BICYCLIC AZA COMPOUNDS AS MUSCARINIC M1 AND/OR M4 RECEPTOR AGONISTS

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 where X.sup.1; X.sup.2; R.sup.1 and R.sup.4 are as defined herein.

##STR00001##

Claims

1. A compound of the formula (1): ##STR00063## or a salt thereof, wherein: X.sup.1 and X.sup.2 are saturated hydrocarbon groups which together contain a total of five to nine carbon atoms and zero or one oxygen atoms and which link together such that the moiety: ##STR00064## forms a monocyclic or bicyclic ring system optionally substituted with one or more fluorine atoms; R.sup.1 is selected from COR.sup.5; COOR.sup.5; CONR.sup.5R.sup.6; C(═NR.sup.5)R.sup.6; OCOR.sup.5; NR.sup.7COR.sup.5; NR.sup.7CONR.sup.5R.sup.6; NR.sup.7COOR.sup.5; OCONR.sup.5R.sup.6; CH.sub.2OR.sup.5; CH.sub.2NR.sup.5R.sup.6; CH.sub.2COR.sup.5; CH.sub.2COOR.sup.5; CH.sub.2CONR.sup.5R.sup.6; CH.sub.2C(═NR.sup.5)R.sup.6; CH.sub.2OCOR.sup.5; CH.sub.2NR.sup.7COR.sup.5; CH.sub.2NR.sup.7CONR.sup.5R.sup.6; CH.sub.2NR.sup.7COOR.sup.5; CH.sub.2OCONR.sup.5R.sup.6; CH.sub.2CH.sub.2NR.sup.5R.sup.6, an optionally substituted 5- or 6-membered ring containing 0, 1, 2 or 3 heteroatoms selected from O, N and S and oxidized forms thereof, or a C.sub.1-6 non-aromatic hydrocarbon group which is optionally substituted with one to six fluorine atoms or which is optionally substituted with a 5- or 6-membered ring containing 0, 1, 2 or 3 heteroatoms selected from O, N and S and oxidized forms thereof and wherein one or two, but not all, carbon atoms of the hydrocarbon group may optionally be replaced by a heteroatom selected from O, N and S and oxidized forms thereof; R.sup.4 is H or a C.sub.1-6 non-aromatic hydrocarbon group which is optionally substituted with one to six fluorine atoms and wherein one or two, but not all, carbon atoms of the hydrocarbon group may optionally be replaced by a heteroatom selected from O, N and S and oxidised forms thereof; and R.sup.5, R.sup.6 and R.sup.7 are the same or different and each is independently selected from hydrogen, a non-aromatic C.sub.1-6 hydrocarbon group optionally substituted with one or more fluorine atoms or optionally substituted with a 5- or 6-membered ring containing 0, 1, 2 or 3 heteroatoms selected from O, N and S and oxidized forms thereof, or R.sup.5 and R.sup.6 can be joined together to form an optionally substituted monocyclic or bicyclic ring containing 0, 1, 2 or 3 heteroatoms selected from O, N and S and oxidized forms thereof.

2. The compound according to claim 1 wherein R.sup.1 is selected from CH.sub.2CONR.sup.5R.sup.6; OCONR.sup.5R.sup.6 or a C.sub.1-6 non-aromatic hydrocarbon group which is substituted with a 5- or 6-membered ring containing 0, 1, 2 or 3 heteroatoms selected from O, N and S and oxidized forms thereof.

3. The compound according to claim 1 wherein R.sup.1 is selected from CH.sub.2CONR.sup.5R.sup.6 or OCONR.sup.5R.sup.6.

4. The compound according to any one of claims 1 to 3 wherein R.sup.5 is selected from C.sub.1-C.sub.3 alkyl or is joined to R.sup.6 to form a monocyclic or bicyclic ring containing 0, 1, 2 or 3 heteroatoms selected from O, N and S and oxidized forms thereof.

5. The compound according to any one of claims 1 to 4 wherein R.sup.6 is selected from C.sub.1-C.sub.3 alkyl or is joined to R.sup.5 to form a monocyclic or bicyclic ring containing 0, 1, 2 or 3 heteroatoms selected from O, N and S and oxidized forms thereof.

6. The compound according to any one of claims 1 to 5 wherein R.sup.5 and R.sup.6 are joined to form a 4 to 7 membered ring containing 0 or 1 oxygen atoms.

7. The compound according to any one of claims 1 to 6 wherein R.sup.1 is selected from ##STR00065##

8. The compound according to any one of claims 1 to 7 wherein R.sup.4 is selected from H, methyl, ethyl, ethynyl and 1-propynyl.

9. The compound according to any one of claims 1 to 8 wherein the bicyclic ring system formed by the moiety: ##STR00066## is selected from ring systems below: ##STR00067##

10. The compound according to any one of claims 1 to 9, wherein the compound is selected from: ##STR00068## ##STR00069## ##STR00070## ##STR00071##

11. The compound according to any one of claims 1 to 9, wherein the compound is selected from: Ethyl-3-(3-(2-(diethylamino)-2-oxoethyl)azetidin-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate; Ethyl-3-(3-(2-(ethyl(isopropyl)amino)-2-oxoethyl)azetidin-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate; Ethyl-3-(3-(2-oxo-2-(1-azaspiro[3.3]heptan-1-yl)ethyl)azetidin-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate; Ethyl-3-(3-(2-oxo-2-(piperidin-1-yl)ethyl)azetidin-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate; Ethyl-5-(3-(2-(diethylamino)-2-oxoethyl)azetidin-1-yl)-2-azabicyclo[2.2.2]octane-2-carboxylate; Ethyl-5-(3-(2-(ethyl(isopropyl)amino)-2-oxoethyl)azetidin-1-yl)-2-azabicyclo[2.2.2]octane-2-carboxylate; Ethyl-5-(3-(2-oxo-2-(piperidin-1-yl)ethyl)azetidin-1-yl)-2-azabicyclo[2.2.2]octane-2-carboxylate; Ethyl-5-(3-(2-(1,4-oxazepan-4-yl)-2-oxoethyl)azetidin-1-yl)-2-azabicyclo[2.2.2]octane-2-carboxylate; Ethyl-5-(3-(2-oxo-2-(1-azaspiro[3.3]heptan-1-yl)ethyl)azetidin-1-yl)-2-azabicyclo[2.2.2]octane-2-carboxylate; Ethyl-3-(3-(2-(diethylamino)-2-oxoethyl)azetidin-1-yl)-9-azabicyclo[3.3.1]nonane-9-carboxylate; Ethyl-3-(3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)azetidin-1-yl)-9-azabicyclo[3.3.1]nonane-9-carboxylate; Ethyl-3-(3-(2-oxo-2-(piperidin-1-yl)ethyl)azetidin-1-yl)-9-azabicyclo[3.3.1]nonane-9-carboxylate; Ethyl 6-(3-((diethylcarbamoyl)oxy)azetidin-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate; Ethyl 2-(3-((diethylcarbamoyl)oxy)azetidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate; 1-(6-(Ethoxycarbonyl)-6-azaspiro[3.4]octan-2-yl)azetidin-3-yl 1,4-oxazepane-4-carboxylate; Ethyl 6-(3-((ethyl(methyl)carbamoyl)oxy)azetidin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate; Ethyl 6-(3-((diethylcarbamoyl)oxy)azetidin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate; Methyl 6-(3-((diethylcarbamoyl)oxy)azetidin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate; Ethyl 6-(3-((pyrrolidine-1-carbonyl)oxy)azetidin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate; 1-(2-(Ethoxycarbonyl)-2-azaspiro[3.4]octan-6-yl)azetidin-3-yl morpholine-4-carboxylate; 1-(2-(Ethoxycarbonyl)-2-azaspiro[3.4]octan-6-yl)azetidin-3-yl 1,4-oxazepane-4-carboxylate; Ethyl 3-(3-((azepane-1-carbonyl)oxy)azetidin-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate; 1-(8-(Ethoxycarbonyl)-8-azabicyclo[3.2.1]octan-3-yl)azetidin-3-yl 1,4-oxazepane-4-carboxylate; Ethyl 5-(3-((diethylcarbamoyl)oxy)azetidin-1-yl)-2-azabicyclo[2.2.2]octane-2-carboxylate; Ethyl 5-(3-((pyrrolidine-1-carbonyl)oxy)azetidin-1-yl)-2-azabicyclo[2.2.2]octane-2-carboxylate; Ethyl 5-(3-((piperidine-1-carbonyl)oxy)azetidin-1-yl)-2-azabicyclo[2.2.2]octane-2-carboxylate; Ethyl 5-(3-((azepane-1-carbonyl)oxy)azetidin-1-yl)-2-azabicyclo[2.2.2]octane-2-carboxylate; 1-(2-(Ethoxycarbonyl)-2-azabicyclo[2.2.2]octan-5-yl)azetidin-3-yl 1,4-oxazepane-4-carboxylate; Ethyl 3-(3-((diethylcarbamoyl)oxy)azetidin-1-yl)-9-azabicyclo[3.3.1]nonane-9-carboxylate; Ethyl 7-(3-((azepane-1-carbonyl)oxy)azetidin-1-yl)-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate; or a salt thereof.

12. The compound according to any one of claims 1 to 11 for use in medicine.

13. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 11 and a pharmaceutically acceptable excipient.

14. The compound according to any one of claims 1 to 11 having muscarinic M.sub.1 and/or M.sub.4 receptor agonist activity.

15. The compound according to claims 1 to 11 for use in the treatment of a cognitive disorder or psychotic disorder or for the treatment or lessening the severity of acute, chronic, neuropathic, or inflammatory pain.

