Pharmaceutical compounds

Abstract

This invention relates to compounds that are agonists of the muscarinic M.sub.1 and/or M.sub.4 receptor and which are useful in the treatment of diseases mediated by the muscarinic M.sub.1 and M.sub.4 receptors. Also provided are pharmaceutical compositions containing the compounds and the therapeutic uses of the compounds. Compounds provided are of formula ##STR00001##
where X.sup.1; X.sup.2; X.sup.3; X.sup.4; R.sup.1 R.sup.2 and R.sup.4 are as defined herein.

Claims

1. A compound of formula (1): ##STR00156## or a salt thereof, wherein: the ring system formed by X.sup.1 and X.sup.2 is selected from: ##STR00157## the ring system formed by X.sup.3 and X.sup.4 is selected from: ##STR00158## R.sup.1 is CONR.sup.5R.sup.6; R.sup.2 is selected from hydrogen, fluorine, cyano and a C.sub.1-3 hydrocarbon group which is optionally substituted with one to six fluorine atoms; R.sup.4 is H or C.sub.1-6 alkyl optionally substituted with one or more fluorine atoms; R.sup.5 is hydrogen or a non-aromatic C.sub.1-10 hydrocarbon group optionally substituted with one or more fluorine atoms; R.sup.6 is hydrogen or a non-aromatic C.sub.1-10 hydrocarbon group optionally substituted with one or more fluorine atoms.

2. The compound according to claim 1 which is a compound of formula (2): ##STR00159## or a salt thereof.

3. The compound according to claim 1 which is a compound of formula (3): ##STR00160## or a salt thereof.

4. The compound according to claim 1, or a salt thereof, wherein the ring system formed by X.sup.1 and X.sup.2 is: ##STR00161##

5. The compound according to claim 1, or a salt thereof, wherein R.sup.5 is methyl, ethyl or methylcyclobutyl.

6. The compound according to claim 1, or a salt thereof, wherein R.sup.5 is methylcyclobutyl.

7. The compound according to claim 1, or a salt thereof, wherein R.sup.6 is H, methyl, ethyl or methylcyclobutyl.

8. The compound according to claim 1, or a salt thereof, wherein R.sup.6 is H.

9. The compound according to claim 1, or a salt thereof, wherein R.sup.1 is selected from: ##STR00162##

10. The compound according to claim 1, or a salt thereof, wherein R.sup.1 is: ##STR00163##

11. The compound according to claim 1, or a salt thereof, wherein R.sup.2 is selected from H, methyl, cyano and F.

12. The compound according to claim 1, or a salt thereof, wherein R.sup.2 is H.

13. The compound according to claim 1, or a salt thereof, wherein R.sup.4 is methyl, trifluoromethyl, ethyl or isopropyl.

14. The compound according to claim 1, which is selected from: N-(1-Methylcyclobutyl)-1-[8-(3-methyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]oct-3-yl]piperidine-4-carboxamide; (1R,5S,6r)-N,N-Diethyl-3-[9-(3-methyl-1,2,4-oxadiazol-5-yl)-3-oxa-9-azabicyclo[3.3.1]non-7-yl]-3-azabicyclo[3.1.0] hexane-6-carboxamide; 1-(8-(3-Methyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)-N-(1-(trifluoromethyl)cyclobutyl)piperidine-4-carboxamide; N-(1-Ethylcyclobutyl)-1-(8-(3-methyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)piperidine-4-carboxamide; N-(1-isopropylcyclobutyl)-1-(8-(3-methyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)piperidine-4-carboxamide; 1-(8-(3-Methyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)-N-(1-methylcyclopentyl)piperidine-4-carboxamide; 1-(8-(3-Methyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)-N-((1-methylcyclobutyl)methyl)piperidine-4-carboxamide; (1R,5S,6r)-3-(8-(3-methyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)-N-(1-methylcyclobutyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide; N-(1-Methylcyclobutyl)-1-(8-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)piperidine-4-carboxamide; (1R,5S,6r)-N-isopropyl-N-methyl-3-(9-(3-methyl-1,2,4-oxadiazol-5-yl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide; (1R,5S,6r)-N,N-diethyl-3-(9-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide; (1R,5S,6r)-N-ethyl-N-methyl-3-(8-(3-methyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide; (1R,5S,6r)-N,N-diethyl-3-(8-(3-methyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide; (1R,5S,6r)-N,N-dimethyl-3-(9-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide; (1R,5S,6r)-N-isopropyl-N-methyl-3-(8-(3-methyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide; (1R,5S,6r)-3-(8-(3-methyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)-N-(1-(trifluoromethyl)cyclobutyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide; or a salt thereof.

15. The compound according to claim 1, which is N-(1-Methylcyclobutyl)-1-(8-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)piperidine-4-carboxamide or a salt thereof.

16. The compound according to claim 1, which is (1R,5S,6r)-N,N-diethyl-3-(9-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide or a salt thereof.

17. A pharmaceutical composition comprising a compound according to claim 1, or a salt thereof, and a pharmaceutically acceptable excipient.

18. A method of treating a cognitive disorder selected from Schizophrenia, Alzheimer's disease and dementia with Lewy bodies, or for the treatment or lessening the severity of acute, chronic, neuropathic, or inflammatory pain comprising administering an effective amount of a compound according to claim 1, or a salt thereof, to a subject in need thereof.

19. The method according to claim 18 wherein the cognitive disorder is Alzheimer's disease.

20. The method according to claim 18 wherein the cognitive disorder is dementia with Lewy bodies.

Description

EXAMPLES

(1) The invention will now be illustrated, but not limited, by reference to the specific embodiments described in the following examples.

Examples 1-1 to 18-2

(2) The compounds of Examples 1-1 to 18-2 shown in Table 1 below have been prepared. Some of their NMR and LCMS properties and the methods used to prepare them are set out in Table 3. The starting materials and intermediates for some of the Examples are listed in Table 2.

(3) TABLE-US-00001 TABLE 1 embedded image Example 1-1 Example 2-1 Example 2-2 Example 2-3 Example 3-1 Example 4-1 0 Example 5-1 Example 6-1 Example 6-2 Example 6-3 Example 6-4 Example 6-5 Example 7-1 Example 8-1 Example 8-2 Example 8-3 0 Example 8-4 Example 9-1 Example 9-2 Example 10-1 Example 10-2 Example 10-3 embedded image Example 10-4 Example 10-5 Example 10-6 Example 10-7 0 Example 10-8 Example 10-9 Example 10-10 Example 10-11 Example 10-12 Example 11-1 Example 11-2 Example 11-3 Example 12-1 Example 12-2 0 Example 12-3 Example 12-4 Example 12-6 Example 12-7 Example 12-8 Example 12-9 Example 12-11 embedded image Example 12-12 Example 12-13 Example 12-14 0 Example 12-15 Example 12-16 Example 12-17 Example 12-18 Example 12-19 Example 12-20 Example 12-21 Example 12-22 Example 12-23 Example 12-24 0 Example 12-25 Example 12-26 Example 12-27 Example 12-28 Example 13-1 Example 13-2 Example 13-3 embedded image Example 13-4 Example 13-5 Example 13-6 0 Example 14-1 Example 14-2 Example 14-3 Example 14-4 Example 14-5 Example 14-6 Example 15-1 Example 15-2 Example 15-3 Example 15-4 00 Example 15-5 01 Example 15-6 02 Example 16-1 03 Example 16-2 04 Example 16-3 05 Example 16-4 06 Example 16-5 07 embedded image Example 16-10 08 Example 16-11 09 Example 16-12 0 Example 16-13 Example 16-14 Example 16-15 Example 16-16 Example 16-17 Example 16-18 Example 16-19 Example 17-1 Example 17-2 Example 17-3 0 Example 17-4 Example 17-5 Example 17-6 Example 17-7 Example 17-8 Example 17-9 Example 17-10 embedded image Example 17-11 Example 17-12 Example 17-13 0 Example 17-14 Example 17-15 Example 17-16 Example 17-17 Example 17-18 Example 17-19 Example 17-20 Example 17-21 Example 17-22 Example 17-23 0 Example 17-24 Example 17-25 Example 18-1 Example 18-2

(4) General Procedures

(5) Where no preparative routes are included, the relevant intermediate is commercially available. Commercial reagents were utilized without further purification. Room temperature (rt) refers to approximately 20-27° C. .sup.1H NMR spectra were recorded at 400 MHz on either a Bruker or Jeol instrument. Chemical shift values are expressed in parts per million (ppm), i.e. (δ)-values. The following abbreviations are used for the multiplicity of the NMR signals: s=singlet, br=broad, d=doublet, t=triplet, q=quartet, quint=quintet, td=triplet of doublets, tt=triplet of triplets, qd=quartet of doublets, ddd=doublet of doublet of doublets, ddt=doublet of doublet of triplets, m=multiplet. Coupling constants are listed as J values, measured in Hz. NMR and mass spectroscopy results were corrected to account for background peaks. Chromatography refers to column chromatography performed using 60-120 mesh silica gel and executed under nitrogen pressure (flash chromatography) conditions. TLC for monitoring reactions refers to TLC run using the specified mobile phase and the Silica gel F254 as a stationary phase from Merck. Microwave-mediated reactions were performed in Biotage Initiator or CEM Discover microwave reactors.

(6) LCMS Analysis

(7) LCMS analysis of compounds was performed under electrospray conditions using the instruments and methods given in the tables below:

(8) TABLE-US-00002 System Instrument Name LC Detector Mass Detector 1 Waters 2695 Photo Diode ZQ-2000 Detector Array 2 Waters Acquity H Class Photo Diode SQ Detector Array 3 Shimadzu Nexera Photo Diode LCMS-2020 Array 4 Agilent 1290 RRLC Photo Diode Agilent 6120 Array 5 Hewlett Packard HP 1100 G1315A DAD Micromass ZQ

(9) TABLE-US-00003 Method Solvent UV Mass Column Flow Rate Name System Column used Gradient Range Range Temp. ° C. ml/min A (A) 2 mM BEH C18 2.1 × 98:2 at 0.01 min up to 0.30 min, 50:50 at 200-400 nm 100-1200 amu Ambient 0.55 ammonium 50 mm, 1.7 μm 0.60 min, 25:75 at 1.10 min, 0:100 at 2.00 acetate + 0.1% or equivalent min up to 2.70 min, 98:2 at 2.71 min up to formic acid in 3.00 min water (B) 0.1% formic acid in acetonitrile B (A) 20 mM X-Bridge C18 90:10 at 0.01 min, 10:90 at 5.00 min, 200-400 nm 60-1000 amu Ambient 1.00 ammonium 4.6 × 150 mm, 5 0:100 at 7.00 min up to 11.00 min, 90:10 acetate in water μm or equivalent at 11.01 min up to 12.00 min (B) methanol C (A) 10 mM YMC Triart C18 100:0 at 0.01 min, 50:50 at 7.00 min, 200-400 nm 60-1000 amu Ambient 1.00 ammonium 4.6 × 150 mm, 5 0:100 at 9.00 min up to 11.00 min, 100:0 acetate in water μm or equivalent at 11.01 min up to 12.00 min (B) acetonitrile D (A) 0.1% X-Bridge C18 95:5 at 0.01 min, 10:90 at 5.00 min, 5:95 200-400 nm 60-1000 amu Ambient 1.00 ammonia in 4.6 × 50 mm, at 5.80 min up to 7.20 min, 95:5 at 7.21 water 3.5 μm or min up to 10.00 min (B) 0.1% equivalent ammonia in acetonitrile E (A) 5 mM BEH C18 2.1 × 95:5 at 0.01 min up to 0.40 min, 60:40 at 200-400 nm 100-1200 amu Ambient 0.55 ammonium 50 mm, 1.7 μm 0.60 min, 40:60 at 1.20 min, 0:100 at 2.30 acetate + 0.1% or equivalent min up to 3.00 min, 95:5 at 3.01 min up to formic acid in 3.50 min water (B) 0.1% formic acid in acetonitrile F (A) 5 mM X-Bridge C18 95:5 at 0.01 min, 10:90 at 5.00 min, 5:95 200-400 nm 60-1000 amu Ambient 1.00 ammonium 4.6 × 50 mm, at 5.80 min up to 7.20 min, 95:5 at 7.21 bicarbonate in 3.5 μm or min up to 10.00 min water equivalent (B) acetonitrile G (A) 2.5 L water + Gemini-NX C- 98:2 at 0.00 min up to 0.10 min, 5:95 at 230-400 nm 130-800 amu 45 1.50 2.5 mL 28% 18, 2.0 × 30 8.40 min up to 10.00 min ammonia mm, 3 μm solution in water B) 2.5 L acetonitrile + 135 mL water + 2.5 mL 28% ammonia solution in water H (A) 2 mM BEH C18 2.1 × 98:2 at 0.01 min up to 0.30 min (flow rate 200-400 nm 100-1200 amu Ambient 0.55-0.60 ammonium 50 mm, 1.7 μm 0.55), 50:50 at 0.60 min (flow rate 0.55), acetate + 0.1% or equivalent 25:75 at 1.10 min (flow rate 0.55), 0:100 formic acid in at 2.00 min up to 2.70 min (flow rate water 0.60), 98:2 at 2.71 min up to 3.00 min (B) 0.1% formic (flow rate 0.55) acid in acetonitrile

(10) LCMS data in the experimental section and Tables 2 and 3 are given in the format: (Instrument system, Method): Mass ion, retention time, UV detection wavelength.

(11) Compound Purification

(12) Final purification of compounds was performed by preparative reversed phase HPLC, chiral HPLC or chiral SFC using the instruments and methods detailed below where data is given in the following format: Purification technique: [phase (column description, column length×internal diameter, particle size), solvent flow-rate, gradient—given as % of mobile phase B in mobile phase A (over time), mobile phase (A), mobile phase (B)].

(13) Preparative HPLC Purification:

(14) Shimadzu LC-20AP binary system with SPD-20A UV detector

(15) Chiral HPLC Purification:

(16) Shimadzu LC-20AP binary system with SPD-20A UV detector

(17) Chiral SFC Purification:

(18) Waters SFC 200

(19) Sepiatec 100

(20) Berger Multigram 2

(21) Purification Method A

(22) Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 15 mL/min, gradient 10%-40% (over 23 min), 100% (over 2 min), 100%-10% (over 4 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1% ammonia in water, (B): 100% acetonitrile].

(23) Purification Method B

(24) Prep HPLC: [Reversed Phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 15 mL/min, gradient 10%-33% (over 25 min), 100% (over 2 min), 10% (over 3 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1% ammonia in water, (B): 100% acetonitrile].

(25) Purification Method C

(26) Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×19 mm, 5 μm), 15 mL/min, gradient 37%-40% (over 23 min), 100% (over 2 min), 37% (over 2 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1% ammonia in water, (B): 100% acetonitrile].

(27) Purification Method D

(28) Prep HPLC: [Reversed Phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 15 mL/min, gradient 30%-40% (over 20 min), 100% (over 2 min), 100-30% (over 3 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1% ammonia in water, (B): 100% acetonitrile].

(29) Purification Method E

(30) Prep HPLC: [Reversed Phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 15 mL/min, gradient 5%-40% (over 20 min), 40% (over 3 min), 100% (over 2 min), 100-5% (over 2 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1% ammonia in water, (B): 100% acetonitrile].

(31) Purification Method F

(32) Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 5 mL/min, gradient 15%-47% (over 15 min), 100% (over 1 min), 10% (over 3 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1% ammonia in water, (B): 100% acetonitrile].

(33) Purification Method G

(34) Prep HPLC: [Reversed Phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 15 mL/min, gradient 5%-50% (over 17 min), 50-70% (over 2 min), 100% (over 3 min), 100-5% (over 3 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1% ammonia in water, (B): 100% acetonitrile].

(35) Purification Method H

(36) Prep HPLC: [Reversed Phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 16 mL/min, gradient 15%-42% (over 20 min), 100% (over 2 min), 100%-15% (over 3 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1% ammonia in water, (B): 100% acetonitrile].

(37) Purification Method I

(38) Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×19 mm, 5 μm), 16 mL/min, gradient 5%-30% (over 19 min), 100% (over 3 min), 100%-5% (over 4 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1% ammonia in water, (B): 100% acetonitrile].

(39) Purification Method J

(40) Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×19 mm, 5 μm), 10 mL/min, gradient 0%-30% (over 45 min), 30-30% (over 48 min), 100% (over 2 min), 100%-0% (over 3 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1% ammonia in water, (B): 100% acetonitrile].

(41) Purification Method K

(42) Prep HPLC: [Reversed Phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 15 mL/min, gradient 5%-38% (over 25 min), 100% (over 2 min), 100-5% (over 5 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1% ammonia in water, (B): 100% acetonitrile].

(43) Purification Method L

(44) Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×19 mm, 5 μm), 16 mL/min, gradient 20%-30% (over 25 min), 30-30% (over 5 min), 100% (over 3 min), 100%-20% (over 5 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1% ammonia in water, (B): 100% acetonitrile].

(45) Purification Method M

(46) Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 15 mL/min, gradient 15%-30% (over 30 min), 30-30% (over 6 min), 100% (over 2 min), 100-15% (over 4 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1% ammonia in water, (B): 100% acetonitrile].

