AU2005293609B2 - Thiazolyl-dihydro indazoles - Google Patents
Thiazolyl-dihydro indazoles Download PDFInfo
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- AU2005293609B2 AU2005293609B2 AU2005293609A AU2005293609A AU2005293609B2 AU 2005293609 B2 AU2005293609 B2 AU 2005293609B2 AU 2005293609 A AU2005293609 A AU 2005293609A AU 2005293609 A AU2005293609 A AU 2005293609A AU 2005293609 B2 AU2005293609 B2 AU 2005293609B2
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D277/82—Nitrogen atoms
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/84—Naphthothiazoles
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Abstract
The invention relates to the compounds of general formula (1), wherein R to R are defined as in claim 1, which are suitable for use in the treatment of diseases that are characterized by excessive or abnormal cell proliferation. The invention also relates to the use of said compounds for producing a drug having the aforementioned properties.
Description
WO 2006/040281 1 PCT/EP2005/055021 88994pct THIAZOLYL-DIHYDRO INDAZOLES The present invention relates to novel thiazolyldihydroindazoles of the general formula (1) R3 R1 S NN (1) R2 where the radicals R 1 to R 3 have the meanings given in the claims and the description, to their isomers, to processes for preparing these thiazolyl dihydroindazoles, 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 mole-c-ul.es.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 (P13 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 P13 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 P13 kinases, the a, and 5 P13 kinases (class IA) are principally activated by receptor tyrosine kinases (RTKs) or soluble tyrosine kinases. On the other hand, the y P13 kinase (class IB) is principally activated by G y 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 P13 kinases inevitably have very different tasks and functions in the intact organism. Many independent findings indicate that class IA P13 kinases are involved in uncontrolled processes of cell growth and differentiation. Thus, the first P13 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 P13 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 p110 subunit of PI3Ka, 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 R 3 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) R3 1 S N N (1) RR in which
R
1 is selected from the group consisting of -NHRc, -NHC(O)Rc, -NHC(O)ORc, -NHC(O)NRcRc and -NHC(O)SRc; R2 is a radical which is optionally substituted by one or more R4 and which is selected from the group consisting of C 1
-
6 alkyl, C 3 -scycloalkyl, 3-8-membered heterocycloalkyl, C 6
-
1 oaryl and 5-10-membered heteroaryl; WO 2006/040281 4 PCT/EP2005/055021 R3 is a radical which is optionally substituted by one or more Re and/or R and is selected from the group consisting of C 6
_
1 oaryl and 5-10-membered heteroaryl;
R
4 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 C 1
-
6 alkyl, C 3 -acycloalkyl,
C
4 1 1 cycloalkylalkyl, C 6 -ioaryl, C- 16 arylalkyl, 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, -ORc, C1-3haloalkyloxy, -OCF3, =S, -SRc, =NRc, =NORc, -NRcRc, halogen, -CF3, -CN, -NC, -OCN, -SCN, -NO,
-NO
2 , =N 2 , -N 3 , -S(O)Rc, -S(0) 2 Rc, -S(0) 2 0Rc, -S(O)NRcR, S (0 )2NRcRc, -OS (0 )Rc, -OS (0 )2Re, -OS (0) 20Rc, -OS (0 )2NRcRc, -C(0)Rc, -C(O)ORc, -C(0)NRcRc, -C(0)N(R9)NRcRc -C (0) N (Rg) ORc, -CN (Rg) NRcRc, -OC (O) Rc, -OC (O) OR, OC (0) NR'Rc, -OCN (Rg) NRcRc, -N (Rg) C (0)Rc, -N (Rg) C(0) Rc, -N (R9) C(S) Rc, -N (R9) S(0) 2Rc, -N (Rg) S(0) 2NRcRc, -N [S(0) 2
]
2 Rc, -N(Rg)C(0)ORc, -N(Rg)C(O)NRcRc, and -N (R9) CN (R9) NRcRe 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 C 1
-
6 alkyl, C3-acycloalkyl, C 4 1 1 cycloalkylalkyl, C 6 -joaryl,
C
7 16 arylalkyl, 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 C 1
-
6 alkyl,
C
3
-
8 cycloalkyl, C4-ncycloalkylalkyl, C 6 -ioaryl,
C
7
-
16 arylalkyl, 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, -OR , Ci- 3 haloalkyloxy, -OCF 3 , =S, -SRf, =NR', =NOR , -NR Rf, halogen, -CF3, -CN, -NC, -OCN, -SCN, -NO, -NO2, =N2, -N3, -S(0)R f, - S(0)2Rf, -S(0)2ORf, -S(0)NRfRf, -S(0) 2 NRfR', -OS(O)R', -OS(0) 2 R', -OS(O) 2 ORf, -OS(0) 2 NR R , -C (O) R, -C (O) OR ,-C (0) NR R , CN (Rg) NR R, -OC (O) R, -OC(0)OR, -OC (0) NR R , OCN(R9) NR R , -N (R9) C(0) R, -N (R9) C (S) R ,M -(R9) S(0) 2R ,-N (R9) C (0) OR, -N(Rg)C (0)NR R , and -N(Rg)CN(Rg)NRfRf; each R is, independently of each other, hydrogen or a radical which is optionally substituted by one or more, identical or different, R9 and which is selected from the group consisting of C 1
-
6 alkyl, C3- 8 cycloalkyl, C4-lcycloalkylalkyl, C 6 -ioaryl, C 7
-
1 6 arylalkyl, 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,
C
1
-
6 alkyl, C 3
-
8 cycloalkyl, C4-ncycloalkylalkyl, C 6
-
1 oaryl,
C
7
-
16 arylalkyl, 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 R 3 is a radical which is selected from the group consisting of phenyl, furyl, pyridyl, pyrimidinyl and pyrazinyl, where appropriate substituted by one or more R 4 . Another aspect of the invention relates to compounds of the general formula (1) where R 3 is pyridyl. Another aspect of the invention relates to compounds of the general formula (1) where R 1 is -NHC(O)Rc. Another aspect of the invention relates to compounds of the general formula (1) where R' is -NHC(O)CH 3 . One aspect of the invention relates to compounds of formula (A) . O X4 N N -(A) H S RY 0 0 where X is -CH 3 , -OR 4 or -SR4, and Y is phenyl, 5-10-membered heteroaryl or the group -C(O)O, and Ry is hydrogen, -NO 2 or C 1
-
6 alkyl and R4 is defined as above. Another aspect of the invention relates to compounds of the general formula (A) where R 4 is -C 1
-
6 alkyl. Another aspect of the invention relates to the use of compounds of the formula (A) as synthesis 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 0, N and S (e. g. dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, diethylaminomethyl, diethylamino ethyl, diethylaminopropyl, 2-diisopropylaminoethyl, bis-2-methoxyethylamino, [2- (dimethylaminoethyl) ethylaminolmethyl, 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
-CF
3 , -CHF 2 , -CH 2 F, -CF 2
CF
3 , -CHFCF 3 , -CH 2
CF
3 , -CF 2
CH
3 ,
-CHFCH
3 , -CF 2
CF
2
CF
3 , -CF 2
CH
2
CH
3 , -CF=CF 2 , -CCl=CH 2 , -CBr=CH 2 , -CI=CH 2 , -C=C-CF 3 , -CHFCH 2
CH
3 and -CHFCH 2
CF
3 . 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, isoquinolinyl, 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-N-oxide, pyrimidinyl-N-oxide, pyridazinyl-N oxide, pyrazinyl-N-oxide, quinolinyl-N-oxide, indolyl N-oxide, indolinyl-N-oxide, isoquinolyl-N-oxide, quinazolinyl-N-oxide, quinoxalinyl-N-oxide, phthalazinyl-N-oxide, imidazolyl-N-oxide, isoxazolyl N-oxide, oxazolyl-N-oxide, thiazolyl-N-oxide, indolizinyl-N-oxide, indazolyl-N-oxide, benzothiazolyl N-oxide, benzimidazolyl-N-oxide, pyrrolyl-N-oxide, oxadiazolyl-N-oxide, thiadiazolyl-N-oxide, triazolyl N-oxide, tetrazolyl-N-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, thiomorpholinyl-S-oxide, thio morpholinyl-S,S-dioxide, tetrahydropyranyl, tetra hydrothienyl, homothiomorpholinyl-s, S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridyl, dihydropyrimidinyl, dihydrofuryl, dihydropyranyl, tetrahydrothienyl-S oxide, tetrahydrothienyl-SS-dioxide, homothio morpholinyl-S-oxide, 2-oxa-5-azabicyclo[2.2.l]heptane, 8-oxa-3-azabicyclo[3.2.l]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-1) cis-l-Methylamino-4- (pyrrolidin-1-yl) cyclohexane O D H3 R-la) tert-Butyl cis-4- (pyrrolidin-1-yl)cyclohexane carbamate 0 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-lb) tert-Butyl N-methyl-cis-4-(pyrrolidin-1-yl) cyclohexanecarbamate 0 ON-KD-- \ R-la (5 g, 18 mmol) is dissolved in 20 ml of N,N-dimethylacetamide and this solution is added, at 370C, 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 480C. 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) trans-l-Amino-4-(8-oxa-3-azabicyclo[3.2.1)oct 3-yl) cyclohexane
NH
2 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 ref lux 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. 300 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) 1-Amino-4- (methylpropylamino) cyclohexane NH
H
3 C 2$
CH
3 R-3a) tert-Butyl cis-4-(2,2,2-trifluoroacetylamino) cyclohexanecarbamate H F N F 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 0 C, the precipitate is filtered off, washed with diethyl ether and dried. Yield: 17.6 g.
WO 2006/040281 14 PCT/EP2005/055021 R-3b) tert-Butyl cis-4-methyl-(2,2,2-trifluoroacetyl) aminocyclohexanecarbamate H 00 F F N O F I 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 N,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 H N O HN' 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 H 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 0 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-1, 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 N-GNH H A solution of 1-tert-butoxycarbonylpiperidin-4-one (1 g, 5 mmol) and cyclopropylamine (352 pl) 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) 1-Cyclopentylpiperidine-4-carboxylic acid 0 OH N 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) 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 0 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 off. R-6) cis-4- (Pyrrolidin-1-yl) cyclohexanecarboxylic acid 0 OH N 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 0 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-1-yl)cyclohexanecarboxylate. The intermediate is then stirred, in 10 ml of methanol, with 25 ml of sodium hydroxide solution (1 N) 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.
