DIAZABICYCLIC SUBSTITUTED IMIDAZOPYRIMIDINES AND THEIR USE FOR THE TREATMENT OF BREATHING DISORDERS

Abstract

The present invention relates to novel diazabicyclically substituted imidazo[1,2-a]pyrimidine derivatives, to methods for producing the same, to the use thereof either alone or in combinations for the treatment and/or prevention of diseases, as well as to their use for preparing medicaments for the treatment and/or prevention of diseases, especially for treatment and/or prevention of breathing disorders, including sleep-related breathing disorders such as obstructive and central sleep apnoea and snoring.

Claims

1-5. (canceled)

6. A method for treatment or prevention of respiratory disorders, sleep-related respiratory disorders, obstructive sleep apnoeas, central sleep apnoeas, snoring, cardiac arrhythmias, neurodegenerative disorders, neuroinflammatory disorders or neuroimmunological disorders, comprising administering to a human or animal in need thereof an effective amount of a compound of formula (I) ##STR00195## wherein the ring Q is a diazaheterobicyclic system of the formula ##STR00196## wherein * denotes the bond to the adjacent CHR.sup.2 group and ** the bond to the carbonyl group; A is CH or N; R.sup.1 is halogen, cyano, (C.sub.1-C.sub.4)-alkyl, cyclopropyl or cyclobutyl, wherein (C.sub.1-C.sub.4)-alkyl is optionally up to trisubstituted by fluorine, and cyclopropyl and cyclobutyl are optionally up to disubstituted by fluorine; R.sup.2 is hydrogen or methyl; and R.sup.3 is (C.sub.4-C.sub.6)-cycloalkyl wherein a ring CH.sub.2 group is optionally replaced by —O—; or R.sup.3 is a phenyl group of the formula (a), a pyridyl group of the formula (b) or (c) or an azole group of the formula (d), (e) or (f) ##STR00197## wherein *** marks the bond to the adjacent carbonyl group; and R.sup.4 is hydrogen, fluorine, chlorine, bromine or methyl; R.sup.5 is hydrogen, fluorine, chlorine, bromine, cyano, (C.sub.1-C.sub.3)-alkyl or (C.sub.1-C.sub.3)-alkoxy, wherein (C.sub.1-C.sub.3)-alkyl and (C.sub.1-C.sub.3)-alkoxy are optionally up to trisubstituted by fluorine; R.sup.6 is hydrogen, fluorine, chlorine, bromine or methyl; R.sup.7 is hydrogen, (C.sub.1-C.sub.3)-alkoxy, cyclobutyloxy, oxetan-3-yloxy, tetrahydrofuran-3-yloxy, tetrahydro-2H-pyran-4-yloxy, mono-(C.sub.1-C.sub.3)-alkylamino, di-(C.sub.1-C.sub.3)-alkylamino or (C.sub.1-C.sub.3)-alkylsulfanyl, wherein (C.sub.1-C.sub.3)-alkoxy may be up to trisubstituted by fluorine; R.sup.8 is hydrogen, fluorine, chlorine, bromine, (C.sub.1-C.sub.3)-alkyl or (C.sub.1-C.sub.3)-alkoxy, R.sup.9A and R.sup.9B are identical or different and are independently hydrogen, fluorine, chlorine, bromine, (C.sub.1-C.sub.3)-alkyl, cyclopropyl or (C.sub.1-C.sub.3)-alkoxy, wherein (C.sub.1-C.sub.3)-alkyl and (C.sub.1-C.sub.3)-alkoxy are optionally up to trisubstituted by fluorine; and Y is O or S; or R.sup.3 is an —OR.sup.10 or —NR.sup.11R.sup.12 group wherein R.sup.10 is (C.sub.1-C.sub.6)-alkyl, (C.sub.4-C.sub.6)-cycloalkyl or [(C.sub.3-C.sub.6)-cycloalkyl]methyl; R.sup.11 is hydrogen or (C.sub.1-C.sub.3)-alkyl; and R.sup.12 is (C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.6)-cycloalkyl, phenyl or benzyl, wherein (C.sub.1-C.sub.6)-alkyl is optionally up to trisubstituted by fluorine; and wherein phenyl and the phenyl group in benzyl are optionally up to trisubstituted by identical or different radicals selected from the group consisting of fluorine, chlorine, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy and (trifluoromethyl)sulfanyl; or R.sup.11 and R.sup.12 are attached to one another and, together with the nitrogen atom to which they are bonded, form a pyrrolidine, piperidine, morpholine or thiomorpholine ring, or a salt, a solvate, or a solvate of the salt thereof.

7-9. (canceled)

10. A method for treatment or prevention of respiratory disorders, sleep-related respiratory disorders, obstructive sleep apnoeas, central sleep apnoeas, snoring, cardiac arrhythmias, neurodegenerative disorders, neuroinflammatory disorders or neuroimmunological disorders, comprising administering to a human or animal in need thereof an effective amount of a pharmaceutical composition comprising a compound of formula (I), ##STR00198## wherein the ring Q is a diazaheterobicyclic system of the formula ##STR00199## wherein * denotes the bond to the adjacent CHR.sup.2 group and ** the bond to the carbonyl group; A is CH or N; R.sup.1 is halogen, cyano, (C.sub.1-C.sub.4)-alkyl, cyclopropyl or cyclobutyl, wherein (C.sub.1-C.sub.4)-alkyl is optionally up to trisubstituted by fluorine, and cyclopropyl and cyclobutyl are optionally up to disubstituted by fluorine; R.sup.2 is hydrogen or methyl; and R.sup.3 is (C.sub.4-C.sub.6)-cycloalkyl wherein a ring CH.sub.2 group is optionally replaced by —O—; or R.sup.3 is a phenyl group of the formula (a), a pyridyl group of the formula (b) or (c) or an azole group of the formula (d), (e) or (f) ##STR00200## wherein *** marks the bond to the adjacent carbonyl group; and R.sup.4 is hydrogen, fluorine, chlorine, bromine or methyl; R.sup.5 is hydrogen, fluorine, chlorine, bromine, cyano, (C.sub.1-C.sub.3)-alkyl or (C.sub.1-C.sub.3)-alkoxy, wherein (C.sub.1-C.sub.3)-alkyl and (C.sub.1-C.sub.3)-alkoxy are optionally up to trisubstituted by fluorine; R.sup.6 is hydrogen, fluorine, chlorine, bromine or methyl; R.sup.7 is hydrogen, (C.sub.1-C.sub.3)-alkoxy, cyclobutyloxy, oxetan-3-yloxy, tetrahydrofuran-3-yloxy, tetrahydro-2H-pyran-4-yloxy, mono-(C.sub.1-C.sub.3)-alkylamino, di-(C.sub.1-C.sub.3)-alkylamino or (C.sub.1-C.sub.3)-alkylsulfanyl, wherein (C.sub.1-C.sub.3)-alkoxy may be up to trisubstituted by fluorine; R.sup.8 is hydrogen, fluorine, chlorine, bromine, (C.sub.1-C.sub.3)-alkyl or (C.sub.1-C.sub.3)-alkoxy, R.sup.9A and R.sup.9B are identical or different and are independently hydrogen, fluorine, chlorine, bromine, (C.sub.1-C.sub.3)-alkyl, cyclopropyl or (C.sub.1-C.sub.3)-alkoxy, wherein (C.sub.1-C.sub.3)-alkyl and (C.sub.1-C.sub.3)-alkoxy are optionally up to trisubstituted by fluorine; and Y is O or S; or R.sup.3 is an —OR.sup.10 or —NR.sup.11R.sup.12 group wherein R.sup.10 is (C.sub.1-C.sub.6)-alkyl, (C.sub.4-C.sub.6)-cycloalkyl or [(C.sub.3-C.sub.6)-cycloalkyl]methyl; R.sup.11 is hydrogen or (C.sub.1-C.sub.3)-alkyl; and R.sup.12 is (C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.6)-cycloalkyl, phenyl or benzyl, wherein (C.sub.1-C.sub.6)-alkyl is optionally up to trisubstituted by fluorine; and wherein phenyl and the phenyl group in benzyl are optionally up to trisubstituted by identical or different radicals selected from the group consisting of fluorine, chlorine, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy and (trifluoromethyl)sulfanyl; or R.sup.11 and R.sup.12 are attached to one another and, together with the nitrogen atom to which they are bonded, form a pyrrolidine, piperidine, morpholine or thiomorpholine ring, or a salt, a solvate, or a solvate of the salt thereof, in combination with one or more inert, nontoxic, pharmaceutically suitable excipients.

11. A method for treatment or prevention of respiratory disorders, sleep-related respiratory disorders, obstructive sleep apnoeas, central sleep apnoeas, snoring, cardiac arrhythmias, neurodegenerative disorders, neuroinflammatory disorders or neuroimmunological disorders, comprising administering to a human or animal in need thereof an effective amount of at least one compound of formula (I) ##STR00201## wherein the ring Q is a diazaheterobicyclic system of the formula ##STR00202## wherein * denotes the bond to the adjacent CHR.sup.2 group and ** the bond to the carbonyl group; A is CH or N; R.sup.1 is halogen, cyano, (C.sub.1-C.sub.4)-alkyl, cyclopropyl or cyclobutyl, wherein (C.sub.1-C.sub.4)-alkyl is optionally up to trisubstituted by fluorine, and cyclopropyl and cyclobutyl are optionally up to disubstituted by fluorine; R.sup.2 is hydrogen or methyl; and R.sup.3 is (C.sub.4-C.sub.6)-cycloalkyl wherein a ring CH.sub.2 group is optionally replaced by —O—; or R.sup.3 is a phenyl group of the formula (a), a pyridyl group of the formula (b) or (c) or an azole group of the formula (d), (e) or (f) ##STR00203## wherein *** marks the bond to the adjacent carbonyl group; and R.sup.4 is hydrogen, fluorine, chlorine, bromine or methyl; R.sup.5 is hydrogen, fluorine, chlorine, bromine, cyano, (C.sub.1-C.sub.3)-alkyl or (C.sub.1-C.sub.3)-alkoxy, wherein (C.sub.1-C.sub.3)-alkyl and (C.sub.1-C.sub.3)-alkoxy are optionally up to trisubstituted by fluorine; R.sup.6 is hydrogen, fluorine, chlorine, bromine or methyl; R.sup.7 is hydrogen, (C.sub.1-C.sub.3)-alkoxy, cyclobutyloxy, oxetan-3-yloxy, tetrahydrofuran-3-yloxy, tetrahydro-2H-pyran-4-yloxy, mono-(C.sub.1-C.sub.3)-alkylamino, di-(C.sub.1-C.sub.3)-alkylamino or (C.sub.1-C.sub.3)-alkylsulfanyl, wherein (C.sub.1-C.sub.3)-alkoxy may be up to trisubstituted by fluorine; R.sup.8 is hydrogen, fluorine, chlorine, bromine, (C.sub.1-C.sub.3)-alkyl or (C.sub.1-C.sub.3)-alkoxy, R.sup.9A and R.sup.9B are identical or different and are independently hydrogen, fluorine, chlorine, bromine, (C.sub.1-C.sub.3)-alkyl, cyclopropyl or (C.sub.1-C.sub.3)-alkoxy, wherein (C.sub.1-C.sub.3)-alkyl and (C.sub.1-C.sub.3)-alkoxy are optionally up to trisubstituted by fluorine; and Y is O or S; or R.sup.3 is an —OR.sup.10 or —NR.sup.11R.sup.12 group wherein R.sup.10 is (C.sub.1-C.sub.6)-alkyl, (C.sub.4-C.sub.6)-cycloalkyl or [(C.sub.3-C.sub.6)-cycloalkyl]methyl; R.sup.11 is hydrogen or (C.sub.1-C.sub.3)-alkyl; and R.sup.12 is (C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.6)-cycloalkyl, phenyl or benzyl, wherein (C.sub.1-C.sub.6)-alkyl is optionally up to trisubstituted by fluorine; and wherein phenyl and the phenyl group in benzyl are optionally up to trisubstituted by identical or different radicals selected from the group consisting of fluorine, chlorine, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy and (trifluoromethyl)sulfanyl; or R.sup.11 and R.sup.12 are attached to one another and, together with the nitrogen atom to which they are bonded, form a pyrrolidine, piperidine, morpholine or thiomorpholine ring, or a salt, a solvate, or a solvate of the salt thereof.

12. A pharmaceutical combination comprising a compound of formula (I), ##STR00204## wherein the ring Q is a diazaheterobicyclic system of the formula ##STR00205## wherein * denotes the bond to the adjacent CHR.sup.2 group and ** the bond to the carbonyl group; A is CH or N; R.sup.1 is halogen, cyano, (C.sub.1-C.sub.4)-alkyl, cyclopropyl or cyclobutyl, wherein (C.sub.1-C.sub.4)-alkyl is optionally up to trisubstituted by fluorine, and cyclopropyl and cyclobutyl are optionally up to disubstituted by fluorine; R.sup.2 is hydrogen or methyl; and R.sup.3 is (C.sub.4-C.sub.6)-cycloalkyl wherein a ring CH.sub.2 group is optionally replaced by —O—; or R.sup.3 is a phenyl group of the formula (a), a pyridyl group of the formula (b) or (c) or an azole group of the formula (d), (e) or (f) ##STR00206## wherein *** marks the bond to the adjacent carbonyl group; and R.sup.4 is hydrogen, fluorine, chlorine, bromine or methyl; R.sup.5 is hydrogen, fluorine, chlorine, bromine, cyano, (C.sub.1-C.sub.3)-alkyl or (C.sub.1-C.sub.3)-alkoxy, wherein (C.sub.1-C.sub.3)-alkyl and (C.sub.1-C.sub.3)-alkoxy are optionally up to trisubstituted by fluorine; R.sup.6 is hydrogen, fluorine, chlorine, bromine or methyl; R.sup.7 is hydrogen, (C.sub.1-C.sub.3)-alkoxy, cyclobutyloxy, oxetan-3-yloxy, tetrahydrofuran-3-yloxy, tetrahydro-2H-pyran-4-yloxy, mono-(C.sub.1-C.sub.3)-alkylamino, di-(C.sub.1-C.sub.3)-alkylamino or (C.sub.1-C.sub.3)-alkylsulfanyl, wherein (C.sub.1-C.sub.3)-alkoxy may be up to trisubstituted by fluorine; R.sup.8 is hydrogen, fluorine, chlorine, bromine, (C.sub.1-C.sub.3)-alkyl or (C.sub.1-C.sub.3)-alkoxy, R.sup.9A and R.sup.9B are identical or different and are independently hydrogen, fluorine, chlorine, bromine, (C.sub.1-C.sub.3)-alkyl, cyclopropyl or (C.sub.1-C.sub.3)-alkoxy, wherein (C.sub.1-C.sub.3)-alkyl and (C.sub.1-C.sub.3)-alkoxy are optionally up to trisubstituted by fluorine; and Y is O or S; or R.sup.3 is an —OR.sup.10 or —NR.sup.11R.sup.12 group wherein R.sup.10 is (C.sub.1-C.sub.6)-alkyl, (C.sub.4-C.sub.6)-cycloalkyl or [(C.sub.3-C.sub.6)-cycloalkyl]methyl; R.sup.11 is hydrogen or (C.sub.1-C.sub.3)-alkyl; and R.sup.12 is (C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.6)-cycloalkyl, phenyl or benzyl, wherein (C.sub.1-C.sub.6)-alkyl is optionally up to trisubstituted by fluorine; and wherein phenyl and the phenyl group in benzyl are optionally up to trisubstituted by identical or different radicals selected from the group consisting of fluorine, chlorine, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy and (trifluoromethyl)sulfanyl; or R.sup.11 and R.sup.12 are attached to one another and, together with the nitrogen atom to which they are bonded, form a pyrrolidine, piperidine, morpholine or thiomorpholine ring, or a salt, a solvate, or a solvate of the salt thereof, in combination with one or more further active compounds selected from the group consisting of respiratory stimulants, psychostimulating compounds, serotonin reuptake inhibitors, noradrenergic, serotonergic and tricyclic antidepressants, sGC stimulators, mineralocorticoid receptor antagonists, antiinflammatory drugs, immunomodulators, immunosuppressives and cytotoxic drugs.

13. A method for treatment or prevention of respiratory disorders, sleep-related respiratory disorders, obstructive sleep apnoeas, central sleep apnoeas, snoring, cardiac arrhythmias, neurodegenerative disorders, neuroinflammatory disorders or neuroimmunological disorders, comprising administering to a human or animal in need thereof an effective amount of a pharmaceutical combination according to claim 12.

14. The method according to claim 6, wherein the ring Q is a diazaheterobicyclic system of the formula ##STR00207## in which * denotes the bond to the adjacent CHR.sup.2 group and ** the bond to the carbonyl group; A is CH; R.sup.1 is chlorine, bromine, isopropyl or cyclopropyl; R.sup.2 is hydrogen; and R.sup.3 is cyclopentyl or cyclohexyl; or R.sup.3 is a phenyl group of the formula (a), a pyridyl group of the formula (b) or an azole group of the formula (d), (e) or (f) ##STR00208## wherein *** marks the bond to the adjacent carbonyl group; and R.sup.4 is hydrogen, fluorine or chlorine; R.sup.5 is fluorine, chlorine, methyl, isopropyl, methoxy or ethoxy; R.sup.6 is hydrogen, fluorine, chlorine, bromine or methyl; R.sup.7 is methoxy, difluoromethoxy, trifluoromethoxy, isopropoxy, cyclobutyloxy or methylsulfanyl; R.sup.9A and R.sup.9B are identical or different and are independently hydrogen, methyl, trifluoromethyl, ethyl, isopropyl or cyclopropyl; and Y is O or S, or a salt, a solvate, or a solvate of the salt thereof.

