1,4-disubstituted 1,2,3-triazoles, methods for preparing same, and diagnostic and therapeutic uses thereof

Abstract

A compound having the following general formula (I): ##STR00001##
wherein: X is a nitrogen atom and Y is a carbon atom; or X is a carbon atom and Y is a nitrogen atom; the Ar group is an aryl or heteroaryl group; and the RN and RN groups, together with the carbon atoms to which they are bound, form a monocyclic or bicyclic azacycloalkane group. The pharmaceutically acceptable salts thereof, the hydrates or polymorphic crystalline structures thereof, and to the racemates, diastereoisomers, or enantiomers thereof are also described.

Claims

1. A compound having the general formula (I) as follows: ##STR00159## wherein: X represents C and Y represents N; or X represents N and Y represents C; the Ar group is selected from among aryl groups comprising from 6 to 30 carbon atoms, optionally substituted by one or more groups selected from the group consisting of: halogen atoms, a OH group, linear or branched alkyl and alkoxy groups comprising from 1 to 10 carbon atoms, possibly substituted, and aryl groups comprising from 6 to 30 carbon atoms, optionally substituted by at least one CH.sub.2OH group, and heteroaryl groups comprising from 1 to 30 carbon atoms, optionally substituted by at least one substituent selected from the group consisting of: a halogen atom, C(O)H, CH.sub.2OH and NO.sub.2, the R.sub.N and R.sub.N groups, together with the carbon atoms to which they are bound, form a monocyclic or bicyclic azacycloalkane group comprising at least one trisubstituted endocyclic nitrogen atom, optionally in quaternary ammonium form, selected from the group consisting of: ##STR00160## said azacycloalkane group being optionally substituted by one or more groups selected from the group consisting of: halogen atoms, OH group, and linear or branched alkyl and alkoxy groups comprising from 1 to 10 carbon atoms, optionally substituted, R.sub.1 is a group selected from the group consisting of: halogen atoms, aryl groups comprising from 6 to 30 carbon atoms and heteroaryl groups comprising from 1 to 30 carbon atoms, optionally substituted, R, OR or SiRRR, R, R and R groups being independently selected from the group consisting of a hydrogen atom and linear or branched alkyl groups comprising from 1 to 10 carbon atoms, optionally substituted, NR.sub.aR.sub.b, R.sub.a and R.sub.b groups being independently selected from the group consisting of hydrogen atom and alkyl and acyl groups comprising from 1 to 10 carbon atoms, optionally substituted, and NHR.sub.c and R.sub.c groups being selected from among aryl groups comprising from 6 to 30 carbon atoms and the heteroaryl groups comprising from 1 to 30 carbon atoms; and R.sub.2 is selected from the group consisting of: H when X is N, halogen atoms, R, OR, C(O)Oalkyl, OC(O)R, OC(O)NHR, O(SO.sub.2)R and O(SO.sub.2)NHR groups, wherein R is as defined here above; and pharmaceutically acceptable salts thereof, hydrates or polymorphic crystalline structures, racemates, diastereoisomers or enantiomers thereof, wherein the following compounds are excluded: 3-(1-(2,3-difluorophenyl)-1H-tetrazol-5-yl)-5-(1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine; and 3-(1-(2,3-difluorophenyl)-1H-tetrazol-5-yl)-5-(1-(quinuclidin-3-yl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine.

2. The compound according to claim 1, wherein the R.sub.N and R.sub.N groups, together with the carbon atoms to which they are bound, form a group selected from the group consisting of tropane, quinuclidine and octahydro-quinolizine groups.

3. The compound according to claim 1, having the general formula (II) as follows: ##STR00161## wherein: the Ar group is selected from the group consisting of phenyl and naphthalenyl groups, optionally substituted by one or more substituents selected from the group consisting of: halogen atoms, a OH group, linear or branched alkyl and alkoxy groups comprising from 1 to 10 carbon atoms, optionally substituted, and aryl groups comprising from 6 to 30 carbon atoms, optionally substituted by at least one CH.sub.2OH group, and heteroaryl groups comprising from 1 to 30 carbon atoms, optionally substituted by at least one substituent selected from the group consisting of: a halogen atom, C(O)H, CH.sub.2OH and NO.sub.2; the R.sub.N and R.sub.N groups, together with the carbon atoms to which they are bound, form a group selected from the group consisting of tropane, quinuclidine and octahydro-quinolizine groups; R.sub.1 is selected from the group consisting of: a hydrogen atom, halogen atoms, aryl groups comprising from 6 to 30 carbon atoms and heteroaryl groups comprising from 1 to 30 carbon atoms, optionally substituted, NR.sub.aR.sub.b groups, wherein R.sub.a and R.sub.b are as previously defined, and NHR.sub.c groups, wherein R.sub.c is as previously defined.

4. The compound according to claim 1, having the general formula (II-1) as follows: ##STR00162## wherein Ar is as previously defined.

5. The compound according to claim 1, having the general formula (II-2) as follows: ##STR00163## wherein the R.sub.2 group represents a linear or branched alkyl group comprising from 1 to 10 carbon atoms, optionally substituted by an aryl group comprising from 6 to 30 carbon atoms or by a heteroaryl group comprising from 1 to 30 carbon atoms, optionally substituted, and the R.sub.1 and Ar groups are as previously defined.

6. The compound according to claim 1, having the general formula (II-3) as follows: ##STR00164## wherein Ar is as previously defined.

7. The compound according to claim 1, having the general formula (III) as follows: ##STR00165## wherein: the Ar group is selected from among phenyl and naphtalenyl groups, optionally substituted by one or more substituents selected from the group consisting of: halogen atoms, R and OR groups, wherein R is as previously defined, and aryl groups comprising from 6 to 30 carbon atoms or heteroaryl groups comprising from 1 to 30 carbon atoms, optionally substituted; R.sub.N and R.sub.N groups, together with the carbon atoms to which they are bound, form a group selected from the group consisting of tropane, quinuclidine and octahydro-quinolizine groups; and R.sub.2 is H, F or OH.

8. The compound according to claim 1, having the general formula (III-1) as follows: ##STR00166## wherein the R.sub.2 and Ar groups are as previously defined.

9. The compound according to claim 1, comprising at least one radioactive isotope selected from the group consisting of D, .sup.18F, .sup.11C and .sup.123I.

10. A drug comprising a compound according to claim 1.

11. An agonist or antagonist for the alpha 7 nicotinic receptor, comprising the compound of claim 1.

12. A radiopharmaceutical marker comprising a compound according to claim 9.

13. The compound according to claim 1, comprising at least one radioactive isotope selected from the group consisting of D, .sup.18F, .sup.11C and .sup.123I as an R.sub.2 group.

14. A method for treating diseases related to disruption of cholinergic systems and involving an alpha 7 nicotinic receptor, comprising administering a pharmaceutically acceptable amount of the compound of claim 1 to a patient in need thereof.

15. A compound having the general formula (I) as follows: ##STR00167## wherein: X represents C and Y represents N; or X represents N and Y represents C; the Ar group is selected from among heteroaryl groups comprising from 1 to 30 carbon atoms, optionally substituted by one or more groups selected from the group consisting of: halogen atoms, a OH group, linear or branched alkyl and alkoxy groups comprising from 1 to 10 carbon atoms, optionally substituted, and aryl groups comprising from 6 to 30 carbon atoms and heteroaryl groups comprising from 1 to 30 carbon atoms, said aryl groups being optionally substituted by at least one substituent selected from the group consisting of: CH.sub.2OH; halogen; CH.sub.2F, CH.sub.2Cl; COOCH.sub.3; ##STR00168## the R.sub.N and R.sub.N groups, together with the carbon atoms to which they are bound, form a monocyclic or bicyclic azacycloalkane group comprising at least one trisubstituted endocyclic nitrogen atom, optionally in quaternary ammonium form, selected from the group consisting of: ##STR00169## said azacycloalkane group being optionally substituted by one or more groups selected from the group consisting of: halogen atoms, OH group, and linear or branched alkyl and alkoxy groups comprising from 1 to 10 carbon atoms, optionally substituted, R.sub.1 is a group selected from the group consisting of: halogen atoms, aryl groups comprising from 6 to 30 carbon atoms and heteroaryl groups comprising from 1 to 30 carbon atoms, optionally substituted, R, OR or SiRRR, R, R and R groups being independently selected from the group consisting of a hydrogen atom and linear or branched alkyl groups comprising from 1 to 10 carbon atoms, optionally substituted, NR.sub.aR.sub.b, R.sub.a and R.sub.b groups being independently selected from the group consisting of a hydrogen atom and alkyl and acyl groups comprising from 1 to 10 carbon atoms, optionally substituted, and NHR.sub.c, R.sub.c groups being selected from among aryl groups comprising from 6 to 30 carbon atoms and heteroaryl groups comprising from 1 to 30 carbon atoms; and R.sub.2 is selected from the group consisting of: H when X is N, halogen atoms, R, OR, C(O)Oalkyl, OC(O)R, OC(O)NHR, O(SO.sub.2)R and O(SO.sub.2)NHR groups, wherein R is as defined here above; and pharmaceutically acceptable salts thereof, hydrates or polymorphic crystalline structures, racemates, diastereoisomers or enantiomers thereof, wherein the following compounds are excluded: 3-(1-(2,3-difluorophenyl)-1H-tetrazol-5-yl)-5-(1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine-; and 3-(1-(2,3-difluorophenyl)-1H-tetrazol-5-yl)-5-(1-(quinuclidin-3-yl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine.

16. The compound according to claim 15, having the general formula (II) as follows: ##STR00170## wherein: the Ar group is selected from the group consisting of pyridyl, thiophenyl, furanyl, benzothiophenyl, and benzofuranyl groups, optionally substituted by one or more substituents selected from the group consisting of: halogen atoms, a OH group, linear or branched alkyl and alkoxy groups comprising from 1 to 10 carbon atoms, optionally substituted, and aryl groups comprising from 6 to 30 carbon atoms and heteroaryl groups comprising from 1 to 30 carbon atoms, optionally substituted; said aryl groups being optionally substituted by at least one substituent selected from the group consisting of: CH.sub.2OH; a halogen; CH.sub.2F; CH.sub.2Cl; COOCH.sub.3; and ##STR00171## the R.sub.N and R.sub.N groups, together with the carbon atoms to which they are bound, form a group selected from the group consisting of tropane, quinuclidine and octahydro-quinolizine groups; R.sub.1 is selected from the group consisting of: a hydrogen atom, halogen atoms, aryl groups comprising from 6 to 30 carbon atoms and heteroaryl groups comprising from 1 to 30 carbon atoms, optionally substituted, NR.sub.aR.sub.b groups, wherein R.sub.a and R.sub.b are as previously defined, and NHR.sub.c groups, wherein R.sub.c is as previously defined.

17. The compound according to claim 1, wherein Ar is an aryl group comprising from 6 to 30 carbon atoms, substituted by one or more heteroaryl groups comprising from 1 to 30 carbon atoms, substituted by at least one CH.sub.2OH group.

Description

EXAMPLES

Preparation of the Compounds of the Invention

Preparation of Precursors of Tropane Type Compounds (Formula (II-1))

Preparation of 3-endo-tropanamine (2)

(1) ##STR00069##

3-Endo-tropanamine (2)

(2) A solution of ammonium formate (25.0 g, 0.40 mol) in 12.5 mL of water was added to a solution of tropanone 1 (6.00 g, 43.0 mmol) in 110 mL of methanol. After complete dissolution of the reaction medium, Palladium on carbon Pd/C (4.60 g, 4.30 mmol) was added and the reaction mixture was stirred at ambient temperature for a period of 12 hours, with care being taken to let out the hydrogen formed. Thereafter, the reaction medium was filtered through Celite and then the filtrate was evaporated under reduced pressure. The resulting oil obtained was diluted in 100 mL of ethanol and then at 0 C., 7.5 mL of a solution of concentrated HCl (37%) was added drop by drop. Finally, the solution was stirred for 2 hours until complete precipitation of the 3-endo-tropanamine 2. The product was recovered by means of vacuum filtration in the form of a white solid with a yield of 98%. Mp: >250 C.; IR (ATR, Diamond): (cm.sup.1): 1032, 1068, 1104, 1175, 1230, 1356, 1385, 1448, 1517, 1532, 1606, 2047, 2551, 2587, 2627, 2649, 2764, 2876; .sup.1H NMR (250 MHz, DMSO-d.sub.6): (ppm) 2.05-2.40 (m, 6H), 2.62-2.80 (m, 5H), 3.40-3.60 (m, 1H), 3.70-3.92 (m, 2H), 8.32-8.75 (m, 3H), 10.98-11.34 (m, 1H); .sup.13C NMR (100 MHz, DMSO-d.sub.6): (ppm) 23.2 (2CH.sub.2), 31.9 (2CH.sub.2), 37.9 (CH.sub.3), 39.2 (CH), 60.2 (2CH); MS (IS): m/z=141.0 [MH].sup.+.

Preparation of True Alkynes (7-9) from Aldehydes (3-5)

(3) ##STR00070##

(4) General Procedure A:

(5) To a solution of dimethyl 1-diazo-2-oxopropylphosphonate 6 (1.15 g, 6.00 mmol) in 60 mL of anhydrous methanol, the following were added successively: aldehyde 3-5 (5.00 mmol) and K.sub.2CO.sub.3 (1.38 g, 10.0 mmol). The reaction mixture was stirred at ambient temperature for a period of 12 hours. After gentle evaporation of the solvent under reduced pressure, the alkynes 7-9 were purified by column chromatography on silica gel with the eluent used being a mixture of petroleum ether/ethyl acetate that enables good separation.

5-Ethynylbenzo[b]thiophene (7)

(6) The product was isolated in the form of a white solid with a yield of 84% by following the general procedure A. R.sub.f: 0.40 (PE/EtOAc: 99/1); Mp: 55 C.; IR (ATR, Diamond): (cm.sup.1): 1050, 1088, 1222, 1258, 1324, 1411, 1431, 3082, 3101, 3277; .sup.1H NMR (250 MHz, CDCl.sub.3): (ppm) 3.11 (s, 1H), 7.31 (d, 1H, J=5.5 Hz), 7.43-7.51 (m, 2H), 7.83 (d, 1H, J=8.4 Hz), 7.99 (s, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 76.9 (CH), 84.1 (C.sub.q), 118.1 (C.sub.q), 122.6 (.sub.aromaticCH), 123.8 (.sub.aromaticCH), 127.6 (.sub.aromaticCH), 127.7 (.sub.aromatic 2CH), 139.6 (C.sub.q), 140.3 (C.sub.q); MS (IS): m/z=159.1 [MH].sup.+.

5-Ethynylbenzo[b]furan (8)

(7) The product is isolated in the form of a yellow oil with a yield of 90% by following the general procedure A. R.sub.f: 0.52 (PE/EtOAc: 95/5); IR (ATR, Diamond): (cm.sup.1): 882, 1029, 1107, 1118, 1195, 1265, 1329, 1436, 1460, 3290; .sup.1H NMR (250 MHz, CDCl.sub.3): (ppm) 3.03 (s, 1H), 6.75 (d, 1H, J=2.2 Hz), 7.43-7.46 (m, 2H), 7.64 (d, 1H, J=2.2 Hz), 7.77 (s, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 76.0 (CH), 84.2 (C.sub.q), 106.7 (.sub.aromaticCH), 111.7 (.sub.aromaticCH), 116.8 (C.sub.q), 125.6 (.sub.aromaticCH), 127.7 (C.sub.q), 128.6 (.sub.aromaticCH), 146.1 (.sub.aromaticCH), 155.0 (C.sub.q); MS (IS): m/z=143.1 [MH].sup.+.

2-Bromo-5-ethynyl thiophene (9)

(8) The product was isolated in the form of a yellow oil with a yield of 92% by following the general procedure A. R.sub.f: 0.50 (PE/EtOAc: 99/1); IR (ATR, Diamond): (cm.sup.1): 966, 1048, 1137, 1209, 1419, 1519, 1669, 2102, 3294; .sup.1H NMR (250 MHz, CDCl.sub.3): (ppm) 3.37 (s, 1H), 6.92 (d, 1H, J=3.9 Hz), 7.02 (d, 1H, J=3.9 Hz); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 76.2 (CH), 82.5 (C.sub.q), 113.7 (C.sub.q), 124.0 (C.sub.q), 130.1 (.sub.aromaticCH), 133.6 (.sub.aromaticCH); MS (IS): m/z=188.1 [MH].sup.+.

Preparation of Alkynes (13-14) by the Sonogashira Coupling Reaction

(9) ##STR00071##

(10) To a solution of 2-fluoro-5-iodopyridine 10 (4.00 g, 17.9 mmol) in 30 mL of previously degassed triethylamine, the following were added successively: ethynyl(trimethyl) silane 11 (2.78 mL, 19.7 mmol), copper iodide (340 mg, 1.79 mmol) and Pd(PPh.sub.3) 2Cl.sub.2 (1.25 g, 1.79 mmol). The reaction mixture was stirred at ambient temperature for a period of 12 hours. Upon completion of the reaction, the reaction medium was diluted with 100 mL of water and then extracted with ethyl ether. The organic phase was dried over anhydrous MgSO.sub.4, filtered and then concentrated under reduced pressure. The product of coupling 12 was engaged in subsequent reactions without further purification.

5-Ethynyl-2-fluoropyridine (13)

(11) The silyl derivative 12 (8.97 mmol) was stirred in 50 mL of THF for 15 minutes in the presence of 9.00 mL of a solution of tetra-n-butylammonium fluoride (1 M in THFtetrahydrofuran) added drop by drop. Upon completion of the reaction, the solvent was evaporated and the alkyne 13 was purified by column chromatography on silica gel with the eluent used being a mixture of petroleum ether/ethyl acetate (95/5). The product was isolated in the form of a red liquid with a yield of 82%. R.sub.f: 0.49 (PE/EtOAc: 95/5); IR (ATR, Diamond): (cm.sup.1): 927, 1020, 1130, 1240, 1365, 1477, 1575, 3074; .sup.1H NMR (250 MHz, CDCl.sub.3): (ppm) 3.19 (s, 1H), 6.90 (dd, 1H, J=8.5 Hz and 3.0 Hz), 7.85 (ddd, 1H, J=8.5 Hz, 7.6 Hz and 2.3 Hz), 8.34 (d, 1H, J=2.3 Hz); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 79.2 (CH), 80.7 (d, C.sub.q, J=1 Hz), 109.6 (d, .sub.aromaticCH, J=38 Hz), 117.3 (d, C.sub.q, J=5 Hz), 144.4 (d, .sub.aromaticCH, J=8 Hz), 151.4 (d, .sub.aromaticCH, J=15 Hz), 163.1 (d, C.sub.q, J=243 Hz); MS (IS): m/z=122.2 [MH].sup.+.

5-Ethynyl-2-methoxy pyridine (14)

(12) The silyl derivative 12 (17.9 mmol) was stirred in 60 mL of methanol for a period of 3 hours in the presence of K.sub.2CO.sub.3 (2.47 g, 17.9 mmol). The reaction medium was evaporated under reduced pressure and the alkyne 14 was purified by column chromatography on silica gel with the eluent used being a mixture of petroleum ether/ethyl acetate (95/5). The product was isolated in the form of a yellow liquid with a yield of 75%. R.sub.f: 96/4). R.sub.f: 0.72 (PE/EtOAc: IR (ATR, Diamond): (cm.sup.1): 1021, 1126, 1251, 1284, 1305, 1367, 1488, 1559, 1600, 3290; .sup.1H NMR (250 MHz, CDCl.sub.3): (ppm) 3.10 (s, 1H), 3.94 (s, 3H), 6.69 (d, 1H, J=8.6 Hz), 7.63 (dd, 1H, J=8.6 Hz and 2.3 Hz), 8.30 (d, 1H, J=2.3 Hz); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 53.9 (CH.sub.3), 78.8 (CH), 80.9 (C.sub.q), 110.9 (.sub.aromaticCH), 112.1 (CO.sub.3141.8 (.sub.aromaticCH), 151.0 (.sub.aromatic CH), 163.9 (C.sub.q); MS (IS): m/z=134.0 [MH].sup.+.

Preparation of Tropane Type Compounds 16-27 (Formula (II-1))

(13) ##STR00072## ##STR00073## ##STR00074##

(14) General Procedure B:

(15) Under argon atmosphere, 3-endo-tropanamine 2 (212 mg, 1.00 mmol) and the 1H-imidazole-1-sulfonyl azide 15 (232 mg, 1.10 mmol) were dissolved in 6 mL of methanol to which the following were then added successively: K.sub.2CO.sub.3 (415 mg, 3.00 mmol) and a catalytic amount of CuSO.sub.45H.sub.2O (25 mg, 0.100 mmol). The reaction medium was stirred at ambient temperature for a period of 2 hours and then concentrated under reduced pressure. The resulting solid obtained was then taken up again in 10 mL of ethyl ether, vacuum filtered and thereafter washed twice with 10 mL of ethyl ether. Finally, the filtrate was evaporated under reduced pressure and the resulting azide thus obtained was engaged in the subsequent step without any further purification.

(16) The latter was dissolved in 6 mL of methanol to which the following were then added successively: the desired alkyne (1.00 mmol), CuSO.sub.45H.sub.2O (25 mg, 0.100 mmol) and the sodium ascorbate (40 mg, 0.200 mmol). The reaction mixture was stirred at ambient temperature for a period of 12 hours. At the end of the reaction time, the methanol was evaporated under reduced pressure and the residue was chromatographed by column chromatography on silica gel with the eluent used being a mixture of CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH that enables good separation. In order to remove the traces of imidazole that are often present in the chromatographed triazole products, the mixture was dissolved in ethyl acetate, washed two times with water, dried over anhydrous MgSO.sub.4 and evaporated to dryness.

Endo-3-(4-phenyl-1H-1,2,3-triazol-1-yl)tropane (16)

(17) The product was isolated in the form of a white solid with a yield of 40% by following the general procedure B. R.sub.f: 0.30 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 90/10/0.1); Mp: 135 C. IR (ATR, Diamond): (cm.sup.1): 1015, 1078, 1116, 1142, 1217, 1335, 1411, 1451, 1481, 2441, 2934; .sup.1H NMR (250 MHz, CDCl.sub.3): (ppm) 1.72-1.80 (m, 2H), 1.99-2.10 (m, 2H), 2.46 (s, 3H), 2.66 (d, 2H, J=15.0 Hz), 2.80-2.89 (m, 2H), 3.40-3.46 (m, 2H), 4.70 (dt, 1H, J=6.8 Hz and 3.6 Hz), 7.31-7.36 (m, 1H), 7.40-7.46 (m, 2H), 7.84 (d, 2H, J=8.1 Hz), 7.87 (s, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 25.2 (2CH.sub.2), 35.0 (2CH.sub.2), 40.1 (CH.sub.3), 51.5 (CH), 60.4 (2CH), 119.1 (.sub.aromaticCH), 125.9 (2CH.sub.aromatic), 128.5 (.sub.aromaticCH), 129.1 (2CH.sub.aromatic), 130.7 (C.sub.q), 148.2 (C.sub.q); HRMS (EI-MS): calculated for C.sub.16H.sub.21N.sub.4 m/z=269.1766. found m/z=269.1757.

Endo-3(4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)tropane (17)

(18) The product was isolated in the form of a white solid with a yield of 31% by following the general procedure B. R.sub.f: 0.28 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 90/10/0.1); Mp: 254 C. IR (ATR, Diamond): (cm.sup.1): 1014, 1081, 1141, 1161, 1224, 1402, 1429, 1452, 1496, 2446, 2470; .sup.1H NMR (250 MHz, CDCl.sub.3): (ppm) 1.89-2.19 (m, 4H), 2.63 (s, 3H), 2.75 (d, 2H, J=15.8 Hz), 3.17-3.30 (m, 2H), 3.62-3.70 (m, 2H), 4.79 (t, 1H, J=7.2 Hz), 7.12 (t, 2H, J=8.6 Hz), 7.81 (dd, 2H, J=8.6 Hz and 5.3 Hz), 7.88 (s, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 24.5 (2CH.sub.2), 34.1 (2CH.sub.2), 39.5 (CH.sub.3), 50.6 (CH), 61.3 (2CH), 116.2 (d, 2CH.sub.aromatic, J=22 Hz), 119.1 (.sub.aromaticCH), 126.7 (d, C.sub.q, J=3 Hz), 127.6 (d, 2CH.sub.aromatic, J=8 Hz), 147.8 (C.sub.q), 163.0 (d, C.sub.q, J=248 Hz); HRMS (EI-MS): calculated for C.sub.16H.sub.20FN.sub.4 m/z=287.1672. found m/z=287.1669.

Endo-3-(4-(4-bromophenyl)-1H-1,2,3-triazol-1-yl)tropane (18)

(19) The product was isolated in the form of a white solid with a yield of 42% by following the general procedure B. R.sub.f: 0.22 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 90/10/0.1); Mp: 226 C. IR (ATR, Diamond): (cm.sup.1): 973, 1009, 1068, 1116, 1148, 1214, 1232, 1334, 1396, 1422, 1450, 1478, 2932; .sup.1H NMR (250 MHz, CDCl.sub.3): (ppm) 1.48-1.57 (m, 2H), 1.90-2.00 (m, 2H), 2.28 (s, 3H), 2.51-2.57 (m, 4H), 3.19-3.27 (m, 2H), 4.58-4.66 (m, 1H), 7.54 (d, 2H, J=8.6 Hz), 7.72 (d, 2H, J=8.6 Hz), 7.85 (s, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 25.9 (2CH.sub.2), 35.9 (2CH.sub.2), 40.6 (CH.sub.3), 52.4 (CH), 59.5 (2CH), 119.1 (.sub.aromaticCH), 122.1 (C.sub.q), 127.4 (2CH.sub.aromatic), 130.0 (C.sub.q), 132.2 (2CH.sub.aromatic), 146.7 (C.sub.q); HRMS (EI-MS): calculated for C.sub.16H.sub.20BrN.sub.4 m/z=347.0871. found m/z=347.0879.

Endo-3-(4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl)tropane (19)

(20) The product was isolated in the form of a white solid with a yield of 21% by following the general procedure B. R.sub.f: 0.27 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 90/10/0.1); Mp: 118 C. IR (ATR, Diamond): (cm.sup.1): 972, 1018, 1036, 1078, 1177, 1219, 1245, 1333, 1397, 1497, 1616, 2943; .sup.1H NMR (250 MHz, CDCl.sub.3): (ppm) 1.65 (d, 2H, J=8.2 Hz), 1.93-2.03 (m, 2H), 2.36 (s, 3H), 2.55-2.75 (m, 4H), 3.29-3.36 (m, 2H), 3.84 (s, 3H), 4.64 (dt, 1H, J=6.2 Hz and 3.3 Hz), 6.96 (d, 2H, J=8.8 Hz), 7.76 (d, 2H, J=8.8 Hz), 7.77 (s, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 25.5 (2CH.sub.2), 35.4 (2CH.sub.2), 40.3 (CH.sub.3), 51.8 (CH), 55.6 (CH.sub.3), 59.9 (2CH), 114.5 (.sub.aromatic 2CH), 118.3 (CH), 123.6 (C.sub.q), 127.2 (2CH.sub.aromatic), 147.8 (C.sub.q), 159.8 (C.sub.q); HRMS (EI-MS): calculated for C.sub.17H.sub.23N.sub.40 m/z=299.1872. found m/z=299.1881.