WO 2006/040281 17 PCT/EP2005/055021 R-7) 3-Morpholin-4-ylcyclobutylamine 0 N NH 2 R-7a) 3-tert-Butoxycarbonylaminocyclobutyl toluene 4-sulphonate 0O /\ __Q - 0 N A solution of toluene-4-sulphonyl chloride (20.5 g, 0.105 mol) in 150 ml of chloroform is added dropwise, at 0 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-7b) 1-Morpholin-1-yl-3-tert-butoxycarbonylamino cyclobutane H O N N 0 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 0 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 0 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-1) Methyl 4-hydrazino-3-methylbenzoate H
N-NH
2 0_ 0 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 0 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 0 C. After stirring at -10 0 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 0 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 H
N-NH
2 F 0 /* The desired compound is obtained in analogy with the preparation of H-1, 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
2 The desired compound is thus obtained, as hydrochloride, in analogy with the preparation of H-1, 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 H
N-NH
2 0 OH The desired compound is obtained in analogy with the preparation of H-1, 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 H
N-NH
2 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-l-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 H H
N-NH
2 N-NH2 N-NH2 O0o cis _ 0 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 chromato graphically 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 H
N-NH
2 / Ci OH Diisobutylaluminium hydride (lM in toluene, 190 ml) is added dropwise, under a nitrogen atmosphere and at -730C, 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 -700C. The reaction mixture is stirred at -73 0 C for 30 min and then warmed to -5 0 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 cyclohexane/ethyl acetate. Yield: 2.9 g H-8) Methyl 3-hydrazinomethylbenzoate ___ H \ N-H2 0_ 0 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 chromato graphically. 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 H N-NH N CF The desired compound is obtained in analogy with the preparation of H-1, 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) -N-methylacetamide H N-NH2 -N The desired compound is obtained in analogy with the preparation of H-1, 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 N-NH \___/ The desired compound is obtained in analogy with the preparation of H-1, 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 H N-NH N H The desired compound is obtained, as the hydrochloride, in analogy with the preparation of H-5, starting from tert-butyl 3 -oxopyrrolidine-l-carboxylate. H-13) [3-( 2 -Methylpropane-l-sulphonyl)phenyllhydrazine The desired compound is obtained, as the hydrochloride, in analogy with the preparation of H-1, 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-1, 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-Methyl-1H-indazol-5-yl)hydrazine M NH 2 N The desired compound is obtained, as the hydrochloride, in analogy with the preparation of H-1, starting from 1-methyl-1H-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-1) N-[7-Oxo-6-(pyrimidine-5-carbonyl)-4,5,6,7-tetra hydrobenzothiazol-2-ylacetamide N3: N 0 0 A solution of 10 g (48 mmol) of Z-6 in 1 1 of THF is cooled to -40 0 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 0 C. After 3.5 h at -40 to -200C, 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 Et 2 0) 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 had's 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.
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 HS N) 0 0 10 g (48 mmol) of Z-6 are added in portions to a suspension of 8.1 g (143 mmmol) of sodium methoxide in 100 ml of DMF in such a way that the temperature does not rise above 300C. After it has been stirred at RT for 1 h, the reaction mixture is heated to 550C, 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 550C 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-Nitrobenzoy'l)-7-oxo-4,5,6,7-tetrahydro benzothiazol-2-yl]acetamide O No 2 N N-< H S o 0 5.2 g of Z-4 are obtained, in analogy with the preparation of intermediate compound Z-1, 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 (lN in THF) . The crude product is used for further syntheses without any additional purification. Z-5) N-[6-(4-Nitrobenzoyl)-7-oxo-4,5,6,7-tetrahydro benzothiazol-2-yl]acetamide WO 2006/040281 25 PCT/EP2005/055021 0 N No2 NO HS 0 0 2.2 g of Z-5 are obtained, in analogy with the preparation of intermediate compound Z-1, 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 0 -0 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 0 C and within 45 min. The suspension is subsequently stirred for 3.5 h at a max. of 100C. 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.: 268-2720C) Z-7) N-(6-Formyl-7-oxo-4,5,6,7-tetrahydrobenzothiazol 2-yl) acetamide H 0 0 0 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 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 OC. 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 0 0 0 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 0 C) Z-10) Methyl (2-acetylamino-7-oxo-4, 5, 6,7-tetrahydro benzothiazol-6-yl)oxo acetate 52 g of Z-10 are obtained, in analogy with the preparation of Z-7, from 40 g (190 mmol)of Z-6, 38 g (0.7 mmol) of sodium methoxide and 84 g (0.7 mol) of dimethyl oxalate. Z-11) ' N-(6-Benzoyl-7-oxo-4,5,6,7-tetrahydrobenzo thiazol-2-yl)acetamide HNI 0 0 3.6 g of Z-11 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 hydrobenzothiazol-2-yl]acetamide N- N 0 0 0 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 0
CH
3 0 N H s 0 0 a) 2-Amino-5, 6-dihydro-4H-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 0 C for 15 h. After it has been cooled down to OOC, 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 pl of methyl chloroformate (7.3 mmol) are added to a solution of 500 mg of 2-amino-5,6-dihydro-4H benzothiazol-7-one (2.4 mmol) in 5 ml of pyridine. The reaction mixture is stirred at 50 0 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-1, from 340 mg of methyl (7-oxo 4, 5, 6, 7-tetrahydrobenzothiazol-2-yl) carbamate (1.5 mmol), 4.7 ml of Li-HMDS (lN in THF) and 520 mg of imidazol-1-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 0 N N 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-1, from 17 g of ethyl (7-oxo 4,5,6,7-tetrahydrobenzothiazol-2-yl)thiocarbamate (67 mmol), 200 ml of Li-HMDS (lN in THF) and 23 g of imidazol-1-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 3 N N NN The desired compound is obtained, in analogy with the preparation of Z-1, from 12 g of ethyl (7-oxo-4,5,6,7 tetrahydrobenzothiazol-2-yl)thiocarbamate (Z-14a, 46 mmol), 140 ml of Li-HMDS (lN in THF) and 12 g of imidazol-1-ylpyrimidin-5-ylmethanone (56 mmol) in 300 ml of THF. Yield: 13 g Wo 2006/040281 30 PCT/EP2005/055021 I-1) 4-(7-Acetylamino-4,5-dihydropyrazolo[3',4':3,4] benzo[1,2-d]thiazol-1-yl)-3-chlorobenzoic acid 0 N < HS N-N / CI A suspension of Z-13 (480 mg, 1.5 mmol) and 2-chlorophenylhydrazine hydrochloride (267 mg, 1.5 mmol) in 10 ml of glacial acetic acid is stirred at 1000C 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-[l-(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 0o S N-N C1 The desired product is obtained in analogy with the preparation of I-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-dihydro pyrazolo[3',4' :3,4]benzo[1,2-d]thiazol-1-yl)-3-chloro benzoic acid 0 N-N / Cl HOOC In analogy with the preparation of I-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-lH-pyrazolo [3',4' :3,4]benzo[1,2-d]lthiazole-3-carboxylic acid
K
0 N-<'I 0 HS ~ N- OH NN 27 g of product are obtained in analogy to the preparation of I-i from 30 g (0.1 mol) of Z-10 and 10.3 ml (0.1 mol) of phenyl hydrazine. (m.p.: 298 300 0 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 0 C) 1-8) 4-(7-Acetylamino-3-phenyl-4,5-dihydropyrazolo [3',41:3,4]benzo[1,2-d]thiazol-1-yl)-3-chlorobenzo nitrile N-</ N-N NC The desired product is obtained in analogy with the preparation of I-1, starting from Z-11 (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-1-yl)-3-chlorbenzoic acid 0 H S -I N-N /C OH The desired compound is obtained in analogy with the preparation of 1-4, starting from Z-11 (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-[l-(2-Chloro-4-nitrophenyl)-3-phenyl-4,5 dihydro-lH-pyrazolo[3',4':3,4]benzo[1,2-d]thiazol 7-yl]acetamide N-N / CI 0 2 N The desired product is obtained in analogy with the preparation of I-1, starting from Z-11 (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 I-11) N-(1-Piperidin-4-yl-3-pyridin-3-yl-4,5-dihydro 1H-pyrazolo[3',4':3,4]benzo[1,2-d]thiazol-7-yl) acetamide WO 2006/040281 33 PCT/EP2005/055021 -N N-N N H In analogy with the preparation of I-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 0 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 0 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-1-yl)cyclo hexanecarboxylic acid N-N O OH N ~N N-</ N N-</ HHs N-N N-N OH cs OH trans 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 Starting Starting No. Structure No. Structure compound _____________compound 0 NCN H s H s .- ' 1-13 Z-12 N-N 1-30 Z-3 N-N N Cl0B Cl N 0 I-15 Z-12 C N-N 1-1 Z3N N N / N \N I-17 Z-12 N-N I-34 z-5 N-N Ol0/B 0 NON NO N-< HK-</ 1-15 Z-12 N 1-32 Z-4 C -O/N-N O N-N CCc 0 NO</ HS H s 1-16 Z-12 N-N 1-33 Z-4 N-N _NC O 0 _NN-<I r- NC 1-17 Z-12 q N-N 1-34 Z-5 O N-N NN H H JN NO 11 Z12N-N 1-35 z-5 N-N O2N 0 N N 11 Z12N-N 1-36 Z-12 CHO N-N NC
OH
