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 (1) ##STR00001##
wherein X.sup.1; X.sup.2; R.sup.1 and R.sup.4 are as defined herein.

Claims

1. A compound of formula (4): ##STR00131## or a salt thereof, wherein: R.sup.1 is CONR.sup.5R.sup.6; 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 R.sup.5 and R.sup.6 are independently selected from hydrogen and a non-aromatic C.sub.1-6 hydrocarbon group optionally substituted with one or more fluorine atoms or R.sup.5 and R.sup.6 are joined together to form a monocyclic or bicyclic ring.

2. The compound according to claim 1, or a salt thereof, wherein R.sup.1 is selected from the group consisting of: ##STR00132##

3. The compound according to claim 1, or a salt thereof, wherein R.sup.1 is: ##STR00133##

4. The compound according to claim 1, or a salt thereof, wherein R.sup.4 is H or methyl.

5. The compound according to claim 1, or a salt thereof, wherein R.sup.4 is H.

6. The compound according to claim 1 which is selected from the group consisting of: ethyl 2-{(1R,5S,6r)-6-[(2-methylpropyl)carbamoyl]-3-azabicyclo[3.1.0]hex-3-yl}-6-azaspiro[3.4]octane-6-carboxylate; ethyl 2-{(1R,5S,6r)-6-[(cyclobutylmethyl)carbamoyl]-3-azabicyclo[3.1.0]hex-3-yl}-6-azaspiro[3.4]octane-6-carboxylate; ethyl 2-{(1R,5S,6r)-6-[(1-methylcyclobutyl)carbamoyl]-3-azabicyclo[3.1.0]hex-3-yl}-6-azaspiro[3.4]octane-6-carboxylate; ethyl 2-{(1R,5S,6r)-6-[ethyl(methyl)carbamoyl]-3-azabicyclo[3.1.0]hex-3-yl}-6-azaspiro[3.4]octane-6-carboxylate; ethyl 2-[(1R,5S,6r)-6-(diethylcarbamoyl)-3-azabicyclo[3.1.0]hex-3-yl]-6-azaspiro[3.4]octane-6-carboxylate; methyl 2-[(1R,5S,6r)-6-(diethylcarbamoyl)-3-azabicyclo[3.1.0]hex-3-yl]-6-azaspiro[3.4]octane-6-carboxylate; ethyl 2-{(1R,5S,6r)-6-[methyl(propan-2-yl)carbamoyl]-3-azabicyclo[3.1.0]hex-3-yl}-6-azaspiro[3.4]octane-6-carboxylate; ethyl 2-{(1R,5S,6r)-6-[ethyl(propan-2-yl)carbamoyl]-3-azabicyclo[3.1.0]hex-3-yl}-6-azaspiro[3.4]octane-6-carboxylate; methyl 2-{(1R,5S,6r)-6-[ethyl(propan-2-yl)carbamoyl]-3-azabicyclo[3.1.0]hex-3-yl}-6-azaspiro[3.4]octane-6-carboxylate; ethyl 2-{(1R,5S,6r)-6-[cyclopropyl(ethyl)carbamoyl]-3-azabicyclo[3.1.0]hex-3-yl}-6-azaspiro[3.4]octane-6-carboxylate; ethyl 2-[(1R,5S,6r)-6-(pyrrolidin-1-ylcarbonyl)-3-azabicyclo[3.1.0]hex-3-yl]-6-azaspiro[3.4]octane-6-carboxylate; ethyl 2-[(1R,5S,6r)-6-(piperidin-1-ylcarbonyl)-3-azabicyclo[3.1.0]hex-3-yl]-6-azaspiro[3.4]octane-6-carboxylate; ethyl 2-[(1R,5S,6r)-6-(azepan-1-ylcarbonyl)-3-azabicyclo[3.1.0]hex-3-yl]-6-azaspiro[3.4]octane-6-carboxylate; ethyl 2-[(1R,5S,6r)-6-(2-azaspiro[3.3]hept-2-ylcarbonyl)-3-azabicyclo[3.1.0]hex-3-yl]-6-azaspiro[3.4]octane-6-carboxylate; ethyl 2-[(1R,5S,6r)-6-(4-azaspiro[2.3]hex-4-ylcarbonyl)-3-azabicyclo[3.1.0]hex-3-yl]-6-azaspiro[3.4]octane-6-carboxylate; ethyl 2-[(1R,5S,6r)-6-(1-azaspiro[3.3]hept-1-ylcarbonyl)-3-azabicyclo[3.1.0]hex-3-yl]-6-azaspiro [3.4]octane-6-carboxylate; methyl 2-[(1R,5S,6r)-6-(1-azaspiro [3.3]hept-1-ylcarbonyl)-3-azabicyclo [3.1.0]hex-3-yl]-6-azaspiro[3.4]octane-6-carboxylate; and ethyl 2-[(1R,5S,6r)-6-(6-oxa-1-azaspiro[3.3]hept-1-ylcarbonyl)-3-azabicyclo[3.1.0]hex-3-yl]-6-azaspiro[3.4]octane-6-carboxylate; or a salt thereof.

7. A method of treating Alzheimer's disease, dementia with Lewy bodies or schizophrenia in a subject, comprising administering to the subject an effective amount of a compound according to claim 1, or a salt thereof.

8. A method of treating Alzheimer's disease in a subject, comprising administering to the subject an effective amount of a compound according to claim 1, or a salt thereof.

9. A method of treating dementia with Lewy bodies in a subject, comprising administering to the subject an effective amount of a compound according to claim 1, or a salt thereof.

10. A method of treating schizophrenia in a subject, comprising administering to the subject an effective amount of a compound according to claim 1, or a salt thereof.

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 12-1

(2) The compounds of Examples 1-1 to 12-1 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.

(3) TABLE-US-00001 TABLE 1 Example 1-1 0 Example 1-2 Example 1-3 Example 1-4 Example 2-1 Example 2-2 Example 2-3 Example 2-4 Example 2-5 Example 2-6 Example 2-7 0 Example 2-8 Example 2-9 Example 2-10 Example 2-11 Example 2-12 Example 2-13 Example 2-14 Example 2-15 Example 2-16 Example 2-17 0 Example 2-18 Example 2-19 Example 2-20 Example 2-21 Example 2-22 Example 2-23 Example 2-24 Example 2-25 Example 2-26 Example 2-27 0 Example 2-28 Example 2-29 Example 2-30 Example 3-1 Example 3-2 Example 3-3 Example 3-4 Example 4-1 Example 5-1 Example 5-2 0 Example 6-1 Example 7-1 Example 7-2 Example 7-3 Example 7-4 Example 7-5 Example 7-6 Example 8-1 Example 8-2 Example 8-3 0 Example 8-4 Example 8-5 Example 8-6 Example 8-7 Example 8-8 Example 8-9 Example 8-10 Example 9-1 Example 9-2 Example 9-3 00 Example 10-1 01 Example 10-2 02 Example 10-3 03 Example 10-4 04 Example 10-5 05 Example 10-6 06 Example 10-7 07 Example 10-8 08 Example 10-9 09 Example 10-10 0 Example 10-11 Example 10-12 Example 10-13 Example 10-14 Example 10-15 Example 11-1 Example 11-2 Example 12-1
General Procedures

(4) 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.

(5) LCMS Analysis

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

(7) TABLE-US-00002 LCMS Instrument Details System 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 5 Hewlett Packard HP 1100 G1315A DAD Micromass ZQ 6 Agilent 1260 Infinity LC Photo Diode Array Agilent 6120B

(8) TABLE-US-00003 LCMS Method Details Method UV Mass Column Flow Rate Name Solvent System Column Gradient Range Range Temp.° C. ml/min A (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 acid 50 mm, 1.7 μm 65:35 at 0.80 min, 45:55 at 1.20 min, nm amu in water or equivalent 0:100 at 2.50 min up to 3.30 min, (B) 0.1% formic acid in 95:5 at 3.31 min up to 4.00 min acetonitrile B (A) 20 mM ammonium X-Bridge C18 90:10 at 0.01 min, 10:90 at 5.00 min, 200-400  60-1000 Ambient 1.00 acetate in water 4.6 × 150 mm, 0:100 at 7.00 min up to 11.00 min, nm amu (B) methanol 5 μm or 90:10 at 11.01 min up to 12.00 min equivalent C (A) 0.1% ammonia in water X-Bridge C18 95:5 at 0.01 min, 10:90 at 5.00 min, 200-400  60-1000 Ambient 1.00 (B) 0.1% ammonia in 4.6 × 50 mm, 5:95 at 5.80 min up to 7.20 min, 95:5 nm amu acetonitrile 3.5 μm or at 7.21 min up to 10.00 min equivalent 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 acid 50 mm, 1.7 μm 60:40 at 0.60 min, 40:60 at 1.20 min, nm amu in water or equivalent 0:100 at 2.30 min up to 3.00 min, (B) 0.1% formic acid in 95:5 at 3.01 min up to 3.50 min acetonitrile E (A) 5 mM ammonium X-Bridge C18 95:5 at 0.01 min, 10:90 at 5.0 min & 200-400  60-1000 Ambient 1.00 bicarbonate in water 4.6 × 50 mm, 5:95 at 5.80 min till 7.20 min, 95:5 at nm amu (B) acetonitrile 3.5 μm or 7.21 min up to 10.0 min equivalent F (A) 2.5 L water + 2.5 mL 28% Gemini-NX C- 9δ:2 at 0.00 min up to 0.10 min, 5:95 230-400 130-800 45 1.50 ammonia solution in 18, 2.0 × 30 at 2.50 min up to 3.50 min nm amu water mm, 3 μm (B) 2.5 L acetonitrile + 135 mL water + 2.5 mL 28% ammonia solution in water G (A) 2.5 L water + 2.5 mL 28% Gemini-NX C- 9δ:2 at 0.00 min up to 0.10 min, 5:95 230-400 130-800 45 1.50 ammonia solution in 18, 2.0 × 30 at 8.40 min up to 10.00 min nm amu water mm, 3 μm B) 2.5 L acetonitrile + 135 mL water + 2.5 mL 28% ammonia solution in water H (A) 2.5 L water + 2.5 mL Gemini-NX C- 95:5 at 0.00 min, 5:95 at 2.00 min up 190-400 150-800 40 1.50 28% ammonia solution in 18, 2.0 × 30 to 2.50 min, 95:5 at 2.60 min up to nm amu water mm, 3 μm 3.0 min (B) 2.5 L acetonitrile + 130 mL water + 2.5 mL 28% ammonia solution in water I (A) 2.5 L water + 2.5 mL Gemini-NX C- 9δ:2 at 0.00 min up to 0.10 min, 5:95 190-400 150-800 40 1.50 28% ammonia solution in 18, 2.0 × 30 at 8.40 min up to 10.00 min nm amu water mm, 3 μm (B) 2.5 L acetonitrile + 130 mL water + 2.5 mL 28% ammonia solution in water

(9) 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.

(10) Compound Purification

(11) 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)].

(12) Preparative HPLC Purification:

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

(14) Gilson semi preparative HPLC system with 321 pump, GX-271 liquid handler and Gilson 171

(15) DAD controlled with Gilson Trilution software

(16) Chiral HPLC Purification:

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

(18) Chiral SFC Purification:

(19) Waters SFC 200

(20) Sepiatec 100

(21) Berger Multigram 2

(22) Purification Method A

(23) Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 150×19 mm, 5 μm), 15 mL/min, gradient 5%-30% (over 30 min), 30% (over 5 min), 100% (over 2 min), 100%-5% (over 3 min), mobile phase (A): 0.1% ammonia in water, (B): 100% acetonitrile].

(24) Purification Method B

(25) Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×19 mm, 5 μm), 17 mL/min, gradient 30%-50% (over 12 min), 100% (over 2 min), 100%-30% (over 2 min), mobile phase (A): 0.1% ammonia in water, (B): 100% acetonitrile].

(26) Purification Method C

(27) Prep HPLC: [Reversed Phase (Gemini C-18, 250×21.2 mm, 5 μm), 15 mL/min, gradient 40%-50% (over 17 min), 100% (over 2 min), 100%-40% (over 3 min), mobile phase (A): 0.1% ammonia in water, (B): 100% acetonitrile].

(28) Purification Method D

(29) Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×19 mm, 5 μm), 17 mL/min, gradient 35%-60% (over 12 min), 100% (over 2 min), 100%-35% (over 2 min), mobile phase (A): 0.1% ammonia in water, (B): 100% acetonitrile].

(30) Purification Method E

(31) Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 150×19 mm, 5 μm), 15 mL/min, gradient 35%-56% (over 12 min), 100% (over 1 min), 100%-35% (over 3 min), mobile phase (A): 0.1% ammonia in water, (B): 100% acetonitrile].

(32) Purification Method F

(33) Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 150×19 mm, 5 μm), 14 mL/min, gradient 27% (over 30 min), 100% (over 3 min), 100%-27% (over 3 min), mobile phase (A): 0.1% ammonia in water, (B): 100% acetonitrile].

(34) Purification Method G

(35) Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 150×19 mm, 5 μm), 17 mL/min, gradient 2%-30% (over 30 min), 30% (over 5 min), 95% (over 3 min), 95%-2% (over 2 min), mobile phase (A): 0.1% ammonia in water, (B): 100% acetonitrile].

(36) Purification Method H

(37) Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 150×19 mm, 5 μm), 10 mL/min, gradient 5% (over 5 min), 5%-30% (over 5 min), 30% (over 23 min), 100% (over 3 min), 100%-5% (over 4 min), mobile phase (A): 0.1% ammonia in water, (B): 100% acetonitrile].

(38) Purification Method I

(39) Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 16 mL/min, gradient 5%-34% (over 40 min), 34% (over 2 min), 100% (over 1 min), 100%-5% (over 3 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.05% ammonia in water, (B) 100% acetonitrile].

(40) Purification Method J

(41) SFC: [(CHIRALPAK AD-H, 250×21 mm, 5 μm), 75 mL/min, Isochratic (A:B) 85:15 (over 6 min), mobile phase (A): 100% liquid CO.sub.2, (B): 0.1% diethylamine in isopropanol methanol (50:50)].

(42) Purification Method K

(43) Prep HPLC: [Reversed Phase (YMC ACTUS TRIART C-18, 250×20 mm, 5 μm), 15 mL/min, gradient 25%-58% (over 18 min), 100% (over 2 min), 100%-25% (over 2 min), mobile phase (A): 10 mM ammonium bicarbonate in water, (B): 100% acetonitrile].

(44) Purification Method L

(45) Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 15 mL/min, gradient 20%-30% (over 10 min), 30% (over 13 min), 100% (over 3 min), 100%-20% (over 4 min), mobile phase (A): 0.1% ammonia in water, (B) 100% acetonitrile].

(46) Purification Method M

(47) Chiral HPLC: [Normal Phase (CHIRALPAK AD-H, 250×21 mm, 5 μm), 10 mL/min, Isochratic (A:B) 85:15 (over 25 min), mobile phase (A): 0.3% diethylamine in hexane, (B): 0.3% diethylamine in isopropanol:methanol (70:30)].

(48) Purification Method N

(49) Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×19 mm, 5 μm), 16 mL/min, gradient 15%-40% (over 32 min), 100% (over 3 min), 100-15% (over 5 min), mobile phase (A): 0.05% ammonia in water, (B): 100% acetonitrile].

(50) Purification Method O

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

(52) Purification Method P

(53) Prep HPLC: [Reversed Phase (GEMINI C-18, 250×21.2 mm, 5 μm), 16 mL/min, gradient 35%-60% (over 18 min), 100% (over 2 min), 100%-35% (over 2 min), mobile phase (A): 10 mM ammonium bicarbonate in water, (B): 100% acetonitrile].

(54) Purification Method 0

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

(56) Purification Method R

(57) Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×19 mm, 5 μm), 14 mL/min, gradient 50% (over 18 min), 100% (over 3 min), 100%-50% (over 4 min), mobile phase (A): 0.1% ammonia in water, (B): acetonitrile:methanol (50:50)].

(58) Purification Method S

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

(60) Purification Method T

(61) Prep HPLC: [Reversed Phase (YMC ACTUS TRIART C-18, 250×20 mm, 5 μm), 15 mL/min, gradient 45%-60% (over 20 min), 100% (over 3 min), 100%-45% (over 2 min), mobile phase (A): 0.1% ammonia in water, (B): 100% acetonitrile].

(62) Purification Method U

(63) Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 15 mL/min, gradient 5% (over 5 min), 5%-24% (over 3 min), 24% (over 34 min), 100% (over 3 min), 100%-5% (over 3 min), mobile phase (A): 0.1% ammonia in water, (B) 100% acetonitrile].

(64) Purification Method V

(65) Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 15 mL/min, gradient 5% (over 5 min), 5%-30% (over 3 min), 30%-35% (over 37 min), 100% (over 2 min), 100%-5% (over 3 min), mobile phase (A): 0.1% ammonia in water, (B) 100% acetonitrile].

(66) Purification Method W

(67) Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 16 mL/min, gradient 40%-55% (over 10 min), 100% (over 2 min), 100%-40% (over 2 min), mobile phase (A): 10 mM ammonium bicarbonate in water, (B) 100% acetonitrile].

(68) Purification Method X

(69) SFC: [(CHIRALPAK AD-H, 250×21 mm, 5 μm), 50 mL/min, Isochratic (A:B) 80:20 (over 5 min), mobile phase (A): 100% liquid CO.sub.2, (B): 0.1% TFA in isopropanol].

(70) Purification Method Y

(71) Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×19 mm, 5 μm), 15 mL/min, gradient 30%-50% (over 20 min), 100% (over 2 min), 100%-30% (over 2 min), mobile phase (A): 10 mM ammonium bicarbonate in water, (B): 100% acetonitrile].

(72) Purification Method Z

(73) Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 150×19 mm, 5 μm), 15 mL/min, gradient 15%-65% (over 16 min), 100% (over 2 min), 100%-15% (over 2 min), mobile phase (A): 10 mM ammonium bicarbonate in water, (B) 100% acetonitrile].

(74) Purification Method AA

(75) SFC: [(CHIRALPAK AD-H, 250×21 mm, 5 μm), 70 mL/min, Isochratic (A:B) 85:15 (over 10 min), mobile phase (A): 100% liquid CO.sub.2, (B): isopropanol].

(76) Purification Method AB

(77) Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 17 mL/min, gradient 10%-30% (over 40 min), 30% (over 3 min), 100% (over 2 min), 100%-10% (over 2 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.05% ammonia in water, (B) 100% acetonitrile].

(78) Purification Method AC

(79) Prep HPLC: [Reversed Phase (GEMINI C-18, 250×21.2 mm, 5 μm), 16 mL/min, gradient 45%-80% (over 12 min), 100% (over 2 min), 100%-45% (over 2 min), mobile phase (A): 0.1% ammonia in water, (B): 100% acetonitrile].

(80) Purification Method AD

(81) Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 15 mL/min, gradient 15%-45% (over 28 min), 100% (over 2 min), 100%-15% (over 2 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.05% ammonia in water, (B) 100% acetonitrile].

(82) Purification Method AE

(83) SFC: [(CHIRALCEL AD-H, 250×21 mm, 5 μm), 70 mL/min, Isochratic (A:B) 85:15 (over 12 min), mobile phase (A): 100% liquid CO.sub.2, (B): 0.1% diethylamine in isopropanol methanol (50:50)].

(84) Purification Method AF

(85) Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×19 mm, 5 μm), 16 mL/min, gradient 38%-45% (over 16 min), 100% (over 2 min), 100%-38% (over 4 min), mobile phase (A): 0.1% ammonia in water, (B): 100% acetonitrile].

(86) Purification Method AG

(87) SFC: [(CHIRALPAK AD-H, 250×21 mm, 5 μm), 60 mL/min, Isochratic (A:B) 80:20 (over 6 min), mobile phase (A): 100% liquid CO.sub.2, (B): 0.1% ammonia in isopropanol].

(88) Purification Method AH

(89) Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 15 mL/min, gradient 22% (over 30 min), 100% (over 2 min), 100%-22% (over 3 min), mobile phase (A): 5 mM ammonium bicarbonate in water, (B) 100% acetonitrile].

(90) Purification Method AI

(91) Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×19 mm, 5 μm), 12 mL/min, gradient 27% (over 35 min), 100% (over 2 min), 100%-27% (over 3 min), mobile phase (A): 0.1% ammonia in water, (B): 100% acetonitrile].

(92) Purification Method AJ

(93) Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×19 mm, 5 μm), 11 mL/min, gradient 33% (over 25 min), 100% (over 2 min), 100%-33% (over 3 min), mobile phase (A): 10 mM ammonium bicarbonate in water, (B): 100% acetonitrile].

(94) Purification Method AK

(95) Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×19 mm, 5 μm), 18 mL/min, gradient 35% (over 85 min), 100% (over 2 min), 100%-35% (over 8 min), mobile phase (A): 0.1% ammonia in water, (B): 100% acetonitrile].

(96) Purification Method AL

(97) Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 15 mL/min, gradient 40% (over 25 min), 100% (over 2 min), 100%-40% (over 3 min), mobile phase (A): 0.02% ammonia in water, (B) 100% acetonitrile].

(98) Purification Method AM

(99) Prep HPLC: [Reversed Phase (YMC ACTUS TRIART C-18, 250×20 mm, 5 μm), 15 mL/min, gradient 60%-92% (over 16 min), 100% (over 2 min), 100%-60% (over 4 min), mobile phase (A): 0.1% ammonia in water, (B): 100% acetonitrile].

(100) Purification Method AN

(101) Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 16 mL/min, gradient 10%-50% (over 10 min), 50% (over 15 min), 100% (over 2 min), 100%-10% (over 3 min), mobile phase (A): 5 mM ammonium bicarbonate in water, (B) 100% acetonitrile].

(102) Purification Method AO

(103) Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 150×19 mm, 5 μm), 15 mL/min, gradient 30% (over 27.5 min), 100% (over 2.5 min), 100%-30% (over 4 min), mobile phase (A): 0.1% ammonia in water, (B): 100% acetonitrile].

(104) Purification Method AP

(105) Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 16 mL/min, gradient 15% (over 2 min), 15%-35% (over 8 min), 35% (over 18 min), 100% (over 3 min), 100%-15% (over 4 min), mobile phase (A): 10 mM ammonium bicarbonate in water, (B) 100% acetonitrile].

(106) Purification Method AQ

(107) Prep HPLC: [Reversed Phase (YMC ACTUS TRIART C-18, 250×20 mm, 5 μm), 17 mL/min, gradient 20%-55% (over 20 min), 100% (over 2 min), 100%-20% (over 3 min), mobile phase (A): 0.1% ammonia in water, (B): 100% acetonitrile].

(108) Purification Method AR

(109) Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×19 mm, 5 μm), 15 mL/min, gradient 60%-70% (over 15 min), 100% (over 2 min), 100%-60% (over 3 min), mobile phase (A): 0.1% ammonia in water, (B): acetonitrile:methanol (50:50)].

(110) Purification Method AS

(111) SFC: [(CHIRALPAK IC, 250×21 mm, 5 μm), 70 mL/min, Isochratic (A:B) 70:30 (over 15 min), mobile phase (A): 100% liquid CO.sub.2, (B): 0.3% diethylamine in methanol].

(112) Purification Method AT

(113) Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 150×19 mm, 5 μm), 15 mL/min, gradient 35%-40% (over 15 min), 100% (over 3 min), 100%-35% (over 2 min), mobile phase (A): 10 mM ammonium bicarbonate in water+0.1% ammonia in water, (B) 100% acetonitrile].

(114) Purification Method AU

(115) Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×19 mm, 5 μm), 15 mL/min, gradient 20%-35% (over 20 min), 100% (over 2 min), 100%-20% (over 2 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1% ammonia in water, (B): 100% acetonitrile].

(116) Purification Method AV

(117) SFC: [(CHIRALPAK IB, 250×20 mm, 5 μm), 70 mL/min, Isochratic (A:B) 85:15 (over 5 min), mobile phase (A): 100% liquid CO.sub.2, (B): 0.1% diethylamine in isopropanol:methanol (50:50)].

(118) Purification Method AW

(119) Prep HPLC: [Reversed Phase (YMC ACTUS TRIART C-18, 150×20 mm, 5 μm), 15 mL/min, gradient 50% (over 17 min), 100% (over 2 min), 100%-50% (over 4 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1% ammonia in water, (B): 100% acetonitrile].

(120) Purification Method AX

(121) SFC: [(CHIRALPAK IC, 250×21 mm, 5 μm), 70 mL/min, Isochratic (A:B) 88:12 (over 11 min), mobile phase (A): 100% liquid CO.sub.2, (B): 0.1% diethylamine in isopropanol:methanol (50:50)].

(122) Purification Method AY

(123) Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 15 mL/min, gradient 20%-70% (over 20 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].

(124) Purification Method AZ

(125) SFC: [(CHIRALPAK AD-H, 250×21 mm, 5 μm), 70 mL/min, Isochratic (A:B) 85:15 (over 4.5 min), mobile phase (A): 100% liquid CO.sub.2, (B): 0.1% diethylamine in methanol].

(126) Purification Method BA

(127) Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 150×19 mm, 5 μm), 15 mL/min, gradient 22%-45% (over 40 min), 100% (over 2 min), 100%-22% (over 3 min), mobile phase (A): 0.02% ammonia in water, (B) 100% acetonitrile].

(128) Purification Method BB

(129) Prep HPLC: [Reversed Phase (Gemini-NX C-18, 100×30 mm, 5 μm), 30 mL/min, gradient 20%-50% (over 8.7 min), 50% (over 0.5 min), 50%-100% (over 0.2 min), 100% (over 1 min), 100%-20% (over 0.2 min), 20% (over 0.9 min), mobile phase (A): 2.5 L of water+5 mL of 28% ammonia solution in water, (B): 100% acetonitrile].

(130) Purification Method BC

(131) Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 15 mL/min, gradient 30%-50% (over 27 min), 50%-100% (over 2 min), 100% (over 1 min), 100%-30% (over 1 min), mobile phase (A): 0.02% ammonia in water, (B) 100% acetonitrile].

(132) Purification Method BD

(133) Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 15 mL/min, gradient 30%-35% (over 28 min), 35%-55% (over 7 min), 100% (over 2 min), 100%-30% (over 2 min), mobile phase (A): 0.02% ammonia in water, (B) 100% acetonitrile].

(134) Purification Method BE

(135) Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 15 mL/min, gradient 15%-65% (over 18 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].

(136) Purification Method BF

(137) Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 15 mL/min, gradient 43% (over 14 min), 43%-70% (over 1 min), 70% (over 7 min), 100% (over 1 min), 100%-43% (over 2 min), mobile phase (A): 10 mM ammonium bicarbonate in water, (B) 100% acetonitrile].

(138) Purification Method BG

(139) Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 150×19 mm, 5 μm), 15 mL/min, gradient 40%-55% (over 16 min), 55% (over 2 min), 100% (over 3 min), 100%-40% (over 3 min), mobile phase (A): 0.1% ammonia in water, (B): 100% acetonitrile].

(140) Purification Method BH

(141) Prep HPLC: [Reversed Phase (Gemini-NX C-18, 100×30 mm, 5 μm), 30 mL/min, gradient 30%-50% (over 8.7 min), 50% (over 0.5 min), 50%-100% (over 0.2 min), 100% (over 1 min), 100%-30% (over 0.2 min), 30% (over 0.9 min), mobile phase (A): 2.5 L of water+5 mL of 28% ammonia solution in water, (B): 100% acetonitrile].

(142) Purification Method BI

(143) SFC: [(CHIRALPAK AS-H, 250×20 mm, 5 μm), 50 mL/min, Isochratic (A:B) 80:20, mobile phase (A): 100% liquid CO.sub.2, (B): 0.1% ammonia in ethanol].

(144) Purification Method BJ

(145) Prep HPLC: [Reversed Phase (Gemini-NX C-18, 100×30 mm, 5 μm), 30 mL/min, gradient 40%-60% (over 8.7 min), 60% (over 0.5 min), 60%-100% (over 0.2 min), 100% (over 1 min), 100%-40% (over 0.2 min), 40% (over 0.9 min), mobile phase (A): 2.5 L of water+5 mL of 28% ammonia solution in water, (B): 100% acetonitrile].

(146) Purification Method BK

(147) SFC: [(LUX C4, 250×21.2 mm, 5 μm), 50 mL/min, Isochratic (A:B) 70:30, mobile phase (A): 100% liquid CO.sub.2, (B): 0.1% ammonia in methanol].

(148) Purification Method BL

(149) Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×19 mm, 5 μm), 15 mL/min, gradient 25%-60% (over 15 min), 100% (over 3 min), 100%-25% (over 2 min) mobile phase (A): 10 mM ammonium bicarbonate in water, (B): 100% acetonitrile].

(150) Purification Method BM

(151) SFC: [(CHIRALPAK AD-H, 250×21 mm, 5 μm), 70 mL/min, Isochratic (A:B) 80:20 (over 15 min), mobile phase (A): 100% liquid CO.sub.2, (B): isopropanol:acetonitrile (50:50)].

(152) Purification Method BN

(153) Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 15 mL/min, gradient 35%-50% (over 17 min), 100% (over 2 min), 100%-35% (over 2 min), mobile phase (A): 0.1% ammonia in water, (B) 100% acetonitrile].

(154) Purification Method BO

(155) Prep HPLC: [Reversed Phase (Gemini-NX C-18, 100×30 mm, 5 μm), 30 mL/min, gradient 50%-70% (over 8.7 min), 70% (over 0.5 min), 70%-100% (over 0.2 min), 100% (over 1 min), 100%-50% (over 0.2 min), 50% (over 0.9 min), mobile phase (A): 2.5 L of water+5 mL of 28% ammonia solution in water, (B): 100% acetonitrile].

(156) Purification Method BP

(157) Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×19 mm, 5 μm), 12 mL/min, gradient 55% (over 28 min), 100% (over 2 min), 100%-55% (over 5 min), mobile phase (A): 10 mM ammonium bicarbonate in water, (B): 100% acetonitrile].

(158) Purification Method BQ

(159) Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×19 mm, 5 μm), 15 mL/min, gradient 20%-45% (over 40 min), 100% (over 3 min), 100%-20% (over 3 min), mobile phase (A): 10 mM ammonium bicarbonate in water, (B): 100% acetonitrile].