(47) Purification Method N

(48) Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 15 mL/min, gradient 25%-35% (over 23 min), 100% (over 1 min), 100-25% (over 4 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1% ammonia in water, (B): 100% acetonitrile].

(49) Purification Method O

(50) Chiral HPLC: [Normal Phase (CHIRALPAK AD-H, 250×21 mm, 5 μm), 18 mL/min, Isochratic (A:B) 45:55 (over 45 min), mobile phase (A): 0.1% diethylamine in hexane, (B): 0.1% diethylamine in isopropanol:methanol (30:70)].

(51) Purification Method P

(52) Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×19 mm, 5 μm), 13 mL/min, gradient 15%-20% (over 30 min), 20-20% (over 6 min), 100% (over 1 min), 100%-15% (over 6 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1% ammonia in water, (B): 100% acetonitrile].

(53) Purification Method Q

(54) Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×19 mm, 5 μm), 15 mL/min, gradient 5%-17% (over 32 min), 17-17% (over 58 min), 100% (over 3 min), 100%-5% (over 4 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1% ammonia in water, (B): 100% acetonitrile].

(55) Purification Method R

(56) Prep HPLC: [Reversed Phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 15 mL/min, gradient 20%-35% (over 25 min), 35-35% (over 3 min), 100% (over 2 min), 100-20% (over 3 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1% ammonia in water, (B): 100% acetonitrile].

(57) Purification Method S

(58) SFC: [(CHIRALCEL OX-H, 250×21 mm, 5 μm), 70 mL/min, Isochratic (A:B) 70:30 (over 8.5 min), mobile phase (A): 100% liquid CO.sub.2, (B): 0.1% diethylamine in isopropanol:methanol (50:50)].

(59) Purification Method T

(60) Prep HPLC: [Reversed Phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 15 mL/min, gradient 18%-30% (over 18 min), 100% (over 2 min), 100-18% (over 2 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1% ammonia in water, (B): 100% acetonitrile].

(61) Purification Method U

(62) Chiral HPLC: [Normal Phase (CHIRALCEL OX-H, 250×21 mm, 5 μm), 18 mL/min, Isochratic (A:B) 90:10 (over 32 min), mobile phase (A): 0.1% diethylamine in hexane, (B): 0.1% diethylamine in isopropanol:acetonitrile (70:30)].

(63) Purification Method V

(64) Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×19 mm, 5 μm), 15 mL/min, gradient 10%-25% (over 25 min), 25-25% (over 7 min), 100% (over 2 min), 100%-10% (over 2 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1% ammonia in water, (B): 100% acetonitrile].

(65) Purification Method W

(66) Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 15 mL/min, gradient 25%-40% (over 15 min), 100% (over 3 min), 100%-25% (over 5 min), mobile phase (A): 0.1% ammonia in water, (B): 100% acetonitrile].

(67) Purification Method X

(68) SFC: [(LUX A1, 250×21.2 mm, 5 μm), 50 mL/min, Isochratic (A:B) 65:35, mobile phase (A): 100% liquid CO.sub.2, (B): 0.1% ammonia in methanol].

(69) Purification Method Y

(70) Prep HPLC: [Reversed Phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 15 mL/min, gradient 8%-20% (over 23 min), 20%-20% (over 2 min), 100% (over 2 min), 100%-8% (over 5 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1% ammonia in water, (B): 100% acetonitrile].

(71) Purification Method Z

(72) SFC: [(CHIRALPAK AD-H, 250×21 mm, 5 μm), 75 mL/min, Isochratic (A:B) 82:18 (over 20 min), mobile phase (A): 100% liquid CO.sub.2, (B): 0.1% diethylamine in methanol].

(73) Purification Method AA

(74) Prep HPLC: [Reversed Phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 15 mL/min, gradient 8%-23% (over 17 min), 23%-23% (over 2 min), 100% (over 2 min), 100%-8% (over 4 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1% ammonia in water, (B): 100% acetonitrile].

(75) Purification Method AB

(76) Prep HPLC: [Reversed Phase (YMC ACTUS TRIART C-18, 250×20 mm, 5 μm), 15 mL/min, gradient 15%-30% (over 28 min), 100% (over 2 min), 100%-15% (over 2 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1% ammonia in water, (B): 100% acetonitrile].

(77) Purification Method AC

(78) SFC: [(CHIRALPAK AD-H, 250×21 mm, 5 μm), 75 mL/min, Isochratic (A:B) 75:25 (over 18 min), mobile phase (A): 100% liquid CO.sub.2, (B): 0.1% diethylamine in methanol].

(79) Purification Method AD

(80) Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×50 mm, 5 μm), 90 mL/min, gradient 5%-35% (over 20 min), 100% (over 2 min), 100%-5% (over 3 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1% ammonia in water, (B): 100% acetonitrile].

(81) Purification Method AE

(82) Chiral HPLC: [Normal Phase (CHIRALPAK AD-H, 250×21 mm, 5 μm), 18 mL/min, Isochratic (A:B) 70:30 (over 35 min), mobile phase (A): 0.1% diethylamine in hexane, (B): 0.1% diethylamine in isopropanol:methanol (50:50)].

(83) Purification Method AF

(84) Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 13 mL/min, gradient 15%-30% (over 30 min), 30%-30% (over 10 min), 100% (over 2 min), 100%-15% (over 3 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1% ammonia in water, (B): 100% acetonitrile].

(85) Purification Method AG

(86) SFC: [(CHIRALPAK AD-H, 250×21 mm, 5 μm), 80 mL/min, Isochratic (A:B) 75:25 (over 13 min), mobile phase (A): 100% liquid CO.sub.2, (B): 0.1% diethylamine in isopropanol:methanol (50:50)].

(87) Purification Method AH

(88) Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×50 mm, 5 μm), 80 mL/min, gradient 5%-18% (over 50 min), 18%-18% (over 10 min), 100% (over 3 min), 100%-5% (over 7 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1% ammonia in water, (B): 100% acetonitrile].

(89) Purification Method AI

(90) SFC: [(CHIRALPAK AD-H, 250×21 mm, 5 μm), 80 mL/min, Isochratic (A:B) 70:30 (over 20 min), mobile phase (A): 100% liquid CO.sub.2, (B): 0.1% diethylamine in methanol].

(91) Purification Method AJ

(92) Prep HPLC: [Reversed Phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 15 mL/min, gradient 0%-27% (over 28 min), 27%-27% (over 6 min), 100% (over 4 min), 100%-0% (over 2 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1% ammonia in water, (B): 100% acetonitrile].

(93) Purification Method AK

(94) Chiral HPLC: [Normal Phase (CHIRALPAK AD-H, 250×21 mm, 5 μm), 18 mL/min, Isochratic (A:B) 90:10 (over 27 min), mobile phase (A): 0.1% diethylamine in hexane, (B): 0.1% diethylamine in isopropanol].

(95) Purification Method AL

(96) Prep HPLC: [Reversed Phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 15 mL/min, gradient 15%-35% (over 20 min), 35%-35% (over 3 min), 100% (over 2 min), 100%-15% (over 3 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1% ammonia in water, (B): 100% acetonitrile].

(97) Purification Method AM

(98) SFC: [(CHIRALPAK AD-H, 250×21 mm, 5 μm), 80 mL/min, Isochratic (A:B) 65:35 (over 16.5 min), mobile phase (A): 100% liquid CO.sub.2, (B): 0.1% diethylamine in methanol].

(99) Purification Method AN

(100) Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×19 mm, 5 μm), 15 mL/min, gradient 10%-30% (over 20 min), 30%-30% (over 5 min), 100% (over 2 min), 100%-10% (over 3 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1% ammonia in water, (B): 100% acetonitrile].

(101) Purification Method AO

(102) Chiral HPLC: [Normal Phase (CHIRALPAK AD-H, 250×21 mm, 5 μm), 18 mL/min, Isochratic (A:B) 85:15 (over 30 min), mobile phase (A): 0.1% diethylamine in hexane, (B): 0.1% diethylamine in isopropanol].

(103) Purification Method AP

(104) Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×19 mm, 5 μm), 16 mL/min, gradient 10%-32% (over 18 min), 100% (over 2 min), 100%-10% (over 2 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1% ammonia in water, (B): 100% acetonitrile].

(105) Purification Method AQ

(106) Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×19 mm, 5 μm), 13 mL/min, gradient 20%-25% (over 17 min), 25%-25% (over 3 min), 100% (over 2 min), 100%-20% (over 3 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1% ammonia in water, (B): 100% acetonitrile].

(107) Purification Method AR

(108) Chiral HPLC: [Normal Phase (CHIRALCEL OX-H, 250×21 mm, 5 μm), 18 mL/min, Isochratic (A:B) 78:22 (over 37 min), mobile phase (A): 0.1% diethylamine in hexane, (B): 0.1% diethylamine in isopropanol:methanol (50:50)].

(109) Purification Method AS

(110) Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 15 mL/min, gradient 25%-38% (over 16 min), 100% (over 2 min), 100%-25% (over 5 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1% ammonia in water, (B): 100% acetonitrile].

(111) Purification Method AT

(112) Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 15 mL/min, gradient 5%-35% (over 20 min), 100% (over 4 min), 100%-5% (over 4 min), mobile phase (A): 0.1% ammonia in water, (B): 100% acetonitrile].

(113) Purification Method AU

(114) Prep HPLC: [Reversed Phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 15 mL/min, gradient 5%-28% (over 18 min), 28%-28% (over 2 min), 100% (over 2 min), 100%-5% (over 2 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1% ammonia in water, (B): 100% acetonitrile].

(115) Purification Method AV

(116) Prep HPLC: [Reversed Phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 15 mL/min, gradient 10%-20% (over 25 min), 20%-20% (over 8 min), 100% (over 2 min), 100%-10% (over 5 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1% ammonia in water, (B): 100% acetonitrile].

(117) Purification Method AW

(118) Prep HPLC: [Reversed Phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 15 mL/min, gradient 15%-20% (over 22 min), 20%-20% (over 5 min), 100% (over 2 min), 100%-15% (over 6 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1% ammonia in water, (B): 100% acetonitrile].

(119) Purification Method AX

(120) Prep HPLC: [Reversed Phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 10 mL/min, gradient 5%-55% (over 18 min), 55%-55% (over 6 min), 100% (over 2 min), 100%-5% (over 6 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1% ammonia in water, (B): 100% acetonitrile].

(121) Purification Method AY

(122) Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×19 mm, 5 μm), 15 mL/min, gradient 20%-45% (over 22 min), 100% (over 2 min), 100%-20% (over 5 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1% ammonia in water, (B): 100% acetonitrile].

(123) Purification Method AZ

(124) Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×19 mm, 5 μm), 16 mL/min, gradient 30%-39% (over 14 min), 100% (over 2 min), 100%-30% (over 4 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1% ammonia in water, (B): 100% acetonitrile].

(125) Purification Method BA

(126) SFC: [(CHIRALPAK AD-H, 250×21 mm, 5 μm), 80 mL/min, Isochratic (A:B) 85:15 (over 7 min), mobile phase (A): 100% liquid CO.sub.2, (B): 0.1% diethylamine in methanol].

(127) Purification Method BB

(128) Prep HPLC: [Reversed Phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 13 mL/min, gradient 25%-35% (over 28 min), 35%-35% (over 2 min), 100% (over 2 min), 100%-25% (over 5 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1% ammonia in water, (B): 100% acetonitrile].

(129) Purification Method BC

(130) Prep HPLC: [Reversed Phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 13 mL/min, gradient 25%-40% (over 30 min), 40%-40% (over 2 min), 100% (over 2 min), 100%-25% (over 6 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1% ammonia in water, (B): 100% acetonitrile].

(131) Purification Method BD

(132) Prep HPLC: [Reversed Phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 14 mL/min, gradient 20%-50% (over 20 min), 50%-50% (over 5 min), 100% (over 2 min), 100%-20% (over 6 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1% ammonia in water, (B): 100% acetonitrile].

(133) Purification Method BE

(134) Prep HPLC: [Reversed Phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 12 mL/min, gradient 5%-50% (over 23 min), 50%-50% (over 5 min), 100% (over 2 min), 100%-5% (over 3 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1% ammonia in water, (B): 100% acetonitrile].

(135) Purification Method BF

(136) Prep HPLC: [Reversed Phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 13 mL/min, gradient 5%-55% (over 22 min), 55%-55% (over 6 min), 100% (over 2 min), 100%-5% (over 3 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1% ammonia in water, (B): 100% acetonitrile].

(137) Purification Method BG

(138) Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×19 mm, 5 μm), 14 mL/min, gradient 25%-52% (over 25 min), 52%-52% (over 9 min), 100% (over 2 min), 100%-25% (over 4 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1% ammonia in water, (B): 100% acetonitrile].

(139) Abbreviations AcOH=acetic acid aq.=aqueous DCM=dichloromethane DIPEA=diisopropylethylamine DMF=dimethylformamide DMSO=dimethylsulfoxide ES(I)=electro spray ionization Et.sub.2O=diethyl ether EtOAc=ethyl acetate EtOH=ethanol h=hour(s) H.sub.2O=water HATU=1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate HCl=hydrogen chloride, hydrochloric acid HPLC=high performance liquid chromatography LC=liquid chromatography MeCN=acetonitrile MeOH=Methanol min(s)=minute(s) MS=mass spectrometry nm=nanometre(s) NMR=nuclear magnetic resonance sat.=saturated SFC=supercritical fluid chromatography STAB=sodium triacetoxyborohydride TFA=trifluoroacetic acid THF=tetrahydrofuran TLC=thin layer chromatography

(140) Prefixes n-, s-, i-, t- and tert- have their usual meanings: normal, secondary, iso, and tertiary.

(141) Synthesis of Intermediates:

(142) Route 1

Typical Procedure for the Preparation of Ketones, as Exemplified by the Preparation of Intermediate 3, 2-(3-methyl-1,2,4-oxadiazol-5-yl)-2-azaspiro[3.3]heptan-6-one

(143) ##STR00144##

(144) tert-Butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate 1) (500 mg, 2.37 mmol) was dissolved in MeOH (10 mL) and the resulting solution was cooled to 0° C. Sodium borohydride (270 mg, 7.10 mmol) was added portion wise and the resulting reaction mixture was stirred at 25° C. for 2 h. The solvents were removed in-vacuo and the residue was partitioned between H.sub.2O (80 mL) and EtOAc (60 mL). The aqueous layer was further extracted with EtOAc (2×60 mL), and the organic layers were combined, dried (Na.sub.2SO.sub.4), and the solvent was removed in-vacuo. The residue was triturated with pentane to give tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (500 mg, 99%) as a solid.

(145) LCMS (System 2, Method E): m/z 214 (M+H).sup.+ (ESI +ve), at 1.54 min, 202 nm.

(146) tert-Butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (500 mg, 2.34 mmol) was dissolved in DCM (10 mL) and the resulting solution was cooled to 0° C. Trifluoroacetic acid (1 mL) was added dropwise and the resulting reaction mixture was stirred at 25° C. for 6 h. The solvents were removed in-vacuo and the residue was triturated with pentane (3×1 mL) to give 2-azaspiro[3.3]heptan-6-ol trifluoroacetic acid salt (260 mg, 98%) as a gum.

(147) LCMS (System 2, Method E): m/z 114 (M+H).sup.+ (ESI +ve), at 0.22 min, 202 nm.

(148) 2-Azaspiro[3.3]heptan-6-ol trifluoroacetic acid salt (250 mg, 2.21 mmol) was dissolved in DCM (10 mL), treated with sat. aq. NaHCO.sub.3 (1 mL) and cooled to 0° C. for 10 min. Cyanogen bromide (255 mg, 2.43 mmol) was added portion wise and the resulting reaction mixture was stirred at 25° C. for 5 h. The solvents were removed in-vacuo and the residue was basified with sat. aq. NaHCO.sub.3 solution. The precipitated solids were removed by filtration and washed with DCM 5 to 6 times. The combined filtrate and washings were then dried (Na.sub.2SO.sub.4), the solvent was removed in-vacuo and the crude product was purified by trituration with pentane to give 6-hydroxy-2-azaspiro[3.3]heptane-2-carbonitrile (230 mg, 75%) as a gum.

(149) LCMS (System 2, Method E): m/z 139 (M+H).sup.+ (ESI +ve), at 0.76 min, 202 nm.

(150) 6-Hydroxy-2-azaspiro[3.3]heptane-2-carbonitrile (180 mg, 1.30 mmol) was dissolved in a mixture of EtOAc:Et.sub.2O (5:1) (5 mL) and N-hydroxyacetamide (Intermediate 2) (125 mg, 1.69 mmol) was added. The resulting mixture was stirred at 25° C. for 5 min, then a solution of ZnCl.sub.2 in diethyl ether (1 M, 1 mL, 1 mmol) was added drop wise. The reaction mixture was stirred at 25° C. for 20 min, during which time a white precipitate formed. The reaction mixture was diluted with Et.sub.2O (3×10 mL) and the solvent was decanted off each time. The remaining solid was dissolved in EtOH (3 mL), treated with aq. HCl (4 M, 2 mL) and heated at reflux for 6 h. The solvents were removed in-vacuo and the residue was basified with aq. NaHCO.sub.3 and then partitioned between H.sub.2O (80 mL) and DCM (60 mL). The aqueous layer was further extracted with DCM (2×60 mL) and the combined organic layers were dried (Na.sub.2SO.sub.4) and the solvent was removed in-vacuo. The residue was purified by trituration with pentane to give 2-(3-methyl-1,2,4-oxadiazol-5-yl)-2-azaspiro[3.3]heptan-6-ol (60 mg, 24%) as a gum.