(4-(1-(Endo-tropan-3-yl)-1H-1,2,3-triazol-4-yl) phenyl) methanol (20)

(21) The product was isolated in the form of a white solid with a yield of 45% by following the general procedure B. R.sub.f: 0.19 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 90/10/0.1); Mp: >250 C. IR (ATR, Diamond): (cm.sup.1): 1013, 1060, 1082, 1401, 1431, 1452, 1493, 1650, 2506, 2556, 2587, 3352; .sup.1H NMR (250 MHz, DMSO-d.sub.6): (ppm) 1.47 (d, 2H, J=8.2 Hz), 1.88-2.07 (m, 2H), 2.44 (s, 3H), 2.60-2.82 (m, 4H), 3.50-3.58 (m, 2H), 4.56 (s, 2H), 4.64-4.75 (m, 1H), 5.28 (s large, 1H, OH), 7.43 (d, 2H, J=8.1 Hz), 7.87 (d, 2H, J=8.1 Hz), 8.88 (s, 1H); .sup.13C NMR (100 MHz, DMSO-d.sub.6): (ppm) 24.4 (2CH.sub.2), 32.9 (2CH.sub.2), 39.8 (CH.sub.3), 50.7 (CH), 59.4 (2CH), 62.6 (CH.sub.2), 120.8 (.sub.aromatic CH), 124.8 (2CH.sub.aromatic), 126.9 (2CH.sub.aromatic), 129.2 (C.sub.q), 142.2 (C.sub.q), 146.4 (C.sub.q); HRMS (EI-MS): calculated for C.sub.17H.sub.23N.sub.4O m/z=299.1872. found m/z=299.1859.

Endo-3-(4-(6-methoxynaphthalen-2-yl)-1H-1,2,3-triazol-1-yl) tropane (21)

(22) The product was isolated in the form of a white solid with a yield of 33% by following the general procedure B. R.sub.f: 0.24 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 90/10/0.1); Mp: >250 C.; IR (ATR, Diamond): (cm.sup.1): 908, 1021, 1123, 1163, 1212, 1262, 1345, 1393, 1453, 1612, 2932; .sup.1H NMR (250 MHz, CDCl.sub.3): (ppm) 1.76 (d, 2H, J=8.0 Hz), 1.97-2.07 (m, 2H), 2.43 (s, 3H), 2.61-2.72 (m, 2H), 2.76-2.90 (m, 2H), 3.35-3.45 (m, 2H), 3.93 (s, 3H), 4.65-4.75 (m, 1H), 7.13-7.20 (m, 2H), 7.75-7.82 (m, 2H), 7.87-7.94 (m, 1H), 7.94 (s, 1H), 8.26 (s, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 25.4 (2CH.sub.2), 35.3 (2CH.sub.2), 40.3 (CH.sub.3), 51.8 (CH), 55.6 (CH.sub.3), 60.2 (2CH), 106.0 (.sub.aromaticCH), 119.0 (.sub.aromaticCH), 119.5 (.sub.aromaticCH), 124.5 (2CH.sub.aromatic), 126.0 (C.sub.q), 217.6 (.sub.aromaticCH), 129.2 (C.sub.q), 129.9 (.sub.aromaticCH), 134.6 (C.sub.q), 148.2 (C.sub.q), 158.2 (C.sub.q); HRMS (EI-MS): calculated for C.sub.21H.sub.25N.sub.4O m/z=349.2028. found m/z=349.2029.

Endo-3-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)tropane (22)

(23) The product was isolated in the form of a white solid with a yield of 34% by following the general procedure B. R.sub.f: 0.23 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 90/10/0.1); Mp: 124 C. IR (ATR, Diamond): (cm.sup.1): 1017, 1087, 1156, 1198, 1227, 1336, 1416, 1450, 1477, 1584, 1620, 2937, 2963, 3094; .sup.1H NMR (250 MHz, CDCl.sub.3): (ppm) 1.47-1.57 (m, 2H), 1.92-2.00 (m, 2H), 2.28 (s, 3H), 2.51-2.57 (m, 4H), 3.18-3.26 (m, 2H), 4.62 (quint, 1H, J=5.2 Hz), 6.94-7.09 (m, 1H), 7.32-7.42 (m, 1H), 7.52-7.65 (m, 1H), 7.58 (s, 1H), 7.86 (s, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 25.9 (2CH.sub.2), 35.9 (2CH.sub.2), 40.6 (CH.sub.3), 52.5 (CH), 59.5 (2CH), 112.8 (d, .sub.aromaticCH, J=22 Hz), 115.1 (d, .sub.aromaticCH, J=22 Hz), 119.4 (.sub.aromaticCH), 121.4 (d, .sub.aromaticCH, J=3 Hz), 130.6 (d, aromatic CH, J=8 Hz), 133.2 (d, C.sub.q, J=8 Hz), 146.6 (d, C.sub.q, J=3 Hz), 163.4 (d, C.sub.q, J=246 Hz), HRMS (EI-MS): calculated for C.sub.16H.sub.20FN.sub.4 m/z=287.1672. found m/z=287.1671.

Endo-3-(4-(pyridin-4-yl)-1H-1,2,3-triazol-1-yl)tropane (23)

(24) The product was isolated in the form of a brown solid with a yield of 43% by following the general procedure B. R.sub.f: 0.12 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 90/10/0.1); Mp: 146 C. IR (ATR, Diamond): (cm.sup.1): 817, 1016, 1060, 1082, 1217, 1340, 1426, 1610, 2936; .sup.1H NMR (400 MHz, CDCl.sub.3): (ppm) 1.48-1.57 (m, 2H), 1.89-2.03 (m, 2H), 2.30 (s, 3H), 2.48-2.66 (m, 4H), 3.21-3.30 (m, 2H), 4.63 (dt, 1H, J=6.8 Hz and 3.3 Hz), 7.72 (d, 2H, J=6.0 Hz), 7.99 (s, 1H), 8.64 (d, 2H, J=6.0 Hz); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 25.9 (2CH.sub.2), 35.9 (2CH.sub.2), 40.6 (CH.sub.3), 52.6 (CH), 59.5 (2CH), 120.1 (2CH.sub.aromatic), 120.6 (.sub.aromaticCH), 138.3 (C.sub.q), 145.2 (C.sub.q), 150.6 (2CH.sub.aromatic); HRMS (EI-MS): calculated for C.sub.15H.sub.20N.sub.5 m/z=270.1719. found m/z=270.1711.

Endo-3-(4-(3,4-dichlorophenyl)-1H-1,2,3-triazol-1-yl)tropane (24)

(25) The product was isolated in the form of a white solid with a yield of 22% by following the general procedure B. R.sub.f: 0.32 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH 90/10/0.1); Mp: 136 C. IR (ATR, Diamond): (cm.sup.1): 825, 1021, 1082, 1117, 1131, 1231, 1336, 1423, 1459, 1473, 2934; .sup.1H NMR (400 MHz, CDCl.sub.3): (ppm) 1.49-1.54 (m, 2H), 1.89-2.03 (m, 2H), 2.29 (s, 3H), 2.48-2.62 (m, 4H), 3.21-3.27 (m, 2H), 4.63 (dt, 1H, J=6.6 Hz and 3.3 Hz), 7.48 (d, 1H, J=8.3 Hz), 7.68 (dd, 1H, J=8.3 Hz and 1.9 Hz), 7.86 (s, 1H), 7.92 (d, 1H, J=1.9 Hz); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 25.9 (2CH.sub.2), 35.9 (2CH.sub.2), 40.6 (CH.sub.3), 52.6 (CH), 59.5 (2CH), 119.2 (.sub.aromaticCH), 125.0 (.sub.aromaticCH), 127.6 (.sub.aromaticCH), 131.0 (.sub.aromaticCH and C.sub.q), 132.0 (C.sub.q), 133.2 (C.sub.q), 145.6 (C.sub.q); HRMS (EI-MS): calculated for C.sub.16H.sub.19N.sub.4Cl.sub.2 m/z=337.0987. found m/z=337.0980.

Endo-3-(4-(1-Benzothiophen-5-yl)-1H-1,2,3-triazol-1-yl)tropane (25)

(26) The product was isolated in the form of a white solid with a yield of 34% by following the general procedure B. R.sub.f: 0.25 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH 90/10/0.1); Mp: 163 C. IR (ATR, Diamond): (cm.sup.1): 818, 896, 1018, 1079, 1114, 1218, 1338, 1394, 1439, 1552, 2100, 2929, 3036; .sup.1H NMR (400 MHz, CDCl.sub.3): (ppm) 1.54-1.62 (m, 2H), 1.93-2.02 (m, 2H), 2.30 (s, 3H), 2.54-2.61 (m, 4H), 3.20-3.28 (m, 2H), 4.64 (quint, 1H, J=5.0 Hz), 7.37 (d, 1H, J=5.4 Hz), 7.47 (d, 1H, J=5.4 Hz), 7.81 (dd, 1H, J=8.4 Hz and 1.2 Hz), 7.91 (s, 1H), 7.92 (d, 1H, J=8.4 Hz), 8.33 (d, 1H, J=1.2 Hz); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 25.8 (2CH.sub.2), 35.8 (2CH.sub.2), 40.5 (CH.sub.3), 52.3 (CH), 59.6 (2CH), 119.0 (.sub.aromaticCH), 120.7 (.sub.aromaticCH), 122.3 (.sub.aromaticCH), 123.0 (.sub.aromaticCH), 124.2 (.sub.aromaticCH), 127.3 (C.sub.q), 127.4 (.sub.aromaticCH), 139.5 (C.sub.q), 140.2 (C.sub.q), 147.9 (C.sub.q); HRMS (EI-MS): calculated for C.sub.18H.sub.21N.sub.4S m/z=325.1487. found m/z=325.1488.

Endo-3-(4-(1-benzofuran-5-yl)-1H-1,2,3-triazol-1-yl)topane (26)

(27) The product was isolated in the form of a white solid with a yield of 35% by following the general procedure B. R.sub.f: 0.23 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH 90/10/0.1); Mp: 104 C. IR (ATR, Diamond): (cm.sup.1): 988, 1030, 1067, 1108, 1224, 1338, 1443, 1457, 1496, 1518, 2361, 2873, 2929, 3115, 3351; .sup.1H NMR (400 MHz, CDCl.sub.3): (ppm) 1.55-1.60 (m, 2H), 1.94-1.99 (m, 2H), 2.30 (s, 3H), 2.55-2.60 (m, 4H), 3.22-3.27 (m, 2H), 4.64 (quint, 1H, J=5.0 Hz), 6.77-6.83 (m, 1H), 7.54 (d, 1H, J=8.6 Hz), 7.64 (d, 1H, J=2.1 Hz), 7.76 (dd, 1H, J=8.6 Hz, 1.5 Hz), 7.85 (s, 1H), 8.10 (d, 1H, J=1.5 Hz); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 25.8 (2CH.sub.2), 35.8 (2CH.sub.2), 40.6 (CH.sub.3), 52.2 (CH), 59.6 (2CH), 107.0 (.sub.aromaticCH), 111.9 (.sub.aromaticCH), 118.6 (.sub.aromatic CH), 118.7 (.sub.aromaticCH), 122.6 (.sub.aromaticCH), 126.0 (C.sub.q), 128.1 (C.sub.q), 145.8 (.sub.aromaticCH), 148.1 (C.sub.q), 155.0 (C.sub.q); HRMS (EI-MS): calculated for C.sub.18H.sub.21N.sub.4O m/z=309.1715. found m/z=309.1709.

Endo-3-(4-(5-bromothiophen-2-yl)-1H-1,2,3-triazol-1-yl)tropane (27)

(28) The product was isolated in the form of a white solid with a yield of 29% by following the general procedure B. R.sub.f: 0.32 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 90/10/0.1); Mp: 138 C. IR (ATR, Diamond): (cm.sup.1): 969, 1016, 1066, 1104, 1132, 1228, 1331, 1407, 1435, 2913, 2940, 2966, 3274; .sup.1H NMR (400 MHz, CDCl.sub.3): (ppm) 1.56-1.66 (m, 2H), 1.96-2.01 (m, 2H), 2.35 (s, 3H), 2.50-2.57 (m, 2H), 2.63-2.73 (m, 2H), 3.28-3.33 (m, 2H), 4.58-4.67 (m, 1H), 7.01 (d, 1H, J=3.8 Hz), 7.10 (d, 1H, J=3.8 Hz), 7.73 (s, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 25.8 (2CH.sub.2), 35.4 (2CH.sub.2), 40.3 (CH.sub.3), 52.2 (CH), 59.8 (2CH), 112.2 (C.sub.q), 118.5 (.sub.aromaticCH), 124.3 (.sub.aromaticCH), 130.6 (.sub.aromaticCH), 134.8 (C.sub.q), 142.3 (C.sub.q); HRMS (EI-MS): calculated for C.sub.14H.sub.18N.sub.4SBr m/z=353.0436. found m/z=353.0447.

Preparation of a Precursor of Octahydro Quinolizine Type Compounds (Formula (II-3))

(29) ##STR00075##

2-(4-Ethoxy-4-oxobutyl)piperidine-1-ethyl carboxylate (30)

(30) To a solution of Ethyl Pipecolinate Hydrochloride 28 (12.4 g, 64.0 mmol) in 300 mL of acetonitrile, the following were added: ethyl 4-bromobutanoate 29 (11.0 mL, 76.8 mmol) and K.sub.2CO.sub.3 (19.5 g, 140.8 mmol). The reaction medium was then heated to reflux for a period of 24 hours. At the end of the reaction time, the solvent was evaporated under reduced pressure and then the residue was taken up again in ethyl acetate. The organic phase was washed with water, dried over anhydrous MgSO.sub.4 and concentrated under vacuum. The crude product was purified by column chromatography on silica gel with the eluent used being a mixture of petroleum ether/ethyl acetate (4/1). The diester 30 was isolated in the form of a colourless liquid with a yield of 80%. R.sub.f: 0.29 (PE/EtOAc: 3/1); IR (ATR, Diamond): (cm.sup.1): 1027, 1123, 1158, 1372, 1446, 1730, 2936; .sup.1H NMR (400 MHz, CDCl.sub.3): (ppm) 1.22 (t, 3H, J=7.1 Hz), 1.24 (t, 3H, J=7.1 Hz), 1.31-1.40 (m, 1H), 1.55-1.61 (m, 3H), 1.73-1.80 (m, 4H), 2.14-2.21 (m, 1H), 2.24-2.40 (m, 3H), 2.50-2.57 (m, 1H), 3.00-3.09 (m, 2H), 4.11 (q, 2H, J=7.1 Hz), 4.17 (q, 2H, J=7.1 Hz); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 14.5 (2CH.sub.3), 22.3 (CH.sub.2), 22.8 (CH.sub.2), 25.5 (CH.sub.2), 29.8 (CH.sub.2), 32.4 (CH.sub.2), 50.5 (CH.sub.2), 55.8 (CH.sub.2), 60.4 (CH.sub.2), 60.5 (CH.sub.2), 65.3 (CH), 173.8 (CO), 174.0 (CO); MS (IS): m/z=272.3 [MH].sup.+.

Hexahydro-2H-quinolizin-1(6H)-one (31)

(31) A solution of 2-(4-ethoxy-4-oxobutyl)piperidine-1-ethyl carboxylate 30 (5.00 g, 18 4 mmol) in 100 mL of anhydrous Tetrahydrofuran (THF) was cooled to 0 C. to which t-BuOK (3.10 g, 27.6 mmol) was then added by portion. The reaction medium was stirred at 0 C. for a period of 30 minutes and then for a period of 2 hours at ambient temperature. Thereafter, the THF was evaporated under reduced pressure and the residue was diluted with ethyl acetate. The organic phase was washed with water, dried over anhydrous MgSO.sub.4 and concentrated under vacuum. The residue was taken up again in 60 mL of diluted hydrochloric acid (4N) and then heated to reflux for a period of 12 hours. Upon completion of the reaction, the reaction medium was neutralised by the addition of solid NaHCO.sub.3 and then the aqueous phase was extracted with CH.sub.2Cl.sub.2. The organic phase was then dried over anhydrous MgSO.sub.4 and concentrated under reduced pressure. The ketone 31 was isolated in the form of a red liquid with a yield of 74%. R.sub.f: 0.20 (EtOAc); IR (ATR, Diamond): (cm.sup.1): 1076, 1145, 1174, 1281, 1319, 1344, 1443, 1718, 2933; .sup.1H NMR (250 MHz, CDCl.sub.3): (ppm) 1.10-1.65 (m, 4H), 1.75-1.87 (m, 1H), 1.90-2.05 (m, 3H), 2.08-2.32 (m, 2H), 2.33-2.55 (m, 3H), 2.87-3.00 (m, 2H); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 24.0 (CH.sub.2), 24.4 (CH.sub.2), 25.6 (CH.sub.2), 25.8 (CH.sub.2), 39.4 (CH.sub.2), 55.0 (CH.sub.2), 57.1 (CH.sub.2), 71.2 (CH), 207.5 (CO), MS (IS): m/z=154.1 [MH].sup.+.

Octahydro-2H-1-quinolizin-ol (32)

(32) To a solution of hexahydro-2H-quinolizin-1(6H)-one 31 (1.70 g, 11.1 mmol) in 100 mL of methanol at 0 C., NaBH.sub.4 (840 mg, 22.2 mmol) was added by portion and the reaction medium was stirred at this temperature for a period of 1 hour. After evaporation of the solvent, the residue was taken up again in dichloromethane and then the organic phase was washed with water, dried over anhydrous MgSO.sub.4 and concentrated under reduced pressure. The alcohol 32 was purified by column chromatography on silica gel with the eluent used being a mixture of CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH (90/10/0.1). It was isolated in the form of a white solid with a yield of 78%. R.sub.f: 0.32 (CH.sub.2Cl.sub.2/MeOH: 4/1); Mp: 70 C. IR (ATR, Diamond): (cm.sup.1): 968, 1020, 1046, 1085, 1107, 1179, 1276, 1346, 1442, 1469, 2761, 2804, 2856, 2925, 2943, 3130; .sup.1H NMR (250 MHz, CDCl.sub.3): (ppm) 1.06-1.34 (m, 3H), 1.51-1.72 (m, 5H), 1.75-1.85 (m, 2H), 1.93-2.08 (m, 3H), 2.09-2.18 (m, 1H), 2.67-2.76 (m, 1H), 2.79-2.88 (m, 1H), 3.28 (ddd, 1H, J=11.1 Hz, 8.8 Hz and 4.6 Hz); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 23.5 (CH.sub.2), 24.3 (CH.sub.2), 25.9 (CH.sub.2), 28.9 (CH.sub.2), 34.2 (CH.sub.2), 56.1 (CH.sub.2), 53.3 (CH.sub.2), 69.0 (CH), 72.8 (CH); MS (IS): m/z=156.1 [MH].sup.+.

1-Azidooctahydro-2-H-quinolizine (33)

(33) To a solution of octahydro-2H-quinolizin-1-ol 32 (700 mg, 4.51 mmol) in 40 mL of CH.sub.2Cl.sub.2 at 0 C., the following were added: triethylamine (760 L, 5.41 mmol) and mesyl chloride (420 L, 5.41 mmol), for a period of 30 minutes. The reaction medium was stirred at 0 C. for a period of 2 hours. The reaction mixture was hydrolysed with the addition of a saturated NaHCO.sub.3 solution. The organic phase was separated, dried over anhydrous MgSO.sub.4 and evaporated under reduced pressure. The mesyl derivative prepared (1.05 g, 4.51 mmol) was heated at 80 C. in 30 mL of DMF (dimethyl formamide) for a period of 18 hours in the presence of sodium azide (1.46 g, 22.6 mmol). Upon completion of the reaction, the solvent was evaporated and then the residue was taken up again in CH.sub.2Cl.sub.2. The organic phase was washed twice with water, dried over anhydrous MgSO.sub.4 and concentrated under reduced pressure. The azide 33 was purified by column chromatography on silica gel with the eluent used being ethyl acetate. It was isolated in the form of a yellow oil with a yield of 71% in the form of two inseparable diastereoisomers in the proportions of (3/2). R.sub.f: 0.15 (EtOAc); IR (ATR, Diamond): (cm.sup.1): 980, 1024, 1113, 1133, 1155, 1254, 1444, 2090, 2799, 2930; .sup.1H NMR (250 MHz, CDCl.sub.3): (ppm) Majority Diastereoisomer d 1.11-1.30 (m, 2H), 1.56-1.82 (m, 6H), 1.95-2.17 (m, 3H), 2.30-2.46 (m, 2H), 2.70-2.79 (m, 1H), 2.94-3.07 (m, 2H). Minority Diastereoisomer d 1.30-1.50 (m, 2H), 1.56-1.82 (m, 6H), 1.95-2.17 (m, 3H), 2.30-2.46 (m, 2H), 2.79-2.88 (m, 1H), 2.98-3.07 (m, 1H), 3.17-3.27 (m, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) Diastereoisomer Majority d 21.8 (CH.sub.2), 23.5 (CH.sub.2), 29.7 (CH.sub.2), 31.8 (CH.sub.2), 33.0 (CH.sub.2), 55.8 (CH.sub.2), 58.1 (CH.sub.2), 68.1 (CH), 68.4 (CH). Minority Diastereoisomer d 23.8 (CH.sub.2), 24.3 (CH.sub.2), 25.8 (CH.sub.2), 29.8 (CH.sub.2), 30.3 (CH.sub.2), 55.8 (CH.sub.2), 56.4 (CH.sub.2), 63.8 (CH), 66.5 (CH); MS (IS): m/z=181.4 [MH].sup.+.

Preparation of Octahydro Quinolizine Type Compounds 34-35 (Formula II-3))

(34) ##STR00076##

(35) General Procedure C:

(36) Under argon atmosphere, the azide 33 (180 mg, 1.00 mmol) was dissolved in 6 mL of methanol and then, the following were added successively: the alkyne (1.00 mmol), CuSO.sub.45H.sub.2O (25 mg, 0.100 mmol) and sodium ascorbate (40 mg, 0.200 mmol). The reaction medium was stirred at ambient temperature for a period of 12 hours. At the end of the reaction time, the methanol was evaporated under reduced pressure and the residue was taken up again in dichloromethane. The organic phase was washed with a saturated NaHCO.sub.3 solution, dried over anhydrous MgSO.sub.4 and concentrated under reduced pressure. The products 34 and 35 were chromatographed by column chromatography on silica gel with the eluent used being a mixture of CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH (99/1/0.1).

1-(4-Phenyl-1H-1,2,3-triazol-1-yl)-octahydro-2H-quinolizine (34)

(37) By following the general procedure C, the product was isolated in the form of a white solid with a yield of 94% in the form of two separable diastereoisomers in the proportions of 3/2.

(38) Minor Diastereoisomer:

(39) R.sub.f: 0.46 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 99/1/0.1); Mp: 150 C. IR (ATR, Diamond): (cm.sup.1): 977, 1023, 1113, 1219, 1294, 1349, 1372, 1434, 1460, 1482, 2754, 2804, 2852, 2925, 3081; .sup.1H NMR (250 MHz, CDCl.sub.3): (ppm) 1.04-1.28 (m, 3H), 1.50-1.74 (m, 3H), 1.81-1.91 (m, 2H), 1.92-2.15 (m, 2H), 2.16-2.30 (m, 3H), 2.81-3.04 (m, 2H), 4.23-4.35 (m, 1H), 7.28-7.36 (m, 1H), 7.38-7.46 (m, 2H), 7.72 (s, 1H), 7.80-7.88 (m, 2H); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 24.0 (CH.sub.2), 24.3 (CH.sub.2), 25.7 (CH.sub.2), 29.0 (CH.sub.2), 32.4 (CH.sub.2), 56.0 (CH.sub.2), 56.5 (CH.sub.2), 64.0 (CH), 66.5 (CH), 118.8 (.sub.aromaticCH), 125.9 (2CH.sub.aromatic), 128.3 (.sub.aromaticCH), 129.0 (2CH.sub.aromatic), 130.9 (C.sub.q), 147.6 (C.sub.q); HRMS (EI-MS): calculated for C.sub.17H.sub.23N.sub.4 m/z=283.1923. found m/z=283.19281.

(40) Majority Diastereoisomer:

(41) R.sub.f: 0.52 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 99/1/0.1); Mp: 140 C. IR (ATR, Diamond): (cm.sup.1): 974, 1049, 1077, 1134, 1196, 1222, 1267, 1433, 1460, 1482, 2780, 2862, 2928; .sup.1H NMR (250 MHz, CDCl.sub.3): (ppm) 1.39-1.56 (m, 1H), 1.60-1.93 (m, 7H), 1.95-2.08 (m, 1H), 2.20-2.35 (m, 1H), 2.41-2.66 (m, 2H), 3.02-3.22 (m, 3H), 4.36-4.53 (m, 1H), 7.28-7.36 (m, 1H), 7.38-7.46 (m, 2H), 7.74 (s, 1H), 7.80-7.89 (m, 2H); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 22.7 (CH.sub.2), 23.4 (CH.sub.2), 29.5 (CH.sub.2), 30.7 (CH.sub.2), 35.7 (CH.sub.2), 55.3 (CH.sub.2), 58.2 (CH.sub.2), 67.4 (CH), 67.9 (CH), 118.3 (.sub.aromaticCH), 125.8 (2CH.sub.aromatic), 128.2 (.sub.aromaticCH), 129.0 (2CH.sub.aromatic), 131.0 (CO.sub.3147.6 (C.sub.q); HRMS (EI-MS): calculated for C.sub.17H.sub.23N.sub.4 m/z=283.1923. found m/z=283.1928.

1-[4-(4-Fluorophenyl)-1H-1,2,3-triazol-1-yl]-octahydro-2H-quinolizine (35)

(42) By following the general procedure C, the product was isolated in the form of a white solid with a yield of 94% in the form of two separable diastereoisomers in the proportions of 3/2.

(43) Minority Diastereoisomer:

(44) R.sub.f: 0.39 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 99/1/0.1); Mp: 142 C. IR (ATR, Diamond): (cm.sup.1): 1048, 1113, 1158, 1222, 1297, 1347, 1449, 1494, 1557, 1611, 2754, 2798, 2926, 3104; .sup.1H NMR (250 MHz, CDCl.sub.3): (ppm) 1.02-1.30 (m, 3H), 1.49-1.74 (m, 3H), 1.81-2.05 (m, 3H), 2.07-2.30 (m, 4H), 2.81-3.02 (m, 2H), 4.20-4.38 (m, 1H), 7.11 (t, 2H, J=8.8 Hz), 7.68 (s, 1H), 7.80 (dd, 2H, J=8.8 Hz and 5.3 Hz); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 24.0 (CH.sub.2), 24.3 (CH.sub.2), 25.7 (CH.sub.2), 29.0 (CH.sub.2), 32.4 (CH.sub.2), 55.9 (CH.sub.2), 56.5 (CH.sub.2), 64.0 (CH), 66.5 (CH), 116.0 (d, 2CH.sub.aromatic, J=22 Hz), 118.6 (.sub.aromaticCH), 127.1 (d, C.sub.q, J=3 Hz), 127.6 (d, 2CH.sub.aromatic, J=8 Hz), 146.7 (C.sub.q), 162.8 (d, C.sub.q, J=247 Hz); HRMS (EI-MS): calculated for C.sub.17H.sub.22FN.sub.4 m/z=301.1829. found m/z=301.1826.

