Substituted bridged diazepane derivatives and use thereof as TASK-1 and TASK-3 inhibitors

Abstract

The present application relates to novel imidazopyridinyl- or imidazopyrimidinyl-substituted, bridged 1,4-diazepane derivatives of formula (I), to processes for their preparation, to their use alone or in combinations for the treatment and/or prevention of diseases, and to their use for preparing medicaments for the treatment and/or prevention of diseases, in particular for treatment and/or prevention of respiratory disorders including, sleep-related respiratory disorders such as obstructive sleep apnoeas and central sleep apnoeas and snoring. Formula (I) in which the ring Q represents a bridged 1,4-diazepane cycle. ##STR00001##

Claims

1. A compound of formula (I) ##STR00234## wherein the ring Q is a bridged 1,4-diazepane cycle of the formula ##STR00235## wherein * denotes the bond to the adjacent methylene group and ** the bond to the carbonyl group; A is CH or N, D 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; and R.sup.2 is (C.sub.4-C.sub.6)-cycloalkyl wherein a ring CH.sub.2 group is optionally replaced by —O—; or R.sup.2 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), (f) or (g), ##STR00236## wherein *** marks the bond to the adjacent carbonyl group; and R.sup.3 is hydrogen, fluorine, chlorine, bromine or methyl; R.sup.4 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.5 is hydrogen, fluorine, chlorine, bromine or methyl, R.sup.6 is hydrogen, (C.sub.1-C.sub.3)-alkoxy, cyclobutyloxy, oxetan-.sub.3-yloxy, tetrahydrofuran-.sub.3-yloxy, tetrahydro-.sub.2H-pyran-.sub.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 is optionally up to trisubstituted by fluorine; R.sup.7 is hydrogen, fluorine, chlorine, bromine, (C.sub.1-C.sub.3)-alkyl or (C.sub.1-C.sub.3)-alkoxy; R.sup.8A and R.sup.8B 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; R.sup.9 is hydrogen, (C.sub.1-C.sub.3)-alkyl or amino; and Y is O or S; or R.sup.2 is an —OR.sup.10 or —NR.sup.11R.sup.12 group wherein R.sup.10is (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 where phenyl and the phenyl group in benzyl is optionally up to trisubstituted by identical or different radicals selected from the group consisting of fluorine, chlorine, methyl, ethyl, trifluoromethyl, methoxy, ethoxy and trifluoromethoxy; 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.

2. The compound of formula (I) according to claim 1, wherein the ring Q is a bridged 1,4-diazepane cycle of the formula ##STR00237## wherein * denotes the bond to the adjacent methylene group and ** the bond to the carbonyl group; A is CH or N; D is CH or N; R.sup.1 is fluorine, chlorine, bromine, methyl, isopropyl, tert-butyl, cyclopropyl or cyclobutyl; and R.sup.2 is cyclobutyl, cyclopentyl or cyclohexyl; or R.sup.2 is a phenyl group of the formula (a), a pyridyl group of the formula (b) or an azole group of the formula (d), (e), (f) or (g), ##STR00238## wherein *** marks the bond to the adjacent carbonyl group; and R.sup.3 is hydrogen, fluorine or chlorine; R.sup.4 is fluorine, chlorine, cyano, (C.sub.1-C.sub.3)-alkyl, (C.sub.1-C.sub.3)-alkoxy or trifluoromethoxy; R.sup.5 is hydrogen, fluorine, chlorine, bromine or methyl; R.sup.6 is (C.sub.1-C.sub.3)-alkoxy, cyclobutyloxy 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.8A and R.sup.8B are identical or different and are independently hydrogen, chlorine, bromine, (C.sub.1-C.sub.3)-alkyl or cyclopropyl, wherein (C.sub.1-C.sub.3)-alkyl may be up to trisubstituted by fluorine; R.sup.9 is methyl or amino; and Y is O or S, or a salt, a solvate, or a solvate of the salt thereof.

3. The compound of formula (I) according to claim 1, wherein the ring Q is a bridged 1,4-diazepane cycle of the formula ##STR00239## wherein * denotes the bond to the adjacent methylene group and ** the bond to the carbonyl group; A is CH or N; D is CH or N; R.sup.1 is chlorine, bromine, isopropyl or cyclopropyl; and R.sup.2 is cyclopentyl or cyclohexyl; or R.sup.2 is a phenyl group of the formula (a), a pyridyl group of the formula (b) or an azole group of the formula (g), ##STR00240## wherein *** marks the bond to the adjacent carbonyl group; and R.sup.3 is hydrogen, fluorine or chlorine; R.sup.4 is fluorine, chlorine, methyl, isopropyl, methoxy or ethoxy; R.sup.5 is hydrogen, fluorine, chlorine, bromine or methyl; R.sup.6 is methoxy, difluoromethoxy, trifluoromethoxy, isopropoxy, cyclobutyloxy or methylsulfanyl; and R.sup.9 is methyl or amino, or a salt, a solvate, or a solvate of the salt thereof.

4. A pharmaceutical composition comprising a compound according to claim 1 in combination with one or more inert, nontoxic, pharmaceutically suitable excipients.

5. A pharmaceutical combination comprising a compound according to claim 1 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.

6. A method for treatment of respiratory disorders, sleep-related respiratory disorders, obstructive sleep apnoeas, central sleep apnoeas, snoring, or cardiac arrhythmias, comprising administering to a human or animal in need thereof an effective amount of a compound of formula (I) according to claim 1.

7. The method of claim 6, wherein the method is a method for treatment of respiratory disorders.

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

9. A method for treatment of respiratory disorders, sleep-related respiratory disorders, obstructive sleep apnoeas, central sleep apnoeas, snoring, or cardiac arrhythmias, in a human or animal in need thereof, comprising administering an effective amount of at least one compound according to claim 1 to the human or animal.

10. The method of claim 9, wherein the method is a method for treatment of respiratory disorders.

11. The method of claim 9, wherein the method is a method for treatment of sleep-related respiratory disorders.

12. A method for treatment of respiratory disorders, sleep-related respiratory disorders, obstructive sleep apnoea, central sleep apnoea, snoring, or cardiac arrhythmias, comprising administering to a human or animal in need thereof an effective amount of a pharmaceutical composition according to claim 4.

13. The method of claim 12, wherein the method is a method for treatment of respiratory disorders.

14. The method of claim 12, wherein the method is a method for treatment of sleep-related respiratory disorders.

15. A method for treatment of respiratory disorders, sleep-related respiratory disorders, obstructive sleep apnoeas, central sleep apnoeas, snoring, or cardiac arrhythmias, comprising administering to a human or animal in need thereof an effective amount of a pharmaceutical combination according to claim 5.

16. The method of claim 15, wherein the method is a method for treatment of respiratory disorders.

17. The method of claim 15, wherein the method is a method for treatment of sleep-related respiratory disorders.

18. A process for preparing a compound of formula (I) according to claim 1, comprising reacting a compound of formula (II) ##STR00241## wherein A, D and R.sup.1 are as defined in claim 1, in the presence of a suitable reducing agent either [A] with a compound of formula (III) ##STR00242## wherein R.sup.2 and the ring Q are as defined in claim 1, to give a compound of formula (I); or [B] with a protected diazabicyclic system of formula (IV) ##STR00243## wherein the ring Q is as defined in claim 1, and PG is a suitable amino protecting group, at first to give a compound of formula (V) ##STR00244## wherein A, D, PG, R.sup.1 and the ring Q are as defined above, then removing the protecting group PG to give a compound of formula (VI), and reacting the resulting compound of formula (VI) ##STR00245## wherein A, D, R.sup.1 and the ring Q are as defined above, depending on the specific meaning of the R.sup.2 radical, [B-1] with a carboxylic acid of the formula (VII) ##STR00246## wherein R.sup.2A is (C.sub.4-C.sub.6)-cycloalkyl wherein a ring CH.sub.2 group is optionally replaced by —O—, or 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), (f) or (g), as defined in claim 1, with activation of the carboxylic acid function in (VII), or with the corresponding acid chloride of the formula (VIII) ##STR00247## wherein R.sup.2A is as defined above, to give a compound of the formula (I-A) ##STR00248## wherein A, D, R.sup.1, R.sup.2A and the ring Q are as defined above; or [B-2] with a chloroformate or carbamoyl chloride of the formula (IX) ##STR00249## wherein R.sup.2B is the —OR.sup.10 or —NR.sup.11AR.sup.12 group wherein R.sup.10 and R.sup.12 are as defined in claim 1, and R.sup.11A has the definition of R.sup.11 in claim 1, but is not hydrogen, to give a compound of the formula (I-B) ##STR00250## wherein A, D, R.sup.1, R.sup.2B and the ring Q are as defined above; or [B-3] with an isocyanate of the formula (X)
R.sup.12—N═C═O  (X), wherein R.sup.12 is as defined in claim 1, to give a compound of formula (I-C) ##STR00251## wherein A, D, R.sup.1, R.sup.12 and the ring Q are as defined above, and optionally separating the compound of formula (I), (I-A), (I-B) or (I-C) into its enantiomers and/or diastereomers and/or optionally converting the compound of formula (I), (I-A), (I-B) or (I-C) with the appropriate (i) solvents and/or (ii) acids to a salt, a solvate, or a solvate of the salt thereof.

19. The process of claim 18, wherein the suitable amino protecting group PG is tert-butoxycarbonyl, benzyloxycarbonyl or (9H-fluoren-9-ylmethoxy)carbonyl.

Description

A. EXAMPLES

Abbreviations and Acronyms

(1) abs. absolute

(2) Ac acetyl

(3) aq. aqueous, aqueous solution

(4) Boc tert-butoxycarbonyl

(5) br. broad (in NMR signal)

(6) Ex. Example

(7) Bu butyl

(8) c Concentration

(9) CAN cerium(IV) ammonium nitrate

(10) cat. catalytic

(11) Cbz benzyloxycarbonyl

(12) CI chemical ionization (in MS)

(13) d doublet (in NMR)

(14) d day(s)

(15) TLC thin layer chromatography

(16) DCI direct chemical ionization (in MS)

(17) dd doublet of doublets (in NMR)

(18) DMF N,N-dimethylformamide

(19) DMSO dimethyl sulfoxide

(20) dq doublet of quartets (in NMR)

(21) dt doublet of triplets (in NMR)

(22) EI electron impact ionization (in MS)

(23) eq. equivalent(s)

(24) ESI electrospray ionization (in MS)

(25) Et ethyl

(26) h hour(s)

(27) HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate

(28) HOBt 1-hydroxy-1H-benzotriazole hydrate

(29) HPLC high-pressure, high-performance liquid chromatography

(30) iPr isopropyl

(31) conc. concentrated (in the case of a solution)

(32) LC liquid chromatography

(33) LC-MS liquid chromatography-coupled mass spectrometry

(34) lit. literature (reference)

(35) m multiplet (in NMR)

(36) Me methyl

(37) min minute(s)

(38) MS mass spectrometry

(39) NMR nuclear magnetic resonance spectrometry

(40) Pd/C palladium on activated charcoal

(41) Ph phenyl

(42) PPS Polyphosphoric acid

(43) Pr propyl

(44) q quartet (in NMR)

(45) quant. quantitative (in chemical yield)

(46) Red-Al® sodium bis(2-methoxyethoxy)aluminiumhydride

(47) R.sub.f retention index (in TLC)

(48) RP reverse phase (in HPLC)

(49) R.sub.t retention time (in HPLC, LC-MS)

(50) RT room temperature

(51) s singlet (in NMR)

(52) SFC supercritical liquid chromatography

(53) t triplet (in NMR)

(54) tBu tert-butyl

(55) TFA trifluoroacetic acid

(56) THF tetrahydrofuran

(57) Ts tosyl (p-toluenesulfonyl)

(58) UV ultraviolet spectrometry

(59) v/v volume to volume ratio (of a solution)

(60) LC-MS and HPLC Methods:

(61) Method 1 (LC-MS):

(62) Instrument: Waters Acquity SQD UPLC System; column: Waters Acquity UPLC HSS T3 1.8 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.

(63) Method 2 (LC-MS):

(64) 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.

(65) Method 3 (LC-MS):

(66) 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.

(67) Method 4 (LC-MS):

(68) 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.

(69) Method 5 (LC-MS):

(70) 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.

(71) Method 6 (LC-MS):

(72) 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).

(73) Method 7 (LC-MS):

(74) 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.

(75) Method 8 (preparative HPLC):

(76) Instrument: Abimed Gilson 305; column: Reprosil C18 10 μm, 250 mm×30 mm; mobile phase A: water, eluent 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.

(77) Method 9 (preparative HPLC):

(78) Instrument: Knauer P 2.1 L-Azura; column: Chromatorex C18 10 μm, 125 mm×40 mm; mobile phase A: water, eluent B: acetonitrile; gradient: 0-3 min 20% B, 3-21 min 20% B.fwdarw.95% B, 21-24 min 95% B, 24-25 min 95% B.fwdarw.20% B, 25-27.5 min 20% B; flow rate: 100 ml/min; room temperature; UV detection: 210 nm.

(79) Method 10 (preparative HPLC):

(80) Instrument: Knauer P 2.1 L-Azura; column: Reprosil C18 10 μm, 250 mm×30 mm; mobile phase A: water, eluent B: acetonitrile; gradient: 0-5 min 10% B, 5-19 min 10% B.fwdarw.50% B, 19-20 min 50% B.fwdarw.95% B, 20-25 min 95% B, 25-26 min 95% B.fwdarw.10% B, 26-28.5 min 10% B; flow rate: 100 ml/min; room temperature; UV detection: 210 nm.

(81) Method 11 (LC-MS):

(82) Instrument: Shimadzu LCMS-2020; column Kinetex 2.6 μm XB-C18 H16-198547, 50 mm×3.0 mm; mobile phase A: water with 0.05% trifluoroacetic acid, mobile phase B: acetonitrile; gradient: 0.0 min 5% B.fwdarw.1.2 min 100% B.fwdarw.1.8 min 100% B.fwdarw.1.9 min 5% B.fwdarw.2.0 min 5% B; flow rate: 1.50 ml/min; UV detection: 190-400 nm; temperature: 40° C.

(83) Method 12 (LC-MS):

(84) Instrument: Shimadzu MS 2020 with LC Shimadzu 20ADxr; column: Kinetex 2.6 μm XB-C18, 50 mm×3.0 mm; mobile phase A: water with 0.05% trifluoroacetic acid, mobile phase B: acetonitrile; gradient: 0.0 min 5% B.fwdarw.2.0 min 80% B.fwdarw.1.8 min 80% B.fwdarw.2.9 min 5% B.fwdarw.3.0 min 5% B; flow rate: 1.50 ml/min; UV detection: 190-400 nm; temperature: 40° C.

(85) Method 13 (LC-MS):

(86) Instrument: Shimadzu shim-pack XR-ODS; column: Kinetex 2.6 μm XB-C18 40332846, 50 mm×3.0 mm; mobile phase A: water with 0.05% trifluoroacetic acid, mobile phase B: acetonitrile; gradient: 0.0 min 5% B.fwdarw.1.2 min 100% B.fwdarw.2.2 min 100% B.fwdarw.2.25 min 5% B.fwdarw.2.6 min 5% B; flow rate: 1.50 ml/min; UV detection: 190-400 nm; temperature: 40° C.

(87) Method 14 (LC-MS):

(88) Instrument: Shimadzu LCMS-2020; column Kinetex 2.6 μm XB-C18 H15-179292, 50 mm×3.0 mm; mobile phase A: water with 0.05% trifluoroacetic acid, mobile phase B: acetonitrile; gradient: 0.0 min 5% B.fwdarw.1.2 min 100% B.fwdarw.1.8 min 100% B.fwdarw.1.9 min 5% B.fwdarw.2.0 min 5% B; flow rate: 1.50 ml/min; UV detection: 190-400 nm; temperature: 40° C.

(89) Method 15 (LC-MS):

(90) Instrument: Shimadzu LCMS-2020; column Kinetex 2.6 m XB-C18 H16-198547, 50 mm×3.0 mm; mobile phase A: water with 0.05% trifluoroacetic acid, mobile phase B: acetonitrile; gradient: 0.0 min 5% B.fwdarw.4.0 min 80% B.fwdarw.4.8 min 80% B.fwdarw.4.9 min 5% B.fwdarw.5.0 min 5% B; flow rate: 1.50 ml/min; UV detection: 190-400 nm; temperature: 40° C.

(91) Further Details:

(92) 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.

(93) 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.

(94) 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.

(95) 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.

(96) Melting points and melting point ranges, if stated, are uncorrected.

(97) 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 center 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.

(98) 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), . . . , δ.sub.i (intensity.sub.i), . . . , δ.sub.n(intensity.sub.n).

(99) 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.

(100) 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%.

(101) 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.

(102) Starting Compounds and Intermediates:

Example 1A

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

(103) ##STR00040##

(104) 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.

(105) LC-MS (method 2): R.sub.t=1.25 min; m/z=230 (M+H).sup.+.

(106) .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

(107) ##STR00041##

(108) Sodium bicarbonate (0.52 g, 6.22 mmol) was added to a solution or 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 the subsequent reactions without further purification.

(109) LC-MS (method 2): R.sub.t=1.48 min; m/z=238 (M+H).sup.+.

(110) .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), 8.21 (d, 1H), 8.33 (s, 1H), 8.51 (dd, 1H).

Example 3A

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

(111) ##STR00042##

(112) To a solution of 20 g (85.65 mmol) of 2-bromo-1-(4-chlorophenyl)ethanone and 8.87 g (94.22 mmol) of pyridin-2-amine in 200 ml of ethanol were added 10.95 g (130 mmol) of sodium hydrogencarbonate, and the mixture was stirred at 80° C. for 5 hours. The mixture was then cooled, first to room temperature and then to 0° C. (ice bath). The resulting precipitate was filtered off and washed repeatedly with an ethanol/water mixture (2:1). The solid was then dried under reduced pressure at 40° C. overnight. This gave 19.8 g of the target product, which was used in the subsequent reactions without further purification.

(113) .sup.1H-NMR (400 MHz, DMSO-d.sub.6, δ/ppm): 6.87-6.94 (m, 1H), 7.23-7.29 (m, 1H), 7.50 (d, 2H), 7.58 (d, 1H), 7.99 (d, 2H), 8.43 (s, 1H), 8.53 (d, 1H).

(114) LC-MS (method 1): R.sub.t=0.58 min; m/z=229/231 (M+H).sup.+.

Example 4A

2-(5-Chloropyridin-2-yl)imidazo[1,2-a]pyridine

(115) ##STR00043##

(116) 5 g (32.14 mmol) of 1-(5-chloropyridin-2-yl)ethanone, 6.96 g (73.92 mmol) of pyridin-2-amine and 9.79 g (38.56 mmol) of iodine were stirred at 120° C. for 2 h. After cooling to room temperature, 15 ml of water and 1.93 g (48 mmol) of sodium hydroxide were added and then the reaction mixture was stirred at 100° C. for another 1 h. Thereafter, the mixture was cooled to room temperature and the precipitate obtained was filtered off and washed repeatedly with water. The solid was dissolved in cyclohexane/ethyl acetate (1:1), silica gel was added, the mixture was concentrated to dryness again and the residue was purified by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 1:1). 4.32 g (18.81 mmol, 59% of theory) of the target compound were obtained.

(117) .sup.1H-NMR (400 MHz, DMSO-d.sub.6, δ/ppm): 6.95 (t, 1H), 7.30 (t, 1H), 7.61 (d, 1H), 8.00 (dd, 1H), 8.12 (d, 1H), 8.50 (s, 1H), 8.59 (d, 1H), 8.65 (d, 1H).

(118) LC-MS (method 1): R.sub.t=0.50 min; m/z=230/232 (M+H).sup.+.

(119) Analogously to Examples 1A-4A, the following compounds were prepared from the starting materials specified in each case:

(120) TABLE-US-00001 Example Name/Structure/Starting materials Analytical data 5A .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.+. 6A .sup.1H-NMR (400 MHz, DMSO-d.sub.6, δ/ppm): 6.88-6.94 (m, 1H), 7.23- 7.29 (m, 1H), 7.58 (d, 1H), 7.63 (d, 2H), 7.92 (d, 2H), 8.44 (s, 1H), 8.53 (d, 1H). LC-MS (method 1): R.sub.t = 0.63 min; m/z = 273/275 (M + H).sup.+. 7A .sup.1H-NMR (400 MHz, DMSO-d.sub.6, δ/ppm): 1.23 (d, 6H), 2.85-2.96 (m, 1H), 6.88 (t, 1H), 7.19-7.26 (m, 1H), 7.31 (d, 2H), 7.56 (d, 1H), 7.88 (d, 2H), 8.34 (s, 1H), 8.51 (d, 1H). LC-MS (method 1): R.sub.t = 0.68 min; m/z = 237 (M + H).sup.+.

Example 8A

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

(121) ##STR00047##

(122) 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. 13.75 g (53.36 mmol, 77% of theory) of the target product were obtained.

(123) LC-MS (method 2): R.sub.t=1.44 min; m/z=258 (M+H).sup.+.

(124) .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 9A

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

(125) ##STR00048##

(126) 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). 3 g (11.3 mmol, 92% of theory) of the target compound were obtained.

(127) LC-MS (method 2): R.sub.t=1.75 min; m/z=266 (M+H).sup.+.

(128) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.27 (d, 6H), 3.00 (dt, 1H), 7.39-7.52 (m, 3H), 7.90 (d, 2H), 8.89 (dd, 1H), 9.83 (dd, 1H), 10.08 (s, 1H).

Example 10A

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

(129) ##STR00049##

(130) 300 ml of DMF were cooled to 0° C. 44 ml (470.08 mmol) of phosphorus oxychloride were then slowly added dropwise. The reaction solution was then slowly warmed to room temperature and stirred at this temperature for another hour. 43 g (188.03 mmol) of 2-(4-chlorophenyl)imidazo[1,2-a]pyridine were then added in portions. During the addition, the reaction solution warmed to 35° C. After the addition had ended, the reaction mixture was heated to 80° C. and stirred at this temperature for 2 hours. After cooling to room temperature, the solution was slowly added to 3 litres of ice-water. The resulting solid was filtered off with suction, washed repeatedly with water and dried in a high-vacuum drying cabinet at 40° C. overnight. 39.6 g (154.27 mmol, 82% of theory) of the target product were obtained.

(131) .sup.1H-NMR (400 MHz, DMSO-d.sub.6, δ/ppm): 7.37 (t, 1H), 7.63 (d, 2H), 7.78 (t, 1H), 7.90-7.99 (m, 3H), 9.58 (d, 1H), 10.02 (s, 1H).

(132) LC-MS (method 1): R.sub.t=0.97 min; m/z=257/259 (M+H).sup.+.

Example 11A

2-(5-Chloropyridin-2-yl)imidazo[1,2-a]pyridine-3-carbaldehyde

(133) ##STR00050##

(134) 80 ml of DMF were cooled to 0° C. 4.4 ml (47.02 mmol) of phosphorus oxychloride were then slowly added dropwise. The reaction solution was then slowly warmed to room temperature and stirred at this temperature for another hour. 4.32 g (18.81 mmol) of 2-(5-chloropyridin-2-yl)imidazo[1,2-a]pyridine were then added in portions. When the addition had ended, the reaction mixture was heated to 80° C. and stirred at this temperature for 1 h. After cooling to room temperature, the solution was gradually added to ice-water. Ethyl acetate was added and, after thorough shaking, the organic phase was removed. The latter was washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness. The residue obtained was purified by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 2:1). cyclohexane/ethyl acetate 2:1). 4.46 g (17.31 mmol, 92% of theory) of the target compound were obtained.

(135) .sup.1H-NMR (400 MHz, DMSO-d.sub.6, δ/ppm): 7.36 (td, 1H), 7.76 (ddd, 1H), 7.94 (d, 1H), 8.15 (dd, 1H), 8.35 (d, 1H), 8.81 (d, 1H), 9.60 (d, 1H), 10.87 (s, 1H).

(136) LC-MS (method 1): R.sub.t=0.92 min; m/z=258/260 (M+H).sup.+.

(137) Analogously to Examples 8A-11A, the following compounds were prepared from the starting material specified in each case:

(138) TABLE-US-00002 Example Name/Structure/Starting material Analytical data 12A .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.+. 13A .sup.1H-NMR (400 MHz, DMSO-d.sub.6, δ/ppm): 7.35 (t, 1H), 7.72-7.80 (m, 3H), 7.85-7.95 (m, 3H), 9.58 (d, 1H), 10.02 (s, 1H). LC-MS (method 2): R.sub.t = 1.76 min; m/z = 301/303 (M + H).sup.+. 14A .sup.1H-NMR (400 MHz, DMSO-d.sub.6, δ/ppm): 1.27 (d, 6H), 2.93-3.05 (m, 1H), 7.33 (t, 1H), 7.44 (d, 2H), 7.74 (t, 1H), 7.85 (d, 2H), 7.91 (d, 1H), 9.58 (d, 1H), 10.03 (s, 1H). LC-MS (method 1): R.sub.t = 1.03 min; m/z = 265 (M + H).sup.+.

Example 15A

2,2′-Oxydiacetaldehyde

(139) ##STR00054##

(140) With stirring, a solution of 2,5-dihydrofuran (50 g, 713.37 mmol) in 1.2 litres of dichloromethane was cooled to −78° C. Excess ozone was then introduced into the reaction solution until the blue colour remained. Thereafter, nitrogen was introduced for 30 min. When the introduction of nitrogen had ended, 185.8 g (218.6 ml, 2.99 mol) of dimethyl sulfide were added to the reaction solution. The reaction mixture was then slowly warmed to room temperature and stirred for 15 hours (reaction monitored by TLC: mobile phase petroleum ether/ethyl acetate 2:1; starting material 2,5-dihydrofuran R.sub.f=0.3, target product R.sub.f=0.1). The reaction mixture was then concentrated to dryness under reduced pressure. This gave 100 g of the title compound as a yellowish oil which was used in the subsequent reaction without further purification.

Example 16A

9-Benzyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-one

(141) ##STR00055##

(142) 71.5 g (490 mmol) of 3-oxopentanedicarboxylic acid and 40.1 g (490 mmol) of sodium acetate were added to a solution of 2,2′-oxydiacetaldehyde (100 g, about 980 mmol) in 600 ml of water. A little at a time, 52.5 g (490 mmol) of benzylamine, dissolved in 200 ml of 3 N hydrochloric acid, were then added and the mixture was stirred at 25° C. for 16 h. The pH of the reaction mixture was then adjusted to pH 10 using 1 N aqueous sodium hydroxide solution and the solution was extracted three times with 1 litre of ethyl acetate. The combined organic phases were concentrated to dryness under reduced pressure. The residue obtained was separated into its components on silica gel (mobile phase: dichloromethane). This gave 36 g (155.65 mmol, 16% of theory) of the title compound.

(143) .sup.1H-NMR (400 MHz, CDCl.sub.3): δ [ppm]=7.44-7.31 (m, 5H), 3.92 (s, 2H), 3.84 (d, 2H), 3.72 (d, 2H), 3.18-3.16 (m, 2H), 2.78-2.73 (m, 2H), 2.36 (s, 1H), 2.33 (s, 1H).

Example 17A

(E/Z)-9-Benzyl-N-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonan-7-imine

(144) ##STR00056##

(145) At 20°-30° C., 22.8 g (329 mmol) of hydroxylamine hydrochloride were metered into a solution of 38 g (164 mmol) of 9-benzyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-one and 53.9 g (657 mmol) of sodium acetate in 600 ml of ethanol and 200 ml of water. The reaction mixture was then heated to 70°-80° C. and stirred at this temperature for 3 h. After cooling, the reaction mixture was concentrated under reduced pressure, i.e. part of the solvent was removed on a rotary evaporator. The reaction solution that remained was extracted three times with 500 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated to dryness. This gave 35 g (142.1 mmol, 87% of theory) of the title compound, which was used in the subsequent reaction without further purification.

(146) .sup.1H-NMR (400 MHz, CDCl.sub.3): δ [ppm]=7.37-7.18 (m, 5H), 3.82-3.76 (m, 4H), 3.69-3.61 (m, 2H), 3.08-3.04 (d, 1H), 2.83-2.81 (m, 2H), 2.68-2.63 (m, 1H), 2.35-2.24 (m, 2H).

Example 18A

10-Benzyl-8-oxa-3,10-diazabicyclo[4.3.1]decan-4-one (racemate)

(147) ##STR00057##

(148) With stirring at 20°-30° C., 40.6 g (213 mmol) of 4-methylbenzenesulfonyl chloride were added to a solution of 35 g (142 mmol) of (E/Z)-9-benzyl-N-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonan-7-imine and 45.2 g (426 mmol) of sodium carbonate in 525 ml of acetonitrile and 175 ml of water. The reaction mixture was then heated to 70°-80° C. and stirred at this temperature for 15 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure (acetonitrile was removed under reduced pressure). The remaining aqueous phase was extracted three times with 1000 ml of ethyl acetate. The combined organic phases were washed with 300 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated to dryness. This gave 25 g (101.5 mmol, 71% of theory) of the title compound which was reacted without further purification.

(149) .sup.1H-NMR (400 MHz, CDCl.sub.3): δ [ppm]=7.37-7.18 (m, 5H), 6.00 (br. s, 1H), 3.90-3.78 (m, 7H), 3.07-3.03 (m, 2H), 2.71 (br. s, 1H), 2.61 (br. s, 1H), 2.41-2.37 (m, 1H).

Example 19A

10-Benzyl-8-oxa-3,10-diazabicyclo[4.3.1]decane (racemate)

(150) ##STR00058##

(151) Under argon and at a temperature of 20°-30° C., 4.62 g (122 mmol) of lithium aluminium hydride were added a little at a time to a solution of 10 g (40.6 mmol) of 10-benzyl-8-oxa-3,10-diazabicyclo[4.3.1]decan-4-one (racemate) in 800 ml of dry THF. The reaction mixture was then stirred at this temperature for 12 h. In parallel, this reaction was carried out a second time. Both reaction mixtures were then cooled to 0° C., and 10 ml of water, 10 ml of 10% strength aqueous sodium hydroxide solution and 30 ml of water were successively added to each mixture. After filtration of the reaction mixtures, the filtrates were combined and extracted three times with 1 litre of ethyl acetate. The combined organic phases were washed with 200 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated to dryness. This gave 22 g of the title compound as a brown oil which was used in the subsequent reaction without further purification.

Example 20A

tert-Butyl 10-benzyl-8-oxa-3,10-diazabicyclo[4.3.1]decane-3-carboxylate (racemate)

(152) ##STR00059##

(153) With stirring and at a temperature of 20°-30° C., 14.1 g (64.6 mmol) of di-tert-butyl dicarbonate were metered into a mixture consisting of 10 g (43.0 mmol) of 10-benzyl-8-oxa-3,10-diazabicyclo[4.3.1]decane (racemate) and 17.9 ml (129 mmol) of triethylamine in 250 ml of dichloromethane. The reaction mixture was then stirred at this temperature for 5 h. The reaction solution was subsequently concentrated to dryness under reduced pressure.

(154) In parallel, this reaction was carried out a second time in exactly the same size. The crude products obtained in this manner were combined and then purified together by column chromatography on silica gel (mobile phase: petroleum ether/ethyl acetate 50:1.fwdarw.3:1). This gave in total 24 g (70.8 mmol, 82% of theory) of the title compound.

(155) .sup.1H-NMR (400 MHz, CDCl.sub.3): δ [ppm]=7.33-7.21 (m, 5H), 3.9-3.7 (m, 2H), 3.75-3.40 (m, 7H), 3.30-3.20 (m, 1H), 2.78-2.74 (m, 2H), 2.00-2.20 (m, 1H), 1.75-1.60 (m, 1H), 1.50-1.40 (m, 9H).

Example 21A

tert-Butyl 8-oxa-3,10-diazabicyclo[4.3.1]decane-3-carboxylate (racemate)

(156) ##STR00060##

(157) At a temperature of 20°-30° C., 2 g (64.6 mmol) of palladium hydroxide were added to a solution of 10 g (30.1 mmol) of tert-butyl 10-benzyl-8-oxa-3,10-diazabicyclo[4.3.1]decane-3-carboxylate in 500 ml of methanol. With stirring, the reaction mixture was subsequently hydrogenated at this temperature under 50 psi (about 3.45 bar) of hydrogen for 4 h. The reaction solution was subsequently filtered and the filtrate was concentrated to dryness under reduced pressure. On silica gel (mobile phase: petroleum ether/ethyl acetate 50:1.fwdarw.1:1), the residue obtained was separated into its components. This gave 5 g (20.6 mmol, 69% of theory) of the title compound.

(158) .sup.1H-NMR (400 MHz, CDCl.sub.3): δ [ppm]=3.92-3.85 (m, 2H), 3.71-3.59 (m, 4H), 3.37-3.24 (m, 2H), 3.07-3.00 (m, 1H), 2.82-2.81 (m, 1H), 2.04-1.99 (m, 2H), 1.48 (s, 9H).

Example 22A and Example 23A

tert-Butyl 8-oxa-3,10-diazabicyclo[4.3.1]decane-3-carboxylate (Enantiomers 1 and 2)

(159) ##STR00061##

(160) 5.91 g (24.4 mmol) of the racemic tert-butyl 8-oxa-3,10-diazabicyclo[4.3.1]decane-3-carboxylate (Example 21A) were separated into the enantiomers by preparative HPLC on a chiral phase [column: YMC Chiral Art Cellulose, 5 μm, 250 mm×20 mm; mobile phase: n-heptane/isopropanol 60:40 (v/v)+0.2% diethylamine; flow rate: 15 ml/min; UV detection: 220 nm; temperature: 45° C.]:

Example 22A (Enantiomer 1)

(161) Yield: 2.95 g

(162) R.sub.t=4.95 min; chemical purity >99%; >99% ee

(163) [column: Daicel Chiralpak IC, 5 μm, 250 mm×4.6 mm; mobile phase: isohexane/isopropanol 60:40 (v/v)+0.2% diethylamine; flow rate: 1 ml/min; temperature: 50° C.; UV detection: 235 nm].

