double bonds, such as cyclopropyl, cyclopropenyl, cyclobutyl, cyclo-butenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclo-hexenyl, norbornyl and norbornenyl. Cycloalkylalkyl comprises a noncyclic alkyl group in which a hydrogen atom which is bonded to a carbon atom, usually to a terminal C atom, has been replaced by a cycloalkyl group. Aryl refers to monocyclic or bicyclic rings having 6-12 carbon atoms, such as phenyl and naphthyl. Arylalkyl comprises a noncyclic alkyl group in which a hydrogen atom which is bonded to a carbon atom, usually to a terminal C atom, has been replaced by an aryl group. Heteroaryl is to be understood as meaning monocyclic or bicyclic rings which contain one or more, identical or different heteroatoms, such as nitrogen, sulphur or oxygen atoms, in place of one or more carbon atoms. Those which may be mentioned by way of example are furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl and triazinyl. Examples of bicyclic heteroaryl radicals are indolyl, isoindolyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, indazolyl, isoguinolinyl, quinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl and benzotriazinyl, indolizinyl, oxazolopyridyl, imidazopyridyl, naphthyridinyl, indolinyl, isochromanyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl, isobenzotetra- WO 2006/040281 10 PCT/EP2005/055021 hydrofuryl, isobenzotetrahydrothienyl, isobenzothienyl, benzoxazolyl, pyridopyridyl, benzotetrahydrofuryl, benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, phenoxazinyl, phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridyl, imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl, dihydrobenzisothiazinyl, benzopyranyl, benzo- thiopyranyl, coumarinyl, isocoumarinyl, chromonyl, chromanonyl, pyridyl-N-oxide tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl, dihydroiso-quinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl, isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl-W-oxide, pyrimidinyl-N-oxide, pyridazinyl-N-oxide, pyrazinyl-W-oxide, quinolinyl-AT'-oxide, indolyl-N- oxide, indolinyl-N-oxide, isoquinolyl-i\7-oxide, quinazolinyl-N-oxide, quinoxalinyl-i\7-oxide, phthalazinyl-iV-oxide, imidazolyl-W-oxide, isoxazolyl-N- oxide, oxazolyl-N-oxide, thiazolyl-N-oxide, indolizinyl-iV-oxide, indazolyl-N-oxide, benzothiazolyl-itf-oxide, benz imidazolyl-A7-oxide, pyrrolyl-.W-oxide, oxadiazolyl-i\7-oxide, thiadiazolyl-N-oxide, triazolyl-2V-oxide, tetrazolyl-I\7-oxide, benzothiopyranyl-S-oxide and benzothiopyranyl-S,S-dioxide. Heteroarylalkyl comprises a noncyclic alkyl group in which a hydrogen atom which is bonded to a carbon atom, usually to a terminal C atom, has been replaced by a heteroaryl group. Heterocycloalkyl refers to saturated or unsaturated, nonaromatic monocyclic, bicyclic or bridged bicyclic rings which comprise 3-12 carbon atoms and which carry heteroatoms, such as nitrogen, oxygen or sulphur, in place of one or more carbon atoms. Examples of these heterocycloalkyl radicals are tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, indolinyl, isoindolinyl, morpholinyl, thiomorpholinyl, WO 2006/040281 11 PCT/EP2005/055021 homomorpholinyl, homopiperidinyl, homopiperazinyl, homothiomorpholinyl, tliiomorpholinyl-S-oxide, thio-morpholinyl-S, S-dioxide, tetrahydropyranyl, tetra-hydrothienyl, homothiomorpholinyl-S1,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridyl, dihydropyrimidinyl, dihydrofuryl, dihydropyranyl, tetrahydrothi enyl-S-oxide, tetrahydrothienyl-S,5-dioxide, homothio- morpholinyl-S-oxide, 2-oxa-5-azabicyclo[2.2.1]heptane, 8-oxa-3-azabicyclo[3.2.1]octane, 3,8-diazabicyclo- [3.2.1]octane, 2 , 5-diazabicyclo[2.2.1]heptane, 3,8-diazabicyclo[3.2.1]octane, 3,9-diazabicyclo[4.2.1]-nonane and 2,6-diazabicyclo[3.2.2]nonane. Heterocycloalkylalkyl refers to a noncyclic alkyl group in which a hydrogen atom which is bonded to a carbon atom, usually to a terminal C atom, has been replaced by a heterocycloalkyl group. The following examples illustrate the present invention without, however, limiting its scope. Synthesizing the reagents R-l) cis-l-Methylamino-4-(pyrrolidin-l-yl)cyclohexane OOP R-la) tert-Butyl cis-4-(pyrrolidin-l-yl)cyclohexane-carbamate oo)> 25 mg of potassium hydrogen carbonate are added to a solution of tert-butyl cis-4-aminocyclohexanecarbamate (10 g, 46 mmol) and 1,4-dibromobutane (12.1 g,' 56 mmol) in 400 ml of DMF, and the mixture is stirred at RT for 24 h. The reaction mixture is then evaporated and the WO 2006/040281 12 PCT/EP2005/055021 residue is taken up in diethyl ether; this solution is washed with water. The organic phase is dried and evaporated in vacuo. Yield: 12 g. R-la (5 g, 18 mmol) is dissolved in 20 ml of N, JV-dimethylacetamide and this solution is added, at 37°C, to a suspension of sodium hydride (60% in liquid paraffin, 0.8 g, 20 mmol) in 20 ml of N,N- dimethyl-acetamide such that the temperature does not exceed 48 °C. After the foam formation has come to an end, methyl iodide (2.9 g, 20 mmol) is added and the mixture is stirred at RT for 10 min. Ethyl acetate is added to the reaction mixture and the whole is washed with water. The organic phase is then treated with oxalic acid and washed with ethyl acetate. After that, the mixture is made alkaline with potassium hydrogen carbonate and extracted with ethyl acetate. The organic phases are evaporated and the residue is reacted without further purification. Yield: 1.4 g. R-lb (1.4 g, 5 mmol) is dissolved in 50 ml of dichloromethane after which 25 ml of trifluoroacetic acid are added and the whole is stirred at RT for 4 h. After the reaction mixture has been evaporated, the desired product is precipitated as the dihydrochloride using hydrochloric acid (1 N in diethyl ether) . Yield: 1 g R-2) traixs-l-Amino-4- (8-oxa-3-azabicyclo [3 .2 .1] oct- 3-y 1)eye1ohexane R-lb) tert-Butyl iV-methyl- cis-4-(pyrrolidin-l-yl.)-cyclohexanecarbamate WO 2006/040281 13 PCT/EP2005/055021 Triethylamine (21 g, 0.21 mol), benzyl trans-4-amino-cyclohexylcarbamate (24.8 g, 0.1 mol) and a catalytic quantity of DMAP are added consecutively to a solution of 2,5-bis(p-tosyloxymethyl)tetrahydrofuran (44 g, 0.1 mol) in 440 ml of toluene. The reaction mixture is heated under reflux for 6 d. After cooling down, the organic phase is decanted off from the insoluble resin and the residue is purified chromatographically. The intermediate which is obtained in this way is suspended in 3 00 ml of methanol in an autoclave, after which 37 ml of hydrochloric acid (6 N in isopropanol) and 6 g of palladium on active charcoal are added. The reaction mixture is stirred under a hydrogen atmosphere (50 bar) at RT for 15 h. After filtering through Celite®, the filtrate is evaporated and the residue is taken up in hot ethyl acetate; 37 ml of hydrochloric acid (6 N in isopropanol) are added to this solution. On cooling, the desired product precipitates as the hydrochloride salt, which is filtered and dried. R-3) l-Amino-4-(methylpropylamino)cyclohexane A solution of tert-butyl cis-4-aminocyclohexane-carbamate (22.1 g, 103 mmol) and methyl trifluoro-acetate (11 ml, 110 mmol) in 110 ml of methanol is stirred at RT for 4 h. After the reaction mixture has been cooled down to 0°C, the precipitate is filtered off, washed with diethyl ether and dried. Yield: 17.6 g. ch3 R-3a) tert-Butyl cis-4-(2, 2, 2-trifluoroacetylamino)- eye1ohexanecarbamate h WO 2006/040281 14 PCT/EP2005/055021 R-3b) tert-Butyl cis-4-methyl-(2,2,2-trifluoroacetyl)-aminocyclohexanecarbamate ^0 f Sodium hydride (60% in liquid paraffin, 1.3 g, 32 mmol) is added, at RT and under a nitrogen atmosphere, to a suspension of R-3a (8.3 g, 27 mmol) in 100 ml of i^N-dimethylacetamide. After 20 min, methyl iodide (4.5 g, 32 mmol) is added and the mixture is stirred at RT for 15 h. Following hydrolysis with 800 ml of ice water, the precipitate is filtered off and washed with water and petroleum ether. The residue is recrystallized from 200 ml of diisopropyl ether to which 10 ml of acetonitrile have been added. Yield: 11 g. R-3c) tert-Butyl cis-4-methylaminocyclohexanecarbamate ryv0 °y: In order to eliminate the trifluoroacetate group, 117 ml of sodium hydroxide solution (2 N) are added to R-3b (39.7 g, 123 mmol) in 536 ml of methanol and the mixture is stirred at RT for 5 h. The reaction mixture is evaporated and the residue is extracted by shaking with water and ethyl acetate. The organic phase is dried, filtered and evaporated in vacuo. Yield: 28.4 g. R-3d) tert-Butyl cis-4-(methylpropylamino)cyclohexane-carbamate Triethylamine (0.98 g, 9.7 mmol) and n-propyl bromide (1.2 g, 9.7 mmol) are added to a solution of R-3c (2 g, 8.8 mmol) in 5 ml of acetonitrile and the mixture is stirred at 60°C for 3 h in a pressure tube. The reaction mixture is then evaporated and the residue is extracted by shaking with water and ethyl acetate. WO 2006/040281 15 PCT/EP2005/055021 Yield: 1 g. The BOC protecting group is eliminated, in analogy with the preparation of R-l, using R-3d (1 g, 3.7 mmol), 20 ml of trifluoroacetic acid and 20 ml of dichloro-methane. Yield: 0.6 g R-4) Cyclopropylpiperidin-4-ylamine A solution of 1-tert-butoxycarbonylpiperidin-4-one (1 g, 5 mmol) and cyclopropylamine (352 pi) in 15 ml of 1,2-dichloroethane is stirred at RT for 20 min after which sodium trisacetoxyborohydride (1.6 g, 7 mmol) and 0.3 ml of acetic acid are added. After having been stirred at RT for 15 h, the reaction mixture is hydrolysed with a saturated solution of sodium hydrogen carbonate and extracted with 2 x 50 ml of dichloromethane. The combined organic phases are washed with a saturated solution of sodium chloride, dried, filtered and evaporated. The residue is taken up in 4 ml of diethyl ether after which 8 ml of hydrochloric acid (4 N in dioxane) are added. After stirring at RT for 15 h, the precipitate is filtered off and washed with diethyl ether. The desired product is obtained as hydrochloride. Yield: 0.96 g R-5) l-Cyclopentylpiperidine-4-carboxylic acid Catalytic quantities of p-toluenesulphonic acid (750 mg) and 12.5 ml of glacial acetic acid are added to a solution of ethyl piperidine-4-carboxylate (22.9 g, 145 mmol) and cyclopentanone (13.5 g, 160 mmol) in 400 ml of THF. After stirring at RT for 30 min, sodium triacetoxyborohydride (42 g, 190 mmol) O WO 2006/040281 16 PCT/EP2005/055021 is added in portions. The reaction mixture is stirred at RT for 15 h and, after evaporating, the residue is extracted by shaking with sodium carbonate solution and dichloromethane. The organic phase is dried, filtered and evaporated. Yield: 32 g of ethyl 1-cyclo-pentylpiperidine-4-carboxylate. The intermediate compound (1 g, 4.4 mmol) is then hydrolysed, in 10 ml of EtOH, at 80°C for 15 h with 10 ml of NaOH (5 N) . After having been cooled down, the reaction mixture is acidified and the resulting precipitate is filtered R-6) cis-4-(Pyrrolidin-l-yl)cyclohexanecarboxylic acid O 1,4-Dichlorobutane (2.3 ml, 21 mmol), potassium carbonate (12.6 g, 91 mmol) and potassium iodide (400 mg) are added to a solution of methyl cis-4-amino-cyclohexanecarboxylate hydrochloride (4 g, 21 mmol) in 32 ml of DMF and the mixture is stirred at 100°C for 6 h and then at RT for 3 d. The reaction mixture is diluted with 200 ml of water, neutralized with glacial acetic acid, saturated with sodium chloride and extracted with dichloromethane. The organic phases are dried, filtered and evaporated. Yield: 3.8 g of methyl cis-4-(pyrrolidin-l-yl)cyclohexanecarboxylate. The intermediate is then stirred, in 10 ml of methanol, with 25 ml of sodium hydroxide solution (IN) at RT for 15 h. After the methanol has been removed in vacuo, the reaction mixture is adjusted to pH 6 with hydrochloric acid and evaporated further. The residue is taken up in methanol and purified by filtration through silica gel. Yield: 3.5 g. off. WO 2006/040281 17 PCT/EP2005/055021 R-7) 3-Morpholin-4-ylcyclobutylamine o N -0- nh. R-7a) - 3-tert-Butoxycarbonylaminocyclobutyl toluene-4-sulphonate A solution of toluene-4-sulphonyl chloride (20.5 g, 0.105 mol) in 150 ml of chloroform is added dropwise, at 0°C, to a solution of 3-tert-butoxycarbonyl-aminocyclobutanol (18.7 g, 0.1 mol) and triethylamine (12.1 g, 0.12 mol) in 500 ml of chloroform and the mixture is then warmed to RT. The organic phase is washed consecutively with water, dilute hydrochloric acid, sodium hydrogen carbonate solution and once again with water before it is dried, filtered and evaporated. R- 7 b) 1-Morpho1in-1-y1-3-1ert-but oxyc arbony1amino- cyclobutane R-7a (34 g, 0.1 mol) is dissolved in 750 ml of morpholine after which a catalytic quantity of DMAP is added and the mixture is stirred at 100°C for 3 h under an argon atmosphere. The reaction mixture is then evaporated in vacuo, after which the residue is coevaporated with 100 ml of toluene and then taken up in 500 ml of ethyl acetate. The organic phase is washed with a saturated solution of sodium hydrogen carbonate, dried, filtered and evaporated, with the desired compound, which is used without any further purification, being obtained. 