Triazolo-azepine derivatives

Abstract

The present invention relates to compounds of formula (I), wherein R is hydrogen or halogen, wherein R may be different if n=2 or 3; n is 1, 2 or 3; (II) is a disubstituted bicyclo[1,1,1]pentane or bicyclo[2,2,2]octane as defined below: (III) or (IV); or to a pharmaceutically active acid addition salt thereof, to a racemic mixture or to its corresponding enantiomer and/or an optical isomer and/or stereoisomer thereof. The compounds may be used for the treatment of Alzheimer's disease, cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis, Dutch-type (HCHWA-D), multi-infarct dementia, dementia pugilistica or Down syndrome. ##STR00001##

Claims

1. A compound of formula I ##STR00053## wherein: R is hydrogen or halogen, wherein R may be different if n=2 or 3; n is 1, 2 or 3; and ##STR00054##  is a disubstituted bicyclo[1,1,1]pentane or bicyclo[2,2,2]octane selected from: ##STR00055## or a pharmaceutically acceptable acid addition salt thereof, or a racemic mixture or its corresponding enantiomer, or stereoisomer thereof.

2. A compound according to claim 1, wherein ##STR00056## or a pharmaceutically acceptable acid addition salt thereof, or a racemic mixture or its corresponding enantiomer, or stereoisomer thereof.

3. A compound of claim 1, wherein ##STR00057## or a pharmaceutically acceptable acid addition salt thereof, or a racemic mixture or its corresponding enantiomer, or stereoisomer thereof.

4. A compound of claim 2, selected from the group consisting of: (9R)-9-(3-chlorophenyl)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine, (9S)-9-(3-chlorophenyl)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine, (9R)-9-(4-fluorophenyl)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine, (9S)-9-(4-fluorophenyl)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine, (9R)-9-(4-chlorophenyl)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine, (9S)-9-(4-chlorophenyl)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine, (9R)-9-(3-chloro-5-fluoro-phenyl)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine, (9S)-9-(3-chloro-5-fluoro-phenyl)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine, (9R)-9-(3,4-difluorophenyl)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine, (9S)-9-(3,4-difluorophenyl)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine, (9R)-9-(2-fluorophenyl)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine, (9S)-9-(2-fluorophenyl)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine, (9R)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-9-(2,3,4-trifluorophenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine, or (9S)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-9-(2,3,4-trifluorophenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine.

5. A compound of claim 3, selected from the group consisting of: (9R)-9-(3-chloro-5-fluoro-phenyl)-N-[4-(4-methylimidazol-1-yl)-1-bicyclo[2.2.2]octanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine, (9S)-9-(3-chloro-5-fluoro-phenyl)-N-[4-(4-methylimidazol-1-yl)-1-bicyclo[2.2.2]octanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine, (9R)-9-(3,4-difluorophenyl)-N-[4-(4-methylimidazol-1-yl)-1-bicyclo[2.2.2]octanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine, (9S)-9-(3,4-difluorophenyl)-N-[4-(4-methylimidazol-1-yl)-1-bicyclo[2.2.2]octanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine, (9R)-9-(2-fluorophenyl)-N-[4-(4-methylimidazol-1-yl)-1-bicyclo[2.2.2]octanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine, (9S)-9-(2-fluorophenyl)-N-[4-(4-methylimidazol-1-yl)-1-bicyclo[2.2.2]octanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine, (9R)-N-[4-(4-methylimidazol-1-yl)-1-bicyclo[2.2.2]octanyl]-9-(2,3,4-trifluorophenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine, or (9S)-N-[4-(4-methylimidazol-1-yl)-1-bicyclo[2.2.2]octanyl]-9-(2,3,4-trifluorophenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine.

6. A pharmaceutical preparation containing one or more compounds of claim 1 and pharmaceutically acceptable excipients.

7. A pharmaceutical preparation containing one or more compounds of claim 4 and pharmaceutically acceptable excipients.

8. A pharmaceutical preparation containing one or more compounds of claim 5 and pharmaceutically acceptable excipients.

9. A method of treating Alzheimer's disease, cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis, Dutch-type (HCHWA-D), multi-infarct dementia, dementia pugilistica or Down syndrome, which method comprises administering to an adult an effective amount of a compound as defined in claim 1.

10. A method of treating Alzheimer's disease, cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis, Dutch-type (HCHWA-D), multi-infarct dementia, dementia pugilistica or Down syndrome, which method comprises administering to an adult an effective amount of a compound as defined in claim 4.

11. A method of treating Alzheimer's disease, cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis, Dutch-type (HCHWA-D), multi-infarct dementia, dementia pugilistica or Down syndrome, which method comprises administering to an adult an effective amount of a compound as defined in claim 5.