16. A compound according to claim 15 wherein the cognitive disorder is Alzheimers disease.

17. A compound according to claim 15 wherein the cognitive disorder is dementia with Lewy bodies.

Description

EXAMPLES

[0254] The invention will now be illustrated, but not limited, by reference to the specific embodiments described in the following examples.

Examples 1-1 to 8-1

[0255] The compounds of Examples 1-1 to 8-1 shown in Table 1 below have been prepared. Their NMR and LCMS properties and the methods used to prepare them are set out in Table 3. The starting materials for each of the Examples are listed in Table 2.

TABLE-US-00001 TABLE 1 [00025] Example 1-1 [00026] Example 1-2 [00027] Example 1-3 [00028] Example 1-4 [00029] Example 2-1 [00030] Example 2-2 [00031] Example 2-3 [00032] Example 2-4 [00033] Example 2-5 [00034] Example 3-1 [00035] Example 3-2 [00036] Example 3-3 [00037] Example 4-1 [00038] Example 4-2 [00039] Example 4-3 [00040] Example 4-4 [00041] Example 4-5 [00042] Example 4-6 [00043] Example 4-7 [00044] Example 4-8 [00045] Example 4-9 [00046] Example 5-1 [00047] Example 5-2 [00048] Example 6-1 [00049] Example 6-2 [00050] Example 6-3 [00051] Example 6-4 [00052] Example 6-5 [00053] Example 7-1 [00054] Example 8-1

[0256] General Procedures

[0257] 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.

[0258] 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.

[0259] LCMS Analysis

[0260] LCMS analysis of compounds was performed under electrospray conditions using the instruments and methods given in the tables below.

[0261] 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.

TABLE-US-00002 System ID Instrument Name LC Detector Mass Detector 1 Waters 2695 Photo Diode Array ZQ-2000 Detector 2 Waters Acquity H Class Photo Diode Array SQ Detector 3 Shimadzu Nexera Photo Diode Array LCMS-2020 4 Agilent 1290 RRLC Photo Diode Array Agilent 6120 with Agilent 6120 Mass detector

TABLE-US-00003 Column Flow Method Solvent Column UV Mass Temp. Rate Name System used Gradient Range Range ° C. ml/min A (A) 5 mM ammonium BEH C18 2.1 × 50 95:5 at 0.01 min up to 0.40 min, 200-400 100-1200 Ambient 0.55 acetate + 0.1% mm, 1.7 μm or 65:35 at 0.80 min, 45:55 at 1.20 nm amu formic acid in water equivalent min, 0:100 at 2.50 min up to 3.30 (B) 0.1% formic acid min, 95:5 at 3.31 min up to in acetonitrile 4.00 min B (A) 20 mM ammonium X-Bridge C18 4.6 × 90:10 at 0.01 min, 10:90 at 200-400  60-1000 Ambient 1.00 acetate in water 150 mm, 5 μm or 5.00 min, 0.100 at 7.00 nm amu (B) methanol equivalent min up to 11.00 min, 90:10 at 11:01 min up to 12.00 min C (A) 0.1% ammonia X-Bridge C18 4.6 × 95:5 at 0.01 min, 10:90 at 5.00 min, 200-400  60-1000 Ambient 1.00 in water 50 mm, 3.5 μm or 5:95 at 5.80 min up to 7.20 min, nm amu (B) 0.1% ammonia equivalent 95:5 at 7.21 min up to 10.00 min in acetonitril D (A) 5 mM ammonium BEH C18 2.1 × 95:5 at 0.01 min up to 0.40 min, 200-400 100-1200 Ambient 0.55 acetate + 0.1% formic 50 mm, 1.7 μm or 60:40 at 0.60 min, 40:60 at 1.20 nm amu acid in water equivalent min, 0:100 at 2.30 min up to 3.00 (B) 0.1% formic acid min, 95:5 at 3.01 min up to in acetonitril 3.50 min E (A) 5 mM ammonium X-Bridge C18 4.6 × 95:5 at 0.01 min, 10:90 at 5.00 min, 200-400  60-1000 Ambient 1.00 bicarbonate in water 50 mm, 3.5 μm or 5:95 at 5.80 min up to 7.20 min, nm amu (B) acetonitrile equivalent 95:5 at 7.21 min up to 10.00 min

[0262] Compound Purification

[0263] 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)].

[0264] Preparative HPLC purification:

[0265] Shimadzu LC-20AP and UV detector

[0266] Chiral HPLC purification:

[0267] Shimadzu LC-20AP binary system with SPD-20A UV detector

[0268] Chiral SFC purification:

[0269] Waters SFC 200

[0270] Purification Method A

[0271] Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×19 mm, 5 μm), 5 mL per min, gradient 40-65% (over 22 min), 65% (over 8 min), 100% (over 4 min), then 100-40% (over 6 min), mobile phase (A): 5 mM ammonium bicarbonate in water, (B) 100% acetonitrile]

[0272] Purification Method B

[0273] Prep HPLC: [Reversed phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 16 mL per min, gradient 20-60% (over 30 min), 100% (over 3 min), then 100-20% (over 2 min), mobile phase (A): 5 mM ammonium bicarbonate+0.05% ammonia in water, (B) 100% acetonitrile]

[0274] Purification Method C

[0275] Prep HPLC: [Reversed Phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 15 mL per min, gradient 30-55% (over 22 min), 100% (over 2 min), then 100-30% (over 3 min), mobile phase (A): 5 mM ammonium bicarbonate+0.1% ammonia in water, (B) 100% acetonitrile]

[0276] Purification Method D

[0277] Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×19 mm, 5 μm), 15 mL per min, gradient 35-45% (over 25 min), 100% (over 5 min), then 100-35% (over 1 min), mobile phase (A): 5 mM ammonium bicarbonate in water, (B) 100% acetonitrile]

[0278] Purification Method E

[0279] Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 9 mL per min, gradient 15-20% (over 10 min), 20-25% (over 70 min), 100% (over 4 min), then 100-15% (over 6 min), mobile phase (A): 5 mM ammonium bicarbonate in water, (B) 100% acetonitrile]

[0280] Purification Method F

[0281] Prep HPLC: [Reversed Phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 15 mL per min, gradient 28% (over 24 min), 100% (over 3 min), then 100-28% (over 4 min), mobile (A): 5 mM ammonium bicarbonate in water, (B) 100% acetonitrile]

[0282] Purification Method G

[0283] Prep HPLC: [Reversed phase (X-BRIDGE C-18, 250×19 mm, 5 μm), 17 mL per min, gradient 20% (over 75 min), 100% (over 5 min), then 100-20% (over 5 min), mobile phase (A): 5 mM ammonium bicarbonate in water, (B) 100% acetonitrile]

[0284] Purification Method H

[0285] Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 15 mL per min, gradient 0-30% (over 25 min), 100% (over 2 min), then 100-0% (over 3 min), mobile phase (A): 5 mM ammonium bicarbonate+0.1% ammonia in water, (B) 100% acetonitrile]

[0286] Purification Method I

[0287] Prep HPLC: [Reversed Phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 15 mL per min, gradient 23-27% (over 20 min), 27% (over 25 min), 27-100% (over 15 min), 100 15% (over 1 min), then 100-23% (over 2 min), mobile phase (A): 5 mM ammonium bicarbonate+0.1% ammonia in water, (B) 100% acetonitrile]

[0288] Purification Method J

[0289] Prep HPLC: [Reversed phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 17 mL per min, gradient 20-55% (over 16 min), 100% (over 3 min), then 100-20% (over 3 min), mobile phase (A): 5 mM ammonium bicarbonate+0.05% ammonia in water, (B) 100% acetonitrile]

[0290] Purification Method K

[0291] Prep HPLC: [Reversed phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 17 mL per min, gradient 20-30% (over 40 min), 100% (over 4 min), then 100-20% (over 6 min), mobile phase (A): 5 mM ammonium bicarbonate+0.05% ammonia in water, (B) 100% acetonitrile]

[0292] Purification Method L

[0293] Prep HPLC: [Reversed phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 17 mL per min, gradient 23-33% (over 20 min), 33% (over 15 min), 100% (over 4 min), then 100-23% (over 4 min), mobile phase (A): 5 mM ammonium bicarbonate+0.05% ammonia in water, (B) 100% acetonitrile]

[0294] Purification Method M

[0295] Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×19 mm, 5 μm), 17 mL per min, gradient 28-34% (over 25 min), 100% (over 2 min), then 100-28% (over 3 min), mobile phase (A): 5 mM ammonium bicarbonate+0.05% ammonia in water, (B) 100 40% acetonitrile]

[0296] Purification Method N

[0297] Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×19 mm, 5 μm), 16 mL per min, gradient 10-26% (over 20 min), 26-29% (over 33 min), 29% (over 23 min), 100% 45 (over 3 min), then 100-10% (over 6 min), mobile phase (A): 5 mM ammonium bicarbonate+0.1% ammonia in water, (B) 100% acetonitrile]

[0298] Purification Method O

[0299] Prep HPLC: [Reversed Phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 15 mL per min, 50 gradient 10-50% (over 28 min), 50% (over 4 min), 100% (over 2 min), then 100-10% (over 3 min), mobile phase (A): 5 mM ammonium bicarbonate+0.1% ammonia in water, (B):acetonitrile:methanol (50:50)]

[0300] Purification Method P

[0301] Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×19 mm, 5 μm), 15 mL per min, gradient 15-30% (over 30 min), 30% (over 5 min), 100% (over 2 min), then 100-15% (over 3 min), mobile phase (A): 5 mM ammonium acetate in water, (B) 100% acetonitrile]

[0302] Purification Method Q

[0303] SFC: [(CHIRALCEL OX—H, 250×21 mm, 5 μm), 70 mL per min, Isocratic (A:B) (80:20) (over 10 min), mobile phase (A): 100% liquid CO.sub.2, (B): 0.1% diethylamine in isopropanol]