(151) LCMS (System 2, Method E): m/z 196 (M+H).sup.+ (ESI +ve), at 1.34 min, 202 nm.

(152) 2-(3-Methyl-1,2,4-oxadiazol-5-yl)-2-azaspiro[3.3]heptan-6-ol (80 mg, 0.41 mmol) was dissolved in DCM (5 mL) and the solution was cooled to 0° C. Pyridinium chlorochromate (132 mg, 0.62 mmol) was added portion wise and the resulting reaction mixture was stirred at 25° C. for 3 h. The solvents were then removed in-vacuo and the residue was basified with NaHCO.sub.3 solution and partitioned between H.sub.2O (60 mL) and EtOAc (45 mL). The aqueous layer was further extracted with EtOAc (2×45 mL), and the combined organic layers were dried (Na.sub.2SO.sub.4), and the solvent was removed in-vacuo. The residue was triturated with pentane to give 2-(3-methyl-1,2,4-oxadiazol-5-yl)-2-azaspiro[3.3]heptan-6-one (Intermediate 3) (60 mg, 76%) as a gum.

(153) The data for Intermediate 3 are in Table 2.

(154) Route 2

Typical Procedure for the Preparation of Alcohols, as Exemplified by the Preparation of Intermediate 6, 6-azaspiro[3.4]octan-2-ol hydrochloride salt

(155) ##STR00145##

(156) tert-Butyl 2-oxo-6-azaspiro[3.4]octane-6-carboxylate (Intermediate 5) (10 g, 44.3 mmol), was dissolved in MeOH (1000 mL) and the resulting solution was cooled to 0° C. Sodium borohydride (2.0 g, 53.2 mmol) was added portion wise and the resulting reaction mixture was stirred at 25° C. for 1 h. The solvents were removed in-vacuo and the residue was partitioned between H.sub.2O (250 mL) and EtOAc (250 mL). The aqueous layer was further extracted with EtOAc (2×150 mL), and the organic layers were combined, dried (Na.sub.2SO.sub.4), and the solvent was removed in-vacuo to give tert-butyl 2-hydroxy-6-azaspiro[3.4]octane-6-carboxylate (9.2 g, 91%) as a gum.

(157) LCMS (System 3, Method F): m/z 228 (M+H).sup.+ (ESI +ve), at 3.09 min, 202 nm.

(158) tert-Butyl 2-hydroxy-6-azaspiro[3.4]octane-6-carboxylate (9 g, 39.6 mmol) was slowly dissolved in HCl solution in 1,4-dioxane (4 M, 90 mL) and the resulting reaction mixture was stirred at 25° C. for 16 h. The solvent was removed in-vacuo and the residue was purified by trituration with diethyl ether (3×50 mL) to give 6-azaspiro[3.4]octan-2-ol hydrochloride salt (Intermediate 6) (7 g, 90%) as a gum.

(159) The data for Intermediate 6 are in Table 2.

(160) Route 3

Typical Procedure for the Preparation of Alcohols, as Exemplified by the Preparation of Intermediate 27, 2-azabicyclo[2.2.2]octan-5-ol hydrochloride salt

(161) ##STR00146##

(162) tert-Butyl 5-oxo-2-azabicyclo[2.2.2]octane-2-carboxylate (Intermediate 26) (500 mg, 2.2 mmol) was dissolved in THF (10 mL) and the solution was cooled to −20° C. under an atmosphere of nitrogen. Lithium aluminium hydride solution in THF (1 M, 3.3 mL, 3.3 mmol) was added at −20° C. and the resulting mixture was stirred at 0° C. for 2 h. The reaction mixture was partitioned between cold H.sub.2O (25 mL) and EtOAc (15 mL) and the aqueous layer was further extracted with EtOAc (2×15 mL). The combined organic layers were dried (Na.sub.2SO.sub.4) and the solvent was removed in-vacuo to give tert-butyl 5-hydroxy-2-azabicyclo[2.2.2]octane-2-carboxylate (500 mg, 99%) as a gum.

(163) LCMS (System 2, Method E): m/z 172 (M+H-56).sup.+ (ESI +ve), at 1.60 min, 202 nm.

(164) tert-Butyl 5-hydroxy-2-azabicyclo[2.2.2]octane-2-carboxylate (500 mg, 2.2 mmol) was dissolved in HCl solution in 1,4-dioxane (4 M, 10 mL) at 0° C. and then stirred at room temperature for 2 h. The solvent was removed in-vacuo and the residue was triturated with n-pentane (2×10 mL) to give 2-azabicyclo[2.2.2]octan-5-ol hydrochloride salt (Intermediate 27) (280 mg, 100%) as a solid. The data for Intermediate 27 are in Table 2.

(165) Route 4

Typical Procedure for the Preparation of Alcohols, as Exemplified by the Preparation of Intermediate 30, 9-azabicyclo[3.3.1]nonan-3-ol trifluoroacetic acid salt

(166) ##STR00147##

(167) Lithium aluminium hydride solution in THF (1 M, 37.6 mL, 37.6 mmol) was added dropwise at 0° C. to a solution of tert-butyl 3-oxo-9-azabicyclo[3.3.1]nonane-9-carboxylate (Intermediate 29) (6 g, 25.1 mmol) in THF (60 mL), and the reaction mixture was stirred at 0° C. for 4 h. The reaction was then quenched by the addition of ice-cold water (20 mL), and the mixture was extracted with ethyl acetate (2×50 mL). The organic layers were combined, dried (Na.sub.2SO.sub.4), and the solvent was removed in-vacuo to give tert-butyl 3-hydroxy-9-azabicyclo[3.3.1]nonane-9-carboxylate (6 g, 99%) as a solid. The product was used crude in the next step without further purification or characterisation.

(168) tert-Butyl 3-hydroxy-9-azabicyclo[3.3.1]nonane-9-carboxylate (6 g, 24.1 mmol) was dissolved in DCM (30 mL) and the resulting solution cooled to 0° C. TFA (15 mL) was added and the mixture was stirred at room temperature for 4 h. The solvent was removed in-vacuo and the residue was triturated with toluene (2×15 mL) to give 9-azabicyclo[3.3.1]nonan-3-ol trifluoroacetic acid salt (Intermediate 30) (8.5 g, 100%) as a gum.

(169) The data for Intermediate 30 are in Table 2.

(170) Route 5

Typical Procedure for the Preparation of Amines, as Exemplified by the Preparation of Intermediate 47, [(2R,4R)-4-fluoro-1-(piperidin-4-yl)pyrrolidin-2-yl]methanol trifluoroacetic acid salt

(171) ##STR00148##

(172) Methyl (2R,4R)-4-fluoropyrrolidine-2-carboxylate hydrochloride salt (Intermediate 45) (11.3 g, 61.7 mmol) was dissolved in methanol (280 mL) and tert-butyl 4-oxopiperidine-1-carboxylate (Intermediate 46) (12.2 g, 61.7 mmol), triethylamine (13 mL, 92.6 mmol) and 10% palladium on carbon catalyst (˜50% wet with H.sub.2O, 6 g) was added. The reaction mixture was stirred under hydrogen at one atmosphere pressure at 25° C. for 18 h, then filtered through Celite and the filtrate was concentrated in-vacuo. The resulting crude product was triturated with pentane to give tert-butyl 4-[(2R,4R)-4-fluoro-2-(methoxycarbonyl)pyrrolidin-1-yl]piperidine-1-carboxylate (18 g, 89%) as a solid.

(173) LCMS (System 1, Method D): m/z 331 (M+H).sup.+ (ESI +ve), at 4.23 min, 210 nm.

(174) tert-Butyl 4-[(2R,4R)-4-fluoro-2-(methoxycarbonyl)pyrrolidin-1-yl]piperidine-1-carboxylate (18 g, 54.5 mmol) was dissolved in THF (200 mL) and the resulting solution was cooled to 0° C. Lithium borohydride solution in THF (3 M, 54 mL, 164 mmol) was then added dropwise, and the mixture was stirred at 25° C. for 17 h. The solvents were removed in-vacuo and the residue was basified with saturated NaHCO.sub.3 solution and partitioned between H.sub.2O (600 mL) and DCM (400 mL). The aqueous layer was further extracted with EtOAc (2×400 mL), then all the organic layers were combined, dried (Na.sub.2SO.sub.4) and the solvent was removed in-vacuo. The residue was purified by trituration with pentane (3×10 mL) to give tert-butyl 4-[(2R,4R)-4-fluoro-2-(hydroxymethyl)pyrrolidin-1-yl]piperidine-1-carboxylate (14.5 g, 88%) as a gum.

(175) LCMS (System 1, Method D): m/z 303 (M+H).sup.+ (ESI +ve), at 3.57 min, 210 nm.

(176) tert-Butyl 4-[(2R,4R)-4-fluoro-2-(hydroxymethyl)pyrrolidin-1-yl]piperidine-1-carboxylate (14.5 g, 0.42 mmol) was dissolved in DCM (100 mL) and the resulting solution was cooled to 0° C. Trifluoroacetic acid (30 mL) was added dropwise and the reaction mixture was stirred at 25° C. for 8 h. The solvents were removed in-vacuo and the residue was purified by trituration with pentane (3×10 mL) to give [(2R,4R)-4-fluoro-1-(piperidin-4-yl)pyrrolidin-2-yl]methanol trifluoroacetic acid salt (Intermediate 47) (9.60 g, 100%) as a colourless gum.

(177) The data for Intermediate 47 are in Table 2.

(178) Route 6

Typical Procedure for the Preparation of Amines, as Exemplified by the Preparation of Intermediate 51, 4-[2-(1-methyl-1H-pyrazol-4-yl)pyrrolidin-1-yl]piperidine trifluoroacetic acid salt

(179) ##STR00149##

(180) 1-Methyl-4-(pyrrolidin-2-yl)-1H-pyrazole (Intermediate 50) (0.25 g, 1.66 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (Intermediate 46) (0.32 g, 1.66 mmoL), ZnCl.sub.2 solution in diethyl ether (1 M, 0.083 mL, 0.083 mmol) and triethylamine (0.72 mL, 4.97 mmol) were dissolved in MeOH (10 mL) and the resulting mixture was stirred at 70° C. for 4 h. The mixture was then cooled to 0° C. and NaBH.sub.3CN (0.21 g, 3.31 mmoL) was added portionwise. The reaction mixture was stirred at room temperature for 16 h and then the solvents were removed in-vacuo. The residue was partitioned between H.sub.2O (50 mL) and EtOAc (100 mL), and the aqueous layer was further extracted with EtOAc (2×100 mL). The combined organic layers were dried (Na.sub.2SO.sub.4) and the solvent was removed in-vacuo to give the crude product which was purified by column chromatography using alumina and MeOH/DCM as solvents to give tert-butyl 4-(2-(1-methyl-1H-pyrazol-4-yl)pyrrolidin-1-yl)piperidine-1-carboxylate (0.33 g, 59%) as a gum.

(181) LCMS (System 3, Method F): m/z 335 (M+H).sup.+ (ESI +ve), at 3.23 min, 215 nm.

(182) To a stirred solution of tert-butyl 4-(2-(1-methyl-1H-pyrazol-4-yl)pyrrolidin-1-yl)piperidine-1-carboxylate (0.30 g, 0.90 mmol) in DCM (3 mL) at 0° C. was added TFA (3 mL) dropwise and the resulting mixture was stirred at room temperature for 3 h. The solvent was evaporated in-vacuo and the residue co-evaporated from toluene (3×5 mL) to give 4-[2-(1-methyl-1H-pyrazol-4-yl)pyrrolidin-1-yl]piperidine trifluoroacetic acid salt (Intermediate 51) (0.20 g, 95%) as a gum.

(183) The data for Intermediate 51 are in Table 2.

(184) Route 7

Typical Procedure for the Preparation of Ketones, as Exemplified by the Preparation of Intermediate 60, 8-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-one

(185) ##STR00150##

(186) Trifluoroacetic acid (25 mL) was added dropwise at 0° C. to a solution of tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (Intermediate 17) (10 g, 44.4 mmol) in DCM (100 mL). The resulting mixture was stirred at room temperature for 2 h, then the solvent was evaporated under reduced pressure and the residue was triturated with toluene (3×15 mL) to give the crude 8-azabicyclo[3.2.1]octan-3-one trifluoroacetic acid salt (16 g, 100%), which was carried forward to the next reaction without further purification.

(187) LCMS (System 4, Method B): m/z 126 (M+H).sup.+ (ESI +ve), at 2.20 min, 214 nm.

(188) A solution of 8-azabicyclo[3.2.1]octan-3-one trifluoroacetic acid salt (16 g, 0.067 mol) in DCM (150 mL) was added dropwise to a solution of sodium bicarbonate (26 g, 0.32 mol) in water (100 mL) with vigorous stirring. A solution of cyanogen bromide (16.3 g, 0.153 mol) in DCM (25 mL) was then added at 0° C., the ice bath was removed and the resulting reaction mixture was stirred at room temperature for 16 h. Solid sodium carbonate was added until the pH was adjusted to 7, then the mixture was extracted with DCM (3×25 mL). The organic phases were dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by column chromatography (Normal phase, Silica gel 60-120 mesh, 0 to 3% MeOH in DCM) to afford 3-oxo-8-azabicyclo[3.2.1]octane-8-carbonitrile (6.5 g, 65%).

(189) LCMS (System 4, Method B): m/z 151 (M+H).sup.+ (ESI +ve), at 4.13 min, 202 nm.

(190) 3-Oxo-8-azabicyclo[3.2.1]octane-8-carbonitrile (1 g, 6.65 mmol) and 2,2,2-trifluoro-N-hydroxyacetimidamide (Intermediate 59) (1 g, 7.99 mmol) were dissolved in ethanol (50 mL), ZnCl.sub.2 solution in diethyl ether (1 M, 7.99 mL, 7.99 mmol) was added and the resulting mixture was stirred at room temperature for 16 h. Aqueous HCl (4 M, 6 mL) was then added and the mixture was heated at reflux at 90° C. overnight. Saturated sodium bicarbonate solution (50 mL) was added and the mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, concentrated under reduced pressure and the residue was purified by column chromatography (Normal phase, Silica gel 60-120 mesh, 0 to 7% EtOAC in hexanes) to give 8-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-one (Intermediate 60) (517 mg, 30%).

(191) The data for Intermediate 60 are in Table 2.

(192) Route 8

Typical Procedure for the Preparation of Amines, as Exemplified by the Preparation of Intermediate 62, (1R,5S,6r)-N-(-methylcyclobutyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide hydrochloride salt

(193) ##STR00151##

(194) Ethyl(1R,5S,6r)-3-azabicyclo[3.1.0]hexane-6-carboxylate (Intermediate 9) (2.0 g, 8.16 mmol) was dissolved in DCM (25 mL) and triethylamine (3.45 mL, 24.5 mmol) was added. The mixture was cooled to 0° C., stirred for 20 mins and di-tert-butyl dicarbonate (2.65 g, 12.2 mmol) was added. The resulting reaction mixture was then stirred at 25° C. for 18 h. The solvents were removed in-vacuo and the residue was partitioned between H.sub.2O (80 mL) and ethyl acetate (60 mL). The aqueous layer was further extracted with ethyl acetate (2×60 mL), the combined organic layers were dried (Na.sub.2SO.sub.4) and the solvent was removed in-vacuo. The residue was purified by column chromatography (Normal-Phase activated Al.sub.2O.sub.3, 0% to 40% ethyl acetate in hexanes) to give 3-(tert-butyl) 6-ethyl(1R,5S,6r)-3-azabicyclo[3.1.0]hexane-3,6-dicarboxylate (1.70 g, 82%) as a liquid.

(195) LCMS (System 3, Method F): m/z 241 (M-15+H).sup.+ (ESI +ve), at 4.06 min, 202 nm.

(196) 1-Methylcyclobutan-1-amine hydrochloride (Intermediate 61) (948 mg, 7.84 mmol) was suspended in toluene (10 mL) and triethylamine (1.70 mL, 11.8 mmol) was added. The mixture was cooled to −10° C., trimethylaluminum solution in toluene (2 M, 5.9 mL, 11.8 mmol) was added dropwise and stirring was continued for 20 min. 3-(tert-Butyl) 6-ethyl(1R,5S,6r)-3-azabicyclo[3.1.0]hexane-3,6-dicarboxylate (1.0 g, 3.92 mmol) was added at −10° C., then the reaction mixture was stirred at 70° C. for 40 h. The solvents were removed in-vacuo and the residue was partitioned between H.sub.2O (80 mL) and ethyl acetate (60 mL). The aqueous layer was further extracted with ethyl acetate (2×80 mL) and the combined organic layers were dried (Na.sub.2SO.sub.4) and the solvent was removed in-vacuo. The residue was purified by column chromatography (Normal-Phase activated Al.sub.2O.sub.3, 0% to 60% ethyl acetate in hexanes) to give tert-butyl (1R,5S,6r)-6-((1-methylcyclobutyl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (560 mg, 49%) as a solid.