(45) Majority Diastereoisomer:

(46) R.sub.f: 0.50 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 99/1/0.1); Mp: 136 C. IR (ATR, Diamond): (cm.sup.1): 1050, 1159, 1223, 1346, 1448, 1493, 1557, 1612, 2794, 2927, 3104; .sup.1H NMR (250 MHz, CDCl.sub.3): (ppm) 1.39-1.57 (m, 1H), 1.60-1.95 (m, 7H), 1.96-2.09 (m, 1H), 2.18-2.38 (m, 1H), 2.42-2.66 (m, 2H), 3.02-3.23 (m, 3H), 4.36-4.53 (m, 1H), 7.11 (t, 2H, J=8.7 Hz), 7.70 (s, 1H), 7.80 (d, 2H, J=8.6 Hz and 5.4 Hz); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 22.7 (CH.sub.2), 23.4 (CH.sub.2), 29.5 (CH.sub.2), 30.7 (CH.sub.2), 35.7 (CH.sub.2), 55.3 (CH.sub.2), 58.2 (CH.sub.2), 67.4 (CH), 67.9 (CH), 116.0 (d, 2CH.sub.aromatic, J=22 Hz), 118.1 (.sub.aromaticCH), 127.2 (d, C.sub.q, J=3 Hz), 127.6 (d, 2CH.sub.aromatic, J=8 Hz), 146.8 (C.sub.q), 162.8 (d, C.sub.q, J=247 Hz); HRMS (EI-MS): calculated for C.sub.17H.sub.22FN.sub.4 m/z=301.1829. found m/z=301.1831.

Preparation of Quinuclidine Type Compounds 37-57 and 80-83 (Formula (II-2))

(47) ##STR00077## ##STR00078## ##STR00079## ##STR00080##

(48) General Procedure D:

(49) Under argon atmosphere, the 3-aminoquinuclidine 36 (212 mg, 1.00 mmol) and 1H-imidazole-1-sulfonyl azide 15 (232 mg, 1.10 mmol) were dissolved in 6 mL of methanol, to which the following were then added successively: K.sub.2CO.sub.3 (415 mg, 3.00 mmol) and a catalytic amount of CuSO.sub.45H.sub.2O (25 mg, 0.100 mmol). The reaction medium was stirred at ambient temperature for a period of 6 hours and then concentrated under reduced pressure. The resulting solid obtained was then taken up again in 10 mL of ethyl ether, vacuum filtered and washed two times with 10 mL of ethyl ether. Finally, the filtrate was evaporated under reduced pressure and the resulting azide thus obtained was engaged in the subsequent step without any further purification.

(50) The latter was dissolved in 6 mL of methanol to which the following were then added successively: the desired alkyne (1.00 mmol), CuSO.sub.45H.sub.2O (25 mg, 0.100 mmol) and sodium ascorbate (40 mg, 0.200 mmol). The reaction medium was stirred at ambient temperature for a period of 12 hours. At the end of the reaction time, the methanol was evaporated under reduced pressure and then the residue was chromatographed by column chromatography on silica gel with the eluent used being a mixture of CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH that enables good separation. In order to remove the traces of imidazole that are often present in the chromatographed triazole products, the mixture was dissolved in ethyl acetate, washed two times with water, dried over anhydrous MgSO.sub.4 and evaporated to dryness.

(R)-3-(4-Phenyl-1H-1,2,3-triazol-1-yl)quinuclidine (37)

(51) The product was isolated in the form of a white solid with a yield of 33% by following the general procedure D. R.sub.f: 0.29 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 80/20/0.1); Mp: 132 C. IR (ATR, Diamond): (cm.sup.1): 973, 1023, 1043, 10.60, 1072, 1211, 1227, 1411, 1453, 1482, 2870, 2937; .sup.1H NMR (250 MHz, CDCl.sub.3): (ppm) 1.45-1.61 (m, 1H), 1.68-1.79 (m, 1H), 1.82-1.92 (m, 1H), 2.32 (q, 1H, J=3.1

(52) Hz), 2.90-3.10 (m, 3H), 3.15-3.35 (m, 1H), 3.56 (dd, 1H, J=9.9 Hz and 2.2 Hz), 3.62 (dd, 1H, J=9.9 Hz and 2.2 Hz), 3.81 (dd, 1H, J=14.4 Hz and 5.2 Hz), 4.69-4.79 (m, 1H), 7.29-7.37 (m, 1H), 7.39-7.47 (m, 2H), 7.81-7.86 (m, 2H), 7.85 (s, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 19.9 (CH.sub.2), 25.6 (CH.sub.2), 28.3 (CH), 47.0 (CH.sub.2), 47.4 (CH.sub.2), 52.4 (CH.sub.2), 58.0 (CH), 119.4 (.sub.aromaticCH), 125.9 (2CH.sub.aromatic), 128.4 (.sub.aromaticCH), 129.1 (2CH.sub.aromatic), 130.7 (C.sub.q), 147.9 (C.sub.q); HRMS (EI-MS): calculated for C.sub.16H.sub.19N.sub.4 m/z=255.1610. found m/z=255.1613.

(R)-(4-(1-(Quinuclidin-3-yl)-1H-1,2,3-triazol-4-yl)phenyl)methanol (38)

(53) The product was isolated in the form of a white solid with a yield of 32% by following the general procedure D. R.sub.f: 0.11 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 80/20/0.1); Mp: 200 C. IR (ATR, Diamond): (cm.sup.1): 978, 1017, 1041, 1059, 1221, 1337, 1428, 1450, 1610, 2878, 2939, 3127, 3353; .sup.1H NMR (250 MHz, DMSO-d.sub.6): (ppm) 1.39-1.56 (m, 2H), 1.71-1.82 (m, 2H), 2.22 (q, 1H, J=3.0 Hz), 2.77-2.87 (m, 3H), 2.95-3.08 (m, 1H), 3.34-3.55 (m, 3H), 4.56 (d, 1H, J=4.4 Hz), 4.74-4.83 (m, 1H), 5.25 (t, 1H, J=4.4 Hz), 7.42 (d, 2H, J=8.3 Hz), 7.87 (d, 2H, J=8.3 Hz), 8.74 (s, 1H); .sup.13C NMR (100 MHz, DMSO-d.sub.6): (ppm) 19.6 (CH.sub.2), 25.3 (CH.sub.2), 27.6 (CH), 46.3 (CH.sub.2), 46.6 (CH.sub.2), 51.9 (CH.sub.2), 57.4 (CH), 62.6 (CH.sub.2), 120.6 (.sub.aromaticCH), 124.9 (2CH.sub.aromatic), 126.8 (2CH.sub.aromatic), 129.3 (C.sub.q), 142.1 (C.sub.q), 146.1 (C.sub.q); HRMS (EI-MS): calculated for C.sub.16H.sub.21N.sub.4O m/z=285.1715. found m/z=285.1702.

(R)-3-(4-(4-Chlorophenyl)-1H-1,2,3-triazol-1-yl)quinuclidine (39)

(54) The product was isolated in the form of a white solid with a yield of 28% by following the general procedure D. R.sub.f: 0.41 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 80/20/0.1); Mp: 144 C. IR (ATR, Diamond): (cm.sup.1): 971, 1014, 1060, 1092, 1190, 1202, 1324, 1401, 1433, 1452, 1468, 1484, 2868, 2939, 3110; .sup.1H NMR (250 MHz, CDCl.sub.3): (ppm) 1.40-1.50 (m, 1H), 1.60-1.73 (m, 1H), 1.73-1.87 (m, 2H), 2.28 (sext, 1H, J=3.1 Hz), 2.84-3.00 (m, 3H), 3.08-3.22 (m, 1H), 3.49 (ddd, 1H, J=14.3 Hz, 9.9 Hz and 2.2 Hz), 3 70 (dd, 1H, J=14.3 Hz and 5.0 Hz), 4.55-4.71 (m, 1H), 7.40 (d, 2H, J=8.7 Hz), 7.77 (d, 2H, J=8.7 Hz), 7.80 (s, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 20.2 (CH.sub.2), 26.2 (CH.sub.2), 28.4 (CH), 47.1 (CH.sub.2), 47.5 (CH.sub.2), 52.9 (CH.sub.2), 58.7 (CH), 119.2 (.sub.aromaticCH), 127.1 (2CH.sub.aromatic), 129.3 (2CH.sub.aromatic), 129.4 (C.sub.q), 134.1 (C.sub.q), 146.7 (C.sub.q); HRMS (EI-MS): calculated for C.sub.15H.sub.18N.sub.4Cl m/z=289.1220. found m/z=289.1211.

(R)-3-(4-(3,4-Dichlorophenyl)-1H-1,2,3-triazol-1-yl)quinuclidine (40)

(55) The product was isolated in the form of a white solid with a yield of 17% by following the general procedure D. R.sub.f: 0.33 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 80/20/0.1); Mp: 108 C. IR (ATR, Diamond): (cm.sup.1): 986, 1029, 1044, 1133, 1231, 1324, 1457, 1561, 1606, 2871, 2942, 3385; .sup.1H NMR (250 MHz, CDCl.sub.3): (ppm) 1.41-1.57 (m, 1H), 1.59-1.74 (m, 1H), 1.76-1.87 (m, 2H), 2.28 (q, 1H, J=3.0 Hz), 2.86-3.00 (m, 3H), 3.08-3.22 (m, 1H), 3.44-3.57 (m, 1H), 3.70 (dd, 1H, J=14.4 Hz and 5.0 Hz), 4.61-4.71 (m, 1H), 7.48 (d, 1H, J=8.4 Hz), 7.65 (dd, 1H, J=8.4 Hz and 1.9 Hz), 7.84 (s, 1H), 7.91 (d, 1H, J=1.9 Hz); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 20.1 (CH.sub.2) 26.0 (CH.sub.2), 28.3 (CH), 47.1 (CH.sub.2), 47.4 (CH.sub.2), 52.7 (CH.sub.2), 58.7 (CH), 119.7 (.sub.aromaticCH), 125.0 (.sub.aromaticCH), 127.6 (.sub.aromaticCH), 130.9 (C.sub.q), 131.0 (.sub.aromaticCH), 132.1 (C.sub.q), 133.2 (C.sub.q), 145.6 (C.sub.q); HRMS (EI-MS): calculated for C.sub.15H.sub.17N.sub.4Cl.sub.2 m/z=323.0830. found m/z=323.0827.

(R)-3-(4-(4-Bromophenyl)-1H-1,2,3-triazol-1-yl)quinuclidine (41)

(56) The product was isolated in the form of a white solid with a yield of 23% by following the general procedure D. R.sub.f: 0.32 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 80/20/0.1); Mp: 158 C. IR (ATR, Diamond): (cm.sup.1): 972, 1009, 1043, 1060, 1070, 1186, 1218, 1315, 1424, 1451, 1479, 2867, 2936; .sup.1H NMR (250 MHz, CDCl.sub.3): (ppm) 1.40-1.57 (m, 1H), 1.60-1.72 (m, 1H), 1.72-1.86 (m, 2H), 2.28 (q, 1H, J=3.1 Hz), 2.86-3.00 (m, 3H), 3.07-3.22 (m, 1H), 3.49 (ddd, 1H, J=14.5 Hz, 9.8 Hz and 2.2 Hz), 3.69 (dd, 1H, J=14.4 Hz and 5.0 Hz), 4.58-4.71 (m, 1H), 7.54 (d, 2H, J=8.6 Hz), 7.71 (d, 2H, J=8.6 Hz), 7.81 (s, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 20.2 (CH.sub.2), 26.2 (CH.sub.2), 28.4 (CH), 47.1 (CH.sub.2), 47.5 (CH.sub.2), 52.9 (CH.sub.2), 58.7 (CH), 119.3 (.sub.aromatic CH), 122.2 (C.sub.q), 127.4 (2CH.sub.aromatic), 129.8 (C.sub.q), 132.2 (2CH.sub.aromatic), 146.8 (C.sub.q); HRMS (EI-MS): calculated for C.sub.15H.sub.18N.sub.4Br m/z=333.0715. found m/z=333.0722.

(R)-3-(4-(4-Fluorophenyl)-1H-1,2,3-triazol-1-yl)quinuclidine (42)

(57) The product was isolated in the form of a white solid with a yield of 29% by following the general procedure D. R.sub.f: 0.37 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 80/20/0.1); Mp: 180 C. IR (ATR, Diamond): (cm.sup.1): 973, 1014, 1044, 1060, 1160, 1225, 1453, 1495, 1560, 2375, 2869, 2936; .sup.1H NMR (250 MHz, DMSO-d.sub.6): g (ppm) 1.49-1.62 (m, 2H), 1.81-1.94 (m, 2H), 2.31-2.36 (m, 1H), 2.94-3.08 (m, 3H), 3.12-3.26 (m, 1H), 3.57-3.71 (m, 2H), 3.91-5.02 (m, 1H), 7.34 (t, 2H, J=8.6 Hz), 7.94 (dd, 2H, J=8.6 Hz and 5.3 Hz), 8.83 (s, 1H); .sup.13C NMR (100 MHz, DMSO-d.sub.6): (ppm) 19.7 (CH.sub.2), 23.8 (CH.sub.2), 27.1 (CH), 45.9 (CH.sub.2), 46.1 (CH.sub.2), 50.8 (CH.sub.2), 56.3 (CH), 115.8 (d, 2CH.sub.aromatic, J=22 Hz), 121.0 (.sub.aromaticCH), 127.1 (d, 2CH.sub.aromatic, J=8 Hz), 127.3 (d, C.sub.q, J=3 Hz), 145.4 (C.sub.q), 161.7 (d, C.sub.q, J=244 Hz), HRMS (EI-MS): calculated for C.sub.15H.sub.18FN.sub.4 m/z=273.1516. found m/z=273.1508.

(R)-3-(4-(3-Fluorophenyl)-1H-1,2,3-triazol-1-yl)quinuclidine (43)

(58) The product was isolated in the form of a solid white with a 29% by following the general procedure D. R.sub.f: 0.31 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 80/20/0.1); Mp: 120 C. IR (ATR, Diamond): (cm.sup.1): 1041, 1061, 1148, 1214, 1266, 1315, 1345, 1449, 1487, 1589, 1620, 2869, 2936; .sup.1H NMR (250 MHz, CDCl.sub.3): g (ppm) 1.40-1.55 (m, 1H), 1.60-1.72 (m, 1H), 1.72-1.86 (m, 2H), 2.28 (q, 1H, J=3.1 Hz), 2.84-3.00 (m, 3H), 3.08-3.22 (m, 1H), 3.50 (ddd, 1H, J=14.5 Hz, 9.8 Hz and 2.0 Hz), 3.70 (dd, 1H, J=14.5 Hz and 5.0 Hz), 4.60-4.70 (m, 1H), 7.03 (td, 1H, J=8.3 Hz and 2.3 Hz), 7.33-7.44 (m, 1H), 7.52-7.63 (m, 1H), 7.59 (s, 1H), 7.82 (s, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 20.2 (CH.sub.2), 26.2 (CH.sub.2), 28.4 (CH), 47.1 (CH.sub.2), 47.5 (CH.sub.2), 52.9 (CH.sub.2), 58.8 (CH), 112.8 (d, .sub.aromaticCH, J=22 Hz), 115.1 (d, .sub.aromaticCH, J=22 Hz), 119.6 (.sub.aromatic CH), 121.5 (d, .sub.aromaticCH, J=3 Hz), 130.6 (d, .sub.aromaticCH, J=8 Hz), 133.0 (d, C.sub.q, J=8 Hz), 146.8 (d, C.sub.q, J=3 Hz), 163.4 (d, C q, J=246 Hz); HRMS (EI-MS): calculated for C.sub.15H.sub.18FN.sub.4 m/z=273.1516. found m/z=273.1516.

(R)-3-(4-(2-Fluorophenyl)-1H-1,2,3-triazol-1-yl)quinuclidine (44)

(59) The product is isolated in the form of a white solid with a yield of 22% by following the general procedure D. R.sub.f: 0.42 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 80/20/0.1); Mp: 94 C. IR (ATR, Diamond): (cm.sup.1): 970, 1045, 1068, 1227, 1328, 1452, 1487, 1644, 2932, 3142, 3352; .sup.1H NMR (250 MHz, CDCl.sub.3): (ppm) 1.41-1.55 (m, 1H), 1.63-1.74 (m, 1H), 1.76-1.88 (m, 2H), 2.30 (q, 1H, J=3.1 Hz), 2.87-3.00 (m, 3H), 3.10-3.24 (m, 1H), 3.50 (ddd, 1H, J=14.4 Hz, 9.8 Hz and 2.2 Hz), 3.75 (dd, 1H, J=14.4 Hz and 4.7 Hz), 4.63-4.72 (m, 1H), 7.09-7.18 (m, 1H), 7.22-7.34 (m, 2H), 7.98 (d, 1H, J=3.7 Hz), 8.32 (dd, 1H, J=7.5 Hz and 2.2 Hz); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 20.2 (CH.sub.2), 26.2 (CH.sub.2), 28.4 (CH), 47.1 (CH.sub.2), 47.5 (CH.sub.2), 52.8 (CH.sub.2) 58.6 (CH), 115.8 (d, .sub.aromaticCH, J=22 Hz), 118.8 (d, C.sub.q, J=13 Hz), 122.4 (d, .sub.aromaticCH, J=13 Hz), 124.8 (d, .sub.aromaticCH, J=3 Hz), 128.0 (d, .sub.aromaticCH, J=3 Hz), 129.5 (d, .sub.aromaticCH, J=8 Hz), 141.2 (CO.sub.3159.4 (d, C.sub.q, J=248 Hz); HRMS (EI-MS): calculated for C.sub.16H.sub.18FN.sub.4 m/z=273.1516. found m/z=273.1529.

(R)-3-(4-(3,4-difluorophenyl)-1H-1,2,3-triazol-1-yl) quinuclidine (45)

(60) The product was isolated in the form of a white solid with a yield of 24% by following the general procedure D. R.sub.f: 0.33 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 80/20/0.1); Mp: 122 C. IR (ATR, Diamond): (cm.sup.1): 969, 989, 1025, 1045, 1059, 1207, 1281, 1449, 1508, 1606, 2869, 2942; .sup.1H NMR (250 MHz, CDCl.sub.3): (ppm) 1.40-1.55 (m, 1H), 1.59-1.74 (m, 1H), 1.74-1.88 (m, 2H), 2.26 (sext, 1H, J=3.1 Hz), 2.85-2.99 (m, 3H), 3.07-3.20 (m, 1H), 3.48 (ddd, 1H, J=14.4 Hz, 9.7 Hz and 2.1 Hz), 3.69 (dd, 1H, J=14.4 Hz and 4.8 Hz), 4.59-4.68 (m, 1H), 7.14-7.26 (m, 1H), 7.50-7.57 (m, 1H), 7.66 (ddd, 1H, J=11.2 Hz, 7.6 Hz and 2.1 Hz), 7.78 (s, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 20.2 (CH.sub.2), 26.2 (CH.sub.2), 28.4 (CH), 47.1 (CH.sub.2), 47.5 (CH.sub.2), 52.8 (CH.sub.2) 58.8 (CH), 114.9 (d, .sub.aromaticCH, J=18 Hz), 117.9 (d, .sub.aromaticCH, J=18 Hz), 119.4 (.sub.aromaticCH), 121.9 (q, .sub.aromaticCH, J=6 Hz and 4 Hz), 128.0 (q, C.sub.q, J=6 Hz and 4 Hz), 146.0 (C.sub.q), 150.3 (q, C.sub.q, J=248 Hz and 13 Hz), 150.8 (q, C.sub.q, J=248 Hz and 13 Hz); HRMS (EI-MS): calculated for C.sub.16H.sub.17F.sub.2N.sub.4 m/z=291.1421. found m/z=291.1423.

(R)-3-(4-(4-Methoxyphenyl)-1H-1,2,3-triazol-1-yl)quinuclidine (46)

(61) The product was isolated in the form of a white solid with a yield of 21% by following the general procedure D. R.sub.f: 0.33 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 80/20/0.1); Mp: 122 C. IR (ATR, Diamond): (cm.sup.1): 1029, 1060, 1106, 1177, 1249, 1307, 1454, 1497, 1561, 1618, 2870, 2937, 3399; .sup.1H NMR (250 MHz, DMSO-d.sub.6): (ppm) 1.38-1.50 (m, 2H), 1.72-1.82 (m, 2H), 2.19-2.26 (m, 1H), 2.74-2.92 (m, 3H), 2.96-3.17 (m, 1H), 3.33-3.62 (m, 2H), 3.83 (s, 3H), 4.74-4.83 (m, 1H), 7.05 (d, 2H, J=8.5 Hz), 7.83 (d, 2H, J=8.6 Hz), 8.66 (s, 1H); .sup.13C NMR (100 MHz, DMSO-d.sub.6): (ppm) 19.6 (CH.sub.2), 25.2 (CH.sub.2), 27.6 (CH), 46.3 (CH.sub.2), 46.6 (CH.sub.2), 51.8 (CH.sub.2), 55.1 (CH.sub.3), 57.2 (CH), 114.2 (2CH.sub.aromatic), 119.9 (.sub.aromaticCH), 123.5 (C.sub.q), 126.5 (2CH.sub.aromatic), 146.1 (C.sub.q), 158.9 (C.sub.q); HRMS (EI-MS): calculated for C.sub.16H.sub.21N.sub.4O m/z=285.1715. found m/z=285.1726.

(R)-3-(4-(3-Methoxyphenyl)-1H-1,2,3-triazol-1-yl)quinuclidine (47)

(62) The product was isolated in the form of a yellowish oil with a yield of 32% by following the general procedure

(63) D. R.sub.f: 0.45 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 80/20/0.1); IR (ATR, Diamond): (cm.sup.1): 1040, 1158, 1243, 1282, 1321, 1455, 1483, 1584, 1610, 2872, 2942; .sup.1H NMR (250 MHz, CDCl.sub.3): (ppm) 1.39-1.54 (m, 1H), 1.61-1.72 (m, 1H), 1.72-1.85 (m, 2H), 2.27 (sext, 1H, J=3.1 Hz), 2.84-2.98 (m, 3H), 3.08-3.22 (m, 1H), 3.48 (ddd, 1H, J=14.5 Hz, 9.8 Hz and 2.2 Hz), 3.71 (dd, 1H, J=14.5 Hz and 4.8 Hz), 3.85 (s, 3H), 4.59-4.68 (m, 1H), 6.85-6.90 (m, 1H) 7.28-7.38 (m, 2H), 7.44-7.47 (m, 1H), 7.80 (s, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 20.2 (CH.sub.2) 26.2 (CH.sub.2), 28.3 (CH), 47.1 (CH.sub.2), 47.5 (CH.sub.2), 52.8 (CH.sub.2), 55.6 (CH.sub.3), 58.6 (CH), 110.9 (.sub.aromaticCH), 114.4 (.sub.aromaticCH), 118.2 (.sub.aromaticCH), 119.4 (.sub.aromaticCH), 130.1 (.sub.aromatic CH), 132.1 (C.sub.q), 147.6 (C.sub.q), 160.2 (C.sub.q); HRMS (EI-MS): calculated for C.sub.16H.sub.21N.sub.4O m/z=285.1715. found m/z=285.1719.

(R)-3-(4-(2-Methoxyphenyl)-1H-1,2,3-triazol-1-yl)quinuclidine (48)

(64) The product was isolated in the form of a white solid with a yield of 28% following the general procedure D. R.sub.f: 0.50 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 80/20/0.1); Mp: 120 C. IR (ATR, Diamond): (cm.sup.1): 969, 1017, 1043, 1067, 1120, 1240, 1322, 1434, 1488, 1583, 2864, 2927; .sup.1H NMR (250 MHz, CDCl.sub.3): (ppm) 1.37-1.52 (m, 1H), 1.63-1.74 (m, 1H), 1.74-1.85 (m, 2H), 2.28 (sext, 1H, J=3.1 Hz), 2.85-2.99 (m, 3H), 3.10-3.24 (m, 1H), 3.46 (ddd, 1H, J=14.3 Hz, 9.8 Hz and 2.2 Hz), 3.75 (dd, 1H, J=14.3 Hz and 5.2 Hz), 3.94 (s, 3H), 4.59-4.68 (m, 1H), 6.97 (d, 1H, J=8.3 Hz), 7.08 (td, 1H, J=7.6 Hz and 1.1 Hz), 7.31 (ddd, 1H, J=8.3 Hz, 7.6 Hz and 1.8 Hz), 8.08 (s, 1H), 8.35 (dd, 1H, J=7.6 Hz and 1.8 Hz); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 20.3 (CH.sub.2), 26.2 (CH.sub.2), 28.4 (CH), 47.2 (CH.sub.2), 47.5 (CH.sub.2), 52.8 (CH.sub.2), 55.6 (CH.sub.3), 58.4 (CH), 111.0 (.sub.aromaticCH), 120.0 (C.sub.q), 121.3 (.sub.aromaticCH), 122.7 (.sub.aromaticCH), 127.8 (.sub.aromaticCH), 129.0 (.sub.aromaticCH), 143.1 (C.sub.q), 155.8 (C.sub.q); HRMS (EI-MS): calculated for C.sub.16H.sub.21N.sub.4O m/z=285.1723. found m/z=285.1715.

(R)-3-(4-(6-Methoxynaphthalen-2-yl)-1H-1,2,3-triazol-1-yl)quinuclidine (49)

(65) The product was isolated in the form of a white solid with a yield of 21% by following the general procedure D. R.sub.f: 0.29 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 80/20/0.1); Mp: 186 C. IR (ATR, Diamond): (cm.sup.1): 906, 1025, 1123, 1162, 1210, 1262, 1344, 1394, 1454, 1479, 1612, 1630, 2869, 2932; .sup.1H NMR (250 MHz, CDCl.sub.3): (ppm) 1.42-1.56 (m, 1H), 1.65-1.76 (m, 1H), 1.76-1.88 (m, 2H), 2.31 (q, 1H, J=3.1 Hz), 2.86-3 02 (m, 3H), 3.10-3.24 (m, 1H), 3.52 (ddd, 1H, J=14.4 Hz, 9.7 Hz and 2.1 Hz), 3.73 (dd, 1H, J=14.4 Hz and 5.2 Hz), 3.93 (s, 3H), 4.58-4.75 (m, 1H), 7.15 (s, 1H), 7.14-7.20 (m, 1H), 7.79 (d, 2H, J=9.2 Hz), 7.89 (s, 1H), 7.91 (dd, 1H, J=8.6 Hz and 1.7 Hz), 8.26 (s, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 20.3 (CH.sub.2), 26.2 (CH.sub.2) 28.4 (CH), 47.2 (CH.sub.2), 47.5 (CH.sub.2), 52.9 (CH.sub.2), 55.6 (CH.sub.3), 58.7 (CH), 106.0 (CH.sub.aro), 119.0 (.sub.aromaticCH), 119.5 (.sub.aromaticCH), 124.5 (.sub.aromaticCH), 124.6 (.sub.aromatic CH), 126.1 (C.sub.q), 127.6 (.sub.aromaticCH), 129.2 (C.sub.q), 129.9 (.sub.aromatic CH), 134.6 (C.sub.q), 148.0 (C.sub.q), 158.1 (C.sub.q); HRMS (EI-MS): calculated for C.sub.20H.sub.23N.sub.4O m/z=335.1872. found m/z=335.1866.

