SUBSTITUTED CYCLOHEXANES AS MUSCARINIC M1 RECEPTOR AND/OR M4 RECEPTOR AGONISTS

Abstract

This invention relates to compounds that are agonists of the muscarinic M.sub.1 receptor or M.sub.1 and M.sub.4 receptors and which are useful in the treatment of muscarinic M.sub.1 or M.sub.1/M.sub.4 receptor mediated diseases. Also provided are pharmaceutical compositions containing the compounds and the therapeutic uses of the compounds. Compounds provided are of formula

##STR00001##

wherein Q.sup.4, Q.sup.5, R.sup.5, p, V, Q.sup.1, Q.sup.2, X.sup.1, X.sup.2 and W are defined herein.

Claims

1. A compound of the formula (1): ##STR00209## or a salt thereof, wherein: p is 0; V is selected from a bond, NH and NH—CH.sub.2; Q.sup.1 and Q.sup.2 are each nitrogen or carbon; provided that at least one of Q.sup.1 or V comprises a nitrogen atom; W is —C(O)OCH.sub.2R.sup.4 or an oxadiazole group optionally substituted with methyl, ethyl or trifluoromethyl, wherein when W is an oxadiazole group optionally substituted with methyl, ethyl or trifluoromethyl, Q.sup.2 is carbon; X.sup.1 and X.sup.2 are saturated hydrocarbon groups which together contain a total of one to nine carbon atoms and which link together such that the moiety: ##STR00210## forms a monocyclic or bicyclic ring system; Q.sup.4 is phenyl optionally substituted with F, methoxy or methyl, or Q.sup.4 is pyridyl optionally substituted with F, methoxy or methyl; Q.sup.5 is cyano; R.sup.4 is hydrogen or methyl; and R.sup.5 is absent.

2. A compound according to claim 1, wherein Q.sup.4 is phenyl optionally substituted with F, methoxy or methyl.

3. A compound according to claim 1, wherein Q.sup.4 is phenyl.

4. A compound according to claim 1, wherein V is a bond and Q.sup.1 is nitrogen.

5. A compound according to claim 1, wherein V is NH.

6. A compound according to claim 1, wherein V is NH—CH.sub.2.

7. A compound according to claim 1, wherein W is 1-oxa-2,4-diazole optionally substituted with methyl, ethyl or trifluoromethyl.

8. A compound according to claim 1, wherein R.sup.4 is methyl.

9. A compound according to claim 1, wherein the moiety: ##STR00211## is selected from groups A to GG below: ##STR00212## ##STR00213## ##STR00214## ##STR00215## where “a” indicates the point of attachment to the cyclohexane ring and “b” indicates the point of attachment to the W group.

10. A compound according to claim 1 which is selected from: ethyl [1-(4-cyano-4-phenylcyclohexyl)piperidin-4-yl]methylcarbamate; ethyl {[1-(4-cyano-4-phenylcyclohexyl)piperidin-4-yl]methyl}carbamate; ethyl 5-(4-cyano-4-phenylcyclohexyl)-1,5-diazocane-1-carboxylate; ethyl 2-(4-cyano-4-phenylcyclohexyl)-2,6-diazaspiro[3.4]octane-6-carboxylate; ethyl 7-(4-cyano-4-phenylcyclohexyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate; ethyl 8-(4-cyano-4-phenylcyclohexyl)-2,8-diazaspiro[4.5]decane-2-carboxylate; ethyl 7-(4-cyano-4-phenylcyclohexyl)-3,7-diazabicyclo[4.2.0]octane-3-carboxylate; ethyl 5-(4-cyano-4-phenylcyclohexyl)hexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylate; ethyl 1-(4-cyano-4-phenylcyclohexyl)hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate; ethyl 3-(4-cyano-4-phenylcyclohexyl)-3,7-diazabicyclo[4.2.0]octane-7-carboxylate; ethyl (4aS,7aS)-1-(4-cyano-4-phenylcyclohexyl)octahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate; 4-{[(1R,3S)-3-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopentyl]amino}-1-(pyridin-2-yl)cyclohexanecarbonitrile; 4-{[(1R,3S)-3-(3-ethyl-1,2,4-oxadiazol-5-yl)cyclopentyl]amino}-1-phenylcyclo hexanecarbonitrile; 1-phenyl-4-{6-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]-2-azaspiro[3.3]hept-2-yl}cyclohexanecarbonitrile; 4-[2-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azaspiro[3.4]oct-6-yl]-1-phenylcyclo hexanecarbonitrile; 1-(2-fluorophenyl)-4-[2-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azaspiro[3.4]oct-6-yl]cyclohexanecarbonitrile; 1-(5-fluoropyridin-2-yl)-4-[2-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azaspiro[3.4]oct-6-yl]cyclohexanecarbonitrile; 1-(5-methoxypyridin-2-yl)-4-[2-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azaspiro[3.4]oct-6-yl]cyclohexanecarbonitrile; 4-[2-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azaspiro[3.4]oct-6-yl]-1-(5-methylpyridin-2-yl)cyclohexanecarbonitrile; 4-({[2-(3-ethyl-1,2,4-oxadiazol-5-yl)cyclopropyl]methyl}amino)-1-phenylcyclohexanecarbonitrile; 1-(5-fluoropyridin-2-yl)-4-({(1R,3S)-3-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]cyclopentyl}amino)cyclohexanecarbonitrile; 1-(5-methylpyridin-2-yl)-4-({(1R,3S)-3-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]cyclopentyl}amino)cyclohexanecarbonitrile; or a salt thereof.

11. A compound according to claim 1 which is a pharmaceutically acceptable salt.

12. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable excipient.

13. A method of treating Alzheimer's Disease, dementia with Lewy bodies or schizophrenia in a subject comprising admintering the compound according to claim 1 to the subject.

Description

EXAMPLES

[0242] The invention will now be illustrated, but not limited, by reference to the specific embodiments described in the following examples.

Examples 1-1 to 25-1

[0243] The compounds of Examples 1-1 to 25-1 shown in Table 1 below have been prepared. Starting materials and intermediates are described in Table 2. The NMR and LCMS properties of the compounds of Examples 1-1 to 25-1 and the methods used to prepare them are set out in Table 3.

TABLE-US-00001 TABLE 1 Example 1-1 [00031] Example 1-2 [00032] Example 1-3 [00033] Example 1-4 [00034] Example 1-5 [00035] Example 1-6 [00036] Example 1-7 [00037] Example 1-8 [00038] Example 1-9 [00039] Example 1-10 [00040] Example 1-11 [00041] Example 1-12 [00042] Example 1-13 [00043] Example 1-14 [00044] Example 1-15 [00045] Example 1-16 [00046] Example 1-17 [00047] Example 1-18 [00048] Example 1-19 [00049] Example 1-20 [00050] Example 1-21 [00051] Example 1-22 [00052] Example 2-1 [00053] [00054] Example 2-2 Example 2-3 [00055] Example 2-4 [00056] Example 2-5 [00057] Example 2-6 [00058] Example 2-7 [00059] Example 2-8 [00060] Example 2-9 [00061] Example 2-10 [00062] Example 2-11 [00063] Example 2-12 [00064] Example 2-13 [00065] Example 2-14 [00066] Example 2-15 [00067] Example 2-16 [00068] Example 2-17 [00069] Example 2-18 [00070] Example 2-19 [00071] Example 2-20 [00072] Example 2-21 [00073] Example 3-1 [00074] Example 3-2 [00075] Example 3-3 [00076] Example 3-4 [00077] Example 3-5 [00078] Example 3-6 [00079] Example 3-7 [00080] Example 3-8 [00081] Example 3-9 [00082] Example 3-10 [00083] Example 3-11 [00084] Example 3-12 [00085] Example 3-13 [00086] Example 3-14 [00087] Example 3-15 [00088] Example 3-16 [00089] Example 3-17 [00090] Example 3-18 [00091] Example 3-19 [00092] Example 3-20 [00093] Example 3-21 [00094] Example 3-22 [00095] Example 3-23 [00096] Example 3-24 [00097] Example 3-25 [00098] Example 3-26 [00099] Example 3-27 [00100] Example 3-28 [00101] Example 3-29 [00102] Example 3-30 [00103] Example 3-31 [00104] Example 3-32 [00105] Example 3-33 [00106] Example 3-34 [00107] Example 4-1 [00108] Example 4-2 [00109] Example 4-3 [00110] Example 4-4 [00111] Example 4-5 [00112] Example 4-6 [00113] Example 4-7 [00114] Example 4-8 [00115] Example 4-9 [00116] Example 4-10 [00117] Example 4-11 [00118] Example 4-12 [00119] Example 4-13 [00120] Example 4-14 [00121] Example 4-15 [00122] Example 4-16 [00123] Example 4-17 [00124] Example 4-18 [00125] Example 4-19 [00126] Example 4-20 [00127] Example 4-21 [00128] Example 4-22 [00129] Example 4-23 [00130] Example 4-24 [00131] Example 5-1 [00132] Example 6-1 [00133] Example 6-2 [00134] Example 7-1 [00135] Example 7-2 [00136] Example 8-1 [00137] Example 9-1 [00138] Example 10-1 [00139] Example 11-1 [00140] Example 12-1 [00141] Example 12-2 [00142] Example 13-1 [00143] Example 14-1 [00144] Example 15-1 [00145] Example 16-1 [00146] Example 17-1 [00147] Example 18-1 [00148] Example 19-1 [00149] Example 19-2 [00150] Example 20-1 [00151] Example 21-1 [00152] Example 21-2 [00153] Example 21-3 [00154] Example 21-4 [00155] Example 21-5 [00156] Example 22-1 [00157] Example 22-2 [00158] Example 22-3 [00159] Example 22-4 [00160] Example 23-1 [00161] Example 24-1 [00162] Example 24-2 [00163] Example 24-3 [00164] Example 25-1 [00165] Example 26-1 [00166] Example 26-2 [00167] Example 26-3 [00168] Example 27-1 [00169] Example 28-1 [00170] Example 28-2 [00171]

General Procedures

[0244] 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. (□)-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.

[0245] Mass spectroscopy was carried out on Shimadzu LC-2010 EV, Waters ZQ-2000, UPLC-Mass SQD-3100 or Applied Biosystem API-2000 spectrometers using electrospray conditions as specified for each compound in the detailed experimental section.

[0246] Preparative HPLC was typically carried out under the following conditions, (Waters HPLC): Column: XSelect CSH Prep C-18, 19×50 mm, 5 μm; Mobile phase: Gradients of water and MeCN (each containing 0.1% Formic Acid); gradient 5% MeCN in 0.1 HCOOH in water (30 sec), 5% to 40% (over 7 min) then 95% MeCN in 0.1 HCOOH in water (1 min) then 5% MeCN in 0.1 HCOOH in water (1.5 min) at 28 mL/min. Additionally, preparative HPLC was also carried out using Method A below:

Preparative HPLC Method A

[0247] Instruments: Gilson Semi Preparative HPLC system including a 321 Pump, GX-271 Liquid Handler with Gilson Trilution software and Gilson 171 DAD with collection at 205 nm unless otherwise stated; Column: Phenomenex Gemini-NX C-18, 5 micron, 30 20×100 mm; Flow rate: 30 mL/min; Solvents: solvent C=2.5 L of water and 5 mL of 28% ammonia in water solution, solvent D=2.5 L of acetonitrile; Gradient: all narrow gradients follow the same profile exemplified for 5-95% below, written in the format, [Time (min)/% C:% D], 12.5 min 5-95% gradient: [0.00/95:5], [0.3/95:5], [9.0/5:95], [9.5/5:95], [9.7/0:100], [10.7/0:100], [10.9/95:5], [11.5/95:5]

[0248] LCMS experiments were typically carried out using electrospray conditions as specified for each compound under the following conditions:

Method A

[0249] Instruments: Waters Alliance 2795, Waters 2996 PDA detector, Micromass ZQ; Column: Waters X-Bridge C-18, 2.5 micron, 2.1×20 mm or Phenomenex Gemini-NX C-18, 3 micron, 2.0×30 mm; Gradient [time (min)/solvent D in C (%)]: Method A: 0.00/2, 0.10/2, 2.50/95, 3.50/95, 3.55/2, 4.00/2; Solvents: solvent C=2.5 L H.sub.2O+2.5 mL ammonia solution; solvent D=2.5 L MeCN+135 mL H.sub.2O+2.5 mL ammonia solution); Injection volume 3 uL; UV detection 230 to 400 nM; column temperature 45° C.; Flow rate 1.5 mL/min.

Method B

[0250] Instruments: Waters Alliance 2795, Waters 2996 PDA detector, Micromass ZQ; Column: Waters X-Bridge C-18, 2.5 micron, 2.1×20 mm or Phenomenex Gemini-NX C-18, 3 micron, 2.0×30 mm; Gradient [time (min)/solvent D in C (%)]: 0.00/2, 0.10/2, 8.40/95, 9.40/95, 9.50/2, 10.00/2; Solvents: solvent C=2.5 L H.sub.2O+2.5 mL ammonia solution; solvent D=2.5 L MeCN+135 mL H.sub.2O+2.5 mL ammonia solution); Injection volume 3 μL; UV detection 230 to 400 nM; column temperature 45° C.; Flow rate 1.5 mL/min.

Method C

[0251] Instruments: Agilent 1260 Infinity LC with Diode Array Detector, Agilent 6120B Single Quadrupole MS with API-ES Source; Column: Phenomenex Gemini-NX C-18, 3 micron, 2.0×30 mm; Gradient [time (min)/solvent B in A (%)]: Method: 0.00/5, 2.00/95, 2.50/95, 2.60/5, 3.00/5; Solvents: solvent A=2.5 L H.sub.2O+2.5 mL of (28% NH.sub.3 in H.sub.2O); solvent B=2.5 L MeCN+129 mL H.sub.2O+2.7 mL of (28% NH.sub.3 in H.sub.2O); Injection volume 0.5 μL; UV detection 190 to 400 nM; column temperature 40° C.; Flow rate 1.5 mL/min.

Method D

[0252] Instrument: Waters Acquity H-class UPLC with SQ detector using BEH C18 (50*2.1 mm id 1.7 μm) and using water (0.1% Ammonium Hydroxide) and MeCN (0.1% Ammonium Hydroxide) as the mobile phase. The eluent gradient program was MeCN (0.1% Ammonium Hydroxide) from 10% to 100% for 2.5 min, 100% MeCN (0.1% Ammonium Hydroxide) for 2 min and MeCN (0.1% Ammonium Hydroxide) from 100% to 10% for 0.5 min. The flow rate was 0.3 mL/min.

Method E

[0253] Instruments: HP 1100 with G1315A DAD, Micromass ZQ; Column: Waters X-Bridge C-18, 2.5 micron, 2.1×20 mm or Phenomenex Gemini-NX C-18, 3 micron, 2.0×30 mm; Gradient [time (min)/solvent D in C (%)]: 0.00/2, 0.10/2, 8.40/95, 10.00/95; Solvents: solvent C=2.5 L H.sub.2O+2.5 mL 28% ammonia in H.sub.2O solution; solvent D=2.5 L MeCN+135 mL H.sub.2O+2.5 mL 28% ammonia in H.sub.2O solution); Injection volume 1 μL; UV detection 230 to 400 nM; Mass detection 130 to 800 AMU (+ve and −ve electrospray); column temperature 45° C.; Flow rate 1.5 mL/min.

Method F

[0254] Instruments: Waters Acquity H Class, Photo Diode Array, SQ Detector; Column: BEH C18, 1.7 micron, 2.1×50 mm; Gradient [time (min)/solvent B in A (%)]: 0.00/5, 0.40/5, 0.8/35, 1.20/55, 2.50/100, 3.30/100 4.00/5; Solvents: solvent A=5 mM Ammonium acetate and 0.1% formic acid in H.sub.2O; solvent B=0.1% formic acid in MeCN; Injection volume 2 μL; UV detection 200 to 400 nM; Mass detection 100 to 1200 AMU (+ve electrospray); column at ambient temperature; Flow rate 0.5 mL/min.

Method G

[0255] Instruments: Waters 2695, Photo Diode Array, ZQ-2000 Detector; Column: X-Bridge C18, 5 micron, 150×4.6 mm; Gradient [time (min)/solvent B in A (%)]: 0.00/10, 5.00/90, 7.00/100, 11.00/100, 11.01/10 12.00/10; Solvents: solvent A=0.1% ammonia in H.sub.2O; solvent B=0.1% ammonia in MeCN; Injection volume 10 μL; UV detection 200 to 400 nM; Mass detection 60 to 1000 AMU (+ve electrospray); column at ambient temperature; Flow rate 1.0 mL/min.

Method H

[0256] Instruments: Waters 2695, Photo Diode Array, ZQ-2000 Detector; Column: X-Bridge C18, 5 micron, 150×4.6 mm; Gradient [time (min)/solvent B in A (%)]: 0.00/100, 7.00/50, 9.00/0, 11.00/0, 11.01/100, 12.00/100; Solvents: solvent A=0.1% ammonia in H.sub.2O; solvent B=0.1% ammonia in MeCN; Injection volume 10 μL; UV detection 200 to 400 nM; Mass detection 60 to 1000 AMU (+ve electrospray); column at ambient temperature; Flow rate 1.0 mL/min.

Method I

[0257] Instruments: Waters 2695, Photo Diode Array, ZQ-2000 Detector; Column: X-Bridge C18, 3.5 micron, 150×4.6 mm; Gradient [time (min)/solvent B in A (%)]: 0.00/5, 5.00/90, 5.80/95, 10/95; Solvents: solvent A=0.1% ammonia in H.sub.2O; solvent B=0.1% ammonia in MeCN; Injection volume 10 □L; UV detection 200 to 400 nM; Mass detection 60 to 1000 AMU (+ve electrospray); column at ambient temperature; Flow rate 1.0 mL/min.

Method K

[0258] Instruments: Waters 2695, Photo Diode Array, ZQ-2000 Detector; Column: X-Bridge C18, 3.5 micron, 50×4.6 mm; Gradient [time (min)/solvent B in A (%)]: 0.01/0, 0.20/0, 5.00/90, 5.80/95, 7.20/95, 7.21/100, 10.00/100; Solvents: solvent A=0.1% ammonia in H.sub.2O; solvent B=0.1% ammonia in MeCN; Injection volume 10 μL; UV detection 200 to 400 nM; Mass detection 60 to 1000 AMU (+ve electrospray); column at ambient temperature; Flow rate 1.0 mL/min.

Method L

[0259] Instruments: Waters Acquity UPLC, Waters 3100 PDA Detector, SQD; Column: Acquity BEH C-18, 1.7 micron, 2.1×100 mm; Gradient [time (min)/solvent B in A (%)]: 0.00/2, 2.00/2, 7.00/50, 8.50/80, 9.50/2, 10.0/2; Solvents: solvent A=5 mM ammonium acetate in water; solvent B=acetonitrile; Injection volume 1 μL; Detection wavelength 214 nm; Column temperature 30° C.; Flow rate 0.3 mL per min.

Method O

[0260] Instruments: Waters Acquity UPLC, Waters 3100 PDA Detector, SQD; Column: Acquity HSS-T3, 1.8 micron, 2.1×100 mm; Gradient [time (min)/solvent B in A (%)]: 0.00/10, 1.00/10, 2.00/15, 4.50/55, 6.00/90, 8.00/90, 9.00/10, 10.00/10; Solvents: solvent A=0.1% trifluoroacetic acid in water; solvent B=acetonitrile; Injection volume 1 μL; Detection wavelength 214 nm; Column temperature 30° C.; Flow rate 0.3 mL per min.

Method P

[0261] Instruments: Waters Acquity H Class, Waters 3100 PDA Detector, SQD; Column: BEH C18 2.1×50 mm, 1.7 micron; Gradient [time (min)/solvent B in A (%)]: 0.00/5, 0.40/5, 2.50/95, 3.50/95, 3.51/5, 4.00/5; Solvents: solvent A=5 mM ammonium acetate and 0.1% formic acid in water; solvent B=0.1% formic acid in acetonitrile.

Method Q

[0262] Instruments: Waters Acquity H Class, Waters 3100 PDA Detector, SQD; Column: BEH C18 2.1×50 mm, 1.7 micron; Gradient [time (min)/solvent B in A (%)]: 0.00/5, 0.40/5, 0.80/35, 1.20/55, 2.70/95, 3.30/95, 3.31/5, 4.00/5; Solvents: solvent A=5 mM ammonium acetate and 0.1% formic acid in water; solvent B=0.1% formic acid in acetonitrile.

Method R

[0263] Instruments: Shimadzu Nexera, Photo Diode Array, LCMS-2020 Detector, Column: X-Bridge C18, 3.5 micron, 50×4.6 mm; Gradient [time (min)/solvent B in A (%)]: 0.01/5, 5.00/90, 5.80/95, 7.20/95, 7.21/100, 10.00/100; Solvents: solvent A=0.1% ammonia in H.sub.2O; solvent B=0.1% ammonia in MeCN; Injection volume 10 μL; UV detection 200 to 400 nM; Mass detection 60 to 1000 AMU (+ve electrospray); column at ambient temperature; Flow rate 1.0 mL/min.

Method S

[0264] Instruments: Agilent 1290 RRLC with Agilent 6120 Mass detector, Photo Diode Array, Agilent 6120 Detector, Column: X-Bridge C18, 3.5 micron, 50×4.6 mm; Gradient [time (min)/solvent B in A (%)]: 0.01/5, 5.00/90, 5.80/95, 7.20/95, 7.21/100, 10.00/100; Solvents: solvent A=0.1% ammonia in H.sub.2O; solvent B=0.1% ammonia in MeCN; Injection volume 10 μL; UV detection 200 to 400 nM; Mass detection 60 to 1000 AMU (+ve electrospray); column at ambient temperature; Flow rate 1.0 mL/min.

[0265] LCMS data in the experimental section are given in the format: Mass ion, retention time, UV activity.

Abbreviations

[0266] AcOH=acetic acid [0267] aq.=aqueous [0268] d=day(s) [0269] DCM=dichloromethane [0270] DIPEA=diisopropylethylamine [0271] DMF=dimethylformamide [0272] DMSO=dimethylsulfoxide [0273] ES=electro spray ionisation [0274] EtOAc=ethyl acetate [0275] h=hour(s) [0276] HATU=1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate [0277] HCl=hydrogen chloride, hydrochloric acid [0278] HPLC=high performance liquid chromatography [0279] LC=liquid chromatography [0280] MeCN=acetonitrile [0281] MeOH=Methanol [0282] min, mins=minute(s) [0283] MS=mass spectrometry [0284] NMR=nuclear magnetic resonance [0285] rt, RT=room temperature [0286] sat.=saturated [0287] sol.=solution [0288] STAB=sodium triacetoxyborohydride [0289] TFA=trifluoroacetic acid [0290] THF=tetrahydrofuran [0291] TLC=thin layer chromatography

[0292] Prefixes n-, s-, i-, t- and tert- have their usual meanings: normal, secondary, iso, and tertiary.

Synthesis of Intermediates

Route 1

Typical Procedure for the Preparation of Amines, as Exemplified by the Preparation of Intermediate 6, Trifluoroacid Salt of Ethyl 2,8-diazaspiro[4.5]decane-2-carboxylate

[0293] ##STR00172##

[0294] tert-Butyl 2,8-diazaspiro[4.5]decane-8-carboxylate (481 mg, 2.0 mmol) was dissolved in DCM (20.0 mL) and triethylamine (0.61 g, 0.84 mL, 6.0 mmol) was added. The reaction mixture was cooled to 0° C., ethyl chloroformate (0.33 g, 0.29 mL, 3.0 mmol) was added and the reaction mixture was stirred at rt overnight. The reaction mixture was partitioned between water (20 mL) and DCM (20 mL), the aqueous layer was further extracted with DCM (3×20 mL), the organic layers were combined and dried (Na.sub.2SO.sub.4). The solvent was removed in vacuo to give crude 8-tert-butyl 2-ethyl 2,8-diazaspiro[4.5]decane-2,8-dicarboxylate as a colourless gum which was used directly without further purification.

[0295] LCMS (Method C): m/z 313 (M+H).sup.+ (ES.sup.+), at 1.45 min, UV inactive.

[0296] 8-tert-Butyl 2-ethyl 2,8-diazaspiro[4.5]decane-2,8-dicarboxylate (assumed 2.0 mmol) was dissolved in DCM (5 mL), cooled to 0° C., trifluoroacetic acid (5 mL) was added and the reaction mixture was stirred at rt overnight. The solvents were removed in vacuo, the residue was dissolved in toluene (20 mL), and then concentrated in vacuo (three times), to give ethyl 2,8-diazaspiro[4.5]decane-2-carboxylate trifluoroacetate salt (0.65 g, 99%) as a colourless gum which was used directly without further purification.

[0297] The data for Intermediate 6 are in Table 2

Route 2

Typical Procedure for the Preparation of Amines, as Exemplified by the Preparation of Intermediate 13, Ethyl (3S)-pyrrolidin-3-ylcarbamate Hydrochloride

[0298] ##STR00173##

[0299] tert-Butyl (3S)-3-aminopyrrolidine-1-carboxylate (1.00 g, 5.37 mmol) was dissolved in DCM (25.0 mL) and NEt.sub.3 (1.63 g, 16.12 mmol) was added. The resulting reaction mixture was cooled to 0° C. and ethyl chloroformate (0.70 g, 6.45 mmol) was added. The reaction mixture was stirred for 30 min at rt, then partitioned between water (25 mL) and EtOAc (30 mL), the aqueous layer was further extracted with EtOAc (2×30 mL), and the organic layers were combined and dried (Na.sub.2SO.sub.4). The solvent was removed in vacuo to give tert-butyl (3S)-3-[(ethoxycarbonyl)amino]pyrrolidine-1-carboxylate (1.3 g, 94.2%) as a colourless gum.

[0300] Mass: (ESI +ve): 259 (M+H).sup.+.

[0301] tert-Butyl (3S)-3-[(ethoxycarbonyl)amino]pyrrolidine-1-carboxylate (1.3 g, 5.03 mmol) was dissolved in 1,4-Dioxane (10 mL) and HCl in 1,4-Dioxane (20.0 mL, 1.0M) was added. The reaction mixture was stirred at rt for 16 h. The solvent was removed in vacuo, and the residue was purified by trituration with acetone (2×10 mL) to give ethyl (3S)-pyrrolidin-3-ylcarbamate hydrochloride (0.5 g, 62.8%) as a white solid.

[0302] The data for Intermediate 13 are in Table 2

Route 3

Typical Procedure for the Preparation of Cyclohexanones Containing Substituted Aryl Groups, as Exemplified by the Preparation of Intermediate 20, 1-(3-fluorophenyl)-4-oxocyclohexanecarbonitrile

[0303] ##STR00174##

[0304] 2-(3-Fluorophenyl) acetonitrile (2.0 g, 14.8 mmol) and methyl acrylate (2.67 g, 31.07 mmol) were dissolved in THF (70 mL). The reaction mixture was cooled to 0° C. and t-BuOK (1.0 M in THF, 17.73 mL, 17.75 mmol) was added. The reaction mixture was stirred at rt for 1 h and then quenched with ice cold water, and the pH adjusted to pH=4 with aqueous 8% citric acid (54 mL). The reaction mixture was extracted with EtOAc (4×75 mL), the organic layers were combined and dried (Na.sub.2SO.sub.4). The solvent was removed in vacuo, and the residue was purified by column chromatography (normal phase, silica, 60-120 mesh, gradient 0% to 5% EtOAc in hexane) to give methyl 5-cyano-5-(3-fluorophenyl)-2-oxocyclohexanecarboxylate (3.2 g, 78.8%) as an off white solid.

[0305] Mass: (ESI +ve): 276 (M+H).sup.+.

[0306] Methyl 5-cyano-5-(3-fluorophenyl)-2-oxocyclohexanecarboxylate (1.05 g, 3.81 mmol) was dissolved in THF/Water (2:1) (36 mL) and t-BuOK (514 mg, 4.58 mmol) was added at rt. The reaction mixture was heated at 105° C. for 5 h, then cooled to rt and partitioned between EtOAc (100 mL) and water (50 mL). The aqueous layer was extracted with EtOAc (2×100 mL) and the organic layers were combined and dried (Na.sub.2SO.sub.4). The solvent was removed in vacuo and the residue was purified by column chromatography (normal phase silica, 0 to 11% EtOAc in hexane) to give 1-(3-fluorophenyl)-4-oxocyclohexanecarbonitrile (0.51 g, 64.6%) as an off white solid.

[0307] The data for Intermediate 20 are in Table 2

Route 4

Typical Procedure for the Preparation of Cyclohexanones Containing Substituted Pyridyl Groups, as Exemplified by the Preparation of Intermediate 27, 1-(5-fluoropyridin-2-yl)-4-oxocyclohexanecarbonitrile

[0308] ##STR00175##

[0309] 1,4-Dioxaspiro-(4,5)-decane-8-carbonitrile (2.0 g, 11.9 mmol) was dissolved in PhMe (20.0 mL) and 2-bromo-5-fluoropyridine (2.0 g, 11.9 mmol) was added. The reaction mixture was cooled to −78° C. and NaHMDS (5.47 g, 29.9 mL 1.0M in THF, 29.9 mmol) was added. The reaction mixture was stirred for 30 minutes at −78° C. and warmed to rt overnight, then quenched with water (100 mL). The reaction mixture was partitioned between PhMe (100 mL) and water (50 mL), the aqueous layer was extracted with PhMe (2×100 mL) and the organic layers were combined and dried (Na.sub.2SO.sub.4). The solvents were removed in vacuo, and the residue was purified by column chromatography (normal phase, silica, 60-120 mesh, gradient 0% to 12% EtOAc in Hexane) to give 8-(5-fluoropyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (1.2 g, 40%).

[0310] 8-(5-Fluoropyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (1.0 g, 3.81 mmol) was dissolved in DCM (5.0 mL) and TFA (3.0 mL) was added. The reaction mixture was stirred at rt for 5 h. The reaction mixture was partitioned between DCM (100 mL) and water (50 mL), the aqueous layer was extracted with DCM (2×100 mL) and the organic layers were combined washed with brine (25 mL) and dried (Na.sub.2SO.sub.4). The solvents were removed in vacuo, and the residue was purified by column chromatography (normal phase, silica, 60-120 mesh, gradient 0% to 10% EtOAc in hexane) to give 1-(5-fluoropyridin-2-yl)-4-oxocyclohexanecarbonitrile (0.8 g, 96%).

[0311] The data for Intermediate 27 are in Table 2

[0312] For less reactive substrates, heating conditions may be required for step 1.

Route 5

Typical Procedure for the Preparation of Cyclohexanone Carboxylates Containing Substituted Pyridyl Groups, as Exemplified by the Preparation of Intermediate 50, Methyl 1-(3-chloropyridin-2-yl)-4-oxocyclohexanecarboxylate

[0313] ##STR00176##

[0314] 1-(3-Chloropyridin-2-yl)-4-oxocyclohexanecarbonitrile (4.0 g, 17.1 mmol) was dissolved in MeOH (40 mL) and H.sub.2SO.sub.4 (20 mL) was added. The reaction mixture was heated at 100° C. for 16 h, cooled to rt and DCM (100 mL) and water (50 mL) were added. The pH was adjusted to pH 8 with the addition of solid NaHCO.sub.3. The aqueous layer was extracted with DCM (2×50 mL) and the organic layers were combined washed with brine (25 mL) and dried (Na.sub.2SO.sub.4). The solvents were removed in vacuo, and the residue was purified by column chromatography (normal phase, silica, 60-120 mesh, gradient 0% to 20% EtOAc in hexane) to give methyl 1-(3-chloropyridin-2-yl)-4-oxocyclohexanecarboxylate (0.4 g, 8.8%).

[0315] The data for Intermediate 50 are in Table 2

Route 6

Typical Procedure for the Preparation of Spiroketones from the Corresponding Oxindole, Exemplified by the Preparation of Intermediate 67, 7′-methyl-4H-spiro[cyclohexane-1,3′-indole]-2′,4(1′H)-dione

[0316] ##STR00177##

[0317] 7-methyl-1,3-dihydro-2H-indol-2-one (2.00 g, 13.5 mmol) and anhydrous potassium tert-butoxide (0.08 g, 0.7 mmol) were dissolved in DMSO (10 mL) under N.sub.2. Methyl acrylate (3.50 g, 40.7 mmol) was added dropwise over 30 min and the reaction mixture stirred at 45° C. for 15 min. Anhydrous potassium tert-butoxide (3.05 g, 27.2 mmol) was added portionwise over 40 min and the reaction mixture allowed to stir at 60° C. for 2 h. Water (20 mL) was added to the reaction mixture with further stirring at 80° C. for 8 h. The mixture was diluted with water (250 mL), extracted with EtOAc (3×100 mL), combined organics dried (Na.sub.2SO.sub.4) and the solvent removed in vacuo. The crude product was purified by column chromatography (normal phase, neutral silica gel, 60-120 mesh, 0 to 30% EtOAc in hexane) to give 7′-methylspiro[cyclohexane-1,3′-indoline]-2′,4-dione (230 mg, 7%) as a brown solid.

[0318] The data for Intermediate 67 are in Table 2

Route 7

Procedure for the Preparation of Pyrrolidines, Exemplified by the Preparation of Intermediate 84, Ethyl methyl[(3R)-pyrrolidin-3-yl]carbamate Trifluoroacetic Acid Salt

[0319] ##STR00178##

[0320] To a solution of (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate (1.5 g, 8.0 mmol), Et.sub.3N (3.4 mL, 24.1 mmol) in DCM (20 mL) was added ethyl chloroformate (1.1 mL, 12.0 mmol) at 0° C. The reaction mixture was stirred at rt for 1 h, partitioned between cold H.sub.2O (25 mL) and DCM (50 mL) and the aqueous layer further extracted with DCM (2×50 mL). Combined organics were dried (Na.sub.2SO.sub.4) and the solvent removed in vacuo. The crude product was purified by column chromatography (normal-phase silica, 0 to 6% MeOH in DCM) to give (R)-tert-butyl 3-(ethoxycarbonylamino) pyrrolidine-1-carboxylate (1.0 g, 49%) as a reddish gum.

[0321] LCMS (Method F): m/z 259 (M+H).sup.+ (ES.sup.+), at 2.05 min, UV active.

[0322] To a solution of (R)-tert-butyl 3-(ethoxycarbonylamino) pyrrolidine-1-carboxylate (500 mg, 1.9 mmol) and NaH (60% w/w in mineral oil, 92 mg, 2.3 mmol) in DMF (10 mL) was added methyl iodide (230 μL, 3.7 mmol) at rt and the reaction stirred for 1 h. The mixture was partitioned between cold H.sub.2O (100 mL) and EtOAc (100 mL) and the aqueous layer further extracted with EtOAc (2×100 mL). Combined organics were dried (Na.sub.2SO.sub.4) and the solvent removed in vacuo to give tert-butyl (R)-3-((ethoxycarbonyl)(methyl)amino)pyrrolidine-1-carboxylate (500 mg, 97%) as a reddish gum.

[0323] LCMS (Method F): m/z 217 [M+H−56].sup.+ (ES.sup.+), at 2.23 min, UV active.

[0324] To a solution of (R)-tert-butyl 3-(ethoxycarbonyl (methyl)amino)pyrrolidine-1-carboxylate (650 mg, 2.3 mmol) in DCM (20 mL) was added TFA (540 μL, 7.1 mmol) at 0° C. and the reaction mixture stirred at rt for 16 h. The mixture was concentrated in vacuo to give (R)-ethyl methyl (pyrrolidin-3-yl) carbamate (400 mg, 61%) as a reddish gum.

[0325] The data for Intermediate 84 are in Table 2

Route 8

Typical Procedure for the Preparation of N-Alkylated Oxindoles, Exemplified by the Preparation of Intermediate 86, 1′-methyl-4H-spiro[cyclohexane-1,3′-indole]-2′,4(1′H)-dione

[0326] ##STR00179##

[0327] To 4H-spiro[cyclohexane-1,3′-indole]-2′,4(1′H)-dione (395 mg, 1.8 mmol) and K.sub.2CO.sub.3 (507 mg, 3.7 mmol) in DMF (5 mL) at rt was added methyl iodide (286 mg, 2.0 mmol) dropwise and the reaction mixture heated to 100° C. for 16 h. The mixture was poured into ice cold water (100 mL), extracted with EtOAc (50 mL) and the aqueous layer further extracted with EtOAc (2×50 mL). Combined organics were dried (Na.sub.2SO.sub.4) and the solvent removed in vacuo. The crude product was purified using column chromatography (normal phase silica, 0 to 10% EtOAc in hexane) to yield 1′-Methyl-4H-spiro[cyclohexane-1,3′-indole]-2′,4(1′H)-dione (250 mg, 57%) as an off-white solid.

[0328] The data for Intermediate 86 are in Table 2

Route 9

Typical Procedure for the Preparation of Oxindole Carbamates, Exemplified by the Preparation of Intermediate 87, Ethyl 2′,4-dioxospiro[cyclohexane-1,3′-indole]-1′(2′H)-carboxylate

[0329] ##STR00180##

[0330] To a solution of spiro [cyclohexane-1,3′-indoline]-2′,4-dione (100 mg, 0.5 mmol) and Et.sub.3N (200 μL, 1.4 mmol) in DCM (5 mL) was added ethyl chloroformate (60 μL, 0.6 mmol) at 0° C. and the reaction mixture stirred at rt for 1 h. The mixture was then partitioned between cold H.sub.2O (25 mL) and DCM (50 mL) and the aqueous layer further extracted with DCM (2×50 mL). Combined organics were dried (Na.sub.2SO.sub.4) and the solvent removed in vacuo. The crude product was purified by column chromatography (normal-phase silica, 0 to 6% MeOH in DCM) to give ethyl 2′,4-dioxospiro[cyclohexane-1,3′-indoline]-1′-carboxylate (117 mg, 87%) as a reddish gum.