260 ml of hydrochloric acid (2 N) are added to R-7b (25.6 g, 0.1 mol) and the mixture is stirred at 40°C for 2 h. After the reaction WO 2006/040281 18 PCT/EP2005/055021 has been completed, the reaction mixture is made alkaline with methanolic ammonia solution, filtered and evaporated. The residue is then recrystallized from ethanol, with R-7 being obtained. H-l) Methyl 4-hydrazino-3-methylbenzoate 50 ml of conc. hydrochloric acid are added to methyl 4-amino-3-methylbenzoate (10 g, 61 mmol) and the mixture is cooled down to -15°C. A solution of sodium nitrite (6.3 g, 91 mmol) in 50 ml of water is added dropwise in such a way that the temperature does not exceed -5°C. After stirring at -10°C for 4 h, a solution of tin(II) chloride dihydrate in 50 ml of conc. hydrochloric acid is added dropwise to the suspension, with the reaction temperature not exceeding -5°C. The viscous suspension is stirred at RT for 15 h before it is adjusted to pH 14 with 200 ml of sodium hydroxide solution (10 N) . The reaction mixture is filtered through kieselguhr and Extrelut® (60 g) and rinsed with 2 1 of chloroform. The organic phase which is obtained is washed with water (2 x 200 ml) , dried over sodium sulphate and evaporated in vacuo. The residue is stirred up with 120 ml of petroleum ether and filtered. Yield: 6.3 g H-2) Methyl 4-hydrazino-3-fluorobenzoate The desired compound is obtained in analogy with the preparation of H-l, starting from methyl 4-amino-3-fluorobenzoate (3.9 g, 23 mmol), sodium nitrite (2.4 g, 34 mmol) and tin(II) chloride dihydrate WO 2006/040281 19 PCT/EP2005/055021 (20.8 g, 92 mmol). Yield: 3.4 g H-3) 3-Iodophenylhydrazine h ,n-nh, i The desired . compound is thus obtained, as hydrochloride, in analogy with the preparation of H-l, starting from 3-iodoaniline (2.75 g, 22.8 mmol), sodium nitrite (1.58 g, 22.8 mmol) and tin(II) chloride dihydrate (15.4 g, 68.5 mmol). Yield: 3.55 g H-4) 3-Hydrazinophenylacetic acid ?^-nh2 oh The desired compound is obtained in analogy with the preparation of H-l, starting from 3-aminophenylacetic acid (2 g, 13.2 mmol), sodium nitrite (0.91 g, 13.2 mmol) and tin(II) chloride dihydrate (6.1 g, 26.4 mmol). H-5) Piperidin-4-yl-hydrazine N—/ h 4-Oxopiperidine-1-tert-butoxycarbonyl (500 mg, 2.5 mmol) is dissolved, under an argon atmosphere, in hexane, after which tert-butyl carbazate (332 mg, 2.5 mmol) is added. After 20 min of heating under reflux, the reaction mixture is cooled down and the resulting precipitate is filtered off. Borane-THF complex (1 M in THF; 2.2 ml) is added to 4-(tert-butoxycarbonylhydrazono)piperidine-1-tert-butoxy-carbonyl (707 mg, 2.3 mmol) and the mixture is stirred at RT for 1 h. The desired product is then WO 2006/040281 20 PCT/EP2005/055021 precipitated, as hydrochloride, with 6 ml of hydrochloric acid (4 N in dioxane), and filtered off. H-6) Ethyl 4-hydrazinocyclohexanecarboxylate h n-nh, o^-- -° /° cis " trans The desired product is obtained, as a cis/trans mixture, in analogy with the preparation of H-5, starting from ethyl 4-oxocyclohexanecarboxylate (4.5 g, 26.4 mmol), tert-butyl carbazate (3.5 g, 26.4 mmol) and borane-THF complex (1 M in THF; 26.5 ml); the cis/trans mixture is then subjected to further use without any additional purification or separated chromatographically on silica gel using 0-33% ethyl acetate in cyclohexane. Yield: cis: 2.2 g trans: 2.6 g H-7) 2-Chloro-4-hydroxymethylphenylhydrazine oh Diisobutylaluminium hydride (1M in toluene, 190 ml) is added dropwise, under a nitrogen atmosphere and at -73°C, to a solution of methyl 3-chloro-4-hydrazino-benzoate (9.5 g, 47 mmol) in 1 1 of toluene in such a way that the temperature does not rise above -70°C. The reaction mixture is stirred at -73°C for 30 min and then warmed to -5°C. Following hydrolysis with 500 ml of water, the precipitate is filtered off and washed with ethyl acetate (5 x 500 ml) . The organic phase is evaporated, after which the residue is taken up in a little ethyl acetate and precipitated with petroleum ether/diethyl ether and filtered off. The solid which is obtained in this way is purified chromatographically WO 2006/040281 21 PCT/EP2005/055021 on silica gel using eyelohexane/ethyl acetate. Yield: 2.9 g H-8) Methyl 3-hydrazinomethylbenzoate A solution of 3 g of methyl 3-bromomethylbenzoate (13 mmol), 2.6 g of tert-butoxycarbonylhydrazine (19 mmol) and 3.1 g of potassium carbonate (23 mmol) in 30 ml of DMF is stirred at RT for 24 h. After water has been added, the reaction mixture is extracted with dichloromethane. The organic phase is dried, filtered and evaporated, and the residue is purified chromatographically. The BOC protecting group is then eliminated using 30 ml of hydrochloric acid (4 M in dioxane). Yield: 1.25 g H-9) (4-Trifluoromethylpyridin-3-yl)hydrazine The desired compound is obtained in analogy with the preparation of H-l, starting from 3-amino-4-trifluoro-methylpyridine (5.1 g, 31 mmol), sodium nitrite (2.2 g, 31 mmol) and tin(II) chloride dihydrate (21.6 g, 94 mmol). Yield: 3.8 g H-10) N- (4-Hydrazinophenyl) -W-methylacetamide h 0 > The desired compound is obtained in analogy with the preparation of H-l, starting from N- (4-aminophenyl)-N-methylacetamide (0.4 g, 2.4 mmol), sodium nitrite (0.2 g, 2.7 mmol) and tin(II) chloride dihydrate (1.6 g, 7.3 mmol). Yield: 0.2 g WO 2006/040281 22 PCT/EP2005/055021 H-11) (4-Morpholin-4-ylmethylphenyl)hydrazine h ,N~NH2 The desired compound is obtained in analogy with the preparation of H-l, starting from 4-morpholin-4-yl-methylphenylamine (1.1 g, 5 mmol), sodium nitrite (0.3 g, 5 mmol) and tin(II) chloride dihydrate (5.8 g, 25 mmol). Yield: 0.3 g H-12) Pyrrolidin-3-ylhydrazine n—nh2 0 h The desired compound is obtained, as the hydrochloride, in analogy with the preparation of H-5, starting from tert-butyl 3-oxopyrro1idine-1-carboxylate. H-13) [3-(2-Methylpropane-1-sulphonyl)phenyl]hydrazine The desired compound is obtained, as the hydrochloride, in analogy with the preparation of H-l, starting from 3-(2-methylpropane-l-sulphonyl)phenylamine (1.5 g, 7 mmol), which can be prepared in analogy with the literature (A. Courtin, Helv. Chim.Acta 1981, 64, 1849), sodium nitrite (0.5 g, 7 mmol) and tin(II) chloride dihydrate (4.9 g, 21 mmol). Yield: 1.8 g H-14) 4-Hydrazinophenylacetonitrile The desired compound is obtained, as the hydrochloride, in analogy with the preparation of H-l, starting from WO 2006/040281 23 PCT/EP2005/055021 4-aminophenylacetonitrile (5 g 37.8 mmol), sodium nitrite (2.6 g, 37.4 mmol) and tin (II) chloride dihydrate (25.8 g, 112 mmol). Yield: 5.4 g H-15) (1-Methy1-lH-indazol-5-yl)hydrazine The desired compound is obtained, as the hydrochloride, in analogy with the preparation of H-l, starting from l-methyl-lH-indazol-5-ylamine (0.9 g 6 mmol), sodium nitrite (0.44 g, 6.4 mmol) and tin(II) chloride dihydrate (2.8 g, 12.6 mmol). Yield: 1.2 g Synthesizing the intermediate compounds Z-l) N-[7-Oxo-6-(pyrimidine-5-carbonyl)-4,5,6,7-tetra-hydrobenzothiazol-2-yl]acetamide A solution of 10 g (48 mmol) of Z-6 in 1 1 of THF is cooled to -40°C after which 143 ml (143 mmol) of Li-HMDS (1 N in THF) are added dropwise in such a way that the temperature does not exceed -20°C. After 3.5 h at -40 to -20°C, pyrimidine-5-carbonyl chloride hydrochloride (10.2 g, 57 mmol) is added to the suspension and the mixture is stirred at RT for 16 h. 200 ml of hydrochloric acid (1 N in Et20) are then added to the clear reaction mixture, in connection with which a precipitate is formed. 300 ml of phosphate buffer are added to a suspension and the mixture is extracted with ethyl acetate after the organic phase has been separated off. The combined organic phases are dried over magnesium sulphate and evaporated to dryness. The residue is crystallized from acetonitrile-. Yield: 13.2 g. The crude product is used for further syntheses without any additional purification. o o WO 2006/040281 24 PCT/EP2005/055021 Z-3) N-[7-Oxo-6-(pyrazine-2-carbonyl)-4,5,6,7-tetra- hydrobenzthiazol-2-yl]acetamide o o o 10 g (48 mmol) of Z-6 are added in portions to a 100 ml of DMF in such a way that the temperature does not rise above 3 0°C. After it has been stirred at RT for 1 h, the reaction mixture is heated to 55°C, at which temperature a solution of 10 g (72 mmol) of methyl pyrazine-2-carboxylate in 40 ml of benzene is added. The solution is stirred at 55°C for a further 3 h, and then at RT for 15 h, before it is adjusted to pH 3 with hydrochloric acid (4 N in dioxane). Following hydrolysis with phosphate buffer, the reaction mixture is extracted with ethyl acetate. The combined organic phases are dried and evaporated in vacuo. The residue is recrystallized from ether/petroleum ether. Yield: 8.7 g. Z-4) N- [6-(3-Nitrobenzoyl)-7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl]acetamide 5.2 g of Z-4 are obtained, in analogy with the preparation of intermediate compound Z-l, from 2.5 g (12 mmol) of Z-6, 4.2 g (22 mmol) of 3-nitrobenzoyl chloride and 36 ml (36 mmol) of Li-HMDS (IN in THF) . The crude product is used for further syntheses without any additional purification. suspension of 8.1 g (143 mmmol) of sodium methoxide in o o Z-5) N- [6-(4-Nitrobenzoyl)-7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl]acetamide WO 2006/040281 25 PCT/EP2005/055021 o o 2.2 g of Z-5 are obtained, in analogy with the preparation of intermediate compound Z-l, from 1 g (4.8 mmol) of Z-6, 1.2 g (6.2 mmol) of 4-nitrobenzoyl chloride and 14.6 ml (14.6 mmol) of Li-HMDS (1 N in THF) . The crude product is used for further syntheses without any additional purification. Z-6) N-(7-Oxo-4,5,6,7-tetrahydrobenzothiazol-2-yl)- acetamide a) 112 g (1 mol) of 1,3-cyclohexanedione are suspended in 700 ml of ice water and 51.6 ml (1 mol) of bromine are added dropwise, at 0°C and within 45 min. The suspension is subsequently stirred for 3.5 h at a max. of 10°C. The mixture is then filtered with suction and the solid is thoroughly stirred in 800 ml of water, filtered off with suction, washed with 3 1 of water and dried. The solid which is obtained is recrystallized from ethanol. Yield: 37 g (Z-6a) b) 15.5 g (0.2 mol) of thiourea are initially introduced, at room temperature, in 200 ml of ethanol. 37.1 g (0.2 mol) of Z-6a are added in portions to this suspension and the mixture is then rewashed with 60 ml of ethanol. The solution, which is forming gradually, is stirred under reflux for 2 h and then evaporated. The residue is extracted with water and diethyl ether; the water phase is made alkaline with sodium carbonate solution. The solid which is formed in this connection is filtered off with suction and washed with water. It is then thoroughly stirred with methanol and this mixture is evaporated to dryness. Yield: 22 g (Z-6b) c) 230 ml (2.4 mol) of acetic anhydride are initially introduced at room temperature after which 22 g WO 2006/040281 26 PCT/EP2005/055021 (0.13 mol) of Z-6b are added and the mixture is stirred under reflux for 3 h. During this period, the suspension partially goes into solution. After the mixture has been cooled down using an ice/sodium chloride bath, the solid is filtered off with suction, boiled up 2x in in each case 150 ml of acetone, filtered off with suction and dried. Yield: 25 g (m.p.: 268-272°C) Z-7) N-(6-Formyl-7-oxo-4,5,6,7-tetrahydrobenzothiazol-2-yl)acetamide 20 g (0.37 mol) of sodium methoxide are suspended in 50 ml of dimethylformamide and a suspension of 21 g (0.1 mol) of Z-6 in 100 ml of DMF is added dropwise. The mixture is subsequently stirred for 15 min and then cooled down to 0°C. A mixture of 29.9 ml (0.37 mol) of ethyl formate and 60 ml of benzene is added dropwise and the reaction mixture is diluted with a further 100 ml of benzene. A precipitate gradually sediments and the mixture is stirred for a further 3.5 h at 0°C. The suspension is hydrolysed with 370 ml of 1 molar hydrochloric acid and the solid which precipitates out in this connection is filtered off with suction. The two phases of the mother liquor are separated and the water phase is extracted with dichloromethane. The organic phase which results from this is dried and evaporated to dryness. The solid and the residue from the extraction are recrystallized from acetonitrile. Yield: 20 g WO 2006/040281 27 PCT/EP2005/055021 Z-8) N-[6-(Furan-2-carbonyl)-7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl]acetamide O O 1.7 g of Z-8 are obtained, in analogy with the preparation of Z-7, from 2 g (10 mmol) of Z-6, 1.6 g (30 mmol) of sodium methoxide and 3.8 g (30 mmol) of methyl 2-furanate. (m.p.: 255-256°C) Z-10) Methyl (2-acetylamino-7-oxo-4,5,6,7-tetrahydro-benzothiazol-6-yl)oxo acetate ° o o 1 52 g of Z-10 are obtained, preparation of Z-7, from 40 g (0.7 mmol) of sodium methoxide and 84 dimethyl oxalate. in analogy with the (190 mmol)of Z-6, 38 g g (0.7 mol) of Z-ll) N-(6-Benzoyl-7-oxo-4,5,6,7-tetrahydrobenzo- thiazol-2-yl)acetamide 3.6 o o g of Z-ll are obtained, in analogy with the preparation of Z-7, from 10 g (50 mmol) of intermediate compound 1, 7.8 g (140 mmol) of sodium methoxide and 17.9 ml (140 mmol) of methyl benzoate. Z-12) N-[7-Oxo-6-(pyridine-3-carbonyl)-4,5,6,7-tetra-hydrobenzbthiazol-2-yl]acetamide o o 3.1 g of the product Z-12 are obtained, in analogy with the preparation of Z-7, from 4 g (19 mmol) of Z-6, WO 2006/040281 28 PCT/EP2005/055021 3.9 g (57 mmol) of sodium methoxide and 7.9 g (57 mmol) of methyl nicotinate. Z-13) Methyl [7-oxo-6-(pyridine-3-carbonyl)-4,5,6,7-tetrahydrobenzothiazol-2-yl]carbamate o o a) 2-Amino-5, 