WO 2006/040281 35 PCT/EP2005/055021 Starting Starting No. Structure No. Structure compound compound N N 1-20 Z-12 N-N 1-37 Z-11-N CI O 0 OH OH I-21K-12 O/ NC 1-21 Z-12 1-38 Z-11 N-N __O__OH_ O NN Z-12 s-<N H H S 1-22 Z-12 N-N 1-39 Z-12 N-N OH ON NI N H s .N-< I Z-12 N-N Z-12 1-23 H-2 F1-40 H-12 ~ N-N 0-N H -KIN N_<' H s S Z-12 / HS -N 1-24 N-N 1-41 Z-14NN H-3 0 N N N--</ _<_ 1-25 Z-12 N-N 1-42 Z-14 N-N O \/z
H(I
36 Starting Starting No. Structure No. Structure compound compound__________ 0 Z-12 s H 1-26 S 1-43 Z-14 1-6 H-4 ,NN ~ N-N O /1 CI OH S- N N~ \I/// _ 1-27 Z-1 N- -44 Z-15 S -~ N-N OH N- H N N-< -N 1-28 N-N N 1-45 Z-3 N-N H-i1- HO-\ / l 00 Z-3 H S 1 ( , i~ HC4N 1-9/- N 1-46 Z-12 -s H-7 OH C WO 2006/040281 37 PCT/EP2005/055021 II-1) N-[l-(4-Amino-2-chlorophenyl)-3-furan-2-yl-4,5 dihydro-1H-pyrazolo[3',4':3,4]benzo[1,2-d]thiazol 7-yl]acetamide H s N-N / ci
H
2 N 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 0 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 0 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 11-3) N-[1-(4-Amino-2-chlorophenyl)-3-phenyl-4,5-di hydro-1H-pyrazolo[3',4' :3,4]benzo[1,2-d]thiazol-7-yl) acetamide N-N /ci
H
2 N 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 0 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 11-4) N-[l-(4-Aminophenyl) -3-pyridin-3-yl-4, 5-dihydro 1H-pyrazolo[3',4':3,4]benzo[1,2-d]thiazol-7-yl] acetamide H S _N/ N-N
H
2 N The desired product is obtained in analogy with the preparation of 11-2, starting from 1-16 (0.2 g, 0.5 mmol). Yield: 0.14 g 11-5) N-[1- (3-Aminophenyl) -3-pyridin-3-yl-4,5-dihydro 1H-pyrazolo[3',4':3,4]benzo[l,2-d]thiazol-7-yl] acetamide N-N
NH
2 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 WO 2006/040281 39 PCT/EP2005/055021 11-6) N-[l- (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 N N-</ N N-N / Ci
H
2 N The desired product is obtained in analogy with the preparation of 11-3, starting from I-18 (10 g, 21 mmol). Yield: 8.4 g 11-9) Ethyl [4-(7-acetylamino-3-phenyl-4,5-dihydro pyrazolo[3',4':3,4]benzo[l,2-d]thiazol-1-yl)-3-chloro phenyl] thiocarbamate 0 HS
X
N-N N /S H Ethyl chlorothioformate (0.7 ml) is added dropwise to a solution of 11-6 (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 0 C for 15 h, is obtained. Yield: 3 g II-10) N-[l- (4-Aminomethyl-2-chlorophenyl)-3-phenyl 4,5-dihydro-lH-pyrazolo[3' ,4' :3,4]benzo[1,2-d]thiazol 7-yl]acetamide N-N
H
2
N
WO 2.006/040281 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 II-11) N-[i- (2-Ch:Loro-4-formylphenyl) -3-pyrazin-2-yl 4,5-dihydro-lH-pyrazolo[3',4 ' :3,4]benzo[1,2-d]thiazol 7-yl]acetamide N-N/ N / Ni N-N 0 2 g of manganese dioxide are added to a solution of 1-29 (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 11-12) N- [1- (3-Aminomethyl) -3-phenyl-4, 5-dihydro-lH pyrazolo[3', 4 ':3,4]benzo[1,2-d]thiazol-7-yl]acetamide
N
N N N-N
H
2 N The desired product is obtained in analogy with the preparation of II-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-1H-pyrazolo[3',4':3,4]benzo[1,2-d]thiazol 7-yl]acetamide 0 N-N \/F
H
2 N The desired product is obtained in analogy with the preparation of 11-3, 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-1-yl)-N,N dimethylbenzamide H2N S ~ N-N /N 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 0 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-1-yl)-3-chloro-N,N dimethylbenzamide dihydrochloride N
H
2 N-</ N S ~ N-N / ci O1 -2 HCI /N 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 0 C for 2.5 h. The clear solution is stirred at 70 0 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-1-yl)-3-fluoro-N,N dimethylbenzamide N S , N-N F
N
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 500C 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 1H-pyrazolo[3',4':3,4]benzo[1,2-d]thiazol-7-ylamine N '
H
2 N-K' N N-N / CI The desired product is obtained in analogy with the preparation of 11-16, starting from 1-46 (10.3 g, 24 mmol) and 280 ml of hydrochloric acid (37%) in 330 ml of water. Yield: 7.6 g 11-18) 1-Phenyl-3-pyridin-3-yl-4, 5-dihydro-lH-pyrazolo [3' 1,4' :3,4]benzo[1,2-d]thiazol-7-ylamine N _
H
2 N-< I N-N 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-1-yl)-3-chlorobenzoic acid N
H
2 N-<' N N-N O CI 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 - WO 2006/040281 44 PCT/EP2005/055021 Method AM1: HPLC: Agilent 1100 series; MS: 1100 series LC/MSD (API-ES (+/- 3000V, Quadrupole, G1946D); mode: Scan pos 100-1000, neg 100-1000 Column: Waters; part no. 186000594; XTerra MS C18 2.5 pm; 2.lx5Omm column Solvent: A: H 2 0, deionized and containing 0.1% added formic acid B: Acetonitrile, HPLC grade and contaiing 0.1% added formic acid Detection: peak width >0.1min (2s); 190-450nm UV 254 nm (bandwidth 8, reference off) UV 230nm (bandwidth 8, reference off) Injection: 1 pl standard injection Flow rate: 0.6 ml/min Column temperature: 35 0 C Pump gradient: 0.0-0.5 min 5% B 0.5-1.5 min 5% -> 50% B 1.5-4.0 min 50% -> 95% B 4.0-6.0 min 95% B 6.0-6.5 min 95% -> 5% B 1.5 min post run 5% B Method AM2 HPLC: Agilent Series 1100 (G1379A/Gl31OA converted to Gl311A/G1313A/G1316A/G1948D/G1315B/Gl946D) mode: Scan pos 100-1000, neg 100-1000 Column: Agilent Zorbax SB-C8, 2.1x50 mm, 3.5 pm Solvent: A: H 2 0, deionized and containing 0.1% added formic acid B: Acetonitrile HPLC grade and containing 0.1% added formic acid Detection: peak width >0.1min (2s); 190-450 nm UV 254 nm (bandwidth 8, reference off) UV 230nm (bandwidth 8, reference off) Injection: 2.5 pl standard injection Flow rate: 0.6 ml/min Column temperature: 35 0
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.Omin 90% -> 10% B Method AM3 HPLC: Agilent Series 1100 (Gl312A/Gl315A/G1316A/G1367A) Agilent MSD SL ESI Mode: Scan pos 150-750 Column: Agilent Zorbax SB-C8, 2.1x5O mm, 3.5 pm Solvent: A: H 2 0 deionized and containing 0.1% added formic acid B: Acetonitrile, HPLC grade and containing 0.1% added formic acid Detection: 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) Injection: 3.0 4 overlap injection Flow rate: 1.1 ml/min Column temperature: 45 0 C Pump gradient: 0-1.75 min 15% -> 95% B 1.75-1.90 min 95% B 1.90-1.92min 950% -> 15% B Method AM4 HPLC: Agilent 1100 series MS: Agilent LC/MSD SL (LCMS1: 1100 series LC/MSD) Column: Waters, Xterra MS C18, 2.5 pm, 2.1x30 mm, part no. 186000592 Solvent A: H 2 0 deionized and containing 0.1% added formic acid B: Acetonitrile, HPLC grade and containing 0.1% added formic acid Detection: MS: positive and negative mass range: 120-900 m/z fragmentor: 120 gain EMV: 1 - WO 2006/040281 46 PCT/EP2005/055021 threshold: 150 step size: 0.25 UV: 254 nm bandwidth: 1 (LCMSl: 2) reference: off spectrum: range: 250-400 nm range step: 1.00 nm threshold: 4.00 mAU peak width: < 0.01 min (LCMS1: >0.05 min) slit: 1 nm (LCMS1: 2 nm) Injection: 5 pl Flow rate: 1.10 ml/min Column temperture: 40 0 C Gradient: 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: Agilent 1100 series MS: Agilent LC/MSD SL (LCMSl: 1100 series LC/MSD) Column: Phenomenex, Synergy Polar RP 80A, 4 pm, 2.0x30 mm, part no. OOA-4336-BO Solvent: A: H 2 0 (Millipore purified purest water) containing 0.1% HCOOH B: Acetonitrile (HPLC grade) Detection: MS: positive and negative mass range: 120-900 m/z fragmentor: 120 Gain EMV: 1 Threshold: 150 Step size: 0.25 UV: 254 nm Bandwidth: 1 (LCMSl: 2) Reference: off Spectrum: . WO 2006/040281 47 PCT/EP2005/055021 range: 250-400 nm range step: 1.00 nm threshold: 4.00 mAU peak width: < 0.01 min (LCMS1: >0.05 min) slit: 1 nm (LCMS1: 2 nm) Injection: inj. vol.: 5 pl Inj. mode: needle wash Separation:flow rate: 1.10 ml/min column temp.: 40 0 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 im, 4.6x30 mm, part no. 186000600 Solvent A: H 2 0, 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 0 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 employed conc. concentrated d day DCM dichloromethane DMAP N,N-dimethylaminopyridine DMF N,N-dimethylformamide DMSO dimethyl sulphoxide EtOH ethanol h hour 0- (7-Azabenzotriazol-1-yl) -N,N,N',N' HATU tetramethyluronium hexafluorophosphate HPLC high performance liquid chromatography Li-HMDS lithium hexamethyldisilazane M molar MeOH methanol min minute ml millilitre m.p. melting point MS mass spectrometry N normal NMR nuclear magnetic resonance spectroscopy ppm parts per million Rf retention factor RP reversed phase RT room temperature Rt retention time TBTU O-Benzotriazol-1-yl-N,N,N',N'-tetra methyluronium tetrafluoroborate tert tertiary THF tetrahydrofuran TLC thin layer chromatography WO 2006/040281 49 PCT/EP2005/055021 Examples 1.1-1.13 R3< H . N-</ sR3 R2N NH 2 H S R3 0 0 R2 Examples 1.1-1.13 are prepared in analogy with the I-1 synthesis. Starting Structure Mass HPLC compound [M+1]* Rt [min] N N 1.1 Z-12 1 H-NM DMSO-d6, 5 [ppm]: 8.86 (s, 394 1.88 1H), 8.53 (d, 4 Hz, 1H), 8.02 (d, 7.7 Hz, 1H), 7.46 (dd, 7.7 and 4.8 Hz, 1H), 4.23 (m, 1H), 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). N 0N 1.2 Z-12 NNN 380 1.67 N-/I 1.3 Z-8 S 449 2.1 H-8 C\ N-N 0 O N-</ Z-12 S / 1.4 H-9 N-N N 457 1.54+1.71 F
F
- WO 2006/040281 50 PCT/EP2005/055021 Starting Structure Mass HPLC compound [M+1]* Rt [min] N S "O Z-12 N-N 1.5 H-11 48 1.45 0 N N N N-N 1.6 Z-12 487 2.53 (NN N39 C N-K/ _N 1.7 Z-1 403 1.81 N 0 N-K -</ N 0 S 3 1.9 Z-12 N- 430 1.53 0 N Z-12 H S . 1.10 H-13 H N 508 1.67 H-13 _O N-N 11 WO 2006/040281 51 PCT/EP2005/055021 Starting Structure Mass HPLC compound [M+1+] Rt [min] NN N-</IN 1.11 Z-12 H S 42 1.4 H-14 N-N 42 1.49 N 0 IN N-< S 1.12 -12 N-N 442 1.48 N ~N) N 1.13 N- N 445 1.19 NO 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 pm; 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 carbo ylic adi'd, 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 Mas 1s HPLC Rt [min] compound Structure or m.p. or TLC:Rf 0
H
3 C- N H N-N 0 C1 N 2.1. 1-9 0 534 2.06 2H-NMR DMSO-d6, d [ppm]: 7.86 (s, 1H), 7.78 (d, 7.9 Hz, 1H), 7.75 (d, 7.7 Hz, 1H), 7.63-7..61 (m, 1H), 7.49-7.46 (m, 2H), 7.41 7.37 (m, 1H), 3.72-3.62 (m, 6H), 3.42-3.38 (m, 2H), 2.07 (s, 3H).
