N-PHENYLAMINOCARBONYL PYRIDINO-, PYRIMIDINO AND BENZO-TROPANES AS MODULATORS OF GPR65

Abstract

One aspect of the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, (I) wherein: ring A is a 5 or 6 membered aromatic or heteroaromatic ring, wherein said aromatic or heteroaromatic ring is optionally substituted with one or more substituents selected from F, Cl, Br, I, CN, alkoxy, NR.sub.11R.sub.11′, OH, alkyl, haloalkyl, aralkyl, aryl, and heteroaryl, and wherein said aryl and heteroaryl substituents are in turn optionally substituted with one or more substituents each independently selected from F, Cl, Br, I, CN, alkoxy, NR.sub.11R.sub.11′, OH, alkyl, haloalkyl, and aralkyl; Y is selected from C═N—OH and CR10R.sub.10′, wherein R.sub.10 and R.sub.10′, are each independently selected from H, F, alkyl, and haloalkyl; R.sub.1, R.sub.4, and R.sub.5 are each independently selected from H, F, Cl, Br, and I; R.sub.2 and R.sub.3 are each independently selected from H, F, Cl, Br, I, CN, methoxy, and haloalkyl; and R.sub.11 and R.sub.11′ wherein R.sub.12 and R.sub.13 are both alkyl; for use as a medicament. Further aspects of the invention relate to compounds of formula (I) for use in the field of immuno-oncology, immunology, and related applications, and compounds of formula (I) per se.

##STR00001##

Claims

1. A compound of formula (If), or a pharmaceutically acceptable salt or solvate thereof, ##STR00367## wherein: ring A is a pyridinyl ring or tautomer thereof, or a phenyl ring, each of which may be optionally substituted with one or more substituents selected from H, F, Cl, Br, I, CN, alkoxy, NR.sub.11R.sub.11′, OH, alkyl, phenyl, and haloalkyl; Y is selected from C═N—OH and CR.sub.10R.sub.10′, wherein R.sub.10 and R.sub.10′ are each independently selected from H, F, alkyl, and haloalkyl; R.sub.a and R.sub.b are each independently selected from H and alkyl; R.sub.1, R.sub.4, and R.sub.5 are each independently selected from H, CN, alkyl, alkoxy, haloalkyl, OH, F, Cl, Br, and I; R.sub.2 and R.sub.3 are each independently selected from H, F, Cl, Br, I, CN, alkoxy, haloalkyl, haloalkoxy, alkyl, aryl, heteroaryl, O-aryl, NHCO-alkenyl and CO.sub.2-alkyl, wherein said aryl, heteroaryl and O-aryl groups are each optionally further substituted by one or more groups independently selected from halo, alkyl and alkoxy; and R.sub.11 and R.sub.11′ are each independently selected from H, alkyl, haloalkyl, COR.sub.12, CO.sub.2R.sub.12 and SO.sub.2R.sub.13, wherein R.sub.12 and R.sub.13 are both independently alkyl.

2. The compound according to claim 1 wherein ring A is selected from the following: ##STR00368## ##STR00369## wherein R.sub.6, R.sub.7, R.sub.8, and R.sub.9 are each independently selected from H, F, Cl, Br, I, CN, alkoxy, NR.sub.11R.sub.11′, OH, alkyl, phenyl, and haloalkyl, and R.sub.14 is H or alkyl.

3. A compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, ##STR00370## wherein: ring A is selected from the groups (i)-(xx): ##STR00371## ##STR00372## ##STR00373## wherein R.sub.6, R.sub.7, R.sub.3, and R.sub.9 are each independently selected from H, F, Cl, Br, I, CN, alkoxy, NR.sub.11R.sub.11′, OH, alkyl, phenyl, and haloalkyl, and R.sub.14 is H or alkyl; Y is selected from C═N—OH and CR.sub.10R.sub.10′, wherein R.sub.10 and R.sub.10′ are each independently selected from H, F, alkyl, and haloalkyl; R.sub.a and R.sub.b are each independently selected from H and alkyl; R.sub.1, R.sub.4, and R.sub.5 are each independently selected from H, CN, alkyl, alkoxy, haloalkyl, OH, F, Cl, Br, and I; R.sub.2 and R.sub.3 are each independently selected from H, F, Cl, Br, I, CN, alkoxy, haloalkyl, haloalkoxy, alkyl, aryl, heteroaryl, O-aryl, NHCO-alkenyl and CO.sub.2-alkyl, wherein said aryl, heteroaryl and O-aryl groups are each optionally further substituted by one or more groups independently selected from halo, alkyl and alkoxy; and R.sub.11 and R.sub.11′ are each independently selected from H, alkyl, haloalkyl, COR.sub.12, CO.sub.2R.sub.12 and SO.sub.2R.sub.13, wherein R.sub.12 and R.sub.13 are both independently alkyl.

4. The compound according to claim 3, wherein ring A is selected from (i), (ii), (iii), (iv), (v), (vi), (viii), (ix), (xiv), (xv) and (xix).

5. The compound according to claim 3, which is of formula: ##STR00374##

6-8. (canceled)

9. The compound according to claim 3, wherein Y is selected from CH.sub.2 and C═N—OH.

10. The compound according to claim 3, wherein R.sub.2 and R.sub.3 are: i) each independently selected from H, F, Cl, Br, CN, methoxy, OCF.sub.3, CF.sub.3, OCHF.sub.2, Me, Ph, pyrazolyl, oxazolyl, thiazolyl, OPh, NHCO—CH═CH.sub.2 and CO.sub.2Me, wherein said Ph, OPh, pyrazolyl, oxazolyl and thiazolyl groups are each optionally further substituted by one or more alkyl groups; (ii) each independently selected from F, Cl, Br, I, CN, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 haloalkoxy and CO.sub.2-alkyl; (iii) each independently selected from Cl, Br, and CF.sub.3; or (iv) are both Cl, or one of R.sub.2 and R.sub.3 is Cl and the other is selected from OCF.sub.3, CO.sub.2Me, OCHF.sub.2 and CF.sub.3.

11-13. (canceled)

14. The compound according to claim 3, wherein R.sub.1 and R.sub.4 are both H.

15. The compound according to claim 3, wherein R.sub.5 is selected from H, F, Me, MeO, Cl, OH and CN.

16. The compound according to claim 3, wherein R.sub.6, R.sub.7, R.sub.8, and R.sub.9 are each independently selected from H, F, Cl, Br, CN, OMe, NH.sub.2, NHBu, NHCO.sub.2Bu and OH.

17. The compound according to claim 3, which is of formula (Ib.1): ##STR00375## or which is in the form of a mixture that is enantiomerically enriched with a compound of formula (Ib.1).

18. The compound according to claim 3 which is selected from the following: ##STR00376## ##STR00377## ##STR00378## ##STR00379## ##STR00380## ##STR00381## ##STR00382## ##STR00383## ##STR00384## ##STR00385## ##STR00386## ##STR00387## ##STR00388## ##STR00389## ##STR00390## ##STR00391## ##STR00392## ##STR00393## ##STR00394## ##STR00395## ##STR00396## ##STR00397## ##STR00398## ##STR00399## ##STR00400## ##STR00401## ##STR00402## ##STR00403## ##STR00404## ##STR00405## ##STR00406## ##STR00407## and enantiomers thereof, and mixtures of enantiomers thereof, including racemic mixtures, and pharmaceutically acceptable salts and solvates thereof.

19. A compound of formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, ##STR00408## wherein: ring A is ##STR00409## wherein R.sub.6 and R.sub.3 are each independently selected from H, F, Cl, Br, I, CN, alkoxy, OH, phenyl, and haloalkyl; Y is selected from C═N—OH and CR.sub.10R.sub.10′, wherein R.sub.10 and R.sub.10′ are each independently selected from H, F, alkyl, and haloalkyl; R.sub.a and R.sub.b are each independently selected from H and alkyl; R.sub.1, R.sub.4, and R.sub.5 are each independently selected from H, F, Cl, Br, and I; and R.sub.2 and R.sub.3 are each independently selected from F, Cl, Br, I, CN, alkoxy, and haloalkyl; with the proviso that that when Y is CH.sub.2, and R.sub.a, R.sub.b, R.sub.1, R.sub.4, R.sub.5, R.sub.6 and R.sub.3 are all H: R.sub.3 is not CN, when R.sub.2 is C.sub.1; and R.sub.2 and R.sub.3 are not both Cl.

20. The compound according to claim 19 wherein R.sub.2 and R.sub.3 are each independently selected from F, Cl, Br, I, CN and haloalkyl.

21. The compound according to claim 19 wherein R.sub.2 is selected from F, Cl, Br and CF.sub.3; and R.sub.3 is selected from F, Cl, Br, OMe, CN and CF.sub.3.

22. (canceled)

23. The compound according to claim 19 wherein R.sub.1, R.sub.4 and R.sub.5 are all H.

24. The compound according to claim 19 wherein Y is selected from CH.sub.2 and CHF.

25. The compound according to claim 19 wherein R.sub.6 is H.

26. The compound according to claim 19 wherein R.sub.8 is selected from H, CF.sub.3, phenyl, OH and F, optionally wherein R.sub.8 is OH, and ring A is: ##STR00410##

27. (canceled)

28. The compound according to claim 19, which is of formula (Ie.1): ##STR00411## or which is in the form of a mixture that is enantiomerically enriched with a compound of formula (Ie.1).

29. The compound according to claim 19 which is selected from the following: ##STR00412## ##STR00413## ##STR00414## ##STR00415## ##STR00416## ##STR00417## ##STR00418## and enantiomers thereof, and mixtures of enantiomers thereof, including racemic mixtures, and pharmaceutically acceptable salts and solvates thereof.

30. A pharmaceutical composition comprising the compound according to claim 1, claim 3, or claim 13, and a pharmaceutically acceptable diluent, excipient, or carrier.

31. (canceled)

32. A method of treating or preventing a disorder selected from the group consisting of a proliferative disorder, an immune disorder, asthma, chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS), said method comprising administering to a subject a therapeutically effective amount of the compound according to claim 1, claim 3, or claim 13.

33-45. (canceled)

46. A method of treating or preventing a disorder selected from the group consisting of a proliferative disorder, an immune disorder, asthma, chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS), said method comprising administering to a subject a compound selected from the following: ##STR00419## ##STR00420## ##STR00421## ##STR00422## ##STR00423## ##STR00424## ##STR00425## ##STR00426## ##STR00427## ##STR00428## ##STR00429## ##STR00430## ##STR00431## ##STR00432## ##STR00433## ##STR00434## ##STR00435## ##STR00436## ##STR00437## ##STR00438## ##STR00439## ##STR00440## ##STR00441## ##STR00442## ##STR00443## ##STR00444## ##STR00445## ##STR00446## ##STR00447## ##STR00448## ##STR00449## ##STR00450## ##STR00451## ##STR00452## ##STR00453## ##STR00454## ##STR00455## ##STR00456## ##STR00457## ##STR00458## ##STR00459## ##STR00460## ##STR00461## ##STR00462## ##STR00463## ##STR00464## ##STR00465## and enantiomers thereof, and mixtures of enantiomers thereof, including racemic mixtures, and pharmaceutically acceptable salts and solvates thereof.

Description

FIGURES

[1290] FIG. 1 depicts the solved X-ray crystal structure for (5R,8S)—N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (compound 52).

[1291] FIG. 2 depicts the solved X-ray crystal structure for (5S,8R)—N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (compound 53).

EXAMPLES

[1292] Where the preparation of starting materials is not described, these are commercially available, known in the literature, or readily obtainable by those skilled in the art using standard procedures. Where it is indicated that compounds were prepared analogously to earlier examples or intermediates, it will be appreciated by the skilled person that the reaction time, number of equivalents of reagents, solvent, concentration and temperature can be modified for each specific reaction and that it may be necessary or desirable to employ different work-up or purification techniques.

[1293] General Schemes

[1294] Abbreviations

[1295] A list of some common abbreviations is shown below—where other abbreviations are used which are not listed, these will be understood by the person skilled in the art. [1296] AcOH: Acetic acid; Boc: tert-butyloxycarbonyl br.: broad; CAN: ceric ammonium nitrate; d: doublet; DCM: dichloromethane; DIPEA: N,N-diisopropylethylamine; DMF: N,N-dimethylformamide; DMSO: dimethylsulfoxide; (ES+): electrospray ionization positive mode; Et.sub.3N: triethylamine; EtOAc: ethyl acetate; EtOH: ethanol; h: hours; HPLC: high performance liquid chromatography; HCl: hydrochloric acid; Hz: hertz; IPA: iso-propyl alcohol; J: coupling constant; I: litre; LDA: lithium diisopropylamide; M: molar; m: multiplet [M+H]+: protonated molecular ion; mCPBA: meta-chloroperoxybenzoic acid; MeCN: acetonitrile; MeOH: methanol; MHz: megahertz; min: minutes; ml: millilitres; MS: mass spectrometry; MTBE: methyl tert-butyl ether; m/z: mass-to-charge ratio; NFSI: N-Fluorobenzenesulfonimide; NMR: nuclear magnetic resonance; Pd-170: chloro(crotyl)(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)palladium(II); Pd-172: chloro(crotyl)(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)palladium(II); Pd-175: allyl(2-di-tert-butylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)palladium(II) triflate Pd-178: chloro(crotyl)(tricyclohexylphosphine)palladium(II); [1297] Pd.sub.2(dba).sub.3:Tris(dibenzylideneacetone)dipalladium(0); PDA: photodiode array; PMP: para-methoxyphenyl; RT: room temperature; Rt: retention time; s: singlet; SFC: supercritical fluid chromatography; SCX: solid supported cation exchange (resin); S-Phos: 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl; t:triplet; TFA: trifluoroacetic acid; THF: tetrahydrofuran; TLC: thin layer chromatography; UPLC: ultra performance liquid chromatography; UV: ultra-violet.

[1298] Other abbreviations are intended to convey their generally accepted meaning.

General Experimental Conditions

[1299] All starting materials and solvents were obtained either from commercial sources or prepared according to literature methods. The appropriate isocyanate and aniline starting materials were obtained from Sigma Aldrich, Fluorochem or Enamine store, or were synthesised as described herein. The appropriate tricyclic amine starting materials were obtained from Enamine store or were synthesised as described herein. Reaction mixtures were magnetically stirred and reactions performed at room temperature (approximately 20° C.) unless otherwise indicated.

[1300] Silica gel chromatography was performed on an automated flash chromatography system, such as CombiFlash Companion, CombiFlash Rf system or Reveleris X2 flash system using RediSep® Rf or Reveleris® or the GraceResolv™ pre-packed silica (230-400 mesh, 40-63 μm) cartridges.

[1301] Analytical UPLC-MS experiments to determine retention times and associated mass ions were performed using a Waters ACQUITY UPLC® H-Class system, equipped with ACQUITY PDA Detector and ACQUITY QDa mass spectrometer or Waters SQD mass spectrometer, running the analytical method described below.

[1302] Analytical LC-MS experiments to determine retention times and associated mass ions were performed using an Agilent 1200 series HPLC system coupled to an Agilent 1956, 6100 or 6120 series single quadrupole mass spectrometer running one of the analytical methods described below or a Shimadzu-2020-P2 system consisting of a Shimadzu LC-20AD series LC system and a Shimadzu-2020, single quadrupole mass spectrometer running one of the analytical methods described below

[1303] Analytical SFC experiments to determine retention times were performed using a Waters SFC system UPC2 system with a column temperature of 40° C. and a back pressure (ABPR) of 1750 psi using one of the analytical methods described below.

[1304] Preparative HPLC purifications were performed either using either a Waters X-Bridge BEH C.sub.18, 5 μm, 19×50 mm column, or a Waters Xbridge Prep OBD C.sub.18, 10 μm, 40×150 mm column, or a Phenomenex Gemini-NX C.sub.18, 3 μm, 30×75 mm column using a gradient of MeCN and 10 mM aqueous ammonium bicarbonate. Fractions were collected following UV detection across all wavelengths with PDA and in some cases an SQD2 or ACQUITY QDa mass spectrometer.

[1305] Preparative SFC purifications were performed using a Waters SFC prep 15 system with either a: Phenomenex Lux® Cellulose-4, Column 1×25 cm, 5 μm particle size column or a Chiralpak® IG (Daicel Ltd.) column (1×25 cm, 5 μm particle size), flow rate 15 ml/min eluting with a mixture of CO.sub.2 and co-solvent (MeOH, EtOH or IPA). Fractions were collected following UV detection at 210-400 nm using a PDA.

[1306] NMR spectra were recorded using either a Bruker Avance Ill HD 500 MHz instrument or a Bruker Avance Neo 400 MHz, using either residual non-deuterated solvent, or tetra-methylsilane as reference or Varian Y 400 MHz instrument, using tetra-methylsilane as reference, or a QOne AS400 400 MHz spectrometer using either residual non-deuterated solvent, or tetra-methylsilane as reference.

[1307] In the absence of the absolute stereochemistry being explicitly indicated through wedged and dashed bonds, chemical structures disclosed throughout the examples (for example, in the configuration (1.3) described hereinabove) are to be interpreted as depicting the racemate. For the avoidance of doubt, the invention encompasses the compounds in either configuration, as well as mixtures thereof.

Analytical Methods

Method 1—Basic 3 Min Method

[1308] Column: Waters ACQUITY UPLC® BEH C.sub.18, 1.7 μm, 2.1×30 mm at 40° C. [1309] Detection: UV at 210-400 nm unless otherwise indicated, MS by electrospray ionisation [1310] Solvents: A: 10 mM aqueous ammonium bicarbonate, B: MeCN [1311] Gradient:

TABLE-US-00001 Time % A % B Flow rate (ml/min) 0.00 95 5 0.77 0.11 95 5 0.77 2.15 5 95 0.77 2.56 5 95 0.77 2.83 95 5 0.77 3.00 95 5 0.77

Method 2—Basic 4 Min Method

[1312] Column: Waters X-Bridge BEH C.sub.18, 2.5 μm, 4.6×30 mm at 40° C. [1313] Detection: UV at 254 nm unless otherwise indicated, MS by electrospray ionisation [1314] Solvents: A: 10 mM aqueous ammonium bicarbonate B: MeCN [1315] Gradient:

TABLE-US-00002 Time % A % B Flow rate (ml/min) 0.0 95.0 5.0 2.5 3.0 5.0 95.0 2.5 3.01 5.0 95.0 4.5 3.6 5.0 95.0 4.5 3.7 95.0 5.0 2.5 4.0 95.0 5.0 2.5

Method 3—Lux® Amylose-2

[1316] Column: Lux® Amylose-2, LC column (150×2 mm, 3 μm particle size) at 40° C. and a flow rate of 1.5 ml/min [1317] Detection: UV detection by DAD at 220-400 nm [1318] Solvents: gradient or an isocratic mixture of a polar solvent, usually methanol, ethanol or IPA in CO.sub.2:

Method 4—CHIRALPAK®IG-3 (Daicel Ltd.) Column

[1319] Column: CHIRALPAK®IG-3 (Daicel Ltd.) column (2.1×150 mm, 3 μm particle size) and a flow rate of 1.5 ml/min [1320] Detection: UV detection by DAD at 220-400 nm [1321] Solvents: gradient or an isocratic mixture of a polar solvent, usually methanol, ethanol or IPA in CO.sub.2:

Method 5—Basic 4 Min Method

[1322] Column: Gemini LC Column C18 50×2 mm, 3 μm particle size at 40° C. [1323] Detection: UV at 220 nm unless otherwise indicated, MS by electrospray ionisation [1324] Solvents: A: 10 mM aqueous ammonium bicarbonate, B: MeCN [1325] Gradient:

TABLE-US-00003 Time % A % B Flow rate (ml/min) 0.0 100 0 0.6 0.4 100 0 0.6 3.00 10 90.0 0.6 3.85 0 100 0.6 3.86 100 0 0.6 4.0 100 0 0.6

Method 6—Basic 4 Min Method

[1326] Column: Waters Sunfire, 3.5 μm, 4.6×50 mm column at 25° C. [1327] Detection: UV at 214 and 254 nm unless otherwise indicated, MS by electrospray ionisation [1328] Solvents: A: 0.05% formic acid in water (v/v) B: 0.05% formic acid MeCN (v/v) [1329] Gradient:

TABLE-US-00004 Time % A % B Flow rate (ml/min) 0.00 85 15 1.0 0.50 85 15 1.0 4.00 0 100 1.0 4.50 0 100 1.0 4.51 85 15 1.0 5.00 85 15 1.0

Experimental Scheme 1

Compound 1 (±)-N-(4-(Trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

[1330] ##STR00136##

[1331] To a solution of 6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine (0.075 g, 0.465 mmol) and Et.sub.3N (97 μl, 0.698 mmol) in THF (4 ml) was added a solution of 1-isocyanato-4-(trifluoromethyl)benzene (0.131 g, 0.698 mmol) in THF (0.75 ml). The resultant mixture was stirred at RT for 20 h. MeOH (5 ml) was added and the crude product was concentrated in vacuo. The product was purified by chromatography on RP Flash C18 (15-75% MeCN/10 mM aqueous ammonium bicarbonate) to afford (±)-N-(4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide as a colourless solid. LC-MS (method 1) m/z 349.3 (M+H).sup.+ (ES.sup.+); at 1.18 min. .sup.1H NMR (500 MHz, DMSO-d6) δ 9.14 (s, 1H), 8.96 (s, 1H), 8.61 (s, 1H), 7.68 (d, J=8.6 Hz, 2H), 7.58 (d, J=8.6 Hz, 2H), 5.31 (d, J=6.2 Hz, 1H), 4.84 (t, J=6.5 Hz, 1H), 3.36-3.33 (m, 1H), 2.79 (d, J=18.4 Hz, 1H), 2.33-2.24 (m, 1H), 2.20 (tt, J=12.2, 6.2 Hz, 1H), 1.90 (ddd, J=12.0, 9.2, 2.5 Hz, 1H), 1.81-1.72 (m, 1H).

[1332] The following compounds were prepared using appropriate starting materials in an analogous procedure to that described in Experimental Scheme 1. Where the starting materials are not described in the literature, their synthesis is described below.

[1333] Key: (a) Reaction performed in DMF (b) reaction performed in DCM (c) Reaction performed in mixture of DMF and DCM (d) product was purified by mass directed HPLC (MeCN/10 mM aqueous ammonium bicarbonate solution, C.sub.18) (e) product was purified by silica gel chromatography (0.7 M Ammonia/MeOH in DCM) (f) reaction performed in DMF/THF (g) product was purified by silica gel chromatography (DCM in heptane) (h) Reaction performed using DIPEA instead of Et.sub.3N (i) product was purified by silica gel chromatography (EtOAc in isohexane) (j) ES.sup.− [M−H].sup.−, parent mass not observed in ES.sup.+