(R)-3-(4-(Pyridin-4-yl)-1H-1,2,3-triazole-1-yl)quinuclidine (50)

(66) The product was isolated in the form of a brown solid with a yield of 30% by following the general procedure D. R.sub.f: 0.21 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 80/20/0.1); Mp: 150 C. IR (ATR, Diamond): (cm.sup.1): 991, 1041, 1058, 1073, 1208, 1227, 1325, 1413, 1430, 1562, 1613, 2869, 2935; .sup.1H NMR (250 MHz, CDCl.sub.3): (ppm) 1.42-1.56 (m, 1H), 1.60-1.76 (m, 1H), 1.76-1.88 (m, 2H), 2.29 (q, 1H, J=3.1 Hz), 2.86-3.00 (m, 3H), 3.07-3.25 (m, 1H), 3.50 (ddd, 1H, J=14.5 Hz, 9.7 Hz and 2.1 Hz), 3.71 (dd, 1H, J=14.4 Hz and 5.0 Hz), 4.63-4.72 (m, 1H), 7.73 (d, 2H, J=6.0 Hz), 7.95 (s, 1H), 8.66 (d, 2H, J=6.0 Hz); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 20.2 (CH.sub.2), 26.2 (CH.sub.2), 28.4 (CH), 47.1 (CH.sub.2), 47.5 (CH.sub.2), 52.9 (CH.sub.2), 59.0 (CH), 120.1 (2CH.sub.aromatic), 120.7 (.sub.aromatic CH), 138.2 (C.sub.q), 145.3 (C.sub.q), 150.7 (2CH aromatic); HRMS (EI-MS): calculated for C.sub.14H.sub.18N.sub.5 m/z=256.1562. found m/z=256.1550.

(R)-3-(4-(6-fluoropyridin-3-yl)-1H-1,2,3-triazol-1-yl) quinuclidine (51)

(67) The product was isolated in the form of a white solid with a yield of 18% by following the general procedure D. R.sub.f: 0.32 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 80/20/0.1); Mp: 147 C. IR (ATR, Diamond): (cm.sup.1): 976, 1024, 1044, 1060, 1237, 1316, 1429, 1471, 1552, 1593, 2870, 2935; .sup.1H NMR (400 MHz, CDCl.sub.3): (ppm) 1.45-1.54 (m, 1H), 1.63-1.72 (m, 1H), 1.74-1.90 (m, 2H), 2.29 (q, 1H, J=3.1 Hz), 2.87-3.02 (m, 3H), 3.11-3.20 (m, 1H), 3.51 (ddd, 1H, J=14.4 Hz, 9.8 Hz and 2.0 Hz), 3.71 (dd, 1H, J=14.4 Hz and 5.1 Hz), 4.63-4.69 (m, 1H), 7.02 (dd, 1H, J=8.5 Hz and 2.9 Hz), 7.87 (s, 1H), 8.28-8.37 (m, 1H), 8.60 (d, 1H, J=2.5 Hz); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 20.2 (CH.sub.2), 26.2 (CH.sub.2), 28.4 (CH), 47.1 (CH.sub.2), 47.5 (CH.sub.2), 52.9 (CH.sub.2), 58.9 (CH), 110.1 (d, .sub.aromaticCH, J=38 Hz), 119.4 (.sub.aromaticCH), 125.3 (d, C.sub.q, J=5 Hz), 138.7 (d, .sub.aromaticCH, J=8 Hz), 143.8 (CO.sub.3144.9 (d, .sub.aromaticCH, J=15 Hz), 163.5 (d, C.sub.q, J=240 Hz); HRMS (EI-MS): calculated for C.sub.14H.sub.17N.sub.5F m/z=274.1468. found m/z=274.1465.

(R)-3-(4-(6-Methoxypyridin-3-yl)-1H-1,2,3-triazol-1-yl)quinuclidine (52)

(68) The product was isolated in the form of a white solid with a yield of 28% by following the general procedure D. R.sub.f: 0.28 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 80/20/0.1); Mp: 155 C. IR (ATR, Diamond): (cm.sup.1): 973, 1027, 1215, 1254, 1282, 1325, 1420, 1481, 1555, 1614, 1729, 2869, 2938; .sup.1H NMR (250 MHz, CDCl.sub.3): (ppm) 1.40-1.55 (m, 1H), 1.62-1.74 (m, 1H), 1.74-1.88 (m, 2H), 2.27 (q, 1H, J=3.0 Hz), 2.84-3.00 (m, 3H), 3.08-3.22 (m, 1H), 3.42-3.56 (m, 1H), 3.72 (dd, 1H, J=14.3 Hz and 4.3 Hz), 3.97 (s, 3H), 4.58-4.69 (m, 1H), 6.81 (d, 1H, J=8.6 Hz), 7.77 (s, 1H), 8.07 (dd, 1H, J=8.6 Hz and 2.2 Hz), 8.56 (d, 1H, J=2.2 Hz); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 20.3 (CH.sub.2), 26.2 (CH.sub.2), 28.4 (CH), 47.2 (CH.sub.2), 47.5 (CH.sub.2), 52.9 (CH.sub.2), 53.8 (CH.sub.3), 58.8 (CH), 111.3 (.sub.aromaticCH), 118.7 (.sub.aromaticCH), 120.5 (C.sub.q), 136.5 (.sub.aromatic CH), 144.3 (.sub.aromaticCH), 145.0 (C.sub.q), 164.2 (C.sub.q); HRMS (EI-MS): calculated for C.sub.15H.sub.20N.sub.5O m/z=286.1668. found m/z=286.1681.

(R)-3-(4-(Thiophen-2-yl)-1H-1,2,3-triazol-1-yl)quinuclidine (53)

(69) The product was isolated in the form of a brown solid with a yield of 38% following the general procedure D. R.sub.f: 0.42 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 80/20/0.1); Mp: 137 C. IR (ATR, Diamond): (cm.sup.1): 931, 973, 1027, 1042, 1062, 1159, 1212, 1295, 1316, 1432, 1451, 2867, 2937, 3074; .sup.1H NMR (250 MHz, CDCl.sub.3): (ppm) 1.38-1.53 (m, 1H), 1.59-1.72 (m, 1H), 1.72-1.85 (m, 2H), 2.26 (q, 1H, J=3.1 Hz), 2.83-2.98 (m, 3H), 3.06-3.20 (m, 1H), 3.47 (ddd, 1H, J=14.5 Hz, 9.7 Hz and 2.0 Hz), 3.68 (dd, 1H, J=14.5 Hz and 5.0 Hz), 4.57-4.66 (m, 1H), 7.07 (dd, 1H, J=5.1 Hz and 3.6 Hz), 7.25-7.30 (m, 1H), 7.38 (dd, 1H, J=3.6 Hz and 1.1 Hz), 7.73 (s, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 20.2 (CH.sub.2), 26.2 (CH.sub.2), 28.3 (CH), 47.1 (CH.sub.2), 47.4 (CH.sub.2), 52.8 (CH.sub.2), 58.7 (CH), 118.7 (.sub.aromaticCH), 124.3 (.sub.aromaticCH), 125.2 (.sub.aromaticCH), 127.8 (.sub.aromatic CH), 133.2 (C.sub.q), 142.9 (C.sub.q); HRMS (EI-MS): calculated for C.sub.13H.sub.17N.sub.4S m/z=261.1174. found m/z=261.1185.

(R)-3-(4-(5-Bromothiophen-2-yl)-1H-1,2,3-triazol-1-yl) quinuclidine (54)

(70) The product was isolated in the form of a white solid with a yield of 42% by following the general procedure D. R.sub.f: 0.46 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 80/20/0.1); Mp: 146 C. IR (ATR, Diamond): (cm.sup.1): 972, 1041, 1057, 1215, 1322, 1433, 1496, 1645, 2867, 2934, 3356; .sup.1H NMR (400 MHz, CDCl.sub.3): (ppm) 1.44-1.51 (m, 1H), 1.59-1.69 (m, 1H), 1.71-1.87 (m, 2H), 2.25 (q, 1H, J=3.0 Hz), 2.83-2.99 (m, 3H), 3.07-3.16 (m, 1H), 3.47 (ddd, 1H, J=14.4 Hz, 9.8 Hz and 2.2 Hz), 3.66 (ddd, 1H, J=14.4 Hz, 5.1 Hz and 1.6 Hz), 4.57-4.63 (m, 1H), 7.00 (d, 1H, J=3.8 Hz), 7.08 (d, 1H, J=3.8 Hz), 7.69 (s, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 20.1 (CH.sub.2), 26.1 (CH.sub.2), 28.3 (CH), 47.0 (CH.sub.2), 47.4 (CH.sub.2), 52.7 (CH.sub.2), 58.7 (CH), 112.1 (C.sub.q), 118.7 (.sub.aromaticCH), 124.3 (.sub.aromaticCH), 130.6 (.sub.aromaticCH), 134.8 (C.sub.q), 142.1 (C.sub.q); HRMS (EI-MS): calculated for C.sub.13H.sub.16N.sub.4SBr m/z=339.0279. found m/z=339.0283.

(R)-3-(4 Benzo[b](thiophen-5-yl)-1H-1,2,3-triazol-1-yl) quinuclidine (55)

(71) The product was isolated in the form of a white solid with a yield of 32% by following the general procedure D. R.sub.f: 0.32 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 80/20/0.1); Mp: 178 C. IR (ATR, Diamond): (cm.sup.1): 1023, 1047, 1202, 1223, 1323, 1440, 2866, 2933; .sup.1H NMR (250 MHz, CDCl.sub.3): (ppm) 1.44-1.53 (m, 1H), 1.66-1.76 (m, 1H), 1.76-1.88 (m, 2H), 2.30 (q, 1H, J=3.0 Hz), 2.86-3.00 (m, 3H), 3.11-3.21 (m, 1H), 3.50 (ddd, 1H, J=14.5 Hz, 9.8 Hz and 2.1 Hz), 3.70 (dd, 1H, J=14.5 Hz and 5.0 Hz), 4.62-4.69 (m, 1H), 7.37 (d, 1H, J=5.4 Hz), 7.47 (d, 1H, J=5.4 Hz), 7.80 (dd, 1H, J=8.4 Hz and 1.1 Hz), 7.86 (s, 1H), 7.92 (d, 1H, J=8.4 Hz), 8.33 (d, 1H, J=1.1 Hz); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 20.3 (CH.sub.2), 26.2 (CH.sub.2), 28.4 (CH), 47.2 (CH.sub.2), 47.5 (CH.sub.2), 52.9 (CH.sub.2), 58.6 (CH), 119.1 (.sub.aromaticCH), 120.8 (.sub.aromaticCH), 122.4 (CH.sub.aromatic), 123.1 (.sub.aromaticCH), 124.2 (.sub.aromaticCH), 127.2 (C.sub.q), 127.4 (.sub.aromaticCH), 139.6 (C.sub.q), 140.2 (C.sub.q), 147.9 (C.sub.q); HRMS (EI-MS): calculated for C.sub.17H.sub.19N.sub.4S m/z=311.1330. found m/z=311.1322.

(R)-3-(4-(Benzofuran-5-yl)-1H-1,2,3-triazol-1-yl)quinuclidine (56)

(72) The product was isolated in the form of a white solid with a yield of 34% by following the general procedure D. R.sub.f: 0.34 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 80/20/0.1); Mp: 178 C. IR (ATR, Diamond): (cm.sup.1): 989, 1029, 1042, 1062, 1109, 1194, 1221, 1321, 1455, 1497, 2870, 2935; .sup.1H NMR (250 MHz, CDCl.sub.3): (ppm) 1.44-1.53 (m, 1H), 1.67-1.77 (m, 1H), 1.77-1.89 (m, 2H), 2.30 (q, 1H, J=3.0 Hz), 2.88-3.00 (m, 3H), 3.12-3.22 (m, 1H), 3.46-3.55 (m, 1H), 3.73 (dd, 1H, J=14.3 Hz and 4.3 Hz), 4.63-4.69 (m, 1H), 6.81 (d, 1H, J=2.1 Hz), 7.54 (d, 1H, J=8.6 Hz), 7.64 (d, 1H, J=2.1 Hz), 7.76 (dd, 1H, J=8.6 Hz and 1.6 Hz), 7.82 (s, 1H), 8.10 (d, 1H, J=1.6 Hz); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 20.3 (CH.sub.2), 26.2 (CH.sub.2), 28.4 (CH), 47.2 (CH.sub.2), 47.5 (CH.sub.2), 52.9 (CH.sub.2), 58.6 (CH), 107.0 (.sub.aromaticCH), 111.9 (.sub.aromaticCH), 118.6 (.sub.aromaticCH), 118.8 (.sub.aromaticCH), 122.6 (.sub.aromaticCH), 125.9 (C.sub.q), 128.2 (C.sub.q), 145.9 (.sub.aromaticCH), 148.2 (C.sub.q), 155.1 (C.sub.q); HRMS (EI-MS): calculated for C.sub.17H.sub.19N.sub.4O m/z=295.1559. found m/z=295.1557.

(S)-3-(4-(4-Fluorophenyl)-1H-1,2,3-triazol-1-yl)quinuclidine (57)

(73) The product was isolated in the form of a white solid with a yield of 33% by following the general procedure D. R.sub.f: 0.37 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 80/20/0.1); Mp: 139 C. IR (ATR, Diamond): (cm.sup.1): 974, 1022, 1042, 1060, 1160, 1225, 1330, 1400, 1452, 1494, 1560, 1612, 2869, 2936; .sup.1H NMR (250 MHz, CDCl.sub.3): (ppm) 1.39-1.54 (m, 1H), 1.60-1.74 (m, 1H), 1.74-1.88 (m, 2H), 2.26 (sext, 1H, J=3.1 Hz), 2.84-2.98 (m, 3H), 3.07-3.21 (m, 1H), 3.48 (ddd, 1H, J=14.4 Hz, 9.8 Hz and 2.3 Hz), 3.70 (dd, 1H, J=14.4 Hz and 5.1 Hz), 4.59-4.68 (m, 1H), 7.11 (t, 2H, J=8.6 Hz), 7.77 (s, 1H), 7.77-7.84 (m, 2H); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 20.3 (CH.sub.2), 26.2 (CH.sub.2), 28.4 (CH), 47.2 (CH.sub.2), 47.5 (CH.sub.2), 52.9 (CH.sub.2), 58.7 (CH), 116.0 (d, 2CH.sub.aro, J=22 Hz), 118.9 (.sub.aromaticCH), 127.1 (d, C.sub.q, J=3 Hz), 127.6 (d, 2CH.sub.aro, J=8 Hz), 146.9 (C.sub.q), 162.8 (d, C.sub.q, J=247 Hz); HRMS (EI-MS): calculated for C.sub.15H.sub.18N.sub.4F m/z=273.1516. found m/z=273.1509.

(R)-3-[4-(5-Bromo-2-furyl)-1H-1,2,3-triazol-1-yl]quinuclidine (80)

(74) The product was isolated in the form of a white solid with a yield of 38% by following the general procedure D. R.sub.f: 0.26 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 95/5/1); Mp: 144 C.; IR (ATR, Diamond): (cm.sup.1): 972, 1047, 1057, 1228, 1343, 1476, 1530, 1624, 2869, 2937, 3126; .sup.1H NMR (400 MHz, CDCl.sub.3): (ppm) 1.44-1.51 (m, 1H), 1.59-1.67 (m, 1H), 1.73-1.87 (m, 2H), 2.25 (q, 1H, J=3.2 Hz), 2.85-3.00 (m, 3H), 3.07-3.15 (m, 1H), 3.49 (ddd, 1H, J=14.4 Hz, 10.0 Hz and 2.4 Hz), 3.64 (dd, 1H, J=14.4 Hz, 4.0 Hz), 4.63-4.66 (m, 1H), 6.40 (d, 1H, J=3.6 Hz), 6.82 (d, 1H, J=3.6 Hz), 7.8 (s, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 19.9 (CH.sub.2), 25.9 (CH.sub.2), 28.0 (CH), 46.9 (CH.sub.2), 47.2 (CH.sub.2), 52.6 (CH.sub.2), 58.5 (CH), 108.8 (CH), 113.2 (CH), 118.6 (CH), 121.4 (C.sub.q), 139.4 (C.sub.q), 148.3 (C.sub.q); HRMS (EI-MS): calculated for C.sub.13H.sub.16N.sub.4OBr m/z=323.05020. found m/z=323.05015.

(R)-3-[4-(4-bromo-2-thienyl)-1H-1,2,3-triazol-1-yl]quinuclidine (81)

(75) The product was isolated in the form of a white solid with a yield of 50% by following the general procedure D. R.sub.f: 0.24 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 98/2/1); Mp: 106 C.; IR (ATR, Diamond): (cm.sup.1): 786, 988, 1054, 1226, 1326, 1452, 1497, 2870, 2938, 3107; .sup.1H NMR (400 MHz, CDCl.sub.3): (ppm) 1.45-1.52 (m, 1H), 1.61-1.69 (m, 1H), 1.76-1.85 (m, 2H), 2.26 (q, 1H, J=3.2 Hz), 2.85-3.00 (m, 3H), 3.09-3.16 (m, 1H), 3.49 (ddd, 1H, J=14.4 Hz, 10.0 Hz and 2.1 Hz), 3.66 (dd, 1H, J=14.4 Hz and 5.2 Hz), 4.60-4.65 (m, 1H), 7.19 (s, 1H), 7.26 (s, 1H), 7.74 (s, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 19.9 (CH.sub.2), 25.9 (CH.sub.2), 28.1 (CH), 46.9 (CH.sub.2), 47.2 (CH.sub.2), 52.6 (CH.sub.2), 58.6 (CH), 110.2 (C.sub.q), 118.7 (CH), 122.1 (CH), 126.4 (CH), 134.3 (C.sub.q), 141.5 (C.sub.q); HRMS (EI-MS): calculated for C.sub.13H.sub.16N.sub.4SBr m/z=339.02766. found m/z=339.02736.

(R)-3-[4-(4-bromo-2-furyl)-1H-1,2,3-triazol-1-yl]quinuclidine (82)

(76) The product was isolated in the form of a white solid with a yield of 43% by following the general procedure D. R.sub.f: 0.22 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 98/2/1); Mp: 129 C.; IR (ATR, Diamond): (cm.sup.1): 785, 980, 1042, 1210, 1325, 1452, 1534, 2869, 2940, 3115; .sup.1H NMR (400 MHz, CDCl.sub.3): (ppm) 1.43-1.50 (m, 1H), 1.58-1.67 (m, 1H), 1.72-1.87 (m, 2H), 2.26 (q, 1H, J=2.8 Hz), 2.85-2.99 (m, 3H), 3.07-3.14 (m, 1H), 3.48 (ddd, 1H, J=14.4 Hz, 10.0 Hz and 2.2 Hz), 3.65 (dd, 1H, J=14.4 Hz and 3.6 Hz), 4.62-4.65 (m, 1H), 6.87 (s, 1H), 7.44 (s, 1H), 7.78 (s, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 19.9 (CH.sub.2), 25.9 (CH.sub.2), 28.0 (CH), 46.8 (CH.sub.2), 47.2 (CH.sub.2), 52.6 (CH.sub.2), 58.5 (CH), 101.3 (C.sub.q), 109.7 (CH), 119.0 (CH), 139.3 (C.sub.q), 140.1 (CH), 147.2 (C.sub.q); HRMS (EI-MS): calculated for C.sub.13H.sub.16N.sub.4OBr m/z=323.05045. found m/z=323.05020.

(R)-3-[4-(3-bromophenyl)-1H-1,2,3-triazol-1-yl]quinuclidine (83)

(77) The product was isolated in the form of a white solid with a yield of 50% by following the general procedure D. R.sub.f: 0.18 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 97/3/1); Mp: 188 C. IR (ATR, Diamond): (cm.sup.1): 970, 1020, 1041, 1060, 1069, 1233, 1341, 14237 1455, 1470, 1603, 2868, 2938; .sup.1H NMR (400 MHz, CDCl.sub.3): (ppm) 1.44-1.50 (m, 1H), 1.61-1.65 (m, 1H), 1.73-1.87 (m, 2H), 2.27 (q, 1H, J=3.2 Hz), 2.86-3.00 (m, 3H), 3.09-3.17 (m, 1H), 3.49 (ddd, 1H, J=14.4 Hz, 9.8 Hz and 2.2 Hz), 3.68 (dd, 1H, J=14.4 Hz and 3.6 Hz), 4.63-4.65 (m, 1H), 7.29 (t, 1H, J=7.6 Hz), 7.45 (d, 1H, J=8.0 Hz), 7.78 (d, 1H, J=8.0 Hz), 7.83 (s, 1H), 7.98 (s, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3) (ppm) 20.0 (CH.sub.2), 26.0 (CH.sub.2), 28.1 (CH), 46.9 (CH.sub.2), 47.2 (CH.sub.2), 52.6 (CH.sub.2), 58.5 (CH), 119.3 (CH), 122.9 (C.sub.q), 124.1 (CH), 128.6 (CH), 130.4 (CH), 131.0 (CH), 132.6 (C.sub.q), 146.1 (C.sub.q); HRMS (EI-MS): calculated for C.sub.15H.sub.18N.sub.4.Br m/z=333.07111. found m/z=333.07094.

Fluorination of Alcohol 38

(78) ##STR00081##

(R)-3-(4-(4-(Fluoromethyl)phenyl)-1H-1,2,3-triazol-1-yl)quinuclidine (58)

(79) The alcohol 38 (140 mg, 0.500 mmol) was dissolved in 10 mL of dichloromethane and then at 0 C., diethylaminosulfur trifluoride (92 L, 0.700 mmol) was added to it drop by drop. The reaction mixture was stirred at 0 C. for a period of one hour and then hydrolysed with the addition of a saturated NaHCO.sub.3 solution. The organic phase was dried over anhydrous MgSO.sub.4, and filtered and concentrated under reduced pressure. The fluorinated compound 58 was purified by column chromatography on silica gel with the eluent used being a mixture of CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH (90/10/0.1). The product 58 was isolated in the form of a white solid with a yield of 51%. R.sub.f: 0.41 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 80/20/0.1); Mp: 138 C.; IR (ATR, Diamond): (cm.sup.1): 974, 1010, 1043, 1060, 1212, 1317, 1382, 1407, 1453, 1500, 2870, 2940; .sup.1H NMR (250 MHz, CDCl.sub.3): (ppm) 1.41-1.56 (m, 1H), 1.62-1.74 (m, 1H), 1.74-1.94 (m, 2H), 2.30 (q, 1H, J=3.1 Hz), 2.86-3.00 (m, 3H), 3.09-3.24 (m, 1H), 3.50 (ddd, 1H, J=14.6 Hz, 9.6 Hz and 2.0 Hz), 3.72 (dd, 1H, J=14.5 Hz and 5.1 Hz), 4.61-4.70 (m, 1H), 5.41 (d, 2H, J=47.8 Hz), 7.44 (dd, 2H, J=8.6 Hz and 1.6 Hz), 7.84 (s, 1H), 7.88 (dd, 2H, J=8.6 Hz and 1.0 Hz); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 20.3 (CH.sub.2), 26.2 (CH.sub.2), 28.4 (CH), 47.1 (CH.sub.2), 47.5 (CH.sub.2), 52.9 (CH.sub.2), 58.7 (CH), 84.5 (d, CH.sub.2, J=166 Hz), 119.4 (.sub.aromaticCH), 126.1 (2CH.sub.aromatic), 128.2 (d, 2CH.sub.aro, J=6 Hz), 131.4 (d, C.sub.q, J=3 Hz), 136.2 (d, C.sub.q, J=17 Hz), 147.3 (C.sub.q); HRMS (EI-MS): calculated for C.sub.16H.sub.20N.sub.4F m/z=287.1672. found m/z=287.1660.

Preparation of the Quinuclidine Type Compound 60 Comprising a Triazole Ring Substituted in Position 4 and 5

(80) ##STR00082##

(R)-4-Phenyl-1-(quinuclidin-3-yl)-1H-1,2,3-triazol-5-amine (60)

(81) Under argon atmosphere, 3(R)-aminoquinuclidine 36 (400 mg, 2.00 mmol) and the and 1H-imidazole-1-sulfonyl azide 15 (464 mg, 2.20 mmol) were dissolved in 12 mL of methanol, to which the following were then added successively: K.sub.2CO.sub.3 (830 mg, 6.00 mmol) and a catalytic amount of CuSO.sub.45H.sub.2O (50 mg, 0.200 mmol). The reaction medium was stirred at ambient temperature for a period of 6 hours and then concentrated under reduced pressure. The resulting solid obtained was then taken up again in 20 mL of ethyl ether, vacuum filtered and then washed two times with 20 mL of ethyl ether. After evaporation of the filtrate under reduced pressure, the azide 59 was engaged in the subsequent step without any further purification. To a solution of azide 59 (2.00 mmol) in 10 mL of anhydrous THF, the following were added at ambient temperature: phenyl acetonitrile (0.28 mL, 2.40 mmol) and t-BuOK (337 mg, 3.00 mmol). The reaction medium was stirred at ambient temperature under argon atmosphere for a period of 12 hours. Thereafter the solvent was evaporated and then the residue was taken up again in dichloromethane and washed with water. The organic phase was dried over anhydrous MgSO.sub.4, and filtered and evaporated under reduced pressure. The product was purified by column chromatography on silica gel with the eluent used being a mixture of CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH (90/10/0.1) and then (70/30/0.1). The amine 60 was isolated in the form of a white solid with a yield of 43%. R.sub.f: 0.11 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 70/30/0.1); mp: 120 C. IR (ATR, Diamond): (cm.sup.1): 982, 1007, 1056, 1266, 1323, 1360, 1445, 1510, 1585, 1607, 1633, 2870, 2940, 3175, 3307; .sup.1H NMR (250 MHz, CDCl.sub.3): (ppm) 1.33-1.48 (m, 1H), 1.72-2.00 (m, 3H), 2.12 (q, 1H, J=3.1 Hz), 2.82-3.01 (m, 3H), 3.26-3.40 (m, 2H), 3.71-3.80 (m, 2H), 4.01 (dd, 1H, J=14.2 Hz, 4.8 Hz), 4.23-4.32 (m, 1H), 7.27-7.35 (m, 1H), 7.41-7.49 (m, 2H), 7.67-7.72 (m, 2H); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 19.9 (CH.sub.2), 26.1 (CH.sub.2), 26.9 (CH), 47.2 (CH.sub.2), 47.4 (CH.sub.2) 51.5 (CH.sub.2), 54.7 (CH), 125.9 (2CH.sub.aromatic), 127.2 (.sub.aromatic CH), 129.2 (2CH.sub.aromatic), 131.7 (C.sub.q), 131.9 (C.sub.q), 137.3 (C.sub.q); HRMS (EI-MS): calculated for C.sub.13H.sub.20N.sub.3 m/z=270.1719. found m/z=270.1732.

Preparation of Quinuclidine Type Compounds 61-63 and 84-111

(82) ##STR00083## ##STR00084## ##STR00085## ##STR00086##

(83) General Procedure E1:

(84) To a solution of a brominated derivative selected from among the compounds 54, 41 and 80-83 (50 mg, 0.147 mmol) in a mixture of 1.5 mL of toluene and 0.5 ml of ethanol, the following were added: the desired boronic acid (0.176 mmol), K.sub.2CO.sub.3 (41 mg, 0.294 mmol) and tetrakis(triphenylphosphine)palladium (17 mg, 0.0147 mmol). After degassing, the reaction mixture was irradiated with microwave at 150 C. for a period of 10 minutes. The solvent was then evaporated and the residue was purified by column chromatography on silica gel with the eluent used being a mixture of CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH (80/20/0.1).