[0304] Purification Method R

[0305] Prep HPLC: [Reversed phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 17 mL per min, gradient 0% (over 3 min), 0-50% (over 30 min), 100% (over 2 min), then 100-0% (over 2 min), mobile phase (A): 5 mM ammonium bicarbonate+0.1% ammonia in water, (B) 100% acetonitrile]

[0306] Purification Method S

[0307] SFC: [(CHIRALCEL OX—H, 250×21 mm, 5 μm), 70 mL per min, Isocratic (A:B) (85:15) (over 10 min), mobile phase (A): 100% liquid CO.sub.2, (B): 0.1% diethylamine in methanol]

[0308] Purification Method T

[0309] Prep HPLC: [Reversed Phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 15 mL per min, gradient 10-40% (over 18 min), 40% (over 5 min), 100% (over 2 min), then 100-10% (over 3 min), mobile phase (A): 10 mM ammonium acetate in water, (B) 100% acetonitrile]

[0310] Purification Method U

[0311] Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 15 mL per min, gradient 0-60% (over 25 min), 100% (over 2 min), then 100-0% (over 3 min), mobile phase (A): 5 mM ammonium bicarbonate+0.1% ammonia in water, (B) 100% acetonitrile]

[0312] Purification Method V

[0313] Chiral HPLC: [Normal Phase (CHIRALCEL OX—H, 250×21 mm, 5 μm), 18 mL per min, Isocratic (A:B) (60:40) (over 25 min), mobile phase (A): 0.1% diethylamine in hexane, (B): 0.1% diethylamine in isopropanol]

[0314] Purification Method W

[0315] Prep HPLC: [Reversed phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 16 mL per min, gradient 20-30% (over 18 min), 30% (over 4 min), 100% (over 2 min), then 100-20% (over 3 min), mobile phase (A): 5 mM ammonium bicarbonate+0.1% ammonia in water, (B) 100% acetonitrile]

[0316] Purification Method X

[0317] SFC: [(CHIRALCEL OX—H, 250×21 mm, 5 μm), 70 mL per min, Isocratic (A:B) (85:15) (over 14 min), mobile phase (A): 100% liquid CO.sub.2, (B): 0.1% diethylamine in isopropanol]

[0318] Purification Method Y

[0319] Prep HPLC: [Reversed Phase (PHENOMENEX LUNA C-18, 250×21.2 mm, 5 μm), 16 mL per min, gradient 15-45% (over 25 min), 100% (over 2 min), then 100-15% (over 3 min), mobile phase (A): 10 mM ammonium acetate in water, (B) 100% acetonitrile]

[0320] Purification Method Z

[0321] Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 16 mL per min, gradient 30-55% (over 30 min), 55% (over 3 min), 100% (over 2 min), then 100-30% (over 2 min), mobile phase (A): 5 mM ammonium bicarbonate+0.1% ammonia in water, (B) 100% acetonitrile]

[0322] Purification Method AA

[0323] Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×19 mm, 5 μm), 15 mL per min, gradient 15-58% (over 23 min), 100% (over 2 min), then 100-15% (over 2 min), mobile phase (A): 5 mM ammonium bicarbonate+0.1% ammonia in water, (B) 100% acetonitrile]

[0324] Purification Method AB

[0325] Prep HPLC: [Reversed phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 18 mL per min, gradient 25-56% (over 20 min), 100% (over 2 min), then 100-25% (over 3 min), mobile phase (A): 5 mM ammonium bicarbonate+0.05% ammonia in water, (B) 100 20% acetonitrile]

[0326] Purification Method AC

[0327] Prep HPLC: [Reversed phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 16 mL per min, gradient 10-45% (over 16 min), 45% (over 6 min), 100% (over 2 min), then 100-10% (over 4 min), mobile phase (A): 5 mM ammonium bicarbonate in water, (B) 100% acetonitrile]

[0328] Purification Method AD

[0329] Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×19 mm, 5 μm), 16 mL per min, gradient 30-42% (over 18 min), 42% (over 10 min), 100% (over 2 min), then 100-30% (over 3 min), mobile phase (A): 5 mM ammonium bicarbonate+0.05% ammonia in water, (B) 100% acetonitrile]

[0330] Purification Method AE

[0331] Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 15 mL per min, gradient 5-25% (over 20 min), 100% (over 2 min), then 100-5% (over 3 min), mobile phase (A): 0.1% formic acid in water, (B) 100% acetonitrile]

[0332] Purification Method AF

[0333] Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×19 mm, 5 μm), 13 mL per min, gradient 10-50% (over 22 min), 100% (over 3 min), then 100-10% (over 5 min), mobile phase (A): 10 mM ammonium acetate in water, (B) 100% acetonitrile]

[0334] Purification Method AG

[0335] Prep HPLC: [Reversed phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 16 mL per min, gradient 32% (over 50 min), 100% (over 3 min), then 100-32% (over 3 min), mobile phase (A): 5 mM ammonium bicarbonate+0.05% ammonia in water, (B) 100% acetonitrile]

[0336] Purification Method AH

[0337] Prep HPLC: [Reversed Phase (SUNFIRE C-18, 250×19 mm, 5 μm), 13 mL per min, gradient 0-17% (over 25 min), 17% (over 7 min), 100% (over 2 min), then 100-0% (over 3 min), mobile phase (A): 0.1% formic acid in water, (B) 100% acetonitrile]

Abbreviations

[0338] DCM=dichloromethane

[0339] ES(I)=electro spray ionisation

[0340] EtOAc=ethyl acetate

[0341] h=hour(s)

[0342] H.sub.2O=water

[0343] HCl=hydrogen chloride, hydrochloric acid

[0344] HPLC=high performance liquid chromatography

[0345] IPA=propan-2-ol

[0346] LC=liquid chromatography

[0347] MeOH=methanol

[0348] min(s)=minute(s)

[0349] MS=mass spectrometry

[0350] nm=nanometre(s)

[0351] NMR=nuclear magnetic resonance

[0352] SFC=supercritical fluid chromatography

[0353] TEA=triethylamine

[0354] TFA=trifluoroacetic acid

[0355] TLC=thin layer chromatography

[0356] Prefixes n-, s-, i-, t- and tert- have their usual meanings: normal, secondary, iso, and tertiary.

[0357] Synthesis of Intermediates:

[0358] Route 1

[0359] Typical Procedure for the Preparation of Esters, as Exemplified by the Preparation of Intermediate 3, ethyl-3-(3-(2-methoxy-2-oxoethyl)azetidin-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate

##STR00055##

[0360] tert-Butyl 3-(2-methoxy-2-oxoethyl)azetidine-1-carboxylate (Intermediate 1) (150 mg, 0.66 mmol) was dissolved in DCM (5 mL) and cooled to 0° C. To this was added TFA (1 mL) drop-wise and the resulting reaction mixture was stirred at room temperature for 5 h. Solvents were removed in vacuo and the residue was purified by trituration with diethyl ether (3×1 mL) to give methyl 2-(azetidin-3-yl)acetate trifluoroacetate (110 mg, >100%) as a gum.

[0361] LCMS (System 1, Method C): m/z 130 (M+H).sup.+ (ESI +ve), at 2.37 min, 202 nm.

[0362] Methyl 2-(azetidin-3-yl)acetate trifluoroacetate (200 mg, 1.55 mmol), ethyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (Intermediate 2) (305 mg, 1.55 mmol), TEA (0.7 mL, 4.65 mmol) and ZnCl.sub.2 (21 mg, 0.16 mmol) were dissolved in MeOH (10 mL) and the reaction mixture was stirred at 65° C. for 8 h. The reaction was then cooled to 0° C. and to this was then added NaBH.sub.3CN (293 mg, 4.65 mmol) portion wise. The resulting reaction mixture was stirred at 60° C. for 30 h. The solvents were removed in vacuo and the residue was partitioned between H.sub.2O (100 mL) and EtOAc (80 mL), extracting the aqueous layer further with EtOAc (2×80 mL). The combined organic phases were dried (Na.sub.2SO.sub.4), concentrated in vacuo and the residue was purified by column chromatography (normal phase neutral activated alumina, 50% to 60% EtOAc in hexane) to give ethyl-3-(3-(2-methoxy-2-oxoethyl)azetidin-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (Intermediate 3) (140 mg, 29%) as a gum.

[0363] The data for Intermediate 3 are in Table 2.

[0364] Route 2

[0365] Typical Procedure for the Preparation of Ketones, as Exemplified by the Preparation of Intermediate 8, ethyl 5-oxo-2-azabicyclo[2.2.2]octane-2-carboxylate

##STR00056##

[0366] A solution of tert-butyl 5-oxo-2-azabicyclo[2.2.2]octane-2-carboxylate (Intermediate 12) (550 mg, 2.44 mmol) and TFA (2.50 mL) in DCM (5 mL) was stirred under nitrogen at room temperature for 3 h. The reaction mixture was concentrated in vacuo and the residue co-evaporated from diethyl ether (2×5 mL) and toluene (2×10 mL) to give 2-azabicyclo[2.2.2]octan-5-one trifluoroacetate (280 mg, 92%) as a gum.

[0367] LCMS (System 1, Method C): m/z 126 (M+H).sup.+ (ESI +ve), at 1.41 min, 202 nm.