[0331] The data for Intermediate 87 are in Table 2

Route 10

Typical Procedure for the Preparation of Oxindoles from Fluoropyridines, Exemplified by the Preparation of Intermediate 90, 4H-spiro[cyclohexane-1,3′-pyrrolo[2,3-b]pyridine]-2′,4(1′H)-dione

[0332] ##STR00181##

[0333] To dimethyl malonate (8.0 mL, 70.0 mmol) in DMF (10 mL) in a sealed tube at 0° C. was added potassium t-butoxide (4.1 g, 36.9 mmol) and the reaction mixture stirred for 10 min at 90° C. The mixture was then cooled to rt before addition of 3-fluoro-2-nitropyridine (2.5 g, 17.1 mmol) and heating at 90° C. for 2 h. The reaction mixture was poured into cold 5% aq. HCl (100 mL) and the organic layer extracted with EtOAc (50 mL). The aqueous layer was further extracted with EtOAc (2×100 mL), combined organics dried (Na.sub.2SO.sub.4) and the solvent removed in vacuo. The crude product was purified using column chromatography (normal phase silica, 0 to 18% EtOAc in hexane) to give dimethyl 2-(2-nitropyridin-3-yl)malonate (3.0 g, 67%) as yellow liquid.

[0334] LCMS (Method F): m/z 255 (M+H).sup.+ (ES.sup.+), at 1.87 min, UV active.

[0335] To dimethyl 2-(2-nitropyridin-3-yl) malonate (5.8 g, 22.8 mmol) and 37-41% formalin (43.5 mL) in a sealed tube at rt was added a solution of K.sub.2CO.sub.3 (4.7 g, 34.0 mmol) in water (17.4 mL). The reaction mixture was stirred for 2 h at 60° C., diluted with ice cold water (250 mL), extracted with EtOAc (250 mL) and the aqueous layer further extracted with EtOAc (2×150 mL). Combined organics were dried (Na.sub.2SO.sub.4) and the solvent removed in vacuo. The crude product was purified by column chromatography (normal phase silica, 0 to 14% EtOAc in hexane) to give methyl 2-(2-nitropyridin-3-yl)acrylate (1.5 g, 31%) as a yellow liquid.

[0336] LCMS (Method F): m/z 209 (M+H).sup.+ (ES.sup.+), at 1.87 min, UV active.

[0337] Methyl 2-(2-nitropyridin-3-yl) acrylate (1.48 g, 7.11 mmol) and 2-trimethylsilyloxy 1,3-butadiene (1.86 g, 13.09 mmol) in xylene (10 mL) were stirred for 20 h at 160° C. in a sealed tube. The resulting reaction mixture was cooled to rt before addition of p-toluene sulfonic acid monohydrate (1.08 g, 5.68 mmol) and further heating at 70° C. for 4 h. The reaction mixture was diluted with ice cold water (200 mL), extracted with EtOAc (200 mL) and the aqueous layer further extracted with EtOAc (2×100 mL). Combined organics were dried (Na.sub.2SO.sub.4), the solvent was removed in vacuo and the crude product purified by column chromatography (normal phase silica, 0 to 10% EtOAc in hexane) to give methyl 1-(2-nitropyridin-3-yl)-4-oxocyclohexane-1-carboxylate (0.40 g, 20%) as a yellow liquid.

[0338] LCMS (Method F): m/z 279 (M+H).sup.+ (ES.sup.+).

[0339] To methyl 1-(2-nitropyridin-3-yl)-4-oxocyclohexane-1-carboxylate (146 mg, 0.52 mmol) in EtOAc (7 mL) was added Raney-Ni (146 mg, w/w) under N.sub.2 and the reaction mixture stirred for 24 h. The reaction mixture was filtered through celite, the filtrate concentrated in vacuo and the residue triturated in diethyl ether to give spiro [cyclohexane-1,3′-pyrrolo [2,3-b] pyridine]-2′,4(1′H)-dione (60 mg, 53%) as an off-white solid.

[0340] The data for Intermediate 90 are in Table 2

Route 11

Typical Procedure for the Preparation of Spiro Oxindoles from the Corresponding Oxindole, Exemplified by the Preparation of Intermediate 93, 5′-chloro-4H-spiro[cyclohexane-1,3′-pyrrolo[2,3-b]pyridine]-2′,4(1′H)-dione

[0341] ##STR00182##

[0342] 5-Chloro-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (1.00 g, 5.9 mmol), potassium t-butoxide (0.67 g, 5.9 mmol) and DMSO (5 mL) were heated at 45° C. before addition of methyl acrylate (1.66 mL, 18.3 mmol) dropwise over 20 min. The reaction mixture was stirred for 30 min at 45° C. before addition of potassium t-butoxide (1.33 g, 11.9 mmol) whilst the reaction temperature was maintained below 55° C. The reaction mixture was then heated at 100° C. for 2 h before addition of water and further stirring at 85° C. for 4 h. The mixture was cooled to rt and allowed to stir for 16 h, diluted with ice cold water (100 mL) and extracted with EtOAc (50 mL). The aqueous layer was further extracted with EtOAc (2×50 mL), combined organics dried (Na.sub.2SO.sub.4), the solvent removed in vacuo and the crude product purified using column chromatography (normal phase silica, 0 to 30% EtOAc in hexane) to give methyl 5′-chloro-2′,4-dioxo-1′,2′-dihydrospiro[cyclohexane-1,3′-pyrrolo[2,3-b]pyridine]-3-carboxylate (0.45 g, 25%) as a white solid.

[0343] LCMS (Method F): m/z 309 (M+H).sup.+ (ES.sup.+), at 2.02 min, UV active.

[0344] To a solution of methyl 5′-chloro-2′,4-dioxo-1′,2′-dihydrospiro[cyclohexane-1,3′-pyrrolo[2,3-b]pyridine]-3-carboxylate (450 mg, 1.5 mmol) in THF/H.sub.2O 2:1 (12 mL) at rt was added potassium t-butoxide (205 mg, 1.8 mmol) and the reaction heated to 105° C. for 5 h. The reaction was cooled to rt before addition of water and extraction with EtOAc (2×200 mL). Combined organics were dried (Na.sub.2SO.sub.4) and the solvent removed in vacuo to yield 5′-chlorospiro[cyclohexane-1,3′-pyrrolo[2,3-b]pyridine]-2′,4(1′H)-dione (210 mg, 57%) as white solid. The crude product was taken on directly to the next step.

[0345] The data for Intermediate 93 are in Table 2

Route 12

Typical Procedure for the Preparation of Spiro Oxindoles, Exemplified by the Preparation of Intermediate 95, 5′-methoxy-4H-spiro[cyclohexane-1,3′-pyrrolo[2,3-c]pyridine]-2′,4(1′H)-dione

[0346] ##STR00183##

[0347] To a stirred solution of diethyl malonate (8.7 mL, 57.3 mmol) in dry THE (300 mL), sodium hydride (2.3 g, 60% w/w in mineral oil, 57.3 mmol) was added portionwise at 0° C. and stirred for 1 h. The reaction mixture was brought to rt and 2,4-dichloro-5-nitropyridine (10.0 g, 52.0 mmol) was added and refluxed for 14 h. After cooling to 0° C., the reaction mixture was carefully quenched with ice cold water and extracted with EtOAc (3×200 mL). The organic layers were combined, washed with brine, dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The residue was purified by flash column chromatography [normal phase, silica gel (100-200 mesh), gradient 10% to 15% EtOAc in hexane] to give diethyl 2-(2-chloro-5-nitropyridin-4-yl)malonate (11.1 g, 68%) as a yellow liquid.

[0348] MS (ESI −ve): 315

[0349] To a stirred solution of diethyl 2-(2-chloro-5-nitropyridin-4-yl)malonate (6.1 g, 19.3 mmol) in MeOH (50 mL) was added sodium methoxide (48.3 mL, 2 M in MeOH, 96.6 mmol) dropwise at 0° C. The reaction mixture was stirred at rt for 16 h. After completion, the volatiles were removed in vacuo, water (100 mL) was added and the aqueous layer extracted with EtOAc (3×200 mL). The organic layers were combined and washed with brine, dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The residue was purified by flash column chromatography [normal phase, silica gel (100-200 mesh), gradient 2% to 5% EtOAc in hexane] to give methyl 2-(2-methoxy-5-nitropyridin-4-yl)acetate (2.0 g, 46%) as a yellow solid.

[0350] MS (ESI +ve): 227

[0351] To a solution of methyl 2-(2-methoxy-5-nitropyridin-4-yl)acetate (6.1 g, 26.9 mmol) in toluene (100 mL), paraformaldehyde (2.3 g, 75.0 mmol), K.sub.2CO.sub.3 (11.1 g, 80.3 mmol) and catalytic tetrabutyl ammonium iodide (0.3 g) were added and refluxed for 30 min. The reaction mixture was cooled to rt, filtered through a pad of celite and washed with EtOAc (100 mL). Water (50 mL) was added to the filtrate and the organic layer was separated. The aqueous layer was extracted with EtOAc (2×50 mL). The organic layers were combined and washed with brine, dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The residue was triturated with Et.sub.2O to give methyl 2-(2-methoxy-5-nitropyridin-4-yl)acrylate (4.0 g, 62%) as a dark brown solid. This was used for the next step without further purification.

[0352] MS (ESI +ve): 239.

[0353] To a suspension of methyl 2-(2-methoxy-5-nitropyridin-4-yl)acrylate (1.0 g, 4.2 mmol) in xylene (65 mL), 2-(trimethylsilyloxy)-1,3-butadiene (3.3 mL, 18.9 mmol) was added at rt and the reaction mixture was refluxed for 24 h. After cooling to rt, catalytic pTSA (0.1 g) was added and the mixture stirred at rt for 1 h. The reaction mixture was diluted with EtOAc (50 mL), water (30 mL) was added and the organic layer was separated. The aqueous layer was extracted with EtOAc (2×200 mL). The organic layers were combined and washed with brine, dried (Na.sub.2SO.sub.4) and concentrated in vacuo to give crude methyl 1-(2-methoxy-5-nitropyridin-4-yl)-4-oxocyclohexane-1-carboxylate (1.2 g, 93%) as a light brown semi solid. The crude product was used for the next step without further purification.

[0354] MS (ESI +ve): 309.

[0355] To a solution of methyl 1-(2-methoxy-5-nitropyridin-4-yl)-4-oxocyclohexane-1-carboxylate (800 mg, 2.6 mmol) in acetic acid (15 mL), iron powder (695 mg, 12.4 mmol) was added at rt and refluxed for 3 h. The reaction mixture was cooled to rt, filtered through a pad of celite and washed with ethanol (50 mL). After removing the volatiles from the filtrate, water (50 mL) was added and organics extracted with EtOAc (3×25 mL). The organic layers were combined and washed with brine, dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The residue was purified by flash column chromatography [normal phase, silica gel (100-200 mesh), gradient 2% to 3% EtOAc in hexane] to give 5′-methoxyspiro-[cyclohexane-1,3′-pyrrolo[2,3-c]pyridine]-2′,4(1′H)-dione, (500 mg, 73% over 2 steps) as a yellow solid.

[0356] The data for Intermediate 95 are in Table 2

Route 13

Typical Procedure for the Preparation of Spiro Oxindoles, Exemplified by the Preparation of Intermediate 97, 5′-methoxy-4H-spiro[cyclohexane-1,3′-pyrrolo[3,2-b]pyridine]-2′,4(1′H)-dione

[0357] ##STR00184##

[0358] To NaH (4.24 g, 60% w/w in mineral oil, 106.0 mmol) in THF (80 mL) was added diethyl malonate (16.16 mL, 106.0 mmol) dropwise at 0° C. and the reaction mixture stirred for 1 h. 2-chloro-6-methoxy-3-nitropyridine (10.00 g, 53.0 mmol) in THF (20 mL) was added dropwise and the resulting mixture stirred at 80° C. for 16 h. The reaction mixture was partitioned between cold H.sub.2O (250 mL) and EtOAc (100 mL), the aqueous layer further extracted with EtOAc (2×100 mL), combined organics dried (Na.sub.2SO.sub.4) and the solvent removed in vacuo. The crude product was purified by column chromatography (normal phase silica, 0 to 20% EtOAc in hexane) to give diethyl 2-(6-methoxy-3-nitropyridin-2-yl)malonate (13.21 g, 80%) as a light green solid.

[0359] LCMS (Method F): m/z 313 (M+H).sup.+ (ES.sup.+), at 2.43 min, UV active.

[0360] Diethyl 2-(6-methoxy-3-nitropyridin-2-yl) malonate (13.0 g, 41.6 mmol), LiCl (4.4 g, 104.0 mmol), and H.sub.2O (0.67 mL, 37.2 mmol) were dissolved in DMSO (130 mL) and the mixture stirred at 100° C. for 16 h. The reaction mixture was partitioned between cold H.sub.2O (150 mL) and EtOAc (75 mL), the aqueous layer further extracted with EtOAc (2×75 mL), combined organics dried (Na.sub.2SO.sub.4) and the solvent removed in vacuo. The crude product was purified by column chromatography (normal phase silica, 0 to 12% EtOAc in hexane) to give ethyl 2-(6-methoxy-3-nitropyridin-2-yl)acetate (1.7 g, 17%) as a yellow gum.

[0361] LCMS (Method F): m/z 241 (M+H).sup.+ (ES.sup.+), at 2.33 min, UV active.

[0362] To copper acetate monohydrate (0.12 g, 0.6 mmol), potassium acetate (0.92 g, 9.4 mmol) paraformaldehyde (1.87 g, 62.3 mmol) and ethyl 2-(6-methoxy-3-nitropyridin-2-yl) acetate (1.50 g, 6.2 mmol) under N.sub.2 was added acetic acid (5 mL) and the solution degassed for 15 min, before stirring at 100° C. for 2 h. The reaction mixture was diluted with ice cold water (20 mL) and basified with aq. NaOH. The reaction mixture was partitioned between cold H.sub.2O (25 mL) and EtOAc (20 mL), the aqueous layer further extracted with EtOAc (2×20 mL), combined organics dried (Na.sub.2SO.sub.4) and the solvent removed in vacuo. The crude product was purified by column chromatography (normal-phase silica, 0 to 10% EtOAc in hexane) to give ethyl 2-(6-methoxy-3-nitropyridin-2-yl)acrylate (1.50 g, 96%) as a yellow gum.

[0363] LCMS (Method F): m/z 253 (M+H).sup.+ (ES.sup.+), at 2.41 min, UV active.

[0364] To a degassed solution of ethyl 2-(6-methoxy-3-nitropyridin-2-yl) acrylate (1.50 g, 5.9 mmol) in xylene (5 mL) was added 2-trimethylsilyloxyl-1,3-butadiene (3.1 mL, 17.8 mmol) and the mixture stirred at 150-160° C. for 21 h. To the mixture was then added pTSA (0.52 g, 3.0 mmol) with further heating at 100° C. for 4 h. The reaction mixture was partitioned between cold H.sub.2O (25 mL) and EtOAc (15 mL), the aqueous layer further extracted with EtOAc (2×15 mL), combined organics dried (Na.sub.2SO.sub.4) and the solvent removed in vacuo. The crude product was purified by column chromatography (normal phase silica, 0 to 20% EtOAc in hexane) to give ethyl 1-(6-methoxy-3-nitropyridin-2-yl)-4-oxocyclohexane-1-carboxylate (0.83 g, 43%) as a yellow gum.

[0365] LCMS (Method F): m/z 323 (M+H).sup.+ (ES.sup.+), at 2.31 min, UV active.

[0366] A mixture of ethyl 1-(6-methoxy-3-nitropyridin-2-yl)-4-oxocyclohexane-1-carboxylate (0.55 g, 1.7 mmol), Fe Powder (0.48 g, 8.5 mmol), NH.sub.4Cl (0.27 g, 5.1 mmol), H.sub.2O (2 mL) and conc. HCl (0.50 mL) in ethanol (8 mL) was stirred at 90° C. for 16 h in a sealed tube. The reaction mixture was partitioned between cold H.sub.2O (25 mL) and EtOAc (15 mL), the aqueous layer further extracted with EtOAc (2×15 mL), combined organics dried (Na.sub.2SO.sub.4) and the solvent removed in vacuo to give 5′-methoxyspiro[cyclohexane-1,3′-pyrrolo[3,2-b]pyridine]-2′,4(1′H)-dione (320 mg, 76%) as a yellow solid.

[0367] The data for Intermediate 97 are in Table 2

Route 14

Typical Procedure for the Preparation of Piperidines, Exemplified by the Preparation of Intermediate 103, 4-[4-(aminomethyl)piperidin-1-yl]spiro[cyclohexane-1,3′-indol]-2′(1′H)-one di-trifluoroacetic Acid Salt, Mixture of Two Isomers

[0368] ##STR00185##

[0369] A solution of spiro[cyclohexane-1,3′-indoline]-2′,4-dione (200 mg, 0.9 mmol), tert-butyl piperidin-4-ylmethylcarbamate (218 mg, 1.0 mmol), ZnCl.sub.2 (37 mg, 0.3 mmol) and Et.sub.3N (470 mg, 4.6 mmol) in MeOH (10 mL) was stirred at 50° C. for 1 h. The mixture was cooled to 0° C. before portionwise addition of NaBH.sub.3CN (243 mg, 3.9 mmol) and further stirring at 50° C. for 7 h. The reaction mixture was concentrated in vacuo, the residue partitioned between H.sub.2O (80 mL) and EtOAc (50 mL), the aqueous layer extracted with EtOAc (2×50 mL), combined organics dried (Na.sub.2SO.sub.4) and the solvent removed in vacuo. The residue was purified by column chromatography (normal silica, mesh size: 60-120, 0% to 2% MeOH in DCM) to give tert-butyl (1-(2′-oxospiro[cyclohexane-1,3′-indoline]-4-yl)piperidin-4-yl)methylcarbamate (300 mg, 78%) as a yellow gum as a mixture of isomers.

[0370] LCMS (Method F): m/z 414 (M+H).sup.+ (ES.sup.+), at 1.78 min (isomer 1) and 1.82 min (isomer 2), UV active.

[0371] To a solution of tert-butyl (1-(2′-oxospiro[cyclohexane-1,3′-indoline]-4-yl)piperidin-4-yl)methylcarbamate (300 mg, 0.7 mmol) in DCM (20 mL) under N.sub.2 at 0° C. was added TFA (248 mg, 2.2 mmol) and the reaction mixture warmed to rt over 2 h. The solvent was removed in vacuo to give 4-(4-(aminomethyl)piperidin-1-yl)spiro[cyclohexane-1,3′-indolin]-2′-one di-TFA salt (200 mg, 53%) as a colorless liquid as a mixture of isomers.

[0372] The data for Intermediate 103 are in Table 2

Route 15

Typical Procedure for the Preparation of 1,4-Diazepanes, Exemplified by the Preparation of Intermediate 107, 1-(1,4-diazepan-1-yl)but-2-en-1-one trifluoroacetic Acid Salt

[0373] ##STR00186##

[0374] To a solution of tert-butyl 1,4-diazepane-1-carboxylate (1.50 g, 7.5 mmol) and Et.sub.3N (2.28 g, 22.5 mmol) in DCM (5 mL) at 0° C. was added crotonyl chloride (1.18 g, 11.3 mmol) and the reaction mixture stirred at rt for 1 h. The mixture was partitioned between cold H.sub.2O (25 mL) and EtOAc (15 mL), the aqueous layer further extracted with EtOAc (2×15 mL), combined organics dried (Na.sub.2SO.sub.4) and the solvent removed in vacuo to yield tert-butyl 4-but-2-enoyl-1,4-diazepane-1-carboxylate (1.80 g, 90%) as a brown liquid.

[0375] LCMS (Method F): m/z 269 (M+H).sup.+ (ES.sup.+), at 1.95 min UV active.

[0376] To a solution of tert-butyl 4-but-2-enoyl-1,4-diazepane-1-carboxylate (1.8 g, 6.7 mmol) in DCM (20 mL) was added TFA (10 mL) at 0° C. and the reaction mixture stirred for 3 h at rt. The reaction mixture was concentrated in vacuo and triturated with acetone (3×10 mL) to give 1-(1,4-diazepan-1-yl)but-2-en-1-one trifluoroacetic acid salt (1.0 g, 53%) as a brown liquid.

[0377] The data for Intermediate 107 are in Table 2

Route 16

Typical Procedure for the Preparation of Spiro Oxindoles, Exemplified by the Preparation of Intermediate 99, 4H-spiro[cyclohexane-1,3′-pyrrolo[3,2-b]pyridine]-2′,4(1′H)-dione

[0378] ##STR00187##

[0379] To NaH (60% in mineral oil, 51 g, 1.3 mol) in THF (300 mL) at 0° C. was added diethyl malonate (202 g, 1.3 mol) dropwise whilst the temperature was maintained between 0-10° C. and the resulting mixture stirred at 0-10° C. for 1 h until hydrogen emission ceased. A solution of 2-chloro-3-nitropyridine (100 g, 0.6 mol) in dry THE (300 mL) was added dropwise and the resulting solution refluxed overnight. The solvent was removed in vacuo, the residue dissolved in EtOAc (10 L), filtered, the organic phase washed with water (5×1 L), dried over Na.sub.2SO.sub.4 and concentrated in vacuo to afford crude diethyl (3-nitropyridin-2-yl)-malonate (50 g, 28%) which was used in the next step without purification

[0380] To a solution of diethyl (3-nitropyridin-2-yl)-malonate (12.5 g, 44 mmol) in DMSO (150 mL) at rt under N.sub.2 was added water (0.8 mL, 44 mmol) and lithium chloride (4.7 g, 110 mmol) and the reaction mixture heated at 100° C. for 12 h. A second batch of lithium chloride (1.0 g, 24 mmol) was then added and the mixture heated for 5 h, cooled to rt and diluted with brine (150 mL). The aqueous layer was then extracted with EtOAc (3×275 mL), combined organics dried over Na.sub.2SO.sub.4, the solution concentrated in vacuo and the resulting solid triturated with diethyl ether to afford ethyl 2-(3-nitropyridin-2-yl)acetate (8.6 g, 93%).

[0381] To a solution of ethyl 2-(3-nitropyridin-2-yl)acetate (50 g, 0.24 mol) in benzene (1 L) was added acetic acid (5 mL), piperidine (5 mL) and 1,3,5-trioxane (62 g, 0.69 mol). The reaction flask was fitted with a Dean-Stark trap and the yellow solution heated under reflux for 24 h. To the hot solution was added further 1,3,5-trioxane (60 g) and the resulting mixture heated for an additional 24 h. The solvents were removed in vacuo and the reside purified by column chromatography (silica, hexane/EtOAc=9:1) to afford ethyl 2-(3-nitropyridin-2-yl)acrylate (34 g, 64%).

[0382] A mixture of ethyl 2-(3-nitropyridin-2-yl)acrylate (5.0 g, 22.5 mmol), 2-trimethylsilyloxy-1,3-butadiene (4.8 g, 33.7 mmol) and xylene (50 mL) was heated in a sealed tube at 130° C. for 20 h. The mixture was then cooled to rt before addition of p-toluenesulfonic acid monohydrate (0.5 g, 2.6 mmol) and further stirring for 2 h. The mixture was then diluted with EtOAc (100 mL), washed with water (1×50 mL) and brine (1×50 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by column chromatography (silica, EtOAc/hexane, 1:9 to EtOAc/hexane, 2:3) to afford ethyl 1-(3-nitropyridin-2-yl)-4-oxocyclohexanecarboxylate (5.0 g, 76%).

[0383] To ethyl 1-(3-nitropyridin-2-yl)-4-oxocyclohexanecarboxylate (2.5 g, 8.6 mmol) in EtOH (80 mL) was added NH.sub.4Cl (0.1 g, 1.9 mmol), H.sub.2O (0.5 mL), conc. HCl (0.5 mL) and iron powder (2.5 g, 44.6 mmol). The reaction mixture was heated at reflux for 2 h, neutralized with aq. sodium hydroxide (2N) to pH 8 and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was triturated with H.sub.2O to yield the desired product (1.0 g, 54%).

[0384] The data for Intermediate 99 are in Table 2

Route 17

Typical Procedure for the Preparation of Spiro Oxindoles, Exemplified by the Preparation of Intermediate 113, 5′-methoxy-4H-spiro[cyclohexane-1,3′-pyrrolo[2,3-b]pyridine]-2′,4(1′H)-dione

[0385] ##STR00188##

[0386] To a solution of 5-methoxy-1H-pyrrolo[2,3-b]pyridine (1.00 g, 6.8 mmol) in t-BuOH (60 mL), pyridinium tribromide (6.48 g, 20.3 mmol) was added and the reaction mixture was stirred at rt for 16 h. The reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc (50 mL). Water (50 mL) was added and the organic layer was separated. The aqueous layer was extracted with EtOAc (2×50 mL). The organic layers were combined and washed with sat. aq. NaHCO.sub.3 solution (20 mL), brine (20 mL), dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The residue was triturated with diethyl ether (1×10 mL) to give 3,3-dibromo-5-methoxy-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (1.5 g, 69%) as a brown solid. This product was used for the next step without further purification.

[0387] To a solution of 3,3-dibromo-5-methoxy-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (3.0 g, 9.3 mmol) in AcOH (60 mL), zinc dust (6.1 g, 93.2 mmol) was added and stirred at rt for 2 h. The reaction mixture was filtered through a pad of celite and washed with EtOAc (2×100 mL). The filtrate was concentrated in vacuo and the residue was dissolved in EtOAc (100 mL), washed with 10% aq Rochelle salt (20 mL), brine, dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The residue was triturated with diethyl ether (2×20 mL) to give 5-methoxy-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (0.9 g, 59%) as a brown solid. This crude product was used for the next step without further purification.

[0388] MS (ESI +ve): 165

[0389] To a solution of 5-methoxy-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (2.00 g, 12.2 mmol) in DMSO (20 mL), .sup.tBuOK (0.54 g, 4.8 mmol) was added at rt and stirred for 10 min. Methyl acrylate (3.0 mL, 33.1 mmol) was slowly added and the reaction mixture was stirred at 45° C. for 1 h. The reaction mixture was quenched with AcOH (3 mL) and poured into ice-water (100 mL) and extracted with EtOAc (3×20 mL). The organic layers were combined and washed with brine, dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The residue was purified by flash column chromatography [normal phase, silica gel (100-200 mesh), gradient 1% to 5% EtOAc in hexane] to give trimethyl 3,3′,3″-(5-methoxy-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1,3,3-triyl)tripropionate (1.8 g, 35%) as a liquid.

[0390] MS (ESI +ve): 423

[0391] To a solution of trimethyl 3,3′,3″-(5-methoxy-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1,3,3-triyl)tripropionate (500 mg, 1.18 mmol) in DMSO (10 mL), .sup.tBuOK (500 mg, 4.45 mmol) was added at rt and the reaction mixture was heated to 75° C. for 1 h. After cooling to rt, the reaction mixture was quenched with AcOH (5 mL), poured into ice-water (50 mL) and extracted with EtOAc (3×15 mL). The organic layers were combined and washed with brine, dried (Na.sub.2SO.sub.4) and concentrated in vacuo to give methyl 5′-methoxy-2′,4-dioxo-1′,2′-dihydrospiro[cyclohexane-1,3′-pyrrolo[2,3-b]pyridine]-3-carboxylate (300 mg, 83%) as a pale yellow solid. This crude product was used for the next step without further purification.

[0392] MS (ESI +ve): 305

[0393] To a solution of methyl 5′-methoxy-2′,4-dioxo-1′,2′-dihydrospiro[cyclohexane-1,3′-pyrrolo[2,3-b]pyridine]-3-carboxylate (800 mg, 2.63 mmol) in MeOH (20 mL), aq. KOH (1 M.sub.1 10 mL) was added at rt and the reaction mixture was refluxed for 7 h. After removal of volatiles, water (20 mL) was added to the residue and extracted with EtOAc (3×20 mL). The organic layers were combined and washed with brine, dried (Na.sub.2SO.sub.4) and concentrated in vacuo to give methyl 5′-methoxy-2′,4-dioxo-1′,2′-dihydrospiro[cyclohexane-1,3′-pyrrolo[2,3-b]pyridine]-3-carboxylate (503 mg, 78%) as a pale yellow solid. This crude product was used for the next step without further purification.

[0394] The data for Intermediate 113 are in Table 2

Route 18

Typical Procedure for the Preparation of Spiro Oxindoles, Exemplified by the Preparation of Intermediate 116, 1′,2′-dihydro-4H-spiro[cyclohexane-1,3′-pyrrolo[2,3-b]pyridin]-4-one

[0395] ##STR00189##

[0396] To a solution of 2-(2-methylpyridin-3-yl)acetonitrile (1.0 g, 6.6 mmol) and methyl acrylate (1.8 mL, 19.9 mmol) in THF (10 mL) at 0° C. was added potassium tert-butoxide (8.6 mL, 8.6 mmol, 1 M in THF) and the resulting reaction mixture stirred at 25° C. for 3 h. The mixture was partitioned between H.sub.2O (100 mL) and EtOAc (80 mL), the aqueous layer further extracted with EtOAc (2×80 mL), combined organics dried (Na.sub.2SO.sub.4) and the solvent removed in vacuo. The residue was purified by column chromatography (normal silica, mesh size: 60-120, 0% to 0.5% MeOH in DCM) to give methyl 5-(2-chloropyridin-3-yl)-5-cyano-2-oxocyclohexane-1-carboxylate (1.2 g, 63%) as a yellow liquid.

[0397] LCMS (Method F): m/z 293 (M+H).sup.+ (ES.sup.+), at 1.97 min UV active.

[0398] To a solution of methyl 5-(2-chloropyridin-3-yl)-5-cyano-2-oxocyclohexane-1-carboxylate (1.20 g, 4.1 mmol) in THF (5 mL) was added potassium tert-butoxide (1.03 g, 9.2 mmol) in water (10 mL), and the resulting mixture stirred at 80° C. for 17 h. The solvents were removed in vacuo and the residue partitioned between H.sub.2O (120 mL) and EtOAc (80 mL). The aqueous layer was extracted with EtOAc (2×80 mL), combined organics dried (Na.sub.2SO.sub.4) and the residue purified by column chromatography (normal silica, mesh size: 60-120, 1.0% to 1.5% MeOH in DCM) to give 1-(2-chloropyridin-3-yl)-4-oxocyclohexane-1-carbonitrile (800 mg, 83%) as a yellow solid.

[0399] LCMS (Method H): m/z 235 (M+H).sup.+ (ES.sup.+), at 7.19 min UV active.

[0400] To a solution of 1-(2-chloropyridin-3-yl)-4-oxocyclohexane-1-carbonitrile (800 mg, 3.4 mmol) in toluene (10 mL) was added p-toluene sulfonic acid (152 mg, 0.9 mmol) and ethylene glycol (500 μL, 9.0 mmol) and the resulting mixture stirred at 100° C. for 4 h. The solvents were removed in vacuo and the residue partitioned between H.sub.2O (100 mL) and EtOAc (70 mL). The aqueous layer was extracted with EtOAc (2×70 mL), combined organics dried (Na.sub.2SO.sub.4) and the residue purified by column chromatography (normal silica, mesh size: 60-120, 1.0% to 1.5% MeOH in DCM) to give 8-(2-chloropyridin-3-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (900 mg, 95%) as a yellow solid.

[0401] LCMS (Method F): m/z 279 (M+H).sup.+ (ES.sup.+), at 1.99 min UV active.

[0402] To 8-(2-chloropyridin-3-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (1.0 g, 3.6 mmol) in THE (10 mL) at 0° C. was added LiAlH.sub.4 (9.9 mL, 9.9 mmol, 1 M in THF) dropwise and the resulting mixture stirred at 25° C. for 3 h. The reaction mixture was partitioned between H.sub.2O (100 mL) and EtOAc (70 mL), the aqueous layer extracted with EtOAc (2×70 mL), combined organics dried (Na.sub.2SO.sub.4) and the solvent removed in vacuo. The residue was purified by column chromatography (normal silica, mesh size: 60-120, 2.0% to 3.5% MeOH in DCM) to give 1,2-dihydrodispiro[pyrrolo[2,3-b]pyridine-3,1′-cyclohexane-4′,2″-[1,3]dioxolane] (700 mg, 79%) as a light yellow solid.

[0403] LCMS (Method F): m/z 247 (M+H).sup.+ (ES.sup.+), at 1.53 min UV active.

[0404] A solution of (1,2-dihydrodispiro[pyrrolo[2,3-b]pyridine-3,1′-cyclohexane-4′,2″-[1,3]dioxolane] (700 mg, 2.8 mmol) in 6 N HCl (10 mL) was stirred at 50° C. for 16 h. The solvent was then removed in vacuo, and the residue partitioned between H.sub.2O (80 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (2×50 mL) combined organics dried (Na.sub.2SO.sub.4) and the solvent removed in vacuo. The crude product was purified by column chromatography (normal silica, mesh size: 60-120, 3.0% to 3.5% MeOH in DCM) to give 1′,2′-dihydrospiro[cyclohexane-1,3′-pyrrolo[2,3-b]pyridin]-4-one (500 mg, 87%) as a yellow solid.

[0405] The data for Intermediate 116 are in Table 2

Route 19

Typical Procedure for the Preparation of Sulfonamides, Exemplified by the Preparation of Intermediate 117, 1′-(methylsulfonyl)-1′,2′-dihydro-4H-spiro[cyclohexane-1,3′-pyrrolo[2,3-b]pyridin]-4-one

[0406] ##STR00190##

[0407] To a solution of 1′,2′-dihydrospiro[cyclohexane-1,3′-pyrrolo[2,3-b]pyridin]-4-one (400 mg, 2.0 mmol) and Et.sub.3N (600 μL, 4.3 mmol) in DCM (5 mL) at 0° C. was added methanesulfonyl chloride (200 μL, 2.6 mmol) dropwise and the resulting mixture stirred at 25° C. for 1 h. The reaction mixture was partitioned between H.sub.2O (70 mL) and EtOAc (50 mL), the aqueous layer further extracted with EtOAc (2×50 mL), combined organics dried (Na.sub.2SO.sub.4) and the solvent removed in vacuo. The crude residue was purified by column chromatography (normal silica, mesh size: 60-120, 0.5% to 1.0% MeOH in DCM) to give 1′-(methylsulfonyl)-1′,2′-dihydrospiro[cyclohexane-1,3′-pyrrolo[2,3-b]pyridin]-4-one (400 mg, 72%) as a yellow gum.

[0408] The data for Intermediate 117 are in Table 2

Route 20

Typical Procedure for the Preparation of Ethyl Carbamates, Exemplified by the Preparation of Intermediate 6, ethyl 2,8-diazaspiro[4.5]decane-2-carboxylate

[0409] ##STR00191##

[0410] To a solution of tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate (0.96 g, 4 mmol) in DCM (25 mL) at rt was added Et.sub.3N (2.78 mL, 20 mmol) and ethyl chloroformate (0.71 mL, 7 mmol) and the mixture stirred at rt for 16 h. Sat. aq. NaHCO.sub.3 (10 mL) was then added and the layers separated. The aqueous layer was extracted with DCM (4×25 mL), combined organics dried through a Biotage Phase Separator cartridge and the solvent removed in vacuo. To the residue was added ether (50 mL) and 4 M HCl in dioxane (5 mL) and the mixture stirred at rt for 16 h. The solvent was then removed in vacuo, the residue dissolved in MeOH (8 mL) and to the solution was added K.sub.2CO.sub.3 (607 mg) as a solution in water (2 mL) and the mixture stirred at rt for 1 h. The solvent was then removed in vacuo and the residue suspended in DCM, filtered and the solvent removed in vacuo to yield Ethyl 2,8-diazaspiro[4.5]decane-2-carboxylate (0.23 g, 27%).

[0411] The data for Intermediate 6 are in Table 2

Route 21

Typical Procedure for the Preparation of 1,2,4-Oxadiazoles as Exemplified by the Preparation of Intermediate 126, (1R,3S)-3-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopentanamine Hydrochloride Salt

[0412] ##STR00192##

di-tert-Butyl dicarbonate (1.25 g, 5.75 mmol) and DIPEA (2.61 mL, 15.0 mmol) were added to a solution of (1 S,3R)-3-aminocyclopentanecarboxylic acid (0.646 g, 5.0 mmol) in 1,4-dioxane (5 mL) and water (5 mL) and the resulting mixture was stirred at RT for 3 h. The reaction mixture was acidified to pH ˜2 using 1 M aqueous HCl and extracted with DCM (×4). The combined organic extracts were passed through a phase separator cartridge and concentrated in-vacuo to give (1 S,3R)-3-[(tert-butoxycarbonyl)amino]cyclopentanecarboxylic acid (1.13 g, 99%).

[0413] .sup.1H NMR (400 MHz, CDCl3) δ: 1.44 (s, 9H), 1.56-2.06 (m, 5H), 2.16-2.33 (m, 1H),

2.79-2.93 (m, 1H), 3.87-4.18 (m, 1H), 4.86 (br. s., 1H). One exchangeable proton not observed.