(R)-3-(4-(2,7-Bithiophen-5-yl)-1H-1,2,3-triazol-1-yl)quinuclidine (61)

(85) The product was isolated in the form of a brown solid with a yield of 73% by following the general procedure E1. R.sub.f: 0.25 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 80/20/0.1); Mp: 182 C. IR (ATR, Diamond): (cm.sup.1): 1042, 1067, 1210, 1340, 1425, 1454, 1503, 1584, 2867, 2937; .sup.1H NMR (400 MHz, CDCl.sub.3): (ppm) 1.44-1.54 (m, 1H), 1.63-1.74 (m, 1H), 1.76-1.88 (m, 2H), 2.26-2.30 (m, 1H), 2.86-3.00 (m, 3H), 3.10-3.20 (m, 1H), 3.45-3.54 (m, 1H), 3.70 (dd, 1H, J=14.3 Hz and 4.6 Hz) 4.60-4 67 (m, 1H), 7.03 (dd, 1H, J=4.9 Hz and 3.8 Hz), 7.14 (d, 1H, J=3.6 Hz), 7.19-7.24 (m, 2H), 7.28 (d, 1H, J=3.6 Hz), 7.73 (s, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 20.1 (CH.sub.2), 26.1 (CH.sub.2), 28.3 (CH), 47.1 (CH.sub.2), 47.4 (CH.sub.2), 52.7 (CH.sub.2), 58.7 (CH), 118.6 (.sub.aromaticCH), 124.0 (.sub.aromaticCH), 124.3 (.sub.aromaticCH), 124.7 (.sub.aromaticCH), 124.8 (.sub.aromaticCH), 128.1 (.sub.aromaticCH), 131.8 (C.sub.q), 137.1 (C.sub.q), 137.3 (C.sub.q), 142.6 (C.sub.q); HRMS (EI-MS): calculated for C.sub.17H.sub.19N.sub.4O.sub.2 m/z=343.1051. found m/z=343.1055.

(R)-3-(4-(5-(Furan-2-yl)thiophen-2-yl)-1H-1,2,3-triazol-1-yl)quinuclidine (62)

(86) The product was isolated in the form of a white solid with a yield of 83% by following the general procedure E1. R.sub.f: 0.27 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 80/20/0.1); Mp: 180 C. IR (ATR, Diamond): (cm.sup.1): 977, 1070, 1442, 1647, 2939, 3243; .sup.1H NMR (400 MHz, CDCl.sub.3): (ppm) 1.44-1.53 (m, 1H), 1.64-1.73 (m, 1H), 1.76-1.88 (m, 2H), 2.28 (q, 1H, J=3.0 Hz), 2.87-3.01 (m, 3H), 3.10-3.20 (m, 1H), 3.49 (ddd, 1H, J=14.4 Hz, 9.8 Hz and 2.1 Hz), 3.68 (ddd, 1H, J=14.4 Hz, 5.0 Hz and 1.5 Hz), 4.61-4.66 (m, 1H), 6.46 (dd, 1H, J=3.4 Hz and 1.8 Hz), 6.54 (d, 1H, J=3.4 Hz), 7.21 (d, 1H, J=3.8 Hz), 7.31 (d, 1H, J=3.8 Hz), 7.41-7.42 (m, 1H), 7.73 (s, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 20.1 (CH.sub.2), 26.1 (CH.sub.2), 28.3 (CH), 47.1 (CH.sub.2), 47.4 (CH.sub.2), 52.8 (CH.sub.2), 58.7 (CH), 105.6 (.sub.aromaticCH), 112.0 (.sub.aromaticCH), 118.6 (CH.sub.aromatic), 123.1 (.sub.aromaticCH), 124.8 (.sub.aromaticCH), 131.8 (C.sub.q), 133.4 (C.sub.q), 142.0 (.sub.aromaticCH), 142.6 (C.sub.q), 149.3 (C.sub.q); HRMS (EI-MS): calculated for C.sub.17H.sub.19N.sub.4OS m/z=327.1280. found m/z=327.1284.

(R)-(4-(5-(1-(quinuclidin-3-yl)-1H-1,2,3-triazol-4-yl)thiophen-2-yl)phenyl)methanol (63)

(87) The product was isolated in the form of a white solid with a yield of 72% by following the general procedure E1. R.sub.f: 0.17 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 80/20/0.1); Mp: 253 C. IR (ATR, Diamond): (cm.sup.1): 983, 1041, 1214, 1306, 1355, 1416, 1454, 1502, 2823, 2872, 2941, 3110; .sup.1H NMR (400 MHz, DMSO-d.sub.6): (ppm) 1.38-1.52 (m, 2H), 1.72-1.80 (m, 2H), 2.20-2.26 (m, 1H), 2.76-2.85 (m, 3H), 2.96-3.05 (m, 1H), 3.34-3.51 (m, 2H), 4.56 (d, 2H, J=4.8 Hz), 4.76-7.82 (m, 1H), 5.27 (t, 1H, J=4.8 Hz), 7.41 (d, 2H, J=7.8 Hz), 7.47 (d, 1H, J=3.1 Hz), 7.54 (d, 1H, J=3.1 Hz), 7.69 (d, 2H, J=7.8 Hz), 8.72 (s, 1H); .sup.13C NMR (100 MHz, DMSO-d.sub.6): (ppm) 19.6 (CH.sub.2), 25.3 (CH.sub.2), 27.6 (CH), 46.3 (CH.sub.2), 46.6 (CH.sub.2), 51.9 (CH.sub.2), 57.6 (CH), 62.5 (CH.sub.2), 120.3 (.sub.aromaticCH), 123.9 (.sub.aromaticCH), 124.9 (2CH.sub.aromatic), 125.1 (.sub.aromaticCH), 127.1 (2CH.sub.aromatic), 131.9 (C.sub.q), 132.1 (C.sub.q), 141.4 (C.sub.q), 142.2 (2C.sub.q); HRMS (EI-MS): calculated for C.sub.20H.sub.23N.sub.4OS m/z=367.1593. found m/z=367.1609.

(R)-[4-[5-[1-[quinuclidin-3-yl]-1H-1,2,3-triazol-4-yl]-2-furyl]-phenyl]-methanol (84)

(88) The product was isolated in the form of a white solid with a yield of 72% by following the general procedure E1. R.sub.f: 0.17 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 96/4/1); Mp: 209 C.; IR (ATR, Diamond): (cm.sup.1): 792, 980, 1042, 1201, 1327, 1413, 1457, 1502, 2879, 2946, 3116; .sup.1H NMR (400 MHz, DMSO-d.sub.6): (ppm) 1.31-1.46 (m, 2H), 1.65-1.77 (m, 2H), 2.20-2.22 (m, 1H), 2.71-2.78 (m, 3H), 2.93-3.01 (m, 1H), 3.34-3.50 (m, 2H), 4.51 (d, 2H, J=5.5 Hz), 4.72-4.81 (m, 1H), 5.23 (t, 1H, J=5.5 Hz), 6.88 (d, 2H, J=3.2 Hz), 7.02 (d, 1H, J=3.2 Hz), 7.38 (d, 1H, J=8.2 Hz), 7.74 (d, 2H, J=8.2 Hz), 8.67 (s, 1H); .sup.13C NMR (100 MHz, DMSO-d.sub.6): (ppm) 20.0 (CH.sub.2), 25.7 (CH.sub.2), 28.1 (CH), 46.8 (CH.sub.2), 47.0 (CH.sub.2), 52.1 (CH.sub.2), 57.9 (CH), 63.0 (CH.sub.2), 107.6 (CH), 108.7 (CH), 121.0 (CH), 123.6 (2CH), 127.3 (2CH), 128.9 (C.sub.q), 139.3 (C.sub.q), 142.5 (C.sub.q), 146.0 (C.sub.q), 152.9 (C.sub.q); HRMS (EI-MS): calculated for C.sub.20H.sub.23N.sub.4O.sub.2 m/z=351.18155. found m/z=351.18154.

(R)-[3-[5-[1-[quinuclidin-3-yl]-1H2,3-triazol-4-yl]-2-thienyl]phenyl]methanol (85)

(89) The product was isolated in the form of a white solid with a yield of 75% by following the general procedure E1. R.sub.f: 0.17 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 98/2/1); Mp: 181 C.; IR (ATR, Diamond): (cm.sup.1): 796, 988, 1040, 1226, 1323, 1452, 1488, 2870, 2938, 3108; .sup.1H NMR (400 MHz, DMSO-d.sub.6): (ppm) 1.35-1.50 (m, 2H), 1.66-1.81 (m, 2H), 2.20-2.22 (m, 1H), 2.72-2.87 (m, 3H), 2.93-3.05 (m, 1H), 3.34-3.51 (m, 2H), 4.57 (s, 2H), 4.74-4.81 (m, 1H), 5.33 (bl, 1H), 7.28 (d, 1H, J=12.0 Hz), 7.39 (t, 1H, J=12.0 Hz), 7.46 (d, 1H, J=6.0 Hz), 7.53 (d, 1H, J=6.0 Hz), 7.58 (d, 1H, J=12.0 Hz), 7.65 (s, 1H), 8.70 (s, 1H); .sup.13C NMR (100 MHz, DMSO-d.sub.6): (ppm) 20.0 (CH.sub.2), 25.7 (CH.sub.2), 28.0 (CH), 46.7 (CH.sub.2), 47.0 (CH.sub.2), 52.2 (CH.sub.2), 57.9 (CH), 63.0 (CH.sub.2), 120.8 (CH), 123.5 (CH), 123.9 (CH), 124.6 (CH), 125.6 (CH), 126.2 (CH), 129.3 (CH), 132.8 (C.sub.q), 133.6 (C.sub.q), 141.8 (Cq), 142.8 (C.sub.q), 144.0 (C.sub.q); HRMS (EI-MS): calculated for C.sub.20H.sub.23N.sub.4OS m/z=367.15871. found m/z=367.15904.

(R)-[4-[5-[1-[quinuclidin-3-yl]-1H-1,2,3-triazol-4-yl]-3-thienyl]phenyl]methanol (86)

(90) The product was isolated in the form of a white solid with a yield of 72% by following the general procedure E1. R.sub.f: 0.18 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 98/2/1); Mp: 196 C.; IR (ATR, Diamond): (cm.sup.1): 749, 785, 981, 1042, 1061, 1211, 1325, 1413, 1452, 1534, 2870, 2941, 3116; .sup.1H NMR (400 MHz, DMSO-d.sub.6) (ppm) 1.34-1.50 (m, 2H), 1.66-1.78 (m, 2H), 2.19 (q, 1H, J=2.8 Hz), 2.74-2.83 (m, 3H), 2.94-3.01 (m, 1H), 3.40 (d, 2H, J=7.2 Hz), 4.51 (s, 2H), 4.75-4.79 (m, 1H), 5.20 (bl, 1H), 7.35 (d, 2H, J=8.2 Hz), 7.68 (d, 2H, J=8.2 Hz), 7.80 (d, 1H, J=0.8 Hz), 7.89 (d, 1H, J=0.8 Hz), 8.70 (s, 1H); .sup.13C NMR (100 MHz, DMSO-d.sub.6): (ppm) 19.9 (CH.sub.2), 25.6 (CH.sub.2), 28.0 (CH), 46.7 (CH.sub.2), 47.0 (CH.sub.2), 52.3 (CH.sub.2), 57.8 (CH), 63.0 (CH.sub.2), 120.1 (CH), 120.7 (CH), 123.3 (CH), 126.0 (2CH), 127.4 (2CH), 133.7 (C.sub.q), 134.3 (C.sub.q), 142.0 (C.sub.q), 142.1 (C.sub.q), 142.2 (C.sub.q); HRMS (EI-MS): calculated for C.sub.20H.sub.23N.sub.4OS m/z=367.15871. found m/z=367.15889.

(R)-3-[4-[5-(6-fluoro-3-pyridyl)-2-thienyl]-1H,1,2,3-triazol-1-yl]quinuclidine (87)

(91) The product was isolated in the form of a white solid with a yield of 80% by following the general procedure E1. R.sub.f: 0.20 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 98/2/1); Mp: 163 C.; IR (ATR, Diamond): (cm.sup.1): 784, 801, 986, 1077, 1241, 1320, 1387, 1447, 1526, 1581, 2871, 2939, 3127; .sup.1H NMR (400 MHz, CDCl.sub.3): (ppm) 1.46-1.52 (m, 1H), 1.64-1.71 (m, 1H), 1.74-1.87 (m, 2H), 2.28 (q, 1H, J=2.8 Hz), 2.86-3.00 (m, 3H), 3.10-3.14 (m, 1H), 3.46 (ddd, 1H, J=14.4 Hz, 10.0 Hz and 2.0 Hz), 3.66 (dd, 1H, J=14.4 Hz, 4.0 Hz), 4.63-4.65 (m, 1H), 6.96 (dd, 1H, J=8.4 Hz and 2.4 Hz), 7.26 (d, 1H, J=3.8 Hz), 7.35 (d, 1H, J=3.8 Hz), 7.78 (s, 1H), 7.97 (td, 1H, J=8.4 Hz and 2.2 Hz), 8.46 (d, 1H, J=2.2 Hz); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 20.0 (CH.sub.2), 25.9 (CH.sub.2), 28.1 (CH), 46.9 (CH.sub.2), 47.2 (CH.sub.2), 52.6 (CH.sub.2), 58.6 (CH), 109.7 (d, CH, J=38 Hz), 118.6 (CH), 124.7 (CH), 124.9 (CH), 128.4 (d, C.sub.q, J=5 Hz), 133.6 (C.sub.q), 138.2 (d, CH, J=8 Hz), 138.3 (C.sub.q), 142.1 (C.sub.q), 144.3 (d, CH, J=14 Hz), 162.8 (d, C.sub.q, J=239 Hz); HRMS (EI-MS): calculated for C.sub.18H.sub.19N.sub.5S m/z=356.13397. found m/z=356.13432.

(R)-3-[4-[4-(6-fluoro-3-pyridyl)-2-thienyl]-1H-1,2,3-triazol-1-yl]quinuclidine (88)

(92) The product was isolated in the form of a white solid with a yield of 79% by following the general procedure E1. R.sub.f: 0.20 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 98/2/1); Mp: 136 C.; IR (ATR, Diamond): (cm.sup.1): 793, 972, 1055, 1219, 1310, 1402, 1459, 1589, 2868, 2938, 3115; .sup.1H NMR (400 MHz, CDCl.sub.3): (ppm) 1.46-1.53 (m, 1H), 1.65-1.73 (m, 1H), 1.77-1.87 (m, 2H), 2.30 (q, 1H, J=2.8 Hz), 2.87-3.01 (m, 3H), 3.11-3.18 (m, 1H), 3.51 (ddd, 1H, J=14.4 Hz, 10.0 Hz and 2.0 Hz), 3.70 (dd, 1H, J=14.4 Hz and 4.0 Hz), 4.65-4.68 (m, 1H), 6.98 (dd, 1H, J=8.4 Hz and 2.8 Hz), 7.41 (s, 1H), 7.63 (s, 1H), 7.81 (s, 1H), 7.98 (td, 1H, J=8.4 Hz and 2.8 Hz), 8.46 (d, 1H, J=1.6 Hz); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 19.9 (CH.sub.2), 25.9 (CH.sub.2), 28.1 (CH), 46.9 (CH.sub.2), 47.2 (CH.sub.2), 52.6 (CH.sub.2), 58.6 (CH), 109.6 (d, CH, J=38 Hz), 118.7 (CH), 120.7 (CH), 122.5 (CH), 129.5 (d, C.sub.q, J=5 Hz), 134.7 (C.sub.q), 138.0 (C.sub.q), 138.8 (d, CH, J=7 Hz), 142.1 (C.sub.q), 145.0 (d, CH, J=15 Hz) 162.8 (d, C.sub.q, J=238 Hz); HRMS (EI-MS): calculated for C.sub.18H.sub.19N.sub.5SF m/z=356.13397. found m/z=356.13430.

(R)-[3-[5-[1-[quinuclidin-3-yl]-1H-1,2,3-triazol-4-yl]-3-thienyl]phenyl]methanol (89)

(93) The product was isolated in the form of a white solid with a yield of 77% by following the general procedure E1. R.sub.f: 0.21 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 98/2/1); Mp: 211 C.; IR (ATR, Diamond): (cm.sup.1): 787, 996, 1041, 1162, 1233, 1324, 1437, 1455, 1603, 2868, 2937, 3367; .sup.1H NMR (400 MHz, CDCl.sub.3): (ppm) 1.43-1.58 (m, 1H), 1.62-1.90 (m, 3H), 2.26-2.32 (m, 1H), 2.47 (bl, 1H), 2.83-3.01 (m, 3H), 3.09-3.19 (m, 1H), 3.46 (ddd, 1H, J=15.6 Hz, 12.0 Hz and 3.6 Hz), 3.66 (dd, 1H, J=15.6 Hz and 7.6 Hz), 4.60-4.69 (m, 1H), 4.76 (s, 2H), 7.32 (d, 1H, J=12.2 Hz), 7.38-7.44 (m, 2H), 7.56 (dd, 1H, J=12.2 Hz and 2.2 Hz), 7.66 (s, 1H), 7.70 (d, 1H, J=2.2 Hz), 7.78 (s, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 19.9 (CH.sub.2), 25.8 (CH.sub.2), 28.0 (CH), 46.8 (CH.sub.2), 47.1 (CH.sub.2), 52.5 (CH.sub.2), 58.4 (CH), 65.0 (CH.sub.2), 118.5 (CH), 119.9 (CH), 123.2 (CH), 124.8 (CH), 125.3 (CH), 125.8 (CH), 129.0 (CH), 133.7 (C.sub.q), 135.7 (C.sub.q), 141.8 (C.sub.q), 142.5 (2C.sub.q); HRMS (EI-MS): calculated for C.sub.20H.sub.23N.sub.4OS m/z=367.15871. found m/z=367.15909.

(R)-[4-[5-[1-[quinuclidin-3-yl]-1H-1,2,3-triazol-4-yl]-3-furyl]phenyl]methanol (90)

(94) The product was isolated in the form of a white solid with a yield of 71% by following the general procedure E1. R.sub.f: 0.2 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 96/4/1); Mp: 202 C.; IR (ATR, Diamond): (cm.sup.1): 795, 986, 1039, 1163, 1273, 1351, 1462, 1528, 1579, 2185, 2946; .sup.1H NMR (400 MHz, DMSO-d.sub.6): (ppm) 1.34-1.46 (m, 2H), 1.69-1.73 (m, 2H), 2.19 (q, 1H, J=2.8 Hz), 2.74-2.83 (m, 3H), 2.94-3.01 (m, 1H), 3.35-3.51 (m, 3H), 4.49 (s, 2H), 4.76-4.80 (m, 1H), 7.250 (s, 1H), 7.33 (d, 2H, J=8.2 Hz), 7.62 (d, 2H, J=8.2 Hz), 7.24 (s, 1H), 8.59 (s, 1H); .sup.13C NMR (100 MHz, DMSO-d.sub.6): (ppm) 19.9 (CH.sub.2), 25.5 (CH.sub.2), 28.0 (CH), 46.7 (CH.sub.2), 46.9 (CH.sub.2), 52.0 (CH.sub.2), 57.8 (CH), 63.1 (CH.sub.2), 105.2 (CH), 121.3 (CH), 125.7 (2CH), 127.3 (2CH), 127.7 (C.sub.q), 130.3 (C.sub.q), 139.1 (CH), 139.2 (C.sub.q), 141.9 (C.sub.q), 147.5 (C.sub.q); HRMS (EI-MS): calculated for C.sub.20H.sub.23N.sub.4O.sub.2 m/z=351.18155. found m/z=351.18173.

(R)-3-[4-[4-(6-fluoro-3-pyridyl)-2-furyl]-1H-1,2,3-triazol-1-yl]quinuclidine (91)

(95) The product was isolated in the form of a white solid with a yield of 73% by following the general procedure E1. R.sub.f: 0.22 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 96/4/1); Mp: 210 C.; IR (ATR, Diamond): (cm.sup.1): 791, 986, 1058, 1247, 1310, 1418, 1491, 1564, 2872, 2944, 3091; .sup.1H NMR (400 MHz, CDCl.sub.3): (ppm) 1.45-1.53 (m, 1H), 1.62-1.68 (m, 1H), 1.76-1.89 (m, 2H), 2.29 (q, 1H, J=3.2 Hz), 2.87-3.01 (m, 3H), 3.10-3.18 (m, 1H), 3.51 (ddd, 1H, J=14.4 Hz, 10.0 Hz and 3.2 Hz), 3.70 (dd, 1H, J=14.4 Hz and 4.8 Hz), 4.66-4.69 (m, 1H), 6.98 (dd, 1H, J=8.4 Hz and 2.8 Hz), 7.13 (s, 1H), 7.74 (s, 1H), 7.85 (s, 1H), 7.90 (td, 1H, J=8.4 Hz and 2.4 Hz), 8.40 (d, 1H, J=2.4 Hz); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 19.9 (CH.sub.2), 25.9 (CH.sub.2), 28.1 (CH), 46.9 (CH.sub.2), 47.2 (CH.sub.2), 52.7 (CH.sub.2), 58.6 (CH), 105.0 (CH), 109.7 (d, CH, J=38 Hz), 118.9 (CH), 124.0 (C.sub.q), 126.1 (d, C.sub.q, J=4 Hz), 137.8 (CH), 138.4 (d, CH, J=8 Hz), 139.7 (C.sub.q), 144.6 (d, CH, J=15 Hz), 148.0 (C.sub.q), 162.8 (d, C.sub.q, J=238 Hz); HRMS (EI-MS): calculated for C.sub.18H.sub.19N.sub.5FO m/z=340.15681. found m/z=340.15696.

(R)-[3-[5-[1-[quinuclidin-3-yl]-1H-1,2,3-triazol-4-yl]-3-furyl]phenyl]methanol (92)

(96) The product was isolated in the form of a white solid with a yield of 72% by following the general procedure E1. R.sub.f: 0.19 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 96/4/1); Mp: 212 C.; IR (ATR, Diamond): (cm.sup.1): 798, 970, 1041, 1205, 1343, 1438, 1455, 1567, 2868, 2939, 3397; .sup.1H NMR (400 MHz, CDCl.sub.3): (ppm) 1.40-1.53 (m, 1H), 1.60-1.66 (m, 1H), 1.74-1.84 (m, 2H), 2.26 (q, 1H, J=2.8 Hz), 2.82-2.96 (m, 3H), 3.03-3.10 (m, 2H), 3.44 (ddd, 1H, J=15.6 Hz, 12.0 Hz and 3.6 Hz), 3.58 (dd, 1H, J=15.6 Hz and 7.6 Hz), 4.62-4.64 (m, 1H), 4.71 (s, 2H), 7.15 (s, 1H), 7.28 (d, 1H, J=7.6 Hz), 7.56 (t, 1H, J=7.6 Hz), 7.43 (d, 1H, J=7.6 Hz), 7.54 (s, 1H), 7.73 (s, 1H), 7.78 (s, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 19.8 (CH.sub.2), 25.8 (CH.sub.2), 27.9 (CH), 46.7 (CH.sub.2), 47.0 (CH.sub.2), 52.4 (CH.sub.2), 58.3 (CH), 64.8 (CH.sub.2), 105.5 (CH), 118.7 (CH), 124.3 (CH), 124.8 (CH), 125.8 (CH), 128.0 (C.sub.q), 129.0 (CH), 132.1 (C.sub.q), 137.9 (CH), 140.0 (C.sub.q), 142.0 (C.sub.q), 147.2 (C.sub.q); HRMS (EI-MS): calculated for C.sub.20H.sub.23N.sub.4O.sub.2 m/z=351.18155. found m/z=351.18165.

(R)-[4-[4-[1-[quinuclidin-3-yl]-1H-1,2,3-triazol-4-yl]phenyl]phenyl]methanol (93)

(97) The product was isolated in the form of a white solid with a yield of 81% by following the general procedure E1. R.sub.f: 0.18 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 97/3/1); Mp: 250 C.; IR (ATR, Diamond): (cm.sup.1): 798, 973, 1042, 1223, 1344, 1429, 1451, 1661, 2869, 2938, 3119; .sup.1H NMR (400 MHz, DMSO-d.sub.6): (ppm) 1.36-1.49 (m, 2H), 1.69-1.75 (m, 2H), 2.20 (q, 1H, J=2.8 Hz), 2.73-2.80 (m, 3H), 2.96-3.03 (m, 1H), 3.35-3.49 (m, 2H), 4.54 (d, 2H, J=3.2 Hz), 4.75-4.77 (m, 1H), 5.21 (bl, 1H), 7.40 (d, 2H, J=8.2 Hz), 7.68 (d, 2H, J=8.2 Hz), 7.76 (d, 2H, J=8.4 Hz), 7.96 (d, 2H, J=8.4 Hz), 8.78 (s, 1H); .sup.13C NMR (100 MHz, DMSO-d.sub.6): (ppm) 20.0 (CH.sub.2) 25.7 (CH.sub.2), 28.1 (CH), 46.8 (CH.sub.2), 47.0 (CH.sub.2), 52.3 (CH.sub.2), 57.8 (CH), 63.0 (CH.sub.2), 121.3 (CH), 126.1 (2CH), 126.6 (2CH), 127.3 (2CH), 127.4 (2CH), 130.2 (C.sub.q), 138.3 (C.sub.q), 139.7 (C.sub.q), 142.3 (C.sub.q), 146.2 (C.sub.q); HRMS (EI-MS): calculated for C.sub.22H.sub.25N.sub.4O m/z=361.20229. found m/z=361.20277.

(R)-3-[4-[4-(6-fluoro-3-pyridyl)phenyl]-1H-1,2,3-triazol-1-yl]quinuclidine (94)

(98) The product was isolated in the form of a yellow solid with a yield of 85% by following the general procedure E1. R.sub.f: 0.22 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 97/3/1); Mp: 181 C.; IR (ATR, Diamond): (cm.sup.1): 811, 987, 1039, 1253, 1372, 1474, 1590, 2871, 2942, 3115; .sup.1H NMR (400 MHz, CDCl.sub.3): (ppm) 1.47-1.53 (m, 1H), 1.67-1.85 (m, 3H), 2.30 (q, 1H, J=3.2 Hz), 2.88-3.02 (m, 3H), 3.13-3.20 (m, 1H), 3.51 (ddd, 1H, J=14.2 Hz, 9.8 Hz and 2.2 Hz), 3.72 (dd, 1H, J=14.2 Hz and 4.0 Hz), 4.66-4.69 (m, 1H), 7.01 (dd, 1H, J=8.4 Hz and 2.8 Hz), 7.61 (d, 2H, J=8.2 Hz), 7.88 (s, 1H), 7.95 (d, 2H, J=8.4 Hz), 8.01 (td, 1H, J=8.2 Hz and 2.4 Hz), 8.45 (d, 1H, J=2.4 Hz); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 20.0 (CH.sub.2), 26.0 (CH.sub.2), 28.1 (CH), 46.9 (CH.sub.2) 47.3 (CH.sub.2), 52.7 (CH.sub.2), 58.5 (CH), 109.5 (d, CH, J=37 Hz), 119.2 (CH), 126.3 (2CH), 127.4 (2CH), 130.6 (C.sub.q), 134.2 (d, C.sub.q, J=4 Hz), 136.2 (C.sub.q), 139.5 (d, CH, J=8 Hz), 145.6 (d, CH, J=15 Hz), 146.8 (C.sub.q), 163.1 (d, C.sub.q, J=238 Hz); HRMS (EI-MS): calculated for C.sub.20H.sub.21N.sub.5F m/z=350.17755. found m/z=350.17782.