12. A process for preparing a compound of formula I of claim 1, which process comprises: a) reacting a compound of formula 7 ##STR00058## with a compound of formula 8 ##STR00059## to form a compound of formula I and, optionally, converting the compound into a pharmaceutically acceptable acid addition salt; or b) Cyclizing a compound of formula 14 ##STR00060## in the presence of KI and K.sub.2CO.sub.3 to form a compound of formula I and, optionally, converting the compound into a pharmaceutically acceptable acid addition salt.

13. A compound prepared by the process of claim 12.

Description

EXPERIMENTAL PART

(1) The following examples are provided for illustration of the invention. They should not be considered as limiting the scope of the invention, but merely as being representative thereof.

(2) General

(3) Analytical Methods

(4) HPLC (method LCMS_fastgradient)

(5) Column: Agilent Zorbax Eclipse Plus C18, Rapid Resolution HT, 2.1×30 mm, 1.8 m, Part. no. 959731-902

(6) Solvent A: Water 0.01% Formic Acid; Solvent B: acetonitrile (MeCN)

(7) Gradients:

(8) TABLE-US-00004 Time [min] Flow Rate [ml/min] % A % B Initial 0.8 97 3 0.2 1.0 97 3 1.7 1.0 3 97 2.0 1.0 3 97 2.1 1.0 97 3

Abbreviations

(9) The following abbreviations were used in the experimental part:

(10) THF=tetrahydrofuran;

(11) MTBE=methyl-tert-butylether;

(12) DMF=dimethylformamide;

(13) TLC=thin layer chromatography;

(14) rt=room temperature, 20-25° C.

General Synthesis of Intermediates 12

(15) ##STR00016##

(16) Intermediates 12 were readily prepared upon alkylation of commercially available acids 15 with 1-chloro-4-iodo-butane in the presence of a base (e.g. NaHMDS) at low temperature.

Intermediates of Type 7

(17) Intermediate 7-1

2-bromo-9-(2,3,4-trifluorophenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepine

(18) ##STR00017##

Step 1: methyl 6-tetrahydropyran-2-yloxy-2-(2,3,4-trifluorophenyl)hexanoate

(19) ##STR00018##

(20) To a stirred solution of methyl 2-(2,3,4-trifluorophenyl)acetate (5.10 g, 25 mmol) in DMF (40 ml) at 0° C. was added NaH (60%, 1.10 g, 27.5 mmol). The reaction mixture was stirred for 1 hour and then canuulated dropwise into a solution of 2-(4-bromobutoxy)tetrahydropyran (5.92 g, 25 mmol) in DMF (40 mL) also at 0° C. The reaction was further stirred at RT for one hour and poured onto an aqueous saturated solution of NH.sub.4Cl. The product was extracted with EtOAc, and the combined organic phase was dried over Na.sub.2SO.sub.4 and concentrated under vacuo. A column chromatography (SiO.sub.2, Heptane/EtOAc) gave 6.07 g (67%) of methyl 6-tetrahydropyran-2-yloxy-2-(2,3,4-trifluorophenyl)hexanoate as a light yellow oil.

Step 2: 6-tetrahydropyran-2-yloxy-2-(2,3,4-trifluorophenyl)hexanehydrazide

(21) ##STR00019##

(22) To a stirred solution of methyl 6-tetrahydropyran-2-yloxy-2-(2,3,4-trifluorophenyl)hexanoate (6.07 g, 16.8 mmol) in MeOH (56 mL) was added hydrazine hydrate (14.1 mL, 219 mmol). The reaction mixture was stirred at 80° C. for 17 hours and concentrated under vacuo. The residue was diluted with water and the product extracted with EtOAc. The combined organic phase was dried over Na.sub.2SO.sub.4 and concentrated under vacuo to give 6.10 g (99%) of 6-tetrahydropyran-2-yloxy-2-(2,3,4-trifluorophenyl)hexanehydrazide as a colorless oil. MS (ES+) m/z: 361.2 [(M+H).sup.+].

Step 3:5-[5-tetrahydropyran-2-yloxy-1-(2,3,4-trifluorophenyl)pentyl]-4H-1,2,4-triazol-3-amine

(23) ##STR00020##

(24) In a sealed reactor, 6-tetrahydropyran-2-yloxy-2-(2,3,4-trifluorophenyl)hexanehydrazide (6.10 g, 16.9 mmol) was dissolved in 2-propanol (44 mL). Et.sub.3N (5.1 mL, 50.8 mmol) and 2-methyl-2-thiopseudourea sulfate (2.36 g, 8.46 mmol) were added and the reaction mixture was heated at 130° C. over night. The reaction mixture was then cooled to RT, concentrated under vacuo and the residue diluted with CH.sub.2Cl.sub.2 and then washed with brine. The organic phase was dried over Na.sub.2SO.sub.4, concentrated under vacuo. A column chromatography (SiO.sub.2, CH.sub.2Cl.sub.2/MeOH) gave (4.2 g, 65%) of 5-[5-tetrahydropyran-2-yloxy-1-(2,3,4-trifluorophenyl)pentyl]-4H-1,2,4-triazol-3-amine as a white foam. MS (ES+) m/z: 385.2 [(M+H).sup.+].