(164) LC-MS (method 4): R.sub.t=1.12 min; m/z=242 (M+H).sup.+

(165) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.38 (d, 9H), 1.77-1.88 (m, 2H), 2.68-2.79 (m, 1H), 2.88-2.97 (m, 1H), 3.04-3.76 (m, 9H).

Example 23A (Enantiomer 2)

(166) Yield: 2.85 g

(167) R.sub.t=6.47 min; chemical purity >99%; >99% ee

(168) [column: Daicel Chiralpak IC, 5 μm, 250 mm×4.6 mm; mobile phase: isohexane/isopropanol 60:40 (v/v)+0.2% diethylamine; flow rate: 1 ml/min; temperature: 50° C.; UV detection: 235 nm].

(169) LC-MS (method 4): R.sub.t=1.12 min; m/z=242 (M+H).sup.+

(170) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.38 (d, 9H), 1.76-1.88 (m, 2H), 2.66-2.81 (m, 1H), 2.87-2.98 (m, 1H), 3.04-3.79 (m, 9H).

Example 24A

2-(4-Methoxyphenyl)-2-azabicyclo[2.2.2]octan-5-one (racemate)

(171) ##STR00062##

(172) Under an atmosphere of nitrogen, 20 litres of DMSO, 1759 g (14.28 mol) of 4-methoxyaniline, 1083 g (37% strength aqueous solution, 13.0 mol) of formaldehyde, 2496 g (26 mol) of cyclohex-2-en-1-one and 448.5 g (3.9 mol) of DL-proline were introduced into a 50 litre reactor. The reaction mixture was then heated to 50° C. and stirred at this temperature for 30 h. The reaction mixture was subsequently cooled to room temperature using a water/ice bath and transferred into a larger vessel, and 100 litres of water were added. The reaction mixture was extracted three times with 20 litres of ethyl acetate. The combined organic phases were washed once with 30 litres of saturated sodium chloride solution. After the organic phase had been removed, it was concentrated to dryness under reduced pressure. On silica gel (mobile phase: petroleum ether/ethyl acetate 15:1), the residue obtained was separated into its components. This gave 600 g (2.60 mol, 18% of theory) of the title compound.

(173) LC-MS (method 11): R.sub.t=0.913 min; m/z=232 (M+H).sup.+.

Example 25A

(E/Z)-N-Hydroxy-2-(4-methoxyphenyl)-2-azabicyclo[2.2.2]octan-5-imine (racemate)

(174) ##STR00063##

(175) Under an atmosphere of nitrogen, 600 g (2.59 mol) of 2-(4-methoxyphenyl)-2-azabicyclo[2.2.2]octan-5-one (racemate), 10 litres of THF, 688 g (6.43 mol) of sodium carbonate and 197 g (2.86 mol) of hydroxylamine hydrochloride were introduced into a 20 litre four-necked flask. The reaction mixture was then stirred at room temperature overnight. The reaction mixture was subsequently filtered and the filtrate was concentrated to dryness under reduced pressure. This gave 700 g of the title compound which was used in the subsequent reaction without further purification.

(176) LC-MS (method 11): R.sub.t=0.71 min; m/z=247 (M+H).sup.+.

Example 26A

6-(4-Methoxyphenyl)-2,6-diazabicyclo[3.2.2]nonan-3-one (racemate)

(177) ##STR00064##

(178) Under an atmosphere of nitrogen, 700 g (2.84 mol) of (E/Z)-N-hydroxy-2-(4-methoxyphenyl)-2-azabicyclo[2.2.2]octan-5-imine (racemate), 3500 g of polyphosphoric acid and 1 litre of toluene were introduced into a 5 litre four-necked flask. The resulting reaction solution was heated to 100° C. with stirring and stirred at this temperature for 5 h. The reaction mixture was subsequently cooled to room temperature using a water bath. After transfer to a larger vessel, 10 litres of water were added. The resulting mixture was extracted with 10 litres of ethyl acetate. After removal of the organic phase, the aqueous phase was adjusted to a pH of 10 using aqueous sodium hydroxide solution. The solution was then extracted twice with 10 litres of dichloromethane, and the combined organic phases were dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure. This gave 270 g (1.12 mmol, 39% of theory) of the title compound.

(179) LC-MS (method 11): R.sub.t=0.76 min; m/z=247 (M+H).sup.+.

Example 27A

2,6-Diazabicyclo[3.2.2]nonan-3-one (racemate)

(180) ##STR00065##

(181) Under an atmosphere of nitrogen, 225 g (914 mmol) of 6-(4-methoxyphenyl)-2,6-diazabicyclo[3.2.2]nonan-3-one (racemate), 2.2 litres of acetonitrile and 440 ml of water were introduced into a 10 litre four-necked flask. At room temperature and with stirring, 1254 g (2.29 mol) of cerium(IV) ammonium nitrate were then added to the reaction mixture a little at a time and stirring was continued overnight. 3 litres of water were then added to the solution and the pH was adjusted to 10 by addition of sodium carbonate. The solution obtained in this manner was used directly, without further work-up, in the next reaction.

(182) LC-MS (method 11): R.sub.t=0.17 min; m/z=141 (M+H).sup.+.

Example 28A

Benzyl 3-oxo-2,6-diazabicyclo[3.2.2]nonane-6-carboxylate (racemate)

(183) ##STR00066##

(184) The solution obtained in Example 27A was transferred into a 20 litre flask, and 310 g (1.82 mol) of benzyl carbonochloridate were added a little at a time with stirring. Stirring of the resulting reaction solution was continued at room temperature overnight. The solution was then filtered, and the filtrate obtained was extracted three times with 3 litres of dichloromethane. The combined organic phases were concentrated to dryness under reduced pressure. On silica gel (mobile phase: dichloromethane/methanol 10:1), the residue obtained was separated into its components. This gave 120 g of the title compound (438 mmol, 48% of theory based on 225 g (914 mmol) of 6-(4-methoxyphenyl)-2,6-diazabicyclo[3.2.2]nonan-3-one).

(185) LC-MS (method 11): R.sub.t=0.81 min; m/z=275 (M+H).sup.+.

Example 29A

Benzyl 2,6-diazabicyclo[3.2.2]nonane-6-carboxylate (racemate)

(186) ##STR00067##

(187) Under an atmosphere of nitrogen, 120 g (438 mmol) of benzyl 3-oxo-2,6-diazabicyclo[3.2.2]nonane-6-carboxylate (racemate) and 1.5 litres of dry THF were introduced into a 5 litre four-necked flask. With stirring, 547 ml (1.1 mol) of a 2 M solution of borane/dimethyl sulfide complex in THF were metered in a little at a time. The reaction solution was then heated to 65° C. and stirred at this temperature overnight. Using an ice/water bath, the reaction solution was then cooled to 0° C., and the reaction was stopped by addition of 3 M hydrochloric acid. Hydrochloric acid was added until a pH of 2 had been reached. The resulting solution was heated to 70° C. and stirred at this temperature for 1 h. The solution was subsequently cooled to room temperature, and sodium carbonate was added carefully until a pH of 10 had been reached. The solution obtained in this manner was used directly, without further work-up, in the next reaction.

(188) LC-MS (method 11): R.sub.t=0.67 min; m/z=261 (M+H).sup.+.

Example 30A

6-Benzyl 2-tert-butyl 2,6-diazabicyclo[3.2.2]nonane-2,6-dicarboxylate (racemate)

(189) ##STR00068##

(190) Under an atmosphere of nitrogen, the solution obtained in Example 29A was transferred into a 5 litre four-necked flask, and 191 g (875 mmol) of di-tert-butyl dicarbonate were added. The resulting solution was stirred at room temperature for 3 h. 3 litres of water were then added slowly. The solution was extracted three times with ethyl acetate, and the organic phases were combined and concentrated to dryness under reduced pressure. On silica gel (mobile phase: petroleum ether/ethyl acetate 10:1), the residue obtained was separated into its components. This gave 100 g of the title compound (278 mmol, 63% of theory based on 120 g (438 mmol) of benzyl 3-oxo-2,6-diazabicyclo[3.2.2]nonane-6-carboxylate).

(191) LC-MS (method 11): R.sub.t=1.23 min; m/z=361 (M+H).sup.+.

(192) .sup.1H-NMR (300 MHz, CDCl.sub.3): δ [ppm]=7.37 (s, 5H), 5.16 (s, 2H), 4.53-4.28 (m, 2H), 3.93-3.75 (m, 2H), 3.35-3.19 (m, 2H), 2.06-1.70 (m, 6H), 1.48 (s, 9H).

Example 31A and Example 32A

6-Benzyl 2-tert-butyl 2,6-diazabicyclo[3.2.2]nonane-2,6-dicarboxylate (Enantiomers 1 and 2)

(193) ##STR00069##

(194) 100 g (277 mmol) of racemic 6-benzyl 2-tert-butyl 2,6-diazabicyclo[3.2.2]nonane-2,6-dicarboxylate (Example 30A) were separated into the enantiomers by preparative SFC-HPLC on a chiral phase [column: ColumnTEK EnantioPak-Al, 5 μm, 250 mm×50 mm; mobile phase: carbon dioxide/ethanol 50:50 (v/v); flow rate: 150 ml/min; pressure: 100 bar; UV detection: 220 nm; temperature: 35° C.]:

Example 31A (Enantiomer 1)

(195) Yield: 30 g

(196) R.sub.t=1.88 min; >98% ee

(197) [column: Daicel Chiralpak ID-H, 5 μm, 150 mm×4.6 mm; mobile phase: carbon dioxide/methanol 10:90 (v/v)+0.1% diethylamine; flow rate: 4 ml/min; pressure: 100 bar; UV detection: 210 nm; temperature: 35.8° C.].

Example 32A (Enantiomer 2)

(198) Yield: 30 g

(199) R.sub.t=2.29 min; >99% ee

(200) [column: Daicel Chiralpak ID-H, 5 μm, 150 mm×4.6 mm; mobile phase: carbon dioxide/methanol 10:90 (v/v)+0.1% diethylamine; flow rate: 4 ml/min; pressure: 100 bar; UV detection: 210 nm; temperature: 35.8° C.].

Example 33A

tert-Butyl 2,6-diazabicyclo[3.2.2]nonane-2-carboxylate (Enantiomer 1)

(201) ##STR00070##

(202) At room temperature, 25 g (69.4 mmol) of 6-benzyl 2-tert-butyl 2,6-diazabicyclo[3.2.2]nonane-2,6-dicarboxylate (enantiomer 1), 250 ml of methanol and 4 g (3.7 mmol) of palladium on carbon (10%) were introduced into a 1 litre flask. With stirring, the reaction mixture was subsequently hydrogenated at room temperature under 1 bar of hydrogen overnight. The reaction solution was subsequently filtered and the filtrate was concentrated under reduced pressure. The residue was then washed once with 50 ml of hexane. The precipitate that remained was filtered off and dried in a vacuum drying oven at 40° C. This gave 10.1 g (44.4 mmol, 64% of theory) of the title compound.

(203) LC-MS (method 12): R.sub.t=0.85 min; m/z=227 (M+H).sup.+.

(204) .sup.1H-NMR (300 MHz, D.sub.2O): δ [ppm]=4.21-4.15 (m, 1H), 3.90-3.34 (m, 2H), 3.26-2.82 (m, 3H), 1.88-1.65 (m, 6H), 1.35 (s, 9H). [α].sub.D.sup.27.2=−17.41° (c=0.494 g/100 ml in methanol).

Example 34A

tert-Butyl 2,6-diazabicyclo[3.2.2]nonane-2-carboxylate (Enantiomer 2)

(205) ##STR00071##

(206) At room temperature, 25 g (69.4 mmol) of 6-benzyl 2-tert-butyl 2,6-diazabicyclo[3.2.2]nonane-2,6-dicarboxylate (enantiomer 2), 250 ml of methanol and 4 g (3.7 mmol) of palladium on carbon (10%) were introduced into a 1 litre flask. With stirring, the reaction mixture was subsequently hydrogenated at room temperature under 1 bar of hydrogen overnight. The reaction solution was subsequently filtered and the filtrate was concentrated under reduced pressure. The residue was then washed once with 50 ml of hexane. The precipitate that remained was filtered off and dried in a vacuum drying oven at 40° C. This gave 10.9 g (47.8 mmol, 69% of theory) of the title compound.

(207) LC-MS (method 12): R.sub.t=0.84 min; m/z=227 (M+H).sup.+.

(208) .sup.1H-NMR (300 MHz, D.sub.2O): δ [ppm]=4.31-4.21 (m, 1H), 4.10-3.41 (m, 2H), 3.22-3.04 (m, 3H), 1.97-1.63 (m, 6H), 1.36 (s, 9H).

(209) [α].sub.D.sup.27.2=+16.590 (c=0.476 g/100 ml in methanol).

Example 35A

3-Benzyl-(E/Z)-N-hydroxy-3-azabicyclo[3.2.1]octan-8-imine

(210) ##STR00072##

(211) 200 g (930 mmol) of 3-benzyl-3-azabicyclo[3.2.1]octan-8-one, 64.6 g (930 mmol) of hydroxylamine hydrochloride, 120 g (929 mmol) of diisopropylethylamine and 1 litre of ethanol were introduced into a 1 litre flask. The resulting solution was heated to 35° C. and stirred at this temperature for 2 h. After cooling to room temperature, the solution was concentrated under reduced pressure and transferred into a larger vessel, and 2 litres of water were added. The solution was then extracted three times with 800 ml of dichloromethane. The organic phases were combined and the solution was then concentrated to dryness under reduced pressure. On silica gel (mobile phase: petroleum ether/ethyl acetate 4:1 to 15:1), the residue obtained was separated into its components. This gave 179 g (780 mmol, 84% of theory) of the title compound.

(212) .sup.1H-NMR (300 MHz, CDCl.sub.3): δ [ppm]=9.53 (s, 1H), 7.39-7.26 (m, 3H), 7.20 (d, 2H), 6.96 (d, 2H), 5.55 (s, 2H).

(213) LC-MS (method 11): R.sub.t=0.54 min; m/z=231 (M+H).sup.+.

Example 36A

3-Benzyl-3,6-diazabicyclo[3.2.2]nonan-7-one (racemate)

(214) ##STR00073##

(215) 800 g of polyphosphoric acid were introduced into a 3 litre four-necked flask and heated to 50° C. 178 g (773 mmol) of 8-benzyl-(E/Z)-N-hydroxy-8-azabicyclo[3.2.1]octan-3-imine, dissolved in 300 ml of toluene, were then added a little at a time with stirring. After the addition had ended, the reaction mixture was heated to 110°-120° C. and stirred at this temperature for 2 h. The solution was then cooled to 80° C., and the reaction was stopped by addition of 500 ml of water. The resulting solution was slowly taken up in 5 litres of water. While stirring, the pH was adjusted to 10-11 by addition of 2 M aqueous sodium hydroxide solution. The solution was then extracted four times with 2 litres of dichloromethane. The combined organic phases were dried over sodium sulfate and the solution was, after filtration, concentrated to dryness under reduced pressure. The solid obtained was washed three times with 400 ml of diethyl ether and, after another filtration, dried. This gave 88 g (379 mmol, 49% of theory) of the title compound.

(216) LC-MS (method 11): R.sub.t=0.49 min; m/z=231 (M+H).sup.+.

Example 37A

3-Benzyl-3,6-diazabicyclo[3.2.2]nonane (racemate)

(217) ##STR00074##

(218) Under an atmosphere of nitrogen, a solution of 331 g (1.64 mol) of sodium bis(2-methoxyethoxy)aluminiumhydride (Red-Al®) in 150 ml of dry THF was introduced into a 3 litre four-necked flask. 88 g (382.1 mmol) of 3-benzyl-3,6-diazabicyclo[3.2.2]nonan-7-one (racemate), dissolved in 1 litre of dry THF, were then added dropwise over 30 min with stirring. During the addition, the temperature of the reaction solution was kept below 5° C. After the addition had ended, the reaction solution was heated to 50° C. and stirred at this temperature for 3 h. The reaction mixture was cooled to 30° C., and 1 litre of ice-water was then added slowly to stop the reaction. The pH was then adjusted to 10 by addition of 1 M aqueous sodium hydroxide solution. The resulting solution was extracted with 500 ml of toluene. The organic phase was separated off and then washed successively with in each case 500 ml of 1 M aqueous sodium hydroxide solution, water and saturated sodium chloride solution. The organic phase was then dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure. This gave 89.7 g (crude product) of the title compound as a yellowish oil which was used in the subsequent reaction without further purification.

(219) LC-MS (method 11): R.sub.t=0.46 min; m/z=217 (M+H).sup.+.

Example 38A

Benzyl 3-benzyl-3,6-diazabicyclo[3.2.2]nonane-6-carboxylate (racemate)

(220) ##STR00075##

(221) Under an atmosphere of nitrogen, 89.7 g (about 379 mmol, crude material) of 3-benzyl-3,6-diazabicyclo[3.2.2]nonane (racemate) in 1 litre of dichloromethane and 57.6 g (569 mmol) of triethylamine were introduced into a 3 litre four-necked flask. Over a period of 20 min, 64.6 g (379 mmol) of benzyl carbonochloridate were then added dropwise with stirring. During the addition, the temperature of the reaction solution was kept below 10° C. The resulting reaction solution was stirred at 10° C. for 1 h. The solution was then diluted with 1 litre of water and extracted twice with 300 ml of dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure. This gave 147 g (crude product) of the title compound as a yellowish oil which was used in the subsequent reaction without further purification.

(222) LC-MS (method 13): R.sub.t=1.05 min; m/z=351 (M+H).sup.+.

Example 39A

Benzyl 3,6-diazabicyclo[3.2.2]nonane-6-carboxylate (racemate)

(223) ##STR00076##

(224) Under an atmosphere of nitrogen, 147 g (about 378 mmol, crude material) of benzyl 3-benzyl-3,6-diazabicyclo[3.2.2]nonane-6-carboxylate (racemate) were introduced into 1 litre of 1,2-dichloroethane in a 2 litre flask. 269.8 g (1.89 mol) of 1-chloroethyl carbonochloridate were then slowly added dropwise with stirring. The resulting reaction solution was heated to 85° C. and stirred at this temperature for 5 h. The reaction solution was then concentrated under reduced pressure, and 500 ml of methanol were added a little at a time. The solution was subsequently stirred at 85° C. for a further hour. Then the reaction mixture was cooled to room temperature and concentrated to dryness under reduced pressure. This gave 150 g (crude product) of the title compound as a brownish oil which was used in the subsequent reaction without further purification.

(225) LC-MS (method 13): R.sub.t=0.95 min; m/z=261 (M+H).sup.+.

Example 40A

6-Benzyl 3-tert-butyl 3,6-diazabicyclo[3.2.2]nonane-3,6-dicarboxylate (racemate)

(226) ##STR00077##

(227) 150 g (about 379 mmol, crude material) of benzyl 3,6-diazabicyclo[3.2.2]nonane-6-carboxylate (racemate) in 800 ml of dichloromethane, 96 g (949 mmol) of triethylamine and 2.3 g (18.8 mmol) of 4-dimethylaminopyridine were introduced into a 3 litre four-necked flask. Over a period of 40 min, 82.8 g (379.4 mmol) of di-tert-butyl dicarbonate in 400 ml of dichloromethane were then added dropwise. During the addition, the temperature of the reaction solution was kept below 10° C. After the addition had ended, the reaction solution was stirred at 10° C. for another 2 h. Thereafter, 1 litre of water was added to the solution. The organic phase was removed and then washed successively with 1 litre of water and 500 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure. On silica gel (mobile phase: petroleum ether/THF 15:1), the residue obtained was separated into its components. This gave 95 g (263 mmol, 69% of theory) of the title compound.

(228) LC-MS (method 11): R.sub.t=1.24 min; m/z=361 (M+H).sup.+.

(229) .sup.1H-NMR (300 MHz, CDCl.sub.3): δ [ppm]=7.40-7.29 (m, 5H), 5.17 (s, 2H), 4.53-4.03 (m, 3H), 3.66-3.51 (m, 1H), 3.39-3.29 (m, 2H), 2.33-2.26 (m, 1H), 1.90-1.59 (m, 4H), 1.49 (s, 9H).

Example 41A and Example 42A

6-Benzyl 3-tert-butyl 3,6-diazabicyclo[3.2.2]nonane-3,6-dicarboxylate (Enantiomer 1 and 2)

(230) ##STR00078##

(231) 84 g (233 mmol) of racemic 6-benzyl 3-tert-butyl 3,6-diazabicyclo[3.2.2]nonane-3,6-dicarboxylate (Example 40A) in methanol were separated into the enantiomers by preparative SFC-HPLC on a chiral phase [column: Daicel Chiralpak AD-H, 5 μm, 250 mm×50 mm; mobile phase: carbon dioxide/ethanol 70:30 (v/v); flow rate: 150 ml/min; pressure: 100 bar; UV detection: 220 nm; temperature: 35° C.]:

Example 41A (Enantiomer 1)

(232) Yield: 38.8 g

(233) R.sub.t=7.15 min; >95.5% ee

(234) [column: Daicel Chiralpak AD-H, 5 μm, 100 mm×4.6 mm; mobile phase: n-hexane/isopropanol (+0.1% diethylamine) 95:5 (v/v); flow rate: 1 ml/min; UV detection: 190-500 nm; temperature: 25° C.].

(235) LC-MS (method 14): R.sub.t=1.25 min; m/z=361 (M+H).sup.+.

(236) .sup.1H-NMR (300 MHz, CDCl.sub.3): δ [ppm]=7.38-7.29 (m, 5H), 5.17 (s, 2H), 4.53-4.03 (m, 3H), 3.66-3.51 (m, 1H), 3.39-3.29 (m, 2H), 2.33-2.26 (m, 1H), 1.90-1.59 (m, 4H), 1.49 (s, 9H).

Example 42A (Enantiomer 2)

(237) Yield: 36.9 g

(238) R.sub.t=5.15 min; >95.5% ee

(239) [column: Daicel Chiralpak AD-H, 5 μm, 100 mm×4.6 mm; mobile phase: n-hexane/isopropanol (+0.1% diethylamine) 95:5 (v/v); flow rate: 1 ml/min; UV detection: 190-500 nm; temperature: 25° C.].

(240) LC-MS (method 14): R.sub.t=1.25 min; m/z=361 (M+H).sup.+.

(241) .sup.1H-NMR (300 MHz, CDCl.sub.3): δ [ppm]=7.40-7.29 (m, 5H), 5.17 (s, 2H), 4.53-4.03 (m, 3H), 3.66-3.51 (m, 1H), 3.39-3.29 (m, 2H), 2.33-2.26 (m, 1H), 1.90-1.59 (m, 4H), 1.49 (s, 9H).

Example 43A

tert-Butyl 3,6-diazabicyclo[3.2.2]nonane-3-carboxylate (Enantiomer 1)

(242) ##STR00079##

(243) 3 g (2.8 mmol) of palladium on carbon (10%) were introduced into a solution of 25.8 g (71.6 mmol) of 6-benzyl 3-tert-butyl 3,6-diazabicyclo[3.2.1]nonane-3,6-dicarboxylate (enantiomer 1) in 250 ml of methanol. With stirring, the reaction mixture was subsequently hydrogenated at room temperature under 1 atm of hydrogen overnight. The reaction solution was subsequently filtered and the filtrate was concentrated under reduced pressure. The residue obtained was dried under an infrared lamp. This gave 16.0 g (70.9 mmol, 99% of theory) of the title compound.

(244) LC-MS (method 15): R.sub.t=1.13 min; m/z=227 (M+H).sup.+.

(245) .sup.1H-NMR (300 MHz, CDCl.sub.3): δ [ppm]=5.06 (s, 2H), 4.06-4.49 (m, 2.4H), 3.47-3.76 (m, 1H), 2.80-3.46 (m, 3.7H), 2.04-2.36 (m, 1H), 1.76-2.04 (m, 1.8H), 1.56-1.72 (m, 1H), 1.48 (s, 9.2H).

(246) [α].sub.D.sup.27.2=+9.130 (c=0.51 g/100 ml in chloroform).

Example 44A

tert-Butyl 3,6-diazabicyclo[3.2.2]nonane-3-carboxylate (Enantiomer 2)

(247) ##STR00080##

(248) 3 g (2.8 mmol) of palladium on carbon (10%) were introduced into a solution of 25 g (69.36 mmol) of 6-benzyl 3-tert-butyl 3,6-diazabicyclo[3.2.2]nonane-3,6-dicarboxylate (enantiomer 2) in 250 ml of methanol. With stirring, the reaction mixture was subsequently hydrogenated at room temperature under 1 atm of hydrogen overnight. The reaction solution was subsequently filtered and the filtrate was concentrated under reduced pressure. The residue obtained was dried under an infrared lamp. This gave 10.6 g (47.2 mmol, 68% of theory) of the title compound.

(249) LC-MS (method 15): R.sub.t=1.14 min; m/z=227 (M+H).sup.+.

(250) .sup.1H-NMR (300 MHz, CDCl.sub.3): δ [ppm]=4.08-4.44 (m, 2H), 3.39-3.71 (m, 2H), 2.84-3.39 (m, 4.7H), 1.83-2.37 (m, 2H), 1.74 (s, 2.6H), 1.49 (s, 9H).

(251) [α].sub.D.sup.27.2=−11.59° (c=0.52 g/100 ml in chloroform).

Example 45A

2-(4-Chlorophenyl)-3-(2,6-diazabicyclo[3.2.2]non-6-ylmethyl)imidazo[1,2-a]pyrimidine bis(trifluoroacetic acid) salt (Enantiomer 2)×

(252) ##STR00081##

(253) tert-Butyl 6-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,6-diazabicyclo[3.2.2]nonane-2-carboxylate (enantiomer 2; 1.05 g, 2.25 mmol) was initially charged in 15 ml of dichloromethane and 7.6 ml of trifluoroacetic acid and stirred at room temperature overnight. The reaction mixture was then concentrated to dryness. The crude product obtained in this manner was used in subsequent reactions without further purification.

(254) LC-MS (method 2): R.sub.t=0.84 min; m/z=368 (M+H).sup.+.

Example 46A

3-(3,9-Diazabicyclo[4.2.1]non-9-ylmethyl)-2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidine dihydrochloride (Enantiomer 1)

(255) ##STR00082##

(256) 745 mg (1.57 mmol) of tert-butyl 9-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,9-diazabicyclo[4.2.1]nonane-3-carboxylate (enantiomer 1) were 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 solids obtained were then filtered off with suction, washed repeatedly with diethyl ether and dried under high vacuum at 40° C. 720 mg of a solid material were obtained, which was used in subsequent reactions without further purification.

(257) LC-MS (method 1): R.sub.t=0.6 min; m/z=376 (M+H).sup.+.

(258) Analogously to Examples 45A and 46A, the following compounds were prepared from the starting material specified in each case:

(259) TABLE-US-00003 Ex- Analytical ample Name/Structure/Starting material data 47A LC-MS (method 1): R.sub.t = 0.50 min; m/z = 368 (M + H).sup.+. 48A LC-MS (method 1): R.sub.t = 0.38 min; m/z = 368 (M + H).sup.+. 49A LC-MS (method 2): R.sub.t = 0.67 min; m/z = 367 (M + H).sup.+. 50A LC-MS (method 1): R.sub.t = 0.42 min; m/z = 367 (M + H).sup.+. 51A LC-MS (method 1): R.sub.t = 0.6 min; m/z = 376 (M + H).sup.+. 52A LC-MS (method 2): R.sub.t = 0.97 min; m/z = 376 (M − H + HCOOH).sup.−. 53A LC-MS (method 2): R.sub.t = 0.97 min; m/z = 376 (M − H + HCOOH).sup.−.

Example 54A

[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methano 1

(260) ##STR00090##

(261) 2-(4-Chlorophenyl)imidazo[1,2-a]pyridine-3-carbaldehyde (15.0 g, 58.4 mmol) was initially charged in 100 ml of ethanol and cooled to 0° C. in an ice bath. A solution of sodium borohydride (4.42 g, 117 mmol) in 50 ml of ethanol was then slowly added dropwise. The mixture was stirred at room temperature and subsequently diluted with saturated ammonium chloride solution and with water. The precipitate formed was filtered off with suction and washed with water. The residue was then suspended in a little 2-methoxy-2-methylpropane and a little methanol and then once more evaporated to dryness. This gave 14.2 g (content 100%, 54.7 mmol, 94% of theory) of the title compound.

(262) LC-MS (method 1): R.sub.t=0.49 min; m/z=259/261 (M+H).sup.+.

(263) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=4.91 (d, 2H), 5.44 (t, 1H), 7.00 (t, 1H), 7.33 (t, 1H), 7.55 (d, 2H), 7.62 (d, 1H), 7.87 (d, 2H), 8.47 (d, 1H).

Example 55A

tert-Butyl 9-[(3-fluoro-6-methoxypyridin-2-yl)carbonyl]-3,9-diazabicyclo[4.2.1]nonane-3-carboxylate (Racemate)

(264) ##STR00091##

(265) tert-Butyl 3,9-diazabicyclo[4.2.1]nonane-3-carboxylate (1.00 g, 4.42 mmol), 3-fluoro-6-methoxypyridine-2-carboxylic acid (907 mg, 5.30 mmol) and 1-[bis(dimethylamino)methylene]-1H-[1,2,3]triazolo[4,5-b]pyridin-1-ium 3-oxide hexafluorophosphate (2.18 g, 5.74 mmol) were initially charged in 10 ml of DMF. N-Ethyl-N-isopropylpropan-2-amine (2.3 ml, 13.2 mmol) was then added, and the mixture was stirred at room temperature overnight. The reaction mixture was then diluted with ethyl acetate and the organic phase was washed with water. The organic phase was dried over magnesium sulfate, filtered and concentrated to dryness. On silica gel (mobile phase: cyclohexane/ethyl acetate gradient), the residue obtained was separated into its components. This gave 1.47 g (96% pure, 3.72 mmol, 84% of theory) of the title compound.

(266) LC-MS (method 1): R.sub.t=0.98 min; m/z=380 (M+H).sup.+

(267) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.35-1.46 (m, 9H), 1.47-1.61 (m, 1.5H), 1.63-1.84 (m, 2H), 1.84-2.25 (m, 2H), 2.28-2.40 (m, 0.5H), 2.74-3.07 (m, 1.7H), 3.26 (br. dd, 0.3H), 3.71-3.80 (m, 1H), 3.81-3.85 (m, 3H), 3.86-4.06 (m, 2H), 4.57-4.76 (m, 1H), 6.97 (dt, 1H), 7.65-7.94 (m, 1H).

Example 56A and Example 57A

tert-Butyl 9-[(3-fluoro-6-methoxypyridin-2-yl)carbonyl]-3,9-diazabicyclo[4.2.1]nonane-3-carboxylate (Enantiomers 1 and 2)

(268) ##STR00092##

(269) 1.47 g (3.72 mmol) of racemic tert-butyl 9-[(3-fluoro-6-methoxypyridin-2-yl)carbonyl]-3,9-diazabicyclo[4.2.1]nonane-3-carboxylate (Example 55A) were separated into the enantiomers by preparative SFC-HPLC on a chiral phase [column: Chiralcel AD-H, 5 μm, 250 mm×30 mm; mobile phase: carbon dioxide/isopropanol 91:9 (v/v); flow rate: 125 g/min; pressure: 135 bar; UV detection: 210 nm; temperature: 38° C.]:

Example 56A (Enantiomer 1)

(270) Yield: 711 mg

(271) R.sub.t=0.93 min; chemical purity >99%; >99% ee

(272) [column: Chiralpak AD-3, 3 μm, 100 mm×4.6 mm; mobile phase: carbon dioxide/isopropanol 95:5.fwdarw.1:1 (v/v); flow rate: 3 ml/min; pressure: 135 bar; UV detection: 220 nm; temperature: 60° C.].

(273) LC-MS (method 2): R.sub.t=1.87 min; m/z=380 (M+H).sup.+.

(274) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.33-1.45 (m, 9H), 1.47-1.61 (m, 1.5H), 1.62-1.81 (m, 2H), 1.83-2.25 (m, 2H), 2.28-2.40 (m, 0.5H), 2.74-3.06 (m, 1.7H), 3.26 (br. dd, 0.3H), 3.73-3.80 (m, 1H), 3.81-3.85 (m, 3H), 3.87-4.06 (m, 2H), 4.56-4.77 (m, 1H), 6.97 (dt, 1H), 7.72-7.87 (m, 1H).

Example 57A (Enantiomer 2)

(275) Yield: 695 mg

(276) R.sub.t=1.07 min; chemical purity >99%; >92% ee

(277) [column: Chiralpak AD-3, 3 μm, 100 mm×4.6 mm; mobile phase: carbon dioxide/isopropanol 95:5-1:1 (v/v); flow rate: 3 ml/min; pressure: 135 bar; UV detection: 220 nm; temperature: 60° C.].

(278) LC-MS (method 2): R.sub.t=1.87 min; m/z=380 (M+H).sup.+.

(279) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.35-1.44 (m, 9H), 1.47-1.61 (m, 1.5H), 1.62-1.81 (m, 2H), 1.84-2.23 (m, 2H), 2.27-2.41 (m, 0.5H), 2.72-3.08 (m, 1.7H), 3.26 (br. dd, 0.3H), 3.72-3.80 (m, 1H), 3.81-3.85 (m, 3H), 3.87-4.06 (m, 2H), 4.55-4.77 (m, 1H), 6.97 (dt, 1H), 7.75-7.84 (m, 1H).