H
3 4 ' N H S 2.5 1-9 N-N 478 m.p.: 206 0 C HA CN N N-N/ H C 2.6 1-9 N-N 54 1. C1 DCM:MeOH 9:1 0 NH 0 2.7 1-9 N-N 546 1.94 H C /a HN 2.8 1-9 N-N 536 2.1 Hs C1 H ,C H \ , . N 2.9 1-9 N--N 523 1.88 H O C _____ H 0 WO. 2006/040281 54 PCT/EP2005/055021 Starting Mass HPLC Rt [min] compound Structure [M+1). or m.p. or TLC:Rf
H,C-
2.10 1-9 N-N 536 2.02 HC-.. C HO 0 HaC N N N-<N N-N 2.11 1-21 576 2.06 ,C j\ HN 0 NN N N-N 2.12 1-21 H NC 616 1.4 N Ca 0 HNC N 2.13 1-21 N-N 465 1.42 HN N-< H C N 2.14 1-21 N-N 479 2.18
H
3 C /CA N HC N N N <N 2.15 1-21 N-N 570 2.02 /CI N-<N
N
2.16 1-21 H3C \/ci 630 1.39
N
00 - WO.2006/040281 55 PCT/EP2005/055021 Starting Mass HPLC Rt [min] compound Structure or m.p. or TLC:Rf HC s HC - NN N-N 2.17 1-21 H 5C 630 1.28 N 000 NH, S H NO H C 2.19 1-21 541 1.38 H N 00 NI HC -N 2.20 I-21 NN547 1.89 N 2.23 I-21 HC N6563 132 O C .NP N-N 2.21 1-21 -541 1.86 H 0
N
2.22 1-21 NN537 1.54
HCP
N 0 N-< H N I, 2.23 1-21 HC N-N 537 3.24 HC-- ' C l ___ ___ ___ ___ _NC4 0 WO.2006/040281 56 PCT/EP2005/055021 Starting Mass HPLC Rt [min] # compound Structure or m.p. or TLC:Rf HNC<N H s -' N 2.24 1-21 N-N 523 1.58 H 2.25C- I-2 N N541. N H C 2.25 1-21 N-N 547 1.5 HOC- N C N H N 2.26 1-21 N-N 563 1.6 HO9 N \/Ci
H
3 C-' N N HN-< H C 2.27 1-21 N-N 549 1.45 N-</ H-C 2.28 1-21 N-N 563 1.55 H _ N C N 2.29 1-21 N-N 549 1.53
H
3 C-'< N ~ N N-</ 2.30 1-21 N-N 535 1.58 ~ \~ Ci - WO,2006/040281 57 PCT/EP2005/055021 HPLC Rt [min] # cartnd Structure [Ma1s or m.p. ompou [M] or TLC:Rf N-<N H S)? -I HC s 2.31 1-21 N-N 537 1.58
H
3 \ Cl H,C- NN N< N H 2.32 1-21 N-N 523 1.47
H
3 Cl HO 0 Hc N N N 0 N-< 2.34 1-21 N-N 509 1.5 H / Ci N C rO c HC 0 HC N N H s):? 2.35 1-21 N-N 549 1.55 ON \-- / C O N N HC <N 2.36 1-21 N-N 549 1.59 /c 0 H 34 -N N-N 2.37 1-21H l6205 HCP H / 632 0.55 N _ _ _ _ ~ o - O_ _ _ _ - WO,2006/040281 58 PCT/EP2005/055021 Starting Mass HPLC Rt [min] S compound Structure [M+1]. or m.p. or TLC:R N N< H s 2.38 1-21 N -N 563 1.53 H3 / CI N 0 HC NN N N-N 2.39 1-21 / c 658 0.52 0 0 0 HC N N N-/I H sl-' '-' 2.40 1-21 N-N 548 2.53 N C'N N 0 HC N N H s 2.41 I-21 N--N 533 1.76 CN-O Cl H,C4 NN Hsx 2.42 -I-21 N-N 576 2.57
H
3 C V-N
H
3 C- N 2.43 1-21 N-N 576 2.56 H 3 N H,C N N 0 H 3 C~ /N N s 2.44 1-21 N-N 519 1.62 CN - CI
OIJ
WO-2006/040281 59 PCT/EP2005/055021 Starting Mass HPLC Rt [min] # d Structure [M1]. or m.p. or TLC:Rr H N N-N 2.45 1-21 H / C 660 1.39
N
0 C~ H,4N-</ y11 N I HC N-N 2.46 1-21 H ,/ C 1 707 1.5 aNN-N 2.47 1-21 H 709 2.75 N HC- N N H -</ N) N-N 2.48 1-21 590 2.69 CH H CC
NN
2.49 I21 CI 30 2'a
_CH
3
H
3 C- N N H s - N N-N 2.49 1-21 / l 630 2.77 _ ~~~ o Q 0___ WO.2006/040281 60 PCT/EP2005/055021 Starting Mass HPLC Rt [min] # compound Structure [M+1] or m.p. or TLC:Rf N-N 2.50 1-21 H C 645 2.56 H,C H 4 N ~ N HC-N N-N/ 2.51 1-20 N-N 528 2 N HC N<N s N-N 2.52 1-20 H 3 C N-N 596 2.11 0C N N-N 2.53 1-20 542 2.06 0 HCC N -I-20/ N- N-N 2.54 1-20 H. I 582 2.1 0 H s N 2.55 1-20 N-N 604 1.26 H /N /\ N __ _ __ K -~ 0 WO.2006/040281 61 PCT/EP2005/055021 Starting Mass HPLC Rt [min] compound Structure [M+1], or m.p. or TLC:Rf
H
3 C- N N H s P 1 N-N 2.56 I-20 584 1.33 N H3CN~ 0
CH
3 N H N N 2.57 1-20 547 1.88 HCH N
HCC
H, N N N-N 2.58 1-20 535 1.84 H HC H N-N 2.59 1-20 OP 556 1.5 H N HS N-N 2.60 1-20 0P 551 1.83 NH 0> WO,2006/040281 62 PCT/EP2005/055021 Starting Mass HPLC Rt [min} # compound Structure [M+1], or m.p. or TLC:Rf HC N N H s 1 2.61 1-22 N-N 459 1.43 0 HCC-.N CH Ha3C- N N 2.62 1-23 H C-O N-N 521 1.54 N-F HC 0 s N -N 2.63 I-23 N-N 519 1.49 O F N H s 2.64 1-23 N-N 477 1.43 H'~ \/ F N ~ H s F 2.65 1-23 N-N 477 1.59
H
3 C F C H 3C Nl N N-<N Hs 2.66 1-23 HNC-O -N 535 1.63 F H3CHN 0 0
H
3 C N N 2.67 1-23 IN-N 533 1.54 O N / F 0 WO 2006/040281 63 PCT/EP2005/055021 # taStructure .HPLC Rt [min] Starting Structure [M+1]- or M.P. compoundor TLC:Rf H 3 4- N 2.68 1-25 N-N 521 1.75 0 N H H S ./ 2.70 1-25 N556 0.14 :MeOH CH H ,C-' N N N -N 2.7 1-25 N 529 1.5 OH HC 2.72 1-25 N-N 556 DCM:MeO . 7:3 o H C
CH
3 N-/ N H s 27 1-5N-N56 Rf = 0.27 2.73 I-25 o - 612 DC:eO22 DCM:MeOH 8:2
IH
WO.2006/040281 64 PCT/EP2005/055021 Starting Mass HPLC Rt [min] # compound Structure [M+1]. or m.p. or TLC:Rf 0 HC4 N H s . N-N 2.74 1-25 535 1.81
H
3 C-~N & N' H S N-N 2.75 1-25 o N-N 517 1.53 CH, HC N N-</I _ H s 2.76 1-25 N-N 499 1.6 0O HC N S -N/ N/ N HX 2.77 1-25 N-N 485 1.48 0 O HC- N ,S - N s N-N 2.78 1-25 528 2.8 CN
H
3 C _N N- N 2.79 1-25 N-N 517 1.51 HO /__ WO.2006/040281 65 PCT/EP2005/055021 HPLC Rt [min] # Starting Structure [Ma1] or m.p. compound[M1 orTCR _____or TLC:Rf H,C4 2.80 1-25 N-N 474 3.38 EtOH /"-0
H
3 C H S 2.81 1-26 N-N 501 1.64 o= H C- CHa 0
H
3 C ~NN H s -? N-N 2.82 1-27 494 1.74 0 / Ci H CH3 0 H HC N N SN 2.83 1-28 N-N 474 m.p.: 283 0 C
H
3 CH,
H
,
C
H
3 C4 NN N-< 2.84 1-45 N-N 494 1.81 HsC1 HC NN
H
3 0I S N 2.85 1-12 O$ ~519 1.77 __ 6 ___P WO 2006/040281 66 PCT/EP2005/055021 Starting HPLC Rt [min] # compound Structure Mass. or m.p. cmon[M1 or TLC:Rf N N H H N 2.86 1-12 507 1.47 N H N_ 2.87 1-12 465 1.39 0 H N-N 2.88 1-36 N 612 1.35 N 2.89 1-36 \ 626 1.33 2.90 1-36 N 612 1.38 0 - N N-N 2.91 1-36 \ N 626 1.36 N: 0 O _ _ _ & c WO,2006/040281 67 PCT/EP2005/055021 Starting Mass HPLC Rt [min] # compound Structure (M+1], or m.p. or TLC:Rf /N N N-N 2.92 1-36 NN626 1.37 N N0 N-</II s 2.93 1-37 N-N 478 2.00 N N/ NN-N 2.94 1-37 /615 1.67 CI N N-K/I s - N N-N 2.95 1-37 /561 1.60 No N-< S N-N 2.96 1-37 615 1.65
,N
WO 2006/040281 68 PCT/EP2005/055021 Starting Mass HPLC Rt [min] # compound Structure [M+1]. or m.p. or TLC:Rf N-/I N-N 2.97 1-37 547 1.60 0 0 N{ N -N 2.98 1-37 / 535 1.60 N 0 s - N NN 2.990 1-9 N625 m.p.: 286 0 C 0
N