Step 4:5-(5-bromo-4H-1,2,4-triazol-3-yl)-5-(2,3,4-trifluorophenyl)pentan-1-ol

(25) ##STR00021##

(26) To a black solution of tert-butyl nitrite (1.88 g, 2.17 mL, 16.4 mmol) and cupric bromide (3.66 g, 16.4 mmol) in CH.sub.3CN (35 mL) at 60° C. was added portion wise 5-[5-tetrahydropyran-2-yloxy-1-(2,3,4-trifluorophenyl)pentyl]-4H-1,2,4-triazol-3-amine (4.20 g, 10.9 mmol). The reaction mixture was then heated at 75° C. for one hour and cooled down to RT. HCl 2N (3 mL) was added and stirring was continued 30 minutes. The reaction mixture was concentrated under vacuo, and the residue diluted with EtOAc and washed with water. The organic phase was dried over Na.sub.2SO.sub.4, concentrated under vacuo. A column chromatography (SiO.sub.2, Heptane/EtOAc) gave 2.15 g (54%) of 5-(5-bromo-4H-1,2,4-triazol-3-yl)-5-(2,3,4-trifluorophenyl)pentan-1-ol as a yellow foam. MS (ES+) m/z: 364.1 [(M+H).sup.+].

Step 5:2-bromo-9-(2,3,4-trifluorophenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepine

(27) ##STR00022##

(28) To a solution of 5-(5-bromo-4H-1,2,4-triazol-3-yl)-5-(2,3,4-trifluorophenyl)pentan-1-ol (2.09 g, 5.74 mmol) and triphenylphosphine (2.26 g, 8.61 mmol) in THF (64 mL) at −10° C. was added DEAD (1.36 mL, 8.61 mmol). The reaction mixture was further stirred for 30 minutes at this temperature and then poured into water. The product was extracted with EtOAc and the combined organic phase was dried over Na.sub.2SO.sub.4 and concentrated under vacuo. A column chromatography (SiO.sub.2, Heptane/EtOAc) gave 0.56 g (28%) of 2-bromo-9-(2,3,4-trifluorophenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepine (7.1) as white solid. MS (ES+) m/z: 347.1 [(M+H).sup.+].

(29) Intermediate 7-2

2-bromo-9-(3-chloro-5-fluoro-phenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepine

(30) ##STR00023##

(31) In analogy to the preparation of the intermediate 7.1, starting from methyl 2-(3-chloro-5-fluoro-phenyl)acetate was prepared the intermediate 2-bromo-9-(3-chloro-5-fluoro-phenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepine (7.2) as a white solid. MS (ES+) m/z: 344.1/346.1 [(M+H).sup.+].

(32) Intermediate 7-3

2-bromo-9-(3,4-difluorophenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepine

(33) ##STR00024##

(34) In analogy to the preparation of the intermediate 7.1, starting from methyl 2-(3,4-difluorophenyl)acetate was prepared the intermediate 2-bromo-9-(3,4-difluorophenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepine (7.3) as a white solid. MS (ES+) m/z: 346.2/348.2 [(M+H).sup.+].

(35) Intermediate 7-4

2-bromo-9-(2-fluorophenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepine

(36) ##STR00025##

(37) In analogy to the preparation of the intermediate 7.1, starting from methyl 2-(2-fluorophenyl)acetate was prepared the intermediate 2-bromo-9-(2-fluorophenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepine (7.4) as a white solid. MS (ES+) m/z: 310.2/312.2 [(M+H).sup.+].

Intermediates of Type 8

(38) Intermediate 8-1

3-(4-methylimidazol-1-yl)bicyclo[1.1.1]pentan-1-amine

(39) ##STR00026##

Step 1: tert-butyl N-[3-(acetonylamino)-1-bicyclo[1.1.1]pentanyl]carbamate

(40) Potassium iodide (0.15 g, 0.92 mmol) and cesium carbonate (1.50 g, 4.61 mmol) were added to tert-butyl N-(3-amino-1-bicyclo[1.1.1]pentanyl)carbamate (0.96 g, 4.61 mmol) in solution in DMF (20 mL). The mixture was cooled to 0° C. and 1-chloropropan-2-one (0.49 g, 5.07 mmol) in solution in DMF (5 mL) was added. Stirring was continued overnight while the temperature was raising to RT. The mixture was filtered, and concentrated under vacuo. Column chromatography (1% to 10% MeOH in TBME) gave the title compound (0.68 g, 58%) as a light brown foam. MS (ES+) m/z 255.2 [M+H].