(197) LCMS (System 3, Method F): m/z 293 (M−H)− (ESI −ve), at 3.80 min, 202 nm.

(198) tert-Butyl(1R,5S,6r)-6-((1-methylcyclobutyl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (550 mg, 1.87 mmol) was dissolved in 1,4-dioxane (6 mL) and the solution was cooled to 0° C. HCl solution in 1,4-dioxane (4 M, 10 mL) was added and the reaction mixture was stirred at 25° C. for 5 h. The solvents were removed in-vacuo and the residue was purified by trituration with pentane (3×3 mL) to give (1R,5S,6r)-N-(1-methylcyclobutyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide hydrochloride salt (Intermediate 62) (408 mg, 95%) as a solid.

(199) The data for Intermediate 62 are in Table 2.

(200) Route 9

Typical Procedure for the Preparation of Amines, as Exemplified by the Preparation of Intermediate 68, N-((1-methylcyclobutyl)methyl)piperidine-4-carboxamide trifluoroacetic acid salt

(201) ##STR00152##

(202) 1-(tert-Butyl) 4-ethyl piperidine-1,4-dicarboxylate (Intermediate 64) (700 mg, 0.0027 mole) and (1-methylcyclobutyl)methanamine (Intermediate 65) (434 mg, 0.0032 mole) were dissolved in toluene (3.0 mL) and triethylamine (1.13 mL, 0.008 mole) was added, followed by trimethylaluminum solution in toluene (2 M, 5.44 mL, 0.0108 mole) added dropwise at −20° C. The mixture was stirred for 30 min at −20° C. and then heated at 80° C. for 48 hrs. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between cold H.sub.2O (200 mL) and DCM (100 mL). The aqueous layer was further extracted with DCM (2×100 mL) and the combined organic layers were dried (Na.sub.2SO.sub.4) and the solvent was removed in-vacuo. The crude product was purified by column chromatography (Normal phase, 100-120 mesh silica gel, 0 to 39% ethyl acetate in hexanes) to give tert-butyl 4-(((1-methylcyclobutyl)methyl)carbamoyl)piperidine-1-carboxylate (320 mg, 38%) as a solid.

(203) LCMS (System 2, Method H): m/z 311 (M+H).sup.+ (ESI +ve), at 1.71 min, 202 nm.

(204) A solution of tert-butyl 4-(((1-methylcyclobutyl)methyl)carbamoyl)piperidine-1-carboxylate (320 mg, 0.00103 mol) in DCM (2 mL) was cooled to 0° C. and TFA (1 mL) was added dropwise, then the resulting reaction mixture was stirred at RT for 2 h. The solvent was removed in-vacuo and the residue was purified by trituration with toluene (3×5 mL) to give the crude N-((1-methylcyclobutyl)methyl)piperidine-4-carboxamide trifluoroacetic acid salt (Intermediate 66) (410 mg, 100%), which was used without further purification.

(205) The data for Intermediate 66 are in Table 2.

(206) General Synthetic Procedures:

(207) Route A

Typical Procedure for the Preparation of Amines as Exemplified by the Preparation of Example 1-1,2-(3-methyl-1,2,4-oxadiazol-5-yl)-6-[4-(1H-pyrazol-1-yl)piperidin-1-yl]-2-azaspiro[3.3]heptane

(208) ##STR00153##

(209) 4-(1H-Pyrazol-1-yl)piperidine (Intermediate 4) (47 mg, 0.31 mmol), 2-(3-methyl-1,2,4-oxadiazol-5-yl)-2-azaspiro[3.3]heptan-6-one (Intermediate 3) (60 mg, 0.31 mmol), triethylamine (0.1 mL, 0.93 mmol) and ZnCl.sub.2 (4 mg, 0.03 mmol) were dissolved in MeOH (10 mL) and the resulting mixture was stirred at 65° C. for 8 h. The mixture was then cooled to 0° C. and NaBH.sub.3CN (58 mg, 0.93 mmol) was added portion wise and the resulting reaction mixture was stirred at 25° C. for 16 h. The solvents were removed in-vacuo, the residue was partitioned between H.sub.2O (50 mL) and EtOAc (40 mL), and the aqueous layer was further extracted with EtOAc (2×40 mL). The combined organic layers were dried (Na.sub.2SO.sub.4), the solvent was removed in-vacuo, and the residue was purified using Purification Method A to give 2-(3-methyl-1,2,4-oxadiazol-5-yl)-6-[4-(1H-pyrazol-1-yl)piperidin-1-yl]-2-azaspiro[3.3]heptane (Example 1-1) (17 mg, 17%) as a solid.

(210) The data for Example 1-1 are in Table 3.

(211) Route B

Typical Procedure for the Preparation of Amines as Exemplified by the Preparation of Example 6-5, N-(1-methylcyclobutyl)-1-[8-(3-methyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]oct-3-yl]piperidine-4-carboxamide

(212) ##STR00154##

(213) Triethylamine (0.12 ml, 0.86 mmol) was added dropwise to a solution of 1-methylcyclobutan-1-amine (Intermediate 25) (27 mg, 0.3 mmol) in toluene (10 mL) and the mixture was stirred at room temperature for 15 min. Ethyl 1-[8-(3-methyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]oct-3-yl]piperidine-4-carboxylate (Intermediate 24) (100 mg, 0.29 mmol) was added and the reaction mixture was stirred at room temperature for 15 min and then cooled to 0° C. Trimethylaluminium solution in toluene (2 M, 0.43 mL, 0.86 mmol) was added at 0° C., and then the reaction mixture was stirred at 80° C. for 16 h. The mixture was partitioned between H.sub.2O (10 mL) and ethyl acetate (20 mL), and the aqueous layer was further extracted with ethyl acetate (2×20 mL). The combined organic layers were dried (Na.sub.2SO.sub.4) and the solvent was removed in-vacuo to give the crude product, which was purified by Purification Method L to give N-(1-methylcyclobutyl)-1-[8-(3-methyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]oct-3-yl]piperidine-4-carboxamide, Example 6-5 Isomer 1 (40 mg, 24%) as a gum and N-(1-methylcyclobutyl)-1-[8-(3-methyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]oct-3-yl]piperidine-4-carboxamide, Example 6-5 Isomer 2 (5 mg, 3%) as a solid.

(214) The data for Example 6-5 Isomer 2 are in Table 3.

(215) Route C

Typical Procedure for the Preparation of Amines as Exemplified by the Preparation of Example 10-12, (2S)-N-methyl-2-{1-[1-(3-methyl-1,2,4-oxadiazol-5-yl)azepan-4-yl]piperidin-4-yl}pyrrolidine-1-carboxamide

(216) ##STR00155##

(217) To a stirred solution of tert-butyl (2S)-2-{1-[1-(3-methyl-1,2,4-oxadiazol-5-yl)azepan-4-yl]piperidin-4-yl}pyrrolidine-1-carboxylate (Intermediate 54) (260 mg, 0.60 mmol) in DCM (3 mL) was added TFA (3 mL) dropwise at 0° C. The reaction mixture was stirred at room temperature for 3 h, then the solvent was evaporated in-vacuo and the residue co-evaporated from toluene (3×5 mL) to give 1-(3-methyl-1,2,4-oxadiazol-5-yl)-4-{4-[(2S)-pyrrolidin-2-yl]piperidin-1-yl}azepane trifluoroacetic acid salt (190 mg, 95%) as a gum.

(218) LCMS (System 3, Method F): m/z 334 (M+H).sup.+ (ESI +ve), at 1.95 min, 225 nm.

(219) To a stirred solution of 1-(3-methyl-1,2,4-oxadiazol-5-yl)-4-{4-[(2S)-pyrrolidin-2-yl]piperidin-1-yl}azepane trifluoroacetic acid salt (300 mg, 1.29 mmol) in DMF (3 mL) was added K.sub.2CO.sub.3 (533 mg, 3.86 mmol) and the resulting mixture was stirred at room temperature for 1 h. Methylcarbamyl chloride (Intermediate 55) (240 mg, 2.58 mmol) was added and the reaction mixture was stirred at 80° C. for 16 h. The reaction mixture was then diluted with ice-cold water (10 mL) and extracted with EtOAc (20 mL). The aqueous layer was further extracted with EtOAc (2×10 mL), then all the organic layers were combined, dried (Na.sub.2SO.sub.4) and evaporated under reduced pressure to give the crude product, which was purified by Purification Method AQ followed by Purification Method AR to give (2S)—N-methyl-2-{1-[1-(3-methyl-1,2,4-oxadiazol-5-yl)azepan-4-yl]piperidin-4-yl}pyrrolidine-1-carboxamide, Example 10-12 Isomer 1 (11 mg, 2%) as a gum and (2S)—N-methyl-2-{1-[1-(3-methyl-1,2,4-oxadiazol-5-yl)azepan-4-yl]piperidin-4-yl}pyrrolidine-1-carboxamide, Example 10-12 Isomer 2 (10 mg, 2%) as a gum.

(220) The data for Example 10-12 Isomer 1 and Example 10-12 Isomer 2 are in Table 3.

(221) TABLE-US-00004 TABLE 2 Table 2 - Starting Materials and Intermediates Intermediate Synthetic Intermediates Number Name Route Used Data 1 tert-Butyl 6-oxo-2- — — Commercially available, azaspiro[3.3]heptane-2- CAS: 1181816-12-5 carboxylate 2 N-Hydroxyacetamide — — Commercially available, CAS: 546-88-3 3 2-(3-Methyl-1,2,4-oxadiazol- 1 1 and 2 LCMS (System 2, Method E): 5-yl)-2-azaspiro[3.3]heptan-6- m/z 194 (M + H).sup.+ (ES.sup.+), at 1.36 one min, 226 nm 4 4-(1H-Pyrazol-1-yl)piperidine — — Commercially available, CAS: 762240-09-5 5 tert-Butyl 2-oxo-6- — — Commercially available, azaspiro[3.4]octane-6- CAS: 203661-71-6 carboxylate 6 6-Azaspiro[3.4]octan-2-ol 2 5 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ hydrochloride salt 9.42 (br. s, 1H), 9.31 (br. s, 1H), 4.13-4.00 (m, 1H), 3.14-2.97 (m, 4H), 2.36-2.25 (m, 1H), 2.23-2.12 (m, 1H), 1.93-1.77 (m, 4H). One exchangeable proton not observed. 7 6-(3-Methyl-1,2,4-oxadiazol- 1 6 and 2 LCMS (System 3, Method F): 5-yl)-6-azaspiro[3.4]octan-2- (from m/z 208 (M + H).sup.+ (ES.sup.+), at 2.25 one Step 3) min, 202 nm 8 4-Phenylpiperidine-4- — — Commercially available, carbonitrile CAS: 40481-13-8 9 Ethyl (1R,5S,6r)-3- — — Commercially available, azabicyclo[3.1.0]hexane-6- CAS: 174456-77-0 carboxylate 10 tert-Butyl 6-oxo-2- — — Commercially available, azaspiro[3.4]octane-2- CAS: 1363382-39-1 carboxylate 11 2-Azaspiro[3.4]octan-6-ol 2 10 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ hydrochloride salt 9.07 (br. s, 1H), 8.12 (br. s, 1H), 4.12-4.03 (m, 1H), 3.93-3.65 (m, 4H), 3.00-2.87 (m, 1H), 2.10-1.94 (m, 1H), 1.84-1.66 (m, 3H), 1.64-1.40 (m, 2H). 12 2-(3-Methyl-1,2,4-oxadiazol- 1 11 and 2 LCMS (System 2, Method E): 5-yl)-2-azaspiro[3.4]octan-6- (from m/z 208 (M + H).sup.+ (ES.sup.+), at 1.39 one Step 3) min, 230 nm 13 Piperidin-4-ol — — Commercially available, CAS: 5382-16-1 14 1-(3-Methyl-1,2,4-oxadiazol- 1 13 and 2 LCMS (System 2, Method E): 5-yl)piperidin-4-one (from m/z 182 (M + H).sup.+ (ES.sup.+), at 1.31 Step 3) min, 228 nm 15 tert-Butyl 6-oxo-3- — — Commercially available, azabicyclo[3.1.1]heptane-3- CAS: 1251013-26-9 carboxylate 16 3-(3-Methyl-1,2,4-oxadiazol- 1 15 and 2 LCMS (System 4, Method B): 5-yl)-3- m/z 194 (M + H).sup.+ (ES.sup.+), at 3.91 azabicyclo[3.1.1]heptan-6- min, 202 nm one 17 tert-Butyl 3-oxo-8- — — Commercially available, azabicyclo[3.2.1]octane-8- CAS: 185099-67-6 carboxylate 18 8-(3-Methyl-1,2,4-oxadiazol- 1 17 and 2 LCMS (System 3, Method F): 5-yl)-8- m/z 208 (M + H).sup.+ (ES.sup.+), at 2.33 azabicyclo[3.2.1]octan-3-one min, 202 nm 19 2,8-Diazaspiro[4.5]decan-3- — — Commercially available, one CAS: 561314-57-6 20 N-Hydroxypropanamide — — Commercially available, CAS: 2580-63-4 21 8-(3-Ethyl-1,2,4-oxadiazol-5- 1 17 and 20 LCMS (System 3, Method F): yl)-8-azabicyclo[3.2.1]octan- m/z 222 (M + H).sup.+ (ES.sup.+), at 2.67 3-one min, 202 nm 22 1-Oxa-3,8- — — Commercially available, diazaspiro[4.5]decan-2-one CAS: 5052-95-9 23 Ethyl piperidine-4-carboxylate — — Commercially available, CAS: 1126-09-6 24 Ethyl 1-[8-(3-methyl-1,2,4- A 23 and 18 LCMS (System 3, Method F): oxadiazol-5-yl)-8- m/z 349 (M + H).sup.+ (ES.sup.+), at 3.21 azabicyclo[3.2.1]oct-3- min, 202 nm yl]piperidine-4-carboxylate 25 1-Methylcyclobutan-1-amine — — Commercially available, CAS: 40571-47-9 26 tert-Butyl 5-oxo-2- — — Commercially available, azabicyclo[2.2.2]octane-2- CAS: 617714-22-4 carboxylate 27 2-Azabicyclo[2.2.2]octan-5-ol 3 26 LCMS (System 4, Method C): hydrochloride salt m/z 128 (M + H).sup.+ (ES.sup.+), at 2.56 and 3.66 min, no UV absorption at 202 nm 28 2-(3-Methyl-1,2,4-oxadiazol- 1 27 and 2 LCMS (System 3, Method F): 5-yl)-2- (from m/z 208 (M + H).sup.+ (ES.sup.+), at 2.27 azabicyclo[2.2.2]octan-5-one Step 3) min, 202 nm 29 tert-Butyl 3-oxo-9- — — Commercially available, azabicyclo[3.3.1]nonane-9- CAS: 512822-27-4 carboxylate 30 9-Azabicyclo[3.3.1]nonan-3- 4 29 LCMS (System 4, Method B): ol trifluoroacetic acid salt m/z 142 (M + H).sup.+ (ES.sup.+), at 1.82 min, 202 nm 31 9-(3-Methyl-1,2,4-oxadiazol- 1 30 and 2 LCMS (System 3, Method F): 5-yl)-9- (from m/z 222 (M + H).sup.+ (ES.sup.+), at 2.46 azabicyclo[3.3.1]nonan-3-one Step 3) min, 202 nm 32 Ethyl 1-[9-(3-methyl-1,2,4- A 23 and 31 LCMS (System 3, Method F): oxadiazol-5-yl)-9- m/z 363 (M + H).sup.+ (ES.sup.+), at 3.08 azabicyclo[3.3.1]non-3- min, 202 nm yl]piperidine-4-carboxylate 33 tert-Butyl 7-oxo-3-oxa-9- — — Commercially available, azabicyclo[3.3.1]nonane-9- CAS: 280761-97-9 carboxylate 34 3-Oxa-9- 3 33 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ azabicyclo[3.3.1]nonan-7-ol 9.40 (br. s, 1H), 9.08 (br. s, 1H), hydrochloride salt 4.98-4.86 (m, 1H), 4.02-3.79 (m, 5H), 3.61-3.52 (m, 2H), 2.37-2.25 (m, 2H), 1.85-1.75 (m, 2H). 35 9-(3-Methyl-1,2,4-oxadiazol- 1 34 and 2 LCMS (System 3, Method F): 5-yl)-3-oxa-9- (from m/z 224 (M + H).sup.+ (ES.sup.+), at 1.84 azabicyclo[3.3.1]nonan-7-one Step 3) min, 202 nm 36 Methyl (1R,5S,6r)-3- — — Commercially available, azabicyclo[3.1.0]hexane-6- CAS: 1024038-72-9 carboxylate 37 Methyl (1R,5S,6r)-3-[9-(3- A 36 and 35 LCMS (System 3, Method F): methyl-1,2,4-oxadiazol-5-yl)- m/z 349 (M + H).sup.+ (ES.sup.+), at 2.90 3-oxa-9-azabicyclo[3.3.1] min, 202 nm nonan-7-yl]-3-azabicyclo [3.1.0]hexane-6-carboxylate 38 N-Ethylethanamine — — Commercially available, CAS: 109-89-7 39 tert-Butyl 4-oxoazepane-1- — — Commercially available, carboxylate CAS: 188975-88-4 40 Azepan-4-ol hydrochloride 2 39 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ salt 9.18-8.88 (m, 2H), 3.90-3.57 (m, 2H), 3.21-3.07 (m, 1H), 3.07-2.87 (m, 3H), 1.98-1.87 (m, 1H), 1.87-1.68 (m, 3H), 1.68-1.53 (m, 2H). 41 1-(3-Methyl-1,2,4-oxadiazol- 1 40 and 2 LCMS (System 4, Method B): 5-yl)azepan-4-one (from m/z 196 (M + H).sup.+ (ES.sup.+), at 3.34 Step 3) min, 202 nm 42 4-Ethyl-1-oxa-3,8- — — See WO2016147011 diazaspiro[4.5]decan-2-one 43 4,4-Dimethyl-1-oxa-3,8- — — See WO2016147011 diazaspiro[4.5]decan-2-one 44 Spiro[indole-3,4′-piperidin]- — — Commercially available, 2(1H)-one CAS: 252882-61-4 45 Methyl (2R,4R)-4- — — Commercially available, fluoropyrrolidine-2- CAS: 1445948-46-8 carboxylate hydrochloride salt 46 tert-Butyl 4-oxopiperidine-1- — — Commercially available, carboxylate CAS: 79099-07-3 47 [(2R,4R)-4-Fluoro-1- 5 45 and 46 LCMS (System 4, Method B): (piperidin-4-yl)pyrrolidin-2- m/z 203 (M + H).sup.+ (ES.sup.+), at 2.10 yl]methanol trifluoroacetic min, 202 nm acid salt 48 [(2R)-4,4-Difluoro-1- — — See WO2017021728 (piperidin-4-yl)pyrrolidin-2- yl]methanol 49 (5S)-5-Ethyl-1-(piperidin-4- — — See WO2017021728 yl)pyrrolidin-2-one 50 1-Methyl-4-(pyrrolidin-2-yl)- — — Commercially available, 1H-pyrazole CAS: 1170640-87-5 51 4-[2-(1-Methyl-1H-pyrazol-4- 6 50 and 46 LCMS (System 2, Method A): yl)pyrrolidin-1-yl]piperidine m/z 235 (M + H).sup.+ (ES.sup.+), at 0.27 min, 202 nm 52 N-Ethyl-N-(piperidin-4- — — Commercially available, yl)acetamide CAS: 139062-99-0 Also see WO2017021730 53 tert-Butyl (2S)-2-(piperidin-4- — — Commercially available, yl)pyrrolidine-1-carboxylate CAS: 1449131-15-0 54 tert-Butyl (2S)-2-{1-[1-(3- A 54 and 41 LCMS (System 3, Method F): methyl-1,2,4-oxadiazol-5- m/z 434 (M + H).sup.+ (ES.sup.+), at 3.69 yl)azepan-4-yl]piperidin-4- min, 202 nm yl}pyrrolidine-1-carboxylate 55 Methylcarbamyl chloride — — Commercially available, CAS: 6452-47-7 56 tert-Butyl 3-oxo-6- — — Commercially available, azabicyclo[3.2.1]octane-6- CAS: 359779-74-1 carboxylate 57 6-Azabicyclo[3.2.1]octan-3-ol 4 56 LCMS (System 4, Method B): trifluoroacetic acid salt m/z 128 (M + H).sup.+ (ES.sup.+), at 1.46 min, 202 nm 58 6-(3-Methyl-1,2,4-oxadiazol- 1 56 and 2 LCMS (System 4, Method B): 5-yl)-6- (from m/z 208 (M + H).sup.+ (ES.sup.+), at 3.88 azabicyclo[3.2.1]octan-3-one Step 3) min, 202 nm 59 2,2,2-Trifluoro-N- — — Commercially available, hydroxyacetimidamide CAS: 4314-35-6 60 8-(3-(Trifluoromethyl)-1,2,4- 7 17 and 59 1H NMR (400 MHz, DMSO-d.sub.6) δ oxadiazol-5-yl)-8- 4.72-4.62 (m, 2H), 2.89-2.77 azabicyclo[3.2.1]octan-3-one (m, 2H), 2.39-2.28 (m, 2H), 2.23-2.09 (m, 2H), 1.79-1.67 (m, 2H). 61 1-Methylcyclobutan-1-amine — — Commercially available, hydrochloride CAS: 174886-05-6 62 (1R,5S,6r)-N-(1- 8 9 and 61 LCMS (System 3, Method F): methylcyclobutyl)-3- m/z 193 (M − H).sup.− (ES.sup.−), at 1.92 azabicyclo[3.1.0]hexane-6- min, 202 nm carboxamide hydrochloride salt 63 1-(Trifluoromethyl)cyclobutan- — — Commercially available, 1-amine hydrochloride CAS: 1260768-75-9 64 1-Ethylcyclobutan-1-amine — — Commercially available, hydrochloride CAS: 279215-56-4 65 1-Methylcyclopentan-1-amine — — Commercially available, hydrochloride CAS: 102014-58-4 66 1-(tert-Butyl) 4-ethyl — — Commercially available, piperidine-1,4-dicarboxylate CAS: 142851-03-4 67 (1-Methylcyclobutyl)methanamine — — Commercially available, CAS: 933722-69-1 68 N-((1-Methylcyclobutyl)methyl)piperidine- 9 66 and 67 LCMS (System 3, Method F): 4-carboxamide trifluoroacetic acid salt m/z 211 (M + H).sup.+ (ES.sup.+), at 2.39 min, 202 nm 69 Ethyl 1-(8-(3-(trifluoromethyl)- A 23 and 60 LCMS (System 3, Method F): 1,2,4-oxadiazol-5-yl)-8- m/z 403 (M + H).sup.+ (ES.sup.+), at 4.06 azabicyclo[3.2.1]octan-3- min, 239 nm yl)piperidine-4-carboxylate