(160) Purification Method BR

(161) Prep HPLC: [Reversed Phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 15 mL/min, gradient 10%-30% (over 10 min), 30% (over 22 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].

(162) Purification Method BS

(163) Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 16 mL/min, gradient 20%-50% (over 20 min), 50% (over 12 min), 100% (over 2 min), 100%-20% (over 3 min), mobile phase (A): 5 mM ammonium bicarbonate in water, (B) acetonitrile:methanol (50:50)].

(164) Purification Method BT

(165) Chiral HPLC: [Normal Phase (CHIRALPAK IC, 250×21 mm, 5 μm), 18 mL/min, Isochratic (A:B) 75:25 (over 38 min), mobile phase (A): 0.1% diethylamine in hexane, (B): 0.1% diethylamine in isopropanol:methanol (50:50)].

(166) Purification Method BU

(167) Prep HPLC: [Reversed Phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 17 mL/min, gradient 30% (over 22 min), 100% (over 2 min), 100%-30% (over 3 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.05% ammonia in water, (B): 100% acetonitrile].

(168) Purification Method BV

(169) Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 15 mL/min, gradient 15%-40% (over 10 min), 40% (over 3 min), 100% (over 2 min), 100%-15% (over 3 min), mobile phase (A): 5 mM ammonium bicarbonate in water, (B) 100% acetonitrile].

(170) Purification Method BW

(171) SFC: [(CHIRALCEL OX-H, 250×21 mm, 5 μm), 70 mL/min, Isochratic (A:B) 80:20 (over 13 min), mobile phase (A): 100% liquid CO.sub.2, (B): 0.1% diethylamine in isopropanol methanol (50:50)].

(172) Purification Method BX

(173) Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 15 mL/min, gradient 15%-40% (over 18 min), 100% (over 2 min), 100%-15% (over 4 min), mobile phase (A): 5 mM ammonium bicarbonate in water, (B) 100% acetonitrile].

(174) Purification Method BY

(175) SFC: [(CHIRALPAK IC, 250×21 mm, 5 μm), 70 mL/min, Isochratic (A:B) 70:30 (over 10 min), mobile phase (A): 100% liquid CO.sub.2, (B): 0.3% diethylamine in isopropanol:acetonitrile (60:40)].

(176) Purification Method BZ

(177) Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 15 mL/min, gradient 20%-35% (over 18 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].

(178) Purification Method CA

(179) SFC: [(CHIRALCEL OX-H, 250×21 mm, 5 μm), 75 mL/min, Isochratic (A:B) 85:15 (over 20 min), mobile phase (A): 100% liquid CO.sub.2, (B): 0.1% diethylamine in isopropanol methanol (50:50)].

(180) Purification Method CB

(181) Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 15 mL/min, gradient 25-35% (over 20 min), 100% (over 2 min), 100%-25% (over 1 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1% ammonia in water, (B) 100% acetonitrile].

(182) Purification Method CC

(183) SFC: [(CHIRALPAK IB, 250×20 mm, 5 μm), 70 mL/min, Isochratic (A:B) 87:13 (over 5 min), mobile phase (A): 100% liquid CO.sub.2, (B): 0.1% diethylamine in isopropanol:methanol (50:50)].

(184) Purification Method CD

(185) Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 16 mL/min, gradient 5%-40% (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].

(186) Purification Method CE

(187) SFC: [(CHIRALPAK IB, 250×20 mm, 5 μm), 70 mL/min, Isochratic (A:B) 85:15 (over 6 min), mobile phase (A): 100% liquid CO.sub.2, (B): 0.1% diethylamine in methanol].

(188) Purification Method CF

(189) SFC: [(CHIRALPAK IC, 250×21 mm, 5 μm), 70 mL/min, Isochratic (A:B) 75:25 (over 21 min), mobile phase (A): 100% liquid CO.sub.2, (B): 0.1% diethylamine in isopropanol].

(190) Purification Method CG

(191) Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 16 mL/min, gradient 5%-37% (over 27 min), 37% (over 2 min), 100% (over 2 min), 100%-5% (over 4 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1% ammonia in water, (B) 100% acetonitrile].

(192) Purification Method CH

(193) SFC: [(CHIRALPAK IB, 250×20 mm, 5 μm), 80 mL/min, Isochratic (A:B) 85:15 (over 5 min), mobile phase (A): 100% liquid CO.sub.2, (B): 0.1% diethylamine in isopropanol:methanol (50:50)].

(194) Purification Method CI

(195) Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 15 mL/min, gradient 0%-55% (over 20 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].

(196) Purification Method CJ

(197) SFC: [(CHIRALPAK IB, 250×20 mm, 5 μm), 50 mL/min, Isochratic (A:B) 85:15 (over 6 min), mobile phase (A): 100% liquid CO.sub.2, (B): 0.1% diethylamine in methanol].

(198) Purification Method CK

(199) Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 150×19 mm, 5 μm), 15 mL/min, gradient 22% (over 60 min), 100% (over 5 min), 100%-22% (over 4 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.05% ammonia in water, (B): 100% acetonitrile].

(200) Purification Method CL

(201) Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 15 mL/min, gradient 10-40% (over 20 min), 40% (over 2 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].

(202) Purification Method CM

(203) SFC: [(CHIRALPAK IB, 250×20 mm, 5 μm), 70 mL/min, Isochratic (A:B) 88:12 (over 10 min), mobile phase (A): 100% liquid CO.sub.2, (B): 0.1% diethylamine in methanol].

(204) Purification Method CN

(205) Prep HPLC: [Reversed Phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 16 mL/min, gradient 15%-16.5% (over 15 min), 16.5% (over 13 min), 100% (over 4 min), 100%-15% (over 5 min), mobile phase (A): 5 mM ammonium bicarbonate in water, (B): 100% acetonitrile].

(206) Purification Method CO

(207) SFC: [(CHIRALCEL OX-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 methanol].

(208) Purification Method CP

(209) Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×19 mm, 5 μm), 15 mL/min, gradient 5%-25% (over 29 min), 25% (over 9 min), 100% (over 3 min), 100%-5% (over 4 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.05% ammonia in water, (B): 100% acetonitrile].

(210) Purification Method CO

(211) SFC: [(CHIRALPAK IB, 250×20 mm, 5 μm), 70 mL/min, Isochratic (A:B) 75:25 (over 14 min), mobile phase (A): 100% liquid CO.sub.2, (B): 0.1% diethylamine in isopropanol:methanol (50:50)].

(212) Purification Method CR

(213) Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 15 mL/min, gradient 0%-33% (over 26 min), 100% (over 2 min), 100%-0% (over 2 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1% ammonia in water, (B): 100% acetonitrile].

(214) Purification Method CS

(215) SFC: [(CHIRALPAK IB, 250×20 mm, 5 μm), 70 mL/min, Isochratic (A:B) 87:13 (over 8 min), mobile phase (A): 100% liquid CO.sub.2, (B): 0.1% diethylamine in isopropanol:methanol (50:50)].

(216) Purification Method CT

(217) Prep HPLC: [Reversed Phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 16 mL/min, gradient 13%-40% (over 32 min), 100% (over 2 min), 100%-13% (over 2 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.05% ammonia in water, (B): 100% acetonitrile].

(218) Purification Method CU

(219) Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 17 mL/min, gradient 5%-23% (over 40 min), 23% (over 30 min), 100% (over 3 min), 100%-5% (over 4 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.05% ammonia in water, (B) 100% acetonitrile].

(220) Purification Method CV

(221) Prep HPLC: [Reversed Phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 15 mL/min, gradient 20%-45% (over 18 min), 45% (over 2 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].

(222) Purification Method CW

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

(224) Purification Method CX

(225) Prep HPLC: [Reversed Phase (X SELECT PHENYL HEXYL, 250×19 mm, 5 μm), 16 mL/min, gradient 5%-37% (over 27 min), 37% (over 2 min), 100% (over 2 min), 100%-5% (over 4 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1% ammonia in water, (B): 100% acetonitrile].

(226) Purification Method CY

(227) Prep HPLC: [Reversed Phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 11 mL/min, gradient 5%-65% (over 25 min), 65% (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].

(228) Purification Method CZ

(229) Prep HPLC: [Reversed Phase (X-BRIDGE C-8, 250×19 mm, 5 μm), 15 mL/min, gradient 30%-45% (over 16 min), 100% (over 2 min), 100%-30% (over 5 min), mobile phase (A): 5 mM ammonium bicarbonate in water+0.1% ammonia in water, (B): 100% acetonitrile].

ABBREVIATIONS

(230) aq.=aqueous conc.=concentrated DCM=dichloromethane DIPEA=diisopropylethylamine DMF=dimethylformamide DMSO=dimethylsulfoxide ES(I)=electro spray ionisation EtOAc=ethyl acetate 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 MeOH=Methanol min(s)=minute(s) MS=mass spectrometry nm=nanometre(s) NMR=nuclear magnetic resonance SFC=supercritical fluid chromatography STAB=sodium triacetoxyborohydride TEA=triethylamine TFA=trifluoroacetic acid THF=tetrahydrofuran TLC=thin layer chromatography

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

(232) Synthesis of Intermediates:

(233) Route 1

(234) Procedure for the preparation of Intermediate 46, methyl 6-oxo-2-azaspiro[3.4]octane-2-carboxylate

(235) ##STR00118##

(236) tert-Butyl 6-oxo-2-azaspiro [3.4] octane-2-carboxylate, (Intermediate 44) (120 mg, 0.533 mmol) was dissolved in DCM (2 mL) at 0° C. and TFA (1 mL) was added. The reaction mixture was allowed to warm to room temperature and was stirred for 2 h, then concentrated in-vacuo. The residue was dried by co-evaporation from diethyl ether (3×10 mL) to give 2-azaspiro[3.4]octan-6-one trifluoroacetic acid salt (120 mg, 100%) as a gum.

(237) LCMS (System 1, Method E): m/z 125 (M+H).sup.+ (ES.sup.+), at 0.60 min, 202 nm.

(238) 2-Azaspiro[3.4]octan-6-one trifluoroacetic acid salt (60 mg, 0.251 mmol) was dissolved in DCM (5 mL) and triethylamine (0.2 mL, 1.25 mmol) was added at 0° C. Methyl chloroformate, (Intermediate 45) (94 mg, 0.37 mmol) was added at 0° C. and the reaction mixture was allowed to warm to room temperature and was stirred for 2 h. The mixture was concentrated in-vacuo and the residue was partitioned between H.sub.2O (25 mL) and EtOAc (25 mL). The aqueous layer was further extracted with EtOAc (2×10 mL) and the combined organic layers were dried (Na.sub.2SO.sub.4) and the solvent was removed in-vacuo to give methyl 6-oxo-2-azaspiro[3.4]octane-2-carboxylate, (Intermediate 46) (30 mg, 34%) as an oil. The data for Intermediate 46 are in Table 2.

(239) Route 2

(240) Procedure for the preparation of Intermediate 53, ethyl 5-oxo-2-azabicyclo[2.2.2]octane-2-carboxylate

(241) ##STR00119##

(242) tert-Butyl 5-oxo-2-azabicyclo[2.2.2]octane-2-carboxylate, (Intermediate 51) (120 mg, 0.53 mmol) was stirred in HCl solution in 1,4-dioxane (4 M, 0.5 mL) for 1 h at room temperature. The mixture was concentrated in-vacuo and triturated with diethyl ether (2×2 mL) to give 2-azabicyclo[2.2.2]octan-5-one hydrochloride salt (80 mg, 93%) as a solid.

(243) LCMS (System 2, Method A): m/z 126 (M+H).sup.+ (ESI+ve), at 2.01 min, 250 nm.

(244) 2-Azabicyclo[2.2.2]octan-5-one hydrochloride salt (80 mg, 0.49 mmol) and triethylamine (0.2 mL, 1.48 mmol) were dissolved in DCM (4 mL) and ethyl chloroformate, (Intermediate 52) (0.07 mL, 0.74 mmol) was added at 0° C. The mixture was stirred at room temperature for 2 h and then partitioned between cold H.sub.2O (15 mL) and EtOAc (15 mL). The aqueous layer was further extracted with EtOAc (2×15 mL), and the combined organic layers were dried (Na.sub.2SO.sub.4) and the solvent was removed in-vacuo to give ethyl 5-oxo-2-azabicyclo[2.2.2]octane-2-carboxylate, (Intermediate 53) (90 mg, 96%) as a gum.

(245) The data for Intermediate 53 are in Table 2.

(246) General Synthetic Procedures

(247) Route A

(248) Typical Procedure for the Preparation of Amines as Exemplified by the Preparation of Example 1-1, ethyl 6-[(1R,5S,6r)-6-(ethoxycarbonyl)-3-azabicyclo[3.1.0]hex-3-yl]-2-azaspiro[3.3]heptane-2-carboxylate

(249) ##STR00120##

(250) Ethyl (1R,5S,6r)-3-azabicyclo[3.1.0]hexane-6-carboxylate, (Intermediate 1) (0.12 g, 0.62 mmol), ethyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate, (Intermediate 2) (0.14 g, 0.82 mmol), triethylamine (0.082 g, 0.82 mmol) and zinc chloride (4.2 mg, 0.031 mmol) were dissolved in methanol (15 mL) under a nitrogen atmosphere. The resulting mixture was stirred for 3 h at 50-60° C. and then NaCNBH.sub.3 (0.052 g, 0.82 mmol) was added portion-wise at 0-10° C. The reaction mixture was stirred for 2 h at room temperature, then partitioned between H.sub.2O (15 mL) and EtOAc (25 mL). The aqueous layer was further extracted with EtOAc (2×25 mL), the combined organic layers were dried (Na.sub.2SO.sub.4) and the solvent was removed in-vacuo. The residue was purified using purification method A to give ethyl 6-[(1R,5S,6r)-6-(ethoxycarbonyl)-3-azabicyclo[3.1.0]hex-3-yl]-2-azaspiro[3.3]heptane-2-carboxylate, Example 1-1 (40 mg, 20%) as a gum.

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

(252) Route B

(253) Typical Procedure for the Preparation of Amines as Exemplified by the Preparation of Example 1-2, ethyl 6-[(1R,5S,6r)-6-(diethylcarbamoyl)-3-azabicyclo[3.1.0]hex-3-yl]-2-azaspiro[3.3]heptane-2-carboxylate

(254) ##STR00121##

(255) Ethyl (1R,5S,6r)-3-azabicyclo[3.1.0]hexane-6-carboxylate, (Intermediate 1) (100 mg, 0.52 mmol), TEA (0.36 mL, 2.61 mmol), tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate, (Intermediate 3) (117 mg, 0.52 mmol) and ZnCl.sub.2 solution in diethyl ether (1 M, 0.02 mL, 0.02 mmol) were dissolved in MeOH (10 mL) under nitrogen and stirred for 4 h at 60° C. NaCNBH.sub.3 (98 mg, 1.57 mmol) was then added portion-wise at 0° C. and the resulting reaction mixture was stirred for 12 h at room temperature. The reaction mixture was partitioned between H.sub.2O (30 mL) and 10% MeOH in DCM (50 mL), and the aqueous layer was further extracted with 10% MeOH in DCM (2×50 mL). The combined organic layers were dried (Na.sub.2SO.sub.4), the solvent was removed in-vacuo and the crude product was purified by column chromatography (Neutral Alumina, 0-2% methanol in DCM) to give tert-butyl 6-[(1R,5S,6r)-6-(ethoxycarbonyl)-3-azabicyclo[3.1.0]hexan-3-yl]-2-azaspiro[3.3]heptane-2-carboxylate (92 mg, 50%) as a gum. LCMS (System 1, Method C): m/z 351 (M+H)+(ESI+ve), at 5.21 min, 202 nm.

(256) tert-Butyl 6-[(1R,5S,6r)-6-(ethoxycarbonyl)-3-azabicyclo[3.1.0]hexan-3-yl]-2-azaspiro[3.3]heptane-2-carboxylate (92 mg, 0.26 mmol), TEA (0.07 mL, 0.53 mmol) and diethylamine, (Intermediate 4) (0.081 mL, 0.79 mmol) were dissolved in toluene (10 mL) at 0° C. under nitrogen and the mixture was stirred for 20 min at room temperature. Trimethylaluminium solution in toluene (2 M, 0.39 mL, 0.79 mmol) was added at 0° C. and the reaction mixture was then heated at 60° C. for 16 h. The reaction mixture was partitioned between ice-cold water (50 mL) and 10% MeOH in DCM (100 mL), and the aqueous layer was further extracted with 10% MeOH in DCM (2×100 mL). The combined organic layers were washed with ammonium chloride solution, dried (Na.sub.2SO.sub.4) and the solvent was removed in-vacuo to give crude tert-butyl 6-[(1R,5S,6r)-6-(diethylcarbamoyl)-3-azabicyclo[3.1.0]hexan-3-yl]-2-azaspiro[3.3]heptane-2-carboxylate (108 mg, >100%) as a gum.

(257) LCMS (System 1, Method C): m/z 378 (M+H)+(ESI+ve), at 4.44 min, 210 nm.

(258) tert-Butyl 6-[(1R,5S,6r)-6-(diethylcarbamoyl)-3-azabicyclo[3.1.0]hexan-3-yl]-2-azaspiro[3.3]heptane-2-carboxylate (108 mg, 0.29 mmol) was dissolved in DCM (10 mL) and trifluoroacetic acid (0.22 mL, 2.86 mmol) was added at 0° C. The resulting reaction mixture was stirred at 25° C. for 16 h. The solvents were removed in-vacuo and the residue was purified by triturating with diethyl ether (3×30 mL) to give (1R,5S,6r)-3-(2-azaspiro[3.3]heptan-6-yl)-N,N-diethyl-3-azabicyclo[3.1.0]hexane-6-carboxamide trifluoroacetic acid salt (110 mg, 95%) as a gum.

(259) LCMS (System 1, Method C): m/z 278 (M+H)+(ESI+ve), at 0.30 min, 202 nm.

(260) (1R,5S,6r)-3-(2-azaspiro[3.3]heptan-6-yl)-N,N-diethyl-3-azabicyclo[3.1.0]hexane-6-carboxamide trifluoroacetic acid salt (79 mg, 0.29 mmol) and TEA (0.12 mL, 0.86 mmol) were dissolved in DCM (10 mL). Ethyl chloroformate, (Intermediate 52) (0.04 mL, 0.43 mmol) was added at 0° C. and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was partitioned between ammonium chloride solution (50 mL) and 10% MeOH in DCM (100 mL) and the aqueous layer was further extracted with 10% MeOH in DCM (2×100 mL). The combined organic layers were dried (Na.sub.2SO.sub.4) and the solvent was removed in-vacuo. The crude product was purified using purification method B to give ethyl 6-[(1R,5S,6r)-6-(diethylcarbamoyl)-3-azabicyclo[3.1.0]hex-3-yl]-2-azaspiro[3.3]heptane-2-carboxylate, Example 1-2 (13 mg, 9%) as a gum.

(261) The data for Example 1-2 are in Table 3.

(262) Route C

(263) Typical Procedure for the Preparation of Amines as Exemplified by the Preparation of Example 1-3, ethyl 6-{(1R,5S,6r)-6-[ethyl(propan-2-yl)carbamoyl]-3-azabicyclo[3.1.0]hex-3-yl}-2-azaspiro[3.3]heptane-2-carboxylate

(264) ##STR00122##

(265) Ethyl 6-[(1R,5S,6r)-6-(ethoxycarbonyl)-3-azabicyclo[3.1.0]hex-3-yl]-2-azaspiro[3.3]heptane-2-carboxylate, Example 1-1 (45 mg, 0.14 mmol), TEA (0.03 mL, 0.28 mmol) and N-ethylisopropylamine, (Intermediate 5) (0.05 mL, 0.42 mmol) were dissolved in toluene (10 mL) at 0° C. under nitrogen and the resulting mixture was stirred for 20 min at room temperature. Trimethylaluminium solution in toluene (2 M, 0.35 mL, 0.70 mmol) was added at 0° C. and the reaction mixture was heated at 60° C. for 16 h. The reaction mixture was partitioned between ice-cold water (25 mL) and 10% MeOH in DCM (50 mL) and the aqueous layer was further extracted with 10% MeOH in DCM (2×50 mL). The combined organic layers were washed with ammonium chloride solution, dried (Na.sub.2SO.sub.4) and the solvent was removed in-vacuo. The crude product was purified using purification method C to give ethyl 6-{(1R,5S,6r)-6-[ethyl(propan-2-yl)carbamoyl]-3-azabicyclo[3.1.0]hex-3-yl}-2-azaspiro[3.3]heptane-2-carboxylate, Example 1-3 (2 mg, 1%) as a gum.

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

(267) Route D

(268) Typical Procedure for the Preparation of Amines as Exemplified by the Preparation of Example 1-4, ethyl 6-[(1R,5S,6r)-6-(2-methyl-1,3-thiazol-4-yl)-3-azabicyclo[3.1.0]hex-3-yl]-2-azaspiro[3.3]heptane-2-carboxylate

(269) ##STR00123##

(270) 3-tert-Butyl 6-ethyl (1R,5S,6r)-3-azabicyclo[3.1.0]hexane-3,6-dicarboxylate, (Intermediate 6) (400 mg, 1.57 mmol) was dissolved in toluene (10 mL). N,O-Dimethylhydroxylamine hydrochloride, (Intermediate 7) (183 mg, 1.88 mmol) and triethylamine (0.7 mL, 4.71 mmol) were added and the resulting mixture was stirred at 25° C. for 30 min. Trimethylaluminium solution in toluene (2 M, 3.1 mL, 6.27 mmol) was added dropwise at 0° C., and the reaction mixture was stirred at 40° C. for 2 h. The solvents were removed in-vacuo, the residue was partitioned between H.sub.2O (120 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), the solvent was removed in-vacuo and the residue was purified by column chromatography (Normal basic activated alumina, 0.5-1.0% MeOH in DCM) to give tert-butyl (1R,5S,6r)-6-[methoxy(methyl)carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (260 mg, 61%) as a gum.

(271) LCMS (System 1, Method C): m/z 271 (M+H)+(ESI+ve), at 3.82 min, 215 nm.

(272) tert-Butyl (1R,5S,6r)-6-[methoxy(methyl)carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (260 mg, 0.96 mmol) was dissolved in THF (5 mL) and the solution was cooled down to 0° C.

(273) Methylmagnesium bromide solution in diethyl ether, (Intermediate 8) (3 M, 1.0 mL, 2.88 mmol) was added dropwise and the resulting reaction mixture was stirred at 0° C. for 1 h. The solvents were then removed in-vacuo, and the residue was partitioned between H.sub.2O (100 mL) and EtOAc (80 mL). The aqueous layer was further extracted with EtOAc (2×80 mL), and the combined organic layers were dried (Na.sub.2SO.sub.4), and the solvents were removed in-vacuo to give crude tert-butyl (1R,5S,6r)-6-acetyl-3-azabicyclo[3.1.0]hexane-3-carboxylate, (Intermediate 40) (190 mg, 88%) as a gum. The crude product was used in the next step without further purification.

(274) LCMS (System 1, Method C): m/z 170 (M+H-56)+(ESI+ve), at 4.00 min, 202 nm.

(275) tert-Butyl (1R,5S,6r)-6-acetyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (50 mg, 0.22 mmol) was dissolved in MeOH (3 mL). Phenyltrimethylammonium tribromide (Intermediate 9) (83 mg, 0.22 mmol) was added and the resulting reaction mixture was stirred at 25° C. for 7 h and then concentrated in-vacuo to give crude tert-butyl (1R,5S,6r)-6-(bromoacetyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (65 mg, 97%) as a gum. The crude product was used in the next step without further workup or purification due to its instability.

(276) LCMS (System 2, Method A): m/z 289/291 (M+H-16)+(ESI+ve), at 2.30 min, 202 nm.

(277) tert-Butyl (1R,5S,6r)-6-(bromoacetyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (65 mg, 0.21 mmol) was dissolved in MeOH (3 mL), thioacetamide, (Intermediate 10) (32 mg, 0.43 mmol) was added and the resulting mixture was stirred at 25° C. for 2 h. The solvents were removed in-vacuo and the residue was partitioned between H.sub.2O (40 mL) and EtOAc (30 mL). The aqueous layer was further extracted with EtOAc (2×30 mL), the combined organic layers were dried (Na.sub.2SO.sub.4) and the solvents were removed in-vacuo. The residue was purified by column chromatography (Normal neutral activated alumina, 15-20% EtOAc in hexane) to give tert-butyl (1R,5S,6r)-6-(2-methyl-1,3-thiazol-4-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (21 mg, 34%) as a gum.

(278) LCMS (System 1, Method C): m/z 281 (M+H)+(ESI+ve), at 4.78 min, 251 nm.

(279) tert-Butyl (1R,5S,6r)-6-(2-methyl-1,3-thiazol-4-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (20 mg, 0.07 mmol) was dissolved in DCM (1 mL) and trifluoroacetic acid (0.3 mL) was added dropwise. The resulting reaction mixture was stirred at 25° C. for 5 h and then the solvents were removed in-vacuo. The residue was purified by triturating with pentane (3×0.5 mL) to give (1R,5S,6r)-6-(2-methyl-1,3-thiazol-4-yl)-3-azabicyclo[3.1.0]hexane trifluoroacetic acid salt (12 mg, 92%) as a solid.

(280) LCMS (System 1, Method C): m/z 181 (M+H)+(ESI+ve), at 3.03 min, 220 nm.

(281) (1R,5S,6r)-6-(2-Methyl-1,3-thiazol-4-yl)-3-azabicyclo[3.1.0]hexane trifluoroacetic acid salt (12 mg, 0.07 mmol), ethyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate, (Intermediate 2) (14 mg, 0.07 mmol), triethylamine (0.03 mL, 0.22 mmol) and ZnCl.sub.2 (1 mg, 0.01 mmol) were dissolved in MeOH (2 mL) and the resulting mixture was stirred at 65° C. for 5 h. The mixture was cooled to 0° C. and NaBH.sub.3CN (13 mg, 0.22 mmol) was added portion-wise. The resulting reaction mixture was stirred at 25° C. for 17 h and then the solvents were removed in-vacuo. The residue was partitioned between H.sub.2O (30 mL) and EtOAc (20 mL) and the aqueous layer was further extracted with EtOAc (2×20 mL). The combined organic layers were dried (Na.sub.2SO.sub.4) and the solvent was removed in-vacuo. The residue was purified using purification method D to give ethyl 6-[(1R,5S,6r)-6-(2-methyl-1,3-thiazol-4-yl)-3-azabicyclo[3.1.0]hex-3-yl]-2-azaspiro[3.3]heptane-2-carboxylate, Example 1-4 (4 mg, 17%) as a gum.

(282) The data for Example 1-4 are in Table 3.

(283) Route E

(284) Typical Procedure for the Preparation of Amines as Exemplified by the Preparation of Example 2-19, ethyl 2-[(1R,5S,6r)-6-(4-azaspiro[2.3]hex-4-ylcarbonyl)-3-azabicyclo[3.1.0]hex-3-yl]-6-azaspiro[3.4]octane-6-carboxylate

(285) ##STR00124##

(286) Ethyl 2-[(1R,5S,6r)-6-(ethoxycarbonyl)-3-azabicyclo[3.1.0]hex-3-yl]-6-azaspiro[3.4]octane-6-carboxylate, Example 2-1 (150 mg, 0.45 mmol) was dissolved in THF (2 mL) and a solution of LiOH (32 mg, 1.34 mmol) in water (2 mL) was added at −20° C. The resulting mixture was stirred at room temperature for 5 h. The reaction mixture was then acidified by the addition of conc. aq. HCl and the solvents were removed in-vacuo to give (1R,5S,6r)-3-[6-(ethoxycarbonyl)-6-azaspiro[3.4]oct-2-yl]-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (115 mg, 84%) as a solid.

(287) LCMS (System 2, Method D): m/z 309 (M+H)+(ESI+ve), at 1.35 min, 202 nm.

(288) (1R,5S,6r)-3-[6-(Ethoxycarbonyl)-6-azaspiro[3.4]oct-2-yl]-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (115 mg, 0.37 mmol) and HATU (212 mg, 0.56 mmol) were dissolved in DMF at 0° C. and DIPEA (0.19 mL, 1.12 mmol) was added. The resulting mixture was stirred at 0° C. for 1 h, then 4-azaspiro[2.3]hexane, (Intermediate 27) (35.0 mg, 0.41 mmol) was added at 0° C. and the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was partitioned between cold H.sub.2O (20 mL) and EtOAc (10 mL), and the aqueous layer was further extracted with EtOAc (2×10 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 using purification method AD followed by purification method AE to give ethyl 2-[(1R,5S,6r)-6-(4-azaspiro[2.3]hex-4-ylcarbonyl)-3-azabicyclo[3.1.0]hex-3-yl]-6-azaspiro[3.4]octane-6-carboxylate, Example 2-19 Isomer 1 (18 mg, 12%) as a gum and ethyl 2-[(1R,5S,6r)-6-(4-azaspiro[2.3]hex-4-ylcarbonyl)-3-azabicyclo[3.1.0]hex-3-yl]-6-azaspiro[3.4]octane-6-carboxylate, Example 2-19 Isomer 2 (18 mg, 12%) as a gum.

(289) The data for Example 2-19 Isomer 1 and Isomer 2 are in Table 3.

(290) Route F

(291) Typical Procedure for the Preparation of Amines as Exemplified by the Preparation of Example 2-25, ethyl 2-[(1R,5S,6r)-6-(N-methoxypropanimidoyl)-3-azabicyclo[3.1.0]hexan-3-yl]-6-azaspiro[3.4]octane-6-carboxylate

(292) ##STR00125##

(293) tert-Butyl (1R,5S,6r)-6-propanoyl-3-azabicyclo[3.1.0]hexane-3-carboxylate, (Intermediate 32) (160 mg, 0.67 mmol) was dissolved in DCM (3 mL) and trifluoroacetic acid (1 mL) was added dropwise. The resulting reaction mixture was stirred at 25° C. for 5 h. The solvents were removed in-vacuo, and the residue was purified by triturating with pentane (3×1 mL) to give 1-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl]propan-1-one trifluoroacetic acid salt (80 mg, 99%) as a gum.

(294) LCMS (System 1, Method C): m/z 140 (M+H)+(ESI+ve), at 2.76 min, 202 nm.