0 Ni ,kNJ s N. 2.101 1-12 P548 1.45 U0 WO.2006/040281 69 PCT/EP2005/055021 Starting Mass HPLC Rt [min] # compound Structure or m.p. or TLC:Rf N \ N NS NN 2.102 1-12 522 1.46 NN -N N N 2.103 trans-I-12 548 1. 43 N N 2.104 trans-I-12 548 1.43 o N
_/N
N N 2.106 trans-I-12 520 1.37 N 2.107 trans-I-12 548 1.45 N 0 N 6 , WO -2006/040281 70 PCT/EP2005/055021 Starting Mass HPLC Rt [min) compound Structure [M+1] or m.p. or TLC:RN N N SN 2.108 trans-I-12 574 1.54 0= _ _ _ _ _ 0 _ N N N 2.109 1-23 N-N 505 1.6 F N 2.110 1-23 N--N 507 1.41 F N 0.112 I-23 N--N 560 1.2 /N N N_<I N-N 2.111 1-23 546 1.52 F N N-</ 2.112 1-23 N- IN 560 1.24 / N N-<N N-N 2.113 1-23 560 1.48 F
N
_ CI _ _ _ _ WO .2006/040281 71 PCT/EP2005/055021 Starting Mass HPLC Rt [min] compound Structure [M+11. or m.P. or TLC:Rf N N-</ N s 2.115 1-23 N N--N 520 1.45 F N 0N ~N* s N 2.116 1-23 N N-N 548 1.49 /F 2.117, __ I 2N-N 53F1 4 F N N F N-/\ 2.117 1-23 1 N-N 534 1.48 F
N
N N. 2.11 1-23 N-N 560 1.61 OF NI s ~ N 2.121 1-23 N-N 588 1.64 N F N-<N s N 2.121 1-23 N- IN 586 1.61
/F
WO,2006/040281 72 PCT/EP2005/055021 Starting Mass HPLC Rt [min] compound Structure [M+1] or m.p. or TLC:Rf NN N-/I S 2.122 1-23 N----N 574 1.27 N F S 2.123 1-23 N-N 603 1.49 NNF ______0_0 F N N / 2.124 1-23 N-N 588 1.28 N F N N 0 -N 2.125 1-23 N-N 532 1.65 -N S RfR= 0.44 2.126 1-25 N-N 517 DCM: MEOH o 9:1 N-KI Rf = 0.18 2.127 125 - 568 DCM: MEOH 7:3 $11 WO.2006/040281 73 PCT/EP2005/055021 Starting Mass HPLC Rt [min] # compound Structure M+. or m.p. or TLC:Rf
N
N-N Rf = 0.24 2.128 1-25 582 DCM: MEOH 7:3 5?) N7 N-N 2.129 1-25 /N 598 1.23 -NO NO 2.130 1-25 N-N 527 1.39 NNN N-</ N 2.131 1-25 N-N 522 1.43 0 N NS</ / Rf 0.
9 1 2.132 1-25 N-N 522 DCM: MEOH o 9:1 S / /Rf = 0.88 2.133 1-25 N-N 522 DCM: MEOM 9:1 Na\ N\ - WO.2006/040281 74 PCT/EP2005/055021 Starting Mass HPLC Rt (min] compound Structure [M+1]. or m.p. or TLC:Rf ~Nj S N N-N Rf =0.42 2.134 1-25 591 DCM: MEOH 9:1 C N N-/I 2 N Rf = 0.4 2.135 -25 N530 DCM: MEOH o 9:1 S N-N Rf = 0.25 2.136 1-25 544 DCM: MEOH 9:1 N NS Rf = 0.-18 0 2.137 1-25 NN550 1.27 M N-_N S -/ Rf =0..18 2.139 1-25 N 590 DCM: MEOH 9:1 WO.2006/040281 75 PCT/EP2005/055021 Starting' Mass HPLC Rt [min] # compound Structure [M+1]. or m.p. or TLC:Rf N N-</I S ~ N-N 2.140 1-25 570 1.43 00
N
0 N-N 2.141 1-20 : 578 1.56 0 .-N 0 N-N 2.142 1-20 0o 591 1.53 N-~ '-/ 0 N-N 2.143 1-20 0"/584 1.53 0 N - </ 0 N-N 2.144 1--20 / 568 1.61 0z WO 2006/040281 76 PCT/EP2005/055021 Starting Has s HPLC Rt [min] # opon Structure [B1] or m.p. compond [+11. or TLC:Rf 0 N-N 2.145 1-20 0:( 582 1.64 0 Nb _ N-</I _ 0 N-N 2.146 1-20 /556 1.50 0 N N-N 2.147 1-20 0 540 1.48 N 0 N-N 2.148 1-20 0-/ 590 1.65 0 -</ 0 N-N 2.149 1-20 o- 568 1.58 0 __ 6
__ON
W0.2006/040281 77 PCT/EP2005/055021 Starting Mass HPLC Rt [min] # compound Structure [M+11* or m. p. _____or TLC:Rf N-/I N-N 2.150 1-20 \/528 1.44 0 N N N-<1I -~ S N-N 2.152 1-20 0- 556 1.54 N ONN 0 N-N 2.153 1-20 0a / 556 1.59 0 N-N 2.154 1-21 CI 556 1.55
-
N
/_NN
W0.2006/040281 78 PCT/EP2005/055021 Starting Mass~ HPLC Rt [min) #t compound Structure [M+1]+ or m.p. or TLC:Rf N N 2.155 1-21 / I550 1.49 N-. -N N~ N-N 2.156 1-21 /CA 562 1.49 0 N N 0 N-N 2.157 1-21 0 618 1.58 NN 0 N-N 2.158 1-21 0630 1.50 0 __ b NN 0 N-N 2.159 1-21 01 625 1.55 0 _________O
N
Wo .2006/040281 79 PCT/EP2005/055021 Starting Mass HPLC Rt [min] # d Structure [M+1] o r m.p. or TLC:Rf N N 0 N-N 2.160 1-21 602 1.65 N N-<I ~ N 0 N-N 2.161 1-21 N C 562 1.47 N N 0 1N-N 2.162 1-21 0616 1.72 0 N 2.163 1-N-</ _N9 12 0 0 N-N 2.163 1-21 0A 574 1.5 0zz\ WO.2O06/040281 80 PCT/EP2005/055021 Starting Mass HPLC Rt (mini] # compound Structure [MI- or M.P. N or TLC:Rf 0 N-N /Ci 2.165 1-21. 0-P 612 1.64 N N -N N / 0 N-N 2.166 1-21 /62i56 1.46 0 0 N-N 2.167 1-21 /CI 562 1.77 0 2.168 1-21Cl 56C1.7 _ _ _ _~~ N
__
WO.2006/040281 81 PCT/EP2005/055021 Starting Mass HPLC Rt [min] compound Structure [M1], or m.p. or TLC:Rf
SX
0 N-N 2.169 1-21 602 1.62 N 0 N-N 2.170 1-21 a 590 1.62 2.171 I-21 590 1.61 N 2.172 1-21 / 604 1.68 0
N
2.172 I-21 / CI 604 1.68 cN N N 2.173 1-21 / 685 2.59 rNN 2.174 1-20 N-N 542 2.56 0- WO 2006/040281 82 PCT/EP2005/055021 HPLC Rt [min] compound Structure [M+1. or m.p. N 2.176 1-41 N-N 505 N 2.177N-< I- 2\ - N S NN 2.178 I-42 N6-N53 N l s \ S___e N N__ NN 2.179 I-12 N- 451.4 ON-N N 2 IN 2.178 1-12 N-N 459 1. N 0 NN N 0 4 N:, N NI 2.181 1-20 459 1.56
NN
WO 2006/040281 83 PCT/EP2005/055021 Starting Mass HPLC Rt [min] # compound Structure [M+11* or M.P. or TLC.Rf 0N N 'N. 2.182 1-23 N-N 477 2.87 \ / F N 0 N-I N N-< 2.183 11-19 N-N 477 1.44 CN /0Cl *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 chromato graphically. Examples 3.2-3.82 Starting HPLC Rt [min] # compound Structure Mass [M+1]* or m.p. or TLC:Rf H3Cf N N-N 3.2 1-1 1Z CI 601 2.08 PJH CH, H s 3.3 11-3 N-N 543 2.2 HC 0 3-CI PS-N
H
3 C 0 H N-N 3.4 II-1 Oci 585 2.12 NH HC 0 HC CH 3 0
H
3 4 ~N) H s 3.10 11-4 N-N 544 1.62 HN 00
H
3 4
NN
HC 3.11 11-4 N-N 445 1.45 HON H3C H WO ,2006/040281 85 PCT/EP2005/055021 Starting HPLC Rt [min] # compound Structure Mass [M+1]* or m.p. or TLC:Rf o CH,NN sN H S ..- ' 3.12 11-4 N-N 473 1.6 H,C- N H N N-N 3.13 11-4 475 1.48 O *0 HC CH, O-N H S N-N 3.14 11-4 489 1.5 /- N H3C'O H CH, N- N H S NN 3.15 11-4 O 529 1.53 N H O C's, =(N 3.16 11-4 N-N 515 1.52 N H 0 CH, S - I ' N-N 3.17 11-4 519 1.58 0 9F WO .2006/040281 86 PCT/EP2005/055021 Starting HPLC Rt [min] # compound Structure Mass [M+1]* or m.p. compound _or TLC:Rf ct, O=N N-N 3.18 II-4 529 1.59 H S S N/ N-N 3.19 11-4 503 1.43 N H 0 3.20 II-4 N-N471. CH, -N 3.21 11-4 51 1.47 N H ON 0 H S N 0=N/' N-N 3.22 11-4 51 481.47 HN 0 N-C NN 3.23 11-4 H NjN 537 1.89
NH