TABLE-US-00005 LCMS method 1 Compound Structure Rt [M + H].sup.+ NMR 2.sup.(a)(d) [00137] 383.3, 385.3 at 1.31 min .sup.1H NMR (500 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.96 (s, 1H), 8.61 (s, 1H), 7.89 (d, J = 2.0 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.62-7.57 (m, 1H), 5.31 (d, J = 6.2 Hz, 1H), 4.84 (t, J = 6.5 Hz, 1H), 3.31 (d, J = 3.8 Hz, 1H), 2.80 (d, J = 18.4 Hz, 1H), 2.34-2.15 (m, 2H), 1.95- 1.86 (m, 1H), 1.81-1.69 (m, 1H). (±)-N-(3-Chloro-4- (trifluoromethyl)phenyl)-6,7,8,9- tetrahydro-5H-5,8- epiminocyclohepta[d]pyrimidine- 10-carboxamide 3.sup.(a)(d) [00138] 383.3, 385.3 at 1.29 min .sup.1H NMR (500 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.96 (s, 1H), 8.60 (s, 1H), 8.04 (d, J = 2.6 Hz, 1H), 7.79 (dd, J = 8.8, 2.6 Hz, 1H), 7.57 (d, J = 8.8 Hz, 1H), 5.30 (d, J = 6.2 Hz, 1H), 4.82 (t, J = 6.4 Hz, 1H), 3.31 (d, J = 4.8 Hz, 1H), 2.79 (d, J = 18.4 Hz, 1H), 2.34-2.13 (m, 2H), 1.89 (dd, J = 12.1, 2.7 Hz, 1H), 1.77 (dt, J = 15.5, 7.7 Hz, 1H). (±)-N-(4-Chloro-3- (trifluoromethyl)phenyl)-6,7,8,9- tetrahydro-5H-5,8- epiminocyclohepta[d]pyrimidine- 10-carboxamide 4.sup.(a)(d) [00139] 349.3, 351.3 at 1.26 min .sup.1H NMR (500 MHz, DMSO-d6) δ 9.07 (s, 1H), 8.96 (s, 1H), 8.60 (s, 1H), 7.58 (d, J = 1.9 Hz, 2H), 7.14 (t, J = 1.9 Hz, 1H), 5.28 (d, J = 6.2 Hz, 1H), 4.80 (t, J = 6.5 Hz, 1H), 3.32- 3.29 (m, 1H), 2.78 (d, J = 18.4 Hz, 1H), 2.28 (q, J = 11.2, 10.7 Hz, 1H), 2.19 (tt, J = 12.0, 6.2 Hz, 1H), 1.92-1.85 (m, 1H), 1.80-1.71 (m, 1H). (±)-N-(3,5-Dichlorophenyl)- 6,7,8,9-tetrahydro-5H-5,8- epiminocyclohepta[d]pyrimidine- 10-carboxamide 5.sup.(b)(d) [00140] 367.3 at 1.2 min .sup.1H NMR (500 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.96 (s, 1H), 8.60 (s, 1H), 7.92 (dd, J = 6.5, 2.7 Hz, 1H), 7.77 (dt, J = 8.2, 3.8 Hz, 1H), 7.39 (t, J = 9.8 Hz, 1H), 5.29 (d, J = 6.2 Hz, 1H), 4.81 (t, J = 6.5 Hz, 1H), 3.37- 3.34 (m, 1H), 2.78 (d, J = 18.2 Hz, 1H), 2.34-2.14 (m, 2H), 1.93-1.85 (m, 1H), 1.76 (dd, J = 18.2, 10.1 Hz, 1H). (±)-N-(4-Fluoro-3- (trifluoromethyl)phenyl)-6,7,8,9- tetrahydro-5H-5,8- epiminocyclohepta[d]pyrimidine- 10-carboxamide 6.sup.(b)(d) [00141] 317.3 at 1.01 min .sup.1H NMR (500 MHz, DMSO-d6) δ 8.95 (s, 2H), 8.59 (s, 1H), 7.61 (ddd, J = 13.6, 7.5, 2.6 Hz, 1H), 7.30 (dt, J = 10.6, 9.1 Hz, 1H), 7.24-7.17 (m, 1H), 5.27 (d, J = 6.2 Hz, 1H), 4.80 (t, J = 6.4 Hz, 1H), 3.36-3.33 (m, 1H), 2.81-2.74 (m, 1H), 2.32- 2.24 (m, 1H), 2.19 (tt, J = 12.1, 6.2 Hz, 1H), 1.93-1.84 (m, 1H), 1.80-1.71 (m, 1H). (±)-N-(3,4-Difluorophenyl)- 6,7,8,9-tetrahydro-5H-5,8- epiminocyclohepta[d]pyrimidine- 10-carboxamide 7.sup.(b)(d) [00142] 393.2, 395.2, 396.3, 397.4 at 1.24 min .sup.1H NMR (500 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.96 (s, 1H), 8.60 (s, 1H), 7.83 (d, J = 2.5 Hz, 1H), 7.60 (d, J = 8.8 Hz, 1H), 7.38 (dd, J = 8.9, 2.5 Hz, 1H), 5.28 (d, J = 6.1 Hz, 1H), 4.80 (t, J = 6.5 Hz, 1H), 3.31- 3.27 (m, 1H), 2.81-2.74 (m, 1H), 2.33-2.25 (m, 1H), 2.25- 2.13 (m, 1H), 1.93-1.85 (m, 1H), 1.76 (dt, J = 15.5, 7.6 Hz, 1H). (±)-N-(4-Bromo-3- chlorophenyl)-6,7,8,9- tetrahydro-5H-5,8- epiminocyclohepta[d]pyrimidine- 10-carboxamide 8.sup.(b)(d) [00143] 345.3, 347.4 at 1.00 min .sup.1H NMR (500 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.74 (s, 1H), 8.58 (s, 1H), 7.58 (d, J = 2.6 Hz, 1H), 7.33 (dd, J = 9.0, 2.6 Hz, 1H), 7.03 (d, J = 9.0 Hz, 1H), 5.25 (d, J = 6.2 Hz, 1H), 4.77 (t, J = 6.4 Hz, 1H), 3.78 (s, 3H), 3.31-3.28 (m, 1H), 2.75 (d, J = 18.4 Hz, 1H), 2.27 (q, J = 11.5, 10.8 Hz, 1H), 2.18 (tt, J = 12.1, 6.2 Hz, 1H), 1.92-1.83 (m, 1H), 1.75 (dt, J = 15.0, 7.6 Hz, 1H). (±)-N-(3-Chloro-4- methoxyphenyl)-6,7,8,9- tetrahydro-5H-5,8- epiminocyclohepta[d]pyrimidine- 10-carboxamide 12.sup.(d) [00144] 393.3, 395.3 at 1.24 min .sup.1H NMR (500 MHz, DMSO-d6) δ 9.01 (s, 1H), 8.96 (s, 1H), 8.59 (s, 1H), 7.95 (d, J = 2.4 Hz, 1H), 7.53-7.44 (m, 2H), 5.28 (d, J = 6.2 Hz, 1H), 4.83- 4.77 (m, 1H), 3.35-3.33 (m, 1H), 2.78 (d, J = 18.3 Hz, 1H), 2.27 (d, J = 10.9 Hz, 1H), 2.19 (dt, J = 11.3, 5.4 Hz, 1H), 1.93- 1.85 (m, 1H), 1.76 (s, 1H). (±)-N-(3-Bromo-4- chlorophenyl)-6,7,8,9- tetrahydro-5H-5,8- epiminocyclohepta[d]pyrimidine- 10-carboxamide 13.sup.(d) [00145] 384.3, 386.3 at 1.07 min .sup.1H NMR (500 MHz, DMSO-d6) δ 9.35 (s, 1H), 8.96 (s, 1H), 8.61 (s, 1H), 8.04 (d, J = 2.0 Hz, 1H), 7.78 (d, J = 8.7 Hz, 1H), 7.64 (dd, J = 8.7, 2.1 Hz, 1H), 5.31 (d, J = 6.2 Hz, 1H), 4.87-4.80 (m, 1H), 3.34 (d, J = 4.7 Hz, 1H), 2.80 (d, J = 18.3 Hz, 1H), 2.31-2.14 (m, 2H), 1.94-1.86 (m, 1H), 1.76 (dd, J = 18.2, 10. Hz, 1H). (±)-N-(3-Bromo-4-cyanophenyl)- 6,7,8,9-tetrahydro-5H-5,8- epiminocyclohepta[d]pyrimidine- 10-carboxamide 16.sup.(b)(d) [00146] 437.3, 439.3, 441.3 at 1.27 min .sup.1H NMR (500 MHz, DMSO-d6) δ 9.01 (s, 1H), 8.96 (s, 1H), 8.59 (s, 1H), 7.96 (d, J = 2.5 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.43 (dd, J = 8.8, 2.5 Hz, 1H), 5.28 (d, J = 6.1 Hz, 1H), 4.83-4.77 (m, 1H), 3.37- 3.33 (m, 1H), 2.78 (d, J = 18.4 Hz, 1H), 2.27 (q, J = 10.9, 10.5, Hz, 1H), 2.19 (tt, J = 12.1, 6.2 Hz, 1H), 1.93-1.85 (m, 1H), 1.76 (dt, J = 15.9, 7.7 Hz, 1H). (±)-N-(3,4-Dibromophenyl)- 6.7,8,9-tetrahydro-5H-5,8- epiminocyclohepta[d]pyrimidine- 10-carboxamide 17.sup.(a)(e) [00147] 349.3, 351.3 at 1.24 min .sup.1H NMR (500 MHz, DMSO-d6) δ 9.09 (s, 1H), 8.92 (s, 1H), 8.56 (s, 1H), 7.84 (d, J = 2.2 Hz, 1H), 7.49-7.42 (m, 2H), 5.12 (d, J = 6.1 Hz, 1H), 4.80 (t, J = 6.1 Hz, 1H), 3.31-3.24 (m, 1H), 2.68 (d, J = 17.2 Hz, 1H), 2.32-2.19 (m, 2H), 1.90- 1.84 (m, 1H), 1.71 (dt, J = 9.7, 5.2 Hz, 1H). (±)-N-(3,4-Dichlorophenyl)- 6,7,8,9-tetrahydro-5H-6,9- epiminocyclohepta[d]pyrimidine- 10-carboxamide 18.sup.(a)(e) [00148] 383.4, 385.3 at 1.35 min .sup.1H NMR (500 MHz, DMSO-d6) δ 9.35 (s, 1H), 8.92 (s, 1H), 8.57 (s, 1H), 7.91 (d, J = 2.1 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.61 (d, J = 9.6 Hz, 1H), 5.15 (d, J = 6.0 Hz, 1H), 4.83 (t, J = 6.1 Hz, 1H), 3.29 (d, J = 7.3 Hz, 1H), 2.70 (d, J = 17.1 Hz, 1H), 2.33-2.17 (m, 2H), 1.94- 1.86 (m, 1H), 1.72 (dt, J = 9.5, 4.9 Hz, 1H). (±)-N-(3-Chloro-4- (trifluoromethyl)phenyl)-6,7,8,9- tetrahydro-5H-6,9- epiminocyclohepta[d]pyrimidine- 10-carboxamide 24.sup.(b)(e)(h) [00149] 417.3, 419.3 at 1.60 min .sup.1H NMR (500 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.87 (s, 1H), 7.82 (d, J = 2.4 Hz, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.44 (dd, J = 8.9, 2.4 Hz, 1H), 5.40 (d, J = 6.1 Hz, 1H), 4.85 (t, J = 6.3 Hz, 1H), 3.42 (dd, J = 18.8, 5.0 Hz, 1H), 2.93 (d, J = 18.8 Hz, 1H), 2.31-2.24 (m, 1H), 2.24- 2.18 (m, 1H), 1.99-1.91 (m, 1H), 1.88-1.77 (m, 1H). (±)-N-(3,4-Dichlorophenyl)-2- (trifluoromethyl)-6,7,8,9- tetrahydro-5H-5,8- epiminocyclohepta[d]pyrimidine- 10-carboxamide 25.sup.(b)(e)(h) [00150] 363.3, 365.3 at 1.23 min .sup.1H NMR (500 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.46 (s, 1H), 7.82 (d, J = 2.3 Hz, 1H), 7.50- 7.42 (m, 2H), 5.24 (d, J = 6.1 Hz, 1H), 4.77 (t, J = 6.5 Hz, 1H), 3.27 (dd, J = 18.2, 5.2 Hz, 1H), 2.71 (d, J = 18.3 Hz, 1H), 2.53 (s, 3H), 2.26 (q, J = 11.1 Hz, 1H), 2.17 (tt, J = 12.0, 6.2 Hz, 1H), 1.85 (dd, J = 12.2, 9.1 Hz, 1H), 1.73 (dt, J = 15.2, 7.9 Hz, 1H). (±)-N-(3,4-Dichlorophenyl)-2- methyl-6,7,8,9-tetrahydro-5H- 5,8- epiminocyclohepta[d]pyrimidine- 10-carboxamide 26.sup.(a)(e)(h) [00151] 425.3, 427.3 at 1.76 min .sup.1H NMR (500 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.70 (s, 1H), 8.38-8.31 (m, 2H), 7.84 (d, J = 2.1 Hz, 1H), 7.54-7.48 (m, 3H), 7.48-7.43 (m, 2H), 5.33 (d, J = 6.1 Hz, 1H), 4.84 (t, J = 6.5 Hz, 1H), 3.40 (dd, J = 18.4, 5.0 Hz, 1H), 2.87 (d, J = 18.2 Hz, 1H), 2.30 (q, J = 10.9, 10.4 Hz, 1H), 2.22 (tt, J = 12.0, 6.1 Hz, 1H), 1.94 (t, J = 10.8 Hz, 1H), 1.86-1.75 (m, 1H). (±)-N-(3,4-Dichlorophenyl)-2- phenyl-6,7,8,9-tetrahydro-5H- 5,8- epiminocyclohepta[d]pyrimidine- 10-carboxamide 27.sup.(b)(d) [00152] 450.4, 452.4 at 1.67 min .sup.1H NMR (500 MHz, DMSO-d6) δ 9.34 (s, 1H), 8.89 (s, 1H), 7.89 (d, J = 2.0 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.60 (d, J = 9.0 Hz, 1H), 5.43 (d, J = 6.2 Hz, 1H), 4.88 (t, J = 6.4 Hz, 1H), 3.44 (dd, J = 19.0, 5.2 Hz, 1H), 2.95 (d, J = 18.8 Hz, 1H), 2.34-2.17 (m, 2H), 1.98 (dd, J = 12.1, 9.0 Hz, 1H), 1.88-1.80 (m, 1H). (±)-N-(3-Chloro-4- (trifluoromethyl)phenyl)-2- (trifluoromethyl)-6,7,8,9- tetrahydro-5H-5,8- epiminocyclohepta[d]pyrimidine- 10-carboxamide 28.sup.(b)(e)(h) [00153] 459.3, 461.3 at 1.77 min .sup.1H NMR (500 MHz, DMSO-d6) δ 9.20 (s, 1H), 8.71 (s, 1H), 8.34 (dd, J = 6.7, 3.1 Hz, 2H), 8.06 (d, J = 2.6 Hz, 1H), 7.80 (dd, J = 8.9, 2.6 Hz, 1H), 7.57 (d, J = 8.9 Hz, 1H), 7.54-7.48 (m, 3H), 5.35 (d, J = 6.1 Hz, 1H), 4.86 (t, J = 6.4 Hz, 1H), 3.42 (dd, J = 18.2, 5.0 Hz, 1H), 2.88 (d, J = 18.2 Hz, 1H), 2.36- 2.27 (m, 1H), 2.27-2.17 (m, 1H), 1.95 (t, J = 10.6 Hz, 1H), 1.87-1.78 (m, 1H). (±)-N-(4-Chloro-3- (trifluoromethyl)phenyl)-2- phenyl-6,7,8,9-tetrahydro-5H- 5,8- epiminocyclohepta[d]pyrimidine- 10-carboxamide 29.sup.(b)(d) [00154] 459.4, 461.4 at 1.78 min .sup.1H NMR (500 MHz, DMSO-d6) δ 9.31 (s, 1H), 8.71 (s, 1H), 8.34 (dd, J = 6.7, 3.0 Hz, 2H), 7.91 (d, J = 2.1 Hz, 1H), 7.71 (d, J = 8.7 Hz, 1H), 7.62 (d, J = 9.5 Hz, 1H), 7.53-7.48 (m, 3H), 5.36 (d, J = 6.1 Hz, 1H), 4.87 (t, J = 6.4 Hz, 1H), 3.41 (dd, J = 18.3, 5.1 Hz, 1H), 2.89 (d, J = 18.3 Hz, 1H), 2.34- 2.18 (m, 2H), 1.95 (t, J = 10.5 Hz, 1H), 1.82 (d, J = 7.9 Hz, 1H). (±)-N-(3-Chloro-4- (trifluoromethyl)phenyl)-2- phenyl-6,7,8,9-tetrahydro-5H- 5,8- epiminocyclohepta[d]pyrimidine- 10-carboxamide 31.sup.(b)(e)(h) [00155] 365.3, 367.3 at 1.06 min .sup.1H NMR (500 MHz, DMSO-d6) δ 11.68 (s, 1H), 8.96 (s, 1H), 7.85 (d, J = 2.1 Hz, 1H), 7.51- 7.43 (m, 2H), 5.10 (d, J = 5.9 Hz, 1H), 4.68 (t, J = 6.4 Hz, 1H), 3.11-3.01 (m, 1H), 2.21 (q, J = 11.1 Hz, 1H), 2.06 (tt, J = 11.7, 6.1 Hz, 1H), 1.81 (t, J = 10.7 Hz, 1H), 1.75-1.68 (m, 1H). (2H underlying DMSO peak) (±)-N-(3,4-Dichlorophenyl)-2- oxo-2,5,6,7,8,9-hexahydro-1H- 5,8- epiminocyclohepta[d]pyrimidine- 10-carboxamide 32.sup.(b)(e)(h) [00156] 399.3, 401.3 at 1.15 min .sup.1H NMR (500 MHz, DMSO-d6) δ 11.73 (s, 1H), 9.20 (s, 1H), 7.91 (s, 2H), 7.72 (d, J = 8.8 Hz, 1H), 7.65-7.56 (m, 1H), 5.12 (d, J = 5.9 Hz, 1H), 4.71 (t, J = 6.6 Hz, 1H), 3.10 (dd, J = 18.6, 5.1 Hz, 1H), 2.56 (d, J = 18.5 Hz, 1H), 2.22 (q, J = 11.2 Hz, 1H), 2.12-2.02 (m, 1H), 1.82 (t, J = 10.6 Hz, 1H), 1.74 (dt, J = 15.7, 8.0 Hz, 1H) (±)-N-(3-Chloro-4- (trifluoromethyl)phenyl)-2-oxo- 2,5,6,7,8,9-hexahydro-1H-5,8- epiminocyclohepta[d]pyrimidine- 10-carboxamide 34.sup.(b)(g)(h) [00157] 347.3, 349.3 at 1.69 min .sup.1H NMR (500 MHz, DMSO-d6) δ 8.87 (s, 1H), 7.86 (t, JJ = 1.3 Hz, 1H), 7.46 (d, JJ = 1.6 Hz, 2H), 7.19-7.12 (m, 3H), 7.10 (d, JJ = 6.8 Hz, 1H), 5.16 (d, JJ = 5.9 Hz, 1H), 4.70 (t, JJ = 6.2 Hz, 1H), 2.62 (d, JJ = 16.9 Hz, 1H), 2.26-2.09 (m, 2H), 1.83- 1.75 (m, 1H), 1.67 (dt, JJ = 15.1, 7.4 Hz, 1H). (1H obscured by water peak) (±)-N-(3,4-Dichlorophenyl)- 6,7,8,9-tetrahydro-5H-5,8- epiminobenzo[7]annulene-10- carboxamide 35.sup.(b)(d)(h) [00158] 382.4, 384.3 at 1.40 min .sup.1H NMR (500 MHz, DMSO-d6) δ 9.22 (s, 1H), 8.35-8.30 (m, 2H), 7.91 (d, J = 2.1 Hz, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.64- 7.59 (m, 1H), 7.19 (d, J = 5.0 Hz, 1H), 5.19 (d, J = 6.3 Hz, 1H), 4.81 (t, J = 6.4 Hz, 1H), 3.28 (d, J = 4.9 Hz, 1H), 2.69 (d, J = 17.1 Hz, 1H), 2.31- 2.13 (m, 2H), 1.87-1.78 (m, 1H), 1.76-1.67 (m, 1H) (±)-N-(3-Chloro-4- (trifluoromethyl)phenyl)-6,7,8,9- tetrahydro-5H-5,8- epiminocyclohepta[c]pyridine- 10-carboxamide 36.sup.(b)(d)(h) [00159] 348.3, 350.3 at 1.33 min .sup.1H NMR (500 MHz, DMSO-d6) δ 8.96 (s, 1H), 8.32 (t, J = 2.4 Hz, 2H), 7.84 (d, J = 2.1 Hz, 1H), 7.50-7.42 (m, 2H), 7.18 (d, J = 4.9 Hz, 1H), 5.16 (d, J = 6.3 Hz, 1H), 4.77 (t, J = 6.3 Hz, 1H), 3.31-3.25 (m, 1H), 2.67 (d, J = 17.1 Hz, 1H), 2.29- 2.12 (m, 2H), 1.85-1.77 (m, 1H), 1.75-1.66 (m, 1H) (±)-N-(3,4-Dichlorophenyl)- 6,7,8,9-tetrahydro-5H-5,8- epiminocyclohepta[c]pyridine- 10-carboxamide 37.sup.(b)(d)(h) [00160] 382.4, 384.3 at 1.42 min 1H NMR (500 MHz, DMSO-d6) δ 9.21 (s, 1H), 8.37 (s, 1H), 8.33 (d, J = 5.0 Hz, 1H), 7.91 (d, J = 2.0 Hz, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.64-7.59 (m, 1H), 7.15 (d, J = 5.0 Hz, 1H), 5.28 (d, J = 6.0 Hz, 1H), 4.75 (t, J = 6.2 Hz, 1H), 3.28 (d, J = 4.9 Hz, 1H), 2.69 (d, J = 17.7 Hz, 1H), 2.29-2.15 (m, 2H), 1.88-1.80 (m, 1H), 1.70 (t, J = 6.4 Hz, 1H) (±)-N-(3-Chloro-4- (trifluoromethyl)phenyl)-6,7,8,9- tetrahydro-5H-6,9- epiminocyclohepta[c]pyridine- 10-carboxamide 48.sup.(e)(h) [00161] 349.3, 351.3 at 1.22 min .sup.1H NMR (500 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.96 (s, 1H), 8.60 (s, 1H), 7.83 (d, J = 2.4 Hz, 1H), 7.51-7.41 (m, 2H), 5.28 (d, J = 6.2 Hz, 1H), 4.80 (t, J = 6.5 Hz, 1H), 3.29 (s, 1H), 2.78 (d, J = 18.4 Hz, 1H), 2.28 (dt, J = 11.0, 10.2 Hz, 1H), 2.19 (tt, J = 12.1, 6.2 Hz, 1H), 1.94- 1.85 (m, 1H), 1.76 (dt, J = 15.5, 7.7 Hz, 1H). (±)-N-(3,4-Dichlorophenyl)- 6,7,8,9-tetrahydro-5H-5,8- epiminocyclohepta[d]pyrimidine- 10-carboxamide 49 [00162] 315.2, 317.2 at 1.05 min .sup.1H NMR (500 MHz, DMSO- d6) δ 8.95 (s, 1H), 8.89 (s, 1H), 8.59 (s, 1H), 7.48 (dd, J = 9.1, 2.6 Hz, 2H), 7.30-7.22 (m, 2H), 5.28 (d, J = 6.2 Hz, 1H), 4.80 (t, J = 6.4 Hz, 1H), 3.36- 3.33 (m, 1H), 2.77 (d, J = 18.4 Hz, 1H), 2.32-2.23 (m, 1H), 2.19 (tt, J = 12.0, 6.1 Hz, 1H), 1.88 (ddd, J = 12.1, 9.3, 2.5 Hz, 1H), 1.75 (td, J = 10.5, 8.8, 6.1 Hz, 1H). (±)-N-(4-Chlorophenyl)-6,7,8,9- tetrahydro-5H-5,8- epiminocyclohepta[d]pyrimidine- 10-carboxamide 50 [00163] 315.2, 317.2 at 1.06 min .sup.1H NMR (500 MHz, DMSO- d6) δ 8.96 (s, 1H), 8.94 (s, 1H), 8.60 (s, 1H), 7.64 (t, J = 2.1 Hz, 1H), 7.42-7.36 (m, 1H), 7.25 (t, J = 8.1 Hz, 1H), 6.99 (dd, J = 8.0, 2.1 Hz, 1H), 5.28 (d, J = 6.2 Hz, 1H), 4.81 (t, J = 6.5 Hz, 1H), 3.30 (s, 1H), 2.77 (d, J = 18.4 Hz, 1H), 2.32-2.25 (m, 1H), 2.19 (td, J = 12.0, 6.2 Hz, 1H), 1.89 (ddd, J = 12.0, 9.2, 2.5 Hz, 1H), 1.76 (dt, J = 15.4, 8.2 Hz, 1H). (±)-N-(3-Chlorophenyl)-6,7,8,9- tetrahydro-5H-5,8- epiminocyclohepta[d]pyrimidine- 10-carboxamide 51 [00164] 333.3, 335.3 at 1.03 min .sup.1H NMR (500 MHz, DMSO-d6) δ 8.96 (s, 1H), 8.78 (s, 1H), 8.59 (s, 1H), 7.60 (dd, J = 6.9, 2.7 Hz, 1H), 7.25 (dd, J = 10.5, 8.8 Hz, 1H), 7.15 (ddd, J = 8.9, 4.1, 2.7 Hz, 1H), 5.25 (d, J = 6.1 Hz, 1H), 4.78 (t, J = 6.5 Hz, 1H), 3.41-3.35 (m, 1H), 2.76 (d, J = 18.3 Hz, 1H), 2.33- 2.14 (m, 2H), 1.93-1.82 (m, 1H), 1.80-1.70 (m, 1H). (±)-N-(5-Chloro-2-fluorophenyl)- 6,7,8,9-tetrahydro-5H-5,8- epiminocyclohepta[d]pyrimidine- 10-carboxamide 54 [00165] 381.3, 383.4 at 1.76 min .sup.1H NMR (500 MHz, DMSO-d6) δ 9.14 (s, 1H), 7.92 (d, J = 2.0 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.62 (dd, J = 8.9, 2.1 Hz, 1H), 7.19-7.08 (m, 4H), 5.19 (d, J = 5.9 Hz, 1H), 4.76-4.70 (m, 1H), 3.37-3.28 (m, 1H), 2.64 (d, J = 16.9 Hz, 1H), 2.28- 2.11 (m, 2H), 1.85-1.77 (m, 1H), 1.69 (dt, J = 15.2, 7.3 Hz, 1H) (±)-N-(3-Chloro-4- (trifluoromethyl)phenyl)-6,7,8,9- tetrahydro-5H-5,8- epiminobenzo[7]annulene-10- carboxamide 55 [00166] 381.3, 383.4 at 1.74 min .sup.1H NMR (500 MHz, DMSO-d6) δ 9.02 (s, 1H), 8.08 (d, J = 2.6 Hz, 1H), 7.81 (dd, J = 8.9, 2.6 Hz, 1H), 7.55 (d, J = 8.9 Hz, 1H), 7.20-7.04 (m, 4H), 5.17 (d, J = 5.9 Hz, 1H), 4.79-4.66 (m, 1H), 3.39-3.35 (m, 1H), 2.63 (d, J = 16.8 Hz, 1H), 2.29- 2.08 (m, 2H), 1.87-1.74 (m, 1H), 1.68 (dt, J = 14.4, 7.3 Hz, 1H (±)-N-(4-Chloro-3- (trifluoromethyl)phenyl)-6,7,8,9- tetrahydro-5H-5,8- epiminobenzo[7]annulene-10- carboxamide 56.sup.(b)(h) [00167] 377.3, 379.3 at 1.65 min .sup.1H NMR (500 MHz, DMSO-d6) δ 8.84 (s, 1H), 7.86 (s, 1H), 7.46 (s, 2H), 7.04 (d, J = 8.2 Hz, 1H), 6.82-6.55 (m, 2H), 5.12 (d, J = 5.9 Hz, 1H), 4.77- 4.53 (m, 1H), 3.70 (s, 3H), 2.58 (d, J = 16.9 Hz, 1H), 2.24- 2.06 (m, 2H), 1.80-1.70 (m, 1H), 1.69-1.60 (m, 1H), 1H obscured by residual water peak. (±)-N-(3,4-Dichlorophenyl)-2- methoxy-6,7,8,9-tetrahydro-5H- 5,8-epiminobenzo[7]annulene- 10-carboxamide 57.sup.(b)(h) [00168] 363.3, 365.3 at 1.35 min .sup.1H NMR (500 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.81 (s, 1H), 7.86 (dd, J = 2.0, 0.8 Hz, 1H), 7.55-7.38 (m, 23), 6.91 (d, J = 8.2 Hz, 1H), 6.51 (dd, J = 8.1, 2.5 Hz, 1H), 6.48 (d, J = 2.4 Hz, 1H), 5.07 (d, J = 5.9 Hz, 1H), 4.63 (t, J = 6.3 Hz, 1H), 3.24 (dd, J = 16.8, 4.9 Hz, 1H), 2.17 (q, J = 10.9 Hz, 1H), 2.13- 2.02 (m, 1H), 1.81-1.69 (m, 1H), 1.68-1.54 (m, 1H), OH proton not visible (±)-N-(3,4-Dichlorophenyl)-2- hydroxy-6,7,8,9-tetrahydro-5H- 5,8-epiminobenzo[7]annulene- 10-carboxamide 73.sup.(b)(h) [00169] 362.2, 364.5 at 1.39 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.77 (s, 1H), 7.86 (d, J = 2.2 Hz, 1H), 7.50-7.42 (m, 2H), 6.76 (d, J = 8.0 Hz, 1H), 6.32 (dd, J = 8.0, 2.3 Hz, 1H), 6.28 (d, J = 2.2 Hz, 1H), 5.00 (d, J = 5.8 Hz, 1H), 4.86 (s, 2H), 4.63- 4.57 (m, 1H), 3.19 (dd, J = 16.5, 4.8 Hz, 1H), 2.44 (d, J = 16.6 Hz, 1H), 2.19-2.13 (m, 1H), 2.12-2.03 (m, 1H), 1.74- 1.68 (m, 1H), 1.62 (br s, 1H). (±)-2-Amino-N-(3,4- dichlorophenyl)-6,7,8,9- tetrahydro-5H-5,8- epiminobenzo[7]annulene-10- carboxamide 74.sup.(b)(i) [00170] 365.2, 367.4 at 1.68 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.88 (s, 1H), 7.84 (t, J = 1.4 Hz, 1H), 7.49-7.43 (m, 2H), 7.17 (dd, J = 9.2, 5.9 Hz, 1H), 6.95 (dd, J = 9.1, 6.1 Hz, 2H), 5.17 (d, J = 5.9 Hz, 1H), 4.68 (t, J = 6.3 Hz, 1H), 2.63 (d, J = 17.2 Hz, 1H), 2.25-2.05 (m, 2H), 1.81-1.72 (m, 1H), 1.71- 1.61 (m, 1H). (Exchangable —NH proton not seen). (±)-N-(3,4-Dichlorophenyl)-2- fluoro-6,7,8,9-tetrahydro-5H- 5,8-epiminobenzo[7]annulene- 10-carboxamide 75.sup.(b) [00171] 365.2, 399.3 at 1.75 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 9.14 (s, 1H), 7.91 (d, J = 2.0 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.61 (dd, J = 8.6, 2.1 Hz, 1H), 7.18 (dd, J = 9.3, 5.8 Hz, 1H), 7.01-6.72 (m, 2H), 5.20 (d, J = 6.0 Hz, 1H), 4.71 (t, J = 6.3 Hz, 1H), 2.65 (d, J = 17.3 Hz, 1H), 2.29-2.06 (m, 2H), 1.86-1.73 (m, 1H), 1.71-1.65 (m, 1H). (Exchangable —NH proton not visible). (±)-N-(3-Chloro-4- (trifluoromethyl)phenyl)-2-fluoro- 6,7,8,9-tetrahydro-5H-5,8- epiminobenzo[7]annulene-10- carboxamide 78.sup.(b)(i) [00172] (5R,8S)-N-(3,4-Dichlorophenyl)- 1-fluoro-6,7,8,9-tetrahydro-5H- 366.1, 368.0 at 1.42 min .sup.1H NMR (500 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.01 (d, J = 5.0 Hz, 1H), 7.82 (d, J = 2.3 Hz, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.44 (dd, J = 8.9, 2.3 Hz, 1H), 7.20 (dd, J = 5.1, 1.6 Hz, 1H), 5.23 (d, J = 6.3 Hz, 1H), 4.98- 4.64 (m, 1H), 3.14 (dd, J = 17.5, 5.0 Hz, 1H), 2.59 (d, J = 17.4 Hz, 1H), 2.38-2.04 (m, 2H), 1.91-1.80 (m, 1H), 1.80- 1.69 (m, 1H). 5,8- epiminocyclohepta[c]pyridine- 10-carboxamide 80.sup.(b)(d) [00173] 365.1, 367.1 at 1.64 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.89 (s, 1H), 7.84 (t, J = 1.4 Hz, 1H), 7.46 (s, 1H), 7.13 (dd, J = 8.3, 5.8 Hz, 1H), 7.03- 6.84 (m, 2H), 5.14 (d, J = 6.1 Hz, 1H), 4.70 (t, J = 6.3 Hz, 1H), 3.25 (dd, J = 16.6, 4.9 Hz, 1H), 2.60 (d, J = 16.7 Hz, 1H), 2.28-2.09 (m, 2H), 1.88- 1.74 (m, 1H), 1.74-1.56 (m, 1H). (Exchangeable NH not observed) (±)-N-(3,4-Dichlorophenyl)-3- fluoro-6,7,8,9-tetrahydro-5H-5,8- epiminobenzo[7]annulene-10- carboxamide 81.sup.(b)(d)(h) [00174] 399.1, 401.1 at 1.71 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 9.16 (s, 1H), 7.91 (d, J = 2.1 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.61 (dd, J = 8.7, 2.1 Hz, 1H), 7.13 (dd, J = 8.4, 5.7 Hz, 1H), 7.04-6.94 (m, 2H), 5.17 (d, J = 6.1 Hz, 1H), 4.77-4.71 (m, 1H), 3.26 (dd, J = 16.4, 4.8 Hz, 1H), 2.62 (d, J = 16.7 Hz, 1H), 2.27-2.05 (m, 2H), 1.84- 1.79 (m, 1H), 1.68-1.62 (m, 1H). (±)-N-(3-Chloro-4- (trifluoromethyl)phenyl)-3-fluoro- 6,7,8,9-tetrahydro-5H-5,8- epiminobenzo[7]annulene-10- carboxamide 83.sup.(b)(d)(h) [00175] 365.7, 367.5 at 1.69 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.92 (s, 1H), 7.84 (t, J = 1.4 Hz, 1H), 7.45 (d, J = 1.5 Hz, 2H), 7.19 (td, J = 7.9, 5.7 Hz, 1H), 7.00 (t, J = 8.0 Hz, 2H), 5.21 (d, J = 6.0 Hz, 1H), 4.75 (t, J = 6.3 Hz, 1H), 3.21-3.13 (m, 1H), 2.60 (d, J = 17.2 Hz, 1H), 2.27-2.19 (m, 1H), 2.18- 2.13 (m, 1H), 1.84-1.76 (m, 1H), 1.74-1.65 (m, 1H). (±)-N-(3,4-Dichlorophenyl)-1- fluoro-6,7,8,9-tetrahydro-5H-5,8- epiminobenzo[7]annulene-10- carboxamide 84.sup.(b)(d)(h) [00176] 399.1, 401.1 at 1.72 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 9.18 (s, 1H), 7.91 (d, J = 2.1 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.61 (dd, J = 8.7, 2.1 Hz, 1H), 7.24-7.16 (m, 1H), 7.01 (dd, J = 9.7, 7.5 Hz, 2H), 5.24 (d, J = 6.0 Hz, 1H), 4.79 (t, J = 6.3 Hz, 1H), 3.22-3.14 (m, 1H), 2.63 (d, J = 17.1 Hz, 1H), 2.28-2.12 (m, 2H), 1.86- 1.78 (m, 1H), 1.75-1.67 (m, 1H). (±)-N-(3-Chloro-4- (trifluoromethyl)phenyl)-1-fluoro- 6,7,8,9-tetrahydro-5H-5,8- epiminobenzo[7]annulene-10- carboxamide 85.sup.(b)(d) [00177] (5R,8S)-N-(3-Chloro-4- (trifluoromethyl)phenyl)-1-fluoro- 400.1, 402.1 at 1.50 min .sup.1H NMR (500 MHz, DMSO-d6) δ 9.26 (s, 1H), 8.01 (d, J = 5.0 Hz, 1H), 7.89 (d, J = 2.1 Hz, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.66-7.52 (m, 1H), 7.21 (dd, J = 5.1, 1.5 Hz, 1H), 5.26 (d, J = 6.3 Hz, 1H), 4.91-4.76 (m, 1H), 3.16 (dd, J = 17.4, 4.9 Hz, 1H), 2.61 (d, J = 17.4 Hz, 1H), 2.33-2.11 (m, 2H), 1.96- 1.81 (m, 1H), 1.77 (dt, J = 15.2, 7.1 Hz, 1H). 6,7,8,9-tetrahydro-5H-5,8- epiminocyclohepta[c]pyridine-10- carboxamide 86.sup.(b)(h)(i) [00178] 378.3, 380.3 at 1.49 min .sup.1H NMR (500 MHz, DMSO-d6) δ 8.89 (s, 1H), 7.94 (s, 1H), 7.83 (dd, J = 2.0, 0.8 Hz, 1H), 7.50-7.41 (m, 2H), 6.58 (s, 1H), 5.22 (d, J = 5.9 Hz, 1H), 4.66 (t, J = 6.2 Hz, 1H), 3.78 (s, 3H), 3.24 (dd, J = 17.7, 5.0 Hz, 1H), 2.64 (d, J = 17.7 Hz, 1H), 2.26-2.05 (m, 2H), 1.86- 1.70 (m, 1H), 1.65 (dt, J = 12.0, 7.5 Hz, 1H). (6S,9R)-N-(3,4-Dichlorophenyl)- 3-methoxy-6,7,8,9-tetrahydro- 5H-6,9- epiminocyclohepta[c]pyridine- 10-carboxamide 87.sup.(b)(e)(h) [00179] 347.9, 350.3 at 1.31 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.96 (s, 1H), 8.35 (dd, J = 4.8, 1.7 Hz, 1H), 7.83 (dd, J = 2.0, 0.8 Hz, 1H), 7.55 (dd, J = 7.6, 1.8 Hz, 1H), 7.49-7.41 (m, 2H), 7.16 (dd, J = 7.6, 4.8 Hz, 1H), 5.20 (d, J = 6.1 Hz, 1H), 4.81-4.75 (m, 1H), 3.35 (d, J = 5.1 Hz, 1H), 2.73 (d, J = 17.5 Hz, 1H), 2.25 (q, J = 11.0 Hz, 1H), 2.17 (tt, J = 11.9, 6.1 Hz, 1H), 1.86-1.78 (m, 1H), 1.72 (dt, J = 15.4, 7.7 Hz, 1H). (±)-N-(3,4-Dichlorophenyl)- 6,7,8,9-tetrahydro-5H-5,8- epiminocyclohepta[b]pyridine- 10-carboxamide 91.sup.(b)(h)(i) [00180] 366.4, 368.3, 370.2 at 1.45 min .sup.1H NMR (500 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.04 (s, 1H), 7.82 (d, J = 2.3 Hz, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.44 (dd, J = 8.9, 2.3 Hz, 1H), 6.96 (s, 1H), 5.29 (d, J = 6.0 Hz, 1H), 4.70 (t, J = 6.3 Hz, 1H), 3.34-3.27 (m, 1H), 2.75 (d, J = 18.1 Hz, 1H), 2.30-2.10 (m, 2H), 1.89- 1.76 (m, 1H), 1.68 (dt, J = 14.8, 7.3 Hz, 1H). (6S,9R)-N-(3,4-Dichlorophenyl)- 3-fluoro-6,7,8,9-tetrahydro-5H- 6.9- epiminocyclohepta[c]pyridine- 10-carboxamide 95.sup.(b)(d)(h) [00181] 366.1, 368.1, 370.2 at 1.44 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.98 (s, 1H), 8.35 (s, 1H), 8.28 (s, 1H), 7.82 (d, J = 2.3 Hz, 1H), 7.50-7.41 (m, 2H), 5.33 (d, J = 5.9 Hz, 1H), 4.78 (t, J = 6.2 Hz, 1H), 3.23-3.16 (m, 1H), 2.71 (d, J = 17.9 Hz, 1H), 2.29-2.15 (m, 2H), 1.85 (dd, J = 11.0, 8.3 Hz, 1H), 1.78- 1.71 (m, 1H). (±)-N-(3,4-Dichlorophenyl)-4- fluoro-6,7,8,9-tetrahydro-5H- 6.9- epiminocyclohepta[c]pyridine- 10-carboxamide 103 [00182] 364.3, 366.3 at 1.10 min .sup.1H NMR (500 MHz, DMSO-d6) δ 11.27 (s, 1H), 8.83 (s, 1H), 7.86-7.82 (m, 1H), 7.49- 7.44 (m, 2H), 7.19 (s, 1H), 6.09 (s, 1H), 5.06 (d, J = 6.0 Hz, 1H), 4.62-4.56 (m, 1H), 3.09 (dd, J = 17.9, 5.1 Hz, 1H), 2.55 (d, J = 17.8 Hz, 1H), 2.16 (q, J = 11.0 Hz, 1H), 2.05 (tt, J = 12.0, 6.3 Hz, 1H), 1.76-1.67 (m, 1H), 1.68-1.59 (m, 1H). (6S,9R)-N-(3,4-Dichlorophenyl)- 3-oxo-3,5,6,7,8,9-hexahydro- 2H-6,9- epiminocyclohepta[c]pyridine- 10-carboxamide 104 [00183] 348.1, 350.1 at 1.29 min 1H NMR: (400 MHz, DMSO-d6) δ 9.07-8.81 (m, 1H), 8.34 (s, 1H), 8.31 (d, J = 5.1 Hz, 1H), 7.83 (d, J = 1.1 Hz, 1H), 7.46- 7.43 (m, 2H), 7.13 (d, J = 5.1 Hz, 1H), 5.24 (d, J = 5.7 Hz, 1H), 4.70 (t, J = 6.0 Hz, 1H), 3.30-3.22 (m, 1H), 2.66 (d, J = 17.9 Hz, 1H), 2.29-2.09 (m, 2H), 1.82 (t, J = 9.5 Hz, 1H), 1.68 (dd, J = 12.2, 5.8 Hz, 1H), (±)-N-(3,4-Dichlorophenyl)- 6,7,8,9-tetrahydro-5H-6,9- epiminocyclohepta[c]pyridine- 10-carboxamide 111 [00184] 348.2, 350.3 at 1.31 min .sup.1H NMR (500 MHz, DMSO-d6) δ 8.93 (s, 1H), 8.35 (s, 1H), 8.31 (d, J = 5.0 Hz, 1H), 7.83 (d, J = 2.1 Hz, 1H), 7.49-7.41 (m, 2H), 7.14 (d, J = 5.0 Hz, 1H), 5.25 (d, J = 5.9 Hz, 1H), 4.71 (t, J = 6.2 Hz, 1H), 3.31- 3.24 (m, 1H), 2.67 (d, J = 17.8 Hz, 1H), 2.28-2.12 (m, 2H), 1.86-1.78 (m, 1H), 1.72-1.66 (m, 1H). (6S,9R)-N-(3,4-Dichlorophenyl)- 6,7,8,9-tetrahydro-5H-6,9- epiminocycloheptan[c]pyridine- 10-carboxamide 112.sup.(b)(e)(h) [00185] 348.3, 350.2 at 1.31 min .sup.1H NMR (500 MHz, DMSO-d6) δ 8.93 (s, 1H), 8.35 (s, 1H), 8.31 (d, J = 5.0 Hz, 1H), 7.83 (d, J = 2.1 Hz, 1H), 7.49-7.41 (m, 2H), 7.14 (d, J = 5.0 Hz, 1H), 5.25 (d, J = 5.9 Hz, 1H), 4.71 (t, J = 6.2 Hz, 1H), 3.31- 3.24 (m, 1H), 2.67 (d, J = 17.8 Hz, 1H), 2.28-2.12 (m, 2H), 1.86-1.78 (m, 1H), 1.72-1.66 (m, 1H). (6R,9S)-N-(3,4-Dichlorophenyl)- 6,7,8,9-tetrahydro-5H-6,9- epiminocyclohepta[c]pyridine- 10-carboxamide 116.sup.(c)(i) [00186] 396.6, 398.4 at 1.54 min .sup.1H NMR (500 MHz, DMSO-d6) δ 9.31 (s, 1H), 8.32 (s, 1H), 8.28 (d, J = 4.9 Hz, 1H), 7.77 (d, J = 2.1 Hz, 1H), 7.65 (d, J = 8.9 Hz, 1H), 7.49 (d, J = 8.9 Hz, 1H), 7.11 (d, J = 5.0 Hz, 1H), 5.33 (d, J = 6.5 Hz, 1H), 3.51 (d, J = 16.8 Hz, 1H), 2.69 (d, J = 16.9 Hz, 1H), 2.31- 2.20 (m, 1H), 1.92 (t, J = 8.0 Hz, 2H), 1.75-1.57 (m, 4H) (5R,8S)-N-(3-Chloro-4- (trifluoromethyl)phenyl)-8- methyl-6,7,8,9-tetrahydro-5H- 5,8- epiminocyclohepta[c]pyridine- 10-carboxamide 134.sup.(b)(h)(i) [00187] 362.3, 364.3 at 1.38 min .sup.1H NMR (500 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.48 (s, 1H), 8.32 (dd, J = 4.9, 0.9 Hz, 1H), 7.83 (dd, J = 2.0, 0.8 Hz, 1H), 7.59-7.38 (m, 2H), 7.14 (d, J = 4.9 Hz, 1H), 5.15 (d, J = 6.3 Hz, 1H), 4.65-4.39 (m, 1H), 3.64-3.39 (m, 1H), 2.13 (tt, J = 12.1, 6.6 Hz, 1H), 2.03-1.82 (m, 2H), 1.73 (ddd, J = 11.9, 8.9, 2.9 Hz, 1H), 1.32 (d, J = 7.1 Hz, 3H). (5R,8S,9S)-N-(3,4- Dichlorophenyl)-9-methyl- 6,7,8,9-tetrahydro-5H-5,8- epiminocyclohepta[c]pyridine- 10-carboxamide 135.sup.(b)(h)(i) [00188] 384.3, 386.3, at 1.65 min .sup.1H NMR (500 MHz, DMSO-d6) δ 8.99 (s, 1H), 7.91 (d, J = 1.4 Hz, 1H), 7.82 (d, J = 2.4 Hz, 1H), 7.50-7.40 (m, 2H), 5.35 (d, J = 5.9 Hz, 1H), 4.77 (t, J = 6.2 Hz, 1H), 3.25 (dd, J = 18.2, 5.1 Hz, 1H), 2.82 (d, J = 18.1 Hz, 1H), 2.28-2.12 (m, 2H), 1.84 (t, J = 10.1 Hz, 1H), 1.75 (dt, J = 14.3, 6.9 Hz, 1H) (±)-N-(3,4-Dichlorophenyl)-3,4- difluoro-6,7,8,9-tetrahydro-5H- 6,9- epiminocyclohepta[c]pyridine- 10-carboxamide 140.sup.(b)(h)(i) [00189] 382.5, 384.2 at 1.64 min.sup.(j) .sup.1H NMR (500 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.21 (s, 1H), 7.83 (d, J = 2.5 Hz, 1H), 7.50 (d, J = 8.8 Hz, 1H), 7.45 (dd, J = 8.9, 2.4 Hz, 1H), 7.25 (s, 1H), 6.05 (dd, J = 49.9, 5.4 Hz, 1H), 5.42 (d, J = 5.1 Hz, 1H), 4.94 (t, J = 6.2 Hz, 1H), 2.11 (m, 2H), 2.03-1.89 (m, 1H), 1.74 (t, J = 9.5 Hz, 1H). (5S,6S,9R)-N-(3,4- Dichlorophenyl)-3,5-difluoro- 6,7,8,9-tetrahydro-5H-6,9- epiminocyclohepta[c]pyridine- 10-carboxamide 198 [00190] 364.2, 366.2 at 1.49 min.sup.(j) .sup.1H NMR (500 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.04 (s, 1H), 7.82 (d, J = 2.3 Hz, 1H), 7.53- 7.37 (m, 2H), 6.96 (d, J = 1.7 Hz, 1H), 5.29 (d, J = 6.0 Hz, 1H), 4.70 (t, J = 6.2 Hz, 1H), 2.75 (d, J = 18.1 Hz, 1H), 2.18 (dtd, J = 24.0, 12.3, 7.3 Hz, 2H), 1.87-1.75 (m, 1H), 1.74- 1.61 (m, 1H), 1H under water peak. (6R,9S)-N-(3,4-dichlorophenyl)- 3-fluoro-6,7,8,9-tetrahydro-5H- 6,9- epiminocyclohepta[c]pyridine- 10-carboxamide

Intermediate 1 (I-1)

[1334] ##STR00191##

[1335] Step 1: tert-Butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate I-1a (10 g, 44 mmol) was dissolved in 1,1-dimethoxy-N,N-dimethylmethanamine (21 g, 24 ml, 0.18 mol) and the reaction mixture was heated at reflux for 16 h. The solvent was removed in vacuo. The product was purified by silica gel chromatography (0-5% (0.7 M ammonia/MeOH) in DCM) to afford tert-butyl (E)-2-((dimethylamino)methylene)-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate I-1b as a yellow solid. LCMS (method 2) m/z 281.2 [M+H].sup.+ (ES.sup.+); at 1.60 min. .sup.1H NMR (500 MHz, DMSO-d6) δ 7.25-7.14 (m, 1H), 5.20 (d, J=5.7 Hz, 1H), 4.21 (t, J=6.3 Hz, 1H), 3.07 (s, 6H), 2.54 (s, 1H), 2.09 (s, 3H), 1.77 (t, J=9.0 Hz, 1H), 1.68-1.56 (m, 1H), 1.38 (s, 9H).

[1336] Step 2: To a solution of 2,2,2-trifluoroacetimidamide (192 mg, 132 μl, 1.71 mmol) in MeOH (10 ml) was added a solution of sodium methoxide in MeOH (661 μl, 5.4 M, 3.57 mmol). A solution of tert-butyl (E)-2-((dimethylamino)methylene)-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate I-1b (400 mg, 1.43 mmol) in MeOH (10 ml) was added and the reaction mixture was heated to 80° C. for 16 h. Water (5 ml) and saturated ammonium chloride solution (5 ml) was added. The product was extracted with 20% IPA in chloroform solution (50 ml). The product was purified by silica gel chromatography (0-3% (0.7 M Ammonia/MeOH) in DCM) to afford tert-butyl 2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxylate I-1c as a yellow oil. LCMS (method 2) m/z 330.1 [M+H].sup.+ (ES.sup.+); at 2.28 min. .sup.1H NMR (500 MHz, DMSO-d6) δ 5.12 (d, J=5.8 Hz, 1H), 4.50 (s, 1H), 4.32 (s, 1H), 3.30 (s, 1H), 2.95-2.84 (m, 1H), 2.29-2.11 (m, 2H), 1.91 (t, J=9.9 Hz, 1H), 1.77-1.68 (m, 1H), 1.41-1.23 (m, 9H).

[1337] Step 3: To a solution of tert-butyl 2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxylate I-1c (85 mg, 0.26 mmol) in DCM (2 ml) was added TFA (0.20 ml, 2.6 mmol). The reaction was stirred at RT for 16 h. The crude reaction mixture was concentrated under reduced pressure. 2 ml of 0.7 M ammonia in MeOH was added and the solvent was removed in vacuo to give 2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine as a yellow oil that was used in subsequent steps without further purification. LCMS (method 2) m/z 230.0 [M+H].sup.+ (ES.sup.+); at 1.20 min.

Intermediate 2 (I-2)

[1338] ##STR00192##

[1339] Step 1: tert-Butyl 2-methyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxylate I-2a was prepared from tert-butyl (E)-2-((dimethylamino)methylene)-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate I-1b using a procedure essentially the same as for compound I-1c: LCMS (method 2) m/z 276.1 [M+H].sup.+ (ES.sup.+); at 1.59 min. .sup.1H NMR (500 MHz, DMSO-d6) δ 8.47 (s, 1H), 4.93 (d, J=6.0 Hz, 1H), 4.44 (s, 1H), 3.21-3.12 (m, 1H), 2.67 (d, J=18.2 Hz, 1H), 2.53 (s, 3H), 2.21 (s, 1H), 2.13 (dq, J=11.8, 5.8 Hz, 1H), 1.78 (t, J=10.2 Hz, 1H), 1.66 (dt, J=15.1, 7.6 Hz, 1H), 1.34 (s, 9H).

[1340] Step 2: 2-Methyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine 1-2 was prepared from tert-butyl 2-methyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxylate I-2a using a procedure essentially the same as for I-1: LCMS (method 2) m/z 176.1 [M+H].sup.+ (ES.sup.+); at 0.70 min.

Intermediate 3 (I-3)

[1341] ##STR00193##

[1342] Step 1: tert-Butyl 2-phenyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxylate (I-3a) was prepared from tert-butyl (E)-2-((dimethylamino)methylene)-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate I-1b using a procedure essentially the same as for I-1c: LCMS (method 2) m/z 338.2 [M+H].sup.+ (ES.sup.+); at 2.55 min. .sup.1H NMR (500 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.44-8.27 (m, 2H), 7.51 (p, J=3.4, 3.0 Hz, 3H), 5.02 (d, J=5.9 Hz, 1H), 4.50 (s, 1H), 3.28 (d, J=23.9 Hz, 1H), 2.82 (d, J=18.1 Hz, 1H), 2.32-2.11 (m, 2H), 1.87 (t, J=10.1 Hz, 1H), 1.75 (dd, J=12.7, 6.4 Hz, 1H), 1.40 (s, 9H).

[1343] Step 2: 2-Phenyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine (1-3) was prepared from tert-butyl 2-phenyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxylate (I-3a) using a procedure essentially the same as for I-1: LCMS (method 2) m/z 230.1 [M+H].sup.+ (ES.sup.+); at 1.18 min.

Intermediate 5 (I-5)

[1344] ##STR00194##

[1345] Step 1: To a solution of urea (0.2 g, 4 mmol) in EtOH (10 ml) was added a solution of sodium ethoxide (2 ml, 21% w/w in EtOH, 4 mmol). tert-Butyl (E)-2-((dimethylamino)methylene)-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate I-1b (1 g, 4 mmol) in EtOH (10 ml) was added and the reaction mixture was heated to 90° C. for 16 h. Saturated ammonium chloride solution (5 ml) was added and the product was extracted with 10% (0.7 M ammonia/MeOH) in DCM solution (2×35 ml). The product was purified by silica gel chromatography (0-10% (0.7 M ammonia/MeOH) in DCM) to afford tert-butyl 2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxylate I-5a as a white solid. LCMS (method 2) m/z 278.1 (M+H).sup.+ (ES.sup.+), at 1.3 min. .sup.1H NMR (500 MHz, DMSO-d6) δ 11.68 (s, 1H), 7.96 (s, 1H), 4.79 (d, J=6.0 Hz, 1H), 4.35 (s, 1H), 2.97 (d, J=17.7 Hz, 1H), 2.16 (s, 1H), 2.02 (dt, J=11.9, 5.6 Hz, 1H), 1.78-1.69 (m, 1H), 1.67 (d, J=17.0 Hz, 1H), 1.36 (s, 9H). 1 proton under DMSO peak

[1346] Step 2: To a solution of tert-butyl 2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxylate I-5a (361 mg, 1.30 mmol) in DCM (10 ml) was added TFA (1.00 ml, 13.0 mmol) slowly. The resultant mixture was stirred ON at RT.

[1347] The reaction mixture was concentrated in vacuo. 0.7 M ammonia in MeOH (5 ml) was added and the mixture concentrated in vacuo. The material was purified by SCX eluting with 0.7 M ammonia in MeOH solution to provide 6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidin-2-ol I-5 as a pale yellow solid. .sup.1H NMR (500 MHz, DMSO-d6) δ 7.79 (s, 1H), 7.27 (s, 1H), 6.67 (s, 1H), 4.05 (d, J=5.7 Hz, 1H), 3.69 (t, J=6.4 Hz, 1H), 2.88-2.78 (m, 1H), 2.34 (d, J=18.5 Hz, 1H), 1.91 (d, J=4.4 Hz, 1H), 1.89-1.81 (m, 1H), 1.74-1.62 (m, 1H), 1.56-1.46 (m, 1H).

Intermediate 7 (I-7)

[1348] The following scheme makes use of synthetic methodology described in Schultz and Wolfe, Organic Letters, 2011, 13 (11), 2962-2965.

##STR00195## ##STR00196##

[1349] Step 1: To a solution of 3-bromo-4-pyridinecarboxaldehyde (42.0 g, 225 mmol) in THF (250 ml) was added titanium (IV) ethoxide (93.6 ml, 451 mmol) in one portion at RT. The mixture was stirred at RT for 5 min before (±)-tert-butylsulfinamide (30.1 g, 248 mmol) was added in one portion. The resulting mixture was stirred at RT for 16 h. Water (50 ml) was added at 0° C., and the product was extracted with EtOAc (3×30 ml). The combined organic layers were concentrated in vacuo. The product was purified by silica gel chromatography (1-100% EtOAc/petroleum ether to give (E)-N-((3-bromopyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide (I-7b) as a yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.91 (s, 1H), 8.86 (s, 1H), 8.62 (d, J=4.8 Hz, 1H), 7.83 (d, J=5.2 Hz, 1H), 1.29 (s, 9H).

[1350] Step 2: To a solution of (E)-N-((3-bromopyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide (I-7b) (53.4 g, 185 mmol) in THF (300 ml) was added but-3-en-1-yl magnesium bromide (0.5 M, 1.59 L) dropwise at 0° C. The mixture was warmed to RT over 1 h. Saturated ammonium chloride solution (200 ml) was added and the product was extracted with EtOAc (3×50 ml). The combined organics were washed with water (30 ml) and saturated brine (30 ml). The organics were dried with sodium sulfate and concentrated in vacuo. The product was purified by silica gel chromatography (1%-100% EtOAc/Petroleum ether) to give N-(1-(3-bromopyridin-4-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide (I-7c) as yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.68 (s, 1H), 8.51-8.48 (m, 1H), 7.31 (d, J=5.2 Hz, 1H), 5.83-5.76 (m, 1H), 5.10 (d, J=1.2 Hz, 1H), 5.05 (d, J=5.2 Hz, 1H), 4.87-4.83 (m, 1H), 3.56 (d, J=3.2 Hz, 1H), 2.16-2.09 (m, 2H), 1.95-1.88 (m, 2H), 1.20 (d, J=11.2 Hz, 9H).

[1351] Step 3: To a solution of N-(1-(3-bromopyridin-4-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide (I-7c) (54.3 g, 157 mmol) in MeOH (326 ml) was added a solution of HCl in EtOAc (4 M, 117 ml) at 0° C. The mixture was warmed to RT over 30 min. The reaction mixture was concentrated in vacuo. The residue was filtered and the filter cake was washed with EtOAc (2×10 ml) and dried in vacuo to give a pale yellow solid which was subsequently dissolved in water. The mixture was basified to pH>11 with NaOH solution and extracted with DCM (3×30 ml). The combined organics were washed with brine (30 ml) and dried with sodium sulfate to give 1-(3-bromopyridin-4-yl)pent-4-en-1-amine (I-7d) as yellow-brown oil. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.64 (s, 1H), 8.48 (d, J=5.6 Hz, 1H), 7.44 (d, J=5.2 Hz, 1H), 5.86-5.81 (m, 1H), 5.07-4.98 (m, 2H), 4.32-4.29 (m, 1H), 2.20-2.13 (m, 2H), 1.81-1.83 (m, 1H), 1.52-1.64 (m, 1H), 1.52 (br. s, 2H).

[1352] Step 4: To a solution of 1-(3-bromopyridin-4-yl)pent-4-en-1-amine (I-7d) (26.5 g, 110 mmol), (4-methoxyphenyl)boronic acid (25.1 g, 165 mmol), 4 Å molecular sieves (53.0 g) and Cu(OAc).sub.2 (20.0 g, 110 mmol) in 1,4-dioxane (530 ml) was added Et.sub.3N (20 ml, 143 mmol) dropwise. The mixture was stirred at 35° C. under O.sub.2 for 16 h. The mixture was filtered and the filter cake was washed with EtOAc (3×15 ml). The filtrate was concentrated in vacuo. The product was purified by silica gel chromatography (1%-100% EtOAc/Petroleum ether) to give N-(1-(3-bromopyridin-4-yl)pent-4-en-1-yl)-4-methoxyaniline (1-7e) as a red-brown solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.68 (s, 1H), 8.40 (d, J=5.2 Hz, 1H), 7.34 (d, J=4.8 Hz, 1H), 6.71-6.67 (m, 2H), 6.36 (t, J=2.0, 3.6 Hz, 2H), 5.87-5.83 (m, 1H), 5.09-5.02 (m, 2H), 4.65-4.62 (m, 1H), 3.94 (s, 1H), 3.69 (s, 3H), 2.31-2.23 (m, 2H), 1.94-1.91 (m, 1H), 1.74-1.71 (m, 1H).

[1353] Step 5: A flame-dried flask was cooled under a stream of N.sub.2 and charged with Pd.sub.2(dba).sub.3 (3.61 g, 3.95 mmol), S-Phos (3.24 g, 7.89 mmol) and NaO.sup.tBu (5.69 g, 59.2 mmol). The flask was purged with N.sub.2 and a solution of N-(1-(3-bromopyridin-4-yl)pent-4-en-1-yl)-4-methoxyaniline (I-7e) (13.7 g, 39.5 mmol) in toluene (274 ml) was added dropwise. The resulting mixture was heated to 90° C. for 12 h. The reaction mixture was filtered and the filter cake was washed with EtOAc (3×10 ml). The filtrate was concentrated in vacuo. The product was purified by silica gel chromatography (1%-100% EtOAc/Petroleum ether to give 10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine (I-7f) as a pale yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.33 (d, J=4.8 Hz, 1H), 8.17 (s, 1H), 7.08 (d, J=5.2 Hz, 1H), 6.77-6.71 (m, 4H), 4.61 (d, J=6.0 Hz, 1H), 4.51 (t, J=5.2, 6.8 Hz, 1H), 3.70 (s, 3H), 3.21 (dd, J=4.8, 12.0 Hz, 1H), 2.43-2.35 (m, 3H), 1.95-1.91 (m, 1H), 1.79-1.78 (m, 1H).

[1354] Step 6: A solution of 10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine (I-7f) (6.32 g, 23.7 mmol) in MeCN (237 ml) was cooled to 0° C. before an aqueous solution of CAN (0.3 M, 316 ml) was added dropwise. After the addition was complete the reaction was stirred for 1 h at 0° C. The reaction mixture was concentrated to dryness in vacuo to afford 6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine (I-7g) as a brown oil, which was used in the subsequent step without any further purification.

[1355] Step 7: To a solution of 6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine (I-7g) (3.82 g, 23.9 mmol) in THF (30 ml) was added K.sub.2CO.sub.3 (8.25 g, 59.7 mmol) and di-tert-butyl dicarbonate (26.0 g, 119 mmol). The mixture was stirred at RT for 16 h. The reaction mixture was filtered and the filter cake was washed with EtOAc (3×15 ml). Water (25 ml) was added to the filtrate. The aqueous layer was extracted with EtOAc (3×25 ml). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The product was purified by silica gel chromatography (1%-100% EtOAc/Petroleum ether) to give tert-butyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxylate (I-7h) as a red-brown solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.34-8.32 (m, 2H), 6.98 (s, 1H), 4.86 (d, J=28.8 Hz, 1H), 4.58 (s, 1H), 3.36 (s, 1H), 2.56 (d, J=16.8 Hz, 1H), 2.24-2.18 (m, 2H), 1.86-1.81 (m, 1H), 1.64-1.65 (m, 1H), 1.42 (s, 9H).

[1356] Step 8: A solution of HCl in EtOAc (4 M, 550 ml) was added to a solution of tert-butyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxylate (I-7h) (2.20 g, 8.45 mmol) in MeOH (400 ml) at RT. The mixture was stirred at RT for 2 h. The reaction mixture was concentrated in vacuo. The crude product was triturated with MTBE (20 ml) at RT for 10 min. The mixture was filtered, the filter cake was washed with MTBE (2×5 ml) and the cake was dried in vacuo to give 6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine hydrochloride as a white solid. LCMS (method 5) m/z 161.2 (M+H).sup.+ (ES.sup.+), at 2.44 min. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.92 (s, 1H), 9.65 (s, 1H), 8.64 (d, J=18.0 Hz, 2H), 7.64 (s, 1H), 5.03 (s, 1H), 4.40 (s, 1H), 3.39 (s, 1H), 3.00 (d, J=17.6 Hz, 1H), 2.36-2.18 (m, 2H), 1.99-2.02 (m, 1H), 1.86-1.75 (m, 1H).

Intermediate 8 (I-8)

[1357] ##STR00197## ##STR00198##

[1358] Step 1: (E)-N-((4-Bromopyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide (I-8b) was synthesised from 4-bromo-3-pyridinecarboxaldehyde (1-8a) using a procedure essentially the same as for I-7b. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.14 (s, 1H), 8.93 (s, 1H), 8.46 (d, J=5.2 Hz, 1H), 7.61 (d, J=5.2 Hz, 1H), 1.30 (s, 9H).

[1359] Step 2: N-(1-(4-Bromopyridin-3-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide (I-8c) was synthesised from (E)-N-((4-bromopyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide (I-8b) using a procedure essentially the same as for I-7c. .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 8.55 (s, 1H), 8.32-8.29 (m, 1H), 7.50 (d, J=5.2 Hz, 1H), 5.85-5.76 (m, 1H), 5.10-5.02 (m, 2H), 4.92-4.90 (m, 1H), 3.57 (d, J=3.6 Hz, 1H), 2.18-1.97 (m, 4H), 1.19 (s, 9H).

[1360] Step 3: 1-(4-Bromopyridin-3-yl)pent-4-en-1-amine (I-8d) was synthesised from N-(1-(4-bromopyridin-3-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide (I-8c) using a procedure essentially the same as for I-7d. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.66 (s, 1H), 8.29-8.24 (m, 1H), 7.48-7.45 (t, J=8.8 Hz, 1H), 5.86-5.79 (m, 1H), 5.06-4.97 (m, 2H), 4.36-4.33 (m, 1H), 2.20-2.12 (m, 2H), 1.89-1.85 (m, 1H), 1.78-1.75 (m, 1H), 1.56 (s, 2H).

[1361] Step 4: N-(1-(4-Bromopyridin-3-yl)pent-4-en-1-yl)-4-methoxyaniline (I-8e) was synthesised from 1-(4-bromopyridin-3-yl)pent-4-en-1-amine (I-8d) using a procedure essentially the same as for 1-7e. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.58 (d, J=15.6 Hz, 1H), 8.26 (s, 1H), 7.49 (d, J=5.2 Hz, 1H), 6.69 (d, J=8.8 Hz, 2H), 6.44-6.41 (m, 2H), 5.88-5.82 (m, 1H), 5.08-5.01 (m, 2H), 4.72-4.68 (m, 1H), 3.86-3.84 (m, 1H), 3.69 (s, 3H), 2.30-2.21 (m, 2H), 2.02-1.89 (m, 1H), 1.88-1.76 (m, 1H).

[1362] Step 5: 10-(4-Methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine (I-8f) was synthesised from N-(1-(4-bromopyridin-3-yl)pent-4-en-1-yl)-4-methoxyaniline (I-8e) using a procedure essentially the same as for I-7f. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.39 (s, 1H), 8.27 (d, J=5.2 Hz, 1H), 6.84 (d, J=4.4 Hz, 1H), 6.77-6.70 (m, 4H), 4.72 (d, J=5.2 Hz, 1H), 4.65 (d, J=5.2 Hz, 1H), 3.69 (s, 3H), 3.25-3.19 (m, 1H), 2.40 (dd, J=3.6, 7.2 Hz, 3H), 1.97-1.92 (m, 1H), 1.79-1.75 (m, 1H).

[1363] Step 6: 6,7,8,9-Tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine (I-8g) was synthesised from 10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine (I-8f) using a procedure essentially the same as for 1-7g.

[1364] Step 7: tert-Butyl-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxylate (I-8h) was prepared from 6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine (I-8g) using a procedure essentially the same as for I-7h. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.36 (d, J=5.2 Hz, 1H), 8.31 (s, 1H), 7.01 (d, J=4.8 Hz, 1H), 4.95 (s, 1H), 4.54 (s, 1H), 3.37 (s, 1H), 2.54 (d, J=17.6 Hz, 1H), 2.33-2.16 (m, 2H), 1.93-1.81 (m, 1H), 1.70-1.59 (m, 1H), 1.47-1.35 (m, 9H).