6-dihydro-4if-benzothiazol-7-one A suspension of 23 g of Z-6 (109 mmol) in a mixture of 300 ml of hydrochloric acid (4 M in dioxane) and 30 ml of water is stirred at 60°C for 15 h. After it has been cooled down to 0°C, the reaction mixture is made alkaline (pH 10) with 8 N sodium hydroxide solution. The precipitate is filtered off, washed with diethyl ether and subjected to further use without any additional purification. Yield: 22.4 g b) Methyl (7-oxo-4,5,6,7-tetrahydrobenzothiazol-2-yl)-carbamate 572 pi of methyl chloroformate (7.3 mmol) are added to a solution of 500 mg of 2-amino-5,6-dihydro-4ff-benzothiazol-7-one (2.4 mmol) in 5 ml of pyridine. The reaction mixture is stirred at 50°C for 15 h and then diluted with ethyl acetate; the mixture is then extracted by shaking, in each case 2 x, with water and cold 1 N hydrochloric acid. The organic phase is dried and evaporated. Yield: 290 mg c) The desired compound is obtained, in analogy with the preparation of Z-l, from 340 mg of methyl (7-oxo-4,5,6,7-tetrahydrobenzothiazol-2-yl)carbamate (1.5 mmol), 4.7 ml of Li-HMDS (IN in THF) and 520 mg of imidazol-l-ylpyridin-3-ylmethanone (3 mmol) in 30 ml of THF. Yield: 480 mg Z-14) Ethyl [7-oxo-6-(pyridin-3-carbonyl)-4,5,6,7-tetrahydrobenzothiazol-2-yl]thiocarbamate WO 2006/040281 29 PCT/EP2005/055021 a) Ethyl (7-oxo-4,5,6,7-tetrahydrobenzothiazol-2-yl)-thiocarbamate The desired thiocarbamate is obtained in analogy with the preparation of Z-13 b, starting from 101 g of 2-amino-5,6-dihydro-4H-benzothiazol-7-one (602 mmol) in 3.4 1 of pyridine and 75 g of ethyl chlorothioformate (602 mmol). Yield: 84 g b) The desired compound is obtained, in analogy with the preparation of Z-l, from 17 g of ethyl (7-oxo-4,5,6,7-tetrahydrobenzothiazol-2-yl)thiocarbamate (67 mmol), 200 ml of Li-HMDS (IN in THF) and 23 g of imidazol-l-ylpyridin-3-ylmethanone (133 mmol) in 400 ml of THF. Yield: 18 g Z-15) Ethyl [7-oxo-6-(pyrimidine-5-carbonyl)-4,5,6,7-tetrahydrobenzothiazol-2-yl]thiocarbamate The desired compound is obtained, in analogy with the preparation of Z-l, from 12 g of ethyl (7-oxo-4,5,6,7-tetrahydrobenzothiazol-2-yl)thiocarbamate (Z-14a, 46 mmol) , 140 ml of Li-HMDS (IN in THF) and 12 g of imidazol-l-ylpyrimidin-5-ylmethanone (56 mmol) in 300 ml of THF. Yield: 13 g WO 2006/040281 30 PGT/EP2005/055021 1-1) 4-(7-Acetylamino-4,5-dihydropyrazolo[3',4':3,4] -benzo[l,2-d]thiazol-l-yl)-3-chlorobenzoic acid A suspension of Z-13 (480 mg, 1.5 mmol) and 1.5 mmol) in 10 ml of glacial acetic acid is stirred at 100°C for 4 h. The reaction mixture is then diluted with 500 ml of water and the precipitate is filtered off. Yield: 116 mg 1-3) N-[1-(2-Chloropyridin-4-yl)-3-furan-2-yl-4,5-dihydro-lH-pyrazolo[3',4':3,4]benzo[1,2-d]thiazol-7-yl]acetamide The desired product is obtained in analogy with the preparation of 1-1, starting from Z-8 (1.5 g, 5 mmol) and 2-chloropyridin-4-ylhydrazine hydrochloride in 25 ml of glacial acetic acid. Yield: 1.6 g 1-4) 4-(7-Acetylamino-3-furan-2-yl-4,5-dihydropyrazolo [3 ',4':3,4]benzo[1,2-d]thiazol-l-yl)-3-chloro-benzoic acid 2-chlorophenylhydrazine hydrochloride (267 mg, ci hooc In analogy with the preparation of 1-1, Z-8 (12 g, WO 2006/040281 31* PCT/EP2005/055021 35 mmol) and methyl 3-chloro-4-hydrazinobenzoate (8.5 g, 35 mmol) are stirred in 80 ml of glacial acetic acid at RT for 4 d. The methyl ester (1.1 g) which is obtained after precipitating in ice water is then hydrolysed using lithium hydroxide (178 mg in 15 ml of dioxane). Acidifying with 2 N hydrochloric acid yields the desired product as a solid. Yield: 0.8 g 1-6) 7-Acetylamino-l-phenyl-4,5-dihydro-lfl-pyrazolo-[3',4':3,4]benzo[1,2-d]thiazole-3-carboxylic acid 27 g of product are obtained in analogy to the preparation of 1-1 from 30 g (0.1 mol) of Z-10 and 10.3 ml (0.1 mol) of phenyl hydrazine. (m.p.: 298-300°C) . 0.1 g of this compound (0.3 mmol) is suspended in 12 ml of methanol/water (1:1) after which 0.4 ml of a 10% potassium hydroxide solution is added. After 1.5 h, the reaction mixture is evaporated and the solution is acidified with dilute hydrochloric acid. The resulting precipitate is recrystallized from acetonitrile. Yield: 0.1 g (m.p.: > 300°C) 1-8) 4-(7-Acetylamino-3-phenyl-4,5-dihydropyrazolo-[3',4':3,4]benzo[1,2-d] thiazol-l-yl)-3-chlorobenzo-nitrile NC The desired product is obtained in analogy with the preparation of 1-1, starting from Z-ll (10 g; 12.7 mmol) and 3-chloro-4-hydrazinobenzonitrile (4.5 g, 26.8 mmol) in 50 ml of glacial acetic acid. WO 2006/040281 32 PCT/EP2005/055021 Yield: 1.6 g 1-9) 4-(7-Acetylamino-3-phenyl-4,5-dihydropyrazolo-[3',4':3,4]benzo[1,2-d] thiazol-l-yl)-3-chlorbenzoic acid The desired compound is obtained in analogy with the preparation of 1-4, starting from Z-ll (2.3 g, 7.1 mmol) and methyl 3-chloro-4-hydrazinobenzoate (1.8 g, 8.5 mmol). Yield: 0.36 g I-10) N- [1-(2-Chloro-4-nitrophenyl)-3-phenyl-4,5-dihydro-lff-pyrazolo[3',4':3,4]benzo[1,2-d]thiazol-7-yl]acetamide The desired product is obtained in analogy with the preparation of 1-1, starting from Z-ll (7.5 g; 13.1 mmol) and 3-chloro-4-hydrazinonitrobenzene (3.2 g, 14.4 mmol) in 100 ml of glacial acetic acid. Yield: 1.1 g o oh I-ll) N-(l-Piperidin-4-yl-3-pyridin-3-yl-4,5-dihydro-lH-pyrazolo[3',4':3,4]benzo[1,2-d]thiazol-7-yl)-acetamide WO 2006/040281 33 PCT/EP2005/055021 In analogy with the preparation of 1-1, Z-12 (2.5 g, 7.9 mmol) and H-5 (1.2 g, 7.9 mmol) are stirred in 50 ml of glacial acetic acid at 60°C for 15 h. The mixture is poured onto ice water and rendered alkaline with 1 N sodium hydroxide solution (pH 12) . The resulting precipitate is filtered off, washed with water and dried at 40°C in vacuo. Yield: 2 g 1-12) 4-(7-Acetylamino-3-pyridin-3-yl-4,5-dihydro-pyrazolo[3',4':3,4]benzo[1,2-d]thiazol-l-yl)cyclo-hexanecarboxylic acid The desired compound is obtained in analogy with the preparation of 1-4 starting from Z-12 (1.9 g, 5.8 mmol) and H-6 (1.3 g, 5.8 mmol). Yield: 0.78 g. The corresponding cis and trans compounds are obtained by using the isomerically pure cisH-6 and transH-6, respectively. Other intermediate compounds which are prepared in analogy with the above-described syntheses. WO 2006/040281 34 PCT/EP2005/055021 no. Starting compound Stzructure no. Starting compound Structure 1-13 Z-12 X 1 s rVvi n-n 0 nc 1-30 Z-3 n^ H~^ X x F=h\ sAfV( J Vtf N 0~a 1 *—1 1 H Z-12 W T1 a s TWJ .n-n 0 cr 1-31 Z-3 hT 1 /-Nx s'Vv( J n-n n 0-0. Br 1-15 Z-12 V-C T 1 r\ s TWi -n-n 1-32 Z-4 n^\ /N°a IKXA A s rVvi N-n o 1-16 Z-12 hi jl r\ stY\J n-n 0 o2n 1-33 Z-4 ,N°2 IH'Xa s rV\i .n-n O-c, 1-17 Z-12 Hi 1 /-\ s rVvi .N-n c? no2 1-34 Z-5 ^CCu>» YrVi .N-n o h I 00 Z-12 hT 1 /=Nx s rVvi n-n 0~c, o2n 1-35 Z-5 .N-n O-c, ct\ rH 1 h Z-12 HT] r\ s rVvi .N-n 0c, NC 1-36 Z-12 HI 1 /A s rV\i n-n 7=0 OH WO 2006/040281 35 PCT/EP2005/055021 No. Starting compound Structure NO. Starting compound Structure 1-20 Z-12 nvj/s. hT i r*\ 8 yV\J .n-n •P oh 1-37 Z-ll K° sKl! r\ s tVAJ .N-n oh 1-21 Z-12 -<0 hT] s yVVJ n-n oh 1-38 Z-ll -( N^V, IKXI r\ s rVvi N-n nc~0 1-22 Z-12 h~^ X X r=H\ 8 rVvi .N-n 0 1-39 Z-12 "i-^Q /-s s rVvi N-n 0- o2n 1-23 Z-12 H-2 ,0 HI 1 r\ s rVAJ N-n c=/^F oh 1-40 Z-12 H-12 K° ^ n n ci n h 1-24 Z-12 H-3 K° N-V^ H T 1 8 TWJ n-n <? 1 1-41 Z-14 —\ ,0 S—'{ hXI rN\ s rVvi .N-n oh 1-25 Z-12 hX) r\ stY\J N-n ho 1-42 Z-14 —v ,0 hXI r\ s rVvi .n-n oh WO 2006/040281 36 PCT/EP2005/055021 No. Starting compound Structure No. Starting compound Structure 1-26 Z-12 H-4 -<0 _/N^ HT) r\ s rVAJ .N-n oh 1-43 Z-14 —^ ,o hT ) /-\ s TVU .n-n 0- 1-27 Z-l X a r\ s rV\\ « ,N-n -P oh 1-44 Z-15 ""WJOI f-, // v—n ,n-n 0- 1-28 Z-3 H-l HT) r\ srV-4 J #4 N -p- oh 1-45 Z-3 0 h3c^( y/n^n f^nvj) N—\ I I s tit n n n 0 1-29 Z-3 H-7 ht) r\ s rv^ J n ^0~c, oh 1-45 Z-12 0 CC WO 2006/040281 37 PCT/EP2005/055021 II-l) N- [1-(4-Amino-2-chlorophenyl)-3-furan-2-yl-4,5-dihydro-lff-pyrazolo[3',4':3,4]benzo[1,2-d]thiazol-7-yl]acetamide Diphenyl phosphoryl azide (1.1 ml, 5 mmol) and 0.7 ml of triethylamine are added to a solution of 1-4 (2.1 g, 4.6 mmol) in 20 ml of DMF and the mixture is stirred at 50°C for 6 h. p-Toluenesulphonic acid (1.5 g, 9.1 mmol) and 3 ml of water are added to the reaction mixture, which is stirred at 50°C for 39 h. The mixture is then poured onto 300 ml of ice water and the resulting precipitate is filtered off. The residue is purified chromatographically on silica gel using dichloromethane:methanol:ammonia 98:2:0.2. Yield: 0.6 g II-3) N- [1-(4-Amino-2-chlorophenyl)-3-phenyl-4,5-di-hydro-lH-pyrazolo[3',4':3,4]benzo[1,2-d]thiazol-7-yl]-acetamide Iron powder (0.77 g, 13.8 mmol) is added to a solution of 1-10 (1.1 g, 2 mmol) in 20 ml of glacial acetic acid and the mixture is stirred at 70°C for 4 h. After filtering through kieselguhr, the solvent is removed in vacuo and the residue is purified chromatographically on silica gel using dichloromethane:methanol 99:1. Yield: 0.8 g WO 2006/040281 38 PCT/EP2005/055021 II-4) N- [1-(4-Aminophenyl)-3-pyridin-3-yl-4,5-dihydro-lff-pyrazolo[3',4':3,4]benzo[1,2-d]thiazol-7-yl]-acetamide H2N The desired product is obtained in analogy with the preparation of II-2, starting from 1-16 (0.2 g, 0.5 mmol). Yield: 0.14 g II-5) N-[1-(3-Aminophenyl)-3-pyridin-3-yl-4,5-dihydro-lH-pyrazolo[3' , 4 ' • 3 ,4]benzo[1,2-d]thiazol-7-yl]-acetamide 1-17 (1.2 g, 2.8 mmol) is suspended in 150 ml of methanol in a 250 ml hydrogenation reactor. Palladium (5% on active charcoal, 120 mg) is added to the suspension and the latter is stirred at RT and a hydrogen pressure of 50 psi. In each, case the same quantity of catalyst is added once again after 18 h and after 40 h. After a further 15 h, the catalyst is filtered off and the solvent is removed in vacuo. Yield: 0.89 g nh. WO 2006/040281 39 PCT/EP2005/055021 II-6) N-[1-(4-Amino-2-chlorophenyl)-3-pyridin-3-yl-4,5-dihydro-lH-pyrazolo[3',4':3,4]benzo[1,2-d]thiazol-7-yl]acetamide h2n The desired product is obtained in analogy with the preparation of II-3, starting from 1-18 (10 g, 21 mmol). Yield: 8.4 g II-9) Ethyl [4-(7-acetylamino-3-phenyl-4,5-dihydro-pyrazolo[3',4':3,4]benzo[1,2-d]thiazol-l-yl)-3-chloro-phenyl]thiocarbamate Ethyl chlorothioformate (0.7 ml) is added dropwise to a solution of II-6 (3 g, 5.8 mmol) in 75 ml of pyridine and the mixture is stirred at RT for 4 h. After the pyridine has been removed on a rotary evaporator, the residue is taken up in water and the precipitate is filtered off. A solid, which is dried in vacuo at 60°C for 15 h, is obtained. Yield: 3 g 11-10) N- [1-(4-Aminomethyl-2-chlorophenyl)-3-phenyl- 4,5-dihydro-lH-pyrazolo[3',4':3,4]benzo[1,2-d]thiazol-7-yl]acetamide /—s h WO 2006/040281 40 PCT/EP2005/055021 20 mg of Raney nickel are added to a solution of 1-8 (1.5 g, 3.3 mmol) in 150 ml of ammoniacal methanol and the mixture is stirred at RT for 15 h under a hydrogen atmosphere (3.5 bar). The mixture is taken up in dichloromethane and this solution is filtered through silica gel. After the solvent has been removed in vacuo, the residue is crystallized from diethyl ether/petroleum ether. Yield: 1.1 g 11-11) N- [1-(2-Chloro-4-formylphenyl)-3-pyrazin-2-yl-4,5-dihydro-lH-pyrazolo[3',4':3,4]benzo[1,2-d]thiazol-7-yl]acetamide 2 g of manganese dioxide are added to a solution of I-29 (0.5 g, 1.1 mmol) in 25 ml of acetone and the mixture is refluxed for 3 h. The reaction mixture is then filtered and the solvent is removed in vacuo. Yield: 0.25 g II-12) N- [1-(3-Aminomethyl)-3-phenyl-4,5-dihydro-lH-pyrazolo[3',4':3,4]benzo[1,2-d]thiazol-7-yl]acetamide h2n The desired product is obtained in analogy with the preparation of 11-10, starting from 1-38 (2.3 g, 5.6 mmol). Yield: 1.4 g WO 2006/040281 41 PCT/EP2005/055021 11-13) N- [1-(4-Amino-2-fluorophenyl)-3-pyridin-3-yl-4,5-dihydro-lH-pyrazolo[3',4':3,4]benzo[1,2-d]thiazol-7-yl]acetamide h2n The desired product is obtained in analogy with the preparation of II-3, starting from 1-39 (1 g, 2.2 mmol). Yield: 1 g 11-14) 4-(7-Amino-3-pyridin-3-yl-4,5-dihydro-pyrazolo[3',4':3,4]benzo[1,2-d]thiazol-l-yl)-N,N-dimethylbenzamide 10 ml of conc. hydrochloric acid and 100 ml of water are added to a solution of 1-20 (6.3 g, 14.5 mmol) in 150 ml of dioxane and the mixture is heated under reflux for 6 h. The clear solution is stirred at 50°C for a further 16 h and then evaporated to dryness in vacuo. The deacetylation product (6.6 g, 14 mmol) is dissolved in 150 ml of DMF after which TBTU (5.1 g, 15 mmol) and 10 ml of triethylamine are added. The reation mixture is stirred at RT for 30 min, after which dimethylamine hydrochloride (1.25 g, 15 mmol) is added and the mixture is stirred at RT for a further 6 h. Following hydrolysis with 1 1 of water, the resulting precipitate is filtered off and dried in vacuo. Yield: 5.5 g / WO 2006/040281 42 PCT/EP2005/055021 11-15) 4-(7-Amino-3-pyridin-3-yl-4,5-dihydropyrazolo-[3',4':3,4]benzo[1,2-d]thiazol-l-yl)-3-chloro-N,N-dimethylbenzamide dihydrochloride 5.5 ml of hydrochloric acid (4 M in dioxane) and 5.5 ml of water are added to a solution of Example 2.180 (500 mg, 1 mmol) and the mixture is heated at 80°C for 2.5 h. The clear solution is stirred at 70°C for a further 15 h and then evaporated to dryness in vacuo. Yield: 580 mg 11-16) 4-(7-Amino-3-pyridin-3-yl-4,5-dihydropyrazolo-[3 ' , 4' : 3 , 4]benzo [1, 2-d] thiazol-l-yl) -3-f l\xoxo-N,N-dimethylbenzamide 30 ml of hydrochloric acid (37%) and 35 ml of water are added to a solution of Example 2.182 (1.37 g, 2.9 mmol) and the mixture is heated at 50°C for 12 h. After evaporating in vacuo, the residue is taken up in water and 4 N sodium hydroxide solution is added. The resulting precipitate is filtered and dried. Yield: 1.1 g WO 2006/040281 43 PCT/EP2005/055021 11-17) 1-(2-Chlorophenyl)-3-pyridin-3-yl-4,5-dihydro-lff-pyrazolo[3',4':3,4]benzo[1,2-d]thiazol-7-ylamine The desired product is obtained in analogy preparation of 11-16, starting from 1-46 24 mmol) and 280 ml of hydrochloric acid 330 ml of water. Yield: 7.6 g 11-18) 1-Phenyl-3-pyridin-3-yl-4,5-dihydro-lH-pyrazolo-[3',4':3,4]benzo[1,2-d] thiazol-7-ylamine The desired product is obtained in analogy with the preparation of 11-16, starting from Example 1.13 (7.7 g, 20 mmol), and 50 ml of hydrochloric acid (37%) in 30 ml of water. Yield: 6.8 g 11-19) 4-(7-Amino-3-pyridin-3-yl-4,5-dihydropyrazolo-[3',4':3,4]benzo[1,2-d]thiazol-l-yl)-3-chlorobenzoic acid oh The desired product is obtained in analogy with the preparation of intermediate compound 11-16, starting from Example 1.21 (2.9 g, 5 mmol) and 2 ml of hydrochloric acid (32%) in a mixture of 10 ml of water and 20 ml of dioxane. Yield: 2.7 g Analytical methods with the (10.3 g, (37%) in WO 2006/040281 44 PCT/EP2005/055021 Method AMI: HPLC: Agilent 1100 series; MS: 1100 series LC/MSD (API-ES (+/- 3000V, Quadrupole, G1946D); mode: Scan pos 100-1000, neg 100-1000 Column: Solvent: Detection: Waters; part no. 186000594; XTerra MS C18 2.5 ]om; 2.1x50mm column A: H20, deionized and containing 0.1% added formic acid B: Acetonitrile, HPLC grade and contaiing 0.1% added formic acid peak width >0.1min (2s); 190-450nm UV 254 nm (bandwidth 8, reference off) UV 230nm (bandwidth 8, reference off) 1 ul standard injection 0.6 ml/min Injection: Flow rate: Column temperature: 35°C Pump gradient: 0.0-0.5 min 0.5-1.5 min 1.5-4.0 min 4.0-6.0 min 6.0-6.5 min 5% B 5% -> 50% B 50% -> 95% B 95% B 95% -> 5% B 1.5 min post run 5% B Method AM2 HPLC: Agilent Series 1100 (G1379A/G1310A converted to G1311A/G1313A/G1316A/G1948D/G1315B/G1946D) mode: Scan pos 100-1000, neg 100-1000 Column: Solvent: Detection: Injection: Flow rate: Agilent Zorbax SB-C8, 2.1x50 mm, 3.5 pm A: H20, deionized and containing 0.1% added formic acid B: Acetonitrile HPLC grade and containing 0.1% added formic acid peak width >0.1min (2s); 190-450 nm UV 254 nm (bandwidth 8, reference off) UV 230nm (bandwidth 8, reference off) 2.5 \il standard injection 0.6 ml/min Column temperature: 35°C WO 2006/040281 45 PCT/EP2005/055021 Pump gradient: 0-3.0 min 10% -> 90% B 3.0-4.0 min 90% B 4.0-5.0min 90% -> 10% B Method AM3 HPLC: Agilent Series 1100 (G1312A/G1315A/G1316A/G1367A) Agilent MSD SL ESI Mode: Column: Solvent: Detection: Injection: Flow rate: Column temperature Pump gradient: Scan pos 150-750 Agilent Zorbax SB-C8, 2.1x50 mm, 3.5 pm A: H20 deionized and containing 0.1% added formic acid B: Acetonitrile, HPLC grade and containing 0.1% added formic acid peak width >0.01 min (0.2s); 190-450nm UV 254nm (bandwidth 16, reference off) UV 230nm (bandwidth 8, reference off) UV 214nm (bandwidth 8, reference off) 3.0 pi overlap injection 1.1 ml/min 45°C 0-1.75 min 15% -> 95% B 1.75-1.90 min 95% B 1.90-1.92min 950% -> 15% B Method AM4 HPLC: MS: Column: Solvent Detection: Agilent 1100 series Agilent LC/MSD SL (LCMS1: 1100 series LC/MSD) Waters, Xterra MS C18, 2.5 pm, 2.1x30 mm, part no. 186000592 A: H20 deionized and containing 0.1% added formic acid B: Acetonitrile, HPLC grade and containing 0.1% added formic acid MS: positive and negative mass range: 120-900 m/z fragmentor: 120 gain EMV: 1 WO 2006/040281 46 PCT/EP2005/055021 threshold: step size: UV: bandwidth: reference: spectrum: range: range step: threshold: peak width: slit: Injection: 5 pi Flow rate: 1.10 ml/min Column temperture: 40°C Gradient: 150 0.25 254 nm 1 (LCMSl off 2) 250-400 nm 1.00 nm 4.00 mAU < 0.01 min (LCMSl: >0.05 min) 1 nm (LCMSl: 2 nm) 0.00 min 5% B 0.00-2.50 min 5% -> 95% B 2.50-2.80 min 95% B 2.81-3.10 min 95% -> 5%.B Method AM5 HPLC: MS: Column: Solvent: Detection: Gain EMV: Threshold: Step size: UV: Bandwidth: Reference: Spectrum: Agilent 1100 series Agilent LC/MSD SL (LCMSl: 1100 series LC/MSD) Phenomenex, Synergy Polar RP 8OA, 4 pni/ 2.0x30 mm, part no. 00A-4336-B0 A: H2O (Millipore purified purest water) containing 0.1% HCOOH B: Acetonitrile (HPLC grade) MS: positive and negative mass range: 120-900 m/z fragmentor: 120 1 150 0.25 254 nm 1 (LCMSl: 2) off WO 2006/040281 47 PCT/EP2005/055021 range: range step: threshold: peak width: slit: Injection: inj. vol.: inj. mode: needle wash Separation:flow rate: column temp. 250-400 nm 1.00 nm 4.00 mAU < 0.01 min (LCMSl 1 nm (LCMSl 5 pi >0.05 min) 2 nm) 1.10 ml/min 40°C gradient: 0.00 min 5% solvent B 0.00-2.50 min 5% -> 95% solvent B 2.50-2.80 min 95% solvent B 2.81-3.10 min 95% -> 5% solvent B Method AM6 HPLC: Waters Alliance 2695 Column: Waters, Xterra MS C18, 2.5 pm, 4.6x30 mm, part no. 186000600 Solvent A: H20, deionized and containing 0.1% added formic acid B: Acetonitrile, HPLC grade and containing 0.08% added formic acid Flow rate: 1 ml/min Column temperature: 25°C Gradient: 0.00 min 5% B 0.00-3.10 min 5% -> 98% B 3.10-4.50 min 98% B 4.50-5.00 min 98% -> 5% B WO 2006/040281 48 PCT/EP2005/055021 Abbreviations conc. d DCM DMAP DMF DMSO EtOH h HATU HPLC Li-HMDS M MeOH min ml m.p. MS N NMR ppm Rf RP RT Rt TBTU tert THF TLC employed concentrated day dichloromethane N,N-dimethylaminopyridine N,N-dimethylformamide dimethyl sulphoxide ethanol hour 0- (7-Azabenzotriazol-l-yl) -N,JN,N' ,N'~ tetramethyluronium hexafluorophosphate high performance liquid chromatography lithium hexamethyldisilazane molar methanol minute millilitre melting point mass spectrometry normal nuclear magnetic resonance spectroscopy parts per million retention factor reversed phase room temperature retention time O-Benzotriazol-l-yl-N, N,N' ,N'-tetra.- methyluronium tetrafluoroborate tertiary tetrahydrofuran thin layer chromatography WO 2006/040281 49 PCT/EP2005/055021 Examples 1.1-1.13 N—& h r2 nh, Examples 1.1-1.13 are prepared in analogy with the I-l synthesis. # Starting compound Structure Mass [M+l]+ HPLC Rt [min] .NL VT 1.1 Z-12 W ^-NMR DMSO-d6, 8 [ppm]: 8.86 (s, IH), 8n53 (d, 4 Hz, IH), 8.02 (d, 7.7 Hz, IH), 7.46 (dd, 7.7 and 4.8 Hz, IH), 4.23 (m, IH), 3.05-3.00 (m, 2H), 2.98-2.93 (m, 2H), 2.18 (s, 3H), 2.05-1.96 (m, 2H), 1.95-1.87 (m, 4H), 1.5-1.4 (m, 2H), 1.32-1.23 (m, 2H). 394 1.88 1.2 Z-12 s Vn 380 1.67 Hil jry 1.3 Z-8 H-8 S^T^I \ /N—N O— 0 449 2.1 1.4 Z-12 H-9 N~f JL j[ s tV\\ n n-n f 457 1.54+1.71 WO 2006/040281 50 PCT/EP2005/055021 # Starting compound Structure Mass [M+1] + HPLC Rt [min] 1.5 Z-12 H-10 /-\ S"TVVJ n-n 0 n 459 1.45 1.6 Z-12 H-11 n n o 487 2.53 1.7 Z-l 0 —\ ,N^N r^S n ft Yf ] 1 " \a/JVn n n 0^ 403 1.81 1.8 Z-l —i WY j r 1 n n cy 423 1.82 1.9 Z-12 n_1\xy j^\ n—n O 0 430 1.53 1.10 Z-12 H-13 -<0 Hi 1 /^\ H srr\J 508 1.67 WO 2006/040281 51 PCT/EP2005/055021 # Starting compound Structure Mass [M+l] + HPLC Rt [min] 1.11 Z-12 H-14 HI 1 F*\ H s'rV\J n—n 427 1.49 1.12 Z-12 H-15 ,0 —{ r^nvii n N NCO n 1 442 1.48 1.13 o n -n )S> 445 1.19 Examples 2 - Reacting the carboxylic acids with amines Synthesis method A TBTU (0.15 mmol) and triethylamine (0.65 mmol) are added to a solution of the carboxylic acid (0.1 mmol) in 5 ml of dichloromethane and the mixture is stirred at RT for 15 min. The appropriate amine (0.1 mmol) is then added and the mixture is stirred at RT until the conversion is complete. The reaction mixture is treated with an aqueous 5% solution of potassium carbonate and extracted with dichloromethane. The combined organic phases are dried and evaporated In vacuo. The residue is crystallized from petroleum ether or purified chromatographically. Synthesis method B HATU (0.55 mmol) and diisopropylethylamine (1.8 mmol) are added to a solution of the carboxylic acid (0.35 mmol) in 5 ml of DMF (or dichloromethane or THF) and the mixture is stirred at RT for 15 min. After the appropriate amine (0.39 mmol) has been added, the WO 2006/040281 52 PCT/EP2005/055021 mixture is stirred at RT for 15 h, after which it is treated with aqueous 5% potassium carbonate solution and extracted with dichloromethane. The combined organic phases are dried and evaporated in vacuo. The residue is purified chromatographically. Synthesis method C The synthesis is carried out in analogy with synthesis method B but using triethylamine instead of diisopropylethylamine. Synthesis method D The carboxylic acid is first of all immobilized on a polymer. For this, 12 ml of dichloromethane are added to 1.2 g of PL-TFP resin (1.25 mmol/g, 150-300 jam; Polymer Laboratories), with the appropriate carboxylic acid (1.2 mmol in 6 ml of DMF), DMAP (0.7 mmol in 6 ml of dichloromethane) and 0.8 ml of diisopropylcarbodiimide then being pipetted in consecutively 5 minutes later. The mixture is left to stand at RT for 36 h. The resin is filtered off through a glass frit (porosity 4) and washed 4 x with in each case 15 ml of DMF, 4 x with in each case 20 ml of dichloromethane and 4 x with in each case 20 ml of THF, with the solvent in each case dripping through the glass frit without any vacuum/pressure and with the frit being sucked dry before each new application of solvent. The washed resin is dried at RT and 0.2 mbar for 2 d. Yield of dry resin: 2.204 g. For the reaction of the immobilized carboxylic acid, 110 mg (0.15 mmol) of the resin which has been prepared in this way are initially introduced in 1 ml of dichloromethane and 0.5 ml of DMF after which the amine (0.1 mmol) and diisopropylethylamine (0.1 mmol) are added. The mixture is then stirred slowly at RT for 15 h. After the reaction has come to an end, the resin is filtered off as described above and washed with 8 x 3 ml of dichloromethane. The filtrate is evaporated in vacuo and the residue is purified by means of RP-HPLC. WO 2006/040281 53 PCT/EP2005/055021 Examples 2.1 - 2.183 # Starting compound Structure Mass [M+1]+ HPLC Rt [min] or m.p. or TLCsRf o H,C—\ N-fii n N N ■ o^a 2.1 1-9 0 1H-NMR DMSO-d6, d [ppm]j 7.86 (s, IH), 7.78 (d, 7.9 Hz, IH), 7.75 (d, 7.7 Hz, IH), 7.63-7..61 (m, IH), 7.49-7.46 (m, 2H), 7.41-7.37 (m, IH), 3.72-3.62 (m, 6H), 3.42-3.38 (m, 2H), 2.07 (s, 3H). 534 2.06 O H3C—\ v-c Till H s^yyv1 2.5 1-9 n H 0 478 . m.p.: 206°C 0 H,C-f VCQYO 2.6 1-9 n n nh o 540 Rf= 0.5 DCM:MeOH 9:1 O h.c—x' uXXO 2.7 1-9 N ^ O 546 1.94 O H3C_A Nv/S HI 1 f 1 h 00 • c* 1-9 n n H'CnJ^CI 536 2.1 0 H3C—\ KX^yO 2.9 1-9 /N N B 0-c, 523 1.88 WO 2006/040281 54 PCT/EP2005/055021 # Starting compound Structure Mass [M+1]+ HPLC Rt [min] or m.p. or TLC:Rf 2.10 1-9 0 H,C-\ N-C T] f 1 N N HO 0 536 2.02 2.11 1-21 0 H=c~< N—K H ,N N Hs9 C^-ci o ° H3c 576 2.06 2.12 1-21 0 H,C-? N^-N, K VyO N N H 1^-CI 0N^ o 616 1.4 2.13 1-21 o H,C—\ ^>Nv. nXPyO N N O 465 1.42 2.14 1-21 O H3C \ N—K N N H39 O-CI Vr< o 479 2 .18 2.15 1-21 o H3c—^ N-^\ WT 1 f 1 N N ^ H,q (/--CI W/ o 570 2.02 2.16 1-21 N N H»9 V^-ci 0"-T o 630 1.39 WO 2006/040281 55 PCT/EP2005/055021 # Starting compound Structure Mass [M+1]+ HPLC Rt [min] or m.p. or TLC:Rf to H 1-21 0 T | \ 1 N N H ^ ° G 630 1.28 2.18* 1-21 0 H3C-\ Y-? T 1 r\ 3 tVvl _/N~N H >>C, <fC m2 520 1.98 2.19 1-21 N-n .0^ 0 0 d 616 1.32 2.20 1-21 ° H,C—\ Vn s Tvvi N-N „ _0-° 0 0 547 1.89 2.21 1-21 rt s TVvi N-N H Cj-a d ° 541 1.86 2.22 1-21 0 H,C—\ HXXX) N N DtP" HO 0 537 1.54 2.23 1-21 0 H.C—\ N-^^s nx^xjs h3c wnjn ■ &P" H3C 0 563 3.2 WO 2006/040281 56 PCT/EP2005/055021 # Starting compound Structure Mass [M+1]+ HPLC Rt [min] or m.p. or TLC:Rf 2.24 1-21 0 n—K h n n HjC-o' ' 0 523 1.58 2.25 1-21 0 h,c-? N-(7 T 1 [ 1 n n "*53^ >>c1 547 1.5 2.26 1-21 0 h3c"< n—k h n n 563 1.6 2.27 1-21 0 n n h°-^\n^0~c1 0 549 1.45 2.28 1-21 0 h3c \ n—& n n 0 563 1.55 2.29 1-21 0 h3c \ jyv, n n 0^° ho o 549 1.53 2.30 1-21 o h,c—\ h 11 ii n n o 535 1.58 WO 2006/040281 57 PCT/EP2005/055021 # Starting compound Structure Mass [M+1]+ HPLC Rt [min] or m.p. or TLC:Rf 2.31 1-21 h3c^° N~\ h n n HaC-o^ 0 537 1.58 2.32 1-21 0 H3C-X HX^X) n n ho' ' 0 523 1.47 2.33 1-21 0 hc—? HX^Q n n h^0~a hjc° ^ ° 537 1.58 2.34 1-21 0 HXjX,X) n n h 1^~-ci ^0n~t h3c u 0 509 1.5 2.35 1-21 0 h3c_a ^"1 wt 1 i 1 _.n n 0 549 1.55 2.36 1-21 ^c-fjY^1 (al KgJUUU n—n h ij^ci cn 549 1.59 2.37 1-21 0 h3c—\ HXJX^Q n n h ij^-a cn a 632 0.55 WO 2006/040281 58 PCT/EP2005/055021 # Starting compound Structure Mass [M+1]+ HPLC Rt [min] or m.p. or TLC:Rf 2.38 1-21 o H3C \ J1 h n-—n Ha<t O 0 563 1.53 2.39 1-21 0 Hi 1 [ J n r/T © 658 0.52 2.40 1-21 0 h3c-\ w 11 r i n n H^O^cl 0 548 2.53 2.41 1-21 0 h3c"< / n—V h n n CI? 0 533 1.76 2.42 1-21 ^8XfJYU n n "%r-\ D-c, H3C 0 576 2.57 2.43 1-21 0 H3C—\ [1 f J n il h3c z®^ N—/ \ JL^CI h3c \ 0 576 2.56 2.44 1-21 O h3C—f N~^\, N-fll f 1 n n Q^p-o o 519 1.62 WO 2006/040281 59 PCT/EP2005/055021 # Starting compound Structure Mass [M+1]+ HPLC Rt [min] or m.p. or TLC:Rf V-f°7/N N—\ 1 I I H s^yv n n 2.45 1-21 h LAci °v ch3 660 1.39 •V5"/ N—? h n n 2.46 1-21 H L/-CI crv o u 707 1.5 HK-/jn rNi h s'n^vv n n /==< 2.47 1-21 °VD 709 2.75 2.48 1-21 0 H3C-\ ^.Nn N-^ fl f I N N H 1>CI ch, 590 2.69 0 N-f 11 1 1 h s^yyv1 2.49 1-21 n n O 630 2.77 WO 2006/040281 60 PCT/EP2005/055021 # Starting compound Structure Mass [M+1] + HPLC Rt [min] or m.p. or TLC:Rf 2.50 1-21 0 H3c—? N N h o-c, r^ 645 2.56 2.51 1-20 0 h3c_n^. N—\ H N N 0 0 H3c 528 2 2.52 1-20 0 H3C—\ N-^\ ^Nn n-< t ] r i __n n h*9 d ch 596 2.11 2.53 1-20 0 h3c \ n—\ H N N h>9 o o v h3c 542 2.06 2.54 1-20 o ".