(295) 1-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl]propan-1-one trifluoroacetic acid salt (80 mg, 0.57 mmol), ethyl 2-oxo-6-azaspiro[3.4]octane-6-carboxylate, (Intermediate 11) (124 mg, 0.63 mmol), triethylamine (0.1 mL, 1.72 mmol) and ZnCl.sub.2 (7 mg, 0.06 mmol) were dissolved in MeOH (10 mL) and the resulting mixture was stirred at 65° C. for 5 h. The mixture was then cooled to 0° C. and NaBH.sub.3CN (109 mg, 0.57 mmol) was added portion-wise. The reaction mixture was stirred at 25° C. for 17 h, then the solvents were removed in-vacuo. The residue was partitioned between H.sub.2O (100 mL) and EtOAc (80 mL), and the aqueous layer was further extracted with EtOAc (2×80 mL). The combined organic layers were dried (Na.sub.2SO.sub.4), the solvent was removed in-vacuo, and the residue was purified by column chromatography (Normal neutral activated alumina, 50% EtOAc in hexane) to give ethyl 2-[(1R,5S,6r)-6-propanoyl-3-azabicyclo[3.1.0]hexan-3-yl]-6-azaspiro[3.4]octane-6-carboxylate (130 mg, 75%) as a gum.

(296) LCMS (System 1, Method C): m/z 321 (M+H)+(ESI+ve), at 4.23 min, 220 nm.

(297) Ethyl 2-[(1R,5S,6r)-6-propanoyl-3-azabicyclo[3.1.0]hexan-3-yl]-6-azaspiro[3.4]octane-6-carboxylate (100 mg, 0.31 mmol) and sodium acetate (77 mg, 0.94 mmol) were dissolved in ethanol (5 mL) and the resulting mixture was stirred at 25° C. for 30 min. O-Methylhydroxylamine hydrochloride, (Intermediate 33) (52 mg, 0.63 mmol) was added and the reaction mixture was stirred at 25° C. for 17 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), the combined organic layers were dried (Na.sub.2SO.sub.4) and the solvent was removed in-vacuo. The residue was purified using purification method AK to give ethyl 2-[(1R,5S,6r)-6-(N-methoxypropanimidoyl)-3-azabicyclo[3.1.0]hexan-3-yl]-6-azaspiro[3.4]octane-6-carboxylate, Example 2-25 Isomer 1 (7 mg, 6%), ethyl 2-[(1R,5S,6r)-6-(N-methoxypropanimidoyl)-3-azabicyclo[3.1.0]hexan-3-yl]-6-azaspiro[3.4]octane-6-carboxylate, Example 2-25 Isomer 2 (9 mg, 8%), ethyl 2-[(1R,5S,6r)-6-(N-methoxypropanimidoyl)-3-azabicyclo[3.1.0]hexan-3-yl]-6-azaspiro[3.4]octane-6-carboxylate, Example 2-25 Isomer 3 (18 mg, 17%) and ethyl 2-[(1R,5S,6r)-6-(N-methoxypropanimidoyl)-3-azabicyclo[3.1.0]hexan-3-yl]-6-azaspiro[3.4]octane-6-carboxylate, Example 2-25 Isomer 4 (17 mg, 16%), all as gums.

(298) The data for Example 2-25 Isomer 2 and Isomer 4 are in Table 3.

(299) Route G

(300) Typical Procedure for the Preparation of Amines as Exemplified by the Preparation of Example 2-27, ethyl 2-{(1R,5S,6s)-6-[ethyl(2,2,2-trifluoroethyl)amino]-3-azabicyclo[3.1.0]hexan-3-yl}-6-azaspiro[3.4]octane-6-carboxylate

(301) ##STR00126##

(302) tert-Butyl (1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylate, (Intermediate 35) (100 mg, 0.51 mmol) was dissolved in THF (5 mL) and N-methyl-2-pyrrolidinone (150 mg, 1.52 mmol) and triethylamine (0.3 mL, 2.02 mmol) were added. The resulting mixture was stirred at 70° C. for 1 h, then 2,2,2-trifluoroethyl trifluoromethanesulfonate, (Intermediate 36) (129 mg, 0.56 mmol) was added at 25° C. The resulting reaction mixture was stirred at 80° C. for 18 h, then the solvents were removed in-vacuo. The residue was partitioned between H.sub.2O (80 mL) and EtOAc (60 mL), and the aqueous layer was further extracted with EtOAc (2×60 mL). The combined organic layers were dried (Na.sub.2SO.sub.4), the solvents were removed in-vacuo and residue was purified by column chromatography (Normal neutral activated alumina, 2-5% MeOH in DCM) to give tert-butyl (1R,5S,6s)-6-[(2,2,2-trifluoroethyl)amino]-3-azabicyclo[3.1.0]hexane-3-carboxylate (118 mg, 84%) as a gum.

(303) LCMS (System 1, Method C): m/z 225 (M+H-56)+(ESI+ve), at 4.61 min, 202 nm.

(304) tert-Butyl (1R,5S,6s)-6-[(2,2,2-trifluoroethyl)amino]-3-azabicyclo[3.1.0]hexane-3-carboxylate (118 mg, 0.43 mmol) was dissolved in methanol (5 mL) and acetaldehyde, (Intermediate 37) (38 mg, 0.86 mmol), triethylamine (0.2 mL, 1.29 mmol) and ZnCl.sub.2 (6 mg, 0.43 mmol) were added. The resulting mixture was stirred at 40° C. for 7 h, then NaBH.sub.3CN (81 mg, 1.29 mmol) was added portion-wise. The reaction mixture was stirred at 25° C. for 17 h, then the solvents were removed in-vacuo. The residue was partitioned between H.sub.2O (100 mL) and EtOAc (80 mL), and the aqueous layer was further extracted with EtOAc (2×80 mL). The combined organic layers were dried (Na2SO.sub.4), the solvent was removed in-vacuo and the residue was purified by column chromatography (Normal basic activated alumina, 0.5-1.0% MeOH in DCM) to give tert-butyl (1R,5S,6s)-6-[ethyl(2,2,2-trifluoroethyl)amino]-3-azabicyclo[3.1.0]hexane-3-carboxylate (125 mg, 96%) as a gum.

(305) LCMS (System 1, Method C): m/z 309 (M+H)+(ESI+ve), at 5.58 min, 202 nm.

(306) tert-Butyl (1R,5S,6s)-6-[ethyl(2,2,2-trifluoroethyl)amino]-3-azabicyclo[3.1.0]hexane-3-carboxylate (125 mg, 0.41 mmol) was dissolved in 1,4-dioxane (5 mL) and HCl solution in 1,4-dioxane (4 M, 3 mL) was added dropwise. The resulting mixture was stirred at 25° C. for 5 h, then the solvents were removed in-vacuo. The residue was purified by triturating with diethyl ether (3×3 mL) to give (1R,5S,6s)-N-ethyl-N-(2,2,2-trifluoroethyl)-3-azabicyclo[3.1.0]hexan-6-amine hydrochloride salt (100 mg, 100%) as a solid.

(307) LCMS (System 2, Method A): m/z 209 (M+H)+(ESI+ve), at 1.42 min, 202 nm.

(308) (1R,5S,6s)-N-ethyl-N-(2,2,2-trifluoroethyl)-3-azabicyclo[3.1.0]hexan-6-amine hydrochloride salt (100 mg, 0.48 mmol), ethyl 2-oxo-6-azaspiro[3.4]octane-6-carboxylate, (Intermediate 11) (95 mg, 0.48 mmol), triethylamine (0.2 mL, 1.44 mmol) and ZnCl.sub.2 (7 mg, 0.05 mmol) were dissolved in MeOH (10 mL) and the resulting mixture was stirred at 70° C. for 8 h. The mixture was cooled to 0° C. and NaBH3CN (91 mg, 1.44 mmol) was added portion-wise. The reaction mixture was stirred at 25° C. for 17 h, then the solvents were removed in-vacuo, The residue was partitioned between H.sub.2O (100 mL) and EtOAc (80 mL), and the aqueous layer was further extracted with EtOAc (2×80 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 AM to give ethyl 2-{(1R,5S,6s)-6-[ethyl(2,2,2-trifluoroethyl)amino]-3-azabicyclo[3.1.0]hexan-3-yl}-6-azaspiro[3.4]octane-6-carboxylate, Example 2-27 (53 mg, 33%) as a gum.

(309) The data for Example 2-27 are in Table 3.

(310) Route H

(311) Typical Procedure for the Preparation of Amines as Exemplified by the Preparation of Example 2-28, ethyl 2-[(1R,5S,6s)-6-(1-phenylethoxy)-3-azabicyclo[3.1.0]hex-3-yl]-6-azaspiro[3.4]octane-6-carboxylate

(312) ##STR00127##

(313) (1R,5S,6s)-3-Azabicyclo[3.1.0]hexan-6-ol, (Intermediate 38) (110 mg, 1.11 mmol) was dissolved in DCM (10 mL) and triethylamine (0.5 mL, 3.30 mmol) was added. The mixture was stirred at 0° C. for 20 min, then di-tert-butyl dicarbonate (362 mg, 1.66 mmol) was added at 0° C. The resulting reaction mixture was stirred at 25° C. for 2 h, then the solvents were removed in-vacuo. The residue was partitioned between H.sub.2O (80 mL) and EtOAc (60 mL), and the aqueous layer was further extracted with EtOAc (2×60 mL). The combined organic layers were dried (Na.sub.2SO.sub.4), the solvent was removed in-vacuo and the residue was purified by triturating with pentane give tert-butyl (1R,5S,6s)-6-hydroxy-3-azabicyclo[3.1.0]hexane-3-carboxylate (180 mg, 81%) as a liquid.

(314) LCMS (System 1, Method C): m/z 144 (M+H-56)+(ESI+ve), at 3.40 min, 210 nm.

(315) tert-butyl (1R,5S,6s)-6-hydroxy-3-azabicyclo[3.1.0]hexane-3-carboxylate (180 mg, 0.90 mmol) was dissolved in DMF (8 mL), cooled to 0° C. and NaH (60% in paraffin oil, 108 mg, 2.71 mmol) was added. The mixture was stirred at 0° C. for 20 min, then (1-bromoethyl)benzene, (Intermediate 39) (250 mg, 1.36 mmol) was added dropwise at 0° C. The resulting reaction mixture was stirred at 25° C. for 5 h, then the solvents were removed in-vacuo. The residue was partitioned between H.sub.2O (100 mL) and EtOAc (60 mL), and the aqueous layer was further extracted with EtOAc (2×60 mL). The combined organic layers were dried (Na.sub.2SO.sub.4), and the solvents were removed in-vacuo to give tert-butyl (1R,5S,6s)-6-(1-phenylethoxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate (250 mg, 91%) as a liquid.

(316) LCMS (System 1, Method C): m/z 248 (M+H-56)+(ESI+ve), at 5.70 min, 210 nm.

(317) tert-Butyl (1R,5S,6s)-6-(1-phenylethoxy)-3-azabicyclo[3.1.0]hexane-3-carboxylate (250 mg, 0.83 mmol) was dissolved in DCM (10 mL) and cooled to 0° C. Trifluoroacetic acid (2 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 purified by triturating with pentane (3×1 mL) to give (1R,5S,6s)-6-(1-phenylethoxy)-3-azabicyclo[3.1.0]hexane trifluoroacetic acid salt (160 mg, 96%) as a gum.

(318) LCMS (System 1, Method C): m/z 204 (M+H)+(ESI+ve), at 3.97 min, 210 nm.

(319) (1R,5S,6s)-6-(1-Phenylethoxy)-3-azabicyclo[3.1.0]hexane trifluoroacetic acid salt (150 mg, 0.74 mmol), ethyl 2-oxo-6-azaspiro[3.4]octane-6-carboxylate, (Intermediate 11) (145 mg, 0.74 mmol), triethylamine (0.3 mL, 2.21 mmol) and ZnCl.sub.2 (10 mg, 0.07 mmol) were dissolved in MeOH (10 mL) and the resulting mixture was stirred at 65° C. for 7 h. The mixture was cooled to 0° C. and NaBH3CN (139 mg, 2.21 mmol) was added portion-wise. The reaction mixture was stirred at 25° C. for 17 h, the the solvents were removed in-vacuo. The residue was partitioned between H.sub.2O (100 mL) and EtOAc (80 mL), and the aqueous layer was further extracted with EtOAc (2×80 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 AN to give ethyl 2-[(1R,5S,6s)-6-(1-phenylethoxy)-3-azabicyclo[3.1.0]hex-3-yl]-6-azaspiro[3.4]octane-6-carboxylate, Example 2-28 Isomer 1 (8 mg, 3%) as a gum and ethyl 2-[(1R,5S,6s)-6-(1-phenylethoxy)-3-azabicyclo[3.1.0]hex-3-yl]-6-azaspiro[3.4]octane-6-carboxylate, Example 2-28 Isomer 2 (7 mg, 3%) as a gum.

(320) The data for Example 2-28 Isomer 1 and Isomer 2 are in Table 3.

(321) Route I

(322) Typical Procedure for the Preparation of Amines as Exemplified by the Preparation of Example 2-29, ethyl 2-[(1R,5S,6r)-6-(1-methyl-1H-pyrazol-5-yl)-3-azabicyclo[3.1.0]hex-3-yl]-6-azaspiro[3.4]octane-6-carboxylate

(323) ##STR00128##

(324) tert-Butyl (1R,5S,6r)-6-acetyl-3-azabicyclo[3.1.0]hexane-3-carboxylate, (Intermediate 40) (200 mg, 0.89 mmol) was dissolved in DMF (10 mL) and N,N-dimethylformamide dimethyl acetal, (Intermediate 41) (211 mg, 1.78 mmol) was added. The resulting mixture was stirred at 100° C. for 24 h, then methylhydrazine sulfate, (Intermediate 42) (269 mg, 1.86 mmol) was added at 25° C., and the mixture was stirred at 100° C. for 30 h. The solvents were removed in-vacuo, and the residue was partitioned between H.sub.2O (150 mL) and EtOAc (100 mL). The aqueous layer was further extracted with EtOAc (2×100 mL), the combined organic layers were dried (Na.sub.2SO.sub.4), and the solvents were removed in-vacuo. The residue was purified by column chromatography (Normal basic activated alumina, 1-3% MeOH in DCM) to give a mixture of tert-butyl (1R,5S,6r)-6-(1-methyl-1H-pyrazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate and tert-butyl (1R,5S,6r)-6-(1-methyl-1H-pyrazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (170 mg, 73%) as a liquid.

(325) LCMS (System 1, Method C): m/z 264 (M+H)+(ESI+ve), at 4.10 min, 202 nm.

(326) A mixture of tert-butyl (1R,5S,6r)-6-(1-methyl-1H-pyrazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate and tert-butyl (1R,5S,6r)-6-(1-methyl-1H-pyrazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (170 mg, 0.65 mmol) was dissolved in 1,4-dioxane (5 mL) and HCl solution in 1,4-dioxane (4 M, 3 mL) was added dropwise. The resulting mixture was stirred at 25° C. for 16 h, then the solvents were removed in-vacuo. The residue was purified by triturating with diethyl ether (3×5 mL) to give a mixture of (1R,5S,6r)-6-(1-methyl-1H-pyrazol-5-yl)-3-azabicyclo[3.1.0]hexane hydrochloride salt and (1R,5S,6r)-6-(1-methyl-1H-pyrazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride salt (120 mg, 93%) as a gum.

(327) LCMS (System 1, Method C): m/z 164 (M+H)+(ESI+ve), at 2.53 min, 221 nm.

(328) A mixture of (1R,5S,6r)-6-(1-methyl-1H-pyrazol-5-yl)-3-azabicyclo[3.1.0]hexane hydrochloride salt and (1R,5S,6r)-6-(1-methyl-1H-pyrazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride salt (120 mg, 0.74 mmol), ethyl 2-oxo-6-azaspiro[3.4]octane-6-carboxylate, (Intermediate 11) (160 mg, 0.81 mmol), triethylamine (0.3 mL, 2.20 mmol) and ZnCl.sub.2 (10 mg, 0.07 mmol) were dissolved in MeOH (10 mL) and stirred together at 65° C. for 8 h. The mixture was then cooled to 0° C., NaBH.sub.3CN (140 mg, 2.20 mmol) was added portion-wise, and the resulting mixture was stirred at 25° C. for 17 h. The solvents were removed in-vacuo, and the residue was partitioned between H.sub.2O (100 mL) and EtOAc (80 mL). The aqueous layer was further extracted with EtOAc (2×80 mL), the combined organic layers were dried (Na.sub.2SO.sub.4), and the solvent was removed in-vacuo. The residue was purified using purification method AO to give ethyl 2-[(1R,5S,6r)-6-(1-methyl-1H-pyrazol-5-yl)-3-azabicyclo[3.1.0]hex-3-yl]-6-azaspiro[3.4]octane-6-carboxylate, Example 2-29 Isomer 1 (9 mg, 4%), ethyl 2-[(1R,5S,6r)-6-(1-methyl-1H-pyrazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]-6-azaspiro[3.4]octane-6-carboxylate Isomer 1 (8 mg, 3%), ethyl 2-[(1R,5S,6r)-6-(1-methyl-1H-pyrazol-5-yl)-3-azabicyclo[3.1.0]hex-3-yl]-6-azaspiro[3.4]octane-6-carboxylate, Example 2-29 Isomer 2 (6 mg, 2%) and ethyl 2-[(1R,5S,6r)-6-(1-methyl-1H-pyrazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]-6-azaspiro[3.4]octane-6-carboxylate Isomer 2 (8 mg, 3%), all as gums.

(329) The data for Example 2-29 Isomer 2 are in Table 3.

(330) Route J

(331) Typical Procedure for the Preparation of Amines as Exemplified by the Preparation of Example 3-3, methyl 6-[(1R,5S,6r)-6-(diethylcarbamoyl)-3-azabicyclo[3.1.0]hex-3-yl]-2-azaspiro[3.4]octane-2-carboxylate

(332) ##STR00129##

(333) 3-tert-Butyl 6-ethyl (1 R,5S,6r)-3-azabicyclo[3.1.0]hexane-3,6-dicarboxylate, (Intermediate 6) (200 mg, 0.78 mmol) and TEA (0.31 mL, 2.35 mmol) were dissolved in toluene and cooled to 0° C. Diethylamine, (Intermediate 4) (0.16 mL, 1.57 mmol) was added, followed by trimethylaluminium solution in toluene (2 M, 0.8 mL, 1.57 mmol). The reaction mixture was heated at 60° C. for 5 h, then diluted with water (150 mL) and extracted with EtOAc (3×60 mL). The combined organic layers were dried (Na.sub.2SO.sub.4) and concentrated in-vacuo to give the crude product, which was purified by column chromatography (Normal neutral activated alumina, 0-30% EtOAc in hexane) to give tert-butyl (1R,5S,6r)-6-(diethylcarbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (130 mg, 59%) as a gum.

(334) LCMS (System 1, Method C): m/z 283 (M+H)+(ESI+ve), at 4.22 min, 210 nm.

(335) tert-Butyl (1R,5S,6r)-6-(diethylcarbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (125 mg, 0.44 mmol) was dissolved in dichloromethane (5 mL) and cooled to 0° C. TFA (2.5 mL) was added and the resulting mixture was allowed to stir at room temperature for 3 h. The mixture was then diluted with toluene (2.5 mL) and concentrated in-vacuo to give the crude (1R,5S,6r)-N,N-diethyl-3-azabicyclo[3.1.0]hexane-6-carboxamide trifluoroacetic acid salt (125 mg, 100%) as a gum, which was used in the next step without further purification.

(336) LCMS (System 1, Method C): m/z 183 (M+H)+(ESI+ve), at 2.60 min, 215 nm.

(337) (1R,5S,6r)-N,N-Diethyl-3-azabicyclo[3.1.0]hexane-6-carboxamide trifluoroacetic acid salt (125 mg, 0.68 mmol), methyl 6-oxo-2-azaspiro[3.4]octane-2-carboxylate, (Intermediate 46) (125 mg, 1.31 mmol) and TEA (0.47 mL, 3.41 mmol) were dissolved in methanol (10 mL). The mixture was degassed for 30 min under nitrogen, ZnCl.sub.2 solution in diethyl ether (1 M, 0.03 mL, 0.03 mmol) was added, and the mixture was stirred at 60° C. for 3 h. The mixture was cooled to 0° C. and NaCNBH.sub.3 (129 mg, 2.04 mmol) was added portion-wise. The reaction mixture was then stirred at room temperature for 5 h, diluted with water (150 mL) and extracted with EtOAc (3×60 mL). The combined organic layers were dried (Na.sub.2SO.sub.4) and concentrated in-vacuo. The residue was purified using purification method AS to give methyl 6-[(1R,5S,6r)-6-(diethylcarbamoyl)-3-azabicyclo[3.1.0]hex-3-yl]-2-azaspiro[3.4]octane-2-carboxylate, Example 3-3 Isomer 1 (20 mg, 8%) as a gum and methyl 6-[(1R,5S,6r)-6-(diethylcarbamoyl)-3-azabicyclo[3.1.0]hex-3-yl]-2-azaspiro[3.4]octane-2-carboxylate, Example 3-3 Isomer 2 (18 mg, 8%) as a gum.

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

(339) Route J

(340) Typical Procedure for the Preparation of Amines as Exemplified by the Preparation of Example 7-5, ethyl 3-[(1R,5S,6r)-6-{[acetyl(ethyl)amino]methyl}-3-azabicyclo[3.1.0]hex-3-yl]-8-azabicyclo[3.2.1]octane-8-carboxylate

(341) ##STR00130##

(342) 3-tert-Butyl 6-ethyl (1R,5S,6r)-3-azabicyclo[3.1.0]hexane-3,6-dicarboxylate, (Intermediate 6) (650 mg, 2.55 mmol) was dissolved in THF (10 mL) and cooled to 0° C. LiBH.sub.4 solution in THF (3 M, 3.4 mL, 10.2 mmol) was added and the mixture was stirred at room temperature for 16 h. The mixture was diluted with water (150 mL) and extracted with EtOAc (3×60 mL). The combined organic layers were dried (Na.sub.2SO.sub.4), concentrated in-vacuo and the residue was purified by column chromatography (Normal phase, neutral silica gel, 60-120 mesh, 0-30% EtOAc in hexane) to give tert-butyl (1R,5S,6r)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (400 mg, 74%) as a liquid.

(343) LCMS (System 1, Method C): m/z 214 (M+H)+(ESI+ve), at 3.37 min, 210 nm.

(344) tert-Butyl (1R,5S,6r)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (230 mg, 1.08 mmol) was dissolved in dichloromethane (10 mL) and cooled to 0° C. Dess-Martin periodinane, (Intermediate 48) (503 mg, 1.19 mmol) was added portion-wise and the reaction mixture was stirred at room temperature for 6 h. The reaction mixture was quenched with a saturated aqueous solution of NaHCO.sub.3, then diluted with water (100 mL) and extracted with EtOAc (3×40 mL). The combined organic layers were dried (Na.sub.2SO.sub.4) and concentrated in-vacuo to give the crude tert-butyl (1R,5S,6r)-6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (240 mg, 100%) as a liquid, which was used in the next step without further purification.

(345) LCMS (System 1, Method C): m/z 156 (M+H-56)+(ESI+ve), at 3.97 min, 210 nm.

(346) tert-Butyl (1R,5S,6r)-6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (230 mg, 1.10 mmol) was dissolved in methanol (10 mL). Ethylamine solution in THF, (Intermediate 49) (2 M, 2.7 mL, 5.45 mmol) was added, followed by ZnCl.sub.2 solution in diethyl ether (1 M, 0.05 mL, 0.05 mmol). The resulting mixture was stirred at 60° C. for 6 h, then cooled to 0° C. and NaCNBH.sub.3 (202 mg, 2.13 mmol) was added. The mixture was stirred at room temperature for 16 h, then concentrated in-vacuo. The residue was diluted with water (160 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were dried (Na.sub.2SO.sub.4) and concentrated in-vacuo to give the crude tert-butyl (1R,5S,6r)-6-[(ethylamino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (200 mg, 77%) as a liquid, which was used in the next step without further purification.

(347) LCMS (System 1, Method E): m/z 241 (M+H)+(ESI+ve), at 3.78 min, 210 nm.

(348) tert-Butyl (1R,5S,6r)-6-[(ethylamino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (20 mg, 0.83 mmol) was dissolved in dichloromethane (10 mL) and cooled to 0° C. TEA (0.3 mL, 2.49 mmol) was added, followed by acetyl chloride, (Intermediate 50) (130 mg, 1.66 mmol).

(349) The reaction mixture was stirred at 0° C. for 2 h, then diluted with water (150 mL) and extracted with EtOAc (3×40 mL). The combined organic layers were dried (Na.sub.2SO.sub.4) and concentrated in-vacuo. The residue was purified by column chromatography (Normal phase, neutral alumina, 0-2% MeOH in DCM) to give tert-butyl (1R,5S,6r)-6-{[acetyl(ethyl)amino]methyl}-3-azabicyclo[3.1.0]hexane-3-carboxylate (130 mg, 55%) as a liquid.

(350) LCMS (System 1, Method E): m/z 227 (M+H-56)+(ESI+ve), at 4.18 min, 202 nm.

(351) tert-Butyl (1R,5S,6r)-6-{[acetyl(ethyl)amino]methyl}-3-azabicyclo[3.1.0]hexane-3-carboxylate (120 mg, 0.43 mmol) was dissolved in dichloromethane (5 mL) and cooled to 0° C. TFA (2.5 mL) was added and the reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with toluene (2.5 mL) and concentrated in-vacuo to give the crude N-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-ylmethyl]-N-ethylacetamide trifluoroacetic acid salt (120 mg, 100%) as a gum, which was used in the next step without further purification.

(352) LCMS (System 1, Method E): m/z 183 (M+H)+(ESI+ve), at 2.31 min, 202 nm.

(353) N-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-ylmethyl]-N-ethylacetamide trifluoroacetic acid salt (103 mg, 0.57 mmol) and TEA (0.4 mL, 2.83 mmol) were dissolved in MeOH (5 mL). Ethyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate, (Intermediate 47) (122 mg, 0.62 mmol) was added, followed by ZnCl.sub.2 solution in diethyl ether (1 M, 0.3 mL, 0.28 mmol). The resulting mixture was stirred at 60° C. for 5 h, then cooled to 0° C. and NaCNBH.sub.3 (105 mg, 1.69 mmol) was added. The mixture was stirred at 60° C. for 12 h, then diluted with water (150 mL) and extracted with EtOAc (3×40 mL). The combined organic layers were dried (Na.sub.2SO.sub.4) and concentrated in-vacuo and the residue was purified using purification method BE to give ethyl 3-[(1R,5S,6r)-6-{[acetyl(ethyl)amino]methyl}-3-azabicyclo[3.1.0]hex-3-yl]-8-azabicyclo[3.2.1]octane-8-carboxylate, Example 4-5 Isomer 1 (52 mg, 25%) as a gum and ethyl 3-[(1R,5S,6r)-6-{[acetyl(ethyl)amino]methyl}-3-azabicyclo[3.1.0]hex-3-yl]-8-azabicyclo[3.2.1]octane-8-carboxylate, Example 4-5 Isomer 2 (21 mg, 10%) as a gum.

(354) The data for Example 4-5 Isomer 2 are in Table 3.