[1365] Step 8: 6,7,8,9-Tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine hydrochloride (1-8) was synthesised from tert-butyl-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxylate (I-8h) using a procedure essentially the same as for 1-7. LCMS (method 5) m/z 161.2 (M+H).sup.+ (ES.sup.+), at 2.42 min. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 10.26 (s, 1H), 9.90 (s, 1H), 8.79 (s, 1H), 8.71 (d, J=6.0 Hz, 1H), 7.77 (d, J=5.6 Hz, 1H), 5.10 (d, J=6.0 Hz, 1H), 4.36 (s, 1H), 3.54 (dd, J=4.8, 19.2 Hz, 1H), 3.19-3.07 (m, 1H), 2.41-2.18 (m, 2H), 2.08 (t, J=11.2 Hz, 1H), 1.88-1.75 (m, 1H).

Intermediate 9 (I-9)

[1366] ##STR00199## ##STR00200##

[1367] Step 1: (E)-N-(2-Bromo-4-methoxybenzylidene)-2-methylpropane-2-sulfinamide (I-9b) was synthesised from 2-bromo-4-methoxybenzaldehyde (I-9a) using a procedure essentially the same as for 1-7b. .sup.1H NMR (500 MHz, d6-DMSO) δ 8.73 (s, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.37 (d, J=2.5 Hz, 1H), 7.13 (dd, J=8.8, 2.4 Hz, 1H), 3.88 (s, 3H), 1.18 (s, 9H).

[1368] Step 2: A solution of (E)-N-(2-bromo-4-methoxybenzylidene)-2-methylpropane-2-sulfinamide (13.0 g, 40.9 mmol) in THF (130 ml) was cooled down to −78° C. But-3-en-1-ylmagnesium bromide (0.5 M in THF) (245 ml, 123 mmol) was added dropwise. The mixture was slowly warmed to RT and the mixture was stirred at RT for 16 h. Saturated aqueous ammonium chloride solution (150 ml) was added and the product was extracted with EtOAc (2×100 ml). The organics were combined, dried over magnesium sulfate and concentrated in vacuo to obtain N-(1-(2-bromo-4-methoxyphenyl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide (I-9c) as a light brown oil. The compound was taken to the next step without any further purification as a 2:1 mixture of diastereoisomers.

[1369] Major diastereoisomer: .sup.1H NMR (500 MHz, d6-DMSO) δ 7.42 (d, J=8.7 Hz, 1H), 7.11 (d, J=2.5 Hz, 1H), 6.99 (dd, J=8.7, 2.6 Hz, 1H), 5.82 (ddt, J=16.9, 10.2, 6.5 Hz, 1H), 5.51 (d, J=6.5 Hz, 1H), 5.06 (d, J=17.4 Hz, 1H), 4.98 (d, J=10.8 Hz, 1H), 4.57 (d, J=6.8 Hz, 1H), 3.76 (s, 3H), 2.19-2.08 (m, 1H), 2.07-1.97 (m, 1H), 1.94-1.84 (m, 1H), 1.78-1.67 (m, 1H), 1.05 (s, 9H).

[1370] Minor diastereoisomer: .sup.1H NMR (500 MHz, d6-DMSO) δ 7.51 (d, J=8.7 Hz, 1H), 7.11 (d, J=2.5 Hz, 1H), 6.99 (dd, J=8.5, 2.5 Hz, 1H), 5.87-5.78 (m, 2H), 5.09-4.9 (m, 2H), 4.56-4.45 (m, 1H), 3.77 (s, 3H), 2.23-2.09 (m, 1H), 2.08-1.97 (m, 1H), 1.83-1.70 (m, 1H), 1.68-1.59 (m, 1H), 1.10 (s, 9H).

[1371] Step 3: To a solution of N-(1-(2-bromo-4-methoxyphenyl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide (I-9c) (16.5 g, 44.16 mmol) in MeOH (65 ml) was added a solution of HCl (4M in 1,4-dioxane) (33 ml, 132.5 mmol) at RT. The reaction mixture was stirred at RT for 2.5 h. Water (200 ml) was added and the aqueous solution was washed with EtOAc (200 ml).

[1372] The aqueous layer was adjusted to pH 8 by the addition of 2M NaOH aqueous solution. The aqueous layer was then extracted with EtOAc (2×100 ml). The organics were combined, dried over magnesium sulfate and concentrated in vacuo to afford 1-(2-bromo-4-methoxyphenyl)pent-4-en-1-amine (I-9d) as a pale brown liquid. The crude product was used in the next step without further purification.

[1373] Step 4: To a solution of 1-(2-bromo-4-methoxyphenyl)pent-4-en-1-amine (I-9d) (7.60 g, 28.1 mmol) in DCM (100 ml) was added (4-methoxyphenyl)boronic acid (12.8 g, 84.4 mmol) followed by copper(II) acetate (7.66 g, 42.2 mmol) and pyridine (11.4 ml, 141 mmol). The blue mixture was vigorously stirred at RT for 72 h. 2M NaOH aqueous solution (100 ml) was added and the mixture was stirred for 30 min. The copper salts were filtered through a pad of Celite. Water (100 ml) was added and the product was extracted with DCM (3×100 ml). The organic layers were combined, dried over magnesium sulfate, and concentrated in vacuo. The product was purified by chromatography on silica gel (5-25% EtOAc/Isohexane) to afford N-(1-(2-bromo-4-methoxyphenyl)pent-4-en-1-yl)-4-methoxyaniline(I-9e) as a yellow liquid. LCMS (method 2) m/z 255 (M-PMP).sup.+ (ES.sup.+), at 1.91 min, .sup.1H NMR (500 MHz, DMSO-d6) δ 7.33 (d, J=8.7 Hz, 1H), 7.12 (d, J=2.6 Hz, 1H), 6.90 (dd, J=8.7, 2.6 Hz, 1H), 6.62 (d, J=8.9 Hz, 2H), 6.37 (d, J=9.0 Hz, 2H), 5.92 (d, J=8.1 Hz, 1H), 5.85 (ddt, J=17.0, 10.2, 6.5, 6.5 Hz, 1H), 5.02 (dq, J=17.2, 1.8, 1.7, 1.7 Hz, 1H), 4.97 (ddt, J=10.2, 2.3, 1.3, 1.3 Hz, 1H), 4.51 (td, J=8.2, 8.2, 5.0 Hz, 1H), 3.73 (s, 3H), 3.57 (s, 3H), 2.34-2.20 (m, 1H), 2.19-2.06 (m, 1H), 1.78-1.61 (m, 2H).

[1374] Step 5: To a flask was added Pd-178 (667 mg, 1.40 mmol) and NaO.sup.tBu (2.02 g, 21.0 mmol) and the flask was purged with nitrogen. A solution of N-(1-(2-bromo-4-methoxyphenyl)pent-4-en-1-yl)-4-methoxyaniline (I-9e) (5.26 g, 14.0 mmol) in degassed toluene (120 ml) was added via syringe at RT. The resulting mixture was heated at 95° C. for 2 h. The reaction mixture was cooled to RT and filtered through celite. The celite was washed with EtOAc (100 ml). The filtrate was concentrated in vacuo. The product was purified by chromatography on silica gel (0-25% EtOAc/isohexane) to afford (±)-2-methoxy-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene (I-9f) as a pale pink oil. LCMS (method 2) m/z 296 (M+H).sup.+ (ES.sup.+), at 1.27 min, .sup.1H NMR (500 MHz, DMSO-d6) δ 7.12 (d, J=8.3 Hz, 1H), 6.76 (d, J=9.1 Hz, 2H), 6.69 (d, J=9.1 Hz, 2H), 6.65 (dd, J=8.3, 2.7 Hz, 1H), 6.48 (d, J=2.6 Hz, 1H), 4.70 (d, J=5.6 Hz, 1H), 4.54-4.38 (m, 1H), 3.64 (s, 3H), 3.61 (s, 3H), 3.10 (dd, J=17.0, 4.7 Hz, 1H), 2.36 (d, J=17.0 Hz, 1H), 2.30-2.13 (m, 2H), 1.80-1.63 (m, 2H).

[1375] Step 6: To a solution of (±)-2-methoxy-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene (1-9f) (680.0 mg, 2.30 mmol) in MeCN (25 ml) was added a solution of CAN (3.79 g, 6.91 mmol) in water (25 ml) was added dropwise over 30 min at 0° C. The mixture was stirred at 0° C. for 1 h, and at RT for 1 h. Water (10 ml) and 2M NaOH (10 ml) were added and the product was extracted with DCM (3×30 ml). The organic layers were combined and concentrated in vacuo to obtain (±)-2-methoxy-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene (1-9) as a brown oil. The compound was used as is without further purification. LCMS (method 2) m/z 190 (M+H).sup.+ (ES.sup.+), at 1.56 min, .sup.1H NMR (500 MHz, DMSO-d6) δ 6.89 (d, J=8.2 Hz, 1H), 6.61 (dd, J=8.2, 2.7 Hz, 1H), 6.58 (d, J=2.6 Hz, 1H), 4.04 (d, J=5.1 Hz, 1H), 3.73-3.66 (m, 4H), 3.01 (dd, J=16.6, 5.0 Hz, 1H), 2.64 (br s, 1H), 2.44 (d, J=16.6 Hz, 1H), 1.95-1.81 (m, 2H), 1.74-1.57 (m, 1H), 1.50-1.39 (m, 1H).

Intermediate 10 (I-10)

[1376] ##STR00201##

[1377] Step 1: (±)-2-Methoxy-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene (1-9) (267 mg, 1.24 mmol) was added to aqueous HBr (48% solution in water) (1.4 ml, 48% w/w, 12.41 mmol) at RT, and then refluxed for 6 h. The mixture was diluted with MeOH (20 ml) and filtered to get a clear dark brown filtrate. SCX (7.00 g, 5.4 mmol) was added and the mixture was further stirred at RT for 1 h. The SCX was washed with MeOH (100 ml) and the product was eluted with 0.7 M ammonia in MeOH (50 ml). The eluant was concentrated in vacuo to obtain (±)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulen-2-ol, as a dark brown oil. LCMS (method 2) m/z 176 (M+H).sup.+ (ES.sup.+), at 0.61 min, 1H NMR (500 MHz, DMSO-d6) b 9.00 (s, 1H), 6.77 (d, J=8.1 Hz, 1H), 6.44 (dd, J=8.1, 2.5 Hz, 1H), 6.41 (d, J=2.5 Hz, 1H), 4.00 (d, J=5.3 Hz, 1H), 3.67 (t, J=5.8 Hz, 1H), 2.96 (dd, J=16.5, 4.9 Hz, 1H), 2.37 (d, J=16.5, 1H), 1.94-1.80 (m, 2H), 1.68-1.59 (m, 1H), 1.48-1.39 (m, 1H), 1 exchangeable proton not visible

Intermediate 11 (I-11)

[1378] ##STR00202##

[1379] Step 1: A vial was charged with Pd-170 (1 mg, 1.45 μmol) and K.sub.2PO.sub.3 (23 mg, 145 μmol), sealed and evacuated/backfilled with N.sub.2 (3 times). A solution of tert-butyl (±)-2-(((trifluoromethyl)sulfonyl)oxy)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene-10-carboxylate (40 mg, 97.0 μmol) and (2,4-dimethoxyphenyl)methanamine (18 mg, 107 μmol) in 1,4-dioxane (1 ml) was added and the reaction mixture heated to 120° C. for 16 h. The reaction mixture was cooled to RT and filtered through a pad of celite washing with EtOAc. The filtrate was concentrated in vacuo. The product was purified by silica gel chromatography (0%-100% EtOAc/isohexane) to give tert-butyl (±)-2-((2,4-dimethoxybenzyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene-10-carboxylate (I-11a) as yellow oil. LC-MS (method 1) m/z 447.1 (M+Na).sup.+ (ES.sup.+) at 1.82 min, .sup.1H NMR (500 MHz, DMSO-d6) δ 7.18 (dd, J=8.3, 1.9 Hz, 1H), 6.84 (br s, 1H), 6.53-6.33 (m, 4H), 4.90-4.72 (m, 1H), 4.60-4.37 (m, 1H), 3.82 (s, 3H), 3.79 (s, 3H), 3.39-3.18 (m, 1H), 2.45 (d, J=16.5 Hz, 1H), 2.30-2.02 (m, 3H), 1.79 (t, J=10.3 Hz, 1H), 1.62 (br s, 2H), 1.39 (s, 9H). (—NH proton not visible).

[1380] Step 2: To a solution of tert-butyl (±)-2-((2,4-dimethoxybenzyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene-10-carboxylate (I-11a) (30 mg, 69.7 μmol) in DCM (1 ml) was added TFA (54 μl, 0.70 mmol) and the reaction mixture stirred at RT overnight. The reaction mixture was concentrated in vacuo. The product was purified by ion exchange using SCX (0.5 g) washing with MeOH and eluting with 0.7 M ammonia in MeOH to give (±)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulen-2-amine (1-11) as a sticky yellow oil. LC-MS (method 1) m/z 175.8 (M+H).sup.+ (ES.sup.+) at 0.71 min.

Intermediate 12 (I-12)

[1381] ##STR00203## ##STR00204##

[1382] Step 1: To a solution of 2-bromo-4-fluorobenzaldehyde I-12a (10.0 g, 49.3 mmol) in THF (170 ml) was added titanium (IV) ethoxide (20.7 ml, 98.5 mmol) in one portion at RT. The mixture was stirred at RT for 5 min before (±)-tert-butylsulfinamide (5.97 g, 49.3 mmol) was added in one portion. The resulting mixture was stirred at RT for 24 h. Brine (100 ml) was added and the mixture stirred for 10 min then filtered through celite. The filtrate was extracted with EtOAc (2×100 ml). The combined organic layers were washed with brine (3×100 ml), dried over magnesium sulfate and concentrated in vacuo to give (E)-N-(2-bromo-4-fluorobenzylidene)-2-methylpropane-2-sulfinamide as pale yellow solid (1-12b). LCMS (method 1) m/z 306.2, 308.1 (M+H).sup.+ (ES.sup.+), at 1.6 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.77 (s, 1H), 8.11 (dd, J=8.8, 6.2 Hz, 1H), 7.81 (dd, J=8.5, 2.6 Hz, 1H), 7.45 (td, J=8.2, 2.6 Hz, 1H), 1.20 (s, 9H).

[1383] Step 2: To a solution of (E)-N-(2-bromo-4-fluorobenzylidene)-2-methylpropane-2-sulfinamide (13.00 g, 42.46 mmol) (1-12b) in THF (150 ml) was added but-3-en-1-yl magnesium bromide (2.17 M, 29.4 ml) dropwise at −78° C. The mixture was warmed to RT over 16 h. Saturated ammonium chloride solution (50 ml) was added and the product was extracted with EtOAc (2×100 ml). The combined organics were dried with magnesium sulfate and concentrated in vacuo, to give N-(1-(2-bromo-4-fluorophenyl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide (I-12c) as an orange oil. LCMS (method 2) m/z 362.1, 364.1 (M+H).sup.+ (ES.sup.+) at 2.48 min

[1384] Step 3: To a solution of N-(1-(2-bromo-4-fluorophenyl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide (I-12c) (15.0 g, 41.26 mmol) in MeOH (65 ml) was added a solution of HCl in 1,4-dioxane (4 M, 10.3 ml) at RT and stirred for 2.5 h. The reaction mixture was concentrated in vacuo. The residue was partitioned between water (200 ml) and EtOAc (200 ml). The aqueous phase was basified to pH 8 with NaOH solution and extracted with EtOAc (2×100 ml). The organic layer was diluted with water (50 ml) basified to pH 10 with NaOH and extracted with ethyl acetate (3×100 ml). The combined organics were dried over magnesium sulfate and concentrated in vacuo to give 1-(2-bromo-4-fluorophenyl)pent-4-en-1-amine (1-12d) as a colourless oil. LCMS (method 2) m/z 258.0, 260.0 (M+H).sup.+ (ES.sup.+), at 2.20 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 7.66 (dd, J=8.7, 6.4 Hz, 1H), 7.47 (ddt, J=8.5, 3.0, 1.6 Hz, 1H), 7.30-7.22 (m, 1H), 5.81 (ddt, J=16.9, 10.2, 6.6 Hz, 1H), 5.09-4.92 (m, 1H), 4.94 (ddt, J=10.3, 2.2, 1.1 Hz, 1H), 4.13 (dd, J=8.1, 5.0 Hz, 1H), 2.19-2.07 (m, 1H), 2.10-1.97 (m, 1H), 1.66-1.58 (m, 1H), 1.57-1.46 (m, 1H) (Exchangeable—NH.sub.2 protons not visible).

[1385] Step 4: To a solution of 1-(2-bromo-4-fluorophenyl)pent-4-en-1-amine (9.60 g, 37.2 mmol) (1-12d), (4-methoxyphenyl)boronic acid (17.0 g, 112 mmol), and Cu(OAc).sub.2 (10.1 g, 55.8 mmol) in DCM (100 ml) was added pyridine (15.0 ml, 186 mmol) dropwise. The mixture was stirred at RT open to air for 16 h. 2 M NaOH aqueous solution (100 ml) was added, the mixture stirred for 30 min and filtered through celite. The filtrate was partitioned between water (100 ml) and DCM (100 ml) and the layers were separated. The aqueous layer was further extracted with DCM (2×100 ml). The combined organics were dried over magnesium sulfate and concentrated in vacuo. The product was purified by silica gel chromatography (0%-10% EtOAc/isohexane) followed by silica gel chromatography (0%-50% DCM/isohexane) to give N-(1-(2-bromo-4-fluorophenyl)pent-4-en-1-yl)-4-methoxyaniline (I-12e) as a colourless oil. LCMS (method 2) m/z 364.3, 366.6 (M+H).sup.+ (ES.sup.+), at 1.55 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 7.52 (dd, J=8.5, 2.6 Hz, 1H), 7.47 (dd, J=8.7, 6.3 Hz, 1H), 7.20 (td, J=8.5, 2.7 Hz, 1H), 6.67-6.60 (m, 2H), 6.40-6.33 (m, 2H), 6.00 (d, J=8.0 Hz, 1H), 5.90-5.79 (m, 1H), 5.06-4.94 (m, 2H), 4.55 (td, J=8.2, 5.0 Hz, 1H), 3.57 (s, 3H), 2.29 (t, J=11.2 Hz, 1H), 2.21-2.10 (m, 1H), 1.79-1.64 (m, 2H).

[1386] Step 5: A three-neck flask was charged with Pd-178 (448 mg, 939 μmol) and NaO.sup.tBu (3.99 g, 41.5 mmol) and purged with N.sub.2. A solution of N-(1-(2-bromo-4-fluorophenyl)pent-4-en-1-yl)-4-methoxyaniline (I-12e) (3.42 g, 9.39 mmol) in toluene (30 ml) was added dropwise. The resulting mixture was heated to 95° C. for 2 h. The reaction mixture was cooled to RT and filtered through celite, washing with EtOAc (100 ml). The filtrate was concentrated in vacuo. The product was purified by silica gel chromatography (0%-5% EtOAc/heptane) to give (±)-2-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene (1-12f) as a pink oil. LCMS (method 2) m/z 384.1 (M+H).sup.+ (ES.sup.+), at 2.52 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 7.26 (dd, J=8.3, 6.0 Hz, 1H), 6.90 (td, J=8.7, 2.7 Hz, 1H), 6.80-6.73 (m, 3H), 6.73-6.66 (m, 2H), 4.79 (d, J=5.6 Hz, 1H), 4.44 (t, J=5.8 Hz, 1H), 3.61 (s, 3H), 3.11 (dd, J=17.3, 4.8 Hz, 1H), 2.41 (d, J=17.3 Hz, 1H), 2.26-2.18 (m, 2H), 1.84-1.62 (m, 2H).

[1387] Step 6: A solution of (±)-2-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene (1-12f) (2.15 g, 7.59 mmol) in MeCN (28 ml) was cooled to 0° C. before a solution of CAN (12.5 g, 22.8 mmol) in water (100 ml) was added dropwise. After the addition was completed the reaction was stirred for 1 h at 0° C., then allowed to warm to RT and stirred for 1 h. Water (30 ml) and 2 M aqueous sodium hydroxide (50 ml) was added and the product extracted with DCM (4×150 ml). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The crude residue was redissolved in MeOH and purified by SCX (15 g) washing with MeOH and eluting with 0.7 M ammonia in MeOH to give (±)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene (1-12) as a brown oil. LCMS (method 2) m/z 178.1 (M+H).sup.+ (ES.sup.+), at 1.65 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 7.02 (dd, J=6.3, 1.9 Hz, 1H), 6.94-6.81 (m, 2H), 4.12-4.07 (m, 1H), 3.68 (t, J=5.5 Hz, 1H), 3.02 (dd, J=16.8, 5.0 Hz, 1H), 2.50-2.43 (m, 2H), 1.95-1.75 (m, 2H), 1.73-1.61 (m, 1H), 1.52-1.39 (m, 1H).

Intermediate 13 (I-13)

[1388] ##STR00205## ##STR00206##

[1389] Step 1: To a solution of 3-chloro-2-fluoroisonicotinaldehyde I-13a (1.00 g, 6.27 mmol) in THF (17 ml) was added titanium (IV) ethoxide (2.63 ml, 12.5 mmol) in one portion at RT. The mixture was stirred at RT for 5 min before (S)-tert-butylsulfinamide (760 mg, 6.27 mmol) was added in one portion. The resulting mixture was stirred at RT for 16 h. Brine (30 ml) was added, and the mixture stirred for 10 min then filtered through celite. The filtrate was extracted with EtOAc (2×20 ml). The combined organics were dried over magnesium sulfate and concentrated in vacuo to give (S)—N-((3-chloro-2-fluoropyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide (I-13b) as a pale yellow solid. LCMS (method 1) m/z 227.5 (M−Cl).sup.+ (ES.sup.+), at 1.36 min. .sup.1H NMR (500 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.33 (dt, J=5.1, 0.8 Hz, 1H), 7.90 (d, J=5.1 Hz, 1H), 1.22 (s, 9H).

[1390] Step 2: To a solution of (S)—N-((3-chloro-2-fluoropyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide (1.38 g, 5.26 mmol) (1-13b) in THF (22 ml) was added but-3-en-1-yl magnesium bromide (0.5 M, 31.6 ml, 15.79 mmol) dropwise at −78° C. The mixture was warmed to RT slowly and stirred for 72 h. Saturated ammonium chloride solution (10 ml) was added and the product was extracted with EtOAc (3×10 ml). The combined organics were dried with magnesium sulfate and concentrated in vacuo. The product was purified by silica gel chromatography (0-100% EtOAc/isohexane) to give (S)—N—((R)-1-(3-chloro-2-fluoropyridin-4-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide (I-13c) as a pale yellow solid. LCMS (method 1) m/z 316.7, 319.1 (M−H).sup.− (ES.sup.−), at 1.39 min. .sup.1H NMR (500 MHz, DMSO-d6) δ 8.21 (dd, J=5.2, 0.8 Hz, 1H), 7.53 (d, J=5.2 Hz, 1H), 5.90 (d, J=7.3 Hz, 1H), 5.81 (dddd, J=17.3, 10.2, 7.1, 6.1 Hz, 1H), 5.10 (dq, J=17.2, 1.7 Hz, 1H), 5.02 (ddt, J=10.2, 2.3, 1.2 Hz, 1H), 4.66 (ddd, J=8.6, 7.3, 5.3 Hz, 1H), 2.27-2.08 (m, 2H), 1.97-1.87 (m, 1H), 1.80-1.70 (m, 1H), 1.07 (s, 9H).

[1391] Step 3: To a solution of (S)—N—((R)-1-(3-chloro-2-fluoropyridin-4-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide (I-13c) (714 mg, 2.015 mmol) in .sup.tBuOH (7.2 ml) was added a solution of HCl in 1,4-dioxane (4 M, 3.0 ml, 12.09 mmol) at RT and stirred for 2.5 h. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (100 ml) and extracted with DCM (3×30 ml). The combined organics were dried over magnesium sulfate and concentrated in vacuo to give (R)-1-(3-chloro-2-fluoropyridin-4-yl)pent-4-en-1-amine as a pale yellow liquid (1-13d) as an orange/brown oil. LCMS (method 1): m/z 215.4, 217.3 (M+H).sup.+ (ES.sup.+); at 1.17 min, 1H NMR (500 MHz, DMSO-d6) δ 8.16 (dd, J=5.1, 0.9 Hz, 1H), 7.62 (d, J=5.1 Hz, 1H), 5.80 (ddt, J=16.9, 10.2, 6.6 Hz, 1H), 5.02 (dq, J=17.4, 1.8 Hz, 1H), 4.96 (ddt, J=10.2, 2.3, 1.3 Hz, 1H), 4.22 (dd, J=8.1, 5.1 Hz, 1H), 2.23-2.01 (m, 2H), 1.76-1.50 (m, 2H), 2 NH protons not observed.

[1392] Step 4: To a solution of (R)-1-(3-chloro-2-fluoropyridin-4-yl)pent-4-en-1-amine (1-13d) (644.3 mg, 3.001 mmol), (4-methoxyphenyl)boronic acid (1.37 g, 9.0 mmol), and Cu(OAc).sub.2 (820 mg, 4.50 mmol) in DCM (100 ml) was added pyridine (1.2 ml, 15.0 mmol) dropwise. The mixture was stirred at RT, open to air for 16 h. 2M NaOH aqueous solution (20 ml) was added followed by water (20 ml) and the mixture extracted with DCM (3×20 ml). The combined organics were dried over magnesium sulfate and concentrated in vacuo. The product was purified by silica gel chromatography (0%-100% DCM/isohexane) to give (R)—N-(1-(3-chloro-2-fluoropyridin-4-yl)pent-4-en-1-yl)-4-methoxyaniline (I-13e) as a yellow oil. LCMS (method 1): m/z 321.1, 323.4 (M+H).sup.+ (ES.sup.+); at 1.73 min, .sup.1H NMR (500 MHz, DMSO-d6) δ 8.10 (d, J=5.1 Hz, 1H), 7.41 (d, J=5.1 Hz, 1H), 6.65 (d, J=8.9 Hz, 2H), 6.38 (d, J=8.9 Hz, 2H), 6.09 (d, J=8.3 Hz, 1H), 5.84 (ddt, J=17.0, 10.2, 6.6 Hz, 1H), 5.10-4.88 (m, 2H), 4.68 (td, J=8.5, 4.7 Hz, 1H), 3.57 (s, 3H), 2.34-2.24 (m, 1H), 2.23-2.12 (m, 1H), 1.87-1.69 (m, 2H).

[1393] Step 5: A three-neck flask was charged with Pd-178 (7.4 mg, 15.6 μmol) and sodium tert-butoxide (22.5 mg, 234 μmol) and purged with N.sub.2. A solution of (R)—N-(1-(3-chloro-2-fluoropyridin-4-yl)pent-4-en-1-yl)-4-methoxyaniline (I-13e) (50.0 mg, 156 μmol) in toluene (1 ml) was added dropwise. The resulting mixture was heated to 95° C. for 1.5 h. The reaction mixture was cooled to RT and filtered through celite, washing with EtOAc (3×20 ml). The filtrate was concentrated in vacuo. The product was purified by silica gel chromatography (0%-50% EtOAc/heptane) to give (5R,8S)-1-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine (I-13f) a white solid. LCMS (method 1) m/z 285.3 (M+H).sup.+ (ES.sup.+), at 1.35 min. .sup.1H NMR (500 MHz, DMSO-d6) δ 7.95 (d, J=4.9 Hz, 1H), 7.29 (dd, J=5.0, 1.7 Hz, 1H), 6.80 (d, J=9.1 Hz, 2H), 6.71 (d, J=9.1 Hz, 2H), 4.92 (d, J=5.6 Hz, 1H), 4.56 (t, J=5.9 Hz, 1H), 3.61 (s, 3H), 2.92 (dd, J=17.6, 4.9 Hz, 1H), 2.35 (d, J=17.5 Hz, 1H), 2.32-2.19 (m, 2H), 1.91-1.82 (m, 1H), 1.81-1.74 (m, 1H).

[1394] Step 6: A solution of (5R,8S)-1-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine (I-13f) (69 mg, 232 μmol) in MeCN (3.2 ml) was cooled to 0° C. before a solution of CAN (381 mg, 696 μmol) in water (3.2 ml) was added dropwise. After the addition was completed the reaction was stirred for 1 h at 0° C. 2 M aqueous NaOH (5 ml) and water (5 ml) were added, and the mixture extracted with DCM (3×10 ml). The combined organics were dried over magnesium sulfate and concentrated in vacuo to give (5R,8S)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine (I-13) as a pale pink solid. LCMS (method 1): m/z 179.2 (M+H).sup.+ (ES.sup.+); at 0.69 min, .sup.1H NMR (500 MHz, DMSO-d6) δ 7.91 (dd, J=5.0, 0.9 Hz, 1H), 7.04 (dd, J=5.0, 1.9 Hz, 1H), 4.17 (d, J=5.3 Hz, 1H), 3.78 (t, J=6.0 Hz, 1H), 2.85 (dd, J=17.1, 5.2 Hz, 1H), 2.74 (s, 1H), 2.38 (d, J=17.0 Hz, 1H), 2.01-1.85 (m, 2H), 1.73 (t, J=9.1 Hz, 1H), 1.51 (dt, J=9.4, 5.4 Hz, 1H).

Intermediate 14 (I-14)

[1395] ##STR00207## ##STR00208##

[1396] Step 1: N-(2-Bromo-5-fluorobenzylidene)-2-methylpropane-2-sulfinamide I-14b synthesised from 2-bromo-5-fluorobenzaldehyde I-14a using a procedure essentially the same as for I-12b. LCMS (method 2): m/z 305.9, 308.0 (M+H).sup.+ (ES.sup.+); at 2.80 min, .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.76 (d, J=2.2 Hz, 1H), 7.86 (dd, J=8.9, 5.1 Hz, 1H), 7.80 (dd, J=9.2, 3.2 Hz, 1H), 7.56-7.36 (m, 1H), 1.20 (s, 9H).

[1397] Step 2: N-(1-(2-Bromo-5-fluorophenyl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-14c was synthesised from N-(2-bromo-5-fluorobenzylidene)-2-methylpropane-2-sulfinamide I-14b using a procedure essentially the same as for I-12c. LCMS (method 2): m/z 362.0, 364.0 (M+H).sup.+ (ES.sup.+); at 2.47 min, .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 7.61 (ddd, J=8.7, 5.4, 4.2 Hz, 1H), 7.38 (dd, J=10.2, 3.2 Hz, 1H), 7.13-7.04 (m, 1H), 5.87-5.79 (m, 1H), 5.69 (d, J=7.2 Hz, 1H), 5.13-5.02 (m, 1H), 5.02-4.95 (m, 1H), 4.62-4.46 (m, 1H), 2.26-2.17 (m, 1H), 2.17-2.04 (m, 1H), 1.86 (dtd, J=13.9, 8.6, 5.4 Hz, 1H), 1.80-1.60 (m, 1H), 1.06 (s, 9H).

[1398] Step 3: To a solution of N-(1-(2-bromo-5-fluorophenyl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-14c (13.6 g, 37.5 mmol) in MeOH (65 ml) was added a solution of HCl in 1,4-dioxane (4 M, 28 ml, 113 mmol) at RT and stirred for 17 h. The reaction mixture was concentrated in vacuo. The residue was dissolved in water (200 ml) and washed with EtOAc (200 ml). The aqueous layer was basified to pH 8 with 2 M NaOH solution and extracted with EtOAc (2×100 ml). The combined organics were dried over magnesium sulfate and concentrated in vacuo to give N-(1-(2-bromo-5-fluorophenyl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-14d as an orange/brown oil. LCMS (method 2): m/z 258.0. 260.0 (M+H).sup.+ (ES.sup.+); at 2.24 min, .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 7.57 (dd, J=8.7, 5.5 Hz, 1H), 7.48 (dd, J=10.4, 3.2 Hz, 1H), 7.03 (td, J=8.4, 3.2 Hz, 1H), 5.81 (ddt, J=16.9, 10.2, 6.6 Hz, 1H), 5.02 (m, 1H), 4.94 (ddt, J=10.2, 2.4, 1.3 Hz, 1H), 4.12-4.00 (m, 1H), 2.21-2.01 (m, 2H), 1.99 (s, 2H), 1.66-1.54 (m, 1H), 1.54-1.43 (m, 1H).

[1399] Step 4: N-(1-(2-Bromo-5-fluorophenyl)pent-4-en-1-yl)-4-methoxyaniline I-14e was synthesised from N-(1-(2-bromo-5-fluorophenyl)pent-4-en-1-amine I-14d using a procedure essentially the same as for I-12e. LCMS (method 2): m/z 364.1, 366.0 (M+H).sup.+ (ES.sup.+); at 2.90 min, .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 7.61 (dd, J=8.8, 5.3 Hz, 1H), 7.26 (dd, J=10.1, 3.2 Hz, 1H), 7.02 (ddd, J=8.8, 8.0, 3.1 Hz, 1H), 6.67-6.61 (m, 2H), 6.41-6.34 (m, 2H), 6.00 (d, J=8.3 Hz, 1H), 5.90-5.81 (m, 1H), 5.06-4.94 (m, 2H), 4.58-4.50 (m, 1H), 3.57 (s, 3H), 2.35-2.24 (m, 1H), 2.22-2.11 (m, 1H), 1.77-1.67 (m, 2H).

[1400] Step 5: (±)-3-Fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene I-14f was synthesised from N-(1-(2-bromo-5-fluorophenyl)pent-4-en-1-yl)-4-methoxyaniline I-14e using a procedure essentially the same as for I-12f. LCMS (method 2): m/z 284.1 (M+H).sup.+ (ES.sup.+); at 2.67 min.

[1401] Step 6: A solution of (±)-3-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene I-14f (2.31 g, 8.15 mmol) in MeCN (100 ml) was cooled to 0° C. before a solution of CAN (13.4 g, 24.5 mmol) in water (100 ml) was added dropwise. After the addition was completed the reaction was stirred for 1 h at 0° C., then allowed to warm to RT and stirred for 1 h. 2 M aqueous NaOH solution (100 ml) and DCM (100 ml) were added and the mixture filtered through celite, washing with DCM (100 ml). The layers were separated and the aqueous layer was extracted with DCM (2×100 ml). The combined organics were dried over magnesium sulfate and concentrated in vacuo to give (±)-3-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene 1-14 as a sticky brown oil. LCMS (method 2): m/z 178.5 (M+H).sup.+ (ES.sup.+); at 1.68 min, .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.02 (dd, J=8.3, 5.8 Hz, 1H), 6.87 (ddd, J=18.0, 9.2, 2.8 Hz, 2H), 4.09 (d, J=5.0 Hz, 1H), 3.70 (t, J=5.8 Hz, 1H), 2.98 (dd, J=16.6, 5.0 Hz, 1H), 2.44 (d, J=16.4 Hz, 1H), 1.96-1.82 (m, 2H), 1.70 (t, J=8.9 Hz, 1H), 1.53-1.37 (m, 1H). (1H obscured by water peak).

Intermediate 15 (I-15)

[1402] ##STR00209## ##STR00210##

[1403] Step 1: N-(2-Bromo-3-fluorobenzylidene)-2-methylpropane-2-sulfinamide I-15b was synthesised from 2-bromo-3-fluorobenzaldehyde I-15a using a procedure essentially the same as for I-12b. LCMS (method 2): m/z 305.9, 308.0 (M+H).sup.+ (ES.sup.+); at 2.42 min, .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.81 (s, 1H), 7.88 (ddd, J=7.6, 1.8, 0.9 Hz, 1H), 7.65-7.54 (m, 2H), 1.20 (s, 9H).

[1404] Step 2: N-(1-(2-Bromo-3-fluorophenyl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-15c was synthesised from N-(2-bromo-3-fluorobenzylidene)-2-methylpropane-2-sulfinamide I-15b using a procedure essentially the same as for I-12c. LCMS (method 2): m/z 362.0, 364.0 (M+H).sup.+ (ES.sup.+); at 2.44 min, .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 7.49-7.41 (m, 1H), 7.44-7.34 (m, 1H), 7.24 (td, J=8.4, 1.6 Hz, 1H), 5.86-5.77 (m, 1H), 5.71 (d, J=7.0 Hz, 1H), 5.12-4.99 (m, 1H), 5.02-4.95 (m, 1H), 4.70-4.57 (m, 1H), 2.25-2.14 (m, 1H), 2.17-2.03 (m, 1H), 1.95-1.60 (m, 2H), 1.08 (s, 9H).

[1405] Step 3: 1-(2-Bromo-3-fluorophenyl)pent-4-en-1-amine I-15d was synthesised from N-(1-(2-bromo-3-fluorophenyl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-15c using a procedure essentially the same as for 1-14d. LCMS (method 2): m/z 258.0, 260.0 (M+H).sup.+ (ES.sup.+); at 2.18 min, .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 7.46 (dt, J=7.8, 1.3 Hz, 1H), 7.40 (td, J=7.9, 5.6 Hz, 1H), 7.20 (ddd, J=8.9, 8.0, 1.6 Hz, 1H), 5.81 (ddt, J=16.9, 10.2, 6.6 Hz, 1H), 5.06-4.98 (m, 1H), 4.94 (ddt, J=10.2, 2.4, 1.3 Hz, 1H), 4.17 (dd, J=8.2, 4.9 Hz, 1H), 2.20-1.96 (m, 2H), 1.96 (s, 2H), 1.67-1.61 (m, 1H), 1.56-1.49 (m, 1H).

[1406] Step 4: To a solution of 1-(2-bromo-3-fluorophenyl)pent-4-en-1-amine (10.3 g, 39.9 mmol) 1-15d, (4-methoxyphenyl)boronic acid (18.2 g, 120 mmol), and Cu(OAc).sub.2 (10.9 g, 59.9 mmol) in DCM (100 ml) was added pyridine (16.1 ml, 200 mmol) dropwise. The mixture was stirred at RT open to air for 4 days. 2 M NaOH aqueous solution (100 ml) was added, the mixture was stirred for 30 min and filtered through celite. The filtrate was partitioned between water (100 ml) and DCM (100 ml) and the layers were separated. The aqueous layer was further extracted with DCM (2×100 ml). The combined organics were dried over magnesium sulfate and concentrated in vacuo. The product was purified by silica gel chromatography (0%-100% DCM/isohexane) to give N-(1-(2-bromo-3-fluorophenyl)pent-4-en-1-yl)-4-methoxyaniline 1-15e as a sticky orange oil. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 7.36-7.31 (m, 1H), 7.27 (dd, J=8.0, 1.7 Hz, 1H), 7.19 (ddd, J=9.5, 8.0, 1.6 Hz, 1H), 6.66-6.58 (m, 2H), 6.40-6.33 (m, 2H), 6.04 (d, J=8.1 Hz, 1H), 5.87-5.82 (m, 1H), 5.06-4.94 (m, 2H), 4.61 (td, J=8.1, 5.2 Hz, 1H), 3.56 (s, 3H), 2.30 (dd, J=14.3, 7.8 Hz, 1H), 2.23-2.12 (m, 1H), 1.80-1.67 (m, 2H).

[1407] Step 5: (±)-1-Fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene I-15f was synthesised from N-(1-(2-bromo-3-fluorophenyl)pent-4-en-1-yl)-4-methoxyaniline 1-15e using a procedure essentially the same as for I-12f. LCMS (method 2): m/z 284.1 (M+H).sup.+ (ES.sup.+); at 2.56 min, .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.19-7.06 (m, 2H), 6.88 (ddd, J=9.5, 7.9, 1.5 Hz, 1H), 6.83-6.74 (m, 2H), 6.73-6.65 (m, 2H), 4.83 (d, J=5.3 Hz, 1H), 4.51 (t, J=5.6 Hz, 1H), 3.60 (s, 3H), 2.96 (dd, J=17.3, 4.8 Hz, 1H), 2.37 (d, J=17.4 Hz, 1H), 2.33-2.17 (m, 2H), 1.88-1.65 (m, 2H).

[1408] Step 6: (±)-1-Fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene 1-15 was synthesised from (±)-1-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene I-15f using a procedure essentially the same as for 1-12. LCMS (method 2): m/z 178.1 (M+H).sup.+ (ES.sup.+); at 1.69 min, .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 7.09 (td, J=7.8, 5.9 Hz, 1H), 6.90 (ddd, J=9.5, 8.2, 1.1 Hz, 1H), 6.86 (dd, J=7.5, 1.1 Hz, 1H), 4.12 (d, J=5.1 Hz, 1H), 3.75 (t, J=6.0 Hz, 1H), 2.88 (dd, J=16.9, 5.2 Hz, 1H), 2.57 (s, 1H), 2.42 (d, J=16.9 Hz, 1H), 1.97-1.85 (m, 2H), 1.70 (t, J=9.0 Hz, 1H), 1.52-1.41 (m, 1H).

Intermediate 16 (I-16)

[1409] ##STR00211## ##STR00212##

[1410] Step 1: To a mixture of 2-bromonicotinaldehyde I-16a (15.0 g, 80.6 mmol) in THF (90.0 ml) was added Ti(OEt).sub.4 (33.5 ml, 161 mmol) and tert-butylsulfinamide (10.8 g, 88.7 mmol). The resulting mixture was stirred at RT for 16 h. The reaction mixture was poured into water (100 ml) at 0° C., and then extracted with EtOAc (3×75 ml). The combined organics were dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography (0-100% EtOAc/petroleum ether) to give N-((2-bromopyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide I-16b as a yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.92 (s, 1H), 8.48 (t, J=2.0 Hz, 1H), 8.31-8.29 (m, 1H), 7.40-7.37 (m, 1H), 1.25 (t, J=3.2 Hz, 9H).

[1411] Step 2: To a solution of N-((2-bromopyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide I-16b (19.0 g, 65.7 mmol) in THF (107 ml) was added but-3-en-1-yl magnesium bromide (0.5 M, 302 ml) dropwise at 0° C. The mixture was warmed to RT for 1 h. The reaction mixture was cooled to 0° C. and water (50 ml) was added carefully. The product was extracted with EtOAc (3×100 ml). The combined organic layers were washed with brine (50 ml), dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography (0-100% EtOAc/petroleum ether) to give N-(1-(2-bromopyridin-3-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-16c as a yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.28 (t, J=2.8 Hz, 1H), 7.69 (t, J=2.5 Hz, 1H), 7.29-7.26 (m, 1H), 5.83-5.76 (t, J=2.4 Hz, 1H), 5.08-5.00 (m, 2H), 4.84 (s, 1H), 2.23-2.10 (m, 2H), 1.97-1.93 (m, 2H), 1.18 (s, 9H). (NH not observed)

[1412] Step 3: To a solution of N-(1-(2-bromopyridin-3-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-16c (11.2 g, 32.5 mmol) in MeOH (70 ml) was added HCl in EtOAc (4 M, 24.4 ml, 97.6 mmol) at 0° C. and the mixture was warmed to RT for 30 min. The reaction mixture was concentrated in vacuo, triturated with MTBE (100 ml) and the solid collected by filtration, washed with MTBE (2×100 ml) and dried in vacuo. The solids were dissolved in water (50 ml), cooled to 0° C. and the mixture was basified to pH 11 with NaOH solution. The aqueous mixture was extracted with DCM (3×30 ml) and the combined organics were washed with brine (30 ml), dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography (0-100% EtOAc/petroleum ether) to give 1-(2-bromopyridin-3-yl)pent-4-en-1-amine I-16d as a yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.26-8.22 (m, 1H), 7.87-7.78 (m, 1H), 7.26 (t, J=5.6 Hz, 1H), 5.85-5.76 (m, 1H), 5.05-4.96 (m, 2H), 4.35-4.30 (m, 1H), 2.21-2.10 (m, 2H), 1.83 (t, J=6.4 Hz, 1H), 1.70-1.64 (m, 1H). (NH.sub.2 not observed)

[1413] Step 4: To a mixture of 1-(2-bromopyridin-3-yl)pent-4-en-1-amine I-16d (6.50 g, 26.9 mmol), (4-methoxyphenyl)boronic acid (7.66 g, 50.4 mmol), 4 Å molecular Sieves (12.1 g) and Cu(OAc).sub.2 (11.4 g, 63.0 mmol) in 1,4-dioxane (100 ml) was added dropwise Et.sub.3N (4.56 ml, 32.8 mmol). The resultant mixture was stirred at 35° C. under O.sub.2 for 16 hrs. The reaction mixture was filtered and the solid was washed with EtOAc (3×10 ml). The filtrate was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography (0-100% EtOAc/petroleum ether) to give N-(1-(2-bromopyridin-3-yl)pent-4-en-1-yl)-4-methoxyaniline I-16e as a red-brown solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.26-8.23 (m, 1H), 7.83-7.70 (m, 1H) 7.26-7.18 (m, 1H), 6.69 (d, J=4.8 Hz, 1H), 6.41-6.38 (m, 2H), 5.86 (d, J=6.8 Hz, 2H), 5.08-5.00 (m, 2H), 4.64 (t, J=4.4 Hz, 1H), 3.69 (s, 3H), 2.31-2.22 (m, 2H), 1.98 (d, J=6.8 Hz, 1H), 1.73 (t, J=8.4 Hz, 1H). (NH not observed)

[1414] Step 5: A three-neck flask was charged with Pd.sub.2(dba).sub.3 (131 mg, 0.144 mmol), tricyclohexylphosphonium; tetrafluoroborate (106 mg, 0.288 mmol) and NaO.sup.tBu (207 mg, 2.16 mmol) and purged with argon. A solution of N-(1-(2-bromopyridin-3-yl)pent-4-en-1-yl)-4-methoxyaniline I-16e (0.50 g, 1.44 mmol) in 1,4-dioxane (1.8 ml) was added and the resulting mixture was heated to 95° C. for 12 h. The reaction mixture was filtered and the solid was washed with EtOAc (3×10 ml). The filtrate was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography (0-100% EtOAc/petroleum ether) to give (±)-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[b]pyridine I-16f as a pale red-brown solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.32-8.31 (m, 1H), 7.45-7.43 (m, 1H), 6.75 (t, J=2.8 Hz, 1H), 6.72 (t, J=6.4 Hz, 4H), 4.67 (d, J=6.8 Hz, 1H), 4.53 (t, J=6.4 Hz, 1H), 3.69 (s, 3H), 3.36 (d, J=17.6 Hz, 1H), 2.61 (d, J=17.6 Hz, 1H), 2.38 (t, J=5.6 Hz, 1H), 1.94-1.83 (m, 2H).

[1415] Step 6: (±)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[b]pyridine I-16 was synthesised from (±)-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[b]pyridine I-16f using a procedure essentially the same as for 1-14. LCMS (method 1): m/z 160.9 (M+H).sup.+ (ES.sup.+); at 0.62 min.