[0368] A solution of 2-azabicyclo[2.2.2]octan-5-one trifluoroacetate (275 mg, 2.20 mmol) and TEA (0.92 mL, 6.59 mmol) in DCM (10 mL) was stirred at 0° C. under nitrogen for 10 min. To this was then added ethyl carbonochloridate (Intermediate 13) (356 mg, 3.30 mmol) drop-wise at 0° C. to 10° C. and the reaction was then allowed to warm to room temperature and stirred for 2 h. The reaction mixture was partitioned between H.sub.2O (20 mL) and EtOAc (15 mL) and the aqueous layer was further extracted with EtOAc (2×15 mL). The combined organic phases were dried (Na.sub.2SO.sub.4), concentrated in vacuo and the residue was purified by column chromatography (normal phase silica, 0% to 2% MeOH in DCM) to give ethyl 5-oxo-2-azabicyclo[2.2.2]octane-2-carboxylate (Intermediate 8) (308 mg, 71%) as a gum.

[0369] The data for Intermediate 8 are in Table 2.

[0370] Route 3

[0371] Typical Procedure for the Preparation of Carbamates, as Exemplified by the Preparation of Intermediate 20, azetidin-3-yl diethylcarbamate trifluoroacetate

##STR00057##

[0372] To a stirred solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (Intermediate 18) (3.0 g, 17.3 mmol) in DCM (90 mL) was added TEA (12.5 mL, 86.7 mmol). The reaction was stirred at room temperature for 15 min and then cooled to 0° C. To this was then added portion wise 4-nitrophenyl carbonochloridate (Intermediate 19) (12.2 g, 60.7 mmol) and the reaction was then allowed to warm to room temperature and stirred for 4 h. To this was then added diethylamine (Intermediate 4) (4.4 mL, 60.7 mmol) and the reaction was stirred at room temperature for 16 h. The reaction mixture was partitioned between H.sub.2O (30 mL) and DCM (50 mL). The organic phases were concentrated in vacuo and the residue was purified by column chromatography (neutral alumina, EtOAc in hexane) to give tert-butyl 3-((diethylcarbamoyl)oxy)azetidine-1-carboxylate (3.6 g, 74%) as a gum.

[0373] LCMS (System 2, Method D): m/z 273 (M+H).sup.+ (ESI +ve), at 1.99 min, 202 nm.

[0374] To the stirred solution of tert-butyl 3-((diethylcarbamoyl)oxy)azetidine-1-carboxylate (1.0 g, 3.7 mmol) in DCM (15 mL) at 0° C. was added TFA (5 mL) drop-wise. The reaction was warmed to room temperature and stirred for 3 h. The reaction mixture was concentrated in vacuo and co-evaporated from toluene (×3) to give azetidin-3-yl diethylcarbamate trifluoracetate (Intermediate 20) (500 mg, 80%) as a gum.

[0375] The data for Intermediate 20 are in Table 2.

[0376] Route 4

[0377] Typical Procedure for the Preparation of Carbamates, as Exemplified by the Preparation of Intermediate 23, azetidin-3-yl 1,4-oxazepane-4-carboxylate hydrochloride

##STR00058##

[0378] To a stirred solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (Intermediate 18) (400 mg, 2.31 mmol) in DCM (20 mL) was added TEA (1.6 mL, 11.6 mmol). The reaction was stirred at room temperature for 15 min and then cooled to 0° C. To this was then added portion wise 4-nitrophenyl carbonochloridate (Intermediate 19) (1.6 g, 8.09 mmol) and the reaction was then warmed to room temperature and stirred for 4 h.

[0379] To this was then added 1,4-oxazepane (Intermediate 10) (310 mg, 2.31 mmol) and the reaction was stirred at room temperature for 16 h. The reaction mixture was partitioned between H.sub.2O (5 mL) and DCM (20 mL). The organics were dried (Na.sub.2SO.sub.4), concentrated in vacuo and the residue was purified by column chromatography (neutral alumina, EtOAc in hexane) to give 1-(tert-butoxycarbonyl)azetidin-3-yl 1,4-oxazepane-4-carboxylate (200 mg, 28%) as a gum.

[0380] LCMS (System 3, Method E): m/z 301 (M+H).sup.+ (ESI +ve), at 3.37 min, 202 nm.

[0381] To the stirred solution of 1-(tert-butoxycarbonyl)azetidin-3-yl 1,4-oxazepane-4-carboxylate (400 mg 1.33 mmol) in 1,4-dioxane (5 ml) at 0° C. was added HCl solution in 1,4-dioxane (4 M, 5 mL, 20 mmol) drop-wise. The reaction was warmed to room temperature and stirred for 3 h. The reaction mixture was concentrated in vacuo and triturated with diethyl ether and pentane to give azetidin-3-yl 1,4-oxazepane-4-carboxylate hydrochloride (Intermediate 23) (200 mg, 75%) as a gum.

[0382] The data for Intermediate 23 are in Table 2.

[0383] Route 5

[0384] Typical Procedure for the Preparation of Alcohols, as Exemplified by the Preparation of Intermediate 34, ethyl 5-(3-hydroxyazetidin-1-yl)-2-azabicyclo[2.2.2]octane-2-carboxylate

##STR00059##

[0385] To a solution of azetidin-3-ol hydrochloride (Intermediate 33) (500 mg, 4.59 mmol) and TEA (3.18 mL, 22.9 mmol) in MeOH (10 mL) were added ethyl 5-oxo-2-azabicyclo[2.2.2]octane-2-carboxylate (Intermediate 8) followed by ZnCl.sub.2 solution in diethyl ether (1 M, 0.23 mL, 0.23 mmol). The reaction mixture was stirred at 80° C. for 5 h and then cooled to 0° C. NaBH.sub.3CN (853 mg, 13.7 mmol) was added and the reaction was warmed to room temperature and stirred for 18 h. The reaction mixture was partitioned between H.sub.2O (150 mL) and EtOAc (40 mL). The aqueous layer was further extracted with EtOAc (2×40 mL) and the combined organic phases were dried (Na.sub.2SO.sub.4), concentrated in vacuo and the residue was purified by column chromatography (neutral alumina, 0 to 4% MeOH in DCM) to give ethyl 5-(3-hydroxyazetidin-1-yl)-2-azabicyclo[2.2.2]octane-2-carboxylate (Intermediate 34) (400 mg, 34%) as a liquid.

[0386] The data for Intermediate 34 are in Table 2.

[0387] General Synthetic Procedures:

[0388] Route A

[0389] Typical procedure for the preparation of amides as exemplified by the preparation of Example 1-1, ethyl-3-(3-(2-(diethylamino)-2-oxoethyl)azetidin-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate

##STR00060##

[0390] To a solution of diethylamine (Intermediate 4) (99 mg, 1.35 mmol) in toluene (10 mL) was added TEA (0.2 mL, 1.35 mmol). The reaction was then cooled to −10° C. and to this was then added trimethylaluminum solution in toluene (2.0 M, 0.7 mL, 1.35 mmol) and the reaction mixture was stirred at −10° C. to 0° C. for 20 mins followed by the addition of ethyl-3-(3-(2-methoxy-2-oxoethyl)azetidin-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (Intermediate 3) (140 mg, 0.45 mmol) at −10° C. The resulting reaction mixture was then stirred at 80° C. for 50 h. The solvents were removed in vacuo and the residue was partitioned between H.sub.2O (10 mL) and DCM (80 mL), further extracting the aqueous layer with DCM (2×80 mL). The combined organic phases were dried (Na.sub.2SO.sub.4), concentrated in vacuo and the residue was purified by purification method A to give ethyl-3-(3-(2-(diethylamino)-2-oxoethyl)azetidin-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate, Example 1-1 Isomer 1 (4 mg, 3%) as a yellow gum and ethyl-3-(3-(2-(diethylamino)-2-oxoethyl)azetidin-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate, Example 1-1 Isomer 2 (47 mg, 30%) as a gum.

[0391] The data for Example 1-1 Isomer 2 are in Table 3.

[0392] Route B

[0393] Typical Procedure for the Preparation of Amines as Exemplified by the Preparation of Example 4-1, ethyl 6-(3-((diethylcarbamoyl)oxy)azetidin-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

##STR00061##

[0394] A solution of azetidin-3-yl diethylcarbamate trifluoroacetate (Intermediate 20) (200 mg, 1.16 mmol) and TEA (0.5 mL, 3.49 mmol) in MeOH (2 mL) was stirred at room temperature for 15 min. To this was then added ethyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate 21) (160 mg, 0.87 mmol), followed by a solution of ZnCl.sub.2 in diethyl ether (1 M, 0.6 mL, 0.060 mmol). The reaction was stirred at 90° C. for 4 h and then cooled to 0° C. before the portion wise addition of NaBH.sub.3CN (146 mg, 2.32 mmol). The resulting reaction mixture was stirred at 90° C. for 16 h. The solvents were removed in vacuo and the residue was partitioned between H.sub.2O (200 mL) and EtOAc (200 mL), extracting the aqueous layer further with EtOAc (2×200 mL). The combined organic phases were dried (Na.sub.2SO.sub.4), concentrated in vacuo and the residue was purified by purification method M to give ethyl 6-(3-((diethylcarbamoyl)oxy)azetidin-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate, Example 4-1 (35 mg, 9%) as a colourless gum.

[0395] The data for Example 4-1 are in Table 3.