(222) TABLE-US-00005 TABLE 3 Table 3 - NMR and LCMS properties and the methods used to prepare and purify compounds represented by Examples 1 - 12-14 Synthetic LCMS Method and System Intermediates Purification and Ex. No. Name Used Method .sup.1H NMR Method LCMS data 1-1 2-(3-Methyl-1,2,4- A A .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.67 (d, J = 2 Hz, 1H), 7.48 System 3 m/z 329 oxadiazol-5-yl)-6-[4-(1H- 3 and 4 (d, J = 2 Hz, 1H), 6.29 (t, J = 2 Hz, 1H), 4.25 (s, 2H), 4.23- Method F (M + H).sup.+ pyrazol-1-yl)piperidin-1-yl]- 4.15 (m, 1H), 4.14 (s, 2H), 3.03-2.93 (m, 2H), 2.81-2.68 (m, (ES.sup.+), at 2-azaspiro[3.3]heptane 1H), 2.51-2.41 (m, 2H), 2.16 (s, 3H), 2.21-1.94 (m, 8H). 2.76 min, 202 nm 2-1 Isomer 2: 6-(3-Methyl- A B .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.68 (d, J = 2 Hz, 1H), 7.49 System 3 m/z 343 1,2,4-oxadiazol-5-yl)-2-[4- 4 and 7 (d, J = 2 Hz, 1H), 6.29 (t, J = 2 Hz, 1H), 4.27-4.15 (m, 1H), Method F (M + H).sup.+ (1H-pyrazol-1-yl)piperidin- 3.59 (t, J = 6.8 Hz, 2H), 3.47 (s, 2H), 3.06-2.99 (m, 2H), 2.94- (ES.sup.+), at 1-yl]-6-azaspiro[3.4]octane 2.83 (m, 1H), 2.24-2.18 (m, 2H), 2.17 (s, 3H), 2.14-2.07 2.82 min, (m, 4H), 2.06-1.96 (m, 6H). 202 nm 2-2 Isomer 2: 1-[6-(3-Methyl- A C .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.58-7.50 (m, 2H), System 3 m/z 378 1,2,4-oxadiazol-5-yl)-6- 7 and 8 7.48-7.39 (m, 2H), 7.40-7.31 (m, 1H), 3.60 (t, J = 6.8 Hz, 2H), Method F (M + H).sup.+ azaspiro[3.4]oct-2-yl]-4- 3.47 (s, 2H), 3.06 (d, J = 12.2 Hz, 2H), 3.03-2.90 (m, 1H), (ES.sup.+), at phenylpiperidine-4- 2.36-2.19 (m, 4H), 2.17 (s, 3H), 2.19-2.06 (m, 6H), 2.06- 3.84 min, carbonitrile 1.97 (m, 2H). 202 nm 2-3 Isomer 2: Ethyl (1R,5S,6r)- A D .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 4.10 (q, J = 7.1 Hz, 2H), System 3 m/z 347 3-[6-(3-methyl-1,2,4- 7 and 9 3.59-3.50 (m, 2H), 3.44 (s, 2H), 3.09-3.00 (m, 3H), 2.44- Method F (M + H).sup.+ oxadiazol-5-yl)-6- 2.36 (m, 2H), 2.16 (s, 3H), 2.13-2.02 (m, 3H), 2.02-1.92 (m, (ES.sup.+), at azaspiro[3.4]oct-2-yl]-3- 6H), 1.24 (t, J = 7.1 Hz, 3H). 3.52 min, azabicyclo[3.1.0]hexane-6- 202 nm carboxylate 3-1 Isomer 2: 2-(3-Methyl- A E .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.68 (d, J = 2 Hz, 1H), 7.48 System 3 m/z 343 1,2,4-oxadiazol-5-yl)-6-[4- 4 and 12 (d, J = 2 Hz, 1H), 6.29 (t, J = 2 Hz, 1H), 4.26-4.12 (m, 2H), Method F (M + H).sup.+ (1H-pyrazol-1-yl)piperidin- 4.12-3.99 (m, 3H), 3.15 (d, J = 11.5 Hz, 2H), 2.77-2.68 (m, (ES.sup.+), at 1-yl]-2-azaspiro[3.4]octane 1H), 2.33-2.18 (m, 2H), 2.16 (s, 3H), 2.15-1.91 (m, 8H), 2.72 min, 1.87-1.76 (m, 1H), 1.66-1.53 (m, 1H). 202 nm 4-1 1′-(3-Methyl-1,2,4- A F .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.68 (d, J = 2 Hz, 1H), 7.48 System 3 m/z 317 oxadiazol-5-yl)-4-(1H- 4 and 14 (d, J = 2 Hz, 1H), 6.29 (t, J = 2 Hz, 1H), 4.21-4.10 (m, 3H), Method F (M + H).sup.+ pyrazol-1-yl)-1,4′- 3.22-3.08 (m, 4H), 2.72-2.67 (m, 1H), 2.53-2.42 (m, 2H), (ES.sup.+), at bipiperidine 2.17 (s, 3H), 2.16-2.09 (m, 2H), 2.08-1.95 (m, 4H), 1.68- 2.60 min, 1.55 (m, 2H). 202 nm 5-1 Isomer 1: 3-(3-Methyl- A G .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.70 (d, J = 2 Hz, 1H), 7.49 System 3 m/z 329 1,2,4-oxadiazol-5-yl)-6-[4- 4 and 16 (d, J = 2 Hz, 1H), 6.29 (t, J = 2 Hz, 1H), 4.28-4.16 (m, 1H), Method F (M + H).sup.+ (1H-pyrazol-1-yl)piperidin- 3.89 (d, J = 10.9 Hz, 2H), 3.72 (d, J = 10.9 Hz, 2H), 3.38- (ES.sup.+), at 1-yl]-3- 3.21 (m, 2H), 2.72-2.63 (m, 1H), 2.57 (d, J = 6.4 Hz, 2H), 2.88 min, azabicyclo[3.1.1]heptane 2.41 (d, J = 5.2 Hz, 1H), 2.20 (s, 3H), 2.16-2.07 (m, 4H), 2.04 202 nm (d, J = 10.9 Hz, 1H), 1.56-1.49 (m, 1H), 1.31-1.26 (m, 1H). 6-1 Isomer 1: 8-(3-Methyl- A H .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.65 (d, J = 2 Hz, 1H), 7.47 System 3 m/z 343 1,2,4-oxadiazol-5-yl)-3-[4- 4 and 18 (d, J = 2 Hz, 1H), 6.27 (t, J = 2 Hz, 1H), 4.46-4.40 (m, 2H), Method F (M + H).sup.+ (1H-pyrazol-1-yl)piperidin- 4.20-4.10 (m, 1H), 3.08 (d, J = 11.8 Hz, 2H), 3.00-2.89 (m, (ES.sup.+), at 1-yl]-8- 1H), 2.34-2.23 (m, 2H), 2.20 (s, 3H), 2.15-2.04 (m, 4H), 2.75 min, azabicyclo[3.2.1]octane 2.02-1.93 (m, 4H), 1.93-1.86 (m, 2H), 1.76-1.66 (m, 2H). 202 nm 6-2 Isomer 1: 8-[8-(3-Methyl- A I .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 4.47-4.35 (m, 2H), 3.17 System 3 m/z 346 1,2,4-oxadiazol-5-yl)-8- 18 and 19 (s, 2H), 2.91-2.78 (m, 1H), 2.66-2.34 (m, 4H), 2.24-2.15 Method F (M + H).sup.+ azabicyclo[3.2.1]oct-3-yl]- (m, 6H), 2.14-2.04 (m, 2H), 2.01-1.91 (m, 2H), 1.91-1.80 (ES.sup.+), at 2,8-diazaspiro[4.5]decan-3- (m, 2H), 1.76-1.53 (m, 5H). One exchangeable proton not 2.14 min, one observed. 202 nm 6-2 Isomer 2: 8-[8-(3-Methyl- A I .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 4.40-4.27 (m, 2H), 3.19 System 3 m/z 346 1,2,4-oxadiazol-5-yl)-8- 18 and 19 (s, 2H), 2.74-2.41 (m, 4H), 2.40-2.29 (m, 1H), 2.28-2.13 Method F (M + H).sup.+ azabicyclo[3.2.1]oct-3-yl]- (m, 7H), 2.11-1.98 (m, 4H), 1.92-1.80 (m, 2H), 1.78-1.62 (ES.sup.+), at 2,8-diazaspiro[4.5]decan-3- (m, 4H). One exchangeable proton not observed. 2.25 min, one 202 nm 6-3 Isomer 2: 8-[8-(3-Ethyl- A J .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 4.38-4.31 (m, 2H), 3.18 System 3 m/z 360 1,2,4-oxadiazol-5-yl)-8- 19 and 21 (s, 2H), 2.56 (q, J = 7.6 Hz, 2H), 2.57-2.39 (m, 4H), 2.32- Method F (M + H).sup.+ azabicyclo[3.2.1]oct-3-yl]- 2.22 (m, 1H), 2.24-2.13 (m, 5H), 2.13-1.98 (m, 2H), 1.88 (ES.sup.+), at 2,8-diazaspiro[4.5]decan-3- (dd, J = 14.5, 5.6 Hz, 2H), 1.74-1.59 (m, 5H), 1.25 (t, J = 7.6 2.56 min, one Hz, 3H). One exchangeable proton not observed. 202 nm 6-4 Isomer 1: 8-[8-(3-Methyl- A K .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 4.48-4.37 (m, 2H), 3.33 System 3 m/z 348 1,2,4-oxadiazol-5-yl)-8- 18 and 22 (s, 2H), 2.98-2.84 (m, 1H), 2.74-2.62 (m, 2H), 2.56 (t, J = Method F (M + H).sup.+ azabicyclo[3.2.1]octan-3- 10.9 Hz, 2H), 2.19 (s, 3H), 2.15-2.03 (m, 2H), 2.00-1.83 (ES.sup.+), at yl]-1-oxa-3,8- (m, 6H), 1.82-1.62 (m, 4H). One exchangeable proton not 2.28 min, diazaspiro[4.5]decan-2-one observed. 202 nm 6-4 Isomer 2: 8-[8-(3-Methyl- A K .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 4.41-4.26 (m, 2H), 3.35 System 3 m/z 348 1,2,4-oxadiazol-5-yl)-8- 18 and 22 (s, 2H), 2.79-2.44 (m, 4H), 2.39-2.29 (m, 1H), 2.18 (s, 3H), Method F (M + H).sup.+ azabicyclo[3.2.1]octan-3- 2.17-2.08 (m, 4H), 2.08-2.01 (m, 2H), 2.00-1.89 (m, 4H), (ES.sup.+), at yl]-1-oxa-3,8- 1.89-1.79 (m, 2H). One exchangeable proton not observed. 2.40 min, diazaspiro[4.5]decan-2-one 202 nm 6-5 Isomer 2: N-(1- B L .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 4.37-4.29 (m, 2H), 3.21 System 3 m/z 388 Methylcyclobutyl)-1-[8-(3- 24 and 25 (d, J = 11.2 Hz, 2H), 2.30-2.20 (m, 2H), 2.20-1.93 (m, Method F (M + H).sup.+ methyl-1,2,4-oxadiazol-5- 10H), 2.18 (s, 3H), 1.93-1.78 (m, 6H), 1.78-1.63 (m, 4H), (ES.sup.+), at yl)-8-azabicyclo[3.2.1]oct- 1.41 (s, 3H). One exchangeable proton not observed. 3.06 min, 3-yl]piperidine-4- 202 nm carboxamide 7-1 Isomer 1: 2-(3-Methyl- A M .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.68 (d, J = 2 Hz, 1H), 7.49 System 3 m/z 343 1,2,4-oxadiazol-5-yl)-5-[4- 4 and 28 (d, J = 2 Hz, 1H), 6.29 (t, J = 2 Hz, 1H), 4.28-4.14 (m, 1H), Method F (M + H).sup.+ (1H-pyrazol-1-yl)piperidin-1-yl]-2- 4.06-3.99 (m, 1H), 3.65-3.58 (m, 1H), 3.52-3.44 (m, 1H), (ES.sup.+), at azabicyclo[2.2.2]octane 3.38-3.15 (m, 2H), 2.46-2.38 (m, 1H), 2.34-2.29 (m, 1H), 2.87 min, 2.29-2.19 (m, 1H), 2.17 (s, 3H), 2.15-1.99 (m, 7H), 1.95- 202 nm 1.78 (m, 2H), 1.66-1.53 (m, 2H). 7-1 Isomer 2: 2-(3-Methyl- A M .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.67 (d, J = 2 Hz, 1H), 7.47 System 3 m/z 343 1,2,4-oxadiazol-5-yl)-5-[4- 4 and 28 (d, J = 2 Hz, 1H), 6.28 (t, J = 2 Hz, 1H), 4.27-4.14 (m, 1H), Method F (M + H).sup.+ (1H-pyrazol-1-yl)piperidin-1-yl]-2- 4.08-4.01 (m, 1H), 3.81-3.71 (m, 1H), 3.44-3.36 (m, 1H), (ES.sup.+), at azabicyclo[2.2.2]octane 3.31-3.18 (m, 2H), 2.46-2.30 (m, 2H), 2.17 (s, 3H), 2.14- 2.99 min, 1.98 (m, 7H), 1.97-1.74 (m, 3H), 1.71 (d, J = 8.2 Hz, 2H). 202 nm 8-1 Isomer 2: 9-(3-Methyl- A N then O .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.66 (d, J = 2 Hz, 1H), 7.48 (d, System 3 m/z 357 1,2,4-oxadiazol-5-yl)-3-[4- 4 and 31 J = 2 Hz, 1H), 6.28 (t, J = 2 Hz, 1H), 4.42-4.33 (m, 2H), 4.24- Method F (M + H).sup.+ (1H-pyrazol-1-yl)piperidin-1-yl]-9- 4.13 (m, 1H), 3.44-3.34 (m, 1H), 3.20 (d, J = 11.8 Hz, 2H), 2.40- (ES.sup.+), at azabicyclo[3.3.1]nonane 2.28 (m, 2H), 2.18 (s, 3H), 2.16-2.07 (m, 4H), 2.06-1.89 (m, 3.01 min, 4H), 1.89-1.77 (m, 3H), 1.76-1.67 (m, 1H), 1.40-1.19 (m, 215 nm 1H), 1.15 (d, J = 6.2 Hz, 0.3H), 0.95-0.82 (m, 0.7H). 8-2 Isomer 1: 8-[9-(3-Methyl- A P .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 4.45 (d, J = 10.7 Hz, 2H), System 3 m/z 360 1,2,4-oxadiazol-5-yl)-9- 19 and 31 3.19 (s, 2H), 2.65-2.55 (m, 4H), 2.44-2.29 (m, 3H), 2.21 (s, Method F (M + H).sup.+ azabicyclo[3.3.1]non-3-yl]- 2H), 2.19-1.99 (m, 2H), 2.16 (s, 3H), 1.79-1.66 (m, 6H), (ES.sup.+), at 2,8-diazaspiro[4.5]decan-3-one 1.62-1.49 (m, 4H). One exchangeable proton not observed. 2.45 min, 202 nm 8-3 Isomer 1: 8-[9-(3-Methyl- A Q .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 4.46 (d, J = 10.3 Hz, 2H), System 3 m/z 362 1,2,4-oxadiazol-5-yl)-9- 22 and 31 3.35 (s, 2H), 2.77-2.63 (m, 4H), 2.48-2.31 (m, 3H), 2.19- Method F (M + H).sup.+ azabicyclo[3.3.1]non-3-yl]-1-oxa- 2.02 (m, 1H), 2.16 (s, 3H), 2.00-1.90 (m, 2H), 1.87-1.67 (m, (ES.sup.+), at 3,8-diazaspiro[4.5]decan-2-one 4H), 1.64-1.49 (m, 5H). One exchangeable proton not 2.43 min, observed. 202 nm 8-4 Isomer 1: N-(1- B R then S .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 4.58-4.36 (m, 2H), 3.11 System 3 m/z 402 Methylcyclobutyl)-1-[9-(3- 32 and 25 (d, J = 11.7 Hz, 2H), 2.49-2.20 (m, 7H), 2.16 (s, 3H), 2.13- Method F (M + H).sup.+ methyl-1,2,4-oxadiazol-5- 2.04 (m, 1H), 2.02-1.90 (m, 3H), 1.88-1.67 (m, 8H), 1.65- (ES.sup.+), at yl)-9-azabicyclo[3.3.1]non-3- 1.48 (m, 5H), 1.41 (s, 3H). One exchangeable proton not 3.16 min, yl]piperidine-4-carboxamide observed. 202 nm 9-1 Isomer 1: 9-(3-Methyl- A T then U .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.66 (d, J = 2 Hz, 1H), 7.47 System 3 m/z 359 1,2,4-oxadiazol-5-yl)-7-[4- 4 and 35 (d, J = 2 Hz, 1H), 6.28 (t, J = 2 Hz, 1H), 4.24-4.10 (m, 3H), Method F (M + H).sup.+ (1H-pyrazol-1-yl)piperidin- 3.95 (d, J = 11.7 Hz, 2H), 3.87-3.72 (m, 3H), 3.18-3.09 (m, (ES.sup.+), at 1-yl]-3-oxa-9- 2H), 2.41-2.29 (m, 2H), 2.23-2.15 (m, 2H), 2.20 (s, 3H), 2.43 min, azabicyclo[3.3.1]nonane 2.15-2.07 (m, 2H), 2.04-1.92 (m, 2H), 1.91-1.79 (m, 2H). 220 nm 9-2 Isomer 2: (1R,5S,6r)-N,N- B V .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 4.13-4.03 (m, 2H), 3.96- System 3 m/z 390 Diethyl-3-[9-(3-methyl- 37 and 38 3.86 (m, 2H), 3.86-3.76 (m, 2H), 3.67-3.61 (m, 1H), 3.52- Method F (M + H).sup.