<k i'v, f»'s ^xjuu n n o 582 2.1 2.55 1-20 0 h3c \ /n-j,—i kxjuu n n o ° 604 1.26 WO 2006/040281 61 PCT/EP2005/055021 WO 2006/040281 62 PCT/EP2005/055021 # Starting compound Structure Mass [M+1]+ HPLC Rt [min] or m.p. or TLC:Rf 0 h3c-< n^-v. T] f I 2.61 1-22 n n % h,c-n. 3 ch3 459 * 1.43 o h3c"\ ny\ N~\ H sA^yV 2.62 1-23 h3c-0 /wn—"n hgc ^ 3 0 521 1.54 0 h=cij/n n—K H 2.63 1-23 n n 0 519 1.49 O h3c—\ n-^\ nhf | 1 h \-YY^ 2.64 1-23 n n h3c' 1, 477 1.43 h3c^° /s, rccjyu 2.65 1-23 n n ch3 0 491 1.59 o HX—^ n-f ii 1 1 h 2.66 1-23 ",0-. n 535 1.63 0 o h3c"a _/•v^i n~^ x jl jlj H 2.67 " 1-23 n n o 533 1.54 WO 2006/040281 63 PCT/EP2005/055021 # Starting compound Structure Mass [M+1] + HPLC Rt [min] or m.p. or TLC:Rf 2.68 1-25 0 h3c—\ n-^\ n-n 521 1.75 2.69 1-25 o h,c—\ 8 tVvi n-n h 568 0.19 2.70 1-25 0 h,c-\ NH XI r\ syWJ .n-n ch3 556 Rf : 0.14 DCM:MeOH 7:3 2.71 1-25 0 h,c—* VXl r\ s'rV\i n-n Q oh 529 1.5 2.72 1-25 o h,c—\ I] /=\ s rVvi n-n ch3 556 Rf = 0.18 DCM:MeOH 7:3 2.73 1-25 0 h3c—\ VI) rN^ s TY\J N—n o CJ 612 Rf = 0.27 DCM:MeOH 8:2 WO 2006/040281 64 PCT/EP2005/055021 # Starting compound Structure Mass [M+1]+ HPLC Rt [min] or m.p. or TLC:rf 2.74 1-25 0 h,c—^ VII r\ s rVvi N-n 6 535 1.81 2.75 1-25 0 hgc—\ s tVu .N-n hn ch3 517 1.53 2.76 1-25 o h3c—\ n-^\ VXl r\ s'rVvi N-n o 499 1.6 2.77 1-25 0 h3c—k iKXl rt s rVvi N-N a 485 1.48 2.78 1-25 0 h.c \ N^X) /=\ s T>Ai .n-n O h3c 528 2.8 2.79 1-25 0 HgC—\ ,N-~^\ HT) /-NX s' rHi .n-n •Wi 3 HO—^ 517 1.51 WO 2006/040281 65 PCT/EP2005/055021 # Starting compound Structure Mass [M+1]+ HPLC Rt [min] or m.p. or TI>C:Rf 2.80 1-25 EtOH 0 h3c \ Vli r\ s tVAJ n-n /—o h3c 474 3 .38 2.81 1-26 0 h3c_a m-C T 1 r\ sTlr\J n-n _/J—\ h3c—' ch3 501 1.64 2.82 1-27 0 h3c—\ n^-\ N-C T 1 1 » n n H-\ ch3 494 1.74 2.83 1-28 n n h3c' ^ 3 0 474 m.p.: 283°c 00 CN 1-45 N N h39n fy~-ci *c & 494 1.81 2.85 1-12 N—. H S i5 519 1.77 WO 2006/040281 66 PCT/EP2005/055021 # Starting compound Structure Mass [M+1]+ HPLC Rt [min] or m.p. or TLC:Rf 2.86 1-12 »c x xQ~< m n <5 507 1.47 2.87 1-12 /N"A hcl xChi °^h3 h3c 465 1.39 2.88 1-36 (fk. O 612 1.35 2.89 1-36 i<JXO h n \ 0 o 626 1.33 2.90 1-36 ^•<9yO n n O ° " .n-—y o 612 1.38 2.91 1-36 p NiXXO n n \ 0 0 ° 0 626 1.36 WO 2006/040281 67 PCT/EP2005/055021 # Starting compound Structure Mass [M+1]+ HPLC Rt [min] or m.p. or TLC:Rf 2.92 1-36 ,0 HXXO n n ■A 9 626 1.37 2.93 1-37 n n n / 478 2.00 2.94 1-37 N^sXjXrXj n n ■X n J3 615 1.67 2.95 1-37 "^-COuO n n rf ' f-' 561 1.60 2.96 1-37 n n /N 0 o 615 1.65 WO 2006/040281 68 PCT/EP2005/055021 # Starting compound Structure Mass [M+1]+ HPLC Rt [min] or m.p. or TLC:Rf 2.97 1-37 \ MXXO n n o n \ 547 1.60 2.98 1-37 n-^sXXA) n n j \ 535 1.60 2.99 1-9 N^slAXJ n n a, /n-y 0 n / 615 m.p.: 280°C 2.100 1-9 n n o^CI n 629 m.p.: 286°C 2.101 1-12 n s^j^n oP 0 r 548 1.45 WO 2006/040281 69 PCT/EP2005/055021 # Starting compound Structure Mass [M+1]+ HPLC Rt [min] or m.p. or TLC:Rf 2.102 1-12 N s N"n oP n- s -N V 522 1.46 2.103 trans-I-12 N—. ArO-P N^s > ^-N d °o n- / 548 1.43 2.104 trans-I-12 X xQ^r d 0=< N 0 1 548 1.43 2.105 trans-I-12 s \ N 0 0=< o V-N Y~ 548 1.46 2.106 trans-I-12 X N^-s \ ^-n d 0=< r> V-n \ 520 1.37 2.107 trans-I-12 X d o=< d~ n / 548 1.45 WO 2006/040281 70 PCT/EP2005/055021 # Starting compound Structure Mass [M+1]+ HPLC Rt [min] or m.p. or TLCsRf 2.108 trans-I-12 \ Jn d o=< Q 574 1.54 2.109 h 1 (0 w ,0 n n 505 1.6 2.110 1-23 0 HXJUQ S J^F N~< 0 507 1.41 2.111 1-23 0 N^sXJoO n n a ° 546 1.52 2.112 1-23 o n n o 560 1.24 2.113 1-23 0 njQyO N N N & n—/ / 560 1.48 WO 2006/040281 71 PCT/EP2005/055021 # Starting compound Structure Mass [M+1 J* HPLC Rt [min] or m.p. or TLC:Rf 2.115 1-23 o - / n n Vs- 0 520 1.45 2.116 1-23 o N--, _/N N o 548 1.49 2.117 1-23 \~J? .z ^z T / 534 1.48 2.118 1-23 ,° n n O 560 1.53 2.119 1-23 O —{ n^\ n^sX^J^JC3 n n n0. 505 1.6 2.120 1-23 0 —\ nxpuo n n °~o^ 0 586 1.61 2.121 1-23 o n n f O^' o 588 1.64 WO 2006/040281 72 PCT/EP2005/055021 # Starting compound Structure Mass [M+1]+ HPLC Rt [min] or m.p. or TLC:Rf 2.122 1-23 0 -4 ^ N N 0 574 1.27 2.123 1-23 o N N kOr1 0 , 0 603 1.49 2.124 1-23 .0 CKQX) N I-ll \ N N o 588 1.28 2.125 1-23 hjCLX) N N 532 1.65 2.126 1-25 N^T j[ /=\ s'rr\J N—N \P /—-N /O-7 \ 517 Rf = 0.44 DCM: MEOH 9:1 2.127 1-25 N—{T | s rWi ,N—N \S$ p □ 568 Rf = 0.18 DCM: MEOH 7:3 WO 2006/040281 73 PCT/EP2005/055021 # Starting compound Structure Mass [M+1]+ HPLC Rt [min] or m.p. or TLC:Rf 2.128 1-25 T j. r=-\ s rVAJ n—n P o 582 Rf = 0.24 DCM: MEOH 7:3 2.129 1-25 n—^ -n—n o 598 1.23 2.130 1-25 -( n—J 1 FsH\ s tVAJ _/N~N © 527 1.39 2.131 1-25 n—^ X 1 s rVvi /n-n 522 1.43 2.132 1-25 n—<f T ] /^\ srr\J n-n o->° 522 Rf = 0.91 DCM: MEOH 9:1 2.133 1-25 N~f j l /^N\ srr\J N-n 522 Rf = 0.88 DCM: MEOH 9:1 WO 2006/040281 74 PCT/EP2005/055021 # Starting compound Structure Mass [M+1]+ HPLC Rt [min] or m.p. or TLC:Rf 2.134 1-25 n-^ T 1 r==-\ S"W\J .N—n \P o 0 591 Rf = 0.42 DCM: MEOH 9:1 2.135 1-25 Hi 1 i^\ s rVAJ .n—n x yP 530 Rf = 0.4 DCM: MEOH 9:1 2.136 1-25 n^XvX/bsM,> N—n 544 Rf = 0.25 DCM: MEOH 9:1 2.137 1-25 -<0 n-n O^- 556 1.27 2.138 1-25 n_c r 1 /=\ Srr-\J ,n—n 459 Rf = 0.34 DCM: MEOH 9:1 2.139 1-25 n—( J[ 1 «=N s rVAJ ,n—n 03 0, —^-N— 570 Rf = 0.-18 DCM: MEOH 8:2 WO 2006/040281 75 PCT/EP2005/055021 # Starting compound Structure Mass [M+1]+ HPLC Rt [min] or m.p. or TLC:Rf 2.140 1-25 -<0 N—^ | ] s rVvi N-n N-—. / 570 1.43 2.141 1-20 p o N o 578 1.56 2.142 1-20 o N 591 1.53 2.143 1-20 /n—JC^I /^\ s yVYJ ° .N—N o o—' 584 1.53 2.144 1-20 XXl r", 'xXsJ 0 N-N P cro 568 1.61 WO 2006/040281 76 PCT/EP2005/055021 WO 2006/040281 77 PCT/EP2005/055021 WO 2006/040281 78 PCT/EP2005/055021 # Starting compound Structure Mass [M+1]+ HPLC Rt [min] or m.p. or TLC:Rt 2.155 1-21 ° N—. 5 • —-N \ 550 1.49 2.156 1-21 N-/T ] N o^0-« Q 562 1.49 2.157 1-21 r^Cl r\ ^0~= O ^0 618 1.58 2.158 1-21 % 630 1.50 2.159 1-21 /^jfl r\ H° °o N 625 1.55 WO 2006/040281 79 PCT/EP2005/055021 # Starting compound Structure Mass [M+1] + HPLC Rt [min] or m.p. or TLC:Rf 2.160 1-21 N^jQ r\ ^ s ' cro 602 1.65 2.161 1-21 /N-/iO r*\ "\ 562 1.47 2.162 1-21 n <? / 616 1.72 2.163 1-21 _y--OOi o^0-° k 590 1.25 2.164 1-21 °o i 574 1.55 WO 2006/040281 80 PCT/EP2005/055021 # Starting compound Structure Mass [M+l] + HPLC Rt [min] or m.p. or TLC:Rf 2.165 1-21 WJTI f^\ -io o^0~c- 0 6 612 1.64 2.166 1-21 /-CQ -< syyO o=^0~°. °o N WD* 625 1.58 2.167 1-21 /X']C) r"\ ~i sryJ\J /N~N N—, G n \ 560 1.46 2.168 H 1 to H o 562 1.77 WO 2006/040281 81 PCT/EP2005/055021 # Starting compound Structure Mass [M+1] + HPLC Rt [min] or m.p. or TLC:Rf 2.169 H 1 10 H 602 1.62 2.170 1-21 '\jr^ °o 590 1.62 2.171 1-21 o V 590 1.61 2.172 H 1 to H /-fjTl /®"n "i s o=0~c, °o 604 1.68 2.173 1-21 .0 —( /"-^S x^S, \XajO N N 0-c, crv AjO 685 2.59 2.174 1-20 p 4 /N\ N N ><>P o 542 2.56 WO 2006/040281 82 PCT/EP2005/055021 # Starting compound Structure Mass [M+1] + HPLC Rt [min] or m.p. or TLC:Rf 2.176 1-41 —\ P N^SXXXJ n n & o 505 —\ ,0 s -4 HXXO n n 2.177 1-42 o 676 2.178 1-42 "Vf nyx ^ iXXU n ll \ jC? / ft ci o 539 2.179 1-12 N^S^N oP / 465 1.46 "^XjyO 2.180 1-21 n n \ 1^^CI 0 493 1.56 2.181 1-20 0 Hll f 1 NsA/yV n n 0 459 1.5 WO 2006/040281 83 PCT/EP2005/055021 # Starting compound Structure Mass [M+1]+ HPLC Rt [min] or m.p. or TLC:Rf 2.182 1-23 o HXXX) n n \ 0- 0 477 2.87 2.183 11-19 X jl JL J N N O ill 1.44 *In Example 2.18, the carboxylic acid is reacted with tert-butyl (2-aminocyclopropyl)carbamate. In the 2nd step, the BOC protecting group is eliminated with trifluoroacetic acid. Examples 3 - Reacting the amines which have been prepared Synthesis method E - reacting with sulphonyl chlorides 0.5 mmol of sulphonyl chloride is added to a solution of 0.2 mmol of amine in 3 ml of pyridine and the mixture is stirred at RT for 15. The reaction mixture is evaporated and the residue is purified chromatographically. Synthesis method F - reacting with carboxylic acids HATU (0.55 mmol) and diisopropylethylamine (1.8 mmol) are added to a solution of the carboxylic acid (0.16 mmol) in 1.3 ml of DMF and the mixture is stirred at RT for 1 h. After a solution of 0.1 mmol of the appropriate amine in DMF has been added, the mixture is stirred at RT for a further 15 h. The reaction mixture is then filtered and evaporated and the residue is purified chromatographically. Synthesis method G - reacting with carbonyl chlorides 0.5 mmol of carbonyl chloride is added to a solution of WO 2006/040281 84 PCT/EP2005/055021 0.2 mmol of amine in 3 ml of pyridine and the mixture is stirred at RT for 15. The reaction mixture is evaporated and the residue is purified chromatographically. Examples 3.2-3.82 # Starting compound Structure Mass [M+1]+ HPLC Rt [min] or m.p. or TLC:Rf 3.2 II-l o h3c—\ 0-, \-e t ] r\ n n 0~c, ojto A^CH3 H3c N 601 to o 00 3.3 II-3 N—f H n n h3c o l/~-ci NtS-n' h3c 0 h 543 2.2 3.4 II-l h3c-^° n^. n—^ i 9 IH n n O-c, nh °*0 hi°yych= n-0 585 2 .12 3.10 IX-4 o h,c—f ^11 rH s r r\J n-n 0 hn .. \ Nas\ o-s'bo 544 1.62 3.11 II-4 o H3C-f n-c i 1 l*»S h s rvvi n-n vP H3c h 445 1.45 WO 2006/040281 85 PCT/EP2005/055021 # Starting compound Structure Mass [M+1]+ HPLC Rt [min] or m.p. or TLC:Rf 3.12 II-4 ch, rllX) n n 10 0 473 1.6 3.13 II-4 ch3 0=^ VXl rs s rvi " \ II n-n 10 /~"n ( h O h3c' 475 1.48 3.14 II-4 ch, °=( Ny^. .n-n "fi~o H 489 1.5 3.15 II-4 ,ch3 i 0=< tr^XJl r\ 1, II N4-N n-n jP O" ho 529 1.53 3.16 II-4 CH, H-^ I A !^\ H s 'Vyi // \ // V-n n-n sP <S~ 515 1.52 3.17 IX-4 ch, o=< n-^\ fi~c JC A f*\ s TV(\ « \ // ^_n .n-n s* CH3 519 1.58 WO 2006/040281 86 PCT/EP2005/055021 # Starting compound Structure Mass [M+1]+ HPLC Rt [min] or m.p. or TLCiRf 3.18 II-4 ch, H-C X A s YV(\ « j, //v-n n-n ^-o 529 1.59 3.19 II-4 /ch3 0=< n-^\ tr^Xl rs s rVA « \ //v-n n-n yP 4" 0 503 1.43 3.20 II-4 ch, 0=< n^.—s. fj-1'(X A s rVA " \, // v-n n-n 471 1.6 3.21 XI-4 ch, 0=< n~^\ H^XjL rs s tV\ \ //v-n n-n 515 1.57 3.22 IX-4 ch3 0=< n^^\ l, //v-n n-n 0 hn ru h3c 3 488 0.47 3.23 II-5 n- JJ&Y* a ?< <y 537 1.89 WO 2006/040281 87 PCT/EP2005/055021 # Starting compound Structure Mass [M+1]+ HPLC Rt [min] or m.p. or TLCsRf 3.24 II-5 G Cr* 535 1:81 3.25 II-6 0 r*XJl rN> s T n-n 0- hn 0=s=q h,c 515 1.54 3.26 II-6 0 H3C-X XI r\ s tV\J n-n 9v /~~n h3c h 479 1.52 3.27 II-6 0 h3c-f r^Xl rY s' rVAJ /n~n V C^cl 0s 541 1.82 3.28 II-6 0 H3c—X n^\ jkXa rN)> n—n d" 547 1.90 3.29 ix-6 0 hjc—\ n-^\ w~< X1 r\ s tVVi n-n 0- hn o=s^0 0 577 1.81 WO 2006/040281 88 PCT/EP2005/055021 # Starting compound Structure Mass [M+ir HPLC Rt [min] or m.p. or TLC:Rf 3.30 II-6 0 h,c~* r*XJl rt s tV\J N-n <0^a hn 616 1.38 3.31 II-6 0 h3c-v n^-"\ Vll rt srr\J n-n 0~c, hn o>~0-0 616 Rf : 0.18 MeOH:NH4OH 92.5:7.5:1 3.32 II-6 ch3 0=\ h-^ XI r*\ s TV\ " v // v-n n—n .o-/ K h3c 509 1.43 3.33 ii-6 ch3 s~-/N~N h^-o' 553 1.55 3.34 11-12 ~Uojo N N <7 A 569 m.p.: 277°c 3.35 11-12 N N <? ~r 569 2.59 WO 2006/040281 89 PCT/EP2005/055021 # Starting compound Structure Mass [M+1]+ HPLC Rt [min] or m.p. or TLCsRf n^sxxx) N N 3.36 11-12 <? & 520 m.p.: 282°C "kxxo 1 II N N 3.37 11-12 617 m.p.: 227°C cf" 3.38 11-12 > N -p*" 631 m.p.: 294°C Mojo I li u N 3.39 11-12 <? 7- 597 3.0 n-<ojo N N 3.40 11-12 & \ 0 605 2.95 WO 2006/040281 90 PCT/EP2005/055021 # Starting compound Structure Mass [M+1]+ HPLC Rt [min] or m.p. or TLCsRf 3.41 I-ll -( .N-^i ^ N^sXpyO N N o °.^N 437 1.28 3.42 I-ll N— N N a 451 1.4 3.43 I-ll ,0 N & J f » N N .0 499 1.56 3.44 I-ll 0 n^SXajCJ N N j3 ^-N 500 1.21 3.45 I-ll N ^ n^sXDLJC N N .8 °srs 0 \ 473 1.38 WO 2006/040281 91 PCT/EP2005/055021 # Starting compound Structure Mass [M+1]+ HPLC Rt [min] or m.p. or TLCtRf 3.46 I-ll n~<xpy^n n n 0 °^s 535 1.68 3.47 I-ll n n o °^s 536 1.52 3.49 1-40 n n 0 PrL° n^n 522 1.47 3.50 I-ll ^pyg n n 536 1.52 3.51 I-ll n^s3^yo n n j3 465 1.47 WO 2006/040281 92 PCT/EP2005/055021 # Starting compound Structure Mass [M+1]+ HPLC Rt [min] or m.p. or TLC:Rf 3.52 I-ll n n 500 1.34 3.53 I-ll h:° /NyN ^ N^sXp^O n n o w> 500 1.46 3.54 11-13 WT 1 rt s TVAJ N-n / 506 1.47 3.55 11-13 WT 1 rt s rV\J N-n 463 1.46 3.56 II-4 ^ jC^X /rt s'tY\J ° .N-n 0 n 502 1.45 WO 2006/040281 93 PCT/EP2005/055021 # Starting compound Structure Mass [M+13+ HPLC Rt [min] or m.p. or TLCiRf 3.57 II-4 °=\ N C N—N —N \ 502 1.45 3.58 11-14 o o=\ r 531 1.48 3.59 11-14 M~Ri ■X $ r 545 1.56 3.60 XX-14 c a cr jl N— / 551 1.77 3.61 11-14 j? r 541 1.67 WO 2006/040281 94 PCT/EP2005/055021 # Starting compound Structure Mass [M+1]+ HPLC Rt [min] or m.p. or TLCsRf 3.62 11-14 v-upv n— / 517 1.46 3.63 11-14 J? n— / 519 1.57 3.64 11-14 j? n—' / 489 1.45 3.65 11-15 c-^-oa ,n—n /- 547 1.74 3.66 11-16 n—^ n n 0 521 1.46 WO 2006/040281 95 PCT/EP2005/055021 # Starting compound Structure Mass [M+1]+ HPLC Rt [min] or m.p. or TLCsRf 3.67 11-16 ^-09 0 567 1.77 3.68 11-17 ° .n-n 0~c, 436 1.64 3.69 11-17 0 n-n O~o, 450 1.75 3.70 11-17 O-. 464 1.87 3.71 11-17 rrX? -o 0 ^ O-. 452 1.59 3.72 11-17 ^' o~. 498 1.88 3.73 11-17 o^oqi 0 n-n 0~° 512 1.95 WO 2006/040281 96 PCT/EP2005/055021 # Starting compound Structure Mass [M+1]+ HPLC Rt [min] or m.p. or TLCsRf 3.74 11-17 506 1. 