Step 2: tert-butyl N-[3-[acetonyl(formyl)amino]-1-bicyclo[1.1.1]pentanyl]carbamate

(41) Acetic anhydride (1.01 g, 0.93 mL, 9.88 mmol) was added to formic acid (1.79 g, 1.50 mL, 39 mmol) and stirred for 1 hour. A solution of tert-butyl N-[3-(acetonylamino)-1-bicyclo[1.1.1]pentanyl]carbamate (0.66 g, 2.60 mmol) in THF (12 mL) was added. The resulting dark solution was stirred for 30 minutes and then poured into H.sub.2O (30 mL). EtOAc (50 mL) was added and the biphase mixture was stirred and the pH adjusted to 8-9 by addition of NaHCO.sub.3 in small portions. The organic phase was then separated, dried over Na.sub.2SO.sub.4 and concentrated under vacuo. A column chromatography (30% to 100% EtOAc in Heptane) gave the title compound (0.33 g, 45%) as a brown foam. MS (ES+) m/z 283.1 [M+H].

Step 3: tert-butyl N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]carbamate

(42) To a solution of tert-butyl N-[3-[acetonyl(formyl)amino]-1-bicyclo[1.1.1]pentanyl]carbamate (0.33 g, 1.17 mmol) in acetic acid (4 mL) was added ammonium acetate (0.45 g, 5.84 mmol). The reaction mixture was heated at 100° C. for 10 hours before a second portion of ammonium acetate (0.45 g, 5.84 mmol) was added and stirring continued for an other 4 hours. The volatiles were removed under vacuo, and a column chromatography (3% to 50% 2N NH/MeOH in TBME) gave the title product (0.096 g, 31%) as an off-white solid which was used directly in the next step.

Step 4: 3-(4-methylimidazol-1-yl)bicyclo[1.1.1]pentan-1-amine

(43) To a solution of tert-butyl N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]carbamate (0.096 g, 0.365 mmol) in CH.sub.2Cl.sub.2 (2 mL) was added TFA (0.88 g, 0.60 mL, 7.78 mmol) and the mixture stirred overnight at RT. The volatiles were removed under vacuo, the residue redissolved in MeOH (2 mL) and an aqueous solution of NH.sub.4OH (25%, 0.5 mL) followed by diatomaceous earth material isolute HM-N (3 g) were added. The mixture was concentrated and a column chromatography (2% to 15% of 2N NH.sub.3/MeOH in CH.sub.2Cl.sub.2) gave the title product (0.032 g, 16%) as a viscous colorless oil. MS (ES+) m/z 164.1 [M+H].

(44) Intermediate 8-2

4-(4-methylimidazol-1-yl)bicyclo[2.2.2]octan-1-amine. hydrochloride

(45) ##STR00027##

Step 1: tert-butyl N-[4-(acetonylamino)-1-bicyclo[2.2.2]octanyl]carbamate

(46) Potassium iodide (0.13 g, 0.78 mmol) and cesium carbonate (3.82 g, 11.7 mmol) were added to tert-butyl N-(4-amino-1-bicyclo[2.2.2]octanyl)carbamate (0.94 g, 3.91 mmol) in solution in DMF (6 mL). The mixture was cooled to 0° C. and 1-chloropropan-2-one (0.90 g, 9.78 mmol) in solution in DMF (5 mL) was added. Stirring was continued for 2 hours at 40° C. The mixture was filtered, and concentrated under vacuo. Column chromatography (0% to 7% 2N NH.sub.3/MeOH in CH.sub.2Cl.sub.2) gave the title compound (0.32 g, 27%) as a light orange solid. MS (ES+) m/z 297.2 [M+H].

Step 2: tert-butyl N-[4-[acetonyl(formyl)amino]-1-bicyclo[2.2.2]octanyl]carbamate

(47) Acetic anhydride (0.42 g, 0.39 mL, 4.1 mmol) was added to formic acid (0.74 g, 0.63 mL, 16.2 mmol) and stirred for 1 hour. A solution of tert-butyl N-[4-(acetonylamino)-1-bicyclo[2.2.2]octanyl]carbamate (0.32 g, 1.08 mmol) in THF (8 mL) was added. The resulting dark solution was stirred for 30 minutes and then poured into H.sub.2O (30 mL). EtOAc (50 mL) was added and the biphase mixture was stirred and the pH adjusted to 8-9 by addition of NaHCO.sub.3 in small portions. The organic phase was then separated, dried over Na.sub.2SO.sub.4 and concentrated under vacuo. A column chromatography (30% to 100% EtOAc in Heptane) gave the title compound (0.29 g, 82%) as a brown foam. MS (ES+) m/z 325.2 [M+H].