15. The method of claim 6, wherein the compound is tert-Butyl 7-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carboxylate of the formula ##STR00209##

16. The method of claim 6, wherein the compound is (5-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo [2.2.2]oct-2-yl)(3-fluoro-6-methoxypyridin-2-yl)methanone of the formula ##STR00210##

17. The method of claim 6, wherein the compound is (3-Fluoro-6-methoxypyridin-2-yl)(3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)methanone of the formula ##STR00211##

18. The method of claim 6, wherein the compound is ((3-Chloro-6-methoxypyridin-2-yl)(3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)methanone of the formula ##STR00212##

19. The method of claim 6, wherein the compound is (3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)[6-(methylamino)pyridin-2-yl]methanone of the formula ##STR00213##

20. The method of claim 6, wherein the compound is (3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)(3-methoxyphenyl)methanone of the formula ##STR00214##

21. The method of claim 6, wherein the compound is (5-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)(cyclopentyl)methanone of the formula ##STR00215##

22. The method of claim 6, wherein the method is a method for treatment of sleep-related respirator disorders.

23. The method of claim 6, wherein the method is a method for treatment of obstructive sleep apnoeas.

24. The method of claim 6, wherein the method is a method for treatment of central sleep apnoeas.

25. The method of claim 10, wherein the method is a method for treatment of sleep-related respirator disorders.

26. The method of claim 10, wherein the method is a method for treatment of obstructive sleep apnoeas.

27. The method of claim 10, wherein the method is a method for treatment of central sleep apnoeas.

Description

A. EXAMPLES

Abbreviations and Acronyms

[0389] abs. absolute [0390] Ac acetyl [0391] aq. aqueous, aqueous solution [0392] Boc tert-butoxycarbonyl [0393] br. broad (in NMR signal) [0394] Ex. Example [0395] Bu butyl [0396] c concentration [0397] cat. catalytic [0398] CI chemical ionization (in MS) [0399] d doublet (in NMR) [0400] d day(s) [0401] DCI direct chemical ionization (in MS) [0402] dd doublet of doublets (in NMR) [0403] DMF N,N-dimethylformamide [0404] DMSO dimethyl sulfoxide [0405] dq doublet of quartets (in NMR) [0406] dt doublet of triplets (in NMR) [0407] EI electron impact ionization (in MS) [0408] eq. equivalent(s) [0409] ESI electrospray ionization (in MS) [0410] Et ethyl [0411] h hour(s) [0412] HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate [0413] HOBt 1-hydroxy-1H-benzotriazole hydrate [0414] HPLC high-pressure, high-performance liquid chromatography [0415] iPr isopropyl [0416] conc. concentrated (in the case of a solution) [0417] LC liquid chromatography [0418] LC-MS liquid chromatography-coupled mass spectrometry [0419] lit. literature (reference) [0420] m multiplet (in NMR) [0421] Me methyl [0422] min minute(s) [0423] MS mass spectrometry [0424] NMR nuclear magnetic resonance spectrometry [0425] Ph phenyl [0426] Pr propyl [0427] q quartet (in NMR) [0428] quant. quantitative (in chemical yield) [0429] RP reverse phase (in HPLC) [0430] RT room temperature [0431] R.sub.t retention time (in HPLC, LC-MS) [0432] s singlet (in NMR) [0433] SFC supercritical liquid chromatography [0434] t triplet (in NMR) [0435] tBu tert-butyl [0436] TFA trifluoroacetic acid [0437] THF tetrahydrofuran [0438] UV ultraviolet spectrometry [0439] v/v volume to volume ratio (of a solution) [0440] tog. together

LC-MS and HPLC Methods

[0441] Method 1 (LC-MS):

[0442] Instrument: Waters Acquity SQD UPLC System; column: Waters Acquity UPLC HSS T31.8 μm, 50 mm×1 mm; mobile phase A: 1 l of water+0.25 ml of 99% strength formic acid, mobile phase B: 1 l of acetonitrile+0.25 ml of 99% strength formic acid; gradient: 0.0 min 90% A.fwdarw.1.2 min 5% A.fwdarw.2.0 min 5% A; temperature: 50° C.; flow rate: 0.40 ml/min; UV detection: 208-400 nm.

[0443] Method 2 (LC-MS):

[0444] MS instrument: Thermo Scientific FT-MS; instrument type UHPLC: Thermo Scientific UltiMate 3000; column: Waters HSS T3 C18 1.8 μm, 75 mm×2.1 mm; mobile phase A: 1 l of water+0.01% formic acid, mobile phase B: 1 l of acetonitrile+0.01% formic acid; gradient: 0.0 min 10% B.fwdarw.2.5 min 95% B.fwdarw.3.5 min 95% B; temperature: 50° C.; flow rate: 0.90 ml/min; UV detection: 210 nm/optimum integration path 210-300 nm.

[0445] Method 3 (LC-MS):

[0446] MS instrument: Waters Micromass QM; HPLC instrument: Agilent 1100 series; column: Agilent ZORBAX Extend-C18 3.5 μm, 50 mm×3.0 mm; mobile phase A: 1 l of water+0.01 mol of ammonium carbonate, mobile phase B: 1 l of acetonitrile; gradient: 0.0 min 98% A.fwdarw.0.2 min 98% A.fwdarw.3.0 min 5% A.fwdarw.4.5 min 5% A; temperature: 40° C.; flow rate: 1.75 ml/min; UV detection: 210 nm.

[0447] Method 4 (LC-MS):

[0448] MS instrument: Waters Micromass Quattro Micro; HPLC instrument: Waters UPLC Acquity; column: Waters BEH C18 1.7 μm, 50 mm×2.1 mm; mobile phase A: 1 l of water+0.01 mol of ammonium formate, mobile phase B: 1 l of acetonitrile; gradient: 0.0 min 95% A.fwdarw.0.1 min 95% A.fwdarw.2.0 min 15% A.fwdarw.2.5 min 15% A.fwdarw.2.51 min 10% A.fwdarw.3.0 min 10% A; temperature: 40° C.; flow rate: 0.5 ml/min; UV detection: 210 nm.

[0449] Method 5 (LC-MS):

[0450] Instrument: Agilent MS Quad 6150 with HPLC Agilent 1290; column: Waters Acquity UPLC HSS T3 1.8 μm, 50 mm×2.1 mm; mobile phase A: 1 l of water+0.25 ml of 99% strength formic acid, mobile phase B: 1 l of acetonitrile+0.25 ml of 99% strength formic acid; gradient: 0.0 min 90% A.fwdarw.0.3 min 90% A.fwdarw.1.7 min 5% A.fwdarw.3.0 min 5% A; flow rate: 1.20 ml/min; temperature: 50° C.; UV detection: 205-305 nm.

[0451] Method 6 (LC-MS):

[0452] MS instrument: Waters Single Quad MS System; HPLC instrument: Waters UPLC Acquity; column: Waters BEH C18 1.7 μm, 50 mm×2.1 mm; mobile phase A: 1 l of water+1.0 ml of 25% strength ammonia, mobile phase B: 1 l of acetonitrile; gradient: 0.0 min 92% A.fwdarw.0.1 min 92% A.fwdarw.1.8 min 5% A.fwdarw.3.5 min 5% A; temperature: 50° C.; flow rate: 0.45 ml/min; UV detection: 210 nm (208-400 nm).

[0453] Method 7 (LC-MS):

[0454] MS instrument: Waters SQD; HPLC instrument: Waters UPLC; column: Zorbax SB-Aq (Agilent), 50 mm×2.1 mm, 1.8 μm; mobile phase A: water+0.025% formic acid, mobile phase B: acetonitrile+0.025% formic acid; gradient: 0.0 min 98% A.fwdarw.0.9 min 25% A.fwdarw.1.0 min 5% A.fwdarw.1.4 min 5% A.fwdarw.1.41 min 98% A.fwdarw.1.5 min 98% A; temperature: 40° C.; flow rate: 0.60 ml/min; UV detection: DAD, 210 nm.

[0455] Method 8 (Preparative HPLC):

[0456] Instrument: Abimed Gilson 305; column: Reprosil C18 10 μm, 250 mm×30 mm; mobile phase A: water, mobile phase B: acetonitrile; gradient: 0-3 min 10% B, 3-27 min 10% B.fwdarw.95% B, 27-34.5 min 95% B, 34.5-35.5 min 95% B.fwdarw.10% B, 35.5-36.5 min 10% B; flow rate: 50 ml/min; room temperature; UV detection: 210 nm.

[0457] Method 9 (Preparative HPLC):

[0458] Instrument: Waters Prep LC/MS System; column: XBridge C18 5 μm, 100 mm×30 mm; mobile phase A: water, mobile phase B: acetonitrile; gradient profile: 0-2 min 10% B, 2-2.2 min.fwdarw.30% B, 2.2-7 min.fwdarw.70% B, 7-7.5 min.fwdarw.92% B, 7.5-9 min 92% B; flow rate: 65 ml/min+5 ml 2% ammonia in water; room temperature; UV detection: 200-400 nm; at-column injection (complete injection).

[0459] Further Details:

[0460] The percentages in the example and test descriptions which follow are, unless indicated otherwise, percentages by weight; parts are parts by weight. Solvent ratios, dilution ratios and concentration data for liquid/liquid solutions are based in each case on volume.

[0461] Purity figures are generally based on corresponding peak integrations in the LC/MS chromatogram, but may additionally also have been determined with the aid of the .sup.1H NMR spectrum. If no purity is stated, the purity is generally >95% according to automated peak integration in the LC/MS chromatogram, or the purity has not been determined explicitly.

[0462] Stated yields in % of theory are generally corrected for purity if a purity of <100% is indicated. In solvent-containing or contaminated batches, the formal yield may be “>100%”; in these cases the yield is not corrected for solvent or purity.

[0463] In cases where the reaction products were obtained by trituration, stirring or recrystallization, it was frequently possible to isolate further amounts of product from the respective mother liquor by chromatography. However, a description of this chromatography is dispensed with hereinbelow unless a large part of the total yield could only be isolated in this step.

[0464] Melting points and melting ranges, if stated, are uncorrected.

[0465] The descriptions of the coupling patterns of .sup.1H NMR signals that follow have in some cases been taken directly from the suggestions of the ACD SpecManager (ACD/Labs Release 12.00, Product version 12.5) and have not necessarily been strictly scrutinized. In some cases, the suggestions of the SpecManager were adjusted manually. Manually adjusted or assigned descriptions are generally based on the optical appearance of the signals in question and do not necessarily correspond to a strict, physically correct interpretation. In general, the stated chemical shift refers to the centre of the signal in question. In the case of broad multiplets, an interval is given. Signals obscured by solvent or water were either tentatively assigned or have not been listed.

[0466] The .sup.1H NMR data of synthesis intermediates and working examples can also be stated in the form of .sup.1H NMR peak lists. Here, for each signal peak, first the δ value in ppm and then the signal intensity in round brackets are listed. The δ value/signal intensity number pairs of different signal peaks are listed separated by commas; accordingly, the peak list for a compound has the form: δ.sub.1 (intensity.sub.1), δ.sub.2 (intensity.sub.2), . . . , δ.sub.i (intensity.sub.i), . . . , δ.sub.n (intensity.sub.n).

[0467] The intensity of sharp signals correlates with the height of the signals (in cm) in a printed example of an NMR spectrum and shows the true ratios of the signal intensities in comparison with other signals. In the case of broad signals, several peaks or the middle of the signal and their relative intensity may be given in comparison to the most intense signal in the spectrum. The lists of the .sup.1H NMR peaks are similar to the conventional .sup.1H NMR printouts and thus usually contain all peaks listed in a conventional NMR interpretation. In addition, like classic .sup.1H NMR printouts, they may comprise solvent signals, signals of stereoisomers of the target compound in question, peaks of impurities, .sup.13C satellite peaks and/or rotation side bands. Peaks of stereoisomers of the target compound and/or peaks of impurities usually have a lower intensity on average than the peaks of the target compound (for example with a purity of >90%). Such stereoisomers and/or impurities may be typical of the particular preparation process. Their peaks can thus help in identifying reproduction of the preparation process with reference to “by-product fingerprints”. An expert calculating the peaks of a target compound by known methods (MestreC, ACD simulation, or using empirically determined expected values) can, if required, isolate the peaks of the target compound, optionally using additional intensity filters. This isolation would be similar to the peak picking in question in conventional .sup.1H NMR interpretation.

[0468] A detailed description of the presentation of NMR data in the form of peak lists can be found in the publication “Citation of NMR Peaklist Data within Patent Applications” (see http://www.researchdisclosure.com/searching-disclosures, Research Disclosure Database Number 605005, 2014, 1 Aug. 2014). In the peak picking routine described in the stated Research Disclosure, the parameter “MinimumHeight” can be set between 1% and 4%. However, depending on the type of chemical structure and/or on the concentration of the compound to be analysed, it may also be advisable to set the parameter “MinimumHeight” to values of <1%.

[0469] All reactants or reagents whose preparation is not described explicitly hereinafter were purchased commercially from generally accessible sources. For all other reactants or reagents whose preparation is likewise not described hereinafter and which were not commercially obtainable or were obtained from sources which are not generally accessible, a reference is given to the published literature in which their preparation is described.

Starting Compounds and Intermediates

Example 1A

2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidine

[0470] ##STR00039##

[0471] Sodium bicarbonate (10.8 g, 128 mmol) was added to a solution of 2-bromo-1-(4-chlorophenyl)ethanone (20.0 g, 85.7 mmol) and pyrimidin-2-amine (8.96 g, 94.2 mmol) in 200 ml of ethanol, and the mixture was stirred at 80° C. for 5 hours. The batch was then cooled to 0° C. (ice bath). The resulting precipitate was filtered off and washed twice with an ethanol/water mixture (1:1). The solid was then dried under reduced pressure at 40° C. overnight. This gave 15.9 g (69.23 mmol, 80.8% of theory) of the target product.

[0472] LC-MS (Method 2): R.sub.t=1.25 min; m/z=230 (M+H).sup.+.

[0473] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, δ/ppm): 7.07 (dd, 1H), 7.53 (d, 2H), 8.03 (d, 2H), 8.41 (s, 1H), 8.54 (dd, 1H), 8.97 (dd, 1H).

Example 2A

2-(4-Isopropylphenyl)imidazo[1,2-a]pyrimidine

[0474] ##STR00040##

[0475] Sodium bicarbonate (0.52 g, 6.22 mmol) was added to a solution of 2-bromo-1-(4-isopropylphenyl)ethanone (1.0 g, 4.15 mmol) and pyrimidin-2-amine (0.43 g, 4.6 mmol) in 50 ml of ethanol, and the mixture was stirred at 80° C. for 5 hours. The mixture was then concentrated to dryness. The residue was stirred with diethyl ether and the solid that remained was filtered off and dried at 40° C. under reduced pressure overnight. This gave 1.15 g of the crude target product, which was used in subsequent reactions without further purification.

[0476] LC-MS (Method 2): R.sub.t=1.48 min; m/z=238 (M+H).sup.+.

[0477] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, δ/ppm): 1.24 (d, 6H), 2.87-3.00 (m, 1H), 7.04 (dd, 1H), 7.34 (d, 2H), 7.92 (d, 2H), 8.33 (s, 1H), 8.51 (dd, 1H), 8.95 (dd, 1H).

[0478] Analogously to Examples 1A and 2A, the following compound was prepared from the starting materials specified:

TABLE-US-00001 Example Name/Structure/Starting materials Analytical data 3A [00041] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 7.07 (dd, 1H), 7.67 (d, 2H), 7.97 (d, 2H), 8.42 (s, 1H), 8.54 (dd, 1H), 8.97 (dd, 1H). LC-MS (Method 2): R.sub.t = 1.34 min; m/z = 274/276 (M + H).sup.+.

Example 4A

2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidine-3-carbaldehyde

[0479] ##STR00042##

[0480] 300 ml of DMF were initially charged and cooled to 0° C. Phosphorus oxychloride (16 ml, 173 mmol) was then slowly added dropwise. The solution was then slowly warmed to room temperature and stirred at this temperature for another hour. 2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidine (15.9 g, 69.2 mmol) was then added a little at a time. After the addition had ended, the reaction mixture was heated to 80° C. and stirred at this temperature for 1 hour. The batch was then cooled to 0° C. (ice bath). The resulting solid was filtered off with suction, washed repeatedly with water and dried in a high-vacuum drying cabinet at 40° C. overnight. This gave 13.75 g (53.36 mmol, 77% of theory) of the target product.

[0481] LC-MS (Method 2): R.sub.t=1.44 min; m/z=258 (M+H).sup.+.

[0482] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=7.46 (dd, 1H), 7.65 (d, 2H), 8.01 (d, 2H), 8.91 (dd, 1H), 9.83 (dd, 1H), 10.07 (s, 1H).

Example 5A

2-(4-Isopropylphenyl)imidazo[1,2-a]pyrimidine-3-carbaldehyde

[0483] ##STR00043##

[0484] 50 ml of DMF were initially charged and cooled to 0° C. Phosphorus oxychloride (2.86 ml, 30.66 mmol) was then slowly added dropwise. The solution was then slowly warmed to room temperature and stirred at this temperature for another hour. 2-(4-Isopropylphenyl)imidazo[1,2-a]pyrimidine (2.91 g, 12.26 mmol) was then added a little at a time. After the addition had ended, the reaction mixture was heated to 80° C. and stirred at this temperature for 1 hour. The batch was then cooled to 0° C. (ice bath). The solid obtained was filtered off with suction and dried under reduced pressure. The resulting crude product was subsequently purified twice by column chromatography (Biotage Isolera, Biotage SNAP-KP-NH column, mobile phase cyclohexane/ethyl acetate gradient). This gave 3 g (11.3 mmol, 92% of theory) of the target compound.

[0485] LC-MS (Method 2): R.sub.t=1.75 min; m/z=266 (M+H).sup.+.

[0486] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.27 (d, 6H), 2.92-3.07 (m, 1H), 7.39-7.52 (m, 3H), 7.90 (d, 2H), 8.89 (dd, 1H), 9.83 (dd, 1H), 10.08 (s, 1H).

[0487] Analogously to Examples 4A and 5A, the following compound was prepared from the starting material specified:

TABLE-US-00002 Example Name/Structure/Starting material Analytical data 6A [00044] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 7.46 (dd, 1H), 7.79 (d, 2H), 7.94 (d, 2H), 8.91 (dd, 1H), 9.83 (dd, 1H), 10.07 (s, 1H). LC-MS (Method 1): R.sub.t = 0.78 min; m/z = 302/304 (M + H).sup.+.

Example 7A

7-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]nonane dihydrochloride

[0488] ##STR00045##

[0489] With stirring, 12 ml of a 4 M solution of hydrogen chloride in dioxane were added to tert-butyl 7-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carboxylate (1.52 g, 3.23 mmol). The mixture was stirred at room temperature overnight. The solids obtained were then filtered off with suction, washed repeatedly with diethyl ether and dried under high vacuum at 40° C. This gave 1.76 g of the target product.

[0490] LC-MS (Method 2): R.sub.t=0.71 min; m/z=370 (M+H).sup.+.

Example 8A

7-{[2-(4-Isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]nonane dihydrochloride

[0491] ##STR00046##

[0492] With stirring, 2.2 ml of a 4 M solution of hydrogen chloride in dioxane were added to tert-butyl 7-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carboxylate (420 mg, 0.88 mmol). The mixture was stirred at room temperature overnight. The solids obtained were then filtered off with suction, washed repeatedly with diethyl ether and dried under high vacuum at 40° C. This gave 430 mg of the target product.

[0493] LC-MS (Method 2): R.sub.t=0.87 min; m/z=378 (M+H).sup.+.