[0396] Route C

[0397] Typical Procedure for the Preparation of Carbamates as Exemplified by the Preparation of Example 6-1, ethyl 5-(3-((diethylcarbamoyl)oxy)azetidin-1-yl)-2-azabicyclo[2.2.2]octane-2-carboxylate

##STR00062##

[0398] To a solution of ethyl 5-(3-hydroxyazetidin-1-yl)-2-azabicyclo[2.2.2]octane-2-carboxylate (Intermediate 34) (100 mg, 0.39 mmol) in DCM (5 mL) at 0° C. were added TEA (0.1 mL, 1.18 mmol) followed by 4-nitrophenyl carbonochloridate (Intermediate 19) (94 mg, 0.47 mmol). The reaction mixture was stirred at 0° C. for 5 h. To this was then added diethylamine (Intermediate 4) (0.1 mL, 0.79 mmol) and the reaction was stirred at room temperature for 16 h. The reaction was partitioned between H.sub.2O (150 mL) and EtOAc (40 mL). The aqueous layer was further extracted with EtOAc (2×40 mL) and the combined organic phases were dried (Na.sub.2SO.sub.4), concentrated in vacuo and the residue was purified by purification method B1 to give ethyl-5-(3-((diethylcarbamoyl)oxy)azetidin-1-yl)-2-azabicyclo[2.2.2]octane-2-carboxylate, Example 6-1 Isomer 1 (28 mg, 20%) as a colourless gum and ethyl-5-(3-((diethylcarbamoyl)oxy)azetidin-1-yl)-2-azabicyclo[2.2.2]octane-2-carboxylate, Example 6-1 Isomer 2 (13 mg, 9%) as a colourless gum.

[0399] The data for Example 6-1 Isomer 1 are in Table 3.

TABLE-US-00004 TABLE 2 Starting Materials and Intermediates Intermediate Synthetic Intermediates Number Name Route Used Data 1 tert-Butyl 3-(2-methoxy-2- — — Commercially available, oxoethyl)azetidine-1- CAS: 497160-14-2 carboxylate 2 Ethyl 3-oxo-8- — — Commercially available, azabicyclo[3.2.1]octane-8- CAS: 32499-64-2 carboxylate 3 Ethyl-3-(3-(2-methoxy-2- 1 1 and 2 LCMS (System 1, Method oxoethyl)azetidin-1-yl)-8- C): m/z 311 (M + H).sup.+ (ESI azabicyclo[3.2.1]octane-8- +ve), at 4.85 min, 202 nm carboxylate 4 Diethylamine — — Commercially available, CAS: 109-89-7 5 N-Ethylpropan-2-amine — — Commercially available, CAS: 19961-27-4 6 1-Azaspiro[3.3]heptane — — Commercially available, oxalate CAS: 1706457-37-5 7 Piperidine — — Commercially available, CAS: 110-89-4 8 Ethyl 5-oxo-2- 2 12 and 13 LCMS (System 1, Method azabicyclo[2.2.2]octane-2- C): m/z 198 (M + H).sup.+ (ESI carboxylate +ve), at 3.06 min, 202 nm Commercially available, CAS: 37778-51-1 9 Ethyl-5-(3-(2-methoxy-2- 1 1 and 8 LCMS (System 1, Method oxoethyl)azetidin-1-yl)-2- C): m/z 311 (M + H).sup.+ (ESI azabicyclo[2.2.2]octane-2- +ve), at 3.68 min and 3.93 carboxylate min, 202 nm 10 1,4-Oxazepane — — Commercially available, CAS: 5638-60-8 11 1-Azaspiro[3.3]heptane — — Commercially available, hydrochloride CAS: 1986337-29-4 12 tert-Butyl 5-oxo-2- — — Commercially available, azabicyclo[2.2.2]octane-2- CAS: 617714-22-4 carboxylate 13 Ethyl carbonochloridate — — Commercially available, CAS: 541-41-3 14 Ethyl 3-oxo-9- 2 13 and 17 LCMS (System 1, Method azabicyclo[3.3.1]nonane-9- C): m/z 212 (M + H).sup.+ (ESI carboxylate +ve), at 3.51 min, 202 nm Commercially available, CAS: 72761-58-1 15 Ethyl-3-(3-(2-methoxy-2- 1  1 and 14 LCMS (System 1, Method oxoethyl)azetidin-1-yl)-9- C): m/z 325 (M + H).sup.+ (ESI azabicyclo[3.3.1]nonane-9- +ve), at 3.97 min, 202 nm carboxylate 16 Pyrrolidine — — Commercially available, CAS: 123-75-1 17 tert-Butyl 3-oxo-9- — — Commercially available, azabicyclo[3.3.1]nonane-9- CAS: 512822-27-4 carboxylate 18 tert-Butyl 3- — — Commercially available, hydroxyazetidine-1- CAS: 141699-55-0 carboxylate 19 4-Nitrophenyl — — Commercially available, carbonochloridate CAS: 7693-46-1 20 Azetidin-3-yl 3 4, 18 and 19 LCMS (System 1, Method diethylcarbamate E): m/z 173 (M + H).sup.+ (ESI trifluoroacetate +ve), at 2.14 min, 202 nm 21 Ethyl 6-oxo-2- — — As prepared in WO azaspiro[3.3]heptane-2- 2017021728 carboxylate CAS: 2011798-96-0 22 Ethyl 2-oxo-6- — — As prepared in WO azaspiro[3.4]octane-6- 2017021729 carboxylate CAS: 1803350-92-6 23 Azetidin-3-yl 1,4- 4 10, 18 and 19 LCMS (System 3, Method oxazepane-4-carboxylate E): m/z 201 (M + H).sup.+ (ESI hydrochloride +ve), at 0.71 min, 202 nm 24 Ethyl 6-oxo-2- — — As prepared in WO azaspiro[3.4]octane-2- 2017021728 carboxylate CAS: 2011798-97-1 25 Azetidin-3-yl 3 18, 19 and 26 LCMS (System 4, Method ethyl(methyl)carbamate B): m/z 159 (M + H).sup.+ (ESI trifluoroacetate +ve), at 2.95 min, 202 nm 26 N-Methylethanamine — — Commercially available, CAS: 624-78-2 27 Methyl 6-oxo-2- — — As prepared in WO azaspiro[3.4]octane-2- 2017021728 carboxylate CAS: 2077964-94-2 28 Azetidin-3-yl pyrrolidine-1- 4 16, 18 and 19 LCMS (System 2, Method carboxylate hydrochloride D): m/z 171 (M + H).sup.+ (ESI +ve), at 0.50 min, 202 nm 29 Morpholine — — Commercially available, CAS: 110-91-8 30 Azetidin-3-yl morpholine-4- 3 18, 19 and 29 LCMS (System 4, Method carboxylate trifluoroacetate B): m/z 187 (M + H).sup.+ (ESI +ve), at 2.37 min, 202 nm 31 Azepane — — Commercially available, CAS: 111-49-9 32 Azetidin-3-yl azepane-1- 3 18, 19 and 31 LCMS (System 3, Method carboxylate trifluoroacetate E): m/z 199 (M + H).sup.+ (ESI +ve), at 2.48 min, 202 nm 33 Azetidin-3-ol hydrochloride — — Commercially available, CAS: 18621-18-6 34 Ethyl 5-(3-hydroxyazetidin- 5 8 and 33 LCMS (System 1, Method 1-yl)-2- E): m/z 255 (M + H).sup.+ (ESI azabicyclo[2.2.2]octane-2- +ve), at 2.47, 2.64 min, 202 carboxylate nm 35 tert-Butyl 7-oxo-3-oxa-9- — — Commercially available, azabicyclo[3.3.1]nonane-9- CAS: 280761-97-9 carboxylate 36 Ethyl 7-oxo-3-oxa-9- 2 13 and 35 LCMS (System 2, Method azabicyclo[3.3.1]nonane-9- A): m/z 214 (M + H).sup.+ (ESI carboxylate +ve), at 1.53 min, 202 nm