WO.2006/040281 87 PCT/EP2005/055021 Starting . HPLC Rt [min] # compound Structure Mass [M+1] or m.p. or TLC:Rf N 3.24 II-5 535 1.8 H,C N S 3.24 II-6S - 535 1.81 HN H N S 3.25 11-6 1N-N 5 1.54 HN 0=s=o
H
3 C
H
3 C4 N
N
S HH 3.26 11-6 o 479 1.52 H,C H S3 N-N 3.27 11-6 0 7-C 541 1.82 N H H34 N N-N 3.28 11-6 0 /0 -C, 547 1.90 H H34 N S 3.29 11-6 0I-0I 577 1.81 N
~I:
WO.2006/040281 88 PCT/EP2005/055021 Starting HPLC Rt [min] # compound Structure Mass [M+1]* or m.p. or TLC:Rt H,C- N N-< N-N 3.30 11-6 cl 616 1.38 HN 0 HH NN N-N Rf: 3.31 11-6 Cl 616 0.18 MeOH:NH 4 0H HN 92.5:7.5:1 CHN N-N 3.32 11-6 509 1.43 HH,
H
3 C CH, ON H s N-N 3.33 11-6 o 553 1.55 C,, H3C-O/- H Nt 3.34 11-12 569 m.p.: 2770C 0 3.35 11-12 569 2.59 *WO.2006/040281 89 PCT/EP2005/055021 Starting HPLC Rt [min] # compound Structure Maos [M+1]* or M.P. ____ _______or TLC:Rf N ' N-N 3.36 11-12 /520 m.p.: 2821C -0 3.37 11-12 q - 617 m.p.: 2271C 3.38 11-12 N 631 m.p.: 2940C 0 0 3.39 11-12 597 3.0 N
N
3.40 11-12 q NN605 2.95 N 0 WO ,2006/040281 90 PCT/EP2005/055021 Starting HPLC Rt [min] # compound Structure Mass [M+1]* or m.p. or TLC:Rf NN N 3.42 I-1 451 1.4 0 N-K' N S I N--N 3.42 I-11 450 1.21 NIN N N sN N-N 3.43 1-11 011NO 499 1.56
N
3.45 I-i 473 50 1.21 0 WO 2006/040281 91 PCT/EP2005/055021 Starting HPLC Rt [min] compound Structure Mass [M+1]+ or m.p. or TLC:Rf N IN N-N 3.46 I-40 535 1.68 QN 9N 7 O N 'N N-N 3.47 I-i536 1.52 ozs 00N N-{ N-N/ 3.49 1-40 C5NN522 1.47 NN 3.50~~ I-i 7s 56 .5 00 S,~ N N-N 3.51 1-11 77 465 1.47 WO 2006/040281 92 PCT/EP2005/055021 Starting HPLC Rt (min] # compound Structure Mass [M+1]* or m.p. or TLC:Rf N-</I N-N 3.52 I-11 N- 500 1.34 ON N N N-KN 3.53 1-11N 500 1.46 N INI N F NF N-N 3.54 11-13 506 1.47 N 3.55 11-13 N-N 463 1.46 /-F N 3.56 11-4 0 0 NN502 1.45 >0
N-
WO,2006/040281 93 PCT/EP2005/055021 Starting HPLC Rt [min] # compound Structure Hass [M+1]+ or m.p. or TLC:Rf S -N N-N 3.57 11-4 502 1.45 N 0 N 3.58 II-14 --- 531 1.48 N 00 N-N 3.59 11-14 o 0 545 1.56 0 / N 3.60 11-14 551 1.77 / N 0 N 3.61 11-14 541 1.67 0 /
N
WO ,2006/040281 94 PCT/EP2005/055021 Starting HPLC Rt [min] # compound Structure Mass [M+1]* or m.p. or TLC:Rf 3.62 11-14 517 1.46 0 / N N s~ S N . 3.63 11-14 519 1.57 o\ N 0 3.64 11-14 489 1.45 0 N{ S ~ N-N 3.65 11-15 547 1.74 CI N- .. S 3.66 11-16 N-N 521 1.46 F NP 0 WO.2006/040281 95 PCT/EP2005/055021 Starting HPLC Rt [min] # cpnd Structure Mass [M+1]* or m.p. compoundorTCR or TLC:Rf N N 3.67 11-16 N 567 1.77 F N 0 N S 3.68 11-17 0 N- 436 1.64 cl S 3.69 11-17 N-N 450 1.75 OC1 3.70 II-17 N-N 464 1.87 / ci N-I 3.71 11-17 O O N- 452 1.59 OC S 3.72 11-17 0 N- 498 1.88 N 31 521 3.73 11-17 0 N 512 1.95 WO 2006/040281 96 PCT/EP2005/055021 HPLC Rt [min] # Starting Structure Mass [M+1]* or m.p. compound or TLC:Rf N N 0 S 3.74 11-17 0N-t 506 1.68 o s 3.75 I-17 0N 507 1.57 -N N 3.76 11-17 N 494 1.64 -o N- N S 3.77 11-17 N- 478 1.58 0 / ci -N N N-K/ S 3.78 11-17 0 493 1.28
N
3.79 11-17 o N 466 1.61 N--o 3.80 1-18 N- 418 1.54 WO .2006./040281 97 PCT/EP2005/055021 Starting HPLC Rt [min] # compound Structure Mass [M+1]* or m.p. or TLC:Rf -N -N 3.81 II-18 0 N- 431 1.53
N
0 S 3.82 II-18 O 473 1.55 -N * 3.56 is synthesized by reacting 11-4 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 pl 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 0 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 800C 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 Examples 4.1-4.32 Starting Mass HPLC Rt [min] # compound Structure [M+1]. or m.p. or TLC:Rf 0 H3C-- N N N H s j N-N N C
H
3 C-N H
CH
3 4.1 11-9 1 H-NMR DMSO-d6, d [ppm]: 508 1.43 8.93 (d, 1.7 Hz, 1H), 8.79 (s, 1H), 8.58 (dd, 1.5 and 4.8 Hz, 1H), 8.22 (s, 1H), 8.12-8.09 (m, 1H), 7.99 (d, 2.1 Hz, 1H), 7.70 (dd 2.3 and 8.8 Hz, 1H), 7.54-7.47 (m, 2H), 3.17-3.12 (m, 2H), 3.05-3.01 (m, 2H), 2.9 (s, 6H), 2.08 (s, 3H). 0 H,C -/ H S / 4.2 11-9 N-N 562 1.86 C1I N /HN H_ 01 N 4.3 11-9 N-N 556 1.85 Q N H H H3 N S _N\/ 4.4 11-9 N-N 509 1.73 /-0 H HC 0 H,C N H S / .... N-N 4.5 11-9 N - 631 1.58
HH
W02006/040281 99 PCT/EP2005/055021 Starting Mass HPLC Rt [min) S compound Structure [M+1]+ or m.p. or TLC:Rf N-< H sDP .- I 4.6 11-9 N-N 493 2.02 C1 H N-</I 4.7 11-9 N-N 585 m.p.: 160 0 C S N-N1 4.8 11-9 N N 562 1.59 _ _ N /_ _CI N N-N 4.9 11-9 'NN 5630 1.68 N N S N-N 4.10 11-9 -. 549 1.65 0 / Ci N N-</Il\f S ~ N/ Rf =0.02 4.11 11-9 NN551 DCM:MeOH C 9:1 W .2006/040281 100 PCT/EP2005/055021 Starting Mass HPLC Rt [min] compound Structure [M+1]. or m.p. or TLC:Rf N s Rf = 0.05 4.12 11-9 N-N 565 DCM:MeOH 0 C9:1 N N N-K/ S _C /N/ 4.13 11-9 N-N 520 1.43 o C I /KN N S j 4.14 11-9 -N 534 1.54 0 0i N NCN S J_ N-N 4.15 11-9 -550 1.43 0 / C' N-K S ~ N-N 4.16 11-9 563 1.3 0 Qi N
NJ
WO 2006/040281 101 PCT/EP2005/055021 Starting Mass HPLC Rt [min] # compound Structure [M+1]. or m.p. or TLC:Rf 4.17 II-9N CN57N18 N-</N s j N-N 4.17 11-9 NN576 1.83 N-~ N_ 4.18 11-9 N-N 574 1.79 N N-</ N-N 4.19 11-9 N 562 1.42 N -N N-</ j _0N 4.20 11-9 N-N 508 1.49 0 N-< N N-N 4.21 11-9 548 1.68 N N-K N N N-</ 4.22 2.176 NN 460 1.43 0_P WO 2006/040281 102 PCT/EP2005/055021 Starting mass HPLC Rt (min] compound Structure [M+1]. or m . or TLC:Rf N N S N-K/I_ 4.23 2.176 N- N 488 1.45 N >-\ N N0 N-< N-N 4.24 2.177 \ 685 1.49 N N N-</ N-N 4.25 2.177 721 1.55 N 00 N N---N N N N 4.26 2.178 N-N 508 1.58 0 N-<N 4.27 1-43 SN437 1.59 N-N NN 4.28 1-44 | 551 m.p.: 199 0 C N-N
ON
WO 2006/040281 103 PCT/EP2005/055021 Starting Mass HPLC Rt [min] compound Structure [M+1]. or m.p. or TLC:Rf O_ N N S 4.29 1-44 439 m.p.: 2730C N-N / Cl N N 4.30 1-44 N I 538 m.p.: 2200C -N-N 0 N N N-/ _N 0 S 4.31 1-43 oNs/ 551 1.94 0 N'N N 4.32 I-1 N 466 3.61 N-N Examples 5 - reacting the chloropyridyl building blocks 0 O
H