Example 9A

2-(4-Chlorophenyl)-3-(3,8-diazabicyclo[3.2.1]oct-3-ylmethyl)imidazo[1,2-a]pyrimidine dihydrochloride

[0494] ##STR00047##

[0495] With stirring, 15 ml of a 4 M solution of hydrogen chloride in dioxane were added to tert-butyl 3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.72 g, 6.00 mmol). The mixture was stirred at room temperature overnight. The solids obtained were then filtered off with suction, washed repeatedly with diethyl ether and dried under high vacuum at 40° C. This gave 3.5 g of the target product.

[0496] LC-MS (Method 6): R.sub.t=1.36 min; m/z=354 (M+H).sup.+.

Example 10A

3-(3,8-Diazabicyclo[3.2.1]oct-3-ylmethyl)-2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidine dihydrochloride

[0497] ##STR00048##

[0498] With stirring, 2.57 ml of a 4 M solution of hydrogen chloride in dioxane were added to tert-butyl 3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (493 mg, 1.03 mmol). The mixture was stirred at room temperature overnight. The reaction solution was then concentrated to dryness and the resulting residue was dried under high vacuum at 40° C. This gave 393 mg of the target product.

[0499] LC-MS (Method 2): R.sub.t=0.93 min; m/z=362 (M+H).sup.+.

Example 11A

2-(4-Chlorophenyl)-3-(2,5-diazabicyclo[2.2.2]oct-2-ylmethyl)imidazo[1,2-a]pyrimidine dihydrochloride (Enantiomer 1)

[0500] ##STR00049##

[0501] With stirring, 7.1 ml of a 4 M solution of hydrogen chloride in dioxane were added to tert-butyl 5-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (Enantiomer 1; 1.29 g, 2.84 mmol). The mixture was stirred at room temperature overnight. The solids obtained were then filtered off with suction, washed repeatedly with diethyl ether and dried under high vacuum at 40° C. This gave 1.4 g of the target product.

[0502] LC-MS (Method 2): R.sub.t=0.79 min; m/z=354 (M+H).sup.+.

Example 12A

2-(4-Chlorophenyl)-3-(2,5-diazabicyclo[2.2.2]oct-2-ylmethyl)imidazo[1,2-a]pyrimidine dihydrochloride (Enantiomer 2)

[0503] ##STR00050##

[0504] With stirring, 3.9 ml of a 4 M solution of hydrogen chloride in dioxane were added to tert-butyl 5-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (Enantiomer 2; 710 mg, 1.56 mmol). The mixture was stirred at room temperature overnight. The solids obtained were then filtered off with suction, washed repeatedly with diethyl ether and dried under high vacuum at 40° C. This gave 740 mg of the target product.

[0505] LC-MS (Method 1): R.sub.t=0.49 min; m/z=354 (M+H).sup.+.

Example 13A

3-(2,5-Diazabicyclo[2.2.2]oct-2-ylmethyl)-2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidine dihydrochloride (Enantiomer 1)

[0506] ##STR00051##

[0507] With stirring, 4.2 ml of a 4 M solution of hydrogen chloride in dioxane were added to tert-butyl 5-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (Enantiomer 1; 774 mg, 1.88 mmol). The mixture was stirred at room temperature overnight. The solids obtained were then filtered off with suction, washed repeatedly with diethyl ether and dried under high vacuum at 40° C. This gave 850 mg of the target product.

[0508] LC-MS (Method 1): R.sub.t=0.54 min; m/z=362 (M+H).sup.+.

Example 14A

3-(2,5-Diazabicyclo[2.2.2]oct-2-ylmethyl)-2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidine dihydrochloride (Enantiomer 2)

[0509] ##STR00052##

[0510] With stirring, 4.0 ml of a 4 M solution of hydrogen chloride in dioxane were added to tert-butyl 5-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (Enantiomer 2; 734 mg, 1.59 mmol). The mixture was stirred at room temperature overnight. The solids obtained were then filtered off with suction, washed repeatedly with diethyl ether and dried under high vacuum at 40° C. This gave 761 mg of the target product.

[0511] LC-MS (Method 1): R.sub.t=0.55 min; m/z=362 (M+H).sup.+.

Example 15A

1-[2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]ethanol (racemate)

[0512] ##STR00053##

[0513] 2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidine-3-carbaldehyde (500 mg, 1.94 mmol) was suspended in 5 ml of THF. Subsequently, with ice cooling, methylmagnesium bromide in diethyl ether (3.0 M, 710 μl, 2.1 mmol) was added and the mixture was stirred at room temperature for 1 h. Then, a further 4 ml of THF and more methylmagnesium bromide in diethyl ether (3.0 M, 237 μl, 0.7 mmol) were added. The mixture was stirred at room temperature overnight. Aqueous ammonium chloride solution was then added, followed by water and ethyl acetate. The resulting organic phase was separated off, washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure on a rotary evaporator. The residue was stirred in diethyl ether. The solid that remained was filtered off with suction and dried in a high-vacuum drying cabinet at 40° C. overnight. This gave 370 mg (1.35 mmol, 70% of theory) of the target product.

[0514] LC-MS (Method 2): R.sub.t=1.22 min; m/z=274 (M+H).sup.+.

Example 16A

2-(4-Chlorophenyl)-3-[1-(3,8-diazabicyclo[3.2.1]oct-3-yl)ethyl]imidazo[1,2-a]pyrimidine dihydrochloride (racemate)

[0515] ##STR00054##

[0516] With stirring, 0.21 ml of a 4 M solution of hydrogen chloride in dioxane and 0.2 ml of dioxane were added to tert-butyl 3-{1-[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]ethyl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (racemate; 39.8 mg, 0.09 mmol). The mixture was stirred at room temperature overnight. The reaction solution was then concentrated to dryness and the resulting residue was dried under high vacuum at 40° C. This gave 41 mg of the target product.

[0517] LC-MS (Method 2): R.sub.t=0.86 min; m/z=256/258 (M+H).sup.+.

[0518] Analogously to Examples 7A-14A, the following compounds were prepared from the starting material specified in each case:

TABLE-US-00003 Example Name/Structure/Starting material Analytical data 17A [00055] LC-MS (Method 6): R.sub.t = 1.65 min; m/z = 398/400 (M + H).sup.+. 18A [00056] LC-MS (Method 6): R.sub.t = 1.56 min; m/z = 398/400 (M + H).sup.+.

Example 19A

2-(4-Cyclopropylphenyl)-3-(3,8-diazabicyclo[3.2.1]octan-3-ylmethyl)imidazo[1,2-a]pyrimidine dihydrochloride

[0519] ##STR00057##

[0520] tert-Butyl 3-{[2-(4-cyclopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (720 mg, 1.57 mmol) was dissolved in 3 ml of dioxane, and 3.92 ml of a 4 M solution of hydrogen chloride in dioxane were added with stirring. The mixture was stirred at room temperature overnight. The reaction solution was then concentrated to dryness and the resulting residue was dried under high vacuum at 40° C. This gave 808 mg of the target product.

[0521] LC-MS (Method 1): R.sub.t=0.48 min; m/z=360 (M+H).sup.+.

Working Examples

Example 1

tert-Butyl 7-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carboxylate

[0522] ##STR00058##

[0523] Under argon and at room temperature, 2-(4-chlorophenyl)imidazo[1,2-a]pyrimidine-3-carbaldehyde (1.50 g, 5.82 mmol) was dissolved in 25 ml of THF, and tert-butyl 3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carboxylate (1.59 g, 6.99 mmol) and acetic acid (670 μl, 12 mmol) were added. Sodium triacetoxyborohydride (1.85 g, 8.73 mmol) was then added a little at a time, and the reaction solution was stirred at room temperature overnight. Then water was gradually and carefully added dropwise (caution: evolution of gas), and subsequently ethyl acetate was added. The resulting organic phase was removed and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure on a rotary evaporator. The residue obtained was crystallized from diethyl ether. The crystals formed were filtered off with suction and dried in a high-vacuum drying cabinet at 40° C. overnight. This gave 1.52 g (3.23 mmol, 56% of theory) of the target compound.

[0524] LC-MS (Method 2): R.sub.t=1.65 min; m/z=470/472 (M+H).sup.+.

[0525] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.40 (s, 9H), 2.42 (br. d, 2H), 2.87 (br. d, 2H), 3.57 (br. d, 2H), 3.72 (br. dd, 2H), 3.84 (br. d, 2H), 3.92 (s, 2H), 7.08 (dd, 1H), 7.55 (d, 2H), 7.96 (d, 2H), 8.58 (dd, 1H), 9.28 (dd, 1H).

Example 2

tert-Butyl 7-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carboxylate

[0526] ##STR00059##

[0527] Under argon and at room temperature, 2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidine-3-carbaldehyde (500 mg, 1.89 mmol) was dissolved in 10 ml of THF, and tert-butyl 3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carboxylate (516 mg, 2.26 mmol) and acetic acid (220 μl, 3.77 mmol) were added. Sodium triacetoxyborohydride (599 mg, 2.83 mmol) was then added a little at a time, and the reaction solution was stirred at room temperature overnight. Then water was gradually and carefully added dropwise (caution: evolution of gas), and subsequently ethyl acetate was added. The resulting organic phase was removed and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure on a rotary evaporator. The residue obtained was purified by column chromatography (Biotage Isolera, Biotage SNAP-KP-NH column; mobile phase: cyclohexane/ethyl acetate gradient). This gave 431 mg (0.9 mmol, 48% of theory) of the target compound.

[0528] LC-MS (Method 2): R.sub.t=1.79 min; m/z=478 (M+H).sup.+.

[0529] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.25 (d, 6H), 1.40 (s, 9H), 2.39 (br. d, 2H), 2.87 (br. d, 2H), 2.90 (m, 1H), 3.57 (br. d, 2H), 3.72 (br. dd, 2H), 3.84 (br. d, 2H), 3.95 (s, 2H), 7.05 (dd, 1H), 7.36 (d, 2H), 7.80 (d, 2H), 8.55 (dd, 1H), 9.27 (dd, 1H).

Example 3

tert-Butyl 5-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (racemate)

[0530] ##STR00060##

[0531] Under argon and at room temperature, 2-(4-chlorophenyl)imidazo[1,2-a]pyrimidine-3-carbaldehyde (4.00 g, 15.5 mmol) was dissolved in 100 ml of THF, and tert-butyl 2,5-diazabicyclo[2.2.2]octane-2-carboxylate (3.95 g, 18.6 mmol) and acetic acid (1.8 ml, 31 mmol) were added. Sodium triacetoxyborohydride (4.93 g, 23.3 mmol) was then added a little at a time, and the reaction solution was stirred at room temperature overnight. Further tert-butyl 2,5-diazabicyclo[2.2.2]octane-2-carboxylate (1.6 g, 7.76 mmol) and sodium triacetoxyborohydride (1.2 g, 5.8 mmol) were then added and the reaction solution was once more stirred at room temperature overnight. Then water was gradually and carefully added dropwise (caution: evolution of gas), and subsequently ethyl acetate was added. The resulting organic phase was removed and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure on a rotary evaporator. The residue obtained was purified by column chromatography (Biotage Isolera, Biotage SNAP-KP-NH column; mobile phase: cyclohexane/ethyl acetate gradient). This gave 3.17 g (6.7 mmol, 43% of theory) of the target compound.

[0532] LC-MS (Method 2): R.sub.t=1.55 min; m/z=454/456 (M+H).sup.+.

Example 4 and Example 5

tert-Butyl 5-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (Enantiomers 1 and 2)

[0533] ##STR00061##

[0534] 3.17 g (6.70 mmol) of racemic tert-butyl 5-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (Example 3) were separated into the enantiomers by preparative SFC-HPLC on a chiral phase [column: Daicel Chiralpak OJ-H, 5 μm, 250 mm×30 mm; mobile phase: carbon dioxide/ethanol 85:15 (v/v); flow rate: 150 ml/min; pressure: 135 bar; UV detection: 210 nm; temperature: 38° C.]:

Example 4 (Enantiomer 1)

[0535] Yield: 1.29 g

[0536] R.sub.t=4.15 min; chemical purity >99%; >99% ee [column: Daicel Chiralpak OJ-H, 3 μm, 100 mm×4.6 mm; mobile phase: carbon dioxide/ethanol 85:15 (v/v); flow rate: 3 ml/min; pressure: 130 bar; temperature: 40° C.; UV detection: 210 nm].

[0537] LC-MS (Method 2): R.sub.t=1.55 min; m/z=454/456 (M+H).sup.+.

[0538] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.36 (d, 9H), 1.42-1.55 (m, 1H), 1.57-1.73 (m, 2H), 1.79-1.92 (m, 1H), 2.63-2.80 (m, 3H), 3.09-3.17 (m, 1H), 3.47-3.56 (m, 1H), 3.80 (br. d, 1H), 4.18-4.29 (m, 2H), 7.12 (dd, 1H), 7.56 (d, 2H), 7.84-7.93 (m, 2H), 8.59 (dd, 1H), 9.02 (br. d, 1H).

Example 5 (Enantiomer 2)

[0539] Yield: 720 mg

[0540] R.sub.t=6.6 min; chemical purity >99%; >99% ee

[0541] [column: Daicel Chiralpak OJ-H, 3 μm, 100 mm×4.6 mm; mobile phase: carbon dioxide/ethanol 85:15 (v/v); flow rate: 3 ml/min; pressure: 130 bar; temperature: 40° C.; UV detection: 210 nm].

[0542] LC-MS (Method 2): R.sub.t=1.56 min; m/z=454/456 (M+H).sup.+.

[0543] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.36 (d, 9H), 1.43-1.55 (m, 1H), 1.57-1.73 (m, 2H), 1.80-1.92 (m, 1H), 2.63-2.80 (m, 3H), 3.14 (br. dd, 1H), 3.47-3.56 (m, 1H), 3.80 (br. d, 1H), 4.18-4.29 (m, 2H), 7.12 (dd, 1H), 7.56 (d, 2H), 7.84-7.94 (m, 2H), 8.59 (dd, 1H), 9.02 (br. d, 1H).

Example 6

tert-Butyl 3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0544] ##STR00062##

[0545] Under argon and at room temperature, 2-(4-chlorophenyl)imidazo[1,2-a]pyrimidine-3-carbaldehyde (1.50 g, 5.82 mmol) was dissolved in 25 ml of THF, and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.48 g, 6.99 mmol) and acetic acid (670 μl, 12 mmol) were added. Sodium triacetoxyborohydride (1.85 g, 8.73 mmol) was then added a little at a time, and the reaction solution was stirred at room temperature overnight. Then water was gradually and carefully added dropwise (caution: evolution of gas), and subsequently ethyl acetate was added. The resulting organic phase was removed and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure on a rotary evaporator. The residue obtained was crystallized from diethyl ether. The crystals formed were taken up in acetonitrile and the precipitate that remained was filtered off with suction and dried in a high-vacuum drying cabinet at 40° C. overnight. This gave 840 mg (1.85 mmol, 32% of theory) of the target compound.

[0546] LC-MS (Method 2): R.sub.t=2.06 min; m/z=454/456 (M+H).sup.+

[0547] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.39 (s, 9H), 1.64 (br. s, 4H), 2.26 (br. d, 2H), 2.42-2.60 (m, 2H, obscured by DMSO signal), 3.96-4.05 (m, 4H), 7.14 (dd, 1H), 7.56 (d, 2H), 7.95 (d, 2H), 8.59 (dd, 1H), 9.03 (dd, 1H).

Example 7

tert-Butyl 5-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidine-3-yl]methyl}-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (racemate)

[0548] ##STR00063##

[0549] Under argon and at room temperature, 2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidine-3-carbaldehyde (1.50 g, 5.65 mmol) was dissolved in 20 ml of THF, and tert-butyl 2,5-diazabicyclo[2.2.2]octane-2-carboxylate (racemate; 1.44 g, 6.78 mmol) and acetic acid (650 μl, 11.31 mmol) were added. Sodium triacetoxyborohydride (1.8 g, 8.48 mmol) was then added a little at a time, and the reaction solution was stirred at room temperature overnight. Then water was gradually and carefully added dropwise (caution: evolution of gas), and subsequently ethyl acetate was added. The resulting organic phase was removed and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure on a rotary evaporator. The residue obtained was purified by column chromatography (Biotage Isolera, Biotage SNAP-KP-NH column; mobile phase: cyclohexane/ethyl acetate gradient). This gave 1760 mg (3.81 mmol, 67% of theory) of the target compound.

[0550] LC-MS (Method 2): R.sub.t=1.71 min; m/z=462 (M+H).sup.+.

Example 8 and Example 9

tert-Butyl 5-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (Enantiomers 1 and 2)

[0551] ##STR00064##

[0552] 1.66 g (3.59 mmol) of racemic tert-butyl 5-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (Example 7) were separated into the enantiomers by preparative SFC-HPLC on a chiral phase [column: Daicel Chiralpak OX-H (SFC), 5 μm, 250 mm×30 mm; mobile phase: carbon dioxide/methanol 62:38 (v/v); flow rate: 80 g/min; pressure: 120 bar; UV detection: 210 nm; temperature: 38° C.]:

Example 8 (Enantiomer 1)

[0553] Yield: 774 mg

[0554] R.sub.t=4.91 min; chemical purity >99%; >99% ee

[0555] [column: Daicel Chiralpak OX-3 (SFC), 3 μm, 100 mm×4.6 mm; mobile phase: carbon dioxide/ethanol 70:30 (v/v); flow rate: 3 ml/min; pressure: 130 bar; temperature: 40° C.; UV detection: 210 nm].

[0556] LC-MS (Method 1): R.sub.t=0.85 min; m/z=462 (M+H).sup.+.

[0557] [α].sub.D.sup.20=+16.21° (c=0.270, Methanol).

[0558] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.25 (d, 6H), 1.36 (2s, 9H), 1.44-1.56 (m, 1H), 1.66 (br. s, 2H), 1.79-1.95 (m, 1H), 2.65-2.83 (m, 3H), 2.89-3.03 (m, 1H), 3.09-3.20 (m, 1H), 3.53 (br. d, 1H), 3.81 (br. d, 1H), 4.24 (s, 2H), 7.10 (dd, 1H), 7.37 (d, 2H), 7.78 (dd, 2H), 8.56 (dd, 1H), 8.99 (br. d, 1H).

Example 9 (Enantiomer 2)

[0559] Yield: 734 mg

[0560] R.sub.t=6.88 min; chemical purity >99%; >99% ee

[0561] [column: Daicel Chiralpak OX-3 (SFC), 3 μm, 100 mm×4.6 mm; mobile phase: carbon dioxide/ethanol 70:30 (v/v); flow rate: 3 ml/min; pressure: 130 bar; temperature: 40° C.; UV detection: 210 nm].

[0562] LC-MS (Method 1): R.sub.t=0.85 min; m/z=462 (M+H).sup.+.