(355) TABLE-US-00004 TABLE 2 Intermediates Intermediate Synthetic Intermediates Number Name Route Used Data 1 Ethyl (1R,5S,6r)-3- — — Commercially available, azabicyclo[3.1.0]hexane-6- CAS: 174456-77-0 carboxylate 2 Ethyl 6-oxo-2-azaspiro[3.3]heptane- — — See WO2016147011 2-carboxylate 3 tert-Butyl 6-oxo-2- — — Commercially available, azaspiro[3.3]heptane-2-carboxylate CAS: 1181816-12-5 4 Diethylamine — — Commercially available, CAS: 109-89-7 5 N-Ethylisopropylamine — — Commercially available, CAS: 19961-27-4 6 3-tert-Butyl 6-ethyl (1R,5S,6r)-3- — — Commercially available, azabicyclo[3.1.0]hexane-3,6- CAS: 134575-37-4 dicarboxylate 7 N,O-Dimethylhydroxylamine — — Commercially available, hydrochloride CAS: 6638-79-5 8 Methylmagnesium bromide — — Commercially available, CAS: 75-16-1 9 Phenyltrimethylammonium tribromide — — Commercially available, CAS: 4207-56-1 10 Thioacetamide — — Commercially available, CAS: 62-55-5 11 Ethyl 2-oxo-6-azaspiro[3.4]octane-6- — — See WO2015118342 carboxylate 12 Isobutylamine — — Commercially available, CAS: 78-81-9 13 Cyclobutylmethylamine hydrochloride — — Commercially available, CAS: 5454-82-0 14 1-Methylcyclobutylamine — — Commercially available, CAS: 40571-47-9 15 N-Methylethylamine — — Commercially available, CAS: 624-78-2 16 Methyl 2-oxo-6-azaspiro[3.4]octane-6- — — See WO2015118342 carboxylate 17 Methyl 2-[(1R,5S,6r)-6- A 1 and 16 LCMS (System 1, Method C): (ethoxycarbonyl)-3- m/z 323 (M + H).sup.+ (ES.sup.+), at azabicyclo[3.1.0]hex-3-yl]-6- 4.33 min, 202 nm azaspiro[3.4]octane-6-carboxylate 18 N-Methylpropan-2-amine — — Commercially available, CAS: 4747-21-1 19 N-Ethylcyclopropanamine — — Commercially available, CAS: 26389-72-0 20 Pyrrolidine — — Commercially available, CAS: 123-75-1 21 Piperidine — — Commercially available, CAS: 98-77-1 22 (2R)-2-Methylpiperidine — — Commercially available, CAS: 1722-95-8 23 (2S)-2-Methylpiperidine — — Commercially available, CAS: 3197-42-0 24 Azepane — — Commercially available, CAS: 111-49-9 25 1,4-Oxazepane — — Commercially available, CAS: 5638-60-8 26 2-Azaspiro[3.3]heptane hydrochloride — — Commercially available, CAS: 1420271-08-4 27 4-Azaspiro[2.3]hexane — — Commercially available, CAS: 125441-13-6 28 1-Azaspiro[3.3]heptane — — Commercially available, hydrochloride CAS: 1986337-29-4 29 6-Oxa-1-azaspiro[3.3]heptane — — Commercially available, hemioxalate CAS: 1380571-72-1 30 N-Methoxyethanamine — — Commercially available, CAS: 1195657-97-6 31 Ethylmagnesium bromide — — Commercially available, CAS: 925-90-6 32 tert-Butyl (1R,5S,6r)-6-propanoyl-3- D 6, 7 and 31 LCMS (System 2, Method A): azabicyclo[3.1.0]hexane-3- (first two m/z 184 (M + H − 56).sup.+ (ES.sup.+), carboxylate steps) at 2.16 min, 202 nm 33 O-Methylhydroxylamine — — Commercially available, hydrochloride CAS: 593-56-6 34 6-(Trifluoromethyl)-3- — — Commercially available, azabicyclo[3.1.0]hexane CAS: 1311314-49-4 hydrochloride 35 tert-Butyl (1R,5S,6s)-6-amino-3- — — Commercially available, azabicyclo[3.1.0]hexane-3- CAS: 273206-92-1 carboxylate 36 2,2,2-Trifluoroethyl — — Commercially available, trifluoromethanesulfonate CAS: 6226-25-1 37 Acetaldehyde — — Commercially available, CAS: 75-07-0 38 (1R,5S,6s)-3-Azabicyclo[3.1.0]hexan- — — Commercially available, 6-ol CAS: 1524707-84-3 39 (1-Bromoethyl)benzene — — Commercially available, CAS: 585-71-7 40 tert-Butyl (1R,5S,6r)-6-acetyl-3- D 6, 7 and 8 LCMS (System 1, Method C): azabicyclo[3.1.0]hexane-3- (first two m/z 170 (M + H − 56).sup.+ (ESI carboxylate steps) +ve), at 4.00 min, 202 nm 41 N,N-Dimethylformamide dimethyl — — Commercially available, acetal CAS: 4637-24-5 42 Methylhydrazine sulfate — — Commercially available, CAS: 302-15-8 43 Ethyl 6-oxo-2-azaspiro[3.4]octane-2- — — See WO2016147011 carboxylate 44 tert-Butyl 6-oxo-2-azaspiro [3.4] — — Commercially available, octane-2-carboxylate CAS: 1363382-39-1 45 Methyl chloroformate — — Commercially available, CAS: 79-22-1 46 Methyl 6-oxo-2-azaspiro[3.4]octane-2- 1 44 and 45 LCMS (System 1, Method E): carboxylate m/z 184 (M + H).sup.+ (ES.sup.+), at 2.47 min, 202 nm 47 Ethyl 3-oxo-8- — — Commercially available, azabicyclo[3.2.1]octane-8-carboxylate CAS: 32499-64-2 48 Dess-Martin periodinane — — Commercially available, CAS: 87413-09-0 49 Ethylamine — — Commercially available, CAS: 75-04-7 50 Acetyl chloride — — Commercially available, CAS: 75-36-5 51 tert-Butyl 5-oxo-2- — — Commercially available, azabicyclo[2.2.2]octane-2-carboxylate CAS: 617714-22-4 52 Ethyl chloroformate — — Commercially available, CAS: 541-41-3 53 Ethyl 5-oxo-2- 2 51 and 52 LCMS (System 2, Method A): azabicyclo[2.2.2]octane-2-carboxylate m/z 198 (M + H).sup.+ (ES.sup.+), at 1.64 min, 229 nm 54 tert-Butyl (1S,4S)-5-oxo-2- — — Commercially available, azabicyclo[2.2.2]octane-2-carboxylate CAS: 1932043-29-2 55 Ethyl (1S,4S)-5-oxo-2- 2 54 and 52 LCMS (System 6, Method H): azabicyclo[2.2.2]octane-2-carboxylate m/z 198 (M + H).sup.+ (ES.sup.+), at 0.83 min, 230-400 nm 56 Ethyl (1S,4S)-5-[(1R,5S,6r)-6- A 1 and 55 LCMS (System 5, Method F): (ethoxycarbonyl)-3- m/z 337 (M + H).sup.+ (ES.sup.+), at azabicyclo[3.1.0]hexan-3-yl]-2- 2.34 min, 230-400 nm azabicyclo[2.2.2]octane-2-carboxylate 57 tert-Butyl (1R,4R)-5-oxo-2- — — Commercially available, azabicyclo[2.2.2]octane-2-carboxylate CAS: 1818843-13-8 58 Ethyl (1R,4R)-5-oxo-2- 2 57 and 52 LCMS (System 6, Method H): azabicyclo[2.2.2]octane-2-carboxylate m/z 198 (M + H).sup.+ (ES.sup.+), at 0.83 min, 190-400 nm 59 Ethyl (1 R,4 R)-5-[(1 R,5S,6r)-6- A 1 and 58 LCMS (System 6, Method H): (ethoxycarbonyl)-3- m/z 337 (M + H).sup.+ (ES.sup.+), at azabicyclo[3.1.0]hex-3-yl]-2- 1.55 min, 190-400 nm azabicyclo[2.2.2]octane-2-carboxylate 60 Methyl 5-oxo-2- 1 51 and 45 LCMS (System 2, Method D): azabicyclo[2.2.2]octane-2-carboxylate m/z 184 (M + H).sup.+ (ES.sup.+), at 1.39 min, 202 nm 61 Methyl 5-[(1R,5S,6r)-6- A 1 and 60 LCMS (System 1, Method C): (ethoxycarbonyl)-3- m/z 323 (M + H).sup.+ (ES.sup.+), at azabicyclo[3.1.0]hex-3-yl]-2- 4.88 min, 220 nm azabicyclo[2.2.2]octane-2-carboxylate 62 tert-Butyl 3-oxo-9- — — Commercially available, azabicyclo[3.3.1]nonane-9- CAS: 512822-27-4 carboxylate 63 Ethyl 3-oxo-9- 1 62 and 52 LCMS (System 1, Method C): azabicyclo[3.3.1]nonane-9- m/z 212 (M + H).sup.+ (ES.sup.+), at carboxylate 3.51 min, 202 nm 64 Ethyl 3-[(1R,5S,6r)-6- A 1 and 63 LCMS (System 1, Method E): (ethoxycarbonyl)-3- m/z 351 (M + H).sup.+ (ES.sup.+), at azabicyclo[3.1.0]hexan-3-yl]-9- 5.30 and 5.39 min, 202 nm azabicyclo[3.3.1]nonane-9-carboxylate 65 Methyl 3-oxo-9- 2 62 and 45 LCMS (System 1, Method E): azabicyclo[3.3.1]nonane-9- m/z 198 (M + H).sup.+ (ES.sup.+), at carboxylate 3.34 min, 215 nm 66 Methyl 3-[(1R,5S,6r)-6- A 1 and 65 LCMS (System 1, Method E): (ethoxycarbonyl)-3- m/z 337 (M + H).sup.+ (ES.sup.+), at azabicyclo[3.1.0]hexan-3-yl]-9- 4.99 and 5.03 min, 202 nm azabicyclo[3.3.1]nonane-9- carboxylate 67 tert-Butyl 7-oxo-3-oxa-9- — — Commercially available, azabicyclo[3.3.1]nonane-9- CAS: 280761-97-9 carboxylate 68 Ethyl 7-oxo-3-oxa-9- 1 67 and 52 LCMS (System 2, Method A): azabicyclo[3.3.1]nonane-9- m/z 214 (M + H).sup.+ (ES.sup.+), at carboxylate 1.53 min, 202 nm 69 Ethyl 7-[(1R,5S,6r)-6- A 1 and 68 LCMS (System 1, Method C): (ethoxycarbonyl)-3- m/z 353 (M + H).sup.+ (ES.sup.+), at azabicyclo[3.1.0]hexan-3-yl]-3-oxa-9- 4.10 min, 202 nm azabicyclo[3.3.1]nonane-9- carboxylate 70 Methyl 7-oxo-3-oxa-9- 1 67 and 45 LCMS (System 2, Method D): azabicyclo[3.3.1]nonane-9- m/z 200 (M + H).sup.+ (ES.sup.+), at carboxylate 1.28 min, 222 nm 71 Methyl 7-[(1R,5S,6r)-6- A 1 and 70 LCMS (System 1, Method C): (ethoxycarbonyl)-3- m/z 339 (M + H).sup.+ (ES.sup.+), at azabicyclo[3.1.0]hexan-3-yl]-3-oxa-9- 3.75 min, 202 nm azabicyclo[3.3.1]nonane-9- carboxylate 72 Ethyl 4-oxopiperidine-1-carboxylate — — Commercially available, CAS: 29976-53-2 73 Ethyl (1R,5S,6r)-3-[1- A 1 and 72 LCMS (System 3, Method E): (ethoxycarbonyl)piperidin-4-yl]-3- m/z 311 (M + H).sup.+ (ES.sup.+), at azabicyclo[3.1.0]hexane-6- 3.92 min, 202 nm carboxylate 74 tert-Butyl 6-oxo-3- — — Commercially available, azabicyclo[3.1.1]heptane-3- CAS: 1251013-26-9 carboxylate 75 Ethyl 6-oxo-3- 1 74 and 52 LCMS (System 4, Method B): azabicyclo[3.1.1]heptane-3- m/z 184 (M + H).sup.+ (ES.sup.+), at carboxylate 4.12 min, 202 nm 76 tert-Butyl 8-oxo-3- — — Commercially available, azabicyclo[3.2.1]octane-3-carboxylate CAS: 637301-19-0 77 Ethyl 8-oxo-3- 1 76 and 52 LCMS (System 2, Method D): azabicyclo[3.2.1]octane-3-carboxylate m/z 198 (M + H).sup.+ (ES.sup.+), at 1.48 min, 202 nm 78 Ethyl 8-[(1R,5S,6r)-6- A 1 and 77 LCMS (System 3, Method E): (ethoxycarbonyl)-3- m/z 337 (M + H).sup.+ (ES.sup.+), at azabicyclo[3.1.0]hexan-3-yl]-3- 5.07 min, 202 nm azabicyclo[3.2.1]octane-3-carboxylate 79 N-Methylcyclopropanamine — — Commercially available, CAS: 5163-20-2 80 Morpholine — — Commercially available, CAS: 110-91-8 81 Ethyl 4-oxoazepane-1-carboxylate — — Commercially available, CAS: 56515-89-0 82 Ethyl (1R,5S,6r)-3-(1- A 1 and 81 LCMS (System 3, Method E): (ethoxycarbonyl)azepan-4-yl)-3- m/z 325 (M + H).sup.+ (ES.sup.+), at azabicyclo[3.1.0]hexane-6-carboxylate 4.18 min, 202 nm 83 tert-Butyl 3-oxo-6- — — Commercially available, azabicyclo[3.2.1]octane-6-carboxylate CAS: 359779-74-1 84 Ethyl 3-oxo-6- 1 83 and 52 LCMS (System 4, Method B): azabicyclo[3.2.1]octane-6-carboxylate m/z 198 (M + H).sup.+ (ES.sup.+), at 4.39 min, 202 nm 85 Ethyl 3-[(1R,5S,6r)-6- A 1 and 84 LCMS (System 3, Method E): (ethoxycarbonyl)-3- m/z 337 (M + H).sup.+ (ES.sup.+), at azabicyclo[3.1.0]hexan-3-yl]-6- 3.83 and 4.71 min, 202 nm azabicyclo[3.2.1]octane-6-carboxylate 86 tert-Butyl 5- — — Commercially available, oxohexahydrocyclopenta[c]pyrrole- CAS: 148404-28-8 2(1H)-carboxylate 87 Ethyl 5- 1 86 and 52 .sup.1H NMR (400 MHz, DMSO-d.sub.6) oxohexahydrocyclopenta[c]pyrrole- δ: 1.19 (t, J = 7.25 Hz, 3 H), 2(1H)-carboxylate 2.05-2.16 (m, 2 H), 2.36-2.47 (m, 2 H), 2.84-2.96 (m, 2 H), 3.12-3.21 (m, 2 H), 3.53-3.63 (m, 2 H), 4.02-4.08 (m, 2 H). 88 ethyl 5-((1R,5S)-6-(ethoxycarbonyl)-3- A 1 and 87 LCMS (System 3, Method E): azabicyclo[3.1.0]hexan-3- m/z 337 (M + H).sup.+ (ES.sup.+), at yl)hexahydrocyclopenta[c]pyrrole- 4.09 min, 202 nm 2(1H)-carboxylate