Step 3: tert-butyl N-[4-(4-methylimidazol-1-yl)-1-bicyclo[2.2.2]octanyl]carbamate

(48) To a solution of tert-butyl N-[4-[acetonyl(formyl)amino]-1-bicyclo[2.2.2]octanyl]carbamate (0.29 g, 0.89 mmol) in acetic acid (4 mL) was added ammonium acetate (0.34 g, 4.47 mmol). The reaction mixture was heated at 100° C. overnight and a second portion of ammonium acetate (0.14 g, 1.82 mmol) was added and stirring continued for an other 14 hours. The volatiles were removed under vacuo, and a column chromatography (0% to 10% 2N NH.sub.3/MeOH in TBME) gave the title product (0.072 g, 26%) as an off-white solid. MS (ES+) m/z 306.2 [M+H].

Step 4: 4-(4-methylimidazol-1-yl)bicyclo[2.2.2]octan-1-amine. hydrochloride

(49) To a suspension of tert-butyl N-[4-(4-methylimidazol-1-yl)-1-bicyclo[2.2.2]octanyl]carbamate (0.072 g, 0.237 mmol) in acetone (4 mL) was added aqeuous HCl (0.20 mL, 2.13 mmol) resulting in a pale yellow solution. The mixture was stirred an additional 5 hours and the solid was collected and dried under vacuo to give the title product (0.054 g, 95%) as a white solid. MS (ES+) m/z 206.2 [M+H].

Intermediates of Type 12

(50) Intermediate 12-1

6-chloro-2-(2,3,4-trifluorophenyl)hexanoic acid

(51) ##STR00028##

(52) To a solution of 2-(2,3,4-trifluorophenyl)acetic acid (2 mmol) in toluene (3 mL) at −45° C. was added NaHMDS 1M in THF (4.2 mmol). The reaction was stirred at this temperature for 1 hour before being cannulated into a solution of 1-chloro-4-iodobutane (2.2 mmol) in toluene also at −45° C. The resulting reaction mixture was then warmed to RT slowly over one hour and stirred an other 30 minutes. HCl 2M was added until pH=1, and the product was extracted with EtOAc. The organic phase was dried over Na.sub.2SO.sub.4, filtered and concentrated under vacuo. Column chromatography (SiO.sub.2, CH.sub.2Cl.sub.2/MeOH) afforded the title product (29%) as a colorless oil. MS (ES+) m/z: 279.2 [(M−H).sup.+].

(53) Intermediate 12-2

6-chloro-2-(3-chlorophenyl)hexanoic Acid

(54) ##STR00029##

(55) With a similar method as for the preparation of intermediate 12-1, from 2-(3-chlorophenyl)acetic acid was prepared the title compound as a solid. MS (ES+) m/z: 259.3 [(M−H).sup.+].

(56) Intermediate 12-3

6-chloro-2-(4-chlorophenyl)hexanoic Acid

(57) ##STR00030##

(58) With a similar method as for the preparation of intermediate 12-1, from 2-(4-chlorophenyl)acetic acid was prepared the title compound as a solid. MS (ES+) m/z: 259.2 [(M−H).sup.+].

(59) Intermediate 12-4

6-chloro-2-(4-fluorophenyl)hexanoic Acid

(60) ##STR00031##

(61) With a similar method as for the preparation of intermediate 12-1, from 2-(4-fluorophenyl)acetic acid was prepared the title compound as a light yellow oil. MS (ES+) m/z: 243.1 [(M−H).sup.+].

(62) Intermediate 12-5

6-chloro-2-(3,4-difluorophenyl)hexanoic Acid

(63) ##STR00032##

(64) With a similar method as for the preparation of intermediate 12-1, from 2-(3,4-difluorophenyl)acetic acid was prepared the title compound as a light yellow oil. MS (ES+) m/z: 261.3 [(M−H).sup.+].

(65) Intermediate 12-6

6-chloro-2-(3-chloro-5-fluoro-phenyl)hexanoic Acid

(66) ##STR00033##

(67) With a similar method as for the preparation of intermediate 12-1, from 2-(3-chloro-5-fluoro-phenyl)acetic acid was prepared the title compound as a light yellow oil. MS (ES+) m/z: 277.3 [(M−H).sup.+].

(68) Intermediate 12-7

6-chloro-2-(2-fluorophenyl)hexanoic acid

(69) ##STR00034##

(70) With a similar method as for the preparation of intermediate 12-1, from 2-(2-fluorophenyl)acetic acid was prepared the title compound as a light yellow oil. MS (ES+) m/z: 243.2 [(M−H).sup.+].