[0563] [α].sub.D.sup.20=−15.67° (c=0.270, Methanol).

[0564] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.25 (d, 6H), 1.36 (2s, 9H), 1.44-1.56 (m, 1H), 1.66 (br. s, 2H), 1.79-1.94 (m, 1H), 2.64-2.83 (m, 3H), 2.95 (dt, 1H), 3.09-3.20 (m, 1H), 3.53 (br. d, 1H), 3.81 (br. d, 1H), 4.24 (s, 2H), 7.10 (dd, 1H), 7.37 (d, 2H), 7.78 (dd, 2H), 8.56 (dd, 1H), 8.99 (br. d, 1H).

Example 10

tert-Butyl 3-{1-[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]ethyl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (racemate)

[0565] ##STR00065##

[0566] 1-[2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]ethanol (473 mg, 1.73 mmol) and triphenylphosphine (906 mg, 3.46 mmol) were initially charged in 10 ml of dichloromethane, and carbon tetrabromide (1.15 g, 3.46 mmol) was added a little at a time with cooling (ice bath). Triethylamine (480 μl, 3.5 mmol) was then added, and the mixture was stirred at room temperature for 1 h. The mixture was then concentrated by evaporation and the residue was dissolved in 10 ml of acetonitrile. tert-Butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (734 mg, 3.46 mmol) was added, and the reaction mixture was stirred at 40° C. overnight. The mixture was then once more concentrated to dryness. 400 mg of the residue obtained in this manner were directly separated into the components by preparative HPLC (Method 8). The remainder of the residue was applied to silica gel and pre-purified by column chromatography (Biotage Isolera, Biotage SNAP-KP-NH column, mobile phase cyclohexane/ethyl acetate gradient). The product thus pre-purified was then re-purified by preparative HPLC (Method 8). This gave 50 mg (0.11 mmol, 6% of theory) of the title compound.

[0567] LC-MS (Method 2): R.sub.t=2.14 min; MS (ESIpos): m/z=468/470 [M+H].sup.+.

[0568] Analogously to Examples 1-3 and 6-7, the following compounds were prepared from the starting materials specified in each case:

TABLE-US-00004 Example Name/Structure/Starting materials Analytical data 11 [00066] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = −0.149 (0.44), −0.008 (3.64), 0.008 (3.55), 0.146 (0.45), 1.345 (14.48), 1.374 (16.00), 1.402 (4.45), 1.489 (0.55), 1.654 (0.95), 1.859 (0.54), 2.328 (0.58), 2.670 (1.91), 2.709 (1.58), 2.774 (0.64), 3.118 (0.57), 3.146 (0.65), 3.155 (0.60), 3.515 (0.56), 3.774 (0.61), 3.827 (0.68), 4.235 (4.16), 5.754 (5.06), 7.108 (1.24), 7.119 (1.32), 7.125 (1.31), 7.136 (1.29), 7.679 (3.52), 7.700 (4.83), 7.812 (1.99), 7.824 (1.97), 7.833 (1.62), 7.845 (1.39), 8.579 (1.48), 8.584 (1.62), 8.590 (1.53), 8.594 (1.45), 9.013 (1.24), 9.030 (1.21). LC-MS (Method 2): R.sub.t = 1.68 min; m/z = 498/500 (M + H).sup.+. 12 [00067] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.39 (s, 9H), 1.56-1.73 (m, 4H), 2.26 (br. d, 2H), 2.46- 2.60 (m, 2H, obscured by DMSO signal), 3.98 (s, 2H), 4.02 (br. s, 2H), 7.14 (dd, 1H), 7.70 (d, 2H), 7.88 (d, 2H), 8.59 (dd, 1H), 9.03 (dd, 1H). LC-MS (Method 5): R.sub.t = 1.42 min; m/z = 498/500 (M + H).sup.+.

Example 13

(7-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]non-9-yl)(6-methoxypyridin-2-yl)methanone

[0569] ##STR00068##

[0570] 6-Methoxypyridine-2-carboxylic acid (35.1 mg, 230 μmol) was dissolved in 1.5 ml of DMF, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (119 mg, 313 μmol) was added and the mixture was stirred at room temperature for 30 min. 7-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]nonane dihydrochloride (100 mg) and N,N-diisopropylethylamine (180 μl, 1.0 mmol) were then added and the mixture was stirred at room temperature overnight. Thereafter, the reaction mixture was separated directly into its components via preparative HPLC (Method 8). 74 mg (0.15 mmol, 70% of theory) of the title compound were obtained.

[0571] LC-MS (Method 2): R.sub.t=1.48 min; m/z=505/507 (M+H).sup.+.

[0572] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=2.46-2.66 (m, 2H, partially obscured by DMSO signal), 2.91 (br. d, 1H), 3.05 (br. d, 1H), 3.66-3.83 (m, 3H), 3.80 (s, 3H), 3.89 (d, 1H), 3.93-4.03 (m, 2H), 4.20 (br. s, 1H), 4.44 (br. s, 1H), 6.93 (d, 1H), 7.09 (dd, 1H), 7.29 (d, 1H), 7.54 (d, 2H), 7.83 (t, 1H), 7.97 (d, 2H), 8.58 (dd, 1H), 9.28 (dd, 1H).

Example 14

(3-Chloro-6-methoxypyridin-2-yl)(7-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]non-9-yl)methanone

[0573] ##STR00069##

[0574] 3-Chloro-6-methoxypyridine-2-carboxylic acid (43.1 mg, 230 μmol) was dissolved in 1.5 ml of DMF, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (119 mg, 313 μmol) was added and the mixture was stirred at room temperature for 30 min. 7-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]nonane dihydrochloride (100 mg) and N,N-diisopropylethylamine (180 μl, 1.0 mmol) were then added and the mixture was stirred at room temperature overnight. Thereafter, the reaction mixture was separated directly into its components via preparative HPLC (Method 8). 78 mg (0.15 mmol, 70% of theory) of the title compound were obtained.

[0575] LC-MS (Method 1): R.sub.t=0.86 min; m/z=539/541 (M+H).sup.+.

Example 15

(7-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]non-9-yl)(3-fluoro-6-methoxypyridin-2-yl)methanone

[0576] ##STR00070##

[0577] 3-Fluoro-6-methoxypyridine-2-carboxylic acid (39.3 mg, 230 μmol) was dissolved in 1.5 ml of DMF, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (119 mg, 313 μmol) was added and the mixture was stirred at room temperature for 30 min. 7-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]nonane dihydrochloride (100 mg) and N,N-diisopropylethylamine (180 μl, 1.0 mmol) were then added and the mixture was stirred at room temperature overnight. Thereafter, the reaction mixture was separated directly into its components via preparative HPLC (Method 8). 82 mg (0.16 mmol, 76% of theory) of the title compound were obtained.

[0578] LC-MS (Method 1): R.sub.t=0.82 min; m/z=523/525 (M+H).sup.+.

[0579] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=2.45-2.60 (m, 2H, obscured by DMSO signal), 2.90 (br. d, 1H), 3.05 (br. d, 1H), 3.58-3.70 (m, 3H), 3.72-3.84 (m, 1H), 3.80 (s, 3H), 3.89 (d, 1H), 3.98 (s, 2H), 4.45 (br. s, 1H), 6.97 (dd, 1H), 7.08 (dd, 1H), 7.55 (d, 2H), 7.80 (t, 1H), 7.97 (d, 2H), 8.58 (dd, 1H), 9.28 (dd, 1H).

Example 16

(7-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]non-9-yl)[6-(methylsulfanyl)pyridin-2-yl]methanone

[0580] ##STR00071##

[0581] 6-(Methylsulfanyl)pyridine-2-carboxylic acid (38.8 mg, 230 μmol) was dissolved in 1.5 ml of DMF, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (119 mg, 313 μmol) was added and the mixture was stirred at room temperature for 30 min. 7-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]nonane dihydrochloride (100 mg) and N,N-diisopropylethylamine (180 μl, 1.0 mmol) were then added and the mixture was stirred at room temperature overnight. Thereafter, the reaction mixture was separated directly into its components via preparative HPLC (Method 8). 84 mg (0.16 mmol, 77% of theory) of the title compound were obtained.

[0582] LC-MS (Method 1): R.sub.t=0.85 min; m/z=521/523 (M+H).sup.+.

[0583] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=2.46 (s, 3H), 2.56-2.65 (m, 2H), 2.91 (br. d, 1H), 3.06 (br. d, 1H), 3.65-3.81 (m, 3H), 3.86-4.03 (m, 3H), 4.15 (br. s, 1H), 4.46 (br. s, 1H), 7.09 (dd, 1H), 7.40 (dd, 2H), 7.55 (d, 2H), 7.77 (t, 1H), 7.98 (d, 2H), 8.58 (dd, 1H), 9.28 (dd, 1H).

Example 17

(7-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]non-9-yl)(cyclopentyl)methanone

[0584] ##STR00072##

[0585] Cyclopentanecarboxylic acid (18 μl, 230 μmol) was dissolved in 1.5 ml of DMF, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (119 mg, 313 μmol) was added and the mixture was stirred at room temperature for 30 min. 7-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]nonane dihydrochloride (100 mg) and N,N-diisopropylethylamine (180 μl, 1.0 mmol) were then added and the mixture was stirred at room temperature overnight. Thereafter, the reaction mixture was separated directly into its components via preparative HPLC (Method 8). 72 mg (0.15 mmol, 74% of theory) of the title compound were obtained.

[0586] LC-MS (Method 1): R.sub.t=0.81 min; m/z=466/468 (M+H).sup.+.

[0587] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.43-1.81 (m, 8H), 2.31-2.61 (m, 2H, partially obscured by DMSO signal), 2.86-2.97 (m, 3H), 3.47-3.54 (m, 1H), 3.56-3.63 (m, 1H), 3.77 (dd, 2H), 3.94 (s, 2H), 4.04 (br. s, 1H), 4.32 (br. s, 1H), 7.08 (dd, 1H), 7.55 (d, 2H), 7.97 (d, 2H), 8.59 (dd, 1H), 9.27 (dd, 1H).

Example 18

(3-Fluoro-6-methoxypyridin-2-yl)(7-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]non-9-yl)methanone

[0588] ##STR00073##

[0589] 3-Fluoro-6-methoxypyridine-2-carboxylic acid (39 mg, 0.23 mmol) was dissolved in 1.5 ml of DMF, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (117 mg, 0.31 mmol) was added and the mixture was stirred at room temperature for 30 min. 7-{[2-(4-Isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]nonane dihydrochloride (100 mg) and N,N-diisopropylethylamine (180 μl, 1.0 mmol) were then added and the mixture was stirred at room temperature overnight. Thereafter, the reaction mixture was separated directly into its components via preparative HPLC (Method 8). 83 mg (0.16 mmol, 76% of theory) of the title compound were obtained.

[0590] LC-MS (Method 1): R.sub.t=0.84 min; m/z=531 (M+H).sup.+.

[0591] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.26 (d, 6H), 2.46-2.58 (m, 2H, obscured by DMSO signal), 2.86-3.01 (m, 2H), 3.06 (br. d, 1H), 3.57-3.70 (m, 3H), 3.75 (br. d, 1H), 3.79 (s, 3H), 3.89 (d, 1H), 3.99 (s, 2H), 4.46 (br. s, 1H), 6.97 (dd, 1H), 7.06 (dd, 1H), 7.36 (d, 2H), 7.74-7.84 (m, 3H), 8.55 (dd, 1H), 9.26 (dd, 1H).

Example 19

[6-(Difluoromethoxy)pyridin-2-yl](7-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]non-9-yl)methanone

[0592] ##STR00074##

[0593] 6-(Difluoromethoxy)pyridine-2-carboxylic acid (43 mg, 0.23 mmol) was dissolved in 1.5 ml of DMF, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (117 mg, 0.31 mmol) was added and the mixture was stirred at room temperature for 30 min. 7-{[2-(4-Isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]nonane dihydrochloride (100 mg) and N,N-diisopropylethylamine (180 μl, 1.0 mmol) were then added and the mixture was stirred at room temperature overnight. Thereafter, the reaction mixture was separated directly into its components via preparative HPLC (Method 8). 72 mg (0.13 mmol, 61% of theory) of the title compound were obtained.

[0594] LC-MS (Method 1): R.sub.t=0.89 min; m/z=549 (M+H).sup.+.

[0595] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.25 (d, 6H), 2.45-2.64 (m, 3H, partially obscured by DMSO signal), 2.86-2.99 (m, 2H), 3.05 (br. d, 1H), 3.65-3.79 (m, 3H), 3.89 (d, 1H), 4.00 (s, 2H), 4.09 (br. s, 1H), 4.44 (br. s, 1H), 7.06 (dd, 1H), 7.21 (d, 1H), 7.36 (d, 2H), 7.54-7.62 (m, 1H), 7.81 (d, 2H), 8.06 (t, 1H), 8.55 (dd, 1H), 9.28 (dd, 1H).

Example 20

(3-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)(6-methoxypyridin-2-yl)methanone

[0596] ##STR00075##

[0597] 6-Methoxypyridine-2-carboxylic acid (36.4 mg, 237 μmol) was dissolved in 1.5 ml of DMF, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (119 mg, 313 μmol) was added and the mixture was stirred at room temperature for 30 min. 2-(4-Chlorophenyl)-3-(3,8-diazabicyclo[3.2.1]oct-3-ylmethyl)imidazo[1,2-a]pyrimidine dihydrochloride (100 mg) and N,N-diisopropylethylamine (190 μl, 1.1 mmol) were then added and the mixture was stirred at room temperature overnight. Thereafter, the reaction mixture was separated directly into its components via preparative HPLC (Method 8). 79 mg (0.16 mmol, 74% of theory) of the title compound were obtained.

[0598] LC-MS (Method 1): R.sub.t=1.76 min; m/z=489/491 (M+H).sup.+.

[0599] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.63-1.84 (m, 4H), 2.45 (br. d, 1H), 2.56-2.65 (m, 2H), 2.73 (dd, 1H), 3.77 (s, 3H), 4.00-4.12 (m, 2H), 4.67 (br. d, 2H), 6.93 (d, 1H), 7.15 (dd, 1H), 7.35 (d, 1H), 7.57 (d, 2H), 7.82 (t, 1H), 7.96 (d, 2H), 8.59 (dd, 1H), 9.06 (dd, 1H).

Example 21

(3-Chloro-6-methoxypyridin-2-yl)(3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)methanone

[0600] ##STR00076##

[0601] 3-Chloro-6-methoxypyridine-2-carboxylic acid (44.5 mg, 237 μmol) was dissolved in 1.5 ml of DMF, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (119 mg, 313 μmol) was added and the mixture was stirred at room temperature for 30 min. 2-(4-Chlorophenyl)-3-(3,8-diazabicyclo[3.2.1]oct-3-ylmethyl)imidazo[1,2-a]pyrimidine dihydrochloride (100 mg) and N,N-diisopropylethylamine (190 μl, 1.1 mmol) were then added and the mixture was stirred at room temperature overnight. Thereafter, the reaction mixture was separated directly into its components via preparative HPLC (Method 8). 56 mg (0.11 mmol, 49% of theory) of the title compound were obtained.

[0602] LC-MS (Method 2): R.sub.t=1.81 min; m/z=523/524/525 (M+H).sup.+.

[0603] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.62-1.82 (m, 4H), 2.34-2.46 (m, 2H), 2.47-2.59 (m, 1H, obscured by DMSO signal), 2.69-2.78 (m, 1H), 3.62 (br. s, 1H), 3.79 (s, 3H), 4.06 (s, 2H), 4.59 (br. s, 1H), 6.92 (d, 1H), 7.15 (dd, 1H), 7.57 (d, 2H), 7.87 (d, 1H), 7.94 (d, 2H), 8.59 (dd, 1H), 9.04 (dd, 1H).

Example 22

(3-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)(3-fluoro-6-methoxypyridin-2-yl)methanone

[0604] ##STR00077##

[0605] 3-Fluoro-6-methoxypyridine-2-carboxylic acid (40.6 mg, 237 μmol) was dissolved in 1.5 ml of DMF, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (123 mg, 324 μmol) was added and the mixture was stirred at room temperature for 30 min. 2-(4-Chlorophenyl)-3-(3,8-diazabicyclo[3.2.1]oct-3-ylmethyl)imidazo[1,2-a]pyrimidine dihydrochloride (100 mg) and N,N-diisopropylethylamine (190 μl, 1.1 mmol) were then added and the mixture was stirred at room temperature overnight. Thereafter, the reaction mixture was separated directly into its components via preparative HPLC (Method 8). 93 mg (0.18 mmol, 85% of theory) of the title compound were obtained.

[0606] LC-MS (Method 2): R.sub.t=1.73 min; m/z=507/509 (M+H).sup.+.

[0607] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.62-1.83 (m, 4H), 2.44 (br. t, 2H), 2.48-2.58 (m, 1H, partially obscured by DMSO signal), 2.75 (dd, 1H), 3.76 (s, 3H), 3.92 (br. s, 1H), 4.01-4.12 (m, 2H), 4.61 (br. s, 1H), 6.95 (dd, 1H), 7.14 (dd, 1H), 7.57 (d, 2H), 7.77 (t, 1H), 7.95 (d, 2H), 8.59 (dd, 1H), 9.06 (dd, 1H).

Example 23

(3-Chloro-6-methoxypyridin-2-yl)(5-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)methanone (Enantiomer 1)

[0608] ##STR00078##

[0609] 3-Chloro-6-methoxypyridine-2-carboxylic acid (44.5 mg, 237 μmol) was dissolved in 1.5 ml of DMF, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (123 mg, 324 μmol) was added and the mixture was stirred at room temperature for 30 min. 2-(4-Chlorophenyl)-3-(2,5-diazabicyclo[2.2.2]oct-2-ylmethyl)imidazo[1,2-a]pyrimidine dihydrochloride (Enantiomer 1; 100 mg) and N,N-diisopropylethylamine (190 μl, 1.1 mmol) were then added and the mixture was stirred at room temperature overnight. Thereafter, the reaction mixture was separated directly into its components via preparative HPLC (Method 8). 87 mg (0.16 mmol, 74% of theory) of the title compound were obtained.

[0610] LC-MS (Method 2): R.sub.t=1.62 min; m/z=523/524/525 (M+H).sup.+.

[0611] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.52-2.00 (m, 4H), 2.57-3.24 (m, 3.75H), 3.35-3.46 (m, 1.25H), 3.70-3.86 (m, 3.75H), 4.20-4.40 (m, 2.25H), 6.84-6.96 (m, 1H), 7.08-7.19 (m, 1H), 7.49-7.61 (m, 2H), 7.79-7.93 (m, 3H), 8.56-8.64 (m, 1H), 8.98-9.07 (m, 1H).