+ 1,2,4-oxadiazol-5-yl)-3-oxa- 3.39 (m, 2H), 3.39-3.31 (m, 2H), 3.20-3.08 (m, 2H), 2.58- (ES.sup.+), at 9-azabicyclo[3.3.1]non-7- 2.32 (m, 3H), 2.24-2.07 (m, 2H), 2.19 (s, 3H), 1.98-1.88 (m, 2.75 min, yl]-3-azabicyclo[3.1.0] 2H), 1.79-1.65 (m, 2H), 1.22 (t, J = 7.1 Hz, 3H), 1.12-1.01 202 nm hexane-6-carboxamide (m, 3H). 10-1 Isomer 1: 1-(3-Methyl- A W then X .sup.1H NMR (400 MHz, Chloroform-d) δ 7.50-7.48 (m, 1H), 7.43- System 5 m/z 331 1,2,4-oxadiazol-5-yl)-4-[4- 4 and 41 7.41 (m, 1H), 6.26-6.22 (m, 1H), 4.17-4.06 (m, 1H), 3.81- Method G (M + H).sup.+ (1H-pyrazol-1-yl)piperidin- 3.67 (m, 2H), 3.56-3.40 (m, 2H), 2.98-2.86 (m, 2H), 2.64- (ES.sup.+), at 1-yl]azepane 2.52 (m, 1H), 2.48-2.32 (m, 2H), 2.21 (t, J = 0.5 Hz, 3H), 2.94 min, 2.20-2.11 (m, 2H), 2.10-1.88 (m, 5H), 1.85-1.73 (m, 1H), 254 nm 1.72-1.59 (m, 1H), 1.58-1.45 (m, 1H). 10-1 Isomer 2: 1-(3-Methyl- A W then X .sup.1H NMR (400 MHz, Chloroform-d) δ 7.50-7.48 (m, 1H), 7.42 System 5 m/z 331 1,2,4-oxadiazol-5-yl)-4-[4- 4 and 41 (d, J = 2.3 Hz, 1H), 6.25-6.23 (m, 1H), 4.15-4.05 (m, 1H), Method G (M + H).sup.+ (1H-pyrazol-1-yl)piperidin- 3.80-3.67 (m, 2H), 3.55-3.40 (m, 2H), 2.95-2.86 (m, 2H), (ES.sup.+), at 1-yl]azepane 2.61-2.52 (m, 1H), 2.45-2.33 (m, 2H), 2.21 (s, 3H), 2.18- 2.95 min, 2.10 (m, 2H), 2.08-1.87 (m, 5H), 1.84-1.72 (m, 1H), 1.72- 254 nm 1.59 (m, 1H), 1.55-1.44 (m, 1H). 10-2 Isomer 1: 8-[1-(3-Methyl- A Y then Z .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 3.82-3.63 (m, 2H), 3.59- System 3 m/z 334 1,2,4-oxadiazol-5- 19 and 41 3.44 (m, 2H), 3.18 (s, 2H), 2.62-2.44 (m, 6H), 2.20 (s, 2H), Method F (M + H).sup.+ yl)azepan-4-yl]-2,8- 2.17 (s, 3H), 2.13-2.02 (m, 1H), 2.03-1.91 (m, 1H), 1.86- (ES.sup.+), at diazaspiro[4.5]decan-3-one 1.74 (m, 1H), 1.73-1.60 (m, 5H), 1.58-1.45 (m, 1H). One 1.98 min, exchangeable proton not observed. 202 nm 10-2 Isomer 2: 8-[1-(3-Methyl- A Y then Z .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 3.82-3.64 (m, 2H), 3.57- System 3 m/z 334 1,2,4-oxadiazol-5- 19 and 41 3.44 (m, 2H), 3.18 (s, 2H), 2.63-2.44 (m, 6H), 2.20 (s, 2H), Method F (M + H).sup.+ yl)azepan-4-yl]-2,8- 2.17 (s, 3H), 2.12-2.04 (m, 1H), 2.04-1.93 (m, 1H), 1.86- (ES.sup.+), at diazaspiro[4.5]decan-3-one 1.74 (m, 1H), 1.73-1.60 (m, 5H), 1.59-1.47 (m, 1H). One 1.99 min, exchangeable proton not observed. 202 nm 10-3 Racemic mixture: 8-[1-(3- A AA .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.46 (s, 1H), 3.70-3.55 (m, System 3 m/z 336 Methyl-1,2,4-oxadiazol-5- 22 and 41 2H), 3.47-3.36 (m, 2H), 3.18 (s, 2H), 2.57-2.44 (m, 3H), Method F (M + H).sup.+ yl)azepan-4-yl]-1-oxa-3,8- 2.44-2.36 (m, 2H), 2.08 (s, 3H), 1.93-1.81 (m, 2H), 1.80- (ES.sup.+), at diazaspiro[4.5]decan-2-one 1.60 (m, 6H), 1.59-1.48 (m, 1H), 1.48-1.37 (m, 1H). 2.13 min, 202 nm 10-4 Isomer 1: 4-Ethyl-8-[1-(3- A AB then AC .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 3.83-3.66 (m, 2H), 3.59- System 3 m/z 364 methyl-1,2,4-oxadiazol-5- 42 and 41 3.46 (m, 2H), 3.40-3.34 (m, 1H), 2.89-2.59 (m, 5H), 2.17 (s, Method F (M + H).sup.+ yl)azepan-4-yl]-1-oxa-3,8- 3H), 2.16-2.07 (m, 1H), 2.06-1.97 (m, 2H), 1.97-1.76 (m, (ES.sup.+), at diazaspiro[4.5]decan-2-one 5H), 1.75-1.66 (m, 1H), 1.65-1.51 (m, 2H), 1.50-1.38 (m, 2.42 min, 1H), 0.99 (t, J = 7.4 Hz, 3H). One exchangeable proton not 228 nm observed. 10-4 Isomer 2: 4-Ethyl-8-[1-(3- A AB then AC .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 3.81-3.67 (m, 2H), 3.58- System 3 m/z 364 methyl-1,2,4-oxadiazol-5- 42 and 41 3.46 (m, 2H), 3.39-3.33 (m, 1H), 2.83-2.58 (m, 5H), 2.17 (s, Method F (M + H).sup.+ yl)azepan-4-yl]-1-oxa-3,8- 3H), 2.14-2.06 (m, 1H), 2.05-1.95 (m, 2H), 1.95-1.73 (m, (ES.sup.+), at diazaspiro[4.5]decan-2-one 5H), 1.72-1.65 (m, 1H), 1.65-1.52 (m, 2H), 1.51-1.39 (m, 2.42 min, 1H), 0.99 (t, J = 7.4 Hz, 3H). One exchangeable proton not 230 nm observed. 10-4 Isomer 3: 4-Ethyl-8-[1-(3- A AB then AC .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 3.82-3.63 (m, 2H), 3.60- System 3 m/z 364 methyl-1,2,4-oxadiazol-5- 42 and 41 3.44 (m, 2H), 3.39-3.33 (m, 1H), 2.77-2.52 (m, 5H), 2.17 (s, Method F (M + H).sup.+ yl)azepan-4-yl]-1-oxa-3,8- 3H), 2.13-2.05 (m, 1H), 2.04-1.92 (m, 2H), 1.92-1.71 (m, (ES.sup.+), at diazaspiro[4.5]decan-2-one 5H), 1.70-1.65 (m, 1H), 1.64-1.50 (m, 2H), 1.50-1.38 (m, 2.40 min, 1H), 0.98 (t, J = 7.4 Hz, 3H). One exchangeable proton not 202 nm observed. 10-4 Isomer 4: 4-Ethyl-8-[1-(3- A AB then AC .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 3.81-3.62 (m, 2H), 3.60- System 3 m/z 364 methyl-1,2,4-oxadiazol-5- 42 and 41 3.46 (m, 2H), 3.38-3.32 (m, 1H), 2.77-2.52 (m, 5H), 2.17 (s, Method F (M + H).sup.+ yl)azepan-4-yl]-1-oxa-3,8- 3H), 2.13-2.04 (m, 1H), 2.04-1.93 (m, 2H), 1.92-1.71 (m, (ES.sup.+), at diazaspiro[4.5]decan-2-one 5H), 1.71-1.63 (m, 1H), 1.62-1.50 (m, 2H), 1.49-1.37 (m, 2.40 min, 1H), 0.98 (t, J = 7.4 Hz, 3H). One exchangeable proton not 228 nm observed. 10-5 Isomer 1: 4,4-Dimethyl-8- A AD then AE .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 3.81-3.62 (m, 2H), 3.58- System 3 m/z 364 [1-(3-methyl-1,2,4- 43 and 41 3.43 (m, 2H), 2.82-2.69 (m, 2H), 2.65-2.48 (m, 3H), 2.17 (s, Method F (M + H).sup.+ oxadiazol-5-yl)azepan-4- 3H), 2.12-2.04 (m, 1H), 2.04-1.78 (m, 5H), 1.77-1.50 (m, (ES.sup.+), at yl]-1-oxa-3,8- 4H), 1.20 (s, 6H). One exchangeable proton not observed. 2.32 min, diazaspiro[4.5]decan-2-one 202 nm 10-6 Isomer 1: 1′-[1-(3-Methyl- A AF then AG .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.38 (d, J = 7.5 Hz, 1H), System 3 m/z 382 1,2,4-oxadiazol-5- 44 and 41 7.24-7.17 (m, 1H), 7.06-6.98 (m, 1H), 6.90 (d, J = 7.7 Hz, Method F (M + H).sup.+ yl)azepan-4-yl]spiro[indole- 1H), 3.97-3.88 (m, 1H), 3.84-3.70 (m, 2H), 3.62-3.51 (m, (ES.sup.+), at 3,4′-piperidin]-2(1H)-one 2H), 3.16-3.05 (m, 2H), 2.86-2.76 (m, 2H), 2.75-2.66 (m, 3.03 min, 1H), 2.26-2.15 (m, 1H), 2.18 (s, 3H), 2.14-2.00 (m, 2H), 202 nm 1.96-1.79 (m, 4H), 1.77-1.58 (m, 2H). One exchangeable proton not observed. 10-7 Isomer 1: [(2R,4R)-4- A AH then AI .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 5.12 (dt, J = 54.2, 4.4 Hz, System 3 m/z 382 Fluoro-1-{1-[1-(3-methyl- 47 and 41 1H), 3.79-3.64 (m, 2H), 3.61-3.45 (m, 3H), 3.45-3.38 (m, Method F (M + H).sup.+ 1,2,4-oxadiazol-5- 1H), 3.24-3.11 (m, 1H), 3.08-2.97 (m, 1H), 2.91-2.83 (m, (ES.sup.+), at yl)azepan-4-yl]piperidin-4- 2H), 2.84-2.68 (m, 1H), 2.60-2.48 (m, 2H), 2.38-2.22 (m, 2.37 min, yl}pyrrolidin-2-yl]methanol 2H), 2.17 (s, 3H), 2.10-1.91 (m, 5H), 1.91-1.72 (m, 3H), 220 nm 1.72-1.59 (m, 1H), 1.59-1.42 (m, 3H). One exchangeable proton not observed. 10-7 Isomer 2: [(2R,4R)-4- A AH then AI .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 5.12 (dt, J = 54.1, 4.4 Hz, System 3 m/z 382 Fluoro-1-{1-[1-(3-methyl- 47 and 41 1H), 3.80-3.65 (m, 2H), 3.61-3.45 (m, 3H), 3.45-3.37 (m, Method F (M + H).sup.+ 1,2,4-oxadiazol-5- 1H), 3.23-3.11 (m, 1H), 3.07-2.98 (m, 1H), 2.91-2.84 (m, (ES.sup.+), at yl)azepan-4-yl]piperidin-4- 2H), 2.84-2.68 (m, 1H), 2.60-2.48 (m, 2H), 2.38-2.26 (m, 2.37 min, yl}pyrrolidin-2-yl]methanol 2H), 2.17 (s, 3H), 2.13-1.91 (m, 5H), 1.91-1.72 (m, 3H), 220 nm 1.72-1.57 (m, 1H), 1.57-1.44 (m, 3H). One exchangeable proton not observed. 10-8 Isomer 1: [(2R)-4,4- A AJ then AK .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 3.81-3.64 (m, 2H), 3.61- System 4 m/z 400 Difluoro-1-{1-[1-(3-methyl- 48 and 41 3.44 (m, 4H), 3.26-3.11 (m, 2H), 3.10-2.97 (m, 1H), 2.95- Method D (M + H).sup.+ 1,2,4-oxadiazol-5- 2.82 (m, 2H), 2.76-2.64 (m, 1H), 2.64-2.52 (m, 1H), 2.41- (ES.sup.+), at yl)azepan-4-yl]piperidin-4- 2.23 (m, 3H), 2.22-2.14 (m, 1H), 2.17 (s, 3H), 2.12-2.03 (m, 2.48 min, yl}pyrrolidin-2-yl]methanol 1H), 2.03-1.92 (m, 2H), 1.87-1.73 (m, 3H), 1.71-1.60 (m, 228 nm 1H), 1.59-1.41 (m, 3H). One exchangeable proton not observed. 10-8 Isomer 2: [(2R)-4,4- A AJ then AK .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 3.81-3.65 (m, 2H), 3.61- System 4 m/z 400 Difluoro-1-{1-[1-(3-methyl- 48 and 41 3.44 (m, 4H), 3.26-3.11 (m, 2H), 3.11-2.98 (m, 1H), 2.95- Method D (M + H).sup.+ 1,2,4-oxadiazol-5- 2.83 (m, 2H), 2.76-2.65 (m, 1H), 2.65-2.53 (m, 1H), 2.41-2.26 (m, 3H), (ES.sup.+), at yl)azepan-4-yl]piperidin-4- 2.24-2.13 (m, 1H), 2.17 (s, 3H), 2.13-2.04 (m, 2.47 min, yl}pyrrolidin-2-yl]methanol 1H), 2.03-1.91 (m, 2H), 1.87-1.75 (m, 3H), 1.74-1.59 (m, 202 nm 1H), 1.58-1.44 (m, 3H). One exchangeable proton not observed. 10-9 Isomer 2: (5S)-5-Ethyl-1-{1- A AL then AM .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 3.79-3.66 (m, 3H), 3.66- System 3 m/z 376 [1-(3-methyl-1,2,4- 49 and 41 3.56 (m, 1H), 3.56-3.45 (m, 2H), 2.95-2.81 (m, 2H), 2.61- Method F (M + H).sup.+ oxadiazol-5-yl)azepan-4- 2.52 (m, 1H), 2.50-2.41 (m, 1H), 2.41-2.30 (m, 2H), 2.30- (ES.sup.+), at yl]piperidin-4- 2.20 (m, 1H), 2.17 (s, 3H), 2.15-1.92 (m, 5H), 1.91-1.74 (m, 2.77 min, yl}pyrrolidin-2-one 5H), 1.73-1.60 (m, 2H), 1.60-1.44 (m, 2H), 0.92 (t, J = 7.4 202 nm Hz, 3H). 10-10 Isomer 1b: 1-(3-Methyl- A AN to give .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.52 (s, 1H), 7.41 (s, 1H), System 3 m/z 414 1,2,4-oxadiazol-5-yl)-4-{4- 51 and 41 Isomers 1 3.92-3.81 (m, 1H), 3.85 (s, 3H), 3.77-3.64 (m, 2H), 3.54- Method F (M + H).sup.+ [2-(1-methyl-1H-pyrazol-4- and 2 then 3.42 (m, 2H), 2.98-2.89 (m, 1H), 2.88-2.77 (m, 2H), 2.76- (ES.sup.+), at yl)pyrrolidin-1-yl]piperidin- AO to give 2.68 (m, 1H), 2.56-2.46 (m, 1H), 2.38-2.29 (m, 1H), 2.26- 2.36 min, 1-yl}azepane Isomers 1a 2.09 (m, 3H), 2.16 (s, 3H), 2.07-1.82 (m, 6H), 1.81-1.68 (m, 225 nm and 1b 3H), 1.67-1.59 (m, 1H), 1.59-1.41 (m, 3H). from Isomer 1 10-10 Isomer 2a: 1-(3-Methyl- A AN to give .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.54 (s, 1H), 7.42 (s, 1H), System 3 m/z 414 1,2,4-oxadiazol-5-yl)-4-{4- 51 and 41 Isomers 1 3.97-3.89 (m, 1H), 3.86 (s, 3H), 3.77-3.64 (m, 2H), 3.55- Method F (M + H).sup.+ [2-(1-methyl-1H-pyrazol-4- and 2 then 3.43 (m, 2H), 3.01-2.91 (m, 1H), 2.89-2.71 (m, 3H), 2.59- (ES.sup.+), at yl)pyrrolidin-1-yl]piperidin- AO to give 2.48 (m, 1H), 2.44-2.33 (m, 1H), 2.28-2.10 (m, 3H), 2.16 (s, 2.34 min, 1-yl}azepane Isomers 2a 3H), 2.09-1.84 (m, 6H), 1.83-1.68 (m, 3H), 1.67-1.41 (m, 226 nm and 2b 4H). from Isomer 2 10-10 Isomer 2b: 1-(3-Methyl- A AN to give .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.52 (s, 1H), 7.41 (s, 1H), System 3 m/z 414 1,2,4-oxadiazol-5-yl)-4-{4- 51 and 41 Isomers 1 3.92-3.82 (m, 1H), 3.85 (s, 3H), 3.76-3.64 (m, 2H), 3.54- Method F (M + H).sup.+ [2-(1-methyl-1H-pyrazol-4- and 2 then 3.42 (m, 2H), 2.98-2.89 (m, 1H), 2.88-2.76 (m, 2H), 2.76- (ES.sup.+), at yl)pyrrolidin-1-yl]piperidin- AO to give 2.68 (m, 1H), 2.56-2.47 (m, 1H), 2.39-2.29 (m, 1H), 2.27- 2.34 min, 1-yl}azepane Isomers 2a 2.09 (m, 3H), 2.16 (s, 3H), 2.08-1.81 (m, 6H), 1.82-1.68 (m, 226 nm and 2b 3H), 1.67-1.54 (m, 2H), 1.54-1.41 (m, 2H). from Isomer 2 10-11 Racemic mixture: N-Ethyl- A AP .