(356) TABLE-US-00005 TABLE 3 Synthetic Method and Purification LCMS System Ex. No. Name Intermediates Used Method .sup.1H NMR and Method LCMS data  1-1 Ethyl 6-[(1R,5S,6r)-6- A A (400 MHz, DMSO-d.sub.6) δ: 1.09-1.22 (m, 6 H), 1.79 (s, 1 H), 1.86-1.90 1 m/z 323   (ethoxycarbonyl)-3- 1 and 2 (m, 2 H), 1.90-1.99 (m, 2 H), 2.12-2.21 (m, 2 H), 2.24 (d, J = 8.6 Hz, C (M + H).sup.+   azabicyclo[3.1.0]hex-3-yl]-2- 2 H), 2.81-2.84 (m, 1 H), 2.92 (d, J = 9.0 Hz, 2 H), 3.73-3.83 (m, 2 (ES.sup.+), at   azaspiro[3.3]heptane-2- H), 3.83-3.91 (m, 2 H), 3.93-4.07 (m, 4 H). 4.36 min,   carboxylate 202 nm  1-2 Ethyl 6-[(1R,5S,6r)-6- B B (400 MHz, METHANOL-d.sub.4) δ: 1.09 (t, J = 7.0 Hz, 3 H), 1.16-1.32 (m, 4 m/z 350   (diethylcarbamoyl)-3- 1, 3, 4 6 H), 1.86-1.90 (m, 2 H), 2.02-2.15 (m, 2 H), 2.18-2.23 (m, 1 H), C (M + H).sup.+   azabicyclo[3.1.0]hex-3-yl]-2- and 52 2.24-2.34 (m, 2 H), 2.42 (d, J = 9.2 Hz, 2 H), 2.94 (quin, J = 7.7 Hz, 1 (ES.sup.+), at   azaspiro[3.3]heptane-2- H) 3.02 (d, J = 9.2 Hz, 2 H), 3.36 (q, J = 7.2 Hz, 2 H), 3.53 (q, J = 7.0 3.46 min,   carboxylate Hz, 2 H), 3.84-3.91 (m, 2 H), 3.95-4.01 (m, 2 H), 4.06 (q, J = 7.0 Hz, 2 210 nm   H).  1-3 Ethyl 6-{(1R,5S,6r)-6- C C (400 MHz, METHANOL-d.sub.4) δ: 1.07-1.17 (m, 3 H), 1.22 (t, J = 7.2 Hz, 1 m/z 364   [ethyl(propan-2-yl)carbamoyl]- Example 3 H), 1.25-1.32 (m, 6 H), 1.89-1.95 (m, 2 H), 2.02-2.14 (m, 2 H), C (M + H).sup.+   3-azabicyclo[3.1.0]hex-3-yl}-2- 1-1 2.16-2.21 (m, 0.7 H), 2.23-2.34 (m, 2.3 H), 2.37-2.48 (m, 2 H), (ES.sup.+), at   azaspiro[3.3]heptane-2- and 5 2.88-2.98 (m, 1 H), 2.99-3.08 (m, 2 H), 3.22-3.29 (m, 1 H), 3.41- 4.07 min,   carboxylate 3.51 (m, 1 H), 3.83-3.91 (m, 2 H), 3.92-4.01 (m, 2 H), 4.06 (q, 202 nm   J = 7.09 Hz, 2 H), 4.41-4.49 (m, 0.3 H), 4.57-4.69 (m, 0.7 H).  1-4 Ethyl 6-[(1R,5S,6r)-6-(2- D D (400 MHz, METHANOL-d.sub.4) δ: 1.22 (t, J = 7.0 Hz, 3 H), 1.80-1.87 (m, 4 m/z 348   methyl-1,3-thiazol-4-yl)-3- 6, 7, 8, 2 H), 2.04-2.15 (m, 2 H), 2.22-2.37 (m, 4 H), 2.43 (d, J = 8.9 Hz, 2 C (M + H).sup.+   azabicyclo[3.1.0]hex-3-yl]-2- 9, 10 H), 2.63 (s, 3 H), 2.93 (quin, J = 7.6 Hz, 1 H), 3.07 (d, J = 9.2 Hz, 2 H), (ES.sup.+), at   azaspiro[3.3]heptane-2- and 2 3.85-3.91 (m, 2 H), 3.93-4.01 (m, 2 H), 4.06 (q, J = 7.0 Hz, 2 H). 4.08 min,   carboxylate 210 nm  2-1 Mixture of isomers: ethyl 2- A E (400 MHz, DMSO-d.sub.6) δ: 1.17 (dt, J = 7.0, 3.5 Hz, 6 H), 1.73-2.03 (m, 1 m/z 337   [(1R,5S,6r)-6- 1 and 11 8 H), 2.24-2.27 m, 2 H), 2.88-3.02 (m, 3 H), 3.10-3.30 (m, 5 H), C (M + H).sup.+   (ethoxycarbonyl)-3- 3.95-4.08 (m, 4 H). (ES.sup.+), at   azabicyclo[3.1.0]hex-3-yl]-6- 4.65 min,   azaspiro[3.4]octane-6- 202 nm   carboxylate  2-2 Isomer 1: ethyl 2-{(1R,5S,6r)- C F (400 MHz, METHANOL-d.sub.4) δ: 0.92 (d, J = 6.6 Hz, 6 H), 1.14-1.36 (m, 1 m/z 364   6-[(2- Example 4 H), 1.72-1.81 (m, 1 H), 1.83-1.97 (m, 7 H), 2.08 (t, J = 9.0 Hz, 2 C (M + H).sup.+   methylpropyl)carbamoyl]-3- 2-1 H), 2.44 (d, J = 9.0 Hz, 2 H), 2.87-3.13 (m, 4 H), 3.35-3.43 (m, 4 H), (ES.sup.+), at   azabicyclo[3.1.0]hex-3-yl}-6- and 12 4.12 (q, J = 7.1 Hz, 2 H). One exchangeable proton not observed. 3.91 min,   azaspiro[3.4]octane-6- 202 nm   carboxylate  2-2 Isomer 2: ethyl 2-{(1R,5S,6r)- C F (400 MHz, METHANOL-d.sub.4) δ: 0.93 (d, J = 6.4 Hz, 6 H), 1.23-1.35 (m, 1 m/z 364   6-[(2- Example 4 H), 1.70-1.84 (m, 1 H), 1.84-2.02 (m, 8 H), 2.02-2.15 (m, 2 H), C (M + H).sup.+   methylpropyl)carbamoyl]-3- 2-1 2.34-2.51 (m, 2 H), 2.93-3.10 (m, 4 H), 3.38-3.45 (m, 3 H), 4.06- (ES.sup.+), at   azabicyclo[3.1.0]hex-3-yl}-6- and 12 4.17 (m, 2 H). One exchangeable proton not observed. 3.96 min,   azaspiro[3.4]octane-6- 202 nm   carboxylate  2-3 Isomer 1: ethyl 2-{(1R,5S,6r)- C G (400 MHz, METHANOL-d.sub.4) δ: 1.27 (t, J = 6.8 Hz, 3 H), 1.63-1.79 (m, 1 m/z 376   6- Example 2 H), 1.80-1.99 (m, 9 H), 1.99-2.19 (m, 4 H), 2.35-2.57 (m, 3 H), C (M + H).sup.+   [(cyclobutylmethyl)carbamoyl]- 2-1 2.93-3.13 (m, 4 H), 3.19 (d, J = 7.1 Hz, 2 H), 3.36-3.46 (m, 3 H), (ES.sup.+), at   3-azabicyclo[3.1.0]hex-3-yl}-6- and 13 4.12 (q, J = 6.9 Hz, 2 H). One exchangeable proton not observed. 4.02 min,   azaspiro[3.4]octane-6- 202 nm   carboxylate  2-3 Isomer 2: ethyl 2-{(1R,5S,6r)- C G (400 MHz, METHANOL-d.sub.4) δ: 1.27 (t, J = 7.0 Hz, 3 H), 1.63-1.80 (m, 1 m/z 376   6- Example 2 H), 1.80-2.00 (m, 9 H), 2.00-2.14 (m, 4 H), 2.33-2.56 (m, 3 H), C (M + H).sup.+   [(cyclobutylmethyl)carbamoyl]- 2-1 2.95-3.16 (m, 4 H), 3.20 (d, J = 7.1 Hz, 2 H), 3.36-3.46 (m, 3 H), (ES.sup.+), at   3-azabicyclo[3.1.0]hex-3-yl}-6- and 13 4.11 (q, J = 7.0 Hz, 2 H). One exchangeable proton not observed. 4.04 min,   azaspiro[3.4]octane-6- 202 nm   carboxylate  2-4 Isomer 1: ethyl 2-{(1R,5S,6r)- C H (400 MHz, METHANOL-d.sub.4) δ: 1.21-1.33 (m, 3 H), 1.43 (s, 3 H), 1.80- 1 m/z 376   6-[(1- Example 2.11 (m, 14 H), 2.19-2.36 (m, 2 H), 2.42 (d, J = 9.2 Hz, 2 H), 2.86- C (M + H).sup.+   methylcyclobutyl)carbamoyl]- 2-1 3.15 (m, 3 H), 3.36(d, J = 5.8 Hz, 3 H), 4.12 (q, J = 7.0 Hz, 2 H). One (ES.sup.+), at   3-azabicyclo[3.1.0]hex-3-yl}-6- and 14 exchangeable proton not observed. 3.96 min,   azaspiro[3.4]octane-6- 202 nm   carboxylate  2-4 Isomer 2: ethyl 2-{(1R,5S,6r)- C H (400 MHz, METHANOL-d.sub.4) δ: 1.27 (t, J = 7.0 Hz, 3 H), 1.43 (s, 3 H), 1 m/z 376   6-[(1- Example 1.72-1.97 (m, 10 H), 1.97-2.18 (m, 4 H), 2.22-2.35 (m, 2 H), 2.35- C (M + H).sup.+   methylcyclobutyl)carbamoyl]- 2-1 2.52 (m, 2 H), 2.94-3.13 (m, 3 H), 3.35-3.47 (m, 3 H), 4.11 (q, (ES.sup.+), at   3-azabicyclo[3.1.0]hex-3-yl}-6- and 14 J = 7.0 Hz, 2 H). One exchangeable proton not observed. 4.00 min,   azaspiro[3.4]octane-6- 202 nm   carboxylate  2-5 Isomer 1: ethyl 2-{(1R,5S,6r)- C I (400 MHz, METHANOL-d.sub.4) δ: 1.10 (t, J = 7.3 Hz, 1 H), 1.18-1.41 (m, 3 m/z 350   6-[ethyl(methyl)carbamoyl]-3- Example then 5 H), 1.74-2.02 (m, 7 H), 2.02-2.19 (m, 2 H), 2.27-2.29 (m, 1 H), E (M + H).sup.+   azabicyclo[3.1.0]hex-3-yl}-6- 2-1 J 2.45 (t, J = 7.3 Hz, 2 H), 2.93 (s, 2 H), 3.06 (d, J = 9.8 Hz, 3 H), 3.19 (s, (ES.sup.+), at   azaspiro[3.4]octane-6- and 15 1 H), 3.35-3.51 (m, 4 H), 3.59 (q, J = 7.3 Hz, 1 H), 4.12 (q, J = 7.1 Hz, 3.08 min,   carboxylate 2 H). 215 nm  2-5 Isomer 2: ethyl 2-{(1R,5S,6r)- C I (400 MHz, METHANOL-d.sub.4) δ: 1.10 (t, J = 7.0 Hz, 1 H), 1.26 (t, J = 7.3 3 m/z 350   6-[ethyl(methyl)carbamoyl]-3- Example then Hz, 5 H), 1.78-2.02 (m, 7 H), 2.02-2.15 (m, 2 H), 2.27-2.29 (m, 1 E (M + H).sup.+   azabicyclo[3.1.0]hex-3-yl}-6- 2-1 J H), 2.37-2.55 (m, 2 H), 2.93 (s, 1 H), 3.00-3.14 (m, 3 H), 3.19 (s, 1 (ES.sup.+), at   azaspiro[3.4]octane-6- and 15 H), 3.24-3.30 (m, 2 H), 3.35-3.48 (m, 3 H), 3.59 (q, J = 6.7 Hz, 1 H), 3.12 min,   carboxylate 4.11 (q, J = 6.7 Hz, 2 H). 215 nm  2-6 Isomer 1: ethyl 2-[(1R,5S,6r)- C K (400 MHz, METHANOL-d.sub.4) δ: 1.12 (t, J = 7.1 Hz, 3 H), 1.22-1.42 (m, 4 m/z 364   6-(diethylcarbamoyl)-3- Example 8 H), 1.87-2.03 (m, 2 H), 2.17-2.33 (m, 5 H), 2.34-2.47 (m, 2 H), C (M + H).sup.+   azabicyclo[3.1.0]hex-3-yl]-6- 2-1 3.35-3.47 (m, 6 H), 3.52-3.61 (m, 2 H), 3.80 (d, J = 11.7 Hz, 2 H), (ES.sup.+), at   azaspiro[3.4]octane-6- and 4 3.85-3.96 (m, 1 H), 4.13 (q, J = 7.1 Hz, 2 H). 3.63 min,   carboxylate 202 nm  2-6 Isomer 2: ethyl 2-[(1R,5S,6r)- C K (400 MHz, DMSO-d.sub.6) δ: 0.31 (t, J = 7.1 Hz, 3 H), 0.41-0.57 (m, 8 H), 4 m/z 364   6-(diethylcarbamoyl)-3- Example 1.11-1.26 (m, 2 H), 1.35-1.78 (m, 7 H), 2.55-2.68 (m, 6 H), 2.70- C (M + H).sup.+   azabicyclo[3.1.0]hex-3-yl]-6- 2-1 2.85 (m, 2 H), 3.00 (d, J = 11.5 Hz, 2 H), 3.04-3.18 (m, 1 H), 3.31 (q, (ES.sup.+), at   azaspiro[3.4]octane-6- and 4 J = 6.8 Hz, 2 H). 3.67 min,   carboxylate 202 nm  2-7 Isomer 1: methyl 2- C L (400 MHz, METHANOL-d.sub.4) δ: 1.11 (t, J = 7.1 Hz, 3 H), 1.28 (t, J = 7.1 1 m/z 350   [(1R,5S,6r)-6- 17 then Hz, 6 H), 1.93 (d, J = 8.8 Hz, 2 H), 2.03-2.25 (m, 6 H), 2.32-2.43 (m, C (M + H).sup.+   (diethylcarbamoyl)-3- and 4 M 1 H), 2.78-2.95 (m, 2 H), 3.35-3.43 (m, 6 H), 3.57 (q, J = 6.8 Hz, 2 (ES.sup.+), at   azabicyclo[3.1.0]hex-3-yl]-6- H), 3.70 (s, 3 H). 3.67 min,   azaspiro[3.4]octane-6- 210 nm   carboxylate  2-7 Isomer 2: methyl 2- C L (400 MHz, METHANOL-d.sub.4) δ: 1.11 (t, J = 6.8 Hz, 3 H), 1.28 (t, J = 7.1 1 m/z 350   [(1R,5S,6r)-6- 17 then Hz, 3 H), 1.91-2.04 (m, 6 H), 2.05-2.14 (m, 2 H), 2.23-2.29 (m, 1 C (M + H).sup.+   (diethylcarbamoyl)-3- and 4 M H), 2.55 (d, J = 9.3 Hz, 2 H), 3.08-3.20 (m, 3 H), 3.29 (s, 2 H), 3.35- (ES.sup.+), at   azabicyclo[3.1.0]hex-3-yl]-6- 3.43 (m, 4 H), 3.56 (q, J = 7.0 Hz, 2 H), 3.68 (s, 3 H). 3.66 min,   azaspiro[3.4]octane-6- 210 nm   carboxylate  2-8 Isomer 1: ethyl 2-{(1R,5S,6r)- C N (400 MHz, METHANOL-d.sub.4) δ: 1.07-1.14 (m, 3 H), 1.21-1.30 (m, 6 3 m/z 364   6-[methyl(propan-2- Example then H), 1.82-1.97 (m, 6 H), 2.04-2.12 (m, 2 H), 2.21-2.25 (m, 0.5 H), E (M + H).sup.+   yl)carbamoyl]-3- 2-1 O 2.29-2.34 (m, 0.5 H), 2.40-2.48 (m, 2 H), 2.74-2.79 (m, 1 H), 2.99- (ES.sup.+), at   azabicyclo[3.1.0]hex-3-yl}-6- and 18 3.08 (m, 4 H), 3.32-3.39 (m, 4 H), 3.53-3.59 (m, 0.5 H), 3.65- 3.32 min,   azaspiro[3.4]octane-6- 3.71 (m, 0.5 H), 4.05-4.15 (m, 2 H), 4.45-4.53 (m, 0.5 H), 4.68- 202 nm   carboxylate 4.77 (m, 0.5 H).  2-8 Isomer 2: ethyl 2-{(1R,5S,6r)- C N (400 MHz, METHANOL-d.sub.4) δ: 1.06-1.14 (m, 3 H), 1.21-1.29 (m, 6 3 m/z 364   6-[methyl(propan-2- Example then H), 1.88-1.99 (m, 6 H), 2.01-2.10 (m, 2 H), 2.21-2.26 (m, 0.5 H), E (M + H).sup.+   yl)carbamoyl]-3- 2-1 O 2.29-2.33 (m, 0.5 H), 2.40-2.47 (m, 2 H), 2.75-2.79 (m, 1 H), 2.99- (ES.sup.+), at   azabicyclo[3.1.0]hex-3-yl}-6- and 18 3.10 (m, 4 H), 3.24-3.28 (m, 2 H), 3.34-3.42 (m, 2 H), 3.53-3.59 3.20 min,   azaspiro[3.4]octane-6- (m, 0.5 H), 3.65-3.71 (m, 0.5 H), 4.04-4.14 (m, 2 H), 4.45-4.55 (m, 202 nm   carboxylate 0.5 H), 4.68-4.76 (m, 0.5 H).  2-9 Isomer 1: ethyl 2-{(1R,5S,6r)- C P (400 MHz, METHANOL-d.sub.4) δ: 1.10-1.18 (m, 4 H), 1.25-1.39 (m, 10 1 m/z 378   6-[ethyl(propan-2- Example then H), 1.85-1.99 (m, 6 H), 2.02-2.14 (m, 2 H), 2.21-2.33 (m, 1 H), C (M + H).sup.+   yl)carbamoyl]-3- 2-1 Q 2.39-2.53 (m, 2 H), 3.06 (d, J = 9.3 Hz, 3 H), 3.21-3.99 (m, 1H), 3.36- (ES.sup.+), at   azabicyclo[3.1.0]hex-3-yl}-6- and 5 3.39 (m, 2 H), 3.48(q, J = 6.8 Hz, 1 H), 4.12(q, J = 6.8 Hz, 2 H), 4.42- 4.23 min,   azaspiro[3.4]octane-6- 4.70 (m, 1H). 215 nm   carboxylate  2-9 Isomer 2: ethyl 2-{(1R,5S,6r)- C P (400 MHz, METHANOL-d.sub.4) δ: 1.08-1.17 (m, 4H), 1.20-1.35 (m, 10 1 m/z 378   6-[ethyl(propan-2- Example then H), 1.94 (q, J = 7.3 Hz, 2 H), 1.98-2.09 (m, 4 H), 2.09-2.16 (m, 2 H), C (M + H).sup.+   yl)carbamoyl]-3- 2-1 Q 2.19 (m, 1 H), 2.61-2.75 (m, 2 H), 3.16-3.25 (m, 2 H), 3.34-3.42 (ES.sup.+), at   azabicyclo[3.1.0]hex-3-yl}-6- and 5 (m, 3 H), 3.46 (q, J = 6.8 Hz, 2 H), 4.09 (q, J = 6.8 Hz, 2 H), 4.42-4.66 4.23 min,   azaspiro[3.4]octane-6- (m, 1 H). 215 nm   carboxylate  2-10 Isomer 1: methyl 2- C R (400 MHz, METHANOL-d.sub.4) δ: 1.09-1.22 (m, 5 H), 1.22-1.38 (m, 8 1 m/z 364   {(1R,5S,6r)-6-[ethyl(propan-2- 17 then H), 1.93 (d, J = 6.8 Hz, 2 H), 2.22-2.41 (m, 7 H), 3.03-3.08 (m, 1 H), C (M + H).sup.+   yl)carbamoyl]-3- and 5 S 3.40-3.51 (m, 4 H), 3.69 (s, 3 H), 3.83 (d, J = 11.7 Hz, 2 H), 4.37- (ES.sup.+), at   azabicyclo[3.1.0]hex-3-yl}-6- 4.64 (m, 1 H). 3.97 min,   azaspiro[3.4]octane-6- 210 nm   carboxylate  2-10 Isomer 2: methyl 2- C R (400 MHz, METHANOL-d.sub.4) δ: 1.06-1.22 (m, 5 H), 1.22-1.43 (m, 8 1 m/z 364   {(1R,5S,6r)-6-[ethyl(propan-2- 17 then H), 1.91-2.07(m, 2 H), 2.19-2.35 (m, 3 H), 2.36 (d, J = 7.8 Hz, 4 H), C (M + H).sup.+   yl)carbamoyl]-3- and 5 S 3.01-3.08 (m, 1 H), 3.40-3.50 (m, 3 H), 3.68 (s, 3 H), 3.84 (d, (ES.sup.+), at   azabicyclo[3.1.0]hex-3-yl}-6- J = 11.2 Hz, 3 H), 4.33-4.66 (m, 1 H). 4.00 min,   azaspiro[3.4]octane-6- 210 nm   carboxylate  2-11 Mixture of isomers: ethyl 2- C T (400 MHz, METHANOL-d.sub.4) δ: 0.99-1.07 (m, 2 H), 1.13 (t, J = 7.1 Hz, 1 m/z 376   {(1R,5S,6r)-6- Example 3 H), 1.21-1.34 (m, 4 H), 1.84-2.01 (m, 6 H), 2.03-2.16 (m, 2 H), C (M + H).sup.+   [cyclopropyl(ethyl)carbamoyl]- 2-1 2.50 (t, J = 7.6 Hz, 2 H), 2.66-2.71 (m, 1 H), 2.80-2.95 (m, 1 H), 3.04- (ES.sup.+), at   3-azabicyclo[3.1.0]hex-3-yl}-6- and 19 3.17 (m, 3 H), 3.25-3.31 (m, 1 H), 3.36-3.47 (m, 6 H), 4.06-4.18 4.22 min,   azaspiro[3.4]octane-6- (m, 2 H). 202 nm   carboxylate  2-12 Isomer 1: ethyl 2-[(1R,5S,6r)- C U (400 MHz, DMSO-d.sub.6) δ: 1.17 (t, J = 6.7 Hz, 3 H), 1.66-1.84 (m, 8 H), 1 m/z 362   6-(pyrrolidin-1-ylcarbonyl)-3- Example 1.84-2.03 (m, 5 H), 2.23-2.37 (m, 2 H), 2.91 (d, J = 8.9 Hz, 2 H), C (M + H).sup.+   azabicyclo[3.1.0]hex-3-yl]-6- 2-1 2.98-3.06 (m, 1 H), 3.17-3.29 (m, 6 H), 3.53 (t, J = 6.7 Hz, 2 H), 4.00 (ES.sup.+), at   azaspiro[3.4]octane-6- and 20 (q, J = 7.0 Hz, 2 H). 3.66 min,   carboxylate 202 nm  2-12 Isomer 2: ethyl 2-[(1R,5S,6r)- C U (400 MHz, DMSO-d.sub.6) δ: 1.16 (t, J = 7.0 Hz, 3 H), 1.68-1.97 (m, 13 H), 1 m/z 362   6-(pyrrolidin-1-ylcarbonyl)-3- Example 2.19-2.38 (m, 2 H), 2.90 (d, J = 8.9 Hz, 2 H), 2.99-3.06 (m, 1 H), C (M + H).sup.+   azabicyclo[3.1.0]hex-3-yl]-6- 2-1 3.16 (d, J = 10.4 Hz, 2 H), 3.20-3.30 (m, 4 H), 3.53 (t, J = 6.7 Hz, 2 H), (ES.sup.+), at   azaspiro[3.4]octane-6- and 20 3.99 (q, J = 6.4 Hz, 2 H). 3.70 min,   carboxylate 202 nm  2-13 Isomer 1: ethyl 2-[(1R,5S,6r)- C V (400 MHz, DMSO-d.sub.6) δ: 1.17 (t, J = 6.8 Hz, 3 H), 1.32-1.45 (m, 2 H), 1 m/z 376   6-(piperidin-1-ylcarbonyl)-3- Example 1.48-1.54 (m 2 H), 1.58 (d, J = 4.6 Hz, 2 H), 1.70-1.87 (m, 6 H), 1.87- C (M + H).sup.+   azabicyclo[3.1.0]hex-3-yl]-6- 2-1 2.01 (m, 2 H), 2.03-2.07 (m, 1 H), 2.28 (d, J = 8.6 Hz, 2 H), 2.90 (d, (ES.sup.+), at   azaspiro[3.4]octane-6- and 21 J = 9.0 Hz, 2 H), 2.94-3.09 (m, 1 H), 3.15-3.28 (m, 4 H), 3.38-3.46 4.05 min,   carboxylate (m, 2 H), 3.46-3.58 (m, 2 H), 4.00 (q, J = 7.0 Hz, 2 H). 202 nm  2-13 Isomer 2: ethyl 2-[(1R,5S,6r)- C V (400 MHz, DMSO-d.sub.6) δ: 1.16 (t, J = 7.0 Hz, 3 H), 1.34-1.46 (m, 2 H), 1 m/z 376   6-(piperidin-1-ylcarbonyl)-3- Example 1.47-1.55 m, 2 H), 1.55-1.65 (m, 2 H), 1.70-1.97 (m, 8 H), 2.05 (s, C (M + H).sup.+   azabicyclo[3.1.0]hex-3-yl]-6- 2-1 1 H), 2.28 (d, J = 8.3 Hz, 2 H), 2.90 (d, J = 8.8 Hz, 2 H), 2.97-3.07(m, 1 (ES.sup.+), at   azaspiro[3.4]octane-6- and 21 H), 3.16 (d, J = 8.8 Hz, 2 H), 3.26 (q, J = 6.9 Hz, 2 H), 3.37-3.44 (m, 2 4.07 min,   carboxylate H), 3.47-3.59 (m, 2 H), 3.99 (q, J = 6.8 Hz, 2 H). 202 nm  2-14 Isomer 1: ethyl 2-[(1R,5S,6r)- C W (400 MHz, METHANOL-d.sub.4) δ: 1.09-1.21 (m. 1 H), 1.22-1.38 (m, 8 1 m/z 390   6-{[(2R)-2-methylpiperidin-1- Example and H), 1.38-1.52 (m, 2 H), 1.52-1.81 (m, 5 H), 1.81-2.01 (m, 5 H), C (M + H).sup.+   yl]carbonyl}-3- 2-1 X 2.01-2.16 (m, 2 H), 2.23-2.33 (m, 1H), 2.45(d, J = 6.8 Hz, 1.5 H), (ES.sup.+), at   azabicyclo[3.1.0]hex-3-yl]-6- and 22 2.73-2.79 (m, 0.5 H), 3.05 (d, J = 9.3 Hz, 2 H), 3.16-3.29 (m, 1 H), 4.35 min,   azaspiro[3.4]octane-6- 3.35-3.40 (m., 3 H), 4.12 (q, J = 6.8 Hz, 2 H), 4.33-4.79 (m, 1 H). 205 nm   carboxylate  2-14 Isomer 2: ethyl 2-[(1R,5S,6r)- C W (400 MHz, METHANOL-d.sub.4) δ: 0.87-0.99 (m, 1 H), 1.13-1.21 (m, 1 1 m/z 390   6-{[(2R)-2-methylpiperidin-1- Example and H), 1.22-1.40 (m, 7 H), 1.56-1.81 (m, 4 H), 1.86-2.01 (m, 4 H), C (M + H).sup.+   yl]carbonyl}-3- 2-1 X 2.02-2.12 (m, 2 H), 2.24-2.33 (m, 1 H), 2.39-2.51 (m, 2 H), 2.70- (ES.sup.+), at   azabicyclo[3.1.0]hex-3-yl]-6- and 22 2.83 (m, 1 H), 3.00-3.11 (m, 2 H), 3.22-3.3 (m, 2 H), 3.35-3.44 4.33 min,   azaspiro[3.4]octane-6- (m, 2 H), 4.05-4.18 (m, 3 H), 4.30-4.41 (m, 1 H), 4.53-4.64 (m, 1 205 nm   carboxylate H), 4.74-4.84 (m, 1 H).  2-15 Mixture of isomers: ethyl 2- C Y (400 MHz, METHANOL-d.sub.4) δ: 1.07-1.21 (m, 2 H), 1.21-1.47 (m, 7 1 m/z 390   [(1R,5S,6r)-6-{[(2S)-2- Example H), 1.47-1.74 (m, 6 H), 1.79-2.02 (m, 6 H), 2.02-2.17 (m, 2 H), C (M + H).sup.+   methylpiperidin-1-yl]carbonyl}- 2-1 2.28 (d, J = 15.7 Hz, 1 H), 2.45 (d, J = 7.8 Hz, 1.5 H), 2.73-2.46 (m, 0.5 (ES.sup.+), at   3-azabicyclo[3.1.0]hex-3-yl]-6- and 23 H), 3.00-3.12 (m, 2 H), 3.28 (m, 1 H), 3.35-3.46 (m, 3 H), 4.06- 4.36 min,   azaspiro[3.4]octane-6- 4.16 (m, 2 H), 4.33-4.82 (m, 1H). 202 nm   carboxylate  2-16 Isomer 1: ethyl 2-[(1R,5S,6r)- C Z (400 MHz, METHANOL-d.sub.4) δ: 1.23-1.42 (m, 5 H), 1.51-1.77 (m, 6 1 m/z 390   6-(azepan-1-ylcarbonyl)-3- Example then H), 1.77-1.99 (m, 7 H), 2.02-2.15 (m, 2 H), 2.29-2.30 (m, 1 H), C (M + H).sup.+   azabicyclo[3.1.0]hex-3-yl]-6- 2-1 AA 2.47 (d, J = 9.3 Hz, 2 H), 3.06 (d, J = 9.8 Hz, 3 H), 3.35-3.41 (m, 3 H), (ES.sup.+), at   azaspiro[3.4]octane-6- and 24 3.52 (t, J = 6.1 Hz, 2 H), 3.70 (t, J = 6.1 Hz, 2 H), 4.12 (q, J = 6.8 Hz, 2 4.27 min,   carboxylate H). 215 nm  2-16 Isomer 2: ethyl 2-[(1R,5S,6r)- C Z (400 MHz, METHANOL-d.sub.4) δ: 1.26 (t, J = 7.1 Hz, 3 H), 1.29-1.39 (m, 1 m/z 390   6-(azepan-1-ylcarbonyl)-3- Example then 2 H), 1.52-1.77 (m, 5 H), 1.83 (quin, J = 5.9 Hz, 2 H), 1.89-2.02 (m, C (M + H).sup.+   azabicyclo[3.1.0]hex-3-yl]-6- 2-1 AA 5 H), 2.02-2.14 (m, 2 H), 2.29-2.30 (m, 1 H), 2.46 (d, J = 9.3 Hz, 2 (ES.sup.+), at   azaspiro[3.4]octane-6- and 24 H), 2.98-3.14 (m, 3 H), 3.28 (d, J = 3.4 Hz, 2 H), 3.36-3.45 (m, 2 H), 4.30 min,   carboxylate 3.52 (t, J = 6.1 Hz, 2 H), 3.70 (t, J = 6.1 Hz, 2 H), 4.11 (q, J = 6.8 Hz, 2 215 nm   H).  2-17 Isomer 1: ethyl 2-[(1R,5S,6r)- C AB (400 MHz, METHANOL-d.sub.4) δ: 1.26 (t, J = 7.3 Hz, 3 H), 1.83-1.90 (m, 3 m/z 392   6-(1,4-oxazepan-4- Example 1 H), 1.90-2.04 (m, 7 H), 2.04-2.12 (m, 2 H), 2.25-2.51 (m, 1 H), E (M + H).sup.+   ylcarbonyl)-3- 2-1 2.41-2.52 (m, 2 H), 3.01-3.15 (m, 3 H), 3.28 (m, 2 H), 3.36-3.43 (ES.sup.+), at   azabicyclo[3.1.0]hex-3-yl]-6- and 25 (m, 2 H), 3.66 (t, J = 6.1 Hz, 2 H), 3.69-3.81 (m, 3 H), 3.81-3.91 (m, 3.10 min,   azaspiro[3.4]octane-6- 3 H), 4.11 (q, J = 6.9 Hz, 2 H). 202 nm   carboxylate  2-17 Isomer 2: ethyl 2-[(1R,5S,6r)- C AB (400 MHz, METHANOL-d.sub.4) δ: 1.23-1.32 (m, 3 H), 1.82-2.04 (m, 8 3 m/z 392   6-(1,4-oxazepan-4- Example H), 2.10 (t, J = 9.2 Hz, 2 H), 2.26-(m, 1 H), 2.47 (d, J = 9.2 Hz, 2 H), E (M + H).sup.+   ylcarbonyl)-3- 2-1 3.06 (dd, J = 9.8, 3.7 Hz, 3 H), 3.35-3.42 (m, 4 H), 3.66 (t, J = 6.1 Hz, 2 (ES.sup.+), at   azabicyclo[3.1.0]hex-3-yl]-6- and 25 H), 3.69-3.81 (m, 3 H), 3.81-3.89 (m, 3 H), 4.12 (q, J = 6.7 Hz, 2 H). 3.14 min,   azaspiro[3.4]octane-6- 202 nm   carboxylate  2-18 Mixture of isomers: ethyl 2- C AC (400 MHz, METHANOL-d.sub.4) δ: 1.26 (t, J = 6.3 Hz, 3 H), 1.79-1.99 (m, 1 m/z 388   [(1R,5S,6r)-6-(2- Example 9 H), 1.99-2.13 (m, 2 H), 2.13-2.32 (m, 4 H), 2.41 (d, J = 9.0 Hz, 2 C (M + H).sup.+   azaspiro[3.3]hept-2- 2-1 H), 2.96-3.07 (m, 3 H), 3.26 (d, J = 2.8 Hz, 1 H), 3.33-3.43 (m, 3 H), (ES.sup.+), at   ylcarbonyl)-3- and 26 3.91 (s, 2 H), 4.10 (qd, J = 7.1, 2.8 Hz, 2 H), 4.25 (s, 2 H). 4.20 min,   azabicyclo[3.1.0]hex-3-yl]-6- 210 nm   azaspiro[3.4]octane-6-   carboxylate  2-19 Isomer 2: ethyl 2-[(1R,5S,6r)- E AD 400 MHz, METHANOL-d.sub.4) δ: 0.53-0.61 (m, 2 H), 1.21-1.29 (m, 3 2 m/z 374   6-(4-azaspiro[2.3]hex-4- Example then H), 1.50-1.58 (m, 2 H), 1.80-1.88 (m, 2 H), 1.88-2.00 (m, 4 H), D (M + H).sup.+   ylcarbonyl)-3- 2-1 AE 2.01-2.10 (m, 2 H), 2.37-2.45 (m, 2 H), 2.44-2.53 (m, 2 H), 2.96- (ES.sup.+), at   azabicyclo[3.1.0]hex-3-yl]-6- and 27 3.09 (m, 2 H), 3.23-3.28 (m, 2 H), 3.34-3.44 (m, 4 H), 3.89-3.96 1.67 min,   azaspiro[3.4]octane-6- (m, 0.5 H), 4.04-4.15 (m, 2 H), 4.27-4.35 (m, 1.5 H). 220 nm   carboxylate  2-20 Mixture of isomers: ethyl 2- C AF (400 MHz, METHANOL-d.sub.4) δ: 1.19 1.30 3 H), 1.62 2.10 12 1 m/z 388   [(1R,5S,6r)-6-(1- Example H), 2.17-2.33 (m, 1 H), 2.33-2.52 (m, 4 H), 2.81 (q, J = 10.3 Hz, C (M + H).sup.+   azaspiro[3.3]hept-1- 2-1 H), 2.87-2.98 (m, 1 H), 2.98-3.16 (m, 3 H), 3.23-3.27 (m, 1 H), (ES.sup.+), at   ylcarbonyl)-3- and 28 3.33-3.42 (m, 3 H), 3.77 (t, J = 7.7 Hz, 1 H), 4.03-4.18 (m, 3 H). 4.28 min,   azabicyclo[3.1.0]hex-3-yl]-6- 202 nm   azaspiro[3.4]octane-6-   carboxylate  2-21 Isomer 1: methyl 2- C AG (400 MHz, METHANOL-d.sub.4) δ: 1.24-1.37 (m, 5 H), 1.56-1.78 (m, 1 1 m/z 374   [(1R,5S,6r)-6-(1- 17 H), 1.80-1.94 (m, 4 H), 1.94-2.19 (m, 4 H), 2.19-2.37 (m, 1 H), C (M + H).sup.+   azaspiro[3.3]hept-1- and 28 2.37-2.54 (m, 3 H), 2.76-2.99 (m, 2 H), 3.00-3.17 (m, 2 H), 3.36- (ES.sup.+), at   ylcarbonyl)-3- 3.41 (m, 4 H), 3.69 (s, 3 H), 3.74-3.84 (m, 1 H), 4.14(t, J = 7.6 Hz, 1 3.95 min,   azabicyclo[3.1.0]hex-3-yl]-6- H). 202 nm   azaspiro[3.4]octane-6-   carboxylate  2-21 Isomer 2: methyl 2- C AG (400 MHz, METHANOL-d.sub.4) δ: 1.23-1.37 (m, 4 H), 1.58-1.77 (m, 1 1 m/z 374   [(1R,5S,6r)-6-(1- 17 H), 1.77-2.14 (m, 9 H), 2.24-2.36 (m, 1 H), 2.36-2.54 (m, 3 H), C (M + H).sup.+   azaspiro[3.3]hept-1- and 28 2.76-2.88 (m, 1 H), 2.88-2.99 (m, 1 H), 2.99-3.18 (m, 2 H), 3.27 (ES.sup.+), at   ylcarbonyl)-3- (s, 1 H), 3.35-3.44 (m, 3 H), 3.68 (s, 3 H), 3.75-3.86 (m, 1 H), 4.14 3.95 min,   azabicyclo[3.1.0]hex-3-yl]-6- (t, J = 7.6 Hz, 1 H). 202 nm   azaspiro[3.4]octane-6-   carboxylate  2-22 Isomer 2: ethyl 2-[(1R,5S,6r)- C AH (400 MHz, METHANOL-d.sub.4) δ: 1.24 (t, J = 7.1 Hz, 3 H), 1.82-1.99 (m, 1 m/z 390   6-(6-oxa-1-azaspiro[3.3]hept- Example 6 H), 1.99-2.11 (m, 2 H), 2.36-2.52 (m, 2 H), 2.52-2.62 (m, 2 H), C (M + H).sup.+   1-ylcarbonyl)-3- 2-1 2.92-3.11 (m, 3 H), 3.23-3.27(m, 2 H), 3.37(q, J = 6.2 Hz, 2 H), 3.73 (ES.sup.+), at   azabicyclo[3.1.0]hex-3-yl]-6- and 29 (t, J = 7.6 Hz, 1 H), 4.10 (quin, J = 6.8 Hz, 4 H), 4.62 (d, J = 6.8 Hz, 2 3.38 min,   azaspiro[3.4]octane-6- H), 5.14 (d, J = 7.8 Hz, 1 H), 5.32 (d, J = 7.3 Hz, 1 H). 210 nm   carboxylate  2-23 Isomer 2: ethyl 2-{(1R,5S,6r)- C AI (400 MHz, METHANOL-d.sub.4) δ: 1.26 (t, J = 7.1 Hz, 3 H), 1.88-2.01 (m, 1 m/z 352   6- Example 6 H), 2.01-2.11 (m, 2 H), 2.46 (d, J = 9.3 Hz, 2 H), 2.56-2.68 (m, 1 C (M + H).sup.+   [methoxy(methyl)carbamoyl]- 2-1 H), 3.02-3.10 (m, 3 H), 3.16-3.24 (m, 2 H), 3.25-3.29 (m, 3 H), (ES.sup.+), at   3-azabicyclo[3.1.0]hex-3-yl}-6- and 7 3.36-3.44 (m, 2 H), 3.80 (s, 3 H), 4.11 (q, J = 6.8 Hz, 2 H). 3.77 min,   azaspiro[3.4]octane-6- 202 nm   carboxylate  2-24 Isomer 1: ethyl 2-{(1R,5S,6r)- C AJ (400 MHz, METHANOL-d.sub.4) δ: 1.18 (t, J = 6.8 Hz, 3 H), 1.27 (td, J = 1 m/z 366   6-[ethyl(methoxy)carbamoyl]- Example 7.0, 3.2 Hz, 3 H), 1.82-2.01 (m, 6 H), 2.04-2.15 (m, 2 H), 2.47 (d, J = 9.3 C (M + H).sup.+   3-azabicyclo[3.1.0]hex-3-yl}-6- 2-1 Hz, 2 H), 2.54-2.56 (m, 1 H), 3.07 (d, J = 9.8 Hz, 3 H), 3.38 (d, J = 5.9 (ES.sup.+), at   azaspiro[3.4]octane-6- and 30 Hz, 4 H), 3.62-3.74 (m, 2 H), 3.79 (s, 3 H), 4.12 (q, J = 6.8 Hz, 2 H). 4.06 min,   carboxylate 202 nm  2-24 Isomer 2: ethyl 2-{(1R,5S,6r)- C AJ (400 MHz, METHANOL-d.sub.4) δ: 1.18 (t, J = 6.6 Hz, 3 H), 1.26 (t, J = 7.1 1 m/z 366   6-[ethyl(methoxy)carbamoyl]- Example Hz, 3 H), 1.88-2.01 (m, 6 H), 2.02-2.13 (m, 2 H), 2.47 (d, J = 9.3 Hz, C (M + H).sup.+   3-azabicyclo[3.1.0]hex-3-yl}-6- 2-1 2 H), 2.53-2.67 (m, 1 H), 3.03-3.10 (m, 3 H), 3.25-3.29 (m, 2 H), (ES.sup.+), at   azaspiro[3.4]octane-6- and 30 3.39 (q, J = 6.7 Hz, 2 H), 3.61-3.73 (m, 2 H), 3.79 (s, 3 H), 4.11 (q, 4.12 min,   carboxylate J = 6.8 Hz, 2 H). 