(R)-[3-[4-[1-[quinuclidin-3-yl]-1H-1,2,3-triazol-4-yl]phenyl]phenyl]methanol (95)

(99) The product was isolated in the form of a white solid with a yield of 80% by following the general procedure E1. R.sub.f: 0.18 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 97/3/1); Mp: 207 C.; IR (ATR, Diamond): (cm.sup.1): 792, 982, 1038, 1225, 1324, 1437, 1455, 1603, 2874, 2941, 3367; .sup.1H NMR (400 MHz, DMSO-d.sub.6): (ppm) 1.32-1.52 (m, 2H), 1.67-1.74 (m, 2H), 2.20 (q, 1H, J=2.8 Hz), 2.73-2.80 (m, 3H), 2.96-3.05 (m, 1H), 3.36-3.50 (m, 2H), 4.58 (s, 2H), 4.76-4.78 (m, 1H), 5.25 (bl, 1H), 7.32 (d, 1H, J=7.2 Hz), 7.43 (t, 1H, J=7.6 Hz), 7.58 (d, 1H, J=7.6 Hz), 7.67 (s, 1H), 7.75 (d, 2H, J=8.2 Hz), 7.97 (d, 2H, J=8.2 Hz), 8.79 (s, 1H); .sup.13C NMR (100 MHz, DMSO-d.sub.6): (ppm) 20.0 (CH.sub.2), 25.7 (CH.sub.2), 28.1 (CH), 46.8 (CH.sub.2), 47.0 (CH.sub.2), 52.2 (CH.sub.2), 57.8 (CH), 63.3 (CH.sub.2), 121.4 (CH), 124.9 (CH), 125.2 (CH), 126.1 (3CH), 127.4 (2CH), 129.1 (CH), 130.4 (C.sub.q), 139.8 (C.sub.q), 139.9 (C.sub.q), 143.7 (C.sub.q), 146.2 (C.sub.q); HRMS (EI-MS): calculated for C.sub.22H.sub.26N.sub.4O m/z=361.20229. found m/z=361.20262.

(R)-[4-[3-[1-[quinuclidin-3-yl]-1H-1,2,3-triazol-4-yl]phenyl]phenyl]methanol (98)

(100) The product was isolated in the form of a white solid with a yield of 87% by following the general procedure E1. R.sub.f: 0.18 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 97/3/1); Mp: 214 C.; IR (ATR, Diamond): (cm.sup.1): 793, 972, 1041, 1222, 1320, 1451, 1481, 1660, 2868, 2939, 3077; .sup.1H NMR (400 MHz, DMSO-d.sub.6): (ppm) 1.31-1.49 (m, 2H), 1.70-1.74 (m, 2H), 2.20 (q, 1H, J=2.8 Hz), 2.74-2.78 (m, 3H), 2.94-3.01 (m, 1H), 3.38-3.46 (m, 2H), 4.55 (s, 2H), 4.74-4.78 (m, 1H), 5.23 (bl, 1H), 7.42 (d, 2H, J=7.6 Hz), 7.51 (t, 1H, J=7.6 Hz), 7.61 (d, 1H, J=7.6 Hz), 7.69 (d, 2H, J=7.6 Hz), 7.87 (d, 1H, J=7.6 Hz), 8.14 (s, 1H), 8.85 (s, 1H); .sup.13C NMR (100 MHz, DMSO-d.sub.6): (ppm) 20.0 (CH.sub.2), 25.7 (CH.sub.2), 28.1 (CH), 46.8 (CH.sub.2), 47.0 (CH.sub.2), 52.3 (CH.sub.2), 57.8 (CH), 63.0 (CH.sub.2), 121.5 (CH), 123.7 (CH), 124.3 (CH), 126.3 (CH), 126.8 (2CH), 127.4 (2CH) 129.9 (CH), 131.9 (C.sub.q), 138.6 (C.sub.q), 141.0 (C.sub.q), 142.5 (C.sub.q), 146.5 (C.sub.q); HRMS (EI-MS): calculated for C.sub.22H.sub.26N.sub.4O m/z=361.20229. found m/z=361.20237.

(R)-[3-[3-[1-[quinuclidin-3-yl]-1H-1,2,3-triazol-4-yl]phenyl]phenyl]methanol (99)

(101) The product was isolated in the form of a white solid with a yield of 80% by following the general procedure E1. R.sub.f: 0.18 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 97/3/1); Mp: 201 C.; IR (ATR, Diamond): (cm.sup.1): 793, 984, 1042, 1262, 1326, 1423, 1436, 1612, 1697, 1719, 2870, 2943, 3133; .sup.1H NMR (400 MHz, DMSO-d.sub.6) (ppm) 1.34-1.48 (m, 2H), 1.69-1.75 (m, 2H), 2.20 (q, 1H, J=2.8 Hz), 2.75-2.79 (m, 3H), 2.94-3.01 (m, 1H), 3.35-3.48 (m, 2H), 4.58 (d, 2H, J=5.6 Hz), 4.72-4.79 (m, 1H), 5.25 (d, 1H, J=5.6 Hz), 7.34 (d, 1H, J=7.6 Hz), 7.44 (t, 1H, J=7.6 Hz), 7.51-7.63 (m, 3H), 7.66 (s, 1H), 7.87 (d, 1H, J=7.6 Hz), 8.14 (s, 1H), 8.85 (s, 1H); .sup.13C NMR (100 MHz, DMSO-d.sub.6): (ppm) 20.0 (CH.sub.2), 25.7 (CH.sub.2), 28.1 (CH), 46.8 (CH.sub.2), 47.0 (CH.sub.2), 52.2 (CH.sub.2), 57.8 (CH), 63.3 (CH.sub.2), 121.5 (CH), 123.8 (CH), 124.5 (CH), 125.2 (CH), 125.5 (CH), 126.2 (CH), 126.5 (CH), 129.1 (CH), 129.9 (CH), 131.9 (C.sub.q), 140.1 (C.sub.q), 141.3 (C.sub.q), 143.7 (C.sub.q), 146.5 (C.sub.q); HRMS (EI-MS): calculated for C.sub.22H.sub.25N.sub.4O m/z=361.20229. found m/z=361.20245.

(R)-3-[4-[3-(6-fluoro-3-pyridyl)phenyl]-1H-1,2,3-triazol-1-yl]quinuclidine (100)

(102) The product was isolated in the form of a white solid with a yield of 82% following the general procedure E1. R.sub.f: 0.23 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 97/3/1); Mp: 164 C.; IR (ATR, Diamond): (cm.sup.1): 789, 980, 1061, 1208, 1344, 1454, 1473, 1590, 2865, 2940, 3059; .sup.1H NMR (400 MHz, CDCl.sub.3): (ppm) 1.42-1.55 (m, 1H), 1.65-1.70 (m, 1H), 1.75-1.87 (m, 2H), 2.30 (q, 1H, J=3.2 Hz), 2.88-2.97 (m, 3H), 3.12-3.19 (m, 1H), 3.51 (ddd, 1H, J=14.4 Hz, 9.8 Hz and 2.2 Hz), 3.72 (dd, 1H, J=14.4 Hz and 4.0 Hz), 4.66-4.68 (m, 1H), 7.01 (dd, 1H, J=8.4 Hz and 2.8 Hz), 7.48-7.54 (m, 2H), 7.82 (d, 1H, J=7.2 Hz), 7.89 (s, 1H), 8.01-8.06 (m, 2H), 8.46 (d, 1H, J=2.0 Hz); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 20.0 (CH.sub.2), 25.9 (CH.sub.2), 28.1 (CH), 46.9 (CH.sub.2), 47.2 (CH.sub.2), 52.6 (CH.sub.2), 58.5 (CH), 109.4 (d, CH, J=37 Hz), 119.2 (CH), 124.3 (CH), 125.3 (CH), 126.7 (CH), 129.6 (CH), 131.6 (C.sub.q), 134.5 (d, C.sub.q, J=4 Hz), 137.4 (C.sub.q), 139.8 (d, CH, J=8 Hz), 145.8 (d, CH, J=15 Hz), 147.0 (C.sub.q), 163.2 (d, C.sub.q, J=238 Hz); HRMS (EI-MS): calculated for C.sub.20H.sub.21N.sub.5F m/z=350.17755. found m/z=350.17766.

(R)-3-[4-(5-phenyl-2-thienyl)-1H-1,2,3-triazol-1-yl]quinuclidine (106)

(103) The product was isolated in the form of a white solid with a yield of 80% by following the general procedure E1. R.sub.f: 0.25 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 98/2/1); Mp: 184 C.; IR (ATR, Diamond): (cm.sup.1): 789, 982, 1060, 1209, 1323, 1404, 1455, 1498, 1590, 2866, 2940, 3059; .sup.1H NMR (400 MHz, CDCl.sub.3): (ppm) 1.43-1.55 (m, 1H), 1.62-1.80 (m, 3H), 2.28 (q, 1H, J=2.8 Hz), 2.85-3.03 (m, 3H), 3.12-3.19 (m, 1H), 3.50 (ddd, 1H, J=14.4 Hz, 10.0 Hz and 2.8 Hz), 4.70 (dd, 1H, J=14.4 Hz and 4.0 Hz), 4.62-4.65 (m, 1H), 7.27-7.32 (m, 2H), 7.35-7.41 (m, 3H), 7.63 (t, 2H, J=7.6 Hz), 7.75 (s, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 20.0 (CH.sub.2), 26.0 (CH.sub.2), 28.1 (CH), 46.9 (CH.sub.2), 47.2 (CH.sub.2), 52.6 (CH.sub.2), 58.3 (CH), 118.4 (CH), 123.5 (CH), 124.9 (CH), 125.6 (2CH), 127.6 (CH), 128.9 (2CH), 132.2 (C.sub.q), 134.0 (C.sub.q), 142.6 (C.sub.q), 143.8 (C.sub.q); HRMS (EI-MS): calculated for C.sub.19H.sub.21N.sub.4S m/z=337.148144. found m/z=337.148472.

(104) ##STR00087## ##STR00088## ##STR00089##

(105) General Procedure E2:

(106) To a solution of a brominated derivative (compound 41, 54, 80, 81, 82 or 83) (1.0 mmol) in a mixture of 3 mL of toluene and 1 mL of methanol, the following were added: the desired boronic acid (1.2 mmol), K.sub.2CO.sub.3 (2.0 mmol) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (II) PdCl.sub.2(dppf) (0.01 mmol). After degassing, the reaction mixture was irradiated by microwave at 70 C. for a period of 50 minutes. The solvent was evaporated and then the residue was purified by column chromatography on silica gel with the eluent used being a mixture of CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH.

(R)-3-[4-[4-(2-thienyl)phenyl]-1H-1,2,3-triazol-1-yl]quinuclidine (96)

(107) The product was isolated in the form of a white solid with a yield of 86% by following the general procedure E2. R.sub.f: 0.17 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 97/3/1); Mp: 214 C.; IR (ATR, Diamond): (cm.sup.1): 791, 988, 1042, 1222, 1314, 1404, 1450, 1493, 2867, 2937, 3120; .sup.1H NMR (400 MHz, CDCl.sub.3): (ppm) 1.45-1.54 (m, 1H), 1.65-1.83 (m, 3H), 2.29 (q, 1H, J=2.8 Hz), 2.87-3.01 (m, 3H), 3.12-3.20 (m, 1H), 3.50 (ddd, 1H, J=14.4 Hz, 10.0 Hz and 3.2 Hz), 3.72 (dd, 1H, J=14.4 Hz and 3.2 Hz), 4.64-4.66 (m, 1H), 7.10 (dd, 1H, J=5.0 Hz and 3.6 Hz), 7.29 (dd, 1H, J=5.0 Hz and 1.2 Hz), 7.33-7.37 (m, 1H), 7.68 (d, 2H, J=8.4 Hz), 7.83-7.87 (m, 3H); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 20.0 (CH.sub.2) 26.0 (CH.sub.2), 28.1 (CH), 46.9 (CH.sub.2), 47.3 (CH.sub.2), 52.6 (CH.sub.2), 58.4 (CH), 118.9 (CH), 123.2 (CH), 124.9 (CH), 126.0 (2CH), 126.2 (2CH), 128.1 (CH), 129.6 (C.sub.q), 134.1 (C.sub.q), 143.9 (C.sub.q), 147.1 (C.sub.q); HRMS (EI-MS): calculated for C.sub.19H.sub.21N.sub.4S m/z=337.14814. found m/z=337.14848.

(R)-5-[4-[1-[quinuclidin-3-yl]-1H-1,2,3-triazol-4-yl]phenyl]thiophene-2-carbaldehyde (97)

(108) The product was isolated in the form of a white solid with a yield of 83% by following the general procedure E2. R.sub.f: 0.19 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 97/3/1); Mp: 228 C.; IR (ATR, Diamond): (cm.sup.1): 806, 972, 1041, 1223, 1315, 1404, 1450, 1660, 2868, 2938, 3117; .sup.1H NMR (400 MHz, CDCl.sub.3): (ppm) 1.42-1.54 (m, 1H), 1.65-1.74 (m, 1H), 1.77-1.88 (m, 2H), 2.29 (q, 1H, J=3.2 Hz), 2.86-3.00 (m, 3H), 3.11-3.18 (m, 1H), 3.50 (ddd, 1H, J=14.4 Hz, 10.0 Hz and 3.6 Hz), 3.71 (dd, 1H, J=14.4 Hz and 3.6 Hz), 4.64-4.67 (m, 1H), 7.42 (d, 1H, J=4.0 Hz), 7.71-7.74 (m, 3H), 7.88-7.91 (m, 3H), 9.88 (s, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 20.0 (CH.sub.2), 26.0 (CH.sub.2), 28.1 (CH), 46.9 (CH.sub.2), 47.2 (CH.sub.2), 52.6 (CH.sub.2), 58.5 (CH), 119.4 (CH), 124.1 (CH), 126.2 (2CH), 126.8 (2CH), 131.7 (C.sub.q), 132.6 (C.sub.q), 137.4 (CH), 142.4 (C.sub.q), 146.6 (C.sub.q), 153.6 (C.sub.q), 182.7 (CH); HRMS (EI-MS): calculated for C.sub.20H.sub.21N.sub.4SO m/z=365.14306. found m/z=365.14334.

(R)-5-[3-[1-[quinuclidin-3-yl]-1H-1,2,3-triazol-4-yl]phenyl]thiophene-2-carbaldehyde (101)

(109) The product was isolated in the form of a white solid with a yield of 80% by following the general procedure E2. R.sub.f: 0.24 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 97/3/1); Mp: 150 C.; IR (ATR, Diamond): (cm.sup.1): 792, 986, 1070, 1223, 1316, 1405, 1450, 1659, 2868, 2938, 3120; .sup.1H NMR (400 MHz, CDCl.sub.3): (ppm)) 1.46-1.56 (m, 1H), 1.66-1.90 (m, 3H), 2.29 (q, 1H, J=2.8 Hz), 2.88-3.02 (m, 3H), 3.13-3.20 (m, 1H), 3.50 (ddd, 1H, J=14.4 Hz, 10.0 Hz and 3.6 Hz), 3.71 (dd, 1H, J=14.4 Hz and 4.2 Hz), 4.67-4.69 (m, 1H), 7.47-7.51 (m, 2H), 7.63 (d, 1H, J=7.2 Hz), 7.76 (d, 1H, J=4.2 Hz), 7.85 (d, 1H, J=8.0 Hz), 7.91 (s, 1H), 8.17 (s, 1H), 9.91 (s, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 20.0 (CH.sub.2), 25.9 (CH.sub.2), 28.1 (CH), 46.9 (CH.sub.2), 47.2 (CH.sub.2), 52.6 (CH.sub.2), 58.5 (CH), 119.4 (CH), 123.5 (CH), 124.5 (CH), 126.0 (CH), 126.5 (CH), 129.7 (CH), 131.7 (C.sub.q), 133.6 (C.sub.q), 137.3 (CH), 142.6 (C.sub.q), 146.7 (C.sub.q), 153.7 (C.sub.q), 182.7 (CH); HRMS (EI-MS): calculated for C.sub.20H.sub.21N.sub.4SO m/z=365.14306. found m/z=365.14324.

(R)-4-[4-[5-[1-[quinuclidin-3-yl]-1H-1,2,3-triazol-4-yl]-2-thienyl]phenyl]methyl]morpholine (102)

(110) The product was isolated in the form of a white solid with a yield of 83% by following the general procedure E2. R.sub.f: 0.21 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 97/3/1); Mp: 222 C.; IR (ATR, Diamond): (cm.sup.1): 791, 987, 1040, 1220, 1345, 1451, 1498, 1662, 2803, 2868, 2938; .sup.1H NMR (400 MHz, CDCl.sub.3): (ppm) 1.41-1.53 (m, 1H), 1.62-1.86 (m, 3H), 2.27 (q, 1H, J=2.8 Hz), 2.45-2.28 (m, 4H), 2.28-3.00 (m, 3H), 3.10-3.19 (m, 1H), 3.46-3.50 (m, 3H), 3.66-3.72 (m, 5H), 4.61-4.64 (m, 1H), 7.27 (d, 1H, J=8.0 Hz), 7.33-7.36 (m, 3H), 7.57 (d, 2H, J=8.0 Hz), 7.73 (s, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 20.0 (CH.sub.2), 26.0 (CH.sub.2), 28.1 (CH), 46.9 (CH.sub.2), 47.2 (CH.sub.2), 52.6 (CH.sub.2), 53.6 (2CH.sub.2), 58.5 (CH), 63.0 (CH.sub.2), 37.0 (2CH.sub.2), 118.3 (CH), 123.4 (CH), 124.9 (CH), 125.5 (2CH), 129.7 (2CH), 132.0 (C.sub.q), 133.0 (C.sub.q), 137.4 (C.sub.q), 142.6 (Cq), 143.6 (C.sub.q); HRMS (EI-MS): calculated for C.sub.24H.sub.30N.sub.5OS m/z=436.216558. found m/z=436.216563.

(R)-3-[4-[5-[4-(1-piperidylmethyl)phenyl]-2-thienyl]-1H-1,2,3-triazol-1-yl]quinuclidine (103)

(111) The product was isolated in the form of a white solid with a yield of 80% by following the general procedure E2. R.sub.f: 0.21 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 97/3/1); Mp: 230 C.; IR (ATR, Diamond): (cm.sup.1): 792, 995, 1103, 1215, 1366, 1415, 1451, 1662, 2866, 2934, 3120; .sup.1H NMR (400 MHz, CDCl.sub.3): (ppm) 1.38-1.52 (m, 3H), 1.56-1.62 (m, 4H), 1.64-1.88 (m, 3H), 2.28 (q, 1H, J=2.8 Hz), 2.32-2.49 (m, 4H), 2.86-3.01 (m, 3H), 3.11-3.18 (m, 1H), 3.45-3.52 (m, 3H), 3.69 (dd, 1H, J=14.4 Hz and 5.2 Hz), 4.62-4.64 (m, 1H), 7.27 (d, 1H, J=8.0 Hz), 7.33-7.35 (m, 3H), 7.57 (d, 2H, J=8.0 Hz), 7.74 (s, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 20.0 (CH.sub.2), 24.3 (CH.sub.2), 25.9 (2CH.sub.2), 26.0 (CH.sub.2), 28.1 (CH), 46.9 (CH.sub.2), 47.2 (CH.sub.2), 52.6 (CH.sub.2), 54.5 (2CH.sub.2), 58.5 (CH), 63.4 (CH.sub.2), 118.3 (CH), 123.2 (CH), 124.9 (CH), 125.4 (2CH), 129.7 (2CH), 131.8 (C.sub.q), 132.6 (C.sub.q), 138.3 (C.sub.q), 142.6 (C.sub.q), 143.8 (C.sub.q); HRMS (EI-MS): calculated for C.sub.25H.sub.32N.sub.5S m/z=434.237293. found m/z=434.237451.

(R)-3-[4-[5-[4-[(4-methylpiperazin-1-yl)methyl]phenyl]-2-thienyl]-1H-1,2,3-triazol-1-yl]quinuclidine (104)

(112) The product was isolated in the form of a white solid with a yield of 75% by following the general procedure E2. R.sub.f: 0.20 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 97/3/1); Mp: 214 C.; IR (ATR, Diamond): (cm.sup.1): 792, 973, 1040, 1222, 1347, 1450, 1661, 2869, 2939, 3120; .sup.1H NMR (400 MHz, CDCl.sub.3): (ppm) 1.42-1.53 (m, 1H), 1.62-1.85 (m, 3H), 2.27-2.70 (m, 12H), 2.84-3.00 (m, 3H), 3.10-3.18 (m, 1H), 3.45-3.52 (m, 3H), 3.69 (dd, 1H, J=14.4 Hz and 5.2 Hz), 4.61-4.64 (m, 1H), 7.27 (d, 1H, J=8.0 Hz), 7.33-7.35 (m, 3H), 7.57 d, 2H, J=8.0 Hz), 7.74 (s, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 20.0 (CH.sub.2), 26.0 (CH.sub.2), 28.1 (CH), 46.0 (CH.sub.3), 46.9 (CH.sub.2), 47.2 (CH.sub.2), 52.6 (2CH.sub.2), 53.1 (2CH.sub.2), 55.1 (CH.sub.2), 58.5 (CH), 62.6 (CH.sub.2), 118.3 (CH), 123.3 (CH), 124.9 (CH), 125.5 (2CH), 129.7 (2CH), 131.9 (C.sub.q), 132.8 (C.sub.q), 137.9 (C.sub.q), 142.6 (Cq), 143.7 (C.sub.q); HRMS (EI-MS): calculated for C.sub.25H.sub.33N.sub.6S m/z=449.248193. found m/z=449.248404.

Methyl-2-fluoro-4-[5-[1-[(3R)-quinuclidin-3-yl]-1H-1,2,3-triazol-4-yl]-2-thienyl]benzoate (105)

(113) The product was isolated in the form of a white solid with a yield of 85% by following the general procedure E2. R.sub.f: 0.20 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 97/3/1); Mp: 250 C.; IR (ATR, Diamond): (cm.sup.1): 785, 926, 1090, 1262, 1326, 1422, 1472, 1612, 1703, 1718, 2870, 2943, 3133; .sup.1H NMR (250 MHz, CDCl.sub.3): (ppm) 1.30-1.52 (m, 2H), 1.63-1.81 (m, 2H), 2.20 (q, 1H, J=2.8 Hz), 2.71-3.03 (m, 4H), 3.33-3.50 (m, 2H), 3.87 (s, 3H), 4.71-4.83 (m, 1H), 7.51 (d, 1H, J=3.5 Hz), 7.62 (d, 1H, J=8.0 Hz), 7.70-7.81 (m, 2H), 7.93 (t, 1H, J=8.0 Hz), 8.76 (s, 1H); .sup.13C NMR (62.5 MHz, CDCl.sub.3): (ppm) 19.6 (CH.sub.2), 25.4 (CH.sub.2), 27.9 CH), 46.5 (CH.sub.2), 46.8 (CH.sub.2), 51.8 (CH.sub.2), 52.3 (CH.sub.3), 58.3 (CH), 113.2 (d, CH, J=38 Hz), 116.7 (d, C.sub.q, J=10 Hz), 119.5 (CH), 120.9 (d, CH, J=6 Hz), 125.5 (CH), 125.9 (CH), 132.8 (CH), 134.1 (C.sub.q), 140.4 (d, C.sub.q, J=15 Hz), 140.9 (d, C.sub.q, J=3 Hz), 142.2 (C.sub.q), 162.3 (d, C.sub.q, J=258 Hz), 164.7 (d, C.sub.q, J=4 Hz); HRMS (EI-MS): calculated for C.sub.21H.sub.22N.sub.4O.sub.2FS m/z=413.144202. found m/z=413.144364.

Methyl-2-chloro-4-[5-[1-[(3R)-quinuclidin-3-yl]-1H-1,2,3-triazol-4-yl]-2-thienyl]benzoate (107)

(114) The product was isolated in the form of a white solid with a yield of 79% by following the general procedure E2. R.sub.f: 0.20 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 97/3/1); Mp: 200 C.; IR (ATR, Diamond): (cm.sup.1): 792, 988, 1028, 1131, 1283, 1433, 1446, 1594, 1701, 2867, 2936, 3134; .sup.1H NMR (400 MHz, CDCl.sub.3): (ppm) 1.43-1.55 (m, 1H), 1.62-1.88 (m, 3H), 2.28 (q, 1H, J=2.8 Hz), 2.87-3.00 (m, 3H), 3.08-3.20 (m, 1H), 3.48 (ddd, 1H, J=14.4 Hz, 10.0 Hz and 2.8 Hz), 3.69 (dd, 1H, J=14.4 Hz and 4.2 Hz), 3.92 (s, 3H), 4.64-4.67 (m, 1H), 7.36 (s, 2H), 7.51 (dd, 1H, J=8.0 Hz and 1.2 Hz), 7.67 (s, 1H), 7.78 (s, 1H), 7.87 (d, 1H, J=8.0 Hz); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 19.9 (CH.sub.2), 25.8 (CH.sub.2), 28.1 (CH), 46.9 (CH.sub.2), 47.2 (CH.sub.2), 52.4 (CH.sub.3), 52.5 (CH.sub.2), 58.5 (CH), 118.8 (CH), 123.3 (CH), 125.1 (CH), 125.6 (CH), 127.6 (CH), 127.8 (C.sub.q), 132.3 (CH), 134.4 (C.sub.q), 134.7 (C.sub.q), 138.4 (C.sub.q), 140.5 (C.sub.q), 142.1 (C.sub.q), 165.5 (C.sub.q); HRMS (EI-MS): calculated for C.sub.21H.sub.22N.sub.4ClO.sub.2S M z 429.114651. found m/z=429.114907.

(R)-3-[4-[3-(6-chloro-3-pyridyl) phenyl]-1H-1,2,3-triazol-1-yl]quinuclidine (108)

(115) The product was isolated in the form of a white solid with a yield of 20% by following the general procedure E2. R.sub.f: 0.17 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 98/2/1); Mp (decom): 80 C.; IR (ATR, Diamond): (cm.sup.1): 831, 987, 1039, 1233, 1343, 1403, 1455, 1581, 2865, 2938, 3053; .sup.1H NMR (400 MHz, CDCl.sub.3): (ppm) 1.43-1.56 (m, 1H), 1.66-1.70 (m, 1H), 1.77-1.90 (m, 2H), 2.31 (q, 1H, J=3.0 Hz), 2.88-3.02 (m, 3H), 3.11-3.21 (m, 1H), 3.51 (ddd, 1H, J=14.4 Hz, 9.8 Hz and 2.2 Hz), 3.72 (dd, 1H, J=14.4 Hz and 3.6 Hz), 4.67-4.69 (m, 1H), 7.42 (d, 1H, J=8.4 Hz), 7.52-7.56 (m, 2H), 7.82 (dt, 1H, J=8.4 Hz and 1.2 Hz), 7.90-7.93 (m, 2H), 8.08 (s, 1H), 8.66 (d, 1H, J=2.4 Hz); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 20.0 (CH.sub.2), 25.9 (CH.sub.2), 28.1 (CH), 46.9 (CH.sub.2), 47.2 (CH.sub.2), 52.6 (CH.sub.2), 58.5 (CH), 119.3 (CH), 124.2 (CH), 124.3 (CH), 125.6 (CH), 126.7 (CH), 129.7 (CH), 131.6 (C.sub.q), 135.3 (C.sub.q), 137.1 (Cq), 137.2 (CH), 146.9 (C.sub.q), 147.9 (CH), 150.5 (C.sub.q); HRMS (EI-MS): calculated for C.sub.20H.sub.21N.sub.5Cl m/z=366.1480. found m/z=366.148142.