[0414] Triethylamine (2.1 mL, 15.0 mmol) and HATU (2.09 g, 5.5 mmol) were added to a solution of (1 S,3R)-3-[(tert-butoxycarbonyl)amino]cyclopentanecarboxylic acid (1.13 g, 5.0 mmol) and N-hydroxyethanimidamide (0.37 g, 5.0 mmol) in DCM (25 mL) and the resulting mixture was stirred at RT overnight. The reaction mixture was diluted with sat. aq. NaHCO.sub.3 and extracted with DCM (×3). The combined organic phases were passed through a phase separator cartridge and concentrated in-vacuo to give the crude uncyclised product, which was immediately dissolved in THF (50 mL), treated with Cs.sub.2CO.sub.3 (3.26 g, 10 mmol) and heated at reflux at 70° C. overnight. The reaction mixture was concentrated to remove the THF and the residue was partitioned between sat. aq. NaHCO.sub.3 and EtOAc. The phases were separated and the aqueous phase was extracted further with EtOAc (×2). The combined organic phases were passed through a phase separator cartridge and concentrated. The crude residue was purified by flash chromatography (normal silica, mesh size: 60-120, 0% to 10% MeOH in DCM) to give tert-butyl [(1R,3S)-3-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopentyl]carbamate (1.15 g, 87

[0415] LCMS (Method C): m/z 168 [M−BOC+H].sup.+ (ES.sup.+), at 1.23 min, UV active.

[0416] tert-Butyl [(1R,3S)-3-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopentyl]carbamate (1.15 g, 4.32 mmol) was dissolved in DCM (22 mL) and treated with 4.0 M HCl in 1,4-dioxane (5.4 mL, 21.6 mmol). The resulting solution was stirred at RT overnight, then diluted with diethyl ether to precipitate a solid that was collected by filtration to give (1R,3S)-3-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopentanamine hydrochloride salt (0.655 g, 91%) as a white solid.

[0417] The data for Intermediate 126 are in Table 2.

Route 22

Typical Procedure for the Preparation of 1,2,4-Oxadiazoles as Exemplified by the Preparation of Intermediate 131, 6-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]-2-azaspiro[3.3]heptane Trifluoroacetic Acid Salt

[0418] ##STR00193##

[0419] Triethylamine (1.67 mL, 12.0 mmol) and HATU (1.67 g, 4.4 mmol) were added to a solution of 2-(tert-butoxycarbonyl)-2-azaspiro[3.3]heptane-6-carboxylic acid (0.965 g, 4.0 mmol) and 2,2,2-trifluoro-N-hydroxyethanimidamide (0.512 g, 4.0 mmol) in THE (20 mL) and the resulting mixture was stirred at RT for 4 h then heated at reflux at 80° C. overnight. The reaction mixture was concentrated to remove the THF and the residue was partitioned between sat. aq. NaHCO.sub.3 (containing some Na.sub.2CO.sub.3) and DCM. The phases were separated and the aqueous phase was extracted further with DCM (×2). The combined organic phases were passed through a phase separator cartridge and concentrated. The crude residue was purified by flash chromatography (normal silica, mesh size: 60-120, 0% to 10% MeOH in DCM) to give impure tert-butyl 6-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]-2-azaspiro[3.3]heptane-2-carboxylate (2.05 g, >100%).

[0420] LCMS (Method C): m/z 278 [M−.sup.tBu+H].sup.+ (ES.sup.+), at 1.59 min, UV active.

[0421] tert-Butyl 6-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]-2-azaspiro[3.3]heptane-2-carboxylate (2.05 g crude, assumed 4.0 mmol) was dissolved in DCM (20 mL) and treated with TFA (5 mL). The resulting solution was stirred at RT overnight, then concentrated in-vacuo. The residue was re-dissolved in DCM and concentrated to give 6-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]-2-azaspiro[3.3]heptane trifluoroacetic acid salt (>100%).

[0422] The data for Intermediate 131 are in Table 2.

Route 23

Typical Procedure for the Preparation of 1,2,4-Oxadiazoles as Exemplified by the Preparation of Intermediate 133, 2-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azaspiro[3.4]octane Hydrochloride Salt

[0423] ##STR00194##

[0424] 60% Sodium hydride suspension in mineral oil (160 mg, 4.0 mmol) was added to a solution of 6-tert-butyl 2-methyl 6-azaspiro[3.4]octane-2,6-dicarboxylate (0.539 g, 2.0 mmol), N-hydroxyethanimidamide (0.148 g, 2.0 mmol) and triethylamine (0.60 mL, 4.0 mmol) in THF (20 mL). The reaction mixture was heated at reflux at 80° C. overnight, then cooled, diluted with water and extracted with EtOAc (×3). The combined organic phases were passed through a phase separator cartridge and concentrated. The crude residue was purified by flash chromatography (normal silica, mesh size: 60-120, 0% to 10% MeOH in DCM) to give tert-butyl 2-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azaspiro[3.4]octane-6-carboxylate (0.384 g, 65%).

[0425] LCMS (Method C): m/z 238 [M−.sup.tBu+H].sup.+ (ES.sup.+), at 1.43 min, UV active.

[0426] tert-Butyl 2-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azaspiro[3.4]octane-6-carboxylate (0.384 g, 1.3 mmol) was dissolved in DCM (13 mL) and treated with 4.0 M HCl in 1,4-dioxane (1.7 mL, 6.5 mmol). The resulting solution was stirred at RT overnight, then concentrated in-vacuo to give 2-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azaspiro[3.4]octane hydrochloride salt (0.282 g, 94%).

[0427] The data for Intermediate 133 are in Table 2.

Route 24

Typical Procedure for the Preparation of 1,2,4-Oxadiazoles as Exemplified by the Preparation of Intermediate 135, (3R)-3-(3-methyl-1,2,4-oxadiazol-5-yl)piperidine

[0428] ##STR00195##

[0429] Triethylamine (36 mL, 254 mmol) and di-tert-butyl dicarbonate (41.6 mL, 191 mmol) were added to a solution of ethyl piperidine-3-carboxylate (20.0 g, 127 mmol) in DCM (150 mL), pre-cooled to 0° C. The resulting reaction mixture was stirred at 0° C. for 2 h. The solvents were then removed in-vacuo, the residue was partitioned between H.sub.2O (400 mL) and EtOAc (250 mL) and the layers were separated. The aqueous layer was further extracted with EtOAc (2×250 mL), and the combined organic layers were dried (Na.sub.2SO.sub.4) and the solvent was removed in-vacuo to give 1-tert-butyl 3-ethyl piperidine-1,3-dicarboxylate (32.0 g, 98%) as a liquid.

[0430] LCMS (Method I): m/z 258 (M+H).sup.+ (ES.sup.+), at 4.93 min, UV active.

[0431] 1-tert-Butyl 3-ethyl piperidine-1,3-dicarboxylate (30.0 g, 117.0 mmol) was dissolved in THE (200 mL) and treated with N-hydroxyethanimidamide (10.36 g, 140 mmol). The reaction mixture was stirred at 25° C. for 10 mins then sodium methoxide (12.6 g, 233 mmol) was added slowly. The resulting reaction mixture was stirred at 65° C. for 6 h, the solvents were removed in-vacuo, and the residue was partitioned between H.sub.2O (400 mL) and EtOAc (300 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (2×300 mL). The combined organic layers were dried (Na.sub.2SO.sub.4), the solvent was removed in-vacuo and residue was purified by column chromatography (Normal neutral activated alumina, 10% to 15% EtOAc in hexane) to give tert-butyl 3-(3-methyl-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate (15.80 g, 51%) as a liquid.

[0432] LCMS (Method F): m/z 268 (M+H).sup.+ (ES.sup.+), at 2.12 min, UV active.

[0433] tert-Butyl 3-(3-methyl-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate (15.5 g, 58.0 mmol) was dissolved in 1,4-dioxane (40 mL) and cooled to 0° C. 4.0 M HCl in 1,4-dioxane (50 mL) was added dropwise and the resulting reaction mixture was stirred at 25° C. for 8 h. The solvents were removed in-vacuo, and residue was purified by triturating with diethyl ether (3×20 mL) to give 3-(3-methyl-1,2,4-oxadiazol-5-yl)piperidine hydrochloride salt (9.10 g, 77%) as a solid.

[0434] LCMS (Method I): m/z 168 (M+H).sup.+ (ES.sup.+), at 2.61 min, UV active.

[0435] 3-(3-Methyl-1,2,4-oxadiazol-5-yl)piperidine hydrochloride salt (5.0 g, 29.9 mmol) was dissolved in a mixture of acetonitrile (250 mL) and MeOH (100 mL). L-Tartaric acid (4.49 g, 29.9 mmol) was added and the mixture was heated at reflux for 15 mins, then cooled to RT. Acetonitrile (250 mL) was added and the mixture was stirred at 25° C. for 16 h. The precipitated amine salt was removed by filtration, washed with a solution of MeOH (50 mL) in acetonitrile (125 mL), and dried. The solid was recrystallized 4 times from a solution of MeOH (50 mL) in acetonitrile 125 mL, isolated by filtration, and dried to give (3R)-3-(3-methyl-1,2,4-oxadiazol-5-yl)piperidine L-tartaric acid salt. The salt was dissolved in sat. aq. NaHCO.sub.3 and extracted with a 10% solution of MeOH in DCM (×3). The combined organic layers were dried (Na.sub.2SO.sub.4) and the solvent was removed in-vacuo to give (3R)-3-(3-methyl-1,2,4-oxadiazol-5-yl)piperidine (980 mg, 20%) as a liquid.

[0436] The data for Intermediate 135 are in Table 2.

Route 25

Typical Procedure for the Preparation of 1,2,4-Oxadiazoles as Exemplified by the Preparation of Intermediate 137, 1-[2-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopropyl]methanamine Hydrochloride Salt

[0437] ##STR00196##

[0438] Triethylamine (1.7 mL, 12.0 mmol) and di-tert-butyl dicarbonate (0.917 g, 4.2 mmol) were added to a solution of methyl 2-(aminomethyl)cyclopropanecarboxylate hydrochloride salt (0.497 g, 3.0 mmol) in DCM (30 mL). The mixture was stirred at RT overnight, then diluted with sat. aq. NaHCO.sub.3 and extracted with EtOAc (×3). The combined organic phases were passed through a phase separator cartridge and concentrated to give methyl 2-{[(tert-butoxycarbonyl)amino]methyl}cyclopropanecarboxylate (0.795 g, >100%).

[0439] .sup.1H NMR (400 MHz, CDCl3) δ: 0.80-0.89 (m, 1H), 1.16-1.24 (m, 1H), 1.45 (s, 9H), 1.51-1.65 (m, 2H), 2.96-3.09 (m, 1H), 3.11-3.23 (m, 1H), 3.68 (s, 3H), 4.64 (br. s., 1H).

[0440] 2-{[(tert-Butoxycarbonyl)amino]methyl}cyclopropanecarboxylate (0.688 g, 3.0 mmol), N-hydroxyethanimidamide (0.222 g, 3.0 mmol) and triethylamine (0.90 mL, 6.0 mmol) were dissolved in THF (30 mL) and treated with 60% sodium hydride suspension in mineral oil (0.24 g, 6.0 mmol). The resulting mixture was heated at reflux overnight, then cooled, diluted with water and extracted with EtOAc (×3). The combined organic phases were passed through a phase separator cartridge and concentrated. The crude residue was purified by flash chromatography (normal silica, mesh size: 60-120, 0% to 10% MeOH in DCM) to give tert-butyl {[2-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopropyl]methyl}carbamate (0.378 g, 50%).

[0441] LCMS (Method C): m/z 198 [M−.sup.tBu+H].sup.+ (ES.sup.+), at 1.19 min, UV active.

[0442] tert-Butyl {[2-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopropyl]methyl}carbamate (0.378 g, 1.5 mmol) was dissolved in DCM (15 mL) and treated with 4.0 M HCl in 1,4-dioxane (1.9 mL, 7.5 mmol). The resulting solution was stirred at RT overnight, then more 4.0 M HCl in 1,4-dioxane (0.95 mL, 3.8 mmol) was added and the mixture was stirred over an additional night. The mixture was then concentrated in-vacuo and the residue triturated with diethyl ether to afford a solid that was removed by filtration to give 1-[2-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopropyl]methanamine hydrochloride salt (0.134 g, 47%).

[0443] The data for Intermediate 137 are in Table 2.

General Synthetic Procedures

Route a

Typical Procedure for the Preparation of Cyclohexanes Via Intermediate 32 and Intermediate 44 as Exemplified by the Preparation of Example 3-19, Ethyl 4-[4-(5-methoxypyridin-2-yl)-4-cyanocyclohexyl]-1,4-diazepane-1-carboxylate

[0444] ##STR00197##

[0445] 1-(5-Methoxypyridin-2-yl)-4-oxocyclohexanecarbonitrile (0.20 g, 0.87 mmol) and ethyl 1,4-diazepane-1-carboxylate hydrochloride (0.18 g, 1.01 mmol) were dissolved in DCM (20 mL) and MeOH (2 mL) and acetic acid (5 drops) were added. The reaction mixture was stirred at rt for 4 h and then cooled to 0° C. STAB (0.73 g, 3.47 mmol) was added portionwise and the reaction mixture stirred at rt overnight. NaHCO.sub.3 (saturated aq., 40 mL) was added, and the reaction mixture was stirred at rt for 1 h, then extracted with DCM (4×40 mL). The organic layers were combined and dried (MgSO.sub.4). The solvents were removed in vacuo to and the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 25 g, 40-63 □m, 60 Å, 25 mL per min, gradient 0% to 10% MeOH in DCM]). The residue further purified by Prep HPLC [reverse phase HPLC (X-Bridge, 250×19 mm, 5 um, 19 mL per min, gradient 35% over 25 min) 0.1% NH.sub.3 in MeCN/water] to give ethyl 4-[4-(5-methoxypyridin-2-yl)-4-cyanocyclohexyl]-1,4-diazepane-1-carboxylate, Example 3-19 isomer 1 (0.05 g, 14.9%) as a pale yellow gum and ethyl 4-[4-(5-methoxypyridin-2-yl)-4-cyanocyclohexyl]-1,4-diazepane-1-carboxylate, Example 3-19 isomer 2 (0.03 g, 8.9%) as a pale yellow gum.

[0446] The data for Example 3-19 Isomer 2 are in Table 3.

Route b

Typical Procedure for the Preparation of Substituted Cyclohexyl Derivatives Via Intermediate 15 and Intermediate 28 as Exemplified by the Preparation of Example 1-15, Ethyl {(3S)-1-[trans-4-(5-chloropyridin-2-yl)-4-cyanocyclohexyl]pyrrolidin-3-yl}carbamate

[0447] ##STR00198##

[0448] tert-Butyl (3S)-pyrrolidin-3-ylcarbamate (0.75 mL, 2.0 mmol) and 1-(5-chloropyridin-2-yl)-4-oxocyclohexanecarbonitrile (0.83 mL, 2.2 mmol) were dissolved in DCM (7.5 mL), and acetic acid (5-10 drops) was added. The reaction mixture was stirred at rt for 4 h and then cooled to 0° C. STAB (0.64 g, 3.0 mmol) was added portionwise and the reaction mixture stirred at rt overnight. NaHCO.sub.3 (saturated aq., 30 mL) was added, and the reaction mixture was stirred at rt for 1 h, then extracted with DCM (4×30 mL) and the organic layers were combined and dried (MgSO.sub.4). The solvents were removed in vacuo to give a crude mixture of tert-butyl {(3S)-1-[4-(5-chloropyridin-2-yl)-4-cyanocyclohexyl]pyrrolidin-3-yl}carbamate which was used directly without further purification. The residue was dissolved in DCM (10 mL) and cooled to 0° C., trifluoroacetic acid (4 mL) was added and the reaction mixture was stirred at rt overnight. The solvents were removed in vacuo, the residue was dissolved in toluene (20 mL), and then concentrated in vacuo (three times), to give the trifluoroacetic acid salt of a mixture of 4-[(3S)-3-aminopyrrolidin-1-yl]-1-(5-chloropyridin-2-yl)cyclohexanecarbonitrile diastereomers which were used directly without further purification. A portion of the residue (assumed 0.75 mmol) was dissolved in DCM (8 mL) and NEt.sub.3 (0.52 mL, 3.75 mmol) was added, the reaction mixture was cooled to 0° C. and ethyl chloroformate (0.11 mL, 1.13 mmol) was added. The reaction mixture was stirred at rt overnight and then partitioned between DCM (30 mL) and sat. NaHCO.sub.3 sol. (20 mL), the aqueous layer was extracted with DCM (3×30 mL) and the organic layers were combined washed with brine (25 mL) and dried (MgSO.sub.4). The residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 50 g, 40-63 □m, 60 Å, 40 mL per min, gradient 0% to 10% MeOH in DCM]) to give ethyl {(3S)-1-[trans-4-(5-chloropyridin-2-yl)-4-cyanocyclohexyl]pyrrolidin-3-yl}carbamate, which was further purified by preparative HPLC [(reverse phase X-Bridge-C18, 250×19×5 μm, Flow rate: 19 mL per min, gradient 50% to 100% (over 16 min) then 50% (2 min) 0.1% NH.sub.3 in MeCN/water, Wavelength-202 nm] to give ethyl {(3S)-1-[cis-4-(5-chloropyridin-2-yl)-4-cyanocyclohexyl]pyrrolidin-3-yl}carbamate, Example 1-15 isomer 1 (104 mg, 36.7%) as a colourless solid and ethyl {(3S)-1-[trans-4-(5-chloropyridin-2-yl)-4-cyanocyclohexyl]pyrrolidin-3-yl}carbamate, Example 1-15 isomer 2 (37 mg, 13.0%) as a colourless gum.

[0449] The data for Example 1-15 isomer 1 and isomer 2 are in Table 3 below.

[0450] The absolute stereochemistry of isomer 1 was determined by small molecule x-ray crystallography. Isomers can also be separated by preparative TLC.

Route c

Typical Procedure for the Preparation of Substituted Cyclohexyl Derivatives Via Intermediate 13 and Intermediate 20 as Exemplified by the Preparation of Example 1-3, Ethyl {(3S)-1-[4-cyano-4-(3-fluorophenyl)cyclohexyl]pyrrolidin-3-yl}carbamate

[0451] ##STR00199##

[0452] 1-(3-Fluorophenyl)-4-oxocyclohexanecarbonitrile (200 mg, 0.92 mmol) and ethyl (3S)-pyrrolidin-3-ylcarbamate hydrochloride (160 mg, 1.01 mmol) were dissolved in MeOH (6.5 mL) and triethylamine (0.64 mL, 4.60 mmol) were added at rt under N.sub.2. ZnCl2 (6.2 mg, 0.046 mmol) was added and the reaction mixture was heated at 55° C. for 1 h. The reaction mixture was cooled to 0° C. and sodium cyanoborohydride (289 mg, 4.60 mmol) was added in three portions. The reaction mixture was then warmed to rt and stirred for at rt for 14 h. The reaction mixture was partitioned between H.sub.2O (100 mL) and EtOAc (100 mL), the aqueous layer was further extracted with EtOAc (2×100 mL) and the organic layers were combined and dried (Na.sub.2SO.sub.4). Solvent was removed in vacuo and the residue was purified by preparative TLC to give (ethyl {(3S)-1-[4-cyano-4-(3-fluorophenyl)cyclohexyl]pyrrolidin-3-yl}carbamate, Example 1-3 isomer 1 (95 mg, 28.8%) as a colourless gum and ethyl {(3S)-1-[4-cyano-4-(3-fluorophenyl)cyclo hexyl]pyrrolidin-3-yl}carbamate, Example 1-3 isomer 2 (55 mg, 16.6%) as a colourless gum.

[0453] The data for Example 1-3 isomer 2 are in Table 3.

Route d

Typical Procedure for the Preparation of Cyclohexanes Via Intermediate 31 and Intermediate 12 as Exemplified by the Preparation of Example 3-28, Methyl 4-(4-cyano-4-phenylcyclohexyl)-1,4-diazepane-1-carboxylate

[0454] ##STR00200##

[0455] 4-Oxo-1-phenyl cyclohexanecarbonitrile (10.0 g, 50.2 mmol), tert-butyl 1,4-diazepane-1-carboxylate (12.0 g, 60.3 mmol), and AcOH (3.44 mL, 60.2 mmol) were dissolved in DCE (100 mL) and heated at 80° C. for 2 h. STAB (16.0 g, 75.4 mmol) was added portionwise and the reaction mixture heated at reflux for 16 h. The reaction mixture was cooled to rt and partitioned between H.sub.2O (100 mL) and DCM (100 mL). The aqueous layer was further extracted with DCM (2×50 mL) and the organic extracts were combined and dried (Na.sub.2SO.sub.4). The solvent was removed in vacuo to give tert-butyl 4-(4-cyano-4-phenylcyclohexyl)-1,4-diazepane-1-carboxylate (5.50 g, 28.6%) as a yellow gum.

[0456] Mass: (ESI +ve): 384 (M+H).sup.+

[0457] tert-Butyl 4-(4-cyano-4-phenylcyclohexyl)-1,4-diazepane-1-carboxylate (5.50 g, 14.3 mmol) was dissolved in 1,4-dioxane (50 mL) and HCl in 1,4-dioxane (50 mL, 1.0M) was added. The reaction mixture was stirred at rt for 2 h. The solvent was removed in vacuo, and the residue was purified by triturating with diethyl ether (2×10 mL) to give 4-(1,4-diazepan-1-yl)-1-phenylcyclohexanecarbonitrile hydrochloride (1.18 g, 25.7%) as a white solid.

[0458] Mass: (ESI +ve): 284 (M+H).sup.+

[0459] 4-(1,4-Diazepan-1-yl)-1-phenylcyclohexanecarbonitrile hydrochloride (0.50 g, 1.56 mmol) and NEt.sub.3 (0.3 mL, 2.12 mmol) were dissolved in DCM (5.0 mL) and cooled to 0° C. A solution of methylchloroformate (0.17 g, 2.12 mmol) in DCM (5.0 mL) was added and the reaction was stirred at rt for 1 h. The solvent was removed in vacuo, and the residue was purified by by column chromatography (normal phase, silica, 60-120 mesh, gradient 0% to 5% MeOH in DCM) to give methyl 4-(4-cyano-4-phenylcyclohexyl)-1,4-diazepane-1-carboxylate, Example 3-28 (0.035 g, 6.6%) as a pale yellow gum.

[0460] The data for Example 3-28 are in Table 3 below.

Route e

Typical Procedure for the Preparation of Cyclohexanes Via Intermediate 31 and Intermediate 44 as Exemplified by the Preparation of Example 3-31, prop-2-yn-1-yl 4-[4-cyano-4-(5-methoxypyridin-2-yl)cyclohexyl]-1,4-diazepane-1-carboxylate

[0461] ##STR00201##

[0462] 1-(5-Methoxypyridin-2-yl)-4-oxocyclohexanecarbonitrile (632 mg, 2.75 mmol), tert-butyl *1,4-diazepane-1-carboxylate (500 mg, 2.50 mmol), ZnCl.sub.2 (102 mg, 0.750 mmol) and NEt.sub.3 (1.8 mL, 12.5 mmol) were dissolved in MeOH (15 mL) and stirred at 50° C. for 1 h. NaBH.sub.3CN (630 mg., 4.50 mmol) was added portionwise at 0° C. and the reaction mixture was stirred at 50° C. for 7 h. The reaction mixture was partitioned between H.sub.2O (80 mL) and EtOAc (50 mL), aqueous layer was further extracted with EtOAc (2×50 mL) and the organic layers were combined and dried (Na.sub.2SO.sub.4). The solvent was removed in vacuo to give tert-butyl 4-[4-cyano-4-(5-methoxypyridin-2-yl)cyclohexyl]-1,4-diazepane-1-carboxylate (800 mg, 77.3%) as a pale yellow solid.

[0463] LCMS (Method C): m/z 415 (M+H).sup.+ (ES.sup.+), at 2.59 min.

[0464] tert-Butyl 4-[4-cyano-4-(5-methoxypyridin-2-yl)cyclohexyl]-1,4-diazepane-1-carboxylate (800 mg, 1.93 mmol) was dissolved in 1,4-dioxane (5.0 mL) and HCl in 1,4-dioxane (15 mL, 1.0M) was added. The reaction mixture was stirred at rt for 16 h. The solvent was removed in vacuo, and the residue was purified by triturating with diethyl ether (3×10 mL) to give 4-(1,4-diazepan-1-yl)-1-(5-methoxypyridin-2-yl)cyclohexane-carbonitrile (660 mg, 97.6%) as a white solid.

[0465] LCMS (Method C): m/z 315 (M+H).sup.+ (ES.sup.+), at 1.98 min.

[0466] 4-(1,4-Diazepan-1-yl)-1-(5-methoxypyridin-2-yl)cyclohexanecarbonitrile (300 mg, 0.86 mmol), prop-2-yn-1-ol (0.1 mL, 1.55 mmol) and NEt.sub.3 (0.5 mL, 3.43 mmol) were dissolved in toluene (5 mL) and stirred at 0° C. for 1 h. Triphosgene (306 mg, 1.03 mmol) was added portionwise and the reaction mixture was stirred at 25° C. for 1 h. The solvent was removed in vacuo, and the residue was partitioned between H.sub.2O (50 mL) and EtOAc (30 mL). The aqueous layer was extracted with EtOAc (2×30 mL) and the organic layers were combined and dried (Na.sub.2SO.sub.4). The solvent was removed in vacuo and crude reaction mixture was purified by Prep HPLC [reverse phase HPLC (X-Bridge, 250×19 mm, 5 um, 19 mL per min, gradient 35% (over 25 min) 0.1% NH.sub.3 in MeCN/water] to give prop-2-yn-1-yl 4-[4-cyano-4-(5-methoxypyridin-2-yl)cyclohexyl]-1,4-diazepane-1-carboxylate, Example 3-31 isomer 1 (9 mg, 2.6%) as a yellow gum and prop-2-yn-1-yl 4-[4-cyano-4-(5-methoxypyridin-2-yl)cyclohexyl]-1,4-diazepane-1-carboxylate, Example 3-31 isomer 2 (10 mg, 3.0%) as a yellow gum.

[0467] The data for Example 3-31 isomer 1 are in Table 3 below.

Route f

Typical Procedure for the Preparation of Imidazoles Via Intermediate 32 as Exemplified by the Preparation of Example 5-1, Ethyl 4-[4-(4-ethyl-5-methyl-1H-imidazol-2-yl)cyclohexyl]-1,4-diazepane-1-carboxylate

[0468] ##STR00202##

[0469] Ethyl 1,4-diazepane-1-carboxylate hydrochloride (2.0 g, 9.66 mmol), ethyl 4-oxocyclohexanecarboxylate (1.80 g, 10.6 mmol), ZnCl.sub.2 (394 mg, 2.90 mmol) and NEt.sub.3 (6.9 mL, 48.3 mmol) were dissolved in MeOH (20 mL) and stirred at 50° C. for 1 h. The reaction mixture was cooled to 0° C. and NaBH.sub.3CN (2.43 g., 38.6 mmol) was added portionwise. The reaction mixture was stirred at 50° C. for 7 h and then the solvents were removed in vacuo, and the residue was partitioned between H.sub.2O (100 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (2×50 mL) and the organic layers were combined and dried (Na.sub.2SO.sub.4). The solvents were removed in vacuo and the residue was purified by column chromatography (normal silica, mesh size: 60-120, 0% to 1.5% MeOH in DCM) to give ethyl 4-[4-(ethoxycarbonyl)-cyclohexyl]-1,4-diazepane-1-carboxylate (1.80 g, 58.0%) as a pale yellow gum.

[0470] LCMS (Method C): m/z 327 (M+H).sup.+ (ES.sup.+), at 2.66 min.

[0471] Ethyl 4-[4-(ethoxycarbonyl)cyclohexyl]-1,4-diazepane-1-carboxylate (1.0 g, 3.07 mmol), LiOH (211 mg, 9.20 mmol) and H.sub.2O (10 mL) were dissolved in THF (10 mL) The reaction mixture was stirred at 80° C. for 16 h. The solvents were removed in vacuo, and the residue was purified by tituration with diethyl ether (3×10 mL) to give 4-[4-(ethoxycarbonyl)-1,4-diazepan-1-yl]cyclohexanecarboxylic acid lithium salt (750 mg, 82.0%) as a white solid.

[0472] LCMS (Method C): m/z 299 (M+H).sup.+ (ES.sup.+), at 1.90 min.

[0473] 4-[4-(Ethoxycarbonyl)-1,4-diazepan-1-yl]cyclohexanecarboxylic acid lithium salt (400 mg, 1.34 mmol), HATU (611 mg, 1.61 mmol), DIPEA (0.7 mL, 4.02 mmol) and N,O-dimethylhydroxylaminehydrochloride (156 mg, 1.61 mmol) were dissolved in acetonitrile (10.0 mL). The reaction mixture was stirred at 25° C. for 4 hrs and solvent was removed in vacuo, the residue was partitioned between H.sub.2O (50 mL) and EtOAc (30 mL), aqueous layer extracted with EtOAc (2×30 mL), organic layers were combined and dried (Na.sub.2SO.sub.4). The solvents were removed in vacuo and the residue was purified by column chromatography (normal silica, mesh size: 60-120, 0% to 1.5% Methanol in DCM) to give ethyl 4-{4-[methoxy(methyl)carbamoyl]cyclohexyl}-1,4-diazepane-1-carboxylate (300 mg, 66.0%) as a yellow gum.

[0474] LCMS (Method C): m/z 342 (M+H).sup.+ (ES.sup.+), at 2.31 min.

[0475] Ethyl 4-{4-[methoxy(methyl)carbamoyl]cyclohexyl}-1,4-diazepane-1-carboxylate (200 mg, 0.590 mmol) was dissolved in THF (5 mL) and cooled to 0° C. for 15 min, LiAlH.sub.4 (1.2 mL, 1.2 mmol, 1.0M sol. in THF) was added slowly and the reaction mixture was stirred at 10° C. for 1 h. The reaction was then quenched with a saturated solution of Na.sub.2SO.sub.4 (15 mL) diluted with H.sub.2O (30 mL), extracted with EtOAc (2×20 mL), and the organic layers were combined and dried (Na.sub.2SO.sub.4). The solvents were removed in vacuo, to ethyl 4-(4-formylcyclohexyl)-1,4-diazepane-1-carboxylate (110 mg, 66.0%) as a pale yellow gum.

[0476] LCMS (Method C): m/z 283 (M+H).sup.+ (ES.sup.+), at 2.24 min.

[0477] Ethyl 4-(4-formylcyclohexyl)-1,4-diazepane-1-carboxylate (100 mg, 0.354 mmol) and pentane-2,3-dione (42 mg, 0.425 mmol) were dissolved in MeOH (2 mL) and 7 M methanolic ammonia (10 mL) was added. The reaction mixture was degassed with nitrogen and heated at 50° C. for 1 h. The solvents were removed in vacuo and the residue was purified by Prep HPLC [reverse phase HPLC (UPLC BEH-C18, 50×2.1 mm, 1.7 um, 0.4 mL per min, gradient 10% to 90% (over 3 min), 100% (1 min) then 10% (over 1 min), 0.1% NH.sub.3 in MeCN/water] to give ethyl 4-[4-(4-ethyl-5-methyl-1H-imidazol-2-yl)cyclohexyl]-1,4-diazepane-1-carboxylate, Example 5-1 isomer 1 (8 mg, 6.2%) as a colourless gum and ethyl 4-[4-(4-ethyl-5-methyl-1H-imidazol-2-yl)cyclohexyl]-1,4-diazepane-1-carboxylate, Example 5-1 isomer 2 (10 mg, 8.0%) as a colourless gum.

[0478] The data for Example 5-1 isomer 2 are in Table 3 below

Route g

Typical Procedure for the Preparation of Pyrrolidines Via Sodium Cyanoborohydride Mediated Reductive Amination, Exemplified by Example 2-19, Ethyl [(3S)-1-(5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-pyrrolo[2,3-c]pyridin]-4-yl)pyrrolidin-3-yl]carbamate Isomer 2

[0479] ##STR00203##

[0480] To a solution of 5′-methoxyspiro[cyclohexane-1,3′-pyrrolo[2,3-c]pyridine]-2′,4(1′H)-dione (343 mg, 1.4 mmol) and ethyl (S)-pyrrolidin-3-yl-carbamate hydrochloride (270 mg, 1.4 mmol) in MeOH (5 mL), catalytic acetic acid was added and the mixture stirred at rt for 1 h. After cooling to 0° C., NaCNBH.sub.3 (262 mg, 4.2 mmol) was added portionwise and stirred at rt for 4 h. The solvent was removed in vacuo before addition of water (20 mL) and DCM (3×30 mL) and the layers separated. Combined organics were washed with brine, dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The residue was purified by prep-HPLC (reverse phase, X BRIDGE SHIELD, 19×250 mm, 5μ, gradient 10% to 95% MeCN in water containing 0.1% NH.sub.4OH, 210 nm to yield ethyl [(3S)-1-(5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-pyrrolo[2,3-c]pyridin]-4-yl)pyrrolidin-3-yl]carbamate, Example 2-19 isomer 1 (77 mg, 14%) as a white solid and ethyl [(3S)-1-(5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-pyrrolo[2,3-c]pyridin]-4-yl)pyrrolidin-3-yl]carbamate, Example 2-19 isomer 2 (38 mg, 7%) as a white solid.

[0481] The data for Example 2-19 isomer 1 are in Table 3 below.

Route h

Typical Procedure for the Preparation of Ethyl Carbamates, Exemplified by the Preparation of Example 7-2, Ethyl {[1-(2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-indol]-4-yl)piperidin-4-yl]methyl}carbamate

[0482] ##STR00204##

[0483] To a solution of 4-(4-(aminomethyl)piperidin-1-yl)spiro[cyclohexane-1,3′-indolin]-2′-one di-TFA salt (200 mg, 0.37 mmol), Et.sub.3N (207 mg, 2.05 mmol) in DCM (10 mL) at 0° C. was added ethyl chloroformate (103 mg, 0.95 mmol) and the reaction mixture stirred at rt for 1 h. The mixture was partitioned between cold H.sub.2O (25 mL) and EtOAc (3×15 mL), combined organics dried (Na.sub.2SO.sub.4) and the solvent removed in vacuo. The crude compound was purified by Prep HPLC (X-bridge-C18, 150×30 mm, 19 mL per min, gradient 38% to 62% (over 13 min) then 100% (2 min) 0.1% NH.sub.3 in MeCN/water] to give ethyl ((1-(2′-oxospiro[cyclohexane-1,3′-indolin]-4-yl)piperidin-4-yl)methyl)carbamate Example 7-2 isomer 1 (21 mg, 15%) as a colourless gum and ethyl ((1-(2′-oxospiro[cyclohexane-1,3′-indolin]-4-yl)piperidin-4-yl)methyl)carbamate Example 7-2 isomer 2 (4 mg, 3%) as a colourless gum.

[0484] The data for Example 7-2 isomer 1 and isomer 2 are in Table 3 below.

Route i

Typical Procedure for the Preparation of 1,4-Diazepanes, Exemplified by the Preparation of Example 4-17, Ethyl 4-(5′-methoxy-2′-oxo-1′,2′-dihydrospiro-[cyclohexane-1,3′-pyrrolo[2,3-b]pyridin]-4-yl)-1,4-diazepane-1-carboxylate

[0485] ##STR00205##

[0486] To a solution of 5′-methoxyspiro[cyclohexane-1,3′-pyrrolo[2,3-b]pyridine]-2′,4(1′H)-dione (230 mg, 0.93 mmol) in DCM (10 mL), ethyl 1,4-diazepane-1-carboxylate (160 mg, 0.93 mmol) and activated 4 A molecular sieves were added and stirred at rt for 16 h. After concentration in vacuo the residue was dissolved in methanol (10 mL) and cooled to 0° C. To the reaction mixture NaCNBH.sub.3 (175 mg, 2.78 mmol) and acetic acid (cat.) were added and stirred at rt for 16 h. After removing the volatiles, water (20 mL) was added to the reaction mixture and extracted with DCM (3×30 mL). The organic layers were combined and washed with brine, dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The residue was purified by prep-HPLC (reverse phase, X BRIDGE C-18, 19×250 mm, 5μ, gradient 20% to 95% MeCN in H.sub.2O containing 0.1% NH.sub.4OH, 210 nm) to yield ethyl 4-(5′-methoxy-2′-oxo-1′,2′-dihydrospiro-[cyclohexane-1,3′-pyrrolo[2,3-b]pyridin]-4-yl)-1,4-diazepane-1-carboxylate, Example 4-17 isomer 1 (19 mg, 5%) and ethyl 4-(5′-methoxy-2′-oxo-1′,2′-dihydrospiro-[cyclohexane-1,3′-pyrrolo[2,3-b]pyridin]-4-yl)-1,4-diazepane-1-carboxylate, Example 4-17 isomer 2 (38 mg, 10%) both as white solids.

[0487] The data for Example 4-17 isomer 1 and isomer 2 are in Table 3 below.

Route j

Preparation of Oxindoles Via Sodium Triacetoxyborohydride and Titanium Isopropoxide Reductive Amination, Exemplified by the Preparation of Example 10-1, Ethyl 6-(2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-indol]-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate

[0488] ##STR00206##

[0489] To ethyl 2,6-diazaspiro[3.4]octane-2-carboxylate trifluoroacetic acid salt (assumed 0.52 mmol) in MeOH was added K.sub.2CO.sub.3 (0.52 mmol) as a solution in H.sub.2O (0.5 mL). The solvent was removed in vacuo and azeotroped with toluene (3×5 mL). The residue was diluted with DCM (10 mL) and the mixture treated with 4H-spiro[cyclohexane-1,3′-indole]-2′,4(1′H)-dione (112 mg, 0.52 mmol) and Ti(O.sup.iPr).sub.4 (148 mg, 0.52 mmol). The mixture was stirred at rt for 2 h before addition of STAB (220 mg,

1.04 mmol) and glacial acetic acid (7 drops) and further stirring at rt for 16 h. To the mixture was added sat. aq. NaHCO.sub.3 (10 mL) and the layers separated. The aqueous layer was further washed with DCM and combined organics washed with brine and dried through a Biotage Phase Separator cartridge. The solvent was removed in vacuo and the crude residue purified using a 10 g SNAP cartridge and eluting with 0-7% MeOH in DCM to yield ethyl 6-(2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-indol]-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate, Example 10-1 (10 mg, 5%).