Intermediate 17 (I-17)

[1416] ##STR00213## ##STR00214##

[1417] Step 1: (S)—N-((4-bromo-6-fluoropyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide I-17b was synthesised from 4-bromo-6-fluoronicotinaldehyde I-17a using a procedure essentially the same as for 1-13b. LCMS (method 2): m/z 307.0, 308.9 (M+H).sup.+ (ES.sup.+); at 2.05 min, .sup.1H NMR (500 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.73 (s, 1H), 7.88 (d, J=2.4 Hz, 1H), 1.21 (s, 9H).

[1418] Step 2: To a solution of ((S)—N-((4-bromo-6-fluoropyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide I-17b (7.00 g, 22.8 mmol) in THF (114 ml) was added but-3-en-1-yl magnesium bromide (2.54 M, 17.9 ml, 45.6 mmol) dropwise at −78° C. The mixture was warmed to RT slowly and stirred for 16 h. Saturated ammonium chloride solution (10 ml) was added and the product was extracted with EtOAc (2×10 ml). The combined organics were dried with magnesium sulfate and concentrated in vacuo. The product was purified by silica gel chromatography (0-10% IPA/isohexane) to give a 2:1 mixture of the diastereomers of (±)-N-(1-(4-bromo-6-fluoropyridin-3-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-17c as a pale yellow oil. LCMS (method 1) m/z 363.3, 365.4 (M+H).sup.+ (ES.sup.+), at 1.39 and 1.42 min.

[1419] Major diastereomer: 1H NMR (500 MHz, DMSO-d6) δ 8.43 (s, 1H), 7.60 (d, J=2.6 Hz, 1H), 6.00 (d, J=9.5 Hz, 1H), 5.82 (ddt, J=16.7, 10.3, 6.6 Hz, 1H), 5.12-4.97 (m, 2H), 4.64-4.50 (m, 1H), 2.26-2.14 (m, 1H), 2.16-2.05 (m, 1H), 1.94-1.78 (m, 1H), 1.78-1.66 (m, 1H), 1.13 (s, 9H).

[1420] Minor diastereomer: 1H NMR (500 MHz, DMSO-d6) δ 8.33 (s, 1H), 7.61 (d, J=2.5 Hz, 1H), 5.82 (ddt, J=16.7, 10.3, 6.6 Hz, 1H), 5.76 (d, J=7.0 Hz, 1H), 5.12-4.97 (m, 2H), 4.64-4.50 (m, 1H), 2.26-2.14 (m, 1H), 2.16-2.05 (m, 1H), 2.03-1.92 (m, 1H), 1.94-1.78 (m, 1H), 1.07 (s, 9H).

[1421] Step 3: (±)-1-(4-Bromo-6-fluoropyridin-3-yl)pent-4-en-1-amine I-17d was synthesised from (±)-N-(1-(4-bromo-6-fluoropyridin-3-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-17c using a procedure essentially the same as for I-13d. LCMS (method 1) m/z 259.2, 261.2 (M+H).sup.+ (ES.sup.+), at 1.21 min. .sup.1H NMR (500 MHz, DMSO-d6) δ 8.41 (s, 1H), 7.55 (d, J=2.7 Hz, 1H), 5.82 (ddt, J=16.9, 10.2, 6.6 Hz, 1H), 5.03 (dq, J=17.2, 1.8 Hz, 1H), 4.95 (ddt, J=10.2, 2.3, 1.3 Hz, 1H), 4.12 (dd, J=8.2, 4.9 Hz, 1H), 2.25-1.98 (m, 4H), 1.75-1.64 (m, 1H), 1.64-1.54 (m, 1H).

[1422] Step 4: (±)-N-(1-(4-Bromo-6-fluoropyridin-3-yl)pent-4-en-1-yl)-4-methoxyaniline I-17e was synthesised from (±)-1-(4-bromo-6-fluoropyridin-3-yl)pent-4-en-1-amine I-17d using a procedure essentially the same as for 1-13e. LCMS (method 1) m/z 365.0, 367.1 (M+H).sup.+ (ES.sup.+), at 1.76 min. .sup.1H NMR (500 MHz, DMSO-d6) δ 8.21 (s, 1H), 7.61 (d, J=2.5 Hz, 1H), 6.66 (d, J=8.9 Hz, 2H), 6.40 (d, J=9.0 Hz, 2H), 6.04 (d, J=8.3 Hz, 1H), 5.86 (ddt, J=17.0, 10.2, 6.6 Hz, 1H), 5.08-4.90 (m, 2H), 4.59 (td, J=8.5, 4.8 Hz, 1H), 3.58 (s, 3H), 2.35-2.26 (m, 1H), 2.23-2.13 (m, 1H), 1.92-1.71 (m, 2H).

[1423] Step 5: A three-neck flask was charged with Pd-178 (0.29 g, 0.61 mmol) and NaO.sup.tBu (0.88 g, 9.2 mmol) and purged with N.sub.2. A solution of N-(1-(4-bromo-6-fluoropyridin-3-yl)pent-4-en-1-yl)-4-methoxyaniline I-17e (2.3 g, 6.1 mmol) in toluene (66 ml) was added dropwise. The resulting mixture was heated to 95° C. for 2 h. The reaction mixture was cooled to RT and filtered through celite, washing the solid with EtOAc (150 ml). The filtrate was concentrated in vacuo. The product was purified by silica gel chromatography (0%-50% EtOAc/isohexane) to give a mixture of enantiomers which were dissolved to 30 mg/ml in DCM:methanol (1:4) and was then separated by chiral SFC on a Waters prep 15 with UV detection at 210 nm, 40° C., 100 bar on a Lux C.sub.3 column (21.2 mm×250 mm, 5 μm particle size), flow rate 50 ml/min using 40% methanol to give (6S,9R)-3-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine (I-17f) as a pale yellow solid. LCMS (method 1) m/z 285.3 (M+H).sup.+ (ES.sup.+), at 1.35 min. 1H NMR (500 MHz, DMSO-d6) δ 8.10 (s, 1H), 6.79 (t, J=9.7 Hz, 3H), 6.70 (d, J=9.1 Hz, 2H), 4.95 (d, J=5.5 Hz, 1H), 4.47 (t, J=6.0 Hz, 1H), 3.61 (s, 3H), 3.11 (dd, J=18.2, 4.9 Hz, 1H), 2.31-2.19 (m, 2H), 1.88-1.55 (m, 2H), 1H obscured by residual DMSO peak.

[1424] and (6R,9S)-3-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine (I-17g) as a pale yellow solid. LCMS (method 1) m/z 285.3 (M+H).sup.+ (ES.sup.+), at 1.35 min. 1H NMR (500 MHz, DMSO-d6) δ 8.10 (s, 1H), 6.79 (t, J=9.7 Hz, 3H), 6.70 (d, J=9.1 Hz, 2H), 4.95 (d, J=5.5 Hz, 1H), 4.47 (t, J=6.0 Hz, 1H), 3.61 (s, 3H), 3.11 (dd, J=18.2, 4.9 Hz, 1H), 2.31-2.19 (m, 2H), 1.88-1.55 (m, 2H), 1H obscured by residual DMSO peak.

[1425] Step 6: (6S,9R)-3-fluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine (I-17) was synthesised from (6S,9R)-3-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine (I-17f) using a procedure essentially the same as for 1-13. LCMS (method 1) m/z 179.2 (M+H).sup.+ (ES.sup.+), at 0.71 min.

Intermediate 18 (I-18)

[1426] ##STR00215##

[1427] (6S,9R)-3-fluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-17 (300 mg, 1.68 mmol) was dissolved in HBr (1.90 ml, 48% w/w in water, 16.8 mmol) and was heated at 100° C. for 18 h. The reaction mixture was cooled to RT, diluted with MeOH, loaded onto a SCX cartridge (20 g) and the product was eluted with ammonia in MeOH solution (0.7 M) to give (6S,9R)-2,5,6,7,8,9-hexahydro-3H-6,9-epiminocyclohepta[c]pyridin-3-one (1-18) as an off white solid. LCMS (method 1) m/z 176.9 (M+H).sup.+ (ES.sup.+), at 0.41 min,

Intermediate 19 (1-19)

[1428] ##STR00216## ##STR00217##

[1429] Step 1: To a solution of 4-chloro-3-fluoropyridine I-19a (25.9 ml, 190 mmol) in THF (120 ml) was added LDA (2 M, 114 ml, 228 mmol) at −70° C. The mixture was stirred at −70° C. for 3 h, before DMF (17.5 ml, 228 mmol) in THF (50 ml) was added. The mixture was slowly warmed to RT and stirred at RT for 1 h. The reaction mixture was cooled to 0° C. and saturated ammonium chloride (100 ml) was added. The aqueous layer was adjusted to pH 6 with HCl (1 M) and extracted with MTBE (3×100 ml). The combined organic layers were washed with brine (100 ml), dried over sodium sulfate and concentrated in vacuo to give 4-chloro-5-fluoronicotinaldehyde I-19b as a yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 10.4 (s, 1H), 8.87 (s, 1H), 8.69 (s, 1H).

[1430] Step 2: N-((4-Chloro-5-fluoropyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide I-19c was synthesised from 4-chloro-5-fluoronicotinaldehyde I-19b using a procedure essentially the same as for I-16b. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.02 (s, 1H), 8.93 (s, 1H), 8.59 (s, 1H), 1.30 (s, 9H).

[1431] Step 3: To a solution of (E)-N-((4-chloro-5-fluoropyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide I-19c (27.0 g, 102 mmol) in THF (150 ml), was added but-3-en-1-yl magnesium bromide (0.5 M, 822 ml) at 0° C. The mixture was warmed and stirred at RT for 1 h. The reaction mixture was cooled to 0° C. and water (50 ml) was added. The product was extracted with EtOAc (3×100 ml). The organic layer was separated, washed with water (100 ml) and brine (100 ml), dried over sodium sulfate and concentrated in vacuo. The product was triturated with petroleum ether (50 ml) and the solid was collected by filtration washing with petroleum ether (2×20 ml). The solid was dried in vacuo to give N-(1-(4-chloro-5-fluoropyridin-3-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-19d as a yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.43 (s, 2H), 5.84-5.76 (m, 1H), 5.10-5.03 (m, 2H), 4.94-4.90 (m, 1H), 3.58 (d, J=2.4 Hz, 1H), 2.22-2.01 (m, 4H), 1.20 (s, 9H).

[1432] Step 4: 1-(4-Chloro-5-fluoropyridin-3-yl)pent-4-en-1-amine I-19e was synthesised from N-(1-(4-chloro-5-fluoropyridin-3-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-19d using a procedure essentially the same as for 1-16d. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.52 (s, 1H), 8.38 (s, 1H), 5.83-5.77 (m, 1H), 5.05-4.97 (m, 2H), 4.39-4.35 (m, 1H), 2.16-2.11 (m, 2H), 1.86-1.60 (m, 2H). (NH.sub.2 not observed)

[1433] Step 5: N-(1-(4-Chloro-5-fluoropyridin-3-yl)pent-4-en-1-yl)-4-methoxyaniline I-19f was synthesised from 1-(4-chloro-5-fluoropyridin-3-yl)pent-4-en-1-amine I-19e using a procedure essentially the same as for 1-16e. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.43 (s, 1H), 8.37 (s, 1H), 6.72-6.69 (m, 2H), 6.44 (t, J=3.6 Hz, 2H), 5.85-5.81 (m, 1H), 5.09-5.03 (m, 2H), 4.76 (t, J=4.8 Hz, 1H), 3.96 (s, 1H), 3.70 (s, 3H), 2.30-2.22 (m, 2H), 1.97-1.87 (m, 2H).

[1434] Step 6: (±)-4-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-19g was synthesised from N-(1-(4-bromo-5-fluoropyridin-3-yl)pent-4-en-1-yl)-4-methoxyaniline I-19f using a procedure essentially the same as for I-16f. .sup.1H NMR (400 MHz, CDCl.sub.3) 8.25 (s, 1H), 8.17 (s, 1H), 6.77-6.73 (m, 4H), 4.79 (d, J=6.0 Hz, 1H), 4.52 (t, J=5.2, 1H), 3.71 (s, 3H), 3.15-3.09 (m, 1H), 2.48-2.40 (m, 3H), 1.99-1.94 (m, 1H), 1.78-1.70 (m, 1H).

[1435] Step 7: A solution of (±)-4-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-19g (0.150 g, 528 μmol) in MeCN (10 ml) was cooled to 0° C. before a solution of CAN (925 mg, 1.69 mmol) in water (10 ml) was added dropwise. After the addition was completed the reaction was stirred for 1 h at 0° C. Further CAN (925 mg, 1.69 mmol) in water (3 ml) was added and the reaction stirred for 1 h. The material was loaded onto an SCX cartridge (20 g), washed with MeOH (40 ml) and the product was eluted using 0.7 M ammonia in MeOH (100 ml) solution to give (6S,9R)-4-fluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine as a yellow oil 1-19. LCMS (method 1): m/z 178.9 (M+H).sup.+ (ES.sup.+); at 0.71 min.

Intermediate 20 (1-20)

[1436] ##STR00218##

[1437] Step 1: To a solution of (6S,9R)-3-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-17f (100.0 mg, 351.7 μmol) in MeOH (1 ml) was added sodium methoxide (5.4 M in MeOH, 391 μl, 2.11 mmol) and the reaction mixture heated at 65° C. for 48 h. The reaction mixture was diluted with DCM (20 ml) and water (50 ml). The layers were separated and the aqueous layer was extracted with DCM (3×30 ml). The combined organics were dried over magnesium sulfate and concentrated in vacuo to give (6S,9R)-3-methoxy-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-20a as a pale yellow oil. LCMS (method 2) m/z 297.1 (M+H).sup.+ (ES.sup.+), at 2.14 min.

[1438] Step 2: (6S,9R)-3-Methoxy-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-20 was synthesised from (6S,9R)-3-methoxy-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-20a using a procedure essentially the same as for 1-13. LCMS (method 1) m/z 191.1 (M+H).sup.+ (ES.sup.+), at 1.33 min.

Intermediate 21 (1-21)

[1439] ##STR00219## ##STR00220##

[1440] Step 1: (S)—N-((4-Bromopyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide 1-21a was synthesised from 4-bromo-3-pyridinecarboxaldehyde (1-8a) and (S)-tert-butylsulfinamide using a procedure essentially the same as for I-7b. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.13 (s, 1H), 8.92 (s, 1H), 8.46 (d, J=5.2 Hz, 1H), 7.60 (d, J=5.6 Hz, 1H), 1.29 (s, 9H).

[1441] Step 2: (S)—N—((R)-1-(4-Bromopyridin-3-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-21b and (S)—N—((S)-1-(4-bromopyridin-3-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-22a was synthesised from (S)—N-((4-bromopyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide I-21a using a procedure essentially the same as for I-7c. .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 8.52 (s, 1H), 8.29 (d, J=5.6 Hz, 1H), 7.50 (t, J=9.6 Hz, 1H), 5.83-5.76 (m, 1H), 5.09-5.01 (m, 2H), 4.91-4.89 (m, 1H), 3.60 (t, J=2.8 Hz, 1H), 2.19-1.96 (m, 4H), 1.18 (s, 9H).

[1442] Step 3: (R)-1-(4-Bromopyridin-3-yl)pent-4-en-1-amine 1-21c was synthesised from (S)—N—((R)-1-(4-bromopyridin-3-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide 1-21b using a procedure essentially the same as for I-7d. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.70 (s, 1H), 8.27-8.22 (m, 1H), 7.45 (t, J=5.6 Hz, 1H), 5.88-5.80 (m, 1H), 5.07-4.98 (m, 2H), 4.37-4.33 (m, 1H), 2.22-2.13 (m, 2H), 1.90-1.75 (m, 2H). (NH.sub.2 not observed)

[1443] Step 4: (R)—N-(1-(4-Bromopyridin-3-yl)pent-4-en-1-yl)-4-methoxyaniline 1-21d was synthesised from (R)-1-(4-bromopyridin-3-yl)pent-4-en-1-amine 1-21c using a procedure essentially the same as for 1-7e. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.68 (s, 1H), 8.40 (d, J=5.2 Hz, 1H), 7.34 (d, J=5.2 Hz, 1H), 6.70 (d, J=9.2 Hz, 2H), 6.39-6.36 (m, 2H), 5.87-5.83 (m, 1H), 5.09-5.02 (m, 2H), 4.66-4.63 (m, 1H), 3.95 (s, 1H), 3.87 (s, 3H), 2.33-2.25 (m, 2H), 1.95-1.93 (m, 1H), 1.75-1.71 (m, 1H), (NH not observed)

[1444] Step 5: To a solution of Pd.sub.2(dba).sub.3 (0.68 g, 0.75 mmol), tricyclohexylphosphonium tetrafluoroborate (551 mg, 1.50 mmol and NaO.sup.tBu (5.69 g, 59.2 mmol) in toluene (50 ml). The flask was purged with N.sub.2 and (R)—N-(1-(4-bromopyridin-3-yl)pent-4-en-1-yl)-4-methoxyaniline I-21d (2.6 g, 7.5 mmol) was added dropwise. The resulting mixture was heated to 90° C. for 12 h. The reaction mixture was filtered, and the filter cake was washed with EtOAc (3×50 ml). The filtrate was concentrated in vacuo. The product was purified by silica gel chromatography (10%-100% EtOAc/Petroleum ether to give (6S,9R)-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-21e .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.40 (s, 1H), 8.28 (d, J=5.2 Hz, 1H), 6.85 (d, J=5.2 Hz, 1H), 6.77-6.71 (m, 4H), 4.73 (d, J=5.2 Hz, 1H), 4.46 (t, J=5.2 Hz, 1H), 3.69 (s, 3H), 3.25-3.20 (m, 1H), 2.42-2.35 (m, 3H), 1.97-1.93 (m, 1H), 1.79-1.77 (m, 1H).

[1445] Step 6: To a solution of (6S,9R)-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine (I-21e) (1.08 g, 4.05 mmol) in MeCN (50 ml) was added a solution of CAN (6.67 g, 12.2 mmol) in water (50 ml) dropwise at 0° C. The reaction mixture was stirred at 0° C. for 1 h before the reaction mixture was warmed to RT for 1 h. The reaction was cooled to 0° C. and a further portion of CAN (4.45 g, 8.11 mmol) in water (20 ml) was added and the mixture was stirred at 0° C. for 1 h. A solution of 2 M NaOH (50 ml) was added and the resultant mixture was filtered through a celite pad. The layers were separated and the aqueous layer was extracted with DCM (3×100 ml). The combined organics were dried over magnesium sulfate and concentrated in vacuo to give (6S,9R)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-21 as an off white solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.27-8.18 (m, 2H), 7.04 (d, J=5.0 Hz, 1H), 4.17 (d, J=5.7 Hz, 1H), 3.71 (s, 1H), 2.99 (dd, J=17.4, 5.0 Hz, 1H), 2.72 (s, 1H), 2.47 (dd, J=17.2, 1.1 Hz, 1H), 1.98-1.86 (m, 2H), 1.71 (t, J=8.9 Hz, 1H), 1.49-1.42 (m, 1H).

Intermediate 22 (I-22)

[1446] ##STR00221##

[1447] Step 1: (S)-1-(4-Bromopyridin-3-yl)pent-4-en-1-amine I-22b was synthesised from (S)—N—((S)-1-(4-bromopyridin-3-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-22a and using a procedure essentially the same as for I-7d. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.56 (d, J=7.2 Hz, 1H), 8.25 (d, J=5.2 Hz, 1H), 7.45 (d, J=5.2 Hz, 1H), 5.87-5.79 (m, 1H), 5.06-4.97 (m, 2H), 4.36-4.33 (m, 1H), 2.20-2.12 (m, 2H), 1.89-1.85 (m, 1H), 1.78-1.75 (m, 1H). (NH.sub.2 not observed)

[1448] Step 2: (S)—N-(1-(4-Bromopyridin-3-yl)pent-4-en-1-yl)-4-methoxyaniline I-22c was synthesised from (S)-1-(4-bromopyridin-3-yl)pent-4-en-1-amine I-22b using a procedure essentially the same as for 1-7e. .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 8.57 (s, 1H), 8.26 (s, 1H), 7.50 (s, 1H), 6.70 (d, J=2.4 Hz, 2H), 6.45-6.42 (m, 2H), 5.86-5.82 (m, 2H), 4.73-4.71 (m, 2H), 4.69-4.67 (m, 1H), 3.70 (s, 3H), 2.31-2.23 (m, 2H), 1.96-1.94 (m, 1H), 1.85-1.82 (m, 1H).

[1449] Step 3: (6S,9R)-10-(4-Methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine) I-22d was synthesised from (S)—N-(1-(4-bromopyridin-3-yl)pent-4-en-1-yl)-4-methoxyaniline I-22c using a procedure essentially the same as for I-21e. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.66 (s, 1H), 8.29-8.24 (m, 1H), 7.48-7.45 (t, J=8.8 Hz, 1H), 5.86-5.79 (m, 1H), 5.06-4.97 (m, 2H), 4.36-4.33 (m, 1H), 2.20-2.12 (m, 2H), 1.89-1.85 (m, 1H), 1.78-1.75 (m, 1H), 1.56 (s, 2H).

[1450] Step 4: (6S,9R)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-22 was synthesised from 1-(4-bromopyridin-3-yl)pent-4-en-1-amine I-22d using a procedure essentially the same as for 1-21. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.23 (d, J=5.0 Hz, 1H), 8.19 (s, 1H), 7.03 (d, J=5.0 Hz, 1H), 4.16 (d, J=5.7 Hz, 1H), 3.70 (t, J=6.0 Hz, 1H), 2.99 (dd, J=17.4, 5.1 Hz, 1H), 2.00-1.86 (m, 2H), 1.70 (t, J=8.9 Hz, 1H), 1.49-1.41 (m, 1H). (NH not observed, 1CH under DMSO peak)

Intermediate 23 (I-23)

[1451] ##STR00222## ##STR00223##

[1452] Step 1: (S)—N-((3-Bromopyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide I-23b was synthesised from 3-bromo-4-pyridinecarboxaldehyde I-7a using a procedure essentially the same as for I-7b. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.92 (s, 1H), 8.87 (s, 1H), 8.64-8.63 (m, 1H), 7.85-7.84 (m, 1H), 1.30 (s, 3H).

[1453] Step 2: To a solution of (S)—N-((3-bromopyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide (I-23b) (6.00 g, 20.7 mmol) in THF (120 ml) was added (3-methylbut-3-en-1-yl)magnesium bromide (0.5 M in THF, 124 ml) then the mixture was stirred at 20° C. for 1 h. Saturated NH.sub.4Cl solution (50 ml) was added, and the product was extracted with EtOAc (3×20 ml). The combined organics were washed with water (20 ml) and brine (200 ml), dried with sodium sulfate, and concentrated in vacuo. The product was purified by silica gel chromatography (EtOAc/Petroleum ether 1%-100%) to give (S)—N—((R)-1-(3-bromopyridin-3-yl)-4-methylpent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-23c as a yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.72-8.64 (m, 1H), 8.61 (s, 1H), 7.33-7.32 (m, 1H), 4.85-4.81 (m, 1H), 4.77-4.73 (m, 2H), 2.14-1.93 (m, 4H), 1.72 (s, 3H), 1.19, (s, 9H)

[1454] Step 3: (R)-1-(3-Bromopyridin-3-yl)-4-methylpent-4-en-1-amine I-23d was synthesised from (S)—N—((R)-1-(3-bromopyridin-3-yl)-4-methylpent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-23c using a procedure essentially the same as for I-7d. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.64-8.61 (m, 1H), 8.49-8.45 (m, 1H), 7.43 (t, J=4.8 Hz, 1H), 4.72-4.69 (m, 2H), 4.30-4.24 (m, 1H), 2.14-2.05 (m, 2H), 1.87-1.70 (m, 1H), 1.68-1.64 (m, 1H).

[1455] Step 4: (R)—N-(1-(3-Bromopyridin-3-yl)-4-methylpent-4-en-1-yl)-4-methoxyaniline I-23e was synthesised from (R)-1-(3-bromopyridin-3-yl)-4-methylpent-4-en-1-amine I-23d using a procedure essentially the same as for 1-7e. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.70 (s, 1H), 8.42 (s, 1H), 7.37 (s, 1H), 6.70 (d, J=8.8 Hz, 2H), 6.36 (t, J=8.8 Hz, 2H), 4.75 (d, J=25.5 Hz, 2H), 4.65-4.62 (m, 1H), 3.70 (s, 3H), 2.26-2.20 (m, 2H), 2.12-1.98 (m, 3H), 1.77-1.75 (m, 4H).

[1456] Step 5: (5R,8S)-10-(4-Methoxyphenyl)-8-methyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine I-23f was synthesised from (R)—N-(1-(3-bromopyridin-3-yl)-4-methylpent-4-en-1-yl)-4-methoxyaniline I-23e using a procedure essentially the same as for I-21e .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.42 (s, 1H), 8.22 (s, 1H), 7.09 (d, J=4.8 Hz, 1H), 6.81 (d, J=8.8 Hz, 2H), 6.67 (d, J=8.8 Hz, 2H), 4.44 (d, J=6.4 Hz, 2H), 3.71 (s, 3H), 2.72-2.68 (m, 1H), 2.49-2.45 (m, 1H), 2.33-2.30 (m, 1H), 2.05-2.02 (m, 1H), 1.99-1.93 (m, 2H), 1.72-1.70 (m, 1H), 1.56 (s, 3H).

[1457] Step 6: (5R,8S)-8-Methyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine (I-23) was synthesised from (5R,8S)-10-(4-Methoxyphenyl)-8-methyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine (I-23f) using a procedure essentially the same as for 1-21. LCMS (method 2) m/z 175 (M+H).sup.+ (ES.sup.+), at 1.15 min.

Intermediate 24 (I-24)

[1458] ##STR00224## ##STR00225##

[1459] Step 1: 1-Cyclopropylethan-1-ol (11.3 ml, 116 mmol) was dissolved in aqueous HBr (45 ml, 47% w/w) at 0° C. The mixture was warmed to RT for 12 h. The product was distilled in vaccuo (60° C., 750 Torr) to give a mixture of (E)-5-bromopent-2-ene I-24b and (Z)-5-bromopent-2-ene I-24c as a yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.58-5.52 (m, 1H), 5.43-5.36 (m, 1H), 3.37-3.33 (m, 2H), 2.56-2.50 (m, 2H), 1.67-1.65 (m, 3H).

[1460] Step 2: To a solution of I.sub.2 (1.69 ml, 8.39 mmol) and Mg (8.66 g, 356 mmol) in THF (250 ml) at 20° C. was added a mixture of (E)-5-bromopent-2-ene I-24b and (Z)-5-bromopent-2-ene I-24c (25.0 g, 167 mmol) in THF (100 ml) at RT. The mixture was stirred at 40° C. for 1 h. The crude mixture of (E)-pent-3-en-1-ylmagnesium bromide I-24d and (Z)-pent-3-en-1-ylmagnesium I-24e was used into the next step without any work up or further purification.

[1461] Step 3: (S)—N—((R,E)-1-(3-Bromopyridin-4-yl)hex-4-en-1-yl)-2-methylpropane-2-sulfinamide I-24f and (S)—N—((R,Z)-1-(3-bromopyridin-4-yl)hex-4-en-1-yl)-2-methylpropane-2-sulfinamide I-24g was synthesised from (S,E)-N-((3-bromopyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide I-23b and a mixture of mixture of (E)-pent-3-en-1-ylmagnesium bromide I-24d and (Z)-pent-3-en-1-ylmagnesium I-24e using a procedure essentially the same as for I-7c. Data for I-24f as I-24g was a minor proportion of the mixture. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.67 (s, 1H), 8.48 (d, J=5.2 Hz, 1H), 5.50-5.39 (m, 2H), 4.88-4.81 (m, 1H), 3.59 (d, J=3.6 Hz, 1H), 2.11-2.03 (m, 3H), 1.93-1.90 (m, 2H), 1.64-1.63 (m, 3H), 1.16 (s, 9H)

[1462] Step 4: (R,E)-1-(3-Bromopyridin-4-yl)hex-4-en-1-amine I-24h and (R,Z)-1-(3-Bromopyridin-4-yl)hex-4-en-1-amine I-24i was synthesised from (S)—N—((R,E)-1-(3-bromopyridin-4-yl)hex-4-en-1-yl)-2-methylpropane-2-sulfinamide I-24f and (S)—N—((R,Z)-1-(3-bromopyridin-4-yl)hex-4-en-1-yl)-2-methylpropane-2-sulfinamide I-24g using a procedure essentially the same as for I-7d.

[1463] Step 5: ((R,E)-N-(1-(3-Bromopyridin-4-yl)hex-4-en-1-yl)-4-methoxyaniline I-24j and (R,Z)—N-(1-(3-bromopyridin-4-yl)hex-4-en-1-yl)-4-methoxyaniline I-24k was synthesised from (R,E)-1-(3-bromopyridin-4-yl)hex-4-en-1-amine I-24h and (R,Z)-1-(3-bromopyridin-4-yl)hex-4-en-1-amine I-24i using a procedure essentially the same as for 1-7e. Data for I-24j as I-24k was a minor proportion of the mixture. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.69 (s, 1H), 8.41 (s, 1H), 7.39 (s, 1H), 6.70-6.67 (m, 2H), 6.38-6.36 (m, 2H), 5.50-5.41 (m, 2H), 4.63-4.60 (m, 1H), 3.68 (s, 3H), 2.19-2.15 (m, 2H), 1.71-1.64 (m, 4H).

[1464] Step 6: To a solution of ((R,E)-N-(1-(3-bromopyridin-4-yl)hex-4-en-1-yl)-4-methoxyaniline I-24j and (R,Z)—N-(1-(3-bromopyridin-4-yl)hex-4-en-1-yl)-4-methoxyaniline I-24k (0.54 g, 1.49 mmol) in dioxane (5 ml) was added NaO.sup.tBu (287 mg, 2.99 mmol) and Pd-178 (71.3 mg, 149 umol) at RT. The mixture was heated at 105° C. for 16 hours. The reaction mixture was filtered, the filter cake was washed with EtOAc (3×50 ml). The filtrate was concentrated in vacuo. The residue was purified by prep-HPLC (30-60% MeCN/10 mM NH.sub.4HCO.sub.3) to afford (5R,8S,9R)-10-(4-methoxyphenyl)-9-methyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine I-24I and as a white solid and (5R,8S,9S)-10-(4-methoxyphenyl)-9-methyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine I-24k as a white solid.

[1465] (5R,8S,9R)-10-(4-methoxyphenyl)-9-methyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine I-24I: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.37 (s, 2H), 7.06-7.01 (m, 1H), 6.88-6.78 (m, 4H), 4.67 (d, J=5.2 Hz, 1H), 4.14 (d, J=6.0, 1H), 3.75 (s, 3H), 2.81 (d, J=7.6 Hz, 1H), 2.23-2.16 (m, 2H), 1.79-1.74 (m, 1H), 1.58-1.50 (m, 1H), 1.37 (d, J=7.6 Hz, 3H).

[1466] (5R,8S,9S)-10-(4-methoxyphenyl)-9-methyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine I-24k: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.35-8.32 (m, 2H), 7.05 (d, J=5.2 Hz, 1H), 6.99-6.73 (m, 4H), 4.57 (d, J=7.6 Hz, 1H), 4.22-4.19 (m, 1H), 3.70 (s, 3H), 3.35-3.32 (m, 1H), 2.34-2.31 (m, 1H), 2.22-2.13 (m, 1H), 1.98-1.83 (m, 2H), 1.31 (d, J=8.0 Hz, 3H).

[1467] Step 7: To a solution of (5R,8S,9S)-10-(4-methoxyphenyl)-9-methyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine I-24k (11.0 mg, 39.2 μmol) in MeCN (0.55 ml) was added a solution of CAN (65 mg, 118 μmol) in water (0.55 ml) was added dropwise at 0° C. The mixture was stirred at 0° C. for 1 h. Water (10 ml) and 2 M NaOH (10 ml) was added, and the product was extracted with DCM (3×20 ml). The combined organics were concentrated in vacuo to give (5R,8S,9S)-9-methyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine I-24 as a colourless oil. The product was used in the next step without further purification or analysis.

Intermediate 25 (I-25)

[1468] ##STR00226## ##STR00227##

[1469] Step 1: To a solution of 2,3-difluoropyridine I-25a (50.0 g, 434 mmol) in hexane (275 ml) and THF (450 ml) was added n-BuLi (2.5 M in hexane, 173 ml) at −70° C. The mixture was stirred at −70° C. for 2 h before 1,1,2-trichloro-1,2,2-trifluoroethane (52 ml, 434 mmol) was added at −70° C. and the resultant mixture was stirred at −70° C. for 1 h. Aqueous ammonium chloride solution (300 ml) was added at 0° C. and the product was extracted with EtOAc (3×100 ml). The combined organics were washed with brine (100 ml), dried with sodium sulfate and concentrated in vacuo to afford 4-chloro-2,3-difluoropyridine I-25b as a yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.92 (d, J=5.2 Hz, 1H), 7.29 (d, J=2.0 Hz, 1H).

[1470] Step 2: To a solution of 4-chloro-2,3-difluoropyridine I-25b (17 g, 113 mmol) in THF (170 ml) was added a solution of LDA in THF/n-heptane/ethylbenzene (2 M, 68 ml) at −90° C. The mixture was warmed −70° C. for 2 h. DMF (10.5 ml, 136 mmol) in THF (170 ml) was added slowly at −90° C. The resultant mixture was slowly warmed to RT and stirred at RT for 1 h. An aqueous 1 M HCl solution (200 ml) was added at 0° C. The product was extracted with MTBE (3×100 ml). The combined organics were washed with brine (100 ml), dried over sodium sulfate and concentrated in vacuo to give 4-chloro-5,6-difluoronicotinaldehyde I-25c as a yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 10.3 (s, 1H), 8.52 (s, 1H).

[1471] Step 3: N-((4-Chloro-5,6-difluoropyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide I-25d was synthesised from 4-chloro-5,6-difluoronicotinaldehyde I-25c using a procedure essentially the same as for I-7b. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.89 (d, J=2.4 Hz, 1H), 8.64 (s, 1H), 1.31 (s, 9H).

[1472] Step 4: N-(1-(4-Chloro-5,6-difluoropyridin-3-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-25e was synthesised from N-((4-chloro-5,6-difluoropyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide I-25d using a procedure essentially the same as for I-7c. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.00 (s, 1H), 5.81-5.76 (m, 1H), 5.09-4.99 (m, 2H), 4.84-4.68 (m, 1H), 3.73-3.56 (m, 1H), 2.13-2.11 (m, 2H), 2.00-1.97 (m, 2H), 1.17 (s, 9H).

[1473] Step 5: 1-(4-Chloro-5,6-difluoropyridin-3-yl)pent-4-en-1-amine I-25f was synthesised from N-(1-(4-chloro-5,6-difluoropyridin-3-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-25e using a procedure essentially the same as for I-7d. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.11 (s, 1H), 5.84-5.76 (m, 1H), 5.06-4.98 (m, 2H), 4.33-4.30 (m, 1H), 2.18-2.12 (m, 2H), 1.85-1.73 (m, 2H).

[1474] Step 6: N-(1-(4-Chloro-5,6-difluoropyridin-3-yl)pent-4-en-1-yl)-4-methoxyaniline I-25g was synthesised from 1-(4-chloro-5,6-difluoropyridin-3-yl)pent-4-en-1-amine I-25f using a procedure essentially the same as for I-7e. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.00 (s, 1H), 6.71-6.69 (m, 2H), 6.42-6.39 (m, 2H), 5.84-5.79 (m, 1H), 5.08-5.03 (m, 2H), 4.67-4.65 (m, 1H), 3.70 (s, 3H), 2.29-2.20 (m, 2H), 1.95-1.86 (m, 2H).

[1475] Step 7: To a solution of N-(1-(4-chloro-5,6-difluoropyridin-3-yl)pent-4-en-1-yl)-4-methoxyaniline I-25g (0.30 g, 885 umol) in 1,4-dioxane (10 ml) was added NaO.sup.tBu (127 mg, 1.32 mmol) and Pd-178 (42 mg, 88.5 umol) at RT. The resultant mixture was heated at 95° C. for 16 h. The reaction mixture was filtered. The filter cake was washed with EtOAc (3×10 ml), the combined organics were dried over sodium sulfate and concentrated in vacuo. The product was purified by chromatography on silica (1-100%, EtOAc/Petroleum ether) to afford (±)-3,4-difluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-25h as a yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.79 (s, 1H), 6.74-6.70 (m, 4H), 4.80-4.78 (m, 1H), 4.52-4.49 (m, 1H), 3.71 (s, 3H), 3.17-3.13 (m, 1H), 2.55-2.38 (m, 2H), 1.96-1.91 (m, 1H), 1.75-1.70 (m, 1H).

[1476] Step 8: (±)-3,4-Difluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-25 was synthesised from (±)-3,4-difluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-25h using a procedure essentially the same as for I-24. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 7.75 (d, J=1.6 Hz, 1H), 4.31-4.26 (m, 1H), 3.76 (t, J=5.9 Hz, 1H), 3.00-2.91 (m, 1H), 2.74 (s, 1H), 2.59 (dd, J=18.0, 1.3 Hz, 1H), 2.00-1.87 (m, 2H), 1.78-1.66 (m, 1H), 1.57-1.46 (m, 1H)

Intermediate 26 (I-26)

[1477] ##STR00228##

[1478] Step 1: To a solution of (±)-3,4-difluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-25h (145 mg, 480 μmol) in MeOH (5 ml) was added a solution of sodium methoxide in MeOH (133 μl, 5.4 M, 719 μmol). The reaction mixture was heated to 65° C. for 18 h. The reaction mixture was diluted with MeOH (5 ml) and an additional portion of sodium methoxide in MeOH (133 μl, 5.4 M, 719 μmol) was added and the reaction mixture was stirred at 65° C. for a further 3 h. The reaction mixture was diluted with DCM (30 ml) and water (10 ml) was added and the layers were separated. The aqueous was extracted with DCM (3×20 ml) and the combined organic layer were dried over sodium sulfate and concentrated in vacuo to give (±)-4-fluoro-3-methoxy-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-26a as a brown oil. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 7.88 (s, 1H), 6.84-6.78 (m, 2H), 6.73-6.68 (m, 2H), 4.92 (d, J=5.3 Hz, 1H), 4.51 (t, J=5.9 Hz, 1H), 3.85 (s, 3H), 3.61 (d, J=2.4 Hz, 3H), 2.97 (dd, J=18.0, 5.0 Hz, 1H), 2.46 (s, 1H), 2.25 (q, J=6.5, 4.5 Hz, 2H), 1.88-1.70 (m, 2H).

[1479] Step 2: (±)-4-Fluoro-3-methoxy-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-26b was synthesised from (±)-4-fluoro-3-methoxy-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-26a using a procedure essentially the same as for I-24. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 7.66 (s, 1H), 4.20 (d, J=4.9 Hz, 1H), 3.87 (s, 3H), 3.73 (t, J=5.9 Hz, 1H), 2.88 (dd, J=17.6, 5.2 Hz, 1H), 2.70 (s, 1H), 2.53 (d, J=1.3 Hz, 1H), 1.95-1.86 (m, 2H), 1.74-1.64 (m, 1H), 1.54-1.44 (m, 1H).

[1480] Step 3: A solution of (±)-4-fluoro-3-methoxy-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-26b (190 mg, 999 μmol) in aqueous HBr (2.8 M, 48% Wt, 25.0 mmol) was refluxed for 16 h. The reaction mixture was concentrated in vacuo. The residue was dissolved in MeOH, loaded onto a SCX cartridge (10 g), the cartridge was washed with MeOH and the product was eluted with 0.7 M ammonia in MeOH solution. The filtrate was concentrated in vacuo to afford (±)-2,5,6,7,8,9-hexahydro-3H-6,9-epiminocyclohepta[c]pyridin-3-one 1-26 as a brown solid. LCMS (method 1) m/z 177.2 (M+H).sup.+ (ES.sup.+), at 0.40 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 11.07 (s, 1H), 7.02 (s, 1H), 6.00 (s, 1H), 4.01 (d, J=5.5 Hz, 1H), 3.60 (t, J=6.1 Hz, 1H), 2.82 (dd, J=17.6, 5.1 Hz, 1H), 2.42-2.34 (m, 1H), 1.90-1.77 (m, 2H), 1.63-1.55 (m, 1H), 1.48-1.39 (m, 1H).

Intermediate 27 (I-27)

[1481] ##STR00229##

[1482] Step 1: To a solution of (6S,9R)-3-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-17f (100 mg, 352 μmol) in THF (3.5 ml) at 0° C. was added a solution of LDA (2 M in THF) (194 μl, 387 μmol) and the reaction was stirred at 0° C. for 1 h. A solution of NFSI (222 mg, 703 μmol) in THF (1 ml) was added and the reaction was stirred at 0° C. for 5 min and warmed to RT for 16 h. The reaction mixture was diluted with EtOAc (5 ml) and water (10 ml) was added. The layers were separated. The aqueous layer was extracted with EtOAc (2×10 ml). The combined organics were dried over magnesium sulfate and concentrated in vacuo to give a brown oil. The product was purified by chromatography on silica gel (0-100% EtOAc/isohexane) to afford (5S,6S,9R)-3,5-difluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-27a as a pale yellow oil. LCMS (method 5) m/z 303.1 (M+H).sup.+ (ES.sup.+), at 2.30 min. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 8.08 (s, 1H), 6.94 (d, J=2.3 Hz, 1H), 6.86-6.63 (m, 4H), 5.70 (ddd, J=50.9, 5.0, 1.3 Hz, 1H), 4.87-4.69 (m, 1H), 4.61 (t, J=5.8 Hz, 1H), 3.72 (s, 3H), 2.46-2.27 (m, 1H), 2.28-2.10 (m, 2H), 1.79 (ddd, J=11.6, 8.6, 2.8 Hz, 1H)

[1483] Step 2: (5S,6S,9R)-3,5-difluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-27 was synthesised from (5S,6S,9R)-3,5-difluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-27a using a procedure essentially the same as for I-24.

Intermediate 28 (I-28)

[1484] ##STR00230##

[1485] Step 1: (6R,9S)-3-fluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine (I-28) was synthesised from (6R,9S)-3-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine (I-17g) using a procedure essentially the same as for I-13. LCMS (method 1) m/z 179.2 (M+H).sup.+ (ES.sup.+), at 0.71 min, .sup.1H NMR (500 MHz, Chloroform-d) δ 7.80 (s, 1H), 6.58 (d, J=2.0 Hz, 1H), 4.28 (d, J=5.6 Hz, 1H), 3.93-3.69 (m, 1H), 3.10 (ddd, J=17.8, 5.2, 1.5 Hz, 1H), 2.57 (d, J=17.8 Hz, 1H), 2.14-1.91 (m, 3H), 1.90-1.77 (m, 1H), 1.67-1.42 (m, 1H).

Experimental Scheme 2

Compound 45: (±)-N-(3-Chloro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

[1486] ##STR00231##

[1487] Step 1: 2-Amino-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide 45b was synthesised from 2-amino-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidin-2-amine 45a using a procedure essentially the same as for 1. LCMS (method 1): m/z 398.1, 400.0 (M+H).sup.+ (ES.sup.+); at 1.19 min. .sup.1H NMR (500 MHz, DMSO-d6) δ 9.16 (s, 1H), 8.01 (s, 1H), 7.91 (d, J=2.0 Hz, 1H), 7.70 (d, J=8.8 Hz, 1H), 7.62 (dd, J=8.8, 2.1 Hz, 1H), 6.45 (s, 2H), 5.12 (d, J=5.9 Hz, 1H), 4.71 (dd, J=7.9, 5.0 Hz, 1H), 3.11 (ddd, J=18.3, 5.3, 1.4 Hz, 1H), 2.23 (q, J=11.3, 10.8 Hz, 1H), 2.11 (tt, J=11.8, 6.2 Hz, 1H), 1.84-1.66 (m, 2H). (1H obscured by residual solvent peak).

[1488] Step 2: To a solution of 2-amino-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide 45b (100 mg, 251 μmol) in THF (2 ml) was added tetrafluoroboric acid in water (2.34 ml, 48% w/w, 15.1 mmol) and the resultant mixture was cooled to 0° C. A solution of sodium nitrite (34.7 mg, 503 μmol) in water (2 ml) was added dropwise and the reaction mixture was stirred at 0° C. for 1 h before warming to RT for 16 h. The reaction mixture was re-cooled to 0° C. and an additional portion of sodium nitrite (34.7 mg, 503 μmol) in water (2 ml) was added. The reaction was stirred for 1 h. The reaction mixture was added to a solution of ice cold NaHCO.sub.3 (10 ml) and the product was extracted using 10% MeOH in DCM solution (3×50 ml). The solvent was dried over sodium sulfate, filtered and concentrated in vacuo. The product was purified by mass directed HPLC (20-50% MeCN/10 mM aqueous ammonium bicarbonate solution, C18) to yield (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide as a light yellow solid. LC-MS (method 1) m/z 399.3, 401.3 (M+H).sup.+ (ES.sup.+); at 1.15 min. .sup.1H NMR (500 MHz, DMSO-d6) δ 9.30 (s, 1H), 8.62 (d, J=1.7 Hz, 1H), 7.89 (d, J=2.1 Hz, 1H), 7.72 (d, J=8.8 Hz, 1H), 7.60 (d, J=9.0 Hz, 1H), 5.39 (d, J=6.1 Hz, 1H), 4.83 (t, J=6.4 Hz, 1H), 3.38 (m, 1H), 2.84 (d, J=18.8 Hz, 1H), 2.32-2.23 (m, 1H), 2.18 (dt, J=11.7, 5.7 Hz, 1H), 1.91 (t, J=10.7 Hz, 1H), 1.78 (dd, J=17.8, 10.6 Hz, 1H).

[1489] The following compound was prepared using appropriate starting materials in an analogous procedure to that described in Experimental Scheme 2.