(R)-3-[4-[5-[3-[(4-methylpiperazin-1-yl)methyl]phenyl]-2-thienyl]-1H-1,2,3-triazol-1-yl]quinuclidine (109)

(116) The product was isolated in the form of a white solid with a yield of 83% by following the general procedure E2. R.sub.f: 0.20 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 97/3/1); Mp: 155 C.; IR (ATR, Diamond): (cm.sup.1): 788, 923, 1013, 1279, 1347, 1453, 1506, 2793, 2870, 2938, 3306; .sup.1H NMR (400 MHz, CDCl.sub.3): (ppm) 1.42-1.60 (m, 1H), 1.65-1.92 (m, 3H), 2.24-2.32 (m, 4H), 2.37-2.73 (m, 8H), 2.86-2.99 (m, 3H), 3.08-3.22 (m, 1H), 3.45-3.56 (m, 3H), 3.70 (dd, 1H, J=14.5 Hz and 5.2 Hz), 4.60-4.70 (m, 1H), 7.26-7.38 (m, 4H), 7.54 (d, 1H, J=7.5 Hz), 7.61 (m, 1H), 7.76 (s, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 20.0 (CH.sub.2), 26.0 (CH.sub.2) 28.1 (CH), 46.0 (CH.sub.3), 46.9 (CH.sub.2), 47.2 (CH.sub.2), 52.6 (CH.sub.2), 53.1 (2CH.sub.2), 55.1 (2CH), 58.5 (CH), 62.8 (CH.sub.2), 118.3 (CH), 123.6 (CH), 124.4 (CH), 124.8 (CH), 126.3 (CH), 128.4 (CH), 128.8 (CH), 132.1 (C.sub.q), 133.9 (C.sub.q), 139.1 (C.sub.q), 142.6 (C.sub.q), 143.8 (C.sub.q); HRMS (EI-MS): calculated for C.sub.25H.sub.33N.sub.6S m/z=449.248193. found m/z=449.247898.

(R)-3-[4-[5-(6-nitro-3-pyridyl)-2-thienyl]-1H-1,2,3-triazol-1-yl]quinuclidine (110)

(117) The product was isolated as a white solid with a yield of 77% by following the general procedure E2. R.sub.f: 0.19 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 98/2/1); Mp: 160 C.; IR (ATR, Diamond): (cm.sup.1): 788, 987, 1013, 1216, 1278, 1347, 1413, 1453, 1528, 2794, 2938, 3307; .sup.1H NMR (250 MHz, CDCl.sub.3): (ppm) 1.48-1.57 (m, 1H), 1.65-1.69 (m, 1H), 1.73-1.90 (m, 2H), 2.30 (q, 1H, J=2.8 Hz), 2.85-3.02 (m, 3H), 3.09-3.19 (m, 1H), 3.49 (ddd, 1H, J=14.4 Hz, 10.0 Hz and 2.8 Hz), 3.70 (dd, 1H, J=14.4 Hz and 4.4 Hz), 4.63-4.71 (m, 1H), 7.45 (d, 1H, J=3.2 Hz), 7.54 (d, 1H, J=3.2 Hz), 7.84 (s, 1H), 8.17 (d, 1H, J=8.2 Hz), 8.31 (d, 1H, J=8.2 Hz), 8.88 (s, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 20.0 (CH.sub.2), 26.0 (CH.sub.2), 28.1 (CH), 46.9 (CH.sub.2), 47.2 (CH.sub.2), 52.6 (CH.sub.2), 58.3 (CH), 118.5 (CH), 119.0 (CH), 125.4 (CH), 127.3 (CH), 135.2 (CH), 135.7 (C.sub.q), 136.6 (C.sub.q), 136.7 (C.sub.q), 141.6 (C.sub.q), 145.0 (CH), 155.0 (C.sub.q); HRMS (EI-MS): calculated for C.sub.18H.sub.19N.sub.6O.sub.2S m/z=383.128471. found m/z=383.128544.

(R)-3-[4-[3-(6-nitro-3-pyridyl) phenyl]-1H-1,2,3-triazol-1-yl]quinuclidine (111)

(118) The product was isolated in the form of a white solid with a yield of 80% by following the general procedure E2. R.sub.f: 0.23 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 98/2/1); Mp: 180 C.; IR (ATR, Diamond): (cm.sup.1): 793, 984, 1016, 1159, 1346, 1455, 1526, 2795, 2870, 2938; .sup.1H NMR (250 MHz, CDCl.sub.3): (ppm) 1.45-1.64 (m, 1H), 1.67-1.94 (m, 3H), 2.33 (q, 1H, J=2.8 Hz), 2.88-3.02 (m, 3H), 3.12-3.22 (m, 1H), 3.55 (ddd, 1H, J=14.5 Hz, 10.0 Hz and 2.8 Hz), 3.76 (dd, 1H, J=14.5 Hz and 4.4 Hz), 4.65-4.77 (m, 1H), 7.63 (d, 2H, J=4.5 Hz), 7.95 (s, 2H), 8.22-8.40 (m, 3H), 8.92 (s, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 20.0 (CH.sub.2), 26.0 (CH.sub.2) 28.2 (CH), 46.9 (CH.sub.2), 47.2 (CH.sub.2), 52.6 (CH.sub.2), 58.6 (CH), 118.2 (CH), 119.4 (CH), 124.6 (CH), 126.7 (CH), 127.0 (CH), 130.0 (CH), 132.0 (C.sub.q), 136.0 (C.sub.q), 137.9 (CH), 142.1 (C.sub.q), 146.5 (C.sub.q), 147.2 (CH), 155.8 (C.sub.q); HRMS (EI-MS): calculated for C.sub.20H.sub.21N.sub.6O.sub.2 m/z=377.172050. found m/z=377.172021.

Fluorination of Alcohols 63 and 85

(119) ##STR00090##

(120) General Procedure H:

(121) The alcohol derivative 63 or 85 (0.500 mmol) was dissolved in 10 mL of dichloromethane and then at 0 C., diethylaminosulfur trifluoride (0.700 mmol) was added therein drop by drop. The reaction mixture was stirred at 0 C. for a period of one hour and then hydrolysed by the addition of a saturated NaHCO.sub.3 solution. The organic phase was dried over anhydrous MgSO.sub.4, filtered and then concentrated under reduced pressure. The corresponding fluorinated compound (112 or 113) was purified by column chromatography on silica gel with the eluent used being a mixture of CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH.

(R)-3-[4-[5-[4-(fluoromethyl)phenyl]-2-thienyl]-1H-1,2,3-triazol-1-yl]quinuclidine (112)

(122) The product was isolated in the form of a white solid with a yield of 45% by following the general procedure H. R.sub.f: 0.25 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 98/2/1); Mp: 199 C.; IR (ATR, Diamond): (cm.sup.1): 962, 1042, 1060, 1219, 1376, 1414, 1454, 1502, 1601, 2163, 2321, 2937; .sup.1H NMR (400 MHz, CDCl.sub.3): (ppm) 1.45-1.54 (m, 1H), 1.66-1.70 (m, 1H), 1.77-1.90 (m, 2H), 2.30 (q, 1H, J=3.2 Hz), 2.88-2.98 (m, 3H), 3.12-3.19 (m, 1H), 3.50 (ddd, 1H, J=14.4 Hz, 9.6 Hz and 2.0 Hz), 3.71 (dd, 1H, J=14.4 Hz and 3.6 Hz), 4.64-4.67 (m, 1H), 5.40 (d, 2H, J=47.6 Hz), 7.31 (d, 1H, J=3.6 Hz), 7.36 (d, 1H, J=3.6 Hz), 7.40 (dd, 2H, J=8.0 Hz and 1.2 Hz), 7.64 (d, 2H, J=8.0 Hz), 7.75 (s, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 20.0 (CH.sub.2), 25.9 (CH.sub.2), 28.1 (CH), 46.9 (CH.sub.2), 47.2 (CH.sub.2), 52.6 (CH.sub.2), 58.5 (CH), 84.2 (d, CH.sub.2, J=166 Hz), 118.4 (CH), 123.9 (CH), 124.9 (CH), 125.8 (2CH), 128.2 (d, 2 CH, J=6 Hz), 132.6 (C.sub.q), 134.5 (d, C.sub.q, J=4 Hz), 135.4 (d, C.sub.q, J=17 Hz), 142.5 (C.sub.q), 143.1 (C.sub.q); HRMS (EI-MS): calculated for C.sub.20H.sub.22N.sub.4FS m/z=369.15437. found m/z=369.15433.

(R)-3-[4-[5-[3-(fluoromethyl)phenyl]-2-thienyl]-1H-1,2,3-triazol-1-yl]quinuclidine (113)

(123) The product was isolated in the form of a white solid with a yield of 39% by following the general procedure H. R.sub.f: 0.25 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 98/2/1); Mp: 144 C.; IR (ATR, Diamond): (cm.sup.1): 792, 971, 1041, 1211, 1364, 1452, 1588, 1606, 2165, 2869, 2939; .sup.1H NMR (400 MHz, CDCl.sub.3): (ppm) 1.46-1.54 (m, 1H), 1.65-1.80 (m, 3H), 2.27-2.31 (m, 1H), 2.88-2.98 (m, 3H), 3.11-3.18 (m, 1H), 3.50 (ddd, 1H, J=14.4 Hz, 9.6 Hz and 2.0 Hz), 3.71 (dd, 1H, J=14.4 Hz and 3.6 Hz), 4.62-4.66 (m, 1H), 5.43 (d, 2H, J=47.6 Hz), 7.29-7.31 (m, 2H), 7.36 (d, 1H, J=3.6 Hz), 7.42 (t, 1H, J=7.6 Hz), 7.61-7.63 (m, 2H), 7.76 (s, 1H); .sup.13C NMR (100 MHz, GPM): (ppm) 20.0 (CH.sub.2), 26.0 (CH.sub.2), 28.1 (CH), 46.9 (CH.sub.2), 47.2 (CH.sub.2), 52.6 (CH.sub.2), 58.5 (CH), 84.3 (d, CH.sub.2, J=166 Hz), 118.5 (CH), 123.9 (CH), 124.5 (d, CH, J=6 Hz), 124.9 (CH), 125.9 (d, CH, J=3 Hz), 126.4 (d, CH, J=6 Hz), 129.2 (CH), 132.6 (C.sub.q), 134.4 (C.sub.q), 137.0 (d, C.sub.q, J=17 Hz), 142.5 (C.sub.q), 143.1 (C.sub.q); HRMS (EI-MS): calculated for C.sub.20H.sub.22N.sub.4FS m/z=369.154372. found m/z=369.154471.

Reduction of Aldehydes 97 or 101

(124) ##STR00091##

(125) General Procedure I:

(126) To a solution of the aldehyde derivative (1.0 mmol) in a mixture of 4 mL of dichloromethane and 2 mL of methanol, sodium borohydride (1.2 mmol) was slowly added at 0 C. The reaction mixture was then stirred at ambient temperature for a period of 15 minutes and then hydrolysed with the addition of 5 mL of water. 10 mL of dichloromethane was then added to the medium and the two phases were separated. The aqueous phase was extracted with 25 mL of dichloromethane. The organic phases were combined, dried over anhydrous MgSO.sub.4, and filtered and evaporated under reduced pressure. The residue thus obtained was purified by column chromatography on silica gel with the eluent used being a mixture of CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH.

(R)-[5-[4-[1-[quinuclidin-3-yl]-1H-1,2,3-triazol-4-yl]phenyl]-2-thienyl]methanol (114)

(127) The product was isolated in the form of a white solid with a yield of 85% by following the general procedure I. R.sub.f: 0.12 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 97/3/1); Mp: 234 C.; IR (ATR, Diamond): (cm.sup.1): 791, 979, 1032, 1204, 1328, 1447, 1500, 1661, 2871, 2939, 3124; .sup.1H NMR (400 MHz, CDCl.sub.3): (ppm) 1.34-1.47 (m, 2H), 1.68-1.74 (m, 2H), 2.29 (q, 1H, J=2.8 Hz), 2.71-2.78 (m, 3H), 2.93-3.02 (m, 1H), 3.38 (m, 2H), 4.62 (d, 2H, J=5.2 Hz), 4.72-4.75 (m, 1H), 5.51 (t, 1H, J=5.2 Hz), 6.95 (d, 1H, J=3.6 Hz), 7.38 (d, 1H, J=3.6 Hz), 7.69 (d, 2H, J=8.4 Hz), 7.89 (d, 2H, J=8.4 Hz), 8.75 (m, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 20.0 (CH.sub.2), 25.8 (CH.sub.2), 28.1 (CH), 46.8 (CH.sub.2), 47.0 (CH.sub.2), 52.3 (CH.sub.2), 57.9 (CH), 58.8 (CH.sub.2), 121.3 (CH), 123.6 (CH), 125.7 (CH), 125.9 (2CH), 126.1 (2CH), 130.2 (C.sub.q), 133.7 (C.sub.q), 142.1 (C.sub.q), 146.1 (C.sub.q), 146.6 (C.sub.q); HRMS (EI-MS): calculated for C.sub.20H.sub.23N.sub.4SO m/z=367.15871. found m/z=367.15900.

(R)-[5-[3-[1-[quinuclidin-3-yl]-1H-1,2,3-triazol-4-yl]phenyl]-2-thienyl]-methanol (115)

(128) The product was isolated in the form of a white solid with a yield of 82% by following the general procedure I. R.sub.f: 0.16 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 97/3/1); Mp: 176 C.; IR (ATR, Diamond): (cm.sup.1): 795, 981, 1029, 1206, 1373, 1416, 1450, 1608, 2877, 2942, 3070; .sup.1H NMR (400 MHz, CDCl.sub.3): (ppm) 1.32-1.51 (m, 2H), 1.65-1.82 (m, 2H), 2.29 (q, 1H, J=2.8 Hz), 2.73-2.80 (m, 3H), 2.95-3.02 (m, 1H), 3.39-3.49 (m, 2H), 4.65 (s, 2H), 4.72-4.81 (m, 1H), 5.54 (bl, 1H), 6.98 (d, 1H, J=3.6 Hz), 7.42 (d, 1H, J=3.6 Hz), 7.47 (t, 1H, J=7.8 Hz), 7.57 (d, 1H, J=7.8 Hz), 7.80 (d, 1H, J=7.8 Hz), 8.11 (s, 1H), 8.85 (s, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 20.0 (CH.sub.2), 25.7 (CH.sub.2), 28.1 (CH), 46.8 (CH.sub.2), 47.0 (CH.sub.2), 52.3 (CH.sub.2), 57.8 (CH), 58.8 (CH.sub.2), 121.6 (CH), 122.0 (CH), 123.8 (CH), 124.4 (CH), 124.8 (CH), 125.6 (CH), 130.1 (CH), 132.0 (C.sub.q), 135.0 (C.sub.q), 142.1 (C.sub.q), 146.1 (C.sub.q), 146.8 (C.sub.q); HRMS (EI-MS): calculated for C.sub.20H.sub.23N.sub.4SO m/z=367.15871. found m/z=367.15892.

Chlorination of Alcohols 63 and 38

(129) ##STR00092##

(130) General Procedure J:

(131) The alcohol derivative 63 or 38 (0.500 mmol) was dissolved in 10 mL of dichloromethane and then at 0 C., thionyl chloride (1.0 mmol) was added therein drop by drop, followed by a catalytic amount of dimethylformamide. The reaction mixture was then stirred at ambient temperature over a one night period. After evaporation of the solvent, the reaction mixture was washed with diethyl ether (510 mL). The precipitate thus formed was filtered and then dried under vacuum.

(R)-3-[4-[5-[4-(chloromethyl)phenyl]-2-thienyl]-1H-1,2,3-triazol-1-yl]quinuclidine, hydrochloride (116)

(132) The product was isolated in the form of a beige solid with a yield of 96% by following the general procedure J. R.sub.f: 0.3 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 98/2/1); Mp: 255 C.; IR (ATR, Diamond): (cm.sup.1): 797, 973, 1042, 1229, 1319, 1455, 1600, 1694, 2880, 3392; .sup.1H NMR (400 MHz, DMSO-d.sub.6): (ppm) 1.56-1.87 (m, 2H), 1.95-2.14 (m, 2H), 2.52-2.55 (m, 1H), 3.20-3.50 (m, 4H), 3.87-3.06 (m, 2H), 4.80 (s, 2H), 5.16-5.32 (m, 1H), 7.42-7.60 (m, 4H), 7.67-7.78 (m, 2H), 8.87 (s, 1H), 11.20 (bl, 1H); .sup.13C NMR (100 MHz, DMSO-d.sub.6): (ppm) 17.5 (CH.sub.2), 21.6 (CH.sub.2), 26.7 (CH), 45.6 (CH.sub.2), 45.8 (CH.sub.2), 46.3 (CH.sub.2), 49.3 (CH.sub.2), 55.1 (CH), 121.5 (CH), 125.3 (CH), 125.9 (2CH), 126.0 (CH), 130.2 (2CH), 132.8 (C.sub.q), 133.8 (C.sub.q), 137.5 (C.sub.q), 142.2 (C.sub.q), 142.3 (C.sub.q); HRMS (EI-MS): calculated for C.sub.20H.sub.22N.sub.4SCI m/z=385.124822. found m/z=385.124944.

(R)-3-[4-[4-(chloromethyl)phenyl]-1H-1,2,3-triazol-1-yl]quinuclidine, hydrochloride (117)

(133) The product was isolated in the form of a beige solid with a yield of 90% by following the general procedure J. R.sub.f: 0.3 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 98/2/1); Mp: 240 C.; IR (ATR, Diamond): (cm.sup.1): 807, 973, 1040, 1210, 1319, 1455, 1613, 2560, 2956, 3398; .sup.1H NMR (400 MHz, DMSO-d.sub.6): (ppm) 1.56-1.88 (m, 2H), 1.99-2.11 (m, 2H), 2.54-2.55 (m, 1H), 3.28-3.46 (m, 4H), 3.87-3.05 (m, 2H), 4.81 (s, 2H), 5.19-5.30 (m, 1H), 7.54 (d, 2H, J=8.2 Hz), 7.98 (d, 2H, J=8.2 Hz), 8.94 (s, 1H), 11.24 (bl, 1H); .sup.13C NMR (100 MHz, DMSO-d.sub.6) (ppm) 17.5 (CH.sub.2), 21.6 (CH.sub.2), 26.7 (CH), 45.6 (CH.sub.2), 45.8 (CH.sub.2), 46.4 (CH.sub.2), 49.3 (CH.sub.2), 54.9 (CH), 122.2 (CH), 125.8 (2CH), 129.9 (2CH), 130.9 (C.sub.q), 137.8 (C.sub.q), 146.6 (C.sub.q); HRMS (EI-MS): calculated for C.sub.16H.sub.20N.sub.4Cl m/z=303.137101. found m/z=303.1373213.

Preparation of a Precursor of Quinuclidine Type Compounds (Formula (III-1))

(134) ##STR00093##

3-Ethynyl-3-hydroxyquinuclidine (67)

(135) A solution of ethynyl(trimethyl)silane 65 (4.44 mL, 31.4 mmol) in 30 mL of THF was cooled to 10 C. and then 12.6 mL of a solution of n-BuLi (2.5 M in hexane) was added therein drop by drop. After 10 minutes of stirring at 10 C., the reaction medium was cooled to 78 C. and a solution of 3-quinuclidone 64 (3.74 g, 29.9 mmol) in 70 mL of THF was added therein. Upon completion of the addition, the cold bath was removed and the reaction mixture was allowed to return to ambient temperature. After an additional hour of reaction, it was hydrolysed with a saturated NaCl solution. The two phases were separated and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous MgSO.sub.4, and filtered and evaporated under reduced pressure.

(136) The silyl derivative 66 (28.1 mmol) thus prepared was directly engaged in the deprotection reaction by means of stirring for a period of 3 hours in 60 ml of methanol in the presence K.sub.2CO.sub.3 (3.89 g, 28.1 mmol). The reaction medium was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel with the eluent used being a mixture of CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH (80/20/0.1). The product 67 was isolated in the form of a white solid with a yield of 43%. R.sub.f: 0.35 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 80/20/0.1); Mp: 201 C.; IR (ATR, Diamond): (cm.sup.1): 989, 1024, 1048, 1071, 1138, 1154, 1317, 1455, 2596, 2754, 2873, 2934, 2950, 2965, 3216; .sup.1H NMR (250 MHz, MeOD): (ppm) 1.38-1.53 (m, 1H), 1.61-1.75 (m, 1H), 1.93-2.10 (m, 3H), 2.73-2.84 (m, 4H), 2.88 (d, 1H, J=13.8 Hz), 2.89 (s, 1H), 3.13 (d, 1H, J=13.8 Hz); .sup.13C NMR (100 MHz, MeOD): (ppm) 20 3 (CH.sub.2), 24.2 (CH.sub.2), 34.2 (CH), 46.9 (CH.sub.2), 47.0 (CH.sub.2), 65.0 (CH.sub.2), 67.4 (C.sub.q); MS (IS): m/z=152.8 [MH].sup.+.

Preparation of Quinuclidine Type Compounds 68-69 (Formula (III-1))

(137) ##STR00094##

(138) General Procedure F:

(139) The alkyne 67 (151 mg, 1.00 mmol) was dissolved in 6 mL of methanol to which the following were then added successively: the desired azide (1.00 mmol), CuSO.sub.45H.sub.2O (25 mg, 0.100 mmol) and sodium ascorbate (40 mg, 0.200 mmol). The reaction medium was stirred at ambient temperature for a period of 12 hours. At the end of the reaction time, the methanol was evaporated under reduced pressure and the residue was chromatographed by column chromatography on silica gel with the eluent used being a mixture of CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH (80/20/01).

3-(1-(4-Methoxyphenyl)-1H-1,2,3-triazol-4-yl)quinuclidin-3-ol (68)

(140) The product was isolated in the form of a white solid with a yield of 87% by following the general procedure F. R.sub.f: 0.22 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 80/20/0.1); Mp: 174 C.; IR (ATR, Diamond): (cm.sup.1): 992, 1049, 1133, 1231, 1251, 1305, 1439, 1517, 2873, 2928, 2998, 3112, 3348; .sup.1H NMR (250 MHz, CDCl.sub.3): (ppm) 1.42-1.58 (m, 3H), 2.17-2.31 (m, 2H), 2.76-2.95 (m, 3H), 2.95-3.14 (m, 2H), 3.20-3.43 (m, 1H), 6.61 (dd, 1H, J=14.4 Hz and 1.6 Hz), 3.86 (s, 3H), 7.00 (d, 2H, J=8.9 Hz), 7.62 (d, 2H, J=8.9 Hz), 7.89 (s, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 21.2 (CH.sub.2), 23.3 (CH.sub.2), 33.7 (CH), 46.5 (CH.sub.2), 47.1 (CH.sub.2), 55.8 (CH.sub.3), 62.4 (CH.sub.2), 69.7 (C.sub.q), 115.0 (2CH.sub.aromatic), 119.2 (.sub.aromaticCH), 122.4 (2CH.sub.aromatic), 130.7 (C.sub.q), 154.5 (C.sub.q), 160.0 (C.sub.q); HRMS (EI-MS): calculated for C.sub.16H.sub.20N.sub.4O.sub.2 m/z=301.1665. found m/z=301.1669.

3-(1-(4-Bromophenyl)-1H-1,2,3-triazol-4-yl)quinuclidin-3-ol (69)

(141) The product was isolated in the form of a white solid with a yield of 91% by following the general procedure F. R.sub.f: 0.22 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 80/20/0.1); Mp: 214 C.; IR (ATR, Diamond): (cm.sup.1): 994, 1040, 1214, 1320, 1445, 1496, 2871, 2927, 3112; .sup.1H NMR (250 MHz, CDCl.sub.3): (ppm) 1.42-1.58 (m, 3H), 2.15-2.31 (m, 2H), 2.72-3.04 (m, 4H), 3.08 (d, 1H, J=14.3 Hz), 3.32 (s, 1H), 3.62 (dd, 1H, J=14.3 Hz and 1.3 Hz), 7.59-7.68 (m, 4H), 7.99 (s, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 21.8 (CH.sub.2), 23.1 (CH.sub.2), 33.7 (CH), 46.4 (CH.sub.2), 47.1 (CH.sub.2), 62.3 (CH.sub.2) 69.7 (C.sub.q), 119.0 (.sub.aromaticCH), 122.1 (2CH.sub.aromatic), 122.7 (C.sub.q), 133.1 (2CH.sub.aromatic), 136.1 (C.sub.q), 155.1 (C.sub.q); HRMS (EI-MS): calculated for C.sub.15H.sub.17BrN.sub.4O m/z=349.0664. found m/z=349.0657.

Preparation of Quinuclidine Type Compounds 70-71 (Formula (III-1))

(142) ##STR00095##

(143) General Procedure G:

(144) The alcohols 68-69 (0.500 mmol) were dissolved in 10 mL of dichloromethane and then at 0 C., diethylaminosulfur trifluoride (92 L, 0.700 mmol) was added therein drop by drop. The reaction mixture was stirred at 0 C. for a period of one hour and hydrolysed with the addition of a saturated NaHCO.sub.3 solution. The organic phase was dried over anhydrous MgSO.sub.4, and filtered and concentrated under reduced pressure. The fluorinated compounds 70-71 were purified by column chromatography on silica gel with the eluent used being a mixture of CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH (80/20/0.1).

3-Fluoro-3-(1-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)quinuclidine (70)

(145) The product was isolated in the form of a yellowish oil with a yield of 64% by following the general procedure G. R.sub.f: 0.54 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 80/20/0.1); IR (ATR, Diamond): (cm.sup.1): 992, 1043, 1110, 1175, 1254, 1306, 1462, 1518, 1611, 2961, 3392; .sup.1H NMR (250 MHz, CDCl.sub.3): (ppm) 1.45-1.64 (m, 2H), 1.62-1.82 (m, 1H), 2.02-2.19 (m, 1H), 2.28-2.36 (m, 1H), 2.74-2.90 (m, 1H), 2.90-3.04 (m, 3H), 3.28 (dd, 1H, J=30.5 Hz and 15.2 Hz), 3.75-3.93 (m, 1H), 3.85 (s, 3H), 7.01 (d, 2H, J=8.9 Hz), 7.62 (d, 2H, J=8.9 Hz), 7.93 (s, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 20.7 (d, CH.sub.2, J=8 Hz), 22.4 (d, CH.sub.2, J=8 Hz), 32.9 (d, CH, J=24 Hz), 46.5 (CH.sub.2), 47.0 (CH.sub.2), 55.8 (CH.sub.3), 59.7 (d, CH.sub.2, J=24 Hz), 93.4 (d, C.sub.q, J=175 Hz), 115.0 (2CH.sub.aromatic), 119.9 (d, CH, J=4 Hz), 122.4 (2CH.sub.aromatic), 130.6 (C.sub.q), 150.4 (d, C.sub.q, J=32 Hz), 160.1 (C.sub.q); .sup.19F NMR (376 MHz, CDCl.sub.3): (ppm)-136.59 (s, 1F); HRMS (EI-MS): calculated for C.sub.16H.sub.19FN.sub.4O m/z=303.1621. found m/z=303.1623.