[0490] The data for Example 10-1 mixture of isomers are in Table 3 below.

Route k

Procedure for Preparation of Oxindoles Via Reductive Amination with Sodium Triacetoxyborohydride, Exemplified by the Preparation of Example 12-1, Ethyl 8-(2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-indol]-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate

[0491] ##STR00207##

[0492] To a solution of ethyl 2,8-diazaspiro[4.5]decane-2-carboxylate (203 mg, 0.94 mmol) and 4H-spiro[cyclohexane-1,3′-indole]-2′,4(1′H)-dione (200 mg, 0.94 mmol) in DCM (5 mL) at rt was added AcOH (5 drops) and the mixture stirred for 4 h. STAB (797 mg, 3.76 mmol) was then added and the mixture stirred at rt for 16 h. To the mixture was added NaOH (20 mL) and the aqueous layer extracted with DCM (4×25 mL).

[0493] Combined organics were dried and the solvent removed in vacuo. The residue was loaded onto a 25 g SNAP chromatography cartridge and eluted with 0-10% MeOH in DCM to yield ethyl 8-(2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-indol]-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate, Example 12-1 isomer 1 (3 mg, 1%) and ethyl 8-(2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-indol]-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate, Example 12-1 isomer 2 (18 mg, 5%).

[0494] The data for Example 12-1 isomer 1 and isomer 2 are in Table 3 below.

Route l

Procedure for Preparation of Amines Via Reductive Amination with Sodium Triacetoxyborohydride in DMF, Exemplified by the Preparation of Example 19-1, 4-{[(1R,3S)-3-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopentyl]amino}-1-(pyridin-2-yl)cyclohexanecarbonitrile

[0495] ##STR00208##

[0496] (1R,3S)-3-(3-Methyl-1,2,4-oxadiazol-5-yl)cyclopentanamine hydrochloride salt (41 mg, 0.20 mmol) and 4-oxo-1-(pyridin-2-yl)cyclohexanecarbonitrile (40 mg, 0.20 mmol) were dissolved in DMF (0.66 mL) and treated with DIPEA (0.04 mL, 0.24 mmol), AcOH (0.08 mL, 1.4 mmol) and STAB (85 mg, 0.40 mmol) in that order. The resulting mixture was stirred under an atmosphere of nitrogen overnight. Water (10 mL) was added and the mixture was concentrated. The residue was partitioned between sat. aq. NaHCO.sub.3 (containing some Na.sub.2CO.sub.3) and DCM. The phases were separated and the aqueous phase was extracted further with DCM (×2). The combined organic phases were passed through a phase separator cartridge and concentrated to give 4-1[(1R,3S)-3-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopentyl]amino-1-(pyridin-2-yl)cyclohexanecarbonitrile as a mixture of diastereomers (73 mg, >100%). The isomers were separated using preparative HPLC (Method A, 30-60% gradient) to afford 4-{[(1R,3S)-3-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopentyl]amino}-1-(pyridin-2-yl)cyclohexanecarbonitrile, Example 19-1 Isomer 1 (39 mg, 55%) and 4-{[(1R,3S)-3-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopentyl]amino}-1-(pyridin-2-yl)cyclohexanecarbonitrile, Example 19-1 Isomer 2 (18 mg, 25%).

[0497] The data for Example 19-1 Isomer 2 are in Table 3 below.

TABLE-US-00002 TABLE 2 Intermediates Table 2 Intermediate Synthetic Intermediates number Name method used Data 1 tert-Butyl methyl(piperidin- — — Commercially available, 4-yl)carbamate CAS: 108612-54-0 2 tert-Butyl (piperidin-4- — — Commercially available, ylmethyl)carbamate CAS: 135632-53-0 3 Ethyl 1,5-diazocane-1- 1 55 and LCMS (Method A): m/z carboxylate 59 187 (M + H).sup.+ (ES+), at trifluoroacetate salt 1.02 min, UV inactive 4 tert-Butyl 2,6- — — Commercially available, diazaspiro[3.4]octane-6- CAS: 885270-86-0 carboxylate 5 tert-Butyl 2,7- — — Commercially available, diazaspiro[3.5]nonane-2- CAS: 236406-55-6 carboxylate 6 Ethyl 2,8- 20 53 and LCMS (Method C): m/z diazaspiro[4.5]decane-2- 55 213 (M + H).sup.+ (ES+), at carboxylate 1.06 min, UV inactive 7 Ethyl 3,7- 1 55 and LCMS (Method A): m/z diazabicyclo[4.2.0]octane- 60 185 (M + H).sup.+ (ES+), at 3-carboxylate 0.95 min, UV inactive trifluoroacetate salt 8 Ethyl 1 55 and LCMS (Method A): m/z hexahydropyrrolo[3,4- 61 185 (M + H).sup.+ (ES+), at b]pyrrole-1(2H)- 0.96 min, UV inactive carboxylate trifluoroacetate salt 9 tert-Butyl — — Commercially available, hexahydropyrrolo[3,4- CAS: 180975-51-3 b]pyrrole-5(1H)- carboxylate 10 tert-Butyl 3,7- — — Commercially available, diazabicyclo[4.2.0]octane- CAS: 885271-73-8 7-carboxylate 11 Ethyl (4aS,7aS)- 1 55 and LCMS (Method A): m/z octahydro-6H-pyrrolo[3,4- 62 199 (M + H).sup.+ (ES+), at b]pyridine-6-carboxylate 1.10 min, UV inactive trifluoroacetate salt 12 4-Oxo-1- — — Commercially available, phenylcyclohexanecarbonitrile CAS: 25115-74-6 13 Ethyl (3S)-pyrrolidin-3- 2 54 and (LCMS Method G) m/z ylcarbamate hydrochloride 55 159 (M + H).sup.+ (ES.sup.+) at 5.32 min, UV active 14 Ethyl (3R)-pyrrolidin-3- 2 55 and (LCMS Method Q) m/z ylcarbamate hydrochloride 63 159 (M + H).sup.+ (ES.sup.+) at 2.01 min, UV active 15 tert-Butyl (3S)-pyrrolidin-3- — — Commercially available, ylcarbamate CAS: 147081-44-5 16 tert-Butyl (3R)-pyrrolidin-3- — — Commercially available, ylcarbamate CAS: 147081-49-0 17 tert-Butyl methyl[(3S)- — — Commercially available, pyrrolidin-3-yl]carbamate CAS: 169750-01-0 18 tert-Butyl methyl[(3R)- — — Commercially available, pyrrolidin-3-yl]carbamate CAS: 392338-15-7 19 1-(2-Fluorophenyl)-4- 3 — Mass: (ESI + ve): 218 oxocyclohexanecarbonitrile (M + H).sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 2.35-2.45 (m, 4 H), 2.53-2.58 (m, 2 H), 2.69-2.78 (m, 2 H), 7.29-7.39 (m, 2 H), 7.47-7.54 (m, 2 H). 20 1-(3-Fluorophenyl)-4- 3 — Mass: (ESI + ve): 218 oxocyclohexanecarbonitrile (M + H).sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 2.38-2.47 (m, 6 H), 2.66-2.74 (m, 2 H), 7.22-7.27 (m, 1 H), 7.45-7.55 (m, 3 H). 21 1-(4-Fluorophenyl)-4- — — Commercially available, oxocyclohexanecarbonitrile CAS: 56326-98-8 22 1-(2-Methylphenyl)-4- 3 — Mass: (ESI + ve): 214 oxocyclohexanecarbonitrile (M + H).sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 2.29-2.45 (m, 4 H), 2.54-2.58 (m, 2 H), 2.62 (s, 3 H) 2.70- 2.79 (m, 2 H), 7.25-7.32 (m, 3 H), 7.37-7.39 (d, J = 7.2 Hz, 1 H). 23 1-(3-Methylphenyl)-4- 3 — Mass: (ESI + ve): 214 oxocyclohexanecarbonitrile (M + H).sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 2.35-2.48 (m, 9 H), 2.65-2.74 (m, 2 H), 7.20 (d, J = 7.2 Hz, 1 H), 7.32-7.43 (m, 3 H). 24 1-(3-Chlorophenyl)-4- 3 — Mass: (ESI + ve): 234 oxocyclohexanecarbonitrile (M + H).sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 2.37-2.48 (m, 6 H), 2.64-2.74 (m, 2 H), 7.46-7.53 (m, 2 H), 7.59-7.62 (m, 1 H), 7.67-7.68 (m, 1 H). 25 1-(3-Methoxyphenyl)-4- 3 — Mass: (ESI + ve): 230 oxocyclohexanecarbonitrile (M + H).sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 2.34-2.47 (m, 6 H), 2.65-2.74 (m, 2 H), 3.79 (s, 3 H), 6.95- 6.98 (m, 1 H), 7.13 (t, J = 2.4 Hz, 1 H), 7.17-7.20 (m, 1 H), 7.38 (t, J = 8.0 Hz, 1 H). 26 4-Oxo-1-(pyridin-2- 4 — Mass: (ESI + ve): 201 yl)cyclohexanecarbonitrile (M + H).sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 2.35-2.48 (m, 6 H), 2.60-2.74 (m, 2 H), 7.39-7.46 (m, 1 H), 7.65-7.73 (m, 1 H), 7.91-7.99 (m, 1 H), 8.60- 8.65 (m, 1 H). 27 1-(5-Fluoropyridin-2-yl)-4- 4 — Mass: (ESI + ve): 219 oxocyclohexanecarbonitrile (M + H).sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 2.35-2.50 (m, 6 H), 2.64-2.69 (m, 2 H), 7.79 (m, 1 H), 7.89 (m, 1 H), 8.65 (d, J = 2.8 Hz, 1 H). 28 1-(5-Chloropyridin-2-yl)-4- 4 — Mass: (ESI + ve): 235 oxocyclohexanecarbonitrile (M + H).sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 1.90-2.29 (m, 6 H), 2.53-2.58 (m, 2 H), 7.70 (d, J = 8.4 Hz, 1 H), 8.02-8.06 (m, 1 H), 8.68 (d, J = 2.4 Hz, 1 H). 29 1-(4-Methylpyridin-2-yl)-4- 4 — Mass: (ESI + ve): 215 oxocyclohexanecarbonitrile (M + H).sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 2.11-2.31 (m, 6 H), 2.33 (s, 3 H), 2.50-2.57 (m, 2 H), 7.24 (m, 1 H), 7.53 (s, 1 H), 8.44 (m, 1 H). 30 1-(6-Methylpyridin-2-yl)-4- 4 — LCMS (Method A): m/z oxocyclohexanecarbonitrile 215 (M + H).sup.+ (ES.sup.+), at 1.26 min, 95%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 2.38-2.46 (m, 6 H), 2.49 (s, 3 H), 2.62-2.70 (m, 2 H), 7.96 (d, J = 8, 1 H), 8.04 (d, J = 8, 1 H), 7.79 (t, J = 8, 1 H). 31 tert-Butyl 1,4-diazepane-1- — — Commercially available, carboxylate CAS: 112275-50-0 32 Ethyl 1,4-diazepane-1- 2 31 and LCMS (Method C): m/z carboxylate hydrochloride 55 173 (M + H).sup.+ (ES.sup.+), at 1.53 min. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 1.20 (t, J = 7.0 Hz, 3 H), 1.93-1.98 (m, 2 H), 3.10-3.17 (m, 4 H), 3.39-3.50 (m, 4 H), 4.06 (q, J = 7.0 Hz, 2 H), 9.30 (br. s, 2 H). 33 Ethyl 6-hydroxy-1,4- 2 51 and LCMS (Method C): m/z diazepane-1-carboxylate 55 189 (M + H).sup.+ (ES.sup.+), at hydrochloride 3.33 min. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 1.20 (t, J = 7.2 Hz, 3 H), 3.09-3.24 (m, 4 H), 3.36-3.67 (m, 5 H), 4.06 (q, J = 7.2 Hz, 2 H), 5.80 (br. s, 1 H), 8.48 (br. s, 1 H), 9.05 (br. s, 1 H). 34 Ethyl 6-fluoro-1,4- 2 52 and LCMS (Method A): m/z diazepane-1-carboxylate 55 191 (M + H).sup.+ (ES.sup.+), at hydrochloride 0.91 min. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 1.21-1.27 (m, 3 H), 3.38-3.80 (m, 8 H), 4.05-4.10 (m, 2 H), 5.14 (d, J = 43.2, 1 H), 8.85 (br. s, 1 H), 9.48 (br. s, 1 H). 35 1-(2-Chlorophenyl)-4- — — Commercially available, oxocyclohexanecarbonitrile CAS: 65618-88-4 36 1-(4-Chlorophenyl)-4- — — Commercially available, oxocyclohexanecarbonitrile CAS: 25115-75-7 37 1-(4-Methoxyphenyl)-4- — — Commercially available, oxocyclohexanecarbonitrile CAS: 5309-14-8 38 4-Oxo-1-[2- — — Commercially available, (trifluoromethyl)phenyl]cyclo- CAS: 943326-34-9 hexanecarbonitrile 40 4-Oxo-1-(pyridin-4- 4 — Mass: (ESI + ve): 201 yl)cyclohexanecarbonitrile (M + H).sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 2.17-2.26 (m, 4 H), 2.35-2.39 (m, 4 H), 7.91-7.93 (m, 2 H), 8.52-8.53 (m, 2 H). 41 1-(3-Chloropyridin-2-yl)-4- 4 — Mass: (ESI + ve): 235 oxocyclohexanecarbonitrile (M + H).sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 2.41-2.44 (m, 2 H), 2.54-2.55 (m, 2 H), 2.64-2.71 (m, 4 H), 7.53-7.53 (m, 1 H), 8.08-8.11 (m, 1 H), 8.60- 8.62 (m, 1 H). 42 1-(5-Bromopyridin-2-yl)-4- 4 — LCMS (Method A): m/z oxocyclohexanecarbonitrile 280/282 (M + H).sup.+ (ES.sup.+), at 1.49 min. .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 2.39-2.61 (m, 6 H), 2.81-2.93 (m, 2 H), 7.60-7.64 (m, 1 H), 7.91-7.95 (m, 1 H), 8.60- 8.62 (m, 1 H). 43 1-(5-Methylpyridin-2-yl)-4- 4 — Mass: (ESI + ve): 215 oxocyclohexanecarbonitrile (M + H).sup.+ .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 2.29-2.34 (m, 4 H), 2.58-2.60 (m, 4 H), 2.61 (s, 3 H), 7.78- 7.84 (m, 1 H), 7.91-7.99 (m, 1 H), 8.84-8.89 (m, 1 H). 44 1-(5-Methoxypyridin-2-yl)- 4 — LCMS (Method A): m/z 4-oxocyclohexanecarbonitrile 231 (M + H).sup.+ (ES.sup.+), at 1.15 min. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 2.36-2.44 (m, 4 H), 2.51-2.69 (m, 4 H), 3.85 (s, 3 H), 7.49- 7.52 (m, 1 H), 7.62-7.65 (m, 1 H), 8.32-8.36 (m, 1 H). 45 1-(5-Ethoxypyridin-2-yl)-4- 4 — LCMS (Method C): m/z oxocyclohexanecarbonitrile 244 (M + H).sup.+ (ES.sup.+), at 3.03 min. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 1.35 (t, J = 6.8 Hz, 3 H), 2.37-2.46 (m, 2 H), 2.62-2.67 (m, 2 H), 3.47-3.51 (m, 2 H), 3.65-3.76 (m, 2 H), 4.13 (q, J = 6.8 Hz, 2 H), 7.47-7.50 (m, 1 H), 7.59- 7.61 (m, 1 H), 8.32 (s, 1 H). 46 4-Oxo-1-[5- 4 — Mass: (ESI + ve): 269 (trifluoromethyl)pyridin-2- (M + H).sup.+ yl]cyclohexanecarbonitrile .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 2.43-2.63 (m, 6 H), 2.84-2.90 (m, 2 H), 7.86-7.91 (m, 2 H), 8.05-8.06 (m, 1 H). 47 4-Oxo-1-[6- 4 — LCMS (Method A): m/z (trifluoromethyl)pyridin-2- 269 (M + H).sup.+ (ES.sup.+), at yl]cyclohexanecarbonitrile 1.60 min. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 2.41-2.45 (m, 2 H), 2.50-2.53 (m, 4 H), 2.65-2.73 (m, 2 H), 7.96-7.98 (m, 1 H), 8.03-8.06 (m, 1 H), 8.23- 8.27 (m, 1 H). 48 4-Oxo-1-(thiophen-2- — — Commercially available, yl)cyclohexanecarbonitrile CAS: 65619-58-1 49 Methyl 4-oxo-1- — — Commercially available, phenylcyclohexanecarboxylate CAS: 75945-90-3 50 Methyl 1-(3-chloropyridin- 5 — Mass: (ESI + ve): 268 2-yl)-4- (M + H).sup.+ oxocyclohexanecarboxylate .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 2.39-2.49 (m, 6 H), 2.52-2.56 (m, 2 H), 3.64 (s, 3 H), 7.39- 7.43 (m, 1 H), 7.93-7.95 (m, 1 H), 8.53-8.56 (m, 1 H). 51 tert-Butyl 6-hydroxy-1,4- — — Commercially available, diazepane-1-carboxylate CAS: 956317-40-1 52 tert-Butyl-6-fluoro-1,4- — — Commercially available, diazepane-1 carboxylate CAS: 1261297-63-5 53 tert-Butyl 2,8- — — Commercially available, diazaspiro[4.5]decane-8- CAS: 236406-39-6 carboxylate 55 Ethyl chloroformate — — Commercially available, CAS: 541-41-3 56 Methyl chloroformate — — Commercially available, CAS: 79-22-1 57 Propargyl chloroformate — — Commercially available, CAS: 35718-08-2 58 2-Butynyl chloroformate — — Commercially available, CAS: 202591-85-3 59 tert-Butyl 1,5-diazocane-1- — — Commercially available, carboxylate CAS: 223797-64-6 61 tert-Butyl 2,7- — — Commercially available, diazabicyclo[3.3.0]octane- CAS: 132414-81-4 7-carboxylate 62 (4AS,7aS)-Octahydro-1H- — — Commercially available, pyrrolo[3,4-b]pyridine-1- CAS: 159991-07-8 carboxylic acid tert-butyl ester 64 2-Fluoroethyl Commercially available, chloroformate CAS: 462-27-1 65 4H-Spiro[cyclohexane- — — Commercially available, 1,3′-indole]-2′,4(1′H)-dione CAS: 52140-59-7 66 7-Methyl-1,3-dihydro-2H- — — Commercially available, indol-2-one CAS: 3680-28-2 67 7′-Methyl-4H- 6 66 LCMS (Method F): m/z spiro[cyclohexane-1,3′- 230 (M + H).sup.+ (ES.sup.+), at indole]-2′,4(1′H)-dione 1.91 min, UV active. 68 6′-Methyl-4H- 6 69 LCMS (Method F): m/z spiro[cyclohexane-1,3′- 230 (M + H).sup.+ (ES.sup.+), at indole]-2′,4(1′H)-dione 1.90 min, UV active. 69 6-Methyl-1,3-dihydro-2H- — — Commercially available, indol-2-one CAS: 56341-38-9 70 5′-Methyl-4H- 6 71 LCMS (Method F): m/z spiro[cyclohexane-1,3′- 230 (M + H).sup.+ (ES.sup.+), at indole]-2′,4(1′H)-dione 1.87 min, UV active. 71 5-Methyl-1,3-dihydro-2H- — — Commercially available, indol-2-one CAS: 3484-35-3 72 4′-Methyl-4H- 6 73 LCMS (Method F): m/z spiro[cyclohexane-1,3′- 230 (M + H).sup.+ (ES.sup.+), at indole]-2′,4(1′H)-dione 1.86 min, UV active. 73 4-Methyl-1,3-dihydro-2H- — — Commercially available, indol-2-one CAS: 13220-46-7 74 6′-Fluoro-4H- 6 75 LCMS (Method F): m/z spiro[cyclohexane-1,3′- 234 (M + H).sup.+ (ES.sup.+), at indole]-2′,4(1′H)-dione 1.83 min, UV active. 75 6-Fluoro-1,3-dihydro-2H- — — Commercially available, indol-2-one CAS: 56341-39-0 76 5′-Fluoro-4H- 6 77 LCMS (Method F): m/z spiro[cyclohexane-1,3′- 234 (M + H).sup.+ (ES.sup.+), at indole]-2′,4(1′H)-dione 1.81 min, UV active. 77 5-Fluoro-1,3-dihydro-2H- — — Commercially available, indol-2-one CAS: 56341-41-4 78 6′-Methoxy-4H- 6 79 LCMS (Method F): m/z spiro[cyclohexane-1,3′- 244 [M − H].sup.− (ES.sup.−), at 1.83 indole]-2′,4(1′H)-dione min, UV active. 79 6-Methoxy-1,3-dihydro-2H- — — Commercially available, indol-2-one CAS: 7699-19-6 80 5′-Methoxy-4H- 6 81 LCMS (Method F): m/z spiro[cyclohexane-1,3′- 246 (M + H).sup.+ (ES.sup.-), at 1.81 indole]-2′,4(1′H)-dione min, UV active. 81 5-Methoxy-1,3-dihydro-2H- — — Commercially available, indol-2-one CAS: 7699-18-5 82 Ethyl methyl[(3S)- 1 55 and LCMS (Method F): m/z pyrrolidin-3-yl]carbamate 83 173 (M + H).sup.+ (ES.sup.+), at trifluoroacetic acid salt 0.95 min, UV active. 83 tert-Butyl (3S)-3- — — Commercially available, (methylamino)pyrrolidine- CAS: 147081-59-2 1-carboxylate 84 Ethyl methyl[(3R)- 7 16, 55 LCMS (Method F): m/z pyrrolidin-3-yl]carbamate and 85 173 (M + H).sup.+ (ES.sup.+), at trifluoroacetic acid salt 0.95 min, UV active. 85 Methyl iodide — — Commercially available, CAS: 74-88-4 86 1′-Methyl-4H- 8 65 and LCMS (Method F): m/z spiro[cyclohexane-1,3′- 85 230 (M + H).sup.+ (ES.sup.+), at indole]-2′,4(1′H)-dione 1.91 min, UV active. 87 Ethyl 2′,4- 9 55 and LCMS (Method F): m/z dioxospiro[cyclohexane- 65 288 (M + H).sup.+ (ES.sup.+), at 1,3′-indole]-1′(2′H)- 2.18 min, UV active. carboxylate 88 2-(2′,4- 8 65 and LCMS (Method F): m/z Dioxospiro[cyclohexane- 89 273 (M + H).sup.+ (ES.sup.+), at 1,3′-indol]-1′(2′H)- 1.69 min, UV active. yl)acetamide 89 2-Chloroacetamide — — Commercially available, CAS: 79-07-2 90 4H-Spiro[cyclohexane- 10 91 and LCMS (Method F): m/z 1,3′-pyrrolo[2,3-b]pyridine]- 92 217 (M + H).sup.+ (ES.sup.+), at 2′,4(1′H)-dione 1.51 min, UV active. 91 3-Fluoro-2-nitropyridine — — Commercially available, CAS: 54231-35-5 92 (Buta-1,3-dien-2- — — Commercially available, yloxy)(trimethyl)silane CAS: 38053-91-7 93 5′-Chloro-4H- 11 94 LCMS (Method F): m/z spiro[cyclohexane-1,3′- 251 (M + H).sup.+ (ES.sup.+), at pyrrolo[2,3-b]pyridine]- 1.73 min, UV active. 2′,4(1′H)-dione 94 5-Chloro-1,3-dihydro-2H- — — Commercially available, pyrrolo[2,3-b]pyridin-2-one CAS: 1190314-60-3 95 5′-Methoxy-4H- 12 92 and LCMS (Method L): m/z spiro[cyclohexane-1,3′- 96 247 (M + H).sup.+ (ES.sup.+), at 3.64 pyrrolo[2,3-c]pyridine]- min, UV active. 2′,4(1′H)-dione 96 2,4-Dichloro-5- — — Commercially available, nitropyridine CAS: 4487-56-3 97 5′-Methoxy-4H- 13 92 and LCMS (Method F): m/z spiro[cyclohexane-1,3′- 98 247 (M + H).sup.+ (ES.sup.+), at 1.93 pyrrolo[3,2-b]pyridine]- min, UV active 2′,4(1′H)-dione 98 2-Chloro-6-methoxy-3- — — Commercially available, nitropyridine CAS: 38533-61-8 99 4H-Spiro[cyclohexane- 16 92 and LCMS (Method E): m/z 1,3′-pyrrolo[3,2-b]pyridine]- 100 217 (M + H).sup.+ (ES.sup.+), at 1.62 2′,4(1′H)-dione min, UV active 100 2-Chloro-3-nitropyridine — — Commercially available, CAS: 5470-18-8 101 Ethyl piperidin-4- 1 55 and LCMS (Method F): m/z ylcarbamate trifluoroacetic 102 173 (M + H).sup.+ (ES.sup.+), at 3.97 acid salt min, UV active 102 tert-Butyl 4- — — Commercially available, aminopiperidine-1- CAS: 87120-72-7 carboxylate 103 4-[4-(Aminomethyl)piperidin-1- 14 2 and LCMS (Method F): m/z yl]spiro[cyclohexane-1,3′- 65 314 (M + H).sup.+ (ES.sup.+), at 0.76 indol]-2′(1′H)-one di- min (isomer 1) and 1.47 trifluoroacetic acid salt, (isomer 2), UV active mixture of two isomers 104 Methyl 1,4-diazepane-1- 2 31 and LCMS (Method H): m/z carboxylate hydrochloride 56 159 (M + H).sup.+ (ES.sup.+), at 5.25 min, UV active 105 1-(1,4-Diazepan-1- 2 31 and LCMS (Method Q): m/z yl)butan-1-one 106 171 (M + H).sup.+ (ES.sup.+), at 2.92 hydrochloride min, UV active 106 Butyryl chloride — — Commercially available, CAS: 141-75-3 107 1-(1,4-Diazepan-1-yl)but- 15 31 and LCMS (Method H): m/z 2-en-1-one trifluoroacetic 108 169 (M + H).sup.+ (ES.sup.+), at 5.28 acid salt min, UV active 108 Crotonyl chloride — — Commercially available, CAS: 625-35-4 109 2-Oxo-2,3-dihydro-1H- — — Commercially available, indole-6-carbonitrile CAS: 199327-63-4 110 2′,4-Dioxo-1′,2′- 6 109 LCMS (Method F): m/z dihydrospiro[cyclohexane- 239 (M − H).sup.− (ES.sup.−), at 1.72 1,3′-indole]-6′-carbonitrile min, UV active 111 2-Oxo-2,3-dihydro-1H- — — Commercially available, indole-5-carbonitrile CAS: 61394-50-1 112 2′,4-Dioxo-1′,2′- 6 111 Mass: (ESI − ve):: 239 dihydrospiro[cyclohexane- (M − H).sup.− 1,3′-indole]-5′-carbonitrile 113 5′-Methoxy-4H- 17 114 Mass: (ESI + ve): 247 spiro[cyclohexane-1,3′- (M + H).sup.+ pyrrolo[2,3-b]pyridine]- 2′,4(1′H)-dione 114 5-Methoxy-1H-pyrrolo[2,3- — — Commercially available, b]pyridine CAS: 183208-36-8 115 (2-Chloropyridin-3- — — Commercially available, yl)acetonitrile CAS: 101012-32-2 116 1′,2′-Dihydro-4H- 18 115 LCMS (Method G): m/z spiro[cyclohexane-1,3′- 203 (M + H).sup.+ (ES.sup.+), at pyrrolo[2,3-b]pyridin]-4- 4.12 min, UV active one 117 1′-(Methylsulfonyl)-1′,2′- 19 116 LCMS (Method F): m/z dihydro-4H- 281 (M + H).sup.+ (ES.sup.+ ), at spiro[cyclohexane-1,3′- 1.73 min, UV active pyrrolo[2,3-b]pyridin]-4- one 118 4H-Spiro[cyclohexane- 13 119 LCMS (Method G): m/z 1,3′-pyrrolo[2,3-c]pyridine]- 217 (M + H).sup.+ (ES.sup.+), at 2′,4(1′H)-dione 3.39 min, UV active 119 4-Chloro-3-nitropyridine — — Commercially available, CAS: 13091-23-1 120 5′-Methyl-4H- 13 121 LCMS (Method F): m/z spiro[cyclohexane-1,3′- 231 (M + H).sup.+ (ES.sup.+), at pyrrolo[3,2-b]pyridine]- 1.67 min, UV active 2′,4(1′H)-dione 121 2-Chloro-6-methyl-3- — — Commercially available, nitropyridine CAS: 56057-19-3 122 Ethyl 2,6- 1 4 and LCMS (Method K): m/z diazaspiro[3.4]octane-2- 55 185 (M + H).sup.+ (ES.sup.+), at carboxylate trifluoroacetic 3.50 min, UV active acid salt 123 (1S,3R)-3- — — Commercially available, Aminocyclopentane- CAS: 71830-07-4 carboxylic acid 124 Di-tert-butyl dicarbonate — — Commercially available, CAS: 24424-99-5 125 N-Hydroxyethanimidamide — — Commercially available, CAS: 22059-22-9 126 (1R,3S)-3-(3-Methyl-1,2,4- 21 123, LCMS (Method E): m/z oxadiazol-5- 124 168 (M + H).sup.+ (ES.sup.+), at yl)cyclopentanamine and 1.20 min, UV active hydrochloride salt 125 127 N- — — Commercially available, Hydroxypropanimidamide CAS: 29335-36-2 128 (1R,3S)-3-(3-Ethyl-1,2,4- 21 123, LCMS (Method E): m/z oxadiazol-5- 124 182 (M + H).sup.+ (ES.sup.+), at yl)cyclopentanamine and 1.82 min, UV active hydrochloride salt 127 129 2-(tert-Butoxycarbonyl)-2- — — Commercially available, azaspiro[3.3]heptane-6- CAS: 1211526-53-2 carboxylic acid 130 2,2,2-Trifluoro-N- — — Commercially available, hydroxyethanimidamide CAS: 4314-35-6 131 6-[3-(Trifluoromethyl)- 22 129 LCMS (Method E): m/z 1,2,4-oxadiazol-5-yl]-2- and 234 (M + H).sup.+ (ES.sup.+), at azaspiro[3.3]heptane 130 2.96 min, UV active trifluoroacetic acid salt 132 6-tert-Butyl 2-methyl 6- — — Commercially available, azaspiro[3.4]octane-2,6- CAS: 203662-61-7 dicarboxylate 133 2-(3-Methyl-1,2,4- 23 132 LCMS (Method E): m/z oxadiazol-5-yl)-6- and 194 (M + H).sup.+ (ES.sup.+), at azaspiro[3.4]octane 125 1.57 min, UV active hydrochloride salt 134 Ethyl piperidine-3- — — Commercially available, carboxylate CAS: 5006-62-2 135 (3R)-3-(3-Methyl-1,2,4- 24 134, LCMS (Method I): m/z oxadiazol-5-yl)piperidine 124 168 (M + H).sup.+ (ES.sup.+), at and 2.57 min, UV active 125 136 Methyl 2- — — Commercially available, (aminomethyl)cyclopropane- CAS: 1630906-92-1 carboxylate hydrochloride salt 137 1-[2-(3-Methyl-1,2,4- 25 136, LCMS (Method E): m/z oxadiazol-5- 124 154 (M + H).sup.+ (ES.sup.+), at yl)cyclopropyl]methanamine and 0.71 min, UV active hydrochloride salt 125 138 (1R,3S)-3-[3- 21 123, LCMS (Method E): m/z (Trifluoromethyl)-1,2,4- 124 222 (M + H).sup.+ (ES.sup.+), at oxadiazol-5- and 2.71 min, UV active. yl]cyclopentanamine 130 hydrochloride salt 139 2-(tert-Butoxycarbonyl)-2- — — Commercially available, azaspiro[3.3]heptane-6- CAS: 1211526-53-2 carboxylic acid 140 6-(3-Ethyl-1,2,4-oxadiazol- 22 129 LCMS (Method E): m/z 5-yl)-2- and 194 (M + H).sup.+ (ES.sup.+), at azaspiro[3.3]heptane 127 2.21 min, UV active. trifluoroacetic acid salt 141 2-(3-Ethyl-1,2,4-oxadiazol- 22 132 LCMS (Method B): m/z 5-yl)-6-azaspiro[3.4]octane and 208 (M + H).sup.+ (ES.sup.+), at hydrochloride salt 127 1.83 min, UV active 142 Cyclopropanecarboxylic — — Commercially available, acid, 2-[[[(1,1- CAS: 1000535-88-5 dimethylethoxy)car- bonyl]amino]methyl]- 143 1-[2-(3-Ethyl-1,2,4- 22 142 LCMS (Method B): m/z oxadiazol-5- and 168 (M + H).sup.+ (ES.sup.+), at yl)cyclopropyl]methanamine 127 1.33 min, UV active hydrochloride salt