Example 24

(5-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)(3-fluoro-6-methoxypyridin-2-yl)methanone (Enantiomer 2)

[0612] ##STR00079##

[0613] 3-Fluoro-6-methoxypyridine-2-carboxylic acid (40.6 mg, 237 μmol) was dissolved in 1.5 ml of DMF, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (123 mg, 324 μmol) was added and the mixture was stirred at room temperature for 30 min. 2-(4-Chlorophenyl)-3-(2,5-diazabicyclo[2.2.2]oct-2-ylmethyl)imidazo[1,2-a]pyrimidine dihydrochloride (Enantiomer 2; 100 mg) and N,N-diisopropylethylamine (190 μl, 1.1 mmol) were then added and the mixture was stirred at room temperature overnight. Thereafter, the reaction mixture was separated directly into its components via preparative HPLC (Method 8). 84 mg (0.17 mmol, 77% of theory) of the title compound were obtained.

[0614] LC-MS (Method 6): R.sub.t=1.52 min; MS (ESIpos): m/z=507/509 [M+H].sup.+.

[0615] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.50-2.00 (m, 4H), 2.62-2.87 (m, 2.25H), 2.92 (br. s, 0.75H), 3.15 (br. d, 0.25H), 3.38-3.50 (m, 1.5H), 3.56 (br. d, 0.25H), 3.70-3.83 (m, 3.75H), 4.20-4.35 (m, 2H), 4.38 (br. s, 0.25H), 6.89-6.99 (m, 1H), 7.07-7.17 (m, 1H), 7.49-7.60 (m, 2H), 7.70-7.83 (m, 1H), 7.84-7.95 (m, 2H), 8.56-8.63 (m, 1H), 8.99-9.09 (m, 1H).

Example 25

(5-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)(6-methoxy-3-methylpyridin-2-yl)methanone (Enantiomer 1)

[0616] ##STR00080##

[0617] 6-Methoxy-3-methylpyridine-2-carboxylic acid (39.7 mg, 237 μmol) was dissolved in 1.5 ml of DMF, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (123 mg, 324 μmol) was added and the mixture was stirred at room temperature for 30 min. 2-(4-Chlorophenyl)-3-(2,5-diazabicyclo[2.2.2]oct-2-ylmethyl)imidazo[1,2-a]pyrimidine dihydrochloride (Enantiomer 1; 100 mg) and N,N-diisopropylethylamine (190 μl, 1.1 mmol) were then added and the mixture was stirred at room temperature overnight. Thereafter, the reaction mixture was separated directly into its components via preparative HPLC (Method 8). 25 mg (0.05 mmol, 23% of theory) of the title compound were obtained.

[0618] LC-MS (Method 2): R.sub.t=1.55 min; MS (ESIpos): m/z=503/505 [M+H].sup.+.

[0619] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.49-1.97 (m, 4H), 2.02-2.12 (m, 3H), 2.58-2.84 (m, 2.25H), 2.91-3.02 (m, 1H), 3.23 (br. s, 0.75H), 3.34-3.45 (m, 1H), 3.65-3.83 (m, 3.75H), 4.19-4.42 (m, 2.25H), 6.71-6.81 (m, 1H), 7.06-7.17 (m, 1H), 7.49-7.65 (m, 3H), 7.82-7.94 (m, 2H), 8.56-8.63 (m, 1H), 8.97-9.08 (m, 1H).

Example 26

(3-Chloro-6-methoxypyridin-2-yl)(5-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)methanone (Enantiomer 2)

[0620] ##STR00081##

[0621] 3-Chloro-6-methoxypyridine-2-carboxylic acid (43 mg, 0.21 mmol) was dissolved in 1.5 ml of DMF, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (121 mg, 0.32 mmol) was added and the mixture was stirred at room temperature for 30 min. 3-(2,5-Diazabicyclo[2.2.2]oct-2-ylmethyl)-2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidine dihydrochloride (Enantiomer 2; 100 mg) and N,N-diisopropylethylamine (190 μl, 1.1 mmol) were then added and the mixture was stirred at room temperature overnight. Thereafter, the reaction mixture was separated directly into its components via preparative HPLC (Method 8). This gave 82 mg (0.15 mmol, content 96%, 70% of theory) of the title compound.

[0622] LC-MS (Method 2): R.sub.t=1.73 min; m/z=531/533 (M+H).sup.+.

[0623] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.20-1.31 (m, 6H), 1.53-2.01 (m, 4H), 2.62 (br. d, 0.75H), 2.69-2.85 (m, 1.5H), 2.89-3.03 (m, 2H), 3.21 (br. s, 0.75H), 3.43 (br. d, 1H), 3.70-3.85 (m, 3.75H), 4.21-4.35 (m, 2H), 4.39 (br. s, 0.25H), 6.85-6.96 (m, 1H), 7.05-7.14 (m, 1H), 7.30-7.43 (m, 2H), 7.70-7.87 (m, 2.75H), 7.90 (d, 0.25H), 8.56 (dd, 1H), 8.95-9.04 (m, 1H).

Example 27

(5-Cyclopropyl-1,3-oxazol-4-yl)(5-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)methanone (Enantiomer 2)

[0624] ##STR00082##

[0625] 5-Cyclopropyl-1,3-oxazole-4-carboxylic acid (32 mg, 0.21 mmol) was dissolved in 1.35 ml of DMF, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (109 mg, 0.29 mmol) was added and the mixture was stirred at room temperature for 30 min. 3-(2,5-Diazabicyclo[2.2.2]oct-2-ylmethyl)-2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidine dihydrochloride (Enantiomer 2; 90 mg) and N,N-diisopropylethylamine (170 μl, 0.96 mmol) were then added and the mixture was stirred at room temperature overnight. Thereafter, the reaction mixture was separated directly into its components via preparative HPLC (Method 8). 67 mg (0.14 mmol, 71% of theory) of the title compound were obtained.

[0626] LC-MS (Method 2): R.sub.t=1.51 min; m/z=497 (M+H).sup.+.

[0627] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=0.83-0.95 (m, 2H), 0.96-1.08 (m, 2H), 1.25 (d, 6H), 1.51-1.61 (m, 1H), 1.67-1.99 (m, 3H), 2.44-2.57 (m, 0.7H, partially obscured by DMSO signal), 2.57-2.66 (m, 0.3H), 2.73-3.01 (m, 4H), 3.37 (dd, 0.7H), 3.64-3.76 (m, 1H), 4.03 (br. d, 0.3H), 4.23-4.33 (m, 2H), 4.37 (br. s, 0.3H), 4.59 (br. s, 0.7H), 7.06-7.14 (m, 1H), 7.31-7.40 (m, 2H), 7.75-7.83 (m, 2H), 8.12-8.20 (m, 1H), 8.53-8.59 (m, 1H), 8.98-9.06 (m, 1H).

Example 28

(3-Fluoro-6-methoxypyridin-2-yl)(3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)methanone

[0628] ##STR00083##

[0629] 3-Fluoro-6-methoxypyridine-2-carboxylic acid (39.2 mg, 0.21 mmol) was dissolved in 1.5 ml of DMF, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (119 mg, 0.31 mmol) was added and the mixture was stirred at room temperature for 30 min. 3-(3,8-Diazabicyclo[3.2.1]oct-3-ylmethyl)-2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidine dihydrochloride (98 mg) and N,N-diisopropylethylamine (180 μl, 1.04 mmol) were then added and the mixture was stirred at room temperature overnight. Thereafter, the reaction mixture was separated directly into its components via preparative HPLC (Method 8). 65 mg (0.13 mmol, 61% of theory) of the title compound were obtained.

[0630] LC-MS (Method 5): R.sub.t=1.22 min; MS (ESIpos): m/z=515 [M+H].sup.+.

[0631] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.26 (d, 6H), 1.63-1.86 (m, 4H), 2.44 (br. t, 2H), 2.48-2.60 (m, 1H, partially obscured by DMSO signal), 2.76 (dd, 1H), 2.96 (quin, 1H), 3.76 (s, 3H), 3.92 (br. s, 1H), 4.00-4.11 (m, 2H), 4.61 (br. s, 1H), 6.95 (dd, 1H), 7.12 (dd, 1H), 7.36 (d, 2H), 7.77 (t, 1H), 7.83 (d, 2H), 8.57 (dd, 1H), 9.02 (dd, 1H).

Example 29

(3-Chloro-6-methoxypyridin-2-yl)(3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)methanone

[0632] ##STR00084##

[0633] 3-Chloro-6-methoxypyridine-2-carboxylic acid (43 mg, 0.23 mmol) was dissolved in 1.5 ml of DMF, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (118 mg, 0.31 mmol) was added and the mixture was stirred at room temperature for 30 min. 3-(3,8-Diazabicyclo[3.2.1]oct-3-ylmethyl)-2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidine dihydrochloride (98 mg) and N,N-diisopropylethylamine (180 μl, 1.04 mmol) were then added and the mixture was stirred at room temperature overnight. Thereafter, the reaction mixture was separated directly into its components via preparative HPLC (Method 8). 67 mg (0.13 mmol, 60% of theory) of the title compound were obtained.

[0634] LC-MS (Method 5): R.sub.t=1.27 min; MS (ESIpos): m/z=531/533 [M+H].sup.+.

[0635] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.26 (d, 6H), 1.63-1.84 (m, 4H), 2.41 (br. t, 2H), 2.46-2.57 (m, 1H, obscured by DMSO signal), 2.75 (br. d, 1H), 2.96 (quin, 1H), 3.63 (br. s, 1H), 3.79 (s, 3H), 4.00-4.11 (m, 2H), 4.60 (br. s, 1H), 6.92 (d, 1H), 7.12 (dd, 1H), 7.37 (d, 2H), 7.82 (d, 2H), 7.87 (d, 1H), 8.56 (dd, 1H), 9.01 (dd, 1H).

[0636] Analogously to Examples 13-29, the following compounds were prepared from the starting materials specified in each case:

TABLE-US-00005 Example Name/Structure/Starting materials Analytical data 30 [00085] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 2.43 (br. d, 1H), 2.47- 2.59 (m, 1H, partially obscured by DMSO signal), 2.87 (br. d, 1H), 3.02 (br. d, 1H), 3.37 (br. s, 1H), 3.59 (br. d, 1H), 3.65-3.76 (m, 2H), 3.87 (d, 1H), 3.97 (s, 2H), 4.47 (br. s, 1H), 7.08 (dd, 1H), 7.24-7.34 (m, 2H), 7.41-7.53 (m, 2H), 7.55 (d, 2H), 7.95 (d, 2H), 8.58 (dd, 1H), 9.27 (dd, 1H). LC-MS (Method 2): R.sub.t = 1.53 min; m/z = 492/494 (M + H).sup.+. 31 [00086] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 2.46-2.55 (m, 1H, obscured by DMSO signal), 2.59 (br. d, 1H), 2.86 (br. d, 1H), 2.99 (br. d, 1H), 3.54-3.75 (m, 4H), 3.77 (s, 3H), 3.85 (d, 1H), 3.98 (s, 2H), 4.39 (br. s, 1H), 6.91-7.12 (m, 4H), 7.36 (t, 1H), 7.55 (d, 2H), 7.97 (d, 2H), 8.57 (dd, 1H), 9.29 (dd, 1H). LC-MS (Method 2): R.sub.t = 1.53 min; m/z = 504/506 (M + H).sup.+. 32 [00087] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.60-1.79 (m, 4H), 2.25 (br. d, 1H), 2.42 (br. d, 1H), 2.47- 2.60 (m, 1H, partially obscured by DMSO signal), 2.68 (br. d, 1H), 3.66 (br. s, 1H), 4.04 (s, 2H), 4.59 (br. s, 1H), 7.14 (dd, 1H), 7.24- 7.32 (m, 2H), 7.40-7.53 (m, 2H), 7.57 (d, 2H), 7.95 (d, 2H), 8.59 (dd, 1H), 9.04 (dd, 1H). LC-MS (Method 2): R.sub.t = 1.73 min; m/z = 476/478 (M + H).sup.+. 33 [00088] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.64-1.83 (m, 4H), 2.40- 2.63 (m, 3H, partially obscured by DMSO signal), 2.43 (s, 3H), 2.74 (br. d, 1H), 3.99-4.11 (m, 2H), 4.63 (br. s, 2H), 7.15 (dd, 1H), 7.42 (dd, 2H), 7.57 (d, 2H), 7.75 (t, 1H), 7.97 (d, 2H), 8.55-8.62 (m, 1H), 9.06 (d, 1H). LC-MS (Method 2): R.sub.t = 1.86 min; m/z = 505/507 (M + H).sup.+. 34 [00089] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.44-1.66 (m, 7H), 1.66- 1.80 (m, 5H), 2.26 (br. d, 2H), 2.47-2.66 (m, 2H, partially obscured by DMSO signal), 2.80- 2.92 (m, 1H), 3.94-4.06 (m, 2H), 4.28 (br. s, 1H), 4.41 (br. d, 1H), 7.14 (dd, 1H), 7.56 (d, 2H), 7.96 (d, 2H), 8.59 (dd, 1H), 9.05 (dd, 1H). LC-MS (Method 2): R.sub.t = 1.83 min; m/z = 450/452 (M + H).sup.+. 35 [00090] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.63-1.81 (m, 4H), 2.42 (br. d, 1H), 2.47-2.62 (m, 2H, partially obscured by DMSO signal), 2.64-2.75 (m, 1H), 2.67 (d, 3H), 3.97-4.09 (m, 2H), 4.60 (br. s, 1H), 4.76 (br. s, 1H), 6.51 (d, 1H), 6.65 (q, 1H), 6.82 (d, 1H), 7.14 (dd, 1H), 7.44 (t, 1H), 7.56 (d, 2H), 7.96 (d, 2H), 8.59 (dd, 1H), 9.05 (dd, 1H). LC-MS (Method 2): R.sub.t = 1.51 min; m/z = 532/534 (M − H + HCOOH)—. 36 [00091] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.64-1.80 (m, 4H), 2.30- 2.47 (m, 2H), 2.57-2.74 (m, 2H), 3.78 (s, 3H), 3.92 (br. s, 1H), 4.05 (s, 2H), 4.54 (br. s, 1H), 6.92-7.08 (m, 3H), 7.30 (br. t, 1H), 7.35 (t, 1H), 7.61 (d, 2H), 7.93 (d, 2H), 8.71 (br. d, 1H), 9.15 (br. d, 1H). LC-MS (Method 2): R.sub.t = 1.73 min; m/z = 488/490 (M + H).sup.+. 37 [00092] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.38-1.79 (m, 11H), 1.82- 1.96 (m, 1H), 2.63-2.86 (m, 4H), 3.19 (dd, 0.5H), 3.37 (dd, 0.5H), 3.54 (br. d, 0.5H), 3.75 (br. d, 0.5H), 3.93 (br. d, 0.5H), 4.18- 4.31 (m, 2.5H), 7.12 (dd, 1H), 7.56 (d, 2H), 7.89 (d, 2H), 8.59 (dd, 1H), 9.03 (dt, 1H). LC-MS (Method 2): R.sub.t = 1.42 min; m/z = 450/452 (M + H).sup.+. 38 [00093] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.44-1.99 (m, 4H), 2.61- 2.72 (m, 1H), 2.76-2.84 (m, 1H), 2.90 (br. s, 1H), 3.17 (br. d, 0.25H), 3.37 (br. d, 0.75H), 3.53 (br. s, 0.75H), 3.63 (br. d, 0.25H), 3.69-3.82 (m, 3.75H), 4.21-4.34 (m, 2.25H), 6.80-6.88 (m, 1.5H), 6.94-7.06 (m, 1.5H), 7.08-7.17 (m, 1H), 7.26-7.39 (m, 1H), 7.50-7.61 (m, 2H), 7.86-7.96 (m, 2H), 8.55- 8.63 (m, 1H), 9.00-9.09 (m, 1H). LC-MS (Method 2): R.sub.t = 1.46 min; m/z = 488/490 (M + H).sup.+. 39 [00094] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.47-1.82 (m, 3H), 1.84- 1.98 (m, 1H), 2.46-2.57 (m, 0.75H, obscured by DMSO signal), 2.60-2.87 (m, 2.25H), 2.92 (br. s, 0.75H), 3.02 (br. d, 0.25H), 3.42 (br. d, 1H), 3.77 (br. d, 0.75H), 4.20-4.33 (m, 2H), 4.37 (br. s, 0.25H), 7.09-7.17 (m, 1H), 7.20-7.40 (m, 3H), 7.41-7.61 (m, 3H), 7.83-7.95 (m, 2H), 8.56-8.63 (m, 1H), 8.98-9.08 (m, 1H). LC-MS (Method 2): R.sub.t = 1.49 min; m/z = 476/478 (M + H).sup.+. 40 [00095] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.46-1.99 (m, 4H), 2.63- 2.73 (m, 1H), 2.80-2.94 (m, 2H), 3.39 (dd, 0.75H), 3.48 (br. d, 0.25H), 3.70-3.83 (m, 3.75H), 3.92 (br. d, 0.25H), 3.98 (br. s, 0.75H), 4.24-4.35 (m, 2H), 4.38 (br. s, 0.25H), 6.84-6.94 (m, 1H), 7.08- 7.20 (m, 1.75H), 7.29 (d, 0.25H), 7.49-7.60 (m, 2H), 7.74-7.94 (m, 3H), 8.55-8.62 (m, 1H), 9.00-9.08 (m, 1H). LC-MS (Method 2): R.sub.t = 1.41 min; m/z = 489/491 (M + H).sup.+. 41 [00096] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.49-2.01 (m, 4H), 2.62- 2.87 (m, 2.25H), 2.92 (br. s, 0.75H), 3.15 (br. d, 0.25H), 3.38- 3.50 (m, 1.5H), 3.56 (br. d, 0.25H), 3.69-3.84 (m, 3.75H), 4.20-4.35 (m, 2H), 4.38 (br. s, 0.25H), 6.87-6.99 (m, 1H), 7.08- 7.17 (m, 1H), 7.49-7.59 (m, 2H), 7.70-7.82 (m, 1H), 7.83-7.95 (m, 2H), 8.56-8.63 (m, 1H), 8.98-9.08 (m, 1H). LC-MS (Method 2): R.sub.t = 1.51 min; m/z = 507/509 (M + H).sup.+. 42 [00097] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.48-1.83 (m, 3H), 1.83- 1.98 (m, 1H), 2.46-2.57 (m, 0.75H, obscured by DMSO signal), 2.60-2.88 (m, 2.25H), 2.92 (br. s, 0.75H), 3.02 (br. d, 0.25H), 3.43 (br. d, 1H), 3.77 (br. d, 0.75H), 4.20-4.34 (m, 2H), 4.38 (br. s, 0.25H), 7.08-7.17 (m, 1H), 7.19-7.40 (m, 3H), 7.41-7.60 (m, 3H), 7.83-7.95 (m, 2H), 8.55-8.63 (m, 1H), 8.97-9.08 (m, 1H). LC-MS (Method 2): R.sub.t = 1.50 min; m/z = 476/478 (M + H).sup.+. 43 [00098] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.44-1.99 (m, 4H), 2.61- 2.72 (m, 1H), 2.74-2.84 (m, 1H), 2.90 (br. s, 1H), 3.17 (br. d, 0.25H), 3.37 (br. d, 0.75H), 3.53 (br. s, 0.75H), 3.63 (br. d, 0.25H), 3.67-3.82 (m, 3.75H), 4.18-4.35 (m, 2.25H), 6.76-6.87 (m, 1.5H), 6.92-7.05 (m, 1.5H), 7.08-7.17 (m, 1H), 7.25-7.39 (m, 1H), 7.49-7.61 (m, 2H), 7.84-7.96 (m, 2H), 8.52- 8.63 (m, 1H), 8.98-9.09 (m, 1H). LC-MS (Method 2): R.sub.t = 1.46 min; m/z = 488/490 (M + H).sup.+. 44 [00099] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.46-1.99 (m, 4H), 2.63- 2.74 (m, 1H), 2.80-2.94 (m, 2H), 3.39 (dd, 0.75H), 3.49 (br. d, 0.25H), 3.69-3.83 (m, 3.75H), 3.92 (br. d, 0.25H), 3.98 (br. s, 0.75H), 4.24-4.35 (m, 2H), 4.38 (br. s, 0.25H), 6.84-6.94 (m, 1H), 7.08- 7.20 (m, 1.75H), 7.29 (d, 0.25H), 7.48-7.60 (m, 2H), 7.73-7.95 (m, 3H), 8.54-8.63 (m, 1H), 9.00-9.09 (m, 1H). LC-MS (Method 2): R.sub.t = 1.41 min; m/z = 489/491 (M + H).sup.+. 45 [00100] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.52-2.00 (m, 4H), 2.72 (br. d, 0.75H), 2.73 (br. d, 1H), 2.80 (br. s, 0.5H), 2.94-3.01 (m, 1H), 3.20 (br. s, 0.75H), 3.35-3.47 (m, 1H), 3.70-3.86 (m, 3.75H), 4.20-4.33 (m, 2H), 4.38 (br. s, 0.25H), 6.85-6.97 (m, 1H), 7.08- 7.19 (m, 1H), 7.49-7.61 (m, 2H), 7.79-7.94 (m, 3H), 8.56-8.64 (m, 1H), 8.97-9.08 (m, 1H). LC-MS (Method 2): R.sub.t = 1.63 min; MS (ESIpos): m/z = 523/524/525 [M + H].sup.+. 46 [00101] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.88-0.97 (m, 2H), 1.03- 1.13 (m, 2H), 2.44-2.65 (m, 3H, partially obscured by DMSO signal), 2.92-3.06 (m, 2H), 3.62- 3.73 (m, 2H), 3.77-3.90 (m, 2H), 3.96 (s, 2H), 4.41 (br. s, 1H), 4.75 (br. s, 1H), 7.08 (dd, 1H), 7.54 (d, 2H), 7.98 (d, 2H), 8.20 (s, 1H), 8.59 (dd, 1H), 9.29 (dd, 1H). LC-MS (Method 1): R.sub.t = 0.76 min; MS (ESIpos): m/z = 505/507 [M + H].sup.+. 47 [00102] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.89-0.98 (m, 2H), 1.00- 1.09 (m, 2H), 1.57-1.87 (m, 4H), 2.08-2.18 (m, 1H), 2.30-2.42 (m, 2H), 2.58-2.70 (m, 2H), 4.02 (s, 2H), 4.53 (br. s, 1H), 5.15 (br. s, 1H), 7.15 (dd, 1H), 7.56 (d, 2H), 7.97 (d, 2H), 8.37 (s, 1H), 8.59 (dd, 1H), 9.05 (dd, 1H). LC-MS (Method 2): R.sub.t = 1.75 min; MS (ESIpos): m/z = 489/491 [M + H].sup.+. 48 [00103] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.59-1.84 (m, 4H), 2.35- 2.44 (m, 2H), 2.52 (s, 3H, partially obscured by DMSO signal), 2.60- 2.69 (m, 2H), 4.02 (s, 2H), 4.57 (br. s, 1H), 5.12 (br. s, 1H), 7.14 (dd, 1H), 7.56 (d, 2H), 7.97 (d, 2H), 8.29 (s, 1H), 8.56 (dd, 1H), 9.06 (dd, 1H). LC-MS (Method 2): R.sub.t = 1.59 min; MS (ESIpos): m/z = 463/465 [M + H].sup.+. 49 [00104] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.21 (t, 6H), 1.63-1.82 (m, 4H), 2.39 (br. t, 2H), 2.64 (br. t, 2H), 3.62 (quin, 1H), 4.02 (s, 2H), 4.57 (br. s, 1H), 4.97 (br. s, 1H), 7.15 (dd, 1H), 7.56 (d, 2H), 7.96 (d, 2H), 8.29 (s, 1H), 8.59 (dd, 1H), 9.05 (dd, 1H). LC-MS (Method 2): R.sub.t = 1.86 min; MS (ESIpos): m/z = 491/493 [M + H].sup.+. 50 [00105] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.74 (br. s, 4H), 2.27 (s, 3H), 2.34-2.45 (m, 2H), 2.40 (s, 3H), 2.60-2.70 (m, 2H), 4.04 (s, 2H), 4.58 (br. s, 2H), 7.17 (dd, 1H), 7.56 (d, 2H), 7.97 (d, 2H), 8.59 (dd, 1H), 9.07 (dd, 1H). LC-MS (Method 2): R.sub.t = 1.53 min; MS (ESIpos): m/z = 477/479 [M + H].sup.+. 51 [00106] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.17 (t, 3H), 1.61-1.83 (m, 4H), 2.39 (br. d, 2H), 2.64 (br. d, 2H), 2.95 (q, 2H), 4.02 (s, 2H), 4.57 (br. s, 1H), 5.07 (br. s, 1H), 7.15 (dd, 1H), 7.56 (d, 2H), 7.96 (d, 2H), 8.30 (s, 1H), 8.59 (dd, 1H), 9.05 (dd, 1H). LC-MS (Method 2): R.sub.t = 1.73 min; MS (ESIpos): m/z = 477/479 [M + H].sup.+. 52 [00107] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.67-1.77 (m, 2H), 1.79- 1.91 (m, 2H), 2.39-2.48 (m, 2H), 2.43 (s, 3H), 2.66 (br. d, 1H), 2.72 (br. d, 1H), 4.04 (s, 2H), 4.57 (br. s, 1H), 5.46 (br. s, 1H), 7.15 (dd, 1H), 7.56 (d, 2H), 7.97 (d, 2H), 8.59 (dd, 1H), 9.06 (dd, 1H). LC-MS (Method 1): R.sub.t = 1.10 min; MS (ESIpos): m/z = 557/559 [M + H].sup.+. 53 [00108] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.86-0.99 (m, 2H), 1.02- 1.13 (m, 2H), 1.61-1.85 (m, 4H), 2.36-2.46 (m, 2H), 2.60-2.75 (m, 3H), 4.03 (s, 2H), 4.58 (br. s, 1H), 5.12 (br. s, 1H), 7.15 (dd, 1H), 7.56 (d, 2H), 7.97 (d, 2H), 8.18 (s, 1H), 8.59 (dd, 1H), 9.06 (dd, 1H). LC-MS (Method 1): R.sub.t = 0.91 min; MS (ESIpos): m/z = 489/491 [M + H].sup.+. 54 [00109] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.31 (d, 6H), 1.63-1.85 (m, 4H), 2.40-2.48 (m, 2H), 2.65 (br. d, 2H), 3.23-3.33 (m, 1H, partially obscured by H.sub.2O signal), 4.04 (s, 2H), 4.59 (br. s, 1H), 4.99 (br. s, 1H), 7.14 (dd, 1H), 7.55 (d 2H), 7.96 (d, 2H), 8.06 (s, 1H), 8.59 (dd, 1H), 9.05 (dd, 1H). LC-MS (Method 1): R.sub.t = 1.01 min; MS (ESIpos): m/z = 507/509 [M + H].sup.+. 55 [00110] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.62-1.94 (m, 4H), 2.39- 2.59 (m, 2H, partially obscured by DMSO signal), 2.68 (dd, 2H), 4.06 (s, 2H), 4.37-4.65 (m, 2H), 7.15 (dd, 1H), 7.57 (d, 2H), 7.97 (d, 2H), 8.29 (s, 1H), 8.60 (dd, 1H), 9.07 (dd, 1H), 9.23 (s, 1H). LC-MS (Method 1): R.sub.t = 0.77 min; MS (ESIpos): m/z = 465/467 [M + H].sup.+. 56 [00111] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.60-1.81 (m, 4H), 2.31- 2.42 (m, 2H), 2.36 (s, 3H), 2.47 (s, 3H), 2.63 (br. d, 2H), 4.02 (s, 2H), 4.54 (br. s, 1H), 5.18 (br. s, 1H), 7.14 (dd, 1H), 7.56 (d, 2H), 7.97 (d, 2H), 8.59 (dd, 1H), 9.05 (dd, 1H). LC-MS (Method 5): R.sub.t = 1.16 min; MS (ESIpos): m/z = 477/479 [M + H].sup.+. 57 [00112] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.62-1.77 (m, 4H), 2.21- 2.40 (m, 2H), 2.63 (br. d, 2H), 3.92 (br. s, 1H), 4.04 (s, 2H), 4.10 (s, 3H), 4.51 (br. s, 1H), 7.15 (dd, 1H), 7.57 (d, 2H), 7.93 (d, 2H), 8.59 (dd, 1H), 9.03 (dd, 1H). LC-MS (Method 5): R.sub.t = 1.30 min; MS (ESIpos): m/z = 563/565 [M + H].sup.+. 58 [00113] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.65-1.89 (m, 4H), 2.45 (br. d, 2H), 2.67 (br. t, 2H), 4.05 (s, 2H), 4.61 (br. s, 1H), 4.74 (br. s, 1H), 7.15 (dd, 1H), 7.56 (d, 2H), 7.97 (d, 2H), 8.59 (dd, 1H), 8.62 (s, 1H), 9.06 (dd, 1H). LC-MS (Method 5): R.sub.t = 1.31 min; MS (ESIpos): m/z = 533/535 [M + H].sup.+. 59 [00114] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.63-1.79 (m, 4H), 2.34- 2.45 (m, 2H), 2.46-2.61 (m, 1H, partially obscured by DMSO signal), 2.55 (s, 3H), 2.68 (dd, 1H), 4.04 (s, 2H), 4.34 (br. s, 1H), 4.60 (br. s, 1H), 7.15 (dd, 1H), 7.57 (d, 2H), 7.96 (d, 2H), 8.59 (dd, 1H), 8.89 (s, 1H), 9.06 (dd, 1H). LC-MS (Method 5): R.sub.t = 1.11 min; MS (ESIpos): m/z = 479/481 [M + H].sup.+. 60 [00115] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.68-1.80 (m, 2H), 1.83- 1.95 (m, 2H), 2.45 (br. d, 1H), 2.48-2.57 (m, 1H, partially obscured by DMSO signal), 2.65 (br. d, 1H), 2.80 (br. d, 1H), 4.05 (s, 2H), 4.61 (br. s, 1H), 5.43 (br. s, 1H), 7.15 (dd, 1H), 7.55 (d, 2H), 7.97 (d, 2H), 8.60 (dd, 1H), 8.79 (s, 1H), 9.06 (dd, 1H). LC-MS (Method 2): R.sub.t = 2.00 min; MS (ESIpos): m/z = 533/535 [M + H].sup.+. 61 [00116] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.75 (br. d, 4H), 2.44 (br. t, 2H), 2.66 (br. t, 2H), 4.03 (s, 2H), 4.62 (br. s, 1H), 5.02 (br. s, 1H), 7.14 (dd, 1H), 7.56 (d, 2H), 7.97 (d, 2H), 8.27 (d, 1H), 8.59 (dd, 1H), 9.06 (dd, 1H), 9.15 (d, 1H). LC-MS (Method 5): R.sub.t = 1.07 min; MS (ESIpos): m/z = 465/467 [M + H].sup.+. 62 [00117] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.25 (d, 6H), 1.64-1.81 (m, 4H), 2.41 (br. d, 1H), 2.58 (br. s, 1.75H), 2.65-2.76 (m, 4.25H), 2.88-3.01 (m, 1H), 3.98-4.09 (m, 2H), 4.60 (br. s, 1H), 4.76 (br. s, 1H), 6.51 (d, 1H), 6.65 (q, 1H), 6.80 (d, 1H), 7.12 (dd, 1H), 7.37 (d, 2H), 7.74 (d, 1H), 7.84 (d, 2H), 8.56 (dd, 1H), 9.02 (dd, 1H). LC-MS (Method 2): R.sub.t = 1.58 min; MS (ESIpos): m/z = 496 [M + H].sup.+. 63 [00118] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.25 (d, 6H), 1.66-1.84 (m, 4H), 2.44 (br. d, 1H), 2.56- 2.66 (m, 2H), 2.74 (dd, 1H), 2.95 (quin, 1H), 3.77 (s, 3H), 3.99-4.11 (m, 2H), 4.64 (br. s, 1H), 4.69 (br. s, 1H), 6.93 (d, 1H), 7.12 (dd, 1H), 7.31-7.40 (m, 3H), 7.77-7.88 (m, 3H), 8.57 (dd, 1H), 9.03 (dd, 1H). LC-MS (Method 5): R.sub.t = 1.24 min; MS (ESIpos): m/z = 497 [M + H].sup.+. 64 [00119] H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.26 (d, 6H), 1.64-1.81 (m, 4H), 2.26 (br. d, 1H), 2.42 (br. d, 1H), 2.58 (br. d, 1H), 2.68 (br. d, 1H), 2.96 (quin, 1H), 3.67 (br. s, 1H), 4.04 (s, 2H), 4.59 (br. s, 1H), 7.12 (dd, 1H), 7.23-7.32 (m, 2H), 7.38 (d, 2H), 7.41-7.54 (m, 2H), 7.83 (d, 2H), 8.56 (dd, 1H), 9.01 (dd, 1H). LC-MS (Method 5): R.sub.t = 1.23 min; MS (ESIpos): m/z = 484 [M + H].sup.+. 65 [00120] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.41-1.60 (m, 4H), 1.61- 1.75 (m, 1H), 1.76-1.90 (m, 1H), 2.01 (br. d, 0.5H), 2.06-2.24 (m, 2.5H), 2.34 (br. d, 1H), 3.12 (br. d, 0.5H), 3.23 (br. dd, 0.5H), 3.59 (s, 1.5H), 3.75 (br. d, 0.5H), 3.85 (s, 1.5H), 4.04 (br. d, 0.5H), 4.07- 4.17 (m, 1H), 4.43 (br. d, 0.5H), 4.71 (br. d, 0.5H), 6.89 (dd, 0.5H), 6.98 (dd, 0.5H), 7.08-7.15 (m, 1H), 7.52-7.61 (m, 2H), 7.66-7.84 (m, 3H), 8.53-8.63 (m, 1H), 9.27 (d, 1H). LC-MS (Method 2): R.sub.t = 1.77 min; MS (ESIpos): m/z = 521/523 [M + H].sup.+. 66 [00121] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.25 (d, 6H), 2.44-2.65 (m, 2H, partially obscured by DMSO signal), 2.86-3.00 (m, 2H), 3.05 (br. d, 1H), 3.66-3.82 (m, 3H), 3.80 (s, 3H), 3.89 (d, 1H), 3.94-4.06 (m, 2H), 4.20 (br. s, 1H), 4.45 (br. s, 1H), 6.92 (d, 1H), 7.06 (dd, 1H), 7.29 (d, 1H), 7.36 (d, 2H), 7.75-7.87 (m, 3H), 8.55 (dd, 1H), 9.28 (dd, 1H). LC-MS (Method 1): R.sub.t = 0.82 min; m/z = 513 (M + H).sup.+. 67 [00122] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.26 (d, 6H), 2.44-2.57 (m, 2H, obscured by DMSO signal), 2.84-3.00 (m, 2H), 3.06 (br. d, 1H), 3.34 (br. s, 1H, partially obscured by H.sub.2O signal), 3.61-3.75 (m, 3H), 3.82 (s, 3H), 3.88 (d, 1H), 3.99 (s, 2H), 4.44 (br. s, 1H), 6.93 (d, 1H), 7.05 (dd, 1H), 7.36 (d, 2H), 7.80 (d, 2H), 8.55 (dd, 1H), 9.28 (dd, 1H). LC-MS (Method 1): R.sub.t = 0.88 min; m/z = 547/549 (M + H).sup.+. 68 [00123] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.26 (d, 6H), 2.41 (br. d, 1H), 2.46-2.58 (m, 1H, obscured by DMSO signal), 2.84-3.06 (m, 3H), 3.37 (br. s, 1H), 3.59 (br. d, 1H), 3.71 (br. t, 2H), 3.87 (d, 1H), 3.99 (s, 2H), 4.47 (br. s, 1H), 7.05 (dd, 1H), 7.24-7.33 (m, 2H), 7.37 (d, 2H), 7.42-7.54 (m, 2H), 7.79 (d, 2H), 8.55 (dd, 1H), 9.28 (dd, 1H). LC-MS (Method 1): R.sub.t = 0.84 min; m/z = 500 (M + H).sup.+. 69 [00124] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.19-1.31 (m, 6H), 1.52- 2.00 (m, 4H), 2.62 (br. dd, 0.75H), 2.70-2.85 (m, 1.5H), 2.89-3.03 (m, 2H), 3.21 (br. s, 0.75H), 3.43 (br. d, 1H), 3.70-3.86 (m, 3.75H), 4.22-4.35 (m, 2H), 4.38 (br. s, 0.25H), 6.85-6.96 (m, 1H), 7.05- 7.15 (m, 1H), 7.30-7.40 (m, 2H), 7.70-7.86 (m, 2.7H), 7.90 (d, 0.3H), 8.56 (dd, 1H), 8.94-9.04 (m, 1H). LC-MS (Method 2): R.sub.t = 1.73 min; m/z = 531/533 (M + H).sup.+. 70 [00125] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.81-0.95 (m, 2H), 0.96- 1.09 (m, 2H), 1.25 (d, 6H), 1.49- 1.63 (m, 1H), 1.66-2.00 (m, 3H), 2.44-2.57 (m, 0.7H, partially obscured by DMSO signal), 2.57- 2.65 (m, 0.3H), 2.73-3.02 (m, 4H), 3.36 (dd, 0.7H), 3.63-3.76 (m, 1H), 4.04 (br. d, 0.3H), 4.22-4.33 (m, 2H), 4.36 (br. s, 0.3H), 4.59 (br. s, 0.7H), 7.06-7.14 (m, 1H), 7.31-7.40 (m, 2H), 7.75-7.83 (m, 2H), 8.12-8.19 (m, 1H), 8.53-8.60 (m, 1H), 8.98-9.06 (m, 1H). LC-MS (Method 2): R.sub.t = 1.52 min; m/z = 497 (M + H).sup.+. 71 [00126] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.20-1.30 (m, 6H), 1.50- 2.01 (m, 4H), 2.69 (br. dd, 0.75H), 2.74 (br. s, 0.25H), 2.77-2.88 (m, 1.25H), 2.90-3.01 (m, 1.75H), 3.13 (br. d, 0.25H), 3.39-3.52 (m, 1.5H), 3.61 (d, 0.25H), 3.69-3.84 (m, 3.75H), 4.21-4.35 (m, 2H), 4.36-4.42 (m, 0.25H), 6.88-6.98 (m, 1H), 7.05-7.15 (m, 1H), 7.30- 7.40 (m, 2H), 7.70-7.83 (m, 3H), 8.52-8.60 (m, 1H), 8.96-9.06 (m, 1H). LC-MS (Method 2): R.sub.t = 1.62 min; m/z = 515 (M + H).sup.+. 72 [00127] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.20-1.31 (m, 6H), 1.51- 2.01 (m, 4H), 2.69 (br. dd, 0.75H), 2.74 (br. s, 0.25H), 2.77-2.87 (m, 1.25H), 2.89-3.02 (m, 1.75H), 3.14 (br. d, 0.25H), 3.39-3.52 (m, 1.5H), 3.61 (d, 0.25H), 3.69-3.83 (m, 3.75H), 4.21-4.35 (m, 2H), 4.36-4.42 (m, 0.25H), 6.88-6.98 (m, 1H), 7.05-7.15 (m, 1H), 7.30- 7.41 (m, 2H), 7.70-7.84 (m, 3H), 8.53-8.60 (m, 1H), 8.96-9.05 (m, 1H). LC-MS (Method 2): R.sub.t = 1.63 min; m/z = 515 (M + H).sup.+. 73 [00128] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.25 (d, 6H), 1.49-2.01 (m, 4H), 2.69-2.76 (m, 1H), 2.83- 3.02 (m, 3H), 3.39 (dd, 0.75H), 3.47 (br. d, 0.25H), 3.70-3.86 (m, 3.75H), 3.93-4.04 (m, 1H), 4.23- 4.35 (m, 2H), 4.39 (br. s, 0.25H), 6.84-6.95 (m, 1H), 7.05-7.14 (m, 1H), 7.17 (d, 0.75H), 7.26-7.40 (m, 2.25H), 7.73-7.85 (m, 3H), 8.52-8.60 (m, 1H), 8.97-9.06 (m, 1H). LC-MS (Method 2): R.sub.t = 1.56 min; m/z = 497 (M + H).sup.+. 74 [00129] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.25 (d, 6H), 1.49-2.01 (m, 4H), 2.69-2.76 (m, 1H), 2.82- 3.01 (m, 3H), 3.39 (dd, 0.75H), 3.47 (br. d, 0.25H), 3.70-3.85 (m, 3.75H), 3.93-4.02 (m, 1H), 4.23- 4.35 (m, 2H), 4.39 (br. s, 0.25H), 6.84-6.94 (m, 1H), 7.05-7.14 (m, 1H), 7.17 (d, 0.75H), 7.25-7.40 (m, 2.25H), 7.73-7.85 (m, 3H), 8.52-8.60 (m, 1H), 8.97-9.05 (m, 1H). LC-MS (Method 2): R.sub.t = 1.55 min; m/z = 497 (M + H).sup.+. 75 [00130] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.20-1.29 (m, 6H), 1.50- 2.01 (m, 4H), 2.71 (dd, 0.75H), 2.75 (br. s, 0.25H), 2.83-3.01 (m, 3H), 3.39 (dd, 0.75H), 3.47 (br. d, 0.25H), 3.73 (d, 0.75H), 3.93 (br. s, 1H), 4.23-4.34 (m, 2H), 4.39 (br. s, 0.25H), 7.05-7.13 (m, 1H), 7.14-7.22 (m, 1H), 7.31-7.41 (m, 2.25H), 7.45 (d, 0.75H), 7.48-7.71 (m, 1H), 7.75-7.82 (m, 2H), 7.97- 8.09 (m, 1H), 8.53-8.60 (m, 1H), 8.96-9.05 (m, 1H). LC-MS (Method 2): R.sub.t = 1.68 min; m/z = 533 (M + H).sup.+. 76 [00131] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.20-1.30 (m, 6H), 1.50- 2.01 (m, 4H), 2.71 (dd, 0.75H), 2.75 (br. s, 0.25H), 2.82-3.02 (m, 3H), 3.39 (dd, 0.75H), 3.47 (br. d, 0.25H), 3.73 (d, 0.75H), 3.93 (br. s, 1H), 4.23-4.35 (m, 2H), 4.38 (br. s, 0.25H), 7.05-7.13 (m, 1H), 7.14-7.23 (m, 1H), 7.31-7.41 (m, 2.25H), 7.45 (d, 0.75H), 7.49-7.71 (m, 1H), 7.75-7.83 (m, 2H), 7.97- 8.09 (m, 1H), 8.52-8.60 (m, 1H), 8.96-9.07 (m, 1H). LC-MS (Method 2): R.sub.t = 1.69 min; m/z = 533 (M + H).sup.+. 77 [00132] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.20-1.31 (m, 6H), 1.51- 2.00 (m, 4H), 2.03-2.12 (m, 3H), 2.63 (dd, 0.75H), 2.70-2.77 (m, 1H), 2.81 (d, 0.5H), 2.89-3.03 (m, 2H), 3.24 (br. s, 0.75H), 3.42 (br. d, 1H), 3.65-3.84 (m, 3.75H), 4.20-4.34 (m, 2H), 4.37-4.43 (m, 0.25H), 6.71-6.80 (m, 1H), 7.06- 7.14 (m, 1H), 7.29-7.41 (m, 2H), 7.54-7.65 (m, 1H), 7.72-7.83 (m, 2H), 8.52-8.60 (m, 1H), 8.95-9.05 (m, 1H). LC-MS (Method 6): R.sub.t = 1.68 min; m/z = 511 (M + H).sup.+. 78 [00133] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.19-1.31 (m, 6H), 1.51- 2.00 (m, 4H), 2.02-2.14 (m, 3H), 2.63 (dd, 0.75H), 2.69-2.78 (m, 1H), 2.81 (d, 0.5H), 2.89-3.03 (m, 2H), 3.24 (br. s, 0.75H), 3.42 (br. d, 1H), 3.65-3.84 (m, 3.75H), 4.20-4.35 (m, 2H), 4.37-4.43 (m, 0.25H), 6.70-6.80 (m, 1H), 7.06- 7.15 (m, 1H), 7.30-7.40 (m, 2H), 7.54-7.64 (m, 1H), 7.72-7.83 (m, 2H), 8.53-8.60 (m, 1H), 8.94-9.05 (m, 1H). LC-MS (Method 6): R.sub.t = 1.68 min; m/z = 511 (M + H).sup.+. 79 [00134] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.45-2.01 (m, 4H), 2.44- 2.57 (m, 0.5H), 2.59-2.86 (m, 2.5H), 2.89-3.07 (m, 1H), 3.36- 3.49 (m, 1H), 3.77 (br. d, 0.7H), 4.17-4.43 (m, 2.3H), 7.04-7.19 (m, 1H), 7.18-7.39 (m, 3H), 7.40-7.58 (m, 1H), 7.62-7.75 (m, 2H), 7.76- 7.91 (m, 2H), 8.54-8.63 (m, 1H), 8.96-9.07 (m, 1H). LC-MS (Method 2): R.sub.t = 1.54 min; m/z = 520/522 (M + H).sup.+. 80 [00135] 81 [00136] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.52-1.99 (m, 4H), 2.67 (dd, 0.75H), 2.72 (br. s, 0.25H), 2.77-2.86 (m, 1.25H), 2.93 (br. s, 0.75H), 3.15 (br. d, 0.25H), 3.43 (dd, 0.75H), 3.48 (br. s, 0.75H), 3.57 (br. d, 0.25H), 3.70-3.83 (m, 3.75H), 4.22-4.34 (m, 2H), 4.36- 4.41 (m, 0.25H), 6.89-6.99 (m, 1H), 7.08-7.17 (m, 1H), 7.64-7.88 (m, 5H), 8.57-8.62 (m, 1H), 9.00- 9.08 (m, 1H). LC-MS (Method 2): R.sub.t = 1.55 min; m/z = 551/553 (M + H).sup.+. 82 [00137] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.60-1.83 (m, 4H), 2.39- 2.58 (m, 3H, partially obscured by DMSO signal), 2.75 (dd, 1H), 3.76 (s, 3H), 3.91 (br. s, 1H), 4.00-4.13 (m, 2H), 4.60 (br. s, 1H), 6.95 (dd, 1H), 7.14 (dd, 1H), 7.70 (d, 2H), 7.77 (t, 1H), 7.89 (d, 2H), 8.59 (dd, 1H), 9.06 (dd, 1H). LC-MS (Method 1): R.sub.t = 0.93 min; m/z = 551/553 (M + H).sup.+. 83 [00138] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.64-1.81 (m, 4H), 2.24 (br. d, 1H), 2.42 (br. d, 1H), 2.47- 2.60 (m, 1H, partially obscured by DMSO signal), 2.68 (br. d, 1H), 3.66 (br. s, 1H), 4.04 (s, 2H), 4.59 (br. s, 1H), 7.14 (dd, 1H), 7.24- 7.32 (m, 2H), 7.40-7.55 (m, 2H), 7.70 (d, 2H), 7.88 (d, 2H), 8.59 (dd, 1H), 9.04 (dd, 1H). LC-MS (Method 1): R.sub.t = 0.93 min; m/z = 520/522 (M + H).sup.+. 84 [00139] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.44-1.66 (m, 7H), 1.66- 1.80 (m, 5H), 2.26 (br. dd, 2H), 2.46-2.65 (m, 2H, partially obscured by DMSO signal), 2.80- 2.91 (m, 1H), 3.95-4.05 (m, 2H), 4.28 (br. s, 1H), 4.37-4.44 (m, 1H), 7.14 (dd, 1H), 7.70 (d, 2H), 7.90 (d, 2H), 8.59 (dd, 1H), 9.05 (dd, 1H). LC-MS (Method 1): R.sub.t = 0.97 min; m/z = 494/496 (M + H).sup.+.