3 C N HC R H S - R H H - R N-N + I N-N Cl NR 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 0 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 N-methylpyrrolidinone, DMSO or DMF is heated at 120 0 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 Mass HPLC Rt [min] compound Structure [M+1]. or m.p. or TLC:Rf 0 N-< H s N-N N\ 5.1 1-3 _ 463 1.67 1H-NMR DMSO-d6, d [ppm]: 8.28 (d, 5.4 Hz, 1H), 7.79 (s, 1H), 7.05 (s, 1H), 6.9-6.88 (m, 1H), 6.8 (d, 3.3 Hz, 1H), 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). HC S 00 5.2 1-3 -N-N 421 1.44 N HNC N-CH, H,C N H s 5.3 1-14 462 0.3 HOH H,C H-~ N-N 5.4 1-14 0/488 0.28 _______ __________
O
WO,2006/040281 105 PCT/EP2005/055021 Starting Mass HPLC Rt [min] compound Structure [M+1]. or m.p. or TLC:Rf
H
3 C N_ N-N 5.5 1-14 N 476 1.5 H C HC HC N N-N 5.6 1-14 N 488 1.34 HO HC kN 5.7 1-14 N N-N 487 1.35 HCN N-N H4 0 HC ) N S HC N-N 5.8 1-14 4500 1.89 H3C
H
3 C- N S -< 5.9* 1-14 N-N 487 1.16 HC N S N-N f 02 5.9b 1-14 NO 445 DCM:MeOH (- N 9:1 NJ H S 5.10 1-14 N N-N 432 1.26 _______________CH 3 Wo 2006/040281 106 PCT/EP2005/055021 Starting Mass HPLC Rt [min] # compound Structure [M1]. or m.p. or TLC:Rf
H
3 C N H s 5.11 1-14 N-N 444 1.31 H 3c ) N N-N 5.12 1-14 N-N 474 1.52 (N0/ 0 H,Clk S N-N 5.14 1-14 N 515 2.78 'CH _ < N_ _ _ _ _ _ _ _ _ HC N HC N N-N 5.15 1-14 N 489 1.26 HC 5.6N-5H 56 Rf = 0.56 5.1* 1N N-N MeOH
N
5.16b 1-15 N-N 522 1.13
N-<
WO 2006/040281 107 PCT/EP2005/055021 Starting Mass HPLC Rt [min] # compound Structure [M+1]+ or m.p. or TLC:Rf 0 HC N N .... P N H S .- Rf = 0.41 5.17 I-15 H \ / 458 DCM:MeOH 8:2 CN 0 HC- N N-/ N H S 5.18 1-15 N 472 1.36 __CN N-N N 0 AN - _ / N-N Rf = 0.06 5.19 1-14 503 DCM:MeOH 9:1 0 N~_ N-N Rf = 0.08 5.20 1-14 N 501 DCM:MeOH 9:1 0 N-N 5.21 1-14 ; ' 531 1.17 NN N-N 5.22 1-14 555 1.28
Q
WO 2006/040281 108 PCT/EP2005/055021 Starting Mass HPLC Rt [min] # compound Structure [M+1] or m.p. or TLC:Rf YN 5.23* 1-14 N-N 472 3.35 N N-N 5.23b 1-14 430 3*12 N 43 3.121 *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 pl of N-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 II-11 (0.5 mmol) and 0.1 ml of benzylamine (1 mmol) in 5 ml of methanol is stirred at 600C 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 Mass HPLC:Rt [min] # compound Method Structure [M+1] or m.p. or TLC:Rf 0 HC N-N 6.1 11-10 I 547 1.27 H -Cl , N N 0 HC N-N C1 6.2 11-11 K C1 542 1.55 HN N 0 N NN HC N S N, H - CI 6.3 II-11 K 603 0.30 6 N N--N 6.4 11-12 I 541 m.p.: 166 0 C N N 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 mg of 1-24 (0.2 mmol) in 3 ml of acetone. 4.4 mg of palladium(II) acetate (19 pmol), 4 pl of diazabicyclooctane (39 pmol) and 80 mg of potassium carbonate are then added and the reaction vessel is heated at 1000C for 20 min in a microwave; after that, it is heated a further 2 x for in each case 40 min at 1200C and 700C. After the solvent has been removed, the reaction mixture is purified chromatographically. Synthesis method M - crosscoupling with alkynes 56 mg of N,N-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 pnol) and 24 mg of triphenylphosphinepalladium(II) chloride (34 pmol) in 25 ml of degassed THF and the reaction mixture is stirred at 801C for 15 h. 100 pl of alkyne, as well as 10 mg of CuI and 20 mg of Pd catalyst, are added and the mixture is left to stir at 550C for a further 24 h. The mixture is then made alkaline with an aqueous solution of NH 3 , 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 pmol) and 111 mg of sodium tert-butoxide (1 mmol) in 4 ml of degassed DMF and the mixture is stirred at 90 0 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 Structure Mass HPLC Rt compound [M+1]* (min] N xH -N 0 N N S NH 7.1 1-24 CH, 506 1.83 H-NMR DMSO-d6, d [ppm]: 8.95 (s, 1H), 8.61-8.58 (m, 1H), 8.14-8.11 (m, 1H), 7.67-7.65 (m, 2H), 7.63-7.58 (m, 3H), 7.56-7.48 (m, 2H), 7.45-7.41 (m, 1H), 3.17-3.12 (m, 2H), 3.06-3.01 (m, 2H), 2.26 (s, 3H), 2.10 (s, 3H). N "NH N N 7.2 I-24 557 3.63 NH CH, N N\ / H 0 N S' \N N 'CH N0 7.3 1-24 557 3.24 NS Oz NH
CH
3 N HaC 0 N HNa N 7.4 1-24 "a 521 1.66 MyS NH ______CH, N N N II ' 7.5 1-24 482 3.57 N S O NH
CH,
WO 2006/040281 112 PCT/EP2005/055021 Starting Structure Mass HPLC Rt compound [M+1]* [min] N NH \N 7.6 1-24 503 1.89 Ny S o NH CH, 0 H 3 C / N S N-N N 7.7 1-31 C1 504 1.47 H,CN'CH,
CH
3 O=( N N N-< H S N N-N 7.8 I-31 Ci515 1.47 HN & _ Example 8 N N N S N N 6 60 mg of N-(3-hydrazinocarbonyl-1-phenyl-4,5-dihydro 1H-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 0 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 11-2. # Starting Structure [M+1]* Rt [min] compound 0 N-/I H S NH 2 N-N 9.1 1-34 O NI N 402 1.63 IH-NMR DMSO-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). 0 N NH 2 9.2 1-33 436 1.67 N-N / CI 0 N-NH/ H s , 9.3 1-32 402 1.56 N-N N-< 0 - NH? 9.4 1-35 436 1.66 N-N / CI 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. HCTll6 (human colon carcinoma cell line) cells are sown in microtiter plates and incubated overnight in culture medium at 37 0 C and 5% C0 2 . The test substances are diluted stepwise in medium and added to the cells such that the total volume is 200 pl/well. Cells to which medium, but not substance, is added serve as controls. After an incubation time of 4-6 days, 20 pl of AlamarBlue are added/well and the cells are incubated at 370C 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.
EC
5 o values are calculated using the GraphPad Prism program. All the examples cited have an EC 50 (HCT-116) of less than 5 pM. The substances of the present invention are P13 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 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 aliquoted, 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.