(71) General Procedure: Buchwald Coupling Reaction

(72) To a solution of an intermediate 7, in 1,4-dioxane was added 1.1 equivalent of an intermediate 8. The reaction mixture was degased and a palladium catalyst [either dibromo-bis-(tritert.-butyl)-phosphine-palladium (0.1 eq. CAS185812-86-6) or tri(dibenzylidenacetonne) dipalladium(0) CAS51364-51-3 in the presence of 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl CAS564483-19-8] and NaOtBu (2.1 eq.) were added. The reaction mixture was heated at 100° C. until completion of the reaction (usually between 2 and 8 hours) and concentrated under vacuo. A purification was done either by column chromatography or reverse phase preparative HPLC to afford the desired product.

Example 1 and 2

(9R)-9-(3-chlorophenyl)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine and (9S)-9-(3-chlorophenyl)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine

(73) ##STR00035##

Step 1: 1-(3-isothiocyanato-1-bicyclo[1.1.1]pentanyl)-4-methyl-imidazole

(74) ##STR00036##

(75) To a solution of 3-(4-methylimidazol-1-yl)bicyclo[1.1.1]pentan-1-amine (intermediate 8-1) (1.08 g, 6.62 mmol) in CH.sub.2Cl.sub.2 (30 mL) was added 1-(2-oxopyridine-1-carbothioyl)pyridin-2-one (1.74 g, 7.28 mmol) and NEt(iPr).sub.2 (1.16 mL, 6.62 mmol). The reaction mixture was stirred at RT over night, concentrated under vacuo and the crude residue was used directly in the next step without further purification.

Step 2: [3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]thiourea

(76) ##STR00037##

(77) To a solution of ammonia 7N in MeOH (20.3 mL, 142 mmol) was added 1-(3-isothiocyanato-1-bicyclo[1.1.1]pentanyl)-4-methyl-imidazole (crude product from step 1) in solution in MeOH (5 mL). The reaction mixture was stirred at RT for two hours. The reaction mixture was concentrated under vacuo and the residue purified by column chromatography (2M NH3/MeOH in CH.sub.2Cl.sub.2; gradient: 2.5-10%) to afford 1.22 g (81% over two steps) of [3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]thiourea as a very light brown solid. MS (ES+) m/z: 223.2 [(M+H).sup.+].

Step 3:2-methyl-3-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]isothiourea hydroiodide

(78) ##STR00038##

(79) In a sealed tube, to a solution of [3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]thiourea (1.22 g, 5.49 mmol) in EtOH (15 mL) was added MeI (0.41 mL, 6.59 mmol). The reaction mixture was stirred for 48 hours. The reaction mixture was concentrated under vacuo and the resulting solid was triturated in Et.sub.2O, the product collected by filtration and dried under vacuo to afford 2.0 g (98%) of 2-methyl-3-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]isothiourea hydroiodide as a white solid. MS (ES+) m/z: 237.2 [(M+H).sup.+].

Step 4: 6-chloro-2-(3-chlorophenyl)-N-[(Z)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-C-methylsulfanyl-carbonimidoyl]hexanamide

(80) ##STR00039##

(81) To a solution of 2-methyl-3-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]isothiourea hydroiodide (453 mg, 1.24 mmol) in DMF (15 mL) was added 6-chloro-2-(3-chlorophenyl) hexanoic acid (intermediate 12-2, 325 mg, 1.24 mmol), HOBt (572 mg, 3.73 mmol), EDC.HCl (716 mg, 3.73 mmol) and NEt(iPr).sub.2 (1.74 mL, 9.96 mmol). The reaction mixture was stirred at RT for five hours and then poured into water. The product was extracted with EtOAc three times, and the combined organic phase was dried over Na.sub.2SO.sub.4, and concentrated under vacuo. The crude product 6-chloro-2-(3-chlorophenyl)-N-[(Z)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-C-methylsulfanyl-carbonimidoyl]hexanamide (light yellow viscous oil) was used directly in the next step without further purification.

Step 5: 5-[5-chloro-1-(3-chlorophenyl)pentyl]-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-4H-1,2,4-triazol-3-amine

(82) ##STR00040##

(83) To a solution of 6-chloro-2-(3-chlorophenyl)-N-[(Z)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-C-methylsulfanyl-carbonimidoyl]hexanamide (crude product from step 4) in THF (15 mL) was added hydrazine monohydrate (312 mg, 6.2 mmol). The reaction mixture was stirred at reflux for four hours and concentrated under vacuo. The residue was taken up in EtOAc and washed with water. The organic phase was dried over Na.sub.2SO.sub.4, concentrated and dried under vacuo to afford 5-[5-chloro-1-(3-chlorophenyl)pentyl]-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-4H-1,2,4-triazol-3-amine as a yellow viscous oil. The crude was used directly in the next last step without further purification.