Example 58A

3,9-Diazabicyclo[4.2.1]non-9-yl(3-fluoro-6-methoxypyridin-2-yl)methanone (Enantiomer 2)

(280) ##STR00093##

(281) tert-Butyl 9-[(3-fluoro-6-methoxypyridin-2-yl)carbonyl]-3,9-diazabicyclo[4.2.1]nonane-3-carboxylate (695 mg, 1.83 mmol, enantiomer 2) was initially charged in 12 ml of dichloromethane and 6.2 ml of trifluoroacetic acid and stirred at room temperature overnight. The reaction mixture was subsequently diluted with ethyl acetate and 1 N aqueous sodium hydroxide solution, the organic phase was removed and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated to dryness (LC/MS analysis was carried out at this point). The residue obtained was dissolved in ethyl acetate and washed with 1 N aqueous sodium hydroxide solution. The organic phase was separated off and the aqueous phase was once more extracted with ethyl acetate. Again, the combined organic phases were dried over magnesium sulfate, filtered and concentrated to dryness. This gave 258 mg (100% pure, 0.93 mmol, 51% of theory) of the title compound.

(282) LC-MS (method 1): R.sub.t=0.38 min; m/z=280 (M+H).sup.+

(283) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.25-1.78 (m, 3H), 1.80-2.28 (m, 4H), 2.57-2.83 (m, 2H), 2.89-3.10 (m, 1H), 3.76-3.93 (d, 4H), 4.47-4.68 (m, 1H), 6.95 (dt, 1H), 7.67-7.85 (m, 1H).

Example 59A

3,9-Diazabicyclo[4.2.1]non-9-yl(3-fluoro-6-methoxypyridin-2-yl)methanone (Enantiomer 1)

(284) ##STR00094##

(285) tert-Butyl 9-[(3-fluoro-6-methoxypyridin-2-yl)carbonyl]-3,9-diazabicyclo[4.2.1]nonane-3-carboxylate (711 mg, 1.87 mmol, enantiomer 1) was initially charged in 13 ml of dichloromethane and 6.3 ml of trifluoroacetic acid and stirred at room temperature overnight. The reaction mixture was subsequently diluted with ethyl acetate and 1 N aqueous sodium hydroxide solution, the organic phase was removed and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated to dryness (LC/MS analysis was carried out at this point). The residue obtained was dissolved in ethyl acetate and washed with 1 N aqueous sodium hydroxide solution. The organic phase was separated off and the aqueous phase was once more extracted with ethyl acetate. Again, the combined organic phases were dried over magnesium sulfate, filtered and concentrated to dryness. This gave 309 mg (100% pure, 1.11 mmol, 59% of theory) of the title compound.

(286) LC-MS (method 1): R.sub.t=0.37 min; m/z=280 (M+H).sup.+

(287) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.25-1.78 (m, 3H), 1.81-2.27 (m, 4H), 2.57-2.78 (m, 2H), 2.90-3.09 (m, 1H), 3.75-3.93 (d, 4H), 4.50-4.66 (m, 1H), 6.95 (dt, 1H), 7.68-7.85 (m, 1H).

Example 60A

tert-Butyl 10-[(3-fluoro-6-methoxypyridin-2-yl)carbonyl]-8-oxa-3,10-diazabicyclo[4.3.1]decane-3-carboxylate (Enantiomer 1)

(288) ##STR00095##

(289) 3-Fluoro-6-methoxypyridine-2-carboxylic acid (169 mg, 990 μmol) and 1-[bis(dimethylamino)methylene]-1H-[1,2,3]triazolo[4,5-b]pyridin-1-ium 3-oxide hexafluorophosphate (408 mg, 1.07 mmol) were initially charged in 1.0 ml of DMF. N-Ethyl-N-isopropylpropan-2-amine (430 μl, 2.5 mmol) was then added, and the mixture was stirred at room temperature for 1 h. tert-Butyl 8-oxa-3,10-diazabicyclo[4.3.1]decane-3-carboxylate (200 mg, 825 μmol, enantiomer 1) in 1 ml of DMF was then added, and stirring of the reaction mixture was continued at room temperature overnight. The reaction mixture was then diluted with tert-butyl methyl ether and saturated sodium carbonate solution, the 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 silica gel (mobile phase: cyclohexane/ethyl acetate 10:1), the residue obtained was separated into its components. This gave 301 mg (100% pure, 0.76 mmol, 92% of theory) of the title compound.

(290) LC-MS (method 1): R.sub.t=1.72 min; m/z=396 (M+H).sup.+

(291) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.30-1.48 (m, 9H), 1.81-2.29 (m, 2H), 2.62-2.80 (m, 0.2H), 2.90-3.18 (m, 1.5H), 3.27 (br. dd, 0.4H), 3.38-3.43 (m, 0.7H), 3.48-4.03 (m, 9.2H), 4.44-4.62 (m, 1H), 6.92-7.01 (m, 1H), 7.81 (td, 1H).

Example 61A

(292) tert-Butyl 10-[(3-fluoro-6-methoxypyridin-2-yl)carbonyl]-8-oxa-3,10-diazabicyclo[4.3.1]decane-3-carboxylate (Enantiomer 2)

(293) ##STR00096##

(294) 3-Fluoro-6-methoxypyridine-1-carboxylic acid (2 mg, 1.49 mmol) and 1-[bis(dimethylamino)methylene]-1H-[1,2,3]triazolo[4,5-b]pyridin-1-ium 3-oxide hexafluorophosphate (612 mg, 1.61 mmol) were initially charged in 1.0 ml of DMF. N-Ethyl-N-isopropylpropan-2-amine (650 μl, 3.7 mmol) was then added, and the mixture was stirred at room temperature for 1 h. tert-Butyl 8-oxa-3,10-diazabicyclo[4.3.1]decane-3-carboxylate (300 mg, 1.24 mmol, enantiomer 2) in 1 ml of DMF was then added, and stirring of the reaction mixture was continued at room temperature overnight. The reaction mixture was then diluted with tert-butyl methyl ether and saturated sodium carbonate solution, the 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 silica gel (mobile phase: cyclohexane/ethyl acetate 10:1), the residue obtained was separated into its components. This gave 443 mg (100% pure, 1.12 mmol, 90% of theory) of the title compound.

(295) LC-MS (method 1): R.sub.t=1.72 min; m/z=396 (M+H).sup.+.

(296) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.29-1.47 (m, 9H), 1.81-2.29 (m, 2H), 2.62-2.81 (m, 0.2H), 2.89-3.21 (m, 1.5H), 3.27 (br. dd, 0.4H), 3.37-3.45 (m, 0.7H), 3.47-4.03 (m, 9.2H), 4.44-4.62 (m, 1H), 6.87-7.05 (m, 1H), 7.81 (td, 1H).

Example 62A

(3-Fluoro-6-methoxypyridin-2-yl)(8-oxa-3,10-diazabicyclo[4.3.1]dec-10-yl)methanone (Enantiomer 1)

(297) ##STR00097##

(298) tert-Butyl 10-[(3-fluoro-6-methoxypyridin-2-yl)carbonyl]-8-oxa-3,10-diazabicyclo[4.3.1]decane-3-carboxylate (4.53 g, 11.5 mmol, enantiomer 1) was initially charged in 40 ml of dichloromethane and 20 ml of trifluoroacetic acid and stirred at room temperature for 2 h. The reaction mixture was then concentrated to dryness and the residue was taken up in ethyl acetate. The organic phase was washed with saturated sodium carbonate solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. This gave 2.36 g (content 100%, 7.98 mmol, 70% of theory) of the title compound.

(299) LC-MS (method 6): R.sub.t=1.00 min; m/z=296 (M+H).sup.+.

(300) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.57-1.80 (m, 1H), 1.82-2.11 (m, 1H), 2.61-2.81 (m, 1.5H), 2.83-3.10 (m, 2.5H), 3.40-3.73 (m, 4H), 3.79-4.01 (m, 4H), 4.33-4.59 (m, 1H), 6.96 (dd, 1H), 7.80 (t, 1H).

Example 63A

(3-Fluoro-6-methoxypyridin-2-yl)(8-oxa-3,10-diazabicyclo[4.3.1]dec-10-yl)methanone (Enantiomer 2)

(301) ##STR00098##

(302) tert-Butyl 10-[(3-fluoro-6-methoxypyridin-2-yl)carbonyl]-8-oxa-3,10-diazabicyclo[4.3.1]decane-3-carboxylate (3.88 g, 9.80 mmol, enantiomer 2) was initially charged in 40 ml of dichloromethane and 20 ml of trifluoroacetic acid and stirred at room temperature for 2 h. The reaction mixture was then concentrated to dryness and the residue was taken up in ethyl acetate. The organic phase was washed with saturated sodium carbonate solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. This gave 1.95 g (content 100%, 6.59 mmol, 67% of theory) of the title compound.

(303) LC-MS (method 6): R.sub.t=1.00 min; m/z=296 (M+H).sup.+.

(304) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.55-1.80 (m, 1H), 1.83-2.11 (m, 1H), 2.63-2.81 (m, 1.5H), 2.82-3.11 (m, 2.5H), 3.39-3.73 (m, 4H), 3.79-4.01 (m, 4H), 4.35-4.61 (m, 1H), 6.96 (dd, 1H), 7.80 (t, 1H).

(305) Analogously to Examples 55A, 60A and 61A, the following compounds were prepared from the starting materials specified in each case:

(306) TABLE-US-00004 Ex- Name/Structure/Starting materials ample Analytical data 64A .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.379 (5.77), 1.406 (9.63), 1.419 (16.00), 1.504 (0.63), 1.528 (0.86), 1.548 (0.74), 1.571 (0.47), 1.689 (0.45), 1.712 (0.83), 1.721 (0.85), 1.739 (0.90), 1.756 (0.54), 2.305 (0.48), 2.336 (0.46), 2.952 (0.53), 3.699 (0.58), 3.736 (1.15), 3.770 (0.64), 3.822 (0.82), 3.842 (0.79), 3.864 (0.54), 3.887 (0.48), 4.638 (0.42), 4.695 (0.55), 5.755 (0.58), 7.263 (0.54), 7.270 (0.64), 7.282 (1.88), 7.289 (1.90), 7.307 (1.87), 7.328 (0.70), 7.336 (0.64), 7.386 (0.50), 7.403 (0.85), 7.474 (0.83), 7.488 (1.58), 7.508 (1.25). LC-MS (method 1): R.sub.t = 0.99 min; m/z = 349 (M + H).sup.+. 65A 00 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.375 (6.26), 1.403 (16.00), 1.422 (8.86), 1.544 (0.54), 1.558 (0.59), 1.730 (0.41), 1.744 (0.50), 1.770 (0.48), 1.959 (0.41), 3.702 (0.41), 3.738 (0.54), 3.825 (0.46), 3.854 (6.39), 3.867 (8.26), 4.694 (0.64), 4.708 (0.73), 4.732 (0.42), 4.761 (0.40), 5.754 (1.87), 6.919 (0.65), 6.938 (0.92), 6.952 (0.72), 7.333 (0.49), 7.351 (0.56), 7.800 (0.58), 7.808 (0.54), 7.819 (0.92), 7.827 (0.91), 7.838 (0.57), 7.846 (0.47). LC-MS (method 1): R.sub.t = 1.00 min; m/z = 362 (M + H).sup.+. 66A 01 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.358 (5.09), 1.395 (8.29), 1.411 (16.00), 1.988 (0.57), 3.437 (0.45), 3.445 (0.50), 3.466 (0.70), 3.473 (0.78), 3.501 (0.46), 3.569 (1.26), 3.588 (1.02), 3.597 (0.86), 3.614 (0.67), 3.728 (0.58), 3.949 (0.63), 3.982 (0.47), 4.523 (0.48), 7.287 (0.67), 7.296 (1.06), 7.304 (1.21), 7.318 (1.15), 7.322 (1.36), 7.341 (0.54), 7.440 (0.52), 7.489 (0.40), 7.504 (0.65), 7.520 (0.52). LC-MS (method 2): R.sub.t = 1.87 min; m/z = 307 (M − C.sub.4H.sub.9].sup.+. 67A 02 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.339 (5.79), 1.391 (11.49), 1.400 (11.63), 1.404 (16.00), 1.989 (0.57), 3.141 (0.47), 3.152 (0.46), 3.412 (0.46), 3.418 (0.49), 3.428 (0.54), 3.439 (0.62), 3.447 (0.50), 3.523 (1.11), 3.551 (0.93), 3.567 (0.80), 3.578 (0.65), 3.587 (0.46), 3.597 (0.63), 3.607 (0.67), 3.618 (0.60), 3.685 (0.77), 3.718 (0.50), 3.756 (0.58), 3.787 (0.82), 3.829 (0.99), 3.847 (14.55), 3.864 (0.78), 3.959 (0.89), 3.988 (0.69), 4.103 (0.46), 4.524 (0.85), 5.754 (0.42), 6.894 (1.33), 6.915 (1.68), 7.112 (0.78), 7.131 (0.94), 7.153 (0.63), 7.162 (0.44), 7.180 (0.44), 7.803 (0.77), 7.823 (1.33), 7.842 (0.70). LC-MS (method 2): R.sub.t = 1.86 min; m/z = 378 (M + H).sup.+. 68A 03 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.227 (0.42), 1.335 (5.04), 1.387 (16.00), 1.948 (0.40), 3.162 (1.47), 3.175 (1.54), 3.278 (0.42), 3.290 (0.47), 3.325 (0.55), 3.498 (0.50), 3.519 (0.53), 3.527 (0.67), 3.537 (0.50), 3.575 (0.53), 3.584 (0.62), 3.600 (1.23), 3.626 (1.15), 3.652 (0.74), 3.692 (0.45), 3.816 (0.41), 3.841 (0.69), 3.974 (0.81), 4.002 (0.83), 4.074 (0.40), 4.575 (0.75). LC-MS (method 2): R.sub.t = 1.92 min; m/z = 297 [M − C.sub.4H.sub.9].sup.+. 69A 04 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = −0.008 (1.17), 0.008 (0.89), 1.106 (0.61), 1.157 (0.55), 1.175 (1.09), 1.193 (0.56), 1.290 (10.65), 1.359 (9.07), 1.369 (13.06), 1.385 (16.00), 1.398 (0.84), 1.911 (0.44), 1.944 (0.46), 1.988 (2.14), 2.037 (0.52), 2.048 (0.50), 2.066 (0.42), 3.267 (0.54), 3.279 (0.59), 3.510 (0.59), 3.519 (0.76), 3.528 (0.57), 3.539 (0.79), 3.548 (0.99), 3.558 (0.58), 3.587 (0.47), 3.596 (0.51), 3.618 (2.61), 3.630 (1.64), 3.643 (2.27), 3.657 (1.45), 3.670 (1.11), 3.778 (0.45), 3.790 (0.57), 3.830 (1.06), 3.859 (0.76), 3.877 (0.57), 3.951 (0.55), 3.978 (1.00), 4.004 (0.65), 4.021 (0.50), 4.039 (0.49), 4.180 (0.63), 4.548 (1.30), 5.754 (0.53), 6.389 (3.00), 6.442 (1.00). LC-MS (method 1): R.sub.t = 0.85 min; m/z = 354 (M + H).sup.+.

(307) Analogously to Examples 58A, 59A, 62A and 63A, the following compounds were prepared from the starting material specified in each case:

(308) TABLE-US-00005 Ex- am- ple Name/Structure/Starting material Analytical data 70A 05 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.13-1.54 (m, 2H), 1.65-2.37 (m, 5H), 2.39-2.60 (m, 2H), 2.64-3.08 (m, 2H), 3.67-3.83 (m, 1H), 4.51-4.65 (m, 1H), 7.18-7.34 (m, 2H), 7.34-7.58 (m, 2H). LC-MS (method 2): R.sub.t = 0.58 min; m/z = 249 (M + H).sup.+. 71A 06 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.28-1.60 (m, 1H), 1.66-2.24 (m, 5H), 2.40-2.48 (m, 0.8H), 2.59-2.70 (m, 1.2H), 2.72- 2.86 (m, 1H), 2.88-3.05 (m, 1H), 3.11-3.22 (m, 0.7H), 3.85 (d, 3H), 4.08 (q, 0.3H), 4.35-4.58 (m, 1H), 4.56- 4.70 (m, 2H), 6.90 (dd, 1H), 7.25 (dd, 1H), 7.80 (td, 1H). LC-MS (method 2): R.sub.t = 0.61 min; m/z = 262 (M + H).sup.+. 72A 07 LC-MS (method 6): R.sub.t = 0.94 min; m/z = 265 (M + H).sup.+. 73A 08 LC-MS (method 6): R.sub.t = 0.91 min; m/z = 278 (M + H).sup.+. 74A 09 LC-MS (method 6): R.sub.t = 0.94 min; m/z = 253 (M + H).sup.+. 75A 0 LC-MS (method 6): R.sub.t = 0.79 min; m/z = 254 (M + H).sup.+.

Example 76A and Example 77A

(309) tert-Butyl 9-[(6-methoxypyridin-2-yl)carbonyl]-3,9-diazabicyclo[4.2.1]nonane-3-carboxylate (Enantiomers 1 and 2)

(310) ##STR00111##

(311) 553 mg (1.53 mmol) of racemic tert-butyl 9-[(6-methoxypyridin-2-yl)carbonyl]-3,9-diazabicyclo[4.2.1]nonane-3-carboxylate (Example 65A) were separated into the enantiomers by preparative SFC-HPLC on a chiral phase [column: Chiralcel AD-H, 5 μm, 250 mm×30 mm; mobile phase: carbon dioxide/isopropanol 88:12 (v/v); flow rate: 125 g/min; pressure: 135 bar; UV detection: 210 nm; temperature: 38° C.]:

Example 76A (Enantiomer 1)

(312) Yield: 274 mg

(313) R.sub.t=1.69 min; chemical purity >98%; >99% ee

(314) [column: Chiralpak AD-3, 3 μm, 100 mm×4.6 mm; mobile phase: carbon dioxide/isopropanol 85:15 (v/v); flow rate: 3 ml/min; pressure: 130 bar; UV detection: 210 nm; temperature: 60° C.].

(315) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.36-1.46 (m, 9H), 1.49-1.62 (m, 1.5H), 1.62-1.84 (m, 1.5H), 1.84-2.30 (m, 3H), 2.76-3.00 (m, 1H), 3.05-3.44 (m, 1H), 3.65-3.95 (m, 5H), 4.49-4.81 (m, 2H), 6.94 (dd, 1H), 7.20-7.42 (m, 1H), 7.69-7.90 (m, 1H).

(316) LC-MS (method 1): R.sub.t=0.97 min; m/z=362 (M+H).sup.+.

Example 77A (Enantiomer 2)

(317) Yield: 273 mg

(318) R.sub.t=1.82 min; chemical purity >96%; >92% ee

(319) [column: Chiralpak AD-3, 3 μm, 100 mm×4.6 mm; mobile phase: carbon dioxide/isopropanol 85:15 (v/v); flow rate: 3 ml/min; pressure: 130 bar; UV detection: 210 nm; temperature: 60° C.].

(320) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.33-1.47 (m, 9H), 1.48-1.63 (m, 1.5H), 1.64-1.81 (m, 1.5H), 1.84-2.36 (m, 3H), 2.77-3.00 (m, 1H), 3.04-3.45 (m, 1H), 3.68-3.98 (m, 5H), 4.50-4.81 (m, 2H), 6.94 (dd, 1H), 7.20-7.45 (m, 1H), 7.82 (td, 1H).

(321) LC-MS (method 2): R.sub.t=1.90 min; m/z=362 (M+H).sup.+.

Example 78A and Example 79A

tert-Butyl 9-(2-fluorobenzoyl)-3,9-diazabicyclo[4.2.1]nonane-3-carboxylate (Enantiomers 1

(322) ##STR00112##

(323) 1.27 g (3.65 mmol) of racemic tert-butyl 9-(2-fluorobenzoyl)-3,9-diazabicyclo[4.2.1]nonane-3-carboxylate (Example 64A) were separated into the enantiomers by preparative SFC-HPLC on a chiral phase [column: Chiralpak OX-H, 5 μm, 250 mm×30 mm; mobile phase: carbon dioxide/isopropanol 85:15 (v/v); pressure: 120 bar; flow rate: 120 g/min; UV detection: 210 nm; temperature: 38° C.]:

Example 78A (Enantiomer 1)

(324) Yield: 628 mg

(325) R.sub.t=2.14 min; chemical purity >99%; >99% ee

(326) [Aligent SFC; column: Chiralpak OX-3, 50 mm×4.6 mm; mobile phase: carbon dioxide/isopropanol, gradient: 0 min 5% isopropanol, 0.5 min 5% isopropanol, 5 min 50% isopropanol, 6 min 50% isopropanol, 6.01 min 5% isopropanol, 7 min 5% isopropanol; flow rate: 3 ml/min; temperature: 40° C.; UV detection: 220 nm].

(327) LC-MS (method 1): R.sub.t=1.00 min; m/z=349 (M+H).sup.+.

(328) [α].sub.D.sup.20=−23.33° (c=0.41, methanol).

Example 79A (Enantiomer 2)

(329) Yield: 602 mg

(330) R.sub.t=2.415 min; chemical purity >99%; >99% ee

(331) [Aligent SFC; column: Chiralpak OX-3, 50 mm×4.6 mm; mobile phase: carbon dioxide/isopropanol, gradient: 0 min 5% isopropanol, 0.5 min 5% isopropanol, 5 min 50% isopropanol, 6 min 50% isopropanol, 6.01 min 5% isopropanol, 7 min 5% isopropanol; flow rate: 3 ml/min; temperature: 40° C.; UV detection: 220 nm].

(332) LC-MS (method 1): R.sub.t=1.00 min; m/z=349 (M+H).sup.+.

(333) [α].sub.D.sup.20=+22.5° (c=0.41, methanol).

Example 80A

3,9-diazabicyclo[4.2.1]non-9-yl(2-fluorophenyl)methanone (Enantiomer 1)

(334) ##STR00113##

(335) With stirring, 4.5 ml of dioxane and 4.5 ml of a 4 M solution of hydrogen chloride in dioxane were added to tert-butyl 9-(2-fluorobenzoyl)-3,9-diazabicyclo[4.2.1]nonane-3-carboxylate (628 mg, 1.80 mmol, enantiomer 1), and the mixture was stirred at room temperature overnight. The reaction mixture was then concentrated to dryness and the residue was taken up in 10 ml of THF. 0.33 ml of triethylamine was then added with stirring, and the mixture was stirred at room temperature for 1 h. The mixture was then diluted with water and ethyl acetate. The organic phase was removed, washed with water, dried over magnesium sulfate and concentrated to dryness. This gave 153 mg (content 100%, 0.61 mmol, 40% of theory) of the title compound.

(336) LC-MS (method 1): R.sub.t=0.32 min; m/z=249 (M+H).sup.+.

(337) Analogously to Example 80A, the following compound was prepared from the starting material stated:

(338) TABLE-US-00006 Example Name/Structure/Starting material Analytical data 81A LC-MS (method 1): R.sub.t = 0.32 min; m/z = 249 (M + H).sup.+.

(339) Analogously to Examples 62A and 63A, the following compound was prepared from the starting material specified:

(340) TABLE-US-00007 Example Name/Structure/Starting material Analytical data 82A LC-MS (method 2): R.sub.t = 0.49 min; m/z = 296 (M + H).sup.+.

(341) Analogously to Examples 55A, 60A and 61A, the following compounds were prepared from the starting materials specified in each case:

(342) TABLE-US-00008 Example Name/Structure/Starting materials Analytical data 83A .sup.1H-NMR (500 MHz, DMSO-d.sub.6): δ [ppm] = 1.29-1.49 (m, 9H), 1.51-1.71 (m, 3H), 1.72-1.95 (m, 1.25H), 2.18-2.29 (m, 0.25H), 2.30-2.42 (m, 0.75H), 2.81-3.00 (m, 0.25H), 3.02-3.26 (m, 1H), 3.35-3.52 (m, 1.5H), 3.52-3.64 (m, 1H), 3.79-3.89 (m, 3H), 3.90-4.22 (m, 2.75H), 4.57 (br. s, 0.25H), 6.90 (d, 1H), 7.12- 7.26 (m, 1H), 7.75- 7.86 (m, 1H). LC-MS (method 1): R.sub.t = 0.98 min; m/z = 362 (M + H).sup.+. 84A .sup.1H-NMR (500 MHz, DMSO-d.sub.6): δ [ppm] = 1.32-1.48 (m, 9H), 1.51-1.72 (m, 3H), 1.72-1.93 (m, 1.25H), 2.20-2.28 (m, 0.25H), 2.30-2.42 (m, 0.75H), 3.02-3.26 (m, 2H), 3.48 (br. d, 0.75H), 3.62 (br. d, 0.75H), 3.76-3.89 (m, 3.75H), 3.90-4.23 (m, 2.25H), 4.56-4.68 (m, 0.25H), 6.91-6.99 (m, 1H), 7.73-7.85 (m, 1H). LC-MS (method 1): R.sub.t = 0.93 min; m/z = 380 (M + H).sup.+. 85A LC-MS (method 1): R.sub.t = 1.04 min; m/z = 396/398 (M + H).sup.+.

Example 86A

3,6-Diazabicyclo[3.2.2]non-6-yl(3-fluoro-6-methoxypyridin-2-yl)methanone hydrochloride (Enantiomer 1)

(343) ##STR00119##

(344) With stirring, 7 ml of a 4 M solution of hydrogen chloride in dioxane were added to tert-butyl 6-[(3-fluoro-6-methoxypyridin-2-yl)carbonyl]-3,6-diazabicyclo[3.2.2]nonane-3-carboxylate (enantiomer 1) (1060 mg, 2.79 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 763 mg of the target product.

(345) LC-MS (method 2): R.sub.t=0.54 min; m/z=280 (M+H).sup.+.

(346) Analogously to Example 86A, the following compounds were prepared from the starting material specified in each case:

(347) TABLE-US-00009 Example Name/Structure/Starting material Analytical data 87A 0 LC-MS (method 2): R.sub.t = 0.54 min; m/z = 262 (M + H).sup.+. 88A LC-MS (method 1): R.sub.t = 0.40 min; m/z = 296/298 (M + H).sup.+.

Example 89A and Example 90A

9-Benzyl 3-tert-butyl 3,9-diazabicyclo[4.2.1]nonane-3,9-dicarboxylate (Enantiomer 1 and 2)

(348) ##STR00122##

(349) 135.7 g (376 mmol) of the racemic 9-benzyl 3-tert-butyl 3,9-diazabicyclo[4.2.1]nonane-3,9-dicarboxylate (prepared according to the original synthesis procedure US 20150132258) were separated into the enantiomers by preparative SFC-HPLC on a chiral phase (column: Chiralcel AZ, 20 m, 360 mm×50 mm; mobile phase: carbon dioxide/MeOH 90:10 (v/v); flow rate: 400 ml/min; pressure: 110 bar; UV detection: 210 nm; temperature: 40° C.]:

Example 89A (Enantiomer 1)

(350) Yield: 57.7 g

(351) R.sub.t=1.92 min; chemical purity >×100%; >99% ee

(352) [Column: Chiralpak AZ-H, 5 μm, 150 mm×4.6 mm; mobile phase: carbon dioxide/methanol 90:10; flow rate: 3 ml/min; pressure: 130 bar; UV detection: 210 nm; temperature: 40° C.].

(353) LC-MS (Method 2): R.sub.t=2.22 min; m/z=305 (M+H-C4H8).sup.+.

(354) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.33-1.45 (m, 9H), 1.49 (br s, 1H), 1.57-1.75 (m, 2H), 1.81-2.07 (m, 2H), 2.14-2.34 (m, 1H), 2.57-2.84 (m, 1H), 2.87-3.18 (m, 1H), 3.52-3.89 (m, 2H), 4.16-4.28 (m, 2H), 4.96-5.17 (m, 2H), 7.24-7.46 (m, 5H).

Example 90A (Enantiomer 2)

(355) Yield: 62.1 g

(356) R.sub.t=2.31 min; chemical purity >99%; >94% ee

(357) [Column: Chiralpak AZ-H, 5 μm, 150 mm×4.6 mm; mobile phase: carbon dioxide/methanol 90:10; flow rate: 3 ml/min; pressure: 130 bar; UV detection: 210 nm; temperature: 40° C.].

(358) LC-MS (Method 2): R.sub.t=2.22 min; m/z=305 (M+H-C4H8).sup.+.

(359) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.33-1.44 (m, 9H), 1.48 (br s, 1H), 1.55-1.74 (m, 2H), 1.78-2.06 (m, 2H), 2.12-2.32 (m, 1H), 2.56-2.86 (m, 1H), 2.90-3.18 (m, 1H), 3.50-3.88 (m, 2H), 4.24 (br t, 2H), 4.98-5.18 (m, 2H), 7.25-7.43 (m, 5H).

Example 91A

tert-Butyl 3,9-diazabicyclo[4.2.1]nonane-3-carboxylate (Enantiomer 2)

(360) ##STR00123##

(361) 9-Benzyl 3-tert-butyl 3,9-diazabicyclo[4.2.1]nonane-3,9-dicarboxylate (Enantiomer 2) (62.0 g, 172 mmol) was initially charged in ethanol (500 ml) and flushed with argon. Pd/C 5 mol % (3.66 g, 1.72 mmol) was then added and the mixture was stirred overnight at room temperature and under a hydrogen atmosphere (1 bar). More Pd/C 5 mol % (3.66 g, 1.72 mmol) was then added and the mixture was stirred at room temperature for another 7 h (hydrogen 1 bar). The mixture was then filtered and concentrated to dryness under reduced pressure. This gave 25.6 mg (content 100%, 157 mmol, 91% of theory) of the title compound.

(362) GC-MS (Method 3): R.sub.t=5.23, min; m/z=226 (M.sup.+)

(363) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.24-1.34 (m, 1H), 1.39 (s, 9H), 1.47-1.74 (m, 4H), 1.86-2.01 (m, 1H), 2.55-2.65 (br. s, 1H), 2.67-2.81 (m, 1H), 2.97-3.16 (m, 1H), 3.35-3.45 (m, 1H), 3.49-3.59 (m, 1.5H), 3.60-3.78 (m, 1.5H).

Example 92A

tert-Butyl 3,9-diazabicyclo[4.2.1]nonane-3-carboxylate (Enantiomer 1)

(364) ##STR00124##

(365) 9-Benzyl 3-tert-butyl 3,9-diazabicyclo[4.2.1]nonane-3,9-dicarboxylate (Enantiomer 1) (57.7 g, 160 mmol) was initially charged in ethanol (500 ml) and flushed with argon. Pd/C 5 mol % (3.41 g, 1.60 mmol) was then added and the mixture was stirred overnight at room temperature and under a hydrogen atmosphere (1 bar). Pd/C 5 mol % (3.41 g, 1.60 mmol) was then added and stirring of the mixture at room temperature was continued overnight (hydrogen 1 bar). The mixture was then filtered and concentrated to dryness under reduced pressure. This gave 35.5 g (content 100%, 157 mmol, 98% of theory) of the title compound.

(366) GC-MS (Method 3): R.sub.t=5.24, min; m/z=226 (M.sup.+)

(367) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.24-1.32 (m, 1H), 1.39 (s, 9H), 1.47-1.73 (m, 4H), 1.84-2.01 (m, 1H), 2.67-2.82 (m, 1H), 2.96-3.17 (m, 1H), 3.36-3.41 (m, 1H), 3.50-3.58 (m, 1.5H), 3.61-3.79 (m, 1.5H).

(368) Analogously to Examples 55A, 60A and 61A, the following compounds were prepared from the starting materials stated in each case:

(369) TABLE-US-00010 Example Name/Structure/Starting material Analytical data 94A 1H NMR (500 MHz, DMSO-d6) δ ppm 1.36-1.45 (m, 9H), 1.48-1.66 (m, 1.5H), 1.67-2.25 (m, 4H), 2.29-2.41 (m, 0.5H), 2.75-3.26 (m, 2H), 3.80-3.87 (m, 6H), 4.57-4.75 (m, 1H), 6.95 (dd, 1H), 7.91 (t, 1H) LC-MS (Method 1): Rt = 1.04 min; MS (ESIpos): m/z = 396 (M + H).sup.+

(370) Analogously to Example 86A, the following compounds were prepared from the starting material stated in each case:

(371) TABLE-US-00011 Example Name/Structure/Starting material Analytical data  96A LC-MS (Method 1): R.sub.t = 0.37 min; MS (ESIpos): m/z = 280 (M + H).sup.+  97A LC-MS (Method 1): R.sub.t = 0.38 min; MS (ESIpos): m/z = 262 (M + H).sup.+  98A LC-MS (Method 1): R.sub.t = 0.41 min; MS (ESIpos): m/z = 262 (M + H).sup.+  99A LC-MS (Method 1): R.sub.t = 0.46 min; MS (ESIpos): m/z = 296 (M + H).sup.+ 100A 0 LC-MS (Method 1): R.sub.t = 0.46 min; MS (ESIpos): m/z = 296 (M + H).sup.+

WORKING EXAMPLES

Example 1

tert-Butyl 6-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,6-diazabicyclo[3.2.2]nonane-2-carboxylate (Enantiomer 2)

(372) ##STR00131##

(373) Under argon, 2-(4-chlorophenyl)imidazo[1,2-a]pyrimidine-3-carbaldehyde (1.00 g, 3.88 mmol), tert-butyl 2,6-diazabicyclo[3.2.2]nonane-2-carboxylate (enantiomer 2; 1.05 g, 4.66 mmol) and acetic acid (440 μl, 7.8 mmol) were initially charged in 26 ml of THF. Subsequently, sodium triacetoxyborohydride (1.23 g, 5.82 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was then first diluted with saturated ammonium chloride solution, and saturated sodium carbonate solution was then added. The organic phase was separated off and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. On silica gel (mobile phase: dichloromethane/methanol 50:1), the residue obtained was separated into its components. This gave 1,056 g (content 100%, 2.25 mmol, 58% of theory) of the title compound.

(374) LC-MS (method 2): R.sub.t=1.50 min; m/z=468/470 (M+H).sup.+

(375) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.23-1.46 (m, 10H), 1.52-1.99 (m, 5H), 2.56-2.73 (m, 2H), 2.93-3.08 (m, 1H), 3.12-3.28 (m, 1H), 3.51-3.75 (m, 1H), 3.94-4.14 (m, 1H), 4.22 (br. s, 2H), 7.11 (dd, 1H), 7.55 (d, 2H), 7.89 (d, 2H), 8.58 (dd, 1H), 8.85-9.04 (m, 1H).