P 'OPER\PDB\Speci\21.A62 " 1sp doc./07/J x1 - 123A The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that 5 that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates. Throughout this specification and the claims which follow, unless the context requires otherwise, the word 10 "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. 15
Claims (15)
1.) Compounds of the general formula (1), 5 R 3 N S INN (1) RR in which R1 is selected from the group consisting of -NHRc, -NHC(O)Rc, -NHC(0)ORc, -NHC(O)NRcRc and -NHC(O)SRc; 10 R 2 is a radical which is optionally substituted by one or more R 4 and which is selected from the group consisting of C- 6 alkyl, C3-Bcycloalkyl, 3-8-membered heterocycloalkyl, C 6 -loaryl, C- 16 arylalkyl and 5-10-membered heteroaryl; 15 R 3 is a radical which is optionally substituted by one or more Re and/or Rf and is selected from the group consisting of C 6 - 1 oaryl and 5-10-membered heteroaryl; 20 R 4 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 25 group consisting of C 1 . 6 alkyl, C3-Bcycloalkyl, C 4 _ 11 cycloalkylalkyl, C 6 -loaryl, C--: 6 arylalkyl, 2-6-membered heteroalkyl, 3-8-membered heterocycloalkyl, 4-14-membered heterocycloalkylalkyl, 5-10-membered heteroaryl and 6-16 membered heteroarylalkyl; 30 each Rb is a suitable radical and in each case selected, independently of each other, from the group consisting of =0, -ORc, C 1 - 3 haloalkyloxy, -OCF 3 , =S, -SRc, =NRc, WO 2006/040281 125 PCT/EP2005/055021 =NORc, -NRcRc, halogen, -CF3, -CN, -NC, -OCN, -SCN, -NO, -NO 2 , =N 2 , -N 3 , -S(O)Rc, -S(O) 2 Rc, -S(O) 2 0Rc, -S(O)NRRc, S(O) 2 NRcRC, -OS(O)R, -OS(O) 2 Rc, -OS(O) 2 ORc, -OS(O) 2 NRcRc, -C (O) Rc, -C (O) ORc, -C (O) NRcRc, -C (0)N (R9) NRcR -C (0) N ( R9) ORc, -CN (R9) NRcRc, -OC(O)Rc, -OC (0) ORc, OC (O)NRcRc, -OCN (Rg) NRcRc, -N (Rg) C(0) Rc, -N (Rg) C (O) R -N(Rg)C(S) Rc, -N (R)S(O)2R, -Na(R)S(0)2NRcRcd -N [ S (0 ) 2] 2Rc, -N ( R9) C (0 ) ORc, -N ( Rg) C (0 ) NRcRc, and -N (Rg) CN (R)NRR 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 C 1 - 6 alkyl, C 3 - 8 cycloalkyl, C 4 - 1 1 cycloalkylalkyl, C 6 - 1 0 aryl, C 7 - 16 arylalkyl, 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 C 1 . 6 alkyl, C3- 8 cycloalkyl, C 4 1 1 cycloalkylalkyl, C 6 - 1 0 aryl, C 7 - 16 arylalkyl, 2-6-membered heteroalkyl, 3-8-membered heterocycloalkyl, 4-14-membered heterocycloalkylalkyl, 5-10-membered heteroaryl and 6-16-membered heteroarylalkyl, each R' is a suitable radical and in each case selected, independently of each other, from the group consisting of =0, -OR , C 1 - 3 haloalkyloxy, -OCF 3 , =S, -SR , =NR , =NOR , -NR Rf, halogen, -CF3, -CN, -NC, -OCN, -SCN, -NO, -NO 2 , =N 2 , -N 3 , -S(O)Rf, -S(0) 2 Rf, -S(O) 2 ORf, -S (0) NRR f, -S(O) 2 NRfR', -OS(O)Rf, -OS(0) 2 Rf, -OS(O) 2 0Rf, OS(0)2NRfRf, -C(O)Rf, -C(O)OR', -C(0)NR Rf, -CN(Rg)NR Rf, -OC (0) Rf, -OC(0)OR , -OC (0) NR R , - OCN (Rg) NR R , 126 -N (Rg) C(0) R , -N (Rg) C(S) R', -N (Rg) S(O)2R, -N(Rg) C (O)OR, -N(R9)C(0)NR Rf, and -N (R9);CN(Rl)NRR; each Rf is, independently of each other, hydrogen or a radical which is optionally substituted by one or more, identical or different, R9 and is selected from the group consisting of C 1 _ 6 alkyl, C3-Scycloalkyl, C4_ 11 cycloalkylalkyl, C 6 - 1 oaryl, C s 1 6arylalkyl, 2-6 membered heteroalkyl, 3-8-membered heterocycloalkyl, 4-14-membered heterocycloalkylalkyl, 5-10-membered heteroaryl and 6-16-membered heteroarylalkyl, each R" is, independently of each other, hydrogen, C- 6 alkyl, C3-scycloalkyl, C 4 _ 1 cycloalkylalkyl, C 6 -ioaryl, C 7 - 16 arylalkyl, 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 racemates, their enantiomers, their diastereomers and their mixtures, as well as, where appropriate, their pharmacologically harmless acid addition salrs. 2.) Compounds according to Claim 1, wherein R 3 is a radical selected from the group consisting of phenyl, furyl, pyridyl, pyrimidinyl and pyrazinyl, optionally substituted by one or more R 4 . 3.) Compounds according to Claim 2, wherein R 3 is pyridyl. 4.) Compounds according to any one of Claims 1 to 3, wherein R 1 is -NHC(O)Rc. 5.) Compounds according to Claim 4, wherein R1 is -NHC (O) CH 3 .
6.) Compounds of the formula (A) 127 0 X N N / (A) H S 'R 0 0 wherein X is -CH 3 , -OR 4 or -SR 4 and Y is phenyl, 5-10-membered heteroaryl or the group -C(0)0, and RY is hydrogen, -NO 2 or C 1 - 6 alkyl and R 4 is defined as in claim 1..
7.) Compounds according to Claim 6, wherein R 4 is -Ci- 6 alkyl.
8.) Compounds of the general formula (A) according to Claim 6 or 7 for use as synthesis intermediates.
9.) Compounds, or their pharmaceutically active salts, according to any one of Claims 1 to 5 as pharmaceuticals.
10.) Compounds, or their pharmaceutically active salts, according to any one of Claims 1 to 5 for producing a pharmaceutical having an antiproliferative effect.
11.) Pharmaceutical preparations which comprise, as active compound, one or more compounds of the general formula (1) according to any one of Claims 1 to 5, or their physiologically tolerated salts, where appropriate in combination with customary auxiliary substances and/or carrier substances.
12.) Use of compounds of the general formula (1) according to any one of Claims 1 to 5 for producing a pharmaceutical for treating and/or preventing cancer.
13.) Pharmaceutical preparation which comprises a 128 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 their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, as well as, where appropriate, their pharmacologically harmless acid addition salts.
14.) Method of treating and/or preventing cancer comprising administering to a patient in need thereof compounds of general formula (I) according to any one of claims 1 to 5.
15.) A compound as defined in any one of claims 1 to 10 substantially as hereinbefore described and with reference to the examples.
16.) Pharmaceutical preparation as defined in claim 11 or claim 13 substantially as hereinbefore described and with reference to the examples.
17.) Use as defined in claim 12 substantially as hereinbefore described.
18.) Method as defined in claim 14 substantially as hereinbefore described.
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| DE102004048877A DE102004048877A1 (en) | 2004-10-07 | 2004-10-07 | New tricyclic thiazole derivatives useful as PI3 kinase inhibitors, for treating e.g. inflammatory and allergic airway and skin diseases, autoimmune and kidney disease |
| DE102004048877.0 | 2004-10-07 | ||
| DE102005005813A DE102005005813A1 (en) | 2005-02-09 | 2005-02-09 | New thiazolo-indazole derivatives useful as PI3 kinase inhibitors, for treating e.g. cancer and other proliferative diseases, viral infections and inflammatory, autoimmune, skin and bone diseases |
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| CN112876503B (en) * | 2021-03-18 | 2022-04-29 | 中国科学院兰州化学物理研究所 | Borate compound for cancer boron neutron capture therapeutic medicine and preparation thereof |
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| KR100423899B1 (en) * | 2000-05-10 | 2004-03-24 | 주식회사 엘지생명과학 | Indazoles substituted with 1,1-dioxoisothiazolidine useful as inhibitors of cell proliferation |
| PE20030968A1 (en) * | 2002-02-28 | 2004-01-12 | Novartis Ag | DERIVATIVES OF 5-PHENYLTIAZOLE AS KINASE INHIBITORS |
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| US20020151544A1 (en) * | 2000-04-27 | 2002-10-17 | Masahiko Hayakawa | Fused heteroaryl derivatives |
| WO2003035618A2 (en) * | 2001-10-24 | 2003-05-01 | Iconix Pharmaceuticals, Inc. | Modulators of phosphoinositide 3-kinase |
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| CN101035795A (en) | 2007-09-12 |
| BRPI0518169A (en) | 2008-11-04 |
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| UY29149A1 (en) | 2006-05-31 |
| KR20070113188A (en) | 2007-11-28 |
| ES2304022T3 (en) | 2008-09-01 |
| JP2008515854A (en) | 2008-05-15 |
| ATE392425T1 (en) | 2008-05-15 |
| EP1799690A1 (en) | 2007-06-27 |
| WO2006040281A1 (en) | 2006-04-20 |
| EP1799690B1 (en) | 2008-04-16 |
| CN101035795B (en) | 2012-03-21 |
| PE20060583A1 (en) | 2006-08-17 |
| DE502005003777D1 (en) | 2008-05-29 |
| PT1799690E (en) | 2008-06-16 |
| TW200630374A (en) | 2006-09-01 |
| CA2579288A1 (en) | 2006-04-20 |
| SI1799690T1 (en) | 2008-08-31 |
| MX2007003802A (en) | 2007-04-23 |
| IL182397A (en) | 2011-11-30 |
| CY1108183T1 (en) | 2014-02-12 |
| NZ554695A (en) | 2010-12-24 |
| IL182397A0 (en) | 2007-07-24 |
| AU2005293609A1 (en) | 2006-04-20 |
| JP5090914B2 (en) | 2012-12-05 |
| DK1799690T3 (en) | 2008-06-30 |
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