Example 85

3-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-N-(2,4-difluorophenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxamide

[0637] ##STR00140##

[0638] 15.5 mg (0.10 mmol) of 2,4-difluorophenyl isocyanate were initially charged in a well of a 96-well multititre plate and cooled to 0° C. Separately, 46.3 mg of 2-(4-chlorophenyl)-3-(3,8-diazabicyclo[3.2.1]oct-3-ylmethyl)imidazo[1,2-a]pyrimidine dihydrochloride were dissolved in 0.8 ml of 1,2-dichloroethane, 0.052 ml (0.3 mmol) of N,N-diisopropylethylamine was added, and the mixture was cooled to 8° C. The two solutions were combined in the multititer plate, 4 Å molecular sieve was added and first subjected to agitation at 0° C. for 1 h. Subsequently, the mixture was allowed to warm up to RT and agitated at RT overnight. Thereafter, the solvent was removed completely by means of a centrifugal dryer. The residue was dissolved in 0.6 ml of DMF and filtered, and the filtrate was separated into its components by preparative LC-MS by one of the following methods:

[0639] MS instrument: Waters, HPLC instrument: Waters; column: Phenomenex Luna 5μ C18(2) 100A, AXIA Tech., 50 mm×21.2 mm; mobile phase A: water, mobile phase B: acetonitrile, with mobile phase gradient; flow rate: 38.5 ml/min+1.5 ml/min 10% aq. formic acid; UV detection: DAD, 210-400 nm

[0640] or

[0641] MS instrument: Waters, HPLC instrument: Waters; column: Phenomenex Luna 5μ C18(2) 100A, AXIA Tech., 50 mm×21.2 mm; mobile phase A: water, mobile phase B: methanol, with mobile phase gradient; flow rate: 38.5 ml/min+1.5 ml/min 10% ammonia in water; UV detection: DAD, 210-400 nm.

[0642] In this way, 17.9 mg (35% of theory, 100% purity) of the title compound were obtained.

[0643] LC-MS (Method 7, ESIpos): R.sub.t=1.14 min; m/z=509 (M+H).sup.+.

[0644] In a parallel synthetic manner analogous to Example 85, the following compounds were prepared starting from 2-(4-chlorophenyl)-3-(3,8-diazabicyclo[3.2.1]oct-3-ylmethyl)imidazo[1,2-a]pyrimidine dihydrochloride and the appropriate isocyanate, carbamoyl chloride or chloroformate:

TABLE-US-00006 Name/structure Example (yield, purity) LC-MS (Method 7)  86 [00141] R.sub.t = 1.03 min; m/z = 439 [M + H].sup.+  87 [00142] R.sub.t = 0.99 min; m/z = 437 [M + H].sup.+  88 [00143] R.sub.t = 1.22 min; m/z = 571 [M + H].sup.+  89 [00144] R.sub.t = 1.19 min; m/z = 507 [M + H].sup.+  90 [00145] R.sub.t = 1.14 min; m/z = 523 [M + H].sup.+  91 [00146] R.sub.t = 1.15 min; m/z = 541 [M + H].sup.+  92 [00147] R.sub.t = 1.14 min; m/z = 501 [M + H].sup.+  93 [00148] R.sub.t = 1.13 min; m/z = 491 [M + H].sup.+  94 [00149] R.sub.t = 1.24 min; m/z = 541 [M + H].sup.+  95 [00150] R.sub.t = 1.17 min; m/z = 501 [M + H].sup.+  96 [00151] R.sub.t = 1.17 min; m/z = 507 [M + H].sup.+  97 [00152] R.sub.t = 1.29 min; m/z = 575 [M + H].sup.+  98 [00153] R.sub.t = 1.18 min; m/z = 515 [M + H].sup.+  99 [00154] R.sub.t = 1.17 min; m/z = 501 [M + H].sup.+ 100 [00155] R.sub.t = 1.14 min; m/z = 479 [M + H].sup.+ 101 [00156] R.sub.t = 1.09 min; m/z = 453 [M + H].sup.+ 102 [00157] R.sub.t = 1.07 min; m/z = 533 [M + H].sup.+ 103 [00158] R.sub.t = 1.27 min; m/z = 573 [M + H].sup.+ 104 [00159] R.sub.t = 1.16 min; m/z = 491 [M + H].sup.+ 105 [00160] R.sub.t = 1.10 min; m/z = 509 [M + H].sup.+ 106 [00161] R.sub.t = 1.25 min; m/z = 575 [M + H].sup.+ 107 [00162] R.sub.t = 1.16 min; m/z = 501 [M + H].sup.+ 108 [00163] R.sub.t = 1.22 min; m/z = 487 [M + H].sup.+ 109 [00164] R.sub.t = 1.16 min; m/z = 453 [M + H].sup.+ 110 [00165] R.sub.t = 1.03 min; m/z = 467 [M + H].sup.+ 111 [00166] R.sub.t = 1.23 min; m/z = 481 [M + H].sup.+ 112 [00167] R.sub.t = 1.30 min; m/z = 507 [M + H].sup.+ 113 [00168] R.sub.t = 1.10 min; m/z = 451 [M + H].sup.+ 114 [00169] R.sub.t = 1.25 min; m/z = 501 [M + H].sup.+ 115 [00170] R.sub.t = 1.14 min; m/z = 453 [M + H].sup.+ 116 [00171] R.sub.t = 1.16 min; m/z = 465 [M + H].sup.+ 117 [00172] R.sub.t = 1.30 min; m/z = 515 [M + H].sup.+ 118 [00173] R.sub.t = 1.33 min; m/z = 549 [M + H].sup.+ 119 [00174] R.sub.t = 1.05 min; m/z = 425 [M + H].sup.+ 120 [00175] R.sub.t = 1.26 min; m/z = 531 [M + H].sup.+ 121 [00176] R.sub.t = 1.23 min; m/z = 531 [M + H].sup.+ 122 [00177] R.sub.t = 1.13 min; m/z = 483 [M + H].sup.+ 123 [00178] R.sub.t = 1.10 min; m/z = 412 [M + H].sup.+ 124 [00179] R.sub.t = 1.15 min; m/z = 426 [M + H].sup.+ 125 [00180] R.sub.t = 1.26 min; m/z = 466 [M + H].sup.+ 126 [00181] R.sub.t = 1.21 min; m/z = 440 [M + H].sup.+ 127 [00182] R.sub.t = 1.35 min; m/z = 494 [M + H].sup.+ 128 [00183] R.sub.t = 1.30 min; m/z = 480 [M + H].sup.+ 129 [00184] R.sub.t = 1.29 min; m/z = 468 [M + H].sup.+

Example 130

tert-Butyl 3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0645] ##STR00185##

[0646] Under argon and at room temperature, 2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidine-3-carbaldehyde (700 mg, 2.64 mmol) was dissolved in 14 ml of THF, and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (672 mg, 3.17 mmol) was added. Sodium triacetoxyborohydride (839 mg, 3.96 mmol) was then added a little at a time, and the reaction solution was stirred at room temperature overnight. Then water was gradually and carefully added dropwise (caution: evolution of gas), and subsequently ethyl acetate was added. The resulting organic phase was removed and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure on a rotary evaporator. The residue obtained was purified by column chromatography (Biotage Isolera, Biotage SNAP-KP-NH column; mobile phase: cyclohexane/ethyl acetate gradient). This gave 896 mg (1.94 mmol, 74% of theory) of the target compound.

[0647] LC-MS (Method 2): R.sub.t=2.14 min; m/z=462 (M+H).sup.+.

[0648] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.25 (d, 6H), 1.39 (s, 9H), 1.65 (br. s, 4H), 2.26 (br. d, 2H), 2.47-2.60 (m, 2H, partially obscured by DMSO signal), 2.95 (quin, 1H), 3.98 (s, 2H), 4.02 (br. s, 2H), 7.12 (dd, 1H), 7.37 (d, 2H), 7.83 (d, 2H), 8.56 (dd, 1H), 8.99 (dd, 1H).