TABLE-US-00006 UPLC method Compound Structure 1 Rt [M + H].sup.+ NMR 46 [00232] 367.2, 369.4 at 1.40 min .sup.1H NMR (500 MHz, DMSO- d6) δ 9.04 (s, 1H), 8.60 (d, J = 1.7 Hz, 1H), 7.82 (d, J = 2.4 Hz, 1H), 7.48 (d, J = 8.9 Hz, 1H), 7.43 (dd, J = 8.8, 2.4 Hz, 1H), 5.35 (d, J = 6.2 Hz, 1H), 4.79 (t, J = 6.4 Hz, 1H), 3.35 (d, J = 5.1 Hz, 1H), 2.81 (d, J = 18.8 Hz, 1H), 2.29- 2.21 (m, 1H), 2.16 (tt, J = 12.1, 6.3 Hz, 1H), 1.89 (t, J = 10.1 Hz, 1H), 1.77 (dt, J = 15.1, 7.7 Hz, 1H) (±)-N-(3,4-Dichlorophenyl)-2- fluoro-6,7,8,9-tetrahydro-5H- 5,8- epiminocyclohepta[d]pyrimidine- 10-carboxamide

Experimental Scheme 3

Compound 47: (±)-N-(3-Chloro-4-(trifluoromethyl)phenyl)-9-(hydroxyimino)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

[1490] ##STR00233##

[1491] To a solution of 2-amino-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide 45b (200 mg, 503 μmol) in AcOH (5 ml) was added a solution of sodium nitrite (208 mg, 3.02 mmol) in water (2 ml) dropwise. The reaction mixture was stirred for 2 h. A further portion of water (2 ml) was added the reaction mixture was stirred for 72 h. The precipitate was washed with water and dried in vacuo to give (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-9-(hydroxyimino)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide 47 as a yellow solid. LC-MS (method 1) m/z 428.3, 430.3 (M+H).sup.+ (ES.sup.+); at 1.15 min. .sup.1H NMR (500 MHz, DMSO-d6) δ 12.40 (s, 1H), 11.82 (s, 1H), 9.42 (s, 1H), 7.83 (d, J=2.0 Hz, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.55 (dd, J=8.5, 2.1 Hz, 1H), 5.80 (d, J=6.8 Hz, 1H), 5.23 (s, 1H), 2.35-2.24 (m, 2H), 1.80 (d, J=9.3 Hz, 1H), 1.71 (d, J=11.6 Hz, 1H). (1NH not observed)

Experimental Scheme 4

Compound 11 (±)-N-(3-chloro-4-cyanophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

[1492] ##STR00234##

[1493] To a solution of 4-amino-2-chlorobenzonitrile (47 mg, 0.31 mmol) in THF (1 ml) was added a solution of triphosgene (37 mg, 0.12 mmol) in THF (1 ml) followed by Et.sub.3N (130 μl, 0.93 mmol). The resultant mixture was stirred at RT for 30 min. A solution of 6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine (50 mg, 0.31 mmol) in DMF (0.5 ml) was added and the resultant mixture was stirred at RT for 72 h. A solution of 2 M NaOH (2 ml) was added and the product was extracted with DCM (3 ml). The organics were passed through a hydrophobic frit and the filtrate was concentrated in vacuo. The product was purified by product mass directed HPLC (20-50% MeCN/10 mM aqueous ammonium bicarbonate solution, C18) to afford (±)-N-(5-(trifluoromethyl)pyrazin-2-yl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide as an off white solid. LC-MS (method 1) m/z 340.3, 342.3 (M+H).sup.+ (ES.sup.+) at 1.05 min, .sup.1H NMR (500 MHz, DMSO-d6) δ 9.38 (s, 1H), 8.96 (s, 1H), 8.61 (s, 1H), 7.91 (d, J=2.0 Hz, 1H), 7.80 (d, J=8.7 Hz, 1H), 7.59 (dd, J=8.7, 2.0 Hz, 1H), 5.31 (d, J=6.2 Hz, 1H), 4.84 (t, J=6.5 Hz, 1H), 3.37-3.34 (m, 1H), 2.80 (d, J=18.4 Hz, 1H), 2.34-2.14 (m, 2H), 1.96-1.86 (m, 1H), 1.81-1.72 (m, 1H).

[1494] The following compounds were prepared using appropriate starting materials in an analogous procedure to that described in Experimental Scheme 4. Where the starting materials are not described in the literature, their synthesis is described below.

[1495] Key: (a) Reaction performed in DCM. (b) purification was by silica gel chromatography (EtOAc/isohexane). (c) purification was by silica gel chromatography ((0.7 M Ammonia in MeOH/DCM) (d) (M−H).sup.− ES.sup.(−) as no ionisation in ES.sup.+ (e) LCMS method 6 (f) purified by prep TLC (MeOH/DCM)

TABLE-US-00007 LCMS method 1 Compound Structure Rt [M + H].sup.+ NMR  15.sup.(a) [00235] 427.3, 429.3 at 1.34 min .sup.1H NMR (500 MHz, DMSO- d6) δ 9.26 (s, 1H), 8.96 (s, 1H), 8.61 (s, 1H), 8.06 (d, J = 2.0 Hz, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.66 (dd, J = 8.9, 2.0 Hz, 1H), 5.31 (d, J = 6.2 Hz, 1H), 4.87-4.81 (m, 1H), 3.39-3.33 (m, 1H), 2.80 (d, J = 18.6 Hz, 1H), 2.34-2.15 (m, 2H), 1.96-1.86 (m, 1H), 1.81-1.72 (m, 1H). (±)-N-(3-Bromo-4- (trifluoromethyl)phenyl)- 6,7,8,9-tetrahydro-5H-5,8- epiminocyclohepta[d]pyrimidine- 10-carboxamide  79.sup.(a)(b) [00236] 382.0, 384.1, 386.3 at 1.47 min .sup.1H NMR (500 MHz, DMSO- d6) δ 8.82 (s, 1H), 8.07-7.93 (m, 1H), 7.88-7.78 (m, 1H), 7.71-7.59 (m, 1H), 7.19 (s, 1H), 5.20 (br s, 1H), 4.77 (br s, 1H), 3.24-3.10 (m, 2H), 2.32-2.12 (m, 2H), 1.89-1.68 (m, 2H). (5R,8S)-N-(4,5-Dichlroo-2- fluorophenyl)-1-fluoro- 6,7,8,9-tetrahydro-5H-5,8- epiminocyclohepta[c]pyridine- 10-carboxamide  88.sup.(a)(c) [00237] 389.4, 390.3, 393.3 at 1.05 min .sup.1H NMR (500 MHz, DMSO- d.sub.6) δ 11.26 (s, 1H), 9.17 (s, 1H), 8.17 (s, 1H), 7.76 (s, 1H), 7.19 (s, 1H), 6.09 (s, 1H), 5.04 (d, J = 6.0 Hz, 1H), 4.57 (t, J = 6.5 Hz, 1H), 3.16 (dt, J = 10.8, 5.7 Hz, 1H), 2.58 (d, J = 17.8 Hz, 1H), 2.18 (q, J = 11.0 Hz, 1H), 2.08 (tt, J = 11.8, 6.3 Hz, 1H), 1.77-1.70 (m, 1H), 1.70- 1.63 (m, 1H). (6S,9R)-N-(4,5-Dichloro-2- cyanophenyl)-3-oxo- 3,5,6,7,8,9-hexahydro-2H- 6,9- epiminocyclohepta[c]pyridine- 10-carboxamide  93.sup.(a) [00238] 416.3, 418.3 at 1.19 min .sup.1H NMR (500 MHz, DMSO- d6) δ 11.27 (s, 1H), 8.89 (s, 1H), 8.04 (d, J = 6.9 Hz, 1H), 7.77 (d, J = 10.9 Hz, 1H), 7.21 (s, 1H), 6.10 (s, 1H), 5.08 (d, J = 6.0 Hz, 1H), 4.61 (t, J = 6.4 Hz, 1H), 3.13 (dd, J = 17.6, 5.2 Hz, 1H), 2.56 (d, J = 17.9 Hz, 1H), 2.17 (q, J = 11.0 Hz, 1H), 2.07 (tt, J = (6S,9R)-N-(5-Chloro-2- 11.9, 6.3 Hz, 1H), 1.80-1.56 fluoro-4- (m, 2H). (trifluoromethyl)phenyl)-3- oxo-3,5,6,7,8,9-hexahydro- 2H-6,9- epiminocyclohepta[c]pyridine- 10-carboxamide  94.sup.(a) [00239] 382.6, 384.6 at 1.08 min .sup.1H NMR (500 MHz, DMSO- d6) δ 7.83 (d, J = 7.5 Hz, 1H), 7.66 (d, J = 10.3 Hz, 1H), 7.19 (s, 1H), 6.10 (s, 1H), 5.03 (d, J = 6.0 Hz, 1H), 4.67- 4.53 (m, 1H), 3.12 (dd, J = 18.0, 5.1 Hz, 1H), 2.54 (d, J = 18.2 Hz, 1H), 2.16 (q, J = 11.1, 10.7 Hz, 1H), 2.12- 2.00 (m, 1H), 1.76-1.58 (m, (6S,9R)-N-(4,5-Dichloro-2- 2H), 2 NH not observed. fluorophenyl)-3-oxo- 3,5,6,7,8,9-hexahydro-2H- 6,9- epiminocyclohepta[c]pyridine- 10-carboxamide  98.sup.(a)(c) [00240] 391.3, 393.3 at 1.36 min .sup.1H NMR (500 MHz, DMSO- d.sub.6) δ 9.36 (s, 1H), 8.15 (s, 1H), 7.99 (d, J = 5.0 Hz, 1H), 7.72 (s, 1H), 7.19 (dd, J = 5.1, 1.5 Hz, 1H), 5.18 (d, J = 6.1 Hz, 1H), 4.75 (t, J = 6.1 Hz, 1H), 3.25 (dd, J = 17.4, 4.9 Hz, 1H), 2.60 (d, J = 7.3 Hz, 1H), 2.32-2.16 (m, 2H), 1.88 (q, J = 10.9, 10.5 Hz, (5R,8S)-N-(4,5-Dichloro-2- 1H), 1.77 (t, J = 6.3 Hz, 1H). cyanophenyl)-1-fluoro- 6,7,8,9-tetrahydro-5H-5,8- epiminocyclohepta[c]pyridine- 10-carboxamide 101.sup.(a)(c) [00241] 418.2, 420.2 at 1.54 min .sup.1H NMR (500 MHz, DMSO- d.sub.6) δ 9.08 (s, 1H), 8.01 (dd, J = 6.0, 3.3 Hz, 2H), 7.77 (d, J = 11.0 Hz, 1H), 7.21 (dd, J = 5.2, 1.6 Hz, 1H), 5.24 (d, J = 6.1 Hz, 1H), 4.82 (t, J = 6.1 Hz, 1H), 3.19 (dd, J = 17.2, 5.1 Hz, 1H), 2.60 (d, J = 17.3 Hz, 1H), 2.28-2.15 (m, 2H), 1.85 (5R,8S)-N-(5-Chloro-2- (t, J = 9.8 Hz, 1H), 1.80- fluoro-4- 1.71 (m, 1H). (trifluoromethyl)phenyl)-1- fluoro-6,7,8,9-tetrahydro-5H- 5.8- epiminocyclohepta[c]pyridine- 10-carboxamide 117.sup.(a)(b) [00242] 380.3, 382.1 at 1.44 min .sup.1H NMR (500 MHz, DMSO- d6) δ 8.44 (s, 1H), 8.00 (d, J = 5.0 Hz, 1H), 7.46 (d, J = 27.8 Hz, 2H), 7.19 (d, J = 5.0 Hz, 1H), 5.17 (d, J = 6.1 Hz, 1H), 4.73 (d, J = 6.4 Hz, 1H), 3.21 (dd, J = 17.2, 5.1 Hz, 1H), 2.57 (d, J = 17.3 Hz, 1H), 2.30-2.16 (m, 2H), 2.01 (s, 3H), 1.90-1.81 (m, 1H), 1.81-1.70 (m, 1H). (5R,8S)-N-(4,5-Dichloro-2- methylphenyl)-1-fluoro- 6,7,8,9-tetrahydro-5H-5,8- epiminocyclohepta[c]pyridine- 10-carboxamide 118.sup.(a)(b) [00243] 396.3, 398.5 at 1.52 min .sup.1H NMR (500 MHz, DMSO- d6) δ 8.13 (s, 1H), 8.00 (d, J = 5.0 Hz, 1H), 7.81 (s, 1H), 7.24 (s, 1H), 7.20 (dd, J = 5.1, 1.6 Hz, 1H), 5.18 (d, J = 6.2 Hz, 1H), 4.74 (t, J = 6.2 Hz, 1H), 3.81 (s, 3H), 3.18 (dd, J = 17.3, 5.0 Hz, 1H), 2.56 (d, J = 17.4 Hz, 1H), 2.22 (ddd, J = 21.7, 12.2, 7.1 Hz, 2H), 1.91-1.79 (m, 1H), 1.75 (dt, J = 14.3, 6.8 Hz, 1H). (5R,8S)-N-(4,5-Dichloro-2- methoxyphenyl)-1-fluoro- 6,7,8,9-tetrahydro-5H-5,8- epiminocyclohepta[c]pyridine- 10-carboxamide 119.sup.(a) [00244] 384.1 at 1.40 min .sup.1H NMR (500 MHz, DMSO- d6) δ 8.85 (s, 1H), 8.01 (d, J = 5.0 Hz, 1H), 7.93 (dd, J = 7.1, 2.4 Hz, 1H), 7.57-7.30 (m, 2H), 7.20 (dd, J = 5.1, 1.6 Hz, 1H), 5.22 (d, J = 6.2 Hz, 1H), 4.80 (t, J = 6.2 Hz, 1H), 3.20 (dd, J = 17.5, 5.0 Hz, 1H), 2.59 (d, J = 17.3 Hz, 1H), 2.32-2.11 (m, 2H), 1.90-1.80 (m, 1H), 1.76 (dt, J = 14.6, 7.1 Hz, 1H). (5R,8S)-1-Fluoro-N-(2-fluoro- 5-(trifluoromethyl)phenyl)- 6,7,8,9-tetrahydro-5H-5,8- epiminocyclohepta[c]pyridine- 10-carboxamide 120.sup.(a) [00245] 384.4 at 1.43 min .sup.1H NMR (500 MHz, DMSO- d6) δ 8.91 (s, 1H), 8.01 (d, J = 5.0 Hz, 1H), 7.76 (t, J = 8.1 Hz, 1H), 7.64 (dd, J = 11.0, 2.1 Hz, 1H), 7.47 (d, J = 8.5 Hz, 1H), 7.21 (dd, J = 5.1, 1.6 Hz, 1H), 5.23 (d, J = 6.1 Hz, 1H), 4.80 (t, J = 6.3 Hz, 1H), 3.19 (dd, J = 17.2, 5.0 Hz, 1H), 2.59 (d, J = 17.3 Hz, 1H), 2.31-2.15 (m, 2H), 1.89-1.81 (m, 1H), 1.76 (dt, J = 13.2, 6.9 Hz, 1H). (5R,8S)-1-Fluoro-N-(2-fluoro- 4-(trifluoromethyl)phenyl)- 6,7,8,9-tetrahydro-5H-5,8- epiminocyclohepta[c]pyridine- 10-carboxamide 121.sup.(a) [00246] 364.3 at 1.41 min.sup.(j) .sup.1H NMR (500 MHz, DMSO- d6) δ 9.11 (s, 1H), 8.01 (d, J = 5.0 Hz, 1H), 7.68 (d, J = 8.6 Hz, 2H), 7.57 (d, J = 8.6 Hz, 2H), 7.21 (dd, J = 5.0, 1.6 Hz, 1H), 5.26 (d, J = 6.3 Hz, 1H), 5.02-4.77 (m, 1H), 3.15 (dd, J = 17.4, 5.0 Hz, 1H), 2.60 (d, J = 17.4 Hz, 1H), 2.31-2.13 (m, 2H), 1.89-1.82 (m, 1H), 1.80-1.71 (m, 1H). (5R,8S)-1-Fluoro-N-(4- (trifluoromethyl)phenyl)- 6,7,8,9-tetrahydro-5H-5,8- epiminocyclohepta[c]pyridine- 10-carboxamide 122.sup.(a)(b) [00247] 390.1, 392.1 at 1.26 min .sup.1H NMR (500 MHz, DMSO- d6) δ 9.19 (s, 1H), 8.01 (d, J = 5.0 Hz, 1H), 7.81- 7.75 (m, 2H), 7.53 (dd, J = 8.7, 2.1 Hz, 1H), 7.21 (dd, J = 5.1, 1.6 Hz, 1H), 5.26 (d, J = 6.1 Hz, 1H), 4.83 (t, J = 6.4 Hz, 1H), 3.80 (s, 3H), 3.15 (dd, J = 17.3, 5.0 Hz, 1H), 2.60 (d, J = 17.3 Hz, 1H), 2.30-2.10 (m, 2H), 1.94- 1.80 (m, 1H), 1.78-1.74 (m, 1H) Methyl 2-chloro-4-((5R,8S)- 1-fluoro-6,7,8,9-tetrahydro- 5H-5,8- epiminocyclohepta[c]pyridine- 10-carboxamido)benzoate 123.sup.(a)(b) [00248] 390.1, 392.1 at 1.25 min .sup.1H NMR (500 MHz, DMSO- d6) δ 9.04 (s, 1H), 7.99 (dd, J = 14.5, 3.8 Hz, 2H), 7.70 (dd, J = 8.9, 2.7 Hz, 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.20 (dd, J = 5.1, 1.5 Hz, 1H), 5.24 (d, J = 6.3 Hz, 1H), 4.81 (t, J = 6.3 Hz, 1H), 3.84 (s, 3H), 3.15 (dd, J = 17.5, 5.0 Hz, 1H), 2.59 (d, J = 17.3 Hz, 1H), 2.25-2.16 (m, 2H), 1.88- 1.80 (m, 1H), 1.80-1.71 (m, 1H). Methyl 2-chloro-5-((5R,8S)- 1-fluoro-6,7,8,9-tetrahydro- 5H-5,8- epiminocyclohepta[c]pyridine- 10-carboxamido)benzoate 124.sup.(a)(b) [00249] 416.1, 418.1 at 1.53 min .sup.1H NMR (500 MHz, DMSO- d6) δ 9.07 (s, 1H), 8.01 (d, J = 5.0 Hz, 1H), 7.84 (d, J = 2.5 Hz, 1H), 7.51 (dd, J = 9.1, 2.6 Hz, 1H), 7.43 (d, J = 9.1 Hz, 1H), 7.23- 7.18 (m, 1H), 5.23 (d, J = 6.2 Hz, 1H), 4.81 (t, J = 6.3 Hz, 1H), 3.15 (dd, J = 17.3, 5.1 Hz, 1H), 2.59 (d, J = 17.3 Hz, 1H), 2.28-2.13 (m, 2H), 1.87-1.83 (m, 1H), 1.78- 1.74 (m, 1H) (5R,8S)-N-(3-Chloro-4- (trifluoromethoxy)phenyl)-1- fluoro-6,7,8,9-tetrahydro-5H- 5,8- epiminocyclohepta[c]pyridine- 10-carboxamide 125.sup.(a)(b) [00250] 408.1, 410.1 at 1.25 min .sup.1H NMR (500 MHz, DMSO- d6) δ 8.83 (s, 1H), 8.04- 7.98 (m, 2H), 7.58 (d, J = 10.4 Hz, 1H), 7.19 (dd, J = 5.0, 1.6 Hz, 1H), 5.20 (d, J = 6.2 Hz, 1H), 4.81-4.74 (m, 1H), 3.82 (s, 3H), 3.18 (dd, J = 17.2, 5.0 Hz, 1H), 2.58 (d, J = 17.3 Hz, 1H), 2.30-2.17 (m, 2H), 1.88- 1.80 (m, 1H), 1.80-1.71 (m, 1H). Methyl 2-chloro-4-fluoro-5- ((5R,8S)-1-fluoro-6,7,8,9- tetrahydro-5H-5,8- epiminocyclohepta[c]pyridine- 10-carboxamido)benzoate 126.sup.(a)(b) [00251] 418.1, 420.1 at 1.48 min .sup.1H NMR (500 MHz, DMSO- d6) δ 8.94 (s, 1H), 8.07 (d, J = 7.8 Hz, 1H), 8.01 (d, J = 5.0 Hz, 1H), 7.77 (d, J = 10.2 Hz, 1H), 7.20 (dd, J = 5.1, 1.6 Hz, 1H), 5.22 (d, J = 6.2 Hz, 1H), 4.82-4.76 (m, 1H), 3.19 (dd, J = 17.4, 5.0 Hz, 1H), 2.59 (d, J = 17.3 Hz, 1H), 2.26-2.18 (m, 2H), 1.89-1.78 (m, 1H), 1.80-1.71 (m, 1H). (5R,8S)-N-(4-Chloro-2- fluoro-5- (trifluoromethyl)phenyl)-1- fluoro-6,7,8,9-tetrahydro-5H- 5,8- epiminocyclohepta[c]pyridine- 10-carboxamide 127.sup.(a)(c) [00252] 396.4, 398.4 at 1.07 min .sup.1H NMR (500 MHz, DMSO- d6) δ 11.30 (s, 1H), 9.24 (s, 1H), 8.64 (d, J = 2.7 Hz, 1H), 8.38 (d, J = 6.0 Hz, 1H), 7.13 (t, J = 73.5 Hz, 1H), 7.23 (s, 1H), 6.10 (s, 1H), 5.13 (d, J = 6.0 Hz, 1H), 4.66 (s, 1H), 3.17 (d, J = 7.2 Hz, 1H), 2.58 (d, J = 17.8 Hz, 1H), 2.21- 2.13 (m, 1H), 2.08 (dt, J = 11.8, 5.8 Hz, 1H), 1.77-1.67 (m, 1H), 1.66 (s, 1H) (6S,9R)-N-(3-Chloro-4- (difluoromethoxy)phenyl)-3- oxo-3,5,6,7,8,9-hexahydro- 2H-6,9- epiminocyclohepta[c]pyridine- 10-carboxamide 128.sup.(a)(c) [00253] 414.3, 416.3 at 1.22 min .sup.1H NMR (500 MHz, DMSO- d6) δ 11.27 (s, 1H), 8.91 (s, 1H), 7.86 (dd, J = 2.6, 1.1 Hz, 1H), 7.55-7.50 (m, 1H), 7.43 (d, J = 9.1 Hz, 1H), 7.19 (s, 1H), 6.09 (s, 1H), 5.07 (d, J = 6.0 Hz, 1H), 4.60 (s, 1H), 3.10 (d, J = 19.4 Hz, 1H), 2.55 (d, J = 17.9 Hz, 1H), 2.17 (d, J = 10.8 Hz, 1H), 2.06 (dd, J = 11.9, 6.0 Hz, 1H), 1.72 (t, J = 10.5 Hz, 1H), 1.66 (d, J = 13.5 Hz, 1H) (6S,9R)-N-(3-Chloro-4- (trifluoromethoxy)phenyl)-3- oxo-3,5,6,7,8,9-hexahydro- 2H-6,9- epiminocyclohepta[c]pyridine- 10-carboxamide 129.sup.(a)(c) [00254] 416.3, 418.3 at 1.19 min .sup.1H NMR (500 MHz, DMSO- d6) δ 11.27 (s, 1H), 8.76 (s, 1H), 8.09 (d, J = 7.8 Hz, 1H), 7.77 (d, J = 10.2 Hz, 1H), 7.19 (s, 1H), 6.10 (s, 1H), 5.05 (d, J = 6.0 Hz, 1H), 4.59 (t, J = 6.5 Hz, 1H), 3.13 (dd, J = 17.8, 5.1 Hz, 1H), 2.55 (d, J = 17.8 Hz, 1H), 2.18 (q, J = 11.2 Hz, 1H), 2.10-2.03 (m, 1H), 1.76- 1.60 (m, 2H) (6S,9R)-N-(4-Chloro-2- fluoro-5- (trifluoromethyl)phenyl)-3- oxo-3,5,6,7,8,9-hexahydro- 2H-6,9- epiminocyclohepta[c]pyridine- 10-carboxamide 130.sup.(a)(c) [00255] 388.3, 390.3 at 0.96 min .sup.1H NMR (500 MHz, DMSO- d6) δ 11.28 (s, 1H), 9.03 (s, 1H), 7.84-7.74 (m, 2H), 7.55 (dd, J = 8.7, 2.1 Hz, 1H), 7.20 (s, 1H), 6.10 (s, 1H), 5.09 (d, J = 6.0 Hz, 1H), 4.65- 4.59 (m, 1H), 3.80 (s, 3H), 3.10 (dd, J = 17.8, 5.1 Hz, 1H), 2.57 (d, J = 17.9 Hz, 1H), 2.17 (q, J = 10.7 Hz, 1H), 2.06 (tt, J = 11.8, 6.1 Hz, 1H), 1.72 (t, J = 10.5 Hz, 1H), 1.69-1.60 (m, 1H). Methyl 2-chloro-4-((6S,9R)- 3-oxo-3,5,6,7,8,9-hexahydro- 2H-6,9- epiminocyclohepta[c]pyridine- 10-carboxamido)benzoate 131.sup.(a)(c) [00256] 388.4, 390.4 at 0.97 min .sup.1H NMR (500 MHz, DMSO- d6) δ 11.27 (s, 1H), 8.88 (s, 1H), 7.99 (d, J = 2.7 Hz, 1H), 7.71 (dd, J = 8.8, 2.7 Hz, 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.18 (s, 1H), 6.09 (s, 1H), 5.07 (d, J = 6.0 Hz, 1H), 4.63- 4.57 (m, 1H), 3.84 (s, 3H), 3.10 (dd, J = 7.9, 5.1 Hz, 1H), 2.55 (d, J = 17.9 Hz, 1H), 2.17 (q, J = 10.9 Hz, 1H), 2.10-2.00 (m, 1H), 1.75-1.60 (m, 2H). Methyl 2-chloro-5-((6S,9R)- 3-oxo-3,5,6,7,8,9-hexahydro- 2H-6,9- epiminocyclohepta[c]pyridine- 10-carboxamido)benzoate 132.sup.(a)(c) [00257] 406.4, 408.4 at 0.74 min .sup.1H NMR (500 MHz, DMSO- d6) δ 11.27 (s, 1H), 8.65 (s, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 10.4 Hz, 1H), 7.18 (s, 1H), 6.10 (s, 1H), 5.03 (d, J = 5.9 Hz, 1H), 4.60- 4.54 (m, 1H), 3.83 (s, 3H), 3.12 (dd, J = 17.7, 5.0 Hz, 1H), 2.55 (d, J = 17.8 Hz, 1H), 2.17 (q, J = 10.6 Hz, 1H), 2.11-2.03 (m, 1H), 1.74-1.61 (m, 2H) Methyl 2-chloro-4-fluoro-5- ((6S,9R)-3-oxo-3,5,6,7,8,9- hexahydro-2H-6,9- epiminocyclohepta[c]pyridine- 10-carboxamido)benzoate 136.sup.(a)(b) [00258] 434.3, 436.3 at 1.77 min.sup.(d) .sup.1H NMR (500 MHz, DMSO- d6) δ 9.09 (s, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.92 (s, 1H), 7.79 (d, J = 10.9 Hz, 1H), 5.36 (d, J = 5.6 Hz, 1H), 4.79 (t, J = 6.0 Hz, 1H), 3.28 (d, J = 5.0 Hz, 1H), 2.83 (d, J = 18.1 Hz, 1H), 2.29- 2.14 (m, 2H), 1.85 (t, J = 9.9 Hz, 1H), 1.75 (dd, J = 12.4, 5.8 Hz, 1H). (±)-N-(5-Chloro-2-fluoro-4- (trifluoromethyl)phenyl)-3,4- difluoro-6,7,8,9-tetrahydro- 5H-6,9- epiminocyclohepta[c]pyridine- 10-carboxamide 137.sup.(a)(b) [00259] 400.3, 402.3 at 1.66 min.sup.(d) .sup.1H NMR (500 MHz, DMSO- d6) δ 8.83 (s, 1H), 7.90 (s, 1H), 7.82 (d, J = 7.5 Hz, 1H), 7.67 (d, J = 10.3 Hz, 1H), 5.32 (d, J = 5.7 Hz, 1H), 4.74 (t, J = 6.0 Hz, 1H), 3.26 (d, J = 5.0 Hz, 1H), 2.83 (s, 1H), 2.23 (d, J = 12.3 Hz, 1H), 2.18 (td, J = 11.6, 6.0 Hz, 1H), 1.83 (t, J = 10.1 Hz, 1H), 1.75 (dd, J = 12.4, 5.7 Hz, 1H) (±)-N-(4,5-Dichloro-2- fluorophenyl)-3,4-difluoro- 6,7,8,9-tetrahydro-5H-6,9- epiminocyclohepta[c]pyridine- 10-carboxamide 138.sup.(a)(c) [00260] 434.3, 436.3 at 1.28 min .sup.1H NMR (500 MHz, DMSO- d6) δ 11.84 (s, 1H), 8.94 (s, 1H), 8.04 (d, J = 6.9 Hz, 1H), 7.78 (d, J = 11.0 Hz, 1H), 7.13 (s, 1H), 5.13 (d, J = 6.1 Hz, 1H), 4.68 (t, J = 6.3 Hz, 1H), 3.10 (d, J = 18.7 Hz, 1H), 2.66 (d, J = 18.2 Hz, 1H), 2.18 (q, J = 11.1, 10.6 Hz, 1H), 2.11 (dt, J = 11.9, 5.8 Hz, 1H), 1.78-1.67 (m, 2H) (±)-N-(5-Chloro-2-fluoro-4- (trifluoromethyl)phenyl)-4- fluoro-3-oxo-3,5,6,7,8,9- hexahydro-2H-6,9- epiminocyclohepta[c]pyridine- 10-carboxamide 139 [00261] 400.2, 402.2 at 1.11 min .sup.1H NMR (500 MHz, DMSO- d6) δ 11.83 (s, 1H), 8.67 (s, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.67 (d, J = 10.3 Hz, 1H), 7.10 (s, 1H), 5.09 (d, J = 6.0 Hz, 1H), 4.67-4.60 (m, 1H), 3.09 (d, J = 14.6 Hz, 1H), 2.64 (d, J = 17.8 Hz, 1H), 2.18 (q, J = 11.9, 11.3 Hz, 1H), 2.09 (dd, J = 11.7, 6.0 Hz, 1H), 1.73 (q, J = 11.8, 11.1 Hz, 2H). (±)-N-(4,5-Dichloro-2- fluorophenyl)-4-fluoro-3-oxo- 3,5,6,7,8,9-hexahydro-2H- 6,9- epiminocycloheptan[c]pyridine- 10-carboxamide 141.sup.(a)(c) [00262] 426.1, 428.1 at 1.15 min .sup.1H NMR (500 MHz, DMSO- d6) δ 11.26 (s, 1H), 8.62 (s, 1H), 7.84 (d, J = 7.5 Hz, 1H), 7.75 (d, J = 10.1 Hz, 1H), 7.19 (s, 1H), 6.10 (s, 1H), 5.04 (d, J = 6.0 Hz, 1H), 4.57 (t, J = 6.5 Hz, 1H), 3.12 (dd, J = 17.9, 5.1 Hz, 1H), 2.54 (d, J = 18.0 Hz, 1H), 2.16 (q, J = 11.0 Hz, 1H), 2.06 (tt, J = 11.6, 6.2 Hz, 1H), 1.68 (ddd, J = 28.8, 11.9, 7.5 Hz, 2H) (6S,9R)-N-(4-Bromo-5- chloro-2-fluorophenyl)-3-oxo- 3,5,6,7,8,9-hexahydro-2H- 6.9- epiminocyclohepta[c]pyridine- 10-carboxamide 142.sup.(a)(c) [00263] 426.1, 428.1 at 1.15 min .sup.1H NMR (500 MHz, DMSO- d6) δ 11.26 (s, 1H), 8.61 (s, 1H), 7.94 (d, J = 7.8 Hz, 1H), 7.66 (d, J = 10.4 Hz, 1H), 7.19 (s, 1H), 6.10 (s, 1H), 5.03 (d, J = 6.0 Hz, 1H), 4.74- 4.35 (m, 1H), 3.12 (dd, J = 18.0, 5.1 Hz, 1H), 2.54 (d, J = 18.0 Hz, 1H), 2.17 (q, J = 11.1 Hz, 1H), 2.06 (tt, J = 11.6, 6.2 Hz, 1H), 1.75-1.58 (m, 2H) (6S,9R)-N-(5-Bromo-4- chloro-2-fluorophenyl)-3-oxo- 3,5,6,7,8,9-hexahydro-2H- 6,9- epiminocyclohepta[c]pyridine- 10-carboxamide 143.sup.(a)(c) [00264] 408.1, 410.1 at 1.14 min .sup.1H NMR (500 MHz, DMSO- d6) δ 8.86 (s, 1H), 7.86 (d, J = 2.5 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.40 (dd, J = 8.9, 2.5 Hz, 1H), 7.20 (s, 1H), 6.09 (s, 1H), 5.08 (d, J = 6.0 Hz, 1H), 4.60 (t, J = 6.6 Hz, 1H), 3.09 (dd, J = 17.9, 5.1 Hz, 1H), 2.55 (d, J = 17.9 Hz, 1H), 2.16 (q, J = 11.0 Hz, 1H), 2.05 (tt, J = 11.6, 6.1 Hz, 1H), 1.69 (tdd, J = 28.1, 13.3, 8.6 Hz, 2H), 1 NH not visible (6S,9R)-N-(4-Bromo-3- chlorophenyl)-3-oxo- 3,5,6,7,8,9-hexahydro-2H- 6,9- epiminocyclohepta[c]pyridine- 10-carboxamide 144.sup.(a)(c) [00265] 460.1, 462.1 at 1.23 min .sup.1H NMR (500 MHz, DMSO- d6) δ 11.28 (s, 1H), 8.88 (s, 1H), 8.19 (d, J = 7.1 Hz, 1H), 7.76 (d, J = 11.1 Hz, 1H), 7.21 (s, 1H), 6.10 (s, 1H), 5.08 (d, J = 6.0 Hz, 1H), 4.68- 4.34 (m, 1H), 3.14 (dd, J = 17.9, 5.1 Hz, 1H), 2.56 (d, J = 17.9 Hz, 1H), 2.23-2.01 (m, 2H), 1.78-1.59 (m, 2H). (6S,9R)-N-(5-Bromo-2- fluoro-4- (trifluoromethyl)phenyl)-3- oxo-3,5,6,7,8,9-hexahydro- 2H-6,9- epiminocyclohepta[c]pyridine- 10-carboxamide 145.sup.(a)(c) [00266] 408.2, 410.1 at 1.13 min .sup.1H NMR (500 MHz, DMSO- d6) δ 8.81 (s, 1H), 7.97 (d, J = 2.4 Hz, 1H), 7.51 (dd, J = 8.9, 2.5 Hz, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.19 (s, 1H), 6.09 (s, 1H), 5.06 (d, J = 6.0 Hz, 1H), 4.67-4.46 (m, 1H), 3.09 (dd, J = 17.9, 5.2 Hz, 1H), 2.55 (d, J = 17.9 Hz, 1H), 2.16 (q, J = 11.1 Hz, 1H), 2.05 (tt, J = 11.6, 6.1 Hz, 1H), 1.68 (ddd, J = 29.8, 11.8, 7.4 Hz, 2H), 1 NH not visible. (6S,9R)-N-(3-Bromo-4- chlorophenyl)-3-oxo- 3,5,6,7,8,9-hexahydro-2H- 6.9- epiminocyclohepta[c]pyridine- 10-carboxamide 151.sup.(a)(b) [00267] 389.2 at 1.49 min.sup.(d) .sup.1H NMR (400 MHz, DMSO- d6) δ 9.43 (s, 1H), 8.21 (d, J = 2.2 Hz, 1H), 8.02 (d, J = 5.0 Hz, 1H), 7.98- 7.91 (m, 1H), 7.87 (d, J = 8.9 Hz, 1H), 7.22 (dd, J = 5.0, 1.6 Hz, 1H), 5.27 (d, J = 6.1 Hz, 1H), 4.85 (t, J = 6.1 Hz, 1H), 3.17 (dd, J = 17.5, 5.0 Hz, 1H), 2.62 (d, J = 17.3 Hz, 1H), 2.28-2.16 (m, 2H), 1.92-1.83 (m, 1H), 1.83- 1.72 (m, 1H). (5R,8S)-N-(3-cyano-4- (trifluoromethyl)phenyl)-1- fluoro-6,7,8,9-tetrahydro-5H- 5,8- epiminocyclohepta[c]pyridine- 10-carboxamide 152 [00268] 393.1 at 1.12 min.sup.(d) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.38 (s, 1H), 8.15-7.93 (m, 2H), 7.64-7.41 (m, 3H), 7.02 (t, J = 6.4 Hz, 1H), 6.83 (dd, J = 8.4, 1.9 Hz, 1H), 5.12 (dd, J = 23.1, 6.3 Hz, 1H), 4.70 (dt, J = 13.7, 6.6 Hz, 1H), 3.94 (d, J = 6.9 Hz, 3H), 3.47-3.28 (m, 1H), 2.73- 2.54 (m, 3H), 2.02 (q, J = 10.6 Hz, 1H), 1.85 (ddd, J = 21.5, 14.1, 8.4 Hz, 2H). (±)-1-Fluoro-N-(3-methoxy-4- (oxazol-5-yl)phenyl)-6,7,8,9- tetrahydro-5H-5,8- epiminocyclohepta[c]pyridine- 10-carboxamide 153 [00269] 442.0, 444.0 at 1.64 min.sup.(d) .sup.1H NMR (400 MHz, DMSO- d6) δ 9.23 (s, 1H), 8.06 (d, J = 1.9 Hz, 1H), 8.01 (d, J = 5.0 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.66 (dd, J = 8.8, 1.9 Hz, 1H), 7.21 (dd, J = 5.0, 1.7 Hz, 1H), 5.26 (d, J = 6.1 Hz, 1H), 4.90- 4.77 (m, 1H), 3.16 (dd, J = 17.3, 5.0 Hz, 1H), 2.61 (d, J = 17.4 Hz, 1H), 2.34-2.10 (m, 2H), 1.91-1.81 (m, 1H), 1.81-1.66 (m, 1H). (5R,8S)-N-(3-Bromo-4- (trifluoromethyl)phenyl)-1- fluoro-6,7,8,9-tetrahydro-5H- 5,8- epiminocyclohepta[c]pyridine- 10-carboxamide 154 [00270] 366.0 at 1.26 min.sup.(d) .sup.1H NMR (400 MHz, DMSO- d6) δ 8.78 (s, 1H), 8.00 (d, J = 5.0 Hz, 1H), 7.38 (td, J = 8.7, 5.9 Hz, 1H), 7.23 (td, J = 9.0, 2.1 Hz, 1H), 7.19 (dd, J = 5.1, 1.8 Hz, 1H), 5.17 (d, J = 6.0 Hz, 1H), 4.75 (d, J = 6.1 Hz, 1H), 3.23-3.14 (m, 1H), 2.58 (d, J = 17.3 Hz, 1H), 2.26 (d, J = 11.7 Hz, 1H), 2.20 (dd, J = 12.2, 6.4 Hz, 1H), 1.89-1.77 (m, 1H), 1.75 (s, 1H). (±)-N-(3-Chloro-2,4- difluorophenyl)-1-fluoro- 6,7,8,9-tetrahydro-5H-5,8- epiminocyclohepta[c]pyridine- 10-carboxamide 155 [00271] 316.3 at 1.17 min .sup.1H NMR (400 MHz, DMSO- d6) δ 8.92 (s, 1H), 8.01 (d, J = 5.0 Hz, 1H), 7.42 (dt, J = 11.7, 1.8 Hz, 1H), 7.30-7.17 (m, 3H), 6.79-6.69 (m, 1H), 5.24 (d, J = 6.1 Hz, 1H), 4.81 (t, J = 6.1 Hz, 1H), 3.14 (dd, J = 18.1, 5.2 Hz, 1H), 2.58 (d, J = 17.3 Hz, 1H), 2.31-2.21 (m, 1H), 2.17 (td, J = 12.0, 11.5, 6.5 Hz, 1H), 1.89-1.80 (m, 1H), 1.80-1.70 (m, 1H). (±)-1-Fluoro-N-(3- fluorophenyl)-6,7,8,9- tetrahydro-5H-5,8- epiminocyclohepta[c]pyridine- 10-carboxamide 156 [00272] 366.3 at 1.36 min .sup.1H NMR (400 MHz, DMSO- d6) δ 9.05 (s, 1H), 8.01 (d, J = 5.0 Hz, 1H), 7.94-7.88 (m, 1H), 7.77-7.70 (m, 1H), 7.46 (t, J = 8.0 Hz, 1H), 7.27 (d, J = 7.7 Hz, 1H), 7.21 (dd, J = 5.1, 1.7 Hz, 1H), 5.25 (d, J = 6.1 Hz, 1H), 4.87-4.79 (m, 1H), 3.16 (dd, J = 17.4, 5.0 Hz, 1H), 2.60 (d, J = 17.3 Hz, 1H), 2.21 (ddt, J = 17.8, 11.5, 8.7 Hz, 2H), 1.90-1.81 (m, 1H), 1.76 (dt, J = 14.1, 6.7 Hz, 1H). (±)-1-Fluoro-N-(3- (trifluoromethyl)phenyl)- 6,7,8,9-tetrahydro-5H-5,8- epiminocyclohepta[c]pyridine- 10-carboxamide 157 [00273] 382.3 at 1.39 min .sup.1H NMR (400 MHz, DMSO- d6) δ 8.93 (s, 1H), 8.00 (d, J = 5.0 Hz, 1H), 7.59-7.51 (m, 2H), 7.26-7.17 (m, 3H), 5.23 (d, J = 6.0 Hz, 1H), 4.84- 4.77 (m, 1H), 3.15 (dd, J = 17.4, 5.0 Hz, 1H), 2.58 (d, J = 17.4 Hz, 1H), 2.20 (ddd, J = 17.3, 14.8, 8.5 Hz, 2H), 1.89- 1.80 (m, 1H), 1.80-1.70 (m, 1H). (±)-1-Fluoro-N-(4- (trifluoromethoxy)phenyl)- 6,7,8,9-tetrahydro-5H-5,8- epiminocyclohepta[c]pyridin- 10-carboxamide 158 [00274] 374.3 at 1.43 min .sup.1H NMR (400 MHz, DMSO- d6) δ 8.84 (s, 1H), 8.01 (d, J = 5.0 Hz, 1H), 7.64-7.58 (m, 2H), 7.54 (s, 4H), 7.42 (dd, J = 8.4, 7.0 Hz, 2H), 7.33- 7.25 (m, 1H), 7.21 (dd, J = 5.0, 1.7 Hz, 1H), 5.26 (d, J = 6.0 Hz, 1H), 4.83 (t, J = 6.1 Hz, 1H), 3.17 (dd, J = 17.5, 5.0 Hz, 1H), 2.59 (d, J = 17.4 Hz, 1H), 2.30-2.09 (m, 2H), 1.92-1.80 (m, 1H), 1.80- 1.67 (m, 1H). (±)-N-([1,1′-Biphenyl]-4-yl)-1- fluoro-6,7,8,9-tetrahydro-5H- 5,8- epiminocyclohepta[c]pyridine- 10-carboxamide 159 [00275] 432.2 at 1.61 min.sup.(d) .sup.1H NMR (400 MHz, DMSO- d6) δ 9.35 (s, 1H), 8.25- 8.16 (m, 2H), 8.02 (d, J = 5.0 Hz, 1H), 7.60 (s, 1H), 7.22 (dd, J = 5.0, 1.6 Hz, 1H), 5.27 (d, J = 6.1 Hz, 1H), 4.91- 4.79 (m, 1H), 3.19 (dd, J = 17.5, 5.0 Hz, 1H), 2.62 (d, J = 17.4 Hz, 1H), 2.35-2.13 (m, 2H), 1.93-1.83 (m, 1H), 1.78 (dt, J = 14.2, 6.8 Hz, 1H). (±)-N-(3,5- Bis(trifluoromethyl)phenyl)-1- fluoro-6,7,8,9-tetrahydro-5H- 5,8- epiminocyclohepta[c]pyridine- 10-carboxamide 160 [00276] 380.2 at 1.44 min .sup.1H NMR (400 MHz, DMSO- d6) δ 8.93 (s, 1H), 8.01 (d, J = 5.0 Hz, 1H), 7.84 (d, J = 2.3 Hz, 1H), 7.63 (dd, J = 8.4, 2.3 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 7.20 (dd, J = 5.0, 1.7 Hz, 1H), 5.24 (d, J = 6.1 Hz, 1H), 4.81 (t, J = 6.1 Hz, 1H), 3.15 (dd, J = 17.4, 5.0 Hz, 1H), 2.58 (d, J = 17.3 Hz, 1H), 2.33 (t, J = 2.0 Hz, 3H), 2.29- 2.09 (m, 2H), 1.90-1.80 (m, 1H), 1.75 (dt, J = 13.9, 6.7 Hz, 1H). (±)-1-Fluoro-N-(4-methyl-3- (trifluoromethyl)phenyl)- 6,7,8,9-tetrahydro-5H-5,8- epiminocyclohepta[c]pyridine- 10-carboxamide 161 [00277] 366.3, 368.2 at 1.35 min .sup.1H NMR (400 MHz, DMSO- d6) δ 8.69 (s, 1H), 8.00 (d, J = 5.0 Hz, 1H), 7.44-7.37 (m, 2H), 7.32-7.24 (m, 1H), 7.20 (dd, J = 5.0, 1.7 Hz, 1H), 5.18 (d, J = 5.9 Hz, 1H), 4.75 (t, J = 6.1 Hz, 1H), 3.24 (dd, J = 17.4, 5.1 Hz, 1H), 2.58 (d, J = 17.4 Hz, 1H), 2.31-2.13 (m, 2H), 1.90-1.81 (m, 1H), 1.81-1.70 (m, 1H). (±)-N-(2,3-Dichlorophenyl)-1- fluoro-6,7,8,9-tetrahydro-5H- 5,8- epiminocyclohepta[c]pyridine- 10-carboxamide 162 [00278] 334.2 at 1.11 min .sup.1H NMR (400 MHz, DMSO- d6) δ 8.56 (s, 1H), 8.00 (d, J = 5.0 Hz, 1H), 7.37 (td, J = 9.0, 6.2 Hz, 1H), 7.26-7.14 (m, 2H), 6.99 (tdd, J = 8.6, 2.9, 1.4 Hz, 1H), 5.17 (d, J = 6.0 Hz, 1H), 4.77-4.66 (m, 1H), 3.18 (dd, J = 17.4, 5.0 Hz, 1H), 2.56 (d, J = 17.3 Hz, 1H), 2.20 (dtd, J = 17.6, 11.9 7.1 Hz, 2H), 1.91-1.79 (m, 1H), 1.79-1.63 (m, 1H). (±)-N-(2,4-Difluorophenyl)-1- fluoro-6,7,8,9-tetrahydro-5H- 5,8- epiminocyclohepta[c]pyridin- 10-carboxamide 163 [00279] 389.2 at 1.33 min.sup.(d) .sup.1H NMR (400 MHz, DMSO- d6) δ 8.03 (d, J = 5.0 Hz, 1H), 7.88 (d, J = 2.1 Hz, 1H), 7.78 (dd, J = 8.6, 2.2 Hz, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.08- 6.94 (m, 2H), 5.12 (d, J = 6.4 Hz, 1H), 4.71 (dd, J = 7.0, 5.5 Hz, 1H), 3.31 (dd, J = 17.5, 4.9 Hz, 1H), 2.71-2.61 (m, 1H), 2.51-2.39 (m, 1H), 2.34 (dq, J = 11.9, 5.8 Hz, 1H), 2.01 (ddd, J = 12.2, 9.2, 2.5 Hz, 1H), 1.84 (ddd, J = 12.4, 9.0, 6.2 Hz, 1H). (±)-N-(4-Cyano-3- (trifluoromethyl)phenyl)-1- fluoro-6,7,8,9-tetrahydro-5H- 5,8- epiminocyclohepta[c]pyridine- 10-carboxamide 164 [00280] 398.2 at 1.55 min.sup.(d) .sup.1H NMR (400 MHz, DMSO- d6) δ 9.19 (s, 1H), 8.02 (d, J = 5.0 Hz, 1H), 7.98-7.80 (m, 2H), 7.37 (d, J = 1.9 Hz, 1H), 7.21 (dd, J = 5.0, 1.6 Hz, 1H), 5.25 (d, J = 6.2 Hz, 1H), 4.83 (t, J = 6.2 Hz, 1H), 3.17 (dd, J = 17.5, 5.1 Hz, 1H), 2.61 (d, J = 17.3 Hz, 1H), 2.32-2.08 (m, 2H), 1.95-1.81 (m, 1H), 1.77 (dt, J = 14.0, 6.7 Hz, 1H). (±)-N-(3-Chloro-5- (trifluoromethyl)phenyl)-1- fluoro-6,7,8,9-tetrahydro-5H- 5,8- epiminocyclohepta[c]pyridine- 10-carboxamide 165 [00281] 339.2 at 1.15 min.sup.(d) .sup.1H NMR (400 MHz, DMSO- d6) δ 9.06 (s, 1H), 8.01 (d, J = 5.0 Hz, 1H), 7.94 (dd, J = 5.8, 2.8 Hz, 1H), 7.76 (ddd, J = 9.3, 4.9, 2.8 Hz, 1H), 7.41 (t, J = 9.2 Hz, 1H), 7.21 (dd, J = 5.1, 1.7 Hz, 1H), 5.23 (d, J = 6.1 Hz, 1H), 4.90-4.68 (m, 1H), 3.16 (dd, J = 17.5, 5.0 Hz, 1H), 2.59 (d, J = 17.4 Hz, 1H), 2.31-2.02 (m, 2H), 1.92-1.79 (m, 1H), 1.79- 1.62 (m, 1H). (±)-N-(3-Cyano-4- fluorophenyl)-1-fluoro- 6,7,8,9-tetrahydro-5H-5,8- epiminocyclohepta[c]pyridine- 10-carboxamide 166 [00282] 398.1, 400.2, 402.2 at 1.58 min.sup.(d) .sup.1H NMR (400 MHz, DMSO- d6) δ 9.09 (s, 1H), 8.01 (d, J = 5.0 Hz, 1H), 7.80 (s, 2H), 7.20 (dd, J = 5.1, 1.6 Hz, 1H), 5.23 (d, J = 6.1 Hz, 1H), 4.80 (t, J = 6.2 Hz, 1H), 3.15 (dd, J = 17.0, 5.0 Hz, 1H), 2.60 (d, J = 17.4 Hz, 1H), 2.29-2.03 (m, 2H), 1.93-1.81 (m, 1H), 1.76 (dt, J = 14.2, 6.7 Hz, 1H). (±)-1-Fluoro-N-(3,4,5- trichlorophenyl)-6,7,8,9- tetrahydro-5H-5,8- epiminocyclohepta[c]pyridine- 10-carboxamide 167 [00283] 378.3 at 1.45 min.sup.(d) .sup.1H NMR (400 MHz, DMSO- d6) δ 9.02 (s, 1H), 8.01 (d, J = 4.7 Hz, 1H), 7.58-7.39 (m, 3H), 7.20 (dd, J = 5.1, 1.7 Hz, 1H), 5.25 (d, J = 6.1 Hz, 1H), 4.82 (t, J = 6.2 Hz, 1H), 3.23- 3.02 (m, 1H), 2.65-2.52 (m, 1H), 2.35 (d, J = 1.8 Hz, 3H), 2.21 (ddt, J = 17.3, 11.7, 6.6 Hz, 2H), 1.93-1.80 (m, 1H), 1.76 (dt, J = 13.6, 6.7 Hz, 1H). (±)-1-Fluoro-N-(3-methyl-4- (trifluoromethyl)phenyl)- 6,7,8,9-tetrahydro-5H-5,8- epiminocyclohepta[c]pyridine- 10-carboxamide 168 [00284] 376.1, 378.2 at 1.29 min .sup.1H NMR (400 MHz, DMSO- d6) δ 8.85 (s, 1H), 8.00 (d, J = 5.0 Hz, 1H), 7.46-7.41 (m, 2H), 7.38 (d, J = 9.0 Hz, 2H), 7.20 (dd, J = 5.0, 1.7 Hz, 1H), 5.23 (d, J = 6.0 Hz, 1H), 4.79 (t, J = 6.2 Hz, 1H), 3.14 (dd, J = 20.3, 5.1 Hz, 1H), 2.57 (d, J = 17.4 Hz, 1H), 2.27-2.06 (m, 2H), 1.91-1.78 (m, 1H), 1.78-1.65 (m, 1H). (±)-N-(4-Bromophenyl)-1- fluoro-6,7,8,9-tetrahydro-5H- 5,8- epiminocyclohepta[c]pyridine- 10-carboxamide 169 [00285] 364.2 at 1.21 min .sup.1H NMR (400 MHz, DMSO- d6) δ 8.80 (s, 1H), 8.00 (d, J = 5.0 Hz, 1H), 7.50-7.43 (m, 2H), 7.19 (dd, J = 5.0, 1.7 Hz, 1H), 7.08 (d, J = 74.7 Hz, 1H), 7.08-7.01 (m, 2H), 5.22 (d, J = 6.0 Hz, 1H), 4.79 (t, J = 6.1 Hz, 1H), 3.15 (dd, J = 17.4, 5.0 Hz, 1H), 2.59 (s, 1H), 2.31-2.11 (m, 2H), 1.88-1.79 (m, 1H), 1.79- 1.69 (m, 1H). (±)-N-(4- (Difluoromethoxy)phenyl)-1- fluoro-6,7,8,9-tetrahydro-5H- 5,8- epiminocyclohepta[c]pyridine- 10-carboxamide 170 [00286] 376.2, 378.2 at 1.30 min .sup.1H NMR (400 MHz, DMSO- d6) δ 8.88 (s, 1H), 8.01 (d, J = 5.0 Hz, 1H), 7.77 (t, J = 2.0 Hz, 1H), 7.44 (ddd, J = 8.2, 2.1, 1.1 Hz, 1H), 7.22-7.18 (m, 1H), 7.17 (d, J = 8.1 Hz, 1H), 7.11 (ddd, J = 7.9, 2.0, 1.1 Hz, 1H), 5.23 (d, J = 6.0 Hz, 1H), 4.86-4.69 (m, 1H), 3.14 (dd, J = 17.4, 5.1 Hz, 1H), 2.58 (d, J = 17.4 Hz, 1H), 2.31-2.12 (m, 2H), 1.90-1.80 (m, 1H), 1.75 (ddd, J = 13.6, 9.5, 4.8 Hz, 1H). (±)-N-(3-Bromophenyl)-1- fluoro-6,7,8,9-tetrahydro-5H- 5,8- epiminocyclohepta[c]pyridine- 10-carboxamide 171 [00287] 382.3 at 1.40 min .sup.1H NMR (400 MHz, DMSO- d6) δ 8.99 (s, 1H), 8.01 (d, J = 5.0 Hz, 1H), 7.61 (s, 1H), 7.49-7.39 (m, 1H), 7.34 (t, J = 8.2 Hz, 1H), 7.21 (dd, J = 4.9, 1.7 Hz, 1H), 6.90 (ddt, J = 8.1, 2.3, 1.0 Hz, 1H), 5.25 (d, J = 6.0 Hz, 1H), 4.82 (t, J = 6.1 Hz, 1H), 3.15 (dd, J = 17.5, 4.9 Hz, 1H), 2.59 (d, J = 17.3 Hz, 1H), 2.30-2.09 (m, 2H), 1.89-1.80 (m, 1H), 1.80-1.66 (m, 1H). (±)-1-Fluoro-N-(3- (trifluoromethoxy)phenyl)- 6,7,8,9-tetrahydro-5H-5,8- epiminocyclohepta[c]pyridine- 10-carboxamide 172 [00288] 394.2, 396.2 at 1.31 min .sup.1H NMR (400 MHz, DMSO- d6) δ 8.89 (s, 1H), 8.01 (d, J = 5.0 Hz, 1H), 7.85 (dd, J = 6.4, 2.6 Hz, 1H), 7.44 (ddd, J = 9.0, 4.4, 2.6 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.20 (dd, J = 5.1, 1.7 Hz, 1H), 5.22 (d, J = 6.1 Hz, 1H), 4.79 (t, J = 6.1 Hz, 1H), 3.15 (dd, J = 17.4, 5.0 Hz, 1H), 2.58 (d, J = 17.3 Hz, 1H), 2.20 (ddd, J = 25.0, 11.9, 6.7 Hz, 2H), 1.90-1.80 (m, 1H), 1.80-1.70 (m, 1H). (±)-N-(3-Bromo-4- fluorophenyl)-1-fluoro- 6,7,8,9-tetrahydro-5H-5,8- epiminocyclohepta[c]pyridine- 10-carboxamide 173 [00289] 334.2 at 1.26 min .sup.1H NMR (400 MHz, DMSO- d6) δ 9.06 (s, 1H), 8.01 (d, J = 5.0 Hz, 1H), 7.32-7.15 (m, 3H), 6.75 (tt, J = 9.3, 2.4 Hz, 1H), 5.24 (d, J = 6.1 Hz, 1H), 4.81 (t, J = 6.1 Hz, 1H), 3.14 (dd, J = 17.4, 5.0 Hz, 1H), 2.60 (d, J = 17.4 Hz, 1H), 2.20 (dtd, J = 23.7, 12.1, 11.7, 7.4 Hz, 2H), 1.96-1.79 (m, 1H), 1.79-1.67 (m, 1H). (±)-N-(3,5-Difluorophenyl)-1- fluoro-6,7,8,9-tetrahydro-5H- 5,8- epiminocyclohepta[c]pyridine- 10-carboxamide 174 [00290] 350.2 at 1.27 min .sup.1H NMR (400 MHz, DMSO- d6) δ 8.69 (s, 1H), 8.00 (d, J = 5.0 Hz, 1H), 7.60 (dd, J = 6.9, 2.7 Hz, 1H), 7.23 (dd, J = 10.4, 8.8 Hz, 1H), 7.19 (dd, J = 5.0, 1.7 Hz, 1H), 7.14 (ddd, J = 8.8, 4.2, 2.7 Hz, 1H), 5.20 (d, J = 5.9 Hz, 1H), 4.77 (t, J = 6.1 Hz, 1H), 3.18 (dd, J = 17.4, 5.0 Hz, 1H), 2.57 (d, J = 17.3 Hz, 1H), 2.29-2.10 (m, 2H), 1.89-1.80 (m, 1H), 1.80-1.69 (m, 1H). (±)-N-(5-Chloro-2- fluorophenyl)-1-fluoro- 6,7,8,9-tetrahydro-5H-5,8- epiminocyclohepta[c]pyridine- 10-carboxamide 175 [00291] 352.2 at 1.18 min .sup.1H NMR (400 MHz, DMSO- d6) δ 8.75 (s, 1H), 8.00 (d, J = 5.0 Hz, 1H), 7.32-7.09 (m, 3H), 5.18 (d, J = 6.0 Hz, 1H), 4.75 (t, J = 6.2 Hz, 1H), 3.18 (dd, J = 17.5, 5.0 Hz, 1H), 2.58 (d, J = 17.3 Hz, 1H), 2.31-2.12 (m, 2H), 1.89- 1.80 (m, 1H), 1.80-1.70 (m, 1H). (±)-1-Fluoro-N-(2,3,4- trifluorophenyl)-6,7,8,9- tetrahydro-5H-5,8- epiminocyclohepta[c]pyridin- 10-carboxamide 176 [00292] 321.1 at 1.09 min.sup.(d) .sup.1H NMR (400 MHz, DMSO- d6) δ 9.09 (s, 1H), 8.01 (d, J = 5.0 Hz, 1H), 7.66 (s, 3H), 7.21 (dd, J = 5.0, 1.6 Hz, 1H), 5.26 (d, J = 6.1 Hz, 1H), 4.84 (t, J = 6.2 Hz, 1H), 3.15 (dd, J = 17.5, 5.1 Hz, 1H), 2.60 (d, J = 17.4 Hz, 1H), 2.30-2.08 (m, 2H), 1.91-1.80 (m, 1H), 1.76 (dt, J = 13.9, 6.5 Hz, 1H). (±)-N-(4-Cyanophenyl)-1- fluoro-6,7,8,9-tetrahydro-5H- 5,8- epiminocyclohepta[c]pyridine- 10-carboxamide 177 [00293] 350.2 at 1.25 min .sup.1H NMR (400 MHz, DMSO- d6) δ 8.62 (s, 1H), 8.00 (d, J = 4.7 Hz, 1H), 7.44 (t, J = 8.7 Hz, 1H), 7.39 (dd, J = 10.5, 2.4 Hz, 1H), 7.25-7.10 (m, 2H), 5.19 (d, J = 5.9 Hz, 1H), 4.76 (dd, J = 7.1, 5.0 Hz, 1H), 3.17 (dd, J = 17.4, 5.0 Hz, 1H), 2.57 (d, J = 17.3 Hz, 1H), 2.29-2.08 (m, 2H), 1.91-1.79 (m, 1H), 1.79- 1.64 (m, 1H). (±)-N-(4-Chloro-2- fluorophenyl)-1-fluoro- 6,7,8,9-tetrahydro-5H-5,8- epiminocyclohepta[c]pyridine- 10-carboxamide 178 [00294] 350.2 at 1.29 min .sup.1H NMR (400 MHz, DMSO- d6) δ 8.90 (s, 1H), 8.01 (d, J = 5.0 Hz, 1H), 7.73 (dd, J = 6.9, 2.6 Hz, 1H), 7.39 (ddd, J = 9.1, 4.3, 2.6 Hz, 1H), 7.28 (t, J = 9.1 Hz, 1H), 7.20 (dd, J = 5.1, 1.7 Hz, 1H), 5.22 (d, J = 6.1 Hz, 1H), 4.85-4.77 (m, 1H), 3.15 (dd, J = 17.4, 4.9 Hz, 1H), 2.58 (d, J = 17.4 Hz, 1H), 2.19 (dtd, J = 17.8, 11.7, 7.1 Hz, 2H), 1.90-1.79 (m, 1H), 1.79-1.67 (m, 1H). (±)-N-(3-Chloro-4- fluorophenyl)-1-fluoro- 6,7,8,9-tetrahydro-5H-5,8- epiminocyclohepta[c]pyridine- 10-carboxamide 179 [00295] 401.3, 403.5 at 1.16 min .sup.1H NMR (400 MHz, DMSO- d6) δ 9.60 (s, 1H), 8.90 (s, 1H), 8.01 (d, J = 5.0 Hz, 1H), 7.71 (d, J = 2.4 Hz, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.36 (dd, J = 8.8, 2.4 Hz, 1H), 7.20 (dd, J = 5.0, 1.6 Hz, 1H), 6.54 (dd, J = 17.0, 10.2 Hz, 1H), 6.23 (dd, J = 17.1, 2.0 Hz, 1H), 5.74 (dd, J = 10.1, 1.9 Hz, 1H), 5.23 (d, J = 6.0 Hz, 1H), 4.80 (t, J = 6.1 Hz, 1H), 3.15 (dd, J = 17.5, 4.9 Hz, 1H), 2.58 (d, J = 17.4 Hz, 1H), 2.35-2.12 (m, 2H), 1.92- 1.67 (m, 2H). (5R,8S)-N-(4-Acrylamido-3- chlorophenyl)-1-fluoro- 6,7,8,9-tetrahydro-5H-5,8- epiminocyclohepta[c]pyridine- 10-carboxamide 180 [00296] 460.0, 462.0 at 1.71 min.sup.(d) .sup.1H NMR (400 MHz, DMSO- d6) δ 9.06 (s, 1H), 8.17 (d, J = 7.1 Hz, 1H), 8.01 (d, J = 5.0 Hz, 1H), 7.76 (d, J = 11.2 Hz, 1H), 7.21 (dd, J = 5.1, 1.6 Hz, 1H), 5.24 (d, J = 5.9 Hz, 1H), 4.81 (t, J = 6.2 Hz, 1H), 3.19 (dd, J = 17.4, 5.0 Hz, 1H), 2.60 (d, J = 17.4 Hz, 1H), 2.32-2.10 (m, 2H), 1.95- 1.79 (m, 1H), 1.80-1.70 (m, 1H). (5R,8S)-N-(5-Bromo-2- fluoro-4- (trifluoromethyl)phenyl)-1- fluoro-6,7,8,9-tetrahydro-5H- 5,8- epiminocyclohepta[c]pyridine- 10-carboxamide 181 [00297] 382.1, 384.1 at 1.55 min.sup.(d) .sup.1H NMR (400 MHz, DMSO- d6) δ 8.79 (s, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.77 (t, J = 8.2 Hz, 1H), 7.66 (d, J = 10.3 Hz, 1H), 6.94 (dd, J = 8.3, 2.6 Hz, 1H), 5.21 (d, J = 5.9 Hz, 1H), 4.74 (t, J = 6.2 Hz, 1H), 3.34 (dd, J = 17.3, 5.0 Hz, 1H), 2.67 (d, J = 17.9 Hz, 1H), 2.32-2.08 (m, 2H), 1.87- 1.77 (m, 1H), 1.76-1.61 (m, 1H) (±)-N-(4,5-Dichloro-2- fluorophenyl)-2-fluoro- 6,7,8,9-tetrahydro-5H-5,8- epiminocyclohepta[b]pyridine- 10-carboxamide 182 [00298] 416.2, 418.2 at 1.68 min.sup.(d) .sup.1H NMR (400 MHz, DMSO- d6) δ 9.05 (s, 1H), 8.02 (d, J = 6.9 Hz, 1H), 7.83- 7.72 (m, 2H), 6.94 (dd, J = 8.2, 2.6 Hz, 1H), 5.26 (d, J = 5.9 Hz, 1H), 4.85-4.63 (m, 1H), 3.35 (d, J = 17.1, 5.0 Hz, 1H), 2.68 (d, J = 17.9 Hz, 1H), 2.31-2.10 (m, 2H), 1.89-1.78 (m, 1H), 1.78- 1.67 (m, 1H). (±)-N-(5-Chloro-2-fluoro-4- (trifluoromethyl)phenyl)-2- fluoro-6,7,8,9-tetrahydro-5H- 5,8- epiminocyclohepta[b]pyridine- 10-carboxamide 183 [00299] 364.3 at 1.22 min .sup.1H NMR (400 MHz, DMSO- d6) δ 8.86 (s, 1H), 8.36 (d, J = 2.4 Hz, 1H), 8.01 (d, J = 5.0 Hz, 1H), 7.70-7.65 (m, 3H), 7.58-7.52 (m, 2H), 7.21 (dd, J = 5.0, 1.7 Hz, 1H), 6.49 (t, J = 2.1 Hz, 1H), 5.25 (d, J = 6.0 Hz, 1H), 4.82 (t, J = 6.2 Hz, 1H), 3.17 (dd, J = 17.6, 4.9 Hz, 1H), 2.59 (d, J = 17.3 Hz, 1H), 2.29-2.13 (m, 2H), 1.88-1.81 (m, 1H), 1.80- 1.71 (m, 1H). (5R,8S)-N-(4-(1H-Pyrazol-1- yl)phenyl)-1-fluoro-6,7,8,9- tetrahydro-5H-5,8- epiminocyclohepta[c]pyridine- 10-carboxamide 184 [00300] 374.3 at 1.62 min .sup.1H NMR (400 MHz, DMSO- d6) δ 8.82 (s, 1H), 8.01 (d, J = 5.0 Hz, 1H), 7.77 (t, J = 2.0 Hz, 1H), 7.61-7.54 (m, 2H), 7.52-7.41 (m, 3H), 7.39- 7.27 (m, 2H), 7.25-7.18 (m, 2H), 5.26 (d, J = 6.0 Hz, 1H), 4.83 (t, J = 6.1 Hz, 1H), 3.18 (dd, J = 17.2, 5.0 Hz, 1H), 2.59 (d, J = 17.3 Hz, 1H), 2.30-2.13 (m, 2H), 1.90- 1.81 (m, 1H), 1.81-1.69 (m, 1H). (5R,8S)-N-([1,1′-Biphenyl]-3- yl)-1-fluoro-6,7,8,9- tetrahydro-5H-5,8- epiminocyclohepta[c]pyridine- 10-carboxamide 185 [00301] 390.3 at 1.60 min .sup.1H NMR (400 MHz, DMSO- d6) δ 8.76 (s, 1H), 8.00 (d, J = 5.0 Hz, 1H), 7.51-7.38 (m, 2H), 7.38-7.28 (m, 2H), 7.20 (dd, J = 5.0, 1.7 Hz, 1H), 7.07 (t, J = 7.4 Hz, 1H), 6.97- 6.83 (m, 4H), 5.23 (d, J = 6.0 Hz, 1H), 4.79 (t, J = 6.0 Hz, 1H), 3.16 (dd, J = 17.3, 4.9 Hz, 1H), 2.57 (d, J = 17.3 Hz, 1H), 2.30-2.11 (m, 2H), 1.90-1.80 (m, 1H), 1.79- 1.69 (m, 1H). (5R,8S)-1-Fluoro-N-(4- phenoxyphenyl)-6,7,8,9- tetrahydro-5H-5,8- epiminocyclohepta[c]pyridine- 10-carboxamide 186 [00302] 381.2 at 1.23 min .sup.1H NMR (400 MHz, DMSO- d6) δ 9.14 (d, J = 1.9 Hz, 1H), 8.85 (s, 1H), 8.01 (d, J = 5.0 Hz, 1H), 7.99 (d, J = 1.9 Hz, 1H), 7.88-7.82 (m, 2H), 7.56-7.51 (m, 2H), 7.21 (dd, J = 5.0, 1.6 Hz, 1H), 5.26 (d, J = 6.0 Hz, 1H), 4.83 (t, J = 6.2 Hz, 1H), 3.21-3.10 (m, 1H), 2.59 (d, J = 17.4 Hz, 1H), 2.29-2.12 (m, 2H), 1.85 (dd, J = 11.3, 8.9 Hz, 1H), 1.80-1.69 (m, 1H). (5R,8S)-1-Fluoro-N-(4- (thiazol-4-yl)phenyl)-6,7,8,9- tetrahydro-5H-5,8- epiminocyclohepta[c]pyridine- 10-carboxamide 187 [00303] 379.2 at 1.20 min .sup.1H NMR (400 MHz, DMSO- d6) δ 8.91 (s, 1H), 8.25 (s, 1H), 8.01 (d, J = 5.0 Hz, 1H), 7.64-7.56 (m, 2H), 7.52- 7.44 (m, 2H), 7.21 (dd, J = 5.0, 1.7 Hz, 1H), 5.26 (d, J = 6.0 Hz, 1H), 4.83 (t, J = 6.1 Hz, 1H), 3.16 (dd, J = 17.5, 5.0 Hz, 1H), 2.59 (d, J = 7.4 Hz, 1H), 2.31 (s, 3H), 2.28- 2.12 (m, 2H), 1.89-1.81 (m, 1H), 1.80-1.69 (m, 1H). (5R,8S)-1-Fluoro-N-(4-(4- methyloxazol-5-yl)phenyl)- 6,7,8,9-tetrahydro-5H-5,8- epiminocyclohepta[c]pyridine- 10-carboxamide 188 [00304] 365.3 at 1.15 min .sup.1H NMR (400 MHz, DMSO- d6) δ 8.91 (s, 1H), 8.36 (s, 1H), 8.01 (d, J = 5.0 Hz, 1H), 7.58 (s, 4H), 7.52 (s, 1H), 7.21 (dd, J = 5.0, 1.7 Hz, 1H), 5.26 (d, J = 6.0 Hz, 1H), 4.83 (t, J = 6.0 Hz, 1H), 3.16 (dd, J = 17.3, 5.0 Hz, 1H), 2.59 (d, J = 17.3 Hz, 1H), 2.31-2.10 (m, 2H), 1.90-1.80 (m, 1H), 1.76 (dt, J = 13.7, 6.7 Hz, 1H). (5R,8S)-1-Fluoro-N-(4- (oxazol-5-yl)phenyl)-6,7,8,9- tetrahydro-5H-5,8- epiminocyclohepta[c]pyridine- 10-carboxamide 189 [00305] 416.1, 418.2 at 1.27 min .sup.1H NMR (400 MHz, DMSO- d6) δ 11.50 (s, 1H), 8.96 (s, 1H), 8.06 (d, J = 6.9 Hz, 1H), 7.78 (d, J = 11.0 Hz, 1H), 7.28 (d, J = 9.2 Hz, 1H), 6.11 (d, J = 9.2 Hz, 1H), 4.97 (d, J = 5.5 Hz, 1H), 4.65 (t, J = 6.4 Hz, 1H), 3.18-3.05 (m, 1H), 2.38 (d, J = 17.7 Hz, 1H), 2.25-2.13 (m, 1H), 2.10- 1.96 (m, 1H), 1.86-1.78 (m, 1H), 1.73-1.64 (m, 1H). (±)-N-(5-Chloro-2-fluoro-4- (trifluoromethyl)phenyl)-2- oxo-2,5,6,7,8,9-hexahydro- 1H-5,8- epiminocyclohepta[b]pyridine- 10-carboxamide 190.sup.(f) [00306] 384.1, 386.1 at 2.73 min.sup.(e) .sup.1H NMR (400 MHz, DMSO- d6) δ 8.91 (s, 1H), 8.33 (s, 1H), 8.22 (s, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.65 (d, J = 10.0 Hz, 1H), 5.39 (d, J = 5.6 Hz, 1H), 4.76 (t, J = 5.2 Hz, 1H), 3.35 (d, J = 4.0 Hz, 1H), 2.75- 2.70 (m, 1H), 2.32-2.14 (m, 2H), 1.89-1.83 (m, 1H), 1.75- 1.68 (m, 1H) (5R,8S)-N-(4,5-Dichloro-2- fluorophenyl)-4-fluoro- 6,7,8,9-tetrahydro-5H-5,8- epiminocyclohepta[c]pyridine- 10-carboxamide 191.sup.(a)(c) [00307] 372.3 at 1.19 min .sup.1H NMR (500 MHz, DMSO- d6) δ 11.26 (s, 1H), 8.67 (s, 1H), 7.64-7.59 (m, 2H), 7.59-7.52 (m, 4H), 7.42 (t, J = 7.7 Hz, 2H), 7.32-7.28 (m, 1H), 7.19 (s, 1H), 6.10 (s, 1H), 5.09 (d, J = 6.0 Hz, 1H), 4.62 (t, J = 6.5 Hz, 1H), 3.13 (dd, J = 18.1, 5.1 Hz, 1H), 2.58-2.53 (m, 1H), 2.23- 2.13 (m, 1H), 2.12-2.03 (m, 1H), 1.77-1.69 (m, 1H), 1.69-1.60 (m, 1H). (6S,9R)-N-([1,1′-Biphenyl]-4- yl)-3-oxo-3,5,6,7,8,9- hexahydro-2H-6,9- epiminocyclohepta[c]pyridine- 10-carboxamide 192.sup.(a)(b) [00308] 374 at 1.56 min .sup.1H NMR (500 MHz, DMSO- d6) δ 8.84 (s, 1H), 8.01 (d, J = 5.0 Hz, 1H), 7.63-7.58 (m, 2H), 7.54 (s, 4H), 7.42 (t, J = 7.7 Hz, 2H), 7.32-7.26 (m, 1H), 7.21 (dd, J = 5.0, 1.6 Hz, 1H), 5.26 (d, J = 6.2 Hz, 1H), 4.83 (t, J = 6.3 Hz, 1H), 3.17 (dd, J = 17.4, 5.0 Hz, 1H), 2.59 (d, J = 17.4 Hz, 1H), 2.31-2.15 (m, 2H), 1.91- 1.82 (m, 1H), 1.80-1.71 (m, 1H). (5R,8S)-N-([1,1′-Biphenyl]-4- yl)-1-fluoro-6,7,8,9- tetrahydro-5H-5,8- epiminocyclohepta[c]pyridine- 10-carboxamide 193.sup.(a)(c) [00309] 367.2, 369.1 at 1.19 min .sup.1H NMR (400 MHz, DMSO- d6) δ 9.04 (d, J = 1.2 Hz, 1H), 8.99 (s, 1H), 8.86 (s, 1H), 7.80 (dd, J = 7.6, 3.7 Hz, 1H), 7.67 (d, J = 10.3 Hz, 1H), 5.18 (d, J = 5.9 Hz, 1H), 4.76 (t, J = 6.2 Hz, 1H), 3.28 (d, J = 5.3 Hz, 1H), 2.68 (d, J = 18.1 Hz, 1H), 2.31- 2.09 (m, 2H), 1.92-1.78 (m, 1H), 1.72 (dd, J = 12.6, 5.7 Hz, 1H) (±)-N-(4,5-Dichloro-2- fluorophenyl)-6,7,8,9- tetrahydro-5H-5,8- epiminocyclohepta[d]pyridazine- 10-carboxamide 194.sup.(a)(b) [00310] 401.2, 403.2 at 1.33 min .sup.1H NMR (400 MHz, DMSO- d6) δ 9.13 (s, 1H), 9.05 (d, J = 1.2 Hz, 1H), 8.99 (s, 1H), 8.00 (d, J = 6.9 Hz, 1H), 7.79 (d, J = 11.0 Hz, 1H), 5.22 (d, J = 5.8 Hz, 1H), 4.81 (t, J = 6.1 Hz, 1H), 3.28 (d, J = 5.7 Hz, 1H), 2.69 (d, J = 18.1 Hz, 1H), 2.31- 2.14 (m, 2H), 1.94-1.82 (m, 1H), 1.78-1.64 (m, 1H) (±)-N-(5-Chloro-2-fluoro-4- (trifluoromethyl)phenyl)- 6,7,8,9-tetrahydro-5H-5,8- epiminocyclohepta[d]pyridazine- 10-carboxamide 195.sup.(a)(b) [00311] 467.0, 469.0 at 1.75 min.sup.(d) .sup.1H NMR (400 MHz, DMSO- d6) δ 9.30 (s, 1H), 8.05 (d, J = 6.9 Hz, 1H), 7.79 (d, J = 11.0 Hz, 1H), 5.34 (d, J = 5.7 Hz, 1H), 4.86 (d, J = 6.2 Hz, 1H), 3.28- 3.20 (m, 1H), 2.68 (d, J = 18.6 Hz, 1H), 2.35-2.14 (m, 2H), 2.04-1.88 (m, 1H), 1.85-1.72 (m, 1H). (±)-1,4-Dichloro-N-(5-chloro- 2-fluoro-4- (trifluoromethyl)phenyl)- 6,7,8,9-tetrahydro-5H-5,8- epiminocyclohepta[d]pyridazine- 10-carboxamide 199.sup.(a)(b) [00312] 355.1, 357.2 at 1.38 min.sup.(d) .sup.1H NMR (400 MHz, DMSO- d6) δ 9.15 (s, 1H), 8.04 (d, J = 2.6 Hz, 1H), 8.01 (d, J = 5.0 Hz, 1H), 7.76 (dd, J = 9.0, 2.6 Hz, 1H), 7.60 (d, J = 9.0 Hz, 1H), 7.21 (dd, J = 5.0, 1.7 Hz, 1H), 5.24 (d, J = 6.1 Hz, 1H), 4.81 (t, J = 6.1 Hz, 1H), 3.15 (dd, J = 17.5, 5.0 Hz, 1H), 2.60 (d, J = 17.4 Hz, 1H), 2.31-2.10 (m, 2H), 1.91- 1.82 (m, 1H), 1.76 (dt, J = 13.9, 6.8 Hz, 1H). (5R,8S)-N-(4-Chloro-3- cyanophenyl)-1-fluoro- 6,7,8,9-tetrahydro-5H-5,8- epiminocyclohepta[c]pyridine- 10-carboxamide 200.sup.(f) [00313] 434.2, 436.2 at 4.40 min .sup.1H NMR (400 MHz, DMSO- d6): δ ppm: 8.87 (s, 1H), 8.49 (d, J = 4.8 Hz, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.65 (d, J = 10.4 Hz, 1H), 7.54 (d, J = 4.8 Hz, 1H), 5.26 (d, J = 4.8 Hz, 1H), 4.77 (t, J = 6.0 Hz, 1H), 3.45 (dd, J = 2.8 Hz, 4.0 Hz, 1H), 2.80 (d, J = 17.6 Hz, 1H), 2.28-2.15 (m, 2H), 1.88- 1.83 (m, 1H), 1.76-1.70 (m, 1H). (5R,8S)-N-(4,5-dichloro-2- fluorophenyl)-1- (trifluoromethyl)-6,7,8,9- tetrahydro-5H-5,8- epiminocyclohepta[c]pyridine- 10-carboxamide