TABLE-US-00005 TABLE 3 NMR and LCMS properties and the methods used to prepare and purify compunds represented by Examples 1-1 to 8-1 LCMS Synthetic Method System Ex. and Intermediates Purification and LCMS No. Name Used Method .sup.1H NMR Method data 1-1 Isomer 2: Ethyl-3-(3-(2- A A .sup.1H NMR (400 MHz, Methanol-δ4) δ 1 m/z 352 (diethylamino)-2-oxoethyl) 3 and 4 1.06-1.14 (m, 3H), 1.17-1.29 (m, 6H), C (M + H).sup.+ azetidin-1-yl)-8-azabicyclo 1.51-1.55 (m, 1H), 1.56-1.60 (m, 1H), (ES.sup.+), at [3.2.1]octane-8-carboxylate 1.68-1.82 (m, 2H), 1.82-1.96 (m, 2H), 4.49 min, 2.06-2.20 (m, 2H), 2.37-2.47 (m, 1H), 210 nm 2.55-2.69 (m, 4H), 2.69-2.79 (m, 2H), 3.33-3.44 (m, 5H), 3.99-4.26 (m, 4H) 1-2 Isomer mixture: Ethyl-3-(3- A B .sup.1H NMR (400 MHz, Methanol-δ4) δ 3 m/z 366 (2-(ethyl(isopropyl)amino)- 3 and 5 1.07-1.28 (m, 12H), 1.50-1.60 (m, 2H), E (M + H).sup.+ 2-oxoethyl)azetidin-1-yl)- 1.64-1.81 (m, 2H), 1.82-1.95 (m, 2H), (ES.sup.+), at 8-azabicyclo[3.2.1]octane- 2.01-2.19 (m, 2H), 2.35-2.47 (m, 1H), 4.09 min, 8-carboxylate 2.55-2.79 (m, 5H), 4.05-4.67 (m, 4H) 202 nm Five protons obscured by solvent peaks 1-3 Isomer 2: Ethyl-3-(3-(2-oxo- A C .sup.1H NMR (400 MHz, Methanol-δ4) δ 3 m/z 376 2-(1-azaspiro[3.3]heptan-1- 3 and 6 1.17-1.31 (m, 3H), 1.49-1.61 (m, 2H), E (M + H).sup.+ yl)ethyl)azetidin-1-yl)-8- 1.64-1.93 (m, 6H), 1.96-2.21 (m, 4H), (ES.sup.+), at azabicyclo[3.2.1]octane-8- 2.22-2.49 (m, 5H), 2.52-2.78 (m, 3H), 4.10 min, carboxylate 2.79-3.01 (m, 2H), 3.19-3.31 (m, 2H), 202 nm 3.73-4.06 (m, 2H), 4.06-4.20 (m, 4H) 1-4 Isomer mixture: Ethyl-3-(3- A D .sup.1H NMR (400 MHz, Methonal-δ4) δ 1 m/z 364 (2-oxo-2-(piperidin-1-yl)ethyl) 3 and 7 1.20-1.28 (m, 3H), 1.45-1.81 (m, 9H), C (M + H).sup.+ azetidin-1-yl)-8-azabicyclo 1.82-1.96 (m, 2H), 2.06-2.20 (m, 2H), (ES.sup.+), at [3.2.1]octane-8-carboxylate 2.31-2.48 (m, 1H), 2.55-2.91 (m, 5H), 5.02 min, 3.34-3.38 (m, 1H), 3.45-3.62 (m, 3H), 210 nm 4.01-4.50 (m, 4H) Three protons obscured by solvent peaks 2-1 Isomer 1: Ethyl-5-(3-(2- A E .sup.1H NMR (400 MHz, Methanol-δ4) δ 1 m/z 352 (diethylamino)-2-oxoethyl) 4 and 9 1.02-1.32 (m, 11H), 1.37-1.53 (m, 1H), C (M + H).sup.+ azetidin-1-yl)-2-azabicyclo 1.59-2.06 (m, 5H), 2.49-2.73 (m, 3H), (ES.sup.+), at [2.2.2]octane-2-carboxylate 2.77-2.92 (m, 2H), 3.22-3.29 (m, 1H), 3.62 min, 3.33-3.50 (m, 5H), 3.52-3.72 (m, 2H), 202 nm 3.88-4.01 (m, 1H), 4.04-4.18 (m, 2H) 2-2 Isomer 1: Ethyl-5-(3-(2-(ethyl A F .sup.1H NMR (400 MHz, Methanol-δ4) δ 1 m/z 366 (isopropyl)amino)-2-oxoethyl) 5 and 9 1.02-1.33 (m, 14H), 1.36-2.06 (m, 5H), C (M + H).sup.+ azetidin-1-yl)-2-azabicyclo 2.50-2.61 (m, 1H), 2.62-2.73 (m, 2H), (ES.sup.+), at [2.2.2]octane-2-carboxylate 2.75-2.95 (m, 3H), 3.19-3.30 (m, 2H), 4.01 min, 3.33-3.51 (m, 3H), 3.52-3.66 (m, 1H), 210 nm 3.90-4.02 (m, 1H), 4.05-4.61 (m, 2H) One proton obscured by solvent peaks 2-2 Isomer 2: Ethyl-5-(3-(2-(ethyl A F .sup.1H NMR (400 MHz, Methanol-δ4) δ 1 m/z 366 (isopropyl)amino)-2-oxoethyl) 5 and 9 1.02-1.32 (m, 13H), 1.34-1.49 (m, 1H), C (M + H).sup.+ azetidin-1-yl)-2-azabicyclo 1.51-2.02 (m, 6H), 2.46-2.60 (m, 1H), (ES.sup.+), at [2.2.2]octane-2-carboxylate 2.62-2.94 (m, 5H), 3.12-3.27 (m, 2H) 4.27 min, 3.38-3.66 (m, 3H), 3.90-4.02 (m, 1H) 210 nm 4.04-4.62 (m, 3H) 2-3 Isomer 1: Ethyl-5-(3-(2-oxo- A G .sup.1H NMR (400 MHz, Methanol-δ4) δ 1 m/z 364 2-(piperidin-1-yl)ethyl)azetidin- 7 and 9 1.20-1.30 (m, 6H), 1.39-1.94 (m, 12H), E (M + H).sup.+ 1-yl)-2-azabicyclo[2.2.2] 2.10-2.52 (m, 2H), 2.56-3.26 (m, 3H), (ES.sup.+), at octane-2-carboxylate 3.34-3.76 (m, 7H), 3.91-4.29 (m, 3H) 4.06 min, 202 nm 2-4 Isomer 1: Ethyl-5-(3-(2-(1, 4- A H .sup.1H NMR (400 MHz, Methanol-δ4) δ 3 m/z 380 oxazepan-4-yl)-2-oxoethyl) 9 and 10 1.15-1.30 (m, 4H), 1.35-1.55 (m, 1H) E (M + H).sup.+ azetidin-1-yl)-2-azabicyclo- 1.60-2.04 (m, 7H), 2.47-2.60 (m, 1H), (ES.sup.+), at [2.2.2]octane-2-carboxylate 2.62-2.94 (m, 5H), 3.23-3.29 (m, 1H), 2.48 min, 3.33-3.52 (m, 2H), 3.53-3.84 (m, 9H), 202 nm 3.91-4.00 (m, 1H), 4.02-4.18 (m, 2H) 2-5 Isomer 1: Ethyl-5-(3-(2-oxo- A I .sup.1H NMR (400 MHz, Methanol-δ4) δ 1 m/z 376 2-(1-azaspiro[3.3]heptan-1- 9 and 11 2.08-2.29 (m, 4H), 2.33-2.47 (m, 1H), C (M + H).sup.+ yl)ethyl)azetidin-1-yl)-2- 2.55-3.07 (m, 8H), 3.14-3.26 (m, 1H), (ES.sup.+), at azabicyclo[2.2.2]octane-2- 3.34-3.43 (m, 1H), 3.43-3.56 (m, 4H), 3.97 min, carboxylate 3.57-4.01 (m, 5H), 4.15-4.58 (m, 4H), 210 nm 4.66-5.00 (m, 3H), 5.01-5.18 (m, 2H) Three protons obscured by solvent peaks 3-1 Isomer 1: Ethyl-3-(3-(2- A J .sup.1H NMR (400 MHz, Methanol-δ4) δ 1 m/z 366 (diethylamino)-2-oxoethyl) 4 and 15 1.01-1.12 (m, 5H), 1.15-1.30 (m, 6H), E (M + H).sup.+ azatidin-1-yl)-9-azabicyclo 1.38-1.67 (m, 5H). 1.90-2.24 (m, 4H), (ES.sup.+), at [3.3.1]nonane-9-carboxylate 2.54-2.71 (m, 2H), 2.73-2.94 (m, 3H), 3.38 min, 3.33-3.43 (m, 4H), 3.47-3.56 (m, 2H), 202 nm 4.02-4.21 (m, 2H), 4.33-4.53 (m, 2H) 3-2 Isomer 1: Ethyl-3-(3-(2-oxo- A K .sup.1H NMR (400 MHz, Methanol-δ4) δ 1 m/z 364 2-(pyrrolidin-1-yl)-9-azabicyclo 15 and 16 1.01-1.16 (m, 2H), 1.23-1.30 (m, 3H) E (M + H).sup.+ [3.3.1]nonane-9-carboxylate 1.39-1.67 (m, 6H), 1.83-1.92 (m, 2H), (ES.sup.+), at 1.93-2.25 (m, 4H), 2.57-2.66 (m, 2H), 4.10 min, 3.35-3.41 (m, 3H), 3.44-3.56 (m, 4H), 214 nm 4.05-4.19 (m, 2H), 4.38-4.51 (m, 2H) 3-3 Isomer 1: Ethyl-3-(3-(2-oxo-2- A L .sup.1H NMR (400 MHz, Methanol-δ4) δ 1 m/z 378 (piperidin-1-yl)ethyl)azetidin- 7 and 15 1.02-1.13 (m, 2H), 1.22-1.30 (m, 3H), E (M + H).sup.+ 1-yl)-9-azabicyclo[3.3.1] 1.37-1.74 (m, 11H), 1.89-2.23 (m, 4H), (ES.sup.+), at nonane-9-carboxylate 2.61-2.69 (m, 2H), 2.73-2.94 (m, 3H), 3.45 min, 3.42-3.59 (m, 6H), 4.04-3.59 (m, 6H), 202 nm 4.04-4.19 (m, 2H), 4.36-4.54 (m, 2H) 4-1 Ethyl 6-(3-((diethylcarbamoyl) B M .sup.1H NMR (400 MHz, Methanol-δ4) δ 1 m/z 340 oxy)azetidin-1-yl)-2-azaspiro 20 and 21 1.07-1.19 (m, 6H), 1.22 (t, J = 7.1 Hz, 3H), E (m + H).sup.+ [3.3]heptane-2-carboxylate 1.96-2.07 (m, 2H), 2.23-2.33 (m, 2H), (ES.sup.+), at 3.05-3.16 (m, 4H), 3.55-3.64 (m, 2H), 3.83 min, 3.84-3.92 (m, 2H), 3.93-4.00 (m, 2H), 202 nm 3.93-4.00 (m, 2H), 4.06 (q, J = 7.1 Hz, 2H), 4.91-5.00 (m, 1H) Three protons obscured by solvent peaks 4-2 Isomer 2: Ethyl 2-(3- B N .sup.1H NMR (400 MHz, Methanol-δ4) δ 1 m/z 354 ((diethylcarbamoyl)oxy) 20 and 22 1.04-1.20 (m, 6H), 1.25 (t, J = 7.1 Hz, 3H), E (M + H).sup.+ azatidin-1-yl)-6-azaspiro[3.4] 1.83-1.98 (m, 4H), 2.00-2.13 (m, 2H), (ES.sup.+), at octane-6-carboxylate 3.17-3.29 (m, 5H), 3.34-3.44 (m, 3H), 4.05 min, 3.62-3.77 (m, 2H), 4.09 (q, J = 7.1 Hz, 2H) 202 nm 4.94-5.02 (m, 1H) Three protons obscured by solvent peaks 4-3 Isomer 2: 1-(6-(Ethoxycarbonyl)- B O .sup.1H NMR (400 MHz, Methanol-δ4) δ 3 m/z 382 6-azaspiro[3.4]octan-2-yl)azetidin-3- 22 and 23 1.20-1.28 (m, 3H), 1.80-1.97 (m, 6H), E (M + H).sup.+ yl 1,4- oxazepane-4-carboxylate 1.99-2.09 (m, 2H), 3.12-3.20 (m, 2H), (ES.sup.+), at 3.21-3.29 (m, 3H), 3.33-3.41 (m, 2H), 3.04 min, 3.51-3.65 (m, 6H), 3.68-3.78 (m, 4H), 202 nm 4.05-4.14 (m, 2H), 4.94-5.02 (m, 1H) 4-4 Isomer 1: Ethyl 6-(3-((ethyl B P then Q .sup.1H NMR (400 MHz, Methanol-δ4) δ 4 m/z 340 (methyl)carbamoyl)oxy) 24 and 25 1.04-1.18 (m, 3H), 1.22 (t, J = 7.1 Hz, 3H), B (M + H).sup.+ azetidin-1-yl)-2-azaspiro 1.35-1.46 (m, 1H), 1.53-1.64 (m, 1H), (ES.sup.+), at [3.4]octane-2-carboxylate 1.69-2.08 (m, 4H), 2.82-2.97 (m, 4H), 5.01 min, 3.02-3.15 (m, 2H), 3.59-3.67 (m, 2H), 202 nm 3.71-3.93 (m, 4H), 4.07 (q, J = 7.1 Hz, 2H) Three protons obscured by solvent peaks 4-5 Isomer 1: Ethyl 6-(3- B R then S .sup.1H NMR (400 MHz, Methanol-δ4) δ 3 m/z 354 ((diethylcarbamoyl)oxy) 20 and 24 1.05-1.18 (m, 6H), 1.22 (t, J = 7.1 Hz, 3H), E (m + H).sup.