Step 6:9-(3-chlorophenyl)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine

(84) ##STR00041##

(85) To a solution of 5-[5-chloro-1-(3-chlorophenyl)pentyl]-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-4H-1,2,4-triazol-3-amine (crude product from step 5) in DMF (15 mL) was added K.sub.2CO.sub.3 (516 mg, 3.73 mmol) and KI (310 mg, 1.87 mmol). The reaction mixture was heated at 85° C. for 4 hours and concentrated under vacuo. A column chromatography (SiO.sub.2, CH.sub.2Cl.sub.2/MeOH) gave 96 mg (18% over the last three steps) of 9-(3-chlorophenyl)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine as a white solid. MS (ES+) m/z: 409.3 [(M+H).sup.+].

Step 7: (9R)-9-(3-chlorophenyl)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine and (9S)-9-(3-chlorophenyl)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine

(86) ##STR00042##

(87) 90 mg (0.22 mmol) of the racemic 9-(3-chlorophenyl)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine was used for chiral HPLC resolution providing 30 mg of (9R)-9-(3-chlorophenyl)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine as a white solid (MS (ES+) m/z: 409.3 [(M+H).sup.+]) and 31 mg of (9S)-9-(3-chlorophenyl)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine as a white solid; MS (ES+) m/z: 409.3 [(M+H).sup.+].

Example 3 and 4

(9R)-9-(4-fluorophenyl)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine and (9S)-9-(4-fluorophenyl)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine

(88) ##STR00043##

(89) In analogy to the preparation of compounds described example 1 and 2, using the intermediate 12-4 in the step 4, was prepared 29 mg of (9R)-9-(4-fluorophenyl)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine as a white solid (MS (ES+) m/z: 393.3 [(M+H).sup.+]) and 29 mg of (9S)-9-(4-fluorophenyl)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine as a white solid; MS (ES+) m/z: 393.3 [(M+H).sup.+].

Example 5 and 6

(9R)-9-(4-chlorophenyl)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine and (9S)-9-(4-chlorophenyl)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine

(90) ##STR00044##

(91) In analogy to the preparation of compounds described example 1 and 2, using the intermediate 12-3 in the step 4, was prepared 35 mg of (9R)-9-(4-chlorophenyl)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine as a white solid (MS (ES+) m/z: 409.3 [(M+H).sup.+]) and 34 mg of (9S)-9-(4-chlorophenyl)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine as a white solid; MS (ES+) m/z: 409.3 [(M+H).sup.+].

Example 7 and 8

(9R)-9-(3-chloro-5-fluoro-phenyl)-N-[4-(4-methylimidazol-1-yl)-1-bicyclo[2.2.2]octanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine and (9S)-9-(3-chloro-5-fluoro-phenyl)-N-[4-(4-methylimidazol-1-yl)-1-bicyclo[2.2.2]octanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine

(92) ##STR00045##

(93) Using the general procedure of the Buchwald coupling between the intermediate (7.2) 2-bromo-9-(3-chloro-5-fluoro-phenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepine and the intermediate (8-2) 4-(4-methylimidazol-1-yl)bicyclo[2.2.2]octan-1-amine hydrochloride following a chiral HPLC separation of the enantiomeres was prepared 13 mg of (9R)-9-(3-chloro-5-fluoro-phenyl)-N-[4-(4-methylimidazol-1-yl)-1-bicyclo[2.2.2]octanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine as a white solid (MS (ES+) m/z: 469.4 [(M+H).sup.+]) and 13 mg of (9S)-9-(3-chloro-5-fluoro-phenyl)-N-[4-(4-methylimidazol-1-yl)-1-bicyclo[2.2.2]octanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine as a white solid (MS (ES+) m/z: 469.4 [(M+H).sup.+]).

Example 9 and 10

(9R)-9-(3-chloro-5-fluoro-phenyl)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine and (9S)-9-(3-chloro-5-fluoro-phenyl)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine

(94) ##STR00046##

(95) In analogy to the preparation of compounds described example 1 and 2, using the intermediate 12-6 in the step 4, was prepared 20 mg of (9R)-9-(3-chloro-5-fluoro-phenyl)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine as a white solid (MS (ES+) m/z: 427.3 [(M+H).sup.+]) and 20 mg of (9S)-9-(3-chloro-5-fluoro-phenyl)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[0.1.1.1]pentanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine as a white solid; MS (ES+) m/z: 427.3 [(M+H).sup.+].

Example 11 and 12

(9R)-9-(3,4-difluorophenyl)-N-[4-(4-methylimidazol-1-yl)-1-bicyclo[2.2.2]octanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine and (9S)-9-(3,4-difluorophenyl)-N-[4-(4-methylimidazol-1-yl)-1-bicyclo[2.2.2]octanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine

(96) ##STR00047##

(97) Using the general procedure of the Buchwald coupling between the intermediate (7.3) 2-bromo-9-(3,4-difluorophenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepine and the intermediate (8-2) 4-(4-methylimidazol-1-yl)bicyclo[2.2.2]octan-1-amine hydrochloride following a chiral HPLC separation of the enantiomers was prepared 63 mg of (9R)-9-(3,4-difluorophenyl)-N-[4-(4-methylimidazol-1-yl)-1-bicyclo[2.2.2]octanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine as a white solid (MS (ES+) m/z: 453.4 [(M+H).sup.+]) and 63 mg of (9S)-9-(3,4-difluorophenyl)-N-[4-(4-methylimidazol-1-yl)-1-bicyclo[2.2.2]octanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine as a white solid (MS (ES+) m/z: 453.4 [(M+H).sup.+]).