Intermediate 29 (I-29)

[1496] ##STR00314##

[1497] Step 1: To a solution of 2-chloro-4-nitroaniline 1-29a (1.00 g, 5.79 mmol) and sodium bicarbonate (1.46 g, 17.4 mmol) in MeCN (10 ml) was added acryloyl chloride (706 μl, 8.69 mmol) at 0° C. over 5 min. The reaction was warmed to RT for 16 h. The reaction mixture was diluted with EtOAc (30 ml) and washed with water (3×20 ml). The organic layer was dried over magnesium sulfate and concentrated in vacuo to obtain N-(2-chloro-4-nitrophenyl)acrylamide I-29b as a yellow solid. The compound was used in the next step without further purification. .sup.1H NMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 8.37 (d, J=2.6 Hz, 1H), 8.31 (d, J=9.1 Hz, 1H), 8.23 (dd, J=9.1, 2.6 Hz, 1H), 6.77 (dd, J=17.0, 10.3 Hz, 1H), 6.36 (dd, J=17.0, 1.8 Hz, 1H), 5.88 (dd, J=10.2, 1.8 Hz, 1H).

[1498] Step 2: To a solution of N-(2-chloro-4-nitrophenyl)acrylamide (1.40 g, 5.232 mmol) in a mixture of EtOH (30 ml) and water (6 ml) was added iron powder (585 mg, 10.46 mmol) followed by 1 ml of saturated ammonium chloride solution. The reaction mixture was heated at 80° C. for 4 h. The reaction mixture was cooled to RT and filtered through celite. The celite was washed with EtOH and ethyl acetate. The filtrate was concentrated in vacuo and the residue was partitioned between 10% MeOH in DCM (50 ml) and water (50 ml). The layers were separated and the aqueous layer was extracted with 10% MeOH in DCM (2×30 ml). The organic layers were combined, dried over magnesium sulfate and concentrated in vacuo to obtain N-(4-amino-2-chlorophenyl)acrylamide 1-29 as a yellow oil. The compound was used in the next step without any further purification. .sup.1H NMR (400 MHz, DMSO-d6) δ 9.37 (s, 1H), 7.18 (d, J=8.6 Hz, 1H), 6.65 (d, J=2.5 Hz, 1H), 6.56-6.35 (m, 2H), 6.18 (dd, J=17.1, 2.1 Hz, 1H), 5.69 (dd, J=10.2, 2.1 Hz, 1H), 5.33 (s, 2H)

Intermediate 30 (I-30)

[1499] ##STR00315## ##STR00316##

[1500] Step 1: (E)-N-((2-Chloro-6-fluoropyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide (130b) was synthesised from 2-chloro-6-fluoronicotinaldehyde (1-30a) using a procedure essentially the same as for I-7b. .sup.1H NMR: (400 MHz, CDCl.sub.3) δ 8.93 (s, 1H), 8.48 (t, J=8.4 Hz, 1H), 7.02-6.99 (m, 1H), 1.28 (m, 9H).

[1501] Step 2: N-(1-(2-Chloro-6-fluoropyridin-3-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide (130c) was synthesised from (E)-N-((2-chloro-6-fluoropyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide (130b) using a procedure essentially the same as for I-7c. .sup.1H NMR: (400 MHz, CDCl.sub.3) δ 7.82-7.87 (m, 1H), 6.87-6.90 (m, 1H), 5.76 (t, J=10.4 Hz, 1H), 5.01-5.05 (m, 2H), 4.98-4.84 (m, 1H), 5.82-3.79 (m, 1H), 2.20-2.05 (m, 2H), 1.94-1.88 (m, 2H) 1.16-1.22 (m, 9H)

[1502] Step 3: 1-(2-Chloro-6-fluoropyridin-3-yl)pent-4-en-1-amine (130d) was synthesised from N-(1-(2-Chloro-6-fluoropyridin-3-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide (130c) using a procedure essentially the same as for I-7d. .sup.1H NMR: (400 MHz, CDCl.sub.3) δ 8.00 (t, J=8.4 Hz, 1H), 6.87-6.90 (m, 1H), 5.72-5.83 (m 1H), 5.96-5.05 (m, 2H), 4.36 (t, J=5.6 Hz, 1H) 2.09-2.15 (m, 2H), 1.65-1.69 (m, 2H), 1.48 (s, 2H).

[1503] Step 4: N-(1-(2-Chloro-6-fluoropyridin-3-yl)pent-4-en-1-yl)-4-methoxyaniline (I-30e) was synthesised from 1-(2-chloro-6-fluoropyridin-3-yl)pent-4-en-1-amine (130d) using a procedure essentially the same as for 1-7e. .sup.1H NMR: (400 MHz, CDCl3) δ 7.88 (t, J=8.0 Hz, 1H), 6.78-6.83 (m, 1H), 6.70 (t, J=4.4 Hz, 2H), 6.40 (d, J=4.4 Hz, 2H), 5.80-5.87 (m, 1H), 5.01-5.05 (m, 2H), 3.70 (s, 3H), 2.19-2.31 (m, 2H), 1.77-1.92 (m, 2H), 1.43 (s, 1H) (1 exchangeable NH not observed)

[1504] Step 5: To a solution of N-(1-(2-chloro-6-fluoropyridin-3-yl)pent-4-en-1-yl)-4-methoxyaniline (1-30e) (3.00 g, 9.35 mmol) in toluene (60 ml) was added NaO.sup.tBu (1.35 g, 14.0 mmol) and Pd-172 (567 mg, 935 umol) at 20° C. The mixture was stirred at 110° C. for 16 h. The reaction mixture was concentrated in vacuo. The product was purified by silica gel chromatography (EtOAc/Petroleum ether 1%-100%) to give (±)-2-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[b]pyridine (I-30f) as a yellow solid. .sup.1H NMR: (400 MHz, CDCl3) δ 7.55 (t, J=8.0 Hz, 1H), 6.68-6.77 (m, 5H), 4.72 (d, J=2.4 Hz, 1H), 4.52 (d, J=5.6 Hz, 1H), 3.71 (s, 3H), 3.28 (dd, J=8.8, 4.4 Hz, 1H), 2.53 (d, J=8.8 Hz, 1H), 2.42-2.56 (m, 3H), 1.82-1.96 (m, 2H).

[1505] Step 6: (±)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[b]pyridine (I-30) was synthesised from (±)-2-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[b]pyridine (I-30f) using a procedure essentially the same as for 1-9. .sup.1H NMR (400 MHz, DMSO-d6) δ 7.60 (t, J=8.3 Hz, 1H), 6.90-6.76 (m, 1H), 4.19 (d, J=5.6 Hz, 1H), 3.84-3.68 (m, 1H), 3.02 (dd, J=17.7, 5.2 Hz, 1H), 2.79 (s, 1H), 2.45 (s, 1H), 2.00-1.82 (m, 2H), 1.77-1.65 (m, 1H), 1.58-1.39 (m, 1H)

Intermediate 31 (I-31)

[1506] ##STR00317##

[1507] Step 1: To a solution of (±)-2-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[b]pyridine (113 mg, 397 μmol) in MeOH (4 ml) was added a solution of sodium methoxide in methanol (110 μl, 5.4 molar, 596 μmol). The resultant mixture was heated at 65° C. for 20 h. THF (1 ml) was added followed by a further portion of sodium methoxide (110 μl, 5.4 molar, 596 μmol). The reaction was stirred at 65° C. for a further 24 h. The reaction was cooled. The solid was filtered off and washed with MeOH (2×5 ml) and the solid was dried in vacuo to give (±)-2-methoxy-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[b]pyridine (I-31a) as a white solid. LC-MS (method 1) m/z 297.1 (M+H).sup.+ (ES.sup.+); at 1.68 min

[1508] Step 2: (±)-2-Methoxy-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[b]pyridine (I-31b) was synthesised from (±)-2-methoxy-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[b]pyridine (I-31a) using a procedure essentially the same as for 1-9. .sup.1H NMR (400 MHz, Chloroform-d) δ 7.17 (d, J=8.2 Hz, 1H), 6.45 (d, J=8.2 Hz, 1H), 4.17 (d, J=5.5 Hz, 1H), 3.97-3.89 (m, 1H), 3.86 (s, 3H), 3.21-3.05 (m, 1H), 2.59 (d, J=17.7 Hz, 1H), 2.35 (s, 1H), 2.19-2.00 (m, 2H), 1.89-1.78 (m, 1H), 1.68-1.57 (m, 1H).

[1509] Step 3: (±)-1,5,6,7,8,9-Hexahydro-2H-5,8-epiminocyclohepta[b]pyridin-2-one (1-31) was synthesised from (±)-2-methoxy-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[b]pyridine (I-31b) using a procedure essentially the same as for 1-10. .sup.1H NMR (400 MHz, DMSO-d6) δ 11.32 (s, 1H), 7.15 (d, J=9.1 Hz, 1H), 6.04 (d, J=9.1 Hz, 1H), 3.91 (d, J=5.3 Hz, 1H), 3.80-3.59 (m, 1H), 2.80 (dd, J=17.5, 4.9 Hz, 1H), 2.18 (d, J=17.5 Hz, 1H), 2.06-1.58 (m, 3H), 1.55-1.26 (m, 1H), 1 exchangeable proton not visible.

Intermediate 32 (I-32)

[1510] ##STR00318## ##STR00319##

[1511] Step 1: To a solution of 3-bromo-5-fluoroisonicotinaldehyde I-32a (4.5 g, 22.2 mmol) and (S)-2-methylpropane-2-sulfinamide (2.7 g, 22.2 mmol) in DCM (50 ml) was added cesium carbonate (7.2 g, 22.2 mmol). After stirring at RT for 16 h, the reaction mixture was filtered and the filter cake was washed with DCM (50 ml). The filtrate was concentrated under reduced pressure to give (S)—N-((3-bromo-5-fluoropyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide I-32b as a yellow solid. .sup.1H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.77 (d, J=1.6 Hz, 1H), 8.63 (s, 1H), 1.22 (s, 9H)

[1512] Step 2: (S)—N—((R)-1-(3-Bromo-5-fluoropyridin-4-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide (I-32c) was synthesised from (S)—N-((3-bromo-5-fluoropyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide (I-32b) using a procedure essentially the same as for I-13c. .sup.1H NMR (400 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.54 (d, J=1.6 Hz, 1H), 5.84-5.72 (m, 2H), 5.08-4.97 (m, 2H), 4.79 (q, J=6.4 Hz, 1H), 2.18-2.10 (m, 2H), 2.05-2.00 (m, 1H), 1.99-1.87 (m, 1H), 1.01 (s, 9H).

[1513] Step 3: To a solution of (S)—N—((R)-1-(3-bromo-5-fluoropyridin-4-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide (I-32c) (5.4 g, 14.9 mmol) in .sup.tBuOH (60 ml) at 0° C. was added a solution of HCl in dioxane (4 M, 19 ml). The reaction mixture was stirred at RT for 2.5 h. Water was added (50 ml) and the mixture extracted with EtOAc (3×50 ml). The aqueous layer was basified with saturated sodium bicarbonate aqueous solution and extracted with EtOAc (3×50 ml). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give (R)-1-(3-bromo-5-fluoropyridin-4-yl)pent-4-en-1-amine (1-32d) as a yellow oil. .sup.1H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 1H), 8.50 (d, J=2.4 Hz, 1H), 5.84-5.74 (m, 1H), 5.03-4.92 (m, 2H), 4.19 (t, J=7.2 Hz, 1H), 2.15-2.10 (m, 3H), 2.02-1.93 (m, 1H), 1.88-1.70 (m, 2H).