TABLE-US-00003 TABLE 3 Ex. Inter- Synthetic LCMS LCMS No. Name mediate method .sup.1H NMR Method data  1-1 Isomer 2: ethyl [(3S)-1- 12 c (400 MHz, CDCl.sub.3) δ: 1.26 (t, J = 5.6 Hz, 3 H), 1.47-1.52 (m, 1 D m/z 342 (4-cyano-4- and H), 1.63-1.65 (m, 1 H), 1.90-1.98 (m, 5 H), 2.28-2.39 (m, 5 (M + H).sup.+ phenylcyclohexyl)pyrrolidin- 13 H), 2.56-2.82 (m, 3 H), 4.12-4.14 (m, 2 H), 4.22-4.28 (m, 1 (ES.sup.+), at 3-yl]carbamate H), 4.83-4.89 (m, 1 H), 7.33 (t, J = 4, 1 H), 7.43 (t, J = 7.2 Hz, 2 5.87 min, H), 7.39 (d, J = 7.6 Hz, 2 H). UV active  1-2 Isomer 2: ethyl [(3R)-1- 12 c (400 MHz, CDCl.sub.3) δ: 1.24 (t, J = 6.6 Hz, 3 H), 1.60-1.65 (m, 1 D m/z 342 (4-cyano-4- and H), 1.87-1.97 (m, 6 H), 2.22-2.27 (m, 3 H), 2.34-2.40 (m, 2 (M + H).sup.+ phenylcyclohexyl)pyrrolidin- 14 H), 2.52-2.56 (m, 1 H), 2.65-2.66 (m, 1 H), 2.79-2.80 (m, 1 (ES.sup.+), at 3-yl]carbamate H), 4.08-4.12 (m, 2 H), 4.20-4.18 (m, 1 H), 4.83-4.88 (m, 1 5.85 min, H), 7.34 (t, J = 7.2 Hz, 1 H), 7.39 (t, J = 7.6 Hz, 2 H), 7.48 (d, J = UV active 7.6 Hz, 2 H).  1-3 Isomer 2: ethyl {(3S)-1- 13 d (400 MHz, DMSO-d.sub.6) δ: 1.14 (t, J = 7.2 Hz, 3 H), 1.49-1.65 (m, C m/z 360 [4-cyano-4-(3- and 1 H), 1.66-1.82 (m, 2 H), 1.82-2.14 (m, 6 H), 2.15-2.31 (m, 3 (M + H).sup.+ fluorophenyl)cyclohexyl] 20 H), 2.31-2.42 (m, 1 H), 2.58-2.70 (m, 1 H), 2.70-2.85 (m, 1 (ES.sup.+) at pyrrolidin-3-yl}carbamate H), 3.96 (q, J = 7.2 Hz, 3 H), 7.17-7.26 (m, 1 H), 7.29-7.42 (m, 2.97 min, 2 H), 7.45-7.55 (m, 1 H). N-H not observed. UV active  1-4 Isomer 2: ethyl {(3S)-1- 13 c (400 MHz, DMSO-d.sub.6) δ: 1.14 (t, J = 7.0 Hz, 3 H), 1.57-1.60 (m, C m/z 360 [4-cyano-4-(4- and 1 H), 1.69-1.81 (m, 2 H), 1.85-1.99 (m, 4 H), 2.01-2.12 (m, 2 (M + H).sup.+ fluorophenyl)cyclohexyl] 21 H), 2.17-2.25 (m, 2 H), 2.30-2.42 (m, 2 H), 2.60-2.67 (m, 1 (ES.sup.+), at pyrrolidin-3-yl}carbamate H), 2.68-2.75 (m, 2 H), 3.96 (q, J = 7.0 Hz, 3 H), 7.26-7.33 (m, 2.97 min, 2 H), 7.55-7.58 (m, 2 H). UV active  1-5 Isomer 2: ethyl {(3R)-1- 14 c (400 MHz, DMSO-d.sub.6) δ: 1.13 (t, J = 7.2 Hz, 3 H), 1.54-1.59 (m, C m/z 360 [4-cyano-4-(2- and 1 H), 1.78-1.92 (m, 2 H), 1.96-2.05 (m, 5 H), 2.19-2.34 (m, 4 (M + H).sup.+ fluorophenyl)cyclohexyl] 19 H), 2.42-2.45 (m, 1 H), 2.53-2.58 (m, 1 H), 2.71-2.75 (m, 1 H), (ES.sup.+), at pyrrolidin-3-yl}carbamate 3.95 (q, J = 7.2 Hz, 3 H), 7.26-7.34 (m, 3 H), 7.43 7.53 (m, 2 2.89 min, H). UV active  1-6 Isomer 2: ethyl {(3R)-1- 14 c (400 MHz, DMSO) δ: 1.14 (t, J = 7.2 Hz, 3 H), 1.56-1.61 (m, 1 C m/z 360 [4-cyano-4-(3- and H), 1.74-1.78 (m, 2 H), 1.87-1.90 (m, 3 H), 2.01-2.08 (m, 1 (M + H).sup.+ fluorophenyl)cyclohexyl] 20 H), 2.15-2.51 (m, 6 H), 2.63-2.66 (m, 2 H), 3.93-3.98 (m, 3 (ES.sup.+), at pyrrolidin-3-yl}carbamate H), 7.20-7.25 (m, 1 H), 7.35-7.39 (m, 3 H), 7.48-7.54 (m, 1 2.97 min, H). UV active  1-7 Isomer 2: ethyl {(3R)-1- 14 c (400 MHz, DMSO-d.sub.6) δ: δ: 1.15 (t, J = 6.8 Hz, 3 H), 1.59-1.65 C m/z 360 [4-cyano-4-(4- and (m, 1 H), 1.74-1.80 (m, 2 H), 1.81-1.96 (m, 4 H), 2.01-2.10 (M + H).sup.+ fluorophenyl)cyclohexyl] 21 (m, 2 H), 2.15-2.55 (m, 4 H), 2.60-2.73 (m, 2 H), 3.93-4.00 (ES.sup.+), at pyrrolidin-3-yl}carbamate (m, 3 H), 7.22-7.28 (m, 3 H), 7.50-7.61 (m, 2 H). 2.93 min, UV active  1-8 Isomer 2: ethyl {(3R)-1- 14 c (400 MHz, DMSO-d.sub.6) δ: 1.14 (t, J = 7.2 Hz, 3 H), 1.55-1.60 (m, C m/z 356 [4-cyano-4-(2- and 1 H), 1.77-1.83 (m, 2 H), 1.92-2.05 (m, 5 H), 2.18-2.20 (m, 2 (M + H).sup.+ methylphenyl)cyclohexyl] 22 H), 2.31-2.34 (m, 2 H), 2.41-2.45 (m, 2 H), 2.57 (s, 3 H), 2.65- (ES.sup.+), at pyrrolidin-3-yl}carbamate 2.74 (m, 2 H), 3.95 (q, J = 7.2 Hz, 3 H), 7.25-7.30 (m, 3 H), 7.40- 3.02 min, 7.42 (t, J = 6.4 Hz, 1 H). UV active  1-9 Isomer 2: ethyl }(3S)-1- 13 c (400 MHz, DMSO-d.sub.6) δ: 1.15 (t, J = 6.8 Hz, 3 H), 1.48-1.59 (m, C m/z 356 [4-cyano-4-(3- and 3 H), 1.70-2.10 (m, 7 H), 2.18-2.39 (m, 2 H), 2.40-2.50 (m, 5 (M + H).sup.+ methylphenyl)cyclohexyl] 23 H), 2.64-2.87 (m, 2 H), 3.94-4.00 (q, J = 7.2 Hz, 3 H), 7.15- (ES.sup.+), at pyrrolidin-3-yl}carbamate 7.17 (m, 1 H), 7.27-7.34 (m, 3 H). 2.71 min, UV active  1-10 Isomer 2: ethyl {(3S)-1- 13 c (400 MHz, DMSO-d.sub.6) δ: 1.14 (t, J = 6.8 Hz, 3 H), 1.57-1.60 (m, C m/z 376 [4-(3-chlorophenyl)-4- and c 1 H), 1.71-1.77 (m, 3 H), 1.87-1.89 (m, 4 H), 2.03-2.07 (m, 1 (M + H).sup.+ cyanocyclohexyl] 24 H), 2.17-2.32 (m, 3 H), 2.25-2.40 (m, 2 H), 2.59-2.68 (m, 2 (ES.sup.+), at pyrrolidin-3-yl}carbamate H), 3.96 (q, J = 6.8 Hz, 3 H), 7.32 (d, J = 7.6 Hz, 1 H), 7.44- 3.10 min, 7.54 (m, 3 H). UV active  1-11 Isomer 2: ethyl {(3S)-1- 13 c (400 MHz, DMSO-d.sub.6) δ: 1.14 (t, J = 6.4 Hz, 3 H), 1.85-1.99 (m, C m/z 372 [4-cyano-4-(3- and 1 H), 1.74-2.09 (m, 7 H), 2.20-2.41 (m, 5 H), 2.61-2.67 (m, 2 (M + H).sup.+ methoxyphenyl) 25 H), 3.79 (s, 3 H), 3.95 (q, J = 6.4 Hz, 3 H), 6.95 (d, J = 8.0 Hz, 1 (ES.sup.+), at cyclohexyl] H), 7.01 (s, 1 H), 7.09 (d, J = 7.6 Hz, 1 H), 7.30-7.39 (m, 2 H). 2.67 min, pyrrolidin-3-yl}carbamate UV active  1-12 Isomer 2: ethyl {(3S)-1- 13 c (400 MHz, CD.sub.3OD) δ: 1.23 (t, J = 7.2 Hz, 3 H), 1.70-1.74 (m, 1 C m/z 343 [4-cyano-4-(pyridin-2- and H), 1.80-2.05 (m, 7 H), 2.17-2.30 (m, 1 H), 2.47-2.55 (m, 1 (M + H).sup.+ yl)cyclohexyl]pyrrolidin-3- 26 H), 2.57-2.67 (m, 4 H), 2.87-2.93 (m, 2 H), 4.06 (q, J = 7.2 Hz, (ES.sup.+), at yl}carbamate 2 H), 4.10-4.21 (m, 1 H), 7.39 (dd, J = 7.2 Hz, 5.2, 1 H), 7.69 (d, 2.50 min, J = 7.6 Hz, 1 H), 7.91 (t, J = 8.0 Hz, 1 H), 8.61 (d, J = 4.4 Hz, 1 UV active H).  1-13 Isomer 2: ethyl {(3R)-1- 14 c (400 MHz, CD.sub.3OD) δ: 1.20 (t, J = 7.2 Hz, 3 H), 1.71-1.76 (m, 1 C m/z 343 [4-cyano-4-(pyridin-2- and H), 1.83-2.05 (m, 7 H), 2.17-2.30 (m, 1 H), 2.50-2.70 (m, 5 (M + H).sup.+ yl)cyclohexyl]pyrrolidin-3- 26 H), 2.87-2.95 (m, 2 H), 4.07 (q, J = 7.2 Hz, 2 H), 4.11-4.20 (m, (ES.sup.+), at yl}carbamate 1 H), 7.28 (d, J = 7.2 Hz, 1 H), 7.70 (d, J = 7.2 Hz, 1 H), 7.91 (t, 2.52 min, J = 6.8 Hz, 1 H), 8.62 (d, J = 4.8 Hz, 1 H). UV active  1-14 Isomer 2: ethyl {(3S)-1- 13 c (400 MHz, DMSO-d.sub.6) δ: 1.15 (t, J = 6.8 Hz, 3 H), 1.56-1.62 (m, m/z 361 [4-cyano-4-(5- and 1 H), 1.66-2.15 (m, 8 H), 2.21-2.45 (m, 4 H), 2.46-2.52 (m, 1 (M + H).sup.+ fluoropyridin-2- 27 H), 2.70-2.80 (m, 1 H), 3.92-4.01 (m, 3 H), 7.28 (d, J = 7.2 Hz, (ES.sup.+), at yl)cyclohexyl]pyrrolidin-3- 1 H), 7.68-7.72 (m,1 H), 7.82-7.86 (m, 1 H), 8.64-8.66 (m, 1 2.62 min, yl}carbamate H). UV active  1-15 Isomer 2: ethyl {(3S)-1- 15, 28 b (400 MHz, DMSO-d.sub.6) δ: 1.14 (t, J = 7.0 Hz, 3 H), 1.38-1.66 (m, B m/z 377 {trans-4-(5-chloropyridin- and 1 H), 1.66-2.19 (m, 8 H), 2.13-2.37 (m, 4 H), 2.40-2.43 (m, 1 (M + H).sup.+ 2-yl)-4- 55 H), 2.74 (t, J = 8.0 Hz, 1 H), 3.87-3.95 (m, 1 H), 3.96 (q, J = 7.0 (ES.sup.+), at cyanocyclohexyl] Hz, 2 H), 7.27 (d, J = 7.0 Hz, 1 H), 7.66 (dd, J = 8.5 Hz, 0.8, 1 B 3.95 min, pyrrolidin-3-yl}carbamate H), 8.04 (dd, J = 8.5 Hz, 2.5 Hz, 1 H) and 8.70 (dd, J = 2.5 Hz, UV active 0.8, 1 H).  1-16 Isomer 2: ethyl {(3R)-1- 16, 28 b (400 MHz, DMSO-d.sub.6) δ: 1.14 (t, J = 7.0 Hz, 3 H), 1.48-1.66 B m/z 377 [4-(5-chloropyridin-2-yl)- and 1 H), 1.66-2.19 (m, 8 H), 2.24-2.37 (m, 3 H), 2.41-2.49 (m, 1 (M + H).sup.+ 4-cyanocyclohexyl] 55 H), 2.53-2.60 (m, 1 H), 2.75 (t, J = 8.0 Hz, 1 H), 3.87-3.95 (m, (ES.sup.+), at pyrrolidin-3-yl}carbamate 1 H), 3.96 (q, J = 7.0 Hz, 2 H), 7.27 (d, J = 7.0 Hz, 1 H), 7.66 3.97 min, (dd, J = 8.5, 0.8 Hz, 1 H), 8.04 (dd, J = 8.5, 2.5 Hz, 1 H), 8.70 UV active (dd, J = 2.5, 0.8 Hz, 1 H)  1-17 Isomer 2: ethyl {(3S)-1- 13 c (400 MHz, DMSO-d.sub.6) δ: 1.14 (t, J = 7.0 Hz, 3 H), 1.56-1.60 (m, C m/z 357 ]4-cyano-4-(4- and 1 H), 1.70-1.93 (m, 6 H), 2.00-2.08 (m, 2 H), 2.25-2.37 (m, 4 (M + H).sup.+ methylpyridin-2- 29 H), 2.38 (s, 3 H), 2.47-2.50 (m, 1 H), 2.74-2.78 (m, 1 H), 3.99- (ES.sup.+), at yl)cyclohexyl]pyrrolidin-3- 3.99 (m, 3 H), 7.22-7.23 (m, 1 H), 7.27-7.29 (m,1 H), 7.43 (s, 2.66 min, yl}carbamate H), 8.46-8.48 (m, 1 H). UV active  1-18 Isomer 2: ethyl {(3S)-1- 13 c (400 MHz, CDCl.sub.3) δ: 1. 28 (t, J = 7.2 Hz, 3H), 1.80-2.00 (m, 3 C m/z 358 [4-cyano-4-(6- and H), 2.19-2.40 (m, 8 H), 2.55 (s, 3 H), 2.64-2.95 (m, 2 H), 3.05- (M + H).sup.+ methylpyridin-2- 30 3.35 (m, 2 H), 4.12 (q, J = 7.2 Hz, 2 H), 4.30-4.45 (m, 1 H), 7.10 (ES.sup.+), at yl)cyclohexyl]pyrrolidin-3- (d, J = 8 Hz, 1 H), 7.43 (d, J = 8 Hz, 1 H), 7.62 (t, J = 8, 1 H). N- 2.65 min, yl}carbamate H not observed. UV active  1-19 Isomer 2: ethyl {(3R)-1- 14 c (400 MHz, DMSO-d.sub.6) δ: 1.14 (t, J = 7.2 Hz, 3 H), 1.56-1.61 C m/z 357 [4-cyano-4-(4- and 1 H), 1.70-2.10 (m, 8 H), 2.25-2.37 (m, 4 H), 2.38 (s, 3 H), (M + H).sup.+ methylpyridin-2- 29 2.45-2.50 (m, 1 H), 2.72-2.77 (m, 1 H), 3.93-4.05 (m, 3 H), (ES.sup.+), at yl)cyclohexyl]pyrrolidin-3- 7.23 (d, J = 4.8 Hz, 1 H), 7.27 (d, J = 8.0 Hz, 1 H), 7.43 (s, 1 H), 7.15 min, yl}carbamate 8.47 (d, J = 5.2 Hz, 1 H,). UV active  1-20 Isomer 2: ethyl [(3S)-1- 12, 17 b (400 MHz, DMSO-d.sub.6) δ: 1.10 (t, J = 7.1 Hz, 3 H), 1.56-1.84 (m, B m/z 356 (4-cyano-4- and 5 H), 1.84-2.22 (m, 7 H), 2.34 (dd, J = 9.5, 8.3 Hz, 1 H), 2.64 (M + H).sup.+ phenylcyclohexyl) 55 (dd, J = 9.9, 3.4, 1 H), 2.74 (s, 3 H), 2.82 (td, J = 8.4 and 2.8 Hz, (ES.sup.+), at pyrrolidin-3-yl]methyl- 1 H), 3.94 (q, J = 7.1 Hz, 2 H), 4.63 (br. s., 1 H), 7.26-7.32 (m, 1 5.00 min, carbamate H), 7.34-7.45 (m, 4 H). UV active  1-21 Isomer 2: ethyl [(3R)-1- 12, 18 b (400 MHz, DMSO-d.sub.6) δ: 1.17 (t, J = 7.2 Hz, 3 H), 1.65-2.01 (m, B m/z 356 (4-cyano-4- and 6 H), 2.01-2.30 (m, 6 H), 2.35-2.45 (m, 1 H), 2.65-2.75 (m, 1 (M + H).sup.+ phenylcyclohexyl) 55 H), 2.82 (s, 3 H), 2.85-2.95 (m, 1 H), 4.01 (q, J = 7.2 Hz, 2 H), (ES.sup.+), at pyrrolidin-3-yl]methyl- 4.70 (br. s., 1 H), 7.33-7.39 (m, 1 H), 7.42-7.52 (m, 4 H). 4.94 min, carbamate UV active  1-22 Isomer 2: ethyl {(3R)-1- 17, 28 b (500 MHz, CDCl.sub.3) δ: 1.25 (t, J = 7.0 Hz, 3 H), 1.49-1.65 (m, 2 B m/z 391 [4-(5-chloropyridin-2-yl)- and H), 1.70-1.81 (m, 1 H), 1.82-2.02 (m, 4 H), 2.03-2.33 (m, 4 (M + H).sup.+ 4-cyanocyclohexyl] 55 H), 2.34-2.55 (m, 3 H), 2.68 (dd, J = 10.0, 3.0 Hz, 1 H), 2.88 (s, (ES.sup.+), at pyrrolidin-3- 3 H), 4.11 (q, J = 7.0 Hz, 2 H), 4.77-5.01 (m, 1 H), 7.50 (d, J = 4.72 min, yl}methylcarbamate 8.5 Hz, 1 H), 7.69 (dd, J = 8.5, 2.5 Hz, 1 H), 8.54 (d, J = 2.5 Hz, UV active 1 H).  2-1 Isomer 1: ethyl [(3S)-1- 13 c (400 MHz, DMSO-d.sub.6) □: 1.16 (t, J = 7.0 Hz, 3 H), 1.52-1.72 B m/z 358 (2′-oxo-1′,2′- and 6 H), 1.93-2.43 (m, 5 H), 2.53-2.69 (m, 3 H), 2.79-2.91 (m, 1 (M + H).sup.+ dihydrospiro[cyclohexane- 65 H), 3.95-4.00 (m, 3 H), 6.87 (d, J = 7.5 Hz, 1 H), 6.96 (td, J = (ES.sup.+), at 1,3′-indol]-4-yl)pyrrolidin- 7.5, 1.0 Hz, 1 H), 7.20 (td, J = 7.5, 1.0 Hz, 1 H), 7.26-7.32 (m, 1 2.67 min, 3-yl]carbamate H), 7.44 (d, J = 7.5 Hz, 1 H), 10.40 (s, 1 H) UV active  2-2 Isomer 1: ethyl [(3R)-1- 14 c (400 MHz, DMSO-d6) □: 1.16 (t, J = 7.0 Hz, 3 H), 1.48-1.73 (m, F m/z 358 (2′-oxo-1′,2′- and 7H), 1.95-2.11 (m, 3 H), 2.27-2.31 (m, 1 H),2.61-2.81 (m,3 (M + H).sup.+ dihydrospiro[cyclohexane- 65 H), 2.91-2.95 (m, 1 H), 3.95-4.01 (m, 3 H), 6.87 (d, J = 7.5 Hz, (ES.sup.+), at 1,3′-indol]-4-yl)pyrrolidin- 1 H), 6.97 (t, J = 7.5 Hz, 1 H), 7.20 (t, J = 7.5 Hz, 1 H), 7.31- 1.62 min, 3-yl]carbamate 7.33 (m, 1 H), 7.46 (d, J = 7.5 Hz, 1 H), 10.41 (s, 1 H) UV active  2-2 Isomer 2: ethyl [(3R)-1- 14 c (400 MHz, DMSO-d.sub.6) □: 1.16 (t, J = 7.0 Hz, 3 H), 1.65-1.83 (m, F m/z 358 (2′-oxo-1′,2′- and 7 H), 2.02-2.13 (m, 3 H), 2.36-2.42 (m, 1 H), 2.57-2.63 (m, 2 (M + H).sup.+ dihydrospiro[cyclohexane- 65 H), 2.73-2.91 (m, 1 H), 3.00-3.11 (m, 1 H), 3.96-4.06 (m, 3 (ES.sup.+), at 1,3′-indol]-4-yl)pyrrolidin- H), 6.81 (d, J = 7.5 Hz, 1 H), 6.95 (t, J = 7.5 Hz, 1 H), 7.16 (t, J = 1.69 min, 3-yl]carbamate 7.5 Hz, 1 H), 7.27 (d, J = 7.5 Hz, 1 H), 7.35-7.36 (m, 1 H), UV active 10.27 (s, 1 H)  2-3 Isomer 1: ethyl [(3S)-1- 13 c (400 MHz, DMSO-d.sub.6) □: 1.16 (t, J = 7.0 Hz, 3 H), 1.52-1.71 (m, F m/z 372 (7′-methyl-2′-oxo-1′,2- and 7 H), 1.96-2.09 (m, 3 H), 2.16-2.21 (m, 4 H), 2.37-2.41 (m, 1 (M + H).sup.+ dihydrospiro[cyclohexane- 67 H), 2.66-2.56 (m, 2 H), 2.82-2.86 (m, 1 H), 3.95-4.00 (m, 3 (ES.sup.+), at 1,3′-indol]-4-yl)pyrrolidin- H), 6.88 (t, J = 7.5 Hz, 1 H), 7.02 (d, J = 7.5 Hz, 1 H), 7.24-7.29 1.63 min, 3-yl]carbamate (m, 2 H), 10.42 (s, 1 H) UV active  2-4 Isomer 1: ethyl [(3S)-1- 13 c (400 MHz, DMSO-d.sub.6) □: 1.16 (t, J = 7.0 Hz, 3 H), 1.43-1.75 (m, F m/z 372 (6′-methyl-2′-oxo-1′,2- and 6 H), 1.92-2.10 (m, 3 H), 2.13-2.22 (m, 1 H), 2.27 (s, 3 H), (M + H).sup.+ dihydrospiro[cyclohexane- 68 2.36-2.40 (m, 1 H), 2.57-2.68 (m, 3 H), 2.82-2.86 (m, 1 H), (ES.sup.+), at 1,3′-indol]-4-yl)pyrrolidin- 3.95-4.00 (m, 3 H), 6.69 (s, 1 H), 6.77 (d, J = 7.5 Hz, 1 H), 7.29 1.67 min, 3-yl]carbamate (m, 2 H), 10.34 (s, 1 H) UV active  2-5 Isomer 1: ethyl [(3S)-1- 13 c (400 MHz, DMSO-d.sub.6) □: 1.16 (t, J = 7.0 Hz, 3 H), 1.51-1.71 (m, F m/z 372 (5′-methyl-2′-oxo-1′,2- and 7 H), 1.93-2.21 (m, 4 H), 2.29 (s, 3 H), 2.32-2.43 (m, 1 H), (M + H).sup.+ dihydrospiro[cyclohexane- 70 2.55-2.70 (m, 2 H), 2.85-2.90 (m, 1 H), 3.95-4.01 (m, 3 H), (ES.sup.+), at 1,3′-indol]-4-yl)pyrrolidin- 6.76 (d, J = 7.5 Hz, 1 H), 7.00 (d, J = 7.5 Hz, 1 H), 7.23 (s, 1 H), 1.67 min, 3-yl]carbamate 7.28 (d, J = 7.0 Hz, 1 H), 10.29 (s, 1 H) UV active  2-6 Isomer 1: ethyl [(3S)-1- 13 c (400 MHz, DMSO-d.sub.6) □: 1.14-1.20 (m, 4 H), 1.61-1.71 (m, 3 F m/z 372 (4′-methyl-2′-oxo-1′,2- and H), 1.95-2.44 (m, 10 H), 2.56-2.63 (m, 3 H), 2.81-2.85 (m, 1 (M + H).sup.+ dihydrospiro[cyclohexane- 72 H), 3.95-4.01 (m, 3 H), 6.60 (d, J = 7.5 Hz, 1 H), 6.70 (d, J = 7.5 (ES.sup.+), at 1,3′-indol]-4-yl)pyrrolidin- Hz, 1 H), 7.02 (t, J = 7.5 Hz, 1 H), 7.19 (d, J = 6.5 Hz, 1 H), 1.73 min, 3-yl]carbamate 10.11 (s, 1 H) UV active  2-7 Isomer 1: ethyl [(3S)-1- 13 c (400 MHz, DMSO-d.sub.6) □: 1.16 (t, J = 7.0 Hz, 3 H), 1.52-1.70 (m, F m/z 376 (6′-fluoro-2′-oxo-1′,2′- and 7 H), 1.97-2.09 (m, 3 H), 2.15-2.24 (m, 1 H), 2.36-2.40 (m, 1 (M + H).sup.+ dihydrospiro[cyclohexane- 74 H), 2.57-2.67 (m, 2 H), 2.82-2.86 (m, 1 H), 3.95-4.00 (m, 3 (ES.sup.+), at 1,3′-indol]-4-yl)pyrrolidin- H), 6.68 (dd, J = 9.0, 2.5 Hz, 1 H), 6.74-6.79 (m, 1 H), 7.28 (d, 1.72 min, 3-yl]carbamate J = 7.0 Hz, 1 H), 7.43 (dd, J = 8.0, 5.5 Hz, 1 H), 10.56 (bs, 1 H) UV active  2-7 Isomer 2: ethyl [(3S)-1- 13 c (400 MHz, DMSO-d.sub.6) □: 1.16 (t, J = 7.0 Hz, 3 H), 1.54-1.76 (m, F m/z 376 (6′-fluoro-2′-oxo-1′,2′- and 7 H), 1.92-2.09 (m, 3 H), 2.19-2.24 (m, 1 H), 2.33-2.37 (m, 1 (M + H).sup.+ dihydrospiro[cyclohexane- 74 H), 2.54-2.65 (m, 2 H), 2.80-2.84 (m, 1 H), 3.90-4.00 (m, 3 (ES.sup.+), at 1,3′-indol]-4-yl)pyrrolidin- H), 6.61 (dd, J = 9.0, 2.0 Hz, 1 H), 6.70-6.76 (m, 1 H), 7.27 (d, 1.96 min, 3-yl]carbamate J = 7.0 Hz, 1 H), 7.33 (dd, J = 8.0, 6.0 Hz, 1 H), 10.38 (s, 1 H) UV active  2-8 Isomer 1: ethyl [(3S)-1- 13 c (400 MHz, DMSO-d.sub.6) □: 1.16 (t, J = 7.0 Hz, 3 H), 1.50-1.70 (m, F m/z 376 (5′-fluoro-2′-oxo-1′,2′- and 7 H), 1.95-2.11 (m, 3 H), 2.15-2.26 (m, 1 H), 2.39-2.43 (m, 1 (M + H).sup.+ dihydrospiro[cyclohexane- 76 H), 2.66-2.71 (m, 2 H), 2.79-2.83 (m, 1 H), 3.95-4.00 (m, 3 (ES.sup.+), at 1,3′-indol]-4-yl)pyrrolidin- H), 6.86 (dd, J = 8.5, 4.5 Hz, 1 H), 7.02-7.07 (m, 1 H), 7.21- 1.64 min, 3-yl]carbamate 7.24 (m, 1 H), 7.30 (d, J = 7.0 Hz, 1 H), 10.42 (s, 1 H) UV active  2-8 Isomer 2: ethyl [(3S)-1- 13 c (400 MHz, DMSO-d.sub.6) □: 1.16 (t, J = 7.0 Hz, 3 H), 1.53-1.81 (m, F m/z 376 (5′-fluoro-2′-oxo-1′,2′- and 7 H), 1.89-2.09 (m, 3 H), 2.17-2.27 (m, 1 H), 2.32-2.40 (m, 1 (M + H).sup.+ dihydrospiro[cyclohexane- 76 H), 2.55-2.66 (m, 2 H), 2.80-2.84 (m, 1 H), 3.90-4.03 (m, 3 (ES.sup.+), at 1,3′-indol]-4-yl)pyrrolidin- H), 6.78 (dd, J = 8.5, 4.5 Hz, 1 H), 6.95-7.00 (m, 1 H), 7.24- 1.72 min, 3-yl]carbamate 7.32 (m, 2 H), 10.25 (s, 1 H) UV active  2-9 Isomer 1: ethyl [(3S)-1- 13 c (400 MHz, DMSO-d.sub.6) □: 1.14-1.20 (m, 3 H), 1.46-1.70 (m, 6 F m/z 388 (6′-methoxy-2′-oxo-1′,2′- and H), 1.95-2.09 (m, 3 H), 2.13-2.23 (m, 1 H), 2.36-2.40 (m, 1 (M + H).sup.+ dihydrospiro[cyclohexane- 78 H), 2.56-2.68 (m, 2 H), 2.83-2.87 (m, 1 H), 3.19-3.25 (m, 1 (ES.sup.+), at 1,3′-indol]-4-yl)pyrrolidin- H), 3.73 (s, 3 H), 3.95-4.00 (m, 3 H), 6.43 (d, J = 2.0 Hz, 1 H), 1.68 min, 3-yl]carbamate 6.51 (dd, J = 8.0, 2.0 Hz, 1 H), 7.27 (d, J = 7.0 Hz, 1 H), 7.32 (d, UV active J = 8.0 Hz, 1 H), 10.36 (s, 1 H)  2-10 Isomer 1: ethyl [(3S)-1- 13 c (400 MHz, DMSO-d.sub.6) □: 1.10-1.22 (m, 4 H), 1.53-1.70 (m, 6 F m/z 388 (5′-methoxy-2′-oxo-1′,2′- and H), 1.91-2.11 (m, 2 H), 2.15-2.25 (m, 1 H), 2.38-2.42 (m, 1 (M + H).sup.+ dihydrospiro[cyclohexane- 80 H), 2.55-2.72 (m, 2 H), 2.79-2.85 (m, 1 H), 2.94-3.17 (m, 1 F (ES.sup.+), at 1,3′-indol]-4-yl)pyrrolidin- H), 3.72 (s, 3 H), 3.95-4.00 (m, 3 H), 6.79 (s, 2 H), 6.98 (s, 1 H), 1.68 min, 3-yl]carbamate 7.28 (d, J = 7.0 Hz, 1 H), 10.24 (s, 1 H) UV active  2-11 Isomer 1: ethyl 65 c (400 MHz, DMSO-d.sub.6) □: 1.19 (t, J = 7.0 Hz, 3 H), 1.55-1.77 (m, F m/z 372 methyl[(3S)-1- and 7 H), 1.99-2.10 (m, 3 H). 2.15-2.23 (m, 1 H), 2.30-2.37 (m, 1 (M + H).sup.+ (2′-oxo-1′,2′- 82 H), 2.56-2.61 (m, 1 H), 2.66-2.74 (m, 2 H), 2.86-2.93 (m, 4 H), (ES.sup.+), at dihydrospiro[cyclohexane- 4.03 (q, J = 7.0 Hz, 2 H), 6.86 (d, J = 7.5 Hz, 1 H), 6.97 (t, J = 1.72 min, 1,3′-indol]-4-yl)pyrrolidin- 7.5 Hz, 1 H), 7.20 (t, J = 7.5 Hz, 1 H), 7.36 (d, J = 7.5 Hz, 1 H), UV active 3-yl]carbamate 10.37 (s, 1 H)  2-12 Isomer 1: ethyl 65 c (400 MHz, Me0D-d4) □: 1.29 (m, 3 H), 1.59-1.70 (m, 2 H), 1.79- F m/z 372 methyl[(3R)-1- and 1.98 (m, 5 H), 2.06-2.23 (m, 3 H), 2.35-2.48 (m, 1 H), 2.68- (M + H).sup.+ (2′-oxo-1′,2′- 84 2.83 (m, 2 H), 2.94-3.02 (m, 5 H), 4.15 (q, J = 7.0 Hz, 2 H), (ES.sup.+), at dihydrospiro[cyclohexane- 4.81-4.89 (m, 1 H), 6.96 (d, J = 7.5 Hz, 1 H), 7.04 (t, J = 7.5 Hz, 1.68 min, 1,3′-indol]-4-yl)pyrrolidin- 1 H), 7.25 (t, J = 7.5 Hz, 1 H), 7.66 (d, J = 7.5 Hz, 1 H) UV active 3-yl]carbamate  2-12 Isomer 2: ethyl 65 c (400 MHz, DMSO-d.sub.6, D.sub.2O wash) □: 1.16 (t, J = 7.0 Hz, 3 H), G m/z 372 methyl[(3R)-1- and 1.57-2.09 (m, 10 H), 2.56-2.86 (m, 7 H), 2.88-2.99 (m, 1 H), (M + H).sup.+ (2′-oxo-1′,2′- 84 4.00-4.03 (m, 2 H), 4.57-4.75 (m, 1 H), 6.84 (d, J = 7.5 Hz, 1 H), (ES.sup.+), at dihydrospiro[cyclohexane- 6.96 (t, J = 7.5 Hz, 1 H), 7.15 (t, J = 7.5 Hz, 1 H), 7.28 (d, J = 1.65 min, 1,3′-indol]-4-yl)pyrrolidin- 7.5 Hz, 1 H) UV active 3-yl]carbamate  2-13 Isomer 1: ethyl [(3S)-1- 13 c (400 MHz, DMSO-d.sub.6) □: 1.16 (t, J = 7.0 Hz, 3 H), 1.53-1.76 (m, F m/z 372 (1′-methyl-2′-oxo-1′,2′- and 6 H), 1.95-2.12 (m, 3 H), 2.17-2.29 (m, 1 H), 2.38-2.41 (m, 1 (M + H).sup.+ dihydrospiro[cyclohexane- 86 H), 2.56-2.70 (m, 3 H), 2.83-2.87 (m, 1 H), 3.14 (s, 3 H), 3.95- (ES.sup.+), at 1,3′-indol]-4-yl)pyrrolidin- 4.01 (m, 3 H), 7.03-7.07 (m, 2 H), 7.27-7.33 (m, 2 H), 7.48 (d, 1.70 min, 3-yl]carbamate J = 7.5 Hz, 1 H) UV active  2-14 Isomer 2: ethyl 4-{(3S)-3- 13 c (400 MHz, DMSO-d.sub.6) □: 1.16 (t, J = 7.0 Hz, 3 H), 1.34 (t, J = F m/z 430 [(ethoxycarbonyl)amino] and 7.0 Hz, 3 H), 1.59-1.83 (m, 4 H), 1.95-2.11 (m, 2 H), 2.21-2.43 (M + H).sup.+ pyrrolidin-1-yl]}-2′- 87 (m, 6 H), 2.60-2.73 (m, 2 H), 2.79-2.84 (m, 1 H), 3.96-4.00 (ES.sup.+), at oxospiro[cyclohexane- 87 (m, 3 H), 4.37 (q, J = 7.0 Hz, 2 H), 7.21-7.38 (m, 3 H), 7.52 1.82 min, 1,3′-indole]-1′(2′H)- (d, J = 7.5 Hz, 1 H), 7.85 (d, J = 7.5 Hz, 1 H) UV active carboxylate  2-15 Isomer 1: ethyl {(3S)-1- 13 c (400 MHz DMSO-d.sub.6) □: 1.16 (t, J = 7.0 Hz, 3 H), 1.61-1.70 (m, G m/z 415 [1′-(2-amino-2-oxoethyl)- and 7 H), 1.95-2.13 (m, 3 H), 2.21-2.31 (m, 1 H), 2.37-2.44 (m, 1 (M + H).sup.+ 2′-oxo-1′,2′- 88 H), 2.58-2.66 (m, 2 H), 2.84-2.88 (m, 1 H), 3.96-4.01 (m, 3 (ES.sup.+), at dihydrospiro[cyclohexane- H), 4.26 (s, 2 H), 6.89 (d, J = 8.0 Hz, 1 H), 7.04 (t, J = 7.5 Hz, 1 4.40 min, 1,3′-indol]-4-yl]pyrrolidin- H), 7.23-7.32 (m, 3 H), 7.48 (d, J = 7.5 Hz, 1 H), 7.62 (s, 1 H) UV active 3-yl}carbamate  2-15 Isomer 2: ethyl {(3S)-1- 13 c (400 MHz, DMSO-d.sub.6) □: 1.16 (t, J = 7.0 Hz, 3 H), 1.54-1.84 (m, G m/z 415 [1′-(2-amino-2-oxoethyl)- and 7 H), 1.91-2.12 (m, 3 H), 2.19-2.28 (m, 1 H), 2.35-2.43 (m, 1 (M + H).sup.+ 2′-oxo-1′,2′- 88 H), 2.56-2.66 (m, 2 H), 2.77-2.90 (m, 1 H), 3.95-4.00 (m, 3 (ES.sup.+), at dihydrospiro[cyclohexane- H), 4.23 (s, 2 H), 6.83 (d, J = 7.5 Hz, 1 H), 7.01 (t, J = 7.5 Hz, 1 4.88 min, 1,3′-indol]-4-yl]pyrrolidin- H), 7.19-7.35 (m, 4 H), 7.61 (s, 1 H) UV active 3-yl}carbamate  2-16 Isomer 1: ethyl [(3S)-1- 13 c (400 MHz, (MSO-d.sub.6, D.sub.2O wash) □: 1.15 (t, J = 7.0 Hz, 3 H), F m/z 360 (2′-oxo-1′,2′- and 1.53-1.79 (m, 7 H), 2.21-2.36 (m, 2 H), 2.59-2.73 (m, 5 H), (M + H).sup.+ dihydrospiro[cyclohexane- 90 2.89-2.97 (m, 1 H), 3.92-4.03 (m, 3 H), 6.97 (dd, J = 7.5, 5.5 Hz, (ES.sup.+), at 1,3′-pyrrolo[2,3- 1 H), 7.24-7.29 (m, 1 H), 7.82 (d, J = 7.5 Hz, 1 H), 8.08 (d, J = 1.48 min, b]pyridin]-4-yl)pyrrolidin- 5.5 Hz, 1 H). UV active 3-yl]carbamate  2-17 Isomer 1: ethyl [(3S)-1- 13 c (400 MHz, DMSO-d.sub.6) □: 1.16 (t, J = 7.0 Hz, 3 H), 1.47-1.77 (m, F m/z 393 (5′-chloro-2′-oxo-1′,2′- and 6 H), 1.94-2.12 (m, 3 H), 2.14-2.26 (m, 1 H), 2.36-2.45 (m, 1 (M + H).sup.+ dihydrospiro[cyclohexane- 93 H), 2.55-2.63 (m, 2 H), 2.64-2.73 (m, 1 H), 2.78-2.90 (m, 1 (ES.sup.+), at 1,3′-pyrrolo[2,3- 93 H), 3.91-4.09 (m, 3 H), 2.28 (d, J = 6.5 Hz, 1 H), 7.77 (s, 1 H), 1.61 min, b]pyridin]-4-yl)pyrrolidin- 8.16 (d, J = 2.0 Hz, 1 H), 11.24 (s, 1 H) UV active 3-yl]carbamate  2-18 Isomer 1: ethyl 84 c (400 MHz, DMSO-d.sub.6) □: 1.19 (t, J = 7.0 Hz, 3 H), 1.55-1.77 (m, G m/z 373 methyl[(3R)-1-(2′-oxo- and 7 H), 1.98-2.09 (m, 3 H), 2.34-2.38 (m, 1 H), 2.44-2.48 (m, 1 (M + H).sup.+ 1′,2′- 90 H), 2.56-2.63 (m, 2 H), 2.68-2.72 (m, 1 H), 2.84-2.92 (m, 4 (ES.sup.+), at dihydrospiro[cyclohexane- H), 4.03 (q, J = 7.0 Hz, 2 H), 6.98 (dd, J = 7.5, 5.5 Hz, 1 H), 4.68 min, 1,3′-pyrrolo[2,3- 7.71-7.73 (m, 1 H), 8.08 (dd, J = 5.5, 1.5 Hz, 1 H), 11.01 UV active b]pyridin]-4-yl)pyrrolidin- (s, 1 H) 3-yl]carbamate  2-18 Isomer 2: ethyl 84 c (400 MHz, DMSO-d.sub.6, D.sub.2O wash) □: 1.17 (t, J = 7.0 Hz, 3 H), G m/z 373 methyl[(3R)-1-(2′-oxo- and 1.43-1.59 (m, 2 H), 1.64-2.09 (m, 7 H), 2.18-2.36 (m, 2 H), (M + H).sup.+ 1′,2′- 90 2.40-2.47 (m, 1 H), 2.54-2.61 (m, 2 H), 2.64-2.71 (m, 1 H), (ES.sup.+), at dihydrospiro[cyclohexane- 2.78-2.92 (m, 4 H), 4.01 (q, J = 7.0 Hz, 2 H), 6.95 (dd, J = 7.0, 5.11 min, 1,3′-pyrrolo[2,3- 5.5 Hz, 1 H), 7.74-7.76 (m, 1 H), 8.03-8.04 (m, 1 H) UV active b]pyridin]-4-yl)pyrrolidin- 3-yl]carbamate  2-19 Isomer 1: ethyl [(3S)-1- 13 g (400 MHz, CDCl.sub.3)□□: 1.27-1.31 (m, 4 H), 1.67-1.85 (m, 5 H), L m/z 389 (5′-methoxy-2′-oxo-1′,2′- and 1.96-2.20 (m, 6 H), 2.7-2.87 (m, 1 H), 3.32-3.77 (m, 4 H), (M + H).sup.+ dihydrospiro[cyclohexane- 95 3.93 (s, 3 H), 4.16 (q, J = 7.0 Hz, 2 H), 7.03 (s, 1 H), 7.35 (s, 1 (ES.sup.+), at 1,3′-pyrrolo[2,3- H), 7.77 (s, 1 H) 4.00 min, c]pyridin]-4-yl)pyrrolidin- UV active 3-yl]carbamate  2-20 Isomer 1: ethyl [(3S)-1- 13 c (400 MHz, DMSO-d.sub.6) □: 1.15 (t, J = 7.0 Hz, 3 H), 1.55-1.82 (m, F m/z 389 (5′-methoxy-2′-oxo-1′,2′- and 7 H), 1.98-2.16 (m, 3 H), 2.26-2.31 (m, 1 H), 2.35-2.39 (m, 1 (M + H).sup.+ dihydrospiro[cyclohexane- 97 H), 2.62-2.65 (m, 2 H), 2.92 (t, J = 8.0 Hz, 1 H), 3.82 (s, 3 H), (ES.sup.+), at 1,3′-pyrrolo[3,2- 3.88-4.05 (m, 3 H), 6.65 (d, J = 8.5 Hz, 1 H), 7.21-7.24 (m, 2 1.64 min, b]pyridin]-4-yl)pyrrolidin- H), 10.30 (s, 1 H) UV active 3-yl]carbamate  2-21 Isomer 2: ethyl 84 c (400 MHz, DMSO-d.sub.6) □: 1.19 (t, J = 7.0 Hz, 3 H), 1.60-1.79 (m, F m/z 373 methyl[(3R)-1-(2′-oxo- and 5 H), 1.85-2.22 (m, 6 H), 2.30-2.41 (m, 1 H), 2.56-2.70 (m, 3 (M + H).sup.+ 1′,2′- 99 H), 2.82-2.91 (m, 4 H), 4.03 (q, J = 7.0 Hz, 2 H), 7.19 (m, 2 H), (ES.sup.+), at dihydrospiro[cyclohexane- 8.10-8.12 (m, 1 H), 10.57 (s, 1 H) 1.64 min, 1,3′-pyrrolo[3,2- UV active b]pyridin]-4-yl)pyrrolidin- 3-yl]carbamate  3-1 Mixture of isomers: ethyl 12 a (400 MHz, CDCl.sub.3) δ: 1.27 (t, J = 7.0 Hz, 3 H), 1.75-1.98 (m, 8 B m/z 356 4-(4-cyano-4- and H), 2.22-2.24 (m, 2 H), 2.58-2.64 (m, 1 H), 2.70-2.82 (m, 4 (M + H).sup.+ phenylcyclohexyl)-1,4- 32 H), 3.46-3.56 (m, 4 H), 4.15 (q, J = 7.0,2 H), 7.28-7.33 (m, 1 (ES.sup.+), at diazepane-1-carboxylate H), 7.35-7.42 (m, 2 H), 7.47-7.51 (m, 2 H). 4.25 and 4.50 min, UV active  3-2 Mixture of isomers: ethyl 20 a (400 MHz, DMSO-d.sub.6) δ: 1.18 (t, J = 7.0,3 H), 1.61-1.72 (m, 4 B m/z 374 4-[4-cyano-4-(3- and H), 1.86-1.96 (m, 4 H), 2.04-2.09 (m, 2 H), 2.61-2.72 (m, 5 (M + H).sup.+ fluorophenyl)cyclohexyl]- 32 H), 3.38-3.42 (m, 4 H), 4.04 (q, J = 7.02, 2 H), 7.19-7.24 (m, 1 (ES.sup.+), at 1,4-diazepane-1- H), 7.36-7.40 (m, 2 H), 7.46-7.54 (m, 1 H). 2.54 and carboxylate 2.68 min, UV active  3-3 Mixture of isomers: ethyl 21 a (400 MHz, CDCl.sub.3) δ: 1.26 (t, J = 7.0, 3 H), 1.76-1.98 (m, 8 H), B m/z 374 4-[4-cyano-4-(4- and 2.20-2.23 (m, 2 H), 2.55-2.65 (m, 1 H), 2.68-2.81 (m, 4 H), (M + H).sup.+ fluorophenyl)cyclohexyl]- 32 3.46-3.53 (m, 4 H), 4.14 (q, J = 7.0, 2 H), 7.05-7.11 (m, 2 H), (ES.sup.+), at 1,4-diazepane-1- 7.43-7.47 (m, 2 H). 2.49 and carboxylate 2.67 min, UV active  3-4 Mixture of isomers: ethyl 32 a (400 MHz, CDCl.sub.3) δ: 1.27 (t, J = 7.0 Hz, 3 H), 1.75-1.98 (m, 8 A m/z 390 4-[4-cyano-4-(2- and H), 2.57-2.61 (m, 3 H), 2.72-2.83 (m, 4 H), 3.47-3.55 (m, 4 (M + H).sup.+ chlorophenyl)cyclohexyl]- 35 H), 4.15 (q, J = 7.0, 2 H), 7.29-7.33 (m, 2 H), 7.43-7.46 (m, 2 (ES.sup.+), at 1,4-diazepane-1- H). 1.79 and carboxylate 1.89 min, UV active  3-5 Mixture of isomers: ethyl 24 a (400 MHz, DMSO-d.sub.6) δ: 1.18 (t, J = 7.0,3 H), 1.60-1.70 (m, 4 B m/z 390 4-[4-cyano-4-(3- and H), 1.86-1.97 (m, 4 H), 2.03-2.05 (m, 2 H), 2.62-2.73 (m, 5 (M + H).sup.