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 4.17-4.01 (m, 1H), 3.75- System 3 m/z 350 N-{1-[1-(3-methyl-1,2,4- 52 and 41 3.52 (m, 2H), 3.52-3.34 (m, 2H), 3.27-3.09 (m, 4H), 2.83- Method F (M + H).sup.+ oxadiazol-5-yl)azepan-4- 2.70 (m, 2H), 2.24-2.12 (m, 2H), 2.09 (s, 3H), 1.98 (d, J = 5.5 (ES.sup.+), at yl]piperidin- Hz, 3H), 1.93-1.81 (m, 2H), 1.80-1.65 (m, 2H), 1.65-1.36 2.37 min, 4-yl}acetamide (m, 5H), 1.03 (dt, J = 40.8, 6.9 Hz, 3H). 202 nm 10-12 Isomer 1: (2S)-N-Methyl-2- C AQ then AR .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 3.90-3.80 (m, 1H), 3.79- System 3 m/z 391 {1-[1-(3-methyl-1,2,4- 54 and 55 3.63 (m, 3H), 3.60-3.43 (m, 3H), 2.93-2.80 (m, 2H), 2.71 (s, Method F (M + H).sup.+ oxadiazol-5-yl)azepan-4- 3H), 2.61-2.50 (m, 1H), 2.35-2.21 (m, 2H), 2.16 (s, 3H), (ES.sup.+), at yl]piperidin-4-yl}pyrrolidine- 2.13-2.05 (m, 1H), 2.03-1.94 (m, 2H), 1.94-1.69 (m, 6H), 2.10 min, 1-carboxamide 1.68-1.45 (m, 4H), 1.43-1.31 (m, 2H). One exchangeable 225 nm proton not observed. 10-12 Isomer 2: (2S)-N-Methyl-2- C AQ then AR .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 3.90-3.81 (m, 1H), 3.80- System 3 m/z 391 {1-[1-(3-methyl-1,2,4- 54 and 55 3.63 (m, 3H), 3.59-3.44 (m, 3H), 3.01-2.86 (m, 2H), 2.76- Method F (M + H).sup.+ oxadiazol-5-yl)azepan-4- 2.58 (m, 1H), 2.71 (s, 3H), 2.46-2.27 (m, 2H), 2.21-2.07 (m, (ES.sup.+), at yl]piperidin-4-yl}pyrrolidine- 1H), 2.17 (s, 3H), 2.07-1.96 (m, 2H), 1.95-1.87 (m, 2H), 2.08 min, 1-carboxamide 1.87-1.71 (m, 4H), 1.71-1.49 (m, 4H), 1.48-1.32 (m, 2H). 225 nm One exchangeable proton not observed. 11-1 Isomer 2: 6-(3-Methyl- A AS .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.61 (d, J = 2 Hz, 1H), 7.45 System 3 m/z 343 1,2,4-oxadiazol-5-yl)-3-[4- 4 and 58 (d, J = 2 Hz, 1H), 6.28 (t, J = 2 Hz, 1H), 4.23-4.16 (m, 1H), Method F (M + H).sup.+ (1H-pyrazol-1-yl)piperidin- 4.13-4.02 (m, 1H), 3.63 (d, J = 9.7 Hz, 1H), 3.52-3.44 (m, (ES.sup.+), at 1-yl]-6- 1H), 3.15-3.05 (m, 1H), 2.61-2.50 (m, 2H), 2.33-2.21 (m, 2.89 min, azabicyclo[3.2.1]octane 1H), 2.17 (s, 3H), 2.11-1.80 (m, 11H), 1.63-1.49 (m, 1H). 202 nm 11-2 Isomer 2: 8-[6-(3-Methyl- A AT .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 4.21-4.15 (m, 1H), 3.58 System 3 m/z 346 1,2,4-oxadiazol-5-yl)-6- 19 and 58 (d, J = 9.6 Hz, 1H), 3.49-3.43 (m, 1H), 3.12 (s, 2H), 2.60- Method F (M + H).sup.+ azabicyclo[3.2.1]oct-3-yl]- 2.52 (m, 2H), 2.52-2.40 (m, 3H), 2.38-2.27 (m, 2H), 2.18 (s, (ES.sup.+), at 2,8-diazaspiro[4.5]decan-3-one 3H), 2.14 (s, 2H), 2.10-2.01 (m, 2H), 1.97-1.92 (m, 1H), 2.10 min, 1.91-1.81 (m, 4H), 1.63-1.52 (m, 1H), 1.52-1.39 (m, 1H). 202 nm One exchangeable proton not observed. 11-3 Isomer 2: 8-[6-(3-Methyl- A AU .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 4.24-4.13 (m, 1H), 3.60 System 3 m/z 348 1,2,4-oxadiazol-5-yl)-6- 22 and 58 (d, J = 9.6 Hz, 1H), 3.52-3.42 (m, 1H), 2.77-2.31 (m, 6H), Method F (M + H).sup.+ azabicyclo[3.2.1]oct-3-yl]-1-oxa- 2.30-2.13 (m, 2H), 2.18 (s, 3H), 2.09-1.98 (m, 2H), 1.97- (ES.sup.+), at 3,8-diazaspiro[4.5]decan-2-one 1.80 (m, 5H), 1.79-1.68 (m, 2H), 1.57-1.42 (m, 1H). One 2.32 min, exchangeable proton not observed. 210 nm 12-1 Isomer 1: 8-(2-(3-Methyl- A AV .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 4.05-3.97 (m, 1H), 3.64- System 3 m/z 346 1,2,4-oxadiazol-5-yl)-2- 19 and 28 3.55 (m, 1H), 3.50-3.42 (m, 1H), 3.21 (s, 2H), 2.73-2.22 (m, Method F (M + H).sup.+ azabicyclo[2.2.2]octan-5-yl)-2,8- 4H), 2.38-2.28 (m, 2H), 2.27-2.20 (m, 3H), 2.16 (s, 3H), (ES.sup.+), at diazaspiro[4.5]decan-3-one 2.07-1.94 (m, 1H), 1.92-1.79 (m, 2H), 1.77-1.65 (m, 4H), 2.17 min, 1.63-1.49 (m, 2H). One exchangeable proton not observed. 229 nm 12-1 Isomer 2: 8-(2-(3-Methyl- A AV .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 4.08-4.01 (m, 1H), 3.76- System 3 m/z 346 1,2,4-oxadiazol-5-yl)-2- 19 and 28 3.68 (m, 1H), 3.41-3.34 (m, 1H), 3.20 (s, 2H), 2.70-2.26 (m, Method F (M + H).sup.+ azabicyclo[2.2.2]octan-5-yl)-2,8- 4H), 2.38-2.31 (m, 2H), 2.22 (s, 2H), 2.17 (s, 3H), 2.13- (ES.sup.+), at diazaspiro[4.5]decan-3-one 2.03 (m, 1H), 1.97-1.88 (m, 1H), 1.87-1.79 (m, 1H), 1.79- 2.25 min, 1.60 (m, 7H). One exchangeable proton not observed. 229 nm 12-2 Isomer 2: 8-(2-(3-Methyl- A AW .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 4.08-4.01 (m, 1H), 3.76- System 3 m/z 348 1,2,4-oxadiazol-5-yl)-2- 22 and 28 3.68 (m, 1H), 3.45-3.35 (m, 2H), 2.73 (s, 2H), 2.46 (s, 2H), Method F (M + H).sup.+ azabicyclo[2.2.2]octan-5-yl)-1-oxa- 2.39-2.30 (m, 2H), 2.17 (s, 3H), 2.13-2.05 (m, 1H), 2.01- (ES.sup.+), at 3,8-diazaspiro[4.5]decan-2-one 1.89 (m, 3H), 1.88-1.64 (m, 7H). One exchangeable proton 2.29 min, not observed. 230 nm 12-3 Isomer 1: 8-(8-(3- A AX 1H NMR (400 MHz, Methanol-d.sub.4) δ 4.56-4.48 (m, 2H), 3.18 System 3 m/z 400 (Trifluoromethyl)-1,2,4- 19 and 60 (s, 2H), 2.95-2.81 (m, 1H), 2.67-2.39 (m, 4H), 2.20 (s, 2H), Method F (M + H).sup.+ oxadiazol-5-yl)-8- 2.18-2.09 (m, 2H), 2.06-1.98 (m, 2H), 1.95-1.86 (m, 2H), (ES.sup.+), at azabicyclo[3.2.1]octan-3- 1.75-1.59 (m, 6H). One exchangeable proton not observed. 3.07 min, yl)-2,8- 239 nm diazaspiro[4.5]decan-3-one 12-3 Isomer 2: 8-(8-(3- A AX 1H NMR (400 MHz, Methanol-d.sub.4) δ 4.68-4.61 (m, 1H), 4.48- System 3 m/z 400 (Trifluoromethyl)-1,2,4- 19 and 60 4.40 (m, 2H), 3.21 (s, 2H), 2.71-2.38 (m, 4H), 2.38-2.30 (m, Method F (M + H).sup.+ oxadiazol-5-yl)-8- 1H), 2.22 (s, 2H), 2.19-2.12 (m, 3H), 2.12-2.04 (m, 2H), (ES.sup.+), at azabicyclo[3.2.1]octan-3- 2.03-1.94 (m, 2H), 1.76-1.66 (m, 4H). One exchangeable 3.40 min, yl)-2,8- proton not observed. 239 nm diazaspiro[4.5]decan-3-one 12-4 Isomer 1: 8-(8-(3- A AY .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 4.60-4.44 (m, 2H), 3.35- System 3 m/z 402 (Trifluoromethyl)-1,2,4- 22 and 60 3.32 (m, 2H), 3.00-2.85 (m, 1H), 2.77-2.47 (m, 4H), 2.22- Method F (M + H).sup.+ oxadiazol-5-yl)-8- 2.07 (m, 2H), 2.07-1.84 (m, 6H), 1.83-1.61 (m, 4H). One (ES.sup.+), at azabicyclo[3.2.1]octan-3- exchangeable proton not observed. 3.24 min, yl)-1-oxa-3,8- 238 nm diazaspiro[4.5]decan-2-one 12-4 Isomer 2: 8-(8-(3- A AY .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 4.50-4.37 (m, 2H), 3.36 System 3 m/z 402 (Trifluoromethyl)-1,2,4- 22 and 60 (s, 2H), 2.85-2.46 (m, 4H), 2.43-2.33 (m, 1H), 2.25-1.91 Method F (M + H).sup.+ oxadiazol-5-yl)-8- (m, 10H), 1.91-1.76 (m, 2H). One exchangeable proton not (ES.sup.+), at azabicyclo[3.2.1]octan-3- observed. 3.58 min, yl)-1-oxa-3,8- 239 nm diazaspiro[4.5]decan-2-one 12-6 Isomer 1: (1R,5S,6r)-3-(2- A AZ then BA .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 4.16-3.97 (m, 4H), 3.13- System 3 m/z 384 (3-Methyl-1,2,4-oxadiazol- 62 and 12 3.03 (m, 2H), 2.71-2.61 (m, 1H), 2.47-2.36 (m, 2H), 2.32- Method F (M − H).sup.− 5-yl)-2-azaspiro[3.4]octan- 2.20 (m, 2H), 2.16 (s, 3H), 2.11-1.90 (m, 6H), 1.88-1.76 (m, (ES.sup.−), at 6-yl)-N-(1- 6H), 1.63-1.48 (m, 1H), 1.41 (s, 3H). One exchangeable 3.12 min, methylcyclobutyl)-3- proton not observed. 227 nm azabicyclo[3.1.0]hexane-6- carboxamide 12-6 Isomer 1: (1R,5S,6r)-3-(2- A AZ then BA .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 4.14-3.97 (m, 4H), 3.13- System 3 m/z 384 (3-Methyl-1,2,4-oxadiazol- 62 and 12 3.03 (m, 2H), 2.70-2.60 (m, 1H), 2.45-2.35 (m, 2H), 2.33- Method F (M − H).sup.− 5-yl)-2-azaspiro[3.4]octan-6- 2.20 (m, 2H), 2.16 (s, 3H), 2.10-1.90 (m, 6H), 1.88-1.74 (m, (ES.sup.−), at yl)-N-(1- 6H), 1.62-1.50 (m, 1H), 1.41 (s, 3H). One exchangeable 3.11 min, methylcyclobutyl)-3- proton not observed. 225 nm azabicyclo[3.1.0]hexane-6- carboxamide 12-7 Isomer 2: 1-(8-(3-Methyl- B BB .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 4.37-4.28 (m, 2H), 3.24- System 3 m/z 442 1,2,4-oxadiazol-5-yl)-8- 24 and 63 3.16 (m, 2H), 2.56-2.39 (m, 4H), 2.29-2.19 (m, 2H), 2.18 (s, Method F (M + H).sup.+ azabicyclo[3.2.1]octan-3- 3H), 2.17-2.12 (m, 2H), 2.10-1.93 (m, 6H), 1.93-1.82 (m, (ES.sup.+), at yl)-N-(1- 4H), 1.82-1.64 (m, 4H). One exchangeable proton not 3.30 min, (trifluoromethyl)cyclobutyl)piperidine-4- observed. 202 nm carboxamide 12-8 Isomer 2: N-(1- B BC .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 4.36-4.29 (m, 2H), 3.25- System 3 m/z 402 Ethylcyclobutyl)-1-(8-(3- 24 and 64 3.17 (m, 2H), 2.28-2.21 (m, 1H), 2.18 (s, 3H), 2.17-2.09 (m, Method F (M + H).sup.+ methyl-1,2,4-oxadiazol-5- 5H), 2.09-1.97 (m, 6H), 1.93-1.79 (m, 8H), 1.79-1.65 (m, (ES.sup.+), at yl)-8-azabicyclo 4H), 0.81 (t, J = 7.3 Hz, 3H). One exchangeable proton not 3.23 min, [3.2.1]octan-3-yl)piperidine- observed. 202 nm 4-carboxamide 12-11 Isomer 2: 1-(8-(3-Methyl- B BD .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 4.33 (s, 2H), 3.24-3.17 System 3 m/z 402 1,2,4-oxadiazol-5-yl)-8- 24 and 65 (m, 2H), 2.29-2.21 (m, 1H), 2.18 (s, 3H), 2.17-1.94 (m, 9H), Method F (M + H).sup.+ azabicyclo[3.2.1]octan-3- 1.93-1.79 (m, 4H), 1.77-1.54 (m, 10H), 1.36 (s, 3H). One (ES.sup.+), at yl)-N-(1- exchangeable proton not observed. 3.61 min, methylcyclopentyl)piperidine- 202 nm 4-carboxamide 12-12 Isomer 2: 1-(8-(3-Methyl- A BE .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 4.36-4.29 (m, 2H), 3.26- System 3 m/z 400 1,2,4-oxadiazol-5-yl)-8- 68 and 18 3.18 (m, 2H), 3.16 (s, 2H), 2.30-2.20 (m, 2H), 2.18 (s, 3H), Method F (M − H).sup.− azabicyclo[3.2.1]octan-3- 2.16-1.98 (m, 6H), 1.95-1.81 (m, 8H), 1.81-1.72 (m, 4H), (ES.sup.−), at yl)-N-((1- 1.69-1.59 (m, 2H), 1.10 (s, 3H). One exchangeable proton 3.33 min, methylcyclobutyl)methyl)piperidine- not observed. 202 nm 4-carboxamide 12-13 Isomer 2: (1R,5S,6r)-3-(8- A BF .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 4.29-4.20 (m, 2H), 2.49- System 3 m/z 384 (3-methyl-1,2,4-oxadiazol- 62 and 18 2.42 (m, 1H), 2.33-2.15 (m, 7H), 2.18 (s, 3H), 2.07-1.79 (m, Method F (M − H).sup.− 5-yl)-8- 14H), 1.41 (s, 3H). One exchangeable proton not observed. (ES.sup.−), at azabicyclo[3.2.1]octan-3- 3.77 min, yl)-N-(1-methylcyclobutyl)- 230 nm 3-azabicyclo[3.1.0]hexane- 6-carboxamide 12-14 Isomer 1: N-(1- B BG .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 4.56-4.48 (m, 2H), 3.04- System 3 m/z 442 Methylcyclobutyl)-1-(8-(3- 69 and 25 2.96 (m, 2H), 2.94-2.83 (m, 1H), 2.30-2.19 (m, 2H), 2.18- Method F (M − H).sup.+ (trifluoromethyl)-1,2,4- 2.05 (m, 5H), 2.03-1.94 (m, 4H), 1.93-1.87 (m, 2H), 1.87- (ES.sup.+), at oxadiazol-5-yl)-8- 1.77 (m, 2H), 1.77-1.60 (m, 6H), 1.40 (s, 3H). One 3.89 min, azabicyclo[3.2.1]octan-3- exchangeable proton not observed. 202 nm yl)piperidine-4- carboxamide 12-14 Isomer 2: N-(1- B BG .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 4.46-4.39 (m, 2H), 3.27- System 3 m/z 442 Methylcyclobutyl)-1-(8-(3- 69 and 25 3.19 (m, 2H), 2.34-2.20 (m, 3H), 2.19-2.09 (m, 5H), 2.08- Method F (M − H).sup.+ (trifluoromethyl)-1,2,4- 2.03 (m, 2H), 2.02-1.93 (m, 4H), 1.90-1.80 (m, 4H), 1.79- (ES.sup.+), at oxadiazol-5-yl)-8- 1.64 (m, 4H), 1.41 (s, 3H). One exchangeable proton not 4.27 min, azabicyclo[3.2.1]octan-3- observed. 202 nm yl)piperidine-4- carboxamide