[1514] Step 4: To a solution of (R)-1-(3-bromo-5-fluoropyridin-4-yl)pent-4-en-1-amine (3 g, 11.6 mmol) (1-32d) in DCM (40 ml) were added (4-methoxyphenyl)boronic acid (5.3 g, 34.8 mmol), copper(II)acetate (3.15 g, 17.4 mmol) and Et.sub.3N (8.1 ml, 58 mmol). The dark blue mixture was vigorously stirred at RT, fully opened to the air, for 20 h. 2 M NaOH aqueous solution (20 ml) was added and the resultant biphasic mixture was filtered and the filter cake was washed with DCM. The layers were separated, and the aqueous layer extracted with DCM (2×50 ml). The combined organic layers were dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The product was purified by silica gel chromatography (10% EtOAc/petroleum ether) to give (R)—N-(1-(3-bromo-5-fluoropyridin-4-yl)pent-4-en-1-yl)-4-methoxyaniline (I-32e) as a yellow oil. .sup.1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 8.45 (d, J=2.0 Hz, 1H), 6.64 (d, J=8.8 Hz, 2H), 6.47 (d, J=8.8 Hz, 2H), 5.88-5.77 (m, 2H), 5.06-5.00 (m, 2H), 4.81-4.75 (m, 1H), 3.57 (s, 3H), 2.32-2.26 (m, 1H), 2.15-2.01 (m, 2H), 1.98-1.80 (m, 1H).

[1515] Step 5: (5R,8S)-4-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine (I-32f) was synthesised from (R)—N-(1-(3-bromo-5-fluoropyridin-4-yl)pent-4-en-1-yl)-4-methoxyaniline (I-32e) using a procedure essentially the same as for 1-13f. .sup.1H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 8.04 (s, 1H), 6.77-6.71 (m, 4H), 5.04 (d, J=5.6 Hz, 1H), 4.55 (t, J=6.4 Hz, 1H), 3.60 (s, 3H), 3.06 (dd, J=4.8, 4.8 Hz, 1H), 2.52-2.47 (m, 1H), 2.35-2.24 (m, 2H), 1.90-1.85 (m, 1H), 1.78-1.73 (m, 1H)

[1516] Step 6: (5R,8S)-4-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine (I-32) was synthesised from (5R,8S)-4-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine (I-32f) using a procedure essentially the same as for 1-13. .sup.1H NMR (400 MHz, DMSO-d6) δ 8.23 (s, 1H), 8.11 (s, 1H), 4.38 (d, J=1.6 Hz, 1H), 3.76 (t, J=6.4 Hz, 1H), 3.02 (dd, J=4.2, 4.2 Hz, 1H), 2.56-2.50 (m, 1H), 2.02-1.89 (m, 2H), 1.76-1.71 (m, 1H), 1.52-1.46 (m, 1H)

Intermediate 33 (I-33)

[1517] ##STR00320##

[1518] Step 1: N-((3-Chloro-2-fluoropyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide (I-33b) was synthesised from 3-chloro-2-fluoroisonicotinaldehyde (1-33a) using a procedure essentially the same as for I-32b. .sup.1H NMR (500 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.33 (d, J=5.1 Hz, 1H), 7.90 (d, J=5.1 Hz, 1H), 1.22 (s, 9H).

[1519] Step 2: A solution of but-3-en-1-ylmagnesium bromide in THF (133 ml, 0.5 M, 66.55 mmol) was slowly added to a solution of N-((3-chloro-2-fluoropyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide (I-33b) (14.6 g, 55.46 mmol) in THF (150 ml) at −78° C. The reaction mixture was allowed to slowly warm to RT over 16 h. The reaction mixture was quenched with saturated ammonium chloride solution (150 ml) and extracted with EtOAc (2×200 ml). The organic layers were combined, dried over magnesium sulfate and concentrated in vacuo to give N-(1-(3-chloro-2-fluoropyridin-4-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide (I-33c) as an orange oil. LC-MS (method 2) m/z 319.0, 321.0 (M+H).sup.+ (ES.sup.+); at 2.12 min.

[1520] Step 3: 1-(3-chloro-2-fluoropyridin-4-yl)pent-4-en-1-amine (1-33d) was synthesised from N-(1-(3-chloro-2-fluoropyridin-4-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide (I-33c) using a procedure essentially the same as for I-13d. .sup.1H NMR (500 MHz, DMSO-d6) δ 8.16 (dd, J=5.1, 0.9 Hz, 1H), 7.62 (d, J=5.1 Hz, 1H), 5.86-5.74 (ddt, J=16.9, 10.2, 6.6 Hz, 1H), 5.02 (dq, J=17.2, 1.8 Hz, 1H), 4.98-4.92 (m, 1H), 4.20 (dd, J=8.2, 5.0 Hz, 1H), 3.31 (s, 1H), 2.27 (br s, 2H), 2.20-2.02 (m, 1H), 1.69-1.51 (m, 2H).

[1521] Step 4: N-(1-(3-Chloro-2-fluoropyridin-4-yl)pent-4-en-1-yl)-4-methoxyaniline (I-33e) was synthesised from 1-(3-chloro-2-fluoropyridin-4-yl)pent-4-en-1-amine (1-33d) using a procedure essentially the same as for I-32e. .sup.1H NMR (500 MHz, DMSO-d6) δ 8.10 (dd, J=5.2, 0.8 Hz, 1H), 7.41 (d, J=5.1 Hz, 1H), 6.69-6.61 (m, 2H), 6.42-6.35 (m, 2H), 6.09 (d, J=8.3 Hz, 1H), 5.80-5.81 (m, 1H), 5.07-4.96 (m, 2H), 4.68 (td, J=8.5, 4.7 Hz, 1H), 3.57 (s, 3H), 2.29 (dd, J=14.3, 8.4 Hz, 1H), 2.24-2.13 (m, 1H), 1.86-1.70 (m, 2H).

[1522] Step 5: (±)-1-Fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine (I-33f) was synthesised from N-(1-(3-chloro-2-fluoropyridin-4-yl)pent-4-en-1-yl)-4-methoxyaniline (I-33e) using a procedure essentially the same as for I-7f. .sup.1H NMR (500 MHz, DMSO-d6) δ 7.95 (d, J=5.0 Hz, 1H), 7.28 (d, J=4.9 Hz, 1H), 6.85-6.76 (m, 2H), 6.71 (d, J=8.6 Hz, 2H), 4.92 (d, J=5.4 Hz, 1H), 4.56 (s, 1H), 3.61 (s, 3H), 2.92 (d, J=16.4 Hz, 1H), 2.35 (d, J=17.4 Hz, 1H), 2.33-2.27 (m, 2H), 1.88-1.75 (m, 2H)

[1523] Step 6: (±)-1-Fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine (I-33) was synthesised from (±)-1-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine (I-33f) using a procedure essentially the same as for 1-14. .sup.1H NMR (400 MHz, DMSO-d6) δ 7.91 (dd, J=5.0, 1.0 Hz, 1H), 7.04 (dd, J=5.0, 1.9 Hz, 1H), 4.17 (d, J=5.4 Hz, 1H), 3.78 (t, J=5.9 Hz, 1H), 3.04-2.68 (m, 2H), 2.38 (d, J=17.1 Hz, 1H), 1.93 (ddt, J=8.6, 5.9, 2.6 Hz, 2H), 1.73 (t, J=9.0 Hz, 1H), 1.63-1.34 (m, 1H).

Intermediate 34 (I-34)

[1524] ##STR00321##

[1525] Step 1: A flask containing palladium(II) trifluoroacetate (270 mg, 812 μmol), Xantphos (940 mg, 1.62 mmol) and benzoic acid (496 mg, 4.06 mmol) and the flask was evacuated under vacuum and backfilled with N.sub.2 (3 times). Toluene (100 ml) was added followed by cyclohepta-1,3,5-triene (1-34a) (16.8 ml, 162 mmol) and the flask was evacuated under vacuum and backfilled with N.sub.2 (3 times). The mixture was stirred at RT for 2-3 min before a solution of 4-methoxyaniline (5.00 g, 40.6 mmol) in toluene (50 ml) which had been sparged with N.sub.2 for 2 minutes. The reaction was heated at 110° C. for 3 h and left to cool overnight. The organics were washed with saturate sodium bicarbonate solution (100 ml) and brine (100 ml). The organic layer was dried over magnesium sulfate and concentrated in vacuo. The product was purified by chromatography on silica gel (0-10% EtOAc/isohexane) to afford (±)-8-(4-methoxyphenyl)-8-azabicyclo[3.2.1]oct-2-ene (1-34 b) as a clear orange oil. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 6.88 (d, J=8.6 Hz, 2H), 6.84-6.78 (m, 2H), 6.07 (m, 1H), 5.50-5.38 (m, 1H), 4.28-4.19 (m, 1H), 4.08 (t, J=5.3 Hz, 1H), 3.76 (s, 3H), 2.57 (d, J=18.0 Hz, 1H), 2.42-2.42 (m, 1H), 2.20-2.08 (m, 1H), 2.06-1.97 (m, 1H), 1.91-1.62 (m, 2H)

[1526] Step 2: (±)-8-(4-Methoxyphenyl)-8-azabicyclo[3.2.1]oct-2-ene (1-34b) (1.03 g, 4.07 mmol) and 3,6-dichloro-1,2,4,5-tetrazine (737 mg, 4.88 mmol) were dissolved in xylenes (40 ml) and the mixture was stirred at 100° C. for 72 h. The reaction mixture was cooled to RT and solvent was concentrated in vacuo. The product was purified by chromatography on silica gel (0-50% EtOAc/isohexane) to afford (±)-1,4-dichloro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyridazine (1-34c) as a pale brown solid. .sup.1H NMR (400 MHz, DMSO-d6) δ 6.85-6.64 (m, 4H), 5.00 (d, J=5.8 Hz, 1H), 4.64 (t, J=5.7 Hz, 1H), 3.62 (s, 3H), 2.91 (dd, J=18.9, 5.0 Hz, 1H), 2.40-2.20 (m, 2H), 2.04-1.91 (m, 1H), 1.89-1.75 (m, 1H) (1H under DMSO peak)

[1527] Step 3: (±)-1,4-dichloro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyridazine (1-34) was synthesised (±)-1,4-dichloro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyridazine (1-34c) using a procedure essentially the same as for 1-14. .sup.1H NMR (400 MHz, DMSO-d6) δ 4.31 (d, J=5.1 Hz, 1H), 3.83 (s, 1H), 2.92 (d, J=4.4 Hz, 1H), 2.44 (d, J=18.6 Hz, 1H), 2.07-1.93 (m, 2H), 1.82 (t, J=9.2 Hz, 1H), 1.61-1.46 (m, 1H). (Exchangeable—NH proton not visible)

Intermediate 35 (I-35)

[1528] ##STR00322##

[1529] To a solution of (±)-1,4-dichloro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyridazine (1-34) (84 mg, 0.37 mmol) in EtOH (2 ml) was added Et.sub.3N (200 μl, 1.5 mmol) followed by Pd/C (86 mg, 5% Wt, 37 μmol). The reaction mixture was stirred for 16 h at RT under H.sub.2 (5 bar). The reaction mixture was filtered and concentrated in vacuo. The resultant residue was dissolved in DCM (30 ml) and washed with distilled water (5 ml). A solution of 2 M NaOH was added to the aqueous until pH ˜10 was reached. The aqueous was extracted with DCM (3×20 ml). The combined organics were dried over magnesium sulfate and concentrated in vacuo to provide (±)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyridazine as a pale yellow oil, which was used without further purification. .sup.1H NMR (400 MHz, DMSO-d6) δ 8.88 (d, J=1.9 Hz, 2H), 4.16 (d, J=6.1 Hz, 1H), 3.78 (t, J=5.9 Hz, 1H), 2.97 (dd, J=17.9, 5.0 Hz, 1H), 2.51-2.43 (m, 1H), 2.02-1.86 (m, 2H), 1.75 (t, J=9.1 Hz, 1H), 1.54-1.38 (m, 1H). (Exchangeable —NH proton not observed)

Intermediate 36 (I-35)

[1530] ##STR00323## ##STR00324##

[1531] Step 1: To a solution of diisopropylamine (9.2 ml, 60 mmol) in dry-THF (20 m) at −70° C. was added a solution of n-BuLi in hexanes (2.5 M, 26.5 ml, 60 mmol). The mixture was stirred at −70° C. for 0.5 h. A solution of 3-chloro-2-(trifluoromethyl)pyridine I-36a (8 g, 40 mmol) in THF (80 ml) was added to the reaction slowly and the mixture was stirred at −70° C. for 1 h. A solution of DMF (8.5 ml, 110 mmol) in THF (30 ml) was added slowly and the mixture was stirred at −70° C. for 1 h. The reaction was quenched with saturated aqueous ammonium chloride solution (60 ml) and the mixture was extracted with EtOAc (3×100 ml). The combined organics were washed with brine, dried over sodium sulfate and concentrated in vacuo. The product was purified by chromatography on silica gel (20% EtOAc/petroleum ether) to give 3-chloro-2-(trifluoromethyl)isonicotinaldehyde I-36b as a yellow solid. .sup.1H NMR: (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.90 (d, J=4.8 Hz, 1H), 8.07 (d, J=4.8 Hz, 1H)

[1532] Step 2: (S)—N-((3-Chloro-2-(trifluoromethyl)pyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide I-36c was synthesised from 3-chloro-2-(trifluoromethyl)isonicotinaldehyde I-36b using a procedure essentially the same as for I-32b. .sup.1H NMR: (400 MHz, DMSO-d6) δ 8.89 (s, 1H), 8.82 (d, J=4.8 Hz, 1H), 8.23 (d, J=4.8 Hz, 1H), 1.23 (s, 9H).

[1533] Step 3: (S)—N—((R)-1-(3-Chloro-2-(trifluoromethyl)pyridin-4-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-36d was synthesised from (S)—N-((3-chloro-2-(trifluoromethyl)pyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide I-36c using a procedure essentially the same as for 1-13c. .sup.1H NMR (400 MHz, DMSO-d6): δ 8.69 (d, J=4.8 Hz, 1H), 7.89 (d, J=4.8 Hz, 1H), 5.93 (d, J=7.2 Hz, 1H), 5.85-5.74 (m, 1H), 5.13-4.99 (m, 2H), 4.78-4.72 (m, 1H), 2.27-2.13 (m, 2H), 1.96-1.86 (m, 1H), 1.81-1.72 (m, 1H), 1.07 (s, 9H).

[1534] Step 4: (R)-1-(3-Chloro-2-(trifluoromethyl)pyridin-4-yl)pent-4-en-1-amine I-36e was synthesised from (S)—N—((R)-1-(3-Chloro-2-(trifluoromethyl)pyridin-4-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-36d using a procedure essentially the same as for I-32d. .sup.1H NMR (400 MHz, DMSO-d6): δ 8.63 (d, J=4.8 Hz, 1H), 8.00 (d, J=4.8 Hz, 1H), 5.85-5.75 (m, 1H), 5.05-4.93 (m, 2H), 4.30-4.27 (m, 1H), 2.22-2.05 (m, 4H), 1.69-1.51 (m, 2H).

[1535] Step 5: (R)—N-(1-(3-chloro-2-(trifluoromethyl)pyridin-4-yl)pent-4-en-1-yl)-4-methoxyaniline I-36f was synthesised from (R)-1-(3-Chloro-2-(trifluoromethyl)pyridin-4-yl)pent-4-en-1-amine I-36e using a procedure essentially the same as for I-32d. .sup.1H NMR (400 MHz, DMSO-d6): δ 8.59 (d, J=4.8 Hz, 1H), 7.77 (d, J=4.8 Hz, 1H), 6.66-6.63 (m, 2H), 6.40-6.36 (m, 2H), 6.13 (d, J=8.4 Hz, 1H), 5.89-5.79 (m, 1H), 5.05-4.97 (m, 2H), 4.77 (q, J=8.8 Hz, 1H), 3.56 (s, 3H), 2.36-2.16 (m, 2H), 1.80-1.74 (m, 2H)

[1536] Step 6: A mixture of (R)—N-(1-(3-chloro-2-(trifluoromethyl)pyridin-4-yl)pent-4-en-1-yl)-4-methoxyaniline I-36f (2 g, 5.4 mmol), NaO.sup.tBu (778 mg, 8.1 mmol), Pd.sub.2(dba).sub.3. CHCl.sub.3 (559 mg, 0.54 mmol) and tricyclohexyl phosphine (302 mg, 1.08 mmol) in toluene (30 ml) was stirred at 95° C. for 4 h under N.sub.2. The mixture was cooled to RT, filtered, and the filter cake was washed with EtOAc (3×20 ml). The filtrate was concentrated in vacuo and the product was purified by chromatography on silica gel (10% EtOAc/petroleum ether) to give (5R,8S)-10-(4-methoxyphenyl)-1-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine I-36g as a yellow solid. .sup.1H NMR (400 MHz, DMSO-d6): δ 8.43 (d, J=4.8 Hz, 1H), 7.62 (d, J=4.8 Hz, 1H), 6.84-6.80 (m, 2H), 6.73-6.69 (m, 2H), 5.00 (d, J=6.0 Hz, 1H), 4.57 (t, J=5.2 Hz, 1H), 3.61 (s, 3H), 3.20 (dd, J=4.8, 4.8 Hz, 1H), 2.58 (d, J=17.6 Hz, 1H), 2.32-2.23 (m, 2H), 1.87-1.74 (m, 2H)

[1537] Step 7: (5R,8S)-1-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine 1-36 was synthesised from (5R,8S)-10-(4-methoxyphenyl)-1-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine I-36g using a procedure essentially the same as for 1-14. .sup.1H NMR (400 MHz, DMSO-d6) δ 8.39 (d, J=4.8 Hz, 1H), 7.37 (d, J=4.8 Hz, 1H), 4.24 (d, J=5.2 Hz, 1H), 3.81-3.77 (m, 1H), 3.12 (dd, J=5.2, 5.2 Hz, 1H), 2.64-2.59 (m, 1H), 1.98-1.91 (m, 2H), 1.73 (t, J=9.6 Hz, 1H), 1.51-1.46 (m, 1H).

Experimental Scheme 5

Compound 58 (±)-10-((3,4-Dichlorophenyl)carbamoyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine 2-oxide

[1538] ##STR00325##

[1539] To a solution of (±)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide 36 (50 mg, 0.14 mmol) in DCM (1 ml) was added mCPBA (62 mg, 0.29 mmol, 80% w/w) at 0° C. The reaction mixture was warmed to RT for 16 h. Water (10 ml) was added and the product was extracted with DCM (3×5 ml). The combined organics were washed with brine (10 ml), dried with sodium sulfate, and concentrated in vacuo. The product was purified by prep-TLC (eluted with 25% MeOH/EtOAc) to afford (±)-10-((3,4-dichlorophenyl)carbamoyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine 2-oxide 58 as a white solid. LC-MS (method 1) m/z 364.1, 366.1 (M+H).sup.+ (ES.sup.+) at 1.07 min, .sup.1H NMR: (400 MHz, CDCl.sub.3) δ 8.01-7.96 (m, 2H), 7.60 (d, J=2.7 Hz, 1H), 7.33 (d, J=8.8 Hz, 1H), 7.22 (dd, J=8.8, 2.7 Hz, 1H), 7.04-7.00 (m, 1H), 6.73 (s, 1H), 5.03 (d, J=6.2 Hz, 1H), 4.66-4.59 (m, 1H), 3.37 (dd, J=17.0, 4.9 Hz, 1H), 2.62 (d, J=17.2 Hz, 1H), 2.47-2.36 (m, 1H), 2.36-2.25 (m, 1H), 2.00-1.91 (m, 1H), 1.84-1.74 (m, 1H)

[1540] The following compounds were prepared using appropriate starting materials in an analogous procedure to that described in Experimental Scheme 5

TABLE-US-00008 LCMS method 1 Compound Structure Rt [M + H].sup.+ NMR 92 [00326] 364.1, 366.1 at 1.12 min .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.98 (d, J = 6.5 Hz, 1H), 7.95 (s, 1H), 7.61 (d, J = 2.4 Hz, 1H), 7.35-7.30 (m, 1H), 7.26- 7.21 (m, 1H), 7.08-7.01 (m, 2H), 5.06 (d, J = 6.2 Hz, 1H), 4.69-4.61 (m, 1H), 3.33 (dd, J = 4.7, 17.3 Hz, 1H), 2.60 (d, J = 17.2 Hz, 1H), 2.46-2.24 (m, 2H), 1.98-1.90 (m, 1H), 1.82-1.71 (m, 1H) (5R,8S)-10-((3,4- Dichlorophenyl)carbamoyl)- 6,7,8,9-tetrahydro-5H-5,8- epiminocyclohepta[c]pyridine 2-oxide

Experimental Scheme 6

Compound 59 (±)-10-((3,4-Dichlorophenyl)carbamoyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine 2-oxide

[1541] ##STR00327##

[1542] (±)-10-((3,4-Dichlorophenyl)carbamoyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine 2-oxide 59 was synthesised from (±)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide 59a using a procedure essentially the same as for 58. LC-MS (method 1) m/z 364.0, 366.1 at 1.07 min (M+H).sup.+ (ES.sup.+), .sup.1H NMR: (400 MHz, CDCl.sub.3-d) δ 8.06 (s, 2H), 7.91 (dd, J=6.6, 1.5 Hz, 1H), 7.73 (d, J=2.2 Hz, 1H), 7.40-7.35 (m, 1H), 7.33-7.28 (m, 1H), 6.98 (d, J=6.4 Hz, 1H), 5.15 (d, J=5.5 Hz, 1H), 4.82 (t, J=5.8 Hz, 1H), 3.31 (dd, J=17.9, 4.9 Hz, 1H), 2.62 (d, J=17.9 Hz, 1H), 2.42-2.24 (m, 2H), 2.03-1.92 (m, 1H), 1.77-1.67 (m, 1H)

Experimental Scheme 7

Compound 60 (±)-2-Chloro-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene-10-carboxamide

[1543] ##STR00328##

[1544] Step 1: To a solution of (±)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulen-2-ol 1-10 (176 mg, 0.93 mmol) in DCM (5 ml) was added di-tert-butyl dicarbonate (224 mg, 1.03 mmol) at 0° C., and then warmed up back to RT for 1 h. Saturated sodium bicarbonate solution (10 ml) and the product was extracted with DCM (3×10 ml). The organic layers were combined, dried over magnesium sulfate and concentrated in vacuo to afford tert-butyl (±)-2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene-10-carboxylate 60a as a pale brown solid. The crude product was used for the next step without further purification. LC-MS (method 2) m/z 274 (M−H).sup.− (ES.sup.−) at 2.02 min

[1545] Step 2: To a solution of tert-butyl (±)-2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene-10-carboxylate 60a (247 mg, 0.83 mmol) in DMF (7.3 ml) was added DIPEA (0.44 ml, 2.50 mmol), followed by 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (447 mg, 1.25 mmol). The mixture was stirred at RT for 16 h. The reaction mixture was diluted with EtOAc (20 ml) and a 2:1 mixture of water and brine (50 ml) was added. The product was extracted with EtOAc (2×20 ml). The organics were combined and washed with water (5×20 ml) and brine (20 ml). The organics were dried over magnesium sulfate and concentrated in vacuo. The product was purified by chromatography on silica gel (0-50% EtOAc/isohexane) to afford tert-butyl (±)-2-(((trifluoromethyl)sulfonyl)oxy)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene-10-carboxylate 60b as a pale yellow oil. LC-MS (method 2) m/z 308 (M+H−Boc).sup.+ (ES.sup.+) at 1.86 min, .sup.1H NMR (500 MHz, DMSO-d6) δ 7.39-7.31 (m, 1H), 7.24 (d, J=7.5 Hz, 2H), 4.90 (br s, 1H), 4.37 (br s, 1H), 3.30-3.15 (m, 1H), 2.67 (d, J=17.3 Hz, 1H), 2.24-2.06 (m, 2H), 1.82-1.70 (m, 1H), 1.67-1.56 (m, 1H), 1.43-1.22 (m, 9H).

[1546] Step 3: To a microwave vial, Pd-175 (11 mg, 14 μmol), potassium chloride (34 mg, 0.46 mmol) and potassium fluoride (6.6 mg, 0.11 mmol), were added, which was sealed, then evacuated and back filled with N.sub.2 (3 times). A solution of tert-butyl (±)-2-(((trifluoromethyl)sulfonyl)oxy)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene-10-carboxylate 60b (93 mg 0.23 mmol) in 1,4-dioxane (3 ml) was added and the resultant mixture was heated to 130° C. for 16 h. The reaction was cooled to RT and filtered through a pad of celite, washing with EtOAc (20 ml). The filtrate was concentrated in vacuo. The product was purified by chromatography on silica gel (0-15% EtOAc/isohexane) to afford tert-butyl (±)-2-chloro-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene-10-carboxylate 60c as a colourless oil. LC-MS (method 2) m/z 194.7 (M+H−Boc).sup.+ (ES.sup.+) at 1.82 min, .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.16-7.02 (m, 2H), 6.98 (d, J=8.1 Hz, 1H), 4.87 (s, 1H), 4.50 (s, 1H), 3.34 (s, 1H), 2.52 (d, J=16.7 Hz, 1H), 2.18 (tdd, J=18.0, 15.8, 9.0 Hz, 2H), 1.88-1.74 (m, 1H), 1.73-1.53 (m, 1H), 1.40 (s, 9H)

[1547] Step 4. A solution of HCl in 1,4-dioxane (294 μl, 4 M, 1.17 mmol) was added dropwise to a mixture of tert-butyl (±)-2-chloro-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene-10-carboxylate 60c (11.5 mg, 11.7 μmol) and the solution was stirred for 16 h at RT. A further portion of HCl in 1,4-dioxane (294 μl, 4 M, 1.17 mmol) was added and the reaction mixture was stirred at RT for 24 h. The reaction mixture was concentrated in vacuo. The resultant mixture was dissolved in DCM (0.2 ml). 1,2-Dichloro-4-isocyanatobenzene (16.6 mg, 88.1 μmol) and DIPEA (31 μl, 180 μmol) were added. The resultant mixture was stirred at RT for 48 h. The reaction mixture was diluted with 10% MeOH in DCM (2 ml) and washed with water (2 ml). The organic layer was dried over magnesium sulfate and concentrated in vacuo. The product was purified by mass directed reverse phase HPLC (45-75% MeCN/(0.1% ammonia in water) to give (±)-2-chloro-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene-10-carboxamide 60 as a colourless solid. LC-MS (method 1) m/z 381.2, 383.4 (M+H).sup.+ (ES.sup.+) at 1.79 min, .sup.1H NMR (500 MHz, DMSO-d6) δ 8.90 (s, 1H), 7.84 (d, J=1.8 Hz, 1H), 7.46 (s, 2H), 7.18 (s, 3H), 5.17 (d, J=6.0 Hz, 1H), 4.69 (t, J=6.2, 6.2 Hz, 1H), 3.33-3.26 (m, 1H), 2.64 (d, J=17.2 Hz, 1H), 2.27-2.06 (m, 2H), 1.78 (t, J=10.4, 10.4 Hz, 1H), 1.67 (dt, J=15.2, 7.6, 7.6 Hz, 1H).

Experimental Scheme 8

Compound 61 (±)-1-Amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

[1548] ##STR00329##

[1549] Step 1: To a solution of (±)-10-((3,4-dichlorophenyl)carbamoyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine 2-oxide 59 (50 mg, 137 μmol) and tert-butylamine (87 μl, 824 μmol) in trifluorotoluene (2.4 ml) and DCM (0.6 ml) were added p-tolylsulfonyl 4-methylbenzenesulfonate (112 mg, 343 μmol) at 0° C. The reaction mixture was stirred at 0° C. for 6 h. The mixture was warmed to RT and concentrated in vacuo. The product was purified by prep-TLC (50% EtOAc/petroleum ether) and susbsequent purification by prep-HPLC (55-85% MeCN/10 mM NH.sub.4HCO.sub.3) to obtain (±)-1-(tert-butylamino)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide 61-a as a white solid and (±)-3-(tert-butylamino)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide 62-a as a white solid.

[1550] 61-a .sup.1H NMR: (400 MHz, CDCl.sub.3) δ 7.92 (d, J=5.1 Hz, 1H), 7.60 (d, J=2.4 Hz, 1H), 7.31 (d, J=8.8 Hz, 1H), 7.17 (dd, J=8.8, 2.7 Hz, 1H), 6.32 (d, J=2.4 Hz, 1H), 6.30 (s, 1H), 4.88 (d, J=5.7 Hz, 1H), 4.54-4.45 (m, 1H), 3.94 (br s, 1H), 3.34 (dd, J=17.2, 4.6 Hz, 1H), 2.48 (d, J=17.0 Hz, 1H), 2.44-2.22 (m, 1H), 2.28-2.16 (m, 1H), 1.96-1.88 (m, 1H), 1.82-1.72 (m, 1H), 1.51 (s, 9H)

[1551] 62-a .sup.1H NMR: (400 MHz, CDCl.sub.3) δ 7.83 (s, 1H), 7.61 (d, J=2.4 Hz, 1H), 7.30 (d, J=8.8 Hz, 1H), 7.18 (dd, J=8.7, 2.5 Hz, 1H), 6.35 (s, 1H), 6.20 (s, 1H), 4.79 (d, J=5.1 Hz, 1H), 4.64 (t, J=5.8 Hz, 1H), 4.57-4.34 (m, 1H), 3.35 (dd, J=17.2, 4.6 Hz, 1H), 2.51 (d, J=17.2 Hz, 1H), 2.37-2.22 (m, 2H), 1.95 (t, J=9.2 Hz, 1H), 1.78-1.67 (m, 1H), 1.41 (s, 9H)

[1552] Step 2: To a solution of (±)-1-(tert-butylamino)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide 61a (25 mg, 60 μmol) in DCM (1 ml) was added TFA (0.3 ml, 4.05 mmol) at RT. The resultant mixture was warmed to 50° C. for 6 h. The reaction mixture was concentrated in vacuo. The residue was diluted with water (5 ml) and DCM (3 ml). The pH was adjusted to 10 with 50% aqueous NaOH. The product was extracted with DCM (3×3 ml). The combined organic layers were washed with brine (2×5 ml), dried over sodium sulfate and concentrated in vacuo. The product was purified by prep-HPLC (35-55% MeCN/10 mM NH.sub.4HCO.sub.3) to obtain (±)-1-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide 61 as a white solid. LC-MS (method 1) m/z 363.1, 365.1 (M+H).sup.+ (ES.sup.+) at 1.23 min, .sup.1H NMR: (400 MHz, CDCl.sub.3) δ 7.78 (d, J=5.5 Hz, 1H), 7.60 (d, J=2.5 Hz, 1H), 7.32-7.28 (m, 1H), 7.25-7.19 (m, 1H), 6.80 (br s, 1H), 6.51 (d, J=5.50 Hz, 1H), 5.52-5.24 (m, 1H), 5.10 (d, J=5.75 Hz, 1H) 4.69-4.57 (m, 1H), 3.88 (s, 1H), 3.43 (dd, J=17.7, 4.5 Hz, 1H), 2.56 (d, J=17.7 Hz, 1H), 2.48-2.37 (m, 1H), 2.29 (ddd, J=17.9, 11.7, 6.2 Hz, 1H), 1.82-1.71 (m, 1H), 2.02-1.95 (m, 1H)

Experimental Scheme 9

Compound 62 (±)-3-Amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

[1553] ##STR00330##

[1554] (±)-3-Amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide 62 was synthesised from (±)-3-(tert-butylamino)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide 62-a using a procedure essentially the same as for 61. LC-MS (method 1) m/z 363.1, 365.1 (M+H).sup.+ (ES.sup.+) at 1.21 min, .sup.1H NMR: (400 MHz, CDCl.sub.3-d) δ 7.77 (s, 1H), 7.60 (d, J=2.43 Hz, 1H), 7.32-7.28 (m, 1H), 7.20 (dd, J=8.8, 2.4 Hz, 1H), 6.62 (br s, 1H), 6.28 (s, 1H), 4.86 (d, J=5.5 Hz, 1H), 4.67-4.62 (m, 1H), 3.35 (dd, J=17.4, 4.6 Hz, 1H), 2.53 (d, J=17.4 Hz, 1H), 2.38-2.22 (m, 2H), 1.90 (br s, 1H), 1.76-1.67 (m, 1H). (NH.sub.2 protons not observed)

Experimental Scheme 10

Compound 63 (±)-1-Amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide, Compound 65 (±)-1-(tert-Butylamino)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide and Compound 66 (±)-3-(tert-Butylamino)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

[1555] ##STR00331##

[1556] Step 1: (±)-1-(tert-Butylamino)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide 65 and (±)-3-(tert-butylamino)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide 66 were synthesised from (±)-10-((3,4-dichlorophenyl)carbamoyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine 2-oxide 58 using a procedure essentially the same as for 61a and 62a 65 LC-MS (method 1) m/z 419.2, 421.1 (M+H).sup.+ (ES.sup.+) at 1.77 min, .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.96 (d, J=5.1 Hz, 1H), 7.59 (d, J=2.5 Hz, 1H), 7.30 (d, J=8.8 Hz, 1H), 7.18 (dd, J=8.7, 2.5 Hz, 1H), 6.34 (d, J=5.1 Hz, 1H), 6.31 (s, 1H), 4.77-4.72 (m, 1H), 4.67 (d, J=5.6 Hz, 1H), 3.89 (s, 1H), 3.01 (dd, J=15.9, 4.8 Hz, 1H), 2.39-2.25 (m, 2H), 2.09-1.99 (m, 2H), 1.80-1.72 (m, 1H), 1.46 (s, 9H)

[1557] 66 LC-MS (method 1) m/z 419.1, 421.1 (M+H).sup.+ (ES.sup.+) at 1.66 min, .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.82 (s, 1H), 7.86-7.79 (m, 1H), 7.60 (d, J=2.5 Hz, 1H), 7.33-7.30 (m, 1H), 7.23-7.18 (m, 1H), 6.33 (s, 1H), 6.19 (s, 1H), 4.83 (d, J=6.1 Hz, 1H), 4.57 (d, J=4.5 Hz, 1H), 3.34-3.23 (m, 1H), 2.54 (d, J=16.0 Hz, 1H), 2.39-2.20 (m, 2H), 1.95 (t, J=10.2 Hz, 1H), 1.85-1.74 (m, 1H), 1.42 (s, 9H).

[1558] Step 2: (±)-1-Amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide 63 was synthesised from (±)-1-(tert-butylamino)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide 65 using a procedure essentially the same as for 61. LC-MS (method 1) m/z 363.1, 365.1 (M+H).sup.+ (ES.sup.+) at 1.98 min, .sup.1H NMR (400 MHz, CDCl3-d) δ 7.94 (d, J=5.1 Hz, 1H), 7.58 (d, J=2.4 Hz, 1H), 7.31 (d, J=8.8 Hz, 1H), 7.18 (dd, J=8.7, 2.5 Hz, 1H), 6.51 (d, J=5.1 Hz, 1H), 6.35 (s, 1H), 4.81-4.77 (m, 1H), 4.78 (d, J=6.2 Hz, 1H), 4.73 (t, J=6.0 Hz, 1H), 4.34 (s, 2H), 3.12 (dd, J=16.1, 4.9 Hz, 1H), 2.43-2.26 (m, 2H), 2.22 (d, J=16.1 Hz, 1H). 2.06-1.98 (m, 1H), 1.83-1.74 (m, 1H).

Experimental Scheme 11

Compound 64 (±)-3-Amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

[1559] ##STR00332##

[1560] (±)-3-Amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide 64 was synthesised from (±)-3-(tert-butylamino)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide 66 using a procedure essentially the same as for 61. LC-MS (method 1) m/z 363.1, 365.1 (M+H).sup.+ (ES.sup.+) at 1.21 min, .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.83 (s, 1H), 7.61 (d, J=2.4 Hz, 1H), 7.31 (d, J=8.6 Hz, 1H), 7.20 (dd, J=8.7, 2.5 Hz, 1H), 6.35 (s, 1H), 6.29 (s, 1H), 4.85 (d, J=6.2 Hz, 1H), 4.57 (t, J=6.2 Hz, 1H), 4.33 (s, 2H), 3.31 (dd, J=16.0, 4.7 Hz, 1H), 2.57 (d, J=16.1 Hz, 1H), 2.41-2.21 (m, 2H), 2.00-1.90 (m, 1H), 1.84-1.75 (m, 1H)

Experimental Scheme 12

Compound 67 (±)-N-(3,4-Dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

[1561] ##STR00333##

[1562] To a solution of (±)-3-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide 62 (10 mg, 27.52 μmol) in HF:Pyridine (0.5 ml, 5.55 mmol, 70% HF) was added a solution of NaNO.sub.2 (4.75 mg, 68.82 μmol) in water (0.25 ml) dropwise at 0° C. for 5 min. After stirring at 0° C. for 0.5 h, the reaction mixture was warmed to RT for 2.5 h. Water (5 ml) was added and the product was extracted with EtOAc (3×2 ml). The combined organics were washed with brine (2×5 ml), dried over sodium sulfate and concentrated in vacuo. The product was purified by prep-HPLC (35-55% MeCN/10 mM NH.sub.4HCO.sub.3) to give (±)-N-(3,4-dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide 67 as a white solid. LC-MS (method 1 m/z 364.5, 366.5, 368.4 (M−H).sup.− (ES.sup.−) at 1.47 min, .sup.1H NMR: (400 MHz, CDCl.sub.3) δ 8.00 (s, 1H), 7.59 (d, J=2.6 Hz, 1H), 7.32 (d, J=8.7 Hz, 1H), 7.18 (dd, J=8.7, 2.5 Hz, 1H), 6.72 (s, 1H), 6.40 (s, 1H), 5.04 (d, J=5.6 Hz, 1H), 4.64 (br t, J=6.1 Hz, 1H), 3.48 (dd, J=17.7, 4.3 Hz, 1H), 2.71 (d, J=17.7 Hz, 1H), 2.47-2.27 (m, 2H), 2.05-1.91 (m, 1H), 1.82-1.71 (m, 1H).

Experimental Scheme 13

Compound 68 (±)-N-(3,4-Dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

[1563] ##STR00334##

[1564] (±)-N-(3,4-Dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide 68 was synthesised from (±)-1-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide 61 using a procedure essentially the same as for 67. LC-MS (method 1) m/z 366.1, 368.1, (M+H).sup.+ (ES.sup.+) at 1.43 min, .sup.1H NMR: (400 MHz, CDCl.sub.3) δ 8.01 (dd, J=5.1, 0.7 Hz, 1H), 7.61 (d, J=2.5 Hz, 1H), 7.32 (d, J=8.8 Hz, 1H), 7.19 (dd, J=8.7, 2.6 Hz, 1H), 6.96 (d, J=4.5 Hz, 1H), 6.46 (s, 1H), 5.17 (d, J=5.8 Hz, 1H), 4.75-4.68 (m, 1H), 3.49 (dd, J=17.8, 4.7 Hz, 1H), 2.66 (d, J=17.7 Hz, 1H), 2.47-2.27 (m, 2H), 2.11-1.99 (m, 1H), 1.82-1.69 (m, 1H).

Experimental Scheme 14

Compound 69 (±)-N-(3,4-Dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

[1565] ##STR00335##

[1566] (±)-N-(3,4-Dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide 69 was synthesised from (±)-3-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide 64 using a procedure essentially the same as for 67 LC-MS (method 1) m/z 366.1, 368.1 (M+H).sup.+ (ES.sup.+) at 1.42 min, .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.97 (s, 1H), 7.60 (d, J=2.6 Hz, 1H), 7.33 (d, J=8.8 Hz, 1H), 7.19 (dd, J=8.7, 2.6 Hz, 1H), 6.73 (d, J=2.7 Hz, 1H), 6.38 (s, 1H), 5.03 (d, J=6.2 Hz, 1H), 4.65-4.57 (m, 1H), 3.41 (d, J=16.4 Hz, 1H), 2.70 (d, J=16.6 Hz, 1H), 2.47-2.27 (m, 2H), 1.94-2.03 (m, 1H), 1.86-1.76 (m, 1H).

Experimental Scheme 15

Compound 71 (±)-2-Chloro-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene-10-carboxamide

[1567] ##STR00336##

[1568] To a solution of tert-butyl (±)-2-chloro-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene-10-carboxylate 60c (19 mg, 65.4 μmol) in DCM (1 ml) was added TFA (50 μl, 654 μmol) dropwise. The resultant mixture was stirred at RT for 16 h. The reaction mixture was concentrated in vacuo. The residue was dissolved in DCM (1 ml). In a separate flask a solution of 3-chloro-4-(trifluoromethyl)aniline (14 mg, 71.9 μmol) was added to a solution of triphosgene (9 mg, 30 μmol) in DCM (1 ml). Triethylamine (28 μl, 203 μmol) was added and the resultant mixture was stirred for 10 min. This solution was then added to the TFA salt solution and the mixture was stirred at RT for 18 h. The reaction was diluted with 10% MeOH in DCM solution (8 ml) and sat. sodium bicarbonate solution (5 ml). The product was extracted with 10% MeOH in DCM solution (2×8 ml). The combined organic layers were passed through a hydrophobic frit and concentrated under reduced pressure. The product was purified by prep HPLC (45-75% MeCN/0.1% NH.sub.4OH in water) to give (±)-2-chloro-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene-10-carboxamide 71 as a colourless solid. LC-MS (method 1) m/z 415.6, 417.5 (M+H).sup.+ (ES.sup.+) at 1.82 min, .sup.1H NMR (500 MHz, DMSO-d6) δ 9.17 (s, 1H), 7.91 (d, J=2.0 Hz, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.64-7.58 (m, 1H), 7.19 (d, J=1.2 Hz, 3H), 5.20 (d, J=6.0 Hz, 1H), 4.73 (t, J=6.4 Hz, 1H), 2.66 (d, J=17.4 Hz, 1H), 2.27-2.09 (m, 2H), 1.83-1.75 (m, 1H), 1.73-1.64 (m, 1H). (1 proton obscured by residual water peak)

Experimental Scheme 16

Compound 72 (±)-2-Cyano-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene-10-carboxamide

[1569] ##STR00337##

[1570] Step 1: A vial was charged with Pd-170 (1.0 mg, 1.5 μmol), potassium carbonate (3.4 mg, νmol) and potassium ferrocyanate trihydrate (21 mg, 49 μmol), sealed and evacuated/backfilled with N.sub.2 (3 times). A solution of tert-butyl (±)-2-chloro-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene-10-carboxylate (29 mg, 99 μmol) 60c in 1,4-dioxane:water (1:1, 0.3 ml) was added and the reaction mixture heated to 120° C. for 17 h. The reaction mixture was cooled to RT and filtered through a pad of celite washing with EtOAc (10 ml). The filtrate was concentrated in vacuo. The product was purified by silica gel chromatography (0%-50% EtOAc/isohexane) to give tert-butyl (±)-2-cyano-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene-10-carboxylate (72-1) as a sticky colourless oil. LC-MS (method 1) m/z 185.3 (M−Boc+H).sup.+ (ES.sup.+) at 1.54 min,

[1571] Step 2: To a solution of tert-butyl (±)-2-cyano-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene-10-carboxylate (72-1) (20 mg, 70 μmol) in DCM (1 ml) was added TFA (54 μl, 0.70 mmol) and the reaction mixture stirred at RT for 16 h. The reaction mixture was concentrated in vacuo. The resultant mixture was dissolved in DCM (1 ml). 1,2-Dichloro-4-isocyanatobenzene (15 mg, 77 μmol) and DIPEA (37 μl, 210 μmol) were added. The resultant mixture was stirred at RT for 16 h. The reaction mixture was diluted with 10% MeOH in DCM (8 ml) and washed with saturated aqueous sodium bicarbonate solution (5 ml). The aqueous layer was extracted with 10% MeOH in DCM (2×8 ml) and the combined organics dried via hydrophobic frit and concentrated in vacuo. The product was purified by mass directed reverse phase HPLC (35-65% MeCN/(0.1% ammonia in water) to give (±)-2-cyano-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene-10-carboxamide (72) as colourless solid LC-MS (method 1) m/z 370.3, 372.6 (M−H).sup.− (ES.sup.−) at 1.57 min, .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.95 (s, 1H), 7.83 (d, J=2.2 Hz, 1H), 7.61 (d, J=9.2 Hz, 2H), 7.50-7.41 (m, 2H), 7.37 (d, J=7.7 Hz, 1H), 5.23 (d, J=6.0 Hz, 1H), 4.73 (s, 1H), 2.70 (d, J=17.3 Hz, 1H), 2.18 (dd, J=12.1, 6.4 Hz, 2H), 1.80 (t, J=10.0 Hz, 1H), 1.72-1.63 (m, 1H) (urea-NH not observed).

Experimental Scheme 17

Compound 76: (±)-N-(3,4-Dichlorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

[1572] ##STR00338##

[1573] To a solution of (±)-3-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide 62 (5 mg, 13.76 μmol) in H.sub.2SO.sub.4 (0.5 ml, 1.41 mmol, 15%) was added a solution of NaNO.sub.2 (2.85 mg, 41.29 μmol) in water (0.2 ml) dropwise at 0° C. for 5 min. The reaction mixture was stirred at 0° C. for 3 h. The reaction mixture was poured into water (3 ml) and basified with ammonium hydroxide to pH 8 and the mixture was extracted with DCM (3×3 ml). The combined organic phase was washed with brine (2×5 ml), dried over sodium sulfate and concentrated in vacuo. The product was purified by reverse phase HPLC (5-95% (0.018% TFA in MeCN)/(0.037% TFA in water)) to give (±)-N-(3,4-dichlorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide 76 as a white solid. LC-MS (method 1) m/z 364.1, 366.1 (M+H).sup.+ (ES.sup.+) at 1.09 min, .sup.1H NMR (400 MHz, CDCl.sub.3-d) δ 11.98-11.17 (m, 1H), 7.66 (d, J=2.0 Hz, 1H), 7.35-7.30 (m, 1H), 7.29 (br d, J=2.5 Hz, 1H), 7.05 (s, 1H), 7.01 (s, 1H), 6.34 (s, 1H), 4.90 (br d, J=5.5 Hz, 1H), 4.57 (t, J=6.0 Hz, 1H), 3.24 (d, J=13.8 Hz, 1H), 2.59 (d, J=17.9 Hz, 1H), 2.39-2.16 (m, 2H), 1.85 (t, J=10.2 Hz, 1H), 1.78-1.68 (m, 1H).