+ chlorophenyl)cyclohexyl]- 32 H), 3.38-3.43 (m, 4 H), 4.04 (q, J = 7.0, 2 H), 7.43-7.49 (m, 4 (ES.sup.+), at 1,4-diazepane-1- H). 2.48 and carboxylate 2.72 min, UV active  3-6 Mixture of isomers: ethyl 32 a (400 MHz, DMSO-d.sub.6) δ: 1.18 (t, J = 7.0, 3 H), 1.60-1.70 (m, 4 B m/z 390 4-[4-cyano-4-(4- and H), 1.87-1.94 (m, 4 H), 2.09-2.10 (m, 2 H), 2.62-2.73 (m, 5 (M + H).sup.+ chlorophenyl)cyclohexyl]- 36 H), 3.38-3.41 (m, 4 H), 4.03 (q, J = 7.02,2 H), 7.46-7.56 (m, 4 (ES.sup.+), at 1,4-diazepane-1- H). 2.68 and carboxylate 2.86 min, UV active  3-7 Mixture of isomers: ethyl 22 a (400 MHz, CDCl.sub.3) δ: 1.27 (t, J = 7.0 Hz, 3 H), 1.77-1.97 (m, 8 B m/z 370 4-[4-cyano-4-(2- and H), 2.43-2.46 (m, 2 H), 2.57-2.63 (m, 1 H), 2.64 (s, 3 H), 2.67- (M + H).sup.+ methylphenyl)cyclohexyl- 32 2.84 (m, 4 H), 3.47-3.55 (m, 4 H), 4.15 (q, J = 7.0 Hz, 2 H), 7.20- (ES.sup.+), at 1,4-diazepane-1- 7.29 (m, 4 H). 2.57 min, carboxylate UV active  3-8 Mixture of isomers: ethyl 23 a (400 MHz, CDCl.sub.3) δ: 1.27 (t, J = 7.0 Hz, 3 H), 1.77-1.97 (m, 8 B m/z 370 4-[4-cyano-4-(3- and H), 2.20-2.23 (m, 2 H), 2.37 (s, 3 H), 2.58-2.62 (m, 1 H), 2.72- (M + H).sup.+ methylphenyl)cyclohexyl- 32 2.82 (m, 4 H), 3.47-3.54 (m, 4 H), 4.14 (q, J = 7.0 Hz, 2 H), 7.12- (ES.sup.+), at 1,4-diazepane-1- 7.17 (m, 1 H), 7.25-7.29 (m, 3 H). 2.35 and carboxylate 2.48 min, UV active  3-9 Mixture of isomers: ethyl 32 a (400 MHz, DMSO-d.sub.6) δ: 1.18 (t, J = 7.0 Hz, 3 H), 1.60-1.72 (m, B m/z 386 4-[4-cyano-4-(4- and 4 H), 1.83-1.91 (m, 4 H), 2.09-2.12 (m, 3 H), 2.62-2.71 (m, 5 (M + H).sup.+ methoxyphenyl)cyclo- 37 H), 3.38-3.41 (m, 4 H), 3.76 (s, 3 H), 4.04 (q, J = 7.02, 2 H), (ES.sup.+), at hexyl]-1,4-diazepane-1- 6.96-7.02 (m, 2 H), 7.42-7.44 (m, 2 H). 2.47 and carboxylate 2.60 min, UV active  3-10 Mixture of isomers: ethyl 32 a (400 MHz, CDCl.sub.3) δ: 1.27 (t, J = 6.8 Hz, 3 H), 1.78-1.97 (m, 8 E m/z 424 4-{4-cyano-4-[2 and H), 2.42-2.78 (m, 7 H), 3.46-3.64 (m, 4 H), 4.14-4.16 (m, 2 (M + H).sup.+ (trifluoromethyl)phenyl] 38 H), 7.49-7.52 (m, 1 H), 7.57-7.59 (m, 1 H), 7.66-7.69 (m, 1 (ES.sup.+), at cyclohexyl}-1,4- H), 7.80-7.82 (m, 1 H). 5.11 min, diazepane-1-carboxylate UV active  3-11 Mixture of isomers: ethyl 26 a (400 MHz, CDCl.sub.3) δ: 1.21-1.28 (m, 3 H), 1.75-1.88 (m, 4 H), B m/z 357 4-[4-cyano-4-(pyridin-2- and 1.95-1.99 (m, 2 H), 2.07-2.21 (m, 3 H), 2.53-2.68 (m, 2 H), (M + H).sup.+ yl)cyclohexyl]-1,4- 32 2.69-2.82 (m, 4 H), 3.46-3.55 (m, 4 H), 4.14 (m, 2 H), 7.23- (ES.sup.+), at diazepane-1-carboxylate 7.26 (m, 1 H), 7.53-7.62 (m, 1 H), 7.71-7.74 (m, 1 H), 8.58- 3.33 and 8.64 (m, 1 H). 3.49 min, UV active  3-12 Mixture of isomers: ethyl 32 a (400 MHz, CDCl.sub.3) δ: 1.27 (t, J = 6.8 Hz, 3 H), 1.647-1.99 (m, 8 E m/z 357 4-[4-cyano-4-(pyridin-4- and H), 2.19-2.26 (m, 2 H), 2.65-2.93 (m, 5 H), 3.49-3.56 (m, 4 (M + H).sup.+ yl)cyclohexyl]-1,4- 40 H), 4.13-4.16 (m, 2 H), 7.37-7.39 (m, 2 H), 8.64-8.66 (m, 2 (ES.sup.+), at diazepane-1-carboxylate H). 4.10 min, UV active  3-13 Isomer 1: ethyl 4-[4-(3- 32 a (400 MHz, CDCl.sub.3) δ: 1.25-1.27 (m, 3 H), 1.78-2.16 (m, 10 H), B m/z 391 chloropyridin-2-yl)-4- and 2.55-2.79 (m, 5 H), 3.48-3.61 (m, 4 H), 4.13-4.17 (m, 2 H), (M + H).sup.+ cyanocyclohexyl]-1,4- 41 7.26-7.27 (m, 1 H), 7.74-7.76 (m, 1 H), 8.46-8.49 (m, 1 H). (ES.sup.+), at diazepane-1-carboxylate 3.88 min, UV active  3-14 Mixture of isomers: ethyl 29 a (400 MHz, DMSO-d.sub.6) δ: 1.16-1.24 (m, 3 H), 1.61-1.68 (m, 5 H), C m/z 371 4-[4-(4-methylpyridin-2- and 1.85-2.01 (m, 3 H), 2.13-2.18 (m, 1 H), 2.36 (s, 1.5 H), 2.38 (s, (M + H).sup.+ yl)-4-cyanocyclohexyl]- 32 1.5 H), 2.58-2.77 (m, 6 H), 3.38-3.44 (m, 4 H), 3.95-4.03 (m, (ES.sup.+), at 1,4-diazepane-1- 2 H), 7.20-7.23 (m, 1 H), 7.41-7.46 (m, 1 H), 8.43-8.48 (m, 1 1.81 min, carboxylate H). UV active  3-15 Mixture of isomers: ethyl 27 e (400 MHz, DMSO-d.sub.6) δ: 1.27 (t, J = 7.0 Hz, 3 H), 1.57-1.77 (m, B m/z 375 4-[4-(5-fluoropyridin-2-yl)- and 4 H), 1.85-2.03 (m, 4 H), 2.12-2.21 (m, 2 H), 2.59-2.74 (m, 5 (M + H).sup.+ 4-cyanocyclohexyl]-1,4- 31 H), 3.38-3.42 (m, 4 H), 4.03 (q, J = 7.0 Hz, 2 H), 7.66-7.70 (m, (ES.sup.+), at diazepane-1-carboxylate 1 H), 7.80-7.86 (m, 1 H), 8.61-8.63 (m, 1 H). 3.64 min, UV active  3-16 Mixture of isomers: ethyl 28 a (400 MHz, DMSO-d.sub.6) δ: 1.15-1.23 (m, 3 H), 1.58-1.69 (m, 4 H), B m/z 391 4-[4-(5-chloropyridin-2- and 1.85-1.99 (m, 4 H), 2.14-2.19 (m, 2 H), 2.59-2.73 (m, 5 H), (M + H).sup.+ yl)-4-cyanocyclohexyl]- 32 3.38-3.45 (m, 4 H), 4.00-4.05 (m, 2 H), 7.63-7.65 (m, 1 H), (ES.sup.+), at 1,4-diazepane-1- 8.01-8.04 (m, 1 H), 8.65-8.67 (m, 1 H). 4.06 min, carboxylate UV active  3-17 Isomer 1: ethyl 4-[4-(5- 32 a (400 MHz, DMSO-d.sub.6) δ: 1.18 (t, J = 7.0 Hz, 3 H), 1.55-1.75 (m, B m/z 435 bromopyridin-2-yl)-4- and 4 H), 1.83-2.02 (m, 4 H), 2.09-2.24 (m, 2 H), 2.57-2.66 (m, 2 and 437 cyanocyclohexyl]-1,4- 42 H), 2.67-2.80 (m, 2 H), 3.35-3.44 (m, 5 H), 4.03 (q, J = 7.0 Hz, (M + H).sup.+ diazepane-1-carboxylate 2 H), 7.59 (dd, J = 8.5, 0.8 Hz, 1 H), 8.15 (dd, J = 8.5, 2.5 Hz, 1 (ES.sup.+), at H), 8.75 (dd, J = 2.5, 0.8 Hz, 1 H). 4.15, UV active  3-18 Mixture of isomers: ethyl 32 a (400 MHz, DMSO-d.sub.6) δ: 1.18 (t, J = 7.2 Hz, 3 H), 1.56-1.68 (m, B m/z 371 4-[4-(5-methylpyridin-2- and 4 H), 1.85-2.01 (m, 4 H), 2.11-2.16 (m, 2 H), 2.29 (s, 3 H), (M + H).sup.+ yl)-4-cyanocyclohexyl]- 43 2.57-2.75 (m, 5 H), 3.38-3.44 (m, 4 H), 4.02 (q, J = 7.2 Hz, 2 (ES.sup.+), at 1,4-diazepane-1- H), 7.44-7.48 (m, 1 H), 7.67-7.69 (m, 1 H), 8.40-8.43 (m, 1 4.31 and carboxylate H). 4.50 min, UV active  3-19 Isomer 2: ethyl 4-[4-(5- 32 a (400 MHz, DMSO-d.sub.6) δ: 1.12-1.16 (m, 3 H), 1.56-1.68 (m, 6 H), B m/z 387 methoxypyridin-2-yl)-4- and 1.88-1.95 (m, 2 H), 2.12-2.18 (m, 2 H), 2.56-2.70 (m, 5 H), (M + H).sup.+ cyanocyclohexyl]-1,4- 44 3.38-3.42 (m, 4 H), 3.86 (s, 3 H), 3.96-4.02 (m, 2 H), 7.45- (ES.sup.+), at diazepane-1-carboxylate 7.49 (m, 1 H), 7.55-7.59 (m, 1 H), 8.34-8.35 (m, 1 H). 3.66 min, UV active  3-20 Isomer 2: ethyl 4-[4- 32 a (400 MHz, DMSO-d.sub.6) δ: 1.16 (t, J = 7.0 Hz, 3 H), 1.34 (t, J = 7.0 B m/z 401 cyano-4-(5-ethoxypyridin- and Hz, 3 H), 1.58-1.67 (m, 4 H), 1.85-1.94 (m, 4 H), 2.14-2.18 (M + H).sup.+ 2-yl)cyclohexyl]-1,4- 45 (m, 2 H), 2.62-2.73 (m, 5 H), 3.30-3.41 (m, 4 H), 4.03 (q, J = (ES.sup.+), at diazepane-1-carboxylate 7.0 Hz, 2 H), 4.11 (q, J = 7.0 Hz, 2 H), 7.42-7.45 (m, 1 H), 7.48- 4.07 min, 7.51 (m, 1 H), 8.28-8.29 (m, 1 H). UV active  3-21 Mixture of isomers: ethyl 32 a (400 MHz, DMSO-d.sub.6) δ: 1.16 (t, J = 7.2 Hz, 3 H), 1.32-1.34 (m, B m/z 425 4-{4-cyano-4[5- and 2 H), 1.58-1.80 (m, 6 H), 1.98-2.03 (m, 2 H), 2.62-2.73 (m, 5 (M + H).sup.+ (trifluoromethyl)pyridin-2- 46 H), 3.30-3.41 (m, 4 H), 4.03 (q, J = 7.2 Hz, 2 H), 7.88-7.90 (m, (ES.sup.+), at yl]cyclohexyl}-1,4- 1 H), 8.32-8.35 (m, 1 H), 9.07 (s, 1 H). 4.31 and diazepane-1-carboxylate 4.50 min, UV active  3-22 Mixture of isomers: ethyl 30 a (400 MHz, CDCl.sub.3) δ: 1.22-1.27 (m, 3 H), 1.62-2.04 (m, 6 H), E m/z 371 4-[4-(6-methylpyridin-2- and 2.10-2.49 (m, 4 H), 2.53 (s, 2.4 H), 2.55 (s, 0.6 H), 2.62-2.85 (M + H).sup.+ yl)-4-cyanocyclohexyl]- 32 (m, 5 H), 3.42-3.56 (m, 4 H), 4.13-4.17 (m, 2 H), 7.05-7.09 (ES.sup.+), at 1,4-diazepane-1- (m, 1 H), 7.35-7.40 (m, 1 H), 7.56-7.60 (m, 1 H). 4.55 and carboxylate 4.63 min, UV active  3-23 Mixture of isomers: ethyl 32 a (400 MHz, CDCl.sub.3) δ: 1.24-1.28 (m, 3 H), 1.68-2.40 (m, 10 H), D m/z 425 4-{4-cyano-4[6- and 2.56-3.01 (m, 5 H), 3.38-3.54 (m, 4 H), 4.12-4.21 (m, 2 H), (M + H).sup.+ (trifluoromethyl)pyridin-2- 47 7.65-7.69 (m, 1 H), 7.83-7.87 (m, 1 H), 7.95-7.99 (m, 1 H). (ES.sup.+), at yl]cyclohexyl}-1,4- 6.11 and diazepane-1-carboxylate 6.22 min, UV active  3-24 Isomer 1: ethyl 4-[4- 32 a (400 MHz, CDCl.sub.3) δ: 1.27 ((t, J = 7.2 Hz, 3 H), 1.70-2.01 (m, 8 B m/z 362 cyano-4-(thiophen-2- and H), 2.38-2.48 (m, 2 H), 2.53-2.85 (m, 5 H), 3.44 (m, 4 H), 4.15 (M + H).sup.+ yl)cyclohexyl]-1,4- 48 (q, J = 7.2 Hz, 2 H), 6.97-6.99 (m, 1 H), 7.11-7.14 (m, 1 H), (ES.sup.+), at diazepane-1-carboxylate 7.27-7.28 (m, 1 H). 4.03 min, UV active  3-25 Mixture of isomers: ethyl 12 a (400 MHz, CDCl.sub.3) δ: 1.09-1.26 (m, 3 H), 1.47-1.70 (m, 2 H), B m/z 374 4-(4-cyano-4- and 1.73-1.99 (4 H, m), 2.08 (d, J = 11.9, 2 H), 2.58-2.72 (m, 2 H), (M + H).sup.+ phenylcyclohexyl)-6- 34 2.72-3.02 (m, 3 H), 3.24-3.36 (m, 1 H), 3.36-3.60 (m, 2 H), (ES.sup.+), at fluoro-1,4-diazepane-1- 3.71 (qd, J = 14.8, 5.0, 1 H), 4.01 (d, J = 11.9, 2 H), 4.56-4.86 4.56 min, carboxylate (m, 1 H), 7.21-7.35 (m, 1 H), 7.35-7.44 (m, 2 H), 7.44-7.56 UV active (m, 2 H).  3-26 Mixture of isomers: ethyl 12 a (400 MHz, CDCl.sub.3) δ: 1.21-1.33 (m, 5 H), 1.81-2.08 (m, 6 H), B m/z 372 4-(4-cyano-4- and 2.19-2.31 (m, 2 H), 2.60-2.89 (m, 4 H), 2.91-3.02 (m,1 H), (M + H).sup.+ phenylcyclohexyl)-6- 33 3.42-3.72 (m, 3 H), 3.89-4.00 (m, 1 H), 4.15 (qd, J = 6.9, 2.8 (ES.sup.+), at hydroxy-1,4-diazepane- Hz, 2 H), 7.30-7.36 (m, 1 H), 7.39 ( t, J = 7.5 Hz, 2 H) 7.46- 3.66 min, 1-carboxylate 7.51 (m, 2 H) UV active  3-27 Mixture of isomers: ethyl 28 a (400 MHz, DMSO-d.sub.6) δ: 1.04-1.28 (m, 3 H), 1.46-1.76 (m, 3 H), B m/z 409 4-[4-(5-chloropyridin-2- and 1.83-2.07 (m, 3 H), 2.18-2.20 (m, 1 H), 2.51-2.87 (m, 7 H), (M + H).sup.+ yl)-4-cyanocyclohexyl]-6- 34 3.36-3.63 (m, 2 H), 3.65-3.78 (m, 1 H), 3.90-4.13 (m, 2 H), (ES.sup.+), at fluoro-1,4-diazepane-1- 4.52-4.83 (m, 1 H), 7.56-7.76 (m, 1 H), 8.05 (ddd, J = 8.6, 6.2, 4.36 min, carboxylate 2.8 Hz, 1 H), 8.69 (dd, J = 17.3, 2.3 Hz, 1 H). UV active  3-28 Mixture of isomers: 12, 31 d (400 MHz, CDCl.sub.3) δ: 1.61-2.01 (m, 7 H), 2.10-2.50 (m, 3 H), B m/z 342 methyl 4-(4-cyano-4- and 2.62-3.02 (m, 4 H), 3.24-3.61 (m, 4 H), 3.71 (s, 3 H), 7.32- (M + H).sup.+ phenylcyclohexyl)-1,4- 56 7.53 (m, 5 H). (ES.sup.+), at diazepane-1-carboxylate 3.78 min, UV active  3-29 Mixture of isomers: 2- 12, 31 d (400 MHz, CDCl.sub.3) δ: 1.53-2.41 (m, 11 H), 2.60-3.11 (m, 4 H), B m/z 374 fluoroethyl 4-(4-cyano-4- and 3.47-3.73 (m, 4 H), 4.40 (d, J = 29.2, 2 H), 4.64 (d, J = 47.6, 2 (M + H).sup.+ phenylcyclohexyl)-1,4- 64 H), 7.32-7.53 (m, 5 H). (ES.sup.+), at diazepane-1-carboxylate 3.98 min, UV active  3-30 Isomer 1: but-2-yn-1-yl 4- 31, 40 e (400 MHz, DMSO-d.sub.6) δ: 1.50-1.71 (m, 4 H), 1.80 (s, 3 H), 1.85- B m/z 381 [4-cyano-4-(pyridin-4- and 1.95 (m, 4 H), 2.11-2.16 (m, 2 H), 2.62-2.74 (m, 5 H), 3.39- (M + H).sup.+ yl)cyclohexyl]-1,4- 58 3.43 (m, 4 H), 4.63-4.65 (m, 2 H), 7.54-7.56 (m, 2 H), 8.62- (ES.sup.+), at diazepane-1-carboxylate 8.64 (m, 2 H). 3.28 min, UV active  3-31 Isomer 1: prop-2-yn-1-yl 31, 44 e (400 MHz, DMSO-d.sub.6) δ: 1.55-1.71 (m, 4 H), 1.84-1.95 (m, 4 H), C m/z 397 4-[4-cyano-4-(5- and 2.14-2.19 (m, 2 H), 2.58-2.76 (m, 5 H), 3.39-3.52 (m, 4 H), (M + H).sup.+ methoxypyridin-2- 57 3.84 (s, 3 H), 4.58-4.61 (m, 1 H), 4.67-4.68 (m, 2 H), 7.43- (ES.sup.+), at yl)cyclohexyl]-1,4- 7.47 (m, 1 H), 7.50-7.53 (m, 1 H), 8.30-8.31 (m, 1 H). 5.82 min, diazepane-1-carboxylate UV active  3-32 Isomer 1: but-2-yn-1-yl 4- 31, 49 a (400 MHz, DMSO-d.sub.6) δ: 1.59-1.70 (m, 4 H), 1.82-1.83 (m, 3 H), B m/z 411 [4-cyano-4-(5- and 1.83-1.95 (m, 4 H), 2.14-2.19 (m, 2 H), 2.58-2.74 (m, 5 H), (M + H).sup.+ methoxypyridin-2- 58 3.39-3.44 (m, 4 H), 3.84 (s, 3 H), 4.62-4.64 (m, 2 H), 7.43- (ES.sup.+), at yl)cyclohexyl]-1,4- 7.47 (m, 1 H), 7.50-7.53 (m, 1 H), 8.30-8.31 (m, 1 H). 3.80 min, diazepane-1-carboxylate UV active  3-33 Isomer 2: ethyl 4-[4- 32 a (400 MHz, CDCl.sub.3) δ: 1.26 (t, J = 7.2 Hz, 3 H), 1.60-2.00 (m, 10 B m/z 389 (methoxycarbonyl)-4- and H), 2.50-2.85 (m, 5 H), 3.42-3.58 (m, 4 H), 3.66 (s, 3 H), 4.14 (M + H).sup.+ phenylcyclohexyl]-1,4- 49 (q, J = 7.0 Hz, 2 H), 7.22-7.24 (m, 1 H), 7.28-7.36 (m, 4 H). (ES.sup.+), at diazepane-1-carboxylate 4.36 min, UV active  3-34 Mixture of isomers: ethyl 32 a (400 MHz, CDCl.sub.3) δ: 1.23-1.28 (m, 3 H), 1.62-2.08 (m, 10 H), D m/z 424 4-[4-(3-chloropyridin-2- and 2.48-2.79 (m, 5 H), 3.42-3.56 (m, 4 H), 3.64 (s, 1.4 H), 3.68 (s, (M + H).sup.+ yl)-4- 50 1.6 H), 4.12-4.16 (m, 2 H), 7.15-7.19 (m, 1 H), 7.61-7.64 (m, (ES.sup.+), at (methoxycarbonyl)cyclo- 1 H), 8.44-8.51 (m, 1 H). 5.49 and hexyl]-1,4-diazepane-1- 5.54 min, carboxylate UV active  4-1 Isomer 2: methyl 4- 65 c (400 MHz, DMSO-d.sub.6) □: 1.51-1.82 (m, 8 H), 2.06-2.19 (m, 2 P m/z 358 (2′-oxo-1′,2′- and H), 2.61-2.78 (m, 5 H), 3.39-3.43 (m, 4 H), 3.59 (s, 3 H), 6.78 (M + H).sup.+ dihydrospiro[cyclohexane- 104 (d, J = 7.5 Hz, 1 H), 6.94 (t, J = 7.5 Hz, 1 H), 7.13 (t, J = 7.5 Hz, (ES.sup.+), at 1,3′-indol]-4-yl)-1,4- 1 H), 7.21 (d, J = 7.5 Hz, 1 H), 10.26 (s, 1 H) 1.86 min, diazepane-1-carboxylate UV active  4-2 Isomer 1: ethyl 4- 32 c (400 MHz, DMSO-d.sub.6) □: 1.18 (t, J = 7.0 Hz, 3 H), 1.42-1.53 (m, P m/z 372 (2′-oxo-1′,2′- and 2 H), 1.67-1.82 (m, 8 H), 2.62-2.86 (m, 5 H), 3.39-3.48 (m, 4 (M + H).sup.+ dihydrospiro[cyclohexane- 65 H), 4.04 (q, J = 7.0 Hz, 2 H), 6.88 (d, J = 7.5 Hz, 1 H), 6.98 (t, J = (ES.sup.+), at 1,3′-indol]-4-yl)-1,4- 7.5 Hz, 1 H), 7.22 (t, J = 7.5 Hz, 1 H), 7.50 (d, J = 7.5 Hz, 1 H), 1.90 min, diazepane-1-carboxylate 10.42 (s, 1 H) UV active  4-2 Isomer 1: ethyl 4- 32 c (400 MHz, DMSO-d.sub.6) □: 1.18 (t, J = 7.0 Hz, 3 H), 1.51-1.60 (m, P m/z 372 (2′-oxo-1′,2′- and 2 H), 1.62-1.83 (m, 6 H), 2.06-2.19 (m, 2 H), 2.61-2.78 (m, 5 (M + H).sup.+ dihydrospiro[cyclohexane- 65 H), 3.38-3.42 (m, 4 H), 4.04 (q, J = 7.0 Hz, 2 H), 6.79 (d, J = 7.5 (ES.sup.+), at 1,3′-indol]-4-yl)-1,4- Hz, 1 H), 6.94 (t, J = 7.5 Hz, 1 H), 7.13 (t, J = 7.5 Hz, 1 H), 7.20 1.94 min, diazepane-1-carboxylate (d, J = 7.5 Hz, 1 H), 10.26 (s, 1 H) UV active  4-3 Isomer 2: 4-(4-butanoyl- 65 c (400 MHz, DMSO-d.sub.6) □: 0.89 (t, J = 7.5 Hz, 3 H), 1.37-1.80 (m, P m/z 370 1,4-diazepan-1- and 11 H), 2.05-2.34 (m, 4 H), 2.59-2.84 (m, 4 H), 3.42-3.55 (m, (M + H).sup.+ yl)spiro[cyclohexane-1,3′- 105 4 H), 6.79 (d, J = 7.5 Hz, 1 H), 6.94 (t, J = 7.5 Hz, 1 H), 7.14 (t, (ES.sup.+), at indol]-2′(1′H)-one J = 7.5 Hz, 1 H), 7.21 (d, J = 7.5 Hz, 1 H), 10.26 (s, 1 H) 1.92 min, UV active  4-4 Isomer 2: 4-{4-[(2E)-but- 65 c (400 MHz, MeOD-d.sub.4) □: 1.72-1.96 (m, 11 H), 2.24-2.34 (m, 2 F m/z 368 2-enoyl]-1,4-diazepan-1- and H), 2.76-2.83 (m, 3 H), 2.92-2.96 (m, 2 H), 3.60-3.71 (m, 4 (M + H).sup.+ yl}spiro[cyclohexane-1,3′- 107 H), 6.44-6.49 (m, 1 H), 6.81-6.91 (m, 2 H), 7.01 (t, J = 7.5 Hz, (ES.sup.+), at indol]-2′(1′H)-one 1 H), 7.18 (t, J = 8.0 Hz, 2 H) 1.62 min, UV active  4-5 Isomer 2: ethyl 4-(7′- 32 c (400 MHz, DMSO-d.sub.6) □: 1.18 (t, J = 7.0 Hz, 3 H), 1.54-1.78 (m, F m/z 387 methyl-2′-oxo-1′,2′- and 8 H), 2.08-2.21 (m, 5 H), 2.74-2.66 (m, 5 H), 3.37-3.42 (m, 4 (M + H).sup.+ dihydrospiro[cyclohexane- 67 H), 4.03 (q, J = 7.0 Hz, 2 H), 6.85 (t, J = 7.5 Hz, 1 H), 6.95 (d, J = (ES.sup.+), at 1,3′-indol]-4-yl)-1,4- 7.5 Hz, 1 H), 7.01 (d, J = 7.5 Hz, 1 H). NH not observed. 1.72 min, diazepane-1-carboxylate UV active  4-6 Isomer 1: ethyl 4-(6′- 32 c (400 MHz, DMSO-d.sub.6) □: 1.18 (t, J = 7.0 Hz, 3 H), 1.43-1.47 (m, F m/z 386 methyl-2′-oxo-1′,2′- and 2 H), 1.71-1.76 (m, 8 H), 2.28 (s, 3 H), 2.59-2.79 (m, 5 H), (M + H).sup.+ dihydrospiro[cyclohexane- 68 3.40-3.43 (m, 4 H), 4.04 (q, J = 7.0 Hz, 2 H), 6.70 (s, 1 H), 6.78 (ES.sup.+), at 1,3′-indol]-4-yl)-1,4- (d, J = 7.5 Hz, 1 H), 7.37 (d, J = 7.5 Hz, 1 H), 10.36 (s, 1 H) 1.72 min, diazepane-1-carboxylate UV active  4-6 Isomer 2: ethyl 4-(6′- 32 c (400 MHz, DMSO-d.sub.6) □: 1.18 (t, J = 7.0 Hz, 3 H), 1.53-1.77 (m, F m/z 386 methyl-2′-oxo-1′,2′- and 8 H), 2.05-2.16 (m, 2 H), 2.25 (s, 3 H), 2.65-2.73 (m, 5 H), (M + H).sup.+ dihydrospiro[cyclohexane- 68 3.37-3.42 (m, 4 H), 4.03 (q, J = 7.0 Hz, 2 H), 6.60 (s, 1 H), 6.74 (ES.sup.+), at 1,3′-indol]-4-yl)-1,4- (d, J = 7.5 Hz, 1 H), 7.07 (d, J = 7.5 Hz, 1 H), 10.20 (s, 1 H) 1.76 min, diazepane-1-carboxylate UV active  4-7 Isomer 1: ethyl 4-(5′- 32 c (400 MHz, DMSO-d.sub.6) □: 1.19 (t, J = 7.0 Hz, 3 H), 1.41-1.52 (m, F m/z 386 methyl-2′-oxo-1′,2′- and 2 H), 1.65-1.83 (m, 8 H), 2.30 (s, 3 H), 2.60-2.86 (m, 5 H), (M + H).sup.+ dihydrospiro[cyclohexane- 70 3.39-3.47 (m, 4 H), 4.05 (q, J = 7.0 Hz, 2 H), 6.77 (d, J = 8.0 (ES.sup.+), at 1,3′-indol]-4-yl)-1,4- Hz, 1 H), 7.02 (d, J = 8.0 Hz, 1 H), 7.28 (s, 1 H), 10.30 (s, 1 H) 1.69 min, diazepane-1-carboxylate UV active  4-7 Isomer 2: ethyl 4-(5′- 32 c (400 MHz, DMSO-d.sub.6) □: 1.18 (t, J = 7.0 Hz, 3 H), 1.54-1.77 (m, F m/z 386 methyl-2′-oxo-1′,2′- and 8 H), 2.07-2.16 (m, 2 H), 2.24 (s, 3 H), 2.61-2.79 (m, 5 H), (M + H).sup.+ dihydrospiro[cyclohexane- 70 3.37-3.42 (m, 4 H), 4.04 (q, J = 7.0 Hz, 2 H), 6.67 (d, J = 7.5 (ES.sup.+), at 1,3′-indol]-4-yl)-1,4- Hz, 1 H), 6.93 (d, J = 7.5 Hz, 1 H), 7.02 (s, 1 H), 10.15 (s, 1 H) 1.73 min, diazepane-1-carboxylate UV active  4-8 Isomer 1: ethyl 4-(4′- 32 c (400 MHz, MeOD-d.sub.4) □: 1.27-1.35 (m, 3 H), 1.74-1.86 (m, 4 F m/z 386 methyl-2′-oxo-1′,2′- and H), 2.30-2.47 (m, 8 H), 2.78-2.97 (m, 6 H), 3.53-3.60 (m, 4 (M + H).sup.+ dihydrospiro[cyclohexane- 72 H), 4.15 (q, J = 7.0 Hz, 2 H), 6.70 (d, J = 7.5 Hz, 1 H), 6.77 (d, (ES.sup.+), at 1,3′-indol]-4-yl)-1,4- J = 7.5 Hz, 1 H), 7.07 (t, J = 7.5 Hz, 1 H) 1.77 min, diazepane-1-carboxylate UV active  4-8 Isomer 2: ethyl 4-(4′- 32 c (400 MHz, MeOD-d.sub.4) □: 1.27-1.36 (m, 3 H), 1.84-1.93 (m, 4 F m/z 386 methyl-2′-oxo-1′,2′- and H), 2.38-2.54 (m, 8 H), 2.78-2.97 (m, 6 H), 3.54-3.61 (m, 4 (M + H).sup.+ dihydrospiro[cyclohexane- 72 H), 4.14-4.19 (m, 2 H), 6.68 (d, J = 8.0 Hz, 1 H), 6.78 (d, J = 8.0 (ES.sup.+), at 1,3′-indol]-4-yl)-1,4- Hz, 1 H), 7.05 (t, J = 8.0 Hz, 1 H) 1.77 min, diazepane-1-carboxylate UV active  4-9 Isomer 1: ethyl 4-(6′- 32 c (400 MHz, DMSO-d.sub.6) □: 1.18 (t, J = 7.0 Hz, 3 H), 1.47-1.50 (m, F m/z 390 fluoro-2′-oxo-1′,2′- and 2 H), 1.71-1.78 (m, 8 H), 2.61-2.85 (m, 5 H), 3.40-3.43 (m, 4 (M + H).sup.+ dihydrospiro[cyclohexane- 74 H), 4.04 (q, J = 7.0 Hz, 2 H), 6.69 (dd, J = 2.5 Hz, 1 H), 6.74- (ES.sup.+), at 1,3′-indol]-4-yl)-1,4- 6.79 (m, 1 H), 7.49-7.52 (m, 1 H), 10.57 (s, 1 H) 1.70 min, diazepane-1-carboxylate UV active  4-9 Isomer 2: ethyl 4-(6′- 32 c (400 MHz, DMSO-d.sub.6) □: 1.18 (t, J = 7.0 Hz, 3 H), 1.54-1.80 (m, F m/z 390 fluoro-2′-oxo-1′,2′- and 8 H), 2.05-2.14 (m, 2 H), 2.60-2.77 (m, 5 H), 3.37-3.41 (m, 4 (M + H).sup.+ dihydrospiro[cyclohexane- 74 H), 4.03 (q, J = 7.0 Hz, 2 H), 6.59 (dd, J = 9.0, 2.0 Hz, 1 H), 6.71- (ES.sup.+), at 1,3′-indol]-4-yl)-1,4- 6.76 (m, 1 H), 7.23 (dd, J = 8.0, 5.5 Hz, 1 H), 10.41 (br s, 1 H) 1.72 min, diazepane-1-carboxylate UV active  4-10 Isomer 1: ethyl 4-(5′- 32 c (400 MHz, DMSO-d.sub.6) □:1.18 (t, J = 7.0 Hz, 3 H), 1.49-1.52 (m, F m/z 390 fluoro-2′-oxo-1′,2′- and 2 H), 1.63-1.78 (m, 8 H), 2.63-2.80 (m, 5 H), 3.42-3.43 (m, 4 (M + H).sup.+ dihydrospiro[cyclohexane- 76 H), 4.04 (q, J = 7.0 Hz, 2 H), 6.87 (dd, J = 8.5, 4.5 Hz, 1 H), 7.04- (ES.sup.+), at 1,3′-indol]-4-yl)-1,4- 7.09 (m, 1 H), 7.29-7.31 (m, 1 H), 10.45 (s, 1 H) 1.68 min, diazepane-1-carboxylate UV active  4-10 Isomer 2: ethyl 4-(5′- 32 c (400 MHz, DMSO-d.sub.6) □: 1.18 (t, J = 7.0 Hz, 3 H), 1.49-1.85 (m, F m/z 390 fluoro-2′-oxo-1′,2′- and 8 H), 2.04-2.17 (m, 2 H), 2.61-2.78 (m, 5 H), 3.37-3.42 (m, 4 (M + H).sup.+ dihydrospiro[cyclohexane- 76 H), 4.04 (q, J = 7.0 Hz, 2 H), 6.76 (dd, J = 8.5, 4.5 Hz, 1 H), 6.93- (ES.sup.+), at 1,3′-indol]-4-yl)-1,4- 6.99 (m, 1 H), 7.18 (dd, J = 2.5, 8.5 Hz, 1 H), 10.28 (s, 1 H) 2.00 min, diazepane-1-carboxylate UV active  4-11 Isomer 1: ethyl 4-(6′- 32 c (400 MHz, DMSO-d.sub.6) □: 1.18 (t, J = 7.0 Hz, 3 H), 1.38-1.48 (m, F m/z 402 methoxy-2′-oxo-1′,2′- and 2 H), 1.63-1.80 (m, 8 H), 2.60-2.84 (m, 5 H), 3.40-3.51 (m, 4 (M + H).sup.+ dihydrospiro[cyclohexane- 78 H), 3.73 (s, 3 H), 4.04 (q, J = 7.0 Hz, 2 H), 6.45 (s, 1 H), 6.52 (d, (ES.sup.+), at 1,3′-indol]-4-yl)-1,4- J = 8.0 Hz, 1 H), 7.39 (d, J = 8.0 Hz, 1 H), 10.38 (s, 1 H) 1.72 min, diazepane-1-carboxylate UV active  4-11 Isomer 2: ethyl 4-(6′- 32 c (400 MHz, DMSO-d.sub.6) □: 1.18 (t, J = 7.0 Hz, 3 H), 1.53-1.76 F m/z 402 methoxy-2′-oxo-1′,2′- and (m,8 H), 2.05-2.15 (m, 2 H), 2.58-2.78 (m, 5 H), 3.38-3.41 (m, (M + H).sup.+ dihydrospiro[cyclohexane- 78 4 H), 3.71 (s, 3 H), 4.03 (q, J = 7.0 Hz, 2 H), 6.35 (d, J = 2.5 Hz, (ES.sup.+), at 1,3′-indol]-4-yl)-1,4- 1 H), 6.48 (dd, J = 2.5, 8.0 Hz, 1 H), 7.09 (d, J = 8.0 Hz, 1 H), 1.74 min, diazepane-1-carboxylate 10.21 (s, 1 H) UV active  4-12 Isomer 1: ethyl 4-(5′- 32 c (400 MHz, DMSO-d.sub.6) □: 1.18 (t, J = 7.0 Hz, 3 H), 1.44-1.53 F m/z 402 methoxy-2′-oxo-1′,2′- and 2 H), 1.65-1.83 (m, 8 H), 2.62-2.86 (m, 5 H), 3.40-3.52 (m, 4 (M + H).sup.+ dihydrospiro[cyclohexane- 80 H), 3.73 (s, 3 H), 4.04 (q, J = 7.0 Hz, 2 H), 6.80 (s, 2 H), 7.01 (s, (ES.sup.+), at 1,3′-indol]-4-yl)-1,4- 1 H), 10.27 (s, 1 H) 1.70 min, diazepane-1-carboxylate UV active  4-12 Isomer 2: ethyl 4-(5′- 32 c (400 MHz, DMSO-d.sub.6) □: 1.18 (t, J = 7.0 Hz, 3 H), 1.53-1.80 (m, F m/z 402 methoxy-2′-oxo-1′,2′- and 8 H), 2.08-2.16 (m, 2 H), 2.64-2.73 (m, 5 H), 3.38-3.41 (m, 4 (M + H).sup.+ dihydrospiro[cyclohexane- 80 H), 3.69 (s, 3 H), 4.03 (q, J = 7.0 Hz, 2 H), 6.69 (s, 2 H), 6.87 (s, (ES.sup.+), at 1,3′-indol]-4-yl)-1,4- 1 H), 10.08 (s, 1 H) 1.73 min, diazepane-1-carboxylate UV active  4-13 Isomer 2: ethyl 4-(6′- 32 c (400 MHz, DMSO-d.sub.6) □: 1.18 (t, J = 7.0 Hz, 3 H), 1.55-1.88 (m, F m/z 397 cyano-2′-oxo-1′,2′- and 8 H), 2.04-2.14 (m, 2 H), 2.63-2.77 (m, 5 H), 3.39-3.48 (m, 4 (M + H).sup.+ dihydrospiro[cyclohexane- 110 H), 4.03 (q, J = 7.0 Hz, 2 H), 7.13 (s, 1 H), 7.42-7.47 (m, 2 H). (ES.sup.+), at 1,3′-indol]-4-yl)-1,4- NH not observed. 1.70 min, diazepane-1-carboxylate UV active  4-14 Isomer 1: ethyl 4-(5′- 32 c (400 MHz, DMSO-d.sub.6) □: 1.18 (t, J = 7.0 Hz, 3 H), 1.53-1.60 (m, F m/z 398 cyano-2′-oxo-1′,2′- and 2 H), 1.65-1.84 (m, 8 H), 2.59-2.88 (m, 5 H), 3.40-3.46 (m, 4 (M + H).sup.+ dihydrospiro[cyclohexane- 112 H), 4.04 (q, J = 7.0 Hz, 2 H), 7.04 (d, J = 8.0 Hz, 1 H), 7.72(d, (ES.sup.+), at 1,3′-indol]-4-yl)-1,4- J = 8.0 Hz, 1 H), 7.85 (s, 1 H), 10.95 (s, 1 H) 1.62 min, diazepane-1-carboxylate UV active  4-14 Isomer 2: ethyl 4-(5′- 32 c (400 MHz, DMSO-d.sub.6 with D.sub.2O wash) □: 1.17 (t, J = 7.0 Hz, F m/z 398 cyano-2′-oxo-1′,2′- and 3 H), 1.55-2.22 (m, 10 H), 2.65-2.94 (m, 5 H), 3.34-3.51 (m, (M + H).sup.+ dihydrospiro[cyclohexane- 112 4 H), 4.03 (q, J = 7.0 Hz, 2 H), 6.97 (d, J = 8.0 Hz, 1 H), 7.64 (d, (ES.sup.+), at 1,3′-indol]-4-yl)-1,4- J = 8.0 Hz, 1 H), 7.72 (s, 1 H) 1.64 min, diazepane-1-carboxylate UV active  4-15 Isomer 2: ethyl 4-(2′- 32 c (400 MHz, DMSO-d.sub.6 with D2O wash) □: 1.17 (t, J = 7.0 Hz, 3 F m/z 374 oxo-1′,2′- and H), 1.59-1.84 (m, 8 H), 2.01-2.14 (m, 2 H), 2.68-2.81 (m, 5 H), (M + H).sup.+ dihydrospiro[cyclohexane- 90 3.36-3.46 (m, 4 H), 4.02 (q, J = 7.0 Hz, 2 H), 6.94-6.97 (m, 1 (ES.sup.+), at 1,3′-pyrrolo[2,3- H), 7.60 (d, J = 7.0 Hz, 1 H), 8.01 (d, J = 4.5 Hz, 1 H) 1.52 min, b]pyridin]-4-yl)-1,4- UV active diazepane-1-carboxylate  4-16 Isomer 1: ethyl 4-(5′- 32 c (400 MHz, DMSO-d.sub.6) □: 1.18 (t, J = 7.0 Hz, 3 H), 1.52-1.86 (m, F m/z 407 chloro-2′-oxo-1′,2′- and 8 H), 2.00-2.14 (m, 2 H), 2.59-2.77 (m, 5 H), 3.37-3.42 (m, 4 (M + H).sup.+ dihydrospiro[cyclohexane- 93 H), 4.03 (q, J = 7.0 Hz, 2 H), 7.77 (s, 1 H), 8.05 (d, J = 2.0 Hz, 1 (ES.sup.+), at 1,3′-pyrrolo[2,3- H). NH not observed. 1.64 min, b]pyridin]-4-yl)-1,4- UV active diazepane-1-carboxylate  4-16 Isomer 2: ethyl 4-(5′- 32 c (400 MHz, DMSO-d.sub.6) □: 1.18 (t, J = 7.0 Hz, 3 H), 1.53-1.89 (m, F m/z 407 chloro-2′-oxo-1′,2′- and 10 H), 2.61-2.88 (m, 5 H), 3.39-3.49 (m, 4 H), 4.04 (q, J = 7.0 (M + H).sup.+ dihydrospiro[cyclohexane- 93 Hz, 2 H), 7.83 (d, J = 2.0 Hz, 1 H), 8.17 (d, J = 2.0 Hz, 1 H), (ES.sup.+), at 1,3′-pyrrolo[2,3- 11.26 (s, 1 H) 1.66 min, b]pyridin]-4-yl)-1,4- UV active diazepane-1-carboxylate  4-17 Isomer 1: ethyl 4-(5′- 32 i (400 MHz, CDCl.sub.3)□□: 1.27 (t, J = 7.0 Hz, 3 H), 1.61-2.05 (m, O m/z 403 methoxy-2′-oxo-1′,2′- and 10 H), 2.69-2.88 (m, 5 H), 3.44-3.60 (m, 4 H), 3.87 (s, 3 H), (M + H).sup.+ dihydrospiro[cyclohexane- 113 4.15 (q, J = 7.0 Hz, 2 H), 7.39 (s, 1 H), 7.80 (s, 1 H), 9.16-9.19 (ES.sup.+), at 1,3′-pyrrolo[2,3- (m, 1 H) 3.99 min, b]pyridin]-4-yl)-1,4- UV active diazepane-1-carboxylate  4-17 Isomer 2: ethyl 4-(5′- 32 i (400 MHz, CDCl.sub.3)□□: 1.26 (t, J = 7.0 Hz, 3 H), 1.61-1.95 (m, 8 O m/z 403 methoxy-2′-oxo-1′,2′- and H), 2.19-2.29 (m, 2 H), 2.62-2.84 (m, 5 H), 3.44-3.57 (m, 4 (M + H).sup.+ dihydrospiro[cyclohexane- 113 H), 3.83 (s, 3 H), 4.14 (q, J = 7.0 Hz, 2 H), 7.02-7.03 (m, 1 H), (ES.sup.+), at 1,3′-pyrrolo[2,3- 7.74-7.76 (m, 1 H), 8.32-8.36 (m, 1 H) 4.02 min, b]pyridin]-4-yl)-1,4- UV active diazepane-1-carboxylate  4-18 Isomer 2: ethyl 4-(1′,2′- 32 c (400 MHz, DMSO-d.sub.6) □: 1.18 (t, J = 7.0 Hz, 3 H), 1.31-1.40 (m, G m/z 359 dihydrospiro[cyclohexane- and 2 H), 1.52-1.72 (m, 8 H), 2.54-2.73 (m, 5 H), 3.30 (s, 2 H), (M + H).sup.+ 1,3′-pyrrolo[2,3- 116 3.35-3.40 (m, 4 H), 4.03 (q, J = 7.0 Hz, 2 H), 6.35 (s, 1 H), 6.39- (ES.sup.+), at b]pyridin]-4-yl)-1,4- 6.42 (m, 1 H), 7.16-7.18 (m, 1 H), 7.68 (dd, J = 5.0, 1.5 Hz, 1 5.25 min, diazepane-1-carboxylate H) UV active  4-19 Isomer 1: ethyl 4-[1′- 32 c (400 MHz, DMSO-d.sub.6) □: 1.18 (t, J = 7.0 Hz, 3 H), 1.31-1.51 (m, G m/z 437 (methylsulfonyl)-1′,2′- and 2 H), 1.60-1.84 (m, 8 H), 2.58-2.84 (m, 5 H), 3.31 (s, 3 H), (M + H).sup.+ dihydrospiro[cyclohexane- 177 3.39-3.48 (m, 4 H), 3.84 (s, 2 H), 4.03 (q, J = 7.0 Hz, 2 H), 7.00- (ES.sup.