(376) Analogously to Example 1, the following compounds were prepared from the starting materials specified in each case:

(377) TABLE-US-00012 Name/Structure/Starting materials Example Analytical data 2 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = −0.008 (1.65), 0.008 (1.51), 1.272 (16.00), 1.360 (10.16), 1.393 (5.02), 1.599 (1.53), 1.629 (1.48), 1.784 (1.07), 1.916 (0.99), 2.328 (0.91), 2.566 (0.99), 2.617 (1.38), 2.670 (1.65), 2.970 (0.69), 3.029 (0.97), 3.209 (0.61), 3.636 (0.87), 3.990 (1.03), 4.111 (0.73), 4.220 (4.73), 5.754 (2.55), 7.092 (3.52), 7.103 (3.60), 7.109 (3.61), 7.120 (3.58), 7.537 (8.91), 7.558 (10.30), 7.881 (7.18), 7.902 (6.41), 8.573 (3.56), 8.578 (4.01), 8.583 (3.80), 8.588 (3.65), 8.947 (1.80). LC-MS (method 2): R.sub.t = 1.52 min; m/z = 468/470 (M + H).sup.+. 3 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = −0.149 (0.44), −0.008 (4.22), 0.008 (3.54), 0.146 (0.46), 1.234 (0.51), 1.316 (16.00), 1.390 (11.89), 1.568 (0.98), 1.597 (0.86), 1.670 (1.53), 1.814 (0.82), 1.924 (0.77), 2.328 (0.41), 2.680 (0.64), 2.711 (1.05), 2.749 (0.60), 2.859 (2.45), 2.888 (1.71), 3.048 (1.40), 3.287 (1.03), 3.622 (1.09), 3.657 (0.92), 4.021 (0.99), 4.123 (0.72), 4.515 (2.25), 4.550 (3.12), 4.676 (0.72), 4.719 (1.20), 4.754 (0.73), 5.755 (0.55), 6.951 (1.59), 6.968 (3.23), 6.984 (1.78), 7.311 (1.85), 7.314 (1.88), 7.334 (2.46), 7.337 (2.29), 7.351 (2.05), 7.353 (1.96), 7.599 (4.37), 7.622 (3.69), 7.982 (3.36), 7.989 (3.41), 8.004 (4.10), 8.010 (4.21), 8.193 (5.92), 8.215 (4.84), 8.411 (2.13), 8.428 (2.11), 8.653 (3.32). LC-MS (method 2): R.sub.t = 1.26 min; m/z = 468/470 (M + H).sup.+. 4 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = −0.008 (0.68), 0.008 (0.80), 1.285 (16.00), 1.365 (10.59), 1.419 (1.11), 1.597 (1.40), 1.659 (1.45), 1.762 (1.01), 1.909 (0.91), 2.367 (0.70), 2.523 (1.33), 2.526 (1.26), 2.558 (1.09), 2.561 (1.04), 2.563 (1.08), 2.587 (0.99), 2.615 (0.56), 2.655 (1.28), 2.670 (0.97), 2.675 (0.89), 2.694 (0.94), 2.710 (1.16), 2.961 (0.70), 3.015 (0.96), 3.170 (0.60), 3.203 (0.60), 3.236 (0.46), 3.643 (0.85), 3.677 (0.51), 4.000 (1.02), 4.120 (0.73), 4.194 (4.78), 5.755 (0.65), 6.932 (1.71), 6.949 (3.48), 6.966 (1.88), 7.277 (1.84), 7.280 (1.96), 7.299 (2.53), 7.302 (2.46), 7.316 (2.03), 7.319 (2.05), 7.507 (8.35), 7.524 (3.12), 7.528 (9.53), 7.579 (4.15), 7.602 (3.55), 7.855 (6.76), 7.876 (6.10), 8.491 (1.21), 8.508 (1.88). LC-MS (method 2): R.sub.t = 1.56 min; m/z = 467/469 (M + H).sup.+. 5 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = −0.008 (1.76), 0.008 (1.74), 1.285 (16.00), 1.365 (10.49), 1.597 (1.39), 1.662 (1.44), 1.764 (1.00), 1.903 (0.88), 2.328 (0.41), 2.367 (0.44), 2.588 (0.96), 2.651 (1.32), 2.670 (1.03), 2.690 (0.93), 2.710 (0.88), 2.963 (0.67), 3.014 (0.93), 3.171 (0.60), 3.201 (0.59), 3.236 (0.47), 3.643 (0.84), 4.002 (1.00), 4.120 (0.71), 4.194 (4.70), 6.933 (1.70), 6.950 (3.46), 6.966 (1.87), 7.280 (1.96), 7.300 (2.49), 7.302 (2.39), 7.317 (2.05), 7.319 (2.03), 7.507 (8.31), 7.528 (9.38), 7.579 (4.11), 7.602 (3.50), 7.855 (6.76), 7.876 (6.04), 8.491 (1.19), 8.508 (1.85). LC-MS (method 1): R.sub.t = 0.80 min; m/z = 467/469 (M + H).sup.+. 6 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.20-1.48 (m, 16H), 1.53-1.84 (m, 4H), 1.86-1.98 (m, 1H), 2.47-2.77 (m, 2H, partially covered by DMSO signal), 2.88-3.09 (m, 2H), 3.12-3.29 (m, 1H), 3.56-3.73 (m, 1H), 3.96-4.07 (m, 0.5H), 4.07-4.16 (m, 0.5H), 4.22 (br. s, 2H), 7.08 (dd, 1H), 7.36 (d, 2H), 7.78 (br. d, 2H), 8.55 (dd, 1H), 8.86-8.97 (m, 1H). LC-MS (method 2): R.sub.t = 1.60 min; m/z = 476 (M + H).sup.+. [α].sub.D.sup.20 = −9.42° (c = 0.29, Methanol). 7 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.20-1.48 (m, 16H), 1.53-1.84 (m, 4H), 1.86-1.98 (m, 1H), 2.47-2.77 (m, 2H, partially covered by DMSO signal), 2.88-3.09 (m, 2H), 3.12-3.29 (m, 1H), 3.56-3.72 (m, 1H), 3.96-4.07 (m, 0.5H), 4.07-4.16 (m, 0.5H), 4.22 (br. s, 2H), 7.08 (dd, 1H), 7.36 (d, 2H), 7.78 (br. d, 2H), 8.55 (dd, 1H), 8.87-8.96 (m, 1H). LC-MS (method 2): R.sub.t = 1.61 min; m/z = 476 (M + H).sup.+. [α].sub.D.sup.20 = +9.49° (c = 0.33, Methanol).

Example 8

tert-Butyl 9-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,9-diazabicyclo[4.2.1]nonane-3-carboxylate (racemate)

(378) ##STR00138##

(379) Under argon and at room temperature, 1.465 g (5.52 mmol) of 2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidine-3-carbaldehyde were dissolved in 20 ml of THF, and 1.5 g (6.63 mmol) of tert-butyl 3,9-diazabicyclo[4.2.1]nonane-3-carboxylate (racemate) and 0.63 ml (11.05 mmol) of acetic acid were added. Subsequently, 1.756 g (8.29 mmol) of sodium triacetoxyborohydride were added in portions, 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 2:1.fwdarw.1:1). This gave 1.75 g (content 96%, 3.53 mmol, 64% of theory) of the target compound.

(380) LC-MS (method 2): R.sub.t=2.06 min; m/z=476 (M+H).sup.+.

Example 9 and Example 10

tert-Butyl 9-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,9-diazabicyclo[4.2.1]nonane-3-carboxylate (Enantiomer 1 and 2)

(381) ##STR00139##

(382) 1.75 g (3.68 mmol) of racemic tert-butyl 9-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,9-diazabicyclo[4.2.1]nonane-3-carboxylate (Example 8) were separated into the enantiomers by preparative HPLC on a chiral phase [column: Daicel Chiralpak IC, 5 μm, 250 mm×20 mm; mobile phase: isopropanol+0.2% diethylamine (v/v); flow rate: 15 ml/min; UV detection: 220 nm; temperature: 40° C.]:

Example 9 (Enantiomer 1)

(383) Yield: 745 mg

(384) R.sub.t=7.652 min; chemical purity >98.9%; >99% ee

(385) [column: Daicel Chiralpak ID, 5 μm, 250 mm×4.6 mm; mobile phase: isohexane/isopropanol 50:50+0.2% diethylamine (v/v); flow rate: 1 ml/min; temperature: 50° C.; UV detection: 235 nm].

(386) LC-MS (method 2): R.sub.t=2.04 min; m/z=476 (M+H).sup.+.

(387) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.25 (d, 6H), 1.29-1.56 (m, 12H), 1.56-1.67 (m, 1H), 1.92-2.07 (m, 1H), 2.14-2.28 (m, 1H), 2.79 (br. d, 1H), 2.88-3.01 (m, 1.5H), 3.01-3.13 (m, 0.5H), 3.17-3.35 (m, 2H, partially covered by H.sub.2O signal), 3.47 (br. d, 0.5H), 3.61 (br. d, 1.5H), 4.16-4.30 (m, 2H), 7.05-7.14 (m, 1H), 7.37 (d, 2H), 7.79 (d, 2H), 8.52-8.61 (m, 1H), 9.02-9.12 (m, 1H).

Example 10 (Enantiomer 2)

(388) Yield: 751 mg

(389) R.sub.t=6.945 min; chemical purity >99%; >99% ee

(390) [column: Daicel Chiralpak ID, 5 μm, 250 mm×4.6 mm; mobile phase: isohexane/isopropanol 50:50+0.2% diethylamine (v/v); flow rate: 1 ml/min; temperature: 50° C.; UV detection: 235 nm].

(391) LC-MS (method 2): R.sub.t=2.04 min; m/z=476 (M+H).sup.+.

(392) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.25 (d, 6H), 1.29-1.56 (m, 12H), 1.56-1.67 (m, 1H), 1.92-2.07 (m, 1H), 2.14-2.27 (m, 1H), 2.79 (br. d, 1H), 2.88-3.01 (m, 1.5H), 3.01-3.12 (m, 0.5H), 3.17-3.35 (m, 2H, partially covered by H.sub.2O signal), 3.47 (br. d, 0.5H), 3.61 (br. d, 1.5H), 4.16-4.29 (m, 2H), 7.05-7.14 (m, 1H), 7.37 (d, 2H), 7.79 (d, 2H), 8.53-8.61 (m, 1H), 9.03-9.12 (m, 1H).

Example 11

3-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-8-oxa-3,10-diazabicyclo[4.3.1]dec-10-yl](3-fluoro-6-methoxypyridin-2-yl)methanone (Enantiomer 1)

(393) ##STR00140##

(394) Under argon, [2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methanol (2.48 g, 9.58 mmol) and triethylamine (10 ml, 72 mmol) were initially charged in 40 ml of dichloromethane. In an ice bath, the mixture was cooled to 0° C., and methanesulfonyl chloride (1.9 ml, 24 mmol) was then added slowly. The mixture was stirred in the ice bath for 30 min. (3-Fluoro-6-methoxypyridin-2-yl)[8-oxa-3,10-diazabicyclo[4.3.1]dec-10-yl]methanone (2.36 g, 7.98 mmol, enantiomer 1) in 40 ml of acetonitrile was then added slowly. The reaction solution was then heated to 40° C. and stirred at this temperature for 2 h. The reaction mixture was subsequently diluted with 1 N aqueous sodium hydroxide solution and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. On silica gel (mobile phase: cyclohexane/ethyl acetate 5:2), the residue obtained was separated into its components. The mixed fraction obtained was then re-purified by preparative HPLC (Method 10). The product fractions obtained in this manner were taken up in ethyl acetate, and the organic phase was washed with saturated sodium carbonate solution, dried over magnesium sulfate, filtered and once more concentrated to dryness. This gave 3.00 g (content 100%, 5.58 mmol, 70% of theory) of the title compound.

(395) LC-MS (method 2): R.sub.t=1.44 min; m/z=536/538 (M+H).sup.+.

(396) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.47-1.65 (m, 1H), 1.72-1.88 (m, 1H), 2.31-2.46 (m, 0.4H), 2.58-2.89 (m, 3H), 2.90-2.98 (m, 0.6H), 3.41 (dd, 0.6H), 3.47-3.82 (m, 7.4H), 4.10-4.29 (m, 2H), 4.38-4.58 (m, 1H), 6.83-7.02 (m, 2H), 7.22-7.36 (m, 1H), 7.45-7.54 (m, 2H), 7.55-7.63 (m, 1H), 7.72-7.84 (m, 1H), 7.85-8.04 (m, 2H), 8.69-8.92 (m, 1H).

(397) [α].sub.D.sup.20=−5.85° (c=0.410, methanol).

Example 12

3-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-8-oxa-3,10-diazabicyclo[4.3.1]dec-10-yl](3-fluoro-6-methoxypyridin-2-yl)methanone (Enantiomer 2)

(398) ##STR00141##

(399) Under argon, [2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methanol (2.05 g, 7.91 mmol) and triethylamine (8.3 ml, 59 mmol) were initially charged in 40 ml of dichloromethane. In an ice bath, the mixture was cooled to 0° C., and methanesulfonyl chloride (1.5 ml, 20 mmol) was then added slowly. The mixture was stirred in the ice bath for 30 min. (3-Fluoro-6-methoxypyridin-2-yl)[8-oxa-3,10-diazabicyclo[4.3.1]dec-10-yl]methanone (1.95 g, 6.59 mmol, enantiomer 2) in 40 ml of acetonitrile was then added slowly. The reaction solution was then heated to 40° C. and stirred at this temperature for 2 h. The reaction mixture was subsequently diluted with 1 N aqueous sodium hydroxide solution and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. On silica gel (mobile phase: cyclohexane/ethyl acetate 5:2), the residue obtained was separated into its components. The mixed fraction obtained was then re-purified by preparative HPLC (Method 10). The product fractions obtained in this manner were taken up in ethyl acetate, and the organic phase was washed with saturated sodium carbonate solution, dried over magnesium sulfate, filtered and once more concentrated to dryness. This gave 2.35 g (content 100%, 4.39 mmol, 67% of theory) of the title compound.

(400) LC-MS (method 1): R.sub.t=0.77 min; m/z=536/538 (M+H).sup.+.

(401) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.35-1.63 (m, 1H), 1.68-1.87 (m, 1H), 2.31-2.46 (m, 0.4H), 2.58-2.88 (m, 3H), 2.89-3.02 (m, 0.6H), 3.41 (dd, 0.6H), 3.46-3.86 (m, 7.4H), 4.07-4.30 (m, 2H), 4.40-4.57 (m, 1H), 6.75-7.02 (m, 2H), 7.13-7.37 (m, 1H), 7.42-7.53 (m, 2H), 7.56-7.67 (m, 1H), 7.72-7.83 (m, 1H), 7.84-8.04 (m, 2H), 8.62-8.94 (m, 1H).

(402) [α].sub.D.sup.20=+8.10° (c=0.395, methanol).

Example 13

3-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-8-oxa-3,10-diazabicyclo[4.3.1]dec-10-yl](3-fluoro-6-methoxypyridin-2-yl)methanone (Enantiomer 1)

(403) ##STR00142##

(404) Under argon, (3-fluoro-6-methoxypyridin-2-yl) [8-oxa-3,1-diazabicyclo[4.3.1]dec-10-yl]methanone (780 mg, 2.64 mmol, enantiomer 1), 2-(4-chlorophenyl)imidazo[1,2-a]pyrimidine-3-carbaldehyde (817 mg, 3.17 mmol) and acetic acid (360 μl, 6.3 mmol) were initially charged in 30 ml of THF. Sodium triacetoxyborohydride (1.01 g, 4.75 mmol) was then added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then diluted with saturated sodium carbonate solution, the 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. On neutral alumina (mobile phase: dichloromethane/methanol 50:1), the residue obtained was separated into its components. 100 mg of the product obtained in this manner were then re-purified by preparative HPLC (Method 9). This gave 81 mg (content 100%, 0.150 mmol, 6% of theory) of the title compound.

(405) LC-MS (method 2): R.sub.t=1.65 min; m/z=537/539 (M+H).sup.+.

(406) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.47-1.66 (m, 1H), 1.73-1.88 (m, 1H), 2.30-2.44 (m, 0.4H), 2.58-2.87 (m, 3H), 2.87-2.97 (m, 0.75H), 3.41 (dd, 0.75H), 3.49-3.83 (m, 7.1H), 4.15-4.30 (m, 2H), 4.40-4.50 (m, 1H), 6.91-6.99 (m, 1H), 7.01-7.08 (m, 1H), 7.54 (d, 2H), 7.73-7.85 (m, 1H), 7.87-8.01 (m, 2H), 8.58 (dd, 1H), 9.15-9.36 (m, 1H).

Example 14

3-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-8-oxa-3,10-diazabicyclo[4.3.1]dec-10-yl](3-fluoro-6-methoxypyridin-2-yl)methanone (Enantiomer 2)

(407) ##STR00143##

(408) Under argon, (3-fluoro-6-methoxypyridin-2-yl)[8-oxa-3,10-diazabicyclo[4.3.1]dec-10-yl]methanone (575 mg, 1.95 mmol, enantiomer 2), 2-(4-chlorophenyl)imidazo[1,2-a]pyrimidine-3-carbaldehyde (602 mg, 2.34 mmol) and acetic acid (270 μl, 4.7 mmol) were initially charged in 22 ml of THF. Sodium triacetoxyborohydride (743 mg, 3.50 mmol) was then added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then diluted with saturated sodium carbonate solution, the 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. On neutral alumina (mobile phase: dichloromethane/methanol 50:1), the residue obtained was separated into its components. 100 mg of the product obtained in this manner were then re-purified by preparative HPLC (Method 9). This gave 85 mg (content 100%, 0.160 mmol, 8% of theory) of the title compound.

(409) LC-MS (method 2): R.sub.t=1.65 min; m/z=537/539 (M+H).sup.+.

(410) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.50-1.62 (m, 1H), 1.70-1.88 (m, 1H), 2.35-2.43 (m, 0.4H), 2.56-2.87 (m, 3H), 2.87-2.95 (m, 0.75H), 3.41 (dd, 0.75H), 3.47-3.69 (m, 3.1H), 3.70-3.81 (m, 4H), 4.14-4.31 (m, 2H), 4.39-4.50 (m, 1H), 6.89-7.00 (m, 1H), 7.01-7.12 (m, 1H), 7.49-7.59 (m, 2H), 7.72-7.84 (m, 1H), 7.87-8.04 (m, 2H), 8.58 (dd, 1H), 9.10-9.38 (m, 1H).

Example 15

[3-{[2-(5-Chloropyridin-2-yl)imidazo[1,2-a]pyridin-3-yl]methyl}-3,9-diazabicyclo[4.2.1]non-9-yl](3-fluoro-6-methoxypyridin-2-yl)methanone (Enantiomer 1)

(411) ##STR00144##

(412) Under argon, 3,9-diazabicyclo[4.2.1]non-9-yl(3-fluoro-6-methoxypyridin-2-yl)methanone (65.0 mg, 233 μmol, enantiomer 1), 2-(5-chloropyridin-2-yl)imidazo[1,2-a]pyridine-3-carbaldehyde (50.0 mg, 194 μmol) and acetic acid (22 μl, 390 μmol) were initially charged in 1.2 ml of THF. Sodium triacetoxyborohydride (62 mg, 291 μmol) was then added, and the mixture was stirred at room temperature overnight. Thereafter, methanol was added and the reaction mixture was separated directly into its components via preparative HPLC (Method 9). This gave 79 mg (100% pure, 0.151 mmol, 78% of theory) of the title compound.

(413) LC-MS (method 2): R.sub.t=1.22 min; m/z=521/523 (M+H).sup.+.

(414) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.21-1.37 (m, 1H), 1.42-1.51 (m, 0.5H), 1.50-1.59 (m, 0.5H), 1.59-1.69 (m, 1H), 1.70-1.90 (m, 1.5H), 1.90-2.05 (m, 1H), 2.08-2.17 (m, 0.5H), 2.35-2.70 (m, 3H), 2.81-3.05 (m, 1H), 3.74-3.83 (m, 3H), 3.84-3.90 (m, 1H), 4.39-4.60 (m, 2H), 4.68 (dd, 1H), 6.94 (ddd, 1H), 7.01 (qd, 1H), 7.30-7.41 (m, 1H), 7.62 (ddt, 1H), 7.77 (dt, 1H), 8.00 (td, 1H), 8.21 (td, 1H), 8.59 (dd, 1H), 8.62-8.71 (m, 1H).

Example 16

[3-{[2-(5-Chloropyridin-2-yl)imidazo[1,2-a]pyridin-3-yl]methyl}-3,9-diazabicyclo[4.2.1]non-9-yl](3-fluoro-6-methoxypyridin-2-yl)methanone (Enantiomer 2)

(415) ##STR00145##

(416) Under argon, 3,9-diazabicyclo[4.2.1]non-9-yl(3-fluoro-6-methoxypyridin-2-yl)methanone (65.0 mg, 233 μmol, enantiomer 2), 2-(5-chloropyridin-2-yl)imidazo[1,2-a]pyridine-3-carbaldehyde (50.0 mg, 194 μmol) and acetic acid (22 μl, 390 μmol) were initially charged in 1.2 ml of THF. Sodium triacetoxyborohydride (62 mg, 291 μmol) was then added, and the mixture was stirred at room temperature overnight. Thereafter, methanol was added and the reaction mixture was separated directly into its components via preparative HPLC (Method 9). This gave 80 mg (100% pure, 0.154 mmol, 79% of theory) of the title compound.

(417) LC-MS (method 2): R.sub.t=1.23 min; m/z=521/523 (M+H).sup.+

(418) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.23-1.37 (m, 1H), 1.41-1.50 (m, 0.5H), 1.51-1.59 (m, 0.5H), 1.58-1.69 (m, 1H), 1.71-1.88 (m, 1.5H), 1.89-2.06 (m, 1H), 2.06-2.19 (m, 0.5H), 2.35-2.46 (dt, 3H), 2.84-3.03 (m, 1H), 3.74-3.83 (m, 3H), 3.84-3.90 (m, 1H), 4.36-4.59 (m, 2H), 4.68 (dd, 1H), 6.93 (ddd, 1H), 7.01 (qd, 1H), 7.27-7.42 (m, 1H), 7.62 (dtt, 1H), 7.77 (dt, 1H), 8.00 (td, 1H), 8.21 (td, 1H), 8.59 (dd, 1H), 8.62-8.74 (m, 1H).

Example 17

[6-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,6-diazabicyclo[3.2.2]non-2-yl](3-fluoro-6-methoxypyridin-2-yl)methanone (Enantiomer 2)

(419) ##STR00146##

(420) 2-(4-Chlorophenyl)-3-(2,6-diazabicyclo[3.2.2]non-6-ylmethyl)imidazo[1,2-a]pyrimidine bis(trifluoroacetic acid) salt (enantiomer 2; 153 mg, 141 μmol), 3-fluoro-6-methoxypyridine-2-carboxylic acid (29.0 mg, 169 μmol) and 1-[bis(dimethylamino)methylene]-1H-[1,2,3]triazolo[4,5-b]pyridin-1-ium 3-oxide hexafluorophosphate (69.8 mg, 184 μmol) were dissolved in 1.7 ml of DMF. N-Ethyl-N-isopropylpropan-2-amine (170 μl, 990 μmol) was then added. The mixture was stirred at room temperature overnight. Thereafter, methanol was added and the reaction mixture was separated directly into its components via preparative HPLC (Method 9). This gave 58.5 mg (100% pure, 0.112 mmol, 80% of theory) of the title compound.

(421) LC-MS (method 2): R.sub.t=1.40 min; m/z=521/523 (M+H).sup.+.

(422) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.33-1.48 (m, 0.6H), 1.59-1.93 (m, 4.4H), 1.93-2.11 (m, 1H), 2.58-2.80 (m, 1.6H), 2.93 (br. d, 0.6H), 2.98-3.16 (m, 1H), 3.24-3.41 (m, 1.4H), 3.60 (s, 1.2H), 3.70 (br. s, 0.4H), 3.78 (s, 1.8H), 4.04-4.16 (m, 0.4H), 4.20-4.37 (m, 2H), 4.57 (br. s, 0.6H), 6.81-6.99 (m, 1H), 7.11 (dd, 1H), 7.49-7.59 (m, 2H), 7.66-7.83 (m, 1H), 7.85-7.98 (m, 2H), 8.53-8.63 (m, 1H), 8.94-9.03 (m, 1H).

(423) Analogously to Example 17, the following compounds were prepared from the starting materials specified in each case:

(424) TABLE-US-00013 Name/Structure/Starting materials Example Analytical data 18 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.37-1.53 (m, 0.3H), 1.56-2.12 (m, 5.7H), 2.71-2.87 (m, 1H), 2.96 (br. d, 0.4H), 3.03-3.20 (m, 1.6H), 3.33-3.55 (m, 1.4H), 3.61 (s, 1.2H), 3.85 (s, 1.8H), 3.87-3.93 (m, 0.6H), 4.00-4.11 (m, 0.4H), 4.49-4.73 (m, 2H), 4.82 (d, 0.6H), 6.77-6.94 (m, 1H), 6.93-7.15 (m, 2H), 7.27- 7.40 (m, 1H), 7.62 (br. d, 1H), 7.68-7.88 (m, 1H), 7.93-8.09 (m, 1H), 8.21 (d, 1H), 8.46 (d, 1H), 8.53-8.72 (m, 1H). LC-MS (method 2): R.sub.t = 1.16 min; m/z = 503/505 (M + H).sup.+. 19 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.37-1.48 (m, 0.7H), 1.56-2.11 (m, 5.3H), 2.69-2.94 (m, 1.6H), 3.03-3.20 (m, 1.8H), 3.32-3.48 (m, 1.2H), 3.61 (s, 1H), 3.71 (br. s, 0.4H), 3.83 (s, 2H), 4.08 (dt, 0.3H), 4.49-4.74 (m, 2H), 4.81 (d, 0.7H), 6.77-7.05 (m, 2H), 7.20-7.41 (m, 1H), 7.57-7.66 (m, 1H), 7.66-7.86 (m, 1H), 7.90-8.04 (m, 1H), 8.21 (d, 1H), 8.45 (d, 1H), 8.54-8.71 (m, 1H). LC-MS (method 2): R.sub.t = 1.11 min; m/z = 521/523 (M + H).sup.+. 20 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.37-1.49 (m, 0.8H), 1.57-2.08 (m, 5.2H), 2.63-2.93 (m, 1.6H), 3.03-3.26 (m, 2.7H), 3.35-3.48 (m, 0.4H), 3.56 (br. s, 0.3H), 3.64 (s, 1H), 3.84 (s, 2H), 4.05-4.15 (m, 0.3H), 4.51-4.62 (m, 1.7H), 4.66- 4.84 (m, 1H), 6.80-7.04 (m, 2H), 7.29-7.39 (m, 1H), 7.58-7.69 (m, 1H), 7.76-7.95 (m, 1H), 8.00 (dd, 1H), 8.21 (d, 1H), 8.45 (d, 1H), 8.56-8.74 (m, 1H). LC-MS (method 2): R.sub.t = 1.19 min; m/z = 537/539 (M + H).sup.+. 21 0 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.36-1.49 (m, 0.6H), 1.57-2.13 (m, 5.4H), 2.62-2.85 (m, 1.6H), 2.90 (br. d, 0.6H), 3.03 (br. d, 0.6H), 3.14 (br. s, 0.4H), 3.22-3.40 (m, 0.8H), 3.42-3.52 (m, 0.6H), 3.58 (s, 1.3H), 3.80 (s, 1.7H), 3.88 (br. s, 0.4H), 4.08 (dt, 0.4H), 4.18-4.37 (m, 2H), 4.56 (br. s, 0.6H), 6.70-6.92 (m, 1H), 6.96-7.16 (m, 2H), 7.42-7.61 (m, 2H), 7.68-7.85 (m, 1H), 7.86-7.99 (m, 2H), 8.58 (td, 1H), 9.01 (ddd, 1H). LC-MS (method 2): R.sub.t = 1.28 min; m/z = 503/505 (M + H).sup.+. 22 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = −0.149 (0.45), −0.008 (3.62), 0.008 (3.77), 1.355 (1.77), 1.367 (1.97), 1.378 (1.57), 1.389 (2.27), 1.401 (2.12), 1.558 (0.70), 1.570 (0.82), 1.596 (1.85), 1.622 (2.85), 1.652 (4.27), 1.731 (2.00), 1.756 (2.70), 1.767 (2.77), 1.795 (3.50), 1.805 (3.15), 1.948 (1.70), 1.979 (2.37), 2.073 (2.50), 2.328 (0.95), 2.366 (0.70), 2.585 (1.45), 2.670 (1.25), 2.716 (2.20), 2.726 (2.42), 2.745 (3.12), 2.755 (2.90), 2.888 (3.85), 2.916 (2.85), 2.975 (3.32), 3.063 (1.10), 3.260 (4.75), 3.653 (1.20), 4.098 (0.52), 4.196 (5.40), 4.232 (0.85), 4.270 (16.00), 4.308 (0.57), 4.598 (3.52), 5.754 (1.20), 7.105 (2.05), 7.122 (4.47), 7.133 (5.02), 7.148 (3.20), 7.197 (2.10), 7.219 (2.30), 7.243 (1.90), 7.270 (5.72), 7.289 (7.35), 7.312 (3.37), 7.393 (0.63), 7.406 (0.97), 7.414 (1.17), 7.427 (1.12), 7.454 (1.65), 7.468 (2.42), 7.475 (2.65), 7.489 (2.80), 7.498 (1.67), 7.511 (1.10), 7.546 (11.40), 7.562 (9.30), 7.567 (14.40), 7.583 (5.00), 7.898 (10.60), 7.901 (10.70), 7.919 (10.67), 8.572 (2.07), 8.577 (2.35), 8.587 (7.40), 8.592 (6.20), 8.597 (5.85), 8.602 (5.40), 8.963 (2.07), 8.968 (2.20), 8.985 (4.55), 9.004 (3.10). LC-MS (method 2): R.sub.t = 1.39 min; m/z = 490/492 (M + H).sup.+. 23 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = −0.008 (1.27), 0.008 (1.34), 1.405 (0.51), 1.416 (0.57), 1.429 (0.45), 1.440 (0.65), 1.451 (0.58), 1.614 (0.50), 1.625 (0.62), 1.648 (1.06), 1.679 (1.30), 1.756 (0.50), 1.766 (0.55), 1.794 (0.86), 1.807 (1.03), 1.819 (0.96), 1.843 (0.91), 1.970 (0.48), 2.002 (0.74), 2.074 (0.44), 2.566 (0.41), 2.583 (0.57), 2.594 (0.52), 2.642 (0.68), 2.671 (0.67), 2.714 (0.74), 2.723 (0.78), 2.743 (1.09), 2.753 (0.99), 2.844 (1.12), 2.873 (0.74), 3.040 (0.94), 3.127 (0.80), 3.149 (0.76), 3.163 (1.05), 3.179 (0.80), 3.191 (0.68), 3.202 (0.62), 3.215 (0.71), 3.540 (0.53), 3.623 (5.48), 3.798 (16.00), 4.234 (2.53), 4.274 (2.71), 4.285 (2.72), 4.321 (0.46), 4.563 (1.13), 6.829 (1.52), 6.851 (1.61), 6.902 (3.28), 6.924 (3.42), 7.099 (2.02), 7.109 (2.12), 7.116 (2.10), 7.126 (2.07), 7.523 (3.92), 7.544 (6.35), 7.566 (2.14), 7.789 (1.55), 7.811 (1.49), 7.869 (3.53), 7.878 (4.61), 7.891 (3.62), 7.899 (4.20), 7.908 (2.41), 7.930 (1.90), 8.567 (0.74), 8.572 (0.85), 8.577 (0.85), 8.585 (1.77), 8.590 (1.78), 8.595 (1.67), 8.600 (1.60), 8.968 (1.48), 8.973 (1.54), 8.986 (1.85), 8.990 (1.90), 9.005 (0.73), 9.009 (0.69). LC-MS (method 1): R.sub.t = 0.75 min; m/z = 537/539 (M + H).sup.+. 24 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.41-1.69 (m, 2H), 1.72-2.05 (m, 4H), 2.70-2.85 (m, 1.4H), 2.91-3.10 (m, 1.6H), 3.38-3.60 (m, 1H), 3.71 (dt, 0.6H), 3.96-4.07 (m, 0.4H), 4.16 (br. s, 0.4H), 4.24 (d, 2H), 4.59 (br. s, 0.6H), 6.31 (br. d, 2H), 7.01-7.13 (m, 1H), 7.42-7.63 (m, 2H), 7.82-7.98 (m, 2H), 8.58 (dd, 1H), 9.00 (dd, 1H). LC-MS (method 2): R.sub.t = 1.25 min; m/z = 479/481 (M + H).sup.+. 25 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = −0.149 (1.11), −0.008 (9.05), 0.008 (8.48), 0.146 (1.05), 1.345 (1.96), 1.356 (2.14), 1.379 (2.51), 1.390 (2.31), 1.563 (0.94), 1.600 (2.11), 1.626 (2.99), 1.656 (4.84), 1.773 (2.76), 1.800 (4.30), 1.945 (1.94), 1.975 (2.56), 2.073 (2.48), 2.328 (1.88), 2.367 (0.88), 2.603 (1.40), 2.670 (2.16), 2.711 (1.31), 2.733 (2.08), 2.756 (2.59), 2.911 (4.33), 2.940 (3.25), 2.970 (3.81), 3.059 (1.14), 3.260 (4.95), 3.661 (1.31), 4.171 (6.80), 4.206 (1.31), 4.242 (9.00), 4.250 (11.27), 4.286 (1.40), 4.604 (3.67), 5.755 (0.63), 6.951 (1.34), 6.968 (4.81), 6.984 (5.98), 7.001 (2.76), 7.203 (2.28), 7.226 (2.51), 7.249 (2.85), 7.270 (6.52), 7.291 (10.65), 7.314 (8.34), 7.331 (4.75), 7.417 (1.28), 7.431 (1.14), 7.453 (2.11), 7.467 (2.56), 7.475 (2.99), 7.488 (3.07), 7.516 (12.44), 7.537 (16.00), 7.554 (5.75), 7.577 (3.10), 7.589 (8.00), 7.600 (2.79), 7.611 (6.78), 7.871 (9.59), 7.877 (13.04), 7.893 (10.51), 7.898 (10.88), 8.524 (2.45), 8.541 (2.70), 8.553 (4.90), 8.571 (4.70). LC-MS (method 1): R.sub.t = 0.73 min; m/z = 489/491 (M + H).sup.+. 26 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = −0.008 (2.10), 0.008 (2.26), 1.396 (0.45), 1.407 (0.51), 1.431 (0.57), 1.442 (0.55), 1.611 (0.44), 1.636 (0.92), 1.648 (0.85), 1.662 (1.28), 1.694 (1.28), 1.727 (0.53), 1.765 (0.55), 1.792 (0.46), 1.864 (1.08), 1.994 (0.51), 2.073 (2.51), 2.328 (0.51), 2.653 (0.45), 2.666 (0.86), 2.682 (0.71), 2.695 (0.62), 2.711 (1.07), 2.720 (0.80), 2.740 (0.97), 2.749 (0.88), 2.793 (0.80), 2.822 (0.54), 2.916 (1.00), 2.944 (0.76), 3.018 (0.84), 3.135 (0.61), 3.339 (0.97), 3.352 (0.52), 3.363 (0.53), 3.450 (0.83), 3.463 (0.47), 3.486 (0.51), 3.589 (10.16), 3.794 (16.00), 3.894 (0.72), 4.063 (0.49), 4.098 (0.45), 4.207 (1.33), 4.217 (3.00), 4.243 (2.05), 4.289 (2.03), 4.326 (0.92), 4.573 (0.98), 6.794 (1.43), 6.815 (1.47), 6.873 (2.08), 6.893 (2.15), 6.944 (1.18), 6.961 (2.39), 6.978 (1.30), 6.996 (1.43), 7.014 (1.47), 7.039 (2.09), 7.057 (2.13), 7.279 (0.69), 7.283 (0.90), 7.286 (0.91), 7.301 (1.52), 7.318 (0.72), 7.323 (0.93), 7.462 (3.80), 7.483 (4.27), 7.523 (2.58), 7.545 (2.88), 7.583 (1.80), 7.585 (1.99), 7.608 (1.68), 7.703 (1.13), 7.721 (1.24), 7.724 (1.27), 7.742 (1.03), 7.779 (1.65), 7.798 (1.82), 7.800 (1.86), 7.819 (1.51), 7.869 (4.32), 7.890 (3.96), 7.902 (3.04), 7.923 (2.60), 8.557 (1.62), 8.574 (1.88), 8.587 (1.08). LC-MS (method 1): R.sub.t = 0.70 min; m/z = 502/504 (M + H).sup.+. 27 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.34-1.47 (m, 0.6H), 1.57-2.05 (m, 5.4H), 2.61-2.79 (m, 1.5H), 2.96 (br. d, 0.6H), 2.99-3.15 (m, 1H), 3.25-3.40 (m, 1.5H), 3.60 (s, 1.1H), 3.71 (br. s, 0.4H), 3.78 (s, 1.9H), 4.11 (dt, 0.4H), 4.18-4.33 (m, 2H), 4.58 (br. s, 0.6H), 6.81-7.01 (m, 2H), 7.19-7.38 (m, 1H), 7.46-7.55 (m, 2H), 7.56-7.63 (m, 1H), 7.68-7.83 (m, 1H), 7.85-7.95 (m, 2H), 8.47-8.63 (m, 1H). LC-MS (method 1): R.sub.t = 0.73 min; m/z = 520/522 (M + H).sup.+. 28 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = −0.008 (2.32), 0.008 (2.30), 1.396 (0.46), 1.407 (0.53), 1.418 (0.41), 1.431 (0.59), 1.443 (0.56), 1.618 (0.47), 1.629 (0.51), 1.652 (0.98), 1.679 (1.19), 1.764 (0.46), 1.773 (0.53), 1.815 (1.01), 1.843 (0.82), 1.963 (0.47), 1.994 (0.67), 2.073 (0.77), 2.328 (0.49), 2.600 (0.54), 2.612 (0.45), 2.675 (0.94), 2.710 (0.56), 2.721 (0.67), 2.731 (0.75), 2.750 (1.01), 2.760 (0.88), 2.872 (1.05), 2.901 (0.73), 3.033 (0.85), 3.125 (0.68), 3.147 (0.55), 3.161 (0.95), 3.182 (0.57), 3.194 (0.63), 3.205 (0.56), 3.217 (0.65), 3.553 (0.49), 3.632 (5.46), 3.798 (16.00), 4.206 (3.17), 4.242 (2.22), 4.266 (2.24), 4.302 (0.70), 4.573 (1.05), 5.754 (1.12), 6.831 (1.54), 6.853 (1.63), 6.900 (3.32), 6.923 (3.45), 6.940 (1.19), 6.957 (2.40), 6.974 (1.30), 7.274 (0.44), 7.288 (1.25), 7.291 (1.31), 7.311 (1.50), 7.313 (1.48), 7.328 (0.93), 7.330 (0.93), 7.493 (3.95), 7.498 (1.31), 7.514 (6.19), 7.535 (2.12), 7.573 (0.94), 7.588 (1.91), 7.596 (0.84), 7.610 (1.59), 7.794 (1.57), 7.816 (1.54), 7.854 (4.54), 7.858 (1.49), 7.868 (3.83), 7.875 (4.11), 7.886 (2.47), 7.890 (3.92), 7.907 (1.88), 8.533 (1.62), 8.550 (1.75), 8.573 (0.73). LC-MS (method 1): R.sub.t = 0.77 min; m/z = 536/538 (M + H).sup.+. 29 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.43-1.70 (m, 2H), 1.73-2.04 (m, 4H), 2.73-2.86 (m, 1.4H), 2.91-3.08 (m, 1.6H), 3.37-3.59 (m, 1H), 3.71 (dt, 0.6H), 4.02 (dt, 0.4H), 4.13-4.29 (m, 2.4H), 4.61 (br. s, 0.6H), 6.32 (br. d, 2H), 6.82-7.06 (m, 1H), 7.20-7.39 (m, 1H), 7.44-7.63 (m, 3H), 7.89 (dd, 2H), 8.56 (d, 1H). LC-MS (method 2): R.sub.t = 1.31 min; m/z = 478/480 (M + H).sup.+. 30 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = −0.120 (0.50), 0.116 (0.46), 1.034 (0.99), 1.045 (0.95), 1.231 (2.16), 1.360 (3.32), 1.369 (3.61), 1.378 (2.86), 1.387 (3.85), 1.397 (3.61), 1.590 (3.19), 1.619 (4.68), 1.638 (3.15), 1.673 (2.69), 1.778 (3.90), 1.801 (4.19), 1.848 (5.72), 1.906 (2.20), 1.979 (3.40), 2.003 (3.85), 2.362 (1.49), 2.636 (1.45), 2.756 (1.78), 2.850 (3.61), 2.867 (4.19), 3.076 (12.19), 3.100 (7.09), 3.448 (0.95), 3.677 (2.07), 4.067 (0.66), 4.553 (3.52), 4.595 (11.03), 4.611 (6.92), 4.755 (4.93), 4.782 (3.77), 6.968 (1.82), 6.982 (3.90), 6.995 (5.06), 7.007 (5.93), 7.019 (3.52), 7.213 (2.16), 7.231 (3.32), 7.250 (2.90), 7.317 (6.92), 7.333 (13.26), 7.349 (16.00), 7.363 (8.79), 7.420 (1.91), 7.435 (1.82), 7.486 (4.89), 7.498 (4.77), 7.601 (4.52), 7.611 (11.52), 7.619 (4.48), 7.629 (9.82), 7.986 (8.54), 7.991 (8.87), 7.996 (4.10), 8.003 (11.44), 8.008 (10.49), 8.013 (4.06), 8.019 (3.40), 8.192 (5.39), 8.203 (13.89), 8.209 (5.72), 8.220 (11.52), 8.422 (3.15), 8.437 (3.19), 8.455 (9.87), 8.468 (9.37), 8.635 (9.08), 8.687 (4.44), 8.691 (4.35). LC-MS (method 1): R.sub.t = 0.66 min; m/z = 490/492 (M + H).sup.+. 31 0 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = −0.150 (0.47), −0.008 (4.05), 0.008 (4.47), 0.146 (0.53), 1.355 (1.74), 1.367 (2.00), 1.378 (1.53), 1.389 (2.32), 1.401 (2.21), 1.621 (2.84), 1.653 (4.16), 1.756 (2.74), 1.766 (2.74), 1.795 (3.53), 1.947 (1.63), 1.980 (2.37), 1.988 (2.47), 2.073 (4.79), 2.328 (1.63), 2.367 (0.84), 2.670 (1.89), 2.716 (2.21), 2.726 (2.47), 2.746 (3.16), 2.755 (2.84), 2.887 (3.89), 2.917 (2.89), 2.985 (3.32), 3.063 (1.11), 3.261 (5.00), 3.652 (1.26), 4.101 (0.53), 4.196 (5.37), 4.232 (0.89), 4.271 (16.00), 4.308 (0.63), 4.597 (3.53), 5.754 (0.47), 7.106 (2.16), 7.122 (4.53), 7.133 (5.11), 7.148 (3.21), 7.198 (2.16), 7.219 (2.21), 7.243 (1.95), 7.270 (5.68), 7.289 (7.37), 7.312 (3.42), 7.407 (1.11), 7.414 (1.16), 7.428 (1.16), 7.454 (1.84), 7.468 (2.53), 7.476 (2.74), 7.489 (2.79), 7.498 (1.79), 7.511 (1.21), 7.546 (11.79), 7.562 (9.37), 7.567 (14.89), 7.583 (5.21), 7.898 (10.68), 7.901 (10.79), 7.919 (10.68), 8.572 (2.16), 8.577 (2.53), 8.587 (7.84), 8.592 (6.58), 8.597 (6.21), 8.602 (5.74), 8.963 (2.11), 8.968 (2.21), 8.985 (4.58), 9.005 (3.11). LC-MS (method 2): R.sub.t = 1.41 min; m/z = 490/492 (M + H).sup.+. 32 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.33-1.50 (m, 0.6H), 1.58-2.12 (m, 5.4H), 2.60-2.84 (m, 1.6H), 2.90 (br. d, 0.6H), 3.03 (br. d, 0.6H), 3.14 (br. s, 0.4H), 3.23-3.40 (m, 0.8H), 3.42-3.53 (m, 0.6H), 3.58 (s, 1.25H), 3.80 (s, 1.75H), 3.88 (br. s, 0.4H), 4.00-4.13 (m, 0.4H), 4.17-4.38 (m, 2H), 4.56 (br. s, 1.6H), 6.74-6.94 (m, 1H), 6.97-7.22 (m, 2H), 7.43-7.63 (m, 2H), 7.66-7.85 (m, 1H), 7.86-7.99 (m, 2H), 8.53-8.65 (m, 1H), 9.01 (ddd, 1H). LC-MS (method 2): R.sub.t = 1.30 min; m/z = 503/505 (M + H).sup.+. 33 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = −0.008 (1.18), 0.008 (1.18), 1.393 (0.49), 1.405 (0.56), 1.416 (0.44), 1.428 (0.65), 1.439 (0.61), 1.615 (0.65), 1.639 (1.17), 1.672 (1.48), 1.684 (1.31), 1.771 (0.74), 1.798 (0.98), 1.830 (0.85), 1.851 (0.70), 1.901 (0.43), 1.975 (0.53), 2.006 (0.82), 2.073 (2.43), 2.615 (0.40), 2.631 (0.72), 2.644 (0.67), 2.670 (0.50), 2.687 (0.92), 2.717 (1.20), 2.725 (0.93), 2.746 (1.07), 2.755 (0.94), 2.916 (1.10), 2.946 (0.83), 3.022 (0.96), 3.121 (0.60), 3.276 (1.37), 3.293 (2.27), 3.343 (0.70), 3.594 (9.37), 3.695 (0.70), 3.783 (16.00), 4.092 (0.48), 4.127 (0.45), 4.230 (4.17), 4.267 (2.36), 4.297 (2.33), 4.333 (0.84), 4.567 (1.14), 6.850 (0.78), 6.858 (0.79), 6.873 (0.89), 6.881 (0.85), 6.928 (1.26), 6.935 (1.29), 6.950 (1.45), 6.958 (1.40), 7.097 (1.77), 7.107 (1.90), 7.114 (1.94), 7.124 (1.86), 7.513 (3.82), 7.535 (4.30), 7.547 (2.43), 7.568 (2.63), 7.683 (0.84), 7.705 (1.42), 7.727 (0.82), 7.766 (1.37), 7.788 (2.24), 7.809 (1.31), 7.889 (4.49), 7.911 (4.36), 7.917 (3.30), 7.938 (2.43), 8.569 (0.93), 8.574 (1.06), 8.583 (2.29), 8.587 (1.80), 8.593 (1.62), 8.598 (1.49), 8.977 (1.46), 8.982 (1.53), 8.995 (2.11), 8.999 (2.10), 9.013 (0.94), 9.018 (0.87). LC-MS (method 2): R.sub.t = 1.41 min; m/z = 521/523 (M + H).sup.+. 34 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = −0.008 (1.24), 0.008 (1.35), 1.405 (0.46), 1.416 (0.53), 1.427 (0.40), 1.439 (0.60), 1.451 (0.56), 1.624 (0.60), 1.648 (0.96), 1.677 (1.24), 1.755 (0.49), 1.765 (0.51), 1.807 (0.97), 1.842 (0.85), 1.970 (0.46), 2.000 (0.70), 2.328 (0.47), 2.582 (0.51), 2.594 (0.47), 2.641 (0.63), 2.670 (0.81), 2.712 (0.72), 2.723 (0.72), 2.742 (1.04), 2.752 (0.92), 2.844 (1.04), 2.872 (0.71), 3.039 (0.89), 3.127 (0.77), 3.148 (0.72), 3.162 (1.02), 3.177 (0.75), 3.191 (0.65), 3.202 (0.58), 3.214 (0.67), 3.538 (0.50), 3.622 (5.31), 3.797 (16.00), 4.233 (2.41), 4.274 (2.59), 4.284 (2.60), 4.320 (0.45), 4.560 (1.09), 6.828 (1.52), 6.850 (1.60), 6.902 (3.31), 6.924 (3.42), 7.098 (1.96), 7.109 (2.03), 7.116 (2.06), 7.126 (2.02), 7.522 (3.95), 7.544 (6.30), 7.565 (2.11), 7.789 (1.56), 7.811 (1.49), 7.868 (3.52), 7.877 (4.58), 7.890 (3.60), 7.898 (4.13), 7.908 (2.35), 7.929 (1.85), 8.567 (0.75), 8.572 (0.83), 8.577 (0.83), 8.585 (1.71), 8.590 (1.78), 8.595 (1.70), 8.600 (1.57), 8.968 (1.46), 8.973 (1.52), 8.985 (1.82), 8.990 (1.85), 9.004 (0.70), 9.009 (0.68). LC-MS (method 2): R.sub.t = 1.55 min; m/z = 537/539 (M + H).sup.+. 35 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = −0.149 (1.14), −0.008 (8.80), 0.008 (8.65), 0.146 (1.08), 1.465 (0.97), 1.476 (1.11), 1.487 (0.91), 1.500 (1.25), 1.511 (1.22), 1.557 (0.65), 1.570 (0.77), 1.604 (1.51), 1.633 (1.77), 1.656 (1.28), 1.776 (2.62), 1.805 (1.48), 1.850 (2.02), 1.875 (2.02), 1.946 (1.31), 1.978 (1.45), 2.073 (16.00), 2.328 (1.62), 2.366 (0.68), 2.670 (1.77), 2.710 (0.83), 2.731 (1.57), 2.740 (1.71), 2.760 (2.08), 2.769 (1.88), 2.807 (3.76), 2.813 (3.93), 2.932 (2.22), 2.961 (1.65), 3.018 (1.99), 3.418 (0.68), 3.442 (1.02), 3.466 (0.71), 3.502 (0.63), 3.514 (0.80), 3.525 (0.71), 3.538 (1.48), 3.551 (1.05), 3.561 (1.11), 3.572 (0.80), 3.687 (1.82), 3.700 (1.00), 3.723 (1.28), 4.002 (1.08), 4.038 (1.00), 4.156 (1.59), 4.227 (7.09), 4.258 (10.16), 4.594 (2.19), 6.307 (7.12), 6.320 (5.69), 7.081 (3.02), 7.091 (3.13), 7.098 (3.16), 7.108 (4.47), 7.117 (2.05), 7.124 (2.05), 7.134 (2.02), 7.527 (7.97), 7.541 (6.23), 7.548 (9.79), 7.562 (6.01), 7.895 (9.42), 7.904 (6.60), 7.911 (3.84), 7.916 (8.57), 7.926 (5.67), 8.576 (4.90), 8.581 (5.38), 8.586 (5.18), 8.591 (4.87), 8.987 (4.47), 8.992 (3.73), 9.004 (4.38). LC-MS (method 2): R.sub.t = 1.26 min; m/z = 479/481 (M + H).sup.+. 36 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = −0.149 (0.91), −0.008 (7.77), 0.008 (7.45), 0.146 (0.86), 1.233 (0.55), 1.345 (2.00), 1.356 (2.23), 1.367 (1.68), 1.379 (2.45), 1.391 (2.41), 1.562 (0.86), 1.600 (2.14), 1.624 (3.05), 1.656 (4.82), 1.763 (2.59), 1.773 (2.82), 1.801 (4.27), 1.944 (1.91), 1.975 (2.64), 2.073 (0.55), 2.328 (1.68), 2.366 (0.59), 2.601 (1.23), 2.670 (1.82), 2.711 (1.00), 2.734 (2.09), 2.757 (2.50), 2.911 (4.41), 2.940 (3.36), 2.969 (3.86), 3.054 (1.18), 3.260 (5.18), 3.663 (1.27), 4.083 (0.59), 4.171 (6.91), 4.206 (1.32), 4.242 (9.14), 4.250 (11.64), 4.286 (1.36), 4.604 (3.73), 6.950 (1.32), 6.967 (4.86), 6.984 (6.14), 7.001 (2.73), 7.204 (2.27), 7.226 (2.59), 7.249 (2.86), 7.270 (6.68), 7.291 (10.59), 7.314 (8.36), 7.333 (4.64), 7.409 (1.05), 7.417 (1.27), 7.431 (1.23), 7.453 (2.09), 7.467 (2.73), 7.475 (2.95), 7.488 (3.23), 7.497 (2.05), 7.516 (12.32), 7.537 (16.00), 7.554 (5.59), 7.577 (3.09), 7.589 (7.82), 7.599 (2.86), 7.611 (6.68), 7.871 (9.55), 7.876 (13.14), 7.893 (10.55), 7.898 (11.05), 8.524 (2.41), 8.541 (2.73), 8.553 (5.00), 8.570 (4.77). LC-MS (method 2): R.sub.t = 1.43 min; m/z = 489/491 (M + H).sup.+. 37 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = −0.149 (0.42), 0.146 (0.42), 1.396 (0.57), 1.407 (0.59), 1.418 (0.48), 1.432 (0.67), 1.441 (0.65), 1.635 (1.14), 1.662 (1.54), 1.694 (1.55), 1.726 (0.65), 1.761 (0.64), 1.791 (0.56), 1.864 (1.35), 1.992 (0.64), 2.073 (0.61), 2.327 (0.71), 2.653 (0.55), 2.665 (1.20), 2.681 (0.89), 2.695 (0.76), 2.710 (1.19), 2.720 (0.95), 2.740 (1.14), 2.748 (1.06), 2.793 (1.02), 2.822 (0.68), 2.915 (1.25), 2.944 (0.95), 3.017 (1.06), 3.137 (0.77), 3.338 (1.25), 3.363 (0.71), 3.375 (0.51), 3.449 (0.97), 3.462 (0.57), 3.486 (0.59), 3.589 (10.54), 3.794 (16.00), 3.893 (0.88), 4.063 (0.57), 4.098 (0.56), 4.216 (3.51), 4.242 (2.30), 4.289 (2.26), 4.325 (1.03), 4.570 (1.25), 6.793 (1.61), 6.814 (1.66), 6.871 (2.31), 6.892 (2.48), 6.943 (1.29), 6.960 (2.65), 6.977 (1.46), 6.995 (1.65), 7.013 (1.76), 7.038 (2.43), 7.055 (2.52), 7.283 (1.06), 7.300 (1.79), 7.315 (0.94), 7.323 (1.11), 7.461 (3.84), 7.482 (4.24), 7.523 (2.64), 7.544 (2.93), 7.584 (2.27), 7.606 (1.96), 7.702 (1.08), 7.722 (1.45), 7.741 (0.98), 7.779 (1.49), 7.798 (2.09), 7.818 (1.41), 7.869 (4.48), 7.890 (4.13), 7.901 (3.28), 7.923 (2.76), 8.557 (1.78), 8.573 (2.23), 8.586 (1.24). LC-MS (method 2): R.sub.t = 1.35 min; m/z = 502/504 (M + H).sup.+. 38 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.30-1.48 (m, 0.6H), 1.54-2.05 (m, 5.4H), 2.60-2.82 (m, 1.6H), 2.89-3.16 (m, 1.6H), 3.21-3.42 (m, 1.4H), 3.60 (s, 1.1H), 3.71 (br. s, 0.4H), 3.78 (s, 1.9H), 4.03-4.16 (m, 0.4H), 4.17-4.36 (m, 2H), 4.58 (br. s, 0.6H), 6.81-7.08 (m, 2H), 7.16-7.36 (m, 1H), 7.46-7.56 (m, 2H), 7.55- 7.64 (m, 1H), 7.66-7.83 (m, 1H), 7.83-7.95 (m, 2H), 8.48-8.64 (m, 1H). LC-MS (method 2): R.sub.t = 1.44 min; m/z = 520/522 (M + H).sup.+. 39 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = −0.008 (2.44), 0.008 (2.27), 1.396 (0.53), 1.408 (0.60), 1.419 (0.47), 1.431 (0.67), 1.442 (0.62), 1.618 (0.53), 1.629 (0.57), 1.652 (1.07), 1.678 (1.32), 1.764 (0.53), 1.774 (0.61), 1.803 (1.18), 1.842 (0.95), 1.963 (0.51), 1.995 (0.78), 2.328 (0.58), 2.600 (0.55), 2.612 (0.49), 2.675 (1.05), 2.710 (0.58), 2.722 (0.73), 2.731 (0.81), 2.750 (1.12), 2.760 (1.00), 2.872 (1.16), 2.901 (0.81), 3.040 (0.98), 3.125 (0.75), 3.148 (0.61), 3.161 (1.06), 3.181 (0.63), 3.194 (0.68), 3.205 (0.61), 3.217 (0.73), 3.556 (0.52), 3.632 (5.59), 3.798 (16.00), 4.206 (3.35), 4.242 (2.43), 4.266 (2.44), 4.302 (0.76), 4.572 (1.18), 6.831 (1.41), 6.853 (1.48), 6.900 (3.11), 6.923 (3.26), 6.940 (1.23), 6.957 (2.52), 6.974 (1.38), 7.274 (0.46), 7.291 (1.41), 7.313 (1.62), 7.329 (1.00), 7.493 (3.98), 7.514 (6.24), 7.535 (2.09), 7.573 (0.92), 7.588 (2.04), 7.596 (0.90), 7.610 (1.70), 7.794 (1.45), 7.816 (1.39), 7.854 (4.57), 7.868 (3.74), 7.875 (4.21), 7.886 (2.49), 7.890 (3.83), 7.907 (1.88), 8.533 (1.75), 8.551 (1.89), 8.573 (0.78). LC-MS (method 2): R.sub.t = 1.52 min; m/z = 536/538 (M + H).sup.+. 40 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.43-1.69 (m, 2H), 1.70-2.03 (m, 4H), 2.73-2.86 (m, 1.4H), 2.92-3.07 (m, 1.6H), 3.39-3.59 (m, 1H), 3.71 (dt, 0.6H), 4.02 (dt, 0.4H), 4.10-4.32 (m, 2.4H), 4.60 (br. s, 0.6H), 6.32 (br. d, 2H), 6.87-7.07 (m, 1H), 7.22-7.37 (m, 1H), 7.44-7.55 (m, 2H), 7.59 (d, 1H), 7.89 (dd, 2H), 8.56 (d, 1H). LC-MS (method 2): R.sub.t = 1.30 min; m/z = 478/480 (M + H).sup.+. 41 0 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.24 (dd, 6H), 1.41-1.53 (m, 0.6H), 1.59-2.13 (m, 5.4H), 2.58-2.85 (m, 1.5H), 2.86-3.00 (m, 1.6H), 3.03-3.21 (m, 1H), 3.23-3.40 (m, 0.9H), 3.49 (dt, 0.6H), 3.57 (s, 1.25H), 3.79 (s, 1.75H), 3.88 (br. s, 0.4H), 4.09 (dt, 0.4H), 4.21-4.42 (m, 2H), 4.58 (br. s, 0.6H), 6.73-6.92 (m, 1H), 6.94-7.14 (m, 2H), 7.24-7.43 (m, 2H), 7.61-7.86 (m, 3H), 8.55 (td, 1H), 8.98 (dt, 1H). LC-MS (method 1): R.sub.t = 0.72 min; m/z = 511 (M + H).sup.+. 