3-Fluoro-3-(1-(4-bromophenyl)-1H-1,2,3-triazol-4-yl)quinuclidine (71)

(146) The product was isolated in the form of a white solid with a yield of 64% by following the general procedure G. R.sub.f: 0.52 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 80/20/0.1); Mp: 127 C.; IR (ATR, Diamond): (cm.sup.1): 991, 1018, 1038, 1075, 1222, 1246, 1321, 1453, 1497, 2869, 2933; .sup.1H NMR (250 MHz, CDCl.sub.3): (ppm) 1.46-1.68 (m, 2H), 1.68-1.84 (m, 1H), 2.05-1.19 (m, 1H), 2.28-2.35 (m, 1H), 2.76-2.92 (m, 1H), 2.92-3.06 (m, 3H), 3.29 (dd, 1H, J=30.5 Hz and 15.2 Hz), 3.82 (dd, 1H, J=24.8 Hz and 15.2 Hz), 7.59-7.69 (m, 4H), 8.01 (s, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 20.6 (d, CH.sub.2, J=8 Hz), 22.3 (d, CH.sub.2, J=6 Hz), 32.9 (d, CH, J=24 Hz), 46.5 (CH.sub.2), 47.0 (CH.sub.2), 59.7 (d, CH.sub.2, J=24 Hz), 93.4 (d, C.sub.q, J=177 Hz), 119.6 (d, .sub.aromaticCH, J=5 Hz), 122.1 (2CH.sub.aromatic), 122.8 (C.sub.q), 133.1 (2CH.sub.aromatic), 136.0 (C.sub.q), 151.0 (d, C.sub.q, J=32 Hz), .sup.19F NMR (376 MHz, CDCl.sub.3): (ppm)-136.65 (s, 1F); HRMS (EI-MS): calculated for C.sub.15H.sub.17BRFN.sub.4 m/z=351.0621. found m/z=351.0637.

Preparation of Quinuclidine Type Compound 79 (Formula (II-2))

(147) ##STR00096## ##STR00097##

2-(Pyridin-3-ylmethylene)quinuclidin-3-one (74)

(148) To a solution of quinuclidone 72 (2.00 g, 12.4 mmol) in 20 mL of methanol, NaOH (1.04 g, 26.0 mmol) was added. After stirring for 30 minutes at ambient temperature, the 3-pyridinecarboxaldehyde 73 (1.28 mL, 13.6 mmol) was added therein drop by drop and the reaction mixture was stirred for a period of 16 hours. The reaction was hydrolysed with the addition of a minimal amount of water until the complete dissolution of the salts present in the medium. The reaction medium was placed in the refrigerator until total precipitation was obtained and then the suspension was filtered under vacuum. The ketone 74 was isolated in the form of a yellow solid with a yield of 79%. R.sub.f: 0.72 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 90/10/0.1); Mp: 113 C.; IR (ATR, Diamond): (cm.sup.1): 972, 1031, 1095, 1168, 1186, 1218, 1244, 1332, 1409, 1451, 1627, 1704, 2869, 2937, 2957; .sup.1H NMR (250 MHz, CDCl.sub.3): (ppm) 1.99 (td, 4H, J=7.9 Hz and 2.8 Hz), 2.60 (p, 1H, J=3.0 Hz), 2.87-3.02 (m, 2H), 3.07-3.21 (m, 2H), 6.93 (s, 1H), 7.25 (dd, 1H, J=8.0 Hz and 4.8 Hz), 8.45 (dt, 1H, J=8. Hz and 1.8 Hz), 8.50 (dd, 1H, J=4.8 Hz and 1.8 Hz), 8.99 (d, 1H, J=2.1 Hz); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 25.8 (2CH.sub.2), 40.2 (CH), 47.5 (2CH.sub.2), 121.5 (.sub.aromaticCH), 123.4 (.sub.aromaticCH), 130.1 (C.sub.q), 138.6 (.sub.aromaticCH), 146.6 (C.sub.q), 150.0 (.sub.aromaticCH), 153.0 (.sub.aromaticCH), 205.7 (CO); HRMS (EI-MS): calculated for C.sub.13H.sub.15N.sub.2O m/z=215.1184. found m/z=215.1192.

2-(Pyridin-3-ylmethyl)quinuclidin-3-one (75)

(149) Under hydrogen atmosphere, the ketone 73 (500 mg, 2.33 mmol) in 20 mL of methanol was reduced by the addition of a catalytic amount of Pd/C 10% (124 mg, 0.117 mmol) and stirred at ambient temperature for a period of 12 hours. Upon completion of the reaction, the reaction medium was filtered through Celite and the filtrate was evaporated under reduced pressure. The product was purified by column chromatography on silica gel with the eluent used being a mixture of CH.sub.2Cl.sub.2MeOH (9/1). The compound 75 was isolated in the form of a white solid with a yield of 63%. R.sub.f: 0.23 (CH.sub.2Cl.sub.2/MeOH: 9/1); Mp: 95 C.; IR (ATR, Diamond): (cm.sup.1): 984, 1028, 1053, 1071, 1096, 1185, 1328, 1422, 1459, 1477, 1576, 1715, 2869, 2962; .sup.1H NMR (250 MHz, CDCl.sub.3): (ppm) 1.93-2.07 (m, 4H), 2.47 (p, 1H, J=3.0 Hz), 2.75 (dd, 1H, J=14.9 Hz and 10.8 Hz), 2.82-2.93 (m, 2H), 3.03-3.24 (m, 3H), 3.31 (dd, 1H, J=10.8 Hz and 4.0 Hz), 7.20 (dd, 1H, J=7.8 Hz and 4.8 Hz), 7.59 (dt, 1H, J=7.8 Hz and 1.7 Hz), 8.45 (d, 1H, J=3.8 Hz), 8.51 (s, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 25.1 (CH.sub.2), 27.1 (CH.sub.2), 30.8 (CH.sub.2), 40.2 (CH), 41.2 (CH.sub.2), 49.0 (CH.sub.2), 71.0 (CH), 123.5 (.sub.aromaticCH), 134.7 (C.sub.q), 136.4 (.sub.aromaticCH), 148.0 (.sub.aromaticCH), 150.4 (.sub.aromaticCH and C.sub.q); HRMS (EI-MS): calculated for C.sub.13H.sub.17N.sub.2O m/z=217.1341. found m/z=217.1350.

2-(Pyridin-3-ylmethyl)quinuclidin-3-ol (76)

(150) To a solution of the ketone 75 (450 mg, 2.08 mmol) in 40 mL of methanol cooled to 0 C. with the use of an ice bath, an excess of NaBH.sub.4 (236 mg, 6.24 mmol) was added by portion. After two hours of stirring, the methanol was evaporated and the residue was taken up again in dichloromethane. The organic phase was washed with water, dried over anhydrous MgSO.sub.4 and filtered and evaporated under reduced pressure. The alcohol 76 was isolated in the form of a white solid with a yield of 93% in the form of two inseparable diastereoisomers in the proportions of 1/1. R.sub.f: 0.26 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 80/20/0.1); IR (ATR, Diamond): (cm.sup.1): 981, 1025, 1042, 1066, 1093, 1130, 1168, 1193, 1311, 1344, 1422, 1454, 1480, 1575, 2364, 2871, 2940, 3143; .sup.1H NMR (250 MHz, CDCl.sub.3): (ppm) 1.26-1.40 (m, 2H), 1.42-1.56 (m, 2H), 1.58-1.72 (m, 2H), 1.77-2.01 (m, 4H), 2.58-2.92 (m, 10H), 2.95-3.25 (m, 6H), 3.47-3.53 (m, 1H), 3.83-3.91 (m, 1H), 7.14-7.23 (m, 2H), 7.57-7.65 (m, 2H), 8.30-8.55 (m, 4H); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 18.7 (CH.sub.2), 19.1 (CH.sub.2), 24.7 (CH.sub.2), 25.7 (CH.sub.2), 29.5 (CH), 30.5 (CH), 31.0 (CH.sub.2), 36.5 (CH.sub.2), 41.0 (CH.sub.2), 41.8 (CH.sub.2), 48.9 (CH.sub.2), 50.0 (CH.sub.2), 62.2 (CH), 67.3 (CH), 68.4 (CH), 74.1 (CH), 123.5 (.sub.aromaticCH), 123.6 (.sub.aromaticCH), 135.2 (C.sub.q), 136.5 (C.sub.q), 137.0 (2CH.sub.aromatic), 147.2 (.sub.aromaticCH), 147.6 (.sub.aromaticCH), 150.3 (.sub.aromaticCH), 150.6 (.sub.aromaticCH) HRMS (EI-MS): calculated for C.sub.13H.sub.19N.sub.2O m/z=219.1497. found m/z=219.1491.

2-(Pyridin-3-ylmethyl)quinuclidin-3-yl methane sulfonate (77)

(151) To a solution of the alcohol 76 (360 mg, 1.65 mmol) in 15 mL of dichloromethane at ambient temperature, the following were added: mesyl chloride (150 L, 1.98 mmol) and triethylamine (350 L, 2.48 mmol). The reaction medium was stirred at ambient temperature for a period of 12 hours and then the reaction was hydrolysed with the addition of a saturated NaHCO.sub.3 solution. The organic phase was separated, dried over anhydrous MgSO.sub.4 and filtered and evaporated under reduced pressure. The product was purified by column chromatography on silica gel with the eluent used being a mixture of CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH (90/10/0.1). The mesylated compound 77 was isolated in the form of a yellow solid with a yield of 70% in the form of two inseparable diastereoisomers in the proportions of 1/1. R.sub.f: 0.35 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 90/10/0.1); IR (ATR, Diamond): (cm.sup.1): 890, 937, 989, 1027, 1166, 1321, 1342, 1428, 1461, 1479, 2873, 2943; .sup.1H NMR (250 MHz, CDCl.sub.3): (ppm) 1.35-1.95 (m, 8H), 2.19-2.31 (m, 2H), 2.62-3.15 (m, 13H), 2.74 (s, 3H), 2.91 (s, 3H), 3.23-3.33 (m, 1H), 4.44-4.49 (m, 1H), 4.89-4.95 (m, 1H), 7.17-7.26 (m, 2H), 7.52-7.62 (m, 2H), 8.41-8.53 (m, 4H); .sup.13C NMR (100 MHz, CDCl.sub.3): (ppm) 18.3 (CH.sub.2), 19.2 (CH.sub.2), 24.1 (CH.sub.2), 25.1 (CH.sub.2), 28.0 (CH), 28.5 (CH), 30.7 (CH.sub.2) 35.7 (CH.sub.2), 38.4 (CH.sub.3), 38.5 (CH.sub.3), 40.6 (CH.sub.2), 41.3 (CH.sub.2), 48.7 (CH.sub.2), 49.8 (CH.sub.2), 60.2 (CH), 64.3 (CH), 80.7 (CH), 84.1 (CH), 123.4 (.sub.aromaticCH), 123.6 (.sub.aromaticCH), 134.1 (C.sub.q), 135.0 (C.sub.q), 136.5 (.sub.aromaticCH), 136.8 (.sub.aromaticCH), 147.8 (.sub.aromaticCH), 148.1 (.sub.aromaticCH), 150.6 (.sub.aromaticCH), 150.7 (.sub.aromaticCH); HRMS (EI-MS): calculated for C.sub.14H.sub.21N.sub.2O.sub.3S m/z=297.1273. found m/z=297.1281.

3-(4-(3-Methoxyphenyl)-1H-1,2,3-triazol-1-yl)-2-(pyridin-3-ylmethyl)quinuclidine (79)

(152) The mesyl derivative 77 (300 mg, 1.01 mmol) and the sodium azide (330 mg, 5.05 mmol) were heated to 140 C. in 10 mL of DMF (dimethylformamide) for a period of 12 hours. Upon completion of the reaction, the solvent was evaporated and then the residue was taken up again in CH.sub.2Cl.sub.2. The organic phase was washed two times with water, dried over anhydrous MgSO.sub.4 and concentrated under reduced pressure. The azide 78 was purified by column chromatography on silica gel with the eluent used being a mixture of CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH (90/10/0.1).

(153) The azide 78 (110 mg, 0.452 mmol) was dissolved in 4 mL of methanol to which the following were then added successively: 3-ethynylanisole (60 L, 0.452 mmol), CuSO.sub.45H.sub.2O (11 mg, 0.045 mmol) and sodium ascorbate (18 mg, 0.090 mmol). The reaction medium was stirred at ambient temperature for a period of 12 hours. Upon completion of the reaction time period, the methanol was evaporated under reduced pressure and then the residue was chromatographed by column chromatography on silica gel with the eluent used being a mixture of CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH (90/10/0.1). The product 79 was isolated in the form of a yellow oil with a yield of 48% in the form of a single diastereoisomer. R.sub.f: 0.24 (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH: 90/10/0.1); IR (ATR, Diamond): (cm.sup.1): 986, 1037, 1074, 1157, 1244, 1282, 1320, 1424, 1458, 1479, 1583, 1609, 2872, 2943; .sup.1H NMR (250 MHz, DMSO-d.sub.6, 80 C.): (ppm) 1.36-1.51 (m, 1H), 1.62-1.96 (m, 3H), 2.21 (q, 1H, J=2.8 Hz), 2.67-3.25 (m, 6H), 3.75-3.84 (m, 1H), 3.87 (s, 3H), 4.48 (d, 1H, J=7.0 Hz), 6.89-7.01 (m, 1H), 7.22 (dd, 1H, J=7.8 Hz and 4.8 Hz), 7.35-7.48 (m, 3H), 7.64 (dt, 1H, J=7.8 Hz and 1.9 Hz), 8.34 (d, 1H, J=3.4 Hz), 8.49 (s, 1H), 8.54 (s, 1H); .sup.13C NMR (100 MHz, DMSO-d.sub.6, 80 C.): (ppm) 19.1 (CH.sub.2), 25.8 (CH.sub.2), 29.2 (CH), 34.9 (CH.sub.2), 40.0 (CH.sub.2), 48.5 (CH.sub.2), 54.8 (CH.sub.3), 61.2 (CH), 63.7 (CH), 110.5 (.sub.aromaticCH), 113.1 (.sub.aromaticCH), 117.3 (.sub.aromaticCH), 120.4 (.sub.aromaticCH), 122.5 (.sub.aromaticCH), 129.4 (.sub.aromaticCH), 132.0 (C.sub.q), 134.1 (C.sub.q), 135.8 (.sub.aromaticCH), 145.6 (C.sub.q), 146.7 (.sub.aromaticCH), 149.7 (.sub.aromaticCH), 159.4 (C.sub.q); HRMS (EI-MS): calculated for C.sub.22H.sub.25N.sub.5O m/z=375.2059. found m/z=376.21334.

(154) Biochemical Activity of the Compounds of the Invention

(155) Determination of the Affinity of the Compounds of the Invention for the Nicotinic Receptors R7

(156) The compounds of the present invention have been tested for their affinity with the R7s in competition with a reference ligand, the [.sup.125I]-bungarotoxin, on rat brain membrane preparation, in accordance with the protocol described by Davies et al. (1999) with slight modification.

(157) Membrane Preparation

(158) Male rats of the Wistar strain (Centre d'Olevage R. Janvier/R. Janvier breeding centre, Saint Berthevin) weighing 250 g were used in accordance with the rules related to animal experimentation currently in effect. After decapitation (2 animals per experiment), the brains were quickly removed, collected on ice, and the frontal cortex was dissected and weighed. The tissue was ground (Janke & Kunkel Ultra Turrax T25, 9500 rev/min.) in 2 ml of cold buffer (HEPES buffer [4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid] 15 mM, containing 120 mM NaCl, 5.4 mM KCl, 0.8 mM MgCl.sub.2 and 1.8 mM CaCl.sub.2, pH 7.4) and then centrifuged (Beckman J2-21 M/E centrifuge) at 45 000g at 4 C. for 10 minutes. The supernatant was removed, the pellet was taken up again in 2 ml of the same buffer and then resuspended. The assay of the proteins was carried out in accordance with the method developed by Bradford (1976) on the dregs (Spectronic 20-Genesys). It was then diluted in the buffer in a manner so as to obtain 0.25 g/ml of protein.

(159) Binding Study

(160) The reference ligand used was [.sup.125I]-bungarotoxin (Perkin Elmer, specific activity 81.4 TBq/mmol). The tubes were prepared in duplicate.

(161) In each tube (BD Vacutainer, AES Chemunex) containing 0.4 ml of 50 mM Tris-HCl buffer containing 120 mM NaCl, 5 mM KCl, 1 mM MgCl.sub.2, 2.5 mM CaCl2, pH 7.4, the following were added: 0.2 ml of the protein suspension, 0.2 ml of a solution of [.sup.125I]-bungarotoxin (that is a concentration of 2 nM) diluted in the Tris buffer, and 0.2 ml of a solution containing the compound to be tested at various concentrations ranging from 10.sup.6 to 10.sup.10 M. Non-specific binding was determined in the presence of 10.sup.6 M of -bungarotoxin (Tocris). The tubes were incubated in an oven at 22 C. for a period of 3 hours.

(162) The content of the tubes was thereafter diluted in 3 ml of Tris buffer at 4 C. supplemented with 0.1% BSA (bovine serum albumin), filtered (Hoefer FH225V Filter Manifold, Fisher Scientific) on GF/C filters (Whatman), pre-soaked in cold Tris buffer supplemented with 0.05% polyethyleneimine and then rinsed three times with 2 ml of cold buffer.

(163) The residual radioactivity of the filters was measured by counting (Cobra 5020, Beckman), the IC.sub.50 was determined graphically and the Ki calculated (Ki=IC.sub.50/(1+[L*]/Kd) (Cheng and Prussof 1973).

(164) TABLE-US-00001 Molar Mass Compound Empirical Formula Activity No. Structure Solubility on R7 16 M = 268.36 g/mol C.sub.16H.sub.20N.sub.4 CHCl.sub.3 DMSO 168 68 nM 17 M = 286.35 g/mol C.sub.16H.sub.19FN.sub.4 CHCl.sub.3 DMSO 210 31 nM 19 00 M = 298.38 g/mol C.sub.17H.sub.22N.sub.4O CHCl3 DMSO 283 76 nM 22 01 M = 286.35 g/mol C.sub.16H.sub.19FN.sub.4 CHCl.sub.3 DMSO 16 9 nM 24 02 M = 337.25 g/mol C.sub.16H.sub.18Cl.sub.2N.sub.4 CHCl.sub.3 DMSO 110 36 nM 25 03 M = 324.44 g/mol C.sub.18H.sub.20N.sub.4S CHCl.sub.3 DMSO 14 4 nM 26 04 M = 308.38 g/mol C.sub.18H.sub.20N.sub.4O CHCl.sub.3 DMSO 13 5 nM 27 05 M = 353.28 g/mol C.sub.14H.sub.17BrN.sub.4S CHCl.sub.3 DMSO 275 43 nM 37 06 M = 254.33 g/mol C.sub.15H.sub.18N.sub.4 CHCl.sub.3 DMSO 8 4 nM 42 07 M = 272.32 g/mol C.sub.15H.sub.17FN.sub.4 DMSO 15 4 nM 46 08 M = 284.36 g/mol C.sub.16H.sub.20N.sub.4O DMSO 11 1 nM 39 09 M = 288.78 g/mol C.sub.15H.sub.17ClN.sub.4 CHCl.sub.3 DMSO 8 3 nM 49 0 M = 334.41 g/mol C.sub.20H.sub.22N.sub.4O CHCl.sub.3 DMSO 196 21 nM 41 M = 333.23 g/mol C.sub.15H.sub.17BrN.sub.4 CHCl.sub.3 DMSO 6 3 nM 38 M = 284.36 g/mol C.sub.16H.sub.20N.sub.4O DMSO 10 3 nM 43 M = 272.32 g/mol C.sub.15H.sub.17FN.sub.4 CHCl.sub.3 DMSO 10 1 nM 50 M = 255.32 g/mol C.sub.15H.sub.17N.sub.5 CHCl.sub.3 DMSO 141 41 nM 58 M = 286.35 g/mol C.sub.16H.sub.19FN.sub.5 CHCl.sub.3 DMSO 21 7 nM 40 M = 323.22 g/mol C.sub.15H.sub.16Cl.sub.2N.sub.4 CHCl.sub.3 DMSO 19 6 nM 55 M = 310.42 g/mol C.sub.17H.sub.18N.sub.4S CHCl.sub.3 DMSO 19 1 nM 56 M = 294.35 g/mol C.sub.17H.sub.18N.sub.4O CHCl.sub.3 DMSO 3 1 nM 54 M = 339.25 g/mol C.sub.13H.sub.15BrN.sub.4S CHCl.sub.3 DMSO 13 4 nM 61 0 M = 342.48 g/mol C.sub.17H.sub.18N.sub.4S.sub.2 CHCl.sub.3 DMSO 20 2 nM 62 M = 326.42 g/mol C.sub.17H.sub.18N.sub.4OS CHCl.sub.3 DMSO 10 1 nM 44 M = 272.32 g/mol C.sub.15H.sub.17FN.sub.4 CHCl.sub.3 DMSO 13 3 nM 48 M = 284.36 g/mol C.sub.18H.sub.20N.sub.4O CDCl.sub.3 DMSO 112 26 nM 47 M = 284.36 g/mol C.sub.16H.sub.20N.sub.4O CDCl.sub.3 DMSO 2.3 1 nM 51 M = 273.31 g/mol C.sub.14H.sub.16FN.sub.5 CDCl.sub.3 DMSO 469 6 nM 52 M = 285.34 g/mol C.sub.15H.sub.19N.sub.5O CDCl.sub.3 DMSO 105 29 nM 57 M = 272.32 g/mol C.sub.15H.sub.17FN.sub.4 CDCl.sub.3 DMSO 114 38 nM 45 M = 290.31 g/mol C.sub.15H.sub.16F.sub.2N.sub.4 CDCl.sub.3 DMSO 10 4 nM 53 M = 260.36 g/mol C.sub.13H.sub.16N.sub.4S CDCl.sub.3 DMSO 9.5 3 nM 60 0 M = 269.34 g/mol C.sub.15H.sub.19N.sub.5 CDCl.sub.3 DMSO 11 4 nM 63 M = 366.48 g/mol C.sub.20H.sub.22N.sub.4OS CDCl.sub.3 DMSO 0.6 0.2 nM 71 M = 351.22 g/mol C.sub.15H.sub.16BrFN.sub.4 CHCl.sub.3 DMSO 150 10 nM 79 M = 375.47 g/mol C.sub.22H.sub.25N.sub.5O CHCl.sub.3 DMSO ND 83 M = 333.23 g/mol C15H17N4Br CH.sub.2Cl.sub.2/MeOH-DMSO 11+/2 nM 84 M = 350.42 g/mol C.sub.2H.sub.22N.sub.4O.sub.2 DMSO 6+/3 nM 85 M = 366.49 g/mol C.sub.20H.sub.22N.sub.4OS DMSO 0.7+/0.3 nM 86 M = 366.49 g/mol C.sub.20H.sub.22N.sub.4OS DMSO 1.5+/0.6 nM 87 M = 355.44 g/mol C.sub.18H.sub.18FN.sub.3S CH.sub.2Cl.sub.2CHCl3 DMSO 13+/2 nM 88 M = 355.54 g/mol C18H18N5F2 CH.sub.2Cl.sub.2/MeOH-DMSO 31+/4 nM 89 0 M = 366.49 g/mol C20H22N4OS CH.sub.2Cl.sub.2/MeOH-DMSO 13+/3 nM 90 M = 350.42 g/mol C20H22N4O2 CH.sub.2Cl.sub.2CHCl.sub.3 DMSO 9+/2 nM 91 M = 339.38 g/mol C18H18N5OF CH2Cl2CHCl3 DMSO 117+/26 nM 92 M = 350.42 g/mol C20H22N4O2 CH.sub.2Cl.sub.2CHCl.sub.3 DMSO 115+/5 nM 93 M = 360.46 g/mol C22H24N4O CH.sub.2Cl.sub.2/MeOH-DMSO 137 nM (n = 2) 95 M = 360.46 g/mol C22H24N4O CH.sub.2Cl.sub.2/MeOH-DMSO 100+/21 nM 96 M = 336.46 g/mol C19H20N4S CH.sub.2Cl.sub.2/MeOH-DMSO 135 nM (n = 2) 97 M = 3664.47 g/mol C20H20N4OS CH.sub.2Cl.sub.2/MeOH-DMSO 90-120 nM 98 M = 360.46 g/mol C22H24N4O CH.sub.2Cl.sub.2/MeOH-DMSO 105 nM (n = 2) 99 M = 360.46 g/mol C22H24N4O CH.sub.2Cl.sub.2/MeOH-DMSO 1.4+/0.6 nM 100 0 M = 349.41 g/mol C20H20N5F CH2Cl2CHCl3 DMSO 16+/4 nM 101 M = 364.47 g/mol C20H20N4OS CH.sub.2Cl.sub.2/MeOH-DMSO 7+/2 nM 102 M = 435 g/mol C24H29N5OS CH.sub.2Cl.sub.2/MeOH-DMSO 0.9+/0.2 nM 103 M = 433 g/mol C25H31N5S CH.sub.2Cl.sub.2/MeOH-DMSO 0.3+/0.1 nM 104 M = 448 g/mol C25H32N6S CH.sub.2Cl.sub.2/MeOH-DMSO 0.3+/0.1 nM 105 M = 412 g/mol C21H21FN4O2S CH.sub.2Cl.sub.2/MeOH-DMSO 85 nM (n = 2) 112 M = 368.48 g/mol C.sub.20H.sub.21FN.sub.4S CH.sub.2Cl.sub.2CHCl.sub.3 DMSO 5+/2 nM 114 M = 366.49 g/mol C20H22N4OS CH.sub.2Cl.sub.2/MeOH-DMSO 160 nM (n = 2) 115 M = 366.49 g/mol C20H22N4OS CH.sub.2Cl.sub.2/MeOH-DMSO 0.5+/0.2 nM
Determination of the Specificity of the Compounds of the Invention for the Nicotinic Receptors R7

(165) The fluorinated compounds presenting a significant affinity for R7 (Ki relative to [.sup.125I]-bungarotoxin20 nM) were evaluated in vitro for their affinity relative to the 42 nicotinic receptors (reference tracer [.sup.3H]cytisine, Pabreza et al. 1991), muscarinic receptors (reference tracer [.sup.3H]QNB, Richards 1990) and serotonin 5-HT3 receptors (reference tracer [.sup.3H]BRL-43694, Hope et al. 1996).

REFERENCES

(166) Bradford et al. (1976) Anal Biochem 72: 248-254. Cheng et al. (1973) Biochem Pharmacol 22: 3099-3108. Davies et al. (1999) Neuropharmacology 38: 679-690. Hope et al. (1996) Br J Pharmacol 118: 1237-1245. Pabreza et al. (1991) Mol Pharmacol 39: 9-12. Richards et al. (1990) Br J Pharmacol 99: 753-761.