68 3.75 11-17 v^:it 507 1.57 3.76 11-17 ~ a. 494 1.64 3.77 11-17 478 1.58 3.78 11-17 / O 0 493 1.28 3.79 11-17 0 N a 466 1.61 3.80 11-18 cf 418 1.54 WO 2006/040281 97 PCT/EP2005/055021 # Starting compound Structure Mass [M+1]+ HPLC Rt [min] or m.p. or TLC:Rf 3.81 CO H 1 H H •<c°Q cf 431 1.53 3.82 00 rH 1 H H 473 1.55 * 3.56 is synthesized by reacting II-4 with 2-bromopropionyl bromide and then performing a nucleophilic substitution with dimethylamine. Examples 4 - reacting the thiocarbamates with amines and alcohols Preparing ureas 0.17 mmol of amine and 30 y.1 of diisopropylethylamine are added to a solution of 0.11 mmol of thiocarbamate in 5 ml of ethanol and the mixture is stirred at 80°C for 15 h in a pressure tube. After the solvent has been removed in vacuo, the residue is purified chromatographically. Preparing carbamates 5 ml of the appropriate alcohol are added to a solution of 0.11 mmol of thiocarbamate (or methylcarbamate) in and the mixture is stirred at 80°C for 15 h in a pressure tube. After the solvent has been removed in vacuo, the residue is purified chromatographically. WO 2006/040281 98 PCT/EP2005/055021 WO 2006/040281 99 PCT/EP2005/055021 # Starting compound Structure Mass [M+1]+ HPLC Rt [min] or m.p. or TLC:Rf 4.6 II-9 0 H3C—\ VX1X) H sA^yV N 1 0--CI w r '"'N 493 2 . 02 4.7 II-9 J* N /—\ \\ °\_/r^ 585 m.p.: 160°C 00 • II-9 n^XXjO N ll °y 0--CI P" 562 1.59 4.9 II-9 -<0 ^ n^sXXjO N ll ^n/0^c, N 630 1.68 4.10 XI-9 N-<X 1 ^ 8 TVvJ _.N-N ^ X^ci oN 549 1.65 4.11 II-9 -<° /s^ ^3x/^n\ .N—N o \ / N " 551 Rf = 0.02 DCM:MeOH 9:1 WO 2006/040281 100 PCT/EP2005/055021 # Starting compound Structure Mass [M+1]+ HPLC Rt [min] or m.p. or TLC:Rf 4.12 II-9 -f /n—n o /n^n\ 565 Rf = 0.05 DCM:MeOH 9:1 4.13 II-9 -i n_h\ j 1 fs*\ s Tr\J n-n a 520 1.43 4.14 II-9 "vfi ,=*, s"~Tyaj N—n y_ o N 534 1.54 4.15 II-9 -( /VN 0 j^kc, /-n o 550 1.43 4.16 II-9 « V-C j J fff\ "rr^J ,n-n p" 563 1.3 WO 2006/040281 101 PCT/EP2005/055021 # Starting compound Structure Mass [M+1]+ HPLC Rt [min] or m.p. or TLC:Rf 4.17 II-9 /N—N ' N 6 576 1.83 CO H II-9 -<0 N—^ J | N s rvvi vN~N 574 1.79 4.19 II-9 K-( j ] sT/rkJ N—n 0 y 'N 0 562 1.42 4.20 IX-9 -<0 .N^ N—<f J } /=\ .N—N o yj-a N 508 1.49 4.21 II-9 -i N~<f J } s tvvj .N—m /""""N N 6 548 1.68 4.22 2.176 0 wjgl x) .N N -P 460 1.43 WO 2006/040281 102 PCT/EP2005/055021 # Starting compound Structure Mass [M+1]+ HPIaC Rt [min] or m.p. or TLC:Rf 4.23 2.176 ' »^sX^X) N N -P /N"~- 488 1.45 4.24 2.177 D>—\ /? n^sX^J\XJ) n n O 685 1.49 4.25 2.177 O^0 „ Hl^X) n n 0^' O 721 1.55 4.26 2.178 N-f X jT 1 N / Yi CI 0 508 1.58 4.27 1-43 N—^ N—<f || | 1 || s^yv N N 0~c, 437 1.59 4.28 1-44 0 rt^n A \ N N Q O- 551 m.p.: 199°C WO 2006/040281 103 PCT/EP2005/055021 # Starting compound Structure Mass [M+1]+ HPLC Rt [min] or m.p. or TLC:Rf 4.29 1-44 0 N—<f | | ll \a^jvn N N 0-° 439 m.p.: 273°C 4.30 1-44 rktxo /""n\ —'n 0 ca-ci 538 m.p.: 220°C 4.31 1-43 0 N—\ H mx 1 r\ o=< s cc 551 1.94 4.32 I-l N N 466 3.61 reacting the chloropyridyl building blocks O h3C^ | H3C^N-/ ~R" Synthesis method H If the amines are present in liquid form, 0.2 mmol of the chloropyridine building block is dissolved in 0.5 ml of amine and the solution is heated at 120°C for 10 min in a microwave (CEM). After the excess amine has been removed, the residue is purified chromatographically. Synthesis method I A solution of 1.2 mmol of chloropyridine building block WO 2006/040281 104 PCT/EP2005/055021 and 3 mmol of amine in 3 ml of iV-methylpyrrolidinone, DMSO or DMF is heated at 120°C for 10 min in a microwave (CEM). After the solvent and the excess amine have been removed, the residue is purified chromatographically. Examples 5.1-5.23 # Starting compound Structure Mass [M+1] + HPLC Rt [min] or m.p. or TLC:Rf o h3c \ //n n-n /*2s< cN~\ 5.1 1-3 V 1H-NMR DMSO-d6, d [ppm]: 8.28 (d, 5.4 Hz, IH), 7.79 (s, IH), 7.05 (s, IH), 6.9-6.88 (m, IH), 6.8 (d, 3.3 Hz, IH), 6.64-6.62 (m, IH), 3.72-3.67 (m, 2H) , 3.58-3.55 (m, 2H), 3.11-3.06 (m, 2H), 3.04-3.00 (m, 2H), 2.13 (s, 3H). 463 1.67 5.2 1-3 o h3c \ .n—n $ n-ch3 h.c 3 421 1.44 5.3 1-14 0 H°c'r* A 1 r\ s rVvi n-n 0 h,c~N^ ho-~y 462 0.3 5.4 rl 1 H hjc h-^ X a r\ s'Wvi 0"" q oh 488 0.28 WO 2006/040281 105 PCT/EP2005/055021 # Starting compound Structure Mass [M+1]+ HPLC Rt [min] or m.p. or TLCsRf 5.5 1-14 h.c'Sj-c jf } s"VVvi .n-n 0 r? HgC 476 1.5 5.6 1-14 0 II jf 1 r*\ s"xvvi n-n 0 0 HO 488 1.34 5.7 1-14 h3c^n-^ 2 I r\ s"rVvi 0"N Q. o 487 1.35 5.8 1-14 0 X n-/\ J[ jl r^\ S'V>Ai n-n 0 H3C-n o 500 1.89 5.9* 1-14 0 h3c-^ n^V. IT 1 /=N\ *r)r\J cr o H3c 487 1.16 5.9b 1-14 ^n-fTX /=n /w" x ' 0 h3c 445 Rf = 0.02 DCM:MeOH 9:1 5.10 1-14 0 hiCVm 1 f^\ 3 TVvi .N-n 0 CH, 432 1.26 WO 2006/040281 106 PCT/EP2005/055021 # Starting compound Structure Mass [M+1] + HPLC Rt [min] or m.p. or TLC:Rt 5.11 1-14 0 H3C^WT ] s t>AJ n-n 0 □ 444 1.31 5.12 1-14 ]T J[ r=-\ s tvaJ .N-n 0 0 474 1.52 5.13 1-14 0 jf H.c-^N-f Jf ] r*\ s'Wvi N-N 0 0 o 541 2.93 5.14 1-14 H,C"%-^ ~T J[ /=N s tV\J .N-n 0 0 ">C-N' \ chg 515 2.78 5.15 1-14 X n-r^i s"Vy-\J .N-n 0 n-ch3 h,c 3 489 1.26 5.16* 1-15 o Hfi-4 ,n-^s u^TI r\ s tVvi _ / 1 ,n-n CfO-0 564 Rf = 0.56 MeOH 5.16b 1-15 h2N-/X^1 n s TV\J /—v .n-n Cf°l3 522 1.13 WO 2006/040281 107 PCT/EP2005/055021 # Starting compound Structure Mass [M+1]+ HPLC Rt [min] or m.p. or TLCsRf 5.17 1-15 0 H3C \ h s^vvo 458 Rf = 0.41 DCM:MeOH 8:2 5.18 1-15 o H3C-y N^--\ (kxl /a s yy\j 472 1.36 5.19 1-14 0 ,N—n 0 J 503 Rf = 0.06 DCM:MeOH 9:1 5.20 1-14 0 ,N—N 0 0 / 501 Rf = 0.08 DCM:MeOH 9:1 5.21 1-14 0 an^xx^tn> ,N—N 0 o / 0 531 1.17 5.22 1-14 0 N' o 555 1.28 WO 2006/040281 108 PCT/EP2005/055021 # Starting compound Structure Mass [M+1] + HPLC Rt [min] or m.p. or TLCtRf 5.23* 1-14 o 472 3 .35 5.23b 1-14 .N—n o 430 3 .12 *Under the reaction conditions, the acetyl group is observed to be eliminated. The corresponding isolated free amine in Examples 5.9b, 5.16b and 5.23b is reacetylated with acetic anhydride in dioxane. Examples 6 - reductive amination Method J A solution of 70 mg of 11-10 (0.15 mmol) and 22 pi of jW-methylpiperidin-4-one (0.18 mmol) in 5 ml of dichloromethane is stirred at RT for 2 h. After 40 mg of sodium triacetoxyborohydride (0.18 mmol) have been added, the reaction mixture is stirred for a further 15 h. The mixture is diluted with dichloromethane and washed with a dilute solution of sodium hydrogen carbonate; the organic phase is dried and evaporated. The residue is solubilized in a very small quantity of ethyl acetate/methanol and crystallized using diethyl ether. The crystals which have precipitated out are filtered off and dried in vacuo. Method K A solution of 220 mg of 11-11 (0.5 mmol) and 0.1 ml of benzylamine (1 mmol) in 5 ml of methanol is stirred at 60°C for 15 h after which 155 mg of sodium triacetoxyborohydride (0.7 mmol) and 40 mg of sodium acetate (0.5 mmol) are added. Following hydrolysis with WO 2006/040281 109 PCT/EP2005/055021 sodium hydrogen carbonate and extraction with dichloromethane, the organic phase is dried and evaporated and the residue is purified chromatographically. Examples 6.1-6.4 # Starting compound Method Structure Mass [M+1]+ HPLC:Rt [min] or m.p. or TLCsRf 6.1 11-10 I n n „Ck h,c'nx^ 547 1.27 6.2 11-11 K 0 r<XX /*>\ s TV-4 J K N hn "o 542 1.55 A 6.3 11-11 K xxfrir h3c^n^s n'n Cr 5 o 603 0.30 iXXO n n 6.4 11-12 I <? n >- 541 m.p.: 166°C Examples 7 Synthesis method L - crosscoupling with arylboronic acids WO 2006/040281 110 PCT/EP2005/055021 0.3 mmol of the appropriate boronic acid is added to a suspension of 100 m£j of 1-24 (0.2 mmol) in 3 ml of acetone. 4.4 mg of palladium(II) acetate (19 umol), 4 y.1 of diazabicyclooctane (39 umol) and 80 mg of potassium carbonate are then added and the reaction vessel is heated at 100°C for 20 min in a microwave; after that, it is heated a further 2 x for in each case 40 min at 120°C and 70°C. After the solvent has been removed, the reaction mixture is purified chromatographically. Synthesis method M - crosscoupling with alkynes 56 mg of i\ir,i\7'-dimethylaminoprop-2-yne (0.7 mmol) and diisopropylethylamine are added, while stirring and under an argon atmosphere, to a solution of 200 mg of 1-31 (0.3 mmol), 6 mg of copper(I) iodide (34 umol) and 24 mg of triphenylphosphinepalladium(II) chloride (34 pmol) in 25 ml of degassed THF and the reaction mixture is stirred at 80°C for 15 h. 100 \il of alkyne, as well as 10 mg of Cul and 20 mg of Pd catalyst, are added and the mixture is left to stir at 55°C for a further 24 h. The mixture is then made alkaline with an aqueous solution of NH3, diluted with water and extracted 2 x with THF. The combined organic phases are extracted by shaking with a saturated solution of NaCl, dried, filtered and evaporated. The residue is purified chromatographically. Synthesis method N - palladium-catalysed amination 30 mg of tri-tert-butylphosphine tetrafluoroborate (0.1 mmol) are added to a solution of 200 mg of 1-31 (0.3 mmol), 38 mg of 4-aminopyridine (0.4 mmol), 47 mg of tris (dibenzylideneacetone)dipalladium (51 iamol) and 111 mg of sodium tert-butoxide (1 mmol) in 4 ml of degassed DMF and the mixture is stirred at 90°C for 4 h under argon. Following hydrolysis with phosphate buffer and water, the mixture is extracted with dichloromethane. The organic phase is dried, filtered and evaporated and the residue is purified chromatographically. WO 2006/040281 111 PCT/EP2005/055021 Examples 7.1-7.8 # Starting compound Structure Mass [M+1] + HPLC Rt [min] 7.1 1-24 o^NH ch3 ^-NMR DMSO-d6, d [ppm]: 8.95 (s, IH), 8.61-8.58 (m, IH), 8.14-8.11 (m, IH), 7.67-7.65 (m, 2H), 7.63-7.58 (m, 3H), 7.56-7.48 (m, 2H), 7.45-7.41 (m, IH) , 3.17-3.12 (m, 2H), 3.06-3.01 (m, 2H), 2.26 (s, 3H), 2.10 (s, 3H). 506 1.83 7.2 1-24 n/==\ h,c 0^NH ch3 557 3.63 7.3 1-24 o ( h 0 ||v ,hCH 0 n^s 0^NH ch3 557 3.24 7.4 1-24 \j> H3CY° n^s o^nh ch3 521 1.66 7.5 1-24 O j= n^s n .NH ch, 482 3.57 WO 2006/040281 112 PCT/EP2 005/055021 # Starting compound Structure Mass [M+1]+ HPLC Rt [min] 7.6 1-24 ^ c r-X/NH ny5 o^NH ch3 503 1.89 7.7 1-31 0 hjc—^ N-<' T "1 W N h3c-n~ch' 504 1.47 7.8 H co 1 H ch3 n n 0-c, hn b n 515 1.47 Example 8 Iff-pyrazolo[3',4':3,4]benzo[1,2-d]thiazol-7-yl)-acetamide (0.16 mmol), which can be prepared from 1-6 and hydrazine in accordance with synthesis method B, are treated with 3 ml of triethyl orthoformate at 180°C for 30 min in a microwave. After the excess ortho ester has been removed in vacuo, the residue is purified chromatographically. Yield 4 mg [M+1]+= 379 Rt = 1.75 min. WO 2006/040281 113 PCT/EP2005/055021 Examples 9.1-9.4 The following compounds are prepared in analogy with the synthesis of Example II-2 # Starting compound Structure [M+1] * Rt [min] 9.1 1-34 s tvO'NH! N-n d ^-NMR r*MSO-d6, d [ppm]: 7.61-7.51 (m, 5H) , 7.40 (d, 8.5 Hz, 2H) , 6.64 (d, 8.5 Hz, 2H), 3.06-2.95 (m, 4H), 2.09 (s, 3H) . 402 1.63 9.2 1-33 ,0 -A /NH2 r^XJL A 3 rVvi •n~N 436 1.67 9.3 1-32 P -4 /NH2 iKXa r\ s rVvi N-n 0 402 1.56 9.4 1-35 N-n O-c, 436 1.66 WO 2006/040281 114 PCT/EP2005/055021 The following example describes the biological effect of the compounds according to the invention without limiting the invention to this example. HCT116 cytotoxicity test The test is based on the reduction of AlamarBlue (Biosource Int., USA) in living (metabolically active) cells to give a fluorometrically detectable product. The substrate can no longer be reduced in the presence of substances which are toxic to the cells, which means that it is not possible to measure any increase in fluorescence. HCT116 (human colon carcinoma cell line) cells are sown in microtiter plates and incubated overnight in culture medium at 37°C and 5% CO2. The test substances are diluted stepwise in medium and added to the cells such that the total volume is 200 ul/well. Cells to which medium, but not substance, is added serve as controls. After an incubation time of 4-6 days, 20 pi of AlamarBlue are added/well and the cells are incubated at 37°C for a further 6-8 h. For measuring the fluorescence, excitation takes place at a wavelength of 545 nm and the emission is measured at 590 nm. EC50 values are calculated using the GraphPad Prism program. All the examples cited have an EC50 (HCT-116) of less than 5 uM. The substances of the present invention are PI3 kinase inhibitors. On account of their biological properties, the novel compounds of the general formula (1) and their isomers and their physiologically tolerated salts, are suitable for treating diseases which are characterized by excessive or anomalous cell proliferation. These diseases include, for example: viral infections WO 2006/040281 115 PCT/EP2005/055021 (e.g. HIV and Kaposi's sarcoma); inflammation and autoimmune diseases (e.g. colitis, arthritis, Alzheimer's disease, glomerulonephritis and wound healing); bacterial, fungal and/or parasitic infections; leukaemias, lymphomas and solid tumours; skin diseases (e.g. psoriasis); bone diseases; cardiovascular diseases (e.g. restenosis and hypertrophy). In addition, the compounds are useful for protecting proliferating cells (e.g. hair cells, intestinal cells, blood cells and progenitor cells) from DNA damage due to irradiation, UV treatment and/or cytostatic treatment (Davis et al., 2001). For example, the following cancer diseases can be treated with compounds according to the invention, without, however, being restricted thereto: brain tumours, such as acoustic neurinoma, astrocytomas such as piloid astrocytomas, fibrillary astrocytoma, protoplasmic astrocytoma, gemistocytic astrocytoma, anaplastic astrocytoma and