+), at 1,3′-pyrrolo[2,3- 7.03 (m, 1 H), 7.63-7.65 (m, 1 H), 8.11-8.12 (m, 1 H) 5.39 min, b]pyridin]-4-yl)-1,4- UV active diazepane-1-carboxylate  4-19 Isomer 2: ethyl 4-[1′- 32 c (400 MHz, MeOD-d.sub.4) □: 1.29 (t, J = 7.0 Hz, 3 H), 1.51-1.60 (m, G m/z 437 (methylsulfonyl)-1′,2′- and 2 H), 1.76-1.96 (m, 8 H), 2.78-3.03 (m, 5 H), 3.28 (s, 3 H), (M + H).sup.+ dihydrospiro[cyclohexane- 117 3.52-3.65 (m, 4 H), 3.95 (s, 2 H), 4.16 (q, J = 7.0 Hz, 2 H), 7.01- (ES.sup.+), at 1,3′-pyrrolo[2,3- 7.04 (m, 1 H), 7.61-7.63 (m, 1 H), 8.10 (dd, J = 1.0, 5.0 Hz, 1 5.49 min, b]pyridin]-4-yl)-1,4- H) UV active diazepane-1-carboxylate  4-20 Isomer 2: ethyl 4-(2′- 32 c (400 MHz, MeOD-d.sub.4) □: 1.29 (t, J = 7.0 Hz, 3 H), 1.76-1.97 (m, G m/z 373 oxo-1′,2′- and 8 H), 2.23-2.33 (m, 2 H), 2.79-2.91 (m, 5 H), 3.50-3.61 (m, 4 (M + H).sup.+ dihydrospiro[cyclohexane- 118 H), 4.15 (q, J = 7.0 Hz, 2 H), 7.36 (d, J = 5.0 Hz, 1 H), 8.12 (s, 1 (ES.sup.+), at 1,3′-pyrrolo[2,3- H), 8.25 (d, J = 5.0 Hz, 1 H) 4.55 min, c]pyridin]-4-yl)-1,4- UV active diazepane-1-carboxylate  4-21 Isomer 1: ethyl 4-(5′- 32 i (400 MHz, CDCl.sub.3)□□: 1.26 (t, J = 7.0 Hz, 3 H), 1.54-1.98 (m, 8 O m/z 403 methoxy-2′-oxo-1′,2′- and H), 2.15-2.29 (m, 2 H), 2.63-2.87 (m, 5 H), 3.45-3.57 (m, 4 (M + H).sup.+ dihydrospiro[cyclohexane- 95 H), 3.89 (s, 3 H), 4.14 (q, J = 7.0 Hz, 2 H), 6.56 (s, 1 H), 7.33 (s, (ES.sup.+), at 1,3′-pyrrolo[2,3- 1 H), 7.67 (s, 1 H) 3.96 min, c]pyridin]-4-yl)-1,4- UV active diazepane-1-carboxylate  4-22 Isomer 2: ethyl 4-(2′- 32 c (400 MHz, DMSO-d.sub.3) □: 1.18 (t, J = 7.0 Hz, 3 H), 1.57-1.86 (m, F m/z 373 oxo-1′,2′- and 8 H), 2.00-2.12 (m, 2 H), 2.60-2.79 (m, 5 H), 3.38-3.42 (m, 4 (M + H).sup.+ dihydrospiro[cyclohexane- 99 H), 4.04 (q, J = 7.0 Hz, 2 H), 7.13-7.14 (m, 2 H), 8.07-8.08 (m, (ES.sup.+), at 1,3′-pyrrolo[3,2- 1 H), 10.48 (s, 1 H) 1.53 min, b]pyridin]-4-yl)-1,4- UV active diazepane-1-carboxylate  4-23 Isomer 1: ethyl 4-(5′- 32 c (400 MHz, DMSO-d.sub.6) □: 1.18 (t, J = 7.0 Hz, 3 H), 1.60-1.87 (m, F m/z 388 methyl-2′-oxo-1′,2′- and 8 H), 2.00-2.13 (m, 2 H), 2.39 (s, 3 H), 2.64-2.82 (m, 5 H), (M + H).sup.+ dihydrospiro[cyclohexane- 120 3.39-3.44 (m, 4 H), 4.04 (q, J = 7.0 Hz, 2 H), 6.99 (d, J = 8.0 (ES.sup.+), at 1,3′-pyrrolo[3,2- Hz, 1 H), 7.04 (d, J = 8.0 Hz, 1 H), 10.35 (s, 1 H) 1.57 min, b]pyridin]-4-yl)-1,4- UV active diazepane-1-carboxylate  4-24 Isomer 1: ethyl 4-(5′- 32 c (400 MHz, DMSO-d.sub.6) □: 1.17 (t, J = 7.0 Hz, 3 H), 1.53-1.76 (m, G m/z 403 methoxy-2′-oxo-1′,2′- and 8 H), 2.21-2.36 (m, 2 H), 2.68-2.80 (m, 5 H), 3.39-3.51 (m, 4 (M + H).sup.+ dihydrospiro[cyclohexane- 97 H), 3.83 (s, 3 H), 4.03 (q, J = 7.0 Hz, 2 H), 6.67 (d, J = 8.5 Hz, 1 (ES.sup.+), at 1,3′-pyrrolo[3,2- H), 7.23 (d, J = 8.5 Hz, 1 H), 10.30 (s, 1 H) 5.48 min, b]pyridin]-4-yl)-1,4- UV active diazepane-1-carboxylate  4-24 Isomer 2: ethyl 4-(5′- 32 c (400 MHz, DMSO-d.sub.6) □: 1.18 (t, J = 7.0 Hz, 3 H), 1.68-1.78 (m, G m/z 403 methoxy-2′-oxo-1′,2′- and 8 H), 2.00-2.13 (m, 2 H), 2.61-2.81 (m, 5 H), 3.38-3.47 (m, 4 (M + H).sup.+ dihydrospiro[cyclohexane- 97 H), 3.80 (s, 3 H), 4.04 (q, J = 7.0 Hz, 2 H), 6.60 (d, J = 8.5 Hz, 1 (ES.sup.+), at 1,3′-pyrrolo[3,2- H), 7.16 (d, J = 8.5 Hz, 1 H), 10.20 (s, 1 H) 5.61 min, b]pyridin]-4-yl)-1,4- UV active diazepane-1-carboxylate  5-1 Isomer 2: ethyl 4-[4-(4- 31 f (400 MHz, DMSO-d.sub.6) δ: 0.91-1.23 (m, 7 H), 1.45-1.68 (m, 7 H), B m/z 363 ethyl-5-methyl-1H- 1.90-2.10 (m, 5 H), 2.28-2.49 (m, 3 H), 2.57-2.62 (m, 2 H), (M + H).sup.+ imidazol-2-yl)cyclohexyl]- 2.64-2.75 (m, 3 H), 3.38-3.43 (m, 4 H), 4.01 (q, J = 6.8 Hz, 2 (ES.sup.+), at 1,4-diazepane-1- H), 10.97 (br. s, 1 H) 3.22 min, carboxylate UV active  6-1 Isomer 2: ethyl [1-(4- 1, 12 b (400 MHz, DMSO-d.sub.6) □: 1.17 (t, J = 7.2 Hz, 3 H), 1.45-1.80 (m, B m/z 370 cyano-4- and 7 H), 1.81-1.99 (m, 5 H), 2.24-2.40 (m, 3 H), 2.70 (s, 3 H), (M + H).sup.+ phenylcyclohexyl) 55 2.95-3.10 (m, 2 H), 3.68-3.85 (m, 1 H), 4.02 (q, J = 7.2 Hz, 2 (ES.sup.+), at piperidin-4-yl]methyl- H), 7.32-7.41 (m, 1 H), 7.41-7.49 (m, 2 H) and 7.50-7.57 (m, 4.57 min, carbamate 2 H). UV active  6-2 Isomer 2: ethyl {[1-(4- 2, 12 b (400 MHz, DMSO-d.sub.6) □: 1.05-1.11 (m, 2 H), 1.14 (t, J = 7.0 Hz, B m/z 370 cyano-4- and 3 H), 1.24-1.32 (m, 1 H), 1.59-1.92 (m, 10 H), 2.23-2.30 (m, (M + H).sup.+ phenylcyclohexyl) 55 3 H), 2.82-2.85 (m, 2 H), 2.91-2.96 (m, 2 H), 3.96 (q, J = 7.0 (ES.sup.+), at piperidin-4-yl]methyl} Hz, 2 H), 7.11 (br. s, 1 H), 7.35-7.39 (m, 1 H), 7.44-7.48 (m, 2 4.17 min, carbamate H) and 7.51-7.54 (m, 2 H). UV active  7-1 Isomer 1: ethyl [1- 65 c (400 MHz, MeOD-d.sub.4) □: 1.26 (t, J = 7.0 Hz, 3 H), 1.72-2.25 (m, F m/z 372 (2′-oxo-1′,2′- and 12 H), 3.13-3.26 (m, 2 H), 3.35-3.42 (m, 1 H), 3.59-3.78 (m, (M + H).sup.+ dihydrospiro[cyclohexane- 101 3 H), 4.08-4.13 (m, 2 H), 7.00 (d, J = 7.5 Hz, 1 H), 7.08 (t, J = (ES.sup.+), at 1,3′-indol]-4-yl)piperidin- 7.5 Hz, 1 H), 7.29 (t, J = 7.5 Hz, 1 H), 7.64 (d, J = 7.5 Hz, 1 H), 1.61 min, 4-yl]carbamate 8.54 (br s, 1 H) UV active  7-1 Isomer 2: ethyl [1- 65 c (400 MHz, MeOD-d.sub.4) □: 1.26 (t, J = 7.0 Hz, 3 H), 1.76-2.20 (m, F m/z 372 (2′-oxo-1′,2′- and 10 H), 2.48-2.57 (m, 2 H), 3.20-3.26 (m, 2 H), 3.37-3.54 (m, (M + H).sup.+ dihydrospiro[cyclohexane- 101 3 H), 3.67-3.80 (m, 1 H), 4.08-4.13 (m, 2 H), 6.90 (d, J = 7.5 (ES.sup.+), at 1,3′-indol]-4-yl)piperidin- Hz, 1 H), 7.04 (t, J = 7.5 Hz, 1 H), 7.20-7.23 (m, 2 H), 8.56 (br 1.64 min, 4-yl]carbamate s, 1 H) UV active  7-2 Isomer 1: ethyl {[1- 55 h (400 MHz, MeOD-d.sub.4) □: 1.22-1.39 (m, 5 H), 1.49-1.67 (m, 3 F m/z 386 (2′-oxo-1′,2′- and H), 1.80-2.06 (m, 8 H), 2.34-2.39 (m, 2 H), 2.55-2.64 (m, 1 (M + H).sup.+ dihydrospiro[cyclohexane- 103 H), 3.03 (d, J = 6.5 Hz, 2 H), 3.15-3.18 (m, 2 H), 4.06-4.17 (m, (ES.sup.+), at 1,3′-indol]-4-yl)piperidin- 2 H), 6.97 (d, J = 7.5 Hz, 1 H), 7.05 (t, J = 7.5 Hz, 1 H), 7.26 (t, 1.63 min, 4-yl]methyl}carbamate J = 7.5 Hz, 1 H), 7.63 (d, J = 7.5 Hz, 1 H) UV active  7-2 Isomer 2: ethyl {[1- 55 h (400 MHz, DMSO-d.sub.6) □: 1.05-1.39 (m, 6 H), 1.59-1.78 (m, 9 F m/z 386 (2′-oxo-1′,2′- and H), 2.09-2.24 (m, 4 H), 2.84-2.89 (m, 4 H), 3.97 (q, J = 7.0 Hz, (M + H).sup.+ dihydrospiro[cyclohexane- 103 2 H), 6.79 (d, J = 7.5 Hz, 1 H), 6.94 (t, J = 7.5 Hz, 1 H), 7.10- (ES.sup.+), at 1,3′-indol]-4-yl)piperidin- 7.15 (m, 2 H), 7.22 (d, J = 7.0 Hz, 1 H), 10.23 (s, 1 H) 1.67 min, 4-yl]methyl}carbamate UV active  8-1 Mixture of isomers: ethyl 3 a (400 MHz, DMSO-d.sub.6) □: 1.17 (t, J = 7.1 Hz, 3 H), 1.54-1.73 (m, B m/z 370 5-(4-cyano-4- and 6 H), 1.82-2.01 (m, 5 H), 2.03-2.30 (m, 3 H), 2.54-2.66 (m, 4 (M + H).sup.+ phenylcyclohexyl)-1,5- 12 H), 2.95-3.10 (m, 2 H), 3.68-3.85 (m, 1 H), 4.03 (q, J = 7.1 Hz, (ES.sup.+), at diazocane-1-carboxylate 2 H), 7.32-7.39 (m, 1 H), 7.40-7.47 (m, 2 H) and 7.50-7.57 5.07 min, (m, 2 H). UV active  9-1 Isomer 1: ethyl 2-(4- 4, 12 b (400 MHz, DMSO-d.sub.6) □: 1.14 (t, J = 6.9 Hz, 3 H), 1.19-1.36 (m, B m/z 368 cyano-4- and 2 H), 1.75-1.89 (m, 4 H), 1.89-1.98 (m, 2 H), 2.01-2.11 (m, 3 (M + H).sup.+ phenylcyclohexyl)-2,6- 55 H), 2.98-3.11 (m, 4 H), 3.20-3.35 (m, 4 H), 3.97 (q, J = 6.9 Hz, (ES.sup.+), at diazaspiro[3.4]octane-6- 2 H), 7.29-7.35 (m, 1 H), 7.36-7.43 (m, 2 H) and 7.45-7.55 3.96 min, carboxylate (m, 2 H). UV active  9-1 Isomer 1: ethyl 2-(4- 4, 12 b (400 MHz, DMSO-d.sub.6) □: 1.17 (t, J = 7.0 Hz, 3 H), 1.63-1.73 (m, B m/z 368 cyano-4- and 4 H), 1.76-1.85 (m, 2 H), 1.85-2.09 (m, 2 H), 2.11-2.26 (m, 2 (M + H).sup.+ phenylcyclohexyl)-2,6- 55 H), 2.38-2.49 (m, 1 H), 2.99-3.10 (m, 4 H), 3.22-3.43 (m, 4 (ES.sup.+), at diazaspiro[3.4]octane-6- H), 4.01 (q, J = 7.0 Hz, 2 H), 7.34-7.40 (m, 1 H) and 7.41-7.55 4.59 min, carboxylate (m, 4 H). UV active 10-1 Mixture of isomers: ethyl 65 j (400 MHz, DMSO-d.sub.6) □: 1.53 (t, J = 7.0 Hz, 3 H), 1.55-2.32 (m, B m/z 384 6-(2′-oxo-1′,2′- and 10 H), 2.55-2.88 (m, 5 H), 3.74-3.90 (m, 4 H), 3.99 (q, J = 7.0 (M + H).sup.+ dihydrospiro[cyclohexane- 122 Hz, 2 H), 6.80 (d, J = 7.5 Hz, 1 H), 6.91-6.95 (m, 1 H), 7.14 (td, (ES.sup.+), at 1,3′-indol]-4-yl)-2,6- J = 7.5, 1.0 Hz, 1 H), 7.29 (d, J = 7.5 Hz, 1 H), 10.22 (s, 1 H) 3.74 min, diazaspiro[3.4]octane-2- UV active carboxylate 11-1 Isomer 2: ethyl 7-(4- 5, 12 b (400 MHz, CDCl.sub.3) □: 1.24 (t, J = 7.2 Hz, 3 H), 1.48-1.59 (m, 3 B m/z 382 cyano-4- and H), 1.67-2.06 (m, 8 H), 2.20-2.51 (m, 4 H), 2.53-2.67 (m, 1 (M + H).sup.+ phenylcyclohexyl)-2,7- 55 H), 2.69-2.84 (m, 1 H), 2.89-3.02 (m, 1 H), 3.44-3.56 (m, 1 (ES.sup.+), at diazaspiro[3.5]nonane-2- H), 3.63-3.76 (m, 2 H), 4.10 (q, J = 7.2 Hz, 2 H) and 7.27-7.70 4.45 min, carboxylate (m, 5 H). UV active 12-1 Isomer 1: ethyl 8-(2′- 6 k (400 MHz, CDCl.sub.3)□□: 1.15-1.23 (m, 3 H), 1.39-2.10 (m, 11 H), B m/z 412 oxo-1′,2′- and 2.28-2.80 (m, 6 H), 3.06-3.46 (m, 6 H), 4.03-4.11 (m, 2 H), (M + H).sup.+ dihydrospiro[cyclohexane- 65 6.76-7.17 (m, 3 H), 7.39-7.72 (m, 2 H) (ES.sup.+), at 1,3′-indol]-4-yl)-2,8- 3.58 min, diazaspiro[4.5]decane-2- UV active carboxylate 12-2 Isomer 1: ethyl 4-[2- Ex h (400 MHz, CDCl.sub.3)□□: 1.17-1.22 (m, 3 H), 1.39 (t, J = 9.5 Hz, 3 B m/z 484 (ethoxycarbonyl)-2,8- 12-1 H), 1.47-2.18 (m, 16 H), 2.46-2.70 (m, 1 H), 3.07-3.42 (m, 5 (M + H).sup.+ diazaspiro[4.5]dec-8-yl]- and H), 3.79-3.87 (m, 1 H), 4.07 (q, J = 9.5 Hz, 2 H), 4.41 (q, J = 9.5 (ES.sup.+), at 2′-oxospiro[cyclohexane- 55 Hz, 2 H), 7.06-7.16 (m, 2 H), 7.25-7.30 (m, 1 H), 7.89 (d, J = 4.54 min, 1,3′-indole]-1′(2′H)- 11.0 Hz, 1 H) UV active carboxylate 13-1 Isomer 2: ethyl 8-(4- 6 a (400 MHz, CDCl.sub.3) □: 1.26 (t, J = 7.2 Hz, 3 H), 1.50-1.62 (m, 5 B m/z 396 cyano-4- and H), 1.63-1.77 (m, 2 H), 1.81-2.06 (m, 6 H), 2.24-2.38 (m, 4 (M + H).sup.+ phenylcyclohexyl)-2,8- 12 H), 2.45-2.60 (m, 2 H), 3.13-3.25 (m, 2 H), 3.34-3.48 (m, 2 (ES.sup.+), at diazaspiro[4.5]decane-2- H), 4.13 (q, J = 7.2 Hz, 2 H), 7.31 (t, J = 7.6 Hz, 1 H), 7.40 (d, 4.71 min, carboxylate J = 7.6 Hz, 2 H) and 7.51 (d, J = 7.6 Hz, 2 H). UV active 14-1 Isomer 1: ethyl 7-(4- 7 a (400 MHz, DMSO-d.sub.6) □: 1.19 (t, J = 6.8 Hz, 3 H), 1.26-1.42 (m, B m/z 368 cyano-4- and 1 H), 1.52-1.69 (m, 2 H), 1.80-2.00 (m, 6 H), 2.04-2.12 (m, 2 (M + H).sup.+ phenylcyclohexyl)-3,7- 12 H), 2.18-2.27 (m, 1 H), 2.38 (t, J = 7.0 Hz, 1 H), 2.91 (t, J = 7.2 (ES.sup.+), at diazaspiro[4.2.0]octane-3- Hz, 1 H), 3.00 (d, J = 6.0 Hz, 1 H), 3.30-3.39 (m, 2 H), 3.47- 4.31 min, carboxylate 3.60 (m, 1 H), 3.81-3.89 (m, 1 H), 4.04 (q, J = 6.8 Hz, 2 H), UV active 7.33-7.38 (m, 1 H), 7.40-7.47 (m, 2 H) and 7.50-7.56 (m, 2 H). 14-2 Isomer 2: ethyl 7-(4- 7 a (400 MHz, DMSO-d.sub.6) □: 1.08-1.22 (m, 3 H), 1.59-1.85 (m, 8 B m/z 368 cyano-4- and H), 2.04-2.27 (m, 2 H), 2.30-2.44 (m, 1 H), 2.87 (t, J = 6.8 Hz, (M + H).sup.+ phenylcyclohexyl)-3,7- 12 1 H), 3.01 (dd, J = 7.0 and 2.3, 1 H), 3.37-3.41 (m, 1 H), 3.42- (ES.sup.+), at diazaspiro[4.2.0]octane-3- 3.77 (m, 5 H), 4.03 (q, J = 7.0 Hz, 2 H), 7.33-7.42 (m, 1 H) and 5.01 min, carboxylate 7.40-7.58 (m, 4 H). UV active 15-1 Isomer 2: ethyl 5-(4- 8 a (400 MHz, DMSO-d.sub.6) □: 1.08-1.24 (m, 3 H), 1.62-1.99 (m, 7 B m/z 368 cyano-4- and H), 2.01-2.43 (m, 5 H), 2.55-2.97 (m, 4 H), 3.12-3.29 (m, 1 (M + H).sup.+ phenylcyclohexyl)hexa- 12 H), 3.42-3.59 (m, 1 H), 3.91-4.06 (m, 2 H), 4.07-4.22 (m, 1 (ES.sup.+), at hydropyrrolo[3,4-b] H), 7.28-7.39 (m, 1 H) and 7.40-7.56 (m, 4 H). 4.92 min, pyrrole-1(2 H)- UV active carboxylate 16-1 Isomer 1: ethyl 1-(4- 9, 12 b (400 MHz, DMSO-d.sub.6) □: 1.18 (t, J = 7.2 Hz, 3 H), 1.42-1.68 (m, B m/z 368 cyano-4- and 4 H), 1.87-2.19 (m, 8 H), 2.41-2.56 (m, 2 H), 2.64-2.79 (m, 2 (M + H).sup.+ phenylcyclohexyl)hexa- 55 H), 2.96-3.06 (m, 1 H), 3.21-3.41 (m, 2 H), 4.02 (q, J = 7.2 Hz, (ES.sup.+), at hydropyrrolo[3,4-b] 2 H), 7.33-7.39 (m, 1 H), 7.41-7.49 (m, 2 H) and 7.50-7.58 4.10 min, pyrrole-5(1H)- (m, 2 H). UV active carboxylate 16-1 Isomer 2: ethyl 1-(4- 9, 12 b (400 MHz, DMSO-d.sub.6) □: 0.96-1.13 (m, 3 H), 1.32-1.48 (m, 2 B m/z 368 cyano-4- and H), 1.63-1.96 (m, 8 H), 2.07-2.23 (m, 2 H), 2.37 (td, J = 9.1 (M + H).sup.+ phenylcyclohexyl)hexa- 55 and 6.15, 1 H), 2.41-2.52 (m, 2 H), 2.59-2.71 (m, 1 H), 2.76- (ES.sup.+), at hydropyrrolo[3,4-b] 2.84 (m, 1 H), 3.14-3.33 (m, 2 H), 3.92 (q, J = 7.0 Hz, 2 H), 4.60 min, pyrrole-5(1H)- 7.27-7.33 (m, 1 H), 7.35-7.42 (m, 2 H) and 7.42-7.49 (m, 2 H). UV active carboxylate 17-1 Isomer 2: ethyl 3-(4- 10, 12 b (400 MHz, DMSO-d.sub.6) □: 1.00-1.12 (m, 3 H), 1.15-1.25 (m, 2 B m/z 368 cyano-4- and H), 1.48-1.77 (m, 3 H), 1.77-1.94 (m, 4 H), 2.03-2.12 (m, 1 (M + H).sup.+ phenylcyclohexyl)-3,7- 55 H), 2.13-2.28 (m, 2 H), 2.31-2.56 (m, 3 H), 2.70 (dd, J = 12 (ES.sup.+), at diazabicyclo[4.2.0]octane- and 5.7, 1 H), 3.40-3.49 (m, 1 H), 3.69-3.82 (m, 1 H), 3.84- 4.43 min, 7-carboxylate 4.02 (m, 2 H), 4.14-4.25 (m, 1 H), 7.25-7.33 (m, 1 H), 7.34- UV active 7.41 (m, 2 H) and 7.42-7.51 (m, 2 H). 18-1 Isomer 1: ethyl 11 a (400 MHz, DMSO-d.sub.6) □: 1.12-1.21 (m, 3 H), 1.22-1.68 (m, 7 B m/z 382 (4aS,7aS)-1-(4-cyano-4- and H), 1.71-1.84 (m, 2 H), 1.86-2.26 (m, 6 H), 2.58-2.74 (m, 1 (M + H).sup.+ phenylcyclohexyl) 12 H), 3.07-3.31 (m, 3 H), 3.36-3.59 (m, 2 H), 3.95-4.09 (m, 2 (ES.sup.+), at octahydro-6H-pyrrolo[3,4- H), 7.32-7.40 (m, 1 H), 7.40-7.48 (m, 2 H) and 7.51-7.58 4.39 min, b]pyridine-6-carboxylate 2 H). UV active 19-1 Isomer 2: 4-{[(1R,3S)-3- 26 l (400 MHz, CDCl.sub.3) □: 1.55-1.66 (m, 2 H), 1.69-1.81 (m, 2 H), E m/z 352 (3-methyl-1,2,4- and 1.88-2.16 (m, 8 H), 2.37 (s, 3 H), 2.38-2.55 (m, 3 H), 2.97- (M + H).sup.+ oxadiazol-5- 126 3.06 (m, 1 H), 3.25-3.40 (m, 2 H), 7.21-7.27 (m, 1 H), 7.53- (ES.sup.+), at yl)cyclopentyl]amino}-1- 7.61 (m, 1 H), 7.73 (t, J = 7.4 Hz, 1 H), 8.62 (d, J = 5.1 Hz, 1 H). 3.58 min, (pyridin-2-yl) UV active cyclohexane-carbonitrile 19-2 Isomer 2: 4-{[(1R,3S)-3- 12 l (400 MHz, CDCl.sub.3) □: 1.32 (t, J = 7.4 Hz, 3 H), 1.55-1.66 (m, 1 E m/z 365 (3-ethyl-1,2,4-oxadiazol- and H), 1.70-1.82 (m, 3 H), 1.84-1.93 (m, 3 H), 1.97-2.17 (m, 5 (M + H).sup.+ 5-yl)cyclopentyl]amino}- 128 H), 2.24-2.35 (m, 2 H), 2.38-2.49 (m, 1 H), 2.74 (q, J = 7.7 Hz, (ES.sup.+), at 1-phenylcyclo- 2 H), 3.02-3.08 (m, 1 H), 3.24-3.42 (m, 2 H), 7.29-7.35 (m, 1 5.02 min, hexanecarbonitrile H), 7.40 (t, J = 7.8 Hz, 2 H), 7.47-7.54 (m, 2 H). UV active 20-1 Isomer 2: 1-phenyl-4-{6- 12 l (400 MHz, CDCl.sub.3) □: 1.68-1.76 (m, 2 H), 1.78-1.93 (m, 4 H), E m/z 417 [3-(trifluoromethyl)-1,2,4- and 2.20-2.31 (m, 2 H), 2.33-2.40 (m, 1 H), 2.57-2.74 (m, 4 H), (M + H).sup.+ oxadiazol-5-yl]-2- 131 3.16 (s, 2 H), 3.25 (s, 2 H), 3.67-3.80 (m, 1 H), 7.28-7.34 (m, 1 (ES.sup.+), at azaspiro[3.3]hept-2-yl} H), 7.40 (t, J = 7.8 Hz, 2 H), 7.52 (d, J = 7.0 Hz, 2 H). 5.90 min, cyclohexanecarbonitrile UV active 21-1 Isomer 3: 4-[2-(3-methyl- 12 l (400 MHz, CDCl.sub.3) □: 1.82-1.90 (m, 2 H), 1.91-1.97 (m, 4 H), E m/z 377 1,2,4-oxadiazol-5-yl)-6- and 2.00-2.06 (m, 2 H), 2.24-2.37 (m, 3 H), 2.38 (s, 3 H), 2.40- (M + H).sup.+ azaspiro[3.4]oct-6-yl]-1- 133 2.52 (m, 4 H), 2.59-2.67 (m, 4 H), 3.62-3.73 (m, 1 H), 7.28- (ES.sup.+), at phenylcyclo- 7.34 (m, 1 H), 7.39 (t, J = 7.6 Hz, 2 H), 7.50 (d, J = 7.0 Hz, 2 H). 5.31 min, hexanecarbonitrile UV active 21-2 Isomer 3: 1-(2- 19 l (400 MHz, CDCl.sub.3) □: 1.90-2.05 (m, 7 H), 2.33-2.51 (m, 8 H), E m/z 395 fluorophenyl)-4-[2-(3- and 2.38 (d, J = 1.2 Hz, 3 H), 2.58-2.68 (m, 4 H), 3.60-3.71 (M + H).sup.+ methyl-1,2,4-oxadiazol-5- 133 H), 7.06-7.19 (m, 2 H), 7.28-7.35 (m, 1 H), 7.46 (t, J = 7.8 Hz, (ES.sup.+), at yl)-6-azaspiro[3.4]oct-6- 1 H). 5.35 min, yl]cyclohexanecarbonitrile UV active 21-3 Isomer 3: 1-(5- 27 c (400 MHz, MeOD-d.sub.4) □: 1.70-1.84 (m, 2 H), 1.85-2.10 (m, 5 R m/z 396 fluoropyridin-2-yl)-4-[2-(3- and H), 2.28-2.36 (m, 4 H), 2.38-2.46 (m, 4 H), 2.51-2.61 (m, 3 (M + H).sup.+ methyl-1,2,4-oxadiazol-5- 133 H), 2.63-2.71 (m, 4 H), 3.65-3.75 (m, 1 H), 7.61-7.75 (m, 2 (ES.sup.+), at yl)-6-azaspiro[3.4]oct-6- H), 8.47-8.57 (m, 1 H). 4.23 min, yl]cyclohexanecarbonitrile UV active 21-3 Isomer 4: 1-(5- 27 c (400 MHz, MeOD-d.sub.4) □: 1.77-2.02 (m, 7 H), 2.31-2.45 (m, 6 R m/z 396 fluoropyridin-2-yl)-4-[2-(3- and H), 2.45-2.54 (m, 3 H), 2.54-2.64 (m, 4 H), 2.78 (s, 2 H), 3.65- (M + H).sup.+ methyl-1,2,4-oxadiazol-5- 133 3.75 (m, 1 H), 7.61-7.73 (m, 2 H), 8.50 (d, J = 2.8 Hz, 1 H). (ES.sup.+), at yl)-6-azaspiro[3.4]oct-6- 4.43 min, yl]cyclohexanecarbonitrile UV active 21-4 Isomer 4: 1-(5- 44 c (400 MHz, MeOD-d.sub.4) □: 1.75-2.01 (m, 10 H), 2.30-2.45 (m, 5 R m/z 408 methoxypyridin-2-yl)-4- and H), 2.54-2.65 (m, 5 H), 2.78 (s, 2 H), 3.63-3.72 (m, 1 H), 3.88 (M + H).sup.+ [2-(3-methyl-1,2,4- 133 (s, 3 H), 7.42 (dd, J = 8.8, 3.0 Hz, 1 H), 7.55 (d, J = 8.8 Hz, 1 H), (ES.sup.+), at oxadiazol-5-yl)-6- 8.26 (d, J = 3.0 Hz, 1 H). 4.25 min, azaspiro[3.4]oct-6- UV active yl]cyclohexanecarbonitrile 21-5 Isomer 1: 4-[2-(3-methyl- 43 c (400 MHz, MeOD-d.sub.4) □: 1.32 (s, 2 H), 1.66-1.82 (m, 3 H), 1.97 R m/z 392 1,2,4-oxadiazol-5-yl)-6- and (dd, J = 13.3, 3.0 Hz, 2 H), 2.05-2.26 (m, 10 H), 2.34-2.50 (m, (M + H).sup.+ azaspiro[3.4]oct-6-yl]-1- 133 5 H), 2.68-2.78 (m, 1 H), 3.12 (s, 2 H), 3.63-3.77 (m, 1 H), (ES.sup.+), at (5-methylpyridin-2- 7.40 (d, J = 8.1 Hz, 1 H), 7.57 (dd, J = 8.0, 2.3 Hz, 1 H), 8.29 (d, 3.50 min, yl)cyclohexanecarbonitrile J = 2.2 Hz, 1 H). UV active 21-5 Isomer 2: 4-[2-(3-methyl- 43 c (400 MHz, MeOD-d.sub.4) □: 1.81 (dt, J = 13.7, 10.2 Hz, 2 H), 2.00 R m/z 392 1,2,4-oxadiazol-5-yl)-6- and (t, J = 7.2 Hz, 2 H), 2.09 (td, J = 13.9, 3.6 Hz, 2 H), 2.19-2.29 (M + H).sup.+ azaspiro[3.4]oct-6-yl]-1- 133 (m, 5 H), 2.34 (s, 3 H), 2.36 (s, 3 H), 2.40-2.50 (m, 2 H), 2.54- (ES.sup.+), at (5-methylpyridin-2- 2.64 (m, 2 H), 2.85 (t, J = 7.2 Hz, 2 H), 3.06 (s, 2 H), 3.65-3.79 3.60 min, yl)cyclohexanecarbonitrile (m, 1 H), 7.53 (d, J = 8.1 Hz, 1 H), 7.69 (dd, J = 8.1, 2.3 Hz, 1 UV active H), 8.41 (d, J = 2.2 Hz, 1 H). 22-1 Isomer 1: 4-[(3R)-3-(3- 65 l (400 MHz, CDCl.sub.3) □: 1.59-1.98 (m, 9 H), 2.12-2.22 (m, 1 H), E m/z 367 methyl-1,2,4-oxadiazol-5- and 2.28-2.38 (m, 2 H), 2.40 (s, 3 H), 2.42-2.54 (m, 1 H), 2.60- (M + H).sup.+ yl)piperidin-1- 135 2.82 (m, 2 H), 2.96-3.12 (m, 1 H), 3.20-3.39 (m, 2 H), 6.85 (d, (ES.sup.+), at yl]spiro[cyclohexane-1,3′- J = 7.4 Hz, 1 H), 7.03 (t, J = 8.2 Hz, 1 H), 7.0-7.23 (m, 2 H), 3.95 min, indol]-2′(1′H)-one 7.78 (s, 1 H). UV active 22-2 Isomer 1: 5′-methoxy-4- 80 c (400 MHz, MeOD-d.sub.4) □: 1.59-1.80 (m, 4 H), 1.87-2.06 (m, 7 I m/z 397 [(3R)-3-(3-methyl-1,2,4- and H), 2.11-2.20 (m, 1 H), 2.36 (s, 3 H), 2.44-2.52 (m, 1 H), 2.59- (M + H).sup.+ oxadiazol-5-yl)piperidin- 135 2.75 (m, 2 H), 3.02-3.10 (m, 1 H), 3.19-3.27 (m, 1 H), 3.33- (ES.sup.+), at 1-yl]spiro[cyclohexane- 3.39 (m, 1 H), 3.79 (s, 3 H), 6.78-6.91 (m, 2 H), 7.14-7.21 4.87 min, 1,3′-indol]-2′(1′H)-one 1 H). One exchangeable proton not observed. UV active 22-3 Isomer 1: 5′-methyl-4- 70 c (400 MHz, MeOD-d.sub.4) □: 1.61 (d, J = 8.9 Hz, 2 H), 1.70-1.80 R m/z 381 [(3R)-3-(3-methyl-1,2,4- and (m, 2 H), 1.87-1.94 (m, 6 H), 2.00-2.10 (m, 2 H), 2.16 (d, J = (M + H).sup.+ oxadiazol-5-yl)piperidin- 135 7.5 Hz, 1 H), 2.34 (s, 3 H), 2.36 (s, 3 H), 2.42-2.52 (m, 1 H), (ES.sup.+), at 1-yl]spiro[cyclohexane- 2.58-2.76 (m, 2 H), 3.06-3.42 (m, 2 H), 6.83 (d, J = 7.9 Hz, 1 3.57 min, 1,3′-indol]-2′(1′H)-one H), 7.06 (d, J = 8.2 Hz, 1 H), 7.43 (s, 1 H). NH not observed. UV active 22-4 Isomer 1: 6′-methyl-4- 68 c (400 MHz, MeOD-d.sub.4) □: 1.59 (d, J = 8.4 Hz, 2 H), 1.65-1.79 R m/z 381 [(3R)-3-(3-methyl-1,2,4- and (m, 2 H), 1.80-2.03 (m, 7 H), 2.10-2.20 (m, 1 H), 2.33 (s, 3 (M + H).sup.+ oxadiazol-5-yl)piperidin- 135 H), 2.36 (s, 3 H), 2.49 (t, J = 10.5 Hz, 1 H), 2.60-2.76 (m, 2 H), (ES.sup.+), at 1-yl]spiro[cyclohexane- 3.05 (d, J = 11.4 Hz, 1 H), 3.18-3.38 (m, 2 H), 6.78 (s, 1 H), 3.61 min, 1,3′-indol]-2′(1′H)-one 6.86 (d, J = 7.8 Hz, 1 H), 7.46 (d, J = 7.7 Hz, 1 H). NH not UV active observed. 23-1 Isomer 1: 4-({[2-(3- 65 l (400 MHz, CDCl.sub.3) □: 1.14-1.21 (m, 1 H), 1.43-1.49 (m, 1 H), E m/z 353 methyl-1,2,4-oxadiazol-5- and 1.64-1.74 (m, 3 H), 1.81-1.90 (m, 1 H), 1.91-1.98 (m, 2 H), (M + H).sup.+ yl)cyclopropyl]methyl} 137 1.98-2.11 (m, 4 H), 2.34 (s, 3 H), 2.72-2.87 (m, 4 H), 6.93 (d, (ES.sup.+), at amino)spiro[cyclo hexane- J = 7.8 Hz, 1 H), 7.02 (t, J = 7.2 Hz, 1 H), 7.24 (t, J = 7.8 Hz, 3.12 min, 1,3′-indol]-2′(1′H)-one 1 H), 7.58 (d, J = 7.8 Hz, 1 H), 7.98-8.23 (m, 1 H). UV active 24-1 Isomer 1: 4-({(1R,3S)-3- 80 c (400 MHz, CDCl.sub.3) □: 1.54-1.77 (m, 5 H), 1.85-2.15 (m, 7 H), S m/z 421 [3-(trifluoromethyl)-1,2,4- and 2.17-2.34 (m, 2 H), 2.34-2.57 (m, 1 H), 2.75-2.88 (m, 1 H), (M + H).sup.+ oxadiazol-5- 133 3.45-3.57 (m, 1 H), 3.58-3.78 (m, 1 H), 6.93-6.98 (m, 1 H), (ES.sup.+), at yl]cyclopentyl}amino) 6.98-7.04 (m, 1 H), 7.24 (t, J = 7.8 Hz, 1 H), 7.52-7.65 (m, 1 4.42 min, spiro [cyclohexane-1,3′- H), 8.52 (br. s., 1 H). UV active indol]-2′(1′H)-one 24-2 Isomer 1: 5′-methyl-4- 70 l (400 MHz, MeOD-d.sub.4) □: 1.47-1.62 (m, 3 H), 1.63-1.85 (m, 3 R m/z 435 ({(1R,3S)-3-[3- and H), 1.85-1.98 (m, 4 H), 1.98-2.09 (m, 2 H), 2.09-2.33 (m, 1 (M + H).sup.+ (trifluoromethyl)-1,2,4- 138 H), 2.35 (s, 3 H), 2.35-2.68 (m, 1 H), 2.79-2.91 (m, 1 H), 3.54- (ES.sup.+), at oxadiazol-5- 3.84 (m, 3 H), 6.83 (d, J = 7.8 Hz, 1 H), 7.05 (d, J = 7.9 Hz, 1 4.19 min, yl]cyclopentyl}amino) H), 7.57 (s, 1 H). NH not observed. UV active spiro[cyclohexane- 1,3′-indol]-2′(1′H)-one 24-3 Isomer 1: 6′-methyl-4- 68 l (400 MHz, MeOD-d.sub.4) □: 1.29 (s, 1 H), 1.59-1.77 (m, 1 H), R m/z 381 {[(1R,3S)-3-(3-methyl- and 1.73-1.81 (m, 4 H), 1.81-1.92 (m, 3 H), 2.00-2.20 (m, 5 H), (M + H).sup.+ 1,2,4-oxadiazol-5- 126 2.30 (s, 3 H), 2.33 (s, 3 H), 2.49 (dt, J = 13.6, 7.0 Hz, 1 H), 2.71- (ES.sup.+), at yl)cyclopentyl]amino} 2.81 (m, 1 H), 3.32-3.53 (m, 2 H), 6.70 (s, 1 H), 6.82 (d, J = 7.7 3.41 min, spiro[cyclohexane- Hz, 1 H), 7.08 (d, J = 7.7 Hz, 1 H). NH not observed. UV active 1,3′-indol]-2′(1′H)-one 25-1 Isomer 1: 4-[6-(3-ethyl- 65 l (400 MHz, CDCl.sub.3) □: 1.33 (t, J = 7.6 Hz, 3 H), 1.49-1.61 (m, 2 E m/z 393 1,2,4-oxadiazol-5-yl)-2- and H), 1.62-1.79 (m, 2 H), 1.82-1.95 (m, 4 H), 2.14-2.25 (m, 1 (M + H).sup.+ azaspiro[3.3]hept-2- 140 H), 2.56-2.70 (m, 4 H), 2.76 (q, J = 7.8 Hz, 2 H), 3.28 (s, 2 H), (ES.sup.+), at yl]spiro[cyclohexane- 3.38 (s, 2 H), 3.57-3.68 (m, 1 H), 6.91 (d, J = 7.8 Hz, 1 H), 6.98 3.77 min, 1,3′-indol]-2′(1′H)-one (t, J = 7.6 Hz, 1 H), 7.22 (t, J = 7.4 Hz, 1 H), 7.60 (d, J = 7.4 Hz, UV active 1 H), 8.08 (br. s., 1 H). 26-1 Isomer 2: 5′-methyl-4-[2- 70 c (400 MHz, MeOD-d.sub.4) □: 1.55 (d, J = 10.7 Hz, 2 H), 1.80-1.96 R m/z 407 (3-methyl-1,2,4- and (m, 4 H), 2.01 (t, J = 7.2 Hz, 2 H), 2.06-2.17 (m, 3 H), 2.34 (s, (M + H).sup.+ oxadiazol-5-yl)-6- 133 2 × 3 H), 2.42-2.53 (m, 2 H), 2.61 (t, J = 10.5 Hz, 2 H), 2.78 (ES.sup.+), at azaspiro[3.4]oct-6- (t, J = 7.1 Hz, 2 H), 2.98 (s, 2 H), 3.65-3.77 (m, 1 H), 6.82 (d, 3.11 min, yl]spiro[cyclohexane- J = 7.9 Hz, 1 H), 7.05 (d, J = 8.0 Hz, 1 H), 7.61 (s, 1 H). NH not UV active 1,3′-indol]-2′(1′H)-one observed. 26-2 Isomer 1: 5′-methoxy-4- 80 c (400 MHz, MeOD-d.sub.4) □: 1.54-1.64 (m, 2 H), 1.76-1.96 (m, 4 S m/z 423 [2-(3-methyl-1,2,4- and H), 2.02 (t, J = 7.3 Hz, 1 H), 2.05-2.15 (m, 2 H), 2.15-2.21 (m, (M + H).sup.+ oxadiazol-5-yl)-6- 133 1 H), 2.28-2.38 (m, 3 H), 2.47-2.65 (m, 4 H), 2.75-2.95 (m, (ES.sup.+), at azaspiro[3.4]oct-6- 4 H), 2.99 (s, 1 H), 3.63-3.83 (m, 4 H), 6.78-6.90 (m, 2 H), 3.00 min, yl]spiro[cyclohexane- 7.36 (dd, J = 9.5, 2.3 Hz, 1 H). NH not observed. UV active 1,3′-indol]-2′(1′H)-one 26-2 Isomer 3: 5′-methoxy-4- 80 c (400 MHz, MeOD-d4) □: 1.76-1.92 (m, 4 H), 2.06-2.27 (m, 4 S m/z 423 [2-(3-methyl-1,2,4- and H), 2.34 (s, 3 H), 2.36 (d, J = 12.1 Hz, 1 H), 2.43-2.51 (m, 5 H), (M + H).sup.+ oxadiazol-5-yl)-6- 133 2.75-2.90 (m, 5 H), 3.68-3.82 (m, 4 H), 6.69-6.85 (m, 3 H). (ES.sup.+), at azaspiro[3.4]oct-6- NH not observed. 3.29 min, yl]spiro[cyclohexane- UV active 1,3′-indol]-2′(1′H)-one 26-3 Isomer 1: 4-[2-(3-ethyl- 65 l (400 MHz, CDCI3) □: 1.27-1.37 (m, 3 H), 1.64-2.02 (m, 7 H), E m/z 407 1,2,4-oxadiazol-5-yl)-6- and 2.00-2.15 (m, 3 H), 2.20-2.33 (m, 1 H), 2.40-2.58 (m, 4 H), (M + H).sup.+ azaspiro[3.4]oct-6- 141 2.64-2.89 (m, 6 H), 3.56-3.72 (m, 1 H), 6.92 (d, J = 7.8 Hz, 1 (ES.sup.+), at yl]spiro[cyclohexane- H), 6.99 (td, J = 7.6, 5.0 Hz, 1 H), 7.17-7.27 (m, 1 H), 7.59 (d, 4.02 min, 1,3′-indol]-2′(1′H)-one J = 7.6 Hz, 1 H), 8.44 (s, 1 H). UV active 27-1 Isomer 2: 4-({[2-(3-ethyl- 12 l (400 MHz, CDCI3) □: 1.12 (ddd, J = 8.6, 6.4, 4.7 Hz, 1 H), 1.30 E m/z 351 1,2,4-oxadiazol-5- and (t, J = 7.6 Hz, 3 H), 1.42 (dt, J = 9.2, 4.8 Hz, 1 H), 1.72-1.92 (M + H).sup.+ yl)cyclopropyl]methyl} 143 (m, 5 H), 1.96-2.08 (m, 3 H), 2.24-2.36 (m, 3 H), 2.61 (dd, J = (ES.sup.+), at amino)-1-phenyl- 12.4, 6.8 Hz, 1 H), 2.64-2.75 (m, 3 H), 2.95-3.05 (m, 1 H), 4.52 min, cyclohexanecarbonitrile 7.25-7.35 (m, 1 H), 7.39 (dd, J = 8.6, 6.8 Hz, 2 H), 7.44-7.54 UV active (m, 2 H). 28-1 Isomer 2: 1-(5- 27 c (400 MHz, MeOD-d4) □: 1.48-1.85 (m, 4 H), 1.86-2.10 (m, 5 R m/z 424 fluoropyridin-2-yl)-4- and H), 2.17-2.40 (m, 2 H), 2.45-2.60 (m, 3 H), 2.91-2.97 (m, 1 (M + H).sup.+ ({(1R,3S)-3-[3- 138 H), 3.29-3.33 (m, 1 H), 3.34-3.44 (m, 1 H), 3.52-3.77 (m, 1 (ES.sup.+), at (trifluoromethyl)-1,2,4- H), 7.61-7.76 (m, 2 H), 8.50 (t, J = 2.6 Hz, 1 H). 4.70 min, oxadiazol-5- UV active yl]cyclopentyl}amino) cyclohexanecarbonitrile 28-2 Isomer 2: 1-(5- 43 c (400 MHz, MeOD-d4) □: 1.64-1.71 (m, 5 H), 1.85-2.05 (m, 5 R m/z 420 methylpyridin-2-yl)-4- and H), 2.08-2.28 (m, 2 H), 2.30-2.40 (m, 4 H), 2.40-2.56 (m, 2 (M + H).sup.+ ({(1R,3S)-3-[3- 138 H), 2.90-2.98 (m, 1 H), 3.29-3.50 (m, 1 H), 3.50-3.76 (m, 1 (ES.sup.+), at (trifluoromethyl)-1,2,4- H), 7.56 (d, J = 8.4 Hz, 1 H), 7.71 (d, J = 8.4 Hz, 1 H), 8.44 (s, 4.98 min, oxadiazol-5- 1 H). UV active yl]cyclopentyl}amino) cyclohexanecarbonitrile