+ azetidin-1-yl)-2-azaspiro[3.4] 1.34-1.47 (m, 1H), 1.53-1.63 (m, 1H), (ES.sup.+), at octane-2-carboxylate 1.69-1.88 (m, 2H), 1.88-2.05 (m, 2H), 3.72 min, 2.80-2.95 (m, 1H), 3.03-3.14 (m, 2H), 202 nm 3.58-3.69 (m, 2H), 3.72-3.93 (m, 4H), 4.07 (q, J = 7.1 Hz, 2H), 4.91-5.02 (m, 2H) Three protons obscured by solvent peaks 4-5 Isomer 2: Ethyl 6-(3- B R then S .sup.1H NMR (400 MHz, Methanol-δ4) δ 3 m/z 354 ((diethylcarbamoyl)oxy) 20 and 24 1.04-1.18 (m, 6H), 1.22 (t, J = 7.1 Hz, 3H), E (M + H).sup.+ azetidin-1-yl)-2-azaspiro[3.4] 1.34-1.48 (m, 1H), 1.53-1.64 (m, 1H), (ES.sup.+), at octane-2-carboxylate 1.70-1.88 (m, 2H), 1.89-2.05 (m, 2H), 3.74 min, 2.82-2.92 (m, 1H), 3.02-3.13 (m, 2H), 202 nm 3.58-3.70 (m, 2H), 3.71-3.94(m, 4H), 4.06 (q, J = 7.1 Hz, 2H), 4.90-5.01 (m, 2H) Three protons obscured by solvent peaks 4-6 Isomer 1: Methyl 6-(3- B T .sup.1H NMR (400 MHz, Methanol-δ4) δ 4 m/z 340 ((diethylcarbamoyl)oxy) 20 and 27 1.04-1.23 (m, 6H), 1.35-1.49 (m, 1H), B (M + H).sup.+ azetidin-1-yl)-2-azaspiro 1.54-1.66 (m, 1H), 1.72-1.89 (m, 2H), (ES.sup.+), at [3.4]octane-2-carboxylate 1.90-2.07 (m, 2H), 2.82-2.89 (m, 1H), 4.78 min, 3.07-3.18 (m, 2H), 3.59-3.72 (m, 5H), 202 nm 3.73-3.99 (m, 4H) Five protons obscured by solvent peaks 4-6 Isomer 2: Methyl 6-(3- B T .sup.1H NMR (400 MHz, Methanol-δ4) δ 4 m/z 340 ((diethylcarbamoyl)oxy)azetidin- 20 and 27 1.03-1.23 (m, 6H), 1.33-1.49 (m, 1H), B (m + H).sup.+ 1-yl)-2-azaspiro[3.4]octane- 1.53-1.64 (m, 1H), 1.70-1.88 (m, 2H), (ES.sup.+), at 2-carboxylate 1.89-2.08 (m, 2H), 2.79-2.97 (m, 1H), 4.95 min, 3.02-3.16 (m, 2H), 3.57-3.70 (m, 5H), 202 nm 3.72-4.00 (m, 4H) Five protons obscured by solvent peaks 4-7 Isomer 1: Ethyl 6-(3- B U then V .sup.1H NMR (400 MHz, Methanol-δ4) δ 3 m/z 352 ((pyrrolidine-1-carbonyl) 24 and 28 1.22 (t, J = 7.1 Hz, 3H), 1.34-1.48 (m, 1H), E (M + H).sup.+ oxy)azetidin-1-yl)-2- 1.53-1.64 (m, 1H), 1.70-2.07 (m, 8H), (ES.sup.+), at azaspiro[3.4]octane-2-carboxylate 2.82-2.93 (m, 1H), 3.04-3.15 (m, 2H), 3.27 min, 3.35-3.44 (m, 2H), 3.58-3.69 (m, 2H), 202 nm 3.73-3.92 (m, 4H), 4.07 (q, J = 7.1 Hz, 2H), 4.90-4.98 (m, 1H) Two protons obscured by solvent peaks 4-8 Isomer 1: 1-(2- B W then X .sup.1H NMR (400 MHz, Methanol-δ4) δ 3 m/z 368 (Ethoxycarbonyl)-2- 24 and 30 1.22 (t, J = 7.1 Hz, 3H), 1.35-1.46 (m, 1H), E (M + H).sup.+ azaspiro[3.4]octane-6- 1.53-1.63 (m, 1H), 1.69-1.87 (m, 2H), (ES.sup.+), at yl)azetidin-3-yl morpholine- 1.89-2.06 (m, 2H), 2.81-2.94 (m, 1H), 3.06 min, 4-carboxylate 3.03-3.17 (m, 2H), 3.37-3.55 (m, 4H), 202 nm 3.58-3.69 (m, 6H), 3.72-3.95 (m, 4H), 4.07 (q, J = 7.1 Hz, 2H), 4.91-4.98 (m, 1H) 4-9 Isomer 1: 1-(2- B Y then V .sup.1H NMR (400 MHz, Methanol-δ4) δ 3 m/z 382 (Ethoxycarbonyl)-2- 23 and 24 1.23 (t, J = 7.1 Hz, 3H), 1.38-1.52 (m, 1H), E (M + H).sup.+ azaspiro[3.4]octane-6- 1.57-1.69 (m, 1H), 1.77-2.02 (m, 5H), (ES.sup.+), at yl)azetidin-3-yl 1,4- 2.05-2.18 (m, 1H), 3.05-3.20 (m, 1H), 2.97 min, oxazepane-4-carboxylate 3.34-3.45 (m, 2H), 3.51-3.66 (m, 4H), 202 nm 3.69-3.96 (m, 10H), 4.07 (q, J = 7.1 Hz, 2H), 4.96-5.06 (m, 1H) 4-9 Isomer 2: 1-(2- B Y then V .sup.1H NMR (400 MHz, Methanol-δ4) δ 3 m/z 382 (Ethoxycarbonyl)-2- 23 and 24 1.23 (t, J = 7.1 Hz, 3H), 1.35-1.47 (m, 1H), E (M + H).sup.+ azaspiro[3.4]octane-6-yl) 1.53-1.65 (m, 1H), 1.70-2.07 (m, 6H), (ES.sup.+), at azetidin-3-yl 1,4- 2.82-2.95 (m, 1H), 3.04-3.17 (m, 2H), 2.97 min, oxazepane-4-carboxylate 3.51-3.68 (m, 6H), 3.69-3.95 (m, 8H), 202 nm 4.07 (q, J = 7.1 Hz, 2H), 4.92-5.01 (m, 1H) 5-1 Isomer mixture: Ethyl 3-(3- B Z .sup.1H NMR (400 MHz, Methanol-δ4) δ 3 m/z 380 ((azepane-1-carbonyl) 2 and 32 1.22-1.28 (m, 3H), 1.53-1.63 (m, 6H), E (M + H).sup.+ oxy)azetidin-1-yl)-8- 1.66-1.93 (m, 8H), 2.05-2.17 (m, 2H), (ES.sup.+), at azabicyclo[3.2.1] 2.77-2.92 (m, 2H), 3.37-3.47 (m, 4H), 5.17 min, octane-8-carboxylate 3.57-3.70 (m, 2H), 4.05-4.22 (m, 4H) 202 nm Two protons obscured by solvent peaks 5-2 Isomer mixture: 1-(8- B AA .sup.1H NMR (400 MHz, Methanol-δ4) δ 3 m/z 382 (Ethoxycarbonyl)-8- 2 and 23 1.18-1.29 (m, 3H), 1.52-1.64 (m, 2H), E (M + H).sup.+ azabicyclo[3.2.1]octane- 1.67-1.96 (m, 6H), 2.00-2.18 (m, 2H), (ES.sup.+), at 3-yl)azetidin-3-yl 1,4- 2.40-2.55 (m, 1H), 2.77-2.93 (m, 2H), 3.85 min, oxazepane-4-carboxylate 3.51-3.61 (m, 4H), 3.61-3.68 (m, 2H), 202 nm 3.68-3.80 (m, 3H), 4.02-4.25 (m, 4H) Two protons obscured by solvent peaks 6-1 Isomer 1: Ethyl 5-(3- C AB .sup.1H NMR (400 MHz, Methanol-δ4) δ 1 m/z 354 ((diethylcarbamoyl)oxy) 4, 19, and 34 1.02-1.20 (m, 6H), 1.20-1.33 (m, 4H), E (M + H).sup.+ azetidin-1-yl)-2- 1.38-1.52 (m, 1H), 1.61-1.88 (m, 3H), (ES.sup.+), at azabicyclo[2.2.2]octane- 1.89-2.07 (m, 2H), 2.53-2.65 (m, 1H), 4.19 min, 2-carboxylate 2.98-3.10 (m, 2H), 3.38-3.47 (m, 1H), 202 nm 3.59-3.68 (m, 1H), 3.71-3.79 (m, 1H), 3.92-4.01 (m, 1H), 4.05-4.18 (m, 2H), 4.94-5.02 (m, 1H) Five protons obscured by solvent peaks 6-2 Isomer 1: Ethyl 5-(3- C AC .sup.1H NMR (400 MHz, Methanol-δ4) δ 1 m/z 352 ((pyrrolidine-1- 16, 19, and 34 1.17-1.32 (m, 4H), 1.37-1.53 (m, 1H), E (M + H).sup.+ carbonyl)oxy)azetidin-1- 1.62-2.08 (m, 9H), 2.51-2.64 (m, 1H), (ES.sup.+), at yl)-2-azabicyclo[2.2.2]octane- 3.00-3.12 (m, 2H), 3.36-3.48 (m, 3H), 3.93 min, 2-carboxylate 3.57-3.66 (m, 1H), 3.69-3.78 (m, 1H), 202 nm 3.91-4.01 (m, 1H), 4.05-4.17 (m, 2H), 4.92-5.04 (m, 1H) Three protons obscured by solvent peaks 6-3 Isomer 1: Ethyl 5-(3- C AD .sup.1H NMR (400 MHz, Methanol-δ4) δ 1 m/z 366 ((piperidine-1- 7, 19, and 34 1.19-1.31 (m, 4H), 1.38-1.58 (m, 5H), E (M + H).sup.+ carbonyl)oxy)azetidin- 1.59-1.87 (m, 5H), 1.88-2.08 (m, 2H), (ES.sup.+), at 1-yl)-2-azabicyclo[2.2.2] 2.52-2.66 (m, 1H), 2.99-3.12 (m, 2H), 4.28 min, octane-2-carboxylate 3.34-3.52 (m, 5H), 3.57-3.66 (m, 1H), 202 nm 3.68-3.76 (m, 1H), 3.92-3.99 (m, 1H), 4.04-4.16 (m, 2H), 4.92-5.01 (m, 1H) One proton obscured by solvent peaks 6-4 Isomer 1: Ethyl 5-(3- B AE .sup.1H NMR (400 MHz, Methanol-δ4) δ 3 m/z 380 ((azepane-1-carbonyl) 8 and 32 1.19-1.30 (m, 4H), 1.38-1.50 (m, 1H), E (M + H).sup.+ oxy)azetidine-1-yl)- 1.52-1.62 (m, 4H), 1.63-2.07 (m, 9H), (ES.sup.+), at 2-azabicyclo[2.2.2] 2.52-2.63 (m, 1H), 2.99-3.09 (m, 2H), 3.99 min, octane-2-carboxylate 3.33-3.37 (m, 1H), 3.38-3.52 (m, 5H), 202 nm 3.57-3.67 (m, 1H), 3.69-3.79 (m, 1H), 3.90-4.01 (m, 1H), 4.03-4.19 (m, 2H), 4.92-5.03 (m, 1H) 6-5 Isomer 1: 1-(2- B AF .sup.1H NMR (400 MHz, Methanol-δ4) δ 3 m/z 382 (Ethoxycarbonyl)-2- 8 and 23 1.18-1.32 (m, 5H), 1.39-1.52 (m, 1H), E (M + H).sup.+ azabicyclo[2.2.2]octane-5- 1.59-2.07 (m, 6H), 2.53-2.67 (m, 1H), (ES.sup.+), at yl)azetidin-3-yl 1,4- 3.03-3.13 (m, 2H), 3.34-3.51 (m, 2H), 2.98 min, oxazepane-4-carboxylate 3.51-3.68 (m, 5H), 3.68-3.79 (m, 5H), 202 nm 3.91-4.00 (m, 1H), 4.03-4.17 (m, 2H), 4.94-5.04 (m, 1H) 7-1 Isomer 1: Ethyl 3-(3- B AG .sup.1H NMR (400 MHz, Methanol-δ4) δ 1 m/z 368 ((diethylcarbamoyl)oxy) 14 and 20 1.04-1.18 (m, 8H), 1.21-1.30 (m, 3H), E (M + H).sup.+ azetidin-1-yl)-9- 1.37-1.67 (m, 5H), 1.92-2.24 (m, 4H), (ES.sup.+), at azabicyclo[3.3.1]nonane- 3.04-3.16 (m, 2H), 3.60-3.75 (m, 2H), 3.93 min, 9-carboxylate 4.04-4.19 (m, 2H), 4.36-4.52 (m, 2H), 202 nm 4.90-5.01 (m, 1H) Four protons obscured by solvent peaks 8-1 Isomer 1: Ethyl 7-(3- B AH .sup.1H NMR (400 MHz, Methanol-δ4) δ 4 m/z 396 ((azepane-1-carbonyl) 32 and 36 1.23-1.32 (m, 3H), 1.35-1.47 (m, 2H), B (M +H).sup.+ oxy)azetidin-1-yl)- 1.51-1.63 (m, 4H), 1.65-1.77 (m, 4H), (ES.sup.+), at 3-oxa-9-azabicyclo 2.03-2.30 (m, 3H), 3.07-3.22 (m, 2H), 4.68 min, [3.3.1]nonane-9-carboxylate 3.37-3.65 (m, 8H), 3.66-3.79 (m, 2H), 202 nm 4.09-4.28 (m, 4H), 4.91-5.01 (m, 1H)