glioblastomas, brain lymphomas, brain metastases, hypophyseal tumour such as prolactinoma, HGH (human growth hormone) producing tumour and ACTH-producing tumour (adrenocorticotrophic hormone), craniopharyngiomas, medulloblastomas, meningiomas and oligodendrogliomas; nerve tumours (neoplasms) such as tumours of the vegetative nervous system such as neuroblastoma sympathicum, ganglioneuroma, paraganglioma (phaeochromocytoma and chromaffinoma) and glomus caroticum tumour, tumours in the peripheral nervous system such as amputation neuroma, neurofibroma, neurinoma (neurilemoma, schwannoma) and malignant schwannoma, as well as tumours in the central nervous system such as brain and spinal cord tumours; intestinal cancer such as rectal carcinoma, colon carcinoma, anal carcinoma, small intestine tumours and duodenal tumours; eyelid tumours such as basalioma or basal cell carcinoma; pancreatic gland cancer or pancreatic carcinoma; bladder cancer or WO 2006/040281 116 PCT/EP2005/055021 bladder carcinoma; lung cancer (bronchial carcinoma) such as small-cell bronchial carcinomas (oat cell carcinomas) and non-small-cell bronchial carcinomas such as squamous epithelium carcinomas, adenocarcinomas and large-cell bronchial carcinomas; breast cancer such as mammary carcinoma, such as infiltrating ductal carcinoma, colloid carcinoma, lobular invasive carcinoma, tubular carcinoma, adenoid cystic carcinoma, and papillary carcinoma; non-Hodgkin's lymphomas (NHL) such as Burkitt's lymphoma, low-malignancy non-Hodkgin's lymphomas (NHL) and mucosis fungoides; uterine cancer or endometrial carcinoma or corpus carcinoma; CUP syndrome (cancer of unknown primary); ovarian cancer or ovarian carcinoma such as mucinous, endometrial or serous cancer; gall bladder cancer; bile duct cancer such as Klatskin's tumour; testicular cancer such as seminomas and non-seminomas; lymphoma (lymphosarcoma) such as malignant lymphoma, Hodgkin's disease, non-Hodgkin's lymphomas (NHL) such as chronic lymphatic leukaemia, hair cell leukaemia, immunocytoma, plasmocytoma (multiple myeloma), immunoblastoma, Burkitt's lymphoma, T-zone mycosis fungoides, large-cell anaplastic lymphoblastoma and lymphoblastoma; laryngeal cancer such as vocal cord tumours, supraglottal, glottal and subglottal laryngeal tumours; bone cancer such as osteochondroma, chondroma, chrondoblastoma, chondromyxoidfibroma, osteoma, osteoid-osteoma, osteoblastoma, eosinophilic granuloma, giant cell tumour, chondrosarcoma, osteosarcoma, Ewing's sarcoma, reticulosarcoma, plasmocytoma, fibrous dysplasia, juvenile bone cyst and aneurysmatic bone cyst; head/neck tumours such as tumours of the lips, tongue, floor of the mouth, oral cavity, gingiva, pallet, salivary glands, pharynx, nasal cavities, paranasal sinuses, larynx and middle ear; liver cancer such as liver cell carcinoma or hepatocellular carcinoma (HCC); leukaemias, such as acute leukaemias, such as acute lymphatic/lymphoblastic leukaemia (ALL), WO 2006/040281 117 PCT/EP2005/055021 acute myeloid leukaemia (AML); chronic leukaemias such as chronic lymphatic leukaemia (CLL), chronic myeloid leukaemia (CML); stomach cancer or stomach carcinoma such as papillary, tubular and mucinous adenocarcinoma, signet ring cell carcinoma, adenoid squamous cell carcinoma, small-cell carcinoma and undifferentiated carcinoma; melanomas such as superficially spreading, nodular malignant lentigo and acral lentiginous melanoma; renal cancer, such as kidney cell carcinoma or hypernephroma or Grawitz's tumour; oesophageal cancer or oesophageal carcinoma; cancer of the penis; prostate cancer; pharyngeal cancer or pharyngeal carcinomas such as nasopharyngeal carcinomas, oropharyngeal carcinomas and hypopharyngeal carcinomas; retinoblastoma such as vaginal cancer or vaginal carcinoma; squamous epithelium carcinomas, adeno carcinomas, in situ carcinomas, malignant melanomas and sarcomas; thyroid gland carcinomas such as papillary, follicular and medullary thyroid gland carcinoma, and also anaplastic carcinomas; spinalioma, prickle cell carcinoma and squamous epithelium carcinoma of the skin; thymomas, urethral cancer and vulvar cancer. The novel compounds can be used for the prevention or short-term or long-term treatment of the abovementioned diseases including, where appropriate, in combination with other state-of-the-art compounds such as other anti-tumour substances, cytotoxic substances, cell proliferation inhibitors, antiangiogenic substances, steroids or antibodies. The compounds of the general formula (1) can be used on their own or in combination with other active compounds according to the invention and, where appropriate, in combination with other pharmacologically active compounds as well. Chemotherapeutic agents which can be administered in combination with the compounds according to the invention include, without being WO 2006/040281 118 PCT/EP2005/055021 restricted thereto, hormones, hormone analogs and antihormones (e.g. tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproterone acetate, finasteride, buserelin acetate, fludrocortisone, fluoxymesterone, medroxyprogesterone and octreotide), aromatase inhibitors (e.g. anastrozole, letrozole, liarozole, vorozole, exemestane and atamestane), LHRH agonists and antagonists (e.g. goserelin acetate and luprolide), inhibitors of growth factors (growth factors such as platelet-derived growth factor and hepatocyte growth factor, examples of inhibitors are growth factor antibodies, growth factor receptor antibodies and tyrosine kinase inhibitors, such as gefitinib, imatinib, lapatinib and trastuzumab); antimetabolites (e.g. antifolates such as methotrexate and raltitrexed, pyrimidine analogs such as 5-fluorouracil, capecitabine and gemcitabine, purine and adenosine analogs such as mercaptopurine, thioguanine, cladribine and pentostatin, cytarabine and fludarabine); antitumour antibiotics (e.g. anthracyclines, such as doxorubicin, daunorubicin, epirubicin and idarubicin, mitomycin C, bleomycin, dactinomycin, plicamycin and streptozocin); platinum derivatives (e.g. cisplatin, oxaliplatin and carboplatin); alkylating agents (e.g. estramustine, meclorethamine, melphalan, chlorambucil, busulphan, dacarbazine, cyclophosphamide, ifosfamide and temozolomide, nitrosoureas such as carmustine and lomustine and thiotepa); antimitotic agents (e.g. vinca alkaloids such as vinblastine, vindesine, vinorelbine and vincristine; and taxans such as paclitaxel and docetaxel); topoisomerase inhibitors (e.g. epipodophyllotoxins such as etoposide and etopophos, teniposide, amsacrine, topotecan, irinotecan and mitoxantrone) and various chemotherapeutic agents such as amifostin, anagrelide, clodronate, filgrastin,. interferon alpha, leucovorin, rituximab, procarbazine, WO 2006/040281 119 PCT/EP2005/055021 levamisole, mesna, mitotan, pamidronate and porfimer. Examples of suitable forms for use are tablets, capsules, suppositories, solutions, in particular solutions for injection (s.c., i.v., i.m.) and infusion, juices, emulsions or dispersible powders. In this connection, the proportion of the pharmaceutically active compound(s) should in each case be in the range of 0.1-90% by weight, preferably 0.5-50% by weight, of the total composition, that is in quantities which are sufficient to achieve the dosage range which is specified below. If necessary, the doses mentioned can be given several times a day. Appropriate tablets can be obtained, for example, by mixing the active compound(s) with known auxiliary substances, for example inert diluents, such as calcium carbonate, calcium phosphate or lactose, disintegrants, such as maize starch or alginic acid, binders, such as starch or gelatine, lubricants, such as magnesium stearate or talc, and/or agents for achieving a depot effect, such as carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate. The tablets can also comprise several layers. Correspondingly, sugar-coated tablets can be produced by coating cores, which have been prepared in analogy with tablets, with agents which are customarily used in sugar coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. The core can also comprise several layers in order to achieve a depot effect or to avoid incompatibilities. In the same way, the sugar coating can also comprise several layers in order to achieve a depot effect, with it being possible to use the auxiliary substances which are mentioned above in the case of the tablets. Juices of the active compounds or active compound WO 2006/040281 120 PCT/EP2005/055021 combinations according to the invention can additionally comprise a sweetening agent, such as saccharine, cyclamate, glycerol or sugar as well as a taste-improving agent, e.g. flavouring agents such as vanillin or orange extract. They can also comprise suspension aids or thickeners, such as sodium carboxymethyl cellulose, wetting agents, for example condensation products of fatty alcohols and ethylene oxide, or protectants such as p-hydroxybenzoates. Injection and infusion solutions are produced in a customary manner, e.g. while adding isotonizing agents, preservatives, such as p-hydroxybenzoates, or stabilizers, such as alkali metal salts of ethylenediaminetetraacetic acid, where appropriate using emulsifiers and/or dispersants, with it being possible, for example, to employ, where appropriate, organic solvents as solubilizing agents or auxiliary solvents when using water as diluent, and aliquoted into injection bottles or ampoules or infusion bottles. The capsules, which comprise one or more active compounds or active compound combinations, can, for example, be produced by mixing the active compounds with inert carriers, such as lactose or sorbitol, and encapsulating the mixture in gelatine capsules. Suitable suppositories can be produced, for example, by mixing with excipients which are envisaged for this purpose, such as neutral fats or polyethylene glycol, or their derivatives. Auxiliary substances which may be mentioned by way of example are water, pharmaceutically unobjectionable organic solvents, such as paraffins (e.g. petroleum fractions), oils of vegetable origin (e.g. groundnut oil or sesame oil), monofunctional or polyfunctional alcohols (e.g. ethanol or glycerol), carrier substances such as natural mineral powders (e.g. kaolins, WO 2006/040281 121 PCT/EP2005/055021 argillaceous earths, talc and chalk), synthetic mineral powders (e.g. highly disperse silicic acid and silicates), sugars (e.g. cane sugar, lactose and grape sugar), emulsifiers (e.g. lignin, sulphite waste liquors, methyl cellulose, starch and polyvinylpyrrolidone) and glidants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulphate). Administration is effected in a customary manner, preferably orally or transdermally, in particular and preferably orally. In the case of oral use, the tablets can naturally also comprise, in addition to the abovementioned carrier substances, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with a variety of further substances such as starch, preferably potato starch, gelatine and the like. It is furthermore also possible to use glidants, such as magnesium stearate, sodium lauryl sulphate and talc, for the tableting. In the case of aqueous suspensions, a variety of taste improvers or dyes can also be added to the active compounds in addition to the abovementioned auxiliary substances. For parenteral administration, it is possible to employ solutions of the active compounds while using suitable liquid carrier materials. The dosage for intravenous administration is 1-1000 mg per hour, preferably between 5 and 500 mg per hour. Despite this, it may be necessary, where appropriate, to diverge from the abovementioned quantities, depending on the body weight or the nature of the route of administration, on the individual response to the medicament, on the nature of its formulation and on the time or interval at which the administration is effected. Thus, it may, in some cases, be sufficient to make do with less than the previously mentioned lowest WO 2006/040281 122 PCT/EP2005/055021 quantity whereas, in other cases, the abovementioned upper limit has to be exceeded. When relatively large quantities are being administered, it may be advisable to divide these into several single doses which are given over the course of the day. The following formulation examples illustrate the present invention without, however, restricting its scope: Pharmaceutical formulation examples A) Tablets per tablet Active compound in accordance with formula (1) 100 mg Lactose 140 mg Maize starch 240 mg Polyvinylpyrrolidone 15 mg Magnesium stearate 5 mg 500 mg The finely ground active compound, lactose and a part of the maize starch are mixed with each other. The mixture is sieved, after which it is moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet-granulated and dried. The granular material, the remainder of the maize starch and the magnesium stearate are sieved and mixed with each other. The mixture is pressed into tablets of suitable shape and size. B) Tablets per tablet Active compound in accordance with formula (1) 80 mg Lactose 55 mg Maize starch 190 mg Microcrystalline cellulose 35 mg Polyvinylpyrrolidone 15 mg Sodium carboxymethyl starch 23 mg Magnesium stearate 2 mg </div>