Example 13 and 14

(9R)-9-(3,4-difluorophenyl)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine and (9S)-9-(3,4-difluorophenyl)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine

(98) ##STR00048##

(99) In analogy to the preparation of compounds described example 1 and 2, using the intermediate 12-5 in the step 4, was prepared 11 mg of (9R)-9-(3,4-difluorophenyl)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine as a white solid (MS (ES+) m/z: 411.3 [(M+H).sup.+]) and 11 mg of (9S)-9-(3,4-difluorophenyl)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine as a white solid; MS (ES+) m/z: 411.3 [(M+H).sup.+].

Example 15 and 16

(9R)-9-(2-fluorophenyl)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine and (9S)-9-(2-fluorophenyl)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine

(100) ##STR00049##

(101) In analogy to the preparation of compounds described example 1 and 2, using the intermediate 12-7 in the step 4, was prepared 15 mg of (9R)-9-(2-fluorophenyl)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine as a white solid (MS (ES+) m/z: 393.2 [(M+H).sup.+]) and 15 mg of (9S)-9-(2-fluorophenyl)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine as a white solid; MS (ES+) m/z: 393.2 [(M+H).sup.+].

Example 17 and 18

(9R)-9-(2-fluorophenyl)-N-[4-(4-methylimidazol-1-yl)-1-bicyclo[2.2.2]octanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine and (9S)-9-(2-fluorophenyl)-N-[4-(4-methylimidazol-1-yl)-1-bicyclo[2.2.2]octanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine

(102) ##STR00050##

(103) Using the general procedure of the Buchwald coupling between the intermediate (7.4) 2-bromo-9-(2-fluorophenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepine and the intermediate (8-2) 4-(4-methylimidazol-1-yl)bicyclo[2.2.2]octan-1-amine hydrochloride following a chiral HPLC separation of the enantiomers was prepared 19 mg of (9R)-9-(2-fluorophenyl)-N-[4-(4-methylimidazol-1-yl)-1-bicyclo[2.2.2]octanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine as a white solid (MS (ES+) m/z: 435.4 [(M+H).sup.+]) and 19 mg of (9S)-9-(2-fluorophenyl)-N-[4-(4-methylimidazol-1-yl)-1-bicyclo[2.2.2]octanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine as a white solid (MS (ES+) m/z: 435.4 [(M+H).sup.+]).

Example 19 and 20

(9R)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-9-(2,3,4-trifluorophenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine and (9S)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-9-(2,3,4-trifluorophenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine

(104) ##STR00051##

(105) In analogy to the preparation of compounds described example 1 and 2, using the intermediate 12-1 in the step 4, was prepared 19 mg of (9R)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-9-(2,3,4-trifluorophenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine as a white solid (MS (ES+) m/z: 429.2 [(M+H).sup.+]) and 19 mg of (9S)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-9-(2,3,4-trifluorophenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine as a white solid; MS (ES+) m/z: 429.2 [(M+H).sup.+].

Example 21 and 22

(9R)-N-[4-(4-methylimidazol-1-yl)-1-bicyclo[2.2.2]octanyl]-9-(2,3,4-trifluorophenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine and (9S)-N-[4-(4-methylimidazol-1-yl)-1-bicyclo[2.2.2]octanyl]-9-(2,3,4-trifluorophenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine

(106) ##STR00052##

(107) Using the general procedure of the Buchwald coupling between the intermediate (7.1) 2-bromo-9-(2,3,4-trifluorophenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepine and the intermediate (8-2) 4-(4-methylimidazol-1-yl)bicyclo[2.2.2]octan-1-amine hydrochloride following a chiral HPLC separation of the enantiomers was prepared 35 mg of (9R)-N-[4-(4-methylimidazol-1-yl)-1-bicyclo[2.2.2]octanyl]-9-(2,3,4-trifluorophenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine as a white solid (MS (ES+) m/z: 471.5 [(M+H).sup.+]) and 35 mg of (9S)-N-[4-(4-methylimidazol-1-yl)-1-bicyclo[2.2.2]octanyl]-9-(2,3,4-trifluorophenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine as a white solid (MS (ES+) m/z: 471.5 [(M+H).sup.+]).