[0400] Biological Activity

Example A

[0401] Phospho-ERK1/2 Assays

[0402] 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 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.

[0403] 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.

[0404] Analytical data for active isomers is reported in Table 3. Data for some weakly active compounds are included in Table 4 to highlight the preference for absolute stereochemistry.

[0405] NT=not tested

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 Isomer 2  6.50 (100)   5.90 (58) <4.70 (28)   6.70 (85) 1-2 Isomer  6.74 (100) NT NT <4.70 (7)  mixture 1-3 Isomer 2  6.94 (103) NT NT <4.70 (19) 1-4 Isomer 6.51 (84) <4.70 (21) <4.70 (6)  <4.70 (17) mixture 2-1 Isomer 1 6.68 (67) <4.70 (13) <4.70 (6)  <4.70 (9)  2-2 Isomer 1 7.72 (95) <4.70 (8)  <4.70 (12)   6.59 (36) 2-2 Isomer 2 6.64 (65) <4.70 (6)  <4.70 (7)  <4.70 (31) 2-3 Isomer 1 6.69 (88) <4.70 (10) <4.70 (9)    5.19 (46) 2-4 Isomer 1 5.99 (58) NT NT <4.70 (9)  2-5 Isomer 1 6.96 (64) <4.70 (53) <4.70 (35) <4.70 (23) 3-1 Isomer 1  6.09 (106) NT NT <4.70 (23) 3-2 Isomer 1 5.32 (68) NT NT   6.03 (68) 3-3 Isomer 1  6.50 (117) <4.70 (5)  <4.70 (9)    5.89 (55) 4-1 6.08 (83) NT NT   5.77 (57) 4-2 Isomer 2  6.80 (105) <4.70 (14) <4.70 (17)   6.55 (89) 4-3 Isomer 2  6.43 (104) NT NT   5.99 (46) 4-4 Isomer 1 7.23 (67) <4.70 (5)  <4.70 (0)    7.64 (37) 4-5 Isomer 1 7.80 (66) <4.70 (6)  <4.70 (54)   7.48 (31) 4-5 Isomer 2 5.95 (44) NT NT <4.70 (10) 4-6 Isomer 1 6.20 (92) NT NT   5.95 (33) 4-6 Isomer 2 6.67 (93) <4.70 (9)  <4.70 (11)   6.47 (32) 4-7 Isomer 1 7.12 (51) <4.70 (7)  <4.70 (8)    7.31 (29) 4-8 Isomer 1 7.24 (72) <4.70 (2)  <4.70 (4)  <4.70 (14) 4-9 Isomer 1 7.24 (37) <4.70 (3)  <4.70 (2)  <4.70 (7)  4-9 Isomer 2 5.25 (84) NT NT   6.41 (85) 5-1 Isomer 7.05 (83) <4.70 (18) <4.70 (45)   6.37 (39) mixture 5-2 Isomer 5.65 (92) NT NT <4.70 (19) mixture 6-1 Isomer 1 5.98 (65) NT NT <4.70 (9)  6-2 Isomer 1 5.16 (83) NT NT   6.19 (55) 6-3 Isomer 1 6.45 (92) NT NT   5.79 (35) 6-4 Isomer 1 6.93 (86) <4.70 (9)  <4.70 (5)    6.31 (50) 6-5 Isomer 1 6.09 (58) NT NT <4.70 (27) 7-1 Isomer 1 5.89 (88) NT NT   5.64 (29) 8-1 Isomer 1  6.59 (104) NT NT   5.73 (43)

EQUIVALENTS

[0406] 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.