202 nm  2-25 Isomer 2: ethyl 2-[(1R,5S,6r)- F AK (400 MHz, METHANOL-d.sub.4) δ: 1.06 (t, J = 7.5 Hz, 3 H), 1.27 (t, J = 7.0 1 m/z 350   6-(N-methoxypropanimidoyl)- 32, 11 Hz, 3 H), 1.81-2.02 (m, 7 H), 2.02-2.15 (m, 2 H), 2.46 (d, J = 9.0 Hz, C (M + H).sup.+   3-azabicyclo[3.1.0]hexan-3- and 33 2 H), 2.55 (t, J = 3.4 Hz, 1 H), 3.06 (d, J = 9.3 Hz, 3 H), 3.28 (d, J = 3.7 (ES.sup.+), at   yl]-6-azaspiro[3.4]octane-6- Hz, 2 H), 3.35-3.47 (m, 3 H), 3.81 (s, 3 H), 4.11 (q, J = 7.0 Hz, 2 H). 5.09 min,   carboxylate 202 nm  2-25 Isomer 4: ethyl 2-[(1R,5S,6r)- F AK (400 MHz, METHANOL-d.sub.4) δ: 1.08 (t, J = 7.6 Hz, 3 H), 1.27 (t, J = 7.1 1 m/z 350   6-(N-methoxypropanimidoyl)- 32, 11 Hz, 3 H), 1.77-1.84 (m., 3 H), 1.89-2.03 (m, 4 H), 2.03-2.14 (m, 2 C (M + H).sup.+   3-azabicyclo[3.1.0]hexan-3- and 33 H), 2.28 (q, J = 7.6 Hz, 2 H), 2.46 (d, J = 9.3 Hz, 2 H), 3.01-3.14 (m, 3 (ES.sup.+), at   yl]-6-azaspiro[3.4]octane-6- H), 3.28 (d, J = 2.9 Hz, 2 H), 3.39 (q, J = 6.6 Hz, 2 H), 3.74 (s, 3 H), 4.11 5.24 min,   carboxylate (q, J = 7.1 Hz, 2 H). 202 nm  2-26 Mixture of isomers: ethyl 2-[6- A AL (400 MHz, METHANOL-d.sub.4) δ: 1.16 (t, J = 7.0 Hz, 3 H), 1.70-1.88 (m, 1 m/z 333   (trifluoromethyl)-3- 34 and 11 6 H), 1.88-2.03 (m, 3 H), 2.16-2.30 (m, 2 H), 2.85-3.05 (m, 3 H), C (M + H).sup.+   azabicyclo[3.1.0]hex-3-yl]-6- 3.09-3.30 (m, 4 H), 3.91-4.10 (m, 2 H). (ES.sup.+), at   azaspiro[3.4]octane-6- 5.28 min,   carboxylate 202 nm  2-27 Mixture of isomers: ethyl 2- G AM (400 MHz, DMSO-d.sub.6) δ: 1.01 (t, J = 7.0 Hz, 3 H), 1.16 (t, J = 7.0 Hz, 3 1 m/z 390   {(1R,5S,6s)-6-[ethyl(2,2,2- 35, 36, H), 1.46 (s, 2 H), 1.65-1.85 (m, 4 H), 1.85-1.99 (m, 2 H), 2.09-2.30 C (M + H).sup.+   trifluoroethyl)amino]-3- 37 and (m, 3 H), 2.71 (q, J = 7.2 Hz, 2 H), 2.79-2.97 (m, 3 H), 3.14 (d, J = 8.9 (ES.sup.+), at   azabicyclo[3.1.0]hexan-3-yl}- 11 Hz, 1 H), 3.17-3.32 (m, 5 H), 3.92-4.07 (m, 2 H). 5.58 min,   6-azaspiro[3.4]octane-6- 202 nm   carboxylate  2-28 Isomer 1: ethyl 2-[(1R,5S,6s)- H AN (400 MHz, METHANOL-d.sub.4) δ: 1.25 (t, J = 6.8 Hz, 3 H), 1.39 (d, J = 5.9 1 m/z 385   6-(1-phenylethoxy)-3- 38, 39 Hz, 3 H), 1.50-1.61 (m, 1 H), 1.61-1.70 (m, 1 H), 1.70-2.17 (m, 7 C (M + H).sup.+   azabicyclo[3.1.0]hex-3-yl]-6- and 11 H), 2.25-2.35 (m, 1 H), 2.35-2.48 (m, 1 H), 2.65-2.95 (m, 3 H), (ES.sup.+), at   azaspiro[3.4]octane-6- 3.20-3.30 (m, 3 H), 3.35-3.51 (m, 1 H), 4.10 (q, J = 6.7 Hz, 2 H), 5.67 min,   carboxylate 4.53 (q, J = 6.4 Hz, 1 H), 7.11-7.33 (m, 1 H), 7.33-7.49 (m, 4 H). 215 nm  2-28 Isomer 2: ethyl 2-[(1R,5S,6s)- H AN (400 MHz, METHANOL-d.sub.4) δ: 1.25 (t, J = 7.1 Hz, 3 H), 1.39 (d, J = 6.4 1 m/z 385   6-(1-phenylethoxy)-3- 38, 39 Hz, 3 H), 1.50-1.62 (m, 1 H), 1.62-1.71 (m, 1 H), 1.74-1.92 (m, 4 C (M + H).sup.+   azabicyclo[3.1.0]hex-3-yl]-6- and 11 H), 1.92-2.02 (m, 2 H), 2.26-2.48 (m, 2 H), 2.71-2.96 (m, 3 H), (ES.sup.+), at   azaspiro[3.4]octane-6- 3.20 (s, 2 H), 3.23-3.27 (m, 1 H), 3.35-3.43 (m, 2 H), 4.09 (q, J = 6.8 5.69 min,   carboxylate Hz, 2 H), 4.53 (q, J = 6.5 Hz, 1 H), 7.20-7.42 (m, 5 H). 215 nm  2-29 Isomer 2: ethyl 2-[(1R,5S,6r)- I AO (400 MHz, METHANOL-d.sub.4) δ: 1.21-1.28 (m, 3 H), 1.70-1.77 (m, 2 1 m/z 345   6-(1-methyl-1H-pyrazol-5-yl)- 40, 41, H), 1.86-2.01 (m, 4 H), 2.01-2.09 (m, 2 H), 2.19-2.26 (m, 1 H), C (M + H).sup.+   3-azabicyclo[3.1.0]hex-3-yl]-6- 42 and 2.40-2.50 (m, 2 H), 3.01-3.11 (m, 3 H), 3.25-3.28 (m, 2 H), 3.34- (ES.sup.+), at   azaspiro[3.4]octane-6- 11 3.41 (m, 2 H), 3.78 (s, 3 H), 4.06-4.13 (m, 2 H), 5.91-5.97 (m, 1 H), 4.10 min,   carboxylate 7.34-7.43 (m, 1 H). 226 nm  2-30 Isomer 1: ethyl 2-[(1R,5S,6r)- D AP (400 MHz, METHANOL-d.sub.4) δ: 1.25-1.32 (m, 3 H), 1.82-2.02 (m, 6 m/z 362   6-(2-methyl-1,3-thiazol-4-yl)-3- 6, 7, 8, H), 2.03-2.15 (m, 2 H), 2.29-2.43 (m, 1 H), 2.47 (d, J = 8.8 Hz, 2 H), (M + H).sup.+   azabicyclo[3.1.0]hex-3-yl]-6- 9, 10 2.65 (s, 3 H), 2.98-3.19 (m, 3 H), 3.35-3.41 (m, 4 H), 4.13 (q, J = 7.1 (ES.sup.+), at   azaspiro[3.4]octane-6- and 11 Hz, 2 H), 6.89 (s, 1 H). 4.60 min,   carboxylate 254 nm  2-30 Isomer 2: ethyl 2-[(1R,5S,6r)- D AP (400 MHz, METHANOL-d.sub.4) δ: 1.24-1.31 (m, 3 H), 1.84-1.91 (m, 2 1 m/z 362   6-(2-methyl-1,3-thiazol-4-yl)-3- 6, 7, 8, H) 1.90-2.03 (m, 4 H) 2.03-2.14 (m 2 H), 2.32-2.42 (m 1 H), C (M + H).sup.+   azabicyclo[3.1.0]hex-3-yl]-6- 9, 10 2.48 (d, J = 8.8 Hz, 2 H), 2.65 (s, 3 H), 3.02-3.19 (m, 3 H), 3.25-3.29 (ES.sup.+), at   azaspiro[3.4]octane-6- and 11 (m, 2 H), 3.36-3.44 (m, 2 H), 4.12 (q, J = 7.1 Hz, 2 H), 6.89 (s, 1 H). 4.61 min,   carboxylate 254 nm  3-1 Mixture of isomers: ethyl 6- A AQ (400 MHz, DMSO-d.sub.6) δ: 1.09-1.23 (m, 6 H), 1.32-1.54 (m, 1 H), 1 m/z 337   [(1R,5S,6r)-6- 1 1.60-1.80 (m, 4 H), 1.80-2.03 (m, 5 H), 2.26 (t, J = 8.7 Hz, 2 H), 2.53- C (M + H).sup.+   (ethoxycarbonyl)-3- and 43 2.68 (m, 3 H), 3.00 (t, J = 8.4 Hz, 2 H), 3.34 (s, 1 H), 4.00 (dq, (ES.sup.+), at   azabicyclo[3.1.0]hex-3-yl]-2- J = 18.5, 7.1 Hz, 4 H). 4.62 min,   azaspiro[3.4]octane-2- 202 nm   carboxylate  3-2 Mixture of isomers: ethyl 6- C AR (400 MHz, METHANOL-d.sub.4) δ: 1.11 (t, J = 7.1 Hz, 3 H), 1.18-1.35 (m, 4 m/z 364   [(1R,5S,6r)-6- Example 6 H), 1.47-1.65 (m, 1 H), 1.75 (dd, J = 12.8, 8.4 Hz, 1 H), 1.81-2.03 C (M + H).sup.+   (diethylcarbamoyl)-3- 3-1 (m, 5 H), 2.08 (dd, J = 12.7, 6.6 Hz, 1 H), 2.23 (t, J = 2.7 Hz, 1 H), 2.44- (ES.sup.+), at   azabicyclo[3.1.0]hex-3-yl]-2- and 4 2.56 (m, 2 H), 2.68 (quin, J = 7.3 Hz, 1 H), 3.15 (dd, J = 9.5, 1.7 Hz, 2 3.66 min,   azaspiro[3.4]octane-2- H), 3.38 (q, J = 7.1 Hz, 2 H), 3.55 (q, J = 7.1 Hz, 2 H), 3.71-3.99 (m, 4 210 nm   carboxylate H), 4.09 (q, J = 7.1 Hz, 2 H).  3-3 Isomer 1: methyl 6- J AS (400 MHz, METHANOL-d.sub.4) δ: 1.11 (t, J = 7.1 Hz, 3 H), 1.27 (t, J = 7.1 1 m/z 350   [(1R,5S,6r)-6- 6, 4 Hz, 3 H), 1.47-1.63 (m, 1 H), 1.67- 2.02 (m, 5H), 2.02-2.13 (m, 1 C (M + H).sup.+   (diethylcarbamoyl)-3- and 46 H), 2.08 (dd, J = 13.0, 6.6 Hz, 1 H), 2.19-2.27 (m, 1 H), 2.42-2.55 (ES.sup.+), at   azabicyclo[3.1.0]hex-3-yl]-2- (m, 2 H), 2.58-2.75 (m, 1 H), 3.14 (d, J = 9.8 Hz, 2 H), 3.36-3.42 (m, 3.68 min,   azaspiro[3.4]octane-2- 2 H), 3.48-3.60 (m, 2 H), 3.65 (s, 3 H), 3.75-3.99 (m, 4 H). 210 nm 210 nm   carboxylate  3-3 Isomer 2: methyl 6- J AS (400 MHz, METHANOL-d.sub.4) δ: 1.11 (t, J = 7.1 Hz, 3 H), 1.27 (t, J = 7.1 1 m/z 350   [(1R,5S,6r)-6- 6, 4 Hz, 3 H), 1.45-1.63 (m, 1 H), 1.74 (dd, J = 13.0, 8.6 Hz, 1 H), 1.82- C (M + H).sup.+   (diethylcarbamoyl)-3- and 46 2.02 (m, 5 H), 2.07 (dd, J = 13.0, 6.6 Hz, 1 H), 2.23 (t, J = 2.7 Hz, 1 H), (ES.sup.+), at   azabicyclo[3.1.0]hex-3-yl]-2- 2.40-2.56 (m, 2 H), 2.68 (quin, J = 7.3 Hz, 1 H), 3.14 (d, J = 9.3 Hz, 2 3.70 min,   azaspiro[3.4]octane-2- H), 3.38 (q, J = 6.8 Hz, 2 H), 3.55 (q, J = 6.8 Hz, 2 H), 3.65 (s, 3 H), 210 nm   carboxylate 3.74-3.97 (m, 4 H).  3-4 Mixture of isomers: ethyl 6- C AT (400 MHz, DMSO-d.sub.6) δ: 1.05-1.16 (m, 5 H), 1.17-1.32 (m, 8 H), 1 m/z 378   {(1R,5S,6r)-6-[ethyl(propan-2- Example 1.46-1.61 (m, 1 H), 1.73 (dt, J = 12.7, 8.3 Hz, 1 H), 1.79-1.90 (m, 2 C (M + H).sup.+   yl)carbamoyl]-3- 3-1 H), 1.90-1.99 (m, 3 H), 2.00-2.10 (m, 1 H), 2.14-2.29 (m, 1 H), (ES.sup.+), at   azabicyclo[3.1.0]hex-3-yl]-2- and 5 2.39-2.53 (m, 2 H), 2.55-2.73 (m, 1 H), 3.12 (d, J = 9.5 Hz, 2 H), 4.28 min,   azaspiro[3.4]octane-2- 3.45 (q, J = 7.0 Hz, 1 H), 3.74-3.92 (m, 4 H), 4.07 (q, J = 7.2 Hz, 2 H), 202 nm   carboxylate 4.37-4.69 (m, 1 H).  4-1 Ethyl 4-[(1R,5S,6r)-6- C AU (400 MHz, DMSO-d.sub.6) δ: 1.05-1.13 (m, 3 H), 1.25 (s, 6 H), 1.29-1.42 3 m/z 338   (diethylcarbamoyl)-3- 73 then (m, 2 H), 1.82-1.91 (m, 2 H), 1.91-1.97 (m, 2 H), 2.17-2.21 (m, 1 E (M + H).sup.+   azabicyclo[3.1.0]hexan-3- and 4 AV H), 2.25-2.35 (m, 1 H), 2.50-2.57 (m, 2 H), 2.79-2.96 (m, 2 H), (ES.sup.+), at   yl]piperidine-1-carboxylate 3.14-3.21 (m, 2 H), 3.32-3.41 (m, 2 H), 3.47-3.57 (m, 2 H), 3.99- 3.24 min,   4.07 (m, 2 H), 4.07-4.14 (m, 2 H). 202 nm  5-1 Isomer 1: ethyl 6-[(1R,5S,6r)- A AW (400 MHz, DMSO-d.sub.6) δ: 1.19-1.26 (m, 3 H), 1.26-1.33 (m, 3 H), 3 m/z 323   6-(ethoxycarbonyl)-3- 1 then 1.35-1.40 (m, 1 H), 1.43-1.49 (m, 2 H), 1.82-1.91 (m, 2 H), 1.91- E (M + H).sup.+   azabicyclo[3.1.0]hexan-3-yl]- and 75 AX 1.98 (m, 2 H), 2.26-2.33 (m, 2 H), 2.34-2.45 (m, 2 H), 2.57-2.63 (ES.sup.+), at   3-azabicyclo[3.1.1]heptane-3- (m, 1 H), 3.00-3.07 (m, 2 H), 3.38-3.55 (m, 3 H), 4.04-4.23 (m, 3 4.65 min,   carboxylate H). 220 nm  5-1 Isomer 2: ethyl 6-[(1R,5S,6r)- A AW (400 MHz, DMSO-d.sub.6) δ: 1.21-1.31 (m, 5 H), 1.33-1.40 (m, 2 H), 1.96- 3 m/z 323   6-(ethoxycarbonyl)-3-  1 then 2.05 (m, 3 H), 2.23-2.33 (m, 4 H), 2.36-2.40 (m, 1 H), 2.46-2.54 E (M + H).sup.+   azabicyclo[3.1.0]hexan-3-yl]- and 75 AX (m, 1 H) 3.19-3.25 (m 2 H), 3.42-3.54 (m, 2 H) 3.65 (s, 3 H), 4.06- (ES.sup.+), at   3-azabicyclo[3.1.1]heptane-3- 4.18 (m, 3 H). 4.69 min,   carboxylate 220 nm  5-2 Isomer 1: ethyl 6-[(1R,5S,6r)- C CY (400 MHz, METHANOL-d.sub.4) δ: 1.03-1.16 (m, 3 H), 1.22-1.34 (m, 6 3 m/z 350   6-(diethylcarbamoyl)-3- Example H), 1.34-1.44 (m, 1 H), 1.90-2.02 (m, 2 H), 2.21-2.44 (m, 6 H), E (M + H).sup.+   azabicyclo[3.1.0]hexan-3-yl]- 5-1 2.48-2.59 (m, 1 H), 3.20-3.27 (m, 2 H), 3.35-3.42 (m, 2 H), 3.43- (ES.sup.+), at   3-azabicyclo[3.1.1]heptane-3- and 4 3.61 (m, 4 H), 3.62-3.75 (m, 2 H), 4.08-4.23 (m, 2 H). E 3.86 min,   carboxylate 202 nm  6-1 Isomer 2: ethyl 8-[(1R,5S,6r)- C AY (400 MHz, METHANOL-d.sub.4) δ: 1.04-1.14 (m, 3 H), 1.24 (s, 6 H), 3 m/z 364   6-(diethylcarbamoyl)-3- 78 then 1.28-1.33 (m, 1 H), 1.34-1.43 (m, 2 H), 1.73-1.81 (m, 2 H), 1.87- E (M + H).sup.+   azabicyclo[3.1.0]hexan-3-yl]- and 4 AZ 1.95 (m, 2 H), 1.99-2.06 (m, 1 H), 2.13-2.24 (m, 2 H), 2.34-2.41 (ES.sup.+), at   3-azabicyclo[3.2.1]octane-3- (m, 2 H), 2.82-2.98 (m, 2 H), 3.07-3.16 (m, 2 H), 3.33-3.40 (m, 2 4.19 min,   carboxylate H), 3.45-3.55 (m, 2 H), 3.78-3.88 (m, 2 H), 4.06-4.15 (m, 2 H). 202 nm  7-1 Isomer 2: ethyl 3-[(1R,5S,6r)- A BA (400 MHz, DMSO-d.sub.6) δ: 1.13-1.21 (m, 6 H), 1.59-1.89 (m, 9 H), 1 m/z 337   6-(ethoxycarbonyl)-3- 1 1.89-1.99(m, 2 H), 2.14-2.21 (m, 2 H), 2.35-2.46 (m, 1 H), 3.15- C (M + H).sup.+   azabicyclo[3.1.0]hex-3-yl]-8- and 47 3.29 (m, 2 H), 3.95-4.07 (m, 6 H). (ES.sup.+), at   azabicyclo[3.2.1]octane-8- 5.28 min,   carboxylate 202 nm  7-2 Isomer 1: ethyl 3-{(1R,5S,6r)- E BB (400 MHz, DMSO-d.sub.6) δ: 0.94 (t, J = 7.0 Hz, 1 H), 1.09 (t, J = 7.2 Hz, 2 5 m/z 350   6-[ethyl(methyl)carbamoyl]-3- Example H), 1.15 (t, J = 7.0 Hz, 3 H), 1.19-1.44 (m, 2 H), 1.57-1.74 (m, 6 H), G (M + H).sup.+   azabicyclo[3.1.0]hex-3-yl]-8- 7-1 1.74-1.88 (m, 2 H), 1.91 (t, J = 2.9 Hz, 1 H), 2.23-2.33 (m, 2 H), 2.50- (ES.sup.+), at   azabicyclo[3.2.1]octane-8- and 15 2.59 (m, 1 H), 2.75 (s, 2 H), 2.92 (dd, J = 9.0, 4.7 Hz, 2 H), 3.00 (s, 1 3.41 min,   carboxylate H), 3.24 (q, J = 7.0 Hz, 1 H), 3.39 (q, J = 7.0 Hz, 1 H), 3.96-4.05 (m, 2 230-400   H), 4.05-4.13 (m, 2 H). nm  7-2 Isomer 2: ethyl 3-{(1R,5S,6r)- E BB (400 MHz, DMSO-d.sub.6) δ: 0.95 (t, J = 7.0 Hz, 2 H), 1.03-1.20 (m, 4 H), 5 m/z 350   6-[ethyl(methyl)carbamoyl]-3- Example 1.56-1.86(m, 10 H), 2.13(d, J = 8.2 Hz, 2 H), 2.36-2.45 (m, 1 H), G (M + H).sup.+   azabicyclo[3.1.0]hex-3-yl]-8- 7-1 2.77 (s, 2 H), 2.83-2.94 (m, 1 H), 3.01 (s, 1 H), 3.22 (d, J = 9.0 Hz, 2 (ES.sup.+), at   azabicyclo[3.2.1]octane-8- and 15 H), 3.26 (d, J = 7.4 Hz, 1 H), 3.38-3.47 (m, 1 H), 3.90-4.14 (m, 4 H). 4.10 min,   carboxylate 230-400   nm  7-3 Isomer 1: ethyl 3-[(1R,5S,6r)- C BC (400 MHz, METHANOL-d.sub.4) δ: 1.10 (t, J = 7.1 Hz, 3 H), 1.19-1.36 (m, 1 m/z 364   6-(diethylcarbamoyl)-3- Example 6 H), 1.55 (q, J = 12.6 Hz, 2 H), 1.67-1.81 (m, 2 H), 1.81-1.90 (m, 2 C (M + H).sup.+   azabicyclo[3.1.0]hex-3-yl]-8- 7-1 H), 1.90-2.09 (m, 4 H), 2.21 (t, J = 2.7 Hz, 1 H), 2.51 (d, J = 9.3 Hz, 2 (ES.sup.+), at   azabicyclo[3.2.1]octane-8- and 4 H), 2.66 (tt, J = 11.1, 5.4 Hz, 1 H), 3.12 (d, J = 8.6 Hz, 2 H), 3.35-3.44 3.94 min,   carboxylate (m, 2 H), 3.53 (q, J = 7.1 Hz, 2 H), 4.14 (q, J = 7.1 Hz, 2 H), 4.22-4.32 202 nm   (m, 2 H).  7-3 Isomer 2: ethyl 3-[(1R,5S,6r)- C BC (400 MHz, METHANOL-d.sub.4) δ: 1.12 (t, J = 7.1 Hz, 3 H), 1.27 (t, J = 7.2 1 m/z 364   6-(diethylcarbamoyl)-3- Example Hz, 6 H), 1.82-2.11 (m, 11 H), 2.28 (d, J = 8.8 Hz, 2 H), 2.49-2.59 C (M + H).sup.+   azabicyclo[3.1.0]hex-3-yl]-8- 7-1 (m, 1 H), 3.35-3.47 (m, 4 H), 3.53 (q, J = 7.1 Hz, 2 H), 4.05-4.35 (m, (ES.sup.+), at   azabicyclo[3.2.1]octane-8- and 4 4 H). 4.66 min,   carboxylate 202 nm  7-4 Isomer 1: ethyl 3-{(1R,5S,6r)- C BD (400 MHz, METHANOL-d.sub.4) δ: 1.05-1.18 (m, 3 H), 1.23-1.34 (m, 9 1 m/z 364   6-[ethyl(propan-2- Example H), 1.45-1.64 (m, 2 H), 1.74 (d, J = 6.3 Hz, 2 H), 1.79-1.88 (m, 2 H), C (M + H).sup.+   yl)carbamoyl]-3- 7-1 1.88-2.07 (m, 4 H), 2.11-2.32 (m, 1 H), 2.39-2.56 (m, 2 H), 2.56- (ES.sup.+), at   azabicyclo[3.1.0]hex-3-yl}-8- and 5 2.72 (m, 1 H), 3.10 (d, J = 9.0 Hz, 2 H), 3.21-3.28 (m, 1 H), 3.44 (q, 4.30 min,   azabicyclo[3.2.1]octane-8- J = 7.0 Hz, 1 H), 4.13 (q, J = 7.0 Hz, 2 H), 4.20-4.30 (m, 2 H), 4.37- 210 nm   carboxylate 4.71 (m, 1 H).  7-4 Isomer 2: ethyl 3-{(1R,5S,6r)- C BD (400 MHz, METHANOL-d.sub.4) δ: 1.10-1.18 (m, 5 H), 1.23-1.36 (m, 7 1 m/z 378   6-[ethyl(propan-2- Example H), 1.80-2.10 (m, 11 H), 2.28 (d, J = 8.8 Hz, 2 H), 2.45-2.58 (m, C (M + H).sup.+   yl)carbamoyl]-3- 7-1 J = 4.8 Hz, 1 H), 3.30-3.40 (m, 2 H), 3.45 (q, J = 7.0 Hz, 2 H), 4.06- (ES.sup.+), at   azabicyclo[3.1.0]hex-3-yl}-8- and 5 4.24 (m, 4 H), 4.28-4.78 (m, 1 H). 4.99 min,   azabicyclo[3.2.1]octane-8- 212 nm   carboxylate  7-5 Isomer 2: ethyl 3-[(1R,5S,6r)- J BE (400 MHz, METHANOL-d.sub.4) δ: 1.13-1.29 (m, 6 H), 1.45 (d, J = 13.6 1 m/z 364   6-{[acetyl(ethyl)amino]methyl}- 6, 48, Hz, 2 H), 1.82-2.00 (m, 9 H), 2.10 (s, 1 H), 2.13 (s, 2 H), 2.19 (dd, E (M + H).sup.+   3-azabicyclo[3.1.0]hex-3-yl]-8- 49, 50 J = 13.6, 8.7 Hz, 2 H), 2.32-2.49 (m, 1 H), 3.21-3.31 (m, 4 H), 3.41- (ES.sup.+), at   azabicyclo[3.2.1]octane-8- and 47 3.55 (m, 2 H), 4.06-4.22 (m, 4 H). 4.17 min,   carboxylate 202 nm  7-6 Isomer 2: ethyl 3-[(1R,5S,6r)- D BF (400 MHz, METHANOL-d.sub.4) δ: 1.25 (t, J = 7.0 Hz, 3 H), 1.74-2.01 (m, 1 m/z 362   6-(2-methyl-1,3-thiazol-4-yl)-3- 6, 7, 8, 8 H), 2.02-2.17 (m, 2 H), 2.24 (t, J = 3.0 Hz, 1 H), 2.28 (d, J = 8.5 Hz, 2 C (M + H).sup.+   azabicyclo[3.1.0]hex-3-yl]-8- 9, 10 H), 2.42-2.54 (m, 1 H), 2.63 (s, 3 H), 3.40 (d, J = 8.8 Hz, 2 H), 3.99- (ES.sup.+), at   azabicyclo[3.2.1]octane-8- and 47 4.24 (m, 4 H), 6.84 (s, 1 H). 5.56 min,   carboxylate 202 nm  8-1 Mixture of isomers: ethyl 5- A BG (400 MHz, DMSO-d.sub.6) δ: 1.08-1.22 (m, 6 H), 1.29-1.41 (m, 1 H), 1 m/z 337   [(1R,5S,6r)-6-  1 1.41-1.52 (m, 1 H), 1.52-1.71 (m, 2 H), 1.71-1.99 (m, 5 H), 2.15- C (M + H).sup.+   (ethoxycarbonyl)-3- and 53 2.35 (m, 3 H), 3.02-3.26 (m, 4 H), 3.37-3.44 (m, 1 H), 3.70-3.89 (ES.sup.+), at   azabicyclo[3.1.0]hex-3-yl]-2- (m, 1 H), 3.93-4.10 (m, 4 H). 5.23 min,   azabicyclo[2.2.2]octane-2- 202 nm   carboxylate  8-2 Isomer 1: ethyl (1S,4S)-5- E BH (400 MHz, DMSO-d.sub.6) δ: 0.95 (t, J = 7.0 Hz, 1 H), 0.99-1.18 (m, 5 H), 5 m/z 350   {(1R,5S,6r)-6- 56 1.36 (d, J = 12.1 Hz, 2 H), 1.49-1.65(m, 2 H), 1.70-1.91 (m, 4 H), G (M + H).sup.+   [ethyl(methyl)carbamoyl]-3- and 15 1.95-2.04 (m, 1 H), 2.14-2.24 (m, 2 H), 2.24-2.35 (m, 1 H), 2.76 (ES.sup.+), at   azabicyclo[3.1.0]hex-3-yl]-2- (s, 1.5 H), 2.82-2.89 (m, 1 H), 2.90-2.98 (m, 1 H), 3.02 (s, 1.5 H), 3.79 min,   azabicyclo[2.2.2]octane-2- 3.09-3.29 (m, 3 H), 3.39-3.51 (m, 2 H), 3.80 (d, J = 13.7 Hz, 1 H), 230-400   carboxylate 3.98 (q, J = 7.0 Hz, 2 H). nm  8-2 Isomer 2: ethyl (1S,4S)-5- E BH (400 MHz, DMSO-d.sub.6) δ: 0.94 (t, J = 7.0 Hz, 1 H), 1.03-1.18 (m, 5 H), 5 m/z 350   {(1R,5S,6r)-6- 56 1.41-1.52 (m, 2 H), 1.52-1.68 (m, 2 H), 1.71-1.87 (m, 4 H), 1.93- G (M + H).sup.+   [ethyl(methyl)carbamoyl]-3- and 15 2.02 (m, 1 H), 2.13-2.22 (m, 2 H), 2.23-2.29 (m, 1 H), 2.76 (s, 1 H), (ES.sup.+), at   azabicyclo[3.1.0]hex-3-yl]-2- 2.79-2.89 (m, 2 H), 3.02 (s, 2 H), 3.06-3.16 (m, 1 H), 3.20-3.28 3.81 min,   azabicyclo[2.2.2]octane-2- (m, 2 H), 3.37-3.46 (m, 2 H), 3.74-3.86 (m, 1 H 3.98 (q, J = 7.0 Hz, 230-400   carboxylate 2 H). nm  8-3 Isomer 1: ethyl (1R,4R)-5- E BI (400 MHz, CHLOROFORM-d) δ: 1.04-1.14 (m, 1 H), 1.17-1.32 (m, 5 m/z 350   {(1R,5S,6r)-6- 5 H), 1.43-1.73 (m, 4 H), 1.74-1.89 (m, 2 H), 1.89-2.01 (m, 2 H), G (M + H).sup.+   [ethyl(methyl)carbamoyl]-3- 2.04-2.13 (m, 1 H), 2.21-2.36 (m, 2 H), 2.92 (d, = 1.56 Hz, 3 H), (ES.sup.+), at   azabicyclo[3.1.0]hexan-3-yl}- 3.00-3.09 (m, 1 H), 3.11 (s, 1 H), 3.13-3.28 (m, 2 H), 3.36-3.45 3.87 min,   2-azabicyclo[2.2.2]octane-2- (m, 1 H), 3.46-3.60 (m, 2 H), 3.92-3.97 (m, 1 H), 4.03-4.08 (m, 1 230-400   carboxylate H), 4.09-4.19 (m, 2 H). nm  8-4 Isomer 1: ethyl (1S,4S)-5- E BJ (400 MHz, CHLOROFORM-d) δ: 1.08 (t, J = 7.0 Hz, 3 H), 1.17-1.28 5 m/z 364   [(1R,5S,6r)-6- 56 then (m, 6 H), 1.41-1.70 (m, 4 H), 1.73-1.87 (m, 2 H), 1.87-1.99 (m, 3 G (M + H).sup.+   (diethylcarbamoyl)-3- and 4 BK H), 2.03 (d, J = 9.8 Hz, 1 H), 2.21-2.33 (m, 3 H), 3.02 (dd, J = 14.8, 9.0 (ES.sup.+), at   azabicyclo[3.1.0]hexan-3-yl]- Hz, 1 H), 3.11-3.21 (m, 2 H), 3.35 (q, J = 6.8 Hz, 2 H), 3.39-3.48 (m, 4.09 min,   2-azabicyclo[2.2.2]octane-2- 2 H), 3.48-3.57 (m, 1 H), 3.89-4.05 (m, 1 H), 4.11 (q, J = 7.0 Hz, 2 230-400   carboxylate H). nm  8-4 Isomer 2: ethyl (1S,4S)-5- E BJ (400 MHz, CHLOROFORM-d) δ: 1.08 (t, J = 7.0 Hz, 3 H), 1.17-1.29 5 m/z 364   [(1R,5S,6r)-6- 56 then (m, 6 H), 1.34-1.48 (m, 2 H), 1.55-1.67 (m, 1 H), 1.67-1.79 (m, 1 G (M + H).sup.+   (diethylcarbamoyl)-3- and 4 BK H), 1.79-1.90 (m, 2 H), 1.90-2.07 (m, 4 H), 2.22-2.37 (m, 3 H), (ES.sup.+), at   azabicyclo[3.1.0]hexan-3-yl]- 2.99 (d, J = 9.0 Hz, 1 H), 3.15 (t, J = 8.2 Hz, 1 H), 3.25-3.32 (m, 1 H), 4.11 min,   2-azabicyclo[2.2.2]octane-2- 3.36 (q, J = 6.8 Hz, 3 H), 3.40-3.50 (m, 2 H), 3.85-4.03 (m, 1 H), 230-400   carboxylate 4.10 (q, J = 7.0 Hz, 2 H). nm  8-5 Isomer 1: ethyl (1R,4R)-5- E BI (400 MHz, CHLOROFORM-d) δ: 1.06-1.14 (m, 3 H), 1.19-1.31 (m, 5 m/z 364   [(1R,5S,6r)-6- 59 7 H), 1.43-1.62 (m, 3 H), 1.78-1.89 (m, 2 H), 1.90-2.01 (m, 2 H), G (M + H).sup.+   (diethylcarbamoyl)-3- and 4 2.02-2.09 (m, 1 H), 2.23-2.35 (m, 3 H), 3.00-3.09 (m, 1 H), 3.14- (ES.sup.+), at   azabicyclo[3.1.0]hexan-3-yl]- 3.26 (m, 2 H), 3.33-3.41 (m, 2 H), 3.41-3.50 (m, 2 H), 3.50-3.59 4.19 min,   2-azabicyclo[2.2.2]octane-2- (m, 1 H), 3.92-3.96 (m, 1 H), 4.02-4.08 (m, 1 H), 4.08-4.19 (m, 2 230-400   carboxylate H). nm  8-5 Isomer 2: ethyl (1R,4R)-5- E BI (400 MHz, CHLOROFORM-d) δ: 1.11 (t, J = 7.22 Hz, 3 H), 1.25 (q, 5 m/z 364   [(1R,5S,6r)-6- 59 J = 7.16 Hz, 6 H), 1.36-1.47 (m, 2 H), 1.69-1.80 (m, 1 H), 1.82-1.93 G (M + H).sup.+   (diethylcarbamoyl)-3- and 4 (m, 2 H), 1.94-2.09 (m, 4 H), 2.27-2.32 (m, 2 H), 2.33-2.40 (m, 1 (ES.sup.+), at   azabicyclo[3.1.0]hexan-3-yl]- H), 2.98-3.04 (m, 1 H), 3.15-3.21 (m, 1 H), 3.27-3.34 (m, 1 H), 4.18 min,   2-azabicyclo[2.2.2]octane-2- 3.35-3.42 (m, 3 H), 3.42-3.52 (m, 2 H), 3.89-3.94 (m, 1 H), 4.00- 230-400   carboxylate 4.06 (m, 1 H), 4.13 (q, J = 7.16 Hz, 2 H). nm  8-6 Isomer 1: methyl 5- C BL (400 MHz, METHANOL-d.sub.4) δ: 1.11 (t, J = 7.1 Hz, 3 H), 1.22-1.37 (m, 4 m/z 350   [(1R,5S,6r)-6- 61 then 6 H), 1.48-1.78 (m, 4 H), 1.90-2.03 (m, 4 H), 2.23 (d, J = 2.4 Hz, 1 C (M + H).sup.+   (diethylcarbamoyl)-3- and 4 BM H), 2.37-2.51 (m, 2 H), 3.11-3.25 (m, 1 H), 3.25-2.30 (m, 1 H), (ES.sup.+), at   azabicyclo[3.1.0]hex-3-yl]-2- 3.36-3.43 (m, 3 H), 3.49-3.63 (m, 2 H), 3.65-3.72 (m, 3 H), 3.91- 3.72 min,   azabicyclo[2.2.2]octane-2- 4.00 (m, 1 H). 210 nm   carboxylate  8-6 Isomer 2: methyl 5- C BL (400 MHz, METHANOL-d.sub.4) δ: 1.11 (t, J = 7.1 Hz, 3 H), 1.23-1.39 (m, 4 m/z 350   [(1R,5S,6r)-6- 61 then 6 H), 1.57-1.77 (m, 4 H), 1.89-2.02 (m, 4 H), 2.19-2.55 (m, 1 H), C (M + H).sup.+   (diethylcarbamoyl)-3- and 4 BM 2.31-2.48 (m, 3 H), 3.09-3.19 (m, 1 H), 3.21-3.30 (m, 1 H), 3.38 (ES.sup.+), at   azabicyclo[3.1.0]hex-3-yl]-2- (q, J = 7.3 Hz, 2 H), 3.51-3.62 (m, 2 H), 3.66-3.71 (m, 3 H), 3.92- 3.69 min,   azabicyclo[2.2.2]octane-2- 4.01 (m, 1 H). 210 nm   carboxylate  8-7 Mixture of isomers: ethyl 5- C BN (400 MHz, METHANOL-d.sub.4) δ: 1.10-1.18 (m, 5 H), 1.24-1.32 (m, 7 1 m/z 378   {(1R,5S,6r)-6-[ethyl(propan-2- Example H), 1.43-1.54(m, 1 H), 1.57-1.85 (m, 3 H), 1.88-2.08 (m, 5 H), C (M + H).sup.+   yl)carbamoyl]-3- 8-1 2.18-2.28 (m, 1 H), 2.31-2.44 (m, 3 H), 3.06-3.20 (m, 1 H), 3.22- (ES.sup.+), at   azabicyclo[3.1.0]hex-3-yl}-2- and 5 3.26 (m, 1 H), 3.34-3.39 (m, 2 H), 3.41-3.52 (m, 2 H), 3.92-4.00 4.71 min,   azabicyclo[2.2.2]octane-2- (m, 1 H), 4.08-4.18 (m, 2 H), 4.40-4.71 (m, 1 H). 210 nm   carboxylate  8-8 Mixture of isomers: ethyl E BO (400 MHz, CHLOROFORM-d) δ: 0.69-0.81 (m, 2 H), 0.81-0.94 (m, 5 m/z 376   (1S,4S)-5-{(1R,5S,6r)-6- 56 2 H), 1.08(t, J = 7.0 Hz, 3 H), 1.18-1.25(m, 3 H), 1.31-2.19 (m, 10 G (M + H).sup.+   [cyclopropyl(ethyl)carbamoyl]- and 19 H), 2.19-2.29 (m, 3 H), 2.48-2.56 (m, 1 H), 2.67-2.78 (m, 1 H), (ES.sup.+), at   3-azabicyclo[3.1.0]hex-3-yl}l-2- 2.93-3.06 (m, 1 H), 3.10-3.21 (m, 1 H), 3.23-3.38 (m, 2 H), 3.39- 4.40 min,   azabicyclo[2.2.2]octane-2- 3.54 (m, 1 H), 3.83-4.02 (m, 1 H), 4.08 (q, J = 7.0 Hz, 2 H). 230-400   carboxylate nm  8-9 Isomer 1: ethyl 5-{(1R,5S,6r)- C BP (400 MHz, METHANOL-d.sub.4) δ: 1.26 (q, J = 7.0 Hz, 3 H), 1.40-1.59 (m, 1 m/z 352   6- Example 2 H), 1.73 (t, J = 12.0 Hz, 2 H), 1.87-1.99 (m, 4 H), 1.99-2.13 (m, 1 C (M + H).sup.+   [methoxy(methyl)carbamoyl]- 8-1 H), 2.27-2.46 (m, 3 H), 2.49-2.63 (m, 1 H), 3.11 (dd, J = 9.3, 3.4 Hz, (ES.sup.+), at   3-azabicyclo[3.1.0]hexan-3- and 7 1 H), 3.16-3.25 (m, 3 H), 3.28 (dd, J = 9.3, 3.4 Hz, 2 H), 3.35-3.46 4.12 min,   yl}-2-azabicyclo[2.2.2]octane- (m, 1 H), 3.78 (s, 3 H), 3.91-3.70 (m, 1 H), 4.12 (q, J = 6.8 Hz, 2 H). 210 nm   2-carboxylate  8-10 Isomer 1: ethyl 5-{(1R,5S,6r)- C BQ (400 MHz, METHANOL-d.sub.4) δ: 1.18 (t, J = 6.8 Hz, 3 H), 1.26 (q, J = 7.3 1 m/z 366   6-[ethyl(methoxy)carbamoyl]- Example Hz, 3 H), 1.41-1.59 (m, 2 H), 1.63-1.85 (m, 2 H), 1.88-2.10 (m, 5 C (M + H).sup.+   3-azabicyclo[3.1.0]hex-3-yl}-2- 8-1 H), 2.29-2.45 (m, 3 H), 2.46-2.62 (m, 1 H), 3.11 (dd, J = 9.0, 3.2 Hz, (ES.sup.+), at   azabicyclo[2.2.2]octane-2- and 30 1 H), 3.29 (dd, J = 9.3, 2.9 Hz, 1 H), 3.35-3.48 (m, 2 H), 3.62-3.73 4.44 min,   carboxylate (m, 2 H), 3.78 (s, 3 H), 3.87-3.99 (m, 1 H), 4.12 (q, J = 6.8 Hz, 2 H). 202 nm  8-10 Isomer 2: ethyl 5-{(1R,5S,6r)- C BQ (400 MHz, METHANOL-d.sub.4) δ: 1.18 (t, J = 6.4 Hz, 3 H), 1.28 (q, J = 7.3 1 m/z 366   6-[ethyl (methoxy)carbamoyl]- Example Hz, 3 H), 1.52-1.68 (m, 3 H), 1.72 (d, J = 3.4 Hz, 1 H), 1.75-1.84 (m, C (M + H).sup.+   3-azabicyclo[3.1.0]hex-3-yl}-2- 8-1 1 H), 1.89-2.00 (m, 3 H), 2.29-2.43 (m, 3 H), 2.47-2.63 (m, 1 H), (ES.sup.+), at   azabicyclo[2.2.2]octane-2- and 30 3.14 (dd, J = 9.3, 5.4 Hz, 1 H), 3.17-3.24 (m, 1 H), 3.27 (dd, J = 9.3, 4.53 min,   carboxylate 3.9 Hz, 2 H), 3.53-3.63 (m, 1 H), 3.67 (d, J = 7.8 Hz, 2 H), 3.77 (s, 3 2.02 nm   H), 3.91-4.02 (m, 1 H), 4.13 (q, J = 7.2 Hz, 2 H).  