(223) Biological Activity

Example A

(224) Phospho-ERK1/2 Assays

(225) Functional assays were performed using the Alphascreen Surefire phospho-ERK1/2 assay (Crouch & Osmond, Comb. Chem. High Throughput Screen, 2008). ERK1/2 phosphorylation is a downstream consequence of both Gq/11 and Gi/o protein coupled receptor activation, making it highly suitable for the assessment of M.sub.1, M.sub.3 (Gq/11 coupled) and M.sub.2, M.sub.4 receptors (Gi/o coupled), rather than using different assay formats for different receptor subtypes. CHO cells stably expressing the human muscarinic M.sub.1, M.sub.2, M.sub.3 or M.sub.4 receptor were plated (25K/well) onto 96-well tissue culture plates in MEM-alpha+10% dialysed FBS. Once adhered, cells were serum-starved overnight. Agonist stimulation was performed by the addition of 5 μL agonist to the cells for 5 min (37° C.). Media was removed and 50 μL of lysis buffer added. After 15 min, a 4 μL sample was transferred to 384-well plate and 7 μL of detection mixture added. Plates were incubated for 2 h with gentle agitation in the dark and then read on a PHERAstar plate reader. pEC.sub.50 and E.sub.max figures were calculated from the resulting data for each receptor subtype and the results are set out in Table 4 below.

(226) For the vast majority of examples at least two diastereomers exist and these have been separated, unless otherwise stated, using the techniques of reversed phase HPLC, chiral HPLC or chiral SFC. Isomer assignment (Isomer 1, Isomer 2, etc.) is based on the retention time of the compound using the separation technique that was performed in the final purification step. By implication, this could be reversed phase HPLC, chiral HPLC or chiral SFC retention time, and this will vary from compound to compound.

(227) Analytical data for active isomers is reported in Table 3. Data for several weakly active compounds are included in Table 4 to highlight the preference for absolute stereochemistry.

(228) TABLE-US-00006 TABLE 4 Muscarinic Activity pEC.sub.50 M1 pEC.sub.50 M2 pEC.sub.50 M3 pEC.sub.50 M4 (% Emax cf. (% Emax cf. (% Emax cf. (% Emax cf. Ex. No. ACh) ACh) ACh) ACh) ACh 8.33 (102) 7.82 (105) 8.12 (115) 8.09 (110) 1-1 4.99 (48) NT NT 6.29 (77) 2-1 Isomer 2 <4.70 (56) <4.70 (2) <4.70 (3) 6.52 (41) 2-2 Isomer 2 6.13 (40) <4.70 (2) <4.70 (3) 6.93 (51) 2-3 Isomer 2 <4.70 (9) NT NT 6.29 (32) 3-1 Isomer 2 5.08 (58) NT NT 5.91 (68) 4-1 4.70 (50) NT NT 6.00 (85) 5-1 Isomer 1 <4.70 (9) NT NT 5.90 (55) 6-1 Isomer 1 <4.70 (23) <4.70 (2) <4.70 (2) 6.53 (51) 6-2 Isomer 1 6.80 (34) NT NT <4.70 (9) 6-2 Isomer 2 7.20 (81) NT NT 6.77 (39) 6-3 Isomer 2 7.49 (33) <4.70 (3) <4.70 (1) <4.70 (7) 6-4 Isomer 1 6.62 (49) NT NT <4.70 (15) 6-4 Isomer 2 6.59 (87) <4.70 (5) <4.70 (32) 6.28 (39) 6-5 Isomer 2 6.83 (100) <4.70 (31) <4.70 (11) 6.71 (79) 7-1 Isomer 1 <4.70 (18) <4.70 (11) <4.70 (7) 6.82 (85) 7-1 Isomer 2 5.64 (33) <4.70 (15) <4.70 (6) 7.07 (99) 8-1 Isomer 2 <4.70 (24) NT NT 5.90 (38) 8-2 Isomer 1 6.67 (30) NT NT <4.70 (9) 8-3 Isomer 1 6.53 (39) <4.70 (4) <4.70 (1) <4.70 (67) 8-4 Isomer 1 6.24 (98) NT NT 6.19 (76) 9-1 Isomer 1 <4.70 (15) <4.70 (21) <4.70 (1) 6.98 (77) 9-2 Isomer 2 6.66 (109) <4.70 (27) 5.20 (42) 6.13 (74) 10-1 Isomer 1 5.87 (32) NT NT 6.89 (73) 10-1 Isomer 2 5.18 (43) NT NT 6.28 (72) 10-2 Isomer 1 7.03 (66) <4.70 (3) <4.70 (5) <4.70 (10) 10-2 Isomer 2 6.31 (53) NT NT <4.70 (15) 10-3 Racemic mixture 6.43 (97) NT NT <4.70 (10) 10-4 Isomer 1 6.17 (123) NT NT 7.00 (85) 10-4 Isomer 2 7.26 (58) NT NT 7.63 (64) 10-4 Isomer 3 5.03 (81) NT NT 5.66 (71) 10-4 Isomer 4 <4.70 (18) NT NT 6.06 (36) 10-5 Isomer 1 <4.70 (21) NT NT 6.66 (33) 10-6 Isomer 1 6.18 (76) <4.70 (60) <4.70 (4) 7.11 (77) 10-7 Isomer 1 5.43 (44) <4.70 (15) <4.70 (2) 6.98 (89) 10-7 Isomer 2 5.37 (70) NT NT 6.40 (76) 10-8 Isomer 1 6.17 (37) NT NT 7.03 (91) 10-8 Isomer 2 5.81 (35) NT NT 6.53 (73) 10-9 Isomer 2 5.88 (53) NT NT 6.32 (56) 10-10 Isomer 1b <4.70 (6) NT NT 6.29 (56) 10-10 Isomer 2a <4.70 (3) NT NT 5.84 (52) 10-10 Isomer 2b <4.70 (14) NT NT 6.50 (72) 10-11 Racemic mixture 5.40 (56) NT NT 6.66 (101) 10-12 Isomer 1 <4.70 (22) NT NT 6.51 (100) 10-12 Isomer 2 <4.70 (24) NT NT 7.26 (119) 11-1 Isomer 2 5.50 (48) NT NT 5.98 (69) 11-2 Isomer 2 8.02 (67) <4.70 (8) <4.70 (5) <4.70 (15) 11-3 Isomer 2 7.15 (65) <4.70 (21) <4.70 (22) <4.70 (11) 12-1 Isomer 1 6.22 (58) NT NT <4.70 (5) 12-1 Isomer 2 7.49 (106) <4.70 (6) <4.70 (2) 6.93 (30) 12-2 Isomer 2 6.40 (80) <4.70 (14) <4.70 (1) <4.70 (18) 12-3 Isomer 1 7.50 (67) <4.70 (19) <4.70 (31) <4.70 (14) 12-3 Isomer 2 8.30 (103) <4.70 (14) <4.70 (70) 6.70 (23) 12-7 Isomer 2 6.27 (109) NT NT 5.70 (109) 12-8 Isomer 2 6.87 (104) 5.61 (33) <4.70 (3) 6.03 (109) 12-11 Isomer 2 6.18 (103) NT NT 5.57 (83) 12-12 Isomer 2 8.43 (80) NT NT 6.68 (107) 12-13 Isomer 2 6.48 (102) NT NT 6.09 (69) 12-14 Isomer 1 6.04 (47) NT NT <4.70 (6) 12-14 Isomer 2 7.73 (115) <4.70 (25) <4.70 (9) 6.48 (40) 12-15 Isomer 2 6.60 (113) <4.70 (18) <4.70 (6) 5.33 (75) 12-16 Isomer 1 7.49 (108) 6.36 (62) <4.70 (13) 7.41 (104) 12-16 Isomer 2 7.28 (118) <4.70 (10) <4.70 (4) 6.25 (62) 12-18 Isomer 1 7.00 (87) 5.23 (27) <4.70 (15) 6.68 (62) 12-18 Isomer 2 8.63 (92) 6.59 (90) 5.72 (48) 7.83 (92) 12-22 Isomer 2 8.06 (102) 5.68 (81) 4.90 (52) 6.23 (108) 12-23 Isomer 2 7.59 (132) <4.70 (13) <4.70 (25) 6.92 (30) 12-24 Isomer 1 6.08 (74) NT NT <4.70 (16) 12-24 Isomer 2 7.58 (102) 5.33 (60) <4.70 (25) 6.02 (83) 12-25 Isomer 1 6.70 (102) <4.70 (31) <4.70 (50) <4.70 (22) 12-25 Isomer 2 8.55 (91) 6.15 (84) 5.29 (57) 6.82 (119) 12-27 Isomer 2 6.92 (76) <4.70 (14) <4.70 (15) <4.70 (21)

EQUIVALENTS

(229) The foregoing examples are presented for the purpose of illustrating the invention and should not be construed as imposing any limitation on the scope of the invention. It will readily be apparent that numerous modifications and alterations may be made to the specific embodiments of the invention described above and illustrated in the examples without departing from the principles underlying the invention. All such modifications and alterations are intended to be embraced by this application.

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Abstract

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