Claims

<div class="application article clearfix printTableText" id="claims"> WO 2006/040281 123 PCT/EP2005/055021 400 mg The finely ground active compound, a part of the maize starch, the lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed with each other, after which the mixture is sieved and worked, together with the remainder of the maize starch and water, into a granular material, which is dried and sieved. The sodium carboxymethyl starch and the magnesium stearate are then added to the granular material and mixed with it, and the mixture is pressed into tablets of suitable size. C) Ampoule solution Active compound in accordance with formula (1) 50 mg Sodium chloride 50 mg Water for injection 5 ml The active compound is dissolved, either at its intrinsic pH or, where appropriate, at pH 5.5-6.5, in water after which sodium chloride is added as isotonizing agent. The resulting solution is rendered pyrogen-free by filtration and the filtrate is aliguoted, under aseptic conditions, into ampoules, which are then sterilized and sealed by melting. The ampoules contain 5 mg, 25 mg and 50 mg of active compound. 124 Claims

1.) A compound of the general formula (1),

(1)

the group consisting of -NHRC, -NHC (0) NRCRC and -NHC (0) SRC;

R2 is a radical which is optionally substituted by one or more R4 and which is selected from the group consisting of Ci_6alkyl, C3-acycloalkyl, 3-8-membered heterocycloalkyl, C6-ioaryl, C7-i6arylalkyl and 5-10-membered heteroaryl;

R3 is a radical which is optionally substituted by one or more Re and/or Rf and is selected from the group consisting of C6-ioaryl and 5-10-membered heteroaryl;

R4 is a radical selected from the group consisting of Ra, Rb and Ra which is substituted by one or more, identical or different, Rc and/or Rb;

each Ra is, independently of each other, selected from the group consisting of Ci_6alkyl, C3-8cycloalkyl, C4-ncycloalkylalkyl, C6-ioaryl, C7-i6arylalkyl, 2-6-membered heteroalkyl, 3-8-membered heterocycloalkyl, 4-14-membered heterocycloalkylalkyl, 5-10-membered heteroaryl and 6-16-membered heteroarylalkyl;

each Rb is a suitable radical and in each case selected, independently of each other, from the group consisting r2

in which

R1 is selected from -NHC (0) Rc, -NHC (0) 0RC,

125

of =0, -0RC, Ci-3haloalkyloxy, -0CF3, =S, -SRC, =NRC, =N0Rc, -NRCRC, halogen, -CF3, -CN, -NC, -OCN, -SCN, -NO, -N02, =N2, -N3, -S(0)Rc, -S(0)2Rc, -S(0)2ORc, -S(0)NRcRc, -S(0)2NRcRc, -0S(0)Rc, -0S(0)2Rc, -0S(0)20Rc, -OS (0) 2NRcRc, -C (0) Rc, -C (0) 0RC, -C(0)NRcRc, -C (0) N (Rg) NRCRC,

-C (0) N (Rg) 0RC, -CN (Rg) NRCRC, -OC (0) Rc, -OC (0) 0RC, OC (0) NRCRC, -OCN (Rg) NRCRC, -N (Rg) C (0) Rc, -N (Rg) C (0) Rc, -N (Rg) C (S) Rc, -N (Rg) S (0) 2Rc, -N (Rg) S (0) 2NRcRc,

-N [S (0) 2] 2Rc, -N (Rg) C (0) 0Rc, -N (Rg) C (0)NRcRc, and -N (Rg) CN (Rg) NRCRC ;

each Rc is, independently of each other, hydrogen or a radical which is optionally substituted by one or more, identical or different, Rd and/or Re and which is selected from the group consisting of Ci_6alkyl, C3-8cycloalkyl, C4-ncycloalkylalkyl, C6-ioaryl,

C7_i6arylalkyl, 2-6-membered heteroalkyl, 3-8-membered heterocycloalkyl, 4-14-membered heterocycloalkylalkyl, 5-10-membered heteroaryl and 6-16-membered heteroarylalkyl;

each Rd is, independently of each other, hydrogen or a radical which is optionally substituted by one or more, identical or different, Re and/or Rf and which is selected from the group consisting of Ci_6alkyl, C3_8cycloalkyl, C4-ncycloalkylalkyl, C6-ioaryl,

each Re is a suitable radical and in each case selected, independently of each other, from the group consisting of =0, -0Rf, Ci_3haloalkyloxy, -0CF3, =S,

-SRf, =NRf, =N0Rf, -NRfRf, halogen, -CF3, -CN, -NC, -OCN, -SCN, -NO, -N02, =N2, -N3, -S (0) Rf, -S(0)2Rf, -S (0) 20Rf, -S (0) NRfRf, -S(0)2NRfRf, -OS (0) Rf, -OS (0) 2Rf, -OS (0) 20Rf, -OS (0) 2NRfRf, -C (0) Rf, -C (0) 0Rf, -C (0) NRfRf, -CN (Rg) NRfRf,

126

-0C(0)Rf, -0C(0)0Rf, -0C(0)NRfRf, -OCN (Rg) NRfRf,

-N (Rg) C (0) Rf, -N (Rg) C (S) Rf, -N (Rg) S (0) 2Rf, -N (Rg) C (0) 0Rf, -N (Rg) C (0) NRfRf, and -N (Rg) CN (Rg) NRfRf ;

each Rf is, independently of each other, hydrogen or a radical which is optionally substituted by one or more, identical or different, Rg and is selected from the group consisting of Ci_6alkyl, C3_8cycloalkyl, C4-ncycloalkylalkyl, C6-ioaryl, C7-i6arylalkyl, 2-6-membered heteroalkyl, 3-8-membered heterocycloalkyl,

4-14-membered heterocycloalkylalkyl, 5-10-membered heteroaryl and 6-16-membered heteroarylalkyl;

each Rg is, independently of each other, hydrogen, Ci_6alkyl, C3_8cycloalkyl, C4-ncycloalkylalkyl, C6-ioaryl, C7_i6arylalkyl, 2-6-membered heteroalkyl, 3-8-membered heterocycloalkyl, 4-14-membered heterocycloalkylalkyl,

5-10-membered heteroaryl and 6-16-membered heteroarylalkyl;

where appropriate in the form of a tautomer, racemate, enantiomer, diastereomer, mixture, or pharmacologically harmless acid addition salt thereof.

2.) The compound according to Claim 1, wherein R3 is a radical selected from the group consisting of phenyl, furyl, pyridyl, pyrimidinyl and pyrazinyl, optionally substituted by one or more R4.

3.) The compound according to Claim 2, wherein R3 is pyridyl.

4.) The compound according to any one of Claims 1 to 3, wherein R1 is -NHC(0)Rc.

5.) The compound according to Claim 4, wherein R1 is -NHC(0)CH3.

127

6.) The compound of the formula (A)

o o wherein

X is -CH3, -OR4 or -SR4 and

Y is phenyl, 5-10-membered heteroaryl or the group -C(0)0, and

Ry is hydrogen, -N02 or C16alkyl and R4 is defined as in claim 1.

7.) The compound according to Claim 6, wherein R4 is -Ci_6alkyl.

8. ) The compound according to Claim 6 or 7 for use as synthesis intermediates.

9.) The compound, or a pharmaceutically active salt thereof, according to any one of Claims 1 to 5 as pharmaceuticals.

10.) The compound, or a pharmaceutically active salt thereof, according to any one of Claims 1 to 5 for producing a pharmaceutical having an antiproliferative effect.

11.) A pharmaceutical preparation which comprises, as an active compound, one or more compounds according to any one of Claims 1 to 5, or a physiologically tolerated salt thereof, where appropriate in combination with customary auxiliary substances and/or carrier substances.

12.) Use of a compound according to any one of Claims 1 to 5 for the manufacture of a medicament for treating and/or preventing cancer.

128

13.) A pharmaceutical preparation which comprises a compound of the general formula (1) according to any one of Claims 1 to 5 and at least one further cytostatic or cytotoxic active substance which differs from formula (1) , where appropriate in the form of a tautomer, racemate, enantiomer, diastereomer, mixture, or pharmacologically harmless acid addition salt thereof.

14.) The compound as defined in any one of claims 1 to

10 substantially as hereinbefore described and with reference to the examples.

15.) A pharmaceutical preparation as defined in claim

11 or claim 13 substantially as hereinbefore described and with reference to the examples.

16.) Use as defined in claim 12 substantially as hereinbefore described.

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