Experimental Scheme 18

Compound 77: (±)-1-Chloro-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

[1574] ##STR00339##

[1575] To a solution of (±)-1-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (63) (15 mg, 41.29 μmol) in HCl (1.62 ml, 16.77 mmol, 37% w/w) was added a solution of NaNO.sub.2 (14.25 mg, 206.47 μmol) in water (0.25 ml) and CuCl (4.09 mg, 41.29 μmol) at RT. The reaction mixture was stirred at RT for 3 h. The reaction mixture was quenched with water (5 ml), basified with aqueous NaOH (15% w/w) to pH 7 and extracted with DCM (3×3 ml). The combined organic phases were washed with brine (2×5 ml), dried over sodium sulfate, and concentrated in vacuo. The product was purified by reverse phase HPLC (35-100% MeCN/(10 mM NH.sub.4HCO.sub.3 in water)) to give (±)-1-chloro-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide 77 as a white solid. LC-MS (method 1) m/z 382.0, 384.0 (M+H).sup.+ (ES.sup.+) at 2.63 min, .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.22 (d, J=4.9 Hz, 1H), 7.59 (d, J=2.6 Hz, 1H), 7.32 (d, J=8.8 Hz, 1H), 7.20 (dd, J=8.8, 2.6 Hz, 1H), 7.01 (s, 1H), 7.04 (d, J=4.9 Hz, 1H), 6.47 (s, 1H), 5.04 (d, J=6.4 Hz, 1H), 4.67-4.58 (m, 1H), 3.31 (dd, J=17.7, 4.8 Hz, 1H), 2.74-2.64 (m, 1H), 2.48-2.26 (m, 1H), 2.02-1.93 (m, 1H), 1.87-1.77 (m, 1H).

Experimental Scheme 19

Compound 82: tert-Butyl ((±)-10-((3,4-dichlorophenyl)carbamoyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridin-1-yl)carbamate

[1576] The following scheme makes use of synthetic methodology described in Fier, Kim and Cohen, J. Am. Chem. Soc., 2020, 142, (19), 8614-8618

##STR00340##

[1577] To a solution of (±)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide 59a (20 mg, 57.43 μmol) and trimethylsilyl-N-trimethylsilylethanimidate (35.05 mg, 172.30 μmol) in 1,4-dioxane (0.23 ml) was added tert-butyl ((3-chloro-5,6-dicyanopyrazin-2-yl)oxy)carbamate (25.47 mg, 86.15 μmol) at RT and the reaction mixture was heated at 80° C. for 3 h. After cooling to RT, the reaction mixture was diluted with glacial AcOH (0.23 ml) and zinc (18.8 mg, 287 μmol) was added at once. The reaction mixture was stirred at RT for 3 h. The reaction mixture was quenched with water (5 ml), neutralised with aqueous NaOH (15% w/w) to pH 7, and extracted with EtOAc (3×5 ml). The combined organics were washed with brine (10 ml), dried over sodium sulfate, and concentrated in vacuo. The product was purified by reverse phase HPLC (45-100% MeCN/(10 mM NH.sub.4HCO.sub.3 in water)) to give tert-butyl ((±)-10-((3,4-dichlorophenyl)carbamoyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridin-1-yl)carbamate 82 as a yellow solid. LC-MS (method 1) m/z 363.1 (M−Boc+H).sup.+ (ES.sup.+) at 1.69 min, .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.76 (s, 1H), 8.15 (br d, J=4.0 Hz, 1H), 7.75 (d, J=2.4 Hz, 1H), 7.59 (dd, J=8.8, 2.4 Hz, 1H), 7.29 (s, 1H), 7.27-7.26 (m, 1H), 7.26-7.26 (m, 1H), 6.97 (br d, J=4.6 Hz, 1H), 6.94 (s, 1H), 5.15 (d, J=6.0 Hz, 1H), 4.93-4.83 (m, 1H), 3.51 (br dd, J=17.9, 4.9 Hz, 1H), 2.57 (d, J=17.4 Hz, 1H), 2.44-2.26 (m, 2H), 1.97-1.86 (m, 1H), 1.72-1.66 (m, 1H), 1.60 (s, 9H).

Experimental Scheme 20

Compound 99: (±)-3-Bromo-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

[1578] ##STR00341##

[1579] A mixture of (±)-N-(3,4-dichlorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (62) (5 mg, 2.75 μmol) and POBr.sub.3 (4 mg, 13.75 μmol) was stirred at 110° C. for 2 h. The reaction mixture was cooled to 0° C. and an aqueous solution of NaOH (35% w/w) was added until pH 10 was reached. The mixture was extracted with EtOAc (3×5 ml) and the organics were combined, washed with brine (10 ml), dried over sodium sulfate and concentrated in vacuo. The product was purified by reverse phase HPLC (50-100% MeCN/(10 mM NH.sub.4HCO.sub.3 in water)) to give (±)-3-bromo-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (99) as white solid. LCMS (method 1) m/z 426.0, 428.0, 430.0 (M+H).sup.+ (ES.sup.+), at 1.51 min, .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.16 (s, 1H), 7.59 (d, J=2.4 Hz, 1H), 7.32 (d, J=8.7 Hz, 1H), 7.28-7.27 (m, 1H), 7.18 (dd, J=2.6, 8.8 Hz, 1H), 6.38 (br s, 1H), 5.00 (d, J=5.9 Hz, 1H), 4.64 (d, J=5.1 Hz, 1H), 3.44 (dd, J=4.4, 17.9 Hz, 1H), 2.65 (d, J=17.6 Hz, 1H), 2.46-2.29 (m, 2H), 1.98 (t, J=9.5 Hz, 1H), 1.83-1.71 (m, 1H).

Experimental Scheme 21

Compound 100: (±)-3-Chloro-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

[1580] ##STR00342##

[1581] To a solution of (±)-3-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (62) (3.5 mg, 9.64 umol) and CuCl (954 μg, 9.64 μmol) in HCl (0.5 ml) was added a solution of NaNO.sub.2 (3.3 mg, 48.2 μmol) in water (0.2 ml) dropwise at 0° C. Then the reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with water (5 ml) and basified by dropwise addition of ammonium hydroxide to pH 9. The aqueous mixture was extracted with EtOAc (3×5 ml) and the combined organics were washed with brine (2×5 ml), dried over sodium sulfate and concentrated in vacuo. The product was purified by reverse phase HPLC (45-100% MeCN/(10 mM NH.sub.4HCO.sub.3 in water)) to give (±)-3-chloro-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (100) as white solid. LCMS (method 1) m/z 382.0, 384.0, 386.0 (M+H).sup.+ (ES.sup.+), at 1.48 min, .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.17 (s, 1H), 7.59 (d, J=2.4 Hz, 1H), 7.32 (d, J=8.8 Hz, 1H), 7.18 (dd, J=2.5, 8.7 Hz, 1H), 7.12 (s, 1H), 6.37 (s, 1H), 5.02 (d, J=5.7 Hz, 1H), 4.63 (t, J=6.0 Hz, 1H), 3.45 (dd, J=4.9, 17.6 Hz, 1H), 2.66 (d, J=17.6 Hz, 1H), 2.48-2.27 (m, 2H), 2.05-1.91 (m, 1H), 1.83-1.69 (m, 1H).

Experimental Scheme 22

Compound 109: (±)-N-(3,4-Dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

[1582] ##STR00343##

[1583] (±)-N-(3,4-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide 109 was synthesised (±)-1-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide 63 using a procedure essentially the same as for 67. LCMS (method 1) m/z 366.1, 368.0 (M+H).sup.+ (ES.sup.+), at 1.45 min, .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.03 (d, J=5.0 Hz, 1H), 7.60 (d, J=2.6 Hz, 1H), 7.33 (d, J=8.8 Hz, 1H), 7.19 (dd, J=8.8, 2.6 Hz, 1H), 7.02-6.97 (m, 1H), 6.38 (s, 1H), 5.06 (d, J=6.5 Hz, 1H), 4.66-4.59 (m, 1H), 3.31 (dd, J=17.6, 4.28 Hz, 1H)

Experimental Scheme 23

Compound 113: Cis-(±)-N-(3,4-Dichlorophenyl)-9-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

[1584] ##STR00344##

[1585] Step 1: A solution of tert-butyl-2-fluoro-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (220 mg, 904 μmol) and DMF-DMA (3 ml, 23 mmol) was stirred at 110° C. for 3 h. The reaction was cooled to RT and the reaction mixture was poured onto ice (30 ml). The product was extracted with EtOAc (3×10 ml). The combined organics were washed with brine (2×10 ml), dried over sodium sulfate and concentrated in vacuo to give tert-butyl-2-((dimethylamino)methylene)-4-fluoro-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate 113b as a yellow oil. The crude product was used in the next step without any further purification.

[1586] Step 2: To a solution of formamidine acetate (17 mg, 161 μmol) in EtOH (2 ml) was added sodium ethoxide (9.9 mg, 145 μmol) at RT. After stirring at RT for 30 min, a solution of tert-butyl-2-((dimethylamino)methylene)-4-fluoro-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate 113b (60 mg, 160 μmol) in EtOH (1 ml) was added and the reaction mixture was stirred at 80° C. for 16 h. The mixture was cooled to RT and poured onto water (50 ml), extracted with EtOAc (3×25 ml). The combined organics were washed with brine (2×20 ml), dried over sodium sulfate, and concentrated in vacuo. The product was purified by prep-TLC (25% EtOAc/petroleum ether) to obtain cis-tert-butyl 9-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxylate 113 c as a yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.23 (s, 1H), 8.67 (s, 1H), 5.23 (d, J=4.6 Hz, 1H), 5.16-4.86 (m, 2H), 2.36 (d, J=10.4 Hz, 1H), 2.17 (br s, 1H), 1.70-1.64 (m, 2H), 1.47-1.44 (m, 9H) and trans-tert-butyl 9-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxylate 114c as a yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3-d) δ 9.19 (s, 1H), 8.55 (s, 1H), 5.90-5.64 (m, 1H), 5.17-4.72 (m, 2H), 2.29-2.18 (m, 3H), 1.85-1.78 (m, 1H), 1.46-1.44 (m, 9H)

[1587] Step 3: A solution of cis-tert-butyl 9-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxylate 113c (170 mg, 609 μmol) in 4 M HCl/EtOAc (10 ml, 40 mmol) was stirred at RT for 2 h. The reaction mixture was concentrated in vacuo to give cis-9-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine hydrochloride 113d as a yellow solid. The material was used in the next step without any further purification. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 9.33 (s, 1H), 8.95 (s, 1H), 5.61-5.42 (m, 1H), 5.20 (d, J=5.7 Hz, 1H), 4.78-4.70 (m, 1H), 2.51-2.39 (m, 2H), 2.12-2.04 (m, 1H), 1.91-1.79 (m, 1H), (NH not observed)

[1588] Step 4: To a solution of cis-9-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine hydrochloride 113d (120 mg, 556 μmol) in DCM (5 ml) was added 1,2-dichloro-4-isocyanato-benzene (105 mg, 556 μmol) and DIPEA (291 μl, 1.67 mmol) at 0° C. Then the reaction mixture was warmed to RT for 16 h. The reaction mixture was diluted with water (20 ml) and extracted with DCM (3×10 ml). The combined organics were washed with brine (2×10 ml), dried over sodium sulfate and concentrated in vacuo. The product was purified by prep-HPLC (20-50% MeCN/(10 mM NH.sub.4HCO.sub.3 in water) to obtain cis-(±)-N-(3,4-dichlorophenyl)-9-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide as a white solid. LCMS (method 1) m/z 365.2, 367.2 (M−H).sup.− (ES.sup.−) at 1.23 min, .sup.1H NMR (500 MHz, DMSO-d6) δ 9.20 (s, 1H), 9.13 (s, 1H), 8.91 (s, 1H), 7.81 (d, J=2.5 Hz, 1H), 7.48 (d, J=8.9 Hz, 1H), 7.42 (dd, J=8.9, 2.5 Hz, 1H), 5.41 (d, J=6.2 Hz, 1H), 5.31 (dd, J=48.5, 1.9 Hz, 1H), 5.21 (t, J=10.1 Hz, 1H), 2.25 (d, J=11.4 Hz, 1H), 2.14-1.95 (m, 1H), 1.72-1.59 (m, 1H), 1.54 (dt, J=16.2, 8.4 Hz, 1H)

Experimental Scheme 24

Compound 114: trans-(±)-N-(3,4-Dichlorophenyl)-9-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

[1589] ##STR00345##

[1590] Step 1: trans-9-Fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine hydrochloride 114d was synthesised from trans-tert-butyl 9-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxylate 114c using a procedure essentially the same as for 113d. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 9.30-9.26 (m, 1H), 8.85 (s, 1H), 6.12-5.89 (m, 1H), 5.14 (d, J=5.6 Hz, 1H), 4.72 (br t, J=6.4 Hz, 1H), 2.53-2.28 (m, 3H), 2.25-2.14 (m, 1H), (NH not observed)

[1591] Step 2: trans-(±)-N-(3,4-dichlorophenyl)-9-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide 114 was synthesised from trans-9-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine hydrochloride 114d using a procedure essentially the same as for 113. LCMS (method 1) m/z 365.3, 367.2 (M−H).sup.− (ES.sup.−) at 1.30 min. .sup.1H NMR (500 MHz, DMSO-d6) δ 9.19 (s, 1H), 9.15 (s, 1H), 8.79 (d, J=1.1 Hz, 1H), 7.83 (d, J=2.5 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.44 (dd, J=8.9, 2.5 Hz, 1H), 5.92 (dd, J=49.5, 5.5 Hz, 1H), 5.40 (d, J=4.9 Hz, 1H), 5.03 (t, J=6.0 Hz, 1H), 2.22-2.12 (d, J=7.9 Hz, 2H), 2.08-1.97 (s, 1H), 1.84 (t, J=9.4 Hz, 1H).

[1592] Separation of Enantiomers by Chiral Chromatography

[1593] It will be appreciated that the enantiomers of the compounds described above can be isolated using techniques well known in the art, including, but not limited to, chiral chromatography. For example, a racemic mixture can be dissolved in a solvent, for example, methanol, followed by separation by chiral SFC on a Waters prep 15 with UV detection by DAD at 210-400 nm, 40° C., 120 bar on a Chiralpak® IG (Daicel Ltd.) column (1×25 cm, 5 μm particle size), flow rate 15 ml/min-1 using 50% ethanol in 0.1% DEA to afford both enantiomers as the separated pure compounds.

[1594] For example, (±)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (compound 48) was dissolved to 100 mg/ml in methanol and was then separated by chiral SFC on a Waters prep 15 with UV detection by DAD at 210-400 nm, 40° C., 120 bar on a Chiralpak® IG (Daicel Ltd.) column (1×25 cm, 5 μm particle size), flow rate 15 ml/min-1 using 50% ethanol in 0.1% DEA to afford (5R,8S)—N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (compound 52) and (5S,8R)—N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (compound 53) both as colourless solids. LCMS and NMR data for compounds 52 and 53 are found in the table below.

[1595] Key: (a) m/z from ES.sup.−

TABLE-US-00009 LCMS method 1 Rt Compound Structure [M + H].sup.+ NMR 52 [00346] 349.2, 351.2 at 1.52 min .sup.1H NMR (500 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.96 (s, 1H), 8.60 (s, 1H), 7.83 (d, J = 2.4 Hz, 1H), 7.51-7.41 (m, 2H), 5.28 (d, J = 6.2 Hz, 1H), 4.80 (t, J = 6.5 Hz, 1H), 3.29 (s, 1H), 2.78 (d, J = 18.4 Hz, 1H), 2.28 (q, J = 11.0, 10.2 Hz, 1H), 2.19 (tt, J = 12.1, 6.2 Hz, 1H), 1.94- 1.85 (m, 1H), 1.76 (dt, J = 15.5, 7.7 Hz, 1H) (5R,8S)-N-(3,4-Dichlorophenyl)- 6,7,8,9-tetrahydro-5H-5,8- epiminocyclohepta[d]pyrimidine-10- carboxamide 53 [00347] 349.2, 351.2 at 1.52 min .sup.1H NMR (500 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.96 (s, 1H), 8.60 (s, 1H), 7.83 (d, J = 2.4 Hz, 1H), 7.51-7.41 (m, 2H), 5.28 (d, J = 6.2 Hz, 1H), 4.80 (t, J = 6.5 Hz, 1H), 3.29 (s, 1H), 2.78 (d, J = 18.4 Hz, 1H), 2.28 (q, J = 11.0, 10.2 Hz, 1H), 2.19 (tt, J = 12.1, 6.2 Hz, 1H), 1.94- 1.85 (m, 1H), 1.76 (dt, J = 15.5, 7.7 Hz, 1H) (5S,8R)-N-(3,4-Dichlorophenyl)- 6,7,8,9-tetrahydro-5H-5,8- epiminocyclohepta[d]pyrimidine-10- carboxamide 42 [00348] 383.2, 385.2 at 1.62 min .sup.1H NMR (500 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.95 (d, J = 6.4 Hz, 1H), 8.60 (d, J = 5.8 Hz, 1H), 8.04 (d, J = 2.7 Hz, 1H), 7.79 (dd, J = 8.9, 2.6 Hz, 1H), 7.57 (dd, J = 10.7, 4.6 Hz, 1H), 5.30 (d, J = 6.4 Hz, 1H), 4.83 (t, J = 6.6 Hz, 1H), 3.36 (s, 1H), 2.78 (dd, J = 18.6, 5.8 Hz, 1H), 2.34-2.12 (m, 2H), 1.90 (t, J = 10.7 Hz, 1H), 1.77 (q, J = 9.9, 7.4 Hz, 1H) (5R,8S)-N-(4-Chloro-3- (trifluoromethyl)phenyl)-6,7,8,9- tetrahydro-5H-5,8- epiminocyclohepta[d]pyrimidine-10- carboxamide 38 [00349] 383.2, 385.2 at 1.61 min .sup.1H NMR (500 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.96 (s, 1H), 8.61 (s, 1H), 7.89 (d, J = 2.0 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.63-7.58 (m, 1H), 5.31 (d, J = 6.2 Hz, 1H), 4.84 (t, J = 6.5 Hz, 1H), 3.35 (d, J = 5.1 Hz, 1H), 2.82- 2.78 (m, 1H), 2.32-2.24 (m, 1H), 2.20 (tt, J = 12.0, 6.0 Hz, 1H), 1.90 (t, J = 10.4 Hz, 1H), 1.76 (d, J = 7.8 Hz, 1H). (5R,8S)-N-(3-Chloro-4- (trifluoromethyl)phenyl)-6,7,8,9- tetrahydro-5H-5,8- epiminocyclohepta[d]pyrimidine-10- carboxamide 39 [00350] 383.2, 385.3 at 1.61 min .sup.1H NMR (500 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.96 (s, 1H), 8.61 (s, 1H), 7.89 (d, J = 2.0 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.63-7.58 (m, 1H), 5.31 (d, J = 6.2 Hz, 1H), 4.84 (t, J = 6.5 Hz, 1H), 3.35 (d, J = 5.1 Hz, 1H), 2.82- 2.78 (m, 1H), 2.32-2.24 (m, 1H), 2.20 (tt, J = 12.0, 6.0 Hz, 1H), 1.90 (t, J = 10.4 Hz, 1H), 1.76 (d, J = 7.8 Hz, 1H). (5S,8R)-N-(3-Chloro-4- (trifluoromethyl)phenyl)-6,7,8,9- tetrahydro-5H-5,8- epiminocyclohepta[d]pyrimidine-10- carboxamide 43 [00351] 399.3, 401.3 at 1.15 min .sup.1H NMR (500 MHz, DMSO-d6) δ 11.73 (s, 1H), 9.20 (s, 1H), 7.95 (s, 1H), 7.91 (d, J = 2.0 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.64-7.59 (m, 1H), 5.12 (d, J = 5.9 Hz, 1H), 4.71 (t, J = 6.6 Hz, 1H), 3.10 (dd, J = 18.7, 5.0 Hz, 1H), 2.56 (d, J = 18.5 Hz, 1H), 2.22 (q, J = 11.3, 10.8 Hz, 1H), 2.13-2.01 (m, 1H), 1.82 (dd, J = 12.0, 9.1 Hz, 1H), 1.74 (dt, J = 15.8, 7.9 Hz, 1H) (5R,8S)-N-(3-Chloro-4- (trifluoromethyl)phenyl)-2-oxo- 3,5,6,7,8,9-hexahydro-2H-5,8- epiminocyclohepta[d]pyrimidine-10- carboxamide 44 [00352] 399.3, 401.3 at 1.15 min .sup.1H NMR (500 MHz, DMSO-d6) δ 11.73 (s, 1H), 9.20 (s, 1H), 7.95 (s, 1H), 7.91 (s, 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.62 (d, J = 8.8 Hz, 1H), 5.12 (d, J = 5.9 Hz, 1H), 4.70 (t, J = 6.5 Hz, 1H), 3.10 (dd, J = 18.2, 5.1 Hz, 1H), 2.56 (d, J = 18.2 Hz, 1H), 2.27-2.19 (m, 1H), 2.08 (dq, J = 11.7, 5.9 Hz, 1H), 1.82 (t, J = 10.8 Hz, 1H), 1.73 (d, J = 8.9 Hz, 1H). (5S,8R)-N-(3-Chloro-4- (trifluoromethyl)phenyl)-2-oxo- 3,5,6,7,8,9-hexahydro-2H-5,8- epiminocyclohepta[d]pyrimidine-10- carboxamide 105 [00353] 365.3, 367.3 at 1.06 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 11.71 (s, 1H), 8.94 (s, 1H), 7.94 (s, 1H), 7.84 (d, J = 2.3 Hz, 1H), 7.58-7.37 (m, 2H), 5.09 (d, J = 5.9 Hz, 1H), 4.77-4.59 (m, 1H), 3.08 (dd, J = 18.4, 5.0 Hz, 1H), 2.55 (s, 1H), 2.21 (q, J = 11.3 Hz, 1H), 2.06 (tt, J = 11.7, 6.3 Hz, 1H), 1.81 (t, J = 10.5 Hz, 1H), 1.77- 1.68 (m, 1H). (5S,8R)-N-(3,4-Dichlorophenyl)-2- oxo-3,5,6,7,8,9-hexahydro-2H-5,8- epiminocyclohepta[d]pyrimidine-10- carboxamide 106 [00354] 365.3, 367.3 at 1.06 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 11.71 (s, 1H), 8.94 (s, 1H), 7.94 (s, 1H), 7.84 (d, J = 2.2 Hz, 1H), 7.52-7.43 (m, 2H), 5.09 (d, J = 5.8 Hz, 1H), 4.73-4.62 (m, 1H), 3.08 (dd, J = 18.7, 5.1 Hz, 1H), 2.55 (d, J = 5.0 Hz, 1H), 2.26-2.15 (m, 1H), 2.06 (dq, J = 11.7, 6.0 Hz, 1H), 1.80 (t, J = 10.5 Hz, 1H), 1.74 (d, J = 13.3 Hz, 1H). (5R,8S)-N-(3,4-Dichlorophenyl)-2- oxo-3,5,6,7,8,9-hexahydro-2H-5,8- epiminocyclohepta[d]pyrimidine-10- carboxamide 107 [00355] 347.7, 348.6 at 1.35 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.96 (s, 1H), 8.42-8.11 (m, 2H), 7.84 (d, J = 2.1 Hz, 1H), 7.58- 7.32 (m, 2H), 7.18 (d, J = 4.9 Hz, 1H), 5.16 (d, J = 6.2 Hz, 1H), 4.77 (t, J = 6.3 Hz, 1H), 3.29 (d, J = 11.8 Hz, 1H), 2.67 (d, J = 17.0 Hz, 1H), 2.31-2.09 (m, 2H), 1.86-1.76 (m, 1H), 1.70 (dt, J = 15.1, 7.0 Hz, 1H). (5S,8R)-N-(3,4-Dichlorophenyl)- 6,7,8,9-tetrahydro-5H-5,8- epiminocyclohepta[c]pyridine-10- carboxamide 108 [00356] 347.6, 348.5 at 1.35 min .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.95 (s, 1H), 8.32 (t, J = 2.4 Hz, 2H), 7.84 (d, J = 2.0 Hz, 1H), 7.59-7.34 (m, 2H), 7.18 (d, J = 4.9 Hz, 1H), 5.16 (d, J = 6.3 Hz, 1H), 4.88- 4.68 (m, 1H), 3.29 (dd, J = 17.6, 5.4 Hz, 1H), 2.67 (d, J = 17.1 Hz, 1H), 2.30- 2.10 (m, 2H), 1.88-1.75 (m, 1H), 1.78-1.62 (m, 1H). (5R,8S)-N-(3,4-Dichlorophenyl)- 6,7,8,9-tetrahydro-5H-5,8- epiminocyclohepta[c]pyridine-10- carboxamide 110 [00357] 366.1, 368.1 at 1.52 min .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.03 (d, J = 4.9 Hz, 1H), 7.60 (d, J = 2.4 Hz, 1H), 7.32 (d, J = 8.8 Hz, 1H), 7.19 (dd, J = 2.5, 8.7 Hz, 1H), 7.01-6.95 (m, 1H), 6.45 (s, 1H), 5.06 (d, J = 6.2 Hz, 1H), 4.66- 4.58 (m, 1H), 3.31 (dd, J = 17.4, 4.5 Hz, 1H), 2.65 (d, J = 17.4 Hz, 1H), 2.49- 2.26 (m, 2H), 2.04-1.94 (m, 1H), 1.83 (ddd, J = 12.7, 9.2, 6.3 Hz, 1H) (5S,8R)-N-(3,4-Dichlorophenyl)-1- fluoro-6,7,8,9-tetrahydro-5H-5,8- epiminocyclohepta[c]pyridine-10- carboxamide 115 [00358] 367.0, 369.4 at 1.22 min .sup.1H NMR (500 MHz, DMSO-d6) δ 9.20 (s, 1H), 9.12 (s, 1H), 8.91 (s, 1H), 7.81 (d, J = 2.5 Hz, 1H), 7.48 (d, J = 8.9 Hz, 1H), 7.42 (dd, J = 8.9, 2.5 Hz, 1H), 5.40 (d, J = 6.2 Hz, 1H), 5.31 (dd, J = 48.4, 1.9 Hz, 1H), 5.21 (t, J = 10.1 Hz, 1H), 2.25 (q, J = 11.6 Hz, 1H), 2.05 (p, J = 8.5, 7.2 Hz, 1H), 1.65 (ddd, J = 11.8, 9.0, 2.3 Hz, 1H), 1.54 (dt, J = 15.3, 8.0 Hz, 1H). (5R,8S,9S)-N-(3,4-Dichlorophenyl)- 9-fluoro-6,7,8,9-tetrahydro-5H-5,8- epiminocyclohepta[d]pyrimidine-10- carboxamide 146 [00359] 434.3, 436.5 at 1.12 min .sup.1H NMR (500 MHz, DMSO-d6) δ 8.06 (d, J = 6.9 Hz, 1H), 7.72 (d, J = 11.1 Hz, 1H), 7.12 (s, 1H), 5.13 (d, J = 6.0 Hz, 1H), 4.67 (t, J = 6.5 Hz, 1H), 3.10 (d, J = 16.9 Hz, 1H), 2.64 (d, J = 17.8 Hz, 1H), 2.17 (q, J = 11.2 Hz, 1H), 2.08 (dt, J = 11.5, 5.7 Hz, 1H), 1.72 (q, J = 15.4, 12.7 Hz, 2H). 2-NH protons not observed (6S,9R)-N-(5-Chloro-2-fluoro-4- (trifluoromethyl)phenyl)-4-fluoro-3- oxo-3,5,6,7,8,9-hexahydro-2H-6,9- epiminocyclohepta[c]pyridine-10- carboxamide 147 [00360] 434.4, 436.2 at 1.12 min .sup.1H NMR (500 MHz, DMSO-d6) δ 8.06 (d, J = 6.9 Hz, 1H), 7.73 (d, J = 10.9 Hz, 1H), 7.12 (s, 1H), 5.13 (d, J = 6.0 Hz, 1H), 4.67 (d, J = 8.2 Hz, 1H), 3.10 (d, J = 15.7 Hz, 1H), 2.64 (d, J = 17.5 Hz, 1H), 2.17 (q, J = 10.5 Hz, 1H), 2.10 (dt, J = 12.1, 6.0 Hz, 1H), 1.73 (q, J = 14.8, 12.2 Hz, 2H). 2-NH protons not observed (6R,9S)-N-(5-Chloro-2-fluoro-4- (trifluoromethyl)phenyl)-4-fluoro-3- oxo-3,5,6,7,8,9-hexahydro-2H-6,9- epiminocyclohepta[c]pyridine-10- carboxamide 196 [00361] 416.2, 418.2 at 1.68 min.sup.(a) .sup.1H NMR (400 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.02 (d, J = 6.9 Hz, 1H), 7.84-7.72 (m, 2H), 6.94 (dd, J = 8.3, 2.5 Hz, 1H), 5.26 (d, J = 5.9 Hz, 1H), 4.78 (t, J = 6.2 Hz, 1H), 3.39-3.32 (m, 1H), 2.68 (d, J = 17.8 Hz, 1H), 2.31- 2.09 (m, 2H), 1.89- 1.78 (m, 1H), 1.79-1.66 (m, 1H). (5R,8S)-N-(5-Chloro-2-fluoro-4- (trifluoromethyl)phenyl)-2-fluoro- 6,7,8,9-tetrahydro-5H-5,8- epiminocyclohepta[b]pyridine-10- carboxamide 197 [00362] 416.2, 418.2 at 1.67 min(a) .sup.1H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.02 (d, J = 6.9 Hz, 1H), 7.85-7.72 (m, 2H), 6.94 (dd, J = 8.2, 2.6 Hz, 1H), 5.26 (d, J = 5.9 Hz, 1H), 4.82-4.72 (m, 1H), 3.40- 3.32 (m, 1H), 2.68 (d, J = 17.8 Hz, 1H), 2.29- 2.11 (m, 2H), 1.91-1.80 (m, 1H), 1.79-1.66 (m, 1H). (5S,8R)-N-(5-Chloro-2-fluoro-4- (trifluoromethyl)phenyl)-2-fluoro- 6,7,8,9-tetrahydro-5H-5,8- epiminocyclohepta[b]pyridine-10- carboxamide

Experimental Scheme 25

Compound 133: (5R,8S)—N-(3-Chloro-4-(difluoromethoxy)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

[1596] ##STR00363##

[1597] To a solution of (5R,8S)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine I-13 (30 mg, 0.16 mmol) and Et.sub.3N (65 μl, 0.47 mmol) in DCM (1 ml) was added a solution of triphosgene (46 mg, 0.16 mmol) in 1 ml of DCM. The resultant mixture was stirred at RT for 5 min. In a separate flask, 3-chloro-4-(difluoromethoxy)aniline, HCl (40 mg, 0.17 mmol) was dissolved in DCM (1 ml), Et.sub.3N (48 mg, 65 μl, 3 Eq, 0.47 mmol) was added and the mixture was stirred until a homogenous solution was formed. The carbamoyl chloride solution was added dropwise into the aniline solution. The mixture was stirred at RT for 4 h. After this time LiHMDS (52 mg, 0.31 mmol) was added, and the reaction was left to stir for 18 h. The reaction mixture was concentrated in vacuo. The product was purified by chromatography on silica gel (0-70% EtOAc/isohexane) to afford (5R,8S)—N-(3-chloro-4-(difluoromethoxy)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide 133 as a pale brown solid. LCMS (method 1) m/z 398.4, 400.4 (M+H).sup.+ (ES.sup.+) at 1.39 min, .sup.1H NMR (500 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.01 (d, J=5.0 Hz, 1H), 7.76 (d, J=2.6 Hz, 1H), 7.43 (dd, J=9.0, 2.6 Hz, 1H), 7.30-7.16 (m, 2H), 7.05 (t, J=73.6 Hz, 1H), 5.23 (d, J=6.3 Hz, 1H), 4.80 (t, J=6.3 Hz, 1H), 3.21-3.07 (m, 1H), 2.58 (d, J=17.3 Hz, 1H), 2.31-2.06 (m, 2H), 1.92-1.79 (m, 1H), 1.78-1.67 (m, 1H).

Experimental Scheme 26

Compound 148: (±)-1-Bromo-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

[1598] ##STR00364##

[1599] Step one: To a solution of (±)-1-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide compound 63 (7 mg, 19 μmol) in H.sub.2SO.sub.4 (0.8 ml, 15% w/w) was added a solution of NaNO.sub.2 (3 mg, 42 μmol) in water (0.2 ml) dropwise at 0° C. The reaction mixture was stirred at RT for 6 h. Water (5 ml) was added and the aqueous was basified with an aqueous solution of NaOH (15%) to pH=8. The product was extracted with EtOAc (3×2 ml). The combined organics were washed with brine (2×5 ml), dried with sodium sulfate and concentrated in vacuo. The product was purified by prep-HPLC (20-55% MeCN/10 mM NH.sub.4HCO.sub.3) to obtain (±)-N-(3,4-dichlorophenyl)-1-oxo-2,5,6,7,8,9-hexahydro-1H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide 148-1 as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 11.03 (br s, 1H), 7.65 (d, J=2.2 Hz, 1H), 7.34-7.30 (m, 1H), 7.24-7.17 (m, 2H), 6.63 (br s, 1H), 6.12 (d, J=6.6 Hz, 1H), 4.87 (d, J=6.4 Hz, 1H), 4.56-4.47 (m, 1H), 3.11 (br dd, J=4.2, 17.9 Hz, 1H), 2.49 (d, J=17.9 Hz, 1H), 2.44-2.32 (m, 1H), 2.24 (tt, J=6.1, 12.0 Hz, 1H), 2.05-1.94 (m, 1H), 1.86-1.75 (m, 1H)

[1600] Step two: A solution of (±)-N-(3,4-dichlorophenyl)-1-oxo-2,5,6,7,8,9-hexahydro-1H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (8 mg, 22 μmol) and phosphorus(V) oxybromide (31 mg, 110 μmol) was stirred at 110° C. for 3 h. The reaction mixture was poured onto water (5 ml), basified with an aqueous solution of NaOH (15% w/w) to pH=9. The product was extracted with EtOAc (3×3 ml). The combined organics were washed with brine (2×5 ml), dried with sodium sulfate and concentrated in vacuo. The product was purified by prep-HPLC (40-70% MeCN/10 mM NH.sub.4HCO.sub.3) to obtain (±)-1-bromo-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide 148 as a white solid. LCMS (method 1) m/z 428.1, 430.1 (M+H).sup.+ (ES.sup.+) at 1.55 min, .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.20 (d, J=4.9 Hz, 1H), 7.60 (d, J=2.4 Hz, 1H), 7.33 (d, J=8.6 Hz, 1H), 7.20 (dd, J=2.5, 8.7 Hz, 1H), 7.06 (d, J=4.9 Hz, 1H), 6.43 (s, 1H), 5.01 (d, J=6.4 Hz, 1H), 4.65-4.58 (m, 1H), 3.28 (dd, J=5.2, 17.5 Hz, 1H), 2.66 (d, J=17.6 Hz, 1H), 2.47-2.27 (m, 2H), 2.01-1.92 (m, 1H), 1.88-1.78 (m, 1H)

Experimental Scheme 27

Compound 149: (5R,8S)—N-(4,5-Dichloro-2-hydroxyphenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

[1601] ##STR00365##

[1602] A solution of (5R,8S)—N-(4,5-dichloro-2-methoxyphenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide 118 (20.0 mg, 50.5 μmol) in DCM (0.5 ml) was cooled down to −78° C. A solution of tribromoborane in DCM (66 μl, 1 M, 65.6 μmol) was added dropwise at −78° C., and the mixture was stirred at −78° C. for 5 min, before warming to 0° C. for 1 h. The reaction mixture was cooled down to −78° C. and anhydrous MeOH (1 ml) was added. The reaction mixture was warmed to RT for 30 min. The reaction mixture was concentrated in vacuo. The product was purified by chromatography on RP Flash C18 (5-40% MeCN/10 mM aqueous ammonium bicarbonate) to afford (5R,8S)—N-(4,5-dichloro-2-hydroxyphenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide 149 as a pale yellow solid. LCMS (method 1) m/z 382.1, 384.0 (M+H).sup.+ (ES.sup.+) at 0.74 min. 1H NMR (500 MHz, DMSO-d6) δ 8.15 (s, 1H), 8.00 (d, J=5.0 Hz, 1H), 7.71 (s, 1H), 7.21 (dd, J=5.1, 1.6 Hz, 1H), 6.98 (s, 1H), 5.20 (d, J=6.2 Hz, 1H), 5.00-4.52 (m, 1H), 3.19 (dd, J=17.3, 5.0 Hz, 1H), 2.57 (d, J=17.3 Hz, 1H), 2.21 (dtd, J=23.8, 12.1, 7.2 Hz, 2H), 1.91-1.80 (m, 1H), 1.79-1.69 (m, 1H), 1 exchangeable proton not visible.

Experimental Scheme 28

Compound 150: (6S,9R)—N-(3,4-Dichlorophenyl)-2-methyl-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

[1603] ##STR00366##

[1604] To a solution of (6S,9R)—N-(3,4-dichlorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (35 mg, 96 μmol) in DMF (2 ml) was added Mel (6.0 μl, 96 μmol) and K.sub.2CO.sub.3 (40 mg, 0.29 mmol). The reaction mixture was stirred for 16 h. A further portion of Mel (3 ul, 48 μmol) was added and the reaction mixture was stirred for a further 16 h. A solution of saturated aqueous sodium bicarbonate solution (5 ml) was added and the product was extracted with 20% 0.7 M Ammonia/MeOH in DCM. The organics were concentrated in vacuo. The product was purified by chromatography on RP Flash C18 (15-50% MeCN/10 mM Ammonium Bicarbonate) to afford (6S,9R)—N-(3,4-dichlorophenyl)-2-methyl-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide 150 as a clear white solid. LCMS (method 1) m/z 378.3, 380.3 (M+H).sup.+ (ES.sup.+) at 1.16 min. .sup.1H NMR (500 MHz, DMSO-d6) δ 8.88 (s, 1H), 7.84 (d, J=2.1 Hz, 1H), 7.51 (s, 1H), 7.50-7.42 (m, 2H), 6.16 (s, 1H), 5.03 (d, J=6.0 Hz, 1H), 4.60 (t, J=6.4 Hz, 1H), 3.35 (s, 3H), 3.10 (dd, J=17.9, 5.0 Hz, 1H), 2.56 (d, J=17.8 Hz, 1H), 2.17 (t, J=10.5 Hz, 1H), 2.08 (tt, J=12.0, 6.5 Hz, 1H), 1.73 (t, J=10.4 Hz, 1H), 1.64 (d, J=8.3 Hz, 1H).

[1605] Determination of Absolute Stereochemistry

[1606] The absolute stereochemistry of compounds according to the invention was determined using X-ray diffraction.

[1607] Description of Equipment and Data Collection

[1608] Data was obtained using a Rigaku Oxford Diffraction XtaLAB Synergy four-circle diffractometer equipped with a HyPix-6000HE area detector.

[1609] Cryogenic system: Oxford Cryostream 800

[1610] Cu: λ=1.54184 Å, 50W, Micro focus source with multilayer mirror (μ-CMF).

[1611] Distance from the crystal to the CCD detector: d=35 mm

[1612] Tube Voltage: 50 kV

[1613] Tube Current: 1 mA

[1614] An example of stereochemistry determination using X-ray diffraction for compounds 52 and 53 are shown below. It will be appreciated that similar methods can be used to identify the absolute stereochemistry of other compounds.

Compound 52: (5R,8S)—N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

[1615] A total of 13407 reflections were collected in the 26 range from 10.794 to 133.11. The limiting indices were: −12≤h≤12, −7≤k≤7, −13≤I≤12; which yielded 2535 unique reflections (Rint=0.0996). The structure was solved using SHELXT (Sheldrick, G. M. 2015. Acta Cryst. A71, 3-8) and refined using SHELXL (against F.sup.2) (Sheldrick, G. M. 2015. Acta Cryst. C71, 3-8). The total number of refined parameters was 208, compared with 2535 data. All reflections were included in the refinement. The goodness of fit on F.sup.2 was 1.038 with a final R value for [I>2σ(I)]R.sub.1=0.0934 and wR.sub.2=0.2203. The largest differential peak and hole were 1.28 and −0.56 Å.sup.−3, respectively. The solved Oak Ridge Thermal Ellipsoid Plot (ORTEP) crystal structure for compound 52 is shown in FIG. 1.

Compound 53: (5S,8R)—N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

[1616] A total of 11160 reflections were collected in the 26 range from 7.75 to 133.182. The limiting indices were: −12≤h≤12, −7≤k≤7, −13≤I≤10; which yielded 2527 unique reflections (Rint=0.0914). The structure was solved using SHELXT (Sheldrick, G. M. 2015. Acta Cryst. A71, 3-8) and refined using SHELXL (against F.sup.2) (Sheldrick, G. M. 2015. Acta Cryst. C71, 3-8). The total number of refined parameters was 208, compared with 2527 data. All reflections were included in the refinement. The goodness of fit on F.sup.2 was 1.066 with a final R value for [I>26 (I)]R.sub.1=0.0947 and wR.sub.2=0.2243. The largest differential peak and hole were 0.87 and −0.39 Å.sup.−3, respectively. The solved Oak Ridge Thermal Ellipsoid Plot (ORTEP) crystal structure for compound 53 is shown in FIG. 2.

[1617] Human GPR65 Cyclic Adenosine Monophosphate (cAMP) Homogeneous Time Resolved Fluorescence (HTRF) Antagonist Assay Procedure

[1618] IC.sub.50 data was obtained by the following procedure:

[1619] 1321N1 human astrocytoma cells stably expressing human recombinant GPR65 (1321N1-hrGPR65 cells, EuroscreenFast) were cultured according to the vendor's instructions.

[1620] Compounds were tested for their ability to antagonise GPR65, through measuring the concentration of cytoplasmic cAMP following treatment of the cells at a pH of 7.2 to activate GPR65 signalling and addition of the compound to be tested. The extent to which the expected rise in cAMP concentration upon GPR65 activation was suppressed by the added compound is indicative of its potency. The assay was carried out according to EuroscreenFast assay methodology as follows.

[1621] On the day of the assay, test compounds were added to 384-well, low volume, white microtiter plates by acoustic dispensing. KRH buffer (5 mM KCl, 1.25 mM MgSO.sub.4, 124 mM NaCl, 25 mM HEPES, 13.3 mM Glucose, 1.25 mM KH.sub.2PO.sub.4 and 1.45 mM CaCl.sub.2) was adjusted to pH 6.5, pH 7.6 and pH 8.4 by adding NaOH. 1321N1-hGPR65 cells were rapidly thawed and diluted in KRH, pH 7.6 prior to centrifugation at 300×g for 5 min and resuspension in assay buffer (KRH, pH 7.6, supplemented with 1 mM 3-isobutyl-1-methylxanthine (IBMX) and 200 μM ethylenediaminetetraacetic acid (EDTA)). Cells were added to assay plates at a density of 2,000 cells per well in a volume of 5 μl. Assay plates were briefly centrifuged at 100×g and then incubated at room temperature for 30 min. Cells were stimulated by the addition of 5 μL KRH, pH 6.5, to achieve an assay pH of 7.2, while control wells received 5 μl KRH, pH 8.4 to achieve an assay pH of 7.9. Assay plates were briefly centrifuged at 100×g and then incubated at room temperature for 30 min.

[1622] Accumulation of cAMP was detected by cAMP HTRF kit (Cisbio). d2-labeled cAMP and cryptate-labeled anti-cAMP antibody in Lysis and Detection Buffer (Cisbio) were added to assay plates, and the plates were incubated at room temperature for 1 h. HTRF measurements were performed using a Pherastar FSX instrument. Acceptor and donor emission signals were measured at 665 nm and 620 nm, respectively, and HTRF ratios were calculated as signal.sub.665 nm/signal.sub.620 nm×104. Data were normalised to high and low control values and fitted with 4-parameter logistic regression to determine hGPR65 IC50 values for the test compounds, which are shown in Table 1.

[1623] Various modifications and variations of the described aspects of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes of carrying out the invention which are obvious to those skilled in the relevant fields are intended to be within the scope of the following claims.

TABLE-US-00010 TABLE 1 Activity of selected compounds according to the invention 1 Medium 2 High 3 Medium 4 Medium 5 Low 6 Low 7 High 8 Low 11 Medium 12 Medium 13 Low 15 High 16 High 17 High 18 High 24 Low 25 Low 26 Medium 27 Low 28 Low 29 Medium 31 High 32 High 34 Medium 35 High 36 High 37 Medium 38 High 39 Low 42 High 43 High 44 Low 45 High 46 High 47 Medium 48 High 49 Low 50 Low 51 Medium 52 High 53 Low 54 Medium 55 Medium 56 Medium 57 Medium 58 High 59 Low 60 High 61 Medium 62 Low 63 Low 64 Medium 65 Medium 66 Medium 67 Medium 68 Medium 69 Medium 71 Medium 72 Medium 73 Low 74 High 75 High 76 High 77 High 78 High 79 High 80 Medium 81 Medium 82 Medium 83 Medium 84 Medium 85 High 86 Low 87 Low 88 High 91 High 92 High 93 High 94 High 95 Medium 98 High 99 Low 100 Medium 101 High 103 High 104 Medium 105 Low 106 High 107 Low 108 High 109 High 110 Low 111 Medium 112 Low 113 Medium 114 Medium 115 Medium 116 Medium 117 High 118 Medium 119 High 120 High 122 High 123 High 124 High 125 High 126 High 127 High 128 High 129 High 130 Medium 131 Medium 132 Medium 133 High 134 High 135 Medium 136 Medium 137 Medium 138 High 139 High 140 High 141 High 142 High 143 High 144 High 145 High 146 High 147 High 148 Medium 149 High 150 Medium 151 High 152 Medium 153 High 154 Medium 155 Medium 156 High 157 High 158 High 159 Medium 160 High 161 Medium 162 Medium 163 High 164 High 165 Medium 166 High 167 High 168 High 169 Medium 170 High 171 High 172 High 173 Medium 174 High 175 Medium 176 Medium 177 High 178 High 179 Medium 180 High 181 High 182 High 183 Medium 184 High 185 High 186 Medium 187 Medium 188 Medium 189 High 190 High 191 High 192 High 193 Medium 194 Medium 195 Medium 196 High 197 Medium 198 Medium 199 High 200 Medium High = IC50 < 500 nM; Medium = IC50 > 500 nM and <5 μM; Low >5 μM

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