Example 131

(5-Cyclopropyl-1,3-oxazol-4-yl)(3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)methanone

[0649] ##STR00186##

[0650] 5-Cyclopropyl-1,3-oxazole-4-carboxylic acid (39 mg, 0.26 mmol) was dissolved in 1.5 ml of DMF, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (121 mg, 0.32 mmol) was added and the mixture was stirred at room temperature for 30 min. 3-(3,8-Diazabicyclo[3.2.1]oct-3-ylmethyl)-2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidine dihydrochloride (100 mg) and N,N-diisopropylethylamine (190 μl, 1.06 mmol) were then added and the mixture was stirred at room temperature overnight. Thereafter, the reaction mixture was separated directly into its components via preparative HPLC (Method 9). 65 mg (0.13 mmol, 61% of theory) of the title compound were obtained.

[0651] LC-MS (Method 2): R.sub.t=1.81 min; MS (ESIpos): m/z=497 [M+H].sup.+.

[0652] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=0.85-0.99 (m, 2H), 1.01-1.13 (m, 2H), 1.25 (d, 6H), 1.63-1.85 (m, 4H), 2.35-2.45 (m, 2H), 2.60-2.74 (m, 3H), 2.88-3.01 (m, 1H), 4.03 (s, 2H), 4.53-4.64 (m, 1H), 5.12 (br. s, 1H), 7.12 (dd, 1H), 7.37 (d, 2H), 7.85 (d, 2H), 8.17 (s, 1H), 8.57 (dd, 1H), 9.03 (dd, 1H).

Example 132

tert-Butyl 3-{[2-(4-cyclopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0653] ##STR00187##

[0654] Under argon and at room temperature, 1090 mg (2.19 mmol) of tert-butyl 3-{[2-(4-bromophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate were initially charged in 15 ml of toluene and 3 ml of water in a 30 ml microwave vessel, and cyclopropylboronic acid (376 mg, 4.37 mmol), potassium phosphate (1625 mg, 7.65 mmol), palladium(II) acetate (49 mg, 0.22 mmol) and tricyclohexylphosphine (123 mg, 0.44 mmol) were then added. The microwave vessel was then closed and the mixture was heated to 120° C. and stirred at this temperature overnight. After cooling to room temperature, the reaction mixture was filtered through kieselguhr and the residue was washed a little at a time with ethyl acetate. More ethyl acetate and water were added to the filtrate obtained, and the phases were separated. The organic phase was washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated to dryness. The residue was then stirred with diethyl ether. After filtration, the solid obtained was dried under high vacuum overnight. This gave 667 mg (1.36 mmol, 62% of theory) of the target compound.

[0655] LC-MS (Method 2): R.sub.t=2.00 min; m/z=460 (M+H).sup.+.

[0656] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=0.69-0.77 (m, 2H), 0.95-1.03 (m, 2H), 1.39 (s, 9H), 1.65 (br. s, 4H), 1.93-2.03 (m, 1H), 2.24 (br. d, 2H), 2.45-2.61 (m, 2H, partially obscured by DMSO signal), 3.97 (s, 2H), 4.02 (br. s, 2H), 7.11 (dd, 1H), 7.20 (d, 2H), 7.78 (d, 2H), 8.55 (dd, 1H), 8.99 (dd, 1H).

[0657] Analogously to Examples 13-29, the following compounds were prepared from the starting materials specified in each case:

TABLE-US-00007 Example Name/Structure/Starting materials Analytical data 133 [00188] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.70-0.77 (m, 2H), 0.95-1.02 (m, 2H), 1.65-1.79 (m, 4H), 1.93-2.02 (m, 1H), 2.24 (br. d, 1H), 2.41 (br. d, 1H), 2.56 (dd, 1H), 2.68 (dd, 1H), 3.66 (br. s, 1H), 4.03 (s, 2H), 4.59 (br. s, 1H), 7.12 (dd, 1H), 7.20 (d, 2H), 7.25-7.32 (br. s, 1H), 7.41-7.53 (m, 2H), 7.78 (d, 2H), 8.55 (dd, 1H), 9.00 (dd, 1H). LC-MS (Method 1): R.sub.t = 0.87 min; m/z = 482 (M + H).sup.+. 134 [00189] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.68-0.79 (m, 2H), 0.94-1.03 (m, 2H), 1.44-1.68 (m, 7H), 1.68-1.78 (m, 5H), 1.97 (tt, 1H), 2.18-2.30 (m, 2H), 2.53-2.65 (m, 2H), 2.80-2.90 (m, 1H), 3.94-4.03 (m, 2H), 4.28 (br. s, 1H), 4.41 (br. d, 1H), 7.11 (dd, 1H), 7.20 (d, 2H), 7.79 (d, 2H), 8.56 (dd, 1H), 9.01 (dd, 1H). LC-MS (Method 1): R.sub.t = 0.90 min; m/z = 456 (M + H).sup.+. 135 [00190] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.69-0.78 (m, 2H), 0.95-1.04 (m, 2H), 1.63-1.84 (m, 4H), 1.93-2.02 (m, 1H), 2.43 (br. t, 2H), 2.52-2.57 (m, 1H), 2.76 (dd, 1H), 3.75 (s, 3H), 3.91 (br. s, 1H), 3.99-4.09 (m, 2H), 4.61 (br. s, 1H), 6.95 (dd, 1H), 7.12 (dd, 1H), 7.20 (d, 2H), 7.73-7.81 (m, 3H), 8.56 (dd, 1H), 9.01 (dd, 1H). LC-MS (Method 1): R.sub.t = 0.86 min; m/z = 513 (M + H).sup.+. 136 [00191] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.68-0.78 (m, 2H), 0.94-1.03 (m, 2H), 1.62-1.83 (m, 4H), 1.93-2.02 (m, 1H), 2.33-2.44 (m, 2H), 2.45-2.56 (m, 1H, partially obscured by DMSO signal), 2.75 (dd, 1H), 3.62 (br. s, 1H), 3.78 (s, 3H), 3.99-4.10 (m, 2H), 4.60 (br. s, 1H), 6.92 (d, 1H), 7.12 (dd, 1H), 7.19 (d, 2H), 7.77 (d, 2H), 7.87 (d, 1H), 8.56 (dd, 1H), 9.00 (dd, 1H). LC-MS (Method 1): R.sub.t = 0.90 min; m/z = 529/531 (M + H).sup.+. 137 [00192] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.65-0.79 (m, 2H), 0.94-1.04 (m, 2H), 1.65-1.82 (m, 4H), 1.93-2.01 (m, 1H), 2.43 (br. d, 1H), 2.55-2.64 (m, 2H), 2.73 (dd, 1H), 3.77 (s, 3H), 3.98-4.09 (m, 2H), 4.63 (br. s, 1H), 4.69 (br. s, 1H), 6.92 (dd, 1H), 7.12 (dd, 1H), 7.20 (d, 2H), 7.35 (dd, 1H), 7.75-7.85 (m, 3H), 8.56 (dd, 1H), 9.02 (dd, 1H). LC-MS (Method 1): R.sub.t = 0.87 min; m/z = 495 (M + H).sup.+. 138 [00193] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.68-0.76 (m, 2H), 0.94-1.02 (m, 2H), 1.67-1.83 (m, 4H), 1.92-2.01 (m, 1H), 2.42 (br. d, 1H), 2.53-2.59 (m, 1H), 2.60-2.66 (m, 1H), 2.72 (dd, 1H), 4.04 (s, 2H), 4.57 (br. s, 1H), 4.64 (br. s, 1H), 7.11 (dd, 1H), 7.16-7.24 (m, 3H), 7.44 (s, 0.25H), 7.56-7.64 (m, 1.5H), 7.73 (s, 0.25H), 7.79 (d, 2H), 8.05 (t, 1H), 8.57 (dd, 1H), 9.03 (dd, 1H). LC-MS (Method 1): R.sub.t = 0.91 min; m/z = 531 (M + H).sup.+. 139 [00194] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.69-0.77 (m, 2H), 0.87-1.01 (m, 4H), 1.02-1.12 (m, 2H), 1.61-1.85 (m, 4H), 1.92-2.01 (m, 1H), 2.39 (br. t, 2H), 2.60-2.74 (m, 3H), 4.01 (s, 2H), 4.59 (br. d, 1H), 5.11 (br. s, 1H), 7.12 (dd, 1H), 7.20 (d, 2H), 7.80 (d, 2H), 8.17 (s, 1H), 8.56 (dd, 1H), 9.02 (dd, 1H). LC-MS (Method 1): R.sub.t = 0.87 min; m/z = 495 (M + H).sup.+.

B. ASSESSMENT OF PHARMACOLOGICAL EFFICACY

[0658] The pharmacological activity of the compounds of the invention can be demonstrated by in vitro and in vivo studies as known to the person skilled in the art. The application examples which follow describe the biological action of the compounds of the invention, without restricting the invention to these examples.

[0659] B-1. In Vitro Electrophysiological Analysis of the Human TASK-1 and TASK-3 Channels Via Two-Electrode Voltage Clamp Technique in Xenopus laevis Oocytes

[0660] Xenopus laevis oocytes were selected as described elsewhere by way of illustration [Decher et al., FEBS Lett. 492, 84-89 (2001)]. Subsequently, the oocytes were injected with 0.5-5 ng of a cRNA solution coding for TASK-1 or TASK-3. For the electrophysiological analysis of the channel proteins expressed in the oocytes, the two-electrode voltage clamp technique [Stüihmer, Methods Enzymol. 207, 319-339 (1992)] was used. The measurements were conducted as described [Decher et al., FEBS Lett. 492, 84-89 (2001)] at room temperature (21-22° C.) using a Turbo TEC 10CD amplifier (NPI), recorded at 2 kHz and filtered with 0.4 kHz. Substance administration was performed using a gravitation-driven perfusion system. Here, the oocyte is located in a measuring chamber and exposed to the solution stream of 10 ml/min. The level in the measuring chamber is monitored and regulated by sucking off the solution using a peristaltic pump.

[0661] Table 1 below shows the half-maximum inhibition, determined in this test, of human TASK-1 and TASK-3 channels (IC.sub.50) by representative working examples of the invention:

TABLE-US-00008 TABLE 1 Example TASK-1 TASK-3 No. IC.sub.50 [nM] IC.sub.50 [nM] 19 239.4 ± 2.7  774.2 ± 67.1 21 19.2 ± 4.3 32.9 ± 6.0 26 31.2 ± 5.8 140.0 ± 34.6 27 17.9 ± 2.2 367.1 ± 67.6 28 20.5 ± 2.7  6.6 ± 0.8 29 21.0 ± 4.1 42.7 ± 8.4 41 44.4 ± 4.4  71.8 ± 15.5 51 21.7 ± 4.6 35.9 ± 8.2

[0662] From the data in Table 1 it is evident that both TASK-1 and TASK-3 are blocked. The results in Table 1 thus confirm the mechanism of action of the compounds according to the invention as dual TASK-1/3 inhibitors.

[0663] B-2. Inhibition of Recombinant TASK-1 and TASK-3 In Vitro

[0664] The investigations on the inhibition of the recombinant TASK-1 and TASK-3 channels were conducted using stably transfected CHO cells. The compounds according to the invention were tested in this case by application of 40 mM potassium chloride in the presence of a voltage-sensitive dye according to the method described in detail in the following references [Whiteaker et al., Validation of FLIPR membrane potential dye for high-throughput screening of potassium channel modulators, J. Biomol. Screen. 6 (5), 305-312 (2001); Molecular Devices FLIPR Application Note: Measuring membrane potential using the FLIPR® membrane potential assay kit on Fluorometric Imaging Plate Reader (FLIPR®) systems, http://www.moleculardevices.com/reagents-supplies/assay-kits/ion-channels/flipr-membrane-potential-assay-kits]. The activity of the test substances was determined as their ability to inhibit a depolarization induced in the recombinant cells by 40 mM potassium chloride. The concentration which can block half of this depolarization is referred to as IC.sub.50.

[0665] Table 2 below lists the IC.sub.50 values from this assay determined for individual working examples of the invention (some as mean values from multiple independent individual determinations):

TABLE-US-00009 TABLE 2 Example TASK-1 TASK-3 No. IC.sub.50 [nM] IC.sub.50 [nM] 1 1700 400 4 470 97 5 17000 1300 6 1400 41 7 8600 570 10 2200 130 11 2500 16 12 220 13 13 1500 33 14 7600 170 15 1100 19 16 670 12 17 1200 33 18 910 8.6 19 22000 59 20 160 38 21 140 4.2 22 340 5.2 23 1600 100 24 410 102 25 1100 71 26 1400 16 27 1200 10 28 290 3.2 29 280 1.8 30 3500 85 31 7100 140 32 370 29 33 190 130 34 76 29 35 6700 1500 36 310 80 37 1500 140 38 9600 320 39 1400 160 40 5700 210 41 1500 100 42 1000 340 43 1000 320 44 1000 190 45 1800 120 46 7600 140 47 2800 110 48 400 23 49 260 12 50 3300 430 51 250 8.7 52 1300 52 53 620 19 54 860 13 55 2900 170 56 5600 54 57 6400 57 58 1600 17 59 3000 39 60 670 430 61 3000 640 62 6900 70 63 1700 15 64 1100 8.4 65 3500 670 66 3700 20 67 1200 17 68 9400 87 69 2800 22 70 1900 20 71 14000 110 72 2100 29 73 9100 81 74 3400 61 75 3800 51 76 13000 56 77 720 4.9 78 3800 24 81 820 21 82 670 37 83 250 14 84 93 4.6 85 30000 1000 86 7700 430 89 30000 850 91 20000 410 92 15000 270 93 12000 260 94 30000 160 95 3000 41 97 31000 450 98 9000 160 99 30000 750 100 19000 630 101 19000 510 103 30000 690 104 19000 460 106 30000 89 107 30000 750 108 7000 90 109 24 1.5 110 13000 230 111 6300 290 112 15000 130 113 1100 62 114 6700 140 115 7400 330 116 2700 65 118 19000 220 119 5300 210 120 15000 230 121 12000 120 122 5000 120 123 14000 230 124 790 17 125 230 27 126 280 14 128 2000 110 130 1700 210 131 3500 410 132 1700 410 133 1600 180 134 770 97 135 420 34 136 320 41 137 1100 180 138 3200 290 139 4500 470

[0666] From the data in Table 2 it is evident that both TASK-1 and in particular TASK-3 are blocked. The results in Table 2 thus confirm the mechanism of action of the compounds according to the invention as dual TASK-1/3 inhibitors.

[0667] B-3. Animal Model of Obstructive Sleep Apnoea in the Pig

[0668] Using negative pressure, it is possible to induce collapse and thus obstruction of the upper respiratory tract in anaesthetized, spontaneously breathing pigs [Wirth et al., Sleep 36, 699-708 (2013)].

[0669] German Landrace pigs are used for the model. The pigs are anaesthetized and tracheotomized. One cannula each is inserted into the rostral and the caudal part of the trachea. Using a T connector, the rostral cannula is connected on the one hand to a device generating negative pressures and on the other hand to the caudal cannula. Using a T connector, the caudal cannula is connected to the rostral cannula and to a tube which allows spontaneous breathing circumventing the upper respiratory tract. By appropriate closing and opening of the tubes it is thus possible for the pig to change from normal nasal breathing to breathing via the caudal cannula during the time when the upper respiratory tract is isolated and connected to the device for generating negative pressures. The muscle activity of the Musculus genioglossus is recorded by electromyogram (EMG).

[0670] At certain points in time, the collapsibility of the upper respiratory tract is tested by having the pig breathe via the caudal cannula and applying negative pressures of −50, −100 and −150 cm water head (cm H.sub.2O) to the upper respiratory tract. This causes the upper respiratory tract to collapse, which manifests itself in an interruption of the airflow and a pressure drop in the tube system. This test is conducted prior to the administration of the test substance and at certain intervals after the administration of the test substance. An appropriately effective test substance can prevent this collapse of the respiratory tract in the inspiratory phase.

[0671] After changeover from nasal breathing to breathing via the caudal cannula, it is not possible to measure any EMG activity of the Musculus genioglossus in the anaesthetized pig. As a further test, the negative pressure at which EMG activity restarts is then determined. This threshold value is, if a test substance is effective, shifted to more positive values. The test is likewise conducted prior to the administration of the test substance and at certain intervals after the administration of the test substance. Administration of the test substance can be intranasal, intravenous, subcutaneous, intraperitoneal or intragastral.

C. WORKING EXAMPLES OF PHARMACEUTICAL COMPOSITIONS

[0672] The compounds of the invention can be converted to pharmaceutical preparations as follows:

[0673] Tablet:

[0674] Composition:

[0675] 100 mg of the compound of the invention, 50 mg of lactose (monohydrate), 50 mg of corn starch (native), 10 mg of polyvinylpyrrolidone (PVP 25) (BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.

[0676] Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm.

[0677] Production:

[0678] The mixture of compound of the invention, lactose and starch is granulated with a 5% solution (w/w) of the PVP in water. The granules are dried and then mixed with the magnesium stearate for 5 minutes. This mixture is compressed using a conventional tableting press (see above for format of the tablet). The guide value used for the pressing is a pressing force of 15 kN.

[0679] Suspension for Oral Administration:

[0680] Composition:

[0681] 1000 mg of the compound of the invention, 1000 mg of ethanol (96%), 400 mg of Rhodigel® (xanthan gum from FMC, Pennsylvania, USA) and 99 g of water.

[0682] 10 ml of oral suspension correspond to a single dose of 100 mg of the compound of the invention.

[0683] Production:

[0684] The Rhodigel is suspended in ethanol; the compound of the invention is added to the suspension. The water is added while stirring. The mixture is stirred for about 6 h until the swelling of the Rhodigel is complete.

[0685] Solution for Oral Administration:

[0686] Composition:

[0687] 500 mg of the compound of the invention, 2.5 g of polysorbate and 97 g of polyethylene glycol 400. 20 g of oral solution correspond to a single dose of 100 mg of the compound of the invention.

[0688] Production:

[0689] The compound of the invention is suspended in the mixture of polyethylene glycol and polysorbate with stirring. The stirring operation is continued until dissolution of the compound of the invention is complete.

[0690] i.v. Solution:

[0691] The compound of the invention is dissolved in a concentration below the saturation solubility in a physiologically acceptable solvent (e.g. isotonic saline solution, glucose solution 5% and/or PEG 400 solution 30%). The solution is subjected to sterile filtration and dispensed into sterile and pyrogen-free injection vessels.

[0692] Solution for Nasal Administration:

[0693] The compound of the invention is dissolved in a concentration below the saturation solubility in a physiologically acceptable solvent (e.g. purified water, phosphate buffer, citrate buffer). The solution may contain further additives for isotonization, for preservation, for adjusting the pH, for improvement in the solubility and/or for stabilization.