Biological Activity

Example A

[0498] Phospho-ERK1/2 assays

[0499] 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 M1, M3 (Gq/11 coupled) and M2, M4 receptors (Gi/o coupled), rather than using different assay formats for different receptor subtypes. CHO cells stably expressing the human muscarinic M1, M2, M3 or M4 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.

[0500] pEC.sub.50 and E.sub.max figures were calculated from the resulting data for each receptor subtype.

[0501] The results are a range of examples are set out in Table 4 below.

[0502] For each example at least two diastereomers exist which, when indicated, have been separated, and assigned based on their retention time on analytical LCMS. Analytical data for all active isomers is reported in Table 3.

TABLE-US-00004 TABLE 4 Muscarinic Activity pEC.sub.50 M1 pEC.sub.50 M2 pEC.sub.50 M3 pEC.sub.50 M4 (% Emax (% Emax (% Emax (% Emax Ex. No. cf. ACh) cf. ACh) cf. ACh) cf. ACh) ACh 8.33 (102) 7.82 (105) 8.12 (115) 8.09 (110) 1-1 Isomer 2 7.29 (117) <4.7 (3) <4.7 (18) <4.7 (18) 1-2 Isomer 2 6.68 (102) <4.7 (23) <4.7 (1) 6.13 (52) 1-3 Isomer 2 7.51 (119) <4.7 (0) <4.7 (1) <4.7 (13) 1-4 Isomer 2 7.45 (98) <4.7 (3) <4.7 (8) <4.7 (7) 1-5 Isomer 2 6.94 (125) <4.7 (5) <4.7 (33) <4.7 (46) 1-6 Isomer 2 6.64 (116) NT NT 5.75 (49) 1-8 Isomer 2 6.6 (120) NT NT <4.7 (0) 1-9 Isomer 2 7.56 (99) <4.7 (6) <4.7 (2) <4.7 (12) 1-10 Isomer 2 7.55 (106) <4.7 (6) <4.7 (9) <4.7 (24) 1-11 Isomer 2 6.83 (99) <4.7 (0) <4.7 (1) <4.7 (9) 1-14 Isomer 2 6.91 (89) <4.7 (2) <4.7 (0) <4.7 (32) 1-15 Isomer 2 6.57 (39) NT NT <4.7 (7) 1-20 Isomer 2 6.83 (78) <4.7 (0) <4.7 (0) <4.7 (19) 1-21 Isomer 2 6.96 (64) <4.7 (1) <4.7 (5) <4.7 (15) 2-1 isomer 1 7.13 (74) <4.7 (2) <4.7 (4) <4.7 (10) 2-2 isomer 1 6.80 (103) NT NT 6.06 (84) 2-3 isomer 1 7.11 (32) NT NT <4.7 (1) 2-4 isomer 1 7.18 (65) <4.8 (3) <4.8 (11) <4.8 (11) 2-5 isomer 1 8.11 (49) <4.7 (13) <4.7 (15) <4.8 (5) 2-6 isomer 1 6.73 (66) <4.7 (11) <4.7 (16) 7.22 (54) 2-7 isomer 2 7.28 (89) <4.7 (5) <4.7 (2) <4.7 (16) 2-7 isomer 1 5.75 (35) NT NT <4.7 (1) 2-8 isomer 1 7.03 (59) NT NT <4.7 (10) 2-9 isomer 1 6.55 (77) NT NT <4.7 51) 2-10 isomer 1 8.10 (64) <4.7 (27) <4.7 (4) <4.7 (39) 2-14 isomer 2 6.93 (77) NT NT <4.7 56) 2-17 isomer 1 7.25 (48) <4.7 (7) <4.7 (7) <4.7 (18) 2-18 isomer 1 6.83 (122) <4.7 (21) <4.7 (11) 6.76 (141) 2-19 isomer 1 5.68 (63) NT NT <4.7 (19) 2-20 isomer 1 6.43 (32) NT NT <4.7 (16) 2-21 isomer 2 6.33 (58) NT NT 6.61 (86) 3-2 mixture of 7.60 (96) <4.7 (7) <4.7 (46) 7.13 (76) isomers 3-3 mixture of 8.01 (101) <4.7 (38) <4.7 (35) 7.20 (85) isomers 3-4 mixture of 6.53 (86) <4.7 (12) <4.7 (40) 6.08 (46) isomers 3-5 mixture of 7.08 (101) <4.7 (5) <4.7 (36) 6.51 (47) isomers 3-6 mixture of 8.02 (105) <4.7 (11) <4.7 (38) 7.00 (62) isomers 3-7 mixture of 6.41 (101) <4.7 (35) <4.7 (34) 5.77 (48) isomers 3-8 mixture of 7.45 (106) <4.7 (18) <4.7 (7) 6.98 (62) isomers 3-9 mixture of 6.94 (98) <4.7 (33) <4.7 (0) <4.7 (2) isomers 3-11 mixture of 7.14 (97) <4.7 (43) <4.7 (15) 6.41 (99) isomers 3-12 mixture of 6.81 (116) <4.7 (5) <4.7 (3) 5.97 (48) isomers 3-16 mixture of 8.18 (103) <4.7 (10) <4.7 (39) 6.90 (90) isomers 3-17 Isomer 1 8.52 (92) <4.7 (0) <4.7 (0) 7.14 (80) 3-19 Isomer 2 7.52 (101) <4.7 (5) <4.7 (6) 5.76 (39) 3-20 Isomer 2 7.94 (139) <4.7 (27) <4.7 (2) <4.7 (7) 3-21 mixture of 6.14 (90) <4.7 (3) <4.7 (2) <4.7 (53) isomers 3-26 mixture of 7.39 (85) NT NT NT isomers 3-28 mixture of 6.11 (116) <4.7 (15) <4.7 (7) 6.61 (91) isomers 3-29 mixture of 6.27 (75) <4.7 (3) <4.7 (3) 6.70 (68) isomers 3-30 Isomer 1 6.53 (104) <4.7 (6) <4.7 (0) 6.64 (72) 3-31 Isomer 1 7.71 (91) <4.7 (8) <4.7 (0) 5.59 (52) 3-32 Isomer 1 7.65 (106) <4.7 (2) <4.7 (0) 6.12 (30) 4-3 isomer 2 6.10 (57) <4.7 (3) <4.7 (2) <4.7 (20) 4-4 isomer 2 6.59 (48) NT NT <4.7 (12) 4-6 isomer 1 6.24 (85) NT NT 5.49 (26) 4-6 isomer 2 7.44 (130) <4.8 (39) <4.8 (17) 7.12 (116) 4-7 isomer 1 7.35 (115) <4.7 (16) <4.7 (20) 5.27 (100) 4-8 isomer 1 5.96 (67) NT NT 6.42 (52) 4-8 isomer 2 6.69 (97) <4.7 (17) <4.7 (9) 7.01 (95) 4-11 isomer 2 6.88 (107) <4.7 (9) <4.7 (2) 6.51 (55) 4-12 isomer 1 7.05 (107) <4.7 (3) <4.7 (34) <4.7 (10) 4-13 isomer 2 6.02 (38) NT NT 6.46 (39) 4-14 isomer 1 6.01 (76) NT NT <4.7 (24) 4-16 isomer 1 6.05 (60) NT NT <4.7 (5) 4-17 isomer 2 6.36 (89) NT NT <4.7 (19) 4-19 isomer 1 5.17 (104) NT NT 6.49 (97) 4-24 isomer 1 6.09 (75) NT NT 6.50 (61) 5-1 Isomer 2 7.18 (115) <4.7 (8) <4.7 (7) 6.29 (26) 6-2 - Isomer 2 7.23 (129) <4.7 (0) <4.7 (12) 7.27 (49) 7-1 isomer 1 6.59 (112) NT NT 6.80 (26) 7-1 isomer 2 6.31 (68) NT NT 6.55 (20) 7-2 isomer 1 7.12 (122) <4.7 (37) <4.7 (3) 6.77 (32) 7-2 isomer 2 6.41 (66) NT NT <4.7 (10) 9-1 Isomer 1 6.67 (84) <4.7 (7) <4.7 (0) <4.7 (14) 10-1 mixture of 7.41 (39) NT NT <4.7 (8) isomers 11-1 Isomer 2 6.56 (105) <4.7 (1) <4.7 (3) <4.7 (19) 12-1 isomer 1 7.86 (109) <4.7 (18) <4.7 (1) 8.32 (82) 12-2 isomer 1 7.59 (65) <4.7 (27) <4.7 (0) 7.97 (48) 13-1 Isomer 2 9.35 (121) <4.7 (21) <4.7 (7) 9.84 (121) 14-1 Isomer 2 7.05 (106) <4.7 (0) <4.7 (1) 6.45 (63) 15-1 Isomer 2 6.81 (117) <4.7 (14) <4.7 (6) 6.84 (21) 17-1 Isomer 2 7.01 (111) <4.7 (9) <4.7 (9) 6.60 (61) 19-1 Isomer 2 5.76 (45) <4.7 (21) <4.7 (8) 6.65 (83) 19-2 Isomer 2 6.72 (118) 5.62 (35) <4.7 (5) 6.86 (96) 20-1 Isomer 2 6.66 (78) <4.7 (61) <4.7 (30) 6.90 (58) 21-2 Isomer 3 7.14 (77) <4.7 (16) <4.7 (15) 7.21 (58) 21-3 Isomer 3 6.25 (51) NT NT <4.7 (15) 21-3 Isomer 4 6.79 (80) NT NT 7.16 (75) 21-4 Isomer 4 5.67 (47) NT NT 6.51 (68) 21-5 Isomer 1 <4.7 (18) NT NT 5.97 (55) 21-5 Isomer 2 4.84 (82) NT NT 5.90 (51) 22-1 Isomer 1 6.64 (83) <4.7 (11) <4.7 (11) 6.40 (47) 22-2 Isomer 1 7.15 (55) <4.7 (12) <4.7 (21) 6.27 (42) 22-3 Isomer 1 6.91 (51) <4.7 (17) <4.7 (59) 6.85 (40) 22-4 Isomer 1 7.10 (76) <4.7 (20) <4.7 (17) 6.66 (39) 23-1 Isomer 1 6.46 (113) NT <4.7 (8) 6.60 (78) 24-1 Isomer 1 6.66 (89) <4.7 (16) <4.7 (23) 6.98 (62) 24-2 Isomer 1 7.20 (62) 5.12 (38) 4.80 (100) 5.36 (85) 24-3 Isomer 1 6.45 (81) NT NT 6.38 (39) 25-1 Isomer 1 6.21 (43) <4.7 (13) <4.7 (6) 6.81 (70) 26-1 Isomer 2 7.82 (74) <4.7 (22) <4.7 (7) 7.39 (50) 26-2 Isomer 1 7.79 (38) <4.7 (6) <4.7 (4) 7.09 (35) 26-2 Isomer 3 6.65 (51) NT NT <4.7 (14) 26-3 Isomer 1 7.03 (31) <4.7 (11) <4.7 (19) 7.54 (72) 27-1 Isomer 2 6.27 (92) NT NT 6.75 (84) 28-1 Isomer 2 6.01 (59) NT NT 6.08 (45) 28-2 Isomer 2 5.46 (40) NT NT 6.02 (55) NT—Not tested

Example B

Pharmaceutical Formulations

(i) Tablet Formulation

[0503] A tablet composition containing a compound of the formula (1) is prepared by mixing 50 mg of the compound with 197 mg of lactose (BP) as diluent, and 3 mg magnesium stearate as a lubricant and compressing to form a tablet in known manner.

(ii) Capsule Formulation

[0504] A capsule formulation is prepared by mixing 100 mg of a compound of the formula (1) with 100 mg lactose and optionally 1% by weight of magnesium stearate and filling the resulting mixture into standard opaque hard gelatin capsules.

EQUIVALENTS

[0505] The foregoing examples are presented for the purpose of illustrating the invention and should not be construed as imposing any limitation on the scope of the invention. It will readily be apparent that numerous modifications and alterations may be made to the specific embodiments of the invention described above and illustrated in the examples without departing from the principles underlying the invention. All such modifications and alterations are intended to be embraced by this application.