42 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = −0.008 (0.92), 0.008 (0.89), 1.224 (11.24), 1.242 (16.00), 1.261 (7.98), 1.404 (0.42), 1.415 (0.49), 1.438 (0.52), 1.450 (0.47), 1.627 (0.47), 1.638 (0.50), 1.662 (0.90), 1.685 (1.25), 1.694 (1.29), 1.788 (0.46), 1.804 (0.52), 1.826 (0.85), 1.861 (0.67), 1.992 (0.51), 2.009 (0.46), 2.023 (0.53), 2.524 (0.63), 2.638 (0.52), 2.650 (0.47), 2.711 (0.84), 2.720 (0.72), 2.730 (0.77), 2.749 (0.87), 2.759 (0.74), 2.915 (0.92), 2.933 (1.42), 2.950 (1.88), 2.967 (0.81), 2.983 (0.84), 3.061 (0.75), 3.155 (0.46), 3.284 (1.02), 3.582 (7.67), 3.698 (0.52), 3.777 (13.47), 4.238 (2.65), 4.267 (1.72), 4.314 (1.71), 4.350 (0.80), 4.581 (0.88), 6.846 (0.66), 6.854 (0.67), 6.868 (0.76), 6.877 (0.72), 6.928 (1.09), 6.936 (1.11), 6.950 (1.26), 6.958 (1.22), 7.069 (1.30), 7.073 (1.01), 7.080 (1.39), 7.086 (1.52), 7.090 (1.05), 7.097 (1.37), 7.100 (0.97), 7.316 (2.86), 7.337 (3.12), 7.360 (1.73), 7.381 (1.90), 7.680 (0.70), 7.702 (1.15), 7.724 (0.67), 7.765 (1.90), 7.769 (3.53), 7.789 (4.21), 7.795 (2.71), 7.809 (1.50), 7.816 (1.87), 8.540 (0.77), 8.545 (0.87), 8.551 (0.96), 8.555 (1.91), 8.559 (1.51), 8.565 (1.34), 8.570 (1.26), 8.951 (1.25), 8.957 (1.63), 8.963 (0.93), 8.968 (1.33), 8.974 (1.55), 8.980 (0.76). LC-MS (method 1): R.sub.t = 0.76 min; m/z = 529 (M + H).sup.+. 43 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = −0.008 (1.19), 0.008 (0.97), 1.237 (15.38), 1.243 (7.80), 1.254 (15.99), 1.260 (7.51), 1.409 (0.54), 1.419 (0.54), 1.431 (0.41), 1.443 (0.60), 1.455 (0.54), 1.647 (0.54), 1.672 (0.96), 1.691 (1.24), 1.780 (0.53), 1.808 (1.02), 1.820 (1.03), 1.843 (0.86), 1.988 (0.52), 2.019 (0.61), 2.524 (0.77), 2.583 (0.43), 2.661 (0.61), 2.670 (0.46), 2.718 (0.66), 2.728 (0.75), 2.747 (0.99), 2.757 (0.87), 2.868 (1.04), 2.898 (0.78), 2.910 (0.50), 2.927 (1.02), 2.944 (1.31), 2.962 (0.97), 3.087 (0.88), 3.124 (0.40), 3.148 (0.68), 3.160 (1.25), 3.184 (0.63), 3.196 (0.60), 3.207 (0.56), 3.219 (0.68), 3.546 (0.41), 3.608 (4.29), 3.793 (16.00), 4.240 (2.20), 4.271 (2.17), 4.299 (2.16), 4.334 (0.77), 4.572 (1.05), 6.823 (1.36), 6.845 (1.39), 6.900 (3.42), 6.922 (3.56), 7.072 (2.11), 7.082 (2.14), 7.089 (2.13), 7.099 (2.13), 7.330 (3.44), 7.351 (4.00), 7.356 (2.05), 7.377 (1.55), 7.756 (4.04), 7.776 (3.70), 7.785 (2.39), 7.807 (2.75), 7.854 (3.49), 7.877 (3.29), 8.538 (0.63), 8.542 (0.72), 8.548 (0.71), 8.556 (1.69), 8.561 (1.77), 8.567 (1.68), 8.572 (1.60), 8.941 (1.45), 8.946 (1.60), 8.958 (1.63), 8.963 (1.51), 8.972 (0.62). LC-MS (method 1): R.sub.t = 0.81 min; m/z = 545/547 (M + H).sup.+. 44 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = −0.008 (0.83), 0.008 (0.75), 1.243 (15.81), 1.260 (16.00), 1.435 (0.68), 1.446 (0.73), 1.457 (0.68), 1.470 (0.87), 1.482 (1.00), 1.488 (1.10), 1.509 (1.23), 1.526 (1.52), 1.546 (1.93), 1.556 (1.63), 1.566 (1.53), 1.608 (0.59), 1.652 (1.31), 1.685 (1.96), 1.734 (0.65), 1.753 (0.65), 1.765 (0.64), 1.932 (0.43), 1.949 (0.40), 2.574 (0.66), 2.583 (0.70), 2.602 (0.93), 2.611 (0.85), 2.747 (0.93), 2.775 (0.73), 2.914 (0.42), 2.932 (1.05), 2.949 (1.42), 2.966 (1.40), 2.976 (1.03), 2.983 (1.09), 3.387 (0.46), 3.647 (0.50), 4.172 (0.57), 4.209 (2.03), 4.218 (2.51), 4.426 (0.76), 7.059 (0.99), 7.069 (1.04), 7.076 (1.10), 7.086 (1.10), 7.097 (0.41), 7.341 (2.40), 7.352 (1.22), 7.361 (2.72), 7.373 (1.08), 7.771 (3.08), 7.775 (2.15), 7.792 (2.92), 8.546 (1.52), 8.551 (1.67), 8.557 (1.61), 8.561 (1.51), 8.909 (1.01), 8.914 (1.03), 8.926 (1.04), 8.931 (1.11), 8.938 (0.46). LC-MS (method 1): R.sub.t = 0.76 min; m/z = 472 (M + H).sup.+. 45 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.17-1.29 (m, 6H), 1.36-1.50 (m, 0.7H), 1.55-1.92 (m, 4.3H), 1.95-2.10 (m, 1H), 2.62-2.79 (m, 1.4H), 2.86-3.00 (m, 1.6H), 3.04-3.16 (m, 1H), 3.35-3.52 (m, 1.4H), 3.90 (br. s, 0.4H), 3.95-4.07 (m, 0.4H), 4.17-4.38 (m, 2H), 4.58 (br. s, 0.6H), 7.03-7.22 (m, 2H), 7.24-7.40 (m, 3.2H), 7.41-7.75 (m, 0.8H), 7.78-7.84 (m, 2H), 7.88-8.09 (m, 1H), 8.56 (td, 1H), 8.90-9.04 (m, 1H). LC-MS (method 1): R.sub.t = 0.79 min; m/z = 547 (M + H).sup.+. 46 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = −0.008 (0.90), 0.008 (0.94), 1.238 (15.45), 1.247 (7.17), 1.255 (16.00), 1.264 (6.62), 1.362 (0.49), 1.374 (0.55), 1.385 (0.44), 1.396 (0.65), 1.408 (0.61), 1.601 (0.49), 1.613 (0.55), 1.662 (1.26), 1.746 (0.50), 1.773 (0.63), 1.783 (0.66), 1.811 (1.08), 1.965 (0.51), 1.979 (0.54), 1.995 (0.55), 2.723 (0.65), 2.733 (0.72), 2.752 (0.89), 2.761 (0.81), 2.916 (0.51), 2.933 (1.80), 2.942 (0.68), 2.951 (1.66), 2.959 (1.37), 2.967 (1.17), 2.977 (0.47), 2.985 (0.44), 3.010 (0.92), 3.269 (1.33), 4.199 (1.88), 4.320 (0.46), 4.266 (2.60), 4.277 (2.30), 4.612 (1.00), 7.079 (0.63), 7.090 (0.81), 7.096 (1.34), 7.106 (1.48), 7.123 (0.82), 7.193 (0.49), 7.216 (0.59), 7.239 (0.47), 7.251 (0.52), 7.268 (1.73), 7.287 (2.55), 7.311 (1.40), 7.355 (3.35), 7.376 (4.38), 7.399 (1.37), 7.454 (0.44), 7.474 (0.79), 7.490 (0.78), 7.777 (1.87), 7.792 (2.10), 7.797 (2.40), 7.809 (1.67), 8.544 (0.62), 8.549 (0.71), 8.554 (0.78), 8.559 (2.15), 8.564 (1.83), 8.569 (1.69), 8.574 (1.58), 8.925 (0.57), 8.930 (0.59), 8.943 (0.65), 8.947 (0.69), 8.961 (0.93), 8.975 (0.90). LC-MS (method 1): R.sub.t = 0.77 min; m/z = 498 (M + H).sup.+. 47 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = −0.008 (0.95), 0.008 (1.00), 1.238 (15.47), 1.247 (7.15), 1.255 (16.00), 1.264 (6.67), 1.363 (0.47), 1.374 (0.53), 1.385 (0.44), 1.397 (0.65), 1.409 (0.62), 1.601 (0.50), 1.614 (0.55), 1.662 (1.22), 1.736 (0.49), 1.773 (0.62), 1.784 (0.66), 1.811 (1.04), 1.965 (0.50), 1.993 (0.54), 2.724 (0.64), 2.732 (0.73), 2.752 (0.87), 2.761 (0.81), 2.916 (0.51), 2.933 (1.77), 2.951 (1.64), 2.959 (1.34), 2.967 (1.14), 2.976 (0.47), 2.985 (0.44), 3.008 (0.90), 3.268 (1.30), 4.199 (1.84), 4.230 (0.45), 4.267 (2.58), 4.277 (2.27), 4.611 (0.97), 7.079 (0.62), 7.090 (0.79), 7.096 (1.32), 7.107 (1.48), 7.123 (0.80), 7.194 (0.49), 7.216 (0.60), 7.240 (0.45), 7.252 (0.50), 7.268 (1.71), 7.288 (2.54), 7.311 (1.41), 7.356 (3.33), 7.377 (4.34), 7.399 (1.36), 7.454 (0.44), 7.475 (0.77), 7.490 (0.77), 7.777 (1.86), 7.792 (2.08), 7.797 (2.39), 7.809 (1.66), 8.544 (0.62), 8.549 (0.69), 8.554 (0.77), 8.559 (2.20), 8.564 (1.84), 8.569 (1.70), 8.574 (1.58), 8.925 (0.57), 8.930 (0.58), 8.943 (0.64), 8.948 (0.68), 8.959 (0.92), 8.975 (0.89). LC-MS (method 1): R.sub.t = 0.76 min; m/z = 498 (M + H).sup.+. 48 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.24 (dd, 6H), 1.39-1.50 (m, 0.6H), 1.58-2.10 (m, 5.4H), 2.60-2.84 (m, 1.5H), 2.85-3.00 (m, 1.6H), 3.09 (br. s, 0.6H), 3.18 (br. s, 0.4H), 3.22-3.40 (m, 0.9H), 3.43-3.54 (m, 0.6H), 3.57 (s, 1.3H), 3.79 (s, 1.7H), 3.88 (br. s, 0.4H), 4.02-4.15 (m, 0.4H), 4.20-4.40 (m, 2H), 4.58 (br. s, 0.6H), 6.72-6.92 (m, 1H), 6.96-7.13 (m, 2H), 7.24-7.43 (m, 2H), 7.63-7.86 (m, 3H), 8.55 (td, 1H), 8.98 (dt, 1H). LC-MS (method 1): R.sub.t = 0.74 min; m/z = 511 (M + H).sup.+. 49 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.15-1.32 (m, 6H), 1.33-1.53 (m, 0.6H), 1.57-2.11 (m, 5.4H), 2.58-2.81 (m, 1.4H), 2.86-3.01 (m, 1.6H), 3.03-3.21 (m, 1H), 3.24-3.43 (m, 1.2H), 3.58 (s, 1.2H), 3.70 (br. s, 0.4H), 3.78 (s, 1.8H), 4.05-4.17 (m, 0.4H), 4.17-4.39 (m, 2H), 4.58 (br. s, 0.6H), 6.80-7.00 (m, 1H), 7.08 (ddd, 1H), 7.27-7.44 (m, 2H), 7.63-7.69 (m, 3H), 8.49-8.59 (m, 1H), 8.97 (dt, 1H). LC-MS (method 1): R.sub.t = 0.77 min; m/z = 529 (M + H).sup.+. 50 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = −0.008 (1.20), 0.008 (1.19), 1.237 (15.36), 1.243 (7.29), 1.254 (16.00), 1.260 (7.11), 1.408 (0.52), 1.419 (0.55), 1.431 (0.42), 1.443 (0.61), 1.455 (0.55), 1.646 (0.48), 1.671 (0.89), 1.691 (1.13), 1.769 (0.44), 1.780 (0.51), 1.807 (0.99), 1.820 (1.01), 1.844 (0.84), 1.988 (0.50), 2.001 (0.50), 2.018 (0.57), 2.524 (0.88), 2.582 (0.41), 2.661 (0.59), 2.670 (0.48), 2.718 (0.67), 2.727 (0.74), 2.747 (1.00), 2.756 (0.88), 2.868 (1.01), 2.897 (0.74), 2.910 (0.49), 2.927 (0.98), 2.944 (1.27), 2.962 (0.94), 3.077 (0.86), 3.147 (0.66), 3.160 (1.18), 3.184 (0.59), 3.196 (0.60), 3.207 (0.54), 3.219 (0.65), 3.608 (3.83), 3.792 (15.73), 4.239 (1.97), 4.271 (2.12), 4.298 (2.12), 4.334 (0.76), 4.572 (1.02), 6.823 (1.23), 6.845 (1.27), 6.900 (3.37), 6.922 (3.48), 7.072 (2.09), 7.082 (2.12), 7.089 (2.08), 7.099 (2.09), 7.330 (3.38), 7.351 (3.88), 7.356 (1.84), 7.377 (1.40), 7.755 (4.00), 7.776 (3.62), 7.785 (2.25), 7.807 (2.51), 7.854 (3.36), 7.877 (3.23), 8.538 (0.58), 8.542 (0.63), 8.548 (0.64), 8.556 (1.61), 8.561 (1.70), 8.566 (1.61), 8.571 (1.49), 8.941 (1.49), 8.946 (1.57), 8.958 (1.62), 8.963 (1.47), 8.972 (0.58). LC-MS (method 1): R.sub.t = 0.81 min; m/z = 545/547 (M + H).sup.+. 51 0 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = −0.008 (0.80), 0.008 (0.84), 1.218 (15.11), 1.236 (16.00), 1.242 (9.88), 1.260 (9.22), 1.423 (0.48), 1.435 (0.54), 1.446 (0.42), 1.458 (0.61), 1.470 (0.56), 1.625 (0.62), 1.651 (0.84), 1.676 (1.00), 1.690 (0.77), 1.703 (0.72), 1.742 (0.48), 1.770 (0.52), 1.779 (0.57), 1.795 (0.42), 1.807 (0.52), 1.845 (0.89), 1.866 (1.09), 1.980 (0.49), 1.996 (0.59), 2.010 (0.75), 2.524 (0.60), 2.665 (0.52), 2.682 (0.65), 2.694 (0.58), 2.731 (1.44), 2.738 (1.09), 2.759 (1.30), 2.767 (1.01), 2.907 (0.93), 2.925 (1.94), 2.934 (1.33), 2.942 (1.09), 2.952 (1.25), 2.958 (1.16), 2.968 (0.65), 3.067 (0.91), 3.076 (0.88), 3.119 (0.52), 3.357 (0.84), 3.369 (0.65), 3.380 (0.77), 3.390 (0.77), 3.426 (0.61), 3.440 (0.93), 3.452 (0.50), 3.475 (0.49), 3.902 (0.61), 3.991 (0.46), 4.026 (0.41), 4.220 (2.90), 4.236 (0.86), 4.272 (2.20), 4.297 (2.24), 4.333 (0.72), 4.577 (1.05), 7.072 (1.55), 7.077 (1.10), 7.082 (1.67), 7.088 (2.22), 7.094 (2.24), 7.099 (1.71), 7.104 (1.03), 7.113 (1.32), 7.161 (2.10), 7.181 (2.21), 7.252 (0.77), 7.266 (1.24), 7.284 (1.31), 7.311 (3.44), 7.331 (3.73), 7.357 (2.31), 7.366 (2.23), 7.370 (2.30), 7.375 (2.59), 7.386 (2.22), 7.433 (1.55), 7.552 (2.69), 7.615 (0.72), 7.734 (1.26), 7.787 (4.08), 7.800 (2.78), 7.808 (3.87), 7.820 (2.15), 7.934 (0.93), 7.954 (1.24), 7.974 (0.84), 8.013 (1.64), 8.033 (2.12), 8.052 (1.47), 8.543 (0.89), 8.548 (1.04), 8.553 (2.38), 8.558 (2.44), 8.563 (1.63), 8.568 (1.46), 8.962 (1.49), 8.967 (1.57), 8.973 (1.08), 8.979 (2.10), 8.984 (1.51), 8.990 (0.95), 8.995 (0.81). LC-MS (method 1): R.sub.t = 0.79 min; m/z = 547 (M + H).sup.+. 52 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = −0.008 (0.63), 0.008 (0.57), 1.243 (15.74), 1.261 (16.00), 1.434 (0.72), 1.447 (0.75), 1.457 (0.70), 1.470 (0.91), 1.481 (1.03), 1.489 (1.15), 1.509 (1.28), 1.526 (1.57), 1.546 (2.00), 1.556 (1.68), 1.566 (1.60), 1.610 (0.62), 1.652 (1.36), 1.685 (2.06), 1.701 (1.19), 1.734 (0.69), 1.753 (0.67), 1.765 (0.66), 1.776 (0.58), 1.931 (0.45), 1.947 (0.42), 2.523 (0.41), 2.574 (0.70), 2.583 (0.73), 2.602 (0.97), 2.611 (0.89), 2.747 (0.97), 2.775 (0.78), 2.914 (0.42), 2.932 (1.07), 2.949 (1.46), 2.966 (1.43), 2.976 (1.07), 2.983 (1.12), 3.387 (0.49), 3.647 (0.52), 3.684 (0.42), 4.173 (0.58), 4.209 (2.11), 4.218 (2.62), 4.426 (0.80), 7.059 (0.98), 7.070 (1.04), 7.076 (1.09), 7.087 (1.11), 7.097 (0.41), 7.341 (2.44), 7.353 (1.24), 7.361 (2.76), 7.373 (1.09), 7.771 (3.12), 7.776 (2.19), 7.792 (2.96), 8.547 (1.46), 8.551 (1.61), 8.557 (1.55), 8.562 (1.45), 8.909 (1.01), 8.914 (1.04), 8.926 (1.06), 8.931 (1.13), 8.938 (0.46), 8.951 (0.40). LC-MS (method 1): R.sub.t = 0.75 min; m/z = 472 (M + H).sup.+. 53 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.24 (dd, 6H), 1.29-1.40 (m, 0.5H), 1.41-1.57 (m, 2H), 1.59-1.82 (m, 1.5H), 1.90-2.30 (m, 2H), 2.88-3.01 (m, 1.5H), 3.06-3.14 (m, 0.5H), 3.16-3.36 (m, 3.4H, partially covered by H.sub.2O signal), 3.44 (br. d, 0.6H), 3.78 (d, 3H), 3.93 (br. d, 0.5H), 4.11-4.33 (m, 2.5H), 6.92 (dd, 1H), 7.04-7.14 (m, 1H), 7.31-7.41 (m, 2H), 7.71-7.84 (m, 3H), 8.52-8.60 (m, 1H), 9.12 (dd, 1H). LC-MS (method 2): R.sub.t = 1.80 min; m/z = 529 (M + H).sup.+. 54 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.13-1.36 (m, 6.5H), 1.38-1.58 (m, 1.5H), 1.58-1.73 (m, 1.5H), 1.78-1.90 (m, 0.5H), 1.90-2.14 (m, 1H), 2.14-2.30 (m, 1H), 2.87-3.00 (m, 1.5H), 3.02-3.14 (m, 1.4H), 3.15-3.37 (m, 2.5H, partially covered by H.sub.2O signal), 3.44 (br. d, 0.6H), 3.79 (d, 3H), 3.94-4.05 (m, 0.5H), 4.12-4.36 (m, 2.5H), 6.90 (dd, 1H), 7.04-7.14 (m, 1H), 7.28-7.42 (m, 2H), 7.70- 7.90 (m, 3H), 8.50-8.62 (m, 1H), 9.06-9.19 (m, 1H). LC-MS (method 2): R.sub.t = 1.88 min; m/z = 545/547 (M + H).sup.+. 55 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.24 (d, 6H), 1.40-1.57 (m, 2.5H), 1.59-1.70 (m, 1H), 1.70-1.81 (m, 0.5H), 1.91-2.12 (m, 1H), 2.12-2.29 (m, 1H), 2.87-3.01 (m, 1.5H), 3.10-3.47 (m, 4H, partially covered by H.sub.2O signal), 3.52 (br. d, 0.5H), 3.75-3.86 (m, 3.5H), 4.12-4.33 (m, 2.5H), 6.86 (dd, 1H), 7.03 (dd, 1H), 7.10 (td, 1H), 7.36 (dd, 2H), 7.70-7.85 (m, 3H), 8.56 (dt, 1H), 9.07-9.15 (m, 1H). LC-MS (method 2): R.sub.t = 1.72 min; m/z = 511 (M + H).sup.+. 56 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.24 (d, 6H), 1.31-1.56 (m, 2.5H), 1.59-1.75 (m, 1.5H), 1.89-2.11 (m, 1H), 2.12-2.29 (m, 1H), 2.88-3.01 (m, 1.5H), 3.05-3.39 (m, 3.5H, partially covered by H.sub.2O signal), 3.40-3.51 (m, 1H), 3.81 (br. d, 0.5H), 4.14 (br. d, 0.5H), 4.24 (br. d, 2H), 7.03-7.19 (m, 2H), 7.30-7.41 (m, 3.25H), 7.54 (d, 0.5H), 7.72 (d, 0.25H), 7.79 (dd, 2H), 7.99 (q, 1H), 8.53- 8.62 (m, 1H), 9.10 (ddd, 1H). LC-MS (method 2): R.sub.t = 1.83 min; m/z = 547 (M + H).sup.+. 57 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.19-1.36 (m, 7.5H), 1.36-1.84 (m, 11H), 1.88-2.24 (m, 2H), 2.72 (dd, 0.75H), 2.81-3.02 (m, 2H), 3.07-3.19 (m, 0.75H), 3.21-3.36 (m, 2H, partially covered by H.sub.2O signal), 3.52 (br. d, 0.4H), 3.57-3.70 (m, 1H), 4.03 (br. d, 0.6H), 4.17-4.30 (m, 2H), 7.09 (dd, 1H), 7.37 (d, 2H), 7.79 (d, 2H), 8.57 (dd, 1H), 9.03-9.13 (m, 1H). LC-MS (method 2): R.sub.t = 1.83 min; m/z = 472 (M + H).sup.+. 58 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.24 (dd, 6H), 1.29-1.40 (m, 0.5H), 1.41-1.56 (m, 2H), 1.59-1.82 (m, 1.5H), 1.91-2.29 (m, 2H), 2.88-3.01 (m, 1.5H), 3.06-3.15 (m, 0.5H), 3.16-3.37 (m, 3.4H, partially covered by H.sub.2O signal ), 3.44 (br. d, 0.6H), 3.78 (d, 3H), 3.93 (br. d, 0.5H), 4.12-4.33 (m, 2.5H), 6.92 (dd, 1H), 7.05-7.14 (m, 1H), 7.32-7.41 (m, 2H), 7.71-7.84 (m, 3H), 8.52-8.60 (m, 1H), 9.12 (dd, 1H). LC-MS (method 1): R.sub.t = 0.92 min; m/z = 529 (M + H).sup.+. 59 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.19-1.36 (m, 6.5H), 1.38-1.58 (m, 1.5H), 1.58-1.72 (m, 1.5H), 1.78-1.90 (m, 0.5H), 1.91-2.14 (m, 1H), 2.14-2.29 (m, 1H), 2.88-3.00 (m, 1.5H), 3.02-3.14 (m, 1.4H), 3.15-3.36 (m, 2.5H, partially covered by H.sub.2O signal), 3.44 (br. d, 0.6H), 3.79 (d, 3H), 3.94-4.05 (m, 0.5H), 4.13-4.36 (m, 2.5H), 6.90 (dd, 1H), 7.05-7.14 (m, 1H), 7.32-7.42 (m, 2H), 7.73- 7.90 (m, 3H), 8.52-8.62 (m, 1H), 9.08-9.19 (m, 1H). LC-MS (method 1): R.sub.t = 0.96 min; m/z = 545/547 (M + H).sup.+. 60 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.24 (d, 6H), 1.39-1.57 (m, 2.5H), 1.59-1.70 (m, 1H), 1.70-1.81 (m, 0.5H), 1.89-2.12 (m, 1H), 2.12-2.29 (m, 1H), 2.87-3.01 (m, 1.5H), 3.10-3.47 (m, 4H, partially covered by H.sub.2O signal), 3.52 (br. d, 0.5H), 3.75-3.88 (m, 3.5H), 4.12-4.34 (m, 2.5H), 6.86 (dd, 1H), 7.03 (dd, 1H), 7.10 (td, 1H), 7.36 (dd, 2H), 7.71-7.84 (m, 3H), 8.57 (dt, 1H), 9.06-9.15 (m, 1H). LC-MS (method 1): R.sub.t = 0.88 min; m/z = 511 (M + H).sup.+. 61 0 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.24 (dd, 6H), 1.31-1.57 (m, 2.5H), 1.59-1.75 (m, 1.5H), 1.89-2.11 (m, 1H), 2.12-2.29 (m, 1H), 2.87-3.01 (m, 1.5H), 3.04-3.39 (m, 3.5H, partially covered by H.sub.2O signal), 3.39-3.51 (m, 1H), 3.81 (br. d, 0.5H), 4.14 (br. d, 0.5H), 4.25 (br. d, 2H), 7.05-7.19 (m, 2H), 7.29-7.41 (m, 3.5H), 7.54 (d, 0.5H), 7.72 (d, 0.25H), 7.79 (dd, 2H), 7.99 (q, 1H), 8.53- 8.62 (m, 1H), 9.10 (ddd, 1H). LC-MS (method 2): R.sub.t = 1.82 min; m/z = 547 (M + H).sup.+. 62 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.20-1.36 (m, 7.5H), 1.36-1.83 (m, 11H), 1.88-2.24 (m, 2H), 2.72 (dd, 0.75H), 2.81-3.02 (m, 2H), 3.07-3.18 (m, 0.75H), 3.21-3.36 (m, 2H, partially covered by H.sub.2O signal), 3.52 (br. d, 0.4H), 3.57-3.70 (m, 1H), 4.03 (br. d, 0.6H), 4.16-4.30 (m, 2H), 7.09 (dd, 1H), 7.37 (d, 2H), 7.79 (d, 2H), 8.57 (dd, 1H), 9.03-9.13 (m, 1H). LC-MS (method 2): R.sub.t = 1.82 min; m/z = 472 (M + H).sup.+. 63 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.00-1.12 (m, 0.5H), 1.16-1.36 (m, 7H), 1.37-1.74 (m, 3.25H), 1.89-2.29 (m, 2H), 2.87-3.39 (m, 5.25H, partially covered by H.sub.2O signal), 3.45 (br. d, 0.5H), 4.07 (br. d, 0.5H), 4.23 (br. d, 2H), 7.05-7.16 (m, 1H), 7.16-7.32 (m, 3H), 7.37 (t, 2H), 7.41-7.51 (m, 1H), 7.78 (dd, 2H), 8.53-8.61 (m, 1H), 9.04-9.15 (m, 1H). LC-MS (method 2): R.sub.t = 1.81 min; m/z = 498 (M + H).sup.+. [α].sub.D.sup.20 = −8.72° (c = 0.260, Methanol). 64 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.00-1.12 (m, 0.5H), 1.17-1.36 (m, 7H), 1.38-1.74 (m, 3.25H), 1.89-2.29 (m, 2H), 2.87-3.40 (m, 5.25H, partially covered by H.sub.2O signal), 3.45 (br. d, 0.5H), 4.07 (br. d, 0.5H), 4.23 (br. d, 2H), 7.05-7.16 (m, 1H), 7.16-7.32 (m, 3H), 7.37 (t, 2H), 7.41-7.51 (m, 1H), 7.78 (dd, 2H), 8.54-8.61 (m, 1H), 9.03-9.15 (m, 1H). LC-MS (method 2): R.sub.t = 1.82 min; m/z = 498 (M + H).sup.+. [α].sub.D.sup.20 = +7.98° (c = 0.280, Methanol). 65 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = −0.149 (0.67), −0.008 (4.28), 0.008 (4.04), 0.147 (0.54), 1.401 (1.79), 1.413 (1.82), 1.435 (2.05), 1.446 (2.05), 1.651 (5.25), 1.681 (3.33), 1.724 (1.68), 1.762 (1.95), 1.790 (1.89), 1.853 (3.67), 1.995 (2.19), 2.328 (1.35), 2.367 (1.25), 2.581 (1.45), 2.594 (1.58), 2.610 (2.09), 2.623 (1.85), 2.671 (1.48), 2.710 (5.39), 2.718 (3.17), 2.738 (5.09), 2.747 (3.54), 2.865 (3.77), 2.894 (2.73), 3.039 (3.23), 3.118 (2.05), 3.330 (3.77), 3.343 (2.80), 3.353 (3.60), 3.364 (2.63), 3.411 (3.40), 3.424 (1.92), 3.447 (1.58), 3.819 (2.22), 4.033 (1.58), 4.067 (1.45), 4.221 (10.91), 4.238 (2.53), 4.274 (8.66), 4.290 (8.56), 4.326 (2.12), 4.569 (3.74), 7.084 (5.22), 7.094 (6.84), 7.101 (5.83), 7.107 (4.01), 7.112 (6.80), 7.123 (3.37), 7.288 (4.95), 7.309 (5.42), 7.376 (8.35), 7.396 (8.62), 7.465 (4.72), 7.484 (6.37), 7.491 (14.18), 7.512 (16.00), 7.527 (8.49), 7.545 (15.43), 7.566 (9.30), 7.882 (15.66), 7.904 (14.28), 7.922 (9.87), 7.943 (8.39), 8.050 (3.60), 8.070 (5.05), 8.089 (3.13), 8.126 (5.89), 8.146 (8.45), 8.166 (5.09), 8.569 (3.40), 8.574 (3.84), 8.580 (8.62), 8.585 (8.89), 8.590 (6.27), 8.595 (5.66), 8.982 (5.12), 8.987 (5.25), 8.999 (5.29), 9.004 (5.29), 9.010 (3.50), 9.015 (3.27), 9.028 (3.03), 9.032 (3.03). LC-MS (method 1): R.sub.t = 0.81 min; m/z = 557/559 (M + H).sup.+. 66 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.36-1.50 (m, 0.6H), 1.55-2.06 (m, 5.4H), 2.57-2.93 (m, 2H), 2.99-3.18 (m, 1H), 3.35-3.49 (m, 1.6H), 3.77-3.86 (m, 0.4H), 4.01-4.11 (m, 0.4H), 4.20-4.36 (m, 2H), 4.52-4.61 (m, 0.6H), 7.10 (dt, 1H), 7.24-7.43 (m, 1H), 7.44-7.62 (m, 3H), 7.84-8.00 (m, 2H), 8.02-8.19 (m, 1H), 8.51-8.64 (m, 1H), 8.91-9.10 (m, 1H). LC-MS (method 2): R.sub.t = 1.57 min; m/z = 557/559 (M + H).sup.+. 67 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = −0.150 (0.63), 0.008 (3.74), 1.423 (1.51), 1.447 (1.69), 1.622 (2.57), 1.637 (3.51), 1.673 (2.97), 1.760 (1.71), 1.852 (2.80), 1.989 (2.37), 2.073 (2.66), 2.327 (1.23), 2.366 (1.00), 2.650 (1.03), 2.679 (2.34), 2.690 (1.80), 2.722 (4.06), 2.750 (3.69), 2.887 (2.97), 2.917 (2.17), 3.021 (2.63), 3.107 (1.63), 3.351 (2.49), 3.373 (2.23), 3.424 (2.89), 3.461 (1.31), 3.893 (1.91), 3.985 (1.31), 4.022 (1.34), 4.221 (8.97), 4.241 (1.51), 4.278 (7.77), 4.286 (7.74), 4.323 (1.09), 4.559 (3.03), 7.094 (4.77), 7.097 (5.06), 7.108 (5.20), 7.114 (9.40), 7.125 (4.69), 7.160 (6.40), 7.180 (6.71), 7.232 (2.20), 7.293 (3.86), 7.311 (4.11), 7.338 (6.34), 7.356 (6.54), 7.406 (3.89), 7.414 (4.66), 7.508 (11.46), 7.529 (12.60), 7.550 (7.23), 7.571 (7.77), 7.588 (7.89), 7.596 (2.40), 7.769 (3.63), 7.900 (12.77), 7.922 (16.00), 7.940 (5.40), 7.944 (7.00), 7.960 (3.94), 7.980 (2.49), 8.010 (4.74), 8.030 (6.14), 8.050 (4.14), 8.571 (2.71), 8.575 (3.51), 8.581 (7.37), 8.586 (7.54), 8.591 (4.91), 8.596 (4.31), 8.988 (4.20), 8.993 (4.11), 9.005 (4.37), 9.010 (4.60), 9.018 (2.77), 9.031 (2.51). LC-MS (method 1): R.sub.t = 0.76 min; m/z = 539/541 (M + H).sup.+. 68 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = −0.149 (0.59), −0.008 (4.53), 0.008 (4.08), 0.146 (0.52), 1.412 (1.34), 1.423 (1.45), 1.435 (1.23), 1.446 (1.71), 1.459 (1.60), 1.623 (2.56), 1.648 (3.53), 1.673 (3.04), 1.759 (1.60), 1.853 (2.82), 1.990 (1.82), 2.073 (3.19), 2.328 (1.11), 2.366 (1.30), 2.524 (3.53), 2.650 (0.89), 2.678 (2.26), 2.691 (1.86), 2.711 (1.82), 2.722 (4.08), 2.750 (3.64), 2.760 (3.04), 2.888 (3.08), 2.916 (2.19), 3.031 (2.52), 3.104 (1.52), 3.350 (2.38), 3.373 (2.26), 3.425 (2.78), 3.438 (1.60), 3.461 (1.30), 3.892 (1.78), 3.986 (1.41), 4.021 (1.26), 4.221 (8.98), 4.241 (1.34), 4.278 (7.76), 4.286 (7.83), 4.322 (1.08), 4.558 (3.04), 7.097 (5.53), 7.101 (3.56), 7.107 (5.16), 7.114 (9.50), 7.124 (4.90), 7.128 (3.23), 7.160 (6.50), 7.181 (6.79), 7.232 (2.34), 7.293 (3.97), 7.312 (4.08), 7.338 (6.46), 7.357 (6.61), 7.406 (4.12), 7.414 (4.94), 7.508 (11.62), 7.529 (13.10), 7.550 (7.20), 7.571 (8.13), 7.588 (8.32), 7.596 (2.41), 7.769 (3.71), 7.900 (13.07), 7.922 (16.00), 7.940 (5.46), 7.945 (7.31), 7.960 (3.94), 7.980 (2.60), 8.010 (4.86), 8.030 (6.27), 8.049 (4.34), 8.570 (2.82), 8.575 (3.42), 8.581 (7.42), 8.586 (7.61), 8.591 (4.94), 8.596 (4.45), 8.988 (4.23), 8.993 (4.34), 9.005 (4.38), 9.010 (4.60), 9.018 (2.67), 9.030 (2.60), 9.035 (2.30). LC-MS (method 1): R.sub.t = 0.75 min; m/z = 539/541 (M + H).sup.+.