9-1 Isomer 1: ethyl 3-{(1R,5S,6r)- C BR (400 MHz, METHANOL-d.sub.4) δ: 1.10 (t, J = 7.2 Hz, 1 H), 1.19-1.38 (m, 1 m/z 364   6-[ethyl(methyl)carbamoyl]-3- 64 7 H), 1.43-1.68 (m, 5 H), 1.91-1.97 (m., 2 H), 1.97-2.13 (m, 2 H), E (M + H).sup.+   3-azabicyclo[3.1.0]hex-3-yl}-9- and 15 2.27(t, J = 7.6 Hz, 3 H), 2.52(d, J = 8.5 Hz, 2 H), 2.92(s, 2 H), 3.13- (ES.sup.+), at   azabicyclo[3.3.1]nonane-9- 3.26 (m, 3 H), 3.41 (q, J = 7.0 Hz, 1 H), 3.58 (q, J = 7.0 Hz, 1 H), 4.13 3.74 min,   carboxylate (q, J = 7.0 Hz, 2 H), 4.40-4.51 (m, 2 H). 202 nm  9-1 Isomer 2: ethyl 3-{(1R,5S,6r)- C BR (400 MHz, METHANOL-d.sub.4) δ: 1.09 (t, J = 7.2 Hz, 1 H), 1.16-1.34 (m, 1 m/z 364   6-[ethyl(methyl)carbamoyl]-3- 64 5 H), 1.53-1.80 (m, 7 H), 1.88-2.04 (m, 5 H), 2.20-2.31 (m, 1 H), E (M + H).sup.+   azabicyclo[3.1.0]hex-3-yl}-9- and 15 2.43-2.64 (m, 2 H), 2.92 (s, 2 H), 2.98-3.12 (m, 1 H), 3.12-3.21 (ES.sup.+), at   azabicyclo[3.3.1]nonane-9- (m, 3 H), 3.40 (q, J = 7.2 Hz, 1 H), 3.57 (q, J = 7.0 Hz, 1 H), 4.14 (q, 3.75 min,   carboxylate J = 7.0 Hz, 2 H), 4.29-4.40 (m, 2 H). 202 nm  9-2 Isomer 1: ethyl 3-[(1R,5S,6r)- C BS (400 MHz, METHANOL-d.sub.4) δ: 1.10 (t, J = 7.2 Hz, 3 H), 1.19-1.37 (m, 1 m/z 378   6-(diethylcarbamoyl)-3- 64 then 6 H), 1.55-1.85 (m, 7 H), 1.87-2.02 (m, 4 H), 2.18-2.27 (m, 1 H), C (M + H).sup.+   azabicyclo[3.1.0]hex-3-yl]-9- and 4 BT 2.53(d, J = 9.5 Hz, 2 H), 2.62-2.66 (m, 1 H), 2.99-3.13 (m, 1 H), (ES.sup.+), at   azabicyclo[3.3.1]nonane-9- 3.16 (dd, J = 9.5, 4.8 Hz, 2 H), 3.35-3.44 (m, 2 H), 3.46-3.60 (m, 2 4.15 min,   carboxylate H), 4.14 (q, J = 7.0 Hz, 2 H), 4.28-4.42 (m, 2 H). 202 nm  9-2 Isomer 2: ethyl 3-[(1R,5S,6r)- C BS (400 MHz, METHANOL-d.sub.4) δ: 1.11 (t, J = 7.2 Hz, 3 H), 1.22-1.37 (m, 1 m/z 378   6-(diethylcarbamoyl)-3- 64 then 9 H), 1.45-1.66 (m, 4 H), 1.92-1.96 (m, 2 H), 1.98-2.12 (m, 2 H), C (M + H).sup.+   azabicyclo[3.1.0]hex-3-yl]-9- and 4 BT 2.23 (t, J = 2.9 Hz, 1 H), 2.24-2.36 (m, 2 H), 2.53 (d, J = 9.2 Hz, 2 H), (ES.sup.+), at   azabicyclo[3.3.1]nonane-9- 3.18 (d, J = 9.5 Hz, 2 H), 3.36-3.45 (m, 2 H), 3.55 (q, J = 7.3 Hz, 2 H), 4.07 min,   carboxylate 4.12 (q, J = 7.0 Hz, 2 H), 4.39-4.58 (m, 2 H). 202 nm  9-3 Isomer 1: methyl 3- C BU (400 MHz, METHANOL-d.sub.4) δ: 1.10 (t, J = 7.0 Hz, 3 H), 1.25 (t, J = 7.2 1 m/z 364   [(1R,5S,6r)-6- 66 Hz, 3 H), 1.57-1.85 (m, 6 H), 1.88-2.03 (m, 4 H), 2.06 (s, 2 H), 2.21 E (M + H).sup.+   (diethylcarbamoyl)-3- and 4 (t, J = 2.6 Hz, 1 H), 2.53 (d, J = 9.2 Hz, 2 H), 3.06 (tt, J = 11.4, 5.5 Hz, 1 (ES.sup.+), at   azabicyclo[3.1.0]hex-3-yl]-9- H), 3.12-3.20 (m, 2 H), 3.36-3.42 (m, 2 H), 3.53 (q, J = 7.0 Hz, 2 H), 3.72 min,   azabicyclo[3.3.1]nonane-9- 3.70 (s, 3 H), 4.27-4.39 (m, 2 H). 202 nm   carboxylate  9-3 Isomer 2: methyl 3- C BU (400 MHz, METHANOL-d.sub.4) δ: 1.11 (t, J = 7.0 Hz, 3 H), 1.22-1.38 (m, 1 m/z 364 [(1R,5S,6r)-6- 66 5 H), 1.45-1.75 (m, 5 H), 1.90-2.01 (m, 3 H), 2.01-2.13 (m, 2 H), E (M + H).sup.+ (diethylcarbamoyl)-3- and 4 2.18-2.37 (m, 2 H), 2.53 (d, J = 9.5 Hz, 2 H), 3.13-3.24 (m, 2 H), (ES.sup.+), at azabicyclo[3.1.0]hex-3-yl]-9- 3.36-3.43 (m, 3 H), 3.49-3.60 (m, 2 H), 3.64-3.76 (m, 2 H), 4.30- 3.74 min, azabicyclo[3.3.1]nonane-9- 4.51 (m, 2 H). 202 nm carboxylate 10-1 Isomer 1: ethyl 7-{(1R,5S,6r)- C BV (400 MHz, METHANOL-d.sub.4) δ: 1.10 (t, J = 7.3 Hz, 1 H), 1.23-1.33 (m, 1 m/z 366 6-[ethyl(methyl)carbamoyl]-3- 69 then 5 H), 1.57 (t, J = 11.9 Hz, 2 H), 1.91-1.95 (m, 2 H), 2.01 (tt, J = 11.8, E (M + H).sup.+ azabicyclo[3.1.0]hex-3-yl}-3- and 15 BW 5.6 Hz, 1 H), 2.28 (d, J = 8.5 Hz, 1 H), 2.31-2.41 (m, 2 H), 2.51 (d, (ES.sup.+), at oxa-9- J = 9.2 Hz, 2 H), 2.92 (s, 2 H), 3.14-3.20 (m, 3 H), 3.37-3.44 (m, 1 3.20 min, azabicyclo[3.3.1]nonane-9- H), 3.48-3.66 (m, 5 H), 4.12-4.28 (m, 4 H). 202 nm carboxylate 10-1 Isomer 2: ethyl 7-{(1R,5S,6r)- C BV (400 MHz, METHANOL-d.sub.4) δ: 1.09 (t, J = 7.0 Hz, 1 H), 1.22-1.32 (m, 1 m/z 366 6-[ethyl(methyl)carbamoyl]-3- 69 then 4 H), 1.62 (t, J = 11.9 Hz, 2 H), 1.89-1.99 (m, 2 H), 2.06 (dd, J = 13.1, E (M + H).sup.+ azabicyclo[3.1.0]hex-3-yl}-3- and 15 BW 5.2 Hz, 2 H), 2.21-2.28 (m, 1 H), 2.54(d, J = 8.5 Hz, 2 H), 2.92 (s, 1 (ES.sup.+), at oxa-9- H), 3.13-3.19 (m, 3 H), 3.35-3.44 (m, 4 H), 3.57 (q, J = 7.3 Hz, 1 H), 3.24 min, azabicyclo[3.3.1]nonane-9- 3.68 (d, J = 11.0 Hz, 2 H), 3.79-3.92 (m, 2 H), 4.06-4.13 (m, 2 H), 202 nm carboxylate 4.17 (q, J = 7.1 Hz, 2 H). 10-2 Isomer 1: ethyl 7-[(1R,5S,6r)- C BX (400 MHz, METHANOL-d.sub.4) δ: 0.80-1.01 (m, 2 H), 1.11 (t, J = 7.1 Hz, 1 m/z 380 6-(diethylcarbamoyl)-3- 69 then 2 H), 1.21-1.44 (m, 9 H), 1.49-1.69 (m, 2 H), 1.92-1.95 (m, 2 H), C (M + H).sup.+ azabicyclo[3.1.0]hex-3-yl]-3- and 4 BY 1.97-2.10 (m, 1 H), 2.26 (t, J = 2.7 Hz, 1 H), 2.28-2.36 (m, 2 H), 2.52 (ES.sup.+), at oxa-9- (d, J = 9.3 Hz, 1 H), 3.18 (d, J = 9.3 Hz, 1 H), 3.35-3.42 (m, 2 H), 3.47- 3.46 min, azabicyclo[3.3.1]nonane-9- 3.68 (m, 4 H), 4.08-4.33 (m, 4 H). 210 nm carboxylate 10-2 Isomer 2: ethyl 7-[(1R,5S,6r)- C BX (400 MHz, METHANOL-d.sub.4) δ: 1.10 (t, J = 6.8 Hz, 3 H), 1.20-1.38 (m, 1 m/z 380 6-(diethylcarbamoyl)-3- 69 then 6 H), 1.53-1.71 (m, 2 H), 1.91-1.98 (m, 2 H), 2.07 (dd, J = 13.2, 5.4 C (M + H).sup.+ azabicyclo[3.1.0]hex-3-yl]-3- and 4 BY Hz, 2 H), 2.18-2.26 (m, 1 H), 2.55 (d, J = 9.3 Hz, 2 H), 3.17 (dd, (ES.sup.+), at oxa-9- J = 9.3, 5.4 Hz, 2 H), 3.35-3.46 (m, 3 H), 3.54 (q, J = 7.3 Hz, 2 H), 3.68 3.49 min, azabicyclo[3.3.1]nonane-9- (d, J = 11.2 Hz, 2 H), 3.79-3.92 (m, 2 H), 4.05-4.14 (m, 2 H), 4.14- 210 nm carboxylate 4.26 (m, 2 H). 10-3 Isomer 1: methyl 7- C BZ (400 MHz, METHANOL-d.sub.4) δ: 1.09 (s, 3 H), 1.20-1.28 (m, 3 H), 1.50- 1 m/z 366 [(1R,5S,6r)-6- 71 then 1.60 (m, 2 H), 1.88-1.94 (m, 2 H), 1.95-2.05 (m, 1 H), 2.21-2.26 E (M + H).sup.+ (diethylcarbamoyl)-3- and 4 CA (m, 1 H), 2.27-2.39 (m, 2 H), 2.45-2.54 (m, 2 H), 3.11-3.20 (m, 2 (ES.sup.+), at azabicyclo[3.1.0]hex-3-yl]-3- H), 3.33-3.40 (m, 2 H), 3.46-3.64 (m, 6 H), 3.70 (s, 3 H), 4.16-4.23 3.06 min, oxa-9- (m, 2 H). 202 nm azabicyclo[3.3.1]nonane-9- carboxylate 10-3 Isomer 2: methyl 7- C BZ (400 MHz, METHANOL-d.sub.4) δ: 1.10 (t, J = 7.3 Hz, 3 H), 1.26 (t, J = 1 m/z 366 [(1R,5S,6r)-6- 71 then 7.0 Hz, 3 H), 1.52-1.72 (m, 2 H), 1.90-1.95 (m, 2 H), 2.06 (dd, J = 13.1, E (M + H).sup.+ (diethylcarbamoyl)-3- and 4 CA 4,6 Hz, 2 H), 2.16-2.28 (m, 1 H), 2.54 (d, J = 9.2 Hz, 2 H), 3.16 (dd, (ES.sup.+), at azabicyclo[3.1.0]hex-3-yl]-3- J = 9.5, 6.4 Hz, 2 H), 3.35-3.46 (m, 3 H), 3.49-3.62 (m, 2 H), 3.62- 3.07 min, oxa-9- 3.71 (m, 2 H), 3.73 (s, 3 H), 3.85 (dd, J = 16.5, 11.6 Hz, 2 H), 4.03- 202 nm azabicyclo[3.3.1]nonane-9- 4.10 (m, 2 H). carboxylate 10-4 Isomer 1: ethyl 7-{(1R,5S,6r)- C CB (400 MHz, METHANOL-d.sub.4) δ: 1.10 (d, J = 6.85 Hz, 3 H), 1.23-1.31 3 m/z 380 6-[methyl(propan-2- 69 then (m, 6 H), 1.55- 1.67(m, 2 H), 1.92-2.00 (m, 2 H), 2.19-2.25 (m, 1 E (M + H).sup.+ yl)carbamoyl]-3- and 18 CC H), 2.28-2.39 (m, 2 H), 2.51-2.63 (m, 2 H), 2.77 (s, 1.5 H), 3.00 (s, (ES.sup.+), at azabicyclo[3.1.0]hexan-3-yl}- 1.5 H), 3.17-3.26 (m, 2 H), 3.48-3.56 (m, 2 H), 3.57-3.71 (m, 2 H), 2.95 min, 3-oxa-9- 4.10-4.25 (m, 4 H), 4.46-4.54 (m, 1 H), 4.67-4.77 (m, 1 H). 202 nm azabicyclo[3.3.1]nonane-9- carboxylate 10-4 Isomer 2: ethyl 7-{(1R,5S,6r)- C CB (400 MHz, METHANOL-d.sub.4) δ: 1.09 (d, J = 6.85 Hz, 3 H), 1.22-1.31 3 m/z 380 6-[methyl(propan-2- 69 then (m, 6 H), 1.55-1.68 (m, 2 H), 1.92-1.98 (m, 2 H), 2.02-2.11 (m, 2 E (M + H).sup.+ yl)carbamoyl]-3- and 18 CC H), 2.17-2.30 (m, 1 H) 2.53-2.65 (m, 2 H), 2.76 (s, 1.5 H), 2.99 (s, (ES.sup.+), at azabicyclo[3.1.0]hexan-3-yl}- 1.5 H), 3.14-3.23 (m, 2 H), 3.62-3.71 (m, 2 H), 3.78-3.90 (m, 2 H), 2.99 min, 3-oxa-9- 4.04-4.12 (m, 2 H), 4.12-4.19 (m, 2 H), 4.43-4.51 (m, 1 H), 4.68- 202 nm azabicyclo[3.3.1]nonane-9- 4.76 (m, 1 H). carboxylate 10-5 Isomer 1: methyl 7- C CD (400 MHz, METHANOL-d.sub.4) δ: 1.10 (d, J = 7.02 Hz, 3 H), 1.25 (d, 3 m/z 366 ((1R,5S,6r)-6- 71 then J = 6.71 Hz, 3 H), 1.50-1.61 (m, 2 H), 1.89-1.95 (m, 2 H), 1.95-2.05 E (M + H).sup.+ (isopropyl(methyl)carbamoyl)- and 18 CE (m, 1 H), 2.26-2.38 (m, 2 H), 2.46-2.54 (m, 2 H), 2.76 (s, 1.5 H), (ES.sup.+), at 3-azabicyclo[3.1.0]hexan-3- 3.00 (s, 1.5 H), 3.12-3.19 (m, 2 H), 3.46-3.66 (m, 4 H), 3.70 (s, 3 2.70 min, yl)-3-oxa-9- H), 4.15-4.23 (m, 2 H), 4.45-4.53 (m, 1 H), 4.66-4.76 (m, 1 H). 202 nm azabicyclo[3.3.1]nonane-9- carboxylate 10-5 Isomer 2: methyl 7- C CD (400 MHz, METHANOL-d.sub.4) δ: 1.09 (d, J = 6.71 Hz, 3 H), 1.20-1.27 3 m/z 366 ((1R,5S,6r)-6- 71 then (m, 3 H), 1.53-1.67 (m, 2 H), 1.90-1.96 (m, 2 H), 2.00-2.10 (m, 2 E (M + H).sup.+ (isopropyl(methyl)carbamoyl)- and 18 CE H), 2.17-2.29 (m, 1 H), 2.46-2.55 (m, 2 H), 2.76 (s, 1.5 H), 2.99 (s, (ES.sup.+), at azabicyclo[3.1.0]hexan-3-yl}-3 1.5 H), 3.10-3.19 (m, 2 H), 3.61-3.69 (m, 2 H), 3.71 (d, J = 0.92 Hz, 2.71 min, yl)-3-oxa-9- 3 H), 3.77-3.89 (m, 2 H), 4.03-4.09 (m, 2 H), 4.43-4.52 (m, 1 H), 202 nm azabicyclo[3.3.1]nonane-9- 4.66-4.76 (m, 1 H). carboxylate 10-6 Isomer 1: ethyl 7-{(1R,5S,6r)- C CF (400 MHz, METHANOL-d.sub.4) δ: 0.85-0.98 (m, 1 H), 1.06-1.18 (m, 4 3 m/z 394 6-[ethyl(propan-2- 69 H), 1.23-1.33 (m, 8 H), 1.49-1.63 (m, 2 H), 1.83-2.09 (m, 3 H), E (M + H).sup.+ yl)carbamoyl]-3- and 5 2.18-2.24 (m, 1 H), 2.25-2.40 (m, 2 H), 2.44-2.56 (m, 2 H), 3.10- (ES.sup.+), at azabicyclo[3.1.0]hexan-3-yl}-3 3.24 (m, 2 H), 3.25-3.29 (m, 1 H), 3.40-3.65 (m, 5 H), 4.09-4.25 3.38 min, oxa-9- (m, 3 H), 4.39-4.70 (m, 1 H). 202 nm azabicyclo[3.3.1]nonane-9- carboxylate 10-6 Isomer 2: ethyl 7-{(1R,5S,6r)- C CF (400 MHz, METHANOL-d.sub.4) δ: 1.05-1.19 (m, 4 H), 1.19-1.33 (m, 6 3 m/z 394 6-[ethyl(propan-2- 69 H), 1.63 (t, J = 12.2 Hz, 2 H), 1.86-1.98 (m, 2 H), 2.07 (dd, J = 13.1, E (M + H).sup.+ yl)carbamoyl]-3- and 5 5.2 Hz, 2 H), 2.15-2.32 (m, 1 H), 2.45-2.61 (m, 2 H), 3.11-3.22 (m, (ES.sup.+), at azabicyclo[3.1.0]hexan-3-yl}-3 2 H), 3.26-3.31 (m, 1 H), 3.37 (s, 2 H), 3.41-3.53 (m, 2 H), 3.68 (d, 3.44 min, oxa-9- J = 11.6 Hz, 2 H), 3.77-3.95 (m, 2 H), 4.03-4.13 (m, 2 H), 4.17 (q, 202 nm azabicyclo[3.3.1]nonane-9- J = 7.1 Hz, 2 H), 4.39-4.70 (m, 1 H). carboxylate 10-7 Isomer 1: methyl 7- C CG (400 MHz, METHANOL-d.sub.4) δ: 1.07-1.19 (m, 6 H), 1.22-1.37 (m, 3 3 m/z 380 {(1R,5S,6r)-6-[ethyl(propan-2- 71 then H), 1.50-1.65 (m, 2 H), 1.90-1.96 (m, 2 H), 1.95-2.07 (m, 1 H), E (M + H).sup.+ yl)carbamoyl]-3- and 5 CH 2.27-2.40 (m, 2 H), 2.45-2.57 (m, 2 H), 3.11-3.21 (m, 2 H), 3.41- (ES.sup.+), at azabicyclo[3.1.0]hexan-3-yl}- 3.66 (m, 6 H), 3.71 (s, 3 H), 4.16-4.26 (m, 2 H), 4.42-4.51 (m, 1 H), 3.03 min, 3-oxa-9- 4.59-4.69 (m, 1 H). 202 nm azabicyclo[3.3.1]nonane-9- carboxylate 10-7 Isomer 2: methyl 7- C CG (400 MHz, METHANOL-d.sub.4) δ: 1.06-1.18 (m, 6 H), 1.23-1.31 (m, 3 3 m/z 380 {(1R,5S,6r)-6-[ethyl(propan-2- 71 then H), 1.53-1.67 (m, 2 H), 1.91-1.97 (m, 2 H), 2.00-2.10 (m, 2 H), E (M + H).sup.+ yl)carbamoyl]-3- and 5 CH 2.16-2.28 (m, 1 H), 2.47-2.58 (m, 2 H), 3.11-3.19 (m, 2 H), 3.34- (ES.sup.+), at azabicyclo[3.1.0]hexan-3-yl}- 3.50 (m, 2 H), 3.61-3.70 (m, 2 H), 3.71 (s, 3 H), 3.78-3.88 (m, 2 H), 3.04 min, 3-oxa-9- 4.03-4.11 (m, 2 H), 4.40-4.49 (m, 1 H) 4.57-4.68 (m, 1 H). 202 nm azabicyclo[3.3.1]nonane-9- carboxylate 10-8 Isomer 1: ethyl 7-{(1R,5S,6r)- C CI (400 MHz, METHANOL-d.sub.4) δ: 0.78-0.84 (m, 2 H), 0.94-1.00 (m, 2 3 m/z 378 6- 69 then H) 1.23-1.32 (m, 3 H), 1.51-1.62 (m, 2 H), 1.89-1.94 (m, 2 H), E (M + H).sup.+ [cyclopropyl(methyl)carbamoyl]- and 79 CJ 2.26-2.39 (m, 2 H), 2.48-2.57 (m, 2 H), 2.65-2.69 (m, 1 H), 2.84- (ES.sup.+), at 3-azabicyclo[3.1.0]hexan-3- 2.93 (m, 3 H), 3.10-3.21 (m, 2 H), 3.47-3.71 (m, 6 H), 4.10-4.24 2.79 min, yl}-3-oxa-9- (m, 4 H). 202 nm azabicyclo[3.3.1]nonane-9- carboxylate 10-8 Isomer 2: ethyl 7-{(1R,5S,6r)- C CI (400 MHz, METHANOL-d.sub.4) δ: 0.76-0.85 (m, 2 H), 0.91-1.03 (m, 2 3 m/z 378 6- 69 then H), 1.22-1.33 (m, 3 H), 1.54-1.69 (m, 2 H), 1.88-1.97 (m, 2 H), E (M + H).sup.+ [cyclopropyl(methyl)carbamoyl]- and 79 CJ 1.99-2.12 (m, 2 H), 2.48-2.59 (m, 2 H), 2.61-2.67 (m, 1 H), 2.89 (ES.sup.+), at 3-azabicyclo[3.1.0]hexan-3- (s, 3 H), 3.10-3.20 (m, 2 H), 3.33-3.45 (m, 2 H), 3.61-3.73 (m, 2 2.88 min, yl}-3-oxa-9- H), 3.77-3.89 (m, 2 H), 4.02-4.11 (m, 2 H), 4.11-4.21 (m, 2 H). 202 nm azabicyclo[3.3.1]nonane-9- carboxylate 10-9 Isomer 1: ethyl 7-{(1R,5S,6r)- C CK (400 MHz, METHANOL-d.sub.4) δ: 0.79-0.85 (m, 2 H), 0.97-1.06 (m, 2 3 m/z 392 6- 69 H), 1.06-1.17 (m, 3 H), 1.28 (t, J = 7.0 Hz, 3 H), 1.48-1.68 (m, 2 H), E (M + H).sup.+ [cyclopropyl(ethyl)carbamoyl]- and 19 1.91-1.96 (m, 2 H), 2.01 (tt, J = 11.6, 5.8 Hz, 1 H), 2.24-2.43 (m, 2 (ES.sup.+), at 3-azabicyclo[3.1.0]hex-3-yl}-3- H), 2.53 (d, J = 9.2 Hz, 2 H), 2.66-2.71 (m, 1 H), 2.83-3.03 (m, 1 H), 3.09 min, oxa-9- 3.18 (d, J = 9.2 Hz, 2 H), 3.43 (q, J = 6.9 Hz, 2 H), 3.48-3.69 (m, 4 H), 202 nm azabicyclo[3.3.1]nonane-9- 4.10-4.27 (m, 4 H). carboxylate 10-9 Isomer 2: ethyl 7-{(1R,5S,6r)- C CK (400 MHz, METHANOL-d.sub.4) δ: 0.78-0.85 (m, 2 H), 0.97-1.05 (m, 2 3 m/z 392 6- 69 H), 1.12 (t, J = 7.0 Hz, 3 H), 1.28 (t, J = 7.0 Hz, 3 H), 1.55-1.71 (m, 2 E (M + H).sup.+ [cyclopropyl(ethyl)carbamoyl]- and 19 H), 1.92-197 (m, 2 H), 2.06 (dd, J = 12.8, 5.5 Hz, 2 H), 2.56 (d, J = 9.2 (ES.sup.+), at 3-azabicyclo[3.1.0]hex-3-yl}-3- Hz, 2 H), 2.63-2.67 (m, 1 H), 2.80-2.92 (m, 1 H), 3.17 (dd, J = 9.5, 3.15 min, oxa-9- 4.0 Hz, 2 H), 3.36-3.46 (m, 3 H), 3.63-3.76 (m, 2 H), 3.80-3.92 (m, 202 nm azabicyclo[3.3.1]nonane-9- 2 H), 4.04-4.13 (m, 2 H), 4.17 (q, J = 6.9 Hz, 2 H). carboxylate 10-10 Isomer 1: methyl 7- C CL (400 MHz, METHANOL-d.sub.4) δ: 0.76-0.86 (m, 2 H), 0.95-1.03 (m, 2 3 m/z 378 {(1R,5S,6r)-6- 71 then H), 1.06-1.15 (m, 3 H), 1.51-1.63 (m, 2 H), 1.89-1.96 (m, 2 H), E (M + H).sup.+ [cyclopropyl(ethyl)carbamoyl]- and 19 CM 1.98-2.09 (m, 1 H), 2.26-2.39 (m, 2 H), 2.49-2.57 (m, 2 H), 2.63- (ES.sup.+), at 3-azabicyclo[3.1.0]hexan-3- 2.69 (m, 1 H), 2.81-2.90 (m, 1 H), 3.11-3.22 (m, 2 H), 3.36-3.46 2.80 min, yl}-3-oxa-9- (m, 2 H), 3.47-3.66 (m, 4 H), 3.71 (s, 3 H), 4.14-4.24 (m, 2 H). 202 nm azabicyclo[3.3.1]nonane-9- carboxylate 10-10 Isomer 2: methyl 7- C CL (400 MHz, METHANOL-d.sub.4) δ: 0.77-0.84 (m, 2 H), 0.96-1.03 (m, 2 3 m/z 378 {(1R,5S,6r)-6- 71 then H), 1.06-1.14 (m, 3 H), 1.56-1.69 (m, 2 H), 1.90-1.97 (m, 2 H), E (M + H).sup.+ [cyclopropyl(ethyl)carbamoyl]- and 19 CM 2.00-2.11 (m, 2 H), 2.54-2.66 (m, 3 H), 2.80-2.88 (m, 1 H), 3.12- (ES.sup.+), at 3-azabicyclo[3.1.0]hexan-3- 3.21 (m, 2 H), 3.35 (s, 1 H), 3.37-3.47 (m, 2 H), 3.62-3.69 (m, 2 H), 2.83 min, yl}-3-oxa-9- 3.71 (s, 3 H), 3.77-3.89 (m, 2 H), 4.03-4.12 (m, 2 H). 202 nm azabicyclo[3.3.1]nonane-9- carboxylate 10-11 Isomer 1: ethyl 7-[(1R,5S,6r)- C CN (400 MHz, METHANOL-d.sub.4) δ: 1.25-1.34 (m, 4 H), 1.51-1.68 (m, 5 3 m/z 392 6-(piperidin-1-ylcarbonyl)-3- 69 then H), 1.71 (d, J = 4.3 Hz, 2 H), 1.94-1.99 (m, 2 H), 2.05-2.17 (m, 1 H), E (M + H).sup.+ azabicyclo[3.1.0]hex-3-yl]-3- and 21 CO 2.27-2.42 (m, 3 H), 2.61 (d, J = 7.9 Hz, 2 H), 3.23 (d, J = 9.8 Hz, 2 H), (ES.sup.+), at oxa-9- 3.51-3.72 (m, 8 H), 4.12-4.27 (m, 4 H). 3.16 min, azabicyclo[3.3.1]nonane-9- 202 nm carboxylate 10-11 Isomer 2: ethyl 7-[(1R,5S,6r)- C CN (400 MHz, METHANOL-d.sub.4) δ: 1.29 (t, J = 7.0 Hz, 3 H), 1.50-1.75 (m, 3 m/z 392 6-(piperidin-1-ylcarbonyl)-3- 69 then 7 H), 1.94-2.00 (m, 2 H), 2.08 (dd, J = 12.8, 4.9 Hz, 2 H), 2.24-2.29 E (M + H).sup.+ azabicyclo[3.1.0]hex-3-yl]-3- and 21 CO (m, 1 H), 2.62 (d, J = 9.2 Hz, 2 H), 3.21 (dd, J = 9.2, 4.3 Hz, 2 H), 3.37 (ES.sup.+), at oxa-9- (s, 1 H), 3.42-3.62 (m, 3 H), 3.62-3.74 (m, 4 H), 3.79-3.94 (m, 2 3.19 min, azabicyclo[3.3.1]nonane-9- H), 4.06-4.13 m, 2 H), 4.17 (q, J = 7.1 Hz, 2 H). 202 nm carboxylate 10-12 Isomer 1: methyl 7- C CP (400 MHz, METHANOL-d.sub.4) δ: 1.48-1.59 (m, 4 H), 1.60-1.66 (m, 2 3 m/z 378 [(1R,5S,6r)-6-(piperidine-1- 71 then H), 1.66-1.74 (m, 2 H), 1.89-1.93 (m, 2 H), 1.94-2.06 (m, 1 H), E (M + H).sup.+ carbonyl)-3- and 21 CQ 2.25-2.38 (m, 3 H), 2.46-2.52 (m, 2 H), 3.11-3.18 (m, 2 H), 3.46- (ES.sup.+), at azabicyclo[3.1.0]hexan-3-yl]- 3.56 (m, 5 H), 3.57-3.60 (m, 1 H), 3.64-3.69 (m, 2 H), 3.70 (s, 3 H), 2.80 min, 3-oxa-9- 4.14-4.24 (m, 2 H). 202 nm azabicyclo[3.3.1]nonane-9- carboxylate 10-12 Isomer 2: methyl 7- C CP (400 MHz, METHANOL-d.sub.4) δ: 1.47-1.55 (m, 2 H), 1.56-1.66 (m, 4 3 m/z 378 [(1R,5S,6r)-6-(piperidine-1- 71 then H), 1.66-1.74 (m, 2 H), 1.89-1.95 (m, 2 H), 2.00-2.09 (m, 2 H), E (M + H).sup.+ carbonyl)-3- and 21 CQ 2.22-2.27 (m, 1 H), 2.47-2.54 (m, 2 H), 3.09-3.16 (m, 2 H), 3.33- (ES.sup.+), at azabicyclo[3.1.0]hexan-3-yl]- 3.41 (m, 1 H), 3.49-3.55 (m, 2 H), 3.61-3.69 (m, 4 H), 3.71 (s, 3 H), 2.83 min, 3-oxa-9- 3.78-3.88 (m, 2 H), 4.03-4.10 (m, 2 H). 202 nm azabicyclo[3.3.1]nonane-9- carboxylate 10-13 Isomer 1: ethyl 7-[(1R,5S,6r)- C CR (400 MHz, METHANOL-d.sub.4) δ: 1.26 (s, 3 H), 1.62-1.74 (m, 2 H), 2.00- 3 m/z 394 6-(morpholine-4-carbonyl)-3- 69 then 2.09 (m, 2 H), 2.21-2.27 (m, 1 H), 2.28-2.40 (m, 2 H), 2.64-2.87 E (M + H).sup.+ azabicyclo[3.1.0]hexan-3-yl]- and 80 CS (m, 2 H), 3.23-3.29 (m, 2 H), 3.35 (s, 2 H), 3.52-3.60 (m, 4 H), 3.61- (ES.sup.+), at 3-oxa-9- 3.66 (m, 2 H), 3.66-3.70 (m, 2 H), 3.71 (s, 3 H), 4.11-4.19 (m, 2 2.55 min, azabicyclo[3.3.1]nonane-9- H), 4.19-4.26 (m, 2 H). 202 nm carboxylate 10-13 Isomer 2: ethyl 7-[(1R,5S,6r)- C CR (400 MHz, METHANOL-d.sub.4) δ: 1.27 (t, J = 7.09 Hz, 3 H), 1.58-1.72 (m, 3 m/z 394 6-(morpholine-4-carbonyl)-3- 69 then 2 H), 2.00-2.06 (m, 2 H), 2.07-2.15 (m, 2 H), 2.22-2.27 (m, 1 H), E (M + H).sup.+ azabicyclo[3.1.0]hexan-3-yl]- and 80 CS 2.67-2.91 (m, 2 H), 3.22-3.30 (m, 2 H), 3.35 (s, 2 H), 3.53-3.59 (ES.sup.+), at 3-oxa-9- (m, 2 H), 3.60-3.66 (m, 2 H), 3.67-3.70 (m, 2 H), 3.70 (s, 3 H), 3.80- 2.59 min, azabicyclo[3.3.1]nonane-9- 3.90 (m, 2 H), 4.08-4.19 (m, 4 H). 202 nm carboxylate 10-14 Isomer 1: ethyl 7-[(1R,5S,6r)- C CT (400 MHz, METHANOL-d.sub.4) δ: 1.28 (t, J = 7.0 Hz, 3 H), 1.51-1.67 (m, 3 m/z 406 6-(azepan-1-ylcarbonyl)-3- 69 6 H), 1.71 (dt, J = 11.3, 6.0 Hz, 2 H), 1.76-1.88 (m, 2 H), 1.93-1.97 E (M + H).sup.+ azabicyclo[3.1.0]hex-3-yl]-3- and 24 (m, 2 H), 1.97-2.13 (m, 1 H), 2.20-2.42 (m, 3 H), 2.42-2.59 (m, 2 (ES.sup.+), at oxa-9- H), 3.11-3.23 (m, 2 H), 3.49-3.76 (m, 8 H), 4.06-4.28 (m, 4 H). 3.48 min, azabicyclo[3.3.1]nonane-9- 202 nm carboxylate 10-14 Isomer 2: ethyl 7-[(1R,5S,6r)- C CT (400 MHz, METHANOL-d.sub.4) δ: 1.28 (t, J = 7.0 Hz, 3 H), 1.52-1.67 (m, 3 m/z 406 6-(azepan-1-ylcarbonyl)-3- 69 6 H), 1.71 (dt, J = 11.3, 6.0 Hz, 2 H), 1.81 (quin, J = 5.8 Hz, 2 H), 1.93- E (M + H).sup.+ azabicyclo[3.1.0]hex-3-yl]-3- and 24 1.98 (m, 2 H), 2.06 (dd, J = 12.8, 5.5 Hz, 2 H), 2.23-2.28 (m, 1 H), (ES.sup.+), at oxa-9- 2.54 (d, J = 9.2 Hz, 2 H), 3.16 (dd, J = 9.8, 5.5 Hz, 2 H), 3.35-3.46 (m, 3.58 min, azabicyclo[3.3.1]nonane-9- 1 H), 3.51 (t, J = 6.1 Hz, 2 H), 3.62-3.76 (m, 4 H), 3.79-3.95 (m, 2 202 nm carboxylate H), 4.06-4.13 (m, 2 H), 4.17 (q, J = 7.3 Hz, 2 H). 10-15 Isomer 1: ethyl 7-[(1R,5S,6r)- C CU (400 MHz, METHANOL-d.sub.4) δ: 1.28 (t, J = 7.0 Hz, 3 H), 1.50-1.78 (m, 3 m/z 404 6-(1-azaspiro[3.3]hept-1- 69 2 H), 1.78-1.89 (m, 2 H), 1.90-1.95 (m, 1 H), 1.97-2.12 (m, 3 H), E (M + H).sup.+ ylcarbonyl)-3- and 28 2.16-2.24 (m, 1 H), 2.25-2.42 (m, 3 H), 2.43-2.58 (m, 3 H), 2.77- (ES.sup.+), at azabicyclo[3.1.0]hex-3-yl]-3- 3.00 (m, 2 H), 3.11-3.24 (m, 2 H), 3.36-3.42 (m, 1 H), 3.49-3.72 3.34 min, oxa-9- (m, 3 H), 3.75-3.91 (m, 2 H), 4.05-4.26 (m, 5 H). 202 nm azabicyclo[3.3.1]nonane-9- carboxylate 10-15 Isomer 2: ethyl 7-[(1R,5S,6r)- C CU (400 MHz, METHANOL-d.sub.4) δ: 1.28 (t, J = 7.0 Hz, 3 H), 1.56-1.89 (m, 3 m/z 404 6-(1-azaspiro[3.3]hept-1- 69 4 H), 1.90-1.95 (m, 1 H), 1.96-2.14 (m, 4 H), 2.15-2.31 (m, 1 H), E (M + H).sup.+ ylcarbonyl)-3- and 28 2.34-2.49 (m, 2 H), 2.49-2.67 (m, 2 H), 2.75-3.04 (m, 2 H), 3.16 (ES.sup.+), at azabicyclo[3.1.0]hex-3-yl]-3- (ddd, J = 19.7, 9.6, 4.9 Hz, 2 H), 3.36-3.50 (m, 1 H), 3.62-3.73 (m, 3 3.41 min, oxa-9- H), 3.74-3.92 (m, 3 H), 4.04-4.25 (m, 5 H). 202 nm azabicyclo[3.3.1]nonane-9- carboxylate 11-1 Isomer 1: ethyl 4-[(1R,5S,6r)- C CV (400 MHz, METHANOL-d.sub.4) δ: 1.05 (t, J = 7.09 Hz, 3 H), 1.16-1.26 (m, 3 m/z 352 6-(diethylcarbamoyl)-3- 82 then 6 H), 1.41-1.68 (m, 3 H), 1.75- 1.94(m, 5 H), 2.15(t, J = 2.93 Hz, 1 E (M + H).sup.+ azabicyclo[3.1.0]hexan-3- and 4 CW H), 2.28-2.36 (m, 1 H), 2.45-2.51 (m, 2 H), 3.05-3.13 (m, 2 H), (ES.sup.+), at yl]azepane-1-carboxylate 3.24-3.36 (m, 4 H), 3.36-3.43 (m, 1 H), 3.44-3.55 (m, 3 H), 4.03- 3.41 min, 4.13 (m, 2 H). 202 nm 11-1 Isomer 2: ethyl 4-[(1R,5S,6r)- C CV (400 MHz, METHANOL-d.sub.4) δ: 0.97-1.13 (m, 3 H), 1.16-1.27 (m, 6 3 m/z 352 6-(diethylcarbamoyl)-3- 82 then H), 1.42-1.68 (m, 3 H), 1.76-1.93 (m, 4 H), 2.13-2.17 (m, 1 H), E (M + H).sup.+ azabicyclo[3.1.0]hexan-3- and 4 CW 2.27-2.37 (m, 1 H), 2.44-2.54 (m, 2 H), 3.04-3.14 (m, 2 H), 3.22- (ES.sup.+), at yl]azepane-1-carboxylate 3.37 (m, 5 H), 3.37-3.44 (m, 1 H), 3.43-3.56 (m, 3 H), 4.04-4.11 3.41 min, (m, 2 H). 202 nm 11-2 Isomer 1: ethyl 3-[(1R,5S,6r)- C CX (400 MHz, METHANOL-d.sub.4) δ: 1.09 (t, J = 7.02 Hz, 3 H), 1.18-1.33 (m, 4 m/z 364 6-(diethylcarbamoyl)-3- 85 7 H), 1.39-1.49 (m, 1 H), 1.53-1.62 (m, 1 H), 1.78-2.01 (m, 4 H), C (M + H).sup.+ azabicyclo[3.1.0]hexan-3-yl]- and 4 2.14-2.24 (m, 2 H), 2.27-2.38 (m, 1 H), 2.40-2.54 (m, 3 H), 3.10 (ES.sup.+), at 6-azabicyclo[3.2.1]octane-6- (dd, J = 9.61, 5.95 Hz, 2 H), 3.20-3.29 (m, 1 H), 3.29-3.43 (m, 3 H), 3.29 min, carboxylate 3.43-3.61 (m, 2 H), 4.05-4.19 (m, 3 H). 202 nm 11-2 Isomer 2: ethyl 3-[(1R,5S,6r)- C CX (400 MHz, METHANOL-d.sub.4) δ: 1.03-1.14 (m, 3 H), 1.21-1.31 (m, 6 4 m/z 364 6-(diethylcarbamoyl)-3- 85 H), 1.50-1.59 (m, 1 H), 1.61-1.77 (m, 2 H), 1.80-1.92 (m, 3 H), C (M + H).sup.+ azabicyclo[3.1.0]hexan-3-yl]- and 4 2.01-2.24 (m, 3 H), 2.26-2.37 (m, 2 H), 2.44-2.53 (m, 1 H), 3.10- (ES.sup.+), at 6-azabicyclo[3.2.1]octane-6- 3.40 (m, 6 H), 3.40-3.56 (m, 2 H), 3.75-3.88 (m, 1 H), 3.94-4.05 4.36 min, carboxylate (m, 1 H), 4.07-4.24 (m, 2 H). 202 nm 12-1 Isomer 1: ethyl 5-[(1R,5S,6r)- C CZ (400 MHz, METHANOL-d.sub.4) δ: 1.08 (t, J = 7.10 Hz, 3 H), 1.24 (t, J = 3 m/z 364 6-(diethylcarbamoyl)-3- 88 7.10 Hz, 6 H), 1.27-1.36 (m, 2 H), 1.86-1.94(m, 2 H), 2.07-2.18 (m, 2 E (M + H).sup.+ azabicyclo[3.1.0]hexan-3- and 4 H), 2.21-2.27 (m, 1 H), 2.49 (d, J = 9.31 Hz, 2 H), 2.55-2.72 (m, 3 (ES.sup.+), at yl]hexahydrocyclopenta[c] H), 3.12 (d, J = 9.61 Hz, 2 H), 3.31-3.40 (m, 4 H), 3.41-3.59 (m, 4 3.35 min, pyrrole-2(1H)-carboxylate H), 4.09 (q, J = 7.02 Hz, 2 H). 202 nm 12-1 Isomer 2: ethyl 5-[(1R,5S,6r)- C CZ (400 MHz, METHANOL-d.sub.4) δ: 1.09 (t, J = 7.10 Hz, 3 H), 1.25 (t, J = 3 m/z 364 6-(diethylcarbamoyl)-3- 88 7.10 Hz, 6 H), 1.28-1.36 (m, 2 H), 1.88-1.94 (m, 2 H), 2.09-2.18 (m, 2 E (M + H).sup.+ azabicyclo[3.1.0]hexan-3- and 4 H), 2.22-2.26 (m, 1 H), 2.50 (d, J = 9.31 Hz, 2 H), 2.56-2.71 (m, 3 (ES.sup.+), at yl]hexahydrocyclopenta[c] H), 3.12 (d, J = 9.61 Hz, 2 H), 3.32-3.40 (m, 4 H), 3.42-3.49 (m, 2 3.36 min, pyrrole-2(1H)-carboxylate H), 3.53 (q, J = 7.17 Hz, 2 H), 4.10 (q, J = 7.17 Hz, 2 H). 202 nm

BIOLOGICAL ACTIVITY

Example A

(357) Phospho-ERK1/2 Assays

(358) 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.

(359) 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.

(360) 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.

(361) TABLE-US-00006 TABLE 4 Muscarinic Activity pEC.sub.50 M.sub.1 pEC.sub.50 M.sub.2 pEC.sub.50 M.sub.3 pEC.sub.50 M.sub.4 (% Emax (% Emax (% Emax (% Emax Example No. cf. ACh) cf. ACh) cf. ACh) cf. ACh) ACh   8.05 (96)   7.74 (106)   8.27 (104)   7.99 (109) 1-1   5.03 (115) <4.70 (12) <4.70 (6)   6.50 (73) 1-2   6.88 (110) NT NT   6.02 (81) 1-4   5.34 (55) NT NT   6.21 (47) 2-1 Mixture of <4.70 (22) <4.70 (7) <4.70 (0)   7.11 (86) isomers 2-2 Isomer 1   6.41 (69) NT NT   5.62 (43) 2-2 Isomer 2   7.10 (101) <4.70 (8) <4.70 (2)   6.56 (63) 2-3 Isomer 1   7.39 (108) <4.70 (14) <4.70 (15)   6.77 (100) 2-3 Isomer 2   6.83 (90) NT NT   5.97 (66) 2-4 Isomer 1   5.64 (49) NT NT   5.97 (37) 2-4 Isomer 2   7.27 (112) <4.70 (18) <4.70 (1)   6.81 (94) 2-5 Isomer 1 <4.70 (26) NT NT   5.71 (37) 2-5 Isomer 1   7.25 (107) <4.70 (9) <4.70 (20)   6.72 (85) 2-6 Isomer 1   5.90 (42) NT NT <4.70 (39) 2-7 Isomer 1   5.80 (66) NT NT   5.60 (50) 2-8 Isomer 1   6.06 (50) NT NT   5.78 (37) 2-8 Isomer 2   7.52 (110) <4.70 (15) <4.70 (17)   7.00 (92) 2-9 Isomer 1   6.39 (57) NT NT   5.96 (28) 2-10 Isomer 1   5.93 (66) NT NT <4.70 (56) 2-11 Mixture of   7.69 (100) <4.70 (20) <4.70 (1615)   7.17 (85) isomers 2-12 Isomer 1   4.88 (65) NT NT   6.14 (85) 2-12 Isomer 2   6.67 (79) NT NT   6.37 (72) 2-13 Isomer 1   6.72 (31) NT NT <4.70 (71) 2-13 Isomer 2   6.94 (83) <4.70 (51) <4.70 (38)   6.32 (72) 2-14 Isomer 1   6.49 (80) NT NT   5.91 (33) 2-14 Isomer 2   7.72 (111) <4.70 (62)   4.85 (100)   7.16 (93) 2-16 Isomer 1   7.29 (30) <4.70 (53) <4.70 (45) <4.70 (11) 2-16 Isomer 2   7.79 (94) <4.70 (87) <4.70 (59)   7.42 (75) 2-17 Isomer 1   6.28 (44) NT NT <4.70 (13) 2-17 Isomer 2   7.19 (96) <4.70 (7) <4.70 (20)   6.55 (63) 2-18 Mixture of <4.70 (11) NT NT   6.04 (34) isomers 2-19 Isomer 2   7.88 (93) <4.70 (16) <4.70 (35)   7.43 (95) 2-21 Isomer 1   6.34 (67) NT NT   5.92 (43) 2-22 Isomer 2   5.76 (95) NT NT   5.67 (71) 2-23 Isomer 2   6.79 (129) NT NT   6.45 (95) 2-24 Isomer 1   6.03 (76) NT NT   5.79 (53) 2-24 Isomer 2   7.47 (115) <4.70 (11)   4.73 (47)   7.30 (102) 2-25 Isomer 2   5.89 (37) NT NT   6.36 (35) 2-25 Isomer 4   6.49 (65) <4.70 (24) <4.70 (4)   6.82 (48) 2-26 Mixture of   5.86 (52) <4.70 (8) <4.70 (12)   7.31 (114) isomers 2-27 Mixture of <4.70 (20) NT NT   5.83 (32) isomers 2-28 Isomer 1   6.24 (58) NT NT <4.70 (21) 2-28 Isomer 2   7.19 (104) <4.70 (7) <4.70 (5)   7.27 (51) 2-29 Isomer 2   6.19 (43) <4.70 (36) <4.70 (2)   7.06 (83) 2-30 Isomer 1 <4.70 (29) NT NT   6.45 (61) 2-30 Isomer 2   6.85 (86) <4.70 (34) <4.70 (7)   7.57 (88) 3-1 Mixture of <4.70 (21) <4.70 (4) <4.70 (2)   7.89 (62) isomers 3-2 Mixture of   8.32 (92) <4.70 (20) <4.70 (21)   7.79 (79) isomers 4-1   6.63 (84) NT NT   6.15 (35) 5-1 Isomer 1   5.21 (78) NT NT   6.53 (81) 5-1 Isomer 2 <4.70 (102) NT NT   6.09 (54) 5-2 Isomer 1   7.00 (134) <4.70 (10) NT   5.58 (95) 6-1 Isomer 2   6.46 (76) NT NT <4.70 (2) 7-1 Isomer 2   5.67 (83) NT NT   5.80 (62) 7-2 Isomer 1   6.11 (116) NT NT <4.70 (14) 7-2 Isomer 2   6.66 (113) NT NT   4.96 (53) 7-3 Isomer 1   6.78 (123) NT NT   5.58 (45) 7-5 Isomer 2 <4.70 (23) NT NT   6.13 (38) 7-6 Isomer 2   5.94 (56) NT NT   6.21 (73) 8-1 Mixture of   5.78 (53) NT NT   6.26 (61) isomers 8-2 Isomer 2   6.20 (134) NT NT   5.20 (52) 8-3 Isomer 1   5.83 (104) NT NT   5.49 (29) 8-4 Isomer 1   6.13 (89) NT NT <4.70 (4) 8-5 Isomer 1   6.89 (106) <4.70 (6) <4.70 (6)   5.72 (47) 8-5 Isomer 2   7.05 (39) <4.70 (2) <4.70 (5) <4.70 (12) 8-6 Isomer 1   6.07 (31) NT NT <4.70 (2) 8-6 Isomer 2   6.45 (39) NT NT <4.70 (2) 8-9 Isomer 1   6.43 (99) NT NT <4.70 (7) 8-10 Isomer 1   7.87 (117) <4.70 (7) <4.70 (21)   7.13 (52) 8-10 Isomer 2   6.03 (123) NT NT <4.70 (16) 9-1 Isomer 1   7.04 (93) <4.70 (19) <4.70 (21)   6.06 (57) 9-1 Isomer 2   6.01 (93) NT NT <4.70 (24) 9-2 Isomer 1   6.56 (102) NT NT   5.87 (41) 9-3 Isomer 1   6.40 (106) NT NT   6.12 (60) 10-1 Isomer 1   5.94 (110) NT NT <4.70 (24) 10-1 Isomer 1   5.76 (78) NT NT <4.70 (15) 10-2 Isomer 2   7.15 (113) <4.70 (25) <4.70 (10)   6.04 (62) 10-3 Isomer 1   6.67 (96) NT NT   6.24 (73) 10-3 Isomer 2   5.75 (81) NT NT <4.70 (25) 10-5 Isomer 1   6.30 (99) NT NT   5.91 (81) 10-5 Isomer 2   5.66 (101) NT NT   4.90 (90) 10-7 Isomer 1   7.42 (99) NT NT   6.79 (69) 10-7 Isomer 2   6.83 (100) NT NT   6.23 (64) 10-8 Isomer 1   5.99 (116) NT NT   4.84 (47) 10-8 Isomer 2   5.65 (85) NT NT   5.67 (32) 10-9 Isomer 2   6.57 (105) NT NT   5.47 (38) 10-10 Isomer 1 NT NT NT NT 10-10 Isomer 2 NT NT NT NT 10-12 Isomer 2   5.99 (99) NT NT   4.85 (86) 10-13 Isomer 1   6.51 (104) <4.70 (24) <4.70 (68)   5.95 (64) 10-13 Isomer 2   6.43 (101) <4.70 (24) <4.70 (22)   4.99 (59) 11-1 Isomer 1   7.98 (97) NT NT   6.90 (84) 11-1 Isomer 2   7.43 (94) NT NT   6.33 (62) 11-2 Isomer 1   6.41 (37) NT NT <4.70 (3) 11-2 Isomer 2   6.93 (113) <4.70 (5) <4.70 (3)   6.02 (65) 12-1 Isomer 1   6.21 (49) NT NT <4.70 (6) 12-1 Isomer 2   5.94 (49) NT NT <4.70 (8)