(425) Analogously to Examples 13-16, the following compounds were prepared from the starting materials specified in each case:

(426) TABLE-US-00014 Name/Structure/Starting materials Example Analytical data 69 [3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl] methyl}-3,9-diazabicyclo[4.2.1]non-9-yl](2- fluorophenyl)methanone (racemtate) from 2-(4-chlorophenyl)imidazo[1,2-a]pyridine-3- carbaldehyde and 3,9-diazabicyclo[4.2.1]non-9-yl (2-fluorophenyl)methanone (racemate) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.21- 1.35 (m, 0.5H), 1.35-1.47 (m, 1.5H), 1.51-1.67 (m, 1H), 1.68-1.79 (m, 0.5H), 1.79-1.93 (m, 1H), 1.93-2.20 (m, 2H), 2.30-2.45 (m, 1.5H), 2.55-2.68 (m, 1H), 2.70-2.85 (m, 1H), 3.62-3.81 (m, 1H), 3.99-4.24 (m, 2H), 4.43- 4.64 (m, 1H), 6.91-7.03 (m, 1H), 7.18-7.28 (m, 2H), 7.28-7.37 (m, 2H), 7.42-7.48 (m, 1H), 7.53 (dd, 2H), 7.60 (dd, 1H), 7.93 (dd, 2H), 8.60 (dd, 1H). LC-MS (method 2): R.sub.t = 1.60 min; m/z = 489/491 (M + H).sup.+. 70 [3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}- 3,9-diazabicyclo[4.2.1]non-9-yl](6-methoxypyridin-2-yl) methanone (racemate) from 2-(4-chlorophenyl)imidazo[1,2-a]pyridine-3- carbaldehyde and 3,9-diazabicyclo[4.2.1]non-9-yl (6-methoxypyridin-2-yl)methanone (racemate) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = −0.008 (2.46), 0.008 (2.02), 1.328 (0.55), 1.365 (0.56), 1.393 (0.56), 1.478 (0.46), 1.633 (1.82), 1.654 (0.70), 1.746 (0.52), 1.776 (0.43), 1.806 (0.48), 1.828 (0.83), 1.856 (1.18), 1.875 (1.04), 1.893 (0.57), 1.989 (0.96), 2.009 (0.83), 2.058 (0.53), 2.092 (0.46), 2.328 (0.66), 2.367 (0.96), 2.390 (0.67), 2.423 (0.72), 2.459 (1.06), 2.524 (1.29), 2.568 (1.07), 2.598 (0.92), 2.621 (0.65), 2.664 (1.20), 2.686 (0.68), 2.710 (0.51), 2.738 (0.62), 2.771 (0.52), 2.826 (0.47), 2.849 (0.41), 3.755 (14.92), 3.791 (16.00), 4.095 (4.59), 4.134 (2.13), 4.154 (2.17), 4.190 (0.61), 4.430 (0.57), 4.451 (1.12), 4.471 (0.60), 4.583 (0.45), 4.611 (1.18), 4.640 (1.06), 4.667 (0.81), 6.890 (3.80), 6.910 (3.98), 6.942 (0.82), 6.957 (2.25), 6.959 (2.26), 6.974 (2.33), 6.991 (0.82), 7.228 (2.00), 7.245 (2.10), 7.286 (2.22), 7.290 (1.87), 7.305 (2.73), 7.312 (2.17), 7.329 (1.71), 7.506 (3.92), 7.513 (4.20), 7.527 (4.44), 7.535 (4.43), 7.585 (2.00), 7.588 (2.02), 7.591 (2.02), 7.608 (1.71), 7.611 (1.73), 7.614 (1.73), 7.765 (1.61), 7.778 (1.79), 7.783 (1.86), 7.786 (1.91), 7.796 (1.95), 7.798 (2.00), 7.804 (1.50), 7.817 (1.48), 7.912 (3.91), 7.934 (3.50), 7.952 (4.15), 7.973 (3.67), 8.587 (1.44), 8.608 (2.15), 8.626 (1.46). LC-MS (method 2): R.sub.t = 1.60 min; m/z = 502/504 (M + H).sup.+. 71 (3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}- 8-oxa-3,10-diazabicyclo[4.3.1]dec-10-yl](2-fluorophenyl) methanone (racemate) 00 from 2-(4-chlorophenyl)imidazo[1,2-a]pyridine-3- carbaldehyde and (2-fluorophenyl)[8-oxa-3,10- diazabicyclo[4.3.1]dec-10-yl]methanone trifluoroacetic acid salt (racemate) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.488 (2.65), 1.661 (1.13), 2.028 (0.96), 2.440 (1.00), 2.456 (1.59), 2.473 (2.09), 2.524 (3.57), 2.671 (0.68), 2.711 (0.81), 2.767 (2.29), 2.780 (1.79), 2.802 (2.15), 2.815 (3.34), 2.848(3.60), 3.039 (1.18), 3.387 (2.69), 3.416 (2.28), 3.448 (5.59), 3.472 (5.42), 3.538 (2.11), 3.546 (2.32), 3.567 (4.55), 3.576 (5.40), 3.604 (6.93), 3.632 (3.21), 3.784 (5.22), 3.813 (4.14), 4.125 (1.55), 4.131 (1.57), 4.161 (8.90), 4.170 (11.10), 4.188 (4.21), 4.207 (1.61), 4.225 (1.14), 4.466 (2.02), 4.484 (2.03), 4.515 (3.24), 4.908 (0.64), 6.854 (0.54), 6.934 (2.39), 6.951 (5.95), 6.968 (5.63), 6.984 (2.15), 7.187 (1.02), 7.210 (1.94), 7.240 (5.01), 7.262 (5.03), 7.285 (5.16), 7.305 (5.49), 7.324 (6.57), 7.341 (4.97), 7.371 (1.56), 7.448 (1.16), 7.462 (2.18), 7.470 (2.52), 7.491 (9.03), 7.514 (16.00), 7.536 (10.46), 7.565 (0.67), 7.595 (5.16), 7.617 (4.66), 7.629 (3.69), 7.652 (2.95), 7.861 (0.58), 7.882 (0.51), 7.944 (5.98), 7.965 (7.09), 7.972 (12.53), 7.993 (10.26), 8.638 (2.48), 8.656 (2.46), 8.733 (3.86), 8.750 (3.82). LC-MS (method 2): R.sub.t = 1.48 min; m/z = 505/507 (M + H).sup.+. 72 [3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}- 8-oxa-3,10-diazabicyclo[4.3.1]dec-10-yl](6-methoxypyridin- 2-yl)methanone (racemate) 01 from 2-(4-chlorophenyl)imidazo[1,2-a]pyridine-3- carbaldehyde and (6-methoxypyridin-2-yl)[8-oxa-3,10- diazabicyclo[4.3.1]dec-10-yl]methanone bis(trifluoroacetic acid) salt (racemate) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.567 (0.87), 1.592 (0.80), 1.788 (0.52), 2.608 (1.26), 2.638 (1.30), 2.657 (0.64), 2.834 (1.95), 2.858 (2.13), 2.884 (0.69), 2.966 (0.86), 2.980 (0.97), 2.996 (0.69), 3.011 (0.60), 3.430 (1.06), 3.437 (1.03), 3.459 (1.38), 3.466 (1.31), 3.484 (0.59), 3.492 (0.60), 3.513 (0.82), 3.521 (0.77), 3.551 (1.85), 3.579 (1.68), 3.598 (1.83), 3.604 (1.80), 3.625 (1.64), 3.741 (16.00), 3.755 (10.52), 3.768 (2.31), 3.798 (1.62), 3.826 (0.99), 3.844 (1.13), 4.030 (0.59), 4.144 (0.83), 4.162 (1.98), 4.171 (2.27), 4.179 (2.74), 4.201 (2.58), 4.237 (0.72), 4.420 (0.60), 4.514 (1.25), 6.831 (1.53), 6.852 (1.73), 6.865 (3.41), 6.880 (3.01), 6.887 (3.01), 6.895 (1.71), 6.912 (1.93), 6.929 (1.02), 7.089 (2.50), 7.106 (2.60), 7.271 (0.69), 7.283 (1.18), 7.297 (1.37), 7.305 (1.44), 7.321 (1.10), 7.469 (2.60), 7.484 (4.84), 7.489 (3.91), 7.505 (4.37), 7.584 (3.37), 7.606 (3.06), 7.620 (1.39), 7.640 (0.89), 7.773 (1.60), 7.792 (2.16), 7.812 (1.47), 7.911 (2.78), 7.932 (2.50), 7.959 (4.47), 7.980 (4.02), 8.728 (2.05), 8.745 (1.91). LC-MS (method 2): R.sub.t = 1.44 min; m/z = 518 (M + H).sup.+. 73 [3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl] methyl}-8-oxa-3,10-diazabicyclo[4.3.1]dec-10-yl](4- methyl-1,2,5-oxadiazol-3-yl)methanone (racemate) 02 from 2-(4-chlorophenyl)imidazo[1,2-a]pyridine-3- carbaldehyde and (4-methyl-1,2,5-oxadiazol-3-yl)[8- oxa-3,10-diazabicyclo[4.3.1]dec-10-yl]methanone trifluoroacetic acid salt (racemate) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.008 (0.45), 1.596 (0.63), 1.631 (0.49), 1.658 (0.43), 1.867 (0.57), 1.888 (0.61), 2.397 (14.19), 2.407 (16.00), 2.616 (0.46), 2.638 (0.42), 2.661 (1.05), 2.666 (0.98), 2.690 (0.81), 2.697 (0.78), 2.815 (0.74), 2.846 (1.68), 2.879 (1.06), 2.897 (0.53), 2.905 (0.65), 2.961 (0.75), 2.977 (0.84), 2.992 (0.60), 3.008 (0.54), 3.124 (0.58), 3.146 (0.76), 3.153 (0.68), 3.175 (0.60), 3.502 (1.34), 3.530 (1.75), 3.603 (1.20), 3.634 (2.86), 3.661 (1.94), 3.688 (0.96), 3.789 (1.53), 3.818 (1.34), 3.826 (1.51), 3.856 (1.09), 3.874 (0.83), 3.896 (0.80), 4.006 (0.71), 4.027 (0.66), 4.143 (0.55), 4.174 (5.38), 4.194 (2.21), 4.230 (0.50), 4.460 (0.74), 4.540 (0.97), 6.709 (0.73), 6.726 (1.45), 6.743 (0.79), 6.819 (0.81), 6.836 (1.65), 6.853 (0.90), 7.197 (0.76), 7.219 (0.96), 7.236 (0.83), 7.268 (0.86), 7.290 (1.09), 7.307 (0.95), 7.451 (3.37), 7.467 (5.00), 7.472 (4.76), 7.488 (4.09), 7.544 (1.78), 7.566 (1.57), 7.578 (1.88), 7.601 (1.61), 7.908 (3.71), 7.929 (3.34), 7.946 (4.19), 7.967 (3.71), 8.545 (1.42), 8.562 (1.36), 8.666 (1.59), 8.683 (1.53). LC-MS (method 1): R.sub.t = 0.80 min; m/z = 493/495 (M + H).sup.+. 74 [3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl] methyl}-8-oxa-3,10-diazabicyclo[4.3.1]dec-10-yl](2- fluorophenyl)methanone (racemate) 03 from 2-(4-chlorophenyl)imidazo[1,2-a]pyrimidine-3- carbaldehyde and (2-fluorophenyl)[8-oxa-3,10- diazabicyclo[4.3.1]dec-10-yl]methanone trifluoroacetic acid salt (racemate) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.500 (2.79), 1.621 (0.96), 2.019 (0.78), 2.074 (0.43), 2.440 (1.66), 2.462 (2.53), 2.479 (2.61), 2.594 (1.63), 2.623 (1.35), 2.670 (0.79), 2.711 (0.53), 2.757 (2.07), 2.770 (1.35), 2.792 (1.80), 2.825 (2.83), 2.852 (3.46), 2.972 (1.24), 3.387 (1.98), 3.441 (3.65), 3.467 (5.66), 3.524 (1.84), 3.533 (1.91), 3.562 (3.97), 3.569 (4.03), 3.589 (3.16), 3.607 (4.51), 3.637 (2.37), 3.762 (1.88), 3.778 (3.80), 3.808 (2.72), 4.157 (1.54), 4.193 (9.08), 4.203 (10.44), 4.239 (1.92), 4.482 (4.20), 6.950 (0.61), 7.082 (2.69), 7.098 (4.45), 7.109 (4.38), 7.124 (1.90), 7.207 (1.12), 7.231 (2.74), 7.251 (5.42), 7.264 (5.91), 7.286 (5.03), 7.309 (3.28), 7.403 (1.40), 7.417 (1.47), 7.452 (1.51), 7.466 (2.25), 7.473 (2.88), 7.486 (2.71), 7.495 (1.60), 7.509 (1.08), 7.523 (6.63), 7.544 (16.00), 7.566 (9.86), 7.601 (0.43), 7.948 (4.54), 7.970 (5.54), 7.976 (10.99), 7.998 (8.96), 8.590 (6.44), 8.595 (6.11), 8.600 (6.16), 9.116 (2.08), 9.131 (2.05), 9.172 (3.27), 9.176 (3.32), 9.190 (3.27). LC-MS (method 2): R.sub.t = 1.69 min; m/z = 506/508 (M +H).sup.+. 75 [3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl] methyl}-8-oxa-3,10-diazabicyclo[4.3.1]dec-10-yl](6- methoxypyridin-2-yl)methanone (racemate) 04 from 2-(4-chlorophenyl)imidazo[1,2-a]pyrimidine-3- carbaldehyde and (6-methoxypyridin-2-yl)[8-oxa- 3,10-diazabicyclo[4.3.1]dec-10-yl]methanone bis(trifluoroacetic acid) salt (racemate) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.570 (0.60), 1.593 (0.57), 1.645 (0.41), 1.825 (0.43), 2.628 (0.86), 2.660 (0.80), 2.805 (1.01), 2.824 (1.36), 2.855 (1.36), 2.919 (0.72), 2.932 (0.88), 2.948 (0.49), 2.964 (0.45), 3.287 (1.05), 3.357 (0.74), 3.371 (0.52), 3.429 (0.89), 3.451 (1.04), 3.457 (1.04), 3.491 (0.52), 3.499 (0.56), 3.520 (0.69), 3.529 (0.67), 3.546 (1.40), 3.576 (1.47), 3.596 (1.73), 3.612 (1.16), 3.624 (1.37), 3.746 (16.00), 3.762 (2.17), 3.791 (1.61), 3.814 (1.06), 3.842 (2.71), 3.870 (0.43), 4.056 (0.41), 4.189 (1.31), 4.197 (1.28), 4.218 (1.73), 4.236 (1.80), 4.272 (0.46), 4.422 (0.49), 4.488 (0.94), 6.848 (0.97), 6.869 (2.62), 6.890 (1.83), 6.951 (0.96), 6.969 (1.00), 7.010 (0.63), 7.020 (0.69), 7.027 (0.69), 7.037 (0.72), 7.045 (1.05), 7.055 (1.10), 7.062 (1.09), 7.072 (1.06), 7.087 (1.75), 7.105 (1.81), 7.503 (1.66), 7.515 (2.91), 7.523 (2.10), 7.536 (3.02), 7.558 (0.49), 7.590 (0.44), 7.655 (0.68), 7.674 (0.88), 7.694 (0.59), 7.777 (1.12), 7.797 (1.58), 7.816 (1.10), 7.915 (1.73), 7.936 (1.54), 7.963 (2.90), 7.984 (2.61), 8.553 (0.73), 8.558 (0.81), 8.569 (1.60), 8.574 (1.32), 8.580 (1.22), 8.584 (1.10), 9.172 (1.05), 9.176 (1.19), 9.188 (1.22), 9.194 (1.15). LC-MS (method 2): R.sub.t = 1.61 min; m/z = 519/521 (M +H).sup.+. 76 [3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl] methyl}-8-oxa-3,10-diazabicyclo[4.3.1]dec-10-yl] (4-methyl-1,2,5-oxadiazol-3-yl)methanone (racemate) 05 from 2-(4-chlorophenyl)imidazo[1,2-a]pyrimidine-3- carbaldehyde and (4-methyl-1,2,5-oxadiazol-3-yl) [8-oxa-3,10-diazabicyclo[4.3.1]dec-10-yl]methanone trifluoroacetic acid salt (racemate) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.607 (0.86), 1.622 (0.95), 1.658 (0.51), 1.909 (0.93), 1.924 (0.91), 2.389 (14.10), 2.407 (16.00), 2.479 (0.60), 2.525 (0.91), 2.639 (1.35), 2.662 (1.45), 2.669 (1.53), 2.814 (0.78), 2.845 (1.77), 2.873 (1.03), 2.900 (1.15), 2.910 (1.31), 2.926 (1.43), 2.941 (0.71), 2.957 (0.58), 3.046 (0.67), 3.067 (0.86), 3.075 (0.77), 3.097 (0.62), 3.475 (0.83), 3.482 (0.97), 3.491 (0.99), 3.503 (1.40), 3.512 (1.24), 3.520 (1.40), 3.527 (1.26), 3.586 (0.91), 3.595 (1.55), 3.626 (3.60), 3.637 (2.10), 3.655 (1.38), 3.668 (1.21), 3.782 (1.80), 3.812 (1.40), 3.829 (1.64), 3.859 (1.91), 3.886 (0.98), 3.940 (0.86), 3.962 (0.82), 4.185 (0.63), 4.209 (6.10), 4.220 (2.95), 4.234 (2.63), 4.270 (0.55), 4.470 (0.91), 4.511 (1.21), 6.875 (1.29), 6.885 (1.37), 6.892 (1.33), 6.902 (1.31), 6.978 (1.43), 6.988 (1.52), 6.995 (1.47), 7.005 (1.45), 7.490 (3.56), 7.502 (4.28), 7.511 (4.08), 7.523 (4.26), 7.924 (4.03), 7.946 (4.01), 7.954 (4.78), 7.975 (3.99), 8.477 (1.41), 8.482 (1.51), 8.487 (1.51), 8.492 (1.39), 8.561 (1.58), 8.565 (1.68), 8.571 (1.66), 8.575 (1.46), 8.948 (1.40), 8.953 (1.38), 8.965 (1.42), 8.970 (1.30), 9.103 (1.56), 9.108 (1.54), 9.120 (1.58), 9.125 (1.43). LC-MS (method 2): R.sub.t = 1.73 min; m/z = 494/496 (M +H).sup.+. 77 (4-amino-1,2,5-oxadiazo1-3-yl)[3-{[2-(4-chlorophenyl) imidazo[1,2-a]pyrimidin-3-yl]methyl}-8-oxa-3,10- diazabicyclo[4.3.1]dec-10-yl]methanone (racemate) 06 from 2-(4-chlorophenyl)imidazo[1,2-a]pyrimidine-3- carbaldehyde and (4-amino-1,2,5-oxadiazol-3-yl) [8-oxa-3,10-diazabicyclo[4.3.1]dec-10-yl] methanone bis(trifluoroacetic acid) salt (racemate) .sup.1H-NMR (500 MHz, DMSO-d.sub.6): δ [ppm] = 1.234 (1.70), 1.567 (1.12), 1.596 (1.63), 1.623 (1.40), 1.834 (1.28), 1.892 (1.22), 2.075 (1.63), 2.365 (0.43), 2.607 (1.25), 2.635 (1.73), 2.664 (1.94), 2.688 (1.96), 2.782 (1.95), 2.807 (2.40), 2.829 (1.46), 2.848 (2.34), 2.869 (2.53), 2.891 (1.06), 2.957 (1.60), 2.970 (1.86), 2.981 (1.60), 2.993 (1.52), 3.052 (1.37), 3.069 (1.87), 3.092 (1.25), 3.377 (2.05), 3.525 (2.11), 3.543 (3.97), 3.561 (2.67), 3.620 (2.85), 3.633 (3.17), 3.644 (3.61), 3.669 (3.93), 3.680 (3.80), 3.691 (3.10), 3.704 (2.75), 3.777 (3.33), 3.801 (2.62), 3.821 (3.15), 3.844 (2.43), 4.108 (2.18), 4.124 (2.09), 4.161 (0.99), 4.193 (16.00), 4.224 (2.81), 4.451 (2.06), 4.494 (2.45), 6.348 (7.64), 6.390 (7.95), 6.888 (2.17), 6.897 (2.48), 6.902 (2.55), 6.910 (2.28), 6.969 (2.37), 6.977 (2.68), 6.982 (2.78), 6.990 (2.49), 7.455 (0.57), 7.486 (6.37), 7.504 (11.79), 7.521 (7.81), 7.571 (0.59), 7.584 (0.57), 7.601 (0.49), 7.830 (0.66), 7.847 (0.50), 7.909 (6.89), 7.926 (7.00), 7.936 (8.05), 7.953 (7.00), 8.002 (0.44), 8.493 (3.05), 8.498 (3.03), 8.501 (2.86), 8.564 (3.37), 8.568 (3.40), 8.572 (3.22), 8.899 (2.70), 8.913 (2.68), 9.066 (3.05), 9.076 (2.91), 9.079 (2.96). LC-MS (method 2): R.sub.t = 1.57 min; m/z = 495/497 (M + H).sup.+. 78 [3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl] methyl}-3,9-diazabicyclo[4.2.1]non-9-yl](3-fluoro- 6-methoxypyridin-2-yl)methanone (enantiomer 1) 07 from 2-(4-chlorophenyl)imidazo[1,2-a]pyridine-3- carbaldehyde and 3,9-diazabicyclo[4.2.1]non-9-yl (3-fluoro-6-methoxypyridin-2-yl)methanone (enantiomer 1) .sup.1H-NMR (500 MHz, DMSO-d.sub.6): δ [ppm] = 1.28- 1.40 (m, 1H), 1.43-1.52 (m, 0.5H), 1.53-1.91 (m, 3H), 1.92-2.05 (m, 1H), 2.08-2.19 (m, 0.5H), 2.31-2.45 (m, 1.5H), 2.46-2.53 (m, 0.5H, partially covered by DMSO signal), 2.53-2.65 (m, 1H), 2.76-2.89 (m, 1H), 3.78 (m, 3H), 3.82-3.94 (m, 1H), 4.07-4.24 (m, 2H), 4.49- 4.61 (m, 1H), 6.94 (dt, 1H), 6.98 (td, 1H), 7.32 (ddt, 1H), 7.49-7.56 (m, 2H), 7.56-7.63 (m, 1H), 7.72-7.81 (m, 1H), 7.85-8.02 (m, 2H), 8.58-8.66 (m, 1H). LC-MS (method 2): R.sub.t = 1.59 min; m/z = 520/522 (M + H).sup.+. 79 [3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl] methyl}-3,9-diazabicyclo[4.2.1]non-9-yl](3-fluoro- 6-methoxypyridin-2-yl)methanone (enantiomer 2) 08 from 2-(4-chlorophenyl)imidazo[1,2-a]pyridine-3- carbaldehyde and 3,9-diazabicyclo[4.2.1]non-9-yl (3-fluoro-6-methoxypyridin-2-yl)methanone (enantiomer 2) .sup.1H-NMR (500 MHz, DMSO-d.sub.6): δ [ppm] = 1.29- 1.40 (m, 1H), 1.43-1.52 (m, 0.5H), 1.53-1.91 (m, 3H), 1.91-2.06 (m, 1H), 2.08-2.17 (m, 0.5H), 2.33- 2.45 (m, 1.5H), 2.47-2.53 (m, 0.5H, partially covered by DMSO signal), 2.53-2.65 (m, 1H), 2.75-2.89 (m, 1H), 3.78 (m, 3H), 3.83-3.93 (m, 1H), 4.07-4.22 (m, 2H), 4.50-4.61 (m, 1H), 6.94 (dt, 1H), 6.98 (td, 1H), 7.32 (ddt, 1H), 7.48-7.56 (m, 2H), 7.57-7.62 (m, 1H), 7.71-7.81 (m, 1H), 7.84-8.10 (m, 2H), 8.45- 8.72 (m, 1H). LC-MS (method 2): R.sub.t = 1.59 min; m/z = 520/522 (M +H).sup.+. 80 (+)−[3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin- 3-yl+methyl}-3,9-diazabicyclo[4.2.1]non-9-yl](2- fluorophenyl)methanone (enantiomer 1) 09 from 2-(4-chlorophenyl)imidazo[1,2-a]pyrimidine-3- carbaldehyde and 3,9-diazabicyclo[4.2.1]non-9-yl (2-fluorophenyl)methanone (enantiomer 1) .sup.1H-NMR (500 MHz, DMSO-d.sub.6): δ [ppm] = 1.21- 1.35 (m, 0.5H), 1.35-1.50 (m, 1.5H), 1.51-1.65 (m, 1H), 1.65-1.76 (m, 0.5H), 1.78-1.93 (m, 1H), 1.94-2.20 (m, 2H), 2.31-2.46 (m, 1.5H), 2.55-2.69 (m, 1H, partially covered by DMSO signal), 2.70- 2.83 (m, 1H), 3.66-3.79 (m, 1H), 4.04-4.24 (m, 2H), 4.47-4.62 (m, 1H), 7.11-7.18 (m, 1H), 7.19-7.39 (m, 3H), 7.42-7.51 (m, 1H), 7.52-7.61 (m, 2H), 7.89- 8.04 (m, 2H), 8.56-8.63 (m, 1H), 8.98-9.09 (m, 1H). LC-MS (method 2): R.sub.t = 1.77 min; m/z = 490/492 (M + H).sup.+. [α].sub.D.sup.20 = +18.1° (c = 0.35, Methanol). 81 (−)-[3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin- 3-yl]methyl}-3,9-diazabicyclo[4.2.1]non-9-yl](2- fluorophenyl)methanone (enantiomer 2) 0 from 2-(4-chlorophenyl)imidazo[1,2-a]pyrimidine-3- carbaldehyde and 3,9-diazabicyclo[4.2.1]non-9-yl (2-fluorophenyl)methanone (enantiomer 2) .sup.1H-NMR (500 MHz, DMSO-d.sub.6): δ [ppm] = 1.24- 1.36 (m, 0.5H), 1.36-1.48 (m, 1.5H), 1.50-1.65 (m, 1H), 1.65-1.76 (m, 0.5H), 1.77-1.92 (m, 1H), 1.93- 2.20 (m, 2H), 2.31-2.46 (m, 1.5H), 2.55-2.69 (m, 1H, partially covered by DMSO signal), 2.70-2.83 (m, 1H), 3.65-3.78 (m, 1H), 4.04-4.24 (m, 2H), 4.47- 4.62 (m, 1H), 7.11-7.18 (m, 1H), 7.19-7.39 (m, 3H), 7.41-7.51 (m, 1H), 7.52-7.61 (m, 2H), 7.90-8.04 (m, 2H), 8.55-8.63 (m, 1H), 8.97-9.08 (m, 1H). LC-MS (method 2): R.sub.t = 1.77 min; m/z = 490/492 (M + H).sup.+. [α].sub.D .sup.20 = −17.69° (c = 0.26, Methanol). 82 [3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3- yl]methyl}-3,9-diazabicyclo[4.2.1]non-9-yl](3- fluoro-6-methoxypyridin-2-yl)methanone (enantiomer 1) from 2-(4-chlorophenyl)imidazo[1,2-a]pyrimidine-3- carbaldehyde and 3,9-diazabicyclo[4.2.1]non-9-yl (3-fluoro-6-methoxypyridin-2-yl)methanone (enantiomer 1) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = −0.008 (1.33), 0.008 (1.51), 1.323 (0.51), 1.351 (1.00), 1.375 (0.65), 1.481 (0.40), 1.597 (1.68), 1.620 (0.66), 1.714 (0.70), 1.805 (0.44), 1.864 (0.57), 1.887 (0.76), 1.988 (0.67), 2.143 (0.41), 2.328 (0.76), 2.350 (0.98), 2.407 (1.09), 2.437 (0.49), 2.569 (1.19), 2.614 (1.24), 2.637 (0.56), 2.670 (0.40), 2.762 (0.64), 2.796 (0.81), 3.761 (16.00), 3.788 (12.13), 3.842 (0.60), 3.862 (1.14), 3.882 (0.67), 3.904 (0.66), 3.923 (0.67), 4.116 (3.08), 4.133 (0.87), 4.168 (2.04), 4.196 (2.11), 4.231 (0.77), 4.540 (0.67), 4.562 (1.14), 4.581 (0.77), 6.923 (1.52), 6.931 (1.89), 6.936 (1.30), 6.946 (1.75), 6.954 (1.91), 6.958 (1.27), 7.124 (1.78), 7.134 (1.89), 7.141 (1.98), 7.151 (1.84), 7.541 (3.17), 7.557 (4.99), 7.562 (4.59), 7.578 (4.61), 7.743 (1.54), 7.754 (1.20), 7.765 (2.47), 7.776 (1.94), 7.787 (1.47), 7.798 (1.10), 7.921 (3.28), 7.943 (2.94), 7.998 (4.43), 8.019 (3.95), 8.594 (2.40), 8.599 (2.44), 9.040 (1.10), 9.045 (1.12), 9.060 (2.05), 9.077 (1.40), 9.082 (1.37). LC-MS (method 2): R.sub.t = 1.76 min; m/z = 521/523 (M + H).sup.+. 83 [3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl] methyl}-3,9-diazabicyclo[4.2.1]non-9-yl](3-fluoro- 6-methoxypyridin-2-yl)methanone (enantiomer 2) from 2-(4-chlorophenyl)imidazo[1,2-a]pyrimidine-3- carbaldehyde and 3,9-diazabicyclo[4.2.1]non-9-yl(3- fluoro-6-methoxypyridin-2-yl)methanone (enantiomer 2) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = −0.008 (1.78), 1.325 (0.60), 1.351 (1.03), 1.482 (0.41), 1.597 (1.78), 1.624 (0.69), 1.693 (0.75), 1.784 (0.40), 1.803 (0.49), 1.835 (0.44), 1.864 (0.60), 1.887 (0.80), 1.987 (0.71), 2.328 (0.88), 2.350 (1.02), 2.407 (1.18), 2.435 (0.54), 2.569 (1.28), 2.613 (1.33), 2.637 (0.62), 2.670 (0.46), 2.764 (0.65), 2.798 (0.87), 3.761 (16.00), 3.788 (12.13), 3.840 (0.66), 3.862 (1.20), 3.881 (0.69), 3.903 (0.71), 3.922 (0.70), 4.115 (3.28), 4.132 (0.89), 4.168 (2.16), 4.196 (2.26), 4.232 (0.79), 4.540 (0.71), 4.562 (1.22), 4.582 (0.86), 6.923 (1.53), 6.931 (1.89), 6.935 (1.31), 6.945 (1.74), 6.953 (1.94), 6.958 (1.38), 7.124 (1.83), 7.134 (1.93), 7.141 (2.04), 7.151 (1.88), 7.541 (3.16), 7.556 (5.03), 7.562 (4.70), 7.578 (4.61), 7.743 (1.53), 7.754 (1.17), 7.765 (2.58), 7.776 (2.00), 7.787 (1.54), 7.798 (1.08), 7.921 (3.42), 7.943 (3.01), 7.998 (4.52), 8.019 (4.03), 8.593 (2.48), 8.599 (2.52), 9.040 (1.05), 9.045 (1.12), 9.060 (2.18), 9.077 (1.45), 9.082 (1.42). LC-MS (method 2): R.sub.t = 1.77 min; m/z = 521/523 (M + H).sup.+. 84 [3-{[2-(5-chloropyridin-2-yl)imidazo[1,2-a]pyridin-3- yl]methyl}-3,9-diazabicyclo[4.2.1]non-9-yl](6- methoxypyridin-2-yl)methanone (enantiomer 1) from 2-(5-chloropyridin-2-yl)imidazo[1,2-a]pyridine-3- carbaldehyde and 3,9-diazabicyclo[4.2.1]non-9-yl(6- methoxypyridin-2-yl)methanone (enantiomer 1) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.008 (1.08), 1.234 (0.44), 1.272 (0.56), 1.296 (0.47), 1.338 (0.72), 1.369 (0.41), 1.455 (0.49), 1.618 (1.49), 1.643 (0.64), 1.759 (0.89), 1.776 (1.43), 1.798 (1.23), 1.826 (1.18), 1.852 (0.79), 1.979 (1.03), 1.999 (0.87), 2.045 (0.74), 2.074 (2.25), 2.367 (0.82), 2.379 (0.83), 2.413 (0.91), 2.576 (1.39), 2.609 (1.34), 2.653 (2.98), 2.711(0.41), 2.827 (0.71), 2.861 (0.55), 2.949 (0.55), 2.971 (0.46), 3.751 (16.00), 3.780 (15.67), 4.421 (1.64), 4.437 (1.22), 4.455 (2.27), 4.503 (1.21), 4.537 (1.75), 4.565 (1.37), 4.586 (2.44), 4.607 (1.32), 4.634 (1.76), 4.661 (2.00), 4.667 (1.62), 4.694 (1.23), 6.882 (3.25), 6.903 (3.37), 6.955 (0.80), 6.970 (1.63), 6.988 (1.68), 7.005 (1.72), 7.020 (0.93), 7.225 (2.06), 7.243 (2.21), 7.254 (2.17), 7.271 (2.27), 7.320 (0.91), 7.329 (1.02), 7.343 (1.88), 7.357 (1.06), 7.366 (1.00), 7.604 (3.20), 7.627 (2.70), 7.765 (1.68), 7.773 (1.69), 7.785 (2.17), 7.791 (2.06), 7.804 (1.55), 7.812 (1.46), 7.978 (1.43), 7.985 (2.22), 7.992 (1.50), 7.999 (1.81), 8.006 (2.76), 8.013 (1.72), 8.188 (2.55), 8.206 (3.33), 8.226 (2.09), 8.560 (2.92), 8.577 (2.85), 8.623 (2.28), 8.628 (2.25), 8.666 (2.15), 8.671 (2.13). LC-MS (method 2): R.sub.t = 1.19 min; m/z = 503/505 (M + H).sup.+. 85 [3-{[2-(5-chloropyridin-2-yl)imidazo[1,2-a]pyridin-3- yl]methyl}-3,9-diazabicyclo[4.2.1]non-9-yl](6- methoxypyridin-2-yl)methanone (enantiomer 2) from 2-(5-chloropyridin-2-yl)imidazo[1,2-a]pyridine-3- carbaldehyde and 3,9-diazabicyclo[4.2.1]non-9-yl(6- methoxypyridin-2-yl)methanone (enantiomer 2) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = −0.008 (1.29), 0.008 (1.29), 1.234 (0.44), 1.271 (0.51), 1.296 (0.47), 1.340 (0.66), 1.469 (0.48), 1.617 (1.38), 1.646 (0.61), 1.760 (0.86), 1.776 (1.32), 1.796 (1.13), 1.826 (1.07), 1.852 (0.75), 1.978 (0.92), 1.999 (0.82), 2.045 (0.66), 2.074 (0.86), 2.367 (0.78), 2.413 (0.82), 2.577 (1.27), 2.609 (1.18), 2.659 (2.73), 2.711 (0.45), 2.827 (0.63), 2.862 (0.51), 2.951 (0.48), 2.972 (0.42), 3.751 (16.00), 3.780 (15.74), 4.421 (1.55), 4.437 (1.13), 4.455 (2.11), 4.503 (1.14), 4.537 (1.64), 4.566 (1.26), 4.586 (2.25), 4.607 (1.19), 4.633 (1.65), 4.660 (1.86), 4.667 (1.53), 4.695 (1.18), 6.882 (3.15), 6.903 (3.25), 6.955 (0.77), 6.972 (1.54), 6.989 (1.58), 7.005 (1.63), 7.023 (0.87), 7.225 (2.02), 7.243 (2.09), 7.254 (2.11), 7.271 (2.13), 7.320 (0.91), 7.329 (0.97), 7.343 (1.79), 7.357 (0.99), 7.365 (0.94), 7.606 (3.07), 7.629 (2.56), 7.765 (1.72), 7.772 (1.70), 7.785 (2.11), 7.793 (1.98), 7.804 (1.58), 7.812 (1.48), 7.977 (1.52), 7.985 (2.27), 7.992 (1.58), 7.999 (1.89), 8.006 (2.77), 8.013 (1.75), 8.188 (2.52), 8.206 (3.16), 8.227 (1.99), 8.560 (2.73), 8.578 (2.64), 8.623 (2.34), 8.628 (2.31), 8.666 (2.22), 8.671 (2.22). LC-MS (method 2): R.sub.t = 1.17 min; m/z = 503/505 (M + H).sup.+. 86 [3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3- yl]methyl}-3,9-diazabicyclo[4.2.1]non-9-yl](6- methoxypyridin-2-yl)methanone (enantiomer 1) from 2-(4-chlorophenyl)imidazo[1,2-a]pyrimidine-3- carbaldehyde and 3,9-diazabicyclo[4.2.1]non-9-yl(6- methoxypyridin-2-yl)methanone (enantiomer 1) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.234 (0.72), 1.336 (0.56), 1.363 (0.61), 1.393 (0.57), 1.500 (0.49), 1.620 (1.56), 1.638 (0.78), 1.669 (0.48), 1.715 (0.50), 1.863 (1.11), 1.881 (1.08), 1.984 (0.97), 2.006 (0.89), 2.022 (0.87), 2.053 (0.54), 2.085 (0.63), 2.329 (0.55), 2.366 (0.77), 2.403 (0.62), 2.428 (0.65), 2.455 (1.02), 2.564 (1.18), 2.583 (1.02), 2.612 (0.66), 2.666 (1.32), 2.689 (0.72), 2.710 (0.66), 2.722 (0.67), 2.755 (0.54), 2.809 (0.49), 3.748 (14.53), 3.791 (16.00), 3.854 (0.41), 3.862 (0.50), 4.113 (3.61), 4.156 (2.20), 4.173 (2.21), 4.209 (0.59), 4.431 (0.55), 4.452 (1.11), 4.471 (0.60), 4.603 (1.39), 4.628 (1.11), 4.661 (0.79), 4.680 (0.80), 6.892 (2.47), 6.913 (2.61), 7.096 (1.38), 7.107 (1.47), 7.114 (2.17), 7.125 (2.21), 7.132 (1.33), 7.142 (1.28), 7.226 (2.08), 7.244 (2.23), 7.290 (1.90), 7.308 (2.06), 7.536 (4.09), 7.541 (4.95), 7.557 (5.15), 7.562 (4.72), 7.766 (1.54), 7.780 (1.80), 7.784 (1.91), 7.800 (2.06), 7.805 (1.57), 7.819 (1.51), 7.942 (3.89), 7.964 (3.53), 7.983 (4.24), 8.004 (3.73), 8.581 (2.38), 8.586 (2.56), 8.591 (2.54), 8.595 (2.33), 9.014 (1.27), 9.019 (1.30), 9.032 (2.36), 9.037 (2.29), 9.050 (1.39), 9.055 (1.30). LC-MS (method 2): R.sub.t = 1.76 min; m/z = 503/505 (M + H).sup.+. 87 [3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3- yl]methyl}-3,9-diazabicyclo[4.2.1]non-9-yl](6- methoxypyridin-2-yl)methanone (enantiomer 2) from 2-(4-chlorophenyl)imidazo[1,2-a]pyrimidine-3- carbaldehyde and 3,9-diazabicyclo[4.2.1]non-9-yl(6- methoxypyridin-2-yl)methanone (enantiomer 2) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.008 (1.21), 1.235 (1.01), 1.337 (0.70), 1.363 (0.73), 1.502 (0.54), 1.621 (1.60), 1.863 (1.23), 1.985 (1.06), 2.085 (0.64), 2.328 (0.65), 2.366 (0.95), 2.392 (0.75), 2.561 (1.25), 2.583 (0.99), 2.612 (0.65), 2.666 (1.30), 2.696 (0.77), 2.710 (0.78), 2.757 (0.57), 2.804 (0.52), 3.748 (14.57), 3.791 (16.00), 3.854 (0.62), 3.862 (0.55), 4.113 (3.54), 4.157 (2.20), 4.173 (2.13), 4.209 (0.60), 4.432 (0.58), 4.452 (1.12), 4.472 (0.61), 4.603 (1.51), 4.662 (0.82), 4.681 (0.79), 6.892 (2.57), 6.913 (2.71), 7.096 (1.43), 7.107 (1.50), 7.114 (2.15), 7.124 (2.14), 7.132 (1.39), 7.142 (1.27), 7.226 (2.02), 7.244 (2.18), 7.291 (1.90), 7.307 (1.99), 7.536 (4.35), 7.541 (5.05), 7.557 (5.23), 7.562 (4.71), 7.766 (1.70), 7.780 (1.92), 7.784 (1.92), 7.798 (2.08), 7.805 (1.61), 7.819 (1.55), 7.942 (3.93), 7.964 (3.51), 7.983 (4.28), 8.005 (3.68), 8.582 (2.49), 8.585 (2.67), 8.592 (2.57), 8.595 (2.36), 9.014 (1.32), 9.019 (1.31), 9.032 (2.35), 9.037 (2.22), 9.050 (1.40), 9.055 (1.26). LC-MS (method 1): R.sub.t = 0.92 min; m/z =503/505 (M + H).sup.+.

Example 88 and Example 89

[3-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-3,9-diazabicyclo[4.2.1]non-9-yl](2-fluorophenyl)methanone (Enantiomers 1 and 2)

(427) ##STR00217##

(428) 117 mg (240 μmol) of racemic [3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-3,9-diazabicyclo[4.2.1]non-9-yl](2-fluorophenyl)methanone (Example 69) were separated into the enantiomers by preparative HPLC on a chiral phase [column: Daicel Chiralpak AD-H, 5 μm, 250 mm×20 mm; mobile phase: n-heptane/ethanol 70:30 (v/v)+0.2% diethylamine; flow rate: 15 ml/min; UV detection: 235 nm; temperature: 50° C.]:

Example 88 (Enantiomer 1)

(429) Yield: 56 mg

(430) R.sub.t=5.70 min; chemical purity >99%; >99% ee

(431) [column: Daicel Chiralpak IA, 5 μm, 250 mm×4.6 mm; mobile phase: isohexane/ethanol 70:30 (v/v)+0.2% diethylamine; flow rate: 1 ml/min; temperature: 50° C.; UV detection: 235 nm].

(432) LC-MS (method 2): R.sub.t=1.62 min; m/z=489/491 (M+H).sup.+.

(433) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.19-1.34 (m, 0.5H), 1.35-1.47 (m, 1.5H), 1.50-1.68 (m, 1H), 1.68-1.78 (m, 0.5H), 1.78-1.93 (m, 1H), 1.94-2.20 (m, 2H), 2.31-2.45 (m, 1.5H), 2.56-2.69 (m, 1H), 2.71-2.86 (m, 1H), 3.65-3.78 (m, 1H), 4.01-4.23 (m, 2H), 4.47-4.64 (m, 1H), 6.95-7.04 (m, 1H), 7.19-7.37 (m, 4H), 7.43-7.49 (m, 1H), 7.49-7.57 (m, 2H), 7.60 (dd, 1H), 7.87-8.02 (m, 2H), 8.49-8.70 (m, 1H).

Example 89 (Enantiomer 2)

(434) Yield: 58 mg

(435) R.sub.t=6.60 min; chemical purity >99%; >99% ee

(436) [column: Daicel Chiralpak IA, 5 μm, 250 mm×4.6 mm; mobile phase: isohexane/ethanol 70:30 (v/v)+0.2% diethylamine; flow rate: 1 ml/min; temperature: 50° C.; UV detection: 235 nm].

(437) LC-MS (method 2): R.sub.t=1.62 min; m/z=489/491 (M+H).sup.+.

(438) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.22-1.33 (m, 0.5H), 1.35-1.46 (m, 1.5H), 1.50-1.68 (m, 1H), 1.69-1.78 (m, 0.5H), 1.79-1.92 (m, 1H), 1.94-2.21 (m, 2H), 2.31-2.45 (m, 1.5H), 2.57-2.69 (m, 1H), 2.72-2.86 (m, 1H), 3.66-3.79 (m, 1H), 4.04-4.22 (m, 2H), 4.49-4.62 (m, 1H), 6.95-7.03 (m, 1H), 7.19-7.37 (m, 4H), 7.43-7.50 (m, 1H), 7.50-7.56 (m, 2H), 7.60 (dd, 1H), 7.77-8.07 (m, 2H), 8.45-8.71 (m, 1H).

Example 90 and Example 91

[3-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-3,9-diazabicyclo[4.2.1]non-9-yl](6-methoxypyridin-2-yl)methanone (Enantiomers 1 and 2)

(439) ##STR00218##

(440) 195 mg (389 μmol) of racemic [3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-3,9-diazabicyclo[4.2.1]non-9-yl](6-methoxypyridin-2-yl)methanone (Example 70) were separated into the enantiomers by preparative HPLC on a chiral phase [column: Daicel Chiralpak IC, 5 μm, 250 mm×20 mm; mobile phase: n-heptane/ethanol 50:50 (v/v)+0.2% diethylamine; flow rate: 15 ml/min; UV detection: 235 nm; temperature: 40° C.]:

Example 90 (Enantiomer 1)

(441) Yield: 92 mg

(442) R.sub.t=7.65 min; chemical purity >99%; >99% ee

(443) [column: Daicel Chiralpak IA, 5 μm, 250 mm×4.6 mm; mobile phase: isohexane/ethanol 50:50 (v/v)+0.2% diethylamine; flow rate: 1 ml/min; temperature: 50° C.; UV detection: 235 nm].

(444) LC-MS (method 2): R.sub.t=1.63 min; m/z=502/504 (M+H).sup.+.

(445) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.26-1.44 (m, 1H), 1.44-1.54 (m, 0.5H), 1.56-1.68 (m, 1H), 1.69-1.92 (m, 2H), 1.95-2.13 (m, 1.5H), 2.31-2.88 (m, 4H), 4.05-4.21 (m, 2H), 4.45 (t, 0.5H), 4.55-4.70 (m, 1.5H), 6.90 (d, 1H), 6.97 (q, 1H), 7.20-7.34 (m, 2H), 7.52 (dd, 2H), 7.60 (dt, 1H), 7.73-7.84 (m, 1H), 7.94 (dd, 2H), 8.61 (t, 1H).

Example 91 (Enantiomer 2)

(446) Yield: 94 mg

(447) R.sub.t=8.93 min; chemical purity >99%; >99% ee

(448) [column: Daicel Chiralpak IA, 5 μm, 250 mm×4.6 mm; mobile phase: isohexane/ethanol 50:50 (v/v)+0.2% diethylamine; flow rate: 1 ml/min; temperature: 50° C.; UV detection: 235 nm].

(449) LC-MS (method 2): R.sub.t=1.64 min; m/z=502/504 (M+H).sup.+.

(450) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.27-1.44 (m, 1H), 1.43-1.54 (m, 0.5H), 1.56-1.69 (m, 1H), 1.69-1.79 (m, 0.5H), 1.79-1.91 (m, 1.5H), 1.95-2.14 (m, 1.5H), 2.31-2.88 (m, 4H), 4.04-4.22 (m, 2H), 4.45 (t, 0.5H), 4.55-4.70 (m, 1.5H), 6.90 (d, 1H), 6.97 (q, 1H), 7.19-7.35 (m, 2H), 7.52 (dd, 2H), 7.60 (dt, 1H), 7.75-7.83 (m, 1H), 7.94 (dd, 2H), 8.61 (t, 1H).

(451) Analogously to Examples 13-16, the following compounds were prepared from the starting materials specified in each case:

(452) TABLE-US-00015 Example Name/Structure/Starting materials Analytical data 92 [3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3- LC-MS (method yl]methyl}-8-oxa-3,10-diazabicyclo[4.3.1]dec-10-yl](3- 2): fluoro-6-methoxypyridin-2-yl)methanone (racemate) R.sub.t = 1.47 min; m/z = 536/538 (M + H).sup.+. from 2-(4-chlorophenyl)imidazo[1,2-a]pyridine-3- carbaldehyde and (3-fluoro-6-methoxypyridin-2-yl)[8- oxa-3,10-diazabicyclo[4.3.1]dec-10-yl]methanone (racemate) 93 [3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3- LC-MS (method yl]methyl}-8-oxa-3,10-diazabicyclo[4.3.1]dec-10-yl](3- 2): fluoro-6-methoxypyridin-2-yl)methanone (racemate) R.sub.t = 1.67 min; 0 m/z = 537/539 (M + H).sup.+. from 2-(4-chlorophenyl)imidazo[1,2-a]pyrimidine-3- carbaldehyde and (3-fluoro-6-methoxypyridin-2-yl)[8- oxa-3,10-diazabicyclo[4.3.1]dec-10-yl]methanone (racemate)

(453) Analogously to Example 17, the following compounds were prepared from the starting materials specified in each case:

(454) TABLE-US-00016 Example Name/Structure/Starting materials Analytical data 94 [3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3- .sup.1H-NMR (500 MHz, DMSO- yl]methyl}-3,6-diazabicyclo[3.2.2]non-6-yl](3- d.sub.6): δ [ppm] = 1.39-1.50 (m, fluoro-6-methoxypyridin-2-yl)methanone 0.25H), 1.50-1.61 (m, 0.75H), (enantiomer 1) 1.61-1.84 (m, 2.75H), 1.87- 1.98 (m, 0.25H), 2.06 (br. s, 0.25H), 2.22-2.35 (m, 1H), 2.43-2.65 (m, 1.75H, partially covered by DMSO signal), 2.73-2.88 (m, 1H), 2.96 (br. dd, 0.75H), 3.00-3.09 (m, 0.25H), 3.17-3.35 (m, 0.5H, partially covered by H.sub.2O signal), 3.39- 3.50 (m, 0.75H), 3.60 (br. d, 0.75H), 3.63-3.71 (m, 3H), 3.83 (s, 0.75H), 4.00-4.14 (m, 2H), 4.54-4.62 (m, 0.25H), 6.88 (dd, 0.75H), 6.92-7.03 (m, 1.25H), 7.26-7.36 (m, 1H), 7.49-7.56 (m, 2H), 7.57-7.64 (m, 1H), 7.73 (t, 0.75H), 7.79 (t, 0.25H), 7.91-8.01 (m, 2H), 8.54-8.63 (m, 1H). from 2-(4-chlorophenyl)imidazo[1,2-a]pyridine- LC-MS (method 2): 3-carbaldehyde and 3,6-diazabicyclo[3.2.2]non- R.sub.t = 1.56 min; m/z = 520/522 6-yl(3-fluoro-6-methoxypyridin-2-yl)methanone (M+H).sup.+. hydrochloride (enantiomer 1) 95 [3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3- .sup.1H-NMR (500 MHz, DMSO- yl]methyl}-3,6-diazabicyclo[3.2.2]non-6-yl](6- d.sub.6): δ [ppm] = 1.42-1.59 (m, methoxypyridin-2-yl)methanone (enantiomer 1) 1H), 1.60-1.85 (m, 2.75H), 1.86-1.98 (m, 0.25H), 2.03- 2.11 (m, 0.25H), 2.23-2.31 (m, 0.75H), 2.31-2.38 (m, 0.25H), 2.45-2.63 (m, 1H, partially covered by DMSO signal), 2.72-2.88 (m, 1.75H), 2.93- 3.04 (m, 1H), 3.37-3.49 (m, 1H), 3.53-3.67 (m, 3.25H), 3.85 (s, 0.75H), 3.98 (br. s, 0.75H), 4.04-4.14 (m, 2H), 4.55 (br. s, 0.25H), 6.82 (d, 0.75H), 6.88 (d, 0.25H), 6.92- 7.01 (m, 1H), 7.09 (d, 0.75H), 7.21 (d, 0.25H), 7.26-7.35 (m, 1H), 7.49-7.57 (m, 2H), 7.57- 7.64 (m, 1H), 7.75 (dd, 0.75H), from 2-(4-chlorophenyl)imidazo[1,2-a]pyridine- 7.81 (dd, 0.25H), 7.92-8.02 (m, 3-carbaldehyde and 3,6-diazabicyclo[3.2.2]non- 2H), 8.59 (d, 1H). 6-yl(6-methoxypyridin-2-yl)methanone LC-MS (method 2): hydrochloride (enantiomer 1) R.sub.t = 1.55 min; m/z = 502/504 (M + H).sup.+. 96 [3-{[2-(5-chloropyridin-2-yl)imidazo[1,2- .sup.1H-NMR (500 MHz, DMSO- a]pyridin-3-yl]methyl}-3,6- d.sub.6): δ [ppm] = 1.36-1.95 (m, diazabicyclo[3.2.2]non-6-yl](3-fluoro-6- 4.25H), 1.99-2.08 (m, 0.25H), methoxypyridin-2-yl)methanone (enantiomer 1) 2.20-2.31 (m, 1H), 2.41-2.60 (m, 1H, partially covered by DMSO signal), 2.77 (br. dd, 0.75H), 2.89 (br. dd, 0.25H), 3.05 (br. dd, 1H), 3.14-3.29 (m, 0.5H), 3.41 (dd, 1H), 3.52-3.64 (m, 4H), 3.83 (s, 0.75H), 4.41- 4.71 (m, 2.25H), 6.85 (dd, 0.75H), 6.91-7.06 (m, 1.25H), 7.28-7.39 (m, 1H), 7.57-7.65 (m, 1H), 7.70 (t, 0.75H), 7.80 (t, 0.25H), 7.96-8.03 (m, 1H), 8.17-8.25 (m, 1H), 8.48-8.59 (m, 1H), 8.67 (d, 1H). LC-MS (method 2): R.sub.t = 1.20 min; m/z = 521/523 (M + H).sup.+. from 2-(5-chloropyridin-2-yl)imidazo[1,2- a]pyridine-3-carbaldehyde and 3,6- diazabicyclo[3.2.2]non-6-yl(3-fluoro-6- methoxypyridin-2-yl)methanone hydrochloride (enantiomer 1) 97 [3-{[2-(4-chlorophenyl)imidazo[1,2- .sup.1H-NMR (500 MHz, DMSO- a]pyrimidin-3-yl]methyl}-3,6- d.sub.6): δ [ppm] = 1.37-1.86 (m, diazabicyclo[3.2.2]non-6-yl](3-fluoro-6- 4H), 1.87-1.98 (m, 0.25H), methoxypyridin-2-yl)methanone (enantiomer 1) 2.06 (br. s, 0.25H), 2.21-2.35 (m, 1H), 2.41-2.62 (m, 1.5H, partially covered by DMSO signal), 2.72-2.89 (m, 1H), 2.97 (br. dd, 0.75H), 3.05 (br. dd, 0.25H), 3.16-3.35 (m, 0.5H, partially covered by H.sub.2O signal), 3.44 (dd, 0.75H), 3.55- 3.70 (m, 3.75H), 3.82 (s, 0.75H), 4.01-4.17 (m,2H), 4.58 (br. t, 0.25H), 6.88 (dd, 0.75H), 6.95 (dd, 0.25H),7.07- 7.19 (m, 1H), 7.52-7.62 (m, 2H), 7.69-7.84 (m, 1H), 7.93- 8.04 (m, 2H), 8.54-8.63 (m, 1H), 8.96-9.07 (m, 1H). LC-MS (method 2): R.sub.t = 1.75 min; m/z = 521/523 (M + H).sup.+. from 2-(4-chlorophenyl)imidazo[1,2- a]pyrimidine-3-carbaldehyde and 3,6- diazabicyclo[3.2.2]non-6-yl(3-fluoro-6- methoxypyridin-2-yl)methanone hydrochloride (enantiomer 1) 98 [3-{[2-(4-chlorophenyl)imidazo[1,2- .sup.1H-NMR (500 MHz, DMSO- a]pyrimidin-3-yl]methyl}-3,6- d.sub.6): δ [ppm] = 1.42-1.86 (m, diazabicyclo[3.2.2]non-6-yl](6-methoxypyridin- 4H), 1.86-1.98 (m, 0.25H), 2-yl)methanone (enantiomer 1) 2.07 (br. s, 0.25H), 2.26 (br. s, 0.75H), 2.34 (br. d, 0.25H), 2.57 (br. d, 0.75H), 2.70-2.88 (m, 1.75H), 2.94-3.05 (m, 1H), 3.37-3.48 (m, 1H), 3.53-3.66 (m, 3.25H), 3.85 (s, 0.75H), 3.97 (br.s, 0.75H), 4.02-4.16 (m, 2H), 4.54 (br. s, 0.25H), 6.82 (d, 0.75H), 6.89 (d, 0.25H), 7.06-7.22 (m, 2H), 7.51-7.61 (m, 2H), 7.71-7.85 (m, 1H), 7.94-8.02 (m, 2H), 8.54-8.62 (m, 1H), 8.98-9.06 (m, 1H). LC-MS (method 2): R.sub.t = 1.74 min; m/z = 503/505 (M + H).sup.+. from 2-(4-chlorophenyl)imidazo[1,2- a]pyrimidine-3-carbaldehyde and 3,6- diazabicyclo[3.2.2]non-6-yl(6-methoxypyridin- 2-yl)methanone hydrochloride (enantiomer 1) 99 (3-chloro-6-methoxypyridin-2-yl)(3-{[2-(4- .sup.1H-NMR (500 MHz, DMSO- chlorophenyl)imidazo[1,2-a]pyrimidin-3- d.sub.6): δ [ppm] = 1.29-2.05 (m, yl]methyl}-3,9-diazabicyclo[4.2.1]non-9- 5.75H), 2.07-2.19 (m, 0.5H), yl)methanone (racemate) 2.27-2.35 (m, 0.5H), 2.36-2.46 (m, 0.5H), 2.46-2.64 (m, 1.75H, partially covered by DMSO signal), 2.74-2.86 (m, 1H), 3.65-3.74 (m, 1H), 3.77 (s, 1.75H), 3.82 (s, 1.25H), 4.08-4.26 (m, 2H), 4.50-4.61 (m, 1H), 6.92 (dd, 1H), 7.10- 7.18 (m, 1H), 7.51-7.61 (m, 2H), 7.87 (dd, 1H), 7.93 (d, 1H), 8.01 (d, 1H), 8.56-8.63 (m, 1H), 9.02-9.11 (m, 1H). LC-MS (method 1): R.sub.t = 0.92 min; m/z = 537/539 (M + H).sup.+ (Rotamer 1), R.sub.t = 0.94 min; m/z = 537/539 (M + H).sup.+ (Rotamer 2). from 2-(4-chlorophenyl)imidazo[1,2- a]pyrimidine-3-carbaldehyde and (3-chloro-6- methoxypyridin-2-yl)(3,9- diazabicyclo[4.2.1]non-9-yl)methanone hydrochloride (racemate) 100 (3-chloro-6-methoxypyridin-2-yl)(3-{[2-(5- .sup.1H-NMR (500 MHz, DMSO- chloropyridin-2-yl)imidazo[1,2-a]pyridin-3- d.sub.6): δ [ppm] = 1.21-1.68 (m, yl]methyl}-3,9-diazabicyclo[4.2.1]non-9- 3.25H), 1.69-1.88 (m, 1.75H), yl)methanone (racemate) 1.89-2.05 (m, 1H), 2.06-2.19 (m, 0.5H), 2.37 (br. d, 0.5H), 2.44-2.62 (m, 1.5H, partially covered by DMSO signal), 2.64-2.73 (m, 0.5H), 2.87-3.02 (m, 1H), 3.63-3.72 (m, 1H), 3.77 (s, 1.6H), 3.87 (s, 1.4H), 4.40-4.59 (m, 2H), 4.61-4.86 (m, 1H), 6.91 (dd, 1H), 6.98- 7.05 (m, 1H), 7.31-7.40 (m, 1H), 7.62 (dd, 1H), 7.87 (dd, 1H), 8.00 (td, 1H), 8.21 (t, 1H), 8.55-8.65 (m, 1.5H), 8.69 (d, 0.5H). LC-MS (method 1): R.sub.t = 0.72 min; m/z = 537/539 (M + H).sup.+. from 2-(5-chloropyridin-2-yl)imidazo[1,2- a]pyridine-3-carbaldehyde and (3-chloro-6- methoxypyridin-2-yl)(3,9- diazabicyclo[4.2.1]non-9-yl)methanone hydrochloride (racemate)

Example 101

(3-Chloro-6-methoxypyridin-2-yl) [3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,9-diazabicyclo[4.2.1]nonan-9-yl]methanone (Enantiomer 1)

(455) ##STR00228##

(456) Under argon, (3-chloro-6-methoxypyridin-2-yl)[(3,9-diazabicyclo[4.2.1]nonan-9-yl]methanone-hydrogen chloride (1/1) (Enantiomer 1) (90 mg, 270 μmol) was taken up in 2 ml of THF, and 98 μl (0.57 mmol) of N,N-diisopropylethylamine were added. The reaction solution was then stirred at room temperature for 2 hours. Subsequently, the reaction solution was concentrated to dryness and the residue obtained was then taken up in 2 ml of THF, and 2-[4-(propan-2-yl)phenyl]imidazo[1,2-a]pyrimidine-3-carbaldehyde (60.0 mg, 230 μmol), 0.25 ml of dichloromethane and acetic acid (32 μl, 570 μmol) were added. Sodium triacetoxyborohydride (72 mg, 340 μmol) was then added and the mixture was stirred at room temperature overnight. After the addition of saturated ammonium chloride solution, the reaction mixture was evaporated to dryness. The resulting residue was then taken up in ethyl acetate and washed with a saturated sodium carbonate solution, and the organic phase obtained was subsequently evaporated to dryness. The reaction mixture was then separated into its components directly by preparative HPLC (Method 9). The main component obtained was subsequently purified by column chromatography (silica gel; mobile phase ethyl acetate). This gave 56 mg (100% pure, 0.1 mmol, 46% of theory) of the title compound.

(457) LC-MS (Method 2): R.sub.t=1.95/1.98 min; m/z=545/547 (M+H).sup.+.

(458) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.25 (d, 6H), 1.31-1.42 (m, 1H), 1.44-1.69 (m, 2H), 1.71-1.88 (m, 1.5H), 1.92-2.03 (m, 1H), 2.07-2.18 (m, 0.5H), 2.26-2.44 (m, 1H), 2.52-2.60 (m, 2H), 2.81 (br s, 1H), 2.95 (quin, 1H), 3.67-3.74 (m, 1H), 3.78 (s, 1.5H), 3.82 (s, 1.5H), 4.10-4.23 (m, 2H), 4.53-4.59 (m, 1H), 6.92 (dd, 1H), 7.12 (dd, 1H), 7.36 (br d, 1H), 7.38 (br d, 1H), 7.79 (d, 1H), 7.87 (d, 2H), 8.57 (s, 1H), 9.03 (t, 1H).

(459) Analogously to Example 101, the following compounds were prepared from the starting materials stated in each case:

(460) TABLE-US-00017 Example Name/Structure/Starting materials Analytical data 102 (3-Fluoro-6-methoxypyridin-2-yl)[3-{[2-(4- .sup.1H NMR (500 MHz, DMSO-d.sub.6) isopropylphenyl)imidazo[1,2-a]pyrimidin-3- δ ppm 1.25 (d, 6H), 1.30-1.41 yl]methyl}-3,9-diazabicyclo[4.2.1]nonan-9- (m, 1H), 1.44-2.17 (m, 5H), yl]methanone (Enantiomer 1) 2.33-2.47 (m, 2H), 2.52-2.64 (m, 1H), 2.76-2.86 (m, 1H), 2.95 (dt, 1H), 3.78 (d, 3H), 3.84-3.93 (m, 1H), 4.10-4.23 (m, 2H), 4.52-4.59 (m, 1H), 6.94 (ddd, 1H), 7.12 (ddd, 1 H), 7.37 (dd, 2H), 7.74-7.82 (m, 2H), 7.87 (d, 1H), 8.57 (dd, 1H), 9.03 (ddd, 1H). LC-MS (Method 2): R.sub.t = 1.88 min; MS (ESIpos): m/z = 529 (M + H).sup.+ from 2-[4-(propan-2-yl)phenyl]imidazo[1,2- a]pyrimidine-3-carbaldehyde and [3,9- diazabicyclo[4.2.1]nonan-9-yl](3-fluoro-6- methoxypyridin-2-yl)methanone-hydrogen chloride (1/1) (Enantiomer 1) 103 (3-Fluoro-6-methoxypyridin-2-yl)[3-{[2-(4- .sup.1H NMR (500 MHz, DMSO-d.sub.6) isopropylphenyl)imidazo[1,2-a]pyrimidin-3- δ ppm 1.25 (d, 6H), 1.31-1.40 yl]methyl}-3,9-diazabicyclo[4.2.1]nonan-9- (m, 1H), 1.43-2.19 (m, 5H), yl]methanone (Enantiomer 2) 2.30-2.47 (m, 2H), 2.55-2.64 0 (m, 1H), 2.76-2.86 (m, 1H), 2.95 (dt, 1H), 3.78 (d, 3H), 3.84-3.93 (m, 1H), 4.09-4.23 (m, 2H), 4.52-4.59 (m, 1H), 6.94 (ddd, 1H), 7.12 (ddd, 1 H), 7.37 (dd, 2H), 7.74-7.82 (m, 2H), 7.87 (d, 1H), 8.57 (dd, 1H), 9.03 (ddd, 1H) LC-MS (Method 2): R.sub.t = 1.87 min; MS (ESIpos): m/z = 529 (M + H).sup.+ from 2-[4-(propan-2-yl)phenyl]imidazo[1,2- a]pyrimidine-3-carbaldehyde and [3,9- diazabicyclo[4.2.1]nonan-9-yl](3-fluoro-6- methoxypyridin-2-yl)methanone-hydrogen chloride (1/1) (Enantiomer 2) 104 [3-{[2-(4-Isopropylphenyl)imidazo[1,2- .sup.1H NMR (500 MHz, DMSO-d.sub.6) a]pyrimidin-3-yl]methyl}-3,9- δ ppm 1.25 (dd, 6H), 1.30- diazabicyclo[4.2.1]nonan-9-yl](6-methoxypyridin- 1.42 (m, 1H), 1.45-1.56 (m, 2-yl)methanone (Enantiomer 1) 0.5H), 1.63 (br s, 1H), 1.70- 1.93 (m, 2H), 1.96-2.13 (m, 1.5H), 2.33-2.47 (m, 1H), 2.52-2.68 (m, 2H), 2.70-2.87 (m, 1H), 2.91-2.99 (m, 1H), 3.74 (s, 1.5H), 3.79 (s, 1.5H), 4.08-4.20 (m, 2H), 4.46 (t, 0.5 H), 4.55-4.72 (m, 1.5H), 6.88- 6.92 (m, 1H), 7.07-7.12 (m, 1H), 7.22-7.31 (m, 1H), 7.36 (dd, 2H), 7.77-7.87 (m, 3H), 8.54-8.58 (m, 1H), 9.01 (t, 1 H) LC-MS (Method 2): R.sub.t = 1.89 min; MS (ESIpos): m/z = 511 (M + H).sup.+ from 2-[4-(propan-2-yl)phenyl]imidazo[1,2- a]pyrimidine-3-carbaldehyde and [3,9- diazabicyclo[4.2.1]nonan-9-yl](6-methoxypyridin- 2-yl)methanone-hydrogen chloride (1/1) (Enantiomer 1) 105 [(3-{[2-(4-Isopropylphenyl)imidazo[1,2- .sup.1H NMR (500 MHz, DMSO-d.sub.6) a]pyrimidin-3-yl]methyl}-3,9- δ ppm 1.25 (dd, 6H), 1.30- diazabicyclo[4.2.1]nonan-9-yl](6-methoxypyridin- 1.44 (m, 1H), 1.45-1.54 (m, 2-yl)methanone (Enantiomer 2) 0.5H), 1.58-1.67 (m, 1H), 1.69-1.92 (m, 2H), 1.96-2.11 (m, 1.5H), 2.32-2.44 (m, 1H), 2.52-2.68 (m, 2H), 2.71-2.88 (m, 1H), 2.95 (quind, 1H), 3.74 (s, 1.5H), 3.79 (s, 1.5H), 4.09-4.20 (m, 2H), 4.46 (t, 0.5 H), 4.58-4.67 (m, 1.5H), 6.90 (ddd, 1H), 7.07-7.12 (m, 1H), 7.21-7.32 (m, 1H), 7.36 (dd, 2 H), 7.77-7.87 (m, 3H), 8.55- 8.58 (m, 1H), 9.01 (t, 1H) LC-MS (Method 2): R.sub.t = 1.89 min; MS (ESIpos): m/z = 511 (M + H).sup.+ from 2-[4-(propan-2-yl)phenyl]imidazo[1,2- a]pyrimidine-3-carbaldehyde and [3,9- diazabicyclo[4.2.1]nonan-9-yl](6-methoxypyridin- 2-yl)methanone-hydrogen chloride (1/1) (Enantiomer 2) 106 (3-Chloro-6-methoxypyridin-2-yl)[3-{[2-(4- 1H NMR (500 MHz, DMSO- isopropylphenyl)imidazo[1,2-a]pyrimidin-3- d6) δ ppm 1.25 (d, 6H), 1.30- yl]methyl}-3,9-diazabicyclo[4.2.1]nonan-9- 1.42 (m, 1H), 1.44-1.69 (m, 2 yl]methanone (Enantiomer 2) H), 1.72-1.88 (m, 1.5H), 1.91- 2.03 (m, 1H), 2.07-2.20 (m, 0.5H), 2.27-2.45 (m, 1H), 2.52-2.60 (m, 2H), 2.81 (br s, 1H), 2.95 (quin, 1H), 3.67- 3.74 (m, 1H), 3.78 (s, 1.5H), 3.82 (s, 1.5H), 4.10-4.23 (m, 2 H), 4.53-4.59 (m, 1H), 6.92 (dd, 1H), 7.12 (dd, 1H), 7.36 (br d, 1H), 7.38 (br d, 1H), 7.79 (d, 1H), 7.87 (dt, 2H), 8.57 (s, 1H), 9.03 (ddd, 1H) LC-MS (Method 2): Rt = 1.94/1.98 min; MS (ESIpos): m/z = 545/547 (M + H).sup.+ from 2-[4-(propan-2-yl)phenyl]imidazo[1,2- a]pyrimidine-3-carbaldehyde and (3-chloro-6- methoxypyridin-2-yl)[(3,9- diazabicyclo[4.2.1]nonan-9-yl]methanone- hydrogen chloride (1/1) (Enantiomer 2)

B. ASSESSMENT OF PHARMACOLOGICAL EFFICACY

(461) 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.

(462) 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

(463) 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 [Stühmer, 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 solvent stream of 10 ml/min. The level in the measuring chamber is monitored and regulated by sucking off the solution using a peristaltic pump.

(464) Table 1 below shows the half-maximum inhibition, determined in this test, of the human TASK-1 channel (IC.sub.50) by representative working examples of the invention:

(465) TABLE-US-00018 TABLE 1 Example TASK-1 TASK-3 No. IC.sub.50 [nM] IC.sub.50 [nM] 11 11.4 ± 2.2 4.8 ± 0.4 12 17.6 ± 2.2  13 ± 0.9 13 40.3 ± 3.4 23.5 ± 5.9 14 20.6 ± 3.1 17.3 ± 1.6 15 7.54 ± 1.4 15.5 ± 1.5 93 35.1 ± 3.5 41.8 ± 8.0

(466) From the data in Table 1 it is evident that the human TASK-3 channel is blocked by compounds of the present invention.

(467) B-2. Inhibition of Recombinant TASK-1 and TASK-3 In Vitro

(468) The investigations on the inhibition of the recombinant TASK-1 and TASK-3 channels were conducted using stably transfected CHO cells. The compounds of the invention were tested here with administration of 40 mM of potassium chloride in the presence of a voltage-sensitive dye using 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.

(469) 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):

(470) TABLE-US-00019 TABLE 2 Example TASK-1 TASK-3 No. IC.sub.50 [nM] IC.sub.50 [nM] 11 113 1.1 12 60.5 2.5 13 1000 2.2 14 760 4.5 15 250 7.3 16 1700 65 17 3300 15 18 1600 167 19 13500 580 20 3350 197 21 18000 140 22 27000 370 23 3000 24 24 3100 24 25 1100 11 26 830 6.9 27 150 3 28 280 5.6 29 660 4.4 30 2300 220 31 910 47 32 130 4.1 33 2600 110 34 4100 200 35 24000 500 36 30000 1000 37 30000 1000 38 250 4 39 370 13 40 3300 29 41 2200 160 43 2500 250 45 2900 170 46 16000 1000 47 3100 180 48 12000 430 49 5500 540 50 2500 440 51 1100 110 52 3800 140 53 1300 380 54 780 290 55 4000 1000 56 8500 1000 57 6200 2000 58 2900 920 59 1100 680 60 5200 1000 61 9400 1000 62 8400 1000 63 8400 800 64 7200 1800 65 1400 220 66 180 19 67 3400 370 68 230 31 69 1400 62 70 305 4.7 71 740 31 72 120 5.1 73 99 5 74 5000 200 75 2300 77 76 1400 66 77 3300 270 78 220 5. 3 79 290 11 80 4500 93 81 590 9.2 82 30 1.4 83 410 17 84 350 25 85 6300 370 86 340 28 87 1600 210 88 91 1.6 89 310 19 90 43 2.8 91 290 5.5 92 85 2.5 93 340 12 94 3200 110 95 4900 710 99 290 34 100 370 42 101 400 16 102 170 36 103 1400 200 104 600 31 105 3700 370 106 1300 140

(471) 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.

(472) B-3. Animal Model of Obstructive Sleep Apnoea in the Pig

(473) 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)].

(474) 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).

(475) 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.

(476) 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

(477) The compounds of the invention can be converted to pharmaceutical preparations as follows:

(478) Tablet:

(479) Composition:

(480) 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.

(481) Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm.

(482) Production:

(483) 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.

(484) Suspension for Oral Administration:

(485) Composition:

(486) 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.

(487) 10 ml of oral suspension correspond to a single dose of 100 mg of the compound of the invention.

(488) Production:

(489) 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.

(490) Solution for Oral Administration:

(491) Composition:

(492) 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.

(493) Production:

(494) 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.

(495) i.v. Solution:

(496) 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.

(497) Solution for Nasal Administration:

(498) 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.